Particle engineering, aerosol physics, and pulmonary deposition of single-inhaler triple ICS/LABA/LAMA therapies in...

Single-inhaler triple therapy (SITT) combining an inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist (ICS/LABA/LAMA) represents the current ceiling of inhaled pharmacotherapy for moderate-to-very-severe chronic obstructive pulmonary disease and severe uncontrolled asthma. Five device platforms are currently approved: two extrafine formulations delivering beclomethasone dipropionate/formoterol/glycopyrronium (the Modulite solution pressurised metered-dose inhaler [pMDI] and the NEXThaler breath-actuated dry powder inhaler [DPI]); the co-suspension pMDI Aerosphere platform (budesonide/glycopyrrolate/formoterol); the standard-particle Ellipta DPI (fluticasone furoate/umeclidinium/vilanterol); and the low-resistance, single-dose capsule-based DPI Breezhaler (mometasone furoate/indacaterol/glycopyrronium). Despite a shared pharmacological class, these systems differ in aerosol physics, particle engineering, intrapulmonary deposition patterns, and device-patient interaction. Furthermore, some of them are authorized only for COPD or asthma. This narrative review examines the technology and in vivo deposition evidence for each SITT platform, discusses real-world performance determinants (particle size, flow dependency, technique robustness), and proposes an expert-informed framework for patient-level device selection. Methodological limitations include reliance on in silico Functional Respiratory Imaging data when in vivo scintigraphy is unavailable, and inconsistent dose denominators across studies (emitted vs. metered dose). Cross-platform comparisons are limited by heterogeneous methodologies, and no SITT platform has demonstrated universal superiority. In platform-specific studies, NEXThaler shows relatively high lung deposition (∼55% of emitted dose) though flow-dependent; Aerosphere is robust to inhalation technique variations; Modulite provides extrafine, peripheral delivery; Ellipta and Breezhaler offer once-daily convenience with moderate deposition. Rational device selection requires structured assessment of patient inspiratory capacity, disease phenotype, coordination, and adherence. Head-to-head scintigraphy and prospective imaging-outcome studies represent major evidence gaps.