微乳遞藥系統(tǒng)在紫杉烷類制劑中的應(yīng)用

ApplicationofMicroemulsionBasedDrugDeliverySysteminDevelopmentofTaxanesZhixiangChen，Doctor，AssistantProfessorNationalPharmaceuticalEngineeringResearchCenter,ChinaStateInstituteofPharmaceuticalIndustry1微乳遞藥系統(tǒng)在紫杉烷類制劑中應(yīng)用陳志祥博士、助理研究員中國醫(yī)藥工業(yè)研究總院藥物制劑國家工程研究中心聯(lián)系方式：2Contents紫杉烷類上市制劑1理想的紫杉烷制劑2微乳遞藥系統(tǒng)3微乳在紫杉烷制劑中的應(yīng)用43紫杉烷類上市制劑紫杉烷類藥物制劑面臨的主要問題溶解度差紫杉醇0.35～0.7μg/ml多西他賽3～25μg/ml4紫杉醇Taxol?，Bristol-MyersSquibb,1992

50%CremophorEL(聚氧乙烯蓖麻油）50%乙醇膠束過敏紫杉烷類上市制劑5紫杉醇ABRAXANE

?，ABRAXISBIOSCIENCELLC,2005

白蛋白納米粒反應(yīng)更高,毒性更低價格昂貴抗腫瘤效果提高不明顯患者生存時間僅延長幾周紫杉烷類上市制劑6多西他賽taxotere?，SANOFIAVENTIS，1996吐溫8013%乙醇膠束不穩(wěn)定，4h內(nèi)滴注完吐溫引起溶血和膽汁淤積紫杉烷類上市制劑7多西他賽DOCEFREZTM，SUNPHARMAGLOBALFZE，2011多西他賽凍干粉吐溫80，35.4%乙醇DOCETAXEL,SANDOZ，2011濃縮注射液吐溫80，PEG300，枸櫞酸DOCETAXEL,ACTAVISINC，2013濃縮注射液吐溫80，35.4%乙醇，聚維酮，枸櫞酸紫杉烷類上市制劑8理想的紫杉烷類抗腫瘤藥物制劑易于產(chǎn)業(yè)化的生產(chǎn)工藝質(zhì)量穩(wěn)定成本低廉臨床給藥簡單靶向腫瘤組織不良反應(yīng)少9乳劑/納米乳/微乳/膠束微乳遞藥系統(tǒng)10膠束膠束CMC（臨界膠束濃度)增溶脂溶性藥物載藥容量有限上市制劑含乙醇，毒性稀釋不穩(wěn)定微乳遞藥系統(tǒng)11乳劑/納米乳/微乳乳劑乳化劑，油相，水相>0.5um，混濁液乳白O/W，黃色W/O微乳遞藥系統(tǒng)12乳劑/納米乳/微乳納米乳表活劑和共-表活劑的兩不混溶液相剪切而成0.05～0.5um透明，半透明或混濁取決與液滴的直徑和連續(xù)相的折光系數(shù)微乳遞藥系統(tǒng)13乳劑/納米乳/微乳微乳透明，熱動力學(xué)穩(wěn)定極性和非極性液相，表活劑或加共表活劑界面張力10-3mNm-1時自發(fā)形成溶液樣體系微乳遞藥系統(tǒng)14乳劑VS納米乳VS微乳ParameterMicroemulsionNanoemulsionEmulsionFormationSpontaneousUltrasonicandhighpressurehomogenizationMechanicalormanualagitationStableThermodynamicallyKineticallyKineticallyDropletsize(μm)0.01–0.100.05–0.500.5–50AppearanceTransparentTransparentoropaqueOpaque(cloudy)Surfacearea(m2

