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INTRODUCTION
The majority of topical products comprise semisolid formulations that include ointments,
creams, and gels. A semisolid preparation intended for external application to the skin or
mucous membranes is officially defined as an ‘ointment.’ In practice, however, this term is
used mainly for those products that have a translucent appearance, whereas preparations with
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an opaque, creamy white appearance are termed as ‘creams.’ Gels are a relatively newer class
of dosage form created by entrapment of large amounts of aqueous or hydro alcoholic liquid
in a network of colloidal solid particles.
Semisolid pharmaceutical systems comprise a body of products, which when applied to the
skin or accessible mucous membranes tend to alleviate or treat a pathological condition or
offer protection against a harmful environment. They have the property to cling to the skin or
mucous membrane for a protracted period of time to exert their therapeutic effect through
protection and occlusion. The adhesion is due to their plastic rheologic behavior which allows
semisolid to retain their shape and cling as film until acted upon by an outside force.
Semisolid dosage forms usually are intended for localized drug delivery. In the past few
years, however, these forms also have been explored for the systemic delivery of various
drugs. Semisolids constitute a significant proportion of pharmaceutical dosage forms. They
can be applied topically to the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue,
urethral membrane, and external ear lining.
Transdermal drug delivery systems (TDDS) are self-contained, discrete dosage forms
designed to deliver the drug(s) through the skin to the systemic circulation. Interest in TDDS
has increased on several fronts over the past several years because of the inherent advantage
of administration by this route. Some of the advantages of TDDS over conventional routes
are as follows:
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Topical formulations are often used for relief of itching due to insect bites, mild cases of
sunburn, poison ivy or oak, and other minor skin irritations. Currently, DPH is available on
the market in few topical dosage forms, containing 2% of drug and its percutaneous
absorption was scantily investigated. In developing novel drug preparations for topical
delivery through the skin, the choice of vehicle formulations for a given drug can greatly
influence the rate and extent of drug permeation across the skin.
The in vitro methodologies for the testing of skin permeability are extensively established
and validated. Skin from a wide range of animals including pigs, rats, guinea pigs, monkeys,
snakes and others has been suggested as a suitable replacement for human skin, since they
offer similar barriers to diffusion for the penetration through human skin of molecules. Where
human or animal skin is difficult to obtain, or where a large number of experiments are to be
carried out, particularly with regard to pre-formulation screening experiments, artificial
membranes have been widely employed. Synthetic membranes selected for use in in vitro
diffusion experiments should usually be commerciallyavailable; these type of membranes
have little capacity to bind to the drug and also have little tendency to interact with the
releasing medium thus offering the least possible diffusional resistance. For design of topical
formulations it is important to consider also the physicochemical properties of the vehicles
and their potential to interact with both permeant and membrane.
OINTMENTS
They are soft hydrocarbon based semisolid preparation, composed of fluid hydrocarbon
meshed in a matrix of higher melting solid hydrocarbon petrolatum being a tasteless,
odorless, unctuous material with a melting range, they are greasy in nature so they stain
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cloths. Principle ingredients forming the system hydrocarbon and silicon oil are generally
poor solvent for most drugs, seemingly setting a low limit on the drug delivery capabilities of
the system.
CREAMS
They are viscous semisolid emulsion system with opaque appearance as contrasted with
translucent ointments. Consistency and rheological character depends on whether the cream
is w/o or o/w.
Properly designed O/W creams are elegant drug delivery system, pleasing in both
appearance and feel post application.
O/W creams are non greasy and are rinsable.
They are good for most topical purpose and are considered particularly suited for
application to oozing wounds.
PASTES
Pastes are basically ointments into which a high percentage of insoluble solid has been added.
The extraordinary amount of particulate matter stiffens the system through direct interactions
of the dispersed particulates and by adsorbing the liquid hydrocarbon fraction the vehicle on
the particle surface.
Pastes are usually prepared by incorporating solids directly into a congealed system by
levigation with a portion of the base to form a paste like mass. The remainders of the base are
added with continuous levigation until the solids are uniformly dispersed in the vehicle. Paste
are less penetrating and less macerating and less heating than ointment. Paste make
particularly good protective barrier when placed on the skin for, in addition to forming an
unbroken film, the solid they contain can absorb and thereby neutralize certain noxious
chemicals before they ever reach the skin.Like ointments, paste forms an unbroken relatively
water – impermeable film unlike ointments the film is opaque and therefore, an effective sun
block accordingly. Skiers apply paste around the nose and lips to gain a dual protection.
Pastes are less greasy because of the absorption of the fluid hydrocarbon fraction to the
particulates.
There are two types of paste:
a) Fatty pastes
b) Non greasy pastes
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They are used for medication, lubrication and some miscellaneous applications like carrier
for spermicidal agents to be used intra vaginally with diaphragms as an adjunctive means of
contraception.
POULTICES
It is soft, viscous, pasty preparation for external use. They are applied to skin while they are
hot. Poultice must retain heat for a considerable time because they are intended to supply
warmth to inflamed parts of body,
(e.g. Kaolin poultice B.P.C.).
PLASTERS
Plasters are solid or semisolid masses adhere to the skin when spread upon cotton felt line or
muslin as a backing material and they are mainly used to,
1- Afford protection and mechanical support.
2- Furnish an occlusive and macerating action.
3- Bring medication into close contact with the surface of the skin.
RIGID FOAMS
Foams are system in which air or some other gas is emulsified in liquid phase to the point of
stiffening, e.g. shaving creams, whipped creams, and aerosolized shaving creams.
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method of administration is useful with medications that are used for relatively long-term
preventive treatment or maintenance therapy of chronic conditions.
The basic components of any transdermal delivery system include the drug(s) dissolved or
dispersed in an inert polymer matrix that provides support and platform for drug release; an
outer backing film of paper, plastic, or foil; and a pressure-sensitive adhesive that anchors the
patch to the skin. The adhesive is covered by a release liner, which needs to be peeled off
before applying the patch to the skin. While the rate-limiting step in drug delivery can be
either the drug release from the delivery system or its absorption into the skin, a well-
designed patch system ensures that the former is the rate-limiting step, in order to provide
drug uptake at a predetermined rate that is independent of inter-patient skin variability.
Route of absorption
Percutaneous absorption of drug molecules is of particular importance in the case of
transdermal drug delivery systems because the drug has to be absorbed to an adequate extent
and rate to achieve and maintain uniform, systemic, therapeutic levels throughout the
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duration of use. In general, once drug molecules cross the stratum corneal barrier, passage
into deeper dermal layers and systemic uptake occurs relatively quickly and easily (Ratna ,
2004).
Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug
transport across the stratum corneum follows Fick’s Law of Diffusion. In other words, the
rate of drug transport depends not only on its aqueous solubility, but is also directly
proportional to its oil/water partition coefficient, its concentration in the formulation vehicle,
and the surface area of the skin to which it is exposed; it is inversely proportional to the
thickness of the stratum corneum. The stratum corneum is thickest in the plantar (soles) and
palmar regions and thinnest in the post auricular, axillary, and scalp regions of the body. An
understanding of the transport behavior of drugs is vital for designing an effective topical or
transdermal product, as well as reasonably predicting and comparing drug behavior in various
formulations.
Semisolid dosage forms for dermatological drug therapy are intended to produce desired
therapeutic action at specific sites in the epidermal tissue. A drug’s ability to penetrate the
skin’s epidermis, dermis, and subcutaneous fat layers depends on the properties of the drug
and the carrier base. Although some drugs are meant primarily for surface action on the skin,
the target for most dermatological disorders lies in the viable epidermis or upper dermis.
Hence, a drug’s diffusive penetration of the skin — percutaneous absorption— is an
important aspect of drug therapy.A substance’s particular route mainly depends on the
physicochemical properties of the drug and the condition of the skin.
The principle physicochemical factor in skin penetration is the hydration state of stratum
corneum, which affects the rate of passage of all substances that penetrate the skin. The
clinical importance of hydration can be found in the use of occlusive plastic film in steroid
therapy. Here, the prevention of water loss from the stratum corneum and the subsequent
increased water concentration in this skin layer apparently enhances the penetration of the
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steroid. The temperature of skin and the concentration of the drug play significant roles, but
they are secondary to that of hydration.
The solubility of a drug determines the concentration presented to the absorption site, the
water or lipid partition coefficient influences the rate of transport. An inverse relationship
appears to exist between the absorption rate and the molecular weight. Small molecules
penetrate more rapidly than large molecules, but within a narrow range of molecular size,
there is little correlation between the size and the penetration rate. The transdermal delivery
depend on
1. Release of the medicament from the vehicle.
2. Penetration through the skin barrier.
3. Activation of the pharmacological response (Chopda,2006).
Furthermore, the skin irritation potential and theformulation effect on skin reaction induced
by histamine were investigated in vivo. The commercial cream of DPH(Allergan®) was used
as reference formulation.The diffusion rate values showed the rank order E > A > B > C > D
>Control, and all prepared formulations are able to improve the diffusion of drug compared
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with commercial cream;among the tested formulations, the hydroxyethylcellulose gel and
microemulsions appear to be the most efficientvehicles in promoting the release of DPH.
After in vivo application, the formulations do not produce skin irritation and determine a
reduction of the response induced by histamine suggesting that their potential use as
alternative topicaldosage forms for effective local antihistaminic therapy.
Instrumental analysis
Determination of diphenhydramine hydrochloride in cream by u/v spectrophotometry:
(LIU Yan1,ZHOU Ben-hong, 2007) establish a UV method for determination of
diphenhydramine hydrochloride in cream. And the calibration curves of Diphenhydramine
hydrochloride were linear in the range of 0.2~0.6 mg/ml,(r=1.0000);The average recovery
was 99.08%(RSD=1.03%), in conclusion, this method is simple,quick, accurate, and it is
suitable for quality control of cream.
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may indicate a general approach to analysis employing the two basic steps of extraction and
cleanup. However, each of them is a specific case which depends upon the physical and
chemical properties of the active component.Therefore, it is reasonable to assume that
different methods of separation may be required for differing formulations containing the
same active ingredientsand for differing active ingredients contained in similar formulations.
Diphenhydramine hydrochloride is found in various combinations in commercially available
pharmaceutical preparations, and various assays for its determination have been reviewed .
No procedure,however, has been reported involving the quantification of diphenhydramine
hydrochloride in an emulsified cream base. The procedure described in this paper is a
modification of an analysis method for the determination of diphenhydramine hydrochloride
in acough mixture. The method entails the recovery of the diphenhydramine by chloroform
extraction and further purification through an alginic acid column, followed by quantitative
spectrophotometry at 258 nm.
Antihistamines
Antihistamines are pharmaceutical agents whichcompetitively displace histamine from its
receptors and are therefore able to counteract its effects (AshutoshKar, 2007). Depending on
the histamine receptors they affect, they are classified as H1antihistamines and H2
antihistamines. In addition to their antihistaminic characteristics, almost all H1 antihistamines
also have a spasmolytic and locally anaesthetizing effect. Inaddition, most of these
preparations have a sedating effect on the central nervous system.
In general, H1 antihistamines are indicated for all diseases based on the release of histamine,
substances with a stronger sedating effect also being used as antiemetic or sleeping drugs. In
any case, the most important side effect isthe influence on the central nervous system, i.e.the
sedatingeffect. Because this sedating effect prevented general application,for example in case
of colds or hay fever, second generation H1 antihistamines with fewer sedating side effects
have been developed. "no sedating H1 antihistamines.
Classification
The commonly used antihistaminics may be classified on the basis of their chemical
structures and these all are of the type histamine H1-receptor antagonists. They are:
(i) Aminoalkylethers: Examples-Diphenhydramine Hydrochloride ;Bromodiphenhydramine
Hydrochloride ;Dimenhydrinate ; Doxylamine Succinate ; Diphenylpyraline
Hydrochloride.
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Diphenhydramine Hydrochloride
Clinical pharmacology
Diphenhydramine hydrochloride is an antihistamine with anticholinergic (drying) and
sedative side effects. Antihistamines appear to compete with histamine for cell receptor sites
on effect or cells. Diphenhydramine hydrochloride is widely distributed throughout the body,
including the CNS. A portion of the drug is excreted unchanged in the urine, while the rest is
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metabolized via the liver.The duration of sedation from diphenhydramine is 3-6 hr. However,
this may be extended in elderly patients or those with delayed metabolism.
Dose :25–50 mg, usual, adult, oral dose 3 to 4 times a day, with maximum of 400 mg daily ;
topical to skin 2% cream 3 or 4 times a day.
Interactions
As for the sedating antihistamines in general,Diphenhydramine inhibits the cytochrome P450
isoenzyme CYP2D6 that is partly responsible for the metabolism of some beta blockers
including metoprolol and the antidepressant venlafaxine.
Adverse effects
Adverse effectof diphenhydramine areanticholinergic, including dry mouth, blur red vision,
constipation, and urinary retention. Diphenhydramine use should be avoided in patients with
glaucoma (narrow-angle), benign prostatic hypertrophy, dementia, or cardiovascular disease.
(USP 2006).
METHODOLOGY
MATERIALS
Diphenhydramine hydrochloride.
Cream base
Ointment base
Gel base
phosphate buffer solution pH 7.4
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Equipments
Modified USP Type I dissolution apparatus.
JENWAY 6305 (UV/visible) spectrophotometer using quartz cells
METHOD
Preparation of Formulations
Simple Ointment
Hard paraffin ,soft paraffin ,wool fat and cetostearyl alcohol were melted together and cool at
room temperature. Finally DPH was incorporated into the ointment.
Emulsifying Ointment
emulsifying wax was melted then white softparaffin was addedand melted together and
paraffinoil was added,then cool at room temperature.
Emulsifying cream
Melt emulsifying wax then add white soft paraffinand melt together and paraffin oil, then
Add water and cool at room temperature.finally DPH was incorporated into cream.
Gel
DPH and EDTA were dissolved in water then carbabol was added finally sodium hydroxide
was added and mixed until gel formed.
DPH was dissolved in water and then carboxymethyl cellulose added and mixed until gel
formed. (pharmaceutical practical 2001)
The skin membrane first hydrated for 30 minutes in the buffer solution (pH 7.4) at room
temperature (25°C) to remove extraneous debris and leachable enzymes,then the skin was
fixed around the basket of a dissolution tester (USP type I).The apparatus consists of 6
vessels, containing 900 ml of dissolution media (phosphate buffer, pH 7.4).
One gm of formulation was put inside the basket.And maintained at 37+ 0.5C, the apparatus
run at 100 rpm through out of the experiment. Samples aliquots (1ml) were withdrawn at
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Calibration Procedure
A standard stock solution of diphenhydramine was prepared by dissolving 1g of drug in a
100- ml volumetric flask. A series of standard solutions at concentrations of 0.01, 0.02,
0.03, 0.04, 0.05, 0.06 were prepared by serial dilution of the stock solution (Emami, 2007).
Gel
Ingredients (%w/w) Cream Ointment
CMC Carbabol
Diphenhydramine HCL 2 2 2 2
carboxymethyl cellulose 2.45
Emulsifuing wax 30
White soft paraffin 50 85
Hard paraffin 5
Liquid paraffin 20
Wool fat 5
cetostearyl alcohol 5
Carbopol 1
EDTA 0.5
NaOH (100 g/L) 1.1
Purified water to 100 100 100 100
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Figure 3. release profiles of DPH through rat skin from ointment base
Carboxymethylcellose (CMC)
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DISCUSSION
The results demonstrated the usefulness of an in vitro drug release test in predicting the
efficacy of semisolid base.
The lipophilicity of the base allows high drug mobility in the vehicle for hydrophilic drugs
such DPH, which would translate into faster drug diffusion through the skin surface and thus
a higher transdermal flux.
On the other hand gel permeability is attributed to its hygroscopic properties, which are said
to increase the water content of the stratum corneum, thereby greatly increasing its
permeability. Also gels tend to be the thinnest and absorb most quickly into the skin.
The results of permeation studies through rat skin were analyzed by UV spectrophotometer.
There was a significant difference in the permeability rates among all formulations studied
.The order for in vitro percutaneous absorption of diphenhydramine from the bases was gel
>ointment >cream > CMC (figure 4.2.5) and this result shared with the result in literature .
REFERENCES
1. Marangon, U. Bock, E. Haltner (2009):In vitro release testing for semisolid
formulationsAcross Barriers GmbH,p 1-5.
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