Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies
- 329 Downloads
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.
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®).
The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state.
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.
KEY WORDSmechanochemical reaction/activation oral absorption physico-chemical characterization solvent-free process vinpocetine citrate
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.
- 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.Google Scholar
- 4.Grandt R, Beitinger R, Schateltenbrand R, Braun W. Vinpocetine pharmacokinetics in elderly subjects. Arzneim-Forsch/Drug Res. 1989;39:1599–602.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.PubMedCrossRefGoogle Scholar
- 16.Calvo F, Manresa MT. Citric acid salt of (+) vinpocetine. U.S. patent 4749707. Spain: Covex S.A.; 1988.Google Scholar
- 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
- 19.Mathieu D, Nony J, Phan-Tan-Luu R. NEMRODW (New Efficient Technology for Research using Optimal Design) software. Marseille: LPRAI; 1999.Google Scholar
- 21.Beleites C, Sergo V. http://hyperspec.r-forge.r-project.org for R (see reference 20); 2009.
- 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.Google Scholar
- 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.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.PubMedCrossRefGoogle 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.Google Scholar