INJECTABLE DRUG
`
`DEVELOPMENT
`
`TECHNIQUES To REDUCE
`PAIN AND IRRITATION
`
`Edited by
`
`Pramod K. Gupta
`
`and
`
`Gayle A. Brazeau
`
`Interpharm Press
`Denver, Colorado
`
`
`
`Page 1 0f 33
`
`CSL EXHIBIT 1006
`
`

`

`Invitation to Authors
`
`dustries, please contact our director of publications.
`
`E 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-
`
`Library of Congress Cataloging-in-Publication Data
`
`Injectable drug deveIOpment : techniques to reduce pain and irritation /
`edited by Pramod K. Gupta and Gayle A. Brazeau.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN ‘1-57491-095-7
`
`1. Injections. 2. lnjections—Complications. 3. Drug development.
`I. Gupta, Pramod K., 1959—
`. II. Brazeau, Gayle A.
`[DNLM: 1. Injections—adverse effects. 2. Pain—chemically induced.
`3. Pain—prevention 81 control. 4. Pharmaceutical Preparations—
`administration 81 dosage. WB 354 ‘156 1999]
`RM169.I49
`1999
`615’.6—dc2‘1
`DNLM/DLC
`
`for Library of Congress
`
`99-26911
`CIP
`
`10987654321
`
`ISBN: 1-57491-095-7
`/\Copyright © 1999 by Interpharm Press. All rights reserved.
`4C3
`‘.1
`All tights 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
`means, electronic, mechanical, photocopying, recording, or otherwise, without
`written permission from the publisher Printedin the United States of America
`Where a product trademark, registration mark, or other protected mark is
`ma
`in the text, ownership of the mark remains with the lawful owner of the
`ma R. No claim, intentional or otherwise, is made by reference to any such marks
`in his book.
`1 While every effort has been made by Interpharm Press to ensure the accuracy
`Vof the information contained in this book, this organization accepts no responsi-
`bility for errors or omissions.
`
`2AUG:3H’i'i
`
`.
`.
`25,;
`K
`
`Interpharm Press
`15 Inverness Way E.
`Englewood, CO 80112-5776, USA
`
`Phone: +1-303-662-9101
`Fax:
`+1-303-754-3953
`Orders/on-line catalog:
`www.interpharm.com
`
`Page 2 of 33
`
`

`

`Contents
`
`
`
`Preface
`
`
`
`Acknowledgments
`
`
`
`
`
`Editors and Contributors
`
`
`
`
`
`
`
`
`A: BACKGROUND OF PAIN, IRRITATION, AND/0R
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`lN B
`
`7
`I
`
`2 2‘2 L"!
`”T I; a.
`
`
`
`’ Q Q Q
`
`xiii
`
`xiv
`
`
`
`
`xv
`
`
`
`
`3
`
`4
`
`5
`
`
`
`
`6
`
`8
`
`10
`
`
`
`
`14
`
`’11
`
`11
`
`’13
`
`
`
`Page 3 of 33
`
`iii
`
`
`
`Page 3 of 33
`
`

`

`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
`
`
`
`
`
`18
`
`
`
`
`
`Cutaneous/Subcutaneous Injections
`
`
`
`Intramuscular Injections
`22
`
`
`
`Intra—arterial Injections
`
`
`Intravenous Injections
`
`
`Conclusions and Perspectives
`
`
`24
`
`
`26
`
`
`
`Acknowledgements
`
`
`References
`
`
`
`
`
`
`3. Mechanisms of Muscle Damage with
`
`
`Injectable Products
`‘
`
`
`
`
`
`Anne McArdIe and Malcolm J. Jackson
`
`
`
`
`
`Abstract
`
`
`Introduction
`
`
`
`
`
`
`Mechanisms of Muscle Damage
`
`
`Elevation of Intracellular Calcium Concentration
`
`
`
`
`
`Increased Free Radical Production
`
`
`
`Loss of Energy Homeostasis
`
`
`
`
`Methods of Assessing Drug-Induced Skeletal
`
`
`Muscle Damage
`Microscopic Analysis of Skeletal Muscle
`
`
`
`
`
`
`
`Muscle Function Studies
`63
`
`
`
`
`
`
`58
`
`
`
`
`60
`
`
`
`
`61
`
`
`
`62
`
`
`
`64
`
`
`64
`
`
`
`
`
`Leakage of Intramuscular Proteins
`
`
`
`
`
`Microdialysis Studies of Individual Muscles
`
`
`
`
`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
`
`
`
`
`
`Methods of Measziring Cellular Energy Levels
`
`Conclusions
`
`
`
`67
`
`
`
`67
`
`Acknowledgments
`
`
`References
`
`
`
`Page 4 0f 33
`
`15
`
`
`
`15
`
`16
`
`I8
`
`
`
`
`
`49
`
`50
`
`50
`
`
`
`
`
`57
`
`
`
`57
`
`57
`
`58
`
`
`
`
`
`62
`
`
`
`66
`
`
`
`
`67
`
`
`58
`
`67
`
`
`
`
`66
`
`Page 4 of 33
`
`

`

`Contents
`
`
`
`V
`
`
`
`
`
`
`
`
`B: METHODS To ASSESS PAIN, IRRITATION, AND
`
`
`
`
`MUSCLE DAMAGE FOLLOWING INJECTIONS
`
`
`
`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
`
`
`
`
`
`
`77
`
`
`
`78
`
`
`
`79
`
`
`
`
`
`
`82
`Dynamic Methods
`
`
`
`
`
`
`
`
`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 Inf1ammation
`
`Lesion Models
`Rabbit
`
`
`92
`
`
`
`
`
`
`Mice
`
`
`
`96
`
`
`
`Rat
`
`
`
`96
`
`
`
`
`Biochemical Models
`Serum Glutamic-Oxaloacetic Transaminase
`
`
`
`
`
`N—Acetyl-B-Glucosaminidase
`
`97
`
`
`
`97
`
`
`
`
`
`
`
`97
`
`
`98
`
`Myeloperoxidase
`Creatine Kinase
`
`
`
`
`Edema Models
`
`
`
`105
`Inducing Edema
`Exudative Models of Inflammation
`
`
`
`
`
`
`105
`
`
`
`
`
`105
`
`
`
`
`
`106
`
`
`
`85
`
`86
`
`87
`
`
`
`
`
`91
`
`
`
`
`91
`
`92
`
`97
`
`
`
`'105
`
`
`
`107
`
`
`
`
`
`107
`
`
`
`
`
`Vascular Permeability Models
`
`
`Footpad Edema Models
`
`
`
`Correlation of Models
`
`
`
`
`
`
`Rabbit Lesion Versus Rabbit Hemorrhage Score Model
`Rabbit Lesion Versus Rabbit CK Model
`
`
`
`
`
`
`
`
`
`
`
`Rabbit Lesion Versus Rat Footpad Edema Model
`Rabbit Lesion Versus Rat CK Model
`109
`
`
`
`
`
`
`
`Rat and Human
`110
`
`
`
`
`
`108
`
`
`
`
`
`109
`
`
`
`
`
`
`
`Page 5 0f 33
`
`Page 5 of 33
`
`

`

`vi
`
`
`
`
`
`Injectable Drug Development
`
`
`
`
`
`
`Models for Extended-Release Formulations
`
`
`
`
`
`
`
`Predicting Muscle Damage from
`Extended-Release Formulations
`
`
`
`
`111
`
`
`
`Future Directions
`
`
`
`
`
`
`112
`
`
`
`
`Muscle Damage and CK
`
`
`
`Gamma Scintigraphy
`Electron Parametric Resonance and
`
`
`
`
`
`
`Nuclear ResonanCe Imaging
`
`112
`
`
`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-Lick Model 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
`
`
`Collimators
`
`
`135
`
`
`
`
`
`
`Electronics and Output
`
`
`Computers
`
`137
`
`
`
`
`Tomographic Imaging
`
`
`
`136
`
`
`
`
`139
`
`
`
`
`
`Quality Control
`
`
`Radionuclides and Radiation
`
`
`
`139
`
`
`
`
`
`
`
`Scintigraphic Detection of Inflammation ‘_
`
`Page 6 0f 33
`
`110
`
`
`
`112
`
`
`
`114
`
`115
`
`
`
`
`119
`
`
`
`120
`
`120
`
`123
`
`126
`
`128
`
`128
`
`
`
`
`
`
`
`
`
`
`131
`
`
`
`132
`
`132
`
`
`
`
`140
`
`141
`
`
`
`
`Page 6 of 33
`
`

`

`Contents
`
`
`
`vii
`
`
`
`Gallium-67
`
`
`
`141
`
`
`
`Radiolabeled Leukocytes
`Radiolabeled Antibodies
`
`
`
`
`
`
`143
`
`
`145
`
`
`Other Radiopharmaceuticals
`
`References
`
`Summary
`
`
`
`
`
`147
`
`
`
`8.
`
`
`
`
`
`
`
`
`
`
`
`A Primer on In Vitro and In Vivo Cytosolic
`
`
`
`Enzyme Release Methods
`
`
`Gayle A. Brazeau
`
`
`
`
`
`148
`
`149
`
`
`
`
`‘155
`
`
`
`157
`
`159
`
`159
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`Cytosolic Enzymes Utilized in Isolated Muscle Studies
`
`
`
`
`
`
`164
`
`
`
`
`
`
`164
`Controls and Data Analysis
`
`
`
`
`
`
`
`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-Induced Toxicity
`
`
`
`
`
`In Vivo Enzymatic Release Methods
`General Considerations
`
`
`Animal Models
`
`
`169
`
`
`
`
`
`170
`
`
`
`
`
`
`Quantification of Tissue Damage
`
`
`Conclusions
`
`
`
`
`171
`
`Acknowledgments
`
`
`References
`
`
`
`
`
`
`
`165
`
`
`
`169
`
`
`
`
`
`168
`
`
`
`172
`
`
`
`
`173
`
`173
`
`9.
`
`
`
`
`
`
`Histological and Morphological Methods
`
`
`
`
`
`
`
`
`Bruce M. Carlson and Robert Palmer
`
`
`
`
`
`
`
`Basic Principles Underlying Morphological Analysis
`
`
`
`
`Techniques of Morphological Analysis
`
`
`
`177
`
`
`
`179
`
`180
`
`
`
`
`Page 7 0f 33
`
`Page 7 of 33
`
`

`

`viii
`
`
`
`
`
`Injectable Drug Development
`
`
`
`
`
`Electron Microscopic Methods
`
`
`Histological Methods
`Histochemical Methods
`
`
`183
`
`
`185
`
`
`
`
`
`
`
`180
`
`
`
`
`
`187
`
`
`
`
`
`
`
`
`lmmunocytochemical Methods
`
`
`189
`Neuromuscular Staining Methods
`
`
`
`
`
`
`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
`
`
`
`
`
`196
`
`197
`
`197
`
`197
`
`197
`
`
`Experimental Procedures
`
`Experiment 1
`
`Experiment 2
`
`Experim ent 3
`
`Experiment 4
`
`Experiment 5
`
`Experiment 6
`
`Experiment 7
`
`Statistical Analyses
`
`Discussion
`
`
`
`
`
`
`
`
`
`197
`
`198
`
`
`
`198
`
`
`
`Results
`
`
`
`
`
`Applications
`
`
`Summary and Conclusions
`
`
`Acknowledgments
`
`
`References
`
`
`
`
`
`
`
`
`
`C: APPROACHES IN THE DEVELOPMENT OF
`
`
`
`LESS-PAINFUL AND LESS-IRRITATING INJECTABLES
`
`
`
`11.
`
`
`
`
`
`
`
`Cosolvent Use in Injectable Formulations
`
`
`
`
`
`Susan L. Way and Gayle Brazeau
`
`
`
`
`
`
`
`Commonly Used Solvents
`
`
`
`
`Polyethylene Glycols
`
`
`
`219
`
`
`
`
`Propylene Glycol
`
`
`
`223
`
`
`
`Ethanol
`
`
`
`225
`
`
`
`Page 8 of 33
`
`
`190
`
`
`191
`
`193
`
`
`
`195
`
`
`
`198
`
`
`
`204
`
`209
`
`210
`
`211
`
`21 1
`
`215
`
`
`
`
`218
`
`Page 8 of 33
`
`

`

`
`
`Glycerin ' 226
`
`
`Con tents
`
`
`
`ix
`
`
`
`
`
`
`
`
`228
`230
`
`
`
`
`
`
`
`
`237
`
`
`233
`
`
`
`
`
`227
`Cremophors
`
`
`Benzyl Alcohol
`Amide Solvents
`
`
`232
`Dimethylsulfoxide
`
`
`
`Hemolytic Potential of Solvents/Cosolvents
`
`
`
`
`In Vitro/ln Vivo Hemolysis Comparisons
`
`
`Muscle Damage
`
`242
`
`245
`
`
`
`
`
`
`250
`
`
`
`251
`
`267
`
`
`
`267
`
`273
`
`295
`
`297
`
`
`
`
`
`
`
`
`307
`
`
`
`308
`
`312
`
`313
`
`319
`
`
`
`
`
`
`
`
`
`Cosolvent—Related Pain on Injection
`Cosolvents Known to Cause Pain
`
`
`
`
`Methods to Minimize Pain
`
`
`
`
`
`
`
`
`
`
`247
`
`Conclusions
`
`
`245
`
`
`
`References
`
`
`
`l
`
`
`12. Prodrugs
`
`
`
`
`
`
`
`
`Laszlo Prokai and Katalin Prokai-Tatrai
`
`
`
`Design of Prodrugs
`
`
`
`
`
`
`Specific Examples of Prodrugs Developed to Improve
`
`
`
`
`Water Solubility of Injectables
`
`
`
`273
`Anticancer Agents
`
`
`
`Central Nervous System Agents
`
`
`
`Other Drugs
`
`
`
`
`288
`
`
`
`283
`
`
`
`Conclusions
`
`References
`
`
`
`
`
`
`
`
`13. Complexation—Use of Cyclodextrins to
`
`
`
`
`Improve Pharmaceutical Properties of
`
`
`Intramuscular Formulations
`
`
`
`
`
`Marcus E. Brewster and Thorsteinn Loftsson
`
`
`
`
`
`
`
`Cyclodextrins
`
`
`
`Preparation of Cyclodextrin Complexes
`
`
`
`Characterization of Cyclodextrin Complexes
`
`
`
`
`
`
`Use of Cyclodextrins in IM Formulations
`
`Methodologies
`319
`
`
`
`
`
`
`IM Toxicity of Cyclodextrins and Their Derivatives
`
`
`
`
`
`
`Use of'Cyclodextrins to Replace Toxic Excipients
`in lM Formulations
`323
`
`
`
`
`
`
`
`
`
`Use of Cyclodextrins to Reduce Intrinsic
`
`
`
`Drug-Related Toxicity
`326
`
`
`
`
`
`
`
`Page 9 of 33
`
`
`
`320
`
`
`
`Page 9 of 33
`
`

`

`
`
`x
`
`
`
`Injectable 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 After
`
`
`
`
`
`
`IntramuscularAdministration
`342
`
`
`
`Studies on the Protective Effect After lntradermal and
`
`
`
`
`
`
`
`Subcutaneous Administration
`345
`
`
`
`
`
`
`
`
`
`
`Discussion
`
`
`Conclusions
`
`
`
`References
`
`
`
`‘
`
`
`
`
`
`‘15. Biodegradable Microparticles for the
`
`
`
`
`Development of Less-Painful and
`
`
`Less-Irritating Parenterals
`
`
`
`
`
`
`
`
`
`
`
`Elias Fattal, Fabiana Quaglia, Pramod Gupta, and Gayle Brazeau
`
`
`
`
`
`
`
`
`
`Rationale for Using Microparticles in the Development
`
`
`
`
`
`of Less-Painful and Less-Irritating Parenterals
`
`
`
`Poly(Lactide—co—Glycolide) Microparticles as Delivery
`
`
`
`
`
`
`
`Systems in the Development of Less-Painful and
`
`
`Less-Irritating Parenterals
`
`
`
`Polymer Selection
`
`357
`
`
`
`
`
`329
`
`
`
`330
`
`330
`
`337
`
`
`
`338
`
`
`
`
`340
`
`341
`
`349
`
`350
`
`
`
`
`351
`
`355
`
`
`
`356
`
`
`
`357
`
`
`
`
`MicroencapSulation Technique
`
`
`
`366
`
`
`
`360
`
`
`
`368
`
`
`
`
`
`368
`
`
`
`
`Drug Release
`Sterilization
`
`Residual Solvents
`
`
`
`
`
`
`Stability of the Encapsulated Drug and
`
`
`
`369
`Microparticle Products
`
`
`
`
`Protection Against Myotoxicity by Intramuscularly/
`
`
`
`Subcutaneously Administered MicrOparticles
`
`
`
`
`
`370
`
`
`
`Page 10 0f 33
`
`Page 10 of 33
`
`

`

`Conclusions
`
`
`
`References
`
`
`
`
`‘16. Emulsions
`
`
`
`
`
`
`
`
`
`Pramod Kl Gupta and John B. Cannon
`
`
`
`Con ten ts
`
`
`
`xi
`
`
`
`371
`
`
`
`372
`
`379
`
`
`
`
`
`
`
`
`
`
`
`
`Rationale for Using Emulsions for Reducing Pain and
`
`
`
`Irritation upon Injection
`
`
`
`
`
`Potential Mechanisms of Pain on Injection
`
`
`Case Studies
`
`Propofol(Diprivan®)
`384
`
`Etomidate
`
`
`Pregnanolone {Eltanolone®)>
`
`
`
`
`
`382
`
`
`
`Diazepam
`
`
`388
`
`388
`
`
`
`
`
`Methohexital and Thiopental
`
`
`Amphotericin B
`
`390
`
`
`
`
`
`389
`
`
`
`
`
`380
`
`
`
`
`
`38']
`
`382
`
`
`
`
`391
`Clarithromycin
`
`
`
`
`
`
`
`Challenges in the Use of Emulsions as Pharmaceutical
`
`
`Dosage Forms
`
`Physical Stability
`393
`
`Dose Volume
`
`Other Issues
`
`
`
`
`
`
`393
`
`
`
`Efficacy
`
`
`
`
`
`
`
`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
`Preform ulation
`402
`
`
`
`
`
`
`
`Formulation
`
`
`
`404
`
`
`
`
`
`
`
`
`
`Focus on Osmolality, Cosolvents, Oils, and pH
`415
`
`pH
`
`
`
`
`
`
`
`410
`
`
`
`Page 11 0f 33
`
`393
`
`
`
`395
`
`395
`
`
`
`
`401
`
`
`
`
`402
`
`Page 11 of 33
`
`

