药物制剂的创新与发展课件

药物制剂的创新与发展

TechnologicalPlatformsandDevelopmentofDrugDeliverySystems发展药物制剂创新技术的重要意义

改进依从性（

compliance）改进或独特的临床效果（outcomes）减少副作用（reductionofadverseeffects）节约研发成本（avoidanceoflaboratorycosts）减少医疗费用（reductioninoveralluse）新的处方及工艺特定处方成分（如高分子、稳定剂、促吸剂）特定的包衣材料和组合特定的溶出速率特定的粒径特定的硬度不同的药动学参数、特定包装二、剂型与制剂的创新

1、经口腔及胃肠道给药—缓释及控释技术—口腔粘附技术—胃肠道定时、定位技术

OralDrugDeliveryTechnicalPlatformsEOP(ElementaryOsmoticPump)Alza,USAMacroCapBiovail,CanadaMicropump(oralcontrolleddeliverysystem)FlamelTech,FranceModas(MultiporousOralDrugAbsorptionSystem)Elan,IrelandSCOT(SingleCompositionOsmoticTabletsSystem)Andrx,Pharmaceuticals,USAZer-Os(Tablettechnology)ADDDrugdeliveryTech,AG,SwissCeformmicrospheretechnologyFuiszTech,USACONSURF(ConstantSurfaceAreaDrugDeliveryShuttle)BiovailCorp.InternationalEOP(ElementaryOsmoticPump)Alza,USAContramidLabopharm,CanadaDimatrix(DiffusionControlledMatrixSystem)BiovailCorp.InternationalDPHS(DelayedPulsatileHydrogelSystemAndrx,Pharmaceuticals,USADUREDAS(DualReleaseDrugAbsorptionSystem)ElanCorporationGastricretentionsystemDepoMedInc,USAGeoMatrixSkyePharmaPlc,USAGMHS(GranulatedModulatingHydrogelSystemAndrx,Pharmaceuticals,USAIPDAS(IntestinalProtedtiveDrugAbsorptionSys)ElanCorporationMultiportechnologyEthicalHoldingsPlc,UKPharmazome(MicroparticulateDrugDeliveryTech)ElanCorporation剂型创新（1）胃肠滞留技术——利用高分子的粘附性：Carbopol,HPMC,CMC-Na——利用低密度辅料:Eudragit,轻质氧化镁,长链醇；——利用高密度辅料：重质氧化镁，碳酸镁——利用气体（CO2）：NaHCO3,Mg(OH)CO3——特异性粘附（生物凝集素）:lectins;ATRIDOX®四环素50mg丙烯酸树脂-EVA共聚物100mg甲基吡咯酮3ml地塞米松5mg卡波沫15mgHPMC5mg三乙醇胺q.s油3ml(3)口腔粘贴凝胶剂粘附片：粘附力、溶胀速率与粘附时间的关系MacromoleculesDrugDeliveryTechnicalPlatformsBEODAS(BioerodableEnhancedOralDrugAbsorptionSystemElanCorporationDepoFoamDepoTechCorporation,USADUROSAlza,USALODAS(LocalizedDrugAbsorptionSystem)ElanCorporationMacromolSystemCortecsInternationalLtd.,UKOralMucosalVaccinesCortecsInternationalLtd.,UKMedipadElanCorporationOralvacccineElanCorporationProleaseandMedisorbAlkermesInc.,TasteMaskingChewabletabletsElanCorporationFlavortechKeyPharmaceuticalsMicromaskKeyPharmaceuticalsLiquetteKeyPharmaceuticalsOraquickKeyPharmaceuticalsTastemaskingAscentPediatricsInc.,USAOralfastdispersingdosageformsZydisR.P.Scherer,UKLYOCFarmalyoc,FranceQuicksolvJanssenPharmaceutica,USAMultiflashPrographarm,FranceOrasolvCimaLabsInc.,USAWowtabYamanouchiPharmaTechnologies,USAFastMeltElanCorporationFlashdoseFuiszTechnologies,USAFlashtabPrographarm,FranceEFVDAS(EffervescentDrugAbsorptionSystem)ElanCorporationOralDrugDeliveryTechnicalPlatforms（1）Stealthliposomedrugcontainingimmunoliposomenoimmunospecificbindingtargetcellnon-targetcell（3）两亲性高分子：PLA-PEG（5）微球与埋植剂

[CH2C]CH3COOCH3Poly(methylmethacrylate)[COROCNHR’NH]OOPoly(urethanes)[OCRC]OOPolyanhydrides二、工艺创新

