Remington: The
`Science and Practice
`of Pharmacy
`
`Volume Il
`
`AUROBINDO EX1018, 1
`
`AUROBINDO EX1018, 1
`
`

`

`1 95
`
`EDITION
`
`Remington:
`Practice of
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`and Editor
`
`AUROBINDO EX1018, 2
`
`

`

`The Science and
`Pharmacy
`
`1995
`
`MACK PUBLISHING COMPANY
`Easton, Pennsylvania 18042
`
`AUROBINDO EX1018, 3
`
`AUROBINDO EX1018, 3
`
`

`

`Enteredaccording to Act of Congress,in the year 1885 by Joseph P Remington,
`in the Office ofthe Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907,1 917, by Joseph P Remington
`
`Copyright 1926, 1936, bythe Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by The Philadelphia College of
`Pharmacyand Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`The use ofstructuralformulasfrom USAN andthe USP Dictionary ofDrug Namesis by
`permission ofThe USP Convention. The Conventionis not responsiblefor any inaccuracy
`contained herein.
`
`Norice—This text is not intendedto represent, norshallit be interpretedto be, the equivalent
`ofor a substituteforthe official United States Pharmacopeia (USP) and/orthe National
`Formulary (NF). Inthe eventofany difference or discrepancy betweenthe current official
`USP or NF standardsofstrength, quality, purity, packaging andlabelingfor drugs and
`representations ofthemherein,the context andeffect ofthe official compendiashall prevail.
`
`AUROBINDO EX1018, 4
`
`

`

`CHAPTER 94.
`
`Sustained-Release Drug Delivery Systems
`
`
`
`Charles S L Chiao, PhD
`Anda SR Pharmaceuticals, Inc
`
`Joseph R Robinson, PhD
`Professor of Pharmacy
`School of Pharmacy
`University of Wisconsin
`Madison, WI 53706
`
`The goal of any drug delivery system is to provide a therapeu-
`tic amount of drug to the propersite in the body to achieve
`promptly, and then maintain, the desired drug concentration.
`Thatis, the drug-delivery system should deliver drug at a rate
`dictated by the needsof the body overthe period of treatment.
`This idealized objective points to the two aspects most impor-
`tant to drug delivery, namely, spatial placement and tempo-
`ral delivery of a drug. Spatial placementrelates to target-
`ing a drug toa specific organortissue, while temporaldelivery
`refers to controlling the rate of drug delivery to the target
`tissue. Anappropriately designed sustained-release drug de-
`livery system can be a major advance toward solving these two
`It is for this reason that the science and technol-
`ogy responsible for developmentof sustained-release pharma-
`ceuticals have been and continue to be the focus of a great
`deal of attention in both industrial and academic laboratories.
`There currently existnumerous products on the market formu-
`lated for bothoral and parenteral routes of administration that
`claim sustained or controlled drug delivery. The bulk of
`researchhas beendirected at oral dosage formsthat satisfy
`the temporal aspect of drug delivery, but many of the newer
`approaches underinvestigation may allow for spatial place-
`This chapterwill define and explain the nature
`of sustained-release drug therapy, briefly outline relevant
`physicochemical and biological properties of a drug that af-
`fect sustained-release performanceand review the more com-
`montypes of oral and parenteral sustained-release dosage
`In addition, a brief discussion of some methods cur-
`rently being used to develop targeted delivery systems will be
`
`Conventional Drug Therapy
`
`To gain an appreciation for the value of sustained drug
`therapy it is useful to review some fundamental aspects of
`conventional drug delivery.! Consider single dosing of a
`hypothetical drug that follows a simple one-compartment phar-
`macokinetic model for disposition. Depending onthe route
`of administration, a conventional dosage form ofthe drug, eg,
`a solution, suspension, capsule, tablet, etc, probably will pro-
`duce a drug blood level versus time profile similar to that
`shownin Fig 1. The term “drug bloodlevel” refers to the
`concentration of drug in bloodorplasma, but the concentra-
`tion in any tissue could be plotted on the ordinate.
`It can be
`seenfrom this figure that administration of a drug by either
`intravenous injection or an extravascular route, eg, orally,
`intramuscularly or rectally, does not maintain drug blood
`levels within the therapeutic range for extended periods of
`time. The short duration of action is due to the inability of
`conventional dosage forms to control temporal delivery.
`If
`an attempt is made to maintain drug blood levels in the thera-
`
`In this case the drug
`is shownin Fig 2 for the oral route.
`bloodlevel reachedandthe time requiredto reachthat level
`dependonthe dose andthe dosing interval. There are sev-
`eral potential problems inherent in multiple-dose therapy:
`1.
`Ifthe dosing intervalis not appropriate forthe biologicalhalf-life of
`the drug, large ‘‘peaks”’ and ‘“‘valleys” in the drug bloodlevel mayresult.
`For example, drugs with short half-lives require frequent dosings to main-
`tain constant therapeutic levels.
`2. The drug bloodlevel may not be within the therapeutic range at
`sufficiently early times, an important consideration for certain disease
`states.
`3. Patient noncompliance with the multiple-dosing regimen canresult
`in failure of this approach.
`
`In manyinstances, potential problemsassociatedwith con-
`ventional drug therapy can be overcome. Whenthis is the
`case, drugs given in conventional dosage forms by multiple-
`dosing can produce the desired drug blood level for extended
`periods of time. Frequently, however, these problems are
`significant enough to make drug therapy with conventional
`dosage forms less desirable than sustained-release drug
`therapy. This fact, coupled with the intrinsic inability of
`conventional dosage forms to achieve spatial placement, is a
`compelling motive for investigation of sustained-release drug
`delivery systems. There are numerouspotential advantages
`of sustained-release drug therapy that will be discussedin the
`next section.
`
`Sustained-Release Drug Therapy
`
`As already mentioned, conventional dosage forms include
`solutions, suspensions, capsules, tablets, emulsions, aero-
`sols, foams, ointments and suppositories. For this discus-
`sion, these dosage forms can be considered to release their
`active ingredients into an absorption pool immediately.
`Thisis illustrated in the following simple kinetic scheme:
`k
`“matt
`k
`‘i
`i
`Absorption
`Target
`?
`’
`Dosage
`a
`Form drug release Pool
`absorption Area
`elimination
`The absorption pool represents a solution of the drug at the
`site of absorption, and the terms k,., k, and k, are first-order
`rate constants for drug release, absorption andoverall elimina-
`tion, respectively.
`Immediate release from a conventional
`dosage form implies that k, >>> k, or, alternatively, that
`absorptionof drug across a biological membrane, suchas the
`intestinal epithelium, is the rate-limiting step in delivery of the
`drug to its target area. For nonimmediate-release dosage
`forms, k, <<< ky, that is, release of drug from the dosage
`formis the rate-limiting step. This causes the above kinetic
`schemeto reduce to
`
`AUROBINDO EX1018, 5
`
`

