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`
`REVIEW ARTECLE
`
`Excifienis and Their Um E3“: Enjgsiabée Pmdum
`
`$ANBEEP NEMAi R. J. WASHKQHNF and R. J. ERENDEL
`
`xifaliénckmn’n‘ Madimi, lnmrpamz‘ed, Sm‘m Lam's, Mismuri
` .....,.....n.m....
`
`ABSTRACT: {brawl-Him: mfg new drug pm: aw? is‘ffiz exripiéims, rim: have been prcvizmsiy adder! :9 ma apprm‘cd
`g'igi’nz'cmbla prodng may save. plmmrmwufmr‘ mmpmrierc: cfm‘ea'vpx'mnm! Aime mm? cash Tim Physicimis’ Dusk
`Rej‘emiacc :1‘PER} (Hid Hamibsak cm Injecmbfe Ersagx wen: wvigwea‘, meracring a?! éry‘brssmzimz w: ex‘ci‘x’easm The?
`infomisziimz was wamir‘dm‘cd item eight mivé’es, smegflriziszg mcfyient: as I) Soireazrs and Ca-sofvwzf', 2)
`Sofeebiflzing Wetting, Suspwaa’ifig; Emué‘sgfjing m- Writ-hazing {13:13:18, 3} Cimimmg Aggy”; 4} Anz‘z‘mr‘dann' mm”
`Reducing Agems, 5) Am‘hén’crobffl Prasenlraiiva ,. 5) Bagel": am“? pH 1433mm Aggms, 7} {Swims Again;
`Pmieckmm‘ was! Tmu’ciiy Atflr‘zfimm, emf 8} Spesazmi Additives. W’eem mopfizymil£2r
`rah-lies his: freqzreszcy 0f use,
`madam-aria”, am’ (1:: example aft: mmnmrciaf p rod:ch mum}; “rig Sim excflzimf. Excipieum which are fuchm'éd in
`{he £996 FEM ‘fmmive 1:133 'édr'mz Guide, " 52m $50 ma: arppmr in she PER 01' Hmfimoi; (m itg’ccmin‘e Drugs, were
`Eazcimiea' as :2 56:35: my fist
`
`L
`
`intraduciian
`
`liajecia‘nle gaméucis tequirfi- :3 unique farmuimian strniegy.
`Tim formuiaied product has in he swim pymgen Free and,
`in {his 3225:: 0f Sifiililifififi, firm of pafiicuiastc mama: {*x‘efembiy.
`the fermuktiinn wiii {at isnwnic, and damnding am aha mum
`cf administratifln {for instance, fur inns-59mm 0r imam
`cisicrami mums}, antinxitmms am} gsmsewmives may m: be
`aflmveei. For a given 3mg, the risk (if adverse wants is
`higher if it is adminisisred
`zm injécfian versus 1: mm—
`paremem mum The requirement f1): sterility demands that
`Rhea :xcigiefim ha abie m whhsiand autuciaving 0r ether
`sieriiézeaaima pmm—zsseg. These. facmrs Simi: the chums uf
`cxcipicms, avaiizahle :0 ma f‘mmulaimsg.
`Gmémfly, a kmwisfige at" which axcipiemg have been
`fittmad gain by the FDA 0: are: a} rmdy prawn: in at mazkeiesd
`gradual pmvidefi increased assurance In the farmuiamr that
`these axeipiemg win pmbabiy b3 safg is); their Haw (3mg
`pmduch Howavsr, thaws is: m guflmmae. that me: MW drug
`§ mde wiii be. gafc. as exciyigms are camhinm with other
`additives andfor mm a new ding.
`flaming lx‘nfcmgeen
`potenfimmn or synergistic taxis. affects. Raguiamry boflies
`may vigw m; fixsipietii ,fireviausiy app:me in am injccmbk:
`desagc form famra‘bEy‘ and wifi frequently require iesg
`sai’ciy data. A new ziédifive in a {armuimed pmdsm wit:
`always Esquirfi addiiiunai sludics adding :0 the cast and
`iimtsline as" pmduct dweiepmem.
`The puzpmse saf
`ihis paper is to prescm {he varimag
`excigzienis {hat have been inciuded in gin: farmufmion cf
`injccmbie products marketed in 1h: USA. This im‘mmatien
`is In)! rcadii}; c. fia‘iabie. A iiicra‘lure search indicates: mat the
`£115: paper dcaiing with this was publigheé in 1988 {i}.
`Pmductz appmvmi measide fin: US are m; covered in Ehis
`
`
`
`Racciwd October I, 5995.9;9029136 for publicaz'mr: May 16“ 1997’.
`*Authm‘ in who“: cgficspcmjence shut-3x3 be afisfircssmfi: E0. E30); 534-5}. SE.
`Lmiifi. MU. 6.33.3
`
`revixew, Aim smile (Engage forms m: adminisstsnzd grammar-
`:fiiy, such {:5 solutiuns for in§gza£i0n, Qphthalmic or mic
`shops, and manning west: excluded.
`
`Mefihudomgy
`
`Physicians” E335}; Referrwca pubiisémé in 5994 38. BEE {2,
`3}, and Rumbas}; 1m ingcctabifi Drugs {4} war: used as she
`primary gimme of information. Eniriesun aii
`injcmnbir:
`firugs were mammal—32w in mm Exec: wmksheet.
`511051
`gradual was ciassified by Manufacmfes‘, dee mama, Drug
`mama: RC:ch cf Adminésirsafien, SVPILVP, pH of Pmduci,
`Sahara! User}. Seinbiiizingis‘xspendisxg Ageng Presewmive,
`Amiuxifizzm, Cheiator and 0231:: Formuiaiinn Additives.
