PARENTERAL
`
`TECHNOLOGY
`
`MANUAL
`
`AN INTRODUCTION TO
`
`FORNIULATION, PRODUCTION AND QUALITY
`
`ASPECTS OF PARENTERAL PRODUCTS
`
`SECOND EXPANDED EDITION
`
`Michael J. Groves
`
`College of Pharmacy
`University of Illinois at Chicago
`
`Astrazeneca Ex. 2086 p. 2
`
`

`
`Pr:’m:tir:g History:
`
`‘Parzznieral Tachnmlogy Manna} ~—« First Edition, 1985
`
`Reprinted, 1986
`Semnd Eciiii-an, I988
`Sacnnti Editiun ISBN: $935334-1Q~4
`
`@Ccspy:'igh1, January I939 by Intarpharm Press Inc.,
`PK). Bax 33$,
`
`Prairie View, IL 60969, USA
`
`AH rights regerved. This izczmxz is protected by cczpgrright. No ‘part of it may be
`reproduced, stored in a rzmicvai system, or iransmitted in any form or by any maans.
`
`eiectranic, nlecixanical, phoiocopying, recording, or mherwise, witham written
`permission from the pubiisher. Made in the United Srtates of America.
`
`Wham‘: a prcuziuct trademark, registration mark or ether protected mark is maria
`in the: text, thfii uwnaraizip «:3? the mark remains wifix the Iawfui owner of the mark.
`
`No claim of ownership, intemécma} or mtherwise, i:; made by reference to any such
`marks in this beak,
`
`While v2:are1‘y effmr has been made by interpharm Press Inc. to ensure the accuracy
`of the infomxaticrn cnntaincci in this mark, this organization accepts nu re3pnn:~:i-
`bility for arrays or Qmissicmg.
`
`Astrazeneca Ex. 2086 p. 3
`
`

`
`PARENTERAL TECHNOLOGY MANUAL
`
`SECOND EDITION
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`Chapter‘ I
`Overview .
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`1
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`Chapter 2
`Perspectiveg on the Use and Egsential
`Rttqnirements of Parenteral Precincts .
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`Chapter 3
`Water..,q..,, ,
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`Chapter 4
`Elesztrcslyms and Adjuvants .
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`Chapter 5
`Non—~Aqueous Systems, Dispersions and Emuisicrns .
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`Chapter §
`Hyperaiimentatien Soluiirzxns and Admixturcs .
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`Chaprex‘ P‘
`Dry Pawders .
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`. 83
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`Cfzazpter 8
`Filtration *
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`Chapter :9
`Containers amii Their Saals .
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`Chaprer Ii?
`Steriiizatian and Depyrogenation .
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`Chapter II
`Steriiiiy Testing, Pymgens and Pymgen Testing .
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`Chapter I2
`Particulate Contaminatian and Testing .
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`Chapter 33
`The Pmduction Emrimnmcznt .
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`Chapter 14
`The Quality sf Irzjectable Prcoducts .
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`Chapter I5
`Regulation Issues Affecting the Parenierai industry .
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`Index .
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`vii
`
`Astrazeneca Ex. 2086 p. 4
`
`

`
`FIGURES
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`Chzzpzer 2
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`1. Injection rzzsntes into and through the skin .
`2. Intrathecal injection mates into the subarachnoid space
`. 8
`surrounding the spinal cord .
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`3. Intracisternal route for withdrawing cerebrospinal fluid . 9
`4. The effect of route of injection can the intensity of
`action of a Vhypothetical drug as meaaured by the
`blood 1evei—time curve .
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`Chapter 3
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`5. Preparaticsn of Water far injecticm (WEI) .
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`‘I9’. Temperature-Jenergy diagram for water .
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`8. Multiple effect stills with bailers and condensers
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`9. Vapor cs:-mpression still .
`10. Relationship between iemperature and pressure 01°
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`12. Water storage: system . .
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`1&1. Preparation af a sterile suspe1::s;'m11 .
`15. Prcsducticm flow ciiagram far a hypmhetical
`intravenous emulsion .
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`Cfiapfer :7
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`16. Preparatian of a crystalline powder fill .
`1?. Freeze drying as applied wiih a pewder fill ctr an
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`18. Water vapor pressure vs temperature curve for water .
`29. Phase aquilibrium diagram for a typical 331%;
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`20. Preparation of 2. szerile Spray dried powder .
`Chapter 8
`21. Mechanisms for partiales to impinge on a capturing
`surface.
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`ix
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`Astrazeneca Ex. 2086 p. 5
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`

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`22. firairzing mechanism for baciieria and debris passing
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`23. Diffusive flew measurements for filter iniegrity testing . .92
`24. Typ.e3 of membrane filtration units used in {he large
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`Chapter 19
`23. Logarithmic death curves for a hypothetical bacteria
`population exposed to a constant heat: stress ,
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`26. Death-time curve for a hypothetical bacterial spare
`suspenszicm exposed to increasing thermal stress .
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`3Q. Generalized structure of endetoxins .
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`. .152
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`31. Cascade effect far producing fever in man .
`Clwp£er- Z2
`32, Particle size ciimibutiens cf six samples of sodium
`chioricie injeetiem se-iutiazm selected from three batches . 165
`33. Low pressure pulmonary circuit and high pressure
`systemic circuit
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`35. Majcsr sites for phageeytesis _
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`36. Principle ef the HIAC counter . .
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`37. Sizes of partieies as seen by the HIAC .
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`39. Relationship between cumulative limiting number (per ml)
`and diameter pm fer officiai iimit tests .
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`40.. Integral between limits it} produce an area under the curve
`used ta iimiz: particulate in injeetien sehxtions .
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`Chapter 13
`41, Flew sheet for a }arge vekme parenteral filled in
`a plastic container.
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`42. Different flow regimes emmd an open neck 0f 3.
`battle .
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`Astrazeneca Ex. 2086 p. 6
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`

`
`TABLES
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`. .39
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`. .43
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`i .41
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`Chapter 4-’
`1. Appngsximatc body mmpartment electrolyte
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`compcasiticsn (mEq) .
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`2. Buffer systems used in maintain the pH of injactable
`sesiutinns .
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`3. Antioxidants used in parenterai products .
`4. Antibacterial cezimpmmds used as preservatives in
`parenteral aquecus scsiutinns .
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`Cfiizaprer 5
`5. Distribution cf fatty acids from the triglycerides cf
`Intralipici and Liposyn intravenous emulsions .
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`6. Components af natural lecithin .
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`7. Quaiity cszsntroi prcroedures carried Gut cm inimitable
`iipid emulsions .
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`Chzrprer 6
`8. The calorie convent cf camman intravenous fluids .
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`Chapter‘ 9
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`9. Basic types gf centainers used for parenterais .
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`10. Additives commonly used in plastics .
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`11. Aciciiiives used to impmve the pmparties of natural
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`12. Syntheiic rubbers used for pharmaceutical closures .
`13. Perfarmance {if elaszomers used for sealing paren1;e,ra1
`praciucts .
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`C}zapz‘e:* EC}
`14. Sterilization methzacis .
`
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`_
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`_ 308
`_
`. .110
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`. .112
`. .113
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`. ..12I
`
`Chapter 12
`15. Approximate sizes {if same contaminants repormd in
`intravenous seluiians ,
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`. .162
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`xi
`
`Astrazeneca Ex. 2086 p. 7
`
`

