發(fā)展藥物制劑創(chuàng)新技術的重要意義

改進依從性（

compliance）改進或獨特的臨床效果（outcomes）減少副作用（reductionofadverseeffects）節(jié)約研發(fā)成本（avoidanceoflaboratorycosts）減少醫(yī)療費用（reductioninoveralluse）當前1頁，總共83頁。當前2頁，總共83頁。一、藥物制劑創(chuàng)新的范疇新制劑品種和劑型(NDF,newdosageforms)新的復方制劑(NC,newcombination)新的用藥途徑(NR,newroute)新的劑量(NS,newstrength)新鹽、新酯或前藥(NE,newsaltorester)新晶型(NP,newpolymorphs)當前3頁，總共83頁。新的處方及工藝特定處方成分（如高分子、穩(wěn)定劑、促吸劑）特定的包衣材料和組合特定的溶出速率特定的粒徑特定的硬度不同的藥動學參數、特定包裝當前4頁，總共83頁。二、劑型與制劑的創(chuàng)新

1、經口腔及胃腸道給藥—緩釋及控釋技術—口腔粘附技術—胃腸道定時、定位技術

當前5頁，總共83頁。當前6頁，總共83頁。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當前7頁，總共83頁。PPDS(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當前8頁，總共83頁。劑型創(chuàng)新當前9頁，總共83頁。定位與定時釋放—局部疾病的治療；胃潰瘍、腸炎、結腸炎—蛋白質及多肽等大分子藥物的給藥；—延長藥物的吸收時間；—脈沖給藥、24小時緩釋的重要手段。當前10頁，總共83頁。（1）胃腸滯留技術——利用高分子的粘附性：Carbopol,HPMC,CMC-Na——利用低密度輔料:Eudragit,輕質氧化鎂,長鏈醇；——利用高密度輔料：重質氧化鎂，碳酸鎂——利用氣體（CO2）：NaHCO3,Mg(OH)CO3——特異性粘附（生物凝集素）:lectins;當前11頁，總共83頁。（2）胃腸定位技術—胃腸pH控制—胃腸轉運時間控制—酶、細菌降解控制—多因素控制當前12頁，總共83頁。ATRIDOX?四環(huán)素50mg丙烯酸樹脂-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)口腔粘貼凝膠劑當前13頁，總共83頁。粘附片：粘附力、溶脹速率與粘附時間的關系當前14頁，總共83頁。MacromoleculesDrugDeliveryTechnicalPlatformsBEODAS(BioerodableEnhancedOralDrugAbsorptionSystemElanCorporationDepoFoamDepoTechCorporation,USADUROSAlza,USALODAS(LocalizedDrugAbsorptionSystem)ElanCorporationMacromolSystemCortecsInternationalLtd.,UKOralMucosalVaccinesCortecsInternationalLtd.,UKMedipadElanCorporationOralvacccineElanCorporationProleaseandMedisorbAlkermesInc.,當前15頁，總共83頁。當前16頁，總共83頁。TasteMaskingChewabletabletsElanCorporationFlavortechKeyPharmaceuticalsMicromaskKeyPharmaceuticalsLiquetteKeyPharmaceuticalsOraquickKeyPharmaceuticalsTastemaskingAscentPediatricsInc.,USAOralfastdispersingdosageformsZydisR.P.Scherer,UKLYOCFarmalyoc,FranceQuicksolvJanssenPharmaceutica,USAMultiflashPrographarm,FranceOrasolvCimaLabsInc.,USAWowtabYamanouchiPharmaTechnologies,USAFastMeltElanCorporationFlashdoseFuiszTechnologies,USAFlashtabPrographarm,FranceEFVDAS(EffervescentDrugAbsorptionSystem)ElanCorporationOralDrugDeliveryTechnicalPlatforms當前17頁，總共83頁。2、注射給藥—脂質體(lipposomes)——微球(microsheres)——納米粒(nanoparticles)——脂肪乳(Fattyemulsion)——膠束(polymericmicells)——埋植劑(implant)——PEG化(PEGylation)當前18頁，總共83頁。（1）Stealthliposome當前19頁，總共83頁。當前20頁，總共83頁。（2）ImmunologicalLiposome當前21頁，總共83頁。drugcontainingimmunoliposomenoimmunospecificbindingtargetcellnon-targetcell當前22頁，總共83頁。（3）兩親性高分子：PLA-PEG當前23頁，總共83頁。（4）PEG化當前24頁，總共83頁。當前25頁，總共83頁。當前26頁，總共83頁。（5）微球與埋植劑

