Exploring the potential of combining menthol-thymol deep eutectic solvent and solid microneedles for cutaneous peptide delivery

While cutaneous administration of bioactive molecules like peptides offers advantages over oral delivery by bypassing first-pass metabolism and increasing bioavailability, it also comes with some challenges, primarily due to poor peptide absorption through the lipophilic stratum corneum, as a result of peptide hydrophilicity and high molecular weight. Recently, deep eutectic solvents (DESs) have gained attention as a new subclass of chemical permeation enhancers, facilitating drug delivery across the skin by disrupting the lipid organization within the stratum corneum, thereby significantly improving drug permeation into deeper skin layers. This study investigated the permeation of the pentapeptide GVAPG in porcine skin using a menthol-thymol DES (MT-DES), both alone and in combination with solid microneedles (MNs) as a physical permeation enhancer, to assess whether the combined use of both chemical and physical enhancers offers additional benefits over individual application. The combination of MT-DES and MNs significantly enhanced GVAPG permeation compared to either enhancer alone. Stability testing showed that MT-DES reduced peptide degradation caused by the skin proteolytic enzymes compared to phosphate-buffered saline. Matrix-assisted laser desorption/ionization mass spectrometry imaging revealed an even distribution of GVAPG and its degradation products across the skin. Molecular dynamics simulations indicated that GVAPG adopted an elongated conformation in MT-DES, with fewer hydrogen bonds with MT-DES as compared to water, which may potentially contribute to an enhanced liberation of GVAPG from the formulation and improved permeation. Overall, these findings suggest that combining MT-DES and MNs is a promising strategy to enhance peptide permeation and stability, potentially reducing application frequency. However, further studies with other peptides are needed to confirm these results.