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.

Enabling Sustainable Chemistry with Ionic Liquids and Deep Eutectic Solvents: A Fad or the Future?

“…A choline geranate DES protects insulin and glucagon-like peptide-1 from the degradative activity of trypsin and dipeptidyl peptidase-4, leading to enhanced pharmacokinetics and pharmacodynamics of the peptides. [68,91] The effect of these solvents on the structural integrity of therapeutic proteins and enzymes depends on the constituents. To illustrate, while choline hydroxide strongly destabilizes stem bromelain, a proteolytic enzyme used in the chemical, medical, and pharmaceutical industries, choline chloride stabilizes the native structure of this enzyme.…”

“…Another trend focuses on using renewable starting materials such as lignin, terpenes, fatty acids, and amino acids to synthesize ILs and DESs in a few reaction steps (Figure 5). [58–67] A remarkable innovation in this direction is the design of DESs by simply mixing two cheap and renewable precursors to form a eutectic mixture [68] . In some cases, the synthesis of these DESs, such as those containing choline and carboxylic acids, takes place under ambient, solvent‐free, low‐energy consuming conditions to yield biodegradable products without the formation of toxic byproducts (Figure 5c) [68] .…”

“…In some cases, the syntheses of bioderived DESs are characterized by low E‐factor, low energy consumption, and good atom economy. Choline geranate, a DES used as an antimicrobial agent and drug delivery vector, is synthesized under ambient conditions by simply mixing cholinium bicarbonate with two molar equivalents of geranic acid with the elimination of non‐toxic carbon dioxide and water (Table 5) [48, 68, 91] . Other cholinium DESs are obtainable by a simple acid–base reaction of cholinium hydroxide and fatty acids or amino acids with the formation of a water byproduct [92] .…”

“…[58][59][60][61][62][63][64][65][66][67] A remarkable innovation in this direction is the design of DESs by simply mixing two cheap and renewable precursors to form a eutectic mixture. [68] In some cases, the synthesis of these DESs, such as those containing choline and carboxylic acids, takes place under ambient, solventfree, low-energy consuming conditions to yield biodegradable products without the formation of toxic byproducts (Figure 5c). [68] Indeed, many DESs containing choline, amino acids, or carboxylic acids are emerging as bioderived alternatives to classic ILs.…”

An overview of biomedical applications of choline geranate (CAGE): a major breakthrough in drug delivery

“…Further mechanistic studies illustrate that CAGE hampers enzymatic degradation due to its self-assembly and helps in the entrapment and facile release of GLP-1. 78 In a recent study, CAGE was used in the effective delivery of apomorphine (a dopamine agonist), used to treat Parkinson's Fig. 8 The scheme of study for oral drug delivery in rats and humans.…”