CHAPTER 94 I
`
`Sustained-Release Drug Deliveryfiystems
`
`_ Clinrlu-5 I. Chino. PhD
`Annie 5?. Phnrrnnceuricols. In:
`' Davie. E33314
`
`'
`
`Joseph ll. Robinson, PhD
`Professor oi Pharmacy
`5-.-hool of.Fhurmory
`University ol Wisconsin '
`Madison, WI 53706
`.
`
`‘
`
`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'mai.ritain, the desired drug concentration.
`_ Thatds, the drug-delivery system should deliverdmg at a rate
`-dictated by the needs of the body over the period of treatment.
`This idealized objective points to the two aspects most impor-
`tantto drug delivery, namely, spatial placement and tempo-
`ral delivery of a drug. Spatial placement relates to target-
`- ing 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 major advance toward solving these two
`problems.
`- It is for this reason that the science and technol-
`ogy responsible for development of 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 exist numerous products on the market forrnu-
`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 of 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
`' physicochernical and biological properties of a dnig 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 cur-
`rently being used to develop targeted delivery systems will be
`presented.
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`
`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 dmg that follows asimple one-compartment phar-
`macolrinetic 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 blood level" refers to the
`concentration of drug in blood or plasma, but‘ the concentra-
`tion in any tissue could be plotted on the ordinate.
`It can be
`seen from this figure that administration of a drugby either
`‘intravenous injection or an extravascular route, ,eg, orally,
`intrarriuscularly 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
`If
`' conventional ‘dosage forrns to control temporal delively.
`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 a_n'intravenous injection, as shown by the dotted
`line in the figure. toxic levels may be produced at early times."
`I
`‘ This approach obviously is undesirable and unsuitable. An
`alternate approach is to administer the drug repetitively using
`a constant dosing interval, as in multiple-dose therapy. This
`
`.
`
`In this case the drug
`is shown in Fig 2 for the-oral route.
`blood level reached and the time required to reach _thal. 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 "pea!-:s" and "valleys" in the drug blood level may result.
`For example, drugs with short half-lives require frequent closings to main-
`tain constant therapeutic levels.
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`_2. The drug blood level may not be ii-irhmthe therapeutic range at
`.sufl'iciently early times, an important consideration for certain disease.
`states.
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`'.
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`3. Patient rioncomplianqe with the mL!lLiple—dosing regimen can result _
`in failure of this approach.
`-
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`l
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`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 irivestigation of sustained-release drug ' ‘I
`Th'ere are numerous potential advantages,
`'
`delivery systems.
`_
`of s'usta'ined-releasedrug therapy that will be “discussed in the
`next section.
`-
`'-
`
`Suslained-l'-l-elease Drug Therapy
`
`Dosage
`
`‘As already mentioned, conventional dosage forms include
`solutions,‘ suspensions, capsules, tablets, emulsions, aer'o-
`sols, foams, ointments and suppositories. For this discus-
`sion, these dosage forrns can be considered to release their
`actlveingredients into _an absorption pool
`immediately.
`This is illustrated in the following simple kinetic scheme:
`. kn
`_
`.
`kl]
`A;F
`——:a.--
`_——-=5...
`Target
`_
`-.
`Absorption
`drug release P001
`elimination
`absorption Area
`The absorption pool represerits 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 and overall elimina-
`tion,_respectively.
`- Immediate_ release from a conventional
`dosage form implies that It... >>> k,, or, alternatively, that
`absorption of drug across a biological membrane, such as the
`intestinal epithelium, is the rate-limiting step i.n delivery of the
`drug to its targetarea. For nonirnmediate-release dosage
`forms, lc,. <<< km that is, release‘ of drug from the dosage
`form is the rate-lirriitingstep. This causes the above kinetic
`scheme to reduce to
`
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`
`kw.
`.
`pr
`.
`.
`Dosage Form '4-"_ Target Area “—"5"
`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 3. nonimmediate-release delivery-
`
`
`
`1650'
`
`Amerigen Ex. 1055, p. 1
`Amerigen Ex. 1055, _p. '1
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`

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`SUSTAINED-RELEASE onus DELIVERY SYSTEMS‘
`
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`Range
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`(amount)/ML)
`DRUGSL060LEVEL
`
`
`
`_‘rII<IE _ rm:
`Fig 3. Typical drug blood level versus time profiles for delayed-
`release drug delivery bya repeat-action ‘dosage form.
