When nanotechnology meets the ocular surface

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    10.1586/17469899.3.3.325 2008 Expert Reviews Ltd ISSN 1746-9899 325www.expert-reviews.com

    When nanotechnology meets the ocular surfaceExpert Rev. Ophthalmol. 3(3), 325332 (2008)

    Claudio Bucolo, Adriana Maltese and Filippo DragoAuthor for correspondenceDepartment of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy Tel.: +39 095 738 4227bucocla@unict.it

    Controlled and sustained delivery of drugs for ophthalmic diseases continues to remain amajor challenge in the field of pharmaceutical drug delivery. To overcome the problems ofconventional ocular therapy, such as short residence time, drug drainage and frequentinstillation, newer drug-delivery systems are being explored to improve the ocularbioavailability of the drug. In this review, research concerning nanoparticles for topical drugdelivery is discussed. We highlight cutting-edge drug-delivery nanotechnologies that improvethe efficacy of current drug-delivery methods or ameliorate the delivery of novel therapeutics.

    KEYWORDS: delivery system nanotechnology ocular drug ocular surface topical ocular route

    The eye consists of two anatomical regions, theanterior (cornea, conjunctiva, sclera and anterioruvea) and posterior (retina, vitreous and choroid)segments. Since they are different and atypicalstructures, challenges for delivering therapeuticdrugs to each of the areas are unique. For anteriorsegment drug delivery, common routes ofadministration include topical instillation andsubconjunctival injection [1,2]. Despite the devel-opment of advanced drug-delivery systems, suchas Ocusert, for sustained topical ocular drugdelivery, eye drops continue to be the most popu-lar drug-delivery system for ophthalmic drugs.This is due to their ease of preparation and theconvenience of self-administration and, thus,patient acceptance. The major problem in oculartherapeutics is the attainment of an optimal drugconcentration at the site of action. Bioavailabilityof drugs from eye drops is severely impeded by ashort precorneal residence time of the drug,mainly due to mechanisms of the eye that protectfrom foreign materials, such as reflex blinking,lacrimation, tear turnover and drainage. Inhumans, approximately 50% of a 2530 l dropof buffered saline is estimated to be cleared in1.3 min [3]. Moreover, the very tight epitheliumof the cornea compromises the permeation ofdrug molecules. Consequently, only a small frac-tion of the administered drug, approximately 1%of the instilled dose, penetrates passively acrossthe cornea and reaches the intraocular tissues [4].This forces clinicians to recommend frequentinstillation of eye drops to maintain therapeuticdrug levels in the tear film or at the site of action,

    resulting in several side effects. In order to over-come the problems of conventional ocular ther-apy, such as short residence time, drug drainageand frequent instillation; newer drug-deliverysystems are being explored to improve the ocularbioavailability of the drug. In general, ocular bio-availability may be enhanced by increasing cor-neal drug penetration and prolonging precornealresidence time of instilled drugs. Variousapproaches, such as viscosity enhancement, useof mucoadhesive agents, hydrogels, microparti-cles, nanoparticles, microemulsions, liposomeand prodrugs have been studied.

    In this review, research work on nanoparticlesfor topical drug delivery will be discussed focus-ing on in vivo studies that have been publishedduring the last 10 years.

    Structural obstacles & protective mechanisms against ocular drug delivery

    Topical delivery into the conjunctival cul-de-sacis the most common route of ocular drug deliv-ery (FIGURE 1). Despite its apparent easy accessibil-ity, the eye is well protected from foreign mate-rials, including therapeutic substances, by anumber of very efficient mechanisms such asblinking, induced lacrimation, tear turnoverand nasolacrimal drainage, which cause rapidremoval of substances from the eye surface, andby the cornea, which forms the physicalbiolog-ical barrier. Consequently, these protectivemechanisms and structural obstacles may causesubtherapeutic drug levels at the intended site.

