Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate.

Abstract

Loteprednol etabonate (LE) is a soft corticosteroid that maintains therapeutic activity with much reduced adverse effects. Yet, its ocular bioavailability is hindered by its poor aqueous solubility. Early attempts of LE complexation with cyclodextrins (CDs) did not involve the study of the effects of various complexation methods on the characteristics of the complexes formed. Formulation of complexes into different delivery systems as well in vitro and in vivo assessments has not been accomplished in the earlier studies. In this study, complexation of LE with each of hydroxypropyl-β-cyclodextrin (HP-β-CD) and β-cyclodextrin (β-CD) by kneading, freeze drying, and co-precipitation was attempted. These complexes were incorporated into gels, drops, and ocuserts using hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and sodium alginate (ALG). These formulae were examined with respect to drug content, pH, viscosity, in vitro release, and stability for 6months. Kinetic analysis of release data was done. Selected formulations were assessed for their efficacy in the treatment of ocular allergic conjunctivitis and their ocular bioavailability in rabbits' eyes. All formulations exhibited accepted drug content, pH, and viscosity. The drug release was increased by complexation particularly with HP-β-CD in the order of ocuserts ≥ drops > gels, being the highest for HPMC preparations that also exhibited the greatest stability and anti-inflammatory activity especially in case of LE-HP-β-CD complexes. Ocuserts of co-precipitated LE-HP-β-CD using HPMC (5% w/w) and Carbopol 934P (0.1% w/w) provided a significantly enhanced stability (p < 0.05), ocular anti-inflammatory efficacy (p < 0.05), and ocular bioavailability (p < 0.0001), to be represented as a potential ocular delivery system of LE.