Skip to main content
SpringerLink
Log in

Sonophoresis. I. The Use of High-Frequency Ultrasound to Enhance Transdermal Drug Delivery

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Previous attempts to use ultrasound (≤1-MHz frequency and 1 to 3-W/cm2 intensity) to enhance transdermal drug delivery (so-called sonophoresis) have produced inconsistent results. Theoretical analysis of ultrasound propagation in tissue predicts that higher-frequency ultrasound (>1 MHz) will increase the concentration of energy deposition in the stratum corneum (SC) (typically, the rate-limiting barrier to percutaneous penetration). This hypothesis was tested by comparing the passive transdermal delivery of salicylic acid with that under the influence of ultrasound at 2-, 10-, and 16-MHz frequency; measurements were performed in vivo in hairless guinea pigs. Total drug absorbed was quantified by determining the amount of salicylic acid (1) present in SC tape strips and (2) eliminated in urine. Sonophoresis for 20 min at 2 MHz caused no significant increase in salicylic acid delivery over passive diffusion; treatment with ultrasound at 10 and 16 MHz, on the other hand, significantly elevated salicylic acid transport, by 4-fold and 2.5-fold, respectively. Kinetic analysis of the sonophoretic data at 10 and 16 MHz also revealed that the diffusion lag time associated with transdermal drug delivery (TDD) was reduced. A shorter period (5 min) of sonophoresis again resulted in enhanced TDD (relative to the corresponding control) at the higher frequencies; the delivered dose, and the level of enhancement, however, were lower than those after the 20-min treatment. In a separate series of experiments, it was shown that (a) ultrasound did not alter the release kinetics of salicylic acid from the gel formulation used and (b) pretreatment of the skin with ultrasound at 10 and 16 MHz lowered skin barrier function such that the subsequent delivery of salicylic acid was enhanced compared to passive transport without sonophoresis pretreatment. It follows that the enhancing effect of sonophoresis is due to a direct effect of ultrasound on (presumably) the stratum corneum.

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

Access this article

Log in via an institution

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. R. H. Guy and J. Hadgraft. Transdermal drug delivery: The ground rules are emerging. Pharm. Int. 6:112–116 (1985).

    Google Scholar 

  2. C. R. Behl, S. Kumar, A. W. Malick, S. DelTerezo, W. I. Higuchi, and R. A. Nash. Iontophoretic drug delivery: Effects of physicochemical factors on the skin uptake of nonpeptide drugs. J. Pharm. Sci. 78:355–360 (1989).

    Google Scholar 

  3. 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 

  4. Y. W. Chien, O. Siddiqui, W. Shi, P. Lelawongs, and J. Liu. Direct current iontophoretic transdermal delivery of peptide and protein drugs. J. Pharm. Sci. 78:376–383 (1989).

    Google Scholar 

  5. P. Tyle. Iontophoretic devices for drug delivery. Pharm. Res. 3:318–326 (1986).

    Google Scholar 

  6. K. A. Walters. Penetration enhancers and their use. In J. Hadgraft and R. H. Guy (eds.), Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Marcel Dekker, New York, 1989, pp. 197–246.

    Google Scholar 

  7. R. B. Stoughton. Percutaneous absorption of drugs. Ann. Rev. Pharmacol. Toxicol. 29:55–69 (1989).

    Google Scholar 

  8. R. R. Burnette and B. Ongpipattanakul. Characterization of the pore transport properties of excised human skin during iontophoresis. J. Pharm. Sci. 77:132–138 (1988).

    Google Scholar 

  9. 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).

    Google Scholar 

  10. P. G. Green, R. S. Hinz, A. Kim, F. C. Szoka, Jr., and R. H. Guy. Iontophoretic delivery of a series of tripeptides across the skin in vitro. Pharm. Res. 8:1121–1127 (1991).

    Google Scholar 

  11. NCRP. Biological Effects of Ultrasound: Mechanisms and Clinical Implications, National Council of Radiation Protection and Measurements Report No. 74, Bethesda, MD, 1983.

  12. K. Fellinger and J. Schmid. Klinik und Therapie des Chronishen, Gelenkreumatismus, Maudrich, Vienna, 1956, pp. 549–554.

    Google Scholar 

  13. D. M. Skauen and G. M. Zentner. Phonophoresis. Int. J. Pharm. 20:235–245.

  14. P. Tyle and P. Agrawala. Drug delivery by phonophoresis. Pharm. Res. 6:355–361 (1989).

    Google Scholar 

  15. J. P. Davick, R. K. Martin, and J. P. Albright. Distribution and deposition of tritiated cortisol using phonophoresis. Phys. Ther. 68:1672–1675 (1988).

