Engineering Inhalable Carboxymethyl Chitosan-Swellable Microgels for Pulmonary Delivery of Charged Hydrophilic Molecules.

Swellable microparticles are a promising strategy for pulmonary drug delivery. They provide good aerosol performance in the dry state and enlarge after deposition in the lungs. In this study, we aimed to develop and characterize spray-dried microparticles composed of carboxymethyl chitosan (CMC), L-leucine, and suramin, a hydrophilic polyanionic drug. Microparticles were obtained by co-spray drying (Co-SD) formulations with increasing leucine content (0-10% w/w) and evaluated for morphology, thermal behavior, crystallinity, swelling, aerodynamic deposition using a Next Generation Impactor (NGI), and cytocompatibility in pulmonary epithelial cells. The 10% leucine formulation produced the highest fine particle fraction (35.2 ± 1.1%) and the lowest mass median aerodynamic diameter (1.0 ± 0.4 µm). These values indicate efficient in vitro deep lung deposition. XRPD and DSC showed that the Co-SD formulations were predominantly amorphous. Hydration studies revealed rapid water uptake and a clear increase in particle size, leading to the formation of swollen microgels. Cell viability assays demonstrated >85% viability up to 100 µM suramin, suggesting that CMC-leucine microgels enable efficient pulmonary delivery of hydrophilic drugs by combining respirable dry-state properties with in situ swelling and reducing immunological clearance. Future in vivo studies will be needed to assess long-term stability, macrophage interaction, and the translational potential of this delivery system.