Pharmaceutical Research

, Volume 11, Issue 12, pp 1809–1814 | Cite as

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

  • D. Bommi Bommannan
  • Janet Tamada
  • Lewis Leung
  • Russell O. Potts


Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, τ = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm2) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm2 fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm2 without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.

transdermal drug delivery LHRH iontophoresis electroporation electropermeabilization electrotransport 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Heit, P. Williams, F. Jayes, S. Chang, and J. Riviere. Transdermal iontophoretic peptide delivery: in vitro and in vivo studies with leuteinizing hormone releasing hormone. J. Pharm. Sci. 82: 240–243(1993).Google Scholar
  2. 2.
    B. R. Meyer, W. Kreis, J. Eschbach, V. O'Mara, S. Rosen, and D. Sibalis. Successful transdermal administration of therapeutic doses of a polypeptide to normal human volunteers. Clinical Pharmacology and Therapeutics. 44: 607–612(1988).Google Scholar
  3. 3.
    V. Srinivasan, M.-H. Su, W. I. Higuchi, and C. R. Behl. Iontophoresis of polypeptides: Effect of ethanol pretreatment of human skin. J. Pharm. Sci. 79: 588–591(1990).Google Scholar
  4. 4.
    L. Miller, C. Kolaskie, G. Smith, and J. Rivier. Transdermal iontophoresis of gonadotrophin releasing hormone (LHRH) and two analogues. J. Pharm. Sci. 79: 490–493(1990).Google Scholar
  5. 5.
    R. Burnette, and D. Marrero. Comparison between the iontophoretic and passive transport of thyrotropin releasing hormone across excised nude mouse skin. J. Pharm. Sci. 75: 738–743 (1986).Google Scholar
  6. 6.
    R. Meyer, H. Katzeff, J. Eschbach, J. Trimmer, S. Zacharias, S. Rosen, and D. Sibalis. Transdermal delivery of human insulin to albino rabbits using electrical current. The American Journal of the Medical Sciences. 297: 321–325(1989).Google Scholar
  7. 7.
    O. Siddiqui, Y. Sun, J.-C. Liu, and Y. W. Chien. Facilitated transdermal transport of insulin. J. Pharm. Sci. 76: 341–345 (1987).Google Scholar
  8. 8.
    V. Srinivasan, W. I. Higuchi, S. M. Sims, A. H. Ghanem, and C. R. Behl. Transdermal iontophoretic drug delivery: mechanistic analysis and application to polypeptide delivery. J. Pharm. Sci. 78: 370–375(1989).Google Scholar
  9. 9.
    Y. W. Chien, O. Siddiqui, W.-M. Shi, P. Lelawongs, and J.-C. Liu. Direct current iontophoretic transdermal delivery of peptide and protein drugs. J. Pharm. Sci. 78: 376–383(1989).Google Scholar
  10. 10.
    J. E. Riviere, N. A. Monteiro-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
  11. 11.
    J. Singh, and M. Roberts. Transdermal delivery of drugs by iontophoresis: a review. Drug design and delivery. 4: 1–12 (1989).Google Scholar
  12. 12.
    E. Neumann. Membrane electroporation and direct gene transfer. Bioelectrochemistry and Bioenergetics. 28: 247–267(1992).Google Scholar
  13. 13.
    L. V. Chernomordik, and Y. A. Chizmadzhev In Electroporation and electrofusion in cell biology; E. Neumann, A. E. Sowers and C. A. Jordan, Ed.; Plenum: New York, 1989; pp 83–95.Google Scholar
  14. 14.
    K. Kinosita, M. Hibino, H. Itoh, M. Shigemori, K. Hirano, Y. Kirino, and T. Hayakawa In Guide to electroporation and electrofusion; D. C. Chang, B. M. Chassy, J. A. Saunders and A. E. Sowers, Ed.; Academic Press, Inc.: New York, 1992; pp 29–46.Google Scholar
