CN110292592A - 植物酚及其在治疗或预防嗜酸性食管炎中的用途 - Google Patents
植物酚及其在治疗或预防嗜酸性食管炎中的用途 Download PDFInfo
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- CN110292592A CN110292592A CN201910603651.2A CN201910603651A CN110292592A CN 110292592 A CN110292592 A CN 110292592A CN 201910603651 A CN201910603651 A CN 201910603651A CN 110292592 A CN110292592 A CN 110292592A
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Abstract
本发明涉及植物酚及其在治疗或预防嗜酸性食管炎中的用途,特别涉及植物酚尤其是植物酚酸如迷迭香酸、鞣花酸和绿原酸在治疗或预防嗜酸性食管炎中的用途。
Description
本申请为2013年9月23日提交的、发明名称为“植物酚及其在治疗或预防嗜酸性食管炎中的用途”的PCT申请PCT/EP2013/069668的分案申请,所述PCT申请进入中国国家阶段的日期为2015年3月20日,申请号为201380048961.3。
技术领域
本发明涉及植物酚在治疗或预防嗜酸性食管炎中的用途。
背景技术
嗜酸性食管炎(Eosinophilic esophagitis)是一种食管的炎症疾病,其可能由抗原引发,或不由抗原引发。症状包括功能性腹痛、呕吐、难以健壮成长、吞咽困难、食物嵌塞以及胃灼热。该疾病最初描述于儿童中,但也发生于成人。嗜酸性粒细胞通常不存在于正常的食管粘膜中。然而,在嗜酸性食管炎中,嗜酸性粒细胞侵润食管上皮,并且通常被发现成群地接近上皮表面。嗜酸性粒细胞的浸润通常与基底层的增厚相关,作为对上皮细胞炎症活动的反应。
存在多种不同的可用于治疗嗜酸性食管炎的策略,包括药物治疗、机械扩张以及饮食调节。
在药物治疗中,发现皮质类固醇和质子泵抑制剂能缓解症状。还观察到可通过施与抗组胺剂而降低过敏反应。在上皮肿胀威胁到阻塞食管的严重病例中,可考虑食管的机械扩张。
此前的营养治疗方案主要在于通过将潜在的食物过敏原排除在饮食之外的饮食调节。因此,进行过敏性评估,从而鉴定可能导致疾病的那些过敏原。随后,调节饮食以排除鉴定出来的过敏原。其他方法在于提供不存在任何潜在过敏原的完全营养。例如,US 2008/0031814描述了无过敏原成分并且由此能够预防过敏性炎症疾病形成的营养组合物。因此,现有技术的饮食目标是在饮食中避免过敏成分,而非通过选择某些营养成分来治疗该疾病。
因此,需要包含天然化合物的组合物,其不仅仅缺少主要的过敏原,而且能主动地预防或治疗嗜酸性食管炎。
发明内容
本发明的目的是提供针对预防或治疗嗜酸性食管炎的问题的新的和替代性的技术方案。已出人意料地发现,植物酚可用于预防或治疗嗜酸性食管炎。可用于治疗或预防嗜酸性食管炎的成分的评估应用已建立的嗜酸性食管炎小鼠模型(Akei等人,“Epicutaneousantigen exposure primes for experimental eosinophilic esophagitis in mice”,Gastroenterology,2005Sep;129(3):985-94)进行。这一模型使用了不同的参数,包括食管中的嗜酸性粒细胞数,作为对嗜酸性食管炎效果的指示符。因此,其理想地适于测试治疗或预防嗜酸性食管炎的候选化合物。
因此,本发明涉及用于预防或治疗嗜酸性食管炎的包含植物酚的组合物。植物酚可选自迷迭香酸(rosemarinic acid)、鞣花酸、安石榴苷(punicalagin)、绿原酸(cholorgenic acid)或其混合物。植物酚可以是多酚或单宁。植物酚可包含于植物提取物中,并且该组合物可包含所述植物酚。因此,本发明还涉及包含植物提取物的组合物,所述植物提取物选自来自百里香(thyme)、石榴(pomegranate)、绿咖啡(green coffee)或其混合物的提取物的植物提取物。
该组合物可口服施用,任选通过管饲或局部口服。该组合物可以施用于人类或宠物动物,尤其是猫或狗。人类可以是1个月至六岁的幼童,6岁至18岁的较大儿童,以及成年人。因此,该营养组合物可选自婴儿喂养组合物、较大婴儿配方食品(follow-up formula)、成长奶(growing-up milk)、婴儿谷物或幼儿(baby)营养组合物。该组合物也可以是营养组合物、宠物营养组合物、口服营养补充剂或药物产品。特别地,营养组合物可选自饮料产品、酸乳产品、发酵乳、果汁或谷物棒。营养组合物可以是用于特定医疗目的的食品,诸如用于口服喂养的保健营养组合物、用于肠道喂养的营养产品或胃肠外喂养产品。
附图说明
图1.实验方案。
图2A和B.食管中的嗜酸性粒细胞数。收获所述食管并进行组织学研究。在苏木素&曙红(H&E)染色的载玻片上识别和计数每高倍视野(hpf)的嗜酸性粒细胞。在整个食管中的1hpf视野中发现的嗜酸性粒细胞的最大数目显示于A中。存在于食管上皮中的嗜酸性粒细胞的最大数目显示于B中。
定义
“嗜酸性食管炎”是食管的炎性病症。症状包括功能性腹痛、呕吐、难以健壮成长、吞咽困难、食物嵌塞和胃灼热。它的特征是在食管上皮中存在嗜酸性粒细胞浸润。嗜酸性粒细胞的浸润可能与基底层的增厚相关。在ICD-9(疾病国际分类修订版9)中,它被指定为530.13。如果在食管粘膜活组织检查中每“高倍视野”(如下定义)中发现超过15个嗜酸性粒细胞,则可以考虑确诊嗜酸性食管炎。
“植物酚”是一类天然有机化合物。它们包含一个或多个酚基。在此仅考虑植物中存在的酚以及与植物中天然存在的酚相同的人工合成的酚。
“酚基”是包含与羟基键合的苯基的基团。酚基的环碳的氢可以被其他残基(如羟基-、烷基-、烯基残基、形成为羧基的环C等)取代。特别优选的取代是另外的羟基。
“高倍视野(HPF)”在本发明中使用时,是指所使用的显微镜物镜最大放大倍数下可见的区域。这可代表400x放大水平。
“局部口服”在本发明中使用时,是指一种施用形式,其中将组合物局部地施用于食管粘膜,从而使该组合物被食管粘膜直接吸收。这种施用形式是为了避免组合物被在食管之后开始的消化道吸收。局部口服施用的典型形式是喷雾形式的施用,其经由口腔喷雾,然后吞咽进入食管。
发明详述
该标题部分用于阐明主题,不能被理解为限制主题。如果公开了值的范围,则认为每一单个值包含在该范围之内,尤其是每一整数。如果没有另外指出,值%涉及重量/重量(w/w)值。出人意料地发现,某些植物酚可用于降低嗜酸性粒细胞的量。在嗜酸性食管小鼠模型中作出了这一发现。因此,可得出结论,植物酚可用于治疗或预防嗜酸性食管炎,一种特征为某些组织中嗜酸性粒细胞数量升高的疾病。
组合物
本发明组合物可包含多种成分,主要活性成分是植物酚,其在以下将更详细地解释。
植物酚
所述组合物包含至少一种植物酚。植物酚包含至少1、2、3、4、5或6个酚残基。尤其优选的是包含1或2个酚残基的植物酚。植物酚优选地仅由氢、碳和氧组成。植物酚优选地包含选自以下的残基或由选自以下的残基组成:至少一个环己烷残基、酚残基、H-残基、OH-残基、C=残基、CO2H-残基、乙基残基、-O-残基。
所述组合物可包含至少一种、至少两种、至少三种、或至少四种不同的植物酚。可预期植物酚的组合将显示出针对嗜酸性食管炎的协同作用。所述酚是存在于天然植物来源中的酚。天然来源可以是百里香、石榴或绿咖啡或其混合物。酚可从这些天然来源中通过已知的提取方法提取,如用水或有机溶剂(如乙醇或醚)提取。
