CN102100739B - 一种含有丹参素和三七皂苷r1的中药组合物及其应用 - Google Patents
一种含有丹参素和三七皂苷r1的中药组合物及其应用 Download PDFInfo
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- CN102100739B CN102100739B CN200910244837XA CN200910244837A CN102100739B CN 102100739 B CN102100739 B CN 102100739B CN 200910244837X A CN200910244837X A CN 200910244837XA CN 200910244837 A CN200910244837 A CN 200910244837A CN 102100739 B CN102100739 B CN 102100739B
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Abstract
本发明公开了一种含有丹参素的中药组合物及其应用，该组合物是由重量比的丹参提取物∶三七提取物＝2-6∶0.5-2组成。同时也公开了该中药组合物对缺血再灌注引起的心脏微循环障碍和心肌损伤有改善作用。
Description
技术领域
本发明涉及医药领域，尤其是涉及一种中药组合物及其在改善心脏微循环障碍和心肌损伤的用途。
背景技术
随着人们生活水平的提高及生活习惯的改变，心血管疾病已经成为威胁人类健康和生命、影响医疗财政收入的主要病种。每年全世界因心血管病而死亡的人数大约有1650万人，其中，中国约300万人，占总死亡人数的45％。
经皮冠状动脉成型术、心脏外科体外循环、冠状动脉搭桥术、复杂先天性心脏病就治术、瓣膜置换术及大血管外科手术等治疗方法的临床应用，某种程度上挽救了心血管患者的生命，但是，术后的缺血再灌注(ischemia/reperfusion，I/R)损伤已经成为影响心脏血管外科手术远期疗效的主要难题。另一方面，心脏骤停后的复苏、心血管痉挛的缓解、血栓溶解后引发的缺血再灌注损伤也已经影响了救治效果。因此预防和改善心肌缺血再灌注损伤是提高心血管疾病就治效果、降低其死亡率的重要环节。
心肌缺血再灌注的早期，冠状血管内皮细胞和白细胞过量释放过氧化物和促炎性因子，过量表达的黏附分子[i]等引起了白细胞与血管内皮细胞黏附。黏附于血管内皮细胞的白细胞释放的过氧化物和蛋白酶，损伤血管内皮细胞和基底膜、导致血浆蛋白的外漏。血浆蛋白外漏引起的血管周围水肿、游出于血管外的白细胞、血管内皮肿胀或微血栓引起的毛血管闭塞等均可以导致周围心肌细胞的坏死或凋亡，形成心肌梗死。改善缺血再灌注引起的微循环障碍是减轻缺血再灌注后的心肌损伤的重要环节。
丹参素(3，4-dihydroxy-phenyl lactic acid)，是中药丹参的主要水溶性成分。我们以往的研究证实了丹参素可以抑制缺血再灌注引起的大鼠肠系膜细静脉血管壁过氧化物的产生、白细胞黏附分子CD11b/CD18的表达，白细胞与细静脉壁的黏附，血浆白蛋白的漏出，但是，有关丹参素对缺血再灌注引起的心脏微循环障碍和心肌损伤是否有影响尚不清楚。三七皂苷R1(notoginsenoside R1)是三七的主要皂苷之一。我们以往的研究已经证实了三七皂苷R1可以抑制缺血再灌注引起的大鼠肝脏黏附白细胞数，改善肝微循环障碍。但是，有关三七皂苷R1对缺血再灌注引起的心脏微循环障碍和心肌损伤是否有影响尚不清楚。因此，预防和改善心肌缺血再灌注损伤的药物时迫在眉睫的。
发明内容
为了解决上述技术问题，本发明提供了一种可以预防和改善缺血再灌注引起的心脏微循环障碍和心肌损伤的中药组合物。
本发明还提供了该中药组合物在制备改善缺血再灌注引起的心肌微循环障碍和心肌损伤药物中的应用。
本发明的技术方案是这样实现的：
本发明的中药组合物，其是重量比的丹参提取物∶三七提取物＝2-6∶0.5-2组成。
优选中药组合物，其是由重量比的丹参提取物∶三七提取物＝4∶1组成。该中药组合物可以显著地改善缺血再灌注引起的大鼠心脏细静脉红细胞流动速度和心脏灌流量，减轻再灌注后的心肌梗死面积比。
本发明所述丹参提取物优选为水溶性提取物，其有效成分药理作用强，其中包括丹参素和多酚酸类成分。优选丹参素，丹参素为咖啡酸的水解产物3，4二羟基苯基乳酸。丹参素(5mg/kg/h)可以一过性地改善缺血再灌注引起的大鼠心脏细静脉红细胞流动速度和心脏灌流量，减轻再灌注后的心肌梗死面积比。
所述的丹参素可以市购，也可以用常规方法提取。例如，丹参药材采用超声波提取，水提醇沉，用聚酰胺、大孔树脂吸附柱除杂提纯。也可以选用申请号为CN02144600、CN02133727、CN90107488中公开的丹参提取物的制备方法。
本发明所述的三七提取物为黄色粉末，可溶于甲醇，水，不溶于乙醚等。具有较明显的调节血脂和免疫调节作用。试验证明：对免疫功能失调及血脂失调的人群又较好的辅助治疗作用，也无毒副作用。选自三七皂苷R1、人参皂苷Rb1、Re或人参皂苷Rg1中一种或几种，优选三七提取物为三七皂苷R1。
上述三七提取物可以通过购买上市的原料或用常规方法或自行摸索工艺的方式获得。例如采用申请号为CN1412163A、CN200510044534.5、
本发明还提供了该中药组合物作为其他药物或保健品有效活性成分制备而成的药物组合物，其活性成分占重量百分比是0.1-99.9％，其余为药物可接受的载体。
本发明的组合物可以结合各种载体如赋型剂或辅助剂制成一定的制剂，其中制剂的剂型分为口服、肌内、腹腔内、皮下或静脉内给药。口服剂分为普通片剂，胶囊剂、滴丸剂、颗粒剂、口服液、软胶囊、口崩片、散剂、膏剂、丹剂、丸剂、栓剂及其这些剂型的速释制剂或长效制剂、粉雾剂、气雾剂、凝胶剂。皮下或静脉给药分为注射剂、冻干粉针剂等。优选口服制剂，如胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
本发明所述的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于滴丸剂，可以选择性的加入适当的药物可接受的载体，所述药物载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁中的一种或几种。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明的组合物及其制剂或保健食品在制备制备改善缺血再灌注引起的心脏微循环障碍和心肌损伤药物中的应用，体现在下述试验例中。
试验例
1、材料与方法
1.1药品和试剂
丹参素(昆明风山渐医药有限公司，批号：09010413)，三七皂苷R1(昆明风山渐医药有限公司，批号：08090318)，4℃下避光保存。于试验前用生理盐水配成适当浓度(1.25mg/ml)，用于静脉滴注给药。
FITC-Albumin(Albumin，Fluorescein isothiocyanate conjugate bovine)，SIGMA，分析存，批号是Ag771-1G。实验前用生理盐水制成10mg/ml的溶液，二周内使用，4℃保存。用前用生理盐水制成20％溶液，常温保存。TTC，批号，2836B041。实验前用磷酸盐缓冲液配成0.375％的溶液，一个月内使用，常温保存。
1.2动物
雄性SD大鼠，体重250±10g，购买于北京大学医学部动物中心，合格证号：SCXK(京)2006-0001。实验动物的管理按卫生部发布的实验动物管理指南执行，动物饲养在温度为24±1℃，湿度为55±5％的条件下，自由饮食、饮水。
1.3缺血再灌注模型的建立
大鼠用20％的乌拉坦(1.25g/kg)肌肉注射麻醉，仰卧位固定，切开颈部皮肤，分离颈前肌，暴露气管，行气管插管。插管另一端连于小动物呼吸机(ALC-V 8，Shanghai Aoteshai Biologyscience and technology Limited company，Shang Hai，China)行加压呼吸(呼吸比1∶1，呼吸频率75次/min，潮气量12mL/kg)。用热毯维持肛温在37-37.5℃(YSI REF 401，Yellow Spring，Ohio，USA)度之间。胸部消毒，沿胸骨左，右缘2～4肋开胸暴露心脏，用穿有3-0缝合线的3/8弯针穿过肺动脉圆锥与左心耳交界稍下(1～2)mm处，结扎缝合线并在丝线与心肌组间放一根聚乙烯小管，拉紧丝线形成造成缺血。30分种后解除结扎，建立缺血再灌注模型。
1.4给药方法
假手术组(Sham)：实验前20分钟，静脉滴注生理盐水(1ml/h)直至整个实验结束。缺血再灌注模型(I/R)组：实验前20分钟，静脉滴注生理盐水(1ml/h)直至整个实验结束。丹参素+缺血再灌注组(DLA+I/R)：在实验前20分钟，静脉滴注丹参素水溶液5mg/kg(溶于生理盐水1.25mg/ml)直至整个实验结束。三七皂苷R1+缺血再灌注组(R1+I/R)：在实验前20分钟，静脉滴注三七皂苷R1水溶液5mg/kg(溶于生理盐水1.25mg/ml)直至整个实验结束。丹参素、R1(4∶1)配伍组+缺血再灌注组(DR+I/R)：在实验前20分钟，静脉滴注丹参素、三七皂苷R1(4∶1)配伍水溶液5mg/kg(溶于生理盐水1.25mg/ml)直至整个实验结束。
