CN112043746A - 一种具有改善微循环障碍作用的丹参茎叶有效部位及其制备与应用 - Google Patents
一种具有改善微循环障碍作用的丹参茎叶有效部位及其制备与应用 Download PDFInfo
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- CN112043746A CN112043746A CN202010942333.1A CN202010942333A CN112043746A CN 112043746 A CN112043746 A CN 112043746A CN 202010942333 A CN202010942333 A CN 202010942333A CN 112043746 A CN112043746 A CN 112043746A
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- salvia miltiorrhiza
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Abstract
本发明公开了一种具有改善微循环障碍作用的丹参茎叶有效部位及其制备与应用。本发明将丹参废弃地上部分资源开发利用,经优化的提取纯化工艺制备得到有效部位。结果显示:丹参茎叶有效部位可改善微循环障碍引起的血流变参数变化、凝血功能指标变化、微血管密度降低以及降低ET‑1、iNOS、VEGF、P‑Selectin、TXA2、TNF‑α、IL‑1β的表达水平,提高6‑keto‑PGF1α的表达水平。本发明提供的丹参茎叶有效部位具有改善微循环障碍的防治作用,可作为微循环障碍治疗的药品或维护血管功能的保健产品。
Description
技术领域
本发明属于医药技术领域,具体涉及一种具有改善微循环障碍作用的丹参茎叶有效部位及其制备与应用。
背景技术
中药丹参为唇形科鼠尾草属植物丹参Salvia miltiorrhiza Bge.的干燥根及根茎,是最常用的活血化瘀中药之一,始载于《神农本草经》,具有祛瘀止痛、养血安神的功效。研究发现丹参中丹酚酸类和丹参酮类有效成分具有良好的药理活性,如抗炎、抗氧化、抗肿瘤、抗动脉粥样硬化、抗糖尿病等。丹参临床用量较大,国内已大量栽培,其地上茎叶未被有效利用而废弃,造成资源浪费及环境污染,因此对丹参茎叶的有效利用有着重要价值
微循环是连接微循环和细胞的灌注毛细血管网络,是直径小于100μm的血管的集合体,微循环负责向组织输送氧气,交换营养物质和废物,以及调节炎症和凝血。微循环和大循环的不一致性近期得到了承认,目前研究表明恢复大循环不足以恢复微循环和维持器官灌注。研究表明,微循环障碍通过影响局部组织血液灌注以及改变血流阻力,导致局部缺血、缺氧及带来再灌注损伤,进一步导致器官功能损伤甚至衰竭,从而在各疾病的发生发展中发挥重要作用。
发明内容
发明目的:本发明目的是通过开发丹参废弃地上部分的医药用资源价值,研究丹参茎叶的活性成分,深入研究丹参茎叶酚酮有效部位和酚酸有效部位对微循环障碍的改善作用,开发出治疗微循环障碍的药物或保健品,挖掘废弃资源的经济价值。
本发明选择尾静脉注射10%高分子右旋糖酐的Wistar大鼠为实验动物模型,应用丹参茎叶酚酮有效部位和酚酸有效部位进行干预治疗,通过对其血流变参数、凝血参数、各项生化指标及免疫组化染色分析,表明本发明提供的丹参茎叶酚酮有效部位和酚酸有效部位对微循环障碍具有明显的改善作用。
技术方案:本发明采用以下技术方案:
丹参茎叶有效部位在制备治疗微循环障碍的药物或保健品中的应用。
丹参茎叶酚酮有效部位和酚酸有效部位在制备治疗微循环障碍的药物或保健品中的应用。
作为优选方案,以上所述的应用,所述药物剂型为口服给药剂型。
作为更加优选方案,以上所述的应用,所述药物或保健品为片剂、胶囊剂、颗粒剂、口服液。
本发明所述的丹参茎叶酚酮有效部位的制备方法为:取丹参茎叶,按料液比为1:10,60%乙醇回流提取1h,提取3次,合并滤液,减压浓缩至无醇味。以NKA-2型号的大孔树脂纯化,用60%的乙醇洗脱,减压浓缩、冷冻干燥。
