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The implications of lipid mobility, drug-enhancers (surfactants)-skin interaction, and TRPV1 activation on licorice flavonoid permeability

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Abstract

Licorice flavonoids (LFs) are derived from perennial herb licorice and have been attaining a considerable interest in cosmetic and skin ailment treatments. However, some LFs compounds exhibited poor permeation and retention capability, which restricted their application. In this paper, we systematically investigated and compared the enhancement efficacy and mechanisms of different penetration enhancers (surfactants) with distinct lipophilicity or “heat and cool” characteristics on ten LFs compounds. Herein, the aim was to unveil how seven different enhancers modified the stratum corneum (SC) surface and influence the drug-enhancers-skin interaction, and to relate these effects to permeation enhancing effects of ten LFs compounds. The enhancing efficacy was evaluated by enhancement ratio (ER)permeation, ERretention, and ERcom, which was conducted on the porcine skin. It was summarized that heat capsaicin (CaP) and lipophilic Plurol® Oleique CC 497 (POCC) caused the most significance of SC lipid fluidity, SC water loss, and surface structure alterations, thereby resulting in a higher permeation enhancing effects than other enhancers. CaP could completely occupied drug-skin interaction sites in the SC, while POCC only occupied most drug-skin interactions. Moreover, the enhancing efficacy of both POCC and CaP was dependent on the log P values of LFs. For impervious LFs with low drug solubility, enhancing their drug solubility could help them permeate into the SC. For high-permeation LFs, their permeation was inhibited ascribed to the strong drug-enhancer-skin strength in the SC. More importantly, drug-surfactant-skin energy possessed a good negative correlation with the LFs permeation amount for most LFs molecules. Additionally, the activation of transient receptor potential vanilloid 1 (TRPV1) could enhance LFs permeation by CaP. The study provided novel insights for drug permeation enhancement from the viewpoint of molecular pharmaceutics, as well as the scientific utilization of different enhancers in topical or transdermal formulations.

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References

  1. Findley K, et al. Topographic diversity of fungal and bacterial communities in human skin. Nature. 2016;498:367-+. https://doi.org/10.1038/nature12171.

  2. Yang DG, Fang L, Yang CR. Roles of molecular interaction and mobility on loading capacity and release rate of drug-ionic liquid in long-acting controlled release transdermal patch. J Mol Liq. 2022;352. https://doi.org/10.1016/j.molliq.2022.118752.

  3. Cardoso G, et al. Supercritical fluid (SCF)-assisted preparation of cyclodextrin-based poly(pseudo)rotaxanes for transdermal purposes. Drug Deliv Transl Res. 2023. https://doi.org/10.1007/s13346-023-01385-w.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen Y, et al. Implications of surfactant hydrophobic chain architecture on the surfactant-skin lipid model interaction. J Colloid Interface Sci. 2022;608:405–15. https://doi.org/10.1016/j.jcis.2021.09.098.

    Article  CAS  PubMed  Google Scholar 

  5. Bjorklund S, et al. The effects of polar excipients transcutol and dexpanthenol on molecular mobility, permeability, and electrical impedance of the skin barrier. J Colloid Interface Sci. 2016;479:207–20. https://doi.org/10.1016/j.jcis.2016.06.054.

    Article  CAS  PubMed  Google Scholar 

  6. Goldmunz E, Aserin A, Garti N. The effect of the structural transition within a direct hexagonal (HI) mesophase on the internal lipid mobility. J Mol Liq. 2023;369. https://doi.org/10.1016/j.molliq.2022.120742.

  7. Wang ZX, et al. 4?-OH as the action site of lipids and MRP1 for enhanced transdermal delivery of flavonoids. ACS Appl Mater Interfaces. 2023;15:14884–900. https://doi.org/10.1021/acsami.2c18086.

    Article  CAS  Google Scholar 

  8. Tian Q, Quan P, Fang L, Xu H, Liu C. A molecular mechanism investigation of the transdermal/topical absorption classification system on the basis of drug skin permeation and skin retention. Int J Pharm. 2021;608. https://doi.org/10.1016/j.ijpharm.2021.121082.

  9. Yang DG, Liu C, Quan P, Fang L. A systematic approach to determination of permeation enhancer action efficacy and sites: molecular mechanism investigated by quantitative. J Control Release. 2020;322:1–12. https://doi.org/10.1016/j.jconrel.2020.03.014.

    Article  CAS  PubMed  Google Scholar 

  10. Wang ZX, et al. Quantitative structure-activity relationship of enhancers of licochalcone A and glabridin release and permeation enhancement from carbomer hydrogel. Pharmaceutics. 2022;14. https://doi.org/10.3390/pharmaceutics14020262.

