SEVENTH EDETION
`
`AND DRUG
`
`DELIVERY SYSTEMS
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`
`
`Howard C. Ansel
`
`Loyd V. Allen, Jr.
`
`Nicholas G. Popovich
`
`AstraZeneca Exhibit 2106 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201—2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor—
`mation storage and retrieval system'without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in—
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack—
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C,
`Ansel, Lode. Allen, Ir., Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. Drugs—Dosage forms.
`11. Popovich, Nicholas G.
`Ill. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, Lode.
`
`99—17498
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`-
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc.The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement.
`
`To purchase additional copies of this book call our customer service department at (800)
`638—3030 or fax orders to (301) 824—7390. International customers should call (301)
`714—2324.
`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`AstraZeneca Exhibit 2106 p. 2
`
`

`

`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`.
`
`Dosage Form Design: Biopharrnaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`‘
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`TO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix'
`
`AstraZeneca Exhibit 2106 p. 3
`
`

`

`x
`
`Contents
`
`Section IV. PHARMAEEUTICAL INSERTS
`
`IT
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`T3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T 4
`
`I 5
`
`lb
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVAN(ED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVIEES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`T 7
`
`18
`
`T9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`AstraZeneca Exhibit 2106 p. 4
`
`

`

`Seaman VI. SterflE Image Rams and Delivery Systems
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PARENTERALS
`
`
`
`Chapter at a Glance
`
`hijacfians
`Parmieml Rmzéea afAdmiflisfi'atésm
`Inwavamua Rama
`Intramuscular Ruute
`Subcutanaoua Rama
`Intraderm :31 Route
`
`Specialized access
`Gficial Types 0f Injefltiana
`Salvems aim? Vehicleg far Iajesfisnfs
`Namqueeus Whisks
`Acidegi Szebsfimzcas
`
`Meihads cngtarilz’zafiimz
`Sfaam Sterilizatian
`
`wafieat Sterilizatinn
`Steriligafitm 1'33: Filt‘ratican
`Gas Stariiizatim
`
`Starilizaficm by Ianizixxg Radiatim
`Vaiféaifm? af Steriiity
`Fyrogena and Pwagen Testing
`The Industriaf Preparatian Bf Paramemz‘
`Pretfucts
`
`Lispm Inszdin Safiufim
`Impfizsma Insulin 3333333185331
`{MPH Insulin)
`{swims Insulin Suspezzsfau :sz
`Insulin: Injecffan
`Insmfifl Zinc Su’speuaimz
`Exféndeai Insulin Zia: Suspenss‘w
`I’mmpt Insult??? Zinc: Szgapemfm
`frgsufiin Imfitsian Pumps
`Large Vulume Parmierals (LVPE)
`Maimwwce Thérapy
`1233;313:362}:th Therapy
`Wafer Requfimmf
`Elecirslyée Requirement
`Calisric Reguiramerzis
`Parenteral Hyperalimenmtfan
`€211:ng Nutrffim
`
`Paskagifig; {(623581ng am? Signage 9f Injgcw
`{fans
`
`szlffy Assurancefm‘ Phammcgfifiepm'ed
`Sfm‘le Pradmts
`
`Availabfe Injgcfifmzs
`Small Volume Famnterals
`IflSulm Injeciian (Regular)
`Human Msuiifi
`
`Infimvemus {fifugim Gamma
`Special consideratians assaciafied with
`parexwteral therapy
`Agisarpiian (3f Ergggs
`Hanéziflgxflfspwal 0f Chematfzémpemfc:
`Agmisfor (3:23:55?
`Qiher hxjectabie Pmduatsmli’eflets m:
`Implants
`Lemmrggatrel fmpfsmts
`Irrigatiam anti Diaiysis Saluéiens
`Imgntima Safutimzs
`Bmfysis Safizgtémw
`
`CONSIDERED EN this chapter are mpmtam pharma-
`centical {insage farms that have the mmmon char
`aateristic: (13f being prepamd ta be sterile; that is, free
`fmm cantaminating micrmrganismafimang these
`sterile damage farms are the varimus small« and
`Eargevmiume immutable preparaflans, irrigatim find!
`
`ids intended ta bathe heady wmmis 0r surgical
`cpmings, anti dialysis saiufimns. Bialegica} prepa-
`ratimg 35 memes: tamidag and amimxins are aim
`
`ammg this gmup and discusseci in Chapter 15*
`Steriiity in these preparatiens is sf utmmst impar-
`tanm because they are piaced in {meat mutant: Mich
`397
`
`Astraleneca Exhibit 2106 p. 5
`
`

`

`398
`
`Parenterels
`
`the inteme¥ baud}? fluids er tissues where infeetien
`can easily arise: Qphthaimie preparatiene, which
`axe aim preeared to be sterile; wili be discueseel
`eeperateiy in Chapter 15.
`
`Inj ectiens
`
`Injectiems ere Sterile, py‘regen-~free preparatians
`intended tea be adminietereti parenteraily. The
`term pareszterei refeee t0 the injeetabie reuiee 0f
`eciminietretien. The teem has its derivetien free:
`
`the Greek wards gram and entemn, meaning
`eutsicie ef the intestines and deueiee reutee £35 each
`
`mieietretien ether than the era! mute. Eyregens
`are feverwpwdueing ergeme embetaneee arising
`fmm miembiei centeminefiae and are respons-
`ible fez: many ef the fe‘eeile reeetiens which DCCLII‘
`En patiente feliewing intraveneus injeetmn. Pyrw
`gene and the determinatien exit" their eresenee in
`parenteral} preparatiens will be {iiseuseed later
`in this chaptee In generei. the earenteral mates
`ef administreeien are mxdetteken when rapid
`drug aei'ier: ie ciesiz‘ed‘ as in emergency situeiiens,‘
`when the patient is unmnpemtiva, unemuficimze:
`Qt unable to aecept m“ reiterate mecficatim by
`the era]. mute, {15' when the shrug itself is ineffective
`by ether meme. Wiih ”the exeeptien {3f 1:15:11 in in“
`jectiens: which are cemmwlj; sefiasimmistered
`by diabetic patients, meet injeeiiens are adminis-
`tered by the physician hisfhet assistant, {31* nurse
`in the meme Gf' medieai treatment, Thus injeee
`titans are empieyeci meetiy in the Meme}, ex«
`tended care fecfiity, and efinie and £333 frequenfly
`in the heme An exceptien waged be in heme health
`care pregame in which health professieneis
`pay scheciuked Weite re patients; in their hemes,
`prewdifig needed teeetmem including mire»
`venaue medicaiiem. These pregame enable paw
`Heme thi} {m 11m require or are unable in page Em
`mere expensive haspitaiizatim m remain in the
`famiiiar surmumiings cf their immes while renew
`ing appmpriate meeiieal care. The pharmacist
`supplies: injectabie preparatimns m the physician
`and nmseg es :eqmired fer thee use in fine mew
`time} setting, {152111; mffice; er heme Inez-31th care
`program.
`Perhaps the earliest injectehle dmg m reeeive ofr
`fieial remgnitian was the hypadermie meerphme
`soiu‘cian‘. which appeared first in the 183% addew
`dum m the 1853’? “Britieh Pharmacopeiaj am? later, in
`1888 in the fire? edifim of the Natianai Fem“: 11131}:
`{if the United States, Tadey, there are literally hmn,«
`dreds of drugs ami drug prmducm awaiieble Em pap
`emerai admfimmafrien.
`
`Parenteral Rautes afAdministrefian
`
`1311th may be injected We eimesi‘ any ergan es:
`area ef the besiy, including the jeims {faire‘eréim~
`Im’}, a jeintifiuid area {femsyneefelg the spmel mi»
`umn {feimspéeel}, ieta epinel fluid (fetmrizeeefx ee-
`teeies {Enfs'aaez'fer‘fe‘f}, am in em emergency even
`mm the heart {Eefireeeréiee}. Heweeexg meet cam»
`maniy ingestiees are perfermed inter: e vein {mere—
`meme IV), irate a muscle {fetmreuseele‘e 1M): mm
`the skin (Regimental, £22. inhemmeeem or meet
`the skin {eeeemeeeaee Si; 5&2an SQ, eypeeemzie,
`Ewe} {Fig 14.1}.
`
`Intraveneus Rflute
`
`The intraveneus injeetien ef {hugs had its scieni
`tiff: eeigin in 1536 in the eepefimeme eff Sir Christe»
`phat Wren, architect a? St. Paul’s Cathedral and
`amateur yhysielegiet‘ Using a hiecider and quill fer
`a syringe and needle: he injected wine, aie, Qpiumg
`and ether substantes inta the veins cf siege and
`studied their effeete, Intreveneue medieefien was
`
`firet gieee m humans by Iehenn Same} Meier of Kiel
`in 3,651 bu: was abandnned far a paged became m?
`the accurrence cf thwmbesis anti embolism in the
`
`patients 3e treeted.’fhei1wentien a? the hypedermie
`
`swinge tweed the middle of the 19th century new
`ext-ed a new interest in intraveneus techniques and
`beware the mm «3% {he cement} intreeefleue admin-
`ietretien ef aeiutieee GE sedium efleride anti glueese
`became peyuia nTedayg the intraveeeus edministre»
`rim :3? cimge is. a mufine eecurreuee in the heeeiteh
`altimetgh there are stili reeegnieeafi cimxgers esseeie
`ateci mm we practice. Thrembus em} emhehzs fen
`matiem may be induced by ineeeeneue medias; and
`are:rheteme end the peseibility ef perticuiare matter in
`parenteral eelutimns peaee ceneem for these in~
`valved in the deveiepment, adminietretiem ami use
`an? intravenme mintiem.
`
`Infieeeneuely ackrfiflistered drugs {swede rapid
`acticm compared with ether mates ef administra-~
`tier: and beeamee drug absmpfiee is net a facts;
`mptimum bioed levels may be achieveci with the ac~
`mracg and immediacy net pessible by ether mate’s.
`In emergency simatiens,‘ the intraveneue adminie
`{ream 0f admg may be e lifesaving procedure flee
`tame of the placement 0f the drug directiy irate the
`circulatimn anti the prempt action weigh enemas;
`On the negative side! fiance a drug is; adminiatered
`intravenousix it cannot be reviewed In the case :21?
`an adverse :eactiem tn the mug, fer iflStEI‘ECE‘, the
`drug mnmt be easily rammed fmm the circuiatim
`as it mum, Em example. by the inducfien 0f Emmi?-
`mg after the ma} afiminietmtian {1f the same (frag.
`
`Astraleneca Exhibit 2106 13* 6
`
`

