美国辛辛那提大学药学院工业药学与药剂学Adel Sakr 教授PPT

COLONICTARGETINGOFAPEPTIDEANTI-BACTERIALAGENTProf.Dr.AdelSakrIndustrialPharmacyGraduateProgramCollegeofPharmacy,UniversityofCincinnatiCincinnati,Ohio,USACONGRESSCHAIR,FIP-INDUSTRIALPHARMACYSECTIONDradelsakr@1Prof.Dr.AdelSakrIntroduction

NisinSignificanceofcolonicdeliveryofNisinMethodsofcolonictargetingEUDRAGITL30D-55Wursterfluidbedcoating2Prof.Dr.AdelSakrIntroductionPeroraldrugdeliveryisthemostconvenientmethodofdrugdelivery.Peroraldeliveryofproteinsandpeptidespresentsachallenge.Targetingdrugstothecolonisbecomingofgreatinterestforsystemicabsorptionorlocalaction.3Prof.Dr.AdelSakrNisinPeptideantimicrobialagentBelongstotheclassofAntibioticsProducedbyLactococcuslactisUsedasafoodpreservativeConsistsof34aminoacidsSolubilitydecreaseswithincreasingpHSolubilitydecreasesinthepresenceofsalt4Prof.Dr.AdelSakrNisinActiveagainstmanyGram-positivebacteriaspecies.Reportedactivityagainst:MycobacteriumActinomycesPenicillin-resistantNeisseriagonorrhoeaeHelibacterpyloriClostridiumdifficileVancomycin-resistantenterococci5Prof.Dr.AdelSakrSignificanceofColonicDeliveryofNisinClostridiumdifficilecausesantibioticassociateddiarrhealeadingtocolitisorbowelinflammation.Vancomycin-resistantenterococciareacauseforuntreatableordifficulttotreatbacterialinfections.Bothtypesoforganismscolonizethecolon.6Prof.Dr.AdelSakrNisinshowsactivityagainstbothtypesoforganisms.Nisinwillbedigestedinthesmallintestine.ProtectionofNisinuntilitreachesthecolonisessential.SignificanceofColonicDeliveryofNisin7Prof.Dr.AdelSakrMethodsofColonicTargetingChemical/MicrobiologicalApproachBacterialcountinthecolonismuchhigherthanthatofthesmallintestine.Colonicbacteriaiscapableofextensiveenzymaticactivity.Colonictargetingisachievedbycompoundsselectivelydegradedbythemicrobialenzymaticactivity(prodrugsoruniversalsystems).Mostofthematerialsarenotapprovedforhumanuse.8Prof.Dr.AdelSakrMethodsofColonicTargeting9Prof.Dr.AdelSakrMethodsofColonicTargetingTechnological/PhysiologicalApproachUtilizationofgastrointestinalpHItwasbelievedthatgastrointestinalpHconstantlyrisesfromthestomachtothecolon.ColonictargetingisaccomplishedbyusingpolymercoatingshavingpHdependentsolubility(solubleabovepH6-7).Goodprotectionagainstgastricconditions,butunpredictablereleaseintheintestineduetopHvariation.10Prof.Dr.AdelSakrMethodsofColonicTargeting11Prof.Dr.AdelSakrMethodsofColonicTargeting12Prof.Dr.AdelSakrMethodsofColonicTargetingUtilizationofgastrointestinaltransittimeGastrictransittimeishighlyvariable.Smallintestinetransittimeislessvariable.Thesystemshouldbebasedontheratherconstantsmallintestinetransittime,andindependentofgastrictransittime.13Prof.Dr.AdelSakrMethodsofColonicTargetingDevelopingacolonicdeliverysystemwithpotentialtosucceedshouldbebasedoncombiningbothpHandtimedependentreleasemechanisms.14Prof.Dr.AdelSakrPolymethacrylatePolymersCommerciallyknownasEudragitR.Generallyareestersofpolymethacrylicacid.Mainlyusedforcoatingofperoraldosageforms.Availableassolidsubstance,organicsolution,andaqueousdispersion.15Prof.Dr.AdelSakrEUDRAGITL30D-55Methacrylicacidcopolymeraqueousdispersion.Formscolorless,transparentfilms.DissolvesatpHhigherthan5.5.OnsetofdrugreleasewilldependmainlyonthepHofthemediumandthicknessofthecoat.16Prof.Dr.AdelSakrHypothesisItispossibletotargetthedeliveryofNisintotheColonthroughtheapplicationoftheappropriatepolymersbyWURSTERFLUIDBEDTECHNOLOGY17Prof.Dr.AdelSakrObjectiveToformulateaTARGETEDcolonicdeliverysystemfortheantimicrobialagentNisinwhichdisintegratesinorneartheproximalcolon.18Prof.Dr.AdelSakrSpecificAims1. ToformulateNisincoretabletshavingthefollowingproperties: a) Disintegrateinareasonabletime inphosphatebufferpH6.8-7.0. b) HardenoughtowithstandfluidizationandcoatingintheWursterfluidizedbed.2. Tovalidatethetabletproductionprocess.19Prof.Dr.AdelSakrSpecificAims3. Tocoatthecoretabletsusingpolymethacrylatepolymerstoresistgastricconditionsfor2hours.4. TostudytheeffectofpolymethacrylatecoatthicknessonthedisintegrationofthetabletsinphosphatebufferpH6.8.20Prof.Dr.AdelSakrSpecificAims5. Toestablishin-vivofeasibilityofcolonicdeliveryofNisininhumanvolunteersbyradiolablingandmonitoringthebehaviorofthedeliverysysteminthegastrointestinaltractusinggammascintigraphy.6. Tostudytheeffectofdifferentstorageconditionsonthestabilityofthedeliverysystem.21Prof.Dr.AdelSakrExperimental&ResultsCoatingofcoretabletsFeasibilityofcolonicdelivery22Prof.Dr.AdelSakrFormulationofNisinCoreTabletsFormulaandManufacturingProcedure:Thecoretabletswereproducedbymeansofrollercompaction.Levelsofsodiumchlorideanddisintegrantinthetabletwereoptimizedusingafullfactorialdesign.Themixingtimeswereoptimized,andtheprocesswasvalidatedfortheproductionofnisincoretablets.23Prof.Dr.AdelSakrFormula24Prof.Dr.AdelSakrX3Mixing(Intragranular)Nisin+Prosolv+NaCl+Ac-Di-solCompactionGranulation+TalcMixing(Intragranular)Mixing(Extragranular)+Prosolv+NaCl+Ac-Di-Sol+PVPMixing(Extragranular)+MgStearateTableting1500lbs25Prof.Dr.AdelSakrProcessValidationThecoretabletformulaandmanufacturingprocessweresuitablefortheproductionofnisintablets:Tablethardness=9.5kpDisintegrationtimeatpH7.0=35minThemanufacturingprocessdidnotaffecttheintegrityofthepeptidemolecule.26Prof.Dr.AdelSakrCoatingNisinCoreTabletsCoatingFormula:

