Enhanced bioavailability of anemoside B4 by dry powder inhalation mitigates high-altitude acute lung injury.

Abstract

BACKGROUND: Anemoside B4 (AB4), a pentacyclic triterpenoid saponin, exhibits potent anti-inflammatory and antioxidant activities; however, it has poor oral bioavailability. Hypobaric hypoxia (HH) can induce high-altitude acute lung injury (ALI) through inflammatory response and oxidative stress pathways, highlighting the need for effective targeted therapies. PURPOSE: This study aimed to develop an AB4 dry powder inhaler (DPI) for improving lung deposition and bioavailability, and to evaluate its prophylactic efficacy against high-altitude ALI. METHODS: AB4 inhalable microparticles were prepared by antisolvent precipitation and developed into a DPI formulation. Aerodynamic properties were characterized by mass median aerodynamic diameter (D) and fine particle fraction (FPF). Anti-inflammatory activity was assessed in vitro using an LPS-stimulated alveolar macrophage model. An in vivo HH/LPS co-induced rat model of high-altitude ALI was established to investigate pharmacodynamic effects and bioavailability. RESULTS: AB4 DPI exhibited excellent aerodynamics (D: 1.92 μm; FPF: 62.86 ± 10.51%). It inhibited LPS-induced release of TNF-α, IL-6, and IL-1β. Inhalation of AB4 DPI attenuated pulmonary inflammation in vivo and restored oxidative balance by reducing malondialdehyde (MDA) and myeloperoxidase (MPO) levels while increasing superoxide dismutase (SOD) activity. The absolute bioavailability reached 18.61 ± 5.81%, representing a 74.44-fold increase compared to oral administration (0.25 ± 0.19%). CONCLUSION: This study successfully combined a traditional Chinese medicine component with advanced particle engineering technology to develop an efficient non-invasive pulmonary drug delivery system. AB4 DPI retained bioactivity while markedly addressing the pharmacokinetic limitations of oral administration, offering a clinically promising prophylactic strategy against high-altitude ALI.