-.......:....'..;......_.................;......~..........__........
`
`-
`
`-
`
`-
`
`~-~~~'-~~-~~ ~-~-~~
`
`'
`
`.
`
`REVIEW A1€Ta’CLE
`
`ExcEp§en€s and Their use in Enfieaiahée Pmdufis
`
`S&f\§E1‘=EEPNEMA*.. R. J. WASHKUHN, and R. J. ERENDEL
`
`fifaliiizcicragif ffiiesiicsxi, §‘::s:12r5mrg7fm’, Swim’ Lam‘.-s, M;'s_-ramri
`
`
`A8STRA£'Ji".- I-‘ormui.-m'oia ofa n.ewcz'r1.-g p.rm.?ae::.' wirix excipierrrs, rim: !:m*e beer: prcw'm.v5I_3' azfsierf :0 cm app:'o1‘cd
`:'::je‘z:en£v!e ;2ro:;«‘a:cr, mr:_;‘ .:':m3 plaarvsrczrezsrfca,’ mxzrgiazxrierrr cfmz-!0p:'::c.r.‘I;1.? A‘i.'.':-E‘
`rears’ can‘. The" PI3_)rss'c:'mis’ Dari;
`fi°9j3:*re:2ce{P£)R)<1i.=(f ?iar:ribs:.u'; an .£’nj.=z:.'t-;'.'ba‘c? E~‘.r:szg:: 1t'<3r‘::‘:*€3'ie:1‘e(.f',
`e.=..°c£mcr;”rag rd’! i::j'c=m:<r.‘:'<Ji2 an c,:‘c:'pEem.s. ?"I:«:
`:':2_for:::zzifwz ;v;r:; cs;;sm'f(fa:‘crf {ma eight rssirfes. a‘fl!eg(.irizi1:g se.>:c:'_ru'c:1t: as I) Soireazsfis mm’ Cr)-.'so.’s"a=2z!.S', 2)
`SoIe:rBi!Ezz':sg. Wetting, S5:sp¢‘m.’i:eg, En:1iI.§{fl.'i)zg sr Tirickmzfsrg age.r:s.:':, 3} ilfieizzrirsg Agesm, 4} ./~i:2rfa.w:r’cizzm’;»' mm’
`Redracivzg Agems, 5) .~‘miin1:’c:'o:‘::"m’ Pr»;=ssn=ai:’:'e3_. 5) Bag§“ers and pH Aa’jse:rif.u'g Agems,
`I’) Bssikiazg Agcamv,
`P:“a:"ec!-rm!.s. mad ?"0m'c.-iiy A<{r‘z:.::o:'s_. mm’ 8) Sp¢s::3'a§ ziea‘a'.r':a“s>es. W:'.=er+.? ::p_;::’.ic:r:1=.F’c,
`Inf:-Hes hsz freqzrcncy Q,’ me,
`e;‘0:rcem‘rm'ior:, am’ an c.m:::p!c afar mm::m.='cir:.5' _:2roc!:rc.r ::a;:m:':aa“r:g L-'19 e.¥ca):z:'e::f. Exc£;2£e::i.c :s*i:s‘ca‘r<xa'ef1zc?1szfrd in
`the 19915 .-'*‘:’)A ‘;'.uzzcr:'v£ !:zgn":di2uea (.r’m'x;’e, ’ Em: sic rm: :T{Jp€'-car
`in she .r"}’)!«.‘ ar Hmarflraoiq 0:; Izijccmlaie Drugs‘, mu-:3
`:'pzcImz’ed as .5: segmj-me? fist. L
`
`
`introduction
`
`lzajectabie gsroduczs requira. :3 unique forxnufiaiion strzxieggy.
`Ths Eannuiaicsi product has in be steriie. gnymgezx Free and,
`in the :::::a:: mi Sitiiullimifi, {me of pamicuieaic matter. Prat zlzrabiy.
`me fmnulaiion wiii bx‘: iscrwnic. and dcpending am she mute
`cf acimiaiistriuiuza {or insmsace,
`fw’ intra-spinai er i::ir.:x-
`cirsienmi muies}. antinxiaéanis; and gmzservzatives may mt be
`zsiinweci. For :1 given drug, the rig}; 01" aeiversaz events is
`hfigher ii‘ it is adminisiered
`an irajeciicm versus 2; mn-
`parssmerai r£3uir:.Ti1e mquirexaxcnt fa): sterility demands that
`ihs :,'<a:ipienL<: be shit in withsmnsl azattzciaviaag or other
`sieriiizeaaimz garéisrc-35:363. These factors;
`iimk the chaise uf
`excipicntsa 2w;)§izai)1e so ma formula!-arse.
`Gsskiraiiy, z: E<m)wEeaige of which cxcipiente; 11:14.15: been
`damned min by the [TIA or 53:55 213 read)’ pmsem in :1 markezesci
`prm.ixee:1 g:r(wi(Ee:s incnmsaii zxssumraczrz m the farrnuia‘-.tm“ that
`these excigaierws win pmbahiy .3 safs fa): their new drug
`pmduct. Howcv:-.r, then: is: no gunmrmze. that the nsw drug
`pmduct wiii be. safe as zzxazigsissuzss are csnnhinrtci with mixer
`adsiitivcs. andfor with :1 slaw drug. creating Isnfcreessseaxx
`potentimion or synergistic toxic effects. Rs:g;u§aaior)' bmiies
`may View an excipiem previuusiy appmvmfi in em injeciabk.
`dosage form fsavorahiy, and M13 frequemiy requires less
`safciy data. A new 2:-:idi:Eve in :2 §"m'rnuEaieIi p£‘0(§!JC‘.‘. wili
`a!w:z}'s sequin: ssdciiiisaneé suzdics zzriding {C2 the cast and
`aismelizue mi’ pmdaxci <§e:w:§:)p:s1eIxt.
`cm the \'a1‘ima:".
`"111: purpezsez caf
`ihis paper is is
`excigzienis ihai hzwe been Enciuded in gin: formuiaaion cf
`injccialbie pmciucts marlxetesl in “If: USA. This infmmatieu
`is us): I‘ adiiy :.w:*.i§:1bie. A iilcraaiure Search indicates mat the
`3115: paper dcaiiiag with this \.\-‘LES puhiigsémi
`in 1988 I3).
`Pa‘-:hduc£.: approved o:si5§d~5‘. the US are new: c0*«'e3‘e<,5 in this
`
`i9§35..e’*n:c»:p1cd far publicaeinn :'\!:.y 16.. 199?.
`ivcd October 1,
`Re
`*;\uih'.':r EB who:n crsrrcspcnzjence sh-oz:-3:3 be afixircsscai: E0. BM. 5340. SE.
`Lmiifi. ML}. 63 E34
`
`re:view.A1s9.atcrE1e desage §‘(az'ms mt adminizmrred ;3aren:er-
`my,
`sur.-1:1 :25 solutiuns for inigzaziosa, czphthsslmic or mic
`drops, and csinunmzs were exciuaicd.
