.
`
`..»-.....~. \».»......,...,
`
`,_,._..
`
`S!
`
`RE‘5/HEW ARTiCLE
`
`Exclplenis anfi "lheir Use in Enfieclabée Pradusts
`
`SANDEEP NEMA*, 8. J. WASHKUHN, and R. .3. ERENDEL
`
`fifalfirzrkmxif Ma:la"rs:r§, 3::mr;mrr:f:2sz’, Sal»: Lnmis, M’:'s.-mrm‘
`
`
`ABSTRACY} Fonzzitimiaii ofa mew rug gzlmltacr wiri: exrfipfersrs, rim! have heart pr~cv.r'm.'5i_)' tzdxied :0 ma apprmed
`:'.v.',$‘ecm£2!e pmta’uc.', nmy .:'zn~e ;»’nrrvvrm*¢*zs.'£cn,’
`i’iIJ?I'_[im3‘.le.‘.‘P cfmflogiialciriai Iézyze mm’ $0.9‘. The PJa_)~_n'cin::s’ Dex}:
`Efeferclzce (PER) ruin’ fiartribuzlk an 1zzjea'z-able Elmgs: 1:-err .r~e'nv‘ewea', extracrfrzg all :‘::fl:=rmm‘x'orz on e_:‘c:'}')Few1’.>1 Tim
`.v':2far::.-:z2io.2z was cs:;;mfr'a'aEe1f farm eigfzr rxsizles, miegcirlzixrg mg-.r'_m'r.=.-ll: as I} »Sa.'?ree2r.s cam’ C0-.sa!va=l3!.s', 2)
`Salub:'_3Ezz':sg. Wetting, Sarspawalisag, Er.~m!.s1;fj.~ing or Tlrlclmzzlsrg sxgexrss, 3) Clmlaritsg Ageszls, 4) A:.vi£a.rfclzzn:s- mmf
`Redsacizzg /lgems, 5} An::'m.‘c:'obfa! Pr«:'I£'n=£iF:'r:.'£_. 6} 32.95%: and ,-:8 Aajfsem.-lg .-igrsms, 7} Bzslkfug Ag-ems,
`P‘m?ec!ar:r.s. mar? ?"csm'z:iIy A<l;izmul'.s', mid’ 8) Sp-escziai Asia’.-':a“s'es.
`lwaera z:p_,-::’imb.l’e,
`r:z£*-Em ifs: freqircazcy af use,
`(.‘fllICt'm‘f(ll'sl0ll'. am’ an cirizlrzgife ofa canmserciaf _.*:rorl:rc.r era.-::m':ai::g1:’:e e.xcfpie:zi. Exx:a';.>r'a::ix w:‘:£clraz'ef1zc?1m’ed in
`nfgg 1995 Ff),z1 ‘;'ugm'y._o 1,:;grgdi2aez C27m'z:’e,"£'1u;' JG rm: gm,-zrar in line .«"}’J!«.‘ or Hcmdlraoic 0:: 1/Ijccuzlwle Drugs, w-tn?!
`Fncll.-afed as .1: scgxm-me Fisl.
`
`
`lnimduclion
`
`izajectable products requirss a uniqm‘. farmulmlan sfrxlleggy.
`This fipmiulaical product has in be sterile‘ pyrogczx Em: and,
`in the :::as:: nf snluliuns, {me of pnniculeale mailer. Prefaumbiy.
`the farznulaiion wiii has lsnwnic, and depending on uh: mule
`Qf aclmiaiislrnlien {Fm insmnce, fur intrmspinai or i1:li‘a-
`cisecrsml mules). antioxidants and gsreservmives may E3-Qt be
`allnweel, For :1 given drug, the risl-: of mlverse events is
`higltcr 3:‘ it is miminisisred as: an injection versus ll rm-
`parenleral i”(3i.I5.B. The requirermznz fa): sterility demands that
`she :,'<a:l{ile*.‘nES ha able to withstansl auluclaving or oiher
`§Es':r§ll3'=:li(m pr<r::c—:5ses. These fzu::m‘:s Simil the chaise uf
`excipacntsl :mxilal>1'.=. so the formula:-nr:~;.
`Generally, a kns)wls:&igs of which excipientes lmw: been
`(3{‘.EEfl€(l. safe by the MBA or sxrt:z1lrc:::£Ey present in :1 muzketescl
`prmlucl gamviclr:/3 increased assumncre it: the farmulrmr that
`these exclg1icna5 will prelmhly be safe is); their new drug
`product. Hwwevt-.r, there is: m gunrant:-.9. that aha new drug
`pmduct will be safe as z:xs:i;.~iams are cumhimd xvith mher
`adsilt§‘s'cs nndfcr with 2: new drug. creating lsnfcreseasn
`potentiation or synergistic toxic cffccts. Regulator)’ bodies
`may viaw an exciglieiii previuusiy apprmcd in em inject;-zblc
`dasagc form fswmzlhiy, and will frcqucmly raquirz:
`lass
`safczy dam. A new ::-fidfitiva in :2 formulated pmclucx will
`always require adaiiiicanal studies adding to the cans: and
`limaelim: mi’ prmlssct tlxsvempznent.
`'}‘hc purpcasa szf
`this paper is is pre cm the Va.-rimas.
`cxcipiems ihat lmve been included in me fcrmulrniion cf
`injecsable pmzlucts anatlxetesl in ill: USA. This in1'mmzu§r.m
`is us): readily ;w:'.lE;1bic. A lllcrzsium search inzlicales mat the
`3115: paper llcasiilng with this was puhliglmi
`in 1980 El).
`Pi‘-.ZidEEl€l's‘
`fippravmi osalside the US are nal cm'er.r:r§ in this
`
`l995.:'\1:cs:;J‘iml Fm‘ mzbllcaainn May 15. 199?.
`Rccwnl‘-S-Eiclober 1,
`‘Author H3 \\‘l1o:nc::=rrcsp<zx1;‘--snce: sh-oi:-‘SL3 Lu: aéaircsscalz E0. EM 5340. SE.
`L-nuifi. MU‘. 6.$l3-S
`
`review. A159. smile dosage §‘<sz-ms mt administered parenter-
`ally,
`sucizw. as salutlurs for inigzzziosa, ophthzslnuie: or mic
`maps, and ¢fiI}iI!'lt§l'iES were excluaied.
`
`Methudulogy
`
`l @395 (2.
`Physicians’ E335}; Rcfercncs publislmd in 5994 3:.
`3}. and HIlK1(§5QOG}{ on injrzctzahle. Drugs (4) xvcm Lastscl as she
`primary sczurce sf infonnatian. E-rx=.n’cs on all
`injcszlabir:
`drugs wrsm stammzzrlzecl
`ix‘: an Excel xvnrksheet. Eacll
`prcduci was clrzssilied by ;\’lunuf;1cm{'es', Tmzle name, Drug
`nz-me: Route of :i.clminis1.rsa1im1, S\’P!i.\’P, pH of Pmducrs,
`Snlvgnt Useti. Snlubilizinglsusysendlzxg Agent, E"ms:rv:2Eive,
`Aniin-xislzmt, Cizciator and Omar Forenuizzlinn Adaiitives.
