药学学报, 2019, 54(4): 737-745
引用本文:
黄浩洲, 林俊芝, 魏夕川, 马鸿雁, 刘海燕, 樊三虎, 邹文铨, 韩丽, 张定堃. 中药口服液中鞣花酸分子稳定储存的制剂学机制与调控策略[J]. 药学学报, 2019, 54(4): 737-745.
HUANG Hao-zhou, LIN Jun-zhi, WEI Xi-chuan, MA Hong-yan, LIU Hai-yan, FAN San-hu, ZOU Wen-quan, HAN Li, ZHANG Ding-kun. Pharmaceutical mechanism and control strategy for storage of ellagic acid stably in traditional Chinese medicine oral liquid[J]. Acta Pharmaceutica Sinica, 2019, 54(4): 737-745.

中药口服液中鞣花酸分子稳定储存的制剂学机制与调控策略
黄浩洲1, 林俊芝2, 魏夕川1, 马鸿雁1, 刘海燕3,4, 樊三虎3,4, 邹文铨5, 韩丽1, 张定堃1
1. 成都中医药大学药学院, 中药资源系统研究与开发利用省部共建国家重点实验室培育基地, 四川 成都 611137;
2. 成都中医药大学附属医院中心实验室, 四川 成都 610072;
3. 成都市三勒浆药业集团, 四川 成都 610000;
4. 乳品营养与功能四川省重点实验室, 四川 成都 610000;
5. 四川大学化学学院, 四川 成都 610064
摘要:
鞣花酸普遍存在于植物中,被认为是具有开发潜力的抗氧化与抗肿瘤候选药物。但鞣花酸极易沉淀,如何提高其生物利用度一直是制药行业关注的问题。本课题组偶然发现,三勒浆口服液在低温条件下储存稳定性非常优异,鞣花酸呈现"低温易溶"的反常现象。为揭示其科学原理,讨论相应的调控策略,本文将该口服液分别在高、中和低3种温度下储存3个月,采用沉淀量、上清液-沉淀HPLC化学轮廓、沉淀形貌和物理相态综合表征等分析方法系统追踪调查存放过程中口服液成分与相态的变化规律。结果显示,低温下的沉淀量仅为室温1/3,温度升高,沉淀量急剧增加。上清液-沉淀物HPLC分析发现鞣花酸沉淀来源于化学降解与物理沉降两条途径。化学降解与诃黎勒酸、柯里拉京等水解鞣质酸性条件下水解产生鞣花酸有关。物理沉降与升温后多酚胶体缔合度与黏度降低有关。该研究阐释了中药液体制剂中鞣花酸稳定机制,为含鞣花酸制剂的高效利用及澄清度改善提供了理论依据。
关键词:    鞣花酸      中药      口服液      澄清度      胶体      化学沉淀     
Pharmaceutical mechanism and control strategy for storage of ellagic acid stably in traditional Chinese medicine oral liquid
HUANG Hao-zhou1, LIN Jun-zhi2, WEI Xi-chuan1, MA Hong-yan1, LIU Hai-yan3,4, FAN San-hu3,4, ZOU Wen-quan5, HAN Li1, ZHANG Ding-kun1
1. Key Laboratory Breeding Base of Systematic Research and Utilization on Chinese Material Medical Resources Co-founded by Sichuan Province and Ministry of Science and Technology, Pharmacy College, Chengdu University of TCM, Chengdu 611137, China;
2. Central Laboratory, Teaching Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China;
3. Sanajon Pharmaceutical Group, Chengdu 610000, China;
4. Sichuan Key Laboratory of Nutrition and Function of Dairy, Chengdu 610000, China;
5. College of Chemistry, Sichuan University, Chengdu 610064, China
Abstract:
Ellagic acid is ubiquitous in plants and is considered as a potential candidate for antioxidant and antineoplastic drugs. However, ellagic acid has poor solubility and precipitates easily even after initial solubilization. Improvement of its bioavailability has been a concern of pharmaceutical industry. It was found that storage in Sanlejiang oral liquid at low temperature keeps its stability. Ellagic acid is anomalous in a way that is easily soluble at low temperatures but precipitates at high temperatures. In order to reveal the mechanism of this phenomenon and develop precipitation prevention and control strategies, ellagic acid in Sanlejiang oral liquid was stored at high, medium and low temperatures for three months. The changes of composition and phase state of the whole system during storage were systematically tracked and studied by means of precipitation amount or morphology, HPLC chemical profile of supernatant versus precipitates, and comprehensive characterization of physical phase state. The results show that the amount of precipitation at low temperature is only 1/3 of that at normal room temperature. As the temperature rises, the sedimentation increases sharply. HPLC analyses of supernatant versus precipitates revealed that ellagic acid precipitation originated from two ways:chemical degradation and physical deposition. The chemical sedimentation is related to the hydrolysis of tannins under acidic condition, forming chebulagic acid and corilagin. Physical sedimentation is related to the decrease of the association degree and viscosity of polyphenol colloids when temperature rises. This study elucidated the stability mechanism of ellagic acid in liquid preparations of TCM, and provided the mechanistic basis for efficient utilization and solution prepartion of ellagic acid.
Key words:    ellagic acid    traditional Chinese medicine    oral liquid    clarity    colloid    chemical precipitation   
收稿日期: 2018-12-20
DOI: 10.16438/j.0513-4870.2018-1131
基金项目: 中国博士后基金面上项目(2017M623308XB);成都中医药大学科技发展基金资助项目(ZRQN1775,ZRYY1717);成都中医药大学中药学学科特色创新科研团队(CXTD2018006);成都中医药大学"杏林学者"学科人才科研提升计划(QNXZ2018003).
通讯作者: 韩丽, 张定堃
Email: 465790643@qq.com;hanliyx@163.com
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