`
`Methudsicgy
`
`Physicians’ E335}; Reihrrmca published in 5994 & 15395 (2,
`33, and Einrldbosk on ingszctzabie. Drugs (4) were user} as she
`primary scarce sf information. Eniries an :-.1§
`in_§:‘.i:iah§e:
`xlrugs wen? stamm:-.riz.e(§ ix‘: an Excel xvnrksheet.
`3321951
`prcsduci was cirsssifiecl by Munu€;1cm{'es', Trade nama, Drug
`mamas, Route 03‘ Adminis1rsa1.icm, SVP1L\’E’, pH of Pmduzzz.
`Sohuant Uscni. SaiubiEizing,’Sus;sendi:1g Agent. Pmservzazive,
`Antitsxidzam, Cizeiator and Omar Fursxauiaiinam Additives.
`The rssealiing Excel sheet had informuiimx an more than
`700 preducis. This irsfcsritazziimx was mndenscd Emu e;1sy~3{)—
`mead tables. Each tzabie. hm: {seen categorized based on aim
`primary fun-ctitm mi‘ enmipiem in the fos'mu‘.IaIiLm. Fm‘
`ex:-.mpir:,. Ciiraies we ciassified as basfékzrs and mm as cimitw
`‘mg agents. and zzsczsrimies. am categofizcd as zzmiszxisinms,
`uiiémuggh may can serve as hu:"fes's. Thia classificafiicm sysicm
`was bzxtsed an mar expcyiencse in fmanulatirm aim-einpmcnt
`and (an we puéflishz-:L€ Em-.r:m2re. Such simpiiiiczsiiun avnirjs
`cisspiirsation (sf enirics and pmviiisas aha ‘alasiiers-':-:3 with
`ezssywtu-z1::1<J iablcs.
`Scams dupfiic-mien was uuuvoidabic. Tnbitss; VIE and ‘Jill
`s:-nntszin sums exeipients which rmy have misc been Eisttsd in
`me 5:33. six Iabics.
`‘Jsr'her:m'er
`the resébrrance 5g.1ecifica‘dy
`dcsignateti
`es specific Eur-M1011 to am Ersgrediem is was
`miistztez‘: in Tilbkii-I W5 and WEE. For -examples, ggiycine car: he
`used as :1 buffer or as a siabiiizing {prosccfing} aganfi.
`T§*.en::i'm‘(:, glycixm is listazi in Thbizs VI and Vii. Iwfieihyl
`parahen is 3 praservzsiive {Table V) hm aim has 3 spcciai
`function iEiA(§FiflIE1}‘€fEfl EDI“? f€)I'a!‘.u§:1tiox1{’l1’:b1&: V113}.
`The corzazenarminn (if axcfpienis is iisiaci
`gnmcemafics
`WcT;_.z1':i by ‘mltxssic (Wi'\I‘} cs-.“ vcxiumaz by vclumat §M'.-W). If ihrc.
`p:'~3LiL2s;I was iisimj :15 iyuphifizeti or powder. mesa percent"
`
`
`1555
`
`FDA Juumai of Pna rmaceuticafi S[‘,?en.'_‘.e .2. ’3“.~5;;g-,;3;_3g;~.;n;§,‘
`
`
`
`
`
`..................._.._.........H-—--.»—-————.r-
`
`
`
`Supplied £33! The British Library - "The wnzrriafs knowiedgef‘
`
`Astrazeneca Ex. 2088 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
`
`

`
`
`
`TABLE I
`Sc-Ivems and <f::2~soIvenEs
`
`Frequency
`
`Rangr:
`
`
`
`'
`
`2
`3
`2
`24
`9
`A
`
`?.{‘e’_’/}; Viv
`73.6% wiv
`6% wfv
`Q.6~3U§7o
`3.5--‘}‘=)% Wa"v'
`*
`
`Drpc--Tesiosrcrun-39 €U;:__iuhn) 20% Viv
`Depo~TesI<1sieronc‘3*‘ {Upj9Im) 73,695 w.-‘v
`V12:-rxsrafi (Brit-‘A21 Myers) 5% wiv
`}I"ragr;xf’~’“> (Faun; vs.) 88% Viv
`Muizitest CMI5” icrazmamghty 70% wiv
`Ba} In 0113 {Beaten Dickinson}
`
`Sccoh:grE*:ir;x3 scdiatm (\‘I¢'_5'eihvA;,i£-mix} 50%
`G. 1 :'>:3E3%
`:1
`\"cP::siLI5' Cflriatszl Pu-fliers) 65% w!\-'
`50--55%
`'3
`Ativanfi (\‘»’y¢!h~Ayers:}
`4‘
`2
`Z)s:pG~IVfc:sin:sI9 (U3':j0Iu1) 2.95% Wfv
`(B.3~3’3E=
`ii
`E13143-migig (S;|_\f'yl:._‘,t:)
`I‘.-7?:
`‘:75
`I
`Termafiycin S-nfuaicz-is {I?.m-rig.) 'l5.2%
`{3.2—‘.'i'S.2%
`25
`Laposyn I13 (Abbcxi) 10%
`5—ma
`2
`Soiganai In;'.<“'v‘ ificherinsg.)
`‘‘
`6
`fniraiipiigi I,Cl§n.I.(‘£‘-),2U".:7o
`5»2€3% wfv
`4
`*
`2
`‘icezisj
`‘v'ir§Ien IMEn_§.® (StuFP‘1ar:na1"
`‘
`
`......mmmmm—. ?m.._.mm............
`
`Erccipicm
`
`Ecnzayl Bcnzsmr:
`Colifiiliiccd (311
`EVEN DI!"-l18Ih§,v'§a!LTt‘.X£lY‘.-‘.'§(I(:
`Eihimsfi
`Glycerin ((3I3I'L‘~t‘-Y-’JT.‘I
`?e:Im3I Oi?
`Pa‘3Iy€:!h_§'lefts giycszl
`PEG
`PEIG 30-3
`PEG =$C)€3
`PEG 3355}
`pflgfif.‘-"~VSI3€i§
`F‘rog.1yIen: Giyc-(3!
`Si£ETiOSS'€r Q5!
`Sezxsme (xi:
`Suybcan OH
`
`Vagcaahic «mi!
`° No dzsm :n'r1J:\bI-:*.
`
`Ike secfiamiitestisxn vsiumc
`ages were derived bases? 0::
`commmiy zssessi. TE): babies Eisi flat: range of cmxccntratien
`Issac}, typical! 0: mast mmrmm cancenuatiota cmyktzyed, and
`cxampies Q!" pmducig committing the axcipicni, wecificaiiy
`Ehnse: which use extrcmeiy Iow m high cunceniraiinns.
