Mechanistic insight into heat enhanced permeation of diclofenac and piroxicam in combination with chemical penetration enhancers across skin

The topical application of heat offers considerable potential for enhancing the delivery of non-steroidal anti-inflammatory drugs across the skin barrier. A better understanding of the mechanisms underpinning the improved skin permeation and how heat can be best used to work with complementary enhancement strategies would help to realise this potential. In this study the effect of heat on the permeation of diclofenac and piroxicam across different membranes, including human skin was investigated along with use of complementary enhancement strategies including selection of formulation pH, drug salt form and inclusion of chemical penetration enhancers. Heat alone improved drug delivery across human skin for both drugs, with larger increases for piroxicam. This increase was produced by improvements in drug release, molecular diffusivity and partitioning into the stratum corneum. In combination with chemical penetration enhancers, heat synergistically increased the skin permeation of diclofenac and piroxicam up to 13 and 40-fold respectively, with the increase in permeation being ascribed primarily to improvements in drug and enhancer partitioning into the stratum corneum. An Arrhenius plot of diclofenac permeation across skin was linear indicating that the orthorhombic to hexagonal stratum corneum lipid packing transition did not have a significant effect on skin permeation in response to heat.