目的: 基于“理化性质-主要成分含量-指纹图谱相似度-类过敏反应”的序贯分析策略,评价丹红注射液与临床常用输液溶媒0.9%氯化钠注射液和5%葡萄糖注射液在不同配伍条件下溶液的稳定性及安全性。方法: 根据临床使用情况,将丹红注射液与0.9%氯化钠注射液或5%葡萄糖注射液分别按20 mL: 100 mL、30 mL: 100 mL、40 mL: 100 mL和30 mL: 250 mL、40 mL: 250 mL的比例进行配伍,在室温条件下10 h内,分别观察和检测各溶液在配伍后不同时间点的性状、渗透压、不溶性微粒和pH;测定溶液在配伍后不同时间点的各主要成分含量;计算配伍后不同时间点各溶液HPLC指纹图谱和1H NMR指纹图谱的相似度;采用RBL-2H3细胞脱颗粒体外类过敏反应检测体系,评价各配伍溶液的安全性。结果: 配伍10 h内溶液性状、渗透压、不溶性微粒含量、pH无明显变化,主要成分含量无显著差异,HPLC和1H NMR指纹图谱均有良好的相似度,且配伍溶液无明显致RBL-2H3细胞脱颗粒作用。结论: 本研究从物理、化学、生物角度综合评价,表明在30 mL:250 mL~40 mL:100 mL浓度范围内,丹红注射液与0.9%氯化钠注射液或5%葡萄糖注射液在配伍10 h内溶液均有良好的稳定性和安全性,可为临床使用提供参考。
Objective: Based on a sequential analysis method of “physicochemical properties-main component content-fingerprint similarity-anaphylactoid reaction”, the stability and safety of Danhong injection with commonly used clinical solvents 0.9% sodium chloride and 5% glucose injections were evaluated. Methods: According to the clinical application, Danhong injection was mixed with 0.9% sodium chloride injection or 5% glucose injection in the ratios of 20 mL: 100 mL, 30 mL: 100 mL, 40 mL: 100 mL and 30 mL: 250 mL, 40 mL: 250 mL, respectively. Then, they were placed at room temperature within 10 h. The properties, osmotic pressure, insoluble particles and pH value in the solutions were observed or measured at different time points. The contents of the main components at different time points were determined. The HPLC and 1H NMR fingerprints at different time points were analyzed by similarity evaluation. The in vitro anaphylactoid reaction assay of RBL-2H3 cell degranulation was used to evaluate the safety of the mixture solutions. Results: The properties, osmotic pressure, insoluble particles and pH value of solutions were stable within 10 h after mixing, and there was no significant difference in the contents of the main components. The HPLC and 1H NMR fingerprints showed good similarity, and the mixture solutions didn't induce obvious degranulation in RBL-2H3 cells. Conclusion: In this study, the comprehensive evaluation from the physical, chemical and biological perspectives showed that in the concentration range of 30 mL: 250-40 mL: 100 mL, Danhong injection combined with 0.9% sodium chloride injection or 5% glucose injection had good stability and safety within 10 h, which provides evidences for the clinical practice.
