Skip to main content
Log in

Electrically-Assisted Transdermal Drug Delivery

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. S. Leduc. Introduction of medicinal substances into the depth of tissues by electric current. Ann. d'Electrobiol. 3:545–560 (1900).

    Google Scholar 

  2. N. A. Monteiro-Riviere. Comparative anatomy, physiology and biochemistry of mammalian skin. In: Dermal and Ocular Toxicology Fundamentals and Methods Hobson DW (Ed)., CRC Press, Boca Raton, Chapter 1, pp. 3–71, (1991).

    Google Scholar 

  3. N. A. Monteiro-Riviere. Anatomical factors affecting barrier function. In Dermatotoxicology, 5th Edition Marzulli FN, Maibach HI (Eds)., Taylor and Francis Publishers, Washington, DC, Chapter 1, pp. 3–18, (1996).

    Google Scholar 

  4. P. M. Elias. Epidermal lipids, barrier function and desquamation. J Invest Dermatol 80:44–49, (1983).

    PubMed  Google Scholar 

  5. L. Landmann. The epidermal permeability barrier. Anat Embryol 178:1–13, (1988).

    PubMed  Google Scholar 

  6. H. J. Yardley. Epidermal Lipids In: The Biochemistry and Physiology of Skin. L. A. Goldsmith (Ed), Oxford University Press, NY 363–381, (1983).

    Google Scholar 

  7. J.-C. Tsai, R. H. Guy, C. R. Thornfeldt, K. R. Faingold, and P. M. Elias. Metabolic approaches to enhance transdermal drug delivery. I. Effect of lipid synthesis inhibition. J. Pharm. Sci. 85:643–648, (1996).

    PubMed  Google Scholar 

  8. C. Cullander. What are the pathways of iontophoretic current flow through mammalian skin? Adv Drug Del Rev 9:119–135. (1992).

    Google Scholar 

  9. H. A. Abramson and M. H. Gorin. The electrophoretic demonstration of the patent pores of the living human skin: its relation to the charge of the skin. J Phys Chem 44:1094–1102, (1940).

    Google Scholar 

  10. R. R. Burnette and B. Ongpipattanakul. Characterization of the pore transport properties and tissue alteration of excised human skin during iontophoresis. J Pharm Sci 77:132–137, (1988).

    PubMed  Google Scholar 

  11. C. Cullander and R. H. Guy. Sites of iontophoretic current flow into the skin; identification and characterization with the vibrating probe electrode. J Invest Derm 97:55–64, (1991).

    PubMed  Google Scholar 

  12. R. D. Lee, H. S. White, and E. R. Scott. Visualization of iontophoretic transport paths in cultured and animal skin models. J. Pharm. Sci. 85:1186–1190, (1996).

    PubMed  Google Scholar 

  13. E. R. Scott, A. I. Laplaza, H. S. White, and J. B. Phipps. Transport of ionic species in skin: contribution of pores to the overall skin conductance. Pharm Res 10:1699–1709, (1993).

    PubMed  Google Scholar 

  14. H. E. Bodde, F. H. N. De Haan, L. Kornet, W. H. M. Craanevan Hinsberg, and M. A. Salomons. Transdermal iontophoresis of mercuric chloride in vitro: electron microscopic visualization of pathways. Proceed Intern Symp Control Rel Bioact Mater 18:301–302, (1991).

    Google Scholar 

  15. N. A. Monteiro-Riviere, A. O. Inman, and J. E. Riviere: Identification of the pathway of transdermal iontophoretic drug delivery: Light and ultrastructural studies using mercuric chloride in pigs. Pharm. Res. 11:251–256, (1994).

    PubMed  Google Scholar 

  16. L. A. R. M. Pechtold, W. Abraham, and R. O. Potts. The influence of an electric field on ion and water accessibility to stratum corneum lipid lamellae. Pharm. Res. 13:1168–1173, (1996).

    PubMed  Google Scholar 

  17. R. R. Burnette. Iontophoresis. In Transdermal Drug Delivery: Developmental Issues and Research Initiatives J. Hadgraft and R. H. Guy (Eds.), Marcel Dekker, Inc., New York. 35:247–291, (1989).

    Google Scholar 

  18. G. B. Kasting. Theoretical models for iontophoretic delivery. Adv Drug Del Rev 9:177–199, (1992).

    Google Scholar 

  19. A. K. Banga and Y. W. Chien. Iontophoretic delivery of drugs: fundamentals, developments and biomedical applications. J Cont Rel 8:1–24, (1988).

