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Flowrate-Independent indomethacin dry powder inhaler for potential treatment of pediatric asthma: In vitro
Nazareth E Ceschan1, Andrea V Dugour2, Beatriz Behrend3
1Planta Piloto de Ingeniería Química (PLAPIQUI, UNS-CONICET), Camino La Carrindanga, Km 7, Bahía Blanca 8000, Argentina; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, Bahía Blanca 8000, Argentina.
Insights
A novel indomethacin dry powder inhaler (DPI) shows promise for pediatric asthma. This non-steroidal anti-inflammatory drug (NSAID) formulation offers a potential alternative to corticosteroids, with effective lung delivery and anti-inflammatory properties.
Area of Science:
- Pharmaceutical Technology
- Respiratory Medicine
- Pediatric Pulmonology
Background:
- Asthma is a chronic respiratory condition prevalent in children, often requiring emergency care.
- Current inhaled corticosteroid treatments for asthma face adherence and side effect challenges.
- Non-steroidal anti-inflammatory drugs (NSAIDs) are generally avoided in asthma due to potential adverse reactions.
Purpose of the Study:
- To develop and evaluate an indomethacin dry powder inhaler (DPI) for pediatric asthma treatment.
- To explore indomethacin as a potential alternative to corticosteroids, aiming to reduce systemic side effects.
- To assess the inhalation properties and anti-inflammatory efficacy of the indomethacin formulation.
Main Methods:
- Indomethacin was processed into inhalable crystalline microparticles (6.0 μm) using cost-effective jet-milling.
- Particle dispersion and aerodynamic properties were evaluated using inhalers with varying intrinsic resistances.
- Pharmacopoeial conditions (4 KPa) were used to assess mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and emitted fraction.
- The fine particle fraction (FPF) was analyzed concerning inspiratory flow rate and inhaler resistance.
- The anti-inflammatory effect was tested in an established asthma model.
Main Results:
- Jet-milling produced suitable microparticles, though agglomeration occurred, which was overcome by inhaler dispersion.
- MMAD values ranged from 3.7-4.0 μm with a narrow particle size distribution (GSD 1.5-1.7).
- High emitted fraction was observed at 4 KPa, with FPF independent of inspiratory flow rate and inhaler resistance.
- Milled indomethacin exhibited anti-inflammatory effects comparable to topical corticosteroids in an asthma model.
Conclusions:
- The developed indomethacin DPI formulation is suitable for pediatric asthma, offering consistent lung drug delivery across different patient inhalation capabilities.
- This NSAID-based inhaler presents a viable alternative to traditional corticosteroid therapies, potentially improving treatment adherence and reducing side effects.
- The formulation's demonstrated anti-inflammatory efficacy supports its potential clinical application in managing pediatric asthma.
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 cost-effective 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.
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