CN113101297A - 用于软骨破坏的组合物 - Google Patents
用于软骨破坏的组合物 Download PDFInfo
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- CN113101297A CN113101297A CN202110405762.XA CN202110405762A CN113101297A CN 113101297 A CN113101297 A CN 113101297A CN 202110405762 A CN202110405762 A CN 202110405762A CN 113101297 A CN113101297 A CN 113101297A
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Abstract
本发明涉及包含橄榄苦苷和/或羟基酪醇的组合物用于维护关节健康或预防或治疗关节疾患的用途。具体地,本发明涉及橄榄苦苷用于预防或治疗软骨破坏。
Description
本申请为2014年5月28日提交的,发明名称为“用于软骨破坏的组合物”的申请No.201480030530.9的分案申请。
技术领域
本发明涉及关节健康,特别是本发明涉及用于预防或治疗软骨破坏或维护关节健康的组合物的用途,所述组合物包含橄榄苦苷和/或羟基酪醇。
背景技术
骨关节炎(OA)是一种高发病率疾病,其具有重要的社会经济影响。它是关节的关节软骨的变性疾病,是关节炎的最常见形式,影响成人人群的10%。OA是导致全世界中高龄残疾和保健开支的首要原因。
关节软骨的逐渐破坏和损失是主要的病理学特征,并伴有其他关节结构的改变,如滑膜增生、硬化和软骨下骨的厚度、关节边缘的骨赘形成、韧带松弛和肌肉萎缩,所有这些都导致了OA的临床症状。这些症状包括严重的疼痛、僵硬、关节运动消失和残疾。
虽然患OA的个体增加了,但仍然没有治愈手段,当前药物治疗仍是缓和疗法,着力减轻症状。例如,使用止痛剂(如对乙酰氨基酚)和非类固醇抗炎药(NSAID)治疗疼痛和炎症。此外,这些药物的使用通常与副作用相关,如胃肠道或心血管风险。
因此,用于治疗OA的改进的组合物将是有利的,尤其是期待更有效和安全的组合物。
发明内容
之前已经观察到橄榄苦苷和羟基酪醇的抗炎和抗氧化性能。然而,本发明人令人惊奇地证明这些化合物也具有对软骨的抗分解代谢作用。
因此,本发明的一个目的涉及提供用于改善关节健康的组合物。尤其是,本发明的一个目的是提供一种通过预防或治疗软骨破坏来改善关节健康的组合物,并解决了上述现有技术中副作用(如胃肠道和/或心血管风险)方面的问题。
因此,本发明的一个方面涉及包含橄榄苦苷和/或羟基酪醇的组合物用于预防或治疗软骨破坏。
本发明的另一方面涉及制备根据本发明使用的组合物的方法。
附图说明
图1A示出了在IL1a不存在时(模拟细胞的正常状态)ADAMTS-5mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图1B示出了在IL1a存在时(模拟细胞的疾病状态)ADAMTS-5mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
图2A示出了在IL1a不存在时(模拟细胞的正常状态)COX-2mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图2B示出了在IL1a存在时(模拟细胞的疾病状态)COX-2mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
图3A示出了在IL1a不存在时(模拟细胞的正常状态)MMP-13mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图3B示出了在IL1a存在时(模拟细胞的疾病状态)MMP-13mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
图4示出了豚鼠膝的组织学切片(苏木紫、快绿和番红精O染色)。4A和4B显示A组(橄榄苦苷);4C和4D显示C组(芦丁);4E和4F显示D组(芦丁和姜黄素);4G和4H显示B组(对照)。
图5示出了各组总的OA评分。
图6A示出了血浆中炎性PGE2生物标志物的浓度。图6B示出了在第4和第35周血浆PGE2水平和相应的OA评分之间的相关性。
图7示出了血浆中Coll 2-1NO2生物标记物的浓度与2型胶原随时间断裂的关联。
图8A示出了血浆中Coll 2-1NO2生物标记物与2型胶原分解的关联。
图8B示出了在第4和第35周血浆Coll 2-1NO2生物标记物浓度和相应的OA评分之间的相关性。
图9示出了血浆中纤蛋白3-1生物标记物的浓度与OA患者中软骨细胞的过度生长作用的关联。
图10A示出了血浆中纤蛋白3-1生物标记物的浓度与OA患者中软骨细胞的过度生长作用的关联。
图10B示出了在第4和第35周血浆纤蛋白3-1生物标记物浓度和相应的OA评分之间的相关性。
发明详述
定义
在进一步详细地讨论本发明之前,首先定义下列术语和常用语:
在本发明的上下文中,提及的百分数都是重量/重量百分比,除非另有说明。
在“X和/或Y”的上下文中使用的术语“和/或”应被解释为“X”、或“Y”、或“X和Y”。
本文所用的数值范围旨在包括在该范围内的每个数字和数字的子集,无论具体公开与否。此外,这些数值范围应被理解为涉及该范围内的任何数字或数字子集的权利要求提供支持。例如,公开了从1到10应被解释为支持从1至8、从3至7、从4至9、从3.6至4.6、从3.5至9.9的范围,等等。
本发明所有引用的单数特征或限制应当包括相应的复数特征或限制,反之亦然,除非另有说明或提及该引用的上下文明显地有相反的暗示。
除非另有定义,本文使用的所有技术和科学术语具有与本领域普通技术人员通常所理解的相同的含义。
使用的组合物
橄榄苦苷是一种多酚,先前已证明其对炎症和骨代谢具有有益作用。羟基酪醇作为橄榄苦苷的代谢物是一种相关化合物,已经表明羟基酪醇也具有这些效果。现在本发明人令人惊奇地表明,橄榄苦苷和羟基酪醇各自也对软骨破坏具有有益效果。
关节疾病可伴随较大或较小程度的炎症。在一些疾病中,炎症是主要的组成,诸如例如在类风湿性关节炎(RA)中。在其他疾病,诸如例如OA,炎症不占主导地位。然而,这两种疾病均有分解代谢组分,其中关节软骨被破坏。
本发明人已经证明,在OA的动物模型中提供橄榄苦苷可以防止软骨破坏。羟基酪醇也已显示在软骨模型系统中抑制分解代谢的酶。
因此,本发明在第一方面涉及包含橄榄苦苷和/或羟基酪醇的组合物,用于预防或治疗软骨破坏。
以另一种方式,本发明的该方面可被描述为橄榄苦苷和/或羟基酪醇在制备用于预防或治疗软骨破坏的药物中的用途。
预防或治疗软骨破坏的用途与抑制或减少软骨破坏的用途是同义的。
因此,本发明的实施方案包括包含橄榄苦苷的组合物用于预防或治疗软骨破坏和包含羟基酪醇的组合物用于预防或治疗软骨破坏。
本发明的又一实施方案包括包含橄榄苦苷和羟基酪醇的组合物用于预防或治疗软骨破坏。
本发明进一步的实施方案包括用于本发明的组合物,其中所述组合物还包含姜黄素,以及用于本发明的组合物,其中所述组合物进一步包含槲皮素。
