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. John’s University,
Jamaica, New York, U.S.A.
INTRODUCTION
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 sys-
tem several times a day. This yields an undesirable
‘‘seesaw’’ drug level in the body (Fig. 1).
A number of advancements have been made
Drug Delivery
Buccal–Mono
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 thera-
peutic action, and/or targeting the delivery of drug to
a specific tissue.[1–6] These advancements have already
led to the development of several novel drug delivery
systems that could provide one or more of the follow-
ing benefits:
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 efficacy-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 classified (Fig. 2)
as follows:
1. Rate-preprogrammed drug delivery systems.
2. Activation-modulated drug delivery systems.
Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001051
1082
3. Feedback-regulated drug delivery systems.
4. Site-targeting drug delivery systems.
In this article, the scientific 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 specific rate profile. 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. Fick’s laws of dif-
fusion are often followed. These CrDDSs can further
be classified as follows:
1. Polymer membrane permeation-controlled drug
delivery systems.
2. Polymer matrix diffusion-controlled drug deliv-
ery systems.
3. Polymer (membrane/matrix) hybrid-type drug
delivery systems.
4. Microreservoir partition-controlled drug deliv-
ery 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 poly-
meric membrane can be fabricated from a homogeneous
Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.
Drug Delivery: Controlled Release 1083

A C
A4 Adverse side effects Sphere Sheet
Polymer
coating
Drug concentration

Toxic level Drug

A3 reservoir
A2 B
A1 Therapeutic range
Cylinder Pore
B
Drug
Minimum effective Drug release impermeable
concentration Drug barrier
reservoir Nonporous
No therapeutic membrane
effects
D Diffusion layer Porous membrane
1 2 3 4 Cp
Cp
Frequencies of dosing Pd
Pm Cm Cb Sink
Fig. 1 Drug concentration profiles in the systemic circu- Cs
Dm Da Elution medium
lation as a result of taking a series of multiple doses of a con-
ventional drug-delivery system (A1, A2, . . . ) in comparison hd
with the ideal drug concentration profile (B). (Adapted from hm
Ref.[6].)
Fig. 3 Release of drug from various shapes of polymer
membrane permeation-controlled drug-delivery systems: (A)
or a heterogeneous non-porous polymeric material or sphere-type, (B) cylinder-type, and (C) sheet-type. In (D),
a microporous or semipermeable membrane. The the drug concentration gradients across the rate-controlling
polymeric membrane and hydrodynamic diffusion layer exist
encapsulation of drug formulation inside the reservoir
in series. Both the polymer membrane, which is either porous
compartment can be accomplished by molding, cap-
or non-porous, and the diffusion layer have a controlled
sulation, microencapsulation, or other techniques. thickness (hm and hd, respectively).
Different shapes and sizes of drug delivery systems
can be fabricated (Fig. 3).
The release of drug from this type of CrDDSs Dm, and Dd are, respectively, the diffusion coefficients

should be at a constant rate (Q/t), which is defined
by the following general equation:
Q Km=r Ka=m Dd Dm
¼ CR
t Km=r Dm hd þ Ka=m Dd hm
where Km/r and Ka/m are, respectively, the partition-
coefficients for the interfacial partitioning of drug
molecules from the reservoir to the membrane and
from the membrane to the aqueous diffusion layer;
Drug Delivery
Buccal–Mono
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
ð1Þ 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 mod-
ulating the partition coefficient and the diffusivity of
drug molecule and the rate-controlling membrane
and the thickness of the membrane. Several CrDDSs

A B C D
Rate-controlling Rate-controlling Rate-controlling Drug Rate-controlling
Drug Drug Drug
surface surface surface reservoir surface
reservoir reservoir reservoir

Drug Drug
Drug Drug
Site-
targeting
moiety

Energy sensor Biochemical responsive/ Biochemical responsive/

Energy sensor Energy sensor

Fig. 2 The four major classes of controlled-release drug delivery systems: (A) Rate-preprogrammed DDS; (B) Activation-modu-
lated DDS; (C) Feedback-regulated DDS and (D) Site-trageting DDS.
 1084 Drug Delivery: Controlled Release

of this type have been successfully marketed for thera- 305μ

13.4mm 74 μ
peutical uses and some representatives are outlined
later for illustration.

5.7mm
Ethylene/vinyl acetate membrane
Pilocarpine-core reservoir
Titanium dioxide-white ring
ProgestasertÕ IUD
60
In this controlled-release intrauterine device, the drug

Pilocarpine release rate

reservoir exists as a dispersion of progesterone crystals
in silicone (medical grade) fluid encapsulated in the 40

(mcg/hr)
vertical limb of a T-shaped device walled by a non-
porous membrane of ethylene–vinyl acetate copolymer
(Fig. 4). It is engineered to release continuously a daily 20
dose of 65 mg progesterone inside the uterine cavity to
achieve contraception for one year.[6] The same tech-
nology has been utilized in the development of the 0
MirenaÕ system, a plastic T-shaped frame with a ster- 0 1 2 3 4 5 6 7 8 9
Time (days)
oid reservoir containing 52 mg levonorgestrel, which is
designed to release a daily dose of levonorgestrel at Fig. 5 Diagrammatic illustration of a unit of OcusertÕ sys-
20 mg/day for achieving effective contraception for tem, showing various structural components, and the ocular
five years.[7–9] release rate profile of pilocarpine from the Ocusert pilo-20
system. (From Ref.[11].)
OcusertÕ system

In this controlled-release ocular insert, the drug reser-
voir is a thin disc of pilocarpine–alginate complex
sandwiched between two transparent discs of micro-
porous membrane fabricated from ethylene–vinyl
Drug Delivery
Buccal–Mono
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 man-
agement of glaucoma.[1,6,10,11]

acetate copolymer (Fig. 5). The microporous mem-

branes permit the tear fluid to penetrate into the drug Transderm-NitroÕ system

In this controlled-release transdermal therapeutic

system, the drug reservoir, which is a dispersion of
A
Polyethylene nitroglycerin–lactose triturate in a silicone (medical
grade) fluid, is encapsulated in an ellipsoid-shaped thin
patch. The drug reservoir is sandwiched between a drug-
impermeable metallic plastic laminate, as the backing
Ethylene membrane, and a constant surface of drug-permeable,
vinylacetate rate-controlling membrane of ethylene–vinyl acetate
copolymer copolymer (Fig. 6). This device is fabricated by an
38 mg of progesterone microcrystals injection-molding process. A thin layer of silicone
(and barium sulfate) adhesive is further coated on the drug-permeable
suspended in silicone oil
membrane in order that an intimate contact of the
B drug-releasing surface with the skin surface is achieved
In Vitro In Vivo and maintained. It is engineered to have nitroglycerin
100
delivered transdermally at a rate of 0.5 (mg/cm2)/day
95% Confidence Level
80
100 for a daily relief of angina.[2,3]
μg/day

80
60 60 The same technology has been utilized in the develop-
40 40 ment of the following: 1) the EstradermÕ system, which
20 20
0 0 administers a controlled dose of estradiol transdermally
0 100 200 300 400 0 100 200 300 400 over 3–4 days for the relief of postmenopausal syndrome
Days Days and osteoporosis;[12–14] 2) the DuragesicÕ system, which
Fig. 4 Diagrammatic illustration of a unit of Progestasert provides a transdermal-controlled administration of
IUD, showing various structural components (A) and the fentanyl, a potent narcotic analgesic, for 72-h relief
in vitro and in vivo delivery rate profiles of progesterone of chronic pain;[14] and 3) the AndrodermÕ system,
for up to 400 days (B). which provides a transdermal-controlled delivery of
Drug Delivery: Controlled Release
Drug reservoir Drug-impermeable
metallic plastic laminate
Adhesive layer
0.25
Plasma nitroglycerin conc.
0.20
(ng/ml ± SD)
0.15
Night Period
0.10
0.05
0 in the polymer matrix; and Dp is the diffusivity of the
0 5 10 15
Time (h)
Fig. 6 Cross-sectional view of a unit of Transderm-NitroÕ
system, showing various structural components, and plasma
concentration profiles 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-deficient patients.[14]
NorplantÕ 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 levonorges-
trel in silicone elastomer matrix (generation II). It is
designed to attain a continuous release of levonorges-
trel, at a daily dosage rate of 30 mg, to each subject (fol-
lowing the subcutaneous implantation of either 6 units
of I or 2 units of II); (Fig. 7) for up to 7 years.[15–18]
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
1085
by either 1) blending a dose of finely ground drug
particles with a viscous liquid (or a semisolid) poly-
mer, followed by a crosslinking of polymer chains
or 2) mixing drug solids with a melted polymer at
Rate-controlling
polymeric membrane
an elevated temperature. The resultant drug-polymer
dispersion is then molded or extruded to form drug-
delivery devices of various shapes and sizes designed
for a specific 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 profile of drug from this matrix dif-
fusion-controlled CrDDS is not constant, because the
rate of drug release is time dependent as defined by:
Q
ð2Þ
t1=2 ¼ ð2ACR DP Þ1=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
20 25
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
Drug Delivery
matrix. Several CrDDSs of this type have been suc-
Buccal–Mono
cessfully marketed for therapeutical uses, and some
representatives are outlined later for illustration.
Nitro-DurÕ system
This controlled-release transdermal therapeutic system
is fabricated by first 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 solidified
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 flat sheet of drug-impermeable
backing support to form a single- or multiple-layer drug
reservoir. This type of transdermal CrDDS (TDD)
 1086 Drug Delivery: Controlled Release

Milligrams Milligrams
216 total load of levonorgestrel 216
~
~ ~
~
90 daily dose 30 μg 90
70 70

50 50
30 30

10 10
1 2 3 4 5 6
Years of use

Concentration of
Levonorgestrel in plasma

ORAL
1.00
Peak (mean)
0.75

0.50
NONPLANT SUBCERNAL INPLANTS
Mean value and
0.25 95% confidence 2.4 mm
intervals
Trough (mean) 34 mm

24 hr 1 2 3 4 5
Time of use (years)
Drug Delivery
Buccal–Mono

Fig. 7 Diagrammatic illustration of the subcutaneous implantation of NorplantÕ implants. The subcutaneous release profile of
levonorgestrel in female volunteers for up to 6 years and the resultant plasma profile as compared to those obtained by oral
administration. (Adapted from Refs.[15–18].)

is best illustrated by the development and marketing
of an isosorbide dinitrate-releasing TDD system,
named FrandolÕ tape, by Toaeiyo/Yamanouchi in
Japan, and of a nitroglycerin-releasing TDD system,
named Nitro-DurÕ 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. Nitro-
Dur II compares favorably with Nitro-Dur (Fig. 10)
and has gradually replaced the first-generation
Nitro-Dur from the marketplace. The same technical
basis has been also utilized in the development of
the following: 1) HabitrolÕ and NicotrolÕ systems,
which provide a controlled dose of nicotine transder-
mally over 24 h for smoking cessation;[14] 2) MinitranÕ
system, which administers a controlled dose of nitrogly-
cerin transdermally over 24 h for the relief of anginal
attacks;[14] 3) TestodermÕ system, which administers a
controlled delivery of testosterone for transdermal per-
meation through a scrotal skin[14] for the replacement
therapy of testosterone-deficient patients for 24 h; and
4) ClimaraÕ system, which provides a controlled
delivery of 17b-estradiol for transdermal permeation
for once-weekly treatment of vasomotor systems[14]
associated with menopause.
CompudoseÕ 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
steer’s ear flap for a duration of 200 or 400 days, dur-
ing which a controlled quantity of estradiol is released
daily for growth promotion.[20]
To improve the Q versus t1/2 drug release profiles
[Eq. (2)], this polymer matrix diffusion-controlled
CrDDS can be modified to have the drug-loading
level varied, in an incremental manner, to form a gradi-
ent of drug reservoir along the diffusional path in the
polymer matrix. A constant drug release profile is thus
Drug Delivery: Controlled Release 1087

A B Furthermore, it was recently demonstrated that the

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

Drug depletion Gel layer

zone 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 poly-
mer membrane permeation-controlled drug delivery
systems with the mechanical superiority of polymer
C
matrix diffusion-controlled drug delivery systems.
Receding boundary
depletion zone The release profile of drug from a sandwich-type drug
Drug reservoir delivery system (Fig. 13) is constant, and the instan-
Diffusion layer taneous rate of drug release is defined by:
dQ ACp Dp
A Matrix Elution medium ¼  2 ð4Þ
dt Dp Km ð1=Pm þ 1=Pd þ 4ACp Dp t1=2
CR
Dp
Perfect sink where A is the initial amount of drug solid impregnated
in a unit volume of polyer matrix with solubility Cp
hd and diffusivity Dp; Km is the partition coefficient for
the interfacial partitioning of drug molecules from
hp + dhp
polymer matrix toward polymer coating membrane;

Drug Delivery
Pm is the permeability coefficient of the polymer coat-

Fig. 8 Release of drug from the polymer matrix diffusion-
controlled 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 þ 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
defined by:
dQ Ka=r Da
¼ Cp ðha Þ
dt ha ðtÞ
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 profile is thus obtained. This
type of CrDDS is best illustrated by the nitroglycerin-
releasing DeponitÕ system (Fig. 12), first marketed
by Pharma-Schwartz/Lohmann in Europe.[21] Wyeth-
Ayerst has received FDA approval for marketing this
system in the United States.
Buccal–Mono
ing membrane with thickness hm; and Pd is the per-
meability coefficient of the hydrodynamic diffusion
layer with thickness hd.
The hybrid system is exemplified by the develop-
ment of clonidine-releasing and scopolamine-releasing
transdermal therapeutic systems (Catapres-TTSÕ
and Transderm-ScopÕ) (Fig. 14), in which a rate-
controlling non-medicated polymeric membrane is
added to coat the surface of the drug-dispersing poly-
mer 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 (NorplantÕ II).
ð3Þ
Microreservoir Partition-Controlled
Drug Delivery Systems
In this type of CrDDS, the drug reservoir is a suspen-
sion 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 biocom-
patible 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
 1088 Drug Delivery: Controlled Release

Absorbent pad
Occlusive baseplate Impermeable backing
(aluminum foil) (polyethylene coverstrip)

Adhesive rim
(microporous acrylic polymer tape) Drug reservoir
(drug/hydrophilic polymer matrix)

0.8
Plasma nitroglycerin conc.

0.6
(ng/ml ± SEM)

Night Period
0.4 off

0.2
Drug Delivery
Buccal–Mono

0
0 5 10 15 20 25
Time (h)

Fig. 9 Cross-sectional view of a unit of Nitro-DurÕ system, showing various structural components, and the plasma nitrogly-
cerin concentration profiles in six human volunteers, each receiving 1 unit of Nitro-DurÕ system (20 cm2, with a delivery rate of
10 mg/day) for 24 h. (From Refs.[55–56].)

microreservoir-type CrDDS by molding or extrusion the polymer coating membrane over drug solubility
techniques. Depending upon the physicochemical in the same polymer. Kl, Km, and Kp are, respectively,
properties of drugs and the desired rate of drug release, the partition coefficients for the interfacial partitioning
the device can be further coated with a layer of bio- of drug from the liquid compartments to the polymer
compatible polymer to modify the mechanism and matrix, from the polymer matrix to the polymer coat-
the rate of drug release. ing membrane, and from the polymer coating mem-
The rate of drug release (dQ/dt) from this type of brane to the elution solution, whereas Dl, Dp, and Dd
CrDDS is defined by: are, respectively, the diffusivities of the drug in the
liquid layer surrounding the drug particles, the poly-
dQ Dp Dd mKp
¼ mer coating membrane enveloping the polymer matrix,
dt Dp hd þ Dd hp mKp and the hydrodynamic diffusion layer surrounding the
  
Dl Sl ð1  nÞ 1 1 polymer coating membrane with respective thicknesses
 nSp  þ ð5Þ of hl, hp, and hd (Fig. 15); and Sl and Sp are the solubi-
ht Kl Km
lities of the drug in the liquid compartments and in the
where m ¼ a/b and n is the ratio of drug concen- polymer matrix, respectively.
tration at the inner edge of the interfacial barrier over The release of drug from the microreservoir-type
the drug solubility in the polymer matrix,[1,6] in which a CrDDS can follow either a dissolution- or a matrix
is the ratio of drug concentration in the bulk of elution diffusion-control process, depending upon the relative
solution over drug solubility in the same medium and b magnitude of Sl and Sp.[24] Representatives of this type
is the ratio of drug concentration at the outer edge of of CrDDS is outlined below.
Drug Delivery: Controlled Release 1089

Drug-loaded Impermeable film Silicone rod

adhesive

Release liner
1000
Estradiol-releasing
500 polymer matrix
Nitroglycerin (pg/ml)

250
75%
1.0
100 40%

50 0.8

25 20%

Q (mg/cm2)
0.6
10
0 5 10 15 20 25
Time (h)
0.4
Fig. 10 Cross-sectional view of Nitro-Dur II, showing
various structural components, and the comparative 24 h
plasma nitroglycerin concentration profiles in 24 healthy 0.2
male volunteers, each receiving randomly 1 unit of Nitro-
Dur 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 0.0
(the arrow indicates unit removal). (From Ref.[56].) 0 1 2 3 4
(Days)½

Nitrodisc system Õ subdermal implant and in vitro release profiles of estradiol
In this transdermal CrDDS (Fig. 16), the drug reser-
voir 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 tech-
nique 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 profile
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 high-
energy dispersion technique.[24] After adding catalyst,
Drug Delivery
Buccal–Mono
Fig. 11 Diagrammatic illustration of a unit of CompudoseÕ
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 polymer-
ized 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 live-
stock’s ear flap; 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 profile has
been achieved, as compared to the Q versus t1/2 release
profile (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
 1090 Drug Delivery: Controlled Release

Drug-impermeable chemical, or biochemical processes and/or facilitated by

metallic plastic laminate 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
R1
activation-modulated CrDDSs can be classified into
R2 Drug reservoir the following categories:
gradient layers
R3 (R1 > R2 > R3)
1. Physical means
a. Osmotic pressure-activated drug delivery
Adhesive layer systems
b. Hydrodynamic pressure-activated drug
400 delivery systems
Cmax = 255 ± 151 pg/ml (tmax = 3.6 ± 3.5 h) c. Vapor pressure-activated drug delivery
Css = 125 ± 50 pg/ml (8-24 h) systems
Plasma nitroglycerin conc. (pg/ml)

AUC = 3.3 ± 1.6 ng·h/ml

d. Mechanical force-activated drug delivery
200 systems
e. Magnetics-activated drug delivery systems
f. Sonophoresis-activated drug delivery systems
g. Iontophoresis-activated drug delivery systems
100 h. Hydration-activated drug delivery systems

80 2. Chemical means

60 Dose = 5.0 ± 0.7 mg/day (n = 6) a. pH-activated drug delivery systems

4.5 ± 0.8 mg/day (n = 17) b. pH-activated drug delivery systems
c. Ion-activated drug delivery systems
40 d. Hydrolysis-activated drug delivery systems
Drug Delivery

0 4 8 12 16 20 24
Buccal–Mono

Duration of Device/Skin contact (h) 3. Biochemical means

Fig. 12 Cross-sectional view of a unit of DeponitÕ system, a. Enzyme-activated drug delivery systems
showing various structural components, and the plasma b. Biochemical-activated drug delivery systems
nitroglycerin concentration profiles in six human volunteers,
each receiving 1 unit of Deponit system (16 cm2, with a deliv- Several CrDDSs have been successfully developed
ery rate of 5 mg/day) for 24 h. (Plasma profiles are plotted and applied clinically to the controlled delivery of
from data from Ref.[21].) pharmaceuticals and biopharmaceuticals. These are
outlined and discussed below.

a dual-controlled release of levonorgestrel, a potent

synthetic progestin, and estradiol, a natural estrogen, Osmotic Pressure-Activated Drug
at constant and enhanced rates, continuously, for a Delivery Systems
period of 7 days.[5] By applying 1 unit (10 or 20 cm2)
of transdermal contraceptive device per week, beginning In this type of CrDDSs, the drug reservoir, which can
on day 5 of an individual’s menstrual cycle, for 3 be either a solution or a solid formulation, is con-
consecutive weeks (3 weeks on and 1 week off), steady- tained within a semipermeable housing with a con-
state serum levels of levonorgestrel have been obtained, trolled water permeability. The drug in solution is
and the secretion of gonadotropins and progesterone released through a special laser-drilled delivery orifice
have been effectively suppressed. 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
ACTIVATION-MODULATED DRUG defined by:
DELIVERY SYSTEMS

In this group of CrDDSs, the release of drug molecules Q Pw Am

¼ ðps  pe Þ ð6Þ
from the delivery systems is activated by some physical, t hm
Drug Delivery: Controlled Release 1091

Sphere

Cylinder

hp(t) hm hd

Drug Delivery
Buccal–Mono
A Drug
reservoir Dp Dm Dd
CR
Perfect sink
pm pd (Cb = 0)

Polymer matrix Drug Polymer Diffusion Solution

depletion coating layer bulk
zone membrane

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 DRUG-IMPERMEABLE
BACKING LAMINATE
constant and is defined by:
ADHESIVE LAYERS
DRUG-DISPERSING

MICROPOROUS

Q P w Am
¼ ðps  pe ÞSd ð7Þ
MEMBRANE

t hm

where Pw, Am, and hm are, respectively, the water per-

meability, the effective surface area, and the thickness
of the semipermeable housing; (ps  pe) is the differen-
tial osmotic pressure between the drug-delivery system
with an osmotic pressure of ps and the environment
DRUG MOLECULES
Fig. 14 Cross-section view of various structural components
in the Transderm-ScopÕ and Catapres-TTSÕ systems.
 1092 Drug Delivery: Controlled Release

Polymer matrix
(cross-linked, solid)

Drug reservoir
(microscopic liquid
compartments)

Coating membrane

Polymer/Solution interface
Drug Delivery
Buccal–Mono

δl δm δd
Interfacial
barrier

Polymer matrix
Dp
Liquid Dm Ds
layer
Solution
sink
Cp
Dl Cp' Cm
Cp'

Drug
particle
Cd
Cb = O
Sl Cl Cm'

Polymer Diffusion
coating layer
membrane

Fig. 15 Microscopic view of a microreservoir-type drug-delivery system, which shows the microscopic structure of various com-
ponents, 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 thera-
peutical uses and some representatives are outlined
later.
Drug Delivery: Controlled Release
Occlusive baseplate
(aluminum foil disc)
Microscopic drug reservoirs
(drug/co-solvents)
Adhesive rim
(acrylic polymer coating) Polymer matrix
(silicone elastomer)
0.6
0.5
Plasma nitroglycerin
conc. (ng/ml ± SEM)
Night Period
0.4
0.3
0.2
(C plasma)ss
0.1
0.0
0 4 8 12 16
Time (h)
Fig. 16 Cross-sectional view of a unit of Nitrodisc system,
showing various structural components, and the plasma
nitroglycerin concentration profiles 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 res-
ervoir, 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 mem-
brane (Fig. 19). At an implantation site, the water
content in the tissue fluid 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
flexible 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
flow 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 1–4 weeks.
In addition to its application in the subcutaneous
controlled administration of drugs for pharmacologi-
cal studies, this technology has recently been extended
to the controlled administration of drugs in the rectum
by zero-order kinetics. The hepatic first-pass metab-
olism of drugs is thus bypassed.[29]
1093
Adhesive foam pad Drug
(flexible polyurethane) reservoir
Polymer coating
membrane
Open ends Medicated MDD core
100
Fraction of drug released (%)
80
60
40
20
20 24 28 32
0
0 5 10 15 20 25 30
Õ Days of implantation
Fig. 17 Syncro-Mate-C implant, a subdermal implant fabri-
cated from the microreservoir dissolution-controlled drug-
delivery system, and subcutaneous controlled release of nor-
gestomet, a potent synthetic progestin, at constant rate for 20
days. The open ends on the implant do not affect the zero-
order in vivo drug release profile. (Adapted from Ref.[57].)
Drug Delivery
Buccal–Mono
AcutrimÕ tablet
In this oral CrDDS, the drug reservoir, which is a solid
tablet of water-soluble and osmotically-active phenyl-
propanolamine (PPA) HCl, is enclosed within a semi-
permeable 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 gastro-
intestinal fluid 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 orifice 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 weight-
control 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 pressure-
activated 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.
 1094 Drug Delivery: Controlled Release

A hydrophilic polymer layer is sandwiched between the

288 drug reservoir compartment and the housing. In the
10 Sq. cm - Patch (n=6) gastrointestinal tract, the laminate will imbibe the gas-
Concentration (pg/ml ± S.E.)

240 20 Sq. cm - Patch (n=6) trointestinal fluid through the annular openings at the
lower end of the housing and become swollen. This
192 generates a hydrodynamic pressure in the system.
The hydrodynamic pressure, thus created, forces the
144
drug reservoir compartment to reduce in volume and
96 causes the liquid drug formulation to release through
the delivery orifice.[32] The drug release rate is
48 defined by:

0 Q Pf Am
0 168 336 504 672 ¼ ðys  ye Þ ð8Þ
m mm mm m p p
t hm
Duration of study (h)
where Pf, Am, and hm are the fluid permeability, the
B effective surface area, and the thickness of the wall
30
Subject Code MM Subject Code MG
with annular openings, respectively; and ys  ye, is
the difference in hydrodynamic pressure between the
Serum progesterone (ng/ml)

(Group A: 1 TCD patch) (Group B: 2 TCD patch)

25 drug delivery system (ys) and the environment (ye).
Pretreatment Pretreatment
Treatment Treatment The release of drug molecules from this type of
20
CrDDS is activated by hydrodynamic pressure and
15 controlled at a rate determined by the fluid per-
meability and effective surface area of the wall with
10 annular openings as well as by the hydrodynamic
Tmax
Tmax pressure gradient.
5
Drug Delivery
Buccal–Mono

0 Vapor Pressure-Activated
0 10 20 30 40 0 10 20 30 40
Day of menstrual cycle Drug Delivery Systems

Fig. 18 (Upper panel) The 4–week serum levonorgestrel In this type of CrDDS, the drug reservoir, which is a
profiles in 12 human volunteers, each receiving 1 or 2 units solution formulation, is contained inside the infusion
of a transdermal contraceptive system (10 cm2, with daily compartment. It is physically separated from the
dosage of 28.3 mg/day) once a week, consecutively for 3 pumping compartment by a freely movable partition
weeks, and the same size of placebo on week 4. (Lower panel)
(Fig. 21). The pumping compartment contains a vapor-
Comparative serum concentration profiles of progesterone
during the pretreatment and treatment cycles in two subjects,
izable fluid, such as fluorocarbon, which vaporizes at
each as the representative for group A (receiving 10 cm2) and body temperature and creates a vapor pressure. Under
group B (receiving 20 cm2), respectively. The suppression of the vapor pressure created, the partition moves upward
progesterone peak during the treatment cycle is an indication and forces the drug solution in the infusion compart-
of effective fertility control. ment to be delivered, through a series of flow regulator
and delivery cannula, into the blood circulation at a
constant flow rate.[1,6,33] The process is defined by:
Hydrodynamic Pressure-Activated
Drug Delivery Systems Q d4 dP
¼ ð9Þ
t 40:74ml
In addition to the osmotic pressure systems discussed
above, hydrodynamic pressure has also been explored where d and l are, respectively, the inner diameter and
as the potential source of energy to modulate the deliv- thelength of the delivery cannula; Dp is the pressure
ery of therapeutic agents.[2] difference between the vapor pressure in the pumping
A hydrodynamic pressure-activated drug-delivery compartment and the pressure at the implantation site;
system can be fabricated by placing a liquid drug for- and m is the viscosity of the drug formulation.
mulation inside a collapsible, impermeable container The delivery of drug from this type of CrDDS is
to form a drug reservoir compartment. This is then activated by vapor pressure and controlled at a rate
contained inside a rigid, shape-retaining housing. A determined by the differential vapor pressure, the for-
laminate of an absorbent layer and a swellable, mulation viscosity, and the size of the delivery cannula.
Drug Delivery: Controlled Release 1095

A B
200
Urine volume
(% of Pretreatment control + S.D.)
Drug solution leaving
175 via delivery portal

150
Daily urine volume

Pump Pump
Removable cap
125 implanted removed Flange
Flow moderator
100
Neck Plug
75

50

25 Flexible impermeable
reservoir wall
0
0 3 6 9 12 15 Osmotic agent

3000
Urine osmolality

2500
(mOsm/ kg H2O + S.D.)

Semipermeable
Urine osmolalilty

2000 membrane
Water entering
1500
semipermeable
membrane
1000
Pump Pump Reservoir
implanted removed
500

0
0 3 6 9 12 15

Drug Delivery
Time (day)

Buccal–Mono
Fig. 19 (A) Cross-sectional view of the AlzetÕ 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 InfusaidÕ, its synthetic analogs, such as buserelin. Through nasal
an implantable infusion pump by Metal Bellows, for absorption, the hepatic first-pass elimination of these
the constant infusion of heparin in anticoagulation peptide drugs is thus avoided.[24]
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] Magnetic-Activated Drug Delivery Systems

Macromolecular drugs, such as peptides, have been

Mechanical Force-Activated known to release only at a relatively low rate from a
Drug Delivery Systems polymer-controlled drug-delivery system. This low rate
of release can be improved by incorporating an electro-
In this type of CrDDS, the drug reservoir is a solution magnetism-triggering vibration mechanism into the
formulation in a container equipped with a mechani- polymeric delivery device. With a hemispheric-shaped
cally activated pumping system. A metered dose of design, a zero-order drug-release profile is achieved.[36]
drug formulation can be reproducibly delivered into By combining these two approaches, a subdermally
a body cavity, such as the nose, through the spray head implantable, magnetic-activated hemispheric drug-
upon manual activation of the drug-delivery pumping delivery device is developed. It is fabricated by first
system. The volume of solution delivered is fixed and positioning a tiny doughnut-shaped magnet at the cen-
is independent of the force and duration of activation. ter of a drug-dispersing biocompatible polymer matrix
A typical example of this type of drug-delivery sys- and then coating the external surface of the medicated
tem is the development of a metered-dose nebulizer for polymer matrix, with the exception of one cavity at the
the intranasal administration of a precision dose of center of the flat surface, with a pure polymer, for
luteinizing hormone-releasing hormone (LHRH) and instance, ethylene–vinyl acetate copolymer or silicone
 1096 Drug Delivery: Controlled Release

Delivery orifice molecule across a biological membrane, such as the

Semi-permeable coating
skin, in a manner similar to passive diffusion under a
Drug reservoir/ Controlled-release concentration gradient but at a much facilitated rate.
osmotically active dose Immediate releasing layer The iontophoresis-facilitated skin permeation rate of
solutes (initial dose)
a charged molecule i consists of three components
and is expressed by:
Cumulative % loading dose released

100 12.16 atm

30.16 atm

80
54.16 atm
Jiisp ¼ J p þ J e þ J c
114.0 atm    
dC Zi Di Fi dE
¼ Ks Ds Ci þ ðkCs Id Þ ð10Þ
60 hs RT hs

40 where J p, J e, and J c represent, respectively, the flux for

20
0 coefficient for interfacial partitioning from the donor
4 8 12
Time (h)
Fig. 20 Cross-sectional view of a unit of AcutrimÕ tablet, a
solid-type osmotic pressure-activated drug delivery system,
and the effect of increased osmotic pressure in the dissolution
medium on the release profiles of phenylpropanolamine HCl
from the Acutrim tablet at intestinal condition. (Adapted
from Refs.[31,58].)
elastomers. This uncoated cavity is designed for allow-
Drug Delivery
the skin permeation by passive diffusion, for the elec-
trical current-driven permeation, and for the convec-
tive flow-driven skin permeation; Ks is the partition
16 20 24
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 fara-
day, proportionality, and gas constant; and T is the

ing a peptide drug to release. absolute temperature.

Buccal–Mono

The hemispheric magnetic delivery device produced A typical example of this type of activation-
can release macromolecular drugs, like bovine serum controlled CrDDS is the development of an iontophore-
albumin, at a low basal rate, by diffusion process, and tic drug delivery system, named Phoresor by Motion
under a non-triggering condition, or it can release the Control, to facilitate the percutaneous penetration of
same drug at a much higher rate, when the magnet is acti- antiinflammatory drugs, such as dexamethasone sodium
vated, to vibrate by an external electromagnetic field. phosphate,[39–41] to surface tissues.
Further development of the iontophoresis-activated
drug delivery technique has yielded a new design of
Sonophoresis-Activated Drug iontophoretic drug delivery system—the transdermal
Delivery Systems periodic iontotherapeutic system (TPIS). This new sys-
tem, which is capable of delivering a physiologically-
This type of activation-controlled drug delivery system acceptable pulsed direct current, in a periodic manner,
utilizes ultrasonic energy to activate (or trigger) the with a special combination of waveform, intensity, fre-
delivery of drugs from a polymeric drug delivery quency, and on/off ratio, for a specific duration, has
device. The system can be fabricated from either a significantly improved the efficiency of transdermal
non-degradable polymer, such as ethylene–vinyl acet- delivery of peptide and protein drugs.[4] A typical
ate copolymer, or a bioerodible polymer, such as poly example is the iontophoretic transdermal delivery of
[bis(p-carboxyphenoxy)alkane anhydride].[37] The insulin, a protein drug, in the control of hyperglycemia
potential application of sonophoresis (or phonophor- in diabetic animals.
esis) to regulate the delivery of drugs was recently
reviewed.[38]

Hydration-Activated Drug Delivery Systems

Iontophoresis-Activated Drug
Delivery Systems In this type of CrDDS, the drug reservoir is homoge-
neously dispersed in a swellable polymer matrix fabri-
This type of CrDDS use electrical current to activate cated from a hydrophilic polymer. The release of drug
and to modulate the diffusion of a charged drug is activated and modulated by hydration-induced
Drug Delivery: Controlled Release 1097

Bacterial Inlet
filter septum
assembly Needle stop

Fluorocarbon Flow
fluid regulator
filling tube
2.4 cm Silicone
polymer
coating

Empty Infusate Bellows

weight = 181 g Fluorocarbon
chamber
fluid
chamber

8.6 cm

1000
A
Pump
800
implanted

600

400
n=7
Dose units/kg per day

200

0
1000
B

Drug Delivery
Buccal–Mono
800

600

400
n = 25
200

0
0 8 16 24 32 40 48 56
Weeks of infusion

Fig. 21 Cross-sectional view of a unit of InfusaidÕ 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 engineered to deliver norgestomet, at a rate of
type of CrDDS are outlined below. 504 mg/cm2/day1/2, in the subcutaneous tissue for up
to 16 days for the control and synchronization of
Syncro-Male-B implant estrus in livestock.[13]

This subcutaneous CrDDS is fabricated by dissolving ValreleaseÕ tablet

norgestomet, a potent progestin for estrus synchro-
nization, in an alcoholic solution of linear ethylene
glycomethacrylate polymer (Hydron S). The drug-
polymer 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 fluid to swell and can be
This oral CrDDS is prepared by granulating Valium, an
antidepression drug, with hydrocolloids (20–75 wt%)
and pharmaceutical excipients. The granules are then
compressed to form an oral tablet. After oral intake,
the hydrocolloids absorb the gastric fluid and are
activated to form a colloid gel matrix surrounding the
tablet surface (Fig. 22). The release of Valium molecules
 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 fluid
(d > 1) and the gelling tablet (d < 1).[2,3]
pH-Activated Drug Delivery Systems
For a drug labile to gastric fluid or irritating to gastric
mucosa, this type of CrDDS has been developed to tar-
get 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 fluid-sensitive drug with a combi-
nation of intestinal fluid-insoluble polymer, like ethyl
cellulose, and intestinal fluid-soluble polymer, like
hydroxylmethyl cellulose phthalate (Fig. 23).
In the stomach, the coating membrane resists the
degrading action of gastric fluid (pH <3), and the drug
molecules are thus protected from the acidic degradation.
After gastric emptying, the CrDDS travels to the small
A
Hydrocolloids
(20–75% w/w)
Gastric fluid (d > 1)
Drug Delivery
Buccal–Mono
intestine, and the intestinal fluid-soluble component
in the coating membrane is dissolved away by the
intestinal fluid (pH >7.5). This produces a micropor-
ous membrane of intestinal fluid-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 fluid-soluble
polymer to the intestinal fluid-insoluble polymer in
the membrane, the rate of drug delivery can be regu-
lated. 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 fluid has regularly main-
tained a relatively constant level of ions, the delivery
of drug by this type of CrDDS can be modulated, the-
oretically, at a constant rate.
Such a CrDDS is prepared by first complexing an
ionizable drug with an ion-exchange resin, such as

