`
`RPTRAR ICHOV CAR SNe BRM
`
`1 SR en 8 i AD He BB
`ae F Ee
`
`(51) BREFAT
`A61K 38/19, 38/22, 38/29, 38/00, 47/16,
`47/26, 47/14
`
`(11) GRABS
`
`W000/51629
`
`(43) EIGRABA A
`
`20004F9.4 8 H (08.09.00)
`
`
`
`
`
`(21) BPRS PCT/JP00/01160|(81) #872 —-AE, AL, AM,AT,AU, AZ, BA, BB, BG, BR,BY,
`
`CA, CH, CN, CR, CU, CZ, DE, DK, DM,EE, ES,FI, GB, GD, GE,
`(22) EPRAARA A 2000425 29 B (29.02.00)|GH, GM, HR, HU, ID,IL,IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO,
`NZ,PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ,
`UA, UG, US, UZ, VN, YU, ZA, ZW, PRI Rest (AT, BE, CH, CY,
`DE,DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`‘$3 (BF, BJ, CF, CG, Cl, CM, GA, GN, GW, ML, MR, NE, SN,
`TD, TG), ARIPO### (GH, GM, KE, LS, MW,SD,SL, SZ, TZ,
`UG, ZW), 2-7 7 Be (AM, AZ, BY, KG, KZ, MD, RU,TJ,
`TM)
`RIAA
`
`PLRa 8 os it
`
`IPR PETITION
`
`(57) Abstract
`Stable G-CSF preparations showing a residual G-CSF ratio of 90 % or more after a long-term storage test at 25 °C for 3 months;
`showing a residual G-CSF ratio of 90 % or more after a long-term storage test at 40 °C for 2 months; showing a residual G-CSF ratio of
`90 % or more after an accelerated test at 50 °C for 1 month; or showing a residual G-CSF ratio of 90 % or more after an accelerated test at
`60 °C for 2 weeks; and showing a ratio of the formation of the methionine residue-oxidized derivative of G-CSF of 1 % orless after an
`accelerated test at 50 °C for 1 month or after an accelerated test at 60 °C for 2 weeks. A method for inhibiting the formation of the
`methionine residue-oxidized derivative of a physiologically active protein having methionine residues characterized by adding methionine to
`a composition containingthis protein.
`
`(30) MESEKEF—
`4BASE 1 1/52314
`
`19994F3 F] 1 A (01.03.99)
`
`(71) HBA. CREAR < $C OER IC OVrT)
`re ArRuesttt
`(CHUGAI SEIYAKU KABUSHIKI KAISHA)[JP/JP]
`F 115-8543 HRABAL EVEMIST ASP 1S Tokyo, (JP)
`(72) HAF; BLU
`(15) BAAWHA CKENC OWTD4)
`tei 48(SATO, Yasushi)[JP/P]
`F 171-8545 FORDEi ST B48
`tHEEL AY Tokyo,(IP)
`(74) {HBA
`#tAR—, 4SHAMOTO,Ichioetal.)
`100-0004 HIMBA RAFAT 2B
`SA EM E-206R 27 UeN 7 ReaTSAT Tokyo,(JP)
`
`(54)Title:
`
`PREPARATIONS STABILIZED OVER LONG TIME
`
`GYBHOAR RRNA
`
`MAIA Exhibit 1006
`
`MAIA V. BRACCO
`
`
`
`
`MAIA Exhibit 1006
`MAIA V. BRACCO
`IPR PETITION
`
`
`
`(57) BB
`
` 25C-3,ABRWRERBEIK BU SZG-CSFREBUIO%N
`
`
`DPkECGChSD., 40CT-2,7,ARMRERREILBUSC-CSFR
`
`
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`
`
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`
`
`
`
`
`
`
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`
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`WO 00/51629
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`WO 00/51629
`
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`
`
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`WO 00/51629
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`
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`
`
`
`
`
`WO 00/51629
`
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`
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`15
