The Increase of Anti-tuberculosis Efficacy of Rifampicin Incorporated Into Phospholipid Nanoparticles with Sodium Oleate

  • M. A. Sanzhakov
  • O. M. Ipatova
  • T. I. TorkhovskayaEmail author
  • E. G. Tikhonova
  • N. V. Medvedeva
  • T. S. Zakharova
  • V. N. Prozorovskiy


A drug formulation of the anti-tuberculosis drug rifampicin, incorporated in nanoparticles (of 20–30 nm in diameter) from soy phosphatidylcholine with the addition of sodium oleate, has been developed in IBMC. Earlier, it demonstrated a higher bioavailability than the free drug substance. In this study we have shown higher anti-tuberculosis activity of this composition. In experiments performed on M. tuberculosis H37Rv cells, rifampicin in nanoparticles more actively inhibited cell growth than the free drug substance. The higher anti-tuberculosis activity was manifested by a 2-fold lower value of the minimum inhibitory concentration (MIC), 0.5 μg/mL, as compared to 1 μg/mL for free rifampicin. After treatment of mice with tuberculosis caused by the M. tuberculosis Erdman strain for 6 weeks with oral administration of rifampicin in nanoparticles (according to the prophylactic scheme, starting from day 3 after infection), the CFU value in the lungs was 22 times lower than after the same treatment with free rifampicin (1.7 units compared with 37.4 units). The LD50 value in mice was 2-fold higher for rifampicin in the nanocomposite due to protective action of nanoparticle phospholipids. In the context of the use of rifampicin, as an essential component of modern schemes of anti-tuberculosis therapy, the data obtained indicate the promise of the developed drug composition.


phospholipid nanoparticles rifampicin oleate, M. tuberculosis cell growth anti-tuberculosis therapy CFU 



This study was performed within the framework of the Program of Basic Scientific Research of the State Academies of Sciences for 2013–2020.


All animal experiments were carried out in accordance with the International Recommendations of the European Convention for the Protection of Vertebrate Animals used for experiments or for other scientific purposes (The European Convention, 1986).


  1. 1.
    Castillo, P.M., Jimenez-Ruiz, A., Carnerero, J.M., and Prado-Gotor, R., Chemphyschem., 2018, vol. 19, no. 21, pp. 2810–2828. CrossRefPubMedGoogle Scholar
  2. 2.
    Pang, L., Zhang, C., Qin, J., Han, L., Li, R., et al., Drug Deliv., 2017, vol. 24, no. 1, pp. 83–91. CrossRefPubMedGoogle Scholar
  3. 3.
    Ferras-Carvalho, R.S., Pereira, M.A., Linhares, L.A., et al., Mem. Inst. Oswaldo Cruz., 2016, vol. 111, no. 5, pp. 330–334. CrossRefGoogle Scholar
  4. 4.
    Rieder, H.L., Indian J. Tuberc., 2014, vol. 61, no. 1, pp. 19–29.PubMedGoogle Scholar
  5. 5.
    Vieira, A.C.C., Chaves, L.L., Pinheiro, S., et al., Int. J. Pharm., 2018, vol. 536, no. 1, pp. 478–485.CrossRefPubMedGoogle Scholar
  6. 6.
    Pinheiro, M., Lúcio, M., Lima, J.L., and Reis, S., Nanomedicine (Lond.), 2011, vol. 6, no. 8, pp. 1413–1428. CrossRefGoogle Scholar
  7. 7.
    Shvets, V.I., Krasnopolsky, Yu.M., and Sorokoumo-va, G.M., Liposomal’nyye formy lekarstvennykh preparatov: tekhnologicheskie osobennosti polucheniya i primenenie v klinike (Liposomal Forms of Drugs: Technological Features of Production and the Use in Clinical Practice), Moscow: Remedium, 2017. ISBN: 9785906499202.Google Scholar
  8. 8.
    Orozco, L.C., Quintana, F.O., Beltran, R.M., et al., Tubercle, 1986, vol. 67, no. 2, pp. 91–97.CrossRefPubMedGoogle Scholar
  9. 9.
    Zaru, M., Sinico, C., De Logu, A., et al., J. Lipid Res., 2009, vol. 71, pp. 88–95.Google Scholar
  10. 10.
    Gürsoy, A., Kut, E., and Ozkirimli, S., Int. J. Pharm., 2004, vol. 271, nos. 1–2, pp. 115–123.CrossRefPubMedGoogle Scholar
  11. 11.
    Vyas, S.P., Kannan, M.E., Jain, S., Mishra, V., and Singh, P., Int. J. Pharm., 2004, vol. 269, pp. 37–49. CrossRefPubMedGoogle Scholar
  12. 12.
    Changsan, N., Chan, H.K., Separovic, F., and Srichana, T., J. Pharm. Sci., 2009, vol. 98, no. 2, pp. 628–639.CrossRefPubMedGoogle Scholar
  13. 13.
    Lankalapalli, S. and Tenneti, V.S., Curr. Drug Deliv., 2016, vol. 13, no. 7, pp. 1084–1099.CrossRefPubMedGoogle Scholar
  14. 14.
    Patil, J.S., Devi, V.K., Devi, K., and Sarasija, S., Lung India, 2015, vol. 32, no. 4, pp. 331–338. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Manca, M.L., Sinico, C., Macconi, A.M., et al., Pharmaceutics, 2012, vol. 4, no. 4, pp. 590–606. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kelly, C., Jefferies, C., and Cryan, S.-A., J. Drug Deliv., 2011, vol. 2011, 727241. CrossRefPubMedGoogle Scholar
  17. 17.
    Minina, A.S., Sorokoumova, G.M., Selishcheva, A.A., Malikova, N.M., Kalashnikova, T.Yu., and Shvets, V.I., Biofizika, 2004, vol. 49, no. 4, pp. 674–679.PubMedGoogle Scholar
  18. 18.
    Barbassa, L., Mamizuka, E.M., and Carmona-Ribeiro, A.M., BMC Biotechnol., 2011, vol. 11, no. 1, pp. 40–47.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pandey, R., Sharma, S., and Khuller, G.K., Tuberculosis (Edinb.), 2005, vol. 85, nos. 5–6, pp. 415–420.CrossRefGoogle Scholar
  20. 20.
    Archakov, A.I., Biomed. Khim., 2010, vol. 56, no. 1, pp. 7–25.PubMedGoogle Scholar
  21. 21.
    Sanzhakov, M.A., Prozorovskiy, V.N., Ipatova, O.M., Tikhonova, E.G., Medvedeva, N.V., and Torkhovskaya, T.I., Biomed. Khim., 2013, vol. 59, no. 5, pp. 585–590.CrossRefPubMedGoogle Scholar
  22. 22.
    Ipatova, O.M., Sanzhakov, M.A., Prozorovskiy, V.N., Torkhovskaya, T.I., Tikhonova, E.G., Medvedeva, N.V., and Archakov, A.I., FEBS J., 2013, vol. 280, suppl. 1, SW04.S16-286.Google Scholar
  23. 23.
    Siddiqi, S.H. and Riisch-Gerdes, S., MGITTM Procedure Manual. For BACTEC™ MGIT 960™ TB System. Becton Dickinson and Company, Maryland, USA, 2006.Google Scholar
  24. 24.
    Aleksandrova, A.E. and Ariel, B.M., Probl. Tuberkuleza, 1993, no. 3, pp. 52–53.Google Scholar
  25. 25.
    Changsan, N., Nilkaeo, A., Pungrassami, P., and Scrichana, T.J., Drug Target, 2009, vol. 17, no. 10, pp. 751–762.CrossRefGoogle Scholar
  26. 26.
    Sanzhakov, M.A., Ipatova, O.M., Prozorovskiy, V.N., Medvedeva, N.V., and Torkhovskaya, T.I., Biomed. Khim., 2014, vol. 60, pp. 348–353. CrossRefPubMedGoogle Scholar
  27. 27.
    Mankertz, J., Nundel, M., von Bayer, H., and Riedel, E., Biochem. Biophys. Res. Com., 1997, vol. 204, no. 1, pp. 112–115.CrossRefGoogle Scholar
  28. 28.
    Florence, A.T., Hillery, A.M., Hussain, N., and Jani, P.U., J. Drug Target, 1995, vol. 3, no. 1, pp. 65–70.CrossRefPubMedGoogle Scholar
  29. 29.
    Küllenberg, D., Taylor, L.A., Schneider, M., and Massing, U., Lipids Health Dis., 2012, vol. 11, no. 3, pp. 1–16.CrossRefGoogle Scholar
  30. 30.
    Ipatova, O.M., Fosfogliv: mekhanizm deistviya i primeneniye v klinike (Phosphogliv: Mechanism of Action and Application in the Clinical Practice), Academician Archakov, A.I., Ed., Moscow: Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, 2005.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • M. A. Sanzhakov
    • 1
  • O. M. Ipatova
    • 1
  • T. I. Torkhovskaya
    • 1
    • 2
    Email author
  • E. G. Tikhonova
    • 1
    • 3
  • N. V. Medvedeva
    • 1
  • T. S. Zakharova
    • 1
  • V. N. Prozorovskiy
    • 1
  1. 1.Institute of Biomedical Chemistry (IBMC)MoscowRussia
  2. 2.Federal Research and Clinical Center of Physical-Chemical MedicineMoscowRussia
  3. 3.PLC IBMH-EcoBioPharmMoscowRussia

Personalised recommendations