Ocular Drug Delivery.pdf

2/19/2015 OcularDrugDelivery

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895432/ 1/23

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AAPSJ.2010Sep12(3):348360.Publishedonline2010May1.doi:10.1208/s1224801091833PMCID:PMC2895432

OcularDrugDeliveryRipalGaudana,HariKrishnaAnanthula,AshwinParenky,andAshimK.MitraDivisionofPharmaceuticalSciences,SchoolofPharmacy,UniversityofMissouriKansasCity,2464CharlotteSt.,KansasCity,Missouri641082718USAAshimK.Mitra,Phone:+18162351615,Fax:+18162355190,Email:[email protected]:BruceAungstandCraigK.SvenssonReceived2009Nov26Accepted2010Feb24.CopyrightAmericanAssociationofPharmaceuticalScientists2010ThisarticlehasbeencitedbyotherarticlesinPMC.

AbstractOculardrugdeliveryhasbeenamajorchallengetopharmacologistsanddrugdeliveryscientistsduetoitsuniqueanatomyandphysiology.Staticbarriers(differentlayersofcornea,sclera,andretinaincludingbloodaqueousandbloodretinalbarriers),dynamicbarriers(choroidalandconjunctivalbloodflow,lymphaticclearance,andteardilution),andeffluxpumpsinconjunctionposeasignificantchallengefordeliveryofadrugaloneorinadosageform,especiallytotheposteriorsegment.Identificationofinfluxtransportersonvariousoculartissuesanddesigningatransportertargeteddeliveryofaparentdrughasgatheredmomentuminrecentyears.Parallelly,colloidaldosageformssuchasnanoparticles,nanomicelles,liposomes,andmicroemulsionshavebeenwidelyexploredtoovercomevariousstaticanddynamicbarriers.Noveldrugdeliverystrategiessuchasbioadhesivegelsandfibrinsealantbasedapproachesweredevelopedtosustaindruglevelsatthetargetsite.Designingnoninvasivesustaineddrugdeliverysystemsandexploringthefeasibilityoftopicalapplicationtodeliverdrugstotheposteriorsegmentmaydrasticallyimprovedrugdeliveryintheyearstocome.Currentdevelopmentsinthefieldofophthalmicdrugdeliverypromiseasignificantimprovementinovercomingthechallengesposedbyvariousanteriorandposteriorsegmentdiseases.

Keywords:nanoparticles,retina,transporter

INTRODUCTIONDesigningadrugdeliverysystemtotargetaparticulartissueoftheeyehasbecomeamajorchallengeforscientistsinthefield.Theeyecanbebroadlyclassifiedintotwosegments:

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anteriorandposterior.Structuralvariationofeachlayerofoculartissuecanposeasignificantbarrierfollowingdrugadministrationbyanyroute,i.e.,topical,systemic,andperiocular.Inthepresentwork,weattemptedtofocusonvariousdrugabsorptionbarriersencounteredfromallthreeroutesofadministration.Structuralcharacteristicsofvariousoculartissuesandtheireffectivenessasbarriersforthedeliveryofdrugsandtheircolloidaldosageformshavebeendiscussed.Theroleofeffluxpumpsandstrategiestoovercomethesebarriersutilizingthetransportertargetedprodrugapproachhavealsobeentouchedupon.Currentdevelopmentsinoculardosageforms,especiallycolloidaldosageforms,andtheirapplicationsinovercomingvariousstaticanddynamicbarriershavebeenelucidated.Finally,variousdevelopmentsinnoninvasivetechniquesforoculardrugdeliveryhavealsobeenemphasized.

MODESOFADMINISTRATION,BARRIERS,ANDTHEIRSIGNIFICANCEINOCULARDRUGDELIVERYComparedwithdrugdeliverytootherpartsofthebody,oculardrugdeliveryhasmetwithsignificantchallengesposedbyvariousocularbarriers.Manyofthesebarriersareinherentanduniquetoocularanatomyandphysiologymakingitachallengingtaskfordrugdeliveryscientists.Thesebarriersarespecificdependingupontherouteofadministrationviz.topical,systemic,andinjectable.Mostoftheseareanatomicalandphysiologicalbarriersthatnormallyprotecttheeyefromtoxicants.Moreover,variouspreformulationandformulationfactorsneedtobeconsideredwhiledesigninganophthalmicformulation.TableIsummarizesvariousroutesofadministration,theirbenefits,andchallengesinoculardrugdelivery.Figure1representsimportantpartsoftheeyealongwithdifferentroutesofdrugadministrationrepresentedinitalics.

TableISummaryofRoutesofAdministration,Benefits,andChallengesinOcularDelivery

Fig.1Routesofdrugadministrationtoeye

Topicaladministration

Topicaladministration,mostlyintheformofeyedrops,isemployedtotreatanteriorsegmentdiseases.Formostofthetopicallyapplieddrugs,thesiteofactionisusuallydifferentlayersofthecornea,conjunctiva,sclera,andtheothertissuesoftheanteriorsegmentsuchastheirisandciliarybody(anterioruvea).Uponadministration,precornealfactorsandanatomicalbarriersnegativelyaffectthebioavailabilityoftopicalformulations.

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Precornealfactorsincludesolutiondrainage,blinking,tearfilm,tearturnover,andinducedlacrimation(1).Tearfilm,whosecompositionandamountaredeterminantsofahealthyocularsurface,offersthefirstresistanceduetoitshighturnoverrate.Mucinpresentinthetearfilmplaysaprotectiverolebyformingahydrophiliclayerthatmovesovertheglycocalyxoftheocularsurfaceandclearsdebrisandpathogens(2).Humantearvolumeisestimatedtobe7l,andtheculdesaccantransientlycontainaround30loftheadministeredeyedrop.However,tearfilmdisplaysarapidrestorationtimeof23min,andmostofthetopicallyadministeredsolutionsarewashedawaywithinjust1530safterinstillation.Consideringalltheprecornealfactors,contacttimewiththeabsorptivemembranesislower,whichisconsideredtobetheprimaryreasonforlessthan5%oftheapplieddosereachingtheintraoculartissues(3).

Inaddition,variouslayersofthecornea,conjunctiva,andscleraplayanimportantroleindrugpermeation.Thecornea,theanteriormostlayeroftheeye,isamechanicalbarrierwhichlimitstheentryofexogenoussubstancesintotheeyeandprotectstheoculartissues.Itcanbemainlydividedintotheepithelium,stroma,andendothelium.Eachlayeroffersadifferentpolarityandapotentialratelimitingstructurefordrugpermeation.Thecornealepitheliumislipoidalinnaturewhichcontains90%ofthetotalcellsinthecorneaandposesasignificantresistanceforpermeationoftopicallyadministeredhydrophilicdrugs.Furthermore,superficialcornealepithelialcellsarejoinedtooneanotherbydesmosomesandaresurroundedbyribbonliketightjunctionalcomplexes(zonulaoccludens)(4,5).Presenceofthesetightjunctionalcomplexesretardsparacellulardrugpermeationfromthetearfilmintointercellularspacesoftheepitheliumaswellasinnerlayersofthecornea.

Thestroma,whichcomprises90%ofthecornealthickness,ismadeupofanextracellularmatrixandconsistsofalamellararrangementofcollagenfibrils.Thehighlyhydratedstructureofthestromaposesasignificantbarriertopermeationoflipophilicdrugmolecules.Endotheliumistheinnermostmonolayerofhexagonalshapedcells.Eventhoughendotheliumisaseparatingbarrierbetweenthestromaandaqueoushumor,ithelpsmaintaintheaqueoushumorandcornealtransparencyduetoitsselectivecarriermediatedtransportandsecretoryfunction(6).Furthermore,thecornealendothelialjunctionsareleakyandfacilitatethepassageofmacromoleculesbetweentheaqueoushumorandstroma(7).Thus,corneallayers,particularlytheepitheliumandstroma,areconsideredasmajorbarriersforoculardrugdelivery.Itisvitaltounderstandthatthepermeantshouldhaveanamphipathicnatureinordertopermeatethroughtheselayers.AschematicofthecorneallayersthatapermeantneedstocrossispresentedbyBararetal.(6).

Comparedtocornea,conjunctivaldrugabsorptionisconsideredtobenonproductiveduetothepresenceofconjunctivalbloodcapillariesandlymphatics,whichcancausesignificantdruglossintothesystemiccirculationtherebyloweringocularbioavailability.Conjunctivalepithelialtightjunctionscanfurtherretardpassivemovementofhydrophilicmolecules(8).Thesclera,whichiscontinuouswiththecorneaoriginatesfromthelimbusandextendsposteriorlythroughouttheremainderoftheglobe.Thescleramainlyconsistsofcollagenfibersandproteoglycansembeddedinanextracellularmatrix.Permeabilitythroughthescleraisconsideredtobecomparabletothatofthecornealstroma.Recentreportsindicatethatthepermeabilityofdrugmoleculesacrossthescleraisinverselyproportionaltothemolecularradius(9).Dextranswithlinearstructureswerelesspermeableascomparedtoglobularproteins(9).Furthermore,thechargeofthedrugmoleculealsoaffectsits



permeabilityacrossthesclera.Positivelychargedmoleculesexhibitpoorpermeabilitypresumablyduetotheirbindingtothenegativelychargedproteoglycanmatrix(10).

Systemic(parenteral)administration

Followingsystemicadministration,thebloodaqueousbarrierandbloodretinalbarrierarethemajorbarriersforanteriorsegmentandposteriorsegmentoculardrugdelivery,respectively.Bloodaqueousbarrierconsistsoftwodiscretecelllayerslocatedintheanteriorsegmentoftheeyeviz.theendotheliumoftheiris/ciliarybloodvesselsandthenonpigmentedciliaryepithelium.Bothcelllayersexpresstightjunctionalcomplexesandpreventtheentryofsolutesintotheintraocularenvironment(6)suchastheaqueoushumor.Bloodretinalbarrierrestrictstheentryofthetherapeuticagentsfrombloodintotheposteriorsegment.Itiscomposedoftwotypesofcells,i.e.,retinalcapillaryendothelialcellsandretinalpigmentepitheliumcells(RPE)knownastheinnerandouterbloodretinalbarrier,respectively.RPE,locatedbetweentheneuralretinaandthechoroid,isamonolayerofhighlyspecializedcells.RPEaidsinbiochemicalfunctionsbyselectivetransportofmoleculesbetweenphotoreceptorsandchoriocapillaris.Furthermore,itmaintainsthevisualsystembyuptakeandconversionofretinoids(11).However,tightjunctionsoftheRPEefficientlyrestrictintercellularpermeation.Followingoralorintravenousdosing,drugscaneasilyenterintothechoroidduetoitshighvasculaturecomparedtoretinalcapillaries.Thechoriocapillarisarefenestratedresultinginrapidequilibrationofdrugmoleculespresentinthebloodstreamwiththeextravascularspaceofthechoroid.However,outerbloodretinalbarrier(RPE)restrictsfurtherentryofdrugsfromthechoroidintotheretina.Eventhoughitisidealtodeliverthedrugtotheretinaviasystemicadministration,itisstillachallengeduetothebloodretinalbarrier,whichstrictlyregulatesdrugpermeationfrombloodtotheretina.Hence,specificoralorintravenoustargetingsystemsareneededtotransportmoleculesthroughthechoroidintodeeperlayersoftheretina(12).

Recentadvancementsinnanotechnologyencouragedresearcherstofindwaystoovercomebloodretinalbarrier.InonesuchstudyusingC57BL/6mice,theresearchersdemonstratedthatintravenouslyadministered20nmgoldnanoparticlescouldpassthroughthebloodretinalbarrieranddistributeinalltheretinallayerswithoutcytotoxicity.Theviabilityofretinalendothelialcells,astrocytes,andretinoblastomacellswasalsonotaffected.Incontrast,larger100nmnanoparticleswerenotdetectedintheretina(13).Afewattemptshavealsobeenmadeforgenedeliverytotheeyebyintravenousrouteofadministration.AdiffuseexpressionofSV40/galactosidasegeneinmouseinnerretina,RPE,iris,aswellasconjunctivalepithelium,wasobserveduponintravenousadministrationofpolyethyleneglycol(PEG)conjugatedimmunoliposomes(14).Amorerecentreportdemonstratestheutilityofintravenousadministrationoftransferrin,arginineglycineasparticacidpeptide,ordualfunctionalizedpoly(lactidecoglycolide)(PLGA)nanoparticles.ThesefunctionalizedPLGAnanoparticlesweresuccessfulintargeteddeliveryofantivascularendothelialgrowthfactorintraceptorplasmidtochoroidalneovascularization(CNV)lesions.ThedeliveryofnanoparticlestotheneovasculareyewasattributedtotheleakybloodretinalbarrierasaresultofCNVinthelasertreatedrateye(15).

Pharmacokineticstudiesinvolvingvariousdrugssuchasmicafungin(16),marbofloxacin(17),andamphotericinB(18)demonstratedthatthesedrugsaredistributedinoculartissuesuponintravenousadministration.Onemarketedintravenouslyadministeredformulationis



visudyne,whichisusedinphotodynamictherapyforthetreatmentofwetagerelatedmaculardegeneration(AMD).However,owingtothetoxicityanddeliveryconcerns,intravenousadministrationisnotverycommonintreatingoculardisorders.

Oraladministration

Oraldelivery(1921)orincombinationwithtopicaldelivery(22)hasbeeninvestigatedfordifferentreasons.Topicaldeliveryalonefailedtoproducetherapeuticconcentrationsintheposteriorsegment.Also,oraldeliverywasstudiedasapossiblenoninvasiveandpatientpreferredroutetotreatchronicretinaldiseasesascomparedtoinjectableroute.However,limitedaccessibilitytomanyofthetargetedoculartissueslimitstheutilityoforaladministrationwhichnecessitateshighdosagetoobservesignificanttherapeuticefficacy.Thiscanresultinsystemicsideeffects.Hence,parameterssuchassafetyandtoxicityneedtobeconsideredwhentryingtoobtainatherapeuticresponseintheeyeuponoraladministration.Forexample,inglaucomatherapy,oralcarbonicanhydraseinhibitors,suchasacetazolamideandethoxzolamide,havebeendiscontinuedinmostofthecasesduetotheirsystemictoxicity(23,24).Theoralrouteisnotpredominant,andonlyalimitednumberofcompoundswereinvestigatedforoculardrugdelivery.Theseincludevariousclassesofdrugssuchasanalgesics(25),antibiotics(21,2628),antivirals(29),antineoplasticagents(30),andomega6fattyacids(31).Amajorprerequisiteoftheoralrouteforocularapplicationsishighoralbioavailabilityofthedrug.Followingoralabsorption,moleculesinsystemiccirculationmustalsocrossthebloodaqueousandbloodretinalbarriers.Thefunctionandbarrierpropertyoftheseprotectiveocularstructureswaspreviouslydiscussed.

Periocularandintravitrealadministration

Althoughnotverypatientcompliant,theseroutesareemployedpartlytoovercometheinefficiencyoftopicalandsystemicdosingtodelivertherapeuticdrugconcentrationstotheposteriorsegment.Moreover,systemicadministrationmayleadtosideeffectsmakingitalessdesirabledeliveryrouteforgeriatricpatients.Theperiocularrouteincludessubconjunctival,subtenon,retrobulbar,andperibulbaradministrationandiscomparativelylessinvasivethanintravitrealroute(SeeFig.1foranatomicallocationofthesitesofadministrationintheeye,representedinitalics).Thedrugadministeredbyperiocularinjectionscanreachtheposteriorsegmentbythreedifferentpathways:transscleralpathwaysystemiccirculationthroughthechoroidandtheanteriorpathwaythroughthetearfilm,cornea,aqueoushumor,andthevitreoushumor(32).

