Physicochemical Properties Of Drugs Affecting Permeability Across Ocular Barriers

Drug permeability prediction across the ocular tissues is important in the development of new drugs and drug-delivery strategies. To develop models that broadly predict permeability, it is necessary to understand the effects of various physicochemical properties of a drug, such as lipophilicity, charge, molecular radius and size, on its transport across ocular barriers.

The cornea is composed of five or six layers of columnar epithelium with tight junction proteins. On the other hand, passive diffusion is the primary route for hydrophilic drugs to permeate the cornea. Thus the lipoidal nature of the corneal epithelium presents a major barrier to the entry of hydrophilic drugs like acyclovir, ganciclovir, epinephrine, and pilocarpine. In humans, ocular bioavailability is predicted to be 1-5% for lipophilic molecules (octanol-to-water distribution coefficient greater than 1) and to be less than 0.5% for hydrophilic molecules (octanol-to-water distribution coefficient less than 0.01) (39). Chemical modifications have been carried out to improve the partition coefficient of hydrophilic drugs by acyl ester prodrug design, and the results showed improved permeability across corneal epithelium (40,41), but one of the major disadvantages is that achieving the desired lipophilicity often requires compromising on the aqueous solubility of the molecule. For a compound to be effective topically and to be formulated into eye drops, it must possess sufficient hydrophilicity, and at the same time exhibit sufficient permeability across the cornea. The cornea is an effective barrier to compounds larger than 10 A, which cannot cross the membrane at any significant rate (42). Also, there is no apparent dependence on corneal permeability for compounds with small molecular radius, but for macromolecular peptides like thyrotropin-releasing hormone (TRH), p-nitrophenyl beta-cellopentaoside (PNP), and luteinizing hormone-releasing hormone (LHRH), a trend is observed with increasing molecular size (43). The ioniza-tion state of the drug molecule can also affect its permeability across corneal epithelium. In vitro corneal transport studies suggest that the permeability of the unionized pilocarpine species is twice that of the ionized species (44). Thus, the lipoidal epithelial layer of the corneal membrane appears to be a predominant barrier to the transport of polar species. The conjunctiva offers an attractive route for drug delivery to the posterior segment of the eye because of its large surface area compared to cornea, but the conjunctival epithelium, like corneal epithelium, restricts the entry of molecules across the membrane. The limited data available regarding conjunctiva show no clear dependence on distribution coefficient, but some dependence on molecular size. However, one would expect conjunctival permeability to show a preference for lipophilic molecules

(45). Also, in general, the conjunctiva appears to possess similar or higher permeability than cornea (45). Considering the posterior segment of the eye, the RPE functions as a protective barrier against the entry of xenobiotics into the retina and vitreous from the systemic circulation. Pitkanen et al. studied the effects of solute molecular weight and lipophilicity on the permeability across a RPE-choroid preparation from bovine eyes

(46). Carboxyfluoresceins, a group of fluorescein isothiocyanate (FITC)-labeled dex-trans with molecular weights of 4-80 kDa, and ^-blockers exhibiting a wide range of lipophilicity, were chosen as permeation markers. Results showed that the RPE-choroid preparation was 35 times more permeable to carboxyfluorescein (376 Da) than to FITC-dextran (80 kDa). The permeabilities of lipophilic ^-blockers were about 8- and 20fold higher than those of hydrophilic atenolol and carboxyfluorescein, respectively (46). Indeed, with ascending partition coefficients, vitreal concentrations, as well as the rate of vitreal penetration of antibiotics, were elevated.

Hence, knowledge of the effect of physicochemical properties on permeation across barriers can lead to the development of theoretical models, which in turn can be broadly applied to predict permeability of new drugs, leading to novel drug-delivery strategies.

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