Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 357–365 | Cite as

Topical delivery of 3,5,4′-trimethoxy-trans-stilbene-loaded microemulsion-based hydrogel for the treatment of osteoarthritis in a rabbit model

  • Xiong-Bin Hu
  • Rong-Rong Kang
  • Tian-Tian Tang
  • Yong-Jiang Li
  • Jun-Yong Wu
  • Jie-Min Wang
  • Xin-Yi Liu
  • Da-Xiong XiangEmail author
Original Article


The aim of this study was to develop a microemulsion-based hydrogel (MBH) formulation of 3,5,4′-trimethoxy-trans-stilbene (BTM) as topical delivery system for the treatment of osteoarthritis (OA). The pseudo-ternary phase diagrams were constructed to optimize the microemulsion (ME) formulation. The ME formulation containing 18.8% Cremopher EL35 (surfactant), 9.4% Transcutol HP (co-surfactant), 3.1% LABRAFIL M 1944 CS (oil), and 68.7% water was selected. The obtained BTM-loaded ME (BTM-ME) had a spherical morphology (17.5 ± 1.4 nm), with polydispersity index (PDI) value of 0.068 ± 0.016 and zeta potential of − 11.8 ± 0.5 mV, and was converted into BTM-loaded MBH (BTM-MBH) using Carbopol 940. Ex vivo skin permeation study showed that both ME and MBH formulations significantly enhanced the amount of BTM permeated. The cumulative amount of BTM permeated after 12 h (Q12) for ME, and MBH formulations were 3.25- and 1.96-fold higher than that for emulsion gel (EG). Pharmacokinetic study showed that the AUC of BTM suspension (oral) was three times higher than that of BTM-MBH (topical). Topical delivery of BTM-MBH demonstrated remarkable anti-OA effect in a rabbit model of OA induced by papain, with decreased levels of pro-inflammatory cytokines. The developed MBH formulation might be a promising strategy for topical delivery of BTM for treatment of OA.


Microemulsion Drug delivery system Transdermal Morphology Permeability 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal procedures in this study were approved by the Animal Ethical Experimentation Committee of The Second Xiangya Hospital of Central South University (Protocol number SYXK-2012-003). The institutional and national guidelines for the care and use of laboratory animals were followed.

Supplementary material

13346_2018_604_MOESM1_ESM.docx (875 kb)
ESM 1 (DOCX 875 kb)


