Skip to main content

Advertisement

SpringerLink
Log in

Enhanced transdermal delivery with less irritation by magainin pore-forming peptide with a N-lauroylsarcosine and sorbitan monolaurate mixture

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Transdermal drug delivery is advantageous over other conventional drug administration routes. However, it can be inefficient because of the natural barrier of the stratum corneum which is the uppermost layer of the skin. A previous study verified that the treatment of magainin pore-forming peptide with N-lauroylsarcosine (NLS) on human skin can increase skin permeability by 47-fold. However, NLS is well known as a potential skin irritant. The irritation potential of NLS is known to decrease when mixed with sorbitan monolaurate (S20). Encouraged by these results, we combined S20 with magainin-NLS to enhance transdermal drug transport with less skin irritation. In this study, nine groups with magainin and NLS:S20 mixtures at different concentrations and weight fractions were screened to maximize their synergistic effect. To quantify the efficacy to toxicity ratio of each formulation, we defined the ratio as the “enhancement ratio/irritation potential (ER/IP).” The ER was observed by Franz cell diffusion of the target drug fluorescein, and the IP was measured by the cytotoxicity of the NIH/3T3 mouse fibroblast cell line. As a result, the magainin with the NLS:S20 mixture increased the permeability of porcine skin as well as decreased the toxicity. Among the various combinations, a formulation of 2% (w/v) NLS:S20 with a weight fraction of 0.6:0.4 had the largest ER/IP. ATR-FTIR spectroscopy of the formulations and skin was done to analyze the interactions in the formulations themselves and between the formulations and the skin. Both the intercellular lipidic route and transcellular route through the stratum corneum protein were involved in the delivery of fluorescein. This study turned pore-forming peptides into an efficient and safe penetration enhancer by combining them with other chemical penetration enhancers. Moreover, this discovery could be a possible method for enabling the transdermal delivery of macromolecules.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004;3:115–24.

    Article  CAS  PubMed  Google Scholar 

  2. Kim Y-C, Late S, Banga AK, Ludovice PJ, Prausnitz MR. Biochemical enhancement of transdermal delivery with magainin peptide: modification of electrostatic interactions by changing pH. Int J Pharm. 2008;362:20–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Prausnitz MR, Elias PM, Franz TJ, Schmuth M, Tsai J-C, Menon GK, et al. Skin barrier and transdermal drug delivery. Dermatology. 2012;3:2065–73.

    Google Scholar 

  4. Wertz PW. Lipids and barrier function of the skin. Acta Derm Venereol Suppl. 2000;208:7–11.

    Article  CAS  Google Scholar 

  5. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.

    Article  Google Scholar 

  6. Nasrollahi SA, Taghibiglou C, Azizi E, Farboud ES. Cell-penetrating peptides as a novel transdermal drug delivery system. Chem Biol Drug Design. 2012;80:639–46.

    Article  CAS  Google Scholar 

  7. Singh G, Karande P. Peptide-mediated transdermal drug delivery. In: Dragicevic N, Maibach HI, editors. Percutaneous penetration enhancers chemical methods in penetration enhancement. Berlin Heidelberg: Springer; 2015. p. 353–61.

    Chapter  Google Scholar 

  8. Kumar S, Narishetty ST, Tummala H. Peptides as skin penetration enhancers for low molecular. In: Dragicevic N, Maibach HI, editors. Percutaneous penetration enhancers chemical methods in penetration enhancement. Berlin Heidelberg: Springer; 2015. p. 337–52.

    Chapter  Google Scholar 

  9. Kumar S, Zakrewsky M, Chen M, Menegatti S, Muraski JA, Mitragotri S. Peptides as skin penetration enhancers: mechanisms of action. J Control Release. 2015;199:168–78. https://doi.org/10.1016/j.jconrel.2014.12.006.

    Article  CAS  PubMed  Google Scholar 

  10. Menegatti S, Zakrewsky M, Kumar S, De Oliveira JS, Muraski JA, Mitragotri S. De novo design of skin-penetrating peptides for enhanced transdermal delivery of peptide drugs. Adv Healthc Mater. 2016;5:602–9.

    Article  CAS  PubMed  Google Scholar 

  11. Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by magainin pore-forming peptide. J Control Release. 2007;122:375–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by antimicrobial peptides. J Biomed Nanotechnol. 2010;6:612–20.

    Article  CAS  PubMed  Google Scholar 

  13. Kaushik S, Krishnan A, Prausnitz MR, Ludovice PJ. Magainin-mediated disruption of stratum corneum lipid vesicles. Pharm Res. 2001;18:894–6.

    Article  CAS  PubMed  Google Scholar 

  14. Ludtke SJ, He K, Heller WT, Harroun TA, Yang L, Huang HW. Membrane pores induced by magainin. Biochemist. 1996;35:13723–8.

    Article  CAS  Google Scholar 

  15. Hall K, Lee T-H, Mechler AI, Swann MJ, Aguilar M-I. Real-time measurement of membrane conformational states induced by antimicrobial peptides: balance between recovery and lysis. Scient Rep. 2014;4

  16. Sato H, Feix JB. Peptide-membrane interactions and mechanisms of membrane destruction by amphipathic alpha-helical antimicrobial peptides. Biochim Biophys Acta. 2006;1758:1245–56. https://doi.org/10.1016/j.bbamem.2006.02.021.

    Article  CAS  PubMed  Google Scholar 

  17. Aioi A, Kuriyama K, Shimizu T, Yoshioka M, Uenoyama S. Effects of vitamin E and squalene on skin irritation of a transdermal absorption enhancer, lauroylsarcosine. Int J Pharm. 1993;93:1–6.

