AAPS PharmSciTech

, 20:277 | Cite as

Strategies for Improving Healing of the Gastric Epithelium Using Oral Solid Dispersions Loaded with Pentacyclic Triterpene–Rich Centella Extract

  • Saowanee Wannasarit
  • Panupong Puttarak
  • Kanidta Kaewkroek
  • Ruedeekorn WiwattanapatapeeEmail author
Research Article


The pentacyclic triterpenoid compounds in Centella asiatica extract, mainly consisting of asiaticoside (AS), asiatic acid (AA), madecassoside (MS), and madecassic acid (MA), possess wound healing and anti-ulcer properties, but their low aqueous solubility and dissolution rate are disadvantageous for oral administration. In this study, pentacyclic triterpene–rich centella extract (PRE) was combined with Eudragit® EPO as a hydrophilic polymer using solvent evaporation to produce a solid dispersion (PRE-ESD). The optimum PRE/Eudragit ratio of 1:2 enhanced the solubility and dissolution of glycosides (AS > 3.5 folds, MS > 2 folds) and aglycones (AA > 65 folds and MA > 56 folds) in 0.1 N hydrochloric acid (pH 1.2). DSC, XRD, and FT-IR analysis showed that the four pentacyclic triterpenes in PRE existed in the amorphous state in the solid dispersion. Moreover, almost 100% of the compounds were released from the solid dispersion within 2 h. The effects of PRE-ESD on cell proliferation and wound healing in vitro were investigated in human gastric epithelial cell lines (AGS cells). Exposure to PRE-ESD (equivalent to PRE concentration of 10 μg/mL) promoted cell proliferation and enhanced ‘wound closure’ in the scratch assay of wound healing by 82% compared with non-treated groups. Unformulated MA and AA aglycones did not exhibit a wound healing effect. Moreover, PRE-ESD was found to accelerate wound closure compared with either AS or MS, indicating that the wound healing properties of PRE-ESD are conferred by the active compounds AS and MS that are presented in PRE.


centella extract solid dispersions asiaticoside Eudragit® EPO gastric epithelium wound healing 



We would like to thank Prof. Allan Coombes for assistance with English editing of the manuscript and scientific/technical advice.

Funding Information

Financial support was granted by the Thailand Research Fund under the Royal Golden Jubilee Ph. D program (PHD/0180/2556) and Prince of Songkla University (PHA610155S).


  1. 1.
    Gohil KJ, Patel JA, Gajjar AK. Pharmacological review on Centella asiatica: a potential herbal cure-all. Indian J Pharm Sci. 2010;72(5):546–56.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Orhan IE. Centella asiatica (L.) Urban: from traditional medicine to modern medicine with neuroprotective potential. Evid Based Complement Alternat Med. 2012.−946259.Google Scholar
  3. 3.
    Cheng CL, Guo JS, Luk J, Koo MWL. The healing effects of Centella extract and asiaticoside on acetic acid induced gastric ulcers in rats. Life Sci. 2004;74(18):2237–49.PubMedCrossRefGoogle Scholar
  4. 4.
    Abdulla M, Al-Bayaty F, Younis L, Abu HM. Anti-ulcer activity of Centella asiatica leaf extract against ethanol-induced gastric mucosal injury in rats. J Med Plants Res. 2010;4(13):1253–9.Google Scholar
  5. 5.
    James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules. 2009;14:3922–41. Scholar
  6. 6.
    Paudel P, Satyal P, Dosoky NS, Setzer WN. Chemical composition and biological activity of Centella asiatica essential oil from Nepal. Am J Essent Oil Nat Prod. 2017;5(4):05–8.Google Scholar
  7. 7.
    Guo JS, Cheng CL, Koo MW. Inhibitory effects of Centella asiatica water extract and asiaticoside on inducible nitric oxide synthase during gastric ulcer healing in rats. Planta Med. 2004;70(12):1150–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Yun K-J, Kim J-Y, Kim J-B, Lee K-W, Jeong S-Y, Park H-J, et al. Inhibition of LPS-induced NO and PGE 2 production by asiatic acid via NF-κB inactivation in RAW 264.7 macrophages: possible involvement of the IKK and MAPK pathways. Int Immunopharmacol. 2008;8(3):431–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Woo JHSJ, Park HJ, Jung HJ, Koh DJ, Jo BG, et al. Anti-inflammatory effects of madecassic acid via the suppression of NF-kappaB pathway in LPS-induced RAW 264.7 macrophage cells. Planta Med. 2010;76(3):251–7.CrossRefGoogle Scholar
  10. 10.
    Puttarak P, Brantner A, Panichayupakaranant P. Biological activities and stability of a standardized pentacyclic triterpene enriched Centella asiatica extract. Nat Prod Sci. 2016;22(1):20–4.CrossRefGoogle Scholar
  11. 11.
    Kimura Y, Sumiyoshi M, Samukawa K, Satake N, Sakanaka M. Facilitating action of asiaticoside at low doses on burn wound repair and its mechanism. Eur J Pharmacol. 2008;584(2–3):415–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu M, Dai Y, Li Y, Luo Y, Huang F, Gong Z, et al. Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice. Planta Med. 2008;74(8):809–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee JH, Kim HL, Lee MH, You KE, Kwon BJ, Seo HJ, et al. Asiaticoside enhances normal human skin cell migration, attachment and growth in vitro wound healing model. Phytomedicine. 2012;19(13):1223–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Soumyanath A, Zhong YP, Gold SA, Yu X, Koop DR, Bourdette D, et al. Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro. J Pharm Pharmacol. 2005;57(9):1221–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Krishnamurthy RG, Senut MC, Zemke D, Min J, Frenkel MB, Greenberg EJ, et al. Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia. J Neurosci Res. 2009;87(11):2541–50.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lin X, Zhang S, Huang R, Wei L, Tan S, Liang C, et al. Protective effect of madecassoside against cognitive impairment induced by D-galactose in mice. Pharmacol Biochem Behav. 2014;124:434–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Brinkhaus B, Lindner M, Schuppan D, Hahn EG. Chemical, pharmacological and clinical profile of the East Asian medical plant Centella aslatica. Phytomedicine. 2000;7(5):427-48.PubMedCrossRefGoogle Scholar
  18. 18.
    Schaneberg BT, Mikell JR, Bedir E, Khan IA. An improved HPLC method for quantitive determination of six triterpenes in Centella asiatica extracts and commercial products. Pharmazie. 2003;58:381–4.PubMedGoogle Scholar
  19. 19.
    Cheng C, Koo M. Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats. Life Sci. 2000;67(21):2647–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Yao CH, Yeh JY, Chen YS, Li MH, Huang CH. Wound-healing effect of electrospun gelatin nanofibres containing Centella asiatica extract in a rat model. J Tissue Eng Regen Med. 2017;11(3):905–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Farnsworth NR, Bunyapraphatsara N. Thai medicinal plants: recommended for primary health care system: Medicinal Plant Information Center; 1992.Google Scholar
  22. 22.
    Puttarak P, Panichayupakaranant P. A new method for preparing pentacyclic triterpene rich Centella asiatica extracts. Nat Prod Res. 2013;27(7):684–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Rafat M, Fong KW, Goldsipe A, Stephenson BC, Coradetti ST, Sambandan T, et al. Association (micellization) and partitioning of aglycon triterpenoids. J Colloid Interface Sci. 2008;325(2):324–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang CZ, Niu J, Chong YS, Huang YF, Chu Y, Xie SY, et al. Porous microspheres as promising vehicles for the topical delivery of poorly soluble asiaticoside accelerate wound healing and inhibit scar formation in vitro & in vivo. Eur J Pharm Biopharm. 2016;109:1–13.PubMedCrossRefGoogle Scholar
  25. 25.
    Hong S-S, Kim J-H, Li H, Shim C-K. Advanced formulation and pharmacological activity of hydrogel of the titrated extract of C. asiatics. Arch Pharm Res. 2005;28(4):502–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Braithwaite MC, Tyagi C, Tomar LK, Kumar P, Choonara YE, Pillay V. Nutraceutical-based therapeutics and formulation strategies augmenting their efficiency to complement modern medicine: an overview. J Funct Foods. 2014;6:82–99.CrossRefGoogle Scholar
  27. 27.
    Vo CL-N, Park C, Lee B-J. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013;85(3):799–813.PubMedCrossRefGoogle Scholar
  28. 28.
    Lu Y, Tang N, Lian R, Qi J, Wu W. Understanding the relationship between wettability and dissolution of solid dispersion. Int J Pharm. 2014;465(1):25–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Saal W, Ross A, Wyttenbach N, Alsenz J, Kuentz M. A systematic study of molecular interactions of anionic drugs with a dimethylaminoethyl methacrylate copolymer regarding solubility enhancement. Mol Pharm. 2017;14(4):1243–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Kaewnopparat N, Kaewnopparat S, Jangwang A, Maneenaun D, Chuchome T, Panichayupakaranant P. Increased solubility, dissolution and physicochemical studies of curcumin-polyvinylpyrrolidone K-30 solid dispersions. World Acad Sci Eng Technol. 2009;55:229–34.Google Scholar
  32. 32.
    Kerdsakundee N, Mahattanadul S, Wiwattanapatapee R. Development and evaluation of gastroretentive raft forming systems incorporating curcumin-Eudragit(R) EPO solid dispersions for gastric ulcer treatment. Eur J Pharm Biopharm. 2015;94:513–20.PubMedCrossRefGoogle Scholar
  33. 33.
    Liao S, Ma Q, An G, Zhang N, Wang J, Xu C, et al. Preparation and evaluation of solid dispersion of asiatic acid with PVPK30. Dig J Nanomater Biostruct. 2013;8(2):685–90.Google Scholar
  34. 34.
    Sudsai T, Wattanapiromsakul C, Nakpheng T, Tewtrakul S. Evaluation of the wound healing property of Boesenbergia longiflora rhizomes. J Ethnopharmacol. 2013;150(1):223–31.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim YW, Lee WH, Choi SM, Seo YY, Ahn BO, Kim SH, et al. DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway. J Gastroenterol Hepatol. 2012;27(2):397–405.PubMedCrossRefGoogle Scholar
  36. 36.
    He X, Li B, Shao Y, Zhao N, Hsu Y, Zhang Z, et al. Cell fusion between gastric epithelial cells and mesenchymal stem cells results in epithelial-to-mesenchymal transition and malignant transformation. BMC Cancer. 2015;15:24. Scholar
  37. 37.
    Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105(9):2527–44.PubMedCrossRefGoogle Scholar
  38. 38.
    Fan N, He Z, Ma P, Wang X, Li C, Sun J, et al. Impact of HPMC on inhibiting crystallization and improving permeability of curcumin amorphous solid dispersions. Carbohydr Polym. 2018;181:543–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Kerdsakundee N, Mahatanadul S, Wiwattanapatapee R. Development and evaluation of gastroretentive raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions for gastric ulcer treatment. Eur J Pharm Biopharm. 2015;84:513–20.CrossRefGoogle Scholar
  40. 40.
    Arora SC, Sharma PK, Irchhaiya R, Khatkar A, Singh N, Gagoria J. Development, characterization and solubility study of solid dispersion of Cefuroxime Axetil by the solvent evaporation method. J Adv Pharm Technol Res. 2010;1(3):326–9.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Sekikawa H, Nakano M, Arita T. Inhibitory effect of polyvinylpyrrolidone on the crystallization of drugs. Chem Pharm Bull. 1978;26(1):118–26.CrossRefGoogle Scholar
  42. 42.
    Stott PW, Williams AC, Barry BW. Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. J Control Release. 1998;50(1):297–308.PubMedCrossRefGoogle Scholar
  43. 43.
    Ruan L-P, Yu B-Y, Fu G-M, Zhu D-n. Improving the solubility of ampelopsin by solid dispersions and inclusion complexes. J Pharm Biomed Anal. 2005;38(3):457–64.PubMedCrossRefGoogle Scholar
  44. 44.
    Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281–302.PubMedCrossRefGoogle Scholar
  45. 45.
    Moneghini M, Carcano A, Zingone G, Perissutti B. Studies in dissolution enhancement of atenolol. Part I. Int J Pharm. 1998;175(2):177–83.CrossRefGoogle Scholar
  46. 46.
    Saoji SD, Raut NA, Dhore PW, Borkar CD, Popielarczyk M, Dave VS. Preparation and evaluation of phospholipid-based complex of standardized centella extract (SCE) for the enhanced delivery of phytoconstituents. AAPS J. 2016;18(1):102–14.PubMedCrossRefGoogle Scholar
  47. 47.
    Jeganathan B, Prakya V. Interpolyelectrolyte complexes of Eudragit® EPO with hypromellose acetate succinate and Eudragit® EPO with hypromellose phthalate as potential carriers for oral controlled drug delivery. AAPS PharmSciTech. 2015;16(4):878–88.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Li J, Lee IW, Shin GH, Chen X, Park HJ. Curcumin-Eudragit® E PO solid dispersion: a simple and potent method to solve the problems of curcumin. Eur J Pharm Biopharm. 2015;94:322–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Gallardo D, Skalsky B, Kleinebudde P. Controlled release solid dosage forms using combinations of (meth) acrylate copolymers. Pharm Dev Technol. 2008;13(5):413–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Tarnawski AS, Ahluwalia A. Molecular mechanisms of epithelial regeneration and neovascularization during healing of gastric and esophageal ulcers. Curr Med Chem. 2012;19(1):16–27.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Saowanee Wannasarit
    • 1
    • 2
  • Panupong Puttarak
    • 2
    • 3
  • Kanidta Kaewkroek
    • 1
    • 2
  • Ruedeekorn Wiwattanapatapee
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical Technology, Faculty of Pharmaceutical SciencesPrince of Songkla UniversitySongkhlaThailand
  2. 2.Phytomedicine and Pharmaceutical Biotechnology Excellence Research Center, Faculty of Pharmaceutical SciencesPrince of Songkla UniversitySongkhlaThailand
  3. 3.Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical SciencesPrince of Songkla UniversitySongkhlaThailand

Personalised recommendations