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. doi: 10.16438/j.0513-4870.2018-1131
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. doi: 10.16438/j.0513-4870.2018-1131
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 liquidJ. Acta Pharmaceutica Sinica, 2019,54(4): 737-745. doi: 10.16438/j.0513-4870.2018-1131
Citation: 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 liquidJ. Acta Pharmaceutica Sinica, 2019,54(4): 737-745. doi: 10.16438/j.0513-4870.2018-1131

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

Pharmaceutical mechanism and control strategy for storage of ellagic acid stably in traditional Chinese medicine oral liquid

  • 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。

     

    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.

     

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