Loyd V. Allen, Dennis B. Worthen, Bill Mink - Suppositories (2007, Pharmaceutical Press) PDF

Royal Pharmaceutical Society of Great Britain September 16, 2007 23:2
Suppositories
i
ii
Suppositories
Loyd V Allen, Jr
PhD
Professor Emeritus
College of Pharmacy
Health Sciences Center
The University of Oklahoma, USA
and
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Edmond, OK, USA
with contributions by
Dennis B Worthen
PhD
Lloyd Scholar
Lloyd Library and Museum
Cincinnati, OH, USA
and
Adjunct Professor
College of Pharmacy
University of Cincinnati
Cincinnati, OH, USA
and
Bill Mink
BSc
Technical Services Engineering Manager
Paddock Laboratories, Inc.
Minneapolis, MN, USA
London • Chicago
iii
Published by the Pharmaceutical Press

An imprint of RPS Publishing
1 Lambeth High Street, London SE1 7JN, UK

100 South Atkinson Road, Suite 200, Grayslake, IL 60030–7820, USA

c Pharmaceutical Press 2008
is a trade mark of RPS Publishing
RPS Publishing is the publishing organisation of the Royal Pharmaceutical

Society of Great Britain
First published 2008
Typeset by Aptara, New Delhi, India

Printed in Great Britain by Cromwell Press, Trowbridge, Wiltshire
ISBN 978 0 85369 646 9
All rights reserved. No part of this publication may be reproduced, stored in

a retrieval system, or transmitted in any form or by any means, without the
prior written permission of the copyright holder.
The publisher makes no representation, express or implied, with regard to
the accuracy of the information contained in this book and cannot accept
any legal responsibility or liability for any errors or omissions that may be
made.
The right of Loyd V Allen, Jr, to be identified as the author of this work
has been asserted by him in accordance with the Copyright, Designs and
Patents Act, 1988
A catalogue record for this book is available from the British Library
iv
Contents
Preface ix
About the author x
1 Introduction to suppositories 1
What is a suppository? 2
Uses and applications 3
Advantages of suppositories 4
Disadvantages of suppositories 4
Background 5
Synonyms/definitions/descriptions 6
Extemporaneous compounding 11
References 11
2 History and development of the suppository 13

Dennis B Worthen
Definitions: Suppository, pessary, bougie 13

Early history 13
Modern period 15
Suppository molds 16
Official status 19
Commercial manufacturing 19
Summary 24
References 24
3 Suppository bases and their characteristics 27
Classification of suppository bases 27

Development of suppository bases 46
References 48
v
vi Contents
4 Pharmaceutic, biopharmaceutic, and pharmacokinetic factors involving

suppositories 51
Anatomical and physiological considerations 51

Bioavailability of rectal suppositories 54
Physicochemical factors 54
Bioequivalence 57
Contemporary studies on the bioavailability of suppositories 58
Miscellaneous 69
References 69
5 Formulation considerations 77
Drug selection 78
Base selection 78
Formulation variables 80
Formulation studies of suppositories in the literature 81
Absorption enhancers 86
References 93
6 Manufacturing suppositories 99
Bill Mink and Loyd V Allen, Jr
Melt-fusion method 99
Cold compression method 102
General controls relative to manufacturing all suppositories 102
7 Compounding suppositories 105
Physicochemical considerations 105

Bases 107
Preparation 108
Preparation by compression 116
Special problems 117
Summary 119
References 119
8 Special types of suppositories 121
Non-rectal suppositories – vaginal suppositories 121

Contents vii
Non-rectal suppositories – urethral suppositories 123

Controlled-release suppositories 123
Coated microsphere/microcapsule suppositories 123
Emulsion and emulsion–gel suppositories 124
Hollow-type suppositories 124
Hydrogel suppositories 126
Layered double or triple suppositories 127
Matrix–agar suppositories 128
Matrix–wax suppositories 128
Mucoadhesive suppositories 128
Nanoparticle suppositories 129
Osmotic suppositories 129
Prolonged-release suppositories 129
Sectile or bisected suppositories 129
Reversed micellar solution suppositories 130
Sustained-release suppositories 130
Thermo-reversible-liquid suppositories 132
Xerogel suppositories 133
Miscellaneous suppositories and bases 133
References 134
9 Quality control of suppositories 139
Physical analysis 139

Chemical testing 147
Content uniformity testing 152
Conductivity 153
Chemical testing procedures 153
Aging and aging tests 156
References 156
10 Packaging and labeling of suppositories 159
Packaging 159
Labeling 165
References 165
11 Stability and storage of suppositories 167
Physical stability 167

Chemical stability 168
viii Contents
Factors affecting stability 168

Microbiological stability 169
Stability studies for suppositories 169
Beyond-use dating for compounded suppositories 170
Expiry dating for manufactured suppositories 170
Storage of suppositories 170
Holding and distribution 171
Transportation 171
Responsibility of pharmacists 171
Drug-specific stability studies 173
References 175
12 Clinical considerations 177
Clinical response factors 177

Patient counseling 177
General toxicity 178
Local toxicity 179
Adverse reactions to suppositories 179
Contemporary studies of clinical effectiveness 180
References 198
Appendix I Glossary 213

Appendix II Compounding formulas 215
Appendix III Manufacturing formulas 225
Appendix IV Calculations involving suppositories 231
Index 235
Preface
A COMPREHENSIVE volume on the suppository and status of the suppository at the turn of the
has not been compiled in about 50 years. It twenty-first century.
was a daunting task to assimilate, evaluate, and Appreciation is extended to all those scientists
organize the material that spans several thousand over the years who have spent time in the
years of history and then emphasize the last research laboratories and to those clinicians who
25 years to compile this book on one of very have worked with patients and have provided
few dosage forms that can be traced throughout much of the background of information pulled
history. The topic is also interesting because it together for this book.
encompasses so many different aspects of phar- Appreciation is also extended to Dr Dennis
maceutics, biopharmaceutics, and pharmaco- Worthen, Lloyd Scholar of the Lloyd Library in
kinetics. Cincinnati, Ohio, for his chapter on the history
The literature review in this volume is gener- and development of the suppository, and to Bill
ally limited to the past 25 years. It was felt this Mink of Paddock Laboratories in Minneapolis,
was necessary because to some degree, what is Minnesota, for contributing to the chapter on
published often tends to repeat itself. Therapeutic manufacturing suppositories.
and scientific advances tend to be reinforced so
it was decided to simply glean from over 2500 Loyd V Allen, Jr
references those we felt best illustrated the story July 2007
ix
About the author
Loyd V Allen, Jr is Editor-in-Chief of the velopment to the pharmaceutical industry both

International Journal of Pharmaceutical Compound- nationally and internationally.
ing, CEO of the Midwest Institute of Research Loyd V Allen, Jr has received numerous awards
and Technology, and Professor Emeritus of the and has served on many US Pharmacopeia Com-
University of Oklahoma College of Pharmacy, mittees continuously since 1980. He has super-
Oklahoma, USA. vised 25 MS and PhD students and was awarded
He taught at the University of Oklahoma 13 patents in drug formulations. He has pub-
College of Pharmacy for almost 30 years where he lished over 200 experimental publications and
was Professor and Chair, Department of Medici- abstracts, 25 books, chapters and monographs,
nal Chemistry and Pharmaceutics. In 1996, he over 400 professional publications, 21 film/book
founded the International Journal of Pharmaceu- reviews, and has authored or co-authored four
tical Compounding, now circulated to over 80 textbooks.
countries. He is a consultant in formulation de-
x
1
Introduction to suppositories
OFTEN SEEN AS a neglected dosage form, suppos- postmenopausal women. The use of HRT with
itories have not gained the level of acceptability, “bio-identical hormones,” which are identical
respect, and usage of most other methods of to the hormones produced by the body rather
administering medications. Nevertheless, a con- than synthetic or semi-synthetic hormones, is
siderable amount of work on suppositories has becoming increasingly popular in the treatment
been conducted in recent years as evidenced by of postmenopausal symptoms (flushing, night
a literature search on the terms “suppository” or sweats, mood swings, etc.).3
“suppositories.” In the past 50 years, there have Even though they have never been very pop-
been over 4000 citations on MEDLINE,1 with ular as a mode of administering drugs, sup-
most of the work having been done in Europe positories will probably always have a place in
and in the United States. medicine. They are primarily employed for three
Suppositories are solid dosage forms intended reasons:
for insertion into body orifices (rectum, vagina
1 to promote defecation,
or urethra), where they melt, soften, or dissolve
2 to introduce drugs into the body, and
and exert localized or systemic effects. The word
3 to treat anorectal diseases.
“suppository” is from the Latin supponere, mean-
ing “to place under,” derived from sub (under) Psychologically, suppositories possess consider-
and ponere (to place). Thus, suppositories are able placebo effect in the treatment of anorec-
described both linguistically and therapeutically tal disorders. The user feels that something is
to be placed “under” the body, as into the really being done at the site involved and this
rectum. The use of rectal suppositories has been results in a positive attitude towards the mode
documented for many centuries, and far back as of treatment of the disease or disorder. This may
the Ancient Egyptian civilization. promote hope and the possibility of avoiding the
In general today, suppositories are used more embarrassment of telling family and friends what
routinely in southern European countries and is happening in the private area.
in Latin American countries than in northern Regardless of the remedy employed, some
European and Anglo-Saxon countries. In the anorectal disorders resolve without any treat-
United States, fewer than 1% of drugs are for- ment whatsoever. Nevertheless, if the symptoms
mulated as suppositories, whereas in Germany it subside after suppository usage, then clearly the
may be as high as 5%.2 suppository gets the credit.
Although there continues to be a trend away Rectal administration is not often the first
from rectal delivery for routine administration route of choice but it sometimes becomes a good
of drugs, urethral and vaginal suppositories are alternative when the oral route is inadvisable.
becoming more acceptable in some areas. For The relatively low cost and lack of technical
example, urethral suppositories are used in the difficulties make rectal drug administration at-
treatment of male erectile dysfunction (MUSE, tractive when compared with parenteral therapy.
alprostadil; Vivus Inc., California, USA) and in The downsides of rectal administration include
the past 5–10 years in the USA, progesterone esthetics and the stigma of violating the patient’s
vaginal suppositories have become more popu- dignity; these factors, along with potential rectal
lar for hormone replacement therapy (HRT) for irritation due to frequent administration, and
1
2 Suppositories
often it does not. Some clinicians have made their

Table 1.1 Analgesic suppositories commercially
own extemporaneous “suppositories” by putting
available in the USA morphine tablet triturates in empty gelatin cap-
sules. This extemporaneous preparation allows
Drug Strengths available (mg) easy dose titration and this method may be
more economical and as well-tolerated as the
Aspirin 60, 120, 125, 200, 300, 600
commercial suppositories.
Acetaminophen 80, 120, 125, 325, 650
Hydromorphone 3
Indometacin 50
Morphine 5, 10, 20, 30 What is a suppository?
Opium + belladonna 30 + 16.2, respectively
extract
Oxmorphone 5 The differing views of various groups should
be considered when looking at definitions of
From Anon. Physicians’ Desk Reference-PDR, 61st edn. Montvale, NJ: suppositories. They are seen very differently by
Thomson PDR, 2007.
different individuals.
To the patient, a suppository is a medication
inserted into the rectal or vaginal cavity that con-
difficulty in titrating a correct dose due to limited tains an “active” ingredient designed to cause a
strengths of commercial suppositories, pose some certain effect. More specifically, it is a small, solid
challenges. “thing” that is either bullet or cone-shaped and
In treating patients in the last days of life (e.g. which might melt if stored in a room in the house
hospice patients), rectally administered medica- or it may melt between the fingers prior to and
tions are an essential part of palliative medicine. during administration. It also is a medicine that
Properly selected drugs and suppository vehicles may be found in the medicine cabinet along with
can enhance the quality of life of these patients. cough syrups, aspirin, acetaminophen, muscle
The importance of extemporaneously com- rubs, and others. It is also a dosage form that
pounding suppositories becomes evident when can be used in children when they are vomiting
one looks at the limited number of analgesic sup- or just will not take their medication.4
positories (Table 1.1), antiemetic suppositories To the physician, a suppository provides an
(Table 1.2), and the lack of anxiolytic and an- alternate dosage form and route of administra-
ticonvulsant suppositories that are commercially tion that can be used in treating a child or adult,
available. Many clinicians have used oral tablets, either at the hospital or in the home, without
oral capsules, oral solutions, emulsions and sus- using injections when the patient cannot take
pensions, and sometimes injectable products for the medication orally. A suppository is also an
rectal administration. Sometimes this works well; excellent dosage form for elderly and hospice
patients who cannot take oral medications and
for patients for whom it is inappropriate to give
numerous injections. It is also a dosage form
Table 1.2 Antiemetic suppositories commercially that can be administered to avoid nausea and
available in the USA vomiting caused by certain medications upon
oral administration, and it is a dosage form that
Drug Strengths available (mg)
can produce a fast onset of action as compared
Chlorpromazine 25, 100 with an oral tablet or capsule.4
Prochlorperazine 2.5, 5, 15 To the pharmacist, a suppository is a dosage
Promethazine 12.5, 25, 50 form that requires consultation with the pa-
Thiethylperazine 10 tient to ensure proper storage, administration
Trimethobenzamide 100, 200 and usage. Many suppositories are commercially
available but many have to be compounded.
From Anon. Physicians’ Desk Reference-PDR, 61st edn. Montvale, NJ:
Thomson PDR, 2007.
Compounded suppositories can be prepared
using different bases for different onsets and
Chapter 1 • Introduction to suppositories 3
durations of action. Pharmacists generally re-

member preparing cocoa butter suppositories in Table 1.3 Official suppositories in the USP
school and often enjoy talking about the ex-
perience. Compounding pharmacists often view Acetaminophen
suppositories as a way to meet individual patient Aminophylline
needs when other routes of administration are Aspirin
not really appropriate. This is especially true for Bisacodyl
pediatric and hospice patients.4 Chlorpromazine
To the pharmaceutical manufacturer, suppos- Ergotamine tartrate and caffeine
itories are a way of presenting an active ingre- Glycerin
Indometacin
dient in a suitable dosage form. Suppositories
Miconazole nitrate vaginal
are not as widely used as capsules and tablets
Morphine sulfate
but remain an important dosage form. In many
Nystatin vaginal
cases, pharmaceutical companies outsource the
Oxymorphone HCl
manufacturing process to companies that have
Prochlorperazine
invested in newer equipment for production, Progesterone vaginal
packaging, and labeling.4 Promethazine hydrochloride
Suppositories provide many clinical benefits Triethylperazine maleate
but often go unused because of national/cultural
and patient prejudice. Some patients may have From U.S. Pharmacopeial Convention Inc., U.S. Pharmacopeia 30-National
difficulty retaining suppositories and may not Formulary 25. Rockville, MD, 2007.
always understand that the medication is not

necessarily intended to stimulate bowel activ- Previously, the rectal pathway was reserved for
ity. Another possible reason for non-use is the the administration of locally active products such
perceived lack of flexibility regarding dosage. as those used in the treatment of hemorrhoids,
Suppositories are commonly used to administer worms, and constipation. In the treatment of
systemic medication in Latin countries. In the hemorrhoids and anal fissures, the suggestion
UK, however, it has been said that the single was made at one time that the suppository should
most significant drawback of this form is the tra- be “hour glass” or “collar button” shaped so
ditional British aversion to this route. The French that it would stay in the anal canal. Many drugs
are quite content to have their temperature taken absorbed from the upper gastrointestinal tract are
via the rectum, while the British find this distaste- also absorbed in the rectum.
ful and embarrassing. The French, in general, are It is well accepted that many active ingredients
also quite content to use suppositories. Germans can be administered rectally and achieve thera-
are even more likely than the French to have no peutic blood levels. Some medications are best
problems with a rectal examination. administered by this route, and others can be if
In a large British study of phenylbutazone needed.
suppositories in general practice, 10% of the As noted earlier, suppositories contain drugs
patients refused to participate because they were such as aspirin and opiates for pain, ergotamine
not prepared to accept a suppository and half did tartrate for treating migraine headaches, and
not complete the eight-week study. Interestingly many other drugs for other uses. These drugs are
though, British physicians who commonly pre- intended to be absorbed into the general circula-
scribed suppositories found their patients more tion to provide systemic effects. Other examples
tolerant and willing to use them.5 of suppositories given for systemic results include
the following:
r Diazepam is useful as an anxiolytic for patients

Uses and applications
who cannot swallow but acts too slowly for
treating epilepsy during emergencies. Epilep-
Some examples of commonly used official sup- tic seizures in children can often be controlled
positories are listed in Table 1.3. by rectal administration of diazepam solution.
4 Suppositories
r Metronidazole is as effective when given r It can be used to administer medication to an

rectally as intravenously. Prophylaxis with ill child who may refuse oral medication and
metronidazole suppositories has reduced the may fear injections.
incidence of postoperative anaerobic infection r It allows the administration of drugs in pa-
in patients undergoing abdominal surgery. tients experiencing nausea and vomiting or
r Progesterone is absorbed from the small intes- when the patient is unconscious.
tine but is then inactivated in the liver. Rectal r It avoids interference with drug absorption
or vaginal absorption is effective and supposi- by the presence of disease of the upper gastroin-
tories are more convenient than intramuscular testinal tract.
injection in the treatment of premenstrual r It can achieve a rapid drug effect systemically (as
syndrome. an alternative to injection).
r Aminophylline and theophylline supposito-
ries were previously used at bedtime for noc- The rectal route is often overlooked as a non-
turnal asthma and early morning wheezing, invasive method for medication administration
but the sustained-release oral preparations in patients unable or unwilling to take medica-
available today are more reliable and have tion orally. Rectal administration can be espe-
replaced them. cially useful in terminal care. In some locations,
r Morphine, oxymorphone, and oxycodone the use of suppositories may be more common in
suppositories are useful in terminal illness, the hospital; but parents and children can easily
especially when oral therapy is difficult. be shown how to insert a suppository.
r Prochlorperazine, chlorpromazine, and thi- Rectal administration can result in rapid, and
ethylperazine suppositories can help patients in many cases, extensive absorption of the active
with severe nausea or vomiting and as a ingredient. The rapidity, intensity, and duration
tranquilizer. of action are three parameters which must be
r Indometacin, diclofenac, ketoprofen, and considered during formulation for rectal admin-
naproxen can be given in suppositories; they istration and, in many cases, can be altered to
all appear to be similarly effective. meet the needs of the individual patient.
r Ondansetron suppositories are useful for the
relief of nausea and vomiting.
Disadvantages of suppositories
Advantages of suppositories
Reasons given for the infrequent use of supposi-
The advantages of rectal administration include tories include the following:
the following: r A perceived lack of flexibility regarding the
r It avoids, at least partially, the first pass effect, dosage of commercially available supposito-
which may result in higher blood levels for ries, resulting in under-use and a lack of
those drugs subject to extensive first pass availability.
metabolism upon oral administration. r Cost – if suppositories are made on demand
r It improves drug stability by avoiding the they may be expensive.
breakdown of certain drugs that are suscep- r Variable effectiveness – this depends upon
tible to gastric degradation. many factors to be discussed later, including
r It allows the administration of somewhat the pathology of the anorectal lesions.
larger doses of drugs than via the oral route. r Different formulations of a drug with a narrow
r It allows drugs to be given that may have an therapeutic margin, such as aminophylline,
irritating effect on the oral or gastrointestinal cannot be interchanged without risk of
mucosa when administered orally. toxicity.
r It allows the administration of unpleasant r A “bullet-shaped” suppository may leave the
tasting or smelling drugs. This is especially anorectal site after insertion and ascend
important in children. to the recto-sigmoid and descending colon.
Suppositories with this shape possibly should used for either local or systemic effects. Local
not be used at bedtime. applications include the treatment of hemor-
r Defecation may interrupt the absorption pro- rhoids, itching, and infections. Systemic appli-
cess of the drug, especially if the drug is cations involve a variety of drugs, including
irritating. antinauseants, antiasthmatics, analgesics, and
r The absorbing surface area of the rectum is hormones.
much smaller than that of the small intestine.
r The fluid content of the rectum is much less
than that of the small intestine; this may affect Local action
dissolution rate, etc.
r Some drugs may be degraded by the microflora Once a suppository designed to treat locally is
present in the rectum. inserted, the suppository base melts, softens, or
Most other barriers to the use of suppositories dissolves, distributing the medication it carries
concern practice issues, such as embarrassment or to the tissues of the region. Rectal suppositories
positioning of patients when administering sup- intended for localized action are most frequently
positories. If treatment is to continue at home, used to relieve constipation or pain, irritation,
conditions such as arthritis that could hamper itching, and inflammation associated with hem-
the patient’s ability to self-administer should be orrhoids or other anorectal conditions. Antihe-
considered. morrhoidal suppositories frequently contain a
Patients sometimes have problems retaining a number of components, including local anes-
suppository; they may not understand that it is thetics, vasoconstrictors, astringents, analgesics,
a medication and is not intended to stimulate soothing emollients, and protective agents. A
bowel action. popular laxative, glycerin suppositories promote
To overcome some of the disadvantages of laxation by local irritation of the mucous mem-
suppositories, clinicians should prepare patients branes, probably because of the dehydrating
before administration: effect of the glycerin. Vaginal suppositories or
inserts intended for localized effects are em-
r Ask about any pre-existing anal conditions ployed mainly as contraceptives, antiseptics in
that might interfere with administration, such feminine hygiene, and as specific agents to
as hemorrhoids or anal fissures. combat an invading pathogen. Most commonly,
r Show the patient the suppository and re- the drugs used are nonoxynol-9 for contracep-
mind them to remove any wrapping before tion, and trichomonacides to combat vagini-
insertion. tis caused by Trichomonas vaginalis, Candida
r Explain the insertion technique. (Monilia) albicans, and other microorganisms.
r Obtain the patient’s informed consent. Urethral suppositories may be used as antibac-
r Remember that suppositories may cause pa- terials and as a local anesthetic prior to urethral
tients embarrassment and anxiety; be sensitive examination.
to their concerns about privacy and allow
them to have an open and frank discussion
before going ahead. Systemic action
r Encourage the patient to retain the supposi-
tory for the correct length of time. One contemporary question that needs to be
addressed for all active drugs to be used in
suppository dosage forms for systemic effects is
Background
the bioavailability of the drug. This is important
so that dosage adjustments can be made if nec-
Suppositories can be used to administer drugs to essary. Numerous orally administered drugs have
infants and small children, to severely debilitated relatively poor bioavailability but the dosage is
patients, to those who cannot take medications adjusted so they are effective; the same situation
orally, and to those for whom the parenteral applies with rectal or vaginal administration of
route might be unsuitable. Suppositories can be suppositories. Some information is available but
6 Suppositories
much more needs to be generated. This is dis-

cussed further in Chapter 4, along with data from
many literature sources on the bioavailability of
drugs in different suppository bases.
Physicians and patients usually only consider
a suppository dosage form for a specific therapy
if, under given conditions, the rectal pathway
will allow for a satisfactory rate and extent of
absorption of the active ingredients.
The overall consensus on work related to
suppositories and rectal administration is that
the suppository dosage form can be relied upon
but one must consider that active ingredients
differ in their physicochemical and biochemical
properties and that the repeated administration
conditions for a suppository are not always the
same. From the administration standpoint, rectal
absorption is variable according to the position
of the patient, the age of the patient and the
properties and secretions of the rectal mucous
membrane and the digestive tract. Hence the re- Figure 1.1 Commercially available suppositories showing
liability of rectal medication can only be assured plastic strip that is packaged inside the carton. Photo
within the broad limits of the defined conditions courtesy of Paddock Laboratories, Inc., Minneapolis, MN.
of its administration. With this in mind the
physician, pharmacist, and nursing staff must
the physical dosage form for distribution and
pay attention to these conditions.
administration.
The mucous membranes of the rectum and
The active part may be used either alone
vagina permit the absorption of many soluble
or in combination with other active ingredi-
drugs, leading to systemic effects. Although the
ents. Numerous combination suppositories are
rectum is mostly used as the site for the systemic
available and provide a convenient means of
absorption of drugs, the vagina is increasingly
administering several drugs with only one dosage
used in hormone replacement therapy using
form.
progesterone.
The inactive part, or excipient, has a role to
disperse or dilute, sometimes to protect and to
allow the introduction of the active drug into
Synonyms/definitions/descriptions the patient. After administration, the role of the
suppository is to release the active principle,
either by melting as a result of body temperature
Synonyms for suppositories include anal cones,
or by dissolving in the local mucosal fluids. The
vaginal cones, pessaries, ovules, and bougies.
active ingredient is then free to produce a local
Example are shown in Figures 1.1–1.5.
effect or to move through the mucosal barriers
into the circulatory system to produce a systemic
effect.
Anatomy of a suppository
The following statement pretty well sums up
the progression of the suppository:4
The suppository dosage form generally consists
of two parts: the active or therapeutic ingredient
and the inactive part, consisting of excipients. Basically then, this Galenic form must be de-
The former is required to produce a specific formed and transformed. In the factory, in the
therapeutic effect and the latter to provide Chemist’s store and in the nurses’ fingers, it is a
Figure 1.2 Commercially available suppositories. Photo courtesy of Paddock Laboratories, Inc., Minneapolis, MN.
8 Suppositories
Figure 1.3 Various sizes and shapes of rectal suppositories.
11
12
Figure 1.4 Some examples of vaginal suppositories and

tablets.
7
macroscopically homogenous product, hard and
shiny; in the rectal cavity on the contrary, it is
a product which melts, dissolves and ensures the
delivery of the medicament.
Suppositories are commonly used rectally, vagi- Figure 1.5 Some examples of urethral suppositories.
nally, and occasionally, urethrally. They come in
various shapes and weights. The shape and size insertion into the male or female urethra. Male
of a suppository must be such that it is capable of urethral suppositories may be 3–6 mm in dia-
being easily inserted into the intended body ori- meter and approximately 140 mm in length,
fice without causing undue distension, and once although this may vary. When cocoa butter is
inserted, it must be retained for the appropriate employed as the base, these suppositories weigh
period. Rectal suppositories are inserted with the about 4 g. Female urethral suppositories are about
fingers (with or without fingercots or gloves), half the length and weight of the male urethral
but certain vaginal suppositories, particularly the suppository, being about 50–70 mm in length
vaginal “inserts” or vaginal tablets prepared by and weighing about 2 g.
compression, may be inserted high in the vaginal r Nasal and otic suppositories used in the nose or
vault with the aid of a special insertion appliance
ear are also called “bougies,” but are not widely
(inserter).
used.
r Rectal suppositories are usually about 1–1.5
inches (2.5–4 cm) in length, cylindrical, and have Suppositories generally consist of an active drug
one or both ends tapered or rounded. Some incorporated into an inert matrix, which may be
rectal suppositories are shaped like a bullet, a either a rigid or semi-rigid base. This intimate
torpedo, or the little finger. The shape of some mixture of the drug and inert matrix must be
is designed so that peristaltic movements will formulated to be free of any interactions between
help to move the suppository higher in the the two to avoid any alteration of either the
rectum. The weight of rectal suppositories varies, active ingredient or the inert matrix. There are
depending on the density of the base and the limitations on the quantity of active ingredient
medicaments present. Adult rectal suppositories that can be used, depending upon the size and
generally weigh about 2 g when cocoa butter desired release characteristics of the suppository.
(theobroma oil) is employed as the suppository Usually, the incorporated drug consists of a solid
base. Rectal suppositories for use by infants and (powder), but it may also be a semi-solid or
children are about half the weight and size liquid (aqueous, alcohol, oils, extracts, etc.) to be
of the adult suppositories and have a more incorporated into the base. The base material may
pencil-like shape. Examples of some rectal sup- be natural, synthetic, or semi-synthetic and is
positories and their compositions are shown in selected based upon its ability to soften, melt, or
Table 1.4. dissolve upon introduction into the body cavity.
r Vaginal suppositories, also called pessaries, are Suppositories are also intended to provide
local action within the perianal area. Local anes-
usually globular, oviform, or cone-shaped and
thetic suppositories are commonly employed to
weigh about 3–5 g when cocoa butter is the
relieve pruritus ani of various causes and the
base. However, depending on the base and the
pain sometimes associated with hemorrhoids.
individual manufacturer’s product, the weights
Commercial hemorrhoidal suppositories contain
of vaginal suppositories may vary widely. Com-
a number of medicinal agents, including astrin-
pounded vaginal suppositories that use water-
gents, protectives, anesthetics, lubricants, and
soluble bases, such as polyethylene glycol (PEG),
others, intended to relieve the discomfort of the
are the preferred form, as they are miscible with
condition. Cathartic suppositories are contact-
vaginal fluids and minimize leakage. Oil or fat-
type agents that act directly on the colonic
based suppositories are immiscible with vaginal
mucosa to produce normal peristalsis. Because
fluids and tend to leak from the vaginal orifice.
the contact action is restricted to the colon, the
Some vaginal suppositories are actually com-
motility of the small intestine is not appreciably
pressed tablets and are often called inserts. Some
affected. Cathartic suppositories are more rapid-
examples of vaginal suppositories and tablets are
acting than orally administered medication. Sup-
shown in Table 1.5.
positories of bisacodyl are usually effective in
r Urethral suppositories, also called bougies, are 15 minutes to an hour, and glycerin suppositories
slender, pencil-shaped suppositories intended for usually within a few minutes following insertion.
10 Suppositories
Table 1.4 Examples of rectal suppositories
Corresponding Active constituent

Suppository commercial product per suppository Type of effect Category and comments
Bisacodyl Dulcolax 10 mg Local Cathartic. See text for

suppositories Suppositories additional discussion.
(Ciba) Base: hydrogenated
vegetable oil
Chlorpromazine Thorazine 100 mg Systemic Antiemetic; tranquilizer. Base:
suppositories Suppositories glycerin, glyceryl
(SmithKline monopalmitate, and
Beecham) monostearate, and
hydrogenated fatty acids
of coconut and palm
kernel oils
Hydrocortisone Anuprep-HC 25 mg Local For use in pruritis ani,
suppositories Suppositories inflamed hemorrhoids, and
(Warner-Lambert) other inflammatory
conditions of the
anorectum. Base:
hydrogenated glycerides
Hydromorphone Dilaudid Suppositories 3 mg Systemic Analgesic. Base: Cocoa butter
suppositories (Knoll) with silicone dioxide
Mesalamine Canasa (Axcan 500 mg Local Anti-inflammatory. Base: Hard
suppositories Scandipharm) fat
Oxymorphone Numorphan 5 mg Systemic Analgesic. Base: Polyethylene
suppositories Suppositories glycols 1000 and 3350
(Endo)
Prochlorperazine Compazine 2.5, 5, and 25 mg Systemic Antiemetic. Base: glycerin,
suppositories Suppositories glyceryl monopalmitate
(SmithKline and monostearate, and
Beecham) hydrogenated fatty acids
of coconut and palm
kernel oils
Promethazine HCl Phenergan 12.5 and 25 mg Systemic Antihistamic, antiemetic and
suppositories Suppositories sedative actions: used to
(Wyeth-Ayerst) manage conditions of
allergic origin; for
preoperative or
postoperative sedation or
nausea and vomiting; and
for motion sickness. Base:
cocoa butter and white
wax
From Anon. American Drug Index 2007 . St. Louis, MO: Wolters Kluwer Health, 2007.
Table 1.5 Examples of vaginal suppositories and tablets
Product/manufacturer Active constituents Category and comments
Monistat 7 Suppositories (Advanced Miconazole nitrate, 100 mg Antifungal for treatment of localized
Care Products) vulvo-vaginal candidiasis (moniliasis)
Mycelex-7 Vaginal Tablets (Bayer) Clotrimazole, 100 mg Treatment of vulvo-vaginal yeast (Candida)
infections
Semicid Vaginal Contraceptive Nonoxynol-9, 100 mg Non-systemic, reversible method of birth control
Inserts (Robins Healthcare)
From Anon. American Drug Index 2007 . St. Louis, MO: Wolters Kluwer Health, 2007.
Some commercially prepared suppositories are morphine alkaloid suppository has been intro-
available for both adult and pediatric use. duced for chronic pain.
In summary, suppositories have been used
throughout history and are increasing in use.
Although not necessarily the first choice as a
Extemporaneous compounding
dosage form, there are many occasions where
they serve a distinct purpose for patients.
It is essential that all healthcare professionals
whose patients receive extemporaneous com-
pounds recognize the criteria by which these
medications must be formulated for optimal References
patient benefit. This knowledge can improve
healthcare professionals’ ability to communi- 1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
cate effectively about the extemporaneous com- (accessed December 29, 2006).
pounds with other providers caring for the pa-
tients and with the patients themselves. It will 2. Gold M, VePuri M, Block LH. Suppository devel-
opment and production. In: Lieberman HA, Rieger
also assist physicians in prescribing and nurses
MM, Banker GS, eds. Pharmaceutical Dosage Forms:
in administration or directing patients to phar-
Disperse Systems, Vol. 2. New York: Marcel Dekker,
macists well qualified to provide this important 1996: 447–496.
service.
The suppository dosage form is being used 3. Gillson GR, Zava DT. A Perspective on HRT for
more frequently in compounded formulations. women: Picking up the pieces after the women’s
health initiave trial, Part I. Int J Pharm Compound
For example, compounded suppositories that
2003; 7: 250–256.
contain metoclopramide, haloperidol, dexa-
methasone, diphenhydramine, and benztropine 4. Guillot BR, Lombard AP, ed. Le Suppositoire. Paris:
can be administered prophylactically to control Maloine S.A., 1973: 6–7.
severe nausea and vomiting; salbutamol can be 5. McIntosh IB, Fowler PD. Phenylbutazone suppos-
administered rectally for long-term prophylactic itories: a multi-centre general practitioner study.
treatment of asthma; and a prolonged-release, Practitioner 1977; 219: 391–395.
12
2
History and development of the
suppository
Dennis B Worthen
The suppository is a form of medicine now very on the neighboring parts, or on the system at
rarely adopted. It is intended for the administra- large (p. 381).”3 In the 1874 edition of Dunglison’s
tion of medicinal agents to the rectum (p. 515).1 Medical Lexicon, the definition was expanded,
noting that the shape of the suppository was
This was how the Father of American Pharmacy, presented in the “form of a cone or cylinder”
William Procter, Jr, in the first pharmaceutical and that some suppositories were intended for
book adapted to the American audience, sum- insertion in the uterine cavity, cervical canal,
marily dismissed the suppository in 1849. Seven and vagina, and further that there were also
years later, in the first pharmacy text written by suppositories or medicated bougies for urethral
and for American practitioners, Edward Parrish, use.4
a fellow professor at the Philadelphia College of Over time, the terms pessary and bougie have
Pharmacy, echoed the same sentiment, noting also become associated with the suppository, al-
that he had little experience with the preparation though not necessarily as synonyms. The pessary
of suppositories.2 originally referred to a device, usually made of a
This appreciation of the suppository in mid- solid substance, which was placed in the vagina
nineteenth century pharmacy was not represen- to support the uterus or reduce a vaginal hernia.
tative of its popularity in early therapeutics or The pessary could also be medicated, in which
those of today. Indeed, the transformation of a case they were referred to as suppositories. The
low-tech delivery system into the increasingly term bougie, French for “wax candle,” initially
sophisticated modern suppository is worthy of was used for dilating passages, such as the rectum,
some understanding. urethra, and esophagus in order to remove or
reduce an obstruction or stricture. Medicated
bougies often included a caustic or escharotic
Definitions: Suppository, pessary, substance.
bougie
The historical definition of suppository has been

Early history
relatively constant since the middle of the nine-
teenth century. In his 1873 Pharmaceutical Lexi-
con, HV Sweringen defined suppositoria (supposi- In his 1953 work on the history of the anal
tories) as “solid bodies intended to be introduced suppository, Paul Diepgen addressed the sup-
into the rectum, with a view either of evacuating posed origin of instinctive healing actions and
the bowels by irritating the mucous membrane their evolution to systematic therapeutics. Part
of the rectum, or of producing a specific effect of the theory of disease and healing was that
13
14 Suppositories
the harmful agent must be removed from While the active ingredients of the Egyptian
the body and one way to accomplish heal- pharmacopeia have passed from use for the most
ing was to evacuate, or defecate, the harmful part, the conditions requiring intervention have
element.5 not and suppositories remain among the dosage
The origin of the suppository as a dosage forms in use three and a half millennia after the
form is hidden in the dark reaches of history. writing of the Ebers Papyrus.
Perhaps the earliest record of it occurs in an The Egyptians, and other early civilized cul-
Egyptian medical papyrus dating from approxi- tures such as the Babylonians and Assyrians,
mately 1550 BC. Acquired by Georg Ebers in 1872, believed that anal therapy had systemic conse-
the papyrus presents a compilation of writings quences based on the notion that the anus was
devoted to medicine and magic and contains a the point at which the vascular system came
large number of prescriptions and their intended together. Diepgen noted the importance of the
uses. Albeit not the oldest papyrus containing anus in the Egyptian period between 3200 and
medical information, the Ebers is the longest. 2270 BC with at least two physicians who had
It lists 811 prescriptions to treat a broad array the sobriquet “Pastor of the Pharaoh’s Anus”
of diseases as well as to provide cosmetic sug- (p. 5).5 On the other hand, ancient Indian prac-
gestions and household management hints. In tices considered suppositories to be secondary to
addition a number of dosage forms are suggested, enemas; suppository use in systemic therapeutics
including ointments, inhalations, pills, and is less clear. The suppository was especially useful
suppositories. for small children, the weak, and women, who
Purgatives for the treatment of constipation were viewed as being little more than children,
were well represented in the papyrus.1 One recipe at least in terms of therapeutics.
for a suppository, for example, included the Early Hippocratic followers used the supposi-
following ingredients (p. 45):6 tory mostly for local action, such as hemorrhoids.
r Honey
Diepgen was not able to document the belief
r Sasa-seeds
in systemic effectiveness for the dosage form.
r Wormwood
The descriptions used for suppositories referred
r Elderberry
to size, such as thick, and ingredients such as
r Berries-of-the-uan tree
hemlock and myrrh.
r Kernel-of-the-ut’ait-fruit
The concept of the whole-body effect of sup-
r Caraway
positories returned in the work of Dioscorides
r Aaam-seeds
in the first century of the Christian era. Sup-
r Xam-seeds
positories were used to restore the balance of
r Sea-salt.
humors. Diepgen notes, however, that distin-
guishing whether the suppository was for anal
Suppositories were also recommended to cool or vaginal use or insertion into a fistula was
and remove the smarting of the anus when frequently unclear. Galen, a hundred years later,
internal remedies were not effective. For exam- restricted the use of suppositories for bowel
ple, readers were instructed to take “Fat-of-the- cleansing and introduced the use of Gallic soap
Antilope” and “Caraway” and to “Roll into a (p. 9).5
Pill and put in the Anus” or to take “Cow- The suppositories of the early period, as noted
horn, Pieces-of-dried-Oil and Yeast-of-Wine” and in the Ebers papyrus, were made up of veg-
to “Make a peg (suppository) for the Man or etable, animal, and mineral ingredients that were
Woman” (p. 57).6 formed into an appropriate shape and inserted
Recommendations for women’s conditions, into the appointed orifice. Diepgen noted that
ranging from abortion, to birth, to lactation, were during the Greco-Roman period the suppository
also included. There were several suggestions to base was likely to be a fabric or lint, twisted to-
induce labor, including a vaginal suppository gether and impregnated with the medicaments.
containing “Fennel, Incense, Garlic, sert-juice, By the late Byzantine period the suppository was
Fresh Salt and Wasp’s dung” (p. 84).6 falling into disuse once again (p. 11).5
Chapter 2 • History and development of the suppository 15
The suppository also appears to have only it is reasonable to look at the time of significant
limited use in the period of Arabic medicine. change as an indication. By the mid-nineteenth
In the tenth century Ali Ibn Al-Abbas-al-Majusi century changes in education, regulation, pro-
mentions the suppository in his Liber Regius but fessional literature, manufacturing, and science
provides only limited use for it. In the eleventh were evident, certainly in America. The first
century, Avicenna’s fifth book of his Cannon of pharmacy text (Procter’s Practice of Pharmacy)
Medicine does not include the anal suppository and journal (American Journal of Pharmacy) were
among other dosage forms. Diepgen concluded in print; a number of colleges were established
that the lack of attention to the suppository along the East Coast and the first west of the
was because of Galen’s influence on the authors Alleghenies (Cincinnati College of Pharmacy);
(p. 13).5 This lack of attention was later evident and the American Pharmaceutical Association
in Hildegard von Bingen’s Causae et Curae, pub- was formed (1852) in response to the need for
lished in the twelfth century. improved standards.
Diepgen noted that the suppository gained In 1847, Friedrich Mohr published a treatise
some notoriety from the twelfth-century Masters in German that he intended to be a com-
of Salerno. Salerno, one of the earliest medical prehensive work on pharmaceutical technology
schools, is considered important because of the for pharmacists, chemists, chemical manufac-
many surviving texts. Roger Frugard, one of turers, and physicians.7 Significantly, there is
the Salerno figures, was the first to separate the no mention of suppositories in his work, im-
terms “suppository” for anal use and “pessary” plying that this dosage form was not a signif-
for vaginal use. Among the uses for suppositories icant item for apothecaries in Germany at the
were bowel cleansing, especially in the fevered time.
patient, psychosis, colic, and hemorrhoids In 1849, Theophilus Redwood, one of the
(p. 15).5 founding fathers of the Pharmaceutical Society
The form, content, and manner of preparation of Great Britain and the first Professor of Phar-
of suppositories changed little over the centuries. macy in the Society’s own school of pharmacy,
The form was frequently a plug or ball of materi- translated and greatly expanded Mohr’s book.
als that could be inserted in the anus or vagina. Redwood added a description of suppositories
Soap, wax, lard, and suet were used as a base noting that they were:
for additional ingredients and to provide shape.
An alternative format was the use of a cloth, a form of medicine now very rarely adopted. It
or lint, with medicament spread on it prior to is intended for the administration of medicinal
insertion. The medicaments included much of agents to the rectum. The ingredients are made
the materia medica of the period and were usually into a paste, which is usually rolled into a conical
intended either to act as bowel cleanser or to form, like a pastil. Soft soap or grease is generally
provide a systemic effect, such as narcotics. The used as the excipients for giving the required
turning point in the production of suppositories consistence to suppositories (p. 363).8
began as early as 1701 when Wilhelm Homberg
first prepared cocoa butter by pressing heated Later that same year, William Procter, Jr, Pro-
cocoa beans, and continued in 1779 when Carl fessor of Pharmacy at the Philadelphia College
Wilhelm Scheele discovered glycerin. However, of Pharmacy enlarged the book, editing it for
these discoveries did not pass into common a North American audience. However, Procter
practice until the mid-nineteenth century. retained Redwood’s comments regarding suppos-
itories with no changes (p. 515).1 This was not
an oversight since Edward Parrish, also on the
faculty of the Philadelphia College of Pharmacy
Modern period
and principal of the Philadelphia School of Prac-
tical Pharmacy, in the first textbook written by
While it is difficult to determine the exact date an American for an American audience, noted in
of the arrival of the modern period in pharmacy, 1856:
16 Suppositories
Suppositories as a class of medicine, are so seldom nor uniform suppositories. The earliest metallic
prescribed, that I can lay claim to little practical suppository molds in America were impressions
familiarity with their preparation. They are used in the shape of a suppository in a metal block
to insert into the rectum to fulfil [sic] several or a tin tray. In 1864, William Chapman of
indications; sometimes their action is mechan- Cincinnati, an early president of the American
ical, but they usually owe their utility either to Pharmaceutical Association, made the molds and
a narcotic, astringent, or cathartic ingredient (p. sold them to pharmacists for $5.00.13 By the
452).9 1870s a number of US patents were granted for
suppository molds including the Spenzer model
In spite of the disclaimer of lack of familiarity, that was divided to facilitate removal of the
Parrish goes on to note that there is an official pill finished product (Figure 2.1). In 1871, Henry
preparation in the United States Pharmacopeia, B. Brady, president of the British Pharmaceuti-
Pilulae Saponis Compositae, which contains opium cal Conference, exhibited a set of suppository
and soap, is formed into a mass, and, after it molds at the American Pharmaceutical Associa-
has been smeared with a bland oil, is inserted tion meeting in St. Louis. The molds were de-
into the anus either with the finger or tube scribed as exquisite, gun-metal and silver-plated,
insertion. Parrish also cites a landmark paper in with form sizes ranging from 15 to 120 grains,
the American Journal of Pharmacy by Alfred Taylor. and costing $125 for the set.13
Pharmacist Alfred B. Taylor of Philadelphia In 1868, Alexander Knowlson patented the
reported that there was no information in the first mold to use compression to form the
National Dispensatory on the valuable class of suppository, but the first successful mold was
medicinal applications (suppositoria) in spite attributed to Henry Heyl in 1879 (Figure 2.2).11
of their long use in France. He cited François Its importance for the compounding pharmacist
Dorvault’s L’officine, ou, Répertoire Général de Phar- has been described:
macie Pratique which included the use of cocoa
butter as a suppository vehicle and formulas for In this progressive age, when the requirements
anthelmintic, anti-hemorrhoidal, astringent, em- of the medical profession demand the greatest
menagogue, laxative, and vaginal suppositories amount of exactness, nicety and expedition on
containing active ingredients such as belladonna, the part of the dispensing chemist, we notice
calomel, and quinine. Taylor also provided for- that Mr. H.C. Archibald, pharmacist, No, 4099
mulas from Samuel Gray’s Supplement to the Lancaster avenue, Philadelphia, has come to the
Pharmacopeia (London) that were originally taken relief of the latter by the invention of a machine
from the 1845 Codex Medicamentarius Hamburgen- which will (and ought to) revolutionize the
sis. Of particular interest to the American reader present tedious, and to some extent inaccurate
were directions on how to make a suppository way of preparing suppositories, and be hailed
using cocoa butter and the inclusion of two for- with delight by those who are required to furnish
them almost daily.14
mulas for opium suppositories used by American
physicians using the fusion method.10 In 1875 the question of preference for the various
types of suppository molds was addressed at
the American Pharmaceutical Association annual
meeting. The “opinions of a large number of
Suppository molds
our most intelligent pharmacists throughout the
Eastern, Middle, and Western States” were re-
As pointed out by Griffenhagen in his history ported by Richard Mattison. The cold or compre-
of the suppository mold, the introduction of sion process was compared to the melting process
cocoa butter brought the need for suppository with 19 different molds. The Knowlson mold
molds to the fore.11,12 While Taylor and others for rectal, vaginal, and urethral suppositories was
recommended the use of a paper cone placed the preferred machine and one of its benefits
in a box of sand to provide support, this ap- was that the youngest apprentice could turn out
proach provided neither ease of compounding as good suppositories as the skilled pharmacist
Figure 2.1 Drawings of the Spenzer suppository mold described in U.S. Patent #142,524, patented September 2, 1873.
18 Suppositories
Figure 2.2 Drawings of the first successful compression suppository mold described in U.S. Patent 214,775 patented
April 29, 1879, by H.R. Heyl.
(Figure 2.3). The preferred mold for the melting Pharmacopeia (USP). The 1867 edition of the
process was one manufactured by Benton, Myers, BP added cocoa butter to the formulas for the
& Cranfield. Mattison noted that some pharma- original two suppositories and added Suppositoria
cists avoided the melting process because of the Hydrargyri and Suppositoria Plumbi Composita.20
potential for the active ingredient to separate and In the 13th edition of the USD in 1876 the
pool at the apex of the suppository and editori- convenient weight for suppositories is reported to
alized “that in the hands of pharmacists [italics be 25 grains with the added note that the BP stan-
in original] such evidences of unpharmaceutical dard, based on Henry Brady’s recommendation,
skill never occur.”15 In 1897 Whitall, Tatum was 15 grains.21 An expanded footnote discussed
introduced the “No. 3 Suppository Machine” the medicated pessaries and their resemblance to
which eventually became the preferred mold for suppositories. This footnote was continued and
use in the pharmacy16 (Figure 2.4). expanded in the 14th edition in 1880 with infor-
mation on medicated bougies and urethral and
vaginal suppositories. Also in the 14th edition,
the suggested weight for suppositories for infants
Official status
and children was provided (5–10 grains).22 There
were formulas for 12 suppositories. By 1883 there
The first mention of oil of theobroma in the were numerous formulas for suppositories in
United States Dispensatory (USD) appeared in the Martindale’s Extra Pharmacopoeia.23
“Drugs and medicines not officinal” Appendix in Glycerin was originally added to the 1850 USP.
the 1834 edition (p. 1079).17 The use given for Used mainly as a vehicle for topical medications,
cocoa butter was in cosmetic unguents although there had been some attempts to use it internally
it was not listed in any formula. The first listing of as a replacement for cod liver oil and even as a
suppositories did not occur until the 1854 edition sweetening agent for diabetics.24 In 1890 glycerin
and, while soap was identified as the common suppositories were added to the USP.25 During
ingredient, Taylor’s recommendation of cocoa the annual American Pharmaceutical Association
butter was cited. However, the information on meeting in 1892, Joseph Remington responded to
the use of cocoa butter did not expand to include a query on the best way to manufacture glycerin
suppositories until the 11th edition in 1858. suppositories, which were used as laxatives.26
In 1866 the USD added suppositories to Part Glycerin had not been considered an ideal ve-
II (preparations) and greatly enlarged the entry. hicle for other medications.
The entry stated that “they [suppositories] would
seem to have a claim to this position quite as
strong as the Enemata, which have long been
Commercial manufacturing
officially recognized (p. 1361).”18 This addition
was due, at least in part, to the appearance of sup-
positories as officinal preparations in the British By the end of the nineteenth century machines
Pharmacopoeia (BP). The entry noted that the had been developed to mass-produce supposito-
BP only had two suppositories (Suppositoria Acidi ries. At the 1893 annual meeting of the American
Tannici and Suppositoria Morphiae19 ); this was not Pharmaceutical Association, Henry Wellcome
meant to be limiting but rather to provide a noted that the shape of the suppository had
pattern for other formulas. In describing the remained the same ever since the introduction
shape and weight of the ideal suppository, the of the dosage form. Although the shape was
entry also suggested that a hollow could be made easy to insert, it was equally easy to expel.
in a preformed suppository, an active ingredient He reported the development of a new shape
placed in the hollow, and the depression closed with a “thick bulb abruptly pointed at the apex
with additional cocoa butter. Another reason for like a fat cigar or minie bullet, and gradually
the expanded information on suppositories was tapered at the base.”27 A patent by Charles Trusler
the statement that provision was made for Oil in 1897 claimed that his invention overcame
of Theobroma to be added to the United States some of the production problems evidenced by
20 Suppositories
Figure 2.3 Drawings of A.M. Knowlson Suppository Machine described in U.S. Patent 79,840 patented July 16, 1805.
Figure 2.4 Drawings of the Tatum Suppository Machine, described in U.S. Patent 536,240 patented March 26, 1895.
22 Suppositories
Figure 2.5 Pages from a Wyeth catalog depicting the various rectal, vaginal, uterine, urethral, nasal and aural-shaped
molds they had available for purchase.
earlier equipment.28 Griffenhagen noted that such as opium, morphine, cocaine, belladonna,
John Wyeth & Brothers began mass manufactur- and atropine, the firm offered to manufacture
ing and advertising of suppositories at least as special formulas within a few hours and upon
early as 1870.11 In the 1901 catalog, Wyeth lists reasonable terms (Figure 2.5).29 Most other major
18 different mold sizes and shapes for rectal, vagi- manufacturers of the period also manufactured
nal, uterine, urethral, nasal, and aural supposi- and sold a broad line of suppositories.
tories and an additional eight for glycerin sup- Hollow suppositories were designed to take ad-
positories. In additional to the pre-manufactured vantage of mass production to ease pharmacists’
items containing numerous active ingredients, compounding. As early as 1881 Hall & Ruckel
Figure 2.5 Continued
Wholesale Druggists of New York City advertised hollow forms was as great as manufacturing
a complete line of hollow suppositories made the entire suppository. In addition, no effect
from cocoa butter. The pharmacist could add any was realized until the suppository was melted,
medicine as long as it was cold and insert the unlike suppositories with the medicament evenly
plug at the back end of the suppository before dis- distributed throughout.30 In 1885, Remington
pensing. However, these did not gain widespread noted the recommendation to use gelatin shells
use since the labor in preparing and filling the having conical caps as suppositories; however,
24 Suppositories
this did not appear to gain any significant to depend on the medicine, its solubility, its
following.31 availability, and its effectiveness for the purpose
In 1937 Bird reported preliminary experiments intended.33
with a new suppository base, propylene glycol It is not the role of the historian to predict
stearate.32 He noted a number of advantages the future. The future role of the suppository
that the excipient provided when used in sup- will depend largely on the need of medicaments
positories, including its stability and ease of to be delivered through the body’s orifices and
shaping. Preliminary data indicated that water- the ability to deliver them in a safe and effective
soluble medicines were easily absorbed from the manner. Indeed, the future belongs to researchers
vehicle. and clinicians; the historian will follow behind to
record their efforts.
Summary
References
Since the 1850s a focus in the history of sup-
positories has been on whether they worked.
1. Mohr F, Redwood T. Practical Pharmacy: the Arrange-
This question was applied at two different levels.
ments, Apparatus, and Manipulations of the Pharma-
The first was whether the suppository worked
ceutical Shop and Laboratory. Edited, with extensive
for the compounding pharmacist or manufac- additions, by William Procter, Jr. Philadelphia: Lea
turer. The second was whether it worked for the and Blanchard, 1849.
patients.
Beginning with Taylor in 1852 the question 2. Parrish E. An Introduction to Practical Pharmacy.
Philadelphia: Lea and Blanchard, 1856: 452.
posed was how to make suppositories that would
accept the addition of the medicinal agent, how 3. Sweringen HV. Pharmaceutical Lexicon: A Dictionary
it could be formed, and how it could be packaged of Pharmaceutical Science. Philadelphia: Lindsay &
and dispensed. The underlying assumption was Blakiston, 1873.
that if the suppository vehicle could be formed, 4. Dunglison R. Medical Lexicon: A Dictionary of Med-
medicines that were effective orally would also ical Science, new edition revised by Richard J
be effective rectal or vaginally. Since many of the Dunglison Philadelphia: Henry C. Lea, 1874: 1002.
active ingredients were intended to cause evacu-
5. Diepgen P. Das Analzäpfchen in der Geschichte der
ation, provide a topical astringent or demulcent
Therapie. Stuttgart: Georg Thieme Verlag, 1953 [all
effect, or deliver an analgesic, this assumption references, including pagination, are to the English
was reasonable. The secondary literature, such as translation The Anal Suppository in the History of
Scoville’s Art of Compounding and Remington’s Therapy, translated by Lowenberg, Georgia Carole].
Practice of Pharmacy, focused more on formulas
6. Bryan CP. The Papyrus Ebers D. New York: Appleton
and physical chemistry than on the question
and Co., 1931.
of effectiveness. Moreover, suppositories were an
alternative, secondary to oral administration, for 7. Mohr F. Lehrbuch der pharmaceutischen Technik: für
any systemic therapeutic action. Apotheker, Chemiker, chemische Fabrikanten, Aerzte
By the mid-twentieth century, with the ad- und Medicinal-Beamt. Braunschweig: F. Vieweg,
vent of new bases and medications, questions 1847.
were again raised about the effectiveness of the 8. Mohr F, Redwood T. Practical Pharmacy: the Ar-
suppository dosage form. The focus was whether rangements, Apparatus, and Manipulations of the Phar-
the suppository was delivering medication to maceutical Shop and Laboratory. London: Taylor,
the patient in an effective fashion. Instead of Walton, and Maberly, 1849.
assuming activity based on other dosage forms 9. Parrish E. An Introduction to Practical Pharmacy:
it became important to show absorption, blood designed as a Text-book for the Student and as a Guide to
levels and concentrations to prove effectiveness. the Physician and Pharmaceuticist. Philadelphia: Lea
Finally, the selection of the dosage form had and Blanchard, 1856.
10. Taylor AB. Suppositories. Am J Pharm 1852; 24: 18– 22. Wood GB, Bache F. The Dispensatory of the United
20. States of America, 14th edn. Philadelphia: J.B. Lip-
pincott and Co., 1868: 1466–1470.
11. Griffenhagen GA. History and evolution of the
suppository mold. Am J Pharm 1953; 125: 135– 23. Martindale W. The Extra Pharmacopoeia of Unofficial
142. Drugs and Chemical and Pharmaceutical Preparations.
London: H.K. Lewis, 1883
12. Griffenhagen G. Tools of the apothecary: 4. Suppos-
itory molds. J Am Pharm Assoc Pract Pharm Ed 1956; 24. King J. The American Dispensatory with
17: 402–403. Supplement by John King and John U. Lloyd,
17th edn. Cincinnati, Ohio: Valley Co., 1895:
13. Lloyd JU. The Chapman Suppository Mold. Proc Am
395.
Pharm Assoc 1905; 50: 501–504.
25. Pharmacopeia of the United States, Seventh Decennial
14. Ellis ET. A new method of making suppositories. Am
Revision. Philadelphia: J.B. Lippincott Co., 1893:
J Pharm 1879; 51: 184–186.
386.
15. Mattison RV. On suppository molds. Proc Am Pharm
26. Remington JP. On the preparation of glycerin
Assoc 1875; 23: 625–627.
suppositories. Proc Am Pharm Assoc 1892; 40:
16. Tatum CA. Suppository machine. US Patent 267–268.
536,240, March 26, 1895.
27. Wellcome HS. An improved shape for suppositories
17. Wood GB, Bache F. The Dispensatory of the United and bougies. Proc Am Pharm Assoc 1893; 41: 103–
States of America, 2nd edn. Philadelphia: J.B. Lip- 104.
pincott and Co., 1834 [“Officinal” was defined as
28. Trusler CL. Suppository machine. US Patent
those medicines designated in either the United
580,021, April 6, 1897.
States Pharmacopeia or the British Pharmacopoeia.]
29. Wyeth J. An Epitome of Therapeutics. Philadelphia:
18. Wood GB, Bache F. The Dispensatory of the United
John Wyeth & Brother, 1901: 126–142.
States of America, 12th edn. Philadelphia: J.B. Lip-
pincott and Co., 1866. 30. Scoville WL. The Art of Compounding, 2nd edn.
Philadelphia: P. Blakiston, Son & Co 1897: 171–
19. British Pharmacopoeia London. Printed for the Gen-
172.
eral Medical Council by Spottiswoode & Co., 1864:
338–339. 31. Remington JP. The Practice of Pharmacy. Philadel-
phia: J.B. Lippincott Co., 1885: 986.
20. British Pharmacopoeia London. Printed for the Gen-
eral Medical Council by Spottiswoode & Co., 1867: 32. Bird JC. A new suppository base. J Am Pharm Assoc
307–308. 1937; 27: 475–479.
21. Wood GB, Bache F. The Dispensatory of the United 33. Eiler JJ. Suppositories. In: Lyman RA (ed.) American
States of America, 13th edn. Philadelphia: J.B. Lip- Pharmacy. Philadelphia: J.B. Lippincott Co., 1945:
pincott and Co., 1867: 1424–1426. 374.
26
3
Suppository bases and their
characteristics
LIKE OINTMENT BASES , suppository bases play an is clear. Below the clear melting point, release
important role in the release of the medication is insignificant. At the clear melting point and
they hold and hence in the availability of the above, the rate of release increases enormously,
drug for absorption for systemic effects or for and the rate of diffusion reaches the values of a
localized action. Of course, one of the first corresponding aqueous solution. Excipients with
requisites for a suppository base is that it should great melting intervals are less favorable than
remain solid at room temperature but should those with small melting intervals.
readily soften, melt, or dissolve at body temper- 3 Release of a drug soluble in fat-like bases is
ature so that the drug it contains may be made relatively little affected by the melting state. Only
fully available soon after insertion. Certain bases occasionally, an evident increase was observed
are more efficient in drug release than others. after reaching the clear melting point. On the
For instance, cocoa butter (theobroma oil) melts whole, however, much less drug is released per
quickly at body temperature, but because the unit of time than by a drug which is insoluble
resulting oil is immiscible with body fluids, fat- in the suppository base. In contrast to a drug
soluble drugs tend to remain in the oil and have insoluble in fatty base, release of a drug soluble
little tendency to enter the aqueous physiologic in such an excipient is markedly influenced by
fluids. For water-soluble drugs incorporated in co- hydrophilia, the release being slowed down as
coa butter the reverse is usually true, and good re- the hydroxyl number increases.
lease results. Fat-soluble drugs seem to be released 4 Water-soluble bases always release the drug
more readily from water-soluble bases such as less quickly than fatty bases, independently of
polyethylene glycol (PEG) or glycerinated gelatin, the melting state.
both of which dissolve slowly in body fluids.
5 Consequently, a fat-like base should have: a
When irritation or inflammation is to be relieved,
clear melting point not exceeding about 36.5◦ C,
as in the treatment of anorectal disorders, cocoa
as small a melting interval as possible, and as
butter appears to be the superior base because of small an hydroxyl number as possible.
its emollient or soothing, spreading action.
In 1958, Eckert and Muhlemann summarized 6 Finally, for practical purposes it results that
the following concerning bases and drugs for when a quick effect is required, a fatty base
suppositories.1 should be used in which the drug is insoluble
and in which the drug must be incorporated in
1 If a drug dissolves in the suppository base, the form of a suspension. If the effect is to be
release and intestinal absorption are much slower delayed, however, a base should be chosen in
and more continuous than in the presence of a which the drug is soluble.
suspension.
2 Release of a drug insoluble in a fat-like suppos- Classification of suppository bases
itory base, but soluble in water, depends in the
first place upon the melting state and the interval
between the moment when the specimen begins Three categories of suppository bases are usu-
to expand and the moment the melted mass ally described. The first category is the fatty,
27
28 Suppositories
Table 3.1 Melting ranges of some suppository bases
Base Composition Melting range (◦ C)
Cocoa butter Mixed triglycerides of oleic, palmitic, stearic acids 34–35

Cotomar Partially hydrogenated cottonseed oil 35
Dehydag Hydrogenated fatty alcohols and esters
Base I 3–36
Base II 37–39
Base III Also contains glycerides of saturated fatty acids C12–C16 9 ranges
Fattibase Triglycerides from palm, palm kernel, and coconut oils with 35.5–37
self-emulsifying glyceryl monostearate and polyoxyl
stearate
Hexaride Base 95 33–35
Hydrokote 25 Higher melting fractions of coconut and palm kernel oil 33.6–36.3
Hydrokote 711 Same as above 39.5–44.5
Hydrokote SP Same as above 31.1–32.3
Polybase A homogeneous blend of PEGs and polysorbate 80 60–71
S-70-XX95 Rearranged hydrogenated vegetable oils 34.4–35.6
S-070-XXA 38.2–39.3
Suppocire OSI Eutectic mixtures of mono-, di-, triglycerides derived from 33–35
natural vegetable oils, each type having slightly different
properties
Suppocire OSIX 33–35
Suppocire A 35–36.5
Suppocire B 36–37.5
Suppocire C 38–40
Suppocire D 42–45
Suppocire DM 42–45
Suppocire H As above but with the addition of poly-oxyethylated glycerides 36–37.5
Suppocire L 38–40
Tegester Specially prepared triglyceride bases:
Triglycerides
TG-95 32.2–34.5
TG-MA 34.5–36.0
TG-57 34.0–36.5
Tween 61 Used alone or in combination with PEG sorbitan monostearate 35–49
Wecobee FS Triglycerides derived from coconut oil 39.4–40.5
Wecobee M 33.3–36
Wecobee R 33.9–35
Wecobee S 38–40.5
Wecobee SS 40–43
Wecobee W 31.7–32.8
Witepsol (Selected Triglycerides of saturated fatty acids C12–C18 with varied
examples) portions of the corresponding partial glycerides
H5 35.2
H12 32–33
H15 33–35
H19 34.8
H85 42–48
Chapter 3 • Suppository bases and their characteristics 29
oleaginous, or oil-type bases that melt at body

temperature to release their medication. The sec- Table 3.2 Considerations in active ingredient and
ond contains the water-soluble or water-miscible suppository base compatibility
bases and includes polymer glycol substitution
products (PEG, poloxamer), surface acting agents,
and glycerin gelatin bases that absorb water 1. Organoleptic Odor
and dissolve to release the medication. The properties Color
third group of bases is the miscellaneous group 2. Physical Boiling point
properties Clouding point
containing disintegrating agents, natural gums,
Crystalline form
effervescent agents, collagen, and others.
Density
Granulometry (particle size)
Ionization
Desirable characteristics Melting point
pH and buffer capacity
A suppository base should be physically and Solubility
chemically stable, non-irritating, non-toxic, non- Solvent properties
sensitizing, chemically and physiologically inert, Surface tension
compatible with a variety of drugs, stable during Vapor pressure or volatility
storage, and esthetically acceptable (free from Viscosity
objectionable odor and a pleasing appearance). 3. Chemical Analytical methods
It should contract slightly on cooling to release characteristics Behavior in the presence of
itself from the mold without requiring mold water, surfactants, fatty acids,
lubricants, have wetting and emulsifying prop- preservatives, etc.
erties, have a high water number and be easy Formula developed
to manufacture by molding by hand, machine, Incompatibility (metals, heat,
compression, or extrusion. It should melt or light, etc.)
dissolve in rectal fluids and should not bind or Molecular weight
otherwise interfere with the release or absorption Radical reactivity
of drug substances. Stability to hydrolysis or
oxidation
Other desirable characteristics depend upon
4. Biological Stability to bacteria and fungal
the drugs to be added. For example, bases with
properties contamination
higher melting points can be used to incorporate
Toxicity
drugs that generally lower the melting points of
the base (e.g. camphor, chloral hydrate, menthol,
phenol, thymol, and volatile oils) or to formulate and purity of the base, as these factors may mod-
suppositories for use in tropical climates. Bases ify the intermolecular forces. Polymorphic bases
with lower melting points can be used when should either be discouraged or used with tight
adding materials that will raise the melting points controls on variables during their preparation
or when adding large amounts of solids. Exam- and use. A number of physical, chemical, and
ples of different types of suppository bases and biological characteristics of bases and active prin-
their melting ranges are shown in Table 3.1. ciples that should be considered for compatibility
The tendency of a suppository base to ex- are listed in Table 3.2.
hibit polymorphism should be considered. When Additional characteristics of importance in
the intermolecular forces between the molecules selecting a suppository base can include the
comprising the base can be arranged in different following:2
ways, and the energy difference between the
potential structural forms is very low, the base r Acid value (acid number, acidity index): This
might be found to be polymorphic. The structure is the number of milligrams of potassium hy-
exhibited by the base may then be dependent droxide necessary to neutralize the free acids
upon temperature, solvent, handling procedure, in 1 g of oil, fat, wax, resin, balsam, or similar
30 Suppositories
organic substance of complex composition. The of bases with a low hydroxyl number (low partial
presence of free acids in oils, fats, and waxes is ester content) is indicated to minimize the risk
due primarily to the hydrolysis of the esters of of interaction with drugs that are chemically re-
which they are composed and may be caused active. Hydroxyl numbers also give an indication
by chemical treatment, bacterial action, or the of the hydrophilic properties of the base, which
catalytic action of light and heat. Generally, fresh can affect both drug release and absorption rates.
or recently prepared fatty substances contain r Solid Fat Index (SFI): This is defined as the
little or no free acids. However, upon aging,
percentage of solid glycerides in the fat mixture
the acid value increases slowly at first and more
at a certain temperature. Methods that can be
rapidly later. High acid values are not necessarily
used include dilatometry, differential thermal
an indication of rancidity since rancidity is a
analysis, and nuclear magnetic resonance (NMR)
result of air, or possibly bacteria, interacting with
spectroscopy. The SFI is important in describing
the liberated fatty acids.
the state of aggregation and the phase transition
r Iodine value (iodine number): This is the number of the fat.
of grams of iodine absorbed under specified
conditions by 100 g of oil, fat, wax, or other
substance. It is a quantitative measure of the
Fatty or oleaginous bases
proportion of unsaturated fatty acids present,
both free and combined as esters, that have the
Fatty bases are perhaps the most frequently
property of absorbing iodine. Drying oils, such as
employed for suppositories, principally because
linseed oil and the fish oils, have very high iodine
cocoa butter is a member of this group of
values, usually above 120, since they contain a
substances. Among the other fatty or oleaginous
large proportion of unsaturated fatty acids. The
materials used in suppository bases are many
non-drying oils, such as olive oil and almond
hydrogenated fatty acids of vegetable oils such as
oil, have relatively low iodine values, below
palm kernel oil and cottonseed oil. Also, fat-based
100. The semi-drying oils, such as cottonseed oil
compounds containing compounds of glycerin
and sesame oil, have intermediate iodine values
with the higher molecular weight fatty acids,
between 100 and 120. Animal fats generally have
such as palmitic and stearic acids, may be found
an iodine value less than about 90. The iodine
in fatty suppository bases. Compounds such as
value can provide information on the degree of
glyceryl monostearate and glyceryl monopalmi-
unsaturation in the substance. It is an indication
tate are examples of these types of agents. The
of resistance to oxidation and rancidity.
suppository bases in many commercial products
r Saponification value (saponification number, employ various and varied combinations of these
Koettsdorfer number): This is the number of mil- types of materials to achieve a base possess-
ligrams of potassium hydroxide required to neu- ing the desired hardness under conditions of
tralize the free acids and saponify the esters shipment and storage and the desired quality
contained in 1 g of fat, fatty or volatile oil, of submitting to the temperature of the body
wax, resin, balsam, or other substance of similar to release their medicaments. These bases gen-
composition. erally have a low water content and minimal
tendency towards hygroscopicity. These bases, if
r Hydroxyl value (hydroxyl number): This is the
not properly packaged, may develop a “bloom”
number of milligrams of potassium hydroxide consisting of powdery crystals on the surface of
equivalent to the hydroxyl content of 1 g of the suppository. This is often the result of the
the substance. It gives an indication of the high-melting-point components in the base and
identity and purity of fatty substances possessing can be overcome by using a different base or
alcoholic hydroxyl groups. Generally, bases with precrystallizing the base prior to pouring; this
a low hydroxyl number tend to be less plastic will cause the crystals to form quickly with more
than those with higher values and, when rapidly complete crystallization into the final crystalline
cooled, may become excessively brittle. The use form. This process is referred to as “tempering.”
In some instances, suppository bases are prepared will be useless to the patient, representing a loss
with the fatty materials emulsified or with an of time, materials, and prestige to the pharmacist.
emulsifying agent present to prompt emulsifica- Cocoa butter must be slowly and evenly
tion when the suppository makes contact with melted, preferably over a water bath of warm
the aqueous body fluids. These types of bases are water, to avoid the formation of the unstable
arbitrarily placed in the third, or “miscellaneous” crystalline form and to ensure the retention in
group of suppository bases. the liquid of the more stable ␤ crystals that will
Cocoa butter, NF, is defined as the fat obtained constitute nuclei upon which the congealing may
from the roasted seed of Theobroma cacao. Cocoa occur during chilling of the liquid.
butter, or theobroma oil, is an oleaginous base Substances such as phenol and chloral hydrate
that softens at 30◦ C and melts at 34◦ C. At room tend to lower the melting point of cocoa butter
temperature it is a yellowish white solid with a when incorporated with it. If the melting point
faint, agreeable chocolate-like odor. Chemically, is lowered to such an extent that it is not feasible
it is a mixture of liquid triglycerides entrapped to prepare a solid suppository using cocoa butter
in a network of crystalline, solid triglycerides. alone as the base, solidifying agents such as
Palmitic and stearic acids make up about half cetyl esters wax (about 20%) or beeswax (about
of the saturated fatty acids, while oleic acid is 4%) may be melted with the cocoa butter to
the one unsaturated fatty acid. Because cocoa compensate for the softening effect of the added
butter melts between 30◦ C and 36◦ C, it is an substance. However, the addition of hardening
ideal suppository base, melting just below body agents must not be so excessive as to prevent
temperature and yet maintaining its solidity at the melting of the base after the suppository has
usual room temperatures. However, because of been inserted into the body, nor must the waxy
its triglyceride content, cocoa butter exhibits material interfere with the therapeutic agent
marked polymorphism, or the property of exist- in any way so as to alter the efficacy of the
ing in several different crystalline forms. product.
Cocoa butter has four different forms – ␣, Other bases in this category include commer-
␤, ␤ , and ␥ – with melting points of 22◦ C, cial products such as Fattibase (triglycerides from
34–35◦ C, 28◦ C, and 18◦ C, respectively. The ␤ palm, palm kernel, and coconut oils with self-
form, which is the most stable, is preferable for emulsifying glyceryl monostearate and polyoxyl
suppositories. Cocoa butter will melt to form a stearate) and the Wecobee bases (triglycerides
non-viscous, bland oil. Because it is immiscible derived from coconut oil) and Witepsol bases
with body fluids, it may leak from the body (triglycerides of saturated fatty acids C12–C18
orifice. Polymorphs with lower melting points with varying portions of the corresponding par-
will eventually convert to a more stable form over tial glycerides). These additional bases, which
time. Because of this polymorphism, when cocoa make up the largest group in this category, are
butter is hastily or carelessly melted at a temper- chemically modified during their preparation
ature greatly exceeding the minimum required to produce a range of products with control-
temperature and then quickly chilled, the result lable characteristics, as described in Tables 3.3
is a metastable crystalline form (␣ crystals) with and 3.4.
a melting point much lower than the original To avoid the base sticking to the molds when
cocoa butter. In fact, the melting point may be suppositories are being prepared, the cocoa butter
so low that the cocoa butter will not solidify at must not be overheated and the molds must be
room temperature. However, since the crystalline clean and dry before use.
form represents a metastable condition, there is
a slow transition to the more stable ␤ form of
Hydrogenated vegetable oil bases
crystals, which have the greater stability and the
higher melting point. This transition may require Fattibase (Paddock Laboratories, Minnesota, USA)
several days. Consequently if suppositories that is a preblended suppository base that offers the
have been prepared by melting cocoa butter for advantages of a cocoa butter base with few of
the base do not harden soon after molding they the drawbacks. It is composed of triglycerides
Royal Pharmaceutical Society of Great Britain
Table 3.3 Suppository bases (Gattefossé, France) for compounding and manufacturing
Acid Iodine Saponification Hydroxyl

value (mg value (g value (mg value (mg Melting
Product name Composition Compendia Description KOH/g) I2 /100 g) KOH/g) KOH/g) range (◦ C)
Multipurpose vehicles: interesterified

Suppocire AI Semi-synthetic USP/NF Versatile base for simple <0.50 <2 224–246 20–30 33.0–35.0
glycerides EP formulations
JPE Adapted to active ingredients
increasing the melting point
Suitable for semi-automatic and
automatic manufacturing
Suppocire A Semi-synthetic USP/NF Versatile base for simple <0.50 <2 224–246 20–30 35.0–36.5
JPE Suitable for semi-automatic and
32
Suppocire B Semi-synthetic USP/NF Similar to Suppocire A, with a <0.50 <2 220–244 20–30 36.0–37.5
glycerides EP higher melting point
JPE
Suppocire C Semi-synthetic USP/NF Versatile base for simple <0.50 <2 218–242 20–30 38.0–40.0
JPE Adapted to active ingredients
decreasing the melting point
Suitable for semi-automatic and
Suppocire D Semi-synthetic USP/NF Similar to Suppocire C, with a <0.50 <2 210–232 20–30 42.0–45.0
glycerides EP higher melting point
JPE
Suppocire Semi-synthetic USP/NF Versatile base suitable for all types <0.50 <2 224–246 15–25 35.0–36.5
AS2 glycerides EP of production equipment
JPE
September 16, 2007

Suppocire Semi-synthetic USP/NF Similar to Suppocire AS2, with a <0.50 <2 224–246 15–25 36.0–37.5
BS2 glycerides EP higher melting point
JPE
23:16
Table 3.3 Continued

Suppocire AT Semi-synthetic USP/NF Versatile base for manual or <0.50 <2 220–244 27–37 35.0–36.5
glycerides EP semi-automatic manufacturing
JPE
Suuppocire Semi-synthetic – Versatile base. The non-ionic <0.50 <2 218–242 15–25 35.0–36.5
AS2X glycerides emulsifying additive enables
incorporation of water or
alcoholic extracts or solutions
Suppocire Semi-synthetic – Simiilar to Suppocire AS2X, with a <0.50 <2 218–242 15–25 36.0–37.5
BS2X glycerides higher melting point
Suppocire Semi-synthetic – Similar to Suppocire BS2X, with a <0.50 <2 218–242 15–25 38.0–40.0
CS2X glycerides higher melting point
Low reactivity vehicles: interesterified
33
Suppocire Semi-synthetic USP/NF Base with a low hydroxyl value to <0.20 <2 231–255 <10 33.0–35.0
AIM glycerides EP avoid interaction between free
JPE OH groups and acidic active
ingredients. Suitable for high
rate manufacturing but
shock-cooling should be avoided
Suppocire Semi-synthetic USP/NF Similar to Suppocire AIM, with a <0.20 <2 228–252 <10 35.0–36.5
AM glycerides EP higher melting point
JPE
Suppocire Semi-synthetic USP/NF Similar to Suppocire AIM with a <0.20 <2 226–250 <10 36.0–37.5
BM glycerides EP higher melting point
JPE
Suppocire Semi-synthetic USP/NF Similar to Suppocire BM, with a <0.20 <2 224–246 <10 36.0–38.0
BCM glycerides EP slightly higher melting point
JPE
September 16, 2007

Suppocire Semi-synthetic USP/NF Similar to Suppocire BM, with a <0.20 <2 224–246 <10 38.0–40.0
CM glycerides EP higher melting point
JPE
23:16
Table 3.3 Continued

Suppocire Semi-synthetic USP/NF Similar to Suppocire CM, with a <0.20 <2 214–236 <10 42.0–45.0
DM glycerides EP higher melting point
JPE
Low reactivity vehicles compatible with large amounts of powders: interesterified
Suppocire Semi-synthetic USP/NF Base with a low hydroxyl value to <0.50 <3 228–252 <10 33.0–35.0
AIML glycerides avoid interaction between free
OH groups and acidic active
ingredients. The phospholipidic
additive enables incorporation
of large amounts of powders
Suppocire Semi-synthetic USP/NF Simiilar to Suppocire AIML, with a <0.50 <3 228–252 <10 35.0–36.5
34
AML glycerides higher melting point

Suppocire Semi-synthetic USP/NF Similar to Suppocire AML, with a <0.50 <3 225–249 <10 36.0–37.5
BML glycerides higher melting point
Amphiphilic suppository bases (P type)
Suppocire AP Saturated poly- – Amphiphilic suppository base that <1.00 <1 206–220 30–60 33.0–35.0
glycolysed enables solubilization and
glycerides absorption enhancement of
active ingredients
Suppocire BP Saturated poly- – Similar to Suppocire AP, with a <1.00 <1 201–215 30–50 35.0–37.0
glycolysed higher melting point
glycerides
Suppocire CP Saturated poly- – Similar to Suppocire BP, with a <1.00 <1 197–211 30–50 38.5–40.5
glycerides
September 16, 2007

Suppocire DP Saturated poly- – Similar to Suppocire CP, with a <1.00 <1 180–210 25–50 41.0–45.0
glycerides
23:16
Table 3.3 Continued

Low reactivity vehicles: esterified

Suppocire Semi-synthetic USP/NF Bases with low hydroxyl value to <0.20 <2 230–250 <3 34.0–36.5
NA O glycerides EP avoid interaction between free
ingredients. Suitable for high
Suppocire Semi-synthetic USP/NF <0.50 <2 228–252 4–14 33.5–35.5
NAI 10 glycerides EP
JPE
Suppocire Semi-synthetic USP/NF 0.50 <2 228–252 4–14 34.5–36.5
35
NA 10 glycerides EP
JPE
Suppocire Semi-synthetic – <1 <2 225–240 <20 35.0–37.0
NAS 10 glycerides
NA 15 glycerides EP
JPE
Suppocire Semi-synthetic – <1.30 <2 220–230 5–15 37.0–39.0
NAIS 10 glycerides
Suppocire Semi-syntheticUSP/NF Versatile base for formulation <0.50 <2 245–260 7–17 37.0–41.0
NCS 10 glycerides EP adapted to active ingredients
JPE decreasing the melting point
JSFA
Large-scale production vehicles: esterified
Suppocire Semi-synthetic USP/NF Bases with a high hydroxyl value <0.30 <2 224–246 20–30 33.5–35.5
September 16, 2007

NAI glycerides EP for large-scale productions with
JPE shock-cooling and/or high
JSFA amounts of powder
23:16
Table 3.3 Continued

Suppocire Semi-synthetic USP/NF <0.50 <2 230–250 <30 33.2–35.2

NAI 25A glycerides EP
JPE
JSFA
NA 35 glycerides EP
JPE
NAI 50 glycerides EP
JPE
36

NA 50 glycerides EP
JPE
NAS 40 glycerides EP
JPE
JPE
JPE
JSFA
Suppocire Semi-synthetic USP/NF <1.00 <1 215–245 80–100 34–36
NAIS 90 glycerides EP
September 16, 2007

JPE
JSFA
23:16
Table 3.3 Continued

Multipurpose vehicles: esterified

Suppocire Semi-synthetic USP/NF Versatile base, suitable for all types <0.30 <2 225–240 20–30 34.5–36.5
NAI 25 glycerides EP of production equipment. Yields
JPE suppositories showing a high
mechanical resistance
Suppocire Semi-synthetic USP/NF Versatile base, suitable for all types <0.50 <2 224–246 20–30 34.5–36.5
NA glycerides EP of production equipment. Yields
mechanical resistance
Suppocire Semi-synthetic USP/NF Similar to Suppocire NA, with a <0.50 <2 214–236 20–30 36.5–38.5
NB glycerides EP higher melting point
JPE
37
glycerides
Suppocire Semi-synthetic USP/NF Similar to Suppocire NB, with a <0.50 <2 214–236 20–30 38.0–40.5
NC glycerides EP higher melting point
JPE
Suppocire Semi-synthetic USP/NF Similar to Suppocire NC, with a <0.50 <2 204–226 20–30 42.0–45.0
ND glycerides EP higher melting point
JPE
Suppocire Semi-synthetic USP/NF Base for suppositories showing a <1.00 <3 224–246 20–30 34.5–36.5
NAL glycerides high mechanical resistance. A
phospholipidic additive enables
incorporation of high amounts
of powder
Suppocire Semi-synthetic USP/NF Similar to Suppocire NAL, with a <0.50 <3 218–242 20–30 36.0–38.0
NBL glycerides higher melting point
Suppocire Semi-synthetic – Base for suppositories showing a <0.50 <2 218–242 20–30 34.5–36.5
September 16, 2007

NAX glycerides high mechanical resistnace. A
non-ionic emulsifying additive
enables incorpation of water or
alcoholic extracts or solutions
23:16
Table 3.3 Continued

Suppocire Semi-synthetic – Similar to Suppocire NAX, with a <0.50 <3 214–236 20–30 36.0–28.5
NBX glycerides higher melting point
Suppocire Semi-synthetic – Similar to Suppocire NBX, with a <0.50 <3 214–236 20–30 38.0–41.0
NCX glycerides higher melting point
Vehicles for vaginal suppositories (pessaries)
Ovucire WL Semi-synthetic USP/NF Versatile base for vaginal <0.50 <8 215–235 43–63 32.5–35.5
2944 glycerides EP suppositories
JPE
Ovucire Semi-synthetic USP/NF Base with an emulsifying additive to <0.50 <3 215–235 40–60 32.0–35.0
38
3264 glycerides improve dispersibility and

wettability of the actives.
Fast melting at body temperature.
Forced cooling is necessary
Ovucire Semi-synthetic USP/NF Base for vaginal suppositories <1.00 <7 215–225 60–70 32.5–34.0
3460 glycerides
Specific hard fat for the Japanese market: interesterified and esterified
Japocire NA Semi-synthetic USP/NF Versatile base, suitable for all types <0.20 <2.0 235–245 <3.0 33.5.35.5
O glycerides EP of production equipment. Yields
JSFA mechanical resistance
Japocire Semi-synthetic USP/NF Excipient used to produce <1.30 <3.0 220–230 5–15 37.0–39.0
NAIS 10 glycerides EP suppositories with high crushing
JPE force
September 16, 2007

JSFA
23:16
Table 3.3 Continued

Japocire NA Semi-synthetic USP/NF Base with a low hydroxyl value to <0.20 <2.0 230–240 <15.0 33.5–35.5
15 glycerides EP avoid interaction between free
JSFA ingredients. Suitable for high
Japocire DM Semi-synthetic USP/NF Base with a low hydroxyl value to <0.30 <2.5 220–230 <15.0 42.0–44.0
glycerides EP avoid interaction between free
39

JSFA ingredients. Suitable for high
Japocire Semi-synthetic USP/NF Suppository base with a high <0.30 <2.5 225–235 40–50 33.5–35.5
NAS 50 glycerides EP hydroxyl value suitable for
JPE large-scale productions with
JSFA shock-cooling and/or high
amounts of powder
Japocire Semi-synthetic USP/NF Excipient for vaginal suppositories <1.00 <3.0 215–230 50–65 33.5–35.5
JPE
JSFA
Adapted from Rectal Route Excipients, Gattefossé, Cedex-France.
September 16, 2007

23:16
40 Suppositories
Table 3.4 Suppository bases (miscellaneous) for compounding and manufacturing
Saponification Hydroxyl
Water Iodine value value value (mg Melting
Product name Composition number (g I2 /100 g) (KOH/mg) KOH/g) range (◦ C)
Adeps Solidus Triglycerides of saturated – <7 225–240 – 33.5–35.5

fatty acids with mono-
and diglycerides
Cotomar Partially hydrogenated – 70 191 – 37
cottonseed oil
Hydrokote 25 Higher melting fractions – <4 235–245 – 33.6–36.3
of coconut and palm
kernel oil.
Hydrokote 711 Higher melting fractions – <4 230–240 – 39.5–44.5
of coconut and palm
kernel oil
Hydrokote SP Higher melting fractions – <6 245–255 – 31.1–32.3
of coconut and palm
kernel oil
Massa Estarinum – <3 240–255 <5 33.5–35.5
299
Massa Estarinum A Mixture of tri-, di- and 30–40 <1 225–240 35–45 33–35
monoglycerides of
saturated fatty acids
Massa Estarinum Mixture of tri-, di- and – <3 235–245 25–40 29–31
AB monoglycerides of
Massa Estarinum – <3 235–245 <6 33.5–35.5
AM
Massa Estarinum B Mixture of tri-, di- and – <3 225–240 20–30 33.5–35.5
monoglycerides of
Massa Estarinum – <3 225–240 30–40 33.5-.35.5
BC
Massa Estarinum C Mixture of tri-, di- and – <3 225–235 20–30 36–38
monoglycerides of
Massa Estarinum D Mixture of tri-, di- and – <3 220–230 30–40 40–42
monoglycerides of
Massa Estarinum E Mixture of tri-, di- and – <3 215–230 45–60 34–36
monoglycerides of
Massa Mf 13 Mixture of di- and – 2–3 225–235 – 36–37
triglycerides of
Wecobee W Triglycerides 30–40 <4 242–252 – 31.7–32.8
Wecobee R Higher melting fractions 30–40 <4 236–246 – 33.9–35
of coconut oil and
palm kernel oil.
Table 3.4 Continued
Wecobee S Higher melting fractions of 30–40 <4 236–246 – 38–40.5

coconut oil and palm kernel
oil
Wecobee M Higher melting fractions of 30–40 <3 238–248 – 33.3–36
oil
Wecobee FS Higher melting fractions of 30–40 <3 236–248 – 39.4–40.5
oil
Witepsol E75 Triglyceride of saturated 45 <7 220–230 5–15 37–39
vegetable fatty acids with
monoglycerides
Witepsol E76 Triglyceride of saturated – <3 220–230 30–40 37.0–39.0
monoglycerides
Witepsol E79 Triglyceride of saturated – <7 220–230 25–35 36–38
monoglycerides
Witepsol E85 Triglyceride of saturated 45 <3 220–230 – 42–44
monoglycerides
Witepsol H5 Triglyceride of saturated – <2 235–245 <5 34.0–36.0
monoglycerides
Witepsol H12 Triglyceride of saturated 100 <3 240–245 5–15 32.3–33.5
monoglycerides
Witepsol H15 Triglyceride of saturated 100 <3 230–245 5–15 33.5–35.5
monoglycerides
Witepsol H19 Triglyceride of saturated – <7 230–240 20–30 33.5–35.5
monoglycerides
monoglycerides
monoglycerides
monoglycerides
monoglycerides
42 Suppositories
Table 3.4 Continued

monoglycerides
Witepsol S51 Triglyceride of saturated – <8 215–230 55–70 30.0–32.0
monoglycerides
monoglycerides
monoglycerides
Witepsol S58 Triglyceride of saturated – <7 215–225 60–70 31.5–33
monoglycerides
Witepsol W25 Triglyceride of saturated – <3 225–240 20–30 33.5–35.5
monoglycerides
Witepsol W31 Triglyceride of saturated – <3 225–240 25–35 35–37
monoglycerides
Witepsol W32 Triglyceride of saturated – <3 225–245 40–50 32–33.5
monoglycerides
Witepsol W35 Triglyceride of saturated – <3 225–235 40–50 33.5-.35.5
monoglycerides
Witepsol W45 Triglyceride of saturated – <3 225–240 40–50 33.5–35.5
monoglycerides
derived from palm, palm kernel, and coconut Wecobee bases (Stepan Co., Northfield, IL,
oils, with self-emulsifying glyceryl monostearate USA) are derived from palm kernel and coconut
and polyoxyl stearate used as emulsifying and oils; they are rendered emulsifiable by the incor-
suspending agents. This base is stable with a poration of glyceryl monostearate and propylene
low irritation profile, needs no special storage glycol monostearate. These bases also exhibit
conditions, is uniform in composition, and has most of cocoa butter’s desirable features but few
a bland taste and controlled melting range. It of its shortcomings. They are stable and also
exhibits excellent mold release characteristics exhibit excellent mold release characteristics.
and does not require mold lubrication. Fattibase There are over 20 Witepsol bases (Dynamit
is a solid with a melting point of 35–37◦ C, has a Nobel AG, Germany) available. These are nearly
specific gravity of 0.890 at 37◦ C, is opaque-white, white and almost odorless. Witepsol H15’s melt-
and is free of suspended matter. ing range and release characteristics are similar to
those of cocoa butter. These bases solidify rapidly Polyethylene glycols

in the mold, and lubrication is not necessary,
as the suppositories contract nicely for ease of Polyethylene glycols are polymers of ethylene ox-
removal from the mold. Witepsol bases with a ide and water, prepared to various chain lengths,
high melting point can be mixed with those with molecular weights, and physical states. They are
a low melting point to provide a wide array of available in a number of molecular weight ranges
possible melting ranges (i.e. 34–44◦ C). Since the and melting ranges, the more commonly used
Witepsol bases contain emulsifiers, they can take being PEG 300 (–15 to –18◦ C), 400 (4–8◦ C),
up or absorb limited quantities of water. Witepsol 600 (20–25◦ C), 1000 (37–40◦ C), 1450 (43–46◦ C),
H products are hard fats which are characterized 3350 (54–58◦ C), 4600 (57–61◦ C), 6000 (56–
by a low hydroxyl value. Witepsol W products 63◦ C), and for the 8000 (60–63◦ C). The numer-
are hard fats characterized by a higher hydroxyl ical designations refer to the average molecular
value. Witepsol S products are those special hard weights of each of the polymers. PEGs with
fats to which non-ionic ethoxylated emulsifiers average molecular weights of 300, 400, and 600
have been added. Witepsol E products are hard are clear, colorless liquids. Those with average
fats with melting points above body temperature. molecular weights of greater than 1000 are wax-
Suppositories made up of hydrogenated cot- like, white solids with the hardness increasing
tonseed oil and hexadienol with other ingre- with an increase in the molecular weight. Various
dients can be prepared with a suitable melt- combinations of these PEGs may be combined by
ing range. Hexadienol is a semi-solid substance fusion; using two or more of the various types
with a melting point of 35◦ C. It has a mild allows one to achieve a suppository base of the
hydrophilic property but is insoluble in water. desired consistency and characteristics.
It is miscible with oils, resulting in a strong In PEG-based suppositories, the drug is re-
affinity and marked reduction in surface tension. leased as a consequence of the progressive disso-
It does, however, have some pharmacological lution of PEG into the intrarectal aqueous phase.
effect, including a sudorific agent and a mild The drug concentration in this small intrarectal
analgesic effect.3 phase produces the gradient against the large
Table 3.3 lists a number of commercially avail- volume of the plasmatic phase, which regulates
able (Gattefossé) fatty acid type bases and charac- the diffusion rate through the barrier. As with
teristics including description, acid value, iodine lipophilic bases, drug solubility in water is an
value, saponification value, hydroxyl value, and important factor influencing suppository release.
melting range. Table 3.4 lists other commercial PEG influences both in vitro and in vivo drug
bases along with their composition, water num- availability considerably, by increasing both drug
ber, saponification value, iodine value, hydroxyl solubility and dissolution rate. In the intrarectal
value, and melting point. compartment, the osmotic effect of PEG influ-
ences the increase in volume of the aqueous
phase. When compared with the lipophilic bases,
there is a higher dissolution rate from PEG
Water-soluble and water-miscible bases excipients, but a higher diffuson rate across the
barrier does not always result. According to some
The main members of this group are bases studies, drugs that are less soluble in water show
of PEGs, glycerinated gelatin, and poloxomers. a greater availability from PEG suppositories and
When a water-soluble base is used, the drug may more soluble drugs show less availability.4
be dissolved or suspended and mixes with the Table 3.5 lists the relevant characteristics of
aqueous body fluids. Water-soluble bases may various PEGs. PEG bases are incompatible with
cause some irritation, however, because they may silver salts, tannic acid, aminopyrine, quinine,
produce slight dehydration of the rectal mucosa ichthammol, aspirin, benzocaine, iodochlorhy-
as they take up water and dissolve. Nevertheless, droxyquin, and sulfonamides due to physical,
they are a widely used base for suppository chemical and/or stability problems. Sodium bar-
formulation. bital, salicylic acid, and camphor will crystallize
44 Suppositories
Table 3.5 Characteristics of selected polyethylene glycols
Molecular weight Molecular weight Water solubility

average (%) range Melting range (◦ C) (approx. % by weight)
300 285–315 –15 to –8 100

400 380–420 4–8 100
600 570–630 20–25 100
1000 950–1050 37–40 80
1450 1300–1600 43–46 72
3350 3000–3700 54–58 67
4600 4400–4800 57–61 65
8000 7000–9000 60–63 63
out of PEG suppositories. High concentrations stearate mixtures, which are designed primarily
of salicylic acid will soften PEGs, and aspirin for prompt evacuation, and glycerin and gelatin
will complex with PEGs. PEG-based suppositories water bases to which medications are added,
may be irritating to some patients. Suppositories which are used for both rectal and vaginal
prepared with PEG should not be stored or applications.
dispensed in a polystyrene prescription vial, as The laxative effect of the first type of base,
PEG interacts adversely with polystyrene. PEG made using glycerin, gelatin, and sodium stearate
suppositories should be dispensed in glass or mixtures, can be attributed to the irritation of the
cardboard containers. mucous membrane by the glycerin–stearate; this
PEG suppository bases are the most popular effect does not depend upon any drug.
water-soluble bases. Their advantage lies in the The second type of glycerinated gelatin base
fact that the ratios of the low to the high has particular utility when other bases become
molecular weight individual PEGs can be altered brittle with the incorporation of drugs. Their
to prepare a base with a specific melting point or consistency can be varied by altering the amount
one that will overcome any problems that result of water present. This makes them suitable for
from having to add excess powder or liquid to a incorporating water-soluble drugs or solid ingre-
suppository. One disadvantage is that PEG bases dients. A number of added ingredients have been
can cause a stinging or burning sensation and can suggested to correct the hygroscopicity, trans-
initiate a defecation reflex when administered parency, brittleness and temperature resistance
rectally. These effects can be minimized by the to shrinkage and weeping of these bases. The
addition of 10% water to the PEG base and by inclusion of water helps to do this, as well as
moistening the suppository prior to insertion. giving them transparency. Agar and acacia have
Polybase (Paddock Laboratories, Minnesota, been used to add firmness.5–8
USA) is a preblended suppository base. A white Glycerinated gelatin suppositories may be pre-
solid, it consists of a homogeneous mixture of pared by dissolving granular gelatin (20%) in
PEGs and polysorbate 80. It is a water-miscible glycerin (70%) and adding a solution or sus-
base that is stable at room temperature, has a pension of the medication (10%). A glycerinated
specific gravity of 1.177 at 25◦ C with an average gelatin base is most frequently used in the
molecular weight of 3440, and does not require preparation of vaginal suppositories, where the
mold lubrication. prolonged localized action of the medicinal agent
is usually desired. The glycerinated gelatin base is
slower to soften and mix with the physiologic
fluids than is cocoa butter and therefore provides
Glycerinated gelatin bases
a more prolonged release.
Two types of glycerin and gelatin bases have Because glycerinated gelatin suppositories
been developed: glycerin, gelatin, and sodium have a tendency to absorb moisture due to the
hygroscopic nature of glycerin, they must be aspirin suppository should be further tested in
protected from atmospheric moisture before use. clinical situations.9
They may also have a dehydrating effect and
be irritating to the tissues upon insertion. The
water present in the formula for the suppositories Miscellaneous bases
minimizes this action; however, if necessary, the
suppositories may be moistened with water prior In the miscellaneous group of bases are included
to insertion to reduce the initial tendency of the those which are mixtures of the oleaginous
base to draw water from the mucous membranes and water-soluble or water-miscible materials,
and irritate the tissues. disintegrating agents, natural gums, effervescent
Urethral suppositories may be prepared from agents, collagen, etc. These materials may be
a glycerinated gelatin base of a formula some- chemical or physical mixtures. Some are pre-
what different from the one indicated above. formed emulsions, generally of the water-in-oil
For urethral suppositories, the gelatin constitutes (w/o) type, or they may be capable of dispersing
about 60% of the weight of the formula, the in aqueous fluids.
glycerin about 20%, and the medicated aque- Polyoxyl 40 stearate is a surface-active agent
ous portion about 20%. Urethral suppositories that is employed in a number of commercial sup-
of glycerinated gelatin are much more easily pository bases. It is a mixture of the monostearate
inserted than suppositories with a cocoa butter and distearate esters of mixed polyoxyethylene
base, owing to the brittleness of cocoa butter diols and the free glycols, the average polymer
and its rapid softening at body temperature. length being equivalent to about 40 oxyethylene
Vaginal suppositories prepared from a glycerin units. The substance is a waxy, white to light tan
base composed of glycerin (87%), sodium stearate solid and is water soluble. Its melting point is
(8%), and purified water (5%) have occasionally generally between 39◦ C and 45◦ C.
been used. Other surface-active agents useful in the prepa-
ration of suppository bases also fall into this
broad grouping. Mixtures of many fatty bases
Poloxamers
(including cocoa butter) with emulsifying agents
Poloxamers are water-soluble, block copolymers capable of forming w/o emulsions have been
with a wide range of uses. Pluronic L44, L62, prepared. These bases have the ability to hold
L64, and F68 (BASF Corporation, USA), have been water or aqueous solutions and are sometimes
investigated as potential suppository bases. The referred to as “hydrophilic” suppository bases.
Pluronics have practically no odor or taste. In The Tweens, especially Tween 61, have a
a study in the 1960s, suppositories were pre- number of advantages when used as, or as a
pared using Pluronic F68 1.5 g and Pluronic L44 component of, suppository bases. Tween 61 has
1.0 mL.9 The suppository was made by placing a melting point that is readily modified by small
the F68 and L44 in a beaker and melting in a quantities of different excipients to different
water bath. The beaker was removed from the ranges. When administered, the suppository dis-
water bath, the mixture thoroughly stirred and perses in the fluids due to its surface active prop-
poured into a mold. After hardening, it was erties and covers the mucous membranes with a
removed from the mold. It had a smooth, greasy smooth, protective coating, helping retention of
feeling to the hand and its disintegration time the suppository and leading to less tendency to
was about 17 minutes. An aspirin-containing leak. The suppository forms an oil-in-water (o/w)
Pluronic suppository base was also prepared using emulsion which also allows ready diffusion of the
Pluronic F68 6.00 g, Pluronic L44 7.00 mL, and medication. These suppositories are non-toxic,
aspirin 1.02 g. The pluronics were placed in a non-irritating, and contain no volatile or odorous
beaker in a water bath and heated until melted. substances; they are not excessively greasy and
The aspirin was added and the mixture stirred are neutral in reaction and stable; they do not
until uniform. The solution was placed in a mold, have a tendency towards rancidity. They are also
allowed to cool, and the suppositories removed. elastic and pliable, which contributes to their ease
The authors concluded that the Pluronic-based of use.
46 Suppositories
Development of suppository bases 1930s
In 1930, the hollow suppository form was in-

The early typical oil and fatty base is exemplified
troduced by Smith.15 In this dosage form, the
by theobroma oil, or cocoa butter. For the most
medication was poured into a hollow shell and
part, references to the base were for the term
sealed. A few years later, the incorporation of
“theobroma oil.” Today, however, “cocoa butter”
lecithin and cholesterol into cocoa butter was
is the more commonly used term. Cocoa butter
suggested by Schroff.16 A compound made up of
is an oil obtained from the seeds of theobroma
hydrogenated peanut oil was introduced in 1934
cacao, or chocolate plant. It is separated from
with a melting range of 38–41◦ C and was named
chocolate by heavy pressure between heated
“Astra-Fat.”17 In 1937, a formula for calculating
plates and is a by-product of the manufacture of
the amounts of wax and fats to be mixed to-
cocoa for drinking or flavoring purposes.
gether to obtain bases with appropriate melting
points was developed. The purpose of these
Early 1900s mixtures was to serve as substitutes for cocoa
butter.18
Cocoa butter was, for many years, the prototype The addition of 3% calcium oleate to cocoa
base. It met many of the requirements for a butter to facilitate the absorption of water into
suitable base since it was innocuous, bland, non- cocoa butter and paraffin suppositories was sug-
reactive, and melted at body temperature. Its gested. This was followed by the addition of
disadvantages, such as rancidity, melting in warm lecithin and cholesterol in conjunction with the
weather, liquefaction when incorporated with cocoa butter. In 1934, a hydrogenated peanut
drugs, and isomerization to a lower melting point oil that melted at 38–41 ◦ C was introduced as
resulted in the constant search for modification a suppository base.
or for a better base. In 1935, a patent was granted for an oleagi-
In 1912, Van Riel and Van der Wielen added nous base made up of combinations of hy-
wax to the cocoa butter10 and in 1918, Terry sug- drocarbons combined with ammonium salts of
gested the addition of kaolin and a 2% chondrus sulfonated olein to lower surface and inter-
mixture.11 That same year, Behrbalk introduced facial tension, and to produce emulsification.
a substitute for cocoa butter consisting of three This patent was assigned to E.R. Squibb &
parts olive oil with one part spermaceti.12 Sons.19
A coating was then proposed consisting of A German patent was issued in 1934 for a base
gelatin, glycerin, and acacia mixtures to add made of cholesterol, lactose, and water, heated to
toughness to the suppository. 80–90◦ C for complete melting and mixing of the
ingredients and then rapidly cooled. In 1937, a
patent was granted for a composition based on
1920s glycerol and glycol esters of stearic, lauric, and
palmitic acids. That same year an Austrian patent
Patents issued during this time period for cocoa was granted for a base composed of a fat dispersed
butter products included one issued in 1924 in a colloidal gelatin mass.20
for a suppository base made by an alcoholic A year later in 1938, the addition of cetyl alco-
saponification of 3–6% stearic acid and higher hol and other higher molecular weight alcohols
fatty acids dissolved in a paraffin oil base.13 was suggested. In 1938, Ferraris suggested cetyl
Later, in 1926, Cooper suggested the addition alcohol and higher molecular weight alcohols for
of 3% calcium oleate to the cocoa butter–paraffin cocoa butter bases, as well as the addition of cod
base to make it an absorption base to incorporate liver oil, triethanolamine stearate, and wax in the
water or aqueous drug solutions.14 following year.21,22
In 1927, a mixture of lard and suet was In 1939, cocoa butter bases were modified by
suggested as a base but this domestic fat quickly the addition of cod liver oil, triethanolamine
became rancid and was not a good substitute. stearate, and wax. The introduction of formulas
for glycerin–cocoa butter bases were presented by emulsifiers for cocoa butter that they studied and
Lehmann and Hediger also in 1939.23 that the emulsifiers were best used in concentra-
In 1937, patents were issued both in Germany tions of about 10%.30 Other bases studied to that
and the United States for a polyethylene oxide time included coconut stearin, hydrogenated
polymer and ricinoleic acid mixture with water peanut oil, and mixtures of oleic and stearic
which was proposed for a suppository base. It was acids.
proposed as a cocoa butter substitute in 1944, The Tweens were also introduced as suppos-
and by 1946 this new base was widely used in itory bases in the early 1940s. Proposed combi-
Europe. Called Carbowax in the United States, nations included a mixture of 90 parts sorbitan
it had some noted incompatibilities, including monostearate hydroxyl polyethylene ether with
with phenol, resorcinol, Peru balsam, and the 10 parts of either sorbitan monoricinoleate, min-
tannins. eral oil, or glyceryl laurate. Ward proposed the
It was soon realized that the polymer itself combination of 60% Tween 61 with 40% Tween
had great possibilities as a non-toxic, water- 60 or 90% Tween 61 with 10% glyceryl laurate.31
absorbable suppository base that could be stored In 1949, Gillham and Tomlinson described a
at high room temperature.24–26 base consisting of one part Carbowax 1500, with
A patent was awarded to Fitzgerald for an two parts Carbowax 6000.32 The Carbowaxes
effervescent suppository base in 1933. This con- were later purified and a new grade introduced
tained citric acid and sodium bicarbonate dry into the market.
mixed and compressed.27 A further refinement
of this basic design was presented in a British
patent granted in 1937 awarded for a suppository 1950s
containing an inner pellet of dry tartaric acid and
sodium bicarbonate dispersed in cocoa butter and In 1950, a new type of water-soluble base was
surrounded by a carrageenan–gelatin shell. Upon described consisting of methylcelluloses and car-
administration water was absorbed, resulting in boxymethylcellulose. A base was proposed in
rupturing of the suppository and the production 1951 consisting of Tween 61, Tween 20 and
of a froth that contained the medication. This Carbowax 1500 W.
particular suppository was especially useful in In 1952 a base was introduced consisting of
delivering contraceptives. polyoxyethylene 30 stearate (Myrj 51), water,
white wax and docusate sodium. It was found to
be compatible with aspirin, belladonna extract,
1940s benzocaine, camphor, coal tar, ichthymol, mer-
bromin, Peru balsam, sulfadiazine, sulfathiazole,
In 1940, the addition of beeswax and spermaceti and thymol. It liquified with sodium bromide
to increase the melting point of cocoa butter to and chloral.33
make it more stable was studied by Jermstad and The use of cellulose derivatives to form
Fretheim.28 There was also, during the Second water-soluble suppository bases was suggested by
World War, a need for a cocoa butter substitute Davies; he discussed the use of methylcelluloses
for blockaded countries. Alternatives considered and sodium carboxymethylcelluloses.34
included such items as wool fat, paraffin, olive A different type of water-soluble supposi-
oil, poppy oil, stearyl alcohol, cetyl alcohol, and tory base with a high melting point range
waxes.29 and good medicinal release was developed from
In 1942, the addition of 10% Lanette Wax SX polyoxyethylene 30 stearate. It was mixed with
(a mixture of cetyl and stearyl alcohols as partial varying percentages of white wax to produce
phosphoric acid esters) allowed the addition a suppository that melted at about 50◦ C. Also,
of large volumes of water to the cocoa butter small quantities of docusate sodium and water
base. were added. Excellent results were obtained with
Work by Waxman and Eiler found that glyc- a mixture of polyoxyethyelene 30 stearate, water,
eryl monostearate was the most effective of the wax, and docusate sodium.33
48 Suppositories
Ward studied the utility and versatility of poly- 5. Scoville WL. The art of compounding. J Am Pharm
oxyalkylene derivatives of sorbitan partial fatty Assoc Am Pharm Assoc (Baltim) 1936; 25: 1123.
acid esters as suppository base materials. These 6. Pegurier G, Luisi M. Tannin ovules. Bull Pharm Sud-
materials are non-toxic, non-irritating, non-ionic Est 1940; 44: 28.
surface-active materials that lend themselves
7. Ulrich A. Chem Drug 1924; 101: 913.
readily to modification with the addition of
various adjuvants. They congeal rapidly, and 8. Blum C, Kasermann H. Pharm Acta Helv 1946; 21:
stable oil-in-water emulsions can be formed 233.
with aqueous fluids. The summary particularly 9. Neville J, Swafford WB. Pluronics as a suppository
states that the Tweens, particularly Tween 61, base. Am J Pharm Sci Support Public Health 1960; 132:
have a number of advantages and can be easily 301–303.
modified.35
10. Van Riel J, Van Der Wielen P. Pharm Weekblad 1912:
Hydrogenated cottonseed oil and hexadienol
25.
along with various other ingredients were studied
by Hartman and LaRocca.3 They found that 11. Terry H. Pharm Zig 1918; 63: 256.
mixtures of completely hydrogenated cottonseed 12. Behrbalk L. Substitute for cocoa butter for making
oil and partially hydrogenated cottonseed oil cast suppositories Chem Zentr 1918; II: 760.
are superior to other fat-type bases in use, that
Veegum has potential as an aid in suppository 13. Crane FD, Schieffelin WJ. Suppository and method
of making same. US Patent 1,499,348 (1924).
disintegration, and that hexadienol and hexane-
ol can be used as suppository bases. 14. Cooper J. Pharm J 1926; 117: 371.
Recently another base was introduced by Dash
15. Smith I. The making of hollow suppositories: a
and Cudworth36 consisting of an acetic acid es- modification of Morgan’s method. Pharm J 1930;
ter of monoglycerides made from hydrogenated 122: 632.
palm oil. Benzocaine and miconazole were used
as the model drugs in this study. Benzocaine was 16. Schroff E. Preparation and resorption of supposito-
ries. Pharm Zig 1931; 76: 1239.
released at a constant rate over at least 4 hours,
possibly due to the formation of cubic phases that 17. Gfeller H. A new basal mass for suppositories. Pharm
act as drug reservoirs during the dissolution of the Acta Helv 1934; 9: 13.
base in the aqueous medium. This can provide 18. Anon. Mfg Chem 1937; 8: 349.
a therapeutic effect over a longer period than
conventional suppository bases.36 19. Nitardy FW, Christiansen WG, Deuble JL. Therapeu-
tic composition. US Patent 1,995,776 (1935).
20. Kremel A. Suppositories and like medical appli-

References ances. Austrian patent 149,187 (1937).
21. Ferraris A. Higher alcohols as excipients for suppos-

1. Eckert V, Muhlemann H. Effect of various properties itories. Boll Chim farm 1938; 77: 725.
of suppository bses on the release of medicinal 22. Ferraris A. Pomades with a cod-liver oil base. Boll
substances. Pharm Acta Helv 1958; 33: 649–661. Chim farm 1939; 78: 379.
2. Jenkins GL, Christian JE, Hager GP. Quantita- 23. Lehmann H, Hediger F. Pharm Acta Helv 1939; 14,
tive Pharmaceutical Chemistry, 5th edn. New York: 83.
McGraw-Hill, 1957: 269–288.
24. Bockmuhl M, Middendorf L, Starch W. Medicinal
3. Hartman CW, LaRocca JP. The use of hydrogenated tablets. German Patent 650,000 (1937).
cottonseed oil and hexadienol as suppository bases.
J Am Pharm Assoc Sci Ed 1956; 45: 86–89. 25. Bockmuhl M, Starck W. Shaped medicinal prepara-
tion. US Patent 2,149,005 (1937).
4. Realdon N, Ragazzi E, Ragazzi E. Effect of drug sol-
ubility on in vitro availability rate from supposito- 26. Middendorf L. A new water-soluble base for suppos-
ries with polyethylene glycol excipients. Pharmazie itories. Munich Med Wochschr 1939; 86: 95 through
2001; 56: 163–167. Chem Abstr 1930; 45: 4742.
27. Fitzgerald G. Suppository for treating vaginal con- 32. Gillham RW, Tomlinson JE. A new suppository base
dition. US Patent 1,878,766 (1933). soluble in water. Pharm J 1949; 162: 472.
28. Jermstad A, Fretheim B. Determination of mannitol 33. Gross HM, Becker CH. A study of suppository
in syrups and in official drug preparations. Q J Pharm bases. III. A new water-soluble suppository base. Am
Pharmacol 1940; 13: 186. Pharm Assoc Am Pharm Assoc (Baltim) 1953; 42: 498–
501.
29. Buchi J, Oesch P. The problem of substitutes for use
in the preparation of suppositories. Ashweiz Apoth 34. Davies REM. Pharm J 1950; 165, 347.
Zig 1941; 79: 385.
35. Ward WC. Hydrophilic suppository bases. J Am
30. Waxman P, Eiler JJ. Emulsifiers in cocao-butter Pharm Assoc Am Pharm Assoc (Baltim) 1950; 39:
suppositories. J Am Pharm Assoc Pract Pharm Ed 1945; 265–266.
6: 232–233.
36. Dash AK, Cudworth GC II. Evaluation of an acetic
31. Gross HM, Becker CH. A study of suppository bases I. acid ester of monoglyceride as a suppository base
review of the literature. J Am Pharm Assoc Am Pharm with unique properties. AAPS PharmSciTech 2001; 2:
Assoc (Baltim) 1953; 42: 90–95. E13.
50
4
Pharmaceutic, biopharmaceutic, and
pharmacokinetic factors involving
suppositories
Pharmaceutics has been defined as the general 5 Pharmaceutical procedures used in the prepa-
area of study concerned with the formulation, ration of the dosage form.
compounding, manufacture, stability, and effec- 6 The stability distribution, packaging, and la-
tiveness of pharmaceutical dosage forms. Biophar- beling requirements for suppositories.
maceutics is a study of the effects of formulation 7 The absorption, distribution, metabolism, and
on the therapeutic activity of dosage forms; also, excretion of the drug after administration.
as the relationship between the physical and
chemical properties of an active principle or its When a drug is administered rectally rather than
dosage form and the observed biological effects orally there can be a reduction in the hepatic first-
after administration of the active principle in pass effect and an improvement in bioavailability
different dosage forms. Pharmacokinetics has been as high as 100%.1
defined as the area of study that elucidates the
time course of drug concentration in the blood
Anatomical and physiological
and tissues. It is the study of the kinetics of
considerations
absorption, distribution, metabolism, and excre-
tion (ADME) of drugs and their corresponding
pharmacologic, therapeutic, or toxic effects in The dose of a drug required for rectal administra-
animals and humans. tion may be greater than or less than the dose of
Pharmaceutics, biopharmaceutics and phar- the same drug given orally, depending on factors
macokinetics all work hand-in-hand to de- such as the constitution and condition of the
scribe the development, formulation, prepara- patient, the physicochemical nature of the drug
tion/production, administration, effects, dura- and its ability to traverse the physiologic barriers
tion, extent of effect, elimination, etc. of a drug. to absorption, and the nature of the suppository
Suppositories are a unique dosage form requiring vehicle and its capacity to release the drug and
special consideration and application of all these make it available for absorption (see Table 4.1).
principles. The factors that affect the rectal absorption
Working together, the factors involved of a drug administered in the form of a sup-
include: pository may be divided into two main groups:
(1) anatomic and physiologic factors, and (2)
1 The nature and form of the active principle
physicochemical factors of the drug and the base.
(esters, salts, complexes, etc).
2 The physical state, particle dimensions and the
specific surface of the product. Anatomy
3 The presence or absence of adjuvants added to
the active principle. Rectum
4 The nature and type of dosage form in which The last few centimeters of the large intestine
the active principle is incorporated. constitute the rectum, terminating at the anus.
51
52 Suppositories
lymphatic vessels. This may be minimal but

Table 4.1 Examples of drugs with different optimal
should not be ignored.
routes
Vagina
Absorbed better rectally Sodium salicylate
than orally Chloral hydrate The vagina is a specialized organ whose primary
Methylene blue function is reproductive. It is a highly elastic
Atropine muscular tube, located between the urethra and
Morphine the rectum. It has three tissue layers: epithelial
Absorbed better orally Iodides tissue, loose connective tissue, and muscle tissue.
than rectally Tetracycline hydrochloride The upper, middle and lower vaginal sections
Sodium penicillin G have separate blood supplies. Branches of the
Oral and rectal Sulfanilamide in a uterine arteries supply blood to the upper vagina;
absorptions glycerinated gelatin the inferior vesical arteries supply blood to the
comparable base middle portion of the vagina; and the hemor-
Prednisone rhoidal and internal pudendal arteries feed into
the lower vagina. Blood is returned through the
venous plexus to the hemorrhoidal, pudendal,
The wall of the gastroinstestinal tract is made
and uterine veins and then to the hypogastric
up of several layers, including the mucosa,
veins.
submucosa, tunica muscularis, and the visceral
With age, atrophy causes the vagina to shorten
peritoneum. The mucous membrane of the rec-
and the mucous lining to become thin, dry,
tum, where suppositories are administered, is
less elastic, and pale from decreased vascularity.
made up of a layer of cylindrical epithelial cells,
This causes the vaginal mucosa to become highly
differentiated from those of the intestine by the
susceptible to abrasion and the pH of the vaginal
absence of villi.
secretions increases, making the vaginal environ-
The rectum contains three types of hemor-
ment more alkaline.
rhoidal veins:
r superior hemorrhoidal vein Urethra

r middle hemorrhoidal vein The urethra is a small duct that transfers urine
r inferior hemorrhoidal vein. from the bladder to the outside of the body. In
the female, it consists of an inner layer of mucous
These transport the active principle absorbed in membrane, a middle layer of spongy tissue, and
the rectum to the blood system either directly by a outer layer of muscle. In the male, it passes
means of iliac veins and the vena cava (inferior vertically through the prostate gland and extends
and middle hemorrhoidal veins) or indirectly by through the urogenital diaphragm and penis.
means of the portal vein and the liver (superior
hemorrhoidal vein).
Physiology
The three hemorrhoidal veins are linked by
an anastomostic network. Since it is difficult to
Rectum
predict the exact location of the suppository in
the rectum, it is not possible to predict with The physiological factors liable to affect rectal
certainty which way the active principle will be absorption are the rectal liquid pH and the rectal
transported. It may be taken up preferentially by liquid buffering capacity. The rectal mucosal fluid
one pathway or another, or by a combination. has a pH very close to neutral and it has a low
It is generally accepted, however, that at least buffer capacity. Hence, after administration of
50–70% of the active ingredients administered the suppository, the pH of the rectal liquid may
rectally take the direct pathway, thus bypassing be determined by the active principle being used.
the liver and avoiding the first-pass effect. There These facts lead us to conclude that the addition
is also the possibility of absorption into the of buffering agents of a suitable pH range to the
Chapter 4 • Pharmaceutic, biopharmaceutic and pharmacokinetic factors 53
suppositories could, in some cases, increase active drug and initiate its circulation throughout the
principle absorption. body, bypassing the liver. Lymphatic circulation
When considering suppositories and rectal also assists in the absorption of rectally adminis-
administration, it is important to look at the tered drugs.
overall view and assess not only the properties r pH and lack of buffering capacity of the rectal
of the active principles favoring rectal absorption
fluids: The pH of the rectal fluid is generally
of a specific drug, but also the technological
in the range of 7.2–7.4 and it has negligible
parameters related to the properties of the ad-
buffer capacity. The form in which the drug
juvants or excipients.
is administered will not generally be changed
The human rectum is approximately 15–20 cm
chemically by the rectal environment; therefore,
long. When empty of fecal material, it contains
the pH of the medium may be determined by the
only 2–3 mL of inert mucosal fluid. In the resting
characteristics of the drug.
state, the rectum is non-motile and there are no
villi or microvilli present on the rectal mucosa.
However, there is abundant vascularization of the The suppository base employed has a marked
submucosal region of the rectum wall with blood influence on the release of active constituents
and lymphatic vessels. incorporated into it. While cocoa butter melts
The surface area of the rectum is only about rapidly at body temperature, because of its im-
200–400 cm2 and is a fraction of the surface miscibility with fluids it fails to release fat-soluble
area of the small intestine, which is about drugs readily. For systemic drug action using a
2 000 000 cm2 . This makes the surface area a lim- cocoa butter base, it is preferable to incorporate
iting factor to be considered in drug absorption. the ionized (salt form) rather than the unionized
Among the physiologic factors that affect (base) form of a drug to maximize bioavailability.
drug absorption from the rectum are the colonic Although unionized drugs partition out of water-
contents, circulation route, and the pH and lack miscible bases such as glycerinated gelatin and
of buffering capacity of the rectal fluids. polyethylene glycol (PEG) more readily, the bases
themselves tend to dissolve slowly and thus
retard the release of the drug.
r Colonic content: When systemic effects are
desired from the administration of a medicated
suppository, greater absorption may be expected Vagina
from a rectum that is void than from one that is The pH of the vagina is in the range of about
distended with fecal matter. A drug will obviously 4–4.5. It is moistened and cleansed daily by
have greater opportunity to make contact with secretions that also serve to lubricate the vaginal
the absorbing surface of the rectum and colon tract. Normal vaginal discharge is about 1.5 g of
in the absence of fecal matter. Therefore, when vaginal fluid daily. This fluid is an odorless, clear
deemed desirable, an evacuant enema may be or white and viscous or sticky fluid consisting
administered and allowed to act before the ad- of endocervical mucus, serum transudate from
ministration of a suppository. Other conditions vaginal capillary beds, endogenous vaginal flora,
such as diarrhea, colonic obstruction due to and epithelial cells. There is an increase in
tumorous growths, and tissue dehydration can all vaginal secretions during ovulation, pregnancy,
influence the rate and degree of drug absorption following menses and with sexual excitement
from the rectal site. or emotional flare. This fluid can be altered
r Circulation route: Unlike drugs absorbed after in response to vaginal irritants, contraceptive
oral administration, drugs absorbed rectally can products and devices, or the use of tampons.
bypass the portal circulation during their first
pass into the general circulation. This enables
Urethra
drugs that are otherwise destroyed in the liver
to exert systemic effects. The lower hemorrhoidal Where it exits the bladder, the urethra is lined
veins surrounding the colon receive the absorbed with epithelium composed of transitional cells.
54 Suppositories
Further along there are stratified columnar cells, Physicochemical factors

then stratified squamous cells near the exter-
nal meatus (exit hole). Small mucus-secreting
The physicochemical factors affecting the drug
urethral glands help to protect this epithelium
and suppository base, or vehicle, include the
from the corrosive urine. The female urethra
nature and form of the active principle (esters,
is supplied by blood vessels called the internal
salts, complexes, etc.), the relative solubility of
pudendal and vaginal arteries. The male urethra is
the drug in lipid or in water (hydrophilic vs.
supplied by the inferior vesical and middle rectal
lipophilic character), the physical state including
arteries. The veins follow these blood vessels. The
particle dimensions and specific surface area,
nerve supply is via the pudendal nerve.
the presence or absence of absorption-enhancing
adjuvants, and its stability.
The absorption of the active principle by the
Bioavailability of rectal rectal mucous membrane is generally a passive
suppositories process and only lipid-soluble molecules and
undissociated organic electrolytes are easily ab-
sorbed. The higher the lipid/water coefficient of
Drug absorption from rectal suppositories is a the non-ionizable organic molecules, the higher
complex process involving suppository melting the proportion of undissociated organic elec-
or dissolution, movement of drug through the trolytes and the higher their rate of absorption.
liquefied base to an interface where it is released, The percentage of drug undissociated at a spe-
dissolution or movement into the rectal or vagi- cific pH can be described by the Henderson–
nal fluids, and drug permeation across the rectal Hasselbalch equations:
or vaginal membranes. The administration of
an enema prior to a suppository increases the Log(Cundis /Cdiss ) = pK a − pH ( f or acids)
absorption of the drug.
Log(Cdiss /Cundiss ) = pK a − pH ( f or bases)
There are three primary types of suppository
bases to consider: oleaginous, water-soluble, and
where C is concentration. Using these equations,
others.
the pKa of the organic electrolyte and the pH
at the rectal membrane, one can calculate the
r Oleaginous bases must melt at body temper-
percentage of the undissociated form that will
ature and the resulting liquid is immiscible with be present and have an idea of the degree of
the fluids in the rectum. The incorporated drug absorption that may occur.
must partition from the fluid oily base into the The excipients, or at least certain of their
aqueous based rectal fluids and into the tissues. component elements (e.g. surfactants), can have
r Water-soluble bases dissolve in the rectal a significant effect on the absorption of drugs.
fluids, where the active drug will diffuse to the This is discussed in more detail in Chapter 5.
mucosal surfaces for absorption.
r The miscellaneous bases, including the emul-
Solubility of the active substance
sion bases, are generally water-in-oil and are not
soluble or readily miscible in water, although The rate at which the active substances are
they may spread or soften at body temperature. released from suppositories and absorbed by the
If the drug is in the oleaginous phase of the rectal mucous membrane is directly linked to the
emulsion it will release as if from an oleaginous solubility of the active substances in the excipient
base, but if it is in the aqueous phase it may either or, in other words, to the partition coefficient of
partition into the oleaginous phase then into the the active substances between the excipient and
rectal fluids, or it may diffuse and mix directly the rectal liquid.
with the aqueous rectal fluids and be available Active substances that are highly soluble in
for absorption. the excipient diffuse much less rapidly out of
the excipient than those that are insoluble or r a water-soluble excipient as a carrier for
have a low excipient solubility, and hence the lipophilic, insoluble active principles or those
former are not so easily absorbed. Barbiturate with a reduced solubility in water, and more
salts, for example, which are water soluble, are particularly in a water-soluble excipient.
better absorbed from a fat excipient than from a
water-soluble excipient whereas ethyl nicotinate, In the first case (hydrophilic active suspended
which is lipid soluble, is absorbed better from a in a lipophilic excipient), the diffusion pro-
water-soluble excipient. cess is relatively slow and depends on several
Water-soluble excipients play a role above all factors including the liquefaction rate, melting
in the rate of diffusion, the liquefaction rate, and point, and rectal temperature. In the second
the high viscosity which these excipients give to case (lipophilic active principle suspended in a
the rectal liquid. It should also be remembered hydrophilic excipient), the diffusion process is
that the concentration of the active principles on determined by the solubilization rate, viscosity
the absorbing membranes is an extremely impor- imposed on the rectal liquid, and the relative
tant factor. As in all passive absorbing processes, proportions of active principle and excipient.
notably in the process of absorption through
the gastric membrane, the degree of rectal ab-
sorption is directly linked to a concentration Tendency for excipients to produce
gradient. water-in-oil emulsions
A common practice in pharmacies dealing

with suppositories containing water-soluble sub-
Lipid–water solubility stances in a fatty vehicle is to incorporate a water
solution of the drug into a water-in-oil type emul-
The lipid–water partition coefficient of a drug is sion by adding appropriate emulsifying agents
an important consideration in the selection of (lanolin, etc.). This may result in a reduction of
the suppository base and in anticipating drug therapeutic activity of the drug. After melting
release from that base. A lipophilic drug that is in the rectum, the resulting liquid contains the
distributed in a fatty suppository base in low water-soluble active principles entrapped in the
concentration has less tendency to escape to form of droplets of a saturated solution that
the surrounding aqueous fluids than a hydro- is dispersed in a continuous fatty vehicle from
philic substance present in a fatty base at levels which they can diffuse only with great difficulty.
approaching its saturation. Water-soluble bases, The diffusion speed can also be reduced sig-
such as PEGs, which dissolve in anorectal fluids, nificantly when a suppository containing water-
release both water-soluble and oil-soluble drugs soluble active principles suspended in a fatty
for absorption. Naturally, the more drug a base vehicle is made from excipients with a high hy-
contains, the more drug will be available for droxyl number. The presence of large quantities
potential absorption. However, if the concen- of mono- and diglycerides in this type of excip-
tration of a drug in the intestinal lumen is ient probably enables the rectal liquid to form
above a certain level, which varies with the drug, an emulsion in the bulk of the melted fat. This
the rate of absorption will not be changed by suspended rectal liquid then dissolves some of
a further increase in the concentration of the the active principle and forms saturated scattered
drug. droplets in the melted excipient, slowing down
For optimal absorption, except when a diffusion of the active principle.
prolonged-release mechanism is needed, it is
better to use:
Particle size
r a fat excipient as a carrier of water-soluble For drugs present in a suppository in the undis-
active principles that are insoluble or have low solved state, the size of the drug particle will
solubility in the excipient/carrier; influence its rate of dissolution and its availability
56 Suppositories
for absorption. The smaller the particle size, the tween the two agents should be ascertained
more readily the particle dissolves and the greater before or during formulation.
the chance for rapid absorption. Long-acting or slow-release suppositories can
If the active principle has limited water sol- be prepared by careful choice of excipient. Slow-
ubility, the use of finely divided products (high release morphine sulfate suppositories are pre-
specific surface area) will lead to an appreciable pared by including a material such as alginic
improvement in absorption. Here, as in oral acid, which prolongs the release of the drug over
medication absorption, the rate of absorption is several hours.2
influenced by the solubilization rate, which in
turn is related to the particle size of the active
principle. Spreading capacity
The nature of the excipient and the prepa-
ration methods used can also affect the par- Clearly, the rapidity and intensity of the thera-
ticle size characteristics of the active material peutic effects of suppositories are closely related
in the finished suppository, particularly when to the surface area of the rectal mucous mem-
the active material is solubilized when hot in brane covered by the melted excipient/active
the excipient and precipitates during cooling. ingredient mixture. This is determined by the
Testosterone, for example, dissolves when hot spreading capacity of the suppositories.
in the semi-synthetic excipient Witepsol Type This spreading capacity is dependent upon the
H and produces crystals of about 2–3 μm as it physicochemical characteristics of the excipient
cools. After being dissolved in coconut butter, and relates to the presence of surfactants in the
on the other hand, the active principle does not excipients.
crystallize during cooling but remains dissolved
as a solid solution. High absorption rates have
been obtained with the semi-synthetic excipient, Factors affecting the penetration of the
whereas with coconut butter rectal absorption is active drug across the rectal mucous
very low. membrane
It is preferable to avoid a too fine particle size
because of the increase in viscosity of the melted Various physicochemical factors will modify the
excipient that can result and possible difficulties properties of the active principle and determine
in flow during production. its absorption capacity (e.g. lipid/water partition
coefficient, pKa , degree of ionization, supposi-
tory vehicle, and lipid solubility). Physiological
factors can also affect absorption. These include
Nature of the base absorption site pH, pH of the rectal liquid, and
anorectal or vaginal physiology.
As indicated earlier, the base must be capable A reduction of rectal absorption was observed
of melting, softening, or dissolving to release its in the presence of PEGs by Kakemi et al. in 1965.
drug components for absorption. If the base in- They showed during a series of experiments on
teracts with the drug, inhibiting its release, drug rats that sulfisoxazole absorption is considerably
absorption will be impaired or even prevented. reduced in the presence of PEG 4000, especially
Also, if the base is irritating to the mucous mem- at pH values (around 4.0) at which this active
branes of the rectum, it may initiate a colonic substance takes on its only slightly dissociated
response and a bowel movement, negating the liposoluble zwitterion structure.3
prospect of complete drug release and absorption.
Because of the possibility of chemical and/or
physical interactions between the medicinal Effects of surfactants
agent and the suppository base, which could
affect the stability and/or bioavailability of the Surfactants can cause either an improvement or a
drug, the absence of any drug interaction be- deterioration of the therapeutic response. Kakemi
et al. studied possible mechanisms whereby sur- The formation of complexes between different
factants affect drug absorption in the rectum.3 active principles or between the active ingredi-
They demonstrated, using rabbits, that all three ents and the excipients may increase or reduce
types of surfactants (anionic, cationic, and non- the degree of rectal absorption. In vitro experi-
ionic) favored rectal absorption of sulfisoxazole mental techniques used to estimate the extent of
administered in suppository form with a coconut the diffusion process are not necessarily helpful
butter base. They also demonstrated a maximum as they do not reproduce the conditions present
therapeutic response at a well-defined surfactant at the rectal mucous membrane where absorption
concentration but found no correlation between occurs.
the results of in vivo observations and solubiliza-
tion in vitro results.
Different interpretations have been provided
to attempt to explain surfactant mechanisms.
Bioequivalence
According to some, the rectal absorption im-
provement obtained with surfactants is primarily
related to a wetting action or as a result of an Rectal and oral routes of administration may, in
effect on the mucous film covering the rectum. some cases, be bioequivalent. The rectal route can
It could be possible, however, that in some be considered as an alternative administration
cases (particularly when a basic medication is route for some drugs, such as etodolac.
associated with an anionic surfactant such as Some prodrugs degrade before they are ab-
ephedrine hydrochloride) the improvement of sorbed through the gastrointestinal tract. The use
rectal absorption may be due to a complex forma- of cyclodextrins to improve the pharmaceutical
tion between the medication, which is basic, and properties of drugs, such as solubility, has been
the surfactant, which has a greater liposolubility well documented. When a cyclodextrin is incor-
than the active principle. porated with a prodrug in a suppository dosage
Workers in Japan3 have shown that the ad- form, the rectal bioavailability of the selected
dition of increasing concentrations of sodium prodrug may be enhanced.
lauryl sulfate to ephedrine hydrochloride sup- The bioavailability of solids can be maximized
positories results in an increase in absorption by using the smallest particle size available. Also,
which is higher with higher quantities of sodium drugs that are available as water-soluble salt
lauryl sulfate. These authors have shown by forms will generally go into solution easier in
means of in vitro experiments that the addi- the mucosal fluids, followed by migration to
tion of increasing amounts of surfactant causes the rectal wall and absorption. The addition of
an increase in the aqueous/oil partition coeffi- sodium caprate increases the bioavailability of
cient of the basic medication. It has also been penicillins and cephalosporins and the addition
shown that addition of sodium lauryl sulfate of bile salts and fatty acids can increase the
to quinine salts, procaine, etc., results in an permeability of some drugs.
increase of the partition coefficient between Caldwell and co-workers showed that min-
lipids and water as well as an increase in rectal imizing the first-pass effect by rectal adminis-
absorption.2 tration may not be the only way to enhance
The reduction in absorption that is sometimes the amount of intact drug circulating through
observed in the presence of surfactants has been the body. Using phenol red, insulin, sodium
explained by the sequestering of the active in- cefoxitin, and theophylline in combination with
gredients by the central lipophilic portion of the sodium salicylate as an absorption adjuvant,
micelles. The degree of sequestration varies with they demonstrated that some of these model
pH for organic electrolytes. It is very low for pH drugs entered the lymphatic system after rectal
values at which the active principle is ionized, administration. The authors conclude that the
becoming important at those pH values where application of this direct lymphatic transport
the active principle occurs in its most dissociated not only may permit avoidance of first-pass liver
lipophilic form. exposure but also may allow site-specific delivery
58 Suppositories
of drugs if they are targeted toward absorption and an emulsifying base (Unilube) to prepare
into the lymphatic tissue.4 an aminopyrine suppository with an anticipated
Numerous other issues affect the bioequiv- good release profile that remained solid at room
alence of rectal administration, including the temperature. The fatty base and the water-soluble
following: base combination resulted in a suppository with
excellent bioavailability, but the addition of the
r The presence of feces can slow or interrupt
emulsifying base reduced the bioavailability. This
absorption. was attributed to its slower dissolution than with
r Hepatic first-pass elimination is reduced. A
the PEG.9
study by de Boer and Breimer compared
oral, intra-arterial, and rectal administration
of etomidate and demonstrated that there Apomorphine
is a substantial avoidance of hepatic first-
pass elimination of etomidate following rectal Apomorphine was studied as a rectal solution
administration in rats.5 (10 or 15 mg), a gelatin suppository (25 and
r Expulsion of the suppository before its con-
50 mg) and a Witepsol H15 suppository (50 and
tents are absorbed is more likely when the drug 100 mg) in five patients with idiopathic Parkin-
causes local irritation.6 son’s disease. The mean bioavailability varied
r Some products may degrade before absorption
between 14.7% and 40.2%; the Cmax values were
through the gastrointestinal tract. similar, averaging 12.7–25.6 ng/mL, but the T max
r The rectal bioavailability of selected prodrugs
values varied widely between 16 min for the
has been enhanced by incorporating the pro- rectal solution and 127.5 min for the Witepsol
drug with a cyclodextrin in a suppository H15 suppository. The duration of effect for the
dosage form. The use of cyclodextrins to im- Witepsol H15 100 mg suppository was 156 min
prove the pharmaceutical properties of drugs versus 50 min for the rectal apomorphine so-
has been well documented in the pharmaceu- lution. The study showed the potential of a
tical literature.7 Witepsol H15 suppository in the treatment of
idiopathic Parkinson’s disease.10
Contemporary studies on the

bioavailability of suppositories Aspirin
Salicylate suppositories were prepared using PEG

Aciclovir 1540 and PEG 6000 in various proportions.
Salicylate release differed markedly for bases
Aciclovir rectal suppositories prepared using a composed solely of PEG 1540 or 6000; but
triglyceride (Vosco S-55 and Vosco S-55 plus when suppositories contained a mixture of the
methylcellulose) gave high plasma concentra- two PEGs, the rate of release approximated that
tions and bioavailabilities of 95.3% and 83.4%, observed for a base composed solely of PEG 6000.
respectively, compared with Witepsol and Macro- The bioavailability of aspirin from five brands
gol suppositories. These results suggested that of aspirin rectal suppositories was determined in
the rectal administration of aciclovir may be an adult panel.11 At best, only 40% of the dose
promising.8 was available, but four out of five brands gave
substantially lower absorption.
Aminopyrine
Chloramphenicol
Ito and colleagues formulated a new type of
suppository base by combining a fatty base (Phar- The absorption of chloramphenicol from three
masol B115), a water-soluble base (PEG 4000), types of suppository bases was studied in the
rabbit.12 The absorption was higher with emulsi- 47%. For ethosuximde, which is water soluble,
fied bases than with oleaginous bases. the drug release from the suppository base affects
its bioavailability; the rapidly dissolving water-
soluble bases yield higher bioavailabilities than
do the oleaginous bases.14
Erythromycin
Ethosuximide was studied in both PEG and
Witepsol fatty bases in rabbits. The systemic
In a study of erythromycin suppositories, differ-
availability was 89.39%, 82.72%, 58.80%, and
ent excipients were used, including sodium lauryl
47.45% when the bases were PEG 400:4000,
sulfate (0.5%), sodium deoxycholate (0.02%),
PEG 400:6000, Witepsol E76 and Witepsol W35,
hyaluronidase, Labrafil M 2130 CS (20–22.5%,
respectively.14
37.5–35%, 40–50%), and local anesthetics (li-
docaine, amylocaine or benzocaine; 2–4%). The
findings were as follows:13
Etodolac
1 Under the experimental conditions used, The influence of administration route on the
PEGs gave a slightly higher erythromycin blood biopharmaceutical behavior of etodolac, a non-
levels than plain semi-synthetic glycerides for the steroidal agent with anti-inflammatory and anal-
first hour after administration, but not later. The gesic activity, has been studied. The blood lev-
quantity of substance absorbed was appreciably els obtained when the same dose of etodolac
higher with the excipient composed of semi- was administered orally (tablets) and rectally
synthetic glycerides. (suppositories) were determined. The results
2 Addition of sodium lauryl sulfate to the indicated that the two routes of administra-
semi-synthetic glyceride perceptibly lowers the tion are bioequivalent and that the rectal
blood level of the antibiotic. Addition of sodium route is an alternative administration route for
deoxycholate allows a quicker appearance of the etodolac.15
antibiotic at a higher level, but at the end of 2–3
hours, the blood level is lower than that obtained
with the semi-synthetic glycerides alone. Fluconazole
3 The addition of PEGs to semi-synthetic glyc- Single dosing of oral fluconazole has been
erides results in altered absorption; if a dose of demonstrated to be as effective in the treatment
20–40% of the suppository base does not produce of Candida as once-daily dosing for 3 days with
a perceptible effect, then a mass composed of vaginal terconazole suppositories contained in a
a mixture of equal amounts of semi-synthetic cocoa butter base (80 mg each). In the case of
glycerides and PEGs will allow a much faster late evaluation of infection, the cure rates for oral
absorption and, above all, will maintain a high and vaginal administration were 75% and 100%,
antibiotic blood level for several hours.13 respectively.16
Ethosuximide Indometacin
Ghazy and colleagues conducted an in vitro Although numerous studies have compared the
release of ethosuximide from four different sup- efficacy of rectally administered drugs with oral
pository bases including Witepsol W35, Witepsol administration, there are many inconclusive re-
E76, PEG 400 with PEG 4000, and PEG 400 with sults. This may be due to the different parameters
PEG 6000. The bioavailability results with the being considered, the experimental conditions
two PEG bases were nearly equal at 89% and and the choice of excipients for the formu-
82%, respectively, while the bioavailability of the lation. Indometacin and aspirin, for example,
Witepsol E76 was 59% and the Witepsol W35 was have been studied with inconclusive results.17–20
60 Suppositories
Indometacin release from suppositories contain- with definite or classical rheumatoid arthritis.
ing polyoxyethylene decreased with increasing According to the protocol, one of the drugs
molecular weight of the polymer.21 Also, in- was administered at bedtime each day for a
dometacin was absorbed into the bloodstream period of three weeks, at which time they were
of rabbits faster when administered in PEG sup- crossed over to the alternative medication for
positories than from those made with a glyceride a second three weeks; no washout time was
base.22 used. A diary was completed each day in which
observations related to their pain were noted.
The results showed that the controlled-release
Insulin tablet formulation of 200 mg ketoprofen was as
effective as the 100 mg indometacin supposi-
The absorption of insulin from suppositories in tory in the treatment of rheumatoid arthritis,
the presence of different amounts and concen- especially with regard to pain upon awakening
trations of sodium salicylate (50 and 100 mg) and morning stiffness. Fewer side-effects over-
and polyoxyethylene-9-lauryl ether (1, 3, and all were noted with ketoprofen compared with
4%) was studied in diabetic beagle dogs after indometacin.26
rectal administration. The incorporation of both
agents resulted in an increase in the absorption of
insulin as evidenced by the reduction in plasma Mesalazine
glucose.23
Insulin solutions at 100 units per kg at various Mesalazine is given rectally for local effect so
pH values were placed in the rectum of rabbits low absorption is desired. The local and sys-
and led to a large decrease in blood glucose temic bioavailability of a mesalazine enema and
concentration except where the pH was close suppository were determined during steady state
to the isoelectric point of insulin. Surface-active conditions. A 1 g enema or suppository was
agents of the non-ionic ether type, anionic, administered twice daily for one week, after
cationic, and amphoteric type surfactants as well which the urine and feces were collected and the
as bile acids resulted in enhanced absorption. The plasma concentrations of drug and metabolite
optimal effect was achieved with suppositories measured hourly during a 12 hour dose interval.
containing 1% polyoxyethylene-9-lauryl alcohol The systemic absorption was low (15%) after
ether.24 enema and 10% after suppository. The authors
A study involving six alloxan-diabetic dogs concluded that the enema and suppository can
was conducted. The fasting glucose levels were be administered continuously to give high fecal
above 200 mg/100 mL and they were treated with concentrations of the drug with low systemic
insulin suppositories twice daily for 6–9 days. absorption.27
The control group was treated with subcuta-
neous insulin injections. The results of the study
show that diabetes can be controlled by the Metoprolol
daily rectal administration of insulin supposito-
ries instead of the conventional subcutaneous Metoprolol suppositories appear to be an effec-
injection.25 tive, safe, and suitable alternative for patients
who are in need of ␤-blocking medication and
who are unable to take oral medication for a
Ketoprofen period of time.28
Uddenfeldt et al. conducted a double-blind com-

parison of oral controlled-release ketoprofen Metronidazole
200 mg with indometacin 100 mg suppository
in the treatment of rheumatoid arthritis. The Vromans and colleagues investigated the ab-
study population consisted of 94 outpatients sorption of metronidazole from a triglyceride
suppository base (Elysol), three PEG bases (PEG Pentobarbital

1000, PEG 6000, and a 1:1 mixture of PEG 1000
and 6000) and an aqueous rectal suspension. Approximate bioequivalence between oral and
The bioavailabilities from the PEG suppositories rectally administered pentobarbital has been re-
were greater than that of the triglyceride base ported, despite its slower rectal absorption.32
suppository. There was no statistical difference Absorption in the rectum, where there is a lack
between the PEG bases and the rectal suspension. of microvilli, is via passive diffusion and there is
These results seem to support the conclusion that no carrier-associated means to assist the passage
the rate-limiting step in drug release from a fatty of drugs through the lipid membrane.33
base suppository was the partitioning from the
base into the aqueous fluids and away from the
lipid–water interface.29
Phenobarbital
A comparison of the bioavailability of pheno-

barbital and sodium phenobarbital from four
Morphine
different suppository bases has been made using
Witepsol H15, Witepsol H15 with 2% Tween
A comparison of the bioavailability of morphine
80, and Novosup (a mixture of PEG esters with
from controlled-release 30 mg tablets (MSC)
free fatty acids of sunflower oil and lard, Tween
and immediate-release 30 mg rectal suppository
20 and 80, Myrj 45 and Brij 58). It was found
(RMS), both administered rectally, and oral
that plasma levels were not statistically different
administration of 30 mg controlled-release oral
from those measured following the administra-
tablets (MSC) was undertaken. Rectally adminis-
tion of a phenobarbital aqueous suspension or
tered MSC plasma morphine area under the curve
a sodium phenobarbital aqueous solution. The
(AUC) was 50.8% that of RMS and was similar for
Cmax and relative bioavailability compared with
MSC administered by either route (rectal MSC =
that of Witepsol H15 in each of the bases was
90% oral MSC). Rectal MSC had a significantly
independent of the salt or acidic form of the drug.
delayed time to peak plasma level of about
The researchers concluded that drug release from
5.4, 1.07 and 2.5 hours for rectal MSC, RMS,
the suppository base was not rate-limiting, but
and oral MSC, respectively and a significantly
that drug permeability across the rectal tissues
attenuated time to maximum concentration (6.1,
was controlling the extent of bioavailability of
25.4, and 9.7 ng/mL, respectively. The authors
the model drug, phenobarbital.34
conclude that further studies must be done to
determine the therapeutic consequences of phar-
macokinetic differences and establish guidelines
for rectal MSC use.30 Progesterone
Progesterone vaginal suppositories at doses of

25 mg, 50 mg, or 100 mg were administered to
Para-aminosalicylic acid 35 healthy ovulating patients with an average
age of 31.54 years. The drug was administered
A study used small dogs and a suppository con- during the follicular phase of the menstrual
taining 50% of sodium para-aminosalicylic acid cycle (between days 7 and 10). The progesterone
in 2.3 g suppository. Blood was obtained every serum concentration reached maximal levels
hour for up to 9 hours. The results showed the within 2 or 3 hours after administration and
Suppocire BS2X with the highest blood level after was similar between the groups, at 7.27, 8.84,
3 hours; second highest blood level was with the and 9.82 ng/mL, respectively. This study demon-
cocoa butter with a peak at 1.5 hours, and lowest strated that vaginally administered progesterone
blood level was with Suppocire C, which peaked could reach levels similar to those obtained by
after 3.4 hours.31 women during the luteal and ovulatory phases.35
62 Suppositories
Promethazine of the theophylline for the base slowed its rate of

absorption into the systemic circulation.38
In a study comparing rectal suppositories at
three dosage strengths with an oral syrup of
promethazine, all formulations were comparable Tioconazole
in terms of dose-normalized AUC and half-lives
and the three suppository treatments were com- Tioconazole 300 mg vaginal ovules were studied
parable in terms of dose-normalized Cmax . The in 10 patients with vaginal candidiasis. The mean
mean relative bioavailability for the three sup- plasma concentration was 21.2 ng/mL at 8 hours
pository treatments ranged from 70% to 97%.36 and was not measurable at 24 hours in nine of the
ten patients. The mean vaginal fluid concentra-
tion at 24 hours was 21.4 mg/L and remained
detectable in seven of nine and two of nine
Salbutamol (albuterol)
patients after 48 and 72 hours, respectively.39
Factors affecting absorption of salbutamol in-
clude anorectal or vaginal physiology, supposi-
Valproic acid
tory vehicle, absorption site pH, drug pKa , de-
gree of ionization, and lipid solubility. In some
Moolenaar and co-workers studied the absorp-
instances, suppositories have been demonstrated
tion rate and bioavailability of valproic acid and
to be advantageous over orally administered
its sodium salt from both solution and supposi-
medications. For example, in a study of rec-
tory dosage forms using Witepsol H15 and cocoa
tally administered salbutamol using a Witepsol
butter bases. They found rectal absorption of
H15 base, significantly higher active ingredient
sodium valproate from an aqueous micro-enema
concentrations were obtained soon after dosing,
to be fast and complete. The free acid was ab-
compared with oral administration.37 The Cmax
sorbed more rapidly from fatty acid suppositories
following rectal administration of salbutamol
than was the sodium salt. Bioavailability “F”
was 17.9 ng/mL (17.0 ng/mL for oral administra-
values of 0.93 for the rectal solution, 0.82–0.84
tion); the t max , 0.67 h (1.5 h for oral administra-
for the Witepsol H15 suppositories and 0.75–0.81
tion); and the AUC, 98.2 ng/mL per h (100 ng/mL
for the cocoa butter suppositories.40
per h for oral administration). An advantage of
rectally administered salbutamol is that it reduces
first-pass metabolism. The authors conclude that
Zonisamide
rectal administration of salbutamol may be a use-
ful method for long-term prophylactic treatment
Zonisamide was prepared in a lipophilic base
of asthma.37
(Witepsol H15:S55, 3:1) and as a hydrophilic
base (PEG 4000:1500, 4:1) and administered to
male Wistar rats, as well as being administered
Theophylline intravenously and orally. The absorption of the
drug from the PEG suppository was more rapid
Cole and Kunka worked with theophylline and than that from the Witepsol suppository or
its bioavailability from an oral elixir, a rectal from the oral preparation. The Cmax after rectal
enema, and a rectal suppository. From the oral administration with either of the suppository
elixir and the rectal solution the rates and ex- bases was significantly higher than that after oral
tents of theophylline absorption were identical. administration; however, the bioavailability of
From the suppository, the rate was much slower all three dosage forms was 100%. Electroshock
than for the other two dosage forms but the studies showed a positive correlation between
extent of absorption was the same. Theophylline seizure threshold and the zonisamide plasma
is relatively water insoluble and the base is concentration. These results indicated that a
lipophilic, therefore, it is likely that the affinity zonisamide rectal suppository is very useful from
Table 4.2 Bioavailability data for suppositories
Drug Strength Base Bioavailability 1 (%) Bioavailability 2 (%) Reference
Allupurinol 300 mg Cocoa butter 5.77 (rel. to tablet) 43
Ampicillin 12.5/25 mg/kg – 53.8–58 (dogs) 44

Ampicillin 12.5–25 mg/kg – 81.0–87.5 (mice) 37.6–45.9 (rats)
75.6–101 (rabbits) 45
Aspirin 600 mg Cocoa 55.8 74 46

butter/
Suppositrin
Bumetanide Unknown Macrogol 52 (with citric acid) 62 (with tartaric 47
acid)
Codeine 60 mg Witepsol H 15 103.6 48
Denaverine 50 mg – 42 (compared to 49
rectal solution)
Diazepam 10 mg PEG 67 50
Diazepam 10 mg Commercial 70 50
Diclofenac 1 mg/kg Commercial 126 51
Diclofenac – – 55 52
Ergotamine 2 mg Commercial 5 53
Ergotamine 2 mg Commercial 0.5–4.2 54
Ethionamide 500 mg Commercial 57.28 55
Fluconazole 200 mg Commercial 93 107 (25 mg supp) 56
Ibuprofen – PEG 4000:1000 73, 62, 73 and 52 57

(3:1, 1:3, 1:24)
and cocoa
butter
Indometacin 100 mg Commercial 50 17
Indometacin Commercial 80 58
100 mg (Confortid)
Ketamine 50 mg Unknown 30 59
Ketobemidone 10 mg Commercial 44 60
Ketoprofen 100 mg Commercial 73–93 61
Ketoprofen 1g Fatty acid and 24.5 to 28.7 (horses; 62

hydrophilic some clinical
effectiveness)
Ketoprofen 25 mg – 73 63
Mebendazole 500 mg Massupol Very low 64
Meptazinol 75 mg Witepsol H12 with 15.8 65

5% Span 20
5% Span 20
5% Span 20
64 Suppositories
Table 4.2 Continued
Drug Strength Base Bioavailability 1 (%) Bioavailability 2 (%) Reference
Mercaptopurine 10 mg/kg Witepsol H-15 43.2 (rats) 66

Mercaptopurine 10 mg/kg Macrogol 85.8 (rats)
Mesalazine 500 mg Unknown 40 67
Methadone 10 mg Fatty acid 35–58 68
Metoclopramide 20 mg Commercial 16.8 69
Metoclopramide 20 mg Commercial 53 70
Metoclopramide 150 mg Witepsol H15 105 71
Metronidazole 1g Commercial 53 72
Metronidazole 500 mg/1 g, 2 g Commercial 90 73
Metronidazole 1g Commercial 53.8 74
Metronidazole 500/1000 mg Unknown 82 (500 mg) 67 (1000 mg) 75
Metronidazole 500 mg PEG 1000:PEG 80 29

6000 (1:1)
Morphine 10 mg Hard Fat 53.3 76
Morphine 0.3 mg/kg 10 mg/mL Injection 31 (12–61) 77

Solution (Westerling)
Naproxen 250 mg PEG 4000 96.7 78
Naproxen 250 mg Commercial 100 79
Ofloxacin 200 mg PEG 6000 49.8 80
Ondansetron 16 mg Fattibase 89.0 men 75.3 women 81
Ondansetron 16 mg Polybase 126.1 men 113.5 women 81
Ondansetron 24 mg Polybase 29 – 82
Ozagrel – Witepsol H-15 92 – 83
Paracetamol 250 mg Commercial 102 (125 mg) 93 (250 mg 84
Paracetamol 500 mg Unknown 100 85
Paracetamol 19–45 mg/kg Witepsol H15 72 86
Paracetamol 600 mg Commercial 30–40 absolute – 87
Paracetamol 0.5/1 g Commercial 80 relative (table) 88
Paracetamol 250/500 mg Commercial 78 89

(Panadol)
Phenytoin 200 mg Polybase 4.7 – 90
Piroxicam 20 mg Commercial 97.9 100.1 91
Thalidomide 100 mg Hard-fat 22 (Nonmicronized) 32 (micronized) 92
Theophylline 250 mg Massa Estarina BB 75 83 93
Theophylline – Commercial 74 – 94
Tinidazole 1g Commercial 39 31
Tramadol 100 mg Commercial 77.4 – 95
Valproate 100 mg/300 mg Commercial 112.4 99.5 96
Valproic acid 500 mg Suppocire C 80 – 97

Table 4.3 Pharmacokinetic data for suppositories
Drug name Strength (mg) Base comm/cmpd AUC C max t max t 1/2 (h) Reference
Acetaminophen 20 mg/kg Commercial 66.9 mg/h.L 10.4 mg/L 3.6 h 3.9 h 98
Acetaminophen 40 mg/kg Commercial 118.2 mg/h.L 17.2 mg/L 4.2 h 4.5 h 98
Aminophylline 500 mg Commercial 1.9 kg/l 9.19 μg/mL 5.33 h – 38
Artemisinin 400 mg Fatty acid 537 μg/L.h 67 μg/L 6.8 h – 99
Artemisinin 500 mg PEG 619 μg/L.h 63 μg/L 6.4 h – 99
Ceftizoxime – – – 4.8–9.5 μg/mL 0.25–0.5 h 0.93 h 100
Cisapride 30 mg Commercial 723 ng.h/mL 50.3 ng/mL 3.8 h 9.3 h 101
Codeine 60 mg Witepsol H15 432 ng/mL.h 121 ng/mL 1.2 h 2.3 h 48
Codeine phos 50 mg with Commercial 320.7 ng.mL/h 51.3 ng/mL 1.33 h 3.67 h 102
Diclofenac sod 50 mg 1441 ng.mL/h 704 ng/mL 0.75 h 1.64 h 102
Diazepam 10 mg PEG – 212 ng/mL 75 min – 50
Diazepam 10 mg Commercial – 131 ng/mL 185 min – 50

65
Diazepam 0.5 mg/kg Commercial (PEG) 7774.4 ng/mL.h 378.5 ng/mL 1.54 h 32.8 h 103
Diazepam 10 mg PEG 3300 213.8 ng/mL 45 min 20.0 h 104
Diclofenac 100 mg Unknown 3.97 mg/h.L 3.2 mg/L 0.5 h 1.3 h 105
Diclofenac 50 mg PEG-Compressed 2578.9 ng.h/mL 1193.5 ng/mL 0.625 h 1.52 h 106
Ethionamide 500 mg Commercial 5.45 μg.h/mL 0.74 μg/mL 4.42 h – 55
Etodolac 200 mg Commercial 92.4 mg.h/L 13.63 mg/L 1.6 h 7.10 h 15
Fluconazole 200 mg Commercial 151.3 μg.h/mL 3.4 μg/mL 4.9 h 32 h 56
Flurbiprofen 50 mg Commercial 77.3 μg.h/mL 15.8 ng/mL 0.7 h 3.22 h 107
Flurbiprofen 75 mg Commercial 57.7 μg.h/mL 11.6 ng/mL 1.0 h 3.15 h 107
Indometacin 100 mg Commercial – 170 μg/mL 2.0 h – 108
Indometacin 50 mg Suppocire A.P 384 mg/L.min 2.0 mg/L 62 min – 109
Indometacin 50 mg PEG 6000:PEG 372 mg/L.min 1.8 mg/L 66 min – 109

4000
Indometacin 100 mg Commercial 904.9 μg mL/min 4.0 μg/mL 1.8 h 3.4 h 110
September 16, 2007

Ketobemidone 10 mg Commercial 83.9 h.ng/mL – – 3.27 h 60
Ketoprofen 100 mg Unknown – 6.6 μg/mL 1.1 h 1.8 h 111
23:18
Table 4.3 Continued
Ketoprofen 100 mg Commercial 18.1 μg.h/mL 7.5 μg/mL 1.05 h 1.25 h 61

Ketoprofen 25 mg
Meptazinol 75 mg Witepsol H12 with 88.8 ng/mL.h 33.3 ng/mL 0.5 h – 65
5% Span 20
Meptazinol 100 mg Witepsol H12 with 112 ng/mL.h 30.7 ng/mL 0.5 h – 65
5% Span 20
Meptazinol 150 mg Witepsol H12 with 174 ng/mL.h 61.3 ng/mL 0.5 h – 65
5% Span 20
6-Mercaptopurine 30 mg/m2 Commercial 539 ng.h/mL 125 ng/mL 1.4 h – 112
Metoclopramide 20 mg Commercial 442.3 h.ng/mL 54.98 ng/mL 1.54 h 5.52 h 69
Metoclopramide 20 mg Commercial 569 mg.h/mL – – 5.0 h 70

71
66
Metoclopramide 150 mg Witepsol H15 6700 μg/L.h – 2.0 h 7.9 h

Metronidazole 1g Commercial 129.8 μg.h/mL 8.8 μg/mL 2.8 h 8.8 h 72
Metronidazole 500/1000/ Commercial 280.78 μg.h/mL – – 9.46 h 73

2000
Metronidazole 1000 Commercial 151.56 mg.h/L 10.13 mg/L 4.83 h 6.77 h 74
Morphine 30 mg High-viscosity 98.6 ng.h/mL 7.75 ng/mL 3.1 h 10.4 h 113
Morphine 30 mg Low-viscosity 105.8 ng.h/mL 9.23 ng/mL 5.0 h 9.5 h 113
Morphine HCl 10 mg Hard fat 64.0 ng/mL.h 16.3 ng/mL 59.6 min – 76
Morphine Sulf Various Controlled release 132.5 ng.h/mL 14.7 ng/mL 3.33 h – 114
Morphine Sulf 5 mg/kg PEG 8724 /min.ng.mL – 98.6 min 115

(dogs)
Morphine HCl 40 mg/kg Witepsol H15 3.24 μg h/mL 2.37 μg/mL 0.208 h 116
(rabbits)
Naproxen 500 mg Comm 1151(mg.h./L 54.5 μg/mL 3.1 h 7.2 h, 117
September 16, 2007

15.2 h
Naproxen 500 mg Massa Estarinum BB 1456 h.μg.mL 65.8 μg/mL 1.4 h 17.2 h 118
23:18
Table 4.3 Continued
Naproxen 250 mg PEG 4,000 668.5 μg.h/mL 41.2 μg/mL 1.7 h 14.6 h 78
Nimulside 100 mg Unknown – 75 mg/L 3.0 h 3.15 h 119
Nimulside 200 mg Unknown 27.26 mg/L.h 2.32 mg/L 4.17 h – 120
Ondansetron 16 mg Fattibase (women) 561.5 ng.h/mL 47.1 ng/mL 4.1 h 7.3 h 81
Fattibase (men) 253.4 ng.h/mL 40.6 ng/mL 4.4 h 3.6 h 81
Ondansetron 16 mg Polybase (women) 768.7 ng.h/mL 82.9 ng/mL 4.4 h 8.2 h 81
Polybase (men) 304.8 ng.h/mL 51.2 ng/mL 2.9 h 3.9 h 81
Ondansetron 16 mg Unknown 140 ng.mL/h 17.1 ng/mL 209 min – 121
Ondansetron 24 mg Polybase 358.6 ng.h/mL 34.7 ng/mL 4.42 h 6.5 h 82
Oxycodone 30 mg Commercial 607.9 μg.h/L 73.2 μg/L 3.12 h 5.4 h 122

67
Paracetamol 500 mg Unknown 18.2 μg.h/mL 3.3 μg/mL 1.6 h 1.1 h, 85

3.55 h
Paracetamol 25 mg/kg Commercial – 10.7 mg/L 2.37 h 3.45 h 123
Paracetamol 800 mg Hard fat with soya 1030 mg/L.min 4.75 mg/L 104.9 min 264 min 124
lecithin oil and
fractionated
coconut oil
Paracetamol 23.9 mg/kg – – 72.4 mM/L 102.4 min 243.6 min 125
Piroxicam 20 mg Commercial 55.4 μg.h/mL 1.44 μg/mL 6.0 h 45.3 h 91
Piroxicam 20 mg Commercial 53.7 μg.h/mL 1.50 μg/mL 6.3 h 46.3 h 91
Piroxicam 20 mg Commercial 63.4 um/mL.h 1.87 μg/mL 3.0 h 59 h 126
Progesterone 400 mg Commercial 257 μg/h/l 29.2 μg/L 8.1 h 31.8 h 127
vaginal
Promethazine 50 mg Cocoa Butter–White 10103 ng/mL.min 14 ng/mL 394 min – 128
Wax
September 16, 2007

23:18
Table 4.3 Continued
Promethazine 50 mg PEG 19041 27.8 ng/mL 267 min – 128

ng/mL.min
Salazosulfapyridine 6.5 mmol Unknown 27.4 μM.h 2.5 uM 5h – 129
Salbutamol 2 mg Suppocire NA with 6% 40.25 ng/mL.h 12.96 ng/mL 1.91 h 0.78 h 130
Eudispert gel
Salbutamol 2 mg Witepsol H15 with 3% 42.16 ng/mL.h 14.87 ng/mL 1.83 h 0.77 h 130
Methylcellulose gel
68
Salbutamol 2 mg Witepsol W25 with 28 ng/mL.h 10.02 ng/mL 2.50 h 0.98 h 130
3% Methylcellulose
gel
Salbutamol 0.1 mg/kg Witepsol H15 98.2 ng/mL/h 17.9 ng/mL 0.67 h – 37
Secobarbital 5 mg/kg Commercial – 1.35 μg/mL 276 min 7.19 h 131
Sumatriptan 12.5–100 mg Witepsol W32 189.2 ng.h/mL 66.7 ng/mL 1.00 h 2.08 h 132
Temazepam 10 mg PEG 1,510 h.μg/L 202 μg/L 1.5 h 14.1 h 133
Theophylline 250 mg Massa Estarina BB 44.1 μg.h/mL 5.7 μg/mL 3.7 h 9.6 h 93
Tinidazole 1g Commercial 169.2 μg.h/mL 7.9 μg/mL 3.4 h 14.2 h 72
Tramadol 100 mg Commercial 2903 h.ng/mL 293.6 ng/mL 3.29 h – 95
Valproic acid 500 mg Suppocire C 573 mg/h/L 29.2 mg/L 3.1 h 12.6 h 97
September 16, 2007

23:18
the viewpoint of both pharmacokinetics and 4. Caldwell L, Nishihata T, Rytting JH, Higuchi T.
pharmacological action.41 Lymphatic uptake of water-soluble drugs after
rectal administration. J Pharm Pharmacol 1982; 34:
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Miscellaneous 5. de Boer AG, Breimer DD. Rectal, oral and I.A.
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1-hexadecanol and hydrogenated castor oil, the anti-inflammatory drug ethyl 4-biphenylacetate
absolute bioavailability increased to 76%.42 in rats by complexation with water-soluble beta-
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76
5
Formulation considerations
PHARMACEUTICAL formulation is the area within small, so that rapid solidification of the melt
the pharmaceutical sciences involved with the can occur after pouring into the mold, but not
development of a “drug” into a suitable dosage so narrow that premature solidification occurs
for administration to the intended patients. As during the pouring process. Also, if solidification
discussed in Chapter 4, many different factors is too slow, it may delay the rate of production of
must be considered, including: the suppositories.
It is generally advantageous to have slight
1 the nature and form of the active principle
contraction upon cooling of the suppository.
(esters, salts, complexes, etc.),
This can aid in the removal of the suppository
2 the physical state, particle dimensions and the
from the mold. Splitting, pitting, and cracking
specific surface of the product,
can be addressed by using a base that crystallizes
3 the presence or absence of adjuvants added to
more slowly, and reducing the temperature dif-
the active principle,
ference between pouring and cooling. Sticking to
4 the nature and type of dosage form in which
the mold can be addressed by using appropriate
the active principle is incorporated,
equipment, prolonging the molding period, us-
5 pharmaceutical procedures used in the prepa-
ing a base that crystallizes more rapidly and/or
ration of the dosage form, and
reducing the cooling temperature. A soft suppos-
6 the stability distribution, packaging, and label-
itory can be altered by changing the base or by the
ing requirements for the suppositories.
addition of thickening/hardening agents. Surface
In addition, formulation considerations can be anomalies, including bloom and whitening, can
divided into those affecting: be addressed by reducing the melting temper-
r production and compounding ature and allowing complete crystallization of
r storage the base during processing. Exudation problems
r use and administration. can be corrected by reformulating the aqueous
solutions and/or using a base containing an
Formulation considerations affecting production emulsifier.
and compounding include inertness, viscosity, so- Formulation factors affecting storage include
lidification, and contraction.1 There must be no softening, stability, impurities, release, and tol-
chemical or physical interaction between the erance. Proper formulation is required to pre-
base and the active ingredients (i.e. the base vent the suppository softening or melting during
should be inert). The viscosity of the melt must transportation and storage. All materials, both
be controlled: if it is too thick, there will be actives and excipients, should be stable and not
difficulty in pouring or completely filling the oxidize upon exposure to air, humidity, or light.
tip of the mold, and if it is too thin, there There should be no impurities in the formulation
may be sedimentation. If there is a high content and minimization of bacterial/fungal contamina-
of fine, suspended particles, there may be an tion should be a goal; this can be assisted by
increase in viscosity which may make pouring using bases with no or minimal water content
difficult, delay melting, and induce brittleness on and non-nutritive bases.
solidification. The temperature range involving Additives that are generally considered to
melting and solidification should be relatively modify the properties of suppositories include:
77
78 Suppositories
(1) dispersants, release, and/or absorption en-

hancers (surfactants), (2) hygroscopicity reducing Table 5.1 General approximate drug release rates
agents (colloidal silicon dioxide), (3) hardeners as they relate to the drug and base characteristics
to increase the melting point (beeswax, cetyl
alcohol, stearic acid, stearyl alcohol, aluminum Approximate drug
monostearate or di- and tristearate, bentonite, Drug/base characteristics release rate
magnesium stearate, colloidal silicon dioxide),
Oil-soluble drug/oily base Slow release; poor
(3) plasticizers to reduce the melting point (glyc-
escaping tendency
eryl monostearate, myristyl alcohol, polysorbate
Water-soluble drug/oily base Rapid release
80 and propylene glycol), (4) preservatives (an-
Oil-soluble Moderate release
timicrobial and antifungal agents), and (5) an-
drug/water-miscible base
tioxidants (including butylated hydroxytoluene Water-miscible Moderate release;
(BHT) and butylated hydroxyanisole (BHA), citric drug/water-miscible base based on diffusion;
acid, propyl gallate, ascorbic acid; a mixture of all water soluble
three parts each of BHT, BHA, and propyl gallate
with one part citric acid has been found to be
generally satisfactory when used at a concen- It becomes apparent that the formulation
tration of 0.01%). Coloring agents have been activities involved in developing suppository
used but are not generally recommended unless dosage forms can be quite complex.
it is important to modify the appearance of the
suppositories.
Formulation considerations affecting use and Drug selection
administration include release and tolerance.
Proper base selection for the formulation is neces-
sary to provide for optimal delivery of the active The first consideration in designing a suppository
drug, whether dissolved, suspended or emulsi- is the drug to be used. What are the requirements
fied. For patient compliance, it is important that for a drug that is to be administered as a sup-
the suppository be non-toxic and non-irritating pository? Is a local or systemic effect desired? If
to sensitive rectal mucosal tissue. The release a systemic effect is needed, one must determine
of the drug and the onset of drug action are whether it will be adequately absorbed via the
dependent upon liquefaction of the suppository rectal mucosa to obtain therapeutic blood levels.
base, dissolution of the active drug, diffusion If not, can a penetration enhancer be included
of the drug through mucosal layers, and the in the formulation to promote absorption to the
characteristics of the drug and base. desired extent?
General approximate drug release rates as they Many drugs are suitable for rectal administra-
relate to the drug and base characteristics are tion, as discussed in Chapter 1. They include
summarized in Table 5.1. drugs that are poorly absorbed orally or that
The water solubility of a drug can be corre- cause irritation to the gastrointestinal mucosa;
lated with the rate of diffusion across the rectal antibiotics that alter the intestinal flora after oral
membrane. A drug with high water solubility administration; and small peptides that would
quickly leaves the vehicle, producing a high be destroyed by enzymatic activity in the upper
concentration in the intrarectal phase, which gastrointestinal tract if administered orally. Any
supports a high diffusion rate across the barrier. drug used for a local effect in the rectum or vagina
A drug with low water solubility saturates the is also suitable for a suppository.
intrarectal phase at a low concentration, resulting
in low diffusion and subsequent low dissolution
of the drug particles remaining in the melted
Base selection
excipient. Drugs with low solubility in water may
result in low availability, while drugs with good
solubility usually give a rapid and intense thera- There are a wide variety of suppository bases
peutic response with the dose administered.2 available, each with its own characteristics as
Chapter 5 • Formulation considerations 79
33.75°C
33
32.80°C
32
31.7°C
31.15°C
31
Temperature (°C)
30.75°C
30.30°C
30
29.0°C
29
27.9°C
28
27
26
5 10 15 20 25 30 35 40 45 50 55 60 65
Solidification time (min)
Figure 5.1 Pichard curves illustrating the effect of hydroxyl index on solidification.
discussed in Chapter 3. Many characteristics must effect on solidification during cooling of the
be considered during the formulation process, excipient because the heat of crystallization be-
some of which have a significant influence on the comes more significant.
production and compounding process, storage, During the formation of glycerides, glyceroly-
and use. sis can occur, causing free hydroxyl moieties to be
A suppository base performs two important formed. This may result in a chemical incompat-
functions. First, it serves as a carrier for the active ibility between the excipient and certain active
drug, both in its physicochemical characteristics ingredients. For this reason, it is preferable to use
and in its requirements during manufacture; and excipients that have a very low hydroxyl index,
second, it can be used to control delivery of the especially when high production speeds require
active drug at the site of absorption. In selecting rapid crystallization of the melt.
the base, consideration should be given to the Appropriate density is important for maintain-
nature of the active drug, the manufacturing ing the uniformity of the drug during suppository
procedures required, and the desired release char- preparation (filling the molds). It can also affect
acteristics of the active drug from the base. The the release rate of the drug during administra-
base must also be non-reactive with the active tion (migration through the melted or dissolved
drug, non-toxic, stable, and non-irritating. suppository base). Silica gel serves as a viscosity
Two physical properties to be considered in agent for lipophilic excipients in suppositories.
selecting a suppository base are its hydroxyl It increases the viscosity, which helps the ho-
index and its viscosity. The hydroxyl index has mogeneous distribution of drug throughout the
an impact on solidification. This can be demon- suppository mass. However, the inclusion of too
strated by the construction of curves that plot much silica gel has been shown in some cases to
solidification time against temperature, demon- inhibit the release of water-soluble drugs, such as
strating the effect of the free hydroxyl content benzydamine hydrochloride.
of a material. These are known as Pichard curves The importance of the viscosity properties of
(Figure 5.1). a base are illustrated by a study in which the
A slight shoulder on the curve during cooling use of ramosetron hydrochloride suppositories
indicates the heat of crystallization. Ingredients containing Witepsol H15 and Carbopol 934P
with a lower hydroxyl index will have a greater were investigated. The study looked at plasma
80 Suppositories
levels and irritation to rectal tissues in rabbits and alterations of the release characteristics of the
at the antiemetic effects of the suppositories in drug.
ferrets. The more Carbopol 934P was added the
greater the viscosity of the base and the suppos-
itories containing the Carbopol exhibited better
Particle size
absorption in rabbits than those containing the
Witepsol H15 alone. Suppositories containing
If a drug is readily soluble, the influence of
2% Carbopol 934P had a 2.5 times larger area
particle size may be minimal. For highly water-
under the curve (AUC) than the Witepsol H15
soluble drugs, the tendency will be to dissolve
suppositories. The mean residence time was 5.8
and migrate to the rectal barrier. For poorly water-
hours longer than that with intravenous admin-
soluble drugs, the dissolution rate will be slower
istration. There was no irritation to the rectal
and a reduction in particle size may increase the
mucosa of the rabbits, even at a 10% Carbopol
rate of dissolution by exposing a greater surface
934P concentration. The results suggested that
area. This can also be affected by the nature of
the ramosetron hydrochloride suppositories con-
the suppository base.
taining Carbopol 934P may be a safe and useful
In a study on the influence of particle size and
once-a-day dosage for the treatment of patients
the correlation between the dissolution profile
with chemotherapy-induced nausea.3
and bioavailability of the rectal absorption of
aspirin, the authors found the drug particles
dissolved faster than a compressed disk of the
Formulation variables drug but that there was no correlation between
bioavailability and the dissolution profiles as de-
Active drugs have a number of physical character- termined by the USP XVIII dissolution method.1
istics. In suppositories, those of interest involve
the drug’s physical state, particle size, solubility,
dielectric constant, and bulk density. Some of Solubility
these characteristics have been discussed in detail
in other chapters. Whether or not the active ingredient is soluble in
the base can alter the manufacturing and com-
pounding processes in several ways. Increased
Physical state solubility of the active ingredient in the base can
improve product homogeneity; however, it may
An active drug can be either a solid, a liquid, or also delay the release of the active ingredient
semi-solid. For solids, the drug’s particle size may if there is too great an affinity of the drug for
be very important, especially if the drug is not the suppository vehicle. In some cases, it may be
very water soluble. The increase in surface area desired to retain the drug in the rectal cavity for
resulting from decreased particle size can serve a longer time. If the drug has a greater affinity
to enhance its activity. For liquids, it is necessary for the melted/dissolved suppository base than
to take up the liquid into the suppository base for the aqueous mucosal fluids, the migration to
using one of various techniques, such as forming the mucosal surface for absorption or to produce
an emulsion, adding a drying powder, or adding a local effect will be slowed.
a suitable thickening agent when the liquid is If the active drug is soluble in the base, there
mixed with the suppository base. For semi-solids will be a lowering of the melting point of the
or paste-type drugs, the drug can be either mixed base; consequently, it may be necessary to in-
with a solid that will thicken the drug prior corporate some higher melting point excipients
to adding it to the base or mixed with a base to accommodate this. One must also consider
to which a thickener has been added. All these the crystallinity of the base and its ingredients
considerations must also address the change in and how these additives may alter the processing
manufacturing flow that may result, as well as steps during manufacturing.
If the active ingredient is insoluble in the base, tion and from several polyethylene glycol (PEG)
as is the case when a “suspension” or “emulsion” base dosage forms in six human subjects, they
is formed, this poses different problems. It is found a relationship between bioavailability and
necessary to maintain homogeneity of the total the dielectric properties of the vehicles below a
mixture; this can usually be achieved by constant dielectric constant of 13.6, but above that value
agitation of the mixture during processing and it was not well defined.6
filling. Emulsions can be handled through the
proper use of surfactants to obtain a homo-
geneous mixture. Often it is best to select a
Formulation studies of suppositories
temperature just above the melting point of the
in the literature
suppository mixture where the mixture is thick
but still pourable. This contributes to a more
uniform mixture and a shorter congealing time, There have been numerous formulation studies
minimizing any sedimentation that might occur related to suppositories published in the past 50
in the mold after filling. years. Some investigated physical or chemical
A study was conducted on the solubility of compatibility of the drug with the base; others
18 different drugs in molten Massa supposito- studied the rates of drug release and drug ab-
rium (a suppository base material) at 37◦ C. The sorption. Still others involved the selection and
undissolved drug was separated from the drug- use of various penetration enhancers to increase
saturated base using an air-heated centrifuge fol- absorption of drugs from select suppository bases.
lowed by partitioning between petroleum ether Some examples from the literature are discussed
and an aqueous medium and photometric de- below.
termination of drug concentration. Solubility
values ranged between 0.002% for theobromine
and 26% for lidocaine. Benzoate, phenobarbi- Adiphenin
tal sodium, and procaine hydrochloride were
insoluble; sodium salicylate had an unexpected The release of adiphenin from various supposi-
solubility of 0.48% so maintenance of a uniform tory bases was studied by Pasich and co-workers.
mixture for these drugs during production should The release rate decreased in the following order:
be carefully monitored.4 PEG 1500; PEG 2000; PEG 4000 (70%) + glycerin
(30%); PEG 1000 (70%) + PEG 4000 (30%); PEG
4000; PEG 6000. Considerably slower release was
Dielectric constant obtained from Witepsol W35, Witepsol W15, and
cocoa butter.7
Shangraw and Walkling conducted a study on
the effect of dielectric properties of the vehi-
cle on the rectal absorption of acetaminophen. Aminophenazone
They compared an aqueous suspension, propy-
lene glycol suspension, and a theobroma oil Aminophenazone and propyphenazone release
suppository. Their results demonstrated that if and dissolution rates from suppositories pre-
acetaminophen is dispersed in a vehicle that has pared with Witepsol H15 and S55, Suppocire
a dielectric constant that meets the dielectric BM and AS2, and Macrogols 400 and 4000
requirement for high solubility, then its rectal were studied using water and a semi-permeable
absorption tends to be relatively low. It the drug is wall. Propyphenazone had more affinity to less
dispersed in vehicles or bases that have dielectric hydrophobic bases and the opposite is true for
constants that are too high or too low for high aminophenazone, resulting in a slower liber-
solubility, then the rectal absorption tends to be ation. The higher proportion of mono- and
relatively high.5 diglycerides in Witepsol S55 and Suppocire AS2
When investigators studied the rectal absorp- influences the solubility of the propyphenazone:
tion of acetaminophen from an aqueous solu- it is liberated more easily than from Witepsol
82 Suppositories
H15 and Suppocire BM. The PEGs increased the Chloramphenicol

solubilities of both drugs in the aqueous solvent.
Higher solubilities in the bases resulted in slower The stability of chloramphenicol in several dif-
liberation. Mixtures with a larger proportion of ferent suppository bases was studied. The sup-
the higher molecular weight components, such pository bases included theobroma oil:yellow
as the Macrogols, were better bases for propy- wax (93:7), theobroma oil:docusate sodium
phenazone suppositories; those with a small pro- (99:1), PEG 1540:6000:400 (33:47:20) and PEG
portion of the higher molecular weight Macro- 1540:4000 (75:25). Zones of inhibition, resulting
gols were more suitable for aminophenazone from the release of chloramphenicol and its
suppositories.8 diffusion and antimicrobial effect on the bacteria
dispersed in the gel in the plates, were measured
over a period of six weeks. All the bases and the
drug proved to be stable, as assessed by their
Buspiron
physicochemical characteristics and the effect of
the drug.12
Buspiron was studied in nine lipophilic sup-
pository bases with different physicochemical
parameters utilizing in vitro drug release. Witepsol
H15, Massa Estarinum 299, and Suppocire AS2X Chloroquine
were found to be excellent for the formulation
of buspiron suppositories based on preparation Chloroquine phosphate was suspended
characteristics, handling, and drug release.9 in various lipophilic and hydro-
philic suppository bases at a concentration
of 250 mg of drug per 2 g of suppository.
The solidity and the disintegration time of
C31G the suppositories as well as the in vitro drug
liberation was investigated with a membrane
Research conducted on C31G, an antimicrobial diffusion method. The study was done to
substance used in vaginal infections, determined develop a formulation suitable for the tropics
that Witepsol H15 and Suppocire CM bases were and was carried out at a temperature of 45◦ C
most suitable for vaginal use from the point of and a relative humidity of 75%, reflecting
view of their preparation, storage, and release the conditions prevalent in malaria-endemic
characteristics.10 countries. The Witepsol H15 base was found to
be the best of the bases studied in maintaining
physical characteristics (shape, form) and drug
release.13,14
Carbamazepine
In a study of carbamazepine prepared with

Witepsol H15, Witepsol S55, or PEG 6000 bases Chlorpromazine
prepared by the fusion/molding procedure, the
release rate was investigated using a dissolu- The release of chlorpromazine from various bases
tion apparatus and the absorption profiles after was studied, including PEGs 1000, 1500, 2000,
administration were obtained. The dissolution 4000, 6000, and their mixtures, as well as the
profiles showed dissolution of carbamazepine lipophilic bases cocoa butter, Witepsol W35, and
from PEG to be faster than that from the H15, Witepsol H15. It was found that the liberation
which was faster than that from the S55. In the of the drug was most rapid from the hydrophilic
plasma concentration–time curve (AUC) com- PEG bases in the following decreasing order: PEG
parison, there were no significant differences 4000:1000 (75:25); PEG 4000:glycerin (75:25);
in the AUC among the five preparations (three PEG 2000 (100%); PEG 1500:6000 (70:30); PEG
suppository, oral, and intravenous forms).11 4000 (100%); PEG 6000 (100%).15
Diazepam Gentamicin
Regdon and co-workers completed a biophar- Several antibacterial regimens are used for the
maceutic study of diazepam suppositories and topical treatment of vaginitis of various ori-
recommended the hydrophilic Macrogol mix- gins. An evaluation of suppository bases for
ture as the optimal vehicle for formulation vaginal suppositories containing sulfadimidine,
of diazepam suppositories, giving predictable chloramphenicol, and gentamicin sulfate was
release and maintenance of physicochemical conducted using in vitro determination of break-
characteristics.16 ing hardness, disintegration time, and spreading
properties. Based on these tests, the Suppocire
NA product and compositions of Macrogols with
Ethacrynic acid lower molecular weight proved to be the better
bases.20
Ethacrynic acid was a model drug in a study
looking at Solutol and Cremophor products as
new additives in suppository formulation. Solutol Glibenclamide
HS 15, Cremophor RH 40, and Cremophor RH 60
were used as additives in concentrations of 1%, Suppositories containing 4, 20, and 40 mg of
3%, 5%, and 10%. The amount of drug released glibenclamide, an oral hypoglycemic drug, were
changed as a function of additive concentration. prepared and examined for drug release, ab-
Depending on the acceptor phase, the best resorption, and blood glucose levels in a rabbit
sults, as measured by amount of drug released, model. The glibenclamide suppositories released
were achieved with additive concentrations in the drug continuously for 6 hours. The AUC
the range 1–3%.17 values for the 20 and 40 mg glibenclamide sup-
positories were respectively 3.5 and 6.2 times
that of the 4 mg. The 4 and 20 mg glibenclamide
suppositories had about the same release profiles
Ethosuximide for 6 hours. All the glibenclamide supposito-
ries produced lower blood glucose levels than
Ethosuximide was formulated in different sup- controls. The authors suggest that glibenclamide
pository bases and the release characteristics suppositories should be useful in hospital for the
studied using an in vitro system and in vivo. treatment of patients with non-insulin depen-
Rectal administration in rabbits resulted in sys- dent diabetes mellitus.21
temic availability of 89.39%, 82.72%, 58.80%,
and 47.45% when the bases were PEG 400:4000,
PEG 400:6000, Witepsol E76, and Witepsol W35, Indometacin
respectively.18
Indometacin was the model drug used to de-
termine in vitro release from suppository bases
Furosemide and in vivo bioavailability in rabbits. Suppos-
itories containing 25 mg of indometacin were
Various formulations of furosemide have been made by the fusion method and prepared with
developed and studied in vitro and in clinical use. either theobroma oil, esterified fatty acids, or
In an in vitro model, release of furosemide sodium PEG 1000. The release rates were determined
from a suppository using Massa Estarinum 299 using the USP dissolution apparatus with or with-
proved to be the highest. Both furosemide and out a cellophane membrane. These investigators
furosemide sodium suppositories induced an in- found that the PEG 1000-based suppositories
crease in urine flow, which was comparable to provided greater release than the esterified fatty
the diuretic effect of the oral tablet at equivalent acids and the theobroma oil provided the slow-
doses.19 est release. The bioavailability studies showed
84 Suppositories
greater indometacin absorption from the PEG ketoprofen rectal absorption and hydrophilicity
bases.22 of the suppository bases tested.25
Isoconazole nitrate Morphine sulfate
Both in vitro and in vivo studies have been con- Morphine sulfate release from three fatty bases
ducted using isoconazole nitrate from different (Witepsol H15, Witepsol W35, and Suppocire AT)
suppository bases, including PEG 1500, 4000, was evaluated in rats. Morphine sulfate in Witep-
and 6000; Witepsol, Novata BD, and Cremao. sol H15 proved to be the most promising material
The release rates of isoconazole nitrate when for the preparation of these suppositories, based
introduced into the vagina of rabbits in the on the more complete release of the drug.26
The bioavailability of morphine in three differ-
various bases was, in decreasing order, PEG 6000
ent suppositories was evaluated in dogs in which
⬎ PEG 4000 ⬎ Witepsol ⬎ PEG 1500 ⬎ Novata
the rectum was either lavaged or non-lavaged.
BD ⬎ Cremao.23
The bases used were fatty bases and included
The influence of the suppository base on the
Witepsol H15, Witepsol W35, and Suppocire AT.
in vitro release of isoconazole nitrate 25 mg was
The suppositories were prepared by the fusion
studied by different means, including dissolu-
method and were stored for two weeks at 30◦ C
tion, physicochemical diffusion, and microbio-
before use. The investigators found that the
logical disk diffusion. The bases used included
presence of contents in the rectum reduced the
PEG 6000, 4000, and 1500, and Witepsol H15,
bioavailability of morphine. They also found that
Novata BD, and Cremao. The sizes of the zones
the Witepsol H15 suppository provided better
of inhibition resulting from the antimicrobial
release than the other two bases and considered
effect of isoconazole nitrate on the bacteria in
it potentially suitable for the care of patients
the gel plates were, in decreasing order, PEG 6000
terminally ill.27
⬎ 4000 ⬎ 1500 ⬎ Witepsol H15 ⬎ Cremao⬎
Four different morphine suppository formu-
Novata BD. The results of the study suggested
lations were investigated using the USP rotat-
that the PEGs are suitable bases for these vaginal
ing basket dissolution apparatus: morphine hy-
suppositories.24
drochloride in PEG (MHP), morphine alkaloid in
PEG, morphine hydrochloride in Novata BBC,
and morphine alkaloid in Novata BBC (MAN).
Ketoprofen The first three formulations released the drug
within about 25 minutes, whereas the MAN sup-
The effect of the hydrophilicity of three suppository released the drug over about 10 hours.
pository bases on the rectal absorption of keto- The MHP suppository was compared with a 15 mg
profen was studied. The rectal formulations oral solution of the drug in eight patients with
included an aqueous solution and three suppos- a time of peak plasma morphine concentration
itory formulations (Massa Estarinum A, Massa being similar for both preparations, showing that
Estarinum B, and Massa Estarinum 299 obtained the MHP suppository was rapidly absorbed. The
from Dynamit Nobel AG). Oral administration MAN and MHP suppositories were compared
of the aqueous solution demonstrated complete further in patients. The prolonged release of the
bioavailability compared with intravenous ad- morphine from the MAN suppository was evident
ministration. After rectal administration, the rate with a t max of 2.5 hours, compared to that of
of absorption was slower for all three bases than the MHP suppository of 0.7 hours. There was no
after oral dosing. The investigators observed no significant difference in the AUC values. Plasma
statistical difference in bioavailability between morphine concentrations were sustained for 7
the different suppository bases, but the bioavail- hours with the MAN suppository. According to
ability values were about 20% lower than those the authors, this study indicates that a simple
of the oral solutions. This study did not reveal MAN suppository formulation may be a useful
a relationship between the rate or extent of long-acting rectal preparation of morphine.28
Omeprazole and a flow rate of 20 mL/min. The results showed

that the formulations containing a surfactant
Omeprazole was formulated in a Witepsol H15- in their composition (AS2X and AP) provided a
based rectal suppository and compared with an better release of paracetamol than those with no
orally administered commercial gelatin capsule surfactant (AM and AML).32
in ten male volunteers. Plasma concentration Paracetamol suppositories were prepared using
profiles were not statistically different, showing two different bases (lipophilic and hydrophilic)
that the rectal route did not produce an improve- and given to children who had fever after oper-
ment in the extent of absorption over an oral ations. The results of this study showed that the
capsule.29 lipophilic base produced better results than the
hydrophilic base.33
Oxyphenbutazone
Progesterone
Oxyphenbutazone in different bases was studied
for its in vitro release and rectal absorption in Progesterone vaginal suppositories prepared from
rabbits. The PEG base gave higher medicament different suppository bases (glycerinated gelatin,
release amounts than fatty bases. A mixture of cocoa butter, and PEG) were prepared and ad-
Witepsol H15 or H12 and Brij 58 (85:5) gave ministered to patients in need of progesterone
the highest in vitro release levels and the highest supplementation. Blood levels and AUC values
rectal absorption of the medication.30 were highest after supplementation by PEG-
based suppositories. The conclusions of these
researchers is that the suppository base is impor-
Papaverine hydrochloride tant in controlling the amount of progesterone
absorbed via this route of administration.34
Papaverine hydrochloride was formulated in sup- A study was conducted to determine the
positories using 12 different suppository vehicles; mechanism of drug release of progesterone from
both lipophilic and hydrophilic bases were used, suppositories consisting of Witepsol W35 and
with both low and high hydroxyl numbers. Five Witepsol E85. The formulation prepared by mix-
different physical parameters were determined, ing Witepsol W35 and E85 at a ratio of 1:1
including melting point, drop points (the tem- showed the maximum strength value. When the
perature at which a suppository will drop or slide suppositories were immersed in pH 7.4 phos-
through a constriction in a tube), disintegration, phate buffer containing 0.5% methylene blue at
special penetration times (the time required at 37◦ C, the penetrating area increased with time.
a constant temperature for a thin metal rod to The weight of the suppositories also increased
penetrate lengthwise through a suppository), and with time. The authors suggested that the release
breaking hardness. The results were repeated after of the progesterone from the mixed type of
six months’ storage. At the end of the study the suppository containing progesterone was via the
Estaram 299 Mass, a triglyceride type of base matrix and pores of the suppository base.35
with a low hydroxyl number, was found to be
satisfactory in every category of the five physical
parameters listed above, either used alone or Salbutamol sulfate (albuterol)
combined with 5% Estasan neutral oil.31
In a study using salbutamol sulfate (albuterol)
formulated as a rectal suppository with emulsi-
Paracetamol (acetaminophen) fying fatty bases (Suppocire and Witepsol) and
water-soluble bases (PEG) using the melt–mold
Paracetamol was formulated with four different technique, the amount of drug dissolved in
suppository bases (Suppocire AM, AML, AS2X, 100 minutes of dissolution time was inversely
and AP) and evaluated using a dissolution appa- affected by the melting point of the fatty base.
ratus using the flow-through method at pH 7.4 The release from PEG bases was found to be
86 Suppositories
molecular weight dependent. The addition of were prepared using the fusion method and
1% methylcellulose or Eudragit gel increased the the intrinsic dissolution rate, solubility, parti-
release from the various formulations. The au- tion coefficients, and in vitro release experiments
thors’ conclusions were that a rectal suppository were conducted. The investigators concluded
of salbutamol sulfate could be prepared as an that it should be possible to improve the qual-
alternative to the oral dosage form to circumvent ity of theophylline suppositories prepared with
first-pass metabolism.36 lipophilic bases and to formulate highly available
theophylline suppositories by using PEG water-
soluble excipients.39
Salicylic acid
Salicylic acid (freely lipophilic), boric acid (less Thiopentone sodium

lipophilic), and copper sulfate (hydrophilic) were
incorporated into cocoa butter, cocoa butter with A combination of thiopentone sodium (500 mg),
kokum butter, cocoa butter with spermaceti, and meperidine hydrochloride (25 mg), and scopo-
cocoa butter with beeswax, all in different ratios. lamine hydrobromide (0.33 mg) was prepared in
The rate of medication release, viscosity index a single suppository using either Witepsol or
and rheology of the mixtures was examined with cocoa butter with 5% beeswax. The triglycerides
a Stormer viscometer. Most bases showed shear of fatty acids (Witepsol) base were found to
rate thickening at low stress rates and revealed a be superior to the cocoa butter with beeswax
marked decrease in consistency between 35 and in producing the desired anesthetic effects of
40◦ C. The release of the drug was found to be narcosis and hypnosis.40
inversely proportional to the consistency of the
bases.37
Absorption enhancers
Tacrolimus There are numerous studies in the literature on

various absorption enhancers that have been
Tacrolimus suppositories were prepared using used to improve the rectal absorption of drugs.
Witepsol H15 and compared to an oral suspen- Examples of the absorption enhancers follow
sion in 0.5% sodium methylcellulose solution along with the results of some studies related to
administered to rats. The Cmax and AUC(0–24 h) their use.
values after rectal administration were 3.9 and
6.9 times greater than those after oral admin-
istration, respectively. These authors concluded Casein and low molecular weight gelatin
that there is a clear possibility that rectal ad-
ministration of tacrolimus is capable of improv- The release rate of ibuprofen alone and in combi-
ing its bioavailability and reducing the costs of nation with either low molecular weight gelatin
tacrolimus treatment.38 or low molecular weight casein was studied in
a Witepsol H15 base in Beagle dogs. The results
showed that the low molecular weight casein
Theophylline accelerated the absorption of ibuprofen from the
rectum.41
Theophylline was studied in lipophilic and
hydrophilic bases to determine the feasibility of
using physicochemical approaches to select the Cholate sodium, deoxycholate, sodium
type of excipient capable of ensuring a rapid taurodeoxycholate, sodium taurocholate
release of the drug in the rectum. Witepsol H12
and W25 were used as well as blends of PEGs In a study of insulin suppositories using Witepsol
400, 1500, 4000, and 6000. The suppositories W35 as a base it was found that a relative
hypoglycemia of about 50% can be obtained faster than the lyophilized AMB alone, possibly
when using sodium deoxycholate plus sodium due to the enhanced surface wettability of the
cholate (100 mg plus 50 mg). Similar reductions drug particles rather than the amorphous state of
in glucose were also obtained when sodium the drug. This was also true of the drug complex
taurodeoxycholate (100 mg) or sodium tauro- prepared as suppositories and also correlated with
cholate (100 mg) were used.42 increased absorption of the drugs, with about
The incorporation of insulin (50 units) with 35 times greater AUC values compared with
50 mg of deoxycholic acid, sodium taurocholate, lyophilized AMB alone. The authors conclude
or both, was studied in a suppository dosage that GLYK is useful for improving the dissolution
form, along with polycarbophil addition. The and bioavailability of AMB in suppositories.46
most pronounced plasma glucose lowering of
56% compared with subcutaneous injection oc-
curred with the combination of deoxycholic acid, Sodium caprate and capric acid
sodium taurocholate, and polycarbophil.43
Recombinant human erythropoietin was com-
bined with either sodium salicylate or sodium
Diclofenac sodium caprate in suppositories to study its extent of
absorption. The bioavailability in a suppository
Sulfanilic acid and sulfaguanidine were inves- containing 5% sodium salicylate compared with
tigated when prepared in suppository bases of that of an intravenous injection was 1.2%. The
Witepsol W35, H15, S55, E75, and the hydro- authors observed in rats that these suppositories,
philic base Macrogol. The drug was included inserted once daily for 6 consecutive days, in-
either alone or in combination with diclofenac creased erythropoiesis in peripheral blood.47
sodium, an absorption enhancer. In all the sup- Capric acid at a concentration of 13% was
positories except the Witepsol E75, the sulfanilic found to enhance the absorption of cefoxitin
acid was released very rapidly. On the addition of sodium by reduced rectal membrane resistance,
diclofenac sodium as absorption promoter, the showing that the enhancing effect was induced
in vitro release of the drugs from all suppositories by widening the paracellular pathway.48
increased by about two- to fourfold compared to Sodium caprate has been demonstrated to be
the drugs in the suppository vehicles alone.44 useful as an absorption enhancer when used with
Diclofenac sodium 125 mg in poloxamer gel- ampicillin suppositories. A study involving 12
forming suppositories was investigated both in healthy human subjects was conducted to deter-
vivo and in vitro to determine the effect of mine the possible mechanism of action of the
sodium chloride on the release rate of the drug. sodium caprate. The authors concluded that the
The results indicated that poloxamer gel with ampicillin–sodium caprate-enhanced absorption
sodium chloride can be a more effective and safe of ampicillin coincides with non-specific damage
rectal delivery system for diclofenac sodium, as to the rectal mucosa. The histological damage was
indicated by a lack of adverse response (irritation, also shown to be reversible.49
inflammation).45
Sodium laurate and lauric acid

Dipotassium glycyrrhizinate
A study was conducted to develop a safe (lack
The effects of dipotassium glycyrrhizinate (GLYK) of adverse response, irritation, or inflammation)
on the dissolution and bioavailability of ampho- suppository formulation to improve the bioavail-
tericin B (AMB) was studied using lyophilization ability of poorly absorbable drugs. This was done
methods. The GLYK and AMB were prepared with the combination of sodium laurate, an ab-
at different molar ratios and the dissolution sorption enhancer, with taurine or L-glutamine,
rates studied. The dissolution profiles showed and adjuvant exerting the cytoprotective action.
the GLYK/AMB mixtures were released markedly The dissolution of rebamipide from Witepsol
88 Suppositories
H15, a fatty base, was very slow but was re- 100 mg of sodium cholate and 200 units of in-
markably improved by the addition of sodium sulin produced a maximum percentage reduction
laurate, taurine, or L-glutamine. When prepared in plasma glucose levels and can serve as an effec-
with a water-soluble base, PEG, dissolution was tive buffer against meal-related hyperglycemia.
very rapid and the addition of adjuvants did The suppositories were safe, effective, accepted,
not influence its dissolution so markedly. The and well tolerated by the individuals.55
authors concluded that if a fatty base is desired, Suppositories were prepared to contain either
the incorporation of sodium laurate, taurine, or 60 mg of salicylic acid or 70 mg of sodium sal-
L-glutamine could be practically considered.50 icylate in PEG bases consisting of PEG 1540
Ogiso and co-workers demonstrated the con- and PEG 6000 in various proportions. The in
cept that a 1:1 complex of propranolol with lauric vitro release of salicylates from the suppositories
acid would penetrate across the rectal mucosa was studied in a closed-system in vitro apparatus
more easily than propranolol alone, using both designed to circulate fluid about the suppository
Witepsol and Macrogol suppositories.51 at 37 ± 0.2◦ C. Release of the salicylate from the
PEG suppositories simulated zero-order kinetics
and the time required for 50% release of the
Sodium salicylate salicylates did not differ significantly for either
salicylic acid or sodium salicylate. The release
The absorption of insulin in dogs has rates were different for PEG 1540 and PEG 6000,
been studied using sodium salicylate and but for the blends they approximated that of the
5-methoxysalicylate as absorption enhancers. PEG 6000 alone.56
The suppository base was Witepsol H15, the
quantity of insulin was 20 units along with
150 mg of sodium 5-methoxysalicylate. There Cyclodextrins
was significant enhancement of the combination
when administered as a microenema but not Flurbiprofen, an anti-inflammatory drug, was
necessarily as a suppository. It was postulated combined with ␤ and ␥ cyclodextrins in 1:1
that the promotion enhancer and insulin must molar ratios to give solid complexes and incor-
both be delivered at the same time. In the porated into a Witepsol W35 suppository base.
suppository, however, the dissolution rate of Compared to the plain flurbiprofen suppositories
insulin lagged behind that of the promotion without the additives, the cyclodextrin com-
enhancer. This was confirmed by additional plexes enhanced the bioavailability of flurbipro-
studies.52 fen by about 1.4 to 1.7 times, as indicated by the
The effect of sodium salicylate and Brij 35 AUC values.57
on the absorption of cefoxitin in suppositories Amylodextrin was investigated as a carrier in
made with Witepsol H15 was studied. The pres- solid dispersions for diazepam or as a complex
ence of the absorption enhancers gave increased with prednisolone in a fatty suppository base in
bioavailability as high as 20% compared to 3% a flow-through model. The suppositories showed
without the adjuvants. The suppositories were an increase in drug release compared to those
well tolerated.53 containing only the drug. Use of the soluble frac-
Sodium salicylate was shown to increase rectal tion of amylodextrin for both the solid dispersion
insulin absorption when administered in suppos- and the complex was demonstrated to enhance
itory form in humans. The quantity of sodium drug release, but it was still below that of the
salicylate used was 200 mg per 100 units of drug–cyclodextrin complexes.58
insulin contained in a Witepsol H15 suppository Solid dispersions and crystallizations of a
base.54 very slightly water-soluble drug, allopurinol, were
A study on the use of sodium salicylate and prepared using urea, sodium salicylate and ␤-
sodium cholate as absorption promoters of in- cyclodextrin as carriers. Suppository bases in-
sulin was conducted in diabetic patients. The cluded Suppocire AM and a mixture of PEGs
results showed that the formulation containing and the suppositories were evaluated using an
in vitro system. The release of allopurinol was Glyceryl monooleate

significantly enhanced from both lipophilic and
hydrophilic bases when crystallized with sodium A study of rectal nicotine delivery was conducted
salicylate, with an enhanced release of about by Dash and co-workers. Their goals were to
100% in 1 hour from the Suppocire AM base. develop a rectal nicotine delivery system with
The PEG formulations were superior, containing bioadhesives for the treatment of ulcerative col-
co-evaporates of the drug to sodium salicylate at itis and to evaluate nicotine transport and cyto-
a ratio of 1:1 or of the drug to ␤-cyclodextrin ratio toxicity of the delivery system using Caco-2 cell
of 1:2 in 12 and 36 minutes, respectively.59 culture systems. Semi-synthetic glyceride bases,
Another study demonstrated that supposito- Suppocire AM and Suppocire AI, were used with
ries containing cyclodextrin complexes of in- the fusion method of preparation. A modified
dometacin and essential oils formed complexes USP dissolution apparatus 1, differential scan-
with ␤-cyclodextrin resulted in increase blood ning calorimetry, powder X-ray diffraction and
levels.60 liquid chromatography methods of analysis were
Hydroxypropyl ␤-cyclodextrin (HPCD) and used. The effect of glyceryl monooleate (GMOL)
its effects on drug solubility and release from and Carbopol on the nicotine flux was evaluated
suppository bases were studied using dexametha- using the Caco-2 cell permeability studies; the
sone, dexamethasone acetate, hydrocortisone, Caco-2 cell viability was determined using the
hydrocortisone acetate, and prednisolone acetate MTT toxicity assay. The results of the in vitro re-
as model drugs. It was found that the HPCD lease studies showed that the lower melting Sup-
significantly increased the aqueous solubility of pocire AI base was superior (better release) to the
all five steroids and the increased solubility Suppocire AM base. GMOL enhanced the release
significantly influenced the drug release from the of nicotine whereas Carbopol produced the oppo-
PEG-based suppository but not from the cocoa site effect. The investigators concluded that rectal
butter-based suppository.61 nicotine formulations containing bioadhesives
can be developed and characterized. The nicotine
release can be manipulated by the incorporation
Enamine of various bioadhesives or the use of different
bases. The results of the cytotoxic studies showed
The use of enamine in a study involving de- that nicotine concentrations below 2% w/v and
pancreatized dogs enhanced the bioavailability bioadhesive concentrations below 10% w/w did
of insulin after rectal administration.62 not have any cytotoxic effect.66
Investigators found that the use of an enamine
derivative, DL-phenylalanine-ethylacetoacetate,
included in insulin suppositories using Witepsol
Lauroyl leucine
H15 as a base, is a more effective absorption
promoter for rectal insulin absorption than the
Hacker and co-workers showed that chloram-
surfactant BL-9-EX. This enamine derivative can
phenicol suppositories without additional surfac-
be considered as an adjuvant to suppositories for
tants did not result in any detectable absorption
the long-term control of diabetes mellitus.63
of the drug. However, the addition of 0.04% of
Similar work to the above was conducted
N-lauroyl leucine provided absorption having the
in dogs and rabbits using enamine derivatives.
same effect as that of an injection of the same
In this study, either sodium phenylalanine or
quantity of the active substance.67
leucine were able to enhance the effect of insulin
when contained in a microenema solution, with
lesser effects when administered as an insulin
suppository.64 Miscellaneous formulations
A possible mechanism for enamine and its
derivatives increasing rectal absorption has been The spreading and retention of vaginal formu-
presented.65 lations has been studied using ␥ scintigraphy.
90 Suppositories
Radiolabeled pessary formulation and Replens, a the bioavailability was increased to 52% and 42%,
polycarbophil gel, were studied in six healthy, respectively.71
postmenopausal female volunteers over a 6-hour
period using ␥ scintigraphy. There was very little
intra-subject variation but there was considerable Polyoxyethylene 2 lauryl ether
inter-subject variation, ranging from less than
2% to about 80% retention at the end of the When amphotericin B is compared in different
6-hour imaging period. There was no evidence bases, its release from Witepsol or medium-chain
to suggest that either of the two formulations triglyceride bases is faster than that from the
dispersed material beyond the cervix into the hydrophilic bases Macrogol. The addition of
uterus in any of the subjects. It is clear that polyoxyethylene 2 lauryl ether (POE(2)LE) to
attention must be paid by the formulator to the fatty bases with amphotericin B led to a marked
spreading and retention characteristics of these increase in the drug release rate, whereas either
formulations.68 POE(2)LE or sodium lauryl sulfate resulted in a
In a study related to the absorption of significantly lower release rate. The addition of
mesalamine in subjects correlated with the time POE(2)LE to the medium-chain triglyceride base
of defecation, two commercial mesalamine sup- resulted in a marked increase in bioavailability,
positories were used: Salofalk 500 mg (Tramedico showing the highest bioavailability of 4.9%; the
BV, the Netherlands) and Mesalazine 500 mg lowest bioavailability was 0.32%, obtained with
Suppository (Disphar International, the Nether- the Macrogol suppository. These results suggest
lands). The suppository of both formulations that amphotericin B in a rectal formulation may
demonstrated differences between subjects in provide a therapeutic alternative to infusion.72
whom mesalazine was released and absorbed
monophasically compared with those in whom it
was biphasic. The difference in release/absorption Salts/esters
correlated with the time of defecation prior to
insertion of the suppository. In other words, Ibuprofen lysinate
the shorter the time the stool mass was present
before insertion, the more monophasic the re- A study of the absorption of ibuprofen compared
lease/absorption was. Fresh stool was likely to with that of ibuprofen lysinate was conducted
bind or metabolize more drug than older and using suppositories prepared from either Witep-
more compact stool.69 sol H15 or PEG 1500 by the fusion process and
administered to rabbits. The results demonstrated
that ibuprofen lysinate was absorbed significantly
more readily than the free acid from the supposi-
Organic acids tories. The lysinate suppository with a lipophilic
surfactant also had a higher absorption rate con-
The vaginal absorption of leuprolide in rats was stant than that with a hydrophilic surfactant.73
studied using different organic acids, namely Ibuprofen lysine salt was found to give higher
citric, succinic, tartaric, and malonic acids. The blood levels in rabbits than the free ibuprofen
results suggested that the acidifying and chelat- when measuring AUC, Cmax , and t max .74
ing abilities of the acids may result in a po-
tent enhancement of the vaginal absorption of
Indometacin calcium and indometacin
leuprolide. The mechanism of the enhanced
magnesium
absorption may be due to the loosening of the
blood–vaginal epithelium barrier.70 The calcium and magnesium salts of indometacin
The addition of citric and tartaric acid to and indometacin base were studied in a suppos-
bumetanide in Macrogol suppositories was stud- itory base of Witepsol H15. The results using
ied. The bioavailability without the weak acids AUC values demonstrated that the calcium salt
was 32%; with 5% citric acid or 5% tartaric acid, of indometacin was sufficiently absorbed from
rectal administration in the form of a suppository pH 7.4 buffer solution using the USP paddle
to produce an effect.75 method at 100 rpm. The results indicated that
PEG 1500:4000 mixes in ratios of 2.5:10 and
10:2.5 appeared to be similar in their rates of
Indometacin/PEG esters release. An interesting observation was that the
It was demonstrated that indometacin esters were addition of sodium lauryl sulfate to the sup-
formed when prepared in PEG suppository bases. pository reduced the release rate of allopurinol
Indometacin (100 mg), representing about 7% of significantly.78
the weight of the suppository, was prepared in a
mixture of PEG 300, 1500, and 6000 using the
fusion method. The results showed that about Polysorbates
2%, 3.5%, and 4.5% of the original amount of
indometacin was esterified with PEG 300 after The careful selection of appropriate adjuvants
storage times of 1, 2, and 3 years, respectively. No for suppositories, such as glyceride mixtures or
significant amounts of indometacin were shown non-ionic surface agents, can increase the rectal
to be esterified with the other suppository base absorption of aminopenicillins, cephalosporins,
components, namely the PEG 1500 and 6000.76 and macrolide antibiotics.79
This esterification may have an adverse impact Aminophenazone 300 mg suppositories were
on the stability of the suppositories prepared in a prepared in Witepsol W35 or Estarinum 299
base containing PEG 300. with the addition of 10 different individual
liquid tensides (surfactants) at concentrations of
5%. The tensides softened the suppositories and
Phenobarbital and phenobarbital sodium favorably shortened their disintegration time in
both suppository vehicles.80
The influence of the suppository base and the
Twenty-eight non-ionic surfactants were
drug solubility of phenobarbital and phenobar-
added to theobroma oil base suppositories
bital sodium were studied using both lipophilic
and used in an in vitro dialyzing study
and hydrophilic bases. The availability of pheno-
employing aminophylline, ephedrine alkaloid,
barbital is higher from a hydrophilic base because
and ephedrine hydrochloride as model drugs.
of its improved solubility. The release of pheno-
Data obtained indicated that surfactants with
barbital sodium is higher from lipophilic bases.
hydrophilic–lipophilic balance (HLB) values over
The bioavailability of both phenobarbital and
11 increased the amount of drug dialyzed.81
phenobarbital sodium after rectal administration
Chloroquine suppositories in a base of PEG
is stated by the authors to be almost equal to that
1000:4000 (75:25) were studied with and without
after oral administration.77
the addition of three surfactants. The surfactant-
containing suppositories released 100% of the
chloroquine, whereas the controls without the
Surfactants surfactant released 88%. Of the three surfac-
tants, Tween 20 was found to be the most
Although the presence of surfactants normally effective.82
enhances the dissolution, rate-of-release, extent The rate and extent of release of an incorpo-
of release and even absorption of a drug, this is rated dye was used to study the effect of different
not always the case, as illustrated by some of the surfactants. About 75 different suppository bases
following examples. were prepared, melting points determined, dye
release determined and in vivo studies using
rabbits were conducted. The results showed that
Sodium lauryl sulfate
bases containing 35–40% of certain of the emul-
An allopurinol suppository was formulated using sifying agents/surfactants seem to enhance dye
PEG mixtures of different molecular weights. In release in suppository bases. The suppository
vitro rate-of-release profiles were obtained in a bases containing the Tween products gave the
92 Suppositories
best dye release and the Span products gave in terms of the micellar solubilization of the drug
somewhat less effective dye release.83 with the non-ionic surfactants.88
Thermal and rheological studies were con- In a study on the effects of Tween 20 and
ducted on ethosuximide suppositories to deter- Tween 80 in both Witepsol H15 and PEG 2850
mine the influence of the drug and adjuvants. bases containing metronidazole, the investiga-
Fatty bases included Witepsol H19 and Sup- tors concluded that the concentration of the
pocire AP, each mixed with 5% w/w polysorbate surfactant had the largest individual effect on
80, 0.1% w/w docusate sodium and 3% w/w the mechanical and release parameters of the
tetranyl AT-1/DP and 150 mg of ethosuximide. drug whereas the nature of the surfactant had
The thermograms of the formulas revealed two the lowest effect.89
melting peaks. The first endothermic peak does Metronidazole suppositories using a glycero-
not appear due to the melting of ethosuximide gelatin base were studied with and without the
but was attributed to the solubility of the drug presence of Tween 80 and a hydrogenated veg-
in the melted excipient, producing a decrease of etable oil lubricant in rabbits. The presence of
the melting temperature of the second peak in Tween 80 enhanced the in vitro release of metron-
the differential scanning calorimetry scan. The idazole, but the presence of a hydrogenated
melted fluids behave as newtonian fluids and vegetable oil lubricant caused retardation in the
the influence of the ethosuximde and adjuvants drug release from the suppositories.90
resulted in an increase in the viscosity of the A study using papaverine was carried out with
suppository mass.84 polysorbate additives. Twelve different vehicles
Insulin absorption from a suppository dosage were used and different additives incorporated.
form was highly significant when Brij 58 was used Polysorbate 20 and 21 at 5% each was found to
as an absorption-promoting surfactant.85 increase diffusion. Neutral oils softening the con-
In a study involving ketoprofen suppositories sistency of the suppositories, including Miglyol
in theobroma oil and PEG 1000 bases, different 812 and Estasan also at a 5% concentration, also
formulations were prepared to study the release had a favorable effect on the in vitro diffusion
of the drug using the USP dissolution method and by increasing the spreading properties of the
in vivo work evaluating rectal absorption studies suppositories. In these cases, only the low hy-
in rabbits. The formulation showing optimum droxyl number bases could be used favorably. The
drug release occurred with the PEG 1000 base triglyceride type Estaram 299 was found to be the
and theobroma oil formulations containing 6% most suitable in every consideration, either alone
polysorbate 40.86 or combined with 5% neutral oil.91
Latamoxef sodium (LMOX), an antibiotic, Tween 80 (2% w/w) and sodium lauryl sulfate
was studied as a suppository using different (0.75% w/w) caused an increase in the dissolution
adjuvants. Witepsol H15 was used as the base rate of salbutamol from suppositories. However,
and the absorption of the drug was very low. sodium lauryl sulfate caused irritation to the mu-
With the addition of 10 mg diclofenac sodium, cosa. The study recommended Tween 80 could
which is also used as an absorption enhancer, be added to salbutamol suppositories to increase
the absorption increased about 1.3-fold. When dissolution rates.92
Tween 80 was added, the rate was also in- The use of solid dispersion techniques in
creased. The rectal absorption of LMOX on mixing sulfamethoxazole with either Tween 20,
the addition of both Tween 80 and diclofenac Tween 80, or Myrj 53, first physically and then
sodium was markedly increased as well as incorporating by fusion into a Witepsol H15 base,
the membrane permeability of LMOX in the was studied. The investigators found that this
rectum.87 mode of incorporation showed a higher rate of
The release rates of meclizine hydrochloride drug release and did not affect the stability of the
from lipophilic suppository bases prepared with drug.93
Tween 20 and 80 in concentrations of 5, 20, and Trimethoprim was investigated with 24 dif-
30% were higher, approximately the same, and ferent suppository bases to determine the fea-
lower, respectively. These results were interpreted sibility of its rectal use. The suppositories
contained 50–200 mg of the drug and its release tions. It appears the Aerosil actually decreased
was studied by the method of dynamic diffusion. the bioavailability of sodium valproate compared
The in vivo examinations were conducted in with the suppository without additives.
anesthetized rats. The best in vivo results were Peneva and co-workers studied the compatibil-
achieved with the lipohydrophilic Witepsol W35 ity of the macromolecular product Novosup-78
vehicle containing 10% polysorbate 20 and 10% with certain drugs used in suppository formu-
polysorbate 61 (bioavailability = 63.8%) and lations. Novosup-78 is a mixture of PEG esters
the Witepsol W35 containing 10% polysorbate with the free acids of sunflower oil and lard.
60 (bioavailability = 63.8%). The hydrophilic Using a solubility procedure and the ultraviolet
Macrogol 1540 base containing 5% Macrogol 400 spectral technique, significant interactions with
was only slightly less bioavailable (52.9%). In the only discrete amounts from both components
case of the lipohydrophilic Witepsol W35 vehicle can occur. An assumption of up to 0.5% micel-
with 10% polysorbate 20 and 10% polysorbate lar solubilization in the Novosup-78 was made.
61 content, there was a significant negative Based upon the results, it was concluded that
exponential relationship between the doses and a minimum ratio of drug to Novosup-78 was
their bioavailability values (as the dose increased, not favorable for complexation interactions to
the bioavailability decreased); this was observed occur.98
also during the in vitro studies.94 It is quite apparent from the studies presented
In a study of trimethoprim as the model drug, that the release rates of various drugs are formula-
the best results, indicated by a bioavailability of tion dependent. Different additives or excipients
63.8%, were achieved with Witepsol W35 con- may alter the physical and chemical character-
taining 10% polysorbate 20 and 10% polysorbate istics of the suppository and even increase or
61, and with Witepsol W35 containing 10% decrease the release rates and extent of drug
polysorbate 60. The hydrophilic Macrogol 1540 absorbed. Consequently, it is vitally important
vehicle containing 5% Macrogol 400 had only to thoroughly investigate the proposed formula-
slightly worse results, with a bioavailability of tions prior to use.
52.9%.95
A study using theophylline demonstrated that
the suppository base Novosup provides higher
in vitro and in vivo availability of theophylline
compared to other lipophilic bases. The inclusion References
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98
6
Manufacturing suppositories
Bill Mink and Loyd V Allen, Jr
THE SELECTION of manufacturing equipment to facturing large quantities of suppositories in a

be used in the production of suppositories can be relatively short time. This equipment allows for a
made according to the following criteria: single continuous manufacturing process, start-
ing with two main components: the packaging
1 Quantity of suppositories to be manufactured
shell material and the molten bulk drug product.
in a batch
Two materials are commonly used in the
2 Speed of production required
automated packaging process to create the sup-
3 Type of manufacturing process to be used:
pository shell. These are a PVC/PE (polyvinyl
manual, semi-automated or automated.
chloride/polyethylene) laminated material and
an aluminum/PE laminated material. Each ma-
Manufactured suppositories are generally pre-
terial has its own advantages:
pared by either the melt–fusion or cold compres-
sion methods. Commercially automated equip- r The PVC/PE material has a PVC layer lam-
ment for melt–fusion or cold compression is
available to produce large quantities of finished inated onto the PE layer. This provides the
suppositories per hour (Figure 6.1). shape of the suppository, allows for printing of
In general, the manufacturing process in- product information, and protects the product
volves preparation of the active and other pow- from moisture and light. The PE layer allows
dered ingredients, preparation of the base, blend- two pieces of material to be welded together. It
ing, incorporation of powders into the base, also provides the contact surface with the drug
formation of the suppository and packaging and product. PVC/PE material can easily be formed
labeling. Before mixing, the powdered active into a variety of shapes.
ingredients must be prepared by first sifting r The aluminum/PE material has an aluminum
or passing through a sieve of the desired size. foil layer laminated to the PE layer. The alu-
The purpose is to separate the particles prior to minum layer provides the same function as
incorporation into the base. Micronized powders the PVC layer in forming the shell, allowing
are usually preferred. This is important in either printing of product information, and protecting
melt–fusion or cold compression manufacture. the product from moisture and light. The PE layer
is the same as the PE layer with the PVC/PE.
The aluminum/PE is preferred by some because
it provides better light and moisture protection
Melt–fusion method than the PVC/PE material.
Automated manufacturing and

packaging process Manufacturing process
The automated equipment for preparing suppos- The primary packaging of suppositories in the
itories provides an efficient method for manu- automated process is made up of five distinct
99
100 Suppositories
Figure 6.1 Commercial automated suppository manufacturing equipment.
stages: forming, dosing, cooling, sealing, and 1

finishing. These stages are completed in a con-
tinuous process, at rates that can reach 30 000
suppositories per hour (Figure 6.2).
The forming process determines the shape and 2
volume of the mold. It begins with two rolls of
3
material. For the PVC process the film is heated
between a set of dies. After the film is heated,
it is transferred to the next station where it is
blow-molded into shape. The sides of the film
are sealed as air is blown in between the heated
film. The cavity is created, while the top remains
open for dosing of the product. This process can
be completed online or preformed shells can be
purchased in rolls for smaller volume machines.
Once the shells are formed, they move to the
dosing station. At the dosing station molten sup-
pository mass is recirculated through the dosing
head. Empty shells are aligned with the nozzles of
the dosing pump. Molten product is drawn from
the recirculating product stream using a piston Figure 6.2 Diagram of a Sarong SpA semi-automatic
system. The molten product is dosed into the suppository manufacturing machine.
empty shells. For high-speed machines, multiple
cavities can be dosed at one time. This can Filled shells are moved to the cooling tunnels.
be accomplished with an accuracy of ± 0.01 g, These reduce the temperature of the molten mass
depending on the product and equipment. in the shells, allowing the product to solidify.
Chapter 6 • Manufacturing suppositories 101
Cooling tunnels blow chilled air around the mity issues. The rate of mixing must be controlled
molds. The cooling is controlled by adjusting the to maintain uniformity and prevent aeration of
time the suppositories spend in the tunnels and the product.
the temperature of the tunnel. This eliminates If the product becomes aerated during filling
cracks and sink holes, which may form if the it will be difficult to maintain fill weights. Pump
suppositories are cooled too quickly. Machines designs for suppository fillers are volumetric in
either have a single tunnel or multiple tunnels. design. They dose a consistent volume of product
Adding multiple tunnels allows for longer cool- to each mold cavity. If the product is aerated
ing times and independent temperature control the suppository weights will fluctuate. When
of the cooling tunnels. the weight fluctuates, the quantity of the active
Once the solidified suppositories leave the ingredient for each suppository may fall outside
cooling tunnel they move to the sealing area, defined specifications.
where the open top of the mold is closed. This Recirculating the molten mass is the key to
process is accomplished by reheating the top edge preventing the product from solidifying in the
of the film above the solidified suppository. After hose that runs from the bulk tank and the filling
passing the shells through a series of reheating heads. The product recirculates from the tank,
jaws, the molds move to sealing jaws. Sealing through the dosing pump, and back into the
jaws are cooled with chilled water. The cooled holding tank. The temperature of the molten
jaws press the plastic film together and seal them. mass must be controlled, keeping it hot enough
Also, during this phase it is possible to press to allow the product to flow easily through the
the lot code and expiration date into the seal hose, while avoiding overheating, which could
area for each individual suppository. Once the cause the materials to degrade.
suppositories are sealed the finishing touches can
be added.
The finishing of the suppositories includes
Box 6.1 Controls necessary for the melt–fusion
perforating, notching, and cutting the molds
procedure
into the appropriate count strips. The perforating
and notching can be performed either before
r Supervision of excipient melting and melting
filling or after sealing of the suppositories. The
process and perforating allows for the individual temperature control.
r Verification of the correct state of the active prin-
suppositories to be easily separated from each
other for dosing. The cutting of the strip length ciples (granulometry, homogeneity, color, etc.).
r Mixture temperature (important in essential oil
allows for the suppositories to be placed in the
final cartons for distribution. evaporation or coagulation of extracts).
r Stirring speed (important for the possibilities of
cavity formation and the incorporation of air, or
Mixing process for filling in the case of insufficient stirring which can result
in decantation).
r Homogeneity of the mixture (is readily evalu-
The mixing process during filling is a key com-
ponent in product quality. The process must be ated by observing color variation in naturally
designed around product uniformity, which is colored suppositories or where coloring agents
maintained by continuously mixing the product are added).
r Refrigeration cupboard or refrigeration tunnel
and recirculating the product to the dosing
heads. temperature.
r Supervision of cycle times between casting,
Mixing prevents the active ingredient, which
is typically suspended in the suppository base, scraping, withdrawing from molds with special
from settling out and becoming concentrated in attention paid to recycling of excesses (avoid
any one portion of the batch. It also helps to overheating).
keep the product temperature uniform, which
prevents the batch solidifying, leading to unifor-
102 Suppositories
Cold compression method r Sticking, coagulation, or precipitation as a re-

sult of an incompatibility between the medica-
tion and the base or between two medications.
The cold compression manufacturing of suppos-
This also occurs when there has been excessive
itories uses the following procedures. First, the
thermal treatment of vegetable extracts or
base is pulverized and blended with the active
as a result of crystalline change in certain
ingredients and other necessary excipients. Fol-
medications.
lowing assurance of a uniform blend, the mixture r Breakdown of an emulsion or dispersion.
is moved into the compression area. This room
and/or equipment may be maintained at a cold
temperature. The mix is placed in the suppository Thickening occurs with a number of active princi-
compression equipment and the process started. ples when the temperature of the mixture is too
The mix is forced through an orifice into molds. low or when there is a change in the distribution
After compression, the suppository is forced out of the active drug in the base.
and sometimes trimmed, then moved on for Air can be introduced into the mixture when
packaging and labeling. the stirrer is running too fast, the stir-blade is
The cold compression method can be fast positioned too high in the mixture, or when
and efficient but it can have its limitations. Its transferring the mix by pouring too rapidly.
main advantage is that heat is not required; this To address these potential problems, the fol-
may be important when heat-sensitive drugs are lowing controls are applicable to all methods of
involved. manufacturing suppositories:
1 Visual examination of finished suppositories

Box 6.2 Controls necessary for the cold compres-
for physical defects introduced during the pro-
sion procedure
duction process can include checking for color,
presence of chips, cracks, depressions, surface
r In addition to the controls described for all sup- irregularities or any other problems. If necessary,
pository manufacturing processes, it is critically adjustments to the equipment and to tempera-
important that the cold compression equipment ture, flow rates, etc. can be made to resolve these
be thoroughly cleaned and maintained. problems.
r Close attention should be paid to all the standard
2 Verification of the homogeneity of the mix
operating procedures specific to the equipment
and final product is carried out both in-process
being used.
and at the end.
3 Weight checks involve periodic weighing of
individual suppositories to reveal any problems
in the filling operation. Note that individual
General controls relative to suppositories should be weighed, rather than
manufacturing all suppositories groups of suppositories. This provides better data
for variation between filling units, etc.
Some of the difficulties that can occur in suppos- 4 Leak tests involve checking the seal integrity
itory manufacturing include dehomogenization, when the suppositories are packaged using a
thickening and introduction of air. sealed package. This can be accomplished by the
Dehomogenization is related to four different vacuum dye method or other suitable leak testing
factors: method. There should be no leaks in a properly
r Evaporation of water, alcohol, and other operating system.
volatile substances. 5 Checks should be made to ensure that auto-
r Sedimentation of substances with a greater matic or semi-automatic packaging is watertight
density than that of the base. (plastic, metal/plastic complex, etc.).
Chapter 6 • Manufacturing suppositories 103
Molding problems can include tearing/ the temperature of the cooling chamber or by
splitting and improper sealing. If the thickness slowing the machine speed to allow more time
of the foil or plastic varies excessively, tearing or in the cooling chamber.
splitting may occur, especially with aluminum Granulation is usually associated with cocoa
foil as its tolerances are quite narrow. These butter bases and results from the formation of
problems may be related to timing and excessive unstable crystalline structures within the sup-
wear in the equipment. Improper sealing often pository base. It appears as large granules that
results from low sealing temperature or too rapid crumble easily, but may not occur for many
a sealing process where there is insufficient time hours (up to about 24 hours) after filling. Gran-
for complete fusion of the two halves of the shell ulation may result from high temperatures in
to occur. preparation, during storage, during time in the
Filling problems can result in surface defects, hopper or filler, or from heat carryover dur-
structural defects and weight variation. ing the sealing stage. It can be addressed by
Surface defects may result from temperature or lowering the temperature at the point where it
cooling problems. If the temperature of the shell is thought to occur or by waiting 8–12 hours
is too high, imperfections may occur in the shell for the material to stabilize, as well as by the
material and be carried over to the suppository. If addition of a small quantity of fresh base, or
too low, the melt may begin to solidify as soon as “seeding.”
it contacts the wall surface of the shell and result Weight variation is usually a problem with
in imperfections. Close temperature tolerances the filler or portioning unit. There may be a
can often correct this problem. misalignment, improper adjustment, premature
Structural defects may result in soft supposito- solidification, or build-up on the outlets or the
ries, suppository cracking, or granulation: incorporation of air. These can be addressed by
Soft suppositories can occur as a result of inad- proper adjustments and attention to the equip-
equate cooling. This can be resolved by reducing ment during processing.
104
7
Compounding suppositories
PHARMACISTS have been compounding sup- to be accurately dispensed. Standard practices

positories throughout history. They have been and precautions for compounding these dosage
especially called on in recent years to extempo- forms include the following:
raneously prepare progesterone vaginal supposi-
tories, analgesic suppositories, and anti-nauseant r Do not use ingredients that are caustic or
suppositories. These are commonly prepared by irritating, and make sure that solids that are
molding using either a polyethylene glycol (PEG) abrasive to the mucous membranes are thor-
base or a fatty acid base (e.g. cocoa butter). oughly comminuted.
Extemporaneously compounded medications r Select a base that allows active ingredients
are an important part of the symptom control to provide the intended local or systemic
armamentarium. According to the US Pharmaco- therapeutic effect.
peia General Chapter (795) Pharmaceutical com- r Reduce solid ingredients to the smallest rea-
pounding – nonsterile, in compounding any sonable particle size.
prescription pharmacists should consider the r Weigh a representative number of supposito-
following questions: ries to ensure that each is not less than 90%
1 Have the physical and chemical properties and not more than 110% of the average weight
and medicinal, dietary, and pharmaceutical of all suppositories in the batch.
uses of the drug substances been reviewed?
2 Are the quantity and quality of each active
ingredient identifiable? Physicochemical considerations
3 Will the active ingredients be effectively
absorbed, locally or systemically according to A number of factors affect the decisions the
the prescribed purpose, from the preparation pharmacist must make when preparing a supposi-
and route of administration? tory. Questions the pharmacist could discuss with
4 Are there added substances, confirmed or the physician before preparing this dosage form
potentially present from manufactured prod- include the following:
ucts, that may be expected to cause an allergic
r Is the desired effect to result from systemic or
reaction, irritation, toxicity, or undesirable
organoleptic response from the patient? Are local use?
r Is the route of administration rectal, vaginal,
there added substances, confirmed or poten-
tially present, that may be unfavorable (eg or urethral?
r Is a rapid or a slow and prolonged release of
unsuitable pH or inadequate solubility)?
the medication desired?
5 Were all calculations and measurements
confirmed to ensure that the preparation will These questions are important in the selection
be compounded accurately?1 of a suppository base, which is also dependent
When compounding suppositories, the com- upon a number of physicochemical variables,
pounder generally prepares an excess amount of including the characteristics of the drug, the base,
total formulation to allow the prescribed quantity and other excipients that are present.
105
106 Suppositories
Rate of drug release support bacterial/fungal growth, requiring the

addition of bacteriostatic agents. Furthermore, if
The rate of drug release is an important factor in the water evaporates, the dissolved substances
the selection of a suppository base. If a drug does may crystallize and possibly become irritating
not release its medication within 6 hours, the upon insertion.
patient may not receive its full benefit, as the drug
remaining in the suppository may be expelled.
Thus, among the factors that must be considered Hygroscopicity
in the selection of a suppository base is the
drug’s solubility. One way to ensure maximum Glycerin and PEG-containing suppositories are
release of the drug from the base is to apply the hygroscopic. The rate of moisture change is
principle of opposite characteristics. This means dependent on the chain length of the molecule as
that water-soluble drugs should be placed in oil- well as the temperature and humidity of the en-
soluble bases while oil-soluble drugs should be vironment. PEGs with molecular weights greater
placed in water-soluble bases. Oil-soluble bases than 4000 have less tendency to be hygroscopic
(e.g. cocoa butter) melt quickly in the rectum than lower weight PEGs.
to release the drug, whereas PEG bases must
dissolve in mucosal fluids, a process that may
take longer. If PEGs with a higher molecular Viscosity
weight are used, the dissolution time is extended.
Moistening the suppositories with warm water Viscosity considerations are also important in the
immediately before insertion facilitates not only preparation of the suppositories and in control-
insertion but also dissolution. ling the rate of release of the drug. If the viscosity
The release of the drug and the onset of drug of a base is low, it may be necessary to add
action are thus dependent on the liquefaction of a suspending agent such as silica gel to ensure
the suppository base, the dissolution of the active that the drug is uniformly dispersed until solidi-
drug, and the diffusion of the drug through the fication occurs. When preparing the suppository,
mucosal layers. For example, the time for lique- the pharmacist should stir the melt constantly
faction of a hydrogenated vegetable oil- or cocoa and keep it at the lowest possible temperature to
butter-based suppository is approximately 3–7 maintain a high viscosity. After the suppository
minutes; for a glycerinated gelatin suppository has been administered, the release rate of the drug
about 30–40 minutes; and for a PEG suppository may be slowed if the viscosity of the base is very
about 30–50 minutes.2 high.
Apart from drug release rates, other fac- To increase the viscosity of a fatty base, the
tors to be considered include the presence pharmacist can increase the fatty acid chain
of water, hygroscopicity, viscosity, brittleness, length of compounds in the base by adding
density, volume contraction, special prob- C-16 and C-18 mono- and diglycerides. Other
lems, incompatibilities, pharmacokinetics, and approaches involve adding cetyl, stearyl and
bioequivalence. myristyl alcohols, and stearic acid in concentra-
tions of about 5%, or adding about 2% aluminum
monostearate.
Presence of water
Brittleness
When preparing suppositories, the pharmacist
should avoid using water to incorporate an Brittle suppositories can be difficult to handle,
active drug. Water may accelerate the oxida- wrap, and use. Cocoa butter suppositories are
tion of fat, increase the degradation rate of usually not brittle unless the percentage of
many drugs, enhance reactions between the drug solids present is high. In general, brittleness re-
and other components in the suppository, and sults when the percentage of non-base materials
Chapter 7 • Compounding suppositories 107
exceeds about 30%. Synthetic fat bases with this cooling process, the melt has a tendency to
high stearate concentrations or those that are contract in size. Although this makes it easier to
highly hydrogenated are typically more brittle. release the suppository from the mold, it may
Shock cooling also causes fat and cocoa butter also produce a cavity at the back, or open end,
suppositories to crack. This condition can be of the mold. Such a cavity is undesirable and can
prevented by ensuring that the temperature of be prevented if the melt is permitted to approach
the mold is as close to the temperature of the its congealing temperature immediately before it
melted base as possible. Suppositories should not is poured into the mold. It is advisable to pour
be placed in a freezer, which also causes shock a small amount of excess melt at the open end
cooling. The addition of a small quantity (usually of the mold to allow for the slight contraction
less than 2%) of Tween 80, Tween 85, fatty acid during cooling. Scraping with a blade or spatula
monoglycerides, castor oil, glycerin, or propylene dipped in warm water will remove the excess
glycol will make these bases more pliable and less after solidification, but care must be taken not
brittle.3 to remove the metal from the mold. The heated
instrument can also be used to smooth out the
back of the suppository.3
Density
To control the weight of individual supposi-

Bases
tories it is important to know the density of
the incorporated materials. For example, if the
density of the insoluble powders is too great, the As discussed in Chapter 3, a suppository base
suspended materials will have a tendency to settle should be stable, non-irritating, chemically and
and stratify in the molds. This results in a poor physiologically inert, compatible with a variety of
appearance and possibly a brittle suppository. drugs, capable of melting or dissolving in rectal
In general, when the quantity of the active fluids, stable during storage, not binding or oth-
drug is less than 100 mg, the volume occupied erwise interfering with the release or absorption
by the powder is insignificant and need not of drug substances, and esthetically acceptable.
be considered. This is usually based on a mold Other desirable characteristics depend upon the
yielding a 2 g suppository. Obviously, if a sup- drugs to be added. For example, higher melting
pository mold weighing less than 2 g is used, or point bases can be selected for incorporating
if the quantity of the active drug to be added is drugs that generally lower the melting points of
greater than 100 mg, the powder volume should the base (e.g. camphor, chloral hydrate, menthol,
be considered. The pharmacist should obtain the phenol, thymol, and volatile oils) or when formu-
density factors of various bases and drugs to lating suppositories for use in tropical climates.
determine the proper weights of ingredients to Lower melting point bases can be used when
be used. The density factors of cocoa butter are adding materials that will raise the melting points
known. For other bases, the density factor can be or if adding large amounts of solids.
calculated as the ratio of the blank weight of the
base and the cocoa butter. Density factors for a
number of ingredients are listed in Appendix 4. Oil-soluble bases
Oil-soluble bases have been extensively used

Volume contraction in the past, especially cocoa butter. Due to
physical changes that may occur with cocoa
Bases, excipients, and active ingredients generally butter (polymorphism), many additional oil-
occupy less space at lower temperatures than soluble bases have been introduced that have
at higher temperatures. When preparing a sup- characteristics similar to cocoa butter without
pository, the pharmacist pours hot melt into the disadvantages. Most of these bases will melt
a mold and allows the melt to cool. During at body temperature after the suppository has
108 Suppositories
been administered. The “pool” of immiscible oily Preparation by hand rolling and shaping
liquid may have a tendency to “leak” from the
closest orifice; consequently, these suppositories With the ready availability of suppository molds
may be a little messy compared with the water- accommodating different shapes and sizes, there
soluble bases. Many of the newer oil-soluble bases is little requirement for today’s pharmacist to
contain surfactants that help them to spread after shape suppositories by hand. Hand rolling and
administration, so leakage may not be as much shaping is a historic part of the art of the
of a problem. Some bases are derived from palm, pharmacist; a description of the method may be
palm kernel, and coconut oils, with additional found in pharmacy compounding texts.3
ingredients to make them emulsifiable and easier Hand molding requires considerable skill but
to manipulate. enables one to avoid using heat while preparing
the suppository, since this technique generally
uses cocoa butter, which can easily be manipu-
Water-soluble bases
lated, shaped, and handled at room temperature.
Hand molding involves grating the cocoa butter,
The use of water-soluble bases may result in some
adding the active ingredient, mixing thoroughly
irritation because, as they take up water and
using either a mortar and pestle or a pill tile
dissolve, they may produce slight dehydration
and spatula, pressing the mix together until it
of the rectal mucosa. They are widely used,
resolidifies, shaping the mixture into a long cylin-
however, and release the drug by dissolving and
der with a diameter the size of the suppository
mixing with the aqueous body fluids.
to be prepared, cutting into the desired length,
rounding the tip(s), packaging, and labeling.
Glycerin bases Plastic gloves should be worn when forming the
suppository; it is also advisable to work through a
Glycerinated gelatin suppositories, composed of filter paper or to use corn starch or talc to reduce
70% glycerin, 20% gelatin and 10% water, should the tackiness of the cocoa butter.
be packaged in tight containers as they are
hygroscopic. Even though they have been used Preparation by molding (fusion)
occasionally, they are not recommended as a
rectal suppository base as they may exert an Basically, the steps in molding (fusion) include (a)
osmotic effect and stimulate a defecation reflex. melting the base, (b) incorporating the required
Glycerin base is now composed of glycerin (91%), medicaments, (c) pouring the melt into molds,
sodium stearate (4%), and purified water (5%). (d) allowing the melt to cool and congeal into
These bases have occasionally been used for the suppositories, and (e) removing the formed sup-
preparation of vaginal suppositories. Glycerin positories from the mold. Suppositories of cocoa
suppositories are still commonly used for their butter, glycerinated gelatin, PEG, and most other
laxative effect. suppository bases are suitable for preparation by
molding.
When using the fusion method, the pharma-
Preparation cist gently heats the base material and then mixes
in the active ingredients and any excipients. The
melt is then poured into the molds (metal or
There are three methods of preparing a suppos- disposable plastic or rubber) and allowed to cool.
itory: hand molding, fusion (molding from a After cooling, the suppositories are trimmed,
melt), and compression. The method most fre- packaged, and labeled.
quently employed in the preparation of supposi-
tories both on a small scale and on an industrial
Selection and preparation of mold
scale is molding. In all cases, powders to be
incorporated into suppositories should generally Suppositories have historically been prepared
be in an impalpable form. using paper cones, metal molds, or by hand
Figure 7.1 A hand-operated compression mold.
shaping.3 Metal suppository molds of pewter and single operation (Figures 7.1 and 7.2). Industrial
tin were introduced into commerce in about molds produce hundreds of suppositories from a
1860. The individual molds were held in place single batch.
in a special lid that was lowered into the bottom Molds in common use today are made from
portion of the mold that contained cold water or stainless steel, aluminum, brass, or soft or hard
ice to chill and harden the suppository. plastic. They separate into sections, generally lon-
Later, two-piece suppository molds were in- gitudinally, are opened for cleaning before and
troduced, which simplified the process. By 1875, after the preparation of a batch of suppositories,
there were over 20 different molds in use (Figures closed when the melt is poured, and opened
7.1 and 7.2) and by 1895, machines were widely again to remove the cold, molded suppositories.
used, although these differed from the earlier Care must be exercised in cleaning the molds, as
molds in that they utilized the technique of cold any scratches on the molding surfaces will detract
compression. from the desired smoothness of the resulting
A range of suppository molds are available suppositories. Plastic molds are especially prone
commercially and are designed to produce indi- to scratching.
vidual or large numbers of suppositories of vari- Although satisfactory reusable and disposable
ous shapes and sizes. Individual plastic supposi- molds are commercially available for the prepara-
tory molds may be used to form a single supposi- tion of rectal, vaginal, and urethral suppositories,
tory; other molds, such as those most commonly if necessary in the extemporaneous preparation
found in the community pharmacy, are capable of suppositories, temporary molds may be suc-
of producing 6, 12, or more suppositories in a cessfully formed by pressing heavy aluminum
110 Suppositories
Changeable
mold
Piston Wheel
Movable
plate
Cylinder
Base
Cavity
Hole for escape of
excess material
Rectal mold Vaginal mold
End views
Basic suppository machine with changeable molds for the compression method.
Figure 7.2 Diagram of a larger hand compression mold.
foil about an object having the shape of the butter or PEG, as these materials contract suffi-
desired suppository, then carefully removing the ciently on cooling within the mold to separate
object, and filling the shaped foil with the melt. from the inner surfaces and allow their easy
For instance, glass stirring rods may be used to removal. Lubrication is usually necessary when
form molds for urethral suppositories, cylindrical glycerinated gelatin suppositories are prepared.
pencils or pens may be used to form molds for A thin coating of mineral oil applied with the
rectal suppositories, and any cone-shaped object finger to the mold surfaces is usually enough to
may be used to form vaginal suppositories.3 provide the necessary lubrication. It should be
Disposable molds, such as the suppository stressed, however, that any materials that might
strips and shells shown in Figure 7.3, can be used cause irritation to the mucous membranes should
for molding and dispensing suppositories. not be employed as a mold lubricant.
A straw or thin glass tube can be used as A proposed formula for a mold lubricant
the mold when preparing urethral suppositories. was provided by Wooley and Forrester in 1929,
A 1 mL tuberculin syringe can also be used if consisting of castor oil (1 part), hard soap (2
the lower portion of the barrel is cut off (a parts), alcohol (18 parts), and water (2 parts).4
pencil sharpener works well for this) (Figure 7.4).
The urethral suppository can be removed from
the syringe barrel by inserting the plunger and
Calibration of the mold
forcing out the suppository after slight warming.
A large-diameter needle, attached to the syringe Each individual mold is capable of holding a
filled with the suppository melt, will aid in specific volume of material in each of its open-
transferring the product into the syringe. ings. If the material is cocoa butter, the weight
of the resulting suppositories will differ from
the weight of suppositories prepared in the same
Lubrication of the mold
mold with a mixture of PEGs as the base because
Depending on the formulation, suppository of the difference in the densities of the materials.
molds may require lubrication before the melt is Similarly, any added medicinal agent will further
poured to facilitate the clean and easy removal of alter the densities of the bases, and the weights of
the molded suppositories. Lubrication is seldom the resulting suppositories will be different from
necessary when the suppository base is cocoa those prepared with base material alone.
(a) (c )
(b)
( d)
Figure 7.3 Disposable molds: suppository strips and shells. (a) Plastic suppository strip molds in holder to be filled. Photo
courtesy of Gallipot, Inc., St. Paul, MN. (b) Plastic suppository strip molds in holder ready to be filled. Photo courtesy of
Gallipot, Inc., St. Paul, MN. (c) Clear plastic strip suppository molds available as a coil in a carton. Photo courtesy of
Gallipot, Inc., St. Paul, MN. (d) White opaque plastic suppository molds available as a coil. Photo courtesy of Gallipot,
Inc., St. Paul, MN.
The pharmacist should calibrate each supposi- the melt determined for the total number as well
tory mold for the suppository bases that are used as for the average of one suppository.
(usually cocoa butter and a PEG base) in order to In method 2, which is used for fusion or cold
prepare medicated suppositories with the proper compression, blanks must be prepared in order to
quantity of medicaments. calibrate the molds. The steps are as follows:
Two methods are used for calibration. In
method 1, the first step is to prepare molded 1 Prepare the suppository molds and confirm
suppositories from base material alone. After that the cavities are clean and dry.
removal from the mold, the suppositories are 2 Obtain and melt sufficient suppository base to
weighed, and the total weight and the average fill 6–12 molds.
weight of each suppository are recorded (for the 3 Pour the base into the molds, cool, and trim.
particular base used). To determine the volume 4 Remove the suppositories and weigh.
of the mold, the suppositories are then carefully 5 Divide the total weight by the number of blank
melted in a calibrated beaker, and the volume of suppositories prepared to obtain the average
112 Suppositories
must be certain that the required amount of

drug is provided in each suppository. Because
the volume of the mold is known (from the
1
determined volume of the melted suppositories
2
3
formed from the base), the volume of the drug
4
substances subtracted from the total volume of
5 the mold will give the volume of base required.
6 In instances in which the added amounts of
7 medicaments are slight, they may be considered
8 to be negligible, and no deduction from the
9 total volume of base may be deemed necessary.
B- 10
However, if considerable quantities of substances
D
are to be incorporated into the suppository, the
volumes of these materials are important and
should be used to calculate the amount of base
actually required to fill the mold completely.
The total volumes of these materials are sub-
tracted from the volume of the mold, and the
appropriate amount of base is added. Because the
suppository bases are solids at room temperature,
the volume of base determined may be converted
to weight from the density of the material. For
Figure 7.4 Syringe (1 mL) modified for urethral supposito-
example, if 12 mL of cocoa butter are required to
ries.
fill a suppository mold, and if the medicaments
in the formula have a collective volume of
weight of each suppository for this particular 2.8 mL, then 9.2 mL of the cocoa butter will be
base. required. By multiplying 9.2 mL by the density
6 Use this weight as the calibrated value for of cocoa butter, 0.86 g/mL, it may be calculated
that specific mold using that specific lot of that 7.9 g of cocoa butter will be required. Af-
suppository base. ter adjusting for the preparation of an extra
suppository or two, the calculated amount is
weighed.
An alternative method for the determination
Determination of the amount of base
of the amount of base in the preparation of
required
medicated suppositories requires the following
In the prescriptions for medicated suppositories steps:
to be prepared extemporaneously by the phar-
1 Weigh the active ingredient for the prepara-
macist, the prescribing physician indicates the
tion of a single suppository.
amount of a medicinal substance desired in each
2 Dissolve it or mix it (depending on its solubil-
suppository, but leaves the amount of base to the
ity in the base) with a portion of melted base
discretion of the pharmacist. Generally, in filling
insufficient to fill one cavity of the mold, and
such prescriptions, the pharmacist calculates the
add the mixture to a cavity.
amount of material needed for the preparation
3 Add additional melted base to the cavity to fill
of one or two more suppositories than the num-
it completely.
ber prescribed to compensate for the inevitable
4 Allow the suppository to congeal and harden.
loss of some material and to ensure having
5 Trim and remove the suppository from the
enough material to prepare the last required
mold and weigh it.
suppository.
In determining the amount of base to be incor- The weight of the active ingredients present,
porated with the medicaments, the pharmacist subtracted from the weight of the suppository,
yields the weight of the amount of base used. excessively. Rather, they should be heated gently
This amount of base multiplied by the number to just a few degrees above their melting range.
of suppositories to be prepared in the mold is the PEG suppositories do not depend on body
total amount of base required. temperature to melt them but rather dissolve
A third method involves the placing of all of slowly in the body’s fluids. This means that the
the required medicaments for the preparation of base need not be formulated to melt at body
the total number of suppositories (including one temperature and it is possible, in fact routine,
extra) in a calibrated beaker. To this is added a to prepare suppositories from PEG mixtures with
portion of the melted base and the drug sub- melting points considerably higher than that of
stances incorporated. Then sufficient additional body temperature. This property not only permits
melted base is added until the volume of mixture a slower release of the medication from the base
is reached that is required for the preparation of once the suppository has been inserted, but it
the necessary suppositories, based on the original also makes it possible to store these suppositories
calibration of the volume of the mold. without refrigeration and without danger of their
softening excessively in warm weather. Their
solid nature also permits them to be inserted
slowly without the fear that they will melt
Preparing the base
in the fingertips (as cocoa butter suppositories
Using the least possible heat, the weighed sup- sometimes do). Because they do not melt at body
pository base material is melted, generally over temperature, but mix with mucous secretions
a water bath. A porcelain casserole, which is a upon their dissolution, PEG-based suppositories
dish having a pouring lip and a handle, works as do not “leak” from the orifice as do many cocoa
well as a beaker with insulation on its outer walls butter-based suppositories.
since it permits the convenient pouring of the If PEG suppositories do not contain at least
melt into the cavities of the mold. Medicinal sub- 20% water to avoid the irritation of the mu-
stances are usually incorporated into a portion of cous membranes after insertion, they should be
the melted base by mixing on a glass or porcelain dipped in water just before use.3 This prevents
tile with a spatula. After incorporation, this moisture being drawn from the tissues after inser-
material is added with stirring to the remaining tion and the “stinging” sensation this produces.
base, which has been allowed to cool almost to
its congealing point. Any volatile materials or
heat-labile substances should be incorporated at
Preparing the active drug
this point with thorough stirring.
The precise method of preparation will depend The active drug should be comminuted to a
on the base being used. For cocoa butter it is uniform, small particle size to ensure that it is
necessary to grate it for either hand molding distributed evenly throughout the base and to
or fusion. Care must be taken not to exceed a minimize settling in the melt. This is especially
temperature of about 34–35◦ C to prevent the true if the source of drug is from a capsule or
formation of an unstable polymorph. In such tablet. Powders should be passed at least through
a case, an ␣ form might result, which would a 60 mesh sieve. Any powder remaining on
produce a suppository with a low melting point the sieve should be comminuted until it passes
that would melt at room temperature and may through the sieve.
stick to the mold. Cocoa butter should be melted The best source of ingredients for the extem-
to form a mixable, pourable liquid that is creamy poraneous compounding of suppositories is the
but hazy in appearance; it should not be melted pure drug powder. If pure powder is unavailable,
to a clear yellow state.3 commercial dosage forms such as injections,
PEG bases can be melted using either a water tablets, or capsules can be used. If any excipients
bath or direct heat to a temperature of approx- are present in these dosage forms, however, they
imately 55–60◦ C. Even though PEG bases are may affect the physicochemical properties and
very heat stable, they should not be heated stability of the finished product. In many cases,
114 Suppositories
depending on the solubility of the drug and the that they have a tendency to settle, constant
excipients, it may be possible to first mix the stirring, even during pouring, is essential, oth-
dosage form with a solvent (alcohol 95%), and erwise the last filled cavity will contain a dis-
then filter, collect the filtrate, dry, and use the proportionate share of the undissolved materials.
resulting active drug powder. The solid materials will remain suspended if the
In general, the maximum quantity of excipi- pouring is performed just above the congealing
ent that can be incorporated is about 30% of the point but if the base is too fluid the solids may
blank weight of the suppository. For example, for settle within the cavity of the mold and end
a 2 mL disposable mold, the maximum excipient up residing at the tips of the suppositories, with
would be about 600 mg.3 the result that the suppositories may break when
Liquids may occupy too much volume to be removed from the mold. A small quantity of silica
easily incorporated, and the vehicles may not gel (about 25 mg per suppository) incorporated
be compatible with selected suppository bases. into the formula will help to keep the active drug
Tablets and capsules may contain excessive pow- suspended.
der, which could produce suppositories that are In filling each suppository cavity, the pour-
too brittle. Adding a large quantity of liquid ing must be continuous to prevent layering,
to an oily suppository base may require the which may lead to a product easily broken on
preparation of a water-in-oil emulsion. This can handling, and pouring should not be stopped
be done by incorporating 10% wool fat or 2% until all the molds have been filled (Figures
cholesterol with up to 15% aqueous solution in 7.5 to 7.8). To ensure a completely filled mold
cocoa butter, or by using one of the modern upon congealing, excess melt is poured over each
triglyceride vegetable oil bases such as Fattibase, opening, actually rising above the level of the
Wecobee, or Witepsol.3 In the case of PEG bases, mold. This excess material may actually form a
a higher percentage of the higher molecular continuous ribbon along the top of the mold
weight PEGs can be used to accommodate the above the cavities, which prevents the formation
liquid. of recessed dips in the ends of the suppositories
and justifies the preparation of extra suppository
melt. When solidified, the excess material can
Mixing be scraped off of the top of the mold with a
spatula.
The drug is either mixed directly into the base or
Sometimes a 10 mL syringe can be used to
“wetted” prior to incorporation. A stirring rod or
fill the molds as long as the melt does not cool
a magnetic stirring setup can be used for mixing.
too rapidly. If disposable molds are used, PEG
The mixing process should be long enough to
melts should be poured at the lowest possible
distribute the drug uniformly but not so long as
temperature, since some molds may collapse at
to lead to drug or base deterioration.
about 70◦ C. If the melt is poured at around
60◦ C, such a collapse should not occur. Other
bases should be kept near their respective melting
Preparing and pouring the melt
temperatures.
Molds should be clean and dry at the start, After pouring, the mold is usually placed in
and equilibrated to room temperature before the refrigerator to hasten the hardening of the
pouring. A cold or frozen mold should never be suppositories.3 When they are hard, the mold
used because it can cause fractures and fissures is removed from the refrigerator and allowed to
throughout the suppository. The melted base come to room temperature. Then the sections of
and incorporated material is poured carefully and the mold are separated, and the suppositories are
continuously into each cavity of the mold, start- dislodged with pressure being exerted principally
ing at one end of the mold and ensuring that no on their ends and only if needed on the tips. In
air bubbles are incorporated into the suppository. general little pressure, if any, is required, and the
If any undissolved or suspended materials in the suppositories simply fall out of the mold when it
mixture are of greater density than the base, so is opened.
(a) ( d)
(b) (e )
(c) (f)
Figure 7.5 (a) Armstrong suppository mold. Photo courtesy of Professional Compounding Centers of America, Houston,
TX. (b) Aluminium and brass suppository molds for compounding 6 or 12 suppositories. Photo courtesy of Professional
Compounding Centers of America, Houston, TX. (c) Brass suppository mold (Hinge-type: open). Photo courtesy of
Professional Compounding Centers of America, Houston, TX. (d) Brass suppository mold (Hinge-type: open). Photo courtesy
of Professional Compounding Centers of America, Houston, TX. (e) Brass suppository mold (Hinge-type: closed). Photo
courtesy of Professional Compounding Centers of America, Houston, TX. (f) Top view of brass suppository mold. Photo
courtesy of Professional Compounding Centers of America, Houston, TX.
116 Suppositories
Figure 7.6 Urethral suppository mold. Photo courtesy of

Gallipot, Inc., St. Paul, MN.
Cooling and finishing

Figure 7.7 Filling plastic suppository molds held in a
After pouring, the molds should be allowed to set holder using a manual filling device. Photo courtesy of
for 15–30 minutes at room temperature followed Gallipot, Inc., St. Paul, MN.
by placing in a refrigerator for an additional 30
minutes. Any excess material can be removed paste-like consistency. On a small scale, a mortar
from the top of the mold (the back of the and pestle may be used. If the mortar is heated
suppository) with the blade of a stainless steel in warm water before use and then dried, the
spatula, which has first been dipped in a beaker softening of the base and the mixing process are
of warm water. Removing this excess will give the greatly facilitated. On a large scale, mechanically
back of the suppository a nice smooth surface. A operated kneading mixers and a warmed mixing
razor blade also works well. vessel are generally used.3
The suppositories should then be carefully The process of compression is especially
removed from the molds, packaged, and labeled. suited for the making of suppositories containing
If the mold is still cool, the suppositories should medicinal substances that are heat labile and for
be slightly contracted, which will make re- suppositories containing a large proportion of
moval easier. Wrapping the individual supposi- substances insoluble in the base. In contrast to
tories with foil wrappers, though not necessary, the molding method, there is no likelihood of
presents an elegant product to the patient.3 If insoluble matter settling during the preparation
plastic molds are used, they can be heat-sealed. of suppositories by compression. The disadvan-
tage to the process is that the special suppository
machine is required and there is some limitation
as to the shapes of suppositories that can be made
Preparation by compression
from the available molds.3
To prepare suppositories with a compression
Suppositories may be prepared by forcing the machine (Figures 7.1 and 7.2), the suppository
mixed mass of the suppository base and mass is placed into a cylinder which is then
the medicaments into special molds using closed, and pressure is applied from one end,
suppository-making machines. In preparation for mechanically, or by turning a wheel, and the
compression into the molds, the suppository mass is forced out of the other end into the
base and the other formulative ingredients are suppository mold or die. When the die is filled
combined by thorough mixing, the friction of with the mass, a movable end plate at the
the process causing the base to soften into a back of the die is removed and when additional
Figure 7.8 Compounding suppositories: filling a suppository shell. Photo courtesy of Professional Compounding Centers
of America, Houston, TX.
pressure is applied to the mass in the cylinder, the Hard, crystalline materials, such as salts, can be
formed suppositories are ejected. The end plate is incorporated either by pulverizing them to a fine
returned, and the process is repeated until all of state, or by dissolving them in a small quantity of
the suppository mass has been used. Various sizes solvent, which is then taken up into the base. An
and shapes of dies are available. It is possible to aqueous solvent and a PEG base are appropriate
prepare suppositories of uniform circumference for water-soluble materials. Alternatively, if the
by extrusion through a perforated plate and by material is water soluble and an oily base must
cutting the extruded mass to the desired length. be used, wool fat could be used to take up the
solution for incorporation into the suppository
base.
When liquid ingredients are mixed with an
inert powder such as starch, they become less
Special problems
fluid, which makes them easier to handle. The
suppository produced will thus hold together
Some active drugs are more difficult to in- better.
corporate into a base and require additional There are several ways of incorporating ex-
preparation steps. For example, vegetable extracts cess powder into a suppository base, depending
sometimes need to be moistened by levigation on the base used. If the base is oil miscible,
with a small amount of melted base. This makes a few drops of a bland oil such as mineral
it easier to distribute the active drug throughout oil can be added. When excess powder is in-
the base. corporated into water-soluble bases, the ratio
118 Suppositories
Box 7.1 Helpful hints in compounding suppositories
r A 10% overage of materials should be calculated

to allow for loss during preparation and overpour-
ing.
r If disposable molds are not marked with filling
lines, the extent of fill should be determined from
the blank.
r If using plastic disposable molds, the temperature
of the melt must be lower than that which will melt
or soften the mold.
r A constant-temperature dry bath filled with sand
set at 37◦ C provides the proper temperature for
softening and melting fatty acid and cocoa butter
bases in a short time.
r Vegetable extracts, moistened by levigation with
a small quantity of melted base, will more readily
distribute the active drug throughout the base.
r A large quantity of powder will be easier to
incorporate into some bases if dampened with
a few drops of a bland oil, such as mineral oil,
or a water-miscible liquid, such as glycerin. Figure 7.9 Compounding suppositories: Preparing a dou-
r Liquid ingredients will be thicker and easier to ble cast suppository.
incorporate into a base if mixed with a powder
such as starch.
r Splitting or halving the suppository is not recom- stored or dispensed in a polystyrene prescription
mended, as the quantity of medication may not vial, as the PEG will adversely interact with
be evenly distributed. polystyrene. All PEG suppositories should be
dispensed in glass or cardboard containers.3
Triglyceride-type bases can sometimes accept
up to about 50% glycerin without much diffi-
of low to high melting point ingredients can culty. In some cases, 10% paraffin wax or light
be varied. For example, since additional pow- magnesium carbonate can be suspended in the
ders will make the suppository harder, using suppository base before the addition of glycerin
a higher percentage of a low-molecular-weight to aid incorporation. Semi-solid extracts can be
PEG would result in a suppository of the proper added at the lowest possible working tempera-
character.3 ture. Some may be dissolved in water or solidified
A number of ingredients are incompatible with Aerosil (colloidal silicon dioxide) prior to
with PEG bases and can cause problems with incorporation. Fluid extracts can be incorporated
solidification, softening, breakage, cracking, etc. at about 35–38◦ C into an emulsifiable triglyceride
These include benzocaine, iodochlorhydroxy- base. Ichthammol and Peru Balsam can be mixed
quin, sulfonamides, ichthammol, aspirin, silver with an equal amount of castor oil prior to incor-
salts, and tannic acid. Other materials reported to poration. Essential oils can be incorporated with-
have a tendency to crystallize out of PEG include out difficulty in small amounts. Larger amounts
sodium barbital, salicylic acid, and camphor. may lower the melting point of the suppository,
It should also be remembered that PEG-based making it necessary to start with a higher melt-
suppositories may be irritating to some patients. ing point base. Due to the volatile nature of
Suppositories prepared with PEG should not be the essential oils, they must be incorporated at
the lowest possible temperature. Inert materials, improved bases and packaging, compounding
such as lactose, magnesium carbonate, or highly of rectal, vaginal and urethral suppositories is
dispersed silicon dioxide, can be used to sorb the now done routinely in pharmacies, especially
essential oils prior to incorporation. Lipophilic for patients needing individualized medications.
drugs with melting points higher than that of The most common method currently used is the
the base can be incorporated by suspending these fusion (heat) method with disposable molds that
drugs in PEG 200–400 to a total amount of about also serve as the package dispensed to the patient.
10%, based on the amount of triglyceride base
used. Fat bloom that sometimes occurs on the
surface of suppositories can be minimized by the
addition of lecithin to the suppository base. References
In the event of incompatible ingredients it
may be appropriate to prepare these suppositories 1. USP-Pharmacists Pharmacopeia, Chapter 795 Phar-
using a double cast method (Figure 7.9). One maceutical compounding practices. Rockville MD:
troublesome ingredient can be prepared as a US Pharmacopeial Convention, Inc, 2005: 411.
melt and poured first, followed by the second
2. Cohen LJ, Lieberman HA. Suppositories. In:
troublesome ingredient that is prepared as a melt
Lachman L, Lieberman HA, Kanig JL, eds.
and poured second. This keeps the ingredients
The Theory and Practice of Industrial Pharmacy,
separate. 3rd edn. Philadelphia: Lea and Febiger 1986:
564–588.
3. Allen Jr LV. The Art, Science and Technol-

Summary ogy of Pharmaceutical Compounding. Washington
DC. American Pharmacists Association, 2002:
Extemporaneous compounding of suppositories 189–211.
has been done by pharmacists for hundreds of 4. Wooley SW, Forrester GP. Pharmaceutical Formula-
years. With new technology, modern equipment, tions, 10th edn, Vol. I. London 1929: 537.
120
8
Special types of suppositories
Much work has been done in the development

of altered release suppository dosage forms. One Table 8.1 Examples of vaginal suppositories and
of the more popular types of suppositories for tablets
research purposes has been the hollow-type sup-
pository, which, although it is easy to prepare, Suppositories Clotrimazole
does have some difficulties. Miconazole
Many studies have investigated how to either Progesterone
enhance or slow down the release of the drug; the Semicid
latter seems to be more prevalent in the literature. Tablets Clotrimazole
Speeding up or slowing down the release and Nystatin
prolonging the action of the drug in suppositories
has been investigated using various coatings, (antibacterials). Nonoxynol-9, a spermicide, is
emulsions, hydrogels, layering, matrices of dif- employed for vaginal contraception. Estrogenic
ferent substances, nanoparticles, osmotic release, substances such as dienestrol are found in vaginal
micellar solutions, thermo-reversible liquids, preparations to restore the vaginal mucosa to its
xerogels and others. normal state.
The purpose of this chapter is to review the In the preparation of vaginal suppositories, the
different methods used by various investigators most commonly used base consists of combina-
around the world in preparing special types of tions of polyethylene glycols (PEGs) of various
suppositories. molecular weights. To this base is frequently
added surfactants and preservative agents, com-
monly the parabens. Many of the vaginal suppos-
Non-rectal suppositories – vaginal
itories and other types of vaginal dosage forms
suppositories
are buffered to an acid pH, usually around pH
4.5, which resembles that of the normal vagina.
Some examples of vaginal suppository and tablets This acidity discourages pathogenic organisms
are listed in Table 8.1. These preparations are and at the same time provides a favorable envi-
employed principally to combat infections occur- ronment for eventual recolonization by the acid-
ring in the female genitourinary area, to restore producing bacilli normally found in the vagina.
the vaginal mucosa to its normal state, and The PEG-based vaginal suppositories are water
for contraception. In combating vaginal infec- miscible and are generally sufficiently firm for
tions, the usual pathogenic organisms involved the patient to handle and insert without great
are Trichomonas vaginalis, Candida (Monilia) al- difficulty. However, to make the task even easier,
bicans or other species, and Hemophilus vagi- many manufacturers provide plastic insertion
nalis. Among the anti-infective agents found in devices with their products which are used to
commercial vaginal preparations are: nystatin, hold the suppository or vaginal tablet during
clotrimazole, butoconazole nitrate, terconazole, insertion for proper placement within the vagina
and miconazole (antifungals) and triple sul- (Figure 8.1).
fas, sulfanilamide, povidone-iodine, clindamycin Pharmacists are frequently called on to prepare
phosphate, metronidazole, and oxytetracycline progesterone vaginal suppositories. Formulas for
121
122 Suppositories
Table 8.2 Examples of formulas for progesterone

vaginal suppositories
Rx Progesterone, micronized q.s.

powder
PEG 400 60%
PEG 8000 40%
powder
PEG 1000 75%
PEG 3350 25%
powder
Cocoa butter 100%
a vaginal suppository product. She should first

be encouraged to read the patient instructions
included with the product. Throughout the entire
course of therapy, the suppository should be
inserted high into the vagina with the provided
applicator, if used. The patient should not discon-
tinue therapy when the symptoms abate. Further,
she should notify her physician if burning, irri-
tation, or any signs of an allergic reaction occur.
When vaginal inserts (i.e. compressed tablets) are
prescribed, the pharmacist should instruct the
woman to dip the tablet into water briefly before
insertion. Because these dosage forms are usually
administered at bedtime and can be somewhat
Figure 8.1 Plastic insertion devices used to hold the messy if formulated into an oleaginous base, it
suppository or vaginal tablet during insertion for proper is advisable to wear a sanitary napkin to protect
placement within the vagina. nightwear and bed linens.1
The controlled-release prostaglandin E2 (PGE2 )
the extemporaneous preparation of these suppos- pessary has been shown to produce predictable
itories are now quite routine and even appear in release of PGE2 both in vitro and in vivo. Its efficacy
the USP/NF. Micronized progesterone powder is has been demonstrated in a clinical trial designed
used in a base of PEG, although in some formulas to ripen the unfavorable cervix.2
cocoa butter is employed. The suppositories are Vaginal tablets are more widely used today
prepared by adding the progesterone to a melt than commercial vaginal suppositories; com-
of the base and molding. Some representative pounded vaginal suppositories are also very com-
formulas are shown in Table 8.2.1 monly used. From a manufacturing standpoint,
The amount of progesterone prescribed per the tablets are easier to manufacture, more stable,
suppository ranges from 25 to 600 mg. The sup- and less messy to handle in use. Vaginal tablets,
positories are used in treating luteal phase defect, frequently referred to as vaginal inserts, are
premenstrual syndrome, luteal phase spotting, usually ovoid in shape and are accompanied in
and in the preparation of the endometrium for their packaging by a plastic inserter, allowing for
implantation. easy placement of the tablet within the vagina
There are several helpful hints the pharmacist (Figure 8.1). Vaginal tablets contain the same
can share with a woman who is about to use types of anti-infective and hormonal substances
Chapter 8 • Special types of suppositories 123
as vaginal suppositories. They are prepared by and each system is individually foil-packaged.
tablet compression, and are commonly formu- The MUSE microsuppository is indicated for the
lated to contain lactose as the base or filler, a treatment of erectile dysfunction.3
disintegrating agent such as starch, a dispersing
agent such as polyvinylpyrrolidone, and a tablet
lubricant such as magnesium stearate. The tablets Controlled-release suppositories
are intended to disintegrate within the vagina,
releasing their medication. Examples of vaginal
The therapeutic efficacy of a once-daily
tablets are listed in Table 8.1.
mesalazine (Pentasa) controlled-release
Some vaginal inserts are capsules of gelatin
suppository was compared with placebo in a
containing medication to be released intravagi-
randomized trial. The results demonstrated that
nally. Capsule insertion into the vagina can be
once-a-day administration of a 1 g mesalazine
facilitated by first lightly wetting the capsule with
controlled-release suppository was effective for
water. Holes may be punched into these capsules
the topical treatment of patients with ulcerative
prior to moistening and insertion to facilitate
proctitis. There was a 69% remission based on
fluid movement into the capsule, if desired. Drugs
endoscopic findings and a 65% remission based
that do not dissolve rapidly and that are irritating
on clinical results. This was compared with 33%
to mucous membranes should not be placed in
remission based on endoscopic findings and
direct contact with such membranes. An example
25% remission based on clinical results of the
of a vaginally administered preparation would be
placebo-treated patients; no side-effects were
boric acid 600 mg capsules.
seen.4
A comparison of the bioavailability of mor-
phine from rectally administered controlled-
Non-rectal suppositories – urethral release 30 mg tablets (rectal MSC) and immediate-
suppositories release 30 mg rectal suppositories with oral ad-
ministration of 30 mg controlled-release oral
tablets (oral MSC) was undertaken. The area
Suppositories for urethral administration tend to
under the curve (AUC) value for the rectal MSCs
be thinner and tapered, often about 5 mm in
was 50.8% that of the rectal suppositories and
diameter and up to about 60 mm in length. They
was similar to that for oral MSCs (rectal MSC =
have been used in the treatment of localized
90% oral MSC). Rectal tablets had a significantly
infections and, more recently, a much smaller
delayed time to peak plasma level (5.4 vs 1.07 and
urethral suppository has been introduced for the
2.5 hours for rectal tablets vs rectal suppositories
administration of alprostadil in the treatment of
and oral tablets, respectively) and a significantly
erectile dysfunction.
attenuated time to maximum concentration (6.1
The MUSE (alprostadil) urethral microsuppos-
vs 25.4 and 9.7 ng/mL, respectively. The authors
itory (Vivus Inc., California, USA) is a single-use,
conclude that further studies must be done to
medicated transurethral system for the delivery
determine the therapeutic consequences of phar-
of alprostadil to the male urethra. The drug is
macokinetic differences and establish guidelines
suspended in a PEG 1450 excipient and is formed
for rectal tablet use.5
into a medicated pellet, or microsuppository,
measuring 1.4 mm in diameter by 3 mm or 6 mm
in length. Available strengths are 125, 250, 500,
Coated microsphere/microcapsule
and 1000 μg per unit. The microsuppository re-
suppositories
sides in the tip of a translucent hollow applicator,
and is administered by inserting the applicator
tip into the urethra after urination. The pellet Indometacin microspheres were prepared by the
is delivered by depressing the applicator button. solvent evaporation method using ethyl cellulose
The PEG 1450 vehicle dissolves in the available as the polymer. The highest loading capacity
fluid, releasing the drug. The applicator system was found to be a drug–polymer ratio of 1:1.
is composed of medical grade polypropylene, Characteristics studied involved shape, surface
124 Suppositories
characteristics, particle size, particle size distribu- A

tion, and preparation methods. In the next part B
of the study, sustained-release suppositories were
formulated using PEG mixtures (400:1500:4000)
and Witepsol H15. The release was studied using 9 mm
an in vitro dissolution method. Release rates up to
8 hours were obtained with these suppositories.6
Two additional studies have been reported 28 mm
on the preparation of sustained-release suppos-
itories; these contained microencapsulated in- 38 mm
dometacin and investigated the bioavailability
Figure 8.2 Example of hollow-type suppositories.
of indometacin sustained-release suppositories in
rabbits.7,8
In a study of the duration of the absorption-
enhancing effect of sodium octanoate, sodium
Emulsion and emulsion–gel hexanoate, and glyceryl-L-monooctanoate on
suppositories gentamicin using the hollow-type suppository in
rabbits, the authors found that there appeared
to be a lowering of the membrane transport
Kim and Ku reported a self-emulsifying system
barrier function for about 1 day after the ad-
(SES) consisting of a mixture of an oil and a
ministration of sodium octanoate or glyceryl-L-
surfactant which forms an oil-in-water emulsion.
monooctanoate.11
The SES was mixed with indometacin and was
The pharmacokinetics of morphine and its
placed into hollow-type gelatin suppositories.
glucuronides in plasma were studied after rec-
The surfactants studied included Tween 85 and
tal administration of hollow-type oleaginous
sorbitol trioleate, and ethyl oleate. The optimal
suppositories containing mixtures of morphine
formulation studied consisted of 30% Tween 85
hydrochloride, ␣-cyclodextrin, and/or xanthan
and 70% ethyl oleate. Upon rectal administration
gum in rabbits. The combination reduced the
to rats, there was a 41% increase in the AUC
first-pass metabolism of morphine in the rectal
compared with a standard indometacin suppos-
mucosa and by the liver and improved the
itory, suggesting that the new dosage form was
bioavailability of the drug about four-fold com-
effective.9
pared to standard morphine suppositories.12
An emulsion–gel suppository was prepared
The pharmacokinetics and pharmacodynam-
using polyvinyl alcohol (PVA) with a given cycle
ics of human chorionic gonadotropin (hCG) ad-
of freezing and thawing. An oil phase (Panacete
ministered rectally were studied using a hollow-
800) and emulsifying agents were used with an
type suppository. To enhance the rectal ab-
apparent emphasis on Pluronic L-44. The gel
sorption of hCG, the effectiveness of its co-
strength, drug release, and the effects of the
administration with ␣-cyclodextrin was investi-
degree of polymerization of PVA were studied.
gated in male rabbits. The results of this study
Drug release was compared with that of a con-
suggest that the hollow-type suppository as a
ventional suppository and the gel structure was
rectal delivery system of hCG is promising as a
examined using a scanning electron microscope.
new mode of hCG therapy.13
The system exhibited a zero-order release profile
Morphine sulfate suppositories were prepared
for both hydrophilic and hydrophobic drugs.10
(1) in an oleaginous base, (2) as a hollow-type
suppository containing a controlled-release mor-
phine tablet (MS Contin), and (3) as a hollow-
Hollow-type suppositories
type suppository containing morphine powder
packed in the hollow space. In vitro release tests
Hollow-type suppositories have been available for and in vivo rectal absorption experiments in
a number of years (Figure 8.2). rabbits were conducted. From this study, the
authors concluded that the administration of a acting effect and the authors concluded that it
hollow-type suppository packed with morphine should have useful clinical applications.17
sulfate powder and administered twice a day is Seven different types of suppositories were
effective as a treatment for cancer pain or surgery prepared using oleaginous base materials Witep-
due to its fast analgesic effect and sustained sol H15 and Witepsol E85. The different types
release up to about 12 hours.14 included a conventional suppository contain-
A study was carried out on the use of ing valproic acid (VPA) mixed with E85 [1],
sodium salicylate (SA) or sodium caprylate (CA) a conventional-type suppository containing the
as absorption-enhancing agents for gentamicin sodium salt of VPA (sodium valproate, S-VPA)
administered via hollow-type suppositories. Two mixed with H15 [2], hollow-type suppositories
types of hollow-type suppositories were used: a containing VPA in the forms of an oily liquid or
conventional one (type I) and a release-restricted free acid [3], macrogol 1000 or 6000 mixture [4
one (type II). Without either the SA or the CA, and 5], powder S-VPA [6] and an aqueous solution
there was no gentamicin absorption. However, of S-VPA in 0.9% sodium chloride solution [7] in
when either SA or CA was added, the bioavail- each cavity. Suppository [1] drug concentration
ability of gentamicin was 58% with SA and 59% was decreased due to its volatility and supposi-
with CA compared to a standard gentamicin tory [2] was hygroscopic; these were not practical.
suppository without the SA or CA. Further study The bioavailability of [3] was about 80%; the Cmax
was done on the type I suppository using SA and AUC values for [3] were lower than those of
or CA in solid or aqueous solution form with [4, 6, or 7]. Suppository [6] gave the highest peak
the gentamicin. The powdered gentamicin with plasma VPA concentrations and the mean AUC
SA or CA appeared to provide higher plasma value, indicating that S-VPA may be the form of
levels than when in solution form. The results choice.18
from this study suggested that the form and In a study of propranolol absorption from
concentration of the drug should not be ignored hollow-type suppositories, three kinds of suppos-
in evaluating the enhancing effects of SA or CA itories were prepared using oleaginous Witep-
on the rectal absorption of poorly soluble drugs sol H15: a conventional-type suppository con-
such as gentamicin.15 taining propranolol hydrochloride mixed with
Matsumoto et al. prepared hollow-type sup- the Witepsol H15, a hollow-type suppository
positories of gentamicin using Witepsol H15 containing the same drug in an aqueous solu-
alone, Witepsol H15 mixed with glyceryl- tion of isotonic sodium chloride in the hollow
L-monooctanoate, or glyceryl-L-monooctanoate cavity, and a hollow-type suppository contain-
alone. Without the glyceryl-L-monooctanoate, ing the drug as powder in its cavity. Rabbits
gentamicin was not absorbed from the rectum of were the model used and rectal administration
rabbits. However, with glyceryl-L-monooctanoate was compared with oral administration. It was
the absorption of gentamicin was enhanced in found that systemic availability was increased
both types of suppositories. It appeared that with rectal administration of the propranolol hy-
addition of 300 mg of glyceryl-L-monooctanoate drochloride hollow-type suppositories compared
per suppository was the optimum as there with the conventional suppository. The drug was
was no further increase in gentamicin absorp- absorbed more efficiently with the hollow-type
tion with increased quantities of glyceryl-L- suppositories containing the drug in solution
monooctanoate. This study demonstrated that or as a powder than with the conventional
glyceryl-L-monooctanoate can be used as an ef- suppository.19
fective enhancing agent for rectal absorption of The bioavailability of morphine hydrochlo-
gentamicin.16 ride (10 mg) contained in three different types
Nifedipine was incorporated into a hollow- of suppositories was evaluated in rabbits. The
type suppository. It was found to be as fast-acting suppositories were of Witepsol H15 and included
as the nifedipine soft capsule but produced a a conventional suppository containing morphine
lower blood concentration than the soft capsule. hydrochloride mixed with the base material, a
An advantage of the suppository was its longer- hollow-type suppository containing morphine
126 Suppositories
hydrochloride in an aqueous solution in its the permeation of morphine and the xanthan
cavity, and a hollow-type suppository contain- gum retarded the plasma morphine levels after
ing morphine hydrochloride as a powder in rectal administration. A combination of the
its cavity. The results demonstrated that the ␣-cyclodextrin and xanthan gum produced
hollow-type suppository containing powdered sustained plasma profiles of morphine along
morphine hydrochloride was a more effective with an increased rectal bioavailability of more
rectal dosage vehicle than the conventional than four times. It appears that the xanthan
suppository.20 gum also serves to prevent the upward spread
Hollow suppositories containing insulin were of the drug after rectal administration. This
evaluated in a study using insulin and five kinds formulation was found to be less irritating to
of cyclodextrins. The suppositories consisted of the rectal mucosa according to both gross and
those containing insulin and varying amounts microscopic observations.23
of each cyclodextrin, those containing cyclodex-
trins without insulin and those containing in-
sulin without cyclodextrins. The results demon-
strated that the cyclodextrins enhanced the effect Hydrogel suppositories
of rectally administered insulin as demonstrated
by an increase in the plasma insulin levels and Cole and co-workers developed a sustained-
a marked decrease in the plasma glucose levels. release monolithic morphine hydrogel supposi-
Chemically modified cyclodextrins (such as ␣, ␤, tory (MHS) prepared by polymerizing PEG 4000,
and ␥ cyclodextrins) had a greater effect than the 1,2,6-hexane triol, and dicyclohexylmethane 4,4
natural cyclodextrins.21 diisocyanate with anhydrous ferric chloride as
The absorption of both porcine and bovine a catalyst (Figure 8.3). The MHS was tested in
pancreas-derived insulin was studied in rabbits five volunteers and the suppositories delivered
when formulated into hollow-type suppositories an average of 55 mg of morphine over 12 hours
containing insulin and glyceryl-L-monooct- and provided an average plasma morphine con-
anoate as an absorption-enhancing agent. The centration of 15 ng/mL from 2 to 12 hours after
presence of the glyceryl-L-monooctanoate re-
sulted in enhanced absorption of insulin and
a decrease in plasma glucose using both types Hydrogel cap
of insulin. Similar results were obtained with
insulin in both an aqueous solution as well as
in a crystalline form.22
Uekama and co-workers made an attempt
Suppository wall
to optimize the rectal delivery of morphine thickness 1.5 mm
using hollow-type suppositories in combination
with ␣-cyclodextrin and a viscosity-increasing
polysaccharide. The morphine/cyclodextrin Central cavity 7 mm
complex was made, as an example, by mixing
morphine hydrochloride 10 or 50 mg with
Silastic button
␣-cyclodextrin 1 g and triturating with a small
quantity of water (1 mL). The slurry was kneaded
thoroughly for 30 minutes and then dried under
reduced pressure at room temperature for 2 days. Polyester withdrawal
The hollow cylinder suppositories were filled thread
with these powders and fused with the molten
Witepsol H15 base. The individual formulations
were prepared and loaded into a 38-mm long
Witepsol H15 hollow-type suppository. The
results showed that the ␣-cyclodextrin enhanced Figure 8.3 Drawing of a morphine hydrogel suppository.
administration, comparable to an oral dosage H15) and a slow-releasing base (Witepsol W35).
response. The authors conclude that the MHS By layering the two suppository bases, different
appears to be an effective means of deliver- release rates could be obtained. The authors
ing morphine in the management of chronic found there was a linear relationship between
pain.24 the in vitro release rate and the in vivo absorption
In another study the MHS was evaluated in rate for both the fast-releasing and the layered
two different configurations. The first configura- excipient suppositories.26
tion (MHS-B) provided a high initial release rate A double-layered sustained-release supposi-
followed by a constant release for the rest of the tory was prepared using progesterone for the
12-hour period. The second (MHS-S) provided treatment of luteal phase defect. Hydroxypropyl
the same constant release rate for 12 hours The cellulose and Carbopol 934 were used as bases for
concentration of morphine was designed to be the inner layer and Witepsol W35 was used as a
greatest at the outer and inner surfaces of the base for the outer layer. Crystalline cellulose was
suppository to provide a release profile closest also studied as an additive in the suppositories.
to that thought to be ideal. The hydrogels have It was suggested from the study that the release
characteristics that contribute to their use for of progesterone from the inner stick could be
sustained administration of drugs. They are bio- controlled by changing the rate of addition of the
logically inert and rehydration and drug release crystalline cellulose. Example suppositories were
are predictable. The drug concentration can be prepared with progesterone only in the stick and
varied to provide for different release rates. In with progesterone both in the stick and in the
fact, the dehydrated form can even be cut in base portion of the suppository. The suppository
half to modify the dose even more. The results with the progesterone only in the stick had about
of this study indicated that the MHS may be a 2-hour lag time. Both suppositories exhibited
of value in the management of postoperative sustained release of the progesterone.27
pain.25 Conventional suppositories, sustained-release
suppositories, and sustained-release two-layered
suppositories of theophylline were prepared us-
ing PEG 4000 and Eudragit RS-100. The conven-
Layered double or triple
tional suppositories released the drug relatively
suppositories
rapidly, the sustained-release matrix supposi-
tories released the drug gradually and over a
Suppositories can be prepared in multiple parts period of time, and the sustained-release two-
or layers by casting using two or three different layered suppositories produced an initial quick
types of excipients, and can even be colored release followed by an extended release of the
differently. This makes it possible to isolate theophylline.28
incompatible active ingredients from each other. A special type of suppository was designed
For example, a three-layer suppository can be to restrict drug absorption from suppositories to
prepared using a layer of the first active drug, the lower rectum only. It consisted of Witepsol
followed by a middle layer of a drug-free base, H15 as base with varying amounts of Carbopol
then a third layer of the second active drug. 934P and white beeswax; the model drug was
The disadvantage is, of course, that it makes lidocaine. The double-phased suppositories con-
the preparation most difficult to cast, requiring sisted of a front layer containing 10% Carbopol
three or even four different layers to be added; and 20% wax and a terminal layer containing
however, it can be done if necessary. Clearly, the lidocaine and various amounts of Carbopol. The
different layers must be stuck to each other firmly results from this study suggest that the double-
enough so they will not separate on handling or phased mucoadhesive suppositories suppress ini-
during administration. tial metabolism of lidocaine, and may be useful
Paracetamol availability from two different for improving the bioavailability of drugs, such as
suppository formulas was studied in eight health lidocaine, which experience extensive first-pass
volunteers using a fast-releasing base (Witepsol metabolism.29
128 Suppositories
Another study compared the pharmacokinet- the rectal absorption of acetaminophen without
ics of nifedipine after intravenous injection with reducing the AUC values. The authors concluded
rectal administration via conventional PEG 4000 that the use of solid fats with relatively high
suppositories and via double-layer sustained- melting points was possible to control the rate of
release suppositories in rabbits. Rectal absorption drug release from fatty base suppositories, thus
demonstrated about 62–80% bioavailability on prolonging plasma drug concentrations.33
average. Using the sustained-release supposito- Matrix-based slow release compressed propra-
ries, the mean absorption time was about six nolol HCl (25 mg) suppositories were formu-
times greater than that of the conventional sup- lated using PEG 4000 and either stearic acid or
pository. In summary, the dissolution process was beeswax at concentrations of 5, 7.5, and 10%. The
the rate-determining step in the sustained-release pharmacokinetics and pharmacodynamics were
suppository.30 evaluated in rabbits. The relative bioavailability
of propranolol was 86.4% (7.5%), 87.8% (10%),
and 83.6% (5%), respectively, and there was
good correlation between pharmacokinetic and
Matrix–agar suppositories pharmacodynamic profiles.34
The bioavailability of insulin embedded in an

agar matrix has been studied. When used in
suppositories, the embedding protected the in- Mucoadhesive suppositories
sulin and resulted in a significant retardation
in its release rate. The effects were followed The effects of sodium chloride and sodium phos-
visually by ␥ scintigraphic methods using phates on the physicochemical properties of in
131
I-insulin in the rectum and thyroid gland and
situ gelling and mucoadhesive liquid supposi-
correlation with the glucose-lowering effect, the
tory bases, gelation temperature, gel strength,
liberation, distribution, and bioavailability of the
and bioadhesive force of the liquid suppository
immobilized hormone.31,32
bases poloxamer 407 and 188 were evaluated.
The study involved solvents (ethanol, propylene
glycol, glycerin), ionic strength-controlling agent
(sodium chloride), and a pH-controlling agent
Matrix–wax suppositories
(hydrochloric acid, sodium monohydrogen phos-
phate, or sodium dihydrogen phosphate). The
The use of high-melting-point fats to produce sodium chloride, sodium monohydrogen phos-
sustained-release suppositories has been studied phate, and sodium dihydrogen phosphate greatly
using acetaminophen as a model drug. Solid increased the gel strength and bioadhesive force
fats such as polyglycerol ester of fatty acids of Poloxamer 407/Poloxamer 188 (15/15%) with
(PGEFs) or beeswax were utilized with Witepsol a decrease in gelation temperature. Glycerin
H15. PGEFs such as decaglycerol heptabehenate slightly reduced the gelation temperature and
(HB750), hexaglycerol pentastearate (PS500), and slightly increased the gel strength and bioadhe-
beeswax have relatively high melting points. sive force. However, the addition of 1% sodium
The addition of these PGEFs did not produce chloride, sodium monohydrogen phosphate, or
any large change in the melting point of the sodium dihydrogen phosphate caused a greater
Witepsol H15 but did produce an increase in than 60-fold increase in gel strength and over
the apparent viscosity of the suppository bases a 10-fold increase in bioadhesive force with a
at 37 ◦ C and it correlated with the amount of 2–4 ◦ C decrease in gelation temperature. This
each solid fat added to the mixed base. The indicates these agents may be useful in adjusting
release of acetaminophen was delayed by all the rigidity and tightness of the gel, its ability
three fats/waxes. Some formulations prolonged to adhere once placed in the body, and the
temperature at which the liquid will gel when compared with subjects taking an oral solution
placed in the body. However, ethanol, propy- of the drug on an empty stomach. In vitro
lene glycol, and hydrochloric acid increased the results showed a perfect zero-order release rate.
gelation temperature and slightly decreased the In all subjects, application of the osmotic system
gel strength and bioadhesive force. The authors resulted in a constant steady-state theophylline
conclude that sodium chloride and sodium phos- level similar to a long, zero-order intravenous
phates may be good additives for in situ gelling infusion. The in vivo and in vitro release rates were
and mucoadhesive liquid suppository bases.35 almost identical and subject independent.37
Nanoparticle suppositories Prolonged-release suppositories
A drug delivery system consisting of a lipophilic A study by Morgan and co-workers described the
model agent embedded into polymer nanopar- evaluation of a Novata BBC-based, prolonged-
ticles in a suppository base was formulated. release morphine alkaloid suppository that main-
Nanoparticles from this dosage form reached the tained plasma morphine levels for at least 7
systemic circulation via fenestrated capillaries or hours.36 These prolonged-release formulations
remained within rectal membranes to release are useful for patients who cannot tolerate oral
their contents. An initial rapid dissolution was morphine and for those in whom a longer-acting
followed by a steady decline over 168 hours and preparation is advisable. Generally, in studies
tissue distribution showed the agent to be present comparing different morphine forms and bases,
in the liver and lungs for a similar time period the release of morphine hydrochloride from a
as in the kidney, small intestines, and blood up PEG base is very rapid, as expected, and is consis-
to 96 hours. Microscopic observations showed tent with the high water solubility of morphine
nanoparticles to be present in blood for up to hydrochloride and PEG. The low water solu-
72 hours.36 bility of morphine alkaloid does not influence
the release of morphine from a morphine alka-
loid/PEG suppository, which is consistent with
the release behavior of other lipophilic drugs in a
Osmotic suppositories hydrophilic base. The release of a water-insoluble
drug from a lipid base depends on diffusion
One study using an osmotic delivery system through the lipid to the lipid–water interface,
incorporated a water-soluble derivative of theo- whereas release of a water-soluble (suspended)
phylline. The osmotic delivery system was similar drug will depend on mechanical transportation
to that of the AlzetR
osmotic minipump. This (e.g. sedimentation) to the lipid–water interface.
minipump had a diameter of 13 mm, length of It is thought that the release of a water-soluble
43 mm, a nominal pumping rate of 48 μL/h and a drug from an oily base is primarily dependent on
filling volume of 1.95 mL. The systems were filled the dissolution rate of the drug in water.38
with an aqueous solution of choline theophylli-
nate (230 mg/mL). The release rate was studied
in vitro (glass flask equipped with a magnetic
Sectile or bisected suppositories
stirrer containing 250 mL isotonic saline) and
in six healthy male volunteers, aged 24–27. In
the volunteers, the osmotic system was inserted Symmetrical suppositories can be composed of
into the subject’s rectum at 9.00 am. After 36 two parts separated by means of a beveled edge
hours, the system was replaced with a second one, (bisect) in the middle of the suppository. The
which remained for another 36 hours. This was purpose here is that a half suppository can be
130 Suppositories
administered to a child and the whole suppos- controlled release of the drug may be possible.
itory to an adult. The manufacturing process Their study also compared the release rate of the
is the same as in normal suppositories but the SRMS suppositories containing 10 mg MCP with
mold has a different shape. It is important commercial Gastrosil suppositories, also contain-
not to make the bevel too deep to avoid the ing 10 mg MCP. They found a five time longer
suppository accidently breaking during handling mean residence time of the SRMS suppository
or administration. compared with the Gastrosil suppository.40
Reversed micellar solution

