Enhanced Oral Bioavailability of Flurbiprofen by Combined Use of Micelle Solution and Inclusion Compound

Abstract

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and beta-cyclodextrin (beta-CD) on the solubility and bioavailability of a poorly water-soluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, beta-CD or mixture of surfactant and beta-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of beta-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to beta-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and beta-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM beta-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 mu g/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or beta-CD, with surfactant, alone, or with beta-CD alone. Therefore, the mixed system consists of surfactant and beta-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.