Choline-Geranate Deep Eutectic Solvent Improves Stability and Half-Life of Glucagon-Like Peptide-1

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.