`The rttsllliing Excel sheet had infurmaiéml an more than
`700 prmlucls. This irsfcsrurnzxiicgn was condensed finite fiES37"lID-
`mead. tallies. Each table hm: been catcgorizeii based (El! ‘me
`primary fun-ctian sf esxcipiem in the fmmtilatiun. For
`exam1ple,, citrate; are classified as haxffcrs and nut as ch:~.1:\=.~
`‘mg agents, and azs;ct3rE3;:ies arc: categozizcd as zzmisxxldams,
`uiihough way can serve as bu§‘fea's. This classification system
`was based on (Jul expcriencs in fm-snulalim-1 dwelapmcnt
`21516. (an lhe puéflislsmi li1er:3mre. Such sirzxplificaliuxu amid.-;
`dsipllcatlon (sf entries and provitlcs the ‘a1aslienc»2 with
`e2s:=y—m-m:1ll Ealalcs.
`Same dupllcauiszan was uimvuidnblc. Tables VIE and VIII
`::4_ml:1in 5.-ume axcipicnis which nmy lmve also been listed its
`me
`six Iablcs. Wlaenmm-.r
`the reference sgwacificaily
`dcsignalai
`as specific Eunction 2:3 am ingredient
`is was
`rmlistcd in Table: V}! and ‘Jill. For examples, glycine can be
`used as is buffer or as a siabiiizing fismscciing) agent
`'T§mr£:fQ1‘(:, glycine: is lisitti in Tablas ‘VI and Vii. lvleihyl
`paraben is n preservzszitre {Table V) hm aim has 2. special
`fmmlon in Adria:ta3,'cE:1 RDF1” f€)rmulati0n{T1‘:blz: VIIE}
`The conczenlrmilxn clf excipienis is lisieci
`pcrccnlagxzs
`svclglai by volume (wlv) air volurn: by vulume ('l:‘:’&’). If the
`pmLiL!i:i was lissczj us lyaaphilizeci 0}‘ powder. these percent»
`
`l>
`
`
`
`
`15$
`
`FDA Jaurnai of P313 rmazsuricai Salas}.-3;: ,3‘ T;5:Jf;g3:_3§a.gy‘
`
`Suppllecl by The British Library — "The wtlricfs linowledge"
`
`Astrazeneca Ex. 2088 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01324
`
`

`
`
`
`TABLE 5
`Soivems and s':<2~s:o!venEs
`
`__
`
`""1
`
`Frequency
`2
`3
`E
`24
`9
`E
`
`Emcipicnt
`Bcnzzyl Ecnzcatr:
`Cofifiiificcd U11
`NN Dimerhyizxcexamide
`Eiharwfl
`Glyccrén ifilyccml}
`i‘-‘enmai GEE
`Paziycihgllens giyc-:3}
`H55
`i’z‘:IG 3!}-3
`2.
`PEG 409
`5
`PEG 335%
`X
`p0§.'?§'~Y3E€G
`23
`Propylene Glycai
`2
`Szzfiiowcroii
`SC11§IFiE(3i§
`6
`Suywan oil
`4
`
`Vegcxahic eii
`‘.2
`.............,..............................
`4 No dzms :n'r:‘.!:1b1-S.
`
`-'1
`
`Sacoi>arEu'r:x§ 5Ga'i1tm(WyezhvA3;a-55:} 50%
`0.1556573
`\’eP'csiLi“l“ fflriiatsa} l\-igiisrs) <'>.‘_S‘.7n- wiw-'
`50-53%
`At§vnn’3' [\Vy¢Eh~AycrsI}
`4‘
`§Z's:§.v{;-h.’ft:s§mI9 (Upjmm) 2.95% wfv
`(B.3~3'3£=
`Eiilicsdgiw (Sgfiiugu) ]%
`1%
`Termufiycin S-tfluiicz-:1 (fiocrigi 75.2%
`(F.2—"i'5.2%
`Liposgn I13 (,c\.bbo::) 19%
`s—m=:as
`Soiganai in;'.<*3 ificimriyzg.)
`“
`Eniraiipiéfl {C!in1cr:.)_?.G%
`5»2£3% wiv
`‘v'i‘.'§§en EM En_i.® (Smr‘P'1arma1<.‘r:uii-1:ezEs)
`*
`_. ?m.._.mm.._.mm
`
`ages we‘: derived based on me zt:cCinsiEtuti:Jn volume
`ccxmmnniy zsseeai. Tire {shim E35: the range of cmscntratima
`ugezf, typical! or mass: mmnmn cGnCez1u'aEi0:1 cmyktzyed, and
`uxampies Q?‘ pmducts ciminifling the gxcipicnii, Sgmcificniiy
`Ehnse vvifath uge extremely Ecw nr high cssncenéraiinns.
`
`ifsiscusssisms
`
`3 list snivcznis and cn-solvents used in pawrnerai
`Table:
`products. Water for injeckican is she. nmstctmxmora solvent but
`‘may he ccamhinezi or sxxhsiituied wish :1 cmsfllvent
`I-3
`impmvc the snluhiiity er :~.ta1b'i3iiy
`at” dings. Q3155 Eike
`snfélnxvcr amt? 3:33/Ercan are um! in mzsai p;.,m::1m;:i uutrilicn
`pmducas where may serve as a fat source and as carriers far
`fapsoizablc vitamisxs, Ethanol and propylene giycci are used,
`either :1lnm‘: 4):‘ in cisszahinatioti wiih mixer s<>E'.'¢=.-rstsz, in more
`ihata 50% of parcnicrai so-soiwzsxc systems. ii is suwprising to
`31::
`;:3'::2pj,rI€:13€
`giyccl usttd mam: after:
`than 1}Q§}'£§E'2y§€ri€
`
`giymls (Ps’3G.s} in spits: of its Ezighszr rrzyoiuxiciiy and
`hesmcaiyzing tsffesans (5., 6). Prcbabiy, ‘me presence car gamma
`{ion M peroxides in Piiiis is 3 :rrasijor}isnit:;:ie>n.
`Tnbie Ii inrsiudes a broad catcg<s:"j.- sf excipiams whose:
`funcij-an in fmrznulsititlm cmxiai brm-—{£}‘v'isms§!y impursiitg er
`suspending agems like casbzzxy methyi czeiiuiom, smiium
`carboxy mem_yIeeE1=.:Iose_. s:‘;u'bi‘I01, acacia, F’ov1’cic)i3c,h_‘}'£§l’(5-—
`{gassed gelatin; {2} Soksbiiizing, waiting 01' emulsifying
`agems; Iiict‘. (fmmnphaxrt EL, suziimn dtssésmycimlzlie, Pi]1j§lS{EF~
`bah‘. 20 02‘ SE}, PEG 4% casmr (iii. PEG iii.) cnsmr ma, zsmlium
`dadecyi suifate,
`lecithin at egg jrcalk phospimlipidt. {3}
`Aiusnintnm rnonosaeraraie xvixich is added 10 fixed oi! ac.» form
`viscous at gei-Hike suspcnriirag nxedéxtn-.. Foiysoxbaic E0 is
`me most cznrarmvn and versatile smuiaiiizing. a-gelling and
`emulsifying agent.
`Oniy as limited number cf cf:-slaiing ugcnfis am used in
`parenteral p:‘oda.=,cis; {'}‘asE3E=: HI). They serve in compicx heavy
`
`TABLE ii
`Suitzbiiizing. Wetting, Stasperadingg. Emuisifying :)rT§‘.ic'Kea1Fng Aganis
`
`Excipicm.
`
`Ensign
`
`Exarsxple
`E-‘J-muons)’
`'1"a:h9r<:uX?n Did Th‘-fiifl (Le-5-mic} 7%
`?'‘/To
`2
`Acacia
`Sralgunul E:zj.““ (Schaing) 2%
`2 ‘FE:
`E
`A2L2r:3i::um monsstutrafie
`B i-siilirfl’ {\Vyeth-Aycrsi) 43.55%
`E
`4
`Czlrbmxy zneihyi miiuics-2
`Luprszm Dcpaxfi (TAP) (5.3% wiv
`ill--9.35%
`9
`Carboxy nmethyl ceiiuiuseg sodium
`Sz:m§immu=3r:'5‘ §S;mdu;v:) 65% wfv
`56-65% wiv
`3
`CFt'$!1‘.0p33Hl'€ F,L*
`Fungizinnefi (Brigid Iviyersfi 0,48% wlv
`114% wfv
`1
`Dcsoxychomxe sodium
`lnirifiipiif-3;’ KCEEHEN) 3.3%
`1.2%
`3
`Egg yolk. pimspholipid
`€.?o.r:r.x:1e3*(?\1¢:rr;ia) 15% wiv
`263% wlv
`E
`Geizafira, Hydxulzyed
`Dipriwwg’ {E'.er.eca)
`wlu
`{M-1.2% wfv
`7'
`Lecithin
`AquaMephytm159{M¢-Eek} TI‘?.3= w.-’v
`’:"?E- xvfv
`E
`Po3;)'01}'eshyla1ed fatty acid
`{Tardaxene X LN“. ('W_¥,'E:ii'l~A)’8rSai) 10%
`0.03-32%
`3E
`PQ§y;3;';_ri_;.'.:2e EU (Tween 8(3)
`
`C"aI::ijc;:® ffiilhflil) 0.4% W/V
`£103»-(3.4%
`5
`*9 ?{J {T’a-:‘.f:x1
`Pvgiyggwr
`
`;‘.'§unismt5" (jzzrzsscrxjl
`I 1.5% 1-Iv
`I 3.5% visv
`E
`PEG 4!} L‘
`IGE‘ nil”
`P.'ug:-33"? (Fujisawa) 20% wlv
`20% uulv
`I
`Pm‘; Si} castes" ui1*~**
`D5-0.6% wlv
`B1cE!IE.-x’5‘- (\‘~a'ye1E:--Ayerst) 6.6% wfv
`_(s
`I'm'iz1m:e (Polyvinyl giyrmiidone)
`3.018% \.v."=.-'
`Prnteukirfii (Cetus) 3.918% wlv
`I
`Smiium dodccyi suiE'.1§I:(N4‘. lauryfi aulfatcj
`
`
`Ariatrospazxx ifujiszxwui SE9?» Viv
`2.5—50%
`3
`Surbitr.-i
`lane: 35 casmmil.
`*‘ Cmmcphvr EL: Ema.-5 35, §:r;F)-cilmxyimcd mswa‘ vii, pnIyo.x3‘e
`
`“ * PEG 40 caster oil; po3:~'m<§'1 49 taxi»?! -nil. caster :-ii P013-$0. Crodurca =31}, pu1ycx:<3-e:§xy’.nxa: -it) r::45'mr ed. Pzcmchem CAM}.
`* ** PEG fi‘JJ's31Jrr;gcz1atc:E caster ui1;C.'cmeph-3: RH 60. hydrogensjied gastcxr mi PDF.-fsfi. Prom?-.cn: [‘.‘;5.’ri-61')»
`
`,
`
`Vo1.5‘,N~').-‘e .1 Juiywkugjuat 1997
`
`Suppiied by The British Limary — "The warid‘s Emowiezzige"
`
`
`
`Astrazeneca Ex. 2088 p. 2
`
`
`
`Range
`2{‘:% Viv
`73.6% wiv
`6% wfv
`U.6~8B%
`3.52--753% wa"v'
`*
`
`
`
`Exaxxxgslg
`Drpc--Tsslusicron-3” €U;:__i::hn) ZGSE v/v
`Depn-Teslusieroncfi (Upjohn) 173.693: wiv
`Vumor:'~"' (Brisml hiyarsj 6% wlv
`l"ragr;xf'~“3 {Faujisasxvafi §2E3‘Ifz': Viv
`Mulzitest C.l\/£15’ {Cr.:nn;m;_z_hE) 75% wlv
`Ba} in QIE3’ (Beams: Dickinson}
`
`aiE!
`i.
`
`El.
`
`3.
`5;
`
`gI;
`
`

`
`
`
`toxicity (7, S). I§s.1EyiL\t<:d i*.yds‘ms}' miisuic, is ulyimcd §1)'d£‘uxy
`loiuene and prispyi gszliate are primaxiiy zzsrsai in ssemi/non»
`aq=aem3_s vehicics Fzecrzmrse of their Em‘: aqumus ::o}L=.i2E1Ei:v.
`Ascorbic acsda'so:1:u2n ascurbatc may scrvc as an m‘:{i<>Xi—
`dar.-t, buffer, and chciating agent in the same, farmuimian.
`Eenr.yi alcnhol was; me mos: cummcm antimicrubiai
`pmsemativc present in paremerai 1‘:-rmuiaiions (Tszbie V).
`This is r:(m:si:sI:nt wiih other suwsys (9). Parabcm: are: Ehs
`maxi mos: mmmon })l'fS5'3:'VE‘:Iii\.',-_=,;’5. ’i'I*xi.r1,_»b,.,;air:~;: products»: had a
`combinaiion ofmaahyl and pmpyi pamhensg eleven had on! 3.’
`methyl, and one had smiy pmpyi pamhen. Thimemsai was
`surprisinggiy common, especiiliiy in vaccimss, even lhuxzgh
`same §ndiy'iduz11s have sensitivity to mztrcurics. Chiorocrcsoi
`1'5 puyportcd to E3:
`:1 good gzmservalivrz for pzmznzerzxis. but
`mar survey did :10:
`{End any c.mz11p'm.5 of commerrsiul
`pnxtiucfis (:cmt,ain§r&g sch!-arocresul.
`Table V! Eisés buffers and chesmietals used so adjust thc pH
`<3? iornmiationsl. Ph-nsplmzrr, ci:;'a:»:~., and acaxale me the: mesa
`common buffisrs used in parenteral products, Mono: arm?
`xiietthantzianainzzzxre added so acijustpfiamd farmcorrespon-:1-—
`Eng saiis. Hydmgésn bmsnicic,suE?uric:a3cid.?acnzcnc: sulfmia:
`amid and mailman: sulfa-mi: acids are aided ta) mugs which
`am bromide {Sc:a;)ca§;:mE:~.e H821. Hy43scine §{Br, UDL),
`3113?’;-.:es {NebCin, Tobramycin sulfate. Lilly), Eaesyiz‘-.ie
`
`T15 3L5 5”
`Qhegafingmgfinta
`____
`____ n
`Emmggfi
`Fmwcmfi.
`Rnngi.
`Emgpicm
`mmmmcflficiumiiisoiggllmmga‘"'3'"
`flm»m% wyduscfinvymh‘
`EDT,“
`mam) (km. W“,
`njggmum §[}j‘A
`Q_[)g__q}_g% {ja{¢§3‘g,;18>{,qli3{mg;)
`0.11‘/a wfv
`F9g’§ff' ‘L‘’‘‘‘"‘“3
`9°30?”
`3
`5”‘fi“‘“ Em“
`Qm% Mfl!';u;;i51,, {germ}
`E
`D.n,A,._,.
`
`ugsgtjg,
`" EDTA -- §:‘:‘::l:-nediarrxinzaarraacetic acid‘
`“‘“"‘
`*9 FITPA == DEr;ihy!eni:irinmincpcntaanreiic sscid'.i’crxic1i: zusiti.
`
`
`
`3;;
`
`metals and tixerezfon: can improve: the efflcacy of aniioxi~
`dam.-; or prea-:=.rvs2iive:s. In our opinion, calcium EDTA has gm
`acivanaage. em‘:-.r tcirasodium saii by mt z:-nmrihuiing sodium
`and mt chsisaiing caiciuzn from t§*z<:- bkmd.
`An unxiiuxisiaxxs us; a cfiasaa is sfciincd as mass. cu-my-ounds
`mm can am :25; mducing agents or may serve as free radiant
`isczzvcngcrs. Table IV summ:-.ri2cs Eh: antioxidants.
`their
`frequency of use, concmairsziimx mugs and :.2:a:mg3ics of
`products containing maria. Suifiia. bisulfisc, and m:2€abisuI~
`fizz: caarzstituie the mzzjomy -sf antiaxidzznfs used in parenteral
`precincts aiespiie several rcpgm sf izacompniiiniiiiics and
`
`TAELE W
`
` Animxidants and Reducing; Agenis
`
`Fmiguexxcy
`4
`'1'
`28
`3
`3
`2
`3
`
`Range
`G.2«~»[?.4‘/‘o wlv
`(3.1-4.15‘/‘*2 wiv
`CW9.-{3.65’3£; wfv
`[}qU'OQ?.8~>fi((33% wi-.v
`€3.00!
`lé-l3.(}3‘.7a wlv
`€11.07--{3.iE)’5é,~ wlv
`E}11fl9‘>
`
`Excipimt
`A-;::mn:: ymliufll ‘aissslfiic
`A3£0rb.'ai¢(sudiurts1as;iL1)
`Bisuifite sodium
`Buiylaled §'.yd;‘uxy £ii1iSGiE(BH.‘5s}
`Butyialed hydraaxy iohaenee (EH '1')
`Cystei niflgrsatéssarc BC:
`Ditliioxtiis s.odi::m (Na hydrusulme, Nu sum
`ox};-late}
`04:1 rcaficanfi (hiaiiixuakrodi)
`€3.{}}',% wfv
`3
`Gcniisic acid
`M.‘J.§. 127“ (A~.='.ra} 2%
`2%
`3
`Gcmisic acid ezhanoiamine
`Vurivasfi (Mem-3:] (13% wiv
`8.1% wiv
`2
`fihxtamafie nxtrrmsuciiism
`Termmycin Sofuzic-n Efirzrzsig) f.‘Lfi‘i'a xvfv
`€.I.€}’75~G.5'“7c wiv
`9
`3"nrma3de'nycEc sulfoxgrfiaic sodium
`Vasmxyii‘ (Biaxu-Wrsilccmc) 0.13%
`(3.§-3%.’:
`E
`Prfielultisuifiec potassium
`Eaalrogz-in“ (DuPont) 1% wiv
`0.02--1% Ms’
`2?
`Meiabisulfiie smiium
`Tcrmmycin Suluiion (R-ucrig) 1%-
`[Liv-§%
`6
`}‘u*!nnn&hi0g1yc5ro\(1hEngig.'cero!}
`Pmpyl galizms
`2
`0.02%
`Nzwanafi ('.'-*.aer§g}
`Sulfite sodium
`1'
`0.U5~—Lh2‘7a wlv
`Emma? (Dim-Edza) (3.2% wiv
`
`TE‘:Ee3§__-Eyco}:.'-.te: stadium
`E
`{B.66% WW
`3:: Piififlfiiw (F&a'c.=,f.i (L66?) xvlv
`
`Exasnyixs
`Novncainxzi? {Smnfi-Wintiianp) €}.=§% wiv
`‘v'ibrcm1ycin“‘ (Rocrigfl 4~.3‘>€: wfv
`Amikinfi (flrisml .MycL'5) 8.66% wiv
`Aqu:zs:)F° (Astra) CI.€33%
`Aqs1as:ai5>{AsEr::)(3,03‘I»'u
`Acihar Gel‘? :;Ri1une~Pn1mn1c}EJ.E% wiv
`Numu-rphan"5‘ (DuP::<s‘-.3} B.if!'§i;
`
`TA 8 LE V
`.
`Antimicmbiaf Presesvaiives
`
`
`lirccipiam
`
`§‘rcqumnc5-
`
`Range
`
`Efmuzple
`
`Cefesione Snluxpaefi’ {Schcriasg} 8.02% wiv
`0.02% wfv
`E
`}3en2a1kon'1urs3 athloxida
`§}:‘.z1:u.*L!'y}3’ {}’ark(:~D;s=.-'55) 6.01% mm
`9.03%
`*1
`Bcxxzciimoniuxaa Chloris}:
`Dimcnhysfrinaicap {Sims} 5%
`(L‘?5—SFJ'a
`‘M
`B:3r1z_yl alto}:-‘J1
`Codinzt p‘h9s;:?:2:i<; {‘x\’yx:sf1-Ajr-$551) 0.5%
`0.25-411.5%
`I7
`Chiom}:uK:1:::>l
`Humaaropfi {Liliyj 6.30%
`{Li-0.3%
`3
`m-Cram!
`1‘J::pu~§’rou‘cr:‘9 (Upjuhn) (B. Efs‘§J‘Jo wlv
`0.0! 95-0. E 59% tviv
`2
`Paiyristyl gmmnai—}1i:o!,ii‘d::m ckiinridc
`15:;
`.
`.5519 (Jurmen) U. 13% wfv
`0.0543. 18?:
`50
`Paraincza met‘.-ayl
`Xyiocainz v.=.-Ifipinepllrizic (Emmi U. 5 93 wiv
`(JD!--(3. } ‘Eu
`46
`Pamben pmpyi
`1",‘.-Jicizvaz-3 {Rhone Poulan-:2) 0.5% wiv
`0.2~{}.5%
`4-S
`P1221101
`H::x'ri,\s3'{SmEs!1E{line §5cec!1s1m}[l.S€3‘/3 wlv
`:35-fl%
`3
`Z-Phcnmyeihanoi
`Ptmsyl n‘.ercuL1'c nitmiaz
`3
`0.83! "/2:
`Amis'enEn‘° tfwycth-Ay“«:rs.t} E3.00§"/Ta
`
`‘Titimcrssn?
`-M:
`i).{)O3—D.(H ‘/2:
`.»“sa_§:am’*'9 iflfsjohn} 0.01%
`
`'
`
`_
`
`_1§_a3_
`
`A
`
`FDA Jeurnai at Pharmasmzeicai Sciam;-3 8. '17e::hnr::'<:gy
`
`»
`i
`‘
`j
`
`‘.
`
`S-uppiied by The British Library — ‘The worEd's knuwiedge"
`
`
`
`
`
`Astrazeneca Ex. 2088 p. 3
`
`

`
`
`
`TABLES Vii
`Esufiking Agents, Pmfiecianis, and Toniciiy Adjusiois
`
`TABLE Vi
`
`Buffers and pH Anijusiing Agents
`Erizcipimi
`Accmtc
`Sodium
`Acetic acid
`Glacial iiciztic acid
`fmimonium
`Amznonium Eiyflruxitie
`
`Miaczsiciu irijecxiunfi (Szmdzi-2'.)
`Miacaicin Enjeciiusfi’ {Sam}-.32}
`Brevibitsc Isajeczionw iflhrnecizz)
`Bumex injeciicnfl (Roche)
`Triosiat Injeciioifi“ {firriiiiziéiisirg
`Bccciiaizii)
`Traci-Eiim injeczicnffi {(:!a,~:o~1VcEicame}
`Valium injection?” {Roche}
`Ccfotan EI1j<:c:tEsmT’ gleneceai
`Hy§mRP1-i)~D’° (Bayer)
`
`D1‘iCT-Sonic” (Bnycfi
`Ceri:Li:zsc°3’ (Gunzyme)
`Cerezysne? f_Ge.rizy:11e:}
`Ccrezgy-mad‘ (Genz;2mc}
`Basin’ :11 EW’ ( Roche)
`Quinidimyf (LiiEy}
`Hep—B Grim mageafi (Merck)
`Ami-;a.r°3’ {Immunex}
`Scopoimmne (EJDL)
`Fentenyi ciimic £1 Dmpeiidoi {Astra}
`Eminaac Iaijcciiorfi {Roberts}
`Liiarium iisjacsierfii {Roche}
`DE-{E-if-5 Enj:;‘:‘:Eiu'-.3‘ {Sands-1)
`Terrnmy:-in'So!::£ir;rs q‘_Iiua;-ig}
`
`Benzene suifmzic acid
`Bemoaie Sfidkllllffltili
`Bicarbonate S-cidiuryi
`Célfbkillflifl Scxiiism
`Citrate
`A»-2E-:i
`Sodium
`Disoiiium
`Trisodium
`Diciitasiulainiins:
`Giumrzc deila §z1L’£C3-.'!iE
`Giycim:
`Hydtochimia‘. acid
`iiydru-gen Es.-‘cnxida
`Lactate zx:id!3a:s.iium
`Lysine
`Maieicr acid
`ieieiisarmizifoiaic mriaj
`Evlmioeihanniamine
`Phcsphairz
`Ara‘:1 qpisrasplwric}
`ivicnohasic paiasa Eum
`Monubasic ss3r.iiL:m*
`Dihasic sodium* *
`Tribasic gr-(hum
`S-miiuai: hydmxitlc
`S;.i‘ifm'ic .'lCi{i
`Tziriraic acirffsnriiuaai
`'E‘r:m:rei}:zi:::im:
`
`Huineg-uni‘-‘ (£'3:'gmmis)
`Z€lE'EEi’a€E
`injection‘ {C3§axo—‘1-\r‘ciimme_)
`Prrrgiiylii (Orgzmisaa)
`F'ruIa.sEin'3“ (B aye!)
`Syi1Ehmi(E9 {Knoll}?
`Gpiirazz/‘*9 Wiaiiincixrrmflti
`Nebcinfi (E.iliyj3
`i9ieshergia1aInjer:ii=.)n5° {S::nd{;z)
`Q37! 5:11}-'® ihiailinckrodt)
`* Sodium biphospimiit, Sodium dihydrogcn g-iI':c.:pE1:sIe 111' N1; dihydmger:
`onhophrssyhnter.
`'
`** Sodium phosphate. Ilisasfassm hydzogen phosphaie.
`
`{’i‘i*.3crium in}, mix-’:cui'ium besyizim} or inesyiaie {DRE -‘$5
`Iiijectioii, D1h_vti:‘0urgoi::mina mesyime) 513:5. Ciiucorm deim
`iacmnc is used to adjust this pH -of Qaiiuidin-.°, g!1:.c<.m;3ac
`(Lifiy). Beimasste buffer, at a cunceenamiinn if 5%, is aisiaai in
`Vziliuin Injctisiiun. Citrate; are common buffers {hat can have
`a duai reds as chelaiing sgcnis. Lysine and giyciue are amino
`aci-:33 wiiich funiifiifiri as buffers um} staiaiiizae prmcin and
`peptide f‘i)i'£1‘:tEifiEi031$. Thciséx -maiirs-I) acids are aim used as
`iyu-additives and ingiy gmzvcm amid :Eenaiis1'atitu:. Lactate‘
`and Essrxrates are iaccasionaliy ussti as buifer systeins.
`Table VI’!
`lists aiiclitivaer; which are {ism lo mnriify
`osmtslaiity, and as buiking or iyén-Nye _;C-E‘l)[»'.’.‘-’.‘.ii'v‘£‘. agents.
