以质量源于设计为基础的盐酸二甲双胍缓解片的研究

发布时间：2019-01-27 15:06

【摘要】：目的：本文以质量源于设计（Quality by Design，QbD）理念为基础，进行盐酸二甲双胍缓释片的开发，要求制备的二甲双胍缓释片和指定的参比制剂释放曲线相似，并具有良好的稳定性。旨在探讨QbD在药物开发中的实际应用，同时建立二甲双胍缓释片的制备技术，为深度开发二甲双胍制剂提供技术储备。方法：（1）首先确认了产品的质量目标（Quality Target Product Profile，QTPP），在此基础上，从用药的安全性和有效性出发，分析、确认产品的关键质量属性（CriticalQuality Attributes，CQAs），对本课题而言，我们关注的CQAs是盐酸二甲双胍的释放度和含量。（2）利用风险评估的方法，结合CQAs，分析、拟定处方筛选中的高风险因素，通过一项含有3个中心点的22全因子实验设计（DOE），确认关键物料属性（CMAs）对CQAs的影响程度并制定控制策略，通过严格控制物料配比，使物料因素可能导致的风险降低。（3）利用风险评估的方法，结合CQAs，分析、拟定了工艺开发中的高风险因素，通过一项含有3个中心点的24-1部分因子实验，确认关键工艺参数（CPPs），同时获取关键工艺参数控制的设计空间，制定合适的控制空间，，将风险降低至可接受水平。（4）建立了盐酸二甲双胍缓释片的释放度检测方法，以相似因子评价法比较制备的二甲双胍缓释片和参比制剂的释放曲线相似性。（5）进行了稳定性试验，包括影响因素试验、加速试验、长期试验。（6）研究了制备的二甲双胍缓释片释放机制。结论：（1）处方筛选实验表明，壳聚糖和羟丙基甲基纤维素（HPMC）的比例是影响释放度的关键因素，当壳聚糖用量占壳聚糖和HPMC总量的5%时，可获取最佳的相似因子f2，因此确定了最终处方。（2）工艺研究实验表明，制粒搅拌桨转速、制粒时间以及片剂硬度是对释放度产生显著影响的关键工艺参数。在此基础上，我们获得了关键工艺参数的设计空间，并在此基础上设置了控制空间：搅拌桨速度260-440rpm，制粒时间120-360s，片剂硬度90-118N。（3）在既定处方、工艺条件下生产的二甲双胍缓释片与参比制剂的释放曲线具有较好的相似性。（4）既定的处方、工艺条件下制备的二甲双胍缓释片具有良好的稳定性，加速和长期条件下6个月，药物含量和释放度没有显著变化。（5）本实验制备的二甲双胍缓释片药物释放机制为Fick’s扩散。结果：开发的盐酸二甲双胍缓释片与参比制剂具有较好的释放一致性，能够达到预期的目标，试验中所获取的方程模型和制定的控制空间能够较好地预测和控制产品质量，表明以质量源于设计（QbD）理念为基础进行的药物开发，能够高效地获得预期结果，通过建立合理的控制空间来控制关键因素，能够提高工艺的灵活性和稳健性，保证稳定的产品质量。
[Abstract]:Aim: to develop metformin hydrochloride sustained-release tablets based on the concept of (Quality by Design,QbD. The release curve of metformin sustained-release tablets is similar to that of reference tablets and has good stability. To explore the practical application of QbD in drug development and to establish the preparation technology of metformin sustained-release tablets to provide technical reserve for the further development of metformin preparation. Methods: (1) the product quality target (Quality Target Product Profile,QTPP) was first confirmed. On this basis, the key quality attributes (CriticalQuality Attributes,CQAs) of the product were analyzed and confirmed from the safety and effectiveness of the drug. The CQAs we are concerned with is the release and content of metformin hydrochloride. (2) using the method of risk assessment and CQAs, analysis, we develop the high risk factors for prescription screening. Through a 22-factor experimental design with three center points, (DOE), is used to confirm the influence of (CMAs) on CQAs, and the control strategy is worked out, and the material ratio is strictly controlled. (3) using the method of risk assessment and CQAs, analysis, the high risk factors in process development are drawn up, and a 24-1 partial factor experiment with three central points is carried out. Confirm that the key process parameter (CPPs), simultaneously obtain the design space of the key process parameter control, make the appropriate control space, reduce the risk to the acceptable level. (4) establish the release rate detection method of metformin hydrochloride sustained-release tablets, The similarity of release curves between metformin sustained-release tablets and reference preparations was compared by similarity factor evaluation method. (5) Stability tests, including influence factor test, accelerated test, were carried out. (6) the release mechanism of metformin sustained-release tablets was studied. Conclusion: (1) the ratio of chitosan to hydroxypropyl methyl cellulose (HPMC) is the key factor affecting the release rate. The best similarity factor f _ 2 can be obtained when the amount of chitosan accounts for 5% of the total amount of chitosan and HPMC. Therefore, the final formulation was determined. (2) the experimental results showed that the speed of the agitator, the time of pelleting and the hardness of the tablet were the key technological parameters which had a significant effect on the release rate. On this basis, we obtained the design space of the key process parameters, and on this basis set up the control space: the speed of impeller 260-440 rpm, the granulation time 120-360s, the tablet hardness 90-118N. (3) in the prescribed prescription, The release curve of metformin sustained-release tablets was similar to that of reference preparations. (4) the prepared metformin sustained-release tablets had good stability. The drug content and release rate did not change significantly at 6 months after accelerated and long-term conditions. (5) the drug release mechanism of metformin sustained-release tablets prepared in this study was Fick's diffusion. Results: the developed metformin sustained-release tablets had good release consistency with the reference preparation and could achieve the expected goal. The equation model and control space obtained in the experiment could predict and control the quality of the product. The results show that the drug development based on the concept of (QbD) design can effectively obtain the expected results, control the key factors by establishing a reasonable control space, and improve the flexibility and robustness of the process. Ensure stable product quality.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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