Skip to main content
Log in

Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies

  • Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid.

Methods

The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solid-state characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine®).

Results

The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state.

Conclusion

From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

REFERENCES

  1. Bencsath P, Debrczeni L, Takács L. Effect of ethyl apovincaminate on cerebral circulation of dogs under normal conditions and in arterial hypoxia. Arzneim-Forsch/Drug Res. 1976;26:1920–3.

    CAS  Google Scholar 

  2. Luo Y, Chen D, Ren L, Zhao X, Qin J. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J Control Release. 2006;114:53–9.

    Article  PubMed  CAS  Google Scholar 

  3. Csanda E, Harcos P, Bacsy Z, Berghammer R, Kenez J. Ten years of experience with Cavinton. Drug Dev Res. 1988;14:185–7.

    Article  Google Scholar 

  4. Grandt R, Beitinger R, Schateltenbrand R, Braun W. Vinpocetine pharmacokinetics in elderly subjects. Arzneim-Forsch/Drug Res. 1989;39:1599–602.

    CAS  Google Scholar 

  5. Szakacs T, Veres Z, Vereczkey L. In vitro-in vivo correlation of the pharmacokinetics of vinpocetine. Pol J Pharmacol. 2001;53:623–8.

    PubMed  CAS  Google Scholar 

  6. Kata M, Lukacs M. Enhancement of solubility of vinpocetine base with γ-cyclodextrin. Pharmazie. 1986;41:151–2.

    PubMed  CAS  Google Scholar 

  7. Ribeiro L, Ferreira D, Veiga F. Physicochemical investigation of the effects of water-soluble polymers on vinpocetine complexationwith β-cyclodextrin and its sulfobutyl ether derivative in solution and solid state. Eur J Pharm Sci. 2003;20:253–66.

    Article  PubMed  CAS  Google Scholar 

  8. Ribeiro L, Falcao AC, Patricio JAB, Ferreira DC, Veiga FJB. Cyclodextrin multicomponent complexation and controlled release delivery strategies to optimize the oral bioavalaibility of vinpocetine. J Pharm Sci. 2007;96:2018–28.

    Article  PubMed  CAS  Google Scholar 

  9. Nie S, Fan X, Peng Y, Yang X, Wang C, Pan W. In vitro and in vivo studies on the complexes of vinpocetine with hydroxypropyl-β-cyclodextrin. Arch Pharm Res. 2007;30:991–1001.

    Article  PubMed  CAS  Google Scholar 

  10. Nie S, Pan W, Li X, Wu X. The effect of citric acid added to hydroxypropyl methylcellulose (HPMC) matrix tablets on the release profile of vinpocetine. Drug Dev Ind Pharm. 2004;30:627–35.

    Article  PubMed  CAS  Google Scholar 

  11. Miskolczi P, Vereczkey L, Szalay L, Göndöcs C. Effect of age on pharmacokinetics of Vinpocetine (Cavinton) and Apovincamininc acid. Eur J Clin Pharmacol. 1987;33:185–9.

    Article  PubMed  CAS  Google Scholar 

  12. Chen Y, Li G, Wu X, Chen Z, Hang J, Qin B, et al. Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment. Biol Pharm Bull. 2008;31:118–25.

    Article  PubMed  CAS  Google Scholar 

  13. Iosio T, Voinovich D, Grassi M, Pinto JF, Perissutti B, Zacchigna M, et al. Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: influence of formulation variables and preliminary study on the in vivo absorption. Eur J Pharm Biopharm. 2008;69:686–97.

    Article  PubMed  CAS  Google Scholar 

  14. Cui SX, Nie SF, Li L, Wang CG, Pan WS, Sun JP. Preparation and evaluation of self-microemulsifying drug delivery system containing vinpocetine. Drug Dev Ind Pharm. 2009;35:603–11.

    Article  PubMed  CAS  Google Scholar 

  15. Hasa D, Voinovich D, Perissutti B, Bonifacio A, Grassi M, Franceschinis E, et al. Multidisciplinary approach on characterizing a mechanochemically activated composite of vinpocetine and crospovidone. J Pharm Sci. 2011;100:915–32.

    Article  PubMed  CAS  Google Scholar 

  16. Calvo F, Manresa MT. Citric acid salt of (+) vinpocetine. U.S. patent 4749707. Spain: Covex S.A.; 1988.

  17. Shakhtshneider TP, Boldyrev VV. Mechanochemical synthesis and mechanical activation of drugs. In: Boldyreva E, Boldyrev V, editors. Reactivity of molecular solids. Chichester: Wiley; 1999. p. 271–311.

    Google Scholar 

  18. Voinovich D, Perissutti B, Grassi M, Passerini N, Bigotto A. Solid state mechanochemical activation of Silybum Marianum dry extract with betacyclodextrins: characterization and bioavailability of the coground systems. J Pharm Sci. 2009;98:4119–29.

    Article  PubMed  CAS  Google Scholar 

  19. Mathieu D, Nony J, Phan-Tan-Luu R. NEMRODW (New Efficient Technology for Research using Optimal Design) software. Marseille: LPRAI; 1999.

    Google Scholar 

  20. R Development Core Team. R: a language and environment for statistical computing. Wien: R Foundation for Statistical Computing; 2009. ISBN 3-900051-07–0. Available from: http://www.R-project.org.

    Google Scholar 

  21. Beleites C, Sergo V. http://hyperspec.r-forge.r-project.org for R (see reference 20); 2009.

  22. Carli F, Motta A. Particle size and surface area distribution of pharmaceutical powders by microcomputerized mercury porosimetry. J Pharm Sci. 1984;73:197–203.

    Article  PubMed  CAS  Google Scholar 

  23. Cadelli G, Zarattini P, Stebel M. Further refinements of tail artery cannulation in conscious rats, Centro Coordinamento e Sviluppo progetti e Apparecchiature (CSPA). Settore stabulario e sperimentazione animale. Università di Trieste., FELASA-ICLAS Joint Meeting –Villa Erba, Cernobbio; 2007.

  24. Vlase L, Bodiu B, Leucuta SE. Pharmacokinetics and comparative bioavailability of two vinpocetine tablet formulations in healthy volunteers by using the metabolite apovincaminic acid as pharmacokinetic parameter. Arzneim-Forsch/Drug Res. 2005;55:664–8.

    CAS  Google Scholar 

  25. Mura P, Faucci MT, Manderioli A, Bramanti G. Multicomponent systems of econazole with hydroxyacids and cyclodextrins. J Incl Phenom. 2001;39:131–8.

    Article  CAS  Google Scholar 

  26. Lu Q, Zografi G. Properties of the citric acid at the glass transition. J Pharm Sci. 1997;86:1374–8.

    Article  PubMed  CAS  Google Scholar 

  27. Voinovich D, Perissutti B, Magarotto L, Ceschia D, Guiotto P, Bilia AR. Solid state mechanochemical simultaneous activation of the constituents of the silybum marianum phytocomplex with crosslinked polymers. J Pharm Sci. 2009;98:215–28.

    Article  PubMed  CAS  Google Scholar 

  28. Colombo I, Grassi G, Grassi M. Drug mechanochemical activation. J Pharm Sci. 2009;98:3961–86.

    Article  PubMed  CAS  Google Scholar 

  29. Rawlinson CF, Williams CA, Timmins P, Grimsey I. Polymer-mediated disruption of drug crystallinity. Int J Pharm. 2007;336:42–8.

    Article  PubMed  CAS  Google Scholar 

  30. Trapani G, Latrofa A, Franco M, Pantaleo MR, Sanna E, Massa F, et al. Complexation of zolpidem with 2-hydroxypropyl-β-, methyl-β-, and 2-hydroxypropyl-γ-cyclodextrin: effect on aqueous solubility, dissolution rate, and ataxic activity in rat. J Pharm Sci. 2000;89:1443–51.

    Article  PubMed  CAS  Google Scholar 

  31. Grassi M, Coceani N, Magarotto L, Ceschia D. Effect of milling time on release kinetics from co-grounded drug-polymer systems. Proceedings of the AAPS Annual Meeting and Exposition, October, Salt Lake City, USA; 2003.

  32. Karagedov GR, Konovalova EA, Boldyrev VV, Lyachov NZ. Influence of reagent biography and reaction conditions on kinetics of lithium ferrite synthesis. Solid State Ionics. 1990;42:147–51.

    Article  CAS  Google Scholar 

  33. Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS. Understanding the behaviour of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27:608–18.

    Article  PubMed  CAS  Google Scholar 

  34. Groen H, Roberts KJ. Nucleation growth and pseudo-polymorphic behavior of citric acid as monitored in situ by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy. J Phys Chem B. 2001;105:10723–30.

    Article  CAS  Google Scholar 

  35. Poerwono H, Higashiyama K, Kubo H, Poernomo AT, Suharjono, Sudiana IK, et al. Citric acid. In: Brittain HG, editor. Analytical profiles of drug substances and excipients, vol. 28. Boston: Academic; 2001. p. 1–76.

    Chapter  Google Scholar 

  36. Stevens JS, Byard SJ, Schroeder SLM. Salt or co-crystal? Determination of protonation state by X-Ray Photoelectron Spectroscopy (XPS). J Pharm Sci. 2010;99:4453–7.

    Article  PubMed  CAS  Google Scholar 

  37. Braga D, Grepioni F, Polito M, Chierotti MR, Ellena S, Gobetto R. A solid-gas route to polymorph conversion in crystalline [Fe-II(eta5-C5H4COOH)2]. A diffraction and solid-state NMR study. Organometallics. 2006;25:4627–33.

    Article  CAS  Google Scholar 

  38. Chierotti MR, Gobetto R. Solid-state NMR studies of weak interactions in supramolecular systems. Chem Commun. 2008;14:1621–34.

    Article  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors thank Linnea (Locarno, CH) and Covex (Madrid, ES) for kindly donating the active ingredients used in this study, D. Lenaz for his precious advices and S. Bhardwaj, from TASC-IOM-CNR AREA Science Park, Trieste, Italy, for assistance during XPS analyses.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Dario Voinovich or Beatrice Perissutti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hasa, D., Voinovich, D., Perissutti, B. et al. Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies. Pharm Res 28, 1870–1883 (2011). https://doi.org/10.1007/s11095-011-0415-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0415-8

KEY WORDS

Navigation