CN1933846A - 含有黄褥花果叶萃取物的血糖水平升高抑制剂和age生成抑制剂以及含有它们的食品 - Google Patents
含有黄褥花果叶萃取物的血糖水平升高抑制剂和age生成抑制剂以及含有它们的食品 Download PDFInfo
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- CN1933846A CN1933846A CNA2005800088971A CN200580008897A CN1933846A CN 1933846 A CN1933846 A CN 1933846A CN A2005800088971 A CNA2005800088971 A CN A2005800088971A CN 200580008897 A CN200580008897 A CN 200580008897A CN 1933846 A CN1933846 A CN 1933846A
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Abstract
本发明目的在于提供由天然成分制得的血糖水平升高抑制剂和AGE生成抑制剂、以及含有这些抑制剂的食品。所述血糖水平升高抑制剂或AGE生成抑制剂中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。
Description
技术领域
本发明涉及血糖水平升高抑制剂和高级糖基化终产物(AGE)生成抑制剂。
背景技术
随着近年来饮食习惯和生活方式的变化,糖尿病患者的数量日益增多。目前,在日本糖尿病患者的数量高达7,000,000,如果加上未来的糖尿病患者,该数目可能多达15,000,000。
糖尿病这种代谢障碍表现出由胰岛素激素活性水平不足所引起的长期血糖过多状态。长期血糖过多状态可能导致引发各种类型的并发症,例如神经疾病、白内障、肾病、视网膜病变、关节硬化、动脉粥样硬化、以及糖尿病性坏疽。并发症主要分为由借助于蛋白质与患者血液中的葡萄糖相结合的非酶促糖基化而引起的血管疾病以及由葡萄糖代谢后生成的山梨糖醇堆积引起的细胞破坏而导致的神经疾病。由蛋白质-葡萄糖结合形成的糖基化蛋白质随着反应的进一步进行生成被称作高级糖基化终产物(advanced glycation end product,AGE)的化合物。据推论,AGE与血管内皮细胞中的特异性受体(RAGE)相结合,促进出现糖尿病性血管疾病。
因此,抑制血糖水平升高以及抑制AGE生成被认为是用于治疗和预防糖尿病及糖尿病并发症的方法。
过去已经开发出很多用于治疗和预防糖尿病及糖尿病并发症的药剂。
这类药剂的实例包括血糖水平升高抑制剂(其被施用至进餐后血糖水平出现异常的糖尿病患者)和α-葡萄糖苷酶抑制剂(它可以抑制碳水化合物的消化和吸收,从而预防血糖水平升高)。已知伏格列波糖和阿卡波糖是α-葡萄糖苷酶的代表性抑制剂。已知羰基试剂氨基胍是AGE生成抑制剂的实例之一。这些药剂作为抗糖尿病药物或抗糖尿病并发症药物备受关注,并为此进行了很多临床试验。
尽管这些药剂具有显著的疗效,但是它们也强加给患者各种各样的副作用,例如摄取后出现胃气胀、因与其它血糖过低药物联合使用而引发的血糖过低状态、以及恶心或头痛。
为了克服上述缺陷,已经开发出各种由天然成分制成的药剂,它们具有缓和的疗效,但是却避免了与副作用相关的问题。例如已知紫苏萃取物(JP专利公开号(未审)2000-102313)、巴拉圭茶萃取物(JP专利公开号(未审)2003-146900)、罗布麻(Apocynum venetum)叶萃取物(JP专利公开号(未审)2002-053486)、以及枇杷叶萃取物(JP专利公开号(未审)2003-128571)是由天然成分制成的α-葡萄糖苷酶抑制剂。作为由天然成分制成的AGE生成抑制剂,例如通过萃取稻谷如野生稻谷得到的抗糖尿病活性物质和抗糖尿病并发症活性物质以及其制备方法(JP专利号3,334,016)是已知的,当然这类药剂的数量还不是足够的多。
