85
and various terpenes could enhance their penetration across human epidermis (Stott
et al. 1998).
Transdermal penetration enhancement by deep eutectic solvents was claimed by
Zakrewsky et al. in 2014 and in several patents (Zakrewsky et al. 2015; Zakrewsky
et al. 2016b; Kellar et al. 2018), with particular reference to treating infections with
microbial biofilms in the skin (Zakrewsky et al. 2014). Skin penetration was first
determined using radiolabelled mannitol as a model drug and pig skin in Franz
diffusion cells. One formulation in particular, a mixture of choline chloride and the
geranate anion, was able to promote penetration into the epidermis and dermis. A
similar result was obtained with the antibiotic cefadroxil incorporated into the deep
eutectic solvent. The efficacy of this deep eutectic solvent, with or without antibiotic, was tested on a biofilm formed by Pseudomonas aeruginosa in simulated
wounds in an in vitro human skin model. The choline chloride:geranate deep eutectic solvent alone caused a very significant reduction in bacterial viability that was
further decreased by the inclusion of a related antibiotic (ceftazidime), whereas the
ceftazidime in saline had only a small effect. Finally, it was important to assess the
tolerance of the skin to deep eutectic solvent application. This was done using
Fourier transform infrared spectroscopy to monitor changes in stratum corneum
structure in full thickness pig skin. The use of the choline chloride:geranate deep
eutectic solvent did not provoke any significant changes (Zakrewsky et al. 2014).
Santos de Almeida et al. also investigated the potential of deep eutectic solvents
(ionic liquids as they call them) for cutaneous applications and in particular compared imidazole and choline as the hydrogen bond acceptor (Santos de Almeida
et al. 2017). They chose two model drugs, caffeine and salicylic acid, and studied
their permeation through full-thickness pig skin in Franz cells under occlusive conditions as well as the toxicity toward the human HaCaT keratinocyte cell line, using
the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction
assay as the endpoint. As reported above, an increase in caffeine solubility of two to
three times was observed with choline-based formulations while the increases in
salicylic acid solubility were more modest. On the other hand, imidazole-based formulations did not increase drug solubility. Permeation across pig skin from saturated solutions of the drug in 5:95 deep eutectic solvent:water was studied. The
imidazole-based formulations increased passage across the skin, while cholinebased ones had no promoting effect. This might have been due to a surfactant effect
of the imidazole side chain. Reduced passage across the skin would be an advantage
for an activity in the skin without systemic toxicity. The choline-based formulations
were less toxic than the imidazole-based ones.
Choline:glutamine and choline:phenylalanine deep eutectic solvents loaded with
caffeine were formulated as oil-in-water emulsions and gels suitable for skin applications. Emulsions containing the deep eutectic solvents had lower viscosity than a
simple caffeine-containing emulsion and needed more surfactant for stability.
However, the presence of the deep eutectic solvents prevented the crystallization of
caffeine within the emulsion. A similar observation was made when gels containing
caffeine were prepared from Carbopol
®
940. Gel stability was not compromised by
the presence of the deep eutectic solvent (Santos de Almeida et al. 2017).
2 Deep Eutectic Solvents for Innovative Pharmaceutical Formulations
and various terpenes could enhance their penetration across human epidermis (Stott
et al. 1998).
Transdermal penetration enhancement by deep eutectic solvents was claimed by
Zakrewsky et al. in 2014 and in several patents (Zakrewsky et al. 2015; Zakrewsky
et al. 2016b; Kellar et al. 2018), with particular reference to treating infections with
microbial biofilms in the skin (Zakrewsky et al. 2014). Skin penetration was first
determined using radiolabelled mannitol as a model drug and pig skin in Franz
diffusion cells. One formulation in particular, a mixture of choline chloride and the
geranate anion, was able to promote penetration into the epidermis and dermis. A
similar result was obtained with the antibiotic cefadroxil incorporated into the deep
eutectic solvent. The efficacy of this deep eutectic solvent, with or without antibiotic, was tested on a biofilm formed by Pseudomonas aeruginosa in simulated
wounds in an in vitro human skin model. The choline chloride:geranate deep eutectic solvent alone caused a very significant reduction in bacterial viability that was
further decreased by the inclusion of a related antibiotic (ceftazidime), whereas the
ceftazidime in saline had only a small effect. Finally, it was important to assess the
tolerance of the skin to deep eutectic solvent application. This was done using
Fourier transform infrared spectroscopy to monitor changes in stratum corneum
structure in full thickness pig skin. The use of the choline chloride:geranate deep
eutectic solvent did not provoke any significant changes (Zakrewsky et al. 2014).
Santos de Almeida et al. also investigated the potential of deep eutectic solvents
(ionic liquids as they call them) for cutaneous applications and in particular compared imidazole and choline as the hydrogen bond acceptor (Santos de Almeida
et al. 2017). They chose two model drugs, caffeine and salicylic acid, and studied
their permeation through full-thickness pig skin in Franz cells under occlusive conditions as well as the toxicity toward the human HaCaT keratinocyte cell line, using
the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction
assay as the endpoint. As reported above, an increase in caffeine solubility of two to
three times was observed with choline-based formulations while the increases in
salicylic acid solubility were more modest. On the other hand, imidazole-based formulations did not increase drug solubility. Permeation across pig skin from saturated solutions of the drug in 5:95 deep eutectic solvent:water was studied. The
imidazole-based formulations increased passage across the skin, while cholinebased ones had no promoting effect. This might have been due to a surfactant effect
of the imidazole side chain. Reduced passage across the skin would be an advantage
for an activity in the skin without systemic toxicity. The choline-based formulations
were less toxic than the imidazole-based ones.
Choline:glutamine and choline:phenylalanine deep eutectic solvents loaded with
caffeine were formulated as oil-in-water emulsions and gels suitable for skin applications. Emulsions containing the deep eutectic solvents had lower viscosity than a
simple caffeine-containing emulsion and needed more surfactant for stability.
However, the presence of the deep eutectic solvents prevented the crystallization of
caffeine within the emulsion. A similar observation was made when gels containing
caffeine were prepared from Carbopol
®
940. Gel stability was not compromised by
the presence of the deep eutectic solvent (Santos de Almeida et al. 2017).
2 Deep Eutectic Solvents for Innovative Pharmaceutical Formulations