Work

A Hydrophobic Ion-Paired Self-Microemulsifying System Enhances Jejunal Absorption and Acute Glycemic Control of Semaglutide in Rats

Year: 2026

Type: article

Abstract: Oral delivery of semaglutide offers a promising strategy for type 2 diabetes mellitus (T2DM) by improving patient adherence. However, its clinical translation is limited by low oral bioavailability, resulting from the peptide’s hydrophilicity, instability in gastrointestinal environments, and poor intestinal permeability. To address these challenges, we developed a self-microemulsifying drug delivery system (SMEDDS) loaded with a hydrophobic ion-pair (HIP) complex of semaglutide and the cationic lipid DOTAP (termed SETAP-SME). Systematic screening identified DOTAP as the optimal counterion, forming a stable complex with semaglutide at a 1:4 molar ratio. The SETAP-SME formulation markedly increased the lipophilicity of semaglutide and enhanced its stability in simulated intestinal fluid, effectively protecting the peptide from enzymatic degradation. In vitro, SETAP-SME promoted cellular uptake in Caco-2 cells via caveolae/lipid-raft-mediated endocytosis, reduced apoptosis, and restored insulin secretion in pancreatic β-cells. In a T2DM rat model, oral administration of SETAP-SME provided sustained glycemic control over 8 weeks, improved insulin resistance, and demonstrated additional metabolic benefits including a favorable lipid profile modulation (elevated HDL levels) and enhanced renoprotective effects compared to the commercial oral formulation (Rybelsus®), alongside a favorable safety profile. These results demonstrate that the HIP-SMEDDS platform is a robust and promising approach for enhancing the oral delivery and therapeutic efficacy of semaglutide.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27219523