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J.J. Arnold, P. Challa, D.L. Epstein; Novel Anti–glaucoma Formulations of Ethacrynic Acid Containing Chitosan . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3680.
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Purpose: To evaluate the ocular permeation, efficacy, and tolerability of ophthalmic preparations containing ethacrynic acid (ECA) with chitosan, a mucoadhesive polysaccharide that has shown promise at increasing drug residence time. Methods: Previous studies have demonstrated the ocular hypotensive effects of ECA, but its use has been limited due to poor corneal permeation and toxicity that are presumed to be due to –SH reactivity. A two–chambered ex vivo diffusion apparatus was used to assess the scleral and/or corneal permeability coefficients (Pe) of formulations containing ECA or ECA conjugated to cysteine (ECA–cysteine) with or without chitosan (1%). Tissue from freshly enucleated porcine eyes was used and ECA permeation was determined by UV spectrophotometry. Drug formulations were prepared containing ECA–cysteine (0%, 0.5%, 1%, 2%) plus chitosan (1%). In vivo data was obtained by single–dose administration to New Zealand White (NZW) rabbits. Intraocular pressure (IOP) was measured, and signs of ocular toxicity were assessed at specific intervals. Results: Experiments conducted in the ex vivo diffusion apparatus indicated that the sclera (Pe= 8.8±1.5x10–6 cm/s) was approximately 1.7 times more permeable to ECA than the cornea (Pe= 5.3±0.8 x10–6 cm/s). A similar result was noted when chitosan was added to the ECA formulation. Chitosan did not significantly hinder the permeation of ECA–cysteine across the cornea (PeECA–cysteine= 4.4±0.5x10–6 cm/s vs. PeECA–cysteine+chitosan= 4.0±0.5 x10–6 cm/s). Studies conducted in NZW rabbits indicated that administration of chitosan alone did not affect rabbit IOPs. Increasing concentrations of ECA–cysteine resulted in dose–dependent reductions in IOP from the untreated control (0.5%= 1.2mmHg (6%); 1%= 1.6mmHg (8%); 2%= 2.1mmHg (11%)). Importantly, no ocular toxicities were noted in any of the treated animals. Conclusions: Despite its chemical nature as a pseudoplastic hydrogel, in vitro, chitosan could be formulated and release ECA at rates similar to those noted with ECA in solution. Administration of ECA–cysteine with chitosan reduced IOP and resulted in no toxicities, suggesting that chitosan may represent a suitable mucoadhesive for ocular drug formulations.
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