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首页 formulation stability and degradation kinetics o…

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

formulation stability and degra…

195592608
2012-07-25 0人阅读 0 0 0 暂无简介 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

InternationalJournalofPharmaceutics()–ContentslistsavailableatScienceDirectInternationalJournalofPharmaceuticsjournalhomepage:wwwelseviercomPharmaceuticalNanotechnologyFormulsolipidemShuaiShDepartmentof,articlArticlehistory:ReceivedNoReceivedinreAcceptedFebAvailableonlinKeywords:CinnarizineFormulationIntravenouslipStabilityDegradationkulsihomrizinendsteinnarledenoftditslipidtesteactiohichThefinalproductswerestableenoughtoresista◦Crotatingsteamsterilizationformin©ElsevierBVAllrightsreservedIntroducCinnarizwidelyusedriosclerosisal,SiisteringthehaspooraqcommerciaBothoftheal,)SCNsaltsoluhavebeeniZhangetalatedwiththcausevenoubeadjustedotherhand,CNinsolutiToensucarrierisnnutritionB∗CorresponEmailadd$–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,seefrontmatter©ElsevierBVAllrightsreservedjpharmation,stabilityanddegradationkineticulsioni,HaoChen,YueCui,XingTang∗Pharmaceutics,ShenyangPharmaceuticalUniversity,WenhuaRoad,ShenyangeinfovembervisedformFebruaryruaryeFebruaryidemulsionineticabstractCinnarizinewasloadedinthelipidemandchemicalstabilityHighpressuretorsinfluencingthestabilityofcinnatemperature,sterilizationmethodsachromatographThedegradationofcapparentfirstorderkineticsApossibrateprofileofcinnarizineLocalizatiothechemicalstabilityofcinnarizineanTheactivationenergyofcinnarizineintothatinaqueoussolutionThisindicanotanalterationofthedegradationrestimatedtobedaysat◦C,wlocateijpharmfintravenouscinnarizineLiaoningProvince,PRChinaontodevelopanintravenousformulationwithgoodphysicalogenizationwasusedtopreparethelipidemulsionThefaclipidemulsion,suchasdifferentdrugloadingmethods,pH,rilizationtimeweremonitoredbyhighperformanceliquidizineinaqueoussolutionandlipidemulsionbothfollowedgradationmechanismwaspostulatedbythebellshapedpHhedrugintheinterfaciallecithinlayersignificantlyimprovedstabilizingmechanismwasthoroughlydiscussedandprovedemulsionwascalculatedtobekJmolwhichwassimilarhatthestabilizingeffectofthedrugcarrieroncinnarizinewasnInaddition,shelflifeofcinnarizineinlipidemulsionwasismuchlongercomparedwithdaysinaqueoussolutionSShietalInternationalJournalofPharmaceutics()–therangeofforinjectionoussolutionvalues(lateapossibstudyofCLofdrugcarroftheprodureportedwWangaformulatiilizationforthecostoftMethodMateriaThefollobrackets:cShangqiu,CLudwigshafDegussaFo(TielingBei(PluronicFmany),TweIndustryLtdGlycerolPlawereofanaPreparaFirstly,CconsistedooilphaseToleate,TweagitatedunaddedslowRURRAX®IKobtaincoarNaOHorHmlAftpressurehoViaMdaErtogetthefinizationproinvials,andCharacThepartroscopy(PParticleSizitoparticlesrangingfromnmto�minsizeandprovidestwoparameters,ameandiameterandthestandarddeviation(SD)ThetwoparametersareusuallyusedtoevaluatetheparticlesizedistributionofCLESampleswerediluted:withpurifiedwateriatelassecopeswefoedfo�m,NicialofSamametermpHaiPrmicrentrthebjechatrickeueoutedbwas=CtoPLCaHPLtectoHiQpan)nolalmngthewaalysmiethaorthrCanaprodgmlxecocyoftheincuraFigStructureofcinnarizinepHvalueswastoonarrowtoincludeasuitablepHrange(pH–)So,thedegradationkineticsofCNinaqueweresupplementedbyprovidingawiderrangeofpH–)tofindthemostappropriatepHvalueandpostuledegradationmechanismAtthesametime,akineticEwasalsocarriedoutinordertoinvestigatetheeffectieronthedegradationofCNandestimatetheshelflifectUntilnow,noinjectablepreparationofCNhasbeenhichcanwithstandautoclavingsterilization(Jiaetal,,Zhangetal,)Ourstudyconcentratedononwhichcouldwithstanda◦Crotatingsteamstermintoimprovethesafetyoftheproductandreduceheindustrialprocessslswingmaterialswerepurchasedfromthesourcesininnarzine(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