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

`

`1 9TH
`
`EDITION
`
`Remington:
`Practice of
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`and Editor
`
`AUROBINDO EX1018, 2
`
`

`

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

`

`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907,1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980,1985, 1990, 1995, by The Philadelphia College of
`Pharmacy and Science
`
`All Rights Reserved
`
`Libraly of Congress Catalog Card No. 60—53334
`
`ISBN 0-912734-0443
`
`The use ofstruclni‘aljbrmnlasfram USAN and the USP Dictionary ofDrug Names is by
`permission ofThe USP Convention. The Convention is not responsiblefora'ny inaccuracy
`contained herein
`
`NOTICE—This terrt is not intended to represent, norshall it be interpreted to be, the equivalent
`ofor a substitutefor the official United States Pharmacopeia (USP) and/or the National
`Fornznlary (NF). In the event ofany (lifierence ordiscrepancy between. the current ofl‘icz‘al
`USP orNFstandards ofstrength, quality, purity, packaging and labelingfordrugs and
`representations oft/lent herein, the context and effect oft/2e oflicial compendia shall prevail.
`
`AUROBINDO EX1018, 4
`
`

`

`CHAPTER 94
`
`Sustained-Release Drug Delivery Systems
`
`Charles S L Chico, PhD
`Anda SR Pharmaceuticals, Inc
`
`Joseph R Robinson, PhD
`Professor of Pharmacy
`School of Pharmacy
`University of Wisconsin
`Madison, WI 50706
`
`The goal of any 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.
`That is, 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
`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-
`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
`In addition, a brief discussion of some methods cur-
`rently being used to develop targeted delivery systems will be
`
`Conventional Drug Therapy
`
`To gain an appreciation for the value of sustained drug
`therapy it is useful to review some fundamental aspects of
`conventional drug delivery.‘ Consider single dosing of a
`hypothetical drug that follows a simple one-compartment phar-
`rnacokinetic 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 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
`
`In this case the drug
`is shown in Fig 2 for the oral route.
`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.
`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 (losings 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 multiple—(losing 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, ointrnents 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:
`1;
`.
`-
`k
`.
`It .
`Absorption
`Target
`I
`I
`Dosage
`a
`F01 m drug release P001
`absorption Al ea
`elimination
`The absorption pool represents a solution of the drug at the
`site of absorption, and the terms It}, It" and It}, are first-order
`rate constants for drug release, absorption and overall elimina-
`tion, respectively.
`Immediate release from a conventional
`dosage form implies that A7,. >>> A?“ 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 rronimrnediate-release dosage
`forms, It, <<< Ir", that is, release of drug from the dosage
`form is the rate-limiting step. This causes the above kinetic
`scheme to reduce to
`
`AUROBINDO EX1018, 5
`
`

`

`
`
`
`
`
`
`DRUGBLOODLEVEL(°m°“"%ni)
`
`ExnavaECMor
`route
`
`
`TIME ('17!)
`
`Inoiiecfive
`Range
`
`
`
`
`
`DRUGBLOODLEVEL
`
`llIll,“UUUUUUUUU”I’llllflflflflllfllflflfllflflUZI
`
`
`
`
`TIME
`(hrl)
`
`Fig 1. Typical drug blood level versus time profiles for intravenous
`injections and an extravascular route of administration.
`
`Fig 3. Typical drug blood level versus time profiles for delayed-
`release drug delivery by a repeat-action dosage form.
`
`system must be directed primarily at altering the release rate
`by affecting the value of k)». The many ways in which this has
`been attempted will be discussed later in this chapter.
`Nonimmediate-release delivery systems may be divided con-
`veniently into four categories:
`1. Delayed release
`2. Sustained release
`a. Controlled release
`b. Prolonged release
`. Site-specific release
`Ll. Receptor release
`
`Delayed-release systems are those that use repetitive, inter-
`mittent closings of a drug from one or more 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 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.
`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 drug levels in the target
`tissue or cells, it is considered a controlled—release system.
`If 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 for a drug within an organ or tissue. Both
`of these systems satisfy the spatial aspect of drug delivery.
`
`nnmannaaanzamazanllanzzwuuuwzvluuuuv
`
`
`Tofic
`Range
`
`Thuapeuflc
`Range
`
`Inlilacfive
`Range
`
`llflflflflll'flflflfluylflfl
`
`
`
`
`
`
`
`DRUGeroooLEVEL(“”me
`
`
`TIME Mrfl
`
`Fig 2. Typical drug blood level versus time profile following oral
`multiple-dose therapy.
`
`Release Rate and Dose Considerati071.92
`
`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 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.
`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 dosage form should follow zero-order kinetics, as shown
`by
`
`k? = Rate In = Rate Out = kc ' Cd ' VII
`
`where It? is the zero—order rate constant for drug release
`(amount/time), Ice is the first-order rate constant for overall
`drug elimination (time’l), Cd is the desired drug level in the
`body (amount/volume) and Vd is the volume space in which
`the drug is distributed. The values of If,” Cd and Vd needed to
`calculate It? 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.
`recognize that while zero-order release may be desirable theo-
`
`I
`
`
`
`
`
`DRUGBLOODLEVEL(amoun/mL)
`
`
`
`TIME
`
`(hr!)
`
`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.
`
`AUROBINDO EX1018, 6
`
`AUROBINDO EX1018, 6
`
`

`

`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 drrrg level.
`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, D,, that re-
`leases drug immediately and a maintenance or sustaining
`dose, D,,,. The total dose, W, thus required for the system is
`
`W=Di+Dm
`
`(2)
`
`For a system where the maintenance dose releases drug by a
`zero-order process for a specified period of time, the total
`
`Table 1—Potential Advantages of Sustained Drug Therapy
`1. Avoid patient compliance problems
`‘2. Employ less total drug
`a. Miuiruize or eliminate local side effects
`b. Minimize or eliminate systemic side effects
`c. Obtain less potentiation or redrrction in drug activity with
`chronic use
`d. Minimize drug accumulation with chronic dosing
`Improve efficiency in treatment
`a. Cure or control condition more promptly
`b. Improve control of condition, ie, redrrce fluctuation in drug
`level
`c. Improve bioavailability of some drugs
`(1. Make use of special effects, eg, sustained-release aspirin for
`morning relief of arthritis by (losing before bedtime
`4. Economy
`
`3.
`
`W = D, + kETd
`
`(3)
`
`where It? is the zero-order rate constant for drug release and
`T,, is the total time desired for sustained release from one
`If the maintenance dose begins the release of drug at
`the time of dosing (t = 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 for the added
`drrrg from the maintenance (lose:
`W = D,- + kgTd — kIQT)1)
`
`(4)
`
`The correction factor, k?T,, is the amount 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 T1,.
`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-
`mations 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
`
`W = Di + (k’P Crl/kr) V11
`
`(5)
`
`where k7,. is the first-order rate constant for drug release
`(time—1), and [cm 0,, and Vd are as defined previously.
`If the
`maintenance dose begins releasing drug att = 0, a correction
`factor is required just as it was in the zero-order case. The
`correct expression in this case is
`
`(6)
`W = Di + (chd/k’r)Vd _ Dmk’e T1)
`In order to maintain drug blood levels within the therapeutic
`range over the entire time course of therapy, 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 is more complex and its analysis is beyond the scope
`of this chapter; Welling and Dobrinska3 provide more detailed
`
`Potential Advantages of Sustained Drug Therapy
`
`drug therapy. Minimizing or eliminating patient compliance
`problems is an obvious advantage of sustained-release therapy.
`Because of the nature of its release kinetics, a sustained-
`release system should be able to use less total drug over the
`time course of therapy than a conventional preparation. The
`advantages of this are a decrease or elimination of both local
`and systemic side effects, less potentiation or reduction in
`drug activity with chronic use and minimization 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 blood levels
`from a 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 bioavailability of some drugs. For example, drugs
`susceptible to enzymatic inactivation or bacterial decomposi-
`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 the sustained-release delivery system in
`certain regions of the gastrointestinal tract.
`Improved effi-
`ciency in treatment also can take the form of a special thera-
`peutic effect not possible with a conventional dosage form
`(see Table 1).
`The last potential advantage listed in Table 1, that of
`economy, can be examined from two points of view.
`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 Properties Relevant to Sustained-Release
`Formulation
`
`The design of sustained-release delivery systems is subject
`to several variables of considerable importance. Among these
`are the route of drug delivery, the type of delivery system, the
`disease being treated, the patient, the length of therapy and
`the properties of the drug. 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
`
`AUROBINDO EX1018, 7
`
`

