The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems

Int J Pharm. 2000 Apr 5;198(2):179-89. doi: 10.1016/s0378-5173(00)00330-6.


The percutaneous permeation of hydrocortisone (HC) was investigated in hairless mouse skin after application of an alcoholic hydrogel using a diffusion cell technique. The formulations contained one of 12 terpenes, the selection of which was based on an increase in their lipophilicity (log P 1.06-5.36). Flux, cumulative receptor concentrations, skin content, and lag time of HC were measured over 24 h and compared with control gels (containing no terpene). Furthermore, HC skin content and the solubility of HC in the alcoholic hydrogel solvent mixture in the presence of terpene were determined, and correlated to the enhancing activity of terpenes. The in vitro permeation experiments with hairless mouse skin revealed that the terpene enhancers varied in their ability to enhance the flux of HC. Nerolidol which possessed the highest lipophilicity (log P = 5.36+/-0.38) provided the greatest enhancement for HC flux (35.3-fold over control). Fenchone (log P = 2.13+/-0.30) exhibited the lowest enhancement of HC flux (10.1-fold over control). In addition, a linear relationship was established between the log P of terpenes and the cumulative amount of HC in the receptor after 24 h (Q(24)). Nerolidol, provided the highest Q(24) (1733+/-93 microg/cm(2)), whereas verbenone produced the lowest Q(24) (653+/-105 microg/cm(2)). Thymol provided the lowest HC skin content (1151+/-293 microg/g), while cineole produced the highest HC skin content (18999+/-5666 microg/g). No correlation was established between the log P of enhancers and HC skin content. A correlation however, existed between the log P of terpenes and the lag time. As log P increased, a linear decrease in lag time was observed. Cymene yielded the shortest HC lag time, while fenchone produced the longest lag time. Also, the increase in the log P of terpenes resulted in a proportional increase in HC solubility in the formulation solvent mixture.

MeSH terms

  • Animals
  • Female
  • Hydrocortisone / administration & dosage*
  • Hydrocortisone / pharmacokinetics
  • Hydrogels
  • Lactose / administration & dosage
  • Lactose / analogs & derivatives*
  • Methylcellulose / administration & dosage
  • Methylcellulose / analogs & derivatives*
  • Mice
  • Mice, Hairless
  • Oxazines
  • Permeability
  • Skin / metabolism*
  • Solubility
  • Terpenes / administration & dosage*
  • Terpenes / chemistry


  • Hydrogels
  • Oxazines
  • Terpenes
  • Methylcellulose
  • MK 458
  • Lactose
  • Hydrocortisone