EVALUATION OF OCULAR PERMEATION ENHANCERS - IN-VITRO EFFECTS ON CORNEAL TRANSPORT OF 4 BETA-BLOCKERS, AND IN-VITRO IN-VIVO TOXIC ACTIVITY

The efficacy and toxicity of a series of prospective ocular penetratio n enhancers (benzalkonium chloride, EDTA, non-ionic surfactants, surfa ce-active heteroglycosides and bile salts) was investigated in vitro, using isolated rabbit corneas. As test drugs four beta-blocking agents were used, chosen in order of increasing lipophilicity: atenolol (AT) , timolol (TM), levobunolol (LB) and betaxolol (EX). The increased cor neal hydration induced by the enhancers was taken as an index of cellu lar and tissue damage; the ocular irritancy of the agents was also tes ted in rabbits in vivo. In the absence of enhancers, the apparent corn eal permeability coefficients of the four drugs were in the order AT c ongruent to TM < LB greater than or equal to BX; in general, the enhan cers increased the permeation rates of the more hydrophilic drugs, AT and TM, more than those of the other two, more lipophilic ones, LB and EX. The study pointed to some agents (in particular, polyoxyethylene alkyl ethers and bile salts) as effective and safe penetration promote rs for AT and TM. Their apparent safety at the tested concentrations w as confirmed by their failure to increase the corneal hydration level beyond the 'normal' value, and by their lack of irritant effect in viv o, as evidenced by a Draize test.