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`
`
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`
`WO 00/51629
`
`PCT/JP00/01160
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`
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`
`20
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`
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`SOA VIRGROIATI; FATURUIVESAFIYL—bh. FATUY
`
`7
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`YIVYAFIL—bh. FAFUVLUIVE/ US V—-bSORU TU CY VRE
`
`LAF; BUAFYLFLY VIVES VES SOL bh, RUAEY LFS
`
`VIVEF VES AVL, RUFSVEFYOVIVESVE/SATT Vr,
`
`RY PEYLFLYVWVESVEINWVET— bh. BUFEYLFLYVIVES
`
`YVRUAYVI— bh. BUFFY LFL LVEF Y RUAFTVU—bhSORUS
`
`FV OLFLYV IVES VIRB LAPIL ; RUASYIFLYV IVEY hFThs
`
`AFT V—bh, BUFEYLLFLLUV Ivey KF RIOT L—hSORU ASL
`
`LFVYV Wey hMEGRLATI ; BUFFY LFLYFURUIVES ATT
`
`L—-hSORUFELLFL YAU VIRB ADI; RULFLY FA
`
`10
`
`—\VAFITV—bSORULFLY YU I—WARRRLAPTI ; RU FSYX
`
`FY ITY WI—FWVSORY FEV LFV YT ELT; RUAEY
`
`LFV URU ASV PFORYY AYIAFI, RU AE Y LF RUS
`
`SYFORVYPFORWIL—PFI,. RUFEYLLFLURU FSV POR Yt
`
`FLI—FWVSORYU ASV LFIL YU RU FEY FOUL YSWAFL|
`
`15
`
`RYU APEYLFLYY JAW rari FIVSORVU FEY LFUY TIS
`
`Joro—F I RUAEV LFV EVD, RUPEYLF UBEEY
`
`ViCRU FAYLF URE VI)SOR FEYLF REE Yi ;
`
`RU APEY LFV YY Wey bi VaovSOeUTFVY LFV YS VUES
`
`HK: RUDYLF YSIS UYSORU AREY LFV YI) VSR; BY
`
`20
`
`PEVELFV VATS ULERY Ss RSORUASL ULF VBR? = ESOH
`
`LB6~1 8280460 5; BIFLDAMBEA MAILE F RRS hUOL,
`
`SIU WRB UDA, AUT VERT hUOLSORBRFRIO~1 80
`
`FVVET SF VERE | RU AY FLY DY VED b UY
`
`LEO, DFVYUASY FOV AHMEVEAM 2~4 C7 WVFENVEORRRTR
`
`25
`
`MLO~1 8 CHSRUAFEY IF LYS VEL FRE | FDU IVAIL
`
`RINDBIAF WF bUILEO, FIV VEORRRTRM8~1 807)
`
`PIVAWARINGRLAPF IE; RRKRORMBER, BAILY FY. FUR
`
`OUVIRB; A74 VAS LUT SO74 TA VRS RRRTR1L2~18
`
`ORMEROD 3 AIRLATSERBCL THI SCEMTCES, BH
`
`8
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`FOMANTIZ, CHOOAMBEAIO LBMELIL 2B LEASEDCHMT
`
`SCEMTES.
`
`PE LAMBS TELPLFL VV IVES VDABEGRLATIVCHD,
`
`SICHELWOWURVUVIVN—b 20, 21, 40. 60. 65. 80, 81,
`
`85 CHO, BOMELMOIHY VIVNA—b 20KRU8 0 THS.
`
`BHAOG-CSFRARAICMINT SHMIEEAIO MMB. —AICILG—
`
`CSF1l1SBRBICHLTO. OOO1L~10OBBMCH), HEL<SIEG-CS
`
`FL BBBICHLTO. O1L~SHRRM CHO. ROMEL<SMG-CSF1E
`
`BEBICMULTO. 2~2BBMCHS.
`
`10
`
`ASAOG—-CSFMRIOpHIssHELSS5~7 THO, SHIHEL< It
`
`pH@5. 5~6. 8CHO, S5tCHEL<IEDHAG~6. 7 THD, Rd
`
`FEL <ldpHM6.
`
`5 CHS.
`
`ARROG-CSF MAIC, MPBCKOIS SARA BARRA, RBA,
`
`pHia#A). SOH(LAl. RGA ARTAMicka eA LTH KEN,
`
`15
`
`AAI, SHBELT. N-TRPIUYAFIY. N-PSRFWREVYA
`
`Ps FAS HB. FTV PUI Sees eos. Feo UE
`
`—lbL. FAVIVE ROL FATVI-NVBROUCOM, FARBIFRUOL,.
`
`AWVIFAY, MONCRBRFRL~ 7 OFA WAYVRSOAVIERU IVE
`
`RATSZOOSMHITFSNS, HK. MeMibAcCUTI, DUVILEVR, Y
`
`20
`
`SFE ROSY hIVLY. FFE ROFL FIV), a-kI7xzoO—I)b.
`
`AR bhI7etO—)), L-YADVEVRRUtOKR,. L-YADIVEVEINY
`
`SF—h, L-FADVEVRBATT Uh. BHMAKRMTbUOL, BHR
`
`hUDA, BRFRLUY SI). BREFRTOEHOWLFLYYT ST
`
`BBoOFhUDL (EDTA). EOULBFRUDA, AFUYRBTRUDA
`
`29
`
`SOL —bhAIDSABTONS, SSCs, BET RUA, BEA UDA, Hie
`
`DWVYIA, UVEBTFRUDA, ULBAUDA, RBKRTbFUDABREOR
`
`HR TOTS UOL, DEV RBAVUOL, BBS hUUDLREORRE
`
`EOMBRMASNSARALEATWITEY.
