給藥系統(tǒng)設(shè)計及分子學(xué)基礎(chǔ)

口服緩控釋制劑潘昕中山大學(xué)藥學(xué)院Email：當(dāng)前第1頁\共有63頁\編于星期五\11點2中國藥典2010年版緩釋制劑：緩慢地非恒速釋放，給藥頻率↓控釋制劑：緩慢地恒速或接近恒速釋放，給藥頻率↓

血藥濃度平穩(wěn)美國藥典USP28版

不區(qū)分緩釋、控釋

extended-releasemodified-release當(dāng)前第2頁\共有63頁\編于星期五\11點3USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease當(dāng)前第3頁\共有63頁\編于星期五\11點4DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon當(dāng)前第4頁\共有63頁\編于星期五\11點5AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms當(dāng)前第5頁\共有63頁\編于星期五\11點6口服緩釋控釋制劑的主要類型片劑Tablet微丸Capsule混懸劑Suspension胃漂浮片F(xiàn)loating/buoyanttablets

乳劑Emulsion脂質(zhì)體

Liposome納米粒Nanoparticle微球Microsphere生物粘附片Bioadhesivetablets

當(dāng)前第6頁\共有63頁\編于星期五\11點7口服緩釋控釋制劑的主要類型1.骨架型制劑

Matrix2.膜控型制劑

Reservoir/Coating3.滲透泵制劑

Osmoticpump4.胃內(nèi)滯留型制劑

Gastricretention

5.脈沖給藥系統(tǒng)

Pulsed當(dāng)前第7頁\共有63頁\編于星期五\11點8口服緩釋控釋制劑的主要類型Rate-specificdrugdelivery

(定速釋放給藥系統(tǒng))Site-specificdrugdelivery

(定位釋放給藥系統(tǒng))Time-specificdrugdelivery(定時釋放給藥系統(tǒng))當(dāng)前第8頁\共有63頁\編于星期五\11點9GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem當(dāng)前第9頁\共有63頁\編于星期五\11點10GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）當(dāng)前第10頁\共有63頁\編于星期五\11點11當(dāng)前第11頁\共有63頁\編于星期五\11點12Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動強(qiáng)烈突發(fā)性收縮過渡階段當(dāng)前第12頁\共有63頁\編于星期五\11點13Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.當(dāng)前第13頁\共有63頁\編于星期五\11點14Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.當(dāng)前第14頁\共有63頁\編于星期五\11點15當(dāng)前第15頁\共有63頁\編于星期五\11點16當(dāng)前第16頁\共有63頁\編于星期五\11點17Strategies當(dāng)前第17頁\共有63頁\編于星期五\11點18CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms當(dāng)前第18頁\共有63頁\編于星期五\11點191968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem當(dāng)前第19頁\共有63頁\編于星期五\11點20MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial當(dāng)前第20頁\共有63頁\編于星期五\11點21EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性當(dāng)前第21頁\共有63頁\編于星期五\11點22Propertyofcastfilms當(dāng)前第22頁\共有63頁\編于星期五\11點23CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets當(dāng)前第23頁\共有63頁\編于星期五\11點24SEMEffervescentlayerModifiedreleaselayer當(dāng)前第24頁\共有63頁\編于星期五\11點25CaseFile—Floatation當(dāng)前第25頁\共有63頁\編于星期五\11點26FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.當(dāng)前第26頁\共有63頁\編于星期五\11點27DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?當(dāng)前第27頁\共有63頁\編于星期五\11點28StabilitystudiesTemperatureof40?Candarelativehumidityof75%當(dāng)前第28頁\共有63頁\編于星期五\11點29CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.當(dāng)前第29頁\共有63頁\編于星期五\11點30CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG當(dāng)前第30頁\共有63頁\編于星期五\11點31Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment當(dāng)前第31頁\共有63頁\編于星期五\11點32MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial當(dāng)前第32頁\共有63頁\編于星期五\11點33CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level當(dāng)前第33頁\共有63頁\編于星期五\11點34SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign當(dāng)前第34頁\共有63頁\編于星期五\11點35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第35頁\共有63頁\編于星期五\11點36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第36頁\共有63頁\編于星期五\11點37PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第37頁\共有63頁\編于星期五\11點38Optimizedformulation當(dāng)前第38頁\共有63頁\編于星期五\11點39OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.當(dāng)前第39頁\共有63頁\編于星期五\11點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)當(dāng)前第40頁\共有63頁\編于星期五\11點41CaseFile—SedimentOptimizedformulation當(dāng)前第41頁\共有63頁\編于星期五\11點42CaseFile—SedimentConventionaltablet當(dāng)前第42頁\共有63頁\編于星期五\11點43FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion當(dāng)前第43頁\共有63頁\編于星期五\11點44MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach當(dāng)前第44頁\共有63頁\編于星期五\11點45CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion當(dāng)前第45頁\共有63頁\編于星期五\11點46CRLayerIRLayerIn-vitrofilmdefoldingstudy當(dāng)前第46頁\共有63頁\編于星期五\11點47CaseⅠCase

ⅡPoordefoldingGooddefolding當(dāng)前第47頁\共有63頁\編于星期五\11點48CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance當(dāng)前第48頁\共有63頁\編于星期五\11點49Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory當(dāng)前第49頁\共有63頁\編于星期五\11點50Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease當(dāng)前第50頁\共有63頁\編于星期五\11點51CharacterizationSEMNocrystalsonsurfaceSideviewIRlayerCRlayer當(dāng)前第51頁\共有63頁\編于星期五\11點52CharacterizationXRD當(dāng)前第52頁\共有63頁\編于星期五\11點53CharacterizationDSCDrugwas