给药系统设计及分子学基础

给药系统设计及分子学基础第一页，共59页。2USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease第二页，共59页。3DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon第三页，共59页。4Advantagesanddisadvantages第四页，共59页。5口服缓释控释制剂的主要类型片剂Tablet微丸Capsule混悬剂Suspension胃漂浮片Floating/buoyanttablets

乳剂Emulsion脂质体Liposome纳米粒Nanoparticle微球Microsphere生物粘附片Bioadhesivetablets

第五页，共59页。6口服缓释控释制剂的主要类型1.骨架型制剂Matrix2.膜控型制剂

Reservoir/Coating3.渗透泵制剂Osmoticpump4.胃内滞留型制剂Gastricretention

5.脉冲给药系统Pulsed第六页，共59页。7口服缓释控释制剂的主要类型Rate-specificdrugdelivery

(定速释放给药系统)Site-specificdrugdelivery

(定位释放给药系统)Time-specificdrugdelivery(定时释放给药系统)第七页，共59页。8SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem第八页，共59页。9GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）第九页，共59页。10第十页，共59页。11Migratingmyloelectriccycle(MMC)静止阶段间歇性蠕动强烈突发性收缩过渡阶段第十一页，共59页。12Migratingmyloelectriccycle(MMC)第十二页，共59页。13Digestivemotilitypattern：comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.第十三页，共59页。14第十四页，共59页。15第十五页，共59页。16Strategies第十六页，共59页。17CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms第十七页，共59页。181968：漂浮型1974：伸展型1980s：膨胀型1980s：粘附型胃沉积型GastricRetentionSystem第十八页，共59页。19MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial第十九页，共59页。20EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr机械性能透湿性第二十页，共59页。21Propertyofcastfilms第二十一页，共59页。22CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets第二十二页，共59页。23SEMEffervescentlayerModifiedreleaselayer第二十三页，共59页。24CaseFile—Floatation第二十四页，共59页。25Floatingstudies第二十五页，共59页。26DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?第二十六页，共59页。27StabilitystudiesTemperatureof40◦Candarelativehumidityof75%第二十七页，共59页。28CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm−3).Adensitycloseto2.5g/cm−3seemsnecessaryforsignificantprolongationofGRT.第二十八页，共59页。29CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG第二十九页，共59页。30Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment第三十页，共59页。31MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4−)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial第三十一页，共59页。32CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level第三十二页，共59页。33SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign第三十三页，共59页。34PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment第三十四页，共59页。35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment第三十五页，共59页。36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment第三十六页，共59页。37Optimizedformulation第三十七页，共59页。38OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.第三十八页，共59页。39CaseFile—SedimentOptimizedformulationConventionaltabletV=3.142×0.352×0.2=0.077cm3

Density=M/V=(40+73+33+115)×(1+7%)/0.077=3.63(gcm−3)第三十九页，共59页。40CaseFile—SedimentOptimizedformulation第四十页，共59页。41CaseFile—SedimentConventionaltablet第四十一页，共59页。42FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：Peakdiuresiseffect

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion第四十二页，共59页。43MarketedformulationLasixRetard®60mgLimitation:insufficienttimeinthestomach第四十三页，共59页。44CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion第四十四页，共59页。45CRLayerIRLayerIn-vitrofilmdefoldingstudy第四十五页，共59页。46CaseⅠCase

ⅡPoordefoldingGooddefolding第四十六页，共59页。47CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance第四十七页，共59页。48Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol®)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory第四十八页，共59页。49Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor®PCremophore®RH40HPβCDPEG400(Lutrol®E400)Polyvinylalcohol(Gohnesol®)Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFSoluphor®PCremophore®RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease第四十九页，共59页。50CharacterizationSEMNoc