Stomach
(pH < 3)
Colloid gel barrier
d< 1 Gastric emptying

B Coating of

Gastric fluid- Intestinal fluid-insoluble polymer

2000 labile drug
Intestinal fluid-soluble polymer
Radioactivity in stomach

1000
800
Valrelease Intestinal fluid
600 (pH > 7.5)
(Placebo)
400

Valium
200 (Placebo) Microporous membrane
of intestinal fluid-
Gastric fluid- insoluble polymer
100 labile drug
0 1 2 3 4 5 6
Time (h)

Fig. 22 (A) Schematic illustration of ValreleaseÕ tablet, a Drug

swelling-activated drug-delivery system, and the hydration-
induced formation of colloid gel barrier. (B) Comparison in Fig. 23 Schematic illustration of a pH-activated drug-
the gastric residence profile between Valrelease with the delivery system and the pH-dependent formation of micro-
conventional Valium capsule. (From Ref.[58].) porous membrane in the intestinal tract.
Drug Delivery: Controlled Release 1099

complexing a cationic drug with a resin containing
SO3 group or an anionic drug with a resin containing
N(CH3)3þ group. The granules of the drug–resin com-
plex 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 drug–resin complex to trigger
the dissociation and release of ionic drug (Fig. 24).
This type of CrDDS is exemplified by the devel-
opment of PennkineticÕ system (by Pennwalt Phar-
maceuticals), which permits the formulation of oral
liquid-type dosage forms with sustained release of a
combination of hydrocodone and chlorpheniramine
(TussionexÕ).[14,42–44]
made possible by the enzymatic hydrolysis of biopoly-
mers by a specific enzyme in the target tissue.[46–48] A
typical example is the development of albumin micro-
spheres, which release 5-fluorouracil, in a controlled
manner, by protease-activated biodegradation.
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 con-
centration 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

Hydrolysis-Activated Drug
Delivery Systems
This type of CrDDS depends on the hydrolysis process
to activate the release of drug molecules. In this sys-
tem, the drug reservoir is either encapsulated in micro-
applied to the development of a bioerosion-regulated
CrDDS by Heller and Trescony.[49] This CrDDS con-
sists 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

Drug Delivery
capsules or homogeneously dispersed in microspheres

Buccal–Mono
erodes very slowly. In the presence of urea, urease at
or nanoparticles. It can also be fabricated as an
implantable device. All these systems are prepared
from a bioerodible or biodegradable polymer, such as Drug-resin complex particles
polylactide, poly(lactide–glycolide) copolymer, poly
Resin – SO3– Drug+
(orthoester), or poly(anhydride). The release of a drug + ]Drug–
Resin [N(CH3)3
from the polymer matrix is activated by the hydrolysis-
induced degradation of polymer chains, and the rate of Polyethylene glycol treatment
drug delivery is controlled by polymer degradation
rate.[45] A typical example is the development of Ethyl cellulose coating
Lupron DepotÕ, an injectable microspheres for the
subcutaneous controlled delivery of luprolide, a potent
biosynthetic analog of gonadotropin-releasing hormone Blood
Gut wall
(GnRH) for the treatment of gonadotropin-dependent Polymer
cancers, such as prostate carcinoma in men and endome- Drug
triosis in the females, for up to 4 months. Another
example is the development of ZoladexÕ system, an
implantable cylinder for the subcutaneous controlled
Ion
delivery of goserelin, also a potent biosynthetic analog Coating
of GnRH for the treatment of patients with prostate membrane
cancer (Fig. 25) for up to 3 months.[14]
H + + Resin – SO3– Drug+ Resin–SO3– H + + Drug +
Enzyme-Activated Drug Delivery Systems
CI – + Resin [N(CH3)3 + ] Drug – Resin [N(CH3)3+ ] CI – + Drug–

In this type of CrDDS, the drug reservoir is either phys- Fig. 24 Cross-sectional view of an ion-activated drug-
ically entrapped in microspheres or chemically bound delivery system, showing various structural components,
to polymer chains fabricated from biopolymers, such and diagrammatic illustration of ion-activated drug release.
as albumins or polypeptides. The release of drugs is (Adapted from Ref.[58].)
 1100 Drug Delivery: Controlled Release

Drug-dispersed Poly (vinyl methyl ether) half-ester

polymer matrix u u u u u (monolithic matrix)

Hydrolytic erosion u u
Phase I: surface erosion u Hydrocortisone u
Micropores Urease
Phase II: bulk erosion u u
(Immobilized)
u u u u u
goserelin
urease
Glp His Trp Ser Tyr (D)
Leu Arg Pro Azgly NH urea 2NH4+ + HCO3− + OH–
Ser H 2O
t-Bu alkaline
polymer erosion
pH
Serum Testosterone
Serum LH (lU/L)

40 30 Hydrocortisone
(nmol/L)

20 15
100

Hydrocortisone released (%)

0 0
80
0 4 8 12 0 4 8 12
Weeks Weeks
60
Fig. 25 Amino acid sequence of goserelin, a biosynthetic
analog of gonadotropin-releasing hormone, and the effect urea (0.1 M)
40
of subcutaneous controlled release of goserelin from the bio-
degradable poly(lactide-glycolide) implant on the serum
20
levels of luteinizing hormone and testosterone.