EudragitL30D-55 30%aqueousdispersion Triethylcitrate 15%w/wofsolidpolymercontent Talc 2%w/wofsolidpolymercontent Water todilutetoa20%aqueousdispersion27Prof.Dr.AdelSakrPreparationoftheCoatingDispersionWaterwasaddedtotheEudragitL30D-55aqueousdispersion.Triethylcitratewasaddedslowlytothedispersiondrop-wisewhilestirring.Thedispersionwasallowedtostirfortwohours.Talcwasaddedgraduallyandallowedtocompletelydispersefor30minutes.28Prof.Dr.AdelSakrCoatingProcess100gofcoretabletswereplacedintheWursterfluidbedandpreheatedto30oC.Thetabletswerefluidized.Coatingdispersionwassprayedusing1.0baratomizationpressure.Theprocesswasstoppedafterreachingthedesiredcoatthickness.29Prof.Dr.AdelSakrWursterChamber30Prof.Dr.AdelSakrBottomsprayfluidized-bedModifiedfromGlatt

brochureFluidizationairPartitionchamberAirdistributionplate31Prof.Dr.AdelSakrExperimental&Methodology

TabletEvaluationEvaluationofcoatedtablets:Coatthickness/coatweightdeterminationResistancetogastricconditionsCoatthicknessandtabletdisintegrationinpH6.832Prof.Dr.AdelSakrResultsThecoretabletswithstoodcoatingintheWursterfluidizedbed.ThecoatedtabletsresisteddisintegrationandnoNisinreleasewasdetectedinacidicmedium.Alinearrelationshipwasobservedbetweenonsetoftabletdisintegrationandcoatthickness/weightinpH6.833Prof.Dr.AdelSakr34Prof.Dr.AdelSakrExperimental&Methodology

FeasibilityofColonicDeliverySamariumoxidewasincorporatedintragranularlyinthecoretablets.Tabletswiththreedifferentcoatthicknesses(40%,120%,and188%w/w)werechosenforin-vivotestinginhumans.Thecoatedtabletswereneutronactivated,toemmitgammarays.35Prof.Dr.AdelSakrExperimental&Methodology

FeasibilityofColonicDeliveryThedeliverysystemswereadministeredto12healthyhumansubjects:Deliverysystem-B(188%coat): 2subjectsDeliverysystem-A(120%coat): 4subjectsDeliverysystem-C(40%coat): 6subjectsThedosageformsweremonitoredbygammaScin