Abstract

Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis

Cystic fibrosis (CF) is defined as a severe lung disease which makes the affected person prone to Pseudomonas aeruginosa colonization. The thick mucus occurring in CF, combined with biofilm formation, limits drug penetration. These factors prevent the drug from being present in sufficient quantity at the site of action. Consequently, bacterial infections cannot be cured efficiently. In addition to antibiotics, it is recommended that mucolytic N-acetylcysteine (NAC) is used during treatment of cystic fibrosis. Although various formulations have been described and designed to improve lung function of CF patients, the combination of antimicrobial agents with NAC as dry powder formulations has not been extensively studied. The development of an innovative dry powder preparation for inhalation (DPI) exploiting salt bridges between NAC and various antibiotics as well as characterizing their solid-state properties and storage stability (physical stability) are the main aims of this work. NAC can be spray-dried with azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro) without using organic solvents. The result is the formation of Azi/NAC, Tobra/NAC and Cipro/NAC complexes as DPI preparations. Spray-drying led to amorphous states which was shown by solid-state characterization. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable when stored under stress conditions. The determined median mass aerodynamic diameter (MMAD) is within the range suitable for inhalation (< 5.0 μm). The preparation of the multifunctional antibiotic/NAC formulations does not affect antimicrobial activity. With respect to the inhibitory effect on biofilm formation of P. aeruginosa PA14 promising results were observed.