Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load.

A major problem in the use of timolol in glaucoma therapy is its relatively high incidence of cardiovascular and respiratory side effects. This report presents preliminary evidence for the feasibility of a prodrug approach to minimize systemic absorption of timolol using a reduced topical dose made possible by improved corneal drug penetration. The results indicate that the O-acetyl, propionyl, butyryl, and pivalyl ester prodrugs of timolol were virtually completely hydrolyzed between 30 and 150 min when incubated with plasma, aqueous humor, and ocular tissue homogenates of pigmented rabbits. Moreover, the in vitro corneal penetration of all but the O-pivalyl prodrug was 2-3 times higher than timolol. This was accompanied by a four- to sixfold increase in aqueous humor concentration at 5 and 30 min post-instillation of 15 mM solutions, although the plasma timolol concentration at the same time points was either unaltered or slightly reduced. Collectively, these preliminary findings suggest that at least a twofold reduction in the topical dose of timolol is possible by using prodrugs, thereby reducing timolol concentration in the systemic circulation and possibly the incidence of cardiovascular and respiratory side effects.