Sustained-release suppositories
suppositories
Lecithin
Diclofenac standard suppositories were compared
with rectally administered diclofenac soft gelatin
Hydrogenated soybean lecithin was used to pro-
capsules. Diclofenac sodium was prepared as a
duce sustained-release indometacin suppositories
reverse micellar solution (RMS) and encapsulated
by the fusion method, using Witepsol H15 as
in soft gelatin capsules for rectal administration.
the base. The drug was released faster from the
The RMS was prepared by dissolving isopropyl
hydrogenated soybean lecithin suppositories
myristate in lecithin at 60◦ C with stirring, obtain-
than from control suppositories without the
ing a yellowish solution. The diclofenac sodium
hydrogenated soybean lecithin. However, in-
and propylene glycol were added with continued
creasing the quantity of hydrogenated soybean
stirring for about 2 hours. The final composi-
lecithin to over 300 mg per suppository produced
tion of the RMS was diclofenac sodium 4.75%,
slow-release profiles and sustained plasma levels
lecithin 27.075%, isopropyl myristate 63.175%,
of indometacin when administered to rabbits.41
and propylene glycol 5%, w/w. When coming in
contact with aqueous media, the capsule content
liquid was transformed into a semi-solid system
of liquid crystals which retarded the rate of Pectic acid
drug release. The soft gelatin capsule formulation
was shown to be bioequivalent in terms of the The bioavailability of bacampacillin hydrochlo-
AUC with the standard diclofenac suppositories. ride was best from Witepsol H15 compared with
The mean residence time of the capsules was other Witepsol bases; however, the time taken
three times longer than that of the diclofenac to achieve an effective plasma concentration was
suppositories, demonstrating sustained release of relatively short (about 2 hours). A sustained-
the drug.39 release suppository of the drug was prepared
Solid reversed micellar solution (SRMS) by reacting bacampacillin with pectic acid and
suppositories containing metoclopramide hy- chondroitin sulfate to form a precipitate. In
drochloride (MCP) were studied. The suppos- solution, the dissolution of the drug was slower
itories consisted of 70% Witepsol W35 and from the adducts than from the plain drug.
30% lecithin. MCP 1% was solubilized in the When incorporated into a suppository base, the
SRMS. Following administration, melting, and absorption rate was prolonged but the bioavail-
coming in contact with water or other phys- abilities were lower than that from the orig-
iological aqueous media, the SRMS exhibits a inal bacampicillin hydrochloride suppository. A
transformation into a semi-solid system of liquid similar prolonged absorption was obtained by
crystalline microstructure. Using polarized light simply mixing the pectic acid or the chondroitin
microscopy, the liquid crystal has been identified sulfate with the drug in the suppository base, thus
by the authors as a lamellar mesophase. The bypassing an intermediate step. The absorption
drug has a low coefficient of diffusion in this rate was found to be controlled by the amount
mesophase and the authors postulated that a of the polymer addition and both a high plasma
level and excellent bioavailability were obtained Curdlan

using this technique.42
Curdlan, a natural ␤-1,3-glucan, was studied for
its potential application in preparing sustained-
release suppositories. The suppositories were
Methacrylate
prepared by mixing either indometacin, pred-
nisolone, or salbutamol sulfate with curdlan gel
Indometacin has been incorporated into a
under different conditions. The heating tempera-
methacrylic acid–methacrylic acid methyl es-
ture during preparation, the drug amount in the
ter copolymer–PEG 2000 solid matrix to pro-
suppository, and the type of release media in the
duce a sustained-release suppository.43 The study
in vitro testing system affected the drug release.
demonstrated that the matrix can be successfully
The tonicity of the media had no effect. It was
used and modified to adjust the rate and duration
found that the drug release was sustained and
of drug release using methacrylic acid and its
diffusion-controlled in all three drugs studies.46
copolymers.
Cellulose derivatives Carboxyvinyl polymer
Ohnishi and co-workers evaluated the sustained Carboxyvinyl polymer was investigated as an
release of indometacin using hydroxypropyl agent to produce sustained-release diclofenac
methylcellulose acetate succinate–PEG 2000 solid sodium suppositories or sodium benzoate sup-
matrix.44 Their findings demonstrate that the positories in a triglyceride base containing other
controlled-release agent hypromellose acetate water-soluble polymers, such as xanthan gum
succinate can be used in a PEG matrix to retard and polyvinyl alcohol. The suppositories con-
and sustain the release of indometacin in a rectal taining carboxyvinyl polymer had half-lives
suppository. twofold longer than those not containing the
A study by Moolenaar et al. compared the polymer.47
efficacy, safety, and pharmacokinetics of a newly
developed controlled-release suppository with
MS Contin tablets in cancer patients with pain.
The fatty suppositories were prepared using mor- Alginic acid
phine sulfate pentahydrate, Aerosil OT (fumed
silica), hydroxypropyl methylcellulose (HPMC), Morphine was incorporated into sustained-
and Witepsol W25. The molten mixture was release suppositories using alginic acid as the
poured into plastic molds (3 mL) and stored at prolonged releasing agent. Witepsol S55 or W35
4◦ C. Each suppository contained 30 mg mor- gave higher plasma peak levels than H15 or E75.
phine sulfate, 108 mg Aerosol R972, 300 mg The prolonged release could be altered by the
HPMC 4000 and 2390 mg Witepsol W25. There amount of alginic acid added. The suppositories
were no significant differences in pain intensity were made by mixing alginic acid with the
scores between the oral and rectal dosage forms morphine in the suppository base. The Witepsol
within the groups, regardless of the treatment bases were preferable to the macrogol bases for
sequence. No treatment differences in nausea, the rectal absorption of morphine in terms of the
sedation, or the demand on escape medication onset and duration of release of the drug.48
between rectal and oral dosage forms was ob- Sustained-release suppositories containing ba-
served. The authors concluded that the newly campicillin were prepared using alginic acid and
developed controlled-release suppository is safe either Witepsol H15 or macrogol bases. The
and effective and may be a useful alternative for authors concluded that bacampicillin sustained-
oral morphine administration in patients with release suppositories using alginic acid may
cancer pain.45 be practically useful as a rectal preparation,
132 Suppositories
giving prolonged action and a high plasma Bruera and others compared the clinical ef-
concentration.49 ficacy and safety of a novel morphine sul-
fate controlled-release suppository (MS-CRS) with
subcutaneous (SC) morphine in patients with
Miscellaneous cancer pain. The results demonstrated that the
daily rectal morphine doses were equivalent
In a study comparing the efficacy and safety of a to 250% of the daily SC morphine dose (i.e.
novel, controlled-release morphine suppository analgesic equivalence ratio of 2.5:1) They con-
(formula not provided for MS Contin Suppos- cluded that MS-CRS administered every 12 hours
itories) and controlled-release morphine tablets provided analgesia that was comparable to SC
(MS Contin Tablets) in patients with cancer pain, morphine and represents a reliable, non-invasive
there were no significant differences between alternative method of pain control for patients
suppositories and tablets in overall scores of pain unable to take oral morphine.53
intensity on a visual analogue scale (VAS), ordinal A clinical trial comparing aminophylline
pain intensity, and sedation. There was a small, suppositories (300 mg; two twice daily) with
but significant, difference in overall nausea VAS sustained-release tablets (225 mg; two twice daily)
score in favor of the suppository. There was no concluded that both dosage forms are satisfactory
significant difference between the two dosage in the treatment of bronchospasm; patients may
forms in the use of daily rescue analgesic. The tend to prefer the tablets over the suppository,
authors concluded that the suppository provides however.54
pain control comparable to that provided by the In a double-blind crossover comparison of
tablet when given every 12 hours at a 1:1 dose sustained-release indometacin capsules and in-
ratio, and represents a reliable alternative method dometacin suppositories there was no advantage
of pain control for patients unable to take oral of efficacy in either preparation. The majority of
opioid agents.50 patients preferred the oral route of administra-
Regular (500 mg twice daily) and slow-release tion over the rectal route.55
(1 g once daily) 5-aminosalicylic acid (5-ASA)
suppositories were compared in a clinical study
of the treatment of active cryptogenic proctitis.
Thermo-reversible-liquid
The results demonstrate that both were equally
suppositories
effective and both were well tolerated. The slow-
release suppositories demonstrated greater toler-
ance and early expulsion was less frequent.51 Propranolol formulated as liquid mucoadhesive
A rectal carbamazepine suppository was devel- suppositories was prepared by adding mucoad-
oped for situations where the oral route of ad- hesive polymers (0.6%) to a formulation of
ministration is unsuitable. Both 125 and 250 mg thermally gelling suppositories that contained
suppositories were developed to be equivalent to poloxamer 407 (15%), poloxamer 188 (15%),
100 mg and 200 mg tablets. The aim of this study and propranolol HCl (2%). Mucoadhesive poly-
was to evaluate the pharmacokinetic variables mers used included hydroxypropyl cellulose,
by comparing conventional suppositories with polyvinylpyrrolidone, carbomer, polycarbophil,
slow-release carbamazepine tablets in children and sodium alginate. Rectal bioavailability in-
with epilepsy and to evaluate the clinical efficacy creased as the mucoadhesive force increased
and the general tolerability of the supposito- (from 430 to 5800 dyne/cm2 ). Retaining pro-
ries. The results show the clinical efficacy, as pranolol at the dosed site in the rectum by
demonstrated by seizure control, of carbamazine the addition of the mucoadhesive appeared to
slow-release tablets and suppositories to be com- be very important in avoiding first-pass hepatic
parable in this study. The bioavailability of the elimination and increasing the bioavailability of
suppository is less than that of the tablets, so the drug. Among the mucoadhesive polymers
a 25% higher dose is required rectally than examined, sodium alginate and polycarbophil
orally.52 exhibited the largest mucoadhesive force and
the smallest intrarectal migration, providing the of rabbits and rats. They were inserted with no
greatest bioavailability of propranolol (84.7 and difficulty, there was no leakage, and they were
82.3%, respectively).56 retained in the rectum of rats for at least 6 hours.
A study was conducted to investigate the These authors suggest that a thermosensitive
potential application of thermoreversible gels liquid suppository system with sodium chloride
formed by a xyloglucan polysaccharide derived and poloxamers is a more physically stable
from tamarind seed for rectal drug delivery. and convenient rectal dosage form for sodium
Model drugs included indometacin and dil- diclofenac.59
tiazem. The gels provided almost linear release Another study was carried out to develop a
over a period of 5 hours with more sustained thermo-reversible-liquid insulin suppository that
release than commercially available suppositories would undergo a phase transition to a bioad-
of the same drug. There was no significant hesive gel at body temperature, enhancing the
difference in bioavailability of indometacin when bioavailability of the insulin. This was investi-
administered by these new vehicles. There was gated using insulin, sodium salicylate, and polox-
no evidence of tissue damage in the rabbit rectal amers P407, P188, and polycarbophil. The liquid
mucosa. The authors suggest that these enzyme- insulin suppository consisting of insulin 100
degraded xyloglucan gels may have potential for units/g, poloxamer P407 15%, poloxamer P188
the rectal delivery of drugs.57 20%, polycarbophil 0.2% and sodium salicylate
A unique ibuprofen-loaded liquid suppository 10% in water was easy to administer without
(administered as a liquid but which gels after any pain during insertion and remained at the
placement in the rectum) was prepared using the administered site. The authors concluded that
eutectic formed between ibuprofen and menthol this liquid dosage form could be developed as
and incorporated into poloxamer 188. Initial a convenient, safe, and effective rectal delivery
studies were done on the solubility of ibuprofen system for insulin.60
and it was found that the optimum mixture for
the liquid suppository was poloxamer 188/men-
thol/ibuprofen at ratio of 15/0.25/2.5. This com-
Xerogel suppositories
bination provided the maximum solubility of
ibuprofen at 1.2 mg/mL. It was also easily ad-
ministered to the rectum and remained without The suitability of xerogel dosage forms for rectal
leakage after the dose. This liquid suppository administration has been studied. Prepared by
gave higher initial plasma concentrations, Cmax , lyophilizing frozen hydrogels of various shapes,
and AUC values of ibuprofen than did the solid they have been shown to be chemically and
suppository.58 physically stable and suitable for application in
The effect of sodium chloride on the gelation body orifices with poor fluid supply as they
temperature of liquid suppository systems com- require little liquid for rehydration.61
posed of poloxamers and bioadhesive polymers
was investigated. The study included various
formulations composed of diclofenac sodium,
Miscellaneous suppositories and
poloxamers, and sodium chloride. Mixtures of
bases
poloxamer P407 (15%) and P188 (15–20%) were
liquid at room temperature but gelled at body
temperature. The addition of diclofenac sodium Aminopyrine prepared in a three-component
to the gel significantly increased the gelation system suppository base consisting of a mix-
temperature and weakened the gel strength and ture of oleaginous base, water-soluble base,
bioadhesive force. The addition of sodium chlo- and the poly-(oxyethylene) poly-(oxypropylene)
ride, however, had the opposite effect. Selecting block copolymer Unilube was investigated. Rab-
sodium chloride concentrations less than 1.0%, bits were used as the model. The bioavailability
the drug was not precipitated at this level and of aminopyrine was 44.3% in the oleaginous
these formulations were studied in the rectum base alone, 82.6% in the water-soluble base,
134 Suppositories
and 100.4% in the three-component system con- 2. Taylor A, MacKenzie IZ. Hyperstimulation and the
taining 5% Unilube. The softening temperature controlled release prostaglandin pessary. Am J Obstet
of the three-component system was 55–57◦ C, Gynecol 1993; 168: 1003–1004.
indicating it would be suitable for storage at room 3. Muse Product Information, Vivus, Inc., Mountain
temperature.62 View, CA, USA
A slow-release suppository base studied by
4. Ngo Y, Gelinet JM, Ivanovic A, Kac J, Schenowitz
Dash and Cudworth consisting of AC-70 (an
G, Vilotte J, Rambaud JC. Efficacy of a daily ap-
acetic acid ester of monoglycerides derived from plication of mesalazine (Pentasa) suppository with
edible, fully hydrogenated palm oil) was com- progressive release, in the treatment of ulcerative
pared with Suppocire AI to evaluate the in vitro proctitis. A double-blind versus placebo randomized
release characteristics of benzocaine and micona- trial. Gastroenterol Clin Biol 1992 16 782–786.
zole. The AC-70 results in a drop in the pH of the
5. Kaiko RF, Fitzmartin RD, Thomas GB, Goldenheim
surrounding medium and this may be advanta-
PD. The bioavailability of morphine in controlled-
geous when a suppository base using a drug that release 30-mg tablets per rectum compared with
requires an acidic environment to maintain its immediate-release 30-mg rectal suppositories and
activity is needed. This base showed a constant controlled-release 30-mg oral tablets. Pharmacother-
release of benzocaine over time; therefore it can apy 1992; 12: 107–113.
be used as a constant-release or sustained-release
6. Uzunkaya G, Bergisadi N. In vitro drug liberation
suppository base.63
and kinetics of sustained release indomethacin
In the development of carbon dioxide- suppository. Farmaco 2003; 58: 509–512.
releasing suppositories containing sodium bi-
carbonate and anhydrous sodium dihydrogen 7. Nakajima T, Takashima Y, Iida K, Mitsuta H,
phosphate, a number of bases were evaluated, Furuya A, Koishi M. Preparation of sustained-
release suppositories containing microencapsulated
including Witepsol H15, W35, and E85; additives
indomethacin and bioavailability of indomethacin
studied were Aerosil 200 and soybean lecithin.
in rabbits. Chem Pharm Bull (Tokyo) 1987; 35: 4249–
In addition to the measured carbon dioxide 4254.
released, the study evaluated melting points,
viscosities and the hydroxyl values of the bases. 8. Nakajima T, Takashima Y, Iida K, Mitsuta H, Koishi
M. Preparation and in vitro evaluation of sustained-
The rate and amount of carbon dioxide released
release suppositories containing microencapsulated
from suppositories prepared with bases having
indomethacin. Chem Pharm Bull (Tokyo) 1987; 35:
different melting points and hydroxyl values 1201–1206.
decreased with increasing melting point and
decreasing hydroxyl value. Aerosil 200 consid- 9. Kim JY, Ku YS. Enhanced absorption of in-
erably reduced the rate and amount of carbon domethacin after oral or rectal administration of
a self-emulsifying system containing indomethacin
dioxide released due to the increasing viscosity
to rats. Int J Pharm 2000; 194: 81–89.
of the melted bases, and the addition of soybean
lecithin increased the rate and amount of carbon 10. Takamura A, Ishii F. Preparation of freeze-thaw
dioxide released, presumably due to improved poly(vinyl alcohol) emulsion gel suppository. Yaku-
wettability. The authors concluded that the rate gaku Zasshi 1991; 111: 45–50.
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be controlled by a combination of the factors M. Duration of absorption-enhancing effect of
studied.64 sodium octanoate, sodium hexanoate or glyceryl-
l-monooctanoate on rectal absorption of gen-
tamicin in rabbits. J Pharmacobiodyn 1990; 13:
591–596.
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J Pharmacobiodyn 1986; 9: 526–531. ministration of nifedipine suppositories in rabbits.
Kobe J Med Sci 1985; 31: 117–131.
20. Matsumoto Y, Watanabe Y, Yamamoto I, Mat-
sumoto M. Difference in rectal absorption of mor- 31. Losse G, Muler F, Kossowicz J, Hacker E. The applica-
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3935–399.
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138
9
Quality control of suppositories
QUALITY CONTROL procedures listed in the US drug substances or excipients, or in the prepara-
Pharmacopeia (USP30-NF25) for manufactured tion of drug products. They are not completely re-
suppositories include identification, assay, and, moved during processing but should be removed
in some cases, water content, residual solvent, to the extent that is possible and reasonable.
dissolution, and content uniformity:
r Identification: Identification tests are com- Stability considerations in dispensing practice
for suppositories also include observations on
monly used for the identification and confirma- excessive softening and oil stains on packaging.
tion of official articles. Compounded suppositories can be checked for
r Assay: Assay and test procedures are used to calculations of theoretical and actual weight and
determine compliance with the pharmacopeial weight variation, color, hardness, surface texture,
standards of identity, strength, quality, and pu- and overall appearance.
rity. Chromatographic methods are commonly Suppository quality control includes physi-
used for detection and quantitation. cal and chemical aspects of the product (Box
r Dissolution: Dissolution testing is used to de- 9.1). Physical analysis includes visual examina-
tion (physical appearance), uniformity of weight,
termine compliance with the dissolution require- uniformity of texture, melting point, liquefac-
ments, if present in the individual monographs. tion time, melting and solidification time, and
The test measures the rate and extent of a drug mechanical strength. Chemical testing includes
dissolving in a defined medium under defined analysis of the activity and dissolution testing.
conditions. The uniformity of texture can be assessed by
r Water: As many pharmacopeial articles either sectioning a suppository longitudinally and lat-
are hydrates or contain water in adsorbed form, erally, and ensuring that each section presents a
the determination of water content may be im- smooth, uniform surface.
portant in demonstrating compliance with Phar- A list of official USP suppositories and required
macopeial standards. Three methods are com- quality tests is given in Table 9.1.
monly used: Method I is a titrimetric method,
Method II is an azeotropic method, and Method
III is a gravimetric method.
Physical analysis
r Content uniformity: Content uniformity is re-
quired in some monographs to ensure the consis-
tency of dosage units. These dosage units should
Visual examination
have a drug substance content within a narrow
Color and the surface characteristics of the sup-
range around the label claim. Weight variation
pository are relatively easy to assess. It is impor-
and content uniformity testing involving groups
tant to check for the absence of fissuring, pitting,
and individual dosage units are used.
fat blooming, exudation, sedimentation, and the
r Residual solvents: For pharmacopeial purposes, migration of the active ingredients. Suppositories
these are defined as organic volatile chemicals can be observed as an intact unit and also by
that are used or produced in the manufacture of splitting them longitudinally.
139
140 Suppositories
Box 9.1 Example standard operating procedure: performing physical quality assessment of compounded
suppositories
I. Purpose – The purpose of this procedure is to 4 Remove the beaker contents, empty and dry the
provide a method of documenting uniformity between beaker.
batches and physical quality assessment tests of and
5 Place the dosage form (and the weight if used) into
observations on suppositories.
the beaker.
II. Materials, balance, graduates, beaker, weights.
6 Measure the same volume of water as in step 2 into
III. Procedures – Conduct the appropriate tests and a graduate.
record the results/observations on the Physical Quality
7 Pour the water into the beaker only to the mark
Assessment Form for Suppositories (Box 9.2).
from step 3. (Note: Do quickly before the dosage form
dissolves.)
A. Weight – Accurately weigh the product on a
balance. 8 Measure the volume of water remaining in the
beaker.
B. Specific gravity – To calculate the specific gravity,
Calculations:
one must know the weight and volume of the product.
Now that the weight and volume of the product
Record the weight of the individual dosage form or
are obtained, the specific gravity can be cal-
a strip/package of the dosage forms (tared weight).
culated by dividing the weight (grams) by the
To determine the volume of water displaced, do the
volume (in milliliters).
following:
C. Active drug assay results – As appropriate, have
Single unit:
representative samples of the product assayed for
1 Place 5.0 mL of water in a 10 mL graduate.
active drug content by a contract analytical laboratory.
2 Add the dosage form and read the water level. Stability can be assessed by storing the product at room,
refrigerated and/or frozen temperatures and having the
3 Subtract 5.0 mL from the level in step 2 to determine
assay repeated on the stored samples.
the volume of water occupied by the dosage form.
D. Color of product – It may be advisable to use a color
4 If the dosage form floats, place a weight attached
chart for determining the actual color of the product.
to a paper clip in the graduate prior to adding the
water to the 5.0 mL mark. Then, wrap one end of the E. Evaluate clarity by visual inspection.
paper clip around the dosage form to hold it below the
F. Texture of surface – Observe the product to deter-
water surface and place it in the graduate. Proceed as in
mine smoothness of the surface.
step 3.
Multiple unit packages (suppository strip): G. Appearance (dry, oily/moist) – Determine whether
1 Place the empty package in a beaker that will hold the product appears dry or oily/moist.
it with minimal extra space. H. Feel (tacky, plastic, elastic) – Touch the product to
2 Add an exact known quantity of water to cover the determine whether it is sticky (tacky) or hard (plastic) or
product. It may be necessary to add a weight to the bounces back (elastic).
package; this same weight should be used for the actual I. Melting test (for fatty acid, cocoa butter and oil-
product. based products):
3 With a fine-line marker and with the beaker setting
on a level surface, mark the water level on the outside
of the beaker.
Chapter 9 • Quality control of suppositories 141
Box 9.1 Continued
1 Heat a 200 mL beaker of water to 37◦ C on a 2 After 30 minutes, record your observations as yes,
magnetic stirring unit set at about 50 rpm. no or partially dissolved on the scale provided.
2 Add a dosage unit to the water.

K. Physical observation – Describe the appearance
3 After 30 minutes, record your observations as yes, and organoleptic qualities of the product.
no or partially melts on the scale provided.
NOTE: It may be necessary to add a weight to these L. Physical stability – Prepare a few additional dosage
dosage units to pull them below the water surface. forms, package and label (“For physical stability ob-
servations”). Weekly, observe the product for signs of
J. Dissolution test (for polyethylene glycol, gelatin and discoloration, dryness, cracking, mottling, mold growth,
water-soluble products): etc. Record a descriptive observation on the form at
each observation interval. There are sufficient lines for
1 Proceed as in the melting test. observations for eight weeks (approximately 60 days).
Shape If the weight is found to be too small, it is advis-

able to check whether the mold is being well filled
It is advisable to check the shape of the sup-
and whether there are axial cavities or air bubbles
pository to see if it is consistent, irrespective
caused by badly adjusted mechanical stirring or
of whether the suppository is ogive or torpedo
the presence of an undesirable surfactant. It is
shaped.
also important to check that the batch of suppos-
itories is homogeneous. If the weight is found
Surface condition to be too high, check that scraping has been
carried out correctly, and also that the mixture
The following can be checked: brilliance, dull- is homogeneous. Lastly, the weight may decrease
ness, mottling, cracks, dark regions, axial cavities, during aging when the suppositories contain
bursts, air bubbles, holes, etc. volatile substances, especially if the packaging is
not airtight.
Color
The intensity, nature and homogeneity of the Melting range (melting point, melting zone)
color should be verified.
Melting range or melting zone is the term often
preferred by some rather than melting point.
Odor Many suppository bases and medicated suppos-
itories are mixtures, and so do not have a precise
Verification of odor can prevent confusion when melting point. Routinely, though, we continue
similar suppositories are being processed. A to call the physical phenomenon obtained under
change in the odor may also be indicative of a rigorous conditions the melting point.
degradation process. The release rate of the suppository is related
to its melting point; it is therefore critical that
this test be evaluated using a non-destructive
Weight method. A number of different techniques are
used to study melting behavior, including the
Suppositories can be weighed on an automatic open capillary tube, the U-tube, and the drop
balance, obtaining the weight of 10 suppositories. point methods (Figures 9.1, 9.2, and 9.3). One
142 Suppositories
Box 9.2 Physical quality assessment form for compounded suppositories
Product: Date:
Lot/Rx number: Form: Suppository

Characteristic Theoretical Actual Normal Range
Weight/volume
Specific gravity
Active drug assay results
Initial assay
After storage No. 1
After storage No. 2
Color of product
Clarity Clear 1 2 3 4 5 Opaque
Texture-surface Smooth 1 2 3 4 5 Rough
Appears dry Yes 1 2 3 4 5 No
Appearance Dry 1 2 3 4 5 Oily/moist
Feels tacky Yes 1 2 3 4 5 No
Feels plastic Yes 1 2 3 4 5 No
Feels elastic Yes 1 2 3 4 5 No
Melting test Yes 1 2 3 4 5 No
Dissolution test Yes 1 2 3 4 5 No
Sample set aside for physical observation: Yes No
If yes, results: Date Observation
shortcoming is the use of limited data to de- must be used because if the suppository is melted
scribe a continuous, complex melting process before a measurement is made, the supposi-
occurring in successive steps involving multiple tory constituents may be transformed into a
components, including various molecular weight metastable state.
triglycerides, polymers, or other ingredients. The melting test consists of placing a suppos-
The methods used are similar in principle itory on the surface of water thermostatically
but include different steps and techniques. In controlled at 37◦ C and verifying the complete
general they include the set-up of the equipment, melting of the suppository in a few minutes. This
placement of the suppository dosage unit in the is not so much a measurement as an evaluation.
apparatus, followed by the application of heat
and observation for a change in the system, such
as melting or movement. The results obtained
Melting point determination
using different methods do not always agree, so
it is important to use a consistent method. The use of a U-shaped capillary tube to determine
In general, the melting point should be equal melting point provides precise information for
to or less than 37◦ C. A non-destructive method excipient control and consistency in production
Table 9.1 Official USP suppositories and required quality testing
Content Residual
Monograph Identification Assay Dissolution Water uniformity solvents
Acetaminophen x x – – – x
Aminophyllinea x x – – –
Aspirinb x x – – –
Bisacodyl x x – – –
Chlorpromazinec x x – – –
Ergotamine tartrate and caffeine x x – – – x
Glycerin x x – x – x
Indometacin x x x – x x
Miconazole nitrate x x – – – x
Morphine sulfate – x – – x x
Nystatin – x – x –
Oxymorphone hydrochloride x x – – – x
Prochlorperazine x x – – –
Progesterone – x – – x x
Promethazine hydrochloride x x – – –
Thiethylperazine maleate x x – – x
a Ethylenediamine content required.

b Limit of free salicylic acid required.
c Other alkylated phenothiazines required.
for those suppositories containing soluble active as amorphous to crystalline transitions. They also
principles. This method is not suitable when the demonstrated a hardening of the suppository ma-
suppositories have a high powder content, which terials over periods of time as short as six weeks,
prevents the fat from sliding inside the capillary using a modified Krowczynski softening time test
tube to give the end-point determination. and differential scanning calorimetry on freshly
When there are more numerous controls, and solidified, incrementally aged, and equilibrated
where studies with a greater precision can be samples. They also demonstrated that plasticizers
undertaken, an apparatus can be used consisting inhibited this hardening phenomenon.1
of a microscope, a heated deck, and a recorder.
This provides for a more detailed observation and
recording of the melting process.
The melting point can also be determined Liquefaction time
by placing a small-diameter wire into the mold
containing the suppository melt before the form Liquefaction testing provides information on
solidifies. The form is then immersed in water, the behavior of a suppository when subjected
held by the wire, and the temperature of the to a maximum temperature of 37◦ C. The test
liquid is raised slowly (about 1◦ C every 2–3 commonly used is Krowczynski’s method (see
minutes) until the suppository slips off the wire; below), which measures the time required for a
this is the melting point of the suppository. suppository to liquefy under pressures similar to
In a study by Coben and Lordi, the changes in those found in the rectum (approximately 30 g)
the melting range of several semi-synthetic sup- in the presence of water at 37◦ C. In general,
pository bases over time were investigated. Using liquefaction should take no longer than about
X-ray diffraction they characterized the changes 30 minutes.
144 Suppositories
Elevating mechanism 6
φ 1,5 φ 3,5 Int.
Thermometer
Ring agitator 1 or —
1 C scale)
(—
n m
guide Rubber
Open-head and open-end Water

capillary tube containing (stirred)
1 cm test material – depth
of immersion in the water
bath: 4 cm – temperature
80 mm
rise: 1 C per minute
Ring agitator
Asbestos plate
covered stand
protected from drafts
Bunsen pilot
flame φ 1,5 Int.
Figure 9.2 U-Tube apparatus for melting point determina-

tion.
Figure 9.1 Open capillary apparatus for melting point

is used. The tube and thermometer are held in
determination.
place by means of a large rubber stopper with
two holes in a 225 mm long tube with a 50 mm
Two example set-ups are shown in Figures diameter, fitted with lateral tubes to allow the
9.4 and 9.5. Numerous techniques have been water at 37◦ C from a constant-temperature water
developed and used over the years. Setnikar bath to circulate.
and Fantelli’s method, for example, consists of Another apparatus is equipped with a 30 g
measuring the liquefaction of the suppositories glass stem 180 mm long and 9 mm wide. The
in a cellophane gut immersed in water at 37◦ C, base has a ring form with a 14 mm diameter. The
at the same pressure as in the rectum. This ring of the stem has a cuneiform shape opening
technique has been described in detail.2 to allow the melted excipient to escape upwards
For Krowczynski’s method, the apparatus con- during the test. At a distance of approximately
sists of a 16 mm diameter glass tube, 235 mm long 100 mm from the ring, three glass projections
with an approximately 6 mm diameter reduction support the stem in a vertical position in the
at the base. One end is blocked with a small tube. The stem is also marked with a dash
rubber stopper to facilitate cleaning after use. A corresponding to its position with respect to the
thermostat graduated in tenths of a centigrade upper level of the tube.
The tube is drawn out of either end of the

cylinder and secured with two elastic bands.
1 Tubing is attached to allow the warm water to
circulate, maintaining the temperature. When
2
5 the appropriate temperature is reached, the sup-
3 pository is placed in the dialysis tubing and the
6
time to liquefaction measured. The apparatus can
also be used to determine the melting point of
suppositories made with both water-soluble and
water-insoluble bases. This can be accomplished
4 7 by increasing the temperature of the water at a
set rate, for example one degree every 10 minutes
8 until the suppository melts.3
1 Heating system 5 Furnace
2 Resistance sensor 6 Sample cup
3 Sample 7 Photoresistor Suppository penetration test
4 Lamp 8 Collector
A suppository penetration test can be used to
Figure 9.3 Drop point apparatus for melting point determi- determine the temperature at which the suppos-
nation. itory becomes sufficiently soft for a penetrating
rod to drop through its length. The apparatus
used is shown in Figure 9.6. The temperature is
The directions for use are as follows: (1) obtain
adjusted to that required for the test, generally
a constant temperature in the circulating water
about 37◦ C. The suppository is placed in the
bath of 37◦ C, (2) pour approximately 5 mL of
device and the penetration rod gently moved
water down the tube so that all the tube is
into place. The device holding the suppository
filled below the narrowed part (and so that the
and penetration rod is lowered into the constant
suppository to be tested is in relatively humid
temperature bath and a stopwatch is started.
conditions similar to those in the rectum, (3)
When the penetration rod drops through the
after 5 minutes (the time necessary to bring
softened suppository the time is recorded.
the 5 mL of water to 37◦ C), insert a suppository
with the end pointed downward into the glass
tube, insert the glass stem so that it is resting
on top of the suppository and start the timer, Melting and solidification time
(4) note the time required for the mark on the
glass stem to drop and come in line with the There is a relationship between melting and
upper edge of the tube, (5) repeat this for two solidification that is important to characterize.
more suppositories, (6) if the difference between The release of the active ingredient from the
the three time measurements is greater than 105 vehicle is related to the melting point of the
seconds, start again on two more suppositories vehicle and the solubility of the drug in the
(making a total of five suppositories), and (7) vehicle. Suppositories undergo three changes in
determine the average liquefaction time. phase during their “life.” First, they are melted
Apparatus using a cellophane bag (Figure 9.5) and then solidified; upon administration, they
consists of a glass cylinder with an external are again melted. An understanding of these
diameter of 50 mm, narrowing down to 22 mm factors and their relationships is critical for eval-
at either end for a length of 30 mm. The cylinder uating the bioavailability of the final suppository
is fitted with two connections through which formulation. The higher the melting point, the
water that is maintained at 37◦ C can circulate. later the drug effects appear. If too high, the drug
A 34–35 cm length of cellulose dialyzer tubing, effect does not appear.
size-inflated diameter of 1.12 inch (2.8 cm), is Melting and solidification is a complex pro-
moistened, opened and placed in the cylinder. cess and difficulties in measurement can arise,
146 Suppositories
Thermometer
internal accurate to
within 0.1°C
30a
17a
161
125
25a
33
18a
2a
5a
Suppository
B A C
KROWCZYNSKI Water at 37 °C
APPARATUS
COMPLETE
ASSEMBLY
Figure 9.4 Liquefaction time apparatus.
leading to different results obtained using dif- temperature in this phase is the solidification
ferent methods. The solidification temperature temperature.
is defined as the highest temperature occurring
during the solidification of a supercooled li-
quid. Various methods are available to measure Mechanical strength/crushing test
it, including Shukoff’s method,4 in which the
liquid is shaken in an evacuated flask until Suppositories can be classified as brittle or elastic
turbid and the temperature noted at which by evaluating the mechanical force required to
a transitory rise in temperature occurs during break them. Tests are used that measure the
cooling. mass (in kilograms) that a suppository can bear
The European Pharmacopoeia also describes without breaking. A good result is at least 1.8–
a procedure that involves heating the material, 2 kg pressure. In the example laboratory set-up
then allowing it to cool slowly while stirring. The shown in Figure 9.7, the suppository is positioned
temperature is recorded at 1 minute intervals. in an upright position and increasing weights
The cooling curve normally passes through a are placed on it until it loses its structure and
minimum, which indicates a supercooled melt. collapses. The purpose of the test is to verify that
Heat is liberated during crystallization and the the suppository can be transported under normal
temperature–time curve rises. The maximum conditions, and administered to the patient.5
50
22
30
260
Cellophane
tube
30
Figure 9.5 Liquefaction time apparatus using cellophane

bag.
Chemical testing
Dissolution testing
One of the most important quality control tools

available for in vitro assessment is dissolution
Figure 9.6 Suppository penetration apparatus.
testing. Dissolution testing is often required for
suppositories to test for hardening and poly-
morphic transitions of active ingredients and method/dialysis method, and the continuous
suppository bases. However, unlike for tablets flow/bead method. The equipments for these
and capsule dosage forms, there are not enough various methods are shown in Figures 9.8–9.11.
dissolution testing methods or validations for The application of the paddle, basket,
suppositories. This can be partly attributable to and flow-through dissolution methods was
the immiscibility of some of the suppository studied by Gjellan and Graffner for seven
vehicles in water. different rectal compositions of hydrophilic and
If the drug is immiscible in an aqueous dissolu- lipophilic-type suppositories. The formulations
tion fluid then it may require a partitioning step; were (1) lipophilic, melting–Witepsol,
unfortunately this involves extra time, which (2) lipophilic, melting–Witepsol with 2%
alters the dissolution rate calculation. Tween 85, (3) lipophilic melting–Novata,
If a filtration step is involved in dissolution (4) hydrophilic dissolving–polyethylene
testing, the filtration membrane may introduce glycol (PEG) 3350 + 1500, (5) hydrophilic
an erroneous result between actual and obtained dissolving–PEG 3350 + 1500 with 2% Myrj 51,
results as it may clog. Variations in density (6) hydrophilic dissolving–gelatin capsule, and
between the suppository and the receiving fluid (7) lipophilic melting–gelatin capsule with a
must also be considered. surfactant.6
Dissolution testing methods include the pad- The melting suppositories with the paddle
dle method, basket method, membrane diffusion method showed fat floating rapidly to the surface
148 Suppositories
Paddle and
flask as defined
for Apparatus 2
Paddle
Disk 25 cm
Figure 9.8 Dissolution apparatus using the paddle method.
basket. In the paddle method, small pieces of

melted fat accumulated about the helix and small
pieces were continuously floating to the surface
of the dissolution medium. In the flow-through
system, there was a spreading of the base at the
Figure 9.7 Mechanical strength/breaking apparatus. cell walls in the first chamber where it was then
forced into the second chamber and collected at
of the fluid instead of staying below the water the top of that chamber.
surface. With the basket method, the surfactant The dissolving suppositories with and with-
produced small droplets of the fat that were out surfactant behaved similarly in all the dif-
dispersed into the medium almost immediately. ferent techniques. The suppositories gradually
Some of the fat particles also blocked the basket decreased in size, just like dissolving tablets, and
mesh. When a surfactant was not used, the basket the content of the surfactant made no difference.
served as the container for all the melted fat. With the melting suppositories, the dissolu-
In the flow-through cell, the two suppository tion rates for those containing surfactant were
compositions behaved differently. The surfactant faster than those without surfactant. With surfac-
makes the fat more sensitive to agitation. A defor- tant, the dissolution profiles using the different
mation of the suppository is seen as a fast release techniques were approximately the same.
of small droplets of fat when the surfactant is With the dissolving suppositories, the paddle
incorporated. For both compositions, the melting method at 50 rpm and the flow-through method
fat accumulates on the top of the chamber during at 16 mL/min produced the same dissolution
the dissolution process.6 profiles with and without surfactant.
The melting suppositories without the surfac- The investigators also concluded that suppos-
tant in the basket method simply stayed in the itories containing a surfactant behave differently
Speed (rpm) as specified in monograph

USP/NF: 25–150 rpm ±4%; BP; ±5%
Shaft 6–10.5 mm diameter: 2-mm vent in drive disk
Centering (or tilt)

±2 mm at all points
Eccentricity
USP/NF: no significant wobble;
BP: no perceptible wobble
Sampling point
USP/NF: midway from top of
basket to top of fluid and no
closer than 1 cm to side of flask;
BP: halfway between basket
and side at middle of basket
A Flask
USP/NF: cylindrical with spherical bottom,
16–17.5 cm high, inside
diameter 10–10.5 cm, plastic or glass
Basket
Basket position
USP/NF: 25 ±0.2 cm; BP: 2.0 ±0.2 cm
Figure 9.9 Dissolution apparatus using the basket method.
Pump
C
A
37°C from attached to A attached to B
water bath pH meter
Na+ electrode
DIALYSIS
to
APPARATUS SECONDARY
water bath
D to VESSEL
B Apparatus
attached
to D
Figure 9.10 Dissolution apparatus using the membrane/dialysis diffusion method.

150 Suppositories
1
2
4
2
5
6
(a) (b)
Figure 9.11 Dissolution apparatus using the continuous flow method: (a) 1 – schematic drawing with the cell in the upper
middle of the diagram; 2 – tubing for moving the dissolution fluid; 3 – constant temperature bath; 4 – pump; 5 – receiver
flask for dissolution fluid; 6 – constant temperature bath; (b) continuous flow cell; 1 – beads; 2 – suppository being tested;
3 – filter (glass filter) to retain the beads.
from those without and produce the fastest to the drug partitioning between the melted
dissolution rates of paracetamol. The presence lipophilic base and the receptor fluid. This may
of the surfactant makes the suppository more result in a distribution equilibrium between the
sensitive to the differences in the dissolution phases as opposed to complete dissolution. In
techniques.6 these cases, sink conditions are essential in order
The flow-through method was slower, possibly to simulate the in vivo situation. In this situation
as a result of the delayed spreading of the melted membranes provide a more elegant way to obtain
mass in the dissolution cell. The subsequent con- a filtrate for immediate assay; however, because
tact area with the dissolution fluid is smaller than this poses an artificial condition, it is not gen-
that achieved with either the paddle method or erally recommended. Recommended equipment
the basket method.6 for lipophilic suppositories, therefore, includes a
In a series of workshops held under the modified basket method, a paddle method with
auspices of the Fédération International Phar- a wired screen and a sinker, and a modified
maceutique (FIP) and co-sponsored by the Royal flow-through cell with a specific dual-chamber
Pharmaceutical Society, the Bundesverband der suppository cell. The flow cell tends to generate
Pharmazeutischen Industrie, Colloquium Phar- more variability in the data due to the behavior
maceuticum, the American Association of Phar- of the suppository within the cell, especially in
maceutical Scientists, and the US Food and formulations that contain spreading agents. In
Drug Administration, it was concluded that these difficult situations, the membrane method
hydrophilic suppositories that release the drug may be preferable.7
by dissolving in the rectal fluids can be eval- It is evident that no single method of dis-
uated by the basket, paddle, or flow-through solution testing is suitable for all the various
cell methods. Lipophilic suppositories, on the suppository formulations and types of suppos-
other hand, release the drug after melting in itories. However, from the methods available,
the rectal cavity and are significantly affected by the authors concluded that a method can gen-
rectal temperature. After determining the proper erally be selected that will be adequate. Even
temperature to use, consideration must be given though it is difficult to make a recommendation,
one might consider starting with the basket the Mühlemann tester and a laboratory-designed
or paddle method for hydrophilic suppositories membrane-diffusion cell. The values for the
and the modified flow-through cell for lipophilic dissolution rates were faster than the perme-
suppositories.7 ation rates, as would be anticipated. There was
A bead-bed suppository dissolution appara- good correlation between the Mühlemann tester
tus was evaluated by measuring the release of and the laboratory-designed membrane-diffusion
benzocaine from various suppository vehicles. cell. Based on this study, the authors concluded
This proposed method using beads as the bed that it is possible to obtain standardized and auto-
and placing the suppository within the beads mated results that show good reproducibility.11
was designed to provide greater constancy of An investigation was conducted to determine
the exposed suppository area for dissolution. The the in vitro dissolution behavior of piroxicam
liquid passed through the bed at a constant rate. suppositories using the flow-through method,
Direct contact of the suppository was maintained conventional stirred vessel–USP paddle and bas-
with the dissolution medium, confining the sup- ket methods. The results indicate that the flow-
pository within the beads.8 through method seems useful for studying the
A study to determine the feasibility of using dissolution process of suppositories containing
the European Pharmacopeia flow-through cell for piroxicam, resulting in reproducible dissolution
dissolution testing of compounded rectal sup- data. The flow-through cell method gives more
positories containing indometacin or sodium di- rapid in vitro dissolution rates for piroxicam than
clofenac investigated various suppository bases. the USP paddle method, possibly due to the
The fastest and most repeatable release rates were steeper concentration gradient in the vicinity of
from the hydrophilic bases; the macrogols had the suppositories as well as a better ability to
more than 80% of the drug released within 60 thoroughly wet the suppositories. The USP basket
minutes. The lipophilic bases were somewhat method gave substantially slower dissolution
slower, showing that after 350 minutes, only rates than either of the other two methods.12,13
18.5–50% of the total amount was released, with Using a dissolution chamber apparatus for
somewhat non-reproducible results. This demon- suppositories introduced in the European Phar-
strates the slow and non-reproducible release macopoeia and the British Pharmacopoeia, one
when the lipophilic suppository base does not study of commercial paracetamol suppositories
melt. The authors concluded that the use of the found that the results obtained are clearly de-
test for formulations that do not melt is not pendent upon the temperature maintained in the
recommended.9 dissolution chamber. Complete melting of a sup-
One study using the paddle dissolution pository in the dissolution chamber was required
method on water- and fat-soluble indometacin for an appropriate dissolution of paracetamol in
suppositories for rectal administration in rats vitro. Associated tests were compared for rele-
determined that the choice of the membrane vance, including disintegration time, softening
is critical. When a cellulose or artificial sausage time, drop point, and particle size.14
membrane of cow protein was used, the amount The release rates of fluconazole in different
of indometacin released from fatty base suppos- types of suppository bases was studied using the
itories was higher than that from water-soluble USP dissolution apparatus I and the permeation
bases. But, the results were reversed when a was studied using Franz diffusion cells with rat
natural sausage membrane of pig colon was rectal membrane with normal saline as the recep-
used. Selection of the proper model system is tor medium. The different bases used included
important.10 hydrophilic (PEG), lipophilic (cocoa butter or
A comparison of different dissolution and Witepsol W45), and amphiphilic (Suppocire AP,
permeation methods was undertaken using dia- a polyglycolized glyceride). The results of the
phyllin, piroxicam, naproxen, and tenoxicam dissolution test concluded that dissolution of
commercial standard suppositories. Dissolution fluconazole from the bases, in decreasing order,
tests were conducted with the Desaga-type flow was PEG ⬎ Suppocire AP = Witepsol W45 ⬎ cocoa
cell. Permeation studies were conducted using butter. The permeation studies showed Suppocire
152 Suppositories
AP ⬎ PEG = Witepsol W45 ⬎ cocoa butter. It 1 unit of the 30 is outside the range of 85.0%
was mentioned that the increased permeation to 115.0% of label claim, and no unit is outside
characteristics seen with the Suppocire AP base the range of 75.0% to 125.0% of label claim and
are probably due to an alteration of the mem- the RSD of the 30 dosage units does not exceed
brane characteristics because of the surface active 7.8%.
properties of the base.15 Limit B (if the average of the limits specified in
In another study a case was presented for two the potency definition in the individual mono-
rotating flask methods (simple and compartmen- graph is greater than 100.0 percent).
tal) for evaluating the liberation of drugs from If the average value of the dosage units tested
is 100.0 percent or less, the requirements are as
commercially available acetaminophen supposi-
in Limit A.
tories. The authors compared numerous suppos-
If the average value of the dosage units tested
itory test methods but decried their complicated
is greater than or equal to the average of the
construction and difficulty in handling. They
limits specified in the potency definition in the
concluded that the two rotating flask methods individual monograph, the requirements are as
correlated well with each other and had relevant specified under Limit A, except that the words
characteristics and bioavailability.16 “label claim” are replaced by the words “label
claim multiplied by the average of the limits spec-
ified in the potency definition in the monograph
Content uniformity testing divided by 100.
If the average value of the dosage units tested
is between 100 percent and the average of the
In order to ensure content uniformity, individ- limits specified in the potency definition in the
ual suppositories must be analyzed to provide individual monograph, the requirements are as
information on dose-to-dose uniformity. Testing specified under Limit A, except that the words
is based on the assay of the individual content “label claim” are replaced by the words “label
of drug substance(s) in a number of individual claim multiplied by the average value of the
dosage units to determine whether the individual dosage units tested (expressed as a percent of
content is within the limits set. “Acceptance label claim) divided by 100 (p. 383).
value calculations are not required for supposi-
tories. Assay 10 units individually as directed in
Content uniformity is important not only be-
the Assay in the individual monograph, unless
tween suppositories, but also within supposito-
otherwise specified in the Procedure for content
ries in the event that a suppository is halved
uniformity” (ref. 17, p. 383).
for administration. A method of determining
The USP 30 “Criteria”17 for suppositories states
the distribution of paracetamol in suppositories
the following:
using differential scanning calorimetry has been
reported. In this study, samples of 2.5–4.0 mg
Limit A (if the average of the limits specified were carefully removed from the tip, middle,
in the potency definition in the individual
and base sections of individual paracetamol
monograph is 100.0% or less) – Unless otherwise
suppositories using a stainless steel scalpel. The
specified in the individual monograph, the re-
contents of paracetamol in the suppositories were
quirements for dosage uniformity are met if the
determined by differential scanning calorimetry
amount of the drug substance in each of the 10
dosage units as determined from the Content
and ultraviolet spectrophotometry. The results
Uniformity method lies within the range of obtained were 10.1 ± 0.2%, 10.1 ± 0.2%, and
85.0% to 115.0% of the label claim, and the RSD 10.3 ± 0.2% w/w paracetamol, indicating that the
is less than or equal to 6.0%. paracetamol was uniformly distributed through-
If 1 unit is outside the range of 85.0% to out the suppositories.18
115.0% of label claim, and no unit is outside the One study reported difficulty in obtain-
range of 75.0% to 125.0% of label claim, or if the ing content uniformity between dispensatory-
relative standard deviation is greater than 6.0%, prepared rectal suppositories when sampling
or if both conditions prevail, test 20 additional numbers were only 10% of a batch of 300 (N
units. The requirements are met if not more than = 30). This was solved by increasing the number
of suppositories tested to 15% (N = 45) of the and where samples are obtained. Here we are con-
total batch prepared.19 cerned with the general homogeneous nature of
Content uniformity tests can be used to mixed products in a single system or unity, or in a
optimize production techniques and sampling single operation being used for the manufacture
methods. In one study a sampling plan was de- of suppositories under constant modalities.
veloped, combining practicality for the consumer Active drug analysis is important for batch-
and a satisfactory discrimination between “good” to-batch uniformity and can also be used for
and “bad” batches. Samples of 50 suppositories within-batch production control. The analysis
obtained from a year’s production of 42 batches of active drugs in suppositories presents some
were studied. There was no difference between interesting and sometimes difficult problems due
the weights of the suppositories obtained during to the matrix in which they are contained, such
the production process. The intent was to deter- as fatty acids and long-chain polymers. Once
mine the variation in content as there was no uni- assay methods have been developed, they can be
form standard. At the time of this study (1970), used to also determine content uniformity and
the German and Russian pharmacopeias allowed dissolution testing parameters.
weight variations of rectal suppositories of within
±5% of the average weight. The Pharmacopoeia
Nordica allowed weight deviation up to ±10% of
the average weight for 90% of the suppositories, Sampling and sample preparation
provided that the variations do not exceed ±20%.
The International (1967), NF XII, BP (1963), Ital- In general, the analytical methods involved
ian VII, Austrian IX, Gallica VIII and Japanese VII require sample preparation prior to using an
pharmacopeias gave no specification for weight instrumental method technique. Sample prepa-
uniformity of suppositories.20 ration involves the preparation of a suitable and
uniform sample composite and the extraction of
the drug from the excipients.
Conductivity For manufactured suppositories, preparation
of a uniform sample may require a minimum of
five to 30 individual doses which are weighed
Siegmund and Leuenberger studied the conduc- and combined together, such as by melting in
tivity of binary mixtures of different volume to a beaker. From this composite, the required
volume ratios of liquid PEG 200 and solid PEG quantity of sample is removed for analysis.
6000 in an attempt to relate this to dissolution The quantities for sampling are usually a
rate processes. The conductivity was measured minimum of 10–15 suppositories. The samples
using a specially designed cell, which could be are taken from the first ten molds, from the
filled with the sample to be analyzed. The results beginning, from the middle of the manufacturing
were analyzed using the percolation theory and and finally from the last ten molds, and are
its relation to the dissolution rate of binary placed in impervious packing, preferably made
mixtures. They demonstrated that the conduc- of glass, and then labeled. The samples can also
tivity and the dissolution rate process can be be taken from directly packaged suppositories.
successfully modeled by the basic equation of Special care must be taken when labeling the
percolation theory and that both processes can sample receptacles, making sure that the date
be correlated.21,22 when the sample was taken, and the batch
number are included.
Sample preparation techniques may require
extraction, heating, the addition of electrolytes
Chemical testing procedures
to the aqueous phase (salting out), modification
of the surface tension by addition of silicones,
Prior to chemical testing, the size of the manu- ricinoleate, octylic alcohol or others, centrifu-
facturing batch must be defined. This may invoke gation, acidification (particularly anionic type
specific requirements on sample size and when emulsion of the soap type) or the addition of an
154 Suppositories
organic solvent. Often it is necessary to combine the water 15 minutes before introducing the
the techniques described above. suppository to be tested; and the third is used
to sample the dialysis water at regular intervals.
These dialysis samples are then quantitatively
Extraction analyzed for the active principle that has diffused
from the suppository.
The method used to extract the active drug The test liquid (350 mL), from which the
from the sample varies depending upon the samples are obtained, with a pH of 7.38, is used
physicochemical characteristics of the drug and in each test. Samples to be analyzed are taken at
the vehicle. Many extraction procedures require 30, 60, 90, 120, 150, 180, 210, and 240 minutes.
partitioning into an aqueous medium after mix- The composition of the test liquid is as follows:
ing with either hexane, pentane, chloroform, Na2 HPO4 .2H2 O (9.50 g), NaH2 PO4 .2H2 O (2.08 g),
ether, or another suitable organic solvent. In NaCl (4.60 g), polyvinylpyrrolidone (35.0 g),
some methods, multiple extractions and back purified water to 1000 mL.
extractions may be required.
Dialysis
Extraction by water at 37◦ C method
A modification of the dialysis membrane method
One suppository per test is placed in a tube
for drug release from suppositories was used
containing 10 mL of water at 37◦ C. After stirring
to analyze dissolution from 50 mg indometacin
in a constant temperature water bath, the tubes
suppositories. The system consisted of a dialysis
are withdrawn at 10-minute intervals and imme-
membrane (17 cm long, 28 mm wide), suspended
diately placed in an ice bath to solidify the melted
in 1000 mL of 50 mM phosphate buffer main-
excipient. The concentration of the active drug in
tained at 37◦ C. This technique also uses a clamp
the supernatant liquid is then determined.
to bind the ends of the tubing rather than thread
(which tends to wrinkle the tubing at the ends).
Extraction by dialysis across a cellophane The results using the apparatus allowed cor-
membrane relation of the release rate with in vivo data
(AUC, Cmax and T max in rabbits). In this method,
Several methods studying the diffusion of active any water remaining in the dialysis tubing after
principles originating from melted supposito- hydration resulted in a decrease in the rate of
ries at a temperature near 37◦ C across a semi- drug release due to lost sample.26
permeable membrane have been used.23–25 Example set-ups are shown in Figure 9.12.
Other methods
Preparation for analysis
There is another method that deserves close
attention as it seems to give excellent corre- Once the sample has been extracted, the next
lation with in vivo absorption results obtained step is the analytical method. Analytical meth-
with different suppository formulas, notably with ods commonly include high-performance liquid
thiazinamium and indometacin. The apparatus chromatography (HPLC), gas chromatography,
consists of a cylindrical dialysis cell placed in a and spectroscopy. Ideally, all methods should be
water bath at 37◦ C. The water bath has a circula- capable of indicating stability.
tion of liquid assured by thermostatic control and In selecting the analytical method, important
a water pump. The dialysis cell has three orifices: factors to be evaluated include (1) the solubility
the first holds a precision thermometer used to characteristics of the active ingredients, (2) par-
control the temperature of the dialysis liquid; ticle fineness, (3) the hydrophilic or lipophilic
the second holds a cellophane gut (diameter character of the excipients, (4) the ability to
18 mm, thickness of 25 μm), which is placed in spread on the rectal mucous membrane, (5) the
bases (Witepsol H15) and simulated rectal fluid

imitated by a phosphate buffer at pH 7.2 utilizing
the routine shaker flask method. Capacity factors
(log k ) of the drugs were determined on a reverse-
Clip
phase C18 column using various methanol/5 mM
Tall beaker phosphate buffer pH 7.2 mobile phases contain-
ing different percentages of methanol. Apparent
capacity factors (log k(w)app ) were derived by
Immersion fluid extrapolation of the methanol concentration to
zero and, using the correction for ionization, the
real capacity factors log k (w) were calculated. The
Raising and lowering
Dialysis cooling
lipophilicity of the compounds was assessed by
the partition coefficients ClogP (calculated log
55 mm
octanol/water partition coefficient) and the dis-

tribution coefficients ClogD7.2, calculated for the
Agitator rings n-octanol/water system. Correlations between
log k (w) and ClogP, log k(w)app and ClogD7.2, log
Suppository
Closure k(w)app and log K were found. This last correlation
suggested that the parameter log k(w)app was
suitable for evaluating the distribution behavior
Figure 9.12 Dialysis apparatus. of the studied drugs in the examined Witepsol
H15/rectal liquid system. The applicability of
this was tested for the nine different drugs used
tendency to give water-in-oil emulsions in the
in this study. It was demonstrated that the
presence of emulsifying agents, and (6) viscosity.
classical shaker flask method for determination
Sample preparation may involve concentra-
of distribution behavior, or partition coefficients,
tion, dilution, solution in various solvents, or
of the studied drugs between suppository base
other manipulation depending upon the analyt-
Witepsol H15 and pH 7.2 phosphate buffer might
ical method selected.
be replaced by the RP-HPLC technique, which is
rapid, stable and reproducible.27
A rapid method was developed for the deter-
Other chemical tests mination of miconazole nitrate in suppositories.
It consisted of dissolving the sample in ethanol,
Any developed and validated analytical method dilution in acetonitrile/water 1:1) and injection
should be as simple as possible to help ensure onto a C18 column. The mobile phase con-
precision and accuracy. The development of a sisted of 55% acetonitrile, a triethylammonium
method can involve many steps. An example of a phosphate buffer and an ion-pairing agent and
“methods development” procedure and the data detection at 214 nm. The mean recovery was
generated follows. A similar approach can be used 98.8% for the suppositories and a total run time
for different chromatographic and spectroscopic of less than 4 minutes.28
methods. Other methods of analysis reported include
A methods development study was conducted HPLC and pulsed proton NMR.29,30
to determine the feasibility of using reverse phase A method was developed for the deter-
high-performance liquid chromatography (RP- mination of bisacodyl and its degradation
HPLC) for in vitro evaluation of the distribu- products using RP-HPLC.A C18 column, ultra-
tion behavior of nine common drugs (para- violet detector at 254 nm and a mobile
cetamol, caffeine, diclofenac, propyphenazone, phase of methanol/acetonitrile/0.02 M citric acid
indometacin, codeine base, codeine phosphate, (1:1:2) was used. The mean recovery for
phenobarbital acid, and phenobarbital sodium) bisacodyl from the commercial suppositories was
between one of the generally used suppository 99.7%.31,32
156 Suppositories
In another study, methods were developed for Some problems associated with aging include
investigating the release of carbon dioxide from the following:
effervescent suppositories containing sodium bi-
r An odor may emanate from suppositories with
carbonate and anhydrous sodium dihydrogen
phosphate for the purposes of formulation devel- vegetable extracts due to fungal contamina-
opment and quality control during production. tion.
r Suppositories with some dyes may discolor
Method 1 was conducted without stirring and
method 2 was with stirring; the evolution of due to oxidation of the dyes.
r The shape of some suppositories may be al-
carbon dioxide was measured using a gas bu-
rette. Three lots of commercial suppositories were tered during storage at incorrect temperatures,
used. Using method 1, only 60% of the carbon especially if they contain essential oils.
r Suppositories containing vegetable extracts or
dioxide was released in the medium without
polysorbate 80; since no stirring was involved, caffeine base may exhibit whitening on the
this was a “native” release profile. In method 2, surface.
r Suppositories containing camphor, menthol,
100% was released containing 1% polysorbate 80
with comparatively low standard deviations. The or other volatile substances that may be lost
authors concluded that method 1 would be most due to vaporization over time may lose weight
beneficial for comparing the effects of various during storage.
r Other aging phenomena, such as hardening,
factors, such as additives and melting points, on
the release profiles of carbon dioxide from the softening, bloom, mottling, discoloration and
suppositories; however, this method would not cracking may occur over time depending upon
be practical for quality control as only about 60% the composition of the suppositories and stor-
of the carbon dioxide was released. Method 2, age conditions.
on the other hand, would be useful because of
its complete release and low standard deviations.
These methods are applicable, therefore, to early
and late formulation studies of effervescent sup- References
positories, respectively.33
In summary, many different analytical meth- 1. Coben LJ, Lordi NG. Physical stability of semisyn-
ods from wet chemistry to modern instrumen- thetic suppository bases. J Pharm Sci 1980; 69: 955–
tal methods can be used for analytical test- 960.
ing of suppositories, after sampling and sample
2. Setnikar I, Fantelli S. Liquefaction time of rectal
preparation. A complete methods development suppositories. J Pharm Sci 1962; 51: 566–571.
is required to ensure accuracy, precision, and
reproducibility. 3. Guillot BR, Lombard AP ed. Le Suppositoire. Paris
Maloine S.A. 1973: 120–124.
4. Gold M, VePuri Murti Block LH. Suppository devel-

