S
`
`N.
`
`ENCYCLOPEDIA OF
`PHARMACEUTICAL
`TECHNOLOGY
`
`Editors
`JAMES SWARBRICK
`Vice President
`Research and Development
`AAI, Inc.
`Wilmington, North Carolina
`JAMES C. BOYLAN
`Director
`Pharmaceutical Technology
`Hospital Products Division
`Abbott Laboratories
`Abbott Park, Illinois
`
`VOLUME 19
`
`SUPPLEMENT 2
`
`MARCEL
`
`I) E K K E R
`
`MARCEL DEKKER, INC.
`
`NEw Youc • BASa.
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1033
`
`Exh. 1033
`
`

`
`Library of Congress Cataloging in Publication Data
`Mail) entry under title:
`
`Encyclopedia of Pharmaceutical Technology.
`editors: James Swarbrick, James C. loylan.
`
`Includes index.
`I. Pharmaceutical technology—Dictionaries.
`II. Boylan, James C.
`l)rugs—
`2.
`1 Chemistry, Pharmaceutical-encyclopedias.
`[DNLM:
`3. Technology, Pharmaceutical-encyclopedias. QV 13 E565J.
`encyclopedias.
`615”,1’0321-dcl9
`RS192J353 1988
`
`I. Swarbrick, James.
`
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`
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`COPYRIGHT © 2000 BY MARCEL DIIKKER, INC. ALL RIGHTS RESERVED,
`Neither this book nor any part may be reproduced or transmitted in any form or by any
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`the publisher.
`
`LIBRARY OF’ CONGRESS CATALOG CARD NUMBER 88-25664
`ISBN: 0—8247--2818--l
`
`Current printing (last digit):
`4
`3
`6
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`
`2
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`1
`
`PRINFED IN TFIE UNITED STATES OF AMERICA
`
`Exh. 1033
`
`

`
`Excipients: Their Role in Parenteral
`Dosage Forms
`
`Introduction
`
`The term pairmaceutical CXCII)ient or additive denotes compounds that are added to the
`linisheti drug product for a variety of reasons. Most often such excipients are the major
`components of the drug product, with the active drug molecule being present only in a
`small percentage. l3xcipients have also been referred to as inactive or inert ingredients to
`distinguish them from the active pharmaceutical ingredients. However, in many instances
`excipients may not be as inert as some scientists may believe. Several countries have
`restrictions on the type or amount of excipient that can be included in the formulation of
`in Japan the use of amino
`parentera] drug products due to safety issues. For example,
`mercuric chloride or thimerosal is prohibited, even though these excipients are present in
`several American products.
`As defined in the European Phal7nacopeia (EP 1997) and the British Phannacopeta
`(HP 1998), “Parenteral preparations are sterile prcparntinJls intended for administration
`by injection, infusion, or implantation into the huuitm or anirnid body.’ However, in this
`article, only sterile preparations for administration by injection or infusion into the ho
`man body are surveyed [1,2]. Injectable products require a unique formulation strategy.
`The formulated product has to be sterile, pyrogco free, and iii the case of solutions, free
`of particulate matter. No coloring agent may be added solely for the purpose of coloring
`ihe parenteral preparation. Preferably, the formulation should be isotonic, and depending
`on the route of administration, certain excipients may not be included. For a given drug,
`the risk of an adverse event may he higher or the effects may he difficult to reverse if it
`is administered as an injection versus a nonparenteral route, since the injected drug by
`passes natural defense harriers. The requirement fur sterility demands that the excipient
`be able to withstand terminal sterilization or aseptic processing. These factors limit the
`choice of excipients available to the formulator.
`Generally, a knowledge of which excipients have been deemed safe by the Food and
`Drug Administration (FDA) or arc already present in a marketed product provides in
`creased assurance to the formulator that these excipients will probably be safe for a new
`drug product. However, there is no guarantee that the new drug product will be safe as
`excipients are combined with other additives and/or with a new drug molecule creating
`unforeseen potentiation or synergistic toxic effects. Regulatory bodies may view an cx
`cipient previously approved in an injectable dosage form favorably, and frequently require
`fewer safety data. A new additive in a formulated product always requires additional stud
`ies adding to the cost and thneline of product development.
`In Japan, if the drug product contains an excipient with no precedence of use in Ja
`pan, the quality and safety attributes of the excipient must be evaluated by the Subcom
`mittee on Pharmaceutical Excipients of the Central Pharmaceutical Affairs Council con
`currently with the evaluation of the drug product application [3]. Precedence of use means
`that the excipient has been used in a drug product in Japan, and is administered via the
`
`137
`
`Exh. 1033
`
`

`
`Exciplorits: Their Role in Parenteral Dosage Forms
`
`138
`same route and in a dose level equal to or higher than the excipient in question in the new
`D pplicauon.
`This arlicle is a comprehensive review of the excipients that have been included in
`the injectable products marketed in the Unitcd States, Eorope, and Japan. A review of the
`literature indicates that only a few articles have been published which specifically deal
`with tire selection of parenteral excipients [4—9]. However, excipients included in other
`sterile dosugc forms not administered parenicrally are not covered here, such as solution
`for irrigation, ophthalmic or otic drops, and ointments. Additionai information on the
`excipierits used in parcnteral products can be found in Vols. 1-4, 6, 11, and 13-15 of this
`encyclopedia.
`Several sources of in.t&mation were used to suninmrize the information compiled in
`1 1—14J. Formulation information no the commercially available in
`this article [4—7, 10,
`jectable products was entered in a worksheet, which is the sotirce of the tables presented
`here. Each table has been categorized based on the primary function of the excipient in
`the formulation. For example, citrates are classiliecl as buffers and not as chelating agents,
`and ascorbares are categorized as rurtioxidants, although they can serve as buffers. This
`classification system minimizes redundancy and provides a reader-friendly format. The
`concentration of excipients is given as percent weight by volume (w/v) or volume by
`the percentages were
`volume (v/v), If the product was listed as lyophilized or powder,
`based on the reconstitution volume commonly used. The tabLes list the range of concen
`[ration and examples of products contair ng the excipient, especially those which are used
`in extremely low or high concentrations. A column in Tables 1—5 indicates the frequency
`with which these excipients are used in parcnteral products.
`
`Types of Excipients
`Solvents and Cosolvents
`lable I list solvents and cosolvents used in parenteral products. Water for injection is the
`most common solvent but may be combined or substituted with a cosolvent to improve
`the solubility or stability of the drugs [15,16). The dielectric constant and solubility pa
`rameters are among the most common polarity indices used for solvent blending [17,18).
`Ethanol and pmpylene glycol are used alone or in combination with other solvents in more
`is used more
`than 50% of parenteral cosolvent systems. Surprisingly, propylene glycol
`often than polyethylene glycols (PEGs) in spite of its higher rnyotoxicity and bernolyz
`ing effects [19-22]. The hemolytic potential of cosolvents is as follows [19]:
`Dimethyl acet.amide <PEG 400 < ethanol <propylene glycol < dimethylsulfoxide
`It is possible that the presence of residual peroxide from the bleaching of PEG or the
`generation of peroxides in PEG may result in the degradation of the drug in the cosolvent
`system. It is important to use unbleached and peroxide-free PEGs in the formulation.
`Oils like safflower and soybean are used in parenteral nutrition products where they
`serve as a fat source and carriers for fat-soluble vitamins. The United States Pharmacopeia,
`USP, requirements for injectable oils are as follows [3]:
`
`• Fixed oils of vegetable origin
`Saponification value, 185—200
`Iodine number, 79—128; Japan Fharmacopeia recommends a value between 79 and 137
`
`Exh. 1033
`
`

`
`I’
`
`C
`0 C-
`
`v C C
`- -
`I CC -
`
`mx
`
`VirilontM(StarPharmaceuticals)
`Intralipid®(Clintec),20%
`Soigana1(Schering)
`Liposynll(Abbott),10%
`Terramycinsolution(Pfizer),75.2%
`Ethiodol(Savage)
`Depo-Medroi®(Upjohn),2.95%w/v
`Ativan®(Wyeth-Ayerst)
`Persanrine(Dupont-Merck)
`VePesid(BristolMyers),65%wiv
`Secobarbiralsodium(Wyeth-Ayerst),50%
`
`BaJinOil®(BectonDickinson)
`MultitestCMI®(PasteurMericox),70%w/v
`Prograt(Fujisawe),80%w/v
`Vurnon®(BdstoMyers).6%wlv
`Depo-Testadiol
`Delestrogen20rnglrnL(BristolMyers).44.8%wiv
`DelesirogenS40mg)mL(BristolMyers),44.8%w/v
`Poisonivyextract(ParkeDavis)
`
`(Upjohn),87.4%w/v
`
`NA’
`5—20%wfv
`NA’
`5—10%
`0.2—752%
`NA’
`0.3—3%
`NA’
`5%wfv
`50—65%
`0.15—50%
`
`NA’
`1.6—70%w/
`0.6.40%
`6%wlv
`73.6—87.4%w/v
`NA
`20-44.7%w/v
`NA
`
`
`3
`5
`1
`
`25
`I
`
`4
`6
`2
`2
`
`25
`
`24
`
`I
`I
`
`I
`
`2
`3
`I
`
`I
`
`‘NodataavaHabic.
`
`Polyethyleneglycol
`Peanutoil
`Glycerin(glycerol)
`Ethanol
`N,N-Dimethylacetarnide
`Cottonseedoil
`Castoroil
`Benzylberizoate
`Almondoil
`
`Vegetableoil
`Soybeanoil
`Seasmeoil
`Saffloweroil
`Propyleneglycol
`Poppyseedoil
`PEG3350
`PEG400
`PEG600
`PEG300
`PEG
`
`Example
`
`ConcentrationRange
`
`Frequency
`
`Excipient
`
`SolventsandCosolvents
`
`TABLE1
`
`Exh. 1033
`
`

`
`140
`
`Excipierits: Their Role In Parenteral Dosage Forms
`
`lest tur U isapon Lfi ib Ic ralt er
`Fest br lee fatty acid
`Solid paraifin test at 10°C
`Acid value nrnt 056 (JP only)
`• Synthetic rnono and di-glycerides of fatty acids which are liquid am! remain So when
`cooled to I 0°C
`I od ne n timber < 140
`Solid paraffIn test at
`
`I 0°C
`
`The oils are used to dissolve drugs with low aqueous solubility and provide a meclm
`nsa to slowly release drugs over a long period of time. Detedoratioti of fixed oils leads
`to rancidity and production of free fatty acids and must be avoided in injectable products.
`ruithei-iiioie, the fixed oils or fatty acid esters must be fl-ce of mineral oil or paraffin which
`the body cannot metabolize.
`
`Polymeric and Surface-Active Compounds
`Table 2 includes a broad category of excipients whose function in formulation could be:
`
`• To impart viscosity or act as suspending agents, for example, carboxymethylcellulose,
`sodium carboxymethylcellulose, acacia, povidone, hydrolyzed gelatin, and sorbitol,
`• To act as solubilizing, wetting, or emulsifying agents, for example, like Cremophor EL,
`sodium desoxychloate, Polysorbate 20 or 80, PEG 40 castor oil, PEG 60 castor oil,
`sodium dodecyl sulfate, lecithin, or egg yolk phospholipid.
`• To form gels as when aluminum monostearate is added to fixed oil to lbrm a viscous
`or gel-like suspension medium.
`
`Polysorbate 80 is the most common and versatile solubilizing, wetting, and cinulsi
`fying gent. Again, one must be concerned about the level of residual peroxides present
`in polysorbates and protect them from air to prevent further oxidation [23]. Polysorhate
`80 is the polyoxyethylene sorbitan ester of oleic acid (aim unsaturated fatty acid), whereas
`Polysorbate 20 is the polyoxyethylene sorbitan ester of laurie acid (a saturated fatty acid).
`Thus, there could be stability differences in the drug product formulated with Polysorhate
`80 versus Polysorbate 20. An example is Neupogen’ which, when exposed to a high
`concentration of Polysorbate 20, is less prone to oxidation than when exposed to a simi
`lar concentration of Polysorbate 80 [24].
`
`Chelating Agents
`Only a limited number of chelating agents are used in parenteral products (Table 3). They
`serve to complex heavy metals and therefore can improve the efficacy of antioxidants or
`preservatives. Citric acid, tartaric acid, and some amino acids can also act as chelating
`agents. It has been wrongly believed that EDTA (as calcium salt) has not been used in
`an approved injectable product in Japan. There are some drug products which contain cal
`cium disodiurn EDTA currently on the market in Japan where it is listed as an official
`excipient. A possible advantage of calcium EDTA over the tetrasodium salt is that it does
`not contribute sodium and does not chelate as much calcium from the blood.
`
`Exh. 1033
`
`

`
`-a
`
`C C
`
`C‘
`
`It
`
`4
`0 -
`
`00
`
`-4
`
`‘C
`
`,
`
`xC
`
`(AlphaTherapectics)
`Diprivan(Zeneca),1.2%wlv
`Cortonea(Merck),16%w/v
`Intralipid(Clintec),1.2%
`Fucgizone(BristolMyers).0.41%w,v
`Sandimrnune(Sandoz),65%wlv
`LupronDepotcrAp),1.0%wlv
`Bici1lin(Wyeth-Ayarst),0.55%
`SoiganalLi.a(Scherng),2%
`TuberculinOdTes:z(Lederie),
`
`Aristrospana(Fujisawa),50%v/v
`Proleukifla(Cetus),0.018%w/v
`BlClllOa(Wyeth-Ayerst),0.6%w!v
`Prngrafx(Fujisaa),20%wlv
`Monistat(Jarissen),11.5%v/v
`Calcijexa(Abbott),0.4%wlv
`AquasolApare0raj(Astra),12%
`AquaMephton(Merck),7%w!
`
`25—50%
`0.018%wlv
`0.5—0.6%w/v
`20%w/v
`i1.5%‘qv
`0.01—0.4%
`0.004—12%
`;%wfv
`
`—
`
`0.4—1.2%wlv
`16%w/v
`1.2%
`0.4%w/v
`50—65%wlv
`0.15—1.0%
`0.50—0.55%
`2%
`7%
`
`PEG60hydrogenatedcastoroihCremophorRH60,hydrogenatedcastoroilP05.60,ProtachemCAH.60.
`PEG40castoroil,polyosyl40castoroil,castoroilPOE4O,Croduret40,polyoxyothylene40castoroil,ProtachersCA-40.
`CzernophorEL,Etocas35.polyethoxyla:edcastoroil,polyoxyethylene35castor01].
`Sorbitol
`Sodiumdodecylsulfate(Nalaurylsulfate)
`Povidone(polyvinylpyrrolidone)
`PEG60castoroilc
`PEG40castoroiI
`Polysorbate20(Tween20)
`Polysorbate80(Tween80)
`Polvoxyethylatcdfattyacid
`PluronicF-68
`LOClthlfl
`Gelatin,hydrolyzed
`Eggyolkphospholipid
`Desoxycholatesodium
`CremophorEU
`Carboxymethylcellulose,sodium
`Carboxymethylcellulose
`Aluminummonostearate
`Acacia
`
`8
`
`1
`1
`
`7
`1
`
`3
`
`46
`
`3
`
`3
`1
`
`8
`1
`1
`I
`
`18
`
`2
`
`1
`
`4
`
`Example
`
`ConcentrationRange
`
`Excipient
`TABLE2Soiubtlizing.Wetting,Susnending,Emulsifying,orThickeningAgents
`
`Frequency
`
`Exh. 1033
`
`

`
`
`
`- CC C‘1C
`
`-C
`
`-I
`
`rnx
`
`—I
`
`Magnevist®(Berlex),0.04%
`Folvite®(Lederle),0.20%
`Calcijex(Abbott),0.11%wlv
`Wydase(Wyetb-Ayersz),0.1%wv
`
`0.04%
`0.20%
`0.01—0.11%
`0.01—0.1%
`
`Example
`
`ConcentrationRange
`
`Frequency
`
`bDTPA=diethylenetriamicepntsacjacidpenteticacid.
`EDTA=cthyleaediamine
`
`aceticacid,
`
`9
`
`38
`
`DTPAb
`SodiumEDTA
`DisodjumEDTA
`CalciumdisodjumEDTA
`
`Excipient
`TABLE3ChelatingAgents
`
`Exh. 1033
`
`

`
`Exciplonts: Their Role in Parenterul Dosage Forms
`netall o—prutein Corn in I a Lions where he
`A co mplc xi ng age itt should ii it be used ii
`in rare instances, can increase the
`1)1 otcin suhunjt aic hound by the metal [25J. PDTA,
`oxidation rate due to the binding of the EDTA— iieUd complex to protein, resulting in site—
`specihc generation of radicals [261,
`
`143
`
`A it i oxidant a
`Antioxidarns axe used to prevent the oxidation of active substances and excipients in the
`!inished product. There arc three main types of antioxidants:
`
`‘Irue tmtioxidants act by a chain-termination mcChUnsflI by reacting with free radicals
`(e.g., butylated hydwxytoluene).
`• Reducing agents have a lower redox potential than the drug and are preferentially oxi
`died (e.g.. ascorbic acid). ‘l’lmus, they can he consumcd during the shell’ ide of the prod
`lict.
`• Antioxidant synergists enhance the effect of antioxidants (e.g., E1YI’A).
`
`‘I’ablc 4 shows the antioxidants, their frequency of use and concentration range, and
`examples of products containing them. Sulfite, bisulfite, and metabisulfite constitute the
`majority of antioxidants used in parenteral products despite several reports of incompat
`ibility and toxicity [27,28]. Butylated hydroxyanisule, butylated hydroxytoluene, and pro
`pYl gatlate are primarily used in semi- or nonaqucous vehicles because of their low aque
`ous solubility [29J. Ascorbic acidlsodiuin ascorbate may serve as an antioxidant, buffer,
`and chelating agent in the same formulation. Some amino acids like cysteine also func
`tion as effective nutioxidants.
`The Committee for Proprietary Medicinal Products (CPMP) guideline calls for a full
`explanation and justification for including antioxidants in the formulation [30]. It further
`states that antioxidants should omdy be included if absolutely necessary. Thus, it is impera
`tive to first try an inert gas (nitrogen or argon) in time head space to prevent oxidation. If
`the antioxidant has to be included, its concentration must be justified in terms of efficacy
`and safety. Antioxidaats such as sulfites and metahisulfites are especially undesirable.
`Some antioxidants possess antimicrobial properties, such us propyl gahlate and buty
`lated hydroxyanisole, which are somewhat effective against bacteria; butylated hydroxy
`toluene has demonstrated some antiviral activity. Compatibility of antioxidants with the
`drug, packaging system, and the body should be studied carefully. For example, toco
`phcrols may be absorbed by plastics; ascorbic acid is incompatible with alkalis, heavy
`metals, and oxidizing materials like phenylephrine or sodium nitrite; propyl gallate forms
`complexes with metal ions like sodium, potassium, and iron,
`
`Preservatives
`l3cnzyl alcohol is the most common antimicrobial preservative present in parenteral for
`mulations (Table 5). This observation is consistent with other surveys [6,31]. Parabens
`are the second most common preservative, Surprisingly, thimerosa] is also frequently used,
`especially in vaccines, even though some individuals are sensitive to mercurics, Several
`preservatives volatilize easily (benzyl alcohol, phenol) and therefore should not be used
`for lyophilized dosage forms. Chiorocresol is supposed to be a good preservative for
`
`Exh. 1033
`
`

