Relationship of chemical structure to corneal penetration and influence of low-viscosity solution on ocular bioavailability.

Current understanding of the mechanism of corneal penetration by organic molecules proposes the epithelial layer as the rate-limiting membrane for water-soluble compounds and the stromal layer as rate limiting for lipid-soluble compounds. This suggests that the relationship between corneal permeability and the logarithm of oil/water partition coefficients, for a series of drugs, should not be the typical, single, continuous, parabolic-shaped curve. Corneal penetration studies have been conducted in unanesthetized albino rabbits using various organic compounds, representing five orders of magnitude in partition coefficient, at a constant concentration of 4 X 10(-5) M dispensed in either a 1- or 90-centipoise (cps) solution. It has been shown that for non-ionizable compounds, a pair of bell-shaped curves were generated, one for lipid-soluble and one for water-soluble compounds. Small water-soluble species demonstrate very high apparent permeabilities, which may relate to the presence of aqueous pores or other paracellular drug movement. Penetration of ionizable compounds does not appear to correlate well with the structural relationships invoked for un-ionized compounds. Consistent with the proposed mechanisms of corneal penetration, oil-soluble drug substances show no improvement in drug bioavailability when dosed from a 90-cps solution, and water-soluble drugs show a modest improvement in ocular drug bioavailability. Small water-soluble substances demonstrate no improvement due to their already high bioavailability. The importance of nonproductive absorption and precorneal drainage on bioavailability is addressed.