Dectin-1 receptor-targeted β-glucan microparticles as dry powder inhalation system – a novel strategy to improve lung pharmacokinetics of rifampicin

Tuberculosis (TB) remains a global health concern due to complex and lengthy treatment, suboptimal drug concentrations in alveolar macrophages (AMs) and increasing drug resistance. This study investigates dectin-1 receptor-targeted dry powder inhalation (DPI) system for rifampicin (Rif) using β-glucan microparticles (GMPs) for enhanced delivery to AMs. Rif-loaded GMP (GMP-R) exhibited >55% drug entrapment and favourable aerodynamic properties (fine particle fraction: 36%, mass median aerodynamic diameter: 4-5 μm) for deep lung deposition. Sustained <i>in vitro</i> drug release fitting Korsmeyer-Peppas model indicated Fickian diffusion as the predominant mechanism. Drug release was more sustained at lysosomal pH. GMP-R demonstrated >99% uptake into RAW 264.7 macrophages within 1 h and minimal cytotoxicity. No significant changes in particle size and aerosolisation characteristics were observed during the 6-month accelerated stability testing (40°C ± 2°C/75% ± 5%RH). <i>In vivo</i> pharmacokinetics in rats revealed ∼23-fold higher drug concentration in AMs and extended lung residence (∼48 h) with intratracheal GMP-R compared to oral Rif. GMP-R exhibited targeting index of 5.01, with intracellular inhibitory concentrations maintained for ∼20 h. Overall, dectin-1 receptor-targeted inhalable GMP-R enhances lung deposition and intracellular concentrations, while reducing systemic toxicity. Pharmacokinetic outcomes indicate its potential for reducing dosing frequency, while warranting further validation of therapeutic efficacy in infection models.