`The remaking Excci shes: had informmémx an more than
`‘E’Qfl pmducxs, This ifiibrmation was madenscd Emu easyfia—
`maid whims. Each maze has; {new categarimfi band an aim
`primmy Elm-ctian a? excipiem in the fm'muiatinn‘ Far
`exampim gimme; am ciassifieé as. hufl'crs and m: as chain?
`Eng agents, and asam‘baies 2.1m. catsgorimd as zzmismidnnts,
`uiiémugh may cam saw: as buffers. Thia classificmisn syslcm
`was
`an em“ experience in fersnuimian deveinpmem
`and (m aha puéflishmi limmmm. Such simpéificaiiuu amid;
`dupiicatinn (3f enirics and gmvkbs aha ‘aaasjieme wfith
`eaayvm—mzul Sables,
`Same dupEEmfi-m was; uimwidabfic. Tabics VIE am! V111
`szflmszin sums exeipients which may have aiso bear: 13316:} if:
`{he fixsfi. six minim. Whmamr the refarence gmcificaiiy
`dcsignated :2 specific Eumtion m an Erigredfem is was
`re~1i3tcd in Tablas Vii and WEE. For exampia, glycine can be
`used as :3 WEEK m‘ as a siabiiizing (proaccfing) agani.
`Therefmc, ngcfizm is Kim} in Tabizs W and WE. Memyl
`parahen is a pmarvaiive {Table V) hm akin Em a special
`function is: Adrinzawctin EDI“? {summation {Table V113).
`The caneenimiicm (2f axcipifims is listed
`percentang
`weighs by voiusaac {WW} 9-.“ vaiumc by vuium: {Viv}. if 2hr;
`product was 133551} as iyuphflizm or powder. mesa: percemv
`
`
`
` 1535
`
`PDA Jauma! cf Pharmaceufim‘. Safenee & Techsmiugy‘
`
`
`
`Supplied by The British Library - “The wcsrid‘s knowiedgfi"
`
`InnoPharma Exhibit 1102.0001
`
`

`

`
`
`TASKS a
` Soivems and Cmsmvams
`
`
`
`
`
`Frequency
`Range
`Emmgfifi
`2
`2%“??? Viv
`Dfp£}-TESRGS§C:'UIEBD {Ugjgmn} 29% v/v
`3
`733593 wiv
`Depo-Tesinsiemncg‘ (Upjahn) H.695 wiv
`2
`6% WV
`Wmsnfi' {Brit-H31 Myers) 6% \va
`
`24
`Qfivfifl‘fis
`ngmf {FEUESW ' mm Viv
`9
`Liv-533% WW
`Hashim CMW {Cezanamgm 27:39:: wiv
`5
`“"‘
`Ba} in {3113’ {Beams} Dickinscm)
`
`
`
`
`Excipicm
`Bcnzyl Benzsme
`Commisch {3'11
`N‘N Dimerhyiacemnfide
`Eihansi
`Glycerin (Giyacrafi
`?eanm OR
`Pniymhylens giym}
`<1
`PEG
`'3
`PEG 39-3
`2
`PEG 40-3
`5
`FEES 335%
`i
`Pfiwflsfifid 35*
`25
`Progykcn: Giymi
`2
`Sufficwcr :35!
`{i
`Sezxsrrhs (xii
`4
`Suybcan 0i!
`
`Vagcmhie 9%!
`2
`9 NO dam umiiabie‘
`
`G. 355E395
`50-63%
`4‘
`0.345%
`1%
`fil—S’Sé‘fi:
`5—: was
`*
`51.33% wf'v'
`
`’=-
`
`Sacohm‘fiiml 3065mm (Wyeihv Agent} 50%
`VcPesifl? {Brian} I‘vfyers} 6.5% wfv
`Ati‘mnf" {Wyéifivflyarsg}
`Dammit:de {Upjcvhu) 235% \va
`Eihiudgii" (3:1)‘ugc3 H7?)
`Termafiycin Sniuiicm {Roerig} 36.2%
`Liganng ms (Abbmi) mix.-
`Soigana! In; {Scherissg}
`fmmiipidfi{Clinfimmgfié
`‘v’iriéan EM in}.
`Q) {SmFP‘w
`armacwiicafis)
`____.....__.§..s.,.......
`.........._.
`
`
`
`ages wens derived b35645; m: We secsazsiitaiism vzximnc
`commmiy usmi. ’E‘ixe 333E125 Eia‘i {hit range"; of mimmratim;
`um}, typical! m mas: mmmim cancemmfion cmyioyed; and
`cxampias QS' pméucig containing the mcipienL apecificniéy
`these which use extremely Eow nr high cuneemmtims.
`
`Dissmzszsians
`
`Tum: I list 591mm; and cn-soivcnts used in paa‘entemi
`Hedwig. Wait: for injeczisn is the mast ctsmmon scivam but
`_ may he can:an or Subsiituieifi wish a cmmlmzt
`(-3
`imprch the salu‘nimy m stabiliigz as” drugs. {ms Eik:
`snfikchr and suyfiman am 12536 in 10:53} lawman} zsuiriiian
`pmducas when: they serve as a fa: smarts and. as carriers far
`fabsofub}: vitamins, Ethanol and pmpyiene giycei are used,
`either mime m— in cmzabinaziou wish mher soiveratza, in more
`ihzm 53% (if partflic'ai co~seivmzt systems‘ It is surprising to
`3m: {ampykme giym] used more Ui'rcn than pgéyezhyicne
`
`glyccls {P885} in spits: 9f its isighm' rszyomxiciiy and
`hesmcaiyzéazg z-zifams (5, 6). thabiy,1he presenm GI gamma
`{ion 93' perexides in PIECES is :1 méjor Eimimfiism.
`Tami: Ii infiudfis a bread {ragga}! of excipimas wheat:
`funcaim in farmuiatimn mum bum-f E 3: Vismséiy impafiing m
`suspending agents like camxy enemy} 52333151081, smfium
`carbmy methyl eeiiu‘mse, sax-him}. acacia, I’miciozic, hydra-
`{yzed gaimin; {2} Soitsbfiizing, wetting or cmuisifying
`agents; Him Cmmnyham EL, sodium desxmydwiaim P231ysmr»
`basis: 2D 01‘ 83, PEG 4% 9mm nil. PEG {it} cnsmr ma, smist
`dociwa sui ate, kcithin :1)! egg yask phosphaiipid;
`(3}
`. Numimam rmnosiersrate which is added m fixeci (ii in farm
`viscous n; gaHAEike suspmdifig medium. Poiysmbaic SQ is
`me mos: commun and versatile sdubiiizing. waiting and
`emulsifying agesnt.
`Oniy a limited number of GEE-aiming ugflms am axscd in
`yarsntemfi pi‘cducis; {Table HI). ’E‘Emy serve its campicx heavy
`
`
`Exaipicm
`
`.
`
`TABLE {E
`Seiubiiizing, Wetting, Susspending; Emuigifying UrTEfickesfing Agenis
`
`
`quucney
`Rn:ng
`‘1‘ 912
`"2
`Armin
`2%
`E
`Aizimimxm manosimmie
`W:
`4
`“ark-my meihy? ceiiuicsa
`'1 E433???
`E?
`Carhcxy methyi ceiiuiuseg 5chqu
`Sgt—65% wiv
`3
`Cmmcphnm FL“
`6.4% My
`1
`Dcsmycholare sodium
`1.2%
`3
`Egg yaw. pimspholipid
`16% wfv
`i
`Geiming Hydmhymé
`{144.2% m’v
`7
`Lecizhin
`E‘fié- \va
`i
`E‘olymyeshyimed fatty acid
`0.034256
`3:
`paw-mags 531; {mean so)
`MN'véM‘Jfi
`5
`Pmiymrbme 2% (mean '29}
`13.5% w’v
`i
`PEG 4% mafia: ail“
`20% WJV
`1
`Pfii‘i 511mm; (3%“
`050.826 wlv
`,6
`i‘m'idone {Poiyvinyi pyrmiidons)
`am 8% 1.31fo
`I
`Sedium deflecyl Eu} Fair: {Na iauryi guii‘am}:
`
`
`21—50%
`3
`Serbimi
`* Cremephur EL: firm“ 35, prfiycihnxyiaxcd casiw oi}, palymg‘efiiyicnfi 35 casxsmii.
`’3 *‘ PEG 4% caster ml; pnija'myl 4i? task»: m‘i. easier an FEES-4C1, Cmdmm :33, 5:01gag-£65431“: 4E) rasmr is“, mechem CAM E}.
`“P” PEG 6'1} fiydmgcmmfi easier nil; Cmmcmhm RH 61}, hydrogenmed 535m? niE FEE—ESE Promth CAM-6:3
`
`
`Exampie
`Tubng :11?Q Did Tera? { Lederic} 7%
`Srfignnul My?!” {Sehfiring} 2%
`Biciilin"? {Wyeth-Away) 955%
`Lispram Dir-30:3 (TAP), {17331233 \w‘v
`Smufiimmsma‘“ ESandux) 65% wfv
`Fungimma» g’ Srésmi Myers) 0.43 {92: wlv
`immiipidfi {minim} L297.“
`Guzman!” (Merck) 16% wiv
`Diprivufl {Riemann}
`w u
`Aquah’iephymnx {Merck} WE: wiv
`flammfim X {32%. (“"yeihflyersi) 19%
`("321$ij (Abhom [553% wlv
`Munistm‘" {Janswn} “45% Viv
`Pmng (Fujiaaxs'a) 29% wiv
`Sicillisfi‘ (Wyeihjzigyers!) 6.6% m’v
`IPrnfeukinIs (Cetus) 3.133 8% WW
`AYEEKTOS‘QRZXE {Fujisawa} 569% m
`
`m. 51, N0, 4 ; Juiy—~Au§usl 139?
`
`Suppiied by The Bré fish Library ‘ "Tha warid's knowisdge"
`
`
`
`InnoPharma Exhibit 1102.0602
`
`

`

`
`
`TABLE iii
`
`Ghefiafing Aganis
`
`Frmumrzy
`Rang:
`----“
`9
`fi.0}~{§.i% Wydass» (Wyeth.
`Ayersi'} (1.3 $7;- wiv
`{ma-4}. E ‘7» {faicijex‘g’ {Abbati}
`L1,} W6 wiv
`036% Falvizcg' (Leaseriej
`0.2%
`3.94% h'iflgrsevimfi {Reflex}
`(184%
`
`3
`
`H
`
`Excipiem
`Cniciumdisatfium
`EDTA*
`fiis-Ds‘lium BETA
`
`Sudinm ED'I‘A
`
`UNA“
`
`“ Ema 55' Elhfienadiamincteiraflcflic 3::ler
`*9 ETE’A == Dim:yienetriamincpmtaamic acid“. i’cmfiiic mint.
`
`metals and (harem: can imprme the: Efficacy sf aniioxi
`drum or pregamaiives. in our opinion, calcium ED‘l‘A has {m
`advamaga mar teimsadium gait by net wmfihufing smiium
`and mm chaiaiing minivan z"er the. bleed.
