川芎嗪乳剂SCI论文手稿.docx
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川芎嗪乳剂SCI论文手稿.docx
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川芎嗪乳剂SCI论文手稿
Developmentofligustrazine-loadedlipidemulsion:
Formulationoptimization,CharacterizationandBiodistribution
LijunWei1#,NirmalMarasini2#,GaoLi1,ChulSoonYong2,JongOhKim2**,QizheQuan3*
1CollegeofPharmacy,YanbianUniversity,YanjiCity,JilinProvince,133000,China
2CollegeofPharmacy,YeungnamUniversity,214-1,Dae-Dong,Gyongsan712-749,SouthKorea
3CollegeofBiochemicalEngineering,BeijingUnionUniversity,No.18,3rdSection,Fatuoxili,ChaoyangDistrict,Beijing,100023,China
*Correspondingauthor:
Prof.QizheQuan,Ph.D
Tel:
+86-010-********,Fax:
+86-010-********
E-mail:
voyager88@
**Co-correspondingauthor:
Prof.JongOhKim,Ph.D.
Tel:
+82-53-810-2813,Fax:
+82-53-810-4654
E-mail:
jongohkim@yu.ac.kr
#LijunWeiandNirmalMarasinicontributedequallytothiswork.
Abstract
LigustrazineisatraditionalChinesemedicineusedtotreatvariouscardiovascularandneurovascularcomplications.However,thiscompoundexhibitsrapidfirstpassmetabolism,shorterbiologicalhalf-life,lowerstabilityandpotentialvascularirritationthatrestrictitsuseforlongtermtherapy.Theuseoflipidemulsionasacarrierforintravenousadministrationofligustrazinemightprovidesustainedandprolongedrelease,therebyreducingthefrequencyofadministrationandimprovingthepatientcompliance.Themainpurposeofourstudywastodevelopahighlystableandsterileoptimalformulationofligustrazinelipidemulsion(LLE)andtoevaluateitspharmacokineticsbehaviorandtissuedistributioninrats.Thefinaloptimumformulationconsistedofsoybeanoil(12.0%),oleicacid(0.6%),lecithin(1.0%),poloxamer188(0.6%)andglycerol(2.25%).Theaverageparticlesize,polydispersityindex(PDI),zeta-potentialandpHofthefinalproductwere215.0±2.5nm,0.076±0.033,-40.4±5.3mVand7.25±0.05,respectively.TheLLEwerestableforatleast3monthsatroomtemperature.InvitrodrugreleasestudiesoftheLLEsuggestedasustainedreleaseprofile,whichwasfurtherconfirmedbyinvivopharmacokineticsstudiesinrats.Theareaunderthedrugconcentrationtimecurvefromzerototenhour(AUC0-10h)forLLEwasincreasedby1.6foldascomparedtocommerciallyavailableligustrazineinjection(LI),suggestingenhancedbioavailabilityfromthelipid-basedemulsion.Furthermore,thetissuedistributionstudyshowedsignificantimprovementindistributionpatternofligustrazinewithhigherAUC0-180minobservedinallthetissuesforLLEcomparedtoLI.Inconclusion,LLE,withexcellentstability,improvedpharmacokineticsandtissuedistributioncomparedtocommercialproduct,demonstratedagreatpotentialforthedeliveryofligustrazineforclinicalapplications.
Keywords:
ligustrazine,lipidemulsion,characterization,pharmacokinetics,tissuedistribution
1.Introduction
Ligustrazine(2,3,5,6-tetramethylpyrazine,C8H12N2,Figure1)isapharmacologicallyactiveamidealkaloidextractedfromtherhizomeofChinesemedicinalplantLigusticumwallichiiFranchat(Juetal.,2010;Wuetal.,2012).InChinesemedicine,ligustrazinehasbeentraditionallyusedtotreatvariouscardiovascularandneurovascularcomplications(ChenandChen,1992;Jian-Shengetal.,2012).Itinhibitsvasoconstrictionandplateletaggregation,providesstrongeffectonscavengingcytotoxicfreeradical,lysesbloodclotsandpromotesbloodflow(Kwanetal.,1990;Chenetal.,2011;Sheuetal.,2001).Furthermore,severalclinicalstudieshavereportedhepato-protectiveeffect,andbeneficialeffectsincancerandosteoarthritispatients(Liuetal.,2002;YangandJiang,2010;Xihaietal.,2011).Duetolowertoxicityandwidertherapeuticeffects,ligustrazinehasbeenextensivelystudiedinpharmacologicalandclinicalsettings(Lietal.,2006).However,oraladministrationofligustrazineofferslowbioavailabilityof10-30%withshorterbiologicalhalf-lifeduetoextensivehepaticfirstpassmetabolism(Meietal.,2008).Therefore,morefrequentadministration(e.g.100mgtds)isrequiredtomaintainanoptimumtherapeuticconcentration,whichmayultimatelyleadtoaccumulativetoxicitiesinpatientsandcompromisethetherapy(Zhangetal.,2007).
Inordertomitigatefrequentadministrationandmaintainthetherapeuticlevelofligustrazineforlongerperiodintheblood,intravenousinfusionhasbeenused.Intravenousinjectionofligustrazine,availablecommerciallyasligustrazinehydrochloride(40mg/2ml)orligustrazinephosphate(50mg/2ml)isdilutedwith250-500mlofisotonicnormalsalineorglucosesolutionandinfusedfor4-6honceaday(Qietal.,2003).Besides,boththehydrochlorideandphosphatederivatesofligustrazinehasbeenreportedtoshowadversedrugreactions,themostprominentbeingstrongvascularirritation(ZengandMei,2008).Thesedrawbacksoflongterminvasiveintravenousinfusiontherapyofligustrazineduetoshortbiologicalhalf-lifeandpotentialvascularirritationhaverestricteditspatientcompliance.Therefore,itisofgreatimportancetodevelopanalternativeformulationapproachforligustrazinewithenhancedbioavailabilityandprolongedcirculation.
Numeroustransdermalformulationapproachessuchasethosomes(Shietal.,2012),ethosomepatches(Liuetal.,2011),microemulsion(Zhaoetal.,2011)havebeenproposedforthedeliveryofligustrazine.However,utilityoftheseapproachesarelimitedowingtotheissuessuchaslackofsufficientbioavailability,poorphysicochemicalstabilityandmanufacturingcomplexityforlargescaleproductionsandclinicalapplications.Inaddition,numeroussideeffectsassociatedwiththetransdermalformulationssuchaslocalirritationatthesiteofinjection,erythema,itching,andedemaduetodrugitselforexcipientshaverestricteditsuse.
Recently,muchattentionhasbeenfocusedindevelopinglipidemulsionasacarrierfordeliveryofdrugswithshorterbiologicalhalflifeandpoorbioavailability(GulatiandGupta,2011).Lipidemulsionsofferseveralpotentialadvantagesasadrugdeliveryvehicleoverotherdrugcarrierssuchashigherdrugloadingcapacities,higherphysicochemicalstability,reducedtoxicityandirritation,easeofmanufacturingandpossibilitiesoflargescaleproduction(DateandNagarsenker,2008;Strickley,2004).Sincethedrugisincorporatedintotheinternalphase,directcontactofthedrugwiththebodyfluidsandtissuesisavoided,whichminimizesthepossibleadverseeffectsandalsoreducesthechancesofdrugprecipitationuponintravenousadministration(Zhaoetal.,2010).Furthermore,thepossibilityofsustainedreleasewithprolongedcirculationinthebloodstreamaswellasdrugtargetingtothespecificsitemakethelipidemulsionaninterestingdrugdeliverysystem(Davisetal.,1987).Theuseoflipidemulsionasacarrierisexpectedtobenovelandsuitabledeliverysystemforintravenousadministrationofligustrazineforsustainedandprolongedrelease.Thereductionintheinjectionfrequencyduetoprolongedreleasemightalsocontributetothepatientcompliance.
Therefore,theobjectiveofthepresentstudyistodevelopoptimizedformulationandtechnologicalmethodforthepreparationofhighlystableligustrazinelipidemulsion.Furthermore,optimalligustrazinelipidemulsionformulationwascharacterizedanditspharmacokineticandtissuedistributionbehaviorwerealsocomparedwithcommerciallyavailableligustrazineinjectioninrats.
2.Materialsandmethods
2.1Materials
Ligustrazinehydrochloride(content>99.28%)waspurchasedfromShandongRizhaoChemicalCo.ltd.(Shandong,China).StandardligustrazinehydrochloridewaspurchasedfromNationalInstituteforFoodandDrugControl(Bejing,China).PL-100MeggyolklecithinwaspurchasedfromKewpieCorporation(Tokyo,Japan).Poloxamer188waspurchasedfromNanjingWellchemicalCo.(Nanjing,China).SoybeanoilandoleicacidwaspurchasedfromTielingBeiyamedicinaloilCo.Ltd(Liaoning,China).GlycerolwaspurchasedfromBeijingchemicalworks(Beijing,China).Ligustrazinehydrochlorideforinjection(LI,80to120mgdilutedto250to500mlwithsalinefori.v.infusionor40to50mgfori.v.injection)wasprovidedbyHarbinSanlianPharmaceuticalCo.Ltd(Heilongjiang,China).OtherreagentswereHPLCgrade;ultrapurewaterwasourownproduct.
2.2Preparationofligustrazinelipidemulsion
Theschematicrepresentationfortheprocessofligustrazinelipidemulsion(LLE)preparationisshowninFigure2.Briefly,ligustrazine,poloxamer188,andglycerolweredissolvedinwatertomakeanaqueousphase.Similarly,PL-100Meggyolklecithinwasdissolvedinsoybeanoilandoleicacidmixturetomakeanoilphase.Bothaqueousandoilphaseweremixedtogetherbyhigh-speedmixingat13000rpmfor5minat70°Ctoproduceacoarseemulsion.Thiscoarseemulsionwaspassedthroughahighpressurehomogenizer(NS1001LNiroSoaviCo,Italy)for0-10cyclesat750to1250bar.Thefinalemulsionwasfilteredbymembranefilter(0.45µm);sterilizedat121°Cfor10min.Nitrogengaswasusedduringalltheprocessestoprotecttheproductfromanywanteddegradationbyatmosphericoxygenandmoisture.TheformulationandprocessparametersforLLEwereoptimizedbasedonunivariateanalysisandorthogonaldesignasshowninTable1.
2.3Measurementofparticlesize,distributionandzetapotential
TheParticlesize,zetapotentialandpolydispersityindex(PDI)oftheLLEweredeterminedbyaZetasizerNano-ZS90(MalvernInstrumentsLtd,Worcestershire,UK)dynamiclightscatteringparticlesizeanalyzeratawavelengthof635nmandatascatteringangleof90o.Alltheexperimentsinthestudywereperformedatleastthreetimesandtheaveragevaluewasusedforfurtheranaly
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