Transdermal delivery of curcumin-loaded supramolecular hydrogels for dermatitis treatment

  • Feilong Zhou
  • Zhimei Song
  • Yi Wen
  • Hongmei Xu
  • Li Zhu
  • Runliang FengEmail author
Delivery Systems Original Research
Part of the following topical collections:
  1. Delivery Systems


Curcumin (CUR) is a hydrophobic polyphenol with anti-inflammatory activity. However, its low water-solubility and poor skin permeation limited its application in the treatment of dermititis. CUR-loaded micelles were prepared using thin membrane hydration method with methoxy poly (ethylene glycol)-block-poly (ε-caprolactone) (MPEG-PCL) as carrier material. The drug loading capacity and encapsulation efficiency were 12.14 ± 0.33 and 93.57 ± 1.67%, respectively. CUR-loaded micelles increased CUR’s water-solubility to 1.87 mg/mL, being 1.87 × 106-folds higher than native CUR. CUR-loaded supramolecular hydrogels (CUR-H) were prepared through mixing the CUR-loaded micelles solution with α-cyclodextrin (α-CD) solution. The CUR-H presented continuous dissolution behaviour in aqueous medium for 4.5 h. The ex vivo skin permeation test and confocal fluorescence microscopy evaluation confirmed that CUR-H obviously enhanced skin deposition of CUR without drug flux from skin. In vivo experimental results confirmed that the CUR-H was more effective than dexamethasone ointments against croton oil-induced ear edema. The CUR-H composed of MPEG-PCL and α-CD is a promising formulation for skin inflammatory treatment.



This work was supported by the Natural Science Foundation of Shandong Province [Grant number ZR2016BL15]; Science and Technology Project of University of Jinan [Grant number XKY1732]; and Shandong Talents Team Cultivation Plan of University Preponderant Discipline [Grant number 10027].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Chen Z, Xing L, Fan Q, Cheetham AG, Lin R, Holt B, et al. Drug-bearing supramolecular filament hydrogels as anti-inflammatory agents. Theranostics. 2017;7:2003–14. CrossRefGoogle Scholar
  2. 2.
    BB A, W Y, S L, SC G. Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric. Mol Nutr Food Res. 2013;57:1529–42. CrossRefGoogle Scholar
  3. 3.
    Kim KM, Pae HO, Zhung M, Ha HY, Ha YA, Chai KY, et al. Involvement of anti-inflammatory heme oxygenase-1 in the inhibitory effect of curcumin on the expression of pro-inflammatory inducible nitric oxide synthase in RAW264.7 macrophages. Biomed Pharmacother. 2008;62:630–6. CrossRefGoogle Scholar
  4. 4.
    Panahi Y, Fazlolahzadeh O, Atkin SL, Majeed M, Butler AE, Johnston TP, et al. Evidence of curcumin and curcumin analogue effects in skin diseases: a narrative review. J Cell Physiol. 2018.
  5. 5.
    Letchford K, Liggins R, Burt H. Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymer micelles: theoretical and experimental data and correlations. J Pharm Sci. 2008;97:1179–90. CrossRefGoogle Scholar
  6. 6.
    Manju S, Sreenivasan K. Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability. J Colloid Interface Sci. 2011;359:318–25. CrossRefGoogle Scholar
  7. 7.
    Harrison IP, Spada F. Hydrogels for atopic dermatitis and wound management: a superior drug delivery vehicle. Pharmaceutics . 2018;10:71 CrossRefGoogle Scholar
  8. 8.
    Li XY, Chen S, Zhang BJ, Li M, Diao K, Zhang ZL, et al. In situ injectable nano-composite hydrogel composed of curcumin, N,O-carboxymethyl chitosan and oxidized alginate for wound healing application. Int J Pharm. 2012;437:110–9. CrossRefGoogle Scholar
  9. 9.
    Chen X, Zhi F, Jia XF, Zhang X, Ambardekar R, Meng ZJ, et al. Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel. J Pharm Pharmacol. 2013;65:807–16. CrossRefGoogle Scholar
  10. 10.
    Gong CY, Wu QJ, Wang YJ, Zhang DD, Luo F, Zhao X, et al. A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing. Biomaterials. 2013;34:6377–87. CrossRefGoogle Scholar
  11. 11.
    Koop HS, de Freitas RA, de Souza MM, Savi-Jr R, Silveira JL. Topical curcumin-loaded hydrogels obtained using galactomannan from Schizolobium parahybae and xanthan. Carbohydr Polym. 2015;116:229–36. CrossRefGoogle Scholar
  12. 12.
    Sun YB, Du LN, Liu YP, Li X, Li M, Jin YG, et al. Transdermal delivery of the in situ hydrogels of curcumin and its inclusion complexes of hydroxypropyl-beta-cyclodextrin for melanoma treatment. Int J Pharm. 2014;469:31–9. CrossRefGoogle Scholar
  13. 13.
    Nguyen HT, Munnier E, Souce M, Perse X, David S, Bonnier F, et al. Novel alginate-based nanocarriers as a strategy to include high concentrations of hydrophobic compounds in hydrogels for topical application. Nanotechnology. 2015;26:255101 CrossRefGoogle Scholar
  14. 14.
    Bachhav YG, Mondon K, Kalia YN, Gurny R, Moller M. Novel micelle formulations to increase cutaneous bioavailability of azole antifungals. J Control Release. 2011;153:126–32. CrossRefGoogle Scholar
  15. 15.
    Poree DE, Giles MD, Lawson LB, He J, Grayson SM. Synthesis of amphiphilic star block copolymers and their evaluation as transdermal carriers. Biomacromolecules. 2011;12:898–906. CrossRefGoogle Scholar
  16. 16.
    Lapteva M, Mondon K, Moller M, Gurny R, Kalia YN. Polymeric micelle nanocarriers for the cutaneous delivery of tacrolimus: a targeted approach for the treatment of psoriasis. Mol Pharm. 2014;11:2989–3001. CrossRefGoogle Scholar
  17. 17.
    Lapteva M, Santer V, Mondon K, Patmanidis I, Chiriano G, Scapozza L, et al. Targeted cutaneous delivery of ciclosporin A using micellar nanocarriers and the possible role of inter-cluster regions as molecular transport pathways. J Control Release. 2014;196:9–18. CrossRefGoogle Scholar
  18. 18.
    Deng P, Teng F, Zhou F, Song Z, Meng N, Feng R. Methoxy poly (ethylene glycol)-b-poly (delta-valerolactone) copolymeric micelles for improved skin delivery of ketoconazole. J Biomater Sci Polym Ed. 2017;28:63–78. CrossRefGoogle Scholar
  19. 19.
    Deng PZ, Teng FF, Zhou FL, Song ZM, Meng N, Liu N, et al. Y-shaped methoxy poly (ethylene glycol)-block-poly (epsilon-caprolactone)-based micelles for skin delivery of ketoconazole: in vitro study and in vivo evaluation. Mater Sci Eng C Mater Biol Appl. 2017;78:296–304. CrossRefGoogle Scholar
  20. 20.
    Zhao SP, Zhang LM, Ma D. Supramolecular hydrogels induced rapidly by inclusion complexation of poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) block copolymers with alpha-cyclodextrin in aqueous solutions. J Phys Chem B. 2006;110:12225–9. CrossRefGoogle Scholar
  21. 21.
    Varan C, Bilensoy E. Development of implantable hydroxypropyl-beta-cyclodextrin coated polycaprolactone nanoparticles for the controlled delivery of docetaxel to solid tumors. J Incl Phenom Macrocycl Chem. 2014;80:9–15. CrossRefGoogle Scholar
  22. 22.
    Qiu L, Zhang L, Zheng C, Wang R. Improving physicochemical properties and doxorubicin cytotoxicity of novel polymeric micelles by poly(epsilon-caprolactone) segments. J Pharm Sci. 2011;100:2430–42. CrossRefGoogle Scholar
  23. 23.
    Khodaverdi E, Heidari Z, Tabassi SA, Tafaghodi M, Alibolandi M, Tekie FS, et al. Injectable supramolecular hydrogel from insulin-loaded triblock PCL-PEG-PCL copolymer and gamma-cyclodextrin with sustained-release property. AAPS PharmSciTech. 2015;16:140–9. CrossRefGoogle Scholar
  24. 24.
    Payyappilly S, Dhara S, Chattopadhyay S. Thermoresponsive biodegradable PEG0-PCL-PEG based injectable hydrogel for pulsatile insulin delivery. J Biomed Mater Res Part A. 2014;102:1500–9. CrossRefGoogle Scholar
  25. 25.
    Gong CY, Wu QJ, Dong PW, Shi SA, Fu SZ, Guo G, et al. Acute toxicity evaluation of biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PEG-PCL-PEG hydrogel. J Biomed Mater Res B. 2009;91b:26–36. CrossRefGoogle Scholar
  26. 26.
    Gong CY, Shi SA, Dong PW, Yang B, Qi XR, Guo G, et al. Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogel: part 1-synthesis, characterization, and acute toxicity evaluation. J Pharm Sci. 2009;98:4684–94. CrossRefGoogle Scholar
  27. 27.
    Fang F, Gong CY, Dong PW, Fu SZ, Gu YC, Guo G, et al. Acute toxicity evaluation of in situ gel-forming controlled drug delivery system based on biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) copolymer. Biomed Mater. 2009;4:025002 CrossRefGoogle Scholar
  28. 28.
    Baek JS, Lim JH, Kang JS, Shin SC, Jung SH, Cho CW. Enhanced transdermal drug delivery of zaltoprofen using a novel formulation. Int J Pharm. 2013;453:358–62. CrossRefGoogle Scholar
  29. 29.
    Rachmawati H, Edityaningrum CA, Mauludin R. Molecular inclusion complex of curcumin-beta-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel. AAPS PharmSciTech. 2013;14:1303–12. CrossRefGoogle Scholar
  30. 30.
    Lee H, Zeng F, Dunne M, Allen C. Methoxy poly(ethylene glycol)-block-poly(delta-valerolactone) copolymer micelles for formulation of hydrophobic drugs. Biomacromolecules. 2005;6:3119–28. CrossRefGoogle Scholar
  31. 31.
    Mathes C, Melero A, Conrad P, Vogt T, Rigo L, Selzer D, et al. Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects. J Control Release. 2016;223:207–14. CrossRefGoogle Scholar
  32. 32.
    Gong C, Deng S, Wu Q, Xiang M, Wei X, Li L, et al. Improving antiangiogenesis and anti-tumor activity of curcumin by biodegradable polymeric micelles. Biomaterials. 2013;34:1413–32. CrossRefGoogle Scholar
  33. 33.
    Rehman K, Zulfakar MHJDD. Pharmacy I. Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev Ind Pharm. 2014;40:433–40. CrossRefGoogle Scholar
  34. 34.
    Che JX, Wu ZS, Shao WY, Guo PH, Lin YY, Pan WH, et al. Synergetic skin targeting effect of hydroxypropyl-beta-cyclodextrin combined with microemulsion for ketoconazole. Eur J Pharm Biopharm. 2015;93:136–48. CrossRefGoogle Scholar
  35. 35.
    Conte C, Costabile G, d’Angelo I, Pannico M, Musto P, Grassia G, et al. Skin transport of PEGylated poly(epsilon-caprolactone) nanoparticles assisted by (2-hydroxypropyl)-beta-cyclodextrin. J Colloid Interface Sci. 2015;454:112–20. CrossRefGoogle Scholar
  36. 36.
    Gou ML, Men K, Shi HS, Xiang ML, Zhang J, Song J, et al. Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. Nanoscale . 2011;3:1558–67. CrossRefGoogle Scholar
  37. 37.
    Yallapu MM, Jaggi M, Chauhan SC. β-Cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostate cancer cells. Colloids Surf B Biointerfaces. 2010;79:113–25. CrossRefGoogle Scholar
  38. 38.
    Ma MF, Sun T, Xing PY, Li ZL, Li SY, Su J, et al. A supramolecular curcumin vesicle and its application in controlling curcumin release. Colloid Surf A. 2014;459:157–65. CrossRefGoogle Scholar
  39. 39.
    Grant N, Zhang HF. Poorly water-soluble drug nanoparticles via an emulsion-freeze-drying approach. J Colloid Interface Sci. 2011;356:573–8. CrossRefGoogle Scholar
  40. 40.
    Ma D, Zhang LM, Xie X, Liu T, Xie MQ. Tunable supramolecular hydrogel for in situ encapsulation and sustained release of bioactive lysozyme. J Colloid Interface Sci. 2011;359:399–406. CrossRefGoogle Scholar
  41. 41.
