固体分散技术对缓释片中非洛地平的体外释放和在Beagle犬体内药动学的影响

Effects of Solid Dispersion Technology on in vitro Release and Pharmacokinetics of Felodipine from Sustained-release Tablets in Beagle Dogs

为增加非洛地平(1)的溶解度,采用溶剂法制备药物与聚乙烯吡咯烷酮(PVP K29/32)载体质量比分别为1∶2、1∶4、1∶6的固体分散体(SD)。差示扫描量热法和X射线衍射法分析表明,药物以无定形存在于载体中。相较于物理混合物和原料药,SD中1的溶出度显著增大。以上述3种SD和1原料药为原料,分别制备亲水骨架型缓释片,并考察了自制品与波依定在1%Tween-80溶液中释放行为的相似性。结果表明,基于SD(1∶PVP=1∶6)的自制品c与波依定的相似因子(f_2)为70;并且二者在水和pH 1.0、4.5和6.8介质中的f_2值均大于50。进一步以Beagle犬为模型,考察二者的体内药动学情况。以LC-MS法测定血中药物浓度。结果表明,自制品c在Beagle犬体内与波依定生物等效,相对生物利用度为103.5%。

To improve the solubility of felodipine（1）, solid dispersions（SD） were prepared by solvent method with polyvidone（PVP） K29/32 as a carrier at three different drug/carrier weight ratios of 1∶2, 1∶4 and 1∶6. The results of differential scanning calorimetry and X-ray diffraction analysis indicated that the drug existed in an amorphous form in the three prepared SDs. Compared with physical mixture and the bulk drug, all SDs significantly increased the dissolution of 1. Four kinds of hydrophilic matrix sustained-release tablets based on the above three SDs and the bulk drug were respectively prepared. The similarities in release profiles between four self-made products and Plendil in 1% Tween-80 solution were investigated. The results showed that the calculated similar factor（f_2） value between the tablets based on SD with drug/carrier weight ratio of 1∶6, named as product c, and Plendil was 70. Furthermore, the f_2 values between product c and Plendil were all above 50 according to the release profiles in water and media with different pH values（1.0, 4.5 and 6.8）. The pharmacokinetics of these two preparations in Beagle dogs were investigated. The drug concentration was determined by LC-MS. The results showed that two preparations were bioequivalent in Beagle dogs. The relative bioavailability of product c was 103.5%.