CN103816095A - 高级糖化终产物的去糖化 - Google Patents
高级糖化终产物的去糖化 Download PDFInfo
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- CN103816095A CN103816095A CN201410105347.2A CN201410105347A CN103816095A CN 103816095 A CN103816095 A CN 103816095A CN 201410105347 A CN201410105347 A CN 201410105347A CN 103816095 A CN103816095 A CN 103816095A
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Abstract
本发明涉及高级糖化终产物的去糖化。具体涉及促进高级糖化终产物去糖化的至少一种物质作为活性成分用于制备组合物、尤其是用于限制组织中高级糖化终产物出现的组合物的用途。本发明尤其涉及这样的物质用于制备下述组合物的用途，所述组合物通过促进组织中高级糖化终产物去糖化来预防和/或防止组织的柔性和/或可塑性和/或弹性和/或功能性的降低，和/或预防和/或防止组织的老化，所述组织优选为皮肤，或者为血管或器官的组织壁。
Description
本申请为2008年7月9日提交的、发明名称为“高级糖化终产物的去糖化”的PCT申请PCT/EP2008/058955的分案申请，所述PCT申请进入中国国家阶段的日期为2010年1月29日，申请号为200880101123.7。
技术领域
本发明涉及药学领域，更具体而言，本发明涉及用于促进糖化蛋白的去糖化、换言之用于促进美拉德反应(Maillard reaction)逆转的活性成分的用途。
本发明尤其涉及可以局部或口服使用以作用于组织中糖化蛋白的物质，所述组织为例如皮肤中的组织、或者是血管或器官的组织壁中的组织，尤其是人体中的组织。
背景技术
在现有技术中，已知糖、尤其是聚糖形式的糖诱发了蛋白尤其是皮肤中蛋白的糖化(将糖结合到蛋白)。然而，当血糖水平升高时，例如，尤其是在糖尿病患者中、在老化过程中或者当食物富含糖时，该糖化是完全正常的。
现有技术中，已知非酶的糖基化或糖化是纯化学且自发的反应，在该反应中，碳水化合物与肽链共价键合。
糖化是由游离糖附着到氨基酸或蛋白而引起的老化基础机理。
糖化蛋白也被称为高级糖化终产物，即高级糖化终产物。这些化合物尤其是可降低皮肤的柔性、弹性和功能性。
糖化过程包括三个步骤：
1－形成席夫碱，这由还原糖(葡萄糖、核糖或果糖)或醛附着到主要是赖氨酸和N端胺部分的蛋白的氨基酸残基而引起。
2－被称为Amadori重排的分子重排，这由席夫碱的异构化引起。这些Amadori产物的形成速率与糖浓度成比例。
3－糖化最终产物或美拉德产物的缓慢且不可逆的累积，这经由非常活泼的中间体的重排、氢转移和形成。这一反应导致高级糖化终产物的形成，更常表述为美拉德产物。这些化合物的形成速率与介质的糖浓度无关，而是取决于高血糖症的持续时间和蛋白周转率。
最初两个阶段(席夫碱形成和Amadori重排)稳定在平台期，并且可以根据血糖水平来逆转。而另一方面，第三阶段的发展与血糖水平无关。
体内的细胞外基质蛋白的寿命非常长，细胞外基质蛋白受糖化影响。糖化能够改变这些蛋白的性质，使得它们更耐蛋白酶解并避免它们周转。此外，高级糖化终产物诱导在胶原纤维之间形成分子桥，使它们更硬且更加不可溶。最后，高级糖化终产物可通过将其自身结合到巨噬细胞、内皮细胞和系膜细胞内存在的特定受体，通过诱导促炎性细胞因子或生长因子的分泌而具有其他作用。蛋白糖化的重要性已经由抑制糖化的药物的作用效果强调，这通过实验室动物的特定功能的老化过程的减缓所体现。在糖尿病期间也发生蛋白的过度糖化，这与血糖升高有关。
在现有技术中所建议的解决方案涉及了使得限制蛋白糖化并且还限制高级糖化终产物形成成为可能的活性物质。
发明内容
本发明的主要目的是解决以下技术问题：提供通过逆转美拉德反应来使得限制特别是在组织中高级糖化终产物出现成为可能的活性物质，所述组织例如皮肤中的组织、或者是血管或器官中的组织壁中的组织，且尤其是皮肤中的组织。
本发明的一个具体目的是在提供化妆品组合物、皮肤病用组合物或药物组合物的情况下解决这一技术问题，该组合物尤其是在组织的老化过程中或者在糖尿病期间预防或防止组织的弹性和塑性的降低，所述组织为例如皮肤中的组织、或者是血管或器官中的组织壁中的组织，且尤其是皮肤中的组织。
