Progesterone-loaded-chitosan-microspheres-a-long-a

JournalofControlledRelease52(1998)17–24Progesterone-loadedchitosanmicrospheres:alongactingbiodegradablecontrolleddeliverysystemabca,*S.RJameela,T.V.Kumary,A.V.Lal,A.JayakrishnanaDivisionofPolymerChemistry,BiomedicalTechnologyWing,SreeChitraTirunalInstituteforMedicalSciencesandTechnology,SatelnondPalaceCampus,Trivandrum695012,IndiabDivisionofPathophysiology,BiomedicalTechnologyWing,SreeChitraTirunalInstituteforMedicalSciencesandTechnology,SatelmondPalaceCampus,Trivandrum695012,IndiacDivisionofVivarium,BiomedicalTechnologyWing,SreeChitraTirunalInstituteforMedicalSciencesandTechnology,SatelmondPalaceCampus,Trivandrum695012,IndiaReceived16December1996;receivedinrevisedform16June1997;accepted6August1997AbstractSmooth,highlyspherical,crosslinkedchitosanmicrospheresinthesizerangeof45–300mmloadedwithprogesteronewerepreparedbyglutaraldehydecrosslinkingofanaqueousaceticaciddispersionofchitosancontainingprogesteroneinanon-aqueousdispersionmediumconsistingofliquidparaffinandpetroleumetherstabilizedusingsorbitansesquioleate.Invitroreleaseofthedrugintophosphatebufferat378Cwasdeterminedasafunctionofcrosslinkingdensityofthemicrospheresandparticlesize.Theextentofdrugreleasehadaremarkabledependenceonthecrosslinkingdensityofthemicrospheres,thehighlycrosslinkedspheresreleasingonlyaround35%oftheincorporatedsteroidin40dayscomparedto70%fromsphereslightlycrosslinked.Determinationoftheinvivobioavailabilityofthesteroidfrommicrosphereformulationbyintramuscularinjectioninrabbitsshowedthataplasmaconcentrationof1to2ng/mlwasmaintainedupto5monthswithoutahigh‘bursteffect’.Dataobtainedsuggestthatthecrosslinkedchitosanmicrosphereswouldbeaninterestingsystemforlongtermdeliveryofsteroids.©1998ElsevierScienceB.V.Keywords:Progesterone;Controlledrelease;Microspheres;Bioavailability;Chitosan1.Introductionreasonabledegreeofclinicalsuccess.Thedisadvan-tageoftheoralrouteistherequirementofdailyThepharmacologicalapproachtofertilitycontrolingestionandthesubsequentdailyvariationsinisstillmainlybyoraladministrationofsteroidsbloodconcentration.Thedevelopmentofbiodegra-althoughcontrolledreleasesystemssuchasdablepolymericdeliverysystemsforanti-fertility®®ProgestasertandNorplant,whichdeliverproges-steroidshasreceivedconsiderableattentionintheteroneandlevonorgestrelrespectivelyfromnon-bio-pasttwentyyears.Implantablerods,fibres,filmsanddegradablepolymermatrices,havemetwithainjectablemicrosphereshavebeenpreparedfromanumberofsyntheticbiodegradablepolymerssuchas*poly(lacticacid),poly(glycolicacid),poly(E-cap-Correspondingauthor.Tel.:[phone];fax:[phone];e-mail:[e-mail])andpoly(hydroxyalkanoate)s[1–7].Al-0168-3659/98/$19.00©1998ElsevierScienceB.V.Allrightsreserved.PIIS0168-3659(97)00187-918S.R.Jameelaetal./JournalofControlledRelease52(1998)17–245thoughthereisconsiderableliteratureontheuseofweightof3.15310andadegreeofdeacetylationofsyntheticbiodegradablepolymersascarriersforanti-74%wasobtainedfromtheCentralInstituteoffertilitysteroids,naturalpolymerssuchasproteinsFisheriesandTechnology,Cochin,Indiaandwasandpolysaccharideshavereceivedlessattention.usedasreceived.Glutaraldehyde(25%aqueousInjectablebiodegradabledrugreservoirsfromsolution,biologicalgrade),sorbitansesquioleate,andglutamicacid/leucinecopolymersintheformofprogesteronewerefromSigmaChemicalCompany,tubesandsolidrodswerepreparedbySidmanetal.St.Louis,USA.Liquidparaffinofviscosity18cPat[8]toprovidecontrolledreleaseofprogesterone.308C,petroleumether,toluene,sodiummetabisul-Norethisteronewascovalentlyboundtopoly(hydro-phite,acetone,ethanolandotherchemicalswerexyalkyl)-L-glutaminesandthereleaseofthedrugfromS.D.FineChemLtd.,Bombay,India.PlasmawasexaminedbyPetersonetal.[9].Leeetal.[10]progesteroneconcentrationinrabbitswasestimated®incorporatedprogesteroneintoglutaraldehydecross-usingOvucheckELISAkitspurchasedfromCam-linkedserumalbuminmicrospheresandshowedthatbridgeVeterinarySciences,Cambridge,UK.anextendedreleaseof1–2ng/h/mlofserumwaspossibleforabout20days.Recentlyalbuminmi-2.2.Methodscrocapsulesandmicrospherescrosslinkedwithform-aldehyde,2,3-butanedioneandglutaraldehydewereA4%solutionofchitosanin5%aceticacidinvestigatedforprogesteronedeliverybyOientiandcontaining2%sodiumchloridewaspreparedand6gZecchi[11].ofthisviscoussolutionwasweighed,mixedwithStudiesreportedfromthislaboratoryinrecentprogesterone(20%byweightofchitosan)andyearshaveshownthatglutaraldehydecrosslinkeddispersedinamixtureof35mlofliquidparaffinandchitosanmicrospheresarelongactingbiodegradable25mlofpetroleumethercontaining0.85gofcarrierssuitableforcontrolleddeliveryofmanysorbitansesquioleate,ina100mlround-bottomeddrugs[12–15].Chitosanisadeacetylatedderivativeflaskatroomtemperature(278C).Thedispersionofchitin,abiopolymersecondinabundancetowasstirredusingastainlesssteelhalfmoonpaddlecellulose.Severalbiomedicalapplicationsofstirrerat2000rpmfor5minand10mlchitosanhavebeensuggestedintheliteratureglutaradehyde-saturatedtoluenewasintroducedinto[16,17].Thepolysaccharideissusceptibletotheflaskandthestirringcontinued.Microspheresbiodegradatio