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

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, semaglutide was converted into a hydrophobic ion-pair (HIP) complex with the cationic lipid DODAB (termed SEDAB), which was subsequently incorporated into a self-microemulsifying drug delivery system (SMEDDS), yielding SEDAB-SME. A comparative screen of two cationic amphiphiles identified DODAB as the selected counterion, which forms a stable complex with semaglutide. Ion pairing with DODAB markedly increased the lipophilicity of semaglutide, and the resulting SEDAB-SME formulation enhanced its stability in simulated intestinal fluid, effectively protecting the peptide from enzymatic degradation. In vitro, FITC-semaglutide delivered by SEDAB-SME showed markedly greater cell association than native FITC-semaglutide, and inhibitor studies suggested the involvement of a cholesterol-sensitive, raft-associated internalization route. In an intra-jejunal (i.j.) regional intestinal absorption study in SD rats, SEDAB-SME enhanced jejunal absorption of semaglutide (Frel = 0.12%) by approximately 28-fold compared with native semaglutide administered via the same i.j. route. In an acute single-dose pharmacodynamic study in STZ-induced T2DM rats, oral administration of SEDAB-SME enteric-coated capsules significantly reduced blood glucose levels. These results demonstrate that the HIP-SMEDDS strategy markedly enhanced regional jejunal absorption and produced acute glucose-lowering effects in a rodent model. This proof-of-concept study highlights a promising approach that warrants further validation of direct oral pharmacokinetics and long-term safety.