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本文檔共59頁；當(dāng)前第1頁；編輯于星期六\14點(diǎn)49分2USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease本文檔共59頁；當(dāng)前第2頁；編輯于星期六\14點(diǎn)49分3DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon本文檔共59頁；當(dāng)前第3頁；編輯于星期六\14點(diǎn)49分4AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms本文檔共59頁；當(dāng)前第4頁；編輯于星期六\14點(diǎn)49分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

本文檔共59頁；當(dāng)前第5頁；編輯于星期六\14點(diǎn)49分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本文檔共59頁；當(dāng)前第6頁；編輯于星期六\14點(diǎn)49分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))本文檔共59頁；當(dāng)前第7頁；編輯于星期六\14點(diǎn)49分8GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem本文檔共59頁；當(dāng)前第8頁；編輯于星期六\14點(diǎn)49分9GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）本文檔共59頁；當(dāng)前第9頁；編輯于星期六\14點(diǎn)49分10本文檔共59頁；當(dāng)前第10頁；編輯于星期六\14點(diǎn)49分11Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動(dòng)強(qiáng)烈突發(fā)性收縮過渡階段本文檔共59頁；當(dāng)前第11頁；編輯于星期六\14點(diǎn)49分12Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.本文檔共59頁；當(dāng)前第12頁；編輯于星期六\14點(diǎn)49分13Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.本文檔共59頁；當(dāng)前第13頁；編輯于星期六\14點(diǎn)49分14本文檔共59頁；當(dāng)前第14頁；編輯于星期六\14點(diǎn)49分15本文檔共59頁；當(dāng)前第15頁；編輯于星期六\14點(diǎn)49分16Strategies本文檔共59頁；當(dāng)前第16頁；編輯于星期六\14點(diǎn)49分17CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms本文檔共59頁；當(dāng)前第17頁；編輯于星期六\14點(diǎn)49分181968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem本文檔共59頁；當(dāng)前第18頁；編輯于星期六\14點(diǎn)49分19MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial本文檔共59頁；當(dāng)前第19頁；編輯于星期六\14點(diǎn)49分20EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性本文檔共59頁；當(dāng)前第20頁；編輯于星期六\14點(diǎn)49分21Propertyofcastfilms本文檔共59頁；當(dāng)前第21頁；編輯于星期六\14點(diǎn)49分22CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets本文檔共59頁；當(dāng)前第22頁；編輯于星期六\14點(diǎn)49分23SEMEffervescentlayerModifiedreleaselayer本文檔共59頁；當(dāng)前第23頁；編輯于星期六\14點(diǎn)49分24CaseFile—Floatation本文檔共59頁；當(dāng)前第24頁；編輯于星期六\14點(diǎn)49分25FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.本文檔共59頁；當(dāng)前第25頁；編輯于星期六\14點(diǎn)49分26DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?本文檔共59頁；當(dāng)前第26頁；編輯于星期六\14點(diǎn)49分27StabilitystudiesTemperatureof40?Candarelativehumidityof75%本文檔共59頁；當(dāng)前第27頁；編輯于星期六\14點(diǎn)49分28CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.本文檔共59頁；當(dāng)前第28頁；編輯于星期六\14點(diǎn)49分29CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG本文檔共59頁；當(dāng)前第29頁；編輯于星期六\14點(diǎn)49分30Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment本文檔共59頁；當(dāng)前第30頁；編輯于星期六\14點(diǎn)49分31MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial本文檔共59頁；當(dāng)前第31頁；編輯于星期六\14點(diǎn)49分32CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level本文檔共59頁；當(dāng)前第32頁；編輯于星期六\14點(diǎn)49分33SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign本文檔共59頁；當(dāng)前第33頁；編輯于星期六\14點(diǎn)49分34PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment本文檔共59頁；當(dāng)前第34頁；編輯于星期六\14點(diǎn)49分35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment本文檔共59頁；當(dāng)前第35頁；編輯于星期六\14點(diǎn)49分36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment本文檔共59頁；當(dāng)前第36頁；編輯于星期六\14點(diǎn)49分37Optimizedformulation本文檔共59頁；當(dāng)前第37頁；編輯于星期六\14點(diǎn)49分38OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.本文檔共59頁；當(dāng)前第38頁；編輯于星期六\14點(diǎn)49分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)本文檔共59頁；當(dāng)前第39頁；編輯于星期六\14點(diǎn)49分40CaseFile—SedimentOptimizedformulation本文檔共59頁；當(dāng)前第40頁；編輯于星期六\14點(diǎn)49分41CaseFile—SedimentConventionaltablet本文檔共59頁；當(dāng)前第41頁；編輯于星期六\14點(diǎn)49分42FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion本文檔共59頁；當(dāng)前第42頁；編輯于星期六\14點(diǎn)49分43MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach本文檔共59頁；當(dāng)前第43頁；編輯于星期六\14點(diǎn)49分44CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion本文檔共59頁；當(dāng)前第44頁；編輯于星期六\14點(diǎn)49分45CRLayerIRLayerIn-vitrofilmdefoldingstudy本文檔共59頁；當(dāng)前第45頁；編輯于星期六\14點(diǎn)49分46CaseⅠCase

ⅡPoordefoldingGooddefolding本文檔共59頁；當(dāng)前第46頁；編輯于星期六\14點(diǎn)49分47CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance本文檔共59頁；當(dāng)前第47頁；編輯于星期六\14點(diǎn)49分48Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory本文檔共59頁；當(dāng)前第48頁；編輯于星期六\14點(diǎn)49分49Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrug