CN103638003A - 富含n-酰基乙醇酰胺化合物的组合物 - Google Patents
富含n-酰基乙醇酰胺化合物的组合物 Download PDFInfo
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- CN103638003A CN103638003A CN201310165801.9A CN201310165801A CN103638003A CN 103638003 A CN103638003 A CN 103638003A CN 201310165801 A CN201310165801 A CN 201310165801A CN 103638003 A CN103638003 A CN 103638003A
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- pea
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Abstract
本发明涉及一些组合物,该组合物包括富含脂肪酸酰胺化合物的油提取物,该脂肪酸酰胺化合物包括:N-酰基乙醇酰胺(NAE)化合物,例如N-十六酰乙醇酰胺(PEA)和N-花生四烯酰乙醇酰胺(AEA)。所述组合物可来源于包括贻贝肉的海产原料。
Description
相关申请的声明
本申请基于与提交的552238号新西兰专利申请的临时说明书,其全部内容经引用并入本文。
技术领域
本发明涉及一种提取物。更具体地说,本发明涉及一些来源于富含脂肪酰胺化合物的海产原料的油提取物,所述脂肪酰胺化合物包括N-酰基乙醇酰胺(NAE)化合物,例如N-十六酰乙醇酰胺(PEA)和N-花生四烯酰乙醇胺(大麻素,AEA)。
背景技术
N-十六酰乙醇酰胺(PEA)是一种内源性脂肪酸酰胺,属于众所周知的N-酰基乙醇胺(NAE)族,该N-酰基乙醇胺族包括“大麻类”化合物,如:N-花生四烯酰乙醇胺(大麻素,AEA)。PEA和AEA有可能治疗一些人/动物的疾病,包括异常炎症和/或免疫反应及相关的疼痛(参见Lambert等,2002,评论)。
PEA和其他NAE的历史和科学文献概述
a)起源
PEA是一种天然生成的脂质,在动物、海产物和植物源的许多不同细胞之中可以发现(参见Lambert等,2002,评论)。在活的生物体内,PEA合成迅速,以响应诸如组织损伤或病理学损害之类的细胞应激源(cellular stressors),它们往往伴随着炎症和疼痛(Darmani等,2005)。虽然PEA在人体中的生物学功能,尚未完全搞清,但人们一直推测,PEA是几种天然的消炎镇痛化学药品化学物质之一(Darmani等,2005)。
使用氯仿和甲醇自冻干的绿贻贝(Perna canaliculus)肉提取的粗脂,由甘油三酸酯、甾醇酯、甾醇、极性脂、游离脂肪酸及其衍生物,例如酰基乙醇酰胺(NAE)的复杂混合物所组成(Sepe等,1998;Murphy等,2002;Murphy等,2003)。PEA和N-硬酯酰乙醇酰胺是贻贝的脂质提取物中最 大量的NAE,还有很少量的N-肉豆蔻酰(C14:0)-,N-油酰(C18:1)-,N-亚油酰(C18:2)-,和N-花生四烯酰(C20:4;大麻素/AEA)-乙醇酰胺。存在于粗提取物或纯化提取物中NAE的性质和数量,可能具有治疗学上的意义,因为在前技术揭示,在动物整体和动物组织中的NAE之间,存在着复杂的协同作用。例如,动物研究数据表明,PEA的一些作用可通过AEA,也可能通过其他NAE来介导。而且,已有人报道了NAE之间的协同效应的证据(详见下文)。
b)化学
PEA是一种饱和的十六碳脂肪酸乙醇酰胺(C16:0),具有以下结构:
AEA是一种多不饱和的二十碳脂肪酸乙醇酰胺(C20:4),具有以下结构:
c)历史回顾
Coburn等人(1954)在50年代初,第一次提到了对PEA的消炎性质的兴趣,他们发现,对天竺鼠喂以高蛋黄食物可以使他们免遭实验性过敏症。随后研究了从蛋黄分离并提纯的PEA,并在动物体上验证了其消炎性质(参见Lambert等,2002,评述)。对NAE的研究兴趣,是在1990年代发现AEA(具有类似于大麻活性成分性质的另一种内源性NAE)之后而再度激发的。大麻素受体(称为CB1和CB2)的克隆以及选择性CB受体配体的生成,提供了进一步加快研究活动的工具(Devane等,1992)。自那时起,对从动物和人体收集的大量身体证据研究表明,当通过不同的施药途径给药时,PEA具有消炎和镇痛性。
d)临床前研究
许多研究表明,合成的PEA,在一些动物模型内具有消炎镇痛性质。一般地,将一种致炎性物质,例如角叉菜胶、胶原蛋白或佛波酯,注射到皮下,然后在数小时(急性模型)或数天(慢性模型)内观测由此产生的病理学变化和行为变化。迄今为止,这些研究的绝大多数,都是以急性炎症的动物模型进行的(例如,Aloe等,1993;Mazzari等,1996;Conti等,2002;Costa等,2002)。
e)临床试验
与动物研究相比较,只进行了少量的人体临床试验,来考察PEA的消炎作用。在1970年代初期,在捷克斯洛伐克进行了几个试验,使用一种商品名为ImpulsinTM的口服制剂(N-2-羟乙基棕榈酰胺,SPOFA United Pharmaceutical Works)。第一组试验评价了PEA(3次/天/12天)对降低1345名成人志愿者(年轻男兵或斯柯达汽车有限公司的雇员,Masek等,1974)呼吸道感染发生率和严重性的疗效。结果表明,当在传染病事件发生之前给药时,ImpulsinTM有助于防止病毒感染,但不能缩短感染症状的持续时间。在1973年至1975年期间,还对总计1864名年轻男性士兵(相同的给药方案),进行了一系列类似试验,结果确认,预防药ImpulsinTM大大地降低了这一人群中急性呼吸道感染的发病率(Kahlich等,1979)。在12周试验期间,副作用的发生率特别低(仅几个百分点;Kahlich等,1979)。这些试验的明显成功,导致ImpulsinTM在前捷克斯洛伐克用于治疗急性呼吸道疾病。在市场上使用几年之后,该药物不明原因地被撤回,而其原因并非与毒性相关(参见Lo Verme等,2005b,评论)。随后的两次临床试验,已经开始对PEA治疗慢性背痛(lumbosciatalgia)和多发性硬化症的疗效进行考察(参见Lambert等,2002,评论)。
也已已开发了一种含有带PEA的“结构化天然脂质”的外用霜剂,(PhysiogelTM A.I.,Stiefel Laboratories),并经两次小规模的临床试验进行了评价。第一次实验是观察研究,指导19位诊断为肛门湿疹的成人患者,涂抹所述霜剂到患处,为时6至63天(Rohde&Ghyczy,2003)。该试验经过4周之后,68%的患者报告疼痛、烧灼感和瘙痒减少,21%记录症状恶化。据报告,有95%的患者对这种霜剂耐受性良好。在第二次试验中,对21例晚期肾衰竭和患有尿毒症瘙痒的成人患者,涂抹了这种霜剂,每天两次,为期三周(Szepietowski等,2005)。据统计,在三周测试期结束时,瘙痒明显减少(只有不到40%的患者完全不存在),81%的患者报告说,患处的干燥症消除。这种霜剂对所有患者均耐受性良好,没有不良作用的 报告。这些结果提供了一个令人鼓舞的征兆,即:含有PEA的霜剂,在治疗皮肤炎症疾病中,可能提供一种替代性的治疗选择方案。
f)作用模式
有关PEA可发挥消炎和镇痛疗效的精确机理,还没有完全搞清。人们普遍认为,PEA的作用不是通过典型的大麻素受体介导的,这可以解释PEA缺乏神经调节作用的原因。相反,AEA的大多数作用,似乎都是通过大脑和神经末梢中的CB1和/或CB2受体介导。使用AEA的一个问题是作用于精神的副作用,而这种副作用一般认为是通过CB1受体介导的。但是,有证据表明,这种不良影响,可通过联合施用低剂量(低于治疗所需量)的AEA和另一种NAE而得以减低或消除(Calignano等,1998;Di Marzo等,2001;De Petrocellis等,2001;Lo Verme等,2005b)。例如,当PEA和AEA以相同低剂量的组合方式给药时,低于镇痛剂量的PEA和AEA提供了镇痛效果(Calignano等,2001)。
在分子和行为水平上,PEA与人体中的一些重要标靶互相作用。由体内和体外研究收集的证据表明,PEA减少浮肿、肥大细胞增生、嗜中性白血球渗透和炎症的许多内源性介质,包括:肥大细胞脱颗粒作用(阻止组胺和血清素的释放),环加氧酶-2(COX-2)活性,内皮源性一氧化氮合成酶活性,由巨噬细胞产生一氧化氮和在急性缺氧期间的脂质过氧化反应(Gulaya等,1998)。此外,PEA可降低炎性疼痛动物模型的痛觉过敏(Jaggar等,1998;Farquhar&Smith,2001;Conti等,2002)。
最近的数据表明,过氧化物酶体增殖激活受体α(peroxisomeprolife rator-activated receptor alpha)(PPAR-α)对PEA的消炎作用至关重要(Lo Verme等,2005a)。
控制炎性疾病的标准治疗方法
A.涉及慢性炎症的疾病
炎症是人体局部对损伤和感染做出的正常反应,并以局部发红、肿胀、发热和疼痛等典型症状为特征。正常的炎症反应都是一种急性过程,该过程需解决刺激物移除、启动修复和组织愈合等问题。在某些情况下,急性炎症可以发展为慢性炎症,而慢性炎症是影响骨骼和关节、呼吸系统、皮肤、胃肠道、心血管和神经系统的大量病理学的关键组成部分。重要的是,急性炎症和慢性炎症的潜在过程,是大不相同的。
用于治疗炎症和疼痛的非甾体消炎药(NSAID)流行甚广,因为与其 他消炎药物相比,其风险状况更为人接受。然而,长期使用NSAID,存在一些主要局限性,包括:造成胃损伤(溃疡病和胃肠道出血)、肾损害以及加大出血的风险。此外,由于非甾体消炎药不改变病情发展,患者可能需要另外一类药物——改变病情消炎药(DMARD;例如,甲氨蝶呤,依那西普(etanercept,皮质类固醇)。不幸的是,这些药物的大多数,它们的安全边际较窄,它们的特征时具有会对生活质量会产生负面影响的经常性不良作用。
B.异位性皮炎/湿疹
异位性皮炎/湿疹(AD)是慢性皮肤疾病,通常表现为发红、发痒和形成可能导致渗水和结壳的囊泡。AD影响到至少发达国家15%的人,并往往与其他形式的过敏症,如哮喘和花粉热hay fever等相关联(Lee,Y-A.等,2000)。
外用皮质类固醇是治疗AD用药物的黄金标准。然而,其中一个主要的缺点是,长期外用皮质类固醇,有产生不良反应的危险,如皮肤皱缩、口腔和过敏性接触性皮炎、痤疮、皮肤色素沉着减少和治疗部位毛发生长过度等。虽然有许多非甾体类产品是可用的(例如:吡美莫司(pimecrolimus)、他克莫司(tacrolimus)、抗生素、环孢霉素、甲氨蝶呤等),但它们常常不太有效,而且都有偶尔还很严重的不良反应(参见Abramovits,2005,评论)。例如,吡美莫司和他克莫司,最近收到(美国)联邦食品及药物管理局关于可能有癌症风险的黑箱警告(Black Box warnings)。显然,需要有一些不良反应较少的有效的消炎产品。
