孟鲁司特钠片的工艺验证研究及其体内外评价

Process Validation and in vitro-in vivo Evaluation of Montelukast Sodium Tablets

根据质量源于设计的研发思路明确了孟鲁司特钠片的关键质量属性,依据关键质量属性对工艺过程进行风险评估和影响因素分析,并对制备工艺过程中涉及的制剂设备和制剂工艺进行评估和确认。3批验证批次样品含量均大于95%,总杂小于1%,且其他各检验项目均符合质量要求。分别考察了自制片剂与原研制剂(Singulair~?)在0.5%十二烷基硫酸钠水溶液、pH 1.2和pH 6.8介质中的溶出度,结果表明自制片剂与原研制剂的体外溶出行为相似。36名健康志愿者在空腹和餐后状态下单剂量口服自制片剂或原研制剂后,2种制剂在体内的药动学参数无统计学差异(P>0.05)。空腹和餐后状态下,自制片剂的口服相对生物利用度分别为(104.69±10.32)%和(102.60±9.57)%。

According to the concept of quality by design(QbD),the critical quality attributes(CQAs) of montelukast sodium tablets were clarified,then the risk analysis was carried out to confirm the influencing factors of formulation and process.The equipment and preparation process were evaluated and verified.The drug contents of three verification batches were all above 95%,total impurities were below 1%,and other inspection items met the quality requirements.The dissolution behaviors of self-made tablets and reference listed drug(RLD,Singulair~?) in 0.5% sodium dodecyl sulfate solution,pH 1.2 and pH 6.8 media were investigated and compared,and the results showing the similarity between self-made tablets and RLD.There were no statistically significant differences in the pharmacokinetic parameters of 36 healthy volunteers after single oral administration of self-made tablets or RLD under fasting condition or fed condition(P>0.05).Under fasting and fed conditions,the oral relative bioavailabilities of self-made tablets were (104.69±10.32)% and (102.60±9.57)%,respectively.