`
`Discusssions
`
`Tub-Ia: I Has! swlwanisz and co-solvents used in parenterzai
`proiiucts. Water for injaeartizm is the. mast summon solvent but
`_ma;«' he cambined GI‘ suhsiitumd wish :1 cmsrsivrant
`I-:)
`impmve tin»:
`sa1u'=33I'x£y an :~.(a1I:a'a3i1y 0:" dings. {ms Eike
`safI]m>e¢:r anti suyinazm are ussea‘ in a.ox:'aI pm-s:1::a:aI zauiriliim
`pmducis when: they serve as I3. fat source and :15; C‘£1l’!'f€.‘.1'S far
`I‘::t«s;0I:.:bIc vitamins, Ethanol and pro;-yicne gfiycoi are used,
`eitiler nllnne 5):‘ in ccxazabinaiioti with ozfixer s<)E\.':=:r:t3;, in more
`ihzaza 5{P% (sf parcnicfai ::o~seIvs2s:t systems. It is sua-paising to
`3:: pmpylessse giymi used more amen man poiycihylcne
`
`glymls {H305} in spies: of its higher my‘omxici£_sr and
`Iiesmcaiyzizsg 2-2I‘.f"e:e;:1s(5, 6). PmbaI:\Iy,1Iae gresence :3: gamma
`{ion :33’ pemxides in PECEE; is :1 :ra;ijor}is11im:i:>n.
`’£‘abIa:
`IE inciudfis :2 bread catcg<saj.- 03° excipiams wheeze:
`funcii-Dn in fm-znuiatiam couiai b::«—-—{£)‘v'isms§iy imparting gr
`suspending agems like ca:bz3>;y anctixyfi czeiiuiosc, sadium
`tarbmy mczihyl eeiluiose, so:-him}, acacia, I’z.w1'c§<)23c, I1y(i1'(I—
`I-yzzed gaimin; {2} Solasbiiizing, wetting or emulsifying
`agaaxzs Eike Cremcyphzzxtt I-EL, mziizaxn deszm‘ VCIEIJIEIIE, Pzxlyszxr»
`bask: 20 or SC), PEG 453 casmr (IE1. PEG iii.) czusmr ma, sndium
`dodeuyi sulfate,
`lecithin -er
`3/£335: ph-osphcdipidg (3)
`~ Aiumimam rnonosiersraie which is added to fixes} oi! In form
`viscous DI gei-Hike saxsprsreaiing m:‘.dE:tm. Foiysoxbaic S0 is
`me mos: ctmmmn and versatile s;(3}u§.=iII’:r.ing. wetting and
`ssmuisifying agent.
`Qniy za Iimited number cf chelafing ug;::n'Is am 3:59;} in
`pamnterztfi pz'0d=.=,cis; {'Fas§.‘.E=: HI). Téxcy serve its complex heavy
`
`TABLE {I
`3oiL.=tviIIzEng_3, Wetting, Stuesgmerading. Ernuisifying Ur Téwickeaming Agganis
`
`Excipicni
`
`Ensign
`
`Exursapie
`F1'£:£;I.ml’:I:23’
`':"a:I5r:r::uI§n Did Ttifiifl (Le-jeric} 7%
`‘Fri:
`2
`Acacia
`Sralguzwal I‘:sj."‘° {Schcringfl 2%
`2%
`E
`Aiumirum snonosicaraie
`B iciilini {\VyetI1-Aycszet) 43.55%
`I
`4%
`Curb-:3:<y zneihyi mifulosa
`Lispmn Dcpmg (TAP) i'J.75‘.7I> wiv
`i"I1.E--[}.?'S‘I{:-
`9
`Carhczxy iuetiayl cdiuiuse, sodium
`S1: m§in\.n':u =33?‘ Eszmdux) 65% wfv
`3(}—-55% W.-"v
`3
`Cmnophnra ED‘
`§"':mgE;::me‘9 (Briana? Myers“; 0.43 E93 wlv
`8.:-I£7i» wiv
`1
`Dcsoxycholaxa sodium
`inimlipiif-3’ (C§iraIer:} 5.3%
`1.2%
`3
`Egg yoik. g:Emsp':‘:o!ip§d
`€:~.n',=.1m-.3“ (kicrck) 15% wiv
`16%: wfv
`I
`Geimin, Hydmlzymi
`Dipriwzufl’ {§:'.enecn)
`w u
`Q.»’I~—I.2‘?é wiv
`7'
`Lecithin
`AquaMepE1yit3239 (Merck) T-“F2: w,-'2'
`755- wfv
`I
`Pe3y0x}'eihyla1ed fatty acid
`Cazdarfinc X E.‘.'.“-"‘. ('W},'E:'.i'I~f\j'8rS.i) 10%
`ICFDE-i2’3’:>
`3E
`E‘033'sz':ria-fie 813 ('1‘w::cn 80)
`C”aI::ije;;® (Aishou) 0.4% wlv
`£101»-€I.4‘.?v.’n.
`5
`Pviysurbate 20 (’I‘v.<~.t=:\ Z9}
`A‘-'§unismt5" (.I':zr:s5cn} 11.5% viv
`I 5.5% WW
`1
`PEG‘ 4!} caster mil”
`
`Prxrgrafi (Fujisasslzfi 213% wiv
`20% vlv
`I
`PIE} 5% C3510!’ r.1§I*’3‘*
`Bficillisfl‘ (Wyeth--Ayerst) 6.6% 's'~u’v
`0.5-0.-5% wlv
`_(s
`§'m'iLIm:e (E’oIyvin3'3 giyrmiidone)
`Prnteukinri {Cains} fI.£>.I8€7o wfv
`EM}! 8% 't.I',I'v
`I
`Sodium dmfccyi suIE':1II: {N41 Iauryfi suifaicy
`
`
`fiurbimi
`II
`‘E5-60%
`Ariatrospgnx {Fujism-:1) 58% Viv
`* Crcmophor EL: Etrxtas 35. §:rsiyc:Imx3,-lgucd mswr oi}, prJI§'9.‘{}‘eII‘iyicnc 35 casmmil.
`2 *‘ PEG 43 caster oii; po13'Ux§'l 49 task»: -xii. easier oi! FQE-40. Crodmra =38, puiynz
`-*:t§xyI::n-2; 4:) -.2-4.<'.-.wr a.>‘:I. Frcmchem CA»~I E}.
`*** PEG 6'1) J':3'1J.mg_:cz1arc:i caster nil; Crcmoph-'3: RH 61}. h§'drogen:1Ied gaszaz rsii PEEK-60. P1'o.(::r:?-.2211 CAH-6:3»
`
`.
`
`Vol. 51, No. 4 : .5u:y~Augus1 199?
`
`Supplied by The British Limary - "The worId's Imowiedge"
`
`II!II.
`I.I
`I.I
`I
`
`
`
`Astrazeneca Ex. 2088 p. 2
`
`

`
`
`
`TABLE EE3
`Gheiafing Agents
`
`
`
`----“F:;ci-gnieni "
`Cnficiurmiisosiiuzal
`EDTA3‘
`Dis-:)diL:m EB”.-"A
`
`Frmaacrzrsy
`9
`
`Rzxngss
`(}.03~—{§.i% Wydascg {Wyc.i11~
`Aycrstj (‘:23 ‘Yo wiv
`0.91-i}.§% {faicijaxw {Await}
`LI} We wiv
`F0}!-'i!Cg‘ (leiiericj
`0.2%
`E-'!agrsevi51‘° {Serf-isx}
`i‘.*.«J—§‘z?-3
`E
`1T>'i’§’A*"‘
`U,€3-1%
`"' EDTA
`iii‘:-.Eenediarrxincaerraaceiic acid,
`*9 F3TE’A == DisrihyIen::triamincp<:ntaan.xic .1cid'.}’crxiciic mini.
`
`m?~:icity (7, S). Baziyiated §';}’£§3‘(!Pé}’ aiaisuie, §su£y§at::d Emimxy
`{cinema and gmspyi gzziiatrs are primaziiy
`fin Semi/non»
`aqeemxs vehicics becrzmse of their Bow aqueous soluhiiiiy.
`Ascorbic acidisodiusn asccrbatc may same as an amiexin
`dank, buffer, and chniating agent in the .S.'.l{2'E*E formuimian.
`Benzyi aiccshoi was me mos: cummcm zmiimicruisiai
`preservzative present in parenierai 1‘c-rmnlaiitms (Tabie V).
`'I'h§s is cmasigient wiih ether suswys (9). Parabens are: the
`maxi mass mmmon pre:«:erva1iva=.:';.Thi.ri.y-rains: products»: had a
`szombinsziizm afmeahyl and pmpyi pamhens; eleven had on} 3.’
`methyi, and one haxi smiy pmpyi psraben. Thimemsai was
`suzpr§.3inggEg.' common, especinliy in vaccirtczs, Ewen Hhuugh
`some individuzais have sensitivity to mitrcurics. Chierocrcscsi
`is purported to be :1 gear} gmaservaiivr: for pzmznzerztis. but
`our survey ci-Ed mt
`find any emnxples of cemmercinl
`gmxtiascas (:cmtain§r:g chi-.aroc1'eso1.
`Table Vi lists buffers am: chfimicnls used so adjust ihc pH
`sf iormuiaiions. Phospllssie. ci:z'ate:, and acetate use the maxi
`common buffi:~.rs used in parenteral products, Mono and
`diesthanzxiarszinee are added as adjust pH and form correspond-—
`ing saiis. Hydm-gen bi'(m’fi£i:2, suifuric: amid. banzcsnc sulfmic
`aczéxi and mathanc sulfa-21$: acids are added :9 drugs whicsh
`are bmmide ificzagmiszmixue H335‘, Hycscinaa HB1", UDL),
`s:ui§'sie {NebCin, Tabramycin sulfate. Lilly),
`§3esy.L“-is
`
`Smiium EEYI‘.-"1
`
`1
`
`finZ€19‘a
`
`niemis and iixerefasu can imgxeves the: afficacy sf antioxi-
`dants or press-:=.z*v:21iveas. In our opinion, calciurr: EDTA has gm
`advanaagget «over tetrasodium 5:12‘: by not C-Driirihuiing smiium
`and not ciasiaiizwg cahzium z"mm that blend.
`Ar: axxiiuxisiarrz as a ciax;-e is defined as mass: mmpounds
`zhai can act as mducing agents or may serve as fie-3 rzuiicai
`ssczwengurs. Tabie EV summarizes Khe antioxidams. aheir
`frequency of R356, concesairsziien range and axazmgzles 5):"
`products «tonznininag témm. Suifiia. bisulfisc, and m:2€abisu}~
`fits: wnstiiui;-e the mzzjmiiy -nf antiaxidanfs used in paremcra}
`proaiucfis despite several reports of i:1compaiiE1i’!iHc.s4 and
`
`TAESLE W
`
`Anfinxiciants and Reducing Agenzs
`
`§*‘r1=-:§uem;y
`4
`7
`38
`3
`3
`2
`E
`
`Excmimt
`A-.‘cmn:: wniium bisuliiic
`A3$0r{1aifi(SudiuriIv'sJCiii)
`Bisuifite sodium
`?3\:SyIa[ed hydmxy as1isuIe(I§§-EA)
`Butylzlle-15 hydraaxy iaizaenee (EH '1')
`Cysi-2in:‘('1ysi::is:::rc HCE
`Ifmhioxxils sodiuasi (Na Elydruzulffls, Na Sui?»
`ox)-late)
`3
`Geniisic acid
`3
`fiemisic acid eihanaiamine
`2
`Cihxtamate nxtrrmsmiiiam
`9
`Formaideizycie 5l£]f()3;_3'§fi§iE! ssdium
`E
`Meiaxhisuifiec potassium
`2’,
`Meiabisulfaze soziium
`6
`Mlnnoihiagiyccml {Ihi-.3gEg.'cero!}
`2
`Pmpgii gallant
`Suifita sodium
`1'
`
`ThEn_,<_:E_vco}ate: stadium
`E
`
`Range
`G.2~»C-'.4‘fb wfv
`(3.1-4.1%‘/7: wiv
`|1=3E'.v-0.65’3E wfv
`E}.0f§f§;‘:8»»0((}3‘}.'a w.I'v
`3.00! lfi-53.63% wlv
`CID?--{3.!E}’3E,~ wh-
`G1}fl"/79
`
`€}.C}£'.% wlv
`2%
`0.1% wiv
`€1.€}’?5~(3.5% wfv
`G.§'3‘3-:':
`0.32"} $7.: wiv
`CL!-E 9?:
`0.82%
`0.05~—Lh2‘7a wfv
`{§.fi6% wiv
`
`Exazxxpie
`
`Navscainefifi {Emmi-wiruE:a'cp) €}.=§% wlv
`'s:'ibr;un)'cinfi' (fioerigk 4.3% wiv
`Amikin” flflrisml .Mym'5) 0.66% wfv
`A«.w::s:3P'°(.t‘v.:s:.1)L'=.€}3%
`Aria.-225039 (Asirsa) (3,839?
`Aczhar Gcli’? (E-1imne~Pm\!m1L‘.} §).E% win:
`Nm'r:orpho.ni' ([iuP:;<r-.1} '13. E093;
`
`Ocircoficanfl fikiaiiimficrodi)
`M.‘J.§. 127“ {Axum} 2%
`Vnrivasfi’ {Means}-:3 -I13 ‘/5 wI'v
`Tsn‘::mycin Sxsfum‘.-n Ekrmig) (15% wiv
`Vasnxyiib (Giaxrs-Wrrilcnmc) 0.10%
`faamagt-in"3‘ (DuPant} 1 E wiv
`Temsrnycin Scluiion (Rccrig) We
`Navaaag (Biaerig)
`Enionfi‘ {0E1m&da‘) (3.2% My
`S::s~F‘E1Iin::® (Forest) 0,66‘;:‘: xvlv
`
`TAR? LE V
`Antimicmbiai P.ra3sesvaiiu'es
`
`
`Rang:
`Fxcqnsency
`lixcipieni
`i).-'J2'% wiv
`E
`Benialkonium chlorida
`Ceiesione Snluxgzaafi’ fifichcriaig} 8.02% wiv
`K'3.=3"i%
`Ii
`Baxxzciiloniussa cixlorigflrz
`§}:*.z1a1dry}9 {}’qr1:r:~D;svi5] 0.01% wiv
`(},'?5—S%
`‘M
`B=:r1z_yl aim}:-01
`Dimcnhyxirinaicip {Starla} 5%
`0.25-(15%
`I7
`('.'.":lm'a7}:uKa::ui
`(iodine p‘a‘msp3r:r.i<: {wyrcsh-Ay<°.is1) 0.5%
`E}. 3-0.3%
`3
`m»-Cress!
`H13mau‘o_pe3 {I..i!!y) 6.30%
`(}.GE 950. E 59% will
`2
`Myristy! _-:;:mrunu—pic0!inimn cizioridc
`Dr:'pu~§’a‘o&'cx:1‘9 {Upjs.1hn) fh. Efs‘§3‘.7o wlv
`9.3543. 189:
`50
`Eflxrufincsa zxxcihyl
`I:=.:.a§3nm:°19 fijzmsssn) 0.!$% wfv
`€3.53--(3.3%
`-‘Efi
`Pmzben pmpyi
`Xyiocaina: v.=.-ffipitxepiwrizae (.3s;::r:1} 0. 5 ‘/5 wiv
`(3.2--GL5‘-'70
`4-S
`Péirzncyl
`l".':1ici:1‘.ar3 {Rhone Pcaulzxnc) 0.5% wiv
`€15-fl%
`3
`Z-P}s:n0.xy:*:!hanoi
`H:wr'Z,\s“' {Smislzminc §}cer!1s3m}D.5€.=*'/E; xvlv
`8.E)Gi%
`3
`Phcnyl nzercuaic nitmie
`AmivenEr3‘° :f‘eVycth-Aycrst} E309} 9?;
`
`Thimcrr32s:\J i).{)03—(3.GI ‘/2: 4%
` Aa_s_sam'39 (U;-john} 0.01%
`
`
`Efwsmpic
`
`
`
`FDA Jeurnai aé Fharmaseazeiaai Science & Te::h.rm:'agy
`
`S-uppiied by The British LEE:-rary — ‘The worfsfs kmzwiedge“
`
`
`
`
`
`Astrazeneca Ex. 2088 p. 3
`
`

`
`
`
`TABLES Vii
`
`Buiking Agents, Pmfiecianis, and Toniciiy Adjusiois
`
`Excipimi
`Aianine
`Albumin
`Aibumin humzm
`Arnim“: acids
`L-A gimme
`Aspurngina
`E.-Aspzmic acid
`Caicium. Eisluride
`CiirE:3 amid
`§3€J€i[l‘(R‘3:“:
`f§c3a:'m Eaydrc-Syzesfl
`Giucoses
`i'iiycw‘in
`f3i_'y'»:§s1e
`Hifiiiiiilfie
`
`Exnnapin
`’1'hmmE3ate EH9 (fiayeerj
`Biutiatrfi (Arm)
`Batnxfi {.!\!icrg::n}
`I-Eavz‘§:e4*(Ss31iE§1F{Iisav: Bccchmn)
`Ac1iv:ase9 (Ganemech)
`Tm:-2 BCGE {Oganon}
`Pepcidg‘ {E\*E¢2zc5:}
`Pizczucrgssn Enjcminnfl” {W’ycah~Ayers1)
`Serssorcaine-.\,{PF3“ (Astra)
`Betasemrfi (Bcflex)
`Ac::~:a:~'F9 (E{}mPe—E’:2uI:3nc Rerer)
`Ivs:r:gam'3 (Emmunu--US)
`Tics ECG3 fiflganan}
`{sigma inj¢cz§0:1‘9 (Upjohn)
`Antiisexmphilic Rctar, human
`(Am. Red Cmss)
`He!ixaic?“{Ann-315:)
`Oc1r(:aStan"5’ Emaliinckrndxj
`Caverjactfi EUpj0}m)
`Te namyciaa Snlutitrrf” (Imerig)
`‘ice ECG” iflgxxncnj
`Eisgmrfi (Merck)
`Bioclmfl {.-ikrcu)
`Ht".]ix:v.tc‘1¢ (Armour)
`V;s:ivax“” {M<3rcis'.)
`.:5.§kcran’5“ (G! axu-W:*.ilcome)
`W'E:1RZ'1-1.‘: SE33‘ {UnZ\'u:<)
`Actinimuncfi Cficnanicch}
`Dc;su~Psm's::'a'3‘ -(fipjtzhn)
`“'a;mhx‘.::~.:*.ii:-3’ (Abbott)
`Pmiastinfi (Bays;=r}
`
`§mi<.iazuk:
`Inosim!
`Lmzmse
`Msgnegium chionide
`Ma_g:,21esium suifzzic
`Man :1 ital
`Poiyeihylene giycoi 335$}
`F-siyscxbate
`Potassium: cizlorlds
`Povidnnc
`S-uiiium chfinrida
`Stadium succinme
`Sodium suifaic
`Smbitc}
`Sucmse
`
`Sgzseciai Aziciftives
`
`Thcse additives have been included in phamiaz-.1-::ut':c:3§
`forrmzlaiism m mrvs: spccific functicms {Table VH1). I.’-slow
`is a auzxznamy of tizct sgcciafi
`'e.ddiEives akmg sxriih their
`inteniied L:se--
`
`(E) Calcium giuconatc injrsction -(American Regan!) is as
`smurateci saiutiorz (bf 10% wfv; czxlcium =.i~succEmra:¢
`tets::h3‘dra1Ee 9.45% wiv is misled £0 prevezai cry:s1;1E€i—
`zaiicm during iemperamm fiuctuaaticms.
`(2) Cipm {W9 {CE;a;-aficomcira. Bayer) mntzsins lactic
`acid as in scxluhiiizsixxgg 34,2131 furlha zamibiotic.
`2:3) Prem::ri:1Injec::i .31“ (flonjazgaieai F..»;trogexss:, W_=,Iezh—
`.-5.y'er:~.§ Labs) is a 3y0p§3§§izr:d pxmilsci that contains;
`simeiixicozm in prevent Ebrmatiota of foam during
`rcccenstizuiican.
`~
`
`3311", _F<:re_s:,
`(4) Dexamaihnsozac uceéate {IZ%aEs1E:.me
`Dcczdmaz-LA, Merck, {)zsi;1imxeE1‘=PEnjess:fics:a, UAD
`Labs) and Dexamexhasane Na phosphaie (Mz.=.m;;)
`are awzqiisabiaa
`susysensitm or seamion. These (iam-
`meihascme fsznnulnrivns cemain crcaiirac er cremi
`nine
`an adriitive.
`
`(I)s)x(3:ruhi::in hydmchiorid-.2,
`EQEJEW3’
`(5) .<‘scEa‘i=.a:I:32ci:a
`Phnrmncia) conmins mcthyi paraben, 0.2 mgImL, Ea
`incmase disstalutiota (£0).
`(£3) Ergfiiratfi zzxaimic (Ergonovins anaksazrz, Liiiyj con-
`iainrs i}. 1% why} Ezaclatee 5325 ex 5-nltihiiizing agent.
