Oral absorption improvement of poorly soluble drug using solid dispersion technique

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 mu g/ml). Solid dispersion systems with an enteric polymer such as hydroxypropylmethylcellulose phthalate (HP-55(R)) and carboxymethylethylcellulose (CMEC(R)), and a nonenteric polymer, hydroxypropylmethylcellulose (Metolose(R)) were evaluated to improve drug 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 crystal 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.