`

`Pamitemls
`
`399
`
`Subcuzanemux
`
`
`
`lmtadermai
`(«a
`
`62$
`' k
`«wk
`
`
`
`
`Subcutauwus
`Tiiwa
`
`Shhmm-memm
`xii-(Signs?
`Tiswe
`
`Mums: and Win
`
`
`
`£01;th Efpstramgmf fidmzziistmtz‘m Numbm at: medias :Jzéicszfg fiézeargauga ckf mafis mm {:12 amsidg dzawstar a}:
`Fig. 1&1
`Hawk sfiafi {Rat-farm we”123:1 Femigsigm fram Threw S; Kiflg RE. Smrfie 3mg: Farm: Thai: Prgpgmfism :3:sz (Ilium? Ayyéém-
`Hams» 3rd Ed. Lat: 53* Fetzigey; WSW
`
`Mrhaugh was: superficial veins are guitable f9:
`wnipumtum the: veins cyf the antesmbitai area {sit'
`uatezi in Emmi: GE the elbuw} are 213MB}! selactacl far
`direct intravenous iajectiwffhe wing in this {Caca*
`titan are large, superficial, afid eag}! 1:0 SEE and enter.
`Must clinicians insert the net‘die with the have} fa?
`
`mg upward, at the must acute angie pcsaihie with
`the vein; m {Ensure that ihe diz‘aaticm :35 flaw :3? the
`inflatable is that inf the flaw {2’5 the 13mm. Sim?
`aseptic grecauticms must be taken at all fix-neg {a
`await? risk af infectian. Nat only ate the injentabie
`seiutians stature,“ fhe gyringes and neefiieg used
`must alga be sterilized and the paint <33? entrance
`must be diainfecteti m reduce the chance 0f carry-
`ing bacteria from the fikin mm the bkmd via the
`needle 1%me injeqtinm afiministgafimx parsmne‘i
`mum mmdmw the 13111:“:gar {if the syringe 0r squefiza
`a special bulb §ound an mast IV 3am in ensure that
`the media has been properly heated. in bath inw
`mamas; a“flashba€k”af mead mm the adminigira—
`
`time set at the syfinge indicates pIQpEE placement
`of the needle within the vein.
`
`[mm 51711312 and fiery: mlumesz a? drug aoiutions
`may be adminis’camd infiavemusiy Tim use @f
`188(3me cantainers of smiutims fflf intravenous
`
`infusi-im is mmmmgiace is“: the haspitaifflwae we
`Iufims mmiaifiing such agents as nutziantg, blami
`axtfinéemé gleetmlytes: amim} acids: am? ether {hay
`apeutir: agents are administered thraugh an in—
`dweiiing aaadlfi m camera: by ccnfinumm infusém.
`Th6: infusifln Ctr flaw rates may be afijusmd by the
`ciiniciafi awarding ta the needs af the patiem.
`{Emerallfi {Ems ratea £13: intravamus fluids aw ax»
`grasseci in mLihmm am} mags: Fran”: £12 tn 1523
`mtham Lawgr rates are useé Ear“keep apart”
`lines. Fm iiitravenmzs infijsian, the aka-mile m: Caitheter
`
`is glacaci in am pramimant veins af the farearm {33'
`kg and "zapsd firmly tax the: patient saw that it m1} nm
`slip 5mm place dufimg infusimfha main hamrci at?
`intravenms infm‘simx E3 the paasibility :31" thwmbxis‘.
`£63113th induced by the teuching 9f the wali 43f
`the vein by this catheter at media. Thmmhi are
`mam Eikei}; {a 13mm? when the infusion Wham i5;
`mi an £31:ng nature t0 the bimlagic tissues. A
`thramixns £3 a Read elm farmed within the blmti
`
`vessel (or heart) cine mauaiiy m a simwing mf the 2:213
`miatim m tea an alteraticm mi the hlvad m vessel
`waii. {Linea “51.35371 2: ciat circulatm it bemmas an my
`
`3mm, carried by the biased stream um} it iadges in
`a b10051 @5395}, abgmmting it? and {making in a
`
`Astraleneca Exhibit 2106 p. 7
`
`

