CN1283258C - 一种抗肝纤维化的药物及其制备方法 - Google Patents
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Abstract
本发明涉及的是一种治疗肝纤维化的药物，特别是应用丹参提取物及赤芍提取物制备抗肝纤维化的药物。所述抗肝纤维化的药物，可以制成各种口服剂型，如片剂、粒剂、粉剂、胶囊、口服液等多种形式。所述抗肝纤维化的药物是由以下成份制成的药剂(重量组份)：丹参提取物8～2份，赤芍提取物2～8份；优选组份配比为丹参提取物∶赤芍提取物＝7∶3。本发明还提供了所述抗肝纤维化药物的制备方法。
Description
技术领域
本发明涉及一种治疗肝纤维化的药物，特别是应用丹参提取物及赤芍提取物制备抗肝纤维化的药物。
背景技术
肝纤维化是肝细胞发生坏死或炎症刺激时，肝内纤维结缔组织异常增生的病理改变过程，各种慢性肝病如病毒性肝炎、酒精性肝病等，均能发展为肝纤维化、肝硬化。肝炎是我国发病率较高的疾病之一，据报道，肝炎在我国的发病率占总人口的10％以上。我国又是世界上的饮酒大国，加上环境污染和饮食结构的改变，目前，肝纤维化的发病率已在不断上升，现已成为我国卫生部门最关心、重视的课题之一。近年来，国内外学者对肝纤维化的形成机制，提出了一系列抗肝纤维化治疗药物与方法，如应用肾上腺皮质素，干扰素等治疗，但这些药物的疗效不能肯定。虽然有秋水仙在抗肝纤维化方面的治疗得到了肯定，但其具有较大的毒副作用，不易长期服用。中草药及其制剂对抗肝纤维化的作用，一直是国内外医疗科研单位重点研究的课题之一。近期，我国已开始出现相关复方抗肝纤维化中药制剂，如葵花牌护肝片等，但其均为中药大复方粗制剂，具有服用量大，服用周期长，疗效不确切，治疗机理难以研究等缺点，难以应付市场抗肝纤维化病人的需要，更无法与世界各国接轨。
中药丹参及赤芍具有一定的活血化瘀、改善微循环、增加肝脏血流量、保护肝细胞、减轻肝细胞变性、坏死及炎症反应，促进肝细胞再生、抑制纤维组织增生、抑制肝细胞脂质过氧化反应、清除氧自由基、抑制胶原生成并增加其分解等作用。
中药丹参的有效部位丹参提取物，是由唇形科丹参(Salvia miltorrhiza Bunge)的干燥根及根茎经提取分离加工制成的粉末，为一种棕黄色的无定形粉末，气特异，味酸，在水、甲醇、乙醇、醋酸乙酯中易溶。
中药赤芍为毛莨科植物芍药(Paeonia lactflora Pall)的干燥根茎，赤芍的有效部位赤芍提取物(Chishao Tiquwu)是由芍药的干燥根茎经提取分离加工制成，为一种棕黄色粉末，味苦，在水、甲醇、乙醇、醋酸乙酯中易溶，在石油醚中不溶。
利用丹参提取物及赤芍提取物制成抗肝纤维化的药物，还未见有报道。
发明内容
本发明的目的是提供一种抗肝纤维化的药物及其制备方法。
本发明的技术方案是：一种抗肝纤维化的药物，主要由以下重量份配比组分制成：丹参提取物8～2份，赤芍提取物2～8份；所述丹参提取物按照下述方法制备：取丹参饮片，水煎煮二次，分别滤过，合并两次的滤液，浓缩至每毫升滤液含生药1.0g，在浓缩后的滤液中加5％明胶沉淀鞣质，放置12小时，滤过，滤液浓缩至每毫升含生药1.5g，调pH2～3，再用等体积醋酸乙酯萃取三次，合并醋酸乙酯，减压回收醋酸乙酯，经80℃真空干燥，即得丹参提取物；所述赤芍提取物按照以下方法制备：取赤芍粗粉，过20目筛，用50％乙醇回流提取二次，合并二次的提取液，滤过，减压回取乙醇，浓缩滤液至相对密度为1.10，在浓缩液中加三倍量热水稀释，放冷后加5％明胶水液，使明胶水液量为原浓缩液重量的15％，放置24小时后过滤，将滤液通过大孔树脂用去离子水冲洗至洗脱液中还原糖反应为阴性，再用40％乙醇洗脱，洗脱液用量为树脂体积的6BV，解吸流速为树脂体积1000.5-1BV/小时，减压回取乙醇，浓缩洗脱液至相对密度为1.30～1.35的稠浸膏，再经80℃下真空干燥，即制成赤芍提取物。
