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.
Highlights
Hypertension is one of the most prevalent chronic adult illnesses today and cannot be cured, but it can be controlled
Similar temperature effects on the stability constants were found by Brunella, et al and Karathanos et al [9,12,17,18]
The FDY produced a significant reduction in arterial pressure after forty minutes and in the first day this reduction was -11.16 ± 0.92 mmHg compared with control period (p < 0.05)
Summary
Hypertension is one of the most prevalent chronic adult illnesses today and cannot be cured, but it can be controlled. The pharmacological treatment for control of hypertension utilizes various drug therapies, single doses or associations of diuretics, beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor (AT1) antagonist (ARA). Valsartan (VAL, Figure 1) is one of the angiotensin II receptor (AT1) antagonists recommended for treatment of hypertension, post-myocardial infarction or congestive heart failure. Other drugs in the same group include losartan, irbesartan, olmesartan and candesartan [3,4]. Only 25% of VAL (Figure 1) is absorbed, food intake being one of the possible causes for the low bioavailability [5]. Other drugs from the ARA group have bioavailabilities ranging between 33% (losartan) and 60–80% (irbesartan) [6,7]. The low bioavailability of VAL is associated with its poor water solubility.
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