Enhancement of dissolution of Cilostazole by complexation method using Cyclodextrins
Abstract
The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like β-CD, γ-CD, and the hydrophilic β-CD derivatives, DM-β-CD and HP-β-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The in vivo study revealed that DM-β-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol–cyclodextrins complexes, cilostazol–DM-β-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.
Downloads
References
2. Larsen KL. Large cyclodextrins. J Inclusion Phenom Macro Chem. 2002;43(1–2):1–13.
3. Szejtli J, Osa T. Comprehensive supramolecular chemistry: cyclodextrins, vol 3. Oxford: Pergamon; 1996.
4. Uekama K, Hirayama F, Irie T. Cyclodextrin drug carrier systems. Chem Rev. 1998;98(5):2045–76.
5. Mosher G, Thompson D. Complexation and cyclodextrins. encyclopedia of pharmaceutical technology, Vol. 19. New York: Marcel and Dekker; 1999. p. 49–88.
6. Homans SW. A molecular mechanical force field for the conformational analysis of oligosaccharides: comparison
of the theoretical and crystal structure of Manα1–3Manβ1–4GlcNAc. Biochemistry 1990;29(39):9110–8.
7. Zuo Z, Kwon G, Stevenson B, Diakur J, Wiebe LI. Flutamide- hydroxypropyl-β-cyclodextrin complex: formulation, physical characterization, and absorption studies using the Caco-2 in vitro model. J Pharm Pharmceut Sci. 2000;3(2):220–7.
8. Dollo G, CorrePL, CholletM, ChevanneF, BertaultM, Burgot JL, et al. Improvement in solubility and dissolution rate of 1,2-dithiole- 3-thiones upon complexation with β-cyclodextrin and its hydrox- ypropyland sulfobutyl ether-7 derivatives. J Pharm Sci.1999;88:889–95.
9. Duchene D. New trends in cyclodextrins and derivatives. Paris: Editios de Sante; 1992. p. 351–407.
10. Fromming KH, Szejtli J. Cyclodextrins in pharmacy (Topics in inclusion science). Dordrecht: Kulwer Academic;1994.
11. Thompson DO. Cyclodextrin-enabling excipients: their present and future use in pharmaceuticals. Crit Rev Ther Drug Carrier Syst.1997;14:1–104.
12. Masson M, Loftsson T, Masson G, Stefansson E. Cyclodextrin as permeation enhancer: some theoretical evaluations and in vitrotesting. J Control Release1999;59(1):107–18.Govt. of India, Ministry of Health and Family Welfare. Pharmacopoeia of India, vol I. 4th ed. New Delhi: Controller of Publication; 1996. p.A–144–7.
Copyright © Author(s) retain the copyright of this article.
