給藥系統(tǒng)設(shè)計(jì)及分子學(xué)基礎(chǔ)

給藥系統(tǒng)設(shè)計(jì)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：現(xiàn)在是1頁\一共有63頁\編輯于星期四2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現(xiàn)在是2頁\一共有63頁\編輯于星期四3USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease現(xiàn)在是3頁\一共有63頁\編輯于星期四4DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon現(xiàn)在是4頁\一共有63頁\編輯于星期四5AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms現(xiàn)在是5頁\一共有63頁\編輯于星期四6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

現(xiàn)在是6頁\一共有63頁\編輯于星期四7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現(xiàn)在是7頁\一共有63頁\編輯于星期四8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(shí)釋放給藥系統(tǒng))現(xiàn)在是8頁\一共有63頁\編輯于星期四9GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem現(xiàn)在是9頁\一共有63頁\編輯于星期四10GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）現(xiàn)在是10頁\一共有63頁\編輯于星期四11現(xiàn)在是11頁\一共有63頁\編輯于星期四12Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動(dòng)強(qiáng)烈突發(fā)性收縮過渡階段現(xiàn)在是12頁\一共有63頁\編輯于星期四13Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.現(xiàn)在是13頁\一共有63頁\編輯于星期四14Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.現(xiàn)在是14頁\一共有63頁\編輯于星期四15現(xiàn)在是15頁\一共有63頁\編輯于星期四16現(xiàn)在是16頁\一共有63頁\編輯于星期四17Strategies現(xiàn)在是17頁\一共有63頁\編輯于星期四18CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms現(xiàn)在是18頁\一共有63頁\編輯于星期四191968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem現(xiàn)在是19頁\一共有63頁\編輯于星期四20MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial現(xiàn)在是20頁\一共有63頁\編輯于星期四21EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性現(xiàn)在是21頁\一共有63頁\編輯于星期四22Propertyofcastfilms現(xiàn)在是22頁\一共有63頁\編輯于星期四23CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets現(xiàn)在是23頁\一共有63頁\編輯于星期四24SEMEffervescentlayerModifiedreleaselayer現(xiàn)在是24頁\一共有63頁\編輯于星期四25CaseFile—Floatation現(xiàn)在是25頁\一共有63頁\編輯于星期四26FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.現(xiàn)在是26頁\一共有63頁\編輯于星期四27DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?現(xiàn)在是27頁\一共有63頁\編輯于星期四28StabilitystudiesTemperatureof40?Candarelativehumidityof75%現(xiàn)在是28頁\一共有63頁\編輯于星期四29CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.現(xiàn)在是29頁\一共有63頁\編輯于星期四30CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG現(xiàn)在是30頁\一共有63頁\編輯于星期四31Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment現(xiàn)在是31頁\一共有63頁\編輯于星期四32MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial現(xiàn)在是32頁\一共有63頁\編輯于星期四33CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level現(xiàn)在是33頁\一共有63頁\編輯于星期四34SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign現(xiàn)在是34頁\一共有63頁\編輯于星期四35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment現(xiàn)在是35頁\一共有63頁\編輯于星期四36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment現(xiàn)在是36頁\一共有63頁\編輯于星期四37PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment現(xiàn)在是37頁\一共有63頁\編輯于星期四38Optimizedformulation現(xiàn)在是38頁\一共有63頁\編輯于星期四39OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.現(xiàn)在是39頁\一共有63頁\編輯于星期四40CaseFile—SedimentOptimizedformulationConventionaltabletV=3.142×0.352×0.2=0.077cm3

Density=M/V=(40+73+33+115)×(1+7%)/0.077=3.63(gcm?3)現(xiàn)在是40頁\一共有63頁\編輯于星期四41CaseFile—SedimentOptimizedformulation現(xiàn)在是41頁\一共有63頁\編輯于星期四42CaseFile—SedimentConventionaltablet現(xiàn)在是42頁\一共有63頁\編輯于星期四43FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion現(xiàn)在是43頁\一共有63頁\編輯于星期四44MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach現(xiàn)在是44頁\一共有63頁\編輯于星期四45CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion現(xiàn)在是45頁\一共有63頁\編輯于星期四46CRLayerIRLayerIn-vitrofilmdefoldingstudy現(xiàn)在是46頁\一共有63頁\編輯于星期四47CaseⅠCase

ⅡPoordefoldingGooddefolding現(xiàn)在是47頁\一共有63頁\編輯于星期四48CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance現(xiàn)在是48頁\一共有63頁\編輯于星期四49Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory現(xiàn)在是49頁\一共有63頁\編輯于星期四50Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease現(xiàn)在是50頁\一共有63頁\編輯于星期四51CharacterizationSEMNocrystalsonsurfaceSideviewIRlayerCRlayer現(xiàn)在是51頁\一共有63頁\編輯于星期四52CharacterizationXRD現(xiàn)在是52頁\一共有63頁\編輯于星期四53CharacterizationDSC