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    Under normal conditions, the humaneye can hold approximately 30 l of anophthalmic solution; however, after asingle blink the volume is reduced to710 l through nasolacrimal drainage,which causes the drug to be systemicallyabsorbed across the nasal mucosa or theGI tract [4]. A significant systemic lossfrom topically applied drugs also occursfrom conjunctival absorption into thelocal circulation. Tear turnover, whichcan also be stimulated by factors such asthe pH and the tonicity of the formula-tion, remove drug solution from theconjunctival cul-de-sac in a few minutes.

    The limited permeability of the corneaalso contributes to the low absorption ofocular drugs. The cornea consists of fivedistinct layers, with three of them epi-thelium, stroma and endothelium beingthe main barriers to absorption. Thelipophilic corneal epithelium contains fiveto seven layers of cells, each connected bytight junctions, and represents the rate-limiting barrier for transcorneal diffusionof most hydrophilic drugs; on the con-trary, the stroma which is mainly com-posed of hydrated collagen exerts a dif-fusional barrier to highly lipophilic drugs.The endothelium is not a significant bar-rier to the transcorneal diffusion, in factits permeability depends on molecularweight and not on the nature of com-pound. Typically, 110% of the instilleddose is absorbed ocularly and less than 1%reaches the aqueous humor [5].

    Approaches to improve ocular bioavailability

    Ocular bioavailability may be enhanced by two strategies;increasing contact time of the drug with the eye surface andpromoting the transfer of drug molecules from the tear intothe eye tissue without causing any inconvenience to thepatient. Patient compliance and comfort considerations indrug instillation, in addition to the matter of bioavailability,must be taken into account in the evaluation of drugs thera-peutic efficacy. Various improved methods have focused onoptimizing drug residence time, prolonging the precornealdrug retention by the use of controlled-release drug-deliverysystems, such as implantable systems, Ocusert and collagenshields, but they have the limitation of poor patient compli-ance. Viscosity enhancers have been used in ophthalmic for-mulation to retain drugs on the eye surface for longer time;

    however, problems can occur associated with viscous solutionduring manufacture and administration such as blurredvision. Liposomes have been extensively investigated as oculardrug-delivery vehicles, but the problem associated with lipo-somes are possible toxicity and irritability, as well as formulationstability [69].

    In order to overcome these problems, micro- and nano-technology involving drug-loaded polymer particles have beenproposed as ophthalmic drug-delivery systems that may controldrug release and maintain therapeutic levels over a prolongedperiod of time [10].

    These systems consist of microcapsules, microspheres, nano-spheres and nanocapsules. Particles ranging from 100 nm to sev-eral nanometers comprise the microparticles. Nanoparticles pos-sess similar characteristics as microparticles, but their size is smallerthan 1 m.

    Figure 1. Movement of drug into the eye on instillation of a formulation.

    Drop

    Kloss: 9099% Kabs: 110%

    Anterior segment

    Aqueous humor

    Cornea

    Precorneal area

    Tear turnover Instilled solution drainage Conjunctival absorption Metabolism Protein binding

    Expert Rev. Ophthalmol., Future Science Group Ltd (2008).

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    Nanoparticle formulations

    Nanoparticles are polymeric colloidal drug-carrier systems,with a size ranging from 10 nm to 1 m [11], in which drugs aredissolved, entrapped or encapsulated, or to which the drugs areadsorbed or attached. Nanoparticles are subdivided into twogroups: nanospheres and nanopcapsules [12]. Nanospheres aresmall solid monolithic spheres constituted of a dense solid poly-meric network, which develops a large specific area [13]. Nano-capsules are small reservoirs consisting of a central cavity sur-rounded by a polymeric membrane in which molecules may bedissolved in an oily core or adsorbed to a surface interface. Sev-eral procedures are used for the preparation of nanoparticlesand we direct the readers to the book coedited by Gupta andKompella for specific details [2].

    Properly formulated nanoparticles achieve sustained drugrelease and prolonged therapeutic effect if the formulation isretained in the cul-de sac after topical administration for a suitableperiod of time, and the drug is released from the nanoparticles ata proper rate.