`
` - Tnnlc
`
`
`baudBLOODLEVEL("""°'_"‘)/mg.)
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`Fig 1; Typicai drug ulood level versus time profiles for intravenous
`, Injections and an extravascular route of administration.
`
`'
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`system must be directed primarily at altering the release rate '
`' by affecting the value of k,.. The many ways i_n whichthis has
`been attempted will be discussed later in this chapter.
`Noninunediate-release delivery systems may be divided con- I
`- veniently into four categories:
`-
`1.
`-Delayed release
`_
`2. Sustained release
`'
`a. Controlled release ,
`b. Prolonged release
`Site—-specific release
`3.
`4. Receptor release
`
`-
`
`Delayed-reteose systems are those that use repetitive, inter- '
`' mittent dosings of a drug from one onmore immediate-release '
`units incorporated into a single dosage form. Enramples 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 ma.intain'uniform drug blood levelswithin
`- the therapeutic range, as shown in Fig _3, but, nonetheless, is
`more eifective for patient compliance than conventional dos-
`‘ age forms.
`,
`.S‘usto.i1wci-retease 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
`g levels in the target
`tissue or cells, it is considered a controfted-1‘eLease'system.
`' Ifit is 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"
`illustrated in Fig 4. _
`-
`Site-spec: c and receptor release refer to targeting of a_
`: rimg directly to a certain biological location.
`In the case of
`site-specific release, the target is adjacent to, or in the disa-
`eased organ or tissue; for receptor release, the. target is the
`_ particular receptor for a drug within anorgan or tissue. Both
`of these systems satisfy the spatial aspect of drug delivery.
`a
`
`Retease Rate rind Dose Consideriitimrsg
`
`'
`
`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 '
`deiiveiy system. _ In fact, in some cases optimurn therapy is
`achieved by oscillating, -rather than constant, drug levels.
`An example of this is antibiotic therapy, where theactivity of
`the drug is required only" during growth phases of the
`microorganism. A constant drug level Willsucceed at curing
`' or controlling the condition, however, and this is true for most
`forms of therapy.
`_
`_
`The objective in 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
`drug is provided to the patient at a constant rate just equal to
`its rate of el'ir_nination. This implies that the rate of delivery _'
`must be independent of the -ar'nount'of drug remaining in the
`dosage form and constant over time. That is, release from
`the dosage. form should follow 2:ero—o'rder' kinetics. as shown
`by
`
`-(1)-
`'
`rcf?=.Ra1;eIn=Raieout_-re,-0,, -V,,_
`where it? is the zei-o—order rate constant fordrug release
`(arnountftirne), fr... is'the first-order rate constant for overall
`drug elimination (time"), Cd is the desired drug level in the
`body (amountfvolume)
`Vd is the volume space in which _
`' the drug is distributed. The values of_k,., Cd and V“, needed_to -
`calculate inf! are obtained from appropriately designed single-
`'dose"pharrnacol<‘1nctic studies. Equation 1 provides the
`method to calculate the zero-order release rate constant nec-
`essary to maintain a constant drug blood or tissue_leve'l for the
`simplest case_where drug is eliminated by first-order ‘kinetics.
`For many drugs, however, more complex elimination kinetics
`and other factors afl'ecting_ their disposition are involved.
`turn affects the nature of therelease kinetics necessary
`to maintain a constant drug blood level.
`_ It-is important to
`recognize that while zero-order release may bedesirable theo-
`
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`-
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`-
`
`_(""°""V..'.}
`-DRUGswanLevel.
`
`
`TIME ihfll
`
`Typical drug blood Ievei versus time profile iollowing oral
`Fig
`rnultiple—dose therapy.
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`Fig 4. Drug blood level versus time profiles showing the relation-
`ship between controlled-release (A), prolonged-release (B) and con-
`ventional—release (C) drug delivery.‘
`Amerigen Ex. 1055, p. 2
`'Amer_igen Ex. 1055, p. _2
`
`
`

`
`‘ 1662
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`' CHIIKPTER-94
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`_._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 o_bservation that, ‘for
`. " many drugs, modest changes in drug tissue‘ levels do not result
`Thus, a noncon~
`' in an improvement in clinical performance.
`stantdrug levelniay ‘be -‘indistinguishable clinically from a_-.'
`.constant drug level.
`-
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`To achieve a.therapeulii'c level_ promptly ,and- sustain the
`‘level for a given period 'of_ time, the dosage form ‘generally’ _
`consists of "two parts:
`an initial priming dose, l3,',_ thatjre-_
`_leas.es Ariig immediately. and a‘ n1aintenance'oi‘.sustaining_
`dose, D,.,.‘ The total dose,?W, thus required for "the system is
`'
`'
`W313: .+l-‘Din
`.
`'
`-. {2} '.
`For a system where the maintenance dose releases drug by a
`zero-order ‘process fora specified period of time; the total .-
`dose2 is
`
`Table i——Potential Advantages of Sustained Drug Therapy =
`
`T
`
`l
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`9:
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`-
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`1. Avoid patient compliance problems
`2. Employ less total drug
`-
`-
`'- a. .Mim'mize or eliminate local side effects .
`.. b. _Minin'|l2.e or eliminate systemic. side effects
`c. Obtain less pbtentiatibn or reduction in dnig activity with
`' chronic use
`"
`-
`,
`'
`,
`.
`_d. Minimize drug accumulation with chronic dosing
`3. . Improve efliciency in treatnient
`_-
`-
`a.. Cure or control condition more promptly
`b.. Improve coiitrol of condition. ie_ reduce l1I1ctuation_in drug
`level"_
`-
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`_
`.
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`. c. -lmprove _bioava.ilability of some drugs
`d.‘ Make use or speciaieifects, cg; sustained-release aspirin for"
`"morning relief of arthritis by closing before bedtime _
`.
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`'l 4. ' Economy '
`
`.
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`I
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`.
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`_
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`'-1
`drug therapy. Minimizing or elirniiiatirig patient compliance -'
`' problems is an obvious advantage ofsustained- release therapy. '
`A. Because of the nature. of its release kinetics, a s._ustained- I 5
`release system should be able to Lose less total drugi over the
`time course ofltherapy th:1_n_ a conventional preparation. The
`advantages of this are a decrease or elimination of both local
`and syfiemic side effects, -less" potentiation orreduction in -
`drug activity with chroniouse and rninimization of drug accu-
`mulation in body tissues with chronic dosing.
`Unquestionably-the most important"reason'_for sustained- -
`drug therapy is improved efficiency in treatment, ie ,. optimized .
`therapy. The result_ of obtaining constant drug bloogl=','levels'
`. from asustained-release system is to -achieve promptly the
`desired effect and maintain it for an extended period of time,
`Reductiori.or elimination of fluctuations in the drug blood.
`level allows better disease state manageinent.
`In addition,
`the method by which sustained release is" achieved" can irri-
`prove the bioavailability of some tlrugsi For example, drugs
`susceptible to enzymatic inactivation or bacterial decomposié,
`tion can be protected by encapsulation. in polymer systems
`suitable for sustained release.
`F012 drugs that have "a "spe- _
`_cific window’? for absorption, increased bioavailability can be _
`attained by localizing the ‘sustained-“release delivery system_'i.n
`certain" regions of the gastrointestinal tract.
`Improved "elli-
`ciency in treatment also can take the form of a‘, special tl‘.era~
`peutic effect‘ not possible with a conventional dosage‘ form
`(se_eTable 1-).
`_
`'
`'
`.Th_e’ last potential advantage listed in Table 1, that of
`econorny,-_ 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 conventional 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 a decrease in nursing
`time/hospitalization, less lost work time, etc.
`‘Drug Propert'ies.Fle'|evanl _to Sustainetl—Release '
`.Form_ulation'_ _
`'
`'
`"
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`'
`
`In
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`J
`
`_(3)-'
`.
`'
`W'=o,+-km '.
`where kl: is the zero-orcler rate constant for drug release and .
`Tu
`the total tirne desired for sustained release from one
`dose.
