Ocular pharmacokinetics of submicron loteprednol etabonate ophthalmic gel, 0.38% following topical administration in rabbits

Abstract

Purpose: Loteprednol etabonate (LE, 0.38%) dosed BID was efficacious in the treatment of inflammation and pain following ocular surgery in a Phase 3 trial when formulated in a non-settling gel as submicron drug particles. This study evaluated the ocular pharmacokinetics of submicron LE gel 0.38% vs micron LE gel at 3 doses in rabbits.

Methods: Dutch Belted rabbits (n=108) received a single 35-μL topical ocular dose of 1 of 4 LE gel formulations varying in concentration and/or particle size; 0.38% with submicron-sized LE particles (0.6 µm diameter); 0.38% with micronized LE particles; 0.75% with unmodified LE particles; and Lotemax^® Gel 0.5% (particle diameter ~3 µm for latter 3 formulations). Animals were euthanized and ocular tissue samples were collected at multiple time points (n=3 rabbits, or 6 eyes per time point) through 24 h post-dose. Concentrations of LE in ocular tissues were determined by LC/MS/MS.

Results: Compared to Lotemax 0.5%, the C_max and AUC_(0-24h) for LE after instillation of submicron LE gel 0.38% were significantly greater (P<0.05) in the aqueous humor (AH; 2.5- and 1.8-fold, respectively), the C_max was numerically greater for the iris/ciliary body (ICB; 1.6-fold) and cornea (1.3-fold), while the AUC_(0-24h) for these tissues were similar. LE 0.38% submicron gel resulted in a C_max and AUC_(0-24h) that were lower in the tear fluid (0.70- and 0.53-fold) and bulbar conjunctiva (BC; 0.73- and 0.35-fold; P<0.05 for AUC) compared to Lotemax 0.5%. The C_max and AUC_(0-24h) for the 0.38% micronized LE gel were lower in the tear fluid (0.23- and 0.33-fold; P<0.05 for AUC) and cornea (0.85- and 0.54-fold; P<0.05 for AUC) and similar/slightly lower in the AH and ICB as compared to Lotemax, while BC values were variable (4.8- and 0.58-fold). With the 0.75% LE formulation, similar exposure values as compared to Lotemax were observed.

Conclusions: Loteprednol etabonate submicron gel, 0.38% affords significantly greater exposure to LE in the AH, and similar/slightly higher exposure in the ICB and cornea compared to Lotemax Gel 0.5%. Overall, exposure to LE after administration of 0.38% or 0.75% gel with micron sized drug particles was less than or equal to Lotemax 0.5%. These data indicate that the submicron particle size enhances drug penetration to key ocular tissues.