Development and characterization of an Indacaterol/Tiotropium Bromide composite dry powder inhalation formulation for COPD.

As a major public health issue, chronic obstructive pulmonary disease (COPD) causes approximately 2.7 million deaths worldwide each year and has a significant negative impact on patients' health. We have developed a novel long-acting fixed-dose combination dry powder inhalation formulation with synergistic therapeutic effects, containing indacaterol maleate (IND, a long-acting β2 agonist) and tiotropium bromide (TIO, a long-acting muscarinic receptor antagonist), aimed at improving the clinical management of COPD and providing patients with superior bronchodilator effects. We prepared composite powder formulations using different ratios of fine lactose powder and magnesium stearate, combined with active pharmaceutical ingredients of varying particle sizes. We conducted preliminary studies on the total mixture content, mixing uniformity, delivered dose (DD), and fine particle dose (FPD) of each formulation using high-performance liquid chromatography (HPLC). Further screening and characterization were performed using scanning electron microscopy (SEM), laser particle size analyzers, and powder X-ray diffraction (XRD); simultaneously, we conducted aerodynamic studies and accelerated stability testing on the selected optimal formulation. This formulation (F7) demonstrated superior performance compared to other formulations. It exhibited excellent mixing uniformity, appropriate content and optimal aerodynamic properties with FPD values near the median standard range. Accelerated stability testing confirmed excellent stability with no significant changes in crystalline form or aerodynamic properties after 6 months. The developed IND/TIO composite inhalation powder represents an innovative dual-bronchodilator DPI formulation. The dual-stage lactose carrier system significantly enhanced drug detachment efficiency and in vitro pulmonary deposition. The introduction of magnesium stearate effectively addressed challenges of poor flowability and particle aggregation in micronized APIs. The formulation exhibits simple preparation process, excellent stability, and superior in vitro pulmonary drug delivery efficacy, making it a promising therapeutic candidate for COPD treatment.