Penetration enhancement of menthol on quercetin through skin: insights from atomistic simulation

  • Changjiang Huang
  • Huangjie Wang
  • Lida Tang
  • Fancui MengEmail author
Original Paper


Menthol is an often used skin penetration enhancer because of its high efficiency and relative safety, but the mechanism how it works has not been fully understood up to date. In this study, quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. The skin is modeled as a ceramide (CER2) bilayer. Potential of mean force (PMF) calculations on quercetin in both CER2 and menthol-involved CER2 bilayers have been performed. The results show that the free energy minimum of quercetin in the presence of menthol molecules shifts toward the headgroup region of the bilayer, and the central energy barrier decreases, facilitating the penetration of quercetin. The presence of menthol molecules enhances the permeability of quercetin. This study may shed light on the mechanism of penetration enhancer, providing useful information in the design of more efficient transdermal drug delivery system.

Graphical abstract

Quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. Potential of mean force calculations reveal that the central energy barrier of quercetin decreases in the presence of menthol, facilitating the penetration of quercetin. Our results are helpful to understand the mechanism of penetration enhancer, aiding in the design of more efficient transdermal drug delivery system.


Molecular dynamics Ceramide Permeability enhancer Menthol Quercetin 



The calculations were performed on TianHe-1(A) at the National Supercomputing Center in Tianjin.

Funding information

This work was supported by the Science and Technology Program of Tianjin (Grant Numbers 18ZXXYSY00040 and 17ZXXYSY00050) and Tianjin 131 Talent Project.

Supplementary material

894_2019_4135_MOESM1_ESM.docx (1.1 mb)
ESM 1 (DOCX 1173 kb)


  1. 1.
    Pham QD, Björklund S, Engblom J, Topgaard D, Sparr E (2006) Chemical penetration enhances in stratum corneum-relation between molecular effects and barrier function. J Control Release 232:175–187CrossRefGoogle Scholar
  2. 2.
    Chen J, Jiang QD, Chai YP, Zhang H, Peng P, Yang XX (2016) Natural terpenes as penetration enhancers for transdermal drug delivery. Molecules 21:E1709CrossRefGoogle Scholar
  3. 3.
    Patil UK, Saraogi R (2014) Natural products as potential drug permeation enhancer in transdermal drug delivery system. Arch Dermatol Res 306:419–426CrossRefGoogle Scholar
  4. 4.
    Wang FL, Ji HM, Zhu JY, Xu GJ, Guan YZ, Chen YJ (2015) Penetration enhancement effect of turpentine oil on transdermal film of ketorolac. Trop J Pharm Res 14:1341–1348CrossRefGoogle Scholar
  5. 5.
    Silva-Abreu M, Espinoza LC, Rodríguez-Lagunas MJ, Fábrega M-J, Espina M, Carcía ML, Calpena AC (2017) Human skin permeation studies with PPARγ agonist to improve its permeability and efficacy in inflammatory processes. Int J Mol Sci 18:2548CrossRefGoogle Scholar
  6. 6.
    Monica SO, Lucia L, Nora BP, Nora BD (2017) Effects of dimethylformamide and L-menthol permeation enhancers on transdermal delivery of quercetin. Pharm Dev Technol 12:481–484Google Scholar
  7. 7.
    Yang SF, Wang R, Wan G, Wu ZM, Guo SJ, Dai XX, Shi XY, Qiao YJ (2016) A multiscale study on the penetration enhancement mechanism of menthol to osthole. J Chem Inf Model 56:2234–2242CrossRefGoogle Scholar
  8. 8.
    Krishnaiah YS, Kumar MS, Raju V, Lakshmi M, Rama B (2008) Penetration-enhancing effect of ethanolic solution of menthol on transdermal permeation of ondansetron hydrochloride across rat epidermis. Drug Deliv 15:227–234CrossRefGoogle Scholar
  9. 9.
    Kamal MAHM, Iimura N, Nabekura T, Kitagawa S (2006) Enhanced skin permeation of salicylate by ion-pair formation in non-aqueous vehicle and further enhancement by ethanol and L-menthol. Chem Pharm Bull 54:481–484CrossRefGoogle Scholar
  10. 10.
    Narishetty ST, Panchagnula R (2005) Effect of L-menthoL and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J Control Release 102:59–70CrossRefGoogle Scholar
  11. 11.
    Narishetty STK, Panchagnula R (2004) Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Control Release 95:367–379CrossRefGoogle Scholar
  12. 12.
    Liu JJ, Fu SY, Wei N, Hou YS, Zhang XN, Cui H (2012) The effects of combined menthol and borneol on fluconazole permeation through the cornea ex vivo. Eur J Pharmacol 688:1–5CrossRefGoogle Scholar
  13. 13.
    dos Anjos JLV, de Sousa ND, Alonso A (2007) Effects of ethanol/L-menthol on the dynamics and partitioning of spin-labeled lipids in the stratum corneum. Eur J Pharm Biopharm 67:406–412CrossRefGoogle Scholar
  14. 14.
    Lan Y, Wang JY, Li H, Zhang YW, Chen YY, Zhao BC, Wu Q (2016) Effect of menthone and related compounds on skin permeation of drugs with different lipophilicity and molecular organization of stratum corneum lipids. Pharm Dev Technol 21:389–398PubMedGoogle Scholar
  15. 15.
    Wang HJ, Meng FC (2017) The permeability enhancing mechanism of menthol on skin lipids: a molecular dynamics simulation study. J Mol Model 23:279CrossRefGoogle Scholar
  16. 16.
    Wan G, Dai XX, Yin QQ, Shi XY, Qiao YJ (2015) Interaction of menthol with mixed-lipid bilayer of stratum corneum: a coarse-grained simulation study. J Mol Graphics Modell 60:98–107CrossRefGoogle Scholar
  17. 17.
    Trivedi JS, Krill SL, Fort JJ (1995) Vitamin E as a human skin penetration enhancer. Eur J Pharm Sci 3:241–243CrossRefGoogle Scholar
  18. 18.
    Fahlman BM, Krol ES (2009) Inhibition of UVA and UVB radiation-induced lipid oxidation by quercetin. J Agric Food Chem 57:5301–5305CrossRefGoogle Scholar
  19. 19.
    Rembiesa J, Gari H, Engblom J, Ruzgas T (2015) Amperometric monitoring of quercetin permeation through skin membranes. Int J Pharm 496:636–643CrossRefGoogle Scholar
  20. 20.
    Lundborg M, Narangifard A, Wennberg CL, Lindahl E, Daneholt B, Norlén L (2018) Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation. J Struct Biol 203:149–161CrossRefGoogle Scholar
  21. 21.
    Paloncýová M, DeVane RH, Murch BP, Berka K, Otyepka M (2014) Rationalization of reduced penetration of drugs through ceramide gel phase membrane. Langmuir 30:13942–13948CrossRefGoogle Scholar
  22. 22.
    Thind R, O'Neill DW, Del Regno A, Notman R (2015) Ethanol induces the formation of water-permeable defects in model bilayers of skin lipids. Chem Commun 51:5406–5409CrossRefGoogle Scholar
  23. 23.
    Norlén L, Nicander I, Lundsjö A, Cronholm F, Forslind B (1998) A new HPLC-based method for the quantitative analysis of inner stratum corneum lipids with special reference to the free fatty acid fraction. Arch Dermatol Res 290:508–516CrossRefGoogle Scholar
  24. 24.
    Hoopes MI, Noro MG, Longo ML, Faller R (2011) Bilayer structure and lipid dynamics in a model stratum corneum with oleic acid. J Phys Chem B 115:3164–3171CrossRefGoogle Scholar
  25. 25.
    Schuettelkopf AW, Aalten DMF (2004) PRODRG-a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D60:1355–1363Google Scholar
  26. 26.
    Lemkul JA, Allen WJ, Bevan DR (2010) Practical considerations for building GROMOS-compatible small-molecule topologies. J Chem Inf Model 50:2221–2235CrossRefGoogle Scholar
  27. 27.
    Jasik M, Szefczyk B (2016) Parameterization and optimization of the menthol force field from molecular dynamics simulations. J Mol Model 22:234CrossRefGoogle Scholar
  28. 28.
    Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  29. 29.
    Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through muti-level parallelism from laptops to supercomputers. SoftwareX 1-2:19–25CrossRefGoogle Scholar
  30. 30.
    Kumar S, Rosenberg JM, Bouzida D, Swendsen RH, Kollman PA (1992) The weighted histogram analysis method for free-energy calculations on biomolecules: I. The method. J Comput Chem 13:1011–1021CrossRefGoogle Scholar
  31. 31.
    Hub JS, de Groot BL, van der Spoel D (2010) g_wham–a free weighted histogram analysis implementation including robust error and autocorrelation estimates. J Chem Theory Comput 6:3713–3720CrossRefGoogle Scholar
  32. 32.
    Kang M, Loverde SM (2014) Molecular simulation of the concentration dependent interaction of hydrophobic drugs with model cellular membranes. J Phys Chem B 118:11965–11972CrossRefGoogle Scholar
  33. 33.
    Wang H, Meng F (2016) Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study. Mol Simul 42:1292–1297CrossRefGoogle Scholar
  34. 34.
    Wang H, Meng F (2016) Molecular simulation study on concentration effects of rofecoxib with POPC bilayer. J Mol Graphic Modell 70:94–99CrossRefGoogle Scholar
  35. 35.
    Cramariuc O, Rog T, Javanainen M, Monticelli L, Polishchuk AV, Vattulainen I (2012) Mechanism for translocation of fluoroquinolones across lipid membranes. Biochim Biophys Acta Biomembr 1818:2563–2571CrossRefGoogle Scholar
  36. 36.
    Kopec W, Khandelia H (2014) Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations. J Comput Aided Mol Des 18:123–134CrossRefGoogle Scholar
  37. 37.
    Witzke S, Duelund L, Kongsted J, Petersen M, Mouritsen OG, Khandelia H (2010) Inclusion of terpenoid plant extracts in lipid bilayers investigated by molecular dynamics simulations. J Phys Chem B 114:15825–15831CrossRefGoogle Scholar
  38. 38.
    da Cunha AR, Duarte EL, Stassen H, Lmy MT, Coutinho K (2017) Experimental and theoretical studies of emodin interacting with a lipid bilayer of DMPC. Biophys Rev 9:729–745CrossRefGoogle Scholar
  39. 39.
    Zhang T, Qiu YG, Luo QC, Zhao LF, Yan X, Ding QC, Jiang HL, Yang HY (2018) The mechanism by which luteolin disrupts the cytoplasmic membrane of methicillin-resistant straphylococcus aureus. J Phys Chem B 122:1427–1438CrossRefGoogle Scholar
  40. 40.
    Ulrih NP, Maričić M, Ota A, Šentjurc M, Abram V (2015) Kaempferol and quercetin interactions with model lipid membranes. Food Res Int 71:146–154CrossRefGoogle Scholar
  41. 41.
    Košinová P, Berka K, Wykes M, Otyepka M, Trouillas P (2012) Positioning of antioxidant quercetin and its metabolites in lipid bilayer membranes: implication for their lipid-peroxidation inhibition. J Phys Chem B 116:1309–1318CrossRefGoogle Scholar
  42. 42.
    Sanver D, Murray BS, Sadeghpour A, Rappolt M, Nelson AL (2016) Experimental modeling of flavonoid-biomembrane interactions. Langmuir 32:13234–13243CrossRefGoogle Scholar
  43. 43.
    Sinha R, Gadhwal MK, Joshi UJ, Srivastava S, Govil G (2012) Modifying effect of quercetin on model biomembranes: studied by molecular dynamics simulation, DSC and NMR. Int J Curr Pharm Res 4:70–79Google Scholar
  44. 44.
    Pawlikowska-Pawlega B, Kapral J, Gawron A, Stochmal A, Zuchowski J, Pecio L, Luchowski R, Grudzinski W, Gruszecki WI (2018) Interaction of a quercetin derivative -lensoside Aβ with liposomal membranes. Biochim Biophys Acta Biomembr 180:292–299CrossRefGoogle Scholar
  45. 45.
    Joshi UJ, Gadge AS, D'Mello P, Sinha R, Srivastava S, Govil G (2012) Anti-inflammatory, antioxidant and anticancer activity of quercetin and its analogues. Int J Pharm Biomed Res 2:1756–1766Google Scholar
  46. 46.
    Pawlikowska-Pawlega B, Dziubińska H, Król E, Trebacz K, Jarosz-Wilkolazka A, Paduch R, Gawron A, Gruszecki WI (2014) Characteristics of quercetin interactions with liposomal and vacuolar membranes. Biochim Biophys Acta Biomembr 1838:254–265CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Tianjin Key Laboratory of Molecular Design and Drug DiscoveryTianjin Institute of Pharmaceutical ResearchTianjinPeople’s Republic of China
  2. 2.State Key Laboratory of Drug Delivery Technology and PharmacokineticsTianjin Institute of Pharmaceutical ResearchTianjinPeople’s Republic of China

Personalised recommendations