t The Theory
`
`and Practice of Industrial
`
`Pharmacy
`
`LEON LACHMAN, Ph.D.
`Lachman Consultant Services, Inc.
`Garden City, New York
`
`HERBERT A. LIEBERMAN, Ph.D.
`H. H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
`
`JOSEPH L. KANIG, Ph.D.
`Kanig Consulting and Research Associates, Inc.
`Ridgefield, Connecticut
`
`THIRD EDITION
`
`@
`
`LEA & FEBIGER' 1986- PHILADELPHIA
`
`Amneal 1069
`Amneal v. Supernus
`|PR2013-00372
`
`~
`
`,
`
`«‘i
`
`
`
`

`

`
`
`
`
`-14
`
`Sustained Release
`Dosage Forms
`
`NICHOLAS G. LORDI
`
`With many drugs, the basic goal of therapy is to
`achieve a steady-state blood or tissue level that is
`therapeutically effective and nontoxic for an ex-
`tended period of time. The design of proper dos-
`age regimens is an important element in accom-
`plishing this goal. A basic objective in dosage
`form design is to optimize the delivery of medi-
`cation so as to achieve a measure of control of
`the therapeutic effect in the face of uncertain
`fluctuations in the in Vivo environment
`in
`which drug release takes place. This is usually
`accomplished by maximizing drug availability,
`i.e., by attempting to attain a maximum rate and
`extent of drug absorption; however, control of
`drug action through formulation also implies
`controlling bioavajlability to reduce drug absorp—
`tion rates. In this chapter, approaches to the for—
`mulation of drug delivery systems, based on the
`deliberate control of drug availability, are consid-
`ered with emphasis on peroral dosage forms.
`
`The Sustained Release Concept
`Sustained release, sustained action, prolonged
`action,
`controlled release,
`extended action,
`timed release, depot, and repository dosage
`forms are terms used to identify drug delivery
`systems that are designed to achieve a prolonged
`therapeutic effect by continuously releasing
`medication over an extended period of time after
`administration of a single dose. In the case of
`injectable dosage forms,
`this period may vary
`from days to months. In the case of orally ad—
`ministered forms, however, this period is meas-
`ured in hours and critically depends on the resi—
`dence
`time
`of
`the
`dosage
`form in the
`gastrointestinal (GI) tract. The term “controlled
`release” has become associated with those sys-
`tems from which therapeutic agents may be au—
`tomatically delivered at predefined rates over a
`long period of time. Products of this type have
`
`been formulated for oral, injectable, and topical
`use, and include inserts for placement in body
`cavities as well.1
`The pharmaceutical industry provides a vari-
`ety of dosage forms and dosage levels of particu-
`lar drugs, thus enabling the physician to control
`the onset and duration of drug therapy by alter-
`ing the dose and/or mode of administration. In
`some instances, control of drug therapy can be
`achieved by taking advantage of beneficial drug
`interactions that affect drug disposition and
`elimination, e.g., the action of probenicid, which
`inhibits the excretion of penicillin, thus prolong—
`ing its blood level. Mixtures of drugs might be
`utilized to potentiate, synergize, or antagonize
`given drug actions. Alternately, drug mixtures
`might be formulated in which the rate and/or
`extent of drug absorption is modified. Sustained
`release dosage form design embodies this ap-
`proach to the control of drug action, i.e., through
`a process of either drug modification or dosage
`form modification, the absorption process, and
`subsequently drug action, can be controlled.