黄褥花果(Acerola)是一种Rutales目Malpighiaceae科Malpighia属热带水果,其原产在加勒比群岛。目前,黄褥花果果实在全世界范围被广泛用作饮料和保健食品。然而,目前尚未检测出黄褥花果叶中的有用组分。黄褥花果叶作为从未使用过的资源,一直期待着发现其工业价值。
发明内容
本发明目的在于提供由天然成分制得的血糖水平升高抑制剂和AGE生成抑制剂以及含有任一种抑制剂的食品。
本发明包括下述发明。
(1)血糖水平升高抑制剂,其中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。
(2)根据(1)的血糖水平升高抑制剂,其中所述黄褥花果叶萃取物和/或其加工产品中含有多酚。
(3)AGE生成抑制剂,其中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。
(4)根据(3)的AGE生成抑制剂,其中所述黄褥花果叶萃取物和/或其加工产品中含有多酚。
(5)根据(1)-(4)中任意一项的血糖水平升高抑制剂或AGE生成抑制剂,其被用于治疗或预防糖尿病或糖尿病并发症。
(6)根据(1)-(5)中任意一项的血糖水平升高抑制剂或AGE生成抑制剂,其将被加入至食品中。
(7)含有根据(1)-(6)中任意一项的血糖水平升高抑制剂或AGE生成抑制剂的食品。
(8)含有黄褥花果叶萃取物和/或其加工产品的食品。
本说明书中包括公开在本申请优先权文本日本专利申请号2004-080520说明书和/或附图中的部分或全部内容。
发明效果
本发明提供了含有天然形成的物质作为活性成分的血糖水平升高抑制剂和AGE生成抑制剂,以及含有任一抑制剂的食品。
附图简述
图1示出了实施例1制备的纯化黄褥花果叶萃取物与纯化黄褥花果果实萃取物的麦芽糖酶抑制活性测量的对比结果。
图2示出了实施例1制备的纯化黄褥花果叶萃取物对AGE生成的抑制活性的测量结果。
发明优选实施方案
本发明涉及血糖水平升高抑制剂和AGE生成抑制剂,其中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。作为本发明所用的黄褥花果叶的萃取来源的黄褥花果的产地或种类并无特别限制。例如,黄褥花果可以生长在日本冲绳、或者巴西。本发明的血糖水平升高抑制剂和AGE生成抑制剂含有天然形成的物质也就是黄褥花果叶萃取物和/或其加工产品作为活性成分。因此,这类抑制剂涉及很低的副作用。本发明有效地利用了从未使用过的资源即黄褥花果叶,这使得本发明更为可取。
黄褥花果叶萃取物可以由新鲜的、半干或干燥黄褥花果叶得到。另外,萃取物还可以由保持未处理状态的叶或者被充分磨碎或切碎的叶得到。
对于黄褥花果叶萃取物并无特殊限制,只要是通过常规技术萃取到的即可。黄褥花果叶萃取物可以视需要进行浓缩。在本发明中,还可以使用黄褥花果叶萃取物的加工产品。本文中所使用的术语“黄褥花果叶萃取物的加工产品”包括但不限于黄褥花果叶萃取物通过各种色谱技术得到的纯化产物。
黄褥花果叶萃取物或其加工产品优选使用水或亲水性有机溶剂得到。至于亲水性有机溶剂,可以使用例如各种已知的有机溶剂,诸如醇类如甲醇、乙醇、甘油、丙二醇和1,3-丁二醇,丙酮,四氢呋喃,乙腈,1,4-二烷,吡啶,二甲亚砜,N,N-二甲基甲酰胺,以及乙酸。这类亲水性有机溶剂优选与水混和。
对于萃取条件并无特殊现制。温度范围通常为0℃-120℃,优选为20℃-50℃。萃取持续时间为大约1-24小时,优选为大约1或2小时。用于萃取的溶剂用量优选为原料质量的1-20倍。
萃取完毕后,残余物可以通过过滤或者离心除去,得到萃取物。萃取物可以视需要进一步浓缩。
所得到的萃取物偶尔含有糖类、有机酸等。因此,为了除去这类物质,优选完成一纯化步骤。纯化可以通过例如正相或逆相色谱法、离子交换色谱法、或凝胶过滤完成。这些技术可以充分地联合使用。
如实施例所述,用于本发明中的黄褥花果叶萃取物和/或其加工产品具有抑制血糖水平升高和抑制AGE生成的活性。这类活性可能是由于所述黄褥花果叶萃取物和/或其加工产品中含有多酚而引起的。尽管对于这些多酚的组成尚不清楚,但是据信这种组成在导致具有抑制血糖水平升高和抑制AGE生成的活性方面是有用的。
对于黄褥花果叶萃取物和/或其加工产品在本发明血糖水平升高抑制剂或AGE生成抑制剂中的含量并无特殊限制,只要可以获得所需效果即可。本发明的血糖水平升高抑制剂或AGE生成抑制剂中除了含有黄褥花果叶萃取物和/或其加工产品之外,还可以含有任意的其它成分。
本发明的血糖水平升高抑制剂或AGE生成抑制剂可以为同时含有黄褥花果叶萃取物和/或其加工产品与常规药物载体的制剂形式。对于剂型并无特殊限制,其完全可以根据需要加以确定。一般来说,剂型可以是口服制剂,例如片剂、胶囊剂、颗粒剂、细颗粒剂、粉剂、液体制剂、糖浆剂、混悬剂、乳剂、或酏剂,非肠道制剂例如注射剂、滴剂、栓剂、吸入剂、透皮吸收剂、透粘膜吸收剂、粘合制剂、或软膏剂。
口服制剂可以通过常规技术,使用各种赋型剂例如淀粉、乳糖、蔗糖、甘露醇、羧甲基纤维素、玉米淀粉、或无机盐制备得到。
除了上述赋型剂之外,这类型制剂还可以含有例如粘合剂、崩解剂、表面活性剂、润滑剂、助流剂、调味剂、着色剂、或者芳香物质。
粘合剂的具体实例包括结晶纤维素、羧甲基纤维素钠、甲基纤维素、羟丙基纤维素、低取代的羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、羧甲基纤维素钠、乙基纤维素、羧甲基乙基纤维素、羟乙基纤维素、小麦淀粉、大米淀粉、玉米淀粉、马铃薯淀粉、糊精、预胶化淀粉、部分预胶化淀粉、羟丙基淀粉、Pullulan、聚乙烯基吡咯烷酮、氨基烷基甲基丙烯酸酯共聚物E、氨基烷基甲基丙烯酸酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物、聚乙烯缩醛二乙氨基乙酸酯、聚乙烯醇、阿拉伯树胶、粉末阿拉伯树胶、琼脂、明胶、白色虫胶、黄蓍胶、纯化蔗糖、以及聚乙二醇(Macrogol)。
崩解剂的具体实例包括结晶纤维素、甲基纤维素、低取代的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、小麦淀粉、大米淀粉、玉米淀粉、马铃薯淀粉、部分预胶化的淀粉、羟丙基淀粉、羧甲基淀粉钠、以及黄蓍胶。
表面活性剂的具体实例包括大豆卵磷脂、蔗糖脂肪酸酯、硬脂酸聚烃氧基酯(polyoxyl stearate)、聚氧乙烯氢化蓖麻油、聚氧乙烯聚氧丙二醇、去水山梨糖醇倍半油酸酯、去水山梨糖醇三油酸酯、去水山梨糖醇单硬脂酸酯、去水山梨糖醇单棕榈酸酯、去水山梨糖醇单月桂酸酯、聚山梨酯、甘油单硬脂酸酯、十二烷基硫酸钠、以及聚桂醇。
润滑剂的实例包括小麦淀粉、大米淀粉、玉米淀粉、硬脂酸、硬脂酸钙、硬脂酸镁、水合二氧化硅、轻质无水硅酸、合成硅酸铝、干燥氢氧化铝凝胶、滑石、硅酸镁铝、磷酸氢钙、无水磷酸氢钙、蔗糖脂肪酸酯、石蜡、氢化植物油、以及聚乙二醇。
助流剂的具体实例包括水合二氧化硅、轻质无水硅酸、干燥氢氧化铝凝胶、合成硅酸铝、以及硅酸镁。
当本发明的血糖水平升高抑制剂或AGE生成抑制剂以液体制剂、糖浆剂、混悬剂、乳剂、或酏剂形式给药时,其中可以含有味道和香味矫正剂或者着色剂。
本发明还涉及含有前述血糖水平升高抑制剂或AGE生成抑制的食品。本发明的食品可以为任意形式,例如糖果(如蜜饯、糖锭、果酱、或口香糖)或饮料(诸如清爽饮料如茶或酒精饮料)形式、以及常见“食品”的形式。本发明的食品可以制备成用于特定保健用途的食品形式(例如用于预防糖尿病或糖尿病并发症的食品)。对于血糖水平升高抑制剂或AGE生成抑制剂在食品中的含量并无特殊限制,只要能够达到所需效果即可。
本发明还涉及含有黄褥花果叶萃取物和/或其加工产品的食品。迄今为止,尚未将黄褥花果叶用于食品中。
下面参照后面的实施例对本发明进行更详细的描述,当然本发明的技术范围并不受这些实施例的限制。
实施例1
黄褥花果叶均匀加工处理后,向其中加入3倍体积的蒸馏水,接着进行1小时萃取。上述步骤进行两次,萃取物离心、过滤、冻干后,再次稀释在蒸馏水中。所得到的溶液装填在C18筒柱(Sep-Pak Vac 35ccC18筒柱,Waters)上,用蒸馏水洗涤,0.2%TFA/甲醇溶液洗脱。洗脱部分蒸发至干,得到纯化的萃取物。
接下来,通过Folin-Denis方法测量所得到的纯化萃取物中的多酚含量。具体地说,将纯化萃取物溶解于蒸馏水中,浓度为0.5mg/ml,将0.1ml所得到的溶液、2.9ml蒸馏水、和0.5ml Folin-Ciocalteu试剂(Merck)进行混和。混合物放置3分钟,向其中加入20%碳酸钠溶液,混合物再放置60分钟,测量650nm处的吸收值。使用儿茶素作为标准参考物质绘制分析曲线。
结果发现,纯化萃取物中的多酚含量为25%。
实施例2
按照下述方法,时实施例1中制得的纯化黄褥花果叶萃取物进行α-葡萄糖苷酶抑制活性(麦芽糖酶抑制活性)测量。
向商购得到的大鼠小肠丙酮粉末中,加入9倍体积的56mM马来酸盐缓冲液(pH6.0),混合物用玻璃匀化器匀化。产物离心后,回收上清液,将其定义为粗制酶溶液。将20倍稀释的该粗制酶溶液用于麦芽糖酶反应中。
开始时,将0.6ml 2mg/ml样本溶液加入至0.6ml 2%麦芽糖溶液中,混合物在37℃下培养5分钟,向其中加入0.6ml上述粗制酶溶液,反应在37℃下进行120分钟。通过在沸水中加热10分钟使酶灭活,离心后,通过HPLC测量上清液中的葡萄糖水平。
HPLC条件如下。
柱:Shim-pack CLC-NH2柱(6.0×150mm)
柱温:室温
流速:2ml/分钟
流动相:75%乙腈
检测:RI
单独地,除了使用蒸馏水而不是样本溶液(用量与样本溶液所用用量相同)之外,类似地重复上述反应,反应产物定义为对照样本,类似地测得其中的葡萄糖水平。将对照样本的测量结果定义为麦芽糖抑制作用为0%。
图1示出了采用上述技术测得的结果。图1还示出了黄褥花果果实的测量结果,作为对照实施例,它是按照与黄褥花果叶相同的方式得到的。
从图1中明显看出,纯化黄褥花果叶萃取物具有麦芽糖酶抑制活性。
实施例3
按照下述方法,对实施例1中制得的纯化黄褥花果叶萃取物进行抗AGE生成的抑制活性测量。
将牛血清白蛋白(16mg/ml,1ml)、1ml 4M葡萄糖、1ml 1/15M磷酸盐缓冲液(pH7.2)、和1ml 0.3mg/ml样本溶液进行混和,产物储存在60℃下。七天后,使用荧光光谱计测量由蛋白质和葡萄糖生成的AGE。使用325nm的激发波长和405nm的发射波长分析AGE初始产物。使用370nm的激发波长和440nm的发射波长分析AGE高级产物。为了进行对照,按照相同方式完成了使用氨基胍的试验。另外,除了使用蒸馏水而不是样本溶液(用量与样本溶液所用用量相同)之外,还重复进行了与上述相同的试验,反应产物定义为对照样本,类似地进行荧光分析。将对照样本的测量结果定义为AGE抑制作用为0%。
采用上述技术测得的结果如图2所示。
从图2中明显看出,纯化的黄褥花果叶萃取物具有与氨基胍相当的抗AGE生成的抑制活性。
在此将本文中所引用的全部出版物、专利、和专利申请的全部内容引入作为参考。
Claims (8)
1.血糖水平升高抑制剂,其中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。
2.根据权利要求1的血糖水平升高抑制剂,其中所述黄褥花果叶萃取物和/或其加工产品中含有多酚。
3.高级糖基化终产物(AGE)生成抑制剂,其中含有黄褥花果叶萃取物和/或其加工产品作为活性成分。
4.根据权利要求3的AGE生成抑制剂,其中所述黄褥花果叶萃取物和/或其加工产品中含有多酚。
5.根据权利要求1-4中任意一项的血糖水平升高抑制剂或AGE生成抑制剂,其被用于治疗或预防糖尿病或糖尿病并发症。
6.根据权利要求1-5中任意一项的血糖水平升高抑制剂或AGE生成抑制剂,其将被加入至食品中。
7.含有根据权利要求1-6中任意一项的血糖水平升高抑制剂或AGE生成抑制剂的食品。
8.含有黄褥花果叶萃取物和/或其加工产品的食品。
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