在本发明的实施方案中,用于本发明的组合物包含橄榄苦苷和/或羟基酪醇、以及一种或多种其他多酚,例如选自姜黄素和槲皮素的一种或多种多酚。
本发明的一个实施方案涉及用于本发明的组合物,其中所述组合物包含橄榄苦苷和/或羟基酪醇,并且还包含姜黄素。
橄榄苦苷和姜黄素的组合,以及羟基酪醇和姜黄素的组合,都被证明在体外软骨模型中抑制分解代谢的酶(参见图1和3,实施例1)。
本发明的另一个实施方案涉及用于本发明的组合物,其中所述组合物包含橄榄苦苷和/或羟基酪醇,并且还包括槲皮素。
橄榄苦苷和槲皮素的组合、以及羟基酪醇和槲皮素的组合,都被证明在体外软骨模型中抑制分解代谢的酶(参见图1和3,实施例1)。
在又一个实施方案中,用于本发明的组合物包含橄榄苦苷和/或羟基酪醇,并进一步包含姜黄素和槲皮素。
橄榄苦苷+姜黄素+槲皮素的组合、或羟基酪醇+姜黄素+槲皮素的组合,已分别被证明对软骨破坏中分解代谢酶的活性具有协同和特异的效果(参见图1和3,实施例1)。
成分-主要的生物活性化合物
橄榄苦苷、羟基酪醇、姜黄素和槲皮素是本发明的主要生物活性分子。它们可以来自任何合适的来源。在优选的实施方案中,橄榄苦苷、羟基酪醇、姜黄素和槲皮素从植物来源获得。橄榄苦苷和羟基酪醇例如可以从橄榄植物获得。
成分-进一步的生物活性化合物
用于本发明的组合物也可以包含至少一种其他生物活性化合物,如选自抗氧化剂、抗炎化合物、糖胺聚糖、益生元、纤维、益生菌、脂肪酸、矿物质、微量元素和/或维生素的化合物。
在本申请的上下文中,术语“生物活性”是指该化合物除满足基本的营养需要之外,其有助于个体健康、或对人体有效果。
至少一个其他生物活性化合物可以来自天然来源。因此,这些化合物可以来自植物、动物、鱼类、真菌、藻类、微生物发酵物的提取物。认为矿物质来自天然来源,属于此定义。
抗炎化合物和/或抗氧化剂
与抗炎化合物组合
在一个方面,本发明涉及组合物,其用于预防或治疗软骨破坏。
在本发明的一个实施方案中,根据本发明的组合物可与至少一种抗炎化合物组合使用。
所述至少一种抗炎化合物可与本发明的组合物组合施用,例如相继或同时施用。
所述至少一种抗炎化合物可以与本发明的组合物在相同的组合物中提供,或者可以在单独的组合物中提供,例如在多部分试剂盒中提供,或以一系列相互作用的产品提供。
如果用于本发明的组合物与至少一种抗炎化合物存在于一个或多个单独的组合物中,它们可以在使用之前混合,或可同时或相继施用。
在进一步的实施方案中,用于本发明的组合物包含作为至少一种其他生物活性化合物的至少一种抗炎化合物。在其他优选的实施方案中,用于本发明的组合物包含作为至少一种其他生物活性化合物的至少一种抗氧化剂。
所述至少一种抗炎和/或抗氧化剂化合物可以是任何具有抗炎和/或抗氧化作用的合适的化合物。
值得注意的是,一些抗炎化合物还具有抗氧化作用。可以根据其具有一种或两种特性选择包含该化合物。
可以包含在本发明组合物中的抗炎化合物的实例是天然来源的抗炎化合物。
因此,本发明的一个实施方案涉及用于本发明的组合物,其中至少一种抗炎化合物包括ω-3多不饱和脂肪酸,其可以例如从鱼中提取。
本发明的其他实施方案涉及用于本发明的组合物,其中包含的至少一种抗炎化合物是至少一种植物提取物。
植物提取物可包括例如黄酮类化合物、多酚、原花色甙(proanthocyanins)、脂质(如鳄梨大豆不皂化物(avocado soybean unsaponifiables)、ω-3多不饱和脂肪酸)。
植物提取物可以来自一种或多种选自下组的植物:钩果草(devil’sclaw)(鬼爪草(Harpagophytum procumbens))、迷迭香(Rosmarinus officinalis)、牛膝草(hyssop)、姜(生姜(Zingiber officinale))、姜黄(turmeric)(姜黄(Curcuma longa))、山金车(ArnicaMontana)、柳树皮(willow bark)、石榴(石榴(Punica granatum))、绿茶(茶(Camelliasinensis))、猫爪草(cat's claw)(钩藤(Uncaria tometosa)和圭亚那钩藤(Uncariaguianensis))、印度乳香(Indian olibaum)(齿叶乳香树(Boswelia serrata))和菠萝(pineapple bromelain)(凤梨(Ananas comosus))、黑种(Black seed)(栽培黑种草(Nigella sativa))、圣约翰草(St.John's wort)、贯叶金丝桃(hyperforin)、白毛茛(Goldenseal)、德国洋甘菊(German Chamomile)(母菊(Matricaria recutita))。
可包含在本发明组合物中的至少一种抗氧化剂可以选自虾青素、类胡萝卜素、辅酶Q10(“CoQ10”)、黄酮类化合物、谷胱甘肽、枸杞(Goji)(西方雪果(wolfberry))、橙皮苷、乳薄叶西方雪果(lactowolfberry)、木脂体、叶黄素、番茄红素、多酚、硒、维生素A、维生素C、维生素E、玉米黄质。
在优选的实施方案中,抗氧化剂来自天然来源,如例如植物提取物。
糖胺聚糖
糖胺聚糖是存在于健康软骨的大的、高带电分子。糖胺聚糖的实例是葡糖胺和硫酸软骨素。
因此,用于本发明的组合物的一个实施方案包括葡糖胺和/或硫酸软骨素。
益生元
在一些实施方案中,用于本发明的组合物包含一种或多种益生元。非限制性益生元的实例包括金合欢树胶、α-葡聚糖、阿拉伯半乳聚糖、β-葡聚糖、葡聚糖、低聚果糖、岩藻糖基乳糖、半乳寡糖、半乳甘露聚糖、低聚龙胆糖、葡萄糖低聚糖、瓜尔胶、菊粉、低聚异麦芽糖、内酯四糖(lactoneotetraose)、乳蔗糖、乳果糖、果聚糖、麦芽糖糊精、乳低聚糖、部分水解的瓜尔胶、果胶寡糖(pecticoligosaccharides)、抗性淀粉、回生淀粉、唾液寡糖(sialooligosaccharides)、唾液酸乳糖、大豆寡糖(soyoligosaccharides)、糖醇、木寡糖,其水解产物,或其组合。
纤维
用于本发明的组合物可以包括纤维。该纤维可以是可溶性纤维、不溶性纤维或它们的组合。可溶性纤维可以包括,例如,低聚果糖、金合欢树胶、菊粉、琼脂、藻酸盐、角豆胶、角叉菜胶,阿拉伯树胶、瓜尔胶、刺梧桐胶、果胶或黄原胶等,这些可溶性纤维是水解或者未水解形式。不溶性纤维可以包括,例如,豌豆外纤维。
益生菌
用于本发明的组合物可以包括一种或多种益生菌。非限制性益生菌的实例包括气球菌属(Aerococcus)、曲霉属(Aspergillus)、拟杆菌属(Bacteroides)、双歧杆菌属(Bifidobacterium)、假丝酵母属(Candida)、梭菌属(Clostridium)、Debaromyces、肠球菌属(Enterococcus)、梭杆菌属(Fusobacterium)、乳杆菌属(Lactobacillus)、乳球菌属(Lactococcus)、明串珠菌属(Leuconostoc)、Melissococcus,微球菌属(Micrococcus)、毛霉属(Mucor)、Oenococcus,片球菌属(Pediococcus)、青霉菌属(Penicillium)、Peptostrepococcus,毕赤酵母属(Pichia)、丙酸菌属(Propionibacterium)、Pseudocatenulatum,根霉菌属(Rhizopus)、酿酒酵母属(Saccharomyces)、葡萄球菌属(Staphylococcus)、链球菌属(Streptococcus)、球拟酵母属(Torulopsis)、魏斯氏菌属(Weissella)、非复制的微生物,以及它们的组合。
