AAPS PharmSciTech

, Volume 19, Issue 4, pp 1574–1581 | Cite as

Influence of a Combination of Chemical Enhancers and Iontophoresis on In Vitro Transungual Permeation of Nystatin

  • Daniela MontiEmail author
  • Emanuele Egiziano
  • Susi Burgalassi
  • Silvia Tampucci
  • Eleonora Terreni
  • Serena Tivegna
  • Patrizia Chetoni
Research Article


To promote transungual permeation of nystatin (NYST), molecule with high molecular weight, no water-soluble, amphoteric by iontophoresis. The synergic effect of the combination of cetylpyridinium chloride, CPC, or polyoxyethylene (20) sorbitan monooleate, TW80, and iontophoresis was investigated. In vitro permeation experiments were carried out through bovine hoof slices using vertical diffusion cells. A low current density (0.2 mA/cm2) was applied by introducing Ag/AgCl electrodes in the donor (anode) and receptor (cathode) chambers. The donor phase consisted of a solution, a suspension, or gel-type vehicles containing NYST and surfactants in pH 5.6 HEPES buffer. The addition of CPC to NYST suspension (SOSP) produced a fivefold increase on the permeability of the bovine hoof membrane to the drug. The application of anodal iontophoresis further improved NYST flux. Conversely, NYST transungual permeation was not influenced by TW80 either in the passive diffusion or iontophoretic flux. Furthermore, the iontophoretic treatment does not appear to induce irreversible alterations to the hoof bovine membranes. The present work demonstrated the efficacy of iontophoresis as a treatment for different nail pathologies with large molecules very slightly soluble in water without irreversibly affecting the nail structure. A synergistic effect between CPC and iontophoresis was observed.


