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Lisa Schopf, Alexey Popov, Elizabeth M Enlow, James R Bourassa, Hongming R Chen; Enhanced Topical Delivery of a Novel Loteprednol Etabonate Ophthalmic Formulation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1533.
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To improve topical drug delivery to the eye, Kala has developed mucus penetrating particle (MPP) technology that facilitates drug penetration through pre-corneal mucus layer, providing superior delivery of drug to ocular tissues. The objective of this work was to evaluate a novel MPP formulation of loteprednol etabonate (LE-MPP).
Two in vivo distribution studies were conducted in rabbits to determine the ocular/systemic pharmacokinetic (PK) profiles of LE following topical administration of various LE-MPP concentrations. An additional distribution study was performed to compare LE-MPP 1.0% to commercially available Lotemax® (ophthalmic suspension) 0.5%. PK analysis was performed using WinNonlin software. To support the clinical evaluation of LE-MPP, a 28-day rabbit ocular toxicity study was conducted and standard ophthalmology, body weight, clinical signs, and histopathology of all ocular-related tissues and adrenal glands were evaluated.
The dose-dependent concentration-time profiles of LE in aqueous humor (AH) revealed a proportional increase, as area under the curve, with doses from 0.4 to 1.0%, while the peak concentration plateaued at 0.6% with no further increase seen at 1.0%. The PK profiles of LE-MPP 1.0% drug product and Lotemax were compared in the AH, cornea, retina and plasma. The enhancement in LE exposure in all tissues was most pronounced over the first 3 hours after a single topical dose of LE-MPP as compared to Lotemax. The same tissues were examined after topical dosing of LE-MPP 1.0% or 0.25%. This analysis revealed that an increase in dose concentration increased exposure in the tissues assessed. The administration of LE-MPP 1.0% drug product to rabbits via ocular instillation four times daily for 28 days was well-tolerated and resulted in no test article-related observations except a mild decrease in body weight and body weight gain, a decrease in absolute lymphocyte count, adrenal cortical and hair follicle atrophy, effects that are expected for a corticosteroid and similar to those observed with Lotemax.
The PK results support the premise that the MPP technology can be used to enhance ocular exposure of topically applied therapeutic agents. The administration of LE-MPP 1.0% drug product was well-tolerated and the observed effects were considered secondary to the expected pharmacology of a corticosteroid and similar to those previously reported for Lotemax.
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