`
`CHAPTER
`
`PERSPECTIVES ON THE USE
`
`AND ESSENTIAL REQUIREMENTS
`
`OF PARENTERAL PRODUCTS
`
`
`
`LEARNING OBJECTIVES
`
`1. Understand why and how a parenteral product is different from
`
`other pharmaceutical products.
`2. Become familiar with routes of administration of injectable prod-
`
`ucts, advantages and disadvantages of each route and the effects pro-
`
`duced on drug action, metabolism and excretion.
`
`3. Be aware of the essential requirements for injectable products.
`
`INTRODUCTION
`
`A substance administered to the body by injection is said to be paren-
`
`teral from the Greek words ttarga (besides, other than) and sirragou (the
`gut). Injections are fluid preparations of drugs introduced into the body,
`
`into or through the skin or through the mucous and the serous mem-
`
`branes. Volumes of up to 100 mL are termed Small Volume Parenterals
`(SVPS). Other injectable products given directly into the venous blood
`
`circulation are termed infusion fluids or, more usually, Large Volume
`
`Parenterals (LVPs).
`
`Because a parenteral product bypasses the usual body defense
`
`mechanisms associated with the oral route of administration, it is essen-
`
`tial that an injectable be free from viable microorganisms. A paren-
`
`teral must not cause reactions on administration due to poor
`formulation, the presence of particulate contamination or pyrogenic
`
`materials. Accordingly, parenteral products have essential requirements
`for their preparation, storage and administration that make them dif-
`
`ferent from other pharmaceutical products.
`
`Astrazeneca Ex. 2086 p. 8
`
`

`
`4
`
`CHAPTER2
`
`Freedom from viable microorganisms may be achieved by heating
`
`the product to a degree that will totally destroy all living matter. This
`
`process is carried out on the final sealed eontainer as a “terminal sterili-
`
`zation”, the conditions being carefully selected so that destruction of
`
`the mieroorganisrns is achieved without damaging the product. Since
`the contents of the container can now be described as “sterile”, there
`
`in no need to risk violating the integrity of the product until irnrnecii~
`ately before administration to the patient.
`
`Some drug products may be damaged by sterilization processes. in
`
`this situation, a product may be assembled from sterile components
`under earefully controlled conditions to rnininiiae contamination with
`microorganisms; the final assembled product inside the sealed eontainer
`is not exposed to a terminal sterilization process. This type of product
`
`is described as “aseptic”, examples being fractionated blood products
`and drug admixtures.
`
`Solutions that contain gram-negative bacteria are capable of pro-
`ducing febrile reactions on injection, even if the solution. is sterile. These
`
`febrile or pyrogenie reactions are due to the presence of bacterial cell
`
`wall fragments ealled “en<lotoxine” that are capable of triggering a
`
`response by the body’s thermal eontrol mechanism. Humans are prob-
`
`ably one of the most sensitive animals to endotortinsl The presence of
`
`small quantities of enciotoxin is an indication that at some stage in pro-
`
`tlttetion there has been bacterial eontarnination of the product. The
`
`sensitive methods for quantification of endotoxins now available pro»
`vide a measurement that serves as an indication of the hygienir: eonrii-«
`rions under which the product has been prepared.
`
`The same eomrnent may be made about extraneous particulate corn
`termination. A product may be sterile but minute particles of extraneous
`insoluble matter are almost impossible to remove completely. However,
`these particles alao serve as an indication of the conditions under which
`
`a product is prepared and are readily measured using the appropriate
`instrumentation. Acceptable limits for particulate eontamination have
`been clefineti in some cases by regulator}; agencies.
`
`H313 TQRICAL BACKGROUND
`
`The intravenous route of drug administration and the other paren-
`teral routes can be dated back to 1656 when 13:: Christopher Wren,
`
`a mathematician but also a Profeasor of Surgery-—lat;er to be architect
`
`Astrazeneca Ex. 2086 p. 9
`
`

`
`Parenteral Products
`
`5
`
`of St. Paul’s Cathedral in Londonminjcctcd opium dissolved in wine
`into a dog ttsing at syringe and a narrow pipe. No one seemed too com
`cernecl about the fact that the same syringe coulo have been used crew»
`
`ously for enemas and (touches. There was even less comment about
`
`the use of a pig’s hlaoderecd goose quill for subseqttect experiments
`leading to the first human trial in 2653. Here the “volunteer”, described
`as “a malefactor who was tmrtlly and deserved to be hanged”, promptly
`
`fainted following injection of an antimony salt. He was then allowed
`to escape; unfortunately, history does not record how long the “patient”
`(or victim) survived. Occasional experiments were carried out over the
`next two hundred years but the only injection therapy with any success
`was intravenous administration of saline solutions into cholera victims
`
`in the middle of the 191;}; century. Injections of painkilling agents were
`
`used with increased frequency following the invention of the graclut-4
`atctl glass syringe fitted with a hollow needle, “like the sting of a wasp”,
`by Alexander Wood of Edinburgh in 1853.
`
`Development of the dosage form continued rapidly after the dis——
`covery of the antisyphilitic, Salvarsan, the first of the magic bullets.
`
`If Salvarsan had been active orally it is doubtful if the progress would
`
`have been so rapid. Although the need for “cleanliness” was recognized
`
`quite early, the requirement for sterility was not documented officially
`until the micl——l920s.
`
`During World War II, dries} blood plasma and penicillin injections
`
`were occasionally reconstituted under battle conditions with available
`water, frequently from stagnant puddles. it was essential to get these
`
`materials into a traumatized patient who would otherwise have lost
`his life. It is probably true that some soldiers may have tiled of “war
`wounds” later but the majority survived with nothing worse than a. few
`
`boils. This anecdote is relatecl to make the point that the human body,
`
`when healthy, is capable of withstanding 21 certain amount of insult.
`
`However, a patient is not healthy. For many years injections were
`
`administered that may not always have been sterile, were occasionally
`pyrogenic, and frequently contained 2. large quantity and variety of car-
`ticulate contamination. Toclay standards have improved and we demand
`
`that our injections should be completely free of viable microorganisms,
`Should not cause febrile reactions, and contain only limited ttumbcrs
`
`of particles.
`
`Astrazeneca EX. 2086 p. 10
`
`

`
`6
`
`CHAPTER?
`
`FQRM AND FUNCTIDN DF INJECTABLES
`
`Drugfi prepared for injection are usually in the forrn of 21 simple
`
`aqueous selutian. However, somt: drugs may nctt be stable in tha prey
`
`SIICQ of water or may be mquired ta be releasecl intc the body more
`
`slowly. Non-aquecms systems such as oil cllspersians of powdersd solids
`or mils emulsified in water may be employed. Alternatively, a product
`
`may be lyophilizetl 01‘ clriecl, to be reconstituted with water prim to use.
`
`Parenteral administraticm of a drug usually has 2: number at advan-
`
`tages (aver the Qral route.
`
`I. Sting action is usually more rapid.
`2. The whole dose of that: drug it"; administered.
`
`3. Some drugs, such as insulin or heparin, are complstely inacti-
`
`vetted when given csralljg and have to be administered parenterally.
`
`4. Same drugs are irritants when given. orally but can be tolerated
`
`when given intravenously“, for example, strong solutitms of dextrese.
`
`5. If a patient is dehydrated or in shack, the administratlen elf
`inttavenzimt fluids will after; tense his at bar life.
`
`RQUTES OI?‘ ADMINISTRATION
`
`Using a ltolltraw needle of the appropriatz diameter, parenteral irtjeo
`
`titms can be: intmdtlcecl into the bcztly by a nutnbzer cf different rmutas
`
`as illustrated in Figures l-3.
`
`1. Subctttcznezms (am) injections are lntmduced into the soft tissues
`
`just underneath the Skin surface. Since the available space in these tissues
`
`is limited, the volume of these injectitms does not exceed 1:31;. Care
`is required ta make certain that the formulation canforms clasely to
`
`physiolagical conditions in terms of pH and tonicity.
`
`2.. Irtt1‘lt:tm.s*ct1Zar (i.m.) il'ljE3Clli{}I'lS are introduced directly illllfil the
`
`muscla, usually of the arm er the glut:-al region. This route is also used
`
`if the drug is irritant at is insoluble in water GI‘ oil St‘) that it must be
`
`usetl in the farm of 3. suspension. The volume of the injection must
`
`be kept small, generally not mare than 21111,. The blood supply to
`
`muscles is usually sufficient to enaure that the entire drug close iii not
`
`immediately available. For this reason, muscle “a::tivity”, i.t::., whetlmt
`
`or not the patient is moving artmncl 01’ is lying supine, may influence
`
`the rate at which the tlmg is active in the body.
`
`31 IIl‘£‘I’r3l‘l?e?t1?l!S (ism) injections; are introduced directly into llhli‘ blood-
`
`stream. It is possible, with care, tcza give: small volumes {sf ccanccutratad
`
`Astrazeneca EX. 2086 p. 11
`
`

`
`Parenteral Precincts
`
`3'
`
`soiuiiens that wzmid normally irritaiie tissues. These are administered
`
`siowiy so thaif the solutions arizdiluted by theblmzad fiewing past the
`in-zedie point 33 may are given. The intravenous route is also: used it}
`
`give larger volumes of replacement and hyperalimentation solutions.
`
`Faklewing major trauma, :1 patient may receive as much as i0!) iiters
`
`of fluid over 21 peried of weeks.
`
`4.
`
`Im‘rc:::zm:nem15 (i.::.) injection is introduced directly into the
`
`epidermis just balms; ihe stratum corneum. This rants is used to give
`
`small vaiumes (O.1—0.5mL) of diagnostic maierials arr vaccines.
`
`5. Imrarizecaf striations are used far inducing spinal or lumbar
`anesthesia by injecting solutions into that} subarachnctid space.
`Cerebrospinal fluid is; usuaily withdrawn first to zzvnicl increasing the
`
`fluid miume anti inducing pressure an the spinal nerve mats. Valumes
`
`of 1~2mL are usualiy administered. The density of the soluiion may
`
`
`Figure 1.
`
`Injection routes inn) and through the skin.
`
`imzracutaneous {intraciarmal} {used For diagnostic solutions)
`if}
`SC subcutanmus
`IM imramzsscuiar
`IV
`imrzwesnaus
`
`LC.
`
`
`
`.
`
`-,-an
`
`Epiidermzs
`cg Dermis
`
`-fiubcuiuneous
`iissue
`
`
`
`Astrazeneca EX. 2086 p. 12
`
`

`
`8
`
`CHAPTER2
`
`be adjusted to make the anesthetic move up or down the spinal canal
`according to the posture of the patient.
`
`6. Infra-articular injections are used to introduce materials such as
`anti—iuflarnmatory drugs directly into damaged or irritated joints.
`7. Intracardm, directly into the heart, is a route which may be used
`
`for injecting into the bloodstream large volumes of hypertonic or
`
`irritating solutions such as 70% dextrose. This requires a central ind-
`
`Intratiwcal injection routes into the subarachnoid space surrounding
`Figure 2.
`the spinal cord.
`
`PD peridural
`IT
`intrath ecai
`
` Perrdurcii space
`
`Fulum termincile
`
`3rd Lumbar
`Durci mater
`
`Arcichnoid
`Nerves
`
`Pia moter
`
`4th Lumbar
`
`SLJb—Cii‘CiChnOlC.i
`
`space
`
`5th Lumbar
`
`Astrazeneca Ex. 2086 p. 13
`
`9'“ ‘TL;
`C!
`°°-° "0
`:20 GA‘,
`
`
`
`Kwhflmm
`
`

`
`Parearerai Products
`
`9
`
`Intracisternai mute far withdrawing cerabrospinai fluid and occasion»
`Figure 3.
`ally fer atiministering antibioiics in cases of meningitis. The procedure is diffi-
`cult, requiring considerable care in the: injection technique and the preparation cf
`the injection salution [complate asepsis, pH, denfiity and frfiedom from particies).
`
`Magma
`
`Césaterncz
`
`Sub—r;1r<1:::hn0:d
`
`spaze
`
`.-_.':3pam::% card
`
`
`
`wefling catheter. Catheterizatien invelves a surgical pracedure and is
`generaliy only encountered in speciaiist units faund in the larger
`
`hospitals.
`8. Inrmperizanerzf (i.p.) is a route used for appiicatians such as the
`rabies vaccine. It may also be used far kidney diaiysis solutions.
`9..
`Izztracisferrzal and periduml routes are injectians into the
`
`Astrazeneca EX. 2086 p. 14
`
`