[1] 王秋婷, 苗秋丽, 张杰, 等. 不同溶媒对中药注射剂稳定性和安全性的影响[J]. 中成药, 2019, 41(1): 233
WANG QT, MIAO QL, ZHANG J, et al. Effects of different solvents on stability and safety of traditional Chinese medicine injectio [J]. Chin Tradit Pat Med, 2019, 41(1): 233
[2] 魏戌, 谢雁鸣. 中药注射剂不良反应的影响因素与发生机制分析[J]. 中国中药杂志, 2012, 37(18): 2748
WEI X, XIE YM. Influencing factor and mechanism analysis of adverse drug reaction in traditional Chinese medicine injection [J]. China J Chin Mater Med, 2012, 37(18): 2748
[3] 石浩强, 许倍铭, 葛覃. 从溶媒的选择谈安全使用中药注射剂[J]. 中国药房, 2012, 23(43): 4125
SHI HQ, XU BM, GE Q. Discussion on safe use of TCM injection from the choice of menstruum [J]. China Pharm, 2012, 23(43): 4125
[4] 李瑞吉, 王婷婷, 刘金辉, 等. 丹红注射液在体外抑制血小板聚集的生物活性测定法研究[J]. 药物分析杂志, 2022, 42(10): 1763
LI RJ, WANG TT, LIU JH, et al. Research on bioassay method of Danhong injection in inhibiting platelet aggregation in vitro [J]. Chin J Pharm Anal, 2022, 42(10): 1763
[5] XU LL, SHANG ZP, BO T, et al. Rapid quantitation and identification of the chemical constituents in Danhong injection by liquid chromatography coupled with orbitrap mass spectrometry[J]. J Chromatogr A, 2019, 1606: 460378
[6] 中华人民共和国药典2020年版. 四部[S]. 2020
ChP 2020. Vol Ⅳ [S]. 2020
[7] 那坤, 武亮, 李滢, 等. 舒血宁注射液、丹红注射液、丹参酮ⅡA磺酸钠注射液治疗冠心病不稳定性心绞痛的临床疗效分析研究[J]. 中国中医基础医学杂志, 2015, 21(10): 1268
NA K, WU L, LI Y, et al. Clinical curative effect analysis of Shuxuening injection, Danhong injection, tanshinone ⅡA sulfonic acid sodium injection in the treatment of coronary heart disease unstable angina [J]. J Basic Chin Med, 2015, 21(10): 1268
[8] ZHANG GX, ZHANG YY, ZHANG XX, et al. Different network pharmacology mechanisms of Danshen-based Fangjis in the treatment of stable angina[J]. Acta Pharmacol Sin, 2018, 39(6): 952
[9] FENG X, LI Y, WANG Y, et al. Danhong injection in cardiovascular and cerebrovascular diseases: pharmacological actions, molecular mechanisms, and therapeutic potential[J]. Pharmacol Res, 2019, 139: 62
[10] 张宇航, 杨静, 吴宿慧, 等. 基于抗凝血活性的丹红注射液生物效价测定方法的建立[J]. 中草药, 2022, 53(8): 2348
ZHANG YH, YANG J, WU SH, et al. Quality evaluation of Danhong injection based on anticoagulant biological potency [J]. Chin Tradit Herb Drugs, 2022, 53(8): 2348
[11] 童彤, 徐光宏, 丁海文, 等. 5种输液调配的注射用尖吻蝮蛇血凝酶成品输液稳定性研究[J]. 中国医院药学杂志, 2023, 43(5): 515
TONG T, XU GH, DING HW, et al. Compatibility stability of Hemocoagulase agkistrodon for injection with 5 infusion solutions [J]. Chin J Hosp Pharm, 2023, 43(5): 515
[12] 徐帆, 梁晓方, 苏莉, 等. 注射剂配伍稳定性研究方法学分析与评价[J]. 中国医院药学杂志, 2009, 29(10):840
XU F, LIANG XF, SU L, et al. Analysis and evaluation of methodology for the stability of injection compatibility [J]. Chin J Hosp Pharm, 2009, 29(10):840
[13] 张弘弛, 刘瑞, 巴德方, 等. 恒山黄芪1H-NMR指纹图谱的研究[J]. 食品工业科技, 2022, 43(1): 47
ZHANG HC, LIU R, BA DF, et al. 1H-NMR fingerprint of Hengshan Astragalus membranaceus [J]. Sci Technol Food Ind, 2022, 43(1): 47
[14] 李学林, 唐进法, 孟菲, 等. 10409例丹红注射液上市后安全性医院集中监测研究[J]. 中国中药杂志, 2011, 36(20): 2783
LI XL, TANG JF, MENG F, et al. Study on 10409 cases of post-marketing safety Danhong injection centralized monitoring of hospital [J]. China J Chin Mater Med, 2011, 36(20): 2783
[15] 周大铮, 肖辉, 万梅绪, 等. RBL-2H3细胞脱颗粒模型评价注射用丹参多酚酸的安全性[J]. 药物评价研究, 2021, 44(11): 2403
ZHOU DZ, XIAO H, WAN MX, et al. Evaluate safety of Salvianolic Acid for Injection with RBL-2H3 cell degranulation model [J]. Drug Eval Res, 2021, 44(11): 2403
