Pharmaceutical Research

, Volume 20, Issue 2, pp 270–274 | Cite as

Transdermal Penetration of Vasoconstrictors—Present Understanding and Assessment of the Human Epidermal Flux and Retention of Free Bases and Ion-Pairs

  • Sheree E. Cross
  • Melanie J. Thompson
  • Michael S. Roberts


Purpose. As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA).

Methods. We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin.

Results. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 ± 11.7 μg/cm2/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 ± 2.3 and 12.0 ± 1.6 μg/cm2/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 ± 0.6, 7.8 ± 0.8 and 1.1 ± 0.1 respectively. Transdermal transport of VC's is discussed.

Conclusions. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.

vasoconstrictor transdermal percutaneous absorption epidermal retention 


  1. 1.
    M. S. Roberts, S. E. Cross, and M. A. Pellett. Skin Transport in Dermatological and Transdermal Formulations ed KA Walters Marcel Dekker, New York (2002) pp 89-195.Google Scholar
  2. 2.
    W. J. Pugh, M. S. Roberts, and J. Hadgraft. Epidermal permeability-penetrant structure relationships: 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum. Int. J. Pharm. 138:149-167 (1996).Google Scholar
  3. 3.
    P. Singh and M. S. Roberts. Effects of vasoconstriction on dermal pharmacokinetics and local tissue distribution of compounds. J. Pharm. Sci. 83:783-791 (1994).Google Scholar
  4. 4.
    C. S. Canepa, S. H. Miller, D. C. Buck, R. J. Demuth, and M. Miller. Effects of phenylephrine on tissue gas tension, bleeding, infection and lidocaine absorption. Plast. Reconstr. Surg. 81:554-560 (1988).Google Scholar
  5. 5.
    J. E. Riviere, B. Sage, and P. L. Williams. The effects of vasoactive drugs on transdermal lidocaine iontophoresis. J. Pharm. Sci. 80:615-620 (1991).Google Scholar
  6. 6.
    J. E. Riviere, N. A. Monterio-Riviere, and A. O. Inman. Determination of lidocaine concentrations in skin after transdermal iontophoresis: Effects of vasoactive drugs. Pharm. Res. 9:211-214 (1992).Google Scholar
  7. 7.
    T. R. P. Ford, M. A. Seare, and F. McDonald. Action of adrenaline on the effect of dental local anaesthetic solutions. Endodon. Dent. Traumatol. 91:31-35 (1993).Google Scholar
  8. 8.
    Y. W. Chien and S.-F. Chang. Intranasal drug delivery for systemic medications. CRC Crit. Rev. Drug Carrier Syst. 4:66-194 (1987).Google Scholar
  9. 9.
    G. M. Irwin, H. B. Kostenbauder, L. W. Dittert, R. Staples, A. Misher, and J. V. Swintosky. Enhancement of gastrointestinal absorption of a quaternarry ammonium compound by trichloroacetate. J. Pharm. Sci. 58:313-315 (1969).Google Scholar
  10. 10.
    D. J. W. Grant and T. Higuchi. Ion pairs and solubility behaviour. In: W. H. Saunders (ed.) Solubility Behaviour of Organic Compounds, Vol XXI of the Techniques of Chemistry Series, Wiley, New York, 1990 pp. 399-439.Google Scholar
  11. 11.
    S. Matschiner, R. Neubert, and W. Wohlrab. The use of ion-pairing to facilitate percutaneous penetration of drugs. In: E. W. Smith, and H. I. Maibach (eds.), Percutaneous Penetration Enhancers. CRC Press, New York, 1995 pp. 407-417.Google Scholar
  12. 12.
    M. Kadono, K. Kubo, H. Miyazaki, N. Tojyo, S. Nakagawa, K. Miyashita, T. Imanishi, J. H. Rytting, and T. Mayumi. Enhanced in vitro percutaneous penetration of saliclyate by ion pair formation with alkylamines. Biol. Pharm. Bull. 21:599-603 (1998).Google Scholar
  13. 13.
    S. A. Megwa, S. E. Cross, H. A. E. Benson, and M. S. Roberts. Ion-pair formation as a strategy to enhance topical delivery of salicylic acid. J. Pharm. Pharmacol. 52:919-928 (2000).Google Scholar
  14. 14.
    S. A. Megwa, H. A. E. Benson, and M. S. Roberts. Percutaneous absorption of SAs from some commercially available topical products containing methylsalicylate or salicylic acid salts in rats. J. Pharm. Pharmacol. 47:891-896 (1995).Google Scholar
  15. 15.
    K. A. Walters and J. Hadgraft. Pharmaceutical skin penetration enhancement. Drugs in the Pharmaceutical Sciences, Vol. 59. Marcel Dekker, New York, 1993.Google Scholar
  16. 16.
    M. Bende. The effect of topical decongestant on blood flow in normal and infected nasal mucosa. Acta. Otolaryngol. (Stockh.) 96:523-527 (1983).Google Scholar
  17. 17.
    E. Lunell, L. Molander, and M. Andersson. Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant. Eur. J. Clin. Pharmacol. 48:71-75 (1995).Google Scholar
  18. 18.
    M. C. Koss. Characterization of adrenoceptor subtypes in cat cutaneous vasculature. J. Pharmacol. Exp. Ther. 254:221-227 (1990).Google Scholar
  19. 19.
    Y. Kaplun-Frischoff and E. Touitou. Testosterone skin permeation enhancement by menthol through the formation of a eutectic with drug and interaction with skin lipids. J. Pharm. Sci. 86:1394-1399 (1997).Google Scholar
  20. 20.
    W. Stott, A. C. Williams, and B. W. Barry. Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. J. Control. Release 50:297-308 (1997).Google Scholar
  21. 21.
    D. B. Larsen, H. Parshad, K. Fredholt, and C. Larsen. Characteristics of drug substances in oily solutions. Drug release rate, partitioning and solubility. Int. J. Pharm. 232:107-117 (2002).Google Scholar
  22. 22.
    M.-W. Hu and L. E. Matheson. The development of a predictive method for the estimation of flux through polydimethylsiloxane membranes. III. Application to a series of substituted pyridines. Pharm. Res. 10:732-736 (1993).Google Scholar
  23. 23.
    T. Kau, T. Isami, K. Kobota, Y. Kurosaki, T. Nakayama, and T. Kimura. Keratinised epithelial transport of beta-blocking agents. I. Relationship between physicochemical properties of drugs and the flux across rat skin and hamster skin cheek pouch. Chem. Pharm. Bull. 40:2498-2504 (1992).Google Scholar
  24. 24.
    T. Izumoto, A. Aioi, S. Uneoyama, K. Kuriyama, and M. Azuma. Relationship between transference of a drug from a transdermal patch and the physicochemical properties. Chem. Pharm. Bull. 40:456-468 (1992).Google Scholar
  25. 25.
    B. Ghosh and L. H. Reddy. Effect of physicochemical parameters on skin permeability of antihypertensive. Indian J. Exp. Biol. 39:710-714 (2001).Google Scholar
  26. 26.
    A. Pardo, Y. Shiri, and S. Cohen. Kinetics of transdermal penetration of an organic ion pair: physostigmine salicylate. J. Pharm. Sci. 81:990-995 (1992).Google Scholar
  27. 27.
    J. C. Smith and W. J. Irwin. Ionization and the effect of absorption enhancers on transport of salicylic acid through silastic rubber and human skin. Int. J. Pharm. 210:69-82 (2000).Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Sheree E. Cross
    • 1
  • Melanie J. Thompson
    • 1
  • Michael S. Roberts
    • 1
  1. 1.Therapeutics Research Unit, Department of MedicineUniversity of Queensland, Princess Alexandra HospitalBrisbaneAustralia

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