Colistin-stabilized antisolvent precipitation enables engineering of microcrystalline niclosamide for inhalable...

Niclosamide and colistin sulfate exhibit strong in vitro synergistic activity against multidrug-resistant Gram-negative pathogens in cystic fibrosis; however, their co-formulation for inhaled delivery is constrained by differences in physicochemical properties and the high drug loading required for activity. Here, we report a formulation-focused strategy to enable excipient-minimized pulmonary co-delivery of niclosamide with colistin sulfate by engineering microparticles through liquid antisolvent precipitation followed by spray drying. Colistin sulfate was intentionally leveraged as a surface-active crystallization excipient, functioning both as an antimicrobial agent and as an interfacial stabilizer during niclosamide microcrystal formation. By varying the colistin:niclosamide molar ratio, median niclosamide particle size could be tuned from ∼7.7 µm at 1:1 to ∼1.3 µm at 24:1. Colistin adsorption inverted particle surface charge and suppressed time-dependent growth, consistent with interfacial stabilization during crystallization. The COL-NIC 8:1 formulation was downstream-processed via spray drying (geometric median size = 1.46 ± 0.50 μm) and exhibited favorable aerosol performance when delivered using a medium-resistance dry powder inhaler (FPF < 5 µm 75.3 ± 1.0%). Solid-state characterization indicated that niclosamide retained its crystalline structure, with no evidence of strong interaction with colistin. Finally, a preliminary in vivo lung infection model was used to assess the feasibility of pulmonary administration and the antibacterial response of the co-processed formulation relative to a standard-of-care comparator. Together, these results establish a particle-engineering platform for producing high-drug-loading niclosamide-colistin inhalation powders, highlighting how one active ingredient can function as a processing aid for excipient-minimized co-delivery of antibiotic combinations.