所述组合物可包含植物提取物,其中所述植物提取物包含植物酚。所述组合物可包含选自百里香、石榴、绿咖啡或其任何可能组合或混合物的植物提取物。特别地,所述组合物包含百里香、石榴和绿咖啡提取物。
植物提取物可以是百里香提取物,并且包含迷迭香酸。
植物提取物可以是石榴提取物,并且包含鞣花酸。
植物提取物可以是绿咖啡提取物,并且包含绿原酸。
植物酚可以是酚酸。特别地,植物酚可以是迷迭香酸、甲基化的迷迭香酸、香豆酸、阿魏酸;鞣花酸、鞣花单宁、安石榴苷、没食子酸、棓单宁;肉桂酸(如咖啡酸、阿魏酸和对香豆酸)以及肉桂酸与(-)-奎尼酸的酯(esther),一个优选的肉桂酸酯是绿原酸,也考虑绿原酸衍生物,如它的3-O-葡萄糖苷、3-O-半乳糖苷和3-O-阿拉伯糖苷。酚也可以是类黄酮或儿茶酚类化合物。还考虑,任何上述植物酚可被从所述组合物排除,如果认为这是适当的。在一特定实施方案中,表儿茶素(epicatechin)被从组合物中排除。这些植物酚的混合物也被考虑在内。特别地,所述混合物可包含至少1、2、3、4、5、6、7、8、9、10、11、12种上述酚。所述组合物可在组合物中包含上述酚的任何排列组合(permutation)。
所述酚的每一种或这些酚的组合的总量(或提取物形式的)可以以0.1%至1%、0.15%至0.8%、0.15%至0.7%、0.15%至0.6%、0.15%至0.5%、0.2%至0.4%的浓度、或以0.3%的浓度存在于所述组合物中,或存在于由粉末或浓缩形式重构的组合物中。
尤其优选的酚是迷迭香酸、鞣花酸以及绿原酸、或其任何可能的组合或混合物。
制剂
上述组合物可以配制成液体或固体形式。液体形式可以配制成适合于喷雾的形式,即喷雾剂形式。这可以通过使含有所述组合物的隔室与喷嘴相连接来实现。当通过喷嘴输送时,液体被雾化,从而允许所得到的液滴均匀分布在表面上。通过喷嘴输送液体的各种方式是本领域技术人员已知的。例如,与周围大气压力相比,含有组合物的容器可以是在压力下。备选地,泵机构可通过喷嘴输送喷雾剂。喷雾的应用使得能够,例如,通过口腔将组合物喷雾到食管中,并由此使所述组合物与食管粘膜直接接触。接着,所述组合物可被粘膜吸收,然后实现体内的全身分布。
所述组合物可进一步包含至少一种其他活性剂、载体、溶媒、赋形剂或辅助剂,这些可由阅读本公开后的本领域技术人员确定。
所述组合物可以是口服营养补充剂、营养组合物或药物产品形式的。营养组合物、口服营养补充剂或药物产品可包含本发明的组合物或套盒(kit)。
营养组合物
在本文中所用时,术语“营养组合物”包括但不限于完全营养组合物、部分或不完全营养组合物和疾病或病症特定的营养组合物。完全营养组合物(即,含有所有必需的宏量和微量营养素的那些)可以用作患者营养的唯一来源。患者可以从这样的完全营养组合物中获得其100%的营养需求。部分或不完全营养组合物不含有所有的必需宏量和微量营养素,并且不能被用作患者营养的唯一来源。部分或不完全营养组合物可以用作营养补充剂。口服补充营养组合物主要或仅含有所要求保护的组合物的必要活性成分(植物酚),并且可以作为患者定期营养的补充而被消费。
疾病或病症特定的营养组合物是递送营养素或药物的组合物,并且可以是完全或部分营养组合物。
营养组合物还可包含以下营养素和微量营养素:蛋白质源、脂质源、碳水化合物源、维生素和矿物质。所述组合物也可含有抗氧化剂、稳定剂(以固体形式提供时)或乳化剂(以液体形式提供时)。在一优选的实施方案中,所述组合物是以基于氨基酸的配方物,这意味着,氨基酸的唯一来源是游离氨基酸。
