Design and development of inhalable cefepime dry powder targeting P. aeruginosa infections

Cefepime is recommended for treating severe pulmonary infections caused by P. aeruginosa using intravenous route that limits sufficient deposition in the bronchi and alveoli of the lungs. To address this, we developed a cefepime dry powder while enabling lower total administered doses using an inhaler. A factorial design (Xⁿ + 1) with two additives, L-leucine and L-tryptophan, was used to prepare inhalable and physicochemical stable powders via spray drying. The preparation parameters retained drug contents above 90 % across all cefepime powder formulations (CPF; n = 10). The particles were spherical with a mean geometric particle diameter 1-2 µm. Leucine significantly improved the aerodynamic properties by increasing the number of dimples on the particles' surfaces. The optimized formulation, CPF-3 (10 % leucine-only), produced the highest fine particle dose (FPD), corresponding to a fine particle fraction (FPF) of approximately 80 %. The minimum inhibitory concentrations (MIC) and 90 % minimum biofilm inhibitory concentrations (MBIC₉₀) of the formulations were comparable to those of the cefepime raw material and safe on the lung epithelial cell line (A549). The powder exhibited moisture-sensitivity and therefore requires storage in a dry environment at room temperature. Overall, this study establishes a robust formulation strategy of inhalable fourth generation β‑lactams.