1.5心脏冠状血管细静脉的血管径和红细胞流速
用连接在正立显微镜(BX51WI，Olympus，Japanese)的高速摄影机(ultimate APXPHOTRON，FASTCAM，US)，在落射光下，用10倍物镜，选直径在30-50μm的细静脉，通过显示屏(20PF5120，PHLIPS，US)观察，并用CD录像机(DVR-560H，PHLIPS，US)记录心脏冠状血管微循环。设定高速摄影机的摄影速度为500幅/秒，记录在缺血前，缺血30分，再灌注30分、再灌注60分时同一视野内细静脉管径和红细胞流动速度。在25幅/秒的速度重放的录像上，用Image-Pro Plus 5.0软件测定细动、静脉管径及红细胞流速。大鼠心脏细动、静脉红细胞流速用mm/s表示。大鼠心脏细动、静脉管径用μm表示。
1.6心脏冠状血管细静脉血浆白蛋白漏出的测定
在缺血再灌注60分时，将FITC标记的血浆白蛋白按50mg/kg的剂量，经股静脉缓慢推注。在正置荧光显微镜下(USS-301，Leica，US)，以455nm激发光，汞灯作为发射光源(100W)，用SIT摄影机记录各组荧光图象。用Image-Pro Plus 5.0软件测定细静脉血管内和相邻的血管外间质的FITC荧光强度，用同一视野内细静脉管外间质与血管内FITC荧光的比表示。
1.7心脏血流量的测定
用连接计算机的激光多普勒血流灌注成像仪(PeriScan PIM3，PERIMED，Sweden)记录在缺血前，缺血5分、30分以及再灌注5分、30分、60分时心脏表面血流量。用LDPIwin软件对图像进行测量和评估数据。以缺血再灌注前的血流量为基础值，计算心脏血流量的变化率。
1.8心肌梗死面积的计算
再灌注60分钟后，取出大鼠心脏(每组N＝6)，从心尖部开始延平行于房室间隔的方向切成1mm厚的5个薄片放入溶于PBS的0.375％的TTC中，在37℃下孵育15分钟，行TTC染色。非梗塞区被染成红色，梗塞区被染成白色，用Digital sight(DS-5M-U1，NIKON，Japan)拍摄图心肌图片，用图像分析软件Image-Pro plus 5.0(Media Cybemetrics Inc，USA)计算心肌的梗死面积，用梗死区面积与总面积的百分比来表示心肌梗死面积。
1.9统计方法
统计分析采用SPSS 11.5数理统计软件包，各组数据用One-Way ANOVA进行统计。数据用x±SE表示，当P＜0.05时表示差异具有统计学意义。
2结果
2.1对心肌缺血再灌注后大鼠心脏细动静脉管径的影响
图1表示Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠冠状血管细静脉管径的连续变化。Sham组大鼠在本观察期间内，大鼠心脏冠状血管细静脉管径没有显著地变化。I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠冠状血管细静脉管径在本观察期间内均没有显著地变化。
2.2对心肌缺血再灌注后大鼠心脏细动静脉红细胞流速的影响
图2表示Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠冠状血管细静脉红细胞流速的连续变化。Sham组大鼠冠状细静脉红细胞流速在本观察期间内没有显著地变化。I/R组大鼠冠状血管细静脉红细胞流速在再灌注开始时就显著地降低，并持续到本观察结束时。丹参素从再灌注30分开始，显著地抑制了缺血再灌注引起的红细胞流速的降低，但到再灌注60分时其效果并不显著。R1没有显著地抑制再灌注引起的大鼠冠状血管细静脉红细胞流速的降低；而DR从再灌注30分开始，显著地抑制了缺血再灌注引起的红细胞流速的降低，并持继到再灌注60分。
2.3对心肌缺血再灌注后大鼠心脏血浆白蛋白渗出的影响
图3A表示Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠在再灌注60分钟时冠状血管细静脉白蛋白的漏出状态。Sham组大鼠仅可以观察到少量的FITC标记白蛋白的血管外漏出。I/R组大鼠可明显观察到FITC标记白蛋白的血管外漏出。R1和DLA给药组，也可以观察到大鼠心脏冠状血管细静脉FITC标记白蛋白的血管外漏，而DR给药组大鼠的FITC标记白蛋白的血管外漏出明显减少。
图4B表示在再灌注60分钟时，Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠心脏冠状血管细静脉内外FITC标记白蛋白的荧光强度比。与Sham组大鼠心脏冠状血管细静脉血管外与血管内FITC标记白蛋白的荧光密度相比，I/R组显著升高。R1和DLA没有显著地抑制FITC标记白蛋白的外漏，而DR显著地抑制了大鼠心脏冠状血管细静脉血管内FITC标记白蛋白的外漏。