`

`
`
`
`
`
`
`DRUGBLOODLEVEL(emount/’)
`
`LEVEL
`
`TIME
`
`(hrs)
`
`
`
`DRUGBLOOD
`
`Ineffective
`
`Range
`
`TIME (hrs)
`
`Fig 1. Typical drug bloodlevel versus time profiles for intravenous
`injections and an extravascular route of administration.
`
`Fig 3. Typical drug blood level versus time profiles for delayed-
`release drug delivery by arepeat-action dosage form.
`
`system must be directed primarily at altering the release rate
`by affecting the value of k,... The many waysin whichthis has
`been attemptedwill be discussedlaterin this chapter.
`Nonimmediate-release delivery systems may be divided con-
`veniently into fourcategories:
`1. Delayed release
`2.
`Sustainedrelease
`a. Controlled release
`b. Prolongedrelease
`. Site-specific release
`4. Receptorrelease
`
`Delayed-release systems are those that use repetitive, inter-
`mittent dosings of a drug from one or more immediate-release
`units incorporated into a single dosage form. Examples of
`delayed-release systemsinclude repeat-action tablets andcap-
`sules, and enteric-coated tablets where timed release is
`achievedby a barrier coating. Adelayed-release dosage form
`does not produce or maintain uniformdrug blood levels within
`the therapeutic range, as shownin Fig 3, but, nonetheless, is
`more effective for patient compliance than conventional dos-
`age forms.
`Sustained-release systems include any drug delivery sys-
`tem that achieves slow release of drug over an extended
`period of time.
`If the systems can provide some control,
`whetherthis be of a temporal or spatial nature, or both, of
`drug release in the body, or in other words, the system is
`successful at maintaining constant drug levels in the target
`tissue orcells, it is considered a controlled-release system.
`Ifitis unsuccessful at this, but nevertheless prolongs therapeu-
`tic bloodortissue level of the drug for an extended period of
`time, it is considered a prolonged-release system. This is
`illustrated in Fig 4.
`Site-specific and receptor release refer to targeting of a
`drug directly to a certain biological location.
`In the case of
`site-specific release, the target is adjacent to, or in the dis-
`eased organortissue; for receptorrelease, the target is the
`particular receptorfor a drug within an organ ortissue. Both
`of these systemssatisfy the spatial aspect of drug delivery.
`
`Release Rate and Dose Considerations?
`
`Although it is not necessary or desirable to maintain a
`constant level of drug in the blood ortarget tissue forall
`therapeutic cases, this is the ideal goal of a sustained-release
`delivery system.
`In fact, in some cases optimumtherapyis
`achieved by oscillating, rather than constant, drug levels.
`An example ofthis is antibiotic therapy, where the activity of
`the drug is required only during growth phases of the
`microorganism. A constant drug level will succeedat curing
`or controlling the condition, however, andthis is true for most
`formsof therapy.
`The objective in designing a sustained-release systemis to
`deliver drug at a rate necessary to achieve and maintain a
`constant drug blood level. This rate should be analogous to
`that achieved by continuous intravenous infusion where a
`drugis provided to the patient at a constant rate just equal to
`its rate of elimination. This implies that the rate of delivery
`must be independent of the amount of drug remaining in the
`dosage form and constant over time. That is, release from
`the dosage form shouldfollow zero-order kinetics, as shown
`by
`
`k® = Rate In = Rate Out =k, Cy + Vg
`where k° is the zero-order rate constant for drug release
`(amount/time), k, is the first-order rate constant for overall
`drug elimination (time~!), Cy is the desired drug level in the
`body (amount/volume) and V, is the volume space in which
`the drug is distributed. The values of k,, C, and V, needed to
`calculate ke are obtained from appropriately designedsingle-
`dose pharmacokinetic studies. Equation 1 provides the
`method to calculate the zero-orderrelease rate constant nec-
`essary to maintain a constant drug blood ortissue level for the
`simplest case where drugis eliminatedby first-orderkinetics.
`For many drugs, however, more complex elimination kinetics
`and other factors affecting their disposition are involved.
`This in turn affects the nature of the release kinetics necessary
`to maintain a constant drug blood level.
`recognize that while zero-orderrelease may be desirable theo-
`
`Range
`
`
`Toxic
`
`Therapeutic
`Range
`
`Range
`
`
`
`
`
`tDRUGBLOOD(anon)LEVEL
`
`
`
`
`
`
`
`DRUGBLOODLEVEL(omount/)
`
`Ineffective
`Range
`
`TIME—(hrs)
`
`TIME (hrs)
`
`Fig 2. Typical drug blood level versus time profile following oral
`multiple-dose therapy.
`
`Fig 4. Drug bloodlevel versus time profiles showing the relation-
`ship between controlled-release (A), prolonged-release (B) and con-
`ventional-release (C) drug delivery.
`
`AUROBINDO EX1018, 6
`
`AUROBINDO EX1018, 6
`
`

`

`CHAPTER 94
`
`retically, nonzero-orderrelease may be equivalentclinically to
`constant release in many cases. Aside from the extent of
`intra- andintersubject variation is the observation that, for
`many drugs, modest changesin drugtissue levels do notresult
`in an improvementin clinical performance. Thus, a noncon-
`stant drug level may be indistinguishable clinically from a
`constant druglevel.
`To achieve a therapeutic level promptly and sustain the
`level for a given period of time, the dosage form generally
`consists of two parts:
`aninitial priming dose, D,, that re-
`leases drug immediately and a maintenance orsustaining
`dose, D,,. The total dose, W, thus required for the system is
`
`W=D,+D,
`
`(2)
`
`For a system where the maintenance dosereleases drug by a
`zero-order process for a specified period of time, the total
`
`Table 1—Potential Advantages of Sustained Drug Therapy
`
`1. Avoid patient compliance problems
`2.
`Employlesstotal drug
`a. Minimize oreliminate local side effects
`b. Minimize or eliminate systemic side effects
`c. Obtainless potentiation or reduction in drug activity with
`chronic use
`d. Minimize drug accumulation with chronic dosing
`Improveefficiencyin treatment
`a. Cure or control condition more promptly
`b.
`Improvecontrol of condition, ie, reduce fluctuationin drug
`level
`Improvebioavailability of some drugs
`c.
`d. Makeuseof special effects, eg, sustained-release aspirinfor
`morningrelief of arthritis by dosing before bedtime
`4, Economy
`
`3.
`
`(3)
`W =D; + kT,
`drug therapy. Minimizing oreliminating patient compliance
`problemsis an obvious advantageof sustained-release therapy.
`where ke is the zero-orderrate constant for drug release and
`Because of the nature of its release kinetics, a sustained-
`Ty is the total time desired for sustained release from one
`release system should be able to use less total drug over the
`Ifthe maintenance dose begins the release of drug at
`time course of therapy than a conventional preparation. The
`the time of dosing (¢ = 0), it will add to that which is provided
`advantagesofthis are a decrease orelimination of both local
`by the initial dose, thus increasing theinitial drug level.
`In
`and systemic side effects, less potentiation or reduction in
`this case a correction factoris needed to accountfor the added
`drug activity with chronic use and minimization of drug accu-
`drug from the maintenance dose:
`mulation in body tissues with chronic dosing.
`W =D, + OT, -— oTty
`Unquestionably the most important reason for sustained-
`drug therapyis improved efficiency in treatment, ie, optimized
`The correction factor, kT’
`/',, is the amount of drug provided
`therapy. The result of obtaining constant drug bloodlevels
`during the period from t =0to the time of the peak druglevel,
`from a sustained-release system is to achieve promptly the
`T,. No correction factor is needed if the dosage form is
`desired effect and maintain it for an extendedperiod oftime.
`constructed in sucha fashionthat the maintenance dose does
`Reduction or elimination of fluctuations in the drug blood
`not beginto release drug until time T,,.
`level allows better disease state management.
`In addition,
`It already has been mentioned that a perfectly invariant
`the method by which sustained release is achieved can im-
`drug bloodortissue level versus time profile is the ideal goal
`provethe bioavailability of some drugs. For example, drugs
`of asustained-release system. The way to achievethis, inthe
`susceptible to enzymatic inactivation or bacterial decomposi-
`simplestcase, is by use of a maintenance dosethatreleasesits
`tion can be protected by encapsulation in polymer systems
`drug by zero-orderkinetics. However, satisfactory approxi-
`suitable for sustained release. For drugs that have a “‘spe-
`mations of a constant drug level can be obtained by suitable
`cific window” for absorption, increased bioavailability can be
`combinationsofthe initial dose and a maintenance dose that
`attained by localizing the sustained-release delivery system in
`releasesits drug by a first-order process.
`The total dose for
`certain regions of the gastrointestinal tract.
`Improvedeffi-
`suchasystemis
`ciency in treatment also can take the form of a special thera-
`peutic effect not possible with a conventional dosage form
`(see Table 1).
`The last potential advantage listed in Table 1, that of
`economy, can be examined from two points of view.
`Althoughtheinitial unit cost of most sustained-drug delivery
`systems usually is greater than that of conventional dosage
`forms because of the special nature of these products, the
`average cost of treatment over an extended time period may
`beless. Economyalso may result froma decreasein nursing
`time/hospitalization, less lost work time, etc.
`
`Drug Properties Relevant to Sustained-Release
`Formulation
`
`The design of sustained-release delivery systemsis subject
`to several variables of considerable importance. Among these
`are the route of drug delivery, the type of delivery system, the
`disease being treated, the patient, the length of therapy and
`the properties of the drug. Eachof these variablesare inter-
`related and this imposes certain constraints upon choicesfor
`the route of delivery, the designof the delivery system and the
`length of therapy. Of particular interest to the scientist de-
`signing the systemare the constraints imposedby the proper-
`ties of the drug.
`It is these properties that have the greatest
`effect on the behaviorof the drug in the delivery systemand in
`
`Potential Advantages of Sustained Drug Therapy
`
`All sustained-release products share the commongoal of
`
`(4)
`
`(5)
`W= D; + (ke Cq/k;,) Va
`where k,. is the first-order rate constant for drug release
`(time~!), and k,, Ca and V, are as defined previously.
`If the
`maintenance dose begins releasing drug at ¢ = 0, a correction
`factor is required just as it was in the zero-order case. The
`correct expressioninthis case is
`
`(6)
`W= dD; + (Ke Cy /k,)Vaq — Dy, ke T,,
`In orderto maintain drug blood levels within the therapeutic
`range overthe entire time course of therapy, most sustained-
`release drug delivery systemsare, like conventional dosage
`forms, administered as multiple rather than single doses.
`Foran ideal sustained-release system that releases drug by
`zero-orderkinetics, the multiple dosing regimenis analogous
`to that usedfor a constant intravenousinfusion, as discussed
`Forthose sustained-release systems having
`release kinetics other than zero-order, the multiple dosing
`regimenis more complex andits analysis is beyond the scope
`of this chapter; Welling and Dobrinska? provide moredetailed
`
`AUROBINDO EX1018, 7
`
`

`

`Physicochemical Properties
`
`Aqueous Solubility and pK,—It is well knownthat in
`order for a drug to be absorbed it first must dissolve in the
`aqueous phase surrounding the site of administration and
`then partition into the absorbing membrane. Two of the
`most important physicochemical properties of a drug that
`influence its absorptive behavior are its aqueoussolubility
`and,
`if it is a weak acid or base (as are most drugs),
`its
`pK,. These properties play aninfluential role in performance
`of nonsustained-release products; their role is even greaterin
`sustained-release systems.
`The aqueous solubility of a drug influencesits dissolution
`rate, which in turn establishes its concentration in solution
`and hence the driving force for diffusion across membranes.
`Dissolutionrate is related to aqueoussolubility as shown by
`the Noyes-Whitney equation which, under sink conditions, is
`
`from the stomach. The same calculation for intestinal pH
`(about 7) yields a ratio close to 1, implying a less-favorable
`driving force for absorption at that location.
`release of an ionizable drug from a sustained-release system
`should be “programmed” in accordance with the variation in
`PH ofthe different segments of the gastrointestinal (GI) tract
`so that the amount of preferentially absorbed species, and
`thus the plasmalevel of drug, will be approximately constant
`throughoutthe time course of drug action.
`In general, extremes in the aqueoussolubility of a drug are
`undesirable for formulation into a sustained-release product.
`A drug with very low solubility and a slow dissolutionrate will
`exhibit dissolution-limited absorption andyield an inherently
`sustained bloodlevel.
`In most instances, formulation of such
`a drug into a sustained-release systemis redundant.
`a poorly soluble drug was considered as a candidate for formu-
`lation into a sustained-release system, a restraint would be
`placed uponthetype of delivery system which could be used.
`For example, any system relying upon diffusion of drug
`(7)
`dC/dt = kpAC,
`throughapolymerastherate-limiting step in release would be
`where dC/dtis the dissolutionrate, kp is the dissolution rate
`unsuitable for a poorly soluble drug, since the driving force for
`constant, A is the total surface area ofthe drug particles and C,
`diffusion is the concentration of drug in the polymerorsolu-
`is the aqueoussaturationsolubility of the drug. The dissolu-
`tion and this concentration would be low. For a drug with
`tion rate is constant only if surface area, A, remains constant,
`very high solubility and a rapid dissolution rate, it often is
`but the importantpointto noteis that theinitial rate is propor-
`quite difficult to decrease its dissolution rate and slowits
`tional directly to aqueoussolubility C,. Therefore, the aque-
`absorption. Preparing a slightly soluble form of a drug with
`ous solubility of a drug can be usedasafirst approximationof
`normally high solubility is, however, one possible method for
`its dissolution rate. Drugs with low aqueoussolubility have
`preparing sustained-release dosage forms. This willbe elabo-
`low dissolution rates and usually suffer oral bioavailability
`rated upon elsewherein this chapter.
`problems.
`Partition Coefficient—Betweenthe time that a drug is
`It will be recalled from Chapter16 that the aqueous solubil-
`adininistered and the time it is eliminated from the body, it
`ity of weak acids and bases is governed by the pK, of the
`must diffuse through a variety of biological membranes which
`compound and the pH of the medium. Fora weak acid
`act primarily as lipid-like barriers. A majorcriterion in evalu-
`ation of the ability of a drug to penetrate these lipid mem-
`branesis its apparent oil/water partition coefficient, defined
`as
`
`S, = SoC + Ka/[H*]) = So(1 + LOPH~PKa)
`
`(8)
`
`where 5S;is the total solubility (both the ionized and unionized
`forms) of the weak acid, So is the solubility of the unionized
`form, K, is the acid dissociation constant and [H*] is the
`hydrogen ion concentration of the medium. Equation 8 pre-
`dicts that the total solubility, S,, of a weak acid witha given pK,
`can be affected by the pH of the medium.
`Similarly, for a
`weak base
`
`S, = So + [H*]/K,) = So+ LOPE PH)
`
`(9)
`
`where 5S; is the total solubility (both the conjugate acid and
`free-base forms) of the weak base, So is the solubility of the
`free-base form and K,, is the acid dissociation constant of the
`conjugate acid. Analogous to Eq 8, Eq 9 predicts that the
`total solubility, S,, of a weak base whose conjugate acid has a
`given pK, can be affected by the pH of the medium.
`Considering the pH-partition hypothesis, the importance of
`Eqs 8 and 9 relative to drug absorption is evident. The pH-
`partition hypothesis simply states that the un-ionized form of
`a drug will be absorbed preferentially, in a passive manner,
`through membranes. Since weakly acidic drugswill exist in
`the stomach (pH = 1 to 2) primarily in the un-ionized form,
`their absorption will be favored fromthis acidic environment.
`On the other hand, weakly basic drugs will exist primarily in
`the ionized form (conjugate acid) at the samesite, and their
`absorption will be poor.
`In the upperportion of the small
`intestine, the pH is more alkaline (pH = 5 to 7) andthe reverse
`will be expectedfor weak acids and bases. The ratio of Eq 8
`or 9 written for either the pH of the gastric orintestinal fluid
`and the pH of blood is indicative of the driving force for
`absorption based on pH gradient. For example, considerthe
`ratio of the total solubility of the weak acid aspirin in the blood
`
`K=0C),/C,,
`whereCy is the equilibrium concentration of all forms of the
`drug, eg, ionized and un-ionized, in an organic phase at equilib-
`rium, and C,, is the equilibrium concentration of all forms in an
`aqueous phase. A frequently used solvent for the organic
`phaseis l-octanol. Although not alwaysvalid, an approxima-
`tion to the value of kK may be obtained by the ratio of the
`solubility of the drug in 1-octanol to thatin water.
`drugswith extremely large values of K are very oil-soluble and
`will partition into membranes quite readily. The relationship
`between tissue permeation and partition coefficient for the
`drug generally is known as the Hanschcorrelation, discussed
`in Chapter 28.
`Ingeneral, it describes a parabolic relation-
`ship between the logarithm of the activity of a drug orits
`ability to be absorbed andthe logarithmofits partition coeffi-
`cient for a series of drugs as shown in Fig 5. The explanation
`for this relationshipis that the activity of a drug is a function of
`its ability to cross membranesand interact with the receptor;
`as a first approximation, the more effectively a drug crosses
`membranes, the greater its activity. There is also an opti-
`mum partition coefficient for a drug at which it most effec-
`tively permeates membranesand thusshowsgreatestactivity.
`Valuesof the partition coefficient below this optimumresult in
`decreasedlipid solubility, and the drug will remain localized in
`the first aqueous phase it contacts. Values larger than the
`optimumresult in poorer aqueoussolubility, but enhanced
`lipid solubility and the drug will not partition out of the lipid
`membrane onceit gets in. The value of K at which optimum
`activity is observed is approximately 1000/1 in 1-octanol/
`water. Drugs with a partition coefficient that is higher or
`
`AUROBINDO EX1018, 8
`
`AUROBINDO EX1018, 8
`
`

`

`CHAPTER 94
`
`
`log K
`
`Fig 5. Typical relationship between drug activity andpartition coef-
`ficient, K, generally knownas the Hanschcorrelation.
`
`Somedrugsthat exhibit greater than 95%binding at therapeu-
`tic levels are amitriptyline, bishydroxycoumarin, diazepam,
`diazoxide, dicumarol and novobiocin.
`Molecular Size and Diffusivity—As previously discussed,
`a drug must diffuse througha variety of biologicalmembranes
`during its time course in the body.
`In addition to diffusion
`throughthese biological membranes, drugs in many sustained-
`release systems mustdiffuse through a rate-controlling mem-
`brane or matrix. The ability of a drug to diffuse through
`membranes, its so calleddiffusivity (diffusion coefficient), is a
`function of its molecular size (or molecular weight). An im-
`portant influence uponthe value ofthe diffusivity, D, in poly-
`mersis the molecularsize (or molecular weight) of the diffus-
`ing species.
`In most polymers, it is possible to relate log D
`empirically to some function of molecularsize, as shown in Eq
`12:4
`
`log D = —-s, logu +k, = —sylog M + k,,
`
`(12)
`
`lowerthan the optimumare, in general, poorer candidates for
`formulationinto sustained-release dosage forms.
`where v is molecular volume, Mis molecular weight and s,,, Sy,
`Drug Stability—Of importance for oral dosage forms is
`k, andk,, are constants.
`The value of D thusis related to the
`the loss of drug throughacid hydrolysis and/or metabolism in
`size and shape of the cavities as well as size and shape of
`the GI tract.|Since a drug in the solid state undergoes
`drugs. Generally, values of the diffusion coefficientfor inter-
`degradationat a much slowerrate than a drug in suspension or
`mediate-molecular-weight drugs, ie, 150 to 400, throughflex-
`solution, it would seempossible to improve significantly the
`ible polymers range from 10-° to 10~-° cm?/sec, with values
`relative bioavailability of a drug, which is unstable in the GI
`on the order of 10-8 being most common.® A value of ap-
`tract, by placing it in a slowly available sustained-release
`proximately 10~° is typical for these drugs through wateras
`form. For those drugs that are unstable in the stomach, the
`the medium.
`It is of interest to note that the value of D for
`most appropriate sustaining unit would be onethat releases
`onegas in anotheris onthe orderof 107! cm?/sec, andfor one
`its contents only in the intestine. The reverseis the case for
`liquid through another, 10-5 cm?/sec. For drugs with a mo-
`those drugs that are unstable in the environmentof the intes-
`lecular weight greater than 500, the diffusion coefficients in
`tine; the most appropriate sustainingunit in this case would be
`many polymers frequently are so small that they are difficult to
`one that releases its contents only inthe stomach. However,
`quantify, ie, less than 10~!? cm?/sec. Thus, high-molecular-
`most sustained-release systems currently in use release their
`weight drugs and/or polymeric drugs should be expected to
`contents overthe entire length of the GI tract. Thus, drugs
`display very slow-release kinetics in sustained-release devices
`with significant stability problemsin any particulararea of the
`GI tract are less suitable for formulation into sustained-
`using diffusion through polymeric membranesor matrices as
`the releasing mechanism.
`release systems that deliver their contents uniformly overthe
`length of the GI tract. Delivery systems that remain localized
`in a certain area of the GI tract eg, bioadhesive drug delivery
`system, and act as reservoirs for drug release are much more
`advantageous for drugs that not only suffer from stability
`problems but have other bioavailability problems as well.
`Developmentof this type of systemis still in its infancy.
`The presence of metabolizing enzymesat the site of absorp-
`tion is not necessarily a negative factorin sustained-release
`Indeed, the prodrug approachto drug delivery
`takes advantage of the presence of these enzymes to regener-
`ate the parent molecule of an inactive drug derivative. This
`will be amplified upon below and in Chapter28.
`
`Biological Properties
`
`Absorption—tThe rate, extent and uniformity of absorp-
`tion of a drug are important factors when considering its
`formulation into a sustained-release system. Since the rate-
`limiting step in drug delivery from a sustained-release system
`is its release from a dosage form, rather than absorption, a
`rapid rate of absorption of the drug relative to its release is
`essential if the system is to be successful. As stated previ-
`ously in discussing terminology, k, <<< k,. This becomes
`most critical in the case of oral administration. Assuming
`that the transit time of a drug throughthe absorptive area of
`the GI tract is between 9 and 12 hours, the maximumabsorp-
`tion half-life should be 3 to 4 hours.® This correspondsto a
`minimumabsorptionrate constant k, of 0.17 hr7! to 0.23 hr7!
`necessary for about 80 to 95% absorptionovera 9- to 12-hour
`transit time. For a drug with a very rapid rate of absorption
`(ie, kg >> 0.23 hr7!), the above discussion implies that a
`first-orderrelease-rate constant k,.less than 0.17 hr! is likely
`to result in unacceptably poorbioavailability in many patients.
`Therefore, slowly absorbed drugswill be difficult to formulate
`into sustained-release systems wherethecriterionthat k,. <<<
`ka must be met.
`The extent and uniformity of the absorption of a drug, as
`reflected byits bioavailability andthe fractionof the total dose
`absorbed, may be quite low for a variety of reasons. This
`usually is not a prohibitive factor in its formulation into a
`sustained-release system. Some possible reasons for a low
`extent of absorption are poorwatersolubility, small partition
`coefficient, acid hydrolysis and metabolism, or site-specific
`absorption. The latter reasonalso is responsible for nonuni-
`
`Protein Binding
`
`Chapters 14 and 43 described the occurrence of drug bind
`ing to plasmaproteins (eg, albumin) and the resulting reten-
`tion of drug in the vascular space. Distribution of the drug
`into the extravascular space is governed by the equilibrium
`process of dissociation of the drug from the protein. The
`drug—protein complex canserve therefore as a reservoirin the
`vascular space for sustained drug release to extravascular
`tissues, but only for those drugs that exhibit a high degree of
`binding. Thus, the protein binding characteristics of a drug
`can play a significant role in its. therapeutic effect, regardless
`of the type of dosage form. Extensive binding to plasma
`proteins will be evidenced bya longhalf-life of eliminationfor
`the drug, and such drugs generally do not require a sustained-
`release dosage form. However, drugs that exhibit a high
`degree of binding to plasma proteins also might bind to bio-
`polymersin the GI tract, which could have aninfluence on
`sustained-drugdelivery.
`
`AUROBINDO EX1018, 9
`
`

`

`fluctuating drug blood level due to intestinal