opment and production. In: Lieberman HA Rieger
MM Banker GS eds. Pharmaceutical Dosage Forms:
Aging and aging tests Disperse Systems, Vol. 2. New York Marcel Dekker
1996: 447–496.
Changes over time may alter the physical and/or 5. Azhgikhin IS. Determination of the hardness of
chemical properties of a suppository. Melting suppository bases using Kaminskii’s device. Aptechn
point fluctuations, for example, may occur either Delo 1965; 14: 14–19.
as a result of polymorphic changes in the ex-
6. Gjellan K, Graffner C. Comparative dissolution
cipient, in which case the temperature variation studies of rectal formulations using the basket, the
will be between 1 and 1.5◦ C maximum, or as a paddle and the flow-through methods. I. Paraceta-
result of evaporation of a volatile medicament mol in suppositories and soft gelatin capsules of
or because of physical or chemical reactions both hydrophilic and lipophilic types. Acta Pharm
between medicaments or excipients. Nord 1989; 1: 343–354.
7. Siewert M, Dressman J, Brown CK et al. FIP/AAPS using differential scanning calorimetry. Drug Dev
guidelines to dissolution/in vitro release testing Ind Pharm 2004; 30: 925–930.
of novel/special dosage forms. AAPS PharmSciTech
19. Ludde H, Nestler D. The content-uniformity of
2003; 4: E7.
dispensary-prepared rectal suppositories. Pharmazie
8. Roseman TJ, Derr GR, Nelson KG, Lieberman BL, 1990; 45: 47–50.
Butler SS. Continuous flow bead-bed dissolution
20. Setnikar I, Pietra V. Weight variations of rectal
apparatus for suppositories. J Pharm Sci 1981; 70:
suppositories; suggestions for weight uniformity
646–651.
specifications. J Pharm Sci 1969; 58: 112–116.
9. Woyczikowski B, Szule J, Sznitowska M, Janicki S,
21. Siegmund C, Leuenberger H. Percolation theory,
Pilichowski J, Urbanska A. Feasibility of the Ph.
conductivity and dissolution of hydrophilic suppos-
Eur. Flow-through cell for dissolution testing of
itory bases (PEG systems). Int J Pharm 1999; 189:
the compounded rectal suppositories containing
187–196.
indomethacin or sodium diclofenac. Acta Pol Pharm
2003; 60: 169–172. 22. Bornschein M. The influence of method/apparatus
conditions on the in vitro liberation of drugs from
10. Furuno K, Gomita Y, Yoshida T, Oishi R, Saeki K,
suppositories. Pharmazie 1986; 41: 852–854.
Araki Y. In vivo and in vitro release of indomethacin
from water-soluble and fatty base suppositories. 23. Hersey JA. Depot medication. In: Banker GS Rhodes
Acta Med Okayama 1992; 46: 223–231. CT eds. Modern Pharmaceutics. New York: Marcel
Dekker, 1979: 565–589.
11. Bozsik E, Kissne CE. Comparative evaluation
of dissolution and membrane transport meth- 24. Realdon N, Ragazzi E, Morpurgo M, Ragazzi E. In
ods of suppositories. Acta Pharm Hung 1993; 63: vitro methods for the evaluation of drug availability
290–295. from suppositories: comparison between biological
and artificial membranes. Pharmazie 2005; 60: 756–
12. Horvath G, Nagy K. Comparative in vitro dissolu-
760.
tion studies of piroxicam suppositories using the
basket, the paddle and the flow through methods. 25. Yamazaki M, Itoh S, Sasaki N, Tanabe K, Uchiyama
Acta Pharm Hung 1994; 64: 135–140. M. Modification of the dialysis membrane method
for drug release from suppositories. Pharm Res 1993;
13. Schobel H, Klaus T, Raguse U, Pflegel P. The determi-
10: 927–929.
nation of the real dissolution rate of drug substances
in melted suppository masses. Pharmazie 1988; 43: 26. Yamazaki M, Itoh S, Sasaki N, Tanabe K, Uchiyama
650–651. M. Modification of the dialysis membrane method
for drug release from suppositories. Pharm Res 1993;
14. Janicki S, Sznitowska M, Zebrowska W, Gabiga H,
10: 927–929.
Kupiec M. Evaluation of paracetamol suppositories
by a pharmacopoeial dissolution test – comments 27. Dimitrova B, Doytchinova I, Zlatkova M. Reversed-
on methodology. Eur J Pharm Biopharm 2001; 52: phase high-performance liquid chromatography
249–254. for evaluating the distribution of pharmaceu-
tical substances in suppository base-phosphate
15. Nair L, Bhargava HN. Comparison of in vitro disso-
buffer system. J Pharm Biomed Anal 2000; 23:
lution and permeation of fluconazole from different
955–964.
suppository bases. Drug Dev Ind Pharm 1999; 25:
691–694. 28. Tyler TA, Genzale JA. Liquid chromatographic de-
termination of miconazole nitrate in creams and
16. Koch HP, Klissenbauer C, Ritzinger A, Wallentin A.
suppositories. J Assoc Off Anal Chem 1989; 72: 442–
In vitro studies of drug liberation from suppositories
444.
with the rotating flask method. Pharmazie 1987; 42:
169–172. 29. Chang ZL, Boller JP, Pacenti DM, Wong CF. Rapid
high-performance liquid chromatographic deter-
17. Anon U.S. Pharmacopeia 30–National Formulary 25.
mination of pramoxine hydrochloride in topical
Rockville, MD U.S. Pharmacopeial Convention
cream and suppositories. J Chromatogr 1984; 291:
2007.
428–433.
18. Noordin MI, Chung LY. A rapid micro quantifi-
30. DeBlaey CJ, Varkevisser FA, Kalk A. Pulsed proton
cation method of paracetamol in suppositories
NMR and solid-liquid fat ratio determinations in
158 Suppositories
suppository vehicles and aminophylline supposito- impurities in enteric coated tablets and supposi-
ries. Pharm Weekbl Sci 1984; 6: 203–208. tory formulations and in vitro dissolution of en-
teric coated tablets. J Pharm Sci 1982; 71: 1049–
31. Valenti LP, Lau-Cam CA. Reverse phase liquid chro- 1052.
matographic determination of bisacodyl in dosage
forms. J Assoc Off Anal Chem 1985; 68: 529–532. 33. Hakata T, Iijima M, Okabe T et al. Methods of evalu-
ation of release of carbon dioxide from effervescent
32. Kirchhoefer RD, Jefferson E, Flinn PE. Aspirin – a suppositories. Chem Pharm Bull (Tokyo) 1993; 41:
national survey V: Determination of aspirin and 346–350.
10
Packaging and labeling of suppositories
THE PROPER packaging, labeling, and storage strip with the individual suppositories separated
of pharmaceutical products are all essential for by perforations between them (Figure 10.1).
product stability and efficacious use. Everyone Suppositories are also commonly packaged in
involved, including the manufacturer, wholesale slide boxes or in plastic boxes.
distributor, pharmacist, and patient, must be
informed and educated about the handling and
storage of the suppository to ensure the patient Containers
receives the intended therapeutic benefit.
Standards for the packaging of pharmaceuti-
cals, including suppositories, by manufacturers
are contained in the current Good Manufac-
Packaging
turing Practice section of the Code of Fed-
eral Regulations, in the United States Pharma-
Suppository packaging varies according to the copeia (USP)/National Formulary, and in the
constitutents and should result in proper stor- FDA’s Guideline for Submitting Documentation
age and attractive presentation of the product. for Packaging for Human Drugs and Biologics.
Suppositories should either be wrapped individ- When submitting a new drug application for
ually or dispensed in the disposable molds in a suppository dosage form, the manufacturer
which they are prepared. If suppositories are not must include all relevant specifications for the
packaged properly, they may become deformed, packaging. During the initial stages of clinical
stained, broken, or chipped. Foil suppository investigations, the packaging must be shown to
wrappers are available in various colors. Wrapped be effective in providing adequate drug stability
suppositories are usually placed in wide-mouthed for the duration of the clinical trials. As the
containers or in slide, folding, or partitioned clinical trials advance to their final stage, infor-
boxes for dispensing to the patient. Suppositories mation must be developed on the chemical and
that are dispensed in disposable molds are often physical characteristics of the container, closure,
placed in cardboard sleeves or plastic bags. and other component parts of the package system
Glycerin suppositories and glycerinated for the proposed suppository product to ensure
gelatin suppositories are generally packaged drug stability for its anticipated shelf-life.
in tightly closed glass containers to prevent The package and closure system must be
moisture change. Suppositories prepared shown to be effective for the particular suppos-
from a cocoa butter base are usually itory composition. Depending on the container,
individually wrapped or otherwise separated among the tests performed are: physicochemical
in compartmentalized boxes to prevent tests; light-transmission tests for glass or plastic;
contact and adhesion. Suppositories containing drug compatibility; leaching and/or migration
light-sensitive drugs are individually wrapped in tests; vapor-transmission test for plastics; mois-
an opaque material such as a metallic foil. In ture barrier tests; toxicity studies for plastics; and
fact, most commercially available suppositories drug stability for all packaging used.
are individually wrapped in either foil or a plastic Suppositories may be individually wrapped in
material. Some are packaged in a continuous a material and the wrapped suppositories placed
159
160 Suppositories
Figure 10.1 Examples of single unit and multiple unit packages. Photo courtesy of Paddock Laboratories, Inc.,
Minneapolis, MN.
in a carton. Or the suppositories may be bulk under the ordinary or customary conditions of
packaged in a glass or plastic jar. This provides handling, shipment, storage, and distribution,
intimate contact for the suppository materials and is capable of tight re-closure. Suppositories
with the containers in both scenarios. Compen- are generally packaged in tight containers.
dial terms applying to types of containers and Suppositories may be packaged in single-unit
conditions of storage have defined meanings. or multiple-unit containers. A single-unit con-
According to the USP, a container is that which tainer is designed to hold a quantity of drug
holds the article and is or may be in direct contact intended for administration as a single dose
with the article. The immediate container is that promptly after the container is opened. Multiple-
which is in direct contact with the article at unit containers contain more than a single unit
all times. The closure is part of the container. or dose of the medication (Figure 10.2). A single-
The container, including the closure, should be unit package is termed a unit-dose package when
clean and dry prior to its being filled with the dispensed to a patient. The single-unit packaging
drug. The container must not interact physically of drugs may be performed on a large scale by a
or chemically with the drug so as to alter its manufacturer or distributor or on a smaller scale
strength, quality, or purity beyond the official by the pharmacy dispensing the medication. In
requirements. either instance, the single-unit package must be
Containers are classified by the USP according appropriately labeled with the product identity,
to their ability to protect their contents from quality and/or strength, name of manufacturer,
external conditions. The minimally acceptable and lot number of product to ensure the positive
container is termed a well-closed container. It identification of the medication.
protects the contents from extraneous solids Although single-unit packaging has particu-
and from loss of the article under ordinary lar usefulness in institutional settings such as
conditions of handling, shipment, storage, and hospitals and extended care facilities, it is not
distribution. A tight container protects the con- limited to such. Many outpatients find single-
tents from contamination by extraneous liquids, unit packages a convenient and sanitary means
solids, or vapors, from loss of the article, and of maintaining and utilizing their medication.
from efflorescence, deliquescence, or evaporation Among the advantages cited for single-unit
Chapter 10 • Packaging and labeling of suppositories 161
Figure 10.2 Plastic/rubber suppository mold (disposable) with package sleeve for dispensing. Photo courtesy of
Professional Compounding Centers of America, Houston, TX.
packaging and unit-dose dispensing are: positive intended to provide protection from light or
identification of each dosage unit and reduction those offered as “light-resistant” must meet the
of medication errors; reduced contamination of USP standards which define the acceptable limits
the drug due to its protective wrapping; reduced of light transmission at any wavelength between
dispensing time; greater ease of inventory con- 290 and 450 nm.
trol in the pharmacy or nursing station; and
elimination of waste through better medication
management with less discarded medication. Glass containers
Some suppository products require light- The glass used in packaging pharmaceuticals is
resistant containers to protect them from photo- classified into four categories, depending upon
chemical deterioration. If the suppositories are the chemical constitution of the glass and its
not individually wrapped, then in most instances ability to resist deterioration. Table 10.1 presents
a bulk container made of a good-quality am- the chemical make-up of the various glasses;
ber glass or light-resistant opaque plastic will types I, II, and III are intended for parenteral
reduce light transmission sufficiently to protect products and type NP is intended for non-
a light-sensitive pharmaceutical. Agents termed parenteral products. Each type is tested according
UV-absorbers may be added to plastic to decrease to its resistance to water attack. Pharmaceutical
the transmission of short ultraviolet rays. The manufacturers must select and utilize containers
USP provides tests and standards for glass and that do not adversely affect the composition or
plastic containers with respect to their ability stability of their products. Type NP can be used
to prevent the transmission of light. Containers in packaging suppositories.
162 Suppositories
the amounts and types of plasticizers, fillers,

Table 10.1 Constitution of official glass types
lubricants, pigments, and other additives used,
the pressure conditions, and the temperature.
Type General description In general, increases in temperature, pressure,
and the use of additives tend to increase the
I Highly resistant, borosilicate glass permeability of the plastic. Glass containers are
II Treated soda-lime glass
less permeable than plastic containers.
III Soda-lime glass
The movement of moisture vapor or gas,
NP General purpose soda-lime glass
especially oxygen, through a pharmaceutical
container can pose a threat to the stability
of the suppository. Specially developed “high-
Plastic containers
barrier” packaging can provide added protection
Today most suppositories are packaged in plastic. to suppositories against the effects of humidity.
The widespread use of plastic containers has been Drug substances in suppositories that are subject
generated by a number of factors, including: its to oxidative degradation may undergo a greater
advantage over glass in lightness of weight and degree of degradation when packaged in plastic
resistance to impact, thus lowering transporta- than in glass. In glass, the container’s void space
tion costs and losses due to container damage; is confined and presents only a limited amount
the versatility of container design and in con- of oxygen to the drug contents, whereas a drug
sumer acceptance; and the popularity of blister- packaged in a gas-permeable plastic container
packaging and unit-dose dispensing, particularly may be constantly exposed to oxygen due to
in healthcare institutions. Plastic is especially the replenished air supply entering through the
appropriate for continuous-mode manufacturing container.
as described in Chapter 6.
Leaching
Packaging problems Leaching is a term used to describe the movement
of components of a container into the contents.
Among the problems encountered in the use of Compounds leached from plastic containers are
plastics in packaging are (1) permeability of the generally the polymer additives such as the plas-
containers to atmospheric oxygen and to mois- ticizers, stabilizers, or antioxidants. The leaching
ture vapor; (2) leaching of the constituents of the of these additives occurs predominantly when
container to the internal contents; (3) absorption liquid or semi-solid dosage forms are packaged
of drugs from the contents to the container; and in plastic, but can occur with solid suppositories
(4) other changes that can lead to alteration of in direct contact with the container walls or
the container upon storage. Further agents are individually packaged in plastic.
frequently added to alter the properties of plastic, Leaching may be influenced by temperature,
including plasticizers, stabilizers, antioxidants, excessive agitation of the filled container, and
antistatic agents, antimold agents, colorants, and by the solubilizing effect of the product contents
others. on one or more of the polymer additives. Thus,
studies of the leaching characteristics of each
plastic material considered for use are undertaken
Permeation as a part of the drug development process.
Permeation is considered a process of solution
and diffusion, with the penetrant initially dis-
Sorption
solving in the plastic material on one side and
diffusing through to the other side. The per- Sorption is a term used to indicate the binding of
meability of a plastic is a function of several molecules to polymer materials. Both adsorption
factors including the nature of the polymer itself, and absorption may be considered within this
term. Sorption occurs through chemical or phys- packaged in a material (plastic) that presents a
ical means due to the chemical structure of the formidable barrier.1
solute molecules and the physical and chemical In another study of 94 patients with rheuma-
properties of the polymer. toid arthritis in the Netherlands, two-thirds
Sorption may occur with active pharmacologic had difficulty with packages used for suppos-
agents or with pharmaceutical excipients. Thus, itories. The suppositories were for the treat-
each ingredient must be examined in the pro- ment of rheumatoid arthritis and included
posed plastic packaging to determine its tendency naproxyn, diclofenac, ketoprofen, ibuprofen,
for sorption from the suppository. The sorption and indometacin contained in plastic or alu-
of an active pharmacologic agent from a suppos- minum wrapping, and two were in a slide-out
itory may reduce its effective concentration. The system. The problems were so great that about
sorption of pharmaceutical excipients as such 28% of the patients could not open these pack-
as colorants, preservatives, or stabilizers would ages themselves at home and almost half required
likewise alter the quality of the product. some kind of aid to open the package. The
aluminum wrapping was the most difficult, the
plastic wrapping intermediate, and the slide-out
Others system the easiest.2
In a study of 50 patients having rheumatoid
Miscellaneous other changes that can occur in
arthritis with hand involvement and 50 normal
suppositories include discoloration, deformation,
subjects, only 54% of the rheumatoid arthritis
softening, hardening, and other physical changes
patients were able to remove a suppository from
in plastic containers that can occur due to the
its plastic wrapping. Clearly, it is difficult for a
action of the container’s contents or to external
pharmacist to be able to identify those patients
factors such as changes in temperature or the
unable to open suppository packages. This may
physical stress placed upon the container in
be alleviated by a closer relationship between the
handling and shipping.
patient and the pharmacist.3
It is always good practice for the pharmacist
to dispense medication to patients in the same
type and quality of container as that used by the
Child-resistant/adult–senior use packaging
manufacturer of the product. In some instances
the original container may be used to dispense
To reduce the occurrence of accidental poison-
the medication.
ings through the ingestion of drugs and other
household chemicals, in the United States the
Poison Prevention Packaging Act was passed into
Special packaging for patients with arthritis law in 1970. The initial regulations called for the
use of “child-proof” closures for aspirin products
Patients with arthritis may have difficulty in and certain household chemical products shown
opening containers and in opening the plastic to have a significant potential for causing acci-
or foil packaging in which suppositories are pack- dental poisoning in youngsters.
aged. In one study of 20 patients with rheumatoid As the technical capability to produce effective
arthritis and mild to moderate impairment of closures was developed, the regulations were
hand function, their ability to open three types extended to include the use of safety closures
of suppository package were investigated. Three in the packaging of both prescription and over-
were unable to open indometacin suppository the-counter medications, unless the product is
packages, six were unable to open the ketoprofen, exempt from the requirement.
and four were unable to open the naproxen. A child-resistant container is defined as one
The summary of the study stated that with that is significantly difficult for a child under
sophisticated plastics currently available, it seems 5 years of age to open or to obtain a harmful
unreasonable that a medication designed for amount of its contents within a reasonable time
the benefit of patients with arthritis should be and is not difficult for “normal adults” to use
164 Suppositories
properly. In recognition that many adults, par- packages for consumer purchase. Today, the
ticularly the elderly or those with arthritis or current Good Manufacturing Practice regula-
weakened hand strength, have difficulty opening tions require tamper-evident packaging for non-
child-resistant packages, the regulations were prescription drug products to improve their secu-
amended and (effective in 1998) to require that rity and to ensure their safety and effectiveness.
child-resistant containers be capable of being A tamper-evident package is defined as “one
readily opened by senior adults. having one or more indicators or barriers to
entry which, if breached or missing, can reason-
ably be expected to provide visible evidence to
Compliance packaging consumers that tampering has occurred”.4 The
indicators or barriers may involve the immediate
Many patients are not compliant with the pre- drug product container and/or an outer container
scribed schedule for taking their medications. or carton. For two-piece hard gelatin capsule
There are many factors associated with non- products, a minimum of two tamper-evident
compliance, such as a misunderstanding of the packaging features is required unless the cap-
dosing schedule, confusion due to the taking of sules are sealed by a tamper-resistant technology.
multiple medications, forgetfulness, or a feeling Table 10.2 lists some examples of tamper-evident
of well-being leading to premature discontinu- packaging.
ance of medication.
To assist patients in taking their medications
on schedule, manufacturers and pharmacists
have devised numerous educational techniques,
Labeling
reminder aids, compliance packages, and devices.
The oral contraceptive compact-type plastic pack-
age was among the earliest product packages Labels must meet the legal requirements for
developed to assist patient adherence to a pre- content. Each label must state expiration date
scribed dosing schedule. Subsequently, many and the production batch or lot number to fa-
other packaging innovations were developed, in- cilitate product identification. For compounded
cluding blister-packaging in a calendar pack. For suppositories, it is a beyond-use date. Special
prescriptions dispensed in traditional containers packaging requirements may apply in certain
(e.g. capsule vials), pharmacists often provide instances, such as tamper-evident packaging for
calendar medication schedules or commercially over-the-counter products.
available compartmentalized devices for the daily Important information for a prescription-only
or weekly scheduling of solid dosage units. These drug is provided to health professionals through
medication compliance techniques and devices the manufacturer’s product package insert. The
are particularly useful for patients taking multiple package insert must provide full disclosure, that
medications, including suppositories. is, a full and balanced presentation of the drug
product to enable the prescriber to use the drug
with sufficient knowledge of important benefit-
Tamper-evident packaging to-risk factors.4
A note of concern about labeling was pub-
On November 5, 1982, the Food and Drug lished by Kitsberg and Belavadi in relation to
Administration published initial regulations on the inclusion of the batch number and the
tamper-resistant packaging in the Federal Reg- expiry date on each individual suppository. This
ister. These regulations were promulgated after is important, the authors indicate, because of
the criminal tampering with non-prescription the pressures to reduce healthcare costs, and if
drug products earlier in that year resulting suppositories are not properly labeled with the
in consumer illness and deaths. In the pri- required information, it would result in their
mary incident, cyanide had been surreptitiously being discarded prematurely and increase drug
placed in acetaminophen capsules in commercial costs.5
Table 10.2 Tamper-evident packaging examples
Package type Tamper protection
Film wrappers Film wrapped and sealed around product and/or product containers; the film must
be cut or torn to remove product
Blister/strip packs Individually sealed dosage units; removal requires tearing or breaking individual
compartment
Bubble packs Product and container sealed in plastic, usually mounted on/in display card; plastic
must be cut or broken open to remove product
Shrink seals/bands Bands or wrappers which are shrunk by heat or drying to conform to cap and
containers must be torn to open
Foil, paper, or plastic pouches Sealed individual packets; must be torn to reach product
Bottle seals Paper or foil sealed to mouth of a container under cap; must be torn or broken to
reach product
Tape seals Paper or foil sealed over carton flap or bottle cap; must be torn or broken to reach
product
Breakable caps Plastic or metal “tearaway” caps over container; must be broken to remove
Sealed tubes Seal over mouth of tube; must be punctured to reach product
Sealed cartons Carton flaps are sealed; carton cannot be opened without damage
Aerosol containers Tamper-resistant by design
References 3. Lisberg RB, Higham C, Jayson MI. Problems for

rheumatic patients in opening dispensed drug con-
tainers. Br J Rheumatol 1983; 22: 95–98.
1. Doube A. Rectal suppositories and packaging. N Z
Med J 1985; 98: 869. 4. Code of Federal Regulations 21, Parts 200 to
299. Revised as of April 1, 2006, pp. 8–89, 145–
2. Verheggen-Laming BN, Phiferons H, Mulder EF, Van 146.
Der Meij NT, van Harten RP, Dijkmans BA. Compar-
ison of packages for suppositories by patients with 5. Kitsberg A, Belavadi P. Packaging of generic di-
rheumatoid arthritis. Scand J Rheumatol 1988; 17: clofenac suppositories. Anaesthesia 2004; 59: 197–
161–165. 198.
166
11
Stability and storage of suppositories
STABILITY , as it relates to a dosage form such

as a suppository, refers to the chemical and Table 11.1 Five types of stability generally
physical integrity of the dosage unit and, when recognized
appropriate, the ability of the dosage unit to
maintain protection against microbiological con- Conditions maintained throughout the
tamination. Type of stability shelf life of the drug product
The United States Pharmacopeia (USP) descrip-
Chemical Each active ingredient retains its
tion of stability considerations for suppositories
chemical integrity and labeled
includes observations of excessive softening and
potency, within the specified limits
evidence of oil stains on packaging materials.
Physical The original physical properties,
The pharmacist may occasionally need to remove
including appearance,
the wrappings of individual suppositories to palatability, uniformity,
check for evidence of instability. In some cases, dissolution, and suspendability,
suppositories may dry out, harden, or shrivel. As are retained
a general rule, the guidelines recommend storage Microbiological Sterility or resistance to microbial
in a refrigerator, unless indicated otherwise. growth is retained according to
Pharmacists should avoid ingredients and the specified requirements.
conditions that could result in excessive physi- Antimicrobial agents that are
cal deterioration or chemical decomposition of present retain effectiveness within
drug preparations, especially when compound- the specified limits
ing. Pharmacists should also establish and main- Therapeutic The therapeutic effect remains
tain compounding conditions that include the unchanged
assurance of drug stability to help prevent ther- Toxicological No significant increase in toxicity
apeutic failure and adverse responses. Suppos- occurs
itories prepared without the aid of water are
reasonably stable.
chemical integrity and labeled potency within
Stability is defined as the extent to which
the specified limits. Microbiological stability in
a product retains, within specified limits, and
suppositories means that resistance to microbial
throughout its period of storage and use (i.e. its
growth is retained according to the specific re-
shelf-life), the same properties and characteristics
quirements.
that it possessed at the time of its manufacture.
The USP recognizes five types of stability, as
listed in Table 11.1. Of these, we are primarily
Physical stability
concerned with physical, chemical, and micro-
biological. Physical stability primarily refers to
the physical characteristics of the suppository Listed in Table 11.2 are the major modifica-
where the original physical properties, including tions of suppository characteristics due to natural
appearance, palatability, uniformity, dissolution, aging, as well as the causes. Physical observa-
and other characteristics, are retained. Chemical tion can generally detect physical stability prob-
stability means each active ingredient retains its lems, including softening, hardening, drying,
167
168 Suppositories
as stable as if the same drug were added to

Table 11.2 Major modifications of suppository
a polyethylene glycol (PEG)-based suppository
characteristics due to natural aging, as well as the containing water.
causes
Modifications Causes Examples

Chemical stability
Odor Fungal contami- Suppositories with
nation vegetable
extracts The majority of suppositories are not anhydrous,
Color Discoloration Suppositories with so the presence of water is not usually an issue.
due to tartrazine However, in some cases, water may be present
oxidation yellow aqueous to help incorporate the drug into the base or it
solution may be present as part of the hydrated form of
Shape Incorrect Suppositories with the drug components’ crystalline structure. Also,
temperature essential oils if emulsions or suspensions are incorporated into
during suppositories, water may be present. Last, some
storage suppositories may be hygroscopic and absorb
Surface Whitening Suppositories with water from the atmosphere. Consequently, some
condition vegetable of the issues related to instability in water will
extracts or also be discussed here.
caffeine base
suppositories
Weight Loss of volatile Suppositories with
substances camphor, Factors affecting stability
menthol, etc.
Each ingredient in a suppository, whether thera-

cracking, separation, formation of polymorphs peutically active or pharmaceutically necessary,
(affecting melting range), and often the odor of can affect the stability of the drug and the
rancidity. suppository itself. The primary environmental
The formation of polymorphs is evidence of factors that can reduce stability include expo-
cocoa butter instability during preparation. These sure to adverse temperatures, light, humidity,
polymorphs may be liquid at room temperature. oxygen, and carbon dioxide. The major dosage
To avoid this situation, an appropriate hydro- form factors that influence drug stability include
genated vegetable oil base can be substituted particle size, pH, solvent system composition,
for the cocoa butter. If necessary, fatty materials primary container, specific chemical additives,
with higher melting points, such as white wax and molecular binding and diffusion of drugs and
or paraffin, can be added to fatty bases or excipients.
cocoa butter, which have low melting points, to In suppositories, the following reactions usu-
increase the melting point of the formulation. ally cause loss of active drug content, and they
However, the suppository must be able to melt usually do not provide obvious visual or olfactory
when administered. To check the melting point, evidence of their occurrence.
the pharmacist can place a sample suppository in
a beaker of water that has been heated to 37 ◦ C.
Hydrolysis
If the suppository does not melt, the formulation
should not be used for patient therapy. Esters and ␤ lactams are the chemical bonds that
If water is incorporated into an oily base using are most likely to hydrolyze in the presence of
an emulsifying agent (non-ionic surfactant, wool water. For example, the acetyl ester in aspirin is
fat, and the like), the product may become rancid. hydrolyzed to acetic acid and salicylic acid in the
In this case the suppository usually will not be presence of moisture (water vapor).
Chapter 11 • Stability and storage of suppositories 169
The amide bond also hydrolyzes, though gen- Photochemical decomposition

erally at a slower rate than comparable esters.
Exposure to, primarily, UV illumination may
For example, procaine (an ester) will hydrolyze
cause oxidation (photo-oxidation) and scission
upon autoclaving, but procainamide will not.
(photolysis) of covalent bonds. Nifedipine, nitro-
The amide or peptide bond in peptides and
prusside, riboflavin, and phenothiazines are very
proteins varies in its lability to hydrolysis.
labile to photo-oxidation. In susceptible com-
The lactam and azomethine (or imine) bonds
pounds, photochemical energy creates free rad-
in benzodiazepines are also labile to hydrolysis.
ical intermediates, which can perpetuate chain
The major chemical accelerators or catalysts of
reactions.
hydrolysis are adverse pH and specific chemicals
(e.g. dextrose and copper in the case of ampicillin
hydrolysis). pH effect
The degradation of many drugs in solution ac-
celerates or decelerates exponentially as the pH
Epimerization is decreased or increased over a specific range
Members of the tetracycline family are most of pH values. This can occur in any suppository
likely to incur epimerization, resulting in loss of containing an aqueous solution of the drug.
antibacterial activity. This reaction occurs rapidly Improper pH ranks with exposure to elevated
when the dissolved drug is exposed to a pH of an temperature as a factor most likely to cause a
intermediate range (higher than 3), and it results clinically significant loss of drug, resulting from
in the steric rearrangement of the dimethylamino hydrolysis and oxidation reactions.
group.
Temperature
In general, the rate of a chemical reaction
Decarboxylation increases exponentially for each 10◦ C increase
Some dissolved carboxylic acids, such as p- in temperature. The pharmacist should also be
aminosalicylic acid (sometimes used in suppos- aware that inappropriately cold temperatures
itories), lose carbon dioxide from the carboxyl may cause harm; freezing may cause some sup-
group when heated. The resulting product has pository bases to become brittle.
reduced pharmacological potency.
Microbiological stability
Dehydration
Acid-catalyzed dehydration of tetracycline forms Most suppository formulations do not contain
epianhydrotetracycline, a product that both lacks preservatives or antioxidants since water is usu-
antibacterial activity and causes toxicity. ally excluded from the formulations. However, in
the event that water is present or the formulation
may support the growth of microorganisms, an
Oxidation appropriate preservative may be indicated.
The molecular structures most likely to oxidize

are those with a hydroxyl group directly bonded
Stability studies for suppositories
to an aromatic ring (e.g. phenol derivatives such
as catecholamines and morphine), conjugated
dienes (e.g. vitamin A and unsaturated free fatty The scope and design of a stability study uti-
acids), heterocyclic aromatic rings, nitroso and lizing suppositories may vary according to the
nitrite derivatives, and aldehydes (e.g. flavor- manufacturer concerned. Ordinarily the formu-
ings). Products of oxidation usually lack thera- lator of the suppository first determines the
peutic activity. effects of temperature, light, air, pH, moisture,
170 Suppositories
trace metals, and commonly used excipients or at the time of use, a commercially manufactured
solvents on the active ingredient(s). From this suppository must bear an expiration date deter-
information, one or more formulations of the mined by appropriate stability testing. Exempt
suppository are prepared, packaged in suitable from this requirement are homeopathic drug
containers, and stored under a variety of en- products, allergenic extracts, and investigational
vironmental conditions, both exaggerated and new drugs providing the latter meet the stan-
normal. At appropriate time intervals, samples of dards established during preclinical and clinical
the suppositories are assayed for potency by use studies.
of a stability-indicating method, and observed for
physical changes, including microbial growth.
Such a study, in combination with clinical and Storage of suppositories
toxicological results, enables the manufacturer to
select the optimum formulation and container To ensure the stability of a pharmaceutical prepa-
and to assign recommended storage conditions ration for the period of its intended shelf-life, the
and an expiry date for each dosage form in its product must be stored under proper conditions.
package. The labeling of each product includes the desired
conditions of storage. The terms generally em-
Beyond-use dating for compounded ployed in such labeling have meanings defined
suppositories by the USP:
r Cold: Any temperature not exceeding 8◦ C

There are numerous suppositories that are rou-
(46◦ F). A refrigerator is a cold place in which
tinely compounded, some of which are listed
the temperature is maintained thermostatically
in Appendix II. The completed compounded
between 2◦ C and 8◦ C (36–46◦ F). A freezer is a cold
suppositories are generally considered dry or non-
place in which the temperature is maintained
aqueous and thus provide a stable dosage form
thermostatically between –25◦ C and –10◦ C (–13◦ F
as long as they are protected from moisture and
to 14◦ F).
heat. According to the USP General Chapter 795
Pharmaceutical compounding – nonsterile, these r Cool: Any temperature between 8◦ C and 15◦ C
preparations should have a beyond-use date of (46–59◦ F). An article for which storage in a cool
25% of the time remaining on the expiry date place is directed may alternatively be stored in
if the compounded preparation is made using a a refrigerator unless otherwise specified in the
manufactured product as the source of the active individual monograph.
drug, or six months, whichever is earlier. If the r Room temperature: The temperature prevail-
product is prepared from USP-NF ingredients, a
ing in a working area. A controlled room temper-
beyond-use date of six months is appropriate,
ature encompasses the usual working environ-
unless evidence is available to support other
ment of 20–25◦ C (68–77◦ F) but also allows for
dating.1
temperature variations between 15◦ C and 30◦ C
If the stability of a compounded water-
(59–86◦ F) that may be experienced in pharma-
containing preparation is unknown and there
cies, hospitals, and drug warehouses.
are no other supporting data for an alternate
beyond-use date, then a beyond-use date of 14 r Warm: Any temperature between 30◦ C and
days when stored in a refrigerator can be used.1 40◦ C (86–104◦ F).
r Excessive heat: Any temperature above 40◦ C
Expiry dating for manufactured (104◦ F).
suppositories r Protection from freezing: Where in addi-
tion to the risk of breakage of the container,
To ensure that a drug product meets applicable freezing subjects a product to loss of strength
standards of identity, strength, quality and purity or potency, or to destructive alteration of the
dosage form, the container label bears an ap- Holding and distribution
propriate instruction to protect the product from
freezing.
Written procedures for the holding and distribu-
tion of suppositories must be established and fol-
Since suppositories are adversely affected by heat,
lowed. Generally, finished pharmaceuticals must
it is necessary to maintain them in a cool place.
be quarantined in storage until released by the
Suppositories stored in environments of high hu-
quality control unit. Products must be stored and
midity may absorb moisture and tend to become
shipped under conditions that do not affect their
spongy, whereas suppositories stored in places of
quality. Ordinarily, the oldest approved stock is
extreme dryness may lose moisture and become
distributed first. A distribution control system
brittle.
must be in place through which the distributed
Suppositories with cocoa butter as the base
point of each lot of drug product may be readily
must be stored below 30◦ C, and preferably in
determined to facilitate its recall if necessary.
a refrigerator (2–8◦ C). Glycerinated gelatin sup-
positories can routinely be stored at controlled
room temperature (20–25◦ C). Suppositories made
from a base of PEG may be stored at usual room Transportation
temperatures without the requirement of refrig-
eration. Glycerin and PEG-based suppositories The stability protection of suppositories during
should be protected from moisture, as they tend periods of transportation is an important con-
to be hygroscopic. Suppositories should not be sideration, especially during summer months.
frozen. However, maintenance of satisfactory conditions
Increase in the storage time of fatty acid-type of temperature and humidity during shipment is
suppositories generally results in increases in not always practiced. Temperature and humidity
the liquefaction times. For the suppository to variations to which suppositories may be exposed
deliver its drug, the fatty acid-type suppositories may occur during shipment from a manufacturer
must first melt. Fatty acid-based suppositories are to a wholesaler or to a pharmacy, from a phar-
composed of short-chain fatty acids that may macy to a patient, during mail-order shipment
undergo gradual, polymorphic changes in the of prescriptions (and their residence in mail-
matrix that may consist of various proportions boxes), or when medications are maintained in
of polymorphic crystals with different melting emergency-care vehicles. Transportation to and
points. Storage at higher temperatures tends to within geographic areas of extreme temperatures
increase the rate of these polymorphic changes. and humidity requires special consideration.
In a study to demonstrate this, 400 suppositories
were made from Witepsol H15, Fattibase, and
cocoa butter. They were packaged in amber plas-
Responsibility of pharmacists
tic prescription vials, labeled and divided equally
into three groups then cured for two days at 25◦ C.
They were then stored at either 10, 25 or 30◦ C for According to the USP, pharmacists help to ensure
13 weeks before determining their liquefaction that the products under their supervision meet
times. After storage for 13 weeks at the higher acceptable criteria of stability by (1) dispensing
temperature, obvious melting did not occur; the oldest stock first and observing expiry dates,
matrix now consisted of crystals suspended in (2) storing products under the environmental
the melted portion of the matrix. The conclusion conditions stated in the individual monographs,
of the study was that if the liquefaction time labeling, or both, (3) observing products for
of a suppository is clinically important, then evidence of instability, (4) properly treating and
suppositories prepared using Fattibase, cocoa but- labeling products that are repackaged, diluted, or
ter, or Witepsol H15 should be stored under mixed with other products, (5) dispensing in the
refrigeration to prevent substantial lengthening proper container with the proper closure, and
of liquefaction time.2 (6) informing and educating patients about the
172 Suppositories
proper storage and use of the products, including Chemical changes may also occur through in-
the disposal of outdated or excessively aged teraction between ingredients within a product,
prescriptions. or rarely between product and container. An ap-
parent loss of potency in the active ingredient(s)
may result from diffusion of the drug into, or its
Rotation of stock and observance of combination with, the surface of the container–
expiry dates closure system. An apparent gain in potency
usually is caused by solvent evaporation or by
Proper rotation of stock is necessary to ensure leaching of materials from the container–closure
the dispensing of suitable products. A product system.
that is dispensed infrequently should be closely The chemical potency of the active ingredi-
monitored so that old stocks are given special at- ent(s) is required to remain within the limits
tention, particularly with regard to expiry dates. specified in the monograph definition. Potency
The manufacturer can guarantee the quality of a is determined by means of an assay procedure
product up to the time designated as its expiry that differentiates between the intact molecule
date only if the product has been stored in the and its degradation products. Chemical stability
original container under recommended storage data should be available from the manufacturer.
conditions. Although chemical degradation ordinarily can-
not be detected by the pharmacist, excessive
chemical degradation sometimes is accompanied
Storage under recommended environmental by observable physical changes. A gross change
conditions in a physical characteristic such as color or odor
is a sign of instability in any product.
In most instances, the recommended storage As previously mentioned, excessive softening
conditions are stated on the label, in which case it is the major indication of instability in supposi-
is imperative to adhere to those conditions. They tories, although some suppositories may dry out
may include a specified temperature range or a and harden or shrivel. Evidence of oil stains on
designated storage place or condition (e.g. “re- packaging material should warn the pharmacist
frigerator,” or “controlled room temperature”). to examine individual suppositories more closely
Supplemental instructions, such as a direction to by removing any foil covering. As a general rule
protect the product from light, also should be (although there are exceptions), suppositories
followed carefully. Where a product is required should be stored in a refrigerator.
to be protected from light and is in a clear
or translucent container enclosed in an opaque
outer covering, such outer covering must not be
removed and discarded until the contents have Informing and educating the patient
been used.
In the absence of specific instructions, the As a final step in meeting responsibility for the
product should be stored at controlled room stability of drugs dispensed, the pharmacist is
temperature. The product should be stored away obliged to inform the patient about the proper
from locations where excessive or variable heat, storage conditions (for example, in a cool, dry
cold, or light prevail, such as those near heating place – not in the bathroom) for both pre-
pipes or in direct sunlight. scription and non-prescription products, and to
suggest a reasonable estimate of the time after
which the medication should be discarded. When
Observing products for evidence of beyond-use dates are applied, the pharmacist
instability should emphasize to the patient that the dates
are applicable only when proper storage condi-
Loss of potency usually results from a chemi- tions are observed. Patients should be encour-
cal change, the most common reactions being aged to clean out their drug storage cabinets
hydrolysis, oxidation–reduction, and photolysis. periodically.
Drug-specific stability studies A study of theophylline (250 mg) and amino-

phylline (300 mg) suppositories formulated with
Suppocire both immediately after preparation
Several studies have been reported in the litera-
and after 1 year storage at room temperature was
ture related to the stability of specific drugs in
conducted in six healthy volunteers. The release
suppositories.
rate of aminophylline after 1 year dropped from
4.8 to 0.5 mg/min. Other changes have also been
reported.6,7
Aminophylline In 1982, a report from Japan evaluated 100 mg
aminophylline suppositories prepared using var-
Absorption from aminophylline suppositories in ious bases in a hospital pharmacy. They investi-
a cocoa butter base administered to a group of gated the melting points and the disintegration
volunteers was determined after storage at 30◦ C and liquefaction with age. They demonstrated
for eight weeks. The absorption was determined that ethylenediamine in the aminophylline re-
in four healthy male volunteers by comparing acted with the Witepsol constituents to form
the suppositories with an oral hydroalcoholic an acid amide linkage. These suppositories were
solution of aminophylline, which had been stable at a lower temperature. PEG-based suppos-
previously shown to be completely absorbed. itories were found to be the most satisfactorily
The results showed that the aged supposito- stable at room temperature.8
ries demonstrated that not more than 20% of The physical and chemical stability of amino-
the administered drug was absorbed, compared phylline 100 mg suppositories prepared using
to the oral solution. The authors recommend Witpesol H15, Witepsol W35, Witepsol E75, a
that the directions “keep cool” or even “keep blend of Witepsol H15 with Witepsol E75 and
in refrigerator” should be mandatory on these a blend of PEG 6000 and 1540 in a hospital
suppositories.3 pharmacy was investigated. There was an in-
Aminophylline suppositories have a limited crease in the melting point and a prolongation
shelf-life, even when refrigerated. Changes that in the liquefaction times when stored at room
occur over time include (a) an increase in melting temperature. The ethylenediamine content in the
range and melting time, (b) reduction of in aminophylline also decreased. Using thin-layer
vitro and in vivo release rates of theophylline, chromatography, the investigators produced ev-
and (c) a decrease of the content of ethylenedi- idence that ethylenediamine may react with
amine. Ethylenediamine reacts with the triglyc- Witepsol to form an acid amide linkage. At lower
erides to form mixtures of amides with melting temperatures, however, the suppositories were
points of about 95◦ C. When evaluating the found to be stable. Suppositories prepared from
stability of aminophylline suppositories in fatty PEG bases were found to be sufficiently stable at
acid bases, the authors recommend using the room temperature.9
ethylenediamine content and not the physical
properties of the suppositories as the governing
factor.4 Amoxicillin
Brower and co-workers also demonstrated
that aminophylline decomposes in suppository Amoxicillin release from different lipophilic sup-
formulations. They prepared 500 mg amino- pository bases using an in vitro USP rotating bas-
phylline suppositories and observed them at ket method was studied. Amoxicillin 250 mg was
0◦ C, 3–8◦ C, and 40◦ C. Over three months, there incorporated in theobroma oil, Witepsol W35,
was a progressive decrease in the ethylene- Suppocire A32, Novata BD, and Novata 299 bases.
diamine content of the suppositories. This con- Both fresh and 1-month-old suppositories were
firms the work of other investigators showing tested. The greatest amount of amoxicillin was
that the ethylenediamine constituent of amino- released from the Novata BD bases and the lowest
phylline can react with suppository base mate- amount from the theobroma oil suppositories
rials to produce insoluble amide decomposition (freshly made) and the 1-month-old Suppocire
products.5 A32 suppositories.10
174 Suppositories
Aspirin 25–30◦ C for about 1 month. The melting point

of suppositories stored at a high temperature was
Aspirin decomposes rapidly when incorporated about 2◦ C higher than that of those stored at a
into mixtures of PEGs. However, aspirin incorpo- low temperature. The in vitro and in vivo results
rated into fatty acid base suppositories is much show that the release of indometacin from fatty-
more stable. The purpose of this study was to base suppositories stored at a high temperature is
incorporate fats of vegetable origin into a PEG less than the release from those stored at a low
base in an attempt to inhibit the decomposition temperature.14
of aspirin in this type of mixture. The quantity
of PEGs in the formulas for the base was PEG
400 (24.8%), PEG 1540 (30.4%), and PEG 6000 Misoprostol
(40.0%); polysorbate 60 (4.8%) also served as
part of a base. The fatty acids incorporated The stability of misoprostol (1 mg) prepared us-
into each formula included hard butter, coating ing the fusion method in a Suppocire semi-
butter, acetylated monoglycerides, cocoa butter, synthetic glyceride suppository base was studied.
and hydrogenated glycerides of palm oil. The The suppositories were stored under refrigeration
degradation process was found to be more tem- (3–8◦ C), at room temperature (20–25◦ C), and at
perature dependent than fatty acid dependent; a high temperature (55–60◦ C). The misoprostol
refrigeration delayed decomposition the most content was analyzed using a high-performance
within the time limits of this study, which was liquid chromatography (HPLC) method. The re-
70–100 days.11 sults showed that these extemporaneously com-
pounded suppositories were stable for 180 days
Chloramphenicol at refrigerated temperature and 120 days at room
temperature.15
The development of colored degradation
products of aged chloramphenicol suppositories
was investigated using various analytical Phenobarbital
methods. The degradation products consisted
of 1-p-nitrophenylaminopropandiol and The release of phenobarbital acid and sodium
p-nitrobenzaldehyde. The authors used a model phenobarbital from suppositories after aging at
system of known chemical reactions to show various temperatures was studied. The supposito-
that discoloration is due to complex formation ries used a Witepsol H15 base. The results showed
of the chloramphenicol in the PEG base.12 no correlation between liquefaction time, melt-
ing point and the release rate of the drugs before
or after storage.16
Codeine phosphate
Voigt and co-workers reported on the effect of Progesterone

storage at different temperatures on the release
of aminophenazone, codeine phosphate, pheno- Progesterone 25 mg and 50 mg suppositories in a
barbital sodium, and trapidil from suppositories. blended PEG 400 and PEG 6000 base were pre-
Drug release was affected and related to the state pared and studied in a hospital pharmacy. After
of subdivision of the drugs in the preparations as storage for 1 year, the suppositories were found
well as on the conditions of storage.13 to be stable and still meet USP requirements.17
Indometacin
Spironolactone
The release of indometacin from fatty-base sup-
positories was studied both in vitro and in vivo In a formulation study involving spironolactone,
for suppositories that had been stored at 4◦ C and the hydrophilic Macrogolum 1540 was found
experimentally to be the optimal base for this agents after a year of storage. Acta Pol Pharm 1985;
drug. During storage, these suppositories re- 42: 165–171.
mained stable and the release values did not 8. Fujii T, Jubota A, Togawa K, Mizushima N. Evalua-
significantly decrease.18 tion of aminophylline suppositories prepared in a
In summary, storage requirements for suppos- hospital pharmacy. Tokai J Exp Clin Med 1982; 7:
itories reflect extensive physical, chemical, and 371–383.
microbiological stability testing. Either expiry
9. Fujii T, Kubota A, Togawa K, Mizushima N. Eval-
dates or beyond-use dates are assigned for the uation of aminophylline suppositories prepared in
suppositories based upon the testing done. Proper a hospital pharmacy. Tokai J Exp Clin Med 1982; 7:
storage requirements are very important in main- 371–383.
taining the potency and efficacy of the supposi-
10. Webster JA, Dowse R, Walker RB. In vitro release of
tories, during manufacture/preparation, storage,
amoxicillin from lipophilic suppositories. Drug Dev
transportation, dispensing, and use.
Ind Pharm 1998; 24: 395–399.
11. Whitworth CW, Luzzi LA, Thompson BB, Jun

HW. Stability of aspirin in liquid and semisolid
bases. II. Effect of fatty additives on stability in
References a polyethylene glycol base. J Pharm Sci 1973; 62:
1372–1374.
1. United States Pharmacopeia 28-National Formulary 23. 12. Fadel H, Abd-Elbary A, Noureldin E, Kassem AA.
Rockville, MD: US Pharmacopeial Convention, Inc., Investigation of the discoloration developed in aged
2006: 330–334. chloramphenicol suppositories. Pharmazie 1981; 36:
362–365.
2. Fulper LD, Cleary RW, Harland EC, Hikal AH, Jones
AB. Liquefaction times of fatty-type suppositories 13. Voigt R, Grohmann A, Bornschein M. Character-
with and without progesterone. Am J Hosp Pharm ization of storage-induced release reductions in
1990; 47: 602–603. suppositories. Pharmazie 1981; 36: 631–633.
3. Tukker JJ, DeBlaey CJ. Prolonged storage of amino- 14. Yoshida T, Itoh Y, Gomita Y, Oishi R. Influence of
phylline suppositories. The impact on physical storage temperature on indomethacin release from
parameters and bioavailability. Pharm Weekbl Sci fatty-base suppositories in vitro and in vivo. Acta
1984; 6: 96–98. Med Okayama 1991; 45: 37–42.
4. Van Dop C, Overvliet GM, Smits HM. Stability 15. Hafirassou H, Chiadmi F, Schlatter J, Ratiney R,
study of aminophylline suppositories. Part I: De- Fontan JE. Stability of misoprostol in suppositories.
composition products and specific assay method Am J Health-Syst Pharm 2005; 62: 1192–1194.
for ethylenediamine. Pharm Acta Helv 1981; 56:
16. Lasserre Y, Peneva MB, Jacob M, Puech A, Sabatier
281–284.
R. Kinetics of liberation from suppository bases
5. Brower JF, Juenge EC, Page DP, Dow ML. Decom- of phenobarbital acid and sodium and a semi-
position of aminophylline in suppository formula- synthetic glyceride (Witepsol H15. II. Suppositories
tions. J Pharm Sci 1980; 69: 942–945. after storage. Pharm Acta Helv 1987; 62: 287–291.
6. Touitou E, Yosselson-Superstine S. Theophylline 17. Roffe BD, Zimmer RA, Derewicz HJ. Preparation of
versus aminophylline in rectal administration. J Clin progesterone suppositories. Am J Hosp Pharm 1977;
Hosp Pharm 1985; 10: 211–217. 34: 1344–1346.
7. Bartkowicz S, Pawlik T, Krowczynski L, Gudowska 18. Regdon G Jr, Deak D, Regdon G Sr, Musko Z, Eros
T, Gacek M. Changes in the pharmaceutical and I. Preformulation experiences and in vitro model
biological availability of aminophylline from sup- studies with spironolactone-containing supposito-
positories containing non-ionogenic surface-active ries. Pharmazie 2001; 56: 70–73.
176
12
Clinical considerations
ACCORDING to common teaching in pharmacy 1 Position the patient on the left side with the
schools worldwide, “If the suppositories are upper leg flexed.
wrapped, it is usually a good idea to include 2 Lubricate the suppository with a water-soluble
the instruction, ‘Unwrap, Moisten, and Insert’ lubricant or a small amount of water, if
or ‘Unwrap and Insert’ on the label.” However, needed.
there is a lot more to clinical considerations of 3 Gently insert the suppository in the rectum a
suppositories than that brief counseling point. finger’s depth at an angle toward the umbili-
cus so the suppository is placed against the
Clinical response factors rectal wall for absorption, rather than being
left in the canal or pushed into a mass of stool.
4 After the finger is withdrawn, hold the but-
The dose of a drug administered rectally may be tocks together until the urge to expel has
greater than or less than the dose of the same ceased.
drug given orally, depending on such factors
as the individual response of the patient, the
physicochemical nature of the drug and its ability The pharmacist should relay information about
to traverse the physiologic barriers to absorption, the proper use of suppositories to the patient,
and the nature of the suppository vehicle and its including the following:
capacity to release the drug and make it available
for absorption. r If they must be stored in the refrigerator,
The factors that affect the rectal absorption of
suppositories should be allowed to warm to room
a drug administered in the form of a suppository
temperature before insertion.
may be divided into physiologic factors and
physicochemical factors of the drug and the r Cocoa butter suppositories should be rubbed
base. These have been discussed in detail in gently with the fingers to melt the surface to
Chapter 4. provide lubrication for insertion. Glycerinated
gelatin or polyethylene glycol (PEG) supposito-
ries should be moistened with water to enhance
Patient counseling
lubrication. If the PEG suppository formulation
does not contain at least 20% water, dipping
Patients should be instructed on how to prop- it into water just prior to insertion prevents
erly store the suppository, unwrap a wrapped moisture from being drawn from the rectal
suppository, and resolidify a melted suppository. tissues after insertion and reduces subsequent
The proper method of disposing of unused sup- irritation.
positories should also be discussed. They should r The shape of the suppository determines how
also be counseled on the proper insertion of
it will be inserted. Bullet-shaped rectal supposito-
the suppository: whether to moisten it prior to
ries should be inserted point-end first.
insertion, how far to insert it, and how long to
remain inactive after insertion. An example of r If half a suppository has been prescribed,
the consultation related to administration of a the patient should cut the suppository in half
suppository may be as follows: lengthwise with a clean razor blade.
177
178 Suppositories
2 Ask about any pre-existing anal conditions

that might interfere with administration, such
as hemorrhoids or anal fissures.
3 Show patients the suppository and remind
them to remove any wrapping prior to inser-
tion.
4 Explain the insertion technique.
5 Obtain the patient’s informed consent prior to
administering a suppository.
6 Remember that suppositories may cause pa-
tients embarrassment and anxiety and one
should be sensitive to their concerns about
privacy.
Figure 12.1 Paper, foil, or plastic wrappings must be 7 Encourage the patient to retain the supposi-
completely removed before insertion. Photo courtesy of tory for at least 20 minutes, dependent upon
Paddock Laboratories, Inc., Minneapolis, MN. the medication and other factors.
r Most suppositories are dispensed in paper,

foil, or plastic wrappings; these must be com-
General toxicity
pletely removed before insertion (Figure 12.1).
r Depending upon the medication, the purpose
The general toxicity of a suppository should be
of the suppository, and associated factors, the
considered under two headings: the toxicity of
prior administration of an enema may increase
the active ingredient and that of the excipient.
the absorption of the drug.
The toxicity of the active ingredient is de-
pendent on the rectal pathway, posology, fre-
Additional information on inserting rectal sup- quency of administration, quantity of active
positories and informed consent has been principle passing into the general circulation
published and may be useful for patient and the susceptibility of the patient. The patient
counseling.1–4 factors aspect of toxicity will not be covered
In one study involving 360 lay individu- here.
als and 260 medical personnel, subjects were The general toxicity of the excipient is the
asked which end of the suppository they in- object of routine investigation and most suppos-
serted first. All but two individuals responded itory excipients have been toxicology tested with
that they inserted the apex (pointed end) determination of LD50 , subacute and chronic
first. However, the results of a follow-up study toxicity, and in some cases study of the terato-
suggest that a suppository is better inserted genic properties. Most suppository excipients
with the base first, as reversed contractions are non-toxic, being composed of hydrogenated
or the pressure gradient in the anal canal glycerides, esters of fatty acids, fatty alcohols and
tend to force the suppository up and improve other inert ingredients. Some excipients have
retention.5 Another author has suggested that added emulsifying agents, coloring agents, and
inserting the blunt end of the suppository first other additives necessary for the preparation
helps to reduce rectal irritation and premature and stability of the Galenic, or pharmaceutic
expulsion.6 form. Excipients used for suppositories have been
Guidelines published for nurses include the generally determined to be safe and free of any
following:7 general toxicity.
It should be mentioned, however, that some
1 Advise patients of the advantages and disad- additives in suppositories, notably emulsifying
vantages of suppositories compared with other agents to incorporate a water-soluble drug, can
methods of drug administration. modify the active ingredient molecule, favoring
Chapter 12 • Clinical considerations 179
its absorption or modifying its diffusion within In one study five cases were reported in
the body and thus changing its general toxicity. which anorectal stenosis was associated with
chronic administration of acetaminophen and
aspirin suppositories.10 Other studies involving
Local toxicity acetaminophen, perhaps related to hepatic fail-
ure, anorectal stenosis, ulceration, and other
problems, have been reported.11–16 Belladonna
It is advisable to remember from the begin-
poisoning has been reported from the use of
ning that many patients, whether pediatric or
hemorrhoidal suppositories.17 Chronic pouchitis
geriatric, will have a sensitive rectal mucous
has been reported after the use of butyrate and
membrane, as in the case of some with parasitic
glutamine suppositories in a pilot study.18 Reac-
infections. These patients may not be candidates
tions to gelatin induced by the use of a chloral
for repeated use of suppositories.
hydrate suppository have been reported.19
Certain rectal intolerances are due to the
Ulcerative colitis of the rectum was reported
excipient and others to the active medication,
in a 45-year-old woman after the use of up to six
and in many cases inadequate preservation of
suppositories containing ergotamine daily over a
the suppositories may be to blame. When the
period of 6 years.20
suppository contains a relatively large quantity
In a 64-year-old woman with chronic lower
of water, the glycerides that form the basis of
backache being treated with ibuprofen supposito-
the excipient can undergo hydrolysis, giving rise
ries, rectal examination detected an area of steno-
to organic acidity; certain free fatty acids are
sis approximately 7 cm above the anal verge. All
known to irritate the rectal mucous membrane.
laboratory parameters were within the normal
The deterioration of the suppository is usually
range. A rectal biopsy showed severe acute and
very slow and rectal intolerance related to acidity
chronic ulceration, chronic granulation, and fi-
of the suppository is not usually very severe.
brosis. The clinicians suggest that the prolonged
Other intolerances can be due to the appear-
use of ibuprofen as a suppository was the cause
ance of crystalline formations on the surface of
of the mucosal destruction and rectal stenosis.21
the suppository, the roughness of which trig-
An adverse reaction to oxyphenbutazone from
gers rectal mucous membrane intolerance. These
a suppository formulation has been reported.22
crystalline formations are composed of active
Other adverse reactions from suppository use
principles which have migrated from the bulk of
have included gastrointestinal hemorrhage and
the suppository to the periphery, or they may be
anorectal side-effects.23,24
micronized active principles that have undergone
Chronic administration of non-steroidal anti-
crystalline enlargement as a result of physical and
inflammatory drug (NSAID) suppositories has
chemical conditions.
been reported to cause anorectal lesions. These
In the particular case of suppositories con-
lesions may be similar to those observed after the
taining aspirin, acetic acid resulting from the
use of ergotamine suppositories.25
hydrolysis of aspirin adds to the intolerance
Ueda and others reported a case where amino-
caused by crystalline formations.
phylline suppositories induced acute proctitis in
Overall, rectal intolerances in the healthy
a 9-year-old boy. This is a rare but important
individual with a healthy mucous membrane are
side-effect of aminophylline suppositories as they
limited, especially when the suppository has been
may be commonly used in asthmatic children.26
correctly formulated.
Eight female patients with recurrent
headaches using suppositories containing
acetylsalicylic acid and paracetamol for over 2
Adverse reactions to suppositories
years were studied. Their symptoms included
anal pain, rectal tenesmus, or bleeding. The
Despite their long record of use, adverse reactions lesions were located within 8 cm from the
to suppositories are relatively rare, although they anal verge and included superficial ulcerations,
have been reported on occasion.8,9 fibrotic scar tissue, and rectal stenosis. Upon
180 Suppositories
discontinuation of the suppositories, the suppositories were studied. The results showed
symptoms resolved. The authors concluded that that both paracetamol 500 mg and pentazocine
when solitary rectal lesions are observed in the 50 mg suppositories were weak analgesics for
absence of rectal prolapse, chemical irritation throat pain after the tonsillectomy and during
and erosion of the rectal mucosa through the use the early postoperative period.32
of suppositories with acetylsalicylic acid should Hahn and co-workers studied high-dose rectal
be considered.27 and oral acetaminophen in postoperative pa-
tients undergoing minor gynecological laparo-
scopic surgery. Patients received 2000 mg acet-
aminophen suppositories after surgery and oral
Contemporary studies of clinical
doses of 1000 mg at 4 and 8 hours postopera-
effectiveness
tively. They concluded that the slow and ongoing
absorption process result in no maximum con-
There are a large number of clinical studies centration within 4 hours after administration
involving suppositories in the literature. These of 2000 mg acetaminophen suppositories and
are arranged according to drug name and sum- thus made the rectal regimen therapeutically irra-
marized below. tional for the treatment of postoperative pain.33
Additional studies on the clinical feasibility
of rectally administered acetaminophen have
Acetaminophen also been reported. These studies demonstrate its
antipyretic and analgesic effectiveness.34–36
A study involving 70 patients from six months to
6 years old demonstrated no difference between
rectal and oral doses of acetaminophen for the
treatment of fever in children. These patients Adriamycin
were treated with 15 mg/kg oral acetaminophen
and the same or twice the dose (30 mg/kg) A combination regimen of adriamycin 20 mg and
administered rectally.28 cytosine arabinoside 200 mg was given intravesi-
A study of paracetamol dosing suggests that cally along with 750 mg tegafur (Futraful) rectally
doses of 40 mg/kg are needed to provide thera- (suppository) administered simultaneously each
peutic concentrations when administered rec- day for a total of 20 applications. The combi-
tally in children.29 nation was simple, completed in three weeks,
Paracetamol was demonstrated to aid in re- had an effectiveness rate of 70%, and no local
ducing morphine use by 36% compared to 40% side-effects were observed.37
for diclofenac when used after abdominal hys-
terectomy in a placebo-controlled, double-blind
study.30
A double-blind, controlled trial of 60 pa- Aminophylline
tients undergoing elective abdominal gyneco-
logical surgery was conducted to evaluate the Rectal suppositories of aminophylline have been
use of paracetamol 1.5 g, diclofenac 100 mg, or used as an alternative to intravenous administra-
a combination of the two before the start of tion in the management of recurrent apnea. One
surgery. Patients received morphine during the study of 41 preterm infants demonstrated that
operation. The authors concluded that the di- therapeutic blood concentrations were obtained
clofenac/paracetamol combination reduced the 2 hours after a rectal loading dose of 10 mg/kg
morphine requirement compared with paraceta- with steady concentrations and maximum reduc-
mol alone.31 tion in apneic episodes within 245 hours on a
In a study of 91 voluntary adult patients maintenance dose of 10 mg/kg/day. There was a
undergoing tonsillectomy, the analgesic effects good correlation between the rectal dose and the
of paracetamol 500 mg or pentazocine 50 mg plasma theophylline concentration.38
5-Aminosalicylic acid (mesalazine, treatments were discontinued. The authors con-

mesalamine) cluded that 5-ASA suppositories are generally well
tolerated and considered suitable for treatments
5-Aminosalicylic acid (5-ASA), used in the treat- for at least 1 year.43
ment of inflammatory bowel disease, is unstable 5-ASA suppositories (1 g) or enemas (2 g in
in acid and is absorbed by the small intestine 100 mL) were given to 39 patients with doc-
but needs to be delivered to the distal small umented active distal proctitis; 20 patients re-
bowel and colon to exert its action. A double- ceived enemas and 19 patients received sup-
blind, placebo-controlled evaluation of 5-ASA positories, for 30 days. There was no difference
suppositories demonstrated a 78.6% remission in efficacy but the patients’ opinion was that
rate in 14 patients and concluded that 5-ASA sup- treatment with suppositories was easier than with
positories are safe, well-tolerated, and effective. enemas.44
They also used 99m Tc-labeled 5-ASA suppositories There have, however, been some problems
and demonstrated no absorbed radioactivity.39 reported in the use of 5-ASA suppositories,
A study was undertaken to evaluate the effi- including leukopenia, thrombocytopenia, and
cacy and safety of a single nightly 500 mg Rowasa hypersensitivity.45,46
(mesalamine) suppository as maintenance ther- Sixty-two patients with ulcerative colitis, di-
apy for ulcerative proctitis patients who were vided into two groups, were treated either with 5-
in remission. Sixty-five patients were in this ASA 500 mg rectal suppositories or placebo three
24-month, multicenter, double-blind trial. The times daily for one month. These results led
results demonstrated that mesalamine supposito- the authors to conclude that the drug treatment
ries are efficacious, well tolerated, and safe for the should be offered as a first choice for patients with
long-term maintenance of remission of ulcerative distal rectosigmoiditis.47
proctitis.40 In another study, improvement occurred in
A study was conducted to compare the efficacy 88.5% of 156 patients treated with 5-ASA sup-
and tolerance of mesalazine suppositories with positories in the treatment of mild or moderate
those of hydrocortisone acetate foam in the treat- ulcerative colitis.48
ment of acute proctitis. The study included 242 Mesalazine (5-ASA) suppositories are effective,
patients randomly assigned to receive once-daily safe, well tolerated and well retained in patients
Pentasa suppository (mesalazine 1 g) or 100 mg with active distal proctitis. Generally, about 85%
hydrocortisone (Colofoam) for 14–21 days (until are healed within four weeks and essentially
remission). Both treatments were effective but 100% by 10 weeks of therapy. The suppositories
mesalazine suppositories were significantly more provide coverage of the last 20 cm of the rectum
effective than hydrocortisone on rectal blood loss with doses varying from 500 to 1000 mg per day
parameters and on the degree of decrease in the in divided doses; suppositories are at least as
endoscopy score.41 effective as oral sulfasalazine, according to the
A study involving 30 patients with distal author.49
ulcerative colitis in remission randomly gave
either 400 mg 5-ASA or placebo suppositories
twice daily. The cumulative remission rate at
the 12-month mark was 92% in the 5-ASA Ampicillin
group and 21% in the placebo group. It was
concluded that 800 mg per day of 5-ASA in Fuji and co-workers studied 105 inpatient chil-
suppository form for 1 year is safe and effective dren from four months to 11 years of age with
in maintaining remission of distal ulcerative bacterial urinary tract infections. The children
colitis.42 were dosed with ampicillin suppositories (54 pa-
Another similar study of 5-ASA involved 34 tients) or the oral liquid (51 patients); both given
patients with inactive distal colitis. These pa- at 125 mg every 6 hours over a period of 5 days.
tients received a single 500 mg 5-ASA suppository The success rate was 70.4% for the suppository
nightly for 12 months and all other colitis and 66.7% for the oral liquid form, and no
182 Suppositories
significant difference was observed between the A pediatric study involving malaria treated
two groups either in therapy or in side-effects.50 with artesunate suppositories (Rectocaps)
Ampicillin suppositories or amoxicillin sus- demonstrated that a dose of 10 or 20 mg/kg
pension were administered three times daily for 5 is appropriate for use in children with
days to 683 patients (454 for the suppository and uncomplicated malaria.58,59
229 for the suspension). Ampicillin was rapidly Other studies involving artesunate supposito-
absorbed and produced plasma concentrations ries alone and in combination with other anti-
well above the minimum inhibitory concentra- malarials have also been reported, demonstrating
tions for common respiratory pathogens. The the drug’s usefulness.60–64
clinical outcomes were satisfactory in 89% of the
suppository patients and 86% of the suspension
patients. Gastrointestinal disturbances occurred Aspirin
in 28.4% of the suppository patients compared
to 14.4% of the suspension patients. Perineal The antiplatelet aggregation effect of aspirin
irritation occurred in 12.1% of the suppository was studied using 200 mg aspirin suppositories
patients and 5.2% of the suspension patients. and compared with that of orally administered
Even with these discomforts experienced by some aspirin. There was no significant difference in the
patients, rectally administered ampicillin is con- suppression of platelet aggregation by either of
sidered to be a good alternative in children when the two administration methods.65
oral medication is not feasible.51
A series of studies was published in the
Japanese Journal of Antibiotics in 1983 concerning Benzalkonium chloride
the use of KS-R1, a new rectal preparation of
ampicillin sodium. The studies demonstrated the Aubeny and co-workers evaluated the accept-
effective use of ampicillin in both adults and ability and safety of the benzalkonium chloride
children and in the treatment of acute respi- vaginal gelatin capsule with the pessary dosage
ratory tract infections, acute bacterial pneumo- form. Eighty-nine women participated in the
nia, infections in patients with heart disease, open crossover design study over two months.
acute febrile upper respiratory infection, urinary The capsule appeared to be slightly superior
tract infection, tonsillitis, pharyngitis, bronchitis, to the pessary regarding discomfort caused by
bronchopneumonia, scarlet fever, otitis media, immediate discharge or leakage, ease of use, and
and various infections.52,53 acceptance by the woman’s partner. The study
Other studies involving ampicillin have also demonstrated good acceptability and local safety
been reported generally indicating the effectiv- for the new capsule dosage form.66
ness of the rectal suppository dosage form in A multicenter trial of 653 women at risk of
treating various bacterial infections.54,55 unwanted pregnancy was studied during 9517
patient-months using an 18.9 mg benzalkonium
vaginal suppository. The authors concluded that
Antibiotics, general this product is a safe and very effective con-
traceptive if used according to the prescribed
Additional references on antibiotics and anti- instructions.67
inflammatory drugs have been reported.56,57
Bisacodyl
Artesunate
In two different published studies of myopathy
The successful use of artesunate suppositories patients, bisacodyl suppositories in two differ-
has been reported in numerous studies. They are ent bases were compared: a PEG base and a
especially useful when the parenteral form of the hydrogenated vegetable oil base. The results
drug is not feasible. conclude that the use of the PEG base reduced
bowel care time in myopathy patients by about Calcitonin

half.68–70
Salmon calcitonin 200 IU suppositories were
demonstrated to cause a dramatic decrease in
Boric acid spinal pain in patients with recent osteoporotic
vertebral fractures and influenced early mobi-
Vulvovaginal candidiasis was treated with lization and the gradual restoration of their
600 mg of boric acid powder in a gelatin capsule locomotor functions. The study involved 40
resulting in cure rates of 92% at 7–10 days after patients who had recently had a non-traumatic
treatment and 72% at 30 days; the nystatin cure osteoporotic vertebral fracture.78
rates were 64% at 7–10 days and 50% at 30 days. A nasal spray and suppository of salmon calci-
The dosage form was accepted by patients as tonin were compared with a placebo and with the
being better than the messy vaginal creams and parenteral route of administration. The nasal and
relatively inexpensive.71 suppository modes were found to be effective, the
Other reports in the literature concern suppository mode being more effective than the
the successful use of boric acid vaginal nasal. The most effective route was the parenteral
suppositories.72–74 route but the nasal and/or rectal routes were
devoid of systemic side-effects and had minimal
local intolerance.79
The efficacy of salmon calcitonin supposito-
Buprenorphine
ries in inhibiting postmenopausal bone deminer-
alization was studied in 10 women at a dose of
Combination therapy consisting of a buprenor-
200 IU per day for 12 months after oophorec-
phine 0.4 mg suppository and an indometacin
tomy. The suppositories were demonstrated to
50 mg suppository administered simultaneously
inhibit calcium loss after the surgery and were
was considered to be useful for postoperative pain
well tolerated.80
relief without producing major side-effects in a
study involving 56 patients.75
Buprenorphine suppositories (0.2 and 0.4 mg)
were compared with buprenorphine intramuscu- Carbamazepine
lar injection (0.2 mg) in postoperative patients.
The percentage pain relief in the suppository Treatment with carbamazepine slow-release
group was smaller than that in the injection tablets in children with epilepsy can be replaced
group, possibly due to the slower rate of in- by carbamazepine suppositories in 25% higher
crease in plasma levels of buprenorphine after dosage, with good clinical effect and appropriate
administration of suppositories than after intra- pharmacokinetic values, when it is unsuitable to
muscular injection. The authors conclude that it use the common oral route of administration.81
seems practical to give the drug to postoperative
patients before the start of pain.76
Ceftizoxime
Butaconazole A series of studies was published in the Japanese

