Drug Delivery: Controlled Release - Semantic Scholar Delivery Buccal–Mono Drug Delivery: Controlled Release Yie W. Chien Research and Development, Kaohsiung Medical University, Kaohsiung,

Drug

Delivery

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ono

Drug Delivery: Controlled Release

Yie W. ChienResearch and Development, Kaohsiung Medical University,Kaohsiung, Taiwan

Senshang LinCollege 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 beenaccomplished by administering drugs to the humanbody via various pharmaceutical dosage forms, liketablets. These traditional pharmaceutical products arestill commonly seen today in the prescription andover-the-counter drug marketplace. To achieve andmaintain the drug concentration in the body withinthe therapeutic range required for a medication, it isoften 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 maderecently in the development of new techniques for drugdelivery. These techniques are capable of regulating therate of drug delivery, sustaining the duration of thera-peutic action, and/or targeting the delivery of drug toa specific tissue.[1–6] These advancements have alreadyled to the development of several novel drug deliverysystems that could provide one or more of the follow-ing benefits:

1. Controlled administration of a therapeutic doseat a desirable rate of delivery.

2. Maintenance of drug concentration within anoptimal therapeutic range for prolongedduration 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 thecontrolled-release drug delivery systems (CrDDSs) thathave been marketed so far, or that are under activedevelopment, the CrDDSs can be classified (Fig. 2)as follows:

1. Rate-preprogrammed drug delivery systems.2. Activation-modulated drug delivery systems.

3. Feedback-regulated drug delivery systems.4. Site-targeting drug delivery systems.

In this article, the scientific concepts and technicalprinciples behind the development of this newgeneration of drug-delivery systems are outlined anddiscussed.

RATE-PREPROGRAMMED DRUGDELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesfrom the delivery systems has been preprogrammed ata specific rate profile. This is accomplished by systemdesign, which controls the molecular diffusion of drugmolecules in and/or across the barrier medium withinor surrounding the delivery system. Fick’s laws of dif-fusion are often followed. These CrDDSs can furtherbe classified as follows:

1. Polymer membrane permeation-controlled drugdelivery systems.

2. Polymer matrix diffusion-controlled drug deliv-ery systems.

3. Polymer (membrane/matrix) hybrid-type drugdelivery systems.

4. Microreservoir partition-controlled drug deliv-ery systems.

Polymer Membrane Permeation-ControlledDrug Delivery Systems

In this type of CrDDS, a drug formulation is eithertotally or partially encapsulated in a drug reservoircompartment whose drug-releasing surface is coveredby a rate-controlling polymeric membrane. The drugreservoir can be drug solid particles, a dispersion ofdrug solid particles, or a concentrated drug solution ina liquid- or solid-type dispersing medium. The poly-mericmembrane can be fabricated from a homogeneous

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001051Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.1082

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or a heterogeneous non-porous polymeric material ora microporous or semipermeable membrane. Theencapsulation of drug formulation inside the reservoircompartment can be accomplished by molding, cap-sulation, microencapsulation, or other techniques.Different shapes and sizes of drug delivery systemscan be fabricated (Fig. 3).

The release of drug from this type of CrDDSsshould be at a constant rate (Q/t), which is definedby the following general equation:

Q

t¼ Km=rKa=mDdDm

Km=rDmhd þ Ka=mDdhmCR ð1Þ

where Km/r and Ka/m are, respectively, the partition-coefficients for the interfacial partitioning of drugmolecules from the reservoir to the membrane andfrom the membrane to the aqueous diffusion layer;

Dm, and Dd are, respectively, the diffusion coefficientsin the rate-controlling membrane with a thickness ofhm, and in the aqueous diffusion layer with a thicknessof hd. For microporous membrane, the porosity, andtortuosity of the pores in the membrane should beincluded in the estimation of Dm and hm. CR is the drugconcentration in the reservoir compartment.

The release of drug molecules from this type ofCrDDS is controlled at a preprogrammed rate by mod-ulating the partition coefficient and the diffusivity ofdrug molecule and the rate-controlling membraneand the thickness of the membrane. Several CrDDSs

A1

1 2 3 4Frequencies of dosing

Dru

g co

ncen

trat

ion

A2A3

A4

B

Adverse side effects

Toxic level

Therapeutic range

No therapeuticeffects

Minimum effectiveconcentration

Fig. 1 Drug concentration profiles in the systemic circu-

lation as a result of taking a series of multiple doses of a con-ventional drug-delivery system (A1, A2, . . . ) in comparisonwith the ideal drug concentration profile (B). (Adapted fromRef.[6].)

Drugreservoir

Rate-controllingsurface

Drug

A

Drugreservoir


Drug

Energy sensor

B

Drugreservoir


Biochemical responsive/Energy sensor

Drug

C

Drugreservoir


Drug

Biochemical responsive/Energy sensor

Site-targetingmoiety

D

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.

Sphere

D

Cp

CbCm

Cs

Pm

Pd

Dm Da

hd

hm

Sink

Elution medium

Polymercoating

Cylinder

Drugreservoir

Drugreservoir

Porous membrane

Pore

Diffusion layer

Drug release

Nonporousmembrane

Drugimpermeablebarrier

Sheet

Cp

A

B

C

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 existin series. Both the polymer membrane, which is either porousor non-porous, and the diffusion layer have a controlled

thickness (hm and hd, respectively).

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of this type have been successfully marketed for thera-peutical uses and some representatives are outlinedlater for illustration.

Progestasert� IUD

In this controlled-release intrauterine device, the drugreservoir exists as a dispersion of progesterone crystalsin silicone (medical grade) fluid encapsulated in thevertical 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 dailydose of 65 mg progesterone inside the uterine cavity toachieve contraception for one year.[6] The same tech-nology has been utilized in the development of theMirena� system, a plastic T-shaped frame with a ster-oid reservoir containing 52mg levonorgestrel, which isdesigned to release a daily dose of levonorgestrel at�20 mg/day for achieving effective contraception forfive years.[7–9]

Ocusert� system

In this controlled-release ocular insert, the drug reser-voir is a thin disc of pilocarpine–alginate complexsandwiched between two transparent discs of micro-porous membrane fabricated from ethylene–vinylacetate copolymer (Fig. 5). The microporous mem-branes permit the tear fluid to penetrate into the drug

reservoir compartment to dissolve pilocarpine from thecomplex. Pilocarpine molecules are then released at aconstant rate of 20 or 40 mg/h for a 4- to 7-day man-agement of glaucoma.[1,6,10,11]

Transderm-Nitro� system

In this controlled-release transdermal therapeuticsystem, the drug reservoir, which is a dispersion ofnitroglycerin–lactose triturate in a silicone (medicalgrade) fluid, is encapsulated in an ellipsoid-shaped thinpatch. The drug reservoir is sandwiched between a drug-impermeable metallic plastic laminate, as the backingmembrane, and a constant surface of drug-permeable,rate-controlling membrane of ethylene–vinyl acetatecopolymer (Fig. 6). This device is fabricated by aninjection-molding process. A thin layer of siliconeadhesive is further coated on the drug-permeablemembrane in order that an intimate contact of thedrug-releasing surface with the skin surface is achievedand maintained. It is engineered to have nitroglycerindelivered transdermally at a rate of 0.5 (mg/cm2)/dayfor a daily relief of angina.[2,3]

The same technology has been utilized in the develop-ment of the following: 1) the Estraderm� system, whichadministers a controlled dose of estradiol transdermallyover 3–4 days for the relief of postmenopausal syndromeand osteoporosis;[12–14] 2) the Duragesic� system, whichprovides a transdermal-controlled administration offentanyl, a potent narcotic analgesic, for 72-h reliefof chronic pain;[14] and 3) the Androderm� system,which provides a transdermal-controlled delivery of

00 100

Days

μg/d

ay

200

In Vitro

300 400

20406080

100

00 100

Days200

In Vivo

300 400

95% Confidence Level

20406080

100

Polyethylene

Ethylenevinylacetatecopolymer

38 mg of progesterone microcrystals(and barium sulfate)

suspended in silicone oil

A

B

Fig. 4 Diagrammatic illustration of a unit of ProgestasertIUD, showing various structural components (A) and thein vitro and in vivo delivery rate profiles of progesteronefor up to 400 days (B).

13.4mm

Ethylene/vinyl acetate membrane

Pilocarpine-core reservoirTitanium dioxide-white ring

305μ74μ

5.7m

m

00 1 2 3

Time (days)

Pilo

carp

ine

rele

ase

rate

(mcg

/hr)

4 5 6 7 8 9

20

40

60

Fig. 5 Diagrammatic illustration of a unit of Ocusert� sys-tem, showing various structural components, and the ocular

release rate profile of pilocarpine from the Ocusert pilo-20system. (From Ref.[11].)

1084 Drug Delivery: Controlled Release

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testosterone, through non-scrotal skin, for the 24hreplacement therapy of testosterone-deficient patients.[14]

Norplant� subdermal implant

The controlled-release subdermal implant is fabricatedfrom a non-porous silicone (medical-grade) tubing, bysealing both ends with silicone (medical-grade)adhesive to encapsulate either levonorgestrel crystalsalone (generation I) or a solid dispersion of levonorges-trel in silicone elastomer matrix (generation II). It isdesigned 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 unitsof I or 2 units of II); (Fig. 7) for up to 7 years.[15–18]

Polymer Matrix Diffusion-ControlledDrug Delivery Systems

In this type of CrDDS, the drug reservoir is producedfrom the homogeneous dispersion of drug particles ineither a lipophilic or a hydrophilic polymer matrix. Thedrug dispersion in the polymer matrix is accomplished

by either 1) blending a dose of finely ground drugparticles with a viscous liquid (or a semisolid) poly-mer, followed by a crosslinking of polymer chainsor 2) mixing drug solids with a melted polymer atan elevated temperature. The resultant drug-polymerdispersion is then molded or extruded to form drug-delivery devices of various shapes and sizes designedfor a specific application (Fig. 8). It can also befabricated by dissolving the drug and the polymer in acommon solvent, followed by solvent evaporation, at anelevated 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 therate of drug release is time dependent as defined by:

Q

t1=2 ¼ ð2ACRDPÞ1=2ð2Þ

where A is the initial loading dose of drug dispersed inthe polymer matrix; CR is the drug solubility in thepolymer, which is also the drug reservoir concentrationin the polymer matrix; and Dp is the diffusivity of thedrug molecules in the polymer matrix.

The release of drug molecules from this type ofCrDDSs may be controlled at a preprogrammed rateby controlling the loading level and the polymersolubility of the drug and its diffusivity in the polymermatrix. Several CrDDSs of this type have been suc-cessfully marketed for therapeutical uses, and somerepresentatives are outlined later for illustration.

Nitro-Dur� system

This controlled-release transdermal therapeutic systemis fabricated by first heating an aqueous solution ofwater-soluble polymer, glycerol, and polyvinyl alcoholand then lowering the temperature of the mixture toform a polymer gel. Nitroglycerin/lactose triturate isdispersed in the gel, and the mixture is then solidifiedat room temperature to form a medicated polymer discby a molding and slicing technique. After assemblyonto a drug-impermeable metallic plastic laminate, apatch-type transdermal therapeutic system is producedwith an adhesive rim surrounding the medicated disc(Fig. 9). It is designed for application onto an intactskin to provide a continuous transdermal infusion ofnitroglycerin, at a daily dose of 0.5mg/cm2, for theprevention of angina pectoris.[2,19]

The drug reservoir can also be formulated bydirectly dispersing the drug in an adhesive polymer,such as poly(isobutylene) or poly(acrylate) adhesive,and then spreading the medicated adhesive by solventcasting or hot melt, onto a flat sheet of drug-impermeablebacking support to form a single- or multiple-layer drugreservoir. This type of transdermal CrDDS (TDD)

00 5

Time (h)10 15 20 25

Drug reservoir

Adhesive layer

Rate-controllingpolymeric membrane

Drug-impermeable metallic plastic laminate

Plas

ma

nitr

ogly

ceri

n co

nc.

(ng/

ml ±

SD

)

0.05

0.10

0.15

0.20

0.25

Night Period

Fig. 6 Cross-sectional view of a unit of Transderm-Nitro�

system, showing various structural components, and plasmaconcentration profiles of nitroglycerin in 14 human volunteers,each receiving one unit of Transderm-Nitro system (20 cm2,

with a delivery rate of 10mg/day) for 24h. (From Refs.[11,55].)


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is best illustrated by the development and marketingof an isosorbide dinitrate-releasing TDD system,named Frandol� tape, by Toaeiyo/Yamanouchi inJapan, and of a nitroglycerin-releasing TDD system,named Nitro-Dur� II system by Key in the UnitedStates, 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-generationNitro-Dur from the marketplace. The same technicalbasis has been also utilized in the development ofthe following: 1) Habitrol� and Nicotrol� systems,which provide a controlled dose of nicotine transder-mally over 24h for smoking cessation;[14] 2) Minitran�

system, which administers a controlled dose of nitrogly-cerin transdermally over 24h for the relief of anginalattacks;[14] 3) Testoderm� system, which administers acontrolled delivery of testosterone for transdermal per-meation through a scrotal skin[14] for the replacementtherapy of testosterone-deficient patients for 24h; and4) Climara� system, which provides a controlled

delivery of 17b-estradiol for transdermal permeationfor once-weekly treatment of vasomotor systems[14]

associated with menopause.

Compudose� implant

This controlled-release subdermal implant is fabricatedby dispersing micronized estradiol crystals in a viscousmixture of silicone elastomer and catalyst and thencoating the estradiol-polymer dispersion around a rigid(drug-free) silicone rod by an extrusion technique toform a cylinder-shaped implant (Fig. 11). This implantis designed for subcutaneous implantation in thesteer’s ear flap for a duration of 200 or 400 days, dur-ing which a controlled quantity of estradiol is releaseddaily for growth promotion.[20]

To improve the Q versus t1/2 drug release profiles[Eq. (2)], this polymer matrix diffusion-controlledCrDDS can be modified to have the drug-loadinglevel varied, in an incremental manner, to form a gradi-ent of drug reservoir along the diffusional path in thepolymer matrix. A constant drug release profile is thus

34 mm2.4 mm

Milligrams Milligrams

total load of levonorgestrel

daily dose 30 μg

Years of use

216

90

70

50

30

10

216

90

70

50

30

10

1 2 3 4 5 6

~~ ~~

Concentration ofLevonorgestrel in plasma

ORAL

1.00

0.75

0.50

0.25

24 hr 1 2 3 4 5

Mean value and95% confidenceintervals

Time of use (years)

Peak (mean)

Trough (mean)

NONPLANT SUBCERNAL INPLANTS

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


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achieved, and the rate of drug release from this drugreservoir gradient-controlled drug delivery system isdefined by:

dQ

dt¼ Ka=rDa

haðtÞ CpðhaÞ ð3Þ

in which the time-dependent thickness [ha(t)] of thediffusional path for drug molecules to diffuse through,which is increasing with time, is compensated by theproportional increase in the drug-loading level [Cp(ha)],and a constant drug release profile is thus obtained. Thistype of CrDDS is best illustrated by the nitroglycerin-releasing Deponit� system (Fig. 12), first marketedby Pharma-Schwartz/Lohmann in Europe.[21] Wyeth-Ayerst has received FDA approval for marketing thissystem in the United States.

Furthermore, it was recently demonstrated that therelease of a drug, such as propranolol, from the multila-minate adhesive-based TDD system can be maintainedat zero-order kinetics by controlling the particle sizedistribution of drug crystals in the various laminatesof adhesive matrix.[22]

Polymer (Membrane/Matrix) Hybrid-TypeDrug Delivery Systems

This type of CrDDS is developed with the objective ofcombining the constant drug release kinetics of poly-mer membrane permeation-controlled drug deliverysystems with the mechanical superiority of polymermatrix diffusion-controlled drug delivery systems.The release profile of drug from a sandwich-type drugdelivery system (Fig. 13) is constant, and the instan-taneous rate of drug release is defined by:

dQ

dt¼ ACpDp

DpKmð1=Pm þ 1=Pd

� �2 þ 4ACpDpt1=2

ð4Þ

where A is the initial amount of drug solid impregnatedin a unit volume of polyer matrix with solubility Cp

and diffusivity Dp; Km is the partition coefficient forthe interfacial partitioning of drug molecules frompolymer matrix toward polymer coating membrane;Pm is the permeability coefficient of the polymer coat-ing membrane with thickness hm; and Pd is the per-meability coefficient of the hydrodynamic diffusionlayer with thickness hd.

The hybrid system is exemplified by the develop-ment of clonidine-releasing and scopolamine-releasingtransdermal therapeutic systems (Catapres-TTS�

and Transderm-Scop�) (Fig. 14), in which a rate-controlling non-medicated polymeric membrane isadded to coat the surface of the drug-dispersing poly-mer matrix, and the release of drug molecules thusbecomes controlled by membrane permeation insteadof matrix diffusion. The same technology has beenutilized in the development of levonorgestrel-releasingsubdermal implants (Norplant� II).

Microreservoir Partition-ControlledDrug Delivery Systems

In this type of CrDDS, the drug reservoir is a suspen-sion of drug solid particles in an aqueous solution of awater-miscible polymer, like polyethylene glycols. Thisforms a homogeneous dispersion of many discrete,unleachable, microscopic drug reservoirs in a biocom-patible polymer, like silicone elastomers (Fig. 15). Themicrodispersion is achieved by applying a high-energydispersion technique.[13,23] Different shapes and sizes ofdrug-delivery devices can be fabricated from this

CR Dp

hd

hp + dhp

Drug reservoir

Receding boundarydepletion zone

Matrix

Diffusion layer

A Elution medium

Perfect sink

C

Drug release

Drug release

Drug depletionzone

A

Drug reservoir(Dispersion)

Gel layer

B

Fig. 8 Release of drug from the polymer matrix diffusion-

controlled drug delivery systems with drug reservoir existsas a homogeneous dispersion in (A) lipophilic, non-swellablepolymer matrix, with a growing thickness of drug depletion

zone, or (B) a hydrophilic, swellable polymer matrix, with agrowing thickness of drug-depleted gel layer. In (C), the drugconcentration gradients across the time-dependent drugdepletion zone, with a growing thickness (hp þ dhp), andthe hydrodynamic diffusion layer, with a controlled thickness(hd), are shown in series.


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microreservoir-type CrDDS by molding or extrusiontechniques. Depending upon the physicochemicalproperties of drugs and the desired rate of drug release,the device can be further coated with a layer of bio-compatible polymer to modify the mechanism andthe rate of drug release.

The rate of drug release (dQ/dt) from this type ofCrDDS is defined by:

dQ

dt¼ DpDdmKp

Dphd þDdhpmKp

� nSp � DlSlð1� nÞht

1

Klþ 1

Km

� �� ð5Þ

where m ¼ a/b and n is the ratio of drug concen-tration at the inner edge of the interfacial barrier overthe drug solubility in the polymer matrix,[1,6] in which ais the ratio of drug concentration in the bulk of elutionsolution over drug solubility in the same medium and bis the ratio of drug concentration at the outer edge of

the polymer coating membrane over drug solubilityin the same polymer. Kl, Km, and Kp are, respectively,the partition coefficients for the interfacial partitioningof drug from the liquid compartments to the polymermatrix, from the polymer matrix to the polymer coat-ing membrane, and from the polymer coating mem-brane to the elution solution, whereas Dl, Dp, and Dd

are, respectively, the diffusivities of the drug in theliquid layer surrounding the drug particles, the poly-mer coating membrane enveloping the polymer matrix,and the hydrodynamic diffusion layer surrounding thepolymer coating membrane with respective thicknessesof hl, hp, and hd (Fig. 15); and Sl and Sp are the solubi-lities of the drug in the liquid compartments and in thepolymer matrix, respectively.

The release of drug from the microreservoir-typeCrDDS can follow either a dissolution- or a matrixdiffusion-control process, depending upon the relativemagnitude of Sl and Sp.

[24] Representatives of this typeof CrDDS is outlined below.

Night Period

Absorbent pad

Impermeable backing(polyethylene coverstrip)

Occlusive baseplate(aluminum foil)

Adhesive rim(microporous acrylic polymer tape) Drug reservoir

(drug/hydrophilic polymer matrix)

Plas

ma

nitr

ogly

ceri

n co

nc.

(ng

/ml ±

SE

M)

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Time (h)

off

Fig. 9 Cross-sectional view of a unit of Nitro-Dur� system, showing various structural components, and the plasma nitrogly-cerin concentration profiles in six human volunteers, each receiving 1 unit of Nitro-Dur� system (20 cm2, with a delivery rate of

10mg/day) for 24 h. (From Refs.[55–56].)


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Nitrodisc� system

In this transdermal CrDDS (Fig. 16), the drug reser-voir is a suspension of nitroglycerin/lactose trituratein an aqueous solution of 40% polyethylene glycol400. It is dispersed homogeneously by a high-energymixing technique, with isopropyl palmitate, a skinpermeation enhancer, in a mixture of viscous siliconeelastomer and catalyst.[25] The resultant drug-polymerdispersion is then formed in situ into a solid medicateddisc on a drug-impermeable metallic plastic laminate,with an adhesive rim, by an injection-molding tech-nique and application of an instantaneous heating. Itis engineered to provide a transdermal administrationof nitroglycerin at a daily rate of 0.5mg/cm2 foronce-a-day medication of angina pectoris.[2,26] AQversus t1/2 (matrix diffusion-controlled) release profileis obtained.

Syncro-Mate-C implant

This subdermal controlled-release implant is fabricatedby dispersing the drug reservoir, which is a suspensionof norgestomet in an aqueous solution of PEG 400, ina viscous mixture of silicone elastomers by a high-energy dispersion technique.[24] After adding catalyst,

the suspension is delivered into a silicone medical-gradetubing, which serves as the mold as well as the coatingmembrane, and then polymerized in situ. The polymer-ized drug-polymer composition is then cut into acylinder-shaped implant with its ends staying open(Fig. 17). This tiny cylindrical implant is designed tobe inserted into the subcutaneous tissue of the live-stock’s ear flap; norgestomet is released continuouslyinto the subcutaneous tissue for up to 20 days for thecontrol and synchronization of estrus and ovulationand up to 160 days for growth promotion. A constantQ versus t (dissolution-controlled) release profile hasbeen achieved, as compared to the Q versus t1/2 releaseprofile (matrix diffusion-controlled drug release) forthe Syncro-Mate-B implant and the Nitrodisc systemdiscussed above.

Transdermal contraceptive device

The transdermal contraceptive device is based on apatentable micro-drug-reservoir technique[26] to achieve

Drug-loadedadhesive

Release liner

Impermeable film

1000

500

250

100

50

25

100 5 10 15 20 25

Time(h)

Nitr

ogly

ceri

n (p

g/m

l)

Fig. 10 Cross-sectional view of Nitro-Dur II, showing

various structural components, and the comparative 24 hplasma nitroglycerin concentration profiles in 24 healthymale 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 10mg/day, over the chest for 24 h(the arrow indicates unit removal). (From Ref.[56].) 0

0.2

0.4

0.6

0.8

1.0

0.01 2 3 4

(Days)½

Q (

mg/

cm2 )

75%

40%

20%

Silicone rod

Estradiol-releasingpolymer matrix

Fig. 11 Diagrammatic illustration of a unit of Compudose�

subdermal implant and in vitro release profiles of estradiol

from the implants immersed in aqueous solution containingvarious volume fractions of polyethylene glycol 400.


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a dual-controlled release of levonorgestrel, a potentsynthetic progestin, and estradiol, a natural estrogen,at constant and enhanced rates, continuously, for aperiod of 7 days.[5] By applying 1 unit (10 or 20 cm2)of transdermal contraceptive device per week, beginningon day 5 of an individual’s menstrual cycle, for 3consecutive weeks (3 weeks on and 1 week off), steady-state serum levels of levonorgestrel have been obtained,and the secretion of gonadotropins and progesteronehave been effectively suppressed.

ACTIVATION-MODULATED DRUGDELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesfrom the delivery systems is activated by some physical,

chemical, or biochemical processes and/or facilitated byan energy supplied externally (Fig. 2). The rate of drugrelease is then controlled by regulating the processapplied or energy input. Based on the nature of theprocess applied or the type of energy used, theseactivation-modulated CrDDSs can be classified intothe following categories:

1. Physical means

a. Osmotic pressure-activated drug deliverysystems

b. Hydrodynamic pressure-activated drugdelivery systems

c. Vapor pressure-activated drug deliverysystems

d. Mechanical force-activated drug deliverysystems

e. Magnetics-activated drug delivery systemsf. Sonophoresis-activated drug delivery systemsg. Iontophoresis-activated drug delivery systemsh. Hydration-activated drug delivery systems

2. Chemical means

a. pH-activated drug delivery systemsb. pH-activated drug delivery systemsc. Ion-activated drug delivery systemsd. Hydrolysis-activated drug delivery systems

3. Biochemical means

a. Enzyme-activated drug delivery systemsb. Biochemical-activated drug delivery systems

Several CrDDSs have been successfully developedand applied clinically to the controlled delivery ofpharmaceuticals and biopharmaceuticals. These areoutlined and discussed below.

Osmotic Pressure-Activated DrugDelivery Systems

In this type of CrDDSs, the drug reservoir, which canbe either a solution or a solid formulation, is con-tained within a semipermeable housing with a con-trolled water permeability. The drug in solution isreleased through a special laser-drilled delivery orificeat a constant rate under a controlled gradient ofosmotic pressure.

For a solution-type osmotic pressure-activatedCrDDS, the intrinsic rate of drug delivery (Q/t) isdefined by:

Q

t¼ PwAm

hmðps � peÞ ð6Þ

Plas

ma

nitr

ogly

ceri

n co

nc. (

pg/m

l)

400

200

100

80

60

400 4 8 12 16 20 24

Duration of Device/Skin contact (h)

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

Cmax = 255 ± 151 pg/ml (tmax = 3.6 ± 3.5 h)Css = 125 ± 50 pg/ml (8-24 h)AUC = 3.3 ± 1.6 ng·h/ml

Drug-impermeablemetallic plastic laminate

Drug reservoirgradient layers(R1 > R2 > R3)

R1

Adhesive layer

R2

R3

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

showing various structural components, and the plasmanitroglycerin concentration profiles in six human volunteers,each receiving 1 unit of Deponit system (16 cm2, with a deliv-ery rate of 5mg/day) for 24 h. (Plasma profiles are plotted

from data from Ref.[21].)


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For a solid-type osmotic pressure-activated CrDDS,the intrinsic rate of drug delivery should also be aconstant and is defined by:

Q

t¼ PwAm

hmðps � peÞSd ð7Þ

where Pw, Am, and hm are, respectively, the water per-meability, the effective surface area, and the thicknessof the semipermeable housing; (ps � pe) is the differen-tial osmotic pressure between the drug-delivery systemwith an osmotic pressure of ps and the environment

Sphere

Cylinder

Perfect sink(Cb = 0)

Dp Dm

pm

Dd

pd

A

CR

hp(t) hm hd

Drugreservoir

Polymer matrix Drugdepletion

zone

Polymercoating

membrane

Diffusionlayer

Solutionbulk

Fig. 13 The controlled release of drug molecules from a (membrane-matrix) hybrid-type drug delivery system in which soliddrug 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.

DRUG MOLECULES

MIC

RO

POR

OU

SM

EM

BR

AN

E

DRUG-IMPERMEABLEBACKING LAMINATE

DR

UG

-DIS

PER

SIN

GA

DH

ESI

VE

LA

YE

RS

Fig. 14 Cross-section view of various structural componentsin the Transderm-Scop� and Catapres-TTS� systems.


Drug

Delivery

Buccal–M

ono

with an osmotic pressure of pe; and Sd is the aqueoussolubility of the drug component in the solid reservoir.

The release of drug molecules from this type ofCrDDS is activated by osmotic pressure and controlledat a rate determined by the water permeability and the

effective surface area of the semipermeable housing aswell as the osmotic pressure gradient. Several CrDDSsof this type have been successfully marketed for thera-peutical uses and some representatives are outlinedlater.

Dp

Polymer matrix

Interfacialbarrier

Liquidlayer

Drugparticle

Dl

Sl Cl

Cp

Cm'

Cd

Cb = O

Solutionsink

Cp

Dm

Polymercoatingmembrane

Diffusionlayer

δmδl δd

Ds

Cm

Polymer matrix(cross-linked, solid)

Drug reservoir(microscopic liquidcompartments)

Coating membrane

Polymer/Solution interface

'Cp'

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].)


DrugDelivery

Buccal–Mono

Alzet osmotic pump

In this implantable or insertable CrDDS, the drug res-ervoir, which is normally a solution formulation, iscontained within a collapsible, impermeable polyesterbag whose external surface is coated with a layer ofosmotically active salt, for example, sodium chloride.This reservoir compartment is then totally sealed insidea rigid housing walled with a semipermeable mem-brane (Fig. 19). At an implantation site, the watercontent in the tissue fluid will penetrate through thesemipermeable membrane at a controlled rate anddissolve the osmotically active salt. This creates anosmotic pressure in the narrow spacing between theflexible reservoir wall and the rigid semipermeablehousing. Under the osmotic pressure created [Eq. (6)],the reservoir compartment is thus reduced in volumeand the drug solution is forced to release through theflow moderator at a controlled rate.[27,28] By varyingthe drug concentration in the solution, different dosesof drug can be delivered at a constant rate for a periodof 1–4 weeks.

In addition to its application in the subcutaneouscontrolled administration of drugs for pharmacologi-cal studies, this technology has recently been extendedto the controlled administration of drugs in the rectumby zero-order kinetics. The hepatic first-pass metab-olism of drugs is thus bypassed.[29]

Acutrim� tablet

In this oral CrDDS, the drug reservoir, which is a solidtablet of water-soluble and osmotically-active phenyl-propanolamine (PPA) HCl, is enclosed within a semi-permeable membrane of cellulose triacetate.[2,30] Thesurface of the semipermeable membrane is furthercoated with a thin layer of immediately releasablePPA dose (Fig. 20). In the alimentary tract, the gastro-intestinal fluid will dissolve away the immediate releaselayer of PPA to provide an initial dose of PPA andthen penetrate through the semipermeable membraneto dissolve the sustained-release dose of PPA. Underthe osmotic pressure created [Eq. (7)], the PPA solutionis released continuously at a controlled rate, throughan orifice pre-drilled by a laser beam.[2,30,31] It isdesigned to provide a controlled delivery of PPA overa duration of 16 h for appetite suppression in a weight-control program.[31] The same delivery system hasalso been utilized for the oral controlled delivery ofindomethacin. An extension of this technology is thedevelopment of a push-pull type osmotic pressure-activated CrDDS for the oral controlled delivery ofnifedipine and metroprolol.[27] It has been furtherextended to the delayed-onset and controlled oraldelivery of verapamil[14] to produce a maximumplasma concentration in the morning hours.

Occlusive baseplate(aluminum foil disc)

Adhesive foam pad(flexible polyurethane)

Adhesive rim(acrylic polymer coating)

Microscopic drug reservoirs(drug/co-solvents)

Polymer matrix(silicone elastomer)

0.0

0.1

0 4 8 12Time (h)

Plas

ma

nitr

ogly

ceri

nco

nc. (

ng/m

l±SE

M)

16 20 24 28 32

0.2

0.3

0.4

0.5

0.6

Night Period

(C plasma)ss

Fig. 16 Cross-sectional view of a unit of Nitrodisc� system,showing various structural components, and the plasmanitroglycerin concentration profiles in 12 human volunteers,

each receiving 1 unit of Nitrodisc system (16 cm2, with adelivery rate of 10mg/day) for 32 h. (From Ref.[23].)

Medicated MDD core

Drugreservoir

Polymer coatingmembrane

Open ends

Days of implantationFr

actio

n of

dru

g re

leas

ed (

%)

00 5 10 15 20 25 30

20

40

60

80

100

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 20days. The open ends on the implant do not affect the zero-order in vivo drug release profile. (Adapted from Ref.[57].)


Drug

Delivery

Buccal–M

ono

Hydrodynamic Pressure-ActivatedDrug Delivery Systems

In addition to the osmotic pressure systems discussedabove, hydrodynamic pressure has also been exploredas the potential source of energy to modulate the deliv-ery of therapeutic agents.[2]

A hydrodynamic pressure-activated drug-deliverysystem can be fabricated by placing a liquid drug for-mulation inside a collapsible, impermeable containerto form a drug reservoir compartment. This is thencontained inside a rigid, shape-retaining housing. Alaminate of an absorbent layer and a swellable,

hydrophilic polymer layer is sandwiched between thedrug reservoir compartment and the housing. In thegastrointestinal tract, the laminate will imbibe the gas-trointestinal fluid through the annular openings at thelower end of the housing and become swollen. Thisgenerates a hydrodynamic pressure in the system.The hydrodynamic pressure, thus created, forces thedrug reservoir compartment to reduce in volume andcauses the liquid drug formulation to release throughthe delivery orifice.[32] The drug release rate isdefined by:

Q

t¼ PfAm

hmðys � yeÞ ð8Þ

where Pf, Am, and hm are the fluid permeability, theeffective surface area, and the thickness of the wallwith annular openings, respectively; and ys � ye, isthe difference in hydrodynamic pressure between thedrug delivery system (ys) and the environment (ye).

The release of drug molecules from this type ofCrDDS is activated by hydrodynamic pressure andcontrolled at a rate determined by the fluid per-meability and effective surface area of the wall withannular openings as well as by the hydrodynamicpressure gradient.

Vapor Pressure-ActivatedDrug Delivery Systems

In this type of CrDDS, the drug reservoir, which is asolution formulation, is contained inside the infusioncompartment. It is physically separated from thepumping compartment by a freely movable partition(Fig. 21). The pumping compartment contains a vapor-izable fluid, such as fluorocarbon, which vaporizes atbody temperature and creates a vapor pressure. Underthe vapor pressure created, the partition moves upwardand forces the drug solution in the infusion compart-ment to be delivered, through a series of flow regulatorand delivery cannula, into the blood circulation at aconstant flow rate.[1,6,33] The process is defined by:

Q

t¼ d4dP

40:74mlð9Þ

where d and l are, respectively, the inner diameter andthelength of the delivery cannula; Dp is the pressuredifference between the vapor pressure in the pumpingcompartment 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 isactivated by vapor pressure and controlled at a ratedetermined by the differential vapor pressure, the for-mulation viscosity, and the size of the delivery cannula.

00 10 20 30 40

5

10

15

Seru

m p

roge

ster

one

(ng/

ml)

20

25

30Subject Code MM

(Group A: 1 TCD patch)

PretreatmentTreatment

TmaxTmax

0 10Day of menstrual cycle

20 30 40

Subject Code MG

(Group B: 2 TCD patch)

PretreatmentTreatment

B

0

m

0 168 336 504 672

48

96

Con

cent

ratio

n (p

g/m

l ± S

.E.)

144

192

240

288

10 Sq. cm - Patch (n=6)

20 Sq. cm - Patch (n=6)

mm mmDuration of study (h)

m p p

A

Fig. 18 (Upper panel) The 4–week serum levonorgestrel

profiles in 12 human volunteers, each receiving 1 or 2 unitsof a transdermal contraceptive system (10 cm2, with dailydosage of 28.3mg/day) once a week, consecutively for 3

weeks, and the same size of placebo on week 4. (Lower panel)Comparative serum concentration profiles of progesteroneduring the pretreatment and treatment cycles in two subjects,

each as the representative for group A (receiving 10 cm2) andgroup B (receiving 20 cm2), respectively. The suppression ofprogesterone peak during the treatment cycle is an indicationof effective fertility control.


DrugDelivery

Buccal–Mono

A typical example is the development of Infusaid�,an implantable infusion pump by Metal Bellows, forthe constant infusion of heparin in anticoagulationtreatment,[34] of insulin in the normoglycermic controlof diabetics,[33] and of morphine for patients sufferingfrom the intensive pain of a terminal cancer.[35]

Mechanical Force-ActivatedDrug Delivery Systems

In this type of CrDDS, the drug reservoir is a solutionformulation in a container equipped with a mechani-cally activated pumping system. A metered dose ofdrug formulation can be reproducibly delivered intoa body cavity, such as the nose, through the spray headupon manual activation of the drug-delivery pumpingsystem. The volume of solution delivered is fixed andis independent of the force and duration of activation.

A typical example of this type of drug-delivery sys-tem is the development of a metered-dose nebulizer forthe intranasal administration of a precision dose ofluteinizing hormone-releasing hormone (LHRH) and

its synthetic analogs, such as buserelin. Through nasalabsorption, the hepatic first-pass elimination of thesepeptide drugs is thus avoided.[24]

Magnetic-Activated Drug Delivery Systems

Macromolecular drugs, such as peptides, have beenknown to release only at a relatively low rate from apolymer-controlled drug-delivery system. This low rateof release can be improved by incorporating an electro-magnetism-triggering vibration mechanism into thepolymeric delivery device. With a hemispheric-shapeddesign, a zero-order drug-release profile is achieved.[36]

By combining these two approaches, a subdermallyimplantable, magnetic-activated hemispheric drug-delivery device is developed. It is fabricated by firstpositioning a tiny doughnut-shaped magnet at the cen-ter of a drug-dispersing biocompatible polymer matrixand then coating the external surface of the medicatedpolymer matrix, with the exception of one cavity at thecenter of the flat surface, with a pure polymer, forinstance, ethylene–vinyl acetate copolymer or silicone

0

Urine volume

Pumpimplanted

Pumpremoved

25

50

75

100

125

150

Dai

ly u

rine

vol

ume

(% o

f P

retr

eatm

ent c

ontr

ol +

S.D

.)

175

200

00

Urine osmolality

Pumpimplanted

Pumpremoved

3 6Time (day)

9 12 15

0 3 6 9 12 15

500

1000

1500

2000

Uri

ne o

smol

alilt

y (m

Osm

/ kg

H2O

+ S

.D.) 2500

3000

Drug solution leavingvia delivery portal

Removable capFlangeFlow moderator

Neck Plug

Flexible impermeablereservoir wall

Semipermeablemembrane

Water enteringsemipermeablemembrane

Reservoir

Osmotic agent

A B

Fig. 19 (A) Cross-sectional view of the Alzet� osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effectof 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.


Drug

Delivery

Buccal–M

ono

elastomers. This uncoated cavity is designed for allow-ing a peptide drug to release.

The hemispheric magnetic delivery device producedcan release macromolecular drugs, like bovine serumalbumin, at a low basal rate, by diffusion process, andunder a non-triggering condition, or it can release thesame drug at amuch higher rate, when themagnet is acti-vated, to vibrate by an external electromagnetic field.

Sonophoresis-Activated DrugDelivery Systems

This type of activation-controlled drug delivery systemutilizes ultrasonic energy to activate (or trigger) thedelivery of drugs from a polymeric drug deliverydevice. The system can be fabricated from either anon-degradable polymer, such as ethylene–vinyl acet-ate copolymer, or a bioerodible polymer, such as poly[bis(p-carboxyphenoxy)alkane anhydride].[37] Thepotential application of sonophoresis (or phonophor-esis) to regulate the delivery of drugs was recentlyreviewed.[38]

Iontophoresis-Activated DrugDelivery Systems

This type of CrDDS use electrical current to activateand to modulate the diffusion of a charged drug

molecule across a biological membrane, such as theskin, in a manner similar to passive diffusion under aconcentration gradient but at a much facilitated rate.The iontophoresis-facilitated skin permeation rate ofa charged molecule i consists of three componentsand is expressed by:

Jispi ¼ Jp þ Je þ Jc

¼ KsDsdC

hs

� �ZiDiFi

RTCi

dE

hs

� �þ ðkCsIdÞ ð10Þ

where J p, J e, and J c represent, respectively, the flux forthe skin permeation by passive diffusion, for the elec-trical current-driven permeation, and for the convec-tive flow-driven skin permeation; Ks is the partitioncoefficient for interfacial partitioning from the donorsolution to the stratum comeum; Ds and Di are,respectively, the diffusivity across the skin and thediffusivity of ionic species i in the skin; Ci and Cs are,respectively, the donor concentration of ionic species iand the concentration in the skin tissue; dE/hs is theelectrical potential gradient across the skin; dC/hs isthe concentration gradientacross the skin; Zi is theelectrical valence of ionic species i; Id is thecurrentdensity applied; F, k, and R are, respectively, the fara-day, proportionality, and gas constant; and T is theabsolute temperature.

A typical example of this type of activation-controlled CrDDS is the development of an iontophore-tic drug delivery system, named Phoresor by MotionControl, to facilitate the percutaneous penetration ofantiinflammatory drugs, such as dexamethasone sodiumphosphate,[39–41] to surface tissues.

Further development of the iontophoresis-activateddrug delivery technique has yielded a new design ofiontophoretic drug delivery system—the transdermalperiodic iontotherapeutic system (TPIS). This new sys-tem, which is capable of delivering a physiologically-acceptable pulsed direct current, in a periodic manner,with a special combination of waveform, intensity, fre-quency, and on/off ratio, for a specific duration, hassignificantly improved the efficiency of transdermaldelivery of peptide and protein drugs.[4] A typicalexample is the iontophoretic transdermal delivery ofinsulin, a protein drug, in the control of hyperglycemiain diabetic animals.

Hydration-Activated Drug Delivery Systems

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

Drug reservoir/osmotically active

solutes

Controlled-releasedose

Delivery orifice

Semi-permeable coating

Immediate releasing layer(initial dose)

04 8 12

Time (h)16 20 24

20

40

60

Cum

ulat

ive

% lo

adin

g do

se r

elea

sed

80

100 12.16 atm30.16 atm

54.16 atm

114.0 atm

Fig. 20 Cross-sectional view of a unit of Acutrim� tablet, asolid-type osmotic pressure-activated drug delivery system,and the effect of increased osmotic pressure in the dissolution

medium on the release profiles of phenylpropanolamine HClfrom the Acutrim tablet at intestinal condition. (Adaptedfrom Refs.[31,58].)


DrugDelivery

Buccal–Mono

swelling of the polymer matrix. Representatives of thistype of CrDDS are outlined below.

Syncro-Male-B implant

This subcutaneous CrDDS is fabricated by dissolvingnorgestomet, a potent progestin for estrus synchro-nization, in an alcoholic solution of linear ethyleneglycomethacrylate polymer (Hydron S). The drug-polymer mixture is then cross-linked by addingethylene dimethacrylate, in the presence of an oxidizingcatalyst, to form a cylinder-shaped subdermallyimplantable implant.[1,6] This tiny subdermal implantcan be activated by tissue fluid to swell and can be

engineered to deliver norgestomet, at a rate of504 mg/cm2/day1/2, in the subcutaneous tissue for upto 16 days for the control and synchronization ofestrus in livestock.[13]

Valrelease� tablet

This oral CrDDS is prepared by granulating Valium, anantidepression drug, with hydrocolloids (20–75 wt%)and pharmaceutical excipients. The granules are thencompressed to form an oral tablet. After oral intake,the hydrocolloids absorb the gastric fluid and areactivated to form a colloid gel matrix surrounding thetablet surface (Fig. 22). The release of Valium molecules

Infusatechamber

Emptyweight = 181g

2.4 cm

Bacterialfilter

assembly

Inletseptum

Needle stop

Flowregulator

Siliconepolymercoating

Bellows

8.6 cm

Fluorocarbonfluid

chamber

Fluorocarbonfluid

filling tube

00 8 16 24 32 40 48 56

200

400

600

800

1000

Dos

e un

its/k

g pe

r da

y

0

200

400

600

800

1000A

Pumpimplanted

n = 7

n = 25

Weeks of infusion

B

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


Drug

Delivery

Buccal–M

ono

is then controlled by diffusion through the gel barrier,while the tablet remains buoyant in the stomach, dueto 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 gastricmucosa, 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 coretablet ofthe gastric fluid-sensitive drug with a combi-nation of intestinal fluid-insoluble polymer, like ethylcellulose, and intestinal fluid-soluble polymer, likehydroxylmethyl cellulose phthalate (Fig. 23).

In the stomach, the coating membrane resists thedegrading action of gastric fluid (pH <3), and the drugmolecules are thus protected from the acidic degradation.After gastric emptying, the CrDDS travels to the small

intestine, and the intestinal fluid-soluble componentin the coating membrane is dissolved away by theintestinal fluid (pH >7.5). This produces a micropor-ous membrane of intestinal fluid-insoluble polymerto control the release of drug from the core tablet.The drug is thus delivered in a controlled manner inthe intestine by a combination of drug dissolutionin the core and diffusion through the pore channels.By adjusting the ratio of the intestinal fluid-solublepolymer to the intestinal fluid-insoluble polymer inthe membrane, the rate of drug delivery can be regu-lated. Representative application of this type of CrDDSis 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 ionizabledrug, this type of CrDDS has been developed.[2]

Because the gastrointestinal fluid has regularly main-tained a relatively constant level of ions, the deliveryof drug by this type of CrDDS can be modulated, the-oretically, at a constant rate.

Such a CrDDS is prepared by first complexing anionizable drug with an ion-exchange resin, such as

Hydrocolloids(20–75% w/w)

Gastric fluid (d>1)

d<1Colloid gel barrier

1000 1

Time (h)

Rad

ioac

tivity

in s

tom

ach

Valium (Placebo)

Valrelease(Placebo)

2 3 4 5 6

200

400

600

800

1000

2000

A

B

Fig. 22 (A) Schematic illustration of Valrelease� tablet, a

swelling-activated drug-delivery system, and the hydration-induced formation of colloid gel barrier. (B) Comparison inthe gastric residence profile between Valrelease with theconventional Valium capsule. (From Ref.[58].)

Coating of

Microporous membraneof intestinal fluid-insoluble polymer

Gastric emptying

(pH < 3)Stomach

Intestinal fluid(pH > 7.5)

Drug

Gastric fluid-labile drug

Gastric fluid-labile drug

Intestinal fluid-insoluble polymer

Intestinal fluid-soluble polymer

Fig. 23 Schematic illustration of a pH-activated drug-delivery system and the pH-dependent formation of micro-porous membrane in the intestinal tract.


DrugDelivery

Buccal–Mono

complexing a cationic drug with a resin containingSO3

� group or an anionic drug with a resin containingN(CH3)3

þ group. The granules of the drug–resin com-plex are further treated with an impregnating agent,like polyethylene glycol 4000, for reducing the rate ofswelling upon contact with an aqueous medium. Theyare then coated by an air-suspension coating techniquewith a water-insoluble but water-permeable polymericmembrane, such as ethylcellulose. This membraneserves as a rate-controlling barrier to modulate therelease of drug from the CrDDS. In the GI tract,hydronium and chloride ions diffuse into the CrDDSand interact with the drug–resin complex to triggerthe dissociation and release of ionic drug (Fig. 24).

This type of CrDDS is exemplified by the devel-opment of Pennkinetic� system (by Pennwalt Phar-maceuticals), which permits the formulation of oralliquid-type dosage forms with sustained release of acombination of hydrocodone and chlorpheniramine(Tussionex�).[14,42–44]

Hydrolysis-Activated DrugDelivery Systems

This type of CrDDS depends on the hydrolysis processto activate the release of drug molecules. In this sys-tem, the drug reservoir is either encapsulated in micro-capsules or homogeneously dispersed in microspheresor nanoparticles. It can also be fabricated as animplantable device. All these systems are preparedfrom a bioerodible or biodegradable polymer, such aspolylactide, poly(lactide–glycolide) copolymer, poly(orthoester), or poly(anhydride). The release of a drugfrom the polymer matrix is activated by the hydrolysis-induced degradation of polymer chains, and the rate ofdrug delivery is controlled by polymer degradationrate.[45] A typical example is the development ofLupron Depot�, an injectable microspheres for thesubcutaneous controlled delivery of luprolide, a potentbiosynthetic analog of gonadotropin-releasing hormone(GnRH) for the treatment of gonadotropin-dependentcancers, such as prostate carcinoma inmen and endome-triosis in the females, for up to 4 months. Anotherexample is the development of Zoladex� system, animplantable cylinder for the subcutaneous controlleddelivery of goserelin, also a potent biosynthetic analogof GnRH for the treatment of patients with prostatecancer (Fig. 25) for up to 3 months.[14]

Enzyme-Activated Drug Delivery Systems

In this type of CrDDS, the drug reservoir is either phys-ically entrapped in microspheres or chemically boundto polymer chains fabricated from biopolymers, suchas albumins or polypeptides. The release of drugs is

made possible by the enzymatic hydrolysis of biopoly-mers by a specific enzyme in the target tissue.[46–48] Atypical example is the development of albumin micro-spheres, which release 5-fluorouracil, in a controlledmanner, by protease-activated biodegradation.

FEEDBACK-REGULATED DRUGDELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesis activated by a triggering agent, such as a biochemicalsubstance, 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 sensorbuilt into the CrDDS.

Bioerosion-Regulated DrugDelivery Systems

The feedback-regulated drug delivery concept has beenapplied to the development of a bioerosion-regulatedCrDDS by Heller and Trescony.[49] This CrDDS con-sists of a drug-dispersed bioerodible matrix fabricatedfrom poly(vinyl methyl ether) half-ester, which wascoated with a layer of immobilized urease (Fig. 26).In a solution with near neutral pH, the polymer onlyerodes very slowly. In the presence of urea, urease at

BloodGut wall

PolymerDrug

IonCoating

membrane

Drug-resin complex particles

Polyethylene glycol treatment

Ethyl cellulose coating

Drug+Resin – SO3–

Resin [N(CH3)3+ ]Drug–

H+ + Resin – SO3– Drug+ Resin–SO3

– H+ + Drug+

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

+ ] CI – +Drug–

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


Drug

Delivery

Buccal–M

ono

the surface of the drug delivery system metabolizesurea to form ammonia. This causes the pH to increaseand activates a rapid degradation of polymer matrix aswell as the release of drug molecules.

Bioresponsive Drug Delivery Systems

The feedback-regulated drug delivery concept has alsobeen applied to the development of a bioresponsiveCrDDS by Horbett et al.[50]. In this CrDDS, the drugreservoir is contained in a device enclosed by a biore-sponsive polymeric membrane whose permeability todrug molecules is controlled by the concentration ofa biochemical agent in the tissue where the CrDDS islocated.

A typical example of this bioresponsive CrDDS isthe development of a glucose-triggered insulin deliverysystem, in which the insulin reservoir is encapsulatedwithin a hydrogel membrane containing pendantNR2 groups (Fig. 27). In an alkaline solution, theNR2 groups exist at neutral state and the membraneis unswollen and thus impermeable to insulin. Asglucose penetrates into the membrane, it is oxidizedenzymatically by the glucose oxidase entrapped in themembrane to form gluconic acid. This process triggersthe protonation of NR2 groups to form NR2H

þ, andthe hydrogel membrane becomes swollen and is thuspermeable to insulin molecules (Fig. 27). The amountof insulin delivered is bioresponsive to the concen-tration of glucose penetrating into the CrDDS.

Self-Regulating Drug Delivery Systems

This type of feedback-regulated CrDDS depends on areversible and competitive binding mechanism to acti-vate and to regulate the release of drug. In this CrDDS,the drug reservoir is a drug complex encapsulatedwithin a semipermeable polymeric membrane. Therelease of drug from the CrDDS is activated by themembrane permeation of a biochemical agent fromthe tissue where the CrDDS is located.

Kim et al. first applied the mechanism of reversiblebinding of sugar molecules with lectin into the designof self-regulating CrDDS.[51] For this CrDDS, a biolo-gically-active insulin derivative, in which insulin iscoupled with a sugar (e.g., maltose), was first preparedand then conjugated with lectin to form an insulin–sugar–lectin complex. The complex is then encapsu-lated within a semipermeable membrane to produceCrDDS. As blood glucose diffuses into the CrDDS, itbinds, competitively, with the binding sites in the lectin

Drug-dispersedpolymer matrix

Hydrolytic erosion

goserelin

Glp His Trp Ser Tyr Leu Arg Pro

t-Bu

NHAzgly(D)Ser

MicroporesPhase I: surface erosionPhase II: bulk erosion

0

0Weeks

Ser

um L

H (

lU/L

)

4 8 12

20

40

0

0Weeks

Ser

um T

esto

ster

one

(nm

ol/L

)

4 8 12

15

30

Fig. 25 Amino acid sequence of goserelin, a biosyntheticanalog of gonadotropin-releasing hormone, and the effect

of subcutaneous controlled release of goserelin from the bio-degradable poly(lactide-glycolide) implant on the serumlevels of luteinizing hormone and testosterone.

u

Hydrocortisone

u

Poly (vinyl methyl ether) half-ester(monolithic matrix)

Urease(Immobilized)

u

u

u

u

u

u u

urea

polymer

Hydrocortisone

erosionalkalinepH

2NH4 + HCO3 + OH–ureaseH2O

u u u

u u u u

00 20

Time (h)

Hyd

roco

rtis

one

rele

ased

(%

)

40

urea (0.1M)

60 80 100 120 140 160

20

40

60

80

100

+ −

Fig. 26 Cross-sectional view of a bioerosion-regulatedhydrocortisone delivery system, a feedback-regulated drugdelivery system, showing the drug-dispersed monolithic

bioerodible polymer matrix with surface-immobilizedureases. The mechanism of release and time course for theurea-activated release of hydrocortisone are also shown.

(From Ref.[49].)


DrugDelivery

Buccal–Mono

molecules and activates the release of the insulin–sugarderivatives from the binding sites. The released insulin-sugar derivatives diffuse out of the CrDDS, and theamount of insulin-sugar derivatives released dependson the concentration of glucose. Thus, a self-regulatingdrug delivery is achieved. However, a potential prob-lem has remained to be resolved: that is, the releaseof insulin is non-linear in response to the changes inglucose level.[52]

Further development of the self-regulating insulindelivery system has utilized the complex of glycosy-lated insulin–concanavalin A, which is encapsulatedinside a polymer membrane.[53] As glucose penetratesinto the system, it activates the release of glycosylatedinsulin from the complex for a controlled release fromthe system (Fig. 28). The amount of insulin released isthus self-regulated by the concentration of glucose thathas penetrated into the insulin delivery system.

SITE-TARGETING DRUG DELIVERY SYSTEMS

Delivery of a drug to a target tissue that needs medi-cation is known to be a complex process that consists

of multiple steps of diffusion and partitioning. TheCrDDSs outlined above generally address only the firststep of this complex process. Essentially, theseCrDDSs have been designed to control the rate of drugrelease from the delivery systems, but the path for thetransport of drug molecules from the delivery systemto the target tissue remains largely uncontrolled.

Ideally, the path of drug transport should also beunder control. Then, the ultimate goal of optimal treat-ment with maximal safety can be achieved. This can bereasonably accomplished by the development of aCrDDS with a site-targeting specificity (Fig. 2). Anideal site-targeting CrDDS has been proposed byRingsdorf.[54] A model, which is shown in Fig. 29, isconstructed from a non-immunogenic and biodegrad-able polymer and acts as the backbone to contain threetypes of attachments: 1) a site-specific targeting moiety,which is capable of leading the drug delivery system tothe vicinity of a target tissue (or cell); 2) a solubilizer,which enables the drug delivery system to be trans-ported to and preferentially taken up by a target tissue;and 3) a drug moiety, which is convalently bonded tothe backbone, through a spacer, and contains a linkagethat is cleavable only by a specific enzyme(s) at thetarget tissue.

N

N

.. ......

..........

...

................

.

. . ... ...... ...... ....... ....

....... .......

...

..

NR2

NR2NR2

Amine-containinghydrogel membrane

Insulinreservoir

Glucose oxidase

Glucose

Glucose

Hydrogel membrane swells

H

H

H

H

H

Swollen membrane

Insulin

Enzyme

HAcidic pH

+Gluconic acidOxidase

–NR2 –N R2H

NR2

N R2

NR2

+

N R2+

N R2+

R2+

N R2+

+

Fig. 27 Cross-sectional view of a bioresponsive insulindelivery system, a feedback-regulated drug delivery system,

showing the glucose oxidase-entrapped hydrogel membraneconstructed from amine-containing hydrophilic polymer.The mechanism of insulin release, in response to the influxof glucose, is also illustrated. (From Ref.[50].)

+

(Biochemical Approach)

Concanavalin A Glycosylated (G) insulin

Glucose in

Pancreatectomized dogs

100

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

Time of day

Blo

od g

luco

se le

vel (

mg/

dl)

200

300

F F F F F F = Feeding

Normoglycemiclevel

G-Insulin out

Polymermembrane

Self-Regulating Insulin Delivery Systems

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 pancreatecto-mized dogs. (From Ref.[53].)


Drug

Delivery

Buccal–M

ono

Unfortunately, this ideal site-targeting CrDDS isonly in the conceptual stage. Its construction remainslargely unresolved and is still a challenging task inthe biomedical and pharmaceutical sciences.

CONCLUSIONS

The controlled-release drug delivery systems outlinedhere have been steadily introduced into the biomedicalcommunity since the middle of the 1970s. There is agrowing belief that many more of the conventionaldrug delivery systems we have been using for decadeswill be gradually replaced in the coming years by theseCrDDSs.

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Site-specifictargetingmoiety

Spacer

Enzyme(at target tissue)

Cell membrane

Cell oftarget tissue

Drug

Solubilizer

Polymer backbone(nonimmunogenicand blodegradable)

Facilitate systemicdistributionand tissue uptake

Cleavablegroup

Drug

Drug

Fig. 29 An ideal site-targeting controlled-release drugdelivery. (From Ref.[54].)


DrugDelivery

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Drug Delivery: Controlled Release - Semantic Scholar Delivery Buccal–Mono Drug Delivery: Controlled Release Yie W. Chien Research and Development, Kaohsiung Medical University, Kaohsiung,