The different factors that influence the permeability of drugs across the cornea are distribution coefficient (log DO/W), ionic equilibrium, and charge. Since the corneal epithelium is negatively charged above its isoelectric point (p! 3.2), cationic molecules with a log DO/W of 2 to 3 at pH 7.4 exhibit good permeation.73-80 The cornea has significant levels of various esterases, peptidases, proteases, and other enzymes that can limit the availability of drugs such as peptides but can transform pro-

drugs to active moieties.

A single layer of flat hexagonal cells of the corneal endothelium covers the posterior corneal surface and hydrates the cornea. The corneal endothelium can allow diffusion of molecules of dimensions up to 20 nm.65 The stroma has a highly organized hydrophilic tissue structure that comprises 90 percent of cornea.63 It has an open structure that can allow molecules up to 500,000 Da in size to pass through. However, the stroma may be a diffusion barrier to lipophilic drugs.65,84 Drug-melanin interactions such as the one with timolol can form a barrier and reduce bioavailability.85

In addition to the corneal route, topically applied ocular drugs may be absorbed via a noncorneal absorption route that involves drug transport across the bulbar conjunctiva and underlying sclera into the uveal tract and vitreous humor.65 The intercellular spaces of the conjunctival epithelium are wider than those of the corneal epithelium. As a result, the conjunctiva has higher permeability than the cornea to agents such as mannitol, inulin, and FITC-dextran.86 The penetration of peptides, however, is limited by enzymatic degradation.87 The limit of molecular size for conjunctival penetration is between 20,000 and 40,000 Da. Vitreous can act as an aqueous and unstirred diffusion barrier to drug permeation.64

Apart from physical barriers, topical drug delivery to eye is also affected by the volume, viscosity, pH, tonicity of vehicle, and type of drug. Constant drainage by tear fluid minimizes topical drug absorption and increases systemic absorption. As a result, only about 5 percent of total dose is effectively absorbed through the intraocular route, resulting in low ocular bioavailability and possible systemic side effects.65 Drug permeation also can be influenced by protein binding in the tear fluid (about 0.7 percent).63

The disadvantages of this route of administration include irritation, stinging, tear formation, and blurring of vision owing to mydriasis or miosis, which could result in patient noncompliance. Drug absorption enhancement has been achieved by increasing the lipophilicity of drugs through prodrug formation, periocular administration (which includes subconjunctival injection, subtenon's injection, etc.), and coadministration of different drugs.88

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