`Dames: and sodium ciiimidc are used its adj-.151 mriiciiy in
`Eh: majority of formulations. Same simiém aciiisjgiycinrz,
`zaixniaxe, hisiidinc, irxiidzxzoie, azgiiiinc, asparagina, aspartic
`acid, are zzsesi as iauikirig agsziiés. for Iyephiiizaiiim and :in:i3'
`serve as stzslziiizers for proteins or peptides and as E3ui‘fcrs.
`Pvianusnccharities; {dcxim-se, giumse, lactose), riisaccliaride
`(sin-rmse), pcaiyiiydric: ziiimimis (Ermsitoi, mamnitol, soibiioll
`glycol {PEG 3350}, Pcwicione. (polyvinyipyrroiidene), and
`- pmieins (aaibiamiii, gcizsiin} are cummcniy uszed as Syn»
`additives.
`
`
`
`Exci
`’m1
`Exnmpie
`_
`. ...e in? {Bayer}
`
`Biofiiniag (Arm)
`E3a:m2‘3 miicrguii}
`Han-iixfi’ issiiiihiflisav: Bccchism)
`Aciivxas-9.9 (Gzneulech)
`Tic:-: BCGE (Og.an0n}
`Fepcidfi {M¢ezr_-5;}
`Phuzucrgun Ergjcmi-an?” {W'ye;h~Ayers1;a
`Scrssorcainvc-MPF3 (Astra)
`Betasemnfi {}3c:}:-Mt)
`Acrhafi? {Iihune—PouIunc Rarer]
`Ivsx:gana'E (iziimum-US)
`Tics ECG?’ mganan}
`Jségani in_§&C:§o:1‘9 (Upjohn)
`Aneihemophilic F«‘J.€.‘C:35’, human
`(Am. Red Cross)
`Heiixak.-7* {Amxmsr3
`Uc1r€:aScai1’5’
`[fiiaiiinckrndij
`Caverj:c£*° {Upjohn}
`Te rramyciaa SDIULEOIYJ’ {Ruerig}
`Ticc ECG” {flgginonj
`Eisgmrg (Marcie)
`I-3inc!:2ic~“—° {Arm}
`Heiixntcfi (Anraour)
`Viizis'ax‘“’ (ivieircii)
`.r5.‘i.k<;ran’-* (GE axu—W‘e:iJcomc_)
`\VE:1RE1-‘J SE33‘ fllnivuz)
`Aclinimuncfi (Gen iir.-ch)
`3kpu~P.rm/s:ia® (Upjulmj
`Paaihcenai in-'9’ (Abbott)
`Pmiastinfi (Bayer)
`
`Alanine
`Aihlsmixi
`Aibumin human
`Arnhm acids
`bzirginifle
`Asparagina
`L-Aspaiziic acid
`Cziicium. -2E2!-.,-ride
`Citric: aciif
`Deiiircasa
`Gelatin: Eiyzirmiyzaeil
`Giucosé
`fiiycttrin
`
`Gig»:
`Histidixie
`
`§i!1iL5'.-'EEl'li§‘.
`inorsitoi
`lazamse
`Magnesium chloiide
`Magnesiuzn suifziic
`M::::nitUi
`Puiyrtihylene glycni 333i)
`Fciysmhaic Bf}
`Fcimssium chloride
`Poviflcenc
`Sixdiuni Chimids:
`Stadium succinaie
`Sodium sulfalc
`Starbitui
`Sucmsc:
`
`Special Aticfftives
`
`These uddiiivas have bean inch:-Lied in phamiaz-.7-czuticai
`fcarrmzlaiicm m sans: specific functicins (Table VIII). I.’-ttlcw
`is :1 suinrnary of Hit: spcciai
`'e.ddiEive5 along wiih ihrsir
`intimiicd use—-
`
`{i) Calcium giuconatc injection -(American Regflnt) is as
`smurzsicd suiutiam 3f 10% wfv;c:13ci1iiIi:i~SaLC(:h;}rzLEe
`Eeii‘.z:i1j,«‘ci mi: {3.«‘«iEa‘Z.% wiv is ndcied to pnaveni cry:amiii-
`zaiion during irampcramrc fiuctuatiens.
`(E) Cipm {KW {Cigar-ofiaxncirs. Bayer) cunizsing lactic
`acid as a snlut2iEi;singngci31 fur lha antibiotic.
`£3) Pragrmrin Injccztiezzfl (flanjizgaizsd E:;tr0g_;exss, Wj,Ir:ih—
`Ayers: Labs} is a iyophéiized [:ri'o;1uc£ that cumairis
`simeiiiicazm in preveiat formaiiozi of foam during
`X‘CCD1‘:SEiilii§DIl.
`-
`:14) Dcxammhasuiie aceizmt {bziislitme EH’,
`.Fore_s:,
`DCCEdfDi3'LA, Merck. I)z=.i;1imieI)?-‘injzzsslicaia, UAD
`Labs) and Dexamemasazie Na phosphate: (Muck)
`are zwai!:3bEs,=
`suspensicszi er soiuiimi. These (Sem-
`meihascme fantmizltions Cemain crfiaiiraiz or crefiti
`nine :13; an adriitivc.
`
`(S) .?scia‘iux1:_yi:i:i §{E3F@ (flsixtariihiuin hydmciaioride,
`Plmrmncia) contains methyl paraben, 8.2 mg,?mE., in
`increase clisasuiutiori (£0).
`(£3) Efrgfiiiatfi z11.*:Js:*£a1c (Ergon-twins nmiieamz, Liiiy} cort-
`Euiazs (}.1% 6311132} Eeacintcs as as 5-nitibiiizirzgg agcm.
`(7) Egtrsidisrfin Enjecti-rm'3’ (Paiyesii-udioi phrssphaie,
`W_‘yc£h—AyersE Labs) uses Niizcinimiide (32.5 mgfnfl)
`
`Vi:-i. 51, Na. 4 J Jui‘,a~.Aug<J:3t ‘I93?’
`
`'1.
`
`Astrazeneca Ex. 2088 p. 4
`
`

`
`..-w..u..~.‘...,,._
`.
`
`
`(E3)
`
`(14)
`
`in-Sim salt. F03‘ cxzunpirc, dia-
`cipient an-LE 30 Ram’:
`trimic acid, an X-my mantras: ageni, is more sitazbie
`when auI:x*§a\/ed as magiuminc 52:1: sh:-.n as sodium
`$53!! {1}}. Mesgitsmini: E3; 3150 zisidsii in M:1g_:n£:vis1°“, a
`mugneaic resonance cssntrast zzggcnt, funnuiaiion‘
`Sn:-préxingiy, smfitsm saccharine is used in Stelnzinefl
`anti (3-:3n1p;1zine?'=‘ Ebrmaxintirmsg our guess; is Lisa! it
`serves as a siaabiiizeztr and tcniciiy adjusier.
`Trim-Ezutyi phcsphezic-. £5 present as an ciuzipiesxi in
`human immune glabuiin soiuticm (Vcaxagiohuiifi).
