CHAPTER 94
`
`Sustained-Release Drug Delivery Systems
`
`Charles S L Chico, PhD
`Ando 51k Pharmaceuticals. Inc
`Doyle, FL 33314
`
`losaph R Robiniop, PhD
`Professor at Pharmacy
`hoof of.Phannocy
`University al Wisconsin
`Madison, WI 53706
`
`is shown in Fig 2 for the-oral route. In this case the drug
`blood level reached and the time required to reach that level
`depend on the dose and the dosing interval. There are sev-
`eral potential problems inherent in multiple-dose therapy:
`1, (cid:9)
`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 half-lives require frequent dosings to main-
`tain constant therapeutic levels, (cid:9)
`'
`2. The drug blood level may not be withirkhe therapeutic range at .
`sufficiently early times, an important consideration for certain disease .
`states.
`3. Patient noncompliance with the multiple-dosing 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 sustained-release.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, 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.
`This is illustrated in the following simple kinetic scheme:
`
`Dosage
`F97 (cid:9)
`
` Target kr
`k, Absorption kn
`drug release Pool
`absorption Area
`elimination
`The absorption pool represents a solution of the drug at the
`site of absorption, and the terms kr, k„ and ke are first-order
`. rate constants for drug release, absorption and overall elimina-
`tion, respectively. Immediate release from a conventional
`dosage form implies that kr, >>> k„ or, alternatively, that
`absorption of drug across a biological membrane, such as the
`intestinal epithelium, is the rate-limiting step in delivery of the
`drug to its target area. For nonimrnediate-release dosage
`forms, kr <<< k„, that is, release of drug from the dosage
`form is the rate-limiting step. This causes the above kinetic
`scheme to reduce to
`
`Dosage Form
`
`k, (cid:9)
`
`- (cid:9)
` Target Area (cid:9)
`'
`elimination -
`drpg release (cid:9)
`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
`
`ke•
`
`-
`
`The goal of any drug delivery system is to provide a therap eu-
`• tic amount of drug to the proper site in the body to achieve
`promptly, and then 'Maintain , the desired drug concentration.
`Thaas, the drug-delivery system should deliver drug 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-
`tant to 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 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 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
`physicochemical 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 cur-
`rently 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) Consider single dosing of a
`hypothetical drug that follows a simple one-compartment phar-
`macokinetic model for disposition. Depending on the route
`of administration, a conventional dosageform 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 I . The term "drug blodd 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 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 injection, 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 Multiple-dose therapy. This
`
`. 1660
`
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`SHIRE EX. 2026
`KVK v. SHIRE
`IPR2018-00293
`
`(cid:9)
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`- Toxic
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`611)
`
`•
`Therapeutic
`Rafe
`
`Pik
`missersmoss...rfisn sig. mmosifississ!
`
`foul'
`
`r
`
`TIME thrill
`
`•
`
`Ins thicliue
`Range
`
`Fig 1. Typical drug •ilood revel versus time profiles for intravenous
`, injections and an extravascurar route of administration.
`
`,
`. (cid:9)
`system must be directed primarily at altering the release rate -
`by affecting the value of kr. The many ways in which-this has
`been attempted will be discussed later in this chapter.
`Nonirnmediate-release delivery systems may be divided con-
`veniently into four categories:
`I. (cid:9) Delayed release
`2. Sustained release
`a. Controlled release
`Prolopged release
`•
`3. Site-specific release
`4. Receptor release
`Delayed-release systems are those that use repetitive, inter-
`mittent closings of a drug from one ormore immediate-release
`units incorporated into a single dosage form. Examples of
`delayed-release systems include repeat-action tablets and cap-
`sules, and enteric-coated tablets where timed release is
`achieved by a barrier coating. A delayed-release dosage form •
`does not produce or maintain uniforna drug blood leyels within
`- the therapeutic range, as shown in 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,
`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 citlg levels in the target
`tissue or cells, it is considered a cont rotted-release system.
`It it 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-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 organ or tissue; for receptor release, the target is the
`- particular receptor fora drug within artbrgan or tissue. Both
`of these systeins satisfy the spatial aspect of drug delivery.
`
`SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS • 1661
`
`Topic
`Rona
`
`ALA ISMAY
`
`1+ies)
`TIME
`Fig 3. Typical drug blood level versus time profiles for delayed-
`release drug delivery by a repeat-action dosage form.
`
`Release Rate and Dose Consideraticms
`
`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 goat of a sustained-release
`delivery system. In fact, in some cases optimum therapy is
`achiev,ed by oscillating, rather than constant, driig levels.
