Mucolytic Core–Shell Particles to Boost Levofloxacin Penetration Through the Mucus Barrier in Cystic Fibrosis

Purpose: The purpose of this study was to investigate multi-fluid spray drying as a formulation strategy to engineer inhalable microparticles containing levofloxacin and mucolytic agents, and to evaluate how formulation and process parameters influence particle properties, aerosol performance, and drug release under mucus-relevant conditions. Methods: Microparticles containing levofloxacin in combination with mucolytic agents were produced using a mini spray dryer equipped with a triple-fluid nozzle. Different compositions and particle architectures were obtained by varying formulation and excipient allocation. The resulting powders were characterized in terms of morphology, bulk, tapped and true density, aerodynamic performance, and in vitro drug release evaluated both in the absence and presence of a mucus layer. Results: Ambroxol showed greater suitability for spray drying than N-acetylcysteine, resulting in markedly higher process yields (up to 74%). The incorporation of L-leucine as a functional excipient reduced particle agglomeration and improved powder handling and aerosolization, with fine particle fractions exceeding 38% for leucine containing formulations. Drug release experiments demonstrated that spray drying altered release behaviour under diffusion limiting conditions imposed by a mucus layer compared to dissolution under sink conditions. Conclusions: Overall, the results indicate that multi-fluid spray drying enables effective modulation of the physicochemical and aerodynamic properties of inhalable microparticles. This study provides mechanistic insight into how formulation composition and process design influence particle behaviour in mucus-relevant environments, supporting the use of this approach as a flexible platform for the development of inhalable formulations.