    The success of nanoparticle systems for ocular drug deliv-ery may depend on optimizing lipophilichydrophilic prop-erties of the polymerdrug system, optimizing rates of bio-degradation in the precorneal area and enhancing theretention efficiency. Polymers used for the preparation ofnanoparticles should be mucoadhesive and biocompatible.The choice of polymer plays an important role in the releasekinetics of the drug from a mucoadhesive nanoparticle sys-tem. Ocular bioavailability from a mucoadhesive dosage formwill depend on the polymers bioadhesion properties, whichare affected by its swelling properties, hydration time, molec-ular weight and degree of crosslinking. The polymers used inophthalmic drug formulations are poly(alkyl cyanoacrylates)(PACA) [14], poly(caprolactone) (PCL) [15,16], poly(lactic acid)(PLA) [17], poly(lactic-co-glycolic acid) (PLGA) [18], chitosan(CS; linear polysaccharide of randomly distributed -(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine) [1923],Eudragit RL100 and Eudragit RS100 (poly[ethylacrylate,methyl-methacrylate and chlorotrimethyl-ammonioethylmethacrylate] copolymer) [2429], poly(acrylic acid) (PAA)and hyaluronic acid [30], and modified polystyrene [31]. In sev-eral cases, albumin [3233], gelatin [34] or lipid matrix [35,36] arealso used. To be used topically the polymers utilized for thepreparation of the nanoparticle ophthalmic formulationshould be transparent and comfortable for patients, andshould fulfill the requirements of controlled degradation timeand minimal inflammatory or toxic potential [11]. It has beenshown that the surface charge of the nanoparticles and bind-ing type of the drug onto the nanoparticles were much moreimportant parameters than the drug adsorption percentageonto nanoparticles. Since both cornea and conjunctiva pos-sess negative surface charge, it is expected that cationic nano-particles may penetrate through the negatively charged oculartissues more efficiently than anionic carriers [37]. Of the listed

    polymers only CS and Eudragit generate nanoparticles withpositive charge, while all other polymers result in negativelycharged nanoparticles.

    In drug-loaded nanoparticles, the active molecules are con-fined within polymeric matrices by relatively strong noncovalentinteractions, such as ionic, hydrogen bonding, hydrophobic ordipole. The solid nanoparticles are formulated, by reconstitu-tion in water or buffer solution, as nanosuspensions in a contin-uous aqueous phase, thus maintaining positive or negative sur-face charges both in the reconstituted nanosuspensions and inbiological fluids.

    The destination of nanoparticles in the body depends ontheir physicochemical properties, such as pH, surfactant andstabilizer, which influence the mucoadhesion properties to theocular membrane and modify the precorneal retention of thenanoparticles [38]. It has been shown that the molecular weightof the polymer influences the residence time of nanoparticles inthe precorneal area [39]. As the molecular weight increases, thepolymer becomes poorly retained, whereas low-molecular-weight polymers are retained for a longer time. The ocular bio-availability of several drugs was studied predominantly in ani-mals after topical administration (TABLE 1). In a study byDe Campos and colleagues, three different ciclosporin A (CsA)formulations CsA-loaded CS nanoparticles, a CsA suspensionin a CS aqueous solution and a CsA suspension in water weretopically administered to New Zealand albino rabbits [19]. Theyshowed that animals treated with CsA-loaded CS nanoparticleshad a significantly higher corneal and conjunctival drug levelsthan those treated with the suspension of CsA in CS aqueoussolution or in water (two- to sixfold increase).

    Surprisingly, no significant effect was observed for the CSsolution containing CsA in terms of conjunctival and cornealretention under the experimental conditions used. Indeed,no evident differences were found between CsA levels in ani-mals treated with CsA suspension in a CS aqueous solution,and a CsA suspension in water. It is also interesting to notethat for all three formulations the corneal and the conjuncti-val levels demonstrated a maximum at 2 h after administra-tion and decreased gradually afterwards. The key differencewas that at 24 h postdosing of the CS solution, the CsA con-junctival concentration descended to subtherapeutic levels,whereas with CS nanoparticles, these levels were sufficientlyhigh to modulate the local immune response and to suppressinflammatory processes.

