CN101185664B - 杨梅果实提取物的制药用途 - Google Patents
杨梅果实提取物的制药用途 Download PDFInfo
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Abstract
本发明涉及天然药物领域，具体涉及一种杨梅果实提取物，本发明还公开了其制备方法及其保肝的用途。
Description
技术领域
本发明涉及天然药物领域，具体涉及一种杨梅果实提取物，本发明还公开了其制备方法及其保肝的用途。
背景技术
杨梅(Myrica rubra Sieb.et Zucc)属杨梅科(Myricaceae)，为药食两用的芳香植物。宋代的《食疗本草》和明代的《本草纲目》中均有杨梅药用功效的记载。在中国大陆、台湾地区以及日本民间有使用杨梅果实、根、树皮和叶入药，治疗痢疾、腹泻、胃痛和风湿疼痛等症。杨梅含有丰富的有机酸、多酚、黄酮、三萜化合物等活性成分(Nonaka G.，Muta M.，NishiokaI.Myricatin，a galloyl flavanonol sulfate and prodelphinidin gallates from Myrica rubra.Phytochemistry，1983，22，237-241；Sakurai N.，Yaguchi Y.，Inoue T.Triterpenoids from Myricarubra Phytochemistry，1987，26：217-219；Sakurai N.，Yaguchi Y.，Hirakawa T.，Nagai M.，InoueT.Two myricanol glycosides from Myrica rubra and revision of the structure of isomyricanone.Phytochemistry，1991，30：3077-3079)。从杨梅枝叶和树皮中分离得到的杨梅素(3，5，7，3’，4’，5’-六羟基黄酮myricetin，Myr)，经研究显示，具有抗血栓、改善微循环，降血糖，保肝护肝，抗氧化，抗肿瘤等作用(陈文梅，红花黄酮成分抑制血小板激活因子介导的血小板活化作用。药学学报，2001，36(12)：881-885；臧宝霞，杨梅素对血小板活化因子拮抗的作用。药学学报，2003，38(11)831-833；钟正贤，广西藤茶中杨梅树皮素降血糖的实验研究。中国现代药学应用杂志，2003，20(6)：466-468；钟正贤，广西藤茶中杨梅树皮素的保肝作用研究。中药药理与临床，2001，17(5)：11-13；Hase K，Ohsugi M，Xiong Q B，et al.Hepatoprotective effect of Hovernia duleis Thunb.On experimental liver injuries induces by carbontetrachloride or D-galactosamine/lipopolysaccharide.Biol and pharma bulletin.1997，20(4)：381-385)。杨梅为我国的特产资源，鉴于地区差异，目前国际上对杨梅的研究刚刚起步，国内也只是对广西藤茶中含有的杨梅素研究较多，而对于经济作物的杨梅的活性成分的研究还较为欠缺。杨梅果实的药理学研究还未见报道。
发明内容
本发明公开了一种杨梅果实提取物，药理学试验证明其具有优良的保肝、护肝、治疗肝 脏疾病的功效。
本发明的杨梅果实提取物用以下方法制备得到：杨梅果实去核，用C1-4的脂肪族醇提取，浓缩即得。浓缩物可以直接加入药用辅料或食品辅料制备成药品或保健食品，也可将浓缩物进一步干燥得到粉末后再进行制备。上述C1-4的脂肪族醇优选乙醇，乙醇的浓度优选20％～80％，为重量百分比。用此方法得到的是杨梅果实的粗提物，简称MC。药理试验发现，MC具有一定的护肝作用。
在得到粗提物的的基础上，发明人对粗提物进一步提取，分别依次用石油醚、氯仿、乙酸乙酯和正丁醇对粗提物萃取，得到其不同部位的精提物，药理试验显示，氯仿提取物(简称MCE)显示了优异的保肝、护肝功能，其效果大大优于其它部位的提取物。
下面是部分药理学实验数据：
一、杨梅果实粗提物(ME)对肝脏的防护作用
1、ME对CCl4诱导的小鼠急性肝损伤的防护作用
小鼠48只分6组，对照组以生理盐水灌胃0.2ml/d，CCl4组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度ME 0.2ml/d，阳性对照药联苯双酯(DDB)以200mg/kg灌胃0.2ml/d，连续灌胃5天，第6天腹腔注射0.3％CCl4 0.1ml/10g，24h后处死动物，取血清测定sALT和sAST水平。
表1 ME对CCl4诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 46.2±9.3 | 72.0±16.5 |
| CCl4组 | 8 | 315.8±120.8** | 169.2±45.1** |
| CCl4+MEL(50mg/kg) | 8 | 282.7±132.4** | 166.8±40.7** |
| CCl4+MEM(150mg/kg) | 8 | 248.2±117.6** | 158.6±47.2* |
| CCl4+MEH(450mg/kg) | 8 | 180.6±98.8*▲ | 127.5±35.5▲ |
| CCl4+DDB(200mg/kg) | 8 | 43.5±8.3▲▲ | 98.6±34.2▲▲ |
注：*p＜0.05vs对照组，**p＜0.01vs对照组，▲p＜0.05vs CCl4组，▲▲p＜0.01 vs CCl4组， 
由表1可知，小鼠腹腔注射CCl4后，其血清ALT和AST活性显著升高，分别为对照组的6.84和2.35倍(p＜0.01)。而小鼠预先给予不同剂量ME灌胃，高剂量组小鼠血清AST及ALT活性与损伤组相比明显下降(p＜0.05)。
2、ME对D-GalN诱导的小鼠急性肝损伤的防护作用
小鼠40只分5组，对照组以生理盐水灌胃0.2ml/d，D-GalN组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度ME 0.2ml/d，连续灌胃5天，第6天腹腔注射 D-GalN(450mg/kg，0.1ml/10g)，于注射D-GalN 1小时后腹腔注射LPS(10ug/kg)，并在注射LPS后12h处死动物，取血清测定sALT和sAST水平。
表2 ME对D-GalN诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 43.7±8.4 | 103.1±26.7 |
| D-GalN组 | 8 | 324.9±78.3** | 327.9±54.3** |
| D-GalN+MEL(50mg/kg) | 8 | 330.4±81.7** | 325.8±62.4** |
| D-GalN+MEM(150mg/kg) | 8 | 286.9±72.8** | 291.6±63.7** |
| D-GalN+MEH(450mg/kg) | 8 | 243.7±53.4**▲ | 264.3±47.9*▲ |
注：*p＜0.05vs对照组，**p＜0.01vs对照组，▲p＜0.05vs D-GalN组，
由表2可知，小鼠腹腔注射D-GalN后，其血清ALT和AST活性显著升高，分别为对照组的7.43和3.18倍(p＜0.01)。而小鼠预先给予不同剂量ME灌胃，高剂量组小鼠血清AST及ALT活性与损伤组相比均明显下降。
3、ME对乙酰氨基酚(APAP)诱导的小鼠急性肝损伤的防护作用
小鼠40只分5组，对照组以生理盐水灌胃0.2ml/d，APAP组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度ME 0.2ml/d，连续灌胃5天，第6天腹腔注射APAP(160mg/kg，0.1ml/10g)，16h后处死动物，取血清测定sALT和sAST水平。
表3 ME对APAP诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 45.0±12.3 | 118.3±43.2 |
| APAP组 | 8 | 156.4±26.4* | 298.6±82.4* |
| APAP+MEL(50mg/kg) | 8 | 153.1±35.7* | 287.4±62.6* |
| APAP+MEM(150mg/kg) | 8 | 110.1±29.4* | 254.9±45.9* |
| APAP+MEH(450mg/kg) | 8 | 103.5±32.9*▲ | 253.9±57.4* |
注：*p＜0.05vs对照组，，▲p＜0.05vs APAP组， 
由表3可知，小鼠腹腔注射APAP后，血清ALT和AST活性升高，分别为对照组的3.48和2.53倍(P＜0.05)。而小鼠预先给予不同剂量ME灌胃，高剂量组小鼠血清AST与损伤组相比明显下降(P＜0.05)。
二、杨梅果实氯仿萃取物(MCE)对肝脏的防护作用
1、MCE对CCl4诱导的小鼠急性肝损伤的防护作用
小鼠48只分6组，对照组以生理盐水灌胃0.2ml/d，CCl4组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度MCE 0.2ml/d，阳性对照药联苯双酯(DDB)以200mg/kg灌胃0.2ml/d，连续灌胃5天，第6天腹腔注射0.3％CCl40.1ml/10g，24h后处死动物，取血清测定sALT和sAST水平。组织切片HE染色，观察形态学变化。
表4 MCE对CCl4诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 36.4±8.4 | 82.1±23.1 |
| CCl4组 | 8 | 283.3±128.1** | 164.9±41.3** |
| CCl4+MCEL(50mg/kg) | 8 | 198.7±101.9*▲ | 128.8±40.1▲ |
| CCl4+MCEM(150mg/kg) | 8 | 148.2+78.4*▲ | 106.9±47.1▲▲ |
| CCl4+MCEH(450mg/kg) | 8 | 33.6±7.6▲▲ | 75.4±25.5▲▲ |
| CCl4+DDB(200mg/kg) | 8 | 33.5±9.1▲▲ | 96.90±32.4▲▲ |
注：*p＜0.05vs对照组，**p＜0.01vs对照组，▲p＜0.05vs CCl4组，▲▲p＜0.01vs CCl4组， 
由表4可知，小鼠腹腔注射CCl4后，其血清ALT和AST活性显著升高，分别为对照组的7.78和2.01倍(p＜0.01)。而小鼠预先给予不同剂量MCE灌胃，各剂量组小鼠血清AST及ALT活性与损伤组相比均显下降。高剂量组可以完全抑制CCl4对肝脏造成的损伤作用，恢复到对照组水平。MCE能以剂量依赖方式抑制CCl4引起的小鼠sALT及sAST活性的显著上升。
肝脏切片显示，给予0.3％CCl424小时后，肝细胞索紊乱，细胞界限不清，以中央静脉为中心的大量细胞坏死、脂肪变性。预先用MCE灌胃的小鼠，CCl4损伤后肝组织结构较损伤组有明显改善，低剂量组小鼠细胞坏死及脂肪变性减少，中剂量和高剂量组细胞界限清楚，肝细胞排列规则，与联苯双酯保护的小鼠肝组织无差异(见图1)。
3、MCE对D-GalN诱导的小鼠急性肝损伤的防护作用
小鼠40只分5组，对照组以生理盐水灌胃0.2ml/d，D-GalN组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度MCE 0.2ml/d，连续灌胃5天，第6天腹腔注射D-GalN(450mg/kg，0.1ml/10g)，于注射D-GalN 1小时后腹腔注射LPS(10ug/kg)，并在注射LPS后12h处死动物，取血清测定sALT和sAST水平。组织切片HE染色，观察形态学变化。
表5 MCE对D-GalN诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 39.4±6.1 | 117.1±28.0 |
| D-GalN组 | 8 | 349.4±83.8** | 336.0±57.9** |
| D-GalN+MCEL(50mg/kg) | 8 | 299.4±131.4**▲ | 324.1±69.1** |
| D-GalN+MCEM(150mg/kg) | 8 | 196.8±102.7*▲ | 266.8±63.3*▲ |
| D-GalN+MCEH(450mg/kg) | 8 | 160.7±87.4*▲▲ | 201.1±49.7*▲▲ |
注：*p＜0.05vs对照组，**p＜0.01vs对照组，▲p＜0.05vs D-GalN组，▲▲p＜0.01vs D-GalN组， 
由表5可知，小鼠腹腔注射D-GalN后，其血清ALT和AST活性显著升高，分别为对照组的8.87和2.87倍(p＜0.01)。而小鼠预先给予不同剂量MCE灌胃，中剂量和高剂量组小鼠血清AST及ALT活性与损伤组相比均显下降。
肝脏切片显示，给予D-GalN 13小时后，中央静脉、肝窦淤血明显，肝窦充溢枯否氏细胞，血管扩张充血，出现弥散性的多发性片状坏死。预先用MCE灌胃的小鼠，肝组织结构较损伤组有明显改善，中央静脉及肝窦淤血减轻，肝窦中枯否细胞减少，血管扩张减轻，高剂量组未见片状坏死(见图2)。
3、MCE对APAP诱导的小鼠急性肝损伤的防护作用
小鼠40只分5组，对照组以生理盐水灌胃0.2ml/d，APAP组及给药组(50、150、450mg/kg)分别以等量生理盐水及不同浓度MCE 0.2ml/d，连续灌胃5天，第6天腹腔注射APAP(160mg/kg，0.1ml/10g)，16h后处死动物，取血清测定sALT和sAST水平。组织切片HE染色，观察形态学变化。
表6 MCE对APAP诱导的小鼠急性肝损伤的防护作用
| 组别 | 动物数/只 | sALT活性(U/L) | sAST活性(U/L) |
| 对照组 | 8 | 40.5±13.2 | 131.8±40.1 |
| APAP组 | 8 | 145.2±24.2* | 280.9±84.2* |
| APAP+MCEL(50mg/kg) | 8 | 131.5±32.5* | 271.4±66.2* |
| APAP+MCEM(150mg/kg) | 8 | 100.1±29.3*▲ | 259.4±49.0* |
| APAP+MCEH(450mg/kg) | 8 | 89.2±29.0*▲ | 173.5±51.7▲ |
注：*p＜0.05vs对照组，，▲p＜0.05vs APAP组，
由表6可知，小鼠腹腔注射APAP后，血清ALT和AST活性升高，分别为对照组的3.57和2.13倍(P＜0.05)。而小鼠预先给予不同剂量MCE灌胃，高剂量组小鼠血清AST及ALT活性与损伤组相比明显下降(P＜0.05)。
肝脏切片显示，给予APAP 24小时后，胞浆成颗粒状、空泡样变性坏死；细胞核浓缩、碎裂、消失；形成以中央静脉为中心的圆盘状大量细胞坏死。预先用MCE灌胃的小鼠，肝组织结构较损伤组有较大改善，胞浆及细胞核细胞坏死减少，中央静脉周的圆盘状细胞坏死 减弱(见图3)。
CCl4、D-GalN和APAP肝损伤常用于筛选护肝药。一般认为，肝细胞的坏死范围与转氨酶活性呈正相关。本研究发现，ME及MCE对三种类型的实验性肝损伤均有不同程度的保护作用，能抑制由药物引起的转氨酶的升高，减轻肝细胞浊肿，脂肪样变，炎症浸润及坏死等病理改变。因此，可以认为，ME和MCE对实验性肝损伤确有明显的保护作用。可以用于研发预防和治疗肝病的新制剂。
附图说明
图1是MCE对抗CCl4诱导的小鼠肝脏组织损伤
图2是MCE对抗D-GalN诱导的小鼠肝脏组织损伤
图3是MCE对抗APAP诱导的小鼠肝脏组织损伤
具体实施方式
实施例1
杨梅果实粗提物的制备
杨梅新鲜果肉1.7kg，加入50％乙醇750ml回流提取1小时，过滤；滤渣再次用500ml 50％乙醇回流提取1小时；合并两次滤液、减压浓缩，干燥。
实施例2
杨梅果实精提物的制备：
杨梅新鲜果肉1.7kg，加入30％乙醇750ml回流提取1小时，过滤；滤渣再次用500ml 30％乙醇回流提取1小时；合并两次滤液、减压浓缩；浓缩液氯仿萃取两次，回收溶剂，减压浓缩、干燥，得精提物4.23g。
实施例3
杨梅果实精提物的制备：
杨梅新鲜果肉2kg，加入50％乙醇1000ml回流提取1小时，过滤；滤渣再次用600ml 50％乙醇回流提取1小时；合并两次滤液、减压浓缩；浓缩液用氯仿萃取两次，回收溶剂，减 压浓缩、干燥，得干浸膏4.49g。
实施例4
杨梅果实精提物的制备：
杨梅冻存果肉1.9kg，加入75％乙醇750ml回流提取1小时，过滤；滤渣再次用500ml 75％乙醇回流提取1小时；合并两次滤液、减压浓缩；浓缩液用氯仿萃取，回收溶剂，减压浓缩、干燥，得4.49g。
实施例5
杨梅果实精提物的制备：
杨梅冻存果肉2.3kg，加入75％乙醇1000ml浸泡提取3天，过滤；滤渣再次用600ml 75％乙醇浸泡提取1天；合并两次滤液、减压浓缩；浓缩液用氯仿萃取，回收溶剂，减压浓缩、干燥，得干浸膏4.95g。
实施例6
杨梅果实提取物片剂
取实施例2方法制备的杨梅果实提取物10g，加微粉硅胶2g，乳糖2g，混匀过100目筛，加水制成软材，30目制粒，60℃干燥，整粒加0.2g硬脂酸镁，混匀压片。
Claims (1)
1.杨梅果实提取物用于制备治疗肝损伤药物的用途，其中杨梅果实提取物用以下方法制备得到：杨梅果实去核，用20％～80％重量百分比的乙醇提取，浓缩，将浓缩液用氯仿萃取，氯仿萃取液浓缩、干燥，即得。
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Owner name: DONGHAI FRUIT JUICE CO. LTD., LIANYUNGANG CITY Free format text: FORMER OWNER: NANJING UNIVERSITY Effective date: 20120824 |
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Free format text: CORRECT: ADDRESS; FROM: 210093 NANJING, JIANGSU PROVINCE TO: 222300 LIANYUNGANG, JIANGSU PROVINCE |
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Effective date of registration: 20120824 Address after: 222300 No. 51, Shanxi Road, Niu Shan town, Jiangsu, Donghai County Patentee after: Donghai Fruit Juice Co., Ltd., Lianyungang City Address before: 210093 Hankou Road, Jiangsu, China, No. 22, No. Patentee before: Nanjing University |
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Granted publication date: 20110907 Termination date: 20191130 |
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| CF01 | Termination of patent right due to non-payment of annual fee |