Drug Delivery: Buccal Route

BIBLIOGRAPHY

BuccalMono

Chidambaran, N.; Srivatsava, A.K. Buccal drug delivery

systems. Drug Dev. Indust. Pharm. 1995, 21, 10091036.
Gandhi, R.B.; Robinson, J.R. Oral cavity as a site for bioadhesive drug delivery. Adv. Drug Del. Rev. 1994, 13, 4374.
Harris, D.; Robinson, J.R. Drug delivery via the mucous membranes of the oral cavity. J. Pharm. Sci. 1992, 81, 110.
Meyer, J.; Squier, C.A.; Gerson, S.J. The Structure and Function
of the Oral Mucosa; Pergamon Press: Oxford, 1984.
Rathbone, M.J.; Tucker, I.G. Mechanisms, barriers and pathways of oral mucosal drug permeation. Adv. Drug Del.
Rev. 1993, 12, 4160.
Rathbone, M.J.; Drummond, B.K.; Tucker, I.G. The oral cavity
as a site for systemic drug delivery. Adv. Drug Del. Rev.
1994, 13, 122.

Drug Delivery

58. Henningeld, J.E. Nicotine medications for smoking

cessation. N. Engl. J. Med. 1995, 333, 11961203.
59. Wallstrom, M.; Sand, L.; Nilsson, F.; Hirsch, J.M. The
long-term effect of nicotine on the oral mucosa. Addiction
1999, 94, 417423.
60. Mossad, S.B.; Macknin, M.L.; Medendorp, S.V.; Mason, P.
Zinc gluconate lozenges for treating the common colda
randomized double-blind, placebo-controlled study. Ann.
Intern. Med. 1996, 125, 8189.
61. Macknin, ML.; Piedmonte, M.; Calendine, C.; Janosky, J.;
Wald, E. Zinc gluconate lozenges for treating the common
cold in childrena randomized controlled trial. JAMA
1998, 279, 19621967.
62. Scott, R.C.; Besag, F.M.C.; Boyd, S.G.; Berry, D.; Neville,
B.G.R. Buccal absorption of midazolam: pharmacokinetics
and EEG pharmacodynamics. Epilepsia 1998, 39, 290294.

1081

Drug Delivery: Controlled Release

Yie W. Chien
Research and Development, Kaohsiung Medical University,
Kaohsiung, Taiwan

Senshang Lin
College of Pharmacy and Allied Health Professions, St. Johns University,
Jamaica, New York, U.S.A.

INTRODUCTION

3. Feedback-regulated drug delivery systems.

4. Site-targeting drug delivery systems.

BuccalMono

Drug Delivery

Over the past decades, the treatment of illness has been

accomplished by administering drugs to the human
body via various pharmaceutical dosage forms, like
tablets. These traditional pharmaceutical products are
still commonly seen today in the prescription and
over-the-counter drug marketplace. To achieve and
maintain the drug concentration in the body within
the therapeutic range required for a medication, it is
often necessary to take this type of drug delivery system several times a day. This yields an undesirable
seesaw drug level in the body (Fig. 1).
A number of advancements have been made
recently in the development of new techniques for drug
delivery. These techniques are capable of regulating the
rate of drug delivery, sustaining the duration of therapeutic action, and/or targeting the delivery of drug to
a specic tissue.[16] These advancements have already
led to the development of several novel drug delivery
systems that could provide one or more of the following benets:
1. Controlled administration of a therapeutic dose
at a desirable rate of delivery.
2. Maintenance of drug concentration within an
optimal therapeutic range for prolonged
duration of treatment.
3. Maximization of efcacy-dose relationship.
4. Reduction of adverse side effects.
5. Minimization of the needs for frequent dose
intake.
6. Enhancement of patient compliance.
Based on the technical sophistication of the
controlled-release drug delivery systems (CrDDSs) that
have been marketed so far, or that are under active
development, the CrDDSs can be classied (Fig. 2)
as follows:
1. Rate-preprogrammed drug delivery systems.
2. Activation-modulated drug delivery systems.
1082

In this article, the scientic concepts and technical

principles behind the development of this new
generation of drug-delivery systems are outlined and
discussed.

RATE-PREPROGRAMMED DRUG
DELIVERY SYSTEMS
In this group of CrDDSs, the release of drug molecules
from the delivery systems has been preprogrammed at
a specic rate prole. This is accomplished by system
design, which controls the molecular diffusion of drug
molecules in and/or across the barrier medium within
or surrounding the delivery system. Ficks laws of diffusion are often followed. These CrDDSs can further
be classied as follows:
1. Polymer membrane permeation-controlled drug
delivery systems.
2. Polymer matrix diffusion-controlled drug delivery systems.
3. Polymer (membrane/matrix) hybrid-type drug
delivery systems.
4. Microreservoir partition-controlled drug delivery systems.
Polymer Membrane Permeation-Controlled
Drug Delivery Systems
In this type of CrDDS, a drug formulation is either
totally or partially encapsulated in a drug reservoir
compartment whose drug-releasing surface is covered
by a rate-controlling polymeric membrane. The drug
reservoir can be drug solid particles, a dispersion of
drug solid particles, or a concentrated drug solution in
a liquid- or solid-type dispersing medium. The polymeric membrane can be fabricated from a homogeneous

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001051

Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.

Drug Delivery: Controlled Release

1083

C
Sphere

Adverse side effects

Sheet

Polymer
coating

Drug
reservoir

Toxic level
A3

A1

Therapeutic range
Minimum effective
concentration

Drug
reservoir

Fig. 1 Drug concentration proles in the systemic circulation as a result of taking a series of multiple doses of a conventional drug-delivery system (A1, A2, . . . ) in comparison
with the ideal drug concentration prole (B). (Adapted from
Ref.[6].)

Fig. 3 Release of drug from various shapes of polymer

membrane permeation-controlled drug-delivery systems: (A)
sphere-type, (B) cylinder-type, and (C) sheet-type. In (D),
the drug concentration gradients across the rate-controlling
polymeric membrane and hydrodynamic diffusion layer exist
in series. Both the polymer membrane, which is either porous
or non-porous, and the diffusion layer have a controlled
thickness (hm and hd, respectively).

Dm, and Dd are, respectively, the diffusion coefcients

in the rate-controlling membrane with a thickness of
hm, and in the aqueous diffusion layer with a thickness
of hd. For microporous membrane, the porosity, and
tortuosity of the pores in the membrane should be
included in the estimation of Dm and hm. CR is the drug
concentration in the reservoir compartment.
The release of drug molecules from this type of
CrDDS is controlled at a preprogrammed rate by modulating the partition coefcient and the diffusivity of
drug molecule and the rate-controlling membrane
and the thickness of the membrane. Several CrDDSs

where Km/r and Ka/m are, respectively, the partitioncoefcients for the interfacial partitioning of drug
molecules from the reservoir to the membrane and
from the membrane to the aqueous diffusion layer;

Drug
reservoir

Drug

Drug
reservoir

Pd
Pm Cm Cb
Sink
Cs
Dm Da Elution medium
hd

C
Rate-controlling
surface

Drug

Porous membrane

Cp

hm

or a heterogeneous non-porous polymeric material or

a microporous or semipermeable membrane. The
encapsulation of drug formulation inside the reservoir
compartment can be accomplished by molding, capsulation, microencapsulation, or other techniques.
Different shapes and sizes of drug delivery systems
can be fabricated (Fig. 3).
The release of drug from this type of CrDDSs
should be at a constant rate (Q/t), which is dened
by the following general equation:

Rate-controlling
surface

Diffusion layer
Cp

Frequencies of dosing

Nonporous
membrane

Km=r Ka=m Dd Dm
Q

CR
t
Km=r Dm hd Ka=m Dd hm

Drug
impermeable
barrier

Drug release

No therapeutic
effects

Pore

Cylinder

Drug
reservoir

Rate-controlling
surface

Drug
reservoir

Rate-controlling
surface

Drug

Drug
Sitetargeting
moiety

Energy sensor

Biochemical responsive/
Energy sensor

Biochemical responsive/
Energy sensor

Fig. 2 The four major classes of controlled-release drug delivery systems: (A) Rate-preprogrammed DDS; (B) Activation-modulated DDS; (C) Feedback-regulated DDS and (D) Site-trageting DDS.

BuccalMono

A2

Drug Delivery

Drug concentration

A4

1084

Drug Delivery: Controlled Release

305
74

13.4mm
5.7mm

of this type have been successfully marketed for therapeutical uses and some representatives are outlined
later for illustration.

Ethylene/vinyl acetate membrane

Pilocarpine-core reservoir
Titanium dioxide-white ring

Progestasert IUD
60

Pilocarpine release rate

(mcg/hr)

In this controlled-release intrauterine device, the drug

reservoir exists as a dispersion of progesterone crystals
in silicone (medical grade) uid encapsulated in the
vertical limb of a T-shaped device walled by a nonporous membrane of ethylenevinyl acetate copolymer
(Fig. 4). It is engineered to release continuously a daily
dose of 65 mg progesterone inside the uterine cavity to
achieve contraception for one year.[6] The same technology has been utilized in the development of the
Mirena system, a plastic T-shaped frame with a steroid reservoir containing 52 mg levonorgestrel, which is
designed to release a daily dose of levonorgestrel at
20 mg/day for achieving effective contraception for
ve years.[79]

40

20

0
0

Time (days)
Fig. 5 Diagrammatic illustration of a unit of Ocusert system, showing various structural components, and the ocular
release rate prole of pilocarpine from the Ocusert pilo-20
system. (From Ref.[11].)

Ocusert system

A
Polyethylene

Ethylene
vinylacetate
copolymer
38 mg of progesterone microcrystals
(and barium sulfate)
suspended in silicone oil
B
In Vitro

g/day

BuccalMono

Drug Delivery

In this controlled-release ocular insert, the drug reservoir is a thin disc of pilocarpinealginate complex
sandwiched between two transparent discs of microporous membrane fabricated from ethylenevinyl
acetate copolymer (Fig. 5). The microporous membranes permit the tear uid to penetrate into the drug

In Vivo

100
80
60
40
20
0

95% Confidence Level

100
80
60
40
20
0
0

100

200

Days

300

400

100

200 300 400

Days

Fig. 4 Diagrammatic illustration of a unit of Progestasert

IUD, showing various structural components (A) and the
in vitro and in vivo delivery rate proles of progesterone
for up to 400 days (B).

reservoir compartment to dissolve pilocarpine from the

complex. Pilocarpine molecules are then released at a
constant rate of 20 or 40 mg/h for a 4- to 7-day management of glaucoma.[1,6,10,11]
Transderm-Nitro system
In this controlled-release transdermal therapeutic
system, the drug reservoir, which is a dispersion of
nitroglycerinlactose triturate in a silicone (medical
grade) uid, is encapsulated in an ellipsoid-shaped thin
patch. The drug reservoir is sandwiched between a drugimpermeable metallic plastic laminate, as the backing
membrane, and a constant surface of drug-permeable,
rate-controlling membrane of ethylenevinyl acetate
copolymer (Fig. 6). This device is fabricated by an
injection-molding process. A thin layer of silicone
adhesive is further coated on the drug-permeable
membrane in order that an intimate contact of the
drug-releasing surface with the skin surface is achieved
and maintained. It is engineered to have nitroglycerin
delivered transdermally at a rate of 0.5 (mg/cm2)/day
for a daily relief of angina.[2,3]
The same technology has been utilized in the development of the following: 1) the Estraderm system, which
administers a controlled dose of estradiol transdermally
over 34 days for the relief of postmenopausal syndrome
and osteoporosis;[1214] 2) the Duragesic system, which
provides a transdermal-controlled administration of
fentanyl, a potent narcotic analgesic, for 72-h relief
of chronic pain;[14] and 3) the Androderm system,
which provides a transdermal-controlled delivery of

Drug Delivery: Controlled Release

1085

Drug-impermeable
metallic plastic laminate

Drug reservoir

Rate-controlling
polymeric membrane
Adhesive layer

0.20

0.15

t1=2

0.10

0.05

0
0

10

15

20

25

Time (h)
Fig. 6 Cross-sectional view of a unit of Transderm-Nitro
system, showing various structural components, and plasma
concentration proles of nitroglycerin in 14 human volunteers,
each receiving one unit of Transderm-Nitro system (20 cm2,
with a delivery rate of 10 mg/day) for 24 h. (From Refs.[11,55].)

testosterone, through non-scrotal skin, for the 24 h

replacement therapy of testosterone-decient patients.[14]
Norplant subdermal implant
The controlled-release subdermal implant is fabricated
from a non-porous silicone (medical-grade) tubing, by
sealing both ends with silicone (medical-grade)
adhesive to encapsulate either levonorgestrel crystals
alone (generation I) or a solid dispersion of levonorgestrel in silicone elastomer matrix (generation II). It is
designed to attain a continuous release of levonorgestrel, at a daily dosage rate of 30 mg, to each subject (following the subcutaneous implantation of either 6 units
of I or 2 units of II); (Fig. 7) for up to 7 years.[1518]

Polymer Matrix Diffusion-Controlled

Drug Delivery Systems
In this type of CrDDS, the drug reservoir is produced
from the homogeneous dispersion of drug particles in
either a lipophilic or a hydrophilic polymer matrix. The
drug dispersion in the polymer matrix is accomplished

2ACR DP 1=2

where A is the initial loading dose of drug dispersed in

the polymer matrix; CR is the drug solubility in the
polymer, which is also the drug reservoir concentration
in the polymer matrix; and Dp is the diffusivity of the
drug molecules in the polymer matrix.
The release of drug molecules from this type of
CrDDSs may be controlled at a preprogrammed rate
by controlling the loading level and the polymer
solubility of the drug and its diffusivity in the polymer
matrix. Several CrDDSs of this type have been successfully marketed for therapeutical uses, and some
representatives are outlined later for illustration.
Nitro-Dur system
This controlled-release transdermal therapeutic system
is fabricated by rst heating an aqueous solution of
water-soluble polymer, glycerol, and polyvinyl alcohol
and then lowering the temperature of the mixture to
form a polymer gel. Nitroglycerin/lactose triturate is
dispersed in the gel, and the mixture is then solidied
at room temperature to form a medicated polymer disc
by a molding and slicing technique. After assembly
onto a drug-impermeable metallic plastic laminate, a
patch-type transdermal therapeutic system is produced
with an adhesive rim surrounding the medicated disc
(Fig. 9). It is designed for application onto an intact
skin to provide a continuous transdermal infusion of
nitroglycerin, at a daily dose of 0.5 mg/cm2, for the
prevention of angina pectoris.[2,19]
The drug reservoir can also be formulated by
directly dispersing the drug in an adhesive polymer,
such as poly(isobutylene) or poly(acrylate) adhesive,
and then spreading the medicated adhesive by solvent
casting or hot melt, onto a at sheet of drug-impermeable
backing support to form a single- or multiple-layer drug
reservoir. This type of transdermal CrDDS (TDD)

BuccalMono

Night Period

Drug Delivery

Plasma nitroglycerin conc.

(ng/ml SD)

0.25

by either 1) blending a dose of nely ground drug

particles with a viscous liquid (or a semisolid) polymer, followed by a crosslinking of polymer chains
or 2) mixing drug solids with a melted polymer at
an elevated temperature. The resultant drug-polymer
dispersion is then molded or extruded to form drugdelivery devices of various shapes and sizes designed
for a specic application (Fig. 8). It can also be
fabricated by dissolving the drug and the polymer in a
common solvent, followed by solvent evaporation, at an
elevated temperature and/or under a vacuum, in a mold.
The release prole of drug from this matrix diffusion-controlled CrDDS is not constant, because the
rate of drug release is time dependent as dened by:

1086

Drug Delivery: Controlled Release

Milligrams
216
~
~
90

total load of levonorgestrel

daily dose 30 g

Milligrams
216
~
~
90

70

70

50

50

30

30

10

10
1

Years of use
Concentration of
Levonorgestrel in plasma

ORAL

1.00
Peak (mean)

0.75
0.50

NONPLANT SUBCERNAL INPLANTS

Mean value and
95% confidence
intervals

0.25
Trough (mean)

24 hr

2.4 mm
34 mm

BuccalMono

Drug Delivery

Time of use (years)

Fig. 7 Diagrammatic illustration of the subcutaneous implantation of Norplant implants. The subcutaneous release prole of
levonorgestrel in female volunteers for up to 6 years and the resultant plasma prole as compared to those obtained by oral
administration. (Adapted from Refs.[1518].)

is best illustrated by the development and marketing

of an isosorbide dinitrate-releasing TDD system,
named Frandol tape, by Toaeiyo/Yamanouchi in
Japan, and of a nitroglycerin-releasing TDD system,
named Nitro-Dur II system by Key in the United
States, for once-a-day medication for angina pectoris.
This second generation of TDD system (NitroDur II)
has also received FDA approval for marketing. NitroDur II compares favorably with Nitro-Dur (Fig. 10)
and has gradually replaced the rst-generation
Nitro-Dur from the marketplace. The same technical
basis has been also utilized in the development of
the following: 1) Habitrol and Nicotrol systems,
which provide a controlled dose of nicotine transdermally over 24 h for smoking cessation;[14] 2) Minitran
system, which administers a controlled dose of nitroglycerin transdermally over 24 h for the relief of anginal
attacks;[14] 3) Testoderm system, which administers a
controlled delivery of testosterone for transdermal permeation through a scrotal skin[14] for the replacement
therapy of testosterone-decient patients for 24 h; and
4) Climara system, which provides a controlled

delivery of 17b-estradiol for transdermal permeation

for once-weekly treatment of vasomotor systems[14]
associated with menopause.
Compudose implant
This controlled-release subdermal implant is fabricated
by dispersing micronized estradiol crystals in a viscous
mixture of silicone elastomer and catalyst and then
coating the estradiol-polymer dispersion around a rigid
(drug-free) silicone rod by an extrusion technique to
form a cylinder-shaped implant (Fig. 11). This implant
is designed for subcutaneous implantation in the
steers ear ap for a duration of 200 or 400 days, during which a controlled quantity of estradiol is released
daily for growth promotion.[20]
To improve the Q versus t1/2 drug release proles
[Eq. (2)], this polymer matrix diffusion-controlled
CrDDS can be modied to have the drug-loading
level varied, in an incremental manner, to form a gradient of drug reservoir along the diffusional path in the
polymer matrix. A constant drug release prole is thus

Drug Delivery: Controlled Release

1087

Drug reservoir
(Dispersion)
Drug release

Drug depletion
zone

Gel layer

Polymer (Membrane/Matrix) Hybrid-Type

Drug Delivery Systems

Drug release

This type of CrDDS is developed with the objective of

combining the constant drug release kinetics of polymer membrane permeation-controlled drug delivery
systems with the mechanical superiority of polymer
matrix diffusion-controlled drug delivery systems.
The release prole of drug from a sandwich-type drug
delivery system (Fig. 13) is constant, and the instantaneous rate of drug release is dened by:

C
Receding boundary
depletion zone

Drug reservoir

Diffusion layer

CR

ACp Dp
dQ

2
dt
Dp Km 1=Pm 1=Pd 4ACp Dp t1=2

Elution medium

Matrix

Perfect sink
hd
hp + dhp

Fig. 8 Release of drug from the polymer matrix diffusioncontrolled drug delivery systems with drug reservoir exists
as a homogeneous dispersion in (A) lipophilic, non-swellable
polymer matrix, with a growing thickness of drug depletion
zone, or (B) a hydrophilic, swellable polymer matrix, with a
growing thickness of drug-depleted gel layer. In (C), the drug
concentration gradients across the time-dependent drug
depletion zone, with a growing thickness (hp dhp), and
the hydrodynamic diffusion layer, with a controlled thickness
(hd), are shown in series.

achieved, and the rate of drug release from this drug

reservoir gradient-controlled drug delivery system is
dened by:
Ka=r Da
dQ

Cp ha
dt
ha t

in which the time-dependent thickness [ha(t)] of the

diffusional path for drug molecules to diffuse through,
which is increasing with time, is compensated by the
proportional increase in the drug-loading level [Cp(ha)],
and a constant drug release prole is thus obtained. This
type of CrDDS is best illustrated by the nitroglycerinreleasing Deponit system (Fig. 12), rst marketed
by Pharma-Schwartz/Lohmann in Europe.[21] WyethAyerst has received FDA approval for marketing this
system in the United States.

where A is the initial amount of drug solid impregnated

in a unit volume of polyer matrix with solubility Cp
and diffusivity Dp; Km is the partition coefcient for
the interfacial partitioning of drug molecules from
polymer matrix toward polymer coating membrane;
Pm is the permeability coefcient of the polymer coating membrane with thickness hm; and Pd is the permeability coefcient of the hydrodynamic diffusion
layer with thickness hd.
The hybrid system is exemplied by the development of clonidine-releasing and scopolamine-releasing
transdermal therapeutic systems (Catapres-TTS
and Transderm-Scop) (Fig. 14), in which a ratecontrolling non-medicated polymeric membrane is
added to coat the surface of the drug-dispersing polymer matrix, and the release of drug molecules thus
becomes controlled by membrane permeation instead
of matrix diffusion. The same technology has been
utilized in the development of levonorgestrel-releasing
subdermal implants (Norplant II).
Microreservoir Partition-Controlled
Drug Delivery Systems
In this type of CrDDS, the drug reservoir is a suspension of drug solid particles in an aqueous solution of a
water-miscible polymer, like polyethylene glycols. This
forms a homogeneous dispersion of many discrete,
unleachable, microscopic drug reservoirs in a biocompatible polymer, like silicone elastomers (Fig. 15). The
microdispersion is achieved by applying a high-energy
dispersion technique.[13,23] Different shapes and sizes of
drug-delivery devices can be fabricated from this

BuccalMono

Dp

Drug Delivery

Furthermore, it was recently demonstrated that the

release of a drug, such as propranolol, from the multilaminate adhesive-based TDD system can be maintained
at zero-order kinetics by controlling the particle size
distribution of drug crystals in the various laminates
of adhesive matrix.[22]

1088

Drug Delivery: Controlled Release

Absorbent pad
Occlusive baseplate
(aluminum foil)

Impermeable backing
(polyethylene coverstrip)

Adhesive rim
(microporous acrylic polymer tape)

Drug reservoir
(drug/hydrophilic polymer matrix)

Plasma nitroglycerin conc.

(ng/ml SEM)

0.8

0.6

Night Period

0.4

off

0.2

BuccalMono

Drug Delivery

10

15

20

25

Time (h)
Fig. 9 Cross-sectional view of a unit of Nitro-Dur system, showing various structural components, and the plasma nitroglycerin concentration proles in six human volunteers, each receiving 1 unit of Nitro-Dur system (20 cm2, with a delivery rate of
10 mg/day) for 24 h. (From Refs.[5556].)

microreservoir-type CrDDS by molding or extrusion

techniques. Depending upon the physicochemical
properties of drugs and the desired rate of drug release,
the device can be further coated with a layer of biocompatible polymer to modify the mechanism and
the rate of drug release.
The rate of drug release (dQ/dt) from this type of
CrDDS is dened by:
Dp Dd mKp
dQ

dt
Dp hd Dd hp mKp



Dl Sl 1  n 1
1
 nSp 

ht
Kl
Km

where m a/b and n is the ratio of drug concentration at the inner edge of the interfacial barrier over
the drug solubility in the polymer matrix,[1,6] in which a
is the ratio of drug concentration in the bulk of elution
solution over drug solubility in the same medium and b
is the ratio of drug concentration at the outer edge of

the polymer coating membrane over drug solubility

in the same polymer. Kl, Km, and Kp are, respectively,
the partition coefcients for the interfacial partitioning
of drug from the liquid compartments to the polymer
matrix, from the polymer matrix to the polymer coating membrane, and from the polymer coating membrane to the elution solution, whereas Dl, Dp, and Dd
are, respectively, the diffusivities of the drug in the
liquid layer surrounding the drug particles, the polymer coating membrane enveloping the polymer matrix,
and the hydrodynamic diffusion layer surrounding the
polymer coating membrane with respective thicknesses
of hl, hp, and hd (Fig. 15); and Sl and Sp are the solubilities of the drug in the liquid compartments and in the
polymer matrix, respectively.
The release of drug from the microreservoir-type
CrDDS can follow either a dissolution- or a matrix
diffusion-control process, depending upon the relative
magnitude of Sl and Sp.[24] Representatives of this type
of CrDDS is outlined below.

Drug Delivery: Controlled Release

1089

Drug-loaded
adhesive

Silicone rod

Impermeable film

Release liner
1000

Estradiol-releasing
polymer matrix

250
75%

1.0

40%

100
50

0.8

10

15

20

25

Time(h)
Fig. 10 Cross-sectional view of Nitro-Dur II, showing
various structural components, and the comparative 24 h
plasma nitroglycerin concentration proles in 24 healthy
male volunteers, each receiving randomly 1 unit of NitroDur II (open circle) or Nitro-Dur (closed circle), 20 cm2 each,
with a delivery rate of 10 mg/day, over the chest for 24 h
(the arrow indicates unit removal). (From Ref.[56].)

0.6

0.4

0.2

0.0
0

(Days)

Nitrodisc system
In this transdermal CrDDS (Fig. 16), the drug reservoir is a suspension of nitroglycerin/lactose triturate
in an aqueous solution of 40% polyethylene glycol
400. It is dispersed homogeneously by a high-energy
mixing technique, with isopropyl palmitate, a skin
permeation enhancer, in a mixture of viscous silicone
elastomer and catalyst.[25] The resultant drug-polymer
dispersion is then formed in situ into a solid medicated
disc on a drug-impermeable metallic plastic laminate,
with an adhesive rim, by an injection-molding technique and application of an instantaneous heating. It
is engineered to provide a transdermal administration
of nitroglycerin at a daily rate of 0.5 mg/cm2 for
once-a-day medication of angina pectoris.[2,26] AQ
versus t1/2 (matrix diffusion-controlled) release prole
is obtained.
Syncro-Mate-C implant
This subdermal controlled-release implant is fabricated
by dispersing the drug reservoir, which is a suspension
of norgestomet in an aqueous solution of PEG 400, in
a viscous mixture of silicone elastomers by a highenergy dispersion technique.[24] After adding catalyst,

Fig. 11 Diagrammatic illustration of a unit of Compudose

subdermal implant and in vitro release proles of estradiol
from the implants immersed in aqueous solution containing
various volume fractions of polyethylene glycol 400.

the suspension is delivered into a silicone medical-grade

tubing, which serves as the mold as well as the coating
membrane, and then polymerized in situ. The polymerized drug-polymer composition is then cut into a
cylinder-shaped implant with its ends staying open
(Fig. 17). This tiny cylindrical implant is designed to
be inserted into the subcutaneous tissue of the livestocks ear ap; norgestomet is released continuously
into the subcutaneous tissue for up to 20 days for the
control and synchronization of estrus and ovulation
and up to 160 days for growth promotion. A constant
Q versus t (dissolution-controlled) release prole has
been achieved, as compared to the Q versus t1/2 release
prole (matrix diffusion-controlled drug release) for
the Syncro-Mate-B implant and the Nitrodisc system
discussed above.
Transdermal contraceptive device
The transdermal contraceptive device is based on a
patentable micro-drug-reservoir technique[26] to achieve

BuccalMono

10

20%

Drug Delivery

25

Q (mg/cm2)

Nitroglycerin (pg/ml)

500

1090

Drug Delivery: Controlled Release

Drug-impermeable
metallic plastic laminate

R1
R2

Drug reservoir
gradient layers
(R1 > R2 > R3)

R3

Adhesive layer

Plasma nitroglycerin conc. (pg/ml)

400
Cmax = 255 151 pg/ml (tmax = 3.6 3.5 h)
Css = 125 50 pg/ml (8-24 h)
AUC = 3.3 1.6 ngh/ml
200

100

chemical, or biochemical processes and/or facilitated by

an energy supplied externally (Fig. 2). The rate of drug
release is then controlled by regulating the process
applied or energy input. Based on the nature of the
process applied or the type of energy used, these
activation-modulated CrDDSs can be classied into
the following categories:
1. Physical means
a. Osmotic pressure-activated drug delivery
systems
b. Hydrodynamic pressure-activated drug
delivery systems
c. Vapor pressure-activated drug delivery
systems
d. Mechanical force-activated drug delivery
systems
e. Magnetics-activated drug delivery systems
f. Sonophoresis-activated drug delivery systems
g. Iontophoresis-activated drug delivery systems
h. Hydration-activated drug delivery systems
2. Chemical means

80
Dose=5.0 0.7 mg/day (n =6)
4.5 0.8 mg/day (n =17)

60

40

BuccalMono

Drug Delivery

12

16

20

24

a.
b.
c.
d.

pH-activated drug delivery systems

pH-activated drug delivery systems
Ion-activated drug delivery systems
Hydrolysis-activated drug delivery systems

3. Biochemical means

Duration of Device/Skin contact (h)

Fig. 12 Cross-sectional view of a unit of Deponit system,

showing various structural components, and the plasma
nitroglycerin concentration proles in six human volunteers,
each receiving 1 unit of Deponit system (16 cm2, with a delivery rate of 5 mg/day) for 24 h. (Plasma proles are plotted
from data from Ref.[21].)

a dual-controlled release of levonorgestrel, a potent

synthetic progestin, and estradiol, a natural estrogen,
at constant and enhanced rates, continuously, for a
period of 7 days.[5] By applying 1 unit (10 or 20 cm2)
of transdermal contraceptive device per week, beginning
on day 5 of an individuals menstrual cycle, for 3
consecutive weeks (3 weeks on and 1 week off), steadystate serum levels of levonorgestrel have been obtained,
and the secretion of gonadotropins and progesterone
have been effectively suppressed.

ACTIVATION-MODULATED DRUG
DELIVERY SYSTEMS
In this group of CrDDSs, the release of drug molecules
from the delivery systems is activated by some physical,

a. Enzyme-activated drug delivery systems

b. Biochemical-activated drug delivery systems
Several CrDDSs have been successfully developed
and applied clinically to the controlled delivery of
pharmaceuticals and biopharmaceuticals. These are
outlined and discussed below.

Osmotic Pressure-Activated Drug

Delivery Systems
In this type of CrDDSs, the drug reservoir, which can
be either a solution or a solid formulation, is contained within a semipermeable housing with a controlled water permeability. The drug in solution is
released through a special laser-drilled delivery orice
at a constant rate under a controlled gradient of
osmotic pressure.
For a solution-type osmotic pressure-activated
CrDDS, the intrinsic rate of drug delivery (Q/t) is
dened by:
Q
Pw Am

ps  pe
t
hm

Drug Delivery: Controlled Release

1091

Sphere

Cylinder

hm

Dp

Dm

Dd

pm

pd

CR

Polymer matrix

Drug
depletion
zone

Polymer
coating
membrane

Perfect sink
(Cb = 0)

Diffusion
layer

Solution
bulk

Fig. 13 The controlled release of drug molecules from a (membrane-matrix) hybrid-type drug delivery system in which solid
drug is homogeneously dispersed in a polymer matrix, which is then encapsulated inside a polymeric membrane, where D, P,
and h are the diffusivity, permeability, and thickness, respectively, and the subscripts p, m, and d denote the drug depletion zone
in the polymer matrix, polymer coating membrane, and diffusion layer, respectively.

For a solid-type osmotic pressure-activated CrDDS,

the intrinsic rate of drug delivery should also be a
constant and is dened by:

where Pw, Am, and hm are, respectively, the water permeability, the effective surface area, and the thickness
of the semipermeable housing; (ps  pe) is the differential osmotic pressure between the drug-delivery system
with an osmotic pressure of ps and the environment

MICROPOROUS
MEMBRANE

DRUG-DISPERSING
ADHESIVE LAYERS

Q
P w Am

ps  pe Sd
t
hm

DRUG-IMPERMEABLE
BACKING LAMINATE

DRUG MOLECULES

Fig. 14 Cross-section view of various structural components

in the Transderm-Scop and Catapres-TTS systems.

