AAPS PharmSciTech

, Volume 18, Issue 6, pp 2067–2076 | Cite as

Preparation and Evaluation of Diosgenin Nanocrystals to Improve Oral Bioavailability

  • Cui-zhe LiuEmail author
  • Jin-hua Chang
  • Lin Zhang
  • He-fei Xue
  • Xi-gang Liu
  • Pei Liu
  • Qiang FuEmail author
Research Article


Diosgenin (DSG), a well-known steroid sapogenin derived from Dioscorea nipponica Makino and Dioscorea zingiberensis Wright, has a variety of bioactivities. However, it shows low oral bioavailability due to poor aqueous solubility and strong hydrophobicity. The present study aimed to develop DSG nanocrystals to increase the dissolution and then improve the oral bioavailability and biopharmaceutical properties of DSG. DSG nanocrystals were prepared by the media milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers. The physicochemical properties of the optimal DSG nanocrystals were characterized using their particle size distribution, morphology, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy data, and solubility and dissolution test results. Pharmacokinetic studies of the DSG coarse suspension and its nanocrystals were performed in rats. The particle size and polydispersity index of DSG nanocrystals were 229.0 ± 3.7 nm and 0.163 ± 0.064, respectively. DSG retained its original crystalline state during the manufacturing process, and its chemical structure was not compromised by the nanonizing process. The dissolution rate of the freeze-dried DSG nanocrystals was significantly improved in comparison with the original DSG. The pharmacokinetic studies showed that the AUC0–72h and C max of DSG nanocrystals increased markedly (p < 0.01) in comparison with the DSG coarse suspension by about 2.55- and 2.01-fold, respectively. The use of optimized nanocrystals is a good and efficient strategy for oral administration of DSG due to the increased dissolution rate and oral bioavailability of DSG nanocrystals.


bioavailability diosgenin media milling nanocrystals pharmacokinetics 



This study received financial support from the Key Discipline Construction Projects of Higher School, Hebei Province Natural Science Foundation of China (no. H2014406036), Science and Technology Research Key Project of Higher School in Hebei Province (no. ZH2012050), and Science and Technology Research Youth Fund Project of Higher School in Hebei Province (no. QN2015127).


Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12249_2016_684_MOESM1_ESM.tif (16.5 mb)
ESM 1 (TIF 16942 kb)
12249_2016_684_Fig8_ESM.gif (207 kb)

High resolution image (GIF 207 kb)

12249_2016_684_MOESM2_ESM.tif (6.2 mb)
ESM 2 (TIF 6334 kb)
12249_2016_684_Fig9_ESM.gif (43 kb)

High resolution image (GIF 42 kb)


  1. 1.
    Fang YW, Zhao JJ, He YZ, Li BG, Xu CJ. Study on the structure of two water-insoluble steroidal saponins of Dioscorea. Acta Pharmaceutical Sinica. 1982;17:388–91.Google Scholar
  2. 2.
    Li YM, He BJ, Liu ZY, Jin GS. Study on the water-soluble active ingredient of Dioscorea. J Chin Med Univ. 1979;8:14–6.Google Scholar
  3. 3.
    Chen PS, Shih YW, Huang HC, Cheng HW. Diosgenin, a steroidal saponin, inhibits migration and invasion of human prostate cancer PC-3 cells by reducing matrix metalloproteinases expression. PLoS One. 2011;6:1–10.Google Scholar
  4. 4.
    He Z, Chen H, Li G, Zhu H, Gao Y, Zhang L, et al. Diosgenin inhibits the migration of human breast cancer MDA-MB-231 cells by suppressing Vav2 activity. Phytomedicine. 2014;21:871–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang WC, Liu SF, Chang WT, Shiue YL, Hsieh PF, Hung TJ, et al. The effects of diosgenin in the regulation of renal proximal tubular fibrosis. Exp Cell Res. 2014;323:255–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Uemura T, Hirai S, Mizoguchi N, Goto T, Lee JY, Taketani K, et al. Diosgenin present in fenugreek improves glucose metabolism by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues. Mol Nutr Food Res. 2010;4:1596–608.CrossRefGoogle Scholar
  7. 7.
    Ebrahimi H, Badalzadeh R, Mohammadi M, Yousefi B. Diosgenin attenuates inflammatory response induced by myocardial reperfusion injury: role of mitochondrial ATP-sensitive potassium channels. J Physiol Biochem. 2014;70:425–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Kang TH, Moon E, Hong BN, Choi SZ, Son M, Park JH, et al. Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor. Biol Pharm Bull. 2011;34:1493–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Accatino L, Pizarro M, Solís N, Koenig CS. Effects of diosgenin, a plant-derived steroid, on bile secretion and hepatocellular cholestasis induced by estrogens in the rat. Hepatology. 1998;28:129–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Gao M, Chen L, Yu H, Sun Q, Kou J, Yu B. Diosgenin down-regulates NF-κB p65/p50 and p38MAPK pathways and attenuates acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 2013;15:240–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Tada Y, Kanda N, Haratake A, Tobiishi M, Uchiwa H, Watanabe S. Novel effects of diosgenin on skin aging. Steroids. 2009;74:504–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Ma HY, Zhao ZT, Wang LJ, Wang Y, Zhou QL, Wang BX. Comparative study on anti-hypercholesterolemia activity of diosgenin and total saponin of Discorea panthaica. Chin J Chinese Mater Med. 2002;27:528–31.Google Scholar
  13. 13.
    Okawara M, Hashimoto F, Todo H, Sugibayashi K, Tokudome Y. Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, diosgenin, after its oral administration to rats. Int J Pharm. 2014;472:257–61.CrossRefPubMedGoogle Scholar
  14. 14.
    Rytting E, Lentz KA, Chen XQ, Qian F, Vakatesh S. Aqueous and cosolvent solubility data for drug-like organic compounds. AAPS J. 2005;7:78–105.CrossRefGoogle Scholar
  15. 15.
    Okawara M, Tokudome Y, Todo H, Suqibayashi K, Hashimoto F. Enhancement of diosgenin distribution in the skin by cyclodextrin complexation following oral administration. Biol Pharm Bull. 2013;36:36–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Müller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001;47:3–19.Google Scholar
  17. 17.
    Kesisoglou F, Panmai S, Wu Y. Nanosizing—oral formulation development a biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59:631–44.CrossRefPubMedGoogle Scholar
  18. 18.
    Junghanns J, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3:295–309.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Jacobs C, Müller RH. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm Res. 2002;19:189–94.CrossRefPubMedGoogle Scholar
  20. 20.
    Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18:113–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Del Rev. 2011;63:427–40.CrossRefGoogle Scholar
  22. 22.
    Pu XH, Sun J, Han JH, Lian H, Zhang P, Yan ZT, et al. Nanosuspensions of 10-hydroxycamptothecin that can maintain high and extended supersaturation to enhance oral absorption: preparation, characterization and in vitro/in vivo evaluation. J Nanopart Res. 2013;15:1–13.CrossRefGoogle Scholar
  23. 23.
    Chan HK, Kwok PC. Production methods for nanodrug particles using the bottom-up approach. Adv Drug Del Rev. 2011;63:406–16.CrossRefGoogle Scholar
  24. 24.
    Rogers TL, Gillespie IB, Hitt JE, Fransen KL, Crowl CA, Tucker CJ, et al. Development and characterization of a scalable controlled precipitation process to enhance the dissolution of poorly water-soluble drugs. Pharm Res. 2004;21:2048–57.CrossRefPubMedGoogle Scholar
  25. 25.
    Ward GH, Schultz RK. Process-induced crystallinity changes in albuterol sulfate and its effect on powder physical stability. Pharm Res. 1995;12:773–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Sharma P, Denny WA, Garg S. Effect of wet milling process on the solid state of indomethacin and simvastatin. Int J Pharm. 2009;380:40–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Kayaert P, Van den Mooter G. Is the amorphous fraction of a dried nanosuspension caused by milling or by drying? A case study with Naproxen and Cinnarizine. Eur J Pharm Biopharm. 2012;81:650–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Sovizi MR, Hajimirsadeghi SS, Naderizadeh B. Effect of particle size on thermal decomposition of nitrocellulose. J Hazard Mater. 2009;168:1134–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Zuo BY, Sun YH, Li H, Liu XH, Zhai YL, Sun J, et al. Preparation and in vitro/in vivo evaluation of fenofibrate nanocrystals. Int J Pharm. 2013;455:267–75.CrossRefPubMedGoogle Scholar
  30. 30.
    Eloy OJ, Marchetti MJ. Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: a comparative study of fusion and solvent methods. Powder Technol. 2014;253:98–106.CrossRefGoogle Scholar
  31. 31.
    Mirza S, Ki JHM, Miroshnyk I, Rantanen J, Christiansen L, Karfalainen M, et al. Understanding processing-induced phase transformations in erythromycin–PEG 6000 solid dispersions. J Pharm Sci. 2006;95:1723–32.CrossRefPubMedGoogle Scholar
  32. 32.
    Janssens S, De Armas HN, Roberts CJ, Van Den Mooter G. Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5. J Pharm Sci. 2008;97:2110–20.CrossRefPubMedGoogle Scholar
  33. 33.
    Yang H, Teng F, Wang PX, Tian B, Lin X, Hu X, et al. Investigation of a nanosuspension stabilized by Soluplus1 to improve bioavailability. Int J Pharm. 2014;477:88–95.CrossRefPubMedGoogle Scholar
  34. 34.
    Cerdeira AM, Mazzotti M, Gander B. Formulation and drying of miconazole and itraconazole nanosuspensions. Int J Pharm. 2013;443:209–20.CrossRefPubMedGoogle Scholar
  35. 35.
    Gao L, Liu G, Ma J, Wang X, Zhou L, Li X. Drug nanocrystals: in vivo performances. J Control Release. 2012;160:418–30.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  1. 1.Hebei Province Key Laboratory of Research and Development for Chinese MedicineChengde Medical CollegeChengdePeople’s Republic of China
  2. 2.Department of Pharmaceutics, School of PharmacyShenyang Pharmaceutical UniversityShenyangPeople’s Republic of China

Personalised recommendations