口服控释改良释放剂型的发展

EvolutionofOralControlled/ModifiedReleaseDosageForms口服控释/改良释放剂型的发展OralCR/MRDosageForms口服CR/MR剂型“Extended-Release”“延长释放”“Delayed-Release”“延迟释放”ControlledRelease↔ModifiedRelease控制释放↔改良释放PotentialBenefitsofControlledReleaseDosageForms控释剂型的潜在优点•Enhancedactivitydurationforshorthalf-lifedrugs•提高短半衰期药物的有效作用时间•Reductionofsideeffects•降低副反应•Lessfrequentdosing-improvedpatientcompliance•减少给药频率-提高患者顺应性•Protectinglabiledrugs-improvedproductstability•保护不稳定药物-提高产品的稳定性•Potentialforlocalizationofdrugtositeofaction•将药物固定于起效部位的可能性•Potentialforextendedpatentprotection•延长专利保护的可能性Howdidwegethereandwherearewegoing?我们是如何达到现在的水平并将向哪方面发展？OralCR/MRDosageForms口服CR/MR剂型“蜡丸者,取其难化,而旋旋取效也”“Usewaxpillsfortheirresistancetodissolvetherebyachievingtheeffectgraduallyandslowly”EarlySlow-ReleaseOralDosageFormsinChineseMedicine中药中的早期缓释口服剂型●2ndCenturyB.C.–Animal-fatsasbinderforpills[“RecipesforFifty-TwoAilment”,MawangduiMedicalManuscript,dated168B.C.]公元前2世纪－动物脂肪作为丸剂的粘合剂〔“52种疾病的处方”，马王堆医学手稿，日期公元前168〕●4thCenturyA.D.–Waxandfatpills[“HandbookofPrescriptionsforUrgentCases”,KoHung(281-341)]公元4世纪－蜂蜡和脂肪丸剂〔”肘后救卒方“葛洪(281-341〕●13thCentury–Waxpillsforslow-release[“RulesandCorrespondencesintheUseofDrugs”,LiKao(1180-1251)&“MedicationsAdministeredasDecoctions”,WangHao-ku(mid-13thcentury)]13世纪－缓慢释放的蜡丸〔”药物使用中的规则和依据“LiKao(1180-1251)&”按汤剂服用“〕“丸者缓也,..其用药之舒缓而治之意也”“Suchpillsareslowacting…theyprovidethedruggraduallyandslowlyfortreatment”Earliestrecordofslow-releasedosageformsfortherapeuticuse!治疗所用缓释剂型的早期记载TypesofLong-ActingPreparations,1959长效制剂的类型，1959•Coatingtheactivedrugwithgastro-resistantandslowlyenterosolublesubstances(e.g.fats,waxes,fattyacids,ets.)•使用抗胃液和减慢肠溶解的物质包裹活性药物（比如，脂肪，蜂蜡，脂肪酸等等）•Theuseofionexchangeresinstobindactivedrugs•使用离子交换树脂与活性药物结合•Theformationofchemicaladditioncompoundsorcomplexes•化学添加物或合成物的形成•Impregnatingorembeddingthedruginabasewhichgraduallyreleasestheactiveprinciple•将药物浸渍或包埋在一个基质中，该基质可缓慢释放活性有效成分From:J.LazarusandJ.Cooper,J.PharmPharmacol.,11,257(1959)MajorHistoricalMilestonesAffectingtheDirectionofOralControlledReleaseDosageForms影响口服控释剂型发展方向的主要历史里程碑•Availabilityofsemi-syntheticandsyntheticpolymersforentericcoating(1940’sthrough1990’s)•半合成和合成聚合物用于肠溶包衣（二十世纪四十年代到九十年代）•IntroductionoffirstoralsustainedreleaseproductsbySmithKline&FrenchusingtheSpansuletechnology:Dexedrine(dextroamphetaminesulfate)(1952)andContac,thecoldremedy(1960).•SmithKline&French介绍了首个口服持续释放产品，使用了缓释胶囊剂（Spansule）技术：Dexedrine（右旋硫酸右苯丙胺）（1952）和Contac（复方盐酸苯丙醇胺），感冒药（1960）•Introductionofsemi-syntheticandsynthetichydrophilicgelformingpolymersfordesigningoralsustainedreleaseproducts(1950’sand1960’s)•半合成和合成亲水凝胶形成的聚合物介入口服持续释放产品设计（二十世纪五十年代和六十年代）•InventionandfirstcommercializationoforalosmoticdrugdeliverysystemsbyALZA(1970’sthrough1980’s)•ALZA发明并首次商业使用的口腔渗透药物释放系统（二十世纪七十年代到八十年代）“Thedelayedactiontabletwhichwasanextensionoftheentericcoatingprinciple,representedtheinitialapproachincontrollingthereleaseofadruginthegastro-intestinaltract”“延迟起效片剂是肠溶包衣原理的扩展，它代表在胃肠道中控制药物释放开始起步”-LazarusandCooper(1959)Reasonsforentericprotection肠溶包衣的目的Preventionofgastricirritation避免胃的刺激Protectionofdrugsunstableingastricfluids避免药物在胃酸条件下被破坏Deliveryofdrugtolocalsiteinintestine药物在肠道特定部位释放Deliveryofdrugtobestabsorptionsiteinintestine药物在肠道最佳吸收部位释放Delayeddrugrelease药物延迟释放ENTERICCOATINGSYSTEMS肠溶包衣系统EntericCoatings肠溶包衣•1884–Dr.PaulUnnaintroducedkeratin-coatedpills•1884–PaulUnna博士引入了角质素包衣丸剂•Late1880’sto1930’s–Numeroussubstancesandtheircombinationwereusedforentericcoatingsuchaskeratin,salol,tolu,shellac,casein,zein,stearicacid,gelatin-formaldehydeproduct,tannicacid-gelatinproduct,cetylalcohol,etc.•十九世纪八十年代晚期到二十世纪30年代－众多物质及其混合物用于肠溶包衣，比如角质素，水杨酸苯酯，妥鲁香脂,紫胶，酪蛋白，玉米蛋白，硬脂酸，明胶－甲醛产品，鞣酸－明胶产品，十六烷醇等等。•1940’s–Celluloseacetatephthalate(CAP)introduced•二十世纪四十年代－引进醋酞纤维素（CAP）•1970’s–Polyvinylacetatephthalate(PVAP)andhydorxypropylmethylcellulosephthalate(HPMCP)becameavailable•二十世纪七十年代－可使用聚醋酸乙烯邻苯二甲酸酯(PVAP)和羟丙基甲基纤维素邻苯二甲酸酯（HPMCP）•1980’s-Methacrylate-methacrylicacidcoplymersonthemarket•二十世纪八十年代－异丁烯酸-甲基丙烯酸共聚物出现在市场•1980’sto1990’s–Variousaqueousdispersionsofentericpolymersintroducedfortabletcoatingshang•二十世纪八十年代到二十世纪九十年代－各种肠溶聚合物水分散系用于片剂包衣●ThedevelopmentofSpansuleprovidedtheimpetustothefurtherdevelopmentofsustainedreleasedosageformsinsubsequentyearsSpansule的发展为延释剂型在今后几年中进一步发展提供了推动力●Italsostimulatednumeroushumanstudiesregardingtheabsorption,distributionandfateofdrugsdeliveredbysuchdosageforms,thusculminatingthestartofthestudyofbiopharmaceutics也刺激了众多针对在使用这种剂型后吸收，分布和药物释放途径的人类研究，因而使生物药剂学的研究开始到达顶峰MultiparticulateDrugDelivery多颗粒药物释放CLINICALADVANTAGES（临床优点）•DispersefreelyintheGItract,invariablymaximizedrugabsorption,reducepeakplasmafluctuation,andminimizepotentialsideeffects.容易通过胃肠道，有利药物吸收，降低不良反应•Reducevariationsingastricemptyingratesandoveralltransittimes.Thusinter-andintra-subjectvariabilityofplasmaprofilesisminimized.减少因胃排空速率和转运时间不同而产生的差异。从而提高体外释放和体内血浆药物浓度的相关性•Highlocalconcentrationofbioactiveagents,whichmayinherentlybeirritativeoranesthetic,canbeavoided.避免具有刺激性和麻醉性的生物活性物质在局部浓度过高•Lesssusceptibletodosedumpingthanthereservoir-type,singleunitformulations.相对于膜控释单剂量药物单元，可减少