Journal of Antibiotics concerning the use of cefti-
Butaconazole 100 mg vaginal suppositories were zoxime suppositories. The studies demonstrated
found to be equivalent to clotrimazole 200 mg the effectiveness of ceftizoxime suppositories
vaginal tablets when administered for 3 days and in pediatric and adult populations and in the
a follow-up evaluation 30 days later. Complete treatment of urinary tract infections, tonsillitis,
clinical relief was achieved in 81% of patients bronchitis, pneumonia, otitis media, staphylo-
in both treatment groups, as noted at the first coccal scalded skin syndrome, pertussis, respira-
follow-up examination.77 tory tract infections, acute bronchopneumonia,
184 Suppositories
acute pharyngobronchitis, and other bacterial Clindamycin

infections. The rectal route is successful and is
recommended for those patients in whom the Clindamycin vaginal suppositories were found
parenteral or oral route may be problematic.82,83 to be as effective as metronidazole vaginal sup-
positories in treating bacterial vaginosis, with
cure rates of 90.3% and 87.5%, respectively.88
Chloral hydrate
Clotrimazole
In a study of 141 pediatric patients between six
months and 7 years of age undergoing radical A comparison was made in the treatment of
operation for inguinal hernia, bromazepam and vaginal candidiasis between clotrimazole 200 mg
chloral hydrate suppositories were compared as vaginal tablets and econazole 150 mg vaginal
anesthetic premedication. Study results demon- ovules with a duration of therapy for 3 days in 54
strated that the chloral hydrate suppository patients. The results showed the effectiveness of
seemed more useful as premedication in short clotrimazole was 86.0–95.8% and for econazole
pediatric operations for its high sedative effect 77.8–88.0%. These differences were not statisti-
without affecting emergence.84 cally significant but suggested that clotrimazole
appeared to be the better agent.89
A double-blind study of treatment of vaginal
Chloroquine candidosis with a single clotrimazole 500 mg
suppository in 72 patients compared with that of
Chloroquine phosphate suppositories consisting a clotrimazole 200 mg suppository inserted once
of PEG 1000 and PEG 6000 (7:3) containing 0.5% daily for 3 days showed no significant difference
polysorbate 80 as an absorption enhancer were between the two regimens.90
studied in children 21 months of age. Based Clotrimazole pessaries were also compared
on the literature blood level values, the blood with clotrimazole cream in treating women with
levels obtained with these 300 mg chloroquine vaginal candidosis, with both dosage forms being
phosphate suppositories would be therapeutic effective.91
in the management of malaria and rheumatoid In a study of 42 women with recurrent can-
disease.85 didal vaginitis, clotrimazole 500 mg vaginal sup-
positories were administered once weekly for two
weeks. Clinical remission was induced in 90.4%
Cimetidine of the patients and mycologic negative status in
83% of the patients. The study summarized that
A prospective randomized study involving 60 clotrimazole therapy was successful in inducing
children between 1 and 8 years of age showed an initial therapeutic response but achieved only
that rectal cimetidine was effective in the pro- a modest long-term protective effect, but did so
phylaxis of acid aspiration syndrome in pediatric with no reported adverse reactions.92
anesthesia.86
Codeine
Cisapride Codeine was administered to nine infants 6–10

months old at a dose of 4 mg/suppository and
A study involving 32 patients demonstrated that to four children 3–4 years old at a dose of
a single suppository dose of cisapride 60 mg 8 mg per suppository. Codeine and its metabolite
significantly accelerates gastric emptying of the morphine were monitored in plasma by gas
solid phase of a meal and of radio-opaque markers chromatography/mass spectroscopy (GC/MS).
in patients with previously demonstrated delayed The conclusion of the study was that at the
gastric emptying.87 age of six months, infants are capable of
O-demethylating codeine to morphine if it is less so by 48 hours. The additional analgesia

administered to them for pain.93 requirements were less in the diclofenac group.98
The use of diclofenac 100 mg suppositories
was found to significantly relieve pain in men
undergoing transrectal ultrasound and prostate
Diazepam
biopsy.99
A diclofenac 100 mg suppository was found to
Diazepam suppositories were found to be more
be effective in reducing post-caesarean epidural
effective in preventing recurrent febrile seizures
local anesthetic/opioid requirements by 33% dur-
than chloral hydrate suppositories in a study
ing the first 24 hours postoperatively.100
including 113 patients (72 given diazepam and
A trial involving 220 patients showed that
41 given chloral hydrate).94
rectal diclofenac 100 mg suppositories given im-
A study involving 24 patients aged 54–89
mediately after endoscopic retrograde cholangio-
years of age, with advanced malignant disease,
pancreatography can reduce the incidence of
investigated either 5 or 10 mg diazepam supposi-
acute pancreatitis.101
tories for five nights. The study used a crossover
A total of 108 patients undergoing ambulatory
design with a 2-day drug-free washout period
inguinal hernia repair under general anesthesia
in between. The results indicated that diazepam
were recruited to receive either intravenous ke-
suppositories provided effective night-time seda-
torolac 30 mg immediately prior to induction
tion in anxious patients with terminal cancer and
of general anesthesia or diclofenac 50 mg rec-
were well-tolerated.95
tally. The study found there was no signifi-
Diazepam rectal absorption was studied in
cant difference in the total amount of analgesia
children with epilepsy in both liquid and suppos-
consumption and that diclofenac suppositories
itory dosage forms. The commercial suppository
are an economical alternative to intravenous
was absorbed slowly and could not be recom-
ketorolac.102
mended for emergency treatment. The solution
In a study involving 40 patients undergo-
was recommended as it provided faster absorp-
ing both emergency and elective caesarean sec-
tion to treat a seizure.96
tion, rectal 100 mg diclofenac suppositories were
found to provide effective analgesia and also to
reduce patients’ opioid requirements.103
Diclofenac Diclofenac sodium suppositories have been
successfully used in the treatment of primary
The antipyretic effect of diclofenac sodium 25 mg nocturnal enuresis.104
suppositories was studied in a placebo-controlled In a study of 30 patients involving diclofenac
double-blind trial in 43 children ranging from 2 sodium and indometacin suppositories using a
to 10 years of age. Children 2–5 years received double-blind, crossover protocol, there was no
25 mg suppositories and children 6–10 received statistically significant difference between the
50 mg suppositories. The results demonstrated a efficacy of indometacin and diclofenac sodium
return to normal temperature after 2 hours in all as determined by both doctors and patients.105
patients receiving diclofenac sodium, whereas in The use of a diclofenac 100 mg suppository
the placebo group only minimal changes were before surgical incision was found to improve
observed.97 the analgesic efficacy of morphine infusion in
In a study involving 110 patients who had post-caesarean analgesia.106
had episiotomies to aid normal vaginal delivery Numerous studies have been conducted on
without epidural analgesia, 56 were allocated to the therapeutic effects of diclofenac and on the
receive diclofenac suppositories and 54 placebo ability of diclofenac to enhance the absorption of
suppositories. The patients’ pain was assessed other active drugs administered rectally. Studies
after 24 and 48 hours. The prophylactic use have included its effectiveness in the treatment of
of diclofenac suppositories significantly reduced arthrosis, rheumatism, and other bone and joint
perineal pain during the first 24 hours and diseases. Diclofenac has also been shown to be
186 Suppositories
effective in enhancing the rectal absorption of treatment of vaginal candidiasis. Both drugs were
flurbiprofen and amino acids.107–113 found to be effective and well tolerated.120
In a study of 44 adult male patients under-
going herniorrhaphy, subjects were given di-
clofenac either as a 75 mg intramuscular injection Ergotamine
or as a 100 mg suppository. This study showed
both formulations provided equivalent analgesia Treatment for acute migraine attacks consists of
but patients receiving the suppository prepara- sleep, sedation, antinauseant, and analgesics, and
tion were discharged earlier.114 in some patients 1 or 2 mg of ergotamine tartrate.
Ergotamine tartrate suppositories are useful in
Dimenhydrinate situations where vomiting is occurring and the
drug must be given by a non-oral route.121
Dimenhydrinate rectal suppositories were found Oral tablets and rectal suppositories of ergot-
to be effective in reducing the incidence of amine were studied in a crossover study. Plasma
postoperative vomiting from 60.1% to 30.7% in levels and the vasoconstrictive effect of 1 mg
a double-blind study of 301 children aged 4–10 dosage forms were compared. Rectal ergotamine
years who underwent strabismus surgery.115 was found to be more biologically active, for
the factors studied, than the oral ergotamine.
The authors suggested that a rectal dose of 1 mg
Domperidone should be tried as the initial dose in the treatment
of migraine attacks.122
Domperidone 60 mg suppositories were studied Other studies on the use of ergotamine have
as an antinauseant in 15 patients suffering from also been reported.123,124
vomiting and nausea occurring with the use of
antitumor agents. As a result, 86.7% showed
improvement of symptoms with no adverse Estriol
reactions.116
Domperidone 60 mg suppositories were also In a Swedish study involving six menopausal
given twice daily for one week as an antiemetic women, 1 mg of commercially available estriol
treatment for 18 patients receiving repeated was administered intravaginally once daily for
administrations of cisplatin in relatively large 21 days and plasma concentrations of un-
amounts. The domperidone was given in a conjugated estriol were measured using radio-
regimen that also included prednisolone and immunoassay. The study concluded that estriol
methylprednisolone. The regimen used reduced is readily absorbed from the vagina but that ab-
the patients’ discomfort to acceptable levels.117 sorption declines significantly during prolonged
A study of 136 patients were used to study four treatment.125
doses of either domperidone 60 mg or prochlor- In a study of 20 postmenopausal women
perazine 25 mg suppositories every 4 hours start- experiencing dyspareunia, pruritis, and kraurosis
ing 30 minutes before chemotherapy. Only 18% vulvae who were treated with commercially avail-
of patients vomited on domperidone and 14% on able estriol vaginal suppositories (Ortho-Gynest),
prochlorperazine. Patients experienced slightly there was a good response to therapy.126
more diarrhea and slightly longer duration of
nausea with domperidone; for these reasons,
most patients preferred the prochlorperazine Fenoterol
suppositories.118,119
Fenoterol 15 mg suppositories have been evalu-
Econazole nitrate ated for their tocolytic effect, tolerance, and main
side-effects under usual clinical conditions in 50
Econazole in a vaginal suppository has been pregnant patients with premature labor in the
compared with clotrimazole vaginal cream in the 24th–36th weeks of gestation. The results of this
study showed that fenoterol suppositories can be local use of 5-FU in rectal cancer may not only
effective where oral tocolytic therapy is not possi- exert an antitumor effect, but can also cause the
ble and may even be used to replace intravenous suppression of antitumor immunity in the local
infusion of fenoterol in some situations.127 lymph nodes.133
Flecainide Gemeprost
Flecainide acetate was studied as an aqueous Gemeprost pessaries have been found to
solution, a fatty suppository, and a PEG supposi- be effective in the treatment of postpartum
tory in a patient with supraventricular tachycar- hemorrhage.134
dia refractory to oral antiarrhythmic treatment.
Flecainide was poorly absorbed from the fatty
suppository, but the PEG suppository exhibited
Glycerin
a bioavailability of 80% compared to the oral
solution, and a half-life of absorption of 1.2
Glycerin suppository chips have been compared
hours.128
with glycerin enemas in neonates and been found
to be effective.135
Fluconazole
Fluconazole 100 mg suppositories were found to Glycyrrhizin

be effective, safe, and well tolerated in an open
multicenter, non-comparative study conducted Glycyrrhizin 300 mg suppositories (as the ammo-
in three countries for the treatment of oropha- nium salt) in conjunction with sodium capric
ryngeal candidosis.129 acid with pH neutralized, was found to be effec-
A study on the use of fluconazole (150 mg tive and safe in improving the quality of life for
orally) compared with clotrimazole vaginal sup- chronic hepatitis C patients. Neutralization of pH
pository (100 mg twice a day for 3 days) for the was important to minimize irritation from the
treatment of vulvovaginal candidiasis demon- suppositories.136
strated that both were effective but the cost was
higher for the fluconazole single oral tablet.130
Hydrocortisone
Fluorouracil A questionnaire was used to evaluate the suit-

ability of rectal hydrocortisone compared to
In a study of 50 patients with rectal carcinoma intramuscular injected hydrocortisone as an
treated with 5-fluorouracil (5-FU) in a Witepsol- emergency glucocorticoid replacement therapy
based suppository, a significant decrease in the in adrenal-insufficient children. The cost of the
tumor mass was noted in 8 of 50 carcinomas. two therapies was similar. The study found that
Thirty-three per cent of the surgically resected rectal hydrocortisone is an acceptable and safe
carcinomas were histologically judged to have emergency therapy but the storage of the sup-
responded to the suppository in this study.131 positories was inconvenient.137
Another study demonstrated that 5-FU sup- A study involving stress in patients with
positories were associated with fewer systemic adrenal insufficiency concluded that rectal
side-effects and higher rectal 5-FU concentrations hydrocortisone is a safe alternative to par-
than intravenous administration of the drug.132 enteral administration in the self-management of
In a study of 23 rectal cancer patients, 12 were addisonian-prone conditions. However, its use is
treated preoperatively with 5-FU suppositories recommended by these authors only after pre-
and 11 were not. The results suggested that the viously confirming that adequate serum cortisol
188 Suppositories
concentrations are achieved 3 hours after receiv- vantage of the indometacin suppositories was the
ing a test dose.138 possibility of self-application by the patient.145
In a study of 60 patients with vulvovaginal The efficacy of indometacin suppositories
lichen planus treated with hydrocortisone 25 mg as a post-episiotomy analgesic was studied in
suppositories twice a day, most symptoms, in- a double-blind, randomized placebo-controlled
cluding vulvar burning, pruritus, dyspareunia, project. Thirty patients received two 100 mg in-
and vaginal discharge were improved. There was dometacin suppositories and 30 patients received
an overall improvement in about 81% of the placebo suppositories, all within 15 minutes of
patients subjectively and 76.8% objectively. The the episiotomy repair operation. The patients
authors concluded that intravaginal hydrocorti- on the placebo exhibited varying degrees of
sone was effective in treating vulvovaginal lichen pain, but none of the patients receiving in-
planus.139 dometacin suppositories complained of post-
Hydrocortisone suppositories have also been episiotomy pain.146
reported in another study in the treatment of vul- Indometacin suppositories have been success-
vovaginal lichen planus. Intravaginal hydrocorti- fully used in the treatment of polyps in the large
sone suppositories were found to be an effective bowel and in the gastroduodenal region.147
treatment for vulvovaginal lichen planus.140 In a double-blind study involving 12
Addisonian crises may be amenable to self- rheumatic patients, 50 mg indometacin suppos-
treatment according to the study by Newrick et al. itories were found to have a significant additive
Plasma cortisol concentrations were assayed after analgesic effect during oral aspirin therapy.148
administration of either 200 mg hydrocortisone In a study involving 40 patients with osteo-
by intramuscular injection (10 healthy patients) arthrosis or rheumatoid arthritis, flurbipro-
or after insertion of an identical-dose rectal fen 100 mg suppositories were compared with
suppository (12 healthy patients). Plasma corti- indometacin 100 mg suppositories. Both treat-
sol concentrations peaked at 1 hour following ments showed statistically significant improve-
intramuscular injection and between 1 and 2 ments and both flurbiprofen and indometacin
hours after rectal administration; administration suppositories were reported to have equal thera-
rectally produced blood levels that persisted for peutic effects on the treatment of night pain and
8 or more hours. The authors concluded that morning stiffness.149
self-treatment by rectal suppository may be useful Indometacin 100 mg suppositories were com-
in the prevention of addisonian crises.141 pared with the same dose given orally. They were
found to be equally effective in a study of 13
patients with rheumatoid arthritis.150
A retrospective study of 297 women under-
Ibuprofen
going cesarean delivery revealed that the use of
indometacin rectal 50 mg suppositories resulted
The use of ibuprofen rectal suppositories has been
in a significant reduction in narcotic (oxycodone,
reported in several studies as an antipyretic and
hydrocodone, morphine, meperidine) use in the
analgesic in orosurgical and other fields.142–144
hospital recovery period.151
Preterm infants with patent ductus were
treated by indometacin suppositories. Successful
Indometacin treatment was achieved in 12 of 21 patients and
took up to 48 hours. The positive results were
In a German study using indometacin supposi- strongly associated with a plasma indometacin
tories in the treatment of recurrent colic caused level greater than 0.5 ␮g/mL up to 8 hours after
by ureteroliths, 37 of 41 patients were treated a dose. The authors suggest that indometacin
successfully. A comparative group of 46 patients therapy for patent ductus is feasible, with a
were treated using analgin/papaverine injections, measurement of the plasma level of the drug.152
but they required on average 10–15 injections to Indometacin and piroxicam suppositories
be free of pain and were hospitalized. One ad- were compared in 261 patients with painful
coxarthrosis who were on the waiting list for 12 girls and seven boys at doses between 50
total hip replacement. The results showed that and 100 mg with comparison to a placebo. The
both drugs provided satisfactory pain relief with- authors stated that indometacin was significantly
out any appreciable variation on weight-bearing more effective than placebo in the treatment of
activities or at rest.153 primary enuresis.168
Fifty-seven adults undergoing elective aorto- Indometacin 50 mg suppositories were shown
coronary bypass surgery participated in a study to to be effective in the treatment of rectal polyps,
evaluate the combination of rectal indometacin possibly due to the direct contact of the drug with
with patient-controlled intravenous morphine the lesions, producing a high local concentration
analgesia on postoperative pain relief and opi- of the drug.169
oid use after surgery. The combination of in- Eighty patients undergoing open cholecys-
dometacin with morphine after cardiac surgery tectomy with nitrous oxide–oxygen–sevoflurane
resulted in reduced postoperative pain scores and anesthesia and lidocaine epidurally and were
opioid use and did not increase side-effects.154 divided into four groups: group A received
The use of indometacin was evaluated in a buprenorphine 0.4 mg and indometacin 50 mg;
study involving 12 patients and is recommended group B, buprenorphine 0.4 mg; group C, in-
for short- to medium-term pain relief following dometacin 50 mg; and group D, no drug. The
scleral buckling and cryotherapy.155 drugs were both administered in suppository
The combination of indometacin 100 mg sup- form. The combination of buprenorphine and
positories with intramuscular morphine after indometacin required fewer analgesics, had a
major abdominal surgery provided better pain longer period of analgesic effect, and produced
control than that provided by intramuscular a better pain score than the other groups.170
morphine alone.156 A study was conducted by Cordell and co-
Indometacin 50 mg suppositories adminis- workers to compare the analgesic efficacy and
tered once or twice daily over a period of four or side-effect profile of indometacin 100 mg sup-
eight weeks may be effective in the management positories with intravenous morphine (5 mg fol-
of rectal adenomatosis in patients with familial lowed by two additional 2.5 mg doses if needed)
adenomatous polyposis.157 in the treatment of uteral colic. The study was a
The use of indometacin 100 mg suppositories randomized, double-blind, double-dummy, two-
with spinal morphine following cesarean delivery period study involving patients aged 18–75 years
led to significantly improved pain relief and high- old. There were 75 patients enrolled in the study.
quality postoperative analgesia in a double-blind The results showed that intravenous morphine
study of 30 patients.158 produced more rapid analgesia than rectally ad-
Numerous other studies have been reported ministered indometacin. There were no signifi-
involving the use of indometacin for several dif- cant differences in the side-effects between the
ferent indications. Indometacin suppositories are two treatment groups.171
effective in supplementing opioid infusion, treat- Thirty children aged 7 years and older who
ing fever in children and chronic rheumatic con- were undergoing open appendectomy were given
ditions, alleviating the pain of ureteric colic, and indometacin suppositories 2 mg/kg or a placebo
controlling postoperative and postepisiotomy suppository, in addition to morphine by a
pain.159–166 patient-controlled analgesia pump. The children
Forty-one patients were studied to determine given indometacin suppositories used 44% less
the effects of indometacin suppositories in the morphine than children given placebo and expe-
treatment of acute colic and the prevention of rienced similar postoperative alalgesia.172
recurrent colic. This study strongly supported
the use of indometacin suppositories in the pre-
vention of recurrent colic secondary to ureteral Insulin
calculi.167
Indometacin suppositories have been used in Normal and non-insulin-dependent non-obese
the treatment of primary nocturnal enuresis in diabetic subjects were given a 100 unit insulin
190 Suppositories
suppository. The decrease in plasma glucose was of postoperative pain, whereas all those patients
four times greater in the diabetic patients than in receiving placebo experienced varying degrees of
normal subjects. Other studies involving rectal pain.178
insulin have reported its effectiveness.173,174 In a study involving 123 children undergoing
adenoidectomy, ketoprofen was compared when
given rectally, intravenously, and with placebo.
Interferon The proportion of patients receiving rescue anal-
gesics was significantly lower among children
Rectal suppositories containing recombinant ␣2b - receiving ketoprofen than in children receiving
interferon and antioxidants were used in com- placebo.179
plex therapy of viral chronic hepatitis B and C in Ketoprofen suppositories have been investi-
children. Results of this investigation revealed an gated in numerous other studies, including their
effective treatment. Side-effects were not found, successful use in spondyloarthrosis, rheumatoid
even after long-term treatment. The investigators arthritis, and migraine.180–182
conclude that the rectal method of administra-
tion has advantages over parenteral delivery due
to its convenience, non-traumatic character and Ketorolac
ease of use for prolonged time periods.175
Ketorolac 30 mg intramuscularly and
indometacin 100 mg suppositories rectally
Interleukin 8 were found to be equally effective analgesics
in women undergoing gynecologic or breast
A study of interleukin 8 (IL-8) suppositories surgery as outpatients.183
containing 100, 200, and 400 ng of IL-8 in Bolis et al. demonstrated that ketorolac 30 mg
Witepsol base and a placebo was conducted. The suppositories are effective in the treatment of
results showed that a pharmacological dosage postcholecystectomy pain.184
of IL-8 exerts an effect on follicular maturation
through granulocyte chemotaxis and activation,
demonstrating that IL-8 can be effective given as
a rectal suppository dosage form.176 Laxatives
Effective administration of laxatives using the

Ketamine suppository dosage form has been reported in
several studies. Tolerance and stenosis issues are
In a study involving 469 children to whom also discussed.185,186
anesthesia was given, a combination of ketamine
and droperidol was given orally and rectally and
compared with the intravenous or intramuscular Loperamide
injection. The combination administered by the
rectal route gave the best results and atropine pre- The effect of the antidiarrheal drug loperamide
medication did not appear to be mandatory.177 hydrochloride on bowel function in patients
with an ileo-anal pouch was studied using a
blinded, three-tailed, case-controlled and ran-
Ketoprofen domized crossover trial with a daily dose of
12 mg in either oral (4 mg three times daily) or
Thirty patients received two ketoprofen 100 mg suppository (6 mg twice daily) form. Ten subjects
suppositories and 30 received placebo supposito- (seven men, three women) aged 23–50 years
ries prior to undergoing extirpation surgery. Sub- (median 38 years) were studied 9–48 months
jective pain symptoms were evaluated; none of (median 27 months) after ileostomy closure. The
the patients who received ketoprofen complained study suggests that the beneficial effect of oral
loperamide is primarily due to its action on abdominal pain with the oral liquid form of the
intestine proximal to the pouch itself.187 drug. The investigators found that rectal supposi-
High-dose loperamide 20 mg suppositories tories of 8-MOP were associated with significantly
twice daily were found to suppress pouch con- fewer gastrointestinal side-effects than the oral
tractions and lower stool frequency following form of the drug and this was accomplished
restorative proctocolectomy in a study of ten without compromising clinical efficacy.193
patients aged 24–63 years.188
Metoclopramide
Mesalazine
In a study involving 150 patients with migraine
Mesalazine suppositories (500 mg each) were attacks, patients were treated with metoclo-
compared with 178 mg of hydrocortisone foam. pramide 10 mg intramuscularly, a 20 mg suppos-
Both were effective but the patients’ evaluation itory or placebo in a double-blind trial. The pa-
of practicality and compliance were significantly tients also simultaneously received paracetamol
better in the mesalazine suppository group.189 1 g and diazepam 5 mg orally. Metoclopramide
in both dosage forms was significantly more
effective in relieving nausea (86% of the patients)
Methadone but did not by itself reduce the pain; it did
enhance the effect of the analgesic or sedative
In a prospective open study 37 advanced can- medication.194
cer patients experiencing poor pain control re- Metoclopramide hydrochloride 25 mg rectal
ceiving high doses of subcutaneous hydromor- suppositories have been effectively used in the
phone were switched to oral methadone cap- treatment of gastroparesis diabeticorum. The use
sules or rectal methadone suppositories. Using of the suppositories resulted in avoiding the need
a visual analog scale for pain intensity, it was for intravenous therapy.195
concluded that a change from subcutaneous Metoclopramide suppositories have been re-
hydromorphone to oral or rectal methadone ported in several other studies, demonstrating
is a safe, effective, and low-cost alternative in its effectiveness in preventing nausea, treating
selected cancer patients receiving high doses of gastroparesis, migraine, and in revealing Hunt-
opioids.190 ington’s disease.196–198
Similar to the above study, in a retrospective
review 50 consecutive patients were switched
from hydromorphone 267 mg subcutaneously Metronidazole
per day to compounded capsules or suppositories
of methadone. It was concluded that methadone In a clinical report, 32 children undergoing
is an effective and inexpensive alternative in surgery for suspected acute appendicitis received
patients receiving high-dose opioids for can- prophylactic metronidazole suppositories. The
cer pain, at dose ratios much lower than rec- clinicians report that this treatment was effective
ommended in the literature.191 Compounded because no wound infections or wound sepsis
methadone suppositories have also been studed were reported.199
in the treatment of severe cancer pain and found Metronidazole is as effective when given rec-
to be effective.192 tally as intravenously. Prophylaxis with metron-
idazole suppositories has reduced the incidence
of postoperative anaerobic infection in patients
Methoxsalen undergoing abdominal surgery.200
In a study involving ten severely ill patients
In a small study of six patients, 8-methoxsalen with life-threatening sepsis, metronidazole sup-
(8-MOP) was given for the treatment of psoriasis positories were used and blood concentrations
vulgaris in patients who had significant nausea or measured twice daily for 5 days. The results
192 Suppositories
showed that in gravely ill patients, metronida- infection and in the treatment of peritonitis and
zole suppositories provide adequate therapeutic trichomoniasis.207–215
serum concentrations of the drug; however, to In a study of 75 women with bacterial vagi-
obtain the appropriate concentration rapidly, nosis, metronidazole 500 mg suppositories were
the first suppository should be given with an used once daily for 7 days. Symptoms improved
intravenous loading dose.201 or disappeared in 80% of those on metronidazole
A double-blind prospective randomized trial compared to 53% on placebo therapy.216
involving appendectomy patients treated with
either intravenous cefoxitin or rectal metronida-
zole suppositories demonstrated no significant Miconazole
difference between the use of the two drugs.202
Metronidazole has been used successfully in Miconazole has been reported to be effective in
the prevention and treatment of postoperative vaginal suppository dosage forms in various clin-
anaerobic infections. Good results were obtained ical studies in the treatment of cervicovaginitis
with a 1 g metronidazole suppository every 8 and vaginal infections.217,218
hours over the 20 hours (two doses) preceding
surgery; then every 12 hours if preparation of
the digestive tract can be done between two
administrations. In emergencies, the authors Midazolam–famotidine
recommend one suppository at least 1 hour
before surgery, then every 12 hours, along with The efficacy of a midazolam–famotidine suppos-
a 500 mg intravenous infusion at the time of itory as premedication for pediatric patients was
surgery.203 demonstrated to be as similar in sedative effect to
Thirty-eight women completed a prospective, an intramuscular injection of hydroxyzine.219
randomized, non-blinded study to compare the
efficacy of a 7-day regimen using a 500 mg
metronidazole suppository once daily with that Misoprostol
of an oral 400 mg metronidazole dose twice daily
for 7 days, in the treatment of non-specific Radiation proctitis was treated with misopros-
bacterial vaginosis. Four weeks after treatment, tol suppositories in a prospective, randomized,
the vaginal therapy group had a cure rate of 79% placebo-controlled, double-blinded trial in pa-
compared to 74% in the oral therapy group. Their tients recently diagnosed with stage B and C
conclusion was that vaginal therapy is as effective prostate cancer undergoing external beam irradi-
as oral therapy.204 ation. The misoprostol or placebo was made from
A single dose of metronidazole 1 g supposi- two 200 μg tablets of Cytotec and/or cocoa butter.
tory administered rectally 1 hour preoperatively A total of 16 patients were enrolled, seven re-
has been found to be adequate for prophylaxis ceiving placebo and nine receiving misoprostol.
against wound infection following emergency The misoprostol rectal suppositories significantly
appendectomy.205 reduced the acute and chronic radiation proctitis
In a study of 29 patients, the combination of symptoms in these patients.220
1 g metronidazole suppository the night before In a study of 118 patents who needed in-
and a second just prior to surgery, along with duction of labor, the efficacy of a vaginal in-
750 mg cefuroxime injected intramuscularly, was sert administering continuous dinoprostone with
found to be effective in preventing postoperative vaginal suppositories containing two different
wound infections.206 doses (35 or 50 μg) of misoprostol for cervical
Metronidazole rectal suppositories have been ripening and induction of labor was studied. The
studied in the treatment of a number of different authors concluded that misoprostol suppositories
indications, including postoperative treatment appeared to be as effective and safe as the con-
following perforated appendicitis, and other op- tinuous dinoprostone vaginal insert in inducing
erative procedures, including preventing wound cervical ripening.221
Morphine 250 mg suppositories, ibuprofen 400 mg suppos-

itories, and naproxen 500 mg suppositories in
The use of a once-a-day controlled-release mor- 30 rheumatoid arthritis patients demonstrated
phine sulfate suppository was found to be more that combinations of two NSAIDs are effective
convenient and equally effective as twice-daily and well tolerated but have no advantage over
administration of morphine sulfate in the treat- treatment with only one drug.228
ment of chronic cancer patients.222 Naproxen sodium suppositories have also
In cancer patients, the oral route is the first been used in the treatment of toothache.229
choice for the administration of analgesics. How-
ever, this may not always be the best choice.
It is important to compare the oral and rectal Natamycin
routes in the administration of morphine to de-
termine if the routes can be interchanged. In one Natamycin has been successfully used in a
study, the steady state pharmacokinetics of mor- vaginal suppository for the treatment of yeast
phine, morphine-3-glucuronide, and morphine- infections.230
6-glucuronide were investigated in six patients
with intractable cancer pain given both oral and
rectal dosage forms of morphine. The parent Nifedipine
drug and glucuronide metabolites were measured
simultaneously using high-performance liquid Nifedipine has been administered rectally in one
chromatography (HPLC) and fluorescence detec- report.231
tion. The results of this study demonstrated that
it is difficult to decide whether or not rectal ad-
ministration can replace oral administration.223 Nimesulide
Other studies involving rectally adminis-
tered morphine suppositories have reported their The acute antipyretic activity of nimesulide
effectiveness.224,225 200 mg suppositories was studied in a double-
blind trial in comparison with diclofenac 100 mg
suppositories and placebo. The study involved
81 patients between the ages of 18 and 90
Naproxen years. Nimesulide proved to be as effective as
diclofenac in normalizing body temperature and
In a study of 105 rheumatic patients (35 in each significantly shortened the duration of fever with
of three groups), a double-blind parallel study was respect to the placebo.232
conducted comparing naproxen 500 mg suppos- Nimesulide suppositories were evaluated in
itories with oxyphenbutazone 250 mg supposi- a double-blind study versus flurbiprofen in
tories and placebo for postoperative pain and pain–inflammatory pathologies of obstetric–
swelling after joint surgery. There was a general gynecologic nature in 100 patients. Both drugs
tendency to favor naproxen for all parameters were effective but nimesulide demonstrated a sig-
studied, but no statistically significant difference nificantly more marked analgesic effect than flur-
between groups was observed.226 biprofen during the first 2 hours of treatment.233
In a double-blind crossover trial between Forty-four patients between 18 and 62 years
naproxen tablets and suppositories in the treat- old with odontostomatological pain and inflam-
ment of primary dysmenorrhea, the results on mation were treated with nimesulide supposito-
32 patients were compared. The overall effects ries. Treatment resulted in complete remission
were similar but the tablets seemed to give a of the symptomatology by the third day and
better effect in relieving spasmodic pain than the tolerance of the drug was excellent.234
suppositories.227 A study of the efficacy and tolerability of
A combination study evaluating the effec- nimesulide and flurbiprofen suppositories was
tiveness of different combinations of naproxen undertaken. The drugs were administered twice
194 Suppositories
daily for 7 days in 98 patients between 18 and control. The dose was one suppository inserted
75 years old suffering from pain–inflammatory daily for 10 consecutive days.239
pathologies involving the ear, nose, and throat.
The results ranged from marked, progressive Oxybutynin
improvement in the typical symptoms of the in-
flammatory state up to their complete remission. One study involved 25 women diagnosed with
Nimesulfide provided faster relief and longer detrusor instability who were treated with oxy-
duration of therapeutic action.235 butynin rectal suppositories (5 mg oxybutynin,
15 mg micronized silica gel, and 1.25 g fatty acid
base). Patients were started on one suppository
Non-steroidal anti-inflammatory drugs twice daily and titrated as tolerated. The authors
concluded that patients who cannot tolerate oral
A study involving diclofenac 100 mg supposito- anticholinergic and antispasmodic agents for this
ries and naprosyn 500 mg suppositories demon- treatment may benefit from oxybutynin rectal
strated that in the treatment of rheumatoid suppositories.240
arthritis NSAIDs were more effective in the form
of suppositories and had a more beneficial effect
on morning stiffness and on pain than did tablets Phenobarbital
of the same drug.236
A study by Matsukura et al. involved intravenous,
intramuscular, oral, and rectal administration of
Ondansetron phenobarbital to five patients 8–20 years of age.
They concluded that rectal administration of
A multinational, multicenter, randomized, paral- phenobarbital is more reliable than intramuscu-
lel group study comparing the safety, tolerability, lar or oral administration of the drug for rapid
and efficacy of ondansetron 8 mg orally twice treatment in children.241
daily with ondansetron 16 mg suppository once
daily was undertaken involving a total of 406 Piroxicam
patients receiving cyclophosphamide-containing
chemotherapy. The results showed that on- The efficacy and tolerability of piroxicam 20 mg
dansetron provided good antiemetic control in suppositories given once daily for four weeks were
81% of patients with the oral route and 73% of studied in 96 patients suffering from degenerative
patients with the suppository.237 joint disease and 20 patients with rheumatoid
A similar study by the French Ondansetron arthritis. The overall evaluation of efficacy and
Study Group involved 3 days using a 16 mg tolerability were excellent or good in more than
once-a-day suppository with 8 mg intravenously 80% of the patients.242
on day 1 followed by 8 mg tablet twice daily A 20 mg piroxicam suppository has been
for days 2 and 3 in patients receiving cisplatin- demonstrated to be bioequivalent to a 20 mg
containing chemotherapy. In the 420 patients capsule. Clinical studies showed that the sup-
in this study, 87% of the suppository group had pository is equal to the capsule in efficacy and
good antiemetic control compared to 92% of the tolerability.243
intravenous group. Both treatments were well Numerous other studies on piroxicam suppos-
tolerated.238 itories have been reported, especially in the suc-
cessful treatment of acute and chronic rheumatic
diseases.244–247
Nystatin A study of 231 patients 16–75 years of age
with osteoarthritis of the knee joint were treated
In a study involving 75 patients with vaginal with a 20 mg piroxicam suppository administered
mycosis, nystatin 200 000 IU suppositories were once daily at bedtime. Overall treatment ratings
effective in 88% of the patients with complete were excellent or good in 73% and fair in 22% of
patients. Side-effects were reported in only 3% of in the treatment of benign vascular or tension
patients. The authors concluded that treatment headaches. A randomized, prospective, double-
of osteoarthritis with piroxicam suppositories is blind trial studied the use of intravenous solu-
safe and effective.248 tions and rectal suppositories of prochlorperazine
in the treatment of benign vascular or tension
headache.254
Povidone-iodine
Jones and others demonstrated the safety and
efficacy of rectal 25 mg prochlorperazine suppos-
A prospective randomized clinical trial was con-
itories for the treatment of acute migranes.255
ducted involving 70 patients to study the ef-
ficacy of povidone-iodine suppositories for the
treatment of bacterial vaginosis in comparison
with lactobaccillus capsules. After 15 days, there
Progesterone
was a trend towards better efficacy with the
povidone-iodine, but this was not significant.
Progesterone 200 or 400 mg vaginal wax sup-
Both treatments were well tolerated. The re-
positories were effective and convenient and
sults of this study show that native lactobacilli
preferable to the use of other progestogens in
rapidly recolonize after antiseptic treatment with
various circumstances in rapidly achieving and
povidone-iodone, therefore there is no need to
maintaining serum progesterone concentrations
use lactobacillus in addition to the povidone-
at physiological levels.256
iodine.249
Progesterone 100 mg vaginal suppositories
Other reports involve povidone-iodine in gy-
were effectively used prophylactically to reduce
necologic and obstetric care, and in pregnancy for
the frequency of uterine contractions and the
effective prophylactic and therapeutic use against
rate of preterm delivery in women at high risk
infections.250,251
for prematurity.257
Povidone-iodine 200 mg vaginal suppositior-
There are other reports of the use of suc-
ies in a water-soluble base once daily for 7
cessful progesterone suppositories and vaginal
days were used in the treatment of vaginitis.
tablets in premenstrual syndromes and other
Thirty-eight patients with vaginitis and com-
indications.258–260
plaining of vaginal discharge and irritation due
Baker and co-workers also confirmed the util-
to trichomonas, candida, or non-specific vaginitis
ity of progesterone 200 mg vaginal suppositories
were selected for this study. There was complete
twice daily in the alleviation of some premen-
remission (symptomatic and microbiological) in
strual syndrome symptoms relating to anxiety
73.3% of the cases and an additional 16.7%
and irritability.261
had a microbiological cure with improvement in
symptoms; no complications or side-effects were
reported.252
Povidone-iodine vaginal suppositories twice
Promethazine
daily for 7 and 14 days were found to be
effective in 82% of patients, with disappearance
In a study on postoperative nausea and vom-
of vaginal discharge and partial improvement in
iting using two promethazine 25 mg suppos-
the remaining 18% of patients. This study also
itories, the authors found promethazine sup-
included monitoring of thyroid function, and
positories to be an inexpensive and efficacious
treatment was found to have no effect on thyroid
treatment for nausea and vomiting in adult out-
function.253
patient surgical patients following discharge from
hospital.262
Prochlorperazine Promethazine suppositories were found to be
an effective treatment for space motion sickness
Prochlorperazine administered intravenously in a study involving crew members on NASA
and rectally has been shown to be effective space shuttle flights.263
196 Suppositories
Rifadin One study involved 431 migraine patients

treated with either sumatriptan 6 mg, 12.5 mg,
Rifadin suppositories have been used as a com- 25 mg, 50 mg, or 100 mg suppositories or a
ponent of combined therapy in the treatment of placebo suppository in a single dose for a single
destructive forms of pulmonary tuberculosis.264 migraine attack. The greatest response was in the
25 mg group (72%) compared to placebo (37%).
From this study it was concluded that sumatrip-
Sertaconazole tan in doses greater than 6 mg is effective and well
tolerated and that doses of 12.5 mg and 25 mg
In a study of 369 women with symptoms and were best in efficacy and safety.270
signs of vulvovaginitis, half were treated with a
300 mg sertaconazole suppository and the other
half with a 150 mg econazole suppository. After
one week, those not cured were provided a Suprofen
second suppository and were re-assessed one
week later. All participants were evaluated one The effectiveness and tolerability of suprofen
month after the last administration. The authors 300 mg suppositories was evaluated in a placebo-
concluded that single topical administration of controlled double-blind trial in 45 informed
sertaconazole and econazole had similar efficacy patients with chronic pain due to osteoarthritis.
and safety but that sertaconazole was associated The patients were treated rectally three times
with a lower rate of recurrence.265 daily for 10 days. The suprofen suppositories were
significantly superior to placebo in all variables
considered for evaluation, including pain inten-
Sulfasalazin sity and relief scores, sum of pain intensity differ-
ence, total pain relief, and global assessments by
Sulfasalazine has been used to successfully investigator and patient. The efficacy was judged
treat lymphoid follicular proctitis in suppository by the physician as good or very good in 86.3%
form.266 of the patients.271
Suprofen has also been successfully used rec-
tally for pain after tonsillectomy in a double-
Sumatriptan
blind study.272
Numerous studies have been reported on the
Sumatriptan 12.5 mg or 25 mg suppositories were
effectiveness of suprofen suppositories in their
used in a randomized, double-blind, parallel-
use as an antipyretic. Its effectiveness has also
group, placebo-controlled trial of patients with
been compared with that of acetaminophen.
moderate or severe migraine attacks. Review
Suprofen was found to be superior to placebo
of the data showed that administration of the
throughout the studies, the differences being
suppositories is a well-tolerated, effective treat-
statistically significant after 3 hours and up to
ment for acute migraine headache and associated
6 hours. The only side-effect experienced by a
symptoms.267,268
subject on suprofen was vomiting.273,274
Sumatriptan suppositories were compared
Temperature was reduced in 85.5% of 90
with a fixed combination of indometacin,
hospitalized pediatric patients with fever of vari-
prochlorperazine, and caffeine suppositories in
ous etiologies following treatment with suprofen
the treatment of two consecutive migraine at-
suppositories.275
tacks of moderate or severe intensity in a mul-
ticenter, randomized, crossover study of 112 pa-
tients. Of these patients, 88 were compliant and
the results showed that the fixed combination of Tambuil
indometacin, prochlorperazine, and caffeine was
significantly more effective than sumatriptan in Tambuil suppositories have been effectively used
the acute treatment of migraine attacks.269 in the treatment of chronic pancreatitis.276
Tegafur Terconazole has been used effectively in nu-

merous additional studies, administered vagi-
Tegafur rectal suppositories have been used with nally in the treatment of vaginal candidosis;
positive results as a preoperative treatment for patients included pregnant and non-pregnant
rectal cancer.277 women.283–289
Thirty-two patients with colorectal carcinoma
were divided into two groups, with one group
treated with 1 g/day tegafur suppositories and the Theophylline
second group receiving no chemotherapy. The
results demonstrated that preoperative tegafur The effectiveness and toxicity of rectally ad-
suppositories treatment enhanced apoptosis and ministered theophylline has been the subject of
suppressed angiogenesis of colorectal carcinomas numerous studies.290–292
in a p53-independent manner.278
Thyrotropin
Tenoxicam Thyrotropin-releasing hormone (TRH) adminis-

tered either intranasally or rectally was found to
Seventy-nine patients with either arthrosis or enter the bloodstream and to stimulate thyroid-
rheumatoid arthritis (equally divided) were in- stimulating hormone (TSH), prolactin, and thy-
cluded in an open, non-comparative multicenter roid hormone release in humans.293
study and were treated rectally with tenoxicam
20 mg suppositories over six weeks, following a
dose of 40 mg for the first 3 days. The study found Tioconazole
that efficacy was considered excellent or good in
22 patients with rheumatoid arthritis and in 28 Tioconazole in cream and ovules has been stud-
of those patients with arthrosis.279 ied in 3-day treatment regimens of patients with
Tenoxicam and piroxicam 20 mg supposito- vaginal candidiasis, with good results.294
ries administered once daily were assessed in a
comparative, randomized, double-blind trial in
48 patients with acute non-articular rheumatism. Trimecaine
The risk/benefit ratio of tenoxicam was found to
be identical to that of piroxicam in the treatment Trimecaine has been studied with good results
of acute non-articular rheumatism.280 when administered both parenterally and rectally
in patients for the prevention of primary ventric-
ular fibrillation.295
Terconazole
Tryptan
Terconazole 80 and 240 mg suppositories and
0.4% cream were found to be effective in the Tryptan has been compared when administered
treatment of vulvovaginal candidiasis.281 Clini- subcutaneously, orally, nasally, and rectally in
cal cure rates with the cream in one study ranged the treatment of migraine.296
from 87.3% to 95.5% and the microbiologic
cure rates from 76.9% to 91.1%. Clinical cure
rates with the 80 mg suppository was 90.0–92.2% Verapamil
and the microbiologic cure ranges from 80.4%
to 85.0%.Both dosage forms demonstrated an A study was conducted involving 51 patients with
excellent safety and efficacy profile in these ischemic heart disease who were treated with
studies.282 verapamil 40 mg suppositories three times daily.
198 Suppositories
Cessation or reduced frequency of stenocardia use a suppository inserter. Br J Pharm Pract 1982; 4:
attacks was noted after a 10-day course of treat- 8–9.
ment in 98.1% of patients.297 7. Henry C. The advantages of using suppositories.
Nurs Times 1999; 95: 50–51.
8. Dagher FJ, Pais SO, Richards W, Queral LA. Severe

Miscellaneous
unilateral ischemia of the lower extremity caused
by ergotamine: treatment with nifedipine. Surgery
Additional reports related to the use of supposi- 1985; 97: 369–373.
tories in controlling nausea, vomiting, pain, and
even in the treatment of falciparum malaria have 9. Fitzsimons EJ, Dagg JH. Lead poisoning in a drug
addict; the intravenous injection of suppository
been published.298–300
extracts. Br J Clin Pract 1982; 36: 284–285.
It was found that gabapentin was not absorbed
after rectal administration to two children to 10. Van Gossum A, Zalcman M, Adler M, Peny MO,
whom the drug was administered both orally and Houben JJ, Cremer M. Anorectal stenosis in pa-
rectally. Oral administration was effective but tients with prolonged use of suppositories contain-
ing paracetamol and acetylsalicylic acid. Dig Dis Sci
rectal was not. The authors concluded that when
1993; 38: 1970–1977.
oral gabapentin therapy is interrupted, clinicians
should consider administration of an alternative 11. Reddy MS, Srinivas P. Hepatic failure after rectal
antiepileptic drug that can be given parenterally acetaminophen. Anesth Analg 2002; 94: 476.
or rectally.301 12. Blanchi A, Delchier JC, Soule JC, Bader JP. Anorec-
In summary, there are hundreds of clinical tal stenosis related to the taking of suppositories
studies reported in the literature related to the combining dextropropoxyphene and paracetamol
effectiveness of the suppository dosage form. (Di-Antalvic). Gastroenterol Clin Biol 1984; 8: 579–
Although not universally effective, the rectal 580.
and vaginal suppository provides an alterna- 13. Marteau P, Flourie B, Froguel E, Contou JF,
tive route of administration that is often effec- Galian A, Rambaud JC. Proctitis following the pro-
tive in patients who cannot take medications longed use of dextropropoxyphene and paraceta-
orally and for whom the parenteral route is not mol suppositories: the risk persists despite change
advisable. of excipients. Gastroenterol Clin Biol 1990; 14:
102–103.
14. Fenzy A, Bogomoletz WV. Anorectal ulceration

due to abuse of dextropropoxyphene and parac-
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Gynecol 1987; 156: 253–256. efficacy and tolerability of suprofen suppositories
in patients with osteoarthritic pain. Arzneimit-
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against vaginal candidosis: conclusions drawn
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212
Appendix I
Glossary
Area The temperature zone below the melting Fat bloom A white surface appearance that
point of an excipient or a suppository, where consists of crystalline fat formed by diffusion
the suppository cannot be kept or handled on the surface of the suppository.
owing to its soft condition. Hard fat A white mass that is almost odorless
Cavity See Chimney. and is free from rancid odor. It is greasy to
Chimney (synonymous with axial cavity, the touch. On warming, it melts to give a
axial hole) Funnel-shaped cavity in the axis of colorless or slightly yellowish liquid. When
the suppository. the molten hard fat is shaken with an
Coagulation Undesirable agglomeration of equal quantity of water, a white emulsion
some of the mixture resulting in a lack of is formed. It is practically insoluble in water,
homogeneity and eventually a precipitation freely soluble in ether and slightly soluble in
and a sticking to the equipment; this is often alcohol.
found with vegetable extracts. Polyethylene glycol (PEG) Non-toxic,
Coalescence (coaptation) A joining-up of water-soluble polymer commonly used as a
small spheres or globules, which occurs par- base in suppositories. PEG bases are usually
ticularly with the dispersed phases in the case designated by a number that corresponds
of emulsions. approximately to average molecular weight.
Cocoa butter A yellowish-white solid, hav- As the molecular weight increases, the water
ing a faint, agreeable odor and a bland, solubility, vapor pressure, hygroscopicity,
chocolate-like taste if obtained by pressing; and solubility in organic solvents decrease,
a bland taste if obtained by extraction. It is while congealing temperature, specific
usually brittle at temperatures below 25◦ C. gravity, flash point and viscosity increase.
It is freely soluble in ether and in chloro- Liquid PEGs are clear to slightly hazy,
form; soluble in boiling dehydrated alcohol; colorless or practically colorless, slightly
slightly soluble in alcohol. hygroscopic, and viscous, with a slight,
Cracks Openings caused by stresses in the solid characteristic odor and a specific gravity at
fat which arise from the different cooling 25◦ C of about 1.12. Solid PEGs are practically
rates at the exterior and interior of the odorless and tasteless, white, waxy, plastic
suppository. materials with a consistency similar to
Dimples (sink holes) Depressions caused by beeswax, or occur as creamy white flakes,
the fat in the center of the suppository beads, or powders.
solidifying more slowly than on the exterior, Post-hardening Excessive hardening that oc-
which, as a result of contraction, draws curs when the melting point of a suppository
material from above down into the core. increases as a function of the fat type, the ac-
Excess (scrapings, casting excess, casting tive ingredients, the method of production,
waste) The surplus material cast onto the mold the storage conditions and time. The cause
terrace and which must be scraped off during is a change in the crystal modification of the
solidification. solid fat.
213
214 Suppositories
Scraping The removal with a scraper of the forms rapidly into the stable crystalline
excess material undergoing solidification on forms.
the surface of the mold. Terrace The horizontal part of the mold on
Sticking Excessive sticking of the suppository which the casting is carried out and which
to the mold wall causes a resistance to normal has a limiting rim with a thickness of 5–
withdrawing from the mold. 12 mm.
Strip-type mold Mold consisting of the Torpedo The most usual suppository shape.
assembly of the semi-cavity metallic There are two types: the classical type with
elements. bulging sides and the type known as the
Super-cooling Physical state of a crystalline ‘English torpedo’ with less bulging sides.
material that remains liquid at a temperature Unsaponifiable matter Matter that consists
which is sometimes as much as 2–12◦ C below of substances that can be extracted with
its melting point. organic solvents after saponification of the
Tail Bottom plate of a suppository opposite the fat and that are not volatile at 100–105◦ C.
rounded off end. Whitening (synonymous with fat-bloom,
Tempering Bringing a crystalline fat material cetyl effect, blooming, bloom) Appea-
to several degrees below its melting point rance on the surface of the suppository or
and keeping it there. The aim of temper- other fat body of crystalline formations
ing is to convert the unstable crystalline which give a white effect.
Appendix II
Compounding formulas∗
ABHR suppository 5-Aminosalicylic acid 500 mg

(Ativan–Benadryl–Haldol–Reglan compound suppository
suppository)
(2.1 g mold)
(2.3 g mold) Aminosalicylic acid 500 mg
Ativan (lorazepam) 0.5 mg Silica gel, micronized 20 mg
Benadryl (diphenhydramine) 25 mg Lidocaine 25 mg
Haldol (haloperidol) 0.5 mg Hydrocortisone, micronized 25 mg
Reglan (metoclopramide) 10 mg Zinc oxide 83 mg
Fatty acid base 2.25 g Fatty acid base 1.647 g
Melt the fatty acid base at about 50◦ C. Slowly Triturate the powders together until uniform.
and with stirring, sprinkle the powders on the Melt the fatty acid base at about 50◦ C. Slowly and
surface of the melted base and mix well. Remove with stirring, sprinkle the powders on the surface
from heat and cool until still fluid and pourable. of the melted base and mix well. Remove from
Pour into a suitable mold. Cool and trim, if heat and cool until still fluid and pourable. Pour
necessary. Package and label. into a suitable mold. Cool and trim, if necessary.
Package and label.
Acetaminophen 650 mg suppository Amitriptyline hydrochloride

suppository
(1.6 g mold)
Acetaminophen 650 mg (2.0 g mold)
Witepsol 1.15 g 10 mg 25 mg 50 mg
Almond oil 0.06 mL Amitriptyline
Melt the Witepsol at about 50◦ C and add the hydrochloride 10 mg 25 mg 50 mg
almond oil. Slowly and with stirring, sprinkle Bentonite 200 mg 200 mg 200 mg
the acetaminophen powder on the surface of Polyethylene
the melt. Remove from heat and cool slightly glycol 1000 1.35 g 1.35 g 1.35 g
until still fluid and pourable. Pour into a suitable Polyethylene
mold. Cool and trim, if necessary. Package and glycol 3350 0.440 g 0.425 g 0.400 g
label. Heat the two polyethylene glycol ingredients
until fluid. Add the bentonite powder and mix
until uniform. Slowly and with stirring, sprinkle
the amitriptyline hydrochloride powder on the
surface of the melt. Remove from heat and cool
∗ slightly until still fluid and pourable. Pour into
Adapted from: Allen Jr LV Allen’s Compounded For-
mulations. Washington DC American Pharmaceutical a suitable mold. Cool and trim, if necessary.
Association 2003. Package and label.
215
216 Suppositories
Ampicillin 250 mg suppository Triturate the belladonna, pentobarbital

sodium, pyrilamine maleate, and tartaric acid
powders together until uniform. If tablets are
(2.0 g mold)
used, pulverize them thoroughly first; if capsules
Ampicillin trihydrate 250 mg
are used, empty the capsules first. Blend in the
Silica gel 20 mg
silica gel and lactose and mix well. Melt the
Sodium caprate 85 mg
fatty acid base at about 50◦ C. Slowly and with
Fatty acid base 1.98 g
stirring, sprinkle the powders on the surface of
Mix the ampicillin trihydrate, silica gel, and
the melted base and mix well. Remove from heat
sodium caprate together. Melt and heat the fatty
and allow to cool until still fluid and pourable.
acid base up to a maximum of 50◦ C. Add the
Pour into a suitable mold. Cool and trim, if
blended powders to the melted base. Mix well
necessary. Package and label.
until homogeneous. Pour into a suitable mold.
Cool and trim if necessary. Package and label.
Antinauseant suppositories #1
Antiemetic suppository
(2.0 g mold)
(2.0 g mold) Pyrilamine maleate 50 mg
Metoclopramide hydrochloride 40 mg Pentobarbital sodium 45 mg
Haloperidol 1 mg Polyethylene glycol suppository
Lorazepam 1 mg base 2g
Benzotropine 0.5 mg Triturate the pyrilamine maleate and pento-
Fatty acid base 1.87 g barbital sodium powders together until uniform.
Optional ingredients: Melt the polyethylene glycol suppository base at
Dexamethasone 20 mg about 55–57◦ C. Slowly and with stirring, sprinkle
Diphenhydramine hydrochloride 25 mg the powders on the surface of the melted base and
Triturate the powders together until uniformly mix well. Remove from heat and allow to cool
mixed. If tablets are used as the source of a until still fluid and pourable. Pour into a suitable
drug, pulverize those first; if capsules, empty the mold. Cool and trim, if necessary. Package and
capsules, then blend in the remaining powders. label.
Melt the fatty acid base at about 50◦ C. Slowly
and with stirring, sprinkle the powders on the
surface of the melted base and mix well. Remove
from heat and allow to cool until still fluid and Antinauseant suppositories #2
pourable. Pour into a suitable mold. Cool and
trim, if necessary. Package and label. (2.0 g mold)
Pyrilamine maleate 50 mg
Pentobarbital sodium 100 mg
Antiemetic–antispasmodic
Polyethylene glycol suppository
suppository
base 1.95 g
Triturate the pyrilamine maleate and pento-
(2.3 g mold) barbital sodium powders together until uniform.
Belladonna powder 20 mg Melt the polyethylene glycol suppository base at
Pentobarbital sodium 60 mg about 55–57◦ C. Slowly and with stirring, sprinkle
Pyrilamine maleate 50 mg the powders on the surface of the melted base and
Tartaric acid 4 mg mix well. Remove from heat and allow to cool
Silica gel 20 mg until still fluid and pourable. Pour into a suitable
Lactose 40 mg mold. Cool and trim, if necessary. Package and
Fatty acid base 2.054 g label.
Appendix II • Compounding formulas 217
Antinauseant suppositories, Pour into a suitable mold. Cool and trim, if

pediatric necessary. Package and label.
(2.0 g mold) Boric acid 600 mg vaginal

Pyrilamine maleate 25 mg suppository
Polyethylene glycol suppository
base 2g (2 g mold)
Triturate the pyrilamine maleate and pento- Boric acid 600 mg
barbital sodium powders together until uniform. Polyethylene glycol
Melt the polyethylene glycol suppository base at suppository base 1.71 g
about 55–57◦ C. Slowly and with stirring, sprinkle Pulverize the boric acid to a fine powder.
the powders on the surface of the melted base and Melt the polyethylene glycol suppository base at
mix well. Remove from heat and allow to cool about 55–57◦ C. Slowly and with stirring, sprinkle
until still fluid and pourable. Pour into a suitable the powder on the surface of the melted base
mold. Cool and trim, if necessary. Package and and mix well. Remove from heat and allow to
label. cool until still fluid and pourable. Pour into
a suitable mold. Cool and trim, if necessary.
Package and label. Note: it may be necessary to
Belladonna and opium suppository substitute a small quantity of the polyethylene
(modified) glycol suppository base with polyethylene glycol
300 if the suppository is too hard.
(2.0 g mold)
Belladonna extract 15 mg
Carbamazepine suppository
Morphine sulfate 7.5 mg
Silica gel 15 mg
Fatty acid base 1.75 g (1.5 g mold)
Triturate the powders together until uniform. 100 mg 200 mg
Melt the fatty acid base at about 50◦ C. Slowly and Carbamazepine 100 mg 200 mg
with stirring, sprinkle the powders on the surface Bentonite 200 mg 200 mg
of the melted base and mix well. Remove from Polyethylene glycol 1000 1.3 g 1.3 g
heat and cool until still fluid and pourable. Pour Polyethylene glycol 3350 0.4 g 0.3 g
into a suitable mold. Cool and trim, if necessary. Heat the two polyethylene glycol ingredients
Package and label. until fluid. Add the bentonite powder and mix
until uniform. Slowly and with stirring, sprinkle
the carbamazepine powder on the surface of the
Bismuth subgallate suppository melt. Remove from heat and cool slightly until
still fluid and pourable. Pour into a suitable mold.
(Mold varies) Cool and trim, if necessary. Package and label.
Bismuth subgallate 2.25%
Bismuth resorcin compound 1.75%
Chloral hydrate 500 mg suppository
Peruvian balsam 1.8%
Zinc oxide 11%
Benzyl benzoate 1.2% (2.0 g mold)
Fatty acid base qs 100% Chloral hydrate 500 mg
Melt the fatty acid base at about 50◦ C. Slowly Polyethylene glycol
and with stirring, sprinkle the ingredients on the suppository base 1.75 g
surface of the melted base and mix well. Remove Melt the polyethylene glycol suppository base
from heat and cool until still fluid and pourable. at about 55–57◦ C. Slowly and with stirring,
218 Suppositories
incorporate the chloral hydrate into the melted maximum of 50◦ C. Incorporate the blended
base and mix well. Remove from heat and allow powders and mix until uniform. Cool slightly
to cool until still fluid and pourable. Pour into and pour into a suitable mold. Cool and trim,
a suitable mold. Cool and trim, if necessary. if necessary. Package and label.
Package and label.
Diazepam 10 mg suppository
Chloroquine 300 mg suppository
(2.0 g mold)
(2 g mold) Diazepam 10 mg
Chloroquine phosphate 500 mg (equivalent Silica gel 20 mg
to 300 mg chloroquine) Fatty acid base 1.9 g
Polyethylene glycol suppository base Melt the fatty acid base until fluid. Slowly and
1.7 g with stirring, sprinkle the diazepam and silica gel
Melt the polyethylene glycol suppository base powder on the surface of the melted base and mix
at about 55–57◦ C. Slowly and with stirring, sprin- well. Remove from heat and allow to cool until
kle the chloroquine phosphate powder on the still fluid and pourable. Pour into a suitable mold.
surface of the melted base and mix well. Remove Cool and trim, if necessary. Package and label.
from heat and allow to cool until still fluid and
trim, if necessary. Package and label. Dihydroergotamine 2 mg
suppository
Clindamycin phosphate 150 mg (2.3 g mold)

vaginal suppository Dihydroergotamine mesylate 2 mg
Silica gel 20 mg
(2.0 g mold) Melt the fatty acid base until fluid. Slowly and
Clindamycin phosphate 150 mg with stirring, sprinkle the dihydroergotamine
Polyethylene glycol mesylate and silica gel powder on the surface of
suppository base 1.95 g the melted base and mix well. Remove from heat
Melt the polyethylene glycol suppository base and allow to cool until still fluid and pourable.
at about 55–57◦ C. Slowly and with stirring, sprin- Pour into a suitable mold. Cool and trim, if
kle the clindamycin phosphate powder on the necessary. Package and label.
surface of the melted base and mix well. Remove
Droperidol 1.25 mg suppository
trim, if necessary. Package and label.
(2.0 g mold)
Droperidol 1.25 mg
Clotrimazole 250 mg suppository
Silica gel 10 mg
(2.0 g mold) Mix the droperidol and silica gel powders
Clotrimazole 250 mg together. Melt the fatty acid base until fluid.
Silica gel 20 mg Incorporate the powders in the melted base
Fatty acid base 1.9 g and mix until uniform. Cool slightly and pour
Mix the clotrimazole and silica gel powders into a suitable mold. Cool and trim, if necessary.
until uniform. Melt the fatty acid base to a Package and label.
Ergotamine tartrate-PB it prior to the addition of the glycerin mixture.

suppositories After cooling to solidification, remove the sup-
positories.
(2.3 g mold)
Ergotamine tartrate 2 mg Hydrocortisone acetate 25 mg
Caffeine, anhydrous 100 mg suppository
Belladonna powder 20 mg
Tartaric acid 4 mg (2.0 g mold)
Silica gel, micronized 20 mg Hydrocortisone acetate 25 mg
Lactose 40 mg Propylene glycol 2 drops
Fatty acid base 2.054 g Polyethylene glycol
Melt the fatty acid base until fluid. Mix the suppository base 1.99 g
ergotamine tartrate, caffeine, belladonna, pento- Melt the polyethylene glycol suppository base
barbital sodium, tartaric acid and lactose powders at about 55–57◦ C. Slowly and with stirring, sprin-
together. Slowly and with stirring, sprinkle the kle the hydrocortisone acetate powder on the
powder mixture on the surface of the melted surface of the melted base and mix well. Remove
base and mix well. Next, incorporate the silica from heat and allow to cool until still fluid and
gel in the same manner. Remove from heat and pourable. Pour into a suitable mold. Cool and
allow to cool until still fluid and pourable. Pour trim, if necessary. Package and label.
into a suitable mold. Cool and trim, if necessary.
Package and label.
Hydrocortisone 100 mg
mucoadhesive suppository
Etodolac 200 mg suppository
(2.0 g mold)
(2.0 g mold) Hydrocortisone 100 mg
Etodolac 200 mg Karaya gum 500 mg
Polyethylene glycol base 1.9 g Polyethylene glycol 3350 700 mg
Melt the polyethylene glycol suppository base Polyethylene glycol 300 700 mg
at about 55–57◦ C. Slowly and with stirring, Heat the polyethylene glycols together to
sprinkle the etodolac powder on the surface of the about 55–57◦ C. Slowly and with stirring, sprinkle
melted base and mix well. Remove from heat and the hydrocortisone powder on the surface of the
allow to cool until still fluid and pourable. Pour melted base and mix well. Sprinkle the karaya
into a suitable mold. Cool and trim, if necessary. gum mixture on the surface of the mixture and
Package and label. mix until uniform. Remove from heat and allow
to cool until still fluid and pourable. Pour into
a suitable mold. Cool and trim, if necessary.
Glycerin suppositories Package and label.
(2.0 g mold)
Indometacin 50 mg suppository
Glycerin 91 g
Sodium stearate 9 g
Purified water 5g (2.2 g mold)
Heat the glycerin in a suitable container to Indometacin powder 50 mg
about 50◦ C. Add and dissolve the sodium stearate Silica gel 25 mg
with stirring in the hot glycerin. Add the purified Propylene glycol 2 drops
water, mix well and immediately pour into the Polyethylene glycol
suppository mold. If the mold is metal, warm suppository base 1.98 g
220 Suppositories
Melt the polyethylene glycol suppository base into a suitable mold. Cool and trim if necessary.
at about 55–57◦ C. Slowly and with stirring, mix Package and label.
the indometacin powder with the propylene
glycol and incorporate into the melted base, Miconazole nitrate 100 mg vaginal
followed by the silica gel and mix well. Remove suppository
(2.0 g mold)
trim, if necessary. Package and label.
Miconazole nitrate 100 mg
Polyethylene glycol
Lorazepam 1 mg suppository suppository base 1.95 g
Melt the polyethylene glycol suppository base
at about 55–57◦ C. Slowly and with stirring,
2.0 g mold) sprinkle the miconazole nitrate powder on the
Lorazepam 1 mg surface of the melted base and mix well. Remove
Bentonite 200 mg from heat and allow to cool until still fluid and
Polyethylene glycol 1000 1.35 g pourable. Pour into a suitable mold. Cool and
Polyethylene glycol 4000 449 mg trim, if necessary. Package and label.
Heat the two polyethylene glycol ingredients
until fluid and mix well. Incorporate the lo- Migraine headache suppository
razepam and bentonite powders and mix until
uniform. Pour into a suitable mold and allow to
cool. Trim if necessary. Package and label. (2.0 g mold)
Ergotamine and caffeine tablets 2
Hyoscyamine sulfate 0.25 mg
Metoclopramide hydrochloride Pentobarbital sodium 50 mg
10 mg suppository OR
Metoclopramide 50 mg
(2.0 g mold) OR
Metoclopramide hydrochloride 10 mg Promethazine 12.5 mg
Fatty acid base 2.0 g Fatty acid base 1.9 g
Melt the fatty acid base until fluid. Slowly Pulverize the tablets to a fine powder. Melt
and with stirring, sprinkle the metoclopramide the fatty acid base until fluid. Slowly and with
powder on the surface of the melted base. Re- stirring, sprinkle the powders to the surface of
move from heat and cool slightly but it must still the melt. Remove from heat and cool slightly
remain fluid and pourable. Pour into a suitable but it must still remain fluid and pourable. Pour
mold. Cool and trim, if necessary. Package and into a suitable mold. Cool and trim, if necessary.
label. Package and label.
Metronidazole 500 mg vaginal Misoprostol 1 mg suppository

suppository
(2.0 g mold)
(2.0 g mold) Misoprostol 200 ␮g tablets 5
Metronidazole 500 mg Fatty acid base 1.7 g
Silica gel 20 mg Pulverize the misoprostol tablets to a fine
Fatty acid base qs 2 g powder. Heat the fatty acid base to melting but
Mix the metronidazole and silica gel powders not to exceed 50◦ C. Incorporate the powder into
together. Heat the fatty acid base using low heat the melted base and mix until uniform. Pour into
until melted. Incorporate the blended powders appropriate mold. Cool and trim, if necessary.
and mix until uniform. Cool slightly and pour Package and label.
Morphine sulfate 10–100 mg Add the powders and the nitroglycerin to the
suppository melted base and mix well. Pour into molds and
allow to cool. Cool, trim, package and label.
(2.0 g mold)
Morphine sulfate 10–100 mg Nitrofurantoin urethral inserts
Silica gel 20 mg
Fatty acid base 1.99–1.95 g
Melt the fatty acid base until fluid. Slowly Nitrofurantoin 3 mg
and with stirring, sprinkle the morphine sulfate Hydrocortisone 15 mg
followed by the silica gel on the surface of the Lidocaine hydrochloride 50 mg
melt. Remove from heat and cool slightly but it Polyethylene glycol
must still remain fluid and pourable. Pour into suppository base qs
a suitable mold. Cool and trim, if necessary. Melt the polyethylene glycol suppository base
Package and label. to about 55–57◦ C. Slowly and with stirring,
sprinkle the powders on the surface of the melted
base and mix well. Remove from heat and allow
to cool until still fluid and pourable. Pour into a
Morphine sulfate 25 mg or 50 mg
suitable urethral mold. Cool and trim, if neces-
slow-release suppository
sary. Package and label.
(2.0 g mold)
Morphine sulfate 25 or 50 mg Nitrofurazone urethral inserts
Alginic acid 500 mg
Witepsol H15 1.75 g Nitrofurazone 2.6 mg
Melt the Witepsol H15 base until fluid. Slowly Hydrocortisone acetate 13 mg
and with stirring, sprinkle the morphine sulfate Lidocaine hydrochloride 20 mg
followed by the alginic acid on the surface of Polyethylene glycol
the melt. Remove from heat and cool slightly suppository base qs
but it must still remain fluid and pourable. Pour Melt the polyethylene glycol suppository base
into a suitable mold. Cool and trim, if necessary. to about 55–57◦ C. Slowly and with stirring,
Package and label. sprinkle the powders on the surface of the melted
base and mix well. Remove from heat and allow
to cool until still fluid and pourable. Pour into a
Nifedipine, lidocaine, and suitable urethral mold. Cool and trim, if neces-
nitroglycerin suppositories sary. Package and label.
(2.5 g mold)
Ondansetron hydrochloride 8 mg
Nifedipine 7 mg
suppository
Lidocaine hydrochloride 30 mg
Nitroglycerin 0.3 mg tablets 1
Polybase or fatty acid base qs 2.5 g (2.3 g mold)
Note: This preparation should be prepared in Ondansetron hydrochloride 8 mg
a room with subdued light due to the light- Fatty acid base 2.3 g
sensitivity of the nifedipine. Calibrate the sup- Melt the fatty acid base until fluid. Slowly
pository mold using the polybase to the fatty and with stirring, sprinkle the ondansetron hy-
acid base. Mix nifedipine and lidocaine powders drochloride powder on the surface of the melt.
together. Levigate the nitroglycerin tablets with a If tablets are used, pulverize them to a fine
small quanitity of ethyl alcohol. Gently melt the powder first. Remove from heat and cool slightly
selected base. but it must still remain fluid and pourable.
222 Suppositories
Pour into a suitable mold. Cool and trim, if powder on the surface of the melt. Remove from
necessary. Package and label. Note: The quantity heat and cool slightly but it must still remain fluid
of fatty acid base will vary depending upon and pourable. Pour into a suitable mold. Cool and
the source of the active ingredient, ondansetron trim, if necessary. Package and label.
hydrochloride.
Progesterone 25–400 mg
Phenytoin (dilantin) 200 mg suppository
suppository
(2.3 g mold)
Progesterone, micronized 25–400 mg
(2.3 g mold)
Polyethylene glycol
Phenytoin 200 mg
suppository base qs
Silica gel 20 mg
Melt the polyethylene glycol suppository base
to about 55–57◦ C. Slowly and with stirring, sprin-
Melt the fatty acid base until fluid. If pheny-
kle the progesterone powder on the surface of the
toin capsules are used, they must be the fast-
melted base and mix well. Remove from heat and
release capsules; it is best if the phenytoin powder
allow to cool until still fluid and pourable. Pour
is used. Slowly and with stirring, sprinkle the
into a suitable urethral mold. Cool and trim, if
phenytoin and silica gel powder on the surface of
necessary. Package and label.
the melted base and mix well. Remove from heat
and allow to cool until still fluid and pourable.
Pour into a suitable mold. Cool and trim, if
necessary. Package and label. Promethazine hydrochloride 25 mg
suppository
Polyethylene glycol suppository (2.0 g mold)

bases Prochlorperazine hydrochloride 25 mg
Melt the fatty acid base until fluid. Slowly
A B C D and with stirring, sprinkle the promethazine
Polyethylene glycol 300 60 48 – – hydrochloride powder on the surface of the
Polyethylene glycol 1000 – – 95 75 melt. Remove from heat and cool slightly but it
Polyethylene glycol 3350 – – 5 25 must still remain fluid and pourable. Pour into
Polyethylene glycol 6000 – 52 – – a suitable mold. Cool and trim, if necessary.
Polyethylene glycol 8000 40 – – – Package and label.
Melt the polyethylene glycols 55–57◦ C. with
stirring. Pour into stock container or into pre-
weighed blocks for later use. Package and label.
Tetracycline 250 mg suppository
Prochlorperazine maleate 25 mg
(2.3 g mold)
suppository
Tetracycline hydrochloride 250 mg
Silica gel, micronized 20 mg
(2.0 g mold) Fatty acid base 2.2 g
Prochlorperazine maleate 25 mg Melt the fatty acid base until fluid. Slowly and
Fatty acid base 1.99 g with stirring, sprinkle the tetracycline hydrochlo-
Melt the fatty acid base until fluid. Slowly ride powder on the surface of the melt. Remove
and with stirring, sprinkle the prochlorperazine from heat and cool slightly but it must still
remain fluid and pourable. Pour into a suitable Verapamil hydrochloride 40 mg

mold. Cool and trim, if necessary. Package and suppository
label.
(2.0 g mold)
Verapamil hydrochloride 40 mg
Trimethobenzamide 100 mg
Polyethylene glycol 1450 1.3 g
suppository
Polyethylene glycol 6000 0.55 g
Purified water 0.15 mL
(2.0 g mold) Melt the polyethylene glycols at about 55–
Trimethobenzamide 100 mg 57◦ C. Dissolve the verapamil hydrochloride in
Fatty acid base 1.95 g the purified water. Slowly and with stirring,
Melt the fatty acid base until fluid. Slowly and add the verapamil hydrochloride solution to
with stirring, sprinkle the trimethobenzamide the melted polyethylene glycols and mix well.
powder on the surface of the melt. Remove from Remove from heat and allow to cool until still
heat and cool slightly but it must still remain fluid fluid and pourable. Pour into a suitable urethral
and pourable. Pour into a suitable mold. Cool and mold. Cool and trim, if necessary. Package and
trim, if necessary. Package and label. label.
224
Appendix III
Manufacturing formulas∗
Acetaminophen 125 mg suppository powder and mix at 10 rpm and homogenize at

speed I for 10 minutes, maintaining the tempera-
ture of 50–55◦ C under vacuum to make a smooth
Acetaminophen 125 mg
mixture. Transfer to a storage vessel maintained
Suppocire AM 785.54 mg
at 45◦ C. Fill 1390 mg in a suppository mold.
Crill-3 3.21 mg
Package and label.
Place the Suppocire AM in a suitable vessel
and heat to 60◦ C. Transfer about a third of the
melt to a Becomix vessel through filter sieves
and maintain the temperature at 60◦ C. Add the Acetaminophen 500 mg suppository
Crill-3 to this; mix at 10 rpm and homogenize at
a speed setting of I for 15 minutes, at 60◦ C and
under vacuum of 0.4–0.6 bar to dissolve. Cool the Acetaminophen 500 mg
mix to 50–55◦ C. Add the acetaminophen powder Suppocire AM 1137.40 mg
and mix at 10 rpm and homogenize at speed Place the Suppocire AM in a suitable vessel
I for 10 minutes, maintaining the temperature and heat to 60◦ C. Transfer to a Becomix vessel
of 50–55◦ C under vacuum to make a smooth through filter sieves and maintain the temper-
mixture. Add the remaining two-thirds of the ature at 60◦ C. Cool to 50–55◦ C and apply a
melted Suppocire AM through the filter sieve, set vacuum of 0.4–0.6 bar. Add the acetaminophen
the temperature at 50◦ C, a speed of 10 rpm, and powder and mix at 10 rpm and homogenize at
homogenize at speed II and under vacuum for 10 speed I for 10 minutes, maintaining the tempera-
minutes. Transfer to a storage vessel maintained ture of 50–55◦ C under vacuum to make a smooth
at 45◦ C. Fill 920 mg in a suppository mold. mixture. Transfer to a storage vessel maintained
Package and label. at 45◦ C. Fill 1640 mg in a suppository mold,
package and label.
Acetaminophen 250 mg suppository

