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`

`
`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 Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, .1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`'
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-O4-3
`
`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 responsible 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) and/or the National
`Formaiary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity. packaging and labeling for drugs and
`representations of them herein, the context and effect of the official cornpendia shall
`prevail.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`Astrazeneca Ex. 2080 p. 2
`
`

`
`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`.
`.
`. . . . . . .
`.
`.
`.
`.
`. .
`. . . . . .
`.
`. . . .
`. . . . .
`.
`.
`Scope .
`1
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`2 Evolution of Pharmacy .
`. . . . . .
`. . .
`.
`. . . . . . . .
`.
`.
`.
`3 Ethics
`.
`.
`.
`. . . . .
`. . . .
`.
`. . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . . .
`. .
`5 Opportunities for Pharmacists in the Pharmaceuti-
`cal industry . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`. . . . . . .
`. .
`. .
`6 Pharmacists in Government
`. . . .
`.
`. . . . . . . . . .
`.
`. .
`7 Druginformation...........................
`8 Research . . .
`. . . . .
`
`Part 2
`
`Pharmaceutics
`
`.
`. . .
`. . . . . . .
`.
`.
`.
`.
`9 Metrology and Calculation . . . .
`.
`.
`.
`.
`. . . . . .
`. .
`.
`.
`10 Statistics . . . . . . . . . .
`. . . . . . . . . .
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`11 Computer Science . .
`.
`. . . . . . . . .
`. . .
`. . . . . . . . . ..
`12 Calculus . .
`. . . . . . .
`13 Molecular Structure. Properties and States of
`. .
`.
`.
`Matter
`. .
`. . . . . . . . . .
`.
`. . . . . . .
`. .
`.
`.
`. . . . . . .
`. ..
`.
`14 Complex Formation .
`. .
`. . . . .
`.
`.
`. . .
`.
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria .
`.
`. .
`.
`. . . . . . . . .
`. .
`17
`Ionic Solutions and Electrolytic Equilibria . . . . . .
`. .
`13 Reaction Kinetics .
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`. . . . . . . . . .
`. .
`19 Dlsperse Systems . . .
`. . . .
`. . . . . . .
`.
`. . . . . . . . .
`.
`. .
`20 Rheology . . . . . .
`. . . .
`. .
`. . . . . .
`.
`.
`. . .
`. . . . . .
`.
`.
`. .
`
`Part 3
`
`Pharmaceutical Chemistry
`
`. . . . .
`inorganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. . .
`.
`. . . .
`. . . . . . .
`.
`. . . . . . . .
`24 Drug Nomenc|ature—United States Adopted
`Names . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . . .
`. . . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design . .
`. . .
`. . . . . . .
`.
`. . . . . . . . . .
`.
`. . . . . . . .
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`
`. .
`
`Part 4
`
`Testing“ and Analysis
`
`.
`. .
`
`.
`.
`
`26 Analysis of Medicinais
`27 Biological Testing . . .
`23 Ci|nicaiAnalysis
`.
`29 Chromatography . . .
`.
`30 instrumental Methods of Analysis
`31 Dissolution . . . .
`. . . .
`.
`. . . . . . . .
`. . .
`
`. . . . . . .
`. . .
`.
`.
`
`. . . .
`. . .
`.
`. . . . . .
`
`. .
`. .
`
`. . . .
`. .
`. .
`
`.
`.
`
`. . . . . . . .
`. . . . . . . .
`
`.
`.
`
`. .
`.
`.
`
`3
`8
`20
`28
`
`33
`38
`49
`60
`
`69
`104
`138
`145
`
`153
`162
`197
`207
`226
`247
`257
`310
`
`329
`356
`380
`
`412
`
`422
`
`435
`434
`495
`529
`555'
`589
`
`Part 5
`
`Iladioisotopes in Pharmacy and Medicine
`
`.
`32 Fundamentals of Raciioisotopes . . . . . . . . . . . .
`33 Medical Applications of Radiolsoiopes
`. . . . . . .
`
`. .
`. .