`

`4.0
`
`PQFEfitemis
`
`blockage er ccctueien referred tc: as an cmbclism.
`Such an chetmctien may be a. entice} hazard to the
`patient, depending upon the site anti eevetiw cf the
`ebettuctien.
`
`htttevemuely administered. :1ng crciinerfiy must
`he in equecue selutien; they must mix; with the cir-
`culeting blece and net precipitate from seletien.
`Such an event cetfici lead te puimcnary miqecep-
`iliaty ccctusiee and; the subsequent blockage cf
`tamed passage. Intravencusly delivered fat emul-
`sicne tag”, Iatralipid, 10%;2G% {Cfintec}, Lipc-Syn
`II, 10%;239e {Abbettig Lipceyn III; 10e;20e [Abw
`beet}? have gained acceptance fer use as e emcee e5
`celaries and essetttiel fatty acids fer patients rew
`cutting patenteta} nuttiticn for extendeci periccie cf
`time {ueueliy fer mete than 5 ciaye}. The precinct
`ceramics up te 28% seybeen eil emulsifieti with egg
`yeik phttegzshczaligpitiet in e vehicte cf glycetitt in waw
`ter fer injectieetThe emuieiett is administered via a
`peripheral vein er by central veneue infueicrt.
`Naturally; the intravencus route is used in the
`edminiettetien of bteed trensfueiens and it else
`
`sewee as the paint ct exit in the temwel of bleed
`item patients fer diegtteetic wed: and for cbteirting
`bleed frem itemize.
`
`and are then inesiequete tc treat the pain. The
`FCA can prevent phermecekinetic and phermacw
`fiynemic differences between patients teem inter—
`fering met the effectiveneee of eneigesie. Because
`epieifi kinetics ciiffer greatly mung patients, the
`rates at infitsien must be teticrezi (2}.
`The P655, aiee genetic: patients te medicete them"
`ashes when there is breakthmugh pain; It elimi—
`nates the tieiay between the time at the patients
`eereeptten cf cam and receiving the analgesic medv
`icatiett. Further; it saves nursing time. chemfise,
`the mime mus: check analgesic etciete gieen by the
`physician, ‘3ng cut the pair: teliever ftem a cert»
`tteileé, ieciceti iccatien, and, then administer the
`medicatien te the patient.
`The PCAL else provides better pair: central with
`less side effecte by minimizing the means be“
`tween subcetimel gain relief eat} caveman: of net»
`cetics. When the eitie effect prefiie cf PCA patients
`is compared it) patients meintaincé an FM nap
`cetics, nausea, sedetien; emit teepitatczy depreseiett
`eccer less cftee in the PCet gteup. Lace}: patients
`eccegt the File as a faeerehle made at reliefi pee
`flaps clue m the acme cf being in centtei anti talc»
`
`ing an active pert itt their pain relief.
`
`in the late 1988a; eutemeted intravencue defieety
`systems became cemmercially eeeitebie for inter»
`mtttent; setfvedmjnieerefiett ef enelgeeies. Egg—metre
`centtefieti aneigesia (13%} has beet: used to centre}
`the pate asseciated with peeteperetive pain from a
`variety of Surgical ptecetiuree, label; sickte cell crisis,
`end chtemc pain aseecieteci with cancer! For patients
`with chrcmic malignant pain, Wile aflewe a greater
`degree of ambuietiett end indeeeedence {1).
`The typical PCA device includes 3 Wings: at
`chamber that remains the analgesic drug and
`a ptcgtemmeble electemechenicei emit. The unit,
`which might be cempact eneugjh m be mm cm a
`bett a: carrieti in. a packet (veg, WalkMetim FCA~
`Medea, Inc}, commie the detivery cf drug by ed‘
`matting a piston when the patient presses a batten.
`The drug can be loaded mm the device by a health
`care prefeesieml (3f disPenseci from preloaded car—
`tridges aeailabie thmugh the manufacturer.The tie»
`eicee take advantage of intravencus balms injec»
`time be praduce rapid analgesia; 31921;; with slower
`in feeicm m pmduce steady-mate epiete cancentraw
`fions fer custained pain central.
`The advantage cf the PCA is its 313in to previde
`conetent and uniferm analgesia, The typical intram
`muscular injectien at an cpicié mm a depct
`muscular site may result in tremble absmptim,
`leading to unpredictable 131:1:ch cencenttafimet Fun
`then these injectiens are 1131121in given when needecl
`
`Fig. 1121.2 Pm Pitta II {lfiefiete emeeemmmmygg
`eeefigesic Mesa: (Cflfiffé’sy sf Acme Hespftef Predacts
` fifeésinm}
`
`AstraZeneca Exhibit 2106 pt 8
`
`

`

`Pile tie-vices can be used fer ietraveneue seems
`
`taneeee. er epiduxel edmieietretien. Usually, theee
`devices are either demand eeeteg (Le... e fixed dese
`et' drug is injectetl intermittently} er eeesfemarete
`iefitslee glee Limited easing {2}. Regarelless of type
`utilized, the physician 0! nurse esteblielmee the leeci~
`mg dese. the rate at beekgteuntl infusien, tiese pet
`demenel. leekeet interval (1e. minimum time be»?
`tween demand eases}; and maximum tiesage ever
`a specified time interval. Figute 14.2 demmetretes
`the Fife Plus ll {Lifeeeze ewe) infuser. With thie
`device, the getient pushes a butten en a pendant is;
`deliver a preeetlbed quantity ef the analgesic.
`
`Intramuscular Route
`
`lntremueeulet injectiees ef tituge prettiafle shrug
`etfecte that are lees tepid, but geréerelly of greater:
`duration than these ehteinecl from tettaeeneue ecl-
`
`minietratien {3}. Aqueeue er eleegineus solutiens
`er suspeneiens ef drug substances may be ecimiw
`letereel intremueeulerly. Depending we the type at
`pteparetien empleyetl. the abeerefien rates may
`easy widely. it wattle be expected that (3133.139: in sea»
`lutien wettlti be mete rapidly abserbecl than theee
`in suepeneiee end that druge in equeeue tempera»
`tiene wettltl he were rapidly ebeetbecl than when
`in eleegineue preparetlene. The ehyeieal type 0f
`prepatetien empleyed is beeeztl err. the prepet‘tiee cf
`the chug itself and en the therapeutic geele deeited.
`lntramueculer injeetlens ere perfermetzl (lee? irate
`the skeletal museleefll'te pellet ef ingestien eheulcl be
`as far as peesible {tam majet nerves anti bleed we?
`eels. Injuries. tie patients Efrem ltflmmusculer injectien
`usually axe related te the peim at which the needle
`ettteted and where the medieatien wee depeeited.
`Such ln‘urlee inelude paralysis resulting; {mm [Ritual
`fismege, sheeeseesg cysts, embolism, hemeteme;
`sleughi g at the skin} and see: formatien.
`ln eel
`ltet the upper miter quatltenl till: the gluteus
`mammals 13 the meet frequently need site fer latte“
`museular injection. In infants. the gluteal area is
`email a cl mmpeeed primarily ef fat. net musrde.
`What muscle there is ie pearly clevelepetl. An in-
`jectien 'n this area might be presented dangerously
`elese ts: the sciatic meme. eepeeially if the child is; re»
`existing the injeetmn and equitmirtg er fighting.
`Thus! '1
`infants; areal yeung Cltlltlren, the deltold
`muscles at the upper arm or the mxiletetal muscles
`at” the high are preferred. An injectien given in the
`upper ex: lewer pettion at the delteid wattle be well
`away team the recital memel’he cleéteini may else be
`used in adults; but the pain is mere netéeeatzle here
`than in the gluteel area. ll? 21 SEl‘lES at mteetims are
`to be given. the indecent: site 15 ueuallv varied. Te be
`
`
`
`Peteuremls
`
`le’l
`
`certeie that e bleed vessel has eat been entered,
`the clinician may aspirate slightly on the syringe
`fellewing leeeetien at“ the neenlle te ebsewe if bleed
`enters the syflnge. Usually. the velume 0f medical
`ticm which may he canveejently administered by
`the tntremueeeler mute ie limited; generally a me»
`imam et' 5 ml. is administered intremusculerly in
`the gluteel raglan and 2 mL in the delteitl 0f the
`arm.
`
`The Kvl‘teelc Injectien technique is useful for in»?
`tremueeeler ixtfeetiene ef medieatiene that state
`upper tissue; tag. li’ClI't dextten mjeetiem er these
`that irritate tissue, ega, Valium, by sealing these
`medieetiens in the lewet muscle. Because er”; its
`
`Staining qualities. tree. deetxen injectten. for exam»
`ple, must be injected Ural}; late the muscle mass at
`the upger enter quadrant ef the betteelcszlte skirt is
`displaced latexelly peter te teteetien. then the nee
`tile is inserted end eming'e eeeireted, and the ifljetle
`ticm performed elem}; and smeathlyfllte needle is
`than Mthdrewn and the skirt released. Thie creates
`
`e“3”eattetn that blacks infiltzetien ef meelieetien
`irate the submteneeue tiee:1e.Ӥlte injectien is 2 to 3
`inches deep, and a 2G te 22 gauge neetlle is utilized.
`To further prevent any staining ef upper tissue.
`mentally sane needle is usetl ta: mealtime: the item
`(lemme {rem its empul. and then replaced with an»
`other fer the puzpesee at the tnieetien.
`
`Subcutaneeus Reute
`
`The subcutaneous route may be utilized fer the
`injectmn 13f smell amaunts of medication. The im
`jectien at a drug beneath the surface at the skirt its:
`usuelly made 51": the lease interstitial tissues at the
`enter emfece et’ the upper arm! the antes-rte: eerfeee
`ml the thigh, anti the lewet eettiefi ef the ebdemen.
`The site 0f injectiefi is: usually retefecl when injeea
`time are frequently given. sing, daily ineulin injeew
`liens. Prim“ m injectleng the Skin at the injeetlem
`site ehmld be thoroughly deemed. The maydmum
`ammmt m? medicatien that can be eemllarta'bly ire
`jectecl subcutaneeuely is ebeut 1.3 ml. and garments
`greater than 2 mL will mast likely: came painful
`pressure. Syringes mete up ta 3 mL eepeelties anti
`utilizing neefilee with 24 m 25 gauges are used fer
`subcutaneous injections. These needles will have
`cannula lengths that vary between BIB inch ta '1
`inch. Mast When}: subcutaneeue insulin needlee
`are between 23 to .30 gauge with needle length he
`Ween {#16 m EIS inch. Upem ineettien, if bleed e§~
`peers in the egimgel a new site eheuld be eelected.
`"Drugs that are irritatmg er these that are preeemt
`in thick suspefleim form may pmduee induretien.
`slmaghéng, er ebecese Eermetien and may be pain Eel
`
`Astraleneca Exhibit 2106 p. 9
`
`

