How an Increase in the Carbon Chain Length of the Ester Moiety Affects the Stability of a Homologous Series of Oxprenolol Esters in the Presence of Biological Enzymes

Abstract

β-Blockers including timolol and propranolol are administered in eye-drops for the treatment of glaucoma. Due to high incidence of cardiovascular and respiratory side-effects, their therapeutic value is limited. As a result of poor ocular bioavailability, many ocular drugs are applied in high concentrations, which give rise to both ocular and systemic side-effects. Therefore, some methods have been employed to increase ocular bioavailability such as (a) the development of drug delivery devices designed to release drugs at controlled rates, (b) the use of various vehicles that retard precorneal drug loss, and (c) the conversion of drugs to biologically reversible derivatives (prodrugs) with increased corneal penetration properties, from which the active drugs are released by enzymatic hydrolysis. A series of structurally related oxprenolol esters were synthesized and investigated as potential prodrugs for improved ocular use. The stability of each ester was studied in phosphate buffer (pH7.4), also in the presence of (a) 30% human plasma, (b) aqueous humor, and (c) corneal extract at pH7.4 and at 37°C. An account is given of how the stability of a homologous series of oxprenolol esters in the presence of biological enzymes is affected by an increase in the carbon chain length of the ester moiety.