Rheological Properties, Dissolution Kinetics, and Ocular Pharmacokinetics of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38.

Purpose: To evaluate rheological properties, in vitro dissolution, and in vivo ocular pharmacokinetics of loteprednol etabonate (LE) (submicron) ophthalmic gel 0.38%. Methods: The viscosity of the LE gel 0.38% formulation was measured with a controlled stress rheometer. Dissolution kinetics were evaluated in a fixed-volume and flow-through assay. Rabbits received a single instillation of LE (submicron) gel 0.38% (both eyes), and concentrations of LE in ocular tissues were determined through 24 h by liquid chromatography with tandem mass spectrometry. Where indicated, comparators included micronized LE gel 0.38%, 0.5% (Lotemax® gel), and 0.75%. Results: LE (submicron) gel 0.38% exhibited shear-thinning characteristics similar to LE gel 0.5% with nearly identical yield stress. LE (submicron) gel 0.38% released 2.6-fold more LE into the dissolution medium than micronized LE gel 0.5% over 30 s in the fixed-volume dissolution assay, and submicron LE attained higher concentrations of dissolved LE than micronized LE gel 0.38% in the flow-through dissolution assay. In rabbits, the maximal concentration and area-under-the-curve over 24 h for LE in aqueous humor were 2.5- and 1.8-fold higher, respectively, for LE (submicron) gel 0.38% versus micronized LE gel 0.5% (both P < 0.001). Pharmacokinetic parameters were similar for most other tissues. Conclusions: LE (submicron) gel 0.38% demonstrated similar rheological properties to micronized LE gel 0.5% but faster dissolution, thus providing similar or higher LE concentrations in the aqueous humor, cornea, and iris-ciliary body after ocular dosing in rabbits despite a lowered concentration of drug in the formulation.

Prolonged exposure to loteprednol etabonate in human tear fluid and rabbit ocular tissues following topical ocular administration of Lotemax gel, 0.5%.

PURPOSE: A new gel formulation containing loteprednol etabonate (LE), a C-20 ester corticosteroid used to treat ocular inflammation, was developed to provide increased retention on the ocular surface for improved drug delivery to intraocular tissues. This investigation evaluated concentrations of LE in tear fluid following topical instillation of LE gel to humans and the ocular and systemic pharmacokinetics of LE following administration to rabbits. METHODS: LE ophthalmic gel 0.5% was administered as a single topical dose to human volunteers (n=12) and Dutch Belted rabbits (n=40). In the human study, tear sampling was performed at 6, 9, 12, and 24 h after instillation. In the rabbit study, tears and ocular tissues were collected from 5 min through 24 h postdose. Serial blood samples were collected from one cohort of rabbits for plasma analysis. Concentrations of LE were determined by high performance liquid chromatography tandem mass spectrometry. RESULTS: In humans, LE was detected in tears at all the time points assessed with mean concentrations of 114 µg/g at 6 h declining to 2.41 µg/g at 24 h postdose. In rabbits, LE was detected in all ocular tissues within 5 min after dosing. Maximum concentrations of LE were achieved within 0.5 h and were highest in tear fluid (1560 µg/g), followed by bulbar conjunctiva (4.03 µg/g), cornea, (2.18 µg/g), iris/ciliary body (0.162 µg/g), and aqueous humor (0.0138 µg/mL). LE remained measurable in all ocular tissues through 24 h with the exception of aqueous humor. In contrast, plasma levels of LE were low with no detectable levels after 4 h. CONCLUSIONS: The gel formulation of LE provided prolonged exposure to LE on the ocular surface, with measurable levels in tears through 24 h in both humans and rabbits, for delivery of LE to anterior segment tissues, as evidenced by sustained levels of LE in rabbit conjunctiva, cornea, and iris/ciliary body.

The use of the African green monkey as a preclinical model for ocular pharmacokinetic studies.

PURPOSE: This investigation evaluated the ocular and systemic pharmacokinetics of besifloxacin in African green monkeys compared with cynomolgus monkeys following topical ocular dosing. METHODS: A suspension formulation containing 0.6% besifloxacin was administered to African green and cynomolgus monkeys. Animals were euthanized at predetermined time intervals, and ocular tissue and systemic blood samples were collected and analyzed by LC/MS/MS. RESULTS: In both African green and cynomolgus monkeys, high concentrations of besifloxacin were detected in anterior segment tissues, while levels in posterior segment tissues and plasma were low. Mean concentration versus time profiles of besifloxacin were generally similar between species, with rapid absorption into ocular tissues after a single dose. In anterior segment tissues, concentrations of besifloxacin were measurable throughout the 24-h sampling period in both species. Quantitatively, concentrations were consistently higher in the conjunctiva of African green monkeys compared with cynomolgus monkeys. Besifloxacin levels were also higher during the first 3 h following dosing in the tear fluid of African green monkeys, but lower in the iris/ciliary body during this timeframe. However after the 3-h time point, concentrations in the tear fluid and iris/ciliary body were similar between species. Exposure in cornea tended to be higher in African green monkeys, but the difference was less pronounced than for conjunctiva. Exposure in aqueous humor was comparable between species. In posterior segment tissues, exposure to besifloxacin tended to be higher in cynomolgus monkeys. Systemic exposure also tended to be higher in cynomolgus monkeys, but measurable levels were present in the plasma of both species throughout the 24-h sampling period. With the exception of iris/ciliary body and vitreous humor, mean ocular tissue weights were generally similar between species although a small, but statistically significant, difference was also observed in the choroid. CONCLUSIONS: African green monkeys may be a suitable model for preclinical ocular pharmacokinetic studies. Additional studies using a variety of compounds would be useful in determining whether the quantitative differences in ocular exposures and ocular tissue weights observed in the present investigation reflect slight variations in the procedures used in these separate experiments, or true physiological and anatomical differences between species.