Preparation Of Felodipine Sustained-release Tablets And Studies In Vivo

Felodipine, a calcium channel blocking agent of 1,4-dihydropyridine-derivative, is widely employed for the treatment of hypertension. Due to low solubility and high permeability of felodipine as a BCSⅡtype compound, improving the dissolution rate is the key to enhance the bioavailability. The goal of the paper is to improve the bioavailability, simultaneously reduce the frequency of administration and the fluctuation of drug plasma concentration by preparing felodipine sustained release tablets combined with the solid dispersion technology using hdroxy-propyl methyl cellulose (HPMC) as matrix material.Ultraviolet spectrophotometry (UV) method for assaying drug content and release properties in vitro of felodipine, and high performance liqid chromatography (HPLC) method for the inspection of related substances in tablets were developed. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for the analysis of drug concentration in dog plasma was set up. The methods were quick and accurate which could meet the requirement of the analysis.By applying solid dispersion technology, the solubility and dissolution of felodipine was enhanced significantly. PVP k3o, Lutrol F68 and Tween 80 with absorbent (crospovidone) used as carriers to prepare the solid dispersions on the influence of dissolution were investigated by the methods of solvent, melting and solvent evaporation-desposition. Applied tween 80 as solubilizer, the study was focused on the influences of different absorbents on the appearance and dissolution of solid dispersion. The results of dissolution rate test demonstrated that all the solid dispersions could improve the dissolution rate of felodipine and the sequence was as follows:Tween80> LutrolF68> PVPK30 The states of felodipine in carriers were identified by Differential scanning calorimetery (DSC) technology. The results of DSC indicated that the drug was amorphous state in solid dispersion. Based on the consequences of dissolution and DSC, Tween 80 with absorbent (Crospovidone) was chosen as carrier to prepare the solid dispersion employing solvent evaporation-desposition technology.The solid system composed of felodipine, Tween 80, absorbent (Crospovidone) was adopted to be intermediate, hydroxy propyl methylcellulose (HPMC) was used as matrix material, and the sustained release tablets were prepared by wet granulation. Based on single factor investigating, Similarity factors (f2) were employed as the evaluation standard to optimize the formulation of the sustained release tablets. The quality studies on self-prepared sustained release tablets showed that the drug release rate was influenced significantly by the concentration of surfactant in dissolution medium and rotation speed of the baskets, but pH value of medium and hardness of the tablets had little influence on drug release. The mechanism of drug release in vitro was confirmed as the combination results of drug diffusion and matrix erosion. Stability studies showed that felodipine sustained release tablets should be protected from light, in hypothermia and package dessication.With Double agents double-cycle cross method, UPLC-MS-MS method was established and applied to pharmacokinetic study of two felodipine formulations oral administrated to six dogs. The pharmacokinetic parameters of the reference and test tablets were as follows:AUC0-14 was 34.6±9.2 ng·mL-1·h and 44.6±14.7 ng·mL-1·h, AUC0-∞was 44.9±12.9 ng·mL-1·h and 52.8±18.1 ng·mL-1·h, Cmax was 10.6±4.2 ng·mL-1 and 13.2±6.6 ng·mL-1, tmax was 2.0±1.3 h and 3.08±2.4 h. Compared with the reference tablet, Cmax and tmax of the test formation increased at different level, and the relative bioavailability of test formulation was (132±34)%, which illustrated that the test formation had higher bioavailability and better slow-release effect compared with the reference tablets. The results of two one side t-test and confidence interval analysis demonstrated that the test and reference formulations is not bioequivalent.In conclusion, the felodipine sustained release tablets prepared by combining solid dispersion technology with wet granulation method was feasible, and successfully achieved the purpose of improving the dissolution and bioavailability of felodipine.