Abstract
A series of terpenes has been assessed as skin penetration enhancers towards the model polar penetrant 5-fluorouracil (5-FU). Cyclic terpenes were selected from the chemical classes of hydrocarbons (e.g., α-pinene), alcohols (e.g., α-terpineol), ketones (e.g., carvone), and oxides (e.g., 1,8-cineole, ascaridole). Permeation experiments were performed on excised human epidermal membranes and the terpenes varied in their activities; α-pinene only doubled the permeability coefficient of aqueous 5-FU, whereas 1,8-cineole caused a near 95-fold increase. Essential oils, e.g., chenopodium (70% ascaridole), were less effective than the corresponding isolated terpenes. 5-FU is less soluble in the terpenes than in water, and the terpenes did not exert their action by increasing partitioning of the drug into the membranes as illustrated by stratum corneum:water partitioning studies. The penetration enhancers increased drug diffusivity through the membranes, an effect which correlated empirically with the enhancer activities. The principal mode of action of these accelerants may be described by the lipid–protein–partitioning theory; the terpenes interacted with intercellular stratum corneum lipids to increase diffusivity, and the accelerant effects were not due to partitioning phenomena. Keratin interaction was assumed negligible.
Similar content being viewed by others
REFERENCES
D. Southwell and B. W. Barry. J. Invest. Dermatol. 80:507–514 (1983).
B. W. Barry, D. Southwell, and R. Woodford. J. Invest. Dermatol. 82:49–52 (1984).
D. Southwell and B. W. Barry. Int. J. Pharm. 22:291–298 (1984).
B. J. Aungst, N. J. Rogers, and E. Shefter. Int. J. Pharm. 33:225–234 (1986).
M. Goodman and B. W. Barry. In R. L. Bronaugh and H. I. Maibach (eds.), Percutaneous Absorption, 2nd ed., Marcel Dekker, New York and Basel, 1989, Chap. 33.
H. Okamoto, M. Hashida, and H. Sezaki. J. Pharm. Sci. 77:418–424 (1988).
J. Hadgraft. Pharm. Int. 5:252–254 (1984).
B. W. Barry. Dermatological Formulations: Percutaneous Absorption, Marcell Dekker, New York and Basel, 1983.
R. Woodford and B. W. Barry. J. Toxicol. Cut. Ocular Toxicol. 5:165–175 (1986).
D. L. J. Opdyke. Fd. Cosmet. Toxicol. 12–14:Supplements (1974–1976).
A. R. Pinder. The Chemistry of the Terpenes, Chapman and Hall, London, 1960.
J. R. Bond and B. W. Barry. J. Invest. Dermatol. 90:810–813 (1988).
S. M. Harrison, B. W. Barry, and P. H. Dugard. J. Pharm. Pharmacol. 36:261–262 (1984).
A. M. Kligman and E. Christophers. Arch. Dermatol. 88:70–73 (1963).
S. A. Akhter, S. L. Bennett, I. L. Waller, and B. W. Barry. Int. J. Pharm. 21:17–26 (1984).
M. Goodman and B. W. Barry. J. Invest. Dermatol. 91:323–327 (1988).
J. L. Cohen and R. B. Stoughton. J. Invest. Dermatol. 62:507–509 (1974).
M. Goodman. Ph.D. thesis, University of Bradford, Bradford, 1986.
C. Hansch and A. Leo. Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York, 1979.
J. R. Bond and B. W. Barry. J. Invest. Dermatol. 90:486–489 (1988).
B. W. Barry. J. Control. Release 6:85–97 (1987).
J. A. Zupan. Eur. Patent Publ. No. 0069385 (1983).
J. R. Bond and B. W. Barry. Int. J. Pharm. 41:91–93 (1988).
R. H. Guy, E. M. Carlstrom, D. A. W. Bucks, R. S. Hinz, and H. I. Maibach. J. Pharm. Sci. 75:968–972 (1986).
W. J. Lambert, W. I. Higuchi, K. Knutson, and S. L. Krill. J. Pharm. Sci. 78:925–928 (1989).
E. S. Nuwayser, M. H. Gay, D. J. De Roo, and P. D. Baskovich. Proc. Int. Symp. Control. Rel. Bioact. Mater. 15:213–214 (1988).
T. Nagai, Q. D. Yi, R. I. Higuchi, Y. Akitoshi, and K. Takayama. Proc. Int. Symp. Control. Rel. Bioact. Mater. 15:154–155 (1988).
J. Yamahara, H. Kashiwa, K. Kishi, and H. Fujimura. Chem. Pharm. Bull. 37:855–856 (1989).
T. Nagai, H. Okabe, A. Ogura, and K. Takayama. Proc. Int. Symp. Control. Rel. Bioact. Mater. 16:181–182 (1989).
H. Okabe, K. Takayama, A. Ogura, and T. Nagai. Drug Design Deliv. 4:313–321 (1989).
B. W. Barry. Int. J. Cosmet. Sci. 10:281–293 (1988).
R. H. Guy and J. Hadgraft. Pharm. Res. 5:753–758 (1988).
D. Chow, S. Tenjarla, M. Tsui, S. Asici, and D. Hsieh. Proc. Int. Symp. Control. Rel. Bioact. Mater. 15:85–86 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Williams, A.C., Barry, B.W. Terpenes and the Lipid–Protein–Partitioning Theory of Skin Penetration Enhancement. Pharm Res 8, 17–24 (1991). https://doi.org/10.1023/A:1015813803205
Issue Date:
DOI: https://doi.org/10.1023/A:1015813803205