`

`41132
`
`Perentemls
`
`re the patient. Such preeeretiene should be mneirlv
`ererl net suitable fer eubeureneeee injeerierr.
`
`Intradermal Renate
`
`germ needle ellewe system access lhmugh the slain
`infer a sellweeallng silicrme plug paelliurred in. the
`water ef the perral,
`
`.fficiel Types eflnjectiens
`
`Aceerciiag re the U313. mleerierre are eegarererfi
`late Eire general rypee all (35 which are suitable far;
`and intensified fer, parenteral erlminietratlen These
`may remain buffers, preservatives, errd ether erlcleri
`eubereneee.
`
`A number {if Substances may be effectively in“
`jeered lrrte the cerium: the mere vascular layer
`ef the eldrt just beneath the epiclerrrrie These
`substances include eerleus agents fer cliegmestic
`rierermirretr‘erre, desenslrlrerien; or immunizatlrm.
`
`The usual sire fer rnlrerlermal injeerien is the ante
`rler surface er the fereerrrr. A Sher: {SIS ire} earl
`narrow gauge (23» t0 26~gaugel needle is usually
`empleyerlr‘l‘he needle is inserted herieerttelly mm
`the skin wirlr the bevel facing ugrrerrlfllre injeerlen
`is mede when the bevel just cliseppeere mm the
`cerium. Usually early sheet 23. 1 rel; velumes may be
`administered in this manner.
`
`Specialized Access
`
`In these instances where it is neeeseery to arl~
`rrrirrleler repeated injectiene ever a perierl 0f time,
`it might be mere prurient re empley devices that
`prerlrle centirrued aeeeee arrel help eliminate rte
`treat pain eseeclered with administrefimrlhtre, it is
`irrrperrerrr its list a few al this junerure.
`Several
`types ef reelral veneer; catheters are
`used in irrelllutlane arrcl an an Qutparlerrl beele. These
`are used fer a variety ef parenteral merlicerlrms leg“
`cancer eherrretherepy; longeerrrr entiblelie therapy,
`rebel parenteral nutrltlerr selullenslr earl their place“
`rrrerrt can remain far a few days re several menths,
`When net in use; these require heperlnieelierr tea
`maintain perency ml the catheter lumen
`The use all plastic,
`indwelling catheters helps
`eliminate the need fer multiple puneneee durirrg ll?
`therapy. Cemeeeed le pulyrérryl ehlrrrirfiefl‘efler‘z, and
`pelyerhylerre, these sheulrl be redlepeqrre re ensure
`that they elemenerrere rdeibllity rm wray films {Jerr—
`ally, rlreee must be removed “ether 218 heme alter inn
`eertlerr'l‘he rheire of catheter depemde upon revere}
`{eaters {egg length ef time el the infeslem perpese
`ml
`the infusion the eonrlillorn’aeailebllll}? of the
`veins}. Three types: rial catheters are available: plain
`plastic; eellreteeerer— needle er earlreter—metelrlr:w
`neerlle‘ and rerlxeterwlrreldemeedle.
`
