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AAPSJ.2010Sep12(3):348360.
Publishedonline2010May1.doi:10.1208/s1224801091833
PMCID:PMC2895432

OcularDrugDelivery
RipalGaudana,HariKrishnaAnanthula,AshwinParenky,andAshimK.Mitra
DivisionofPharmaceuticalSciences,SchoolofPharmacy,UniversityofMissouriKansas
City,2464CharlotteSt.,KansasCity,Missouri641082718USA
AshimK.Mitra,Phone:+18162351615,Fax:+18162355190,Email:mitraa@umkc.edu.
Correspondingauthor.
CommunicatedbyGuestEditors:BruceAungstandCraigK.Svensson
Received2009Nov26Accepted2010Feb24.
CopyrightAmericanAssociationofPharmaceuticalScientists2010
ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract

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Oculardrugdeliveryhasbeenamajorchallengetopharmacologistsanddrugdelivery
scientistsduetoitsuniqueanatomyandphysiology.Staticbarriers(differentlayersof
cornea,sclera,andretinaincludingbloodaqueousandbloodretinalbarriers),dynamic
barriers(choroidalandconjunctivalbloodflow,lymphaticclearance,andteardilution),and
effluxpumpsinconjunctionposeasignificantchallengefordeliveryofadrugaloneorina
dosageform,especiallytotheposteriorsegment.Identificationofinfluxtransporterson
variousoculartissuesanddesigningatransportertargeteddeliveryofaparentdrughas
gatheredmomentuminrecentyears.Parallelly,colloidaldosageformssuchasnanoparticles,
nanomicelles,liposomes,andmicroemulsionshavebeenwidelyexploredtoovercome
variousstaticanddynamicbarriers.Noveldrugdeliverystrategiessuchasbioadhesivegels
andfibrinsealantbasedapproachesweredevelopedtosustaindruglevelsatthetargetsite.
Designingnoninvasivesustaineddrugdeliverysystemsandexploringthefeasibilityof
topicalapplicationtodeliverdrugstotheposteriorsegmentmaydrasticallyimprovedrug
deliveryintheyearstocome.Currentdevelopmentsinthefieldofophthalmicdrugdelivery
promiseasignificantimprovementinovercomingthechallengesposedbyvariousanterior
andposteriorsegmentdiseases.
Keywords:nanoparticles,retina,transporter

INTRODUCTION

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Designingadrugdeliverysystemtotargetaparticulartissueoftheeyehasbecomeamajor
challengeforscientistsinthefield.Theeyecanbebroadlyclassifiedintotwosegments:
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anteriorandposterior.Structuralvariationofeachlayerofoculartissuecanposea
significantbarrierfollowingdrugadministrationbyanyroute,i.e.,topical,systemic,and
periocular.Inthepresentwork,weattemptedtofocusonvariousdrugabsorptionbarriers
encounteredfromallthreeroutesofadministration.Structuralcharacteristicsofvarious
oculartissuesandtheireffectivenessasbarriersforthedeliveryofdrugsandtheircolloidal
dosageformshavebeendiscussed.Theroleofeffluxpumpsandstrategiestoovercomethese
barriersutilizingthetransportertargetedprodrugapproachhavealsobeentouchedupon.
Currentdevelopmentsinoculardosageforms,especiallycolloidaldosageforms,andtheir
applicationsinovercomingvariousstaticanddynamicbarriershavebeenelucidated.
Finally,variousdevelopmentsinnoninvasivetechniquesforoculardrugdeliveryhavealso
beenemphasized.

MODESOFADMINISTRATION,BARRIERS,AND Goto:
THEIRSIGNIFICANCEINOCULARDRUG
DELIVERY
Comparedwithdrugdeliverytootherpartsofthebody,oculardrugdeliveryhasmetwith
significantchallengesposedbyvariousocularbarriers.Manyofthesebarriersareinherent
anduniquetoocularanatomyandphysiologymakingitachallengingtaskfordrugdelivery
scientists.Thesebarriersarespecificdependingupontherouteofadministrationviz.
topical,systemic,andinjectable.Mostoftheseareanatomicalandphysiologicalbarriersthat
normallyprotecttheeyefromtoxicants.Moreover,variouspreformulationandformulation
factorsneedtobeconsideredwhiledesigninganophthalmicformulation.TableI
summarizesvariousroutesofadministration,theirbenefits,andchallengesinoculardrug
delivery.Figure1representsimportantpartsoftheeyealongwithdifferentroutesofdrug
administrationrepresentedinitalics.

TableI
SummaryofRoutesofAdministration,Benefits,andChallengesinOcularDelivery

Fig.1
Routesofdrugadministrationtoeye

Topicaladministration
Topicaladministration,mostlyintheformofeyedrops,isemployedtotreatanterior
segmentdiseases.Formostofthetopicallyapplieddrugs,thesiteofactionisusually
differentlayersofthecornea,conjunctiva,sclera,andtheothertissuesoftheanterior
segmentsuchastheirisandciliarybody(anterioruvea).Uponadministration,precorneal
factorsandanatomicalbarriersnegativelyaffectthebioavailabilityoftopicalformulations.
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Precornealfactorsincludesolutiondrainage,blinking,tearfilm,tearturnover,andinduced
lacrimation(1).Tearfilm,whosecompositionandamountaredeterminantsofahealthy
ocularsurface,offersthefirstresistanceduetoitshighturnoverrate.Mucinpresentinthe
tearfilmplaysaprotectiverolebyformingahydrophiliclayerthatmovesovertheglycocalyx
oftheocularsurfaceandclearsdebrisandpathogens(2).Humantearvolumeisestimatedto
be7l,andtheculdesaccantransientlycontainaround30loftheadministeredeyedrop.
However,tearfilmdisplaysarapidrestorationtimeof23min,andmostofthetopically
administeredsolutionsarewashedawaywithinjust1530safterinstillation.Consideringall
theprecornealfactors,contacttimewiththeabsorptivemembranesislower,whichis
consideredtobetheprimaryreasonforlessthan5%oftheapplieddosereachingthe
intraoculartissues(3).
Inaddition,variouslayersofthecornea,conjunctiva,andscleraplayanimportantrolein
drugpermeation.Thecornea,theanteriormostlayeroftheeye,isamechanicalbarrier
whichlimitstheentryofexogenoussubstancesintotheeyeandprotectstheoculartissues.It
canbemainlydividedintotheepithelium,stroma,andendothelium.Eachlayeroffersa
differentpolarityandapotentialratelimitingstructurefordrugpermeation.Thecorneal
epitheliumislipoidalinnaturewhichcontains90%ofthetotalcellsinthecorneaandposes
asignificantresistanceforpermeationoftopicallyadministeredhydrophilicdrugs.
Furthermore,superficialcornealepithelialcellsarejoinedtooneanotherbydesmosomes
andaresurroundedbyribbonliketightjunctionalcomplexes(zonulaoccludens)(4,5).
Presenceofthesetightjunctionalcomplexesretardsparacellulardrugpermeationfromthe
tearfilmintointercellularspacesoftheepitheliumaswellasinnerlayersofthecornea.
Thestroma,whichcomprises90%ofthecornealthickness,ismadeupofanextracellular
matrixandconsistsofalamellararrangementofcollagenfibrils.Thehighlyhydrated
structureofthestromaposesasignificantbarriertopermeationoflipophilicdrugmolecules.
Endotheliumistheinnermostmonolayerofhexagonalshapedcells.Eventhough
endotheliumisaseparatingbarrierbetweenthestromaandaqueoushumor,ithelps
maintaintheaqueoushumorandcornealtransparencyduetoitsselectivecarriermediated
transportandsecretoryfunction(6).Furthermore,thecornealendothelialjunctionsare
leakyandfacilitatethepassageofmacromoleculesbetweentheaqueoushumorandstroma
(7).Thus,corneallayers,particularlytheepitheliumandstroma,areconsideredasmajor
barriersforoculardrugdelivery.Itisvitaltounderstandthatthepermeantshouldhavean
amphipathicnatureinordertopermeatethroughtheselayers.Aschematicofthecorneal
layersthatapermeantneedstocrossispresentedbyBararetal.(6).
Comparedtocornea,conjunctivaldrugabsorptionisconsideredtobenonproductivedueto
thepresenceofconjunctivalbloodcapillariesandlymphatics,whichcancausesignificant
druglossintothesystemiccirculationtherebyloweringocularbioavailability.Conjunctival
epithelialtightjunctionscanfurtherretardpassivemovementofhydrophilicmolecules(8).
Thesclera,whichiscontinuouswiththecorneaoriginatesfromthelimbusandextends
posteriorlythroughouttheremainderoftheglobe.Thescleramainlyconsistsofcollagen
fibersandproteoglycansembeddedinanextracellularmatrix.Permeabilitythroughthe
scleraisconsideredtobecomparabletothatofthecornealstroma.Recentreportsindicate
thatthepermeabilityofdrugmoleculesacrossthescleraisinverselyproportionaltothe
molecularradius(9).Dextranswithlinearstructureswerelesspermeableascomparedto
globularproteins(9).Furthermore,thechargeofthedrugmoleculealsoaffectsits
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permeabilityacrossthesclera.Positivelychargedmoleculesexhibitpoorpermeability
presumablyduetotheirbindingtothenegativelychargedproteoglycanmatrix(10).