本发明的另一个目的是提供筛选具有上述性质的活性成分的方法。
本发明的一个具体目的是通过提供优选地可以局部施用的无毒活性物质，从而可以可靠的且可再现的方式来解决该技术问题，所述活性物质尤其用于化妆品行业、皮肤病学行业、皮肤药物行业或制药行业。
本发明的一个具体目的是提供具有低毒性且皮肤病学上可接受的物质。
本发明的另一个目的是提供活性成分，该活性成分的制备是不昂贵的且能够以可靠且简单的方式在工业规模上实施。
糖化涉及与老化有关的许多进行性疾病，所述进行性疾病诸如血管疾病(例如动脉粥样硬化)、肾疾病、关节炎、糖尿病并发症、瘢痕形成等。重要的是，由糖化引起的糖尿病并发症可以甚至在平均血糖浓度比正常人高的糖尿病患者个体中较年轻的年龄发生。
大量文献充分证明，在糖尿病过程中涉及自由基，在糖尿病中，氧化应激与高血糖症有直接关系。然后，以太大的量存在于血液中的糖很容易被氧化。糖的这一氧化尤其导致了糖/蛋白接枝或糖化。在糖尿病的情况中糖化血红蛋白水平升高是典型的例子。
糖化产物水平在很长时间段内与血糖水平成比例，糖化产物也是组织老化的部分原因，弹性和塑性的降低是组织老化的原因之一。
因此，本发明描述了促进高级糖化终产物去糖化或者促进关于高级糖化终产物的美拉德反应逆转的活性物质的用途，其用于制备组合物，尤其用于限制组织中高级糖化终产物的出现。
有利地，这一组合物例如用于防止组织的柔性和/或弹性和/或可塑性和/或功能性的降低，所述组织为例如在皮肤中的组织、或在血管或器官的组织壁中的组织。
本发明还涉及用于通过皮肤组织中高级糖化终产物去糖化或通过皮肤组织中高级糖化终产物的美拉德反应逆转来防止和/或预防皮肤的老化、预防和/或防止组织且尤其是皮肤中组织的弹性和塑性的降低的组合物，所述组合物包括作为活性物质的促进高级糖化终产物去糖化的物质。
本发明涉及促进高级糖化终产物去糖化或促进高级糖化终产物的美拉德反应逆转的至少一种活性物质用于制备促进高级糖化终产物去糖化的组合物的用途，所述活性物质选自：3,5-二甲氧基-4-羟基肉桂酸(芥子酸)、反式-3,3',4',5,7-五羟基黄烷(儿茶素)、羟吲哚、3,4-二羟基苯乙酸(DOPAC)、1,3,5-三羟基苯(间苯三酚)、4-氨基苯酚、2-羟基苯甲酸(水杨酸)、6-羟基-2,5,7,8-四甲基色满-2-甲酸(trolox)、去甲二氢愈创木酸、6-甲基-5,7a,13,13b-四氮杂戊芬-8,14-二酮、6-羟基-吲哚、氢溴酸猪毛菜酚、7-羟基-4,6-二甲基苯酞、3,4-二羟基肉桂酸(咖啡酸)、毒扁豆碱、2-羟基甲基-5-羟基-γ-吡喃酮(曲酸)；以及含有它们的植物提取物，选自至少一种下列植物的提取物：Awati、胡椒属槲寄生(piper mistletoe)、蓝马鞭草(blue vervain)、号角树(Cecropia)、鹿蹄草(wintergreen)、樱树(cherry tree)、肉桂(Cassia)和印度美人蕉(Indian shot)；及其混合物。
优选地，促进高级糖化终产物去糖化或促进高级糖化终产物的美拉德反应逆转的活性物质为选自下列植物的植物提取物：
－awati(Maprounea guyanensis)，且优选叶；
－假马鞭(Stachytarpheta jamaicensis)；
－号角树(Cecropia obtusa)，且优选叶和/或芽；以及
－鹿蹄草(伞形喜冬草(Chimaphila umbellata))。
根据一个可选择的优选实施方案，促进高级糖化终产物去糖化或促进高级糖化终产物的美拉德反应逆转的活性物质是选自下列的特征分子：
－3,5-二甲氧基-4-羟基肉桂酸(芥子酸)；
－反式-3,3',4',5,7-五羟基黄烷(儿茶素)；
－羟吲哚；
－3,4-二羟基苯乙酸(DOPAC)；
－1,3,5-三羟基苯(间苯三酚)；
及其混合物和也含有它们的植物提取物。
有利地，组合物是优选地可以被局部施用的化妆品组合物、皮肤病用组合物、皮肤药物组合物或药物组合物，或食物(营养)补充品。
本发明涉及活性物质用于制备防止与糖尿病期间血糖上升相关的尤其是皮肤组织中的糖化蛋白的糖化的组合物的用途。
本发明涉及活性物质用于制备防止神经纤维球中形成的高级糖化终产物且尤其是减少糖尿病患者中白蛋白排泄的组合物的用途。
活性物质可以通过冷冻干燥、喷雾干燥等来浓缩。
