119
In another study was formulated an eutectic mixture with choline bicarbonate
and geranic acid in the ratio 1:2, that is called CAGE, for enhancing topical drug
delivery of proteins like bovine serum albumin, ovalbumin, and insulin. The proteins were dispersed in the DES to increase their penetration through epidermis and
dermis, and it was observed that insulin, for example, when dispersed in CAGE
presents a decrease of blood glucose levels 4 h later. And it was proven that these
CAGE eutectic mixtures could potentiate the transdermal delivery of therapeutic
peptides and proteins and increase the permeability of macromolecules through the
skin (Banerjee et al. 2017). Zakrewsky et al. reported the use of this eutectic solvent
CAGE as antimicrobial agent against some of the drug-resistant bacterial strains,
like Mycobacterium tuberculosis, Staphylococcus aureus, Candida albicans, and
herpes simplex virus (Zakrewsky et al. 2016; Zainal-Abidin et al. 2019).
Li et al. have investigated the solubility enhancement of some poorly watersoluble drugs, such as itraconazole, piroxicam, lidocaine, and posaconazole. The
DES prepared were based on choline chloride and carboxylic acids; they showed an
improvement of the solubility of 6700-fold for itraconazole, 430-fold for piroxicam,
28-fold for lidocaine, and 6400-fold for posaconazole, when compared to water
solubility. They also prepared a ternary system with choline chloride:glycolic
acid:oxalic acid (1:1.6:0.4) that increases the solubility of itraconazole to 53,600fold (Li and Lee (2016); Álvarez and Zhang 2019). In another study, Shekaari et al.
tested the solubility enhancement of acetaminophen in DES of choline chloride and
glycerol or ethylene glycol. The solubility of acetaminophen was higher in DES
with ethylene glycol than with glycerol, and complementary studies indicate that
the interactions established between the DES and acetaminophen are stronger with
increasing concentration of the cosolvent (Shekaari et al. 2018).
Recently, Silva and coworkers reported the use of fatty acids to formulate DES
with antimicrobial properties, preparing DES with capric acid, myristic acid, stearic
acid, and lauric acid. The system that shows better antimicrobial activity for grampositive bacteria and C. albicans was capric acid:lauric acid (2:1). This system
seems to be promising for detachment of biofilms of several types of microorganisms including gram-positive and gram-negative bacteria (Silva et al. 2019a, b, c).
The same group has investigated the preparation and application of THEDES with
fatty acids for wound healing. They prepared systems with menthol and lauric acid,
myristic acid, and stearic acid in different molar ratios. All the systems were characterized, and it was observed that the hydrophobic THEDES with menthol:stearic
acid exhibit important properties as wound healing agents, since it was noticed a
recover of the cell layer with HaCaT after 24 hour, which could be important for the
development of new formulations (Silva et al. 2019a, b, c).
The antitumor potential of DES was studied by Mbous and coworkers; they prepare natural DES and studied their anticancer activity in different cell lines and
observe that NADES present a higher cellular tolerance and potential for the development of anticancer agents. Despite this, the mixtures studied by Mbous et al. do
not have incorporated active pharmaceutical ingredients or compounds that have
anticancer activity reported (Mbous et al. 2017a, b). Later, Pereira et al. studied the
antiproliferative properties of THEDES prepared with limonene that present
3 Therapeutic Deep Eutectic Systems for the Enhancement of Drug Bioavailability
In another study was formulated an eutectic mixture with choline bicarbonate
and geranic acid in the ratio 1:2, that is called CAGE, for enhancing topical drug
delivery of proteins like bovine serum albumin, ovalbumin, and insulin. The proteins were dispersed in the DES to increase their penetration through epidermis and
dermis, and it was observed that insulin, for example, when dispersed in CAGE
presents a decrease of blood glucose levels 4 h later. And it was proven that these
CAGE eutectic mixtures could potentiate the transdermal delivery of therapeutic
peptides and proteins and increase the permeability of macromolecules through the
skin (Banerjee et al. 2017). Zakrewsky et al. reported the use of this eutectic solvent
CAGE as antimicrobial agent against some of the drug-resistant bacterial strains,
like Mycobacterium tuberculosis, Staphylococcus aureus, Candida albicans, and
herpes simplex virus (Zakrewsky et al. 2016; Zainal-Abidin et al. 2019).
Li et al. have investigated the solubility enhancement of some poorly watersoluble drugs, such as itraconazole, piroxicam, lidocaine, and posaconazole. The
DES prepared were based on choline chloride and carboxylic acids; they showed an
improvement of the solubility of 6700-fold for itraconazole, 430-fold for piroxicam,
28-fold for lidocaine, and 6400-fold for posaconazole, when compared to water
solubility. They also prepared a ternary system with choline chloride:glycolic
acid:oxalic acid (1:1.6:0.4) that increases the solubility of itraconazole to 53,600fold (Li and Lee (2016); Álvarez and Zhang 2019). In another study, Shekaari et al.
tested the solubility enhancement of acetaminophen in DES of choline chloride and
glycerol or ethylene glycol. The solubility of acetaminophen was higher in DES
with ethylene glycol than with glycerol, and complementary studies indicate that
the interactions established between the DES and acetaminophen are stronger with
increasing concentration of the cosolvent (Shekaari et al. 2018).
Recently, Silva and coworkers reported the use of fatty acids to formulate DES
with antimicrobial properties, preparing DES with capric acid, myristic acid, stearic
acid, and lauric acid. The system that shows better antimicrobial activity for grampositive bacteria and C. albicans was capric acid:lauric acid (2:1). This system
seems to be promising for detachment of biofilms of several types of microorganisms including gram-positive and gram-negative bacteria (Silva et al. 2019a, b, c).
The same group has investigated the preparation and application of THEDES with
fatty acids for wound healing. They prepared systems with menthol and lauric acid,
myristic acid, and stearic acid in different molar ratios. All the systems were characterized, and it was observed that the hydrophobic THEDES with menthol:stearic
acid exhibit important properties as wound healing agents, since it was noticed a
recover of the cell layer with HaCaT after 24 hour, which could be important for the
development of new formulations (Silva et al. 2019a, b, c).
The antitumor potential of DES was studied by Mbous and coworkers; they prepare natural DES and studied their anticancer activity in different cell lines and
observe that NADES present a higher cellular tolerance and potential for the development of anticancer agents. Despite this, the mixtures studied by Mbous et al. do
not have incorporated active pharmaceutical ingredients or compounds that have
anticancer activity reported (Mbous et al. 2017a, b). Later, Pereira et al. studied the
antiproliferative properties of THEDES prepared with limonene that present
3 Therapeutic Deep Eutectic Systems for the Enhancement of Drug Bioavailability