`
`‘1
`
`0
`
`0 0C
`
`s
`
`0
`
`‘a
`Cs
`
`C,
`SC
`rn
`
`Sus-Phrine(Forest),0.66%w/v
`En1on(Ohmeda),0.2%w/v
`Navane(Pfizer),0.02%
`Terramyci.nsolution(Pfizer),1%
`Intropina(DuPont),1%wlv
`Vasoxyl(Glaxo-Weilcorrte),0.10%
`Terrarnycinsolution(Pfize.r),0.5%w/v
`Varivaxz(Merck),0.1%w/v
`MV.).12®(Astra),2%
`OctreoScan(Mallinckrcdt),0.02%w/v
`Nurnorphan(EndoLab),0.10%
`Acthrei(Ferring),1.3%w/v
`AquasolA(Astra),0.03%w/
`AquasolA(Astra),0.03%w/v
`Arni1dn(BñstclMyers),0.66%w/\
`Vibramycirt(Pfizer),4.8%w/v
`Novocn±ne(Sanofi.Wrtthrop),0.4%wiv
`
`Example
`
`0.66%wfv
`0.05—0.2%w/v
`0.02%
`0.1—1%
`0.02—1%w/v
`0.10%
`0.02—0.5%wiv
`0,1%wlv
`2%
`0.02%w/v
`
`0.10%
`0.00—1.3%wlv
`0.00116—0.03%wlv
`O.00028-.03%w/v
`0.02—0.66%wfv
`0.1—4.8%wlv
`0.2—0.4%‘.iV
`ConcentrutionRange
`
`6
`
`2
`7
`
`1
`
`32
`
`9
`1
`
`3
`3
`3
`1
`
`2
`1
`1
`
`8
`
`31
`
`4
`
`Frequency
`
`Thioglycolatesodium
`Sulfitesodium
`Propylgallate
`Monothioglycerol(thioglycerol)
`Metabisulf,ltesodium
`Metabisuifitepotassium
`Formaldehydesulfoxylatesodium
`Glutamatemonosodium
`Gentisjcacidetbanolamine
`Gentisicacid
`Dithioriitesodium(Nahydrosulfite,
`ystein,cysteinateMCI
`Butylatcdhydroxytoluene(BHT)
`Butylatedbydroxyanisole(BHA)
`Bisulfitesodium
`Ascorbate(sodiumsaltoracid)
`Acetonesodiumbisulfite
`Excipient
`TABLE4AntioxidantsandReducingAgents
`
`Nasulfoxylate)
`
`Exh. 1033
`
`

`
`C
`
`C
`
`C C C
`
`Agama(Pbarmacia-Upjohn),0.01%
`Antivenin(Wyeth-Ayers:).0.001%
`Havrix(SmithCiineBeecharn),0.50%w!v
`Caicimarx(Rhone-Poulanc).0.5%w/v
`Xylocainew/Epiaephrine(Astra),0.%w)v
`inaspinex(Janssen),0.18%w/v
`DepoProverax(Pharrnacia-piohn).C169%w/v
`Hurnatrope(Lilly).0.3%
`Codinephosphate(Wyeth-Ayersr),0.5%
`Progestercne(UnitedRe.s).10%
`Beeadrvl(ParkeDavis).0.01%wi’
`CelestoneSoluspan(Schering),0.02%v,/v
`
`Exanpie
`
`0.003—0.012%
`0.001%
`0.50%
`0.2—0.5%
`0.01—C1%
`0.05—018%
`0.0195—0.169%wfv
`0.1—0,3%
`0.25—05%
`075—10%
`0.01%
`0.02%wfv
`ConcentrationRange
`
`Frequency
`
`3
`
`48
`
`50
`
`4
`
`4
`2
`
`52
`
`4
`1
`
`83
`
`Thimerosal
`Phenylmercuricnitrate
`2-Phenoxyethanol
`Phenol
`Parabenpropyl
`Parabenmethyl
`Myristyl‘y-picohniurnchloride
`tn-Cresol
`Chiorbutanol
`Benzylalcohol
`Benzathoniumchloride
`Benzalkoniumchloride
`Excipient
`TABLE5AntimicrobialPreservatives
`
`Exh. 1033
`
`

`
`146
`
`Exciplents: Their Role in Parentaral Dosage Forms
`
`TABLE 6 Maximum Permissible Amount of
`lkeservatives and A.n(ioxidants
`Maximum IJSP Limit, %
`Exclpient
`Mercutal compounds
`0.01
`0.01
`Cationic surfactants
`Chlorobuttumi
`0.50
`Cresol
`0.50
`Phenol
`0.50
`Sulfur dioxides
`1)20
`Or an equivalent amount of the sulfite, bisulfite, or nietubisulfite
`of potassium or sodium.
`
`parenterals, but the authors survey did not find any examples of commercial products
`containing chiorocresol, The British Pharmaceutical Codex and Martindale list
`chiorocresol as a preservative in multidose aqueous injections at concentration of 0. 1%
`but no examples of injectable products are provided [32,33).
`Antimicrobial preservatives are allowed in multidose injections to prevent growth of
`microorganisms which may accidentally enter the container during withdrawal of the dose.
`However, they are discouraged from being used in single-dose injections in the United
`States, although both liP and BP allow aqueous preparations that are manufactured us
`ing aseptic techniques to contain suitable preservatives. It should be emphasized that pre
`servatives should never be used as a substitute for inadequate current Good Manufactur
`ing Practices (cGMP). Both BP and liP prohibit antimicrobials in single-dose injections
`where the dose volume is higher than 15 mL or if the drug product is to be injected via
`intracisternal or any route which gives access to the cerebrospinal fluid. Toxicity is the
`primary reason for rnininuzing the use of antimicrobial preservatives. For example, many
`individuals are allergic to mercury preservatives, and benzyl alcohol is contraindicated
`in children under the age of two. The USP has also placed some restrictions on the maxi
`mum concentration of preservatives allowed in formulations to address toxicity and al
`lergic reactions (Table 6). The World Health Organization (WHO) has set an estimated
`total acceptable daily intake for sorbate (as sorbic acid or calcium, potassium, and sodium
`salts) as not more than 25 mg/kg body weight. The efficacy of the preservative should
`be assessed during product development by preservative effectiveness testing (PET) [34—
`36]. Thus, an aqueous preserved parenteral product can be used up to a maximum of 28
`days after the container has been opened [37), Obviously 28 days has to be justified by
`performing PET on the finished product in the final package. Products free of preserva
`tives should preferably be used immediately after opening, reconstitution, or dilution.
`
`Buffers
`Buffers are added to a formulation to adjust the pH in order to optimize solubility and
`stability. For parenteral preparations, it is desirable that the pH of the product be close
`to physiologic pH. The selection of buffer concentration (ionic strength) and buffer spe
`cies is important. For example, 5—15 mM of citrate buffers are used in the formulation,
`but increasing the buffer concentration to >50 mM will result in excessive pain on sub
`cutaneous injection and toxic effects due to the chelation of calcium in the blood.
`
`Exh. 1033
`
`

`
`Excipionts: Their Role in Paronterul Dosage Forms
`147
`Butters have Inaxijltuni butler capacities near their pka. For products which may be
`,suhjecicd to eXcessive temperature fluctuations during processing (sterilization or lyo
`plnhzauon), it is
`iriportant to select buffers with a sinai] pKa/°C. Thus, the pH of the
`Uris buffer made at 25°C (pKaJ°C of -0.028/°C) changes from 7.1 to 5.0 at 100°C. This
`nmy dramatically affect the stability or solubility of the drug. Similarly, the best buffers
`for a lyophilizcd product may be those which show the smallest pH change upon cool
`ing do not crystallize out, and can remain in the amorphous state protecting the drug. For
`example, replacing succmate by glycolate buffer increases the stability of lyophilizcd
`interferoet—y [3$j. F)uring the lyophilizatiun of mannitol containing succinate buffer at p1-I
`5, monosodium succinate crystallizes, reducing the pH and resulting itt the unfolding of
`interfcron-y. This pH shift is not seen with glyeolate buffer.
`The buffers and chemicals in Table 7 arc used to adjust the pH and its range of for
`inulations, Phosphate, citrate, and acetate are the most conunon buffers used in parenteral
`products. Mono- and diethanolansines are added to adjust the p14 and form the correspond—
`ing salts. Hydrogen brominde, sulfuric acid, bensene sulfonic acid, and methane sulfunic
`acid.s are added to drugs which ate salts of bromide (Scopolamine Hllr, Hyoscinc [IBm),
`sulfate (Nebcin, ‘l’obrainycin sulfate), besylate (‘l’racrium Injcction, Atracurium besylate),
`or niesylate (Dliii 45 Injection, dihydrocrgotatnine niesylate). Glucono ö-lactone is ucd
`to adjust the pH of qoinidine gluconate. Benzonte buffer, at a concentration of 5%, is used
`in Valium Injection. Citratcs are common buffers that can also act as chelating agents.
`Amino acids, lysine, and glycine function as buffers and stabilize proteins and peptide
`foritiulations. ‘l’liese amino acids are also used as lyo-additives and ittay pre.’ent cold
`denaturation. Lactate and tartrate arc occasionally used as buffer systems. Acetates are
`good bufICr.s at
`low pH, but they are not generally used for lyophilization because of
`potential so bli in au on.
`
`Hulking Agents, Protectants, and Tonicity Adjusters
`The additives shown in Table 8 are used to modify osinolality and as bullring or lyo/cryo
`protective agents. Dextrose and sodium chloride are used to adjust tonicity in the major
`ity of formulations. Some amino acids such as glycine, alanine, histidine, imidazole, atgi
`nine, asparagine, and aspartic acid are used as bullring agents for lyophilizadon and may
`also serve as stabilizers and/or as buffers. Monosaccharides (dextrose, glucose, maltose,
`lactose), disaccharides (sucrose, trehalose), polyhydric alcohols (inositol, mannitol, sor
`bitol), glycols (PEG 3350), Povidone (polyvinylpyrrolidone, PVP), and proteins (albumin,
`gelatin) arc commonly used as lyo-additives. Hydroxyethyl starch (hetastarch) and
`pentastarch, which are currently used as plasma expanders in commercial injectable prod
`licts like Hespan and Pen taspan, are being evaluated as protcctarns during the freeze drying
`of proteins.
`Povidone has been used for injectable products as solubilizing agent, protectant, and
`bullring agent. Only pyrogen-free grade, with low molecular weight (K value < 18) should
`he used in parenteral products to allow for rapid renal elimination. Povidone solubilizes
`drugs like rifampicin and may redtice local toxicity as seen with oxytetracycline injec
`tion.
`Many proteins can be stabilized in the lyophilized state if the stabilizer and protein
`do not phase-separate during freezing and the stabilizer does not crystallize. In the case
`of Neupogen® (granulocyte colony stimulating factor, GCSP), the original formulation was
`modified by replacing mannitul with sorbitol to prevent the loss of activity if a liquid
`
`Exh. 1033
`
`