`An amiuxiaam as a aim; is sicféned as 311038. camp-wads
`mm mm am as maimng agents at may serve as free x'adicai
`scavengers. Tabie 1‘! summarizes 31m aminxidams. aheir
`{magmacy 0f E353, cmmmatmiinn mugs and ammpiss 0f
`products «swimming mam. Suifiia‘ bisulfiim and mciabismi~
`fits cansmute the: Mammy 0f amiaxidnnm aged in paremcmi
`groducfis despiie gamma} 52mm of ancnmpmiifiziam and
`
`toxicity ("1, S)‘ Buiyiatad 3}}’€§£‘(3;’é}' maisutm huiyiated hydmxy
`when: and {anspyi gzziiam am pa‘imariiy
`in semiinmu
`aqemus vehicics because 9%“ their Law aquseus salubilim
`Asccrhic acidisodium aswrbatc may mm: as an amicxin
`dam, buffer, and chsiating aggm in the 53mg farmuimim.
`Emmy} aim-“301 was: aha mes: autumn an’iimicrubia!
`preservative: wasem in, paremerzfi fermulmiang (Tabie V}.
`This £5: cmazsigiem wiih other airways (9}. Pambms are: :12:
`mm mas: mmmon preegervaaives. Thifly’flifii pmducis had a
`combinmizm cfimazhy} and pmpyi 53-933mm; driver: had only
`methyi, and one bag} smiy’ pmpyi paraben. Thimfii‘fiszfl was
`suzprisingiy mmmcn, Espacialiy
`vacnims, avian fihuagh
`some individuals have sensiiivizy to mitrcurics. Chiemcrcscsi
`is gumomd m be :1 goad pstger‘mfive for parcnzerais. but:
`mar survey did not
`find any exampias of cammercial
`pnxtiamfis mmaining chimmrewl.
`Tame Vi iiszs Sniffers ami chfimicals mad :9 adjusi 1%}: pH
`6f iornmiaiions. flwsphme, sigma; and imagine me the, must
`cemmon bm‘fars used in parenteral predeims, Mano and
`difiihanifiaminis are. added 3:: adjusi pH and farm correspon-‘ju
`ing saits. Hydmgm bromiiig, suifurit: amid‘ banzcne sulfmic
`acfid and mailman: sulfcmic acids are added :0 drugs which
`are bmmide {Seagmiamine Hm,
`I‘iytsscinaa HBr. URL},
`sulfate iNabc‘m, Tmmmyciu wifme. Liliy), Emsyme
`
`TASLE W
`
`Anfinxidams and Reducing; Agenzs
`Range
`REE—£4?) Wis;
`(LL-463% wiv
`(ml-0.66% wr'v
`Gqflfimgufi‘flfiifa wiv
`3.0m ifs—5.3.6390 wlv
`Elfin-D. 15155; \va
`0131691;
`
`
`Exmnpie
`
`
`
`Newca‘imi’? (Simfi—Wmma‘cp) 6.4% wlv
`Vibramycinfi' (fiesrig'fi 4.3% wiv
`A mikin$1 (i3 risml Myers} 0.66% My
`Ag{3525:3159 {Ayn} [1.33%
`Aquamim (Asirsa) {3,83%
`{mitt-3r (31:13 {Khan—EJ01de 93% My
`Nunmrphmfl (Bumnfi 8.155%
`
`
`
`
`Excspiem
`E‘rflgueucy
`Enchant: wuium bi‘éfllfiw
`4
`Aasorbaxc (Sudiu mincm}
`7
`Eisulfite sodium
`218
`Buiylated fzydg‘uxy asiisufe. (REA)
`3
`Butyimed hyflmxy when: (EMT)
`3
`Cyszeinfiijminam BC:
`2
`flimioniis sodium (Na hydmmifils, Na sum
`i
`oxylaic)
`Geniisic acid
`i
`fiemisic mic! cthanoiamins
`3
`Giummaie mmmmfium
`2
`Formaidahyfit,‘ sulfa”:51mm ssdium
`9
`Meiubisuifiec potassium
`E
`Meiabisulfize smiium
`Monotmagiyceml {1his3}3mm};
`Pmpy': gamma
`Sulfim sodium
`‘Thingiycoiai: Stadium
`
`"
`
`6
`2
`“1'
`i
`
`(3.02‘70 WV
`2%
`G. 1 % M»;
`flfifififlfi '95 wfv
`01395:
`0.632"! 91: Wis:
`CI. 3 ~§ %
`{3.82%
`0.05%}{2‘73 wfv
`
`{3.56% wiv
`
`0c! rcoScan“ (MaiiEnd-cmdx)
`Mn‘ufj. 1214’“ {Asia's} 2%
`Varivas‘i‘ (Merck) {13% w v"
`Termmycin Schn‘mn (Remig) {35% wiv
`Vasnxyig‘ {GEam-Wfilmmc} 9.10%
`humping {Dupant} 1% wiv
`Temsmycin Sv'luiian (Rcerig) 1%
`Navaaafi (Racrig)
`Enioni“ (Gamma) 0.2% My
`3:: S~Hflifi3® {Fa-ms,th 0,66% wlw
`
`
`
`TABLE V
`Anthicmbiaf Fmfiewafives
`
`
`
`
`Excipimi
`Benzalkonium flhiofifia
`Banzaxhonium $313042}:
`Einzyi {Limbo}
`Chim‘chumnoi
`m—Ca‘esoi
`Myristyi gmmnzi—piwiinmm mamas
`Famine“ mm‘nyi
`Paman pmpyi
`9222:2431
`'
`2-Phammyeihanoi
`Pheny] aercua‘jc min-ate
`’Yhimcmsa‘.
`
`
`EFL-mummy
`E
`*1
`M
`I?
`3
`2
`51'}
`4i}
`48
`3
`3
`4%
`
`
`Rangss
`8.02% “W
`{3.33}:
`€1,?5-5%
`0.2S-U.5%
`E}. 343,393
`8m 95-»0‘ E r39‘2’a wa‘v
`9.33435 33%
`(mp-0.1%
`0.2‘4}.S%
`{1.53%
`8.83! 9%
`
`{3.333411}: $79
`
`Ceiesmne Sniuspmfi (Echo.er 8.02% wfv
`fimmdryig {Furkc~Dgsva-isj (3.03% velar
`Dimenhydrinaicfi {Staris} 5%
`{iodine phgsghaif: {Wycsh-Ayaisi) 8.5%
`Humw‘opefi‘ {Lifly} {130%
`Dcpmf’mvcmfl {Upjuhn} (5. E6???) wlv
`
`nine“; {finnssanj 0,!
`wiv
`hug
`Xyiocains. wifipint‘phrizae (Agata: 0. E 9;: wiv
`{Suicimara {Rhona I’muiam) (3.5% wiv
`Hawk” {Smishifiinc Ecechsam} {3.553% m";
`Agatha-nits” {Wycth-Aymt} 9.0m "Kc
`
`Asgamw (Upjohn)- 0.0i%
`
` f
`
`_
`
`.3 15%
`
`A
`
`__
`
`
`
`Fiji: Jeuma‘: w. F‘harma
`
`
`ffiliiifi‘ai Scianca & Techrmz'agy
`
`Suppiied by The British Library — "The warfd‘s knswiedge"
`
`
`
`InnoPharma Exhibit 1102.0003
`
`

`

`Tfifiifi W
`Buffers ant! 31H Adjusfing Agents,
`
`Exsipicm
`Example
`Katmai:
`
`Sodium
`Acetic acid
`Glam} acexi‘t acid
`flammanium
`Ammanium hyfimxizia
`
`Miaca‘icin En‘iectinnfi (Sanding
`Miacaicin EnjectiauE {Sand-.32}
`Brem'ibiac Isajm'é'rona’ (Uhnzecia)
`Bumax injeazieng‘ {Racks}
`Tsiosmt injeciimf-‘V {Smifixifilim
`Bentham)
`Tracxi‘um injeciicniv (mamwcazmme)
`Viilium injecgim” {Emile}
`Ccfomn Enjcctirm“ mascara}
`HypeRhmDfl {Bayer}
`
`
`
`DTECrUOHIEQ (Bayer)
`{29273513323 (Gcnzyme)
`Careryme? (Germanic)
`Ccrezymaa‘ (Genzymc)
`Bacifim W” (Racks)
`Quinidimfl/ (Liiiy;
`HepB Sam magm‘m (Merck)
`Ami-:21??? {Immunex}
`Smpfiimnma {BBL}
`Fentenyi ciimzc & flrapafidoi (Astra)
`Emimsc Iaajcmiun?’ {Roberts}
`Librimn injm'sienfl (Roche)
`DHvaf-S Enjatiicn? {Sandmfl
`Tefi‘n mycin ’Sgiu: Ems {Roarig}
`
`353126223 suiffinic acid
`Bantams. Swmm'acid
`Bicarbsnute Sndium
`Czsrhumm Swim“
`‘krzsts:
`Afliii
`Sadium
`Disodium
`Trisodium
`fliciimzmlaminc
`Giumno dclm Bantam
`Giycim
`Hydmchiariu amid
`Hydmgm bromide
`Lactate acini’fiufiium
`Lysine:
`Malta: acid
`Methanesuifmaic mid
`Mmloeihanmamina
`Phosphaze
`Husnegcn’g‘ (fjxgazrgml
`Acid {pismpiim‘ic}
`Monabasic palasxium flaminc Emma‘s-ME {Chm—REE:me
`Monubasie sssfiium”
`Pregnyii‘ {Organsaaa}
`Dibuxic smfiumM
`F‘roiasiinfl' {Bayer}
`Tribasic mfiium
`Symmth {Knoll}!
`Sudium hydmxidc
`Gpiiray‘a {Maiiinckmfii}
`Sulfuric acki
`Nebcin"? {Lilly}
`“Fatima sci dismifum
`Mashergiue: lnjerfiiimfi (Sandra)
`
`'E‘runmlhnmina
`Qpiimy® {Maiiinckmfii}:
`5“ Sodium biphusphasc, Sodium dihydmgan phmphmc m- Nu dihydmgen
`onhfighnsphma,
`'
`** Sadium phosphaic. Bisuéiiism hydwgen phosphate.
`
`{Tmrzrium in}, Atmcum’um besyimc} or mesyime {DRE 4'5
`Injeni‘aon, DIhyda‘Gcrthaminc mcsylate} 531:5. (Human dam:
`iacmnc is used to adjust the pH of iniuidinc glucmmm
`{Léiiy}. B enmate b ufi'er, an: a cunmmmfizm {3f $71.3, is azsaaii in
`Valium Enjcsssiun. CiErates are: comma buffers {has can have:
`a duai mle as shaming agcnis. Lygism and giycine are mine
`36533 which funitfiim :15 buffers ans} staiaifize prnicin and
`pegzid’c fimi‘smtimions~ T {:53 maxim) acids are»
`used as
`lyn-addiiives and may pmvmt mm dmmmmtim Lactam
`anci Emmi: are: eccasienaliy UStii at; flui‘fer systems.
`Tame V?! H.513 additiws which are used as mudify
`nsmniaiity‘ and :13 buiking or iyEI-L‘ryfl ps'oieciive agents.
`Dams»: and sedium chzmidc {ma used mg udjmga mniciiy is:
`an: majm—ity of formulations, Same aamim acids/giycénm
`alanine, hisiidinc, insidazoie, arginim-z, asparagine, aspartic
`acid, are US$38 as. buffing agenm for Iyaphiiizafimx and may
`serve as stahiiizers for ps’omim er geptizics and as baffcrs.
