CHAPTER 94
`
`Sustained-Release Drug Delivery Systems
`
`Charles S L Chino. PM)
`' Anon Si Pharrnncnmknls. IN:
`'Davlo, N. 33314
`
`'
`
`Joseph ll. Robinson, PhD
`Professor of Pharmacy
`$rhool of Fmoq
`mun-any cl Hamil-1
`Hoditon. WI 5:1?06
`
`-
`
`The goal ofany drug delivery system is to provide a therapeu- '
`tic amount of drug to the proper site in the body .to achieve
`promptly, and then maintain, the desired drug concentration.
`. Thesis, the drug-delivery system should deliverdrug at a rate
`dictated by the needs of the body over the period of treatment.
`This idealized objective points to the two aspects moat impor-
`tant to drug delivery, namely, spot-int placement and tempo-
`ral delivery of a drug. Spatial placement relates to target-
`- log a drug to a. specific organ or tissue, while temporal delivery
`refers to controlling the rate of drug delivery to the target
`tissue. An appropriately designed sustained-release drug de-
`livery system can be a maior advance toward solving these two
`problems.
`- It is for this reason that the science and technol-
`ogy responsible for development ofsustalnedtrelease pharma-
`ceuticals have been and continue to be the'focus of a great
`deal of attention in both industrial and academic laboratories:
`There currently exist numerous products on the market formu-
`lated for both oral and parenteral routes of administration that
`claim sustained or controlled drug delivery. The bulk of
`research has been directed at oral dosage forms that Satisfy
`the temporal aspect of drug' delivery, but many 01' the newer
`approaches under investigation may allow for- spatial place-
`ment as well.
`This chapter will define and explain the nature
`of sustained-release drug therapy, briefly outline relevant
`physlcochemical and biological properties of a drug that af-
`fect sustained-release performance and review the more com-
`mon types of oral and parenteral sustained-release dosage
`forms.
`In addition a brief discussion of some methods curs
`rentiy being used to develop targeted delivery systems will be
`presented.
`
`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.1 Consider single dosing of a
`hypothetical drug that follows asimple one-compartment phar-
`macokinetic model for disposition. Depending on the route
`of administration, a conventiOnal dosage-form of the drug, eg,
`a solution, suspension, capsule, tablet, etc, probably will pro-
`duce a drug blood level versus time profile similar to that
`shown in Fig .1. The term "drug blodd level" refers to the
`concentration of drug in blood or plasma, but the concentra-
`tion'1n any tissue could be plotted on the ordinate.
`It can be
`seen from 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-
`peutic range for longer periods by, for example, increasing the
`initial dose of an intravenous iniection, as shown by the dotted
`line in the figure. toxic levels may be produced at early times.
`' This approach obviously is undesirable and unsuitable. An
`alternate approach is to administer the drug repetitively using
`a constant dosing interval, as in_rnuitiple-d'ose therapy. This
`
`is shown in Pig 2 for the-oral route. ' In this case the drug
`blood level reached and the time required to reachthai level
`depend on the dose and the dosing interval. There are sev-
`eral potential problems inherent in multiple -dose therapy:
`1.
`If the dosing interval is not appropriate for the biological half-life of
`the drug, large ”peaks" and "valleys" in the drug blood level may result.
`For example. drugs with short hair-lives require frequent closings to main-
`tain constant therapeutic levels
`'
`2. The drug blood level may not be within the therapeutic range at
`sufficiently early times. an important consideration for certain disease
`states
`
`3 Patient noncompliance with the multipledosing regimen can result
`in failure of this approach
`
`In many instances, potential problems associated with con-
`_
`ventional drug therapy can be overcome.
`‘When this 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 numerous potential advantages
`of sustainedrelease.drug therapy that will be discussed in the
`next section
`
`'.
`
`‘
`
`Sustained-Release Drug Therapy
`
`As already mentioned, conventional dosage forms include
`solutions, suspensions, capsules,
`tablets, emulsibns, aero- '
`For this discus
`sols, foams, ointments and suppositories.
`sion, these dosage forms can be considered to release their
`active ingredients into an absorption pool
`immediately.
`Thisls illustratedin the following simple kinetic scheme:
`Jr,_+
`elimination
`
`Absorption
`Dosage
`Form mamas, Pool
`
`Target
`*u
`absorption 1U ea
`
`The absorption pool represents a solution of the drug at the
`site of absorption, and the terms k... 31:,, and k, are first-order
`rate constants for drug release. absorption and Overall elimina-
`tionhrespectively.
