Rate control of ocular pilocarpine delivery with bispilocarpic acid diesters

Ocular delivery of pilocarpine as bispilocarpic acid diester prodrugs was studied in albino rabbits using miosis as a bioassay of pilocarpine availability in the iris. Bispilocarpic acid diester fumarate eyedrops, in a dose equivalent to 0.5% pilocarpine, were administered at pH 5.0. Bispilocarpic acid diesters increased the duration of miosis and decreased the peak miotic response of pilocarpine. The time of peak miosis was delayed from 40 min to 55-135 min with the prodrugs. The duration of action was extended with seven compounds from 3 h to 4-5 h. Plateauing responses indicating sustained release of pilocarpine from the prodrug were seen in some cases. Compared with 1% pilocarpine, the prodrugs showed either increased, decreased or equal biphasic availability of pilocarpine in the iris. Neither lipophilicity nor enzymatic lability of prodrug alone could explain the miosis profile of pilocarpine. Eye irritation increased with increasing lipophilicity of the prodrugs. It appears that the ocular bioavailability of pilocarpine and its duration of action can be improved by bispilocarpic acid diesters, but in predicting their performance both lipophilicity and prodrug cleavage rate should be taken into account.