`_If the maintenance dose begins the release of drug at_
`' the time of dosing_(£ = 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 ne_-ecI'ed_ toaccount for the added
`drugfrom the maintenance dose:
`_
`-
`'-
`,
`;
`'~
`.(4)-_
`'
`vpf;n,+i-.£r,,—-eff, ‘_
`-
`' The.co1'rection factor, k,'3T , is the amoiLnt.'of drug provided
`during the -period from t = to the time of the peak drug level,
`T,,.
`' No‘ correction factor is needed if the dosage form" is
`" constructed in such a fashion that the maintenance dose does.
`not begin to release drug until time T,,. '
`_
`It already has been mentioned that a perfectly invariant_
`drug blood or tissue level versus time profile is the ideal goal
`of a sustained-reiease system. The way to achieve this, in th_e_
`simplest case, is by use of a maintenance dose_ that releases’ its
`However,'satisfactory approxi-
`-drug by zero-order kin_etics.
`"“rn?i'tions of a constant drug level can be obtained by suitable
`combinations of the initial ‘dose and a maintenance dose that
`releases its dnig by a first-order‘ process.
`Tlrie.to_tal dose for '
`such-asystem is .
`Z
`.
`»-
`:_'
`-
`'
`'. w=n,+ gic,c,,,vc,)v,-,
`{5}
`where it, is the. first-order rate constant for drug release
`If the
`(t_iri_1e‘ 1), and ice, Cd and if‘, are as defined previously.
`' maintenance dose begins_ releasing drug at t .= 0, a correction
`factor is required just as it was in the zero-order case.‘ The
`1 correct expression in this case is _
`-(6)..
`_'
`-'l’VfDs"fCk¢Ca/krll/a‘Ds~.l€eTp
`‘ In order to maintain drug blood levels within thetherapeutic
`range over the entire time course of the]"apy',. most.sustairied—
`. release drug: delivery ‘systems are, like -conventional dosage
`fo'rn'is','adn1inistered 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
`I The design of sustairtedarelease delivery systems is subject
`to that used for a constant intravenous irifusion,'as discussed -
`to.severaIvai1'ables of considerable importance. Amongthese
`in Chapter 42.", For those sustai.ned~release systems having
`are the route of drug delivery, the type of delivery system," the.
`release kinetics other than zeroworder, the'multiple dosing I
`‘disease being treated, the patient, the length of therapy and
`_regi-men is-more complex and its analysis is beyond the scope .
`the properties of_th'e drug. Each of these-variables are inter-
`of this chapter; Welling and Dobrinsltaa, provide more detailed
`‘related andthis imposes certain constraints upon choices for
`discussion..
`‘
`-
`-
`_
`"
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`the route of delivery, the design of thedelivery system and the
`length of therapy. ' .Of particula_r_interest to the scientist de- .
`Potential Advantages of Sustained Drug Therapy. _
`signing the system are the constraints imposed by the proper«_ -
`ties of the drug.
`It is these properties that have the greatest,
`All sustained-_release products share the common goal of
`efiect on the behavior of the drug in the "delivery system and in
`_'im;.-roving drug therapy over.that achieved with their non-"
`the body. For the. purpose of discussion, it is convenient to‘
`sustained counterparts.
`- This improvement in drug therapy
`. describe the properties of agdiug as being either physicocherni-
`cal or "biological.
`Obviously, there is no clearcut distinction _
`is represented by several potential advantages of the use of
`- sustained-release systems, a's:show11 in Table _l .
`' between these two categories since the biological properties -
`Patient compliance‘ has been recognized as a necessary and
`of. a drug are a furiction'o_f its physicochenucal properties;
`Foripurposes ofthis disc__ussion, however, those attributes that '
`important component -in the success oi‘ all self-administered .
`“Amerlgeh
`T055,
`Amerigen Ex. 1055, p. 3
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`

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`S_lJSTlill~lED-H_ELEASE DRUG DEIJVEFIY Sl(STEMS
`
`1863
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`-' can be det_ermi.n_ed from in vi'i‘ro experiments "will be consid-
`ered as physicochemical properties.
`‘
`_
`_
`_
`Included as biological v
`' ‘properties will be.those that result from typical pharmacolci-'
`netic studies on the absorption, distribution, metabolism and"
`excretion (ADME) characteristics of a drug and those result:
`ing from pharmacological studies.
`.
`'
`
`Ph.ysr'cochen1ical_Pr‘operlies -
`
`i
`
`_ Aqueous Solubility and pK_,—lt iswell known that 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
`irdluence its absorptive behavior are"its aqueous solubility
`and, if it is a weak acid or base (as are most drugs), its
`pK,;. These properties p lay an influential role in perforniance
`iof nonsustained-r'elea'se products; their role is even greaterin
`"sustained-release systems.
`'
`_
`‘
`'
`_ The aqueous solubility of a drug influences its dissolution
`rate, which in turn establishes‘ its concentration in solution
`and hence the driving force for diflusion across-membranes.
`Dissolution rate is related to aqueous solubility _as sliown by‘
`_ the Noyes—Wl1itney equation which, under;-ink conditions, is
`' acre: =.k,,A_c,
`‘
`" -
`_
`' (7)
`
`'
`
`_
`andgastric fluic_l:_-
`.tmr
`RéU+w“rsm+dwvo)
`where pH;-, is the pH of blood (pH 7.2), pHg is the‘ pH of the '-
`gastricfluid (p_H 2).‘ and the. pit, of aspirin is about'3.4.
`‘Substituting these values into -Eq 10 gives a value for}? of 103-“.-
`which indicates that aspirin is in a form to be well-absorbed '
`from the-stomach. _The same calculation for intestinal pH _
`- (about 7) yieldsa ratio close to'l, implying a less«favo1"able '-
`driving force for absorption at that location:
`Ideally,‘ the
`release of an lonizable drug from a sustained-release system '
`should be “programmetl” in accordance with the variation in -
`pH of the different segments ofthe gastrointestinal (GI) tract
`-.so that the amount of preferentially absorbed species, and '
`thus the plasrnavlevel of drug,.will be approximately constant
`throughout the time course of drug action.
`In general, exjtremes in_the aqueous solubility of a drug are" '
`undesirable -for formulation into a sustained~relea.se product."
`A drug with very low solubility and ‘a slow dissolution rate will-
`‘ exhibit dissolutiort—limited' absorption and yield aniinherently
`'- sustained blood level.
`In most instances, forrnulation of such
`a drug into a sustained-release system is redundant. Even if
`a poorly soluble drugwas considered as a candidate for fo'rrnu-
`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 diffusioii -of drug '
`through apolymer as the rate—limiting'-step in release would be
`' unsuitable for a poorlysoluble drug, since the driving force for -
`diffusion is the concentration of drug in the polymer or solu- -
`tion and this concentration would be low. For a drug with
`very high solubility and a rapid dissolution rate, it ofi;en'is'
`quite difficult to decrease its dissolution rate and slow its
`absorption. Preparing a_sl‘1g'htly soluble form of a drug with
`norrnally high solubility is, however, one possiblemethod for
`' preparing sustained-release dosage forms.
`Thiswilllbe el_abo— ,
`rated upon elsewhere in this chapter. '
`.
`_ PartitionCoefi’1cient—Between' thetime that a drug is
`administered and the time it is eliminated from the body, it
`must diffuse through a variety of biological membranes which
`-act primarily as lipid-like barriers. A major criterion-in evalu-
`-a_tion- of the abilityof a drug to penetrate these lipid -mcrn--
`branes is its apparent oil'i’wateI‘ partition coefficient, defined
`.-as
`
`where clC/ oil is the diss-olution.rate, kg is theflissolution rate
`constant.A is the total-‘surface area of the drug particles and C,
`The dissdlu- -
`is the aqueous saturation solubility of the-drug.
`tionrate is" constant only if surface area, A, remains constant,"
`-._but the important point to note is thatthe initial rate is propor-
`_'tional_d‘Lrectly to-aqueous solubility C5; __ Therefore, the aque-
`ous solubility of a drug can be used as alfirst approximation of
`-its dissolution rate. Drugs'with’low aqueous solubility ‘have.
`low dissolution rates and usually suffer oral bioavailability
`problems.
`,
`-
`.