本发明提供的丹参茎叶酚酸有效部位的制备方法为:取丹参茎叶,按料液比为1:10,60%乙醇回流提取1h,提取3次,合并滤液,减压浓缩至无醇味。以NKA-2型号的大孔树脂纯化,用60%的乙醇洗脱,减压浓缩,稀释至0.1g/ml,用盐酸调至pH=2后,用两倍量的乙酸乙酯萃取三次,合并乙酸乙酯部分后旋蒸去除乙酸乙酯,冷冻干燥。
本发明所述的丹参茎叶酚酮有效部位中含下列质量百分比有效成分:
20%~30%迷迭香酸,1.5%~3.0%紫草酸,20%~35%丹酚酸B,0.2%~0.5丹酚酸A,1%~3%丹酚酸C,1.5%~2.5%芦丁,1.5%~2.5异槲皮苷,0.5%~1.5%山柰酚3-O-芸香糖苷和0.1%~0.5%紫云英苷。
作为更优选方案,本发明所述的丹参茎叶酚酮有效部位中含下列质量百分比有效成分:
迷迭香酸(21.47%),紫草酸(1.67%),丹酚酸B(23.70%),丹酚酸A(0.29%),丹酚酸C(1.20%),芦丁(1.91%),异槲皮苷(1.77%),山奈酚3-O-芸香糖苷(0.86%)和紫云英苷(0.28%)。
本发明所述的丹参茎叶酚酸有效部位中含有下列质量百分比有效成分:
25%~35%迷迭香酸,1%~3%紫草酸,35%~50%丹酚酸B,0.3%~1.2%丹酚酸A和1%~3%丹酚酸C、0.01~0.05%丹参素,0.01%~0.05%原儿茶醛。
作为更优选方案,本发明所述的丹参茎叶酚酸有效部位中含有下列质量百分比有效成分:
迷迭香酸(27.24%),紫草酸(1.21%),丹酚酸B(37.25%),丹酚酸A(0.45%)和丹酚酸C(1.29%)、丹参素(0.01%),原儿茶醛(0.03%)。
本发明提供的丹参茎叶有效部位可明显改善血流变参数、。
有益效果:
本发明对丹参地上部分资源开发利用,推动废弃部位资源再利用,减少资源浪费和环境污染,开发出治疗微循环障碍的药物或保健品。
本发明制备得到的丹参茎叶有效部位,通过改善血液流变、改善凝血和改善微血管密度减少。改善血管内皮功能和炎症,具有良好的改善微循环障碍作用。
附图说明
图1实施例1制备得到的丹参茎叶提取物超高效液相色谱图(酚酸和酚酮有效部位)
图2丹参茎叶有效部位对微循环障碍大鼠的血液流变学与凝血功能的影响结果。##P<0.01:模型组vs空白组;**p<0.01,*p<0.05:给药组vs模型组
图3丹参茎叶有效部位对微循环障碍大鼠6-keto-PGF1α,TXA2,ET-1,iNOS,P-selectin,VEGF,TNF-α和IL-1β的表达水平的影响。##P<0.01:模型组vs空白组;**p<0.01,*p<0.05:给药组vs模型组
图4胸腺(a)、肺(c)和脑(f)的微血管密度染色结果(400倍)。b,d和f为微血管密度(MVD)。A空白;B模型;C羟苯磺酸钙;D丹参茎叶酚酸有效部位高剂量;E酚酸有效部位低剂量;F丹参茎叶酚酮有效部位高剂量;G酚酮有效部位高剂量。##P<0.01:模型组vs空白组;**p<0.01,*p<0.05:给药组vs模型组。
具体实施方式
根据下述实例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的具体的工艺条件及结果仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1
丹参茎叶酚酮有效部位的制备方法,包括以下步骤:
取100g丹参茎叶的干燥粉末,以体积浓度60%的乙醇对茎叶进行回流提取3次,每次提取时间1h,滤过;丹参茎叶和乙醇的重量体积比为1:10,合并滤液,减压浓缩至无醇味。以NKA-2型号的大孔树脂纯化,用60%的乙醇洗脱,减压浓缩、冷冻干燥既得。采用超高效液相检测,色谱柱:Thermo C18色谱柱(4.6mm×250mm,5μm);流动相:乙腈(A)-0.1%甲酸水(B),梯度洗脱(0~5min,10%A;5~10min,10%~12%A;10~20min,12%~14%A;20~25min,14%~20%A;25~60min,20%~30%A;60~65min,30%~40%A)。流速:1mL·min-1,柱温:30℃,进样量:10μL,检测波长:280nm(丹酚酸类成分)和254nm(黄酮类成分)。结果见图1,结果表明丹参茎叶酚酮有效部位中含的有效成分为:迷迭香酸(21.47%),紫草酸(1.67%),丹酚酸B(23.70%),丹酚酸A(0.29%),丹酚酸C(1.20%),芦丁(1.91%),异槲皮苷(1.77%),山奈酚3-O-芸香糖苷(0.86%)和紫云英苷(0.28%)。
实施例2
丹参茎叶酚酸有效部位的制备方法,包括以下步骤:
取100g丹参茎叶的干燥粉末,以料液比为1:10的60%乙醇回流提取1h,提取3次,合并滤液,减压浓缩至无醇味。以NKA-2型号的大孔树脂纯化,用60%的乙醇洗脱,减压浓缩,稀释至0.1g/ml,用盐酸调至pH=2后,用两倍量的乙酸乙酯萃取三次,合并乙酸乙酯部分后旋蒸去除乙酸乙酯,冷冻干燥。采用超高效液相,色谱柱为ACQUITY UPLC BEH C18(1.7μm,2.1mm×100mm),流动相为0.1%甲酸水(A)-乙腈(B),以0.4mL·min-1的恒定流速进行梯度洗脱,进样体积:2μL,柱温:35℃。洗脱条件为0~1min,95%→95%A;1~3min;95%→90%A;3~7min,90%→85%A;7~11min,85%→79%A;11~15min,79%→67%A;15~17min,67%→30%A;17~18min,30%→20%A;18~20min,20%→20%A;20~21min,20%→95%A);酚酸类成分检测波长为280nm。结果见图1,结果表明丹参茎叶酚酸提取物中含有的有效成分为:丹参素(0.01%),原儿茶醛(0.03%),迷迭香酸(27.24%),紫草酸(1.21%),丹酚酸B(37.25%),丹酚酸A(0.45%)和丹酚酸C(1.29%)。
实施例3改善微循环的药理实验
1.实验方法
采用体重200±20g的雄性Wistar大鼠适应性饲养1周,进行微循环障碍造模,大鼠随机分组给药,每组10只,分别为空白、模型、羟苯磺酸钙阳性对照组(0.1g·kg-1)、实施例2的丹参茎叶酚酸有效部位高剂量组/FSH(200mg·kg-1)、实施例2的丹参茎叶酚酸有效部位低剂量组/FSL(100mg·kg-1)、实施例1的丹参茎叶酚酮有效部位高剂量组/FTH(200mg·kg-1)、实施例1的丹参茎叶酚酮有效部位低剂量组/FTL(100mg·kg-1),空白组每天尾静脉注射生理盐水5mL·(kg·d)-1,模型组、阳性对照组与给药组每日尾静脉注射10%高分子右旋糖苷5mL·(kg·d)-1,造模结束后立即灌胃给药,每次10mL·kg-1,连续灌胃7天。末次给药结束后收集全血、血浆与组织测定血流变参数、凝血参数、生化指标、微血管密度,研究丹参茎叶有效部位对微循环障碍的治疗作用。
2.实验结果
2.1 丹参茎叶有效部位对微循环障碍大鼠血液流变学和凝血功能的影响
本研究中,对1s-1、5s-1、30s-1、200s-1高低剪切速率的WBV、PV、ESR、HCT、凝血四项(APTT、PT、TT、FIB)几项指标进行检测分析。结果如图2所示。与对照组相比,模型组的WBV、PV、ESR、HCT指标明显升高(P<0.01),模型组的APTT、TT、PT明显缩短(P<0.01),FIB显著升高(P<0.01)。这些结果表明,MCDF模型的建立成功。与模型组相比,FSH和FSL组大鼠的WBV指数在低剪切速率(30s-1,5s-1和1s-1)下显著降低(P<0.05,0.01)。与模型组相比,在高剪切速率和低剪切速率下(200s-1,30s-1,5s-1和1s-1)的WBV,FTL组显著降低。FSL、FTH和FTL组的PV均被显著降低(P<0.01)。FSL和FTL组ESR和HCT显著降低(P<0.05,0.01)。数据显示,与对照组相比,模型组APTT、PT、TT明显降低(P<0.05、0.01),FIB明显升高(P<0.05)。FTH组的APTT、PT、TT、FIB(P<0.05、0.01)显著延长。这些结果提示丹参茎叶酚酸和酚酮有效部位可通过降低大鼠红细胞聚集指数、调节异常血液流变学和凝血功能来改善微循环障碍。
2.2 丹参茎叶有效部位对微循环障碍大鼠6-keto-PGF1α,TXA2,ET-1,iNOS,P-selectin,VEGF,TNF-α和IL-1β的表达水平的影响
如图3所示,与对照组相比,模型组TXA2,ET-1,iNOS,P-selectin,VEGF,TNF-α,和IL-1β的表达水平升高,6-keto-PGF1α的表达水平明显降低(P<0.01)。给药后,与模型组相比,FTH组的6-keto-PGF1α水平显著改善(P<0.01),四个给药组中TXA2,P-selectin,TNF-α和IL-1β的表达均显著降低(P<0.05,0.01)。除FSL组外,其余3个给药组的ET-1和iNOS表达均显著降低(P<0.05,0.01),FTH组和FTL组VEGF表达显著降低(P<0.05,0.01)。模型组TXA2/6-keto-PGF1α的值与对照组相比,显著增加(P<0.01),FSL和FTH可显著降低数值(P<0.05,0.01)。以上结果证明,本发明丹参茎叶有效部位可以改善微循环障碍引发的炎症和血管内皮功能障碍。
2.3 MVD分析结果
通过免疫组化法测定胸腺、肺和脑的微血管密度。如图4所示,结果显示微血管经CD34染色后呈褐色。与对照组相比,模型组胸腺、肺和脑的微血管密度显著降低(P<0.01)。实施例1和2给药组显著回调MVD(P<0.01,0.05)。给药组对胸腺、肺和脑的治疗效果优于CD组。这提示着丹参茎叶有效部位具有明显减轻微循环障碍的作用。
以上实验结果表明,本发明提供的丹参茎叶有效部位具有很好的治疗微循环障碍的功效。
上述实施例仅是本发明的优选实施方式,并非是对本发明的实施方式的限定。对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下还可以做出其它不同形式的变化和改进。而这些基于本发明的实质精神所引伸出的的变化也应视为本发明的保护范围。
Claims (10)
1.丹参茎叶有效部位在制备治疗微循环障碍的药物或保健品中的应用。
2.丹参茎叶酚酮有效部位和丹参茎叶酚酸有效部位在制备治疗微循环障碍的药物或保健品中的应用。
3.根据权利要求1或2所述的应用,其特征在于,所述药物剂型为口服剂型。
4.根据权利要求1或2所述的应用,其特征在于,所述药物或保健品为片剂、胶囊剂、颗粒剂或口服液。
5.根据权利要求2所述的应用,其特征在于,所述的丹参茎叶酚酮有效部位的制备方法为:取丹参茎叶,按料液比为1:8~12,加体积浓度50%~80%乙醇回流提取1h~3h,提取2~3次,合并滤液,减压浓缩至无醇味;以NKA-2型号的大孔树脂纯化,用体积浓度50%~70%的乙醇洗脱,减压浓缩、冷冻干燥。
6.根据权利要求2所述的应用,其特征在于,丹参茎叶酚酸有效部位的制备方法为:取丹参茎叶,按料液比为1:8~11,取50%~80%乙醇回流提取1h~3h,提取1~3次,合并滤液,减压浓缩至无醇味,以NKA-2型号的大孔树脂纯化,用50%~80%的乙醇洗脱,减压浓缩,稀释至0.1g/ml,用盐酸调至pH=2后,用两倍量的乙酸乙酯萃取三次,合并乙酸乙酯部分后旋蒸去除乙酸乙酯,冷冻干燥。
7.根据权利要求2所述的应用,其特征在于,所述的丹参茎叶酚酮有效部位中含有下列质量百分比有效成分:20%~30%迷迭香酸,1.5%~3.0%紫草酸,20%~35%丹酚酸B,0.2%~0.5丹酚酸A,1%~3%丹酚酸C,1.5%~2.5%芦丁,1.5%~2.5异槲皮苷,0.5%~1.5%山柰酚3-O-芸香糖苷和0.1%~0.5%紫云英苷。
8.根据权利要求7所述的应用,其特征在于,所述的丹参茎叶酚酮有效部位中含有下列质量百分比有效成分:迷迭香酸21.47%,紫草酸1.67%,丹酚酸B 23.70%,丹酚酸A 0.29%,丹酚酸C 1.20%,芦丁 1.91%,异槲皮苷1.77%,山柰酚3-O-芸香糖苷0.86%和紫云英苷0.28%。
9.根据权利要求2所述的应用,其特征在于,丹参茎叶酚酸有效部位中含有下列质量百分比有效成分:25%~35%迷迭香酸,1%~3%紫草酸,35%~50%丹酚酸B,0.3%~1.2%丹酚酸A和1%~3%丹酚酸C、0.01%~0.05丹参素,0.01%~0.05原儿茶醛。
10.根据权利要求9所述的应用,其特征在于,丹参茎叶酚酸有效部位中含有下列质量百分比有效成分:
迷迭香酸27.24%,紫草酸1.21%,丹酚酸B 37.25%,丹酚酸A 0.45%和丹酚酸C 1.29% 、丹参素0.01%,原儿茶醛0.03%。
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