`implantable rlevlrzer prerede lengnrerrrr rerrmre
`access lrr verifier rlieeeeee. firmer 23ml Hickman
`
`ratherere are nrrrelnle erempleellreee r30 carry a risk
`er marblrlltg including freelure el Elle catheters; errw
`trance sire infection; and Gatherer sepsislhese have
`been derelmperl
`rm eeerceme rarlreter campfire
`rims and are deeignerl to premier: repealed arreee re
`the infusierr elterl‘he delivery catheter can be placed
`lr: a vein; eerily! arreryr rrr CNS system. A Huber
`
`1.
`
`2.
`
`
`
`
`
`" rug] Injecrlenmllquirl preeeretierre that are
`drug euberarreee er eelutlerre rhereef. {Be In»
`sullrr lnjecrleng USP}
`" rug} ferlrrjecrfrmmlfiry solids that; upen the edw
`ditierr er ereralale relrleles, yield eelerlerre can»
`arming in all respects tr} Elle rer;reirerrrer1telferlrrw
`'eerlerre (Ex: Celemerrrlele Smallerrr Ear injeclien}
`3. Drug} lrrjrrrelale Eerrrlereemhiquiri pregaraljens
`ef drug substances. cliesrrlrerl rxr disyereerl irr e
`euiteble emulelerr medium. {Ex Frepelel)
`prew-
`ll. Drug}
`Irrjerrelzle
`Seeperrslerrmlriquirl
`perefime rsl? eelirle suspended in a suitable liq»
`uld medium. (Ex: Methylpredrrleelerre Acetate
`Seepensim)
`5. {Drug} fer lefeclrrlrle Sespensleemllry solids that,
`upen the
`eeldirlerr
`at?
`suitable
`vehicles,
`yield ereperatiene ceralerrrrlrrg in all respeete t0
`the requiremente Ear Infrelelile Srrsperrslarrs. {Ere
`lmiperrem}
`
`The farm in which a giver: drug is prepared fer
`parenteral use by the menufeerurer depends upon
`the nature ef the rlrugg itself; with respect tr; its
`physical and Chemise] chamelerlefics, and alert: upon
`certairr rhereeeutic weelderetlerxe. Generally if a
`drug is unstable in selufier’r, it may be prepared as
`a rlr}: pewder intended fer reenrre‘ri’mrierr with the
`prayer solvent at the lime 0f rte administratiem er
`it may be prepared as e suspenelen flf the clmg par»
`lilClEZ‘S in a vehicle in which the drug is Ensemble. If
`the drug is unstable in the preeenee elf were); that
`selrem may be replaced in inert rrr retally by e eel»
`rent in whichtlre drug is ineeluble. ll rhe rlrugis irr-
`seluble in. water, arr injerricm may be preparerl as arr
`aqueeus suspension er as a eelurirm rrf the drug in
`a suitable noraqueeue seleerrr; such as a regetable
`all if err eqeemrs solemn is desired; a water-sale
`Elle sell ‘5er ml? the lneeluble drug 13 frequently grew
`parerl m sell-35y rhe required selublliqr characterise
`tire. Aqueme er bleedqrrleclble relations may” be
`injerred air-ml); late the bleed stream "Bleerlwlmn
`Humble liqulrle, rag, eleegirxoue mjecrlone and sue»
`
`AstraZeneca Exhibit 2106 p. 10
`
`