    Google Scholar 

  20. J. C. Keister, and G. B. Kasting. Ionic mass transport through a homogenous membrane in the presence of a uniform electric field. J Membr Sci 29:155–167, (1986).

    Google Scholar 

  21. T. Masada, W. I. Higuchi, V. Srinivasan, U. Rohr, J. Fox, C. Behl, and S. Pons. Examination of iontophoretic transport of ionic drugs across skin: baseline studies with the four-electrode system. Int J Pharm 49:57–62, (1989).

    Google Scholar 

  22. L. P. Gangarosa, H. H. Park, C. A. Wiggins, and J. M. Hill. Increased penetration of nonelectrolytes into mouse skin during iontophoretic water transport (iontohydrokinesis). J Pharmacol Exp Ther 212:377–381, (1980).

    PubMed  Google Scholar 

  23. R. 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).

    PubMed  Google Scholar 

  24. H. A. Abramson, and M. H. Gorin. Relationship of skin permeability to electrophoresis of biologically active materials into the living human skin. J Phys Chem 43:335–346, (1939).

    Google Scholar 

  25. H. Rein. Experimental studien uber elektroendosmose an uberlebender menschlicher haut. Z Biol (Munich) 81:81–125, (1924).

    Google Scholar 

  26. R. R. Burnette and B. Ongpipattanakul. Characterization of the permselective properties of excised human skin during iontophoresis. J Pharm Sci 76:765–773, (1987).

    PubMed  Google Scholar 

  27. J. B. Phipps, and J. R. Gyory. Transdermal ion migration. Adv Drug Del Rev 9:137–176, (1992).

    Article  Google Scholar 

  28. A. M. Rodriquez-Bayou, and R. H. Guy. Iontophoresis of nafarelin across human skin in vitro. Pharm Res. 13:798–800, (1996).

    Article  PubMed  Google Scholar 

  29. P. G. Green, R. S. Hinz, C. Cullander, G. Yamane, and R. H. Guy. Iontophoretic delivery of amino acids and amino acid derivatives across the skin in vitro. Pharm Res 8:1113–1120, (1991).

    Article  PubMed  Google Scholar 

  30. 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).

    Article  PubMed  Google Scholar 

  31. 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).

    Article  PubMed  Google Scholar 

  32. M. J. Pikal. The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Del Rev 9:201–237, (1992).

    Article  Google Scholar 

  33. K. D. Peck, V. Srinivasan, S. K. Li, W. I. Higuchi and A-H Ghanem. Quantitative description of the effect of molecular size upon electroosmotic flux enhancement during iontophoresis for a synthetic membrane and human epidermal membrane. J. Pharm. Sci. 85:781–788, (1996).

    Article  PubMed  Google Scholar 

  34. R. R. Burnette, and T. M. Bagniefski. Influence of constant current iontophoresis on the impedance and passive Na+ permeability of excised nude mouse skin. J Pharm Sci 77:492–497, (1986).

    Google Scholar 

  35. M. J. Pikal and S. Shah. Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in transport of low and high molecular weight solutes. Pharm Res 7:222–229, (1990).

    Article  PubMed  Google Scholar 

  36. S. M. Sims, W. I. Higuchi, and V. Srinivasan. Skin alterations and convective solvent flow effects during iontophoresis: I neutral solute transport across human skin. Int J Pharm 69:109–121, (1991).

    Article  Google Scholar 

  37. 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).

    PubMed  Google Scholar 

  38. N. A. Monteiro-Riviere. Altered epidermal morphology secondary to lidocaine iontophoresis: In vivo and in vitro studies in porcine skin. Fundam Appl Toxicology 15:174–185, (1990).

    Article  Google Scholar 

  39. Y. N. Kalia, L. B. Nonato, and R. H. Guy. The effect of iontophoresis on skin barrier integrity: Non-invasive evaluation by impedance spectroscopy and transepidermal water loss. Pharm Res 13:957–960, (1996).

    Article  PubMed  Google Scholar 

  40. D. Bommannan, J. Tamada, L. Leung, and R. O. Potts. Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro. Pharm. Res. 11:1809–1814, (1994).

    PubMed  Google Scholar 

  41. 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. USA 90:10504–10508, (1993).

    PubMed  Google Scholar 

  42. M. R. Prausnitz, E. R. Edelman, J. A. Gimm, R. Langer and J. C. Weaver. Transdermal delivery of heparin by skin electroporation. Bio/Technology 13:1205–1209, (1995).

