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. 2025 Jun 11;17(6):770.
doi: 10.3390/pharmaceutics17060770.

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

Gracia Molina  1 , Dolores R Serrano  1   2 , María Auxiliadora Dea-Ayuela  3 , Carmina Rodriguez  4 , Elena González-Burgos  5 , Brayan J Anaya  1
Affiliations

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

Gracia Molina et al. Pharmaceutics. .

Abstract

Background/Objectives: 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. Methods: Using a quality-by-design approach, an optimized formulation (4% AZM, 20% leucine, and 76% mannitol) was achieved. Results: 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 Pseudomonas aeruginosa 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 Streptococcus pneumoniae. AZM microparticles demonstrated good biocompatibility with red blood cells and bronchial epithelial cells at therapeutic concentrations. Conclusions: These findings establish a promising lactose-free antibiotic formulation for targeted pulmonary delivery with enhanced antimicrobial efficacy.

Keywords: azithromycin; dry powder inhaler; lactose-free; microparticles; pulmonary drug delivery.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Haemolysis methodology representation.
Figure 2
Figure 2
Influence of AZM and leucine on the yield and particle size. Key: (A1,A2) yield (%) and (B1,B2) particle size (µm).
Figure 3
Figure 3
Morphological analysis. (A1,A2) SEM and (B1,B2) TEM.
Figure 4
Figure 4
pXRD analysis (A) and FTIR spectra (B). Key: (a) AZM-MP, (b) Physical mixture, (c) Unprocessed mannitol, (d) Unprocessed leucine, and (e) Unprocessed AZM.
Figure 5
Figure 5
(A) DSC and (B) TGA. Keys: (a) AZM-MP (purple), (b) Physical mixture (green), (c) Unprocessed mannitol (blue), (d) Unprocessed leucine (red), and (e) Unprocessed AZM (black).
Figure 6
Figure 6
AZM deposition in different stages of the NGI. Key: (IP/MA/HI) device + mouth adaptor + induction port (St) stage, and (MOC) micro-orifice collector. Data are expressed as mean ± SD (n = 3).
Figure 7
Figure 7
Antibacterial Efficacy at different AZM concentrations. Keys: (A) P. aeruginosa and (B) S. pneumoniae.
Figure 8
Figure 8
(A) In vitro haemolysis. (B) In vitro cytotoxicity. Data are expressed as mean ± SD (n = 5). * p < 0.05 vs. control and # p < 0.05 vs. formulation. (C) Cell morphology of Calu-3 cells micrographs with 10 µg/mL and 25 µg/mL AZM concentration for 24 h.
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