Inhaled nintedanib dry powder formulation for the treatment of idiopathic pulmonary fibrosis: Pharmacodynamic and pharmacokinetic study

Nintedanib has been clinically proven to slow the progression of idiopathic pulmonary fibrosis (IPF); however, its therapeutic utility is limited by the side effects resulting from extensive tissue distribution following oral administration. To minimize systemic exposure and related adverse effects, an inhalable dry powder formulation of nintedanib was developed to directly deliver the drug to the lung. The spray-dried formulation of nintedanib (SD-NTB), incorporating leucine as a dispersion enhancer, was successfully prepared, achieving favorable in vitro aerodynamic performance. The ex vivo fluorescence images of dissected rat lungs further confirmed successful lung deposition of SD-NTB following intratracheal insufflation. The inhalable SD-NTB formulation also demonstrated significant therapeutic efficacy by improving lung function and decreasing fibrotic cytokines in the lung. Histological analysis further supported these findings, showing reduced inflammatory infiltration and collagen deposition in the lung. The SD-NTB also demonstrated well-tolerance after consecutive administration. Pharmacokinetic analysis revealed that inhaled nintedanib remained predominantly localized in the lung with minimal systemic exposure. In conclusion, the pulmonary delivered nintedanib achieved comparable antifibrotic efficacy to oral nintedanib, but at a much lower dose and with reduced systemic exposure. These results underscore the potential of SD-NTB as a safe and effective inhalation therapy for IPF, offering substantial advantages over conventional oral delivery.