CN1233182A - 作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的桔皮提取物 - Google Patents

作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的桔皮提取物 Download PDF

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CN1233182A
CN1233182A CN97198801A CN97198801A CN1233182A CN 1233182 A CN1233182 A CN 1233182A CN 97198801 A CN97198801 A CN 97198801A CN 97198801 A CN97198801 A CN 97198801A CN 1233182 A CN1233182 A CN 1233182A
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citrus peel
peel extract
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卜成海
孙光熙
郑泰淑
权柄穆
金永国
崔度一
金成郁
裴基焕
朴镛福
崔明淑
黄仁奎
文锡植
权容国
安贞娥
李恩淑
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Korea Advanced Institute of Science and Technology KAIST
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Abstract

本发明涉及一种用于抑制哺乳动物中3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶活性的药物组合物,其包括有效量之作为活性成分的桔皮提取物以及药物学上可接受的载体。本发明还涉及用于抑制3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶活性的食品或饮料组合物,其包括有效量的桔皮提取物。

Description

作为3-羟基-3-甲基戊二酰辅酶A(HMG-CoA) 还原酶抑制剂的桔皮提取物
发明领域
本发明涉及抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的药物组合物，该组合物包括有效量之作为活性成分的桔皮提取物以及药物学上可接受的载体，本发明还涉及用于抑制HMG-CoA还原酶活性的食品或饮料组合物，该组合物包含有效量的桔皮提取物。
发明背景
近些年来，冠状心血管循环疾病，例如动脉粥样硬化和高胆固醇血症，已逐渐成为主要的致死原因。已有报道称，血浆胆固醇浓度增高导致脂肪、巨噬细胞和泡沫细胞沉积在血管壁上，此等沉积则导致斑块形成，并由此引发动脉粥样硬化(Ross,R.,Nature,362,801-809(1993))。降低血浆胆固醇浓度的方法之一是饮食料法，以降低胆固醇和脂质的摄入。另一种方法是降低在肝脏中进行的胆固醇的生物合成速率。已有报道称，高胆固醇血症可通过抑制HMG-CoA还原酶并由此降低胆固醇的生物合成速率来有效地治疗，所述HMG-CoA还原酶介导3,5-二羟基-3-甲基戊酸的合成，该化合物是甾醇或类异戊二烯之生物合成中的中间体(Cardiovascular Pharmacology,William W.Parmley and Kanu Chatterjee Ed.,Wolfe Publishing,pages8.6-8.7,1994)。
因此，已进行了许多努力来研制可以抑制HMG-CoA还原酶的药物；其结果是已有几种从Penicillium sp.和Aspergillus sp.得到的化合物进入市场销售。具体而言，Merck Co.,USA研制的Lovastatin和Simvastatin以及Sankyo Co.,Japan研制的Pravastatin已在市场上销售(C.D.R.Dunn,Stroke:Trends,Treatment and Markets,SCRIPT Report,PJB Publications Ltd.,1995)。但是，这些药物非常昂贵，而且已知长期给药会诱发肝脏中肌酸激酶增加的副作用。因此，仍有必要继续研制价格低廉而且无毒性的HMG-CoA还原酶抑制剂。
桔皮提取物已被用作助消化的药物。但是，尚没有报道桔皮提取物具有HMG-CoA还原酶抑制剂的活性。
发明简述
因此，本发明的目的是提供一种用于抑制哺乳动物中HMG-CoA还原酶活性的药物组合物。
本发明的另一个目的是提供一种用于抑制哺乳动物中HMG-CoA还原酶活性的食品或饮料组合物。
