Preliminary evaluation of a series of amphiphilic timolol prodrugs: possible evidence for transscleral absorption.

A series of amphiphilic esters of timolol malonate (octanoyl, decanoyl, dodecanoyl, myristoyl and palmitoyl timolol) were tested in rabbits for their capacity to antagonise the isoproterenol-induced ocular hypotension, using timolol maleate as reference standard. The most active prodrug, palmitoyl timolol malonate (PTM) was also evaluated for its capacity: (a) to decrease IOP in a model of bethamethasone-induced ocular hypertension, and (b) to permeate "in vitro" through rabbit corneal tissues. PTM, the prodrug with the longest aliphatic chain and therefore the greatest amphiphilic/lipophilic character, showed "in vivo" significant activity differences with respect to timolol maleate: the beta-antagonism was more important at earlier and later experimental times, and the IOP decrease was more marked at longer times. The prodrug, however, showed "in vitro" an inferior corneal permeability when compared with timolol maleate. The significant differences observed for the beta-antagonism of PTM at earlier times of the test might be attributed to transscleral absorption, due to the physicochemical characteristics of the prodrug, while the prolonged action (also observed in the IOP-depression test) might be due to sustained release, resulting from accumulation of the prodrug in the corneal epithelium. The present preliminary results are indicative of the potentiality of amphiphilic properties in a prodrug molecul