Evaluation of ocular permeation enhancers: In vitro effects on corneal transport of four beta-blockers, and in vitro/ in vivo toxic activity

The efficacy and toxicity of some ocular penetration enhancers (benzalkonium chloride, EDTA, non-ionic surfactants, surface-active heteroglycosides and bile salts) was investigated in vitro, using isolated rabbit corneas in comparison with four beta-blocking agents, chosen in order of increasing lipophilicity: atenolol (AT), timolol (TM), levobunolol (LB) and betaxolol (EX). The increased corneal hydration induced by the enhancers was taken as an index of cellular and tissue damage; the ocular irritancy of the agents was also tested in rabbits in vivo. In the absence of enhancers, the apparent corneal permeability coefficients of the reference substances was in the order AT congruent to TM < LB greater than or equal to BX. The study suggests that some agents (in particular, polyoxyethylene alkyl ethers and bile salts) are effective and safe penetration promoters for AT and TM. Their apparent safety at the tested concentrations was confirmed by their failure to increase the corneal hydration level beyond the 'normal' value, and by their lack of irritant effect in vivo, as evidenced by a Draize test.