Cystic fibrosis (CF) is an inherited lung disease characterised by the accumulation of thick layers of dried mucus in the lungs which serve as a nidus for chronic infection. Pseudomonas aeruginosa is the predominant cause of chronic lung infection in cystic fibrosis. The dense mucus coupled with biofilm formation hinder antibiotic penetration and prevent them from reaching their target. Mucoactive agents are recommended in the treatment of CF in combination with antibiotics. In spite of the extensive research in developing novel drug combinations for the treatment of lung infection in CF, to our knowledge, there is no study that combines antibiotic, antibiofilm and mucoactive agent in a single inhaled dry powder formulation. In the present study, we investigate the possibility of adding a mucoactive agent to our previously developed ciprofloxacinquercetin (antibiotic-antibiofilm) dry powder for inhalation. Three mucoactive agents, namely mannitol (MAN), N-acetyl-L-cysteine (NAC) and ambroxol hydrochloride (AMB), were investigated for this purpose. The ternary combinations were prepared via spray drying without the addition of excipients. All ternary combinations conserved or improved the antibacterial and biofilm inhibition activities of ciprofloxacin against P. aeruginosa (ATCC 10145). The addition of AMB resulted in an amorphous ternary combination (SD-CQA) with superior physical stability as indicated by DSC and nonambient XRPD. Furthermore, SD-CQA displayed better in vitro aerosolization performance (ED ∼ 71 %; FPF ∼ 49 %) compared to formulations containing MAN and NAC (ED ∼ 64 % and 44 %; FPF ∼ 44 % and 29 %, respectively). In conclusion, a ternary drug combination powder with suitable aerosolization, physical stability and antibacterial/antibiofilm properties was prepared by a single spray drying step.
Quercetin (QUE) has recently attracted increasing interest as a co-former in co-amorphous systems owing to its multiple hydrogen-bonding functionalities. However, the relationship between its intermolecular interactions and co-amorphous performance remains poorly understood. This study investigated the influence of co-former chemistry on the molecular interactions, stability, and aqueous performance of quercetin-based co-amorphous systems using arginine (ARG) and glutamic acid (GLU) as model amino acid co-formers. Co-amorphous formulations were prepared by spray drying and characterized using molecular modelling, solution-state 1H NMR titration, FTIR spectroscopy, PXRD, mDSC, dynamic vapour sorption, solubility, and dissolution studies. Molecular simulations predicted stronger miscibility and intermolecular interactions in the QUE-ARG systems than in the corresponding QUE-GLU systems, which was supported by NMR and FTIR analyses. Although all formulations were initially amorphous, the QUE-GLU systems crystallized within one week of storage, whereas the QUE-ARG systems remained amorphous for at least three months. Notably, the QUE-GLU formulations exhibited comparable or higher glass-transition temperatures, indicating that Tg alone was not predictive of physical stability. The stronger interactions observed in the QUE-ARG systems were also associated with substantially improved saturated solubility and dissolution performance. These findings demonstrate that the effectiveness of quercetin as a co-former depends on the nature and specificity of intermolecular interactions and highlight their importance in the rational design of quercetin-based co-amorphous systems.