Formulation influence on ocular and systemic absorption of topically applied atenolol in the pigmented rabbit

The objective of this study was to determine the relative efficacy of various formulations in maximizing the ratio of ocular to systemic absorption of topically applied atenolol following solution instillation in the pigmented rabbit. Formulations of various pH's and tonicities and containing various preservatives and polymers were tested. Ocular absorption was determined by monitoring atenolol concentrations in various anterior segment tissues at 30 min following solution instillation, while systemic absorption was determined by monitoring the time course of atenolol concentration over 480 min. Reversed phase HPLC was the analytical methodology. All formulations except those containing 0.025% benzalkonium chloride or 0.5% EDTA showed similar drug concentration vs. time profiles in plasma, attaining a peak concentration of 30-50 ng/ml at about 100 min. For benzalkonium chloride and EDTA, there was an undesirable increase in systemic absorption, although ocular absorption was also increased. By contrast, lowering the solution tonicity to 80 mOsm/kg increased the ratio of aqueous humor to plasma peak concentrations 2 times and the ratio of iris-ciliary body to plasma peak concentrations 3 times. Incorporation of 3.75% poly(vinyl alcohol) into the formulation afforded yet a larger increase in the iris-ciliary body to plasma drug concentration ratio (52 times.) It may therefore be concluded that, for a hydrophilic drug like atenolol, formulation changes that increase membrane permeability and/or enhance noncorneal drug access may be more promising than those that increase drug residence in the conjunctival sac with respect to maximizing the ratio of ocular to systemic drug absorption.