INJECTABLE DRUG
`
`DEVELOPMENT
`
`TECHNIQUES TO REDUCE
`PAIN AND IRRITATION
`
`Edited by
`
`Pramod K. Gupta
`
`and
`
`Gayle A. Brazeau
`
`Interpharm Press
`Denver, Colorado
`
` ~/
`
`'INTERT’HA.R?\‘-I‘
`P R E S S
`
`Astrazeneca Ex. 2087 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`

`

`
`
`Invitation to Authors
`
`m__,._.
`E-'=-‘_...-==“'
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`
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`Interpharm Press publishes books focused upon applied tech-
`nology and regulatory affairs impacting healthcare manufactur—
`ers worldwide. If you are considering writing or contributing to
`a book applicable to the pharmaceutical, biotechnology, medical
`device, diagnostic, cosmetic, or veterinary medicine manufacturing in-
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`
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`
`Library of Congress Cataloging~in—Publication Data
`
`Injectable drug development : techniques to reduce pain and irritation /
`edited by Prarnod l<. Gupta and Gayle A. Brazeau.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN 1-57'49‘l—095—7
`
`’l. Injections. 2. injections—=«Complications. 3. Drug development.
`I. Gupta, Pramod l(., 1959-
`. II. Brazeau, Gayle A.
`[DNLM: ‘i. Injections—adverse effects. 2. Pain—Chemically induced.
`3. Pain—prevention 8; control. 4. Pharmaceutical Preparations——
`administration 82 dosage. WB 354 156 1999]
`B'.l\/1169.149
`1999
`I3’l5‘.6~—dc21
`DNLM/DLC
`
`for Library of Congress
`
`99-26911
`ClP
`
`10987654321
`
`ISBN: l—57491—09t5—7
`
`Copyright © 1999 by Interpharrn Press. All rights reserved.
`
`All rights reserved. This book is protected by copyright. No part of it may be re-
`produced, stored in a retrieval system, or transmitted in any form or by any
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`written permission from the publisher. Printed in the United States of America.
`Where a product trademark, registration mark, or other protected mark is
`made in the text, ownership of the mark remains with the lawful owner of the
`mark. No claim, intentional or otherwise, is made by reference to any such marks
`in this book.
`
`While every effort has been made by Interpharrn Press to ensure the accuracy
`of the information contained in this book, this organization accepts no responsi~
`bility for errors or omissions.
`
`Interpharm Press
`15 Inverness Way E.
`Englewood, CO 80112-5776, USA
`
`Phone: +1-303-662—9”lU‘l
`Fax:
`+‘l—303—754—3953
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`
`Astrazeneca Ex. 2087 p. 2
`
`

`

`Contents
`
`Preface
`
`Acknowledgments
`
`Editors and Contributors
`
`A: BACKGROUND OF PAIN, IRRITATION, AND/OR
`MUSCLE DAMAGE WITH INJECTABLES
`
`'1.
`
`Challenges in the Development of
`Injectable Products
`
`Michael J. Akers
`
`General Challenges
`
`Safety Concerns
`
`Microbiological and Other Contamination Challenges
`
`Stability Challenges
`
`Solubility Challenges
`
`Packaging Challenges
`
`Manufacturing Challenges
`
`Delivery/Administration Challenges
`
`References
`
`xiii
`
`xiv
`
`XV
`
`CXJO'JU'I>-P-
`
`'10
`
`1'1
`
`11
`
`13
`
`14
`
`iii
`
`Astrazeneca Ex. 2087 p. 3
`
`

`

`iv
`
`lnjectable Drug Development
`
`Pain, Irritation, and Tissue Damage
`with Injections
`
`Wolfgang Klement
`
`Must Injections Hurt?
`
`Mechanisms of Pain and Damage
`
`Routes of Drug Injection
`
`Cutaneous/Subcutaneous Injections
`
`‘I8
`
`Intramuscular Injections
`
`22
`
`Intra-arterial Injections
`
`24
`
`Intravenous Injections
`
`26
`
`Conclusions and Perspectives
`
`Acknowledgements
`
`References
`
`Mechanisms of Muscle Damage with
`Injectable Products
`
`Anne McArclle and Malcolm J. Jackson
`
`Abstract
`
`Introduction
`
`Mechanisms of Muscle Damage
`Elevation of Intracellular Calcium Concentration
`
`58
`
`Increased Free Radical Production
`
`60
`
`Loss offinergy Homeostasis
`
`61
`
`Methods of Assessing Drug»Inclucec1 Skeletal
`Muscle Damage
`
`Microscopic Analysis of Skeletal Muscle
`Muscle Function Studies
`63
`
`62
`
`Leakage of Intramuscular Proteins
`
`64
`
`Microclialysis Studies oflndividual Muscles
`
`54
`
`Cellular Stress Response
`
`65
`
`Techniques to Assess the Mechanisms of Muscle Damage
`Models ofMuscle Damage
`66
`
`Techniques to Show Changes in Muscle Calcium Content
`
`66
`
`Markers oflncreased Free Radical Activity
`
`67
`
`Methods of Measuring Cellular Energy Levels
`
`67
`
`Conclusions
`
`Acknowledgments
`
`References
`
`‘15
`
`'15
`
`16
`
`'18
`
`49
`
`50
`
`50
`
`57
`
`57
`
`57
`
`58
`
`62
`
`66
`
`67
`
`67
`
`68
`
`Astrazeneca Ex. 2087 p. 4
`
`

`

`Cements
`
`‘V
`
`I3: METHQDS TC) A3555:-3 FAIN, IRRITATION, AND
`MUSCLE DAMAGE FOLLQWING INJECTIONS
`
`In Vitrn Methods for Evaluating
`Intravascular Hemolysis
`
`Jeseph Pi Kirzyzaniak and Sanmei H. Yaficawsky
`
`Significance
`
`In Vim) Methods for Evaluating Henmlysis
`Static Meflmcfs
`81
`
`Dynamfc fvietheds
`
`82
`
`Comparisczrn of In V‘itr<:,~ and in Vivo Hemolysis Data
`
`Summary of In Vitzm Methods
`
`References
`
`Lesion and Edema Models
`
`Steven C. Suzmn
`
`Edema and Inflammation
`
`Lesion Modeis
`
`Rabbit
`
`92
`
`Mice
`
`95
`
`R3?
`
`96
`
`Biochemicafmcadeis
`
`Serum Gfutami::~{3Xa10aCe2‘i:: Transaminase
`
`.9?’
`
`N~,.~%cetyI»{3—Giuzirosamfnidasa
`
`9?‘
`
`2‘v1‘ye1opemxfd3se
`Creatine Kinase
`
`9?
`Q5’
`
`Edema Mockeizs
`
`105
`Indzzcing Edema
`E:«:udarz'w3 Moczflm of Inflammation
`
`105
`
`Vascular Psrmeabiiity Arfodels
`
`105
`
`Foaipad Eczfema hzI<:>c2'e?s
`
`T06
`
`Cnrreiaticn 0? Medals
`
`Rabbi? Lesion Versus Rabbit Henmrmage Score Mode!
`
`10?
`
`Rabbit Lésfon Versus Rabbit CK Made}
`
`168
`
`Rabbit Lesion Versus 83% Footpad E-fZ3r.’:‘f’I}a Mafia!
`Rabbit Lesion ‘£:’e,rsus fiat CK Mode!
`10.?
`
`T09
`
`Rat and Human
`
`I10
`
`T7
`
`?’8
`
`7'9
`
`85
`
`86
`
`87"
`
`93
`
`91
`
`92
`
`9?’
`
`“I05
`
`107'
`
`Astrazeneca Ex. 2087 p. 5
`
`

`

`vi
`
`lnjectable Drug Development
`
`Models for Exter1ded—Release Formulations
`
`Predicting Muscle Damage from
`Extended-Release Formulations
`
`111
`
`Future Directions
`
`Muscle Damage and CR"
`
`112
`
`112
`Gamma Scintigraphy
`Electron Parametric Resonance and
`
`Nuclear Resonance Imaging
`
`1'12
`
`Effect of Edema and Lesion on Bioavailability
`Formulation
`113
`
`‘H3
`
`Conclusions
`
`References
`
`Rat Paw-Lick Model
`
`Pramod K. Gupta
`
`Methodology
`
`Correiation Between Rat Paw-Lick and Other
`Pain/Irritation Models
`
`Application of Rat Paw-Lick Mode] to Screening
`Cosolvent-Based Formulations
`
`Limitations of the Rat Paw-Lick Model
`
`Concluding Remarks
`
`References
`
`Radiopharmaceuticals for the Noninvasive
`Evaluation of Inflammation Following
`Intramuscular Injections
`
`Agatha Feltus, Michael Jay, and Robert M. Beihn
`
`Gamma Scintigraphy
`
`Gamma Cameras
`
`Detectors
`
`133
`
`Coltimamrs
`
`135
`
`Electronics and Output
`
`136
`
`Computers
`
`137
`
`Tomographic Imaging
`
`139
`
`Quality Control
`
`139
`
`Raclionuclides and Radiation
`
`Scintigraphic Detection of Inflammation
`
`1'10
`
`112
`
`114
`
`115
`
`119
`
`120
`
`‘I20
`
`123
`
`126
`
`128
`
`‘I28
`
`131
`
`132
`
`‘I32
`
`‘I40
`
`‘I41
`
`Astrazeneca Ex. 2087 p. 6
`
`

