Inhalable Inclusion Cocrystal of Exocarpium Citri Grandis Volatile Oil for Treatment of Acute Lung Injury

Acute lung injury (ALI) is the major cause of respiratory failure, often triggered by inflammatory responses resulting in disruption of the pulmonary gas-blood barrier. Existing treatments are limited by the poor bioavailability via systemic administration, whereas volatile oils are unsuitable for developing into inhalable formulations. In this study, we developed an inhalable cocrystal of Exocarpium Citri Grandis volatile oil (EVO) using crystallization technology with β-cyclodextrin (EVO-βCD), aiming to improve the drug's bioavailability and enhance its therapeutic efficacy for ALI. In vitro studies revealed that EVO-βCD exhibited no significant cytotoxicity at concentrations of 7.5-120.0 µg/mL and did not cause hemolysis at concentrations between 3.75-60.0 µg/mL, suggesting favorable safety profiles. Additionally, EVO and EVO-βCD significantly reduced the ROS production in LPS pretreated 16HBE cells, highlighting their antioxidant potential. In vivo experiments demonstrated that EVO-βCD cocrystals were more effective than free EVO in reducing inflammatory cytokines (TNF-α, IL-1β, IL-6) and improving pulmonary edema in LPS-induced acute lung injury in mice. The cocrystal formulation enhanced the release rate of the drug, addressing the challenges of conventional powder inhalants. These findings suggest that EVO-βCD cocrystals hold promise as a novel therapeutic approach for ALI treatment with enhanced safety and efficacy.