给药系统设计及分子学基础演示文稿

给药系统设计及分子学基础演示文稿现在是1页\一共有58页\编辑于星期五（优选）给药系统设计及分子学基础现在是2页\一共有58页\编辑于星期五3USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease现在是3页\一共有58页\编辑于星期五4DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon现在是4页\一共有58页\编辑于星期五5AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms现在是5页\一共有58页\编辑于星期五6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

现在是6页\一共有58页\编辑于星期五7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现在是7页\一共有58页\编辑于星期五8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)现在是8页\一共有58页\编辑于星期五9GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem现在是9页\一共有58页\编辑于星期五10GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）现在是10页\一共有58页\编辑于星期五11现在是11页\一共有58页\编辑于星期五12Migratingmyloelectriccycle(MMC)静止阶段间歇性蠕动强烈突发性收缩过渡阶段现在是12页\一共有58页\编辑于星期五13Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.现在是13页\一共有58页\编辑于星期五14Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.现在是14页\一共有58页\编辑于星期五15现在是15页\一共有58页\编辑于星期五16现在是16页\一共有58页\编辑于星期五17Strategies现在是17页\一共有58页\编辑于星期五18CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms现在是18页\一共有58页\编辑于星期五191968：漂浮型1974：伸展型1980s：膨胀型1980s：粘附型胃沉积型GastricRetentionSystem现在是19页\一共有58页\编辑于星期五20MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial现在是20页\一共有58页\编辑于星期五21EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr机械性能透湿性现在是21页\一共有58页\编辑于星期五22Propertyofcastfilms现在是22页\一共有58页\编辑于星期五23CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets现在是23页\一共有58页\编辑于星期五24SEMEffervescentlayerModifiedreleaselayer现在是24页\一共有58页\编辑于星期五25CaseFile—FloatationFormulationsEffervescentlayeredpellets50g50g50g50gEudragitNE30D5%10%15%20%Talc1g2g4g6gPurifiedwater10g15g30g40g现在是25页\一共有58页\编辑于星期五26FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.现在是26页\一共有58页\编辑于星期五27DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?现在是27页\一共有58页\编辑于星期五28StabilitystudiesTemperatureof40◦Candarelativehumidityof75%现在是28页\一共有58页\编辑于星期五29CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm−3).Adensitycloseto2.5g/cm−3seemsnecessaryforsignificantprolongationofGRT.现在是29页\一共有58页\编辑于星期五30CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG现在是30页\一共有58页\编辑于星期五31Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment现在是31页\一共有58页\编辑于星期五32MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4−)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial现在是32页\一共有58页\编辑于星期五33CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level现在是33页\一共有58页\编辑于星期五34SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign现在是34页\一共有58页\编辑于星期五35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment现在是35页\一共有58页\编辑于星期五36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment现在是36页\一共有58页\编辑于星期五37PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment现在是37页\一共有58页\编辑于星期五38OptimizedformulationPEO(X1)60-85mgNaCl(X2)30-35mgPharmaceuticalironpowder(X3)110-120mgCoatingweightgainofthetablet(X4)6.25-7.25%现在是38页\一共有58页\编辑于星期五39OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.现在是39页\一共有58页\编辑于星期五40CaseFile—SedimentOptimizedformulationConventionaltabletV=3.142×0.352×0.2=0.077cm3

Density=M/V=(40+73+33+115)×(1+7%)/0.077=3.63(gcm−3)现在是40页\一共有58页\编辑于星期五41CaseFile—SedimentOptimizedformulation现在是41页\一共有58页\编辑于星期五42CaseFile—SedimentConventionaltablet现在是42页\一共有58页\编辑于星期五43FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion现在是43页\一共有58页\编辑于星期五44MarketedformulationLasixRetard®60mgLimitation:insufficienttimeinthestomach现在是44页\一共有58页\编辑于星期五45CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion现在是45页\一共有58页\编辑于星期五46CRLayerIRLayerIn-vitrofilmdefoldingstudy现在是46页\一共有58页\编辑于星期五47CaseⅠCase

ⅡPoordefoldingGooddefolding现在是47页\一共有58页\编辑于星期五48CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance现在是48页\一共有58页\编辑于星期五49Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol®)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory现在是49页\一共有58页\编辑于星期五50Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor®PCremophore®RH40HPβCDPEG400(Lutrol®E400)Polyvinylalcohol(Gohnesol®)Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFSoluphor®PCremophore®RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease现在是50页\一共有58页\编辑于星期五51CharacterizationSEMNocrystalsonsurfaceSideviewIRlayerCRlayer现在是51页\一共有58页\