`Its exact funaraitm in the fnrmuimimx is rem known,
`but it may serve as 3 scavenging ageram.
`wt: Wi'iE=:=brzs1:n“} f:,acto:' is used so fiiabiiizc remmt-i—
`nan: aniiimemcphiléc factor {Bior;§mc@).
`Erialioéc servaes ;1sa::<anE:it.y adjuslcr and si&biii;¢a::' in
`immurm ginbulin i‘um1u.lz:ii0n {Gumimune N3’).
`Epsilnn amino czzpmic acid (flaming hczxanois; acid)
`is used as a smbiiizer in xmisfirepfase {Emiams¢ in_ie:;:-
`tizznfl}.
`' Zinc and pmE::snint': in.-aw: been added {(2 ialsuiin i-Q
`fairs corrspicxrcwza and confirm} iha dxtratiml of ncliun.
`
`TABLE VH5
`S_:1s2ciaiA-miiilves
`
`
`
`Ezszcipiena
`Acetyi irypzophamtee
`
`Aiuminum h;dru3.idc:
`Aiuminum phospimic
`
`-----“Mm
`Emnxgsic
`Human Albumin {Americma Red
`Cross)
`Rccaszabinani H1339 (Merck)
`Tetimus; Toxcziai Jkaisorbcdy
`(L(:d<:r}c)
`TD/‘xdsort-ed Aduixs“
`{Cv‘mn:n.:5_zh1)
`Enrimasefi’ :‘.Rc3§3e.:£s)
`Caiciuan Giucnnaisi {.~‘am€:1'i:::':n
`Regent)
`Human Mbumisr (Américs-.3‘: Red
`Cross)
`Dilncnhydrinflte (Sicris)
`Dalnione DP’? (Fares!)
`
`tan:
`E{3'(§:'occ:rlcnc Pm:
`(Me:'ci<)
`Ctmnay {lviuiliauckrodl}
`Cnrdimea (Squibb)
`Engmxata mafcatca {Lilly}
`Aazzinsgsfiyllinefl’ imxhmi)
`Kab Ekinasei‘ (PB:=m1aciaJ
`Tic: BEG” (Dgamn)
`Cipro IV“ {Bayer}:
`Eula-éexfi’ (izleaxecn)
`
`AI1m:Enum pstaxsium sulfate
`
`E-Amirmczxpr-mic ziciai
`Caici-um dvsnccharsssa
`
`Capryiate scdiunx
`
`8—FCh1L)rmhe:sphylEine
`Crcsaiaine
`Creazinisaa
`Dizurizoic acid
`Gamma Cycindexirin
`Etiayl !::cmi::
`Ethylenediatmine
`§..-Giuianuates so:.';i11m
`Ems: nmmcmium citrate
`La-mic acid
`D,¥_pLac:ic and Giycaiic acid
`tmpoiysner
`Makes:
`Meglumine
`Niaacrinsamidc
`§‘m'abcn mrsmyl
`Pr-zmmine
`
`Simcihfict-ne:
`
`h's';sIi:um sacchnrin
`
`Tr}-n-buty] phssphasc
`
`Gamimurmfi {l‘$nycz{]
`Msxgncvislfi {Berfex}
`Esirasduri :1“? {‘.‘s’yeth—Ay:::5s)
`‘ Atiriamysin R.DF1° (Phazwrulcia)
`Iaasuiasmrci NPH3 {Nu-m
`Norciiék}
`P:-::ss1:u'En Injeciic».-'s’3 (\‘v'yeah-
`a‘xye:r5;§)
`Cnmpszim Ezsjza-‘:1i<vz1"“(3rr~,isE:~
`Kiinc Beach:-.m)
`‘\.’em)gEo!:uiEn‘~’* (Apha'E'herza—
`peutiw)
`BEnc];x1c‘~° (Arm)
`wan Wiiiebrand frutinr
`Lem: Ensuiinfi’ {Mm-0 Nardiaké
`
`'
`
` EEI
`
`TABLE EX
`
`
`List of Excigbient Ercsm 1996 FDA ‘inactive lrmgrsdient Guide‘
`Ammnnium suifaia
`Pemelme {DTPM caiciuxn
`tfisacliurrs
`B23211}-E chloride.
`Polczxzzrmr E65
`Buzyl pnmben
`Crdniiarnide soziiasm
`PEG 4993
`Cmtcridoi calcium
`PEG MK!
`Casio: sail
`P-ciygiactin
`Pnfiylaczlde
`Cellulose imicrmtrystullinc)
`Clzoiesmoi
`Foiytsxycihicnc fatay acid
`zsaers
`E)e:a-xyerhaiic acid
`Dimrimh: acid
`}’niyn;cyc1hyZene ssrbitrm
`mozmsteraze
`Dicyclohexyl cnrhndiimide _
`Diethyl aminc
`P01yoK)'13S Cizsiuwaii
`Polysmiyaic 40
`Diszayrisioyl Eeciihin
`P01 rsurbaae S5
`Dirrxyrirmzyi phosphaaidyi-
`
`glycctmi
`:
`ium hydroxieias
`Disaferxisw
`?omssi'um phosphxuc, dibasirs
`Du-‘:u:mie sodium
`Sodiu.'s1 bisuifiuc
`Iidamine
`Sac-"ium c‘nk.u-at’:
`Eixumetazisne
`Smiiu m hypochioriaic
`Smiizsiri iodide
`Uiucmpmc stadium
`Glucepzaua calcium
`Sudium pyr-xxphusgxiamga
`Gimzumnic acid
`Sodium ehiowlfuze, anhydrous
`Gmmislinc HG}
`Sotiiuns :;'Enxr:mpE2:.=aphni&
`Ioféiamine HCI
`Sorbim: mtmcapulmiiaiz‘.
`Imciobimaic acid
`E-tsiimous cl-‘a!on'L§:
`Slzmnmus fi::0rid:~.
`Lmzialain hfiircgenated soy
`I..iLFuf4:ni.=1
`St.-m:mu§ '.'am::Kr:
`3‘s’§cdmfcn§:':
`Starch
`Waslmnaie séisndiaam
`Succisaltr
`Mer.lrorxic: acid
`Succinic acid
`Sltlfumus acid
`Meihyi hcmnic acid
`Maeiiiyl celiulosc
`Teimkis (E-imcyann-2~nm-
`Mmhylcnc blur:
`ihoxy-2.meLh_yl~pr0p:1nEc)
`copper (E) T:
`N-(sari:-amuyl-siazsahoxy poly»
`Thia' ximic acid
`e:!1yiene—g3}'-col I-’.0O0'3—1,2.~
`'I‘rii?1i;320ximin‘. Asia!
`disica. ‘-yi
`Usczl
`N-2~§13icflrox§,*uIhyi pipemzine.
