Development of Dorzolamide Loaded 6-O-Carboxymethyl Chitosan Nanoparticles for Open Angle Glaucoma

Chitosan (CS) is a biodegradable, biocompatible, and mucoadhesive natural polymer soluble in acidic pH only and can be irritating to the eye. Objective of the study was to synthesize water soluble 6-O-carboxymethyl (OCM-CS) derivative of CS, and to develop CS and OCM-CS nanoparticles (NPs) loaded with dorzolamide hydrochloride (DRZ). CS was reacted with monochloroacetic acid (MCA) for OCM-CS synthesis and was characterized by FT-IR, DSC, and 13C NMR. CS and OCM-CS NPs were prepared by ionic gelation method. Ocular irritation potential were evaluated and therapeutic efficacy was measured by reduction in intraocular pressure (IOP) in normotensive rabbits. Maximum yield was obtained when the ratio of water/isopropyl alcohol was 1/4 at 55°C. The FT-IR, DSC and 13C NMR confirmed the formation of an ether linkage between hydroxyl groups of CS and MCA. The particle size and zeta potential of optimised CSNPs was 250.3 ± 2.62？nm and +33.47 ± 0.723？mV, whereas those for OCM-CSNPs were 187.1 ± 2.72？nm and 30.87 ± 0.86？mV. The entrapment efficiency was significantly improved for OCM-CSNPs, compared to CSNPs. OCM-CSNPs had tailored drug release and improved bioavailability with reduction in pulse entry as compared to CSNPs. Hence, it can be concluded that DRZ loaded OCM-CSNPs would be better alternative option to available eye drops for glaucoma treatment. 1. Introduction Open-angle glaucoma, the most common form of glaucoma, accounts for at least 90% of all glaucoma. It is caused by clogging of Schlemm’s canal, develops slowly, and has a wide angle between iris and cornea. Its symptoms and damage are unnoticeable and it is a lifelong condition. The major risk factor for glaucoma is elevated IOP. Lowering IOP is currently the only proven method for reducing the risk of glaucomatous visual field loss and remains the primary goal of therapy [1]. DRZ is a carbonic anhydrase inhibitor (CAI) used in the treatment of glaucoma. Carbonic anhydrase (CA) is responsible for generation of bicarbonate anions secreted by the ciliary process into the posterior chamber of the eye. Inhibition of CA results in reduction of IOP. Orally administered CAIs, such as acetazolamide, are very effective ocular hypotensive agents but their oral administration results in systemic side effects including general malaise, depression, loss of appetite, fatigue, weight loss, gastrointestinal disturbances, parenthesis, and renal calculi [2]. Dorzolamide is reported to have 20 times higher potency than acetazolamide and is topically active [3]. When dorzolamide solution is instilled in ocular cul de