Probing the skin permeation of fish oil/EPA and ketoprofen: 1. NMR spectroscopy and molecular modelling

The complexation of EPA with ketoprofen was probed in order to rationalise co-operative skin permeation enhancement behaviour observed previously. The modulation of aromatic protons of ketoprofen was determined using 1H NMR spectra from different formulations containing varying concentrations of fish oil and a control saturated triglyceride. Molecular modelling of possible complexes of ketoprofen with constituents of fish oil was performed. NMR data revealed a dose-dependent change in chemical shift in the aromatic protons of ketoprofen on addition of fish oil and/or EPA. Similar patterns were observed in both cases, although the free fatty acid induced changes in more protons. Molecular modelling results indicate quite large binding energies of all complexes considered, varying between ca. 90 and 160 kJ mol−1. The geometries of these complexes shows strong O–H⋯O hydrogen bonds in all cases, and in the case of the complex of ketoprofen with free EPA there is also some evidence of C–H⋯π and/or π–π interactions, giving rise to regiospecifically solvated complexes. If strongly bound ketoprofen:EPA complexes can form, then the permeation enhancement of EPA by ketoprofen could be attributed to such a complex. Once the complex is formed, the triglyceride/free fatty acid could aid permeation of associated ketoprofen into the lipophilic stratum corneum via the pull effect. Once permeated, the more hydrophilic ketoprofen could aid the permeation of the triglyceride/free fatty acid through the epidermis, again via the pull effect. This could explain the synergistic permeation enhancement seen with these compounds.