`Immediate release from a conventional
`doaage form implies that k,.. >>>- in. or. alternatively, that
`absorption ofdrug across a biological membrane, such as the
`intestinal epithelium, is the rate-limiting step in delivery of the
`drug to its targetarea For nonimmedia'te-release dosage
`forms. k... («K k,” that is, release of drug from the dosage
`form is the ratedirniting step. This causes the above kinetic
`scheme to reduce to
`
`hr
`-
`-
`'klr
`Dosage Form .—:- Target Area —3""
`drug release
`elimination
`
`Essentially, the absorptive phase of the kinetic scheme be
`comes insignificant compared to the drug release phase
`Thus, the effort to develop a nonimmediate-release delivery
`
`1660 '
`
`SHIRE EX. 2012
`KVK v. SHIRE
`IPR2018-00293
`
`p. 1
`p. 1
`
`SHIRE EX. 2012
`KVK v. SHIRE
`IPR2018-00293
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`

`

`SUSTAINED-RELEASE DldUG DELIVERY SYSTEMS‘
`
`1661 '
`
`
`
`unmet!"
`“M
`
`
`TIME _Ihfll
`Fig 3. Typical dru'g blood level versus time profiles for delayed-
`release drug delivery by a repeat-action 'dosage form.
`
`Release Rate and Bose Considerations-9
`
`Although it is not necessary or desirable to maintain a
`constant level of drug in the blood or target tissue for all
`therapeutic cases this is the ideal goal of a sustained-release
`delivery system. In fact, in some cases optimum therapy'is
`achieved by oscillating, rather than constant, drug levels.
`An example of thisIs antibiotic therapy, where theactivity of
`the drug is required only during growth phases of the
`microorganism. A constant drug level will succeed at curing
`or controlling the condition. howefer and this“:3 true for most
`forms of therapy
`‘
`The objectivein designinga sustained-release system is 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
`drug15 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 should follow zeromrder kinetics. as shown
`by
`
`'0)-
`k?=RateIn=RateOut=_k-Cd-Vq
`where it"is the zero-order rate constant for drug release
`(amountl'time). k is the first-order rate constant for overall
`drug elimination (tirne' l), 6,,is the desired drug level in the
`body (timeout/volume) and Va is the volume space in which .
`the drug is distributed. The values of k... 0,, and V“. needed, to -
`calculate k? are obtained from appropriately designed single-
`dose‘ 'pharrnacokinetic studies. Equation 1 provides the
`method to calculate the zero--order release rate constant nec-
`essary to maintain a constant drug blood or tissue level for the
`simplest case where drug is eliminated by first-order kinetics.
`For many drugs. however, more complex elimination kinetics
`and other factors aflecting their disposition are involved.
`This in turn affects the nature of therelease kinetics necessary
`to maintain a constant drug blood level.
`lt-is important to
`recognize that while zero-order release may be desirable theo-
`
`
`onusILOODLEVEL(“'9'"er
`
`
`
`Iii-mum
`
`Hallo]
`
`TllrlE Illnl
`
` '
`
`‘
`
`‘I'alls
`HM!
`
`mama:
`Ham
`
`Fig 1. Typical drug ulooo level versus time proftea for Intravenous
`, lnlecilons and an extravascular route oi administration.
`
`system must be directed primarily at altering the release rate
`‘ by aflecting the value of k,.. The many ways in which-this has
`been attempted will be discussed later in this chapter.
`Nonirrunediate-release deliverysystems may be divided con-
`- veniently into four categories:
`.
`l. Delayed release
`2. Sustained release
`'
`a. Controlled release _
`b. Prolonged release
`3. Site-specific release
`4. Receptor release
`
`Delayed—release systems are those that use repetitive, inter- '
`mlttent closings of a drug from one orrnore immediate-release '
`units incorporated into a single dosage form. Examples of
`delayed-release systems include repeat—action tablets and cap-
`. soles. and enteric-coated tablets where timed release is
`achieved by a barrier coating. ' A delayed-release dosage form
`does not produce or mamtain'uniform drug blood levels within
`- the therapeutic range, as shown in Fig 3, but. nonetheless, is
`more effective for patient compliance than conventional dos-
`age forms
`Sustainedscience 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,
`whether this 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
`levels'in the target
`tissue or cells it is considered a controlled-release nsystem
`lfitIs unsuccessful at this but nevertheless prolongs therapeu-
`tic blood or tissue level of the drug for an extended period of
`time it is considered a prolonged-release system. This is
`illustratedin 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 adiace'nt to, or in the dis-'-
`eased organ or tissue; for receptor release the target is the
`. particular receptor for a drug within an 'organ or tissue Both
`of these systems satisfy the Spatial aspect of drug delivery
`a
`
`
`
`
`
`'anusstoop(my...)Lever.
