Parenteral Medications
`Volume 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. lieberman, and lean luthmun
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`AstraZeneca Exhibit 2107 p.
`InnoPhamia Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017—01910
`
`

`

`
`
`
`
`ParenterIal
`
`Sum Efiéfiimg “We mi Epndxnmfi
`
`KennAih E. AME
`
`The Univetsity of Tennessee
`Memphis, Tennessee
`
`
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`L @ 1.,
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`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
`
`
`
`Lachman Consultant Services
`
`Westbum New York
`
`Marcel Dekker, inc.
`
`New Yen-k A Basel 9 Hang Knng
`
`AstraZeneca Exhibit 2107 p 2
`
`

`

`Library of Gangress Cataloging - in“ Publication Data
`
`Pharmafleutical dmsaga farms; paranteral medicatians / edited by
`Kenna/t1": E. Avis, Herberi A“ Lieberman, and Leon Lachman. M 21163 ed. .
`rev, anti expanded.
`En
`cm.
`
`Includes bibliographical references and inaax.
`ISBN G-82é%83’3$v2 (v. 1 : am. paper}
`1. Parenteral salutiens.
`2. i‘hm’maceutical technniagyfi
`Kenneth E.
`II. Lieberman, Havbert A.
`III.‘ Lachman, Leann.
`
`It Atria,
`
`[DNLMr 1* Infusimns. Parenteral. 2. Techmlegy, Pharmaceutical.
`WE 35:: P535;
`RSBBLPE'ENS 1932
`615’. Lia-"dew
`‘DN LEW 1'1}ij
`
`im- Library of Cungress
`
`91 »38053
`{ZIP
`
`This beak is printefi 0n acid-free paper.
`
`Cflpyright LC} 1992 by MARCEL IEKKER, INC. Ali Rights Reserved
`
`Neithar thii book my: any part may be repmfiucsd er trangmittad in any farm
`(it by any means, algctmnic m mechanirsal, inclufiing phatompyingt micrw
`filming, and regarding, m by any infarmatiorz manage and retrievaf system,
`withom permissian in writing fmm the: pnhtishan
`
`MARCEL DEKKER, INC.
`2‘20 Madiscnn Avanue, NW Yen-k, New Yark 10016
`
`Current printing (last digit);
`10 9 8 7 6 5 4 3 2 I
`
`
`PRINTED IN THE UNITED STA‘WES OF AMERICA
`
`Astraleneca Exhibit 2107 13* 3
`
`

`

`Confiaemtg
`
`I’refaae
`Cantributora
`
`Cantams cf Phavmaeeutical hostage Emma: Parenteral Medicatians,
`Sewncfi Editiang Revisad and Expandad. Valumes 2 and 3
`Cantents 0f Pharmaceuticzal Bflaage: Farms: Tablets, 852mm: Editicm,
`Revised and Expanded. Valumes 1*3
`(laments af Pharmaceutical Baggage mes: DiSperse Systems,
`Vulumes 1 and 2
`
`iii
`xi
`
`xiii
`
`3W
`
`xvii
`
`Chapter 1
`
`The Parenteral Bewge Farm and 11:5 Hismricgtl Davelapmant
`
`1
`
`Kenneth E. Avis
`
`I. The Dasage Farm
`II. Histary Bf Parenterai Medicatians
`flippemfix A: Glossary of “Karma
`Agapandix 1E3: Highiigghts in the Rigatm‘y of
`‘Parentewl Meclicatians
`References
`
`Chapter 2
`
`Parenteral Ilrug; Adminigtratmn: Routes, Ereeautiuns,
`Emblems, Complications, and Brug flelivery Sygtamfi
`
`Richard J. Duma. Michael J. Akin-‘3. and
`Saivmare J. Tame;
`
`Intraductimz
`l. Generai lnciicatiana for Parenteral
`
`Administration :31" Drugs
`H . Pharmaceutical Factars Affecting Parenteral
`Administratifin
`
`UL Specific Relates of Administratiun
`IV. Distribution 63f Farenterally Administered Agents
`
`1
`4
`12
`
`1%
`15
`
`17
`
`1 7
`
`18
`
`19
`
`21
`3‘3
`
`vii
`
`Astraleneca Exhibit 2107 p* 4
`
`

