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`
`
`INJECTABLE DRUG
`DEVELOPMENT
`
`TECHNIQUES TO REDUCE
`PAIN AND IRRITATION
`
`Edited by
`
`Pramod K. Gupta
`
`and
`
`Gaer A. Brazeau
`
`
`
`
`
`InnoPharma Exhibit 1101.0001
`
`

`

` i lrE
`
`Informa Healthcare USA. inc.
`52 Vanderbilt Avenue
`New York. NY 10017
`
`0 2008 by Informa Healthcare USA, Inc. (original copyright 1999 by lnterpharm Press)
`Informa Healthcare is an Informa busineSs
`
`No claim to original US. Government works
`Printed in the United States of America on acid-free paper
`10 9 8 7 6 S 4 3 2
`
`International Standard Book Number-10: 1-5749-1095-7 (Hardcover)
`International Standard Book Number-is: 978-1574940954 (Hardcover)
`
`»
`
`Prefac‘
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted:
`with permission. and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to.
`publish reliable data and information, but the author and the publisher cannot assume responsibility for the validityoli
`all materials or for the consequences of their use.
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`A'
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`Ed,
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`No part ofthis book may be reprinted, reproduced, transmitted. or utilized in any form by any electronic. mechanical, 0i-
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`1 .
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`Trademark Notice: Product or corporate names may be trademarks or registered trademarks. and are used only for
`identification and explanation without intent to infringe.
`
`Library of Congress Cataloging-in-Publicatlon Data
`
`injectable drug development : techniques to reduce pain and irritation /
`edited by Pramod K. Gupta and Gayle A. Brazeau.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN—l3: 978-1-5749—10954 (hardcover : alk. paper)
`[SEN-10: 1-5749—1095-7 (hardcover: alk. paper)
`1. Injections. 2. Injections-Complications. 3. Drug development. 1. Gupta, Pramod K.. 1959—. ll.
`Bremen, Gayle A. {DNLMz 1. injections-vadverse effects. 2. Palm-chemically induced. 3. Pain--
`prevention 8c control. 4. Pharmaceutical Preparations~administration & dosage. WB 354 156 1999}
`RM169149 1999
`99-2691 1
`‘
`615'.6~dc21
`
`
`Visit the inform: Web site at
`www.informa.com
`
`and the inform Healthcare Web site at
`www.informahealthcare.com
`
`=0
`
`mmvmmm'i‘wm
`
`
`
`InnoPharma Exhibit 1101.0002
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`

`

`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Editors and Contributors
`
`_
`
`A: BACKGROUND OF PAIN, IRRITATION, AND/0R
`MUSCLE DAMAGE wrm INJECTABLES
`
`1.
`
`Challenges in the Development of
`Injectable Products
`
`Michael J. Akch
`
`General Challenges
`
`Safety Concerns
`
`Microbiological and Other Contamination Challenges
`
`Stability Challenges
`
`Solubility Challenges
`
`Packaging Challenges
`
`Manufacturing Challenges
`
`Delivery/Administration Challenges
`References
`
`xiii
`
`xiv
`
`xv
`
`iii
`
`3
`
`4
`
`5
`
`6
`
`8
`
`10
`
`11
`
`11
`
`13
`14
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`
`
`iv
`
`2.
`
`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
`Intramuscular Injections
`22
`Intro—arterial Injections
`24
`Intravenous Injections
`26
`Conclusions and Perspectives
`Acknowledgements
`References
`
`18
`
`3
`l
`
`3. Mechanisms of Muscle Damage with
`Injectable Products
`Anne McArdle and Malcolm J. Jackson
`
`Abstract
`
`Introduction
`
`Mechanisms of Muscle Damage
`Elevation of Intracellular Calcium Concentration
`
`58
`
`Increased Free Radical Productior:
`
`60
`
`Loss of Energy Homeostasis
`
`61
`
`Methods of Assessing Drug-Induced Skeletal
`Muscle Damage
`
`Microscopic Analysis of Skeletal Muscle
`Muscle Function Studies
`63
`
`62
`
`Leakage of Intramuscular Proteins
`
`64
`
`Mlcrodialysis Studies of Individual Muscles
`
`64
`
`Cellular Stress Response
`
`65
`
`Techniques to Assess the Mechanisms of Muscle Damage
`Models of Muscle Damage
`66'
`Techniques to Show Changes in Muscle Calcium Content
`Markers of Increased Free Radical Activity
`67
`Methods ofMeasuring Cellular Energy Levels
`67
`Conclusions
`Acknowledgments
`References
`
`66
`
`15
`
`15
`16
`18
`
`49
`50
`50
`
`57
`
`57
`
`57
`
`58
`
`62
`
`66
`
`67
`67
`68
`
`4.
`
`5.
`
`I
`
`i
`
`g
`a
`E
`E
`ir
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`li li I
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`
`
`Contents
`
`v
`
`8: METHODS T0 Assess PAIN, IRRITATION, AND
`MUSCLE DAMAGE FOLLOWING INJECTIONS
`
`2
`
`f
`
`4.
`
`In Vitro Methods for Evaluating
`Intravascular Hemolysis
`
`Joseph F. Krzyzaniak and Samuel H. Yalkowsky
`
`Significance
`
`In Vitro Methods for Evaluating Hemolysis
`Static Methods
`81
`
`Dynamic Methods
`
`82
`
`Comparison of In Vitro and In Vivo Hemolysis Data “
`
`Summary of In Vitro Methods
`
`References
`
`5.
`
`Lesion and Edema Models
`Steven C. Sutton
`Edema and Inflammation
`Lesion Models
`Rabbit
`92
`Mice
`96
`
`Rat
`96
`Biochemical Models
`Serum GIutamioOxaloacetic Transaminasc
`
`9?
`
`N-Acetyl-B-Glucosaminidase
`
`97
`
`97
`98
`
`Myeloperoxidase
`Creatine Kinase
`Edema Models
`105
`Inducing Edema
`Exudan've Models of Inflammation
`
`Vascular Permeability Models
`
`105
`
`Footpad Edema Models
`
`106
`
`Correlation of Models
`
`1'05
`
`Rabbit Lesion Versus Rabbit Hemorrhage Score Model
`Rabbit Lesion Versus Rabbit CK Model
`108
`
`107
`
`Rabbit Lesion Versus Rat Footpad Edema Model
`Rabbit Lesion Versus Rat CK Model
`109
`Rat and Human
`110
`
`109
`
`
`
`
`
`mvr‘mM...rm...~,..v.lw..fl...qwmmnmupmmwwemwww
`
`77
`
`78
`
`79
`
`85
`
`86
`
`87
`
`91
`
`91
`92
`
`97
`
`r
`
`105
`
`107
`
`
`
`
`
`‘
`
`f
`.5
`
`j
`
`.
`
`j‘
`
`.s...‘
`
`“
`'"'
`
`
`
`
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`
`nevi-mm»:0.:wA,.
`
`vi
`
`Injectable Drug Development
`
`Models for Extended~Reiease Formulations
`
`Predicting Muscle Damage from
`Extended~Release Formulations
`
`111
`
`Future Directions
`
`Muscle Damage and CK
`
`112
`
`112
`Gamma Scintigraphy
`Electron Parametric Resonance and
`Nuclear Resonance Imaging
`
`112
`
`Effect of Edema and Lesion on Bioavailabflity
`FormulatiOn
`113
`
`113
`
`Conclusions
`
`References
`
`Rat Paw«Lick Model
`
`Framed K. Gupta
`
`Methodology
`Correlation Between Rat Paw-Lick and Other
`Pain/Irritation Models
`
`Application of Rat Paw-Lick Model to Screening
`Cosolvent-Based Formulations I»
`Limitations of the Rat Paw-Lick Model
`
`Concluding Remarks
`References
`
`Radiopharmaceuticals for the Noninvasive
`Evaluation of Inflammation Following
`intramuscular Injections
`
`Agatha Feitus, Michael Jay, and Robert M. Beihn
`
`Gamma Scintigraphy
`Gamma Cameras
`Detectors
`133
`
`Collimators
`
`135
`
`Electronics and Output
`
`136
`
`Computers
`
`137
`
`Tomograpnic Imaging
`
`139
`
`139
`Quality Control
`Radionuclides and Radiation
`
`Scintigraphic Detection of Inflammation
`
`1‘10
`
`112
`
`114
`
`115
`
`119
`
`120
`
`120
`
`123
`
`126
`
`128
`
`128
`
`131
`
`132
`
`132
`
`140
`141 ‘
`
`
`
`
`
`
`
`v.w’y-uam'v;a"NEVanI"wMawmwwfi~wxiwflamvffl~‘“a\~nm‘Momum
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`
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`Contents
`
`vii
`
`Gallium~67
`
`141
`
`Radiolabeled Leukocytes
`Radioiabeled Antibodies
`
`143
`145
`
`Other Radiopharmaceuticals
`
`1'47
`
`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
`Muscle Exposure to the Test Formulation
`162
`Incubation Media
`164
`
`160
`
`Cytosolic Enzymes Utilized in Isolated Muscle Studies
`
`164
`
`Controls and Data Analysis
`
`164
`
`148
`
`149
`
`155
`
`157
`
`159
`
`159
`
`Muscle Cell Culture Methods to Evaluate Muscle Injury
`General Considerations
`165
`
`1155
`
`General Considerations in the Optimization of Experimental
`Cell Culture Systems
`166
`
`
`
`
`
`A..1.'.an.g.t‘.:.u.a;u.dam—e
`
`Selected Cell Lines in Screening for Drug-Induced Toxicity
`In Vivo Enzymatic Release Methods
`General Considerations
`169
`Animal Models
`170
`
`168
`
`169
`
`Quantification of Tissue Damage
`
`171
`
`Conclusions
`
`Acknowledgments
`
`References
`
`Histological and Morphological Methods
`
`Bruce M. Carlson and Robert Palmer
`
`Basic Principles Underlying Morphological Analysis
`
`Techniques of Morphological Analysis
`
`'«Ix-‘40"hevarWmmmwwmémmwmmrmlwmwmw-muwwkhx-,u1:x_
`
`
`
`mammal».va:n.w:..
`
`
`ans—cmwih."""’
`
` someuwwmJMi‘m‘a“a.a..1.
`
`
`172
`
`173
`
`173
`
`177
`
`179
`
`180
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`
`
`viii
`
`Injecrable Drug Development
`
`Electron Microscopic Methods
`
`180
`
`Histological Methods
`Histochemical Methods
`
`183
`185
`
`Immunocytochemical Methods
`
`187
`
`Neurom uscular Staining Methods
`
`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. Marcek
`
`Experimental Procedures
`Expen‘ment 1
`196
`
`Experiment 2
`
`Experiment 3
`
`Experiment 4
`
`Experiment 5
`
`Experiment 6
`
`197
`
`197
`
`197
`
`197
`
`197
`
`198
`Experiment 7
`Statistical Analyses
`Results
`
`198
`
`Discussion
`
`Applications
`
`Summary and Conclusions
`
`Acknowledgments
`References
`
`C: APPROACHES IN THE DEVELOPMENT or
`LESS—PAINFUL AND LESS-IRRI’I‘ATING INJECTABLES
`
`11.
`
`Cosolvent Use in lnjectable Formulations
`
`Susan L. Way and Gayle Brazeau
`
`Commonly Used Solvents
`
`Polyethylene Glycols
`
`219
`
`Propylene Glycol
`Ethanol
`225
`
`223
`
`190
`
`191
`
`193
`
`195
`
`198
`
`204
`
`209
`
`210
`
`211
`
`211
`
`215
`
`218
`
`“vs.Vs
`
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`
`(mmnwerwwmumcaw.w.uA41.101:va.wmzawfimms‘Nr.m
`
`
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`InnoPharma Exhibit 1101.0008
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`

`

`Contents
`
`ix
`
`.,_www.mwMv
`
`‘
`
`{
`
`z
`i
`!
`
`t
`f
`3
`i
`
`,
`l
`
`Glycerin
`
`226
`
`Cremophors
`Benzyl Alcohol
`Amide Solvents
`
`227
`228
`230
`
`Dimethylsulfoxfa‘e
`
`232
`
`Hemolytic Potential of Solvents/Cosolvents
`
`In Vitro/ln Viva Hemolysis Comparisons
`Muscle Damage
`Cosolvent-Related Pain on Injection
`Cosolvenls Known to Cause Pain
`Methods to Minimize Pain
`24.7
`
`245
`
`237
`
`Conclusions
`
`References
`
`12. Prodrugs
`
`Laszlo Prokai and Katalin Prokai-Tatral
`
`Design of Prodrugs
`
`Specific Examples of Prodrugs Developed to Improve
`Water Solubility of lnjectables
`Anticancer Agents
`273
`Central Nervous System Agents
`Other Drugs
`288
`
`283
`
`Conclusions
`
`References
`
`13. Complexation—Use of Cyclodextrins to
`Improve Pharmaceutical Properties of
`Intramuscular Formulations
`
`Marcus E. Brewsterand Thorsteinn Lofisson
`Cyclodextrins
`Preparation of Cyclodextrin Complexes
`Characterization of Cyclodextrin Complexes
`
`Use of Cyclodextrins in “VI Formulations
`Methodologies
`319
`
`{M Toxicity of Cyclodexm'ns and Their Derivatives
`
`320
`
`Use of Cyclodexm‘ns to Replace Toxic Excipiems
`in [M Formulations
`323
`
`Use of Cyclodextrins to Reduce intrinsic
`Drug~Relaled Toxicity
`326
`
`233
`
`242
`245
`
`250
`
`251
`
`267
`
`267
`
`273
`
`295
`
`297
`
`307
`
`308
`312
`313
`
`319
`
`
`
`l I
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`nnoPharma Exhibit 1101.0009
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`
`
`x
`
`Injectable Drug Development
`
`Conclusions and Future Directions
`
`Acknowledgments
`References
`
`14. Liposomal Formulations to Reduce
`Irritation of Intramuscularly and
`Subcutaneously Administered Drugs
`
`Fan‘da Kadir, Christien Oussoren, and Dean J. A. Crommelin
`
`Liposomes: A Short Introduction
`
`Liposomes as lntramuscular and Subcutaneous
`Drug Delivery Systems
`Studies on Reduction of Local Irritation
`
`Studies on the Protective Effect After
`IntramuscularAdministration
`342
`
`Studies on the Protective Effect After Intradermal and
`Subcutaneous Administration
`345
`
`Discussion
`
`Conclusions
`
`References
`
`15. Biodegradable Microparticles for the
`Development of Less-Painful and
`Less-Irritating Parenterals
`
`Elias Fattal, Fabiana Quagiia, Pramod Gupta, and Gayle Brazeau
`
`Rationale for Using Micropartictes in the Development
`of Less-Painful and Less-Irritating Parenterals
`
`PomLactide-co-Glycolide) Micropartlcles as Delivery
`Systems in the Development of Less-Painful and
`Less-Irritating Parenterals
`
`Polymer Selection
`357
`Microencapsulation Technique
`Drug Release
`366
`Sterilization
`368
`
`Residual Solvents
`
`368
`
`360
`
`Stability of the Encapsulated Drug and
`Micropam'cle Products
`369
`
`329
`
`330
`330
`
`337
`
`338
`
`340
`341
`
`349
`
`350
`
`351
`
`355
`
`356
`
`357
`
`Protection Against Myotoxicity by lntramuscularly/
`Subcutaneously Administered Microparticles
`
`370
`
`16
`
`17
`
`
`
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`
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`
`
`
`InnoPharma Exhibit 1101.0010
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`
`
`
`
`Contents
`
`xi
`
`371
`
`372
`
`379
`
`380
`
`381
`382
`
`393
`
`395
`
`395
`
`401
`
`402
`
`Conclusions
`
`References
`
`'16.
`
`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
`
`iQIi2 ili5l
`
`Propofol(Diprivan®)
`Diazepam 384
`Etomidatc
`388
`
`382
`
`Pregnanolonc (Eltonoloncfl)
`Methohcxilal and Thicpontal
`
`388
`389
`
`Amphotericin B
`
`390
`
`Clarithromycln
`
`391
`
`Challenges in the Use of Emulsions as Pharmaceutical
`Dosage Forms
`Physical Stability
`Efficacy
`393
`Dose Volume
`
`.393
`
`394
`
`Other Issues
`
`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
`
`Lam/A. Catlin and Carol A. Catlin
`
`Formulation Development
`Preformuiatlon
`402
`
`Formulation
`
`404
`
`Focus on Osmolality, Cosolvents, OHS, and pH 410
`
`pH 4:5
`
`
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`InnoPharma Exhibit 1101.0011
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`

`Injectabfe Drug Deveiopment
`
`xii
`
`
`
`Post~Formulati0n Procedures
`
`pH, Additives, and Soivents
`
`416
`
`Devices and Physical Manipulations
`
`417
`
`References
`
`Index
`
`'
`
`416
`
`420
`
`423
`
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`InnoPharma Exhibit 1101.0012
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`
`
`11
`
`Cosolvent Use in
`
`Injectable Formulations
`
`Susan L. Way
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Ridgefield, Connecticut
`
`Gayle Brazeau
`
`University of Florida
`Gainesvillc, Florida
`
`Formulators today must routinely deal with pregressively more water—
`insoluble compounds. This makes deveIOping solution dosage forms par-
`ticularly challenging. Identification and utilization of clinically acceptable
`excipientsfias well as scalable methods to formulate solubilized com—
`pounds—has been, and continues to be, a subject of great importance to
`formulation scientists
`
`One of the most common approaches used in parenteral formulation
`of water—insoluble compounds is the use of organic cosolvent systems.
`These systems utilize certain organic solvents combined with physiologi-
`cally compatible aqueous solutions. These systems are primarily used to
`provide higher solubility for poorly watensoluble compounds, which al-
`lows for these compounds to be administered in solution form, The ability
`to administer compounds in solution form by the parenteral route elimi‘
`nates particle size considerations and dissolution barriers, generally pro—
`viding for complete bioavailability of poorly absorbed and/or highly
`metabolized compounds by avoiding hepatic first—pass effects. Cosolvents
`may also be used to improve the chemical stability of compounds prone to
`hydrolytic or photolytic degradation, or occasionally to decrease the aque~
`ous solubility of a given compound when administered intramuscularly.
`’i‘here are numerous products on the market for parenteral use that utilize
`cosolvent systems. Table 11.1 lists a number of these products with their co—
`solvent compositions {Trissel 1996).
`
`
`
`3,x
`
`3 I
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`
`216
`
`Injectable Drug Development
`
`
`
`Table 11.1. Cosolvent Composition of Selected Marketed and
`lnvestigational Parenteral Products fl‘rlssel 1996)
`General Name
`Trade Name Manufacturer m Cosolvent Composition
`40% PG. 10% EtOH.
`Lanoxin®
`pH 6.8
`
`Digoxin
`
`Wellcome
`
`'D‘lmethoprim-
`sulfamethoxazole
`
`Septra‘D
`
`
`
`Phenytoin
`
`Diazepam
`
`Lorazepam
`
`Pentobarbital
`
`Chlordiazepoxide
`HCl
`
`Eleposide
`
`Miconazole
`
`Secobarbital
`sodium
`
`Dilamln®
`
`Valium®
`
`Atlvan®
`
`Nembutal®
`
` cartridge
`
`Libn'um®
`
`VePesld®
`
`MonistatG’
`
`mbex®
`
`Glaxo
`Wellcome
`
`Parke-Davis
`
`Roche
`
`Wyeth-Ayerst
`
`Abbott
`
`Roche
`
`Bristol—Myers
`Squibb
`Janssen
`
`Wyethfiyerst
`
`Nitroglycerln
`
`Nitro-Bid®
`
`Hoechst Marion
`Roussel, Abbott
`
`Multivitamins
`
`M.v.x.®-12
`
`Astra
`
`lnvestlgational
`Compounds
`S‘Amino-
`camptothecln
`
`Bryostatin
`
`
`10% DNA, pH 6.5
`Diaziqoune
`
`Abbreviations: IV: Intravenous; lM: lntramuwular; PG: propylene glycol; PEG: polyethylene glycol; EIOH:
`ethanol; BA: benzyl alcohol; DMA: dimethylacetamide
`
`60% PEG 400.
`30% dehydrated alcohol,
`10% Mean 30%
`
` Burroughs
`
`
`
`LMJV
`
`IM
`
`40% PG. 10% EtOH, 0.3%
`diethanolamlne, 1% BA
`
`40% PG, 10% EtOH, pH 12
`
`40% PG, 10% EtOH.
`1.5% BA
`
`41% PG. 9% PEG 400,
`2% BA
`
`40% PG. 10% EtOH,
`pH 9.5
`
`20% PG. 1.5% BA
`
`55% PG, 30.5% EtOH,
`3% Ween eo®. 3% BA
`
`11.5% Cremophor‘D EL
`
`50% PEG. pH 9540.5
`
`70% EtOH.
`4.5% PG
`
`30% PG, 116% Tween 80®.
`0.028% Mean :20®
`
`
`
`2% DMA. 50% PEG 400
`
`
`
`rm
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`of
`Hit
`mi
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`
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`lik-
`co
`
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`no
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`the
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`
`
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`
`InnoPharma Exhibit 11010014
`
`