矿物质和微量元素
可包含在本发明组合物中的矿物质和微量元素的例子包括矿质元素和微量元素,如钙、镁、钠、钾、磷、铜、锌、铁、硒、铬和钼,以及它们的组合。
维生素
用于本发明的组合物也可包含一种或多种选自以下的其他维生素:维生素A、维生素D、维生素E、维生素K、维生素C、叶酸、硫胺素、核黄素、维生素B6、维生素B12、烟酸、生物素和泛酸。
含量
用于本发明的组合物可包含各主要生物活性成分橄榄苦苷、羟基酪醇、姜黄和槲皮素的含量为每份中各组分的量从0.01mg至约1g,优选0.1mg至1g,甚至更优选1mg至约1g。
营养组合物
用于本发明的组合物可以是营养组合物或药物组合物,并且可以用于人类或兽医用途。
因此,在优选的实施方案中,用于本发明的组合物是营养组合物。
“营养组合物”在本发明上下文中指的是个体营养来源的任何组合物。
本发明的营养产品或组合物可以是完全营养的来源,或者可以是不完全营养的来源。
如本文所用,“完全营养”包括这样的营养产品和组合物,其包含足够类型和水平的常量营养物(蛋白质、脂肪和碳水化合物)和微量营养素,从而足以使其作为所施用动物的唯一营养来源。患者可以从这样的完全营养组合物获得其营养需求的100%。
如本文所用,“不完全营养”包括这样的营养产品或组合物,其不包含充足水平的常量营养物(蛋白质、脂肪和碳水化合物)或微量营养素,因而不足以使其作为所施用动物的唯一营养来源。部分或不完全营养组合物可以用作营养补充剂。
本发明的营养组合物可以是药膳。药膳是特殊类型的营养组合物,其设计为提供特定适应症的膳食管理。药膳符合1983年《罕见病药物法》(Orphan Drug Act)第5部分[360ee](b)(2)(D)设定和规定的某些标准。
营养组合物成分
蛋白质源
在一个实施方案中,用于本发明的组合物包括蛋白质源。蛋白质源可以是膳食蛋白质,包括但不限于:动物蛋白(如乳蛋白、肉蛋白或卵蛋白)、植物蛋白(如大豆蛋白、小麦蛋白、大米蛋白和豌豆蛋白),或它们的组合。在一个实施方案中,蛋白质选自乳清、鸡肉、玉米、酪蛋白、小麦、亚麻、大豆、角豆、豌豆或它们的组合。
碳水化合物源
在一个实施方案中,组合物包括碳水化合物源。任何合适的碳水化合物可以用于本发明的组合物中,包括但不限于,淀粉、蔗糖、乳糖、葡萄糖、果糖、淀粉糖浆干粉、麦芽糖糊精、改性淀粉、直链淀粉、木薯淀粉、玉米淀粉、木糖醇、山梨糖醇或它们的组合。
脂肪源
在一个实施方案中,组合物包括脂肪源。脂肪源可以包括任何合适的脂肪或脂肪混合物。例如,脂肪源可以包括但不限于,植物脂肪(如橄榄油、玉米油、葵花籽油、高油酸葵花籽油、油菜籽油、芸苔油、榛子油、大豆油、棕榈油、椰子油、黑加仑籽油、琉璃苣油、卵磷脂等)、动物脂肪(如乳脂肪),或它们的组合。脂肪源也可以是以上列出脂肪的精炼程度较低的形式(例如,就多酚成分而言,精炼程度较低的橄榄油)。
调味料等
此外,用于本发明的组合物也可包含天然或人工香料,例如水果香料如香蕉、橙、桃、菠萝或覆盆子或其他植物香料如香草、可可、咖啡等。
营养组合物形式
营养组合物可以包括,除了主要生物活性成分和任何其他生物活性成分外,任选一种或多种蛋白质、碳水化合物和脂肪源,任何数量的任选其他食品成分,包括常规食品添加剂(合成的或天然的),例如一种或多种酸化剂、添加的增稠剂、用于pH调节的缓冲剂或试剂、螯合剂、着色剂、乳化剂、赋形剂、调味剂、矿物质、渗透剂、可药用的载体、防腐剂、稳定剂、糖、甜味剂、调质剂和/或维生素。可以任何合适的量加入任选成分。
营养组合物可以以任何合适的形式提供。
其中可提供用于本发明的组合物的营养组合物形式的实例包括溶液、即时消费的组合物(如即饮组合物或速溶饮品)、液体食物、软饮料、果汁、运动饮料、乳饮料、奶昔、酸奶饮料、汤等。
在另一个实施方案中,营养组合物可以以浓缩物、粉末或颗粒(例如泡腾颗粒)形式提供,其用水或其他液体(如牛奶或果汁)稀释,以提供即时消费的组合物。
其他营养组合物形式包括烘焙制品、乳制品、甜点、糖果制品、谷物棒和早餐谷物片。乳制品的例子包括乳和乳饮料、酸奶和其他发酵奶制品、冰淇淋和干酪。烘焙制品的例子包括面包、饼干和蛋糕。
在一个实施方案中,用于本发明的组合物也可以设计成动物食品以多种不同的形式提供,尤其是用于狗或猫的动物食品,以湿态形式、半湿形式或干燥形式,特别以饼干形式提供。
施用途径
本公开的营养组合物可通过适于人类施用,特别是适于胃肠道任何部位施用的任何方式施用。肠内施用、口服施用、以及通过管或导管施用都包括在本公开中。营养组合物也可通过选自以下的方式施用:口服、直肠施用、舌下施用、唇下施用、颊施用、局部施用等等。
可以以任何已知的形式施用营养组合物,包括,例如,常规剂型中的片剂、胶囊、液体、咀嚼片、软凝胶、小药囊、粉末、糖浆、液体悬浮剂、乳剂和溶液。在软胶囊中,活性成分优选溶解或悬浮在合适的液体中,如溶解或悬浮在脂肪油、石蜡油或液体聚乙二醇中。任选地,可以加入稳定剂。
如果营养组合物通过管饲施用,则营养组合物可于短期或长期管饲。
抑制或减少病理学的软骨破坏
本发明组合物已经显示出减少软骨的破坏,尤其是关节软骨的软骨破坏。
关节软骨存在于关节中,例如在手指、膝、髋、颚、肘关节。
因此,在一个实施方案中本发明涉及根据本发明的组合物用于预防或治疗软骨破坏。换句话说,在一个实施方案中,本发明涉及根据本发明的组合物用于抑制或减少软骨破坏。
软骨破坏可能是病理学(慢性或急性)的、外伤或其组合的结果。
软骨破坏发生在炎症为主的病理学的(如类风湿性关节炎)或者炎症不显著的病理中(例如骨关节炎)。
外伤也可能导致软骨破坏过程的启动。例如,膝中韧带撕裂导致膝关节不稳定,而且将启动破坏过程。
在本申请的上下文中外伤指由外部源引起的生理损伤,所述外部源指例如跌倒或汽车冲击等。外伤还包括所谓的关节“磨损”。
然而通常优选用手术治疗外伤,在一个实施方案中,本发明涉及一种治疗方法,其中外伤是通过手术以及还通过施用本发明的组合物治疗。
因此,根据本发明的用途的实施方案包括用于抑制或减少软骨破坏,其中所述软骨破坏是病理学的或外伤的结果。
因此,涉及软骨破坏的并且本发明组合物对其可以是有用的病理学的例子包括:骨关节炎、类风湿性关节炎、痛风和假性痛风、脓毒性关节炎、强直性脊柱炎、青少年特发性关节炎、斯提尔氏病、牛皮癣(银屑病关节炎)、反应性关节炎、埃勒斯-当洛斯综合征、血色病、肝炎、莱姆病、炎症性肠病(包括克罗恩氏病和溃疡性结肠炎)、过敏性紫癜(purpura)、有反复发热的高免疫球蛋白血症D、结节病、TNF受体相关的周期性综合征、韦格纳肉芽肿(和许多其他血管炎综合征)、家族性地中海热、系统性红斑狼疮。
在优选的实施方案中,本发明的组合物用于抑制或减少RA和/或OA中的软骨破坏。
在进一步优选的实施方案中,本发明的组合物用于抑制或减少OA中的软骨破坏。
抑制或减少非炎性病理学的和外伤中的破坏
本文已经表明,本发明的组合物可以预防软骨破坏。
