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Ultrasound Mediated Transdermal Insulin Delivery in Pigs Using a Lightweight Transducer

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Abstract

Purpose

In previous studies, ultrasound mediated transdermal drug delivery has shown a promising potential as a method for noninvasive drug administration. For prospective future human application, this study was designed to determine the feasibility of lightweight cymbal transducer array as a practical device for noninvasive transdermal insulin delivery in large pigs.

Materials and Methods

Six Yorkshire pigs (100–140 lbs) were divided into two groups. As the control (n = 3), the first group did not receive any ultrasound exposure with the insulin. The second group (n = 3) was treated with ultrasound and insulin at 20 kHz with an Isptp = 100 mW/cm2 at a 20% duty cycle for 60 min. With the pigs in lateral recumbency after anesthesia, the ultrasound transducer with insulin was placed on the axillary area of the pig. At the beginning and every 15 min up to 90 min, the blood glucose level was determined using a glucose monitoring system. To compare the results of individual animals, the change of blood glucose level was normalized to each animal’s initial glucose value at the start of the experiment.

Results

Although each animal had a different initial glucose level, the mean and standard error for the six animals was 146 ± 13 mg/dl. For the control group, the blood glucose level increased to 31 ± 21 mg/dl compared to the initial baseline over the 90 min experiment. However for the ultrasound with insulin treated group, the glucose level decreased to −72 ± 5 mg/dl at 60 min (p <  0.05) and continued to decrease to −91 ± 23 mg/dl in 90 min (p < 0.05).

Conclusion

The results indicate the feasibility of ultrasound mediated transdermal insulin delivery using the cymbal transducer array in animal with a similar size and weight to a human. Based on these result, the cymbal array has potential as a practical ultrasound system for noninvasive transdermal insulin delivery for diabetes management.

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References

  1. M. R. Prausnitz. Reversible skin permeabilization for transdermal delivery of macromolecules. Crit. Rev. Ther. Drug Carrier Syst. 14:455–483 (1997).

    PubMed  CAS  Google Scholar 

  2. M. R. Prausnitz. A practical assessment of transdermal drug delivery by skin electroporation. Adv. Drug Deliv. Rev. 35:61–76 (1999).

    Article  PubMed  CAS  Google Scholar 

  3. F. Montorsi, A. Salonia, G. Guazzoni, L. Barbieri, R. Colombo, M. Brausi, V. Scattoni, P. Rigatti, and G. Pizzini. Transdermal electromotive multi-drug administration for Peyronie’s disease: preliminary results. J. Androl. 21:85–90 (2000).

    PubMed  CAS  Google Scholar 

  4. Y. Wang, R. Thakur, Q. Fan, and B. Michniak. Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery. Eur. J. Pharm. Biopharm. 60:179–191 (2005).

    Article  PubMed  CAS  Google Scholar 

  5. A. Nanda, S. Nanda, and N. M. Ghilzai. Current developments using emerging transdermal technologies in physical enhancement methods. Curr. Drug Deliv. 3:233–242 (2006).

    Article  PubMed  CAS  Google Scholar 

  6. J. Kost. Ultrasound-assisted insulin delivery and noninvasive glucose sensing. Diabetes Technol. Ther. 4:489–497 (2002).

    Article  PubMed  Google Scholar 

  7. M. J. King, I. Badea, J. Solomon, P. Kumar, K. J. Gaspar, and M. Foldvari. Transdermal delivery of insulin from a novel biphasic lipid system in diabetic rats. Diabetes Technol. Ther. 4:479–488 (2002).

    Article  PubMed  Google Scholar 

  8. K. Tachibana and S. Tachibana. The use of ultrasound for drug delivery. Echocardiography 18:323–328 (2001).

    Article  PubMed  CAS  Google Scholar 

  9. W. G. Pitt, G. A. Husseini, and B. J. Staples. Ultrasonic drug delivery—a general review. Expert Opin Drug Deliv. 1:37–56 (2004).

    Article  PubMed  CAS  Google Scholar 

  10. S. Mitragotri. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat. Rev. Drug Discov. 4:255–260 (2005).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. S. Mitragotri, D. Blankschtein, and R. Langer. An explanation for the variation of the sonophoretic transdermal transport enhancement from drug to drug. J. Pharm. Sci. 86:1190–1192 (1997).