较佳方案是所述丹参提取物7份，所述赤芍提取物3份。
本发明的药物可以添加各种药学上可接受的载体。
本发明的药物，可以是各种口服剂型，如片剂、粒剂、粉剂、胶囊、口服液等多种形式。
所述抗肝纤维化药物是胶囊剂型时，由以下组份制成：丹参提取物77g，赤芍提取物33g，辅料140g，共制成胶囊1000粒。
所述辅料是微晶纤维或玉米淀粉或羟甲基淀粉。
本发明抗肝纤维化药物的制备方法，包括如下步骤：
A、丹参提取物的制备：取丹参饮片，水煎煮二次，第一次加水10倍量，第二次加水6倍量，两次煎煮各1.5小时，分别滤过，弃去药渣，然后合并两次的滤液，浓缩至每毫升滤液含生药1.0g，在浓缩后的滤液中加5％明胶沉淀鞣质，放置12小时，滤过，滤液浓缩至每毫升含生药1.5g，用稀盐酸调pH2～3，再用等体积醋酸乙酯萃取三次，合并醋酸乙酯，减压回收醋酸乙酯，然后经80℃真空干燥，即得丹参提取物，丹参提取物中含丹参甲素以丹参甲素钠计算不得少于10％，含丹参水溶性总酚以原儿茶醛计算不得少于60％；
B、赤芍提取物的制备：取赤芍粉碎成粗粉，过20目筛，用50％乙醇回流提取二次，第一次回流提取用10倍量乙醇，第二次回流提取用6倍量乙醇，每次1.5小时，合并二次的提取液，滤过，减压回取乙醇，然后浓缩滤液至60℃的相对密度为1.10，在浓缩液中加三倍量≤90℃的热水稀释，放冷后加5％明胶水液，使明胶水液量为原浓缩液重量的15％，放置24小时后，过滤，然后将滤液通过大孔树脂用去离子水冲洗至洗脱液中还原糖反应为阴性，再用40％乙醇洗脱，洗脱液用量为树脂体积的6BV，解吸流速为树脂体积1000.5-1BV/小时，再次减压回取乙醇，然后浓缩洗脱液至50℃的相对密度为1.30～1.35的稠浸膏，再经80℃下真空干燥，即制成赤芍提取物；
C、丹参提取物及赤芍提取物抗肝纤维化药物胶囊的制备：取丹参提取物8～2重量份，赤芍提取物2～8重量份，加辅料，混匀过筛，用80％乙醇湿法制粒，干燥后装入胶囊，即得抗肝纤维化药物胶囊。
本发明所提供的丹参提取物及赤芍提取物制备抗肝纤维化的药物经过药理学研究和药效动物试验研究结果证明：中药丹参及赤芍的有效成分提取物的相关活性部位，按一定比例配比，能明显增加肝对透明质酸、层粘蛋白的摄取与分解，抑制谷丙转氨酶、谷草转氨酶升高；动物病理切片同样显示对肝纤维化具有良好的防治作用。对以四氯化碳致试验性大鼠肝纤维化的影响试验结果如表1、2、3所示，丹参提取物∶赤芍提取物＝7∶3的抗肝纤维化药物对透明质酸(HA)、层粘连蛋白(LN)有较显著的影响；丹参提取物∶赤芍提取物＝5∶5或3∶7的抗肝纤维化药物对谷草转氨酶(AST)有显著性差异；各个剂量的丹参提取物及赤芍提取物抗肝纤维化药物试验组对谷丙转氨酶(ALT)及肝组织羟脯氨酸有显著影响，动物实验表明，丹参提取物及赤芍提取物抗肝纤维化药物对实验性大鼠肝纤维化具有良好的防治作用。
表1：丹参提取物及赤芍提取物抗肝纤维化药物
对实验性大鼠肝功能检测的影响(X±SE)
| 组别 | n | 古丙转氨酶(ALT) | 古草转氨酶(AST) | 球蛋白(TP) | 白蛋白(ALB) |
| 正常组 | 8 | 61.65±15.24* | 159.84±37.14* | 62.94±4.00* | 27.06±2.10* |
| 模型组 | 9 | 124.32±78.50 | 293.29±132.00 | 61.33±3.36 | 28.40±2.69 |