`Physicians can achieve several desirable ther—
`apeutic advantages by prescribing sustained re-
`lease forms. Since the frequency of drug admin—
`istration is reduced, patient compliance can be
`improved, and drug administration can be made
`more convenient as well. The blood level oscilla—
`tion characteristic of multiple dosing of conven-
`tional dosage forms is reduced, because a more
`even blood level is maintained. A less obvious
`advantage, implicit in the design of sustained
`release forms, is that the total amount of drug
`administered can be reduced, thus maximizing
`availability with a minimum dose. In addition,
`better control of drug absorption can be attained,
`since the high blood level peaks that may be ob—
`served after administration of a dose of a high—
`availability drug can be reduced by formulation
`in an extended action form. The safety margin of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`big
`inc:
`Sidt
`OV<
`fon
`
`tair
`suc
`clur
`tair
`pro:
`ch 2
`
`mig
`feet
`
`(a
`ing
`for!
`des:
`has:
`que
`tion
`are
`mu:
`essr
`turi
`
`wor
`rele
`
`(e-g
`acti
`
`ble
`
`Not
`th
`
`AbSl
`
`idly:
`live:
`
`Lon
`(>1
`
`Larg
`(> 1
`Gun
`und
`drug
`indi
`
`Fret
`indi
`
`No
`tain
`
`

`

`
`
`from the integrated form of equation (14) (the
`cube-root law):
`
`W5 = (Wot — ks’t)
`
`(15)
`
`If ks’ = 3 mgi/hr and the maintenance dose is
`900 mg, then 324 mg of drug would be available
`after 4 hours, and only 36 mg would be available
`after 8 hours of dissolution.
`Drug adsorbates represent a special case of
`complex formation in which the product is es-
`sentially insoluble. Drug availability is deter-
`mined only by the rate of dissociation (desorp-
`tion), and therefore, access of the adsorbent
`surface to water as well as the effective surface
`area of the adsorbate.
`Prodrugs are therapeutically inactive drug
`derivatives that regenerate the parent drug by
`enzymatic or nonenzymatic hydrolysis. Figure
`14-7 shows the scheme that identifies the poten-
`tial processes for achieving sustained action.
`The solubility, specific absorption rate, and/or
`elimination rate constant of an effective prodrug
`should be significantly lower than that of the
`parent compound. Kwan has described the phar—
`macokinetics of a prodrug in which the sus-
`tained blood level is determined by the meta-
`bolic rate, i.e., by formation of the active moiety
`after absorption.6 If the solubility of a drug has
`been significantly reduced by the formation of
`prodrug, and if breakdown of the prodrug takes
`place at the absorption site, then availability is
`limited by dissolution rate, and the same argu—
`ments as in the case of an insoluble drug com-
`plex apply. Examples of drugs from which
`prodrugs designed for prolonged action have
`been synthesized include isoproterenol, isonia—
`zid, and penicillin.7
`Approaches based on drug modification are
`sensitive to in vivo conditions. An important ob~
`jective of sustained release formulation is to
`minimize the effect of in vivo variables on drug
`release. An alternate approach, which has been
`advanced by Banker,
`involves preparation of
`drug dispersions through “molecular scale drug
`entrapment” in suitable carrier materials that
`act to retard release.8 Compositions of this type
`can be prepared by induced flocculation of a
`polymer latex (eg, acrylic copolymers). Control
`of drug release is accomplished by varying the
`nature of the carrier material, the loading dose of
`drug, and particle size of the product (i.e., sur-
`face area). These systems follow a scheme simi-
`lar to that suggested for drug adsorbates. They
`also have the advantage of allowing formulation
`of different dosage forms and may, with appro-
`priate selection of the carrier, be less influenced
`by in vivo variables.
`
`Since the extended release form of the drug,
`whether complex, prodrug, or solid dispersion,
`when formulated as a liquid suspension, is in
`contact with a fluid medium, an equilibrium is
`established in the formulation with respect to
`“free” drug and “bound” drug. The chemical sta-
`bility of these systems with respect to the con-
`version of “bound” to “free” drug, in addition to
`physical stability problems characteristic of sus-
`pensions, adds an additional dimension to their
`overall formulation. The development of injecta—
`ble depot forms as suspensions of physicochemi-
`cally modified drugs has been proven to be an
`effective means of achieving controlled release
`in antibiotic therapy.
`
`Approaches Based On Dosage
`Form Modification
`
`Most peroral sustained release products have
`been formulated as encapsulations or tablets.
`Formulations based on modification of the phy—
`sicochemical properties of these dosage forms
`can be classed into three product types: encap—
`sulated slow release beads
`(or granules),
`tabletted mixed or slow release granulations,
`and slow release (core) tablets. Fabrication of
`tablets allows for direct incorporation of loading
`doses, by preparation of either multilayered or
`press-coated tablets. One layer or the outer coat
`of the tablet is prepared from a potentially rapid
`disintegrating granulation,
`leaving the less
`quickly disintegrating layer or core, which con-
`tains the maintenance dose. Systems prepared
`as tabletted mixed released granulations may or
`may not be designed to disintegrate quickly,
`simulating the administration of an encapsu—
`lated form in the latter case.
`Encapsulated sustained release dosage forms
`have two specific advantages over core tablet
`designs. (1) Undisintegrated tablets may remain
`in the stomach for extended periods of time, ex—
`cessively delaying absorption of the mainte-
`nance dose. Disintegration of the capsule shell
`in the gastric fluid releases particles that can
`pass unimpeded through the pyloric valve.
`(2) There is statistical assurance of drug release
`with encapsulated forms, since release of drug
`by a significant fraction of the granules is highly
`probable. If a core tablet fails to release drug, all
`of the maintenance dose is lost.
`Two general principles are involved in retard-
`ing drug release from most practical sustained
`release formulations
`involving dosage form
`modification. These are the embedded matrix
`and the barrier principle, which are schematic—
`ally shown in Figures 14-8 and 14-9. In the
`
`442 - The Theory and Practice of Industrial Pharmacy
`
`FIG. 14-5
`Network 1;
`material. 1
`
`former c.
`matrix 0:
`
`capsulats
`into tablt
`tion of 56
`
`FIG. 14-E
`dosage for?
`B, Permea
`diffusion.
`of barrier
`
`

`

`
`
`
`
`drug,
`rsion,
`is in
`um is
`act to
`al sta-
`: con—
`ion to
`if sus-
`, their
`
`.jecta-
`herni-
`be an
`elease
`
`; have
`ablets.
`e phy—
`forms
`encap-
`rules),
`ations,
`ion of
`
`Jading
`:red or
`er coat
`
`y rapid
`a
`less
`h con—
`
`epared
`may or
`uickly,
`capsu-
`
`:forms
`: tablet
`remain
`ne, ex-
`nainte-
`Ie shell
`lat can
`valve.
`release
`
`
`
`MATRIX
`
`EXTRACTING MEDIA
`
`a.
`
`b.
`
`c.
`
`/o
`
`C
`
`A
`
`C
`
`DEPLETION ZONE
`
`
`
`I
`
`L
`
`., _
`/
`
`HYDRODYNAMIC
`
`DIFFUSION LAYER
`
`FIG. 14—8. Embedded matrix concept as a mechanism of controlled release in sustained release dosage form design.
`Network model (a): drug is insoluble in the retardant material. Dispersion model (b): drug is soluble in the retardant
`material. Diffusion profile (c) characterizes drug release from a matrix system.
`
`former case, drug is dispersed (embedded) in a
`matrix of retardant material, which may be en-
`capsulated in particulate form or compressed
`into tablets. Release is controlled by a combina—
`tion of several physical processes. These include
`
`
`
`
`RESERVOIR
`
`FIG. 14-9. Barrier—mediated models of sustained release
`dosage form designs. A, Drug diffusion through the barrier.
`B, Permeation of barrier by elution media followed by drug
`diffusion. C, Erosion of barrier, releasing drug. D, Rupture
`of barrier as a result of permeation of elation media.
