~
`
`.·
`
`INGTON .
`
`ALKERMES EXHIBIT 2034
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 32
`
`

`

`2· 0
`
`T H
`
`E D I T I O N
`
`l
`
`~emington: The
`Science and .
`·
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`Page 2 of 32
`
`

`

`-..
`
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`I
`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Ai.me Smith
`
`Lippincott Williams & Wilkins
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`:- L..J pu~jcation contains information relati~1g t?, gener~l princiJ?le~ ~f medic~ care
`,::::;::i whi.ch should not be construed as specific mstruct10ns for mdiv1dual patients.
`M:;&mfacturers' product information and package inserts should be reviewed for
`) tll.Tent information, including contraindications, dosages and precautions.
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`'-......,- Printed in the United States of America
`
`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
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`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila(cid:173)
`: delphia College of Pharmacy and Science
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`~ the Univ~sity of the Sd=~s in Philadelphia
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`/ ~tsReserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-306472
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`material. If they have inadvertently overlooked any, they will be pleased to make
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`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon(cid:173)
`sible for any inaccuracy contained herein.
`Notice- This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
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`Page 3 of 32
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`

`

`j
`
`Tobie of Contents
`
`Part 1 Orientation
`
`1 Scope of Pharmacy . . . . . . . . . . . . . . . . . . . . . . . .
`2 Evolution of Pharmacy . . . . . . . . . . . . . . . . . . . . . .
`,3 Ethics and Professionalism . . . . . . . . . . . . . . . . . . . .
`, 4 The Practice of Community Pharmacy . . . . . . . . . . .
`5 Pharmacists in Industry . . . . . . . . . . . . . . . . . . . . . .
`6 Pharmacists in Government . . . . . . . . . . . . . . . . . .
`7 Pharmacists and Public Health. . . . . . . . . . . . . . . . .
`8 Information Resources in Pharmacy and the
`Pharmaceutical Sciences. . . . . . . . . . . . . . . . . . . . .
`9 Clinical Drug Literature . . . . . . . . . . . . . . . . . . . . . .
`10 Research. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .
`
`Part 2 Pharmaceutics
`
`11 Pharmaceutical Calculations . . . . . . . . . . . . . . . . . .
`12 Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`13 Molecular Structure, Properties, and States of Matter. . .
`14 Complex Formation. . . . . . . . . . . . . . . . . . . . . . . .
`15 Thermodynamics . . . . . . . . . . . . . . . . . . . . . . . . . .
`16 Solutions and Phase Equilibria . . . . . . . . . . . . . . . . .
`17 Ionic Solutions and Electrolytic Equilibria . . . . . . . . . .
`18 Tonicity, Osmoticity, Osmolality, and Osmolarity. . . .
`19 Chemical Kinetics . . . . . . . . . . . . . . . . . . . . . . . . .
`20 lnterfacial Phenomena. . . . . . . . . . . . . . . . . . . . . .
`21 Colloidal Dispersions. . . . . . . . . . . . . . . . . . . . . . . .
`22 Coarse Dispersions . . . . . . . . . . . . . . . . . . . . . . . . .
`23 Rheology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Part 3 Pharmaceutical Chemistry
`
`24 Inorganic Pharmaceutical Chemistry . . . . . . . . . . . .
`25 Organic Pharmaceutical Chemistry . . . . . . . . . . . . .
`26 Natural Products. . . . . . . . . . . . . . . . . . . . . . . . . . .
`27 Drug Nomenclature-United States Adopted
`Names.................................
`28 Structure-Activity Relationship and Drug Design. . . . .
`29 Fundamentals of Radionuclides . . . . . . . . . . . . . . .
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`30 Analysis of Medicinals. . . . . . . . . . . . . . . . . . . . . . .
`31 13iological Testing
`. . . . . . . . . . . . . . . . . . . . . . . . .
`32 Clinical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .
`33 Chromatography. . . . . . . . . . . . . . . . . . . . . . . . . .
`34 Instrumental Methods of Analysis . . . . . . . . . . . . . . .
`35 Dissolution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Part 5 Pharmaceutical Manufacturing
`
`36 Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`37 Powders ............................... .
`38 Preformulation ........................... .
`39 Solutions, Emulsions, Suspensions, and Extracts .... .
`40 Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`41 Parenteral Preparations . . . . . . . . . . . . . . . . . . . . .
`42 Intravenous Admixtures .................... .
`43 Ophthalmic Preparations . . . . . . . . . . . . . . . . . . . .
`44 Medicated Topicols ....................... .
`45 Oral Solid Dosage Forms ............ , ...... .
`46 Coating of Pharmaceutical Dosage Forms ....... .
`47 Controlled-Release Drug-Delivery Systems ....... .
`48 The Introduction of New Drugs ............... .
`
`3
`7
`19
`28
`33
`38
`47
`
`60
`70
`81
`
`91
`124
`159
`1 83
`198
`208
`227
`246
`263
`27 5
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`721
`753
`780
`807
`821
`836
`858
`894
`903
`930
`
`49 13iotechnology and Drugs ................... .
`50 Aerosols ............................... .
`51 Quality Assurance and Control ..... · .......... .
`52 Stability of Pharmaceutical Products ............ .
`53 13ioovoilability and 13ioequivalency Testing ....... .
`54 Plastic Pacl~aging Materials . . . . . . . . . . . . . . . . . . .
`55 Pharmaceutical Necessities .................. .
`
`Part 6 Pharmacodynamics
`
`56 Diseases: Manifestations and Pothophysiology
`57 Drug Absorption, Action, and Disposition ........ .
`58 13osic Pharmacol~inetics ..................... .
`59 Clinical Phormacol~inetics . . . . . . . . . . . . . . . . . . . .
`60 Principles of Immunology . . . . . . . . . . . . . . . . ... .
`61 Adverse Drug Reactions .................... .
`62 Pharmocogenetics . . . . . . . . . . . . . . . . . . . . . . . . .
`63 Pharmacological Aspects of Substance Abuse . . . . . .
`
`Part 7 Pharmaceutical and Medicinal Agents
`
`64 Diagnostic Drugs and Reagents ............... .
`65 Topical Drugs ....................•.........
`66 Gastrointestinal and Liver Drugs ............... .
`67 131ood, Fluids, Elecirolytes, and Hematological Drugs ... .
`68 Cardiovascular Drugs ...................... .
`69 ·Respiratory Drugs. . . . . . . . . . . . . . . . . . . . . . . . . .
`70 Sympathomimetic Drugs ................... .
`71 Cholinomimetic Drugs ..................... .
`72 Adrenergic and Adrenergic Neuron 131ocl~ing Drugs ..
`73 Antimuscarinic and Antispasmodic Drugs ........ .
`7 4 Sl~eletal Muscle Relaxants . . . . . . . . . . . . . . . . . . . .
`7 5 Diuretic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`76 Uterine and Antimigraine Drugs .............. .
`77 Hormones and Hormone Antagonists . . . . . . . . . . .
`7 8 General Anesthetics . . . . . . . . . . . . . . . . . . . . . . . .
`79 Local Anesthetics ......................... .
`80 Sedative and Hypnotic Drugs . . . . . . . . . . . . . . . . .
`81 Antiepileptic Drugs. . . . . . . . . . . . . . . . . . . . . . . . .
`82 Psychopharmacologic Agents ............ : ... .
`83 Analgesic, Antipyretic, and Anti-lnflommat?ry
`Drugs ................................. .
`84 Histamine and Antihistaminic Drugs ............ .
`85 Central Nervous System Stimulants ............. .
`86 Antineoplastic and lmmunoactive Drugs ........ .
`87 Anti-lnfectives ........................... .
`88 Parasiticides ............................. .
`89 Immunizing Agents and Allergenic Extracts . . . . . . .
`
`Part 8 Pharmacy Practice
`
`Part &A Pharmacy Administration
`
`90 Laws Governing Pharmacy
`. . . . . . . . . . . . . . . . . .
`91 Pharmacoeconomics ...................... .
`92 Marl~eting Pharmaceutical Care Services . . . . . . . . .
`93 Documenting and 13illing for Pharmaceutical Care
`Services ................................ .
`94 Community Pharmacy Economics and
`Management ........................... .
`95 Product Recoils and Withdrawals ............. .
`
`Part 80 Fundamentals of Pharmacy Practice
`
`944
`963
`980
`986
`995
`1005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400-
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`96 Drug Education . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`1677
`
`xiv
`
`Page 4 of 32
`
`

`

`97 The Prescription .......................... .
`98 Extemporaneous Prescription Compounding ..... .
`99 Poison Control
`. . . . . . . . . . . . . . . . . . . . . . . . . ..
`100 Nutrition in Pharmacy Practice ............... .
`101 Self-Care/Diagnostic Products ................. .
`1 02 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . .. .
`103 Complementary and Alternative Medical Health
`Care ....... > ..... : ................... .
`1 04 Nuclear Pharmacy Practice
`. . . . . . . . . . . . . . . . . .
`105 Enzymes
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`1 06 Vitamins and Other Nutrients . . : • . . . . . . . . . . . . .
`1 07 Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1 08 Surgical Supplies . . . . . . . . . . . . . . . . . . . . . . . . . .
`109 Health Accessories ........................ .
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`Part &C Patient Care
`
`113 The Patient: Behavioral Determinants . . . . . . . . . . .
`114 Patient Communication . . . . . . . . . . . . . . . . . . . . .
`115 Patient Compliance
`. . . . . . . . . . . . . . . . . . . . . . .
`116 Pharmacoepidemiology . . . . . . . . . . . . . . . . . . ..
`117 Integrated Health-Care Delivery Systems . . . . . . . . .
`118 Home Health Patient Care ................. .
`119 Aseptic Technology for Home-Care
`Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`Appendixes
`
`Dose Equivalents . . . . . . . . . . . . . . . . . . . . . . . . . .
`Periodic Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Logarithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`
`2033
`2034
`2036
`
`11 0 Ambulatory Patient Care . . . . . . . . . . . . . . . . . . ..
`111 Institutional Patient Care
`. . . . . . . . . . . . . . . . . . ..
`112 Long-Term Care Facilities ................... .
`
`1893"
`1911
`1932
`
`Glossary and Index
`
`Glossary ............................... .
`Index ................................. .
`
`2037
`2039
`
`xv
`
`Page 5 of 32
`
`

`

`CH APTER 47
`Controlled-Release Drug-Delivery Systems
`
`Thomas Wai-Yip Lee, BPharm
`Research Assistant
`School of Pharmacy
`University of Wisconsin
`Madison, WI 53706
`
`Joseph R Robinson
`Professor of Pharmacy and Ophthalmology
`School of Pharmacy
`University.of Wisconsin
`Madison, WI 53706
`
`The goal of any drug-delivery system is to provide a therapeutic
`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 a specified period of treatment. This ide(cid:173)
`alized objective points to the two aspects most important to drug
`delivery, namely, spatial placepient and temporal delivery of a
`drug. Spatial placement relates to targeting 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 de(cid:173)
`signed controlled-release drug-delivery system can be a major
`advance toward solving these two problems. It is for this reason
`that the science and technology responsible for development of
`· controlled-release pharmaceuticals has been, and continues to be,(cid:173)
`the focus of a great deal of attention in both industrial and aca(cid:173)
`demic laboratories. The history of controlled-release technology
`can be divided roughly into three time periods. From 1950 to 1970
`is the period of sustained' drug release. A number of systems
`containing hydrophobic polymers and waxes were fabricated with
`drugs into dosage forms with the aim of sustaining drug levels
`and hence drug action for an extended period of time. However, a
`lack of understandings of anatomical and physiological barriers
`imposed impediments on the development of efficient delivery
`systems. The period 1970 to 1990 was involved in the determina(cid:173)
`tion of the needs in controlled drug delivery and to understand the
`barriers for various routes of administration. Post 1990 is the
`modern era of controlled release technology and represents the
`period in which an attempt at drug optimization is emphasized.
`Recently, considerable effort has been expended to develop bio(cid:173)
`compatible polymers, polymer carriers, etc.1 There currently exist.
`numerous products on the market, formulated for both oral and
`parenteral routes of administration, that claim sustained or con(cid:173)
`trolled drug delivery. The bulk of research has been directed
`toward oral dosage forms that satisfy the temporal aspect of drug
`delivery. In addition, some of the newer approaches under inves(cid:173)
`tigation may allow for spatial placement as well. This chapter
`defines and explains the nature of controlled-release drug ther(cid:173)
`apy, briefly outlines relevant biological barriers and physicochem(cid:173)
`ical properties of a drug that affect controlled-release perfor(cid:173)
`mance, and reviews the more common types of oral and
`- parenteral controlled-release dosage forms. In addition, a brief
`discussion of some methods currently being used to develop tar(cid:173)
`geted delivery systems is presented. Finally, we comment on
`future advances on delivery of biotechnology products as well ·as
`introduce some novel delivery systems.
`
`a simple,_one-compartment pharmacokinetic model for disposition.
`Depending on the route of administration, a conventional dosage
`form of the drug, eg, a solution, suspension, capsule, tablet, etc, can
`produce a drug blood level versus time profile similar to that shown
`in Figure 4 7-1. The term drug blood level refers to the concentration
`of drug in blood or plasma, but the concentration 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 ex(cid:173)
`travascular 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 therapeutic range for
`longer periods by, for example, increasing the initial dose of an
`intravenous injection, as shown by the dotted line in 1;4e figure, toxic
`levels may be produced at early times. This approach obviously is
`undesirable and unsuitable. An alternative approach is to adminis(cid:173)
`ter the drug repetitively using a constant dosing interval, as in
`multiple-dose therapy. This is shown in Figure 47-2 for the oral
`route. In this case the drug blood level reaclied and the time required
`to reach that level depend on the dose and the dosing interval: There
`are several poteitial problelllS 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 dosings to
`maintain constant therapeutic levels.
`2. The drug blood level may not be within the therapeutic range at
`sufficiently early times, an important consideration for certain dis(cid:173)
`ease states.
`3. Patient noncompliance with the multiple-dosing regimen can result
`in failure of this .approach.
`In many instances, potential problems associated with conven(cid:173)
`tional 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 controlled-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 controlled-release drug-delivery systems.
`There are numerous potential advantages of controlled-release
`drug therapy that are discussed in the next section.
`
`CONTROLLED-RELEASE DRUG· THERAPY
`
`CONVENTIONAL DRUG THERAPY
`
`Terminology
`
`To gain an appreciation for the value of controlled drug therapy it is
`useful to review some fundamental aspects of conventional drug
`delivery.2 Consider single dosing of a hypothetical drug that follows
`
`Modified-release delivery systems may be divided conveniently
`into four c:;J.tegories:
`
`903
`
`Page 6 of 32
`
`

