Ocular Pharmacokinetics of Topically-Applied Ketoconazole Solution Containing Hydroxypropyl Beta-Cyclodextrin to Rabbits

Abstract

Purpose:

The aim of this study was to develop an aqueous ketoconazole (KET) eye drop in order to increase the corneal permeability and improve ocular bioavailability following topical application.

Methods:

Hydroxypropyl beta-cyclodextrin (HP-β-CD) was used to formulate an aqueous eye drop to improve the aqueous solubility of KET. A single dose of of either KET suspension (1.5%; KET-SP) or KET (1.5%)/HP-β-CD (12.5%) solution (KET-CD) was applied to rabbits. Aqueous humor and cornea were collected after 5, 10, 20, 30, 45, 60, 90, 120, and 180 min. KET concentrations were determined by high-performance liquid chromatography after extraction.

Results:

After topically applying KET-CD, the KET concentrations in aqueous humor were significantly increased at 10∼120 min, compared with those of KET-SP (P < 0.05), whereas KET concentrations became undectable at 180 min after topically applying KET-SP. The highest levels of KET in aqueous humor (C_max, 2.67 μg/mL) were obtained after a 20-min application of KET-CD, 6.1 times greater than that corresponding to the KET-SP at 30 min. The KET concentrations in aqueous humor for post-120- and 180-min instillations of KET-CD were 57.9 and 34.5 times higher than that of KET-SP post-120 min, respectively. The KET-CD produced an over eightfold bioavailability (AUC_0–120, area under the concentration-time curve between 0 and 120 min) increase in aqueous humor over the KET-SP. Peak KET concentration in the cornea (118.24 μg/g) was achieved within 5 min after the instillation of KET-CD, 18.4 times higher than that of KET-SP at the same time point, whereas the highest KET level in cornea was only 8.57 μg/g after a 10-min application of KET-SP. The KET levels in corneas obtained after the application of KET-CD were all much higher than those obtained by KET-SP (P < 0.01). The KET-CD produced an over twelvefold bioavailability (AUC_0–120) increase in corneas over the KET-SP.

Conclusions:

KET-CD is superior to KET-SP by increasing ocular bioavailability.