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A. K. Mitra, S. Natesan, S. Hariharan, M. Minocha, B. C. Gilger, C. P. Moore, S. L. Weiss, P. Velagaleti; Development and Characterization of a Clear, Mixed Micellar Formulation of LX211, a Next-Generation Calcineurin Inhibitor, for Treatment of Dry Eye Syndrome. Invest. Ophthalmol. Vis. Sci. 2008;49(13):114.
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To develop and characterize a clear, mixed micellar formulation containing a rationally-designed next-generation calcineurin inhibitor, LX211 (also known as ISA247), for the treatment of dry eye syndrome and potentially other relevant ocular diseases.
Mixed micelles of LX211 were created utilizing a novel solvent evaporation method with varying amounts of two polymeric surfactants: D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and octoxynol-40. Measurements performed to characterize the formulations were: osmolarity (osmometer), mixed micelle particle size (dynamic light scattering technique), viscosity (rotoviscometer), and thermal stability (controlled heating). Tolerability of formulations containing varying LX211 concentrations was evaluated in rabbit eyes using slit lamp microscopy, and compared with 0.05% cyclosporine A emulsion (Restasis®[Allergan, Inc., Irvine, CA]).
Formulations with different concentrations of LX211 (0.002-1%) were produced by varying the amounts of the polymeric surfactants. Increased concentrations of vitamin E TPGS and octoxynol-40 enhanced solubility of LX211 and thermal stability of the formulation. Different polymers were incorporated to enhance viscosity (ranging from 0.11-0.17 poise), thereby increasing residence time in the eye. Mixed micellar size was 12-18 nm, thus resulting in a clear formulation. The dissociation temperature at which mixed micelles disintegrate and release the hydrophobic LX211 into a suspension ranged from 53-59°C. Mixed micelles regenerated when cooled below the dissociation temperature. Teflon, nylon or polycarbonate filters (0.22µM size) were used for sterilization. LX211 formulations were well-tolerated and did not produce any irritation in rabbits. In contrast, Restasis® treatment demonstrated distinct signs of irritation.
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