微乳递药系统在紫杉烷类制剂中的应用

ApplicationofMicroemulsionBasedDrugDeliverySysteminDevelopmentofTaxanesZhixiangChen，Doctor，AssistantProfessorNationalPharmaceuticalEngineeringResearchCenter,ChinaStateInstituteofPharmaceuticalIndustry1微乳递药系统在紫杉烷类制剂中应用陈志祥博士、助理研究员中国医药工业研究总院药物制剂国家工程研究中心联系方式：2Contents紫杉烷类上市制剂1理想的紫杉烷制剂2微乳递药系统3微乳在紫杉烷制剂中的应用43紫杉烷类上市制剂紫杉烷类药物制剂面临的主要问题溶解度差紫杉醇0.35～0.7μg/ml多西他赛3～25μg/ml4紫杉醇Taxol®，Bristol-MyersSquibb,1992

50%CremophorEL(聚氧乙烯蓖麻油）50%乙醇胶束过敏紫杉烷类上市制剂5紫杉醇ABRAXANE

®，ABRAXISBIOSCIENCELLC,2005

白蛋白纳米粒反应更高,毒性更低价格昂贵抗肿瘤效果提高不明显患者生存时间仅延长几周紫杉烷类上市制剂6多西他赛taxotere®，SANOFIAVENTIS，1996吐温8013%乙醇胶束不稳定，4h内滴注完吐温引起溶血和胆汁淤积紫杉烷类上市制剂7多西他赛DOCEFREZTM，SUNPHARMAGLOBALFZE，2011多西他赛冻干粉吐温80，35.4%乙醇DOCETAXEL,SANDOZ，2011浓缩注射液吐温80，PEG300，枸橼酸DOCETAXEL,ACTAVISINC，2013浓缩注射液吐温80，35.4%乙醇，聚维酮，枸橼酸紫杉烷类上市制剂8理想的紫杉烷类抗肿瘤药物制剂易于产业化的生产工艺质量稳定成本低廉临床给药简单靶向肿瘤组织不良反应少9乳剂/纳米乳/微乳/胶束微乳递药系统10胶束胶束CMC（临界胶束浓度)增溶脂溶性药物载药容量有限上市制剂含乙醇，毒性稀释不稳定微乳递药系统11乳剂/纳米乳/微乳乳剂乳化剂，油相，水相>0.5um，混浊液乳白O/W，黄色W/O微乳递药系统12乳剂/纳米乳/微乳纳米乳表活剂和共-表活剂的两不混溶液相剪切而成0.05～0.5um透明，半透明或混浊取决与液滴的直径和连续相的折光系数微乳递药系统13乳剂/纳米乳/微乳微乳透明，热动力学稳定极性和非极性液相，表活剂或加共表活剂界面张力10-3mNm-1时自发形成溶液样体系微乳递药系统14乳剂VS纳米乳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微乳递药系统15稳定性VS粒径微乳递药系统16脂质递药系统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微乳递药系统17微乳在紫杉醇制剂中的应用处方三辛酸甘油酯一三丁酸甘油酯CremophorELPoloxamer188蛋黄卵磷脂乙醇10～50nm微乳在紫杉烷制剂中的应用18动物实验过敏试验药动学评价微乳在紫杉烷制剂中的应用19药时曲线微乳在紫杉烷制剂中的应用20药动学参数微乳在紫杉烷制剂中的应用21过敏反应微乳制剂1级轻微的竖毛少数颤抖参比制剂3级频繁的抓鼻、颤抖、打喷嚏、竖毛、抽搐、呼吸困难个别大小便失禁微乳在紫杉烷制剂中的应用22微乳在紫杉醇制剂中的应用处方四甘醇CremophorELPLabrafil1944PLGA自乳化微乳在紫杉烷制剂中的应用23体内外试验体外释放抗肿瘤实验体外小鼠荷瘤微乳在紫杉烷制剂中的应用24体外释放PLGA分子量8K33K90K微乳在紫杉烷制剂中的应用25细胞毒-体外BlankMEPCTMEPCTME+PLGA微乳在紫杉烷制剂中的应用26抗肿瘤-体内SalineBlankMEPCTMEPCTME+PLGA微乳在紫杉烷制剂中的应用27微乳在多西他赛制剂中的应用处方Capryol90CremophorELTranscutol微乳在紫杉烷制剂中的应用28溶解度试验Fig.3.ChangeofdocetaxelsolubilityinTaxotere®andmicroemulsionsafter20timesdilutionbysalinesolutionat37°C.Dataareexpressedasthemean±S.D.(n=3).微乳在紫杉烷制剂中的应用29体外释放Fig.4.ReleaseprofilesofdocetaxelfrommicroemulsionsandTaxotere®determinedby（b）thedialysismethodat37°CinPBS(pH=7.4)containing0.1%(w/v)Tween80.Eachdatapointrepresentsthemean±S.D.ofthreedeterminations.微乳在紫杉烷制剂中的应用30体外转运实验Fig.5.(a)apicaltobasolateraland(b)basolateraltoapicaltransportprofilesofdocetaxelfromTaxotere®ormicroemulsionsacrosstheCaco-2cellmonolayerat37°C.微乳在紫杉烷制剂中的应用31药动学试验Fig.6.Plasmaconcentration-timeprofilesofdocetaxelafterbolusintravenousinjectionof