CN103191186A - 丹参制剂在制备抗肝纤维化药物中的应用 - Google Patents
丹参制剂在制备抗肝纤维化药物中的应用 Download PDFInfo
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- CN103191186A CN103191186A CN2012100005576A CN201210000557A CN103191186A CN 103191186 A CN103191186 A CN 103191186A CN 2012100005576 A CN2012100005576 A CN 2012100005576A CN 201210000557 A CN201210000557 A CN 201210000557A CN 103191186 A CN103191186 A CN 103191186A
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- radix salviae
- salviae miltiorrhizae
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Abstract
本发明属于医药领域，具体涉及丹参或丹参制剂在制备抗肝纤维化药物中的应用。
Description
技术领域：
本发明属于医药领域，具体涉及丹参或丹参制剂在制备抗肝纤维化药物中的应用。
背景技术：
肝纤维化是肝硬化的必经阶段，抗肝纤维化至关重要。目前对于肝纤维化的治疗，临床上尚缺乏有效的治疗药物，细胞因子类、抗氧化剂等几类药物已被用于实验研究，但在临床上的治疗效果却不理想。近年来，中药抗肝纤维化作用日益受到人们的重视，并已展示良好的应用前景。
丹参味苦，性微寒，具有活血化瘀，养血安神，凉血排痈和排毒生肌的功效，是中药活血化瘀的常用药物。丹参药材主含脂溶性的二萜类成分和水溶性的酚酸类成分，尚含有黄酮类、三萜类、甾醇等其他成分。二萜类成分中属醌、酮型结构的有丹参酮I、IIA、IIR、V、VI，隐丹参酮，异丹参酮I、II、IIB，二氢丹参酮I等。水溶性的酚酸类成分有丹参素、原儿茶醛、原儿茶酸、咖啡酸及丹参素与咖啡酸的衍生物或二聚物酯化而成的缩酚酸如丹酚酸A、B、C、D、E、G、紫草酸B、迷迭香酸、迷迭香酸甲酯等。丹参酮IIA是丹参二萜类活血化瘀的代表成分之一。现代药理研究证明丹参具有扩张冠状动脉、抗心肌缺血、抗凝、抗血栓形成、镇静止痛以及降血脂和抗动脉粥样硬化等作用。
本发明用CCl4复合因素法诱导肝纤维化模型，并同时ig给予高、中、低受试药物丹参制剂，实验进行7周，测定血清中丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)的活性及总蛋白(TP)、白蛋白(ALB)、IV型胶原的量；测定肝组织中超氧化物歧化酶(SOD)活性、丙二醛(MDA)、羟脯氨酸(Hyp)的水平；HE和Masson染色观察肝组织病理形态学改变；免疫组化学检测α-平滑肌肌动蛋白(α-SMA)的表达。结果显示丹参制剂能明显抑制血清中ALT、AST、NAG的活性，降低血清中IV型胶原的量，升高血清中TP和ALB的量；降低肝组织中Hyp和MDA的水平，亦能升高肝组织中SOD的活性；抑制肝组织中胶原纤维的增加，亦能降低肝组织中α-SMA的表达。
发明内容：
本发明的目的一是提供丹参或丹参制剂在制备抗肝纤维化的药物中的应用。
本发明的另一个目的是提供丹参或丹参制剂在抗肝纤维化相关疾病例如肝硬化，肝炎，肝癌等方面的应用。
本发明所述的丹参包括丹参新鲜的或经炮制的药材，以及丹参药材经加工处理后制成的产品，例如丹参药材经粉碎或提取后得到的产品，丹参药材的提取可以采取水提、醇提、水提醇沉等方式，还可以进一步包括精制步骤，例如树脂纯化等。
本发明所述丹参制剂是由丹参作为原料药制备而成的药物，目前已经上市的丹参制剂包括丹参片，丹参胶囊，丹参滴丸等。
本发明所述丹参制剂由以下方法制备而成，先将原料药经过加工制备成药物活性成分，再进一步制备成药物制剂。