`An example of this is antibiotic therapy, where the'activity of
`the drug is required only during growth phases of the
`microorganism. A constant drug level will succeed at curing
`or controlling the condition, howeVer, and this is true for most
`forms of therapy. (cid:9)
`-
`-
`The objective in designing, a 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 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 &sage form should follow zero-order kinetics, as shown
`by
`
`• Cd Vd (cid:9)
`.= Rate In =, Rate Out =
`( 1)
`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-1], Cd is the desired drug level in the
`body (amount/volume) and Vri is the volume space in which
`the drug is distributed. The values of ke1 Cd and V d needed to
`calculate are obtained from appropriately designed single-
`dose pharmacokinetic 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 affecting_ their disposition are involved.
`This in turn affects the nature of the release kinetics necessary
`to maintain a constant drug blood level. It •is important to
`recognize that while zero-order release may be desirable theo-
`
`I E
`
`a
`• 0
`
`prlrrirrrrrrll (cid:9)
`
`1111,10~11ifirlpl.1,'
`
`Telic
`Rouge
`
`s (cid:9) ll
`
`Therapeutic
`Rapp
`
`Inof I active
`Range
`
`••-7.
`
`TOiiC
`Rungs
`
`WIAIZALIWAVIMISIAIIMFAUZIFififfilif
`
`Therepeutia -
`Feint
`
`0
`c
`
`Inetleclire
`Rang.
`
`0'
`1'
`
`TIME WO
`Fig 2. Typical drug blood level versus time profile following oral
`•
`multiple-dose therapy. (cid:9)
`
`• TIME Nei -
`Fig 4. Drug blood level versus time profiles showing the relation-
`ship between controlled-release (Al, prolonged-release (B) and con-
`ventional-release (C) drug delivery.-
`
` Page 2
`
`

`

`1662 (cid:9)
`
`CHAPTER 94
`
`..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. •.' IL (cid:9)
`To achieve a therapeutic level. promptly .and sustain the
`level for a given period -of time, the dosage form -generallY-
`consists of -two- parts: an initial priming dose, Di,. that-.re
`leases driig immediately and a maintenance' .or. sustaining
`dose; Dm." The total dose,W, thus required for the system is
`iL`= Di ;1-• zy„, (cid:9)
`(2)
`For a system where the maintenance dose releases drug by a
`zero-order process fora specified period of timer the total
`-
`dose2 Is (cid:9)
`
`Table 1—Potential Advantages of Sustained Drug Therapy
`
`' (cid:9)
`
`1. (cid:9) Avoid patient compliance problems
`• 2. Employ less total drug
`'• a. .Minimize or eliminate local side effects
`b. Minimize or eliminate systemic side effects
`c. Obtain less pntentiation or reduction in drtig activity with
`chronic use
`d. Minimize drug accumWation with chronic dosing
`3.. Improve efficiency in treatment -
`a.. Cure or control condition more promptly (cid:9)
`•
`. • b.. Improve control of condition, ie, reduce fluctuation in drug
`•
`- (cid:9)
`level •• (cid:9)
`c. Improve Unavailability of sortie drugs •
`d: Make use of speciateffects, eg; sustained-release aspirin for
`' 'morning relief of arthritis by dosing before bedtime •
`• 4. Economy
`
`W L- (cid:9)
`drug therapy. Minimizing or eliminating patient compliance
`(3)'
`problems is an obvious advantage of sustained-release therapy. -
`where Ic° is the zero-order rate constant for drug release and .
`..Because of the nature of its release kinetics, a sustained-:
`TT is the total time desired for sustained release frond one
`.release system should be able to use less total drug; over the '
`dose. If the maintenance dose begins the release of drug at
`time course of therapy thiip a conventional preparation. The
`the time of dosing (t = 0),- it will add to that which is provided
`advantages of this are a decrease or elimination of both local
`by the initial dose, thus increasing the initial drug level. In.
`and systemic side effects, less potentiation or, reduCtion in
`(cid:9) for the added
`this case a correction factor is needed .to
`drug activity with chronic use and minimization of drug accu-
`drug from the maintenance dose:
`mulation in body tissues with chronic dosing.
`Unquestionably-the most important 'reason for sustained- •
`• • (4)
`W .1- Di + 4,7'a (cid:9)
`drug therapy is improVed efficiency in treatment, ie ;optimized .
`The correction factor, 47; , is the amount'of drug provided
`therapy. The result of obtaining constant drug bloodjevels-
`during the -period from t = I9 to the time of the peak drug level,
`from a .sustained-release system is to achieve promptly the
`To.. No correction factor is needed if the dosage form- is
`desired effect and maintain it for an extended period of time.,
`•constructed in such a fashion that the maintenance dose does
`Reduction or elimination of fluctuations in the drug blood,
`not begin to release drug until time Tp.
`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 blood or tissue level versus time pi-ofile is the ideal goal
`prove the bioavailability of some drugs. For example, drugs
`Of a sustained-release system. The way to achieve this, in the.
`susceptible to enzytriatic inactivation or bacterial decomposiL,
`simplest case, is by use of a maintenance dose that releases its
`tion can be protected by encapsulation. in polymer systems
`• drug by zero-order kinetics. HoweVer,Satisfactory appr-oxi-
`suitable for sustained release.' For drugs that have a "spe-
`'anitions of a constant drug level -cap be obtained by suitable
`cific window" for absorption, increased bioavailability Can be ,
`combinations of the initial -dose and a maintenance dose that
`attained by localizing the-sustained-release deli-Very systemin
`releases its drug by a first-order process. 'The-total dose for
`certain regions of the gastrointestinal tract. Improved effi-
`such a system is •
`ciency in treatment also can take the form of a', special thera-
`peutic effect not possible with a conventional dosage' form
`(see Table (cid:9)
`,
`.The last potential advantage listed in Table I, 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 conventional doage
`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.
`
`W = Di + (kedlkji7d (cid:9)
`(5)
`where ica is the first-order rate constant for drug release
`(time" r), and k, Ca and vd are as defined previously. If the
`maintenance dose begins releasing drug at t = 0, a correction
`factor is required just as it was in the zero-order case: The
`•
`correct expression in this case is (cid:9)
`= Di 1- (k. Ca /kr) —
`(6)
`p
`In order to Maintain drug blood levels within the therapeutic
`range over the entire time course of therapy,- mostsustairied-
`release drug:delivery systems are, like conventional dosage
`farina, 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 infusioni.as discussed •
`in Chapter 42 For those sustained-release systems having
`release kinetics other than zero-order, the - multiple dosing
`regimen is-more complex and its analysis is beyond the scope
`of this chapter; Welling and D obrirtska3. provide more detailed
`discussion. - (cid:9)
`•
`
`. (cid:9)
`• (cid:9)
`.
`
`Potential Advantages of Sustained Drug Therapy.
`
`All sustained-release prOducts share the common goal of
`improving drug therapy over . that achieved with their non:
`sustained counterparts. - This improvement in drug therapy
`is repres6nted by several potential advantages of the use of
`sustained-release systems, asshown in Table I.
`Patient compliance has been recognized as a necessary and
`impottant component in the success of all seif-administered
`
`Drug Properties.Reievant to Sustained-Release
`Formulation .
`
`The design of sustained-release delivery systems is subject
`to seimral Variables Of considerable importance. Amongthese
`are the route of drug delivery, the type of delivery system, the.,
`disease being treated, the patient, the length of thera'py and
`the Properties of the drug. Each of these variables are. inter-
`-related and this imposes 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 a; drug as being either physicochemi- •
`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 physicochemical properties:
`For'piirpos es of this discussion, however, those attributes that
`
` Page 3
`
`(cid:9)
`

`

`(cid:9) (cid:9)
`
`• .
`
`- can be determined from in vitro experiments will be consid-
`ered as phySicochemical properties. _ Included as biological •
`'properties will be those that result from typical pharrnacoki-
`netic studies on the absorption, distribution, metabolism and
`excretion (ADME) characteristics of a drug and those result,-
`ing from pharmacological studies.
`
`Physicochemical Properties
`
`•
`AqUeous Solubility and (cid:9)
`is. Well 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
`influence its- absorptive behavior are
`(cid:9) aqueous solubility
`and, if it is a weak acid or base (as are most drugs), its
`pile. These properties play an influential role in performance
`nonsustaiiaed-release products; their role is even greater in
`-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 diffusion across membranes.,
`Dissolution rate is related to aqueous solubility .as shown by
`the Noyes-Whitney equation which, under sink conditions, is
`
`dC / (cid:9)
`
`knAC, - ' (cid:9)
`
`(8)
`
`(7)
`where dC/ dt is the dissolution.rate, kn is thedissblution rate
`cOnStan t, A is the tOtal-s urfaee area of the drug particles and
`is the aqueous• saturation solubility of the-drug. The dissdlu-
`tion rate is constant only if surface area, A, remains constant;
`- but the important point to note is that the initial rate is prop or--
`Alonaldirectly to aqueous solubility (cid:9)
`, Therefore, the aque-
`ous solubility of a drug can be used as afirst approximation of
`-its dissolution rate. Drugs !Marlow aqueous solubility have,
`low dissolution rates and usually suffer oral bioavailability
`problems.
`It will be recalled from Chapter 16 that the aqueous solubik
`ity of weak acids and bases is governed, by the plc of the
`compound and the pH of the mediUrn. For a weak acid
`SO -I- K, / [H± ]) = Si(1 1004-P9 (cid:9)
`where Si is the total solubility (both the ionized and unionized
`forms) Of the weak acid, So is the 'solubility of the unionized
`form, l(,„ is the 'acid dissociation constant and [H+] is the
`hydrogen ion concentration of the mediuni. Equation 8 pre-
`dicts that the total solubility, Si, of a weak acid with a given pl.c
`can be affected by the pH of the medium. Similarly, for a
`weak base - • . (cid:9)
`•
`
`SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS (cid:9)
`
`1663,.
`
`- (cid:9)
`
`and gastric fluid:.
`• - (cid:9)
`- - R = (1 + 100b7010. /(1 (cid:9)
`100-19-PHa) (cid:9)
`(10) ,
`where pflb is the pH of blood (pH 7.2), pH, is the pH of the :-
`gastric - fluid (pH 2) and the• plc of aspirin is about - 3.4. - '
`-Substituting these values into Eq 10 gives a value for R of 103-8.-
`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 1, implying a less-favorable •
`driving force for absorption at that location: Ideally; the
`releese of an ionizable drug from a sustained-release system
`should be "programmed" in accordance with the variation in •
`PH of the different segments of the gastrointestinal (GI) tract
`so that the amount of preferentially absorbed species, and
`thus the plasma•Ievel of drug, will be approximately constant
`throughout the time course of drug action.
`In general, extremes in the aqueous solubility. of a drug are
`Undesirable for formulation into a sustained-release product:
`A drug with very low solubility and a slow dissolution rate will
`exhibit dissolution-limited 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 drug was 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 diffusion of drug '
`through a polymer as the rate-limiting step in release would be
`unsuitable for a poorly soluble drug, since, the driving force for
`diffusion is the concentration of dnig 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 often is -
`quite difficult to decrease its dissolution rate and slow its
`absorption. Preparing aslightly soluble form of a drug with
`- normally high soltibility is, however, one possible- method for (cid:9)
`• preparing sustained-release dosage forms. This Willbe elabo-
`rated upon elsewhere in this chapter.'
`, Partition Coefficient—Between the time 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-
`ation of the ability- of a drug to penetrate these lipid -mem-
`branes is its apparent oil/water partition coefficient, defined
`,as
`
`"
`
`So(1 (cid:9)
`
`[H+]/3Ca (cid:9)
`
`Sd (1 ± 10PK.- pH) (cid:9)
`
`(9)
`
`K = ColCi, (cid:9)
`•
`• (11)
`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 equilibrium concentration of all forms in an
`aqueous phase. A frequently used solvent for the organic
`phase is 1-octanol. Although not always valid, an approlcirna- -
`tion to the value of K may be obtained by the ratio of the
`solubility of the drug in 1-octanol to that in water.' In general,-
`drugs with extremely large values of K are very oil-soluble and.
`where 8, is the total solubility (both the conjugate acid and
`free-base forms) of the weak base,. So is the solubility- of the
`will partition into membranes quite readily. The relationship
`free-base form and K„ is the acid dissociation constant of the
`between tissue permeation and partition coefficient 'for the
`' conjugate acid. Analogous to Eq 8, Eq 9 predicts that the
`drug generally is known as the Hunch correlation, discussed
`in Chapter-28. In general, it describes a parabtilic relation- -
`total solubility, 8,, of a weak base whose conjugate acid-has a
`. given' plc 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 pH-partition hypothesis, the, importance of
`Eqs 8 and 9 relative to drug absorption is evident. The pH-, •
`' cient for a series of drugs as shown in-Fig 5. The explanation
`-.for thisrelationShip is that the activity of a drug is a function of
`partition hypothesis simply states that the un-ionized form of
`its ability to cross membranes and interact with the receptor;
`a drug will-be absorbed preferentially, in a passive manner,
`As a first approximation, the More effectively a drug crosses
`through membranes. Since weakly acidic drugs will exist in
`membranes, the greater its activity.-- There- is also an opti-
`the stortiach (pH = -1 to 2) primarily in the un-ionized form,
`mum partitign coefficient for a drug at which it most effecr
`.their absorption will be favored frOm this acidic environment.
