給藥系統(tǒng)設(shè)計(jì)及分子學(xué)基礎(chǔ)

1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目前一頁\總數(shù)五十九頁\編于十四點(diǎn)2USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease目前二頁\總數(shù)五十九頁\編于十四點(diǎn)3DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon目前三頁\總數(shù)五十九頁\編于十四點(diǎn)4AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms目前四頁\總數(shù)五十九頁\編于十四點(diǎn)5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

目前五頁\總數(shù)五十九頁\編于十四點(diǎn)6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目前六頁\總數(shù)五十九頁\編于十四點(diǎn)7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(shí)釋放給藥系統(tǒng))目前七頁\總數(shù)五十九頁\編于十四點(diǎn)8GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem目前八頁\總數(shù)五十九頁\編于十四點(diǎn)9GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）目前九頁\總數(shù)五十九頁\編于十四點(diǎn)10目前十頁\總數(shù)五十九頁\編于十四點(diǎn)11Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動(dòng)強(qiáng)烈突發(fā)性收縮過渡階段目前十一頁\總數(shù)五十九頁\編于十四點(diǎn)12Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.目前十二頁\總數(shù)五十九頁\編于十四點(diǎn)13Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.目前十三頁\總數(shù)五十九頁\編于十四點(diǎn)14目前十四頁\總數(shù)五十九頁\編于十四點(diǎn)15目前十五頁\總數(shù)五十九頁\編于十四點(diǎn)16Strategies目前十六頁\總數(shù)五十九頁\編于十四點(diǎn)17CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms目前十七頁\總數(shù)五十九頁\編于十四點(diǎn)181968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem目前十八頁\總數(shù)五十九頁\編于十四點(diǎn)19MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial目前十九頁\總數(shù)五十九頁\編于十四點(diǎn)20EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性目前二十頁\總數(shù)五十九頁\編于十四點(diǎn)21Propertyofcastfilms目前二十一頁\總數(shù)五十九頁\編于十四點(diǎn)22CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets目前二十二頁\總數(shù)五十九頁\編于十四點(diǎn)23SEMEffervescentlayerModifiedreleaselayer目前二十三頁\總數(shù)五十九頁\編于十四點(diǎn)24CaseFile—Floatation目前二十四頁\總數(shù)五十九頁\編于十四點(diǎn)25FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.目前二十五頁\總數(shù)五十九頁\編于十四點(diǎn)26DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?目前二十六頁\總數(shù)五十九頁\編于十四點(diǎn)27StabilitystudiesTemperatureof40?Candarelativehumidityof75%目前二十七頁\總數(shù)五十九頁\編于十四點(diǎn)28CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.目前二十八頁\總數(shù)五十九頁\編于十四點(diǎn)29CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG目前二十九頁\總數(shù)五十九頁\編于十四點(diǎn)30Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment目前三十頁\總數(shù)五十九頁\編于十四點(diǎn)31MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial目前三十一頁\總數(shù)五十九頁\編于十四點(diǎn)32CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level目前三十二頁\總數(shù)五十九頁\編于十四點(diǎn)33SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign目前三十三頁\總數(shù)五十九頁\編于十四點(diǎn)34PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十四頁\總數(shù)五十九頁\編于十四點(diǎn)35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十五頁\總數(shù)五十九頁\編于十四點(diǎn)36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment目前三十六頁\總數(shù)五十九頁\編于十四點(diǎn)37Optimizedformulation目前三十七頁\總數(shù)五十九頁\編于十四點(diǎn)38OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.目前三十八頁\總數(shù)五十九頁\編于十四點(diǎn)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)目前三十九頁\總數(shù)五十九頁\編于十四點(diǎn)40CaseFile—SedimentOptimizedformulation目前四十頁\總數(shù)五十九頁\編于十四點(diǎn)41CaseFile—SedimentConventionaltablet目前四十一頁\總數(shù)五十九頁\編于十四點(diǎn)42FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion目前四十二頁\總數(shù)五十九頁\編于十四點(diǎn)43MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach目前四十三頁\總數(shù)五十九頁\編于十四點(diǎn)44CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion目前四十四頁\總數(shù)五十九頁\編于十四點(diǎn)45CRLayerIRLayerIn-vitrofilmdefoldingstudy目前四十五頁\總數(shù)五十九頁\編于十四點(diǎn)46CaseⅠCase

ⅡPoordefoldingGooddefolding目前四十六頁\總數(shù)五十九頁\編于十四點(diǎn)47CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance目前四十七頁\總數(shù)五十九頁\編于十四點(diǎn)48Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory目前四十八頁\總數(shù)五十九頁\編于十四點(diǎn)49Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatr