PERMEABILITY OF PILOCARPIC ACID DIESTERS ACROSS ALBINO RABBIT CORNEA INVITRO

Corneal uptake and permeability of various alkyl and aryl diesters of pilocarpic acid in isolated albino rabbit cornea were investigated in vitro in diffusion cells. The permeability coefficient for pilocarpine was 2.77 x 10(-6) cm/s. The fractional distribution of pilocarpine in the epithelial side, cornea and endothelial side at 4 h was 85.0, 11.0 and 4.0% respectively. The corneal permeability coefficient of some pilocarpic acid diesters was several times higher (maximum 3.4-fold). No intact prodrug was observed in the endothelial side. A parabolic relationship between the logarithm of the apparent partition coefficient (1-octanol-pH 7.4 phosphate buffer) (log PC) and the corneal permeability was noticed and the permeability of the most lipophilic derivate was less than that of pilocarpine. In contrast, corneal uptake was increased with increasing lipophilicity being almost complete with a log PC value of 7.70. Corneal permeability and the rate of enzymatic hydrolysis of the compounds correlated well. The corneal permeability of lipophilic pilocarpine diesters (log PC greater-than-or-equal-to 2.87) given as prodrug seems to be controlled by the formation of pilocarpine in the corneal epithelium rather than by the absorption of prodrugs into the epithelium or their epithelium-stroma transport rate. The optimal lipophilicity for improving corneal permeability (i.e., rate of ocular pilocarpine delivery), was observed at log PC values of 3-4, but more extensive corneal uptake by the most lipophilic compounds suggests that the largest ocular bioavailability may be obtained with larger values of log PC.