`

`premium: cara interrupt the marina} flow of blame?
`admin the circuiamry systara, and their 113a is. gem
`arail}; restricted ta rather than intravamus admirais‘w
`rratiarr. The ansat and duratiarr {if simian {if a ring
`may be aamawhat cantrrrilad by the chemical farm
`{If the drug used, the physical state rs? ma irr§ectim
`(grammar a: auapaaairanl arrd the xrahicla ampiayad.
`Drugs that are very salable in bed}; Bahia ganeraily
`hava the mast rapizi abaarprian anti mast saf artisan
`Thus, drugs in aquamua salutian have 3 meta rapid
`unset ea? aaricn than dc: drugs in aiaagimus 3011:»
`tiara. Drags irr aquaaua aaaparraien are alas mare
`rapid acting than drugs in aiaagimus ausperrsian
`due rat) the: greater miscibility of the arguewua prapaa
`radar“: with the body fluids after injectim and tha
`suhsaquam mare rapid canister fifths drug particiea
`with the bad}? fluids. erentimas more pmimgaci
`drug actiort is daaireri ta reduce the necessity (3f frav
`quantify rapaarad in}er:tianaThaaa lang-arring types
`af injectiana are crammanly rafarreci m as rapasimr‘y
`ar"ri2§ar“‘typaa ca preparatiwa‘
`Tha aaruriana and auspanar‘ans :3}? drugs intansiaci
`far in§acriarr arr: pregarai in fire aama gamma} man -
`net 35 was dismaaed prefirmsly in this text for 50*
`Miriam {Chapter 12} arrri disparae ayatems {Chap
`far 133‘ with the faiirawing differences:
`
`1. Salvants r31" vehiclaa uaari mus: meat spacial pu—
`rify and rather Sta rrdaxds assuring their aafafy‘ by
`injectirm.
`2. The uaa «:15 added substances; as buffers, stabi—
`
`lizers, and antinfirrabia} prasawativeag fail Lifh
`tier specific gradalirras 051136: and are restriatad
`in certain parenteral pruciuctafl‘ha use: of calcar—
`ing agerrta is striatiy grahibitari.
`3. Parenteral praducts are aiways sterilized and
`meat sterility atarrriarris anri must be pymgan-
`fraa.
`
`4, Parm‘rtarai salutimla must meet mmpamiia} stem»
`darda far particulate matter.
`5. Paranterai precincts must be grammar in 321%
`mnmentaily mmmilerfi areas: undar strict army
`terrier: standards, amt by personnel apecially
`trained and claimed to maintain the sanitation
`atanciarria.
`
`{:1 Parenteral products ara yackaged in apeciai her—
`metic containers rrf apatifir and high quality.
`Sperm} quafity rantml prmraduras are utilizes} to
`enaure their hermetic seal and steriirz condirimn.
`
`7, Each remainer flf arr ingecfian is fiiiaxi m a ml~
`nma in sfight «3246933 sf the 1abelred”siae"r3r ml»
`rum: to be Mrhdrawrr. Thia merffll permitg the
`reaae at? withdrawal and administrarim 0f the la—
`belari mirrmea.
`
`Parentamls
`
`4553
`
`8. There are rearriariarra mar rha vealrzrrra af $113639
`rim panaitteci irr muitipla—daae cantair‘aara and
`aim a imitatiarr war the types af containers
`(singiamriasa m muifiplawdasa) which may be
`used far certain injectiana
`9r Spaaific labeling ragularirma apply to injaciianar
`ED. Starfie pawriars intarrdad far salutian var aria»-
`panama :mmadiataiy prim ta irrjecticarr are fra—
`rguarttiy yaakagad a3 fyagahiliaad r3: freazawdriari
`pawdar’s ta permit ease {3f saiaticm a: suspaw
`aim upaa the addirirm surf the salvarrt car vehicia‘
`
`Solvents and Vehicles far Injectians
`
`Thar meat frequanfly used ambient in the larga
`scare manufacmrar 0f injectiana ia Waferfar Irrjactiara
`113?: This watar is purified by distiliarian err by re»
`versa Damasis and meats the aama ataxrdarda far the
`
`presence {3? ratai aafifia aa dmaa Purified Water; LISP,
`am meta than 1 mg per 103 mL Water for Irafiectiam
`US? and may rrat remain added substances. Ab
`margin water far ingaariarr is not required tr) be star—
`fir; it must be pyragamfraeffha water is intendad tr)
`be used in the manufactura 9f injectable pradurta
`whiah are in be stariiiaad after weir prapararicrrr. Wa-
`ter fr): injactian Emma bra atarad if! tight cantainars
`at ramaeramres balaw far abava the rarrge in which
`micmbiai grawth occurs? Water