Possibility of lipid microsphere-encapsulated Y-24180 as an injectable drug and an inhaler for the treatment of bronchoconstriction

Abstract

Y-241 80 ((±)-4-(2-chloro-phenyl)-2-[2-(4-isobuthyl- phenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2f][1,2,4] triazolo[4,3-a)[1,4]diazepine) is a lipophilic platelet- activating factor (PAF) antagonist. In the present study, we incorporated Y-24180 into lipid microspheres (LM) and its activity was evaluated in vivo. When Lipo Y-24180 was intravenously given 3 min before PAF injection, the maximal bronchoconstriction was reduced. The mean (±SEM) PAF-induced respiratory flow resistance in Lipo Y-24180 (1 μg/kg)-treated animals at 0.5 min was 19.0 ± 8.0%, which was significantly lower than that of the vehicle-treated control (61.5 ± 13.0%; P < 0.05). Three and 10 μg/kg Lipo Y-24180 almost completely inhibited the respiratory flow resistance. Alone, Y-24180 dose-dependently suppressed the bronchoconstriction; however, a significant decrease was only seen in 10 μg/kg-treated animals. There were also significant differences between the Lipo Y-24180 (1 μg/kg)-treated group and Y-24180 (1 and 3 mg/kg) treated groups. Aerosol inhalation of Lipo Y-24180 (10 μg/mL) caused no significant suppression; however, a significant inhibition was observed in guinea pigs that were administered more than 30 μg/mL. Therefore, it would be concluded that Lipo Y-24180 would have a potency as a bronchodilator and would be promising as both an injectable drug and an inhaler.

Keywords

• bronchoconstriction
• inhaler
• intravenous treatment
• lipid microspheres
• platelet-activating factor antagonist
• Y-24180