2.4对心肌缺血再灌注后大鼠心脏血流量的影响
图4表示的是激光多普勒测得的Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠心脏血流量的图像。Sham组大鼠心脏血流量在本过程中没有明显的变化。I/R组大鼠从缺血开始到再灌注60min时血流量明显降低。R1+I/R组、DLA+I/R组大鼠心脏血流量在再灌注30min和60min时与I/R相比有所恢复。DR+I/R组大鼠从再灌注5min开始心脏血流量明显恢复。
图4B的表示Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠心脏血流量的连续变化。Sham组大鼠心脏血流量在本观察过程中没有明显变化。I/R组大鼠在缺血过程中血流量降到基础值的63％，再灌开始后恢复到基础值的73％，再灌注60分时，为基础值的72％。R1没有显著地抑制缺血再灌注后的大鼠心脏血流量的降低。DLA在再灌注5分时，可以显著地抑制缺血再灌注后的大鼠心脏血流量的降低，而DR从再灌注5分开始显著地抑制了缺血再灌注引起的大鼠心脏血流量的降低。
2.5对大鼠心肌缺血再灌注损伤心肌梗死面积的影响
Sham组大鼠心脏未见梗死区域，I/R组大鼠心脏可见较大的呈白色染色的梗死区域。R1组的心肌梗死区域略有减少，而DLA+I/R组和DR+I/R组心肌梗死区域明显地减少。
图6表示Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠再灌注60分钟时心脏心肌梗死区域的面积与心脏面积的比。与Sham组比较，I/R组大鼠心肌梗死面积比显著增加。R1没有显著抑制缺血再灌注后大鼠心肌梗死面积比的增加，而DLA和DR可以显著地抑制缺血再灌注引起的心肌梗死面积比的增加。
附图说明
图1表示的是Sham组、I/R组、R1+I/R组、DLA+I/R组、DR+I/R组大鼠心脏冠状血管细静脉血管径的变化
图2表示的是Sham组、I/R组、R1+I/R组、DLA+I/R组、DR(4∶1)+I/R组大鼠心脏冠状血管细静脉红细胞流速的变化。
图3表示的是Sham组、I/R组、R1+I/R组、DLA+I/R组、DR(4∶1)+I/R组大鼠在再灌注60min时心脏冠状血管细静脉FITC标记白蛋白漏出的结果，其中A表示的各组在再灌注60分时FITC标记白蛋白漏出的图像。B表示的是各组再灌注组60分钟时细静脉血管外FITC标记白蛋白的荧光强度与细静脉血管内荧光强度的比
图4用激光多普勒测获得的Sham组、I/R组、R1+I/R组、DLA+I/R组、DR(4∶1)+I/R组大鼠心脏血流量的图像
图5表示的是Sham组、I/R组、R1+I/R组、DLA+I/R组、DR(4∶1)+I/R组大鼠心脏血流量的连续变化大鼠心脏血流量的连续变化图像
图6表示的是Sham组、I/R组、R1+I/R组、DLA+I/R组、DR(4∶1)+I/R组大鼠在再灌注60分时心肌梗死面积百分比的比较
其中，图示标注1为Sham组(假手术组)，标注2为I/R组(缺血再灌注组)，标注3为R1+I/R组(三七皂苷R15mg/kg/h+缺血再灌注组)，标注4为DLA+I/R组(丹参素5mg/kg/h+缺血再灌注组)，标注5为DR(4∶1)+I/R组(丹参素与三七皂苷R1(4∶1)配伍5mg/kg/h+缺血再灌注组)。
下面通过具体实施方式仅仅是解释本发明的内容，并不是对本发明权利要求保护范围的进一步限定。
具体实施例
实施例1
取丹参素8g，三七皂苷R1 2g混合均匀得本发明的组合物。
实施例2
取丹参素8g，三七皂苷R1 2g与淀粉，与淀粉，羧甲基纤维素钠、滑石粉混合均匀，制粒，压片即得片剂。
实施例3
取丹参素10g，三七皂苷R1 10g与淀粉，加入100g的聚乙二醇，混合均匀，熔融，上滴丸机，制成滴丸。
实施例4
取丹参提取物12g，三七皂苷R1 0.5g，入5％交联聚维酮，0.1％的硬脂酸镁，50％的微晶纤维素，用适量乙醇溶液制成软材，制粒，60℃鼓风干燥，制粒，整粒，压制成片，即得口腔崩解片。
实施例5
取丹参提取物20g，三七提取物20g，加入等量淀粉，蔗糖和硬脂酸镁，制粒，装入胶囊，即得胶囊剂。
实施例6
取丹参素2g，三七皂苷0.5g，葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1ml，上述组分混合均匀后，冷冻干燥，分装500支，即得粉针剂。
实施例7
取丹参提取物12g，人参皂苷R1 0.5g，入5％交联聚维酮，0.1％的硬脂酸镁，50％的微晶纤维素，用适量乙醇溶液制成软材，制粒，60℃鼓风干燥，制粒，整粒，压制成片，即得口腔崩解片。
Claims (6)
1.中药组合物在制备治疗缺血再灌注引起的心肌损伤、心肌梗死药物中的应用，其特征在于：所述的中药组合物是由下述重量比的提取物组成，
丹参提取物∶三七提取物＝2-6∶0.5-2。
2.中药组合物在制备治疗介入治疗前和后，治疗心肌损伤药物中的应用，所述的中药组合物是由下述重量比的提取物组成，
丹参提取物∶三七提取物＝2-6∶0.5-2。
3.如权利要求1或2所述的应用，其特征在于：所述的中药组合物是由下述重量比的提取物组成，
丹参提取物∶三七提取物＝4∶1。
4.如权利要求3所述的应用，其特征在于：所述的丹参提取物为丹参素。
5.如权利要求3所述的应用，其特征在于：所述的三七提取物选自三七皂苷R1。
6.如权利要求1或2所述的应用，其特征在于：所述中药组合物制成药剂学上可接受的剂型，包括片剂，胶囊剂、滴丸剂、颗粒剂、口服液、散剂、膏剂、丹剂、栓剂、粉雾剂、气雾剂、凝胶剂、注射剂、冻干粉针剂。
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| CN200910244837XA CN102100739B (zh) | 2009-12-17 | 2009-12-17 | 一种含有丹参素和三七皂苷r1的中药组合物及其应用 |
| CA2782967A CA2782967C (en) | 2009-12-17 | 2010-12-17 | Traditional chinese drug comprising danshen extracts and sanqi extracts and use thereof |
| EA201200754A EA023625B1 (ru) | 2009-12-17 | 2010-12-17 | Традиционное китайское лекарственное средство, содержащее экстракты дан-шен (danshen) и сан-ки (sanqi), и его применение |
| PCT/CN2010/079928 WO2011072619A1 (zh) | 2009-12-17 | 2010-12-17 | 一种含有丹参提取物和三七提取物的中药组合物及其应用 |
| AU2010333525A AU2010333525B2 (en) | 2009-12-17 | 2010-12-17 | Traditional chinese drug comprising Danshen extracts and Sanqi extracts and use thereof |
| EP10837056.0A EP2514418B1 (en) | 2009-12-17 | 2010-12-17 | Traditional chinese drug comprising danshen extracts and sanqi extracts and use thereof |
| MYPI2012002585A MY160218A (en) | 2009-12-17 | 2010-12-17 | Traditional chinese drug comprising danshen extracts and sanqi extracts and use thereof |
| US13/516,209 US9034398B2 (en) | 2009-12-17 | 2010-12-17 | Traditional Chinese drug comprising Danshen extracts and Sanqi extracts and use thereof |
| JP2012543459A JP5701897B2 (ja) | 2009-12-17 | 2010-12-17 | ダンシェン抽出物とサンキ抽出物を含む漢方薬、及びそれらの使用 |
| DK10837056.0T DK2514418T3 (en) | 2009-12-17 | 2010-12-17 | TRADITIONAL CHINESE PHARMACEUTICAL INCLUDING DANSHEN EXTRACTS AND SANQI EXTRACTS AND USE THEREOF |
| KR1020127017124A KR20120101701A (ko) | 2009-12-17 | 2010-12-17 | 단삼 추출물 및 삼칠근 추출물을 포함하는 전통 한약 및 그 용도 |
