Integrated continuous manufacturing of inhalable remdesivir nanoagglomerate dry powders: Design, optimization and therapeutic potential for respiratory viral infections.

While inhalable nanoparticle-based dry powders have demonstrated promising potential as next-generation respiratory medicines, erratic particle redispersibility and poor manufacturing reproducibility remain major hurdles hindering their translation from bench to bedside. We developed a one-step continuous process for fabricating inhalable remdesivir (RDV) nanoagglomerate dry powder formulations by integrating flash nanoprecipitation and spray drying. The nanosuspension formulation was optimized using a three-factor Box-Behnken design with a z-average particle size of 233.3 ± 2.3 nm and < 20% size change within six hours. The optimized inhalable nanoagglomerate dry powder formulation produced by spray drying showed adequate aqueous redispersibility (S/S = 1.20 ± 0.01) and in vitro aerosol performance (mass median aerodynamic diameter of 3.80 ± 0.58 µm and fine particle fraction of 39.85 ± 10.16%). In A549 cells, RDV nanoparticles redispersed from the inhalable nanoagglomerate powders displayed enhanced and accelerated RDV cell uptake and negligible cytotoxicity at therapeutic RDV concentrations. No statistically significant differences were observed in the critical quality attributes of the inhalable nanoagglomerate powders produced from the continuous manufacturing and standalone batch modes. This work demonstrates the feasibility of large-scale continuous manufacturing of inhalable nanoagglomerate dry powder formulations, which pave the way for their clinical translation.