INJECTABLE DRUG
`
`DEVELOPMENT
`
`TECHNIQUES TO REDUCE
`PAIN AND IRRITATION
`
`Edited by
`
`Pramod K. Gupta
`
`and
`
`Gayle A. Brazeau
`
`Interpharm Press
`Denver, Colorado
`
`
`
`AstraZeneca Exhibit 2079 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB [PR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`
`
`Invitatian to Authm‘s
`
`Interpharm Press pubiishes hawks facuseci upon applied tech»
`% {thingy and I‘egutamry affairs Impacting healthcare manufactur-
`% erg waridwidta. If yhu are CGfiSidE‘I‘iI‘Ig writing 01' cantributimg tan
`a hawk appiicabla to the pharmacevticai, biatechnwlcgyg medica}
`device, diagnasticr cwsmetic‘. m veterifiary medicine manufacturing in»
`dustries, pit-2.213% contact «Eur attractant” {31“ hubiicatians,
`
`Library a? Gangress Catalogingain—Publicatimn Data
`
`Injectahle thug stavsmpment: techniques t0 reduce pain and irritatiwn /
`edited by Framed K. Gupta and Gayle At Brazeau.
`p.
`cm,
`
`lnciudes hibhagraghicai references and index.
`§SBN ’EfiMQ‘LBQSJ
`
`1. Injectiwng. 2. Injeationsmilflmplicatinnst 3. "Eitrug deveit‘spment.
`I. Gama. Pramad K, ”195%
`t EL Brazeau: Gayle A.
`IDNLM: “l. Injectionswadverse effects. 2. @ainwchemicatly induced.
`3‘ E’aihmwawntifln S: controi. it». Pharmawutimi Pregaratiflnsm
`administratiw 8: dosage. W3 35% ‘iiifi EQQ’Q}
`8M153.i49
`1999
`mafia—mam
`DNLMJDLZZ
`
`far Library 0!” Chngress
`
`9926911
`(ZIP
`
`10987€354321
`
`ISBN: 1~57£%in095»7
`
`Ctjpyright (£3 1999 by Interpharm Press. all rights reserved.
`
`All rights reserved? This hm}: is pmtecwd by copyright N0 part at it may he re~«
`pmducm, stared in a retrieval System, at“ transmitted in any farm at by any
`maanst etectmnic‘t mechanical, ghfltsempying, ramming, hr Otherwise? withaut
`writta‘n permissian from the pubiishen Printed in :he United States at“ America.
`Where: a practuct trade-mark, registratihn mark, or other protected mark is
`made in the text; Gwnemhip 0f the mark; remains- with the tawful owner of the
`mark. NC) ctaim, intentionai or ntherwise, is mafia by reference to any such marks
`in this beak.
`
`While every effart has been made by lnterpharm Press to ensure the accuracy
`[if the infarmatian cantaéned in this beak, this Urganization accepts m3 responsi~
`bility for errors 01' amissions.
`
`Intetpharm Press
`
`’15 Invemess Way Em
`Englewom, CO 881126776, USA
`
`Phane: +1w383~86391m
`Fax:
`+1~303«754«3953
`Grders/omline catalog:
`wwwjnterpharmcom
`
`Astraleneca Exhibit 2079 pt 2
`
`

`

`Cameras
`
`Preface
`
`Acknwwledgments
`
`Editors and Cantrihutars
`
`A: EACKGROUNB OF PAIN, IRRITATION, AND/OR
`
`
`MUSCLE DAMAGE WITH INJECTABLES
`
`1.
`
`Chalienges in the levempment 0f
`Injectable Praducts
`
`Michael J, Alters
`
`Genera: Challenges
`
`Safety Cancerns
`
`Micrabialmgical and Other Cantamination Chailenges
`
`Stability Challenges
`
`Salubility Chafienges
`
`Packaging Challenges
`
`Manufacturing Chafienges
`
`Delivery/Administratian Chafienges
`
`References
`
`xiii
`
`xiv
`
`xv
`
`3
`
`4
`
`5
`
`6
`
`8
`
`10
`
`11
`
`“1’1
`
`‘13
`
`'14
`
`iii
`
`Astraleneca Exhibit 2079 13* 3
`
`

`

`iv
`
`2.
`
`lnjc’clable Qrug Bevelapmenr
`
`Pain, Irritaticn, and Tissue Damage
`with lujectians
`
`Wolfgang Klemem
`
`Must Injectians Hurt?
`
`Mechanisms Elf Pain anal Damage
`
`llcmtes 0? Drug lnjectlc‘m
`
`Cutaneous/Subcutanmuslnjacllmns
`
`IF}
`
`Intramuscular Injectlm‘ls
`
`22
`
`Intra~—arterlal Injcctians
`
`24
`
`lnlravenaus Injections
`
`25
`
`Canclusicns and Perslnectives
`
`Acknowledgements
`
`References
`
`3. Mechanisms cf Muscle Damage with
`Injectable Products
`
`Anne McArclle and Malcolm J» Jacksan
`
`Abstract
`
`lntmcluctian
`
`Mechanisms of Muscle Damage
`
`Elevallan oflntraccllular Calcium Cenccntratlefin
`
`58"
`
`Increased Free Radical Production
`
`:38
`
`L055 0f Energy Ilomeaglasls:
`
`l3?
`
`Methads cal" Assessing Drugdnclucecl Skeletal
`Muscle [361me
`
`Mlcmscwplc Analysis Of Skeletal Muscle
`
`£32
`
`Muscll: Functlan Studies
`
`63
`
`Leakage of Intramuscular Pratefns
`
`6t?
`
`Mlcroclfalysls 5tudles of Individual Muscles
`
`54
`
`Cellular Stress Rcsponse
`
`55
`
`‘15
`
`15
`
`”1&3
`
`‘18
`
`ell-l
`
`50
`
`50
`
`57
`
`57
`
`57
`
`58
`
`62
`
`Techniques ta Assess the Mechanisms of Muscle Damage
`
`66
`
`Models ofMuscle Damage
`
`56‘
`
`“Techniques :9 Show Changes in Muscle Calcium Content
`
`65
`
`Markers Dl‘lncreasecl Free Radical Acfivlty
`
`l3?
`
`Methcds cal" Measuring Cellular Energy Levels
`
`6?
`
`Canclusions
`
`Acknawleclgments
`
`References
`
`67
`
`67
`
`68
`
`Astraleneca Exhibit 2079 p 4
`
`

`

`Cantenrs
`
`v
`
`I: METHGDS TQ ASSESS PAIN, IRRITATIDN, AND
`MUSCLE DAMAGE mewms INJECTIGNS
`
`In Vitm Methads er Evaluating
`Intravascular Hemelysis
`
`Jgaseph F. Krzyzaniak and Samuel H. Yalmwsky
`
`Significance
`
`In Vitro Methads for Evaiuating Hemmysis
`
`Static Methads
`
`81
`
`Q‘s/namic Methaéyds
`
`82
`
`Comparison ofln Vitm and In Viva Hemmysis Data
`
`Summary 0‘? In Vitro Methads
`
`References
`
`Lesian and Edema Mmdels
`
`Steven (1'. Surfer;
`
`Edema and Inflammatien
`
`Lesian Madels
`
`Rabbit
`
`92
`
`Mice
`
`95
`
`Rat
`
`96
`
`Biachemical'Madels
`
`Serum Giutamic-Oxamacefic Tmnxaminase
`
`9
`
`N~AccfyH§§a~Glucasamfnidase
`
`9?
`
`Mycfopermidase
`
`97
`
`Creatfne Kinase
`
`98
`
`Edema Medals
`
`Inducing Edema
`
`105
`
`Exudative Madcis @f'mflammafion
`
`1:195
`
`Vascui’ar Permeability Medals
`
`185
`
`Fmtpad Emma Models
`
`1:395
`
`Correlaticm 0f Madels
`
`Rabbit Lesion Versus Rafibr’t Hemorrhage Scan: Model
`
`MP7
`
`Rabbit Lcsmn Versus Rabbit CK Made}
`
`1053
`
`Rabbit Lesian Versus Rat Foamad Edema Model
`
`‘1 09
`
`Rabbi! Lesion Vertsus Fiat CK Medal mg
`
`Rat and Human
`
`I TO
`
`3‘1
`
`91
`
`92
`
`97
`
`105
`
`107
`
`Astraleneca Exhibit 2079 p. 5
`
`

`

`vi
`
`Injectabfe Brag Deveimpment
`
`Madeis Fm Extendedfielease Fmrmulations
`
`Predicting M93636: Qamagm fram
`Extendsdufiefease Fflmmfaféam H?
`
`Future Birectians
`
`Mumle fiamagc and CK
`
`1 “L2
`
`Gamma Scintigraphy
`
`1'12
`
`Erectmn Pammetric RGSGHQHCE and
`
`Nuclear Remnance Imaging
`
`3‘72
`
`Efi‘ect af‘Edema and Lesion an Bioavailabmty
`
`3'13
`
`Fal‘mukimm
`
`1‘13
`
`Conciusians
`
`Réferences
`
`Rat Paw-Lick Madel
`
`Pramwd K. Gupta
`
`Methmdalogy
`
`Carrelatian Between Rat Paw-Lick and Other
`
`Pain/Irritation Modem
`
`Applicatien 01“ Rat Paw~Lick Made! t0 Screening
`Cosolventwlased Formuiatians
`
`Limitatians @f the Rat Pawiick Mandel
`
`Concluding Remarks
`
`References
`
`Radiapharmawuticals for the Noninvasive
`Evaluation of Inflammatian Following
`Intramuscular Injections
`
`Agatha Fcftus, Michaeljay, and Robert M. Seihn
`
`Gamma Scintigraphy
`
`Gamma Cameras
`
`Detectors
`
`133
`
`Callimators
`
`Efectronics ane? Qutput
`
`“I35
`
`336
`
`Computers
`
`137
`
`Tamegrézphic Imaging
`
`139
`
`Quality Contra!
`
`139
`
`Radimnuclides and Radiatimn
`
`Scintigraphic Detectign 0f Inflammaticm
`
`1’10
`
`’1’12
`
`1‘14
`
`115
`
`1‘19
`
`120
`
`120
`
`123
`
`125
`
`128
`
`128
`
`131
`
`132
`
`132
`
`140
`
`141
`
`Astraleneca Exhibit 2079 p. 6
`
`