Acetylsalicylic acid suppository
Acetaminophen 250 mg
Suppocire AM 1137.40 mg Acetylsalicylic acid 100 mg
Place the Suppocire AM in a suitable vessel Suppocire AM 400 mg
and heat to 60◦ C. Transfer to a Becomix vessel Place the Suppocire AM in a suitable vessel and
through filter sieves and maintain the temper- heat to 50◦ C. Allow to cool to 40◦ C and add the
ature at 60◦ C. Cool to 50–55◦ C and apply a acetylsalicylic acid while stirring with a turbine
vacuum of 0.4–0.6 bar. Add the acetaminophen mixer. Continue mixing while cooling. Chill the
mold at 0 to –5◦ C then warm to 35◦ C and pour
∗ Adapted from Niazi SK. Handbook of Pharmaceutical the melt into the molds; the quantity poured
Manufacturing Formulations: Semisolid Products, Vol 4. into the molds will determine the strength of the
New York: CRC Press, 2004. suppositories. Cool, package and label.
225
226 Suppositories
Antihemorrhoidal suppositories vacuum. Transfer to a storage vessel maintained

at 40◦ C. Fill a suppository mold. Package and
label.
Benzocaine 0.93%
Bismuth iodosubgallate 2.33%
Bismuth subgallate 2.33%
Zinc oxide 9.33% Clotrimazole and clindamycin
Aesculus extract 0.57% vaginal suppository (glycerinated
Witch hazel extract 0.57% gelatin base)
Demineralized water 0.57%
Suppocire AS2X 83.37%
Melt the Suppocire AS2X at 50◦ C. Allow to Clotrimazole 100 mg
cool to 40◦ C. Add the benzocaine, bismuth iodo- Clindamycin hydrochloride 22.7 mg
subgallate, bismuth subgallate, and zinc oxide Calcium lactate pentahydrate 77.3 mg
with thorough mixing. Dissolve the aesculus ex- Gelatin 250 mg
tract and witch hazel extract in the demineralized Purified water 250 mL
water and add to the heated mixture at about Glycerin 1.25 g
38◦ C. Cool to 34◦ C and pour into a suitable Dissolve the clotrimazole and clindamycin
suppository mold. Package and label. hydrochloride in the purified water. Heat the
gelatin and glycerin in a separate vessel and add
the calcium lactate pentahydrate and mix until
uniform. Add the drug mixture and mix well
Betamethasone and cinchocaine until uniform. Fill 2.0 g into a suppository mold,
suppository package and label.
Betamethasone valerate 1 mg
Cinchocaine hydrochloride 1 mg
Clotrimazole and clindamycin
Witepsol W45 1.798 g
vaginal suppository (Macrogol
Place the Witepsol W45 in a suitable vessel
base)
and heat to 55◦ C. Transfer the melt to a Becomix,
passing it through a stainless steel sieve. Maintain
the temperature at 50◦ C. Add the betamethasone Clotrimazole 100 mg
valerate and cinchocaine hydrochloride, main- Clindamycin hydrochloride 22.7 mg
tain at 50◦ C and mix for 20 minutes. Homogenize Calcium lactate pentahydrate 77.3 mg
at 0.6 bar vacuum also at 50◦ C. Transfer to a Macrogol 400 1g
storage vessel maintained at 40◦ C. Fill 1.8 g into Macrogol 6000 800 mg
a suppository mold. Package and label. Lactic acid 200 mg
In a suitable container, heat the Macrogols
and the lactic acid to 70◦ C. Add the calcium lac-
tate pentahydrate, clotrimazole and clindamycin
Bisacodyl 10 mg suppository hydrochloride and mix well while maintaining
70◦ C. Cool to 40◦ C and fill into a suppository
mold.
Bisacodyl, micronized 10 mg
Witepsol E76 895 mg
Witepsol W45 895 mg
Place both Witepsol bases in a suitable vessel
Diclofenac sodium suppository
and heat to 50◦ C. Transfer to a Becomix through
a filter sieve and maintain at 40◦ C. Add the
bisacodyl and mix carefully at 40◦ C at a speed of 12.5 mg 25 mg 50 mg 100 mg
10 rpm for 20 minutes. Homogenize the mixture Diclofenac sodium, micronized
for 3 minutes and continue to mix under a 12.5 mg 25 mg 50 mg 100 mg
Appendix III • Manufacturing formulas 227
Suppocire CM 530 mg 522.7 mg 1.045 g Indometacin 50 mg suppository

1.015 g
Suppocire AS2X
Indometacin 50 mg
353 mg 348 mg 696 mg 675 mg
Butylated hydroxytoluene 8.3 μg
Crill-3 2.9 mg 2.9 mg 5.8 mg 6.0 mg
Lutrol E 4000 141 mg
Aerosil 200 1.15 mg 1.15 mg 2.3 mg 2.5 mg
Lutrol E 6000 14 mg
Place the Suppocire CM, Suppocire AS2X, and
EDTA 16.3 μg
Crill-3 in a suitable vessel and heat to 55◦ C.
Purified water 3 mg
Transfer to another suitable vessel through filter
In a suitable container, dissolve the EDTA in
sieve and maintain the temperature at 50◦ C. Add
the purified water. In a separate container, melt
the diclofenac sodium and Aerosil 200 to the
the Lutrol E 4000, Lutrol E 6000 and add the
melt and mix well at 10 rpm and homogenize at
indometacin and butylated hydroxytoluene. Add
speed I for 15 minutes at 0.6 bar vacuum. Cool to
the aqueous phase to the heated phase and mix
50–55◦ C then transfer into a storage vessel and set
well. Fill 1.6 g in a suppository mold. Package and
the temperature at 50◦ C. Fill 900 mg (12.5 mg),
label.
900 mg (25 mg), 1.8 g (50 mg), or 1.8 g (100 mg)
into a suppository mold. Package and label.
Laxative suppository
Ephedrine sulfate and zinc oxide
suppository Glycerin 10%
Suppocire BS2X 90%
Ephedrine sulfate 3.86 mg Heat the Suppocire BS2X to 50◦ C. Cool to 45◦ C
Zinc oxide 96.5 mg and add the glycerin with stirring. Cool slightly
Hydrogenated vegetable oil qs and pour into molds. Cool and trim if necessary.
Heat the hydrogenated vegetable oil until Package and label.
melted. Mix the ephedrine sulfate and zinc oxide
powders together. Sift the blended powders into
the melted suppository vehicle (hydrogenated
vegetable oil) and blend well. Pour into a sup-
Lidocaine and tribenoside
pository mold. Package and label.
suppository
Lidocaine 40 mg
Tribenoside 400 mg
Glycerin suppository
Witepsol E85 281 mg
Witepsol W35 1124.6 mg
Pediatric Adult Miglyol 812 N 4.4 mg
Glycerin 900 mg 1.8 g Place the Witepsol E85 and Witepsol W35 in
Sodium stearate 89 mg 178 mg a suitable container and heat to 50◦ C. Transfer
Purified water 49.5 mg 99 mg the melt to a Becomix through filter sieves,
Place the glycerin in a suitable container and keeping a small portion separate. Add the lido-
heat to 120◦ C with constant stirring at low caine, tribenoside, and Miglyol 812 N to the
speed. Add the sodium stearate and mix until large heated base, rinsing the container with the
completely dissolved. Cool the mixture to 105◦ C. molten portions set aside. Mix for 20 minutes
Add the purified water slowly to the mixer and at 10 rpm while maintaining a temperature of
mix for 20 minutes. Immediately transfer the 50◦ C; homogenize at speed II for 4 minutes under
hot liquid to a heated storage vessel or heated 0.6 bar vacuum. Check for clarity and if not
suppository filling machine and maintain at clear, homogenize again. Adjust the temperature
105◦ C. Fill 1.039 g (pediatric) or 2.077 g (adult) to 39◦ C and mix at 10 rpm. Fill 1.85 g into a
into a suppository mold. Package and label. suppository mold. Package and label.
228 Suppositories
Mesalamine 500 mg suppository In a suitable container, place the Witepsol

bases and heat to 50◦ C. Check the melt for any
separation. Transfer the melt through filter sieves
Mesalamine 500 mg
to a mixer set at 40◦ C. Add the miconazole nitrate
Hard fat NF qs
to the mixture and mix at 10 rpm for 10 minutes.
Place the hard fat in a suitable container and
Apply a 0.6 bar vacuum and homogenize at low
heat until melted. Slowly and with continued
speed while mixing for 5 minutes; then, homog-
stirring, add the mesalamine and mix well. Pour
enize at high speed with mixing for 3 minutes.
into a suppository mold. Package and label.
Continue mixing under vacuum. Preheat the
storage vessel at 40◦ C. Transfer the melt form the
mixer to the storage vessel. While mixing contin-
uously, fill into a suppository mold. Package and
Metoclopramide suppository label.
5 mg 10 mg 20 mg
Metoclopramide 5 mg 10 mg 20 mg Povidone-iodine vaginal ovule
Hard fat or Suppocire AM
894.75 mg 1.340 g 1.78 g 100 mg 200 mg
Ethanol 95% qs qs qs Povidone-iodine 30/06 M 10
In a suitable container, place the hard fat or 100 mg 200 mg
Suppocire AM and heat to 65◦ C. Transfer the Lutrol E400 200 mg 100 mg
melt through clean polyester cloths into a mixer Lutrol E1500 – 100 mg
maintained at 65◦ C. Heat the ethanol in a water Lutrol E 4000 1.7 g 1.6 g
bath to 65◦ C. Dissolve the metoclopramide in In a suitable container, melt the Lutrol ingre-
the heated alcohol and add the solution to the dients using gentle heat. Sir in the micronized
molten base while mixing and maintaining the povidone-iodine in small portions at a time into
65◦ C. Wash the drug container with 2.5 g of the melt. After a uniform suspension is obtained,
additional hot alcohol and add the rinsing to the pour 2.0 g into a polyethylene suppository mold.
mixer while still mixing. Set the mixer under vac- Package and label.
uum with air circulation. Maintain a temperature
of 50◦ C, mixing at 10 rpm, homogenize under
vacuum with air circulation at 50◦ C for 1 hour Pramoxine suppository
and 45 minutes. After complete evaporation of
the ethanol, continue the mixing of the mass
under vacuum 0.4–0.6 bar while cooling it to Pramoxine hydrochloride 18 mg
40◦ C. Preheat the storage vessel at 40◦ C and Witepsol H15 1.782 g
transfer the mixture to the storage vessel. Fill In a suitable jacketed, stainless steel container,
900 mg (5 mg), 1.35 g (10 mg), or 1.8 g (20 mg) in premelt the Witepsol H15 at 35–45◦ C. Transfer
a suppository mold. Package and label. about 12% of the premelted Witepsol H15 to a
suitable premixing tank with an efficient agitator
and maintain the 35–45◦ C temperature. Slowly
add the pramoxine hydrochloride and mix for 15
minutes. Run this premix through a homogenizer
Miconazole nitrate suppository
while maintaining the 40◦ C temperature. Flush
the premix tank and mixing system with about
200 mg 400 mg 5% of the premelted Witepsol H15 and add to the
Miconazole nitrate, micronized batching tank. Homogenize the batching tank at
200 mg 400 mg high speed for 15 minutes. Incorporate the re-
Witepsol H37 1.25 g 1.15 g mainder of the premelted Witepsol H15 into the
Witepsol H35 1.25 g 1.15 g mixture and homogenize for 15 minutes. Cool,
Appendix III • Manufacturing formulas 229
with continued mixing, to 27–38◦ C. Recirculate Vitamin A 150 000 IU suppository

the batch through a 150 μm aperture screen while
filling 1.8 g per suppository mold. Package and
Vitamin A palmitate 150 000 IU
label.
Butylated hydroxytoluene 1 mg
Cremophor RH 40 400 mg
Pramoxine suppository (alternate) Lutrol E 1500 800 mg
Lutrol E 4000 500 mg
Dissolve the butylated hydroxytoluene in the
Pramoxine 17.1 mg pre-warmed vitamin A palmitate. Add the Cre-
Pramoxine hydrochloride 1.01 mg mophor and mix well. Heat the Lutrol base until
Witepsol W32 1.781 g it melts and add to the mixture and mix well. Fill
In a suitable stainless steel tank with a good ag- 2 g into a suppository mold (depending upon the
itator, melt the Witepsol W32 at about 45◦ C. Pre- activity of the vitamin A palmitate). Package and
mix the pramoxine base and pramoxine hydro- label.
chloride in a suitable stainless steel container
making sure that the mixture is uniform and
free of lumps. Maintain the Witepsol at 45◦ C
(must be below 50◦ C) and add the premixed
Zinc oxide suppository
powders to the melted base. Continue mixing
for at least 15 minutes while maintaining the
45◦ C temperature. Recirculate the batch through Zinc oxide 100 mg
a 150 ␮m aperture stainless steel screen until the Hard fat 1.9 g
batch is filled. Cool the batch slowly (about 3◦ C Melt the hard fat until fluid. Sift the zinc oxide
per hour) to 31◦ C and with constant recirculation powder into the melted hard fat suppository
or mixing throughout the filling operation, fill base and blend well. Pour into an appropriate
1.8 g per suppository mold. Package and label. suppository mold. Package and label.
230
Appendix IV
Calculations involving suppositories
Density (dose replacement) Cocoa butter is arbitrarily assigned a value of

calculations for suppositories 1 as the standard base. Examples of other dosage
replacement factors are shown in Table IV.2.
In the preparation of suppositories, it is generally Example 1

assumed that if the quantity of active drug is
less than 100 mg, then the volume occupied Prepare a suppository containing 100 mg pheno-
by the powder is insignificant and need not barbital (f = 0.81) using cocoa butter as the base.
be considered. This is usually based on a 2 g The weight of the pure cocoa butter suppository
suppository weight. Obviously, if a suppository is 2.0 g. Since 100 mg of phenobarbital is to be
mold of less than 2 g is used, the powder volume contained in an approximately 2.0 g suppository,
may need to be considered. it will be about 5% phenobarbital. What will be
The density factors of various bases and drugs the total weight of each suppository?
need to be known to determine the proper
weights of the ingredients to be used. Density 0.81 = [100(2 − G)]/[(G)(5)] + 1 = 2.019 g
factors relative to cocoa butter have been de-
termined. If the density factor of a base is not
known, it is simply calculated as the ratio of the Density factor method
blank weight of the base and cocoa butter. Den-
sity factors for a selected number of ingredients
are shown in Table IV.1. 1 Determine the average blank weight, A, per
Four different methods used to calculate the mold using the suppository base of interest.
quantity of base that the active medication 2 Weigh the quantity of suppository base neces-
will occupy and the quantities of ingredients sary for 10 suppositories.
required will be illustrated here: (1) dosage 3 Weigh 1.0 g of medication.
replacement factor, (2) density factor, (3) oc- The weight of medication per suppository,
cupied volume, and (4) displacement value B, is then equal to 1 g/10 supp = 0.1 g/supp.
methods. 4 Melt the suppository base and incorporate the
medication, mix, pour into molds, cool, trim,
and remove from the molds.
Dosage replacement factor method 5 Weigh the 10 suppositories and determine the
average weight (C).
6 Determine the density factor as follows:
f = [100(E − G)]/[(G)(X)] + 1
Density f actor = B/( A − C + B)
where E is the weight of the pure base supposito- where A is the average weight of blank, B
ries, and G is the weight of suppositories with X% is the weight of medication per suppository,
of the active ingredient, and f is the replacement and C is the average weight of medicated
factor. suppository.
231
232 Suppositories
Table IV.1 Density factors for cocoa butter Table IV.2 Dosage replacement factors for selected
suppositories drugs
Active drug Density factor

Acetylmorphine hydrochloride 0.71
Aloin 1.3
Aspirin 0.63
Alum 1.7
Peruvian balsam 0.83
Aminophylline 1.1
Beeswax 1.00
Aminopyrine 1.3
Aspirin 1.1 Benzocaine 0.68
Barbital sodium 1.2 Bismuth subgallate 0.37
Beeswax 1.0 Bismuth subnitrate 0.33
Belladonna extract 1.3 Boric acid 0.67
Benzoic acid 1.5 Camphor 1.49
Bismuth carbonate 4.5 Castor oil 1.0
Bismuth salicylate 4.5 Codeine phosphate 0.80
Bismuth subgallate 2.7 Ichthammol 0.91
Bismuth subnitrate 6.0 Menthol 1.53
Boric acid 1.5 Phenobarbital 0.81
Castor oil 1.0 Phenobarbital sodium 0.62
Chloral hydrate 1.3 Phenol 0.9
Cocaine hydrochloride 1.3 Procaine HCl 0.81
Cocoa butter 1.0 Quinine HCl 0.83
Codeine phosphate 1.1 Resorcin 0.71
Digitalis leaf 1.6 Silver protein, mild 0.61
Dimenhydrinate 1.3
Spermaceti 1.0
Diphenhydramine hydrochloride 1.3
Theophylline 0.63
Gallic acid 2.0
White/yellow wax 1.0
Glycerin 1.6
Zinc oxide 0.15–0.25
Ichthammol 1.1
Iodoform 4.0
Menthol 0.7 7 Take the weight of the medication required for
Morphine hydrochloride 1.6
each suppository and divide by the density fac-
Opium 1.4
tor of the medication to find the replacement
Paraffin 1.0
Pentobarbital sodium 1.2
value of the suppository base.
Peruvian balsam 1.1 8 Subtract this quantity from the blank suppos-
Phenobarbital 1.2 itory weight.
Phenol 0.9 9 Multiply by the number of suppositories re-
Potassium bromide 2.2 quired to obtain the quantity of suppository
Potassium iodide 4.5 base required for the prescription.
Procaine 1.2 10 Multiply the weight of drug per suppository by
Quinine hydrochloride 1.2 the number of suppositories required to obtain
Resorcinol 1.4 the quantity of active drug required for the
Salicylic acid 1.3
prescription.
Secobarbital sodium 1.2
Sodium bromide 2.3
Spermaceti 1.0
Sulfathiazole 1.6
Example 2
Tannic acid 1.6
White wax 1.0
Witch hazel fluid extract 1.1 Prepare 12 acetaminophen 300 mg suppositories
Zinc oxide 4.0 using cocoa butter, where the average weight of
Zinc sulfate 2.8 the cocoa butter blank is 2 g and the average
Appendix IV • Calculations involving suppositories 233
weight of the medicated suppository is 1.8 g. From step 3: The density ratio is 3.0/0.9 =
3.3.
DF = 0.3/2 − 1.8 + 0.3 = 0.6 From step 4: The amount of suppository base
displaced by the active drug is 2.0 g/3.3 =
From step 7: (0.3 g)/0.6 = 0.5 (the replace-
0.6 g.
ment value of the base)
From step 5: The weight of the suppository
From step 8: 2.0 g – 0.5 g = 1.5 g
base required is 20 g – 0.6 g = 19.4 g.
From step 9: 12 × 1.5 g = 18 g cocoa butter
From step 6: The quantity of active drug
required
required is 0.2 g × 10 = 2.0 g.
From step 10: 12 × 0.3 g = 3.6 g acet-
aminophen The required weight of the suppository base is
19.4 g and the active drug is 2 g.
Occupied volume method

Displacement value method
1 Determine the average weight per mold
(blank) using the suppository base of interest. If the displacement value of the drug is 1, then
2 Weigh the quantity of suppository base neces- the weight of the drug can be subtracted from the
sary for 10 suppositories. base. However, this will not generally be the case
3 Divide the density of the active drug by the and it is necessary to use the displacement value
density of the suppository base to obtain a for the calculations. The following equation can
ratio. be used:
4 Divide the total weight of active drug required
for the total number of suppositories by the Wt o f base = Wt o f suppositor ies − (Wt o f active)/
ratio obtained in step 3 (this will give the (Displacement value)
amount of suppository base displaced by the
active drug).
5 Subtract the amount obtained in step 4 from
the total weight of the prescription (number of Example 4
suppositories multiplied by the weight of the
blanks) to obtain the weight of suppository Prepare 10 suppositories, each containing 300 mg
base required. of zinc oxide in cocoa butter. The capacity of the
6 Multiply the weight of active drug per suppos- mold is 2 g of cocoa butter and the displacement
itory times the number of suppositories to be value for zinc oxide is 4.7.
prepared to obtain the quantity of active drug First, insert the values into the equation:
required.
Wt o f base f or 10 suppositor ies = (10 × 2 g)−
Example 3 (10 × 300 mg)/(4.7)
Prepare 10 suppositories, each containing 200 mg Then solve for the quantity of base that will
of a drug with a density of 3.0. The supposi- be required:
tory base has a density of 0.9 and a prepared
blank weighs 2.0 g. Using the “occupied volume Wt o f base = 20 g − 3000 mg/4.7
method,” prepare the requested suppositories.
Wt o f base = 20 g − 0.638 g = 19.362 g
From step 1: The average weight per mold is
2.0 g. To prepare the suppositories, accurately weigh
From step 2: The quantity required for 10 3 g of zinc oxide and 19.362 g of cocoa butter. The
suppositories would be 2 g × 10 supp = total weight of ingredients will be 22.362 g. Each
20 g. suppository will weigh 2.236 g.
234
Index
ABHR suppository, 215 release from base see release, drug formulation, 91
absorption salts/esters, 90 pharmacokinetics, 65
anatomical factors, 51 selection, 78 stability, 173
enhancers, 86 solubility see solubility of active aminopyrine
factors affecting, 51 drug base incompatibility, 43
formulation considerations, 78 stability see stability bioavailability, 58
optimal routes, 52 toxicity, 178 three-component system
physicochemical factors, 54 Addisonian crises, 188 base, 133
physiological factors, 52 additives, 77 5-aminosalicylic acid (5-ASA) see
see also rectal absorption toxicity, 178 mesalamine
AC-70, 134 Adeps Solidus, 40 amitriptyline hydrochloride, 215
acetaminophen (paracetamol) adiphenin, 81 amoxicillin, 173
adverse reactions, 179 administration of suppositories amphotericin B (AMB), 87, 90
bioavailability, 64 formulation considerations, 78 ampicillin
clinical effectiveness, 180 guidelines for nurses, 178 bioavailability, 63
compounding formula, 215 patient counseling, 177 clinical effectiveness, 181
dielectric constant of base, 81 see also insertion compounding formula, 216
double-layered suppositories, 127 adrenal insufficiency, 187 formulation, 87
formulation, 85 adriamycin, 180 amylodextrin, 88
manufacturing formulas, 225 advantages of suppositories, 4 anal cones, 6
pharmacokinetics, 65, 67 adverse reactions, 179 anal fissures, 3
wax matrix suppositories, 128 Aerosil see silicon dioxide, colloidal analgesic suppositories, 2, 3
acetic acid ester of agar matrix suppositories, 128 anatomy
monoglycerides, 48, 134 aging and aging tests, 156, 167, rectal, vaginal and urethral, 51
acetylsalicylic acid see aspirin 168 of suppositories, 6
aciclovir, 58 see also stability anesthesia
acid value (acid number, acidity air, introduction of, 101, 102 acid aspiration prophylaxis,
index), 29 albuterol see salbutamol 184
active drugs, 6, 9 alginic acid, 56, 131 ketamine, 190
absorption see absorption Ali Ibn Al-Abbas-al-Majusi, 15 premedication, 184, 192
base compatibility, 29 allopurinol anorectal disorders, 1, 3
chemical analysis, 153 bioavailability, 63 actions of suppositories, 5, 9
compounding, 113, 117 formulation, 88, 91 complicating use of
density, 107, 231 alprostadil, 1, 123 suppositories, 179
density factors, 232 aluminum/polyethylene (PE) antiarrhythmic agents, 187, 197
dosage replacement factors, 232 laminated shell material, 99 antibiotic suppositories, 182
extraction methods, 154 American Journal of Pharmacy, 15 vaginal, 121
formulation variables, 80 American Pharmaceutical antiemetic suppositories, 2
loss of potency, 172 Association, 15, 16, 19 compounding formula, 216
particle size, 55, 80, 113 aminopenicillins, 91 see also nausea and vomiting
PEG base compatibility, 43, 118 aminophenazone, 81, 91 antiemetic–antispasmodic
penetration of rectal mucous aminophylline, 4 suppository, 216
membrane, 56 adverse reactions, 179 antifungal vaginal
physical state, 80 clinical effectiveness, 132, 180 suppositories, 121
235
236 Index
antihemorrhoidal suppositories, 3, desirable characteristics, 29 bioadhesive suppositories see

5, 9 dielectric constant, 81 mucoadhesive suppositories
manufacturing formula, 226 effervescent, 47 bioavailability, 5
antinauseant suppositories fatty or oleaginous, 30, 54 physicochemical factors
compounding formulas, 216 compounding influencing, 54
pediatric, 216 considerations, 106, 107, 118 rectal suppositories, 54, 63
see also nausea and vomiting drug release rates, 27 specific drugs, 58
antioxidants, 78, 169 hardening agents, 31, 106 see also absorption
antipyretics, 180, 185, 193, 196 history, 46 bioequivalence, 57
Anuprep-HC, 10 storage considerations, 171 biopharmaceutics, 51
apomorphine, 58 functions, 79 bisacodyl, 9, 10
applications of suppositories, 3 history of development, 46 clinical effectiveness, 182
Arabic medicine, 15 hydroxyl value see hydroxyl manufacturing formula, 226
Archibald, HC, 16 value bisected suppositories, 129
area, 213 inertness, 77 bismuth subgallate
artemisinin, 65 liquefaction time see liquefaction suppository, 217
artesunate, 182 time bloom (fat bloom), 213
arthritis melting point see melting point formation, 30
effectiveness of miscellaneous, 45, 54 minimizing, 119
suppositories, 188 polymorphism, 29, 31, 168 boric acid vaginal
packaging for patients with, 163 preparation for suppositories, 123
see also osteoarthritis; compounding, 113 clinical effectiveness, 183
rheumatoid arthritis rectal drug absorption and, 53, compounding formula, 217
aspirin (acetylsalicylic acid), 3 56 bougies, 6, 9
bioavailability, 58, 63, 80 release of drug see release, drug historical definition, 13
clinical effectiveness, 182 selection, 78 see also urethral suppositories
compounding, 118 solubility of active substance in Brady, Henry B, 16, 19
compounding formula, 215 see solubility of active drug breaking test, 146, 148
manufacturing formula, 225 stability during storage, 77 British Pharmacopoeia (BP), 19,
PEG interactions, 43 toxicity, 178 151
Pluronic-based suppository, 45 vaginal suppositories, 121 brittleness, 106
rectal intolerance, 179 water soluble/miscible, 43, 54 buffering capacity, rectal liquid, 52,
stability, 168, 174 compounding 53
assays, 139, 153 considerations, 106, 108 bumetanide
Astra-Fat, 46 drug release, 27 bioavailability, 63
Ativan–Benadryl–Haldol–Reglan basket method, dissolution formulation, 90
(ABHR) suppository, 215 testing, 147, 149 buprenorphine, 183
Avicenna, 15 batch number, 164 buspiron, 82
bead-bed suppository dissolution butaconazole, 183
bacampicillin, 130, 131 apparatus, 151 butylated hydroxyanisole
bacterial vaginosis, 184, 192, beeswax, 31, 47 (BHA), 78
195 belladonna and opium suppository butylated hydroxytoluene
barbiturates (modified), 217 (BHT), 78
bioavailability, 55 belladonna poisoning, 179
see also pentobarbital; Benton, Myers & Cranfield C31G, 82
phenobarbital; secobarbital mold, 16 calcitonin, 183
barriers to use of suppositories, 3, 5 benzalkonium chloride, 182 calcium oleate, 46
bases (excipients), suppository, 6, benzocaine calculations, 231
9, 27 acetic acid ester of camphor, 43, 118
calculation of amount monoglyceride base, 48, 134 Canasa, 10
required, 112 base incompability, 43, 118 cancer pain management, 191,
classification, 27, 54 benzodiazepines, stability, 169 193
compatibility with active betamethasone and cinchocaine candidiasis
ingredients, 29 suppository, 226 oropharyngeal, 187
compounding beyond-use dates, 170 vulvovaginal, 183, 184, 186, 187,
considerations, 107 labeling, 164 197
density, 107, 231 patient education, 172 capric acid, 87
Index 237
carbamazepine clotrimazole vaginal compression method, 116, 117

clinical effectiveness, 132, 183 suppositories, 11 double cast method, 118, 119
compounding formula, 217 clindamycin combination, 226 formulas, 215
formulation, 82 clinical effectiveness, 184, 186 formulation considerations, 77
carbon dioxide-releasing compounding formula, 218 hand rolling and shaping, 108
suppositories see effervescent coagulation, 213 helpful hints, 118
suppositories coalescence (coaptation), 213 molding (fusion) method, 108
Carbopol, 79, 89 coated microsphere/microcapsule physicochemical
Carbowax, 47 suppositories, 123 considerations, 105
carboxyvinyl polymer, 131 cocoa butter (theobroma oil), 31, preparation methods, 108
cardiac arrhythmias, 187, 197 213 quality control, 139, 140, 142
casein, 86 calculation of amount compression method see cold
casting excess (waste), 213 required, 112 compression method
cathartic suppositories see laxative development of modifications/ conductivity testing, 153
suppositories alternatives, 46 containers, 159
cavity (chimney), 213 drug release, 27, 53 child-resistant, 163
cefoxitin, 87, 88 history, 15, 16, 19, 46 glass, 161, 162
ceftizoxime, 65, 183 melting ranges, 28, 31 PEG-based suppositories, 43,
cellulose derivatives, 47, 131 polymorphism, 31 118
cephalosporins, 91 preparation for molding, 113 plastic, 162
cetyl alcohol, 46 solidifying agents, 31 tight, 160
cetyl effect see bloom cocoa butter suppositories well closed, 160
cetyl esters wax, 31 compounding, 107, 112, 113 contamination, 77
Chapman, William, 16 density calculations, 231, 232 content uniformity testing, 139,
chemical stability, 167, 168 hand rolling and shaping, 108 152
chemical testing, 147 hollow, 22 continuous flow/bead method,
analytical methods, 154 insertion, 177 dissolution testing, 147, 150
procedures, 153 packaging, 159 contraception, 182
sample preparation, 153, 154 stability, 168 see also nonoxynol-9
chemotherapy-induced nausea and storage, 171 contraction, volume, 77, 107
vomiting, 186, 194 codeine controlled-release suppositories, 56,
child-resistant packaging, 163 bioavailability, 63 123
chimney (cavity), 213 clinical effectiveness, 184 cooling
chloral hydrate, 179, 184 pharmacokinetics, 65 compounded suppositories,
compounding formula, 217 stability, 174 114
chloramphenicol cold compression method contraction on, 77, 107
bioavailability, 58 compounding, 116, 117 manufacturing process, 100
formulation, 82, 89 manufacturing, 102 problems, 103, 107
stability, 174 colloidal silicon dioxide see silicon see also solidification
chloroquine dioxide, colloidal Cotomar, 28, 40
clinical effectiveness, 184 color, assessment, 141 cottonseed oil, hydrogenated, 43,
compounding formula, 218 colorectal polyps, 188 48
formulation, 82, 91 coloring agents, 78 cracks, 213
chlorpromazine, 4, 10 commercial manufacturing, crushing test, 146, 148
formulation, 82 history, 19 crystallization, heat of, 79
cholate sodium, 86, 88 commercially available curdlan, 131
cholesterol, 46 manufacturing cyclodextrins, 57, 88
cimetidine, 184 equipment, 99, 100 cytosine arabinoside, 180
cisapride, 65, 184 commercially available molds, 109
citric acid, 78, 90 commercially available decarboxylation, 169
clindamycin vaginal suppositories suppositories, 6, 7 definitions, 6
clinical effectiveness, 184 compliance historical, 13
clotrimazole combination, 226 formulation considerations, 78 suppository, 1
compounding formula, 218 packaging, 164 dehomogenization, 102
clinical considerations, 177 compounding suppositories, 2, 105 Dehydag bases, 28
clinical effectiveness studies, 180 bases, 107 dehydration, 169
clinical response factors, 177 beyond-use dating, 170 denaverine, 63
238 Index
density dosing process, 100 ethyl nicotinate, 55

calculations, 112, 231 double cast method, 118, 119 etodolac
compounding double-layered suppositories, 127 compounding formula, 219
considerations, 107 drop point method, melting range pharmacokinetics, 65
density factors, 107, 231, 232 determination, 141, 145 rectal administration, 59
calculation method, 231 droperidol, 218 etomidate, 58
deoxycholate, sodium, 59, 86 drugs, active see active drugs European Pharmacopoiea, 146,
descriptions of suppositories, 6 Dulcolax, 10 151
detrusor instability, 194 Dunglison’s Medical Lexicon, 13 excess, 213
dexamethasone, 89 dysmenorrhea, 193 excipients
dialysis in compounded dosage
dissolution testing, 147, 149 econazole, 184, 186 forms, 113
extraction, 154 education, patient see patient suppository see bases
procedure, 154, 155 counseling expiration dates, 170
diazepam, 3 effectiveness, clinical studies, 180 labeling, 164
bioavailability, 63 effervescent suppositories, 134 observing, 172
clinical effectiveness, 185 bases, 47 expulsion of suppositories, 58
compounding formula, 218 quality control, 156 extemporaneous compounding see
formulation, 83, 88 Egypt, ancient, 14 compounding suppositories
pharmacokinetics, 65 emulsifying agents, 45, 47, 55 extraction, active drug, 154
diclofenac, 4 toxicity considerations, 178
as absorption enhancer, 87, 92, emulsion gel suppositories, 124 familial adenomatous
185 emulsion suppositories, 124 polyposis, 189
bioavailability, 63 emulsions, 45, 54 fat bloom see bloom
clinical effectiveness, 185, 194 formulation considerations, 80 Fattibase, 28, 31
formulation, 87 see also water-in-oil (w/o) effects of storage, 171
manufacturing formula, 226 emulsions febrile seizures, 185
pharmacokinetics, 65 enamine, 89 feces, effects on absorption, 53,
reversed micellar solution (RMS) enemas, before suppository 58
suppositories, 130 administration, 53, 54 fenoterol, 186
sustained-release ephedrine alkaloid, formulation, 91 fever, antipyretics see antipyretics
suppositories, 131 ephedrine hydrochloride filling
dielectric constant, 81 formulation, 91 automated process, 100
dienestrol, vaginal, 121 rectal absorption, 57 mixing process for, 101
Diepgen, Paul, 13 ephedrine sulfate and zinc oxide molds, 114, 116
dihydroergotamine, 218 suppository, 227 problems, 103
Dilantin see phenytoin epilepsy, 183, 185 finishing
Dilaudid, 10 epimerization, 169 compounded suppositories,
diltiazem thermo-reversible liquid episiotomy, 185, 188 116
suppositories, 133 erectile dysfunction, 1, 123 manufactured suppositories,
dimenhydrinate, 186 ergotamine, 3 101
dimples, 213 adverse reactions, 179 first-pass metabolism, avoidance
Dioscorides, 14 bioavailability, 63 of, 52, 53, 57
dipotassium glycyrrhizinate clinical effectiveness, 186 flecainide, 187
(GLYK), 87 compounding formula, 219 flow-through method, dissolution
disadvantages of suppositories, 4 erythromycin, 59 testing, 147, 150
displacement value method, erythropoietin,recombinant fluconazole
233 human, 87 bioavailability, 59, 63
dissolution testing, 139, 147 essential oils, 118 clinical effectiveness, 187
distribution, 171 esters, active drug, 90 pharmacokinetics, 65
docusate sodium, 47 estriol, vaginal, 186 fluorouracil, 187
domperidone, 186 estrogens, vaginal, 121 flurbiprofen
Dorvault, François, 16 ethacrynic acid, 83 clinical effectiveness, 188
dosage forms, commercial, ethionamide, 63, 65 formulation, 88
compounding, 113 ethosuximide pharmacokinetics, 65
dosage replacement factors, 232 bioavailability, 59 foil suppository wrappers, 159
calculation method, 231 formulation, 83, 92 forming process, 100
Index 239
formulation, 77 granulation, 103 bioavailability and, 55

absorption enhancers, 86 Griffenhagen, GA, 16, 22 impact on solidification, 79
base selection, 78 hydroxypropyl beta-cyclodextrin
drug selection, 78 Hall & Ruckel Wholesale (HPCD), 89
production and compounding Druggists, 22 hygroscopicity, 168
considerations, 77 hand rolling and shaping, compounding
published studies, 81 108 considerations, 106
salts/esters of active drugs, 90 hard fat, 213 reducing agents, 78
storage considerations, 77 hardeners, 31, 78, 106 hyoscine (scopolamine), 86
surfactants, 91 headaches, 195
use and administration see also migraine ibuprofen
considerations, 78 heart disease, ischemic, 197 adverse reactions, 179
variables, 80 heat of crystallization, 79 bioavailability, 63
freezing, protection from, hemorrhoidal veins, 52 clinical effectiveness, 188
170 hemorrhoids see antihemorrhoidal formulation, 86
Frugard, Roger, 15 suppositories lysinate salt, 90
furosemide, 83 Henderson–Hasselbalch thermo-reversible liquid
fusion (molding) compounding equations, 54 suppositories, 133
method, 108 hepatitis B, chronic, 190 ichthammol, 43, 118
hepatitis C, chronic, 187, 190 identification tests, 139
gabapentin, 198 hexadienol, 43, 48 impurities, 77
Galen, 14 Hexaride Base 95, 28 indometacin, 4
gastroparesis diabetocorum, 191 Heyl, Henry, 16, 18 bioavailability, 59, 63
Gattefossé bases, 32, 43 high-performance liquid calcium and magnesium
gelatin chromatography (HPLC), salts, 90
adverse reactions, 179 reverse phase, 155 clinical effectiveness, 132,
capsules, vaginal inserts, 123 history of suppositories, 13 188
low molecular weight, 86 bases, 46 compounding formula, 219
gemeprost, 187 definitions, 13 formulation, 83, 89
gentamicin, 83, 124 early, 13 manufacturing formula, 227
glass containers, 161, 162 modern, 15 microspheres, 123
glibenclamide, 83 molds, 16, 108 PEG esters, 91
glossary, 213 official status, 19 pharmacokinetics, 65
L-glutamine, 87 holding and distribution, 171 self-emulsifying system
glycerin hollow-type suppositories, 124 (SES), 124
compounding history, 22, 46 stability, 174
considerations, 108, 118 Homberg, William, 15 sustained-release
history, 15, 19 hormone replacement therapy suppositories, 130
glycerin suppositories, 9, 108 (HRT), 1, 186 thermo-reversible liquid
clinical effectiveness, 187 human chorionic gonadotrophin suppositories, 133
compounding formula, 219 (hCG), 124 induction of labor, 192
manufacturing formula, 227 humidity, 171 inertness, base, 77
mechanism of action, 5 hydrocortisone, 10 inflammatory bowel disease, 181
packaging, 159 clinical effectiveness, 187 insertion, 9
storage, 171 compounding formulas, 219 guidelines for nurses, 178
glycerinated gelatin bases, 44 formulation, 89 moistening before,
glycerinated gelatin suppositories hydrogel suppositories, 126 106, 113
compounding, 108, 110 hydrogenated vegetable oil patient counseling,
insertion, 177 bases, 31, 32, 40, 46 177, 178
packaging, 159 Hydrokote bases, 28, 40 urethral suppositories, 123
storage, 171 hydrolysis, 168 vaginal suppositories, 122
glycerolysis, 79 hydromorphone, 10 insertion devices
glyceryl monooleate, 89 hydrophilic bases, 45 MUSE, 123
glyceryl monostearate, 47 hydrophilic suppositories, vaginal suppositories,
glycyrrhizin, 187 dissolution testing, 147 121, 122
glycyrrhizinate, dipotassium hydroxyl value (hydroxyl inserts see vaginal tablets
(GLYK), 87 number), 30, 79 instability see stability
240 Index
insulin lidocaine melt-fusion manufacturing

absorption enhancers, 86, 88, 89, double-layered suppositories, 127 method, 99, 101
92 nifedipine and nitroglycerin melting
agar matrix suppositories, 128 suppository, 221 bases, 113
bioavailability, 60 and tribenoside suppository, during storage, 77
clinical studies, 189 227 time test, 145
hollow-type suppositories, 126 light melting point (range, zone), 141
thermo-reversible liquid protection from, 172 additives for altering, 78
suppositories, 133 sensitivity, 169 bases, 28, 29
interferon, 190 light-resistant containers, 161 determination procedure, 142
interleukin 8 (IL-8), 190 lipid–water solubility, 55 effects on drug release, 27
iodine value (iodine number), 30 lipophilic suppositories, methods of determining, 141,
iodochlorhydroxyquin, 43, 118 dissolution testing, 147 144, 145
isoconazole nitrate, 84 liquefaction time, 106 membrane diffusion method,
effects of storage, 171 dissolution testing, 147, 149
Japocire bases, 38 testing, 143, 146, 147 meperidine, 86
John Wyeth & Brothers, 22 liquid active drugs, 80 meptazinol, 63, 66
compounding, 114, 117 mercaptopurine, 64, 66
ketamine liquid suppositories, mesalamine (mesalazine;
bioavailability, 63 thermo-reversible, 132 5-aminosalicylic acid), 10
clinical effectiveness, 190 local action, 5, 9 bioavailability, 60, 64
ketobemidone, 63, 65 local anesthetic suppositories, 9 clinical effectiveness, 181, 191
ketoprofen, 4 local toxicity, 179 controlled-release
bioavailability, 60, 63 loperamide, 190 suppositories, 123
clinical effectiveness, 190 lorazepam, 220 formulation, 90
formulation, 84, 92 lot number, 164 manufacturing formula, 228
pharmacokinetics, 65 lubrication, mold, 110 slow-release suppositories, 132
ketorolac, 190 lymphatic system, absorption methacrylate, 131
Knowlson, Alexander, 16 into, 52, 57 methadone
Knowlson mold, 16, 20 bioavailability, 64
Koettsdorfer number, 30 machines, suppository clinical effectiveness, 191
Krowczynski’s liquefaction testing compression, 116, 117 methoxsalen, 191
method, 143 macrolide antibiotics, 91 5-methoxysalicylate, 88
malaria, 182 metoclopramide
labeling, 164 malonic acid, 90 bioavailability, 64
compounded suppositories, 116 manufacturing, 99 clinical effectiveness, 191
storage conditions, 170 automated process, 99, 100 compounding formula, 220
labor cold compression method, 102 manufacturing formula, 228
induction of, 192 controls, 102 pharmacokinetics, 66
premature, 186, 195 equipment, 99, 100 reversed micellar solution
Lanette Wax SX, 47 formulas, 225 suppositories, 130
latamoxef sodium (LMOX), 92 formulation considerations, 77 metoprolol, 60
lauric acid, 87 history of commercial, 19 metronidazole, 4
lauroyl leucine, 89 melt-fusion method, 99, 101 bioavailability, 60, 64
laxative suppositories, 190 Martindale’s Extra clinical effectiveness, 191
history, 14 Pharmacopoeia, 19 compounding formula, 220
manufacturing formula, 227 Massa Estarinum bases, 40 formulation, 92
mechanism of action, 9 Massa Mf 13, 40 pharmacokinetics, 66
see also glycerin suppositories Massa suppositorium, drug miconazole, 11
layered double or triple solubility, 81 acetic acid ester of
suppositories, 127 matrix-based suppositories, 128 monoglyceride base, 48, 134
leaching, 162 Mattison, Richard, 16 clinical effectiveness, 192
leak tests, 102 mebendazole, 63 compounding formula, 220
lecithin, 46, 119, 130 mechanical strength/crushing manufacturing formula, 228
leucine, 89 test, 146, 148 microbiological stability, 167, 169
leuprolide, 90 meclizine hydrochloride, 92 microspheres/microcapsules,
lichen planus, vulvovaginal, 188 melt, preparing and pouring, 114 coated, 123
Index 241
midazolam–famotidine, 192 slow-release suppositories, 56, current USP listing, 3

migraine, 3 221 history, 19
clinical studies, 186, 191, sustained-release ofloxacin, 64
195–197 suppositories, 131 oil-in-water (o/w) emulsion, 45
suppository compounding motion sickness, 195 omeprazole, 85
formula, 220 mucoadhesive suppositories, 89, ondansetron, 4
mineral oil, 110, 117 128 bioavailability, 64
misoprostol liquid, 132 clinical effectiveness, 194
clinical effectiveness, 192 MUSE, 1, 123 compounding formula, 221
compounding formula, 220 Mycelex-7 Vaginal Tablets, 11 pharmacokinetics, 67
stability, 174 open capillary tube method,
mixing nanoparticle suppositories, 129 melting range
during compounding, 114 naprosyn, 194 determination, 141, 144
during manufacturing, 101 naproxen, 4 organic acids, 90
Mohr, Friedrich, 15 bioavailability, 64 osmotic suppositories, 129
molding clinical effectiveness, 193 osteoarthritis, 188, 194, 196
method of compounding, 108 pharmacokinetics, 66 osteoporosis, 183
problems, 103 nasal suppositories, 9 otic suppositories, 9
molds natamycin, 193 Ovucire bases, 38
calculation of amount of nausea and vomiting ovules, 6
base, 112 chemotherapy-induced, 186, 194 oxidation, 169
calibration, 110 compounding formulas, 216 oxybutynin, 194
cleaning, 109 metoclopramide oxycodone, 4, 67
cold compression manufacturing suppositories, 191 oxygen, permeation of
process, 102 postoperative, 186, 195 packaging, 162
commercially available, 109 nicotine, 89 oxymorphone, 4, 10
for compounding, 115, 116 nifedipine oxyphenbutazone
compression, 116 clinical study, 193 adverse reactions, 179
hand-operated, 109, 110 double-layered suppositories, 127 formulation, 85
history, 16, 18, 109 hollow-type suppositories, 125 ozagrel, 64
disposable, 110, 111 lidocaine and nitroglycerin
filling, 114, 116 suppository, 221 package inserts, 164
history, 16, 108 stability, 169 packaging, 159, 160
lubrication, 110 nimesulide for arthritic patients, 163
as packaging, 159, 161 clinical effectiveness, 193 automated process, 99
preparation, 108, 112 pharmacokinetics, 67 checks, 102
removal of suppositories nitrofurantoin urethral inserts, 221 child-resistant/adult-senior
from, 77, 114 nitrofurazone urethral inserts, use, 163
selection, 108 221 compliance, 164
strip-type, 214 nitroglycerin, nifedipine and compounded suppositories, 116
see also shells lidocaine suppository, 221 containers, 159
Monistat 7 Suppositories, 11 nitroprusside, 169 problems, 162
morphine, 4 nocturnal enuresis, 185, 189 single- and multiple-unit, 160
bioavailability, 61, 64 nonoxynol-9, 11, 121 tamper-evident, 164, 165
clinical effectiveness studies, non-steroidal anti-inflammatory paddle method, dissolution
193 drugs (NSAIDs) testing, 147, 148
compounding, 2 adverse reactions, 179 palliative medicine, 2, 185
compounding formulas, 221 clinical effectiveness, 194 see also cancer pain management
controlled-release see also individual agents pancreatitis, chronic, 196
suppositories, 123, 132 Novosup-78, 93 papaverine, 85, 92
formulation, 84 Numorphan, 10 para-aminosalicylic acid
hollow-type suppositories, 124, nurses, guidelines for, 178 bioavailability, 61
125 nystatin, 194 stability, 169
hydrogel suppositories, 126 paracetamol see acetaminophen
pharmacokinetics, 66 occupied volume method, 233 Parrish, Edward, 13, 15
prolonged-release odor, assessment, 141 particle size, active drugs, 55, 80,
suppositories, 129 official status of suppositories 113
242 Index
partition coefficient, 55, 57 physical stability, 167, 168 postoperative analgesia

paste-type drugs, 80 physical state, active drug, 80 acetaminophen, 180
patent ductus arteriosus, 188 physicians, view of suppositories, 2 buprenorphine, 183
patient counseling, 177 physicochemical factors diclofenac, 185
storage conditions, 172 drug absorption, 54 indometacin, 188
use of suppositories, 5, 178 extemporaneous ketoprofen, 190
patients compounding, 105 postoperative infections, 191
acceptability of suppositories, 3, physiology, rectal, vaginal and postoperative nausea and
5 urethral, 52 vomiting, 186, 195
compliance see compliance Pichard curves, 79 postpartum hemorrhage, 187
view of suppositories, 1, 2 Pilulae Saponis Compositae, 16 pouchitis, chronic, 179
peanut oil, hydrogenated, 46 piroxicam povidone iodine vaginal ovules
pectic acid, 130 bioavailability, 64 clinical effectiveness, 195
pediatric patients, antinauseant clinical effectiveness, 194 manufacturing formula, 228
suppositories, 216 pharmacokinetics, 67 Practice of Pharmacy (Procter), 15
PEG see polyethylene glycol placebo effect, 1 pramoxine suppositories, 228
penetration test, suppository, 145, plastic containers, 162 prednisolone
147 problems with, 162 formulation, 88
pentazocine, 180 plasticizers, 78 sustained-release
pentobarbital, 61 Pluronic bases, 45 suppositories, 131
permeation, packaging, 162 poloxamers, 45 premature labor, 186, 195
Peru Balsam, 118 Polybase, 28, 44 premedication, 184, 192
pessaries, 6 polycarbophil, 87 premenstrual syndrome, 195
historical definition, 13 polyethylene glycol (PEG), 43, preservatives, 78, 169
shapes and sizes, 9 213 preterm infants
see also vaginal suppositories aspirin bioavailability, 58 patent ductus arteriosus, 188
pethidine (meperidine), 86 characteristics, 44 recurrent apnea, 180
pH compounding formula, 222 procainamide, 169
drug stability and, 169 effects on rectal drug procaine, 169
rectal liquid, 52, 53 absorption, 56 prochlorperazine, 4, 10
vaginal, 53 erythromycin bioavailability, 59 clinical effectiveness, 195
Pharmaceutical Lexicon ethosuximide bioavailability, 59 compounding formula, 222
(Sweringen), 13 incompatible active proctitis
pharmaceutical manufacturers, 3 ingredients, 43, 118 lymphoid follicular, 196
pharmaceutics, 51 indometacin esters, 91 ulcerative, 181
pharmacists metronidazole bioavailability, 60 Proctor, William, 13, 15
responsibilities for stability and vaginal suppositories, 121 prodrugs, 57
storage, 171 valproic acid bioavailability, 62 production see manufacturing
view of suppositories, 2 zonisamide bioavailability, 62 progesterone, 4
pharmacokinetics, 51, 65 polyethylene glycol (PEG) bioavailability, 61
Phenergan, 10 suppositories double-layered suppositories,
phenobarbital compounding, 113, 118 127
bioavailability, 61 insertion, 177 pharmacokinetics, 67
clinical effectiveness, 194 storage, 171 stability, 174
sodium salt, 91 polymorphism, 29, 31, 168 progesterone vaginal
stability, 174 polyoxyalkylene derivatives of suppositories, 1, 121
phenothiazines, 169 sorbitan esters, 48 clinical effectiveness, 195
DL-phenylalanine- polyoxyethylene 2 lauryl ether, 90 compounding formula, 222
ethylacetoacetate, 89 polyoxyethylene 30 stearate, 47 formulas, 122
phenytoin polyoxyl 40 stearate, 45 formulation, 85
bioavailability, 64 polyps, gastrointestinal, 188 prolonged-release
compounding formula, 222 polysorbates, 91 suppositories, 129
photochemical decomposition, 169 polyvinyl alcohol (PVA), 124 promethazine, 10
physical analysis, 139, 140 polyvinyl chloride/polyethylene bioavailability, 62
physical quality assessment form (PVC/PE) shell material, 99 clinical effectiveness, 195
for compounded post-hardening, 213 compounding formula, 222
suppositories, 142 postmenopausal symptoms, 1, 186 pharmacokinetics, 67
Index 243
propranolol Remington, Joseph, 19 urethral, 9

formulation, 88 renal colic, 188 vaginal, 9
hollow-type suppositories, 125 Replens, 90 visual examination, 141
liquid mucoadhesive residual solvents, 139 shells
suppositories, 132 reversed micellar solution (RMS) filling process, 100
wax matrix suppositories, 128 suppositories, 130 forming process, 100
propyl gallate, 78 rheumatoid arthritis materials, 99
propylene glycol stearate, 24 packaging for patients with, 163 problems, 103
propyphenazone, 81 treatment, 188, 193, 194, 197 silica gel, 79, 106, 114
prostaglandin E2 (PGE2 ) riboflavin, 169 silicon dioxide, colloidal
pessaries, 122 rifadin, 196 (Aerosil), 78, 93, 118
pruritus ani, 9 rotating flask method, dissolution silver salts, 43, 118
psoriasis vulgaris, 191 testing, 152 sink holes (dimples), 213
psychological effects of rotation, stock, 172 size
suppositories, 1 rectal suppositories, 8, 9
S-70-XX95, 28 urethral suppositories, 9, 123
quality control, 139 S-070-XXA, 28 vaginal suppositories, 9
quinine, 43 salazosulfapyridine, 68 see also weight of suppositories
salbutamol (albuterol) slow-release suppositories, 56, 123
radiation proctitis, 192 bioavailability, 62 sodium barbital, 43, 118
radiosensitizer, hypoxic cell, 69 formulation, 85, 92 sodium benzoate, 131
ramosetron hydrochloride pharmacokinetics, 68 sodium caprate, 87
suppositories, 79 sustained-release sodium chloride, 128, 133
rebamipide, 87 suppositories, 131 sodium cholate, 86, 88
rectal absorption, 51, 52 Salerno medical school, 15 sodium deoxycholate, 59, 86
anatomical factors, 51 salicylic acid sodium laurate, 87
enhancing agents, 86 compounding, 118 sodium lauryl sulfate, 57, 59, 91
factors affecting, 51 formulation, 86, 88 sodium phenylalanine, 89
physicochemical factors, 54 PEG interactions, 43 sodium phosphates, 128
physiological factors, 52 salts, active drug, 90 sodium salicylate, 88
rectal adenomatosis, 189 sample sodium taurocholate, 86
rectal cancer, 187, 197 extraction, 154 sodium taurodeoxycholate, 86
rectal drug administration, 1, 5 preparation for analysis, 153, 154 softening
advantages, 4 sampling, 153 manufacturing defects
anatomy and physiology, 51 saponification value (number), 30 causing, 103
applications, 3 Scheele, Carl Wilhelm, 15 during storage, 77, 167, 172
bioequivalence, 57 scopolamine, 86 solid active drugs, 80
clinical response factors, 177 scraping, 214 compounding, 113, 117
disadvantages, 4 scrapings (excess), 213 Solid Fat Index (SFI), 30
rectal intolerance, 179 sealing solid reversed micellar solution
rectal suppositories compounded suppositories, 116 (SRMS) suppositories, 130
bioavailability, 54, 63 manufacturing process, 101 solidification
drug selection, 78 problems, 103 contraction on, 77, 107
examples, 10 secobarbital, 68 formulation considerations, 77
history, 14 sectile suppositories, 129 hydroxyl index and, 79
insertion, 9, 177 sedation, 185, 192 manufacturing process, 100
local actions, 5 self-emulsifying system (SES), 124 problems, 103
shapes and sizes, 8, 9 Semicid Vaginal Contraceptive temperature, determination, 146
systemic action, 5 Inserts, 11 time test, 145
trends in use, 1 semi-solid active drugs, 80 solubility of active drug, 54, 78
Redwood, Theophilus, 15 sertaconazole, 196 compounding
release, drug Setnikar and Fantelli’s liquefaction considerations, 106
cocoa butter bases, 27, 53 testing method, 147 formulation considerations, 80
factors affecting, 27, 54 shape of suppositories, 214 lipid–water, 55
formulation considerations, 78 history, 19 solvents, residual, 139
polyethylene glycol bases, 43 insertion guidance, 177 sorption, 162
rates, 106 rectal, 8, 9 Spans, 91, 93
244 Index
special types of suppositories, sustained-release suppositories, 56, toothache, 193

121 130 torpedo, 214
Spenzer suppository mold, 16, 17 Sweringen, HV, 13 toxicity
spermaceti, 47 synonyms, 6 general, 178
spironolactone, 174 systemic action of suppositories, 5 local, 179
spreading capacity, 56 tramadol, 64, 68
Squibb & Sons, E. R., 46 tacrolimus, 86 transportation, 171
stability, 167 tail, 214 Triglyceride bases, 28
checks by pharmacists, 167, tambuil, 196 trimecaine, 197
172 tamper-evident packaging, 164 trimethobenzamide, 223
defined, 167 tannic acid, 43, 118 trimethoprim, 92
factors affecting, 168 tartaric acid, 90 triple-layered suppositories, 127
formulation considerations, 77 Tatum suppository mold, 19, 21 Trusler, Charles, 19
published studies, 173 taurine, 87 tryptan, 197
quality control, 139, 169 taurocholate, sodium, 86 tuberculosis, pulmonary, 196
responsibilities of taurodeoxycholate, sodium, 86 Tween 61, 28, 45
pharmacists, 171 Taylor, Alfred B., 16 Tweens, 45, 47, 91, 92
types, 167 tegafur, 197 two-layered suppositories, 127
starch, 117 Tegester, 28
sticking, 214 temazepam, 68 ulcerative colitis/proctitis, 179, 181
stock rotation, 172 temperature United States Dispensatory
storage, 167, 170 storage, 169, 170, 172 (USD), 19
formulation considerations, 77 transportation, 171 United States Pharmacopeia (USP)
PEG-containing tempering, 30, 214 19th century, 16, 19
suppositories, 118 tenoxicam, 197 compounding guidance, 105
responsibilities of tensides, 91 containers, 160
pharmacists, 171 terconazole, 197 content uniformity criteria, 152
see also containers; packaging terrace, 214 dissolution testing
succinic acid, 90 testosterone, 56 apparatus, 151
sulfaguanidine, 87 tetracycline official suppositories, 3
sulfamethoxazole, 92 compounding formula, 222 quality control, 139, 143
sulfanilic acid, 87 stability, 169 stability, 167
sulfasalazine, 196 thalidomide, 64 storage conditions, 170
sulfisoxazole, 56 theobroma oil see cocoa butter unsaponifiable matter, 214
sulfonamides, 43, 118 theopentone sodium, 86 urethra
sumatriptan theophylline, 4 anatomy, 52
clinical effectiveness, 196 bioavailability, 62, 64 physiology, 53
pharmacokinetics, 68 clinical effectiveness, 197 urethral infections, 123
super-cooling, 214 double-layered suppositories, 127 urethral suppositories, 123
Suppocire bases, 28, 32 formulation, 86, 93 examples, 8
suppositories osmotic suppositories, 129 glycerinated gelatin bases, 45
definitions, 1, 13 pharmacokinetics, 68 local actions, 5
differing viewpoints, 2 thermo-reversible-liquid molds, 110, 112, 116
examples, 6–8 suppositories, 132 shape and size, 9, 123
official USP, 3 thickening, during trends in use, 1
suppository penetration test, 145, manufacturing, 102 uses of suppositories, 3
147 thiethylperazine, 4 formulation considerations, 78
suprofen, 196 Thorazine, 10 USP see United States
surface defects, 103 three-layered suppositories, 127 Pharmacopeia
checking for, 141 thyrotropin, 197 U-tube method, melting range
surfactants (surface-active tinidazole, 64, 68 determination, 141, 144
agents), 45, 78, 91 tioconazole
dissolution testing and, 147 bioavailability, 62 vagina
emulsion suppositories, 124 clinical effectiveness, 197 anatomy, 52
formulation considerations, 81 tocolytic therapy, 186 physiology, 53
rectal drug absorption and, 56 tolerance, formulation vaginal cones, 6
suspensions, 80 considerations, 78 vaginal infections, 121, 192, 195
Index 245
see also bacterial vaginosis; clinical effectiveness, 197 checks during

candidiasis, vulvovaginal compounding formula, 223 manufacturing, 102
vaginal suppositories viscosity, 77 density of ingredients and, 107
(pessaries), 121 compounding effects of aeration, 101
advice to patients, 122 considerations, 106 mold calibration, 110
in ancient history, 14 formulation considerations, 79 quality control, 141
bases, 121 visual examination, 102, 139 variation, 103, 153
bioavailability, 61 vitamin A suppositories, 229 Wellcome, Henry, 19
examples, 8, 11, 121 volume contraction, 77, 107 Whitall, Tatum suppository
glycerinated gelatin bases, 44 vomiting see nausea and vomiting mold, 19, 21
insertion, 9 Vosco S-55, 58 whitening, 214
insertion devices, 121, 122 vulvovaginitis, 196 see also bloom
mechanisms of action, 5 Witepsol bases, 31, 42
Ovucire bases, 38 water apomorphine bioavailability, 58
shapes and sizes, 9 dipping suppositories in, before Carbopol 934P with, 79
systemic action, 6 use, 106, 113 characteristics, 40
trends in use, 1 extraction method, 154 effects of storage, 171
vaginal tablets (inserts), 9, 122 permeation, packaging, 162 ethosuximide bioavailability, 59
examples, 11, 121 water content melting ranges, 28
gelatin capsules, 123 compounded suppositories, 106 phenobarbital bioavailability, 61
insertion, 9, 122 determination, 139 salbutamol bioavailability, 62
valproate glycerinated gelatin bases, 44 valproic acid bioavailability, 62
bioavailability, 64 PEG bases, 44 zonisamide bioavailability, 62
formulation, 93 physical stability and, 168 wound infections,
hollow-type suppositories, 125 water-in-oil (w/o) emulsions, 45 postoperative, 191
valproic acid compounding, 114 John Wyeth & Brothers, 22
bioavailability, 62, 64 drug release, 54, 55
hollow-type suppositories, 125 tendency for excipients to xerogel suppositories, 133
pharmacokinetics, 68 produce, 55 xyloglucan thermoreversible
Veegum, 48 wax matrix suppositories, 128 gels, 133
vegetable extracts, Wecobee bases, 28, 31, 40, 42
compounding, 117 weight of suppositories, 9 zinc oxide suppositories, 229
verapamil 19th century, 19 zonisamide, 62

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Royal Pharmaceutical Society of Great Britain September 16, 2007 23:2

Published by the Pharmaceutical Press

1 Lambeth High Street, London SE1 7JN, UK

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical

First published 2008

Typeset by Aptara, New Delhi, India

ISBN 978 0 85369 646 9

All rights reserved. No part of this publication may be reproduced, stored in

2 History and development of the suppository 13

Deﬁnitions: Suppository, pessary, bougie 13

3 Suppository bases and their characteristics 27

Classiﬁcation of suppository bases 27

4 Pharmaceutic, biopharmaceutic, and pharmacokinetic factors involving

Anatomical and physiological considerations 51

7 Compounding suppositories 105

Physicochemical considerations 105

8 Special types of suppositories 121

Non-rectal suppositories – vaginal suppositories 121

Non-rectal suppositories – urethral suppositories 123

9 Quality control of suppositories 139

Physical analysis 139

10 Packaging and labeling of suppositories 159

11 Stability and storage of suppositories 167

Physical stability 167

Factors affecting stability 168

12 Clinical considerations 177

Clinical response factors 177

Appendix I Glossary 213

About the author

Loyd V Allen, Jr is Editor-in-Chief of the velopment to the pharmaceutical industry both

often it does not. Some clinicians have made their

Chapter 1 • Introduction to suppositories 3

durations of action. Pharmacists generally re-

always understand that the medication is not

r Diazepam is useful as an anxiolytic for patients

r Metronidazole is as effective when given r It can be used to administer medication to an

Chapter 1 • Introduction to suppositories 5

much more needs to be generated. This is dis-

Chapter 1 • Introduction to suppositories 7

Figure 1.3 Various sizes and shapes of rectal suppositories.

Figure 1.4 Some examples of vaginal suppositories and

Chapter 1 • Introduction to suppositories 9

Table 1.4 Examples of rectal suppositories

Corresponding Active constituent

Bisacodyl Dulcolax 10 mg Local Cathartic. See text for

Chapter 1 • Introduction to suppositories 11

Table 1.5 Examples of vaginal suppositories and tablets

Product/manufacturer Active constituents Category and comments

The historical deﬁnition of suppository has been

Chapter 2 • History and development of the suppository 15

Chapter 2 • History and development of the suppository 17

Chapter 2 • History and development of the suppository 19

Chapter 2 • History and development of the suppository 21

Chapter 2 • History and development of the suppository 23

Figure 2.5 Continued

Chapter 2 • History and development of the suppository 25

Table 3.1 Melting ranges of some suppository bases

Base Composition Melting range (◦ C)

Cocoa butter Mixed triglycerides of oleic, palmitic, stearic acids 34–35

Chapter 3 • Suppository bases and their characteristics 29

oleaginous, or oil-type bases that melt at body

Chapter 3 • Suppository bases and their characteristics 31