給藥系統(tǒng)設(shè)計(jì)及分子學(xué)基礎(chǔ)演示文稿

給藥系統(tǒng)設(shè)計(jì)及分子學(xué)基礎(chǔ)演示文稿當(dāng)前1頁，總共58頁。（優(yōu)選）給藥系統(tǒng)設(shè)計(jì)及分子學(xué)基礎(chǔ)當(dāng)前2頁，總共58頁。3USP28SustainedreleaseControlledreleaseProlongedreleaseExtendedreleaseModifiedrelease

Delayedrelease當(dāng)前3頁，總共58頁。4DrugreleaseprofilesDrugconcentrationTimeControlledSustainedCommonTherapeuticwindowTimeDrugconcentrationQ:thedifferencesbetweenthesetwodrugreleaseprofiles?Q:pointoutsustained,controlled,prolonged,extended,

modified,delayed,commondrugreleaseprofiles.ControlledSustainedCommon當(dāng)前4頁，總共58頁。5AdvantagesanddisadvantagesAdvantages(multi-unitdosageform)ReducegastrointestinalirritationReducetheinter-andintra-subjectvariabilitiesBetterreproduciblepharmacokineticbehaviorHigherpatients’compliance…Disadvantages(single-unitdosageform)All-or-nothingUn-dividablepropertyofthedosageforms當(dāng)前5頁，總共58頁。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6頁，總共58頁。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7頁，總共58頁。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))當(dāng)前8頁，總共58頁。9GastricRetentionSystemisretainedinthestomachforanumberofhours,whileitcontinuouslyreleasestheincorporateddrugata

controlledrate

toabsorptionsitesintheupperintestinaltract.SustainedReleaseGastricRetentionDrugswithnarrowAbsorptionwindowGastricRetentionSystem當(dāng)前9頁，總共58頁。10GastricRetentionSystemOralstomach-retaineddrugdeliverysystemAppropriatemodeldrug：NarrowabsorptionwindowIncompletereleasefromthedrugdeliverysystemabovetheabsorptionzoneInstabilityinalkalinemediumAnti-ulcerate（Stomach,duodenal）當(dāng)前10頁，總共58頁。11當(dāng)前11頁，總共58頁。12Migratingmyloelectriccycle(MMC)靜止階段間歇性蠕動(dòng)強(qiáng)烈突發(fā)性收縮過渡階段當(dāng)前12頁，總共58頁。13Migratingmyloelectriccycle(MMC)PhaseI(basalphase)lastsfrom40to60minuteswithrarecontractions.PhaseII(preburstphase)lastsfor30to45minuteswithintermittentactionpotentialandcontractions.Asthephaseprogressestheintensityandfrequencyalsoincreasesgradually.PhaseIII(burstphase)lastsfor5to15minutes.Itincludesintenseandregularcontractionsforshortperiod.Itisduetothiswavethatalltheundigestedmaterialissweptoutofthestomachdowntothesmallintestine.Itisalsoknownasthehousekeeperwave.PhaseIVlastsfor0to5minutesandoccursbetweenphasesIIIandIof2consecutivecycles.當(dāng)前13頁，總共58頁。14Digestivemotilitypattern：