    PubMed  Google Scholar 

  43. J. E. Riviere, N. A. Monteiro-Riviere, R. A. Rogers, D. Bommannan, J. A. Tamada, and R. O. Potts: Pulsatile transdermal delivery of LHRH using electroporation. Drug delivery and skin toxicology. J. Contr. Release 36:229–233, (1995).

    Article  Google Scholar 

  44. G. Hofman, W. Rustrum W, Suder K. Electroincorporation of microcarriers as a method for the transdermal delivery of large molecules. Bioelectrochem. Bioenergetics 38:209–222, (1995).

    Article  Google Scholar 

  45. M. C. Heit, P. L. Williams, F. L. Jayes, S. K. Chang, and J. E. Riviere. Transdermal iontophoretic peptide delivery; in vitro and in vivo studies with luteinizing hormone releasing hormone. J Pharm Sci 82:240–243, (1993).

    PubMed  Google Scholar 

  46. J. E. Riviere, K. F. Bowman, N. A. Monteiro-Riviere, L. P. Dix, and M. P. Carver. The isolated perfused porcine skin flap (IPPSF) 1. A novel in vitro model for percutaneous absorbtion and cutaneous toxicologic studies. Fundam Appl Toxicol 7:444–453, (1986).

    Article  PubMed  Google Scholar 

  47. J. E. Riviere and N. A. Monteiro-Riviere. The isolated perfused porcine skin flap as an in vitro model for percutaneous absorption and cutaneous toxicology. CRC Critical Review in Toxicology, 21:329–344, (1991).

    Google Scholar 

  48. J. E. Riviere, P. L. Williams, R. Hillman, and L. Mishky: Quantitative prediction of transdermal iontophoretic delivery of arbutamine in humans using the in vitro isolated perfused porcine skin flap (IPPSF). J. Pharm. Sci. 8:504–507, (1992).

    Google Scholar 

  49. M. H. Su, V. Srinivasan, A. H. Ghanem, and W. I. Higuchi. Quantitative in vivo iontophoretic studies. J Pharm Sci 83:12–17, (1994).

    PubMed  Google Scholar 

  50. P. L. Williams and J. E. Riviere: A “full-space” method for predicting in vivo transdermal plasma drug profiles reflecting both cutaneous and systemic variability. J. Pharm. Sci. 83:1062–1064, (1994).

    PubMed  Google Scholar 

  51. M. C. Heit, A. McFarland, R. Bock, and J. E. Riviere. Isoelectric focusing and capillary zone electrophoretic studies using luteinizing hormone releasing hormone and its analog. J Pharm Sci 83:654–656, (1994).

    PubMed  Google Scholar 

  52. B. B. VanOrman, C. R. Daniels, G. G. Liversidge, and G. L. McIntire. Capillary electrophoresis: a physic-chemical model of iontophoretic drug delivery. Pharm Res 7:S-184, (1990).

    Google Scholar 

  53. N. H. Yoshida and M. S. Roberts. Solute molecular size and transdermal iontophoresis across excised human skin. J Contr Rel 25:177–195, (1993).

    Article  Google Scholar 

  54. S. Del Terzo, C. R. Behl, and R. A. Nash. Iontophoretic transport of a homologous series of ionized and unionized model compounds: influences of hydrophobicity and mechanistic interpretation. Pharm Res 6:85–90, (1989).

    Article  PubMed  Google Scholar 

  55. L. L. Wearley, K. Tojo, and Y. W. Chien. A numerical approach to study the effect of binding on the iontophoretic transport of a series of amino acids. J Pharm Sci 79:992–998, (1990).

    PubMed  Google Scholar 

  56. J. Hirvonen, Y. N. Kalia, and R. H. Guy. Transdermal delivery of peptides by iontophoresis. Nature Biotechnology 14:1710–1713, (1966).

    Article  Google Scholar 

  57. L. L. Miller and G. A. Smith. Iontophoretic transport of acetate and carboxylate ions through hairless mouse skin. A cation exchange membrane model. Int J Pharm 49:15–22, (1989).

    Article  Google Scholar 

  58. P. Lelawongs, J. C. Liu, O. Siddiqui, and Y. W. Chien. Transdermal iontophoretic delivery of arginine-vasopressin I: physicochemical considerations. Int J Pharm 56:13–22, (1989).

    Article  Google Scholar 

  59. N. H. Bellantone, S. Rim, M. L. Francoeur, and B. Rasadi B. Enhanced percutaneous absorption via iontophoresis I. Evaluation of an in vitro system and transport of model compounds. Int J Pharm 30:63–72, (1986).

