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當(dāng)前第1頁\共有59頁\編于星期三\13點(diǎn)2USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease當(dāng)前第2頁\共有59頁\編于星期三\13點(diǎn)3DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon當(dāng)前第3頁\共有59頁\編于星期三\13點(diǎn)4AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms當(dāng)前第4頁\共有59頁\編于星期三\13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

當(dāng)前第5頁\共有59頁\編于星期三\13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當(dāng)前第6頁\共有59頁\編于星期三\13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))當(dāng)前第7頁\共有59頁\編于星期三\13點(diǎn)8GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem當(dāng)前第8頁\共有59頁\編于星期三\13點(diǎn)9GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）當(dāng)前第9頁\共有59頁\編于星期三\13點(diǎn)10當(dāng)前第10頁\共有59頁\編于星期三\13點(diǎn)11Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動(dòng)強(qiáng)烈突發(fā)性收縮過渡階段當(dāng)前第11頁\共有59頁\編于星期三\13點(diǎn)12Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.當(dāng)前第12頁\共有59頁\編于星期三\13點(diǎn)13Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.當(dāng)前第13頁\共有59頁\編于星期三\13點(diǎn)14當(dāng)前第14頁\共有59頁\編于星期三\13點(diǎn)15當(dāng)前第15頁\共有59頁\編于星期三\13點(diǎn)16Strategies當(dāng)前第16頁\共有59頁\編于星期三\13點(diǎn)17CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms當(dāng)前第17頁\共有59頁\編于星期三\13點(diǎn)181968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem當(dāng)前第18頁\共有59頁\編于星期三\13點(diǎn)19MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial當(dāng)前第19頁\共有59頁\編于星期三\13點(diǎn)20EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性當(dāng)前第20頁\共有59頁\編于星期三\13點(diǎn)21Propertyofcastfilms當(dāng)前第21頁\共有59頁\編于星期三\13點(diǎn)22CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets當(dāng)前第22頁\共有59頁\編于星期三\13點(diǎn)23SEMEffervescentlayerModifiedreleaselayer當(dāng)前第23頁\共有59頁\編于星期三\13點(diǎn)24CaseFile—Floatation當(dāng)前第24頁\共有59頁\編于星期三\13點(diǎn)25FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.當(dāng)前第25頁\共有59頁\編于星期三\13點(diǎn)26DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?當(dāng)前第26頁\共有59頁\編于星期三\13點(diǎn)27StabilitystudiesTemperatureof40?Candarelativehumidityof75%當(dāng)前第27頁\共有59頁\編于星期三\13點(diǎn)28CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.當(dāng)前第28頁\共有59頁\編于星期三\13點(diǎn)29CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG當(dāng)前第29頁\共有59頁\編于星期三\13點(diǎn)30Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment當(dāng)前第30頁\共有59頁\編于星期三\13點(diǎn)31MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial當(dāng)前第31頁\共有59頁\編于星期三\13點(diǎn)32CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level當(dāng)前第32頁\共有59頁\編于星期三\13點(diǎn)33SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign當(dāng)前第33頁\共有59頁\編于星期三\13點(diǎn)34PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第34頁\共有59頁\編于星期三\13點(diǎn)35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第35頁\共有59頁\編于星期三\13點(diǎn)36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前第36頁\共有59頁\編于星期三\13點(diǎn)37Optimizedformulation當(dāng)前第37頁\共有59頁\編于星期三\13點(diǎn)38OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.當(dāng)前第38頁\共有59頁\編于星期三\13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)當(dāng)前第39頁\共有59頁\編于星期三\13點(diǎn)40CaseFile—SedimentOptimizedformulation當(dāng)前第40頁\共有59頁\編于星期三\13點(diǎn)41CaseFile—SedimentConventionaltablet當(dāng)前第41頁\共有59頁\編于星期三\13點(diǎn)42FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion當(dāng)前第42頁\共有59頁\編于星期三\13點(diǎn)43MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach當(dāng)前第43頁\共有59頁\編于星期三\13點(diǎn)44CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion當(dāng)前第44頁\共有59頁\編于星期三\13點(diǎn)45CRLayerIRLayerIn-vitrofilmdefoldingstudy當(dāng)前第45頁\共有59頁\編于星期三\13點(diǎn)46CaseⅠCase

ⅡPoordefoldingGooddefolding當(dāng)前第46頁\共有59頁\編于星期三\13點(diǎn)47CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance當(dāng)前第47頁\共有59頁\編于星期三\13點(diǎn)48Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory當(dāng)前第48頁\共有59頁\編于星期三\13點(diǎn)49Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermat