Design of inhalable dry powders for pulmonary infection in non-cystic fibrosis bronchiectasis

Pulmonary drug administration represents an effective strategy for local delivery in the treatment of pulmonary diseases or, alternatively, to obtain systemic therapeutic effects. So far, the pulmonary delivery of antibiotics, which typically require high doses to reach effective concentrations in the lungs, remains a major challenge in the field of inhalation therapy. In this perspective, dry powder inhalers (DPIs), consisting in powder formulations combined with a dedicated device for inhalation, offer several potential advantages as they are easy to use and portable devices, enabling rapid drug administration, which usually increase patient compliance. Furthermore, they provide enhanced stability, as the drug is supplied in powder form. In this research project different particle engineering techniques were explored to assess the feasibility of developing high dose DPIs containing β-lactam antibiotics for local drug delivery in pulmonary infections, associated with non-cystic fibrosis bronchiectasis (NCFB). For the first active pharmaceutical ingredient (API) candidate, ceftazidime pentahydrate, a third-generation cephalosporin, the superiority of co-jet milling approach over spray drying was demonstrated by providing evidence of the crucial role played by the maintenance of the pentahydrate crystalline structure of the API. In particular, our results evidenced structural variations following powder preparation by different techniques, through the characterization of powders’ solid state. The selected formulation approach, consisting in co-jet milling by including L-leucine (L-leu) and magnesium stearate (MgSt), enabled the preparation of dry powders with suitable aerodynamic properties for pulmonary delivery and evidenced the different contribution provided by the two modifier surfaces tested. The superior benefit apported by L-leu incorporation was underscored. In the second part of the project, a co-spray drying approach was investigated for the development of a combination powder for pulmonary delivery, containing the β-lactam antibiotic piperacillin (PIP) and a β-lactamase inhibitor tazobactam (TZB) in a clinical effective ratio (8:1 w/w ratio). Previous studies demonstrated that the association of these two drugs effectively extend the antibacterial activity spectrum against various gram-negative pathogens, including Pseudomonas aeruginosa. In this case a formulation approach based on spray drying starting from a methanolic solution allowed for the preparation of powders with promising aerodynamic diameter (dae < 2 µm). Subsequently, the inclusion in the formulation composition of surface modifiers (L-leu and sodium stearate (NaSt)), previously tested for the first formulation, was considered to overcome the electrostatic behaviour and improve poorly defined morphology of powders containing pure drugs, by controlling their surface properties. During stability studies the excipients selected did not prove to be effective in reducing moisture absorption from the storage environment and a slight decrease in aerosol performance was observed after three weeks storage at 25°C-60%RH and 40°C-75%RH, whether the dae of powders was maintained below 5 µm. Finally, in the third part of the project inhalable microparticles with high N-acetylcysteine (NAC) payload, as a possible adjuvant treatment in chronic lung diseases, were prepared. The formulation strategy selected allowed for overcoming the technological issue related to the low glass transition temperature of NAC during spray drying, by including a high molecular weight biocompatible polymer, sodium hyaluronate (NaHYal) and L-leu as a force controlling agent, without using organic solvents. Recently, beside the well establish mucolytic activity of NAC, the potential benefit provided by its antioxidant and cytoprotective properties in the treatment of chronic pulmonary diseases have been highlighted. Our study demonstrated that spray dried powders retained promising antioxidant attitude following the preparation process, which was exerted as radical-specific scavenging activity. Additionally, stability studies demonstrated that the selected formulation maintained aerodynamic properties suitable for pulmonary administration at least over six months storage at 25°C.