  1. 1.
    Ozturk C, Atamaz F, Hepguler S, Argin M, Arkun R. The safety and efficacy of intraarticular hyaluronan with/without corticosteroid in knee osteoarthritis: 1-year, single-blind, randomized study. Rheumatol Int. 2006;26(4):314–9.CrossRefGoogle Scholar
  2. 2.
    Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249–57.CrossRefGoogle Scholar
  3. 3.
    Hunter DJ. Pharmacologic therapy for osteoarthritis-the era of disease modification. Nat Rev Rheumatol. 2011;7(1):13–22.CrossRefGoogle Scholar
  4. 4.
    Durrant DE, Richards J, Tripathi A, Kellogg GE, Marchetti P, Eleopra M, et al. Development of water soluble derivatives of cis-3,4′,5-trimethoxy-3′-aminostilbene for optimization and use in cancer therapy. Investig New Drugs. 2009;27(1):41–52.CrossRefGoogle Scholar
  5. 5.
    Matsuda H, Tewtrakul S, Morikawa T, Yoshikawa M. Anti-allergic activity of stilbenes from Korean rhubarb (Rheum undulatum L.): structure requirements for inhibition of antigen-induced degranulation and their effects on the release of TNF-alpha and IL-4 in RBL-2H3 cells. Bioorg Med Chem. 2004;12(18):4871–6.CrossRefGoogle Scholar
  6. 6.
    Yuan Q, Peng J, Liu SY, Wang CJ, Xiang DX, Xiong XM, et al. Inhibitory effect of resveratrol derivative BTM-0512 on high glucose-induced cell senescence involves dimethylaminohydrolase/asymmetric dimethylarginine pathway. Clin Exp Pharmacol Physiol. 2010;37(5–6):630–5.CrossRefGoogle Scholar
  7. 7.
    Peng W, Ma YY, Zhang K, Zhou AY, Zhang Y, Wang H, et al. Synthesis and biological evaluation of novel resveratrol-NSAID derivatives as anti-inflammatory agents. Chem Pharm Bull (Tokyo). 2016;64(6):609–15.CrossRefGoogle Scholar
  8. 8.
    Tong M, Cao G, Xiang D. The effect of resveratrol methylated derivatives on the level of iNOS and NO among synovial fluid and serum in osteoarthritis rabbits. J Hunan Univ Tradit Chin Med. 2007;27(5):44–6.Google Scholar
  9. 9.
    Kang R, Jiang D, Xiang D. Pharmacodynamic study of 3,5,4′-trimethoxy-trans-stilbene on osteoarthritis rats after long-term administration. Chin Pharm J. 2014;49(3):199–203.Google Scholar
  10. 10.
    Efe T, Sagnak E, Roessler PP, Getgood A, Patzer T, Fuchs-Winkelmann S, et al. Penetration of topical diclofenac sodium 4% spray gel into the synovial tissue and synovial fluid of the knee: a randomised clinical trial. Knee Surg Sports Traumatol Arthrosc. 2014;22(2):345–50.CrossRefGoogle Scholar
  11. 11.
    Bae J, Park JW. Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model. Drug Dev Ind Pharm. 2016;42(2):254–62.CrossRefGoogle Scholar
  12. 12.
    Singh M, Kanoujia J, Parashar P, Arya M, Tripathi CB, Sinha VR, et al. Assessment of improved buccal permeation and bioavailability of felodipine microemulsion-based cross-linked polycarbophil gel. Drug Deliv Transl Re. 2018;8(3):591–601.CrossRefGoogle Scholar
  13. 13.
    Sahle FF, Wohlrab J, Neubert RHH. Controlled penetration of ceramides into and across the stratum corneum using various types of microemulsions and formulation associated toxicity studies. Eur J Pharm Biopharm. 2014;86(2):244–50.CrossRefGoogle Scholar
  14. 14.
    Mehta T, Bhagchand, Manchanda S. Formulation, characterization, and ex vivo evaluation of microemulsion based gel of nicotinamide. Asian J Pharmaceut. 2018;12(1):S115–S21.Google Scholar
  15. 15.
    Wang Z, Mu H-J, Zhang X-M, Ma P-K, Lian S-N, Zhang F-P, et al. Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies. Int J Nanomedicine. 2015;10:633–44.Google Scholar
  16. 16.
    Fouad SA, Basalious EB, El-Nabarawi MA, Tayel SA. Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: in vitro/in vivo evaluation. Int J Pharm. 2013;453(2):569–78.CrossRefGoogle Scholar
  17. 17.
    Yi H, Guang-Hua L, Hai-Le L, Fei C, Shi-Ying H, Yan-Bin Z, et al. Preparation of 3,5,4′-trimethoxy-trans-stilbene and its transdermal absorption ex vivo. Centr South Pharm. 2011;9(5):324–8.Google Scholar
  18. 18.
    Murat N, Karadam B, Ozkal S, Karatosun V, Gidener S. Quantification of papain-induced rat osteoarthritis in relation to time with the Mankin score. Acta Orthop Traumatol Turc. 2007;41(3):233–7.Google Scholar
  19. 19.
    Garg NK, Singh B, Tyagi RK, Sharma G, Katare OP. Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model. Colloid Surface B. 2016;147:17–24.CrossRefGoogle Scholar
  20. 20.
    Kaur A, Bhoop BS, Chhibber S, Sharma G, Gondil VS, Katare OP. Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis. Int J Pharm. 2017;533(1):206–24.CrossRefGoogle Scholar
  21. 21.
    Laverty S, Girard CA, Williams JM, Hunziker EB, Pritzker KPH. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthr Cartil. 2010;18:S53–65.CrossRefGoogle Scholar
  22. 22.
    Aggarwal N, Goindi S, Khurana R. Formulation, characterization and evaluation of an optimized microemulsion formulation of griseofulvin for topical application. Colloid Surface B. 2013;105:158–66.CrossRefGoogle Scholar
  23. 23.
    Qu D, Guo M, Qin Y, Wang L, Zong B, Chen Y, et al. A multicomponent microemulsion using rational combination strategy improves lung cancer treatment through synergistic effects and deep tumor penetration. Drug Deliv. 2017;24(1):1179–90.CrossRefGoogle Scholar
  24. 24.
    Baspinar Y, Borchert H-H. Penetration and release studies of positively and negatively charged nanoemulsions—is there a benefit of the positive charge? Int J Pharm. 2012;430(1–2):247–52.CrossRefGoogle Scholar
  25. 25.
    Fernandez Campos F, Calpena Campmany AC, Rodriguez Delgado G, Lopez Serrano O, Clares Naveros B. Development and characterization of a novel nystatin-loaded nanoemulsion for the buccal treatment of candidosis: ultrastructural effects and release studies. J Pharm Sci. 2012;101(10):3739–52.CrossRefGoogle Scholar
  26. 26.
    Farghaly DA, Aboelwafa AA, Hamza MY, Mohamed MI. Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation. J Liposome Res. 2018;28(2):126–36.CrossRefGoogle Scholar
  27. 27.
    Zhao L, Wang Y, Zhai Y, Wang Z, Liu J, Zhai G. Ropivacaine loaded microemulsion and microemulsion-based gel for transdermal delivery: preparation, optimization, and evaluation. Int J Pharm. 2014;477(1–2):47–56.CrossRefGoogle Scholar
  28. 28.
    Patel DV, Sawant MG, Kaur G. Evaluation of anti-osteoarthritic activity of Vigna mungo in papain induced osteoarthritis model. Indian J Pharm. 2015;47(1):59–64.CrossRefGoogle Scholar
  29. 29.
    Li X, Lang W, Ye H, Yu F, Li H, Chen J, et al. Tougu Xiaotong capsule inhibits the tidemark replication and cartilage degradation of papain-induced osteoarthritis by the regulation of chondrocyte autophagy. Int J Mol Med. 2013;31(6):1349–56.CrossRefGoogle Scholar
  30. 30.
    Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier J-P, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33–42.CrossRefGoogle Scholar
  31. 31.
    Lopez-Armada MJ, Carames B, Lires-Dean M, Cillero-Pastor B, Ruiz-Romero C, Galdo F, et al. Cytokines, tumor necrosis factor-alpha and interleukin-1beta, differentially regulate apoptosis in osteoarthritis cultured human chondrocytes. Osteoarthr Cartil. 2006;14(7):660–9.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  • Xiong-Bin Hu
    • 1
    • 2
  • Rong-Rong Kang
    • 1
    • 2
  • Tian-Tian Tang
    • 1
    • 2
  • Yong-Jiang Li
    • 1
    • 2
  • Jun-Yong Wu
    • 1
    • 2
  • Jie-Min Wang
    • 1
    • 2
  • Xin-Yi Liu
    • 1
    • 2
  • Da-Xiong Xiang
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacy, The Second Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Institute of Clinical PharmacyCentral South UniversityChangshaChina

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