Skip to main content
SpringerLink
Log in

An Investigation of the Role of Cavitation in Low-Frequency Ultrasound-Mediated Transdermal Drug Transport

Pharmaceutical Research volume 19, pages 1160–1169 (2002)Cite this article

Abstract

Purpose. Low-frequency ultrasound (20 kHz) has been shown to increase the skin permeability to drugs, a phenomenon referred to as low-frequency sonophoresis (LFS). Many previous studies of sonophoresis have proposed that ultrasound-induced cavitation plays the central role in enhancing transdermal drug transport. In this study, we sought to definitively test the role of cavitation during LFS, as well as to identify the critical type(s) and site(s) of cavitation that are responsible for skin permeabilization during LFS.

Methods. Pig full-thickness skin was treated by 20 kHz ultrasound, and the effect of LFS on the skin permeability was monitored by measuring the increase in the skin electrical conductance. A high-pressure LFS cell was constructed to completely suppress cavitation during LFS. An acoustic method, as well as chemical and physical dosimetry techniques, was utilized to monitor the cavitation activities during LFS.

Results. The study using the high-pressure LFS cell showed definitively that ultrasound-induced cavitation is the key mechanism via which LFS permeabilizes the skin. By selectively suppressing cavitation outside the skin using a high-viscosity coupling medium, we further demonstrated that cavitation occurring outside the skin is responsible for the skin permeabilization effect, while internal cavitation (cavitation inside the skin) was not detected using the acoustic measurement method under the ultrasound conditions examined. Acoustic measurement of the two types of cavitation activities (transient vs. stable) indicates that transient cavitation plays the major role in LFS-induced skin permeabilization. Through quantification of the transient cavitation activity at two specific locations of the LFS system, including comparing the dependence of these cavitation activities on ultrasound intensity with that of the skin permeabilization effect, we demonstrated that transient cavitation occurring on, or in the vicinity of, the skin membrane is the central mechanism that is responsible for the observed enhancement of skin permeability by LFS.

Conclusions. LFS-induced skin permeabilization results primarily from the direct mechanical impact of gas bubbles collapsing on the skin surface (resulting in microjets and shock waves).

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

REFERENCES

  1. D. Bommannan, H. Okuyama, P. Stauffer, and R. H. Guy. Sonophoresis. I. The use of high-frequency ultrasounnd to enhance transdermal drug delivery. Pharm. Res. 9:559–564 (1992).

    Google Scholar 

  2. K. Tachibana and S. Tachibana. Transdermal delivery of insulin by ultrasonic vibration. J. Pharm. Pharmacol. 43:270–271 (1991).

    Google Scholar 

  3. S. Mitragotri, D. Edwards, D. Blankschtein, and R. Langer. A mechanistic study of ultrasound-enhanced transdermal drug delivery. J. Pharm. Sci. 84:697–706 (1995).

    Google Scholar 

  4. S. Mitragotri, D. Blankschtein, and R. Langer. Transdermal drug delivery using low-frequency sonophoresis. Pharm. Res. 13:411–420 (1996).

    Google Scholar 

  5. K. A. Walters. Penetration enhancers and their use in transdermal therapeutic systems. In J. Hadgraft and R. H. Guy (eds.), Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Vol. 35. Drugs and the Pharmaceutical Sciences, Marcel Dekker, New York, 1989 pp. 197–246.

    Google Scholar 

  6. B. J. Barry. Mode of action of penetration enhancers in human skin.J. Control Rel. 6:85–97 (1987).

    Google Scholar 

  7. M. E. Johnson, D. A. Berk, D. Blankschtein, D. E. Golan, R. K. Jain, and R. Langer. Lateral diffusion of small compounds in human stratum corneum and model lipid bilayer systems. Biophysical Journal 71:2656–2668 (1996).

    Google Scholar 

  8. R. R. Burnette. Iontophoresis. In J. Hadgraft and R. H. Guy (eds.), Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Vol. 35. Drugs and the Pharmaceutical Sciences, Marcel Dekker, New York, 1989 pp. 247–292.

    Google Scholar 

  9. V. Srinivasan and W. I. Higuchi. A model for iontophoresis incorporating the effect of convective solvent flow. Int. J. Pharm. 60:133–138 (1990).

    Google Scholar 

  10. S. B. Barnett. WFUMB Symposium on safety of ultrasound in medicine. Conclusions and recommendations on thermal and non-thermal mechanisms for biologic effects of ultrasound. Kloster-Banz, Germany 14-19 April, 1996. Ultrasound in Med. & Biol. 24:S1–S49 (1998).

    Google Scholar 

  11. L. A. Frizzell. Biologic Effects of Acoustic Cavitation. In K. S. Suslick (ed.), Ultrasound, Its Chemical, Physical, and Biologic Effects. VCH Publishers, Inc, New York, 1988 pp. 287–303.

    Google Scholar 

  12. P. Riesz and T. Kondo. Free radical formation induced by ultrasound and its biologic implications. Free Radic. Biol. Med. 13:247–270 (1992).

    Google Scholar 

  13. A. A. Atchley and L. A. Crum. Acoustic cavitation and bubble dynamics. In K. S. Suslick (ed.), Ultrasound. Its Chemical, Physical, and Biologic Effects. VCH Publisher, Inc, New York, 1988 pp. 1–64.

    Google Scholar 

  14. D. Bommanan, G. K. Menon, H. Okuyama, P. M. Elias, and R. H. Guy. Sonophoresis. II. Examination of the mechanism(s) of ultrasound-enhanced transdermal drug delivery. Pharm. Res. 9:1043–1047 (1992).

    Google Scholar 

  15. K. Tachibana. Transdermal delivery of insulin to alloxan-diabetic rabbits by ultrasound exposure. Pharm. Res. 9:952–954 (1992).

