Clinically translatable anti-fibrotic nanosuspension for inhaled treatment of idiopathic pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic pulmonary fibrosis, irreversible lung function decline, and high mortality rate. Oral nintedanib (NTB) is one of the rare anti-fibrotic drugs clinically available for managing the condition but suffers from poor bioavailability and lung delivery efficiency as well as numerous off-target adverse effects. To address these critical limitations, we developed a nanosuspension (NS) formulation of NTB (NTB-NS) for inhaled treatment of IPF. The formulation is composed entirely of FDA-approved materials, including NTB and polysorbate 80, a surfactant approved for respiratory use in a clinic, and can be freeze-dried to a powder form for long-term storage and remote shipping without perturbing the physicochemical properties and drug activity. NTB-NS locally administered via oropharyngeal administration exhibited favorable pharmacokinetics over the standard oral administration of nintedanib esylate (NTB-esy), resulting in comprehensive anti-inflammatory and anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrosis. Notably, locally administered NTB-NS, but not oral NTB-esy, normalized several key lung function parameters in the model despite the use of 60-fold and 3-fold lower dose and dosing frequency, respectively. The findings here may open a new avenue for the treatment of IPF and potentially other fibrotic lung diseases in the clinic.