`
`AHAOG-CS F MANIA, RRNA. BBRAl ceed.
`
`9
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`ROM EL< LRBRRBA CHS.
`
`BRAORAI. CHSORPe -MRBR GFEL<SIU YR—KRTh
`
`UILA—-YYROKRTbUDAR) RU/RMILURRGR GELS
`
`LVEF hUDLORGR®) BEOBRBAODE COAOKERERICERT
`
`ScrEK LT THRBACARL. SSWIECOLSDICL CHHRANEERBA
`
`JERICHO Meee, KMIDRBRRT SC cic ko THESES.
`
`ARRORELENEG-CSFRARALARHRORSRRC. PARE
`
`SA CRPE, ARE, ARTE EC)
`
`. ER, ARR. ER. BMA TRSE SNS
`
`AM, PORSGD HCTHS.
`
`10
`
`ARMOG-CSFRAL. BHBH. MRMENEAFIAFYVERIWAZA
`
`ABS HiMMSVCHO. GRRICMIZK CESA EZK) CBRL CREAT S.
`
`BRROHAIPICGENSG-CSFORI. BRINZERBORR,. RBO
`
`BEE, BHOFMEECDCTRETE SOM, —RICIMRBRESFBETI~1
`
`O00ug/ml, FEL<1LO~800ug/m1, S5RHREL<ESO
`
`15
`
`~500ueg/m1TH4S.
`
`ARAOMAMS, RRYECROLFCRICHY TC. REM, Teer, TUBA!
`
`TEORAIZRSTORIARRSTOL, BRON, BEBELWIDER
`
`BISSHA CBOEARREKEBTSCEMHALCTHO, BRL CAR
`
`CHS. HoT. SHRORMALCHSOBAICHARSTSCEMTES.
`
`20
`
`ARWOG-CS FRANLEMRORMAICRTESIC. 25C-37 ABM
`
`ARBMIL4 OC-27 A RMRERRETOREICS., HSWlE50C-1>
`
`AROMRRR MIL 6 OC 2ARIOUERRETORRICS, MOTRHEG
`
`—-CSFREBERT. EK. 50C-17AMOMRRREXIL6 0CT- 218
`
`PIOURRRATORERICS, G-CSFOAF AIT RARHEMEML
`
`25
`
`AERBENZM OK. BHAOG-CSFMAL25C-37 A RMRFAR
`
`BIC BIUISG—CS FRBNY OBE. HELIS KBUAETH SM, 4
`
`OC-27,A RMRFRRRICHWSCG-CSFREBMIOKDE. HEELS
`
`h95%UECHSD, 50C-17 AMOMRRBRIBUSG-CS FRE
`
`BMAQAO*AE. RPEL<SMISKUNECHSA,. 60C— 2 AMOMRARE
`
`10
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`ITLBWSG—CS FRABMNI OCDE, HEL <I SKBUETHO, MDS
`
`0C-1+ AMO mMRRRE RI 6 OC— 2 AMOMRRRERICSITSG-CS
`
`FORFARRAB ERBA 1 OA. RUS ISRMRARLE CHS.
`
`ARHAOMA Cis. BRT SAHMPHORCBRA 5. UY Y. EAFYY. FIVE
`
`ol
`
`=y. VANS VE. FAIVISVEB. YALL. FTANSSLDOMSHRE
`
`NBiSNS-BULOVS/BL. BOK SBD OBINS-BULOTS
`
`JBERMTSTECKLOB CHRIS SEMREROG-CSFREREW
`
`MTSTEMCE, FLAFAFAULSRMTScTeEIED. G-CSFOAFF
`
`=RACERBERORR PICT SC EMARENE. BRRB SI,
`
`10
`
`ee ORICA TSDS OMA. G-CSFOAFFOTDREICRAT,
`
`MMSNKAFFARUVAMBMLSHNSTEIC END. G-CSFOAFFXIYREB
`
`(HIRE RBEE< TS CHRMILE.
`
`XS SICA HENKIC, AF AFOUL REOMIERERI. LOBBLS
`
`JOT <. ME CERBHEATS, AFFOV RECAST SERBS UND
`
`15
`
`BOMRMICAFFARLYRMRMTST LICKED, REBBEYYVNIBOAFT
`
`—YVREOBILFEREMILTSCEMCES. BI. RERBEYUNY BA
`
`RmPic, SEtMCLCHOS VY NIReGERURA, FUNI BM
`
`HRA NCSRE, HSVILIO NT BAMMABRABOREICI, Y
`
`VNDRODOAFARY REECAMERLETWCEDS, AFAXILY OMS
`
`20
`
`BUACHSLBAAD,
`
`SSIRRAOMRMIZ. TOMO-BMULOT S/BMERMTSc CLICHE,
`
`AFARVREOMIERERE MEL. HO, SRIEEVY VND ROD, BER
`
`EMAAR. REISNK, AFFOVRELAT SEBS NO RSA
`
`ee BETS CEMCES.