`tively permeates membranes and thus shows greatest activity: ,
`On the-other hand, weakly basic drugs-will-exist primarily in
`Values of the partition-coefficient below this optimum result in
`the ionized forM (conjugate -acid) at the same site,• and their
`absorption will be poor. In the upper portion of the small
`decreased lipid solubility, and the-drug will remain localized in
`intestine, the pH 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
`membrane once it gets in.. The value of K at which optimum
`and the pH of blood is indicative of the driving .force for
`absorption based on pH gradient. For example, consider the
`activity is observed is approximately 1000/1 in l:Octariol/
`water. Drugs with a partition coefficient that is higher or
`ratio of the total solubility of the weak acid aspirin in the blood
`
` Page 4
`
`(cid:9)
`

`

`1664 (cid:9)
`
`CHAPTER 94
`
`Some drugs that exhibit greater than 95% binding at therapeu-
`tic levels are amitriptyline, hishydroxycournarin, diazepam; ,
`diazoxide, dicumarol and nOvobiocin. -
`Molecular Size and Diffusivity—As previously discussed,
`a drug must diffuse through a variety of biological membranes
`during its time course in the body. In addition to diffusion
`through these biological membranes, drags in Many sustained-
`release systems must diffuse through a rate-controlling mem-
`brane or matrix. The ability of a •drug to diffuse through
`membranes, its so called diffusivity (diffusion coefficient), isa
`function of its molecular size (or molecular weight). An im-
`portant influence, upon the value of the diffusivity, D, in poly-
`mers is the molecular size (or molecular weight) of the diffus-
`ing species. In most polymers, it is possible to relate log D
`empirically to some funCtion of molecular size, 'as shown-in Eq
`12:4 (cid:9)
`•
`• (cid:9)
`log D = -sy log v
`ky -= (cid:9)
`+ km (cid:9)
`(12)
`where v is molecular volume, Mis molecular weight ands,,;
`k„ and k„, are constants. The value of D thus is related to the
`size and shape of the cavities as well as size arid shape of
`drugs. Generally, values of the diffusion coefficient for inter-'.
`mediate-molecular-Weight drugs, ie, .150 to 400, through flex-
`, ible polymers range from 10-6 to 10-9 cm2/sec, with values
`on the order of 10-2 being most commons A value of ap-
`proximately .10-6 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 14-1 cm2/sec; and for One
`liquid through another, 10-2 cm2/sec. For drugs with a mo-.
`lecular weight greater than 500, the diffusion coefficients in
`many polymers frequently are so small that they are difficult to
`quantify, ie, less than 10-12 crn2/sec. Thus,•high-molecular-
`weight drugs and/br polymeric drugs shoidd be expected to
`display very-slow-release kinetics in sustained-release devices
`using diffusion through polymeric membrane's or matrices as
`the releasing mechanism.
`
`Biological•Properties
`
`Absorption—The 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 successfid. As stated previ-
`ously in discussing terminology, k, <<< ka. This becomeS
`most critical in the case of oral 'administration, 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
`minim-urn absorption rate constant ka of 0.17 hr'-1 to 0.23 hr-
`necessary for about 80 to 95% absorption over a 9- to 12-hour
`transit time, For a drug with a very rapid rate of absorption
`• (ie, k,2 s 0.23 hr-1), the above discussion implies that a
`first-order release-rate constant kr less tban0.17 Yir- I is likely
`to result in unacceptably poor bioavailability in many patients.
`Therefore, slowly absorbed drugs will be difficult to formulate
`into sustained-release systems where the criterion that k, <<<
`ka must be met.
`The extent and uniformity of the absorption of a drug, as
`reflected by its bioaxqllability and the fraction of the total dose
`absorbed, may- be quite row 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 arid 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 designed sustained-release 'system,
`as exemplified by .the discussion under the pOtential advan-
`tages of sustained drug therapy.
`Distribution—For the design of sustained-release sys-
`tems it is desirable to have • as much information as pOssible
`
`top K
`F145. Typical relationship between drug activity and partition coef-
`ficient, K, generally known as the Hansch correlation. (cid:9)
`.
`
`lower than the optimum are, i