Oral Absorption Improvement of Poorly Soluble Drug Using Solid Dispersion Technique

Abstract

A new triazol antifungal agent, (+)-2-(2, 4-difluorophenyl)-3-methyl-1-(1H-1, 2, 4-triazol-1-yl)-3-[6-(1H-1, 2, 4-triazol-1-yl)pyridazin-3-ylthio]butan-2-ol (MFB-1041), shows poor oral absorption and is practically insoluble in water (1.2 μg/ml). Solid dispersion systems with an enteric polymer such as hydroxypropylmethylcellulose phthalate (HP-55^<[〇!R]> and carboxymethylethylcellulose (CMEC^<[〇!R]>, and a nonenteric polymer, hydroxypropylmethylcellulose (Metholose^<[〇!R]> were evaluated to improve durg absorption and solubility. The oral bioavailabilities of these solid dispersions in beagle dogs were over 6 times higher than that of a suspension system with increasing drug solubility in an alkaline medium. X-Ray powder diffraction measurement of the solid dispersion showed a complete drug phase change from a cystal to an amorphous state. Further, from the results of a stability test, the preparations were stable in a desiccated condition and the absorption profiles also showed no change. From the results, it was suggested that the oral administrative preparation of MFB-1041 having a superior absorption profile and a high stability could be obtained by a drug phase change from a crystal to an amorphous state, especially in the spray-drying method using enteric polymers.