不希望受约束于理论,已经观察到尽管炎症常常导致关节中的软骨破坏,软骨破坏确实也出现在炎性成分非常不显著的的情况下,甚至出现在炎性成分可忽略不计的情况下。
例如,在OA中,炎症继发于软骨破坏,即,其是疾病的后果或症状,而不是引发疾病的原因或驱动因子。
例如,关节外伤非常可能引发软骨破坏,而没有例如存在于RA中的显著的炎症成分。外伤例如可以包括关节(例如膝,手指)的韧带撕裂或冲击外伤。外伤还可能是小损伤随时间的累积,即所谓的“磨损”。
在另一实施例中,OA主要是关节退行性疾病,其具有较少的炎性成分。
本文已经表明,橄榄苦苷除了具有消炎作用外,还可以防止软骨破坏和胶原分解。
因此,在一个实施方案中本发明涉及一种用于本发明的组合物,其抑制或减少软骨破坏,并且其中软骨破坏发生在很少或没有炎性成分的病理学的情况下,如外伤或例如OA。
在优选的实施方案中,本发明涉及用于本发明的组合物,其中用途是抑制或减少OA中的软骨破坏。
在进一步的实施方案中,本发明涉及橄榄苦苷,其用于抑制或减少软骨破坏,其中软骨破坏发生在很少或没有炎性成分的病理学的情况下,如外伤或例如OA。
抑制或减少胶原分解
橄榄苦苷在本文中示出减少胶原分解产物的出现(例如,图8A)。因此,橄榄苦苷的作用是抑制或减少软骨中胶原的分解。
因此,本发明在一个实施方案中涉及橄榄苦苷用于抑制或减少软骨破坏的用途。在进一步的实施方案中,本发明涉及橄榄苦苷用于抑制或减少胶原分解的用途,特别是抑制或减少在软骨中的胶原分解。进一步的实施方案涉及橄榄苦苷用于抑制或减少II型胶原分解的用途,特别是用于抑制或减少在软骨中的II型胶原分解。
其他实施方案涉及如本文其他地方描述的用于本发明的组合物,其抑制或减少软骨破坏。在本发明的另一个实施方案中,涉及用于本发明的组合物,其中用途是抑制或减少软骨中胶原的分解,例如软骨中II型胶原的分解。
II型胶原分解是软骨破坏的一个重要事件。不希望受到理论的束缚,人们认为从关节软骨释放糖胺聚糖是可逆的事件。然而,胶原的分解意味着原纤维网络受到损害。胶原分解是糖胺聚糖缺失之后的事件,可能比糖胺聚糖缺失的可逆性小。这意味着,抑制或减少关节中的胶原(尤其是II型胶原)分解是非常重要的。
预防和/或治疗软骨破坏包括抑制和/或减少软骨破坏,并且还包括抑制和/或减少胶原分解。软骨中主要的胶原是II型胶原,因而抑制或减少胶原分解包括抑制和/或减少II型胶原分解。
已经表明,本发明的组合物可以抑制已知在软骨破坏中有活性的蛋白酶。抑制或减少蛋白水解活性将抑制或减少软骨组分的分解。抑制或减少胶原原纤维网络的降解是特别重要的,因为该网络对保持软骨结构的完整性是重要的。
因此,在一个实施方案中,本发明涉及用于本发明的组合物,其中用途是抑制或减少软骨中的胶原分解。在进一步的实施方案中,本发明涉及用于本发明的组合物,其中用途是抑制或减少软骨中II型胶原的分解。
治疗或预防随年龄的运动性下降
用于本发明的组合物已示出能抑制或减少蛋白水解活性。
老龄化导致软骨破坏。所用的豚鼠模型表明,软骨破坏随年龄自发出现。
因此,本发明涉及本发明的组合物,其用于抑制或减少老龄化相关的软骨破坏。
在另一个实施方案中,本发明涉及本发明的组合物,其用于抑制或减少与老龄化相关的软骨破坏中的胶原分解,例如用于抑制或防止与老龄化相关的软骨中II型胶原分解。
软骨的破坏可导致关节僵硬和关节疼痛,从而导致病人的运动性下降。
用于本发明的组合物在其他实施方案中可用于维持或改善关节功能,包括老龄化过程中的软骨功能。
在进一步的实施方案中,本发明涉及用于本发明的组合物,其用于改善受试者的运动性,例如改善成人或老年哺乳动物的运动性。
因此,在一个优选实施方案中,根据本发明的组合物可以用于改善个体的活动性和/或运动性,例如通过防止或骨关节炎,和/或通过抑制或减少软骨破坏。
其他优选的实施方案涉及用于本发明的组合物,其中用途是防止软骨破坏,从而维持健康的关节,或维持或改善运动性。
在进一步的实施方案中,本发明的组合物可以用于维持软骨的状态。
橄榄苦苷+姜黄素+槲皮素;和羟基酪醇+姜黄素+槲皮素的具体的组合
根据本发明的包含橄榄苦苷、姜黄素和槲皮素的组合物,或根据本发明的包含羟基酪醇、姜黄素和槲皮素的组合物均能强烈下调与软骨破坏相关的蛋白酶。
特别是在模拟疾病的情况下,这两种组合在下调与软骨破坏相关的蛋白酶中是非常有效的。
因此,本发明在一个实施方案中涉及这些组合物,其用于治疗或预防软骨破坏。
例如,这些组合物对于预防或治疗OA是有用的。
炎症和软骨破坏
根据本发明的包含橄榄苦苷和/或羟基酪醇,并进一步包含姜黄素和槲皮素中的至少一种的组合物,已显示出既下调在软骨破坏中有活性的蛋白酶,又下调炎症标记物。
因此,本发明在另一个实施方案中涉及这些组合物,其用于抑制或减少软骨破坏,以及用于抑制或减少炎症。
根据本发明的包含橄榄苦苷、姜黄素和槲皮素的组合物,或根据本发明的包含羟基酪醇、姜黄素和槲皮素的组合物既能强烈下调与软骨破坏相关的蛋白酶,还能下调炎症标记物。
因此,本发明在一个实施方案中涉及这些组合物,其用于治疗或预防软骨破坏和炎症。
例如,这些组合物在治疗或预防RA中是有用的。
关节疾病
在进一步的实施方案中,本发明涉及用于本发明的组合物,其中组合物包含橄榄苦苷和/或羟基酪醇,并进一步包括选自姜黄素和槲皮素中的至少一个。
示出本发明的这些组合物下调与软骨破坏相关的蛋白水解酶,并且还对COX2有下调作用,COX2是一种炎性标志物。
因此,本发明的一个实施方案涉及这些所述本发明的组合物,其用于预防或治疗关节疾病。所述关节疾病可以是任何关节疾病,诸如例如具有显著炎性成分的关节疾病,例如RA;或例如退行性关节疾病,例如OA。
靶标组
用于本发明的组合物的靶标组可以是出现软骨破坏的任何哺乳动物,例如,因为其遭受一种或多种涉及本文提及的软骨破坏的病理学的疾病。软骨破坏可以通过影像手段(visual means)来检测,例如通过放射线照相术检测。或者,软骨分解产物的检测可以在体液中检测。例如,可以在例如样品(如血浆或尿液样品)中检测一种或多种II型胶原表位,如(Col2-1,Col2-1 NO,CTX-II)。
另一个靶标组可以是尚未出现软骨破坏的任何哺乳动物,但这些哺乳动物具有软骨破坏的风险,例如具有OA、RA或涉及本文提及的软骨破坏的任何病理学疾病的风险。
本发明的一个具体实施方案涉及组合物,其用于改善个体的活动性和/或运动性,例如通过预防或治疗骨关节炎,和/或通过抑制或减老人(elderly)或老龄化(aging)个体的软骨破坏。
在进一步的实施方案中,用于本发明的组合物可以用于哺乳动物,例如人或宠物中。宠物的例子包括猫、狗和马。
虽然本发明可能在许多不同年龄组中是有用的,在一个优选实施方案中,本发明的用于增加运动性的组合物是针对老龄化人口的,尤其是针对健康老龄化和/或老人哺乳动物。
制备本发明营养组合物的方法
在另一方面,本发明涉及一种制备用于本发明的营养组合物的方法,所述方法包括以下步骤:
-提供营养组合物的各成分和橄榄苦苷并混合,使得所述营养组合物包含橄榄苦苷。
在进一步的实施方案中,制备用于本发明的营养组合物的方法包括以下步骤:
-提供一种或多种营养组合物的成分、橄榄苦苷和/或羟基酪醇,并任选进一步地提供姜黄素和槲皮素的一种或多种,并混合。
使用的药物组合物。
在进一步的实施方案中,本发明涉及一种组合物,其根据本发明用于抑制或预防软骨破坏,其中所述组合物是药物组合物。
