Controlled and sustained delivery of ophthalmic drugs continues to remain a major focus area in the field of pharmaceutical drug delivery with the emergence of new, more potent drugs and biological response modifiers that may also have very short biological half-lives. The major objective of clinical therapeutics is to provide and maintain adequate concentration of drugs at the site of action. In ocular drug delivery, the physiological constraints imposed by the protective mechanisms of the eye lead to poor absorption of drugs with very small fractions of the instilled dose penetrating the cornea and reaching the intraocular tissues. The reasons for inefficient drug delivery include rapid turnover, lacrimal drainage, reflex blinking, and drug dilution by tears (1,2). The limited permeability of cornea also contributes to the low absorption of ocular drugs. As shown in Figure 1, tear drainage causes a major portion of the administered dose to be transported via the nasolacrimal duct to the gastrointestinal (GI) tract, where it may be absorbed, leading to unwanted systemic side effects and occasional toxicity due to the drug (3). The rapid elimination of administered eye drops often results in a short duration of the ocular therapeutic effect, making a frequent dosing regimen necessary.

Current affiliation: Bristol-Myers Squibb Company, New Brunswick, New Jersey, U.S.A.

Fig. 1 Schematic diagram of ocular distribution. (From Ref. 3.)

Three main factors have to be considered when drug delivery is attempted to the intraocular tissues (4): (a) how to cross the blood-eye barrier (systemic to ocular) or cornea (external to ocular) to reach the site of action, (b) how to localize the pharmacodynamic action at the eye and minimize drug action on other tissues, and (c) how to prolong the duration of drug action such that the frequency of drug administration can be reduced. There is a clear need for effective topical formulations providing superior bioavailability of drugs along with a reasonable frequency of application, and the goals during the development of appropriate delivery systems should include increased contact time of the drug with the eye surface and promotion or facilitation of transfer of drug molecules from the tear phase into the eye tissue without causing any inconvenience to the patient. Approaches to optimize drug residence time have included prolongation of precorneal drug retention by the use of viscous gels, colloidal suspensions, and erodible or nonerodible inserts (5,6). Besides the issue of bioavailability, patient compliance and comfort considerations in drug instillation are very important factors that may impact the drug's therapeutic efficacy. Patient discomfort excludes inserts from the list of potentially popular drug delivery systems. Although adding soluble polymers to ophthalmic solutions can increase drug retention by increasing viscosity and decreasing the rate of drainage, there are problems associated with viscous solutions during their manufacture and administration that usually result in vision blurring, limiting their chances of becoming popular dosage forms. Liposomes have been extensively investigated as ocular drug delivery vehicles for over a decade as they offer potential benefits of controlled and sustained drug release and protection from metabolic processes while the therapeutic agent remains sequestered within the vesicles. But the problems associated with liposomes are possible toxicity and irritability. The primary factors that determine the relative toxicity of liposomes appear to be the lipid composition and irritability associated with the charge of liposomes (7-10). These factors may limit their chances of becoming popular ocular dosage forms of the future. Attempts to reduce systemic absorption have been made based on the design of prodrug derivatives with a higher lipophilic character (11-13). However, results obtained from these studies are inconclusive because most prodrugs are unstable in an aqueous solution.

In order to address the above-stated problems, micro- and nanotech-nology involving drug-loaded polymer particles has been proposed as an ophthalmic drug delivery technique that may enhance dosage form acceptability while providing sustained release in the ocular milieu (14). Particulate drug delivery consists of systems described as microparticles, nanoparticles, microspheres, nanospheres, microcapsules, and nanocap-sules. They consist of macromolecular materials and can be used therapeutically by themselves, e.g., as adjuvant in vaccines, or as drug carriers, in which the active principle (drug or biologically active material) is dissolved, entrapped, encapsulated, and/or to which active principle is absorbed, adsorbed, or attached. Particles ranging from 100 nm to the order of several hundred micrometers are included in the microparticulate category, which is divided into two broad groups (15): microcapsules are almost spherical entities of the order of several hundred micrometers in diameter where the drug particles or droplets are entrapped inside a polymeric membrane, and microspheres are polymer-drug combinations where the drug is homogeneously dispersed in the polymer matrix. Nanoparticles possess similar characteristics as microparticles, except their size is approximately three orders of magnitude smaller (< 1 ^m). Nanoparticles are also subdivided into two groups: nanospheres and nano-capsules (11). Nanospheres are small solid monolithic spheres constituted of a dense solid polymeric network, which develops a large specific area (16). The drug can be either incorporated or adsorbed onto the surface. Nanocapsules are small reservoirs consisting of a central cavity (usually an oily droplet containing dissolved drug) surrounded by a polymeric membrane. Several studies have shown nanoparticles to be more stable in biological fluids and during storage compared to other carriers that are similar in size distribution and controlled-release properties, such as liposomes. Furthermore, they can entrap and retain various drug molecules in their stable state.

Polymers used for the preparation of microparticulates may be erod-ible, biodegradable, nonerodible, or ion exchange resins (17). Nanoparticles made of nonbiodegradable polymers are neither digested by enzymes nor degraded in vivo through a chemical pathway (18). The risk of chronic toxicity due to the intracellular overloading of nondegradable polymers would be a limitation of their systemic administration to human beings, making these materials more suitable for removable inserts or implants. Erodible systems have an inherent advantage over other systems in that the self-eroding process of the hydrolyzable polymer obviates the need for their removal or retrieval after the drug is delivered. Upon the administration of particle suspension in the eyes, particles reside at the delivery site and the drug is released from the polymer matrix through diffusion, erosion, ion exchange, or combinations thereof (19).

Nanoparticles, when formulated properly, provide controlled drug release and prolonged therapeutic effect. To achieve these characteristics, particles must be retained in the cul-de-sac after topical administration, and the entrapped drug must be released from the particles at an appropriate rate. As mentioned before, the utility of nanoparticles as an ocular drug delivery system may depend on (19) (a) optimizing lipophilic-hydro-philic properties of the polymer-drug system, (b) optimizing rates of biodegradation in the precorneal pocket, and (c) increasing retention efficiency in the precorneal pocket. It is highly desirable to formulate the particles with bioadhesive materials in order to enhance the retention time of the particles in the ocular cul-de-sac. Without bioadhesion, nanoparti-cles could be eliminated as quickly as aqueous solutions from the precor-neal site. Bioadhesive systems can be either polymeric solutions (20) or particulate systems (21). With several pilot studies using natural bioadhesive polymers demonstrating promising improvements in ocular bioavail-ability, synthetic biodegradable and bioadhesive polyalkylcyanoacrylate systems were developed, and these may prove to be the most promising particulate ocular drug delivery systems of the future. Polyalkylcyanoacrylates gained popularity because of their apparent lack of toxicity, proven by decades of safe and successful use in surgery (22), which from a toxicological point of view is a very favorable characteristic for a preferred pharmaceutical drug delivery system.

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