| 秋水仙碱组 | 8 | 50.58±8.30* | 202.06±57.78 | 65.66±2.97 | 26.34±1.52 |
| 丹7：赤3大组 | 8 | 57.39±12.95* | 227.79±44.59 | 70,55±5.27 | 32.64±2.72 |
| 丹7：赤3小组 | 9 | 57.18±13.53* | 245.58±53.98 | 64.10±5.59 | 29.77±2.44 |
| 丹5：赤5大组 | 8 | 50.28±10.54* | 163.51±38.61* | 65.10±4.00 | 29.79±2.10 |
| 丹5：赤5小组 | 8 | 45.10±15.14* | 119.06±31.29* | 60.58±5.52 | 26.29±2.91 |
| 丹3：赤7大组 | 8 | 44.00±15.04* | 114.21±15.20* | 64.53±7.71 | 28.53± |
| 丹3：赤7小组 | 9 | 53.73±14.76* | 152.23±27.13* | 63.64±5.96 | 28.22±3.11 |
与模型组比较：*P＜0.05
表2：丹参提取物及赤芍提取物抗肝纤维化药物
对实验性大鼠肝纤维化相关指标的影响(X±SE)
| 组别 | n | 透明质酸(HA)ng/ml | 层粘连蛋白(LN)ug/l | 肝羟脯氨酸ug/mgprot |
| 正常组 | 8 | 79.91±18.68* | 16.77±7.37* | 1.35±0.29* |
| 模型组 | 9 | 155.14±57.12 | 29.92±12.20 | 2.56±0.70 |
| 秋水仙碱组 | 8 | 97.27±23.98* | 16.06±10.68* | 1.61±0.40* |
| 丹7：赤3大组 | 8 | 96.14±33.34* | 15.73±6.33(#)* | 1.73±0.37* |
| 丹7：赤3小组 | 9 | 94.50±32.48* | 6.69±2.01(#)* | 1.83±0.56* |
| 丹5：赤5大组 | 8 | 92.05±31.40* | 3.21±0.79(#)* | 1.78±0.70* |
| 丹5：赤5小组 | 8 | 102.08±28.31* | 8.96±4.19(#)* | 1.87±0.35* |
| 丹3：赤7大组 | 8 | 111.99±37.87 | 17.93±9.46 | 1.85±0.61* |
| 丹3：赤7小组 | 9 | 93.40±27.55* | 11.87±6.96* | 1.99±0.48 |
与模型组比较：*P＜0.05
表3：丹参提取物及赤芍提取物抗肝纤维化药物
对实验性大鼠病理观察结果
| 组别 | 肝纤维化 | ||||||
| 0级 | 1级 | 2级 | 3级 | 4级 | 5级 | 6级 | |
| 正常组 | 8 | 0 | 0 | 0 | 0 | 0 | 0 |
| 模型组 | 0 | 1 | 2 | 4 | 1 | 1 | 0 |
| 秋水仙碱组 | 0 | 4 | 7 | 1 | 0 | 0 | 0 |
| 丹7：赤3大组 | 2 | 2 | 7 | 0 | 0 | 0 | 0 |
| 丹7：赤3小组 | 3 | 6 | 3 | 0 | 0 | 0 | 0 |
| 丹5：赤5大组 | 1 | 2 | 7 | 0 | 0 | 0 | 0 |
| 丹5：赤5小组 | 1 | 0 | 9 | 1 | 0 | 0 | 0 |
| 丹3：赤7大组 | 0 | 3 | 7 | 1 | 0 | 0 | 0 |
| 丹3：赤7小组 | 1 | 2 | 7 | 0 | 0 | 0 | 0 |
