Although pilocarpine is widely used as a topical miotic for controlling elevated intraocular pressure in glaucoma, it faces significant delivery challenges: very low ocular bioavailability (1-3% or less) due to rapid precorneal loss, poor corneal permeability (attributed to low lipophilicity), short duration of action (~3 h, requiring 3-6 daily administrations with poor patient compliance), and systemic toxicity from nasolacrimal absorption. A successful pilocarpine prodrug should exhibit high lipophilicity for corneal penetration, sufficient aqueous solubility and stability for eye drop formulation, convert to the active parent drug in/after crossing the cornea, and enable controlled release for prolonged action. We report that pilocarpic acid esters, especially diesters, are promising pilocarpine prodrugs. A series of alkyl/aralkyl monoesters (2) were synthesized by reacting pilocarpic acid sodium salt with alkyl/aralkyl halides; these monoesters undergo specific-base-catalyzed lactonization to pilocarpine, with cyclization rates correlating with the Taft polar substituent constant σ* (log t1/2 = 1.44σ* + 2.73, n=8, r=0.998). In rabbit ocular studies, monoesters showed delayed onset, prolonged duration of miotic effect (from ~2 h to ~3 h), and increased bioavailability (AUC) without enhancing peak response, with activity dependent on cyclization rate. However, monoesters had inadequate solution stability at physiological pH. Diesters (3) prepared by 0-acylation of monoesters solved this stability issue: they are highly stable in aqueous solutions (shelf-life >5 years at 25 °C, pH 5-6) and undergo sequential enzymatic hydrolysis (of the 0-acyl bond) followed by spontaneous lactonization of the intermediate monoester to pilocarpine in human plasma or rabbit eye tissue homogenates (half-times for enzymatic hydrolysis: 3-17 min vs. ~5×10³ h for chemical stability in pH 7.4 buffer). In rabbit studies, diesters exhibited enhanced absorption, longer-lasting activity (similar to zero-order delivery), and good water solubility (as nitrate salts, due to the imidazole moiety’s basicity, pKa~7.0). Conclusion: Pilocarpic acid esters are potentially useful pilocarpine prodrugs; diesters are of particular interest as they combine enhanced bioavailability, greatly prolonged duration of action, and high formulation stability. The pro-prodrug/sequential cascade concept (enzymatic cleavage prior to chemical reaction) utilized in diester design may also have broader applicability in prodrug development.