    Article  Google Scholar 

  60. G. A. Lattin, R. V. Padmanabhan, and J. B. Phipps. Electronic control of iontophoretic drug delivery. Annals NY Acad Sci 8:450–464, (1991).

    Google Scholar 

  61. P. Lelawongs, J. C. Liu, and Y. W. Chien. Transdermal iontophoretic delivery of arginine-vasopressin (II): Evaluation of electrical and operational factors. Int J Pharm 61:179–188, (1990).

    Article  Google Scholar 

  62. J. B. Phipps, R. V. Padmanabhan, and G. A. Lattin. Iontophoretic delivery of model inorganic and drug ions. J Pharm Sci 78:365–369, (1989).

    PubMed  Google Scholar 

  63. J. C. Liu, Y. Sun, O. Siddiqui, Y. W. Chien, W. M. Shi and J. Li. Blood glucose control in diabetic rats by transdermal iontophoretic delivery of insulin. Int J Pharm 44:197–204, (1988).

    Article  Google Scholar 

  64. M. J. Pikal and S. Shah. Study of the mechanisms of flux enhancement through hairless mouse skin by pulsed DC iontophoresis. Pharm Res 8:365–369, (1991).

    Article  PubMed  Google Scholar 

  65. O. Siddiqui, Y. Sun, J. C. Liu and Y. W. Chien. Facilitated Transport of Insulin. J Pharm Sci 76:341–345, (1987).

    PubMed  Google Scholar 

  66. D. F. Hager, M. J. Laubach, J. W. Sharkey, and J. R. Siverly JR. In vitro iontophoretic delivery of CQA 206–291: influence of ethanol. J Cont Rel 23:175–182, (1993).

    Article  Google Scholar 

  67. A. K. Banga and Y. W. Chien. Hydrogel-based iontotherapeutic delivery devices for transdermal delivery of peptide/protein drugs. Pharm Res 10:697–702, (1993).

    Article  PubMed  Google Scholar 

  68. L. L. Wearley, J. C. Liu, and Y. W. Chien, Iontophoresis-facilitated transdermal delivery of verapamil II. Factors affecting the reversibility of skin permeability. J Cont Rel 9:231–242, (1989).

    Article  Google Scholar 

  69. M. C. Heit, N. A. Monteiro-Riviere, F. L. Jayes, and J. E. Riviere. Transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH): effect of repeated administration. Pharm Res 11:1000–1003, (1994).

    Article  PubMed  Google Scholar 

  70. V. Srinivasan, M. H. Su, W. I. Higuchi, and C. R. Behl. Iontophoresis of polypeptides: effect of ethanol pretreatment on human skin. J Pharm Sci 79:588–591, (1990).

    PubMed  Google Scholar 

  71. C. L. Gay, P. G. Green, R. H. Guy, and M. L. Francoeur. Iontophoretic delivery of piroxicam across the skin in vitro. J Cont Rel 22:57–68, (1992).

    Article  Google Scholar 

  72. J. E. Riviere, B. Sage, and P. L. Williams. Effects of vasoactive drugs on transdermal lidocaine iontophoresis. J Pharm Sci 80:615–620, (1991).

    PubMed  Google Scholar 

  73. P. L. Williams and J. E. Riviere. A model describing transdermal iontophoretic delivery of lidocaine incorporating consideration of cutaneous microvascular state. J. Pharm Sci 82:1080–1084, (1993).

    PubMed  Google Scholar 

  74. D. L. Chu, H. J. Chiou, and D. P. Wan. Characterization of transdermal delivery of nefopam hydrochloride under iontophoresis. Drug Dev Ind Pharm 20:2775–2785, (1994).

    Google Scholar 

  75. A. K. Banga and Y. W. Chien. Characterization of in vitro transdermal iontophoretic delivery of insulin. Drug Dev Ind Pharm 19:2069–2087, (1993).

    Google Scholar 

  76. R. H. Guy. Current status and future prospects of transdermal drug delivery. Pharm. Res. 13:1765–1769, (1996).

    Article  PubMed  Google Scholar 

  77. S. K. Gupta, S. Kumar, S. Bolton, C. R. Behl, and A. W. Malick. Optimization of iontophoretic transdermal delivery of a peptide and a non-peptide drug. J Cont Rel 30:253–261, (1994).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Riviere, J.E., Heit, M.C. Electrically-Assisted Transdermal Drug Delivery. Pharm Res 14, 687–697 (1997). https://doi.org/10.1023/A:1012129801406

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012129801406

Navigation