Systemic(parenteral)administration
Followingsystemicadministration,thebloodaqueousbarrierandbloodretinalbarrierare
themajorbarriersforanteriorsegmentandposteriorsegmentoculardrugdelivery,
respectively.Bloodaqueousbarrierconsistsoftwodiscretecelllayerslocatedintheanterior
segmentoftheeyeviz.theendotheliumoftheiris/ciliarybloodvesselsandthe
nonpigmentedciliaryepithelium.Bothcelllayersexpresstightjunctionalcomplexesand
preventtheentryofsolutesintotheintraocularenvironment(6)suchastheaqueoushumor.
Bloodretinalbarrierrestrictstheentryofthetherapeuticagentsfrombloodintothe
posteriorsegment.Itiscomposedoftwotypesofcells,i.e.,retinalcapillaryendothelialcells
andretinalpigmentepitheliumcells(RPE)knownastheinnerandouterbloodretinal
barrier,respectively.RPE,locatedbetweentheneuralretinaandthechoroid,isamonolayer
ofhighlyspecializedcells.RPEaidsinbiochemicalfunctionsbyselectivetransportof
moleculesbetweenphotoreceptorsandchoriocapillaris.Furthermore,itmaintainsthevisual
systembyuptakeandconversionofretinoids(11).However,tightjunctionsoftheRPE
efficientlyrestrictintercellularpermeation.Followingoralorintravenousdosing,drugscan
easilyenterintothechoroidduetoitshighvasculaturecomparedtoretinalcapillaries.The
choriocapillarisarefenestratedresultinginrapidequilibrationofdrugmoleculespresentin
thebloodstreamwiththeextravascularspaceofthechoroid.However,outerbloodretinal
barrier(RPE)restrictsfurtherentryofdrugsfromthechoroidintotheretina.Eventhoughit
isidealtodeliverthedrugtotheretinaviasystemicadministration,itisstillachallengedue
tothebloodretinalbarrier,whichstrictlyregulatesdrugpermeationfrombloodtothe
retina.Hence,specificoralorintravenoustargetingsystemsareneededtotransport
moleculesthroughthechoroidintodeeperlayersoftheretina(12).
Recentadvancementsinnanotechnologyencouragedresearcherstofindwaystoovercome
bloodretinalbarrier.InonesuchstudyusingC57BL/6mice,theresearchersdemonstrated
thatintravenouslyadministered20nmgoldnanoparticlescouldpassthroughtheblood
retinalbarrieranddistributeinalltheretinallayerswithoutcytotoxicity.Theviabilityof
retinalendothelialcells,astrocytes,andretinoblastomacellswasalsonotaffected.In
contrast,larger100nmnanoparticleswerenotdetectedintheretina(13).Afewattempts
havealsobeenmadeforgenedeliverytotheeyebyintravenousrouteofadministration.A
diffuseexpressionofSV40/galactosidasegeneinmouseinnerretina,RPE,iris,aswellas
conjunctivalepithelium,wasobserveduponintravenousadministrationofpolyethylene
glycol(PEG)conjugatedimmunoliposomes(14).Amorerecentreportdemonstratesthe
utilityofintravenousadministrationoftransferrin,arginineglycineasparticacidpeptide,
ordualfunctionalizedpoly(lactidecoglycolide)(PLGA)nanoparticles.Thesefunctionalized
PLGAnanoparticlesweresuccessfulintargeteddeliveryofantivascularendothelialgrowth
factorintraceptorplasmidtochoroidalneovascularization(CNV)lesions.Thedeliveryof
nanoparticlestotheneovasculareyewasattributedtotheleakybloodretinalbarrierasa
resultofCNVinthelasertreatedrateye(15).
Pharmacokineticstudiesinvolvingvariousdrugssuchasmicafungin(16),marbofloxacin
(17),andamphotericinB(18)demonstratedthatthesedrugsaredistributedinoculartissues
uponintravenousadministration.Onemarketedintravenouslyadministeredformulationis
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visudyne,whichisusedinphotodynamictherapyforthetreatmentofwetagerelated
maculardegeneration(AMD).However,owingtothetoxicityanddeliveryconcerns,
intravenousadministrationisnotverycommonintreatingoculardisorders.

Oraladministration
Oraldelivery(1921)orincombinationwithtopicaldelivery(22)hasbeeninvestigatedfor
differentreasons.Topicaldeliveryalonefailedtoproducetherapeuticconcentrationsinthe
posteriorsegment.Also,oraldeliverywasstudiedasapossiblenoninvasiveandpatient
preferredroutetotreatchronicretinaldiseasesascomparedtoinjectableroute.However,
limitedaccessibilitytomanyofthetargetedoculartissueslimitstheutilityoforal
administrationwhichnecessitateshighdosagetoobservesignificanttherapeuticefficacy.
Thiscanresultinsystemicsideeffects.Hence,parameterssuchassafetyandtoxicityneedto
beconsideredwhentryingtoobtainatherapeuticresponseintheeyeuponoral
administration.Forexample,inglaucomatherapy,oralcarbonicanhydraseinhibitors,such
asacetazolamideandethoxzolamide,havebeendiscontinuedinmostofthecasesdueto
theirsystemictoxicity(23,24).Theoralrouteisnotpredominant,andonlyalimitednumber
ofcompoundswereinvestigatedforoculardrugdelivery.Theseincludevariousclassesof
drugssuchasanalgesics(25),antibiotics(21,2628),antivirals(29),antineoplasticagents
(30),andomega6fattyacids(31).Amajorprerequisiteoftheoralrouteforocular
applicationsishighoralbioavailabilityofthedrug.Followingoralabsorption,moleculesin
systemiccirculationmustalsocrossthebloodaqueousandbloodretinalbarriers.The
functionandbarrierpropertyoftheseprotectiveocularstructureswaspreviouslydiscussed.

Periocularandintravitrealadministration
Althoughnotverypatientcompliant,theseroutesareemployedpartlytoovercomethe
inefficiencyoftopicalandsystemicdosingtodelivertherapeuticdrugconcentrationstothe
posteriorsegment.Moreover,systemicadministrationmayleadtosideeffectsmakingita
lessdesirabledeliveryrouteforgeriatricpatients.Theperiocularrouteincludes
subconjunctival,subtenon,retrobulbar,andperibulbaradministrationandiscomparatively
lessinvasivethanintravitrealroute(SeeFig.1foranatomicallocationofthesitesof
administrationintheeye,representedinitalics).Thedrugadministeredbyperiocular
injectionscanreachtheposteriorsegmentbythreedifferentpathways:transscleralpathway
systemiccirculationthroughthechoroidandtheanteriorpathwaythroughthetearfilm,
cornea,aqueoushumor,andthevitreoushumor(32).
Subconjunctivalinjectionobviatestheconjunctivalepithelialbarrier,whichisratelimiting
forpermeationofwatersolubledrugs.Thus,thetransscleralroutebypassescornea
conjunctivabarrier.Nevertheless,variousdynamic,static,andmetabolicbarrierslimitdrug
accesstotheposteriorsegment.Dynamicbarriersincludeconjunctivalbloodandlymphatic
circulation.Variousauthorsreportedrapiddrugeliminationviathesepathwaysfollowing
subconjunctivaladministration(3335).Asaresult,theformulationisdrainedintosystemic
circulationtherebyloweringocularbioavailability.Thus,drugeliminationfromthe
subconjunctivalspacebecomesamajordeterminantofthevitreousdruglevelsfollowing
subconjunctivaladministration.Themoleculesthatescapeconjunctivalvasculature
permeatethroughscleraandchoroidtoreachtheneuralretinaandphotoreceptorcells.The
scleraisnotamajorbarrierasitismorepermeablethanthecornea.Moreover,permeability
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acrossthescleraisindependentoflipophilicityunlikecornealandconjunctivallayersbut
dependsprimarilyonthemolecularradius(12,36).However,choroidisasignificantbarrier
ashighchoroidalbloodflowcanalsoeliminateaconsiderablefractionofdrugbeforeitcan
reachtheneuralretina.Furthermore,bloodretinalbarrierslimitdrugavailabilitytothe
photoreceptorcells.
Unlikeperiocularinjections,theintravitrealinjectionoffersdistinctadvantagesasthe
moleculesaredirectlyinsertedintothevitreous.However,drugdistributioninthevitreous
isnonuniform.Smallmoleculescanrapidlydistributethroughthevitreous,whereasthe
diffusionoflargermoleculesisrestricted.Thisdistributionalsodependsonthe
pathophysiologicalconditionandmolecularweightoftheadministereddrug(37).The
vitreousalsoactsasabarrierforretinalgenedeliveryfollowinganintravitrealinjection.
Hyaluronan,anegativelychargedglycosaminoglycanpresentinthevitreous,caninteract
withcationiclipid,polymeric,andliposomalDNAcomplexes(38).Thisinteractioncanlead
tosevereaggregationandcompleteimmobilizationofDNA/cationicliposomecomplexes
(39).Similarly,mobilityofnanoparticlesinthevitreousdependsontheirstructureand
surfacecharge.Polystyrenenanospheresdonotdiffusefreelyintothevitreousduetotheir
adherencetocollagenfibrillarstructures(39).Hence,surfacemodificationofnanospheres
withhydrophilicPEGchainshasbeenperformed.Arecentstudyusinghumanserum
albuminnanoparticlesalsodemonstratedthatanionicnanoparticleswithazetapotentialof
33.3mVdiffusedmorefreelyinthevitreousthancationicparticleswithazetapotentialof
11.7mV(40).
Theinnerlimitingmembrane(ILM),thecelllayerseparatingtheretinaandthevitreous,isa
barrierforretinaldeliveryfollowingintravitrealadministrationofgenebasedtherapeutics.
Forexample,theILMposesabarrierforpenetrationoftheadenoassociatedvirusintothe
retinafromthevitreous.MilddigestionofILMenhancedtransductionofmultipleretinalcell
typesfromthevitreousindicatingitshighbarrierproperty(41).Moreover,drugtransport
fromvitreoustotheoutersegmentsofretinaandchoroidismorecomplexduethepresence
ofRPE.
Thehalflifeinthevitreousisanotherfactorthatcandeterminethetherapeuticefficacy.
Followingintravitrealinjection,thedrugiseliminatedeitherbytheanteriorrouteor
posteriorroute.Theanterioreliminationrouteinvolvesdrugdiffusionacrossthevitreous
intotheaqueoushumorthroughzonularspacesfollowedbyeliminationthroughaqueous
turnoveranduvealbloodflow.Theposterioreliminationpathwayinvolvesdrugpermeation
acrossthebloodretinalbarrierandrequiresoptimumpassivepermeabilityoractive
transportmechanisms.Asaresult,hydrophilicityandlargemolecularweighttendto
increasethehalflifeofthecompoundsinthevitreoushumor(12).

MELANINBINDING

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Thepresenceofmelaninmayalteroculardrugdisposition.Interactionwiththispigment
mayaltertheavailabilityoffreedrugatthetargetedsite.Thereby,melaninbindingmay
significantlylowerpharmacologicalactivity(42).Inoculartissues,melaninispresentin
uveaandRPE.ItbindstofreeradicalsanddrugsbyelectrostaticandVanderWaalsforces
orbysimplechargetransfer(43).Basedonavailableinformation,itmaybeconcludedthat
allbasicandlipophilicdrugsbindtomelanin(44).Eventhoughdrugbindingtomelaninis
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notnecessarilypredictiveofoculartoxicity,ithassignificantpharmacologicalconsequences
andrequirescarefulconsiderationinoculardrugdelivery.Melaninbindingintheirisciliary
bodyaffectsdrugconcentrationsinanterioroculartissuesanddrugresponse(45).A
melaninbounddrugisnotusuallyavailableforreceptorbindingnecessitatingthe
administrationoflargerdoses(46).Likewise,melaninpresentinchoroidandRPEaffects
theextentofdruguptakeintotheretinaandvitreousfollowingtransscleralorsystemicdrug
administration.Asaresultofmelaninbinding,permeationlagtimeoflipophilicbeta
blockersthroughbovinechoroidRPEismuchlongerthanmorehydrophilicbetablockers
(11).Similarly,bindingoflipophiliccompoundstothebovinechoroidBruch'smembrane
wasdemonstratedtobehigherduetothepresenceofmelanin.Consequently,thereisa
greaterresistancetosolutepermeationacrosschoroidBruch'smembranethanthesclera,
whichisdevoidofmelanin(47).

TRANSPORTERSINEYE

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Thetraditionalapproachtoimproveocularbioavailabilityistomodifythedrugchemicallyto
achievethedesiredsolubilityandlipophilicity.However,amorerationalapproachwouldbe
atransportertargetedmodificationofthedrug.Transportersaremembraneboundproteins
thatplayanimportantroleinactivetransportofnutrientsacrossbiologicalmembranes.The
presenceoftransportershasbeenreportedonvariousoculartissues.However,inthe
presentarticle,wehavefocusedonthetransportersthatarelocalizedintheepitheliaofthe
cornea,conjunctiva,andretina.Thesetransportersmaybeamenabletobindandtransport
specifictargetedligandsattachedtodrugmoieties.
Twotypesoftransportersystemsareofinterestinoculardrugdelivery:effluxtransporters
andinfluxtransporters.WidelystudiedeffluxtransportersbelongtotheATPbinding
cassettesuperfamily,whereasinfluxtransportersbelongtothesolutecarrier(SLC)
superfamily.Effluxtransporterslowerbioavailabilitybyeffluxingthemoleculesoutofthe
cellmembraneandcytoplasm.Prominenteffluxtransportersidentifiedonoculartissues
includePgp,multidrugresistanceprotein(MRP),andBCRP.Variousauthorsreviewedthe
emergingroleoftransportersinoculardrugdelivery(4850).Pgphasanaffinitytoefflux
lipophiliccompoundsinnormalaswellasincancerouscells,possiblyleadingtoemergence
ofdrugresistance.ExpressionandfunctionalactivityofPgpwasidentifiedonvarious
ocularcelllinesandtissuessuchasthecornea(5153),conjunctiva(54,55),andRPE
(5658).However,someauthorsrecentlyindicatedthattheexpressionofPgponhuman
cornealepitheliummaybenegligibleorabsent(59,60).MRPworksinasimilarmannerbut
effluxesorganicanionsandconjugatedcompounds.OutofnineknownisoformsoftheMRP
family,onlythreewereidentifiedinoculartissues.MRP2andMRP5wereidentifiedin
cornealepithelium(61,62),whereasMRP1wasidentifiedinrabbitconjunctivalepithelial
cells(63).RPEexpressesMRP1(64).ThepresenceofBCRPwasalsoreportedonthecorneal
epithelium(65).Expressionpatternsofthesetransporterproteinsinthecelllinesmayvary
basedonitsoriginandculturecondition(5860).Someoftherecentreportshighlightedthe
expressionofpharmaceuticallyrelevanttransportersusingculturedhumanocularcell
modelsandhumanoculartissues(59,60,66).Urttietal.(59)reportedthatonlyMRP1,
MRP5,andBCRPwereexpressedinthefreshlyexcisedhumancornealepithelialtissue,
whereascellmodelsoverexpressedmanyothereffluxtransporterscomparedtothatofthe
normalcornealepithelium.
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Influxtransportersfacilitatethetranslocationofessentialnutrientsandxenobioticsacross
biologicalmembranes.Theseincludecarriersforaminoacids,peptides,vitamins,glucose,
lactate,andnucleoside/nucleobases.Stirredbythesuccessofvalacyclovirandthe
characterizationofdifferentinfluxtransportersinoculartissues,ophthalmicdrugdelivery
scientistsinvestigatedvariousprodrugstargetingtheseinfluxtransporters.Transporter
targetedprodrugsoffermultipleadvantages.Theprodrugsoranaloguesdesignedtotarget
theinfluxtransporterscansignificantlyenhancetheabsorptionofpoorlypermeatingparent
drugs,astheseconjugatesbecomesubstratesfortheinfluxtransportersandsimultaneously
evadetheeffluxpumps.Furthermore,physicochemicalpropertiesofthedrugsuchas
solubilityandstabilitycanbeimprovedcomparedtotheparentdrug.
Themostcommonlyapplicableinfluxtransportersforoculardrugdeliveryareaminoacid
andpeptidetransporters.Theseproteinsmayhaveaputativeroleinoculardrugdelivery
alongwiththeirphysiologicalroleoftransportingvariousaminoacidsandnutrientsinto
oculartissues.AminoacidtransportersthatbelongtoSLC1,SLC6,andSLC7genefamilies
wereidentifiedatthemolecularlevelinoculartissues,andtheirfunctionalrolewas
examinedaswell.TheSLC1familyconsistsoffivehighaffinityglutamatetransporters
(EAAT1EAAT5)andtwoneutralaminoacidtransporters(ASCT1andASCT2).Fewofthese
transporterswereidentifiedsofarinoculartissues.mRNAexpressionofASCT1(SLC1A4)
hasbeendetectedinrabbitcorneaandinrabbitprimarycornealepithelialcells(rPCEC)
(67).FunctionalactivityofASCT1onrabbitcorneawasalsodemonstratedbystudyingthe
saturable,Na+dependentuptakeoflalanineinrPCECcelllineandbydeterminingits
permeabilityacrossisolatedrabbitcornea.MolecularevidenceforASCT2(SLC1A5)
expressionwasconfirmedinretinalMullercells,anditwassuggestedthattheaminoacidd
serine,synthesizedinMullercells,iseffluxedthroughthistransportersystem(68).B0,+
(SLC6A14)isaneutralandcationicaminoacidtransporterwithbroadsubstratespecificity.
Blisseandcoworkerscarriedoutarealtimequantitativepolymerasechainreaction(RT
PCR)ontotalRNAisolatedfromrabbitcornea,rabbitcornealepithelium,andhuman
cornea.ThisreportconfirmedtheexpressionoftheaminoacidtransporterB(0,+)oncornea
(69).Thisstudyalsoconcludedthatprimarycarrierinvolvedinlargininetransportacross
cornealepitheliumistheB0,+system.Thiscarriersystemisalsoattributedtolarginine
transportinpigmentedrabbitconjunctiva(70).Identificationandfunctional
characterizationofanNa+independentlargeneutralaminoacidtransporter,LAT1
(SLC7A5),wasreportedinhumanandrabbitcornea(71).Presenceofthistransportersystem
alongwithLAT2(SLC7A8)wasalsoconfirmedintheposteriorsegmentwithaninvitro
humanmodelusingRPEcellline(hTERTRPE)atmRNAlevel(72).mRNAexpressionof
LAT2wasalsoshowninARPE19cells,anditsroleinNa+independenttransportofl
phenylalaninewasemphasized(73).
Peptidetransportershavebeenwidelyinvestigatedforoculardrugdelivery.Usingexcised
rabbitcornea,Anandetal.reportedfunctionalevidenceforthepresenceoftheoligopeptide
transportersystemakintothepeptidetransporterspresentintheintestine(74).Recent
reportsalsoindicatethedetectionofbothPEPT1andPEPT2onthenewlyintroduced
cloneticshumancornealepithelium(cHCE)celllineandonhumancorneawithRTPCR
(60,75).Furthermore,thedifferenceinthetransporterexpressioninvariousspecieswas
studied(60).TheextenttowhichmRNAlevelscorrelatewithproteinexpressionand
transporteractivityneedstobestudiedingreaterdetail.Existenceofaprotoncoupled
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dipeptidetransportsystemhasbeenreportedonconjunctivalepithelialcellsby
demonstratingitsroleinmediatingtheuptakeofmodeldipeptidelcarnosine(76).Peptide
transporterexpressionwasalsostudiedinthebackoftheeyetissues.Bergeretal.reported
expressionofPepT2mRNAonretinalMullercells(77).Expressionofpeptidetransporters
acrossretinawasalsoshownbyusingocularmicrodialysistechnique.Thisstudyinvolved
vitreousclearanceofcephalosporins,whicharesubstratesofthistransportersystem(78).
Otherthanaminoacidandpeptidetransporters,organiccation/anion(SLC22),
monocarboxylate(SLC16),andnucleosidetransporters(SLC28and29)havebeenidentified
onvariousoculartissues.Moreover,variousvitamintransporterswerestudiedfortheir
functionalroleinoculartissues(7982).
Transportertargetedprodrugsweredevelopedfollowingtheidentificationand
characterizationofvariousinfluxandeffluxtransportersonoculartissues.Thesestudiesare
clinicallyverysignificantsincetransportertargetedprodrugshavethepotentialof
improvingocularabsorptionofpoorlypermeatingparentdrug.Improvementinocular
bioavailabilityuponprodrugadministrationwasattributedtotheinvolvementofvarious
oculartransporters,changeinphysicochemicalproperties,oracombinationofthesetwo
factors.Prodrugsarerecognizedbythemembranetransportersassubstratesresultingin
theirtranslocationacrosstheepithelia.Aschematicrepresentationofeffluxevasionbythe
prodrugandconcomitantcellularentrymediatedbytheinfluxtransporterisdepictedin
Fig.2.TableIIprovidesasummaryofvarioustransportertargetedprodrugsinvestigatedfor
drugdeliverytovariousoculartissuessuchascornea,conjunctiva,andRPE.

Fig.2
Circumventionofeffluxproteinsbyprodrugapproach

TableII
TransporterTargetedProdrugsforOcularDrugDelivery

COLLOIDALDOSAGEFORMSFOROCULAR
DRUGDELIVERY

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Colloidaldosageformshavebeenwidelystudiedandemployedinthefieldofoculardrug
delivery(48).Thesedosageformsincludeliposomes,nanoparticles,microemulsions,and
nanoemulsionsetc.Barrierstooculardrugdeliveryhavealreadybeendescribedearlierin
thecontextofstructureandfunctionofvariousoculartissuesandhoweachtissuecanactas
abarrier.Thechronicnatureofmanyoculardiseasesnecessitatesfrequentdrug
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administration.
Advantagesofcolloidaldosageformsincludesustainedandcontrolledreleaseofthedrugat
thetargetedsite,reducedfrequencyofadministration,abilitytoovercomebloodocular
barriers,andeffluxrelatedissuesassociatedwiththeparentdrug(83).Further,these
carrierscanalsobypassorovercomevariousstabilityrelatedproblemsofdrugmolecules,
e.g.,proteinsandpeptides.Designinganidealdeliverysystemforanyoculardisease
dependsonmolecularpropertiesofthedrugsuchassize,charge,andaffinitytowards
variousoculartissuesandpigments.
Forsuccessfultranscornealdeliverywithcolloidaldosageform,natureandcharacteristicsof
eachlayerofthecorneashouldbeunderstood.Cornealepitheliumandstromaare
formidablebarriersforhydrophilicandhydrophobicdrugs,respectively.Cornealepithelial
mucosapossessesanoverallnegativecharge,thuspermeabilityofpositivelycharged
moleculesisfavoredatphysiologicalpH(84).Whiledesigningaliposomebased
formulation,selectionofthelipidplaysanimportantrole.Investigatorshavecompared
transcornealpermeationusingcationic,anionic,andneutralliposomes.Mostly,cationic
liposomescontainingvariousdrugmoleculessuchaspenicillinG,tropicamide,and
acetazolamideappeartoprovidemaximumdrugtransportacrossthecornearelativetothe
anionicandneutralliposomes(8587).Similarchargebehaviorisalsoexpectedforother
colloidaldosageformssuchasnanoparticlesandmicroemulsions.Chitosancoated
nanoparticlesappeartoexhibithigherpermeationrelativetouncoatednanoparticles.Table
IIIsummarizesavailableliteratureonvariousformulationsdevelopedtosustaindrugrelease
viaboththetranscornealandtransscleralpathways.Apartfromtranscornealabsorption,
transscleralandconjunctivalabsorptionalsoplayanimportantrolefollowingtopical
administration.

TableIII
DrugsFormulatedinColloidalDosageFormforOcularDelivery
Transscleralpermeabilityofacompounddependsonvariousparameterssuchasmolecular
weight,molecularradius,hydrophilicity,andchargeofthemolecule.Furthermore,thein
vivoperformanceofcolloidaldosageformscanbeaffectedbysize,dynamicbarrierssuchas
bloodandlymphaticflow,affinityoftheencapsulateddrugtowardsmelanin,andsurface
conjugationofnanoparticleswithvariousendogenousmolecules.Followingperiocular
administrationofnanoparticles,sizeplaysacrucialroleindeterminingthefateofthe
particlesandtheentrappeddrug.Studiesinferredthatclearanceof20nmparticlesbyblood
andlymphaticcirculationwassignificantlyhigher,while200nmparticlescouldbefoundat
theinjectionsiteforover2months.Also,thestudyconcludedthat20nmparticleswereable
tocrossthescleraltissuetoaverylowextent,while200nmparticlescouldnotcrossthe
sclera(88,89).Affinityofdrugmoleculestowardsmelaninpigmentpresentinthechoroid
RPEalsoplaysanimportantroleinoculardisposition.Moleculeshavingahigheraffinityfor
melanincanbindtothepigment,andhencedeliverytotheinnerretinallayersandthe
vitreoushumorcanbedelayed(90).Drugtargetingbyfunctionalizationwithsomeofthe
endogenouscarriermolecules,whicharenaturalsubstratesforaparticularreceptoror
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transportersuchasluteinizinghormonereleasinghormoneagonistandtransferrin,was
successful.Diseaseconditionscanalsoaffectdrugavailabilityintotheinnerretinaltissues
includingMullerandphotoreceptorcells(92).
Indiabetes,disruptionofthebloodretinalbarriercanresultinsignificantdrugtransportto
thetargetsite(92).Followingintravitrealinjectionofadosageform,thefateofcolloidal
carriersdependsonnumerouscriticalparameters.Vitreoushumorisacolloidalfluid
containingsmallamountsofsolutes,ions,andlowmolecularweightcompounds.Itmainly
containscollagen(40120g/ml)andhyaluronicacid(100400g/ml).Duetonegative
chargeofvitrealhyaluronan,positivelychargedmoleculestendtoaggregateinthevitreous
humor.ThiswasobservedinitiallywiththeDNAlipoplex.Hence,itisverycrucialto
estimatethezetapotentialofacolloidaldosageformunderphysiologicalcondition(38).
PEGylationofparticlescansignificantlyminimizeoravoidthisproblemtoalargeextent
(93).ILMisalsoknowntorestrictthemovementofparticlesfromvitreoushumortoinner
retinallayers.Achievingsustaineddruglevelsfromperiocularadministrationisnecessary
fortreatingAMD,diabeticmacularedema,anddiabeticretinopathy.Aftersubconjunctival
administration,colloidaldosageforms(sizeupto20nm)andreleaseddrugmoleculescan
berapidlyclearedbyconjunctival,choroidal,andlymphaticcirculations.TableIV
summarizesavailableliteratureinthisfield.

TableIV
FactorsAffectingTransportofDrugMoleculeorItsColloidalDosageForm
Variousstrategieshavebeenemployedtoavoidclearancefromthesevasculatures.Onesuch
strategyisthedevelopmentofafibrinsealantcontainingthedrugforposteriorsegment
diseasessuchasretinoblastoma,wetAMD,macularedema,andproliferative
vitreoretinopathy.FibrinsealanthasbeenapprovedbytheUSFoodandDrug
Administration.Onceinjectedalongwiththedrugsolution,thissealantimmediatelyformsa
gelbasedsemisolidstructure,whichsustainsdrugreleaseoveralongerperiod(94).TableV
summarizesrecentadvancesintheuseoffibrinsealantforoculardrugdelivery.This
approachwassuccessfullystudiedfordeliveryoftobramycin(keratitis),topotecan,
carboplatin(retinoblastoma),andinsulin(diabeticretinopathy).

TableV
StrategiestoSustaintheDrugReleaseUsingFibrinSealantandGel

MICRONEEDLE,ULTRASOUND,AND
IONTOPHORESISBASEDOCULARDRUG
DELIVERYSYSTEMS
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Allthesedeliverysystemsarenoninvasivemethodsdesignedtodeliverdrugstointraocular
regions,mainlyforthetreatmentofposteriorsegmentdiseases.Researchershavedeveloped
drugcoatedmicroneedleswithalengthof500to750m.Thedrugtobedeliveredcanbe
coatedonthesolidmetal.Followingadministration,coatedmoleculesdissolverapidly,and
subsequently,microneedlesareremovedfromthetissue.Thisdeliverysystemgeneratesa
muchhigherconcentrationcomparedtoafreedrugsolution(95).Sodiumfluoresceinand
pilocarpinewerecoatedanddeliveredusingasimilartechnique.Inthecaseofsodium
fluorescein,permeationwasfoundtobe60foldhigher,andinthecaseofpilocarpine,rapid
constrictionofpupilwasobserved.Similarly,intrascleralhollowmicroneedleshavealso
beendeveloped.Thisdeliverysystemisabletodelivermicroparticles,nanoparticles,and
drugsinasolutionwithminimalinvasion.Todelivermicroparticles,concomitant
administrationofspreadingenzymessuchashyaluronidaseandcollagenaseisalso
necessary.Theseenzymesrapidlyhydrolyzethecollagenousandextracellularmatrix
structureofthescleramakingthedeliveryofmicroparticlesfeasible(96).
Similarly,ultrasoundmediateddrugdeliveryhasalsoreceivedattentioninrecentyears.
Deliveryofbetablockerssuchasatenolol,carteolol,timolol,andbetaxolol,wasattempted
withultrasoundapplication(20kHzfor1h)acrosscorneainthetreatmentofglaucoma.
Cornealpermeabilityofthesecompoundshasbeensignificantlyenhancedwithultrasound.
Recently,researchershaveattemptedtodeliverahydrophilicmolecule,sodiumfluorescein,
atanultrasoundfrequencyof880kHzandintensitiesof0.190.56W/cm2withanexposure
durationof5min.Thisstudyreportedatenfoldenhancementincornealpermeationwith
minorchangesintheepithelium(97).
Oculariontophoresishasreceivedalotofattentioninrecentyearsparticularlytodeliver
drugsacrosscorneaandsclera.Transcornealiontophoresisofciprofloxacinhydrochloride
(ocularinfection),gentamicin(pseudomonaskeratitis),andantisenseoligonucleotides
(treatmentofangiogenesisincornea)appearedtoproduceencouragingresults(98100).
Dexamethasonephosphate,methylprednisolone(posteriorsegmentinflammation),
carboplatin(retinoblastoma),andmethotrexate(inflammatorydiseasesandintraocular
lymphoma)werealsosuccessfullydeliveredusingthistechnique(101104).

TOPICALDELIVERYOFDRUGSFOR
POSTERIORSEGMENTEYEDISEASES

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Drugdeliverytoposteriorsegmenttissuesfollowingtopicaladministrationremainsa
challengingtask.Intheearliersection,wehavebrieflydescribedthebarrierswhichrestrict
drugmovementtotheposteriorsegment.Barringafew,mostmoleculescannotreachthe
posteriorsegmenttissuesupontopicaladministration.Insomecases,significantlyhigher
permeationofdrugmoleculesacrosscornea,sclera,orconjunctivafollowedbytopical
administrationresultedinsignificantdistributionintointraoculartissues,e.g.,brimonidine,
betaxolol,andnepafenac(105107).Higheraffinityofmemantinehydrochloridetowards
melaninpigmentalsoplayedanimportantroleinthedistributiontotheposteriorsegment
(108).TableVIsummarizesalistofmoleculesforwhichtopicalapplicationresultedin
significantlevelsinposteriorsegmenttissuessuchastheretina,choroid,andvitreous
humor.Inonesuchapproach,ourlaboratoryhasdevelopedanovelplatformtechnology
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consistingofmixednanomicellarformulationofadrugmoleculetodeliverittotheposterior
segmentupontopicalapplication(USpatentapplication20090092665).VitaminETPGS
andoctoxynol40wereusedassurfactantstoprepareamixednanomicellarclearaqueous
formulationofalipophiliccompound.SelectionofasurfactanthavingtheHLBdifference
greaterthanthreewasverycrucialforthisformulation.Hydrophobicdrugssuchas
voclosporinanddexamethasoneweresuccessfullyincorporatedinthemicellarbased
formulation.Upontopicalapplicationofmicellarformulation(1020nm),theresearchers
wereabletodeliverdrugstotheretinaintherapeuticlevels.Anotherimportantbenefitof
thisapproachwastheabsenceofdruglevelsinthelensorvitreous.Thisdistributionpattern
canbecrucialtoavoidordelaythedevelopmentofmajorsideeffectsofsteroidssuchas
cataractformationandintraocularpressureelevation,whichoftenresultindiscontinuation
ofthetherapy.

TableVI
SummaryofDrugsWhichCanBeDeliveredtoPosteriorSegmentTissuesFollowingTopical
Administration

CONCLUSION

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Effectivetreatmentofoculardiseasesisaformidabletaskbecauseofthenatureofdiseases
andpresenceoftheocularbarriers.Challengesindrugdeliverytooculartissueshavebeen
partiallymetbytheidentificationoftransportersandmodificationofdrugsubstancesto
targetthesetransporters.Thespecificityoftransportersaidsintargetingspecifictissues
therebyloweringsideeffectsandimprovingbioavailability.Developmentofnoninvasive
deliverytechniqueswillrevolutionizeoculardrugdelivery.Thepotentialforthegrowthof
sustaineddrugdeliverysystemsinvolvingpolymericsystemsislimitless,andnewer
polymerswouldservethepurposeofcontrolledandsustaineddeliveryfortreatingvision
threateningdiseases.Advancesinnanotechnologyandnoninvasivedrugdeliverytechniques
willremainintheforefrontofnewandnovelophthalmicdrugdeliverysystems.

Acknowledgements

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ThisresearchhasbeensupportedbygrantsR01EY0917114andR01EY1065912fromthe
NationalEyeInstitute.

Footnotes

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RipalGaudanaandHariKrishnaAnanthulacontributedequallytothiswork.

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