`
`Tani:
`Rm!
`
`Tllllflflill":
`
`l'IllItI!!!I!IIIUIIIIIIIIIIIIIIIIIII
`
`
`no: {In}
`
`Fig 2. Typical drug blood level versus time profile following oral
`multiple-dose therapy.
`-
`
`
`
`‘fnri:
`
`
`Therauulle '
`Hem
`
`
`Reno. (“fl/u) ’ill!IIII!II!"IIIIIIIIIIIIIIIIIIIIIII
`“U6BLOODEVIL
`
`
`TIME "'0'
`
`Fig 4. Drug blood level versus lime profiles showing the relation-
`ship between controllod-release {A}. prolonged-release [B] and con-
`ventional-release {Ci druo deliverv.
`p. 2
`p. 2
`'
`_'.__——.'—-———_
`
`

`

`' 1652
`
`CHAPTER 94
`
`J
`
`_ retically. nonzero-order release may be equivalent clinically to
`constant release in many cases Aside from the extent of
`'intra- and intersubject variation is the observation that. for
`‘many drugs. modest changes in drug tissue levels do not result
`' in an improvement in clinical performance Thus a noncon-
`stant drug level may be indistinguishable clinically from a]
`constant drug level.
`To achieve a therapeutic level promptlyand sustain the
`level for a given period of time, the dosage form generally I
`consists oftwo parts:
`an initial priming dose Di, that re«.
`leases drug immediately and a maintenance or sustaining
`doseiflm. The total dose,W thus required for the system is
`W— 111-30
`'-.{2).
`For a system where the maintenance dose releases drug by a
`zero-order process for a specified period of time; the total .-
`dosesls
`
`E
`
`I
`'
`
`'
`
`Table ‘l—Potenllal Advantages 61 Sustained Drug Therapy
`1. Avoid patient compliance problems
`2. Employ less total drug
`- a..hi1'nirnlr.e or eliminate local side effects .
`b Minimize or eliminate systemic side efl'ecrs
`1: Obtain less potentiati'on or reduction in drug activity with
`chronic use
`.d. Minimize drug accumulation with chronic dosing
`3. . Improve efliciency in 1rea1n1er11
`-
`a. Cure or control condition more promptly
`1:.
`improve control or condition. ie reduce fluctuation‘111 drug
`'
`level
`. 1:.
`Improve bioavailability of some drugs
`d; Make use of specialefi'ecis. eg'. sustained-release aspirin for
`' morning relief of arthritis by dosing before bedtime .
`'
`'
`
`. .4. ' Economy _
`
`
`
`'
`
`.
`
`‘1
`
`drug therapy. Mmimizing or ellininsting patient compliance '
`' problems is an obvious advantage of sustained-mic ase therapy. '
`Becaiise of the nature of its release kinetics, a sustained-
`release system should be able to .us'e less total drug'- over the
`time course oftherapy than aconventional preparation. The
`advantages of this are 11 decrease or elimination of both local
`and systemic side effects. less potentiatlon or reducdon in
`drug activity with chronic use and minimization of drug accu-
`mulation in body tissues With chronic dosing.
`Unquestionably the most importantreason for sustained-
`drug therapy15 improved efficiencyin treatment, is. optimized
`therapy. The result of obtaining constant drug blood levels'
`- from :1 sustained-release system is to achieve promptly the
`desired effect and maintain it for an extended period of time
`Reduction or elimination of fluctuations in the drug blood
`level allows better disease state management.
`In addition.
`the method by which sustained release is' achieved can im-
`prove the bioavallability of some drugs; For example, drugs
`susceptible to enzymatic inactivation or bacterial decomposii
`tion can be protected by encapsulation in polymer systems
`suitable for sustained release. For drugs that have a "spe-
`cific window“ for absorption, increased bioavailability can be
`attained by localizing thesustained-release delivery system in
`certain regions of the gastrointestinal tract.
`Improved effi-
`' clency in treatment also can take the form of aspecial 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
`Although the initial unit cost of most sustained--drug delivery
`systems usually is greater than that of contrentional dosage
`forms because of the special nature of these products, the
`average cost of treatment over an extended time period may
`' be less. Economy also may result frOm adecrease in nursing
`timefhospitalization. less lost work lime, etc.
`
`'
`
`
`
`(3) '
`-
`I
`W= D, + 1:21",
`_. where k‘"15 the zero-order rate constant for drug release and .
`Ta is the total time desired {01 sustsined release from one
`dose.
`If the maintenance dose begins the release of drug at
`' thetimé 01110311130 =
`0).-it will add to that which is provided
`by the initial dose, thus increasing the initial drug level.
`In
`this case a correction factor is needed to account f0]the added
`drug from the maintenance dose:
`_
`_
`.
`‘
`(4)_
`" W": award—Hr
`is the amount. of drug provided
`' The correction factor. k”T
`during theperiod from t =5to the time ofthe peak drug level,
`T,-. No correction factor is needed if the dosage form is
`' constructed1.11 such a ffihion that the maintenance dose does
`nut begin to release drug until time 51“,.
`It already has been mentioned that a perfectly invariant
`drug blood or tissue level versus time profile is the ideal goal
`Of a sustained-release system. The way to achieve this, in the
`simplest case, is by use of a maintenance dose that releases'its
`drug by zero-order kinetics. However, satisfactory approxi-
`"nmtions of a. constant drug level can be obtained by suitable
`combinations of the initial dose and a maintenance dose that
`releases its drug by a first—order process The. total dose for
`sdch a system is
`
`.
`
`{5).
`-
`'
`W= D, + (k CdkaVd
`where k, is the first-order rate constant for drug release
`(time 1), and ice, 0,; and Va are as defined previously If the
`maintenance dose begins releasing drug at: = 0, a correction
`factoris required just as it was in the zero-order case. The
`- correct expression in this case is
`
`-W-ID; + (k Cdfkr)Vd—-
`135,11 1',
`(a)
`In order to maintain drug blood levels within thethe1apeutic
`range over the entire time course of therapyr most.sustained
`release drug- delivery systems are, like conventional dosage
`forms. administered as multiple rather than single doses.
`For an ideal sustained-release system that releases drug by
`zero-order kinetics, the multiple dosing regimen is analogous
`to that used for a constant intravenous infusion, as discussed-
`in Chapter 42.. For those sustained-release systems having
`release kinetics other than zero-order, the multiple dosing
`regimen'15- more complex and its analysis is beyond the scope
`ofthis chapter; Welling and Dobrtnskaa provide more detailed
`discussion -
`-
`_
`Potential Advantages of Sustained Drug Therapy
`
`_ All sustained-release products share the corrunon goal of
`improving drug therapy over that achieved with their non—
`sustained counterparts.This improvement in drug therapy
`is represented by several potential advantages of the use of
`sustained-release systems, asshownin Table 1.
`Patient compliance has been recognized as a necessary and
`important componentin the success of all self-administered
`
`Drug PropertiesRelevant to Sustained~Release
`_ Formulation
`
`I The design of sustainedwrelease delivery systems is subject
`toseveral variables of considerable importance. Amung‘these
`are the route of drug delivery, the type of delivery system the.,
`- disease being treated. the patient, the langth of therapy and
`' the properties of the ding. Each of thesevariables are Inter-
`related and thisimposes certain constraints upon choices for
`the route of delivery, the design of the delivery system and the
`length of therapy Of particular interest to the scientist de-
`signing the system are the constraints imposed by the proper-
`ties of the drug.
`It is these properties that have the greatest
`effect on the behavior of the drug in the delivery system and in
`the body. For the purpose of discussion, it is convenient to'
`describe the properties of ardrug as being either physico chemi-
`cal or biological. Obviously, there is no clearcut distinction
`between these two categories since the biological properties- -
`of. a drug are a function of its physicochemlcal properties;
`Forporpos es of this discussion, however, those attributes that
`
`p. 3
`10.3
`
`

`

`SUSTAINED-RELEASE DRUG DEUVEFIY SYSTEMS
`
`1583
`
`- can be determined from in 1.111111 experiments ‘will be consid—
`Included as biological -
`ered as physicochendcal properLles._
`"properties will'be. those that result from typical pharmacold-
`netic studies on the absorption distribution. metabolism and '
`excretibn (ADME) characteristics of a drug and those result-
`ing horn pharmacological studies.