本发明所述丹参制剂，其制备方法属于现有技术，可以从现有专利公开文件中获得，或根据公开的药品标准制备。
本发明所述丹参制剂优选丹参滴丸。
本发明所述的丹参制剂，是用丹参制备成的药物组合物，该组合物根据需要可以含有药物可接受的载体，药物可接受的载体在制剂中所占重量百分比可以是0.1-99.9％。本发明的药物组合物，以单位剂量形式存在，所述单位剂量形式是指制剂的单位，如片剂的每片，胶囊的每粒胶囊，口服液的每瓶，颗粒剂每袋，注射剂的每支等。
本发明的丹参制剂可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、滴丸剂、贴剂。
本发明的丹参制剂，其口服给药的制剂可含有常用的赋形剂，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。
本发明的丹参制剂，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体包括但不限于以下物质，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、硬脂酸镁等。
本发明的丹参制剂在使用时根据病人的情况确定用法用量。例如，可以给予按照实施例1的方法制备的丹参滴丸一次20粒，一日3次，24-32周为一个疗程。
肝纤维化发生的关键是肝星状细胞(hepatic stellate cell，HSC)的激活和细胞外基质(ECM)的过度沉积，活化的HSC大量增殖，并转化为肌成纤维细胞，进而产生大量的ECM。本实验采用CCL4模型诱导肝纤维化的原理是：对肝细胞膜有直接溶解作用，致使肝细胞变性坏死，但是CCl4的毒性主要与其活性代谢产物有关，CCl4在肝细胞内被混合功能氧化酶代谢，生成活泼的三氯甲烷自由基和氯自由基，这些自由基可以使肝细胞中酶功能丧失、膜脂质过氧化、胞浆钙离子浓度升高，导致肝细胞损伤坏死和纤维化。但是，该模型形成的纤维化自愈倾向明显，所以采用预防给药。血清ALT、AST活性是肝细胞损伤的敏感指标，TP、ALB的降低程度与肝脏合成功能的损害程度成正相关。
肝纤维化发生的关键因素之一是ECM的过度沉积，胶原是细胞外基质(ECM)的主要组成部分，而Hyp是胶原蛋白的主要成分，在纤维化过程中，肝组织中Hyp随着胶原的消长而变化，是评估胶原蛋白含量和肝纤维化程度的重要指标。NAG是溶酶体中的一种蛋白水解酶，参与结缔组织基质的水解代谢在血清中的活性被认为与肝纤维化过程有关，可揭示结缔组织---胶原的分解程度。血清中IV型胶原含量的变化，也同样被证明是判断肝纤维化程度极具实用价值的指标。
在正常状态下，HSC处于静止状态；病理状态下，HSC被激活，活化的HSC表达α-SMA，而HSC表达α-SMA是其活化的显著特征之一。应用免疫组化技术和图像分析软件对α-SMA进行分析，能够显示药物的作用。
本发明根据以上影响因素，设计了丹参制剂的研究实验，实验方法如下：
1材料
1.1实验动物
雄性Wistar大鼠，体重140-160g，由天津市山川红实验动物科技有限公司提供，许可证号SCXK(津)2009-0001。
1.2药品与试剂
丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总蛋白(TP)及白蛋白(ALB)测定试剂盒均为中生北控生物科技股份有限公司产品；超氧化物歧化酶(SOD)、丙二醛(MDA)、羟脯氨酸(Hyp)及N-乙酰-β-D-氨基葡萄糖苷酶(NAG)测定试剂盒均为南京建成生物工程研究所产品；IV型胶原试剂盒为Adlitteramdiagnostic laboratories产品；α-SMA小鼠单克隆抗体为abcam公司产品；超敏二步法检测测试盒、DAB显色试剂盒均为北京中杉金桥生物公司产品；CCl4为天津天河化学试剂厂产品；扶正化瘀胶囊(批号：100403)，为上海黄海制药有限责任公司产品，实验时用蒸馏水配置成混悬液；丹参滴丸(批号：100101)为天津天士力制药股份有限公司产品，按实施例1的方法制备。
1.3实验仪器
