Prospective pulmonary drug delivery system of pirfenidone microparticles for pulmonary fibrosis

Orally administered pirfenidone in pulmonary fibrosis therapy induces numerous systemic adverse effects. This study aims to develop pirfenidone microparticles for pulmonary delivery to reduce the systemic adverse effects of pirfenidone. Ten formulations of pirfenidone microparticles were prepared using the spray drying method, including sodium carboxymethyl cellulose and sodium alginate as polymers, ammonium bicarbonate as porogen, and L-leucine as dispersing agent. These microparticles were evaluated using physicochemical characterization, stability, and in vitro cytotoxicity studies. The F10 formulation, which consisted of sodium alginate 1.0%, ammonium bicarbonate 0.3%, and L-leucine 0.4%, had the most relevant results for inhalation. The mass median aerodynamic diameters (MMADs) of F10 were 0.065, 0.597, 2.212, and 5.626 μm, ideal for deposition in the bronchiolar to the alveolar region. The stability study showed that the pirfenidone contents were 99.08%–100.00% and 98.83%–100.00%, with an increasing MMAD up to 5.895 and 6.273 μm at 30°C ± 2°C and 40°C ± 2°C, respectively. The in vitro cytotoxicity study revealed that the pulmonary epithelial cells (A549 cells) were less sensitive to the excipients in the formulation than pirfenidone (p = 0.018). Furthermore, F10 caused significantly lower interleukin-6 release than pirfenidone (p < 0.05). In conclusion, F10 shows suitable characteristics for pulmonary pirfenidone delivery in pulmonary fibrosis therapy.