`

`Contents
`
`vii
`
`Galliumua‘i?
`
`I41
`
`Radiolabefed Leukacyms
`
`Rammabeied Antibodies
`
`‘1 43
`
`1 45
`
`Orr-her Radiapharmaceurfcafs
`
`‘14 7
`
`S ummary
`
`References
`
`A Primfzr an In Vitm and In Viva Cytasmlic
`Enzyme Release Methods
`
`Gayle A. Erazeau
`
`Ratimnale far Utilizing Release 3f Cymsmlic Cmmpmnents
`as a Marker cf TiSSutE‘ Damage
`
`Experimentai Madeis
`
`Isalated Rodent Skeletal Muscle Mariel
`
`General Experimental Overview
`
`159
`
`Isafatiwn, Extraciiwn, and Viability aflsolated Muscies
`
`150
`
`Muscfe Expmum m the Test Farmullation
`
`162
`
`Incubatian Meiji}:
`
`184
`
`Cfiasafic Enzymcs Urifized in Isafared Muscle Studies
`
`164
`
`Contrels and Dara Analysis
`
`164
`
`“i 48
`
`149
`
`355
`
`‘15”?
`
`”159
`
`“15%)
`
`Muscle Cell Culture Methmds to: Evaluate Muscle Injury
`
`165
`
`GenEMJCOnsfiderafions
`
`1'65
`
`Genera} Cansiééraiians in Hm Opfimizaiz‘m an“ Experimental}
`Cal} Cuffure Sysmms
`”366
`
`Selected Cell Lines in Screening fbr Qrugwlnfluced ’I’bxicity
`
`1'68
`
`In Viva: Enzymatic: Release Methads
`GeneraIConsfflerariens
`169
`
`Animal Model};
`
`170
`
`Quantif‘icatian 22f Tissue fiamage
`
`1??
`
`Canclusimns
`
`Acknfiwiedgmems
`
`References
`
`Histological and Marpholagical Methods
`
`Bruce M. Carlsan and Haber? Palmer
`
`Basic Principles Underlying Morphalogical Analysis
`
`Techniques wf Marphamgicai Anaiysis
`
`169
`
`172
`
`1’73
`
`173
`
`177
`
`1??)
`
`180
`
`Astraleneca Exhibit 2079 13* 7
`
`

`

`viii
`
`Injectable Drug Bevelmpment
`
`Electra!) Mfcmscapfc Merhads
`
`1&0
`
`Histafngicai Methods
`
`183
`
`HfstachemfcaiMethods
`
`185
`
`Immunacymdwmica! Methads
`
`15:3?
`
`Neuromuscuiar Staining Methmds
`
`189
`
`Summary :3? Strengths and Limitatimns 0f
`Marphaiegital Techniqueg in assessing
`Mugabe: {Damage After Injectiflns
`
`References
`
`H}.
`
`Consciaus Eat Model t0 Assess Pain
`
`Upon lntravenaus Injectinn
`
`Jehn M“ Marcek
`
`Experimental Procedurfis
`
`Experinwnt 1
`
`Experiments
`
`Exgerimentli
`
`Experiment 4
`
`Experiment 5
`
`Experiment 6
`
`Eerfmenr ?
`
`1596
`
`19?
`
`1.9?
`
`153?
`
`1??
`
`19?
`
`198
`
`StatisticafAnaIyses
`
`798
`
`Results
`
`Discussimn
`
`Applicatmns
`
`Summary and Cannciusimns
`
`Acknowiedgments
`
`References
`
`C: APPRGACHES IN THE DEVELOPMENT 0F
`
`LESS—«PAINFUL AND LESS-«IRRITATING INJECTABLES
`
`‘11.
`
`Casolvent Use in Injectable Formulations
`
`Susan L. Way and Gayle fimzeau
`
`Cmmmonly Used Solvents
`
`Pofyet‘hyfene Glycms
`
`219
`
`Pmpylene Gym!
`Ethano}
`225
`
`223
`
`190
`
`191
`
`193
`
`195
`
`198
`
`253%
`
`.2639
`
`21C?
`
`21']
`
`211
`
`215
`
`218
`
`Astraleneca Exhibit 2079 p* 8
`
`

`

`Contents
`
`ix
`
`Glycerin
`
`225
`
`Cremaphors
`
`237
`
`Ecnzfl Alcaha!
`flmide Swlwnts
`
`228
`23E?
`
`Bimethylsulfoxide
`
`$332
`
`Henmly’dc Patential {if Sfllvents/Casalvents
`
`In Vina/1n Viva Hemmysis Campars’sans
`
`23?
`
`Muscle Damage
`
`Cascalvemfielated Fair: on Injection
`
`Casalvents Known :0 Cause Pain
`
`245
`
`Memads [1:3 Ms’nimfze Pain
`
`2635?
`
`Canclusiwns
`
`References
`
`12.
`
`Pragcirus
`
`Laszle Prokai and Kafaffn Prokaf»Tatrai
`
`Design «:3? Prodrugs
`
`Specific Examples 0? Pradrugs Deveiaped m Immme
`Water Salubility of injectables
`
`Anticancer Agents
`
`22?
`
`Comm! Nermus System Agéms
`
`283
`
`Other Drugs
`
`283‘
`
`Conclusigns
`
`References
`
`'13.
`
`Camplexatiunm’flsa 0f Cycladextrins It}
`Imfiruve Pharmaceutical Pmperties of
`Intramuscular Foormulatins
`
`Marcus E? Brewster and Tharstefnn Lofi'ssan
`
`Cycloflextrins
`
`Preparation of Cycledextrin Camplexes
`
`Characterizatian 0f Cycladextrin Camplexes
`
`Use 0f Cycladextrins in IN! Formulations
`
`Methadalflgies
`
`3'19
`
`{M Tbxica‘ty Uf’Cyclcadextrins and Their Derivatives
`
`3263'
`
`Use 0:“ Cycleflext‘rins to Replace Toxic: Exciggwienm
`in IM Farmularians
`323
`
`Use of {:mfecfaxmng m Reduce Intrinsic
`mmg-Refamé Toxicity
`326
`
`233
`
`242
`
`245
`
`250
`
`251
`
`26'?
`
`257'
`
`273
`
`295
`
`297
`
`3.7
`
`308
`
`312
`
`3‘13
`
`319
`
`Astraleneca Exhibit 2079 p. 9
`
`

`

`
`Injectable Drug leveiepmem
`
`Canclusians and Future Directions
`
`Acknewledgments
`
`References
`
`15%.
`
`Lipasomai Farmuiations ta Reduce
`Irritatiau of Intramuscularly and
`Subcutanwusly Administered Drugs
`
`Farida Kadfl: Christien Ousmrcn‘. and lean J. A. Crommefin
`
`Liposames: A Short“ Intmduction
`
`Lipasomes as Intramuscuiar and Subcutaneous
`Drug Deiivery Systams
`
`Studies on Heductian Qt“ Lesa! Irritatian
`
`Studies on tfw Pmrmfim Eflbct After
`Infranmsgaslfir Adlllfnistratffln
`3-112
`
`Studies on the Prgatectivc Effect Aficr Intracrfermal and
`Subcutanemss Aflministration
`34$
`
`Discussiejn
`
`Canclusiens
`
`References
`
`‘15.
`
`Biaflegradahie Micropartickzs far the
`Deveiupmaut (rcf Less»?ainful and
`Less-Irritating Parenterais
`
`Efias Farm}, Fabiana Quagiia, Pramgd Gupta, and Gayle Erazeau
`
`Ratianale fm‘ Using} Micmparticles in the) Daveiwpmem
`0f LeastainfuI and Lass4rritating Parenterais
`
`FahdLactidwCQ-Glycmide} Micmparticlfis as Daiivery
`Systems én the Bevelapmem 9f LegsfiPainfm am}
`Less-Irritating Parenterals
`
`329
`
`334;)
`
`336:!
`
`337
`
`338
`
`340
`
`341
`
`349
`
`350
`
`351
`
`355
`
`356
`
`35"?
`
`Polymer Selection
`
`35?“
`
`M’icmencapsularfan Technique
`
`360
`
`Drug Release
`
`366
`
`Sterilizatian
`
`368
`
`Rasiciuaa‘SoIvmts
`
`36$?
`
`Stability a? the Encapmiamd Drug and
`Micmparfide Praducm 369
`
`Pratectivan Against Myotaxicity by Intramuscularly/
`Subcutanemsiy Adminigtered Micropamcies
`
`370
`
`AstraZeneca Exhibit 2079 p. 10
`
`

`

`Contents
`
`xi
`
`Canclusians
`
`Reféerences
`
`’18.
`
`Emulsians
`
`Prammd K. Gupta and Jahn 5‘. Cannon
`
`Ratianaké for Using Emuigiens far Reducing Pain and
`Irritation upon InjECticm
`
`Petemial Mechanisms 0f Pain cm Injectim
`
`Case Studies
`
`Prmpafaf {Diprivan®)
`
`38.2
`
`Diazepam 384
`
`Etomfdatr:
`
`388
`
`Pregnanomne (E'!tan0!wne®)
`
`388
`
`Memalmxfm} and Thimpenta]
`
`389
`
`Amphmericén E3
`
`3235;?
`
`Clarithromycfn
`
`3.91
`
`Chaliengeg in their»: Lise Qf Emulsions as Pharmaceutical}
`Desage mes
`
`PhysicalStabflily
`
`393
`
`Efficacy
`
`393
`
`{Jase Volume
`
`394
`
`@the:- Issues
`
`39%
`
`Conclusions
`
`References
`
`
`
`D: FUTURE PERSPECTIVES IN THE DEVELQPMEN’F 01F
`
`LESS-*PALINFUL AND LEssanITATlNG INJECTABLES
`
`’17.
`
`meulatian and Administratmn Techniques
`10 Minimize Injection Pain and Tissue
`Damage Assaciateci with Parenteral. Precincts
`
`Larry A. Garfin anal Carr)! A. Gath‘n
`
`Formulatian Beveimpment
`Prefmmulaticm 402
`
`Formuian‘an
`
`404
`
`Focus on anmiahty, Cosaiventg, GUS. and pH «$10
`
`pH $115
`
`371
`
`372
`
`37'9
`
`380
`
`38'!
`
`382
`
`393
`
`395
`
`395
`
`401
`
`402
`
`AstraZeneca Exhibit 2079 13* l 1
`
`