因此,在另一个实施方案中,所述营养组合物还包含一种或多种氨基酸。氨基酸的非限制性实例包括丙氨酸、精氨酸、天冬酰胺、天冬氨酸、瓜氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、羟脯氨酸、羟丝氨酸、羟酪氨酸、羟赖氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、牛磺酸、苏氨酸、色氨酸、酪氨酸、缬氨酸、HICA(α-羟基异己酸)、HIVA(α-羟基异戊酸)、HIMVA(α-羟甲基缬草酸)或其组合。在一优选的实施方案中,氨基酸的非限制性实例包括脯氨酸、羟脯氨酸、羟酪氨酸、羟赖氨酸和羟丝氨酸及其组合。
在另一其他实施方案中,营养组合物可以包含矿物质,如钠、钾、钙、磷、镁、氯化物(chloride)、铁、锌、铜、锰、氟化物(fluoride)、铬、钼、硒、碘或其任意组合。
在另一实施方案中,营养组合物进一步包含维生素,如维生素A、维生素E、维生素C、维生素B1、维生素B2、泛酸、维生素B6、维生素B12、烟酸、叶酸、生物素和胆碱或其任意组合。
在一个实施方案中,所述营养组合物选自婴儿喂养组合物、较大婴儿配方食品、成长奶、婴儿谷物、或幼儿营养组合物。这些产品特别适合于处理和解决预防或减轻幼儿和幼童(young children)嗜酸性食管炎症状的问题。然而,也可以选择其他产品,如饮料和粉末(小袋形式),用于较大的儿童和成年人,如以下所述。
在另一实施方案中,营养组合物选自饮料产品、基于氨基酸的饮料、酸乳产品、发酵乳、果汁、小袋形式的干燥粉末或谷物棒。这些营养组合物非常适合用于施用植物酚至较大的儿童和成人。所述营养组合物可以很好地富含植物酚且具有可靠的形象,为消费者提供健康定向的功能营养组合物。
对减少嗜酸性食管炎症状的产品的特别需求可能在临床环境中,如在医院、诊所和老年人家庭中。因此,在又一个实施方案中,营养组合物是用于特定医疗目的的食品,如用于口服喂养的保健营养组合物、和/或用于肠内或肠胃外喂养(feeding)的营养产品。在后一种情况下,将只包含适合于肠胃外喂养的成分。适合于肠胃外喂养的成分是本领域技术人员所熟知的。特别地,肠胃外喂养组合物将含有纯的或基本上纯的植物酚(即,通常不以仅富集植物酚的植物提取物形式提供),但所述组合物也可包含已知对于肠胃外营养适合的其它成分。本发明的另一优点是:植物酚可以以相对高的局部浓度和低体积的医用营养组合物提供,并因此有效地施用至有这样需要的患者。
套盒
上述组合物也可作为套盒提供。在这些套盒中,上述组合物成分的全部或一部分以单独的(即不混合)的形式提供。本发明套盒可以以单独的形式一方面包含植物酚,另一方面包含所有剩余成分。本发明的套盒可以包含以单独形式提供的至少两种或三种植物酚。在一可选实施方案中,所述套盒可以以独立形式包含上述组合物的每一成分。
治疗用途和方法
本发明的组合物或套盒可用于治疗或预防嗜酸性食管炎或减少嗜酸性粒细胞(尤其是上皮中的、特别是食管上皮中的)的数量。本发明的组合物或套盒也可用于治疗或预防嗜酸性食管炎或减少嗜酸性粒细胞(尤其是上皮中的、特别是食管上皮中的)数量的方法中。
嗜酸性粒细胞数量的减少定义为在显微镜高倍视野中发现患有嗜酸性食管炎的人类的食管粘膜活组织检查中的嗜酸性粒细胞低于10-20、特别是15的减少。因此,本发明意义上的减少是动物模型中相比阳性对照的显著减少。本发明意义上的减少可以是在人食管粘膜活组织检查中在显微镜高倍视野中减少到低于19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1或0的值。或者,所述减少可以通过参照患有嗜酸性食管炎具有的或如果未采取使用本发明组合物的预防措施将预期具有的嗜酸性粒细胞数量来定义。因此,减少可以是相比于患有嗜酸性食管炎的动物或人类食管的粘膜活组织检查的显微镜高倍视野中发现的嗜酸性粒细胞数量的减少百分比(至少50%、60%、70%、80%、90%、95%、99%或100%)。或者,本发明意义上的减少也可以是相比于患有嗜酸性食管炎的人类食管的粘膜活组织检查的显微镜高倍视野中发现的嗜酸性粒细胞数量的绝对数减少5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20或超过20。参考值可以是10-20,或者是15。减少可以在治疗5、10、15、20、25、30、60、120天后观察到。
