卡維地洛納米混懸滲透泵給藥系統(tǒng)的研究

卡維地洛納米混懸滲透泵給藥系統(tǒng)的研究沈陽藥科大學(xué)潘衛(wèi)三Researchof

Carvedilol

NanosuspensionOsmoticPumpDrugDeliverySystem

ShenyangPharmaceuticalUniversityPan

WeisanContentsIntroduction1Fabricationandevaluationofcarvedilol

nanosuspension2Preparationofosmoticpumpcapsulefilledwithnanosuspension3Summary41ToimproveSolubilityanddissolutionrateofwaterinsolubledrugs,itisimminentlyneedtodevelopnewpharmaceuticaltechnologyandnewdosageforms.申請(qǐng)的中國發(fā)明專利今年獲得授權(quán)IntroductionSectionI2drugnanosuspensions----newtechnologyosmoticpump----newformulationstrategySolubility～particlesizeDissolutionrate～particlesizeNoyes－WhitneyParticlesizer

↓CS↑Dissolutionrate↑

Ostwald

FreundlichParticlesizer↓SolubilityCS↑

ThefundamentaltheoryIntroductionSectionI3制備納米藥物的一般方法

Preparationmethodsofnanometersizedrugs4TopdownBottomupIntroductionSectionIOsmoticPumpNanosuspensionsPros:ImprovethesolubilityandbioavailabilityofdrugsCons:

Increasetheblood

concentrationfluctuationPros:Decreasetheblood

concentrationfluctuationCons:

EOPisnotsuitablefordeliveryofdrugshavingpoorwatersolubilityTheaimofourstudyIntroductionSectionI5卡維地洛（Carvedilol）——Class:BCSⅡ6模型藥物（ModelDrug）IntroductionSectionICAR在pH>6.0的堿性條件下溶解度極低，嚴(yán)重阻礙了其在小腸和結(jié)腸部位的溶出和吸收，也使其不適合被制備成緩控釋制劑，因此有必要通過制劑手段來首先改善其溶解性、提高BA。CSCS絕對(duì)生物利用度低僅為25%～35％7溶解度Solubility

有機(jī)溶劑organicsolventOrganicsolventSolubility(mg/mL)Boilingpoint(°C)Ethylacetate22.17±0.8077.1N-propylalcohol15.33±0.2497.2Propyleneglycol10.90±0.19188.2Isopropylalcohol8.31±0.0282.5Ethanol20.33±0.3878.4Methanol47.62±3.4264.7Acetone174.18±5.2356.5Dimethyl

sulfoxide

541.23±4.10189.2Dimethylformamide

578.34±6.50152.8SolubilityofCARindifferentorganicsolvent(n=3)IntroductionSectionI納米混懸劑的制備與表征CARCo-stabilizer(VES)DrugorganicsolutionInjectionAnti-solvent

containingstabilizers（SDS)PrecipitationUltrasonificationKeptundervacuumatroomtemperaturefor24hAnti-solventPrecipitation--UltrasonicationMethodHighpressurehomogenisation

10000rpm

制備過程PreparationprocessSectionⅡ

8反溶劑沉淀--超聲法制備納米混懸劑的工藝流程示意圖（Schematicrepresentationoftheformationofnanosuspension

preparedbytheprecipitation–ultrasonicationmethod）

納米混懸劑的制備與表征

SectionⅡ

9ⅡPreparationandCharacterization

ofNanosuspension（NS）處方篩選formulationscreeningtest

StabilizerCo-stabilizerAppearanceStabilitySDSF68Milky-F127Opalescent+VESTranslucent++PVPK30F68Milky-F127Milky-VESSedimentary-HPMCE15LVF68Milky-F127Opalescent+VESSedimentary-F68/127:Poloxamer188/Poloxamer407

VES：VitaminESuccinate++:unchangedwithin2hours;+:precipitationappearedafter1hour;-:precipitationimmediately納米混懸劑的制備PreparationofNS制備過程Preparationprocess10VariablesSymbolsRangeandlevels-1.682-1011.682CAR(mg/ml)X1200241300359400VES(mg/ml)X2120144180216240SDS(g/100ml)X30.200.320.500.680.80IndependentvariablesandtheirlevelsinvestigatedinCCD—RSM星點(diǎn)設(shè)計(jì)-效應(yīng)面法Centralcompositedesign-responsesurfacemethod

處方優(yōu)化*

formulationOptimization

制備過程Preparationprocess*DandanLiu,Heming

Xu,Baocheng

Tian,XinggangYang,WeisanPan*FabricationofCarvedilol

NanosuspensionsThroughtheAnti-SolventPrecipitation–UltrasonicationMethodfortheImprovementofDissolutionRateandOralBioavailability.AAPSPharmSciTech,Vol.13,No.1,納米混懸劑的制備PreparationofNS11結(jié)果ResultNo.LevelsofindependentfactorsResponseCAR(mg/mL)VES(mg/mL)SDS(g/100mL)ParticleSize(nm)12001800.5011622412160.6817732412160.3252942411440.6816452411440.3262963001800.5023373001800.5022283002400.5048993001800.50240103001200.50514113001800.20832123001800.50218133001800.80171143001800.50203153001800.50222163592160.68567173591440.321558183592160.32684193591440.68478204001800.501425納米混懸劑的制備PreparationofNS12擬合方程FittedEquation

