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Discovery of transdermal penetration enhancers by high-throughput screening

Nature Biotechnology volume 22, pages 192–197 (2004)Cite this article

Abstract

Although transdermal drug delivery is more attractive than injection, it has not been applied to macromolecules because of low skin permeability. Here we describe particular mixtures of penetration enhancers that increase skin permeability to macromolecules (∼1–10 kDa) by up to ∼100-fold without inducing skin irritation. The discovery of these mixtures was enabled by an experimental tool, in vitro skin impedance guided high-throughput (INSIGHT) screening, which is >100-fold more efficient than current tools. In vitro experiments demonstrated that the mixtures delivered macromolecular drugs, including heparin, leutinizing hormone releasing hormone (LHRH) and oligonulceotides, across the skin. In vivo experiments on hairless rats with leuprolide acetate confirmed the potency and safety of one such mixture, sodium laureth sulfate (SLA) and phenyl piperazine (PP). These studies show the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch.

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Figure 1: The process of discovery of transdermal formulations.
Figure 2: Results from INSIGHT screening.
Figure 3: Potency phase maps of two SCOPE formulations.
Figure 4: ER-IP relationships of two SCOPE formulations.
Figure 5: In vitro and in vivo assessment of the efficacy of SLA:PP SCOPE formulation.

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References

  1. Zaffaroni, A. Overview and evolution of therapeutic systems. Ann. NY Acad. Sci. 618, 405–421 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Bos, J.D. & Meinardi, M.M. The 500 dalton rule for the skin penetration of chemical compounds and drugs. Exp. Dermatol. 9, 165–169 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Wertz, P.W. & Downing, D.T. in Transdermal Drug Delivery: Developmental Issues and Research Initiatives (eds. Hadgraft, J. & Guy, R.H.) 1–17 (Marcel Dekker, New York, Basel, Hong Kong, 1989).

    Google Scholar 

  4. Guy, R. et al. Iontophoresis: electrorepulsion and electroosmosis. J. Control. Release 64, 129–132 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Finnin, B.C. & Morgan, T.M. Transdermal penetration enhancers: applications, limitations and potential. J. Pharm. Sci. 88, 955–958 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Williams, A.C. & Barry, B.W. Skin absorption enhancers. Crit. Rev. Ther. Drug Carrier Syst. 9, 305–353 (1992).

    CAS  PubMed  Google Scholar 

  8. French, E., Potton, C. & Walters, K. in Pharmaceutical Skin Penetration Enhancement (eds. Walters, K. & Hadgraft, J.) 113–144 (Marcel Dekker, New York, Basel, Hong Kong, 1993).

    Google Scholar 

  9. Kanikkannan, N., Kanimalla, K., Lamba, S.S. & Singh, M. Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery. Curr. Med. Chem. 7, 593–608 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Lashmar, U.T., Hadgraft, J. & Thomas, N. Topical application of penetration enhancers to the skin of nude mice—a histopatholgical study. J. Pharm. Pharmacol. 41, 118–122 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Akimoto, T. & Nagase, Y. Novel transdermal drug penetration enhancer: synthesis and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group. J. Control. Release 88, 243–252 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Takanashi, Y., Higashiyama, K., Komiya, H., Takayama, K. & Nagai, T. Thiomenthol derivatives as novel percutaneous absorption enhancers. Drug Dev. Ind. Pharm. 25, 89–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Suhonen, M., Bouwstra, J. & Urtti, A. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J. Control. Release 59, 149–161 (1999).

    Article  CAS  Google Scholar 

  14. Mitragotri, S. Effect of bilayer disruption on transdermal transport of low-molecular weight hydrophobic solutes. Pharm. Res. 18, 1022–1028 (2001).

    Google Scholar 

  15. Robinson, M.K. & Perkins, M.A. A strategy for skin irritation testing. Am. J. Contact Dermat. 13, 21–19 (2002).

    Article  PubMed  Google Scholar 

  16. Mitragotri, S. Synergistic effect of enhancers for transdermal drug delivery. Pharm. Res. 17, 1354–1359 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Funke, A.P. et al. Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers and solvents from liquid formulations. Pharm. Res. 19, 661–668 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Bronaugh, R.L. in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery (eds. Bronaugh, R.L. & Maibach, H.I.) (Marcel Dekker, New York, Basel, Hong Kong, 1989).

    Google Scholar 

  19. Karande, P. & Mitragotri, S. High-throughput screening of transdermal formulations. Pharm. Res. 19, 655–660 (2001).

    Article  Google Scholar 

  20. Black, G. in Pharmaceutical Skin Penetration Enhancement. (eds. Walters, K. & Hadgraft, J.) 145–174 (Marcel Dekker, New York, Basel, Hong Kong, 1993).

    Google Scholar 

  21. Fentem, J.H. & Botham, P.A. ECVAM's activities in validating alternative tests for skin corrosion and irritation. Altern. Lab. Anim. 30, 61–67 (2002).

    CAS  PubMed  Google Scholar 

  22. Lanigan, R.S. Final report on the safety assessment of cocoyl sarcosine, lauroyl sarcosine, myristoyl sarcosine, oleoyl sarcosine, stearoyl sarcosine, sodium cocoyl sarcosinate, sodium lauroyl sarcosinate, sodium myristoyl sarcosinate, ammonium cocoyl sarcosinate and ammonium lauroyl sarcosinate. Int. J. Toxicol. 20, 1–14 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Loffler, H. & Happle, R. Profile of irritant patch testing with detergents: sodium lauryl sulfate, sodium laureth sulfate and alkyl polyglucoside. Contact Dermatitis 48, 26–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Berardesca, E. et al. Ranking of surfactant skin irritancy in vivo in man using the plastic occlusion stress test (POST). Contact Dermatitis 23, 1–15 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Hall-Manning, J., Holland, H., Basketter, A. & Barratt, D. Skin irritation potential of mixed surfactant systems in a human 4-hour covered patch test. Allergologie 18, 465 (1995).

    Google Scholar 

  26. Fentem, J. et al. A prevalidation study on in vitro tests for acute skin irritation: results and evaluation by the Management Team. Toxicology In Vitro 15, 57–93 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Periti, P., Mazzei, T. & Mini, E. Clinical pharmacokinetics of depot leuprorelin. Clin. Pharmacokinet. 41, 485–504 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Frydman, A. Low-molecular weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 26, 24–38 (1996).

    CAS  PubMed  Google Scholar 

  29. Peck, K., Ghanem, A. & Higuchi, W. Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane. Pharm. Res. 11, 1306–1314 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Tang, H., Mitragotri, S., Blankschtein, D. & Langer, R. Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis. J. Pharm. Sci. 90, 543–566 (2001).

    Article  Google Scholar 

  31. Tezel, A., Sens, A. & Mitragotri, S. A theoretical description of transdermal transport of hydrophilic solutes induced by low-frequency sonophoresis. J. Pharm. Sci. 92, 381–393 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Mitragotri, S. et al. Determination of the threshold energy dose for ultra-sound-induced transdermal drug delivery. J. Control. Release 63, 41–52 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Mitragotri, S. Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. J. Control. Release 86, 69–92 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the technical assistance of Maricella Castaneda, Jeffery O'Neil and Drew Lassen. The authors also thank ISIS pharmaceuticals for providing oligonucleotides and Chemron for providing betaines. This research was funded in part by Cottage hospital research program, Santa Barbara, California, USA.

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

    Pankaj Karande, Amit Jain & Samir Mitragotri

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  1. Pankaj Karande
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Correspondence to Samir Mitragotri.

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The technology described in the paper is licensed to fqubed, in which S.M. is a shareholder.

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Karande, P., Jain, A. & Mitragotri, S. Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol 22, 192–197 (2004). https://doi.org/10.1038/nbt928

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