`

`
`
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`”
`
`i
`
`1’—
`
`;;
`
`;
`\
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`
`Cosolvent Use in Injectable Fonnuiatmns
`
`217
`
`in terms of solubility enhancement, the use of cosolvents is one of the
`most powerful methods available to formulators. The solubilizing potential
`of cosolvents compares very favorably to other generally accepted tech—
`niques used for solubilization of water~insoiuble compounds,
`including
`micellar solubilization, complexation, prodrugs, and salt formation.
`in
`many instances, cosolvents may be the technique of choice for parenteral
`applications given that (1) micellarization using surface active agents could
`likely be problematic from an irritation/toxicity perSpective,
`(2) suitable
`complexing agents may not be appropriate for the compound of interest,
`(3) formation of either prodrugs or salt forms may not be possible for a
`given compound, and (4) appropriate cosolvent vehicle selection may re-
`duce tissue irritation.
`‘
`Numerous factors must be considered before a cosolvent system is se-
`lected. Ideally, the water-miscible organic solvent must be nontoxic; should
`cause minimal or no hemolysis, irritation, or muscle damage on injection;
`and should be nonsensitizing. The solvent should also be devoid of any in-
`herent pharmacological activity that may interfere with that of the drug it—
`self. Obviously,
`the cosolvent formulation should provide the desired
`pharmaceutical/biopharmaceutical profiles and should allow for a reason-
`able shelf life following manufacture. These solvents are rarely used undi—
`luted due in part to their inherent properties, for example, viscosity and
`tonicity. Therefore, the physicochemical properties of the cosolvent system
`must also be considered (viscosity, pH, lipOphilicity), as well as the safety of
`the various solvents used. A summary of some of the physicochemical
`properties of common solvents used in parenteral formulations is given in
`Table 11.2.
`ideally, it is best to select and use solvents that would maximize the
`solubility of the compound. Maximizing the solubility of a compound in a
`particular cosolvent system would result in lower total levels of the non-
`aqueous solvent(s) being administered to the patient, thereby lowering the
`chance for potential side effects. This will also reduce the chance of precip-
`itation of the solution on administration, which is a major concern when
`administering doses via the 1V route. There are numerous reports in the lit-
`erature regarding cosolvency theory, and potentially useful methods based
`on various physicochemi‘cal properties for predicting solubilities in various
`solvents and solvent mixtures, as well as the effects of cosolvent systems on
`the physicochemical properties of compounds solubiliZed in them (Hilde-
`brand 1916, 1917, 1919; Hildebrand and Scott 1950; Higuchi et al. 1953; E"
`monson and Goyan 1958; Moore 1958; Paruta et al. 1962, 1964; German
`Hall 1964; Fedors 1974; Martin et a1. 1980, 1982; Yalkowsky et a1. 1976
`tin and Miralles 1982; Yalkowsky and Roseman 1981; Rub‘
`Yalkowsky 1985, 1987; Yalkowsky and Rubino 1985; Rubino et al
`blue 1987, 1990,- Rubino and Berryhili 1986; RajagOpalanet a'
`son et al. 1993; Bendas et al. 1995; Darwish and Bloomfield 1995;
`
`3
`
`,
`f
`3
`
`if
`
`
`
`InnoPharma Exhibit 1101.0015
`
`

`

`beam.»
`
`
`
`218
`
`Injectable Drug Development
`
`
`
`PEG 400
`EtOH
`
`PG
`
`Benzyl alcohol
`
`Glycerin
`Water
`
`
`
`Table 11.2. Physicochemical Parameters for Commonly Used
`
`Organic Solvents (at 25°C)
`Molecular Dielectric
`Intel-facial
` Solubility
`
`
`Constant, Parameter. 8
`Tension
`
`
`(cal/c1313)
`Solvent
`E
`(dyne/cm)
`
`
`
`DMF
`36.73
`
`DMA
`37.8a
`4.63
`
`13.63
`
`24.33
`
`3205(3)“)
`
`13.1d
`
`
`42.58
`
`78.53
`
`DMSO
`46. 7a
`
`Dec: decommsition
`a: Rubino and Yalkowsky11987l
`b: Budavari 11989)
`c.- Wade and Weller (1994)
`d: Weast and have (1967)
`
`11.73
`0.58
`
`12‘43
`
`——
`
`32.7la
`45.66'
`
`Wang and 1
`Academy 0
`lightly et al.
`1990; Doeni
`
`rooqui et 3!,
`high doses -
`of different
`
`portant to l
`tolerated sol
`
`pediatric pa
`Gershanik e
`al. 19901 Su
`sures for or
`
`presented in
`should be us
`der to avoic
`though they
`on the pump»
`certain orga
`
`logical studiv
`following dis
`the literature
`
`Polyether
`
`PEGs are poi
`
`
`
`
`where n repr '
`
`lgnated by a
`weight for a
`molecular we
`mers are real
`
`enteral dosag
`
`tyF
`products,
`Weller 1994).
`
`irritating. Tht
`toxicological V
`1982).
`PEGS he
`
`(CNS) effects
`et al. 1979}.
`mice with 15
`
`l‘
`
`al. 1995). Therefore, this chapter focuses more on the conventional solvents
`and use levels encountered in parenteral dosage forms, safety/toxicity of
`these cosolvents, and ways in which to minimize cosolvent-related side
`effects.
`
`COMMONLY USED SOLVENTS
`
`There are numerous solubilizing agents available to formulators, particu-
`larly for use in preclinical work. How/ever, the solubilizers available to for-
`mulators for use in humans are considerably more limited, usually on the
`basis of available safety/toxicity data. The most common organic solvents
`encountered in cosolvent systems for human clinical/commercial use in-
`clude PEG 400, PG, glycerol, and ethanol. In general, these solvents are
`considered to possess a low order of toxicity This is essential, and obvious,
`since parenteral administration can result in fairly large amounts of these
`solvents being placed in the body over a short period of time.
`Although the solvents used in cosolvent formulations are generally
`considered to be of low orders of toxicity, there have been numerous rev
`ports of adverse effects related to the vehicles themselves (Carpenter 1947;
`
`
`
`InnoPharma Exhibit 1101.0016
`
`

`

`
`
`
`
`iv
`‘5
`
`iZ 5
`
`,~§
`
`Cosoivent Use in injectable Formulations
`
`219
`
`Wang and Kowal 1980,- Singh et al. 1982; Smith and Dodd 1982; American
`Academy of Pediatrics Committee on Drugs 1985; Demey et al. 1988; Go-
`lightly et al. 1988; Lolin et al. 1988; Andersen et a1. 1989; Napke and Stevens
`1990; Doenicke et al. 1992; Rhodes et al. 1993; Windebank et al. 1994; Fa-
`
`rooqui et al. 1995) These adverse effects may result from administration of
`high doses of a single cosolvent formulation or concurrent administration
`of different formulations that contain similar cosolvent systems. It is imv
`portant to note that any side effects associated with these usually well«
`tolerated solvent systems may be much more serious when administered to
`pediatric patients {Sweet 1958; Martin and Finberg 1970; Brovm et a1. 1982;
`Gershanik et all 1982, Lurch et al. 1985; MacDonald et ai. 1987; Huggon et
`ai. 1990). Summaries of single dose LD50 values and reported human expo~
`sures for organic solvents commonly used in parenteral formulations are
`presented in Tables 11.3 and 11.4. It has been suggested that these solvents
`should be used at levels oi‘ no more than 25 percent of the LDSO value in or-
`der to avoid any unwanted pharmacological or toxicological effects, al-
`though they may he used at considerably higher concentrations depending
`on the purpose of the study (Bartsch et a1. 1976). Others recommend that
`certain organic solvents should not be used in pharmacological or toxico—
`logical studies at concentrations above 10 percent {Singh et al. 1982). The
`following discussion addresses the reported safety/toxicity data reported in
`the literature for many of the solvents used in parenteral formulations.
`
`Polyethylene Glycols
`
`PEGS are polymers of ethylene oxide with the general formula
`
`HO«CH2v(CH2—O~CH2),{CH20H
`
`where n represents the number of oxyethylene groups. The PEGS are des-
`ignated by a numerical value, which is indicative of the average molecular
`weight for a given grade. Molecular weights below 600 are liquids, and
`molecular weights above 1,000 are solids at room temperature. These poly~
`mers are readily soluble in water, which make them quite useful for par-
`enteral dosage forms. Only PEG 400 and PEG 300 are utilized in parenteral
`products,
`typically at concentrations up to 30 percent (v/vl (Wade and
`Weller 1994). These polymers are generally regarded as nontoxic and non-
`irritating. There are numerous reviews regarding the pharmaceutical and
`toxicological properties of these polyols (Smyth et a]. 1950; Rowe and Wolf
`1982i
`
`PEGs have been shown to possess marked central nervous system
`(CNS) effects following IV administration (Lockard and Levy 1978; Lockard
`et al. 1979). Klugmann and coworkers (1984) found that pretreatment of
`mice with 15 percent PEG 400 at 20 mng given three hours prior to the
`
`
`
`InnoPharma Exhibit 11010017
`
`iii
`ioti
`,5
`:3
`
`