g?1)High(200)Moderate(50–100)Low(15)InterfacialtensionUltralowLowLowSystemtypeW/O,O/WandbicontinuousW/OorO/WW/O,O/WorW/O/WandO/W/OSurfactantconcentrationHighModerateLowCo-surfactanttypeShortchainalcoholLong-chainalcoholNone微乳遞藥系統(tǒng)15穩(wěn)定性VS粒徑微乳遞藥系統(tǒng)16脂質(zhì)遞藥系統(tǒng)typeMaterialsCharacteristicsAdvantagesDisadvantagesTypeIOilswithoutsurfactants(e.g.tri-,di-andmonoglycerides)Non-dispersing,requiresdigestionGRASstatus;simple;excellentcapsulecompatibilityFormulationhaspoorsolventcapacityunlessdrugishighlylipophilicTypeIIOilsandwater-insolublesurfactantsSEDDSformedwithoutwater-solublecomponentsUnlikelytolosesolventcapacityondispersionTurbido/wdispersion(particlesize0.25–2

μm)TypeIIIOils,surfactants,cosolvents(bothwater-insolubleandwater-solubleexcipients)SEDDS/SMEDDSformedwithwater-solublecomponentsClearoralmostcleardispersion;drugabsorptionwithoutdigestionPossiblelossofsolventcapacityondispersion;lesseasilydigestedTypeIVWater-solublesurfactantsandcolsolvents(nooils)FormulationdispersestypicallytoformamicellarsolutionFormulationhasgoodsolventcapacityformanydrugsLikelylossofsolventcapacityondispersion;maynotbedigestible微乳遞藥系統(tǒng)17微乳在紫杉醇制劑中的應(yīng)用處方三辛酸甘油酯一三丁酸甘油酯CremophorELPoloxamer188蛋黃卵磷脂乙醇10～50nm微乳在紫杉烷制劑中的應(yīng)用18動物實驗過敏試驗藥動學(xué)評價微乳在紫杉烷制劑中的應(yīng)用19藥時曲線微乳在紫杉烷制劑中的應(yīng)用20藥動學(xué)參數(shù)微乳在紫杉烷制劑中的應(yīng)用21過敏反應(yīng)微乳制劑1級輕微的豎毛少數(shù)顫抖參比制劑3級頻繁的抓鼻、顫抖、打噴嚏、豎毛、抽搐、呼吸困難個別大小便失禁微乳在紫杉烷制劑中的應(yīng)用22微乳在紫杉醇制劑中的應(yīng)用處方四甘醇CremophorELPLabrafil1944PLGA自乳化微乳在紫杉烷制劑中的應(yīng)用23體內(nèi)外試驗體外釋放抗腫瘤實驗體外小鼠荷瘤微乳在紫杉烷制劑中的應(yīng)用24體外釋放PLGA分子量8K33K90K微乳在紫杉烷制劑中的應(yīng)用25細(xì)胞毒-體外BlankMEPCTMEPCTME+PLGA微乳在紫杉烷制劑中的應(yīng)用26抗腫瘤-體內(nèi)SalineBlankMEPCTMEPCTME+PLGA微乳在紫杉烷制劑中的應(yīng)用27微乳在多西他賽制劑中的應(yīng)用處方Capryol90CremophorELTranscutol微乳在紫杉烷制劑中的應(yīng)用28溶解度試驗Fig.3.ChangeofdocetaxelsolubilityinTaxotere?andmicroemulsionsafter20timesdilutionbysalinesolutionat37°C.Dataareexpressedasthemean±S.D.(n=3).微乳在紫杉烷制劑中的應(yīng)用29體外釋放Fig.4.ReleaseprofilesofdocetaxelfrommicroemulsionsandTaxotere?determinedby（b）thedialysismethodat37°CinPBS(pH=7.4)containing0.1%(w/v)Tween80.Eachdatapointrepresentsthemean±S.D.ofthreedeterminations.微乳在紫杉烷制劑中的應(yīng)用30體外轉(zhuǎn)運(yùn)實驗Fig.5.(a)apicaltobasolateraland(b)basolateraltoapicaltransportprofilesofdocetaxelfromTaxotere?ormicroemulsionsacrosstheCaco-2cellmonolayerat37°C.微乳在紫杉烷制劑中的應(yīng)用31藥動學(xué)試驗Fig.6.Plasmaconcentration-timeprofilesofdocetaxelafterbolusintravenousinjectionof