根据本发明的一个方面，其提供一种用于抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶之活性的药物组合物，该组合物包括有效量之作为活性成分的桔皮提取物以及药物学上可接受的载体。发明详述
本发明提供一种用于抑制HMG-CoA还原酶活性的药物组合物，该组合物包括作为活性成分的桔皮提取物以及药物学上可接受的赋形剂、载体或稀释剂。
柑桔属植物可为柑桔、橙、柠檬、葡萄柚和枸桔(Poncirus trifoliata)。
桔皮提取物可通过任何常规方法使用醇或水来制备。例如，5-100升醇或水加至1kg干燥桔皮中，然后使混合物在5-80℃(溶剂为醇时)或20-140℃(溶剂为水时)静置10分钟-48小时。该提取过程可重复1-3次。例如通过真空来浓缩所得的提取物，以得到浓缩桔皮提取物。另外，桔皮提取物也可如下制备：用氢氧化钙溶液处理桔皮，加入盐酸调节溶液的pH值至4.0-4.5，然后离心所得溶液，得到作为桔皮提取物的沉淀物黄酮类似物(FDA Report No.FDA-8F-82/62,“Evaluation of health aspects of hesperidin,naringin and citrusbiolfavonoide extracts as food ingredient”,Natl.Technical InformationService PB 82-192931(1982))。
桔皮提取物在10mg/kg/天或更高的剂量时对HMG-CoA还原酶具有抑制作用，该抑制作用随剂量而增高。
而且，尽管有强的效力，但桔皮提取物在鼠实验中几乎没有表现出毒性或促有丝分裂性。更具体而言，当以1000mg/kg的剂量给鼠口服给药时，桔皮提取物没有产生毒性，对于50kg重的人来说，上述剂量相当于口服给药50-100g桔皮提取物/kg体重。另外，桔皮提取物对肝功能没有副作用。
可使用上述组合物根据任何常规方法来制备药物制剂。在制备制剂时，活性成分优选与载体混合或用载体稀释，或者包封在胶囊、小药囊或其他容器之形式的载体中。如果载体为稀释剂，其可为固体、半固体或液体物质，作为活性成分的载体、赋形剂或介质。因此，制剂可为片剂、丸剂、粉末、小药囊剂、甘香酒剂、混悬剂、乳剂、溶液、糖浆、气雾剂、软和硬明胶胶囊、无菌注射液、无菌包装的粉末等剂型。
合适的载体、赋形剂和稀释剂的例子是乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油。药物制剂可另外包括填料、抗附聚剂、润滑剂、润湿剂、调味剂、乳化剂、防腐剂等。本发明的组合物可用任何本领域已知的方法配制成在给药于哺乳动物后快速、持续或延迟释放活性成分的制剂。
本发明的药物制剂可通过各种途径给药，包括口服、透皮、皮下、静脉和肌肉给药。对于人，桔皮提取物的典型日剂量是约10-500mg/kg体重，优选为20-100mg/kg，而且该剂量可以单剂量或多份剂量给药。但是，实际给药的活性成分的量应根据各种相关因素来确定，所述因素包括待治疗的疾病、所选择的给药途径、每个患者的年龄、性别和体重、以及患者症状的严重程度；因此，上述剂量绝不是用于限制本发明的范围。
另外，本发明的桔皮提取物可掺入在食品或饮料中，用于抑制HMG-CoA还原酶活性。因此，本发明还提供用于抑制HMG-CoA还原酶活性的食品或饮料组合物，该组合物包括有效量的桔皮提取物。在此情况下，食品或饮料中的桔皮提取物含量可在0.1-50％之间。
如上所述，桔皮提取物可用作有效抑制HMG-CoA还原酶活性的非毒性药物。
以下实施例用于进一步阐明本发明，而不是限制其范围。
另外，以下固体混合物中之固体、液体中之液体、以及液体中之固体的百分比分别是以wt/wt、vol/vol和wt/vol计算，而且所有的反应都是在室温下进行，除非另有说明。实施例1：桔皮提取物的制备和分析
在室温下干燥桔皮，然后在6.7kg的干燥桔皮中加入80升的95％乙醇。该混合物在室温下静置24小时，然后过滤得到提取液和固体残渣。该固体残渣用相同的方法再被提取一次。合并所得的提取液，使用大容量蒸发器(EYELA旋转真空蒸发器N-11)在减压下浓缩，得到浓缩提取物(d=1.3g/ml)。
用DMSO/甲醇混合物(1∶1)稀释该浓缩提取物至浓度为10mg/ml。将100μl所得溶液注入高效液相色谱(HPLC)中，该色谱使用Phenomenex Prodigy柱(5μODS(3)100，4.6×250mm)，所述色谱柱用0.01M磷酸/甲醇(70∶30)混合物预平衡。样品用0.01M磷酸/甲醇(70∶30)混合物以0.6ml/min的流速洗脱55分钟，其中逐渐增加甲醇的浓度至45％。使用100μl(1mg/ml)橙皮苷和柚皮苷(SigmaChemical Co.,USA)作为标准物质。在280nm下检测洗脱液，发现1kg的桔皮提取物包含5950mg橙皮苷和280mg柚皮苷。
进一步根据常规方法鉴定桔皮提取物的成分。例如，用干法在105℃下测定水含量；用Kjeldahl法测定粗蛋白；用Soxhlet法测定粗脂质；用Bertrand法测定游离糖；在550-600℃下燃烧测定粗灰份；以及用HPLC法测定橙皮苷和柚皮苷。结果见下表Ⅰ。
                            表Ⅰ
成分     含量(％)
水含量      39.1
粗蛋白      2.7
粗脂质      1.8
游离糖 果糖      20.0
葡萄糖      16.5
蔗糖      8.6
粗灰份      1.0
橙皮苷      0.6
柚皮苷      0.03
其他糖      9.67
实施例2：向动物给药桔皮提取物
随机将体重为90-110g的20只4周龄Sprague-Dawley小鼠(Taihanlaboratory animal center,Korea)平均分成2个组。两个组的小鼠分别用两种不同的高胆固醇食物喂养，即包含1％胆固醇的AIN-76实验室动物饲料(ICN Biochemicals,Cleveland,OH,USA)(对照组)，以及1％胆固醇加16.7％桔皮提取物。两个组所用饲料的成分见下表Ⅱ。
                              表Ⅱ
饲料成分     对照组 桔皮提取物组*2
酪蛋白      20       20
D,L-蛋氨酸      0.3       0.3
玉米淀粉      15       15
蔗糖      49       32.3
纤维素粉末*1       5        5
矿物质混合物*1      3.5       3.5
维生素混合物*1       1        1
柠檬酸胆碱      0.2       0.2
玉米油       5        5
胆固醇       1        1
桔皮提取物       16.7
总计      100       100
*1：从TEKLAD Premier Co.(Madison,WI,USA)购得*2：0.1％橙皮苷等价物
无限制地用具体饲料和水喂养小鼠共6周，每日记录摄取量，然后每7天称重，并分析记录数据。所有小鼠都显示正常的生长速度，而且两个组之间在食物摄取量和体重增加方面没有显著差异。实施例3：血浆中总胆固醇、HDL-胆固醇和中性脂质含量的测定
以下测定向小鼠给药桔皮提取物对血浆胆固醇和中性脂质含量的影响。
从上两个组的小鼠中采取血样，并用包含葡萄糖硫酸酯的HDL-胆固醇试剂(Sigma Chemical Co.,Cat.No.352-2)从中分离血浆HDL成分。用Sigma Diagnostic Kit Cat.No.352-100(Sigma Chemical Co.,USA)测定总胆固醇和HDL-胆固醇浓度(Allain et al.,Clin.Chem.,20,470-475(1974))。用Sigma Diagnostic Kit Cat.No.339-50(SigmaChemical Co.,USA)测定中性脂质浓度(Bucolo,G.And David,H.,Clin.Chem.,19,476-482(1973))。结果见表Ⅲ，其中，与对照组小鼠相比，桔皮提取物饲养组中小鼠的总血浆胆固醇浓度下降35％。
                                表Ⅲ
组     对照组   桔皮提取物组
总胆固醇(mg/dl)   147.8±34.8     94.2±23
HDL-胆固醇(mg/dl)       22.2       23.5
HDL-胆固醇/总胆固醇(％)     15.7±5.3     26.3±7.5
TG(mg/dl)     99.2±18.9    108.5±15.9
动脉粥样硬化指数      6.3±3.4      3.1±1.2
TG：甘油三酯实施例4：桔皮提取物在HMG-CoA抑制中的活性(步骤1)制备微粒体
为确定用桔皮提取物饲养小鼠对HMG-CoA还原酶活性的作用，从肝组织中制备微粒体作为酶源，所述还原酶是调节肝脏中胆固醇之生物合成的酶。
首先，将上述两组小鼠断头处死，取出肝脏，并立即放置在冰冷却的匀浆介质(50mM KH2PO4(pH7.0),0.2M蔗糖，2mM二硫苏糖醇(DTT))中。在匀浆介质(2ml介质/g肝脏)中用Waring混合器(三冲程的Potter-Elvehjem型玻璃匀浆器，带有一个马达驱动的Teflon研杵)使肝脏匀浆15秒。在15000×g下离心匀浆10分钟，由此得到的上清液在100000×g下离心75分钟，得到微粒体沉淀，然后将该沉淀重新悬浮在包含50mM EDTA的匀浆介质中，然后在100000×g下离心60分钟。用包含微粒体的上清液作为酶源。(步骤2)HMG-CoA还原酶实验
如下根据Shapiro等人的方法(Biochemical et Biophysica Acta,370,369-377(1974))使用[14C]HMG-CoA测定HMG-CoA还原酶的活性。
在37℃下活化含微粒体之上清液(步骤1中得到的)中的酶30分钟。在反应试管中加入20μl的HMG-CoA还原酶实验缓冲液(0.25MKH2PO4(pH7.0),8.75mM EDTA,25mM DTT,0.45MKCl和0.25mg/mlBSA)、5μl的50mM NADPH、5μl的[14C]HMG-CoA(0.05μCi/试管，最终浓度120μM)和10μl之经活化的微粒体酶(0.03-0.04mg),然后混合物在37℃下培育该混合物30分钟。在该混合物中加入10μl的6M盐酸，由此使反应停止，然后在37℃下培育该混合物15分钟，使产物(甲羟戊酸)完全内酯化。在10000×g下离心1分钟，由此除去沉淀物，然后将上清液用在硅胶60G TLC板(Altech,Inc.,Newark,USA)上，并用苯∶丙酮(1∶1,v/v)展开。用一次性载玻片刮下Rf值在0.65-0.75之间的区域，并用1450Microbeta液体闪烁计数器(Wallacoy,Finland)进行放射活性实验。以pmol合成的甲羟戊酸/分钟/mg蛋白计算酶活性。结果见表Ⅳ。
                           表Ⅳ
组     对照组    桔皮提取物组
HMG-CoA还原酶活性(pmol/min/mg蛋白)   147±12.5     112.1±12.8
从表Ⅳ的结果可以看出，对照组小鼠具有相对较高的HMG-CoA还原酶活性，而桔皮提取物组小鼠中观察到的HMG-CoA活性则低于对照组34％。实施例5：口服给药桔皮提取物的毒性
在22±1℃的温度、55±5％的湿度和光照周期12L/12D的条件下，饲养7-8周龄、无特定病原的ICR雌鼠(8只)和雄鼠(8只)，雌鼠重量在25-29g，雄鼠重量在34-38g。将饲料(Cheiljedang Co.，鼠饲料)和水消毒，然后喂给小鼠。
将桔皮提取物溶解在0.5％Tween80中，至浓度为100mg/ml，然后将该溶液口服给药至小鼠，用量为0.2ml/20g小鼠体重。给药所述溶液后，按以下程序观察小鼠10天并记录副作用或死亡现象：给药后1、4、8和12小时，以后则每隔12小时观察。每天记录小鼠体重变化，以检查桔皮提取物的作用。另外，在第10天时，将小鼠处死，并肉眼检查内部器官。
在第10天时所有小鼠都存活，而且1000mg/kg剂量的桔皮提取物没有毒性。尸检结果是，小鼠没有形成任何病理非正常性，而且在10天的检查期间没有观察到体重减轻。因此，可得出以下结论：桔皮提取物在口服给药动物时没有毒性。
以下制剂实施例仅用于说明本发明，而绝不是限制本发明的范围。制剂实施例
使用以下成分制备硬明胶胶囊：
                                    量(mg/胶囊)活性成分(桔皮提取物)                        20干燥淀粉                                   160硬脂酸镁                                    20总计                                       200mg
虽然已参考上述具体实施方案对本发明进行了描述，但应认识到，本领域技术人员在本发明的范围内还可进行各种改进和变化，而本发明的范围为以下权利要求书所限定。

Claims (6)

1、一种用于在哺乳动物中抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的药物组合物，其包括有效量之作为活性成分的桔皮提取物以及药物学上可接受的载体。
2、如权利要求1所述的药物组合物，其中，所述哺乳动物是人。
3、如权利要求1所述的药物组合物，其中，所述柑桔属植物是柑桔、橙、柠檬、葡萄柚和枸桔。
4、如权利要求2所述的药物组合物，其中，桔皮提取物的有效量为10-500mg/kg体重/天。
5、一种用于抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的食品组合物，其包括有效量的桔皮提取物。
6、一种用于抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的饮料组合物，其包括有效量的桔皮提取物。
CN97198801A 1996-10-14 1997-10-13 作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的桔皮提取物 Pending CN1233182A (zh)

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EP0930889B1 (en) 2002-12-18
WO1998016239A1 (en) 1998-04-23
CA2268439C (en) 2003-12-23
KR100213899B1 (ko) 2000-03-15
EP0957911B1 (en) 2004-03-10
EP1014968A1 (en) 2000-07-05
KR100213898B1 (ko) 2000-03-15

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