`

`
`
`
`
`
`
`EIOH
`
`Glycerin
`
`DMA
`
`
`
`
`
`2.3—3.5
`
`2.5-3.0
`
`2.8—4.4
`
`2.8—3.5
`
`2.642
`
`4.4411
`
`»
`
`3.4—7.6 8240.1
`
`
`
`DMF
`
`. 1.2-5.9
`
`Crema-
`phor‘D EL
`DMSO
`
`2643.9
`
`BA
`
`1.0
`
`0.9"
`
`< 0.52
`
`> 52
`
`220
`
`Im'ectable Drug Development
`
`Table 11.3. Single Dose LDSO Values in Rodents for Various Organic
`Solvents Commonly Encountered in Parenteral Formulations
`
`Parenteral L050 Values (g/kg) for Various Species
`m References
`ip
`iv
`1p
`sc
`iv
`
`Solvent
`PEG 300
`
`PEG 400 13.2—14.5
`
`PG
`
`9.6414
`
`
`
`
`17
`
`7.1
`
`Rawe and Wolf(1982);
`Carpenter and Shaffer
`(1952)
`
`V
`
`8.6
`
`2,344.7
`
`6.6»80 6.7435
`
`4.7—7.3 Budden et a1. (1978);
`Rowe and Wolf (1982}:
`Bartsch et al. {1976)
`6.4—6.8 Davis ahd Jenner (1959);
`Bartsch et al. (1976);
`Latven and Molitor (1939)
`
`1.2—3.2
`
`8340.5 2.0—2.5
`
`4.1~5.0
`
`8.7—9.0 009-100 4.3-6.2
`
`8.7
`
`0.10
`
`
`
`1.4—1.8 Latven and Molitor£1939h
`Bartsch et a]. (1976):
`"Irémoliéres and Lowy
`(1964)
`Budden etal.(1978);
`Anderson et a]. (1950);
`Bartsch et at (1976);
`Tao et al. (1983)
`
`5.6
`
`Latveneta1.(1939);
`
`5.3 2.6-4.8 Davis and Jenner (1959);
`Sherman et al.11978}.
`Bartsch et al. (1976);
`Auclalr and Hameau (1964);
`Wiles and Narcisse {1971);
`Thiersch (1962)
`
`6.1 2.8-5.7 Davis and Jenner {1959);
`Bartsch et al. (1976);
`
`Wiles and Narcisse {1964);
`Theirsch (1962)
`
`AuclairandHameau(1964);
`
`BASF (1988)
`
`5.4—8.1 Bansch et a! (1976);
`Wiles and Narcisse11971);
`Willson et at. (1965)
`
`0.05—
`
`0.08 McCloskey et a]. (1986);
`> 41.6 Kimura et 3111971}
`
`
`
`i
`
`9.
`E,
`1
`:_
`‘
`
`3
`
`f
`
`g
`
`1x
`1
`‘
`
`f
`
`References
`
`E
`56
`
`
`(1within2—3hnost'
`
`
`
`2040?.»solutions.whichcleare
`10to40%solutions
`
`Hemog
`
`
`
`ClinicalObservations
`
`AdministeredAs
`
`lobinuriaobservedfollowingadministrationof
`
`
`
`
`
`
`
`InnoPharma Exhibit 1101.0018
`
`

