聚β-环糊精载药微球的制备及药物释放性能的研究

广东药学院硕士学位论文聚β-环糊精载药微球的制备及药物释放性能的研究姓名：曹蕾申请学位级别：硕士专业：药剂学指导教师：谭载友20090501I(DiclofenacSodium,DFS)β-β-β-β-(β-CDP)β-CDPβ-CDP(ECH)n(ECH):n(β-CD)15:11.5h30Span80:Tween203:17h50900r/min40.45±3.8µm1±0.15(n=5)β-CDβ-CD(1)(2)pHII-β-CDP-β-CDPpH(1)β-CDP24hβ-CDP(2)-β-CDP-β-CDPKorsmeyer-Peppasnβ-CDPCrankDβ-iPreparationandDrugReleaseStudyofβ-CDPMicrosphereCAOLEIPharmaceuticaldepartmentofGuangdongPharmaceuticalUniversitySupervisorProf.TANZaiyouABSTRACT:Inthispaper,DiclofenacSodiumwaschosenasmodeldrugandβ-CDwasusedasmaterialtopreparedrug-β-CDPmicrospheres(MS).Furthermore,theswellingpropertiesofthepolymermicrosphereanddrugreleasebehaviorinvitroandtheirreleasemechanismweredeeplystudied.Inthestudyofpreparationmethod,β-CDPMSwasfirstpreparedbythetechniqueofinverseemulsionpolymerization.Andthesynthesisofβ-CDPMSwasoptimizedbyusingthesinglefactorinvestigationandtheorthogonaltesttotesttheeffectofvariousfactorsonresults.ThecriteriatoevaluatetheMSincludedtheappearance,particle’ssizeandyield.OptimalformulationwaschosenandMSwereformedwithgoodquality.Theresultsshowedthatthestirringrateandemulsifiermainlyaffecttheparticle’ssizeandyieldseparately.Thetesttechnologicalconditionswere:keroseneastheoilphase,n(ECH):n(β-CD)=15:1,crosslinkingtime=1.5h,crosslinkingtemperature=30,Span80:Tween20=3:1,emulsiontimeis7h,emulsiontemperature=50,thestirringrateis900r/min.Therepeatabilityofthetechnologywasprecise.β-CDPMSwereshapespherical,sizeequality,regularinmorphology,surfacesmooth,withthemeandiameterof40.45±3.8µmandthespanof1±0.15(n=5).Preparedmicrospherereservedthecavitystructureofβ-CDandwithahighcontentofit.Theβ-CDPMShadaunconsolidated,honeycomb,cross-linkingthreedimensions,reticularinternalstructure.Theyalsohadagoodliquidityandhighwater-absorbent.Afterestablishmentofoptimalformulationofsynthesizingβ-CDPMS,weprepareddrug-β-CDPMSwiththreemethods.Onewasdirectmethod,andtheotheronewasinclusioncompound,thethirdwasinfusionmethod.Theexperimentalresultsindicatethat:first,drugcontentpercentoftheinfusionmethodwashigherthanthedirectmethodandiiinclusioncompoundmethod.Second,drugcrystalswereseenonthesurfaceofdrug-β-CDPMSbythedirectmethodandinclusioncompoundmethod.Inthestudyoftheswellingpropertiesofthepolymermicrosphere,theswellingrateofthepolymermicrosphereincreasedwiththeincreasingofthebuffersolutionpHanditsconcentrationindifferentconditions.Thehigherthedrugloaded,thefasterthedrugreleased,buttheswellingspeedcontrolledbyion-dependentswellingmechanismwaslimitedinthehighconcentrationbuffersolution.Then,amathematicalmodelofdrugreleasewasestablished,basedonthediffusionlaw.Weappliedelastomerequationsaboutstress-strainrelationship,DeandSwtodescribethewater-absorbedofpolymerandthedrugreleaseprocess,takingintoaccountthematerialexpansioncausedbysolventinfiltration.InthestudyofdrugreleasefromMSinvitro,commonlyuseddialysismethodwasstudiedcomprehensively.Inthisexperiment,DFS-β-CDPMSwasthekeypoint,andstudiedtheeffectofvariousfactors(preparationmethod,pHofmedia,solutionvolumeinsidethedialytic-bags,drugcontentpercentandparticle’ssize)ondrugreleasebehavior.Theexperimentalresultsindicatethat:first,β-CDPMShadasustainedreleaseeffectonDFS,achieving24h.Thisindicatedthatcavitystructureofβ-CDPMSintercalatedwithdrugtomakeitreleaseslowly;second,forDFS-β-CDPMS,allthefactors,especiallytheparticle’ssize,hadaneffectondrugreleasebehavior.ThearticlealsovaluatedtheresultsofdrugreleasefromMSinvitrowithtwomathematicalmodels.Firstly,empiricalandhalf-empiricalmathematicalmodelwereusedtoprovethatreleaseofDFS-β-CDPMSaccordingwithfirst-orderreleaseandKorsmeyer-Peppasmodel.Themechanismofdrugreleasewasbonesolutionanddiffusionmainly.Secondly,diffusivity(D)wascalculatedbymodelof“radialdiffusioninasphere”(Crank).Keywords:β-CDP,inverseemulsionpolymerization,microspheres,swelling,dialysismethod.Figure1-1verticalviewofβ-CD······································································································4Figure1-2stereochemicalstructureofβ-CD····················································································4Figure1-3Cyclodextrincrosslinkedwith1-chloro-23-epoxypropane·········································15Figure1-4Polyallylaminewithpendentcyclodextrins··································································15Figure1-5InclusioncomplexformationofCDmoleculesandalinearpolymerchain·················15Figure2-1normalphaseandreversedphasecolloidparticle·························································24Figure2-2Colloidofreversephaseemuls·····················································································24Figure2-3Inverseemulsionpoly-merization················································································25Figure2-4Reactionschemeofthepoly-condensationβ-CDoftheECH·······································27Figure2-5Equipmentoftest···········································································································34Figure2-6FESEMofpictureβ-CDPmicrosphere····························································