Intratracheal therapy using nintedanib amorphous particles in murine pulmonary fibrosis

<bold>Introduction:</bold> Nintedanib, an oral medicine for human progressive pulmonary fibrosis, still has several issues of concern, such as systemic adverse events (AEs) of liver dysfunction/diarrhea and low bioavailability. <bold>Aims and objectives:</bold> Inhalable nintedanib directly targeting the fibrotic lung is expected to prove more effective and tolerable than oral nintedanib. We thus investigated whether intratracheal (IT) nintedanib could attenuate the change in bleomycin-induced murine pulmonary fibrosis at relatively low doses compared to intraperitoneal (IP) nintedanib. <bold>Methods:</bold> Inhalable nintedanib was developed using fine droplet drying (FDD) technology (Ricoh Company, Ltd., Tokyo, Japan). FDD-nintedanib formed amorphous spherical solid dispersion particles 1–5 µm in size, showing over 10-times higher solubility compared to the original nintedanib crystals. In mouse experiments, IT or IP FDD-nintedanib solution was administered 48 h before bleomycin administration (day 1). The effect was evaluated by pulmonary function test (PFT), histological change, and amount of lung collagen on day 21. <bold>Results:</bold> Compared to mice pretreated with IP FDD-nintedanib even with the highest dose (120 µg/mouse) in a bleomycin-induced pulmonary fibrosis model, mice pretreated with IT FDD-nintedanib showed significant attenuation of: 1) PFT declines in compliance and static compliance in a dose-dependent manner (20–120 µg/mouse); 2) fibrinous exudation and cell proliferation; and 3) lung collagen content. No apparent AEs were seen. <bold>Conclusions:</bold> FDD-nintedanib IT significantly attenuated PFT declines, histological damage, and amount of lung collagen, with no apparent systemic/local AEs in a murine pulmonary fibrosis model.