  15. 15.
    L. V. Chernomordik, S. I. Sukharev, I. G. Abidor, and Y. A. Chizmadzhev. Breakdown of lipid bilayer membranes in an electric field. Biochim. et Biophys. Acta. 736: 203–213(1983).Google Scholar
  16. 16.
    D. C. Chang, and T. S. Reese. Changes in membrane structure induced by electroporation as revealed by rapid-freezing electron microscopy. Biophysics Journal. 58: 1–12(1990).Google Scholar
  17. 17.
    T. Y. Tsong. On electroporation of cell membranes and some related phemomena. Bioelectrochemistry and Bioenergetics. 24: 271–295(1990).Google Scholar
  18. 18.
    R. J. Scheuplein. Permeability of the skin: a review of major concepts. Curr. Probl. Dermatol. 7: 172–186(1978).Google Scholar
  19. 19.
    P. M. Elias. Plastic wrap revisited. Arch. Dermatol. 123: 1405–1406 (1987).Google Scholar
  20. 20.
    R. O. Potts, and R. H. Guy. Predicting Skin Permeability. Pharm. Res. 9: 663–669(1992).Google Scholar
  21. 21.
    I. H. Blank, and R. J. Scheuplein. Transport into and within the skin. Br. J. Derm. 81: 4–10(1969).Google Scholar
  22. 22.
    P. M. Elias. Epidermal barrier function: intercellular lamellar lipid structures, origin, composition and metabolism. J. Control. Rel. 15: 199–208(1991).Google Scholar
  23. 23.
    R. J. Scheuplein. Mechanism of percutaneous adsorption. I. Routes of penetration and the influence of solubility. J. Invest. Dermatol. 45: 334–346(1965).Google Scholar
  24. 24.
    P. Elias. Epidermal lipids, barrier function, and desquamation. JID 80: 44s–49s(1983).Google Scholar
  25. 25.
    D. Bommannan, L. Leung, J. Tamada, J. Sharifi, and R. Potts. Transdermal delivery of luteinizing hormone releasing hormone: comparison between electroporation and iontophoresis in vitro. Proceedings of International Symposium on Controlled Release of Bioactive Materials. 20: 97–98(1993).Google Scholar
  26. 26.
    M.-y. F. Lu, Lee, and G. S. Rao. Percutaneous absorption enhancement of leuprolide. Pharm. Res. 9: 1575–1579(1992).Google Scholar
  27. 27.
    L. Miller, C. Kolaskie, G. Smith, and J. Rivier. Transdermal iontophoresis of gonadotrophin releasing hormone (LHRH) and two analogues. J. Pharm. Sci. 79: 490–493(1990).Google Scholar
  28. 28.
    M. R. Prausnitz, V. G. Bose, R. Langer, and J. C. Weaver. Electroporation of mammalian skin: A mechanism to enhance transdermal drug delivery. Proc. Natl. Acad. Sci. 90: 10504–10508 (1993).Google Scholar
  29. 29.
    L. L. Wearley, and Y. W. Chien. Iontophoretic transdermal permeation of verapamil (III): Effect of binding and concentration gradient on reversibility of skin permeation rate. Int. J. Pharm. 59: 87–94(1990).Google Scholar
  30. 30.
    J. B. Phipps, and J. R. Gyory. Transdermal ion migration. Advanced drug delivery reviews. 9: 137–176(1992).Google Scholar
  31. 31.
    N. Monteiro-Riviere. Altered epidermal morphology secondary to lidocaine iontophoresis: in vivo and in vitro studies in porcine skin. Fundamental and Applied Toxicology. 15: 174–185(1990).Google Scholar
  32. 32.
    N. A. Monteiro-Riviere, A. O. Inman, and J. E. Riviere. Identification of the Pathway of Iontophoretic Drug Delivery: Light and Ultrastructural Studies Using Mercuric Chloride in Pigs. Pharm. Res. 11: 251–256 (1994).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • D. Bommi Bommannan
    • 1
  • Janet Tamada
    • 1
  • Lewis Leung
    • 1
  • Russell O. Potts
    • 1
  1. 1.Cygnus Therapeutic SystemsRedwood City

Personalised recommendations