LXJ-IIB型低速大容量多管离心机，上海安亭科学仪器有限公司；SUNRISE酶标仪，奥地利日升；PL203电子天平，梅特勒-托利多仪器(上海)有限公司；日立7080全自动生化仪，日本日立株式会社；Olymus BH-2普通光学显微镜，日本Olymus公司。
2方法1
2.1模型制备
除对照组外，其余各组每只首次sc纯CCl45ml/kg，以后每隔3天sc40％CCl4-橄榄油3ml/kg，共7周。前2周喂饲20％猪油加0.5％胆固醇的玉米粉饲料，在3-6周喂饲单纯玉米粉饲料。
2.2实验分组和给药
取健康大鼠90只，体重140-160g，雄性，随机分为6组：对照组(n＝10)，模型组(n＝16)，扶正化瘀(1500mg/kg)组(n＝16)，丹参滴丸高、中、低剂量(700、350、175mg/kg)组(n＝16)。各给药组均于造模当日起每天ig相应药物，对照组和模型组给予蒸馏水(10mL/kg)，共7周。末次给药1h后，用戊巴比妥钠麻醉大鼠，腹主动脉取血，离心收集血清备用。迅速取同一部位肝组织，固定于12％福尔马林液中，用于HE染色、Masson染色；另取另一部位肝组织固定于10％福尔马林液中，用于免疫组化染色；剩余肝组织用生理盐水制成10％肝组织匀浆。
2.3指标检测
检测血清ALT、AST活性及TP、ALB、NAG、IV型胶原含量；检测肝组织中SOD活性与MDA、Hyp含量；免疫组化染色观察α-SMA的表达；石蜡切片后，进行HE和Masson染色。
2.4免疫组化方法检测肝组织中α-SMA的表达
切片常规脱蜡、水化，PBS洗15min，3％H2O2封闭内源性过氧化化酶，室温孵育10min，PBS洗15min；置0.01mol/L枸橼酸钠盐缓冲溶液电磁炉修复15min，自然冷却后PBS洗15min，甩去多余液体；滴加α-SMA(1∶100)单抗，37℃孵育1h，PBS洗15min；滴加Polymer Helper，37℃孵育20min，PBS洗15min；滴加poly-HRP anti-Mouse IgG抗体，37℃孵育20min，PBS洗15min，DAB显色，自来水冲洗10min。苏木素复染，脱水，透明，封片，镜检。α-SMA染色呈棕黄色，采用Image-Proplus 6.0图像分析软件进行图像分析，每张切片随机取5个视野，记录每个视野的积分光密度(IOD))，IOD值越大，表明阳性表达产物越强。
2.5病理组织学检测
HE和Masson染色后镜下检查肝脏纤维化程度并做半定量分析，肝细胞纤维化分级标准：“-”正常肝脏，只见汇管区内极少量纤维结缔组织，为正常结构成分；“+”汇管区、小叶中央静脉周围胶原纤维增生，中央静脉及门静脉有少量纤维束放散延伸，但无纤维间隔形成，小叶结构仍保存；“++”胶原纤维增生，中央静脉和门静脉区纤维束向周围延伸，形成不完全间隔，小叶结构大部分保留；“+++”胶原纤维大量增生，有少量菲薄的完全间隔形成，小叶结构破坏；“++++”完全间隔增厚，假小叶形成。
2.6统计学处理
所有数据均采用统计软件SPSS11.5进行统计分析，以t检验分析组间差异，计量数据以平均数±标准差表示
病理组织的病变程度采用SPSS11.5NPar Tests Mann-Whitney Test，并采用Excel作图。
3结果
3.1对肝纤维化大鼠血清ALT、AST、TP、ALB的影响
结果见表1。与对照组比较，模型组大鼠血清ALT、AST活性显著升高(P＜0.01)，TP、ALB含量显著下降(P＜0.01)。与模型组比较，丹参滴丸中、低剂量组血清中TP、ALB含量明显升高(P＜0.05))；ALT、AST活性明显下降(P＜0.05)。
3.2对肝纤维化大鼠血清中NAG和IV型胶原的影响
结果见表2。与对照组比较，模型组大鼠血清中NAG活性明显升高(P＜0.01)，IV型胶原水平升高。与模型组比较，丹参滴丸各剂量组血清中NAG活性显著下降(P＜0.01)，且中、低剂量组IV型胶原水平明显下降(P＜0.05)。
3.3对肝纤维化大鼠肝组织中SOD活性及MDA、Hyp水平的影响
结果见表3。与对照组比较，模型组大鼠肝组织中SOD活性明显降低(P＜0.05)，MDA、Hyp水平显著升高(P＜0.01)。与模型组比较，丹参滴丸各剂量组大鼠肝组织中SOD活性明显升高(P＜0.05)，而低剂量组MDA水平明显下降(P＜0.05)，各剂量组Hyp水平显著降低(P＜0.01)。
3.4对肝纤维化大鼠肝组织中α-SMA表达的影响
结果见图1和表4。对照组阳性染色仅见于血管壁。与对照组比较，模型组α-SMA阳性表达明显增强，主阳性染色广泛表达于纤维间隔、血管壁以及纤维组织增生区，胆管细胞无表达。与模型组比较，丹参滴丸各剂量组大鼠肝组织中α-SMA阳性染色分布区与模型组相似，但黄染区域有所减少。通过IOD的测定，与对照组比较，模型组IOD值明显变大(P＜0.05)。与模型组比较，丹参滴丸中、低剂量组IOD值明显变小(P＜0.05)。结果表明，丹参滴丸能对抗肝纤维化大鼠肝组织中α-SMA表达的增强，抑制HSC的增殖。
3.5对肝纤维化大鼠肝组织中病理形态的影响
结果见表5、图2、图3。对照组大鼠肝脏肝小叶结构完整，组织结构清晰，肝细胞形态正常并以中央静脉为中心成条索状排列，肝窦清晰，较大汇管区有极少量纤维组织存在为正常结构。与对照组比较，模型组大鼠肝脏肝小叶均有不同程度的破坏，肝细胞排列紊乱，汇管区、中央静脉、门静脉均有不同程度的纤维组织增生，提示造模成功。各给药组亦有上述病变，但病变程度明显轻于模型组。依据肝组织病理所见和参照国内外纤维化分级标准，将大鼠肝纤维化程度分级划分，将结果进行等级资料的显著性检验。丹参滴丸各剂量组对大鼠的肝纤维化程度有明显改善(P＜0.05，P＜0.01)。结果表明，丹参滴丸对肝纤维化大鼠有明显的保护作用。
表1丹参滴丸对CC14诱导的肝纤维化大鼠血清ALT、AST、TP、ALB的影响
与对照组比较：△△P＜0.01；与模型组比较：*P＜0.05**P＜0.01△△P＜0.01vs control group；*P＜0.05**P＜0.01vs model group
表2丹参滴丸对CCl4肝纤维化大鼠血清中NAG和IV型胶原的影响
与对照组比较，△△P＜0.01；与模型组比较，*P＜0.05**P＜0.01△△P＜0.01vs control group；*P＜0.05**P＜0.01vs model group
表3丹参滴丸对CCl4诱导的肝纤维化大鼠肝组织SOD活性及MDA、Hyp的影响
与对照组比较，△P＜0.05△△p＜0.01；与模型组比较，*p＜0.05**p＜0.01△p＜0.05△△P＜0.01vs control group；*P＜0.05**p＜0.01vs model group
表4丹参滴丸对CCl4诱导的肝纤维化大鼠肝组织中α-SMA表达的影响
与对照组比较，△P＜0.05；与模型组比较，*P＜0.05**P＜0.01△P＜0.05vs control group；*P＜0.05**P＜0.01vs model group
表5丹参滴丸对CCl4诱导的肝纤维化大鼠的肝组织病理改变的影响
与模型组比较*P＜0.05**P＜0.01
*P＜0.05**P＜0.01vs model group
实验结果表明，丹参滴丸可明显抑制CCl4诱导的肝纤维化大鼠的ALT、AST的升高，使TP、ALB合成增加，且中、低剂量效果明显，说明丹参滴丸具有保护肝细胞、抑制肝损伤的作用。
实验显示，丹参滴丸能抑制Hyp、IV型胶原水平的升高，使NAG活性降低，且中、低剂量效果明显，说明丹参滴丸抑制胶原蛋白的沉积，促进胶原降解，可以明显改善肝纤维化的程度。SOD、MDA的变化直接或间接反映了肝损伤的程度。本实验显示，丹参滴丸能增加SOD活性，使MDA水平下降，且中、低剂量效果明显，说明丹参滴丸有降低自由基生成和减少脂质过氧化的作用。
实验显示，丹参滴丸能抑制α-SMA的表达增强，且中、低剂量效果明显，说明丹参滴丸能抑制HSC的增殖，其抗纤维化机制与抑制HSC表达α-SMA有密切关系。病理检查结果显示，丹参滴丸各剂量组能明显改善肝纤维化的损伤程度，且中、低剂量效果明显，说明丹参滴丸对肝纤维化大鼠有保护作用。
参考文献
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附图说明
图1丹参滴丸对CCl4诱导的肝纤维化大鼠肝组织中α-SMA表达的影响(10×20)
图2丹参滴丸对CCl4诱导的肝纤维化大鼠的肝组织病理形态的影响(HE染色，10×10)
图3丹参滴丸对CCl4诱导的肝纤维化大鼠的肝组织病理形态的影响(Masson染色，10×10)
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1
丹参滴丸的制备：
处方：丹参100g，制成滴丸1000粒。
制法：丹参加7倍水煎煮二次，每次2小时，合并煎煮液，滤过，滤液经浓缩至生药体积比为1∶1，离心，上清液过大孔树脂，水冲洗，乙醇洗脱，洗脱液浓缩出膏，相对密度1.31-1.38(50-60℃)，每克含丹参素不小于10mg。丹参浸膏加入适量的聚乙二醇中，搅匀，水浴溶化，移至制备滴丸装置的贮藏器中，保温75-85℃，按每克重选用适宜口径的滴管，以每分钟60-80粒的滴速，滴入用冰浴冷却的液体石蜡中，成形后将丸取出，用吸水纸吸去表面的液体石蜡，即得。
实施例2
丹参片的制备
处方：丹参浸膏262g 淀粉40g 轻质氧化镁60g 硬脂酸镁7g滑石粉80g 制成1000片。
制法：丹参粉碎成中粉，用95％乙醇作溶剂进行提取，提取3次，每次2小时，回收乙醇并浓缩成稠膏，药渣加水煎煮2次，每次1小时，滤过，滤液浓缩至适量，与上述稠膏合并的丹参浸膏。
取浸膏加热(不用直火)至60℃～70℃，搅拌使熔化，将轻质氧化镁、滑石粉(60g)及淀粉依次加入混匀，分铺烘盘上，于60℃以下干燥至含水量3％以下。然后将烘干的片(块)状物粉碎成14目以下的颗粒，最后加入硬脂酸镁、滑石粉(20g)混匀，过12目筛整粒，压片、质检、包糖衣。
实施例3
丹参胶囊的制备
处方：丹参浸膏406g，10％淀粉浆适量，共制成硬胶囊剂1000粒
制法：丹参粉碎成中粉，用95％乙醇作溶剂进行提取，提取3次，每次2小时，回收乙醇并浓缩成稠膏，药渣加水煎煮2次，每次1小时，滤过，滤液浓缩至适量，与上述稠膏合并的丹参浸膏。
取上述丹参浸膏粉碎，过80目筛；将10％淀粉浆分别制成软材后，过14目尼龙筛制粒，于70℃干燥至水分3％以下；将上述颗粒混合均匀后，填入1号空胶囊中，即得。
实施例4
丹参颗粒的制备
处方：丹参100g，制成滴丸1000粒。
制法：丹参加7倍水煎煮二次，每次2小时，合并煎煮液，滤过，滤液经浓缩至生药体积比为1∶1，离心，上清液过大孔树脂，水冲洗，乙醇洗脱，洗脱液浓缩出膏，相对密度1.31-1.38(50-60℃)，每克含丹参素不小于10mg。丹参浸膏加入5倍量的糖粉，混合均匀，加入70％乙醇少许，制成软材，过14目尼龙筛制粒，湿颗粒于60℃干燥，干颗粒过14目筛整粒，再过4号筛(65目)筛去细粉，然后分装，密封，包装即得。
Claims (10)
1.丹参或丹参制剂在制备抗肝纤维化的药物中的应用。
2.根据权利要求1的应用，其特征在于，所述应用，包括在与肝纤维化相关的疾病中的应用。
3.根据权利要求2的应用，其特征在于，所述应用，包括在抗肝硬化，肝炎，肝癌方面的应用。
4.根据权利要求1的应用，其特征在于，所述应用包括抑制血清中ALT、AST、NAG的活性。
5.根据权利要求1的应用，其特征在于，所述应用，包括降低血清中IV型胶原的量，升高血清中TP和ALB的量；降低肝组织中Hyp和MDA的水平。
6.根据权利要求1的应用，其特征在于，所述应用，包括升高肝组织中SOD的活性；抑制肝组织中胶原纤维的增加。
7.根据权利要求1的应用，其特征在于，所述应用，包括降低肝组织中α-SMA的表达。
8.根据权利要求1的应用，其特征在于，所述丹参制剂是由丹参作为原料药制备而成的药物。
9.根据权利要求8的应用，其特征在于，所述丹参制剂包括丹参片，丹参胶囊，丹参滴丸。
10.根据权利要求9的应用，其特征在于，所述丹参制剂是丹参滴丸。
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| EP13733640.0A EP2801365A4 (en) | 2012-01-04 | 2013-01-04 | USE OF DANSHEN OR A DANSHENE PREPARATION IN THE MANUFACTURE OF MEDICAMENTS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH LIVER FIBROSIS |