納米混懸劑的制備PreparationofNS結(jié)果Result其相關(guān)系數(shù)R2值為0.9260，P<0.05，說明擬合方程的相關(guān)性良好，可以用此數(shù)學(xué)模型進(jìn)行處方分析和預(yù)測(cè)。TheR2valueis0.9260,P<0.05.Accordingly,thefittedequationcanpredictthebestformulationforCARnanosuspensions.13Effectofdrugconcentrationonparticlesize

3DResponsesurfacesand2DcontourplotforparticlesizeCARParticleSizeParticleSizeCAR14EffectofVESconcentrationonparticlesize

3D

Responsesurfacesand2DcontourplotforparticlesizeVESParticleSizeParticleSizeVES15EffectofSDSconcentrationonparticlesize

3D

Responsesurfacesand2DcontourplotforparticlesizeSDSParticleSizeParticleSizeSDS16TheoptimizedformulationIngredientAmountCAR592mgVES390mgAcetone2mLSDS0.470gDistilledwater100mLThenanosuspensionspreparedwiththeoptimizedformulationyieldedameanparticlesizeof212nm,whichisingoodagreementwiththevaluepredicted(225nm)bytheequation（model）.驗(yàn)證

Validation

17EffectsofPreparationFactorsonParticleSizePrecipitationtemperature（制備工藝因素對(duì)粒徑的影響）18UltrasonicpowerinputEffectsofPreparationFactorsonParticleSize19TimeofultrasonictreatmentEffectsofPreparationFactorsonParticleSize20lyophilizationOrSpray-dryingTablets,pelletsfreelyflowablepowdersnanosuspensionliquidsolidSolidificationofNS21SolidificationofNS22

保護(hù)劑種類cryoprotectantsCryoprotectantAppearanceReconstitutionNoneSmooth,compactVeryDifficultMannitolSmooth,compactEasySucroseCollapseAlittledifficultLactoseCollapseVerydifficultMaltoseCompactEasyGlucoseCollapseAlittledifficult保護(hù)劑用量Conc.cryoprotectants凍干固體化lyophilizationCharacterizationofcarvedilolNSMeanparticlesize(nm)Sizedistribution(nm)SPANZetapotential(mV)D10D50D90212

±

12177

±

7212±

12255

±

150.37

±

0.02-42

±

3ParticleSizeandZetaPotential23Morphology(SEM)CARVESSDSNSNS（NoVES）CharacterizationofcarvedilolNS24X-raydiffractionCARVESSDSMicrosuspensionPhysicalMixtureNanosuspensionCharacterizationofcarvedilolNS結(jié)果表明：CAR和VES在制備成納米或者微米混懸劑后，均以無定型的狀態(tài)存在.25DSCCARVESSDSMicrosuspensionPhysicalMixtureNanosuspensionCharacterizationofcarvedilolNS同樣表明：CAR和VES在制備成納米或者微米混懸劑后，均以無定型的狀態(tài)存在.26FTIRCARVESSDSPhysicalMixtureNanosuspensionCharacterizationofcarvedilolNS27CARInVitroDissolutionStudies—pHvaluepH1.0pH6.8CharacterizationofcarvedilolNS28InVitroDissolutionStudies—LyophilizationCharacterizationofcarvedilolNS29Short-TermPhysicalStabilityCharacterizationofcarvedilolNS30InVivoStudiesofNSPlasmaconcentration-timeprofilesofCARafteroraladministrationofnanosuspensionsandthereferenceformulationinrats.Eachvaluerepresentsthemean±S.D.(n=5)31SectionⅢPreparationofosmoticpumpcapsulefilledwithnanosuspensionOrganicsolution100mLStirringPerfusateCapsuleCAsemipermeablecapsuleCADEPPEG400InjectDryingat4-8℃

*DEP:鄰苯二甲酸二乙酯

SectionⅢPreparationofosmoticpumpcapsulefilledwithnanosuspensionPreparationprocessofsemipermeablecapsuleshellCARNSpowderandotherexcipientswerefilledintothecapsulesintheformofpowders.Anorificewasdrilledwithamicrodrilloneithersideofthecapsule.SectionⅢPreparationofosmoticpumpcapsulefilledwithnanosuspensionPreparationprocessofosmoticpumpcapsuleThecompositionoftheosmoticpumpcapsuleCapsulecontentsSemipermeablecapsuleshellNanosuspensionpowder95mgCA8gSuspendingagent200mgDEP0.96gOsmoticagent100mgPEG4002.24gMagnesiumstearate5mgAcetone100mLEffectofdifferentsuspendingagentondrugreleasePreparationprocessofosmoticpumpcapsule√EffectofamountofPlasdoneS-630ondrugreleasePreparationprocessofosmoticpumpcapsule√EffectofdifferentosmoticagentondrugreleasePreparationprocessofosmoticpumpcapsule√EffectofamountofMannitolondrugrelease√PreparationprocessofosmoticpumpcapsuleEffectofamountofCAondrugrelease√PreparationprocessofosmoticpumpcapsuleEffectofamountofDEPondrugrelease√PreparationprocessofosmoticpumpcapsuleEffectofamountofPEG400ondrugrelease√PreparationprocessofosmoticpumpcapsuleEffectofpHvalueondrugreleasePreparationprocessofosmoticpumpcapsulePharmacokineticStudies√Meanplasmadrugconcen