`

`904
`
`CHAPTER 47
`
`..J
`bJ
`>
`~
`0
`.. 0
`3
`ID
`"' ::,
`0: "
`
`Tox.ic
`Ranoe
`
`Therapeutic
`Ranoe
`
`Ineffective
`Ranoe
`
`TIME (hrs)
`Figure 47-1. Typical drug blood level versus time profiles for intra(cid:173)
`venous injections and an extravascular route of administration.
`
`1. Delayed release
`2. Sustained release
`3. Site-specific targeting
`4. Receptor targeting
`D~layed-rel~ase systems are those that use repetitive, inter(cid:173)
`mittent dosmgs 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(cid:173)
`sules, and enteric-coated tablets where timed release is
`achieved by a barrier coating.
`Sustained-release systems include any drug-delivery sys(cid:173)
`tem that achieves slow release of drug over an extended period ·
`of time. If the systems can provide some control, whetlier 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 main(cid:173)
`taining constant drug levels in the target tissue or cells, it is
`considered a controlled-release system.
`Site~specific and receptor targeting 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 diseased
`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 and are also
`considered to be controlled drug-delivery systems.
`More precisely; controlled delivery can be defined as2
`l. Sustr;ined drug action at a predetermined rate by maintaining a
`relatively constant, effective drug level in the body with concomi(cid:173)
`tant minimization of undesirable side effects that may be associated
`with a sawtooth kinetic pattern of controlled release.
`2. Localized drug action by spatial placement of a controlled release
`system (usually rate-controlled) adjacent to or in the diseased tis(cid:173)
`sue or organ.
`3. Targeted drug action by using carriers or chemical derivatives to
`..
`deliver drug to a particular target cell type.
`4. Provide a physiologically/therapeutically based drug release system.
`In other words, the amount and the rate of drug release are deter(cid:173)
`mined by the physiological/therapeutic needs of the body.
`
`Release Rate and Dose Considerations3
`
`As already mentioned, conventional dosage forms include so(cid:173)
`lutions, _suspensions, capsules, tablets, emulsions, aerosols,
`foams, omtments, and suppositories. For purposes of this dis(cid:173)
`cussion, these dosage forms can be considered to release their
`?-ctive ingr~dients into an absorption pool immediately. This is
`illustrated m the following simple kinetic scheme:
`
`Dosage ~ Absorption ~ Target ~
`Form
`drug release Pool
`absorption Area
`elimination
`
`The absorption pool represents a solution of the drug at the site
`of absorption, and the terms kr, ka, and ke are first-order rate
`constants for drug release, absorption, and overall elimination
`respectively. Immediate release from a conventional dosag~
`
`form implies that ~r >::C:-> ka or, alternatively, that absorption
`of drug across a b10logi.cal membrane, such as the intestinal
`epithelium, is the rate-limiting step in delivery of the drug
`to its target area. For nonimmediate-release dosage forms k
`< < < ka, that is,. release of drug from the dosage form is th~
`rate-limiting step. This causes the above kinetic scheme to
`reduce to
`
`k,.
`
`ke
`Target Area ------
`Dosage Form -
`elimination
`drug release
`Essentially, the absorptive phase of the kinetic scheme be(cid:173)
`comes insignificant compared with the drug release phase.
`Thus, the effort to develop a nonimmediate-release delivery
`systen;i must be directed primarily at altering the release rate
`by affecting the value of kr. The many ways in which this has
`been attempted are discussed later in this chapter.
`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 starting ideal goal of a controlled(cid:173)
`release delivery system. In fact, in some cases optimum ther(cid:173)
`apy is achieved by providing 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 often succeed at
`curing or controlling the condition, however, and this is true for
`most forms of therapy.
`The ideal goal in designing a controlled-release system is to
`deliver drug to the desired site at a rate according to the needs
`of the body, ie, a self-regulated system based on feedback con(cid:173)
`trol. However, this is a difficult assignment.· Although some
`attempts have been made to achieve this goal, such as with a
`self-regulating insulin pump, there is ·no commercial product
`representing this type of system. In the absence of feedback
`control, we are left with a simple sustaining effect. The pivotal
`question is at what rate should drug be delivered to maintain a
`constant blood drug level? This constant rate should be analo(cid:173)
`gous 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
`~elivery must be independent of the amount of drug remaining
`m 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= k, ·Cd· Vd
`
`(1)
`
`where k~ is the zero-order rate constant for drug release
`(amount/time), ke is the first-order rate constant for overall
`drug elimination (time- 1
`), Cd is the desired drug level in the
`body (amount/volume), and V dis the volume space in which the
`drug is distribhted. The values of ke, Cc1,, and Va needed to
`calculate k~ are obtained from appropriately designed single(cid:173)
`dose pharmacokinetic studies. Equation 1 provides the method
`to calculate the zero-order release rate constant necessary to
`maintain a constant drug blood or tissue level for the simplest
`case, where drug is eliminated.by first-order kinetics. For many
`
`-
`
`..-=,.
`~
`8
`e
`~
`
`..J
`bJ
`>
`bJ
`..J
`0
`0
`3
`
`ID
`
`"' ::,
`
`0:
`0
`
`Toxic
`Range
`
`Therapeutic
`Range
`
`Ineffective
`Range
`
`TIME
`(hrs)
`Figure 47-2. Typical drug blood level versus time profile following
`oral multiple-dose therapy.
`
`Page 7 of 32
`
`

