微乳递药系统在紫杉烷类制剂中的应用

1ApplicationofMicroemulsionBasedDrugDeliverySysteminDevelopmentofTaxanesZhixiangChen，Doctor，AssistantProfessorNationalPharmaceuticalEngineeringResearchCenter,ChinaStateInstituteofPharmaceuticalIndustry2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：[e-mail]3Contents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44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/ml5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6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7多西他赛taxotere®，SANOFIAVENTIS，1996–吐温80–13%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8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9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10乳剂/纳米乳/微乳/胶束微乳递药系统11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12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13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14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15乳剂VS纳米乳VS微乳ParameterMicroemulsionNanoemulsionEmulsionFormationSpontaneousUltrasonicandhighpressurehomogenizationMechanicalormanualagitationStableThermodynamicallyKineticallyKineticallyDropletsize(μm)0.01–0.100.05–0.500.5–50AppearanceTransparentTransparentoropaqueOpaque(cloudy)Surfacearea(m2g−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16稳定性VS粒径微乳递药系统17脂质递药系统typeMaterialsCharacteristicsAdvantagesDisadvantagesTypeIOilswithoutsurfactants(e.g.tri-,di-andmonoglycerides)Non-dispersing,requiresdigestionGRASstatus;simple;excellentcapsulecompatibilityFormulationhaspoorsolventcapacityunlessdrugishighlylipophilicTypeIIOilsandwater-insolublesurfactantsSEDDSformedwithoutwater-solublecomponentsUnlikelytolosesolventcapacityondispersionTurbido/wdispersion(particlesize0.25–2μm)TypeIIIOils,surfactants,cosolvents(bothwater-insolubleandwater-solubleexcipients)SEDDS/SMEDDSformedwithwater-solublecomponentsClearoralmostcleardispersion;drugabsorptionwithoutdigestionPossiblelossofsolventcapacityondispersion;lesseasilydigestedTypeIVWater-solublesurfactantsandcolsolvents(nooils)FormulationdispersestypicallytoformamicellarsolutionFormulationhasgoodsolventcapacityformanydrugsLikelylossofsolventcapacityondispersion;maynotbedigestible微乳递药系统18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–CremophorEL–Poloxamer188–蛋黄卵磷脂–乙醇10～50nm微乳在紫杉烷制剂中的应用19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20药时曲线微乳在紫杉烷制剂中的应用21药动学参数微乳在紫杉烷制剂中的应用22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23微乳在紫杉醇制剂中的应用处方–四甘醇–CremophorELP–Labrafil1944–PLGA自乳化微乳在紫杉烷制剂中的应用24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25体外释放PLGA分子量8K33K90K微乳在紫杉烷制剂中的应用26细胞毒-体外BlankMEPCTMEPCTME+PLGA微乳在紫杉烷制剂中的应用27抗肿瘤-体内SalineBlankMEPCTMEPCTME+PLGA微乳在紫杉烷制剂中的应用28微乳在多西他赛制剂中的应用处方–Capryol90–CremophorEL–Transcutol微乳在紫杉烷制剂中的应用29溶解度试验Fig.3.ChangeofdocetaxelsolubilityinTaxotere®andmicroemulsionsafter20timesdilutionbysalinesolutionat37°C.Dataareexpressedasthemean±S.D.(n=3).微乳在紫杉烷制剂中的应用30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31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32药动学试验Fig.6.Plasmaconcentration-timeprofilesofdocetaxelafterbolusintravenousinjectionofTaxotere®(8mg/kg),oraladministrationofTaxotere®ormicroemulsions(equivalentto10mg/kgasdocetaxel)torats.微乳在紫杉烷制剂中的应用33BA提高溶解度提高吸收促进–油/表面活性剂–P-GP抑制微乳在紫杉烷制剂中的应用34紫杉烷微乳相关中国专利序号申请号专利名称102153674.0一种抗癌药物新制剂——紫杉醇微乳2200810228905.9注射用紫杉醇冻干微乳剂及其制备方法3200910011752.7一种多烯紫杉醇自微乳组合物及其制备方法4200910074954.6紫杉醇微乳的制备方法5200910077564.4一种紫杉醇自乳化制剂及其制备方法和用途6201010177659.6一种紫杉醇纳米自微乳及其制备方法7201310059937.1一种紫杉醇微乳药物组合物及其制备方法8200710152095.9一种治疗肿瘤的含有多西他赛的微乳药物组合物及其制备方法9201010220818.6多西他赛静脉注射组合物及其制备方法10200480020339.2紫杉烷类口服给药的自乳化和自微乳化制剂微乳在紫杉烷制剂中的应用35