`It will be recalled from Chapter 16' that the aqueous 'solubil~_
`.ity of weak acids and bases is governed by the pH, of the
`compound and the pH of the rnediurn. For a weak acid
`'
`5,: s,,(-1 +K,,{[H*lj _=}5‘_¢(1 + 1o.vH"I3I<«)“
`(3)
`where S, is the total solubility (both the ionized and unionized
`forms) of the weak acid, 39 is the solubility" of the unionized
`,form, K,, is the acid dissociation constant and [H+} is the
`hydrogen lon'concentrati.on of the medium. Equation 8 pre-
`dicts that the total solubility, S,.,‘ of a wealt acid with a given pit,
`can be affected by the -p_H of the medium. Similarly, for 3,
`'weal(base
`'
`'_
`~
`'
`
`._
`-
`
`,
`
`-
`
`.'
`
`-I
`-
`
`.
`
`_
`
`'
`
`_
`'
`
`.
`
`I
`
`. 1
`
`(9)
`.-5} = 300 + lH"l/_K..) ”—‘ 5'60 + 10""‘f""”l
`.
`where S, is the total solubility (both the conjugate acidland
`free-base forms) of the weak ba.<:e,_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, 8,, of a weak base whose conjugate acid-has a
`_given' pig can be affected by the pH of‘ the medium.
`J Considering the pH-partition hypothesis, the. importance of
`The pH-
`Eqs 8 and 9 relative to drug absorption is evident.
`‘
`partition hypothesis simply states that-_the'un-iortized form of
`a drug will~bc absorbed preferentially, in a passive manner,
`through membranes. Since weakly a_cidic drugs will exist in
`is the ‘stomach (pH = -1 to 2) primarily. in the un-ionized form,
`_
`.th_eir absorption will be favored from this acidic environment. _
`On the-other hand, weakly basic drugs-willexist primarily in
`the ionized forrn (coniugate acid) at the same site,-and their ;
`absorption will be poor.
`In the upper portion of the small.
`intestine, the pH is more alkaline (pH = 5 to 7) and the reverse
`The ratio of Eq_8
`' will be expected for weak acids and_base5. _
`H
`or 9 written for either the pH of. the gastric or intestinal fluid '
`and the pH of blood is indicative of the driving .for.t_:e for
`absorption based on pH gradient. For example, consider the
`ratio of the total solubility of the weak acid aspirin in the blood
`
`on
`K=wa‘
`_
`where Co. 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 equilibritiin concentration of all forms in an
`aqueous phase. A frequently used solvent for the organic
`phase is 1-octanol. although not alwaysvalid. an approxirna-
`tion to the value of If may .be obtained by _the ratio of the
`solubility of the drug iri_1—octanol_ to that in water.‘
`In general;
`drugs with e__xtrernely.large values of K are veryoil-soluble and
`will partition into membranes quite readily. The relationship
`between ‘ tissue permeation and partition coeflicient "for the
`drug generally is known as the Homsch. cmirelation, discussed
`-in Cl1apter‘28. ' In general, it describes a parabolic _relation- -
`ship. between the logarithmof the activity of a drug or its
`ability to be absorbed and the logarithm of its partition coefil-
`cient for a series ofdrugs as shown in -Fig 5. The explanation
`-" . for this relationship is that the activity of a drug is a function of -'
`its ability to cross membranes and in_te.ract with the receptor;
`_as_ a first approxirnatlon, the -more effectively a drug crosses
`membranes, the greater its activity." The-re'is also an'opti~
`_mum partition coefficient for a drtlg at which it most efi'ec¥
`tively permeates membranes and thus shows greatest activity; _
`. Values of the par1;itio_n.coeflicient below this optimum result in
`decreased lipid solubility, and the'drL1'g will remain localized
`' the first aqueous phase it contacts.
`,Values larger than the '
`optirnurn result in poorer aqueous solubility, but enhanced"
`lipid solubility and the drug will not partition out of the lipid "
`membrane once it gets in.
`lThc'value of K at which optimum -
`activity is observed is approximately 100011 in l-dctanol/l
`water. Drugs with a .partition_ coefficlent that is‘ higher" or
`
`.
`
`-
`
`_
`
`Amerigen Ex. 1055, p. 4
`L Ame_rigenEX. 1055, p.41_
`
`
`

`
`J
`
`.
