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Synergistic Effect of Enhancers for Transdermal Drug Delivery

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Abstract

Transdermal drug delivery offers a non-invasive route of drug administration, although its applications are limited by low skin permeability. Various enhancers including iontophoresis, chemicals, ultrasound, and electroporation have been shown to enhance transdermal drug transport. Although all these methods have been individually shown to enhance transdermal drug transport, their combinations have often been found to enhance transdermal transport more effectively than each of them alone. This paper summarizes literature studies on these combinations with respect to their efficacy and mechanisms.

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REFERENCES

  1. R. L. Bronaugh, and H. I. E. Maibach. Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, Marcel Dekker, New York and Basel, 1989.

    Google Scholar 

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

    Google Scholar 

  3. S. Mitragotri, D. Blankschtein, and R. Langer. Ultrasoundmediated transdermal protein delivery. Science 269:850-853 (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. Tachibana. Transdermal delivery of insulin to alloxan-diabetc rabbits by ultrasound exposure. Pharm. Res. 9:952-954 (1992).

    Google Scholar 

  6. J. Kost, D. Levy, and R. Langer. Ultrasound as a transdermal enhancer. In R. Bronaugh and H. I. Maibach (eds.), Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, New York and Basel, 1989 pp. 595-601.

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

    Google Scholar 

  8. D. Bommannan, 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 

  9. M. E. Johnson, S. Mitragotri, A. Patel, D. Blankschtein, and R. Langer. Synergistic effect of ultrasound and chemical enhancers on transdermal drug delivery. J. Pharm. Sci. 85:670-679 (1996).

    Google Scholar 

  10. A. C. Williams and B. W. Barry. Skin Absorption Enhancers. Crit. Rev. Ther. Drug Carrier Syst. 9305-353 (1992).

    Google Scholar 

  11. P. G. Green, M. Flalagan, B. Shroot, and R. H. Guy. Iontophoretic drug delivery. In K. A. Walters and J. Hadgraft (eds.), Pharmaceutical Skin Penetration Enhancement, Marcel Dekker, New York, 1993.

    Google Scholar 

  12. M. R. Prausnitz, V. 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).

    Google Scholar 

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

    Google Scholar 

  14. K. S. Bhatia and J. Singh. Mechanism of transport enhancement of LHRH through porcine epidermis by terpenes and iontophoresis: Permeability and lipid extraction studies. Pharm. Res. 15: 1857-1862 (1998).

    Google Scholar 

  15. K. S. Bhatia and J. Singh. Effect of linoleic acid/ethanol or limonene/ethanol and iontophoresis on the in vitro percutaneous absorption of LHRH and ultrastructure of human epidermis. Int. J. Pharm. 180:235-250 (1999).

    Google Scholar 

  16. T. Murakami, C. Ihara, G. Kiyonaka, R. Yumoto, S. Shigeki, Y. Ikuta, and N. Yata. Iontophoretic transdermal delivery of salicylic acid dissolved in ethanol-water mixture in rats. Skin Pharmacol. Appl. Skin Physiol. 12:221-226 (1999).

    Google Scholar 

  17. J. Singh and S. Singh. Transdermal iontophoresis: Effect of penetration enhancer and iontophoresis on drug transport and surface characteristics of human epidermis. Curr. Probl. Dermatol. 22:179-183 (1995).

    Google Scholar 

  18. K. S. Bhatia, S. Gao, T. P. Freeman, and J. Singh. Effect of penetration enhancers and iontophoresis on the ultrastructure and cholecystokinin-8 permeability through porcine skin. J. Pharm. Sci. 96:1011-1015 (1998).

    Google Scholar 

  19. K. S. Bhatia and J. Singh. Synergistic effect of iontophoresis and a series of fatty acids on lhrh permeability through porcine skin. J. Pharm. Sci. 87:462-469 (1998).

    Google Scholar 

  20. S. Y. Oh, S. Y. Jeong, T. G. Park, and J. H. Lee. Enhanced transdermal delivery of azt (zidovudine) using iontophoresis and penetration enhancer. J. Control Release. 51:161-168 (1998).

    Google Scholar 

  21. E. H. Choi, S. H. Lee, S. K. Ahn, and S. M. Hwang. The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis. Skin Pharmacol. Appl. Skin Physiol. 12:326-335 (1999).

    Google Scholar 

  22. M. Kirjavaninen, A. Urtti, J. Monkkonen, and J. Hirvonen. Influence of lipids on the mannitol flux during transdermal iontophoresis in vitro. Eur. J. Pharm. Sci. 10:97-102 (2000).

    Google Scholar 

  23. J. Y. Fang, K. C. Sung, H. H. Lin, and C. L. Fang. Transdermal iontophoretic delivery of diclofenac sodium from various formulations: in vitro and in vivo studies. Int. J. Pharm. 178:83-92 (1999).

    Google Scholar 

  24. V. Srinivasan, W. I. Higuchi, S. M. Sima, 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).

    Google Scholar 

  25. L. Ilic, T. R. Gowrishankar, T. E. Vaughan, T. O. Herndon, and J. Weaver. Spatially constrained skin electroporation with sodium thiosulfate and urea creates transdermal microconduits. J. Control. Release 61:185-202 (1999).

    Google Scholar 

  26. T. E. Zewert, U. F. Pliquett, R. Vanbever, R. Langer, and J. C. Weaver. Creation of transdermal pathways for macromolecule transport by skin electroporation and a low toxicity, pathway-enlarging molecule. Bioelectrochem. Bioenerg. 49:11-20 (1999).

    Google Scholar 

  27. R. Vanbever, M. R. Prausnitz, and V. Preat. Macromolecules as novel transdermal transport enhancers for skin electroporation. Pharm. Res. 14:638-644 (1997).

    Google Scholar 

  28. S. Wang, M. Kara, and T. R. Krishnan. Transdermal delivery of cyclosporin-A using electroporation. J. Control. Release 50:61-70 (1998).

    Google Scholar 

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

    Google Scholar 

  30. S. Mitragotri, D. Ray, J. Farrell, H. Tang, B. Yu, J. Kost, D. Blankschtein, and R. Langer. Enhancement of transdermal transport using ultrasound and surfactants. Proc. Intl. Symp. Control. Rel. Bioact. Mater. 26:176-177 (1999).

    Google Scholar 

  31. L. Le, J. Kost, and S. Mitragotri. Synergistic effect of ultrasound and iontophoresis on transdermal drug delivery: Applications to heparin delivery. Pharm. Res. In Press.

  32. D. Bommanon, J. Tamada, L. Leung, and R. Potts. Effects of electroporation on transdermal iontophoretic delivery of leutinizing hormone releasing hormone. Pharm. Res. 11:1809-1814 (1994).

    Google Scholar 

  33. S. Chang, G. Hofmann, L. Zhang, L. Deftos, and A. Banga. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J Control. Release 66:127-133 (2000).

    Google Scholar 

  34. J. Kost, U. Pliquett, S. Mitragotri, A. Yamamoto, J. Weaver, and R. Langer. Enhanced transdermal delivery: synergistic effect of ultrasound and electroporation. Pharm. Res. 13:633-638 (1996).

    Google Scholar 

  35. R. H. Guy, Y. Kalia, M. Delgado-Charro, V. Merino, A. Lopez, and D. Marro. Iontophoresis: Electrorepulsion and electroosmosis. J. Control. Release 64:129-132 (2000).

    Google Scholar 

  36. W. I. Higuchi, S. Li, A. Ghanem, H. Zhu, and Y. Song. Mechanistic aspects of iontophoresis in human epidermal membrane. J. Control. Release 62:13-23 (1999).

    Google Scholar 

  37. K. Knutson, S. L. Krill, W. Lambert, J, and W. I. Higuchi. Physico-chemical aspects of transdermal permeation. J. Control. Release 6:59-74 (1987).

    Google Scholar 

  38. H. E. Junginger, H. E. Bodde, and F. H. de Haan de, N. Visualization of drug transport across human skin and the influence of penetration enhancers. In D. S. Hsieh (ed.), Drug Permeation Enhancement, Marcel Dekker, Inc., New York, Basel, Hong Kong, 1994 pp. 59-90.

    Google Scholar 

  39. T. Marjukka Suhonen, J. Bouwstra, and A. Urtti. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J. Control. Release 59:149-161 (1999).

    Google Scholar 

  40. K. A. Walters. Surfactants and percutaneous absorption. In R. C. Scott, R. H. Guy, and J. Hadgraft (eds.), Predictions of Percutaneous Penetration, IBC Technical Services, London, 1990 pp. 148-162.

    Google Scholar 

  41. 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, Marcel Dekker, New York, 1989 pp. 197-233.

    Google Scholar 

  42. L. Wearley and Y. W. Chien. Enhancement of the in vitro skin permeability of azidothymidine (azt) via iontophoresis and chemical enhancers. Pharm. Res. 7:34-40 (1990).

    Google Scholar 

  43. S. Ganga, J. Ramarao, and J. Singh. Effect of azone on the iontophoretic transdermal delivery of metoprolol tartarate through human epidermis in vitro. J. Control. Release 42:57-64 (1996).

    Google Scholar 

  44. C. L. Gay, P. G. Green, R.H. Guy, and M. L. Francoeur. Iontophoretic delivery of piroxicam across the skin in-vitro. J. Control. Release 22:57-68 (1992).

    Google Scholar 

  45. K. S. Bhatia, S. Gao, and J. Singh. Effect of penetration enhancers and iontophoresis on the FT-IR spectroscopy and LHRH permeability. J. Control. Release 47:81-89 (1997).

    Google Scholar 

  46. Y. N. Kalia and R. H. Guy. Interaction between penetration enhancers and iontophoresis: Effect on human skin impedance in vivo. J. Control. Release 44:33-42 (1997).

    Google Scholar 

  47. S. Mitragotri, D. Blankschtein, and R. Langer. Sonophoresis: Ultrasound mediated transdermal drug delivery. In J. Swarbrick and J. Boylan (eds.), Encylopedia of Pharmaceutical Technology, Marcel Dekker, 1995 pp. 103-122.

  48. B. Ongpipattnakul, R. R. Burnette, R. O. Potts, and M. L. Francoeur. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm. Res. 8:350-354 (1991).

    Google Scholar 

  49. T. Chen. Thesis in Chemical Engineering. Massachusetts Institute of Technology, Cambridge, MA (1998).

    Google Scholar 

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

    Google Scholar 

  51. J. Weaver, R. Vanbever, T. E. Vaughn, and M. Prausnitz. Heparin alters transdermal transport associated with electroporation. Biochim. Biophys. Res. Com. 24:637-640 (1997).

    Google Scholar 

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  1. Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106

    Samir Mitragotri

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Mitragotri, S. Synergistic Effect of Enhancers for Transdermal Drug Delivery. Pharm Res 17, 1354–1359 (2000). https://doi.org/10.1023/A:1007522114438

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