CN109394801A - 含有栗寄生提取物的用于抑制糖基化终产物的生成及促进糖基化终产物的分解的组合物 - Google Patents
含有栗寄生提取物的用于抑制糖基化终产物的生成及促进糖基化终产物的分解的组合物 Download PDFInfo
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Abstract
本发明涉及一种用于预防或治疗与抑制糖基化终产物(AGEs,A dvanced glycation end‑products)的生成及促进糖基化终产物的分解有关的疾病的组合物,其含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分,根据本发明,通过栗寄生提取物所具有的抑制糖基化终产物的生成的效果和裂解糖基化终产物与胶原蛋白之间的交联的效果,能够用于预防或改善因AGEs的沉积而引起的诸如糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或者阿尔茨海默病等的与糖基化终产物有关的疾病及皮肤老化。
Description
技术领域
本发明涉及抑制糖基化终产物(AGEs,Advanced glycation end-products)的生成及促进糖基化终产物的分解的组合物,其含有栗寄生(Korthalsella japonica(Thunb.)Engl.)提取物作为有效成分,更具体地,涉及通过抑制糖基化终产物的生成及裂解糖基化终产物与胶原蛋白之间的交联,而预防或治疗糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或者阿尔茨海默病的组合物,或抑制及改善皮肤老化的组合物,所述组合物包含栗寄生提取物。
背景技术
糖化反应(Maillard reaction,Glycation)是指通过还原糖的羰基(carbonyl)与作为蛋白质的游离氨基(amino)的赖氨酸(lysine)或精氨酸(arginine)的非酶性反应而生成初级阶段的产物席夫碱(shiff base),继续通过缩合、重排、氧化、分裂、环化等一系列的复杂反应,形成褐色的不可逆的糖基化终产物(Advanced glycation end-products,AGEs)的生成过程。
已知,一旦生成这种不可逆的反应产物糖基化终产物就不再分解,而是通过与晶状体蛋白质、胶原蛋白(Collagen)等进行交联(Crosslinking)而沉积于皮肤或组织中,并使其结构和功能变为非正常化,以干涉于多种疾病。尤其,已知很多研究报告称,糖尿病并发症、动脉硬化、晚期肾功能衰竭、类风湿性关节炎、阿尔茨海默病、皮肤皱纹的形成等与老化相关的多种疾病的发展过程都与糖基化终产物有着密切的关系(Semin Nephrol.2007Mar;27(2):130-43;及Curr Alzheimer Res.2004 Feb;1(1):39-46)。
其中,已知糖尿病并发症是与糖基化终产物相关的最具代表性的疾病。糖尿病是指体内胰岛素(insulin)的分泌和活性出现障碍的状态为特征的具有代表性的慢性疾病,禁食8~12小时后所测定的血糖达到126mg/dL以上或在口服葡萄糖耐量试验中,摄取葡萄糖2小时后所测定的血糖达到200mg/dL以上时,将被确诊为是糖尿病,糖尿病的最高危险人群是源于高血糖的并发症。
促进糖尿病并发症的因素之一为糖与血管壁的蛋白质或脂质和蛋白质之间的非酶性交联反应。正常血管内胶原蛋白的交联一般发生在N-与C-末端的特定部位中,但是因糖基化终产物的胶原蛋白的交联却随意地发生于任何部位中,并形成非正常的交联。一旦生成这种非正常的交联,即使血糖恢复到正常,也不会被分解,并且在蛋白质的生存期间沉积于组织当中,成为神经血管性障碍的病发原因,并引发糖尿病性视网膜病变、糖尿病白内障、糖尿病肾病等致命性的慢性糖尿病并发症。
此外,也有研究报告称,糖基化终产物与阿尔茨海默病的发病有关。阿尔茨海默病(Alzheimer’s disease,AD)是由大脑疾病引起的的一种综合症,是指包括记忆力、思考能力、学习能力、言语及判断能力等的大脑功能的多发性障碍,大部分表现为慢性的和进行性。
阿尔茨海默病的病因虽然迄今未明,但是推测其与老化有着密切的关系,且其主要原因推测为是叫作β-淀粉样蛋白(β-amyloid)的蛋白质沉积于大脑中并聚集(Aggregation)而发病的。根据之前的研究,在正常的生理条件下,β-淀粉样蛋白聚合缓慢,而另一方面,与糖基化终产物的交联而变性的β-淀粉样蛋白(AGE-modifiedβ-amyloid)的聚合则非常急速(Neurobiology,91,4766-4770,1994)。
此外,糖基化终产物与胶原蛋白的非正常的交联与皮肤老化有着密切的关系。皮肤老化大致可分为内因性老化和外因性老化。内因性老化是指随着年龄的增长而发生的自然的衰老现象,其受遗传因子等的影响,而外因性老化是指因紫外线、吸烟、环境污染等的外部因素而出现的衰老现象,其中老化的最大因素为紫外线,因此也被称之为光老化。
作为皮肤老化的主要外观变化表现为,因真皮的结构变化而出现的皱纹的形成和皮肤弹性的降低。皮肤真皮层的90%是由胶原蛋白组成,胶原蛋白作为对皮肤赋予弹性的主要成分,当这种胶原蛋白的结构被打乱时会生成皮肤皱纹。半衰期较长的胶原蛋白容易发生糖化反应,并且,随着糖基化终产物与胶原蛋白的交联,降低皮肤弹性并形成皱纹,从而促进皮肤老化。根据之前的研究表明,当糖基化终产物以增加的浓度存在时,观察到大鼠(Rats)的胶原微丝发生非正常的结构变化(Odetti P,Aragno I,et al.Gerontology,1998,44(4);187-91)。另一种皮肤老化的外观变化表现为老年斑。老年斑是因皮肤老化而在皮肤上出现的黑斑,已知其的发病原因有很多种,其中,其与糖基化终产物的沉积也有着密切的关系。
如上所述,糖基化终产物与多种疾病都有相关,因此,包括韩国在内的很多发达国家都在集中于研究和开发可抑制糖基化终产物的生成或可分解已经形成的糖基化终产物的交联的素材。尤其,最近随着对能够使副作用降低到最小化的安全素材的关注度越来越高,基于天然物的素材开发也开始备受重视。
槲寄生寄生于乔木或者灌木的树枝,并通过自身光合作用而产生叶绿素的半寄生植物,属檀香目的显花植物,槲寄生还有多种混用的别称,如:寄生木、桑寄生、柏寄生、槲寄生(mistletoe)、槲寄生(viscum)等。
韩国分布有2科4属5分类群(Korean J.Pl.Taxon.Kim chansu等4人,韩国产槲寄生种(Viscum,Korthalsella,Loranthus and Taxillus)的分类及生态学考察。43(2):81-89(2013)),有檀香科的槲寄生(Viscum coloratum(Komarov)Nakai f.coloratum)、红果槲寄生(Viscum coloratum(Komarov)Nakai f.rubroaurantiacum(Makino)Kitagawa)、栗寄生(Korthalsella japonica(Thunb.)Engl.)等的3分类群和北桑寄生科的北桑寄生(Loranthus tanakae Franch.et Sav)、桑寄生(Taxillus yadoriki(Sieb.ex Maxim.)Danser)等的2分类群。
其中,栗寄生(Korthalsella japonica)主要自生于韩国的南部地区和济州岛,叶退化呈鳞片状,附着于枝节间,看似凸起,花被片具有不易脱落的特性,栗寄生不仅因其外形,而且还因其成分及功效等的不同,而与一般的槲寄生另行区分。
关于上述的栗寄生的功效,大韩民国授权专利10-1599458号记载了含有柏寄生(栗寄生,Korthalsella japonica(Thunb.)Engl)乙醇提取物的预防或治疗皮肤炎症的组合物,大韩民国公开专利第10-2008-0107922号涉及槲寄生提取物的制备方法及含有槲寄生提取物的增强记忆力、或预防和治疗老年痴呆症的组合物,其公开了作为老年痴呆症发病原因之一的β-淀粉样蛋白(Aβ,beta-amyloid)向神经细胞引发毒性时,槲寄生(Viscumalbum)及韩国产槲寄生(Viscum album var.coloratum)提取物具有缓解该毒性的活性,而且,在利用东莨菪碱及β-淀粉样蛋白诱导的健忘鼠的水迷宫模型(Water Maze Model)中显示具有增强记忆力的效果,大韩民国公开专利第10-2015-0010414号涉及含有源自槲寄生(Viscum album var.coloratum)的具有抗糖尿活性的蛋白质作为有效成分的抗糖尿槲寄生提取物,在此,公开了槲寄生为欧洲产槲寄生(Viscum album Loranthaceae)、生长在东亚地区的槲寄生(Viscum album var.coloratum),大韩民国授权专利第10-1685829号涉及增进抗氧化活性的槲寄生提取发酵物的制备方法,在此,公开的槲寄生(Loranthaceae)为寄生于柞树、朴树、日本桤木等的多年生植物,属于槲寄生(Viscum)属。此外,日本公开专利第2013-184974号记载了含有属于落新妇属(Astilbe)的植物及/或属于山茶属(Camellia)山茶树节的植物作为有效成分的酶勒反应(Maillard reaction)抑制剂、糖化物生成抑制剂或AGEs形成抑制剂,大韩民国公开专利第10-2010-0047253号提供了作为促进AGEs的去糖基化或促进对AGEs的酶勒反应的逆转的物质叫作Phoradendron piperoides的槲寄生。而至今为止,还没有报告表明,栗寄生(Korthalsella japonica(Thunb.)Engl)通过抑制AGEs生成及促进AGEs分解而预防或治疗糖尿病并发症、阿尔茨海默病及皮肤老化的功效。
另外,大韩民国公开专利第10-2006-0066180号公开了由韩国产槲寄生(KoreanViscum album,var.coloratum)提取的分离物的美白用化妆品组合物,文献(关于槲寄生与北桑寄生的美白及改善皱纹的功能性成分的研究,江原大学研究生院生命健康工学科理科硕士论文,2016)中虽然公开了韩国产桑寄生(Viscum album var.coloratum)与北桑寄生(Loranthus tanakae)的抗氧化、美白及改善皱纹的功效,但是,至今为止,还没有报告表明,栗寄生(Korthalsella japonica(Thunb.)Engl)的抑制及改善皮肤老化的功效。
据此,本发明确认了栗寄生(Korthalsella japonica(Thunb.)Engl)提取物抑制糖基化终产物的生成,以及裂解糖基化终产物的交联的功效,并确认了所述提取物可用于预防或治疗诸如糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或阿尔茨海默病等的与糖基化终产物相关的疾病及皮肤老化,从而完成了本发明。
发明内容
要解决的技术问题
本发明所要解决的技术问题在于,提供一种含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物的用于预防或治疗与抑制糖基化终产物的生成及促进糖基化终产物的分解有关的疾病的药学组合物。
本发明所要解决的另一个技术问题在于,提供一种含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物的通过抑制糖基化终产物的生成及促进糖基化终产物的分解,以抑制或改善皮肤老化的化妆料组合物。
本发明所要解决的又一个技术问题在于,提供一种含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物的用于预防或改善与抑制糖基化终产物的生成及促进糖基化终产物的分解有关的疾病的食品组合物。
技术方案
为了解决上述技术问题,本发明提供一种含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分的用于预防或治疗选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病的药学组合物。
此外,为了解决上述另一个技术问题,本发明提供一种含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物作为有效成分的用于预防或者改善皮肤老化的化妆品组合物。
此外,为了解决上述又一个技术问题,本发明提供一种含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物作为有效成分的用于预防或者改善选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病或皮肤老化的的食品组合物。
此外,本发明提供一种利用栗寄生(Korthalsella japonica(Thunb.)Engl)提取物来预防或治疗选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病的方法。
此外,本发明提供一种利用栗寄生(Korthalsella japonica(Thunb.)Engl)提取物来预防或者改善皮肤老化的方法。
就本发明的用于抑制糖基化终产物的生成及促进糖基化终产物的分解的组合物的有效成分栗寄生(Korthalsella japonica(Thunb.)Engl)而言,其为自生在韩国全罗南道木浦及济州岛、韩国南海岛屿等标高700m以下的暖带林地区的常绿寄生小灌木,高为5~30cm,小枝呈绿色,无毛,枝节分为多个,各个节间均偏平;长2~20mm的倒披针形的枝节多,各个节间对生有小枝;叶退化呈鳞片状,结于枝节的顶部,看似凸起,叶退化而小,结于枝节的顶部,看似凸起;花为两性花,开于4~5月,花径小于1mm,每个枝节结有5~6个,无花梗,花被分为三个,花药结于花被内部,且有很多孔;子房为下位;果实为浆果,果实成熟期为10~12月,直径为2mm,呈宽椭圆状,端部结有花柱,每个果实有一个种子,种子从果皮中突出。
本发明的栗寄生可利用本领域公知的提取方法及提取溶剂来获取,优选地可以利用水、碳原子数为1~4的无水或含水的低级醇(甲醇、乙醇、丙醇、丁醇等)、所述低级醇与水的混合溶剂、丙酮、乙酸乙酯、三氯甲烷或1,3-丁二醇作为提取溶剂。
此外,所述栗寄生提取物除了通过所述提取溶剂提取的方法来获取以外,还可以通过常规的精制过程来获取。例如,利用具有一定分子量截留值(cut-off)的超滤膜的分离、利用各种色谱法(为了基于尺寸、电荷、疏水性或亲和性进行分离而被制作)的分离等的通过进一步实施的多种精制方法所得的分离也能够获取栗寄生(Korthalsella japonica(Thunb.)Engl)提取物。
根据本发明的一个具体实施方式,可以通过如下方法获取栗寄生提取物,所述方法为,分别将整株栗寄生阴干并磨碎,然后利用干燥后试料重量的0.5~20倍的量,优选利用1~15倍量的诸如水、乙醇、甲醇等的C1~C4的低级醇,或利用水与乙醇的混合溶液,所述水和乙醇的混合比为1:0.1~1:10(kg/l),优选为1:0.2~1:9(kg/l),并在常温下,使用搅拌提取、热水提取、冷浸提取、回流冷凝提取或超声波提取等的提取方法,提取约0.5~48小时,优选提取1~30小时,优选为,通过超声波提取,然后将所获取的提取液进行过滤、减压浓缩或进行干燥来获取栗寄生提取物。
本发明的栗寄生提取物均包括在提取、分离或精制各个步骤中所获得的所有提取物、分离及精制物,及其的稀释液、浓缩液或者干燥物。
根据本发明的具体实施方式,栗寄生提取物具有抑制糖基化终产物的生成,且裂解糖基化终产物与胶原蛋白之间的交联的功效,因此,具有预防或治疗糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或阿尔茨海默病的效果,并且,具有抑制及改善皮肤老化的效果。
根据本发明的一个优选实施例,本发明涉及含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分的用于预防或治疗糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或阿尔茨海默病的药学组合物,其特征为,所述疾病是通过栗寄生提取物抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或治疗的。
本发明的药学组合物中,相对于总组合物,可以含有0.001~10重量%,优选可以含有0.001~5重量%的栗寄生提取物。当所述栗寄生提取物的含量小于0.001重量%时,抑制糖基化终产物(AGEs)的生成及分解AGEs活性效果甚微,而当栗寄生提取物的含量超过10重量%时,随栗寄生提取物的含量增加的效果增加过于微弱,从而具有无法确保剂型稳定性的问题。
本发明的药学组合物除了栗寄生提取物以外,还可以进一步包含药物组合物中常用的成分。例如,可以包含润滑剂、润湿剂、甜味剂、香味剂、乳化剂、悬浮剂、保存剂及载体。
作为所述药学组合物的合适的载体,可以列举为乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡络烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯(Propylhydroxybenzoate)、滑石、硬脂酸镁及矿物油等,但并不限于此。作为合适的药学上可接受的载体及制剂,举例而言,详细记载于Remington’s Pharmaceutical Sciences(19th ed.,1995)。
所述药学组合物可以以口服或非口服等多种途径对大鼠、小鼠、家畜、人类等哺乳动物给药,给药的所有方式均可预测,例如,可以通过口服,直肠或静脉、肌肉、皮下、子宫内膜或脑血管内(intracere broventricular)注射来给药。
所述药学组合物以药理学有效剂量来给药。本发明的药理学有效剂量是指,可适用于医学治疗或预防的以合理的受惠/危险比率来治疗或预防疾病所需的充分的剂量,有效剂量的程度可根据以下要素而决定:疾病的种类及其的危重程度、药物活性、患者的年龄、体重、健康及性别、患者对药物的敏感度、所使用的特定提取物的给药时间、给药路径及排出比率、治疗疗程、所使用的特定提取物之间的配合或包含同时使用的药物的要素及其他医学领域公知的要素。一般而言,以成年人为标准,每日给药剂量可以为0.1~1,000mg/kg,优选可以为10~100mg/kg,其可以以一日一次或分为一日数次的量来给药。此外,如果是外用剂时,以成年人为标准,其每日涂药剂量为1.0~3.0ml,每日涂药次数为一次~五次,并持续涂药一个月以上为佳。但是,本发明并不限于上述给药剂量。
所述药学组合物可以根据本领域具有通常知识的技术人员易于实施的方法通过与药学上可接受的载体及/或赋形剂一起制剂化,可以以单位容量的形式制备或注入于多容量容器中的形式制备。这时,剂型可根据治疗目的剂型化为药剂学领域中常用的制剂,例如,可以剂型化为片剂、胶囊、散剂、颗粒、悬浮剂、乳剂、糖浆剂、乳浊剂、硬膏剂、软膏剂、喷雾剂、油剂、凝胶剂、醑剂、酊剂、浴剂、擦剂、乳液剂、贴剂、药棉块(pad)、霜剂等。此外,优选地,可以用作直接涂摸于患部的局部给药为目的皮肤外用剂来使用,这种情况下,优选的剂型为软膏剂、乳液剂、喷雾剂、凝胶等形态。该皮肤外用剂还可以包含于直接适用于治疗部位的基片(support base)或基质(matrix)等,所述基片的例为包含纱布或绷带。
根据本发明的一个优选实施例,本发明涉及含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分的用于预防或改善皮肤老化的化妆料品组合物,其特征为,所述抑制及改善皮肤老化是通过栗寄生提取物抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或治疗。
相对于总组合物,优选包含0.001~10重量%的所述栗寄生提取物。当所述栗寄生提取物的含量小于0.001重量%时,抑制AGEs的生成及分解AGEs的活性的效果甚微,而当所述栗寄生提取物的含量超过10重量%时,随着栗寄生提取物的含量增加的效果增加过于微弱,因而存在无法确保剂型稳定性的问题。更优选地,相对于总组合物,含有0.001~5重量%的栗寄生提取物。
本发明的化妆品组合物除了栗寄生提取物以外,还可以进一步包含化妆品组合物中常用的成分。例如,可以包含抗氧化剂、稳定剂、增溶剂、维生素、颜料及香料等的常用助剂及载体。此外,为了增进皮肤美白效果,所述化妆品组合物可进一步包含促进皮肤吸收的物质。
所述化妆品组合物可以制备成本领域通常的各种剂型,例如可以制备成溶液、混悬液、乳液、膏剂、凝胶、面霜、乳液、粉饼、香皂、含表面活性剂的清洁剂、油、粉状粉底、乳液粉底、蜡状粉底液(wax foundation)及喷雾剂等,但并不限于此。更具体地,可以剂型化为,营养霜、紧肤水、柔肤水、乳液、精华素、营养凝胶或按摩霜。
当所述化妆品组合物的剂型为膏剂、面霜或者凝胶时,作为载体成分可以利用:动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、二氧化硅、滑石或氧化锌等。
当所述化妆品组合物的剂型为粉饼或喷雾剂时,作为载体成分可以使用:乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末,尤其,当其剂型为喷雾剂时,可以进一步包含含氯氟代烃(chloroflu orohydrocarbon)、丙烷/丁烷或二甲醚等的推进剂。
当所述化妆品组合物的剂型为溶液或乳浊液时,作为载体成分可以使用:溶剂、增溶剂或乳化剂,举例而言,作为溶剂,可以使用,水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇,作为增溶剂或乳化剂,可以使用甘油脂肪酸酯、聚乙二醇或山梨糖醇脂肪酸酯等。
当所述化妆品组合物的剂型为悬浮液时,作为载体成分可以使用:水、乙醇或如丙二醇等的液相稀释剂、如乙氧基异硬脂醇、聚氧乙烯山梨醇酯及聚氧乙烯脱水山梨醇酯等的悬浮剂、微晶纤维素、偏氢氧化铝(aluminium metahydroxide)、膨润土、琼脂或黄蓍胶等。
当所述化妆品组合物的剂型为含有表面-活性剂的清洁剂时,作为载体成分可以使用:脂肪醇硫酸盐、脂肪醇酯硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉衍生物、甲基牛磺酸盐、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物、乙氧基化甘油脂肪酸酯等。