`

`viii
`
`Cantrnts
`
`Vr
`
`Freeautiens, Prablems, Hazards, and
`
`Campiirations Associated with Parenteral Drug
`Afiministratian
`
`VI; Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`Raferencas
`
`Clzaptar 3 Bimpharmaceuties af Injectable Medicatians
`
`Seal Mamie
`
`I.
`
`II.
`
`Intrfiductifm
`
`Physiwchamica}. and Physiaiagieal Faewrs
`Afircting Drug Absmrptian by; Inferticm: An
`Overview
`
`IV.
`
`I11. Applicatinn 13f Pharmacakinafias to Biogharmw
`cautic: Investigations: Pharmacokinatic Madam
`Examgglas at" Bimpharmacautic{Pharmawkmetic
`Prinuigales
`V. Regulamry Consifierstians far Bioequivalenca
`Studies;
`
`VI; Biaequivalence Study @f Twm Inimitable Farmg
`0f the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 63
`
`Prefarmulation Research 9f Parenteral Medicatians
`
`5'0? Mamie} and Shreeram N. Agharkar
`
`I.
`
`Intrudnctian
`
`II. Drug Substance: Phyaicachemiéal Properties
`III. Acuaieramd Stability Evaluatinn
`IV. Gangral Macias 0f Brag Degraflafiun
`V,
`Prefurmulation Studies fur Framing and Peptides
`VI.
`Prefarmuiation Screaming cf Parentrm]
`Packaging Compnnema
`Summary
`VII,
`VIII. Prefarmulatien Worksheet
`
`References
`
`Chapter 5
`
`Formulatian of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylcm
`
`I.
`
`introductian
`
`II.
`Farmulation Principles
`
`III. Cmntainer Effecta an Farmulmicm
`
`IV Stability Evaluatian
`V.
`Pracesa Effects
`Referéncas
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`$0
`
`??
`
`993
`
`1138
`
`189
`111
`112
`
`115
`
`1 15
`
`118
`1%
`150
`1551
`
`1.58
`163
`1&3
`
`169
`
`1?3
`
`173
`
`1%
`22'?
`
`23%
`244
`245
`
`Astraleneca Exhibit 2107 p* 5
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`

`

`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterels
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong John Wong
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`SteriIe Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul Abendroth and Robert N. Clark
`
`1.
`II.
`III.
`
`IV .
`V .
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2107 p. 6
`
`

`

`:-
`
`Canlents
`
`Chapter If) 05% 0f Plasticg for Parentserafi Packaging?
`
`Jahn M. Ana's. Raher‘t S. N339‘ and
`Charms H, White
`
`Intmductimn
`I.
`Fundamentalg
`II .
`III. Fabricatian Pmcesses
`
`Imgortant Criteria {car Selectian 0i” Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parentera? Contaiflew
`Raferences
`
`Chapter 11 Elaatameric Cifisures far Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`I. Elagtomeric Parenteral Packaging Companents:
`A Physieai Descriptmn
`Phyaical Dessrigtion (sf Rubber
`II.
`III. Typas :35 Rubber Usaci in Parenteral Packaging
`IV‘ Ciasura Besign
`V. Rubber Campuunding
`V1. Vulcanizatinn Franzen
`VII. Closure: Manufaczture and Contra!
`
`{Ensure Eesigfi Qualifieatian
`VIII.
`1X . Regulatory Qansifietatims
`X .
`Intarantiun {if 13mg Farmmatiuns with
`Rubber Clasures
`
`XI. Cmntgmpm'ary Closure-Related Issues
`References
`
`Chapter 12 Pamnmra: Praducts in Hospital anefl Heme Care
`Fharmaey Practice
`
`Jam: W. Levchuk
`
`l.
`
`Introdumifin
`
`II. The Frepawfiinn {3f Sterile baggage Farms in the
`Haspita} and in Rama Care
`III. DiSpensing and Comgounding P‘mcessas
`IV. Tenhnolug’y 3f Sterile Cnmpaunfiing in the
`Hmspital thmaey
`V. Clinical: Supply and Use at“ Sterile product&
`VI. Qualify Assurance
`V11 . Canclusien
`
`Appendix: Abbreviated Sequence for Preparing 5-1
`Sraries of Extempomnmuglgr Campaunded LV.
`admixtures
`Refemnces
`
`~
`
`Index
`
`387
`
`38?
`. 339
`393
`
`($07
`422
`c139
`4&3
`
`1145
`
`445
`450
`451
`462
`483
`£170
`4'77
`
`€394
`583
`
`$05
`
`58‘?
`508
`
`513
`
`51 3
`
`513
`52%
`
`532
`547
`552
`5&2
`
`563
`56%
`
`569
`
`Astraleneca Exhibit 2107 13* 7
`
`

`

`2 P
`
`almtami Igm Administmim; Rmtgg
`Mmmtég, Problemg, Complicatians;
`and Drug Delivery Systems
`
`
`
`N
`
`Richard J . Duma
`
`Mediaai @3339 (If Virginia, Virginia Cemmanwealth University, Richmand,
`Virginia
`
`Michaet J. Akers
`
`Eli Lilly and Campany, Indianapolis, Indiana
`
`Saivatere J. Turw
`
`Temple University, Philadelphim Pennsylvania
`
`Parenteral, fmm para enter-fin (Greek) , meaning "m amid the intestines,“
`
`includes in its bmadest sense, any drug (or fluid) whase deliver}; fines net
`utilize the alimentary Gama: for entry ink: 1:302:33; tissues. Altmugh drugs ap-
`pliati tapically t0 the: eye, ear? and skin, or even inhaled, may be hraadly
`interpreted as parenterals, maximal anti pharmaceutical health care deliveries
`generally limit the dafinitiun it} these fir‘ugs injected 0r infusaé directly inm
`tissues. tissue 51368638; vessels, OE badly comxgsartmeants.
`The develapmem cf techniques for administering parenterais. cauplad
`with innavative fiasigna 0f new dQViCBS to: achieve and manitw their delivery”,
`Qccur faintest daily and are enabling therapeutics t0 appmfich an exact sciatica
`In acitiitiuni, parenteral therapy is n01: restricted tea hospitaig or clinics but is
`being inereaaingly employefig even in its mmt invasive farms 0f delivery (a. g. .
`intravanoua} , ta manage yatiemts at home and in the work placing. Mast; pm
`tients reality accept 0r easily afiapt ta almmst every form mi“ parenteral ther*
`apy, and many selfmdminiater their own (11%.thP even when the mute of de-
`livery i5 intravencms (mg , Emma infusirm prggrams) .
`Parenteral adminiatmtéon offers many advantages eve:- therapy given by
`nonparenteral routes. M031: notably , therapeutista can raliably predict with
`canaiderabla accuracy the pharmacakineties and pharmacolmgy 0f the agents
`they yreacx-ibe; the}? can quickly intardict a rapidly progressive mum pro“
`cess er disease; and, even ttmugh the physimmg}; and patholegy 0f patientg
`may be flomplicated,
`the}? can "fine tune," stratify and quantitate results.
`flawever, despite these advantages‘ parenteral, administratmn iii neat without
`
`I?
`
`Astraleneca Exhibit 2107 pt 8
`
`

`

`18
`
`£1qu ct cl.
`
`certain, measurable risks and limitations that the prcfcscicnnl must intelligent—
`13; weigh in terms cf risks, benefits, anti coats.
`This; chapter will attempt in review and update the usage at narcnteral
`administration in tcday*s granting of mcc‘licinc. chcvcr, cincc thc subject is.
`dynamic anti the techncicgy is granting, the reader must nppreciate that came
`cf the material contained herein may became quickly nuttlntcd.
`
`
`
`1. GENERAL lNDlCATEQNS {PEER PARENTERAL
`
`
`ADMINXS RATIQN {3F DRUGS
`
`
`
`The narcntcral in ten of drug administration are indicated far One 01' mere
`0f the facile-wing reasons:
`
`1. Tc ensure delivery cf adequate ccnccntraticnc cf the drug in QUES*
`ticn ta iiaeascti tissuec 0r target areas cf the bctflyz capacially when
`inadequate or marginal thansnnrt cf that drug; into the tissuca tar tar
`get great; is anticipated. Example: Direct intrancnii’icmar injccticn
`cf drugs (mg. , nntibictics such as the aminnglyccaidcc) which crccs
`the *‘blccciwbraiwmcningcn barrier" pawl}? may he used. in certain
`patients with bacterial Q3“ fungal meningitis antifcr ventriculitis.
`Tc permit the user to exert direct ccntrci nvcr certain pharmacclcgic
`ncramctcrs, Such as the time cf drug onset. scrum peak and trough
`levels, tissue ccncentrcticns. and rate cf eliminaticn cf thc drug fmm
`the batty, Example:
`lntrnvcncus or direct canfiicintraventricflat‘
`routes may be desirable tn achieve immediate effects in emergencies
`such as might want in the central of life-threatening ltypctcnsicn.
`hypertensicn, {21' arrhythmics; or intramusculm' mutcs may be icsiw
`able to attain protracted cr sustained effects, Such as the use of
`hencathinc penicillin G in the treatment cf infccficns.
`Tc allcw the therapist, when outnnticnt management is flccimblc, tc
`guarantce 6103333 and drug ccmplianne, especially when the patient
`cannot be relied upcn t0 ccli‘mmadicntcg Example: The use of 1cng~
`acting {mnnthly} intramuscular penicillins may he usecl tc managn
`children ymphyincticaliy fnr rhcwnntic heart disease in crcicr t0 pic»—
`vent Gran? A ctrcptccccccl nitaryngitia.
`To deliver a binlngic cffcc't that cannct he achicvctl through oral att-
`ministraticn, Epcrhnps because (if ncnahnorbancc fram the alimentary
`canal m- dcgrntlaticn by gastric acidity. Emamnlc: Therapeutic new
`titles anti nmteinc such as insulin, human grnwth hcrmcne, cther
`products frcm recombinant DNA technclcgy, and polyene antihictica
`{such an the antifungcl agent amphcter-icin El).
`Tc aflministcr a flrug when the ficcired route (tag. , Meal) may not be
`available. Example:
`In gaticnts whc are aspirating or who have him
`the upper gastrointestinal tract stream diverted 0r rcmcvccl (gag. ,
`because cf a carcincmn) c parenteral mute may be necesccry.
`To provide a lccal effect when it is desirable tc minimice 0r avcici sys~
`temic taxic effects the reacticnc. Example: Mcthctrcxate may be given
`intrathccaily t0 patients with leukemia and leukemic invclvemcnt cf
`the meninges ta amid the systcmic, toxic cffectc that wuuld occur if
`an intravcncus rcutc was employed.
`
`Astraleneca Exhibit 2107 pt 9
`
`

`

`Par-nmgrfll Qrug Adminintmtinn
`
`'
`
`19
`
`‘F. Tn administez‘ drugs to tha unconscinus, uncooperative, er uncnna-
`tmllnlale patient. Examl‘lla: Patients with uncontmllable grand mal
`aeizuren after: will. net owner-ate in film oral administratinn of druga
`01‘ will be: at risk tn aspirnte if enmnelled m take medicnnas by mnuth.
`Similarly, patientsa nneonscicus frnm namntin abuse, anesthetic usage,
`a}? trauma, 0r unnnoperative panama nuuh as thnse suffering delerium
`tremenn or a. psychnsis, may be satiafaetnnily managea‘l by using narem
`tern] mutas.
`
`8. Tn permit ranid Gwyneth}: of fluid and electrclyte imbalances and. “(a
`supply annrt- or Dang-term nutxitiunal {leads (hyperalimentaticn an
`narentet‘al feedingll Example: Patients suffering severe dehydration
`or electrnlyte depieiinn fer a variety 9f rensnns (tang . heat strnke)
`can be rapidly narrentad with intraveneus alectrnlyta snlutiana ; anal
`patients whusa intestinal tracts have been resactezd for we reasnn
`an another may be: intravennusly ”fed" a complete diet of all the nieces"
`Ear}! amine: acids, glucczase, minerals. and vitamins far nrnlnnged and
`indefinite periads of time.
`Inca} annsthetica fm‘
`Tc: achieve a desired 101ml effect. Example:
`tnnth antraetinns ei’ar Incnl antiwinflammntory agents fnr inflamed inints
`may be in§eatad (lireutly int. the site: in question tn avnid systemic
`effects a}? “ayatemic” (images.
`
`‘9.
`
`H. PHARMACEUTICAL FRCTORS AFFECTING
`PARENTERAL ADMINISTRATiON
`
`Certain pharmaceutical characteristics dictate the method or route 0)? paren»
`feral adminfiatratinn, and nnce the dosage farm is injected {31' infused, influ-
`ence the rate and extant 23f drug availability. Them characteristics will be
`reviewed briefly in this sectinn, but the reader is .3150 referred to Chapter 3
`far a mare cletailad treatment 91' the. binpharmnceuticnl factnrs affecting pare-n"
`tarsal drug availability
`
`A. Snlubility nf the Drug and anume [IF the tnjectlnn
`
`A drug must he camglateiy sulubilizac}, prsfemhly in water, befnm it can be
`admininteretfi by intravennns injectien. Bath the extent nf érng solubility in
`its intended velnclez: and Th3 rinse required for the desired thanapnutic effect
`will determine the valume of the injectmn. Parenteral routes lather than the
`intravenaus {me have limitations mgarding the maximum volume of medicatinn
`administered {engl , intradermnl, intramuscular, intrnncular, intrnvantriculnr,
`and. intrntheeal, to name a few).
`
`8. Vehicle Characteristics
`
`flrngg in aquecrus vehiaies may be administerncl by any parenteral route,
`whereas firugs in nnnaqueans vehicles. which may nr may not be water mis~
`cible, are administerefl most frequently by the intramuscular rnutm The ina~
`travemua mute may he used for: a few drugs in mixed snlvent systems (a. gm. ,
`éiazeyam, dig-min, and phenytoin) 3 but yreonutinns must be applied in animat-
`ing the rate of flrug infuninn tn avoid drug precipitatinn at the site of infngian.
`
`AstraZeneca Exhibit 2107 pl 10
`
`

`

`20
`
`Dunn: at all.
`
`Large volume parenteral fat emulsions are also available by the intravenous
`route. Nonaqueous vehicles that are more viscous than water vehicles will
`affect the rate of injection through a small~gauge needle and the rate of ab-
`sorption from the injection site.
`
`C.
`
`pH and Osmolality of lnjectable Solutions
`
`Ideally, administered injections should be formulated at a pH and osmolality
`similar to that of biological fluids. Unfortunately , this is not possible for
`many parenteral dosage forms, as many parenteral drugs are unstable at new
`tral pH. Therefore, such drugs are formulated at the pH at which they are
`most stable. For example, diazoxide (a nondiuretic benzothiadiazine deriva-
`tive) is formulated at a pH of 11.6, the pH at which it is most stable. Many
`parenteral drugs are salt forms of weak bases. Thus the pH of a dosage form
`Containing the salt of a weak base may he as low as 2.0 (mg. , tetracycline
`hydrochloride), or the pH of a dosage form containing the salt of a weak acid
`may be as high as 12.0 (egg. , Dilantin) in order to maintain the active in»
`gredient in solution. Although dosage forms with extreme pH values may be
`administered by any parenteral route, the rate and volume of injection must
`be controlled to minimize pain and irritation to the patient and damage to the
`surrounding tissues.
`Certain parenteral formulations are hyperosmotic with biological fluids
`and contain a relatively high dose of active ingredienfis) in order to achieve
`a desired level of biological activity. For example, water—soluble contrast
`media, spinal anesthetics, Ophthalmic sodium sulfacetamide, diazoxide, and
`
`osmotic diuretics are a few hypertonic parenteral formulations containing high
`drug concentrations to achieve an appropriate biological actionCS).
`l3roducts
`of parenteral nutrition are formulated or admixed with high concentrations
`of amino acids, dextrose, and other essential ingredients, resulting in very
`hypertonic solutions These solutions, called hyperalimentation solutions,
`are so hypertonic that they must be administered via a large vein such as the
`subclavian. The blood in this vein enters directly into the heart, which allows
`the hypertonic solution to be rapidly diluted by a still larger volume of blood.
`Generally, hypertonic parenteral dosage forms are contraindicated for
`subcutaneous or intramuscular injections. Whereas the vitreous humor, can
`tolerate only very narrow ranges of osmotic values from an injected medicatiOn.
`Therefore, although stability and solubility problems may prevent dosage forms
`from being formulated at physiolOgical pH, they should be formulated with
`solute contents approximately equal to those of biological fluids.
`
`D. Type of Dosage Form
`
`Parenteral dosage forms include solutions, suspensions, and sterile solids
`for reconstitution.
`If the dosage form is a suspension, it may be administered
`only by the intramuscular or sulscutaneous route. Particles should not be
`present in dosage forms administered intravenously or by other parenteral
`routes in which the medication enters directly into a biological fluid or sensi»
`tive tissue (e.g. , brain or eye). Reconstituted solids should be completely
`dissolved in the reconstituting diluent before they are administered intravenw
`ously.
`
`AstraZeneca Exhibit 2107 p. 11
`
`