组合物和套盒可以以适于口服或局部施用的形式提供,并然后相应地施用。可以在受试者出现嗜酸性食管炎症状之前、症状出现的同时或症状已经显示之后开始施用。施用可以进行1、20、30、60、120、360天或更长时间。如果受试者是人,施用所述组合物的受试者可以是4个月至6岁、6岁至18岁,或者成年人。
在一个实施方案中,组合物是用于被动物优选猫或狗消费。与人类类似,可在动物中观察到嗜酸性食管炎,特别是家养动物和作为宠物饲养的动物。有利的是,本发明提供了可以由其主人提供给伴侣动物的液体。
施用至人类的组合物中植物酚的总量优选是每天3mg/kg体重至每天100mg/kg体重、优选10-50mg/kg体重天的量。优选地,所述组合物提供每天约25mg克至10g、每天50mg克至10g、优选每天100mg克至5g、甚至更优选每天300mg克至1g。这些优选的剂量一方面可以每天给相关患者提供足够量的植物酚,以提供预期的健康有益效果,另一方面不会提供过量的植物酚,以预防对患者的任何可能的不希望的或毒性作用风险。
制备方法
本发明提供了用于生产上述组合物的方法,包括提供至少一种上述植物酚,任选地添加至少一种其它成分(例如选自一种或多种氨基酸、脂肪或碳水化合物),任选地添加至少一种营养素或微量营养素,添加载体和/或水。
本领域技术人员将理解,他们可以自由地组合本文所公开的本发明的所有特征。特别是,可以组合本发明不同实施方案中描述的特征。根据附图和实施例,本发明的其他优点和特征是显而易见的。
具体实施方式
实施例
实施例1:植物酚对嗜酸性粒细胞计数的影响
通过在表皮应用200μg过敏性提取物而将5-8周龄雌性Balb/c小鼠敏化。剃光小鼠背部的一小部分。用生物闭合透明敷料2461(强生)和绷带将一块含过敏原的无菌纱布(1×1厘米)固定在皮肤上。使贴片保持在皮肤上,持续4至7天的致敏期,直到它粘结或在第8天除去。在最后的致敏日后的数天(第21至28天),在第30天使小鼠暴露于麻醉小鼠的鼻内攻击(challenge)(100μg),并在第32天收获小鼠。
从Greer Laboratories,Lenoir,NC获取烟曲霉菌(Aspergillus fumigatus)抗原提取物和屋尘螨提取物,并用生理盐水稀释至100μg/μL。
使用食物中的植物酚提取物测试植物酚效果,所述提取物是来自Monteloeder(西班牙)的6%(w/w)百里香(5%迷迭香酸)、1%(w/w)石榴(30%鞣花酸)和1%(w/w)绿咖啡(30%绿原酸)。
收获食管并用苏木素曙红染色,计数嗜酸性粒细胞(最大/高倍视野,参见图2)。
与阳性对照相比,在食管中对于百里香和咖啡多酚观察到食管中嗜酸性粒细胞的显著减少,在食管上皮中对于所有植物提取物观察到食管中嗜酸性粒细胞的显著减少。这提示来自植物的酚对于减少由过敏原引起的嗜酸性粒细胞载量具有广泛的作用。
实施例2:临床试验
7组20-30位年龄为18-60岁的嗜酸性食管炎患者接受了还含有下表所示提取物的基于氨基酸的组合物 PEDIATRIC,所述嗜酸性食管炎被食道胃十二指肠镜检查期间获得的粘膜活组织检查的每高倍视野中存在超过15个嗜酸性粒细胞所表明。
在标准稀释中, PEDIATRIC是0.8kcal/ml配制物,其具有以下%kcal:12%蛋白质(游离氨基酸);63%碳水化合物以及25%脂肪。70:30的MCT:LCT比;7.7:1的n6:n3比;360的摩尔渗透压浓度(mOsm/kg水);89%的游离水;对于蛋白质以及25种关键维生素和矿物质,其满足或超过100%DRI;补充谷氨酰胺:3.0g/L;补充L-精氨酸:2.0g/L。
百里香提取物含有5%的植物酚迷迭香酸,石榴提取物含有30%的植物酚鞣花酸,且1%绿咖啡30%的植物酚绿原酸(Monteloeder,Spain)。
受试者接受这样量的提取物,其使得每天施用500mg各自的植物酚。将在开始研究后的第15天和第30天在食道胃十二指肠镜检查期间获得的粘膜活组织检查的高倍视野中可见嗜酸性粒细胞数确定为嗜酸性粒细胞数。在该研究中还观察了已知的相关症状,例如吞咽困难、食物嵌塞和胃灼热。
Claims (14)
1.用于预防或治疗嗜酸性食管炎的包含植物酚的组合物。
2.根据权利要求1的组合物,其中所述酚选自迷迭香酸、鞣花酸、绿原酸或其混合物。
3.根据权利要求1的组合物,其中所述植物酚是多酚。
4.根据前述任一项权利要求的组合物,其中所述植物酚包含于植物提取物中。
5.根据权利要求4的组合物,其中所述植物提取物是选自来自百里香、石榴、绿咖啡或其混合物的提取物的植物提取物。
6.根据前述任一项权利要求的组合物,其中所述组合物待被口服施用。
7.根据前述任一项权利要求的组合物,其中所述组合物局待被部口服施用。
8.根据前述任一项权利要求的组合物,其中所述组合物以喷雾剂的形式施用。
9.根据前述任一项权利要求的组合物,其中所述组合物待被施用于人类或宠物动物,尤其是猫或狗。
10.根据权利要求10的组合物,其中所述人类是1个月至六岁的幼童、6岁至18岁的较大儿童以及成年人。
11.根据前述任一项权利要求的组合物,其中所述组合物是营养组合物、口服营养补充剂或药物产品。
12.根据权利要求11的组合物,其中所述营养组合物选自婴儿喂养组合物、基于氨基酸的饮料或配方食品、较大婴儿配方食品、成长奶、婴儿谷物或幼儿营养组合物。
13.根据权利要求11的组合物,其中所述营养组合物选自饮料产品、酸乳产品、发酵乳、果汁、小袋形式的干粉或谷物棒。
14.根据权利要求11的组合物,其中所述营养组合物是用于特定医疗目的的食品,诸如用于口服喂养的保健营养组合物、用于肠道喂养的营养产品或胃肠外喂养产品。
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JP6290896B2 (ja) | 2018-03-07 |
CN104640539A (zh) | 2015-05-20 |
WO2014044836A1 (en) | 2014-03-27 |
CA2884294A1 (en) | 2014-03-27 |
BR112015005921A2 (pt) | 2017-07-04 |
EP2897606B1 (en) | 2020-05-06 |
US11382891B2 (en) | 2022-07-12 |
HK1212893A1 (zh) | 2016-06-24 |
CN104640539B (zh) | 2019-08-02 |
EP2897606A1 (en) | 2015-07-29 |
AU2013320148A1 (en) | 2015-03-26 |
JP2015535822A (ja) | 2015-12-17 |
US10548873B2 (en) | 2020-02-04 |
US20150238461A1 (en) | 2015-08-27 |
ES2795104T3 (es) | 2020-11-20 |
CA2884294C (en) | 2022-08-09 |
US20200222363A1 (en) | 2020-07-16 |
AU2013320148B2 (en) | 2018-05-10 |
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