1、熔融挤出2、液体填充硬胶囊3、纳米方法——（1）高压均质（2）超临界流体技术RapidExpansionofSupercriticalSolution(RESS)PrecipitationfromGasSaturatedSolution(PGSS)GasAnti-solvent(GAS)AerosolSolventExtractionSystem(ASES)SchematicDiagramoftheApparatusUtilizingSCFforInclusion（3）生物芯片TIMERxÒisapatented,controlledreleasetechnologybasedonanagglomeratedhydrophilicmatrixwhichconsistsoflocustbeangumandxanthangum.Interactionsbetweenthesecomponentsinanaqueousenvironmentformatightgelwithaslowlyerodingcore.TheTIMERxÒdeliverysystemiscompatiblewithabroadrangeofactivedrugsubstances。三、辅料创新壳聚糖衍生物pH敏感水凝胶基于氢键和次级疏水键的交联；交联与pH有关且可逆；交联程度控制水凝胶孔径。PEG接枝的pH敏感水凝胶优点:*相容性 *水溶性*无毒 *迅速从体内清除聚乳酸与壳聚糖接枝共聚物难溶性药物的增溶剂——

Lip’ralTM

和GalactolipidsTechnologyPlatform由类脂组成的生物相容性辅料；适合于小于50ug/ml的难溶性药物；在体内自动形成胶束、微乳或溶液；药物不析出；方便制备；四、设备与给药器创新1、透皮吸收TransdermalDeliverySystemsDermaflexElanCorporationDermasiteKVPharmaceuticalsD-transAlza,USAE-trans(Iontophoresis)Alza,USAMicrospongesystemsAdvancedPolymerSystemsInc.,USATransdermaldrugdeliverysystemsCygnusInc.,USAPolytrapsystemsAdvancedPolymerSystemsInc.,USATheraDerm-LRSTheratech,Inc.,USATheraPatchLecTecCorporation,USAFentanylNicotineTestosteroneDermocypionalTD

OneTestosteroneinaTransdermal/LiposomalDeliverySystemDermalin-ApgTransdermalEmulsifyingGel,Lecithin,Aminophylline,.

超声波促渗Phonophoresis1)cavitation2)microstreaming3)heatgenerationPhonophoresisistheintroductionofsubstancesintothebodybyultrasonicenergy.Unlikeiontophoresiswhichinvolvesthetransferofionsintothetissue,phonophoresistransmitsmolecules-adifferentprocessalthoughsimilarinconcept.

Someofthecommonchemicalscompoundedforphonophoresisinclude:BetamethasoneDipropionateUSPDexamethasoneUSPDexamethasoneUSP&LidocaineUSPFluocinonideUSPHydrocortisoneUSPHydrocortisoneUSP&LidocaineUSPKetoprofenUSPNaproxenUSPPiroxicamUSPSodiumSalicylate

机械技术Microflux@TransdermalTechnology

离子导入及电致孔IontophoresisandElectroporationINTOPHORESIS无针头溶液注射器2、吸入给药InhalabledrugforsystemictherapyEfficientlydelivertothelungperipheryReproducibletherapeuticdrugdoseAccommodateflexibledosingStableformulationatroomTemp.Devicemustbeportableandeasytouse口腔吸入器鼻腔喷雾器五、基础研究和多学科结合是制剂创新的动力1、药物剂型与给药途径2、药剂学的分支学科和课程

工业药剂学(IndustrialPharmaceutics)

物理药剂学(PhysicalPharmaceutics)

药用高分子材料学(PolymersinPharmaceutics)

制剂工程学（PharmaceuticalEngineering)

生物药剂学(Biopharmaceutics)

药物动力学(Pharmacokinetics)

临床药学(ClinicalPharmacy)

药物多晶型研究：多晶型形成示意图药物在熔融—冷却过程中发生的晶型变化互变型转换的晶型均相及多相体系的研究：微乳液相图吸收动力学研究1、生物药剂学分类系统（BiopharmaceuticsClassficationSystem,BCS）溶解性i渗透性类型2低溶解度高渗透性类型3高溶解度高渗透性类型4低溶解度低渗透性类型1高溶解度低渗透性高溶解度=最大剂量在250mL

pH1-7.5溶液中溶解高渗透性=吸收分数90%未表示代谢性质有效成分的生物利用度分类系统溶解性渗透性类型2低溶解度高渗透性类型3高溶解度高渗透性类型4低溶解度低渗透性类型1高溶解度低渗透性红花黄色素川芎嗪丹参素三七总皂苷冰片挥发油

柠檬苦素水飞蓟素中药复方对有效成分生物利用度分类的作用溶解性渗透性类型2低溶解度高渗透性类型3高溶解度高渗透性类型4低溶解度低渗透性类型1高溶解度低渗透性红花黄色素三七总皂苷冰片挥发油？低渗透性低溶解度低溶解度低渗透性川芎嗪丹参素低溶柠檬苦素水飞蓟素中药苷类成分吸收机理：肠肠循环和肠肝循环

肠壁

b-糖苷酶

苷 苷元 葡糖苷酸

硫酸化

苷

苷元

结合物LPH

血液循环肝脏心

门脉MRP

微绒毛

MRP

OATOAT胆??

MRP

SGLT1小肠微绒毛转运肠腔侧血液外排中药苷类成分的胃肠吸收机理

外排泵与代谢酶对苷的偶合作用苷类成分酶转运肠腔侧肠壁侧外排中药复方成分或剂型因素的作用

苷类酶代谢物苷元在体肠段灌流技术

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