`
`148
`
`TABLE 7
`
`lixci pient
`
`Exclpients: Their Role in Purentertil Dosage Forms
`Flutters nd pH Adjusting Agents
`
`pH Range
`
`lixainple
`
`Syntocinon® (Nuvartis)
`Synocinun® (Novartis)
`Brevjbloc® (OhxnecJs)
`Bumex Injection® (Roche)
`Ititto Var® (Astrri)
`Triostat® (Jones Medical)
`Retavase® (Boehringcr)
`Pepcid® (Merck)
`Nirnhex (Gitixu Wcljcojiie)
`Va1ium (Roche)
`Cenolate® (Abbott)
`Comvax® (Merck)
`Hyperab® (Bayer)
`
`DTIC-Dome® (Ilayer)
`Amikin® (Bristol Myers)
`Cerezywe® (Geazyine)
`Cerezytne® (Geozyme)
`Iiactirn lV (Roche)
`Quinidine Gluconate(Lilly)
`Hap-B (iarnrnagec (Merck)
`Doxil® (Sequos)
`Amicar® (Irnmunex)
`Scopolamine (UDL)
`[nnovar (Janssen)
`Etninase® (Roberts)
`Libriurn® (Roche)
`Magnevist® (lierlex)
`DHE-45® (Novartis)
`Terrainycin (Pfizer)
`
`31—4.3
`3,7—4.3
`3,5—5,5
`6.8—,1.8
`
`—
`
`—
`
`7.0—1.4
`5.7—6.4
`3.25—3.65
`6.2—6.9
`5.5—11.0
`
`—
`
`5.0—11.0
`
`3,0-4,0
`3.5—5.5
`
`—
`
`—
`
`9.5—10.5
`5.5-7.0
`6.4—7.2
`6.5
`6.0—7.6
`3.5—6.5
`2.7-5.7
`
`—
`
`3.0—5.0
`6.5—8.0
`3.2-4.0
`8.0—9.0
`
`6.5--8 5
`6.7—7.3
`6.0-8.0
`6.7—7.3
`
`Aectuic
`Sodium
`Acetic acid
`Glacial acetic acid
`Ammoni urn
`Amnioniutu sulfate
`Ammoniurn hydroxide
`Arginine
`Aspar tic acid
`Ucnzcne ulfonic acid
`Benroate sodium, acid
`Bicarbonate
`Boric ncid, sodium salt
`Carbonate, sodium
`Citrate
`Acid
`Sodium
`Disudiurn
`‘Frisodium
`)ierha,iolatnine
`Glucono b-lacione
`Glycine, glycine IICJ
`ilistidine, liistidine HCI
`Hydrochloric acid
`I lydrobroniic acid
`Lactate sodium, acid
`Lysine (L)
`Maleic acid
`Meglitinine
`Methanesolfonic acid
`Monocthanolaxriiue
`Phosphate
`Acid
`Saizen® (Serono Labs)
`Monobasic potassium
`Zanlac® (Glaxo-Welicorne)
`Monobasic sodium°
`Pregoyl® (Drganou)
`Djbasic sodiumt’
`Zantac® (Glaxo-Weilcome)
`Tribasic sodium
`Syothroid® (Knoll)
`Sodium hydroxide
`Optiray® (Mallinckrodt)
`Sodium succirlate
`Actimanune® (Genentech)
`Sulfuric acid
`3.0—6.5
`Nebcin® (Lilly)
`‘ranrate sodium, acid
`Metiserginc® (Novartis)
`2.7—3.5
`Tromethamine
`6.0—7.5
`Optiray® (Mallinckrodt)
`-‘Sodium biphosphate, sodium dihydrogen phosphate, or sodium dihydrogen orthophosphate.
`t’Sodian, phosphate, disodiutri hydrogen phosphate.
`
`Broad range
`
`—
`
`formulation accidentally freezes [24]. Man.nitol crystallizes if the solution freezes, whereas
`sorbitol remains in an amorphous state protecting GCSF. Similarly, it is useful that the
`drug remains dispersed in the stabilizer upon freezing of the solution. Thus, Cefoxitin, a
`cephalosporin, is more stable when freeze-dried with sucrose than with trehalose, although
`
`Exh. 1033
`
`

