`
`INJECTABLE DRUG
`DEVELOPMENT
`
`1
`
`TECHNIQUES To REDUCE
`PAIN AND IRRITATION
`
`
`
`
`
`
`.-.~,.~......w,..4.......‘..::._...x.........~...,...,M.........~.‘
`
`Edited by
`
`Pramod K. Gupta
`
`and
`
`Gayie A. Brazeau
`
`|nnoPharma Exhibit 1101.0001
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` Q E1E
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`Informa Healthcare USA. inc.
`52 Vanderbilt Avenue
`New York. NY 10017
`
`0 2008 by lnforma Healthcare USA, Inc. (original copyright 1999 by lnterpharm Press)
`Informa Healthcare is an Informa business
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`No claim to original U.S. Government works
`Printed in the United States of America on acid-free paper
`10 9 8 7 6 5 4 3 2
`
`International Standard Book Number-10: 1-5749-1095-7 (Hardcover)
`International Standard Book Number-13: 978~l~S749-1095-7 (Hardcover)
`
`»
`
`Prefacl
`
`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 validityoi
`all materials or for the consequences of their use.
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`No part ofthis book may be reprinted, reproduced. transmitted. or utilized in any form by any electronic. mechanical, 01-
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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-Publication Data
`
`injectable drug development : techniques to reduce pain and irritation I
`edited by Pramod K. Gupta and Gayle A. Brazeau.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN-13: 978-1-5749-1095-7 (hardcover : alk. paper)
`ISBN-10: 1-5749-109557 (hardcover: alk. paper)
`1. Injections. 2. Injections--Complications. 3. Drug development. i. Gupta. Pramod K.. 1959—. ll.
`Brazeau, Gayle A. 1’DNLM: 1. injections-«adverse effects. 2 Pain--chemically induced. 3. Pain»
`prevention 8: control. 4. Pharmaceutical Preparationsnadministration & dosage. WB 354 156 1999}
`RM1i69.l-4-9 1999
`99-2691 1
`‘
`61516-dc2l
`
`
`Visit the inform: Web site at
`www.informa.com
`
`and the lnforma Healthcare Web site at
`www.informahealthcare.c0m
`
`EC‘)
`
`-r-it-'t7"1'1(/if/l7‘U3C'l
`
`
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`|nnoPharma Exhibit 1101.0002
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`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Editors and Contributors
`
`xiii
`
`xiv
`
`L
`
`xv
`
`A: BACKGROUND OF PAIN, IRRITATION, AND/OR
`Muscuz DAMAGE wrm INJECTABLES
`
`1.
`
`Challenges in the Development of
`Injectable Products
`
`Michael J. Akcrs
`
`General Challenges
`
`Safety Concerns
`
`Microbiological and Other Contamination Challenges
`
`Stability Challenges
`
`Solubility Challenges
`
`Packaging Challenges
`
`Manufacturing Challenges
`
`Delivery/Administration Challenges
`References
`
`3
`
`4
`
`5
`
`6
`
`8
`
`10
`
`11
`
`11
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`13
`14
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`iii
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`|nnoPharma Exhibit 11010003
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`5
`I
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`iv
`
`2.
`
`Injectable Drug Development
`
`Pain, Irritation, and Tissue Damage
`with Injections
`
`Wolfgang Klement
`
`L
`Must Injections Hurt?
`Mechanisms of Pain and Damage
`Routes of Drug injection
`Cutaneous/Subcutaneous Injections
`Intramuscular Injections
`22
`Intra—arter:'al Injections
`24
`Intravenous Injections
`26
`Conclusions and Perspectives
`Acknowledgements
`References
`
`18
`
`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 Production
`
`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
`
`Microclialysis Studies of Individual Muscles
`
`64
`
`Cellular Stress Response
`
`65
`
`Techniques to Assess the Mechanisms of Muscle Damage
`Models of Muscle Damage
`661
`Techniques to Show Changes in Muscle Calcium Content
`Markers of Increased Free Radical Activity
`67
`Methods ofMeasuring Cellular Energy Levels
`67
`Conclusions
`Acknowledgments
`References
`
`15
`
`15
`16
`18
`
`49
`S0
`50
`
`57
`
`57
`
`57
`
`58
`
`62
`
`66
`
`66
`
`67
`67
`68
`
`4.
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`5_
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`I
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`i
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`E
`E
`E
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`E
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`Contents
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`v
`
`8: METHODS T0 Assess PAIN, IRRITATION, AND
`MUSCLE DAMAGE FOLLOWING Imecnoms
`
`2
`
`f
`
`4.
`
`In Vitro Methods for Evaluating
`Intravascular Hemolysis
`
`Joseph F. Krzyzaniak and Samuel H. Yaikowsky
`
`Significance
`
`In Vitro Methods for Evaiuating 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 Modeis
`Steven C. Sutton
`Edema and Inflammation
`Lesion Models
`Rabbit
`92
`Mice
`96
`
`Rat
`96
`Biochemical Models
`Serum Glutamic-Oxaloacetic Transaminasc
`
`97
`
`N-Acety!-B-Glucosaminidase
`
`97
`
`97
`98
`
`Myeloperoxidasc
`Creatinc Kinase
`Edema Models
`105
`Inducing Edema
`Exudative Models of Inflammation
`
`Vascular Permeability Modeis
`
`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 Foofpad Edema Model
`Rabbit Lesion Versus Rat CK Model
`109
`Rat and Human
`110
`
`109
`
`
`
`
`
`-.um«...rm.rm«-~,-:v..w.«n........~.-..-up-—¢-.~mn~mmm.~ ».w..mm~m_%__.*.*¥¢
`
`77
`
`78
`
`79
`
`85
`
`86
`
`87
`
`91
`
`91
`92
`
`97
`
`1
`
`105
`
`10?
`
`5
`;,.
`.5
`
`_
`AV
`
`‘
`
`T‘
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`.,...4
`
`.
`
`H
`1' 10
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`n»~,~p-wrung»:,:.wu.
`
`vi
`
`Injectable Drug Development
`
`Models for Extended~Release Formulations
`
`Predicting Afuscle Damage from
`Extended~Re1ease 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 Bioavailability
`Formulation
`113
`
`113
`
`Conclusions
`
`References
`
`Rat Paw-Lick Model
`
`Pramod K. Gupta
`
`Methodology
`Correlation Between Rat Paw-Lick and Other
`Pain/Irritation Models
`
`Application of Rat Paw—l.ick Model to Screening
`Cosolvent-Based Formulations Mb
`Limitations of the Rat Paw-Lick Model
`
`Concluding Remarks
`References
`
`Radiopharmaceuticais for the Noninvasive
`Evaluation of Inflammation Following
`Intramuscular Injections
`
`Agatha Feltus, Michael Jay, and Robert M. Beihn
`
`Gamma Scintigraphy
`Gamma Cameras
`Detectors
`133
`
`Collimators
`
`135
`
`Electronics and Output
`
`136
`
`Computers
`
`137
`
`Tomographic Imaging
`
`139
`
`139
`Quality Control
`Radionuclides and Radiation
`
`Scintigraphic Detection of Inflammation
`
`110
`
`112
`
`114
`
`115
`
`119
`
`120
`
`120
`
`123
`
`126
`
`128
`
`128
`
`131
`
`132
`
`132
`
`140
`141 '
`
`
`
`
`
`
`
`;.«..’f~l.K4D\U;-~n«~w";-moM.»-vi-son;-,1¢¢-,~'e.v-»(x.oeo«M~fi1-m*_¢sQ~««n«\~vo-ow‘:-vqactvun:vum
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`Contents
`
`vii
`
`Galllum~6?
`
`14‘?
`
`Radlolabcled Leukocytes
`Radiolabeled 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
`
`165
`
`General Considerations in the Optimizan'on of Expenmental
`Cell Culture Systems
`166
`
`
`
`
`
`
`
`.«....-....c.z-.3...ll.’~..o.«o.«Lu
`
`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
`
`
`
`“"—v&»..:xufl~v,vo~;v-’V:u'rx-/.7-u«qnv-wevarNvnnflvrnnm«O0:‘kucvvqwnmata-g~nuuawcv~unwwuI:w~wKn:p?mw|$vJun~uwavIuvIvaIW¢A2.1~'U»A¢~1».,~.».~».
`
`
`
`......cum..v-'1
`
`
`
`V79aafio.-¢..:«.....«.u;¢...»»«..«:..'..~.:.u.a....;.».uh...
`
`
`172
`
`173
`
`173
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`177
`
`179
`
`180
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`viii
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`Injecrabfe Drug Development
`
`Electron Microscopic Methods
`
`180
`
`Histological Methods
`Histochemical Methods
`
`183
`185
`
`Immunocytochemical Methods
`
`187
`
`Neurom uscular Staining Methods
`
`189
`
`Summary of Strengths and Limitations of
`Morphological Techniques in Assessing
`Muscle Damage After Injections
`References
`
`10.
`
`Conscious Rat Model to Assess Pain
`
`Upon Intravenous Injection
`John M. Marcek
`
`Experimental Procedures
`Experfment 1
`I96
`
`Experiment 2
`
`Experiment 3
`
`Experiment 4
`
`Experiment 5
`
`Experiment 6
`
`197
`
`197
`
`197
`
`197
`
`197
`
`198
`Experiment 7
`Statistical Analyses
`Results
`
`198
`
`Discussion
`
`Applications
`
`Summary and Conclusions
`
`Acknowledgments
`References
`
`C: APPROACHES IN THE DEVELOPMENT or
`LESS-PAINFUL AND LESS—IRRITATlNG INJECTABLES
`
`11.
`
`Cosolvent Use in lnjectable Formulations
`
`Susan L. Way and Gayle Brazeau
`
`Commonly Used Solvents
`
`Polyethylene GI;/cols
`
`219
`
`Propylene Glycol
`Ethanol
`225
`
`223
`
`190
`
`191
`
`‘I93
`
`195
`
`198
`
`204
`
`209
`
`210
`
`211
`
`211
`
`215
`
`218
`
`-><.u,«:I‘¢».-A'wo‘Ylv¢10~c7!$t‘w:.u,;rsu.as.4.
`
`
`«A“\M¢h.ntQ\'>’1A‘«9f‘nPi>‘t'VU|31Mawrat‘.un44,..:nv,-.nt—v-vv.r.>v:~ny~za;v»uo~n.~“..u»»\.1‘-..cI.A»
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`Contents
`
`ix
`
`Glycerin
`
`226
`
`Cremophors
`Benzyl Alcohol
`Amide Solvents
`
`227
`228
`230
`
`Dimethylsulfoxfde
`
`232
`
`Hemolytic Potential of Solvents/Cosolvents
`
`In Vitro/In Viva Hemolysis Comparisons
`Muscle Damage
`Cosolvent—Related Pain on injection
`Cosolvents Known to Cause Pain
`Methods to Minimize Pain
`24.7
`
`245
`
`237
`
`Conclusions
`
`References
`
`12. Prodrugs
`
`Laszlo Prokai and Katalin Prokai-Tatrai
`
`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 Cyclodextrlns 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 WI Formulations
`Methodologies
`319
`
`320
`
`{M ToxicityofCyclodextrinsand TheirDerivatives
`Use ofCyclodcxtrins to Replace Toxic Excipients
`
`in {M Formulations
`
`323
`
`Use of Cyclodextrins to Reduce intrinsic
`Drug-Related Toxicity
`326
`
`
`
`-,..'4‘/."'r‘k~‘Q1/YM.
`
`‘
`
`i
`
`{
`E
`E
`
`E
`I
`3
`Q
`,
`l
`
`f
`k
`
`233
`
`242
`245
`
`250
`
`251
`
`267
`
`267
`
`273
`
`295
`
`297
`
`307
`
`308
`312
`313
`
`319
`
`
`
`i |
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`nnoPharma Exhibit 1101.0009
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`
`
`x
`
`Injectabfe Drug Development
`
`Conclusions and Future Directions
`
`Acknowledgments
`References
`
`14. Liposomal Formulations to Reduce
`Irritation of Intramuscularly and
`Subcutaneously Administered Drugs
`
`Farida Kadir, Christien Oussoren, and Dean J. A. Crommelin
`
`Liposomes: A Short Introduction
`
`Liposomes as Intramuscular and Subcutaneous
`Drug Delivery Systems
`Studies on Reduction of Local Irritation
`
`Studies on the Protective Effect Afier
`IntramuscularAdministration
`342
`
`Studies on the Protective Effect After Inrradermal and
`Subcutaneous Adminfstration
`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 Braze-an
`
`Rationale for Using Micropartickes in the Development
`of Less-Painful and Less-Irritating Parenterals
`
`Poiy(Lactide-co-Glycolide) Microparticles as Delivery
`Systems in the Development of Less-Painful and
`Less-Irritating Parenterals
`
`Polymer Selection
`357
`Microencapsuiarion Technique
`Drug Release
`366
`Sterilization
`368
`
`Residual Soivents
`
`368
`
`360
`
`Stability of the Encapsulated Drug and
`Microparticfe Products
`369
`
`329
`
`330
`330
`
`337
`
`338
`
`340
`341
`
`349
`
`350
`
`351
`
`355
`
`356
`
`357
`
`Protection Against Myotoxicity by intramuscularlyl
`Subcutaneously Administered Microparticles
`
`370
`
`16
`
`17
`
`
`
`,\.,;.,;-.v...-e.-_;...,,~.~,.1._._
`
`ur
`
`
`
`v>._..»».vl<h-‘iv’,~.-»,;»_~;.;:v
`
`
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`|nnoPharma Exhibit 1101.0010
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`
`Contents
`
`xi
`
`371
`
`372
`
`379
`
`380
`
`381
`382
`
`393
`
`395
`
`395
`
`401
`
`402
`
`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
`
`iIi3 5i
`
`.z23
`
`PropofoI(Di'pr:'van®)
`Diazepam 384
`Etomidate
`388
`
`382
`
`Prognanolonc (Eltunolone@)
`Mothohexilal and Thioponta!
`
`388
`389
`
`Amphotericin B
`
`390
`
`Clarithromycin
`
`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 01:
`LESS-PAINFUL AND LESS-IRRITATING INJECTABLES
`
`17.
`
`Formulation and Administration Techniques
`to Minimize Injection Pain and Tissue
`Damage Associated with Parenteral Products
`
`LarryA. Catlin and Carol A. Catlin
`
`Formulation Development
`Prcformuiation
`402
`
`Formulation
`
`404
`
`Focus on Osmolality, Cosolvents, Oils, and pH 410
`
`pH 4:5
`
`
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`|nnoPharma Exhibit 1101.0011
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`Injectable Drug Deveiopmem‘
`
`xii
`
`
`
`P0st~Formulati0n Procedures
`
`pH, Additives, and Solvents
`
`416
`
`Devices and Physical Manipulations
`
`417
`
`References
`
`Index
`
`"
`
`416
`
`420
`
`423
`
`
`
`''‘'I»»‘\.-.‘..x,<,Maw."t-Va:x«a~«~s~rm...«..«~u4.~-
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`|nnoPharma Exhibit 1101.0012
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`11
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`Cosolvent Use in
`
`Injectable Formulations
`
`Susan L. Way
`
`Boehringer Ingclheim Pharmaceuticals, Inc.
`Ridgefieid, Connecticut
`
`Gayle Brazeau
`
`University of Florida
`Gainesvillc, Florida
`
`Formulators today must routinely deal with progressively more water—
`insoluble compounds. This makes developing solution dosage forms par-
`ticularly challenging. Identification and utilization of clinically acceptable
`excipients——as 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 water-soluble 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~
`nus solubility of a given compound when administered intramuscularly.
`‘there are numerous products on the market for parenteral use that utilize
`cosolvent systems. Table 11.1 lists a number of these Ptoducts with their co-
`solvent compositions {Trissel 1996).
`
`
`
`5>
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`3 |
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`
`Injectable Drug Development
`
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`Table 11.1. Cosolvent Composition of Selected Marketed and
`lnvestigational Parenteral Products {Trlssel 1996)
`General Name
`Trade Name Manufacturer M Cosolvent Composition
`40% PG. 10% EIOH.
`I.anoxin®
`Burroughs
`Wellcome
`pH 6.8
`
`Digoxin
`
`IM.IV
`
`
`
`Tl*lme:hoprim-
`sulfamethoxazole
`
`Sept:-a@
`
`Phenytoin
`
`Diazepam
`
`Dilamln®
`
`va:mm®
`
`Glaxo
`Wellcome
`
`Parke-Davis
`
`Roche
`
`Lorazepam
`
`Ativan®
`
`Wyeth-Ayerst
`
`Pentobarbital
`
`Nembutal®
`
`Abbott
`
`40% PG. 10% EtOH, 0.3%
`dlethanolamlne, 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
`
`Chlordiazepoxide
`HCI
`
`Etoposide
`
`Miconazole
`
`Secobarbltal
`sodium
`
`Nit:-oglycerln
`
`Libn'um®
`
`VePesid‘9
`
`Monistat@
`
`'mbex®
`cartridge
`
`Nitro-Bid”
`
`Roche
`
`IM
`
`20% PC. 1.5% BA
`
`Bristol—Myers
`Squibb
`Janssen
`
`Wyeth-Ayerst
`
`55% PG. 30.5% 13:011.
`3% Tween 303’. 3% BA
`
`11.5% Cremophor@ El.
`
`50% PEG. pH 9.5—‘lO.5
`
`Hoechst Marion
`Roussel, Abbott
`
`70% EtOH.
`4.5% PG
`
`Multivitamins
`
`M.V.I.®-12
`
`Astra
`
`30% PC, 1.6% Tween 803.
`0.028% Tween 200
`
`rm
`
`of
`nit
`mi
`ma
`
`3?
`lik-
`co
`
`(3)
`gn
`
`lec
`ca»
`an
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`he
`sel
`
`ab
`lut
`tot
`ml
`the
`
`pr:
`Ta]
`
`s
`s
`
`sol
`
`aq~
`ch:
`ita'
`ad:
`ere
`on
`
`sol
`the
`bra
`mc
`
`Ha
`tin
`Ya}
`bin
`so:
`
`Investigations)
`Compounds
`9-Amino-
`camptothecin
`
`Bryostatin
`
`
`10% DMA, pH 6.5
`Diaziqoune
`
`Abbreviations: IV: Intravenous; IM: Intramuscular; PG: propylene glycol; PEG: polyethylene glycol; Et0H:
`ethanol; BA: benzyl alcohol; DMA: dimethylacetamide
`
`2% DMA. 50% PEG 400
`
`60% PEG 400.
`30% dehydrated alcohol,
`10% Tween 80%
`
`
`
`
`
`|nnoPharma Exhibit 1101.0014
`
`
`
`
`
`—
`,
`
`»
`
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`[;
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`;
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`
`Cosolvent Use in Injectable Formulations
`
`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/biopharmaceuticaI 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 cosoivent 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 IV route. There are numerous reports in the lit-
`erature regarding cosolvency theory, and potentially useful methods based
`on various physicochemical 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 (l~lilde-
`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 al. 1980, 1982; Yalkowsky et al. 1976
`tin and Miralles 1982; Yalkowsky and Roseman 1981; Rub‘
`Yalkowsky 1985, 1987; Yalkowsky and Rubino 1985; Rubino et al
`bino 1987, 1990; Rubino and Berryhill 1986; Rajagopalanet a’
`son et al. 1993; Bendas et al. 1995; Darwish and Bloomfield 1995;
`
`3
`
`,
`3
`1
`
`@
`
`
`
`|nnoPharma Exhibit 1101.0015
`
`
`
`
`
`
`4.63
`
`11.73
`0.55
`
`12. 43
`
`-
`
`32.?“
`45.63
`
`37.83
`
`13.63
`24.33
`
`32.0“(20°l
`
`13.1“
`
`
`
`42.53
`78.53
`
`DMA
`
`PEG 400
`E(OH
`
`PG
`
`Benzyl alcohol
`
`Glycerin
`Water
`
`Wang and l
`Academy 0
`lightly et al.
`1990; boeni
`
`rooqui et al.
`high doses -
`of different
`
`portant to l
`tolerated so.
`
`pediatric pa
`Gershanik e
`al. 1990). Su
`sures for or
`
`
`
`"5
`E
`
`‘
`
`é
`
`E
`
`presented in
`should be us
`der to avoic
`
`though they
`on the purpc
`certain orga
`logical studi»
`following dis
`the literature
`
`Polyethyle
`
`PEGS are poi
`
`where n repr '
`
`ignated by a
`weight for a
`molecular we
`mers are real
`
`enteral dosag
`
`pr0duCtS.- WE
`Weller 1994).
`
`irritating. Tht
`toxicological V
`1982}.
`PEGS he
`
`(CNS) effects
`et al. 1979}.
`mice with 15
`
`1‘
`
`218
`
`Injectable Drug Development
`
`
`
`Table 11.2. Physicochemical Parameters for Commonly Used
`
`Organic Solvents (at 25°C)
`Molecular Dielectric
`lnterfacial
` Solubility
`
`Constant, Parameter. 8
`Tension
`
`2
`(cal/cm3)
`(dyne/cm)
`
`
`DMF
`36.73
`
`
`DMSO
`46. 73
`
`Dec: decomposition
`a: Rubino and Yalkowslzy (1987)
`b: Budavari (1989)
`c.- Wade and Weller (1994)
`d: Weast and Tbve (1967)
`
`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. However, 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 re
`ports of adverse effects related to the vehicles themselves (Carpenter 1947;
`
`
`
`|nnoPharma Exhibit 1101.0016
`
`
`
`
`
`
`
`§3
`-z
`
`i2 5~
`
`$ 3ilQ
`
`—,atV
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`it
`
`Cosolvent Use in lnjectable Formulations
`
`219
`
`Wang and Kowal 1980; Singh et al. 1982; Smith and Dodd 1982; American
`Academy of Pediatrics Committee on Drugs 1985; Derney et al. 1988; Go
`lightly et al. 1988; Lolin et al. 1988; Andersen et al. 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 im«
`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; Brown et al. 1982;
`Gershanik et al. 1982, Lorch et al. 1985; MacDonald et al. 1987; Huggon et
`al. 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 of no more than 25 percent of the LD50 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 al. 1976). Others recommend that
`certain organic solvents should ‘not be used in pharmacological or toxico-
`logical studies at concentrations above 1.0 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«CH2—(CH2—O-CH2),,vCH2OH
`
`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/v) (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 al. 1950; Rowe and Wolf
`1982).
`
`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 ml./kg given three hours prior to the
`
`
`
`|nnoPharma Exhibit 1101.0017
`
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`
`
`
`Injectable Drug Development
`
`220
`
`Table 11.3. Single Dose LD50 Values in Rodents for Various Organic
`Solvents Commonly Encountered in Parenteral Formulations
`
`Parenteral LD5o Values (9/kg) for Various Species
`T W
`ip
`iv
`ip
`sc
`
`iv
`
`References
`
`Solvent
`
`PEG 300
`
`17
`
`7.1
`
`Rowe and Wolf (1982);
`Carpenter and Shaffer
`(1952)
`
`V
`
`PG
`
`9.6—11.4
`
`EIOH
`
`1.2-3.2
`
`8.3-10.5
`
`8.6
`
`2,344.7
`
`6.&~8.0 6.7~13.5
`
`2.0-2.5
`
`4.i~5.0
`
`Glycerin
`
`3.7.9.0 0.09-10.0 4.3-5.2
`
`3.7 mo
`
`DMA
`
`2.3-3.5
`
`2.5-3.0
`
`2.8-4.4
`
`DMF
`
`. ‘l.2v-5.9
`
`Crema-
`pnor® BL
`DMSO
`
`2.5-13.9
`
`BA
`
`1.0
`
`0.9°
`
`2.8-3.5
`
`4.4~6.1
`
`6.1 2.8-5.7 Davis and Jenner (1959);
`
`Auciair and Hameau (1964);
`Wiles and Narcisse H964);
`Theirsch (1962)
`
`Bartschetal.(1976);
`
`BASF (1988)
`
`5.4-8.1 Bartscheta1(1976);
`Wiles and Narcisse (1971);
`Willson et at. (1965)
`
`0.05-
`
`0.08 McCIoskey et al. (1986);
`> 41.6 Kimura et 22111971)
`
`2.64.2
`
`--
`
`3.4-7.6 8.2-10.1
`
`< 0.52
`
`> 52
`
`References
`
`E
`53 1
`
`
`
`ClinicalObservations
`
`lobinuriaobservedfollowingadministrationof
`
`
`
`dwithin2-3hnost-
`
`
`
`Hemog_20~40%solutions.whichcleare
`
`10to40%solutions
`
`AdministeredAs
`
`§
`
`;
`
`§ 1
`
`;
`‘
`
`3
`
`I
`
`3
`
`1x
`1
`
`{
`
`|nnoPharma Exhibit 1101.0018
`
`4.7-7.3 Budden et al. (1973);
`Rowe and Wolf (1982):
`Bartsch et al. (1976)
`6.4-6.8 Davis ahd Jenner (1959);
`Bartsch et al. (1976);
`Latven and Moiitor (1939)
`
`1.4-1.8 Latven and Mo1itor(i939);
`Bartsch et al. (1976);
`"lrémolieres and Lowy
`(1964)
`Budden etal.(1978);
`Anderson et al. (1950);
`Bartsch et at (1976);
`Tao et al. (1983)
`
`5.6
`
`Latvenetal.(1939);
`
`5.3 2.6-4.8 Davis and Jenner (1959);
`Sherman et a1.(1978),
`Bartsch et al. (1976);
`Auclair and Hameau (1964);
`Wiles and Narcisse (1971);
`Thiersch (1962)
`
` PEG 400 13.244-.5
`
`
`
`
`
`DMSO
`
`*1 gm/kg
`
`IV
`
`10 to 40% solutions
`
`DMA
`
`100-610
`mg/kg/day
`for 2-5 days
`
`IV
`
`10% solution
`administered over
`5 to 10 min
`
`Creme-
`pnor® EL
`
`2-20 ml.
`
`IV
`
`PG
`
`BA
`
`5-21 g/day
`
`N
`
`130405
`mg/kg/day
`
`IV
`
`incremental doses
`administered every
`4 min, each over a
`30 sec period
`
`Administered as an
`infusion over a
`4 h period
`0.9% BA
`(bacteriostatic
`concentration)
`
`..,. rII74“vw _.......l, ,,l,.;,. ......,,,
`
`.l
`
`‘M.-....«.-~......4..~...,,,.r
`
`
`
`Table 11.4. Human Exposures to Selected Organic Solvents Commonly Encountered in Parenteral Formulations
`References
`Solvent
`’
`Dose
`Route
`Administered As
`Clinical Observations
`
`Hemoglobinuria observed following administration of
`20-40% solutions. which cleared within 2-3 h post-,
`infusion; No indication of shonoterm nephrotoxicity
`following evaluation of betaozvrnicroglobulin.
`
`Dose-related side effects included nausea and vomiting
`within 14 n 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 functionw»
`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 after the 20 ml. dose.
`
`No alterations in plasma osmolality, free hemoglobin.
`or haptoglobin.
`
`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 parabens.
`
`
`
`Bennett and Muther
`(1981)
`
`Weiss et at (1962)
`
`Savege et al. (1973)
`
`Speth et al. (1987)
`
`Brown et al. (1982);
`Santiero (1989);
`Evens (1975);
`Gershanik (1982):
`Novak et al; (1972)
`
`
`
`122suogtefnwaogagqeloafufugamwe/x1oso_j
`
`|nnoPharma Exhibit 1101.0019
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`
`
`
`*
`i
`i
`l
`
`1
`
`‘
`E
`Q
`E
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`i
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`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 PEGs affect
`Cardiovascular and autonomic systems. PEG 300, PEG 400, and PEG 600
`administered intravenously and intra-arterialiy 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 giycols 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 tonicity of the resulting solutions was also observed to
`be inversely related to molecular weight——low 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 PEGS, 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