`

`
`
`
`pH, Additives, and SoIvents
`
`
`
`Devices and Physical Manipulations
`
`
`416
`
`
`
`
`
`417
`
`
`
`416
`
`
`
`420
`
`
`
`423
`
`
`
`xii
`
`
`
`
`
`Injectable Drug Development
`
`
`
`
`Post-Formulation Procedures
`
`
`
`
`
`References
`
`Index
`
`
`
`Page 12 0f 33
`
`Page 12 of 33
`
`

`

`’17
`
`
`
`
`
`Formulation and
`
`
`Administration Techniques
`
`
`
`
`to Minimize Injection Pain
`
`
`
`and Tissue Damage
`
`
`Associated with Parenteral
`
`Products
`
`
`
`
`
`Larry A. Gatlin
`
`
`Biogen, Inc.
`
`
`Cambridge, Massachusetts
`
`
`
`
`
`
`Carol A. Brister Gatlin
`
`
`
`
`Genzyme
`
`
`Cambridge, Massachusetts
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Parenteral products significantly contribute to global health by providing
`
`
`
`
`
`
`
`
`effective and immediate therapy through direct delivery of therapeutic
`
`
`
`
`
`
`
`
`
`
`
`compounds to the patient. However, as with most routes of delivery, par—
`
`
`
`
`
`
`
`
`enteral drug administration has both real and perceived disadvantages.
`
`
`
`
`
`
`
`
`
`The two potential disadvantages that are typically associated with par-
`
`
`
`
`
`
`
`
`
`
`
`
`enteral therapy are tissue damage and injection pain. Whether this pain is
`
`
`
`
`
`
`
`
`
`
`
`
`
`real or imagined makes little difference to the patient, and there exists a
`
`
`
`
`
`
`
`
`
`
`significant literature that both highlights the pain caused by injectable
`
`
`
`
`
`
`
`
`
`drug products and offers methods to reduce these effects.
`
`
`
`
`
`
`
`
`
`
`
`The first section of this chapter provides a strategy that can be used
`
`
`
`
`
`
`
`
`
`
`
`to develop a parenteral product. Emphasis is placed on the two formula-
`
`
`
`
`
`
`
`
`
`
`tion parameters, pH and tonicity, that are usually associated with tissue
`
`
`
`
`
`
`
`
`
`
`
`damage and injection pain. It is through the adjustment of these parame-
`
`
`
`
`
`
`
`
`
`
`
`ters that the product formulator can minimize adverse effects. The second
`
`
`
`
`
`
`
`
`
`section of this chapter describes administration techniques used by
`
`
`
`
`
`Page 13 of 33
`
`
`
`40‘
`
`Page 13 of 33
`
`

`

`402
`
`
`
`
`
`Injectable Drug Development
`
`
`
`
`
`
`
`
`
`
`
`
`
`healthcare professionals to reduce tissue damage or pain caused by com—
`
`
`
`
`
`
`
`
`
`mercial parenteral products. By recognizing the potential risks these al—
`
`
`
`
`
`
`
`
`, terations may confer to commercial formulations (such as decreased
`
`
`
`
`
`
`
`
`
`
`product stability or modified efficacy), the formulator will be better pre-
`
`
`
`
`
`
`
`
`
`pared to support the ”real-world” use of the product.
`
`
`
`
`FORMULATION DEVELOPMENT
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The development strategy for parenteral products is similar for all prod-
`
`
`
`
`
`
`
`
`
`
`
`ucts. The challenge is in the details of solving the physical/chemical diffi-
`
`
`
`
`
`
`
`
`
`
`culties encountered with a specific molecule within the timeline allowed
`
`
`
`
`
`
`
`
`
`for development. This section provides a parenteral product development
`
`
`
`
`
`
`
`
`
`
`
`outline with an emphasis on two formulation parameters, pH and tonicity,
`
`
`
`
`
`
`
`
`
`
`
`
`which may be modified to minimize tissue damage and pain caused by a
`
`
`parenteral product.
`
`
`
`
`
`
`
`
`
`The activities necessary to develop a parenteral product can be placed
`
`
`
`
`
`
`
`
`into the following three broad areas: preformulation, formulation, and
`
`
`
`
`
`
`
`
`scale—up. While there are alternative development perspectives, all devel-
`
`
`
`
`
`
`
`
`opment ultimately needs to accomplish the same activities. Preformulation
`
`
`
`
`
`
`
`
`
`
`
`includes the characterization of the bulk drug plus initial screening for ex—
`
`
`
`
`
`
`
`
`
`cipient compatibility with the drug. Formulation activities inciude the iden—
`
`
`
`
`
`
`
`
`
`tification and selection of a suitable vehicle (aqueous, nonaqueous, or
`
`
`
`
`
`
`cosolvent system), necessary excipients with appropriate concentrations
`
`
`
`
`
`
`
`(buffers, antioxidants, antimicrobials, chelating agents, and tonicity con-
`
`
`
`
`
`
`
`
`
`tributors), and the container/closure system. Scale-up activities aid in mov-
`
`
`
`
`
`
`
`
`
`
`ing the product to a manufacturing site (although not discussed here,
`
`
`
`
`
`
`references are available to provide guidance).
`
`
`
`
`
`
`Preformulation
`
`
`
`
`
`
`
`
`
`
`
`Preformuiation studies provide fundamental data and the experience nec-
`
`
`
`
`
`
`
`
`
`
`essary to develop formulations for a specific compound. Activities are
`
`
`
`
`
`
`
`
`
`initiated and experiments performed for the purpose of characterizing
`
`
`
`
`
`
`
`specific and pharmaceutically significant physicochemical properties of
`
`
`
`
`
`
`
`
`
`
`
`the drug substance. These properties include interactions of the drug with
`
`
`
`
`
`
`
`
`
`excipients, solvents, packaging materials, and, specifically relating to the
`
`
`
`
`
`
`
`
`
`
`subject of this book, biological systems. These investigations also evaluate
`
`
`
`
`
`
`
`
`
`
`the drug under standard stress conditions of temperature, light, humidity,
`
`
`
`
`
`
`
`
`
`
`
`
`and oxygen. Many of these factors should be considered critically prior to
`
`
`
`
`
`
`
`
`
`
`
`animal testing, since these data will influence activities such as samples
`
`
`
`
`
`
`
`
`
`prepared for toxicology and animal testing, solubilization techniques, and
`
`
`
`
`design of subsequent studies.
`
`Page 14 0f 33
`
`Page 14 of 33
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`