    Many polymers in nanoparticle technology have been modi-fied in order to improve their properties. Yuan and colleaguesmodified CS by covalent coupling with cholesterol; obtaining1.74.7 cholesterol groups for each 100-anhydroglucosaminefunction [20]. These molecules self aggregate into nanoparticleswith a size of approximately 200 nm. Ciclosporin was incorpo-rated with a drug loading of 6.2%. Using single photon emis-sion computed tomography (SPECT) and scintillation counter,the authors demonstrated that, after 112 min, 71% was stillpresent at the ocular surface.

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    PLA and PLGA are widely used as building blocks for nano-carriers owing to their biocompatibility and biodegradability.Giannavola et al. modified the surface properties of PLA nano-particles loaded with acyclovir by incorporating pegylated1,2-distearoyl-3-phosphatidyllethanolamine (DSPE-PEG) intothe polymer instead of coating the external surface, as in thecase of PACA nanoparticles [17]. The ocular bioavailability ofacyclovir-PLA nanospheres was evaluated in New Zealandrabbits following a single topical instillation and comparedwith the bioavailability of free drug aqueous suspension. ThePLA nanospheres showed significantly higher drug levels com-pared with the free drug formulation and provided a sustainedrelease of drug in the aqueous humor, with respect to the freedrug, by ensuring effective acyclovir levels for up to 6 h. Thearea under the concentrationtime curve values were signifi-cantly greater for the PEG-coated PLA nanospheres than foruncoated PLA nanospheres and the free drug suspension(1.8-fold and 12.6-fold increase, respectively). The pharmaco-kinetic profile of acyclovir nanospheres showed a controlleddrug release, which could be elicited by the colloidal carriermucoadhesion on the cell surface, thus allowing a long ocularpermanence and a prolonged release in comparison with thedrug suspension. The increase of acyclovir bioavailability pro-vided by PEG-coated PLA nanospheres could be due to animproved mucoadhesion and an enhancer effect. The possiblepenetration enhancer effect seems to be a nanosphere-medi-ated phenomenon because a simple mixture of PEG-coatedPLA nanospheres and acyclovir determined no significantincrease in drug penetration compared with free acyclovir.

    Eudragit Retard polymer nanoparticle suspensions have beenreported in several studies to represent a valid carrier system forthe ophthalmic release of nonsteroidal anti-inflammatorydrugs, such as ibuprofen and flurbiprofen [2426]. Pignatelloet al. demonstrated that Eudragit RS100 nanoparticle suspen-sions loaded with ibuprofen or flurbiprofen were able to signif-icantly inhibit the miotic response induced by surgical traumain the rabbit eye [24,25]. A series of polymeric nanoparticle sys-tems were obtained by codispersion of drug and polymer inwater. The resulting nanosuspensions showed interesting meansizes for ophthalmic application and a positive surface chargethat can help corneal adhesion. In the in vivo test on rabbit eye,the nanosuspension containing 0.1% ibuprofen showed a verygood ocular tolerability. The comparison with an aqueous solu-tion of ibuprofen lysine salt showed that the nanoparticle sys-tem is able to give a gradual and prolonged release of the drugand an increased retention to the corneal surface, whichresulted in a higher drug levels in the aqueous humor.

    Poly(lactic-co-glycolic acid) nanoparticles incorporating flurbi-profen were prepared by Vega et al. using poloxamer 188 as a stabi-lizer to improve the bioavailability of the drug for the prevention ofthe inflammation caused by ocular surgery [18]. In vivo anti-inflam-matory efficacy was assessed in the rabbit eye after topical instilla-tion of sodium arachidonate. Nanoparticle formulations werecompared with commercial eye drops after induction of inflamma-tion. The commercial eye drops showed a suppression of inflam-mation, with minimal inflammation reached after 90 min, whereasPLGA nanoparticles demonstrated a higher suppression thatincreased throughout the 150-min observation time of the study.

    Table 1. Recent in vivo studies of topical nanoparticle delivery in the eye.

