Preparation.docx

Preparation.docx

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Preparation

Preparation,characterizationandpharmacokineticstudiesoftacrolimus-dimethyl-β-cyclodextrininclusioncomplex-loadedalbuminnanoparticles

∙ShanshanGaob,

∙JunSunb,

∙DongjunFub,

∙HongliZhaoa,

∙MinboLana,

∙FengGaoa,b,c,

∙aShanghaiKeyLaboratoryofFunctionalMaterialsChemistry,EastChinaUniversityofScienceandTechnology,Shanghai200237,PRChina

∙bDepartmentofPharmaceutics,SchoolofPharmacy,EastChinaUniversityofScienceandTechnology,Shanghai200237,PRChina

∙cShanghaiKeyLaboratoryofNewDrugDesign,EastChinaUniversityofScienceandTechnology,Shanghai200237,PRChina

Received15November2011

Revised30December2011

Accepted24January2012

Availableonline2February2012

∙http:

//dx.doi.org/10.1016/j.ijpharm.2012.01.054,HowtoCiteorLinkUsingDOI

∙Permissions&Reprints

Abstract

Thepurposeofthestudyistodevelopanewformulationforclinicallyusedanti-canceragenttacrolimus（FK506）tominimizetheseveresideeffects.Towardthisend,anewformulationmethodhasbeendevelopedbycomplexationofFK506withanhydrophiliccyclodextrinderivative,heptakis（2,6-di-O-methyl）-β-cyclodextrin（DM-β-CD）usingultrasonicmeans.TheresultingcomplexdisplaysdramaticallyenhancedsolubilityofFK506.Thenbovineserumalbumin（BSA）nanoparticleswereprepareddirectlyfromthepreformedFK506/DM-β-CDinclusioncomplexbythedesolvation-chemicalcrosslinkingmethod,withthesizeof148.4–262.9 nm.Stablecolloidaldispersionsofthenanoparticleswereformedwithzetapotentialsoftherangeof−24.9to−38.4 mV.TheentrapmentefficiencyofFK506wasincreasedashighas1.57-fold.Moreover,notablyFK506wasreleasedfromthenanoparticlesinasustainedmanner.Asdemonstrated,pharmacokineticstudiesrevealthat,ascomparedwithFK506-loadedBSAnanoparticles,theFK506/DM-β-CDinclusioncomplex-loadedBSAnanoparticleshavesignificantincreaseatTmax,t1/2,MRTanddecreaseatCmax.Insummary,theseresultssuggestthatthedrug/DM-β-CDinclusioncomplex-loadedBSAnanoparticlesdisplaysignificantlyimproveddeliveryefficiencyforpoorlysolubleFK506oritsderivatives.

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Keywords

∙FK506/DM-β-CDinclusioncomplex;

∙BSAnanoparticle;

∙Sustained-release

1.Introduction

Tacrolimus（FK506,molecularweightof822.05,watersolubilityof1.3 μg/ml）,ahydrophobicmacrolidelactonesnaturalproductisolatedfrombyStreptomycestsukubaensis,exertspotentimmunosuppressiveeffectsandhasbeeninclinicaluseasprophylaxisagainstorganrejectionafterliverandrenaltransplantation（Hidetoshietal.,2001）.Recently,ithasbeenreportedthatFK506canbewidelydistributedinthebodywithahighdegreebindingofredbloodcellsandplasmaproteins.However,thedistributionissignificantlyaffectedbyindividualdifferences,andtheadministrationroutes.Forexample,thegastrointestinaltracthasanarrowtherapeuticwindowduetolowbioavailability（Taheretal.,2009）,andsideeffects.Inaddition,FK506isknowntoexhibitloworalbioavailabilityandawiderangeofvariabilityinabsorption,rangingfrom4to89%inkidneyandlivertransplantrecipients（Venkataramananetal.,1995）.Fortheintravenousadministration,becauseofitslowsolubility,somesolubilizerorinjectionoilwasused,thusinducinggreatertoxicity.

β-Cyclodextrin（β-CD）anditsderivatives,asdistinctsolubilizers,havereceivedconsiderableattention,givingprominencetotheirlowbiotoxicityandhighbiocompatibility.Asattractivematerialsfordruginclusion,β-CDcanbefurtherchemicallymodifiedtoimproveitsphysicochemicalproperties（[HassanandAsghar,2009] and [Songetal.,2009]）.Anumberofstudieshaveshownthataddingβ-CDcanimprovetheloadingefficiencyofnanoparticlesandslowdownthereleaseofdrugs（[AlexanderandMaria,2007],[Boudadetal.,2001] and [Maestrellietal.,2006]）.Ferreiraandcollaboratorspreparedinclusioncomplexeswithhydroxypropyl-β-cyclodextrinandtheaqueoussolubilityofthedrugincreasedlinearlywiththeconcentrationofthecyclodextrins（Deniseetal.,2004）.Thecavitydepthandsurfaceactivityof2,6-di-O-methyl-β-cyclodextrin（DM-β-CD）,aderivativeofβ-CD,improvedsignificantly,aswellasthesolubilityincreasedasmuchasby25times（Gamaletal.,1986）.Variousβ-CDderivativeshavebeenevaluatedtoprobetheirenhancingeffectonsolubilityandstabilityofFK506inrats.ItwasfoundthatDM-β-CDhadadramaticimprovementonsolubilizationandstabilizationofFK506（Hidetoshietal.,2001）.

Modernnanotechnologyisconsideredasanemergingandconvergingtechnology（Roco,2008）andthatissaidtobeoneofthekeytechnologiesofthe21stcentury.Nanotechno