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首页 formulation stability and degradation kinetics …

formulation stability and degradation kinetics of intravenous cinnarizine lipid emulsion.PDF

formulation stability and degra…

上传者: 195592608 2012-07-25 评分 0 0 0 0 0 0 暂无简介 简介 举报

简介:本文档为《formulation stability and degradation kinetics of intravenous cinnarizine lipid emulsionpdf》,可适用于人文社科领域,主题内容包含InternationalJournalofPharmaceutics()–ContentslistsavailableatScienceDirec符等。

InternationalJournalofPharmaceutics()–ContentslistsavailableatScienceDirectInternationalJournalofPharmaceuticsjournalhomepage:wwwelseviercomPharmaceuticalNanotechnologyFormulsolipidemShuaiShDepartmentof,articlArticlehistory:ReceivedNoReceivedinreAcceptedFebAvailableonlinKeywords:CinnarizineFormulationIntravenouslipStabilityDegradationkulsihomrizinendsteinnarledenoftditslipidtesteactiohichThefinalproductswerestableenoughtoresistaCrotatingsteamsterilizationforminElsevierBVAllrightsreservedIntroducCinnarizwidelyusedriosclerosisal,SiisteringthehaspooraqcommerciaBothoftheal,)SCNsaltsoluhavebeeniZhangetalatedwiththcausevenoubeadjustedotherhand,CNinsolutiToensucarrierisnnutritionBCorresponEmailadd$–doi:jitionine(CN),acerebralbloodflowpromoter(Fig),isforthetreatmentofcerebralapoplexy,cerebralarteandposttraumaticcerebralsymptoms(Godfraindetngh,)However,theoptimummethodofadmindrughasnotbeenfullyestablished,sincecinnarizineueoussolubilityandchemicalinstabilityThecurrentlyllymarketabledosageformsaretabletsandcapsulesseexhibitlowanderraticoralbioavailability(Ogataeteveralintravenousdosageforms,suchaswatersolubletionandCN–cyclodextrininclusioncomplexsolution,nvestigatedtoovercometheseproblems(Wang,,)However,therearetwomainproblemsassocieiruseOnonehand,theinjectabledosageformsmaysirritationbecausethepHvalueofthesolutionmustacid(pH<)toenhancethesolubilityofCNOnthenoneofthesecaneffectivelyreducethedegradationofonrebothhighsolubilityandstabilityofCN,asuitableeededLipidemulsionsarefirstlyusedinparenteralut,significantly,theiradvantagesintermsofthereducdingauthorTel:fax:ress:tangpharmyahoocomcn(XTang)tioninirritationortoxicityoftheincorporateddrugandthepossibilityofsustainedreleaseandtargeteddeliveryofthedrugtovariousorgansmakethemexcellentvehicles(Gettingsetal,SinghandRavin,)Thelipidemulsion,whichconsistsofaninterioroilphaseandanexteriorwaterphase,ispreparedbyincorporatingdrugsintotheinterioroilphaseandtheoil–waterinterfacialfilmThismeansthatthedrugwithpooraqueoussolubilitycanbeeasilyloadedandthehydrolysisofunstabledrugscanbeminimized(Floyd,)AlltheseexcellentcharacterizationsoftheemulsionmaycontributetoinvestigationofintravenousCNandmakethelipidemulsionbeaappropriatecarrierforCNInourstudy,cinnarizinelipidemulsion(CLE)wasinitiallydesignedandpreparedbyoptimizingtheformulationsWecarriedoutadetailedinvestigationofthedegradationofCNindifferentoilsandtheeffectoftheamountoflecithinonthechemicalstabilityofCLEinordertoreducethedegradationofCNduringtheinitialstagesConsideringthatdegradationofCNoccursinboththeoilandwatermedium,wetriedtolocalizethedrugintheinterfaciallecithinlayeroftheemulsiontoisolatethedrugfromwateroroilmediumThiswasachievedbythemethodeverusedforthesolubilizationofpoorsolubledrug(DavisandWashington,Lanceetal,)Then,otherfactorsinfluencingthestabilityofCLEwereinvestigatedtoevaluatethefeasibilityofusingCLEforintravenousinjectionItwasreportedpreviouslythatCNisverylabileinaqueoussystemsfollowinganinvestigationofthedegradationkineticsofCNinacidicsolutions(pH<)(Tokumuraetal,)However,seefrontmatterElsevierBVAllrightsreservedjpharmation,stabilityanddegradationkineticulsioni,HaoChen,YueCui,XingTangPharmaceutics,ShenyangPharmaceuticalUniversity,WenhuaRoad,ShenyangeinfovembervisedformFebruaryruaryeFebruaryidemulsionineticabstractCinnarizinewasloadedinthelipidemandchemicalstabilityHighpressuretorsinfluencingthestabilityofcinnatemperature,sterilizationmethodsachromatographThedegradationofcapparentfirstorderkineticsApossibrateprofileofcinnarizineLocalizatiothechemicalstabilityofcinnarizineanTheactivationenergyofcinnarizineintothatinaqueoussolutionThisindicanotanalterationofthedegradationrestimatedtobedaysatC,wlocateijpharmfintravenouscinnarizineLiaoningProvince,PRChinaontodevelopanintravenousformulationwithgoodphysicalogenizationwasusedtopreparethelipidemulsionThefaclipidemulsion,suchasdifferentdrugloadingmethods,pH,rilizationtimeweremonitoredbyhighperformanceliquidizineinaqueoussolutionandlipidemulsionbothfollowedgradationmechanismwaspostulatedbythebellshapedpHhedrugintheinterfaciallecithinlayersignificantlyimprovedstabilizingmechanismwasthoroughlydiscussedandprovedemulsionwascalculatedtobekJmolwhichwassimilarhatthestabilizingeffectofthedrugcarrieroncinnarizinewasnInaddition,shelflifeofcinnarizineinlipidemulsionwasismuchlongercomparedwithdaysinaqueoussolutionSShietalInternationalJournalofPharmaceutics()–therangeofforinjectionoussolutionvalues(lateapossibstudyofCLofdrugcarroftheprodureportedwWangaformulatiilizationforthecostoftMethodMateriaThefollobrackets:cShangqiu,CLudwigshafDegussaFo(TielingBei(PluronicFmany),TweIndustryLtdGlycerolPlawereofanaPreparaFirstly,CconsistedooilphaseToleate,TweagitatedunaddedslowRURRAXIKobtaincoarNaOHorHmlAftpressurehoViaMdaErtogetthefinizationproinvials,andCharacThepartroscopy(PParticleSizitoparticlesrangingfromnmtominsizeandprovidestwoparameters,ameandiameterandthestandarddeviation(SD)ThetwoparametersareusuallyusedtoevaluatetheparticlesizedistributionofCLESampleswerediluted:withpurifiedwateriatelassecopeswefoedfom,NicialofSamametermpHaiPrmicrentrthebjechatrickeueoutedbwas=CtoPLCaHPLtectoHiQpan)nolalmngthewaalysmiethaorthrCanaprodgmlxecocyoftheincuraFigStructureofcinnarizinepHvalueswastoonarrowtoincludeasuitablepHrange(pH–)So,thedegradationkineticsofCNinaqueweresupplementedbyprovidingawiderrangeofpH–)tofindthemostappropriatepHvalueandpostuledegradationmechanismAtthesametime,akineticEwasalsocarriedoutinordertoinvestigatetheeffectieronthedegradationofCNandestimatetheshelflifectUntilnow,noinjectablepreparationofCNhasbeenhichcanwithstandautoclavingsterilization(Jiaetal,,Zhangetal,)OurstudyconcentratedononwhichcouldwithstandaCrotatingsteamstermintoimprovethesafetyoftheproductandreduceheindustrialprocessslswingmaterialswerepurchasedfromthesourcesininnarzine(ShanghaiXiandaiHashenPharmaLtdCo,hina),mediumchaintriglyceride(MCT)(LipoidKG,en,Germany),egglecithin(EPIKURON,PC,odIngredients,Germany),longchaintriglyceride(LCT)yaPharmaceuticalCo,Tieling,China),Poloxamer)waspurchasedfromBASFAG(Ludwigshafen,Gerenforparenteraluse(ShenyuMedicineandChemicalCo,Shanghai,China),andglycerol(ZhejiangSuichangnt,Zhejiang,China)AllchemicalsandreagentsusedlyticalorchromatographicgradetionofCLENtogetherwithegglecithinwasdissolvedinoilwhichfLCTandMCT,andheatedatCtoobtainaclearhen,theaqueousphaseconsistingofglycerin,sodiumen,FandEDTAwasalsoheatedtoCandtiluniformlydissolvedFinally,thewaterphasewaslytotheoilphasewithhighspeedshearmixing(ULTRAATbasic,Germany)at,rpmformintoseemulsionThepHwasadjustedtowithmollCl,andthevolumemadeupwithpurifiedwatertoerthat,thecoarseemulsionwassubjectedtohighmogenization(NiroSoaviNSkhomogenization,ba,APARMA,Italy)atbarforeightcyclesimmedscopicmicrossamplewithanalyzthanThepotentniquetothesThedeTheShanghwithaThesuringwassuforwereptheaqestimatheEEetal,EE()HTheUVdeandaCo,JatriethaofmwavelevolumAnOnewithmjing)ffilteredtoHPLdationy=,atthreaccurawhiledayacnalemulsionThetemperatureoftheentirehomogecesswasmaintainedatCThen,theCLEwassealedrotatedinaCwatersteambathforminterizationofCLEticlesizewasmeasuredbyphotoncorrelationspecCS,dynamiclightscattering,DLS)withaNicompTMngsystem(SantaBarbara,USA)ThesystemissensitiveaccuracyofrequiremenThedegsolutionApH(UnitedaliquotsandybeforemeasurementatCInaddition,themicrossmentwascarriedoutonusingaMoticDMBA(MoticChinaGroupCoLtd,Beijing,China)Emulsionreinvestigatedwithoutdilutedusinganoilimmersionldmagnificationtypicallymicroscopicfieldswererthedetectionofmicrons,thesizeofwhichwasgreaterparticularlythosedrugcrystalsompTMsystemwasalsousedtodeterminedzetatheCLEbyelectrophoreticlightscattering(ELS)techpleswerediluted:withpurifiedwateradjustedpHastheCLEusingmollHClorNaOHbeforehandinationwasperformedatCvaluesofCLEweremeasuredusingapHmeter(Leici,ecisionScienceInstrumentLtd,Shanghai,China)fittedoelectrodeatroomtemperature(C)apmentefficiency(EE)ofCLEwasdeterminedbymeaconcentrationofCNinthedispersionphaseTheCLEttoaHitachiultracentrifugeoperatedat,rpmCPolyallomertubeswereusedandtheirbottomsdaftercentrifugationwithasyringeneedletocollectsphaseTheamountofCNintheaqueousphasewasyhighperformanceliquidchromatography(HPLC)andcalculatedaccordingtothefollowingequation(FerezouGrovesetal,):talVtotalCwaterVwaterCtotalVtotalnalysisCsystemconsistedofanLpump,anLr,anLautosampler(HitachiCompany,Japan)silCWcolumn(mmmm,m,KyaTechThemobilephaseconsistedofmethanol–water–mine–glacialaceticacid(:::)ataflowratein,modifiedfromtheliterature(Guoetal,)TheoftheUVdetectorwassetatnmandtheinjectionslisofcinnarizineanditsdegradationproductslliliterofemulsion(mgml)wasdilutedtomlnol,vortexed,andthencentrifuged(LGA,Beimin(rpm)ThesupernatantwascollectedandoughammembraneThefiltratewassubjectedlysistoestimatetheamountofcinnarizineanddegrauctsThecalibrationgraphofCNrangingfromtowaslinearanddescribedbythefollowingequation:(r=)TherecoveryoftheCNevaluatedncentrationswasfromtoTheintradaythemethodforcinnarizinerangedfromto,tradayprecisionrangedfromtoTheintercyrangedfromtoTheprecisionandthemethodwerebothwellconsistentwithanalysistradationkineticsofcinnarizineintheaqueousphosphatebufferwaspreparedaccordingtoUSPStatesPharmacopeia)ThebufferwasdividedintothepHadjustedwithNaOHorHPOtopH,,SShietalInternationalJournalofPharmaceutics()–,,,,,andCNwasdissolvedinthesebufferstoobtainsolutionsofmollEachbuffercontainingmollCNwasplacedinamlampule,whichwasthensealedandkeptinawaterbathatCSampleswerewithdrawnatintervalsof,,,,,,,handcooledimmediatelytoterminatethereactionbeforeHPLCanalysisTheresidualCNcontentwaStabilitThedCNwasbathThen,inaCteatintervalstureThecodeterminedwasevaluatEffectInourstCLETheme•MethodA:wasdispe•MethodB:AfterdissratedbyremainingwasdispeThefolloSectionThesampleimmediatelTheconcenbeforehandEffectsolutionandCNwasAttheSectionat,,,,,,determinatexaminedaEffectTheCLEtionThinvolvingroinaCwsteambathaftersterilizzetapotentEffectTheCLEdescribedinsteambathminTheicalstabilitysizesandpHseudofirstorderplotsofthedegradationofCNinbuffersolutionsoverapHvalues(–)atCLongewbCtermoomtedbentraedultsedegdegraluenshipndthtimesAnk)anigexedfrnificantlydecreasedFigRatepHprofileforthedegradationofCNinbuffersatCscalculatedbyacalibrationcurvepreparedinadvanceystudyegradationofcinnarizineindifferentoilsdissolvedindifferentoilsbyagitatinginaCwatertheoilswhichcontainCNweresealedinvialsandputmperatureconstantovenThesampleswerewithdrawnof,anddaysandallowedtotheroomtemperancentrationsofCNinoilsatdifferenttimepointwerebyHPLCAndthedegradationofCNindifferentoilsedbythechangesoftheCNconcentrationofthedrugloadingmethodudy,twomethodswereinvestigatedtoloadCNinthethodswereasfollows:CNwasdissolvedintheoilphaseinwhichthelecithinrsedthoroughlyinadvanceCNandlecithinweredissolvedindehydratedalcohololvinguniformly,thedehydratedalcoholwasevapostirringonawaterbathatCuntiltheweightoflecithin–drugmixturewasconstantThen,themixturersedinoilforfurtherprocessingwingstepsforpreparingtheCLEswereconsistentwithThefinalproductswereplacedinanCwaterbathswerewithdrawnatappropriateintervalsandcooledytoterminatethereactionthenanalyzedbyHPLCtrationofCNwascalculatedbyacalibrationpreparedoftemperatureondegradationrateofCNinaqueouslipidemulsiondissolvedinwatertogiveamgmlsolutionatpHsametime,mgmlCLEwaspreparedaccordingtoatthesamepHBothofthesewerekeptinawaterbath,andCSampleswerecollectedatintervalsof,,,,,,,andhandcooledimmediatelyforionbyHPLCThephysicalappearancesoftheCLEweretthedifferenttimeintervalsofthethermalstabilitymethodcontainingmgmlCNwaspreparedaccordingtoSecesamplesweresterilizedunderdifferentconditionstatinginaCwatersteambathformin,rotatingatersteambathformin,androtatinginaCwaterforminThen,thecorrespondingsamples,beforeandation,wereanalyzedbyHPLCTheirparticlesizesandialswerealsodeterminedofthethermalsterilizationtimewiththeconcentrationofmgmlwaspreparedasSectionThesampleswererotatedinaCwaterfordifferentsterilizationtimeof,,,,andn,allthesampleswereanalyzedbyHPLCAndthephysofCLEwasevaluatedbyphysicalappearances,particlevaluesFigPrangeofAnandpredetotherevaluavalue,performResThTheofpHvrelatioscaleaversuskineticstant(fromF–increasCNsigtermstabilityinvestigationatchofoptimumCLEwaspreparedandstoredat,whichwasclosetotheparticlestorageconditionAtinedtimeintervals,sampleswereremovedandallowedtemperatureTheirphysicalandchemicalstabilitywereyphysicalappearance,particlesizedistribution,pHpmentefficiencyanddrugremainingThestudywasintriplicateanddiscussionradationkineticsofcinnarizineinaqueousmediaadationofCNinbufferedsolutionsatCoveraranges(–)wasmonitoredbyHPLCFigshowsthebetweenconcentrationofCNonanaturallogarithmicetimeataseriesofpHvaluesThelnC(concentration)waslinearatallpHvaluesfollowingpseudofirstorderdtherelationshipbetweenthedegradationratecondthepHvaluesisexhibitedinFigItcanbeobservedthatthedegradationofCNwasextremelyrapidatpHhibitinganincreaseinthecurveWhile,asthepHvalueomto,thecorrespondingdegradationrateofSShietalInternationalJournalofPharmaceutics()–FigThedegradationpathwayofCNinbuffers(pH–)Thisprofileappearsabellshape,whichishardtointerpretasthekineticsoftheionizationconstantsofthereactantsAnexpressionofkinThisbehavimaybedesreactionwiimpliestheinthereaccanbeisolaanalysisHomediatemacationicimofhydroxymbaseformatdationprod(pH–TwopieimineinterilartothatJencks,inFigwa(Allewijn,TheresuthanaCNConsidefinallyselecCNPreparaOilphLCTsasicalsituatiosideeffects,endothelialafterlongtreducethetandmayaletal,Hence,tandMCTatoinvestigachemicalstigeastedwandle,ormuatrofCLEThismightbebecausethatexcessMCTintheoilresultedinanincreaseinthemeanparticlesizeandstandardionorevenoildropsTheEEofeachformulationwasalmostgedsuggestingthattheoilphasedidnothaveasignificantnEEedontheseresults,thechoiceofasuitableoilphasewastoLCTandthemixtureofLCTandMCTatratiosof:ddition,consideringCNmaybealsoliabletodegradeinoils,gradationofCNindifferentoilswasacceleratedbybeingatCandevaluatedbythechangeoftheCNconcentrationdaysAccordingtoFig,itsuggeststhatthedegradationlsooccurintheoilHowever,astheamountofMCTintheoilincreased,thedegradationofCNreducedItcanbeconsidattheadditionofMCTintheoilphaseofCLEmaycontributeeductioninthedegradationofCNTherefore,takingaccountofthedesiredcharacterizationandchemicalstabilityofCLE,ixtureofLCTandMCTseemstobethebestchoiceTableTheeffectofoLCTF:F:F:F:F:F,FormulationeticsofthereactionismorereasonableatthistimeorhasbeenrecognizedinanumberofreactionsandcribedasachangeintheratedeterminingstepofthethchangingpHAchangeintheratedeterminingsteppresenceofatleasttwostepsandoneintermediatetion(Mollicaetal,)Untilnow,nointermediatetedandobservedbychromatographicorspectroscopicwever,itcanbeinferredthatacationicimineinterybeexistintheseriesofdegradationreactionsTheineintermediate,R–NCH–Rwhichupondehydrationethylamine,R–N–CHOH–RwassubjectedtotheSchiffion,hydrolysisreactionsanddecomposedtothedegrauctsThedegradationpathwayofCNinbuffersolutions)ispresumedtobethatexhibitedinFigcesofevidencemadetheexistenceofthecationicmediatereasonable:thelnk–pHprofileofCNwassimobservedforahydrolysisofaSchiffbase(Cordesand)Beside,l(diphenylmethyl)piperazine(M)displayedspreviouslyreportedasadegradationproductofCN)ltsobtainedabovesuggestthatthepHmustbehigherndasbasicaspossibletoreducethedegradationofringtheallowedpHvaluerangeforinjection(–),wetedthepHvalueoftominimizethedegradationoftioninvestigationsofCLEasecompositioninCLEtheoilphaseoflipidemulsionhavebeenusedinclinnsforoveryearsHowever,theystillhavesomesuchasimmunedysfunction,accumul

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