`
`Exciplonts: Their Role in Par&mteral Dosage Forms
`
`149
`
`Llulkirig Agents, l’roteclants, and Touicity Adjusters
`
`TABLE 8
`Excipient
`
`A liiniite
`Albuittin
`Albumin (tiuinait)
`Amino acids
`At gini tic (s.)
`Aspingine
`Aspartic acid (i)
`Calciuni chloride
`Cyclodex inn
`y-Cyclodextnni
`Dcxtrari 40
`Dextrose
`Gelatin (cross-linked)
`Gelatin (hydrolyzed)
`Lactic—glycolic ucid copolyiners
`(ilucose
`(;Jyceiine
`Glyc Inc
`I listidiiic
`liniduzoic
`Inusitol
`l,cttis
`Magnesium chloride
`MagneSium sulfate
`Maltose
`M anni tol
`Polyethylene glycol 3350
`Pulylactic acid
`Polysorbale 80
`Ptitnssiu in chloride
`Povidone
`Sodium chloride
`Sodium chotcsteryl sulfate
`Sodium succinate
`Sodium sulfate
`Sorbitoi
`Sucrose
`a,a-Trchalose
`
`Example
`‘litrombate Ill® (Bayer)
`liioclutc® (Arco)
`Botuxt’ (Allergan)
`llavrix® (Smith Kline lleechani)
`Activase® (Gcnentecti)
`‘l’iee OCO® (Organon)
`l’epcid® (Merck)
`Phenergan® (Wycth-Aycrst)
`Pdrx® (Schwartz)
`Gardiotec® (Squibb)
`Itopophos® (Bristol Myers)
`iJetascron® (l3erlex)
`Kabikinase® (Phamiacia-Upjohn)
`Acthar® (Rhone-Poulcoc Rorer)
`Lupron Depot® (TAP)
`Iveegam® (Immuno-LJS)
`‘)‘iee BCG® (Organon)
`Atgann® (Pharrnacia-Upjohn)
`Antihetnophilic factor, human (Am. Red Cross)
`lielixate® (Armour)
`OctreoScan® (Mallinekrodt)
`Caverjcct® (Pharrnacia-Upjohn)
`Terrurnycin solution (Pfizer)
`Tice BCG® (Organoii)
`Gamimunc N® (Bayer)
`Jilspar® (Merck)
`l3ioclate® (Arco)
`Lupron Depot® (TAP)
`Helixate® (Armour)
`Varjvax® (Merck)
`Alkeran® (Glaxo-Welicome)
`WjniRlso SD® (Univax)
`Arnphotec® (Scquus)
`Actinnmune® (Genentecb)
`Depo_Proveru® (Phnrmncia-Upjohn)
`PailhciIiatin® (Abbott)
`Prolasun® (Bayer)
`lIerceptin1 (Genentccb)
`
`the glass transition temperature is much higher and structural relaxation time is much
`longer for trehalose than for sucrose [39]. The Fl’IR data indicated that the trehalose—
`cefoxitin system phase-separated into two nearly pure components resulting in [to protec
`tion (stability). Similarly, dextran was not found to be as useful a cryoprotectant for pro
`tein as sucrose because dextran and protein undergo phase segregation as the solution
`freezes. The mechanism of cryoprotection in the solution has been explained by the pref
`erential exclusion hypothesis [40].
`Trehalose is a nonreducing disaccharide composed of two n-glucose monomers, It is
`found in several animals that can withstand dehydration, and therefore has been suggested
`
`Exh. 1033
`
`

`
`150
`
`Exclplents: Their Role In Pareritoral Dosage Forms
`
`to stabilize drugs which undergo denaturation during spray drying or freeze drying [41J.
`Herccptin (Trastuzumab) is a recombinant DNA-derived monoclonal antibody (MAb)
`which is used for treating inetastatic breast cancer. The M.Ab has been stabilized in the
`lyophilized formulation using tr,a-trehalose dihydrate. Trebalose has also been used as
`a cryoprotectant to prevent liposomal aggregation and leakage. In the dried state, carbo
`hydrates like trehalose or inositul exert their protective effect by acting as a water sub
`stitute 142].
`Additives may have to be included in the formulation to adjust the specific gravity.
`This is important for drugs which, upon administration, may come in contact with cere
`brospinal fluid (CSP) which has a specific gravity of 1.0059 at 37°C. Solutions with the
`same peci1ic gravity as CSF are termed isobaric, whereas solutious with a specific gravity
`greater than that of CSF are called hyperbaric. Upon administration of a hyperbaric so
`lution in the spinal cord, [lie injected solution settles and affects spinal nerves at the end
`of the spinal cord. For example, dibucaine hydrochloride solution (Nupcrcaine 1:200)
`is isobaric, while Nupercaine 1:500 is hypobaric (specific gravity 1.0036 at 37’C).
`Nupercaine heavy so]utiori is made hyperbaric by the addition of 5% dextros