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 micrograms/ml). Solid dispersion systems with an enteric polymer such as hydroxypropylmethylcellulose phthalate (HP-55) and carboxymethylethylcellulose (CMEC), and a nonenteric polymer, hydroxypropylmethylcellulose (Metolose) 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.
Kai
T
T
Pharmaceutics, Research Laboratories, Roussel Morishita Co., Ltd, Shiga, Japan.
Akiyama
Y
Y
Nomura
S
S
Sato
M
M
D000818:Animals; D000935:Antifungal Agents / Q000032:analysis / Q000493:pharmacokinetics; D003028:CME-Carbodiimide; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004355:Drug Stability; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives; D011208:Powders; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013535:Suspensions; D014230:Triazoles / Q000032:analysis / Q000493:pharmacokinetics; D014961:X-Ray Diffraction
D000935:Antifungal Agents; D011208:Powders; D013535:Suspensions; D014230:Triazoles; C102251:MFB 1041; D003028:CME-Carbodiimide; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate