甲磺酸哌啶醇黄芩素的稳定性研究

发布时间：2018-04-19 02:18

  本文选题：甲磺酸哌啶醇黄芩素 + 稳定性　； 参考：《大连理工大学》2014年硕士论文

【摘要】：黄芩为传统中药材,主要有效成分为黄芩苷,其水解产物黄芩素(BA)活性更强。BA是一种天然黄酮类选择性CDK1抑制剂。但存在溶解度差、生物利用度低、血药浓度较低等问题,直接使用远达不到临床治疗癌症和艾滋病的要求。因此,BA的结构修饰引起人们的广泛关注。最有成效为黄芩素Mannich碱衍生物。本课题组以BA为先导化合物经Mannich反应得到了一种新型结构的CDK1抑制剂甲磺酸哌啶醇黄芩素(BA-j),相比于先导化合物BA,其具有更好的选择性诱导肿瘤细胞和被激活的淋巴细胞凋亡的作用。 本文对BA-j稳定性进行了实验研究。采用液相色谱与多级质谱联用(LC-MS/MS)方法,在BA-j水溶液中分离鉴定出8种BA-j氧化降解物,7个为新化合物。BA-j水溶液在光照下首先被氧化成水溶性8-羟甲基氧化黄芩素(M298),M298不稳定,进一步聚合成水不溶性8,8’-亚甲基双黄芩素(M552)。分离得到M552进行了波谱结构表征。氧化降解物中主要成分为M298、其次为M552,以及少量BA和双黄芩素等。BA-j水溶液在室温下可被Fe3+完全氧化降解为M298,提示在药物制剂生产过程中注意水分和不锈钢设备的影响。 采用HPLC-UV法建立了氧化降解物M298和M552的测定方法,并对其进行了实验验证。在1.25-20μg/ml范围内,BA-j, M298,M552回归方程分别为y=233619x+19454(R2=0.9997, n=6), y=133164x+2026.2(R2=0.9998, n=5), y=241023x-23460(R2=0.9998, n=5),线性关系良好；相对BA-j校正因子M298和M552分别为1.75和0.97；精密度RSD%分别为2.32%(n=6),4.32%(n=6),符合规定(5.0%)；定量限分别为0.24μg/ml和0.34μg/ml。在避光操作下,该方法选择性良好,准确度、重复性、耐用性均符合测定要求,可用于BA-j氧化降解物限量检查。 对BA-j进行了稳定性影响因素、加速试验及长期稳定性试验。试验结果表明BA-j原料稳定性良好。采用HPLC-UV法对BA-j进行了临床条件下的药品稳定性试验。BA-j水溶液光照后可产生降解物M552黄色沉淀,提示本品不适宜制备成注射液。BA-j原料药稳定,溶解性能良好,可制备成注射用粉针剂。用氯化钠葡萄糖注射液溶解BA-j稀释后4h内稳定性良好。用复方氯化钠注射液溶解稀释4h后出现降解物M552黄色沉淀。提示BA-j注射用粉针剂不能用复方氯化钠注射液稀释后静脉点滴给药。BA-j在模拟人工胃液和肠液中4h内稳定。提示BA-j可制成口服给药剂型。上述研究结果为进一步药剂学研究提供了依据。
[Abstract]:Scutellaria baicalensis is a traditional Chinese medicine and its main active component is baicalin. The hydrolysate baicalin has stronger activity. BA is a natural flavonoid selective CDK1 inhibitor.However, there are some problems such as poor solubility, low bioavailability and low blood drug concentration, which can not meet the requirements of clinical treatment of cancer and AIDS.Therefore, the structural modification of BA has attracted wide attention.The most effective is baicalin Mannich base derivative.A new type of CDK1 inhibitor, baicalein mesylate, was synthesized by Mannich reaction with BA as the lead compound. Compared with the lead compound BA, it has better selectivity in inducing tumor cells and activated lymphoid.The role of apoptosis in human paracellular apoptosis.In this paper, the stability of BA-j is studied experimentally.By means of liquid chromatography and multistage mass spectrometry, eight kinds of BA-j oxidative degradation compounds were isolated and identified from BA-j aqueous solution. Seven new compounds. BA-j aqueous solution was first oxidized to water-soluble 8-hydroxymethyl baicalin oxide M298M298 under light irradiation.Further polymerization was carried out to form water insoluble 8o 8U-methylene bis-baicalein M 552.The spectral structure of M 552 was characterized.The main component of oxidation degradation is M298, followed by M552, and a small amount of BA and dibaicalein can be completely oxidized to M298 by Fe3 at room temperature, indicating that attention should be paid to the effects of water and stainless steel equipment in the production of pharmaceutical preparations.An HPLC-UV method was established for the determination of M298 and M552, and the results were verified by experiments.鍦，

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