经统计学检验：
模型组：正常组x2＝11.22＞x2 0.001(1)P＜0.001，模型组与正常组之间有非常显著的差异，显示造模成功。
秋水仙碱组：模型组x2＝6.115＞x20.05(1)P＜0.05
丹赤73大组：模型组x2＝6.960＞x20.01(1)P＜0.01
丹赤73大组：模型组x2＝10.433＞x20.01(1)P＜0.01
丹赤55大组：模型组x2＝6.110＞x20.05(1)P＜0.05
丹赤55大组：模型组x2＝4.763＞x20.05(1)P＜0.05
丹赤37大组：模型组x2＝4.287＞x20.05(1)P＜0.05
丹赤37大组：模型组x2＝6.110＞x20.05(1)P＜0.05
由此可见，各组药物治疗组与肝纤维化模型组都有显著差异，说明丹参提取物与赤芍提取物各个剂量配伍对肝纤维化均有积极的治疗作用。其中丹7：赤3的大小剂量组无论从病理切片本身还是统计验证，疗效均更为明显。
本发明经过急性毒性动物试验研究结果表明，丹参提取物及赤芍提取物制备的抗肝纤维化的药物，在所选择的剂量范围内给药，无毒副作用。
本发明的优点在于：采用中药有效部位丹参提取物与赤芍提取物研究开发出了治疗肝纤维化的新药物，对肝纤维化具有良好防治作用和效果，是一个极其有前途的中药新药，对维护人民健康具有积极的意义。
具体实施例
实施例1、丹参提取物的制备
(1)丹参原料的准备与前处理：
取产地为河南洛阳的中药丹参，要求符合中国药典2000年版一部丹参项下有关规定。药材经挑选后，取净药材50Kg切成薄片，备用。
(2)制备工艺：
取丹参饮片50Kg，水煎煮二次，第一次加水10(重量)倍量，第二次加水6(重量)倍量，两次煎煮各1.5小时，分别滤过，弃去药渣，然后合并两次的滤液，浓缩至每毫升滤液含生药1.0g。在浓缩后的滤液中加5％明胶沉淀鞣质，放置12小时，滤过，滤液浓缩至每毫升含生药1.5g，用稀盐酸调PH2～3，再用等体积醋酸乙酯萃取三次，合并醋酸乙酯，减压回收醋酸乙酯，然后经80℃真空干燥，即得丹参提取物1.285Kg。本品含丹参甲素以丹参甲素钠计算为12.52％；含丹参水溶性总酚以原儿茶醛计算为82.79％。
实施例2、赤芍提取物的制备
(1)赤芍原料的准备与前处理：
取产地为内蒙古赤峰的中药赤芍，要求符合中国药典2000年版一部赤芍项下有关规定。粉碎赤芍成粗粉25Kg备用。
(2)具体制备工艺：
取赤芍粗粉25Kg，过20目筛，用50％乙醇回流提取二次，第一次回流提取用10倍量乙醇，第二次回流提取用6倍量乙醇，每次1.5小时，合并二次的提取液，滤过，减压回取乙醇，然后浓缩滤液至相对密度为1.10(60℃)，在浓缩液中加三倍量的热水(≤90℃)稀释，放冷后加5％明胶水液，使明胶水液量为原浓缩液的15％(w/w)，放置24小时后，达到10℃以下时过滤，然后将滤液通过ZTC-1型大孔树脂(柱变径比24∶1；药材与树脂用量比为4∶1；吸附流速为树脂体积2-3BV/小时)用去离子水冲洗至洗脱液中还原糖反应为阴性，再用40％乙醇洗脱，洗脱液用量为树脂体积的6BV，解吸流速为树脂体积1000.5-1BV/小时，再次减压回取乙醇，然后浓缩洗脱液至相对密度为1.30～1.35(50℃)的稠浸膏，再经80℃下真空干燥，即制成赤芍提取物0.962Kg。本品含芍药苷54.26％；含赤芍酚酸以没食子酸计算为8.39％。
实施例3、丹参提取物及赤芍提取物制备抗肝纤维化药物胶囊
(1)处方：
丹参提取物 77g
赤芍提取物 33g
微晶纤维 140g
共制成胶囊1000粒。
(2)制备方法：
将上述处方原料混匀过筛，用80％乙醇湿法制粒，干燥后装入胶囊即可。
实施例4、丹参提取物及赤芍提取物制备抗肝纤维化药物胶囊
