口服控释改良释放剂型的发展.ppt

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”,ControlledReleaseModifiedRelease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(281-341,13thCenturyWaxpillsforslow-release“RulesandCorrespondencesintheUseofDrugs”,LiKao(1180-1251)HPC;PEO;NaAlginate羟丙基甲基纤维素：HPC：聚氧化乙烯：藻(朊)酸钠ExamplesofSwellableTabletProducts可溶胀片剂产品实例Indocin(Indomethacin;Merck)（吲哚美辛；Merck）IsoptinSR(VerapamilHCL;Knoll)（盐酸维拉帕米；Knoll）Trental(Pentoxifylline;HMR)（己酮可可碱；HMR）,SwellingPfizer)（硝苯地平,；Pfizer）Covera-HS(VerapamilHCl;Searle)（盐酸维拉帕米；Searle）DynaCircCR(Isradipine;Norvartis)）（依拉地平；Norvartis）Concerta(MethylphenidateHCl;McNeil)（盐酸哌甲酯；McNeil）,Controlled-ReleaseOROSDeliverySystems(OsmoticPump)控释口腔渗透的渗透泵缓释剂（OROS）释放系统（渗透泵）,ElementaryOsmoticPump初级渗透泵Constantreleaserateismaintainedbyaconstantosmoticdrivingforce(fromexcesssolubledrugand/orosmoticadjuvant)通过持续渗透驱动力保持恒定的释放率（从极易溶药物和/或渗透佐剂）Push-PullOsmoticPump推-拉渗透泵Constantreleaserateismaintainedbytheconstantswellingofhydrogelpushlayer通过水凝胶挤压层持续溶胀保持恒定释放率Usefulfordeliveringlowsolubilitydrugs(inasuspension)对释放不易溶药物有用（在混悬液中）Pulsatiledeliveryfeasiblewithmultiplecompartments(OROSTri-Layer)可行的多层室脉冲式释放（OROS三层）Canbeadaptedforliquidformulations(L-OROS)适用于液体处方（L-OROS）,OsmoticPumpingMechanism:渗透泵原理ReleaseCharacteristics释放特征,PhenylpropanolamineOROSTablet1stOsmoticTabletProduct:“Acutrim”n-去甲麻黄碱OROS片剂第一个渗透泵片剂产品：“Acutrim”,InVivo()&InVitro()DeliveryProfiles体内()&体内()释放曲线,Predicted&ExperimentalPlasmaConcentrationProfiles期望&试验血浆浓度,GoodandLee(1984),MembraneSystems-Drugcoresurroundedbyarate-controllingmembrane(e.g.,microcapsules&coateddrugpellets,granulesorbeads)膜系统-药芯为速率控制膜包围（比如，微胶囊&包衣药物小丸，颗粒或小球）MatrixSystems-Drugdissolvedordispersedinacarriermatrix(e.g.,microspheres,beads,pellets,granules&tablets)基质系统-药物溶解或分散于载体基质中（比如，微球，小球，小丸，颗粒&片剂）HybridSysrtems-Acombinationofmembraneandmatrixsystems(e.g.,coatedpelletsorbeadsimbededinatabletmatrix,coatedmatrixbeads,press-coatedmatrixtablets)混合系统-膜系统和基质系统的联合使用（比如，包衣小丸或串珠包埋到片剂基质中，包衣基质串珠，压制包衣基质片剂）,OralCR/MRDosageFormClassifications口服CR/MR剂型分类,OralCRMechanisms口服CR机理,Diffusion扩散Dissolution溶出Swelling&Erosion溶胀&侵蚀Geometry/AreaChanges几何形状/面积变化NonuniformDrugDistribution/Gradientmatrix不均一药物分布/梯度基质,Solution-Diffusion溶解-扩散OsmoticPumping渗透泵,MatrixSystems基质系统,MembraneSystems膜系统,AchievableReleaseProfiles完成的释放曲线,FirstOrder(includingtdependence)一级（包括t依赖性）Zero-Order零级Bimodal(includingacceleratedrelease)双峰（包括加速释放）Pulsatile(includingdelayedrelease)脉冲式（包括延迟释放）,MajorDevelopmentImpactingOralControlledReleaseSincethe1950s自二十世纪五十年代以来影响口服控制剂型的主要发展,TheemergenceofPhysicalPharmacyandPharmacokineticsasnewdisciplinesinthe1960s二十世纪六十年代作为一种新学科出现的物理药剂学和药物代谢动力学Theestablishmentofcontrolledreleaseasafieldwhichhasgrownmoreinterdisciplinarysincethe1970s自二十世纪七十年代开始，控释作为一个学科交叉发展的领域开始建立SignificantprogressintheunderstandingofGIphysiologyanditsimpactoncontrolledreleasedelivery对胃肠道生理学及其对控释释放的影响出现了重大进步Integrationofbiopharmaceuticsandpharmacokineticsintothedesignoforalcontrolledreleasedosageforms生物药剂学和药代动力学与口服控释释放剂型设计的整合,MajorDevelopmentImpactingOralControlledReleaseSincethe1950s(continued)自二十世纪五十年代以来影响口服控制剂型的主要发展（续）,Greaterknowledgeonmaterialproperties,drugreleasemechanisms,andphysicochemicalfactorsaffectingtheoraldosageformdesignandperformance对影响口服剂型设计和性能的材料性质，药物释放原理和物理化学因子的更多认识Proliferationofnoveldrugdeliverytechnologies新型药物释放技术的增加Majoradvancesinanalyticalchemistry,instrumentation,computermodeling,processequipment&monitoring分析化学，仪器操作，计算机模型设计，工艺设备&监控的主要进步,FutureProspects未来展望,ChallengesinControlledReleaseOralDelivery控释口服释放所面临的挑战,ImprovingBioavailabilityofPoorlySolubleDrugs提高难溶药物的生物利用度ProlongationofGITransitTime延长胃肠道通过时间DeliveryofPeptideandProteinDrugs肽类和蛋白药物的释放,ApproachestoImproveSolubility&RateofDissolution提高溶解度&溶出速度的方法,ParticleSizeReduction(surfacearea)颗粒尺寸降低（表面积增加）Micronization微粉化NanosizedSystems纳米系统Complexation/Solubilization(solubility&surfacearea)络和作用/增溶作用（溶解度&表面积）Surfactants/Self-EmulsifyingSystems表面活性剂/自身乳化系统Cyclodextrins环糊精MolecularDispersioninCarriers(solubility&surfacearea)载体中的分子分散作用（溶解度&表面积）SolidSolutions(Coprecipitates)固溶体（共沉物）SolidDispersions固态分散体ChemicalModification(solubility)化学修饰（溶解度）SolubleProdrugs可溶前体药物SolubleSalts可溶盐,EnablingextendedabsorptionforcompoundswithabsorptionwindowinupperGItract对于吸收窗在上胃肠道的化合物能延长吸收窗Betterbioavailability更好的生物利用度,PotentialBenefit:潜在的优点,Rationale:原理,ToincreasegastricresidencetimefordrugsmainlyabsorbedintheupperGItract为了增加主要在上胃肠道吸收药物的胃部停留时间,ProposedApproaches:推荐方法,Floatingdosageforms漂浮剂型Expandingdosage增加剂量Highdensitypellets高密度小丸Bioadhesives生物粘附-Co-administ