`Mmusncshurides {sicxh‘ir&e, gimme, iacmse). disaccharide
`{smazwsse}c paiyhydrfic aimhnis (inesitai, mannimi, sorhimi);
`giymi (PEG 3353), Psvidone (pfiiyvin’y!pyrmfiidene), and
`- pmieifls {aibumian 3:33am} gm: cummmxiy use-5r:
`an: $31»
`additiveg.
`
`TABLE Vii
`
`
`Buikingfisgants, Pmteciafiis, and "fig-midis; Adjusiom
`Excigsi‘mi
`Maniac
`Albumin
`AIbumin human:
`Angina acids
`Laérginma
`Aspumgma
`L-Aspuztic add
`{Iaicium uhluride
`Citric acid
`Bexirme
`Edam; Ea yam: 512m
`Giuwsr:
`fiiycwin
`Giycisza
`Hifitidine
`
`Exampie
` e m» (Bay-err}
`Biucimfi (Arm)
`Bum.” {Micrgan}
`Hawk” (Sssfiiifififim Eccchmn}
`Aciivaseg (Genentech)
`Tm: BCGE {Oganon}
`Papcid'i‘ {Merck}
`Pimnurgun Enjcminn‘m {\‘v’fymmAycrsQ
`SEHSOI‘CELEEEHJ‘I‘EPFR (A5113)
`Betasemn’fi" (Reflex)
`A :3an (Bunne—E’auhnc Reset)
`Iivsmgam'E (Emmum-US)
`Tics EC :3 (03mm)
`Aégam injéc‘siong {Upjohn}
`Antihamophiiic mum. human
`(Am. Red 12:93:)
`Hm Exam?“ {Aim-3155')
`GarcisStau-rE {Maliinakmdt}
`{Z‘m'srrjesca’E {Uiijohfl}
`Te n‘amyciaa Snluliun'” (Rflerig)
`'E‘ice ECG” {anmmj
`Eisparfi (Merck)
`Bier“ £2123 {Arm}
`Hclixms‘“ (Arman?)
`Viii'i‘fi'flxgt {Merci-z)
`Amman?“ (SE axe-’Weilcome}
`W'EuRhu SD? {Unk’ux}
`Actimmunc” [ficnamccm
`DfimewvmaS‘ {Upjaim}
`*anhcmminx’ (Anthem)
`Pmiass'm’k" {Bayer}
`
`imidazurc
`inositoi
`mciase
`Msgnegissm {him—Ede
`Magnefium warm
`Man nim!
`Pafiyeihylena giycoi 3353C:
`Pciysnzbam 8.1}
`Pomsgium cialmids
`Pavia-am
`Smfium Chimids.
`Stadium succinmc
`Smfium suifaiu
`Smbitoi
`Sucmsez
`
`Special fidfifiives
`
`These miéifives have hem Enciuded in phamua-z-smim}
`femulaiisn m sews: spacific functims (Table VH1). Balm;
`is a summary 9f {ha Specini additives ainng xvii}:
`their
`intended use——
`
`(E) Cafcium glucomtfi injection {Arzaericm Regent) is a
`smuratcd animation (sf 10% wk; talcium d~succ§mrase
`Eetmhyd ms: {3.535% wiv is. addad in prevent cryrsmii-
`zaiic’m dining temperature fluctuatimxs.
`(CZ) Chm: W39 {Cipwflmncm‘ Bayefl mniains izsciic
`am} as. a solubiiizsiug 332m fur aha :aaazibiotic.
`{3) Presmrin Inject} .31“? {Canjtzgamd Egtmgans, Wyezh—
`Ayers: Labs} is. a Eyophfiiized Fromm that mmaim;
`sémeihimnc 20 prevtnt formation of foam during
`recensliéuléon.
`
`=14} Dexamaihasmm aceéam {Daiflitsne DP, Perm,
`Decadmu-LA, March 1333510319.DPEHjsEefiG-EL UAD
`Lahg} and [fiexamcihasme
`phospham (Merck)
`are swaifinbie
`suspensiml at mifiim. These dem-
`mei‘msme formulations mmain mealtime. or crami
`nine
`an aéditive.
`
`(5) Ada‘iamycin R853") {Dexmubicin hydrochloridsa,
`Pharmacia) ramming methyi pant)an 9.2 nugme, i=3
`inflame dissumiiota (USA
`{{5} Emma-1m gamma: (Ergofimins makiazc, Liiiy} cor:—
`Eains 1’}. l 92:1 why} {awaits 5325 33 snitihiiizing agent?
`{3‘} Bxfmdurfin Injectinn"? {Palyesmdinl ghgspmw,
`Wyemfxyersi Lam.)
`Niacimmidie {E235 mgimi}
`
`
`
`V4151, Neat? 1' Jui‘y‘wAug‘Jfit 189?
`
`.169‘
`
`InnoPharma Exhibit 1102.0604
`
`

`

`
`
`Aiuminum ixydnmide
`Aiuminum phcsphaic
`
`Aluminum pmmsium sulfata
`
`Efimirmc‘pmic acid
`Caicium dusacchamm
`
`Capgylntc sadism
`
`8—Chlnrmhmghyliine
`Crcaisine
`Creatinism
`
`y
`
`TABLE VH3
`SmeciaiAddiuves
`
`Excipieni Examgfic
`Huszmn Albumin {American had
`Acetyi irygmphanaia
`Cross}
`Ramszi‘cinam HE“; {Merck}
`Tctzsssusz Tmuiai Adsorbcd”
`(Led-aria)
`TD Adswhed Adi:in
`(Cnnn:mght}
`Emimse‘s’ (313533313)
`Caicium Giucmate {American
`.
`chtm)
`Human Aéémmia {Amc'ricaai Red
`Cross)
`Dimmhydrinntc {Ennis}
`Dalnione E393? (Russ!)
`HM? wnnnc Pimphazic
`(Merck)
`Canny {Mailinckmdi}
`Cnrdimec {Squibb}
`Ergmmm mnlgaigfi‘ (Lilly)
`Aminwihyliimg“ {Abbmt}
`Iinb Ekinasci“ (Pharmaciaj
`Tics BCGQ {Ogamn}
`Cipro EX”) {Bayer}
`Zaiafiex’? (Emacs)
`
`
`
`Binarizaic acid
`Gamma Cycladéxirin
`Emyl Mamie
`Ethyiencdiamins
`1,-Glmamate sedium
`Ema: mnmmium cinema
`Lawn acid
`fiirLaciic and GEycoIEc acid
`capo!ymcr
`Mahastz
`Meglumifie
`Nimsimsmide
`H‘ambm mcii‘ay]
`Melamine
`
`Gamimunafi {Snycfl
`M1131313323333 {Ber-fax}
`fistmcfiaarin“ {Wyeth-Ayamé)
`‘ Adriamycin RQFE {Phammcifl}
`Iawiazmd NPR?“ {Nova
`Noztiié‘s}
`R‘s-“min injcciiosifi‘ (Wycfl’x-
`Aye-mi)
`Cnmpszim injesiimlfi (Srni:§2~
`Kiim Bcccham}
`‘u’ezmgiabulinfi {Apha Them»
`ptufic)
`Sinclaicfi‘ (Arm)
`Lents: Ensuiin‘x {Mm-Q Nardisk}
`
`'
`
`Simcmimne
`
`firm-luau sacchzirin
`
`Ti'iun-bmy} phcsphnic
`
`my: Wiiiehmnd {mew
`
`as a sslubilizing
`mmains nizmimmide.
`
`Hyifieimsaw {Merck} aim
`
`Mumfinum in we form cf aluminum hydroxide,
`aiixmimsm ghflsgfimte m“ aiuminum pmmsium suifase
`is used as aifijxwam in various vaccine: fnmuimimns
`m CHER an increafiafi immufiogenic respansfi.
`Eaiasicfi {(Essereiin magma. Zenaca} is adminis~
`med subcuwnwusiy mierosphems. These spheres
`aw made 01’ Dishing: 21nd giycniic acid copolymer.
`Lupmn Dem: iajfictimfli (TAP) are iyephilinad mi~
`cmsphcres 3f gelatin and giycoliwaczic acid fur
`intramuscular inja-zaizm,
`Gamma cycmdexsrin is used as a stabilizer in
`Cuniimec‘?‘ at a cancsmraiien OFSG 1113mm.
`Sodium empty-{me {sadium Gamma} has antifungal
`pmpmics, but i: is aim used 1-3 imprm'e she stabifity
`of afibumifi ssiuiim against (fleets
`1mm, Albumin
`salutim’: can Em Shani gumicurimaai by heating m 60°C
`far :9 haw-s 3:2 5 .c garments 0f ssdium Capryiate.
`AceéyE ifypmphmms sodium is $1150 added so albu—
`min fermuhtians‘
`{E2} Meggluminc (Nnnmihyigiucamina is; wed as an ex~
`
`
`m"... «Inmvfl
`
`__________gnaw“:
`
`
`‘1
`
`TABLE n:
`List of Excipimm‘om $96 FDA‘EnactEve ingredient Guida"
`Ammnnium sump:
`Banzyi chlorifia
`Suzy; pamben
`Cnidiamide sodium
`Cahcrida} caia‘aum
`Casio; ail
`Calluiosc (nfitmmystufiins)
`Chaieswmi
`Umxychaiic acid
`Dimrizch; acid
`Bicyciohexyl carbmiiimid: _
`Dietisyl amine.
`Di myfiseoyi Eecé‘ahin
`Dimyrianxlyi phosphaiifiyl-
`g‘iycctmi
`Disofznin
`Dutusaie sodium
`Edzsmine
`Exumetazim:
`Champme amiium
`Gluceptale caicium
`Ghzcumnic acid
`Gumisfiine RC}
`Eofélamine HCE
`Lacisbimfit as?
`Luciahin hysimgennted my
`litiufsmiii
`Mcdmfenin
`Mes} rumba £31306
`Madranic acid
`botanic asicfi
`Meihyi
`Meihyi ceiitetasa
`hicihyicm blur:
`NgcmbamuyE-imahcxy m3)!—
`ezhyicnc-giywi 20003—1,2~
`disicarc-yi
`inufiyciroxyclhy‘: pipemzina
`185*?“ ethane sulphonéc acid
`Nimime
`NEW: acid
`(flyquinoiina
`
`Panama (DTP; ,5 caicium
`:résadiurra
`i‘oloxamw £65
`PEG 4995‘
`PEG 6%
`Fciygiazsin
`Palyiacfide
`Poiymycihicnc fatay acié
`Estera
`Palymymhyaeng sorbitan
`msmstemie
`Polyoxyl 3S Castm‘flfi
`Polysur‘baae 4i)
`P‘olys'urbaaa 85
`Emasium hydroxéde
`Potassium phosphate, dibasic
`$0.6qu“ hisuii‘atc
`Smiinm shim-:33:
`Smiiu m hypochiozE-Ii:
`Sudium iodide
`Sodium pymphusgmm:
`Stadium micsaifaze, aahydmus
`Sodium Erinmfaphmphnic
`Sorbimr: mtsmapaflmiiaaa
`Simmons chlmidn
`Srm‘mnus fl amide.
`Siannous’ {amaze
`3mg}:
`Suzcinm
`Succinic acid
`Suifiums acid
`Teimlzis “diagram-alanin-
`mow-2mm:\‘ybpmpamcz
`ciwpper (l) Tt‘.