    Anitha A, Maya S, Deepa N, Chennazhi KP, Nair SV, Jayakumar R. Curcumin-Loaded N,O-Carboxymethyl chitosan nanoparticles for cancer drug delivery. J Biomater Sci Polym Ed. 2011;23:1381–400. CrossRefGoogle Scholar
  42. 42.
    Zhu W, Li Y, Liu LX, Chen YM, Xi F. Supramolecular hydrogels as a universal scaffold for stepwise delivering Dox and Dox/cisplatin loaded block copolymer micelles. Int J Pharm. 2012;437:11–9. CrossRefGoogle Scholar
  43. 43.
    Master AM, Rodriguez ME, Kenney ME, Oleinick NL, Gupta AS. Delivery of the photosensitizer Pc 4 in PEG-PCL micelles for in vitro PDT studies. J Pharm Sci. 2010;99:2386–98. CrossRefGoogle Scholar
  44. 44.
    Li J, Li X, Ni X, Wang X, Li H, Leong KW. Self-assembled supramolecular hydrogels formed by biodegradable PEO-PHB-PEO triblock copolymers and alpha-cyclodextrin for controlled drug delivery. Biomaterials . 2006;27:4132–40. CrossRefGoogle Scholar
  45. 45.
    Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems. Nature . 1997;388:860–2. CrossRefGoogle Scholar
  46. 46.
    Guo MY, Jiang M, Pispas S, Yu W, Zhou CX. Supramolecular hydrogels made of end-functionalized low-molecular-weight PEG and alpha-cyclodextrin and their hybridization with SiO2 nanoparticles through host-guest interaction. Macromolecules. 2008;41:9744–9. CrossRefGoogle Scholar
  47. 47.
    Feng RL, Zhu WX, Song ZM, Zhao LY, Zhai GX. Novel star-type methoxy-poly(ethylene glycol) (PEG)-poly(epsilon-caprolactone) (PCL) copolymeric nanoparticles for controlled release of curcumin. J Nanopart Res. 2013;15:1748–59. CrossRefGoogle Scholar
  48. 48.
    Zhao SP, Lee JH, Xu WL. Supramolecular hydrogels formed from biodegradable ternary COS-g-PCL-b-MPEG copolymer with alpha-cyclodextrin and their drug release. Carbohydr Res. 2009;344:2201–8. CrossRefGoogle Scholar
  49. 49.
    Khodaverdi E, Aboumaashzadeh M, Tekie FSM, Hadizadeh F, Tabassi SAS, Mohajeri SA, et al. Sustained drug release using supramolecular hydrogels composed of cyclodextrin inclusion complexes with PCL/PEG multiple block copolymers. Iran Polym J. 2014;23:707–16. CrossRefGoogle Scholar
  50. 50.
    Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients. 6th edn. 2215 Constitution Avenue NW. Washington, DC: Pharmaceutical Press, American Pharmacists Association; 2009.Google Scholar
  51. 51.
    Miller T, van Colen G, Sander B, Golas MM, Uezguen S, Weigandt M, et al. Drug loading of polymeric micelles. Pharm Res. 2013;30:584–95. CrossRefGoogle Scholar
  52. 52.
    Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997;15:1867–76. CrossRefGoogle Scholar
  53. 53.
    Pradhan M, Singh D, Singh MR. Novel colloidal carriers for psoriasis: current issues, mechanistic insight and novel delivery approaches. J Control Release. 2013;170:380–95. CrossRefGoogle Scholar
  54. 54.
    Firooz A, Nafisi S, Maibach HI. Novel drug delivery strategies for improving econazole antifungal action. Int J Pharm. 2015;495:599–607. CrossRefGoogle Scholar
  55. 55.
    Klaewklod A, Tantishaiyakul V, Hirun N, Sangfai T, Li L. Characterization of supramolecular gels based on beta-cyclodextrin and polyethyleneglycol and their potential use for topical drug delivery. Mater Sci Eng C Mater Biol Appl. 2015;50:242–50. CrossRefGoogle Scholar
  56. 56.
    Fang JY, Fang CL, Liu CH, Su YH. Lipid nanoparticles as vehicles for topical psoralen delivery: solid lipid nanoparticles (SLN) versus nanostructured lipid carriers (NLC). Eur J Pharm Biopharm. 2008;70:633–40. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Biological Science and TechnologyUniversity of JinanJinanChina

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