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As well as their possible applications for the cutaneous delivery of small molecules, deep eutectic solvents have potential for the delivery of proteins to the skin.
Banerjee et al. observed that the choline:geranate (1:2) solvent, which they refer to
as CAGE formulation, could promote the topical delivery of proteins as varied as
bovine serum albumin, ovalbumin, and insulin (Banerjee et al. 2017). Labelled proteins were found to penetrate pig skin, reaching the epidermis and the dermis and
passing into the acceptor compartment. Confocal microscopy allowed the
penetration to be visualized. Fourier transform infrared spectroscopy revealed that
the choline:geranic acid formulations modified some peaks in a way that could be
interpreted as lipid extraction from the skin. Circular dichroism studies of the
secondary structure of insulin showed that the α-helical content of the protein was
not affected by incorporation into the deep eutectic solvents. Finally, the effect of
insulin solubilized in choline:geranic acid solvent on the blood glucose levels of
nondiabetic rats was tested. Application of insulin in choline:geranic acid
formulation onto the skin resulted in a fall in blood glucose that was more sustained
than that obtained after an injection of insulin (although the injected dose was 1 U/
kg while the topical dose was 25 U/kg). Choline:geranic acid solvent alone or
insulin in buffer applied to the skin had no effect.
In a later study, the solvent formulation was studied in more detail by varying the
ratio of choline to geranic acid from 1:4 to 2:1 (Tanner et al. 2018). Nuclear magnetic resonance spectroscopy was used to map the interactions between the protons
in the two components, and this was found to differ as the proportions changed. This
would modify the ability of the solvent to accommodate solutes and allow the composition to be tailored for different types of molecules. Both the viscosity and conductivity of the formulation decreased as the proportion of geranate increased. The
thermal stability of the formulations was quite similar over the different ratios, with
temperatures of decomposition of 169 to 210 °C. As in previous articles, Fourier
transform infrared spectroscopy was used to assess the impact of the deep eutectic
solvent on stratum corneum structure, looking at peak height between 2800 and
3000 cm
−1
that shows the vibrations in lipid bonds. A decrease in peak height suggests that deep eutectic solvent can extract lipids, and as the solvent becomes more
hydrophobic, with a higher proportion of geranate, this effect is more pronounced.
Finally, the different formulations were tested for their ability to promote the
passage of fluorescently labelled insulin across pig skin in a diffusion cell. The formulations with a higher proportion of geranate (1:2 and 1:4) showed the presence of
the protein in the stratum corneum, epidermis, and dermis, while for the 1:1 and 2:1
formulations, and for phosphate-buffered saline, it showed fluorescence restricted
to the stratum corneum (Fig. 2.6).
The “CAGE” formulation was also employed for a low-molecular-weight
glucose- lowering agent, the flavonoid nobiletin (Hattori et al. 2019). The transdermal passage of this molecule was significantly increased by the use of this solvent,
and plasma concentrations were enhanced compared with the drug formulated in
aqueous buffer or ethanol. Lowering of blood glucose concentrations was observed
after transdermal administration to normal rats (Hattori et al. 2019).
C.-H. Nguyen et al.
As well as their possible applications for the cutaneous delivery of small molecules, deep eutectic solvents have potential for the delivery of proteins to the skin.
Banerjee et al. observed that the choline:geranate (1:2) solvent, which they refer to
as CAGE formulation, could promote the topical delivery of proteins as varied as
bovine serum albumin, ovalbumin, and insulin (Banerjee et al. 2017). Labelled proteins were found to penetrate pig skin, reaching the epidermis and the dermis and
passing into the acceptor compartment. Confocal microscopy allowed the
penetration to be visualized. Fourier transform infrared spectroscopy revealed that
the choline:geranic acid formulations modified some peaks in a way that could be
interpreted as lipid extraction from the skin. Circular dichroism studies of the
secondary structure of insulin showed that the α-helical content of the protein was
not affected by incorporation into the deep eutectic solvents. Finally, the effect of
insulin solubilized in choline:geranic acid solvent on the blood glucose levels of
nondiabetic rats was tested. Application of insulin in choline:geranic acid
formulation onto the skin resulted in a fall in blood glucose that was more sustained
than that obtained after an injection of insulin (although the injected dose was 1 U/
kg while the topical dose was 25 U/kg). Choline:geranic acid solvent alone or
insulin in buffer applied to the skin had no effect.
In a later study, the solvent formulation was studied in more detail by varying the
ratio of choline to geranic acid from 1:4 to 2:1 (Tanner et al. 2018). Nuclear magnetic resonance spectroscopy was used to map the interactions between the protons
in the two components, and this was found to differ as the proportions changed. This
would modify the ability of the solvent to accommodate solutes and allow the composition to be tailored for different types of molecules. Both the viscosity and conductivity of the formulation decreased as the proportion of geranate increased. The
thermal stability of the formulations was quite similar over the different ratios, with
temperatures of decomposition of 169 to 210 °C. As in previous articles, Fourier
transform infrared spectroscopy was used to assess the impact of the deep eutectic
solvent on stratum corneum structure, looking at peak height between 2800 and
3000 cm
−1
that shows the vibrations in lipid bonds. A decrease in peak height suggests that deep eutectic solvent can extract lipids, and as the solvent becomes more
hydrophobic, with a higher proportion of geranate, this effect is more pronounced.
Finally, the different formulations were tested for their ability to promote the
passage of fluorescently labelled insulin across pig skin in a diffusion cell. The formulations with a higher proportion of geranate (1:2 and 1:4) showed the presence of
the protein in the stratum corneum, epidermis, and dermis, while for the 1:1 and 2:1
formulations, and for phosphate-buffered saline, it showed fluorescence restricted
to the stratum corneum (Fig. 2.6).
The “CAGE” formulation was also employed for a low-molecular-weight
glucose- lowering agent, the flavonoid nobiletin (Hattori et al. 2019). The transdermal passage of this molecule was significantly increased by the use of this solvent,
and plasma concentrations were enhanced compared with the drug formulated in
aqueous buffer or ethanol. Lowering of blood glucose concentrations was observed
after transdermal administration to normal rats (Hattori et al. 2019).
C.-H. Nguyen et al.