Methylmethacrylate sulfopropylmethacrylate copolymer nanoparticles for drug delivery: Part III: Evaluation as drug delivery system for ophthalmic applications

Abstract

Copolymer nanoparticles were investigated as carrier systems for the topical ophthalmic application of the muscarinic agonists arecaidine propargyl ester (APE) and (S)-(+)-aceclidine in rabbits and compared to conventional eye drop preparations. The copolymer nanoparticles were prepared by free radical polymerization of methylmethacrylate (MMA) and sulfopropylmethacrylate (SPM). The in-vivo activity of the drug-containing carrier systems was tested by the measurement of the miotic effect observed after local administration in rabbits. It has been found that the copolymer nanoparticles were able to produce a significant increase of the ocular APE bioavailability as determined by the area under the miosis-time-curve (AUC). The nanoparticle preparations were tolerated without any irritating effect in the rabbit eye. Besides the copolymer nanoparticles, different formulations containing bioadhesive or viscosity-enhancing polymers with and without additional nanoparticles were tested. The administration of APE-loaded copolymer nanoparticles was found to be equivalent in efficacy to solutions containing the soluble polymers without nanoparticles. The combination of the nanoparticles with bioadhesive polymers further increased the ocular drug bioavailability. Hyaluronic acid alone or in combination with copolymer nanoparticles was observed to be the most effective soluble polymer for ophthalmic application by enhancing the AUC of miosis-time-curve 2-fold. Similar effects induced by the carrier systems were obtained with (S)-(+)-aceclidine. However, the magnitude of the enhancement of the miotic effect that is achievable by the binding of the drug to nanoparticles over free drug is much more pronounced with the short acting drug APE than with (S)-(+)-aceclidine.