Inhalable quercetin dihydrate nanosuspension mitigates silica-induced pulmonary fibrosis in rats.

In the current scenario, safe and efficacious drugs for the therapy of pulmonary fibrosis have been extremely rare. Moreover, the oral dosage forms available in the market offer limited therapeutic efficacy with numerous side effects. Hence, pulmonary fibrosis is untreatable to date. Quercetin dihydrate (QD) is a traditional medicine reported to have mast cell-stabilizing, anti-fibrotic, and anti-inflammatory properties for the treatment of pulmonary fibrosis. QD has poor bioavailability; hence, a nanosuspension (NS) was developed to enable efficient pulmonary delivery. QD-NS through inhalation therapy is a novel targeted drug delivery for the therapy of pulmonary fibrosis. To overcome the limitations of oral dosage forms, we have developed an inhalation therapy of quercetin dihydrate nanosuspension (QD-NS) through a top-down approach. The NS was optimized by adjusting factors like stabilizer, pressure, and cycle of high-pressure homogenizer (HPH). The quality and stability of the optimized formulation were evaluated through in vitro and stability studies, whereas the efficacy of the formulation was determined with in vivo studies. The % fine particle fraction was obtained as 69.07 ± 0.135% thereby indicating aerosol drug deposition into the lower region of the lungs. The value for MMAD and GSD was recorded as 0.28 µm and 2.30 µm, respectively, which indicates drug targeting into the lungs with a narrow distribution of particles with uniform particle size. The drug release profile of QD-NS expresses sustained release of the drug, and the formulation was most stable at storage conditions of 2-8 °C. In pharmacodynamic studies, the QD-NS (inhalation group) exhibited significant decreased levels of transforming growth factor β (TGF-β) (p < 0.01 and p < 0.001), lactate dehydrogenase (LDH) (p < 0.001 and p < 0.01), and alkaline phosphatase (ALP) (p < 0.01 and p < 0.0001) in both preventive and treatment aspects, compared with the silica-induced diseased group. Moreover, it also reduced the inflammatory cell infiltration of lymphocytes (p < 0.01 and p < 0.0001), granulocytes (p < 0.01 and p < 0.0001), monocytes (p < 0.01 and p < 0.0001), monocytes (p < 0.01 and p < 0.0001), and WBC (p < 0.0001 and p < 0.0001) in the lungs for co- and post-treatment. Additionally, on comparing QD-NS (inhalation group) with QD-NS (oral group), the inhalation therapy showed better efficacy due to its targeted action. The data reveal that QD-NS inhalation therapy offers improved efficacy with enhanced bioavailability for the treatment of pulmonary fibrosis.