Glycopyrrolate/Indacaterol Maleate

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.

Bronchodilators are the cornerstone for treating patients with chronic obstructive pulmonary diseases (COPD), although some studies have shown that dual bronchodilators may exacerbate incidence of adverse cardiovascular events. Here, we evaluated the cardiopulmonary safety of indacaterol/glycopyrronium (IND/GLY) using a meta-analysis.

We searched PubMed, OVID, Cochrane Library and Web of Science databases, using "indacaterol/glycopyrronium", "indacaterol/glycopyrrolate", "IND/GLY", "QVA149", "chronic obstructive pulmonary diseases", "COPD", "chronic obstructive airway disease", "chronic obstructive lung disease" as key words. Acute exacerbation of COPD and FEV₁ as indicators of pulmonary function and occurrence of hypertension, atrial fibrillation, myocardial infarction and heart failure as indicators of cardiovascular safety.

A total of 23 articles, comprising 21,238 participants, were included in the analysis. FEV₁ values were significantly different compared to IND/GLY and single bronchodilator therapy (LABA or LAMA), with the MD 0.11 L (95%CI: 0.10-0.13, P<0.01). Hypertension was more frequent in the IND/GLY, than the single bronchodilator therapy group, although this difference was insignificant (IND/GLY vs LABA, RR=1.88, P = 0.09; IND/GLY vs LAMA, RR=1.42, P = 0.08; IND/GLY vs LABA+ICS, RR=1.85, P = 0.23). In addition, IND/GLY did not significantly increase the risk of myocardial infarction (IND/GLY vs LAMA or double therapy, total RR: 1.49, 95%CI: 0.72-3.08, P = 0.28), atrial fibrillation (IND/GLY vs LAMA, RR: 1.62, 95%CI: 0.64-4.10, P = 0.31) and heart failure (IND/GLY vs LAMA, RR: 0.40, 95%CI: 0.07-2.33, P = 0.31) in COPD patients.

IND/GLY significantly reduced incidence of acute COPD exacerbations, and slowed down the decline of FEV₁. Adequate safety measures are needed to control incidence of adverse cardiovascular events.