Choline‐Geranate Deep Eutectic Solvent Improves Stability and Half‐Life of Glucagon‐Like Peptide‐1
Christian Agatemor, Tyler Brown, Yongsheng Gao, Naoya Ohmori, Kelly N. Ibsen, Samir Mitragotri
Abstract
Abstract Deep eutectic solvents (DESs) and ionic liquids (ILs) have shown promise as a platform to deliver drugs, particularly biologics, through transdermal and oral routes. This ability is made possible through several key DES/IL attributes, including protein solubilization and stabilization, enzyme inhibition, and enhanced permeation across epithelial barriers. It is hypothesized herein, that some of these attributes enable subcutaneous delivery. To test this hypothesis, a native (non‐analog) glucagon‐like peptide‐1 (GLP‐1) is delivered subcutaneously in varying concentrations of a DES, choline geranate (CAGE). Native GLP‐1 is rapidly cleared from the circulatory system by enzymatic degradative action of dipeptidyl peptidase‐4 (DPP‐4). However, when delivered in neat or diluted CAGE, the area under the curve (AUC) of GLP‐1 increases by up to four‐fold compared to that in saline, suggesting a notable increase in the peptide concentration in the circulatory system. Mechanistic studies reveal that CAGE inhibits the degradative activity of DPP‐4 and that CAGE undergoes self‐assembly, which may be responsible for the entrapment and sustained release of GLP‐1. These studies demonstrate that upon additional testing, CAGE can be a potential excipient to improve the pharmacokinetic profile of GLP‐1.