Expert Review Recent Perspectives in Ocular Drug Delivery

20 Pages·2009·0.4 MB·English

PharmaceuticalResearch,Vol.26,No.5,May2009(#2008)
DOI:10.1007/s11095-008-9694-0
Expert Review
Recent Perspectives in Ocular Drug Delivery
Ripal Gaudana,1 J. Jwala,1 Sai H. S. Boddu,1 and Ashim K. Mitra1,2
ReceivedMay11,2008;acceptedJuly22,2008;publishedonlineAugust29,2008
Abstract.Anatomyandphysiologyoftheeyemakesitahighlyprotectedorgan.Designinganeffective
therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable
task. Limitations of topical and intravitreal route of administration have challenged scientists to find
alternative mode of administration like periocular routes. Transporter targeted drug delivery has
generated a great deal of interest in the field because of its potential to overcome many barriers
associatedwithcurrenttherapy.Applicationofnanotechnologyhasbeenverypromisinginthetreatment
ofagamutofdiseases.Inthisreview,wehavebrieflydiscussedseveraloculardrugdeliverysystemssuch
as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and
hydrogels.Potentialforoculargenetherapyhasalsobeendescribedinthisarticle.Innearfuture,agreat
deal of attention will be paid to develop non-invasive sustained drug release for both anterior and
posteriorsegmenteyedisorders.Abetterunderstandingofnatureofoculardiseases,barriersandfactors
affecting in vivo performance, would greatly drive the development of new delivery systems. Current
momentum in the invention of new drug delivery systems hold a promise towards much improved
therapiesforthetreatmentofvisionthreateningdisorders.
KEYWORDS:nanotechnology;oculardrugdelivery;transporter.
INTRODUCTION achievedfollowingtheirinhibitionorevasion.Butprolonged
useofsuchinhibitors mayresult inundesirableeffects(4).
Ocular drug delivery has remained as one of the most Treatment of posterior segment diseases still remains a
challenging task for pharmaceutical scientists. The unique herculean task for the formulation scientists. The tight
structure of the eye restricts the entry of drug molecules at junctions of blood retinal barrier (BRB) restrict the entry of
the required site of action. Drug delivery to the eye can be systemically administered drugs into the retina (5). High
broadly classified into anterior and posterior segments vitreal drug concentrations are required in the treatment of
(Fig. 1). Conventional systems like eye drops, suspensions posterior segment diseases. This can be made possible only
andointmentscannotbeconsideredoptimalinthetreatment with the local administration (intravitreal injections/implants
ofvisionthreateningoculardiseases(1).However,morethan andperiocularinjections).Periocularinjectionsareassociated
90%ofthemarketedophthalmicformulationsareintheform with fairly high patient compliance as compared to intra-
of eye drops. These formulations mainly target the anterior vitrealinjections (6).
segmenteyediseases(2).Mostofthetopicallyapplieddrugs Dramatic changes have been observed in the field of
are washed off from the eye by various mechanisms ocular drug delivery over a decade. Insight into various
(lacrimation, tear dilution and tear turnover) resulting in membrane transporters/receptors present on the eye opened
low ocular bioavailability of drugs. Moreover, human cornea a new window of opportunities. Especially polar drug
comprisingofepithelium,substantiapropriaandendothelium molecules, which fail to permeate ocular barriers, can be
also restricts the ocular entry of drug molecules (3). As a convenientlydeliveredviatransporter/receptortargeteddrug
result of these factors less than 5% of administered drug delivery systems (7). This review article briefly covers
enters the eye. Alternative approaches like incorporation of pathology of various ocular diseases and their current
permeation enhancers/cyclodextrins and increasing the vis- therapies.Wehavealsogivenemphasisontheroleofvarious
cosity of solutions did not provide any significant improve- oculartransportersandrecentdevelopmentsindrugdelivery
ment.Recentlymanydrugeffluxpumpshavebeenidentified strategies including gene therapy. We have briefly discussed
and significant enhancement in ocular drug absorption was ocular deliver systems, gene therapy, and recent develop-
mentslikemicroneedleandiontophoresis
Alltheauthorscontributedequallytothiswork.
OVERVIEWON ANATOMYAND DISEASES
1Division of Pharmaceutical Sciences, School of Pharmacy, Univer-
AFFECTINGEYE
sity of Missouri-Kansas City, 5005 Rockhill Road, Kansas City,
Missouri64110-2499,USA.
2To whom correspondence should be addressed. (e-mail: mitraa@ Broadly we discuss the structure of eye under two
umkc.edu) subheadings (a) anterior segment and (b) posterior segment.
1197 0724-8741/09/0500-1197/0#2008SpringerScience+BusinessMedia,LLC
1198 Gaudana,Jwala, BodduandMitra
Anterior segment consists of front one-third of eye that Intravitreal injections have gained considerable momen-
mainly includes pupil, cornea, iris, ciliary body, aqueous tum during the past two decades. This method involves
humor, and lens while the posterior segment consists of the injectionofdrugsolutiondirectlyintovitreousviaparsplana
back two-thirds of the eye that includes vitreous humor, using a 30 G needle. Unlike other routes, intravitreal
retina,choroid,macula,andopticnerve(Fig.1)(8,9).Inthis injection offers higher drug concentrations in vitreous and
article we made an attempt to briefly discuss the major retina.Eliminationofdrugsfollowingintravitrealadministra-
diseasesaffectingtheeye.Theseincludeage-relatedmacular tion depends on their molecular weight. Linear and globular
degeneration (AMD), diabetic macular edema (DME), shapedmolecules(especiallyproteinandpeptidedrugs)with
cataract, proliferative vitreoretinopathy (PVR), uveitis, cyto- molecular weight greater than 40 and 70 kDa respectively
megalovirus (CMV), and glaucoma. Table I highlights the tendtocauselongerretentionin vitreoushumor (14).
classification, signs and symptoms and current treatment Though intravitreal administration offers high concentra-
optionsforthesediseases. tionsofdrugsinretina,itisassociatedwithvariousshortterm
complicationssuchasretinaldetachment,endophthalmitisand
DELIVERYROUTES intravitreal hemorrhages (15). Moreover, patients need to be
carefullymonitoredfollowingintravitrealinjections.
Conventionally, many ocular diseases are treated with Periocular route has been considered as the most
either topical or systemic medications. Topical application of promising and efficient route for administering drugs to
drughasremainedthemostpreferredmethodduetoeaseof posterior eye segment. Periocular refers to the region
administration and low cost. Topical application is useful in surrounding the eye. It is a broad term which includes
the treatment of disorders affecting the anterior segment of peribulbar, posterior juxtascleral, retrobulbar, subtenon and
the eye (10). Anatomical and physiological barriers hinder subconjunctival routes (Fig. 2). Drug solutions are placed in
drugs from reaching posterior segment of eye mainly at closeproximitytothesclerawhichresultsinhighretinaland
choroidandretina.Amajorfractionofdrugfollowingtopical vitreal concentrations. Sclera which is made up of fibrous
administration is lost by lacrimation, tear dilution, nasolacri- tissue offers less resistance to permeability of drugs (16).
maldrainageandtearturnover.Suchprecorneallossesresult Ghateetal.,studiedthepharmacokineticsofsodiumfluores-
in very low ocular bioavailability. Typically, less than 5% of ceinfollowingperiocularadministrationinrabbits.Thestudy
thetotal administereddose reachesaqueoushumor(11).So, concluded that administration of drug via subtenon injection
in order to maintain minimum inhibitory concentrations, the resultedinthehighestandsustainedvitreousconcentrationof
agents need to be frequently dosed resulting in poor patient sodiumfluoresceincomparedtoretrobulbarandsubconjunc-
compliance. Upon topical instillation drugs are absorbed tival routes (17). Anterior segment complications have been
either by corneal route (cornea → aqueous humor → observed in some patients following periocular injections.
intraocular tissues) or non-corneal route (conjunctiva → Theseincluderiseinintraocularpressure,cataract,hyphema,
sclera→choroid/RPE).Thepreferredroutedependsmainly strabismus andcornealdecompensation(18).
on the corneal permeability of drug molecules (12). Unlike
topicaladministration,systemicdosinghelpsinthetreatment
NUTRIENT TRANSPORTERSAND EFFLUXPUMPS
of diseases affecting posterior segment of the eye. A major
drawback associated with systemic administration is only 1– INTHEEYE
2% of administered drug reaches to vitreous cavity. Blood
Epithelialcellsexpressvariousnutrienttransportersand
retinal barrier which is selectively permeable to more
receptors on their membrane surface. These nutrient trans-
lipophilic molecules mainly governs the entry of drug
porters aid in the movement of various vitamins and amino
molecules into posterior segment of the eye. This results in
acids across the cell membrane. Our laboratory has exten-
frequent administration of high amounts of drugs leading to
sively studied various transporters and receptors which are
systemicsideeffects(13).Thoughtopicalandsystemicroutes
present on ocular structures. We have also shown that
areconvenient,lackofadequatebioavailabilityandfailureto
attachment of various transporters/receptors targeted ligands
deliver therapeutic amounts of drugs to the retina prompted
enhances ocular bioavailability significantly. A detailed dis-
the vision scientists to search for alternative routes of
cussion of all influx transporters is beyond the scope of this
administration.
review.So,wehavementionedsometheimportant ones.
PEPTIDE TRANSPORTER
It is a fairly robust transporter which has gained
considerable attention in recent years for targeted drug
delivery (19). These proton coupled transporters help in the
translocationofdiandtripeptidesacrosstheepithelium(20).
These proteins are mainly classified into PepT1, PepT2 and
peptide/histidine transporters (PHT 1 and PHT 2). Many
drug molecules are known to be substrates for these trans-
porters. Our laboratory has shown the presence of an
oligopeptide transporter on rabbit cornea (21). Other drugs
including β-lactam antibiotics, renin inhibitors and ACE-
Fig.1. Structureofeye. inhibitors are known to be substrates for PepT1 and PepT2.
RecentPerspectivesin OcularDrugDelivery 1199
) ) ) ) ) ) ) )
8 1 4 7 9 4 8 3
7 8 8 8 8 9 9 0
Ref –01 –91 –21 –51 –71 –01 –51 –92
7 7 8 8 8 9 9 9
1 1 1 1 1 1 1 1
( ( ( ( ( ( ( (
atment Treatment Specifichigh-doseformulationscontainingantioxidants,zincandvitaminsupplementsIntravitrealinjectionofanti-VEGFagentslikeranibizumab,pegaptanibsodiumandbevacizumab Focalorgridlasersandsteroids Surgeryandadjunctivetreatmentaftersurgerysoastoavoidrelapses(5-fluorouracilandlowmolecularweightheparin) Corticosteroidsandimmunosuppressiveagents Cidofovir,ganciclovir(GCV)andfoscarnet Prostaglandinanalogs,beta-adrenergicreceptorantagonists,alpha2-adrenergicagonistsparasympathomimetics,carbonicanhydraseinhibitorsAllergicinfectionsaretreatedusinganti-histaminicsandnon-steroidalanti-inflammatoryagentsandbacterialconjunctivitisistreatedusingantibioticsandcorticosteroids Surgicaltreatmentmayeitherinvolveextracapsularsurgeryandphotoemulsification
e
Tr
d
ummaryofMajorOcularDiseases,Symptomsan Signsandsymptoms Breakdownofphotoreceptors,retinalpigmentepithelium(RPE)andchoriocapillarisGrowthofabnormalbloodvesselsbehindtheretina,macula,disruptionofBruch'smembraneanddegenerationofRPEleadingtocompletelossofvisionSmallaberrationsinretinalbloodvesselsfollowedbyintra-retinalleakageFormationofmicrocystsanddilationofretinalcapillariesSimplescarformationandproliferationofcellsinvitreousandretina Inflammationoccursinthemiddlelayerofeye(uvea)Inflammationoftheretina,retinaldetachmentandcompleteblindnessObstructiontotheoutflowofaqueoushumorfromtheanteriorsegment Inflammationoftheconjunctiva,redness,irritation,grittinessandwateringofeyes Lensopacitiesthatobstructthepassageoflight
S
I.
Table Classification DryAMD(non-exudative) WetAMD(exudative) Focalornon-cystoidDME DiffuseorcystoidDME Basedontheinflammationofretina:focal,diffuse,subretinal,circumferential,anteriordisplacementbasedonthelocationofscartissue:anterior,posteriorAnterioruveitis,intermediateuveitisposterioruveitis,pan-uveiticuveitis Primaryopenangleglaucoma(POAG)angleclosureglaucoma(ACG) Basedonthestructures:blepharoconjunctivitis(inflammationofeyelids),keratoconjunctivitisinflammationofthecornea)andepiscleritis(inflammationbetweenconjunctivaandsclera)Basisofetiology:agerelated,congenital,secondary,traumatic;basisoflocationofopacity:anteriorcortical,anteriorpolar,anteriorsubcapsular,nuclear,posteriorcortical,posteriorsubcapsular
)
r
o
(
Disease AMD DME PVR Uveitis CMV Glaucoma Conjunctivitisredeye Cataract
1200 Gaudana,Jwala, BodduandMitra
any other nutrient transporter. But high substrate specificity
of glucose transporters renders them inefficient for drug
delivery purpose.
VITAMINCTRANSPORTER
Vitamin C or ascorbic acid (AA) acts as an antioxidant
andtherebyprotectsthecorneaandotheroculartissuesfrom
UVradiations.AqueoushumoristhemainsourceofAAfor
cornea and lens. AA levels in aqueous humor are partly
responsible for preventing cataract (28). Two specific trans-
porters(SVCT-1andSVCT-2)ofvitaminCwereidentifiedin
the ocular tissues of human, rabbit and rat. These trans-
porters have identical sequence homology. Transport of AA
across the cells is mediated by two different transporter
Fig.2. Routesofoculardrugdelivery.
families. One consists of the low affinity and high capacity
facilitative hexose transporters (GLUT) which translocate
Ocheltree et al., demonstrated the expression of PHT1 in dehydro ascorbic acid (oxidized form of ascorbic acid), and
BRPE, HRPE (human RPE cells), ARPE-19 (human RPE the other consists of high affinity and low capacity sodium
cell line), and bovine and human neural retina. However, dependent vitamin C transporters (SVCT1 and SVCT2) that
they could find the expression PEPT2 and PHT2 only in ferriesL-ascorbicacid(reducedformofascorbicacid)(29).
bovineandhumanretina;andPEPT1wasnotdetected.They
also concluded that glycylsarcosine uptake studies did not AMINO ACIDTRANSPORTER
demonstrate any significant functional activity of PHT1 on
plasma membranes of RPE (22). We have also investigated Amino acids are responsible for protein synthesis and
themechanismofmodeldipeptide(glycylsarcosine)transport maintenanceofstructuralandfunctionalintegrityofconjunc-
across the blood-ocular barriers following systemic adminis- tiva and retina/RPE. These transporters help in transferring
tration in our laboratory. A time and concentration depen- amino acids from circulating blood to various organs. The
dent, carrier mediated uptake of glycylsarcosine across the presence of various amino acid transporters (ASCT1, LAT1
blood-ocular barrier was reported (23). Prodrugs (valine- and ATB0+) on the cornea has been confirmed by gene
ACVandvaline-valine-ACV)exhibitedhigherconcentrations expression. These transporters are actively involved in the
ofACVin aqueoushumor following systemic administration transportation of L-alanine, L arginine and L-phenylalanine
ascomparedtoparentdrug.Thisstudyindicatesthatpeptide across the cornea. Amino acid transporters can be classified
prodrugsaretakenupviacarrier mediatedtransportmecha- on the basis of their sodium dependency and substrate
nism(24). Hence, drugs with poor ocular bioavailability can specificity (30). System L (large) and system y+ (cationic)
be suitably modified so that they can be recognized by amino acid transporters belong to sodium independent
peptidetransporters. transporters while system X- (anionic), system A, B0,+, ASC
(anionic,cationic,andneutralaminoacidtransporters)belong
GLUCOSE TRANSPORTER tosodiumdependenttransportercategory(21).Largeneutral
aminoacidtransporterisexpressedintwoisoformsLAT1and
Glucoseisutilizedbytheretinatomeettheenergyneed LAT2. LAT1 is mainly involved in the transport of large
of oxidative metabolism. Neural retina is considered to have neutral amino acids, such as Leu, Phe, Ile, Trp, Val, Tyr, His
the highest metabolic rate per unit weight (25). So, an andMetwhileLAT2transportsbothlargeneutralaminoacids
alteration in the metabolic rate can lead to potential ocular andsmallneutralaminoacids(31,32).Transportsystemsfor
complications.Glucoseistransportedacrosstheblood-retinal amino acids have been characterized on corneal epithelium
and blood aqueous barriers by a stereo-specific, saturable and endothelium. Gandhi et al., studied the biochemical
process of facilitated diffusion. Glucose transporters are evidence of sodiumindependent facilitative transport system,
expressed in various isoforms GLUT1, GLUT2, GLUT3, LAT2, with high substrate specificity on ARPE-19 cell line
GLUT4,GLUT5,GLUT6andGLUT7.OutoftheseGLU1, (33).Blisseetal.,reportedthepresenceofsodium-dependent,
GLU3, and GLU4 are high-affinity glucose transporters B0,+aminoacidtransporterwithbroadsubstratespecificityon
where as GLUT5 is a high-affinity fructose transporter. rabbitcornealepitheliumandhumancornea.Thistransporter
GLUT2 is considered to be low affinity glucose transporter. belongs to neurotransmitter gene family and found to have
GLUT6 is a pseudogene which does not encode for a affinity comparable to PEPT1 in the transport of prodrugs,
functionaltransporter.GLUT7issimilartoGLUT2butonly like valine-ACV and valine-GCV (34, 35). Such transport
expressed in endoplasmic reticulum (26). Mantych et al., systems may be efficiently targeted for enhancing ocular
studiedthepresenceofvariousisoformsofglucosetransport- deliveryofdrugs.
er (Glut 1, Glut 3, Glut 4, and Glut 5) in human eye using
western blot and immunohistochemical techniques. This EFFLUX TRANSPORTERS
study reported presence of Glut 1 in RPE, choroid, pars
plana,retinalMueller cells,andlensfibercells(27).Glucose Effluxofvarioussubstratesacrossplasmamembraneand
transporters are more efficient and have more capacity than cytoplasmintoextracellularfluidismainlygovernedbyABC
RecentPerspectivesin OcularDrugDelivery 1201
(ATP-binding cassette) superfamily of proteins which are Shirasakihasrecentlyreviewedvariousmolecularapproaches
encodedbyMDR1 gene (36).ABC transportersare broadly to enhance drug permeation across the cornea (54). Our
classified into two types (a) complete transporter, contains laboratory has also aggressively pursued the exploitation of
four units (two nucleotide-binding domains and two mem- manyofthesetransportersforoculardrugabsorption.Amino
brane bound domains) and (b) half transporter, which acidandpeptideprodrugsofacyclovir(ACV)andganciclovir
possesses only two units (one nucleotide-binding domain (GCV),targetingvariousaminoacidandpeptidetransporters
and one membrane-bound domain). Half transporter must have been developed and evaluated in our laboratory.
attachwithanotherhalftransportertoperformitsaction(37). Dipeptide (glycine–valine and tyrosine–valine) monoester
These ABC proteins are actively involved in detoxification prodrugs of GCV were found to show superior corneal
process by regulating the transport of various sterols, lipids, absorption and bioavailability compared toparent drug(55).
endogenous metabolic products and xenobiotics (38). Litera- Theseattemptsarehighlyeffectiveintreatingherpessimplex
ture search reveals that mainly two multidrug efflux pumps virus-1 (HSV-1) induced corneal epithelial and stromal
are responsible for the development of chemoresistance (a) keratitis (56). Permeability values of valine–GCV, tyrosine–
P-glycoprotein (ABCB1) and (b) multidrug resistant protein valine–GCV, and glycine–valine–GCV were found to be
(MRP)(ABCC1)(39). higher than parent GCV which was attributed to their
P-gp is a 170 kDa membrane bound efflux protein interaction with oligopeptide transporter present on the
generally expressed on the apical surface of polarized cells retina (57). Sustained release microsphere formulations of
(40). P-glycoprotein is actively involved in the efflux of drug GCV and its lipophilic prodrug GCV–monobutyrate, with
molecules thereby reducing drug accumulation inside cells higherentrapmentefficiency,weredevelopedusingPLGAin
(41).ThepresenceofP-gpintheeyehasbeenconfirmedon our laboratory (58). By using a similar strategy, L-valyl ester
conjunctival epithelial cells (42), ciliary non-pigmented epi- ofacyclovir(ACV)wasalsodevelopedandfoundtobemore
thelium (43), human and rabbit cornea (44), retinal capillary permeableacrossrabbitcorneaduetoitsinteractionwiththe
endothelial cells, iris and ciliary muscle cells (45). Constable oligopeptide transporter (24). Ocular penetration of peptide
etal.,studiedthepresenceofP-gponthreehumanRPEcell prodrug of ACV (valine–valine–ACV), was higher than the
lines, ARPE19, D407 and h1RPE. They concluded that only parentdrugfollowingsystemicadministrationinrabbits.The
D407cellfunctionallyexpressP-gpandhencecanbeusedfor prodrugs appear to be less cytotoxic, highly water-soluble
invitrodrugtransportstudieswithoutanymodifications(46). with excellent in vivo activity against HSV-1 in rabbit
MRP is a 190 kDa membrane bound efflux protein epithelial and stromal keratitis (59). Our laboratory has also
encoded by MRP1 gene. It is generally expressed on the demonstrated that prodrug derivatization can effectively
basolateral surface of intestine, hepatocytes and kidney cells circumvent P-gp mediated efflux of quinidine across rabbit
(47, 48). Till now 12 different members of MRP family have cornea(60).
been studied (49). MRP's are actively involved in the TG100801,whichconvertstoTG100572byde-esterification,
effluxing glucuronide, sulfate conjugated compounds and was found to be effective in the treatment of ocular neo-
organic anions. Aukunuru et al., studied the presence of vascularizationandretinaledemafollowingtopicaladminis-
functionally and biochemically active MRP on human RPE tration (61). Due to this prodrug approach, incidence of
cell line (50). Further studies by Steueret al., confirmed that systemictoxicitywasfoundtobegreatlydiminished.Roleof
MRP is present on the choroidal side of the outer blood phase I and phase II ocular metabolic activities was also
retinal barrier (51). Recently, studies from our laboratory reviewed recently to rationalize design of prodrug and co-
revealed the presence of ABCC2 (a MRP homologue) on drug for ocular delivery by Crooks et al., (62). UNIL088, a
human corneal epithelium and rabbit cornea (52). Recently water-soluble prodrug of cyclosporine Awas developed via
Zhang et al., have performed an extensive research on an ester linkage which gets converted into parent drug by
implications of drug transporter and CYP P450 mRNA chemicalorenzymatichydrolysisoftheterminalestergroup
Expression in ocular drug disposition. They concluded that (63). Cannabinoids usually lowers IOP by their interaction
bothBCRPandMRP2haveverylowexpressionlevelsinthe withtheocularcannabinoidreceptors.Thesolubilityrelated
human cornea while there were moderate MRP1 and low problemofcannabinoidswassolvedbymakingarachidony-
MRP3 expression levels in the human cornea. Moreover, lethanolamide, R-methanandamide, noladin ether and their
designing drugs that can efficiently evade MRP1 efflux may water-solublephosphateesterprodrugs(64).Thismodifica-
playanimportantroleinenhancementofocularpenetration tion has resulted in higher corneal permeation which could
(53). result in more efficient reduction in IOP. In another study,
Effluxpumpsconstitutesignificantbarrierstotheentryof combretastatin A-4-phosphate (CA-4-P), a water soluble
drug molecules. It is indeed necessary to develop alternative prodrugofcombretastatinA-4(CA-4),wasfoundtosuppress
strategieswhichcanimproveoculardrugabsorption. thedevelopmentofVEGF-inducedneovascularizationinthe
retina and also block development of CNV (65). Topical
formulationofnepafenacwasfoundtoeffectivelypenetrate
PRODRUG APPROACHTOENHANCE OCULAR into the corneal tissue which also reaches intothe posterior
BIOAVAILABILITY segment.Inanimal modelsit was foundtoinhibit CNVand
ischemia-induced retinal neovascularization. Nepafenac is
Prodrug strategy has been attempted for improving converted to amfenac which has significant higher perme-
therapeutic efficacy of many drug molecules. Significant ability across the cornea. This property is primarily respon-
advantages in various properties like solubility, stability, sible for appearance of the nepafenac to the posterior
permeability and evasion of efflux pump have been gained. segmentandcausinginhibitionofVEGF(66).
1202 Gaudana,Jwala, BodduandMitra
NOVELOCULAR DRUGDELIVERYSYSTEMS with conventional eye drops in a day. This was due to
enhancement of the permeation by surfactant-co-surfactant
Colloidalcarriershavebeenwidelyexploitedinthefield combination. Another microemulsion system consisting of
ofdrugdeliveryscience.Itprovidesamoreselectivetargeting pilocarpine hydrochloride (73) was shown to convert in
along with sustained release of molecules at the desired site. different forms like (liquid crystalline and coarse emulsion)
Applications of nanotechnology can be very exciting in the with a change in rheological parameters which changed
treatmentofagamutofdiseasesaffectingtheanterioraswell depending upon change in water content. This results in
as the posterior segment of the eye. One has to understand higher viscosity which will retain the formulation on the
the physiological and biochemical factors involved in normal cornea resulting in its enhanced effect. Timolol in micro-
and pathological conditions for designing a successful ocular emulsion system was laden in a 2-hydroxyethyl methacrylate
drugdeliverysystem. (HEMA) gels which was studied to modulate its transport
An ideal therapy requires selectively targeting of active across the gel (74). The authors have achieved higher drug
agent to various diseases like CNV, diabetic retinopathy and loading but could not control its release. In another attempt
solid tumors in the eye. Retina does not possess lymphatic to deliver timolol, a stable o/w and w/o emulsion was
system moreover angiogenesis in this part of eye has similar formulated which met all the requirements of an eye drop
features to the solid tumor with enhanced permeability and according to Polish Pharmacopeia V. Sirolimus, a highly
retention (EPR) effects (67, 251). Delivery of a drug via lipophilic drug with aqueous solubility of 2.6 μg/mL was
nanotechnologybasedproductfulfillsmainlythreeobjectives formulatedinmicroemulsionsystemwhichcouldhold1mgof
as follows (1) enhances drug permeation (2) controls the drug in the system with excellent stability and tolerability
releaseofdrug(3)targetsdrug(251).Mainfocuswasgivento (75). An alcohol free, microemulsion based formulation
colloidal systems consisting of micro/nanoparticles, micro/ consisting chloramphenicol was developed. This formulation
nanoemulsions, nanosuspensions and liposomes. In the last exhibited excellent stability when compared to commercially
decade, dendrimers, niosomes, and cyclodextrins have also availableformulation.Thoughmicroemulsionshaveexcellent
been exploited to achieve optimal drug delivery. Ocular advantages limitations in selection of surfactant/co-surfactant
implants have also been emerged as an alternative to the system and potential toxicity associated with higher concen-
conventionaldelivery systems. Therole of iontophoresis and trationsofsurfactant/co-surfactant oftenrestrictsitsuse(76).
ultrasound has also gained momentum in ocular delivery.