`(1?) Esztrsarjurin Injection” (Pclyesmdisl phcesphate,
`W_§vv3£h—AyersE Labg)
`Nfiixcinnmide (32.5 mgfmi)
`
`TMSLE W
`Buffers anti pH Adjusiing Agents
`Excipiczii
`Kxcciaic
`Sodium
`Acetic acid
`(312932! acetic acid
`!%.mn*.<mium
`Ammonium Ezyairuxizie
`
`Exaznple
`
`Miacaicin §n_iec:ir3n@ (Szmdtr-2'.)
`Miacaicin Enjeciiaafi {Sam}-.3z_3
`fsrevitfmc I33j&»:'§io:17" iflhmecizz)
`Bumex injeaaicng‘ (Roche;
`Triosmt In}:-:::{§mf5‘ {fimiléziéiisxrz
`Bccciutan)
`Tracx-Eum injeciicz-(35 (G!axo~WcE!come}
`Valium Enjeczicn-“'9 (E-§0ch2}
`Ccfomn Enjeciirirsw gzcnemi
`Hy§mRE10~D‘~'” (Bayer)
`
`D'H‘E(.‘,—[3-orwsfl {Bayer}
`Ceredascx’ (Genzyme)
`Cerezysmzfi (f.3'enzy:a1a)-
`Ccrez)-1:15“ (ficnzymci
`Bncixins EV” (Racks)
`Qa3ini:2ir:zE°’* (Liiiyj
`Heg:—B Gum m:;§_:ees'39 (Merck)
`Ami-gar?’ ilmmlmex}
`Scopoimmnc: (UDL}
`Fentenyi mimic 8; ijropeaidoi (Astra)
`Eminaac Iaajccaion?’ {Roberts}
`Libriuan lxsjetsiondi (Rocha)
`DEE-if-5 Erxjatiictx-.5" (fiandmc)
`Term myci:1’30§:It§uri q‘_Ruar§g}
`
`Benzene suffimic acid
`E&‘.nzome Sodiuammic!
`Bicarbonate S-udismx
`5:£!TbUI}‘.lii’! Scxiinsm
`Citrate
`A»-si-;i
`Sodium
`Disodium
`Tri sodium
`Diraiinasaulaanizxr:
`G uccno dc-13:2 Eascicams
`Gfyszimz
`Ewiyxlzociaéaric acid
`Hyiirogen Esmnxida
`Lactate acici-'Ss3s.iium
`Lysine:
`Maieicr acid
`Zbieiisarscszzifezaic aa:Ea;i
`Mmxoeihanmamina
`Phosphate:
`Acid {;3§sr:§pIs<;s‘ic}
`Mcnahasic patasmxm
`Monubasic ss3dium*
`Dibusic sodium“
`Tribasic sr-fiium
`S-.3s.EEa.am hyzlr-nxiclc
`Eiulfmic acid
`Tzmraic rxcidfsnrifuxam
`’E‘r:3n:el}:.um§ne
`
`Hu:megcn’5‘ (wgamml
`'Z:\fiEnc Injcczionfi {(3¥ax0—‘p‘e'cE3::om¢}
`Pre;_:nyii° (Orgarmaa)
`F'ru!:1siin'”' (fiayex)
`S3.-:1Ehrui£i9 {Knoll}!
`Opiirayfi {MaiEinc}:rfid1}
`Nebcinfi Eijiiyji
`I»3e:sher§;Ea1e:Injc:r:rE=.2n“5“' {E‘;:‘.nd<;z)
`Q;?!ir:1}-"~‘?7t'i\.’i:x3Einc3<m<€E‘9
`* SD-flit.‘-m biphaspimic, Sodium dihydrcgen ;1I':(;.<pE1:sI¢ £31’ Nu dihydmgen
`onhophnsphmr.
`'
`** Ssxiium phosphaic. ilismiissm hydaogen phossahaic.
`
`Cfracrium Haj, sits‘.-’:curimn besyizms} or me5.'};*i;1te (Y3H~EE-Z 45
`Ixajersfaosa, D1hy:l:‘ocrgot::minc, mcsylazefi sums. (}!u::0m) deilzx
`incmnc is used to adjust ah: pH of Qaziuidine gluctairflifi
`{i'..iEiy_). Bexzzrasste buffer, 232, a conr:eenam1i:)n af 5%‘ is assazsi ‘an
`Vziliusn Enjctczizm. Cieratcs are common buffers {hat can have
`2.! dual rel as chefiaiirsg agcnis. Lysine and giycine are amino
`sci-:15 which famitfiirtm as bliffezfis am} staiaiiize preicin and
`pepzific fersmtiatiom. ‘Fhcsc atazino acids are aim used as
`iyu-asldiaives and snag gnrcvcm mic} (EtSm2.i:11‘ZzEiCx-£3. Lactate‘
`and zamratcs are caccasionaliy Usti as bui‘fer systems.
`Tame ‘HE Eirsts aciciitiwr; which are used is nmriify
`osnmiaiity, and as buiking or i;,rr..e«-L~ryr3 ps'ob':.ciivs. agents.
`Dextrose and sodium cixluridc are used is ;1dju:;i inniciiy in
`ma majority of fmnuizuions. Same aaméém acids,'giycine,
`zalzmine, hiszidinc, irtzidazeie, azginine, asparagine, aspanic
`acid, are 12345:} as buiizirsg agszms for Iyephiiizaiimx and 31133’
`serve as stabilizers for proteins or gteptizics and {ES buffers.
`Tvianusacchatides: {s5¢:xi1me, giucese, iacmse), ziiszsccharide
`(su::mse), psi}-hydric aimhuis (innsitai, marmizol, sorbitoix
`giyml {PEG 3358), P<wi<t0ns: (5;:(33}'Vinyip}'rrQ§idonc), and
`- pmieins Qaaibtamiaa,
`_s_3::ie:f.in) gm: cummtmiy used as Syn»
`additives.
`
`V:-i. 51, Ne. :3 1‘ JuE‘;~Augu:3E 199?
`
`
`W ..
`
`Astrazeneca Ex. 2088 p. 4
`
`

`
`TJEBLIE WEE
`8_:1s3ciaiAdt§i=.Zves
`
`Exaznmic
`Human Albumin {Amcrieasa Red
`Cross)
`Rccaszabinant H539 {Merck}
`Tetzzssiss Tmsziai rkaisurbcdfi
`(L£d{:s]c)
`TD /‘xdsorhezi Aduixg“
`(Ci3flflEJi.lS_h1)
`Em‘m:ase‘5’ :‘.R{:=§3e.:1s)
`Caictium Glutamate {AH1}E31'§L’£':I:":
`.
