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

Abstract

Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF. Although several formulations have been developed for inhalation therapy to improve the pulmonary condition in CF patients, there is still no comprehensive study on a combined multifunctional dry powder formulation of antibiotics with NAC. In this work, we developed an innovative multifunctional dry powder inhaler (DPI) formulation based on salt formation between NAC and antibiotics and characterized their solid state properties and physical stability. NAC could be spray dried together with three different antibiotics, azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro), without the use of organic solvents to form Azi/NAC, Tobra/NAC and Cipro/NAC DPI formulations. Solid-state characterization of these DPI formulations showed that they were amorphous after spray drying. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable under storage at stress conditions. For particle characterization, the obtained mass median aerodynamic diameters were in a suitable range for inhalation (< 5.0 µm). The multifunctional antibiotic/NAC formulations conserved or improved the antibiotic susceptibility and showed promising results regarding the inhibition of P. aeruginosa PA14 biofilm formation.

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS

“…NGI was a widely recognized evaluation approach for the in vitro aerosolization performance of DPIs 63 , 64 , 65 . In the present study, the modular concept was also applied in NGI experiments to explore the aerosolization performance of model DPIs under different U 0 in detail.…”

Current and Emerging Therapies to Combat Cystic Fibrosis Lung Infections

“…From Pollini, S. et al, 2018, PLoS ONE 13: e0203941 [144]. Dry powder formulations of N-acetylcysteine with and without added antibiotic, have also been trialled on biofilms of P. aeruginosa, to identify synergistic or additive effects [147]. N-acetylcysteine and the antibiotics were separately dissolved, and mixing was carried out slowly until the correct ratios were achieved.…”

Pulmonary Drug Delivery of Antimicrobials and Anticancer Drugs Using Solid Dispersions

“…CASDs are believed to be able to provide an increase in drug kinetic solubility thanks to the high energy of the amorphous state driving faster dissolution [ 128 ]. In addition, improved physical stability is offered through an increase in the glass transition temperature (T g ) and the presence of intermolecular interactions between the API and coformer, as reported by several research papers [ 124 , 129 ]. CASDs are said to reduce hygroscopicity, as API hydrogen bonding regions are strongly bound to the coformer.…”

“…In a separate study, Lababidi et al, further examined the success CASDs had in pulmonary drug delivery by which azithromycin and ciprofloxacin were spray dried with L-leucine and n-acetyl cysteine (NAC), an amino acid derivative and known mucolytic [ 129 ]. Mucolytics are used in combination with antibiotics to dissolve thick mucus found in the CF lung [ 157 , 158 ].…”