`
`605
`624
`
`Pharmaceutical and Medicinal Agents
`Part 6
`34 Diseases: Manifestations and Patho-
`physiology 655
`35 Drug Absorption. Action and Disposition . . . .
`.
`.
`.
`.
`697
`36 Basic Pharmacokinetics . . . . .
`. .
`.
`. . . . . . . . . .
`. . .
`.
`725
`37 Clinical Pharmacol-rlnetics . . . . .
`.
`. . .
`. . . . .
`. . . .
`.
`.
`746
`36 Topical Drugs . . . . .
`. .
`. .
`. . . . . .
`.
`. . .
`. . . . .
`. . . . . .
`757
`:39 Gastrointestinal Drugs . . . . . . . . .
`.
`.
`. . . . . . . . . . .
`.
`774
`40 Blood, Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . .
`.
`. . . . . . . . .
`‘41
`Cardiovascular Drugs
`. .
`. .. . . . .
`.
`.
`.
`.
`. . . . .
`. . . . . .
`42 RespiratoryDrugs
`.
`. . . . ..
`43 Sympathomimetic Drugs . . . . . .
`. . . . .
`. . . .
`.
`.
`
`.
`
`. . .
`
`800
`631
`860
`870
`
`44
`45
`
`46
`47
`45
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`
`71
`72
`
`73
`74
`
`75
`76
`77
`73
`79
`B0
`31
`82
`33
`
`64
`35
`36
`87
`86
`89
`90
`9 1
`92
`
`93
`94
`95
`96
`
`xv
`
`. . . .
`
`339
`. . . . . .
`. . . . . .
`. . .
`Chollnomimetic Drugs . . . .
`‘
`Adrenergic and Adrenergic Neuron Blocking
`Drugs 898
`Antlmuscarinic and Antisposmodic Drugs
`. . . . . . .
`907
`1 Skeletal Muscle Relaxants . . .
`. . . . .
`. - -
`- '-
`-
`-
`- - - -
`916
`DlureticDrUgs
`. . . .
`929
`. . . . . . . . . . . . . .
`Uterine and Antimigralne Drugs
`943
`Hormones . . . .
`. .
`. . . .
`. . . .
`. .-.
`. . . . . . . . . . . .
`. . . .
`943
`Vitamins and Other Nutrients .
`. . .
`. . . . . . . . . . . . .
`1002
`Enzymes
`. . . . .
`.
`. . . . .
`. . . .
`.
`.
`. . .
`. . . . . . . . . . . . .
`1035
`General Anesthetics . .
`. . . . . .
`. . .
`. . . . . .
`.
`.
`. . . . .
`1039
`Local Anesthetics . . . . . . . . . . .
`. . .
`. . . . . .
`. . . . . . .
`1043
`Sedatlves and Hypnatics . .
`. . .
`. .
`. . .
`. . . .
`.
`.
`. . . . .
`1057
`Antlepileptlcs
`. . . . . . . . . ..
`1072
`. . .
`Psychopharmacologic Agents
`. . . . . .
`.
`. . . . . .
`1052
`Analgesics and Antlpyreiics .. . . .
`. . .
`. . .
`.
`. .
`. . . .
`1097
`Histamine and Antihistamines . . .
`. . .
`. . .
`.
`. . . . ..
`1123
`Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1132
`Antineoplastlc and immunosuppressive Drugs . . .
`1133
`Antimicrobial Drugs . . . . . . .
`.
`.
`. . . . . . . . .
`.
`.
`. . . . .
`1163
`Parasiticides . .
`.
`. .
`. . . . . . .
`. . .
`. . . . . . . . .
`.
`. . . . . .
`1242
`Pesticides . . .
`.
`. . . .
`. . . .
`. .
`.
`.
`.
`. . . . . . . . . . . . . . . .
`1249
`Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . .
`.
`.
`. . . . .
`1272
`Pharmaceutical Necessities
`. . . . . .
`. . . . .
`.
`.
`. . . . .
`1266
`Adverse Drug Reactions .
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`1330
`_Pharmacogenetics
`1344
`. . . . . . .
`Pharmacological Aspects of Drug Abuse .
`1349
`introduction of New Drugs
`.
`.
`. .
`. . . . . . . . . . . . . . .
`1365
`
`Port 1
`
`Ilioiogical Products
`
`. . .
`. . .
`. .
`. .
`Principles oi Immunology . . .
`immunizing Agents and Diagnostic Skin
`Antigens
`A|iergenicEr-(tracts
`Biotechnology and Drugs . .
`
`.
`
`.
`
`. . .
`
`. . . .
`
`. .
`
`.
`
`.
`
`. . . . .
`
`1379
`
`1369
`1405
`1416
`
`.
`
`.
`
`. . . . .
`
`Part 8
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`. . . . . . . . . . ..
`Preformulation
`Bioavailobility and Bioequivalency Testing . . . . .
`Separation . . .
`. .
`. . . .
`. . . .
`. .
`.
`. . . . .
`. . . . . .
`. . . . .
`Sterilization . . . .
`. . . . . . . . .
`.
`. . .
`. . . . .
`. . . . . . . . .
`Tonlclty, Osmoticity, Osmoiaiity and Osmolarity .
`Plastic Packaging Materials
`.
`.
`. .
`. . . . . . .
`.
`.
`. . . . .
`Stability of Pharmaceutical Products
`. . . . . .
`. . . . .
`Quality Assurance and Control
`. . . . . . . .
`.
`. .
`. . . .
`Solutions, Emulsions, Suspensions and
`Extractives .
`. . . . .
`.
`.
`. . . .
`. . . . .
`.
`.
`. . . . . . .
`Parenteral Preparations . . . . . .
`.
`. .
`. . . . . .
`intravenous Admixtures . . . . . .
`. . .
`. . . . . .
`Ophthalmic Preparations . . .
`.
`.
`. . .
`. . . . . .
`Medicated Applications .
`. .
`. . .
`.
`. .
`. . . . . .
`Powders . . . . . .
`.
`. . .
`. . . . . . .
`.
`.
`.
`. . . . . . . .
`Oral Solid Dosage Forms .
`. . . . .
`.
`. . . . . . . .
`Coating of Pharmaceutical Dosage Forms .
`Sustained-Release Drug Delivery Systems
`Aerosols
`
`. . .
`.
`. .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`. . . . . .
`. . . . . .
`
`1435
`1451
`1459
`1470
`1431
`1499
`1504
`1513
`
`1519
`1545
`1570
`1561
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`. . .
`. .
`Ambulatory Patient Care . . . .
`. . .
`institutional Patient Care .
`.
`.
`. . .
`Long-Term Care Facilities . . . .
`. . . . .
`The Pharmacist and Public Health . .
`
`. . . .
`. . . .
`. . . .
`. .
`. .
`
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`. . . . .
`. . . . .
`. . . . .
`. . . . .
`
`1715
`1737
`1758
`1173
`
`Astrazeneca Ex. 2080 p. 3
`
`

`
`97
`96
`99
`100
`101
`102
`103
`104
`105
`
`The Patient: Behavioral Determinants . .
`Patlentcommunlcotion
`DrugEducation
`. . . . . . .
`. .
`.
`.
`Patient Compliance
`. . . . . ._ . . . .
`.
`The Prescription . . . .
`.
`. . . . . . . . .
`.
`Drug Interactions . . .
`Clinical Drug Literature . .
`. . .
`. . . .
`Health Accessories
`.
`.
`. . . . . .
`. . . .
`
`.
`.
`.
`. . .
`. . .
`.
`.
`.
`.
`.
`.
`
`. . .
`. . .
`. .
`.
`. . .
`. . .
`
`.
`
`. . . . .
`
`.
`
`.
`
`. . . . . . .
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.-
`
`106
`107
`105
`
`109
`
`1788
`1796
`1803
`1813
`1628
`1642
`1859
`1664
`
`. . . . .
`. . .
`.
`.
`. . . .
`. . . . .
`.
`.
`.
`.
`.
`Poison Control
`. . . . . . . .
`.
`.
`Laws Governing Pharmacy . . .
`Community Pharmacy Economics and
`. . . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . .
`. .
`.
`. . .
`Dental Services .
`.
`.
`.
`-. . .’.
`. . . . . .
`._
`. . .
`. . . . .
`.
`.
`
`.
`.
`
`.
`.
`
`. . .
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`Index
`
`Surgical Supplies . . . . .
`
`. . . . . . . . .
`
`. . .
`
`. .
`
`. . . . . .
`
`. .
`
`1895'
`
`Alphabetic Index .
`
`. . . . . . . . . . .
`
`.
`
`.
`
`. . . .
`
`. . . . .
`
`.
`
`. .
`
`1967
`
`xvi
`
`Astrazeneca Ex. 2080 p. 4
`
`

`
`CHAPTER 91
`
`Sustained-Release Drug Delivery Systems
`
`Marl: A Longer, PhD
`MRC Research Fellow
`Department of Biological Sciences
`Universily of Keele
`Keele. Srclffoldshire ST5 .506
`England
`
`Joseph P. Robinson. PhD
`Professor of Fhurmncy
`School of Pharmacy
`University of Wisconsin
`Madison. WI 53706
`
`The goal of any drug delivery system is to provide athero-
`peutic amount of drug to the proper site in the body to
`achieve promptly, and then maintain, the desired drug con-
`centration. This idealized objective points to the two as-
`pects most important to drug delivery, namely, spatial
`placement and temporal delivery of a drug. Spatial place-
`ment 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 designed
`sustained-release drug delivery system can be a major ad-
`vance toward solving these two problems. _ It is for this
`reason that the science and technology responsible for devel-
`opment of sustained-release pharmaceuticals 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 formulated 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 as-
`pect of drug delivery, but many of the newer approaches
`under investigation may allow for spatial placement as well.
`This chapter will define and explain the nature of sustained-
`release drug therapy, briefly outline relevant physicochemi-
`cal and biological properties of a drug that affect sustained-
`release performance and review the more common types of
`oral and parenteral sustained-release dosage forms.
`In ad-
`dition, a brief discussion of some methods currently being
`used to develop targeted delivery systems will be presented.
`
`Conventional Drug Therapy
`as shown by the dotted line in the figure, toxic levels may be
`To gain an appreciation for the value of sustained drug
`therapy it is useful to review some fundamental aspects of
`produced at early times. This obviously is undesirable and
`conventional drug delivery} Consider single closing of a
`the approach therefore is unsuitable. An alternate ap-
`hypothetical drug that follows a simple one-compartment
`proach is to administer the drug repetitively using a con-
`stant dosing interval, as in multiple-dose therapy. This is
`pharmacokinetic model for disposition. Depending on the
`route of administration, a conventional dosage form of the
`shown in Fig 91-2 for the oral route.
`In this case the drug
`drug, eg, a solution, suspension, capsule, tablet, etc, proba-
`blood level reached and the time required to reach that level
`depend on the dose and the dosing interval. There are
`bly will produce a drug blood level versus time profile similar
`to that shown in Fig 91-1. The term “drug blood level”
`several potential problems inherent in multiple-dose thera-
`P373
`refers to the concentration of drug in blood or plasma, but
`the concentration in any tissue could be plotted on the ordi-
`nate. 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 main-
`tain drug blood levels within the therapeutic range for ex-
`tended periods of time. The short duration of action is due
`to the inability of conventional dosage forms to control tem-
`poral delivery.
`If an attempt is made to maintain drug
`blood levels in the therapeutic range for longer periods by,
`for example, increasing the dose of an intravenous injection,
`
`Ifthe dosing interval is not appropriate for the biological half-
`1.
`life of the drug, large "peaks" and “valleys” in the drug blood level
`may result. For example, drugs with short half-lives require fre-
`quent 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
`disease states.
`3. Patient noncompliance with the multiple-dosing regimen can
`result in failure of this approach.
