【作者】 陈斌；

【导师】 段更利； 严伟民；

【作者基本信息】 复旦大学 ， 药物分析学， 2010， 硕士

【摘要】 药品质量控制和稳定性研究是药物临床前研究的一个重要内容。药品质量标准研究过程中,需要对药品的质量做一个全面的检查,保证药品质量的安全和可靠,保证临床前研究和临床研究的顺利进行,以至药品上市后的用药安全。药品的贮藏条件,例如：是否需要避光,是否需要低温贮藏等；药品在一定条件下贮藏多长时间仍有效,即药品的有效期等内容都是通过药品稳定性研究来确定的。本文在中国药典和国家有关药品质量研究的技术规定的指导下,对创新药物SM934的质量标准和稳定性进行了系统的研究,初步建立了SM934的质量标准(草案)。论文分为以下五部分：1、SM934结构确证本部分论文通过元素分析、紫外光谱、红外光谱、核磁共振(13C、1H)和质谱,对SM934进行结构确证,确证结构正确,为质量标准和稳定性研究提供可靠的原料。2、SM934质量控制研究本部分论文根据中国药典和有关新药质量标准研究的技术规范对SM934进行质量标准研究。建立了SM934质量标准研究方法和内容,根据SM934的结构和性质,选择合适的方法对其进行质量控制。进行了溶解度、熔点、比旋度、鉴别、无机杂质检查、水分、吸湿增重、炽灼残渣等项目的研究,确定相应项目的检测方法和结果。检测结果符合药典的有关规定。首次建立了SM934的有机溶剂残留的检查方法、有关物质检查的方法和含量测定的方法,分别进行方法学的验证,并将其用于SM934的相关内容的测定。SM934样品经质量控制研究,有机溶剂残留检查中,二氯甲烷和DMF未检出,甲醇、乙醇、石油醚和乙酸乙酯的残留量符合药典规定。有关物质检查结果在0.2-0.5%之间,并对主要有关物质的可能结构进行推测。非水滴定和高效液相色谱法测定SM934的含量,均大于99%。结果符合国家有关原料药质量标准的规定。3、SM934稳定性研究本部分论文根据药物稳定性试验指导原则,对SM934进行稳定性研究。分别进行影响因素试验、加速试验和长期试验。对稳定性样品的性状、主成分含量和有关物质含量进行分析。通过试验发现,SM934对强光、高温和高湿都比较敏感。SM934经过在40℃,湿度75%条件下的加速试验后,性状发生明显变化,有关物质从0.2%增加到3.5%,主成分含量从99.4%减少到94.5%。经过30℃,湿度65%的加速试验,性状未发生变化,有关物质增加到0.8%,含量在98.5%。经过25℃,湿度60%的长期试验后,有关物质增加到0.4%,主成分含量为99.0%。SM934的有效期以长期试验结果为准,目前样品保存的时间为15个月,已经有3、6、9、12个月的数据。对长期试验的结果进行有效期进行统计学分析后,SM934的主成分含量达到98.5%时,保存时间为22.5个月,即SM934原料药主成分含量达到98.5%时的有效期可以暂定为两年,具体的有效期以长期试验测定结果为准。根据稳定研究结果,SM934需在干燥、凉暗处保存。4、SM934质量标准草案及起草说明根据前两章的研究内容,起草并制订SM934质量标准草案及起草说明,为SM934的质量控制提供规范和依据。5、SM934体内HPLC分析方法的初步研究本部分论文初步建立了一种柱前衍生化-HPLC法测定SM934在血浆中浓度的方法,并将其用于测定大鼠的药-时曲线。通过衍生化反应条件的优化选择,选择最佳的反应条件为pH8.0, FMOC-Cl浓度为8mM,反应时间15min。在此条件下,SM934浓度在0.025～0.8μg/ml范围内线性关系良好(r=0.9989)。检测限(S/N=3)为0.01μg/ml。该方法灵敏度高,选择性好,能够快速、简便地测定SM934在血浆中的浓度,且成本较低。该方法能够用于测定大鼠灌胃给药后的药-时曲线,且结果准确、可靠。更多还原

【Abstract】 The study on quality control and stability of drugs is an important content of drug pre-clinical studies. During the study on drug quality standards, it needs to do a thorough check of drug quality to ensure the safety and reliability of drugs, and ensure the smooth progress of pre-clinical research, as well as the safety of post-marketing drugs. Drug storage conditions and validity of drugs are determined by the stability.Based on the study on drug quality standards and stability, the contents and methods of the quality standards and stability of SM934 and the draft quality standards of SM934 were established. The work was divided into the following five parts:1. The structure confirmation of SM934By elemental analysis, UV, IR, NMR (13C,1H) and mass spectrometry for structural confirmation of SM934, reliable raw material for the study on quality standards and stability was provided.2. The quality control of SM934The quality standard of SM934 was investigated according to Chinese Pharmacopoeia and technical specifications of the drug quality standards. According to the structure and property of the SM934, we selected the appropriate method for its quality control. The items of solubility, melting point, rotation, identification, examination of inorganic impurities, moisture, weight of moisture absorption, residue on ignition et al were studied to determine the appropriate test methods and results.The methods of residual organic solvents inspection, the related substances inspection and assay were established for the first time. Verification methodology was conducted, and was used for the determination of relevant contents of SM934.The results indicated that organic solvent residues of SM934 met Chinese Pharmacopoeia requirements. The results of related substances inspection were between 0.2-0.5% and the main structure of the related substances was speculated. The SM934 content determined by nonaqueous titration and high performance liquid chromatography were greater than 99%.3. The stability study of SM934Stability of SM934 was conducted according to the guiding principles of drug stability test. Impact factors test, accelerated test and long-term test were carried out respectively. The sample characteristics, the main component content and related substances content of stability samples were analyzed. It is found that SM934 is sensitive to light, temperature and humidity and should be stored under the condition of low temperature, dark and dry. After the accelerated tests at 40℃, humidity of 75%, sample characteristics of SM934 changed, related substances content increased, and main component content decreased significantly. After the accelerated test at 30℃, humidity of 65% and long-term test at 25℃, humidity of 60%, the related substances content increased to 0.8% and 0.4% and main component content were decreased to 98.5% and 99.0%. For statistical analysis on the validity, if main component content of SM934 becomes 98.5%, the retention time is 22.5 months. So the SM934 is valid for 22.5 months.SM934 should be stored under the condition of room temperature, dark and dry.4. The draft quality standards of SM934 and drafting instructionsThe draft quality standards of SM934 and drafting instructions were formulated and drafted according to the first two chapters of the research content. This chapter provides norms and basis for quality control of SM934.5. The initial study of SM934 in vivoA method of pre-column derivatization-HPLC determination of SM934 concentrations in plasma was initially established and used to determine its concentration-time curve in rats. Through the optimization of derivation conditions, the best reaction conditions pH8.0, FMOC-C1 concentration 8mM, reaction time 15min were selected. Under these conditions, SM934 concentration in the range of 0.025～0.8μg/ml had good linear relationship (r= 0.9989). Detection limit (S/N=3) was 0.01μg/ml. This method was used to determine the concentration-time curve in rats after oral administration of SM934.更多还原