`
`25
`
`COeSEmit sry s/Bev-ud Uru. AFL YU. PFS. TA
`
`KIEV, PVPS YR, Pea say. FUTPIFS, D44
`
`WII NUS FISYM: FOYH FUP. BUH kero7
`
`AND#Y., ANI ZY. FOL YSMBISN, HMELS. EAFYY. 7
`
`Wresy., FRITS SY tae,
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`BEAR OLRBES NOBEL TIS. PIAIE.
`
`4 RA Vet yeaoseY CIL-1~1TL-13e2&). 206
`
`BAT ARIMA (G-CSF). Y7O77—-YA0I— AR
`
`RF (M-CSF). RAR/V7O77-YI0nI— AMA (GM-CSF),
`
`or
`
`LUADRILFY (EPO) #) . f>9-7xruYy (I FN—-a,
`
`8B. 7) .
`
`[Bmx At (TNF-a, TNF-£8) . Transforming growthfactor
`
`(T
`
`GF) , platelet-derived growth factor (PDGF). L I F (leukemia inhibitory
`factor)
`. oncostation M (OSM) . migration inhibitory factor
`(MIF) ,
`
`Fe SY. IL-8. LD78. MCP-12ée,
`
`10
`
`EPIBER SFE; Trvaury AAdY, Noto RHVEY (PT
`
`H)
`
`. HARUM Beet ALVYA POS. Hep vo Seek
`
`—, RBUATFE, PTAP YAP, EFUY,. BRUATFR, Ma -oF
`
`\!
`
`vu, LYTaTWAS Ss. BARU ORAS. UR RAPT 2 8.
`
`PA IVP AY: HGaY. NASM NOP VAP IM CATV VBE
`
`15
`
`RRB » A FAMREAP DICRET SBR PAIS. UY ORTeEK
`OYF—VH) RE,
`KRIS. TNHSORREMSISNS.
`
`BRO LBIEHS VINDRELTIL. HELLS. Ut hAT VY RRER
`
`FMEA TFECTHO. KOMELSI. G-CSF. DU AZUALIFYSoOI0
`
`20
`
`——FIBBTFERIPTHERL, SSCHEL<I. G-CSF, LYUAOR
`
`EP YR TAR.
`
`ABRAMFORMRMICKED TA SIHL< HAT SM, RHRROMRIECHN
`
`ICRRESHAW, ARAOMMICHOSMe ORB, EMMARSICILAATH
`
`0, CHOORER, EMoSARHICEENS.
`
`25
`
`Ei
`
`ae77
`
`NAF WHED OSB ORMRMSTORL RVR CHSLIICS MAM
`
`SL. RRMIBZTO RE. BRNICANT IVC ImMLSOERICGAL,
`
`RRSROIRITHE LL 7. RISER TR. SESHTHL. G-CSF RBMRBAISH
`
`12
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`
`
`10
`
`[7STETAPART vate
`
`
`
`aaaa
`
`gpo50mg
`Ee=
`
`=
`eeLiae|Seens=s|_visss—t0—|te+}—t
`
`
`Jaan7325 08R T27 RIOR
`
`Biz, FG i002
`iz. comes (7 5
`(60nNt= 234)
`JBAESEM)
`
`15
`
`e p
`
`EE“Ease a
`
`a
`
`
`
`Cesioee| riges|—ree|ee||Feesas ate
`
`
`
`Hees5 100ue|—pees—|FSS|s0ag [019g|
`
`
`
`LBA.28|W0ne|7be=>|Faye [—s0ag[0a
`
`
`
` WFNSiOng OMNIS i. s0—MIGM (7S
`
`20
`
`4)
`
`PR AEBEI)
`
`25
`
`
`
`
`|oose|oie|a|Mt
`
`ee|te ysiipHa
`Feesas[as[one|ne|sooue|tome|some|
`
`
`
`||vomnnccanse
`
`
`
`| itnoe|
`cL aime |v verre on.
`
`
`oH HO
`
`
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`COLDICRANIHRLEG-CSFSARBREMAIZ.
`
`6 0 COE
`
`AT2MMROUISA; SOCOMEHMATIZA. 277A. 837A; 40TO
`
`(HIRE 27HA. 47H. 645; OIC 2 SCOMBMINT3S>A. 64757
`
`BEL.
`
`on
`
`De MHA, RORDABANI.
`
`1 mL OM CIEMICIARL. FidODIE
`
`ORmRBAE LE.
`
`NIT VPOG-CSFSSR (RE) EPHROAIE 1 CHOSHELE.
`EK. NIV VEOG-CSFAFARY BABE MBEFROME 2 ICH
`
`DHE LE.