绿贻贝(Perna Canaliculus)的消炎作用
新西兰绿唇贻贝(Perna Canaliculus,NZGLM)的“稳定化的”脂质提取物,对若干不同的炎症动物模型,以及人体的慢性炎症疾病,已显现出有益效果(Whitehouse等,1997;Whitehouse等,1999;Shiels&Whitehouse,2000;Tenikoff等,2005;Gibson&Gibson,1998;Emelyanov等,2002;Cho等,2003年;Gruenwald等,2004)。所述稳定化,通常需要添加有机酸,例如酒石酸,以减少在处理之前PUFA(多不饱和脂肪酸)的氧化(WO85/05033;NZ211928)。然而,并非在使用稳定化的贻贝脂质提取物治疗炎症的所有人体研究中,都报道积极的结果(Lau等人,2004;参见Cobb和Ernst,2006,评论),或者已经能够证明健康志愿者中炎症血液标标记减少(Murphy等,2006)。
贻贝专利
本技术领域中贻贝专利涉及贻贝提取物制剂的各个方面,例如:
NZ211928描述了一种制剂,通过向悬浮于刚刚收集的悬浮于盐水中的贻贝肉中添加有机酸(醋酸,柠檬酸,酒石酸,乳酸)和/或金属盐的方法,来稳定绿壳贻贝提取物。
NZ270754描述了悬浮在鱼油中的细磨贻贝提取物的一种组合物。
NZ314867描述了一种从绿壳贻贝提取的与糖胺聚糖相结合的蛋白质提取物。
NZ514389描述了以宠物食品的方式向宠物施用绿壳贻贝提取物,每天每千克动物体重施用0.18至114毫克。
其他专利描述了富集提取物中选定组分的提取过程,例如:
NZ329018描述了一种通过在水中用蛋白水解酶处理,分离固体残渣,然后从水溶液中回收肝糖,以从贻贝中提取肝糖的方法。
NZ510407介绍了一种绿壳贻贝提取物,其含有碳水化合物、脂质,以除去蛋白质组分。
NZ328489描述了一种得自绿壳贻贝的蛋白质提取物,以及生产所述提取物的方法:搅拌苯酚溶液中的贻贝肉45分钟,然后离心/抽吸上层液,再使用乙醇沉淀出含有产品的蛋白质。
上述专利都没有涉及富集了NAE化合物的提取物的生产,也没有认识到这些化合物在多种治疗中的有效性。
商业化的贻贝制品
两种广泛销售的NZGLM制品是SeatoneTM和LyprinolTM。SeatoneTM由从全部贻贝肉得到的稳定的冻干粉组成,而LyprinolTM是一种从稳定的冻干肉(通过超临界CO2流体),通过添加橄榄油和维生素E而萃取得到的油,其被加工成胶囊(Pharmalink International Ltd.,Cayman Islands)。Lyprinol TM包含五种主要脂质:游离脂肪酸、甘油三酯、甾醇酯s、甾醇及磷脂(Sinclair等,2000;Wolyniak等,2005)。LyprinolTM中最大量的游离脂肪酸是:棕榈酸(C16:0),亚油酸(C18:2n-6),EPA(C20:5n-3),DHA(C22:6n-3),棕榈酸油(C16:1n-7),C16:1n-9,7,5和肉豆蔻酸(C14:0)(Sinclair等,2000;Wolyniak等,2005)。虽然还鉴定出了许多其他的脂肪酸(合计约91种),但单个而言,这些酸仅存在很少量(低于总脂质的5%w/w;Wolyniak等,2005)。ω-3PUFA占总脂肪酸的40%,而且EPA 和DHA是最大量的(Wolyniak等,2005)。有证据表明,LyprinolTM的消炎活性多数都在于脂肪酸部分(Whitehouse等,1999;Treschow等,2007)。
经过LyprinolTM的一段疗程后,被试人的几个促炎化合物的含量降低,所述促炎化合物包括:血栓素B2、前列腺素E2和白细胞介素-1β,类似于使用低剂量ω-3多不饱和脂肪酸补充剂后观察到的情况(Sinclair等,2000)。这表明,LyprinolTM活性的一个重要因素可能在于其ω-3含量,这种可能性与最近的体外试验证据相一致(McPhee等,2007;Treschow等,2007)。LyprinolTM作用的假设模型,是通过抑制5-脂加氧酶和环加氧酶(COX)两种途径。
考虑到上述概述PEA和其他NAE化合物治疗效果的证据,应该理解,富含这些化合物的产品可能是有利的。
本发明的目的,在于解决前面提到的问题,或者至少向公众提供有用的选择。
所有的参考文献,包括本说明书中引用的任何专利或专利申请,均通过引用合并于此。不承认任何参考文献都构成现有技术。所述参考文献的讨论的内容陈述了其作者的看法,申请人保留挑战所引用文件的准确性和正确性的权利。可清楚地理解,虽然本文引用了许多现有技术出版物,但该引用并不构成这样的承诺,即任意这些文件在新西兰或任何其他国家都形成本领域的公知常识部分。
应理解,术语“包括comprise”,在各种管辖范围之下,可以认为是排他的或非排他的含义。在本说明书中,除非另有说明,词语“包括”具有非排他的含义,也就是说,它将不仅包含其直接提及的列出的组分,而且还包含其他非指明的组分或元件。在使用与方法或工艺中一个或多个步骤相关的词语“包括comprised”或“包括comprising”时,该基本原理也适用。
本发明更多的方面和优点,将通过下述仅以举例方式给出的描述,而变得清楚。
发明内容
在本说明书中,术语“海产”,是指在海水或淡水里,或在海水或淡水周围生活的贝类生物体。
所用术语“N-酰基乙醇胺”(NAE),但还可使用这类化合物技术上通用的其他名称,包括:“N-酰基乙醇酰胺”或脂肪酸乙醇酰胺。
按照本发明的第一个方面,提供一种包含油提取物的组合物,所述油 提取物来源于富含脂肪酸酰胺化合物的海产生物体。
按照本发明的另一方面,提供一种包含油提取物的组合物,所述油提取物来源于富含NAE化合物海产生物体。
更好的是,所述提取物富含N-十六酰乙醇酰胺(PEA)。本领域普通技术人员应该认识到,PEA也具有许多不同的名称,包括但不限于N-羟乙基棕榈胺(palmidrol)和N-(2-羟乙基)-十六碳酰胺。
按照本发明的另一方面,提供一种包含来源于海产生物体的油提取物的组合物,所述海产生物体含有按提取前所述海产生物的肉的湿重测得的至少0.10微克/克的PEA。
按照本发明的另一方面,提供一种包含来源于富含NAE化合物的海产生物体的油提取物的组合物,所述海产生物体含有按提取前所述海产生物的肉的湿重测得至少为0.10微克/克的PEA。
如上所述,所述组合物富含一些NAE化合物。举例来说,所述组合物包括(但不限于)的NAE的量,以提取之前湿肉计为:N-硬酯酰乙醇酰胺(18:0),70纳克/克;N-油酰乙醇酰胺(C18:1),5纳克/克;和N-亚油酰乙醇酰胺(C18:2),5纳克/克;和N-花生四烯酰乙醇酰胺(C20:4,大麻素),8纳克/克。这不应视为对所述组合物的限制,所述组合物可包含其他NAE化合物,包含的NAE量可大于和小于所公开的量。
更好的是,所述海产生物体是一种双壳类软体动物。还更好的是,所述生物体是贻贝类。最好的是,所述生物体是绿贻贝属(Perna)或蓝贻贝属(Mytilus)(分别为绿贻贝或蓝贻贝)类的贻贝。这不应当被看作是限制性的,也可包括其它物种,例如,蛤类和牡蛎类。
更好的是,所述脂肪酸酰胺化合物包括NAE化合物。
更好的是,所述NAE化合物包括:N-肉豆蔻酰乙醇酰胺,C14:0;N-棕榈酰乙醇酰胺(PEA),C16:0;N-硬酯酰乙醇酰胺,C18:0;N-油酰乙醇酰胺,C18:1;N-亚油酰乙醇酰胺,C18:2;N-花生四烯酰乙醇酰胺(大麻素,AEA),C20:4;N-二十烯酰乙醇酰胺,C20:1;以及它们的组合物。
在优选的实施方式中,所述油提取物中含有按在提取前所述海产生物体的湿组织测得含量至少是0.10微克/克的PEA。更好的是,上述PEA含量至少为0.50微克/克。在经由选择的实施方式中,所述PEA含量可大于3.0微克/克。
更好的是,所述油提取物中含有按提取前所述海产生物体的湿组织测得含量至少是0.008微克/克的AEA。还更好的是,所述含量大于0.01微克 /克,所述含量按提取前所述海产生物体的湿组织测得。在经由选择的实施方式中,所述AEA含量可大于0.05微克/克。
更好的是,所述组合物,包括在油提取物中含有按进一步提取前所述海产生物体的干组织测得含量大于1.0微克/克的PEA。
更好的是,所述组合物,包括在油提取物中含有按进一步提取前所述海产生物体的干组织测得含量大于0.09微克/克的AEA。
应该理解,本发明油提取物中至少PEA和AEA的含量大大高于现有技术,现有技术根本没有教示PEA含量,或者没有教示上述含量。在最近的现有技术中,Sepe等教示了从地中海贻贝的湿组织仅产出0.053±0.0039微克/克PEA和0.0018±0.003微克/克的AEA。
要强调的是,上述数值是指湿肉中的PEA和AEA含量。应理解,降低水分含量(如干燥)的方法,也可浓缩包括PEA和AEA在内的活性化合物的含量。本发明的提取物,在所述脱水工艺完成之前,已经大大浓缩。
按照据本发明的另一个方面,海产物原材料的上述脂肪酸酰胺含量,基本如上所述,可以富集。
在本专利说明书中,术语“富集”意思是指,在通过干燥工艺进行浓缩之前,提高海产原料中脂肪酸酰胺化合物的含量/量。
在一个优选的实施方式中,通过收获、破碎、然后将该海产原料以破碎状态保持在4至10℃温度下至少24个小时,来进行富集。在一个实施方式中,该原料被保持多达144个小时。
发明人已经发现,通过完成上述富集步骤,脂肪酸酰胺化合物的含量/量增加。这被认为缘于所述海产原料死后的生化反应。出乎意料的是,该过程导致了贻贝肉的脂肪酸酰胺含量大大富集。还有一点出乎意料的是,发明人发现,通过采用用上述工艺参数不会出现微生物污染到不利于适合人食用该提取物的地步。一般理解是,正常的处理海产原料的程序,需要采取尽可能快的步骤,以防止微生物生长,例如可采取冷冻或干燥的方法。与现行的实践相反,让所述原料在10℃下保持数天,在这样的时间和温度下,微生物污染水平依然出乎意料地低。
如上所述,富含包括PEA和AEA在内的脂肪酸酰胺的所述组合物,还可包括其他化合物(脂肪酸酰胺和其他化合物)。事实上,发明者们认识到,除了PEA之外还存在多个NAE化合物是非常期望的,因为根据现有技术(已公开文献)中对于NAE的经验,NAE之间的协同作用是普遍的,因此与仅有一种NAE的产品相比,含有多种NAE的产品的效能可大大增加。
在另一实施例中,所述组合物也包括至少一个多不饱和脂肪酸(PUFA)化合物。还更好的是,所述PUFA化合物包括ω-3型PUFA。可以理解到,具有包括脂肪酸酰胺化合物和PUFA化合物两者的油提取物,是最可取的。还可以理解到,由于脂肪酸酰胺化合物和PUFA化合物具有不同的化学性质,无法预料可以获得这两种化合物含量都相当高的提取物。不过,应当理解,PUFA化合物对于本发明的组合物来说并非必不可少,而且PUFA化合物的存在不应视为是限制性的。
更好的是,所述油提取物包括至少一种PUFA化合物。还更好的是,PUFA是ω-3型的。更好的是,PUFA选自:4,7,10,13,16,19-二十二碳六烯酸(DHA;22:6n3),5,8,11,14,17-二十碳五烯酸(EPA,20:5n3),6,9,12,15-十八碳四烯酸酸(OTA,18:4n3),9,12,15-十八碳三烯酸(ALA,18:3n3),7,10,13,16,19-二十二碳五烯酸(DPA,22:5n3),11,14,17-二十碳三烯酸(ETA,20:3n3),8,11,14,17-二十碳四烯酸(20:4n3)及其组合物。在优选实施方式中,如在所述提取物中所测,所述DHA含量大于3g/100g。更好的是,如在所述提取物中所测,所述EPA含量大于5g/100g。
更好的是,所述组合物制成口服粉末、溶液、悬浮液、乳剂、油、片剂或胶囊。或者,所述组合物可制成外用制剂,例如霜剂、洗剂、软膏或油。在另一实施方式中,所述组合物制成作为“功能性食品”施用的固体或液体食物。
按照本发明的另一方面,提供一种口服或外用制剂,该制剂含有治疗有效量的来源于富含脂肪酸酰胺化合物的海产生物体的油提取物。
按照本发明的另一方面,提供一种口服或外用制剂,该制剂含有治疗有效量的来源于富含NAE的海产生物体的油提取物。
按照本发明的另一方面,提供一种口服或外用制剂,该制剂含有治疗有效量的富含PEA的油提取物。
按照本发明的另一方面,提供一种口服或外用制剂,该制剂含有治疗有效量的来源于含有至少0.10微克/克PEA的海产生物体的油提取物,所述含量按提取前海产生物体的肉的湿重测得。
按照本发明的另一方面,提供一种口服或外用制剂,该制剂含有治疗有效量的来源于富含包括至少0.10微克/克的PEA的NAE化合物的海产生物体的油提取物,所述含量按提取前海产生物体的肉的湿重测得。
更好的是,所述油提取物还包括按提取前海产生物体的肉的湿重测得至少为0.008微克/克的AEA。
更好的是,如上所述的所述制剂,还包括至少一种PUFA。还更好的是, 所述PUFA包括ω-3脂肪酸。
在本发明者们所设计的实施方式中,所述制剂包括载体物质,还可包括公认的食品级抗氧化剂,以帮助被提取的活性化合物长期稳定。
在一个优选的实施方式中,所述制剂是一种口服胶囊,其中该胶囊填充了源于贻贝肉的油提取物。
在另一优选的实施例中,所述制剂是一种外用的霜剂或洗剂,其中所述霜剂/洗剂包括源于贻贝肉的油提取物。
应理解,上述制剂是仅仅作为例子提供的,不应该被看作是限制性的,因为应理解,可在不偏离本发明范围的条件下生产其它制剂。
按照本发明的另一方面,提供一种通过口服或外用基本如上所述的组合物或制剂来治疗炎症及相关疼痛的方法。
在一个实施例中,所述炎症是慢性的,而不是急性的。举例来说,有关慢性炎症的疾病包括:湿疹/异位性皮炎、哮喘,炎性肠病(包括克罗恩病和溃疡性结肠炎),类风湿和骨关节炎,血管球性肾炎,动脉粥样硬化,阿尔茨海默病和成人呼吸窘迫综合症。作为第二个实施例,有关慢性疼痛的疾病包括:神经性疼痛和关节疼痛。
在替换实施方式中,所述炎症是急性的,包括通过将含有本发明的组合物或制剂的霜剂,局部涂敷到损伤处的外部,治疗软组织损伤。
按照本发明的另一方面,提供一种通过口服或外用基本如上所述的组合物或制剂,来治疗与炎症有关的疾病的方法。
按照本发明的另一方面,提供一种通过口服或外用基本如上所述的组合物或制剂,来缓解炎症发展的方法。
按照本发明的另一方面,提供一种通过外用基本如上所述的组合物或制剂,来治疗皮肤病的方法。
按照本发明的另一方面,提供一种通过口服或外用基本如上所述的组合物或制剂,来治疗皮肤病的方法。
按照本发明的另一方面,提供一种通过口服或外用基本如上所述的组合物或制剂,来缓解皮肤病症状的方法。
在优选的实施方式中,被治疗的所述皮肤病,包括异位性皮炎/湿疹和接触性皮炎。
在优选的实施方式中,缓解的症状包括瘙痒、干燥、肿胀,并减少对人角质形成细胞增殖。
在一个实施例中,基本如上所述的疗法,与至少一种非甾体消炎药(NSAID)合并使用。可以设想,所述提取物可提高甚至是低剂量(低于 治疗所需量)的NSAID的活性,因此,可降低副作用的严重性。此外,本发明的组合物和制剂也可发挥增强NSAID活性的作用,因此可具有疗效更好以及/或者NSAID的所需给药量降低的优点。
按照本发明的另一方面,提供了基本如上所述的油提取物在制造上述治疗用制剂的用途。
通过以上说明应该意识到,提供了一种油提取物,其含有的活性化合物的含量大幅提高,所述活性化合物,根据本技术领域,至少有益于关节灵活性。还提供了相关的口服和外用制剂,以及用于治疗各种与炎症相关疾病和症状的方法。
目前迫切需要一些与目前的医药品相比,可长期使用且不良作用更少的有效的消炎产品。本发明的提取物可应对这一需求。可以设想,每日施用包含富含NAE的海产原料提取物的食品或制剂,提出了一种预防或治疗炎症的理想疗法。
附图说明
通过下面仅以举例方式给出的说明,并参照附图,本发明更多方面将变得清楚,其中:
图1是典型的绿贻贝Perna canaliculus提取物的LC/MS(液相色谱/质谱)色谱图示出了时间=10分钟时的含有PEA(下方图中箭头所指)的峰。所述峰的相对大小表明,PEA占到总离子流(上方图)相当大的部分,提示在所述提取物中存在大量的PEA。
具体实施方式
以下提供的实施例,表示由本发明人生产和设计的与富含NAE的油提取物相关的各种制剂。
实施例1
通过以实验室规模的试验来测定用商业方式从新西兰水域收获的蓝贻贝(Mytilus edulis)和绿唇贻贝(Perna canaliculus)中的PEA含量(试验1)。第二次试验是以模拟工业规模测定Perna canaliculus中的PEA和AEA含量(试验2)。
方法
PEA和AEA的含量,是通过LC/MS法,在从新鲜收获的蓝贻贝和绿贻贝的干肉提取的粗脂质中测定出来的,并以μg/g湿肉计(见下表1; Giuffrida等,2000)。
通过如图1所示的LC/MS确认了Perna canaliculus的脂质提取物中存在PEA,图中的箭头标示PEA峰。
结果
表1 三种不同贻贝种类中的NAE含量
注1:NAE含量是通过由脂质提取物数据进行反算(back-calculation)确定的。
注2:NAE含量是使用基于试验1数据(表1)的换算系数估计得到的。
结论-试验1和2
1)Perna canaliculus中的PEA含量比两种蓝贻贝的都高。因为Perna canaliculus在同等重量的基础上含稍多的肉,因此有略高的干物质比例,这至少是其相对于蓝贻贝具有较高PEA含量的部分原因。
2)AEA在Perna canaliculus中的含量也比蓝贻贝(Mytilus galloprovincialis)高,尽管其绝对含量较低。
实施例2
记载了一种在提取前富集新鲜Perna canaliculus中内源性NAE含量的方法。在本实施例中,将采取商业方式收集的均质的/完整的贻贝肉,在实验室中,如下所述,在不同条件下进行孵育。在大气压力下,于4或10℃,好氧或厌氧条件下,孵化0至144小时。在整个试验期间间隔进行组织pH值的监测。在孵化期结束时,冷冻所述组织,随后进行冻干。实验条件严格控制,尽量减少潜在混杂因素,如贻贝各批次、冷冻或冻干条件的差异 等。测定冻干贻贝中的NAE和ω-3含量。
实验结果表明,用均质贻贝经10℃以及需氧条件下孵化高达144小时制得的干肉,与从同一批贻贝均质化后立即冷冻后制得的干肉相比,其PEA和AEA含量要高5至10倍。
本发明人还意外地发现,在相同的干贻贝样品中,主要多不饱和脂肪酸ω-3(DHA(二十二碳六烯酸),EPA(二十碳五烯酸)和ALA(α-亚麻酸)),甚至在孵化144小时之后都还保留。
此外,在干燥产品中的微生物量,在规定的有关时间和温度下,都出乎意料地低。
实施例3
如上所述,我们都知道,本发明的油提取物富含NAE化合物,所述NAE化合物包括但不限于PEA。例如,本发明的提取物含有PEA、AEA和/或多不饱和脂肪酸。在脂质提取物中的含量数据预期为:3.0-57.0微克/克或更高的PEA;0.1-5.2微克/克或更高的大麻素;以及/或者至少3克/100克的DHA,和至少5克/100克的EPA。
实施例4
在本发明的一个实施方式中,描述了一种口服制剂。例如,一种典型的口服制剂,包括包含在胶囊内的本发明的贻贝脂质提取物(油),具有或不具有载体脂质和抗氧化剂。对于成年人的设计剂量为,每天用药1-2次,每次约1-4个胶囊。可以预期,这一给药方式将减轻由慢性炎症,尤其是涉及关节的慢性炎症(关节炎)引起的疼痛和肿胀。
实施例5
在另一实施方式中,本发明的油提取物用于外用制剂。例如,一种外用制剂,包括含有本发明的脂质提取物(油)的霜剂/洗剂,可具有或不具有载体脂质和抗氧化剂。其他可用于霜剂/洗剂的物质,包括但不限于以下物质:丙二醇、水、甘油、甘油酯、氢化卵磷脂、甜菜碱、羟乙基纤维素、卡波姆钠(sodium carbomer)、鲨烯(squaline)、黄原胶。
霜剂外敷到患处每天1-3次,以减缓皮肤干燥,发红,肿胀,瘙痒和减少皮肤增厚。
实施例6
在另一实施例中,如上所述的口服或外用制剂用于治疗急性炎症。在一个实施例中,该提取物可在炎症发作4小时之内给药(如软组织损伤),以减少症状的严重度和缩短可能的痊愈时间。
实施例7
在另一个实施例中,本发明的油提取物用于功能性食品。在一个这样的实施方式中,为了降低包括上述炎性疾病在内的炎症疾病发生的风险,可以食用这种食品。
例如,该产品可以是由消费者或通过所述产品制造商加入(例如混合)到各种食物产品中的,处于准备使用状态的本发明的油提取物。
在一个实施例中,本发明的油提取物被雾化以生产微球体,并通过制造商添加到一些食品中。
实施例8
本发明的油提取物可以与非甾体消炎药联合给药。例如,将一种低剂量的非甾体消炎药和一种口服剂量的本发明提取物用于治疗慢性炎症(如风湿性关节炎和骨关节炎;成人剂量:在相同的时间服用1-4粒胶囊,频度同所述非甾体消炎药)。本发明的提取物增强了低剂量非甾体消炎药消炎作用,从而减少不良副作用的风险。
实施例9
通过与现有技术的商品(Perna canaliculus制品;记载于US6083536和US6346278)相比较,对本发明提取物做了进一步研究。本发明提取物富含包括诸如PEA和AEA之类的NAE化合物的脂肪酸酰胺。本发明提取物还包括诸如EPA和DHA之类的多不饱和脂肪酸。本发明提取物中每一关键组分的相对量,都与商业化的贻贝制品进行了对比(见下表2)。
表2 比较数据
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1乙醇酰胺通过液相色谱法和质谱分析法(LC/MS;三级四级质谱)进行定量。
2ω-3脂肪酸转化成它们的脂肪酸甲酯,并按照经验证的方法(AOAC#963.22),通过气相色谱法定量。
3每粒胶囊含有:50毫克Perna canaliculus提取物,100毫克橄榄油和0.225毫克d-α-生育酚。
表2所列数据表明,本发明的提取物,相对于商业化贻贝制品,含有相当高含量的NAE(高17倍的PEA,高26倍的AEA)和ω-3(尤其是DHA和EPA)。
应该理解,使用本发明组合物的制剂,可以简单地是未经稀释的提取物,也可以是与其他配料相混合,从而以不同程度稀释上述组分,但上述组分含量仍高于商业化贻贝制品。
仅通过举例的方式对本发明的各个方面进行了描述,应该理解,只要不脱离所附权利要求书中限定的范围,可对其进行修改和补充。
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Claims (11)
1.一种包含油提取物的组合物,该油提取物来源于富含N-酰基乙醇酰胺化合物的双壳类软体动物,所述N-酰基乙醇酰胺化合物包括按提取前所述双壳类软体动物的肉的湿重测得至少为0.10微克/克的N-十六酰乙醇酰胺。
2.如上述权利要求1所述的组合物,其中所述组合物包括选自以下化合物的N-酰基乙醇酰胺化合物:十二酰乙醇酰胺,C12:0;N-十四酰乙醇酰胺,C14:0;N-十六酰乙醇酰胺,C16:0;N-十八酰乙醇酰胺,C18:0;N-油酰乙醇酰胺,C18:1;N-亚油酰乙醇酰胺,C18:2;N-花生四烯酰乙醇酰胺,C20:4;N-二十烯酰乙醇酰胺,C20:1;以及它们的组合。
3.如上述权利要求1所述的组合物,其中,所述组合物包括按提取前所述双壳类软体动物的肉的湿重测得含量大于0.008微克/克的N-花生四烯酰乙醇酰胺。
4.如上述权利要求1所述的组合物,其中所述双壳类软体动物是来自绿贻贝属(Perna)或蓝贻贝属(Mytilus)的贻贝。
5.如上述权利要求1所述的组合物,其中所述组合物还包括至少一种多不饱和脂肪酸化合物。
6.如权利要求5所述的组合物,其中所述多不饱和脂肪酸化合物是ω-3型脂肪酸。
7.如权利要求5所述的组合物,其中在粗提取物中,二十二碳六烯酸的含量大于4g/100g。
8.如权利要求5所述的组合物,其中在粗提取物中,二十碳五烯酸的含量大于6g/100g。
9.如上述权利要求1所述的组合物,其中所述组合物制成为口服制剂。
10.如权利要求1所述的组合物,其中所述组合物制成为外用制剂。
11.如权利要求1所述的组合物在治疗慢性炎症中的用途。
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CN (2) | CN103638003A (zh) |
CA (1) | CA2710054C (zh) |
DE (1) | DE112007003136T5 (zh) |
GB (1) | GB2458599B (zh) |
HK (1) | HK1136218A1 (zh) |
NZ (1) | NZ552238A (zh) |
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Cited By (1)
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CN106714792A (zh) * | 2014-08-08 | 2017-05-24 | R·米利亚乔 | 用于治疗炎症性和过敏性病理学的脂肪酸和十六酰胺乙醇的混合物 |
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PT2076508E (pt) | 2006-10-18 | 2011-03-07 | Pfizer Prod Inc | Compostos de ureia de éter biarílico |
NZ552238A (en) | 2006-12-20 | 2009-07-31 | Seperex Nutritionals Ltd | An extract |
CA2722491C (en) * | 2008-04-28 | 2016-09-06 | Vermont Italia Srl | Pharmaceutical formulation containing palmitoyl ethanolamide and stearoyl ethanolamide |
NZ575985A (en) * | 2009-03-31 | 2010-04-30 | Bomac Research Ltd | Medicament Uptake |
GB0909643D0 (en) | 2009-06-04 | 2009-07-22 | Avexxin As | Glomerulonephritis treatment |
ITPD20090360A1 (it) * | 2009-12-01 | 2011-06-02 | Vermont Italia Srl | Composizione per uso topico |
CA2788717A1 (en) * | 2010-02-04 | 2011-08-11 | Monell Chemical Senses Center | Compounds and methods for enhancing salty taste |