`Regcrxz)
`Human Mémmisi {Amc'ric:-.3‘: Red
`Cross)
`Diancnhydrinnte (Sieris)
`Damione D?” {Fares-)
`
`H_v<§3'ucorlcnc PE:
`(Merck)
`Cmlnay (I‘»’§.'A§3§:1cE~;rodl}
`Cnrdimer: {Sq11E'L1b}
`Engmma maicaicfi‘ {Lilly}
`Aaxuinsgsiiyllirmfi {Abhmfi
`Iinbikinascfi“ (PImrmac§a}
`Tics RSS3‘ (Ogarzrsn)
`Cipro EX”) {Bayer}
`Ealaeiexfi’ (fiieamca)
`
`Altznzinum potassium sulfatrs
`
`Ewsipiena
`
`Acct}-i irypmphzi FEZIIEE
`
`Aiuwinum h3'dr::r.1ide
`Aiuminum phosphate
`
`E-Amirmcapr-mic :3-;:i-d
`Caicium <§~sz2:char:s:¢
`
`Czxprylatc smii-.:m
`
`8—Ch1urmhe:a;3hylEine
`Crcsaasi ne
`Creari nisaa
`
`Dinzrizoic acid
`Gamma Cyciadexia-in
`Ethyl !::ci:1Ee
`Ethylenediamine
`1..-Giummate sr.::..'fium
`Irma ammcmium citrate
`La-xsic acid
`D.!_rLac:ic and Giycaiir: acid
`mpo!_5':nr:r
`Mxahosrs
`hieglumine
`Niaaarinsamide
`H’a1'ahcn :'r1r:my]
`E’:-umrnine
`
`Simcihicct-as:
`
`E*:'s';sIi:L1m szaccharin
`
`TIE-n-bI,:s.yl phosphaic
`
`
`
`‘
`
`Gamimunafi’ {K33}-ci]
`Mngnevistfi (BerIr:.=:}
`§sEr;sL§13r§n“9 {Swath-Ayersi)
`.»"uirEamyc‘m RDF1° (Pha1'rr1z1c§a) .
`Iafiuiasmrci NFH3‘ (Nova
`Norciiéici
`?r::sn:u'En Hnjcciic».-'s’3 €Wye£h-
`Ayersi)
`Cnmpszinc injeciiozlfi (Srni:§1~
`Kiim: Bnccham)
`‘\.'ezmgi:r‘csu]in'='-‘ {Apha Them-
`ptrutiw.)
`Binclasicfi‘ (Arcs)
`Lem: Ensuiinfi {Nova Nardisk)
`
`
`..~--n-..u..\~.‘....,,._
`
`TABLE Hi
`
`
`List of Excipisnt =‘rcsm 1995 FDA ‘inactive irsgmdient Guide‘
`Ammenivm suifate
`Bttnzyi chloride
`Buzyl pamben
`Crdtiiarnide smiium
`ifaltcridmi calcium
`Caste: oi]
`Cellulose imicrucrystasliinc)
`Clzoiesmoi
`E330-xye:ha’§Ec acid
`Dimrizck acid
`
`Psszsatimc (DTPA) caicium
`tiésediurrs
`§’o1c>:<:una:r E65
`PEG 4090
`PEG 2%.’!
`Fciygiacsin
`Poiyiactidr:
`Pofyaxycihicnc fatay acid
`asaera
`}’oij;c3;cymhyiene. ssrbitan
`mozmsteraze
`F‘oIy‘ox'yl 35 Czesturoii
`§’o1ysm'E>:-.39 40
`}‘-‘oIys;ur§3s.a«:=. E5
`Pr:-zaszsium Bay-riroxizias
`Fomssiasm phosphzlm, dlibasic
`Sudiuzsa bisuifzuc
`Stadium chksraie
`S-miiu m hypuchioxiaic
`Smiium iodide
`Sodium pyrnphusgxmig
`Sszdi-um £§:io:3=.xIfa:e, zmhydrous
`Soziiurn :;‘En1r:rapE2mph.'m:
`Sorbimn mtmszpasimiiaitt
`Srzmnous chionlizw.
`Stzmnmus flaaoridv:
`Smn:1m2s‘:a:1r::Ir;=
`Starch
`Sxsccisaati
`Succinic acid
`Suifmmxs acid
`Temslzis (E-i.mcyann-'Z~:m1-
`ihoxy-2.mer.h_y£~pr0p:1nic)
`copper (E) T:
`Thiazsuximic acid
`Triihizznxinxic acid
`Uscu
`Zinc acetate
`Zinc ciwiosidc
`Zinc oxide
`Zethyl he): ursrgic ::¢:i:J'
`PEG vegeiabie 0::
`
`Diuyclohexyl caritmdiimida _
`Diethyl szminc
`I3is:1;n'isE0§'E Eeciihin
`Dim}.'rir;1:3yi p?1osphafiidyԤ-
`giyceroi
`Dis0f<:nE::
`Dis-tussle sodium
`Edamine
`Exumetaziana
`Ciucepme stadium
`Gluceptaae cutcium
`GI’-.:cumn'u: acid
`Gxmrsiaiinc HG}
`Iofausmine HCE
`Lncicsbimaic acid
`Lvzciahin hfiircgenated soy
`I..iL§ufs:z'iE.=1
`Mcdmfcnirz
`Priedremata aéisodiaam
`M:.*.dr0!x§£: acid
`Meihyi hcmnic acid
`Mteiiiyl cclititrxsc
`Mmhyicnc bluc
`N~§ca:bazmuyE»-zzassshoxy poly»
`e:i1yicnc~g1_'y-mi I-’.GO0)—1,2.~
`disiearc-gyi
`N-Zuizyciroxyclhyi pipeamzinza
`N52‘ mhatne sI.=,EphonEr.'. acid
`Nioaime
`Nilric acid
`Ox}:-quinoiine
`
`as as suiubilizing zxgem. H;~;<§s3i:ra:sa§‘3 {Merck} aim
`mmains nizzcinamicic.
`
`form of aiuminum hydroxide,
`Aiuminxsm in ihae
`aiumimsm ghraspimte or aiumimzm potassium suifase
`is Lssassci as acijtevzam in various vamcim-: fnnmxiaiiians
`to cficit an incmasscssi immusislgenic response.
`EcEassicx® ((}os:ere§in zuceia
`Zcnaca} is :1dminis~
`zercd suiacuaanmusiy mirsrospheres. These spheres
`are nrizide cn1’D,E_.-=Izza:i.i: zmd giycstnlic acid copolymer.
`Lumen Depot izsjectianfli (TAP) are iym:-hilimd mi~
`crosphirres af gciatin mac! gEyc0lic~i:1c£ic acid is:
`immnlusculm‘ irajectizzn.
`Galmms. cyc.(,=eie:<srin is used as :1 stabilizer in
`Czmiimecfi at a cancemration of 50 mgfmL.
`Sodium -:::_\pr3.'l::E<.: {sadium ocwaze} has sxntifungzai
`pmpcnics, but it is 315,0 used 1:: imprawe she siaa§3iIEL;.'
`of aibumin ssiuii-on a1g::inst<:E'fes;1s
`maxi, Albumin
`satutima can En: heat g1;:.~si::uri:r:sa&i by heating :1‘-I 69°C?
`for ii} Hams:-s in Le presence «pf sodium capayiate.
`Ac-eayi E;”3'§3!.C:}’3h:1n£xE5 so-;iium is also added so aims-
`min f<3rm‘.}§:3t.i:3ns.