所述活性物质通常按总组合物重量计对于植物提取物而言以0.001～10%、优选地0.01～5%且更特别是以1%的浓度来使用，且对于特征分子而言以1×10-7～1%、优选地1×10-7～1×10-1%、更优选地1×10-5～1×10-1%的浓度来使用，而这不会限制将被使用的浓度。
在所有的这些活性物质中，优选参照由15mM氨基胍所产生的作用促进高级糖化终产物去糖化至少50%的那些活性物质。
本发明还涉及能够被局部施用或作为食物补充品的化妆品组合物、或者药物组合物，所述组合物尤其是通过促进皮肤中高级糖化终产物的美拉德反应逆转来预防和/或防止皮肤的柔性和/或可塑性和/或弹性和/或功能性的降低、和/或预防和/或防止皮肤老化，所述组合物包括作为活性成分的促进皮肤中高级糖化终产物去糖化的至少一种物质，所述物质优选选自：3,5-二甲氧基-4-羟基肉桂酸(芥子酸)、反式-3,3',4',5,7-五羟基黄烷(儿茶素)、羟吲哚、3,4-二羟基苯乙酸(DOPAC)、1,3,5-三羟基苯(间苯三酚)、4-氨基苯酚、2-羟基苯甲酸(水杨酸)、6-羟基-2,5,7,8-四甲基色满-2-甲酸(trolox)、去甲二氢愈创木酸、6-甲基-5,7a,13,13b-四氮杂戊芬-8,14-二酮、6-羟基吲哚、氢溴酸猪毛菜酚、7-羟基-4,6-二甲基苯酞、毒扁豆碱及其任何混合物；或选自至少一种下列植物的提取物：awati、胡椒属槲寄生、假马鞭、号角树、鹿蹄草、樱树、肉桂和印度美人蕉；任选地作为与以下物质的混合物：抑制糖化尤其是通过矿化抑制糖化的化合物，如EDTA衍生物、肌醇六磷酸或壬二酸，或促进皮肤蛋白保护的化合物，如氨基胍、胍，或酶抑制剂如戊糖素，或减少可用于参加糖化反应的糖的量的物质，如肌肽、抗坏血酸或α-生育酚。
在根据本发明的一种优选的组合物中，促进高级糖化终产物去糖化或促进高级糖化终产物的美拉德反应逆转的活性物质是选自下列植物的植物提取物：
－await(Maprounea guyanensis)，且优选叶；
－假马鞭(Stachytarpheta jamaicensis)；
－号角树(Cecropia obtusa)，且优选叶和/或芽；以及
－鹿蹄草(伞形喜冬草)。
根据一个可选择的优选实施方案，促进高级糖化终产物去糖化或促进高级糖化终产物的美拉德反应逆转的活性物质是选自下列的特征分子：
－3,5-二甲氧基-4-羟基肉桂酸(芥子酸)；
－反式-3,3',4',5,7-五羟基黄烷(儿茶素)；
－羟吲哚；
－3,4-二羟基苯乙酸(DOPAC)；
－1,3,5-三羟基苯(间苯三酚)。
根据植物的不同，优选以1～10%(w/w)的浓度使用在溶剂或溶剂混合物(优选极性质子溶剂)中，优选水、醇、二醇、多元醇、100/0到0/100(v/v)的水/醇、水/二醇或水/多元醇混合物(如，与乙醇、甘油、丁二醇或其他二醇如木糖醇等混合的水)中的整个植物或植物部分，所述植物部分选自根、根茎、茎、壳、花、果实、种子、胚芽和叶。然后，优选过滤或蒸馏所获得的提取物，以便回收可溶部分，然后过滤该可溶部分。活性物质有利地是溶剂中的植物提取物，所述溶剂例如水、醇、多元醇、二醇或其混合物，优选将所述活性物质稀释至0.01～10%(v/v)的浓度。
在抑制糖化(即减少高级糖化终产物形成)的化合物中，可以使用所提取的化合物，优选通过在溶剂或溶剂混合物中浸渍，如在水、醇、二醇、多元醇或这些溶剂的混合物且优选水中，(优选使用可溶于这些溶剂的化合物，优选在过滤之后)，化合物是选自以下植物的植物中的化合物：下述植物的提取物：瓜拉那(Paullinia cupana)，优选种子；淫羊藿(Epimediumbrevicornum)，优选叶；皱叶酸模(Rumex crispus)，优选壳；洋菝(Smilaxornata)，优选根；本地葡萄藤(Davilla rugosa)，优选叶；儿茶(优选木)，乳蓟(优选果实)；松树，优选松物种(Pinus species)(优选根)；中国大黄(Chineserhubarb)(优选根)；山楂(hawthorn)(优选叶)；无色花青素(leucocyanidins)(优选种子)；槟榔(areca)(优选种子)；越桔(bilberry)(优选果实)；接骨木(elder)(优选果实)；胡桃木(walnut)(优选叶)；柳树(willow)(优选树皮)；莴苣(lettuce)(优选叶)和胡枝子(lespedeza)(优选叶)；和/或选自以下物质的化合物：赤藓红钠、1,4-蒽醌、儿茶酚、4-羟基查耳酮、4-氨基苯酚、OPC(PCO原花青素低聚物(procyanidolic oligomer))如草莓植物OPC、樱桃苷和1-氨基-2-羟甲基蒽醌、或这些物质的混合物。
