盐酸普拉克索双相缓释胶囊的制备及体内外评价

Preparation and in vitro-in vivo Evaluation of Pramipexole Dihydrochloride Diphase Sustained-release Capsules

采用流化床底喷包衣工艺制备含盐酸普拉克索的两种膜控小丸,分别达到速释和缓释目的,再将其按一定比例混合后制备成盐酸普拉克索双相缓释胶囊。采用单因素试验和星点设计-效应面法,以自研胶囊和原研制剂(Siforl)在pH 6.8磷酸盐缓冲液(PBS)中释放行为的相似性为评价指标,优化了自制胶囊的处方。验证试验表明,优化后的自制胶囊与原研制剂在pH 6.8磷酸盐缓冲液(未经历或经历在pH 1.2盐酸中释放1或2 h)中的释放行为相似(相似因子均大于50)。以Beagle犬为模型,考察了自制胶囊和原研制剂的体内药动学行为。采用LC-MS/MS法测定血浆中盐酸普拉克索浓度,并采用非房室模型计算两制剂的药动学参数。结果表明,自研双相缓释胶囊与原研制剂的c_(max)为(1 118.3±121.9)和(1 108.6±183.2)pg/ml,AUC_(0→∞)为(18 227.5±1 870.8)和(16 321.8±2 327.5)pg·ml^(-1)·h,提示两制剂相似。

The pramipexole dihydrochloride diphase sustained-release capsules were prepared by mixing two kinds of membrane-moderated pellets, which were coated with different layers by bottom spray fluid bed coating technology at certain proportion to obtain rapid- and sustained-release characteristics. The formulation was optimized by single factor experiment and central composite design-response surface methodology with the release similarity between self-made capsules and reference listed drug （Siforl） in pH 6.8 phosphate buffer （PBS）. The results of validation test showed that the drug release behaviors of both preparations were similar in PBS or in pH 1.2 hydrochloric acid for first 1 or 2 h, followed by PBS, those similarity factor （f2） values were all above 50. In vivo pharmacokinetics of the self-made capsule and Siforl were investigated with Beagle dog model. The drug concentration in plasma was determined by LC-MS/MS, and pharmacokinetic parameters of these two formulations were calculated by non-compartmental model. The results showed that the self-made diphase phase sustainedrelease capsules and Siforl of cmax （1 118.3±121.9） and （1 108.6±183.2） pg/ml, AUC0→∞ （18 227.5±1 870.8） and （16 321.8±2 327.5）pg·ml^-1·h, suggesting a similarity of these two preparations.