`Meggluminc (N«m:iEa_y1g}ucaxn§ne§ is u5;e:i as an ex-
`
`{E4}
`
`{E3}
`
`in-Sim salt. F03‘ exzzrnpiah, dia-
`cigiient mini 30 fem’:
`trimic acid, am X-my contrasi ngem, is mcarc stash}:
`when auzmiaved as megiuminc seal: than as soziium
`sait (H). Z'Vi«:gitsrnin: is aim zisidsd in M21g_:n{:vi's1°°, a
`rmgnse1icz'eson;1nce ::s3ntm.s*; zaggent, furmulaiion.
`Sumdsingiy, susfixsm saccharine is used in S£ei::1ine@
`and (fonipazinfl fornmiaticms; mar guess is than it
`serves; as a siaabiiizer and tcnEciIg.'adjas.~;1er.
`’E'riA-1':-Ezutyl phnsphsaic is present as
`cmipiesxi in
`Ezuman immune gksbuiin sniutian (‘u’camgEahuEis1®}.
`I15 exact filriiiiitiil in the fornmimimx is not lazrmwn,
`but it may serve as a scavenging agem.
`wan \“«'i'iEr:br;su1d factor is usezi so smbiiizc recombi-
`sum: zmiiixmzcphiiéa: factor {Bior;§sx1e@j1.
`Eflaliosc servaes as a: :<mE:ia.; adjuster anti s§z£biii;=.v::' in
`immune ginbulin f<ar1:1u.l£aiE0n {Gumimune N3’).
`Epsilnn amim) Capra-it acid {flaming lmmnoic acid)
`is used as a stzabiiizrsr in zmimregxizzse{E:niams::i:1§:e»;:-
`tiz)n'5*“}.
`Zinc and pm=.::misa:': 5:.-we been uddad its iazsuiin in
`f::n‘n corrmiexrczi and central aha dm-atiarm ofnciinn.
`
`
`
`PDA Jcurna! :2!‘ Pharnmceuiicai Science & Tschnoiogy
`
`é
`
`(9‘=
`
`E2}
`
`‘WC!
`
`Supplied by The British Library ~ "The worEd‘s kno::wiedge"
`
`
`
`Astrazeneca Ex. 2088 p. 5
`
`

`
`Recently, FDA. has gsaxbiisfmi ‘lnacstive Ingmciient Guide’
`'
`'
`which H335 325 this excipiems in aiphzlbaticni arder Each
`irsggresdieni
`is foflmvszd by the route of aiimizxisitafiion (for
`csmmpis. iv, era!) mad, in £0m«:: ceases, this range afc0nccr3tr;:—
`.
`,
`_
`mm ijsggj in mg gym};-;;\,:g;§ fimg pmdgm, ¥'}Q“,'e\:g:gf’ this 555;
`goes rm: Pmwda me Emma of Cnminammi ?md“:§(3) 59759‘
`Sporzdirzg ii? each axcipient. T.-’:E3}t‘. IX E3 3.1 Sl!rEi3‘I1¢’XE’}’ Sf 23“ the
`excipients which are: incfuded in the ‘Iamcfiiw: ingrcdiani
`C 3 ob W;
`_I A
`._ Fnré
`H ‘db R
`i am 1?”
`SHE 6.,
`U;
`0flUi'Zi§.}‘.>.,£1a‘ 1:3
`.
`. .01‘
`an
`no on n_;..g,{aL...
`Drugs.
`
`-
`
`References
`
`'
`
`'
`
`‘
`
`.
`
`i. Y. J. Wang and R. R. Hfiovmi. “Pm-Iew of cxcipicnas and nH°s my
`pur(.'nEc:r:1Ipr<:duv::s used in the United S:a:e.<.“‘ J. PtIr;'n.'r-': S»;-5.
`'!'ccf:~
`imii. 34(5),/ifil {i981}.-3.
`2. E‘hysicians’D.:sk RC9:-‘1‘t.‘-ii‘-“-31‘-,5-Y‘ 43. 3994‘
`_
`3. Pixysicians‘ Des}; ReIm:rzc¢.::d.SG, £995.
`4. L. A. Trisscl, “E{az:dEmoL am Enjccrabiz‘: B31233," ed. 3, Amctiren
`Scaciety 11:" Ha:-sp:‘:aI Pinnrrnacisrs, inc, 1994.
`
`.. K.w, Reecaénéé S.Y:§!1:bxv.-s}.j,j_‘:I.‘ysi§afhumxmrr:dbh\s«,E»:¢i1sin the
`(1.35).
`5”§5°"” “r "’m“"‘3 "°5"3"""“;*“”“"' P"""'”""" ‘W’ T""1""""" 39m'm
`
`.
`‘
`‘_
`’
`.
`{U57 L
`£’5.,
`,
`1
`v
`;1;$'s\‘:.\ ;cmE:(g4;n7g2:i£;;§;§:cEab::x!y wxih maxed sslvcm .<;y,s'E-.‘.n1s‘:.
`. E. W. Muriszorn A, §¥'.:5saii1.and R. Eiiuus, "P1‘EL‘ili!i§B_-’a.'lI')‘ new Is! 11:2
`of bisuiliis in p3n:.-rrnacfculicai
`lT::hrm:I?:r{':on." J. F:':arrJ:. 5:‘.-Z, 66{i2',>.
`SW5 (»m{?J}
`.. .
`.
`.
`M _
`.
`0
`.
`.
`t
`,,
`.LC.SEhIuF.‘cr,
`isunumnsaciglsansasph...m.u:cuuca!amnxadms.
`,1 pjm,-,;;<5(,_,§{3{[3}'3gg :\;g;,[;_
`.
`I-2. Dabbah. "Th: use of'_nrcsm':x:ives in cnzxapendiai nniciesf‘ P!'1amJ(?-
`:'cvp6.’x:r' Fxsrmii. 2&4?‘ 25963 (3 996»).
`Kaufmann. E. Miiohuazetvski, 3.
`. T. 3. Ei:mm;m.':. \I. A. Smyiha.
`i’.B‘h’:'.1ii::3v'. isnd R, F. Fudggvs. “Dx'.<.s:>Iu:iu:a iimes mi‘
`::dri:srn}.‘ciza and
`nfiriszmycin EDP?’ .~‘im. .5. Ham. P.".1<1r~a=. 45, E55‘? (1938).
`‘:1 1 W.'ms_:,
`‘E’. C. Bah}, G, E), E,.~:csnm.v: Md 1), C. Morkh-smsr-,
`“flptimimsion cf amocizive v:yr;}::s amd 5:: man 01' fairmaflaiion for
`parentern! product, Pant H: Ei'fr:<:t uni‘ counter-3'-an on pH and stabiiily of
`diasrizufc acid at uulociavrz :cs;‘.pcm:ure.i.‘“.i'. Pssrwsmn
`?‘m'z:;aL.
`3E(‘3}.‘I2{i538::).
`‘!nn¢1i\'cl‘:1gr:-flicni Giiidfiv’1'}E‘.'iS§0t:0fUfE!§jEfifflrniafinza Ecsazjrtns.
`Cf}ER,.F.':n::;uja 3396.
`
`.
`
`V63. 51. Na. 4 .' Juiy-Angus! 1997
`
`Suppiied by The British Library — "The wcr|d’s knawEea:£ge“
`
`Astrazeneca Ex. 2088 p. 6