transungual permeation bovine hoof membrane iontophoresis nystatin 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Akhtar N, Sharma H, Pathak K. Onychomycosis: potential of nail lacquers in transungual delivery of antifungals Scientifica Hindawi Publishing Corporation 2016; 1–12. doi:, 2016.
  2. 2.
    Khengar RH, Jones SA, Turner RB, Forbes B, Brown MB. Nail swelling as a pre-formulation screen for the selection and optimisation of ungula penetration enhancers. Pharm Res. 2007;24:2207–12. Scholar
  3. 3.
    Hao J, Smith KA, Li SK. Iontophoretically enhanced ciclopirox delivery into and across human nail plate. J Pharm Sci. 2009;98:3608–16. Scholar
  4. 4.
    Elkeeb R, Alikhan A, Elkeeb L, Hui X, Maibach HI. Transungual drug delivery: current status. Int J Pharm. 2010;384:1–8. Scholar
  5. 5.
    Manevitch Z, Lev D, Palhan M, Lewis A, Enk CD. Direct antifungal effect of femtosecond laser on trycophyton rubrum onychomycosis 2010; 86(2):476–479. doi:
  6. 6.
    Kasting GB. Theoretical models for iontophoretic delivery. Adv Drug Deliv Rev. 1992;9:177–99.CrossRefGoogle Scholar
  7. 7.
    Pikal MJ. The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev. 1992;9:201–37. Scholar
  8. 8.
    Chizmadzhev YA, Indenbom AV, Kuzmin PI, Galichenko SV, Weaver JC, Potts RO. Electrical properties of skin at moderate voltages: contribution of appendageal macropores. Biophys J. 1998;74:843–56. Scholar
  9. 9.
    Glaser RW, Leikin SL, Chernomordik LV, Pastushenko VF, Sokirko AI. Reversible electrical breakdown of lipid bilayers: formation and evolution of pores. Biochim Biophys Acta. 1988;940:275–87.CrossRefPubMedGoogle Scholar
  10. 10.
    Murthy SN, Wiskirchen DE, Bowers CP. Iontophoretic drug delivery across human nail. J Pharm Sci. 2007a;96:305–11. Scholar
  11. 11.
    Hao J, Li SK. Transungual iontophoretic transport of polar neutral and positively charged model permeants: effect of electrophoresis and electroosmosis. J Pharm Sci. 2008;97:893–905. Scholar
  12. 12.
    Angelo T, Neves Borghetti-Cardoso L, Martins Gelfuso G, Fleury Taveira S, Gratieri T. Chemical and physical strategies in onychomycosis topical treatment: a review. Med Mycol. 2017;55(5):461–75.
  13. 13.
    Nair AB, Sammeta SM, Vaka SRK, Murthy SN. A study on the effect of inorganic salts in transungual drug delivery of terbinafine. J Pharm Pharmacol. 2009a;61:431–7. Scholar
  14. 14.
    Nair AB, Kim HD, Chakraborty B, Singh J, Zaman M, Gupta A, et al. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J Pharm Sci. 2009b;98(11):4130–40. Scholar
  15. 15.
    Nair AB, Chakraborty B, Murthy SN. Effect of polyethylene glycols on the transungual delivery of terbinefine. Curr Drug Del. 2010;7:407–14. Scholar
  16. 16.
    Nair AB, Vaka SR, Murty SN. Transungual delivery of terbinafine by iontophoresis in onhycomycotic nails. Drug Develop Ind Pharm. 2011;37:1253–8. Scholar
  17. 17.
    Murthy SN, Waddell DC, Shivakumar HN, Balaji A, Bowers CP. Iontophoretic permselective property of human nail. J Dermatol Sci. 2007b;46:150–2. Scholar
  18. 18.
    Dutet J, Delgado Charro MB. Transungual iontophoresis of lithium and sodium: effect of pH and co-ion competition on cationic transport numbers. J Control Release. 2010a;144:168–74. Scholar
  19. 19.
    Dutet J, Delgado Charro MB. Electroosmotic transport of mannitol across human nail during constant current iontophoresis. J Pharm Pharmacol. 2010b;62:721–9. Scholar
  20. 20.
    Michel GW. Nystatin in analytical profiles of drug substances volume 6 edited by Florey K., The Squibb Institute for Medical Research, New Brunswick, New Jersey Academic Press, New York, 1977: 342–421.Google Scholar
  21. 21.
    Monti D, Saccomani L, Chetoni P, Burgalassi S, Tampucci S, Mailland F. Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation. Br J Dermatol. 2011;165:99–105. Scholar
  22. 22.
    Monti D, Tampucci S, Burgalassi S, Chetoni P, Lenzi C, Pirone A, et al. Topical formulations containing finasteride. Part I: in vitro permeation/penetration study and in vivo pharmacokinetics in hairless rat. J Pharm Sci. 2014;103:2307–14. Scholar
  23. 23.
    Krishna GS, Kumar PP, Murugan KB. Nail as a promising drug delivery system for controlled release. IJPSR. 2013;4(3):907–15.Google Scholar
  24. 24.
    Smith KA, Hao J, Li SK. Effects of organic solvents on the barrier properties of human nail. J Pharm Sci. 2011;100(10):4244–57. Scholar
  25. 25.
    Setty CM, Jawarkar Y, Pathan IB. Effect of essential oils as penetration enhancers on percutaneous penetration of furosemide through human cadaver skin. Acta Pharmaceutica Sciencia. 2010;52:159–68.Google Scholar
  26. 26.
    Mallard C, Willcox N. Use of a cationic, advantageously amphoteric, surfactant for the preparation of an antifungal solution that can be applied to the nail. 2010; US 20120328543 A1 PCT/EP2010/070083.Google Scholar
  27. 27.
    Jones T, Flack M, Ijzerman M, Baker J. Safety, tolerance, and pharmacokinetics of topical nanoemulsion (NB-002) for the treatment of onychomycosis. supplement to Journal of the American Academy of dermatology. 2008;58(2):P1410.Google Scholar
  28. 28.
    Ciotti S, Eisma R, Vengroff L,. Baker JR Jr. Mechanism of skin penetration and distribution of a novel nanoemulsion. Presented at: 48th Annual Interscience. Conference on Antimicrobial Agents and. Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America. Washington, DC, USA 25–28.Google Scholar
  29. 29.
    Banga AK. Iontophoretic transdermal drug delivery in: Electrically assisted transdermal and topical drug delivery, Taylor & Francis Ltd, London, 1998; 2:13–28.Google Scholar
  30. 30.
    Alvarez-Figueroa MJ, Delgado-Charro MB, Blanco-Mendez J. Passive and iontophoretic transdermal penetration of methotrexate. Int J Pharm. 2001;212:101–7. Scholar
  31. 31.
    Amichai B, Nitzan B, Mosckovitz, Shemer A. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol. 2010;162(1):46–50. Scholar
  32. 32.
    Smith KA, Hao J, Li K. Effect of ionic strength on passive and iontophoretic transport of cationic permeant across human nail. Pharm Res. 2009;26:1444–55. Scholar
  33. 33.
    Baswan SM, Li SK, LaCount TD, Kasting GB. Size and charge dependence of ion transport in human nail plate. J Pharm Sci. 2016;105:1201–8. Scholar
  34. 34.
    Thatai P, Sapra B. Transungual delivery: deliberations and creeds. Int J Cosm Sci. 2014;36:398–411. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Department of PharmacyUniversity of PisaPisaItaly
  2. 2.Menarini Ricerche SpAPisaItaly

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