CN102711780A - 包含氨基酸和植物的制剂及其在酒精解毒作用中的活性 - Google Patents
包含氨基酸和植物的制剂及其在酒精解毒作用中的活性 Download PDFInfo
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Abstract
本发明涉及包含一些氨基酸和植物提取物的制剂及其酒精解毒作用的活性。制剂中的组分(a)包含两种或多种氨基酸或其衍生物的混合物;制剂中的组分(b)包含三种以上植物提取物的混合物。本发明中使用一些植物提取物,比如人参根提取物、银杏叶提取物、水飞蓟宾提取物、枸杞子提取物和茶多酚。本发明还涉及所述制剂的生物学活性,比如防止化学损伤的肝保护,增强低氧耐受性和快速降低直到消除血液酒精含量。
Description
技术领域
本发明涉及用于饮食、食品补充剂或医学目的的制剂,更特别地,涉及包含氨基酸和一些植物提取物的制剂或组合物及其在酒精解毒作用中的活性。本发明的组合物可被用于防护化学肝损伤、增强低氧耐受性、加快清除体内酒精量及减少缺氧环境和增强缺氧环境中的生存力。
背景技术
已知L-鸟氨酸和瓜氨酸参与人体中至少三个重要的环形代谢途径。所述三个代谢途径分别为脲循环、柠檬酸循环和氮氧化物循环。通过采用L-鸟氨酸和瓜氨酸,可以经由相关代谢途径获得内源生物分子信使一氧化氮(NO)。人体中的血液循环系统不能在没有NO的血管舒张作用下起作用,内源NO具有调节和控制多种生理功能的作用,例如可以调节神经突触间的能量;可以调节学习和记忆过程,等。
人体中内源NO是通过一氧化氮合成酶(NOS)催化L-精氨酸(L-Arg)分解产生的。L-Arg是人体中一种重要的物质,除了NO生成和参与蛋白质合成之外,L-Arg还是脲、果仁糖、胍丁胺、多胺等的前体,并且可刺激激素比如生长素和胰岛素的分泌,直接影响人体健康。当人体处于特定应激状态下,例如处于缺氧条件下,人体中的内源NO不足,其可引起高原反应或疾病。
除了高原反应和局部缺血再灌注损伤的预防和治疗、及心脑血管系统和免疫系统的保护作用之外,L-Arg可以延长小鼠负载游泳时间和减少由无氧酵解引起的乳酸蓄积,从而产生抗疲劳功能。
然而,因为服用L-精氨酸(L-Arg)的半衰期非常短(仅仅为约1小时),直接补充精氨酸不能有效地增加血液和细胞中精氨酸的浓度。
已知L-瓜氨酸(L-cit)是一种非蛋白质氨基酸,具有大量重要的生理功能,比如自由基清除、血管舒张和血压稳定作用,而且,内源精氨酸(L-Arg)和NO可以经由人体中L-cit-NO循环不断地产生,以确保明显地增加体内精氨酸水平,和同时维持较高的基础水平,因此,增强了生物体的缺氧耐受性。
L-鸟氨酸是一种组织和细胞中存在的重要非蛋白质氨基酸,也是精氨酸、瓜氨酸及其它氨基酸代谢的前体物质。L-鸟氨酸几乎参与脲循环活化和氨解毒的全部过程,促进了氨甲酰磷酸合成酶和谷氨酰胺的合成,且增强肝脏的解毒功能;因此,L-鸟氨酸对于人体的肝细胞很重要。
参提取物来自人参的干燥的参根和根茎或者红参的根和根茎。其主要活性成分,人参提取物可以显著地保护肝细胞免于化学损伤;动物试验证实人参皂苷也可以保护脑细胞免于局部缺血-再灌注损伤,且对于动物的化学学习和记忆功能性障碍具有明显的改善作用。
银杏提取物来自银杏的银杏叶。银杏提取物可以通过降低Ca2+水平预防NO的代谢异常、防止谷氨酸神经毒性、拮抗血小板活化因子、且对于患有低氧缺血性脑病的脑组织具有保护功能、保护肝脏和具有转氨酶还原作用。
水飞蓟宾,来自水飞蓟的种子,是一种有效的自由基清除剂和脂质过氧化抑制剂,对肝脏具有保护、愈合和解毒作用。水飞蓟宾对于肝脏细胞的酶增强和膜稳定活性有助于减少和修复酒精、高脂肪饮食、烟草消耗和许多处方药物可引起的肝脏损伤。
枸杞子提取物来自宁夏枸杞的果实。枸杞子是补益肝和肾的传统中药,颜色为猩红色,味道的甜味。现代医学研究证实枸杞子包含甜菜碱、多糖、粗脂肪、粗蛋白、胡萝卜素、维生素A、维生素C、维生素B1、维生素B2、钙(C)、磷(P)、铁(Fe)、锌(Zn)、锰(Mn)、亚油酸及其它营养成分。枸杞子的提取物具有促进造血功能,和具有抗衰老、抗突变、抗肿瘤、抗脂肪肝和血糖水平降低功能。中医医生通常使用枸杞子治疗肝肾阴不足,腰膝酸痛无力、头晕、健忘、视力模糊、视力减退和泪溢流、止渴、遗精及其它疾病症状对于患有肾不足的人,枸杞子无疑是一种保健营养品。枸杞子是从古至今维护健康的最佳选择,且具有延长生命的功能。
茶多酚是茶叶所包含的多酚物质的通称,包括黄烷醇类、花色素苷类、黄酮类、黄酮醇类、酚酸类等,其中黄烷醇物质(儿茶酚)是最重要的。茶多酚也称为茶鞣质或茶丹宁,其为形成茶叶的颜色、气味和香味的主要组分,也是茶叶中具有保健功能的主要组分。茶多酚具有解毒和抗辐射作用,可以有效地阻止侵入骨髓的辐射物质,且可以引起锶(Sr)90和钴(Co)60快速从体内释出,因此,其被称为辐射不可战胜的对手,构建了对人类健康有利的抗放射性损伤的防线。茶多酚具有预防脑中风、缓解肠胃紧张和辅助消化功能,并且可以清除人体多余的自由基、抑制脂质过氧化、增强免疫功能和延缓衰老。
包含草药和/或其它天然物质的某些组合物是现有技术已经已知的,其包括例如在中国国家知识产权局中医药数据库[在线];2003-10-29,漆又毛:“一种药用组合物及其用途”XP002585364公开号CN 1451426,或者中国国家知识产权局中医药数据库[在线];2004-10-13,刘义国等人:“橡籽冻”XP002585369公开号为CN1535617,以及US 2005/01 9427 A1,或者中国国家知识产权局中医药数据库[在线];2005-01-26,成进学:“用蛇、蜂、宏、微量元素强化中药方剂的内服功能性药剂及其生产工艺”XP002585371公开号CN 1569123中描述的组合物。某些其它组合物描述在中国国家知识产权局中医药数据库[在线];2005-11-23,蔺益民:“具有解酒护肝功能的产品及制备方法和用途”XP002585357公开号CN 1698879,以及WO 99/61 038 A1;中国国家知识产权局中医药数据库[在线]1997-12-03,夏小琳:“含锌化合物和谷氨酰胺类的组合物/一种用于治疗胃溃疡的药物组合物”XP002585373公开号CN 1166320和DE19929993A1或中国国家知识产权局中医药数据库[在线]1998-07-29,达瀚实业总公司:“护肝酒及其生产方法”XP002585383公开号CN 1188800中。
然而,仍然需要治疗或减缓酒精中毒的有效安全的组合物。
发明内容
本申请人令人惊奇地发现根据本发明的制剂显示出在酒精解毒作用中令人感兴趣的潜能。该安全的天然制品在保护肝脏免于化学损伤、增强低氧耐受性和快速降低直到消除血液酒精含量方面特别有前景。
根据本发明的制剂的多种功能和作用同时得到提高和增强。本发明的制剂可以避免酒精性肝损伤,且可以快速降低人类中酒精含量。现今,饮酒是一种社交方式,也是一种传统的生活方式,越来越多的人患有由长期饮酒或过量饮酒引起的脂肪肝或肝硬化,同时,喝醉之后的冲动也是一种危险的行为。在相应时间口服给药本发明的制剂之后,可以获得特别的医学效果,以缓解饮酒和醉酒后现象。
另外,由于本发明制剂的所有组分之间的相互协同作用,可以有效地克服力量不足、易疲劳、情绪不稳定、衰老和失眠的现象,且增强了对环境污染、激烈竞争、生活节奏紧张、过度脑力工作、饮食结构失衡及其它方面的适应性。
在本发明的一个方面,提供一种制剂,其包括包含由瓜氨酸和鸟氨酸盐酸盐和/或其衍生物组成的组合物(a),和包含人参或人参提取物、银杏叶提取物和水飞蓟宾提取物的混合物的组合物(b),任选地与合适的赋形剂的组合。
在另一个方面,本发明提供一种包含本发明制剂的饮食或食品补充剂、食物制品、饮料和药物。
在一个进一步的方面,本发明的制剂提供用于治疗或预防酒精中毒。
在一个更进一步的方面,本发明提供一种治疗或预防酒精中毒、化学肝损伤、低氧耐受性、体内酒精量及减少缺氧环境和增强缺氧环境中的生存力的方法,其包括向需要其的受试者给药有效量的本发明的制剂或药物。
具体实施方式
尽管在实施或试验本发明的实施方案中可以使用与本文描述的那些类似或等效的方法和物质,但是合适的方法和/或物质描述如下。将本文提及的所有出版物、专利申请、专利、及其它参考文献的全部内容引入作为参考。本文讨论的出版物和申请仅仅提供在本申请的申请日之前的其公开内容。在本文中没有内容被看作是由于现有发明而使本发明没有先于这样的公开内容的许可。另外,所述物质、方法和实施例仅仅是示例性的,而不意味着限定。
在出现矛盾的情况下,以本发明的说明(包括定义)为准。
除非另有定义,本文使用的所有技术术语和科技术语具有与本文的主题所属领域的普通技术人员通常理解的相同的含义。如本文使用的,提供下述定义是为了促进对本发明的理解。
术语“包括”通常以包括,即允许存在一个或多个特征或组分的意义使用。
除非上下文另有清楚的规定,如在说明书和权利要求书中使用的,单数形式“一个”、“一种”和“所述”包括复数引用。
如本文使用的术语“提取物”包括使用提取方法从植物、果实或蔬菜得到的任何制品。
术语“食物制品”通常指植物或动物来源、或合成来源的物质,其包含生物体内使用的维持发育、恢复和生命过程和供给能量的必需营养素,比如碳水化合物、蛋白质、脂肪、维生素、矿物质等。
“饮食或食品补充剂”指包含物质如维生素、矿物质、食物、植物性药材、氨基酸的产品,用于补充这些物质的日常摄入。食品补充剂以药丸、片剂、胶囊、粉剂或液体形式存在,意味着可以口服摄入。
术语“营养制品”指食品或食品一部分的任何物质,其提供医学或健康益处,包括预防和治疗疾病。这样的产品可以为分离的营养物、食品补充剂和特定饮食,以至遗传工程防癌食品、草药产品和加工食品比如谷类食品、汤和饮料。其还指分离或从食物中纯化的产物,通常以与食品无关的药用形式销售,证实具有生理学益处,或提供抵抗疾病如慢性疾病的保护。
术语“饮料”指液体饮料,其可以是水、调味水、软饮料、酒精饮料、保健饮料或浓缩饮料如基于日用品(牛奶)或果汁的饮料。
“可药用赋形剂或载体”为不会影响活性成分的药理学活性或降低可以给药的受试者的身体功能、但有助于制造剂型或给药所述组合物的任何物质。可药用赋形剂的实例包括,但不限于麦芽糖糊精、磷酸钙和熔融石英。可药用赋形剂可还包括香料,以及各种添加剂比如其它的维生素和矿物质、所有溶剂、分散介质、包衣、等渗剂和吸收延迟剂、甜味剂等、无毒辅助物质比如润湿剂或乳化剂、pH缓冲剂等,比如乙酸钠、脱水山梨醇单月桂酸酯、油酸三乙醇胺酯和惰性成分比如滑石粉和硬脂酸镁,其为在片剂、胶囊及其它剂型的制备中的标准赋形剂。
如本文使用的术语″受试者″或″患者″是本领域熟知的,在本文中可互换地使用,指哺乳动物,包括狗、猫、大鼠、小鼠、猴、母牛、马、山羊、绵羊、猪、骆驼,最优选人类。在某些实施方案中,受试者为需要治疗的受试者或患有疾病或病症的受试者。然而,在其它的实施方案中,受试者可以为正常受试者。该术语不代表特定年龄或性别。因此,成年人和新生儿受试者,无论是男性或女性,都被涵盖。
术语“有效量”指获得生理效应所必需的量。可以通过应用剂量或反复应用获得所述生理效应。当然,给药剂量可以变化,取决于已知因素比如具体组合物的生理特征;受试者的年龄、健康和体重;症状的性质和程度;同时治疗的种类;治疗频率和期望的效果,且可以由本领域技术人员调节。
本申请人研究了特定植物和一些氨基酸,及其在酒精解毒方面的潜在应用。令人惊奇地,据发现给药根据本发明的制剂,在其它未预期的生物学活性中,意想不到地显著地降低了体内血液酒精量。
根据本发明制剂的协同作用似乎独立于任何其它的药理作用(参见实施例)。
本发明提供一种制剂,其包括包含由瓜氨酸和鸟氨酸盐酸盐和/或其衍生物组成的组合物(a),和包含人参或人参提取物、银杏叶提取物和水飞蓟宾提取物的混合物的组合物(b),任选地与合适的赋形剂的组合。
根据本发明,预期涵盖瓜氨酸和/或鸟氨酸盐酸盐“衍生物”的任何结构及其功能性衍生物。其衍生物可以是例如所述氨基酸的前体以及其产物(也定义为降解产物)。
“氨基酸前体”为来源于代谢途径比如糖酵解、TCA循环(三羧酸循环)或戊糖磷酸途径的代谢物。更特别地,这些前体包括α-酮戊二酸、3-磷酸甘油酸、草酰乙酸盐、丙酮酸盐、磷酸烯醇丙酮酸和赤藓糖4-磷酸盐、核糖-5-磷酸盐和导致这些代谢性前体的途径的任何其它上游或下游分子。
“氨基酸的降解产物”为可以进行初始降解以通过转氨作用或氧化作用除去氨基的氨基酸。铵离子再生且再利用形成另外的氨基酸,或者被消除。除去胺基之后得到的碳骨架也可以再生以合成相应氨基酸或作为前体用于合成糖类(在氨基酸糖形的情况下)或转变为乙酰辅酶A用于脂肪酸合成(即,生酮的脂肪酸)。
术语瓜氨酸和/或鸟氨酸盐酸盐的衍生物的定义还涵盖其可药用盐。根据本发明,可药用盐是由酸性无机或有机化合物、或碱性无机或有机化合物生成的。如本文使用的短语″可药用盐″指保留具体化合物的游离酸和碱的生物有效性的盐,并且其不是生物学或其它方式不需要的。根据本发明的氨基酸的可药用盐为与可药用酸的酸加成盐。
期望的盐可以通过本领域已知的任何合适的方法制备,包括用无机酸或有机酸处理游离碱,所述无机酸比如盐酸、氢溴酸、硫酸、硝酸、磷酸等,所述有机酸比如甲酸、乙酸、马来酸、琥珀酸、扁桃酸、马来酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸;吡喃糖酸(pyranosidyl acid),比如葡糖醛酸或半乳糖醛酸;α-羟酸,比如柠檬酸或酒石酸;氨基酸,比如天门冬氨酸或谷氨酸;芳香酸,比如苯甲酸或肉桂酸;磺酸,比如甲磺酸、对甲苯磺酸或乙磺酸;等。
在本发明中,优选的铵盐衍生自盐酸、氢溴酸、甲磺酸、醋酸、丙酸、苯甲酸、柠檬酸、酒石酸、苹果酸、马来酸、富马酸、乳酸、硝酸和磷酸或琥珀酸。
通常,所述盐是在合适的溶剂或不同溶剂组合中,由游离碱与化学当量的或过量的期望形成盐的无机酸或有机酸反应制备的。例如,可以将游离碱溶于合适酸的混合水溶液中,通过标准技术例如蒸发溶液回收盐。另外,将游离碱溶于有机溶剂比如低级链烷醇、包含2-10个碳原子的对称或不对称醚、烷基酯或其混合物等之中,然后用合适的酸处理,形成相应盐。通过标准回收技术例如从混合物中过滤期望的盐来回收盐,或者可以通过加入其中盐不溶的溶剂中将其沉淀出,然后回收。
用于进行各种反应的合适的无机溶剂和有机溶剂的实例包括不会不利地影响反应物或最终产物的任何无机或有机溶剂,包括卤化溶剂,比如二氯甲烷、氯仿、醚溶剂比如二乙醚、及其它溶剂比如四氢呋喃、二噁烷、二甘醇二甲醚、环辛烷、苯或甲苯、庚烷、环己烷、脂肪族以及脂环族和芳香族烃溶剂、水、酸化水溶液、混合有机和无机溶液、乙酸乙酯、乙酸丙酯及其混合物。
本发明还涵盖由酸性前药比如磷酸盐和碱性无机化合物或有机化合物形成的盐。包含在盐中的优选的无机阳离子为锂、钠、钾、铷、铵、钙、镁、锌和锰。磷酸盐的制备描述在例如G.R.Pettit等人,Anti-Cancer Drug Design16(2001)185-193中。
常用盐还包括由酸性前药和有机胺形成的那些,包括,但不限于咪唑和吗啉。也可以使用碱性氨基酸盐。
根据本发明优选的盐为例如瓜氨酸苹果酸盐,其为氨基酸瓜氨酸和有机盐苹果酸盐组合:L-瓜氨酸DL-苹果酸盐。
以及D-瓜氨酸(1),也称为:(R)-2-氨基-5-脲基戊酸,DL-瓜氨酸(1),也称为:(±)-2-氨基-5-脲基戊酸,DL-2-氨基-5-脲基缬草酸,L-瓜氨酸(3)L-瓜氨酸7-酰氨基-4-甲基香豆素氢溴酸盐(1),也称为:L-瓜氨酸4-甲基-7-香豆素基酰胺氢溴酸盐,L-瓜氨酸-4,4,5,5-d4(1);N-2,4-DNP-DL-瓜氨酸(1);硫代-L-瓜氨酸(2)或L-瓜氨酸一盐酸盐。还涉及鸟氨酸的药用盐,比如鸟氨酸α-酮异己酸盐,鸟氨酸α-酮戊二酸盐(OαKG)、鸟氨酸盐酸盐。
根据本发明,术语“瓜氨酸和/或鸟氨酸盐酸盐衍生物”特别地指天然存在的α-氨基酸,但是也包括其同系物、异构体、类似物,所有这些术语都属于如上所述的衍生物定义下。对映异构体可以是上述异构体的实例。类似物可以为例如具有保护基的氨基酸。
而且,因为具有天然肽(L型中)的固有问题是会被天然蛋白酶类降解,可以将本发明的氨基酸制备成包括其D-形式和/或“逆反转(retro-inverso)异构体”。
由于防止了被天然蛋白酶类降解,当与包含类似物的非逆反转物相比时,预测包含氨基酸的逆反转物具有较高的生物活性。而且,已经表明它们显示出增加的稳定性和降低的免疫原性[Sela M.and Zisman E.,(1997)Differentroles of D-amino acids in immune phenomena-FASEB J.11,449]。
逆反转氨基酸是如例如在Sela和Zisman(1997)中描述的制备的。
衍生物的定义还涵盖包括在体内火体外化学衍化例如乙酰化或羧化的″瓜氨酸和/或鸟氨酸盐酸盐″的修饰物。还包括糖基化的修饰物,例如通过在其合成和加工期间或在进一步处理步骤(例如哺乳动物糖基化或脱糖基化酶)中改变氨基酸的糖基化方式制备的那些。还包括具有磷酸化氨基酸残基例如磷酸酪氨酸、磷酸丝氨酸或磷酸苏氨酸的序列。
在根据本发明的制剂中,通常不需要加入载体或可药用载体或合适的赋形剂。然而,可以任选地加入合适的赋形剂。
本发明的合适的赋形剂的实例包括,但不限于防粘剂、粘合剂(例如粗晶纤维素、黄蓍树胶或明胶)、包衣、崩解剂、填充剂、稀释剂、软化剂、乳化剂、调味剂、着色剂、助剂、润滑剂、功能剂(例如营养品)、粘度调节剂、填充剂、助流剂(例如胶态二氧化硅)、表面活性剂、渗透剂、稀释剂或任何其它非活性成分、或其组合。
例如,本发明的制剂可以包括选自下述的赋形剂物质:碳酸钙、着色剂、增白剂、防腐剂和调味剂、三醋精、硬脂酸镁、氢化植物油(sterotes)、天然或人工调味剂、精油、植物提取物、水果香精、明胶、或其组合。
任选地,本发明的制剂可以包括其它人工或天然甜味剂、填充型甜味剂、或其组合。填充型甜味剂包括产热和不产热化合物。填充型甜味剂的非限制性实例包括蔗糖、葡萄糖、麦芽糖、糊精、无水转化糖、果糖、高果糖玉米糖浆、左旋糖、半乳糖、淀粉糖浆干粉、塔格糖、多元醇(例如山梨醇、甘露醇、木糖醇、拉克替醇、赤藓(糖)醇和麦芽糖醇)、氢化淀粉水解产物、异麦芽糖醇、海藻糖及其组合。
在根据本发明的制剂中的活性物质,比如氨基酸或植物提取物的浓度可以在宽范围内变化。有利地是一种活性物质的重量为制剂中所有活性物质重量的1%-90%。
优选地,包含氨基酸的组合物(a)具有瓜氨酸和鸟氨酸盐酸盐和/或其衍生物的重量比分别为0.1%-99%:99%-0.1%。
分别地,组合物(b)具有的人参或人参提取物、银杏叶浸出物和水飞蓟宾提取物的重量比优选地分别为0.01%-99%、0.01%-99%和0.01%-99%。
在本发明的一个特别的实施方案中,包含氨基酸的组合物(a)进一步包括选自精氨酸、鸟氨酸、苏氨酸、色氨酸或5-羟色氨酸和/或其衍生物(如上定义的)的另外的氨基酸。
优选地,所述附加氨基酸和组合物(a)的重量比分别为0.0001%-50%:99.9999%-50%,所述组合物(a)包含由瓜氨酸和鸟氨酸盐酸盐和/或其衍生物组成的氨基酸。
在本发明的一个更特别的实施方案中,组合物(b)进一步包含选自枸杞子的提取物和茶多酚的另外的植物提取物。
在后者的实施方案中,本发明的制剂的重量比优选地包括:
0.001%-99%的人参或人参提取物的混合物,,
0.001%-99%的银杏叶提取物,
0.001%-99%的水飞蓟宾提取物,
0.0001%-70%的枸杞子提取物,
和0.0001%-60%的茶多酚。
根据本发明的制剂可以为固体制剂比如胶囊或片剂的形式,或者为液体或油溶液的形式。在本发明中描述的制品的剂型可以通过保健品或药理学领域中任何已知的方法来制备。
可以采用本领域技术人员熟知的任何方法,即,将由氨基酸和植物提取物制备的组合物制备成固体制剂,比如胶囊和片剂,或液体制剂,比如在采用或者不采用合适的载体系统施用的口服液体和油溶液。
优选地,每个制备的胶囊或片剂可以包含每剂量单位:
80mg-816mg的瓜氨酸或等同量的其衍生物,
50mg-512mg的鸟氨酸或等同量的其盐或衍生物,
0.0001mg-430mg的精氨酸或等同量的其衍生物,
0.0001mg-310mg的色氨酸或等同量的其衍生物,
0.0001mg-450mg的5-羟色氨酸或等同量的其衍生物,
0001mg-500mg的苏氨酸或等同量的其衍生物,
1mg-500mg的人参提取物、银杏叶提取物、水飞蓟宾提取物或枸杞子提取物,和
0.0001mg-250mg的茶多酚。
就口服给药人类而言,本发明的推荐剂量可以例如每剂量单位分别包含250mg、500mg、1000mg、1500mg或2000mg的制剂,所述制剂可以每日服用两次或三次,且可以根据使用者的年龄和体重调节剂量。
在药物的情况下,合适的赋形剂或载体系统也可以为可药用赋形剂。
合适的载体系统包括助流剂,比如微粉硅胶和玉米淀粉,其可以增加压缩性,且可以防止粘结。例如,羟丙基纤维素、甲基纤维素、甲基纤维素、交联羧甲纤维素钠、各种淀粉衍生物、二氧化硅和具有崩解促进功能的任何其它崩解剂比如tylose(一种纤维素的商品名)、交联羧甲基纤维素钠、各种淀粉衍生物;
另外,合适的载体系统也可以包括防潮剂比如山萮酸甘油酯,其有助于增加抗潮性能力。
而且,合适的载体系统也可以包括具有润滑功能的润滑剂,比如硬脂酸镁、法国白等。
优选地,合适的载体选自羟丙基纤维素、甲基纤维素、甲基纤维素、交联羧甲纤维素钠、各种淀粉衍生物、二氧化硅、硬脂酸镁、法国白、山萮酸甘油酯和防潮剂。
本发明进一步提供包含本发明的制剂的食品制品、饮食或食品补充剂、营养制品、饮料以及药物。如上所述,所述药物可以进一步包括可药用赋形剂。
优选地,本发明的药物、营养制品或食品补充剂的给药剂量为0.1mg/kg/天-1g/kg/日。
根据本发明的制剂可以用于:
-防护化学肝损伤,
-增强低氧耐受性,
-加快清除体内酒精量,和
-减少缺氧环境和增强缺氧环境中的生存力。
特别地,本发明的药物可用于治疗或预防酒精中毒、以及化学肝损伤、低氧耐受性、体内酒精量和减少缺氧环境和增强缺氧环境中的生存力。
本发明还提供一种治疗或预防酒精中毒、以及化学肝损伤、低氧耐受性、体内酒精量以及减少缺氧环境和增强缺氧环境中的生存力的方法,其包括向需要其的受试者给药有效量的本发明的制剂或药物。需要其的受试者为哺乳动物,优选人类。
所述制品或药物是口服、肠胃外或局部给药的。
如果设计用于口服给药,则本发明的药物可以为形式例如片剂、囊片剂、丸剂、硬胶囊或软胶囊、锭剂、扁囊剂、可分散粉末、颗粒剂、混悬剂、酏剂、分散体、液体或合理地适合于这样的给药的任何其它形式。如果设计用于肠胃外给药,其可以为形式例如静脉内、肌内或皮下注射的溶液。
根据本发明的局部制剂可以为,但不限于霜剂、贴剂、凝胶、软膏剂、洗剂、酊剂、喷雾剂、摩丝、清洁组合物或泡沫。本发明的局部制剂也可以为在溶剂或脂肪物质中的混悬剂或分散体形式,或者为乳剂或微乳剂、PET-乳剂、复合型乳剂、皮克林乳剂(bickering emulsions)、水凝胶、含酒精凝胶、脂凝胶、单相或多相溶液或多孔分散液及其它常见组合物,其还可以由笔提供、作为面膜或作为喷雾剂提供。所述乳剂也可以包含阴离子、非离子、阳离子或两性表面活性剂。
令人惊奇地,已经观察到本发明的制剂在治疗或预防头痛或偏头痛中也有效。
患有头痛的人可经历不同头部区域的疼痛,所述区域包括遍布头皮的神经网状结构和脸、口和咽喉的一些神经。头部肌肉和沿着脑表面和脑底存在的血管也对疼痛敏感,因为它们包含敏感神经纤维。头颅的骨骼和脑组织本身不会受损,因为它们没有疼痛敏感的神经纤维。这些疼痛敏感的神经末端,称为伤害感受器,可能受到应力、肌紧张、膨胀血管及其它头痛触发器的刺激.血管性头痛(比如,例如偏头痛)被认为涉及脑血管或血管系统的功能异常;肌肉收缩性头痛似乎涉及面部和颈部肌肉的变紧或绷紧;而牵引性头痛和炎症性头痛是其它疾病(从脑肿瘤到发作或窦感染)的症状。某些类型的头痛是更严重疾病的信号:突发、剧烈头痛;与惊厥有关的头痛;伴有意识错乱或意识丧失的头痛;头部吹风后的头痛;与眼睛或耳朵疼痛相关的头痛;以前没有头痛的人的持续性头痛;儿童的复发性头痛;与发烧相关的头痛;影响正常生活的头痛。
头痛诊断为血管性头痛、肌肉收缩性(紧张性)头痛、牵引性头痛或炎症性头痛。
最常见类型的血管性头痛是偏头痛。偏头痛是发展中世界的常见神经病学疾病。其影响约10%的人群,比糖尿病、癫痫和哮喘的组合更普遍。偏头痛不仅仅是头痛。其可能是一种使人虚弱的病症,对于患者及其家庭的生活质量具有相当大的影响。发作可以是完全致残性的,迫使患者放弃日常活动至少3天。即使在无症状时期,患者可能生活在下次发作的恐惧中。偏头痛的疼痛通常描述为在一个头部区域的强脉冲性疼痛或搏动性疼痛。其通常伴有对光和声音的极度敏感、恶心和呕吐。偏头痛在女性中的普遍性是在男性中的三倍。一些个体可以预测偏头痛的发病,因为其首先出现“先兆”视力障碍,表现为闪光、锯齿线或暂时性失明。患有偏头痛的人易于被缺少食物或缺乏、暴露于光或激素不规律(只在女性中)触发的复发性发作。焦虑、紧张或紧张之后的弛豫也可以是触发器。许多年来,科学家认为偏头痛与头部血管扩张和收缩有关。现在,研究者认为偏头痛是由控制脑内一些细胞群活性的基因遗传异常引起的。有两种药物治疗偏头痛的方法:预防发作或缓解发作期间的症状。许多患有偏头痛的人采用两种方法:服用最初开发用于癫痫和抑郁的药物以预防未来的发作,和当其发生时用具有止痛和修复功能的称为曲普坦类(triptans)的药物治疗发作。
在偏头痛之后,最常见类型的血管性头痛是发烧产生的毒性头痛。肺炎、麻疹、腮腺炎以及扁桃体炎属于可引起严重的毒性血管性头痛的疾病。
毒性头痛也可由体内存在的外来化学品引起。
其它类型的血管性头痛引起包括导致剧烈疼痛反复发作的“丛集性头痛”和由血压升高引起的头痛。丛集性头痛,因为其在数周或数月内在白天或夜间大致相同的时间反复丛集性发生而命名,以一只眼周围轻微的疼痛开始,最终蔓延到那侧的面部。疼痛迅速加剧,例如迫使受害者在地板上踱步或在椅子内摇摆。其它症状包括鼻塞和流鼻涕以及红和流泪的眼睛眼睑下垂。丛集性头痛持续30-45分钟,但在发作结束时人的减轻感觉通常伴随他们等待再发生的恐惧。丛集性头痛可神秘地消失数月或数年。许多人在春季和秋季期间集中发作一阵。他们最糟糕的是,慢性丛集性头痛可连续持续好几年。丛集性发作可在任何年龄发生,但通常在20-40的年龄开始。与偏头痛不同,丛集性头痛在男性中更常见,并且不具有家族性。自相矛盾的是,使动脉收缩的尼古丁和扩张动脉的乙醇,两者都能触发丛集性头痛。这些物质和丛集性发作之间的确切关系未知。
在本发明的一个实施方案中,还没有关于皮层传播抑制(CSD)的抑制的报道。
因此,本发明涉及根据本发明的制剂用于预防、减缓或/和治疗头痛,特别是慢性头痛比如偏头痛的用途。进一步,本发明涉及根据本发明的制剂用于预防、减缓或/和治疗各种类型的与CSD有关或/和由其引起的疼痛的疾病,比如但不限于发作或心血管外科手术期间的脑缺血,例如外伤性脑损伤、蛛网膜下腔出血或暂时性完全性遣忘症。优选的,但不限于本发明的制剂用于预防、减缓或/和治疗与CSD有关的或/和由其引起的慢性头痛,比如偏头痛或中枢和外周性来源的其它形式慢性头痛,比如但不限于例如丛集性头痛、紧张型头痛或与过度使用药物有关的继发性头痛、颅神经痛、脑外伤和血管或代谢病症。特别优选的是治疗急性偏头痛。
本领域技术人员应当理解本文描述的本发明易于进行与特别地描述的那些不同的变化和修饰。应当理解在没有背离其精神或主要特征的情况下,本发明包括所有这样的变化和修饰。本发明还包括单独的说明书中提及或指出的所有步骤、特征、组合物和化合物或其组合,以及所述步骤或特征的任两种或多种的任何或所有组合。因此,本发明被被认为在阐述而非限制的所有方面中,由附加权利要求书表示本发明的范围,在等同含义和范围内的所有变化都意味着被本发明所涵盖。
在整个说明书引用了多篇参考文献,将每篇的全部内容都并入本文作为参考。
通过参考下述实施例可以更充分地理解前述说明。然而,这些实施例是实施本发明的方法的示例,并不意味着限制本发明的范围。
实施例
在下述实施例中,可能根据下述方法制备人参提取物、银杏叶提取物、枸杞子提取物和水飞蓟宾提取物。
人参提取物:将红参捣碎,加入红参八倍量的70%乙醇,进行回流提取两次,每次提取持续三小时,合并提取溶液,并在浓缩提取溶液之后,进行喷雾干燥。得到黄白色粉末;在通过紫外分光光度法测定之后,总人参人参皂苷含量不能低于80%。
银杏叶提取物:根据中国药典(2005版)中规定的制备方法制备银杏叶提取物,并且其符合中国药典质量标准(2005版)。
枸杞子提取物:在用水加热之后,提取枸杞子,然后浓缩,并用乙醇沉积,得到沉积物,通过去油、去蛋白、脱色和干燥获得枸杞子提取物。提取率为1∶10、1∶15、1∶20或1∶30。
用乙酸乙酯培养水飞蓟的种皮,进行超声提取3小时,之后移除提取溶液,并重复该步骤3次。将冷凝物用乙醇结晶两次,之后用丙酮-石油醚(90∶10)重结晶,获得浓度为80-90%的水飞蓟宾。