`
`10
`
`£?£!.é P T E.R 2
`
`
`
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`
`Astrazeneca EX. 2086 p. 15
`
`an
`
`4m>m¢
`
`
`

`
`Parenteral Products
`
`11
`
`intrecreniai cistern and dura meter :3’? the spine} ecmi. Both are diffk
`
`cult procedures, with critical requirements for the injections.
`
`The effect (:i.e., rate and intensity of aetien} produced by 3 drug
`
`may vary according :0 the route of aeminietretien. I:1travenous1y, the
`
`drug is ciistributed rapidly throughout the body so the effect an the
`target organ is usually seen quiekiy. However, if the drug is excreted
`
`through the kidney, the action may also be shortdived. A subcutaneous
`
`injection, en the ether hand, farms a depot from which the drug is
`
`elewly released. The onset of action is therefore slower, the intensity
`
`is reduced, and the duration -of aeticm is longer .233 seen in Figure 4,
`
`Injections do have drawbacks.
`
`I. Some email element of pain may be present that ie often
`
`unpleasant fer the patient, especially if there is difficuity in finding
`a suitable vein for intravenous administrzeiien.
`
`2,. In most cases: a cieeter or nurse is required to administer 3. dose.
`
`3, Qnee administered, a drug is immediately available te its target
`
`organ. If the patient is hypersensitive to the drug, or an everdese is
`
`administered, the effects are difficult to reverse.
`
`4. Administretien csf any materiel through the skin requires con-
`
`siderable care since air or miemnrgaeisms may be intreduced into the
`
`body. These side effects are usuaiiy manifested as reactiens, such as
`
`phlehitie, at the injeetien site.
`
`S UMMARY 017 THE ESSENTIAL REQUIREMENTS FOR
`AN INJECTABLE PRODUCT
`
`Because of their critical nature, parenterels must be prepared under
`
`carefully eentreiieci erwirenmental conditions and paekeci to ensnreethat,
`at the point of use, the product is:
`
`1. Free from microorganisms, sterile, or prepared fmm sterile mate-
`rials under eenciiiicns that minimize the chances efeentamifnatien with
`
`microerganisms (aseptic processing)
`
`2. Seubetantialiy free frem bacterial endemxins and other pyrogenie
`emateriais.
`
`3. Substantially free from extraneous insoluble rnaterieis.
`
`REFERENCES
`
`Avis, K.E., Laehman, L. and Lieberman, H.A., Pharmaceutical
`
`Dosage Forms: Parenteral Medications, Vols. 1 and 2, Maree1Dekker,
`New York (1984,
`.1986}.
`
`Astrazeneca EX. 2086 p. 16
`
`

`
`12
`
`CHAPTER 2
`
`Burma, RJ. and Akers, M.3., Chapter 2 in Pharmaceutical Desage
`
`Farms: Parenteral medications (Editors: Avis, I{.E., Lachrnan, L. and
`
`Lieberman, RA.) Marcel Qekker, New York, 1, 13 (1984),.
`
`Graves, M.,}., Parenteral Products: The Preparation and Quaiity
`Czmtml :31‘ Products for Injection: Heinemann Medical, London (1 973).
`
`Olson, W.P., and Graves, MJ. (Edimrs), Aseptic Pharmaceutifial
`
`Manufacturing: Technoiogy far the 19903, Interpharm Press, Prairis
`View, IL (1987).
`
`Tri:-rsel, L.A., Handbaok on Injectable Drugs, American Society of
`Hospital Fharrnacists, Washingmn, DC‘ (1936).
`
`Astrazeneca EX. 2086 p. 17