    Google Scholar 

  16. L. Machet, J. Pinton, F. Patat, B. Arbeille, L. Pourcelot, and L. Vaillant. In vitro phonophoresis of digoxin across hairless mice and human skin: Thermal effect of ultrasound. Int. J. Pharm. 133:39–45 (1996).

    Google Scholar 

  17. N. Yamashita, K. Tachibana, and K. Ogawa. Scanning Electron Microscopy Evaluation of the Skin Surface After Ultrasound Exposure. The Anatomic Record 247:455–461 (1997).

    Google Scholar 

  18. S. Mitragotri, D. Blankschtein, and R. Langer. Ultrasound-mediated transdermal protein delivery. Science 269:850–853 (1995).

    Google Scholar 

  19. H. Tang, S. Mitragotri, D. Blankschtein, and R. Langer. Theoretical description of transdermal transport of hydrophilic permeants: Application to low-frequency sonophoresis.J. Pharm. Sci. 90:545–568 (2001).

    Google Scholar 

  20. S. Mitragotri, J. Farrell, H. Tang, T. Terahara, J. Kost, and R. Langer. Determination of threshold energy dose for ultrasound-induced transdermal drug transport. J. Control. Rel. 63:41–52 (2000).

    Google Scholar 

  21. A. Allenby, F. J. Schok, and T. F. S. Tees. The effects of heat and organic solvents on the electrical impedance and permeability of excised human skin. Br. J. Derm. 81:31–62 (1969).

    Google Scholar 

  22. S. Mitragotri, D. Ray, J. Farrell, and H. Tang. B. Yu, J. Kost, D. Blankschtein, R. Langer. Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J. Pharm. Sci. 89:892–900 (2000).

    Google Scholar 

  23. R. O. Potts. Physical characterization of the stratum corneum: The relationship of mechanical and barrier properties to lipid and protein structure. In J. Hadgraftand and R. H. Guy (eds.), Transdermal Drug Delivery. Developmental Issues and Research Initiatives. Marcel Dekker, Inc., New York and Basel, 1989 pp. 23–57.

    Google Scholar 

  24. J. A. Rooney. Other Nonlinear Acoustic Phenomena. In K. S. Suslick (ed.), Ultrasound. Its Chemical, Physical, and Biologic Effects. VCH Publisher, Inc, New York, 1988 pp. 65–95.

    Google Scholar 

  25. E. A. Neppiras. Subharmonic and other low-frequency emission from bubbles in sound-irradiated field. J. Acoust. Soc. Am. 46:587–601 (1968).

    Google Scholar 

  26. J. Liu, T. N. Lewis, and M. R. Prausnitz. Non-invasive assessment and control of ultrasound-mediated membrane permeabilization. Pharm. Res. 6:920–926 (1998).

    Google Scholar 

  27. Leighton. The Acoustic Bubble, Academic Press, London, 1994.

    Google Scholar 

  28. G. J. Price and E. J. Lenz. The use of dosimeters to measure radical production in aqueous sonochemical systems. Ultrasonics 31:451–456 (1993).

    Google Scholar 

  29. J. R. McLean. A cavitation and free radical dosimeter for ultrasound. Ultrasound in Med. & Biol. 14:59–64 (1988).

    Google Scholar 

  30. J. P. Simonin. On the mechanisms of in vitro and in vivo phonophoresis. J. Control. Rel. 33:125–141 (1995).

    Google Scholar 

  31. R. J. Scheuplein. Mechanism of Percutaneous Absorption II. Transient Diffusion and the Relative Importance of Various Routes of Skin Penetration. J. Invest. Dermatol. 81:79–88 (1967).

    Google Scholar 

  32. P. Huber, K. Jochle, and J. Debus. Influence of shock wave pressure amplitude and pulse repetition frequency on the lifespan, size and number of transient cavities in the field of an electromagnetic lithotripter. Phys. Med. Biol. 43:3113–3128 (1998).

    Google Scholar 

  33. P. R. Williams, P. M. Williams, and S. W. Brown. Cavitation phenomena in water involving the reflection of ultrasound pulses from a free surface, or from flexible membranes. Phys. Med. Biol. 43:3101–3111 (1998).

    Google Scholar 

  34. T. Benjamin and A. Ellis. The collapse of cavitation bubbles and the pressures thereby produced against solid boundaries. Philos. Trans. R. Soc. London Ser. A 260:221–240 (1966).

    Google Scholar 

  35. M. S. Plesset and R. B. Chapman. Collapse of an initially spherical vapour cavity in the neighbourhood of a solid boundary. J. Fluid Mech. 47:283–290 (1971).

    Google Scholar 

  36. W. Lauterborn and H. Bolle. Experimental investigations of cavitation bubbles collapse in the neighborhood of a solid boundary. J. Fluid Mech. 72:391–399 (1975).

    Google Scholar 

  37. K. S. Suslick. Ultrasound. Its Chemical, Physical, and Biologic Effects, VCH Publishers, New York (1988).

    Google Scholar 

  38. B. Krasovitski and E. Kimmel. Gas bubble pulsation in a semiconfined space subjected to ultrasound. J. Acoust. Soc. Am. 109:891–898 (2001).

    Google Scholar 

Download references

Authors
  1. Hua Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiao Chun Joanne Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Blankschtein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Langer
    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

Tang, H., Wang, C.C.J., Blankschtein, D. et al. An Investigation of the Role of Cavitation in Low-Frequency Ultrasound-Mediated Transdermal Drug Transport. Pharm Res 19, 1160–1169 (2002). https://doi.org/10.1023/A:1019898109793

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1019898109793

search

Navigation