根据本发明的一个优选实施例,本发明涉及含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分的用于预防或改善糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎、阿尔茨海默病、皮肤老化的食品组合物,其特征在于,所述抑制及改善疾病及皮肤老化的食品组合物是根据栗寄生提取物抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或者改善。
本发明的食品组合物,除了含有栗寄生提取物作为有效成分以外,可以进一步包含制造食品时通常添加的成分,例如,蛋白质、碳水化合物、脂肪、营养素、调味剂及香味剂等。
举例而言,所述碳水化合物为葡萄糖、果糖等的单糖;麦芽糖、蔗糖、低聚糖等的二糖;及糊精、环糊精等的多糖等的常规的糖以及木糖醇、山梨糖醇、赤藻糖醇等的糖醇。作为香味剂可以使用天然香味剂(索马甜、甜菊提取物(如,甜叶菊甙A、甘草甜素等))及合成香味剂(糖精、阿斯巴甜等)。
例如,当本发明的食品组合物制备为饮料时,除了本发明的栗寄生提取物以外,还可以进一步包含柠檬酸、液相果糖、砂糖、葡萄糖、醋酸、苹果酸、果汁、杜仲提取液、红枣提取液、甘草提取液等。
相对于总组合物,优选包含0.001~10重量%的所述栗寄生提取物。当所述栗寄生提取物的含量小于0.001重量%时,抑制AGEs的生成及分解AGEs的活性的效果甚微,而当所述栗寄生提取物的含量超过10重量%时,随栗寄生提取物含量增加的效果增加过于微弱。
根据本发明的一个实施例,本发明涉及通过利用含有栗寄生提取物的组合物来预防或治疗选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病的方法。
根据本发明的一个实施例,本发明涉及通过利用含有栗寄生提取物的组合物来预防或改善皮肤老化的方法。
另一方面,本发明的栗寄生提取物作为天然物质,对人体无害,且几乎不没有毒性及副作用,因此,使用长时间时,也可以放心地使用,尤其,可安全的适用于如上所述的药学、化妆品及食品组合物中。
发明的效果
如上所述,根据本发明,栗寄生提取物通过抑制糖基化终产物的生成的效果和裂解糖基化终产物与胶原蛋白之间的交联的效果,可用于预防或改善由AGEs沉积而引起的糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎或者阿尔茨海默病等的与糖基化终产物相关的疾病及皮肤老化。
附图说明
图1表示栗寄生提取物裂解糖基化终产物与胶原蛋白的交联的效果进行比较评价的结果图。
具体实施方式
以下,为了有助于对本发明的理解,通过列举实施例等,对本发明进行更详细的说明。但是本发明的实施例可以变形为其他多种形式,且本发明范围不应被理解为受限于下述实施例。本发明实施例仅仅是为了使本领域具有普通知识的技术人员更佳完整地理解本发明而提供的。
实施例1:栗寄生提取物的抑制糖基化终产物的生成的功效评价(在体外(invitro))
将10mg/mL的牛血清白蛋白(Bovine serum albumin,BSA)、10mM的乙醇醛(Glycolaldehyde)、1mM的二乙烯三胺五乙酸(DTPA)、0.1M的磷酸盐缓冲液(phosphatebuffer,pH 7.4)、0.02%的叠氮化钠(sodium azide)与栗寄生提取物进行混合的反应物,在37℃下,培养5天,作为阳性对照组,使用作为抑制糖基化终产物的生成抑制剂而熟知的氨基胍(Aminoguanidine,AG)来处理。关于糖基化终产物的形成程度,将通过利用分光荧光计在Ex=340nm/Em=430nm下测定的荧光值代入到下述数学式1中计算。其结果示于下表1中。
【数学式1】
糖化反应(Glycation)(%)=[(被处理的试料的荧光值)/(对照组的荧光值)x100]
【表1】
如上述表1所示,可知栗寄生提取物具有浓度依赖性的抑制糖基化终产物的效果。另外,可知普通的槲寄生提取物和桑寄生提取物及山茶树枝提取物均没有抑制糖基化终产物的效果。
实施例2:栗寄生提取物的裂解糖基化终产物与胶原蛋白的交联的功效评价(在体外(in vitro))
将标记有山葵过氧化酶(Horseradish peroxidase)的糖基化终产物接种于涂覆有胶原蛋白的96孔板(well plate)中,然后,在37℃下培养(incubation)4个小时,以使胶原蛋白和糖基化终产物交联。利用0.05%的PBST清洗3次,以去除未与胶原蛋白附着的糖基化终产物,然后,在37℃下,将作为糖基化终产物的交联裂解剂而熟知的ALT-711和栗寄生提取物处理16小时。利用0.05%的PBST清洗3次,并以TMB作为基质(substrate)发色后,在450nm下检测其吸光度。胶原蛋白和糖基化终产物的交联程度按照下述数学式2计算。其结果示于下表2及图1中。
图1是表示栗寄生提取物对糖基化终产物与胶原蛋白的交联起到裂解的效果进行比较评价的结果图。
【数学式2】
胶原蛋白与糖基化终产物的交联(%)=[(被处理的试料的吸光度)/(对照组的吸光度)x100]
【表2】
如上述表2所示,可知栗寄生提取物的交联裂解功效比作为阳性对照组而使用的ALT-711的交联裂解功效更佳优秀。此外,虽然未在实施例中记载,相比于栗寄生提取物,普通的槲寄生提取物和桑寄生提取物均没有裂解交联的功效。
实施例3:关于糖基化终产物与胶原蛋白交联的体外(in vivo)评价
对2型糖尿病模型db/db小鼠施用空白对照剂(placebo)和栗寄生提取物4周,然后测定血红蛋白A1C(HbA1c)来观察对糖尿病并发症的预防功效。作为血红蛋白的糖基化产物的HbA1c是最为熟知的体内糖基化产物,其被利用于糖尿病患者的血糖控制指标。
对照组(Control):空白对照剂(placebo)处理组
BSDB#1:栗寄生提取物100mg/kg/天给药组
BSDB#2:栗寄生提取物250mg/kg/天给药组
【表3】
如上述表3所示,可观察到与摄取空白对照剂的组相比,摄取栗寄生提取物的组的HbA1c的数据浓度依赖性地降低。
以下,例示利用本发明组合物的化妆品的制剂例。
制剂例1:化妆品制剂
1-1.柔肤水
【表4】
成分 | 重量% |
栗寄生提取物 | 0.05 |
丙三醇 | 3.0 |
丁二醇 | 2.0 |
丙二醇 | 2.0 |
聚羧乙烯 | 0.1 |
乙醇 | 10.0 |
三乙醇胺 | 0.1 |
防腐剂、微量色素、微量香料及微量精制水 | 82.75 |
总计 | 100.0 |
1-2.营养化妆水
【表5】
1-3.营养霜
【表6】
1-4.按摩霜
【表7】
成分 | 重量% |
栗寄生提取物 | 0.05 |
蜂蜡 | 10.0 |
聚山梨醇酯60 | 1.5 |
山梨坦倍半油酸酯 | 0.8 |
液体石蜡 | 40.0 |
角鲨烷 | 5.0 |
辛酸/癸酸甘油酯 | 4.0 |
丙三醇 | 5.0 |
丁二醇 | 3.0 |
丙二醇 | 3.0 |
三乙醇胺 | 0.2 |
防腐剂、微量色素、微量香料及微量精制水 | 27.45 |
总计 | 100.0 |
1-5.面膜
【表8】
制剂例2:药学制剂
2-1.散剂的制备
【表9】
成分 | 重量(g) |
栗寄生提取物 | 2 |
乳糖 | 1 |
将上述成分进行混合后,填充于气密袋,从而制备了散剂。
2-2.片剂的制备
【表示10】
成分 | 重量(mg) |
栗寄生提取物 | 100 |
玉米淀粉 | 100 |
乳糖 | 100 |
硬脂酸镁 | 2 |
将上述成分进行混合后,按照通常的制备片剂的方法,进行压片而制备了片剂。
2-3.胶囊的制备
【表11】
将上述成分进行混合后,按照通常的制备胶囊的方法,填充于明胶胶囊中,从而制备了胶囊。
Claims (6)
1.一种用于预防或治疗选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病的药学组合物,其含有栗寄生(Korthalsella japonica(Thunb.)Engl)提取物作为有效成分。
2.根据权利要求1所述的药学组合物,其特征在于,
所述疾病是通过栗寄生提取物的抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或治疗。
3.一种用于预防或改善皮肤老化的化妆品组合物,其含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物作为有效成分。
4.根据权利要求3所述的化妆品组合物,其特征在于,所述皮肤老化是通过栗寄生提取物的抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或改善。
5.一种用于预防或改善选自糖尿病并发症、动脉硬化、肾功能衰竭、类风湿性关节炎及阿尔茨海默病中的一种以上疾病或皮肤老化的食品组合物,其含有栗寄生(Korthalsellajaponica(Thunb.)Engl)提取物作为有效成分。
6.根据权利要求5所述的食品组合物,其特征在于,所述疾病或皮肤老化是通过栗寄生提取物的抑制糖基化终产物的生成及促进糖基化终产物的分解来预防或改善。
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