Flowrate-Independent indomethacin dry powder inhaler for potential treatment of pediatric asthma: In vitro aerodynamic and anti-inflammatory evaluation

Abstract

Asthma, a chronic respiratory condition affecting millions globally, is particularly common in children and a leading cause of emergency visits and hospitalizations. Characterized by airway inflammation and increased bronchial sensitivity, asthma is typically treated with inhaled corticosteroids. Despite their effectiveness, these treatments often face challenges related to adherence and adverse effects. Non-steroidal anti-inflammatory drugs (NSAIDs), though not traditionally used for asthma due to potential adverse reactions in sensitive patients, could be beneficial when administered via inhalation to minimize systemic side effects. In this work, an indomethacin (a NSAID) dry powder inhaler (DPI) is proposed for pediatric asthma treatment as a potential alternative for reducing doses of traditional anti-asthmatic therapies using corticosteroids. Crystalline microparticles, with mean volumetric diameter of 6.0 μm and suitable for inhalation, were obtained by jet-milling, an easy and costeffective technology. Although the milled particles tended to agglomerate, they were readily dispersed through inhalers with different intrinsic resistances. Under pharmacopoeial conditions (4 KPa), mass median aerodynamic diameter values were 3.7–4.0 μm for inhalers with different intrinsic resistance while aerodynamic particle size distribution was narrow considering GSD was 1.5–1.7. The emitted fraction was high when assays were performed at a 4 KPa pressure drop, but decreased with lower pressure drops in subsequent tests. The fine particle fraction of indomethacin (indicating the emitted amount of drug entering the lungs) was independent of the inspiratory flowrate and inhaler internal resistance, making the formulation suitable for patients with different respiratory capabilities, like children. Finally, milled indomethacin demonstrated an anti-inflammatory effect similar to that of a topical corticosteroid in an asthmatic model.