Effect of 2-hydroxypropyl-beta-cyclodextrin on the ocular absorption of dexamethasone and dexamethasone acetate.

Abstract

Complexation of dexamethasone (DX) and dexamethasone acetate (DXA) with 2-hydroxypropyl-beta-cyclodextrin (HPCD) was investigated with an ultimate goal of formulating a topical ophthalmic solution of DXA. Aqueous solubility of DX and DXA was markedly increased due to formation of soluble inclusion complexes with HPCD. Based on characterization of complex formation by phase solubility and UV-spectroscopy methods, a stoichiometry of 1:1 and 1:1, 1:2 was assumed for DX-HPCD and DXA-HPCD complexes, respectively. The stability constants for complex formation estimated by phase solubility and UV-spectroscopy methods, respectively, were as follows: for DX-HPCD complex, K1:1 = 2193 and 2221 M-1; and for DXA-HPCD complex, K1:1 = 2240 and 2445 M-1 and K1:2 = 3 and 17 M-1. K1:1 of 2266 M-1 and K1:2 of 20 M-1 were also estimated for the DXA-HPCD complex by kinetics. The kinetics of DXA degradation in pH 7 phosphate buffer at 25 degrees C followed pseudo first order. The addition of HPCD decreased the rate but the order of reaction remained unchanged. Free DXA degraded at a faster rate than complexed DXA. Ocular bioavailability in conjunctiva, cornea, iris, and aqueous humor postadministration of a 25-microliters dose of formulations containing an equivalent of 0.1% (w/v) DX followed a rank-order of DXA-HPCD solution greater than DXA suspension greater than DX-HPCD solution greater than DX suspension.