## 2 Applications Related to Peculiar Solubility Properties of DESs
In another study carried out by [PERSON] and [PERSON], the release of fluconazole in a system made up of this type of substance and prepared as a transdermal spray was carried out to evaluate the antifungal activity in vivo in patients with ringworm was also evaluated. The results were also positive, demonstrating that this type of system improves drug release [56]. Finally, it has also been proven that some NADES combined with collagen allowed for the chemotactic properties and structure of collagen in topical formulations to be retained [57]. In a study carried out by [PERSON] et al., the lidocaine:ibuprofen THEDES was developed and the permeability of API through a porous membrane was reported. Additionally, it was demonstrated that some differences between the dissolution and permeation of the API because of the formulation [9; 58]. Some other THEDES based on choline chloride and menthol with acetylsalicylic acid, benzoic acid, and phenylacetic acid has been also described. The dissolution rate was studied, and it was found that the antibacterial activity of the API was retained for all THEDES [9]. Recently, a paper has been published using a choline and geranic acid deep eutectic solvent. In this case, this compound has been used for the treatment of rosacea; the study describes how to apply this THEDES from the synthesis to the medical application and shows the scale-up, characterization, stability analysis, mechanism of action, dose analysis, GLP toxicity, and human clinical study [59]. One of the key points that limit the use of THEDES is the lack of evidence related with safety, toxicity, and some other pharmaceutical issues such as pharmacokinetic behavior. However, there have been some studies that point out the safe use of most DESs. Regarding the toxicity of DES, it has been tested both in vitro and in vivo. Focusing on in vitro tests, several analyses in bacteria (_Allivibrio fischeri, Escherichia coli, Staphylococcus cereus aureus, Salmonella enteriditis, Aspergillus niger_, _Listeria monocytogenes_, _Mycobacterium tuberculosis_, and proponinlacterium_) [60; 61; 62], virus (Herpes simplex), fish cells (CCO) [63], human cells (MCF-7, PC3, A375. OKF6, HepGG2, HT29, and H413) [64], fungi (_Aspergillus niger_, _Candida albicans_, _Candida cylindracea_, _Lentius tigrinus_, _Panerchaete chrysosporium_) [47] and plants (_Tritcium aestivum_ or _Allium sativum_) have been measured [65] while in vivo, some studies in animals (mice) [66] and marine organisms (_Hydra sinensis_ and _Cpyrimus carpio_) have been carried out [67; 68]. [PERSON] et al. studied the therapeutic role of DESs based on menthol and saturated fatty acids. They prepared and characterized some DESs using menthol and lauric acid, stearic acid, and myristic acid. After the preparation, they studied their cytotoxicity in the HaCaT cell line. They also carried out an antibacterial assay using _Staphylococcus aureus_, _Staphylococcus epidermis_, _Pseudomonas aeruginosa_, and _Escherichia coli_. No significant halo has been observed for pure compounds, however, all THEDES presented antimicrobial activity being more effective at higher concentrations. These results can be explained because of the molar ratio (1 menthol:8 saturated fatty acid). Menthol amount was lower in THEDES than the pure compound, nevertheless, a synergistic interaction between menthol and saturated fatty acid has been observed [14]. Additionally, [PERSON] et al., in another paper, prepared a THEDES, formed by perillyl alcohol and ibuprofen, and studied their antimicrobial activity and the cytotoxic profile in colorectal cancer (CRC). They observed that this system presented a possible alternative to conventional therapies because of its properties against microorganisms and toward CRC cells [69]. [PERSON] et al. developed a THEDES delivery system for the treatment of tuberculosis. The system was prepared by encapsulating L-arginine based THEDES with a lipidic matrix and using supercritical technology.