`

`Physicochenrical. Properties
`
`Aqueous Solubility and pKa—It 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 its aqueous solubility
`and,
`if it is a weak acid or base (as are most drugs),
`its
`pKa. These properties play an influential role in performance
`of nonsustained-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/dt = kDAc,
`
`(7)
`
`where dC/dt is the dissolution rate, kl, is the dissolution rate
`constant,A is the total surface area of the drug particles and C,
`is the aqueous saturation solubility of the drug. Tire dissolu—
`tion rate is constant only if surface area, A, remains constant,
`but the important point to note is that the initial rate is propor-
`tional directly to aqueous solubility Cs. Therefore, the aque-
`ous solubility of a drug can be used as a first 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 pKa of the
`compound and the pH of the medium. Fora weak acid
`
`u’
`S, = 50(1 + K ’[H+]) = 80(1 + 10PH‘I’K")
`
`(8)
`
`where S, is the total solubility (both the ionized and unionized
`forms) of the weak acid, SO is the solubility of the unionized
`form, K“ is the acid dissociation constant and [H+] is the
`hydrogen ion concentration of the medium. Equation 8 pre-
`dicts that the total solubility, 8,, of a weak acid with a given pKa
`can be affected by the pH of the medium.
`Similarly, for a
`weak base
`
`5; = 30(1 + [H+]/K(r) = 50(1 + IOPKFPH)
`
`(9)
`
`where S, is the total solubility (both the conjugate acid and
`free-base forms) of the weak base, So is the solubility of the
`free-base form and K" is the acid dissociation constant of the
`conjugate acid. Analogous to Eq 8, Eq 9 predicts that the
`total solubility, 5,, of a weak base whose conjugate acid has a
`given pKa can be affected by the pH of the medium.
`Considering the pH-partition hypothesis, the importance of
`Eqs 8 and 9 relative to drug absorption is evident. The pH-
`partition hypothesis simply states that the Lin-ionized form of
`a drug will be absorbed preferentially, in a passive manner,
`through membranes. Since weakly acidic drrrgs will exist in
`the stomach (pH = l to 2) primarily in the un-ionized form,
`their absorption will be favored from this acidic environment.
`On the other hand, weakly basic drugs will exist primarily in
`the ionized form (conjugate 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
`will be expected for weak acids and bases. The ratio of Eq 8
`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
`absorption based on pH gradient. For example, consider the
`ratio of the total solubility of the weak acid aspirin in the blood
`
`from the stomach. The same calculation for intestinal pH
`(about 7) yields a ratio close to 1, implying a less-favorable
`driving force for absorption at that location.
`release of an ionizable drug from a sustained-release system
`should be ”programmed” in accordance with the variation in
`pH of the different segments of the gastrointestinal (GI) tract
`so that the amount of preferentially absorbed species, and
`thus the plasma level 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 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 often is
`quite difficult to decrease its dissolution rate and slow its
`absorption. Preparing a slightly soluble form of a drug with
`normally high solubility is, however, one possible method for
`preparing sustained-release dosage forms. This will be 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 drrrg to penetrate these lipid mem-
`branes is its apparent oil/water partition coefficient, defined
`as
`
`K: CO/C",
`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 Cu. 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 approxima-
`tion to the value of K may be obtained by the ratio of the
`solubility of the drug in l-octanol to that in water.
`drugs with extremely large values of K are very oil-soluble and
`will partition into membranes quite readily. The relationship
`between tissue permeation and partition coefficient for the
`drug generally is known as the H(msch correlation, discussed
`in Chapter 28.
`In general, it describes a parabolic relation-
`ship between the logarithm of the activity of a drug or its
`ability to be absorbed and the logarithm of its partition coeffi—
`cient for a series of drugs 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 interact with the receptor;
`as a first approximation, the more effectively a drug crosses
`membranes, the greater its activity. There is also an opti-
`mum partition coefficient for a drug at which it most effec-
`tively permeates membranes and thus shows greatest activity.
`Values of the partition coefficient below this optimum result in
`decreased lipid solubility, and the drug will remain localized in
`the first aqueous phase it contacts. Values larger than the
`optimum result in poorer aqueous solubility, but enhanced
`lipid solubility and the drug will not partition out of the lipid
`membrane once it gets in. The value of K at which optimum
`activity is observed is approximately 1000/1 in l-octanol/
`water. Drugs with a partition coefficient that is higher or
`
`AUROBINDO EX1018, 8
`
`AUROBINDO EX1018, 8
`
`

`

`CHAPTER 94
`
`
`log K
`
`Fig 5. Typical relationship between drug activity and partition coef-
`ficient, K, generally known as the Hansch correlation.
`
`lower than the optimum are, in general, poorer candidates for
`formulation into sustained-release dosage forms.
`Drug Stability—Of importance for oral dosage forms is
`the loss of drug through acid hydrolysis and/01‘ metabolism in
`Since a drug in the solid state undergoes
`degradation at a much slower rate than a drug in suspension or
`solution, it would seem possible to improve significantly the
`relative bioavailability of a drug, which is unstable in the GI
`tract, by placing it in a slowly available sustained—release
`form. For those 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 in the environment of the intes-
`tine; the most appropriate sustaining unit in this 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
`with significant stability problems in any particular area of the
`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 the site of absorp-
`tion is not necessarily a negative factor in sustained—release
`Indeed, the prodr'ug approach to drug delivery
`takes advantage of the presence of these enzymes to regener-
`ate the parent molecule of an inactive drug derivative. This
`will be amplified upon below and in Chapter 28.
`
`Protein Binding
`
`Chapters 14 and 43 described the occurrence of drug bind
`ing to plasma proteins (eg, albumin) and the resulting reten-
`tion of drug in the vascular space. Distribution of the drug
`into the extravascular space is governed by the equilibrium
`process of dissociation of the drug from the protein. The
`drug—protein complex can serve therefore as a reservoir in the
`vascular space for sustained drug release to extravascular
`tissues, but only for those drugs that exhibit a high degree of
`binding. Thus, the protein binding characteristics of a drug
`can play a significant role in its therapeutic effect, regardless
`of the type of dosage form. Extensive binding to plasma
`proteins will be evidenced by a long 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-
`polymers in the GI tract, which could have an influence on
`sustained-drug delivery.
`
`Some drugs that exhibit greater than 95% binding at therapeu-
`tic levels are amitriptyline, bishydroxycoumarin, diazepam,
`diazoxide, dicumarol and novobiocin.
`Molecular Size and Difi'usivity—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, drugs in many sustained-
`release systems nurst diffuse 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 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:“
`
`logD = —.5‘,, log 0 + k, = —5M logM + kt,”
`
`(12)
`
`where r) is molecular volume, M is molecular weight and 5,, SM,
`It, and k,,, 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 polymers range from 10’“ to 10‘9 cmZ/sec, with values
`on the order of 10’8 being most common.5 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 10’1 c1112/ sec, and for one
`liquid through another, 10“3 cmz/sec.
`F‘or 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 cmZ/sec. Thus, high-molecular-
`weight drugs and/ or polymeric drugs should be expected to
`display very slow-release kinetics in sustained-release devices
`using diffusion through polymeric membranes 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-
`lirniting step in drug delivery from a sustained-release system
`is its release from a dosage form, rather than absorption, a
`rapid rate of absorption of the drug relative to its release is
`essential if the system is to be successful. As stated previ-
`ously in discussing terminology, k, <<< It... 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.6 This corresponds to a
`minimum absorption rate constant It}, of 0.17 hi“1 to 0.28 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" >> 0.23 hr"), the above discussion implies that a
`first-order release-rate constant k,- less than 0.17 hr—l 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, <<<
`It}, must be met.
`The extent and uniformity of the absorption of a drug, as
`reflected by its bioavailability and the fraction of the total dose
`absorbed, may be quite low for a v