Influence of pH and buffer concentration on the ocular bioavailability of ophthalmic AGN 191103 formulations in albino rabbits

We investigated the effect of formulation pH and buffer concentration on the ocular 'bioavailability of AGN 191103, a basic amine that lowers intraocular pressure. Our objective was to increase AGN 191103's ocular bioavailability enough to allow a clinically significant reduction in dose. Formulations contained C-14-AGN 191103 (0.1-1% w/v), phosphate or berate buffer (0-30 mM), HCl to pH of 7.4-8.5 and benzalkonium chloride. The first experiment assessed the effect of pH and buffer concentration on the ocular bioavailability of 1% formulations; the second identified conditions of drug and buffer concentration and pH that would yield ocular concentrations comparable to that of a 1%, pH 7.2, 30 mM phosphate formulation known to be effective in vivo. Albino rabbits were given one 35-mu l eyedrop, 6 h after which aqueous humors (AqH), corneas and iris-ciliary bodies (ICB) were collected. AGN 191103 is not metabolized by rabbit eyes, so samples were analyzed by liquid scintillation counting with or without combustion. Concentrations in AqH and cornea increased with increasing pH; this trend became more pronounced with increasing buffer concentration. As pH increased from 7.4 to 8.5: (1) corneal concentrations increased 94% and 300%, respectively, after unbuffered and 30 mM buffered formulation administration; (2) AqH concentrations increased 197% and 462%, respectively, after unbuffered and 30 mM buffered formulation administration; and (3) ICB concentrations did not significantly change, or increased 84%, respectively, after ubbuffered or 30 mM buffered formulation administration. Increasing buffer concentration did not affect tissue concentrations at pH 7.4, but significantly increased them at pH 8.5. A 0.2%, pH 8.2, 30 mM berate formulation elicited AqH concentrations comparable to those produced by the 1%, pH 7.2, 30 mM phosphate formulation. Our results indicate that increasing the formulation pH from 7.2 to 8.2 may allow a 5-fold reduction in the dosing concentration, which will markedly reduce the potential for systemic side effects. (C) 1997 Elsevier Science B.V.