`
`
`
`_
`
`.
`
`....-....,..‘.-,»-wV~,.~».
`
`....,...
`
`RE'V:’EW ARTECLE
`
`Excéfienis and Their use in Enjeciabée Pmdufis
`
`SANDEEP NEMA2 E. J. WASHKUHN, and R. .3. ESRENDEL
`
`flzialffirzcicrqxcif Ma‘.ria‘cai, lrtmrpargwfed, Suits! Lr:m':r, Misxariri
` ............_..........
`
`A£?3TRr=lC?': :"‘ors12m':m'z2ia afa new drug p.nr;v:.<’e:'c? wfriz excigafarrrs, rim: 1:m*e beet: prcw'z,wz:5E_3' azisiezf :9 ma (:p_,m'm‘cd
`:'.*:f:.?‘z:eaiH!e ;2ro:.’¢’ucr, mrg‘ szzve ;>Im:vsrm*azs.'£ca." mxxrpmrierc: cfm*ea'0g.I-:'::c::m1 Ii-.'::.9 fists? e:a.s:". Tires P13_}*sa'c§mi:»" Desk
`féejkreiacc {PER} Mia‘ iiariribszgf; ma Ixzject-;:':'2§c flrsagz: 3:*»2rw::~es*ie:1‘e:.r‘, esscfmcrireg .:?!.<‘ érgfarssszsiknz an e.:‘c:'*2r’eas:.s( ?":’:«.?
`i:2_for::::2ia1>.2z wars c.';::m:'f(f:::‘a:¥ 592:9 eight Msivfes, mregavrizissg mc:’_ru':2:zt: as I) Soireazrs mm’ Cr)-.'so.’s~c=2z:'. 2)
`So£e:bEIEzi::g, Wetting, :1’usp¢~:az:’.-':ag, E!r.'1ifx{fj.‘iI:g ar Tirfclmzzfsvg :1g:.’.rm:, 3} Cizeizzrirzg Agerzu, 4} .4.z2i£c.r.vr‘:.<’zz:rJs' mm’
`Redracizsg Agems, 5) A:m'm:’cro:‘>:"r:! £’r»;=sen!xai:'va _. 5) Bagfeaw am“? pa‘! »’ir2’jae:rif.I:g zfigsmrs,
`?} Iizsikfasg Agcam.',
`Pm‘:‘ec!-37:37.5, aim‘ ?‘mz€z.-iiy A:{r‘:;s:m'.?_. mm‘ 8,} a5';.=e:'a:.=(:§ .»‘3.:Ia'I!is*e.§. Wéeu? appi‘i:.~cr£zfe,
`ref:-{es ifs: freqiie?m:‘_)* qf me,
`csarraeam-axiarr, am’ mt amzrzgzlc afar r_"a§§£::m!'L‘i:'!§' ;: rocfsrc: sic,-:::z:':e§.~;-_:; she a.m“p:'.m£'. Exc.z}-z£e::z.s w:‘::‘a~a"r :1 re fzzcfizszféd in
`{lie £996 F:').4 ‘;'.uz2m'v.:»* lug: 'e":d:'e:ez Gzcizfe, ’ Em: sic: ma: ¢T,I3;Ir'.czr in she .r"39f«3 or F:'m?.'f£>(s03: rm Izzjccirzizfe Drugs, mm:
`Eazcimied as as :«‘€{3:f.‘.5'{J5'!?
`iisf.
`
` L
`
`immdutziian
`
`lzajeciable produczs requirs. 23 urniqac fcrmuimitan s*:m:‘egy.
`The formuiaied pz'0d\3c{ has to ba sieriém pyr::>gc::1 Free and,
`in the 52:25:: uf Si(?§U1[§(3\'I2€~, {rm of particuieatc matter. i*z‘e:"em3>}j,v.
`the farznukziion ml: {at isawnic, and dcpiinding am she smstc
`cf acizniaxistraiiaza {for instance,
`1&1’
`ieitra-spizmi ur imrau
`cisierami z‘0uLes}, antinxiaézmis ant} preservatives army not be
`aiinweei, For :1 given -firug, the risk of £!£}‘.*e:’sz2 events is
`higher if it is adminiaisred
`am ‘ifijfitclitm versus a t‘».s)fi—
`parenierai rc:-ui:.Ti1e mquirexixent Em‘ s1erili:§,' demands that
`me e:<a:i_{sients; ha able to wiihstzmsl auiucziaving er other
`sieriiizeaaimz pr<rs:s-:5;se§. These. factors; Sinai: the chem: uf
`cxcipicnisa :w;3.‘:§:a§>1e so me €‘ermuia:u::«;.
`Gamiraliy,
`krsuwisaige of which axcipiente; Emir: been
`Kktalwd safe by the ITIA or 53K‘f5 all rztzaaiy present in at marizeiesci
`pmsmezi gJI'(I~Vi({2‘:$ increased assurance In the farrnuiater that
`these excigaierrzs win prnbailiy be saft: fa): their mzw drug
`product. Hcrwev:-.r, there. is: us: gtinramtce. that me: nsw drug
`pr-.‘.)dL‘:a:t wiii be. safce as &:<a:i§si£ms; are cmnhinctci with other
`adsiitiws cmdfor Wm:
`:1 naxv dang. crcaaiing Iaxafcreesssasxx
`poteniizuion or synergistic mxir: cffccts. ReguIaaa.ory hcaziies
`may view an axsipiexsa gzwviausiy amsmvcd in am injccsabk‘.
`desaggc form f:3mr::b§y, and xx/£13 frequemiy reqzsirss iesg
`saékziy data. A new 2:-:§c:§§§§v.e. in :2 §'m'r:mEr:ueI1 pm(§uc': wili
`always :‘equ§r:: ssddiiisanai shzdics aciding to the cast and
`simtaline (x-E’ gsrmiasct i§:3‘a‘t:§()p£E1EP&{.
`The purpmst: mi‘
`ihis paper is to present Elie varimaa
`excigzienis that have been Enciuded in we fermufaiion cf
`injézcsazbie prociucts marketed in the IECA. This infmmatien
`is me): €<!:‘.(.§i§};'
`:w:':iI=abie. A liieraaiure search indicates mat me
`ha: paper dcaiiiagg with this waxs pL:h}is;E1ed in 1988 Cf).
`Ps‘OdEi<:€.=; apprnveii omssidét ‘JV: US are HG! ‘c0'«'a‘.3‘£:s'§ in Ehis
`
`
`
`ifn 199?.
`Rccciwd October I, E99£S.Acc»:g>1cd for pmblicazinru E\€:.y
`~‘-Auzha: in whom Cfirrcspcnzfience simuixfi be zxris.‘-risssirciz E0. E30); 5343. SE.
`L-mm}. MU. 6.3¥3o$
`
`review. A159. smile dusags forms mt administcred gxasemexn
`aiiy,
`s:u::i1 5:5 solutiuns far ia~.r§g.ea:icm, Qpixtlxalnmic or (am:
`shops, and n-':nimc:'1ts were exsfiuaied.
`
`Mefihudoingy
`
`Physicians’ E3353: Rei"e:r¢ncr: pubiishefi in E994 3c‘. 1595 {Z
`3}, and Hzxnsjisosi; on ingcctzabie: Drugs {4} wars: Laser} as she
`primary xcmrce of Enfmmatéxm. Eniriesmi £115
`injcs:mi:-Es:
`airugs wen‘:
`.=.s3mm:-.r3z.e<§
`in rm Exec} wnr§::s1*1eeL 3311051
`pzcsduci was ciassifiecl by Munu€;1cm{'es‘, Trade mama, Drug
`mama, Roum ef .{1.dmin§:;1rsa1.i:m, S‘»’Pa’L\’§’, pH of Pmdutri,
`Sniwant Um}, Soiubiiiziragisusysendisxg Agenn E"’mserv:eeive,
`Antitsxifizaazt, Cézeiator and 0211:: Famnuizaiicrn Additives.
`The rsseaising Excei shes: had infunmlimw an more than
`‘?(}{3 preducis. This its?’-csrxsmtixm was mmdenracxi Emu a:asy~X-::-
`mead tahiess. Each mhie has; {seen categorized based cm we
`gzrimzaxjx
`fxm-ctisn (sf ezxcipiem in the fmmuiaiitm. For
`exzampic, citraies we cfiassifieé as hasflhrs and nm as cixszicw
`‘mg agents, and aascxarimies um categozimd as z::1iis3,xi(irm.ts,
`uiiémugh may cam sewn as bu§?ex‘s. '1"E':i5 classificaiicm syslcm
`wszs
`mi Qur csxptsriemtse in feranuimim dsweinpmcnt
`and (an aha puéziisfsa-xii
`liits-,r:3mr:.=.. Such simpéiiiczaiima amids
`chxpiirsation (sf enirics zmci’ pnwizisas aha ‘azadiessc-2 with
`E335]!-v[<J—i\f:3xJ Eabics,
`Same dupfiicmf-cm was uzmvoidabfie. Tabiets VIE and "Vii!
`smzxtszin szume excipients which may Emve aiso been Ei$I»':‘:i its
`me fixsai six rabies.
`‘€s:'E:e.naw:r
`the reébrence specificaiiy
`dcsignateti
`es specific Eur-mica: $0 an Ersgrediem is was
`re-1:31:42? in Tilbltifi Vii and WEE. For example, glycine C:-4:518
`used as :: buffer {pr
`:33; a sfiabiiissing (prosecfing)
`zzggeani.
`'1‘§~.en::£':.m:, gwcfizm is listszi in Thbizs Vi amd V11.
`I»’!:::h3-'1
`parahen is :: pmervaiive {Table V) 131:‘: am Em :1 special
`function in Adrinzamtizz EDI”? fcnnuiatioxx {’1‘ab1:: viii).
`The conazenimxiicxn €21" axcipifinis is listed
`pm'cen§agcs
`xvciglxs by miusaac (~m’v} 0-.“ voiumc by voiuma iv.-5v). if aha‘.
`pnzdmi was iisiczj as iyuphflizezi or powder. ihessa percem»
`
`
`
` “ESE
`
`FDA .3-Lmma! of Emarmaseuiicsai 3c.Een.;-.e. 3‘ 3‘.~5;;g-,5-,;_3gg.,;_;§;~
`
`Supplied £33! The British Library - "The wcsrhfs kmwiairdge"
`
`TFF?FAFF?F«F«LTFgLTi::::::::»L::V;;::::::4;;:;:;:::::i:1:::::::::::::::;;.j:%%L:;;:;;W.¢,MW%,_T4
`
`
`
`|nnoPharma Exhibit 1102.0001
`
`

`

`TABLE 5
`Esoivenls and Cmsosvanis
`.................u
`
`
`‘
`Frequency
`Range
`Emxlzglia
`2
`?.{‘a‘_’/fa Viv
`Dry-2}-Tasiastcrunefi :jU;:__iuhn) 20% v/v
`3
`73.6% wiv
`Depo~Tes1<1si+2ronc‘3*‘ (Ugzjahn) ?3.6‘P£2 wfv
`2
`6% W12»
`V$.‘zm9n5'(Bri*-‘A31Myt:IS~}59fr wfv
`
`24
`f.L£-8G‘;'3
`}"ragr;x1-“*9 {Fa1_pr;"'
`' }8E3% Viv
`9
`3.5--73% wa"v'
`Muizitcsz CMW iiizazaxxaxughty 70% wiv
`E
`“-“
`‘Ba! in 313133’ {Heston Dicicinscaafl
`
`
`
`.E§r:n;ayl Eenmairz
`Coiifiiisccd {B11
`NN Di111e:?1yEs2cetan1§:Ee
`Eihansi
`Glyccréss ((3i3I'L“~t‘-Y-’J1'.‘#
`?em'2m GEE
`Pa:i3.'ct!1_g<l.=:r2.*: giycssi
`<1
`PEG
`'3
`PESIG 39%
`2
`PEG 40-53
`5
`}‘:‘'LS 3355.}
`f
`Exfifififlsfifiii *3“
`25
`E‘rog:vyk=nc Giymi
`2
`Szzffimvcr :35!
`6
`Sezxsme (xii
`4
`Saybcan ma
`
`Vagcaahie -mi!
`2
`* Ha dzsm uvaiiabis.
`
`Sscolxrgafiizai scdiatm (Wymhv A3‘:-m::'; 50%
`G. 3543E".>%
`\"cP::sitI1’*‘ 1:Hriatu} I‘v‘{yé2i”:s} 6."_i‘I’:- wh-
`50-65%
`!§.tivr:n’5" {k‘»’y&i§1~.Ay::r35}
`4‘
`Z)s:p:;~IVfc:s§mI9 ifU3':jcvE111) 2.95% wfi’
`0.3»-3%
`Eiildmkpii“ ($;g_§‘u;._-,.::) H7?)
`V70
`Termafiycin Sniuaicm {Rocrig} 'I5.2%
`{?.?.—?'5.2%
`Lipasgm ms (Abbmi) £922..
`54 we
`Soigzmal In; ificheriszg}
`3
`fniraiigsiiiflf.{C'!§n_u‘r:)2€3%
`5..2:3% wiv
`’=
`‘v'Et§§an EM En}? {Stu'F?fi::rznru;euz§-taxis)
`-
`_. ?m.._.wm.........._.
`
`
`
`ages wens derived basesf; 0:: we secfiazsiitesiisyn vzxhxmc
`cmnmoniy urstsni. դԤ3c mhics Eisi Ԏhit mngra of cmascntratimz
`tam}, typical! 0: mast mmmma cancenmltion cmyioyed, and
`cmmpkss Q!" pmaéucis crmmirsing the §:.x:c1'pi.-':nL éspecificniiy
`Ehcma which use extremely Eow :2: high ciznceniratinns.
`
`Disgmxszsizms
`
`Tubic I list sulvszmsz maxi ca-soivcnts nsszd in ;':zi3‘er".tt‘.£‘-:33
`products. Water for injéesrtiesn is the mast ccmmnen ssivttnt but
`_ma}'
`fir: cambinezi or subsiitunzfi wish 3 cfl~s~I3}vs2:n$
`(-3
`improve zinc saluhifiay er s.ta1b':}i132 ms” dmgs. {Eds ask:
`siafiknvszr anti suybczm am messed in amiss} }3;;am11£&E;=3 zauimizzn
`pmducas Mxem they serve .15 :1 fan: saurce anzfi :15 Ci1IfE€.fi'S far
`£":1t«s;cE:.:b}c vitamins. Bshzmcai. and propyiene gfiycsi are used,
`either shims: er in cczzzahinaiiotz with mixer soiveratza, in rm>ra
`iZ‘:z1sa5{P% (sf pzarcnicmi ::o~seEv~::s:t systems. It is surpaising to
`3:2: garagxylessse giyml used mm: (men than p0Ey£§hy3€r:e
`
`giyccls {P585} in spin: of its Esighetr zszyomxiciiy and
`hesancaiyzézzg z-2§3f"ec1s-(S, 6). PI{:hL"sbiy,1h:’: gmsenrcaz car gamma
`{ion :33’ pemxides in PIECES is :1 xra;§jc>r}i311i€:Afiis>n.
`Tabic Ii insiudas :2 bread <:ata_g<saj.' of excipiezaas whcszzs
`funcii-Dn in fcmnuiatiasn ceuizfi but-——{ E 3: Vismséiy impariintg ar
`suspending agezits like ca:bz3>;y mctiayi czeiiuixm, scwfium
`carézoxy methyl eciiasiose, sorhimi. acacia, I’:I1\iic§¢)E3L’,E1_‘,‘~'(§1'(‘a-
`I-yzed g-aialin; {2} Solasbiéizing, wearing or cmuisifying
`zzgems; Him ifreawinphem 5-EL, soziium de::~;miyd:s3Ez1ie. Pi31_‘}.‘SCii‘»
`bask: 20 or 80, PEG 4% Castor nii. PEG iii} CHSEGI‘ ma, smiimn
`dodeayi sui ate,
`lecithin -1): egg ycsik ph-xasphcdipidg (3)
`. Aiumimam rmrsosaersrate which is added to fixcci oil in form
`viscous Q}? gs:HiE<e .’$':J5pi27FEi}i2“:g mcdE::m, Poiysoxbaic Si} is
`me mos: cmnmun and versatile smutaiiizeing. =.-mating and
`emulsifying ngesnt.
`Qniy :3 limited number of ch-elaiing ug::n%s am axscd in
`parsnterai pmdu.c&s; {Tabie HI). Timy serve its wmpicx heavy
`
`
`Exazipkzsii
`
`.
`
`TABLE {E
`Smiubiiizing, Wetting, Su:spem.r;':'rrg;. Emuigifying UrT§‘.ir.:kee1Fng Aggenis
`
`
`Frcsgucmzy
`Range
`?‘“/‘a
`1'!
`Aracizz
`2%
`E
`A2L:m§nLx:n sraonosscmaie
`W:
`4
`"ark-:.a:4y math;-E ceiiaaicsa
`'1E--{}.?'§‘?E.~
`E?
`Carhcxy methyi ceiiuiziseg sodium
`.if5—-55% W.-"V
`3
`Cmznopimra EU‘
`$19.:-WE» win:
`1
`Dcsoxycholare sosiiuzn
`1.2%
`3
`Egg yzxéfi. pimspholipid
`16% wfv
`E
`Geiazfin, Hydrulzyeafi
`J*.»’£~i .2875: \w"v
`7'
`Letrilhin
`}‘€5- wfv
`E
`Palyozzyasshyiateci may amid
`€3.03-32%
`3:
`£"0§y.9z':.ri:a%e 813 (Ywcen 8(3)
`ilfiiv-(}.4‘Jé
`5
`Prnlysurbate 2% (’F‘v.ee:x1 Z9}
`13.5% WV
`1
`PEG 45} cmsiar mil“
`20% wlv
`I
`Pfiéfi 5% Casio; rs§1***
`0.5-—().€:l% wlv
`,6
`i‘<widm:£-. {Po!yvin3'i gsyrraiirions)
`EM}? 3% w,*‘*.-'
`I
`Smiium dmfecyi st;§E‘:1iI:{I‘-1;: iauryi 5uii‘z‘::::}:
`
`
`2?-50%
`3
`Surbitr:-E
`* Crcmephur EL: fircxtzvs 35, gsrsiyciimxyigucd casaavr oi}, ,:ul5':>.*{3‘€E3iy§cn<: 35 casxczmii.
`" *‘ PEG -13 caster 0-E; pc>33'Ux§'l «iii t::st«:~: -xii. easier ad ‘FGE-U}. Cmd~m:e =38, ;m1;;'::<_s--.«t§xyE.~.ms 40 rasmr ail. Pmmchem CA4 0-.
`‘PW PECS §‘{3i'l3~'1l.fQgCiTfli’£!I;i £::1s:orui1; C‘~.'cm:1ph-'3: RH 61}, h;»'drogen;sied ;:as£cse' nifl §r‘£“)‘t7.—-SD. P1‘m:;r.“?:L‘r11 CA’éi-6:3»
`
`
`Ex-amgxie
`':"a:hr,'rcuIi’n Ofd Twat? {Lefieric} 7%
`Sgzlgnzmi ‘a‘:aj."5‘ {Schcringfl 2%
`Bi-:i§lin"3 {\Vye:h-A3:::*s.t) 43.55%
`LBpi’(ié': L‘.?:.~_+;r:-:3 (TAP) {i.7.‘S*.7Ea wfv
`S::rs:§i:1‘.smt=3a1° ES;:ndu;c) fiS% wfv
`Fungizciznc” s’ Srésiai Myers) 0.43 E92: wlv
`1.-‘limiipiiifi (C1in€e<:} E.2%
`€.Tor£=.1m-.3‘
`(.’\1<:r¢.‘§E) 16% wiv
`Dibprivuxfi’ {Beasts}
`w u
`AquaI\’ieph§.:m239 Afimercla) WE: xv,-‘v
`£'_T£3a'd;m::<m3 X {.‘.'fi“. (R-'yeih~Ayers.i) 10%
`C':z1x:ije.:;"7° {Abhom fi.d".?:'.~ wlv
`I‘-'§unist:!i5" {.F:ms5cn} 13.5% VA‘
`Pru-g:';1§"> (Fujiaawa) 29% wiv
`Bficillisxfi‘ (wyeii:-Ayers!) 5.6% wiv
`Prnfeukirfii (Cetus) {L133 8% WV
`Ariatrespazzxfi {Fuj§sawa) 5G‘-3'52 vim!
`
`V93. 5*, No. 4 : my-—Au§us1 199?
`
`Suppiied by The Bré fish Limary - "The: warid“s Emowiedg,e"
`
`|nnoPharma Exhibit 11020602
`
`

`

`
`
`mxicity £3’, 8). Esmyiatad §‘.yt3s‘(3;vé}' zmisufiza, Lmiyiatzzd E1)-dzmzy
`wiucne and gmspyi gzziiam arc primariiy
`in stimiimm
`aqisemxs vehixzhzs beczmse of their Law aquceus s433u.i3E1E4§2
`Ascorbic acidisodium asccrbatc may serve as an antiexin
`dant, §mi”r'er, am! chsiating agent in the Sam: farmuiaiien.
`Benrgxi alccshoi
`swan: aha mos: aummtm smiinaicrxzbiai
`presevmiivv: pisses: in parr:mera§ it-rm:1L'xEicms (Tabie V}.
`"ihits Es: cmazsigaem wiih ether suwrsys (9). Pambams are :12:
`maxi most common pre:~:erv:aaive:';. 'FE':iz1._y-nine. prvaducis had a
`szombinzziixm ofimazhyl and pmpyi pamhens; driver: had (swig:
`methyi, and one hat} smiy propyi pamben, Thimemsai was
`suzprisinggiy cc-mmcm, sspaciaiiy
`vaccinccs, ezven fihuzsgh
`some individuzzis have §€:”1.‘3iiEViEy to mitrcmics. Chierocrcscsi
`is gurperccd to be :1 good gmzservaiivc for pzrrcnzerztis. but
`mar survey did not
`find any axanlpisas of e:mmnerci:11
`pnxian-:33 (:cmtai:'1ing chi-:Jmc1'esu:1.
`Table Vi Eiszs hufikrs ami chamicsals us:-.cE in adjust 1%}: pH
`235 iorzmsiaiions. ?hfi:Spl‘.fl1€=, cixratsz, and acetate use the must
`common buiflwrs used in parenteral pmdeiczs, Mono and
`déathanixiauzinzs are added 3%: acijust pH ans’ firm cortespor:-5-1
`irsg saits. Hydm-gen bmsnixizz, suifuriz: amid. bsnzcnc: sulfmic
`zn::§:i and mailman: sulfcsnic acids are added :9 drugs which
`are ‘uremia:
`{Sc(ag)c:r§2zmi3*.e H83’, Hycscinaa HBr. UDL},
`:'-.41xEE';xie
`iifiebcin, Tmmmyciu suifate, Liliyj,
`‘m:sy.E?-.16.:
`
`‘FABLE iii
`Gflsfiafing f-xgania
`
`Frnq:a£:r:r:5'
`Range
`0
`9
`!l}.0}~{B.i€7o Wydasc’9{Wyo.i1:~
`Aycrsi} 0.} ‘Yo wiv
`ifaicijexfi’ {Abbott}
`0.1%‘/E» wiv
`F01vizc5' (Le:§crE::j
`0,2‘.Tu
`Es'!agrse\'i5i?° ffiierfrsx}
`0,6493
`
`0.{}i-3}. E V;
`
`0n3:fl9‘a
`
`i‘.4.~'.}—§%
`
`3
`
`H
`
`
`
`-----‘E;+:5-pieni “
`Cnisiurzuiisasiiuzn
`EDTA*
`Iéismiixzm EDTA
`
`Sudinm ED'§}"\
`
`1T>'i“§’A*"‘
`
`“ E£)“i‘A =—'-' En‘:-.Eenediarrxincterraaccric acid?
`*9 EETPA == Disrihylenetriamincpcntaaccxic m:id'.?cni¢1§c ztcinfi.
`
`metals and iixeremzt: can §r.regx:’;ves the efflcacy sf aniioxi
`dams or pres;:A.rv:2iivaas. in our opinion, calcium EDTA has gm
`advanaage: «aver teirascxiium saii’. by me: st-nnzzflz-.m‘n§; szxiium
`and net ciasiaiizig caicimn mam the. hilmxi.
`Ar: amiuxizialns as: :3 aim‘. is siefincd .-as 33:93:: cozrmp-ouneis
`mm man 2221 as mducisag agezuts strr may starve as f1‘€::3 rauiicai
`Eéiléivenggizrs. Tabie IV summarizes the anzioxidams. aheir
`fmagueacy cf E353, cosacesairaziinzu rzuxgc: and azuzmgzlcs of
`products xtomnining mm. Suifiia‘ bisuifiec, and m-c§abisuI~
`fits iIOI1§fi§UEr;3£hii I‘£1EljI)§'i§§r‘ of amirsxidants aged in pzsremcrai
`gsrodilcfis aiespiie ':~<;‘:vcml smart: of azacoznpatiixiiiaicg and
`
`TAESLE W
`
`Anzinxiciants and Redunia"-.5; Agen2s
`
`
`F.'x<:§p$em
`Frfi-:;1:ex:cy
`Range
`Exmxxpiss.
`
`J’;-;.céun':. :~;~0Ll’:um bisuiiitzz
`Assmrbaxe. isudiurssfaciafi}
`Eisuifite sodium
`?3\:SyI:.-ted fsgidnzsxy aszfisufe: (REA)
`Butyiale-xi hydranxy icizaene (EMT)
`Cysz-2i n:‘Cys'1£:in::re HQ:
`1.?-ithimxias sodiuan (Na Enydrmuifile, Na suif»
`ox},-late)
`Gcniisic acid
`fiemisic acid ethanofiamins
`Giitxtamate nxtrrmscsciiism
`Fnrma3deE2yfi¢ sulfcsxyfimu ssdium
`Evfleiuhisuifiec potassium
`Meiabisulfiie sotiium
`Mmothmgiyc-;=rea\ ("Em-3g§;.'ct:rc~!,l
`Pmpgi‘: galizm
`Sui 58:: sodium
`
`‘Thingiycoiaia sodium
`
`_
`
`4
`7
`28
`3
`3
`2
`i
`
`E
`3
`2
`9
`3
`2-’?
`6
`2
`1'
`
`E
`
`E3.?,«-0.4‘/‘a wfv
`0.3-4.8% w.r‘v
`€U3E‘.«-0.65-’3E wfv
`0.60028--0J33% w,I'v
`€}.0{Bi
`l€:-5}.(}3€Ic- wlv
`C%.I)7--0.151% wfv
`011091;
`
`Novmaincfi? (380013-WlfiiEii‘Gp) €}.=§‘.7n win:
`'v'ibr;xmy::'ir:’~’i' ifioerigl 4.3% wiv
`Amikin” tfirisml .l\’Iym'5} 0.66% wfv
`!\qu::sA3P"‘ {.1—’*.».:::3‘:1} 0.03%
`A:ga.=as§aI19(AsErsa) 0,03%
`{xcmzr £3213 {E{5\0ne—Pe11!nx1c}9.E% wiv
`Nu:'r:orpho.r:3 (fluY’c:!E‘-.1} 0.10%
`
`€}.C)£'.% wfv
`2%
`0.1% wb;
`€1.{}’7S~{3.5'~?E wfv
`0.§*39'f:
`0.532"! 91: Wis‘
`CL!-E F/Z:
`0.02%
`0.05~0x2% wfv
`
`0.06% wiv
`
`Ocircoficanfl imaiiimtf-crodx)
`M.‘J.§. 123“ {Ame} 2%
`-
`Varivasfi‘ (ikfieercxi-:3-113% xx;
`Tem':mycin S<3i=::‘u‘,-n Ekrmig) 0:593 wiv
`Vasnxyw {Siam-Wrrilmmcr} 0.10%
`faamagt-3n"3‘ {DuPant} 1% wiv
`Temsmycin Ssiiuiian (Rcerig) 1%
`Na»-ans? {RacrEg_t)
`Enioni" {D§1mE.r.‘-2:‘) 0.2% wiv
`
`m ____ Sus~?E1:in::"-‘(Fa-rest) 0,('>{r‘-A: xvlu
`
`TA F3 LE V
`Antimicmbiaf Fresesvaiives
`
`
`lixcipiani
`
`F:-cqxsmxcy
`
`Ranges
`
`Efwauapie
`
`Ceiesmnee Sniusgsaza?’ fifichcriaig} 0.02‘?-E» w.:’v
`0.-'J2*.'7~.~ wlv
`E
`Fien2:11£»;on'1um cfixiorifia
`§}:‘.1‘aa1fir}-'3?” {}’qrk(:~D;svis’j 0.03% wiv
`E"3.=3“i‘?¢:
`*1
`Baxxzaximoniusaa cixlmigflr:
`Dimenhjmrinaicfi {3EEriS} 5%
`(1,’?5-5%
`‘M
`E=:nz_yi.1§s:r.=31~'31
`{iodine p‘a‘ms;:}:r.i<: {3V§rcsh-Ayaisi) 8.5‘-I»E.~
`0.2S~U.5%
`17
`('.‘}niom}.=uKa::u§
`Hummmpefi‘ {LiE!y) 0.30%
`E}. E-03%
`3
`m--Cresoi
`Dc;‘;,wu~
`:’ot'cm‘9{U;njs:111:) fl.E6‘§5‘Jo wlv
`am 95-~0.Er39‘§‘n wiv
`2
`Mgrristyi ga:nm;a—pico§,inim1r: chéuridc
`
`
`Izaag nine“? fifizmssfinj 0,!