`
`'
`
`1664
`
`QHAPTEH 94
`
`"InIlellvily
`
`‘-
`
`.
`
`.
`
`.
`
`16¢ K
`
`_
`
`Fig‘ 5. Typical relationship‘ between drug activity and partition coef-
`jicient, K. generally known as the Hansch correlation.
`'
`'
`-
`
`_
`
`that exhibit greater than Q5% binding at therapeu;
`Some
`tic levels are amitriptyline, .bis_hydroxycournarin, din,-gepa;-n,'
`diazoxide, dicurnarol and novobiocin. -
`_
`Moleclllar Size and Di1_fu_sivity—As_ previously discussed,
`a drug must diffuse through avariety of biological membranes
`during its time course in the body.‘
`In addition to diffusion '
`throughthese biological membranes, drugs in many sustained.
`‘ release systems must diifuse through a. rate-controlling mem-
`brane or matrix.
`"The ability of a-drug to diffuse through
`- membranes, -its so called diffusivity (diffusion coefficient), is-a
`function of its molecular size (or molecular weight). An 1m-
`portant influenceupon the value of the diffusivity, D, in poly- "
`mers is the molecular size (or molecular weight) of the djifug.
`ing species.
`In most polymers, it is possible to relate log D
`, empirically to some function of molecularsize, ‘as shownin Eq
`12:‘
`
`
`
`H"
`
`‘log_D = —s,, logo + rc, = és,,1og_M + km '
`(12) '
`where 12 is molecularvolume, Mis molecularweight and S,,,~s',1,,,
`k,, and :'c,,, are constants.
`The value of D thus is related to the
`size and shape of the cavities as well as size and shape of
`drugs. Generally, values of the diffusion coefficient for inter-'.
`mediate-molecular-weight drugs, ie, .150 to 400,, through flex-
`_ ible poly_mers range from 10"‘ to '1O‘9 cmefsec, with values
`on the order of 104 being most common? A value of ap-
`proximately'_l0‘5 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* cmzfsecgand for one '
`liquid through another, lO‘5 crnzfsec. For drugs with a mo-'
`lecular weight greater than 500, the diffusion coefficients in .
`- many polymers frequently are so small thatthey are difficult to
`quantify, ie, less than 10' 12 cmzfsec. Thus,.high-molecular-
`weight drugs andlbr polymeric drugs should be expected to
`display veryslow-release kinetics in sustained-release devices '
`using difiusion through polymeric membranes or matrices as
`the r_el_eas_ing mechanism.
`-
`'
`
`.
`
`_
`
`‘
`
`I
`
`' Biotogicoi-Properties
`
`Ah§Ol;ptiOfl—The rate, extent and uniformity of "absorp-
`tion of a ‘drug are important factors -when considering its
`formulation into _a sustained-release system. Sinee the rate-
`limiting step iI1 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 indiscussing terrninology,.ic, <<< k,,. This becomes '
`most critical in the case of oral 'ad:miI1istration. Assuming
`that the transit time of a drug through the absorptive area of
`the GI tract is between 9 and 12 hours, the maximum absorp-
`tion _half-life should ‘be 3 to 4 hours.“ This corresponds to a
`minimum absorption rate constant !c,, of 0. 17 hr‘ to 0.23 hr"‘
`necessary for about 80 to 95% absorption over a 9- to 1 2-hour
`transit time. For a drug with a'very rapid rate of absorption
`-(ie,_k,, .» 0.-23 hr‘1), the above discussion implies that a '
`first-order release-rate constant #6,. less tl_ian.0. l 7-hr“ is likely
`to result in unacceptably poor bioavailability in many patients.
`Therefore, slowly absorbed drugs will be diflicult to formu_late.
`into sustained-release systems where the criterion that it," '<<<
`lo, must be met. .
`The extent and uniformlt;y of the absorption of a drug, as ,
`reflected by its bioayailability and the fraction of the total dose
`absorbed, .ma_y~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 poor water solubility, small partition
`coefficient, acid hydrolysis and metabolism, or site-specific
`absorption. The latter reason also is responsible for nonuni-
`formity of absorption. Many of these problems can be over-
`come by" an appropriately desi