`T‘Eaiawximic acid
`Triihhznximic avid
`Useu
`Zinc swam:
`Zinc c'niorizic
`Zinc wide
`2mm hemrmk‘. said
`PEG vegetabk mi
`
`rm. m I»;-...z
`
`(14}
`
`cipiem and m fem: in-sx‘m 531:, Far exampieg dia-
`trimic acid, an X~my contrast agem, is mere 3:213:26
`when aum-Eavad as magiumine sash man :15 sodium
`sai: (1}). Mfigiumine is sfisn added in Magnawisiw, a
`magnmic {93071331 *5 mums: agent, furmulméora.
`Surprisingly, Smfitim saccharine is used in Steiazine®
`and (fompazinafi‘ §hrmuiatiofisg our guess; is thaw it
`searvas as a smbiiizar mad taniciiy adjugier.
`’E‘x‘i~:2-E3uty} phesphefie is presem as
`cacipiem in
`human immune: glabufiin saiutian (Vcnogioéauiifl).
`Kiss exact f’umriiun in {he {Qmmimian 55 (mi gnu-om,
`but it may same as a fitavenging agent
`was: Wine:me factor is 11333 H) ambiiizc recembi»
`mm aniihcmbphifia factor {Siocimqu}.
`Mama's firms as a: militia; adjusier and siabiiim' is;
`Emmi: ma gimbuiir: Ranzmimifin {Gamimme N53“).
`Epsiinn amino capmic acid {flaming lmmnoic mid}
`is men! as a smbiiizer in anisgrepiase {Emiams injec»
`tizmfl}.
`' Zinc and mammisx'c have {men addfld m- iasuiin in
`{mm corrzpiexes and central aha filirfififlil ofaclien.
`
`$36
`
`
`
`PEA quma! a? F‘harmaceuificai science & Technoiogy
`
`
`
`
`Suppfiad by The Swish Library ~ "The woréd‘s kncwiedga“
`
`
`
`InnoPharma Exhibit 1102.0005
`
`

`

`Recently, FDA has pubiishei “Inactive ingredient Guids’
`which £3315 ail 1h: cxcipisms in aiphaheza‘mi (mien Each
`irsgrfidicni
`i5 {OHDWEd E3)" EEK {flute 03‘ miminis‘nafiiufl (far
`cmmpie. 53’, 8371?} and, in some 13515335‘ EEK? rmgc GfCOnCCIIiI’EE"
`tier: mud in ms agpmvcd dmg pmdgct, nggygf’ this gig;
`dues rm: provide {3m name of cczmancrciai 3310(3me 9mm
`spending in each excipiant. Tahie IX is a summasy Sf aii Ex;
`-s.
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`Imam: iflgrgd'fiT
`(smzie, bu: (is nomppear m Film at I‘Eandhmk on anfictabuz
`Drugs.
`
`-
`
`Réfemncea
`
`*
`
`‘
`
`.
`
`n KW, chdan‘é S.X’éikbxfi'sg)’.f:Lysi§ofhunmnred Maw] mfilsin 1?]:
`.
`,.
`9‘? Wms WWW“:
`J1 Werner, m. nah-mg" 399L551
`. G. A. Human and Hsimng 55mg. “ii-'53 ohm ire—vim mode} for 392$:
`fisstgmcm oi'n‘wscic (inning? {rm-5i inimlnuscafiar injectinng: Ina-vine:
`Iggcgizciabmiy wxih mixed saimu syszmsx
`‘ L W. Mung“, Afflulssain‘ ané} R. Eiiuus, " :ccauairmary mu: 1‘0: m
`22” hisufliw in pharmamufical rannnhmm" J, lerm. 5:2,, mm
`??5(§977}.
`. Lasmmser, “’Sun‘umns acid snixs asphazmuscmim!aufimfidam.”
`,1; {pg-mm 51“; 59.513339; 1 gym},
`. R fiabbah. "Th: use ofprescn'arivcs in enmmndiai anisies," manna»
`rcpefifl' Hiram. 2R4; 2595 g H 996),
`Knufsmnn. E. Mjiohmztmki, E.
`_ T. i, Ekmmam. M. A. Silly-me.
`fi’hmia}; ism} R, P. Fudgc. “Dissulmioza times (a? adfismyciza and
`ndrfiamycin RDF,” Am. .5. Hagan Pharmq 45, E66"! {1938}.
`Y. 1 Wang.
`'E’. C. Dam, G, E}, Lag-5mm, Md 11 (Y. Monkh-ausfi,
`“fipefmimtion 0f alzaociavs cycfcs and :i
`:t’ian 0f furnxuimisn for
`parenterai product, Pant H: Effect 9! caumer’i-m on p3! and stabiiiry 0f
`diasrimfc acid at uchiave :empcmwrefi.” J. Pm'wia‘er.
`Remain
`33(2). 72 mats).
`‘Innmis'cl‘n‘gwflicm Quid-cf Division of Drug Enfarmgfim: Ecscumg,
`mm January 139:3.
`
`Suppiied by Thfs British Library — "The wnrid’s knawkzdge“
`
`i. “:1 J“ Wang and R. a. chni. “Rm-Ian; 03‘ examich and nm: in:
`purmmm! pmdmcas mad in {he Uriihzd 3:211:53“ J, Paryrtlrr: Sci.
`'I‘ccfi~
`mi“ 34(6L4fil $3938}.
`2. Physi “ans’ Dusk Rcfmcasm, ed‘ 48, 1994‘
`‘
`3. thgicmns‘ Des}; Refescrzce. ed, M, i995.
`4‘ L A. TtiSSCi, “Handhwk am Enjcura‘cin Gangs," w. 3; Ametimn
`fimiety m" Hit-53333! Pimmacism. inc, 1994.
`
`Vc-L 51. Na. 4 I Junk-Angus! 1997
`
`InnoPharma Exhibit 11020606
`
`