最特别有利的是将通过逆转美拉德反应来使限制高级糖化终产物出现成为可能的活性物质与抑制糖化的上述活性物质中的至少一种进行组合，活性物质优选选自单独或组合获得的以下物质的提取物：瓜拉那(Paulliniacupana)，优选种子；淫羊藿(Epimedium brevicornum)，优选叶；皱叶酸模(Rumex crispus)，优选壳；洋菝(Smilax ornata)，优选根；本地葡萄藤(Davillarugosa)，优选叶；或下列物质：3,5-二甲氧基-4-羟基肉桂酸(芥子酸)；反式-3,3',4',5,7-五羟基黄烷(儿茶素)；羟吲哚；3,4-二羟基苯乙酸(DOPAC)；1,3,5-三羟基苯(间苯三酚)。
因此，本发明涉及化妆护理方法，该方法包括局部施用组合物或作为食物(营养)补充品来施用组合物，所述组合物包括作为化妆品活性成分的上述活性成分或下面提及的活性成分中的至少一种。
本发明还涉及治疗人体的方法，该方法包括施用，优选地通过局部施用前述药物组合物或下面提及的药物组合物来预防和/或防止组织中的蛋白糖化，尤其是当血糖水平升高和/或是高的时，例如在糖尿病期间。本发明尤其涉及减少糖尿病患者中白蛋白排泄的方法。
本发明还涉及筛选促进高级糖化终产物去糖化的活性成分的方法，该方法包括：
a)生产高级糖化终产物；
b)使高级糖化终产物与就其高级糖化终产物去糖化活性而待筛选的物质接触；以及
c)选择促进高级糖化终产物去糖化的至少一种活性成分。
有利地，步骤a)包括在糖(例如：葡萄糖、核糖、果糖等)的存在下，在允许形成高级糖化终产物的条件下，且优选地在40℃和60℃之间的温度且更优选在约50℃的温度下温育皮肤或血管壁的至少一种类型的蛋白达1周和5周之间且优选3周的持续时间。
有利地，步骤b)包括在将待筛选的至少一种物质的存在下，在40℃和60℃之间的温度，优选在约50℃的温度下温育高级糖化终产物。
通过将所测试的活性成分存在下所获得的结果与对照存在下获得的结果进行比较来进行活性成分的选择。
可以将本发明的化合物制备为局部组合物、尤其是化妆品组合物、皮肤药物组合物或药物组合物的形式。因此，对于这些组合物来说，赋形剂包括例如选自下列的至少一种化合物：防腐剂、软化剂、乳化剂、表面活化剂、补湿剂、稠化剂、调节剂、控油剂、稳定剂、抗氧化剂、调质剂、增白剂、成膜剂、增溶剂、颜料、染料、香料和遮光剂。
这些赋形剂优选选自：氨基酸及其衍生物、聚甘油、酯、聚合物及纤维素衍生物、羊毛脂衍生物、磷脂、乳铁蛋白、乳过氧化物酶、基于蔗糖的稳定剂、维生素E及其衍生物、天然的和合成的腊、植物油、甘油三酸酯、不皂化物、植物甾醇、植物酯、硅酮及其衍生物、蛋白水解物、荷荷芭油及其衍生物、脂溶性/水溶性的酯、甜菜碱、氨基氧化物、植物提取物、蔗糖酯、二氧化钛、甘氨酸和尼泊金酯类，且更优选选自：丁二醇、硬脂醇聚醚-2、硬脂醇聚醚-21、二醇-15硬脂醚、鲸蜡硬脂醇、苯氧乙醇、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、丁二醇、天然的生育酚、甘油、二羟鲸蜡醇磷酸酯钠、异丙基羟基鲸蜡醚、硬脂酸乙二醇酯、三异壬精、椰油酸辛酯、聚丙烯酰胺、异链烷烃、月桂醇聚醚-7、卡波姆、丙二醇、甘油、没药醇、二甲硅油、氢氧化钠、PEG-30二聚羟基硬脂酸酯、癸酸/辛酸甘油三酸酯、鲸蜡硬脂醇辛酸酯、己二酸二丁酯、葡萄籽油、荷荷芭油、硫酸镁、EDTA、环甲硅脂、黄原胶、柠檬酸、十二烷基硫酸钠、矿物油及腊、异硬脂酸异硬脂醇酯、二壬酸丙二醇酯、异硬脂酸丙二醇酯、PEG-8蜂腊、氢化棕榈仁油的甘油酯、氢化棕榈油的甘油酯、羊毛脂油、芝麻油、乳酸鲸蜡醇酯、羊毛脂醇、蓖麻油、二氧化钛、乳糖、蔗糖、低密度聚乙烯和等渗盐溶液。
特别有利的是将根据本发明的活性物质与具有补充性质的其他活性剂进行组合，以便进一步改善对抗皮肤老化、对抗皮肤的柔性和/或可塑性和/或弹性和/或功能性降低的功效。有利地，这些其他活性剂选自：
－刺激细胞增殖和/或分化的具有抗老化效果的活性物质，尤其是下列分子：NGF、α-MSH、β-内啡肽或其衍生物，尤其是专利申请FR2857874中所描述的那些活性物质；