`
`10
`
`Zité1
`
`ames, CAMHAIA (4. 6mmMx250mm,. 3004F>7KRbO—A)
`
`AAV, MK, FREORUIL. FU DIT ORREBICAORPA
`
`MAZVOVEKAS74-HCKNG-CSFEBEHELE. G-CSFELT
`
`5u ctH4BeeaAlL, FVAIORUIOFIVYIYTEHICENG-CSFReBHW
`
`15
`
`St. 215 nmMOKECHHFHICRHLE.
`
`AAIECHELEG-CSFEREAYW, FIRORICBOZ,. 60°C — 2i0R.
`
`RU5 0C—-17 AMIRERUG OCT2ZMHRULSTA;: 50CTC1ITA,
`
`27H. 374A; 40CTC27H. 477, 647A; MUIC25TC38+H#.
`
`6
`
`sARmELECEOG—-CSFREREREER (%) ZRWLE.
`
`20
`
`(#1)
`
`(ATEFAI ODO G-CS FES)
`eB (%) = ——_——_———__ x 100
`(AMEBROG-CSFSB)
`
`25
`
`FE 2
`
`Re. C4WHASTA (4. 6mmx250mm. 3004>7AZhO—-A)
`
`@AW Mik, FREOKUIL, KU DF ORREBEIA
`
`BREZOV EAST HRCKENOG-CSFRALERU. G-CSF Met
`
`RARER LK. PRE RORUIOFFTYLIYbICENG-CSFeBH
`
`14
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`at. 215 nmMORRCHHFHICRHLE.
`
`BRIE CHELEG-CSFRAIEHRUG-CSF Me t RARER IC
`
`—TMRMEAW, FidORicHOE. 60C- 2i0R. RU50C-—1+ARiM
`
`REOG-CSF Me t RERILAERE (%) ZRWLEK.
`
`[xt 2]
`
`G-CSF Met Peaks mk (%) =
`(G-CSF Met 72281)
`
`
`x100
`
`(G-CSF RAM) + (RMB O G-CSF FH)
`
`10
`
`Al 1 : SBDHOG—-CS FREBICKIETMR
`
`#LICHMOBM pH THMHRLERE 1 RUMAH 2, 60T- 218, RUS
`
`0C-17 ARIMRRRETIEROG-CS FREBEAE 1 cacmoOKizk
`
`ORW LK. HONKBRERIICKT.
`
`[#3]
`
`15
`
`H 7.4 =a|50°C-14ARS|14 Ai|ott||997
`
`
`
`ap
`
`g0'C-2 sR
`
`DH7. 4MAICHENT, DHE. SITBWT. ABSSUZHULORE
`
`20
`
`Mea LZ.
`
`Khel 2 : SHY ST /BOGC-CS FREBICKIZTOR (1)
`
`RLICGMOSMT S/RCHRLERA 3 ~6 (G-CSFRH1
`
`O0ug) . MOICMAHT~10 (G-CSFEHB250ug) & 60-2
`
`25
`
`fl, RUS OC—- 17 ARMRRRETORROG—-CS FRERBEAE 1 Ic
`
`AOMOBRICKOBWLK. BONKBMRER 4 RURSICAT.
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`(#4)
`
`100ug G-CSF 2A BAl
`
`[tees|ate|ates
`aah 20% NO
`10mg
`Ses HO
`10mg
`
`
`
`FIFI Y
`
`SE76 0
`
`Sesh
`
`(Omg
`
`Omg
`
`50-17 Aff
`
`72.9 %
`
`84.8 %
`
`82.4 %
`
`98.3 %
`
`60°C-2 i
`
`
`
`
`
`68.8. %
`
`
`
`
`
`(#25)
`
`250 » ¢ G-CSF 2AAl
`
`
`
`
`
`
`
`
`
`50°C-1 + AREA
`60°C -2 Wafal
`
`74.0 %
`
`
`78.1%
`
`97.1%
`
`96.3 %
`
`
`
`
`
`
`
`
`
`WFEROG-CSFEBISWTSH, FI /BRRMMAICIENT. FeO
`
`FIXIVeMMHRM. HOV IFIY SBR LERA CieEEMAE
`
`LUWSAaS, THCHB. PEIVVSIVEV NFO VERATACECE
`
`THEORSSCMLMBMO ONE.
`
`3 : SBP ST /BMOG-CSFREBICRISTMOR (2)
`
`HLICHAMOSHT SBR CHHLERBR11~20 (VS/H1e
`
`LEGS eove. FE/SRB2EVCUYS: EAE, FIVE,
`
`FARILTR. 7WISZTR. VUY. KYA SY. FOYY. TANSEY
`
`ROAWVI ZT VOWTHHYERM . WUICMEH21~33 (VS/SBIELT
`
`JWHFIVe, VYSE/RB2ELTVIIUY. NYY aotyvy, ftvatyvey
`
`RPGS FUP RSS, PROT eae Pou we PUSS, VU,
`
`bLYADY. FANFGFYRUAWVISYLOUNFHNMOSRM =. 60CT-28
`
`fl. RO50C-—17 AMiMmRRETOEEOG—-CS FRERBEAIE 1 Ica
`
`MORICKOBWLE. BONKRRERS RUR7 loMT.
`
`16
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`(#6)
`
`[CdSOC-1ARH]60°C-238 fal
`|oe.it|92.8%| 9L2%97. 5%
`98. 0%
`96. 0%
`
`
`
`RE. 16
`
`94. 0%
`
`
`
`
`
`
`
`
`
`(#7)
`
`10
`
`
`
`96. 2%
`
`|101.4%|98.6%|
`
`
`
`
`y90.9%[71.2%
`
`15
`
`Fa—IF FSP EU SS: Fey SST eEAFVO: FEST S=
`
`VET WES, PREV PeVeT ANGER. Peay ea rea
`
`#5 R, Dea eSr ova. PSSBley Ae SO
`
`MASH, MUKPVWFIVeotyy, FWFRVYERUTRI-TY FI
`
`20
`
`SVEFIEAINVI SAV OMASHUICSY CENENRSCEMRFREM
`
`MBBA nz.
`
`ZH 4 : RRR
`
`IJor-ysg-—y1i0me, V¥AY1Omg, AFFIY limgetsa,
`
`25
`
`G-CSFS@BM*100ugRkRO2 50 ug ORHIZDWT, 600 C2iAMK
`
`O1l7A;50CCIZA. 277. 37H; 40TT27H, 47, 658;
`
`WUIT2ASTC3I7 A, OF ARFLELEOG—CS FREBEAIE 1 cick
`
`ORICKOBMLA. BONKGRER 8 ICKT.
`
`17
`
`
`
`
`
`
`WO 00/51629
`
`(#8)
`
`PCT/JP00/01160
`
`G-CSF
`ug)
`
`|100|98.3|96.2|99.9|100.1 [95.9|101.0|100.0 |98.8|97.0|98.0
`
`96.7 _|99.4|99.3|98.1 [98.5|100.6
`
`1: week
`
`
`
`2: month
`
`WTTbBNEG—-CS FREBERLE.
`
`HPI : FS /BIRMOG-CSF Me t RAM(LAERABICRIZTOR
`
`RH 2ICiMORBOAFALY SRNL CHBMLERR 3 4~36 (Fr
`
`PIDRVEV WHO LYOR—ECAFARLLTRMBAtNeHOMmsS, 0.
`
`1
`
`10
`
`mg.
`
`lmg) &. 60C— 2 ARIMRRRET SRR LAH 2 THMLE
`
`JOVEAFFLOIMSH1IC, MBBBBRUS 0C-17 AMmRReETOR
`
`Bic LAK 2 CHMLEZOVEFIAOI AEM 2ICRT.
`
`AFAXRLY RRMA HEB 4) CMBBECOIS OC-1T7 ARE
`
`OWFMCBWYTSG-CSF Me t RAMLAOLRMRBSNEM, 0.
`
`15
`
`lmgYBbOAFFNRY ORME, RMRFEICD G-CSF Met RAMIKH
`
`DEKRECS ICMAT SCEMCER.,
`
`EE. G-CSF Me t RAM(CAERBEAIE 2 ICHMORICLOSHL
`
`TRERER IIT.
`
`[9]
`
`20
`
`
`
`ton
`
`Met 0 mg
`
`Met 0.1 mg
`
`Met 1 mg
`
`
`
`
`
`LT %
`
`N.D. : @RHABRIRLA
`
`TOKD(IK. O.
`
`lmgVWkOAFFALYORMCEY. G-CSF Met RABE
`
`25
`
`(ADERCE SELITMAT ST EMCEE,
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`HA 6 : NSU OT RRLELD BRBAIAO AFALROMIMCKES, AFA
`
`= RARECEB
`
`1~84RRZATSNIU(OTEALEY (QAFPTHEME)
`
`(WOO
`
`01441 SICRMOAHTHE) F200ug/mML#ESA, NAV IME
`
`5 OSMAOMMEMSFOR 1 OIRSKS, MH3 7~RE3 IOOBMAIRE
`aL. RAMBSHO RE. RAMAN IVIClmMLPOERICFAL,
`
`SeHTRL., PTHBRMAIZSESLZE.
`
`{ #10 )
`
`
`
`CORD ICRRNICMBLEPTHERARBAIZ.
`
`5 OCORMEANIc 3 A,
`
`MBL.
`
`meld, C1 SWAT (4. 6mmx250mm, 3007 >7Aha-—
`
`dA) BA, Mik, TREOBRUIL, UDF ORREBRICA EMR
`
`15 MRA OV hKYS7 4 —-RICKLOPTHSBEMELE. PTHELT,
`
`1
`
`Ou gH BeizaAlL. FEKAIbKUWVOFSVIYECKEDPTHeBwWSt,
`
`215 nmMOKRRCHHLFWICRULE.
`
`ASHER Tid. PTHRAMEAOBANC. MB8ICRLEEBD, 8BAOAF
`
`ALL RAMBUESNEPTH,
`
`1 8SBROAFAXULRAMMILS NP TH
`
`20 DRHENS. COVOVEAFSAIRATEBO, PTHFPOSBAOAFAR
`
`VRE ICSI SBE. BEKO, PTHFO!1 8SBHOAFALYREICBVSE
`
`{E2, BAPADAFANY OFMHA ARE TH SOT EMARENTIS,
`
`S565, HAPAOAFAXNILT ORM. AF FOL RADIOLEAR IBIC
`
`SHRBERIELTEC eESOMS. THOS, RAPOAFAIXILV BM
`
`25
`
`(CKO. (HOLLER IDICSBBES AS. YUNDRBHOAF ART RARE
`
`19
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`{KARERM OASHRRAITHKBT ST LEDRAETH STC ERARULUTHIS,
`
`Hee| OFRIA
`
`ARAOG-CS FMA. RRARICBEYTHG—-CS FORFBARD
`
`TES. ZFEG-CS FOAFALRY RABE ERBE IETEL ICMAT Se
`
`EDCE SREB TCHS.
`
`20
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`ZERO aA
`
`Ll. 25C-3>7 A RMRERREICBUSGC—-CS FREBNIOKWETH
`
`D>, 40C-27, AH BW RGRBREICBSU4SG-CS FREEMIOXULET
`
`HS, 50C-1LTAMOMBRREICBUSG-—CS FRERAS 0%LUE
`
`CHSD, 60C— 2MMOMRRREICBUISG-CSFREBAMIO*DUE
`
`CHO. PD50C—-17AMOMMAREXIL6 0C— 2 MMOMRRRERIC
`BUSG-CS FOAFART BRBLAEREM 1 KLECHS, RERG—
`
`CS FSA.
`
`10
`
`2. UYY, ERFYY. FHI. TANGER AVISVB bs
`
`=Y, FANGS YVPSORMSHRKENBENS—BULOT S/BML, BOK S
`
`JD > BlENS-BULOT S/R. ROAFAFOIY SUA 1 acROG
`
`—-CS FSAI.
`
`3. BOKHEY S/VBMAIcOVV II. bUPhITYRVUOTY YP ORR
`
`15
`
`XT SDRPRIR 2 MOG—CS FMA.
`
`4,
`JUDY. ERFUY. FURY, PANSSYVE,. FVII VED OMS
`HAOMIENS—-MULOT SIBLE, PED IOY, bUThKIT YARD
`Of YYPSMoBk ORNS -BULOT S/R RUAFFIY FSD
`
`SRIA 1 HOG -CS FMA.
`
`20
`
`5. PeOyerIY. FWFRYROUAF ART LSU RA 1 MOG —C
`
`S F &#il.
`
`6. REMELT. FBWIKIUNIRESERVIRAL~SOWTNAN
`
`aca O G—CS F RAI.
`
`7. TRSRRBIA CH SARA 1 ~ 6 OWTHAICIMOG—CS F MAI.
`
`25
`
`8. VrLObOVES SICSDBRAL~ 7 OWTHAICAIMOG—CS F HFA,
`
`9. AMIEMAS & ICSU1 ~ 8 OWTNMICIMOG—CS F RF.
`
`10. PMSA TEL LFV LV IVEY VY TEV LAF VCH SMR
`
`189 AcMOG—CS F MAI.
`
`Ll. AMVECERMAARY VIVA—b 2 ORU/RIL8 0 TH SFAKIA 1 O BRO
`
`21
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`G-CSF RAIL.
`
`.
`
`12. pHAS~7 CHSRRAL~1LOWSTNADITICMOG—CS F MAI,
`
`13. pHat5. 5~6.
`
`8 CH SHARIA 1 2scMOG—-CS FRA,
`
`14. pHa6.
`
`5 CH SMR 3MMOG-—CS FRA,
`
`or
`
`15. G-CSFACHOMMMSHBEENKG-CSFCHSMRB1~14
`
`Ovwseqn~AicicMOG—-—CS F HF,
`
`16. UYY, EAFYY, PNWFRY, FANSYVB. FTV B. RL
`
`AMY. FSANSLUMSCMSHREDBINS-BULOTS/RL, RKTT
`
`3 /BMDSBIINS-BULOVS/MEGA, PHM5~7 CTHSCLERR
`
`10
`
`EGS, 25C-37, A RMRARREICHUSGC-CS FREBMNI OK“ULE
`
`CHSD, 40CT-27, A BMRFRRERICBISG—CS FREBAI 0%
`
`ECHSD, 50C-17 AMOMRRRBEICKISG-—CS FRBNY 0%
`
`DLECH SD. 60C— 2 HMOMRRRERICSITSG—CS FRRBAI 0%
`
`DECHS, REEG—CS FMA.
`
`15
`
`17. UYY ERFYY, PWR. PANGS UR. AVIS VRBDY OM
`
`SHRED BSN S-BULOVS/BL. PeoNTIryY. KUTFKIT VR
`
`OOTY YPSMoeHEO BINS -BOULOTS/MtEG4. DHMS5~7T
`
`HSTLEBRETS, 25C-37 A RWRERREICHUSCG-CS FRE
`
`BRIOSULTH SD, 40C-27, A RMRFRRRICHISG-CSFR
`
`20
`
`FREMAIOSCAETHSD, 50CT-17AMOMMRRRICKUSOG-CSF
`
`RBM IOKVUECH SD, 60C— 2]AMOMRRKREICBIOG-CSF
`
`REBRIO*NELCHS, REEG-CSF RAIL
`
`18. pHa%6.
`
`5 CHDMRAL S Rid1 6 MOG-CSFRA.
`
`19. RBAWICAFAFAI LBS ERLE, G-CSFRELHAL,
`
`25
`
`20. AFAXULYLHO-BULOVS/BLGs, RBWIAF FOS Mike
`
`em la. G-CSF REEMA.
`
`21. RE(IMELT. SBMS U NT RESERVB RAL OMiL2 Odom
`
`DG-CSFRE(LHAI.
`
`22. AFFRVE. AFAR RREAT SEBS UNI BSRARMC
`
`22
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`MMTSLCLeRBeT Ss, BIVNIRBOAF FART RARIKEKROMADA
`
`ik.
`
`23. EHIBHES UNDER, Ut hAT VERISEBRECTS CH SRR
`
`TH 2 2 acHROAK.
`
`24. £RRHESUNT RS,
`
`ITOK —RRRT REP THCH SIR 2 2
`
`MOAI.
`
`25. RIBS UNDE, G-CSF, LUADRUTFLEXRIUPTHCHS
`
`SMA 2 2 MOAIE.
`
`26. REMAMECU THOS VNAPRESERUCLERMCT SRR 2 2~
`
`10
`
`25 OwFHNAITARMOAK.
`
`27. AFALVRBCAT SERBS NTRSMROM, RRS
`
`TWADPELIBMRRBCHS CLERBA CT SHRI 2 2~2 6OWSTNAIC
`
`HM OAT.
`
`28. AFAIMVEMO-BULOV ST /REED. AFFOVRRTATSE
`
`15
`
`BEES VND RSARELARD.
`
`29. FRASBM. UYU. EAFYY. FIDL. PANIXVE. TNH
`
`SB. Pee room KUDKoro, BtoB oo, AUS:
`
`ea, FOAUSK. FUP. BUA PUTED, TANSEY 2S
`
`VRUF OLY MSRSRLO BINS 1 BERS 2 BLL TH SRSA 2 8 ct
`
`20
`
`KO FAR.
`
`30. REMMECL THOS YNZ RESERV CCERMCT SARA 2 BE
`
`IL 2 9 MOAR.
`
`23
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`xq
`
`7
`
`G-CSF
`
`ABE
`
`G-CSF
`
`ARE
`
`mee
`
`G-CSF Met Fede
`
`1/3
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`x} 2
`
`0.005
`
`
`
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`
`(1)
`
`2So8S|aee
`
`0.005
`
`22.00
`
`24.00 , 26.00
`
`: 28.00
`
`22.00
`
`‘ 24.00
`
`26.00 ,
`
`28.00
`
`22.00
`
`24.00
`
`26.00 ,
`
`29.00
`
`AFAA=Y Omg
`
`O.lmg FF=yY
`
`Img *FA=L
`
`E 50°C—1 4 Aiwa
`0.08:
`
`0.06
`
`0.04
`
`0.02
`
`0.0
`
`0.08:
`
`0.06
`
`0,04
`
`0.02
`
`0.01
`
`|
`
`0.06
`
`0.04
`
`0.02
`
` a 7
`
`0.08
`
`
`a ay T
`22.00
`24.00
`26,00
`28.00
`22.00
`
`24.00
`
`26.00
`
`28,00
`
`T
`22.00
`
`IN LED
`24,00
`26.00
`
`28,00
`
`AFAILYRRO mg
`
`Olmg #FA=Y
`
`Img *F7=
`
`F
`
`G
`
`u
`
`2/3
`
`
`
`
`
`
`WO 00/51629
`
`PCT/JP00/01160
`
`S| 3
`
`A pn 0.1% Mettsin
`
`A———— 0.01% Metis i
`
`_~A—————_ Met7M
`
`
`
`
`