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Eric Phillips, Martin J Coffey, Mohannad Shawer; Viscoelastic and dissolution characterization of submicron loteprednol etabonate ophthalmic gel, 0.38%. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1525.
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The effectiveness of topical corticosteroids is limited by their dissolution and residence time on the ocular surface. We designed a non-settling submicron formulation of loteprednol etabonate ophthalmic gel, 0.38% (LE gel). This study examined the dissolution and viscoelastic characteristics of this new formulation.
Yield stress and oscillatory rheology measurements were performed using a TA Instruments rheometer fitted with a vane rotor and cup containing 40 g undiluted product at 25˚C. Dissolution of LE submicron particles (0.6-µm diameter) and LE micronized particles (3-µm diameter; used in Lotemax® Ophthalmic Gel, 0.5%) was measured at 200% of saturation in PBS/0.45% SDS using a VanKel dissolution tester. Dissolution was also determined in a flow-through assay simulating tear flow on the eye. An 8-ml LE submicron or micronized suspension was mixed with 3 ml of PBS/3.75% BAK. PBS/3.75% BAK was then flowed through the diluted LE suspension at 10 ml/min. Samples were taken from the outflow and the amount of dissolved LE was determined by HPLC. This method simulates an 11-µl tear volume with a flow rate of 10 µl/min.
Rheology analysis of submicron LE gel, 0.38% shows a yield stress of ~2 Pa and a G-crossover point of ~4 Pa confirming the gel structure is similar to Lotemax® Ophthalmic Gel, 0.5%. There was a 2.6-fold increase in dissolution with the submicron LE (0.38%) as compared to micron LE (0.5%) at 30 sec. The 0.38% submicron sample reached saturation at ~1.5 min compared to ~5 min for the 0.5% micronized sample. In the flow-through model there was an increase in dissolution over a longer time period for the submicron vs. micronized LE at 0.38%. Comparison of the AUC of the concentration vs. time curve at increasing drug concentration indicated that there was a 1.3 fold increase overall in the rate of dissolution with the 0.38% submicron vs. the 0.5% micronized formulation.
The submicron LE gel, 0.38% has similar viscoelastic characteristics as Lotemax® Ophthalmic Gel, 0.5% and therefore is expected to be non-settling, provide uniform drug delivery from the bottle and have enhanced ocular surface retention due to its viscosity on the eye. Increased drug dissolution with sub-micron LE suggests there may be enhanced delivery of soluble drug to the anterior segment of the eye thus allowing a reduction in dosing frequency and/or drug concentration.
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