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

    Review Bucolo, Maltese & Drago

    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.


    Kloss: 9099% Kabs: 110%

    Anterior segment

    Aqueous humor


    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)(