Ionic Liquid Pilocarpine Serves as Therapeutic Cosolvent and Permeation Enhancer for Glaucoma Medication.

The efficacy of hydrophobic ocular drugs is significantly hindered by their low bioavailability, for which poor water solubility is a major contributing factor. In this work, we synthesized pilocarpine-derived ionic liquid [Pilo-OEG] Cl (PO) and evaluated its cosolvent properties for the codelivery of the hydrophobic antiglaucoma drug brimonidine (BM) for glaucoma therapy. Pilocarpine was quaternized with 2-[2-(2-chloroethoxy)-ethoxy] ethanol in a one-pot reaction to yield PO, and its structure was confirmed using 1H NMR and FT-IR spectroscopy methods and further characterized for its rheological property and thermal stability. The HET-CAM assay and cell viability study showed that PO was nonirritating and cytocompatible with trabecular meshwork cells. As a cosolvent, PO increased the solubility of BM and shifted its logP toward hydrophilicity and increased its ex vivo corneal permeability to be 2.7-fold higher. Following topical administration, a single dose of the PO:BM formulation decreased intraocular pressure (IOP) in rats and effectively maintained the IOP reduction for 48 h, whereas the IOP in the rats topically treated with brimonidine tartrate returned to the baseline in less than 12 h. A sustained IOP reduction over 7 days was achieved in a multiple-dose experiment, with efficacy still observed on day 8 by PO: BM. By combining intrinsic muscarinic activity with potent cosolvent properties, PO ionic liquid addresses the solubility and bioavailability challenges of hydrophobic drugs (BM) in a simple formulation (PO:BM), presenting a promising next-generation therapy for the treatment of glaucoma.