Enhanced dissolution and oral bioavailbility of cinacalcet hydrochlorde nanocrystals with no food effect

This study was aimed at improving oral bioavailbility and reducing the food effect of cinacalcet hydrochlorde (CINA), a poorly soluble drug for the treatment of chronic kidney disease, by preparing its nanocrystals (NCs) utilizing the precipitation-ultrasonication method. Based on the single factor method and Box-Behnken design, with the particle size and polydispersity index (PDI) as indexes, the optimal formulation was achieved. It was investigated that the particle size and PDI of the NCs prepared on the basis of optimal formulation were 244 ±2 nm and 0.168 ±0.001, respectively. The NCs were solidificated by lyophilization. Scanning electron microscopy, differential scanning calorimetry and x-ray powder diffraction were used to characterize the CINA-NCs, and there was no crystalline change during preparation and lyophilization. The CINA-NCs capsules prepared with 30% (w/v) MCC, 8% (w/v) CCNa and 2% (w/v) talcum powder by orthogonal experimental design presented an enhanced in vitro dissolution rate in four media compared with commercial tablets Sensipar® and raw material. The raw material, blank NCs and CINA-NCs were confirmed to be non-toxic to Caco-2 cells when the drug concentration was below 250 μg ml^-1. In the in vivo pharmacokinetic study, the C_max (the peak concentration of CINA in plasma) and AUC_0-t (area under curve by trapezoidal area method) of the CINA-NCs capsules were approximately 1.90-fold and 1.64-fold greater than that of Sensipar® in the fasted state. Overall, this nanotechnology is a promising way to optimize the dosage form of CINA oral administration.