`
`
`
`onusnoonLEVEL(“"‘“‘"'Vn|>
`
`
`
`
`
`FIIIIIIIJIIJIIIIIIIIIIIIIIIIIJIIIIII
`
`
`Taxis
`Hanus
`
`Thaoanuilc
`Renae
`
`'
`
`Inoflucliva
`flange
`
`rm:
`
`in-:1
`
`\
`
`Toxic
`
`‘
`
`mgrgrulpsuus
`
`Range
`
`
`
`Tnernpaulic
`Range
`
`\
`-..
`TI .#h'.IIIIIIII;'.f l"'l'."I IIIIIIIIIIIIIIII
`\“~‘_‘
`Eli muscular
`Inaffeclive
`no I
`Range
`
`TIME Urn)
`
`
`
`onussLoonLEVEL(“'"°“"%.|)
`
`
`
`
`
`Fig 91-1. Typical drug blood level versus time profiles for intrave-
`nous injections and an extravascular route of administration.
`
`Fig 91-2. Typical drug blood level versus time profile following oral
`multiple-dose therapy.
`
`1676
`
`Astrazeneca Ex. 2080 p. 5
`
`

`
`SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS
`
`167?
`
`In many instances, potential .problems associated with
`conventional drug therapy can be overcome. When this is
`the case, drugs given in conventional dosage forms by multi-
`ple-dosing can produce the desired drug blood level for ex-
`tended periods of time. Frequently, however, these prob-
`lems are significant enough to make drug therapy with con-
`ventional 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 deliverysystems. There are numerous potential ad-
`vantages of sustained-release drug therapy that will be dis-
`cussed 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:
`
`Toxic
`Runqu
`
`Thurnpnulic
`Bung!
`
`VIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`(‘""°""V-v)
`
`
`DRUGBLOODLEVEL
`
`
`
`TIME
`
`lhrll
`
`Fig 91-3. Typical drug blood level versus time profiles for delayed-
`release drug delivery by a repeal-action dosage form.
`
`amwnyml)
`
`--_a
`
`
`
`
`
`DRUGBLOODLEVEL
`
`31':
`
`Inuiiucllvu
`Range
`
`TIME
`
`lhrsl
`
`Flg 91-4. Drug blood level versus time profiles showing the relation--
`ship between controlled-release (A), prolonged-release (B) and con-
`ventional-release {G) drug delivery.
`
`site-specific release, the target is a certain 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.
`
`Release Rate and Dose Considerationsz
`
`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 remain-
`ing in the dosage form and constant over time. That is,
`release from the dosage form should follow zero-order kinet-
`ics, as shown by the following equation:
`
`Astrazeneca Ex. 2080 p. 6
`
`Absorption
`hr
`Dosage
`Form drug release P001
`
`;Target
`in
`absorption Area
`
`14.
`elimination
`
`The absorption pool represents a solution of the drug at the
`site of absorption, and the terms 32,, kg and he are first- order
`rate constants for drug release, absorption and overall elimi-
`nation, respectively.
`Immediate release from a convention-
`al dosage form implies that k, >>> kg 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 nonimmediate-release dos-
`age forms, 12,. <<< kc, that is, release of drug from the dosage
`form is the rate-limiting step. This causes the above kinetic
`scheme to reduce to the following:
`1:,
`la,
`Dosage Form —j> Target Area —-:9
`drug release
`elimination
`
`Essentially, the absorptive phase of the kinetic scheme he-
`comes insignificant compared to the drug release phase.
`Thus, the effort to develop a nonimmediate-release delivery
`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 chap-
`ter.
`
`Nonimmediate-release delivery systems may be divided
`conveniently into four categories:
`1. Delayed release
`2. Sustained release
`a. Controlled release
`b. Prolonged release
`3. Site—specific release
`4. Receptor release
`
`De loyed-re lease 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. Exam-
`ples of delayed-release systems include repeat-action tablets
`and capsules, 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 91-3, but,
`nonetheless, is more effective for patient compliance than
`conventional dosage forms.
`Sustained-release systems include any drug delivery sys-
`tem that achieves slow release of drug over an extended
`period of time.
`If the system is successful at maintaining
`constant drug levels in the blood or target tissue, it is consid-
`ered a controlled-release system.
`If it is unsuccessful at
`this, but nevertheless extends the duration of action over
`that achieved by conventional delivery, it is considered a
`prolonged-release system. This is illustrated in Fig 91-4.
`Site-specific and receptor release refer to targeting of a
`drug directly to a certain biological location.
`In the case of
`
`

`
`1678
`
`CHAPTER 91
`
`I2,” = Rate In = Rate Out = kg-Ca-V,,
`
`(1)
`
`where k,” is the zero-order rate constant for drug release
`(amount/time), he is the first-order rate constant for overall
`drug elimination (time'1), Cd is the desired drug level in the
`body (amount/volume) and V1 is the volume space in which
`the drug is distributed. The values of Ike, Cd and Vd needed
`to calculate ie,.” are obtained from appropriately designed
`single-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 drugs, however, more complex elimina-
`tion 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, 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 nonconstant drug level may be indis-
`tinguishable 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 re-
`leases drug immediately and a maintenance or sustaining
`dose,D,,,. The total dose, W, thus required for the system is
`
`‘
`
`W=D;+Dm
`
`For a system where the maintenance dose releases drug by a
`zero—order process for a specified period of time, the total
`dose? is
`
`W = D; + k,.°T,,
`
`(3)
`
`where 32,.“ is the zero-order rate constant for drug release and
`Td is the total time desired for sustained release from one
`dose. 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 drug from the maintenance dose:
`
`W = D, + 12,021, — k,.°T,,
`
`(4)
`
`The correction factor, k,°T,,, is the amount of drug provided
`during the period from t = D to the time of the peak drug
`level, T,,. No correction factor is needed if the dosage form
`is constructed in such a fashion that the maintenance dose
`
`does not begin to release drug until time T,,.
`It already has been mentioned that a perfectly invariant
`drug blood or tissue level versus time profile is the ideal goal
`of a sustained-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, satisfac-
`tory approximations of a constant drug level can be obtained
`by suitable combinations of the initial dose and a mainte-
`nance dose that releases its drug by a first-order process.
`The total dose for such a system is
`
`W = D,» + (k,_,C,,»/k,)V,,
`
`(5)
`
`where it, is the first-order rate constant for drug release
`'(tirne‘1), and he, Cd 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
`
`W = D,- + (keCd/k,.)Vd -- Dmk,T,,
`
`(6)
`
`In order to maintain drug blood levels within the thera-
`peutic range over the entire time course of therapy, most
`sustained-release drug delivery systems are, like conven-
`tional 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 36. For those sustained-
`release systems having release kinetics other than zero-on
`der, the multiple dosing regimen is more complex and its
`analysis is beyond the scope of this chapter; Welling and
`Dobrinskai‘ provide more detailed discussion.
`
`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 represented by several potential advantages of the use of
`sustained-release systems, as shown in Table I.
`Patient compliance has been recognized as a necessary
`and important component in the success of all self-adminis-
`tered drug therapy. Minimizing or eliminating patient
`compliance problems is an obvious advantage of sustained-
`release therapy. Because of the nature of its release kinet-
`ics, 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 elimi-
`nation of both local and systemic side effects, less potentia-
`tion or reduction in drug activity with chronic use and mini-
`mization of drug accumulation in body tissues with chronic
`dosing.
`Unquestionably the most important reason for sustained-
`drug therapy is improved efficiency in treatment, ie, opti-
`mized therapy. The result of obtaining constant drug blood
`levels from a sustained-release system is to achieve promptly
`the desired effect and maintain it. Reduction or elimination
`of fluctuations in the drug blood level allows better disease
`state management.