`

`Parenteral Drug Administrmian
`
`21
`
`E. Fut‘mulatiun ingredients
`
`As discussed in Chapter 5, {latenterm formulations may cantain variaus active
`anti inactive excipieuts ether than the main thwapeutic agent. for a variety
`Of reaaons. For multiduse paxamemls, antimirzmbial agents are added t0 the
`furmulation fur the preservation {if sterility. Believer, these ugenta may be
`cuntrainciicated in meflicatians ta) be admimaterud into the cerebmupina} fluid
`at inti'uoculm' fluid because (if the tuxieity they may praciuce. Several parem
`tam] furmulfltiuns calntain surface“ active agents (such as pmlysurbate 83:1) to
`maintain drug solubility in tha seluticsn vehielu. Surfacgvactive agents are
`knewn t0 alter membrane permeability, so their grasenue must. be recugnized
`when administering such sausage fmmg by the subcu‘tamuua czar intrumusculgsr
`routes.
`
`Thu uxpanfiing fiald of sustained and prolnngesci refleasa uf drug" daiivery
`empluys various fDrmulatians and additives that at times aid in achieving the
`deuirefi duratiun {if drug autism. These additives are Frimarily highmmecularv
`weight poiymara 01* [Lily suiuents- Formulatiunéa cuntaining these maerumeiw
`cules are afiministarad by the subcutanuous @r intramuscular mums ta permit
`the delayed release uf the active ingredient within designer tissues {if the body.
`
`Hi. SPECIFIC ROUTES OF ADMINISTRATION
`
`
`Three primary routas cf garanteral administratiun are commonly empleyeci:
`intramuscular. intravauuus. and subcutaneuus. These three ruutes satisfy
`ta 5:: large lament the fault principal mascms fur administering parenteralea:
`(1} fax: therapy (definitive or palliatiue}. (3) far pravemian, (3) far diagnosis,
`and (Q) fur tampurarfiy alluring tissue functiufls) in 02‘er ta facilitate lather
`farms Gf tharapy. Besideivé these threa primary mules. additianal ones are
`utilized under special cireumstancea:
`far example, subcunjunetival, intruw
`uuuiur, intrathesa’i. intrawartiuular, and so on.
`In the sections is: follcl-w,
`the primary and special mules uf parenteral aflmmistratiun are reviewefl in
`alphabetical girder. Each raview will include £91m subheadiugs:
`fiegcriptiem.
`indicatiuns. precautions. and methad 91‘ drug 0r fluid delivery.
`
`A. Primary Routes
`
`Intramuscular
`
`Descriptmn.
`
`Injection directly inter: the badly of a relaxed mugcle.
`
`Indications. The intramuscular (i.m.) route is cane 0f the must gapumr
`and convenient routes available, bath fur the administrator and fur the patient
`[1} , aapeeially for a child [2}. Therefore, whenever it is passi’blc and prac»
`tieahie, the intramuscular mutt;l is used. The intramuscular mute provides
`a means. far praionged release «of drugs formulated as aquecms an: oily sulutionu
`0r suapensians. The intramumular mute is preferrad ever the anhmxtanamw
`mute when a rapid rate 0f absorptian is desired anti ate? the intravenuus
`mute when fur cme reascm r31“ anuther the drug cannot be administered direct“
`13; into the vascular campartment.
`Many factors affect the rate of drug absurptian fmm an intramuscuiar
`injectmn [2}; they will be discugsud later in this chapter.
`111*qu cammonly
`
`AstraZeneca Exhibit 2107 p. 12
`
`

`

`22
`
`Bums et al.
`
`injected by intramuscular administration include lidoceine, cephslosporins,
`eminoglycosides. diazepam, insoluble salts of penicillin G (procene penicillin
`G) , corticosteroids, narcotics, narcotic antagonists, and contraceptive steroids,
`to name a few.
`
`Precautions. Although intramuscular injections are much easier to ad
`minister than other injections, the main precaution is to avoid entering a blood
`vessel (especially an artery), which might lead to infusion of a toxic agent
`or a toxic vehicle directly to an organ or tissue. This can be prevented usu-
`ally by pulling back on the plunger of the syringe; if blood does not appear,
`the needle is probably not in a vessel. Also, the accidental striking of or
`injection into s peripheral nerve may result in a peripheral nerve palsy with
`or without sensory damage. Occasionally, when s large bolus of drug is in»
`jected into the muscle, local damage or muscle infarction may result, leading
`to a sterile abscess or to elevation of serum levels of muscle enzymes. The
`latter complication may present confusing diagnostic problems, espeCially in
`patients under suspicion of having a myocsrcisl infarction or hepatitis.
`If materials contaminated with microorganisms are injected, a septic abscess
`may result. Therefore, appropriate precautions must be taken to ensure ster-
`ility prior to injection.
`In patients with poor hygiene or skin care, microorga-
`nisms from the skin flora may he punched in by the needle at the time of in“
`jection, resulting in staphylococcal or streptococcal abscesses; and rarely in
`such situations as gas gangrene [3] (especially if epinephrine is injected)
`or tetanus [4] .
`
`the intramuscular route should never be
`An important note of caution:
`employed in patients with significant heart failure or shock, when uptake into
`
`the vascular compartment may he expectsntly poor. This caution should be
`followed especially if immediately high serum or plasma concentrations of the
`drug are desired or if rapid distribution to a distal organ is mandatory.
`
`Method. Various muscle sites are available for delivery (Fig. 1) , include
`ing the gluteel, deltoid, triceps, pectoral, and vestus leterelis muscles.
`In
`adults the site of choice often is the gluten] muscle, because large volumes
`of drug may be injected and tolerated. However, the vsstus laterslis of the
`thigh may also be used because it not only tolerates large volumes of medica-
`tion, but it is also away from any major vessels or nerves. For rapid absorp~
`tion and small volumes (<2 ml) , the deltoid muscle is nreferred, as some stud-
`ies suggest that blood flow in the deltoid muscle is 7% greater than that of
`the vsstus lsteralis and 17% greater than that of the gluteus msximus [5] .
`For this reason, in adults the deltoicl is the preferred site for vaccine sdmin~
`istretion.
`In infants and small children, the vastus lsterslis of the thigh is
`often preferred because it is better developed than other muscle groups. de~
`pending on the site selected. The skin is first cleaned with alcohol or e suit~
`able disinfectant, end the plunger on the syringe is always retracted prior
`to injeciton to he sure that the needle is not in a vessel. For deep intramus~
`culsr injections, as might be used for irritating medications such as iron prep-
`arations, e "z~track“ injection method is employed.
`
`Intravenous
`
`Description.
`
`Injections or infusions directly into a vein.
`
`AstraZeneca Exhibit 2107 p. 13
`
`

`

`Parenteral! Drug Adminiatmtiun
`
`23
`
`
`
`Figure 1 Same common sites empleyed fur intramuscular irxieatiuns. Upper
`left: puateriar gluteal, lacateti in the auter uppa? quadrant abaut 2 in. beluw
`
`the iliac crest. prer right: deflate! lucated about 3 in. below the acrtjmia‘
`pmcess. Luwar left: ventrugjlutaal. heated in the triangle farmed by fine
`finger an the anteriar supéyiur mac spine and the other an the fliae crest.
`Laure}: right: vastus taterslis, located along the middle third and lateral as»
`pact 0f the thigh. 'The ‘*bu11’s-eye" indicates the approximate site at” injectiun.
`
`Intravanaus Gav.) administration of drugat fluicis, andfor
`indications.
`telectrcalytes is one 0f the most summon pafienteral ruutes amplayed in husyitals
`teday.
`It is especially convenient fur rapid‘iy infusing large volumes uf fluid.
`The most common indicatiun for use of this mute are:
`(i) to guarantee tie“
`livery and ciistrtbutian when hypotensmn 0r shock exists; {2) to restarg rapid».
`1y electmlyte and fluid balance; (3) tea achieve an immediate pharmaculagic
`effect, eayeeially in amergencias, such m the treatment of certain arrythmias
`01‘ of seizures; (4) ta treat set-10m, lifwthreatening intentions gr ennfiitiona;
`(5) tea provide mntinuauss nutrition {hypermimemafiom when patients are
`unable to be fed by muuth; and (6} ta avaid complicatiens which might result
`if ether administratiun routes were empmyed (e.g., hematumaa at the site of
`intramuscular injections in a patient with a blaming diathesis) .
`In adfiition,
`the intravenuus mute may be used far a val-mt}- at»? other purpuses, such as
`plasmapheresis, blazed transfusiun, and hemudynumic monitaring, to name a few.
`
`AstraZeneca Exhibit 2107 pt 14
`
`

`

`2431mm st st.
`
`is large number and variety sf complications may Occur 113*
`Prscautinns.
`ing the intravensus mute! A fat: of these are:
`(1) thrt‘am‘msis with or with~
`out somylicsting infection at the site sf injectisn er infusicxn; (2) injection sf
`mismm‘g‘snisms, tsxins, partisslsts matter, tar air; (3) the scentrsncs sf plays
`fies] 0:- chemical inssmpstibititiss between agents prist- t0 DP at the time of in~
`jsctisn; (4) unssntmllsd nr sxssssivs sdmisistratisn sf drugs 4231' fluids; and
`{5) extrsvssatisn 0f injectisns 91* infusions at the site at sdministrstinn. When
`indwslting catheters are utilizsd, rarely the catheter tip may bras}: eff sud
`lsdge in a major vssssl. in the hssrt. or in the lung.
`
`Method. The upper extremities are chosen whenever psssibls far the
`sits at injectisn s1? infusion. As many vsnsus sites as possible should he prsa
`served fer futurs use; thus ths msst peripheral veins (sugt , these ever the
`hand) are selected far initisl usst When arm sites are no Ringer available?
`the let“: veins (femoral and ssphsnsus) sr dorsal fest vsins may be utilized:
`amt in small children the scalp usins.
`Sslsctitm of s vein depends an the stzs of the needle 01' cstheter intended
`far use, type of fluids ts be infused, flow rate anticipated, volume to be re»-
`csived, csncsmitsnt msdicstisns to be given}. degree at patient mobility as»
`six-ed, sad at cause the skill sf the psrssn performing the Vsniguncturs sr
`csthstsfizstisn. The veins in the snte~cubttsl fosss are among the mast com-—
`manly chases, because they are large and readily punctured.
`(Ether veins
`utilissd sentiment? are basilic, ssyhslis, radial at the wrist. anti the metacarpal
`and dsrssl venting plsxuses.
`Mint-mg}: the risk at infectisn sppssts to be less with needles than with
`indwelling intrsvsnsus catheters [6} , an Elwin. lung intrsvsnsus, Lilsstic maths“
`tar is ssmmsnly used far delivery at fluids vita ssriplisrsl veins. Such oaths»
`tars reduce the risk sf infiltratisn csnsidsrsbly, thus pmvitling mars csmfsrt
`t0 the patient, reducing time and lsbsr casts sf nursing; in managing the in“
`fusinn, rendering phsrmssnkinstic predictions mare reliable, and avoiding
`If
`traverse side effects. such as cellufitis and occssiensny tissue stoughing.
`peripheral inssi'tisn sites became exhausted, surgical cut—dawns sf asst: twins
`with implantation sf indwelling catheters may be performed. When lung~tsrm,
`rspsstect, 0r prolangsd sssgs is anticipated, the subclsvisn (31" internal jugu—
`lsr (central) veins in the upper chest may be utilized. These veins are 65*
`pscitflly useful if hypsrosmolsr fluids are to be infused, as physicschemicsl
`irritation and transssssm produced by the hygswsmslarity or chemical fsrmw
`lstisfi sf the fluids may be reduced tn: nsgstscl.
`In such instances: silsstic
`turmslleti1 implantes, central vsnsus access catheters (sag. . Brotisc. Hick~
`man, Groshsng, Partwfikcmh) tailored to each patient 50 that the tip sf the
`catheter rests just shave the right atrium, {are oftsn utilizeci. Thsss devices
`sre designers so that they can remain in plsce snti be msintsinstl indefinitely
`far the life of the patient.
`{if needles are is be used fur intravsnsus infusinm s 1w to 2411. long,
`beveled, 18 m 22 gangs (Table 1}, stainless steel needle is ssmmnnly ussti.
`Whethsr using; a catheter 0r needle, the fiestas is inserted {isi‘sutanssusly
`ints the vein silly after thorsugfhly clashing the skin—insertisn sits and prev—
`paring it ssesticslly. Since infections sppssr to be more mmmenly associated
`with indwelling intravensus catheters than with needles, more time amt cars
`newts ts be given to skin preparation with catheter use than with nssdls in“
`ssrtisn. Such aseptic practices are espscislly impel-taint when “tong-term"
`
`AstraZeneca Exhibit 2107 pt 15
`
`

`

`Parenteral Drug; Administr‘mtifln
`
`25
`
`Table 1 Needle Selection
`
`Injection gite
`Gauge rmga
`Length range (in. )
`
`Intra» at: minimal
`
`Intra— articular
`
`Intracardiac
`
`Intradermai
`
`Intraaeuiar
`Anterier chamber
`Intrafitreal
`Retrobulb ar
`
`Subconjunctiai
`
`Intrapleural
`
`Intrathecai
`Afiuit
`Pediatric
`fiezmatai
`
`Intravenaus
`Metal naefile
`
`Winged neefiie
`Plastic needle
`intracathaier
`
`Inwlyingg catheter
`Silastic catheter
`
`Hypadez’maaiyais
`Adult
`Pediatric
`
`4—6
`
`1-3
`
`4M6
`
`wwra
`
`P"r-‘r"1—”Its-aub-ia‘ 03CA)
`
`I
`
`((1
`
`(33
`
`bub}
`
`1448
`
`1% ‘22
`
`1a~ 21
`
`24*26
`
`25
`25
`25
`25
`
`13-18
`
`2!} 22
`25
`27
`
`15~25
`15- 23
`154* 21
`15-21
`
`1&1 15
`12-19
`
`1%
`213—22
`
`
`
`Subcutaneous 24*25
`1361-518
`
`siiastie catheters insertaé mm the subclavian vein 0r vena cava are utilized
`
`(Vidé’ supra} . The mechanics 0f insertion usuaily invelve a taurniqnet being
`applied gmximal in the site 01‘ insertion in order m cangfist the vein (thus,
`If a catheter
`expanding the vein) , 30 that the device may be @38in inserted.
`Afterwards:
`is used, it is; inserted over a, needle used. for the initial puncture.
`the neg-file is tea-mama, amfi the catheter is left in 131309.
`The indweiling catha-
`ter 01* needle, wifichever is utiiized, is anchared to the extremity orb-c137
`by 1119381118 of apgropria‘te, sterile moclusive or nenecclusive drawings, often
`impregnated with antibiotic ointments t0 reeziuce the rials: 0f a cemgilicating in-
`feciivzm.
`Indwefling catheters often contain heparin lacks to engulfs: against
`wetting and loss 0f patency {ram venous thrombosis.
`
`Subcutaneous
`
`Descriptian.
`the skin (dermis).
`
`Injection into the lease cannective and adipese tissue beneath
`
`AstraZeneca Exhibit 2107 p. 16
`
`

`

`326
`
`Dunn: et at.
`
`indicatinns. This mute may be utilized if {lungs cennnt be administered
`Orally beca