Influence of drug lipophilicity on terpenes as transdermal penetration enhancers

Drug Dev Ind Pharm. 1999 Aug;25(8):905-15. doi: 10.1081/ddc-100102251.


Percutaneous absorption-enhancing effects on the skin of hairless mice of 11 monoterpenes [1, (+)-limonene; 2, (-)-menthone; 3, (+)-terpinen-4-ol; 4, alpha-terpineol; 5, 1,8-cineole; 6, (+)-carvone; 7, (-)-verbenone; 8, (-)-fenchone; 9, p-cymene; 10, (+)-neomenthol; and 11, geraniol] were investigated using three different model drugs (caffeine, hydrocortisone, triamcinolone acetonide [TA]) with varying lipophilicities. Terpenes were applied at 0.4 M in propylene glycol (PG) to mouse skin. The model drugs were applied as suspensions in PG 1 hr following enhancer pretreatment. The combination of terpenes in PG provided significant enhancement of the permeation of caffeine through mouse skin. The most active compounds 10 and 11 increased permeation by between 13-fold and 16-fold. The terpenes also enhanced the delivery of hydrocortisone, but not to as great an extent. The most active compounds 3 and 4 increased permeation between 3.9-fold and 5-fold. The compounds examined did not significantly increase the delivery of TA. The most active compound 4 only increased delivery 2.5-fold, while the next most active compound 6 only increased delivery 1.7-fold. Overall, these results indicate that the combination of terpenes with PG can significantly increase the transdermal penetration of the hydrophilic drug caffeine and the polar steroid hydrocortisone.

MeSH terms

  • Animals
  • Caffeine / pharmacokinetics*
  • Drug Synergism
  • Hydrocortisone / pharmacokinetics*
  • Lipids / chemistry*
  • Mice
  • Mice, Hairless
  • Permeability / drug effects
  • Propylene Glycol
  • Skin Absorption / drug effects*
  • Solubility
  • Terpenes / pharmacology*
  • Triamcinolone Acetonide / pharmacokinetics*


  • Lipids
  • Terpenes
  • Caffeine
  • Propylene Glycol
  • Triamcinolone Acetonide
  • Hydrocortisone