`wiv
`9.0343. 33%
`50
`E’sr;AE::.*.sa szxcihyi
`Xyiocainz‘. v.w'Epim‘pi1rim=: (Astra: 0. E V/E: wiv
`f_3.=}i--(3.1%
`40
`Pzmzben pmpyi
`i".'.'1i<:i:1~,ar*" {Rhone Piauizazwi 9.5% -.-xiv
`0.2~{}.S%
`48
`Pizezml
`H::vrEx*”' ifimishifiinc §}s:ex:}1sars1}{!.5=3‘/Es wiv
`€I.:'-0-‘.72:
`3
`Z-Phcncaztyeahanoi
`Phcnyl nzemzaic ni:r-:-.t::
`3
`8.00! 9%
`Amix'en2:a1°fivycth-Aycrst») 0.00§%
`
`‘rmmcmsm.
`4::
`~:s.:1:;343..m%
`.=kig.am"9 (U'g'.-john} 0.01%
`
`'
`
`_ mi gag
`
`A
`
`__
`
`PEA .im:.'nas’= af. Fhanna:sazzeicai Scianca 8. Txzcrsrmiagy
`
`Suppiied by The British Lit:-rary — ‘The w<2rfd's knswiedge“
`
`
`
` I
`
`|nnoPharma Exhibit 11020003
`
`

`

`TMELE W
`Buffers ant! 33H Adjusfing Asgsaztsv
`
`Erusigvicm
`Exaznple
`Kmciaic
`
`Sudi‘-Am
`Acetic acid
`Glam} acetic acid
`fismnzaauizzm
`Amsnonium hyfiruxizie
`
`Miamicin §‘n_i«ecI§nn® (San<l:r2'.}
`Miacaicin Enjectianfi {Sand-.32}
`Brew-Ebiac Isaje-:'§':or.x3’ iflhnzeda)
`Bumax injexszieni“ {Racks}
`Tsiosmt isijeciinzf-‘V {Sr:1,i:§xE(limr:
`53cm-.31a1;n)
`Tracxéum injeciicz-0'“ (G!ax.o~"M~.i§cam.e)
`Valium Enjecéionfi’ {Ruck}
`Ccfomn Efljaciffififi gzenemai
`Hygm-Rh¢)~D33 {E ayerj
`
`D'i‘EC—L‘.-orur:9 (Bayer)
`Cercdasfl’ (Genzyme)
`Carezymszie (f.3§.rs2_'yms:}
`Ccrez;.-me°“ {fiesazymc}
`Bncirim EV” (R<>ci\e)
`Qa3in§:2ia'::t9’* (Lifiy)
`Hep-B Sam m::5._:ea'39 (Merck)
`Ami-gwfl’ ilmmzmex}
`Scspaiazmrzrs (U{5L}
`Fentenyi céxmzc & §.3mpe.:idr.=§ (Astra)
`Eminasc Eaajccliun?’ {Robem}
`Librimn lsujwsionfl (Roche)
`D}§Ew~'f-5 Er:ji:*tii(m5" {fiandmij
`Term mg,-sin ‘Sofia: Ems q'}«iuar§g}
`
`Benzcfie suifimic acid
`Bem.ome Sc>»jir.1am'ac§d
`Eicarbsnute Smfim:
`Czsrhkwzzaia Scxii um
`‘firzsttt
`Peri-:i
`Scsdium
`Disodium
`Tri sodium
`L}Er:Li::,m;3I;1ani::1':
`Giuccno delsn Eamtrszm
`Giycine
`E~Iyd:ach£m'i;~. amid
`}§321.irU>gisI1 fsmnxida
`Lactate attixi-‘5fsJs.i§um
`Lysine:
`Maleic acid
`ficietisarscszzifozaic mriaj
`Mmxoeihanmamina
`Phosphazc:
`Husazegcxig‘ (f3xga:‘:;srs3
`Acid {§>§sr3§p!:s:s‘ic}
`Mcnohasic palasxium ’2.‘:m£n:: injccxéonfi {G§.'sxo—‘s\"cEEmmc}
`fvionubasix‘. ss3r.iium*
`P.re;_:s1yi5° {Orgarmm
`Dibuxir: sodium“
`‘E‘rc2asiin'*” (Bayer)
`Tsibasic szr-fiium
`S3.-ri£hrui£E3’ {Knoll}!
`Susiium hyzlmxiclc
`Gpiiragfi‘ e{Ma§€inc}x:m:fli}
`Sulfaaric .-mic!
`Nebcisfi {E.iHy,§
`Tartrste rxcidfsmifum
`Mezshergiua lnjcscriaanfi iflandsz)
`
`'E‘r:3:1:e1}m:::§na
`Qp3:'my® zfiksiaifiinclcmzfis)
`* Sodium bigahuspimsc, Sodium diE;ycirr:ge:n ;aE:u=pE1n1c ar Nu dihyd:-rage:
`onimphnsyhma.
`'
`** Scxiium phosphaic. Bisuéiunx hydaogen phosphate.
`
`{’§'r:1r:rium in}, zktracurhaxn be-3.‘-zy§:11c}or' mesyime (2“3H—EE. 45
`Ixajeniiosa, D1§1y<h‘ocrg0tamim?, sncsylatefi 531:5. (}!us:om) daissx
`iaceanc is used to adjust the pH of Qeaiuidisac giucxaatflifi
`{Liiiy}. B e1:z.:3s3€ehs;f‘{'er, at a c<:»nr:cenLr:.s1i:)n sf Wu, ‘:2; azsazsi in
`‘valimn Enjstszsiun. Ciera:-as are commas: buffers {hat can have:
`as duai ml: as theiming agcnis. Lysine and giycine are amino
`acicis which famitfiirtm :15 bliffezts ans} Siahiiize prnicir: and
`pepziii-‘c fersmtiaaions. T as‘; atamin.-5:» acids are
`used as
`Eyaa-asldiaivess and may §nrcv'r:r.vt
`ate-Es} (E mtzaxzxticxsa. Lzuztatrr
`and Issmaia are eccasionaliy ustzi as §:'u§‘f<.=:r systems.
`Tame V?!
`Ei:sI.r»; miclitivess which are used 1:} nlndify
`n.<..rm2§a{Ety. and as buiking or Eye‘:-rryrs ;'.:-s'<:.::cc.$ivs. agents.