Subconjunctivalinjectionobviatestheconjunctivalepithelialbarrier,whichisratelimitingforpermeationofwatersolubledrugs.Thus,thetransscleralroutebypassescorneaconjunctivabarrier.Nevertheless,variousdynamic,static,andmetabolicbarrierslimitdrugaccesstotheposteriorsegment.Dynamicbarriersincludeconjunctivalbloodandlymphaticcirculation.Variousauthorsreportedrapiddrugeliminationviathesepathwaysfollowingsubconjunctivaladministration(3335).Asaresult,theformulationisdrainedintosystemiccirculationtherebyloweringocularbioavailability.Thus,drugeliminationfromthesubconjunctivalspacebecomesamajordeterminantofthevitreousdruglevelsfollowingsubconjunctivaladministration.Themoleculesthatescapeconjunctivalvasculaturepermeatethroughscleraandchoroidtoreachtheneuralretinaandphotoreceptorcells.Thescleraisnotamajorbarrierasitismorepermeablethanthecornea.Moreover,permeability

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acrossthescleraisindependentoflipophilicityunlikecornealandconjunctivallayersbutdependsprimarilyonthemolecularradius(12,36).However,choroidisasignificantbarrierashighchoroidalbloodflowcanalsoeliminateaconsiderablefractionofdrugbeforeitcanreachtheneuralretina.Furthermore,bloodretinalbarrierslimitdrugavailabilitytothephotoreceptorcells.

Unlikeperiocularinjections,theintravitrealinjectionoffersdistinctadvantagesasthemoleculesaredirectlyinsertedintothevitreous.However,drugdistributioninthevitreousisnonuniform.Smallmoleculescanrapidlydistributethroughthevitreous,whereasthediffusionoflargermoleculesisrestricted.Thisdistributionalsodependsonthepathophysiologicalconditionandmolecularweightoftheadministereddrug(37).Thevitreousalsoactsasabarrierforretinalgenedeliveryfollowinganintravitrealinjection.Hyaluronan,anegativelychargedglycosaminoglycanpresentinthevitreous,caninteractwithcationiclipid,polymeric,andliposomalDNAcomplexes(38).ThisinteractioncanleadtosevereaggregationandcompleteimmobilizationofDNA/cationicliposomecomplexes(39).Similarly,mobilityofnanoparticlesinthevitreousdependsontheirstructureandsurfacecharge.Polystyrenenanospheresdonotdiffusefreelyintothevitreousduetotheiradherencetocollagenfibrillarstructures(39).Hence,surfacemodificationofnanosphereswithhydrophilicPEGchainshasbeenperformed.Arecentstudyusinghumanserumalbuminnanoparticlesalsodemonstratedthatanionicnanoparticleswithazetapotentialof33.3mVdiffusedmorefreelyinthevitreousthancationicparticleswithazetapotentialof11.7mV(40).

Theinnerlimitingmembrane(ILM),thecelllayerseparatingtheretinaandthevitreous,isabarrierforretinaldeliveryfollowingintravitrealadministrationofgenebasedtherapeutics.Forexample,theILMposesabarrierforpenetrationoftheadenoassociatedvirusintotheretinafromthevitreous.MilddigestionofILMenhancedtransductionofmultipleretinalcelltypesfromthevitreousindicatingitshighbarrierproperty(41).Moreover,drugtransportfromvitreoustotheoutersegmentsofretinaandchoroidismorecomplexduethepresenceofRPE.

Thehalflifeinthevitreousisanotherfactorthatcandeterminethetherapeuticefficacy.Followingintravitrealinjection,thedrugiseliminatedeitherbytheanteriorrouteorposteriorroute.Theanterioreliminationrouteinvolvesdrugdiffusionacrossthevitreousintotheaqueoushumorthroughzonularspacesfollowedbyeliminationthroughaqueousturnoveranduvealbloodflow.Theposterioreliminationpathwayinvolvesdrugpermeationacrossthebloodretinalbarrierandrequiresoptimumpassivepermeabilityoractivetransportmechanisms.Asaresult,hydrophilicityandlargemolecularweighttendtoincreasethehalflifeofthecompoundsinthevitreoushumor(12).

MELANINBINDINGThepresenceofmelaninmayalteroculardrugdisposition.Interactionwiththispigmentmayaltertheavailabilityoffreedrugatthetargetedsite.Thereby,melaninbindingmaysignificantlylowerpharmacologicalactivity(42).Inoculartissues,melaninispresentinuveaandRPE.ItbindstofreeradicalsanddrugsbyelectrostaticandVanderWaalsforcesorbysimplechargetransfer(43).Basedonavailableinformation,itmaybeconcludedthatallbasicandlipophilicdrugsbindtomelanin(44).Eventhoughdrugbindingtomelaninis



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notnecessarilypredictiveofoculartoxicity,ithassignificantpharmacologicalconsequencesandrequirescarefulconsiderationinoculardrugdelivery.Melaninbindingintheirisciliarybodyaffectsdrugconcentrationsinanterioroculartissuesanddrugresponse(45).Amelaninbounddrugisnotusuallyavailableforreceptorbindingnecessitatingtheadministrationoflargerdoses(46).Likewise,melaninpresentinchoroidandRPEaffectstheextentofdruguptakeintotheretinaandvitreousfollowingtransscleralorsystemicdrugadministration.Asaresultofmelaninbinding,permeationlagtimeoflipophilicbetablockersthroughbovinechoroidRPEismuchlongerthanmorehydrophilicbetablockers(11).Similarly,bindingoflipophiliccompoundstothebovinechoroidBruch'smembranewasdemonstratedtobehigherduetothepresenceofmelanin.Consequently,thereisagreaterresistancetosolutepermeationacrosschoroidBruch'smembranethanthesclera,whichisdevoidofmelanin(47).

TRANSPORTERSINEYEThetraditionalapproachtoimproveocularbioavailabilityistomodifythedrugchemicallytoachievethedesiredsolubilityandlipophilicity.However,amorerationalapproachwouldbeatransportertargetedmodificationofthedrug.Transportersaremembraneboundproteinsthatplayanimportantroleinactivetransportofnutrientsacrossbiologicalmembranes.Thepresenceoftransportershasbeenreportedonvariousoculartissues.However,inthepresentarticle,wehavefocusedonthetransportersthatarelocalizedintheepitheliaofthecornea,conjunctiva,andretina.Thesetransportersmaybeamenabletobindandtransportspecifictargetedligandsattachedtodrugmoieties.

Twotypesoftransportersystemsareofinterestinoculardrugdelivery:effluxtransportersandinfluxtransporters.WidelystudiedeffluxtransportersbelongtotheATPbindingcassettesuperfamily,whereasinfluxtransportersbelongtothesolutecarrier(SLC)superfamily.Effluxtransporterslowerbioavailabilitybyeffluxingthemoleculesoutofthecellmembraneandcytoplasm.ProminenteffluxtransportersidentifiedonoculartissuesincludePgp,multidrugresistanceprotein(MRP),andBCRP.Variousauthorsreviewedtheemergingroleoftransportersinoculardrugdelivery(4850).Pgphasanaffinitytoeffluxlipophiliccompoundsinnormalaswellasincancerouscells,possiblyleadingtoemergenceofdrugresistance.ExpressionandfunctionalactivityofPgpwasidentifiedonvariousocularcelllinesandtissuessuchasthecornea(5153),conjunctiva(54,55),andRPE(5658).However,someauthorsrecentlyindicatedthattheexpressionofPgponhumancornealepitheliummaybenegligibleorabsent(59,60).MRPworksinasimilarmannerbuteffluxesorganicanionsandconjugatedcompounds.OutofnineknownisoformsoftheMRPfamily,onlythreewereidentifiedinoculartissues.MRP2andMRP5wereidentifiedincornealepithelium(61,62),whereasMRP1wasidentifiedinrabbitconjunctivalepithelialcells(63).RPEexpressesMRP1(64).ThepresenceofBCRPwasalsoreportedonthecornealepithelium(65).Expressionpatternsofthesetransporterproteinsinthecelllinesmayvarybasedonitsoriginandculturecondition(5860).Someoftherecentreportshighlightedtheexpressionofpharmaceuticallyrelevanttransportersusingculturedhumanocularcellmodelsandhumanoculartissues(59,60,66).Urttietal.(59)reportedthatonlyMRP1,MRP5,andBCRPwereexpressedinthefreshlyexcisedhumancornealepithelialtissue,whereascellmodelsoverexpressedmanyothereffluxtransporterscomparedtothatofthenormalcornealepithelium.



Influxtransportersfacilitatethetranslocationofessentialnutrientsandxenobioticsacrossbiologicalmembranes.Theseincludecarriersforaminoacids,peptides,vitamins,glucose,lactate,andnucleoside/nucleobases.Stirredbythesuccessofvalacyclovirandthecharacterizationofdifferentinfluxtransportersinoculartissues,ophthalmicdrugdeliveryscientistsinvestigatedvariousprodrugstargetingtheseinfluxtransporters.Transportertargetedprodrugsoffermultipleadvantages.Theprodrugsoranaloguesdesignedtotargettheinfluxtransporterscansignificantlyenhancetheabsorptionofpoorlypermeatingparentdrugs,astheseconjugatesbecomesubstratesfortheinfluxtransportersandsimultaneouslyevadetheeffluxpumps.Furthermore,physicochemicalpropertiesofthedrugsuchassolubilityandstabilitycanbeimprovedcomparedtotheparentdrug.

Themostcommonlyapplicableinfluxtransportersforoculardrugdeliveryareaminoacidandpeptidetransporters.Theseproteinsmayhaveaputativeroleinoculardrugdeliveryalongwiththeirphysiologicalroleoftransportingvariousaminoacidsandnutrientsintooculartissues.AminoacidtransportersthatbelongtoSLC1,SLC6,andSLC7genefamilieswereidentifiedatthemolecularlevelinoculartissues,andtheirfunctionalrolewasexaminedaswell.TheSLC1familyconsistsoffivehighaffinityglutamatetransporters(EAAT1EAAT5)andtwoneutralaminoacidtransporters(ASCT1andASCT2).Fewofthesetransporterswereidentifiedsofarinoculartissues.mRNAexpressionofASCT1(SLC1A4)hasbeendetectedinrabbitcorneaandinrabbitprimarycornealepithelialcells(rPCEC)(67).FunctionalactivityofASCT1onrabbitcorneawasalsodemonstratedbystudyingthesaturable,Na+dependentuptakeoflalanineinrPCECcelllineandbydeterminingitspermeabilityacrossisolatedrabbitcornea.MolecularevidenceforASCT2(SLC1A5)expressionwasconfirmedinretinalMullercells,anditwassuggestedthattheaminoaciddserine,synthesizedinMullercells,iseffluxedthroughthistransportersystem(68).B0,+(SLC6A14)isaneutralandcationicaminoacidtransporterwithbroadsubstratespecificity.Blisseandcoworkerscarriedoutarealtimequantitativepolymerasechainreaction(RTPCR)ontotalRNAisolatedfromrabbitcornea,rabbitcornealepithelium,andhumancornea.ThisreportconfirmedtheexpressionoftheaminoacidtransporterB(0,+)oncornea(69).ThisstudyalsoconcludedthatprimarycarrierinvolvedinlargininetransportacrosscornealepitheliumistheB0,+system.Thiscarriersystemisalsoattributedtolargininetransportinpigmentedrabbitconjunctiva(70).IdentificationandfunctionalcharacterizationofanNa+independentlargeneutralaminoacidtransporter,LAT1(SLC7A5),wasreportedinhumanandrabbitcornea(71).PresenceofthistransportersystemalongwithLAT2(SLC7A8)wasalsoconfirmedintheposteriorsegmentwithaninvitrohumanmodelusingRPEcellline(hTERTRPE)atmRNAlevel(72).mRNAexpressionofLAT2wasalsoshowninARPE19cells,anditsroleinNa+independenttransportoflphenylalaninewasemphasized(73).

Peptidetransportershavebeenwidelyinvestigatedforoculardrugdelivery.Usingexcisedrabbitcornea,Anandetal.reportedfunctionalevidenceforthepresenceoftheoligopeptidetransportersystemakintothepeptidetransporterspresentintheintestine(74).RecentreportsalsoindicatethedetectionofbothPEPT1andPEPT2onthenewlyintroducedcloneticshumancornealepithelium(cHCE)celllineandonhumancorneawithRTPCR(60,75).Furthermore,thedifferenceinthetransporterexpressioninvariousspecieswasstudied(60).TheextenttowhichmRNAlevelscorrelatewithproteinexpressionandtransporteractivityneedstobestudiedingreaterdetail.Existenceofaprotoncoupled



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dipeptidetransportsystemhasbeenreportedonconjunctivalepithelialcellsbydemonstratingitsroleinmediatingtheuptakeofmodeldipeptidelcarnosine(76).Peptidetransporterexpressionwasalsostudiedinthebackoftheeyetissues.Bergeretal.reportedexpressionofPepT2mRNAonretinalMullercells(77).Expressionofpeptidetransportersacrossretinawasalsoshownbyusingocularmicrodialysistechnique.Thisstudyinvolvedvitreousclearanceofcephalosporins,whicharesubstratesofthistransportersystem(78).

Otherthanaminoacidandpeptidetransporters,organiccation/anion(SLC22),monocarboxylate(SLC16),andnucleosidetransporters(SLC28and29)havebeenidentifiedonvariousoculartissues.Moreover,variousvitamintransporterswerestudiedfortheirfunctionalroleinoculartissues(7982).

Transportertargetedprodrugsweredevelopedfollowingtheidentificationandcharacterizationofvariousinfluxandeffluxtransportersonoculartissues.Thesestudiesareclinicallyverysignificantsincetransportertargetedprodrugshavethepotentialofimprovingocularabsorptionofpoorlypermeatingparentdrug.Improvementinocularbioavailabilityuponprodrugadministrationwasattributedtotheinvolvementofvariousoculartransporters,changeinphysicochemicalproperties,oracombinationofthesetwofactors.Prodrugsarerecognizedbythemembranetransportersassubstratesresultingintheirtranslocationacrosstheepithelia.AschematicrepresentationofeffluxevasionbytheprodrugandconcomitantcellularentrymediatedbytheinfluxtransporterisdepictedinFig.2.TableIIprovidesasummaryofvarioustransportertargetedprodrugsinvestigatedfordrugdeliverytovariousoculartissuessuchascornea,conjunctiva,andRPE.

Fig.2Circumventionofeffluxproteinsbyprodrugapproach

TableIITransporterTargetedProdrugsforOcularDrugDelivery

COLLOIDALDOSAGEFORMSFOROCULARDRUGDELIVERYColloidaldosageformshavebeenwidelystudiedandemployedinthefieldofoculardrugdelivery(48).Thesedosageformsincludeliposomes,nanoparticles,microemulsions,andnanoemulsionsetc.Barrierstooculardrugdeliveryhavealreadybeendescribedearlierinthecontextofstructureandfunctionofvariousoculartissuesandhoweachtissuecanactasabarrier.Thechronicnatureofmanyoculardiseasesnecessitatesfrequentdrug

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administration.

Advantagesofcolloidaldosageformsincludesustainedandcontrolledreleaseofthedrugatthetargetedsite,reducedfrequencyofadministration,abilitytoovercomebloodocularbarriers,andeffluxrelatedissuesassociatedwiththeparentdrug(83).Further,thesecarrierscanalsobypassorovercomevariousstabilityrelatedproblemsofdrugmolecules,e.g.,proteinsandpeptides.Designinganidealdeliverysystemforanyoculardiseasedependsonmolecularpropertiesofthedrugsuchassize,charge,andaffinitytowardsvariousoculartissuesandpigments.

Forsuccessfultranscornealdeliverywithcolloidaldosageform,natureandcharacteristicsofeachlayerofthecorneashouldbeunderstood.Cornealepitheliumandstromaareformidablebarriersforhydrophilicandhydrophobicdrugs,respectively.Cornealepithelialmucosapossessesanoverallnegativecharge,thuspermeabilityofpositivelychargedmoleculesisfavoredatphysiologicalpH(84).Whiledesigningaliposomebasedformulation,selectionofthelipidplaysanimportantrole.Investigatorshavecomparedtranscornealpermeationusingcationic,anionic,andneutralliposomes.Mostly,cationicliposomescontainingvariousdrugmoleculessuchaspenicillinG,tropicamide,andacetazolamideappeartoprovidemaximumdrugtransportacrossthecornearelativetotheanionicandneutralliposomes(8587).Similarchargebehaviorisalsoexpectedforothercolloidaldosageformssuchasnanoparticlesandmicroemulsions.Chitosancoatednanoparticlesappeartoexhibithigherpermeationrelativetouncoatednanoparticles.TableIIIsummarizesavailableliteratureonvariousformulationsdevelopedtosustaindrugreleaseviaboththetranscornealandtransscleralpathways.Apartfromtranscornealabsorption,transscleralandconjunctivalabsorptionalsoplayanimportantrolefollowingtopicaladministration.

TableIIIDrugsFormulatedinColloidalDosageFormforOcularDelivery

Transscleralpermeabilityofacompounddependsonvariousparameterssuchasmolecularweight,molecularradius,hydrophilicity,andchargeofthemolecule.Furthermore,theinvivoperformanceofcolloidaldosageformscanbeaffectedbysize,dynamicbarrierssuchasbloodandlymphaticflow,affinityoftheencapsulateddrugtowardsmelanin,andsurfaceconjugationofnanoparticleswithvariousendogenousmolecules.Followingperiocularadministrationofnanoparticles,sizeplaysacrucialroleindeterminingthefateoftheparticlesandtheentrappeddrug.Studiesinferredthatclearanceof20nmparticlesbybloodandlymphaticcirculationwassignificantlyhigher,while200nmparticlescouldbefoundattheinjectionsiteforover2months.Also,thestudyconcludedthat20nmparticleswereabletocrossthescleraltissuetoaverylowextent,while200nmparticlescouldnotcrossthesclera(88,89).AffinityofdrugmoleculestowardsmelaninpigmentpresentinthechoroidRPEalsoplaysanimportantroleinoculardisposition.Moleculeshavingahigheraffinityformelanincanbindtothepigment,andhencedeliverytotheinnerretinallayersandthevitreoushumorcanbedelayed(90).Drugtargetingbyfunctionalizationwithsomeoftheendogenouscarriermolecules,whicharenaturalsubstratesforaparticularreceptoror

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transportersuchasluteinizinghormonereleasinghormoneagonistandtransferrin,wassuccessful.DiseaseconditionscanalsoaffectdrugavailabilityintotheinnerretinaltissuesincludingMullerandphotoreceptorcells(92).

Indiabetes,disruptionofthebloodretinalbarriercanresultinsignificantdrugtransporttothetargetsite(92).Followingintravitrealinjectionofadosageform,thefateofcolloidalcarriersdependsonnumerouscriticalparameters.Vitreoushumorisacolloidalfluidcontainingsmallamountsofsolutes,ions,andlowmolecularweightcompounds.Itmainlycontainscollagen(40120g/ml)andhyaluronicacid(100400g/ml).Duetonegativechargeofvitrealhyaluronan,positivelychargedmoleculestendtoaggregateinthevitreoushumor.ThiswasobservedinitiallywiththeDNAlipoplex.Hence,itisverycrucialtoestimatethezetapotentialofacolloidaldosageformunderphysiologicalcondition(38).PEGylationofparticlescansignificantlyminimizeoravoidthisproblemtoalargeextent(93).ILMisalsoknowntorestrictthemovementofparticlesfromvitreoushumortoinnerretinallayers.AchievingsustaineddruglevelsfromperiocularadministrationisnecessaryfortreatingAMD,diabeticmacularedema,anddiabeticretinopathy.Aftersubconjunctivaladministration,colloidaldosageforms(sizeupto20nm)andreleaseddrugmoleculescanberapidlyclearedbyconjunctival,choroidal,andlymphaticcirculations.TableIVsummarizesavailableliteratureinthisfield.

TableIVFactorsAffectingTransportofDrugMoleculeorItsColloidalDosageForm

Variousstrategieshavebeenemployedtoavoidclearancefromthesevasculatures.Onesuchstrategyisthedevelopmentofafibrinsealantcontainingthedrugforposteriorsegmentdiseasessuchasretinoblastoma,wetAMD,macularedema,andproliferativevitreoretinopathy.FibrinsealanthasbeenapprovedbytheUSFoodandDrugAdministration.Onceinjectedalongwiththedrugsolution,thissealantimmediatelyformsagelbasedsemisolidstructure,whichsustainsdrugreleaseoveralongerperiod(94).TableVsummarizesrecentadvancesintheuseoffibrinsealantforoculardrugdelivery.Thisapproachwassuccessfullystudiedfordeliveryoftobramycin(keratitis),topotecan,carboplatin(retinoblastoma),andinsulin(diabeticretinopathy).

TableVStrategiestoSustaintheDrugReleaseUsingFibrinSealantandGel

MICRONEEDLE,ULTRASOUND,ANDIONTOPHORESISBASEDOCULARDRUGDELIVERYSYSTEMS

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Allthesedeliverysystemsarenoninvasivemethodsdesignedtodeliverdrugstointraocularregions,mainlyforthetreatmentofposteriorsegmentdiseases.Researchershavedevelopeddrugcoatedmicroneedleswithalengthof500to750m.Thedrugtobedeliveredcanbecoatedonthesolidmetal.Followingadministration,coatedmoleculesdissolverapidly,andsubsequently,microneedlesareremovedfromthetissue.Thisdeliverysystemgeneratesamuchhigherconcentrationcomparedtoafreedrugsolution(95).Sodiumfluoresceinandpilocarpinewerecoatedanddeliveredusingasimilartechnique.Inthecaseofsodiumfluorescein,permeationwasfoundtobe60foldhigher,andinthecaseofpilocarpine,rapidconstrictionofpupilwasobserved.Similarly,intrascleralhollowmicroneedleshavealsobeendeveloped.Thisdeliverysystemisabletodelivermicroparticles,nanoparticles,anddrugsinasolutionwithminimalinvasion.Todelivermicroparticles,concomitantadministrationofspreadingenzymessuchashyaluronidaseandcollagenaseisalsonecessary.Theseenzymesrapidlyhydrolyzethecollagenousandextracellularmatrixstructureofthescleramakingthedeliveryofmicroparticlesfeasible(96).

Similarly,ultrasoundmediateddrugdeliveryhasalsoreceivedattentioninrecentyears.Deliveryofbetablockerssuchasatenolol,carteolol,timolol,andbetaxolol,wasattemptedwithultrasoundapplication(20kHzfor1h)acrosscorneainthetreatmentofglaucoma.Cornealpermeabilityofthesecompoundshasbeensignificantlyenhancedwithultrasound.Recently,researchershaveattemptedtodeliverahydrophilicmolecule,sodiumfluorescein,atanultrasoundfrequencyof880kHzandintensitiesof0.190.56W/cm2withanexposuredurationof5min.Thisstudyreportedatenfoldenhancementincornealpermeationwithminorchangesintheepithelium(97).

Oculariontophoresishasreceivedalotofattentioninrecentyearsparticularlytodeliverdrugsacrosscorneaandsclera.Transcornealiontophoresisofciprofloxacinhydrochloride(ocularinfection),gentamicin(pseudomonaskeratitis),andantisenseoligonucleotides(treatmentofangiogenesisincornea)appearedtoproduceencouragingresults(98100).Dexamethasonephosphate,methylprednisolone(posteriorsegmentinflammation),carboplatin(retinoblastoma),andmethotrexate(inflammatorydiseasesandintraocularlymphoma)werealsosuccessfullydeliveredusingthistechnique(101104).

TOPICALDELIVERYOFDRUGSFORPOSTERIORSEGMENTEYEDISEASESDrugdeliverytoposteriorsegmenttissuesfollowingtopicaladministrationremainsachallengingtask.Intheearliersection,wehavebrieflydescribedthebarrierswhichrestrictdrugmovementtotheposteriorsegment.Barringafew,mostmoleculescannotreachtheposteriorsegmenttissuesupontopicaladministration.Insomecases,significantlyhigherpermeationofdrugmoleculesacrosscornea,sclera,orconjunctivafollowedbytopicaladministrationresultedinsignificantdistributionintointraoculartissues,e.g.,brimonidine,betaxolol,andnepafenac(105107).Higheraffinityofmemantinehydrochloridetowardsmelaninpigmentalsoplayedanimportantroleinthedistributiontotheposteriorsegment(108).TableVIsummarizesalistofmoleculesforwhichtopicalapplicationresultedinsignificantlevelsinposteriorsegmenttissuessuchastheretina,choroid,andvitreoushumor.Inonesuchapproach,ourlaboratoryhasdevelopedanovelplatformtechnology

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consistingofmixednanomicellarformulationofadrugmoleculetodeliverittotheposteriorsegmentupontopicalapplication(USpatentapplication20090092665).VitaminETPGSandoctoxynol40wereusedassurfactantstoprepareamixednanomicellarclearaqueousformulationofalipophiliccompound.SelectionofasurfactanthavingtheHLBdifferencegreaterthanthreewasverycrucialforthisformulation.Hydrophobicdrugssuchasvoclosporinanddexamethasoneweresuccessfullyincorporatedinthemicellarbasedformulation.Upontopicalapplicationofmicellarformulation(1020nm),theresearcherswereabletodeliverdrugstotheretinaintherapeuticlevels.Anotherimportantbenefitofthisapproachwastheabsenceofdruglevelsinthelensorvitreous.Thisdistributionpatterncanbecrucialtoavoidordelaythedevelopmentofmajorsideeffectsofsteroidssuchascataractformationandintraocularpressureelevation,whichoftenresultindiscontinuationofthetherapy.

TableVISummaryofDrugsWhichCanBeDeliveredtoPosteriorSegmentTissuesFollowingTopicalAdministration

CONCLUSIONEffectivetreatmentofoculardiseasesisaformidabletaskbecauseofthenatureofdiseasesandpresenceoftheocularbarriers.Challengesindrugdeliverytooculartissueshavebeenpartiallymetbytheidentificationoftransportersandmodificationofdrugsubstancestotargetthesetransporters.Thespecificityoftransportersaidsintargetingspecifictissuestherebyloweringsideeffectsandimprovingbioavailability.Developmentofnoninvasivedeliverytechniqueswillrevolutionizeoculardrugdelivery.Thepotentialforthegrowthofsustaineddrugdeliverysystemsinvolvingpolymericsystemsislimitless,andnewerpolymerswouldservethepurposeofcontrolledandsustaineddeliveryfortreatingvisionthreateningdiseases.Advancesinnanotechnologyandnoninvasivedrugdeliverytechniqueswillremainintheforefrontofnewandnovelophthalmicdrugdeliverysystems.

AcknowledgementsThisresearchhasbeensupportedbygrantsR01EY0917114andR01EY1065912fromtheNationalEyeInstitute.

FootnotesRipalGaudanaandHariKrishnaAnanthulacontributedequallytothiswork.

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