,andheatedat◦Ctoobtainaclearhen,theaqueousphaseconsistingofglycerin,sodiumen,FandEDTAwasalsoheatedto◦CandtiluniformlydissolvedFinally,thewaterphasewaslytotheoilphasewithhighspeedshearmixing(ULTRAA®Tbasic,Germany)at,rpmformintoseemulsionThepHwasadjustedtowithmollCl,andthevolumemadeupwithpurifiedwatertoerthat,thecoarseemulsionwassubjectedtohighmogenization(NiroSoaviNSkhomogenization,ba,APARMA,Italy)atbarforeightcyclesimmedscopicmicrossamplewithanalyzthanThepotentniquetothesThedeTheShanghwithaThesuringwassuforwereptheaqestimatheEEetal,EE()HTheUVdeandaCo,JatriethaofmwavelevolumAnOnewithmjing)ffilteredtoHPLdation�y=,atthreaccurawhiledayacnalemulsionThetemperatureoftheentirehomogecesswasmaintainedat◦CThen,theCLEwassealedrotatedina◦CwatersteambathforminterizationofCLEticlesizewasmeasuredbyphotoncorrelationspecCS,dynamiclightscattering,DLS)withaNicompTMngsystem(SantaBarbara,USA)ThesystemissensitiveaccuracyofrequiremenThedegsolutionApH(Unitedaliquotsandybeforemeasurementat◦CInaddition,themicrossmentwascarriedoutonusingaMoticDMBA(MoticChinaGroupCoLtd,Beijing,China)Emulsionreinvestigatedwithoutdilutedusinganoilimmersionldmagnificationtypicallymicroscopicfieldswererthedetectionofmicrons,thesizeofwhichwasgreaterparticularlythosedrugcrystalsompTMsystemwasalsousedtodeterminedzetatheCLEbyelectrophoreticlightscattering(ELS)techpleswerediluted:withpurifiedwateradjustedpHastheCLEusingmollHClorNaOHbeforehandinationwasperformedat◦CvaluesofCLEweremeasuredusingapHmeter(Leici®,ecisionScienceInstrumentLtd,Shanghai,China)fittedoelectrodeatroomtemperature(±◦C)apmentefficiency(EE)ofCLEwasdeterminedbymeaconcentrationofCNinthedispersionphaseTheCLEttoaHitachiultracentrifugeoperatedat,rpm◦CPolyallomertubeswereusedandtheirbottomsdaftercentrifugationwithasyringeneedletocollectsphaseTheamountofCNintheaqueousphasewasyhighperformanceliquidchromatography(HPLC)andcalculatedaccordingtothefollowingequation(FerezouGrovesetal,):talVtotal−CwaterVwaterCtotalVtotal×nalysisCsystemconsistedofanLpump,anLr,anLautosampler(HitachiCompany,Japan)silCWcolumn(mm×mm,�m,KyaTechThemobilephaseconsistedofmethanol–water–mine–glacialaceticacid(:::)ataflowratein,modifiedfromtheliterature(Guoetal,)TheoftheUVdetectorwassetatnmandtheinjections�lisofcinnarizineanditsdegradationproductslliliterofemulsion(mgml)wasdilutedtomlnol,vortexed,andthencentrifuged(LGA,Beimin(rpm)Thesupernatantwascollectedandougha�mmembraneThefiltratewassubjectedlysistoestimatetheamountofcinnarizineanddegrauctsThecalibrationgraphofCNrangingfromtowaslinearanddescribedbythefollowingequation:−(r=)TherecoveryoftheCNevaluatedncentrationswasfromtoTheintradaythemethodforcinnarizinerangedfromto,tradayprecisionrangedfromtoTheintercyrangedfromtoTheprecisionandthemethodwerebothwellconsistentwithanalysistradationkineticsofcinnarizineintheaqueousphosphatebufferwaspreparedaccordingtoUSPStatesPharmacopeia)ThebufferwasdividedintothepHadjustedwithNaOHorHPOtopH,,SShietalInternationalJournalofPharmaceutics()–,,,,,andCNwasdissolvedinthesebufferstoobtainsolutionsof×−mollEachbuffercontaining×−mollCNwasplacedinamlampule,whichwasthensealedandkeptinawaterbathat◦CSampleswerewithdrawnatintervalsof,,,,,,,handcooledimmediatelytoterminatethereactionbeforeHPLCanalysisTheresidualCNcontentwaStabilitThedCNwasbathThen,ina◦CteatintervalstureThecodeterminedwasevaluatEffectInourstCLETheme•MethodA:wasdispe•MethodB:AfterdissratedbyremainingwasdispeThefolloSectionThesampleimmediatelTheconcenbeforehandEffectsolutionandCNwasAttheSectionat,,,,,,determinatexaminedaEffectTheCLEtionThinvolvingroina◦CwsteambathaftersterilizzetapotentEffectTheCLEdescribedinsteambathminTheicalstabilitysizesandpHseudofirstorderplotsofthedegradationofCNinbuffersolutionsoverapHvalues(–)at◦CLongewb◦CtermoomtedbentraedultsedegdegraluenshipndthtimesAnk)anigexedfrnificantlydecreasedFigRatepHprofileforthedegradationofCNinbuffersat◦Cscalculatedbyacalibrationcurvepreparedinadvanceystudyegradationofcinnarizineindifferentoilsdissolvedindifferentoilsbyagitatingina◦CwatertheoilswhichcontainCNweresealedinvialsandputmperatureconstantovenThesampleswerewithdrawnof,anddaysandallowedtotheroomtemperancentrationsofCNinoilsatdifferenttimepointwerebyHPLCAndthedegradationofCNindifferentoilsedbythechangesoftheCNconcentrationofthedrugloadingmethodudy,twomethodswereinvestigatedtoloadCNinthethodswereasfollows:CNwasdissolvedintheoilphaseinwhichthelecithinrsedthoroughlyinadvanceCNandlecithinweredissolvedindehydratedalcohololvinguniformly,thedehydratedalcoholwasevapostirringonawaterbathat◦Cuntiltheweightoflecithin–drugmixturewasconstantThen,themixturersedinoilforfurtherprocessingwingstepsforpreparingtheCLEswereconsistentwithThefinalproductswereplacedinan◦CwaterbathswerewithdrawnatappropriateintervalsandcooledytoterminatethereactionthenanalyzedbyHPLCtrationofCNwascalculatedbyacalibrationpreparedoftemperatureondegradationrateofCNinaqueouslipidemulsiondissolvedinwatertogiveamgmlsolutionatpHsametime,mgmlCLEwaspreparedaccordingtoatthesamepHBothofthesewerekeptinawaterbath,and◦CSampleswerecollectedatintervalsof,,,,,,,andhandcooledimmediatelyforionbyHPLCThephysicalappearancesoftheCLEweretthedifferenttimeintervalsofthethermalstabilitymethodcontainingmgmlCNwaspreparedaccordingtoSecesamplesweresterilizedunderdifferentconditionstatingina◦Cwatersteambathformin,rotatingatersteambathformin,androtatingina◦CwaterforminThen,thecorrespondingsamples,beforeandation,wereanalyzedbyHPLCTheirparticlesizesandialswerealsodeterminedofthethermalsterilizationtimewiththeconcentrationofmgmlwaspreparedasSectionThesampleswererotatedina◦Cwaterfordifferentsterilizationtimeof,,,,andn,allthesampleswereanalyzedbyHPLCAndthephysofCLEwasevaluatedbyphysicalappearances,particlevaluesFigPrangeofAnand±predetotherevaluavalue,performResThTheofpHvrelatioscaleaversuskineticstant(fromF–increasCNsigtermstabilityinvestigationatchofoptimumCLEwaspreparedandstoredat±,whichwasclosetotheparticlestorageconditionAtinedtimeintervals,sampleswereremovedandallowedtemperatureTheirphysicalandchemicalstabilitywereyphysicalappearance,particlesizedistribution,pHpmentefficiencyanddrugremainingThestudywasintriplicateanddiscussionradationkineticsofcinnarizineinaqueousmediaadationofCNinbufferedsolutionsat◦Coveraranges(–)wasmonitoredbyHPLCFigshowsthebetweenconcentrationofCNonanaturallogarithmicetimeataseriesofpHvaluesThelnC(concentration)waslinearatallpHvaluesfollowingpseudofirstorderdtherelationshipbetweenthedegradationratecondthepHvaluesisexhibitedinFigItcanbeobservedthatthedegradationofCNwasextremelyrapidatpHhibitinganincreaseinthecurveWhile,asthepHvalueomto,thecorrespondingdegradationrateofSShietalInternationalJournalofPharmaceutics()–FigThedegradationpathwayofCNinbuffers(pH–)Thisprofileappearsabellshape,whichishardtointerpretasthekineticsoftheionizationconstantsofthereactantsAnexpressionofkinThisbehavimaybedesreactionwiimpliestheinthereaccanbeisolaanalysisHomediatemacationicimofhydroxymbaseformatdationprod(pH–TwopieimineinterilartothatJencks,inFigwa(Allewijn,TheresuthanaCNConsidefinallyselecCNPreparaOilphLCTsasicalsituatiosideeffects,endothelialafterlongtreducethetandmayaletal,Hence,tandMCTatoinvestigachemicalstigeastedwandle,ormuatrofCLEThismightbebecausethatexcessMCTintheoilresultedinanincreaseinthemeanparticlesizeandstandardionorevenoildropsTheEEofeachformulationwasalmostgedsuggestingthattheoilphasedidnothaveasignificantnEEedontheseresults,thechoiceofasuitableoilphasewastoLCTandthemixtureofLCTandMCTatratiosof:ddition,consideringCNmaybealsoliabletodegradeinoils,gradationofCNindifferentoilswasacceleratedbybeingat◦CandevaluatedbythechangeoftheCNconcentrationdaysAccordingtoFig,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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