`

`
`
`Table 11.4. Human Exposures to Selected Organic Solvents Commonly Encountered in Parenteral Formulations
`References
`Solvent
`Dose
`Route
`Administered As
`Clinical Observations
`
`DMSO
`‘1 gm/kg
`IV
`10 to 40% solutions
`Hemoglobinuria observed following administration of
`20-40% solutions, which cleared within 2—3 h post:
`infusion; No indication of shonoterm nephrotoxicity
`following evaluation of betaozvmicroglobulin.
`
`
`
`
` 5 to 10 min
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DMA
`
`100-610
`mg/kg/day
`for 2—5 days
`
`W
`
`10% solution
`administered over
`
`Crcmo-
`ph0r® EL
`
`2-20 mi.
`
`N
`
`incremental doses
`administered every
`4 min, each over a
`30 sec period
`
`PG
`
`BA
`
`5—21 g/day
`
`lV
`
`130—405
`mg/kg/day
`
`lV
`
`Administered as an
`infusion over a
`4 h period
`0.9% BA
`(bacterlostatic
`concentration)
`
`Dose-related side effects included nausea and vomiting
`within ‘14 h of administration, anorexia; liver toxicity
`as indicated by increased SGOT levels {5—7 days after
`start of therapy), returning to normal within 2—5 days
`after achieving peak levels; altered CNS function—m
`depression, lethargy, confusion, hallucinations—
`returning to normal within several days after therapy;
`hypotension and high fever observed at high doses
`
`Small transient fall in blood pressure and rise in
`pulse rate following each dose. No marked changes
`in respiratory rate and no consistent alterations in
`central venous pressure observed. Statistically
`significant effects only observed alter the 20 ml. dose.
`
`No alterations in plasma Osmolality, free hemoglobin,
`or haptoglobin.
`
`Bennett and Muthcr
`(1981)
`
`Weiss et at (1962)
`
`Savege et al. (1973)
`
`Speth et a1. (1987)
`
`Neonates: Progressive metabolic acidosis, bradycardia,
`gasping respirations. seizures, and subsequent death in
`low birth weight neonates.
`.
`Adults: No clinically significant changes observed in
`healthy males (hematology, vital signs, electrocardiograms,
`EEG, laboratory parameters), shown to be as well
`tolerated as same formulation preserved with parabensv
`
`Brown et al. (1982);
`Santiero (1989);
`Evens (1975);
`Gershanik (1982):
`Novak et al; (1972)
`
`
`
`
`
`
`
`suoltemuuodamalgam;u;canins/nosey
`
`122
`
`
`
`W‘ w...” “.0”, mm». «no...
`u M~«..N‘.IWM
`
`
`InnoPharma Exhibit 1101.0019
`
`

`

`
`
`
`
`~ ~
`
`
`
` ‘Ltmu
`
`3
`
`,w
`
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`i
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`f
`Q
`i
`
`i
`
`222
`
`Injectable Drug Development
`
`administration of adriamycin (a potent antineoplastic agent] resulted in al-
`leviation of some of the toxicity associated with the compound. They also
`showed that PEG 400 decreased both the acute high«dose and chronic low-
`dose adriamycin-associated lethality, as well as afforded protection against
`cardiomyopathy—one of the dose-limiting side effects observed in patients.
`
`Additionally, PEG 400 did not interfere with the antitumor activity of the
`
`compound. Laine et al. (1995} reported nephrotoxicity due to PEG 400 sec-
`ondary to chronic high-dose intravenous administration of lorazepam.
`PEG 300, PEG 400, and PEG 4000 administered intraperitoneally have
`been shown to have adverse effects onrat gastrointestinal physiology (Cho
`et al. 1992). The PEGs caused a decrease in gastric mucosal blood flow
`(GMBF) as well as gastric secretory function. They also exacerbated
`ethanol‘induced gastric damage in a dose-dependent manner. The gastric
`damage appeared to be inversely related to molecular weight (PEG 300 >
`PEG 400 > PEG 4000). Other investigators have shown that the P865 affect
`cardiovascular and autonomic systems. PEG 300, PEG 400, and PEG 600
`administered intravenously and intra-arterially to dogs produced a dose-
`dependent enhancement of the blood pressure response to epinephrine
`and acetylcholine (Hellman et al. 1972). PEG 300 has also been implicated
`as the causative agent responsible for fatalities and near fatalities due to se—
`vere metabolic acidosis in patients (Sweet 1958).
`Smith and Cadwallader (1967) evaluated the behavior of erythrocytes
`in PEG—water solutions. They observed that solutions of PEG 300 in water
`were hemolytic. They also observed that solutions of water—PEG 400 or
`water—PEG 600 could afford some protection from hemolysis. They con-
`cluded that polyethylene glycols could protect both rabbit and human ery-
`throcytes in the order (MW): 200 < 300 < 400 < 600. The ability of the PEGs
`to contribute to the tonicin of the resulting solutions was also observed to
`be inversely related to molecular weight—40w molecular weight PEGS con-
`tributed to tonicity, and the higher molecular weight species did not. They
`suggested that this lack of contribution to tonicity was related to decreased
`membrane permeability of the higher molecular weight species.
`Nishio and coworkers (1982) investigated the effects of PEG 300 and
`PEG 400 on erythrocytes. They showed that incubation of erythrocyte sus-
`pensions in the presence of PEG~saline solutions resulted in the release of
`potassium ions and hemoglobin. They found that hemolysis and potassium
`ion loss decreased with increasing concentrations of P863, and that no loss
`was observed in iso-osmotic and hyperosmotic concentrations following a
`2 min incubation time. However, longer incubation times (through 2 h) re-
`sulted in potassium loss and hemolysis in iso~osmotic and hyperosmotic so-
`lutions (PEG 300 > PEG 400).
`Fort and coworkers (1984) evaluated the hemolytic potentials of mix~
`tures of ethanol and water or saline with PEG 400 by both in vitro and in
`vivo methods. They showed that 3 PEG 400:ethanol:water mixture of 3:2:5
`resulted in no hematuria in vivo in rats, while partial hemolysis was
`
` W I
`
`nnoPharma Exhibit 1101.0020
`
`

`

`
`
`(Insolvent Use in Injectable Fonnulations
`
`223
`
`observed in vitro using dog blood. All other mixtures resulted in hematuria
`a