IMPROVED ORAL ABSORPTION OF A POORLY WATER-SOLUBLE DRUG, HO-221, BY WET-BEAD MILLING PRODUCING PARTICLES IN SUBMICRON REGION

N-[[[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl]-2-nitrobenzamide (HO-221) is being developed as an anticancer agent with a novel mode of action. HO-221 shows poor oral absorption and is only slightly soluble in water (0.055 mug/ml at 37-degrees-C). In this study, it was shown that the reduction in particle size of HO-221 to the submicron region (0.453 mum, mean by volume) could be achieved by a wet milling in a decaglycerin monolaurate aqueous solution with small glass beads. The wet milling suspension obtained showed improved dissolution rate and oral absorption in rats. A solid dosage form be could also made from that suspension with addition of sucrose palmitate which prevented aggregation caused by the hydrophobic interaction. The solid dosage form thus obtained showed twice as much oral absorption in dogs as the preparation made by dry milling.