Pharmaceutical Research

, Volume 8, Issue 9, pp 1113–1120

lontophoretic Delivery of Amino Acids and Amino Acid Derivatives Across the Skin in Vitro

  • Philip G. Green
  • Robert S. Hinz
  • Christopher Cullander
  • Grace Yamane
  • Richard H. Guy


The effects of penetrant properties (lipophilicity and charge) and of vehicle pH on the iontophoretically enhanced delivery of amino acids and their N-acetylated derivatives have been examined in vitro. The penetrants were nine amino acids (five were zwitterionic, two positively charged, and two negatively charged) and four N-acetylated amino acids, which carry a net negative charge at pH 7.4. Iontophoresis at constant current (0.36 mA/cm2), using Ag/AgCl electrodes, was conducted across freshly excised hairless mouse skin. Iontophoretic flux of the zwitterions was significantly greater than passive transport. Delivery from the anode was greater than from the cathode for all zwitterions. The level of enhancement was inversely proportional to permeant octanol/pH 7.4 buffer distribution coefficient. Cathodal iontophoresis of the negatively charged amino acids and of the N-acetylated derivatives produced degrees of enhancement which were significantly greater than those measured for the “neutral” zwitterions. Furthermore, the enhanced flux reached a steady-state level within a few hours for the negatively charged species, whereas the transport of the zwitterions continued to increase with time. Anodal iontophoresis of histidine and lysine, the two positively charged amino acids studied, induced substantial enhancement which was sensitive to the pH of the delivery vehicle. For example, the flux of histidine from an applied solution at pH 4 (where the amino acid carries a net positive charge) was significantly greater than that from a vehicle at pH 7.4 (where histidine is essentially neutral). The behavior of lysine was more complex and suggested a certain degree of neutralization of the skin's net negative charge.

iontophoresis transdermal drug delivery amino acid delivery percutaneous penetration enhancement skin barrier function 


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  1. 1.
    P. Tyle. Iontophoretic devices for drug delivery. Pharm. Res. 3:318–326 (1986).Google Scholar
  2. 2.
    R. R. Burnette. Iontophoresis. In J. Hadgraft and R. H. Guy (eds.), Transdermal Drug Delivery. Developmental Issues and Research Initiatives, Marcel Dekker, New York, 1989, pp. 247–291.Google Scholar
  3. 3.
    R. R. Burnette and B. Ongpipattanakul. Characterization of the permselective properties of excised human skin during iontophoresis. J. Pharm. Sci. 76:765–773 (1987).Google Scholar
  4. 4.
    R. R. Burnette and D. Marrero. Comparison between the iontophoretic and passive transport of thyrotropin. J. Pharm. Sci. 75:738–743 (1986).Google Scholar
  5. 5.
    L. P. Gangarosa, N. H. Park, C. A. Wiggins, and J. M. Hill. Increased penetration of nonelectrolytes into mouse skin during iontophoretic water transport (iontohydrokinesis). J. Pharm. Exp. Ther. 212:377–381 (1980).Google Scholar
  6. 6.
    P. G. Green, R. S. Hinz, A. Kim, F. Szoka, and R. H. Guy. Iontophoretic delivery of a series of tripeptides across the skin in vitro. Pharm. Res. 8:1121–1127 (1991).Google Scholar
  7. 7.
    A. Kim and F. Szoka. The distribution of tripeptides between octanol and water (submitted for publication).Google Scholar
  8. 8.
    P. Glikfeld, C. Cullander, R. S. Hinz, and R. H. Guy. A new system for in vitro studies of iontophoresis. Pharm. Res. 5:443–446 (1988).Google Scholar
  9. 9.
    D. R. Crow. Principles and Applications of Electrochemistry, 2nd ed., Chapman and Hall, London, 1979.Google Scholar
  10. 10.
    R. C. Thomas, Ion-Selective Intracellular Microelectrodes: How to Make and Use Them, Academic Press, London, 1978.Google Scholar
  11. 11.
    L. M. Yunger and R. D. Cramer. Measurement and correlation of partition coefficients of polar amino acids. Mol. Pharmacol. 20:602–608 (1981).Google Scholar
  12. 12.
    J. L. Fauchere and V. Pliska. Hydrophobic parameters P of amino-acid side chains from the partitioning of N-acetyl-amino-acid amides. Eur. J. Med. Chem. Chim. Ther. 18:369–375 (1983).Google Scholar
  13. 13.
    Handbook of Chemistry and Physics, 66th ed., CRC Press, Boca Raton, Fla., 1985.Google Scholar
  14. 14.
    G. Kortüm, W. Vogel, and K. Andrusson. I.U.P.A.C. Dissociation Constants of Acids in Aqueous Solution, Butterworth, London, 1961.Google Scholar
  15. 15.
    S. Del Terzo, C. R. Behl, and A. R. Nash. Iontophoretic transport of a homologous series of ionized and nonionized model compounds: Influence of hydrophobicity and mechanistic interpretation. Pharm. Res. 6:85–90 (1989).Google Scholar
  16. 16.
    M. J. Pikal and S. Shah. Transport mechanisms in iontophoresis. II. Electroosmotic flow and transference number measurements for hairless mouse skin. Pharm. Res. 7:213–221 (1990).Google Scholar
  17. 17.
    J. B. Phipps, J. M. Sunram, and R. V. Padmanabhan. The effect of extraneous ions on the transdermal iontophoretic delivery of hydromorphone. Proc. Int. Symp. Control. Rel. Bioact. Mater. 16:50–51 (1989).Google Scholar
  18. 18.
    B. W. Barry. Dermatological Formulations—Percutaneous Absorption, Marcel Dekker, New York, 1983, p. 236.Google Scholar
  19. 19.
    M. J. Pikal and S. Shah. Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in the transport of low and high molecular weight solutes. Pharm. Res. 7:222–229 (1990).Google Scholar
  20. 20.
    L. L. Wearley, K. Tojo, and Y. W. Chien. A numerical approach to study the effect of binding on the iontophoretic rate of transport of a series of amino acids. J. Pharm. Sci. 79:992–998 (1990).Google Scholar
  21. 21.
    R. S. Hinz, C. D. Hodson, C. R. Lorence, and R. H. Guy. In vitro percutaneous penetration: Evaluation of the utility of hairless mouse skin. J. Invest. Dermatol. 93:87–92 (1989).Google Scholar
  22. 22.
    M. J. Pikal. Transport mechanisms in iontophoresis. I. A theoretical model for the effect of electroosmotic flow on flux enhancement in transdermal iontophoresis. Pharm. Res. 7:118–126 (1990).Google Scholar

Copyright information

© Plenum Publishing Corporation 1991

Authors and Affiliations

  • Philip G. Green
    • 1
  • Robert S. Hinz
    • 1
  • Christopher Cullander
    • 1
  • Grace Yamane
    • 1
  • Richard H. Guy
    • 1
  1. 1.Departments of Pharmacy and Pharmaceutical ChemistryUniversity of CaliforniaSan Francisco
  2. 2.Zyma SANyonSwitzerland

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