Abstract: Valsartan, a water-insoluble drug, is mainly used in the treatment of hypertension albeit with reduced oral bioavailability. The aim of work was to develop a valsartan:β-cyclodextrin (VAL:β-CD) pharmaceutical composition in order to improve its water solubility and bioavailability. The VAL:β-CD complexes were prepared by the kneading, solid dispersion and freeze-drying methods, of which the freeze-drying method (FDY) was found to be the best to prepare an inclusion complex. A physical mixtyure PM was also prepared. Complexes were characterized by thermal analysis, Fourier transformed- infrared (FTIR) spectroscopy, Powder X-ray diffractometry, intrinsic dissolution and NMR (2D-ROESY). Phase-solubility analysis showed AL-type diagrams with β-cyclodextrin (β-CD). Microcalorimetric titrations suggested the formation of 1:1 inclusion complex between VAL and β-CD. The apparent stability constants K1:1 calculated from phase-solubility plots were 165.4 M-1 (298 K), 145.0 M-1 (303 K) and 111.3 M-1 (310 K). In vivo experiments in rats showed that reduction in arterial pressure for the FDY complex is better than with valsartan used alone. The better activity of FDY can be attributed to the higher solubility of valsartan after inclusion in the cyclodextrin cavity, as suggest by the intrinsic dissolution studies.
Keywords: valsartan; β-cyclodextrin; intrinsic dissolution; ROESY; anti-hypertensive evaluation
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De Matos Jensen, C.E.; Dos Santos, R.A.S.; Denadai, A.M.L.; Santos, C.F.F.; Braga, A.N.G.; Sinisterra, R.D. Pharmaceutical Composition of Valsartan: β-Cyclodextrin: Physico–Chemical Characterization and Anti-Hypertensive Evaluation. Molecules 2010, 15, 4067-4084.
De Matos Jensen CE, Dos Santos RAS, Denadai AML, Santos CFF, Braga ANG, Sinisterra RD. Pharmaceutical Composition of Valsartan: β-Cyclodextrin: Physico–Chemical Characterization and Anti-Hypertensive Evaluation. Molecules. 2010; 15(6):4067-4084.
De Matos Jensen, Carlos Eduardo; Dos Santos, Robson Augusto Souza; Denadai, Angelo Márcio Leite; Santos, Cynthia Fernandes Ferreira; Braga, Aline Nardoni Gonçalves; Sinisterra, Rubén Dario. 2010. "Pharmaceutical Composition of Valsartan: β-Cyclodextrin: Physico–Chemical Characterization and Anti-Hypertensive Evaluation." Molecules 15, no. 6: 4067-4084.