BuccalMono

hd

Drug Delivery

Drug
reservoir

hp(t)

1092

Drug Delivery: Controlled Release

Polymer matrix
(cross-linked, solid)

Drug reservoir
(microscopic liquid
compartments)

Coating membrane

Polymer/Solution interface

BuccalMono

Drug Delivery

Interfacial
barrier

Polymer matrix
Dp

Liquid
layer

Cp
Dl

Cp'

Dm

Ds
Solution
sink

Cp'

Cm

Drug
particle

Cd
Sl

Cl

Cm'

Cb = O

Polymer
Diffusion
coating
layer
membrane

Fig. 15 Microscopic view of a microreservoir-type drug-delivery system, which shows the microscopic structure of various components, and the physical model developed for the mechanistic analysis of the controlled release of drug. (Adapted from Refs.[1,57].)

with an osmotic pressure of pe; and Sd is the aqueous

solubility of the drug component in the solid reservoir.
The release of drug molecules from this type of
CrDDS is activated by osmotic pressure and controlled
at a rate determined by the water permeability and the

effective surface area of the semipermeable housing as

well as the osmotic pressure gradient. Several CrDDSs
of this type have been successfully marketed for therapeutical uses and some representatives are outlined
later.

Drug Delivery: Controlled Release

1093

Occlusive baseplate
(aluminum foil disc)

Adhesive foam pad

(flexible polyurethane)

Polymer coating
membrane

Drug
reservoir

Microscopic drug reservoirs

(drug/co-solvents)

Adhesive rim
(acrylic polymer coating)

Medicated MDD core

Open ends

Polymer matrix
(silicone elastomer)

0.3
0.2
(C plasma)ss

0.1
0.0

12

16

20

24

28

32

60
40
20
0

Time (h)

Fig. 16 Cross-sectional view of a unit of Nitrodisc system,

showing various structural components, and the plasma
nitroglycerin concentration proles in 12 human volunteers,
each receiving 1 unit of Nitrodisc system (16 cm2, with a
delivery rate of 10 mg/day) for 32 h. (From Ref.[23].)

Alzet osmotic pump

In this implantable or insertable CrDDS, the drug reservoir, which is normally a solution formulation, is
contained within a collapsible, impermeable polyester
bag whose external surface is coated with a layer of
osmotically active salt, for example, sodium chloride.
This reservoir compartment is then totally sealed inside
a rigid housing walled with a semipermeable membrane (Fig. 19). At an implantation site, the water
content in the tissue uid will penetrate through the
semipermeable membrane at a controlled rate and
dissolve the osmotically active salt. This creates an
osmotic pressure in the narrow spacing between the
exible reservoir wall and the rigid semipermeable
housing. Under the osmotic pressure created [Eq. (6)],
the reservoir compartment is thus reduced in volume
and the drug solution is forced to release through the
ow moderator at a controlled rate.[27,28] By varying
the drug concentration in the solution, different doses
of drug can be delivered at a constant rate for a period
of 14 weeks.
In addition to its application in the subcutaneous
controlled administration of drugs for pharmacological studies, this technology has recently been extended
to the controlled administration of drugs in the rectum
by zero-order kinetics. The hepatic rst-pass metabolism of drugs is thus bypassed.[29]

10

15

20

25

30

Days of implantation

Fig. 17 Syncro-Mate-C implant, a subdermal implant fabricated from the microreservoir dissolution-controlled drugdelivery system, and subcutaneous controlled release of norgestomet, a potent synthetic progestin, at constant rate for 20
days. The open ends on the implant do not affect the zeroorder in vivo drug release prole. (Adapted from Ref.[57].)

Acutrim tablet
In this oral CrDDS, the drug reservoir, which is a solid
tablet of water-soluble and osmotically-active phenylpropanolamine (PPA) HCl, is enclosed within a semipermeable membrane of cellulose triacetate.[2,30] The
surface of the semipermeable membrane is further
coated with a thin layer of immediately releasable
PPA dose (Fig. 20). In the alimentary tract, the gastrointestinal uid will dissolve away the immediate release
layer of PPA to provide an initial dose of PPA and
then penetrate through the semipermeable membrane
to dissolve the sustained-release dose of PPA. Under
the osmotic pressure created [Eq. (7)], the PPA solution
is released continuously at a controlled rate, through
an orice pre-drilled by a laser beam.[2,30,31] It is
designed to provide a controlled delivery of PPA over
a duration of 16 h for appetite suppression in a weightcontrol program.[31] The same delivery system has
also been utilized for the oral controlled delivery of
indomethacin. An extension of this technology is the
development of a push-pull type osmotic pressureactivated CrDDS for the oral controlled delivery of
nifedipine and metroprolol.[27] It has been further
extended to the delayed-onset and controlled oral
delivery of verapamil[14] to produce a maximum
plasma concentration in the morning hours.

BuccalMono

Night Period

0.4

80

Drug Delivery

Plasma nitroglycerin
conc. (ng/ml SEM)

0.5

Fraction of drug released (%)

100
0.6

1094

Drug Delivery: Controlled Release

hydrophilic polymer layer is sandwiched between the

drug reservoir compartment and the housing. In the
gastrointestinal tract, the laminate will imbibe the gastrointestinal uid through the annular openings at the
lower end of the housing and become swollen. This
generates a hydrodynamic pressure in the system.
The hydrodynamic pressure, thus created, forces the
drug reservoir compartment to reduce in volume and
causes the liquid drug formulation to release through
the delivery orice.[32] The drug release rate is
dened by:

Concentration (pg/ml S.E.)

288
10 Sq. cm - Patch (n=6)

240

20 Sq. cm - Patch (n=6)

192
144
96
48
0

0
m

168
mm

336
mm

504
m p

672
p

Duration of study (h)

Serum progesterone (ng/ml)

30
25

Subject Code MG
(Group B: 2 TCD patch)
Pretreatment

Pretreatment
Treatment

20

Treatment

15
10
Tmax

Tmax

BuccalMono

Drug Delivery

0
0

10

20

30

40 0

10

20

30

where Pf, Am, and hm are the uid permeability, the

effective surface area, and the thickness of the wall
with annular openings, respectively; and ys  ye, is
the difference in hydrodynamic pressure between the
drug delivery system (ys) and the environment (ye).
The release of drug molecules from this type of
CrDDS is activated by hydrodynamic pressure and
controlled at a rate determined by the uid permeability and effective surface area of the wall with
annular openings as well as by the hydrodynamic
pressure gradient.

B
Subject Code MM
(Group A: 1 TCD patch)

Q
Pf Am

ys  ye
t
hm

40

Day of menstrual cycle

Fig. 18 (Upper panel) The 4week serum levonorgestrel
proles in 12 human volunteers, each receiving 1 or 2 units
of a transdermal contraceptive system (10 cm2, with daily
dosage of 28.3 mg/day) once a week, consecutively for 3
weeks, and the same size of placebo on week 4. (Lower panel)
Comparative serum concentration proles of progesterone
during the pretreatment and treatment cycles in two subjects,
each as the representative for group A (receiving 10 cm2) and
group B (receiving 20 cm2), respectively. The suppression of
progesterone peak during the treatment cycle is an indication
of effective fertility control.

Hydrodynamic Pressure-Activated
Drug Delivery Systems
In addition to the osmotic pressure systems discussed
above, hydrodynamic pressure has also been explored
as the potential source of energy to modulate the delivery of therapeutic agents.[2]
A hydrodynamic pressure-activated drug-delivery
system can be fabricated by placing a liquid drug formulation inside a collapsible, impermeable container
to form a drug reservoir compartment. This is then
contained inside a rigid, shape-retaining housing. A
laminate of an absorbent layer and a swellable,

Vapor Pressure-Activated
Drug Delivery Systems
In this type of CrDDS, the drug reservoir, which is a
solution formulation, is contained inside the infusion
compartment. It is physically separated from the
pumping compartment by a freely movable partition
(Fig. 21). The pumping compartment contains a vaporizable uid, such as uorocarbon, which vaporizes at
body temperature and creates a vapor pressure. Under
the vapor pressure created, the partition moves upward
and forces the drug solution in the infusion compartment to be delivered, through a series of ow regulator
and delivery cannula, into the blood circulation at a
constant ow rate.[1,6,33] The process is dened by:
Q
d4 dP

t
40:74ml

where d and l are, respectively, the inner diameter and

thelength of the delivery cannula; Dp is the pressure
difference between the vapor pressure in the pumping
compartment and the pressure at the implantation site;
and m is the viscosity of the drug formulation.
The delivery of drug from this type of CrDDS is
activated by vapor pressure and controlled at a rate
determined by the differential vapor pressure, the formulation viscosity, and the size of the delivery cannula.

Drug Delivery: Controlled Release

1095

B
200

Urine volume

150
Pump
implanted

125

Removable cap
Flange
Flow moderator

Pump
removed

100
Neck Plug

75
50
25
0

Flexible impermeable
reservoir wall
3

3000

12

15

Osmotic agent

Urine osmolality

2500
Semipermeable
membrane

2000

Water entering
semipermeable
membrane

1500
1000
Pump
implanted

500
0

Reservoir

Pump
removed

12

15

Time (day)

Fig. 19 (A) Cross-sectional view of the Alzet osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effect
of 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urine
osmolality in the Brattleboro rats with diabetes insipidus.

A typical example is the development of Infusaid,

an implantable infusion pump by Metal Bellows, for
the constant infusion of heparin in anticoagulation
treatment,[34] of insulin in the normoglycermic control
of diabetics,[33] and of morphine for patients suffering
from the intensive pain of a terminal cancer.[35]
Mechanical Force-Activated
Drug Delivery Systems
In this type of CrDDS, the drug reservoir is a solution
formulation in a container equipped with a mechanically activated pumping system. A metered dose of
drug formulation can be reproducibly delivered into
a body cavity, such as the nose, through the spray head
upon manual activation of the drug-delivery pumping
system. The volume of solution delivered is xed and
is independent of the force and duration of activation.
A typical example of this type of drug-delivery system is the development of a metered-dose nebulizer for
the intranasal administration of a precision dose of
luteinizing hormone-releasing hormone (LHRH) and

its synthetic analogs, such as buserelin. Through nasal

absorption, the hepatic rst-pass elimination of these
peptide drugs is thus avoided.[24]
Magnetic-Activated Drug Delivery Systems
Macromolecular drugs, such as peptides, have been
known to release only at a relatively low rate from a
polymer-controlled drug-delivery system. This low rate
of release can be improved by incorporating an electromagnetism-triggering vibration mechanism into the
polymeric delivery device. With a hemispheric-shaped
design, a zero-order drug-release prole is achieved.[36]
By combining these two approaches, a subdermally
implantable, magnetic-activated hemispheric drugdelivery device is developed. It is fabricated by rst
positioning a tiny doughnut-shaped magnet at the center of a drug-dispersing biocompatible polymer matrix
and then coating the external surface of the medicated
polymer matrix, with the exception of one cavity at the
center of the at surface, with a pure polymer, for
instance, ethylenevinyl acetate copolymer or silicone

BuccalMono

Urine osmolalilty
(mOsm/ kg H2O + S.D.)

Drug solution leaving

via delivery portal

175

Drug Delivery

Daily urine volume

(% of Pretreatment control + S.D.)

1096

Drug Delivery: Controlled Release

Delivery orifice

Cumulative % loading dose released

Semi-permeable coating

Controlled-release
dose

Drug reservoir/
osmotically active
solutes
100

12.16 atm
30.16 atm

80

54.16 atm
114.0 atm

Immediate releasing layer

(initial dose)

Jiisp J p J e J c

 

dC
Zi Di Fi dE
Ks Ds
Ci
kCs Id
hs
hs
RT

60
40
20
0

molecule across a biological membrane, such as the

skin, in a manner similar to passive diffusion under a
concentration gradient but at a much facilitated rate.
The iontophoresis-facilitated skin permeation rate of
a charged molecule i consists of three components
and is expressed by:

12

16

20

24

Time (h)
Fig. 20 Cross-sectional view of a unit of Acutrim tablet, a
solid-type osmotic pressure-activated drug delivery system,
and the effect of increased osmotic pressure in the dissolution
medium on the release proles of phenylpropanolamine HCl
from the Acutrim tablet at intestinal condition. (Adapted
from Refs.[31,58].)

BuccalMono

Drug Delivery

elastomers. This uncoated cavity is designed for allowing a peptide drug to release.
The hemispheric magnetic delivery device produced
can release macromolecular drugs, like bovine serum
albumin, at a low basal rate, by diffusion process, and
under a non-triggering condition, or it can release the
same drug at a much higher rate, when the magnet is activated, to vibrate by an external electromagnetic eld.
Sonophoresis-Activated Drug
Delivery Systems
This type of activation-controlled drug delivery system
utilizes ultrasonic energy to activate (or trigger) the
delivery of drugs from a polymeric drug delivery
device. The system can be fabricated from either a
non-degradable polymer, such as ethylenevinyl acetate copolymer, or a bioerodible polymer, such as poly
[bis(p-carboxyphenoxy)alkane anhydride].[37] The
potential application of sonophoresis (or phonophoresis) to regulate the delivery of drugs was recently
reviewed.[38]

10

where J p, J e, and J c represent, respectively, the ux for

the skin permeation by passive diffusion, for the electrical current-driven permeation, and for the convective ow-driven skin permeation; Ks is the partition
coefcient for interfacial partitioning from the donor
solution to the stratum comeum; Ds and Di are,
respectively, the diffusivity across the skin and the
diffusivity of ionic species i in the skin; Ci and Cs are,
respectively, the donor concentration of ionic species i
and the concentration in the skin tissue; dE/hs is the
electrical potential gradient across the skin; dC/hs is
the concentration gradientacross the skin; Zi is the
electrical valence of ionic species i; Id is thecurrent
density applied; F, k, and R are, respectively, the faraday, proportionality, and gas constant; and T is the
absolute temperature.
A typical example of this type of activationcontrolled CrDDS is the development of an iontophoretic drug delivery system, named Phoresor by Motion
Control, to facilitate the percutaneous penetration of
antiinammatory drugs, such as dexamethasone sodium
phosphate,[3941] to surface tissues.
Further development of the iontophoresis-activated
drug delivery technique has yielded a new design of
iontophoretic drug delivery systemthe transdermal
periodic iontotherapeutic system (TPIS). This new system, which is capable of delivering a physiologicallyacceptable pulsed direct current, in a periodic manner,
with a special combination of waveform, intensity, frequency, and on/off ratio, for a specic duration, has
signicantly improved the efciency of transdermal
delivery of peptide and protein drugs.[4] A typical
example is the iontophoretic transdermal delivery of
insulin, a protein drug, in the control of hyperglycemia
in diabetic animals.

Hydration-Activated Drug Delivery Systems

Iontophoresis-Activated Drug
Delivery Systems
This type of CrDDS use electrical current to activate
and to modulate the diffusion of a charged drug

In this type of CrDDS, the drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymer. The release of drug
is activated and modulated by hydration-induced

Drug Delivery: Controlled Release

1097

Bacterial
filter
assembly

Inlet
septum

Needle stop

Fluorocarbon
fluid
filling tube

Flow
regulator
Silicone
polymer
coating

2.4 cm

Empty
weight = 181 g

Infusate
chamber

Bellows
Fluorocarbon
fluid
chamber
8.6 cm

1000
A
Pump
implanted

800
600

n=7

200

B
800
600
400
n = 25

200
0
0

16

24

32

40

48

56

Weeks of infusion
Fig. 21 Cross-sectional view of a unit of Infusaid system, a vapor pressure-activated drug-delivery system, and daily heparin
dose (mean  S.E.) delivered to 25 dogs for 6 months and to 7 dogs for 12 months. (Adapted from Ref.[34].)

swelling of the polymer matrix. Representatives of this

type of CrDDS are outlined below.
Syncro-Male-B implant
This subcutaneous CrDDS is fabricated by dissolving
norgestomet, a potent progestin for estrus synchronization, in an alcoholic solution of linear ethylene
glycomethacrylate polymer (Hydron S). The drugpolymer mixture is then cross-linked by adding
ethylene dimethacrylate, in the presence of an oxidizing
catalyst, to form a cylinder-shaped subdermally
implantable implant.[1,6] This tiny subdermal implant
can be activated by tissue uid to swell and can be

engineered to deliver norgestomet, at a rate of

504 mg/cm2/day1/2, in the subcutaneous tissue for up
to 16 days for the control and synchronization of
estrus in livestock.[13]
Valrelease tablet
This oral CrDDS is prepared by granulating Valium, an
antidepression drug, with hydrocolloids (2075 wt%)
and pharmaceutical excipients. The granules are then
compressed to form an oral tablet. After oral intake,
the hydrocolloids absorb the gastric uid and are
activated to form a colloid gel matrix surrounding the
tablet surface (Fig. 22). The release of Valium molecules

BuccalMono

0
1000

Drug Delivery

Dose units/kg per day

400

1098

Drug Delivery: Controlled Release

is then controlled by diffusion through the gel barrier,

while the tablet remains buoyant in the stomach, due
to a density difference between the gastric uid
(d > 1) and the gelling tablet (d < 1).[2,3]

pH-Activated Drug Delivery Systems

For a drug labile to gastric uid or irritating to gastric
mucosa, this type of CrDDS has been developed to target the delivery of the drug only in the intestinal tract,
not in the stomach.[2] It is fabricated by coating a core
tablet ofthe gastric uid-sensitive drug with a combination of intestinal uid-insoluble polymer, like ethyl
cellulose, and intestinal uid-soluble polymer, like
hydroxylmethyl cellulose phthalate (Fig. 23).
In the stomach, the coating membrane resists the
degrading action of gastric uid (pH <3), and the drug
molecules are thus protected from the acidic degradation.
After gastric emptying, the CrDDS travels to the small
A
Hydrocolloids
(2075% w/w)

intestine, and the intestinal uid-soluble component

in the coating membrane is dissolved away by the
intestinal uid (pH >7.5). This produces a microporous membrane of intestinal uid-insoluble polymer
to control the release of drug from the core tablet.
The drug is thus delivered in a controlled manner in
the intestine by a combination of drug dissolution
in the core and diffusion through the pore channels.
By adjusting the ratio of the intestinal uid-soluble
polymer to the intestinal uid-insoluble polymer in
the membrane, the rate of drug delivery can be regulated. Representative application of this type of CrDDS
is in the oral controlled delivery of potassium chloride,
which is highly irritating to gastric epithelium.

Ion-Activated Drug Delivery Systems

For controlling the delivery of an ionic or an ionizable
drug, this type of CrDDS has been developed.[2]
Because the gastrointestinal uid has regularly maintained a relatively constant level of ions, the delivery
of drug by this type of CrDDS can be modulated, theoretically, at a constant rate.
Such a CrDDS is prepared by rst complexing an
ionizable drug with an ion-exchange resin, such as
Stomach
(pH < 3)

Colloid gel barrier

Gastric emptying

d<1

Coating of

Gastric fluidlabile drug

2000

Radioactivity in stomach

BuccalMono

Drug Delivery

Gastric fluid (d >1)

1000
800
600

Intestinal fluid-insoluble polymer

Intestinal fluid-soluble polymer

Intestinal fluid
(pH > 7.5)

Valrelease
(Placebo)

400
Valium
(Placebo)

200

100

Gastric fluidlabile drug

Microporous membrane
of intestinal fluidinsoluble polymer

Time (h)
Fig. 22 (A) Schematic illustration of Valrelease tablet, a
swelling-activated drug-delivery system, and the hydrationinduced formation of colloid gel barrier. (B) Comparison in
the gastric residence prole between Valrelease with the
conventional Valium capsule. (From Ref.[58].)

Drug

Fig. 23 Schematic illustration of a pH-activated drugdelivery system and the pH-dependent formation of microporous membrane in the intestinal tract.

Drug Delivery: Controlled Release

This type of CrDDS depends on the hydrolysis process

to activate the release of drug molecules. In this system, the drug reservoir is either encapsulated in microcapsules or homogeneously dispersed in microspheres
or nanoparticles. It can also be fabricated as an
implantable device. All these systems are prepared
from a bioerodible or biodegradable polymer, such as
polylactide, poly(lactideglycolide) copolymer, poly
(orthoester), or poly(anhydride). The release of a drug
from the polymer matrix is activated by the hydrolysisinduced degradation of polymer chains, and the rate of
drug delivery is controlled by polymer degradation
rate.[45] A typical example is the development of
Lupron Depot, an injectable microspheres for the
subcutaneous controlled delivery of luprolide, a potent
biosynthetic analog of gonadotropin-releasing hormone
(GnRH) for the treatment of gonadotropin-dependent
cancers, such as prostate carcinoma in men and endometriosis in the females, for up to 4 months. Another
example is the development of Zoladex system, an
implantable cylinder for the subcutaneous controlled
delivery of goserelin, also a potent biosynthetic analog
of GnRH for the treatment of patients with prostate
cancer (Fig. 25) for up to 3 months.[14]

FEEDBACK-REGULATED DRUG
DELIVERY SYSTEMS
In this group of CrDDSs, the release of drug molecules
is activated by a triggering agent, such as a biochemical
substance, in the body via some feedback mechanisms
(Fig. 2). The rate of drug release is regulated by the concentration of a triggering agent detected by a sensor
built into the CrDDS.
Bioerosion-Regulated Drug
Delivery Systems
The feedback-regulated drug delivery concept has been
applied to the development of a bioerosion-regulated
CrDDS by Heller and Trescony.[49] This CrDDS consists of a drug-dispersed bioerodible matrix fabricated
from poly(vinyl methyl ether) half-ester, which was
coated with a layer of immobilized urease (Fig. 26).
In a solution with near neutral pH, the polymer only
erodes very slowly. In the presence of urea, urease at

Drug-resin complex particles

Resin SO3
Resin [N(CH3)3

Polyethylene glycol treatment

Ethyl cellulose coating

Blood
Gut wall
Polymer
Drug

Ion
Coating
membrane
H + + Resin SO3 Drug+

Enzyme-Activated Drug Delivery Systems

In this type of CrDDS, the drug reservoir is either physically entrapped in microspheres or chemically bound
to polymer chains fabricated from biopolymers, such
as albumins or polypeptides. The release of drugs is

Drug+

+ ]Drug

CI + Resin [N(CH3)3 + ] Drug

ResinSO3 H + + Drug +
Resin [N(CH3)3+ ] CI + Drug

Fig. 24 Cross-sectional view of an ion-activated drugdelivery system, showing various structural components,
and diagrammatic illustration of ion-activated drug release.
(Adapted from Ref.[58].)

BuccalMono

Hydrolysis-Activated Drug
Delivery Systems

made possible by the enzymatic hydrolysis of biopolymers by a specic enzyme in the target tissue.[4648] A
typical example is the development of albumin microspheres, which release 5-uorouracil, in a controlled
manner, by protease-activated biodegradation.

Drug Delivery

complexing a cationic drug with a resin containing

SO3 group or an anionic drug with a resin containing
N(CH3)3 group. The granules of the drugresin complex are further treated with an impregnating agent,
like polyethylene glycol 4000, for reducing the rate of
swelling upon contact with an aqueous medium. They
are then coated by an air-suspension coating technique
with a water-insoluble but water-permeable polymeric
membrane, such as ethylcellulose. This membrane
serves as a rate-controlling barrier to modulate the
release of drug from the CrDDS. In the GI tract,
hydronium and chloride ions diffuse into the CrDDS
and interact with the drugresin complex to trigger
the dissociation and release of ionic drug (Fig. 24).
This type of CrDDS is exemplied by the development of Pennkinetic system (by Pennwalt Pharmaceuticals), which permits the formulation of oral
liquid-type dosage forms with sustained release of a
combination of hydrocodone and chlorpheniramine
(Tussionex).[14,4244]

1099

1100

Drug Delivery: Controlled Release

Drug-dispersed
polymer matrix

Micropores

0
0

Weeks

12

urease
2NH4+ + HCO3 + OH
H2O
alkaline
polymer
erosion
pH

urea

NH

Hydrocortisone

30
15
0
0

12

Weeks

Fig. 25 Amino acid sequence of goserelin, a biosynthetic

analog of gonadotropin-releasing hormone, and the effect
of subcutaneous controlled release of goserelin from the biodegradable poly(lactide-glycolide) implant on the serum
levels of luteinizing hormone and testosterone.

Hydrocortisone released (%)

Serum Testosterone
(nmol/L)

Serum LH (lU/L)

20

Urease
(Immobilized)

t-Bu

40

Leu Arg Pro Azgly

Poly (vinyl methyl ether) half-ester

(monolithic matrix)

u
u

u
(D)
Ser

Hydrocortisone

goserelin
Tyr

Hydrolytic erosion
Phase I: surface erosion
Phase II: bulk erosion

Glp His Trp Ser

100
80
60

20
0

BuccalMono

Drug Delivery

the surface of the drug delivery system metabolizes

urea to form ammonia. This causes the pH to increase
and activates a rapid degradation of polymer matrix as
well as the release of drug molecules.

Bioresponsive Drug Delivery Systems

The feedback-regulated drug delivery concept has also
been applied to the development of a bioresponsive
CrDDS by Horbett et al.[50]. In this CrDDS, the drug
reservoir is contained in a device enclosed by a bioresponsive polymeric membrane whose permeability to
drug molecules is controlled by the concentration of
a biochemical agent in the tissue where the CrDDS is
located.
A typical example of this bioresponsive CrDDS is
the development of a glucose-triggered insulin delivery
system, in which the insulin reservoir is encapsulated
within a hydrogel membrane containing pendant
NR2 groups (Fig. 27). In an alkaline solution, the
NR2 groups exist at neutral state and the membrane
is unswollen and thus impermeable to insulin. As
glucose penetrates into the membrane, it is oxidized
enzymatically by the glucose oxidase entrapped in the
membrane to form gluconic acid. This process triggers
the protonation of NR2 groups to form NR2H, and
the hydrogel membrane becomes swollen and is thus
permeable to insulin molecules (Fig. 27). The amount
of insulin delivered is bioresponsive to the concentration of glucose penetrating into the CrDDS.

urea (0.1 M)

40

20

40

60

80

100

120

140

160

Time (h)
Fig. 26 Cross-sectional view of a bioerosion-regulated
hydrocortisone delivery system, a feedback-regulated drug
delivery system, showing the drug-dispersed monolithic
bioerodible polymer matrix with surface-immobilized
ureases. The mechanism of release and time course for the
urea-activated release of hydrocortisone are also shown.
(From Ref.[49].)

Self-Regulating Drug Delivery Systems

This type of feedback-regulated CrDDS depends on a
reversible and competitive binding mechanism to activate and to regulate the release of drug. In this CrDDS,
the drug reservoir is a drug complex encapsulated
within a semipermeable polymeric membrane. The
release of drug from the CrDDS is activated by the
membrane permeation of a biochemical agent from
the tissue where the CrDDS is located.
Kim et al. rst applied the mechanism of reversible
binding of sugar molecules with lectin into the design
of self-regulating CrDDS.[51] For this CrDDS, a biologically-active insulin derivative, in which insulin is
coupled with a sugar (e.g., maltose), was rst prepared
and then conjugated with lectin to form an insulin
sugarlectin complex. The complex is then encapsulated within a semipermeable membrane to produce
CrDDS. As blood glucose diffuses into the CrDDS, it
binds, competitively, with the binding sites in the lectin

Drug Delivery: Controlled Release

1101

Amine-containing
hydrogel membrane

Glucose oxidase
NR2 ......
.. ..
.........
NR
NR2 . 2
........
.
NR2
..........
NR2

Insulin
reservoir

Polymer
membrane

Glucose in
G-Insulin out

Pancreatectomized dogs
300

200

Normoglycemic
level

100
F

F = Feeding

9am 3pm 9pm 3am 9am 3am 9pm

Time of day
Fig. 28 Various components of a self-regulating insulin
delivery system, a feedback-regulated drug delivery system,
and its control of blood glucose level in the pancreatectomized dogs. (From Ref.[53].)

Glucose

Glucose
NR2

Glycosylated (G) insulin

Concanavalin A

Oxidase
H+

Acidic pH

Gluconic acid
+
N R2H

Hydrogel membrane swells

N Enzyme
+
N R2 .... .. .
.
.
.
.
... . .. .
H
+
...........
N R2
..
H
+
N R2
H
Insulin
+
N R2
H ..........
+
..
N R2
H
Swollen membrane

Fig. 27 Cross-sectional view of a bioresponsive insulin

delivery system, a feedback-regulated drug delivery system,
showing the glucose oxidase-entrapped hydrogel membrane
constructed from amine-containing hydrophilic polymer.
The mechanism of insulin release, in response to the inux
of glucose, is also illustrated. (From Ref.[50].)

of multiple steps of diffusion and partitioning. The

CrDDSs outlined above generally address only the rst
step of this complex process. Essentially, these
CrDDSs have been designed to control the rate of drug
release from the delivery systems, but the path for the
transport of drug molecules from the delivery system
to the target tissue remains largely uncontrolled.
Ideally, the path of drug transport should also be
under control. Then, the ultimate goal of optimal treatment with maximal safety can be achieved. This can be
reasonably accomplished by the development of a
CrDDS with a site-targeting specicity (Fig. 2). An
ideal site-targeting CrDDS has been proposed by
Ringsdorf.[54] A model, which is shown in Fig. 29, is
constructed from a non-immunogenic and biodegradable polymer and acts as the backbone to contain three
types of attachments: 1) a site-specic targeting moiety,
which is capable of leading the drug delivery system to
the vicinity of a target tissue (or cell); 2) a solubilizer,
which enables the drug delivery system to be transported to and preferentially taken up by a target tissue;
and 3) a drug moiety, which is convalently bonded to
the backbone, through a spacer, and contains a linkage
that is cleavable only by a specic enzyme(s) at the
target tissue.

BuccalMono

Delivery of a drug to a target tissue that needs medication is known to be a complex process that consists

(Biochemical Approach)

Drug Delivery

SITE-TARGETING DRUG DELIVERY SYSTEMS

Self-Regulating Insulin Delivery Systems

Blood glucose level (mg/dl)

molecules and activates the release of the insulinsugar

derivatives from the binding sites. The released insulinsugar derivatives diffuse out of the CrDDS, and the
amount of insulin-sugar derivatives released depends
on the concentration of glucose. Thus, a self-regulating
drug delivery is achieved. However, a potential problem has remained to be resolved: that is, the release
of insulin is non-linear in response to the changes in
glucose level.[52]
Further development of the self-regulating insulin
delivery system has utilized the complex of glycosylated insulinconcanavalin A, which is encapsulated
inside a polymer membrane.[53] As glucose penetrates
into the system, it activates the release of glycosylated
insulin from the complex for a controlled release from
the system (Fig. 28). The amount of insulin released is
thus self-regulated by the concentration of glucose that
has penetrated into the insulin delivery system.

1102

Drug Delivery: Controlled Release

Polymer backbone
(nonimmunogenic
and blodegradable)

Site-specific
targeting
moiety

Spacer

Solubilizer

5.
Cleavable
group

Enzyme
(at target tissue)

Facilitate systemic
distribution
and tissue uptake

Drug

Cell of
target tissue

4.

6.
7.

Drug

Drug

8.

9.
Cell membrane

10.
11.
12.

Fig. 29 An ideal site-targeting controlled-release drug

delivery. (From Ref.[54].)

BuccalMono

Drug Delivery

Unfortunately, this ideal site-targeting CrDDS is

only in the conceptual stage. Its construction remains
largely unresolved and is still a challenging task in
the biomedical and pharmaceutical sciences.

13.
14.
15.
16.

CONCLUSIONS

17.

The controlled-release drug delivery systems outlined

here have been steadily introduced into the biomedical
community since the middle of the 1970s. There is a
growing belief that many more of the conventional
drug delivery systems we have been using for decades
will be gradually replaced in the coming years by these
CrDDSs.

18.

19.
20.
21.

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Drug Delivery: Controlled Release