`

`Contents
`
`vii
`
`Gallium-67
`
`141
`
`Radiolabeled Leukocytes
`Radiolabeleo’ Antibodies
`
`14-3
`145
`
`OtherRadiopiiarmaceuticals
`
`147
`
`Summary
`
`References
`
`A Primer on In Vitro and In Vivo Cytosolic
`Enzyme Release Methods
`
`Gayle A. Brazeau
`
`Rationale for Utilizing Release of Cytosolic Components
`as a Marker of Tissue Damage
`
`Experimental Models
`Isolated Rodent Skeletal Muscle Model
`
`General Experimental Overview 159
`
`Isolation, Extraction, and Viability of‘ Isolated Muscles
`
`160
`
`Muscle Exposure to the Test Formulation
`Incubation Media
`164
`
`162
`
`Cytosoiic Enzymes Utilized in Isolated Muscle Studies
`
`‘I64
`
`Controls and Data Analysis
`
`154
`
`Muscle Cell Culture Methods to Evaluate Muscle Injury
`General Considerations
`165
`
`General Considerations in the Optimization of Experimental
`Cell Culture Systems
`166
`
`Selected Cell Lines in Screening for Drug—Ino'uced Toxicity
`
`168
`
`In Vivo Enzymatic Release Methods
`General Considerations
`169
`
`Animal Models
`
`170
`
`Quantification of Tissue Damage
`
`17?
`
`Conclusions
`
`Acknowledgments
`
`References
`
`Histological and Morphological Methods
`
`Bruce M. Carlson and Robert Palmer
`
`Basic Principles Underlying Morphological Analysis
`
`Techniques of Morphological Analysis
`
`148
`
`149
`
`155
`
`15?
`
`159
`159
`
`1155
`
`169
`
`172
`
`173
`
`173
`
`‘I77
`
`179
`
`180
`
`Astrazeneca Ex. 2087 p. 7
`
`

`

`viii
`
`Injectable Drug Development
`
`Electron Microscopic Methods
`183
`
`Histological Methods
`Histochemical Methods
`
`185
`
`Imm un ocytoch emical Merhods
`
`Neuromuscular Staining Methods
`
`180
`
`187
`
`189
`
`Summary of Strengths and Limitations of
`Morphological Techniques in Assessing
`Muscle Damage After Injections
`References
`
`10. Conscious Rat Model to Assess Pain
`
`Upon Intravenous Injection
`
`John M. Maroek
`
`Experimental Procedures
`
`Experiment 1'
`
`Experiment 2
`
`Experiment 3
`
`Experiment 4
`
`Experiment5
`
`Experiment 6
`
`Experiment 7
`
`196
`
`197
`
`197
`
`197
`
`‘I97
`
`‘l9?
`
`198
`
`Statistical Analyses
`
`T98
`
`Results
`
`Discussion
`
`Applications
`
`Summary and Conclusions
`
`Acknowledgments
`
`References
`
`C: APPROACHES IN THE DEVELOPMENT OF
`
`LESS-PAINFUL AND LESS-IRRITATING INJECTABLES
`
`11. Cosolvent Use in Injectahle Formulations
`
`Susan L. Way and Gayle Brazeau
`
`Commonly Used Solvents
`219
`
`Polyethylene Glycols
`223
`
`Propylene Glycol
`Ethanol
`225
`
`190
`
`191
`
`‘I93
`
`‘I95
`
`198
`
`204-
`
`209
`
`210
`
`211
`
`21']
`
`215
`
`218
`
`Astrazeneca Ex. 2087 p. 8
`
`

`

`Ccrntenig
`
`ix
`
`G35/Carin
`
`226
`
`Cremophors
`Bcnzya‘ macho}
`Amide Solvents
`
`22?
`228
`230
`
`Dimethyisuffoxfde
`
`232
`
`Hiemmyti-:3 Patentia} of Saiventsfiosolvents
`
`In ‘Mitre/In Viva Hemoiysis Cemparfisens
`
`.23?
`
`Muscle Damage
`
`C0s0ivent—Re}ated Pain an injection
`Casalvents Knawn ta Cause Pain
`
`2345
`
`Mefhocfs ta Minimize Pain
`
`2%?
`
`Ccsnclusions
`
`References
`
`12.
`
`Prodrugs
`
`Laszio Prokai and Kataiin Prakai-Ta traf
`
`Ire:-zign of Prodrugs
`
`Specific: Z.x:a:11pIes of Pmdrugs Developed to Impmve
`Water Solubility of Injectables
`
`Anticancer‘ Agents
`
`2?‘3
`
`Cenfrai Newaus System Agents
`
`283
`
`Other Drugs
`Cenciusmns
`
`288
`
`R€f€:I”E31‘lCE3S
`
`13.
`
`Complexatian-——~«Use (‘If Cycladextrins to
`Improve Pharmaceutical Properties of
`Intramuscular Formulations
`
`Marcus E. Brewster and Tharsieinn Laftsson
`
`Cyciodextrirxs
`
`Prepanation 01° Cyciodextrin Ccmpiexes
`
`Characterization of Cyciadextrin Complexes
`
`Use Qf Cyclodextrins in IM Formulatiuns
`
`Mefhodofogies
`
`319
`
`IM Taxicfty 01“ Cycladexfrins and Their Derivafivs$
`
`32!}
`
`Use G2“ Cyciadexmns ta Repface Toxic Extfpienrs
`in {M Farmufafiens
`333
`
`Use at” C3/cfadexfrins to Reduce fmrinsic
`Dftzg-Refated Taxiisiry
`3'25
`
`233
`
`2é2
`
`2-55:5
`
`7258
`
`251
`
`267
`
`25?
`
`273
`
`295
`
`29?
`
`307
`
`Astrazeneca Ex. 2087 p. 9
`
`

`

`lnjectable Drug Development
`
`Conclusions and Future Directions
`
`Acknowledgments
`References
`
`'14.
`
`Liposomal Formulations to Reduce
`Irritation of Intramuscularly and
`Subcutaneously Administered Drugs
`
`Farida Kaclir, Chrlstien Oussoren, and Daan J. A. Crommefln
`
`Liposomes: A Short introduction
`
`Liposomes as intramuscular and Subcutaneous
`Drug Delivery Systems
`
`Studies on Reduction of Local Irritation
`
`Studies on the Protective Effect After
`Intramuscular Administration
`342
`
`Studies on the Protective Eltect Ai°terfntraclern1al and
`Subcutaneous Administration
`345
`
`Discussion
`
`Conclusions
`
`References
`
`‘I5.
`
`Biodegradable Microparticles for the
`Development of Less-Painful and
`Less-Irritating Parenterals
`
`Elias Fattal, Fabiana Qua-glia, Pramod Gupta, and Gayle Brazeau
`
`Rationale for Using Microparticles in the Development
`of Less—Painful and Less—Irritating Parenterals
`
`Poly(Lactide—co-Glycoiide] Microparticles as Delivery
`Systems in the Development of Less—Painful and
`Less—Irritating Parenterals
`
`Polymer Selection
`
`35?
`
`Microencapsulation Technique
`
`350
`
`Drug Release
`Sterilization
`
`365
`368
`
`ResidualSolvenIs
`
`368
`
`Stability of the Encapsulated Drug and
`Microparticle Products
`369
`
`329
`
`330
`330
`
`337
`
`338
`
`340
`
`341
`
`349
`
`350
`
`351
`
`355
`
`355
`
`357
`
`Protection Against Myotoxicity by Intrarnuscularlyl
`Subcutaneously Administered Microparticles
`
`370
`
`AstraZeneca Ex. 2087 p. 10
`
`

`

`Contents
`
`xi
`
`Conclusions
`
`References
`
`‘I6.
`
`Emulsions
`
`Pramod K. Gupta and John B. Cannon
`
`Rationale for Using Emulsions for Reducing Pain and
`irritation upon Injection
`
`Potential Mechanisms of Pain on Injection
`Case Studies
`
`Propofol {Diprivan®)
`384
`
`Diazepam
`Etomida to
`
`388
`
`382
`
`Pregnanoione (Eitanolone®,l
`
`Methohexitai and Thiopental
`390
`
`Aniphotericin B
`
`Clarithromycin
`
`391
`
`388
`
`389
`
`Challenges in the Use of Emulsions as Pharmaceutical
`Dosage Forms
`
`Physical Stability
`
`393
`
`393
`Efficacy
`Dose Volume
`
`Other issues
`
`394-
`
`394
`
`Conclusions
`
`References
`
`D: FUTURE PERSPECTIVES IN THE DEVELOPMENT OF
`
`LESS-PAINFUL AND LESS-IRRITATING INJECTABLES
`
`17.
`
`Formulation and Administration Techniques
`to Minimize Injection Pain and Tissue
`Damage Associated with Parenteral Products
`
`Larry A. Gatlin and Carol A. Gatlin
`
`Formulation Development
`402
`Preformulation
`
`Formulation
`
`404
`
`Focus on Osmolality, Cosoivents, Oils, and pH 410
`pH 415
`
`371
`
`372
`
`379
`
`380
`
`381
`
`382
`
`393
`
`395
`
`395
`
`401
`
`402
`
`Astrazeneca Ex. 2087 p. 11
`
`

`

`xii
`
`Injectable Drug Devefopmenf
`
`P031:-Formulation Pmceczlurea
`
`pH, Additivrgs, and Eolvents
`
`436
`
`Devices and Physicaf Manipuiarfons
`
`41?
`
`References
`
`Index
`
`416
`
`‘$236
`
`423
`
`Astrazeneca EX. 2087 p. 12
`
`

`

`1
`
`Challenges in the
`Development of Inj ectable
`Products
`
`Michael J. Akers
`
`Biophannaceutical Products Development
`Lilly Research Laboratories
`Indianapolis, Indiana
`
`The injection of drugs is necessary either because a need exists for a very
`rapid therapeutic effect, or the drug compound is not systemically avail-
`able by non-injectable routes of administration. Early use of injections led
`
`to many adverse reactions because the needs for sterility and freedom
`
`from pyrogenic contamination were poorly understood [Avis 1992]. Al-
`
`though Pasteur and Lister recognized the need for sterilization to eliminate
`pathogenic microorganisms during the 18605, sterilization technologies
`did not advance until much later. For example, the autoclave was discov-
`
`ered in 1884, membrane filtration in 1918, ethylene oxide in 1944, high ef-
`ficiency particulate air (HEPA) filters in 1952, and laminar airflow in 1961.
`
`Increases in body temperature and «chills in patients receiving injections
`were observed in 1911, which were found in 1923 to be due to bacteria-
`
`produced pyrogens. The science and technology of manufacturing and us-
`
`ing injectable products have both come a long way since their inception in
`the mid-1850s. However, the assurance of sterility, particularly with in-
`jectable products manufactured by aseptic manufacturing processes, con-
`tinues to be tremendously challenging to the parenteral drug industry.
`
`Injectable products have some very special characteristics unlike any
`other pharmaceutical dos age form (Table 1.1]. Each of these characteristics
`offers unique challenges in the development, manufacture, testing, and use
`of these products. These will be discussed more specifically in later sec-
`
`tions of this chapter.
`
`AstraZeneca Ex. 2087 p. 13
`
`

`

`4-
`
`Injectable Drug Development
`
`Table 1.1. Special Characteristics of and Requirements for Injectahle
`Dosage Forms
`
`-
`
`0
`
`0
`
`-
`
`''
`
`-
`
`0
`
`Toxicologically safe--many potential formulation additives are not sufficiently safe for in-
`jectable drug administration
`
`Sterile
`
`Free from pyrogenic (including endotoxin} contamination
`
`Free from foreign particulate matter
`
`Stable‘-not only physically and chemically but also microbiologically
`
`Compatible with intravenous admixtures if indicated
`
`isotonic
`
`GENERAL CHALLENGES
`
`From a formulation development standpoint, the injectable product for-
`mulation must be as simple as possible. As long as there are no major
`stability, compatibility, solubility, or delivery problems with the active in-
`gredient, injectable product formulation is relatively easy to accomplish.
`Ideally, the formulation will contain the active ingredient and water in a ve-
`
`hicle [e.g., sodium chloride or dextrose) that is isotonic with bodily fluid.
`Unfortunately, most active ingredients to be injected do not possess these
`ideal properties. Many drugs are only slightly soluble or are insoluble in
`aqueous media. Many drugs are unstable for extended periods of time in
`solution and even in the solid state. Some drugs are very interactive with
`surfaces such as the container/closure surface, surfaces of other formula-
`
`tion additives, or surfaces of administration devices.
`
`There are three interesting phenomena that make injectable drug for-
`
`mulation, processing and delivery so complicated compared to other phar-
`maceutical dosage forms:
`
`1.
`
`There are relatively few safe and acceptable formulation addi-
`tives that can be used. If the drug has significant stability, solu-
`bility, processing, contamination, andfor delivery problems, the
`
`formulation scientist does not have a plethora of formulation
`
`materials that can be used to solve these problems.
`
`2.
`
`In non-parenteral processing, because of the frequent potential
`for powder toxicology concerns, the process is set up to protect
`
`personnel from the product. In injectable product processing, the
`opposite exists—-the process is set up to protect the product from
`
`personnel because the major sources of contamination are people.
`
`AstraZeneca Ex. 2087 p. 14
`
`

`

`Challenges in the Development of lnjectable Products
`
`5
`
`3. When a manufacturer releases a non—injectable dosage form to
`the marketplace, the ultimate consumer takes that dosage form
`
`from its package and consumes it. Because there is little manip-
`ulation of the non-injectable dosage form, potential problems
`created by the consumer of these products are infrequent. How-
`ever, most injectable dosage forms experience one or several ex-
`tra manipulations before administration to the patient. lnjectable
`drug products are withdrawn from vials or ampoules, placed in
`administration devices, and/or combined with other solutions,
`
`and they are sometimes combined with other drugs. The point
`here is that something is usually done to the injectable product
`that can potentially affect its stability or solubility, or another
`performance factor; such manipulations are done beyond the
`
`control of the manufacturer. Yet when problems occur, e.g., sta-
`bility or solubility issues, the manufacturer is responsible for
`solving them even though the manufacturer did not cause them.
`
`SAFETY CONCERNS
`
`Drug products administered by injection must be safe from two stand-
`points: ['1] the nature of the formulation components of the product and
`
`(2) the anatomical/physiological effects of the drug product during and af—
`ter injection.
`
`Compared to other pharmaceutical dos age forms, there are relatively
`few formulation additives a formulation scientist can choose from to solve
`
`solubility and/or stability problems, maintain sterility, achieve and main~
`
`tain isotonicity, extend or control the release of drugs from depot injec-
`tions, or accomplish some other need from a formulation standpoint (e.g.,
`bulking agent, viscosity agent, suspending./emulsifying agent). Because of
`the irreversibility of the injectable route of aclministration and the immedi-
`
`ate effect and Contact of the drug product with the bloodstream and sys-
`temic circulation, any substance that has potential toxic properties, either
`related to the type of substance or its close, will either be unsuitable for
`parenteral administration or will have restrictions for the maximum
`
`amount to be in the formulation. For example, the choices of antimicrobial
`preservative agents for parenteral administration are very limited, and
`even these agents that are acceptable have limits on how much of the agent
`
`can be contained in a marketed dosage form. Similar restrictions exist for
`antioxidant agents, surface active agents, solubilizers, cosolvents, and
`other stabilizers (e.g., disodium ethylenediaminetetraacetic acid IEDTAD.
`
`There are many potential clinical hazards that may result from the ad-
`
`ministration of drugs by injection [Duma et al. 1992] [Table 1.2]. Several of
`
`these hazards (e.g., hypersensitivity reactions, particulate matter, phlebitis)
`
`AstraZeneca Ex. 2087 p. 15
`
`

`

`6
`
`Injectable Drug Development
`
`Table 1.2. Clinical Hazards of Parenteral Administration
`
`Air ernboli
`
`0
`
`Limited to IV or IA (imra-arterial] usage
`
`Bleeding
`
`0
`
`Usually related to patient’s condition
`
`Fever and Toxicity
`
`°
`
`0
`
`Local or systemic
`
`Secondary to allergic or toxic reaction
`
`Hypersensitivity
`
`°
`
`Immediate and delayed
`
`incompatibilities
`
`Can be most threatening if occurring in the vascular compartment
`a
`Infiltration and extravasation
`
`0
`
`Limited to IV or IA usage
`
`Overdosage
`
`-
`
`Drugs or fluids
`
`Particulate matter
`
`- Most serious in [V or L0. administration
`
`0
`
`Can cause foreign body reaction
`
`Phlebitis
`
`'
`
`Usually with IV administration
`
`Sepsis
`
`' May be localized, systemic, or metastatic
`Thrombosis
`
`I
`
`Limited to IV or IA administration
`
`can be directly related to formulation andfor packaging components. For
`example, some we11—lcnowI1 hypersensitivity reactions exist with the use of
`bisulfites, phenol, thimerosal, parabens, and latex rubber.
`
`MICROBIOLOGICAL AND
`
`OTHER CONTAMINATION CHALLENGES
`
`There are three primary potential contamination issues to deal with. The
`first is to achieve and maintain sterflity. Sterility, obviously, is the uniquely
`premier attribute of a sterile product. The concept of sterility is intriguing
`
`AstraZeneca Ex. 2087 p. 16
`
`

`

`Challenges in the Development of Injectable Products
`
`7
`
`because it is an absolute attribute, ie, the product is either sterile or not
`
`sterile. The achievement, maintenance, and testing of sterility involve chal-
`lenges that occupy the time, energy, and money of thousands of people and
`numerous resources. Sterility, by definition, is simp1e—-the absence of mi-
`
`crobial life. However, how does one prove sterility? Compendiai sterility
`tests use a very small sample from a much larger product population. How
`confident can one be of the sterility of each and every unit of product
`based on the test results of a very small sample size? Sterility essentially
`
`cannot be proved; it can only be assured. This is a huge challenge to the
`parenteral drug and device industry.
`Sterility can be achieved by a variety of methods, including saturated
`
`steam under pressure [the autoclave), dry heat, gases such as ethylene ox-
`ide and vapor phase hydrogen peroxide, radiation such as cobalt 60
`gamma radiation, and aseptic filtration through at least 0.2 pm filters. Dif-
`ferent types of materials and products are sterilized by different methods.
`
`For example, glass containers are usually sterilized by dry heat; rubber clo-
`
`sures and filter assemblies by saturated steam under pressure; plastic and
`
`other heat labile materials by gaseous or radiation methods; and final
`product solutions either by saturated steam under pressure (if the product
`
`can withstand high temperatures], or, more commonly, by aseptic filtra-
`tion. Each of these sterilization procedures must undergo significant study
`(process validation) in order to ensure that the method is dependable to a
`high degree of assurance to sterilize the material/product in question un-
`
`der normal production conditions. Great challenges exist in performing
`
`sterilization process validation and monitoring. There are also continuous
`efforts to find newer or better sterilization methods to increase the conve-
`
`nience and assurance of sterility (Akers et al. 1997).
`
`Injectable products must be free from pyrogenie contamination. Pyro-
`gens are metabolic by-products of microbial growth and death. Pyrogenic
`contamination must be prevented since the most common sterilization
`methods [e.g., steam sterilization, aseptic filtration) cannot destroy or re-
`
`move pyrogens. Prevention can occur using solutes prepared under pyro-
`genic conditions, pyrogen-free water produced by distillation or reverse
`osmosis, pyrogen-free packaging materials where glass containers have
`been depyrogenated by validated dry heat sterilization methods, and rub-
`
`ber closures and plastic materials that have been sufficiently rinsed with
`pyrogen-free water. The reason for Good Manufacturing Practice [GMPJ
`
`requirements for time limitations during parenteral product processing is
`to eliminate the potential for pyrogenic contamination, since subsequent
`sterilization of the product will remove microbial Contamination but not
`
`necessarily pyrogens.
`in sufficient injected amounts, pyrogens can be very harmful to
`
`humans. Pyrogens are composed of lipopolysaccharides that will react with
`the hypothalamus of mammals, producing an elevation in body tempera-
`
`ture [hence its Greek roots [pyro means fire and gen means beginningll.
`
`AstraZeneca Ex. 2087 p. 17
`
`