－保护成纤维细胞生长因子(FGF)尤其是FGF2的活性物质，尤其是以申请人名义以第GB244036号公开的专利申请中所描述的那些活性物质，尤其是黄葵(Hibiscus abelmoschus)的提取物；
－刺激成纤维细胞的活性和/或增殖的活性物质，尤其是发酵大豆肽，尤其是由申请人以名称PhytokineTM出售的发酵大豆肽，有利地与黄葵提取物组合；
－刺激玻璃糖醛酸酵素合酶(hyaluronase synthase)尤其是HAS2的活性物质，尤其是在专利FR2893252中描述的那些活性物质；
－刺激赖氨酰氧化酶尤其是LOX的活性和/或合成的活性物质，尤其是在专利申请FR2855968中描述的那些活性物质，且优选地为莳萝(dill)提取物；以及
－具有抗炎性的活性物质，诸如抑制PLA2的那些活性物质，尤其是葛(Pueraria lobata)根的提取物，如专利FR2847267中所描述的
有利地，将上述组合物配制为选自下列的形式：水溶液或油溶液、乳膏或含水凝胶或含油凝胶，尤其是在盒中或在管中的，尤其是洗浴凝胶或洗发剂；乳状物；乳剂、微乳剂或纳米乳剂，尤其是水包油或油包水的或多重的或硅酮基类型的；洗剂，尤其是在玻璃瓶或塑料瓶中或在量瓶中或在气溶胶中的；安瓿；液体皂；皮肤用皂；软膏；泡沫；优选为液体、膏状或固体的无水产物，例如以棒的形式，尤其是以唇膏形式。
在此使用的表述“局部施用”意指将根据本发明的组合物施用或喷在皮肤表面上。
在此使用的表述“皮肤病学上可接受的”意指组合物或后者的组分适于与人的皮肤接触使用而不会引起毒性、不相容性、不稳定性、过敏反应等。
表述“促进高级糖化终产物去糖化的”或“有利于高级糖化终产物的美拉德反应逆转的”意指该物质使得可以从高级糖化终产物(高级糖化终产物)获得比阴性对照(不存在活性成分)更多量的非糖化蛋白，例如，如通过根据实施例1在对照样品(不存在活性成分)和含有促进高级糖化终产物去糖化的物质的样品之间的荧光差异所评价的。优选地，用含有促进高级糖化终产物去糖化的物质的样品获得的荧光与在氨基胍的存在下评价所获得的荧光进行比较。表述“促进高级糖化终产物去糖化的物质”尤其涉及这样的物质：对于该物质来说，在该物质的存在下所获得的荧光至少等于在15mM氨基胍的存在下且在不存在活性成分下所获得的荧光的70%。表述“高级糖化终产物去糖化”意指美拉德反应的逆转。
本领域的技术人员知道用于改善皮肤的健康和/或实际外表的许多化妆品用活性成分。本领域的技术人员知道如何配制化妆品组合物或皮肤病用组合物以获得最好的效果。另一方面，当本发明中所描述的化合物相互组合的时候，它们可以具有协同效应。本发明也包括这些组合。CTFACosmetic Ingredient Handbook(CTFA化妆品成分手册)第二版(1992)描述了通常用于化妆品行业和制药行业的、尤其适于局部使用的各种化妆品成分和药物成分。这些类别的成分的例子包括但不限于下列化合物：研磨剂、吸收剂、具有美学目的的化合物如香料、颜料、染料、精油、收敛剂等(例如：丁香油、薄荷醇、樟脑、桉树油、丁香油酚、乳酸薄荷酯、金缕梅馏出物)、抗痤疮剂、防絮凝剂、消泡剂、抗微生物剂(例如：丁基氨基甲酸碘代丙酯)、抗氧化剂、粘合剂、生物学添加剂、缓冲剂、溶胀剂、螫合剂、添加剂、杀虫剂、变性剂、外用镇痛剂、成膜材料、聚合物、不透明剂、pH调节剂、还原剂、脱色剂或浅色剂(lightening高级糖化终产物nt)(例如：氢醌、曲酸、抗坏血酸、抗坏血酸磷酸镁(magnesium ascorbylphosphate)、抗坏血酸葡萄糖胺(ascorbylglucosamine))、调节剂(例如：保湿剂)、皮肤舒缓剂和/或创伤修复剂(例如：泛醇及其衍生物(例如：乙基泛醇)、芦荟、泛酸及其衍生物、尿囊素、没药醇和甘草酸二钾)、稠化剂、维生素、以及后者的衍生物或等价物。
本领域的技术人员在阅读说明性描述后可以清楚地获知本发明的其他目的、特征和优点，该说明性描述是指仅仅为了阐释所给出的且决不应限制本发明范围的实施例。
实施例是本发明的组成部分，且相对于任何现有技术，在包括实施例在内的描述中出现的任何新特征在功能上和总体上均是本发明的组成部分。
因此，每个实施例具有一般性范围。
此外，在实施例中，除非另外指出，所有的百分比均以按重量计给出，而且除非另外指出，温度以摄氏度表示，而且除非另外指出，压力是大气压。
具体的实施方式
实施例
实施例1：美拉德反应的逆转
1－高级糖化终产物的制备：
含有蛋白和还原糖的溶液的制备即时地如下进行：将1.5μM和1.5M之间、优选15μM和500μM之间的浓度的牛血清白蛋白(BSA)溶液与诸如葡萄糖、果糖等的还原糖的溶液一起温育，优选与0.1M和10M之间且优选0.5M和5M之间的浓度的葡萄糖一起温育。
牛血清白蛋白溶液可以用人胶原蛋白代替。
温育进行1周－5周，优选3周。
温育温度维持在20℃和70℃之间，优选50℃。
2－高级糖化终产物与潜在活性化合物一起温育并检测美拉德反应的逆转现象：
在有或没有(阴性对照)待测试其高级糖化终产物去糖化活性的化合物的存在下，在40℃和60℃之间、优选约50℃的温度温育含有在1中制备的高级糖化终产物的溶液达1周到5周、优选3周。以在总组合物重量计的0.001～10%、优选0.01～5%、且更优选1%的浓度测试化合物。所使用的阳性对照是在15μM和150mM之间浓度的氨基胍、优选在1.5mM和15mM之间浓度的氨基胍。通过测量荧光来测定高级糖化终产物抑制(激发波长在350nm和375nm之间，优选为355nm；发射波长在420nm和450nm之间，优选为430nm)。通过比较设定为100%(最大荧光)的高级糖化终产物的荧光与高级糖化终产物+所测试的活性试剂的荧光来计算美拉德反应的逆转。
实施例2：特征分子的高级糖化终产物去糖化作用
根据在实施例1(第1段)中所描述的方法来制备蛋白/还原糖溶液。以例如在水或DMSO中的1×10-7～1×10-1%、优选1×10-5～1×10-1%、且特别为1×10-1%的浓度测试分子，如实施例1(第2段)所描述的。
在所描述的条件下，以至少相当于15mM浓度的氨基胍的方式促进高级糖化终产物去糖化的分子是：
表1
| 通用名 | INCI | CAS | %去糖化 |
| 3,5-二甲氧基-4-羟基肉桂酸(芥子酸) | 530-59-6 | 100 | |
| 羟吲哚 | 59-48-3 | 100 | |
| 4-氨基苯酚 | 对氨基苯酚 | 123-30-8 | 100 |
| 反式-3,3',4',5,7-五羟基黄烷(儿茶素) | 7295-85-4 | 100 | |
| 3,4-二羟基苯乙酸(DOPAC) | 102-32-9 | 100 | |
| 1,3,5-三羟基苯(间苯三酚) | 108-73-6 | 100 | |
| 2-羟基苯甲酸(水杨酸) | 69-72-7 | 100 | |
| 6-羟基-2,5,7,8-四甲基色满-2-甲酸(trolox) | 100 | ||
| 去甲二氢愈创木酸 | 500-38-9 | 100 | |
| 6-甲基-5,7a,13,13b-四氮杂戊芬-8,14-二酮 | 100 | ||
| 吲哚醇胺II | 6-羟基吲哚 | 100 | |
| 7-羟基-4,6-二甲基苯酞 | 100 | ||
| 2-羟基甲基-5-羟基-γ-吡喃酮(曲酸) | 501-30-4 | 97 | |
| 氢溴酸猪毛菜酚 | 94 | ||
| 3,4-二羟基肉桂酸 | 咖啡酸 | 331-39-5 | 88 |
| 毒扁豆碱 | 87 |
%去糖化：活性成分获得的荧光与阳性对照(15mM氨基胍)获得的荧光之比，以%计。
实施例3：植物提取物的高级糖化终产物去糖化作用
根据在实施例1(第1段)中所描述的方法来制备蛋白/还原糖溶液。
来自表2的化合物是由在水中浸渍而获得的提取物。以按总组合物重量计0.01～5%、特别是1%的浓度测试这些化合物。
表2
| 通用名 | 拉丁名 | 植物部分 | %去糖化 |
| Awati | Maprounea guyanensis | 叶 | 100 |
| 胡椒属槲寄生 | Phoradendron piperoides | 整个植物 | 100 |
| 假马鞭 | Stachytarpheta jamaicensis | 叶 | 100 |
| 号角树 | Cecropia obtusa | 叶 | 100 |
| 号角树 | Cecropia obtusa | 芽 | 96 |
| 鹿蹄草 | Chimaphila umbellata | 93 | |
| 樱树 | Prunus cerasus | 树皮 | 81 |
| 肉桂 | Senna alata | 叶 | 77 |
| 印度美人蕉 | Indian shot | 根 | 72 |
%去糖化：活性成分获得的荧光与用阳性对照(15mM氨基胍)获得的荧光之比，以%计。
实施例4：根据本发明的物质对人胶原蛋白的去糖化活性
根据实施例1(第1段)中所描述的方法来制备蛋白/还原糖的溶液，使用人胶原蛋白代替BSA。
1－人胶原蛋白的制备。
从源于整形外科手术的人类活组织来进行人胶原蛋白的提取。以溶液的形式获得的胶原蛋白与诸如葡萄糖、果糖或核糖的还原糖的溶液一起温育，优选与核糖一起温育。温育浓度与前述实施例中描述的相同。
2－潜在活性成分的制备和测试
在与实施例2和实施例3中所列举的条件相同的条件下使用“植物提取物”类型和“特征分子”类型的潜在活性成分。
3－结果
在所描述的条件下，以至少相当于15mM浓度的氨基胍的方式促进高级糖化终产物去糖化的分子与在实施例2和实施例3中所列举的那些分子相同。
实施例5－实施例10：可以局部施用的抗老化组合物
在下列实施例中，“本发明的产物”表示根据本发明的活性物质，尤其是根据实施例2或实施例3获得的那些活性物质。
实施例5：本发明的产物在水包油型乳剂的化妆品制剂或药物制剂中的用途。
制剂5a：
制剂5b：
制剂5c：
实施例6：本发明的产物在油包水型制剂中的用途
实施例7：本发明的产物在含水凝胶(眼圈轮廓等)制剂中的用途
实施例8：本发明的产物在洗发或洗浴凝胶类型的制剂中的用途
实施例9：本发明的产物在唇膏类型和其他无水产物制剂中的用途
实施例10：本发明的产物在片剂、软膏或可注射制剂中的用途
制剂10a：片剂的制备
*活性成分例如根据实施例中描述的提取工艺，继之以干燥步骤来获得。
制剂10b：软膏的制备
*活性成分例如根据实施例中描述的提取工艺，继之以干燥步骤来获得。
制剂10c：可注射制剂的制备
*活性成分例如根据实施例中描述的提取工艺，继之以干燥步骤来获得。
相A和相B被封装在分离的安瓿中，并在使用之前混合。
Claims (18)
1.促进高级糖化终产物的美拉德反应逆转的至少一种物质作为活性成分在制备用于限制人类皮肤组织中高级糖化终产物出现和/或促进去糖基化的经由局部施用的组合物中的用途，其中所述活性成分为植物肉桂的提取物。
2.根据权利要求1所述的用途，其中所述植物肉桂提取物为以水作为溶剂获得的提取物。
3.根据权利要求1或2所述的用途，其中所述植物肉桂提取物为以水作为溶剂获得的叶的提取物。
4.根据权利要求1－3中任一项所述的用途，其特征在于，所述组合物是能够局部施用的化妆品组合物。
5.根据权利要求1－4中任一项所述的用途，其特征在于，所述组合物通过促进皮肤组织中高级糖化终产物去糖化来预防和/或防止组织的柔性和/或可塑性和/或弹性和/或功能性的降低、和/或预防和/或防止组织的老化。
6.根据权利要求1－5中任一项所述的用途，其特征在于，所述物质按总组合物重量计对于植物提取物而言以0.001～10%的浓度来使用。
7.筛选促进高级糖化终产物去糖化的活性成分的方法，该方法包括：
a)生产高级糖化终产物；
b)使所述高级糖化终产物与就其高级糖化终产物去糖化活性而待筛选的物质接触；以及
c)选择促进所述高级糖化终产物去糖化的至少一种活性成分，
其特征在于，所述步骤a)包括在还原糖的存在下、在能够形成高级糖化终产物的条件下温育来自皮肤或来自血管壁的至少一种类型的蛋白，和/或
所述步骤b)包括在待筛选的至少一种物质的存在下，在40℃和60℃之间的温度下温育高级糖化终产物。
8.根据权利要求7的筛选方法，其特征在于，步骤a)中的还原糖为果糖、葡萄糖或核糖。
9.根据权利要求7或8的筛选方法，其特征在于，步骤a)在40℃和60℃之间的温度下进行1－5周。
10.根据权利要求7－9中任一项的筛选方法，其特征在于，皮肤的蛋白类型为人胶原蛋白或牛血清白蛋白溶液。
11.根据权利要求7－10中任一项的筛选方法，其特征在于，通过将活性成分与15nM的氨基胍获得的结果相比来选择活性成分。
12.化妆品组合物，其能够被局部施用或作为食物补充品，其特征在于，该组合物通过促进皮肤中高级糖化终产物去糖化来预防和/或防止皮肤的柔性和/或可塑性和/或弹性和/或功能性的降低、和/或预防或防止皮肤老化，所述组合物包括作为活性成分的促进皮肤中高级糖化终产物的美拉德反应逆转的物质，所述物质为植物肉桂的提取物。
13.根据权利要求12的化妆品组合物，其中所述植物肉桂提取物为以水作为溶剂获得的提取物。
14.根据权利要求12或13所述的化妆品组合物，其中所述植物肉桂提取物为以水作为溶剂获得的叶的提取物。
15.药物组合物，用于预防和/或防止皮肤的柔性和/或可塑性和/或弹性和/或功能性的降低，其特征在于，所述药物组合物包括作为活性成分的促进皮肤中高级糖化终产物的美拉德反应的逆转的物质，所述物质为植物肉桂的提取物。
16.根据权利要求15的药物组合物，其中所述组合物能够局部施用。
17.根据权利要求15或16的药物组合物，其中所述植物肉桂提取物为以水作为溶剂获得的提取物。
18.根据权利要求15－17中任一项的药物组合物，其中所述植物肉桂提取物为以水作为溶剂获得的叶的提取物。
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| EP (1) | EP2170358A2 (zh) |
| JP (2) | JP2010533143A (zh) |
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| CN105832724A (zh) * | 2015-10-16 | 2016-08-10 | 北京冠瑞金生物科技有限公司 | 吲哚醇在制备抗抑郁症药物中的用途 |
| CN109468370A (zh) * | 2018-11-09 | 2019-03-15 | 广州益养生物科技有限公司 | 一种快速检测遗传性皮肤糖基化能力基因的方法 |
| CN110684212A (zh) * | 2019-10-31 | 2020-01-14 | 东南大学 | 一种仿贻贝的水下高粘性水凝胶的制备方法 |
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| FR2951085B1 (fr) * | 2009-10-09 | 2012-05-18 | Inst Substances Vegetales | Utilisation de composes phenoliques pour la deglycation des proteines |
| FR2954702B1 (fr) | 2009-12-31 | 2013-07-05 | Basf Beauty Care Solutions F | Agent stimulant l'expression de loxl |
| CN102883733B (zh) * | 2010-02-10 | 2014-08-13 | 奥力榨油化株式会社 | Age生成抑制剂 |
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-
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832724A (zh) * | 2015-10-16 | 2016-08-10 | 北京冠瑞金生物科技有限公司 | 吲哚醇在制备抗抑郁症药物中的用途 |
| CN109468370A (zh) * | 2018-11-09 | 2019-03-15 | 广州益养生物科技有限公司 | 一种快速检测遗传性皮肤糖基化能力基因的方法 |
| CN110684212A (zh) * | 2019-10-31 | 2020-01-14 | 东南大学 | 一种仿贻贝的水下高粘性水凝胶的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009007412A2 (fr) | 2009-01-15 |
| FR2975495B1 (fr) | 2017-06-09 |
| KR20100047253A (ko) | 2010-05-07 |
| US20100203175A1 (en) | 2010-08-12 |
| JP2010533143A (ja) | 2010-10-21 |
| CN101765432A (zh) | 2010-06-30 |
| FR2918570B1 (fr) | 2012-10-05 |
| WO2009007412A3 (fr) | 2009-04-02 |
| EP2170358A2 (fr) | 2010-04-07 |
| FR2918570A1 (fr) | 2009-01-16 |
| FR2975495A1 (fr) | 2012-11-23 |
| BRPI0813925A2 (pt) | 2014-12-30 |
| JP2014028814A (ja) | 2014-02-13 |
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Application publication date: 20140528 |