comprisescontinuouscontractionsasinphaseIIoffastedstate.Thesecontractionsresultinreducingthesizeoffoodparticles(tolessthan2mm),whicharepropelledtowardthepylorusinasuspensionform.DuringthefedstateonsetofMMCisdelayedresultinginslowdownofgastricemptyingrate.ThepHofthestomachinfastingstateis1.5to2.0andinfedstateis2.0to6.0.AlargevolumeofwateradministeredwithanoraldosageformraisesthepHofstomachcontentsto6.0to9.0.當(dāng)前14頁，總共58頁。15當(dāng)前15頁，總共58頁。16當(dāng)前16頁，總共58頁。17Strategies當(dāng)前17頁，總共58頁。18CaseFile—FloatationClassificationofFloatingDrugDeliverySystems(FDDS)EffervescentFloatingDosageFormsNon-effervescentFloatingDosageForms當(dāng)前18頁，總共58頁。191968：漂浮型1974：伸展型1980s：膨脹型1980s：粘附型胃沉積型GastricRetentionSystem當(dāng)前19頁，總共58頁。20MaterialZolpidemtartratePolyvinylpyrrolidoneK30(PVPK30)HydroxypropylmethylcelluloseE5LVSodiumbicarbonateEudragitNE30DSugarpellets(#25–30,ASTM)Emptyhardgelatincapsules(Size0)CaseFile—FloatationModeldrugEffervescentagentCoatingmaterial當(dāng)前20頁，總共58頁。21EudragitNE30DEudragitL30D-55Talc(GMS)TECTween-80Preparationofcastfilmsr機(jī)械性能透濕性當(dāng)前21頁，總共58頁。22Propertyofcastfilms當(dāng)前22頁，總共58頁。23CaseFile—FloatationDruglayeredsugarpelletsEffervescentlayerModifiedreleaselayerMethod：FluidizedbedcoaterSugarpellets當(dāng)前23頁，總共58頁。24SEMEffervescentlayerModifiedreleaselayer當(dāng)前24頁，總共58頁。25CaseFile—FloatationFormulationsEffervescentlayeredpellets50g50g50g50gEudragitNE30D5%10%15%20%Talc1g2g4g6gPurifiedwater10g15g30g40g當(dāng)前25頁，總共58頁。26FloatingstudiesEudragitNE30Dcoatedzolpidemtartaratepelletsfloatingatthesurfaceofthetestfluidafter10h.當(dāng)前26頁，總共58頁。27DissolutionstudyEudragitNE5%10%15%20%Q1:WiththeincreasingofEudragitNE30D,drugreleaseratewillincrease/decrease?Q2:Withtheincreasingofeffervescentagent,drugreleaseratewillincrease/decrease?當(dāng)前27頁，總共58頁。28StabilitystudiesTemperatureof40?Candarelativehumidityof75%當(dāng)前28頁，總共58頁。29CaseFile—SedimentGastriccontentshaveadensityclosetowater(about1.004g/cm?3).Adensitycloseto2.5g/cm?3seemsnecessaryforsignificantprolongationofGRT.當(dāng)前29頁，總共58頁。30CaseFile—SedimentOsmoticpumptablet1975:Elementaryosmoticpump1982:Two-layerpush–pull1989:Three-layerDRUGDRUGDRUGDRUGDRUGDRUG當(dāng)前30頁，總共58頁。31Modeldrug:Famotidine(FMTD)法莫替丁prolongedantisecretoryeffectinthetherapyofduodenal,gastric,andpepticulcerlowsolubility25g/mlrelativelyshorteliminationhalf-lifetime(about3h)inhumansaswellaslowbioavailability(45–50%)CaseFile—Sediment當(dāng)前31頁，總共58頁。32MaterialsCaseFile—SedimentPolyethyleneoxide(PEO)Mw1,000,000(WSRN12K)Pharmaceuticalironpowder(100mesh)NaClCelluloseacetate(CA)AcetonePolyethyleneglycol4000(PEG4000)Technetium-99m(99mTcO4?)CommerciallyavailableFMTDconventionaltabletsHighdensitygastricresidentosmoticpumptabletCoatingmaterial當(dāng)前32頁，總共58頁。33CaseFile—SedimentCentralcompositedesignPEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)4factor5level當(dāng)前33頁，總共58頁。34SedimentY1

Thecriticalresponseswereultimatecumulativereleasein12h

Y2

CorrelationcoefficientofdrugreleaseprofileCentralcompositedesign當(dāng)前34頁，總共58頁。35PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前35頁，總共58頁。36PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前36頁，總共58頁。37PEO(X1)NaCl(X2)Pharmaceuticalironpowder(X3)Coatingweightgainofthetablet(X4)Y1Ultimatecumulativereleasein12hY2CorrelationcoefficientofdrugreleaseprofileCaseFile—Sediment當(dāng)前37頁，總共58頁。38OptimizedformulationPEO(X1)60-85mgNaCl(X2)30-35mgPharmaceuticalironpowder(X3)110-120mgCoatingweightgainofthetablet(X4)6.25-7.25%當(dāng)前38頁，總共58頁。39OptimizedformulationOptimizedformulationA:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceuticalironpowder(X3)115mg;Coatingweightgainofthetablet(X4)7%.當(dāng)前39頁，總共58頁。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40頁，總共58頁。41CaseFile—SedimentOptimizedformulation當(dāng)前41頁，總共58頁。42CaseFile—SedimentConventionaltablet當(dāng)前42頁，總共58頁。43FurosemideBCSIVpKa3.9Halflifelessthan2hSolubilitypHdependentSideeffect：PeakdiuresiseffectMajorabsorptionsite：uppergastrointestinaltract

Erraticabsorption,poorbioavailability3-4timesaday，non-complianceCaseFile—Bioadhesion當(dāng)前43頁，總共58頁。44MarketedformulationLasixRetard?60mgLimitation:insufficienttimeinthestomach當(dāng)前44頁，總共58頁。45CRLayerIRLayerDesignedformulationTotal:60mgLoadingdose30%Maintenancedose70%Bioadhesion&Expansion當(dāng)前45頁，總共58頁。46CRLayerIRLayerIn-vitrofilmdefoldingstudy當(dāng)前46頁，總共58頁。47CaseⅠCase

ⅡPoordefoldingGooddefolding當(dāng)前47頁，總共58頁。48CompleteDefodingIn-vitrofilmdefoldingstudyCaseⅠCase

ⅡPoordefoldingperformanceGooddefoldingperformance當(dāng)前48頁，總共58頁。49Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFCRlayerHighglasstransitiontemperatureIRlayerPolyvinylalcohol(Gohnesol?)GlasstransitionnearroomtemperatureMechanism:ProlongedShapeMemory當(dāng)前49頁，總共58頁。50Solvent&SolubilizerofdrugSolvent&SolubilizerofdrugSoluphor?PCremophore?RH40HPβCDPEG400(Lutrol?E400)Polyvinylalcohol(Gohnesol?)Eudragit?RLPOHPMCE4M(Methocel?E4M)Carbopol?971PNFSoluphor?PCremophore?RH40HPβCDCRlayerIRlayerMaterialsPlasticizerPolymermatrixPolymermatrixBioadhesiveRretarddrugrelease當(dāng)前50頁，總共58頁。51CharacterizationSEMNocrystalsonsurfaceSideviewIRlayerCRlay