A Hydrophobic Ion-Paired Self-Microemulsifying System Enhances Jejunal Absorption and Acute Glycemic Control of Semaglutide in Rats
- 1Laboratory of Innovative Formulations and Pharmaceutical Excipients, Peking University Ningbo Institute of Marine Medicine, Ningbo 315832, China
- 2Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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, 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.
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BibTeX
@article{wang2026hydrophobic,
title = {{A Hydrophobic Ion-Paired Self-Microemulsifying System Enhances Jejunal Absorption and Acute Glycemic Control of Semaglutide in Rats}},
author = {Ke Wang and Yijie Hu and Yicheng Jiang and Ruixin Fan and Yuzhang Bao and Sikai Wang and Qian Liang and Kaili Lu and Junjie Xue and Yi Yan and Xiaoyan Liu and Wanhui Liu and Yuanjun Zhu and Jiancheng Wang},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219523},
url = {https://www.mdpi.com/1422-0067/27/21/9523},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Hydrophobic Ion-Paired Self-Microemulsifying System Enhances Jejunal Absorption and Acute Glycemic Control of Semaglutide in Rats
AU - Ke Wang
AU - Yijie Hu
AU - Yicheng Jiang
AU - Ruixin Fan
AU - Yuzhang Bao
AU - Sikai Wang
AU - Qian Liang
AU - Kaili Lu
AU - Junjie Xue
AU - Yi Yan
AU - Xiaoyan Liu
AU - Wanhui Liu
AU - Yuanjun Zhu
AU - Jiancheng Wang
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219523
UR - https://www.mdpi.com/1422-0067/27/21/9523
AB - 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.
SN - 1422-0067
ER -