`
`permeation of the matrix by water, leaching (ex-
`traction or diffusion) of drug from the matrix,
`and erosion of matrix material. Alternately, drug
`may dissolve in the matrix material and be re-
`leased by diffusion through the matrix material
`or partitioned between the matrix and extracting
`fluid. Matrices may be prepared from insoluble
`or erodable materials (e.g., silicone polymers or
`lipids).
`Higuchi has provided the theoretic basis for
`defining drug release from inert matrices.9 The
`equation describing drug release from the planar
`surface of an insoluble matrix is:
`
`Q == [(DeCs/rXZA ~ eCs)t]é
`
`(16)
`
`where Q is the amount of drug released per unit.
`surface after time t, D is the diffusion coefficient
`of the drug in the elution medium, 1' is the tortu—
`osity of the matrix, 6 is the porosity of the ma-
`trix, Cs is the solubility of the drug in the elution
`medium, and A is the initial loading dose of drug
`in the matrix. This expression was derived as-
`suming a linear diffusion gradient as
`dia—
`grammed in Figure 14—8c. Drug release is trig—
`
`SUSTAINED RELEASE DOSAGE FORMS ~ 443
`
`
`
`

`

`
`
`“—
`
`Matrix Tablets
`
`lith the latter,
`the reaction is
`3 in which the
`
`rsed in the liq—
`:ase from such
`atrix diffusion
`
`[nation (19).
`
`granulations
`encapsulation.
`to disintegrate
`ie administra—
`
`re advantages
`3e encapsula-
`ges of the tab—
`each utilizing
`type of formu—
`rnixed release
`h different re—
`pare three dif—
`olor coded for
`‘tted. The first
`
`alease granular.
`inder; the sec—
`aird uses shel—
`
`controlled by
`estinal fluid—
`integrates at a
`ilation.
`
`these formulations is liquid penetration into the
`One of the least complicated approaches to
`matrix unless channeling (wetting) agents are
`the manufacture of sustained release dosage
`included to promote permeation of the polymer
`forms involves the direct compression of blends
`matrix by water, which allows drug dissolution
`of drug, retardant material, and additives to form
`and diffusion from the channels created in the
`a tablet in which drug is embedded in a matrix
`matrix. Formulations should be designed so that
`core of the retardant. Alternately, retardant-dimg
`pore diffusion becomes rate-controlling, release
`blends may be granulated prior to compression.
`is defined by equation (16) or (17), and the re-
`Table 14—7 identifies examples of the three
`lease profile is represented by curve C (Fig. 14-
`classes of retardant material used to formulate
`10). Drug bioavailability, which is critically de—
`matrix tablets, each class demonstrating a differ-
`pendent on the drug:polymer ratio, may be
`ent approach to the matrix concept. The first
`modified by inclusion of diluents such as lactose
`class consists of retardants that form insoluble
`in place of polymer in low-milligram-potency
`or “skeleton” matrices; the second class repre-
`formulations.33
`sents water-insoluble materials that are potenti-
`Egested tablets contain unreleased drug in the
`ally erodable; and the third class consists ofpoly—
`core. In one study of polyvinyl chloride matrix
`mers that form hydrophilic matrices. Loading
`tablets containing prednisolone disodium phos—
`doses are best included as the second layer of a
`phate, egested tablets contained 72% of the
`two—layer tablet or in a coating applied to the
`maintenance dose for matrices containing 87%
`matrix core.
`plastic and 2% drug, and 28% drug for matrices
`Insoluble, inert polymers such as polyethyl—
`containing 84% plastic and 3% drug.“ These
`ene, polyvinyl chloride, and acrylate copolymers
`forms of matrix tablets are not useful for high-
`have been used as the basis for many marketed
`milligram—potency formulations in which the
`formulations. Tablets prepared from these mate-
`polymer content would be insufficient to form a
`rials are designed to be egested intact and not
`matrix, or for highly water-insoluble drugs in
`break apart in the GI tract. Tablets may be di-
`which dissolution in the matrix would become
`rectly compressed from mixtures of drug and
`rate—limiting. Release of water-soluble drugs,
`ground polymer; however, if ethyl cellulose is
`however, should be unaffected by the amount of
`used as the matrix former, a wet granulation
`liquid, pH-value, enzyme content, and other
`procedure using ethanol can be employed. The
`
`physical properties of digestive fluids, unless
`rate-limiting step in controlling release from
`the drug is in a salt form that precipitates within
`
`
`
`
`ated by a sus-
` TABLE 14-7. Materials Used as Retardants in Matrix Tablet Formulations
`n based on the
`
`
`Matrix Characteristics
`Material
`tin crystals are
`
`--———_._.________fi_
`
`barrier and are
`
`lnselm‘zk, their
`
`rapidiiy disinte-
`nules. The bar-
`
`lvantageous for
`
`potency drugs
`l'nSoluble, erodable
`relatively small
`in the formula-
`
`
`
`
`SUSTAINED RELEASE DOSAGE FORMS - 453
`
`
`
`
`:ented by a sus-
`
`lline, which is
`
`3r for a 12—hour ;
`)rmulated as a :r
`
`iylline contain-
`
`lated in a semi“
`
`n of the matrix
`
`
`rded action pel—
`
`m should have
`a, similar to the
`
`ure homogene-
`
`
`
`ns during com-
`
`Polyethylene
`Polyvinyl chloride
`Methyl acrylate—methacrylate copolymer
`Ethylcellulose
`Camauba wax
`Stearyl alcohol
`Stearic acid
`
`Polyethylene glycol
`Castor wax
`
`Polyethylene glycol monostearate
`Triglycerides
`
`Methylcellulose (400 cps, 4000 cps)
`Hydroxyethylcellulose
`Hydroxypropylmethylcellulose
`(60 HG, 90 HG, 25 cps, 4000 cps, 15,000 cps)
`Sodium carlboxymethylcellulose
`Carboxypolymethylene
`Galactomannose
`Sodium alginate
`
`
`
`
`
`
`
`
`

`

`
`
`The wanglycol ratio could be adjusted to vary
`the release characteristics.
`
`A novel approach to the development of a lipid
`matrix utilizes pancreatic lipase and calcium
`carbonate as additives, with triglycerides as re-
`tardants. The lipase is activated on contact with
`moisture and thus promotes erosion indepen-
`dent of intestinal fluid composition. The release
`profile is controlled by the calcium carbonate,
`since calcium ions function as a lipase accelera-
`tor.36 In another technique, drug is mass-
`blended with stearyl alcohol at a temperature
`above its glass transition (approximately 60°C),
`and the mass is cooled and granulated with an
`alcoholic solution of zein. This formulation is
`claimed to produce tablets with stable release
`characteristics. Since natural waxes and lipids
`are complex mixtures, and a fusion process is
`usually required for processing, hardening with
`decrease in effective drug release on aging may
`be observed, owing to polymorphic and amor-
`phous to crystalline transitions.
`The third group of matrix formers represents
`nondigestible materials that form gels in situ.
`Drug release is controlled by penetration of
`water through a gel layer produced by hydration
`of the polymer and diffusion of drug through the
`swollen, hydrated matrix, in addition to erosion
`of the gelled layer (curve D, Fig. 14—10). The ex-
`tent to which diffusion or erosion controls re—
`lease depends on the polymer selected for the
`formulation as well as on the drug: polymer
`ratio. Low-molecular—weight methylcelluloses
`release drug largely by attrition, since a signifi-
`cant intact hydrated layer is not maintained.
`Anionic polymers such as carboxymethyl cellu-
`lose and carpolene can interact with cationic
`drugs and show increased dissolution in intesti-
`nal fluid. Carboxypolymethylene does not by-
`drate in gastric fluid. The best matrix former in
`this group is hydroxymethylcellulose 90 HG
`15,000 cps, an inert polymer that does not ad-
`versely interact with either acidic or basic drugs,
`and that on contact with water slowly forms a gel
`that is more resistant to attrition. Release rates
`can be adjusted for low-milligram—potency for-
`mulations by replacing polymer with lactose.
`High drug: polymerratios result in formulations
`from which drug release is controlled by attri-
`tion.37
`
`The process used to prepare formulations for
`compression depends on the polymer and
`drug:polymer ratio. With high drugcpolymer
`ratios, a wet granulation process is required.
`Low-milligram~potency formulations may be
`directly compressed or granulated using alcohol
`if the polymer is not in a form amenable to direct
`
` prepare sustained release theophylline tablets.
`
`
`the matrix pores on dissolution when penetrated
`by acid or basic media.
`Waxes, lipids, and related materials form ma—
`trices that control release through both pore dif-
`fusion and erosion (curve D, Fig. 14-10). Re—
`lease
`characteristics
`are
`therefore more
`sensitive to digestive fluid composition than to
`the totally insoluble polymer matrix. Total re-
`lease of drug from wax-lipid matrices is not pos
`sible, since a certain fraction of the dose is
`coated with impermeable wax films. Release is
`more effectively controlled by the addition of
`surfactants or wicking agents in the form of hy-
`drophilic polymers, which promote water pene—
`tration and subsequent matrix erosion.
`Carnauba wax in combination with stearyl
`alcohol or stearic acid has been utilized as a re—
`tardant base for many sustained release matrix
`formulations. Mixtures of (1:1) hydrogenated
`castor oil and propylene glycol monostearate and
`of carnauba wax and stearyl alcohol or stearic
`acid have been extensively studied as retardants
`for both water—soluble and waterainsoluble com—
`pounds. Materials with melting points that are
`too low or materials that are too soft cannot be
`readily processed to form tablets with good phys-
`ical stability. Such retardants as carnauba wax
`or hydrogenated castor oil provide the necessary
`physical characteristics to form an easily com-
`pressible stable matrix. If used singly,
`these
`materials excessively delay drug release.
`Three methods may be used to disperse drug
`and additive in the retardant base. A solvent
`evaporation technique can be used, in which a
`solution or dispersion of drug and additive is in—
`corporated into the molten wax phase. The sol—
`vent is removed by evaporation. Dry blends of
`ingredients may be slugged and granulated. A
`more uniform dispersion, however, can be pre—
`pared by the fusion technique, in which drug
`and additive are blended into the molten wax
`matrix at temperatures slightly above the melt—
`ing point (approximately 90° C for carnauba
`wax). The molten material may be spray—
`congealed, solidified and milled, solidified and
`flaked, or poured on a cold rotating drum to form
`sheets, which are then milled and screened to
`form a granulation.
`In the absence of additives, drug release is
`prolonged and nonlinear. Apparent zero-order
`release can be obtained by addition of additives
`such as polyvinyl pyrrolidone or polyoxyethylene
`lauryl ethers. In a study by Dahkuri et al., 10 to
`20% hydrophilic polymer effectively controlled
`release from carnauba-wax/stearyl—alcohol ma—
`trices of tripelennamine hydrochloride.35 Matri-
`ces prepared from carnauba—wax/polyethylene-
`glycol compositions have also been used to
`
`454 ° The Theory and Practice of Industrial Pharmacy
`
`
`
`

`

`
`
`compression. Forrnulations of this type are de-
`signed to release 100% of drug in vivo, unlike
`the other matrix forms, which may be partially
`egested and consequently must be formulated to
`contain drug in excess of that required to attain
`the desired therapeutic effect.
`Pseudo-latex forms of the normally water—
`insoluble enteric polymers, such as cellulose
`acetate phthalate and acrylic resin, can be used
`as granulating agents
`for . high—milligram-
`potency drugs. Erodable matrix tablets can be
`prepared from these granulations. This ap-
`proach has been tested with theophylline.38
`
`a”
`
`4
`‘
`
`A
`
`OSMOTIC PUMP
`
`,DELIVERY ORIFICE
`
`/
`CORE
`/
`
`\SEMl-PERMEABLE
`MEMBRANE
`
`DELlVERY RATE
`
`
`
`
`
`
`
`
`
`
`
`
`
`TIME
`
`(3-
`
`
`
`
`
`
`Controlled Release Technology
`Controlled release dosage forms are designed
`to release drug in vivo according to predictable
`
`
`M'CROSEAL DEUVERY SYSTEM
`rates that can be verified by in vitro measure-
`
`
`
`
`0 o o /BARR'ER
`ments. Of the many approaches to formulation
`
`
`0 °
`of sustained-release medication described in
`
`
`
`
`0 0
`this chapter, those fabricated as insoluble matrix
`
`
`tablets come closest to realization of this objec-
`O o 0
`
`
`tive, since release of water-soluble drug from
`0° 30
`
`
`this form should be independent ofin vivo varia—
`o o
`
`
`bles. Controlled release technolo
`
` DlSPERSED LlQUlD
`lcalmechanism 0fdrug availability to the eXtegt
`FIG. 14-14. Controlled release dosage forms. A, Cross-
`
`section ofosmotic pump. B, Release rateprofile character-
`that the dosage form release rate can be specr—
`
`
`fied. Potential developments and new ap-
`istic ofosmotic pump. C, Micro-seal drug delivery system.
`
`proaches to oral controlled release drug delivery
`
`include hydrodynamic pressure controlled sys-
`tems, intragastric floating tablets, transmucosal
`increases to its maximum value, drug release is
`
`tablggs, and microporous membrane coated tab-
`lets.
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`zero—order, as shown in Figure 14-14B, until all
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`solid material is dissolved. Thereafter, the deliv—
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`One example of a dosage form design that il-
`ery rate decreases parabolically to zero.
`lustrates the application of controlled release
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`The diameter of the orifice must be smaller
`technology to pharmaceutical formulation is the
`than a maximum size to minimize drug delivery
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`orally administered elementary
`osmotic pump
`by diffusion through the orifice, and larger than
`show in Figure 14-14A. This device is fabri-
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`cated from a tablet that contains water-soluble
`pressure in the system, which acts in opposition
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`osmotically active drug, or that is blended with
`to the osmotic pressure. For devices containing
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`an osmotically active diluent, by coating the tab—
`potassium chloride, orifices can range from 75 to
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`let with a cellulose triacetate barrier, which
`275 ,am in diameter. The device can be used as
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`functions as a semipermeable membrane.40 A
`a drug delivery system for any water—soluble
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`laser is used to form a precision orifice in the
`drug and can be designed to deliver significant
`barrier. Since the barrier is permeable only to
`fractions of the total dose at zero—order rates
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`water, initial penetration of water dissolves the
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`unaffected by in vivo conditions. Since ions do
`outer part of the core, resulting in the develop-
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`not diffuse into the device, release of acidic and
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`ment of an osmotic pressure difference across
`basic drugs is independent of gastrointestinal
`the membrane. The system imbibes water at a
`pH.
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`rate proportional to the water permeability and
`A design that provides zero-order release of
`effective surface area of the membrane and to
`potassium chloride consists of the soluble tablet
`the osmotic gradient of the core formulation.
`core coated with a microporous membrane,
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`The device delivers a volume of saturated solu-
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`tion equal to the volume ofwater uptake through
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`brane is produced in situ by leaching out sucrose
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`the membrane. After an initial lag time (approxi-
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`that hasbeen suspended in a polyvinyl chloride
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`mately 1 hour) during which the delivery rate
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`membrane.41
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`SUSTAINED RELEASE DOSAGE FORMS . 455
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