`Zinc acetate:
`N’-2' mhune sulphonir: acid
`Nimim:
`Zinc chlorixi:
`Nilric acid
`Zinc oxide
`Qty-quinoiine
`Zethyl hex urwkt acid
`PEG vcgelabic mi
`
`as ax soiubilizing ugem. Eiytlezilraseifi‘ {Merci-:) aim
`contains nizwinamide.
`
`{9}
`
`{E0}
`
`{E1}
`
`ex-
`
`A§um§r1'.5in in the Form of ahxminum hydroxide,
`aiuminum phosphate 0: aiuminum potassium suifzua
`55 uses! as adjtwzmt in various vaccim: fonmxlmicns
`in ciicifi an increased immunsigenic responsae.
`Zaia-:icJ<® ((}o5:ere§in znceiaza. Z-x:n::c::} is :1:§minis~
`zcrcd subcuiamsousiy mE(:msphcrcs.TE1cse spheres
`are made: of D,I_.—izL::1.§: and giycoiic acid copolysner.
`Lupmn Depot izajectiunflb {TAP} are iyophilizad mi~
`cmsphsmes af gcintin and g£yc02ic~l:1c£ic acid .f‘:
`intramuscular injectism.
`G:1mm£=. cyc.(?eie:<srin is used as as stabilizer in
`Curaiizasecfifl at a mnceniration of 50 mgf:'nL.
`Sodium -;':.1pryl:1Ee {indium cc.-30:1:-e} has antifungai
`prepcxiics, but it} is .1150 used 1:: imgxruve she sisafixiiity
`of aibumin ssiuiicm a1g::inst<:E'fecIs of ‘racist, A!‘-msmin
`sUIuiim'a can Em heat gJ;x:;icuri:v:z2ii by heating :11 69°C?
`for :0 Eutxurs in she presence -of sodium Cflpzjiiate.
`Awszyi irypiophanzxse 5::-:i'u:m is also added so albu-
`min farmuimitans.
`{E2} Megiumina (N—n1:ih3rig}ucaxn§ne§ is lififiii as
`WE!
`
`
`
`PDA Jcumai nf Pharmacez. ‘ca! Science Ex Tachncoiogy
`
`
`
`Suppiiad by The British Library ~ "The wor!x:s":s kncawiedge"
`
`Astrazeneca Ex. 2088 p. 5
`
`

`
`Recently, FDA. has pubiished ‘Inactive Ingswierai Gums’
`which 13335 :11! the cxcipients in alphabcticni crder. Each
`irzggresaiiené is foflmvcd Hay the route of acimizxismxkimz {for
`c:.‘«s;1mpEe, iv, era!) mad, in some ceases. the range m‘::m1cemr;:—
`rim used in the apprmred drug pmducx. Hcsvever, this iist
`does rm: provide me name of cnmmercizzi prcrdu:§(s} CQ§T{‘.~
`sporxding it: each axcipient. Tzubic IX is an sazrnmzxsy £31‘ all me
`cxcipients wifich are inciudcd in the ‘iamcfiivc ingrcdéani
`Guicie,’ but do not appear in FE);-“*2 of Hztndhsok am injectabie
`Drugs.
`
`References
`
`i. Y. J. Wang and R. R. Kow . "Review of cxcipicnaa and mfg for
`pureniemi pmduccas umi in the United S:aues“‘ J. Pam-um: Sc-5. ‘firin-
`nnfl. 3-5(6),/152 If I980).
`2. Physicians’ Dusk Rcfmcazcc. ed. 48, 5994.
`_
`3. §’hy.<ici:ms' Des}; Re!’esL:nc¢.m<3. 50, {$195.
`-L L. A. Trissci, “HandEm<:!. am Enjcctabic Dm_-.;:~;," ed. 3. Amrticnn
`Scrcicty a.ii'Hosp:‘:aIPh:sm1.:¢::fst§,Em:.. 1994.
`
`_"Lysi; of humxm mi blnarj mills in the
`v.-.-_
`S. K. W. Rccdariéi S.
`presence: stf vmiaus cosolvttmrs." J‘. Pizmrrrer. Jci. 7Tec!J.'mI., 39(2), 53
`(1935).
`6. G. A. Bram:-.u .-mt? 3-irkimng Fung. “Use: ohm in-vism modzfi for the
`asss:s'sm::1:oi'A12usc:!c drumgaz i'rur:: 1mr.1x11::u‘.::i:1rE::jee:1im:3: IJ'!«U§!1'iI-»
`in-vim cncrmfaai-as: and prcdiciabiiiiy with mixed solvcm sys£':.1ns.“
`P}:::n:r. Rani, 6(9), 766 (5 989).
`7. F. W. Muriscn, A, Eiussfiiri, and R. Biiuus, “Prcc:m1irsna:}' new In: um:
`OE bisuifiw in gaiaarrrimulicai 3'23-::::'.Ii::{':orI"' J. Pr':arrJJ.
`.5‘:‘!,, 6G{!2;L.
`§7?5 (E3177).
`3, L. C. SC§‘ar-.3e{cx, “'Su1f'u1r.‘:|.Is acid Saks as g:h3:mu::cuu'c.a! auiimiclamts.“
`J’. P5‘m;7rL .S’ri., Sfllfl i).89i (£951),
`I-E. Dflbbflh. “Thas use cf‘ g3IcSCr\'::tivcs in mzxxpendiai 2:13:-fies," §‘i.iam1a-
`mpe.’x7r' Fr.1r"llJh‘, 22{4:, 25915 ( E 99tS)r
`Knufmann. Z. Miiohuazetvski, .7.
`{:1 T. 3. B:mm:mr:. U. A. S‘m;,v-1h;-..
`f.!‘I’*a‘:'.1ii::y. imd Ru 5’. Fxxdgc. “Dx'.c.s<>Zu:io:a iimes ni‘ adtiamyafiza and
`acfriszmycin RDF,” Am. J. Hnsp. Pi.v<1r~a=. 45, E65‘? (1938).
`‘L’. 1 Wurst}, T. C. mm, (3. i), E.::c.=.nmn dad 11 C. Morikh-:x:sr-.
`“Optimization 1:1‘ amocigxvs cycics smd :3 cciion of fmmuflalinn fur
`pamnlerai product, Pan H: Effcct uf counts:-ion 9:: pi! and stafiiiizy cf
`ciiasrimfc acid at zxumcim: :cs;‘.pcm:ur¢.s.‘“.i. Pmwmrn .
`Ikrixzaair.
`33(2). ‘E2 (ISIS-’3).
`E13, ‘innciivc Engreflicni Guide,’ 1)h'is§o:: of Drug Erafnrnxztima Ezcsaasrccs.
`Cf>Efi..Fr:n::azja P396.
`
`H.
`
`‘.3.
`
`WE. 51. Na. 4 I Juiy-August 1997
`
`Suppiied by The British Library — "The wmhfs knnwEe<:z'ge"
`
`Astrazeneca Ex. 2088 p. 6