GB201014633D0 (en) | 2010-09-02 | 2010-10-13 | Avexxin As | Rheumatoid arthritis treatment |
EP2444078B1 (en) * | 2010-10-04 | 2017-09-13 | EPITECH GROUP S.p.A. | Use of amides of mono and dicarboxylic acids in the treatment of renal diseases |
FR2965478B1 (fr) * | 2010-10-05 | 2015-04-24 | Oreal | Utilisation d'anandamide pour lutter contre la secheresse cutanee |
WO2012070905A2 (ko) * | 2010-11-26 | 2012-05-31 | Kim Young-Moon | 인체의 희귀 난치성 질환 예방 및 치료용 연체동물 추출물 |
CN103113253A (zh) * | 2013-01-28 | 2013-05-22 | 国家海洋局第三海洋研究所 | 一种不饱和脂肪酸醇胺衍生物及其制备方法与应用 |
ITMI20130354A1 (it) | 2013-03-08 | 2014-09-09 | Again Life Italia Srl | Miscela di acidi grassi (f.a.g. fatty acids group) per uso nel trattamento di patologie infiammatorie. |
US20160128961A1 (en) * | 2013-06-07 | 2016-05-12 | Loma Linda University | Dietary omega-3 fatty acid derived glycerophospholipids to treat neuropathic pain |
GB201409363D0 (en) | 2014-05-27 | 2014-07-09 | Avexxin As | Skin cancer treatment |
US10966937B2 (en) * | 2015-05-04 | 2021-04-06 | Cytometix, Inc. | Compositions and methods for delivery of polyunsaturated fatty acid derivatives and analogs |
GB201604316D0 (en) | 2016-03-14 | 2016-04-27 | Avexxin As | Combination therapy |
JP2019529555A (ja) | 2016-09-21 | 2019-10-17 | アヴェクシン エーエス | 医薬組成物 |
AU2017380470B2 (en) * | 2016-12-20 | 2022-12-22 | Sanford Limited | Method of processing shellfish and resulting compositions |
AU2017380471B2 (en) * | 2016-12-23 | 2023-12-21 | Mm Health Ltd | Topical formulation comprising green lipped mussel and honey |
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CN106714792A (zh) * | 2014-08-08 | 2017-05-24 | R·米利亚乔 | 用于治疗炎症性和过敏性病理学的脂肪酸和十六酰胺乙醇的混合物 |
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WO2008075978A2 (en) | 2008-06-26 |
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HK1136218A1 (en) | 2010-06-25 |
DE112007003136T5 (de) | 2009-11-19 |
GB2458599B (en) | 2011-03-23 |
CA2710054A1 (en) | 2008-06-26 |
NZ552238A (en) | 2009-07-31 |
CN101641089A (zh) | 2010-02-03 |
GB2458599A (en) | 2009-09-30 |
WO2008075978A3 (en) | 2008-07-31 |
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CA2710054C (en) | 2012-11-20 |
KR20090103918A (ko) | 2009-10-01 |
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