`Daxtmse and smlium chin-risic {ma used its :1£{ju:;i iaaniaiiy in
`ma majm'it}' of fnrxnuiatimas. Same aamiém acEds,'g3y<:§z:e,
`zslzugine, hisiidinc, imiciazeis, argixxima, asparagine, aspartisr:
`unit}, are Uéifiii as Ezuhlzing :1g;e:1E§ for Ijmphiiizaiiou and ma)’
`sesrve as stzsiziiizers for pmteins er gzemizics and as buffers.
`Miamsszuzcimridesz {sicxim-se, giucese, iacmse). disacchariaie
`(SEEEEBGSE), pal}-iaydric zshzoimis iimsitai, mcmnimi, sorhitoix
`giymi {PEG 3353), §’(svi<f0nfi (pr-iyvinyigayrrofiidene), and
`- pmieifls iaibumisa, ggeiessirei) gm: cummmziy used as $312»
`aciditives.
`
`TABLE Vii
`
`
`Buikingfisgents, Praafiecianis, and "fa:-nicity Ad§aA:si0!6
`Excigsimi
`Akxnine
`Albumin
`Albumin human:
`.5.m3m“: :u.‘.§r35
`L-firginina
`Aspurngina
`L-Aspamic mid
`Creicium uhlurida
`Ciirési ztcicf
`§)e:sIm9:e
`fficiatixa Eaydrrafiyzesfi
`Giumsr:
`f.3i_vcm‘in
`Giycézze
`§§i::t§<iine
`
`Exmnapie
` me $519 (Bayer;
`Biuciaifi (Arm)
`Bcxtcsfl {.:5di::rg:m;=
`I-Eavréxfi (fissxiihfiiisar Ecechaan}
`Aciivas-229 (Gextemech)
`Tine ECG’? iflgz.-non)
`Pepcidfi‘ {§‘.'E¢3zcF<}
`Pmnuurgun Enjcclinrfl‘ {Wfye1h~AycrsL)
`Sr:rs5orc:z1§nvm\*EPF3” (Aytra)
`Betasemrflfi (Bering)
`Acrixafli (E2jmne—E’au}anc RGFQF]
`Ivs:agar:a® (§mm'.:n'.)-US)
`Tics ECG3 tffiganen)
`Aégana i'r._;f¢cE§0:13{Upjohn)
`Antifzaxmphiiic Fsmtas, human
`(Am. Red floss)
`E-’!e1ixatc3'“{Ann-rust)
`CI<:1r€:(:S=.:an’5’ Emaliinckmdtj
`Cave-rjesctfi {Upjohn}
`'1"en'am_'-xciaa SnIuL$<.m'-"5 {Rsmrig}
`‘ice ECG” iflgzxmnj
`EE5g3:r@ (Mercia)
`Bieclaicfi (Arr.-u}
`Helixntsi‘ {.3srm~3ur)
`*:.’aa:ix-ax“ {Merci-z)
`.:i.'i!;cran’3“‘ (GE a.m-Wei! come}
`W'Ez1RZ'1-23 SD?’ {Unfvuid
`Actinimuncfi [ficnac-each}
`Dt1;3u~F‘wv::(a'5‘ {‘L}§.7j'\7im)
`§"a3nhmn:‘.2in"" (Abbott)
`Pruiaszinfi {Bayer}
`
`imidaiznkr
`inositei
`Lizciase
`Exfisgnegissm C31E0:’§d(3
`Magnesium snaifzzic
`Man nim!
`Pofiyesihylena giycei 3350
`F-rsiysnzbate Si}
`Pemsziunn cialmids
`Poviti-ans
`Svmiiunx chimide.
`Stadium succinafic
`Smiiunt suifz-.12
`Snrbitoi
`Sucmsez
`
`Special mififtéves
`
`in phamiza-marina}
`Tficse additives have hem Encludeci.
`ferrmzlaiian m servsz spccific functicms (Table VH1). Bstlew
`is 21 sunmmry sf {ha spcciafi additives aknng xvii}:
`their
`inteniied Lr5e—-
`
`(E) Cafcium giuconatt injection imzaericma Regent) is as
`saiuratcci saiuiiors (sf E093 wfv; calcium d~succ§z-arase
`Eetsiaiwd mfie {3.«=35‘.2s wiv is. misled £0 prevent <:ry:s1;1E€i—
`zaiicm during iempemmre fiuczumicans.
`(:3) Cigms HW9 {CEp§'(.i§](:-Jiillflfh Bayes’) contains iaciic
`acizi as a scn]uE23i'usi‘:1gg;3':,::..r:1 fur me zamibiotic.
`{3} Presmrin In_§ec::%<_\.:2® {ifonjnzgafieei Esatmgarss, W_re:h—
`Ayers: Labs} fs. 3 Eyophiiized [Jx':2-Liam that canmins;
`sémeiixicsne 20 pr‘€5vI:nt
`formation; of foam during
`rz:ccm:ski§u1§c:n.
`
`.%7<::re_s:,
`{4} Dexamaihasozaez aceéate {fiaiuitszle DP,
`Iiccmmaz-LA, Merci-1. i)zsiaiox1eI1‘iPEn_isss:fi<s:1, UAD
`Labs} and [‘sexamezhasaz1e
`pizospmfier (mmsk)
`are :w;.niE:3bi::a
`Sl.I$«’}'3E£I1S§fiE1 at sahtiizm. These dem-
`naeihzesme fcnnnulmions «remain Crcaiirac or crflnti
`nine
`an adriitive.
`
`fiE3F@’ {{)s:x(3ruhir;in iiydmciaiorkizs,
`(5) .<‘sda‘iazI:yci:a
`Phnrmacia) zcanmins mcsthyi parabcn, 0.2 mg?mL, E0
`iztcrease dissxaiiztiora (£0;-.
`{(5) Ergnzrut-6 m:J:%aic (firgosz-wiaxs anaieaaic, £.iiIy,‘= CDT!-
`Eains 1'}.}‘3'Za why} §€EL‘!:‘.iE5
`5325 33 snltihiiizing agent,
`(1?) Eisirzadisrin Inject?-r:n'3° {Pssiyestradinl phaspime,
`Wy<:£h«AyersE Lam)
`Niacin:-.m§<§e ($2.5 rzzgimi}
`
`Vui.51,Nc.w3 I Jul"y~Augu:“»E 189?
`
`.169‘
`
`|nnoPharma Exhibit 1102.0004
`
`

`

`T;‘iBE..§§ WEE
`8_m3cia§Adrs'ia§ves
`
`E3s:3n:g3}c
`Huszmn Albumin {skmericass luzd
`Cross}
`Rccaszibinant BEE {Merck}
`Tctzassezx Tmssiai Axisurbcd”
`(E4543-::iic)
`T33 /‘xdscnrhe-J Afluizfi’
`(C'nnn:Ji.:g.h!}
`Eaxrinssefi (Rcmens)
`Caktiuan Giuconate {Ame1'i::.=m
`.
`Regent)
`Human :1€&.mmi:L{Amc'r§<::-.3‘: Red
`Cross)
`Dimcnhydrimtc iiliezis)
`Dalnione DP’? {Farm}
`H_v<§s'- -mnnm: Pimgstzazsc
`IjMe='e:i;)
`Cxmnay {lviaiiirxcizrodi}
`Crxrdimec {SLԤI1i'a"o}
`Ergatmta mfl1c:r:E§3‘(LiI3_y)
`Aazzinwgsiiyliinesfi’ {Ahhmfi
`Iinb Ekinaszcfl‘ (Pimrmaciaj
`Tics BCG33’ {fjgtsrwsa}
`Cipro EX”? {Sayer}
`2:23;:-:}ex’3’ (Samara)
`
`.
`
`Emsipieazi
`Acetyi irygamphzmaia
`
`Aiuwixium i13'dn:r.2tide
`Aiumimsm phosphate
`
`Alizminum pntaxsixxm Sulfata
`
`E~An~.Erm<.upr-mid acid
`Caici-am <§~szz::c!2ar:s£-5
`
`Czxpgylntc suzzliunz
`
`8—Ch1a)rathe:aphyliir:e
`Crcsaasine
`Ci'eaEifi§saa
`
`i)3:1:_riz.aic acid
`(‘samma Cycifldfixiril}
`Exjayl !::cE:1ie
`Ethyienediamins
`1..-Glutamate sqmfium
`Ema: mnmcsniasm ciiraue
`Lame acid
`§).LLac:ic mm Giycoiir: acid
`a,:s1pai_5'mcr
`Mzalmsrz
`ixieglumine
`Niaaasinssmidc
`§‘a1'abcn :'r1r:ii‘a3.']
`Prozzxmine
`
`Gamimunafi -(i’3sy:::]
`Magnevissa {Berfax}
`Esirasciaarinfi {Wyeth-Ay::tse3
`‘ Mriamgzcin £iBF1°{?ha1Tr1z1c§a) _
`Ia15u1azmcH\'F}§3‘{Novo
`Noztiiséci
`?rn::n3_ain ialjcciio.-‘E3 (Wyc£I’x-
`a‘\ye-rseij
`Cnmpazim ifijiiiliiflllfi (Srr:i:§3»
`Kiim: Br:ech:!m}
`Ve3mgia‘csn1in’='~‘ {Apha Thera»
`pm-tic)
`Binclzxifi‘ (Arse)
`Lame: Ensutiaufi’ :[!*§m-<3 ,N;>r<3i5§;‘,:
`
`Simciiiisx.-as:
`
`E*ic';1Jium szzcchztrin
`
`Ti}-n-busy} phusph:-.3:
`
`
`m-nu.» ........,.,v.
`
`...........:...,.~.,‘,_,_>‘*1
`
`‘
`
`TAELE 3%
`List of Excipisrmmm YQQ6 Ff.3A‘EnactEve irrgrsdient Guide‘
`Ammcnium suifaze
`Banzyi chloride.
`Buzyi pamben
`Crdniianuiaie smiimrs
`Caltcridai caaiazium
`Casio: ail
`Cellulose fxnicrur.-rystazliinc)
`Clzuiesmoi
`Dmxyarhrflic acid
`D§m:'izc“:r: acid
`Diuyzziohexyl r:'ari:3aeiEim§d:
`Dfetisyl amine
`Di szzyfiseoyri §ec§1Ezin
`Iiirrayriezmyi p?10sphaiifi3rԤ-
`glycctmi
`Disofmrizz
`D43-‘Jessie sodium
`Edzsmine
`Exumetazi sue
`Gitwepauae an-Ilium
`Gluceptaza caicium
`{'_'iI’-.i:cL3m,n‘u: acid
`Gxszmisiinc RC}
`Eofaiamine HCE
`Lncisbimfit ad-d
`L-uciahin hycErc;:enr.te<i my
`3..iLEufs:nE.=1
`Med:-nfcniri
`Mes} remaie disod
`;\§~.*.=.1r<:nic: acid
`Meihyi hcmnic acicfi
`Mleiisyi ceiitetasa
`Mciixyicne blur:
`P3-gcazbamuyl-'22assahox;; pun-ly-
`ezhyicnc-giy-mi I’.G00‘3—1 ,2.~
`disicarc-3;:
`Nsfiufiyeiroxyclhys pipezazina
`I~."’~2‘ mhzunc sulphossér: acid
`Nioaiaaw
`Nihic acid
`f3,1:yquinoiine
`
`I’ss:::t~.1aic(DTP.~ ,5 caiciuxn
`(:3 sadiurr;
`E‘01ox:;ma:r Z65
`PEG 4905‘
`PEG am
`E-‘oiygiazsin
`Pnfiyiacfidr:
`Poiyexyeihicn.-: fatay acid
`esaera
`}’oE3;s3:cycmy3ene. ssrbitan
`Irivnmsteraze
`Polyoxyi 3S Ci:s'mr5EE
`Po‘:ysr:41'§>::ie 44}
`}‘~‘oJys;ur§:3.a«:e 85
`I’tI~I;3f~2Si‘LI:”i‘: hycfroxéries
`Potassium: phosphaus, dlibasir:
`Sudium hisuii‘-.:!c
`Sodium chizsraie
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`|nnoPharma Exhibit 1102.0005
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`Rccsntiy, FDA. has gmbiisheii ‘Intuitive: Ingstcéiani Guide’
`which ii.»-is 035 the cxcipisms in aipiaah-czimi nrder. Each
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`Réferenczés
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