    Google Scholar 

  16. J. E. Griffin, J. L. Echternach, R. E. Price, and J. C. Touchstone. Patients treated with ultrasonic driven hydrocortisone and with ultrasound alone. Phys. Ther. 47:594–601 (1967).

    Google Scholar 

  17. J. E. Griffin and J. C. Touchstone. Ultrasonic movement of cortisol into pig tissues. I. Movement into skeletal muscle. Am. J. Phys. Med. 42:77–85 (1963).

    Google Scholar 

  18. J. E. Griffin, J. C. Touchstone, and A. C-Y. Liu. Ultrasonic movement of cortisol into pig tissues. I. Movement into paravertebral nerve. Am. J. Phys. Med. 44:20–25 (1965).

    Google Scholar 

  19. D. Levy, J. Kost, Y. Meshulam, and R. Langer. Effect of ultrasound on transdermal drug delivery to rats and guinea pigs. J. Clin. Invest. 83:2074–2078 (1989).

    Google Scholar 

  20. H. A. Benson, J. C. McElnay, and R. Harland. Use of ultrasound to enhance percutaneous penetration of benzydamine. Phys. Ther. 69:113–118 (1989).

    Google Scholar 

  21. J. C. McElnay, M. P. Matthews, R. Harland, and D. F. McCafferty. The effect of ultrasound on the percutaneous absorption of lignocaine. Br. J. Clin. Pharmacol. 20:421–424 (1985).

    Google Scholar 

  22. H. Pratzel, P. Dittrich, and W. Kukovetz. Spontaneous and forced cutaneous absorption of indomethacin in pigs and humans. J. Rheumatol. 13:1122–1125 (1986).

    Google Scholar 

  23. R. J. Scheuplein. Permeability of the skin: A review of major concepts. Curr. Prob. Dermatol. 7:172–186 (1976).

    Google Scholar 

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

    Google Scholar 

  25. A. R. Williams. Ultrasound: Biological Effects and Potential Hazards, Academic Press, San Francisco, 1983.

    Google Scholar 

  26. W. L. Nyborg. Mechanisms. In W. L. Nyborg and M. C. Ziskin (eds.), Biological Effects of Ultrasound, Churchill Livingstone, New York, 1985, pp. 23–33.

    Google Scholar 

  27. P. L. Carson, P. R. Fischella, and T. V. Oughton. Ultrasonic power and intensities produced by diagnostic ultrasound equipment. Ultrasound Med. Biol. 3:341–350 (1978).

    Google Scholar 

  28. M. J. Lunt and B. Ashley. A simple balance for measuring ultrasonic power. J. Med. Eng. Technol. 3:194–196 (1979).

    Google Scholar 

  29. R. O. Potts and M. L. Francoeur. Lipid biophysics of water loss through the skin. Proc. Natl. Acad. Sci. 87:3871–3873 (1990).

    Google Scholar 

  30. G. M. Golden, J. E. McKie, and R. O. Potts. Role of stratum corneum lipid fluidity in transdermal drug flux. J. Pharm. Sci. 76:25–28 (1987).

    Google Scholar 

  31. L. R. Brown, C. L. Wei, and R. Langer. In vivo and in vitro release of macromolecules from polymeric drug delivery systems. J. Pharm. Sci. 72:1181–1185 (1983).

    Google Scholar 

Download references

Author information

Author notes

  1. D. Bommannan

    Present address: Cygnus Therapeutic Systems, Redwood City, California, 94063

Authors and Affiliations

  1. Graduate Group in Bioengineering, University of California—Berkeley, and University of California—San Francisco, San Francisco, California, 94143

    D. Bommannan, Paul Stauffer & Richard H. Guy

  2. Departments of Pharmacy and Pharmaceutical Chemistry, University of California—San Francisco, San Francisco, California, 94143

    Hirohisa Okuyama & Richard H. Guy

  3. SS Pharmaceutical Co., Ltd., Tokyo, Japan

    Hirohisa Okuyama

  4. Department of Radiation Oncology, University of California—San Francisco, San Francisco, California, 94143

    Paul Stauffer

Authors
  1. D. Bommannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirohisa Okuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Stauffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard H. Guy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bommannan, D., Okuyama, H., Stauffer, P. et al. Sonophoresis. I. The Use of High-Frequency Ultrasound to Enhance Transdermal Drug Delivery. Pharm Res 9, 559–564 (1992). https://doi.org/10.1023/A:1015808917491

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015808917491

Search

Navigation