| AU2013207295A AU2013207295B2 (en) | 2012-01-04 | 2013-01-04 | Use of radix salviae miltiorrhizae (danshen) or its preparations in preparation of drugs for treating diseases related to hepatic fibrosis |
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| PCT/CN2013/070037 WO2013102437A1 (zh) | 2012-01-04 | 2013-01-04 | 丹参或丹参制剂在制备治疗肝纤维化相关疾病的药物中的应用 |
| CA2862442A CA2862442A1 (en) | 2012-01-04 | 2013-01-04 | Uses of danshen or danshen preparation in preparation of drugs for treating diseases related to hepatic fibrosis |
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| JP2014550629A JP2015503572A (ja) | 2012-01-04 | 2013-01-04 | 肝線維症に関連する疾患の治療用薬剤の調製におけるラディックス・サルビアエ・ミルチオルヒザエ（タンジン）又はその製剤の使用 |
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| CN115192585B (zh) * | 2022-06-02 | 2023-09-15 | 上海中医药大学附属曙光医院 | 一种包含丹酚酸a、二氢丹参酮i和隐丹参酮的组合物及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2801365A1 (en) | 2014-11-12 |
| RU2623147C2 (ru) | 2017-06-22 |
| CA2862442A1 (en) | 2013-07-11 |
| JP2015503572A (ja) | 2015-02-02 |
| RU2014130412A (ru) | 2016-02-20 |
| US9895405B2 (en) | 2018-02-20 |
| AU2013207295B2 (en) | 2017-10-19 |
| EP2801365A4 (en) | 2016-03-02 |
| KR20140114398A (ko) | 2014-09-26 |
| US20150044310A1 (en) | 2015-02-12 |
| AU2013207295A1 (en) | 2014-07-24 |
| WO2013102437A1 (zh) | 2013-07-11 |
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Address after: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Applicant after: Tasly Pharmaceutical Group Limited by Share Ltd Address before: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Applicant before: Tasly Pharmaceutical Group Co., Ltd. |
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