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| CN104147028A (zh) * | 2013-05-14 | 2014-11-19 | 天士力制药集团股份有限公司 | 三七皂苷r1对心脏的保护作用 |
| CN111358834B (zh) * | 2020-03-20 | 2022-04-05 | 南京昌润生物科技有限公司 | 用于改善微循环及降血脂的二十八烷醇组合物及应用 |
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| CN1470255A (zh) * | 2002-07-22 | 2004-01-28 | 王智民 | 自丹参三七中提取的制备物及其复方制备方法和医疗用途 |
| CN1200916C (zh) | 2002-11-13 | 2005-05-11 | 吉林省中医中药研究院 | 三七叶中总皂苷和黄酮提取物的制备方法 |
| US20050037094A1 (en) | 2003-07-31 | 2005-02-17 | Xijun Yan | Composition for heart disease, its active ingredients, method to prepare same and uses thereof |
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| CN1732964A (zh) * | 2004-07-03 | 2006-02-15 | 山东绿叶天然药物研究开发有限公司 | 一种药物组合物及其制备方法和用途 |
| CN101006984B (zh) * | 2007-02-01 | 2010-05-19 | 北京本草天源药物研究院 | 一种丹参丹酚酸a、三七提取物的注射制剂及其制备方法和应用 |
| CN101244123A (zh) * | 2008-02-25 | 2008-08-20 | 药都制药集团股份有限公司 | 三七丹参含片制备新工艺 |
| CN101574391B (zh) * | 2008-05-05 | 2012-08-29 | 天士力制药集团股份有限公司 | 丹参总酚酸和三七总皂苷的配伍对微循环障碍引发的疾病的预防和治疗 |
| CN102048720A (zh) | 2009-11-05 | 2011-05-11 | 天津天士力制药股份有限公司 | 丹参素、三七皂苷r1,及其配伍对微循环障碍引发的疾病的预防和治疗 |
| CN102100739B (zh) | 2009-12-17 | 2013-12-25 | 天士力制药集团股份有限公司 | 一种含有丹参素和三七皂苷r1的中药组合物及其应用 |
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| CA2782967A1 (en) | 2011-06-23 |
| EP2514418B1 (en) | 2016-11-02 |
| AU2010333525B2 (en) | 2013-08-15 |
| JP2013514283A (ja) | 2013-04-25 |
| JP5701897B2 (ja) | 2015-04-15 |
| DK2514418T3 (en) | 2017-02-13 |
| MY160218A (en) | 2017-02-28 |
| EP2514418A4 (en) | 2013-10-23 |
| WO2011072619A1 (zh) | 2011-06-23 |
| CA2782967C (en) | 2017-06-27 |
| EP2514418A1 (en) | 2012-10-24 |
| KR20120101701A (ko) | 2012-09-14 |
| EA201200754A1 (ru) | 2012-12-28 |
| CN102100739A (zh) | 2011-06-22 |
| AU2010333525A1 (en) | 2012-06-21 |
| US20120251634A1 (en) | 2012-10-04 |
| US9034398B2 (en) | 2015-05-19 |
| EA023625B1 (ru) | 2016-06-30 |
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