`

`8
`
`Injecrtable Drug Development
`
`Depending an the amount at‘ pymgen injected, other physiological prob»
`lems can occur, including death. Compendial te$ts, both in Vivo [rabbit
`
`model} and in vitro {Limulus amelmcyte lysate}, are established to ensure
`
`that products used in humans are tested and ck) Imt ccmtain levels sf }::yro»-
`gens that will dc any harm.
`
`lnjectable products, if injecztecl or infused as solutlens, must be free
`from particulate matter Cantamlnatien. Particulate matter in injectables C0n~
`
`notates at least three important perceptions:
`
`'1.
`
`The degree at" product quality and the subsequent reflection of
`the quality of the precinct manufacturer.
`
`2.
`
`The degree of product quality in the “’customer’s"‘ view (patient,
`
`medical professional, regulatory agency}.
`
`3.
`
`The clinical implications of the potential hazards of particulate
`matter.
`
`The first two perceptionsmrelated to the manufacturer and to the user Gr
`cu,stomer—-are relatively well-deflnecl and understoml in that evidence of
`particulate matter will trigger a series of reactions, ranging from product
`canxplaints to product recalls and other regulatory actiuns. However, the
`third perception, that particulate matter is clinically hazardcsus, begs more
`questions and discussion. There is substantial evidence of the adverse
`
`physialogical effects of injected. particulate matter, but still much c::'mjec~
`ture regarding the relaticzmship between the clinical hazard and the type,
`size, and number cf particulates (Groves 1993).
`
`STABILITY CHALLENGES
`
`lnjectable drugs are administered either as solutions or as clispersecl sys~
`tems (suspensions, emulsicsns, lipasomas, lather micmpartlculate systems}.
`The majcarity of injectable drugs have some kind of instability problem.
`Many clruga that are sufficiently stable in readyutownse salutians have some
`stability restrictions such as storage in light-pmtectecl packaging systems
`or storage at refrigerated canditions, or there may be formulation ingredi-
`ents that stabilize the drug but can themselves undergo degradation.
`The chemical sfabilify of injectable products generally involves two
`primary routes crwf clegradationwhydrolytlc and oxiclative. Other, less pre-
`dominant, chemical degradation mechanisms of injectable drugs involve
`racemizatlon, plmtelysis, and some special types cl" chemical reactions oc~
`curing with large molecules. A majority of injectahle drug products are too
`unstable in solution to be marketed as reacly~to~use solutions. Instead, they
`are available as sterile solids praduced by lycphllization (freeze-~~;:lrying) er
`sterile czrystallizaticsnfpawcler filling technolegies. Drugs that can he
`
`Astrazeneca EX. 2087 p. 18
`
`

`

`Challenges in the Development of Injectable Products
`
`9
`
`marketed as ready-to-use solutions or suspensions still offer the challenge
`
`of needing suitable buffer systems or antioxidant formulations for long-
`term storage stability. Freeze—dried products can undergo degradation
`during the freezing and/or freezedrying process and, therefore, require
`
`formulation additives to minimize degradation or other physical-chemical
`instability problems. Drugs sensitive to oxidation require not only suitable
`antioxidants and chelating agents in the formulation, but they also require
`special precautions during manufacturing {e.g., oxygen—free conditions),
`and special packaging and storage conditions to protect the solution from
`light, high temperature, and any ingress of oxygen. Stabilization of in-
`
`jectable drugs against chemical degradation offers a huge challenge to for-
`mulation scientists.
`
`Physical stability problems are well-known for protein injectabie
`dosage forms as proteins tend to selfaaggregate and eventually precipitate.
`
`Many injectable drugs are poorly soluble and require cosolvents or solid
`additives to enhance and maintain drug solubility. However, improper
`
`storage conditions, temperature cycling, or interactions with other com-
`
`ponents of the product/package system can all contribute to incompatibil-
`ities resulting, usually, in the drug falling out of solution (manifested as
`haze, crystals, or precipitate). Again, the formulation scientist is challenged
`with finding solutions to physical instability problems. Such solutions can
`he found with either creative formulation techniques or special handling
`
`and storage requirements.
`Microbiological issues arise with storage stability related to the con-
`tainer-closure system being cap able of maintaining sterility of the product;
`the antimicrobial preservative system, if present, still meeting compendial
`
`microbial challenge tests; and the potential for inadvertent contamination
`
`of non-terminally sterilized products and the degree of assurance that such
`
`products will not become contaminated. The concern for microbiological
`purity as a function of product stability has caused the Food and Drug Ad-
`ministration (FDA) and other worldwide regulatory bodies to require man-
`ufacturers of injectable products to perform sterility tests at the end of the
`product shelflife or to have sufficient container-closure integrity data to
`ensure product sterility over the shelf life of the product.
`
`The compatibility of injectable drugs when combined with one an-
`other and/or combined with intravenous fluid diluents can create signifi-
`cant issues for formulation scientists. Unlike solid and semisolid dosage
`
`forms, which are used as they were released from the manufacturer, in-
`jectable dosage forms are usually manipulated by people (pharmacist,
`nurse, physician] other than the ultimate consumer (patient) and are com-
`
`bined with other drug products and/or diluents before injection or infu-
`sion. These manipulations and combinations are beyond the control of the
`
`manufacturer and can potentially lead to an assortment of problems.
`
`For example, faulty aseptic techniques during manipulation (e.g., reconsti—
`tution, transfer, admixture) can lead to inadvertent contamination of the
`
`AstraZeneca Ex. 2087 p. 19
`
`

`

`10
`
`lnjectable Drug Development
`
`final product. In addition, drug combinations and additions to certain
`
`intravenous diluents can lead to physical and chemical incompatibilities. It
`is a great challenge to the injectable product formulator and Quality Con-
`trol (QC) management to anticipate these potential problems and do what-
`ever can be done to avoid or eliminate them.
`
`SOLUBILITY CHALLENGES
`
`Many drugs intended for injectable administration are not readily soluble in
`
`water. Classic examples include steroids, phenytoin, diazeparn, ampho«-
`tericin B, and digoxin. While most insolubility problems can be solved, they
`
`usually require a great amount of effort from the formulation development
`scientist. If a more soluble salt form of the insoluble drug is not available
`
`(e.g., poor stability, difficulty in manufacture, cost, etc.), then two basic for-
`mulation approaches can be attempted. One involves using formulation acl—
`clitives such as water miscible cosolvents, complexating agents {such as
`
`cyclodextrin derivatives], and surface active agents. If none of these addi-
`tives work, then the other approach involves the formulation of a more
`Complex dosage form such as an emulsion or liposorne. Table 1.3 lists the
`
`most common approaches for solving solubility problems with injectable
`drugs.
`
`Table 1.3. Approaches for Increasing Solubility
`
`Salt formation (~’lD00>< increase}
`
`pH adjustment
`
`Use of cosolvents (~1.000>< increase)
`
`Use of surfacevactive agents [~ 10D>< increase): e.g.. polyoxyethylene sorbitan monooleate
`(0.1 to 0.5%) and polyoxyethylene-polyozq/propylene ethers (0.05 to 025%]
`
`Use of complexing agents [-5OIf)>-< increase]; e.g., B—cyclodextrins and polyvinyl pyrroliclone
`(Pi/Pl
`
`Microemulsion formulation
`
`Liposome formulation
`
`Mixed micelle formulation (bile salt + phospholipid)
`
`"’Heroic” measures: e.g_, for cancer clinical trial formulations, use dirnethylsulfoxide
`[DMSO]. high concentrations of surfactants, polyols, alcohols, fatty acids. etc.
`
`Astrazeneca Ex. 2087 p. 20
`
`

`

`Challenges in the Development of Injectable Products
`
`111
`
`PACKAGING CHALLENGES
`
`A forrnulator can create an excellent injectable formulation that is Very sta-
`
`ble, easily manufacturable, and elegant. Yet the formulation must be com-
`
`patible with a packaging system. Currently, the most common injectable
`
`packaging systems are glass vials with rubber closures and plastic vials
`and bottles with rubber closures. Glass-sealed ampoules are not as popu-
`
`lar as in the past because of concerns with glass breakage and particulates.
`
`Other packaging systems include glass and plastic syringes, g