Optimization and Application of an Efficient and Stable Inhalation Exposure System for Rodents.

ABSTRACT

Inhalation is a promising and challenging method in pharmaceutical and biological science research. A stable environment is critical in dynamic inhalation administration. However, the establishment of a stable inhalation system is very challenging. Indacaterol glycopyrronium bromide inhalation powder (IM/GP mixed powder) is composed of indacaterol maleate and glycopyrronium bromide powder to treat chronic obstructive pulmonary disease (COPD). The aim of this study is to build suitable inhalation conditions and then to evaluate the pulmonary safety of this drug in Sprague-Dawley(SD) rats. In the research, through the coordination of the atomization flow, air pump flow, and scraper speed, aerosols were stabilized at 200 ± 20% mg/m3, and then rats were nose-only administered with the IM/GP mixed powder, Ultibro, and lactose-magnesium stearate mixed powder at 2.6 mg/kg/day for 14 days and 14 days of recovery period, respectively. After exposure, hematology, inflammatory cytokines in rats bronchoalveolar lavage fluid (BALF) and serum, histopathological examination were performed. Results showed that the stability of powder aerosols can be realized under the atomization generation flow 10 L/min, sampling flow 2 L/min, system pumping capacity 10 L/min and powder scraper speed 8-10 L/min, and there were no significant adverse effects on body weight, clinic signs, hematology, and pathology in rats. Overall, the results suggested that the IM/GP mixed powder inhalation at the dose of 2.6 mg/kg/d can be reached when the aerosol concentration is within the range of 200 ± 20% mg/m3, and there were no pulmonary toxicity effects in rats.