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

Abstract

Y‐24180 ((±)‐4‐(2‐chloro‐phenyl)‐2‐[2‐(4‐isobuthylphenyl)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.

Lipid Microsphere Formulation Containing Rifampicin Targets Alveolar Macrophages

“…For example, the inhalation of LM-encapsulated PGE 1 delayed the onset and decreased the severity of dyspnea and bronchial irritation compared with inhalation of free PGE 1 in animals and asthma patients (Mizushima et al 1983). In addition, the inhalation of an LM-encapsulated TXA 2 antagonist (Takenaga et al 1993b) or PAF antagonist (Takenaga et al 2000) resulted in enhancement of their pharmacological activity.…”