    Drug Materials Type of study Ref.

    Acyclovir PLA coated with PEG Pharmacokinetic [17]

    Cloricromene Eudragit RL Toxicity; pharmacokinetic [27]

    Ciclosporin A CS Pharmacokinetic [19]

    Ciclosporin A CS coupled with cholesterol Pharmacokinetic [20]

    Dexamethasone Hydroxyethylcellulose Efficacy; pharmacokinetic [51]

    Flurbiprofen Eudragit RS Efficacy; toxicity [24]

    Flurbiprofen PLGA Efficacy [18]

    Hydrocortisone Hydroxyethylcellulose Efficacy; pharmacokinetic [51]

    Ibuprofen Eudragit RS Efficacy; toxicity; pharmacokinetic [25,26]

    Methylprednisolone Eudragit RS Efficacy [29]

    Piroxicam Eudragit RS Efficacy [28]

    Prednisolone Hydroxyethylcellulose Efficacy; pharmacokinetic [51]

    Tobramycin F-SLN Toxicity; pharmacokinetic [35]

    None LCS-NP Toxicity [21]

    CS: Chitosan; F-SLN: Fluorescent solid lipid nanoparticles; LCS-NP: Liposomes and chitosan nanoparticles; PEG: Poly(ethylene glycol); PLGA: Poly(lactic-co-glycolic acid); PLA: Poly(lactic acid).

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    By using the quasi-emulsion solvent-diffusion technique,we obtained Eudragit RL nanoparticles containing cloricro-mene, a coumarine derivative drug, with a mean particle sizeof 80 nm and positive zeta-potential values [27]. Topical appli-cation of the new formulation based on Eudragit nanoparti-cles to the rabbit eyes showed no sign of toxicity or irritationto ocular tissues. In vivo evaluation demonstrated that thepolymeric colloidal drug delivery system made up of EudragitRL is able to enhance the concentration of cloricromene inrabbit aqueous humor, improving the bioavailability of thedrug compared with the conventional aqueous drug solution(1.7-fold increase).

    Adibkia and colleagues formulated nanoparticles withEudragit RS and piroxicam and investigated the anti-inflamma-tory effect of the drug in rabbits with endotoxin-induced uveitis(EIU) [28]. The in vivo examinations revealed that the inflam-mation could be inhibited by the Eudragit RS nanoparticlescontaining piroxicam more efficiently than the microsuspensionof the drug alone. In another work by the same group methyl-prednisolone acetate nanosuspension were prepared withEudragit RS [29]. The evaluation of the clinical symptoms ofuveitis showed a significant reduction of redness, presence offibrin, photophobia and lacrimation, with the maximum inhib-itory effect from the methylprednisolone nanosuspension for upto 36 h, compared with the control eyes and those treated withdrug alone. A higher inhibition of leukocyte migration (up to36 h) and protein infiltration into the aqueous humor (up to24 h) was found for the methylprednisolone nanosuspensionthan the drug-alone suspension (up to 12 h).

    An interesting alternative to traditional colloidal carriers isrepresented by solid lipid nanoparticles (SLN), whose systemconsists of lipid nanoparticles, solid at room temperature,which are dispersed in an aqueous surfactant solution [40]. In astudy by Cavalli and colleagues, the residence time of fluores-cent solid lipid nanoparticles (F-SLN) in rabbit eyes was deter-mined, and the tobramycin concentration profile in the aque-ous humor was determined after topical administration torabbits of SLNs containing tobramycin as an ion complex withhexadecyl phosphate [35]. They showed that the F-SLN disper-sion was perfectly tolerated and formed a stable precorneal film,and was retained longer in the eye, while the fluorescent solu-tion formed a short-lived, weakly fluorescent film on the cor-neal surface and disappeared rapidly from the eye surface.Moreover, after administration to rabbit eyes of SLN contain-ing tobramycin, the concentration of the drug in aqueoushumor was significantly higher with respect to a commercialformulation of tobramycin, with a fourfold area under thecurve increase.

