Available online at http://www.japsonline.com ISSN 2231-3354 Online First Prospective pulmonary drug delivery system of pirfenidone microparticles for pulmonary fibrosis Uqie Shabrina Hasyyati 1 , Silvia Surini 1* , Gatot Suhariyono Suhariyono 2 1 Laboratory of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia. 2 Nuclear Metrology and Quality Safety Technology Research Center - Nuclear Power Research Organization, National Research and Innovation Agency, Tangerang Selatan, Indonesia. ARTICLE INFO Available Online: XX Key words: Pirfenidone, pulmonary delivery, pulmonary fibrosis, microparticle, cytotoxicity study. ABSTRACT Orally administered pirfenidone in pulmonary fbrosis 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 signifcantly lower interleukin-6 release than pirfenidone (p < 0.05). In conclusion, F10 shows suitable characteristics for pulmonary pirfenidone delivery in pulmonary fbrosis therapy. INTRODUCTION Pirfenidone, an anti-infammation, antioxidant, and antifbrotic drug, is used in treating pulmonary fbrosis, such as idiopathic pulmonary fbrosis (IPF) (Canestaro et al., 2016). IPF is a progressive, chronic, age-related interstitial lung disease. It is expected to increase as the population ages, with an average untreated life expectancy of 3–5 years after diagnosis (Spagnolo et al., 2021). Pirfenidone has also been studied in clinical trials to treat post-COVID-19 pulmonary fbrosis (Bazdyrev et al., 2021), reported in patients with severe and moderate COVID-19 based on artifcial intelligence analysis (Halawa et al., 2021). A meta-analysis study concluded that about 44.9% of COVID-19 survivors appear to have developed pulmonary fbrosis, which may mainly persist over time (Hama Amin et al., 2022). Fibrosis causes stiffness in the walls of the alveolus, which reduces the lungs’ functional capacity and disrupts the respiratory process. A persistent decline in lung function can be fatal (Martinez et al., 2017; Spagnolo et al., 2021). In the current treatment of pulmonary fbrosis, pirfenidone is taken orally in high doses (up to 2,403 mg/day) (Sayf, 2021). However, this route could lead to therapeutic discontinuation due to systemic adverse effects, including photosensitivity, gastrointestinal problems, anorexia, tiredness, and dizziness (Lancaster et al., 2017). Consequently, numerous studies have been conducted to identify an alternative route for pirfenidone administration. Delivering pirfenidone to the lungs through pulmonary delivery could reduce systemic exposure and subsequently reduce its adverse effect (Khoo et al., 2020). Pulmonary delivery also offers other benefts, such as reducing drug doses, duration, and the cost of the therapy (Putri et al., 2022). *Corresponding Author Silvia Surini, Laboratory of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia. E-mail: silvia @ farmasi.ui.ac.id © 2023 Uqie Shabrina Hasyyati et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Journal of Applied Pharmaceutical Science Vol. 0(00), pp 001-011, 2023 DOI: 10.7324/JAPS.2023.125985 Received on: 31/02/2023 Accepted on: 27/05/2023