Encapsulation of drugs in these colloidal carriers can also NANOSUSPENSIONS
significantly enhance permeation across the membrane and
prevent degradation from the ocular enzymes (68, 69). Such Thiscanbedefinedassub-microncolloidalsystemwhich
biodegradable carriers can be developed as an alternative to consists of poorly water-soluble drug, suspended in an
the implant prepared from nonbiodegradable polymers, appropriate dispersion medium stabilized by surfactants.
which has to be removed surgically after a certain period. Nanosuspenisons usually consist of colloidal carriers like
Sometimes the surgical process can cause complications like polymeric resins which are inert in nature. They help in
astigmatism, vitreoushemorrhage andpatientincompliance. enhancement of drug solubility and thus bioavailability.
Unlike microemulsions, they are also popular because of
MICROEMULSIONS their non irritant nature. Flurbiprofen encapsulated in
eudragit RS 100® and RL 100® polymer resins prevents
Microemulsions are dispersions of water and oil facili- myosis,whichmightbeinducedduringextracapsularcataract
tated by a combination of surfactant and co-surfactant in a surgery (77). Charge on the surface of nanoparticles facili-
manner to reduce interfacial tension. These systems are tates its adhesion to the cornea. Methylprednisolone acetate
usually characterized by higher thermodynamic stability, (MPA) was encapsulated in a copolymer of poly (ethyl-
small droplet size (∼100 nm) and clear appearance (70). A acrylate, methyl-methacrylate and chlorotrimethyl-ammo-
review on application of microemulsions in ocular drug nioethyl methacrylate) and examined for its effect on the
delivery by Vandamme et al., deals systematically with the anti-inflammatory symptoms in rabbits with endotoxin-in-
various developments and challenges happening in the field. duced uveitis (EIU) (78). Animal studies have revealed that
Selection of aqueousphase, organic phase and surfactant/co- anti-inflammatory effect of nanosuspensions was more than
surfactant systems are critical parameters which can affect microsuspensions. Similar studies were carried out using
stability of the system. Optimization of these components piroxicam ineudragit RS100. Invivostudies inrabbits have
results in significant improvement in solubility of the drug shown significant anti-inflammatory effects compared to
molecule e.g. indomethacin, chloramphenicol (71). Apart microsuspensions (79). In another approach, three different
from solubility, microemulsion systems have also been types of glucocorticoids; hydrocortisone, prednisolone and
exploited to improve permeation across the cornea. An oil- dexamethasonewereformulatedasnanosuspensions.Invivo
in-water system consisting of pilocarpine using lecithin, study in rabbits suggested that the nanosuspensions signifi-
propylene glycol, PEG 200 as surfactant/co surfactants, and cantlyenhancedtheocularabsorptionofglucocorticoids(80).
isopropylmyristateastheoilphasehasbeendesigned,which These nanosuspensions also produce sustained drug release
is nonirritating to the rabbit animal model (72). Such and were more effective over a longer duration. Nano-
formulations often provide sustained drug release thereby suspensionsalsoimpartstabilitytothedrugintheformulation.
reducing frequency of the drug administration. In case of Cloricromene (AD6) was formulated in nanosuspensions by
pilocarpine,microemulsionbasedsystemlowersthefrequen- using eudragit RS100 and RL100. AD6-loaded eudragit
cy of administration to two times as compared to four times retarded nanoparticle suspension offered a significant edge in
RecentPerspectivesin OcularDrugDelivery 1203
enhancing the shelf life and bioavailability of the drug ticles of indomethacin resulted in twofold enhancement in
followingophthalmicapplication(81). ocular bioavailability (88). Enhanced permeation across the
cornea was also observed when poly (epsilon-caprolactone)
NANOPARTICLES nanoparticles were coated with polyethylene glycol (89). In
another study, a formulation comprising dexamethasone
AccordingtoSahooet al., “Nanoparticles are defined as acetate encapsulated in biodegradable PLGA nanoparticles
particles with a diameter of less than 1 μm, comprising of was administered by the intravitreal route and the effect on
various biodegradable or non biodegradable polymers, lipids, CNV was studied. This study demonstrated a triphasic
phospholipids or metals” (251). They can be classified as patternofdrugrelease.Thedruglevelwasfoundtobemore
nanospheres or nanocapsules depending upon whether the than the level required to treat CMV (90). In another study,
drughasbeenuniformlydispersedorcoatedwithinpolymeric mucoadhesive chitosan-sodium alginate nanoparticles were
material.Recentstudieshave revealedthemigrationofintact prepared and evaluated for topical delivery of gatifloxacin.
nanoparticles to the RPE cells following intravitreal injection This system resulted in burst release during the first hour
ofnanoparticlessuspension(82,251).Thismigrationhadbeen followedbysustainedreleasefor24h.Thisapproachhelpsin
attributed to the rupture of the internal limiting membrane reducingthedosingfrequencyoftheantibioticbecauseofthe
(ILM) and activation of non-specific retinal microglial cells. sustainedactionobservedafter singleadministration(91).
Such mild transient mechanism in the inflammatory process Moshfeghi et al., have extensively reviewed the perspec-
also modifies permeability and the anchoring mechanism of tives of particulate delivery system (micro and nanoparticles)
the ILM. These findings are crucial for the diseases affecting in ophthalmology (92). Intravitreal administration of red
the posterior segment of the eye. Uptake and distribution of nuclear fluorescent protein entrapped in PLGA has been
nanoparticlesdependonthesizeofthenanoparticles.Kinetics shown to localize in RPE cells where red nuclear fluorescent
offluoresceinnanospheres(2000,200and50nm)wasstudied proteinplasmidexpressionwas alsoobserved(93).Phosphor-
followingintravitrealinjectioninrabbits.Nanospheressmaller othioate ODNs were either adsorbed or incorporated in
than200nmwerealsoobservedintheretinalcellsotherthan albumin nanoparticles and antiviral efficacy was examined.
thevitreouscavityandtrabecularmeshworkwhereonlylarger Nanoparticles having entrapped ODNs were found to exhibit
diameter particles were distributed. This study has shown the higher antiviral activity than nanoparticles with the adsorbed
importance of particle size in ocular tissue distribution (83). drug on the surface. This may be due to the protection of
Many formulation parameters have to be considered in ODNs from enzymatic degradation (94). Particulate delivery
designing an ideal formulation. Surface charge interaction of system of ODNs has resulted in their higher stability, efficacy
the drug and polymer has played an important role in drug and reduction in non specific toxicity (95, 96). Currently, we
release from thepolymer.Incomplete releaseof progesterone are working on the delivery of varioussteroidal nanoparticles
from the polybutyl cyanoacrylate nanospheres was attributed of mean particle diameter ≈200 nm via subconjunctival
tothesurfacechargeinteractionofthedrugandpolymer(84, administration. In our laboratory, we are also working to
251). A solid lipid nanoparticulate system of tobramycin was optimize various in vitro properties of steroidal nanoparticles.
developed fortopical drugdelivery. Sucha particulatesystem Thesenanoparticles can besuspendedinthermosensitive gels
canberetainedforlongerdurationonthecornealsurfaceand for subconjunctival administration. Further attachment of
also ontheconjunctival sac compared toan aqueous solution various ligands (folate and biotin) to the surface of these
of the drug. In vivo testing has shown sustained drug release nanoparticleshelpsinincreasingtheuptakebyRPEcells.This
over a period of 6 h compared to short duration from equal approachcanbeappliedforthetreatmentofvariousposterior
dose of eye drops (85). Recently Kompella et al., have segmentdiseasessuchaswetAMD,PVRandDME.
evaluated how the ocular disposition and distribution of Microspheres can sustain the release of the ODNs after
different size of nanoparticles (20 and 200 nm) vary due to intravitrealinjectionforlongertimeperiod.Asmicrospheresdo
blood and lymph circulations following periocular administra- not enter the cells, a new approach called “Trojan” delivery
tion in Sprague Dawley rats (86). They found that particles systemwasinvented.Inthistypeofdeliverysystem,polymeric
with 20 nm size were transported across the sclera to a small microspheresweredesignedtocontrolreleaseofthenanosized
extent and no significant transport was noted across the anti-TGFβ2 phosphorothioate ODNs complexes. Such “Tro-
sclera-choroid-RPE. Such low permeation was attributed to jan” delivery was much more efficient for bleb survival
periocular circulation (blood and lymphatic) which play a followingtrabeculectomythanthemicrosphereorcontrolalone
crucial role in clearing the 20 nm particles. A higher (97). Macugen® was also entrapped in microspheres and
concentration of particles in the ocular tissues was observed studied following transscleral delivery. In vitro release study
in dead animals by the post-mortem studies which they hasshownreleaseofmacugen(2μg/day)upto20daysacross
concluded because of the lack of physiological barrier follow- thesclera.Inhibitionofendothelialcellproliferationconfirmed
ingperiocularadministration.Anidealnanoparticulateformu- thatbiologicalactivitywasnotaffectedbyencapsulation(98).
lation should have low clearance by blood and lymphatic
circulation in order for it to be effective in the treatment of LIPOSOMES
posteriorsegmentdiseasesfollowingperiocularadministration.
Various naturally occurring polymers were studied as Liposomes are lipid vesicles containing aqueous core
carriers for the nanoparticulate system. Albumin nanopar- which have been widely exploited in ocular delivery for
ticles can effectively encapsulate both positively (GCV) and various drug molecules. Liposomes containing GCV were
negatively charged (oligonucleotides (ODNs)) molecules formulated by a reversed phase evaporation method and in
(87). Chitosan coated poly (epsilon-caprolactone) nanopar- vivo pharmacokinetic evaluation was performed in a rabbit
1204 Gaudana,Jwala, BodduandMitra
model.PermeabilityofGCVsolutionwascomparedwiththe oped. It released the drug independent of pH resulting in
liposomal formulation containing GCV. Transcorneal perme- significant enhancement of ocular bioavailability (108, 251).
abilityandareaunderthecurve(AUC)werewas3.9and1.7 Niosomalformulationofcoated(chitosanorcarbopol)timolol
fold higher than the solution. Ocular tissue distribution was maleateexhibitedsignificantIOPloweringeffectinrabbitsas
higher in the sclera, cornea and vitreous humor from comparedtotimololsolution.Anothernoveldeliverysystem
liposomal formulation (99). Vasoactive intestinal peptide known as discomes has been developed. These are large
(VIP) was formulated in liposomal formulation (VIP-Lip). structures witha size rangeof 12–16μm derivedby incorpo-
Concentration of VIP following intravitreal injection was rating nonionicsurfactantSolutan C24inniosomes. Amajor
about 15 times higher in ocular fluid than the concentration advantageofthissystemwaslesssystemicdrainagebecauseof
achieved by administration of VIP solution alone. The thelargesizeandlargeresidencetimeinthecul-de-sacdueto
peptide was effective only when formulated in liposomal theirdiscshape.Timololmaleatewassuccessfullyentrappedin
form (100). Ciprofloxacin (CPFX) was also formulated in discomesandniosomes.Invivobioavailabilityofthediscomes
liposomal environmental which lowered tear-driven dilution wasbetterthantheniosomes(109,251).
in the conjunctival sac. Multilamellar vesicles from lecithin
and alpha-L-dipalmithoyl-phosphatidylcholine were used to DENDRIMERS
prepareliposomecontainingCPFX.Thisapproachproduced
sustainedreleaseofthedrugdependingonthenatureofthe According to Sahoo et al., “Dendrimers are macro-
lipid composition selected (101). Acetazolamide was encap- molecularcompoundsmadeupofaseriesofbranchesaround
sulatedinliposomalformulationfordeliveryviatopicalroute. a central core. Their nanosize, ease of preparation, function-
Liposomes were prepared using reversed-phase evaporation alization and possibility to attach multiple surface groups
(REVs) and multilamellar vesicles (MLVs). Different molar render them suitable alternative vehicle for ophthalmic drug
ratios of phosphatidylcholine and cholesterol were added in delivery” (110, 111, 251). Previously, poly (acrylic) acids were
thepreparationofMLVswhichresultedinhigherentrapment prepared as bioadhesive polymers to achievebetter residence
efficiency as compare to REV. Entrapment efficiency time and decrease the frequency of administration. Major
ascended with higher amounts of lipid and charge inducers drawbacksassociatedwiththesesystemsareblurredvisionand
such as cholesterol and stearylamine. In-vivo intraocular formationofaveilleadingtovisionloss(112).Dendrimersare
pressure was examined for selective formulation and lip- liquid or semi-solid polymers and contain amine, carboxylic
osomes. MLVs exhibited prolong efficacy than liposomes andhydroxyl surfacegroups,whichkeep onincreasing as the
prepared byREV (102).Inanotherstudycationic liposomes generation number increases (G0, G1, G2, and so on).
containing herpes simplex virus type 1 (HSV-1) glycoprotein Dendrimersconsistingofpoly(amidoamine)(PAMAM)have
B (gB1s) or, DTK1 and DTK2 (two related polylysine rich been widely employed in drug delivery. This system of
peptides) were prepared and examined in the rabbit ocular branched polymers represent unique architecture, and can
model of HSV-1 keratitis. These peptides (antigen) in entrapbothhydrophilicandlipophilicdrugsintotheirstructure
liposomal formulation have the potential to act as very (113–115, 251). Selection of functional group on the surface
effective anti-HSV vaccine (103). In a similar manner, (amine, carboxylate and hydroxyl),sizeand molecular weight
liposomes of tilisolol were also prepared and studied follow- ofthedendrimerareimportantparameterstobeconsideredin
ingtopicalandintravitrealadministrations.Positivelycharged designingadeliverysystem.
liposomal formulation of tropicamide and oligolamellar lip- Dendrimerbasedapproachhasshownbetterbioavailabil-
osomes of ACV were generated. Both formulations resulted ity of pilocarpine and tropicamide, when DG1.5 and DG4.0
insignificantly higherabsorption acrossthecornea(104). (OH) dendrimers with carboxylate and hydroxyl surface
Antisense ODNs encapsulated in liposomes have been groups were instilled (116). Some of the researchers have
studied for their potential to treat ocular disorders. Various synthesizedwatersolubleconjugatesofD(+)-glucosamineand
factors need to be carefully considered before such a system D(+)-glucosamine 6-sulfate to obtain synergistic immuno-
isadoptedclinically.Intopicaldelivery,liposomemaynotbe modulatory and antiangiogenic effect by using anionic
able to release the entire payload of high molecular weight PANAM(G3.5)dendrimers(117).Theinvestigatorshavealso
ODNs relative to a free solution form (105). Liposomal shownsuccessfulincreaseinlongtermsurgeryaftertestingthe
formulation can release ODNs in a sustained manner formulation in a rabbit model of scar tissue formation after
following intravitreal injection (106). PEGylated liposome glaucoma filtration surgery. Cell-adhesion peptides were also
containing ODNs, results in higher percentage of intact attached to dendrimers which were later used to link with
ODNs (30% of the total dose) after 2 weeks. Some collagenscaffolds(118).Stratificationofcornealepithelialcell
researchers have formulated liposomes coated with an wasstudiedusingtheabovementionedcollagenscaffolds.All
envelope of inactivated hemagglutinating virus of Japan peptides have shown promoted effect on stratification. The
(HVJ) to treat CNV in rats. They successfully delivered same investigators have actively developed biocompatible
phosphorothioateODNstoinhibitVEGF (107). conjugates of dendrimers with collagen scaffolds to obtain
better mechanical property and adhesion ability. In another
NIOSOMES approach,dendrimersbasedapproachwasusedtodeliveranti-
VEGFODNandsuccessfullytestedinratstotreatCNV(119).
Niosomes are bilayered structural vesicles made up of Effectofsize,molecularweightandnumberofsurfacegroups
non-ionic surfactant which are capable ofencapsulating both (amine,carboxylateandhydroxyl)ofPANAMwasstudiedto
lipophilic and hydrophilic compounds. In a recent approach understand feasibility for its controlled release of pilocarpine
to deliver cyclopentolate, niosomal formulation was devel- nitrateandsometropicamide(116).
RecentPerspectivesin OcularDrugDelivery 1205
CYCLODEXTRINS lens was shown to be more beneficial to the patient with
hypoxia butalso foundtoform morelipid depositcompared
As per Sahoo et al., “Cyclodextrins (CDs) belong to a to the other. The same investigators have prepared silicon
group of cyclic oligosaccharides capable offorming inclusion basedhydrogelusingdifferentratiostosustainthereleaseof
complexes with many guest molecules (120). Through CD the timolol, dexamethasone, and dexamethasone 21-acetate
complexation,aqueoussolubilityofhydrophobicdrugscanbe over the time of several weeks to 3 months (131). The
enhanced without changing their molecular structure and different ratios of monomers could be changed depending
their intrinsic ability to permeate biological membranes upon the delivery required. The prepared lenses were also
(251)”. Molecules having low aqueous solubility have been studied for its mechanical and physical properties. The
delivered as CD complexes. These complexes have been residencetimeofasystemcouldbelengthenedbysuspending
proven to increase corneal permeation of drugs like dexa- nanoparticulate based drugs in thermogelling polymers. The
methasone, cyclosporine and so on. CD complexation contact lens, containing a nanoparticulate based drug, is an
approach can significantly increase ocular bioavailability of attractive alternative to the topical drug delivery, especially
poorly water soluble drugs. In some cases such inclusion eye drops (3, 132). A major benefit of this strategy is to
complexes can impart aqueous stability to drugs within the prolong residence time in post tear film which in case of
formulationaswell(121).Recentlyastudywascarriedoutto topicaldropsisjustafewminutes.Duetoincreasedresidence
determine relative concentration of dexamethasone in CDs time in eye, drug permeation through the cornea is higher
following topical and systemic absorption in the rabbit eye. with specific delivery of the drug to targeted tissue. In
Investigators observed a significant amount of drug reaching another study, drug molecule entrapped in a nanoparticulate
totheposteriorsegmenttissuelikeretinaandvitreoushumor system was later dispersed in lens made up of poly-2-
following topical application of eye drops. Such an approach hydroxyethyl methacrylate (p-HEMA) hydrogels. This ap-
might be very valuable in the treatment of vitreoretinal proach provide controlled drug release over a few days and
diseases which require long term delivery of drug molecules deliveryratecouldbefurthermodulatedbychangingloading
(122).Inanother study,theresearchers haveprepared inclu- doseoftheparticlesin thegel(133).
sion complex of HP-β-CD with zinc diethyldithiocarbamate
and disulfiram which resulted in higher corneal permeability INTRAOCULAR IMPLANTS
and also lower side effects like development of cataract
relative to drug alone (123, 124). In a similar approach, Implants have been widely employed to extend the
inclusion complexes were prepared with rhEGF/HP-β-CD releaseinocularfluidsandtissuesparticularlyintheposterior
whichweresuspendedinpoloxamergel.Thisformulationhas segment. Implants can be broadly classified into two catego-
resulted in significant increase in AUC of the drug. This ries based on their degradation property (1) biodegradable
approachhasanadditionaladvantageofimpartingstabilityto and (2) non-biodegradable. With implants, the delivery rate
the drug (125). Inclusion complexes of drugs like dexameth- could be modulated by varying polymer composition.
asone,dexamethasoneacetateandpilocarpinewithHP-β-CD Implantscanbeintheformofsolid,semi-solidorparticulate
resulted in higher bioavailability than the conventional eye based delivery systems (134). These implants have been
drops (126, 127). This complexation approach does not applied in the treatment of diseases affecting both anterior
disrupt the biological membrane compared to conventional and posterior segments of the eye. The diseases include
permeationenhancerlikebenzalkoniumchloride.Apartfrom anterior segment disorders like glaucoma filtering surgery
that,duetoinclusion,thefreedrugisnotavailable,sodrugs and posterior segment disorders like proliferative vitroretin-
withinherentirritantpropertiescanbesuccessfullydelivered opathy,CMVretinitis,endophthalmitis,andposteriorcapsule
bythisapproach.CDmoleculesareinertinnatureandHP-β- opacification. Table II summarizes the recent strategies of
CD (up to 45%) was found to be non irritant to the human formulatinganimplantforvariousocularpathologies.
andanimaleye(120). Drug release from Poly lactic acid (PLA), poly glycolic
acid (PGA) and poly lactic-co-glycolic acid (PLGA) usually
CONTACT LENSES followsthreephasesofdrugreleasewhichconstituteaninitial
burst, a middle diffusive phase and a final burst of the drug.
Liewen et al., reported an extensive study on polymeric In recent years, much attention has been paid to manipulate
hydrogels for contact lens-based ocular drug delivery (128). releaseprofilestoachievelongerdurationofreleasefromthe
Traditionally used soaked contact lenses provide a drug implants (135, 136). In one study, two PLA monomers of
release for a few hours. Current challenges in this mode of differentmolecularweightwereusedindifferentratiosand,a
drugdeliveryaretosustainreleaseforlongerperiodandalso pseudo-zero order release was obtained with minimum burst
to incorporate sufficient drug amounts in the lens matrix. effect(137).Recently,co-polymerizationofcaprolactonewith
Recently, surfactant loaded (Brij 98) poly-hydroxy ethyl poly-glycolide-co-lactide lead to the development of glyco-
methacrylate (p-HEMA) gel has shown sustained release of lide-co-lactide-co-caprolactonecopolymer(PGLC)whichwas
cyclosporine-A(129).Ina similar approach,dexamethasone, successfullyappliedtotreatcornealallograftanduveitis(138,
dexamethasone 21-disodium phosphate and dexamethasone 139). Polyanhydrides have also been utilized for these
21-acetate were suspended in p-HEMA based gel to achieve indications (140). Polyorthoesters (POE) are hydrophobic in
controlled release (130). The bioavailability of the formula- natureandusuallydegradebysurfaceerosionthusproviding
tion was found to be better than the topical eye drops. In a zeroorderreleasekinetics.Amongthefourgenerations,third
differentkindofapproach,twodifferentkindofsiliconeand generation POE forms gel like matrix at room temperature.
hydrogellens werecomparedfor1 month.Thesiliconbased Fourth generation POEs have gained much attention cur-
1206 Gaudana,Jwala, BodduandMitra
TableII. ImplantsfortheTreatmentofOcularPathologies
Drug Polymer Characteristic/treatment Ref
Episcleralimplantofbetamethasone PVA-EVA Zeroorderreleaseupto4weeks (204)
Triamcinoloneacetonide(TA) PVA ControlsCNVinaratmodel (205)
Dexamethasonescleralimplant(Surodex®) PLGA Afterphacotrabeculectomysurgery (206)
Intracameralimplantofcyclosporine PLGA Preventscornealgraftrejectionor (207)
post-operativeinflammationinrats
5-Fluorouracil(5-FU) POE Lesstoxicityandpersistencebleb (208)
forlongertime
Combinationofdrug5-fluorouridine,TAand PLGA TreatmentofPVRafterintravitreal (209)
recombinanttissueplasminogenactivator injection
Cis-4-hydroxyproline PLGA65/35+PLGA50/50 TreatmentofPVR (210)
SubretinalimplantofsirolimusandTA Polybutylmethacrylate,poly Treatmentofocularinflammation (211)
ethylene-co-vinylacetate
Intravitrealimplantoffluocinoloneacetonide PVA Controlledreleaseformorethan (212)
1yeartotreatsevereuveitis
FK506 PGLC Prolongationofcornealallograft (139)
survival
CyclosporineA PGLC Treatmentofuveitis (138)
Intracameralimplantofdexamethasone Cornealgraftrejection (213)
ScleralimplantsofGCV PLA CMVretinitis (137)
ScleralimplantofEthacrynicacid(ECA) PLGAfilms ToreduceIOPfor10days (214)
CyclosporinA(OculexDrugDeliverySystem) PLGA Prophylaxisandtreatmentofcorneal (215)
transplantrejectioninhumans
Dexamethasone PLGA Anteriorsegmentdrugdeliverysystem (216)
inpatientsafterphacoemulsification
Intracapsularringreleasing5-FU – Preventingposteriorcapsuleopacification (217)
(PCO)inrabbiteyes
Heparin PLGA Posteriorcapsularopacification(PCO) (218)
inrabbits
PVA–EVAPolyvinylalcohol–ethylenevinylacetate,PVApolyvinylalcohol,PGLCployglycolide-co-clatide-co-caprolactonepolymer,PLGA
polylatide-co-glycolide-acid,PLApolylacticacid,POEpolyorthoesters
rently because of their slow erosion property due to the mostwidelyusedpolymer,containthehydrophobicpartinthe
presenceoflatentacidinthepolymerbackbone(141). centre surrounded by a hydrophilic part. Though they are
Recently, researchers have also focused on intravitreal widely employed to enhance the residence time, they suffer
injectionofimplantusingcellencapsulationtechnology.FGF- from a major drawback of having weak mechanical strength,
2 implant embedded in AN69 copolymer delayed photore- rapid erosion and non-biodegradability (148). Many attempts
ceptor degeneration (142). Various synthetic polymers like havebeenmadetoaddressthisproblem.Oligomerizationwas
polyether sulfone, caprolactone and polyvinylpyrrolidone carried out to change the critical gelling temperature. In case
were developed and then positioned with a titanium anchor of cellulose derivative like HPMC, gelation is a result of
in the vitreous cavity (143). In a similar study, ciliary interactionofhydrophobiccomponentsathighertemperature
neurotrophic factor (CNTF) was released from cells (149). Pilocarpine formulation has shown enhanced miotic
implantedwithoutanysideeffectsforseveralweeks.Adose responseatlowerconcentrationofxyloglucanthanpoloxamer
dependent protective effect on photoreceptors was noticed 407 (150). Pseudolatexes are artificial latexes obtained by
withCNTFinrabbits(144).AnoveldeviceECTNT-501was dispersing pre-existing polymers in aqueous medium. They
developedtosupporttheimplantedcells(145).Afterloading offer physical stability of gel along with the drug molecule
CNTF secreting cells in the device, a controlled release of whicharesensitivetoaqueousmedia(151).
proteinwasobservedfor1yearintherabbiteye.Inaclinical In a different sort of gel approach also known as
trial, this device appeared to protect photoreceptors in ATRIGEL, a polymer is dissolved in a suitable carrier. The
severalpatients(146). polymer and carrier are both biodegradable and biocompat-
ible. Once injected into the subcutaneous space, water in
HYDROGELSYSTEMS surrounding tissue causes the precipitation of polymer which
immediately entraps the drug and releases it in a controlled
These are three-dimensional, hydrophilic, polymeric net- manner(www.qltinc.com).Theinventorsoftheproducthave
workscapableofimbibinglargeamountsofwaterorbiological claimedtousethissystemforawidevarietyofmoleculesi.e.
fluids. Nanjawade et al., have extensively reviewed hydrogels proteins and peptides. Targeted delivery of drugs, compati-
in ocular delivery (147). Residence time can be significantly bility with a wide variety of molecules, potential to achieve
enhanced with a hydrogel formulation. The gelation can be controlledreleaseandbiocompatibilitywerethekeyfeatures
obtained by changing temperature and pH. Poloxamers, the ofthesystem(www.qltinc.com).Currentlymarketedproduct,