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目前一页\总数五十八页\编于十四点（优选）给药系统设计及分子学基础目前二页\总数五十八页\编于十四点3USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease目前三页\总数五十八页\编于十四点4DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon目前四页\总数五十八页\编于十四点5AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms目前五页\总数五十八页\编于十四点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

目前六页\总数五十八页\编于十四点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目前七页\总数五十八页\编于十四点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)目前八页\总数五十八页\编于十四点9GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem目前九页\总数五十八页\编于十四点10GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）目前十页\总数五十八页\编于十四点11目前十一页\总数五十八页\编于十四点12Migratingmyloelectriccycle(MMC)静止阶段间歇性蠕动强烈突发性收缩过渡阶段目前十二页\总数五十八页\编于十四点13Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.目前十三页\总数五十八页\编于十四点14Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.目前十四页\总数五十八页\编于十四点15目前十五页\总数五十八页\编于十四点16目前十六页\总数五十八页\编于十四点17Strategies目前十七页\总数五十八页\编于十四点18CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms目前十八页\总数五十八页\编于十四点191968：漂浮型1974：伸展型1980s：膨胀型1980s：粘附型胃沉积型GastricRetentionSystem目前十九页\总数五十八页\编于十四点20MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial目前二十页\总数五十八页\编于十四点21EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr机械性能透湿性目前二十一页\总数五十八页\编于十四点22Propertyofcastfilms目前二十二页\总数五十八页\编于十四点23CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets目前二十三页\总数五十八页\编于十四点24SEMEffervescentlayerModifiedreleaselayer目前二十四页\总数五十八页\编于十四点25CaseFile—FloatationFormulationsEffervescentlayeredpellets50g50g50g50gEudragitNE30D5%10%15%20%Talc1g2g4g6gPurifiedwater10g15g30g40g目前二十五页\总数五十八页\编于十四点26FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.目前二十六页\总数五十八页\编于十四点27DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?目前二十七页\总数五十八页\编于十四点28StabilitystudiesTemperatureof40◦Candarelativehumidityof75%目前二十八页\总数五十八页\编于十四点29CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm−3).Adensitycloseto2.5g/cm−3seemsnecessaryforsignificantprolongationofGRT.目前二十九页\总数五十八页\编于十四点30CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG目前三十页\总数五十八页\编于十四点31Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment目前三十一页\总数五十八页\编于十四点32MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4−)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial目前三十二页\总数五十八页\编于十四点33CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level目前三十三页\总数五十八页\编于十四点34SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign目前三十四页\总数五十八页\编于十四点35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十五页\总数五十八页\编于十四点36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十六页\总数五十八页\编于十四点37PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十七页\总数五十八页\编于十四点38OptimizedformulationPEO(X1)60-85mgNaCl(X2)30-35mgPharmaceuticalironpowder(X3)110-120mgCoatingweightgainofthetablet(X4)6.25-7.25%目前三十八页\总数五十八页\编于十四点39OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.目前三十九页\总数五十八页\编于十四点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)目前四十页\总数五十八页\编于十四点41CaseFile—SedimentOptimizedformulation目前四十一页\总数五十八页\编于十四点42CaseFile—SedimentConventionaltablet目前四十二页\总数五十八页\编于十四点43FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion目前四十三页\总数五十八页\编于十四点44MarketedformulationLasixRetard®60mgLimitation:insufficienttimeinthestomach目前四十四页\总数五十八页\编于十四点45CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion目前四十五页\总数五十八页\编于十四点46CRLayerIRLayerIn-vitrofilmdefoldingstudy目前四十六页\总数五十八页\编于十四点47CaseⅠCase

ⅡPoordefoldingGooddefolding目前四十七页\总数五十八页\编于十四点48CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance目前四十八页\总数五十八页\编于十四点49Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol®)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory目前四十九页\总数五十八页\编于十四点50Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor®PCremophore®RH40HPβCDPEG400(Lutrol®E400)Polyvinylalcohol(Gohnesol®)Eudragit®RLPOHPMCE4M(Methocel®E4M)Carbopol®971PNFSoluphor®PCremophore®RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease目前五十页\总数五十八页\编于十四点51CharacterizationSEMNocrystalsonsurfaceSideviewIRlayerCRlayer目前五十一页\总数五十八页\