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 to check access.
Porcine skin was kindly donated by the Heart Research Center of Chonnam National University.
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004;3:115–24.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedPubMedCentralGoogle Scholar
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
Wertz PW. Lipids and barrier function of the skin. Acta Derm Venereol Suppl. 2000;208:7–11.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by antimicrobial peptides. J Biomed Nanotechnol. 2010;6:612–20.CrossRefPubMedGoogle Scholar
Kaushik S, Krishnan A, Prausnitz MR, Ludovice PJ. Magainin-mediated disruption of stratum corneum lipid vesicles. Pharm Res. 2001;18:894–6.CrossRefPubMedGoogle Scholar
Ludtke SJ, He K, Heller WT, Harroun TA, Yang L, Huang HW. Membrane pores induced by magainin. Biochemist. 1996;35:13723–8.CrossRefGoogle Scholar
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;4Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch Dermatol. 1963;88:702–5.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
Asbill CS, Michniak BB. Percutaneous penetration enhancers: local versus transdermal activity. Pharm Sci Technol Today. 2000;3:36–41.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
Kim YC, Ludovice PJ, Prausnitz MR. Optimization of transdermal delivery using magainin pore-forming peptide. J PhyChem Solids. 2008;69:1560–3.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
Huang HW, Chen F-Y, Lee M-T. Molecular mechanism of peptide-induced pores in membranes. Phy Rev Lett. 2004;92:198304.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar