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. 2021 Nov 23;13(12):1988.
doi: 10.3390/pharmaceutics13121988.

Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics

Beatriz Arauzo  1   2   3 , Tania B Lopez-Mendez  3   4 , Maria Pilar Lobera  1   2   3 , Javier Calzada-Funes  1   2   3 , Jose Luis Pedraz  3   4   5 , Jesus Santamaria  1   2   3
Affiliations

Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics

Beatriz Arauzo et al. Pharmaceutics. .

Abstract

Inhalation therapy offers several advantages in respiratory disease treatment. Azithromycin is a macrolide antibiotic with poor solubility and bioavailability but with a high potential to be used to fight lung infections. The main objective of this study was to generate a new inhalable dry powder azithromycin formulation. To this end, an electrospray was used, yielding a particle size around 2.5 µm, which is considered suitable to achieve total deposition in the respiratory system. The physicochemical properties and morphology of the obtained microparticles were analysed with a battery of characterization techniques. In vitro deposition assays were evaluated after aerosolization of the powder at constant flow rate (100 L/min) and the consideration of the simulation of two different realistic breathing profiles (healthy and chronic obstructive pulmonary disease (COPD) patients) into a next generation impactor (NGI). The formulation was effective in vitro against two types of bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the particles were biocompatible, as evidenced by tests on the alveolar cell line (A549) and bronchial cell line (Calu-3).

Keywords: azithromycin; dry powder; electrospray; microparticles; pulmonary administration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Particle size in function of flow (mL/h) at 10% w/w concentration with chloroform as solvent: (A) 1 mL/h; (B) 1.5 mL/h; (C) 2 mL/h; (D) 2.5 mL/h; (E) Influence of flow on particle size distribution (mean ± SD, n = 3).
Figure 2
Figure 2
Particle size according to the concentration (% w/w) and the flow used (1.5 mL/h) with chloroform as solvent: (A) 1% w/w; (B) 2.5% w/w; (C) 5% w/w; (D) 10% w/w; (E) Influence of azithromycin concentration on particle size distribution (mean ± SD, n = 3).
Figure 3
Figure 3
X-ray diffraction patterns: (A) raw azithromycin; (B) azithromycin microparticles.
Figure 4
Figure 4
Equilibrium solubility: Raw azithromycin and azithromycin microparticles at different pH (6.8–8.2), (A) 24 h; (B) 48 h (mean ± SD, n = 3).
Figure 5
Figure 5
Aerodynamic particle size distribution: (A) mass deposited in the next generation impactor at constant flow (100 L/min); (B) mass deposited in the next generation impactor with respiratory profile from healthy and COPD patient (mean ± SD, n = 3).
Figure 6
Figure 6
Antibacterial activity of azithromycin microparticles against S. aureus and P. aeruginosa. Control was C.A (bacteria untreated). OD600 (A) S. aureus; (B) P. aeruginosa (mean ± SD, n = 3).
Figure 7
Figure 7
SEM images S. aureus (A) control; (B) after 24 h of treatment with AZT MPs; P. aeruginosa (C) control; (D) after 24 h treatment with AZT MPs at MIC concentrations.
Figure 8
Figure 8
Cell viability measured by Alamar blue. A549 cell viability after (A) 24 h and (B) 48 h. Calu-3 cell viability after (C) 24 h and (D) 48 h. Both types of cells were exposed to increasing concentrations of microparticles in cell culture medium. Significant differences (p < 0.05) between different samples were tested in relation to raw AZT (mean ± SD, n = 3).
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