CN1243743A - 一种治疗慢性肝病的药物及其制备方法 - Google Patents
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Abstract
本发明涉及一种治疗慢性肝病的药物及其制备方法。本发明涉及的药物采用桃仁、丹参、绞股蓝、发酵虫草菌粉、松花粉、五味子和适量淀粉作为原料制备成药剂。具有改善慢性乙型肝炎患者的临床症状、抑制和逆转肝纤维化进展及对肝炎后肝硬化综合治疗起良好作用,对阻止、逆转慢性肝纤维化的进展,抑制或延缓肝硬化的形成及肝硬化的治疗具有重要的意义及应用价值。
Description
本发明涉及一种治疗慢性肝病的药物。具体说是以中草药为原料制备的中成药及其制备方法。
我国慢性乙型肝炎病毒感染者约占总人口的10％，其中慢性乙型肝炎患者约有1.5千万人，有30％以上的慢性肝炎病人发展为肝硬化，且多为中年人。即对于我国的HbsAg携带者来说，死于肝病(主要为肝硬化和肝癌，后者60％以上均由肝硬化发展而来)的危险率男性为50％，女性为14％，其中肝纤维化的形成与发展是影响其预后，转归的关键病理变化之一，也是临床慢性肝病治疗中最为棘手的疑难问题。而迄今为止，国内外用于治疗该病的药物种类虽有许多，但大多没有特别公认的疗效，治疗后病情易反复，且价格昂贵。
本发明的目的在于提供一种具有改善慢性乙型肝炎患者的临床症状、抑制和逆转肝纤维化进展及对肝炎后肝硬化综合治疗起良好作用的慢性肝病治疗胶囊制剂及其制备方法。
本发明在我国中医理论和临床实践基础上，结合慢性肝病、肝纤维化与中医学的“血瘀”、“正虚”病机有着紧密联系的共识，采用扶正化瘀治疗原则，取丹参(莪术、三棱)活血化瘀，取虫草菌丝(黄芪、人参、黄精)扶正补虚，取桃仁助丹参活血化瘀，取松黄助虫草扶正补虚。
本发明采用药品原料药(药材)的质量符合中国药典有关规定。
1.桃仁
本品为蔷薇科植物[Prunus Persica(L.)Batsch]或山桃[Prunusdavidiana(Carr.)Franch]的干燥成熟种子。主要产地：四川、云南、陕西、山东。
2.发酵虫草菌粉
本品系从青海产新鲜冬虫夏草[Cordyceps Sinensis(Berk Sacc)]中分离所得的虫草菌—蝙蝠蛾拟青霉素[Paccilomyces hepiali Chen]Cs-4经深层发酵培养，将发酵产物过滤干燥制成，由江西国药厂生产提供。
3.丹参
本品为唇形科植物丹参[Salvia miltiorrhiza Bge.]的干燥根及根茎。主要产地：安徽、山东、河北。
4.五味子
本品为木兰科植物[Schisandra chinensis (Turcz.)Baill]或华中五味子[Schisandra Sphenanthera Rehd.et Wits]的干燥成熟果实。主要产地：辽宁、吉林、黑龙江、河北、四川、湖北、陕西、山西、云南。
5.绞股兰
本品为葫芦科植物[Gynostemma Pentaphyllam (Thunb)mak.]的干燥地上部分。主要产地：浙江、广西。
6.松花粉(松黄)
本品为松科植物马尾松[Pinus massoniana Lamb.]油松[Pinustabulaeformis Carr]同属数种植物的干燥花粉。主要产地：浙江、江苏。
本发明药物胶囊制剂是由下列组分制成的(用量为重量份，每1000粒胶囊内含)
桃仁 50-250 丹参 300-700 绞股兰 200-600 发酵虫草菌粉 150-450 松花粉 50-250 五味子 50-250
淀粉适量
制备本发明药物的配方优选重量(份)配比范围是：
桃仁 100-200 丹参 500-600 绞股兰 300-500 发酵虫草菌粉 200-300 松花粉 100-200 五味子 100-200
淀粉适量
本发明药物的最佳重量(份)配比是：
桃仁 130 丹参 530 绞股兰 400 发酵虫草菌粉 260松花粉 130 五味子 130
淀粉适量。
将上述各组分制成本发明药物胶囊制剂的生产方法是：
称取丹参、桃仁、绞股兰加水煎煮，合并煎液，取上清液，浓缩成浸膏，冷却，加乙醇，沉淀，滤过；另称取发酵虫草菌粉，五味子加乙醇热回流，冷却，合并乙醇液，滤过，滤液浓缩干燥；另称取松花粉加入乙醇温浸，合并浸出液，浓缩干燥成干膏，取上述三种干膏，混合粉碎，加淀粉适量，混匀，灌装胶囊，即得。
本发明质量标准如下：
性状：本品内容物为棕褐色粉末。
鉴别：发酵虫草菌粉、丹参，以薄层色谱法(中国药典1990年版一部附录57页)。
检查：符合胶囊剂项下有关各项规定(中国药典1990年版一部附录第16页)。
规格：每粒重0.3克。
本发明经动物试验结果表明：能有效地阻抑CCl4诱导的大鼠肝纤维化的形成，又可显著促进分别由CCl4和二甲基亚硝胺诱导的大鼠肝纤维化的逆转；与秋水仙碱、大黄虫丸比较，无论是抑制纤维化的进展，还是促进纤维化的逆转，抑或保护、恢复肝功能方面，均有较明显的优势；对CCl4大鼠急性肝损伤，具有良好的拮抗作用，不但可显著降低血清ALT活性，对增高的血清AST活性也有显著的抑制效果，显著优于阳性对照药联苯双酯；对D-半乳糖胺引起的大鼠血清AST活性急剧升高有显著的抑制效果；对二乙基亚硝胺诱发大鼠肝癌的癌前期肝细胞增生灶及相关指标有显著抑制作用，对诱癌24周后癌变程度也有一定的阻抑作用。
表1为大鼠各组肝组织蛋白、Hyp含量的变化(X±SD)组别 n 肝蛋白(mg/g肝) 肝Hyp(mg/g蛋白)正常对照组 8 242.8±32.1** 0.46±0.16***模型对照组 12 182.6±46.2 1.28±0.42秋水仙碱组 12 240.7±22.6*** 0.57±0.18***本发明组 9 243.2±26.7*** 0.59±0.07***注：与模型对照组比较，**P＜0.01；***P＜0.001
表2为14周及24周时各组大鼠肝组织中CGT阳性灶的变化(X±SD)组别 n 平均直径 平均面积 平均体积 面积密度 体积密度
(mm) (mm2/个) (mm3/个) (mm2/cm2) (mm3/cm2)模型14周 11 0.36±0.08 0.14±0.07 0.007±0.006 19.63±18.71 24.14±28.51对照组24周 11 1.10±0.58 2.48±3.09 0.352±0.340 83.24±17.56 417.75±320.60本发明组14周 11 0.26±0.04** 0.07±0.02** 0.002±0.001* 3.47±1.88** 2.52±1.74*24周 13 0.37±0.11*** 0.32±0.43* 0.014±0.008* 22.48±13.28*** 61.48±100.10注：与同期模型组比较，*P＜0.05；**P＜0.01；***P＜0.001表3为CCl4模型大鼠各组病理肝组织Hyp、MDA含量和SOD活性变化(X±SD)组别 n 脂肪变性 胶原纤维 MDA(nM/g肝) SOD(NU/1％肝匀浆)模型组 12 2.58±0.79 2.42±0.90 329.2±67.9 837.6±209.2秋水仙碱组11 1.64±0.67** 1.55±0.93* 312.6±109.6 917.0±208.3本发明组 12 1.60±0.70** 1.40±0.70*** 273.8±48.2* 1105.8±142.0**注：与模型对照组比较，*P＜0.05，**P＜0.0l；***P＜0.001．本发明组SOD活性在正常组水平。
本发明浸膏粉在鸭乙型肝炎病毒感染鸭体内进行口服治疗试验，3批实验用北京1日龄雏鸭75只静脉注射鸭乙型肝炎病毒，7天全部感染。阳性药阿昔洛韦口服100mg/kg，1天2次，10天和停药后3天有非常显著抑制(P＜0.01)说明有显著疗效。有效剂量纯浸膏粉每次1.36g/kg、一日二次。表4为本发明药物口服对鸭乙型肝炎感染鸭血清病毒DNA抑制率药名 剂 量 实验 鸭数 鸭血清 DHBV-DNA 抑制率％(g/kg) 批数 (只) T5 T10 P3本发明 粗 纯 I 6 50.01** 71.97** 27.71浸膏粉 2.0 1.36 II 6 42.97* 47.77* 36.67Bid×10po. III 6 42.68* 53.00** 30.94无环 0.1g/kg III 6 17.01 60.72** 30.70鸟苷 Bid×10po．注：给药治疗组不同时间DHBV-DNA抑制率分别与病毒对照组相同时间抑制率比较*P＜0.05；**P＜0.01
经对临床诊断为慢性乙型肝炎的95例患者进行的治疗观察，以传统的具有扶正化瘀作用的大黄虫丸作为对照，观察本发明对肝组织病理形态学变化及对纤维化血清学指标一血清单胺氧化酶活性、金属蛋白酶组织抑制因子、IV型胶原、透明质酸、层粘蛋白含量及24小时尿羟脯氨酸排出量的影响，结果证明本发明药物对肝组织学上的纤维化逆转率达58.3％，并有效地降低显著增高的血清ALT活性及血清总胆红质含量，提高血清白蛋白含量及白/球蛋白比值；6项纤维化血清学指标均有不同程度的改善，其中血清MAO活性及LN含量的下降值显著大于对照组，同时治疗后尿Hyp的排泄量较治疗前显著增加。表明本发明药物不但能有效地促进慢性乙型肝炎患者的肝功能恢复，对其显著增高的纤维化血清学诸指标呈现出明显的改善效果，其综合效果明显优于大黄虫丸。
本发明药物既可抑制慢性乙型肝炎肝内结缔组织合成的异常亢进，又能促进肝内结缔组织的分解代谢，对阻止、逆转慢性肝纤维化的进展，抑制或延缓肝硬化的形成以及肝硬化的治疗具有重要的意义及应用价值。表5慢性肝炎患者有关纤维化血清学指标及治疗前后的变化(X±SD)项目 正常人 慢乙肝 观 察 组 对 照 组
治疗前 治疗后 治前-治后 治疗前 治疗后 治前-治后MAO(u) 28±13 63±29△ 64±30 28±16** 36±27▲ 60±30 47±33 13±14
(20) (37) (30) (7)TIMP 164±20 192±39△△ 184±58 153±54** 31±44▲ 204±59 39±39*** 65±47
(60) (42) (24) (18)P-III-P 0.31±0.12 1.41±2.19△ 1.81±3.90 0.80±1.69* 1.0l±2.08 1.57±1.46 1.71±3.14 -0.14±2.51
(15) (34) (20) (14)IV-C 99±23 494±300△ 547±345 386±212** 161±262 404±179 333±150* 72±121
(60) (46) (29) (17)HA 38±36 371±295△ 377±293 208±85*** 167±199 356±313 220±218* 136±251
(60) (61) (44) (17)LN 234±69 373±71△ 369±73 210±241*** 161±116▲ 382±68 282±103*** 99±92(ng/ml) (60) (61) (42) (18)尿Hyp 33.7±21.9 21.4±8.4△△ 21.6±8.9 24.5±7.8* 3.2±7.5 20.7±7.3 22.6±5.6 2.0±6.5(mg/24h) (18) (29) (11)注：与正常人比较△P＜0.001，△△P＜0.01；与治疗前作比较*P＜0.05，**P＜0.01，***P＜0.001；与对照组治疗前后差值比较▲P＜0.05；内为病例数。
本发明药物治疗肝炎后肝硬化，经80例患者研究观察表明：①显著提高患者血清白蛋白、降低γ-球蛋白含量。②调整患者血浆支链氨基酸/芳香族氨基酸比值的异常。③显著地降低患者增高的血清LM和HA含量。④提高CD3 +、CD4 +、CD4 +/CD8 +比值，NK细胞活性及补体C3含量，降低呈显著增高的血清IgG及IgM含量。同时还能调节内分泌激素的异常变化。对肝炎后肝硬化具有良好的综合治疗效果，在预防肝性脑病的发生方面也有一定的实际意义。治疗后BCAA/AAA(1.676±0.324)较治疗前(1.410±0.385)明显回升；对照组(1.278±0.506)较治疗前(1.620±0.443)下降；观察组7例中6例上升，1例轻微下降；对照组为1例上升，1例不变，5例下降。两组间以治疗前后差值比较，有显著差异(P＜0.05)。
表6为两组患者治疗前后激素代谢的变化(X±S)项目 正常人 肝硬化 观察组 对照组
患者 治疗前 治疗后 治疗前 治疗后T(pmol/L) 180±58 130±55** 133±61 188±78△ 127±58** 113±54(28) (40) (12) (12) (10) (10)E2/T 0.80±0.25 1.50±1.02** 1.44±1.11 0.89±1.08△ 1.43±0.97** 1.65±1.04(28) (40) (12) (12) (10) (10)尿17-KS 9.24±2.08 5.68±2.72* 5.48±2.99 7.56±4.79 6.01±2.57* 4.91±0.53(mg/24h) (12) (40) (16) (16) (12) (12)注：与正常人比较，*P＜0.05，**P＜0.001；与治疗前比较，△P＜0.05；()内为病例数。表7为两组患者治疗前后血清HA、LM含量及尿Hyp排出量变化比较(
X±S)观测项目 正常人 观察组 对照组
治疗前 治疗后 治疗前 治疗后HA(μg/L) 30±48 570±273* 490±224△ 648±348* 712±316
(30) (19) (19) (18) (18)LM(ng/L) 354±193 504±163* 429±113△ 538±149* 547±158
(37) (13) (13) (15) (15)尿Hyp 33.7±21.9 25.3±14.7 27.1±19.8 31.1±9.6 31.9±13.5(mg/24h) (18) (16) (16) (13) (13)注：与正常人比较，*P＜0.001；与治疗前比较，△P＜0.05；()内为病例数。
实施例：
按下述配比称取原料(克)
桃仁 140 丹参 550 绞股兰450 发酵虫草菌粉 230松花粉 150 五味子 150 淀粉适量
按下述方法制备：
将称取的丹参、桃仁、绞股兰加水煎煮，合并煎液，静置24hr，取上清液，浓缩成浸膏，冷却，加乙醇，沉淀，滤过；另称取发酵虫草菌粉，五味子加乙醇热回流，冷却，合并乙醇液，滤过，滤液浓缩干燥；另称取松花粉加入乙醇温浸，合并浸出液，浓缩干燥成干膏，取上述三种干膏，混合粉碎，加淀粉适量，混匀，灌装胶囊，即得。
Claims (5)
1.一种用于治疗慢性肝病的药物，其特征在于采用下述重量配比的原料制成药剂：
桃仁 50-250 丹参 300-700 绞股兰 200-600 发酵虫草菌粉 150-450 松花粉 50-250 五味子 50-250
淀粉适量
2.按权利要求1所述的用于治疗慢性肝病的药物，其特征在于其中各原料的重量配比是：
桃仁 100-200 丹参 500-600 绞股兰 300-500 发酵虫草菌粉 200-300 松花粉 100-200 五味子 100-200
淀粉适量
3.按权利要求1所述的用于治疗慢性肝病的药物，其特征在于其中各原料的重量配比是：
桃仁 130 丹参 530 绞股兰 400 发酵虫草菌粉 260松花粉 130 五味子 130
淀粉适量。
4.按权利要求1、2或3所述的用于治疗慢性肝病的药物，其特征在于所述的药剂是胶囊剂。
5.按权利要求4所述用于治疗慢性肝病的药物的制备方法，其特征在于生产方法是：将按重量配比称取的丹参、桃仁、绞股兰加水煎煮，合并煎液，取上清液，浓缩成浸膏，冷却，加乙醇，沉淀，滤过；另称取发酵虫草菌粉，五味子加乙醇热回流，冷却，合并乙醇液，滤过，滤液浓缩干燥；另称取松花粉加入乙醇温浸，合并浸出液，浓缩干燥成干膏，取上述三种干膏，混合粉碎，加淀粉适量，混匀，灌装胶囊，即得。
