Lung Delivery of Lactose-Free Microparticles Loaded with Azithromycin for the Treatment of Bacterial Infections

<b>Background/Objectives:</b> Respiratory bacterial infections remain a significant global health challenge, with effective drug delivery to the lungs being crucial for successful treatment. This study aimed to develop a lactose-free dry powder inhaler (DPI) formulation containing azithromycin (AZM) microparticles for enhanced pulmonary delivery. <b>Methods:</b> Using a quality-by-design approach, an optimized formulation (4% AZM, 20% leucine, and 76% mannitol) was achieved. <b>Results:</b> The formulation demonstrated excellent aerodynamic properties with a mass median aerodynamic diameter (MMAD) of 2.72 μm ± 0.01 μm and fine particle fraction (FPF) (<5 μm) of 65.42% ± 5.12%. AZM-loaded microparticles exhibited enhanced efficacy against <i>Pseudomonas aeruginosa</i> with a two-fold reduction in the minimum bactericidal concentration (7.81 μg/mL vs. 15.62 μg/mL) compared to unprocessed AZM, while maintaining activity against <i>Streptococcus pneumoniae</i>. AZM microparticles demonstrated good biocompatibility with red blood cells and bronchial epithelial cells at therapeutic concentrations. <b>Conclusions:</b> These findings establish a promising lactose-free antibiotic formulation for targeted pulmonary delivery with enhanced antimicrobial efficacy.