瑞舒伐他汀钙片的研制及其体内外评价

Preparation and in vitro/in vivo Evaluationof Rosuvastatin Calcium Tablets

采用湿法制粒压片技术制备瑞舒伐他汀钙包衣片。以30 min溶出率为指标,采用单因素试验筛选并优化了羟丙甲纤维素型号、交联聚维酮用量和包衣增重等处方因素。以市售参比制剂为对照,计算了优化包衣片与参比制剂溶出曲线的相似因子(f2)。并且采用单剂量双周期交叉试验方案,比较了自制和参比制剂在Beagle犬体内的药动学特征。结果表明,采用羟丙甲纤维素E5 LV为黏合剂、崩解剂交联聚维酮用量为3.2%、包衣增重为3%的优化处方制得的瑞舒伐他汀钙片符合30 min内溶出率超过80%的要求。3批优化片剂的工艺重现性良好、质量稳定。自制与参比制剂在pH 6.6的枸橼酸缓冲液中溶出曲线的f2值为99.35,提示二者体外溶出行为相似。加速和长期稳定性试验表明,自制包衣片稳定性较好。采用LC-MS/MS法检测了Beagle犬血浆中的药物浓度,并计算2种制剂的主要药动学参数。结果二者在Beagle犬体内的tmax、cmax和AUC0→t均无统计学差异(P>0.05),自制瑞舒伐他汀钙片的相对生物利用度为(106.00±12.88)%。

The rosuvastatin calcium tablets were prepared by wet granulation followed by coating process. The formulation factors, such as adhesive type, disintegrant amount and weight gain, were optimized by single factor experiment with dissolution at 30 min as the index. The results showed that the drug dissolved more than 80% within 30 min from the optimal coated tablets with hydroxypropyl methylcellulose (HPMC) E5 LV as adhesive, 3.2% of cross-linked polyvidone (PVPP) as disintegrant and weight gain of 3%. The dissolution behaviors of three batches of the optimal tablets (10 000 tablets per batch) and the results of accelerated and long-term stability tests proved the reproducibility of the preparation process and the stable quality of products. The dissolution similarity between the self-made coated tablets and the commercial reference tablets was assessed. The results showed that the similarity factor (f2) was 99.35, indicating the dissolution profiles of the two preparations in pH 6.6 citric acid buffer were similar. Furthermore, a single-dose two-period cross-over study was carried out to evaluate the pharmacokinetics of these two preparations in Beagle dogs. The drug concentration in plasma was determined by LC-MS/MS and the main pharmacokinetic parameters were calculated by DAS 2.0 software. The results showed that there were no significant differences in tmax, cmax and AUC0→t between the self-made and reference preparations (P>0.05). The relative bioavailability of self-made rosuvastatin calcium tablets was (106.00±12.88)%.