Systemic delivery of nintedanib using PLGA-based discoidal polymeric particles for idiopathic pulmonary fibrosis treatment

Nintedanib is an approved tyrosine kinase inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF); however, the bioavailability is low due to low solubility. In this study, nintedanib-loaded poly (lactic-co-glycolic acid)-based discoidal polymeric particles (Nib-PLGA-DPPs) were prepared, and their effectiveness was evaluated for the treatment of IPF. Nib-PLGA-DPPs with a uniform size and shape were manufactured using a top-down method by adjusting the lactide:glycolide molar ratio (50:50, 75:25, and 85:15) of PLGA. The physicochemical properties, drug loading content, and in vitro nintedanib release behavior were characterized; ex vivo biodistribution was performed in mice. The therapeutic efficacy of Nib-PLGA-DPPs was evaluated in a murine model of IPF induced by bleomycin (BLM). The synthesized Nib-PLGA-DPP showed an average size of 2.8 ± 0.2 μm with a zeta potential value of approximately −23.5 mV and 15.7% drug loading content. Approximately 40% of the nintedanib was initially released from Nib-PLGA (50:50)-DPPs during the first 24 h; however, the initial burst was significantly reduced to 18% by increasing the lactide:glycolide ratio from 50:50 to 85:15. Nib-PLGA (50:50)-DPPs showed rapid nintedanib release reaching completion within 3 days; however, Nib-PLGA (85:15)-DPPs sustained drug release over 7 days. Notably, ex vivo imaging showed that lung accumulation of fluorescent-labeled PLGA-DPPs in BLM-treated mice was approximately 2-fold higher than that in normal mice at early time points. In the IPF murine model, Nib-PLGA-DPPs showed a greater reduction in the total BALF cell numbers and severity of pulmonary fibrosis than nintedanib alone. In addition, the higher lactide content of the PLGA polymer exhibited a lower degree of pulmonary inflammation and fibrosis. Our findings indicate that the lactide ratio of the PLGA composition could enhance the bioavailability of drug molecules and that micro sized Nib-PLGA-DPPs could be a promising systemic delivery vehicle for treating IPF. [Display omitted] •Fabricated biodegradable discoidal polymeric particles containing nintedanib.•Stability was improved by increasing the lactide/glycolide ratio of PLGA.•Nintedanib-loaded PLGA-DPPs significantly reduced severity of pulmonary fibrosis.•Nib-PLGA-DPPs have potential for improving the bioavailability of anti-fibrotic drugs.