药物指不是营养组合物的组合物,其中在身体上或身体内使用物质,以预防、诊断、缓解、治疗或治愈人或动物在医学上的疾病。根据本发明,所述药物可以用于抑制或减少软骨破坏。
所述药物可以用于人类。或者其可以是兽医组合物,例如适合于狗、猫或马,特别是纯种马。
在一个优选的实施方案中,本发明的药物组合物包含橄榄苦苷。
在另一个优选的实施方案中,本发明的药物组合物包含橄榄苦苷和/或羟基酪醇。
本发明还涉及根据本发明的药物的用途,如本文中描述为本发明组合物的用途。
用于本发明的组合物包含橄榄苦苷、或一种或多种或橄榄苦苷和/或羟基酪醇、或进一步包含姜黄素和/或槲皮素,与至少一种赋形剂组合,所述赋形剂选自可药用的赋形剂。制备本发明药物组合物的步骤可以很容易地被本领域的专业技术人员找到,例如在手册Remington'sPharmaceutical Sciences,Mid.Publishing Co,Easton,Pa.,USA。生理学上可接受的赋形剂、载体和佐剂也在题为Handbook of Pharmaceutical Excipients,Second edition,American Pharmaceutical Association,1994中描述了。为了配制本发明的药物组合物,本领域的专业技术人员能够有利地参照最新版的欧洲药典或美国药典(USP)。特别是,本领域的专业技术人员能够有利地参照欧洲药典第四版“2002”或参照美国药典USP 25-NF 20版(美国药典)。
有利的是,如上所定义的药物组合物适合于口服、肠胃外或静脉内施用。当用于本发明的药物组合物包含至少一种药学上或生理学上可接受的赋形剂时,其具体地是适合于通过口服途径施用组合物的赋形剂、或适合于通过肠胃外途径施用组合物的赋形剂。
用于本发明的药物组合物无差别地以固体或液体形式提供。对于口服施用,优选是片剂、胶囊或明胶胶囊形式的固体药物组合物。
在液体形式中,药物组合物优选是水性或非水性悬浮液的形式,或者是油包水或水包油乳液的形式。
固体药物形式可以包括,如载体、佐剂或赋形剂、至少一种稀释剂、一种香料、一种增溶剂、一种润滑剂、一个悬浮剂、一种粘合剂、一种崩解剂和一种包封剂。这类化合物是例如碳酸镁、硬脂酸镁、滑石、乳糖、果胶、糊精、淀粉、明胶、纤维素材料、可可脂等。液体形式的组合物还可以包含水,可能作为与丙二醇或聚乙二醇的混合物,以及可能还有着色剂、香料、稳定剂和增稠剂。
治疗方法
本发明还涉及预防或治疗软骨破坏的方法,例如预防或治疗其中发生软骨破坏的病理学疾病或者与软骨破坏相关的外伤,所述方法包括向有需要的个体施用有效量的本发明组合物。例如,该方法包括施用有效量的橄榄苦苷。在其他实施例中,本发明的方法包括施用有效量的一种或多种橄榄苦苷和/或羟基酪醇。在优选的实施方案中,治疗方法包括施用有效量的用于本发明的组合物,所述组合物包含橄榄苦苷和/或羟基酪醇,以及一种或多种其他多酚,例如选自姜黄素、槲皮素和芦丁中的一种或多种其他多酚。
如本文所用,“有效量”是在个体中预防缺陷、治疗疾病或医学病症的量,或者更一般地,减少症状、管理疾病的进展或为个体提供营养、生理或医学益处的量。
当然,根据本发明的组合物实现治疗作用所需的有效量,将随特定的组合物、施用途径、接受者年龄和身体状况,以及正在治疗的特定病患或疾病而不同。
本发明还提供预防或治疗涉及软骨破坏的病理学疾病的方法,如,例如OA或RA;抑制或减少软骨破坏的方法;抑制或减少软骨中胶原分解的方法;抑制或减少软骨中II型胶原分解的方法;所述方法包括向个体施用有效量的用于本发明的组合物。
在一个实施方案中,根据本发明的治疗方法涉及预防或治疗骨关节炎。
根据本发明的治疗方法可以在哺乳动物中,如人或宠物,例如狗、猫和/或马中进行。
在某些实施方案中,在治疗方法中施用的本发明组合物可以是一种或多种本发明的营养组合物和/或本发明的药物组合物。
公开的组合
应当指出的是,在本发明一个方面的上下文中描述的实施方案和特征也适用于本发明的其他方面。
用于本发明的组合物在文中以不同的参数描述,如成分、营养组合物形式、使用、靶标组等。应注意的是,用于本发明的组合物的参数之一的上下文中描述的实施方案和特征,也可与另一参数的上下文中描述的其他实施方案和特征组合,除非另有明确说明。
在本申请中引用的所有专利和非专利参考文献,在此通过引用整体并入本文。
现在将进一步在以下非限制性实施例中详细地描述本发明。
实施例
实施例1-体外研究-藻酸盐珠中的牛原代软骨细胞
材料和方法
橄榄苦苷。基本上纯的橄榄苦苷(>98%)购自Extrasynthese(GENAY,法国)。
羟基酪醇。基本上纯的羟基酪醇(>98%)购自Extrasynthese(GENAY,法国)。橄榄苦苷的代谢物。
槲皮素。基本上纯的槲皮素(>97%)购自HWI Analytik GmbH(Ruelzheim,德国)。芦丁的代谢物。
芦丁。基本上纯的芦丁(>94%)购自Sigma-Aldrich公司(Buchs,Switzerland)。
姜黄素。基本上纯的芦丁(>70%)购自Sigma-Aldrich公司(Buchs,Switzerland)。
细胞培养
洗涤年青的牛的蹄,除去泥土。将皮肤从蹄除去。横向打开关节。横断关节内韧带。用磷酸盐缓冲盐水洗涤打开的关节。用解剖刀片,切出软骨全厚度切片,并收集在含有10mMhepes和1%青霉素-链霉素的DMEM高糖中。在含有10mM hepes和1%青霉素-链霉素的DMEM高糖中洗涤软骨切片。
然后依次通过0.5mg/ml透明质酸酶(hyluronidase)30分钟、1.0mg/ml链霉蛋白酶E 60分钟和1.0mg/ml胶原酶在缓慢搅动下过夜消化软骨。
酶孵育后,通过70μm的细胞过滤器过滤细胞悬浮液以分离细胞簇并除去组织碎片。将细胞悬浮液离心以沉淀细胞。
将培养基弃去,通过离心以及重新悬浮于含有10mM hepes的0.9%氯化钠溶液洗涤细胞沉淀物。
将细胞悬浮在含有1.2%藻酸盐的0.9%NaCl、10mM HEPES的溶液中,得到每毫升4.3x106个细胞的密度。使该悬浮液通过针以逐滴的方式滴入102mM CaCl2溶液中。10分钟后,将珠聚合,并用0.9%NaCl、10mM HEPES洗涤。含有1ml完全培养基(含有2mM L-谷氨酰胺、0.5mg/ml抗坏血酸、0.2mg/ml L-脯氨酸和10%胎牛血清的DMEM高糖培养基)的24孔培养板的每个孔中沉积10个珠。细胞在培养基中维持2天,然后在有或无白细胞介素-1α存在下用以下处理:1.5μM橄榄苦苷、1.5μM羟基酪醇、1.5μM槲皮素、1.5μM姜黄素、1.5μM橄榄苦苷+1.5μM槲皮素、1.5μM的橄榄苦苷+1.5μM姜黄素、1.5μM羟基酪醇+1.5μM槲皮素、1.5μM羟基酪醇+1.5μM姜黄素、1.5μM槲皮素+1.5μM姜黄素、1.5μM橄榄苦苷+1.5μM槲皮素+1.5μM姜黄素、1.5μM羟基酪醇+1.5μM槲皮素+1.5μM姜黄素。处理液溶于二甲基亚砜(DMSO)中。DMSO终浓度为0.1%。细胞暴露于处理3天。
在各处理结束时,洗涤珠并悬浮于0.1M柠檬酸钠+0.15M氯化钠溶液中。离心悬浮液,并收集含有细胞的沉淀以提取总RNA。
基因表达
总RNA分离自40个珠的收集物,使用Qiagen公司的RNeasy试剂盒分离。使用来自Takara的Primescript 1st strand cDNA Synthesis试剂盒、通过RNA的逆转录获得cDNA。在实时PCR(SYBR Green)中定量ADAMTS-5、COX-2、MMP-13和GAPDH的mRNA表达。
(来自牛(Bos Taurus))的引物列于下表1:
表1引物
结果
图1至3表明培养3天后由GAPDH mRNA表达归一化的ADAMTS-5、COX-2和MMP-13的mRNA表达。数据表示为与阴性对照(在完全培养基中培养的细胞)相比的基因表达的倍数变化。根据2-ΔΔCT方法计算结果。
CTL- 阴性对照
OLP 橄榄苦苷
HTY 羟基酪醇
QRC 槲皮素
CUR 姜黄素
IL1a 10ng/ml白介素-1α
数据表示为中位数±S.E.中位数(每个3次重复的2个实验)。通过Kruskal Wallis检验以及之后的Mann Whitney U检验(2尾)进行统计学。*p<0.05;**<0.01;***p<0.001对阴性对照(CTL-)或白介素-1α(IL1A)。
图1A示出了在IL1a不存在时(模拟细胞的正常状态)ADAMTS-5mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图1B示出了在IL1a存在时(模拟细胞的疾病状态)ADAMTS-5mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
在正常条件下,添加OLP、HTY、QRC或CUR降低了ADAMTS-5(软骨破坏的标记物)的表达。这些不同的多酚组合具有协同作用。
在疾病条件下,添加OLP、HTY、QRC或CUR能够对抗IL-1α刺激的软骨细胞,并降低ADAMTS-5表达。这些不同的多酚组合具有协同作用。
图2A示出了在IL1a不存在时(模拟细胞的正常状态)COX-2mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图2B示出了在IL1a存在时(模拟细胞的疾病状态)COX-2mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
在正常条件下,添加QRC降低COX-2(炎性状态的标记物)的表达。OLP、HTY、QRC或CUR中二或三种的组合具有协同作用。
在疾病条件下,添加QRC或CUR能够对抗IL-1α刺激的细胞,并降低COX-2表达。OLP、HTY、QRC或CUR中二或三种的组合具有协同作用。
图3A示出了在IL1a不存在时(模拟细胞的正常状态)MMP-13mRNA相对于GAPDH的表达。各条件与CTL-进行统计学比较。
图3B示出了在IL1a存在时(模拟细胞的疾病状态)MMP-13mRNA相对于GAPDH的表达。各条件与IL1a进行统计学比较,而IL1a与CTL-进行比较(验证实验)。
在正常条件下,单独或组合添加OLP、HTY、QRC或CUR降低MMP-13(参与细胞外基质的破坏,与OA中关节软骨翻转有关)的表达。
在疾病条件下,添加OLP、HTY、QRC或CUR能够对抗IL-1α刺激的软骨细胞,并降低MMP-13表达。OLP、HTY、QRC或CUR中三种的组合具有协同作用。
实施例2体内研究-Hartley豚鼠中自发形成的骨关节炎
动物和治疗
65只3周龄雄性Hartley豚鼠获得自Charles River实验室(巴黎)。每5只动物饲养在一个固体底笼子中,用含维生素C(1mg/g)和维生素D3(3.4IU/g)的标准豚鼠食物饲养,水可以随意获得。在施用橄榄苦苷、芦丁和/或姜黄素之前,允许所有动物在饲养条件中适应一周。PVC管引入笼子,以改善饲养条件、并减少压力。
一周后,4周龄雄性Hartley豚鼠随机分为实验组:
-A组(n=15)在31周内接受每日剂量的橄榄苦苷
-B组(n=15)在31周内接受标准食物(对照);
-C组(n=15)在31周内接受每日剂量的芦丁
-D组(n=15)在31周内接受每日剂量的芦丁和姜黄素
-E组(n=5,参考组)包含于安乐死组,并没有接受任何干预。
橄榄苦苷、芦丁和姜黄素掺合在食物中。每星期给动物称重,并由微芯片鉴定。通过称重每日加入的食物数量和剩余的数量,在W9、W15、W21、W26和W34控制食物摄入。
血液收集
每6周:W4(=T0)、W10、W16、W22、W28,在氯胺酮/甲苯噻嗪镇静下,在耳际的浅静脉,在早晨获得6小时空腹血液。在W35,在安乐死之前,在全身麻醉下通过心内穿刺收集血液。
安乐死
称重后,在戊巴比妥钠100mg/kg下进行心内血液穿刺后,进行安乐死。观察主要的重要器官,检测异常(心脏、消化道和泌尿道、肾上腺)。称重肝脏和肾上腺。来自每只动物的右膝关节在4%缓冲的低聚甲醛中固定24小时,随后在HCl酸(DC2,Labonord,比利时)中在4℃下脱钙4小时,而后用石蜡包埋。
组织学
用显微切片机(Leica)切片石蜡包埋的右膝,切成6μm的切片,根据OARSI的推荐,切片沿垫面(Cushin plane)切在不由关节盘覆盖的中心区域。
3个切片以200μm的间隔用苏木精、快绿和番红精O染色,和1个补充的中央切片用甲苯胺蓝染色。
根据OARSI的推荐,由经过训练的2个专家盲法为切片的各隔间评分(胫骨中部、胫骨外侧,股骨中部和股骨外侧),并评估总体得分,各隔间得分相加。
结果示于图4和5。
PGE2、Coll2-1NO2和Fib3-1测定法
用竞争性ELISA试剂盒(Arbor Assays,USA)测定豚鼠血清中PGE2。
结果示于图6中。橄榄苦苷治疗可以在35个星期的治疗之后降低血浆中PGE2水平。
血浆PGE2水平可以与OA评分正相关。这证实了PGE2是豚鼠模型中OA发生和进展、以及评估治疗效率的相关生物标记物。使用多克隆兔抗血清(D37,Artialis,比利时),通过竞争性ELISA一式三份定量豚鼠血清中定位于II型胶原螺旋结构域的亚硝基化表位Coll2-1NO2。Coll2-1NO2免疫测定法以高特异性和亲和性定量硝化的氨基酸序列。
结果示于图7和8。通过测定血浆中coll2-1 NO2水平,橄榄苦苷、芦丁和芦丁+姜黄素处理可减少胶原分解。coll2-1 NO2的量与OA得分呈正相关。这证实了Coll-2-1NO2是豚鼠模型中OA发生和进展、以及评估治疗效率的相关生物标记物。
Fib3-1是OA患者血清中增加的纤蛋白3的片段。用多克隆兔抗血清(AS88,Artialis,比利时),通过竞争性ELISA一式三份定量豚鼠血清中Fib3-1。
结果示于图9和10。芦丁+姜黄素处理可降低血浆中纤蛋白3-1水平。血浆中纤蛋白3-1水平可与OA得分正相关。这证实了Fib 3-1是豚鼠模型中OA发生和进展、以及评估治疗效率的相关生物标记物。
测定法内和测定法间的CV低于10%,稀释度曲线平行于两个测定法的标准曲线。
结果
计算出各参数的结果(平均值±SD)。经过正态性检验,对所有实验用Dunnettpost-检验或Pearson相关性进行参数的ANOVA。*P<0.05;**<0.01;***P<0.001。
对照W4 E组(n=5,参考组)动物包括在安乐死内,并没有接受任何干预。
对照W35 B组(n=15)在31个星期内接受标准食物。
AW35 A组(n=15)在31个星期内接受每日剂量的橄榄苦苷。
