DMPS is known to enhance the transdermal transport of small polar solutes by electroporation significantly. Understanding the modus operandi of this enhancement is essential for the further improvement and development of lipid transdermal drug delivery enhancers. The main barrier to transdermal transport of polar drugs lies within the intercellular lipid matrix (ILM) of the stratum corneum. A biophysical approach was taken to study how DMPS modifies the structure and hydration capacity of the ILM and how this affects transport parameters of small polar solutes in the ILM.

X-ray diffraction showed that acyl chain packing density and crystallinity are reduced in ILM lipid models containing DMPS, which can be expected to diminish their diffusional resistance. FTIR-spectroscopy data indicated that incorporation of DMPS into the stratum corneum and ILM lipid models improves the hydration of these structures significantly. This increase in hydration is supported by freeze fracture electron microscopy data and can be expected to increase the partitioning of small polar solutes into the ILM. Time-resolved fluorescence spectroscopy measurements determined that the improved transport of small polar solutes upon the incorporation of DMPS into ILM lipid models is characterized by an increase in partitioning and possibly diffusivity. Finally, fluorescence microscopy revealed that the life-time and size of transport regions created by electroporation in the presence of DMPS are not increased and, therefore, do not contribute to the transport enhancement. Consequently, treatment with DMPS does not compromise the skin barrier for longer times and, hence, does not lead to the prolongation of potential side effects.

In summary, the research presented here supports the hypothesis that electroporation in the presence of DMPS leads to the creation of better hydrated and less dense transport regions, which have a higher affinity and less diffusional resistance for small polar solutes as compared to transport regions created by electroporation alone. This provides a mechanism of this enhancement and directs future transdermal enhancer development towards compounds that affect ILM hydration as well as structural lipid arrangement.