  11. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37. https://doi.org/10.1016/j.addr.2012.09.032.

    Article  Google Scholar 

  12. Lee J, et al. Skin penetration enhancer-incorporated lipid nanovesicles (SPE-LNV) for skin brightening and wrinkle treatment. ACS Appl Mater Interfaces. 2022;14:36331–40. https://doi.org/10.1021/acsami.2c07135.

    Article  CAS  PubMed  Google Scholar 

  13. Liu XC, et al. Time dependence of the enhancement effect of chemical enhancers: molecular mechanisms of enhancing kinetics. J Control Release. 2017;248:33–44. https://doi.org/10.1016/j.jconrel.2017.01.017.

    Article  CAS  PubMed  Google Scholar 

  14. Song WT, et al. Probing the role of chemical enhancers in facilitating drug release from patches: mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis. J Control Release. 2016;227:13–22. https://doi.org/10.1016/j.jconrel.2016.02.027.

    Article  CAS  PubMed  Google Scholar 

  15. Yang C, et al. Multiscale study on the enhancing effect and mechanism of borneolum on transdermal permeation of drugs with different log P values and molecular sizes. Int J Pharm. 2020;580. https://doi.org/10.1016/j.ijpharm.2020.119225.

  16. Ruan SF, Wang ZX, Xiang SJ, Chen HJ, Liu Q. Mechanisms of white mustard seed (Sinapis alba L.) volatile oils as transdermal penetration enhancers. Fitoterapia. 2019;138:104195.

  17. Kis N, Gunnarsson M, Berko S, Sparr E. The effects of glycols on molecular mobility, structure, and permeability in stratum corneum. J Control Release. 2022;343:755–64. https://doi.org/10.1016/j.jconrel.2022.02.007.

    Article  CAS  PubMed  Google Scholar 

  18. Williams AC, Barry BW. Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res. 1991;8:17–24. https://doi.org/10.1023/a:1015813803205.

    Article  CAS  PubMed  Google Scholar 

  19. Kovacik A, Kopecna M, Vavrova K. Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin Drug Deliv. 2020;17:145–56. https://doi.org/10.1080/17425247.2020.1713087.

    Article  CAS  PubMed  Google Scholar 

  20. Xu WW, et al. An investigation on the effect of drug physicochemical properties on the enhancement strength of enhancer: the role of drug-skin-enhancer interactions. Int J Pharm. 2021;607. https://doi.org/10.1016/j.ijpharm.2021.120945.

  21. Ruan JH, et al. Sustainable and efficient skin absorption behaviour of transdermal drug: the effect of the release kinetics of permeation enhancer. Int J Pharm. 2022;612. https://doi.org/10.1016/j.ijpharm.2021.121377.

  22. Olsen RV, Andersen HH, Moller HG, Eskelund PW, Arendt-Nielsen L. Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers. Eur J Pain. 2014;18:1333–42. https://doi.org/10.1002/j.1532-2149.2014.494.x.

    Article  CAS  PubMed  Google Scholar 

  23. Sakai M, Imai T, Ohtake H, Azuma H, Otagiri M. Effects of absorption enhancers on cytoskeletal actin filaments in Caco-2 cell monolayers. Life Sci. 1998;63:45–54. https://doi.org/10.1016/s0024-3205(98)00235-5.

    Article  CAS  PubMed  Google Scholar 

  24. Yin Y, et al. Structure of the cold- and menthol-sensing ion channel TRPM8. Science. 2018;359:237–41. https://doi.org/10.1126/science.aan4325.

    Article  CAS  PubMed  Google Scholar 

  25. Joshi A, Joshi A, Patel H, Ponnoth D, Stagni G. Cutaneous penetration-enhancing effect of menthol: calcium involvement. J Pharm Sci. 2017;106:1923–32. https://doi.org/10.1016/j.xphs.2017.03.041.

    Article  CAS  PubMed  Google Scholar 

  26. Xu LZ, et al. Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel. Nat Commun. 2020;11. https://doi.org/10.1038/s41467-020-17582-x.

  27. Xing MZ, et al. Novel dissolving microneedles preparation for synergistic melasma therapy: combined effects of tranexamic acid and licorice extract. Int J Pharm. 2021;600. https://doi.org/10.1016/j.ijpharm.2021.120406.

  28. Ruan SF, et al. Explore the anti-acne mechanism of licorice flavonoids based on metabonomics and microbiome. Front Pharmacol. 2022;13. https://doi.org/10.3389/fphar.2022.832088.

  29. Dong Y, et al. Absorption and desorption behaviour of the flavonoids from Glycyrrhiza glabra L. leaf on macroporous adsorption resins. Food Chem. 2015;168:538–545. https://doi.org/10.1016/j.foodchem.2014.07.109.

  30. Wang LQ, Yang R, Yuan BC, Liu Y, Liu CS. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharmaceutica Sinica B. 2015;5:310–5. https://doi.org/10.1016//j.apsb.2015.05.005.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ruan SF, et al. Potential role of mTORC1 and the PI3K-Akt pathway in anti-acne properties of licorice flavonoids. J Funct Foods. 2020;70. https://doi.org/10.1016/j.jff.2020.103968.

  32. Hong JH, et al. Glycyrrhiza flavonoids and its major component, licochalcone A, inhibit melanogenesis through MAPK/ERIC pathway by activating ERIC phosphorylation. J Dermatol Sci. 2018;91:222–5. https://doi.org/10.1016/j.jdermsci.2018.04.016.

    Article  CAS  Google Scholar 

  33. Yang XH, Dang XW, Zhang X, Zhao SR. Liquiritin reduces lipopolysaccharide-aroused HaCaT cell inflammation damage via regulation of microRNA-31/MyD88. Int Immunopharmacol. 2021;101. https://doi.org/10.1016/j.intimp.2021.108283.

  34. Du QQ, Liu Q. ROS-responsive hollow mesoporous silica nanoparticles loaded with glabridin for anti-pigmentation properties. Micropor Mesopor Mater. 2021;327. https://doi.org/10.1016/j.micromeso.2021.111429.

  35. Liu YY, et al. Isoliquiritin promote angiogenesis by recruiting macrophages to improve the healing of zebrafish wounds. Fish Shellfish Immunol. 2020;100:238–45. https://doi.org/10.1016/j.fsi.2020.02.071.

    Article  CAS  PubMed  Google Scholar 

  36. Yang G, et al. Licochalcone A attenuates acne symptoms mediated by suppression of NLRP3 inflammasome. Phytother Res. 2018;32:2551–9. https://doi.org/10.1002/ptr.6195.

    Article  CAS  PubMed  Google Scholar 

  37. Kang TH, et al. Natural compound licochalcone B induced extrinsic and intrinsic apoptosis in human skin melanoma (A375) and squamous cell carcinoma (A431) cells. Phytother Res. 2017;31:1858–67. https://doi.org/10.1002/ptr.5928.

    Article  CAS  PubMed  Google Scholar 

  38. Shi H, et al. Liquiritigenin potentiates the inhibitory effects of cisplatin on invasion and metastasis via downregulation MMP-2/9 and PI3 K/AKT signaling pathway in B16F10 melanoma cells and mice model. Nutrition And Cancer-an International Journal. 2015;67:761–70. https://doi.org/10.1080/01635581.2015.1037962.

    Article  CAS  Google Scholar 

  39. Yuan WY, et al. Formononetin attenuates atopic dermatitis by upregulating A20 expression via activation of G protein-coupled estrogen receptor. J Ethnopharmacol. 2021;266. https://doi.org/10.1016/j.jep.2020.113397.

  40. Yang ZB, Zeng BY, Pan Y, Huang P, Wang C. Autophagy participates in isoliquiritigenin-induced melanin degradation in human epidermal keratinocytes through PI3K/AKT/mTOR signaling. Biomed Pharmacother. 2018;97:248–54. https://doi.org/10.1016/j.biopha.2017.10.070.

    Article  CAS  PubMed  Google Scholar 

  41. Olivier JC, et al. Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: in vitro vs. in vivo studies. Eur J Pharm Biopharm: official journal of Arbeitsgemeinschaft fuer Pharmazeutische Verfahrenstechnik e.V 2014;86:133–144. https://doi.org/10.1016/j.ejpb.2013.12.004.

  42. Smejkalova D, et al. Hyaluronan polymeric micelles for topical drug delivery. Carbohyd Polym. 2017;156:86–96. https://doi.org/10.1016/j.carbpol.2016.09.013.

    Article  CAS  Google Scholar 

  43. Kong R, Bhargava R. Characterization of porcine skin as a model for human skin studies using infrared spectroscopic imaging. Analyst. 2011;136:2359–66. https://doi.org/10.1039/c1an15111h.

    Article  CAS  PubMed  Google Scholar 

  44. Quan P, Wan XC, Tian Q, Liu C, Fang L. Dicarboxylic acid as a linker to improve the content of amorphous drug in drug-in-polymer film: effects of molecular mobility, electrical conductivity and intermolecular interactions. J Control Release. 2020;317:142–53. https://doi.org/10.1016/j.jconrel.2019.11.033.

    Article  CAS  PubMed  Google Scholar 

  45. Song Y, et al. Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy. Mol Pharm. 2015;12:857–66. https://doi.org/10.1021/mp500692a.

    Article  CAS  PubMed  Google Scholar 

  46. Ruan JH, et al. Efficacy and safety of permeation enhancers: a kinetic evaluation approach and molecular mechanism study in the skin. Int J Pharm. 2022;626. https://doi.org/10.1016/j.ijpharm.2022.122155.

  47. Arunprasert K, et al. Nanostructured lipid carrier-embedded polyacrylic acid transdermal patches for improved transdermal delivery of capsaicin. Eur J Pharm Sci. 2022;173. https://doi.org/10.1016/j.ejps.2022.106169.

  48. Al-Akayleh F, Ali HH, Ghareeb MM, Al-Remawi M. Therapeutic deep eutectic system of capric acid and menthol: characterization and pharmaceutical application. J Drug Deliv Sci Technol. 2019;53. https://doi.org/10.1016/j.jddst.2019.101159.

  49. Pham QD, Bjorklund S, Engblom J, Topgaard D, Sparr E. Chemical penetration enhancers in stratum corneum - relation between molecular effects and barrier function. J Control Release. 2016;232:175–87. https://doi.org/10.1016/j.jconrel.2016.04.030.

    Article  CAS  PubMed  Google Scholar 

  50. Kim AV, et al. Glycyrrhizin-assisted transport of praziquantel anthelmintic drug through the lipid membrane: an experiment and MD simulation. Mol Pharm. 2019;16:3188–98. https://doi.org/10.1021/acs.molpharmaceut.9b00390.

    Article  CAS  PubMed  Google Scholar 

  51. Warner KS, et al. Structure-activity relationship for chemical skin permeation enhancers: probing the chemical microenvironment of the site of action. J Pharm Sci. 2003;92:1305–22. https://doi.org/10.1002/jps.10367.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang S, et al. High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch. J Control Release: official journal of the Controlled Release Society. 2022;353:475–89. https://doi.org/10.1016/j.jconrel.2022.11.058.

    Article  CAS  PubMed  Google Scholar 

  53. Ferreira LG, Faria JV, dos Santos JPS, Faria RX. Capsaicin: TRPV1-independent mechanisms and novel therapeutic possibilities. Eur J Pharmacol. 2020;887. https://doi.org/10.1016/j.ejphar.2020.173356.

  54. Domene C, Darre L, Oakes V, Gonzalez-Resines S. A potential route of capsaicin to its binding site in the TRPV1 ion channel. J Chem Inf Model. 2022;62:2481–9. https://doi.org/10.1021/acs.jcim.1c01441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kwon DH, et al. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat Struct Mol Biol. 2021;28:554-+. https://doi.org/10.1038/s41594-021-00616-3.

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Acknowledgements

The authors acknowledge the help rendered by Suzhou Deyo Bot Advanced Materials Co., Ltd.

Funding

This work was financially supported by the National Natural Science Foundation of China (grant number 82074023), Guangzhou Municipal Science and Technology Project (grant number 202206010105), and Guangdong Provincial Drug Administration Cosmetic Science and Technology Achievement Transformation Base Project (grant number 2021JDB03).

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Authors and Affiliations

  1. School of Traditional Chinese Medicine, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, 510515, China

    Zhuxian Wang, Hongkai Chen, Tao Liang, Yi Hu, Yaqi Xue, Yufan Wu, Quanfu Zeng, Yixin Zheng, Yinglin Guo, Zeying Zheng, Dan Zhai, Peiyi Liang, Chunyan Shen, Cuiping Jiang, Li Liu, Qun Shen, Hongxia Zhu & Qiang Liu

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  1. Zhuxian Wang
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Contributions

ZW: methodology, formal analysis, validation, conceptualization, investigation, writing—original draft; HC and TL: software, investigation and supervision; YH and YX: software, supervision; YW: data curation; QZ: investigation; YZ: investigation; YG: methodology; PL, ZZ, and DZ: methodology; CS: data curation; CJ: conceptualization; LL: software; QS: conceptualization; HZ: supervision, resources; QL: conceptualization, supervision, project administration, resources.

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Correspondence to Hongxia Zhu or Qiang Liu.

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Wang, Z., Chen, H., Liang, T. et al. The implications of lipid mobility, drug-enhancers (surfactants)-skin interaction, and TRPV1 activation on licorice flavonoid permeability. Drug Deliv. and Transl. Res. 14, 1582–1600 (2024). https://doi.org/10.1007/s13346-023-01473-x

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