`

`
`
`
`Formulation and Administration Techniques
`
`
`
`403
`
`
`
`
`
`
`
`
`
`
`
`
`Areas of specific interest during preformulation are provided in out—
`
`
`
`
`
`
`
`
`
`
`line form below, along with an outline of additional characterization infor-
`
`
`
`
`
`
`
`
`
`
`mation needed to formulate a protein drug substance. Since analytical
`
`
`
`
`
`
`
`
`
`methods are usually developed concurrently with the preformulation data
`
`
`
`
`
`
`
`
`
`
`and then refined during formulation activities, the team must effectively
`
`
`
`
`
`
`
`
`
`
`communicate and collaborate to ensure appropriate assays are used to ob—
`
`
`
`
`
`
`
`tain data having sufficient accuracy and precision.
`
`
`
`Preformulation Physicochemical Properties
`
`
`
`
`
`1. Molecular weight
`
`
`
`2
`
`
`
`Color
`
`
`
`
`3. Odor
`
`
`
`4
`
`5
`
`
`
`
`
`
`
`
`
`Particle size, shape, and crystallinity
`
`
`
`
`Thermal characteristics
`
`
`
`
`
`5.1. Melting profile
`
`
`
`
`
`5.2. Thermal profile
`
`
`
`
`6. Hygroscopicity
`
`
`
`
`
`7. Absorbance spectra
`
`
`
`8.
`
`
`
`Solubility
`
`
`
`8.1.
`
`
`
`
`
`
`
`
`
`Selected solvents (water, ethanol, propylene glycol, poly—
`
`
`
`
`
`
`
`ethylene glycol 400, plus others as necessary)
`
`8.2.
`
`
`
`
`pH profile
`
`
`
`
`
`8.3. Temperature effects
`
`
`
`8.4.
`
`
`
`
`Partition coefficient
`
`
`
`
`9.
`
`Stability
`
`
`
`9.1.
`
`9.2.
`
`
`
`
`
`
`Selected solvents
`
`
`
`
`pH profile
`
`
`
`10.
`
`
`
`
`
`
`
`Ionization constant (pK or pl)
`
`
`
`
`
`11. Optical activity
`
`
`
`Page 15 0f 33
`
`Page 15 of 33
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`

`

`404
`
`
`
`
`
`Injectable Drug Development
`
`
`
`
`
`
`
`Additional Characterization for Protein Drugs
`
`
`
`
`
`1.
`
`
`Physical stability
`
`
`
`
`1.1. Aggregation
`
`
`
`
`2.
`
`3.
`
`
`
`Solubility
`
`
`
`
`Chemical stability
`
`
`
`3.1.
`
`
`
`Beta—elimination
`
`
`
`
`3.2. Deamidation
`
`
`
`3.3.
`
`
`
`Isomerization/cyclization
`
`
`
`
`3.4. Oxidation
`
`
`
`3.5.
`
`
`
`
`
`Thiol disulfide exchange
`
`
`
`
`
`4. Analytical methods
`
`
`
`4.1.
`
`
`
`
`Fluorescence spectroscopy
`
`
`
`
`4.2. Electrophoresis
`
`
`
`
`4.3. Calorimetry
`
`
`
`4.4.
`
`
`
`
`
`Size exclusion chromatography
`
`
`
`
`
`
`
`
`
`4.5. Reverse phase high performance liquid chromatography
`
`(HPLC)
`
`
`
`
`
`4.6. Circular dichroism
`
`
`
`
`
`4.7. Mass spectrometry
`
`
`
`4.8.
`
`
`
`
`Light scattering
`
`
`
`Formulation
`
`
`
`
`
`
`
`
`
`
`
`
`Formulation activities include the identification and selection of a suitable
`
`
`
`
`
`
`
`
`vehicle (aqueous, nonaqueous, or cosolvent system), necessary excipientsr
`
`
`
`
`
`
`with appropriate concentrations (buffers, antioxidants, antimicrobials,
`
`
`
`
`
`
`
`
`chelating agents, and tonicity contributors), and the container/closure sys-
`
`
`
`
`
`
`
`
`
`
`
`
`
`tem. The formulator is interested in the same list of activities given for pre-
`
`
`
`
`
`
`
`
`
`formulation; however, the activities are focused on specific excipients and
`
`
`
`
`
`
`
`
`
`characterization of the formulation. The principles of formulating a par-
`
`
`
`
`
`
`
`
`
`
`enteral product have been outlined by several authors, although most do
`
`
`
`
`
`
`
`
`
`
`
`not specifically include the evaluation of tissue damage or pain caused by
`
`
`
`
`
`
`
`
`
`
`
`
`injection of the final product. This is likely due to the assumption that
`
`
`
`
`
`
`
`Page 16 0f 33
`
`Page 16 of 33
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`

`

`
`
`
`
`Formulation and Administration Techniques
`
`405
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`deviation of pH or tonicity from physiological conditions causes these ef—
`
`
`
`
`
`
`
`
`
`
`
`fects. It is, however, important to consider that a product may cause tissue
`
`
`
`
`
`
`
`
`
`
`
`damage with little associated pain, pain with little tissue damage, or both
`
`
`
`
`
`
`
`
`
`
`
`pain and tissue damage. Therefore, the models utilized to assess either the
`
`
`
`
`
`
`
`
`
`
`
`pain or tissue damage associated with a product need to be selected care—
`
`
`
`
`
`
`
`
`
`fully. Several complementary methods may be needed, and these models
`
`
`
`
`
`are provided throughout this book.
`
`
`
`
`
`
`Significant formulation activities begin with initial preformulation
`
`
`
`
`
`
`
`
`
`
`data and knowledge of the specific route of administration. These data
`
`
`
`
`
`
`
`
`
`
`‘ provide the formulator with the requirements and limitations for the final
`
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`formulation. Due to the location of human pain receptors, formulation ap-
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`proaches to reduce pain are more critical for subcutaneous (SC) and intra—
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`dermal injections and less critical for intramuscular (IM) and intravenous
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`(IV) administration.
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`Injection volume is one of the most important considerations in the
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`formulation deve10pment of a commercial product. This volume is selected
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`based on the proposed injection route. Since veins have a relatively large
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`volume and blood flow rate, a product administered by the IV route can
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`have a volume greater than 10 mL; as the volume increases, the delivery
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`rate may need to be controlled. This is in contrast to IM injections, which
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`are normally limited to 3 mL, SC injections to 1 mL, and intradermal injec-
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`tions to 0.2 mL. Recommended maximum injection volumes are author de-
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`pendent but not radically different.
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`Thus, the factors that need to be considered in evaluating the hemol—
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`ysis caused by a product include both the quantity and proportions of the
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`substances and how rapidly the blood dilutes the product. The data in
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`Table 17.1 provide some perspective on the vascular system’s capability of
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`diluting an injected IV product,
`in terms of both volume and rate. The
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`choice of solvent is dependent both on the route of administration, which
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`Table 17.1. Physical Characteristics of the Arteriovenous System
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` Anatomical Section Volume (cm3) Velocity (cm/sec)
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`Aorta
`100
`40
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`325
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`50
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`250
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`300
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`2.200
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`300
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`40-100
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`10—0.1
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`0.1
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`0.3
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`0.3—5
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`5—30
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`Arteries
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`Arterioles
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`Capillaries
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`Venules
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`Veins
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`Vena cava
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`'
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`Page 17 0f 33
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`Page 17 of 33
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`406
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`lnjectable Drug Development
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`as noted above imparts volume limitations, and on drug solubility in the se-
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`lected solvent. IV injections are typically restricted to dilute aqueous solu-
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`tions to ensure compatibility with the blood; however, IM or SC injections
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`allow for oily solutions, cosolvent systems, suspensions, or emulsions.
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`Pain, soreness, and inflammation of tissues are frequently observed in the
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`administration of parenteral Suspensions, particularly with products hav—
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`ing a high solid content.
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`A third important consideration in the development of a parenteral
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`product is compatibility of the formulation with the tissue. An isotonic so-
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`lution is less irritating, causes less toxicity and pain, and minimizes hemol-
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`ysis. An isotonic product, however, is not always the goal since for SC or
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`IM injections a hypertonic solution may facilitate drug absorption. Having
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`an isotonic product is, however, very important for intraspinal injections,
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`where the fluid circulation is slow and abrupt changes in osmotic pressure
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`can contribute to unwanted and potentially severe side effects.
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`The choice of acceptable excipients in parenteral product develop-
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`ment remains limited compared to other dosage forms, due to concerns of
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`injection safety and feasibility of sterilization. In order to avoid uncertainty
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`and reduce development time, most formulators select excipients success-
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`fully used in marketed products. A short list of commonly used additives,
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`their functions, and typical concentrations is given in Tables 17.2 and 17.3.
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`As the number of biotechnology products increases, excipients such as hu—
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`man serum albumin (HSA), amino acids, and sucrose are finding increas—
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`ing utility. In Europe, the use of animal—derived excipients such as HSA and
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`some polysorbate surfactants has become problematic due to the increas—
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`ing concern with bovine spongiform encephalitis (BSE). This concern is
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`expanding to the rest of the world and has impact on the selection of
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`excipients.
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`An excipient selected for a parenteral product may serve one or more
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`purposes. For example, benzyl alcohol is primarily a preservative; how-
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`ever, it has a transient local anesthetic property. Dual roles may help in the
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`goal to minimize both the number of product ingredients and their quan«
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`tity. The justification for each selection will become a part of the formula—
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`tion development report.
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`Antimicrobials
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`Preservatives are always included in a product when multiple doses will be
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`drawn from a single vial unless the drug itself is bacteriostatic. The addi—
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`tion of an antimicrobial is not a substitute for good manufacturing prac—
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`tices; however, many times they are added to single-use containers. They
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`are specifically excluded from large-volume products intended for
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`infusion. In some cases, as with benzyl alcohol, the excipient may have
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`multiple functions. Therefore, the decision whether or not to include a
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`preservative in a single-use product may be product specific. The rationale
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`Page 18 0f 33
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`Page 18 of 33
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`Formulation and Administration Techniques
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`407
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`Table 17.2. Additives Commonly Used in Parenteral Products
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`Substance ‘ Concentration (percent)
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`Antimicrobial
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`0.01
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`0.01
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`1—2
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`0.25—0.5
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`0.1—0.3
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`0.1—0.3
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`0.5
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`0.18
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`0.02
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`I
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`0.015
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`0.2
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`0.1
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`0.015
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`0.02
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`0.02
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`0.5
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`0.5
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`0.15
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`0.2
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`0.5
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`0.1
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`Benzalkonium chloride
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`Benzethonium chloride
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`Benzyl alcohol
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`Chlorobutanol
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`Chlorocresol
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`Metacresol
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`Phenol
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`Methyl p-hydroxybenzoate
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`Propyl p-hydroxybenzoate
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`Butyl p-hydroxybenzoate
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`Antioxidants
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`Acetone sodium bisulfite
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`Ascorbic acid
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`Ascorbic acid esters
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`Butylhydroxyanisole (BHA)
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`Butylhydroxytoluene (BHT)
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`Cysteine
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`Monothioglycerol
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`Sodium bisulfite
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`Sodium metabisulfite
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`Tocopherols
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`Glutathione
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`Surfactants
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`Polyoxethylene sorbitan monooleate
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`Sorbitan monooleate 0.05—0.5
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`0.1—0.5
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`for any preservative addition should be a part of the product development
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`report.
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`Common antimicrobial agents are given in Table 17.2. These agents
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`are grouped into five chemical classes: quaternary ammonium com-
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`pounds, alcohols,-esters, mercurials, and acids. The alcohols and esters are
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`commonly used in parenteral products. The quaternary compounds, which
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`are commonly used in ophthalmic products, are not compatible with neg-
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`atively charged ions or molecules.
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`Page 19 0f 33
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`Page 19 of 33
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`408
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`Injectable Drug Development
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`Table 17.3. Common Buffers Used in Parenteral Formulations
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` Buffer pKa Usual Buffering Range
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`Acetic acid
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`Citric acid
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`Glutamic acid
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`Phosphoric acid
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`Benzoic acid
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`Lactic acid
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`Ascorbic acid
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`4.8
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`3.14, 4.8, 5.2
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`2.2, 4.3, 9.7
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`2.1, 7.2, 12.7
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`4.2
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`3.1
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`4.2, 11.6
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`3.5—5.7
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`2.1—6.2
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`8.2—10.2
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`2—3.1, 6.2—8.2
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`3.2—5.2
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`2.1—4.1
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`3.2—5.2
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`2.0—5.3
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`Tartaric acid
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`Succinic acid
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`Adipic acid
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`Glycine
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`Malic acid
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`Triethanolamine
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`Diethanolamine
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`Tr