Influence of Drug Lipophilicity on Bovine Sclera and Sclera-Choroid-RPE Permeability of Corticosteroids

Abstract

Purpose: : Corticosteroids are of therapeutic value in treating back of the eye complications such as macular edema. Transscleral drug delivery, although in its developmental stages, can be potentially applied for treating back of the eye disorders. One objective of this study was to determine the influence of lipophilicity on corticosteroid permeability across sclera and sclera-choroid-RPE (SCRPE). Another objective of this study was to correlate melanin binding with corticosteroid permeability across sclera and SCRPE.

Methods: : n-octanol:PBS (pH 7.4) partition coefficient (Log D) at 37 °C was determined for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide, using a shake flask method. In vitro melanin binding was determined using natural melanin (Sepia Officinalis) and binding parameters were estimated using Langmuir binding isotherm. A high throughput LC/MS/MS method was developed for quantifying the above corticosteroids. Bovine sclera and SCRPE transport of a cocktail of the above corticosteroids (10 µg/ml each; pH 7.4) was assessed at 37 °C over 6 h using Ussing chambers.

Results: : Log D of the above corticosteroids ranged from 0.7 to 3. All corticosteroids bind to natural melanin, with binding capacity and affinity values ranging from 3-15 nanomoles/mg melanin and 1-12 µM, respectively. The cumulative % transport at the end of 6 h for all corticosteroids across sclera and SCRPE was in the range of 3.9-10.7 and 0.3-1.8, respectively. Budesonide, the most lipophilic corticosteroid, showed highest levels in sclera and SCRPE at 6 h, which were significantly (p<0.05) different from other corticosteroids. The cumulative % transport showed strong inverse correlation (R²>0.9) with the drug lipophilicity for both sclera as well as SCRPE. Additionally, the drug transport across both these tissues showed inverse correlation with melanin binding capacity (R²~0.6). Tissue accumulation of corticosteroids in sclera as well as SCRPE showed positive correlation with lipophilicity (R²~0.5).

Conclusions: : Upon exposure at low concentrations as anticipated in vivo, transscleral transport of corticosteroids declines with an increase in drug lipophilicity, melanin binding, and tissue accumulation.

Keywords: retinal pigment epithelium • choroid • sclera