Pulmonary delivery of low-dose dexamethasone significantly reduces toxicity in acute lung injury therapy.

Dexamethasone (DEX), a potent glucocorticoid with anti-inflammatory and immunosuppressive properties, exhibits dose-limiting systemic toxicity during long-term use. Inhalation therapy enables targeted pulmonary delivery, enhancing therapeutic efficacy while minimizing systemic exposure compared to oral routes. This study designed a DEX dry powder inhaler (DPI) formulation exhibiting excellent aerodynamic performance with a good fine particle fraction (FPF = 49.01%), which achieved approximately 7.1-fold higher pulmonary exposure relative to intravenous injection at an equivalent dose. Additionally, a 10-fold dose reduction of DEX achieved equivalent efficacy to the i.v. DEX group and significantly alleviated acute lung injury (ALI). The elevation ratios of lung coefficient in the intragastric administration of DEX raw material solution (i.g. DEX) group at 7, 14, and 28 days were approximately 4.0-, 2.1-, and 5.8-fold higher than those of in the inhalation of low-dose DEX DPI formulation (inhal. L-DEX) group in tolerability evaluation, indicating the less severe pulmonary edema in the inhalation group. Notably, a 10-fold lower DEX dose administered via inhalation reduced significantly systemic and pulmonary toxicity by organ and blood indicators at 7, 14 and 28 days, compared to high-dose intragastric administration (p < 0.01). Overall, this optimized pulmonary DEX delivery strategy demonstrated significant potential for clinical translation, offering enhanced lung targeting, efficacy at reduced doses, and a favorable safety profile.