當前27頁，總共83頁。當前28頁，總共83頁。[CH2C]CH3COOCH3Poly(methylmethacrylate)[COROCNHR’NH]OOPoly(urethanes)[OCRC]OOPolyanhydrides當前29頁，總共83頁。二、工藝創(chuàng)新

1、熔融擠出當前30頁，總共83頁。2、液體填充硬膠囊當前31頁，總共83頁。當前32頁，總共83頁。當前33頁，總共83頁。3、納米方法——（1）高壓均質當前34頁，總共83頁。（2）超臨界流體技術RapidExpansionofSupercriticalSolution(RESS)PrecipitationfromGasSaturatedSolution(PGSS)GasAnti-solvent(GAS)AerosolSolventExtractionSystem(ASES)當前35頁，總共83頁。SchematicDiagramoftheApparatusUtilizingSCFforInclusion當前36頁，總共83頁。（3）生物芯片當前37頁，總共83頁。當前38頁，總共83頁。當前39頁，總共83頁。TIMERxòisapatented,controlledreleasetechnologybasedonanagglomeratedhydrophilicmatrixwhichconsistsoflocustbeangumandxanthangum.Interactionsbetweenthesecomponentsinanaqueousenvironmentformatightgelwithaslowlyerodingcore.TheTIMERxòdeliverysystemiscompatiblewithabroadrangeofactivedrugsubstances。三、輔料創(chuàng)新當前40頁，總共83頁。殼聚糖衍生物當前41頁，總共83頁。pH敏感水凝膠基于氫鍵和次級疏水鍵的交聯；交聯與pH有關且可逆；交聯程度控制水凝膠孔徑。當前42頁，總共83頁。PEG接枝的pH敏感水凝膠優(yōu)點:*相容性 *水溶性*無毒 *迅速從體內清除當前43頁，總共83頁。聚乳酸與殼聚糖接枝共聚物當前44頁，總共83頁。難溶性藥物的增溶劑——

Lip’ralTM

和GalactolipidsTechnologyPlatform由類脂組成的生物相容性輔料；適合于小于50ug/ml的難溶性藥物；在體內自動形成膠束、微乳或溶液；藥物不析出；方便制備；當前45頁，總共83頁。當前46頁，總共83頁。當前47頁，總共83頁。當前48頁，總共83頁。當前49頁，總共83頁。四、設備與給藥器創(chuàng)新1、透皮吸收當前50頁，總共83頁。當前51頁，總共83頁。TransdermalDeliverySystemsDermaflexElanCorporationDermasiteKVPharmaceuticalsD-transAlza,USAE-trans(Iontophoresis)Alza,USAMicrospongesystemsAdvancedPolymerSystemsInc.,USATransdermaldrugdeliverysystemsCygnusInc.,USAPolytrapsystemsAdvancedPolymerSystemsInc.,USATheraDerm-LRSTheratech,Inc.,USATheraPatchLecTecCorporation,USA當前52頁，總共83頁。FentanylNicotineTestosteroneDermocypionalTD

OneTestosteroneinaTransdermal/LiposomalDeliverySystemDermalin-ApgTransdermalEmulsifyingGel,Lecithin,Aminophylline,.

當前53頁，總共83頁。超聲波促滲Phonophoresis1)cavitation2)microstreaming3)heatgeneration當前54頁，總共83頁。Phonophoresisistheintroductionofsubstancesintothebodybyultrasonicenergy.Unlikeiontophoresiswhichinvolvesthetransferofionsintothetissue,phonophoresistransmitsmolecules-adifferentprocessalthoughsimilarinconcept.

Someofthecommonchemicalscompoundedforphonophoresisinclude:BetamethasoneDipropionateUSPDexamethasoneUSPDexamethasoneUSP&LidocaineUSPFluocinonideUSPHydrocortisoneUSPHydrocortisoneUSP&LidocaineUSPKetoprofenUSPNaproxenUSPPiroxicamUSPSodiumSalicylate

當前55頁，總共83頁。

機械技術Microflux@TransdermalTechnology

當前56頁，總共83頁。

離子導入及電致孔IontophoresisandElectroporation當前57頁，總共83頁。INTOPHORESIS當前58頁，總共83頁。無針頭溶液注射器當前59頁，總共83頁。2、吸入給藥InhalabledrugforsystemictherapyEfficientlydelivertothelungperipheryReproducibletherapeuticdrugdoseAccommodateflexibledosingStableformulationatroomTemp.Devicemustbeportableandeasytouse口腔吸入器當前60頁，總共83頁。當前61頁，總共83頁。當前62頁，總共83頁。鼻腔噴霧器當前63頁，總共83頁。五、基礎研究和多學科結合是制劑創(chuàng)新的動力1、藥物劑型與給藥途徑當前64頁，總共83頁。2、藥劑學的分支學科和課程

工業(yè)藥劑學(IndustrialPharmaceutics)

物理藥劑學(PhysicalPharmaceutics)

藥用高分子材料學(PolymersinPharmaceutics)

制劑工程學（PharmaceuticalEngineering)

生物藥劑學(Biopharmaceutics)

藥物動力學(Pharmacokinetics)

臨床藥學(ClinicalPharmacy)

當前65頁，總共83頁。藥物多晶型研究：多晶型形成示意圖當前66頁，總共83頁。藥物在熔融—冷卻過程中發(fā)生的晶型變化當前67頁，總共83頁?；プ冃娃D換的晶型當前68頁，總共83頁。均相及多相體系的研究：微乳液相圖當前69頁，總共83頁。當前70頁，總共83頁。吸收動力學研究當前71頁，總共83頁。1、生物藥劑學分類系統(tǒng)（BiopharmaceuticsClassficationSystem,BCS）溶解性i滲透性類型2低溶解度高滲透性類型3高溶解度高滲透性類型4低溶解度低滲透性類型1高溶解度低滲透性高溶解度=最大劑量在250mL

pH1-7.5溶液中溶解高滲透性=吸收分數90%未表示代謝性質當前72頁，總共83頁。有效成分的生物利用度分類系統(tǒng)溶解性滲透性類型2低溶解度高滲透性類型3高溶解度高滲透性類型4低溶解度低滲透性類型1高溶解度低滲透性紅花黃色素川芎嗪丹參素三七總皂苷冰片揮發(fā)油

檸檬苦素水飛薊素當前73頁，總共83頁。中藥復方對有效成分生物利用度分類的作用溶解性滲透性類型2低溶解度高滲透性類型3高溶解度高滲透性類型4低溶解度低滲透性類型1高溶解度低滲透性紅花黃色素三七總皂苷冰片揮發(fā)油？低滲透性低溶解度低溶解度低滲透性川芎嗪丹參素低溶檸檬苦素水飛薊素當前74頁，總共83頁。中藥苷類成分吸收機理：腸腸循環(huán)和腸肝循環(huán)

腸壁

b-糖苷酶

苷 苷元 葡糖苷酸

硫酸化

苷

苷元

結合物LPH

血液循環(huán)肝臟心

門脈MRP

微絨毛

MRP

OATOAT膽??

MRP

SGLT1小腸微絨毛當前75頁，總共83頁。轉運腸腔側血液外排中藥苷類成分的胃腸吸收機理

外排