DW35 D组(n=15)在31个星期内接受每日剂量的芦丁和姜黄素。
橄榄苦苷、芦丁、芦丁+姜黄素治疗可以通过不同机制减少豚鼠中的OA得分。
序 列 表
<110> 雀巢产品技术援助有限公司
<120> 用于软骨破坏的组合物
<130> NO13110
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 23
<212> DNA
<213> 牛(Bos taurus)
<220>
<221> misc_feature
<223> 引物
<400> 1
aagggcattc taggctacac tga 23
<210> 2
<211> 24
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
<400> 2
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<210> 3
<211> 20
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
<400> 3
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<210> 4
<211> 20
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
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<210> 5
<211> 24
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
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<210> 6
<211> 20
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
<400> 6
agtactctgg cccgaaggtc 20
<210> 7
<211> 28
<212> DNA
<213> 牛
<220>
<221> misc_feature
<223> 引物
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Claims (17)
1.含有橄榄苦苷和/或羟基酪醇的组合物,其用于预防或治疗软骨破坏。
2.用于根据前述权利要求任一项的用途的组合物,其中所述组合物还包含姜黄素。
3.用于根据前述权利要求任一项的用途的组合物,其中所述组合物还包含槲皮素。
4.用于根据前述权利要求任一项的用途的组合物,其中所述组合物还包含选自以下的至少一种化合物:抗氧化剂、抗炎化合物、糖胺聚糖、益生元、纤维、益生菌、脂肪酸、矿物质、微量元素和/或维生素。
5.用于根据权利要求4的用途的组合物,其中所述组合物还包含至少一种抗炎化合物。
6.用于根据权利要求4和5的用途的组合物,其中至少一种抗炎化合物是植物提取物。
7.用于根据权利要求6的用途的组合物,其中植物提取物来自一种或多种选自下组的植物:钩果草(鬼爪草(Harpagophytum procumbens))、迷迭香(Rosmarinus officinalis)、牛膝草、姜(生姜Zingiber officinale)、姜黄(姜黄Curcuma longa)、山金车(ArnicaMontana)、柳树皮、石榴(石榴(Punica granatum))、绿茶(茶(Camellia sinensis))、猫爪草(钩藤(Uncaria tometosa)和圭亚那钩藤(Uncaria guianensis))、印度乳香(齿叶乳香树(Boswelia serrata))和菠萝(凤梨(Ananas comosus))、黑种(栽培黑种草(Nigellasativa))、圣约翰草、贯叶金丝桃、白毛茛、德国洋甘菊(母菊(Matricaria recutita))。
8.用于根据权利要求4至7的用途的组合物,其中所述组合物还包含至少一种抗氧化剂。
9.用于根据权利要求8的用途的组合物,其中至少一种抗氧化剂选自虾青素、类胡萝卜素、辅酶Q10(“CoQ10”)、黄酮类化合物、谷胱甘肽、枸杞(西方雪果)、橙皮苷、乳薄叶西方雪果、木脂体、叶黄素、番茄红素、多酚、硒、维生素A、维生素C、维生素E、玉米黄质。
10.用于根据前述权利要求任一项的用途的组合物,其中所述组合物是营养组合物。
11.用于根据权利要求1至9任一项的用途的组合物,其中所述组合物是药物组合物。
12.用于根据权利要求10的用途的组合物,其中所述营养组合物是药膳。
13.用于根据前述权利要求任一项的用途的组合物,其中所述用途是抑制或减少软骨中的胶原分解。
14.用于根据前述权利要求任一项的用途的组合物,其中所述用途是用于维持或改善个体的活动性和/或运动性。
15.用于根据前述权利要求任一项的用途的组合物,其中所述用途是用于降低关节疼痛。
16.一种制备根据前述权利要求任一项的用途的营养组合物的方法,所述方法包括步骤:提供一种或多种用于营养组合物的成分、橄榄苦苷和/或羟基酪醇,和任选地进一步的姜黄素和槲皮素的一种或多种,并混合。
17.预防或治疗软骨破坏的方法,其包括向有需要的个体施用有效量的根据前述权利要求1至13任一项的组合物。
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CN201480030530.9A CN105263505A (zh) | 2013-05-29 | 2014-05-28 | 用于软骨破坏的组合物 |
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EP (2) | EP3003339B1 (zh) |
JP (2) | JP2016524614A (zh) |
CN (2) | CN113101297A (zh) |
AU (1) | AU2014273185B2 (zh) |
BR (1) | BR112015029611B1 (zh) |
CA (1) | CA2912957A1 (zh) |
ES (1) | ES2944868T3 (zh) |
HK (1) | HK1219659A1 (zh) |
WO (1) | WO2014191447A1 (zh) |
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JP6497675B2 (ja) * | 2015-01-22 | 2019-04-10 | 国立研究開発法人産業技術総合研究所 | 活動量の低下及び/又は不安の改善用組成物 |
US20180139997A1 (en) * | 2015-06-15 | 2018-05-24 | Gexnano S.R.L. | Food supplement for use in a process of metabolic rebalancing |
ITUB20154001A1 (it) * | 2015-09-15 | 2017-03-15 | Scotto Dabusco Anna | Metodo di integrazione dietetica e uso per la preparazione di prodotti per l'integrazione personalizzata. |
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IT201600124013A1 (it) * | 2016-12-06 | 2018-06-06 | Solarpharm Srl | Prodotto alimentare a base di astaxantina |
CN106727652A (zh) * | 2016-12-30 | 2017-05-31 | 福建中医药大学 | 一种用于缓解骨关节炎疼痛的分子中药缓释片及其制备方法 |
GR1009331B (el) * | 2017-03-14 | 2018-07-31 | Ευαγγελια Παναγιωτη Λαγου | Λαδι με βοτανα που ανακουφιζει τους ταλαιπωρημενους μυς |
JP2021502327A (ja) * | 2017-11-08 | 2021-01-28 | ソシエテ・デ・プロデュイ・ネスレ・エス・アー | オレウロペインの生物変換 |
WO2019092069A2 (en) | 2017-11-08 | 2019-05-16 | Nestec S.A. | Homovanillyl alcohol (hva), hva isomer, methods of making compositions comprising such compounds, and methods using such compounds |
ES2925635T3 (es) * | 2017-11-08 | 2022-10-19 | Nestle Sa | Bioconversión de oleuropeína |
EP3706760B1 (en) | 2017-11-08 | 2023-08-02 | Société des Produits Nestlé S.A. | Method of selecting a probiotic |
CN108686119A (zh) * | 2018-06-27 | 2018-10-23 | 陶燃 | 一种治疗痛风的药物组合物及其应用 |
CN111286205A (zh) * | 2019-12-17 | 2020-06-16 | 陕西科技大学 | 一种具有抗氧化活性及沙门氏菌检测能力的羟基酪醇鲟鱼鱼皮明胶薄膜及其制备方法 |
JPWO2021124912A1 (zh) * | 2019-12-17 | 2021-06-24 | ||
US11364255B2 (en) * | 2020-07-01 | 2022-06-21 | Karallief, Inc. | Therapeutic herbal compositions for improving joint health |
WO2022106410A1 (en) * | 2020-11-18 | 2022-05-27 | Société des Produits Nestlé S.A. | Compositions and methods using a combination of oleuropein and quercetin for use in cartilage degeneration |
CN113475624A (zh) * | 2021-06-10 | 2021-10-08 | 云南农业大学 | 一种菲牛蛭配合饲料 |
CN116196319B (zh) * | 2021-11-30 | 2024-06-04 | 内蒙古伊利实业集团股份有限公司 | 低聚糖在保护软骨中的应用 |
WO2023222704A1 (en) * | 2022-05-17 | 2023-11-23 | Société des Produits Nestlé S.A. | Compositions and methods using a combination of oleuropein and fisetin for use in cartilage degeneration |
WO2024099885A1 (en) * | 2022-11-09 | 2024-05-16 | Société des Produits Nestlé S.A. | Compositions and methods using a combination of oleuropein and taurine for use in prevention or treatment of joint disorders |
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- 2014-05-28 ES ES14728500T patent/ES2944868T3/es active Active
- 2014-05-28 EP EP14728500.1A patent/EP3003339B1/en active Active
- 2014-05-28 EP EP23155898.2A patent/EP4218743A3/en active Pending
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Publication number | Publication date |
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CN105263505A (zh) | 2016-01-20 |
US20160120891A1 (en) | 2016-05-05 |
WO2014191447A1 (en) | 2014-12-04 |
CA2912957A1 (en) | 2014-12-04 |
EP4218743A3 (en) | 2023-12-20 |
EP3003339A1 (en) | 2016-04-13 |
AU2014273185B2 (en) | 2019-04-18 |
JP2016524614A (ja) | 2016-08-18 |
BR112015029611A2 (pt) | 2017-09-26 |
EP4218743A2 (en) | 2023-08-02 |
EP3003339B1 (en) | 2023-03-22 |
ES2944868T3 (es) | 2023-06-26 |
BR112015029611B1 (pt) | 2023-01-17 |
HK1219659A1 (zh) | 2017-04-13 |
JP2019110899A (ja) | 2019-07-11 |
AU2014273185A1 (en) | 2015-11-05 |
JP6859313B2 (ja) | 2021-04-14 |
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