`

`mu.
`
`x11
`
`Injectable Drug Bevefopmé'nt
`
`
`
`PashFOrmu mien Pracedures
`
`pH. Additivea and Salve-Ms
`
`416
`
`Swims; and Physical Mémmuféztions
`
`4??
`
`References
`
`index
`
`4—16
`
`420
`
`5323
`
`AstraZeneca Exhibit 2079 p. 12
`
`

`

`2
`
`Pain, irritatiaht anti Tissus
`Damaga Wlth injectians
`
`Walfgang Kiemant
`
`Department sf Anasthasioiogy and Intensive Care
`£12: Jur:g—Stiiiing~fiaspitai
`Sit/agar}, Federal Rspuhiic 01“ Germany
`
`MUST INJECTIONS HURT?
`
`Parenteral aciministration sf drugs is camrnan in medical practice. espe—
`cially far drugs with iittia (31' n0 hioavailahflity feliflwing gastmintestinai
`
`absarptian, with more rapid (inset times than passihla with nral adminisv
`tratian, tar with desired lacai affects. Sinca Readies are used ta penetrate the
`
`skin, same amaunt 0f pain is talented by the physician {when times nat fsal
`it) and by the patient (wha preferably wants ta get help}, Pain, however, is
`an sssentiai sensation warning the organism against possible tissue dalfl'
`age. Scrutiny sf knawladga ahaut the possibility of irritation and damage
`with certain drugs and their farmulatians reveals that the physician’s
`knawledga at“ irritation and damage is often small camparsd tn the inn
`
`creasing numbers sf injectians and infusions he or she applies;
`This chaptar’s paint (if viaw derives frnm the authar’s experiences
`with years sf intravenous (IV) administration of infusions and anesthetic
`drugs with relatively high incidsnces at“ pain, itching, edema, and thram~
`hatic complications; shah, there is little knowledge about the underlying
`mechanisms and tnisrance (if the "usual” problems Anasthasialagists, in
`particular, are canfrnnteci with prahlems associated with injectians, ashes
`ciaily with W rhutas, for the fallawing raascjns:
`
`s
`
`Anesthesia, ragianai 8r general, is usually perfsrmati thraugh an IV
`line.
`
`15
`
`AstraZeneca Exhibit 2079 pt 13
`
`

`

`16
`
`Injectsbie Urn Develepment
`
`e
`
`By means at“ their daily training, snesthesiulegists are considered
`
`"IV specialists” and are eften called in case of preblems with IV
`lines and administratien.
`
`*9 Mest efthe anesthetic drug formulations, minimally, have the pe-
`
`tency t0 eveke pain.
`
`Thus, [nest ef the studies dealing with pain eni discemfert en injectien are
`related t0 data frem anesthesiewelstecl drugs
`Systematic studies in humans abeut serious sequelee of injections are
`lacking, This may be due is ethical reasons or to the scarcity (if such com-
`elicetiens, since new drug formuletlens have been tested extensively in am
`imals before stiministrstien in humans is ellowecl. Nevertheless, there are
`
`uumereus case reset-ts dealing with thremiaetic complications, tissue dam»
`
`age, and necresis et‘ter cirug injectiens. This helps us keep in mind that
`
`pain, irritatien, and damage are still problems with injecteble preducts and
`that we must net diminish eur efferts to design safer drug fermulstiens.
`
`MECHANISMS 0s PAIN AND DAMAGE
`
`Frem a theuretical paint ei‘ View, there are at number ef fecters that can leacl
`
`te pain and damage.
`Petr: is mediated by the stimulatien ef necicepters, which are sprescl
`
`threugheut the whale ergenism in clifiierent densities, Neciceptors can be
`stimulated by streng mechanical pressure,
`lew or high temperatures,
`anti/er chemical irritants. The possible chemical agents are numereus and
`
`may be released item sexless cellular damage {e,g., petessium end hydrw
`gen lens, sclenesine triphosphete [ATP]) or they may be e. chain link in the
`inflammation cascade that takes place after a noxious stimulus (eg,
`kinines, histamine, seretenin, etc; see Figure 2.1).
`Thus, injectiens may cause pain mechanically by framing a nonfitting
`volume of injectien inte tissue or a smell vessel, by law [< 209C) er high
`[> will) temperature ef the injected sclutien, at by chemical activetien {dis
`
`rectly er by causing cellular damage). Remember that pain not eniy warns
`
`ef pessible tissue damage, but that serieus and nuxiuus stimuli also cause
`the necicepters to release medieters fer starting the inflammatory cascade
`(cg, substance P, calcitenin gene—related peptide, etc), which in turn
`causes weal, flare reactien, anti edema. in sum, chemical irritants may
`cause net enly pain but also merphelogical changes like inflammatiun vie
`excessive stimulatinn of nccicepters.
`Cellular and tissue damage can be caused by cellular er tissue specific
`toxicity er by aggressive physicechemical properties leg, acidity, besicity,
`high or law esmeiaiity} leading te cellular membrane destabilizatiun.
`In bath cases, the extent of pessilile damage depends on the local peak
`concentration cf the irritant, as well es en the time ccurse of lecal
`
`AstraZeneca Exhibit 2079 p, 14
`
`

`

`Pain, Irritating and Tissue Damage with lnjsctinns
`
`’1?
`
`
`
`Figure 2:1. Interactisns 0f nnciceptnn tissue, and vessels {luring
`inflamatian fhunwing trauma.
`
`INFLAMMMQRY EEACT‘ZUN
`
`macmphagcs
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`mediator release {Xi H": ATP}
` direct: stimulattun
`
`Trauma causes cellular damage: and thus direct and indirsct anxious stimulatian at
`the nsciceptar. The mediatms released by the activated nociceptor start the
`inflammation cascade, leading to an increase in nnciceptor activatisnt mediator
`release, and vascular and tissue rsactisns.
`
`concentration. The peak concentration in the tissue or blend is determined
`by the cnncentration ancl velums of the injectinn and the speed at injscw
`tlUn. lmrnefiiate processes like dilution in blood, 10cm binding (3.9“. 1:31-53w
`teinsf fat)! enzymatic degradation! and chemical reactions all contribute t0
`the effective peak concentration during injectians,
`
`The time course 0f Incal concentration depends on the distributian
`(diffusion) of the substance in the tissue and the vslocity at“ chemical react
`
`ticms with the Surrounding tissue! This, in turn, cispends can the supply sf
`reacting substances and thus is after: determined by lncal blend flow. Thus,
`
`the passihility far serinus ssquslas is highest with injectinns 0f anxious farw
`mnlatinns designed far specific: areas inta the wrnng ares (alga snlutinns
`far artery emhalizstim‘t of artsrimenous malfnrmatinns into the wrnng ves-
`ssl or paravsscularly; paravascular administratinn of chemntherapy; injec-
`tinn at“ a solutinn far an intramuscular [1M] mute intn subcutanenus fat].
`
`Variants kinds 0f allsrgic reactisns can £1150 Gauss mmplicatians, bath
`at the site of injectinn as well” as systemically The reasnn far damage is
`
`AstraZeneca Exhibit 2079 pt 15
`
`

`

`18
`
`Injecteisle Drug Develeement
`
`kissed en the molecular structure nf ell substances. Aspects Of as drug fen—
`muletinn ether then the actual drug (vehicles. diluents. stabilizers} are else
`able is cause allergic reactinns. This mixture sheulcl he tsileretl tn the gas
`
`tient’s dispesitinn anti allergies. In meet cases, Inca] reactiens ere mantel-ate
`anti transient. Therei‘ure. allergic: reactiens will Only he discussed when
`their likeliheecl is high er there is n pessibility fer severe damage.
`This chapter presents an everview ef the problems and sequelae that
`can eccur using different reutes ef injectien, primarily IV. Certain drugs
`
`and fermulstions will serve as examples {where pessihle sequelne with in-
`
`jectiens were ehservecl and studied). If knewn, lessens and mechanisms
`fer pain, irritatien, and damage are described, and Suggesnens are ere"
`
`visited tel prevent pessihle damage.
`
`ROUTES er: DRUG lNJECTIin
`
`(Intenseus/Suiscutaneeus Injections
`
`Subcutaneous end. in particular, perevesculer injections have been per»
`fermeti where intrevescular injectiens were intended. Since it is unclear
`
`whether er net insttentive parevssculsr injectiens will eccur with incorrect
`needle pesitien exclusively. this emblem is discussed later.
`Suhautsneeus injectiens ere eerie mere frequently inte tissues with
`
`relatively lew bleed flew like fat and cennective tissue. Du the ene hand,
`this weuld hepel‘ully produce the desired effect (if slew abseretien and
`lenger duratien sf ection. Irritant drug fermulstiens, en the ether hencl,
`
`else form leng acting subcutaneeus depesits and stay in centect with the
`tissue, vessels, and nerve fibers, slewly decreasing in concentratien. There
`
`fete. the theereticel pessibility ef causing damage is high. and, this is the
`reason that same drug fermulntiens tiesigneci fer injectinn inte the muscles
`with a used bleed supply may cause severe damage when injected inte
`subcutaneeus fnt.
`
`A review ef possihle cuteneeus reactiens te injectehles was published
`recently (Martian 1995s; Mergen 1995b). it included special aspects ef skin
`patheingy and histnpathelogy. In mest of the cutanenus encl subcutaneeus
`injectiens three greues {3f drugs were stiministereti: insulins, hepatitis. and
`lecel anesthetics. Therefore. these drugs will serve as examples fer segue
`has at cutaneeus injectinns for the fellowing discussinn.
`'
`In the case of insulin,
`lune] reactions to injection are frequently imw
`
`munelegic emblems. in early furmuiatiens. pain, itching, flare, edema, and
`inclurstiens eccurreci in more than 50 percent of the patients during ther-
`apy. These preparatinns were impure and acidic (pH 3.5), which may ex»
`plain the high incidence sf allergic reactiens and pain en injectinn. The
`incidence sf allergic reactiens decreased with highly purified insulins
`end. is minimal with human insulin precluced using recemhinant DNA
`
`AstrsZeneca Exhibit 2079 p. 16
`
`

`

`Pain, Irfitntitfm, and Tissue Damage with Injections
`
`‘39
`
`(decxyt‘ihhnucleic acid) technelagy {Gaidfinh and Kahrt 1994), Since the in"
`ciclence 6:}? latex allergies warns in be increasing, care: should he taken that
`the sealing semi-sounds hf vials and syringes used in insulin therapy {it} that
`cantain rubber. This may exert an allergic reaction that dates nht depend {in
`insulin allergy (Tawse ct a1. 1995). A special case (if damage tea the cutis anti
`
`suhcutis is caused by insulinwinduceci lipatrophy, which occurs with re—
`peated injectians at the same injectihn site. The incidence is said to be up
`its» 3 percent in adults and even higher in children. The underlying mecha,w
`nism is thaught it: he immunhlngic (33:2ch at al. 1980). The additihn if can-
`ticosterclids {Kumar et a1, 19??), use of highly purified insulins, regular
`chhnge 0f injectihn site, anti intramuscular administratihn shnulcl prevent
`
`its development.
`With subcutanchus hhparin injectian, a heparinlinducee‘i skin necrhsis
`may accur clays after the drug administration {starting with edema, flare,
`and pain at the injectihn site) and lead ta necrcltic lesions 01’ the cutis anti
`
`suhcutis, An impressive image hf such a reactih" was recently published
`(Christiaens and Nieuwcnhuis 1996). This Chmplication is rare and its
`
`causes are unknown, but the: delay between first injections and necrosis
`(lacs neat indicate a direct chemical reactihn to the: drug formulatian- Since
`
`hcparindnduced skin necrosis is often accempanied by thrcmbhcympcnia,
`it may regiment a lhcalizecl farm hf the heparinwinduacd thmmhhcythpenia
`syncirhme {Mar at al. 1995) and. cause Incal thrombotic lesihns hf small ves—
`sels fQHQWE-l‘d by tissue nemesis,
`
`Lhcai anesthetics, usually administered intraw or suhcutancausly fer
`minor surgical pmcetiures, were knawn t0 cause pain on injcctihn, espe-
`
`cially in the case Gf litic‘cainei That pain can injectihn accurs with the applid
`
`catihn of lhcal anesthetics, which the patient is mid will minimize his Q)" her
`pain during surgery, tithes that help improve the patiem‘s hhnfidence in
`madam medicine, Numemus studies have been perfhrmeci, examinmg haw
`to avhid pain can injectian ism: Tahiti: 231i
`'
`, Since the pH of varihus farmulaiicns hf iidhcaine varies between 4 and
`S {authar’s unpublished data; Lugodaner at al- 1993), the acidity was 139*
`lieveci ta cause pain, thus, the salutiong were buffered, usually with small
`amaunts of 8.4 percent éhdium hicarhhnate. With the use of buffered vex»
`
`sus plain iicicacainc, the intensity of pain on intra- and subcutaneous injec—
`
`tihn decreased by 40 til 80 percent (Fireman at all ”1995; Matsummn at hi,
`1994; Christelph at al. 193%). Similar results were obtained with buffered ii-
`docaine in digital nerve 131mm (Barmeld et at. 1993], buffered prilhcaine in
`
`IV regianal anesthesia {Armstmng at al. 1990], and intracutanmusly in“
`jected buffered mepivacaine (Christhph at all 1988).
`Some anthers tried it) use warmed plain lidhcainc (37 t0 409C) to min~
`
`imize pain on injection. While pain intensity sametimes decreased by 40 tit)
`70 percent (Bragzin et a]. 1995; Davidsan and Eltmm 1992), gathers faiigd t0
`svelte beneficial effects with warming (Mader et iii. ”19%; Balthn et ai.
`“1989), Buffered licihcaine pmvakecl the same law pain intensity with 37°C
`
`AstraZeneca Exhibit 2079 p. 17
`
`

`

`26
`
`Injectable Brag Devalepment
`
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`AstraZeneca Exhi
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`it 2079 p* 18
`
`
`

`

`Pain, Irritation, and Tissue liismsge with Injections
`
`21
`
`rather than 20% (Martin et al. 1998:), but others described no benefit of
`warming or buffering except when liclocainc was warms-ti and buffered
`[Master st 3!. 1994]. To add furthcr to the confusion, saline solutions of lid
`
`cocaine with a pH of 4.2 and 5.3 evoked less pain than buffered liclocainc
`with a pH of 8s {Lugowjaner et al. 1993). In the latter study, however, only
`solutinns with epinephrine were used, uncl its possible psinucvoking (or in
`creasing) properties may hsvc contributed to the ccnfusinn.
`The reason for the painful injecticns is not easy to determine. None of
`the pain-«reducing methods described hafnrc is chic to make the injections
`painless. Although intrs~ and subcutancous injections cause some pain
`mechanically lay distracting the tissue (which may explain thc pain occur—
`ring even with buffered local anesthetics), it remains unclear whether or
`not the substances themselves cause pain. Controlled studies using a
`placsbc its. pain testing with clerical injectiuns of nuns buffered diluent
`versus buffered diluent with lscsl anesthetic] have not been performed
`with two exceptions:
`
`’l.
`
`Lugowlaner and colleagues [1993) tested hactcriostntic saline so”
`luticn with epinephrine 1:300,000. which was found to he signif‘
`icantly less painful on mtrsdcrmsl inffltrnticn than lidocstne with
`epinephrine monon- with sodium bicnrhcnate Ell meq/rnLt Un»
`i‘crtunstcly, two different amounts of epinephrine were used,
`
`thus decreasing the amount of information on liclocaine’s intrin—
`
`sic painacvoking properties.
`
`2.
`
`In contrast, Farley and associates (1994) fcuncfil more discomfort
`
`with the injecticn of normal saline than with lidocaino in normal
`saline. which goes against its pain-euckihg prnpcrtiss. Unfortua
`nstoly, their preparation of normal saline had an aciti pH of fills
`versus a mare: normal {DH of 6.5 with liclocsinc in saline. Therew
`fore, the acid pit of the preparations, not the local anesthetics,
`seem to evoke the pain with dermal injections.
`
`Thus, pain on intra— and subcutancous injections of local anesthetics is
`
`common. is mcompatihic with the idea of local anesthetics, depends in all
`likelihood on acid pH values, and thus can be avoided by buffering the drug
`
`solutions, which apparently does not affect the numbing activity.
`
`Severe local reactions like skin necrosis: hswcvsr, are rare, Allergic rc~
`
`actions. especially with local anssthetics (3f the csther type did occurt The
`systemic immstliate type reactions can he serious and require immedistc
`treatment. Local reactions were transient and usuallyr clicl not cause lesions.
`
`Vasosctive uclditivcs like epinephrine may cause tissue damage, especially
`when applied in car lobes hr digits. The cause for necrosis is a long-lasting
`vssoconstriction and, therefore, is most likely due to ischemia. This type of
`
`necrosis is not related to local anesthetics but to alphsuadrenergic acticns
`of vascconstriaors it may also happen following accidental application of
`
`AstraZencca Exhibit 2079 pl 19
`
`

`

`22
`
`
`Injectahls Brug stclnnment
`
`such drugs, and ssricus sequelss can he prevented by immediate trcsnncnt
`with alnhsficlrencrgic blocking agents like phentclsmine (Hardy and Agus—
`tini 1995).
`
`Intramuscular Injccticns
`
`1M injectinns were widely used f0)“ mare than a century antimcnmparcd
`ts lV shministrstinnmwcrs thcught tn he less harmful and equally reliable
`in effect. The tisvsicpmsnt 0f msthcds tn msssurc drug cancsntrstinns in
`island, liswevcr, revealed interindividual as well as interdrug differences
`
`in hinavsilahility (chthsssr 197%, h). Since this time, and paralleled by
`
`the development sf better materials and techniques cf iV application, 1M
`injecticns may nut be used as Often clinically. Nevsrthslsss, many drugs are
`still injected intramusculsrly, sq, analgesics and sntihintics, and some
`prnhlcms tic nccur with this mute cf application. Due to the hicccl finw
`through skeletal muscle, injectinn cnncentraticn in the tissue dccressss
`
`muss quickly than in subcutansous fat, with pccr 131000! supply. lut slurs
`ticm nf ccntact cf the cnncsntrated injectinn tn the tissue is long, when com--
`
`pared. tn iV injecticns with rapid dilutinn by Island.
`
`Althcugh skeletal muscle is pnnrly innsruatsd nucicsptivcly, pain is
`
`frequent with intramuscular injections, and the: rsasuns for this have been
`studied far years (Trsvcll 1955; Taggsrt “1972]. Research has shown that 89‘
`luticns with pH lsvsls far ahczve the physinlcgicaliy tnlsrshls range, and
`with high B‘I‘ very law nsmnlality give rise tn pain an injectinn, The vslums
`
`si’ the injectisn relates ts pain intensity, 30 that, in additinn to chemical ac»
`
`tivaticn, muscular nnciceptcrs nhvinusly rests-and tn tissue distention. The
`size and cut cf the needle used 3150 ccntrihute to pain cm intramuscular ins
`jectinn, The nerve fibers stimulated by the needle, hhwcvsr, seem to he 10—
`
`csterl in the skin and in Subcutansnus cunnective tissue, since this type 01’
`
`pain can he rsrluccd by Inca] cccling. Adding local anesthetics t0 the injec»
`tisn has been reccmmenclscl for pain relief, but are ncut used very Often.
`Digital pressure applied to the raglan immsdistely hefnrc intrsm usculsr in»
`jcctinn reduced pain intensity by 37 percent {Barnhiii st al. 1996),
`lamsgs the muscle cells seems tn nccur with each intramuscular injec-
`tion, Issuing t0 measurable elevations in serum creatinc kinass (CK) ccns
`
`centratisns, Numercaus studies rcpnrtcd this nuisance in the diagnostic use
`Of the cnzytnc in patients after intramuscular injections, Direct muscle t0x«
`icity hf drugs, the distentinn trauma, the effects (if certain drugs on cell
`membrane permeability, and cthcr mechanisms were all accused Elf being
`
`responsible far enzyme release-2.
`Ont» ingenious stun); related the dimensinn sf muscle damage tn the
`physiccchemicsl data m“ the: injection (Sicilsll ct a], 1974):
`
`a With injecticn cf ccnstam valumss, CKrespnnsc depends 0n the
`concentraticn cf the clrug and the csmclality cf the sclvents.
`
`AstraZeneca Exhibit 2079 p. 20
`
`

`

`Pain, Irritation, and Tissue flamage with Injectidns
`
`23
`
`Injections of saline ahcwc an osmdlality cf 1.5 csmol/L increase