`
`Physicochem iccl 191-9111111111 -
`
`. Aqueous solubility and pli..—lt is'well known that in
`order for a drug to be absorbed it first must dissolve in the
`aqueous phase surrounding the site of adrruniso'ation and-
`' then partition into. the absorbing membrane. Two of the
`_ most unportant physicochemical properties of a drug that
`influence its absorptive behavior are‘l‘ts aqueous solubility
`and, if it
`is a weak acid or base (as are most drugs},
`113.
`pl“. These properties play an influential rolein performance
`of nonsustained—release products. their roleis even greaterin
`sustained-release systems.
`The aqueous solubility of a drug influences it's dissolution
`rate. which in turn establishes its concentration in solution
`and hence the driving force for diffusion across membranes.
`Dissolution rate is related to aqueous solubility as shown by
`the Ndyes~Whlrney equation which. under sink conditions. is
`
`'
`
`' (7)
`516.3111: 111.1116,
`where (10/ cit is the dissolution. rate. 110'1a the-dissolution rate
`constant,A15 the total surface area of the drug particles and C
`is the aQueous saturation solubility of the drug. The dissolu-
`tion rate is constant only if surface area. A. remains constant
`- but the important point to note is that the initial rate"as propor-
`. tionaldirectly to aqueous solubility 6.; The.refore the aque-
`ous solubility of a drug can be used as afirst approximation of
`its dissolution rate. Drugs with'low aqueous solubility have
`[ow dissolution rates and usually suffer oral l'iioavailability1
`problems.
`It will be recalled from Chapter 16' that the aqueous 3111111111..
`.lty of weak acids and bases15- governed by the pH of the
`compound and the pI-l of the medium. For a weak acid
`
`.
`
`3. = 3.0 + 11.11111) =.9..(1 + low-m) '
`
`(81
`
`and gastric fluid;
`(10) _
`12 = (1 + lOFlle’F‘f-MII + lowrvi‘a)
`where p111 is the pH of blood (pl-I 7.2). [11-10 is the pH of the
`gastric fluid (pH 2) and the pit. of aspirin is about 34.
`Substituting these values into Eq 10 gives a value for)? of 1033.
`which indicates that aspirin is in a form to be well-absorbed
`from the stomach. The same calculation for intestinal pH .
`(about 7) yields a ratio close to l. implying a less-favorable '-
`111111113 force for absorption at' that location:
`Ideallyy, the
`release of an ionizable drug from a sustained-release System '
`should be “programmed" in accordance with the variation in '
`'pH of the difi'erent segments of the gastrointestinal (GI) tract
`.50 that the amount of preferentially absorbed species. and
`thus the plasma IeVel of dn1g,w-ill be approximately constant
`throughout the time course of drug action.
`In general. extrames in the aqueous solubility of a drug are
`mrdeslrable for formulation into a sustained~release product.
`A drug with very low solubility and a slow dissolution rate will
`exhibit dissolution—1111mm absorption and yield an inherently
`- sustained blood level
`In most instances. formulation of such
`a drug into a sustained-release system is redundant. Even if
`a poorly soluble drugwas considered as a candidate for formu-
`lation into. a sustained-release system. a restraint would be
`placed upon the type of delivery system which could be used.
`For example. any system relying upon difiusion of drug
`through a poly'm er as the rate-limiting step'111 release would be
`‘ unsuitable fora poorly soluble drug. sirlce the driving force for
`difiusion'Is the concentration of drugin the polymer or solu—
`tion and this concentration would be low. For a drug with
`very high solubility and a rapid dissolutiOn rate, it often 15'
`quite difficult to decrease its dissolution rate and slow its
`absorption. Preparing aslig'htly soluble form of a drug with
`. normally high solubility1s. however. one possible method for
`' preparing sustained-release dosage forms. ThisWill be elabo- .
`rated upon elsewhere1n this chapter.