`

`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 theoretically, non(cid:173)
`zero-order release may be equivaleiit clinically to constant re(cid:173)
`lease in many cases. Aside from the extent of intra- and inter(cid:173)
`subject variation is the observation that for many drugs,
`modest changes in drug tissue levels do not result in an im(cid:173)
`provement in clinical performance. Thus, a nonconstant drug
`level may be indistinguishable clinically from a constant drug
`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 releases
`drug immediately and a maintenance or sustaining dose, Dm.
`The total dose, W, thus required for the system is
`
`(2)
`
`For a system in which the maintenance dose releases drug by a
`zero-order process for a specified period of time, the total dose,3
`is
`
`(3)
`
`where k~ is the zero-order rate constant for drug release an,d Ta
`is the total time desired for sustained release from one dose. If
`the maintenance dose begins release of drug at the time of
`dosing (t = O), 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 drug from
`the maintenance dose
`'
`
`(4)
`
`The correction factor, k~Tp, is the amount of drug provided
`during the period from t = 0 to the time of the peak drug level,
`Tr No correction factor is needed if the dosage form is con(cid:173)
`structed 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 starting
`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
`approximations 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 such a system is
`
`W = D, + (k,Cik,)Vd
`
`(5)
`
`where k, is the first-order rate · constant for drug release
`(time- 1
`), and ke, Ca, and Va 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
`
`(6)
`
`To maintain drug blood levels within the therapeutic range
`over the entire time course of therapy, most controlled-release
`drug-delivery systems are, like conventional dosage forms, ad(cid:173)
`ministered as multiple rather than single doses. For an ideal
`controlled-release system that releases drug by zero-order ki(cid:173)
`netics, the multiple dosing regimen is analogous to that used
`for a constant intravenous infusion, as discussed in Chapter 58.
`For those controlled-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 Dobrinska4 provide a more detailed discussion.
`
`CONTROLLED-RELEASE DRUG-DELIVERY SYSTEMS
`
`905
`
`Pharmacokinetic and Pharmacodynamic
`Considerations 5
`
`To achieve controlled drug delivery, it is desirable to have a
`zero-order drug input. Under steady state, rate in = rate out,
`then
`
`R 0 = C.,CL
`
`(7)
`
`This equation shows that the input rate of a controlled-release
`system is determined solely by steady-state concentration and
`plasma clearance. t 112, a common pharmacokinetic parameter,
`is not directly needed to determine the input rate. However, it
`does play a role in determining the benefits of formulating a
`drug into a controlled-release dosage form. Usually, drugs
`of t 112 longer than 8 hours are not suitable candidates for
`controlled- or sustained-release dosage forms because they do
`not provide benefits over conventional dosage forms. In addi(cid:173)
`tion, t 112 may be useful in determining the dosing interval of a
`controlled-release dosage form. Similarly, volume of distribu(cid:173)
`tion is not a major consideration in designing controlled-release
`delivery systems, although often a larger volume of distribution
`. requires a higher drug load to achieve a therapeutic blood level.
`However, there may not exist a direct correlation between
`the pharmacokinetics and pharmacodynarnics of a drug. In
`other words, it may be difficult to predict the effect of a drug
`based only on pharmacokinetic data. As a result, a PK/PD
`model may be required to obtain a rational design of a
`controlled-release dosage form. Typically, a graded response
`can be represented by
`
`E =PC+ E 0
`
`(8)
`
`where P is a proportionality constant, C is the plasma concen(cid:173)
`tration, and E 0 is the baseline effect. In some cases, a more
`satisfactory relationship is obtained by usjng
`
`E = P log C +E0
`In fact, in most cases, the relationship is much more complex
`than a simple linear one, and sometimes it can be represented
`only by an expression closely related to enzyme kinetics.
`
`(9)
`
`E = Eo + (Ema,C")/(E~o + C")
`
`(10)
`
`where Em= is the maximal effect, E 50 is the drug concentration
`to produce 50% of a maximal effect, and n is a constant. This
`equation is sometimes subject to variability. Patients differ
`widely in their values of E50 and n for a given drug. Figure
`47-35 shows a typical response-concentration relationship.
`Hysteresis may often be found in response-concentration rela(cid:173)
`tionships when there is a delayed response due to a slow
`-distribution phase. In this case, an effect compartment model
`may be useful to correlate the response and concentration (Fig
`4 7-4A and B 6
`). It should be borne in mind that maintenance of
`a constant blood level by zero-order release does not necessarily
`produce a constant pharmacological effect. Nitroglycerin is a
`good example for illustrative purposes. A constant level of
`nitroglycerin can lead to tolerance arid result in a decreased
`pharmacological response. Hence, an off period is required for
`adequate nitroglycerin therapy. To conclude, it is necessary to
`have a profound knowledge of the relationship between concen(cid:173)
`tration and effect and its dependence on disease and time
`profile of drug input to have a more rational design of con(cid:173)
`trollyd drug-delivery systems.
`
`POTENTIAi;; ADVANTAGES OF CONTROLLED
`DRUG THERAPY
`
`All controlled-release products share the common goal of im(cid:173)
`proving drug therapy over that achieved with their non-
`
`Page 8 of 32
`
`

`

`906
`
`CHAPTER 47
`
`(].)
`rn
`C
`0
`0.
`rn
`(].) a::
`
`Efficacy
`
`Toxicity
`
`Concentration or Log Concentration
`Figure 47-3. Relationship between pharmacological and toxicolog-_
`ical responses and concentration. The rel