    Article  CAS  Google Scholar 

  18. Aioi A, Shimizu T, Kuriyama K. Effect of squalene on superoxide anion generation induced by a skin irritant, lauroylsarcosine. Int J Pharm. 1995;113:159–64.

    Article  CAS  Google Scholar 

  19. Shimizu T, Aioi A, Horiguchi T, Kuriyama K. Effect of vitamin E on keratinocyte-modulation induced by lauroylsarcosine. The Japanese Aust J Pharm. 1995;67:291–5.

    Article  CAS  Google Scholar 

  20. Karande P, Jain A, Arora A, Ho MJ, Mitragotri S. Synergistic effects of chemical enhancers on skin permeability: a case study of sodium lauroylsarcosinate and sorbitan monolaurate. European J Pharm Sci. 2007;31:1–7.

    Article  CAS  Google Scholar 

  21. Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch Dermatol. 1963;88:702–5.

    Article  CAS  PubMed  Google Scholar 

  22. Jung EC, Maibach HI. Animal models for percutaneous absorption. J Appl Toxicol. 2015;35:1–10.

    Article  CAS  PubMed  Google Scholar 

  23. Welss T, Basketter DA, Schröder KR. In vitro skin irritation: facts and future. State of the art review of mechanisms and models. Toxicol in Vitro. 2004;18:231–43.

    Article  CAS  PubMed  Google Scholar 

  24. Qin G, Geng S, Wang L, Dai Y, Yang B, Wang J-Y. Charge influence of liposome on transdermal delivery efficacy. Soft Matter. 2013;9:5649–56.

    Article  CAS  Google Scholar 

  25. Tomankova K, Kejlova K, Binder S, Daskova A, Zapletalova J, Bendova H, et al. In vitro cytotoxicity and phototoxicity study of cosmetics colorants. Toxicol in Vitro. 2011;25:1242–50.

    Article  CAS  PubMed  Google Scholar 

  26. Asbill CS, Michniak BB. Percutaneous penetration enhancers: local versus transdermal activity. Pharm Sci Technol Today. 2000;3:36–41.

    Article  CAS  PubMed  Google Scholar 

  27. Gennari CG, Franzè S, Pellegrino S, Corsini E, Vistoli G, Montanari L, et al. Skin penetrating peptide as a tool to enhance the permeation of heparin through human epidermis. Biomacromolecules. 2015;17:46–55.

    Article  PubMed  Google Scholar 

  28. Cilurzo F, Vistoli G, Selmin F, Gennari CG, Musazzi UM, Franzé S, et al. An insight into the skin penetration enhancement mechanism of N-methylpyrrolidone. Mol Pharm. 2014;11:1014–21.

    Article  CAS  PubMed  Google Scholar 

  29. Kim YC, Ludovice PJ, Prausnitz MR. Optimization of transdermal delivery using magainin pore-forming peptide. J PhyChem Solids. 2008;69:1560–3.

    Article  CAS  Google Scholar 

  30. Yuan H, Zhao S, Cheng G, Zhang L, Miao X, Mao S, et al. Mixed micelles of Triton X-100 and cetyl trimethylammonium bromide in aqueous solution studied by 1H NMR. The J Phy Chem B. 2001;105:4611–5.

    Article  CAS  Google Scholar 

  31. Lémery E, Briançon S, Chevalier Y, Bordes C, Oddos T, Gohier A, et al. Skin toxicity of surfactants: structure/toxicity relationships. Coll Surf A: Physicochemical Eng ASp. 2015;469:166–79.

    Article  Google Scholar 

  32. Hall-Manning T, Holland G, Rennie G, Revell P, Hines J, Barratt M, et al. Skin irritation potential of mixed surfactant systems. Food and Chemical Toxicology. 1998;36:233–8.

    Article  CAS  PubMed  Google Scholar 

  33. Huang HW, Chen F-Y, Lee M-T. Molecular mechanism of peptide-induced pores in membranes. Phy Rev Lett. 2004;92:198304.

    Article  Google Scholar 

  34. Matsuzaki K, Sugishita K-i, Harada M, Fujii N, Miyajima K. Interactions of an antimicrobial peptide, magainin 2, with outer and inner membranes of Gram-negative bacteria. Biochim Biophy Acta (BBA)-Biomembranes. 1997;1327:119–30.

    Article  CAS  Google Scholar 

  35. Thind R, O'Neill D, Del Regno A, Notman R. Ethanol induces the formation of water-permeable defects in model bilayers of skin lipids. Chem Comm. 2015;51:5406–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Porcine skin was kindly donated by the Heart Research Center of Chonnam National University.

Funding

This work was supported financially by the Ministry of Science, ICT, and Future Planning (Project No. NRF-2014M3A9E4064580); Advanced Biomass R&D Center (ABC) of the Global Frontier Project funded by the Ministry of Science, ICT, and Future Planning (NRF-2015M3A6A2074238); and the KUSTAR-KAIST Institute at KAIST.

Author information

Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Haerin Lee, Juhyun Park & Yeu-Chun Kim

Authors
  1. Haerin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juhyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeu-Chun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yeu-Chun Kim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, H., Park, J. & Kim, YC. Enhanced transdermal delivery with less irritation by magainin pore-forming peptide with a N-lauroylsarcosine and sorbitan monolaurate mixture. Drug Deliv. and Transl. Res. 8, 54–63 (2018). https://doi.org/10.1007/s13346-017-0433-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-017-0433-0

Keywords

Search

Navigation