`Partition Coefficient—Between the time that a drugis
`administered and the time 11'1s eliminated from the body. It
`must diffusa through a variety of biological membranes which
`act primarily as lipid-like barriers A major criterionin evalu-
`ation of the ability of a drug to penetrate these lipid mem-
`branes is its apparent oilfwater partition coefficient. defined
`as
`
`-
`
`-
`
`-
`
`-
`
`K = 0010..
`
`(111'
`
`.
`
`_
`
`"—"-—"—=u=-1‘————-- -———-...—'__..—.__.—.-‘.
`
`p. 4
`p.4-
`
`where S. is the total solubility (both the ionized and unionized
`forms) of the weak acid. 89 is the Solubility of the unionized
`form, K0 is the acid dissociation constant and [H l is the
`hydrogen'ton concentration of the medium. Equation 3 pre-
`dicta that the total solubility. 3.. of a weak acid with a given p11.
`can be affected by the pH of the medium. Similarly, for a
`weak base
`'
`'
`.
`
`.31 = Soil + lunar.) = Still + 10"“"”*I)
`
`(9)
`
`where Co15 the equilibrium concentration of all forms of the
`drug. cg. ionized and Lin—ionized. in an Organic phase at equilib-
`rium. and C... is the equilibriuln concentration of all forms'1n an
`aqueous phase. A frequently used solvent for the organic
`phase ls l-octanol. Although not always valid. anapproxima-
`tion to the value of K' may .be obtained bythe ratio of the
`solubility of the drug:11 l -octanol to thatin water.
`In general '
`where .S'. is the total solubility (both the conjugate acid and
`drugs with extremely large values 0”: are very oil-soluble and
`free-base forms) of the weak base. Su 15 the solubility‘oi’ the
`will partition into membranes quite readily. The relationship
`between tissue permeation and partition coelficient for the
`free-base form and it, is the acid dissociation constant of the
`conjugate acid. Analogous to Eq 8. Eq 9 predicts that the
`drug generally is known as the Hausa): correlatimz. discussed
`total solubility. 3., of aweak base whose conjugate acid has a
`in Chapter 23. ' In general, it describes a parabolic relation-
`. given" pK. can be affected by the pH of‘ the medium.
`ship. between the logarithm of the activity of a drug or its
`ability to be absorbed and the logarithm of its partition coeffi-
`Considering the pl-l-partition hypt‘ithesis. the importance of
`The pHv ' '
`Eqs 8 and 9 relative to drug absorption'is eVidenr.
`cient for a series of drugs as shownto Fig 5. The explanation
`partition hypothesis simply states that the un-ionized form of
`‘ for thisIrelations‘hip'is that the activity of a drugts a function of
`a drug will be absorbed preferentially. in a passive manner,
`its ability to cross membranes and interact with the receptor;
`through membranes. Since weakly acidic drugs will exist in
`as a first approximation themore effectively a drug crosses
`the stomach [pH = -1 to 2) primarily in the unionized form.
`membranes 11111 greater its activity. There is also an opti-
`their absorption will be favored fi'dni this acidic environment. _
`mum partition coefficient for a drug at which it most efi'ec-
`0n the- other hand, weakly basic drugs will-exist primarily in
`lively permeates membranes. and thus shows greatest activity.
`the ionized form (conjugate acid) at the same site.-and their '
`. Values of the partition.coelficient below this optimum result in
`absorption will be poor.
`In the upper portion of the small
`decreased lipid Solubility. and the drug will remain localized in
`intestine, the pll is more alkaline (pH = 5 to 7) and the reverse
`the first aqueous phase it contacts Values larger than the
`' will he expected for weak acids and bases. The ratio of Eq 8
`optimum result in poorer aqueous solubility. but enhanced
`lipid Solubility and the drug will not partition out of the lipid '
`or 9 written for either the pH of. the gastric or intestinal fluid '
`and the pH of blood is indicative of the driving .force for
`membrane once it gets in. The value of K at which optimum
`absorption based on pH gradient. For example. consider the
`activity is observed is approximately moon in l—dct'anoll
`water. Drugs with a partition coefficient that is‘ higher or
`ratio ofthe total solubility of the weak acid aspirin in the blood
`
`

`

`J
`
`.
`
`1664
`
`oHAPTE'n' 94
`
`noactivity
`
`'Flg' 5. Typical relationshlp Dennison drag actlvity and partition coef-
`talent. K. generally known asthe Hansch correlation.
`
`lower than the optimum are, in general, poorer candidates for I
`formulation'into sustained-release dosage forms.
`Drug Stability—0f importance for oral dosage formsIS
`the loss of drug through acid hydrolysis and!or metabolism'in
`the GI tract.
`Since a drug in the solid state undergoes
`degradation at month slower rate than a drug in suspension or
`splufion, it would seem possible to improve significantly the
`relative bioavallability of a drug. which is unstable in the GI
`tract, by placing it in a slowly. available sustained-release
`form. Forthose drugs that are unstable in the-stomach, the
`most appropriate sustaining unit would be one that releases
`its contents only in the intestine. The reverse is the case for
`those drugs that are unstable lnthe envirorunent of the bites-
`tine; the most appropriate sustaining unit inthis case would be
`. one that releases its contents only-in the stomach. However,
`most sustained-release systems currently in use release their
`contents over the entire length of the GI tract. Thus; drugs
`billty problems in any particular area of the "
`with significant
`_
`GI tract are less suitable for formulation into sustained»
`release systems that deliver their-contents uniformly over the
`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.
`Development of this type of system is still in its infancy.
`The presence of metabolizing enzymes at thesite of absorpn
`tion is not necessarily a negative factor in sustained-releabe
`formulation.-
`indeed, the prodrug approach to drug delivery
`takes advantage of the presence of-these enzymes to regener-
`ate the parent molecule of an inactive drug derivative. This
`willbe amplified upon below and in Chapter 28.
`
`Hotein Binding
`
`Chapters 14 and 43 described the occurrence of drug bind
`ing to plasma proteins (cg, albumin) and. the resulting reten-
`tion of drug in the vascular space. Distribution of the drug
`into the extravasculsr space is governed by the equilibrium
`process of dissociation of the drug from the protein The
`. drug—protein complex can servetherefore as a reservoir in the
`vascular space for sustained drug release to extravaScular'
`tisaues. 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 by along half-life of elimination for
`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 an influence on
`sustained-drug delivery.
`-
`The main forces of attraction responsible for binding are
`van der Wasls forces, hydrogen bonding and electrostatic
`forces: In general, charged compounds have a greater ten-
`dency tobind a protein than uncharged compounds. due to
`electrostatic streets. . The presence of a hydrophobic moiety
`on the drug molecule also increariesits binding potential.
`
`
`Some drugs that exhibit greater than 95% binding at therapeu.
`tic levels are amitriptylme, bishydroxycoumafin diazepsm
`diaaoxide, dicurnarol and novobiocin
`Molecular Size and Difl’usivity—As previously discussed,
`a drug must difiuse througha varlety of biological membranes
`during its time course in the body.
`in addition to diffusion '
`through these biological membranes. drugs in manysustained.
`' release systems must difque thro
`ugh a rate-controlling mem-
`brane or matrix. The ability of a - drug to dilfuse through
`membranes, its so called dilfushrity (diffusion coelficient], is-a
`function of its molecular size (or molecular weight). An kn.
`portant influenceupon the value of the dlfi‘usivity, D, in poly. "
`mere 15 the molecular size (or molecular Weight] of the difl‘us—
`ing species
`In most polymers it is poseible to relate log D
`errlpirically to come function of molecularsizel,‘as shownin Eq
`12
`.
`_
`.
`.
`.
`
`logD = —s,, logo + in. = —leogM + k,“
`
`(12}
`
`where u is molecularvolume, M is molecularweight ands” .- 53,,
`kt, and k... are constants. The value of D thus is related to the
`3:11;and shape of the cavities as well as size and shape of
`s.
`Generally, values of the difibsion coeflicient for inter- I
`mediate-molecular—weight drugs, 1e, 150 to 400.. through flex-
`ible polymers range from 10““ to 10'“ cmzi'sec; with values
`on the order of 10-3 being most common.5 A value of ap-
`proximately ,10'“ is typical for these drugs through water as
`the medium.
`It is of interest to note that the value of D for
`one gas in another is on the order of 10—1 cmafsec. and for one
`liquid through another, 10““ cm‘lsec. For drugs with a mo-
`lecular weight greater than 500. the diflusion coefficients in
`- many polymers frequently are so small that'the‘y are difficult to
`quantify, ie. less than 10‘ ‘2 cmzz’sec. Thus,.liigh-molecular-
`weight drugs andf'or polymeric drugs should be 'expemed to
`display very slow-releas