    The efficacy of a formulation containing biodegradable cal-cium phosphate nanoparticles (CAP) and 7-hydroxy-2-dipro-pyl-aminotetralin (OH-DPAT) and a dopamine D2/D3 recep-tor agonist, was evaluated in pigmented and nonpigmentedrabbits by Chu and collegues, investigating its action in low-ering intraocular pressure (IOP) and suppressing aqueous

    humor flow [41]. The decrease of IOP induced by topicaladministration of 7-OH-DPAT with CAP in both non-pigmented and pigmented rabbits was more pronounced andsustained than that of the drug alone. Furthermore, IOP-low-ering effects of 7-OH-DPAT alone were markedly diminishedin pigmented compared with nonpigmented rabbits. It waspresumed that the drug alone binds to pigments in the ante-rior segment of the pigmented rabbits eyes and this bindinglimits the action of 7-OH-DPAT. It was concluded that CAPcould act as drug carrier, thereby preventing the binding ofdrug to the pigment.

    Diebold et al. studied a class of colloidal system (liposomesand chitosan nanoparticles [LCS-NP]) that combines lipo-somes and CS nanoparticles as a potential drug-delivery sys-tem [21]. This nanosystem was prepared using a technique thatallowed the coating of CS nanoparticles with a phospholipidshell. They showed that LCS-NP formulations were well tol-erated in rabbit. The clinical macroscopic sign score was com-patible with a nonirritated ocular surface as expected, takinginto account the ocular tolerance previously reported for CS-NP and liposome [22,42]. Enrquez de Salamanca et al. testedin vivo the ocular tolerance to CS-NP labelled with fluores-cein isothiocyanate-bovine serum albumin (FITC-BSA) [22].The absence of histological alterations and abnormal inflam-matory cells in cornea, conjunctiva and lids was consistentwith the lack of clinical sign on exposure to CS-NP. Anotherin vivo study of ocular tolerance was performed by Salgueiroet al. [43]. They developed several formulations of cyclophos-phamide-loaded polybutylcyanoacrylate (PBCA) nano-spheres, which indicated a good tolerance for an ophthalmicapplication as an immunosuppressive agent.

    Poorly water-soluble compounds are difficult to formulateusing conventional techniques. In addition to the use of cyclo-dextrins, microemulsions, hydrogels and polymeric micelles[4450], the use of nanotechnology to formulate poorly water-soluble drugs as nanosuspensions offers the opportunity toaddress many of the deficiencies associated with this class ofmolecules. In a study by Kassem and coworkers [51], three insol-uble glucocorticoid drugs, hydrocortisone, prednisolone anddexamethasone were formulated as nanosuspensions. Theauthors studied the effect of particle size in the micro- andnanosize ranges, as well as the effect of viscosity of the nanosus-pension on the ocular bioavailability, measuring the IOP ofnormotensive rabbits. The increase in IOP was taken as a toolfor evaluation of the corticosteroid drug effect. For each drug,they prepared a drug solution, two drug suspensions of differ-ent mean particle diameter in the microsize range and one for-mulation in the nanosize range. Results showed marked differ-ences between the mean percentage increase in IOP/timeprofile of the drug solutions and suspensions and these differ-ences increased with decreasing the particle diameter. The great-est increase occurred after instillation of the nanosuspensions,which nearly doubles the percentage maximum increase in IOP(IOPmax) observed for the solution. The nanosuspensions

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    enhanced the rate and extent of ophthalmic drug absorption aswell as the intensity of drug action. The data confirmed thatnanosuspensions differed from microcrystalline suspensionsand solution as ophthalmic drug-delivery systems, and that thedifferences were very highly and highly statistically significant.

