Enhancement of the extra-fine particle fraction of levofloxacin embedded in excipient matrix formulations for dry powder inhaler using response surface methodology.

Extra-fine particle fraction (eFPF, the fraction of particles with aerodynamic size <2 µm) is an essential metric to evaluate the deep lung delivery of dry powder inhalers (DPIs). The product of spray-drying has the potential to be applied in DPI formulations regarding its controllable size. This study performed an eFPF enhancement of levofloxacin DPI formulations by optimizing the spray-drying process parameters such as inlet temperature, feed flow rate, and gas flow rate, using a design space compiled from response surfaces. A polysaccharide, phytoglycogen, was used as an excipient matrix to prepare DPI formulations containing the antibiotic levofloxacin hydrate and the amino acid L-leucine. The aerodynamic-related properties and the percentage yield of spray-dried particles were evaluated as target outcomes. The influence of process variables on the product outcomes was also summarized. The most critical factor controlling inhalation properties was gas flow rate, owing to its significant contributions (p<0.05), which is coherent to most articles of engineering. A design space was plotted using response surfaces to optimize process parameters. The performance of the design space was evaluated. Most responses of the optimized runs were within the 95% prediction interval. The design space was adopted to successfully fabricate levofloxacin-containing deep lung delivery inhalable particles (eFPF >5%). The usefulness of the design space in another drug was also studied. The predicted design space may support future studies that aim to prepare composite particles with fair alveolar inhalation performance for DPI formulations using a hydrophilic macromolecular polysaccharide excipient matrix and leucine.