RESUMEN
A powder coating mixture was investigated with a view toward improving the dissolution property of the anxiolytic 2-(4-chlorophenyl)-5,6-dihydro-[1]benzo-thiepino-[5,4-c]-pyrida zin-3(2H)-one 7-oxide (1), which was barely water soluble. The powder coating mixture in various ratios of 1 and cornstarch was prepared in an automated mortar. Among these mixtures, at the optimum ratio of 1 and cornstarch (2:1, 67% drug content), the powder coating mixture gave a maximized effect for solubilizing 1 on the bases of stability and solubility. Conventional granules were made from the 67% powder coating mixture. The granules showed an excellent absorption profile in beagle dogs. The mechanism of the solubilizing effect resulting from a pharmaceutical process was also discussed.
Asunto(s)
Ansiolíticos/farmacocinética , Benzotiepinas/farmacocinética , Piridazinas/farmacocinética , Animales , Disponibilidad Biológica , Química Farmacéutica , Perros , Masculino , Polvos , SolubilidadRESUMEN
The effects of triglycerides on the gastrointestinal absorption of 2-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1- yl]ethyl acetate (1) were investigated in dogs. The enhancing abilities of the triglycerides on the absorption of 1 were demonstrated as in the order of trilinolein greater than triolein greater than tristearin greater than tripalmitin. Among the series of fatty acids and monoglycerides, namely, digestive products of triglycerides by pancreatic lipase, linoleic acid and monolinolein showed the most potent solubilizing activities of 1 in a solution of bile salt. The incorporation of 1 into mixed micelle formed by lipids and bile salts was presumed to play an important role in the accelerated absorption of 1 after ingestion of triglycerides. On the basis of these findings, an emulsion containing 1 was prepared with soybean oil. The emulsion exhibited a remarkable improvement of the absorption of 1 compared to a suspension of the drug in methylcellulose solution.