Enhanced antihypertensive activity of candesartan cilexetil nanosuspension: formulation, characterization and pharmacodynamic study

Sci Pharm. Jul-Sep 2011;79(3):635-51. doi: 10.3797/scipharm.1103-17. Epub 2011 Jul 5.

Abstract

The objective of the present investigation was to enhance the oral bioavailability of practically insoluble Candesartan cilexetil [CC] by preparing nanosuspension. The nanosuspension was prepared by media milling using zirconium oxide beads and converted to solid state by spray drying. The spray dried nanosuspension of CC [SDCN] was evaluated for particle size, zeta potential, saturation solubility, crystallanity, surface morphology and dissolution behavior. SDCN showed particle size of 223.5±5.4 nm and zeta potential of -32.2±0.6 mV while saturation solubility of bulk CC and SDCN were 125±6.9 μg/ml and 2805±29.5 μg/ml respectively, showing more than 20 times increase in solubility. Differential Scanning Calorimetry [DSC] and X-ray diffraction [XRD] analysis showed that crystalline state of CC remained unchanged in SDCN. Dissolution studies in phosphate buffer pH 6.5 containing 0.7% Tween 20 showed that 53±5% of bulk drug dissolved in 15 min whereas SDCN was almost completely dissolved exhibiting higher dissolution velocity and solubility. Transmission electron microscopy [TEM] revealed that nanocrystals were not of uniform size, and approximately of oval shape. Pharmacodynamic study based on deoxycorticosterone acetate [DOCA] salt model was performed in rats to evaluate in-vivo performance, which showed 26.75±0.33% decrease in systolic blood pressure for nanosuspension while plain drug suspension showed 16.0±0.38% reduction, indicating that increase in dissolution velocity and saturation solubility leads to enhancement of bioavailability of SDCN when compared to bulk CC suspension. Thus, the results conclusively demonstrated a significant enhancement in antihypertensive activity of candesartan when formulated as nanosuspension.

Keywords: Bioavailability; Candesartan; DOCA salt model; Nanosuspension; Saturation solubility.