    Expert commentary

    In general, the principal goal of all pharmacotherapeutics isto obtain an effective drug concentration at the site of actionfor an appropriate period of time in order to recieve theexpected pharmacological response. Specifically, the poorbioavailability of drugs from ocular pharmaceutical formsmakes drug delivery particularly relevant in developing newsystems. Ophthalmic drug delivery, more than any otherroute of administration, may benefit to a full extent from thecharacteristics of nanosized drug particles. The nanotechnol-ogy applied to ocular drug-delivery systems broughtundoubted advantages such a higher solubility, higher areaavailable for dissolution, higher dissolution rate, higher bio-adhesion and corneal penetration, lower tearing and drain-age of instilled dose. The published works on topical nano-ocular drug-delivery systems indicated the great potentialityof nanotechnology in ophthalmic clinical practice. However,even though large amounts of research have been carried outon nanosized systems in ocular drug delivery, some issuesremain to be solved. One of the major problems is the rapidclearance, which, in some cases, is more rapid than therelease of the drug. Another major issue is the correlationbetween human and animal studies. In general, the most-used animal species in the ocular field is the rabbit. The rab-bit eye is comparable to the human eye in terms of size but ithas substantial differences such as lower tear production,higher surface sensitivity, lower blinking frequency, andhigher mucous production. Taken together these factorscould likely improve mucoadhesiveness and reduce clearancefrom the ocular surface, and ultimately increase the ocularresidence time that could be not superimposable in humans.

    Five-year view

    The last 5 years have seen the highest publication of scientificarticles on nanoparticles and the eye than ever before. However,even though a large amount of research has been performed onnanoscaled drug-delivery systems in anterior ocular drug deliv-ery, little work in vivo has been accomplished and no clinicalstudies have been performed.

    We believe that the next 5 years will see a tremendousincrease of work in this field, with a multidisciplinaryapproach (ophthalmology, biomaterial science, pharmacologyand pharmaceutical science) that will bring clinical use of thesenew nanosystems.

    Financial & competing interests disclosure

    The authors have no relevant affiliations or financial involvement withany organization or entity with a financial interest in or financialconflict with the subject matter or materials discussed in themanuscript. This includes employment, consultancies, honoraria, stockownership or options, expert testimony, grants or patents received orpending, or royalties.

    No writing assistance was utilized in the production of this manuscript.

    Key issues

    The common goal of all pharmacotherapeutics is to achieve an effective drug concentration at the intended site of action for a sufficient period of time and reducing side effects.

    In ocular pharmacotherapeutics, traditional drug delivery has limited bioavailability due to ocular tissues barriers, tear turnover, lacrimal drainage and reflex blinking.

    Drug residence time on the ocular surface is increased by the use of nanosystems.

    Nanotechnology provides sustained drug release and prolonged therapeutic effect.

    A multidisciplinary approach is the key to success in ocular nanotechnology.

    References

    Papers of special note have been highlighted as:

    of interest

    of considerable interest

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  • 332 Expert Rev. Ophthalmol. 3(3), (2008)

    Review Bucolo, Maltese & Drago

    44 Lallemand F, Felt-Baeyens O, Besseghir K, Behar-Cohen F, Gurny R. Cyclosporine A delivery to the eye: a pharmaceutical challenge. Eur. J. Pharm. Biopharm. 56, 307318 (2003).

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    46 Loftsson T, Stefnsson E. Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol. Scand. 80, 144150 (2002).

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    49 Nanjawade BK, Manvi FV, Manjappa AS. In situ-forming hydrogels for sustained ophthalmic drug delivery. J. Control. Rel. 122, 119134 (2007).

    50 Ebrahim S, Peyman GA, Lee PJ. Application of liposomes in ophthalmology. Surv. Ophthalmol. 50, 167261 (2005).

    51 Kassem MA, Abdel Rahman AA, Ghorab MM, Ahmed MB, Khalil RM. Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int. J. Pharm. 340, 126133 (2007).

    Affiliations

    Claudio Bucolo, PhDProfessor of Pharmacology, Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy Tel.: +39 095 738 4227bucocla@unict.it

    Adriana Maltese, MSFellow, Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Viale A Doria 6, 95125 Catania, ItalyTel.:+39 095 384 227adrimalt@yahoo.it

    Filippo Drago, MDProfessor of Pharmacology, Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Viale A Doria 6, 95125 Catania, ItalyTel.: +39 095 738 4236fdrago@tin.it

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