Single-chain bolalipids PC-C24-PC and PC-C32-PC: impact on skin permeation and penetration of caffeine ex vivo, structural organization of the stratum corneum and corneocyte morphology

Synthetic symmetric single-chain bolalipids (SSCBs) are of interest as new pharmaceutical excipients and might offer new prospects to modulate dermal drug delivery. In contrast to classic anionic surfactants and conventional amphiphilic phospholipids, they have been found to hinder drug penetration of charged permeants into the skin rather than acting as enhancers. However, since only a limited number of permeants have been investigated to date and the underlying mechanism is still unknown, this study aims to investigate the effect of two SSCBs with different alkyl chain length, PC-C24-PC and PC-C32-PC, on ex vivo skin permeation/penetration of an uncharged hydrophilic drug, caffeine, using diffusion cells with dermatomed porcine ear skin as membrane and a quantitative confocal Raman spectroscopy (CRS) approach. In addition, both CRS and attenuated total reflection FTIR spectroscopy (ATR-FTIR) were used to evaluate the effect of the SSCBs on stratum corneum (SC) proteins and the lipid matrix. A novel method was also employed using atomic force microscopy (AFM) to visualize potential SSCB effects on corneocyte surface morphology. Results showed that SSCBs (5 % w/w) reduced skin permeation of caffeine through dermatomed porcine ear skin in comparison to water and 5 % w/w sodium dodecyl sulfate (SDS) solutions as comparator vehicles. Quantitative CRS confirmed these observations. ATR-FTIR studies demonstrated the presence of SSCBs within the SC surface and indicated effects on SC lipid order and protein conformation. AFM revealed trends towards altered corneocyte surface topography after surfactant treatment when compared to the effect of water as solvent. In conclusion, while SSCB formulations interacted with the SC, they did not promote the penetration of caffeine into deeper layers of the epidermis.