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Megan E Cavet, Shellise Glogowski, Christopher DiSalvo, Mary Elise Richardson; Ocular pharmacokinetics of submicron loteprednol etabonate ophthalmic gel, 0.38% following topical administration in rabbits. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1524.
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© ARVO (1962-2015); The Authors (2016-present)
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.
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.
Compared to Lotemax 0.5%, the Cmax 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 Cmax 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 Cmax 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 Cmax 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.
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.
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