Development of inhalable extra-fine particles of vancomycin for the treatment of pulmonary methicillin-resistant Staphylococcus aureus infections.

Pulmonary infections caused by Methicillin-resistant Staphylococcus aureus represent a major therapeutic challenge, highlighting the need for efficient local antibiotic delivery. This study aimed to develop an extra-fine dry powder inhaler (DPI) formulation containing vancomycin (VAN) using nano spray drying. L-leucine (LEU) and D-mannitol (MAN) were applied as excipients to improve aerosolization. A Box-Behnken design was used to optimize the formulation parameters. Particle size analysis showed that the formulations had a mean diameter of approximately 2 μm, enabling effective lung targeting. The optimized formulation (VAN_SPD; VAN:MAN:LEU ratio 3:2:1) exhibited spherical morphology and acceptable flowability (Hausner ratio 1.25; Carr index 19.99). Structural analyses (DSC and FTIR) confirmed the absence of significant physicochemical interactions. The formulation demonstrated excellent in vitro aerodynamic performance with a mass median aerodynamic diameter of 2.37 μm and a fine particle fraction of 79.72%, exceeding that of commercially available formulations. In silico deposition modeling predicted efficient delivery to the bronchial and acinar regions of the lung, with approximately 56-60% deposition. In vitro cytotoxicity studies on alveolar cell lines confirmed good biocompatibility. Overall, the developed DPI formulation represents a promising platform for pulmonary VAN delivery. Further studies, including stability and in vivo efficacy investigations, are required to support its potential clinical application.