    Article  PubMed  CAS  Google Scholar 

  13. H. R. Guzman, A. J. McNamara, D. X. Nguyen, and M. R. Prausnitz. Bioeffects caused by changes in acoustic cavitation bubble density and cell concentration: a unified explanation based on cell-to-bubble ratio and blast radius. Ultrasound Med. Biol. 29:1211–1222 (2003).

    Article  PubMed  Google Scholar 

  14. R. K. Schlicher, H. Radhakrishna, T. P. Tolentino, R. P. Apkarian, V. Zarnitsyn, and M. R. Prausnitz. Mechanism of intracellular delivery by acoustic cavitation. Ultrasound Med. Biol. 32:915–924 (2006).

    Article  PubMed  Google Scholar 

  15. N. B. Smith. Perspectives on transdermal ultrasound mediated drug delivery. International Journal of Nanomedicine 2(2). (2007). (in press).

  16. Congressionally established diabetes research working group. Conquering diabetes: a strategic plan for the 21th century. NIH Publication No. 99-4398. 1999.

  17. The Whitaker Foundation. Biomedical engineering and the fight against diabetes, 2003 Annual Report. The Whitaker Foundation, Arlington, VA, 2004.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. I. Zhang, K. K. Shung, and D. A. Edwards. Hydrogels with enhanced mass transfer for transdermal drug delivery. J. Pharm. Sci. 85:1312–1316 (1996).

    Article  PubMed  CAS  Google Scholar 

  21. A. Boucaud, L. Tessier, L. Machet, L. Vaillant, and F. Patat. Transdermal delivery of insulin using low frequency ultrasound. In Proceedings of the IEEE 2000 Ultrasonics Symposium, San Juan Porto Rico, 2000, pp. 1453–1456.

  22. A. Boucaud, M. A. Garrigue, L. Machet, L. Vaillant, and F. Patat. Effect of sonication parameters on transdermal delivery of insulin to hairless rats. J. Control. Release 81:113–119 (2002).

    Article  PubMed  CAS  Google Scholar 

  23. N. B. Smith, S. Lee, E. Maione, R. B. Roy, S. McElligott, and K. K. Shung. Ultrasound mediated transdermal transport of insulin through in vitro human skin using novel transducer designs. Ultrasound Med. Biol. 29:311–317 (2003).

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. D. Stansfield. Underwater electroacoustic transducers. Bath University Press, Bath, UK, 1990.

    Google Scholar 

  26. O. B. Wilson. An introduction to the theory and design of sonar transducers. Peninsula, Los Altos, CA, 1988.

    Google Scholar 

  27. K. K. Shung, M. B. Smith, and B. Tsui. Principles of medical imaging. Academic, San Diego, 1992.

    Google Scholar 

  28. R. E. Newnham, Q. C. Xu, and S. Yoshikawa. Transformed stress direction acoustic transducer. US Patent 4,999,819, March 12, 1991.

  29. R. E. Newnham, Q. C. Xu, and S. Yoshikawa. Metal-electroactive ceramic composite actuators. US Patent 5,276,657, January 4, 1994.

  30. E. Maione, K. K. Shung, R. J. Meyer, J. W. Hughes, R. E. Newnham, and N. B. Smith. Transducer design for a portable ultrasound enhanced transdermal drug delivery system. IEEE Trans. Ultrason. Ferroelectr. Freq. Contr. 49:1430–1436 (2002).

    Article  Google Scholar 

  31. N. B. Smith, S. Lee, and K. K. Shung. Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays. Ultrasound Med. Biol. 29:1205–1210 (2003).

    Article  PubMed  Google Scholar 

  32. S. Lee, R. E. Newnham, and N. B. Smith. Short ultrasound exposure times for noninvasive insulin delivery in rats using the light weight cymbal array. IEEE Trans. Ultrason. Ferroelectr. Freq. Contr. 51:176–180 (2004).

    Article  Google Scholar 

  33. S. Lee, B. Snyder, R. E. Newnham, and N. B. Smith. Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array. Diabetes Technol. Ther. 6:808–815 (2004).

    Article  PubMed  CAS  Google Scholar 

  34. B. Snyder, S. Lee, R. E. Newnham, and N. B. Smith. Ferroelectric transducer arrays for transdermal insulin delivery. J. Mater. Sci. 41:211–216 (2006).

    Article  CAS  Google Scholar 

  35. S. Lee, V. Nayak, J. Dodds, M. Pishko, N. B. Smith. Ultrasonic mediated glucose measurements in vivo using the cymbal array. Ultrasound Med. Biol. 31:971–977 (2005).

    Article  PubMed  Google Scholar 

  36. R. J. Meyer, A. Dogan, C. Yoon, S. M. Pilgrim, and R. E. Newnham. Displacement amplification of electroactive materials using the cymbal flextensional transducer. Sens. Actuators 87:157–162 (2001).

    Article  Google Scholar 

  37. IEEE. IEEE guide for medical ultrasound field parameter measurements. Institute of Electrical and Electronics Engineers, Inc., New York, 1990.

    Google Scholar 

  38. AIUM. Acoustic output labeling standard for diagnostic ultrasound equipment. American Institute of Ultrasound in Medicine, Laurel, MD, 1998.

    Google Scholar 

  39. W. G. Pond and K. A. Houpt. The biology of the pig. Cornell University Press, Ithaca, NY, 1978.

    Google Scholar 

  40. D. Danfaer. A quantitative biology of the pig. CABI, New York, NY, 1998.

    Google Scholar 

  41. J. F. Tressler, W. Cao, K. Uchino, and R. E. Newnham. Finite element analysis of the cymbal-type flextensional transducer. IEEE Trans. Ultrason., Ferroelect. Freq. Contr. 45:1363–1369 (1998).

    Article  Google Scholar 

  42. J. E. Harkness and D. J. Wagner. The biology and medicine of rabbits and rodents. Williams and Willkins, Baltimore MD, 1995.

    Google Scholar 

  43. M. Pavlovic, K. Wroblewski, Y. Manevich, S. Kim, and J. E. Biaglow. The importance of choice of anaesthetics in studying radiation effects in the 9L rat glioma. Br. J. Cancer., Suppl. 27:S222–S225 (1996).

    CAS  Google Scholar 

  44. E. Hillyer and K. E. Quesenberry. Ferrets, rabbits, and rodents: clinical medicine and surgery. Saunders, Philadelphia PA, 1997.

    Google Scholar 

  45. N. Kawai, R. F. Keep, and A. L. Betz. Hyperglycemia and the vascular effects of cerebral ischemia. Stroke. 28:149–154 (1997).

    PubMed  CAS  Google Scholar 

  46. K. E. Heim, J. S. Morrell, A. M. Ronan, and A. R. Tagliaferro. Effects of ketamine-xylazine and isoflurane on insulin sensitivity in dehydroepiandrosterone sulfate-treated minipigs (Sus scrofa domestica). Comp. Med. 52:233–237 (2002).

    PubMed  CAS  Google Scholar 

  47. H. Rifkin and D. Porte. Ellenberg and rifkin’s diabetes. Elsevier, New York, NY, 1990.

    Google Scholar 

  48. J. E. Shaw, P. Z. Zimmet, de Court, G. K. Dowse, P. Chitson, H. Gareeboo, F. Hemraj, D. Fareed, J. Tuomilehto, and K. G. Alberti. Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius? Diabetes Care. 22:399–402 (1999).

    Article  PubMed  CAS  Google Scholar 

  49. G. P. Carnevale Schianca, A. Rossi, P. P. Sainaghi, E. Maduli, and E. Bartoli. The significance of impaired fasting glucose versus impaired glucose tolerance: importance of insulin secretion and resistance. Diabetes Care. 26:1333–1337 (2003).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Department of Defense Technologies for Metabolic Monitoring Award Number W81XWH-05-1-0617.

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Correspondence to Nadine Barrie Smith.

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Park, E.J., Werner, J. & Smith, N.B. Ultrasound Mediated Transdermal Insulin Delivery in Pigs Using a Lightweight Transducer. Pharm Res 24, 1396–1401 (2007). https://doi.org/10.1007/s11095-007-9306-4

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  • DOI: https://doi.org/10.1007/s11095-007-9306-4

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