0
0 20 40 60 80 100 120 140 160
the surface of the drug delivery system metabolizes
Time (h)
urea to form ammonia. This causes the pH to increase
and activates a rapid degradation of polymer matrix as
Drug Delivery

Fig. 26 Cross-sectional view of a bioerosion-regulated

Buccal–Mono

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 biore-
sponsive 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 NR2Hþ, and
the hydrogel membrane becomes swollen and is thus
permeable to insulin molecules (Fig. 27). The amount
of insulin delivered is bioresponsive to the concen-
tration of glucose penetrating into the CrDDS.
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 acti-
vate 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. first applied the mechanism of reversible
binding of sugar molecules with lectin into the design
of self-regulating CrDDS.[51] For this CrDDS, a biolo-
gically-active insulin derivative, in which insulin is
coupled with a sugar (e.g., maltose), was first prepared
and then conjugated with lectin to form an insulin–
sugar–lectin complex. The complex is then encapsu-
lated 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

molecules and activates the release of the insulin–sugar Self-Regulating Insulin Delivery Systems
derivatives from the binding sites. The released insulin-
sugar derivatives diffuse out of the CrDDS, and the (Biochemical Approach)
amount of insulin-sugar derivatives released depends
on the concentration of glucose. Thus, a self-regulating Concanavalin A Glycosylated (G) insulin
drug delivery is achieved. However, a potential prob-
lem has remained to be resolved: that is, the release + Glucose in
Polymer
of insulin is non-linear in response to the changes in membrane
G-Insulin out
glucose level.[52]
Further development of the self-regulating insulin
delivery system has utilized the complex of glycosy-
lated insulin–concanavalin A, which is encapsulated Pancreatectomized dogs
inside a polymer membrane.[53] As glucose penetrates

Blood glucose level (mg/dl)

into the system, it activates the release of glycosylated 300
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 200
has penetrated into the insulin delivery system.

100 Normoglycemic
level
SITE-TARGETING DRUG DELIVERY SYSTEMS
F F F F F F = Feeding

Delivery of a drug to a target tissue that needs medi- 9am 3pm 9pm 3am 9am 3am 9pm
cation is known to be a complex process that consists Time of day

Fig. 28 Various components of a self-regulating insulin

delivery system, a feedback-regulated drug delivery system,
Amine-containing
hydrogel membrane and its control of blood glucose level in the pancreatecto-

Drug Delivery
Buccal–Mono
Glucose oxidase mized dogs. (From Ref.[53].)
NR2 ......
.. ..
.... ..... Glucose
NR
NR2 . 2 of multiple steps of diffusion and partitioning. The
........
.
NR2 CrDDSs outlined above generally address only the first
..........
NR2 step of this complex process. Essentially, these
CrDDSs have been designed to control the rate of drug
Insulin Glucose Oxidase Gluconic acid
release from the delivery systems, but the path for the
reservoir transport of drug molecules from the delivery system
–NR2 H+ +
–N R2H
Acidic pH to the target tissue remains largely uncontrolled.
Hydrogel membrane swells
Ideally, the path of drug transport should also be
under control. Then, the ultimate goal of optimal treat-
ment with maximal safety can be achieved. This can be
+ N Enzyme
N R2 ... reasonably accomplished by the development of a
H ...............
CrDDS with a site-targeting specificity (Fig. 2). An
........... +
.. N R2 ideal site-targeting CrDDS has been proposed by
+ H
N R2 Ringsdorf.[54] A model, which is shown in Fig. 29, is
H
Insulin constructed from a non-immunogenic and biodegrad-
+
N R2 able polymer and acts as the backbone to contain three
H .......... +
.. N R2 types of attachments: 1) a site-specific targeting moiety,
H
which is capable of leading the drug delivery system to
Swollen membrane the vicinity of a target tissue (or cell); 2) a solubilizer,
which enables the drug delivery system to be trans-
Fig. 27 Cross-sectional view of a bioresponsive insulin
delivery system, a feedback-regulated drug delivery system,
ported to and preferentially taken up by a target tissue;
showing the glucose oxidase-entrapped hydrogel membrane and 3) a drug moiety, which is convalently bonded to
constructed from amine-containing hydrophilic polymer. the backbone, through a spacer, and contains a linkage
The mechanism of insulin release, in response to the influx that is cleavable only by a specific enzyme(s) at the
of glucose, is also illustrated. (From Ref.[50].) target tissue.
 1102 Drug Delivery: Controlled Release

Polymer backbone of Pharmacy, Proceedings Published in Drug Develop. &

(nonimmunogenic Ind. Pharm. 1983; 9, 1077–1396.
and blodegradable) 4. Chien, Y.W. International Pharmaceutical R&D
Symposium on Advances in Transdermal Controlled Drug
Administration for Systemic Medication. Piscataway, New
Jersey, June 20&21, 1985; Rutgers University, College of
Pharmacy, Proceedings Published in Transdermal Controlled
Systemic Medications; Chien, Y.W., Ed.; Marcel Dekker, Inc.:
Site-specific Spacer Solubilizer New York, 1987.
targeting
moiety 5. Chien, Y.W. Rate-control drug delivery systems: controlled
Cleavable Facilitate systemic release vs. sustained release. Med. Prog. Technol. 1989,
group distribution 15 (1–2), 21–46.
and tissue uptake 6. Chien, Y.W. Novel Drug Delivery Systems: Second Edition,
Revised and Expanded; Marcel Dekker, Inc.: New York,
1992.
Enzyme Drug 7. Luukkainen, T.; Allonen, H.; Haukkamaa, M.;
(at target tissue) Lahteenmaki, P.; Nilsson, C.G.; Toivonen, J. Five years’
experience with levonorgestrel-releasing IUDs. Contracep-
tion 1986, 33 (2), 139–148.
Cell of Drug 8. Andersson, K.; Odlind, V.; Rybo, G. Levonorgestrel-
target tissue releasing and copper-releasing (Nova T) IUDs during five
years of use: a randomized comparative trial. Contracep-
tion 1994, 49 (1), 56–72.
Drug 9. Sivin, I.; Stern, J. Health during prolonged use of levonor-
gestrel 20 micrograms/d and the copper TCu 380Ag
Cell membrane intrauterine contraceptive devices: a multicenter study.
International committee for contraception research
(ICCR). Fertil. Steril. 1994, 61 (1), 70–77.
10. Robinson, J.R. Sustained and Controlled Release Drug
Delivery Systems; Marcel Dekker, Inc.: New York, 1978.
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13. Chien, Y.W. Microsealed Pharmaceutical Delivery Device.
Drug Delivery
Buccal–Mono

US Patent 3,992,518, Nov 16, 1976.

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.
CONCLUSIONS
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.
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