平其能-药剂的创新与发展

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）一、药物制剂创新的范畴新制剂品种和剂型(NDF,newdosageforms)新的复方制剂(NC,newcombination)新的用药途径(NR,newroute)新的剂量(NS,newstrength)新盐、新酯或前药(NE,newsaltorester)新晶型(NP,newpolymorphs)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)ElanCorporationPPDS(PelletizedPulsatileDelivrySystemAndrx,Pharmaceuticals,USAPeltabSystemAndrx,Pharmaceuticals,USAPRODAS(ProgrammableOralDrugAbsorptionSystems)ElanCorporationReducedIrritationsystemDepoMed,Inc.,RingCapAlkermesInc.,USASODAS(SpheroidalOralDrugAbsorptionSystemElanCorporationSMHS(SolubilityModulatingHydrogelSystemAndrx,Pharmaceuticals,USASPDAS(StabilizedPelletDeliverySystem)Andrx,Pharmaceuticals,USASQZGeloralcontrolled-releasesystemMacromed,Inc.,USAKV/24KVPharmaceuticals,USAMeterReleaseKVPharmaceuticals,USASymatrixKVPharmaceuticals,USASpheroidKVPharmaceuticals,USAOrasertKVPharmaceuticals,USAOrasiteKVPharmaceuticals,USATriglastechnologyEthicalHoldingsIc.,RhotardEthicalHoldingsIc.,OralDrugDeliveryTechnicalPlatforms剂型创新定位与定时释放—局部疾病的治疗；胃溃疡、肠炎、结肠炎—蛋白质及多肽等大分子药物的给药；—延长药物的吸收时间；—脉冲给药、24小时缓释的重要手段。（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;（2）胃肠定位技术—胃肠pH控制—胃肠转运时间控制—酶、细菌降解控制—多因素控制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)ElanCorporationOralDrugDeliveryTechnicalPlatforms2、注射给药—脂质体(lipposomes)——微球(microsheres)——纳米粒(nanoparticles)——脂肪乳(Fattyemulsion)——胶束(polymericmicells)——埋植剂(implant)——PEG化(PEGylation)（1）Stealthliposome（2）ImmunologicalLiposomedrugcontainingimmunoliposomenoimmunospecificbindingtargetcellnon-targetcell（3）两亲性高分子：PLA-PEG（4）PEG化（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-adifferentprocessalthoug