An Ionic Liquid-Based Enteric Formulation for Enhanced Oral Delivery of Semaglutide in Type 2 Diabetes Mellitus

Oral delivery of peptide therapeutics remains challenging due to gastrointestinal degradation, poor epithelial permeability, and extremely low bioavailability. To address these limitations, we developed an enteric solid formulation based on sorbic acid-choline ionic liquids (ILs) for the oral delivery of semaglutide (Sema), a glucagon-like peptide-1 (GLP-1) analogue. The IL-based enteric system was designed to enhance peptide stability, reduce gastric degradation, and promote intestinal absorption. In vitro studies demonstrated strong resistance to acidic conditions and pH-responsive release in simulated intestinal fluid. In vivo imaging further revealed prolonged intestinal retention of the IL-loaded enteric particles. Pharmacokinetic evaluation showed a 2.3-fold increase in maximum plasma concentration compared to the reference Rybelsus. In type 2 diabetes mellitus (T2DM) mice, the formulation achieved glucose-lowering efficacy comparable to subcutaneous Sema administration, with additional improvements in hepatic histology. Importantly, repeated-dose studies indicated favorable systemic and gastrointestinal tolerability under the tested conditions. Collectively, these results demonstrate that IL-based enteric formulation enhances oral peptide exposure while maintaining safety, offering a promising strategy for noninvasive T2DM management.