STUDIES SHOWING THE EFFECT OF ENZYMES ON THE STABILITY OF ESTER PRODRUGS OF PROPRANOLOL AND OXPRENOLOL IN BIOLOGICAL SAMPLES

A number of beta-adrenergic blockers, including timolol and propranolo l, are administered in eye-drops for the treatment of glaucoma. Their therapeutic value is limited by a relatively high incidence of cardiov ascular and respiratory side-effects. Because of poor ocular bioavaila bility, many ocular drugs are applied in high concentrations, which gi ve rise to both ocular and systemic side-effects. Among the methods em ployed to increase ocular bioavailability are (a) the development of d rug 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 (prodr ugs) with increased corneal penetration properties, from which the act ive drugs are released by enzymatic hydrolysis. A series of esters of propranolol and oxprenolol were synthesised and investigated as potent ial prodrugs for improved ocular use. The stability of each ester was studied in phosphate buffer (pH 7.4), also in the presence of (a) 25% human plasma, (b) aqueous humor and (c) corneal extract at pH 7.4 and at 37 degrees C.