Abstract
Purpose:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
Keywords: 487 corticosteroids •
607 nanotechnology •
445 cataract