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Cystic fibrosis (CF) lungs are usually susceptible to Pseudomonas aeruginosa colonization and this bacterium is resistant to immune system clearance and drug control. Particularly, the biofilm mode of growth protects several microorganisms from host defenses and antibacterial drugs, mainly due to a delayed penetration of the drug through the biofilm matrix. Biofilm, together with lung mucus viscosity and tenacity, reduces, therefore, the effectiveness of conventional antibiotic therapy in CF. The aim of this research was to design and develop a stable, portable, easy to use dry powder inhaler (DPI) for CF patients, able to release directly to the lung an association of macrolide antibiotics (clarithromycin) and a mucolytic agent (N-Acetyl-Cysteine). Its effectiveness is based on the counteracting of the characteristics of P. aeruginosa infections in CF (lung bacterial adhesion to lung epithelium, biofilm formation and mucus viscosity) and the ability to let the antimicrobial drug exert their pharmacological action.A solution of these two drugs, without any excipients, was spray-dried to obtain respirable microparticles, characterized by aerodynamic diameters suitable for inhalation (<5.0 μm). The morphology evaluation evidenced particles shape dependent on water content in the spray drying feeds, with wrinkled particles more evident with higher water content. Moreover, thanks to the presence of N-acetylcysteine which can interact with clarithromycin dimethyl-amino group, a consistent enhancement of drug solubility was obtained, compared to raw material and to the drug sprayed alone. The mucolytic agent added in the DPI may improve the macrolide diffusion into the mucus, enabling its action.