`In addition, the method by which sus-
`tained release is achieved can improve the bioavailability of
`some drugs. For example, drugs susceptible to enzymatic
`inactivation or bacterial decomposition can be protected by
`encapsulation in polymer systems suitable for sustained re-
`lease. For drugs that have a “specific window” for absorp-
`tion, increased bioavailability can be attained by localizing
`the sustained-release delivery system in certain regions of
`the gastrointestinal tract.
`Improved efficiency in treatment
`also can take the form of a special therapeutic effect not
`possible with a conventional dosage form (see Table I).
`The last potential advantage listed in Table I, that of
`economy, can be examined from two points of view. Al-
`though the initial unit cost of most sustained-drug delivery
`systems usually is greater than that of conventional dosage
`
`Table l—PotentiaI Advantages oi Sustained Drug Therapy
`
`1. 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 potentiation or reduction in drug activity with
`chronic use
`cl. Minimize drug accumulation with chronic dosing
`Improve efficiency in treatment
`a. Cure or control condition more promptly
`eve
`b. lmplrove control of condition, ie, reduce fluctuation in drug
`:3. Improve bioavailability of some drugs
`d. Make use of special effects, eg, sustained-release aspirin for
`morning relief of arthritis by closing before bedtime
`‘Economy
`
`3.
`
`4.
`
`Astrazeneca Ex. 2080 p. 7
`
`

`
`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.
`
`SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS
`
`1679
`
`s, = sou + [I-1+]/Kn) = sou + 10?“-“P”;
`
`(9)
`
`Drug Properties Relevant to Sustained-Release Formulation
`The design of sustained-release delivery systems is subject
`the hydrogen ion concentration of the medium. Equation 8
`to several variables of considerable importance. Among
`predicts that the total solubility, S“ of a weak acid with a
`these are the route of drug delivery, the type of delivery
`given pK,, can be affected by the pH of the medium. Simi-
`larly, for a weak base
`system, the disease being treated, the patient, the length of
`therapy and the properties of the drug. Each of these vari-
`ables are interrelated 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 designing the system are the con-
`straints imposed by the properties 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 prop-
`erties of a drug as being either physicochemical 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 purposes of
`this discussion, however, those attributes that can be deter-
`mined from in uitro experiments will be considered as physi-
`cochemical properties.
`Included as biological properties
`will be those that result from typical pharmacokinetic stud-
`ies on the absorption, distribution, metabolism and excre-
`tion (ADME) characteristics of a drug and those resulting
`from pharmacological studies.
`
`where Si: is the total solubility (both the conjugate acid and
`free-base forms) of the weak base, 80 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, S;, of a weak base whose conjugate acid has a
`given pKa can be affected by the pH of the medium. Con-
`sidering 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 un-ionized form
`of a drug will be absorbed preferentially, in a passive man--
`ner, through membranes. Since weakly acidic drugs will
`exist in the stomach (pH = 1 to 2) primarily in the un-ionized
`form, their absorption will be favored from this acidic envi-
`ronment. 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 and gastric fluid:
`
`R = (1 + 1o°“~‘“K»)/(1 + 10"*‘~‘*"“-)
`
`(10)
`
`where pH;, is the pH of blood (pH 7.2), pH; is the pH of the
`gastric fluid (pH' 2) and the pK,, of aspirin is about 3.4.
`Substituting these values into Eq 10 gives a value for R of
`103'“ which indicates that aspirin is in a form to be well-
`absorbed from the stomach. The same calculation for irites-
`tinal pH (co '7) yields a ratio close to 1, implying a less-
`favorable driving force for absorption at that location.
`Ide-
`ally, the 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 gastrointes-
`tinal (GI) tract so that the amount of preferentially absorbed
`species, and thus the plasma level of drug, will be approxi-
`mately 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 prod-
`uct. 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, formu-
`lation of such a drug into a sustained-release system is re-
`dundant. Even if a poorly soluble drug was considered as a
`candidate for formulation 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 solution 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 slight-
`ly soluble form of a drug with normally high solubility is,
`however, one possible method for preparing sustained~re—
`
`Astrazeneca Ex. 2080 p. 8
`
`Physicochemical Properties
`
`Aqueous Solubility and pK,,
`
`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 abso