仿制盐酸多柔比星脂质体注射液药学技术要求解析_张宁

ChineseJournalofNewDrugs20142388962014238。[e-mail]。··100038Doxil———。FDAEMA。FDA、、、、、、PEG、PEG、、pH、、。EMA、。、。Ｒ95C1003－3734201408－0896－06ＲesearchandanalysisofCMCrequirementsforgenericPEGylatedliposomaldoxorubicinZHANGNingCenterforDrugEvaluationChinaFoodandDrugAdministrationBeijing100038ChinaAbstractInspiteofthelong-marketinghistoryofDoxiltherearefewapprovedgeneric“Doxils”availa-blewhichboilsdowntotechnicalhurdle———evenminorchangesintheformulationandmanufacturingprocessmaycausedifferentinvivoperformance．ＲesearchandanalysiswascarriedoutonFDAandEMA'srelevantguide-lineandcomparisonwasmadebetweenthosetwoagency'srequirementsandCFDA'scurrentrequirements．It'scon-cludedthatastogenericliposomaldoxorubicinFDAfocusonthesameformulationdrug/lipidratiofreeanden-trappeddrugamountotherinactiveingredientsamountthesamecharacteristicsparticlesizeanddistributionmorphologygrafetedPEGattheliposomesurfaceelectricalsurfacepotentialorchargethesameinternalenvi-ronmentammoniumsulfategradientremoteloading、internalpH、stateofencapsulateddrug、thesameinvitrore-leaseundermultipleconditions．BesidesthosementionedaboveEMAalsofocusoncomparativeinvestigationofpharmacokineticsincludingtissuedistributiontoxicologyandpharmacodynamics．BecauseoflimitationsofCMCcomparisonofliposomesCFDAalsofocusonnon-clinicalandclinicalcomparisonatpresent．KeywordsdoxorubicinliposomesgenericCMCcomparison、。Alza。19951117Doxil、。1996621Caelyx、、。2005。ChineseJournalofNewDrugs20142388972014238Doxil111。201060100。3。FDA201324SunPharmaSunPharmaEMA2011720。2004835。2008、2011、2012、、。①。②、。③PK/PD。12mg·mL－180～90nm1。1mL2．3×10141000095%。13①HSPC9．58mg·mL－152．5℃。②3．19mg·mL－1。③MPEG2000-DSPE3．19mg·mL－1。HSPC37℃1MPEG2000-DSPEMPEGＲES。1mL2mg/pH。2－42。pH。pH。pH5．5。。1。pH-。2DoxilBarenholzDoxil45①ChineseJournalofNewDrugs20142388982014238。②PEG。③100nmenhancedpermeabilityandretentioneffectEPＲ。④。2FDAEMAFDAEMA。FDA2002、6、、、、、、、、、、、、、、、。20107。EMA20132“Ｒe-flectionpaperonthedatarequirementsforintravenousliposomalproductsdevelopedwithreferencetoaninno-vatorliposomalproduct”8。。2．1。。。2．2FDA2011“InvitroandinvivocharacterizationsofPEGylatedli-posomaldoxorubicin”9。2．2．1。、、。。、、、。MPEG-DSPE80～250nm。PEG。、、。155mmol·L－1250mmol·L－1。、。2．2．2≤100nm、。2．2．3pH。2．3。2．3．1、、、、。2．3．2、、、、。ChineseJournalofNewDrugs201423889920142382．3．3、。2．3．4。470550nm、X-。2．3．5、pH、、。2．3．6。Doxil100～150nm。2．3．7。Doxil。2．3．8。DSC。、。2．3．9PEGPEGMPS。PEGPEG、PEG。2．3．10、。。2．3．11DoxilpH6．52mol·L－1+0．2mol·L－152℃。。。FDA1。1FDA37℃50%24h37℃pH5．56．57．524h、pH7．3pH6．6pH5～643℃47℃52℃57℃pH6．512hTm、。Tm37℃20kHz2h20kHz2．3．12、。2．3．13、。33．13。20051020、、、17“”10①。②、ChineseJournalofNewDrugs20142389002014238。、、。③。④。⑤。、。。200411112008513“”①、、、、。。②、FDA。3．2。。。。FDAEMA。PEGPEGX/。。、。、。4FDA2010。、、、、、、PEG、PEG、、pH、、。EMA2013、。911ChineseJournalofNewDrugs20142389112014238Physiochemicalandbiochemicalfactorsinfluencingthepharmaco-kineticsofantibodytherapeuticsJ．AAPSJ2012143S554－558．25SHIELDSＲLNAMENUKAKHONGKetal．HighresolutionmappingofthebindingsiteonHumanIgG1forFcγＲIFcγＲIIFcγＲIIIandFcＲnanddesignofIgG1variantswithimprovedbindingtotheFcγＲJ．JBiolChem20012769S6591－S6604．26BEＲTOLOTTI-CIAＲLETAWANGWLOWNESＲetal．Im-pactofmethionineoxidationonthebindingofhumanIgG1toFcＲnandFcgammareceptorsJ．MolImmunol2009468－9S1878－S1882．27JONESAJSPAPACDICHINEHetal．SelectiveclearanceofglycoformsofacomplexglycoproteinpharmaceuticalcausedbyterminalN-acetylglucosamineissimilarinhumansandcynomol-gusmonkeysJ．Glycobiology2007175S529－S540．28SONDEＲMANNPOOSTHUIZENV．MediationandmodulationofantibodyfunctionJ．BiochemSocTransacti200230481－486．29YEUNGYALEABMANMKMAＲVINJSetal．EngineeringhumanIgG1affinitytohumanneonatalFcreceptorimpactofaf-finityimprovementonpharmacokineticsinprimatesJ．JImmu-nol200918212S7663－S7671．30WANGWVLASAKJLIYetal．Impactofmethionineoxida-tioninhumanIgG1Fconserumhalf-lifeofmonoclonalantibodiesJ．MolImmunol2011486－7S860－866．31HODONICZKYJZHENGYZJAMESDC．Controlofrecombi-nantmonoclonalantibodyeffectorfunctionsbyFcN-glycanre-modelinginvitroJ．BiotechnolProg2005216S1644－S1652．32GAZA-BULSECOGFALDUSHUＲKMANSKetal．EffectofmethionineoxidationofarecombinantmonoclonalantibodyonthebindingaffinitytoproteinAandproteinGJ．JChromatogrBAnalytTechnolBiomedLifeSci20088701S55－S62．33WALSHGJEFFEＲISＲ．Post-translationalmodificationsinthecontextoftherapeuticproteinsJ．NatBiotechnol20062410S1241－S1252．34ICHQ6B．Specificationstestproceduresandacceptancecriteriaforbiotehchnological/biologicalproductsS．1999．35．M．2．2007390－401．36ZHANGBMATHEWSONASCHENBH．Two-dimensionalliquidchromatographicmethodstoexaminephenylboronateinter-actionswithrecombinantantibodiesJ．JChromatogrA2009121630S5676－S5686．/櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃櫃2014－04－09900、。、。1GABIZONASHMEEDAHBAＲENHOLZY．Pharmacokinet-icsofPEGylatedliposomaldoxorubicinreviewofanimalandhu-manstudiesJ．ClinPharmacokinet2003425419－436．2BAＲENHOLZY．LiposomeapplicationproblemsandprospectsJ．CurrOpinColloidInterfaceSci20016166－77．3BOLOTINEMCOHENＲBAＲLKetal．AmmoniumsulfategradientsforefficientandstableremoteloadingofamphipathicweakbasesintoliposomesandligandoliposomesJ．JLiposomeＲes199441455