Enhanced semaglutide bioavailability via spray freeze dried powder for inhalation: Unveiling safety and broad potential applications

Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has been approved for blood glucose management in Type 2 diabetes (T2D) and obese patients. However, its clinical use is limited by poor oral bioavailability and suboptimal adherence to subcutaneous injections, highlighting the need for alternative delivery routes. In this study, we developed semaglutide dry powder for inhalation (sema-DPI) using spray drying (SD) and spray freeze drying (SFD) techniques, and evaluated their characteristics of particle and pharmacokinetics through modern preparation assessment methods. The results indicated that under similar parameters, SFD-sema-DPI exhibited a rougher particle surface compared to the SD-sema-DPI, which provided better aerodynamic performance. Additionally, SFD-sema showed prolonged plasma presence in rats and enhanced bioavailability. Furthermore, the inhalation safety of SFD-sema-DPI was evaluated in rats. Continuous inhalation at a dose of 4.1 mg/kg/day for 28 days did not produce any significant pulmonary or systemic lesions. Our findings suggest that SFD-sema-DPI may offer a superior alternative for T2D and obese patients.