Compare drug release profiles.docx

Compare drug release profiles.docx

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Comparedrugreleaseprofiles

Comparedrugreleaseprofilesofwaterpoorsolubledrugsfromanovelchitosanandpolycarbophilinterpolyelectrolytescomplexation（PCC）andhydroxylpropyl-methylcellulose（HPMC）basedmatrixtablets

ZhileiLu*,WeiyangChen,EugeneOlivier,JosiasH.,Hamman

DepartmentofPharmaceuticalSciences,TshwaneUniversityofTechnology,PrivateBagX680,Pretoria,0001,SouthAfrica

*Correspondingauthor:

ZhileiLu（Dr.）

DepartmentofPharmaceuticalSciences,

TshwaneUniversityofTechnology,

PrivateBagX680,

Pretoria,

0001,

SouthAfrica

（e-mail:

luzj@tut.ac.za）

Abstract

Theaimofthisstudywastocomparethedrugreleasebehavioursofwaterpoorsolubledrugsfromaninterpolyelectrolytecomplex（IPEC）ofchitosanwithpolycarbophil（PCC）andhydroxylpropylmethylcellulose（HPMC）basedmatrixtablets.Anovelinterpoly-electrolytecomplex（IPEC）ofchitosanwithpolycarbophil（PCC）wassynthesizedandcharacterized.WaterpoorsolubledrugsHydrochlorothiazideandKetoprofenwereusedinthisstudyasmodeldrugs.Polymers（includingPCC,HPMCK100MandHPMCK100LV）basedmatrixtabletsdrugcontrolledreleasesystemwerepreparedusingdirectcompressionmethod.TheresultsillustratePCCbased-matrixtabletsofferaswellingcontrolledreleasesystemforwaterpoorsolubledruganddrugreleasemechanismfromthismatrixdrugdeliverysystemcanbeimprovedbyadditionofmicrocrystallinecellulose（Avicel）.Analysisoftheinvitroreleasekineticparametersofthematrixtablets,PCCbasedmatrixtabletsexhibitedsimilarorhigherdrugreleaseexponent（n）andmeandissolutiontime（MDT）valuescomparedtotheHPMCbasedmatrixtablets.ItdemonstratedthatPCCpolymercanbesuccessfullyusedasamatrixcontrolledreleasesystemforthewaterpoorsolublemodeldrugssuchashydroxylpropylmethylcellulose（HPMC）.

1Introduction

Overthelastthreedecadesyears,astheexpenseandcomplicationsinvolvedinmarketingnewdrugentitieshaveincreased,withconcomitantrecognitionofthetherapeuticadvantagesofcontrolleddrugdelivery,greaterattentionhasbeenfocusedonthedevelopmentofnovelandcontrolledreleasedrugdeliverysystemstoprovidealong-termtherapeuticofdrugsatthesiteofactionfollowingasingledose（Mandal,2000;JantzenandRobinson,2002）.Manyformulationtechniqueshavebeenusedto“build”thebarrierintotheperoraldosageformtoprovideslowreleaseofthemaintenancedose.Thesetechniquesincludetheuseofcoatings,embeddingofthedruginawax,polymericorplasticmatrix,microencapsulation,chemicalbindingtoion-exchangeresinsandincorporationintoanosmoticpump（CollettandMoreton,2002:

293）.Amongdifferenttechnologiesusedincontrolleddrugdelivery,polymericmatrixsystemsarethemostmajoritybecauseofthesimplicityofformulation,easeofmanufacturing,lowcostandapplicabilitytodrugswithwiderangeofsolubility（Colombo,etal.,2000;JamzadandFassihi,2006）.

Drugsreleaseprofilesfrompolymericmatrixsystemcaninfluencebydifferentfactors,butthetype,amount,andphysicochemicalpropertiesofthepolymersusedplayaprimaryrole（JamzadandFassihi,2006）.Hydroxylpropyl-methylcellulose（HPMC）isthemostimportanthydrophiliccarriermaterialusedfororaldrugsustaineddeliverysystems（Colombo,1993;SiepmannandPeppas,2001）.BecauseHPMCiswatersolublepolymer,itisgenerallyrecognizedthatdrugreleasefromHPMCmatricesfollowstwomechanisms,drugdiffusionthroughtheswellinggellayerandreleasebymatrixerosionoftheswollenlayer（Fordetal.,1987;Raoetal.,1990;Colombo,1993;Taharaetal.,1995;Reynolds,Gehrkeetal.,1998;Siepmannetal.,1999;SiepmannandPeppas,2001）.However,diffusion,swellinganderosionaremostimportantrate-controllingmechanismsofcommercialavailablecontrolledreleaseproducts（LangerandPeppas,1983）,themajoradvantagesofswelling/erosionHPMCbasedmatrixdrugdeliverysystemare:

（i）minimumthedrugburstrelease;（ii）thedifferentphysicochemicaldrugsreleaserateapproachaconstant;（iii）thepossibilitytopredicttheeffectofthedevicedesignparameters（e.g.shape,sizeandcompositionofHPMC-basedmatrixtablets）ontheresultingdrugreleaserate,thusfacilitatingthedevelopmentofnewpharmaceuticalproducts（Colombo,1993;SiepmannandPeppas,2001）.

Interpolyelectrolytecomplexes（IPEC）areformedasprecipitatesbytwooppositelychargedpolyelectrolytesinanaqueoussolution,havebeenreportedasanewclassofpolymercarriers,whichplayanimportantroleincreatingneworaldrugdeliverysystems（PeppasandKhare,1993;Bergeretal.,2004）.AvarietychemicalstructureandstoichiometryofbothcomponentsininterpolyelectrolytecomplexesdependsonthepHvaluesofthemedia,ionicstrength,concentration,mixingratio,andtemperature（Peppas,1986;DumitriuandChornet,1998;Bergeretal.,2004;Moustafineetal.,2005a）.Chitosanisapositivelycharged（aminogroups）deacetylatedderivativeofthenaturalpolysaccharide,chitin（PaulandSharma,2000）.Chitosanhasalreadybeensuccessfullyusedtoformcomplexeswithnaturalanionicpolymerssuchascarboxymethylcellulose,alginicacid,dextransulfate,carboxymethyldextran,heparin,carrageenan,pectinmethacrylicacidcopolymers（Eudragit®polymers）andxanthan（DumitriuandChornet,1998,Bergeretal.,2004,Sankaliaetal.,2007,MargulisandMoustafine,2006）.

Inthisstudy,anovelpolymer-IPECbetweenchitosanandpolycarbophil（PCC）wassynthesized,characterizedandusedasdirectcompressedexcipientsinthematrixtablet.AlthoughithavebeenwellknownthatvariousIPEChavebeenusedasapolymercarriersindrugcontrolledreleasesystem（PeppasandKhare,1993,GarciaandGhaly,1996,Lorenzo-Lamozaetal.,1998,SoppirnathandAminabhavi,2002,Chenetal.,2004,Nametal.,2004,Moustafineetal.,2005b）,IPECchitosanandpolycarbophilwasusedasapolymercarriershavebeeninvestigatedbyLuetal.,（2006,2007a,2007b,2008a;2008b）.

TheaimofthisstudywastocompareinvitrowaterpoorsolubledrugsreleaseprofileofHPMCbasedmatricessystemtoPCCbasedmatricessystematsameformulation.WaterpoorsolublemodeldrugsHydrochlorothiazideandketoprofenwereusedinthisstudy.TwotypesHPMC（K100MandK100LV）andPCCpolymerswereusedindirectcompressedpolymersbasedmatrixdrugreleasesystem.TheresultsofthehydrationanderosionstudiesshowedPCCbasedmatrixsystemshavesuperiorswellingproperties.Drugreleaseexponent（n）ofeachformulationPCCbasedmatricestabletsarehigherthanHPMCbasedmatricestabletsatpH7.4buffersolutions.ItdemonstratedthatPCChashighpotentialtouseinpolymerbasedmatrixdrugcontrolledreleaseddeliveryforwaterpoorsolubledrugs.

2.Materialsandmethods

2.1Materials

Chitosan（WarrenChemSpecialities,SouthAfrica,DeacetylationDegree=91.25%）,Polycarbophil（Noveon,Cleveland,USA）,Hydroxylpropylmethylcellulose（MethocelK100M,K100LVPremium,ColorconLimited,Kent,England）,Ketoprofen（ChangzhouSiyaoPharma.China）,Hydrochlorothiazide（HuzhouKonchPharmaceuticalCo.,Ltd.China）,Microcrystallinecellulose（Avicel,pH101,FMCcorporationNV,Brussels,Belgium）,Sodiumcarboxymethylstarch（Explotab,EdwardMendellCo.,IncNewYork,USA）.Allotherchemicalswereofanalyticalgradeandusedasreceived.

2.2Preparationofinterpolyelectrolytescomplexationbetweenchitosanandpolycarbophil（PCC）

Chitosan（30g）wasdissolvedin1000mlofa2%v/vaceticacidsolutionandpolycarbophil（30g）wasdissolvedin1000mlofa2%v/vaceticacidsolution.Thechitosansolutionwasslowlyaddedtothepolycarbophilsolutionunderhomogenisation（5200rpm,ZKA®,Germany）overaperiodof20minutes.Themixturewasthenmechanicallystirredforaperiodof1hourataspeedof1200rpm（HeidolphRZR2021,Germany）.Thegelformedwasseparatedbycentrifugingfor5minat3000rpmandthenwashedseveraltimeswitha2%v/vaceticacidsolutiontoremoveanyunreactedpolymericmaterial.Thegelwasfreezedriedforaperiodof48hours（JouanLP3,France）andthelyophilisedpowderwasscreenedthrougha300µmsieve.

2.3Differentialscanningcalorimetry（DSC）

DSCthermogramsofthePCCwererecordedwithaShimadzuDSC50（Kyoto,Japan）instrument.Thethermalbehaviourwasstudiedbysealing2mgsamplesofthematerialinaluminiumcrimpcellsandheatingitataheatingrateof10oCperminundertheflowofnitrogenataflowrateof20ml/min.Thecalorimeterwascalibratedwith2mgofindium（Kyoto,Japan,meltingpoint156.4oC）ataheatingrateof10oCpermin.

2.4Fouriertransforminfrared（FT-IR）

Fouriertransforminfrared（FT-IR）spectraldataofthePCCpolymerwasobtainedonaFTS-175Cspectrophotometer（BIO-RAD,USA）usingtheKBrdiskmethod.

2.5Preparationofthematrixtablets

Inordertocomparethereleaseprofilesofwaterpoorsolubledrugsfrompolymerbasedmatrixtablets,monolithicmatrixtypetabletscontaininghydrochlorothiazideorketoprofenwerepreparedbycompressingamixtureoftheingredientswithvaryingconcentrationsofthePCC,HPMCK100MandHPMCK100LVasindicatedinTable1.Theingredientsofthedifferentformulationsweremanuallypre-mixedbystirringina1000mlglassbeakerfor30minuteswithaspatula.Aftertheadditionof0.05gofmagnesiumstearate（0.5%w/w）,thepowdermasswasmixedfor10min.Thepowdermixturewascompressedusingarotatingtabletpress（Cadmach,India）fittedwithround,shallowpunchestoproducematrixtypetabletswitha6mmdiameter.

2.6Weight,hardness,thicknessandfriabilityoftablets

Weightvariationwastestedbyweighing20randomlyselectedtabletsindividually,thencalculatin