石菖蒲挥发油自纳米乳滴丸的制备及其对急性心肌缺血损伤的保护作用研究
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摘要
该研究采用固体分散技术制备石菖蒲挥发油自纳米乳滴丸(VOA-SNEDDS-DP),并评价其对急性心肌缺血损伤的保护作用。以滴丸外观、丸重差异、溶散时限为评价指标,通过正交试验优化VOA-SNEDDS-DP制备工艺及处方,并考察其体外释放情况;采用ip盐酸异丙肾上腺素的方法建立大鼠急性心肌缺血模型,观察VOA-SNEDDS-DP对大鼠血清中超氧化物歧化酶(SOD)、丙二醛(MDA)、肌酸激酶(CK)水平及心肌组织的病理变化的影响。结果显示,VOA-SNEDDS-DP最佳处方及制备工艺为PEG6000-PEG8000为1∶1,VOA-SNEDDS与基质比例为1∶2.5,药液温度为75℃,滴速为35滴/min,滴距为5 cm,冷凝剂温度2～10℃;制得滴丸中β-细辛醚质量分数为42.46 mg·g~(-1);滴丸在10 min内累积溶出率达到93.85%。药效实验结果显示,VOA-SNEDDS-DP可显著增加血清中SOD含量,减少MDA和CK水平(P<0.05),有效改善心肌组织的病理组织形态。结果证明采用固体分散技术制备VOA-SNEDDS-DP工艺稳定、可行,VOA-SNEDDS-DP对急性心肌缺血损伤有一定的保护作用。
In this study, solid dispersion technology was used to develop volatile oil from Acorus tatarinowii self-nanoemulsion dropping pills(VOA-SNEDDS-DP) and its protective effect on acute myocardial ischemia injury was evaluated. Taking exterior quality, weight variation and the resolving time as comprehendsive evaluation indexes, the preparation process and formulation of the dropping pills were optimized by orthogonal design, and the dissolution rate in vitro of the optimized VOA-SNEDDS-DP was investigated. The rat model of acute myocardial ischemia was induced by intraperitoneal injection of isoproterenol hydrochloride and the serum levels of superoxide dismutase(SOD), malondialdehyde(MDA), creatine kinase(CK) and pathological changes of myocardial tissue were determined to evaluate therapeutic effect of the dropping pills on acute myocardial ischemia. The results showed that the optimal formulation and preparation process of VOA-SNEDDS-DP were as follows: PEG6000-PEG8000 was 1∶1, proportion of VOA-SNEDDS and matrix was l∶2.5, the temperature of drug fluids was 75 ℃, drop rate was 35 drops/min, drop distance was 5 cm, the condensing agent temperature was 2-10 ℃. The content of β-asarone in the dropping pills was 42.46 mg·g~(-1). The accumulated dissolution rate of the dropping pills reached 93.85% in 10 min. The results of pharmacodynamic experiments showed that VOA-SNEDDS-DP could significantly increase the SOD content(P<0.05), reduce the levels of MDA and CK(P<0.05) in serum, and effectively improve the pathological morphology of myocardial tissue. These results revealed that the preparation of VOA-SNEDDS-DP by solid dispersion technology was stable and feasible, and VOA-SNEDDS-DP had protective effect on acute myocardial ischemia injury.
In this study, solid dispersion technology was used to develop volatile oil from Acorus tatarinowii self-nanoemulsion dropping pills(VOA-SNEDDS-DP) and its protective effect on acute myocardial ischemia injury was evaluated. Taking exterior quality, weight variation and the resolving time as comprehendsive evaluation indexes, the preparation process and formulation of the dropping pills were optimized by orthogonal design, and the dissolution rate in vitro of the optimized VOA-SNEDDS-DP was investigated. The rat model of acute myocardial ischemia was induced by intraperitoneal injection of isoproterenol hydrochloride and the serum levels of superoxide dismutase(SOD), malondialdehyde(MDA), creatine kinase(CK) and pathological changes of myocardial tissue were determined to evaluate therapeutic effect of the dropping pills on acute myocardial ischemia. The results showed that the optimal formulation and preparation process of VOA-SNEDDS-DP were as follows: PEG6000-PEG8000 was 1∶1, proportion of VOA-SNEDDS and matrix was l∶2.5, the temperature of drug fluids was 75 ℃, drop rate was 35 drops/min, drop distance was 5 cm, the condensing agent temperature was 2-10 ℃. The content of β-asarone in the dropping pills was 42.46 mg·g~(-1). The accumulated dissolution rate of the dropping pills reached 93.85% in 10 min. The results of pharmacodynamic experiments showed that VOA-SNEDDS-DP could significantly increase the SOD content(P<0.05), reduce the levels of MDA and CK(P<0.05) in serum, and effectively improve the pathological morphology of myocardial tissue. These results revealed that the preparation of VOA-SNEDDS-DP by solid dispersion technology was stable and feasible, and VOA-SNEDDS-DP had protective effect on acute myocardial ischemia injury.
引文
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[12] 郁丹红, 贾晓斌, 宋捷, 等. 药效学筛选表征丹参二萜醌组分整体性质的代表性成分的研究[J]. 中国中药杂志, 2013, 38(12): 1851.
[13] 董林娟, 张文娟, 刘诗雨, 等. 龙脉宁方中葛根素在心肌缺血大鼠体内药动学-药效学相关性研究[J]. 中国中药杂志, 2016, 41(8): 1535.
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[15] 孙娟娟, 张靖, 郭清清, 等. 固体自微乳载体、固体化方法及稳定性研究进展[J]. 中国医院药学杂志, 2017, 37(16): 1645.
[16] 荣立新, 鲁爽, 张保献. 中药滴丸剂研究概况[J]. 中国实验方剂学杂志, 2013, 19(20): 325.
[17] Kim D W, Kwon M S, Yousaf A M, et al. Comparison of a solid SMEDDS and solid dispersion for enhanced stability and bioavailability of clopidogrel napadisilate[J]. Carbohyd Polym, 2014, 114: 365.
[18] 严蓓, 阿基业, 郝海平, 等. 基于血浆和心肌内小分子的代谢组学方法评价心肌缺血大鼠模型[J]. 药学学报, 2013, 48(1): 104.
[2] 吴启端, 陈小露. 石菖蒲挥发油的药效指纹图谱研究[J]. 中药新药与临床药理, 2017, 28(2): 211.
[3] 陈小露. 石菖蒲挥发油谱效关系的初步研究[D]. 广州:广州中医药大学,2015.
[4] 吴启端. 谱效研究结合偏最小二乘法在石菖蒲挥发油有效成分筛选中的应用[J]. 中药新药与临床药理, 2018, 29(4): 497.
[5] 吴启端, 吴清和, 王绮雯, 等. 石菖蒲挥发油及β-细辛醚的抗血栓作用[J]. 中药新药与临床药理, 2008, 19(1): 29.
[6] 吴启端. 石菖蒲挥发油及β-细辛醚防治急性心肌梗死的药效学研究及机理探讨[D]. 广州: 广州中医药大学, 2006.
[7] 钟芮娜, 汪小涵, 王欣桐, 等. 石菖蒲挥发油自纳米乳的制备与质量评价[J].中国中药杂志, 2018, 43(20): 4062.
[8] 刘翠, 张雁翎, 黄华, 等. 度他雄胺固体自微乳给药系统的制备及评价[J]. 中国新药杂志, 2015, 24(3): 344.
[9] 郑娟, 李娟娟, 程玲, 等. 肝能滴丸纳米混悬剂的制备[J]. 中成药, 2016, 38(9): 1918.
[10] 宋凤兰, 潘育方, 侯冬枝, 等. 葛根总黄酮滴丸的制备与溶出度研究[J]. 中草药, 2014, 45(9): 1252.
[11] 冷雪,臧安缘,李其芳.人参皂苷Rg1通过PI3K/Akt/eNOS信号通路调控异丙肾上腺素致急性心肌缺血大鼠心肌的抗氧化作用[J].中国实验方剂学杂志,2017,23(11):145.
[12] 郁丹红, 贾晓斌, 宋捷, 等. 药效学筛选表征丹参二萜醌组分整体性质的代表性成分的研究[J]. 中国中药杂志, 2013, 38(12): 1851.
[13] 董林娟, 张文娟, 刘诗雨, 等. 龙脉宁方中葛根素在心肌缺血大鼠体内药动学-药效学相关性研究[J]. 中国中药杂志, 2016, 41(8): 1535.
[14] Dening T J, Rao S, Thomas N, et al. Novel nanostructured solid materials for modulating oral drug delivery from solid-state lipid-based drug delivery systems[J]. AAPS J, 2016, 18(1): 23.
[15] 孙娟娟, 张靖, 郭清清, 等. 固体自微乳载体、固体化方法及稳定性研究进展[J]. 中国医院药学杂志, 2017, 37(16): 1645.
[16] 荣立新, 鲁爽, 张保献. 中药滴丸剂研究概况[J]. 中国实验方剂学杂志, 2013, 19(20): 325.
[17] Kim D W, Kwon M S, Yousaf A M, et al. Comparison of a solid SMEDDS and solid dispersion for enhanced stability and bioavailability of clopidogrel napadisilate[J]. Carbohyd Polym, 2014, 114: 365.
[18] 严蓓, 阿基业, 郝海平, 等. 基于血浆和心肌内小分子的代谢组学方法评价心肌缺血大鼠模型[J]. 药学学报, 2013, 48(1): 104.
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