(1)处方：
丹参提取物 55g
赤芍提取物 55g
玉米淀粉 140g
共制成胶囊1000粒。
(2)制备方法：同实施例3。
实施例5、丹参提取物及赤芍提取物制备抗肝纤维化药物胶囊
(1)处方：
丹参提取物 33g
赤芍提取物 77g
羟甲基淀粉 140g
共制成胶囊1000粒。
(2)制备方法：同实施例3。
Claims (6)
1、一种抗肝纤维化的药物，主要由以下重量份配比组分制成：丹参提取物8～2份，赤芍提取物2～8份；
所述丹参提取物按照下述方法制备：取丹参饮片，水煎煮二次，分别滤过，合并两次的滤液，浓缩至每毫升滤液含生药1.0g，在浓缩后的滤液中加5％明胶沉淀鞣质，放置12小时，滤过，滤液浓缩至每毫升含生药1.5g，调pH2～3，再用等体积醋酸乙酯萃取三次，合并醋酸乙酯，减压回收醋酸乙酯，经80℃真空干燥，即得丹参提取物；
所述赤芍提取物按照以下方法制备：取赤芍粗粉，过20目筛，用50％乙醇回流提取二次，合并二次的提取液，滤过，减压回取乙醇，浓缩滤液至相对密度为1.10，在浓缩液中加三倍量热水稀释，放冷后加5％明胶水液，使明胶水液量为原浓缩液重量的15％，放置24小时后过滤，将滤液通过大孔树脂用去离子水冲洗至洗脱液中还原糖反应为阴性，再用40％乙醇洗脱，洗脱液用量为树脂体积的6BV，解吸流速为树脂体积1000.5-1BV/小时，减压回取乙醇，浓缩洗脱液至相对密度为1.30～1.35的稠浸膏，再经80℃下真空干燥，即制成赤芍提取物。
2、根据权利要求1所述的药物，其特征是所述丹参提取物7份，所述赤芍提取物3份。
3、根据权利要求1或2所述的药物，其特征是所述抗肝纤维化药物是口服剂型。
4、根据权利要求1或2所述的药物，其特征是所述抗肝纤维化药物是胶囊剂型，由以下组份制成：丹参提取物77g，赤芍提取物33g，辅料140g，共制成胶囊1000粒。
5、根据权利要求4所述的药物，其特征是所述辅料是微晶纤维或玉米淀粉或羟甲基淀粉。
6、制备权利要求4所述的抗肝纤维化药物的方法，包括如下步骤：
A、丹参提取物的制备：取丹参饮片，水煎煮二次，第一次加水10倍量，第二次加水6倍量，两次煎煮各1.5小时，分别滤过，弃去药渣，然后合并两次的滤液，浓缩至每毫升滤液含生药1.0g，在浓缩后的滤液中加5％明胶沉淀鞣质，放置12小时，滤过，滤液浓缩至每毫升含生药1.5g，用稀盐酸调pH2～3，再用等体积醋酸乙酯萃取三次，合并醋酸乙酯，减压回收醋酸乙酯，然后经80℃真空干燥，即得丹参提取物，丹参提取物中含丹参甲素以丹参甲素钠计算不得少于10％，含丹参水溶性总酚以原儿茶醛计算不得少于60％；
B、赤芍提取物的制备：取赤芍粉碎成粗粉，过20目筛，用50％乙醇回流提取二次，第一次回流提取用10倍量乙醇，第二次回流提取用6倍量乙醇，每次1.5小时，合并二次的提取液，滤过，减压回取乙醇，然后浓缩滤液至60℃的相对密度为1.10，在浓缩液中加三倍量≤90℃的热水稀释，放冷后加5％明胶水液，使明胶水液量为原浓缩液重量的15％，放置24小时后，过滤，然后将滤液通过大孔树脂用去离子水冲洗至洗脱液中还原糖反应为阴性，再用40％乙醇洗脱，洗脱液用量为树脂体积的6BV，解吸流速为树脂体积1000.5-1BV/小时，再次减压回取乙醇，然后浓缩洗脱液至50℃的相对密度为1.30～1.35的稠浸膏，再经80℃下真空干燥，即制成赤芍提取物；
C、丹参提取物及赤芍提取物抗肝纤维化药物胶囊的制备：取丹参提取物8～2重量份，赤芍提取物2～8重量份，加辅料，混匀过筛，用80％乙醇湿法制粒，干燥后装入胶囊，即得抗肝纤维化药物胶囊。
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