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| CN1127917C (zh) * | 2000-10-09 | 2003-11-19 | 北京长寿保健品有限公司 | 一种延缓衰老的功能性营养保健品 |
| CN100394946C (zh) * | 2004-12-17 | 2008-06-18 | 上海中医药大学 | 一种能改善肺纤维化的中药制剂 |
| JP2008201749A (ja) * | 2007-02-21 | 2008-09-04 | Okayama Univ | 肝細胞増殖因子産生誘導剤及びその医薬品組成物 |
| CN1899415B (zh) * | 2006-01-12 | 2010-05-12 | 上海现代中医药技术发展有限公司 | 一种治疗慢性肝病的中药复方制剂及其制备方法 |
| US20100119541A1 (en) * | 2007-04-29 | 2010-05-13 | Xu Lieming | Use of a vegetable drug composition in the manufacturing of pharmaceutical preparation for the treatment of portal hypertension caused by hepatocirrhosis |
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| CN1056423A (zh) * | 1990-05-11 | 1991-11-27 | 陈江辉 | 清肝宝口服液的配制方法 |
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Owner name: SHANGHAI HYUNDAI CHINASE MEDICAL TECHNOLOGY DEVEL Free format text: FORMER OWNER: ZHONGYIYAO COLLEGE, SHANGHAI CITY Effective date: 20021227 |
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Effective date of registration: 20021227 Address after: 200051 days in Shanghai City Road 600 Lane 4, building 7F-C, Sichuan Patentee after: Shanghai Modern Chinese Traditional Medicine Technology Development Co., Ltd. Address before: 200032 No. 530, Lingling Road, Shanghai Patentee before: Shanghai University of Traditional Chinese Medicine technology services |
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Owner name: SHANGHAI HUANG HAI PHARMACEUTICAL CO. LTD. Free format text: FORMER OWNER: SHANGHAI HYUNDAI CHINASE MEDICAL TECHNOLOGY DEVELOPMENT CO., LTD. Effective date: 20080829 |
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Effective date of registration: 20080829 Address after: Shanghai City, Baoshan District Sheng Qiao Zhen Shi Tai Road No. 1288 Patentee after: Shanghai Huanghai Pharmaceutical Co., Ltd. Address before: Shanghai City Days Road 600 Lane 4, building 7F-C, Sichuan Patentee before: Shanghai Modern Chinese Traditional Medicine Technology Development Co., Ltd. |
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Granted publication date: 20010815 |
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