Pharmaceutical composition of valsartan: beta-cyclodextrin: physico-chemical characterization and anti-hypertensive evaluation.
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:beta-cyclodextrin (VAL:beta-CD) pharmaceutical composition in order to improve its water solubility and bioavailability. The VAL:beta-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 mixture 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 A(L)-type diagrams with beta-cyclodextrin (beta-CD). Microcalorimetric titrations suggested the formation of 1:1 inclusion complex between VAL and beta-CD. The apparent stability constants K(1:1) 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.
Jensen
Carlos Eduardo de Matos
CE
Departamento de Química, ICEx, Universidade Federal de Minas Gerais, Avenida Pres. Antônio Carlos 6627, 31270-901, Belo Horizonte, Brazil. cej.jensen@gmail.com
dos Santos
Robson Augusto Souza
RA
Denadai
Angelo Márcio Leite
AM
Santos
Cynthia Fernandes Ferreira
CF
Braga
Aline Nardoni Gonçalves
AN
Sinisterra
Rubén Dario
RD
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000627:therapeutic use*; D003505:Cyclodextrins / Q000737:chemistry*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D017550:Spectroscopy, Fourier Transform Infrared; D013777:Tetrazoles / Q000737:chemistry*; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry; D000068756:Valsartan
D000959:Antihypertensive Agents; D003505:Cyclodextrins; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine