Improvement of Dissolution and Oral Absorption of ER-34122, A Poorly Water-Soluble Dual 5-Lipoxygenase/Cyclooxygenase Inhibitor With Anti-Inflammatory Activity by Preparing Solid Dispersion

Abstract

Several formulation approaches were attempted to improve the dissolution and the oral absorption of ER‐34122, which is a novel dual 5‐lipoxygenase/cyclooxygenase inhibitor with potent anti‐inflammatory activity. The solid dispersion of ER‐34122 with hydroxypropylmethylcellulose (TC‐5RW), which is an inert solid carrier, resulted in a significant improvement in the dissolution rate of ER‐34122. The solid dispersion was prepared by a solvent evaporation method using ethanol and water. The solid‐state characteristics of the solid dispersion, the corresponding physical mixture, and ER‐34122 alone were investigated by X‐ray powder diffraction, Fourier transform infrared spectroscopy (FTIR), and an automated controlled‐atmosphere microbalance. The X‐ray powder diffraction patterns suggest that the solid dispersion exists in a totally amorphous state and the others exist in a crystalline state. The FTIR spectra results suggest that ER‐34122 can interact with TC‐5RW through intermolecular hydrogen bonding in the solid dispersion. This interaction may cause a stabilization of ER‐34122 in the higher‐energy, faster‐dissolving amorphous state. The dissolution rate of ER‐34122 from the solid dispersion was significantly greater than that from the physical mixture or the pure drug. Furthermore, when orally administrated to beagle dogs, ER‐34122 showed about a 100‐fold increase in both maximum concentration (Cmax) and area under the curve of concentration versus time (AUC) compared with the pure drug. Consequently, it was determined that the solid dispersion technique with TC‐5RW provides a promising way to increase the dissolution rate and the oral absorption of poorly water‐soluble drugs such as ER‐34122. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:258–266, 2002