实施例1
提供采用不同制剂的小鼠急性脑缺血缺氧存活时间。
剂量:800mg/kg/日/组。通过重蒸馏水制备试验样品,并连续七天,经口灌服到胃中。
试验方法:在最后一次胃灌服之后一小时,分别处死小鼠,用秒计数器记录从处死小鼠到其停止用口喘息的时间。
表1:在小鼠急性脑缺血诱导的缺氧之后,不同组合物制剂对存活时间的影响。
实施例2
分别用80目筛过筛原料、增量剂和辅助材料,之后进行混合物制备。根据配方比例,称重原料比如瓜氨酸、鸟氨酸盐酸盐、人参提取物、银杏叶提取物和枣(ziziphus jujube)的提取物和辅助材料比如山萮酸甘油酯和一半配方量的羟基丙基纤维素,混合10-15分钟,加入80%的乙醇,以制备软料;将软料制备成能穿过16目筛的颗粒;在60-65度的温度下干燥该颗粒;收集颗粒,并装入助流剂微粉硅胶、润滑剂硬脂酸镁和其余崩解剂羟基丙基纤维素,然后均匀地混合该混合物,压制成片,并包衣。
包衣材料采用Shanghai Lekang Coating Technology Co.,Ltd.提供的包衣粉末85G60997。制备方法采用下述步骤:将1000ml的去离子水加入到纯净的开口烧杯中,启动搅拌装置,保证转速为100-300rpm。在恒定的搅拌速度条件下,在5分钟内,将180g的包衣材料慢慢全部加入。在加入之后,保持最初搅拌速度,在再搅拌45分钟之后,获得需要的包衣液体。
每片重600mg,且包含272mg的瓜氨酸、128mg的鸟氨酸盐酸盐、人参提取物、银杏叶提取物、水飞蓟宾提取物等(参见表2)。
表2
实施例3
进行小鼠的平衡失调试验,将在3分钟内没有从转棒仪上落下的小鼠随意分成对照组和试验组。对于试验组,经胃灌服给药1200mg/kg的本发明组合物,而对于对照组,经胃灌服给药1200mg/kg的生理盐水。在15分钟之后,经胃灌服向对照组和试验组的小鼠灌服56%的中国白酒,胃灌服剂量为8ml/kg。在给药酒精10分钟、30分钟、90分钟和120分钟之后,将对照组和试验组的小鼠分别以15rpm的速度置于转棒型疲劳仪器,每只小鼠一个仪器,记录在三分钟内没有从转竿落下的小鼠的数量。
结论:观察到两组之间的显著性差异,在摄入组合物之后没有从转竿落下的小鼠的数量令人惊奇地高于对照组的。
表3
实施例4
进行小鼠自发性活动试验。将小鼠随意地分成给药组和模型组。将800mg/kg的组合物和9.0g/l的氯化钠注射液液体分别灌服到小鼠胃内。在15分钟之后,经胃灌服向所有小鼠灌服18ml/kg的56%中国白酒,并在20分钟、90分钟和120分钟之后,将其置于自发性活动仪器中,每只小鼠一个仪器,在适应一分钟之后,将在5分钟之内的活动时间记录为自发性活动指数。
结论:两组具有显著性差异,给药组中给药所述组合物的小鼠的自发性活动令人惊奇地高于模型组的。
表4
实施例5
进行小鼠抗醉酒和醉酒治疗试验。抗醉酒试验:二十只小鼠(雌雄各半)进料三天,分成给药组和模型组,每组十只小鼠。各组小鼠禁止饮食和饮水六小时,对于给药组,经胃灌服给药800mg/kg的组合物,对于模型组,经口灌服同样数量的9.0g/l的氯化钠注射液。在15分钟之后,经胃灌服给两组中的所有小鼠灌服18ml/kg的56%中国白酒,记录小鼠从翻正反射丧失到翻正反射恢复所需时间。
醉酒治疗试验:小鼠数量、分组合试验方法与上述试验相同,然而,交换药物灌服时间和白酒灌服时间,记录小鼠从翻正反射丧失到翻正反射恢复所需要的时间。
结论:两组具有显著性差异,给药组令人惊奇地优于模型组。
表5
实施例6
测定小鼠的全血酒精浓度。将二十只小鼠分成模型组和给药组,每组十只小鼠。首先对模型组的小鼠进行胃灌服9.0g/l的氯化钠注射液,体积与处理组相同;给药组小鼠灌服1200mg/kg的所述组合物。在60分钟之后,两组小鼠全部灌服16ml/kg的56%中国白酒。向每个5ml的顶空小瓶中加入0.1ml的肝素钠,在灌服白酒120分钟之后,处死两组小鼠,采血,精确地采集0.6ml的血液,用液体转移枪转移到顶空小瓶内,加入5μl的正丁醇作为内标准,用加盖装置将血液快速密封,均匀振药,并在80度的恒温水浴中气化20分钟,用1ml的玻璃注射器抽取顶空小瓶中的上层气体,装入气相色谱仪以检测酒精含量。
气相色谱仪的条件:RTX-5色谱柱,膜厚度0.25μm,柱长30m,内径0.25nm,柱温40℃,进样温度140℃,检测器温度200℃,载气N2,柱流速2ml/分钟,分流比1∶9.0,H2压力50kPa,气压50kPa。
结论:两组具有显著性差异,给药组中全血的平均酒精含量令人惊奇地低于模型组的。
组 | 动物数量 | 全血中平均酒精含量(g/L) |
模型组 | 10 | 0.543±0.088 |
给药组 | 10 | 0.133±0.024 |
表6
实施例7:
肝和胃ADH(醇脱氢酶)测定
将二十只小鼠分成处理组和模型组,每组十只小鼠。各组小鼠禁止饮食和饮水16小时。处理组的小鼠灌服800mg/kg的所述组合物,对照组的小鼠灌服同样数量的9.0g/l的氯化钠注射液。在15分钟之后,给两组的小鼠的胃灌服16ml/kg的56%中国白酒。在120分钟之后,取出小鼠的肝胃,根据ADH试剂盒和考马斯亮蓝蛋白质试剂盒的使用手册制备相关试剂,用千分之一精确度的天平精确地称重小鼠肝和胃的质量,根据质量比容1∶10加入9.0g/l的氯化钠注射液,经由玻璃匀浆器制备成100g/l的组织匀浆,并以2500r/分钟的速度离心10分钟,用微量添加进样器吸取上清液。将上清液分成两份,一份按照1∶9的比例用9.0g/l的氯化钠注射液稀释到组织匀浆中,用7520型紫外分光光度计测定上清液中ADH活性(每mg(单位)匀浆液蛋白中的单位数量);另一份用于测定肝和胃中的蛋白质含量。
结论:两组具有显著性差异,给药组中ADH活性惊奇地低于模型组的。
表7
实施例8:
人体酒精浓度试验-吹气法
男性组有十名男性,年龄为20-29岁;女性组有十名女性,年龄20-29岁;按照未服用所述组合物、饮酒之前15分钟服用所述组合物和饮酒之后立即服用所述组合物,进行三次酒精浓度试验,服用的组合物剂量为每人每次1200mg。每人每次服用50ml的56%中国白酒,在饮酒后15分钟、30分钟、45分钟、60分钟、90分钟和120分钟用酒精浓度测试仪器测定每个人呼出的气体。
结论:服用所述组合物之后人的酒精浓度令人惊奇地低于未服用所述组合物的人的,男性组和女性组之间的差异不大,饮酒之前给药的效果比饮酒之后给药的效果好。
表8:男性组
表9:女性组
实施例9:
采用本发明的组合物的动物正常压力缺氧耐受性功能增强试验
实验动物:选择一百四十四只ICR种二级健康雌性小鼠,根据体重随意分成四组,每组12只小鼠。
剂量设计:设计三个剂量组,400mg/kg/日(相当于对于成年人每千克体重每天推荐摄入量的十倍)、800mg/kg/日和1200mg/kg/日,同时设置正常对照组。用重蒸馏水制备试验样品,每天将20ml/kg体重的剂量灌服到每组小鼠胃内,连续灌服30天。正常对照组,将相同量的重蒸馏水灌服到小鼠胃内。
实验方法:在最后一次胃灌服之后1小时,将小鼠分别置于250ml(体积误差±1ml)装有5g碱石灰的磨口玻璃瓶中,应用凡士林密封瓶口,立即进行计时,以获得呼吸终止作为指数,观察和记录小鼠在正常压力下的缺氧耐受性和存活时间,当差异均匀时,用SPSS统计软件进行原始数据的方差齐性,取大量实验组之间的平均数和对照组进行成对比较统计学。
实验结果:将试验前后每组动物的体重和存活时间显示在表10中。
可以看到在试验前后动物的体重没有任何差异(P大于0.05)。与对照组相比,剂量组的动物缺氧耐受性存活时间高于对照组,由此具有显著性差异(P低于0.01)。
表10:所述组合物对小鼠正常压力缺氧耐受性存活时间的影响(X±S n=12)
实施例10
采用本发明组合物的动物亚硝酸钠中毒生存增强试验。
剂量设计:设计三个剂量组,400mg/kg/日(相当于对于成年人每千克体重每天推荐摄入量的十倍)、800mg/kg/日和1200mg/kg/日,同时设置正常对照组。用重蒸馏水制备试验样品,每天将20ml/kg体重的剂量灌服到每组小鼠胃内,连续灌服30天。正常对照组,将相同量的重蒸馏水灌服到小鼠胃内。
实验方法:在最后一次灌服之后一小时,按照220mg/kg体重的剂量,别将亚硝酸钠(注射量0.1ml/10g(体重))注入每组小鼠腹腔,立即进行计时,且以获得呼吸终止作为指数,观察和记录小鼠的存活时间。
试验结果:将试验前后每组动物的体重和存活时间显示在表11中。在试验前后,两组动物的体重没有任何差异(P>0.05),与对照组相比,每个剂量组的小鼠存活时间延长了,但是没有显著性差异(P>0.05)。
表12:本发明的组合物对于小鼠亚硝酸钠中毒存活时间的影响(X±S n=12)
实施例11:
采用所述组合物的动物急性脑缺血缺氧存活时间延长试验
剂量设计:设计三个剂量组,400mg/kg/日(相当于对于成年人每千克体重每天推荐摄入量的十倍)、800mg/kg/日和1200mg/kg/日,同时设置正常对照组。用重蒸馏水制备试验样品,每天将20ml/kg体重的剂量灌服到每组小鼠胃内,连续灌服30天。正常对照组,将相同量的重蒸馏水灌服到小鼠胃内。
实验方法:在最后一次胃灌服之后一小时,分别处死每组小鼠,用秒计数器记录从处死小鼠到其停止用口喘息的时间。
将实验前后动物的体重和从处死小鼠到其停止用口喘息的时间显示在表12中。在试验前后,两组的动物体重没有任何差异(P大于0.05)。与其它剂量组相比,对照组的从处死小鼠到其停止用口喘息的时间增加,中等剂量组和高剂量组之间动物停止喘息的时间具有非常令人惊奇的差异(P低于0.01)。
表12:所述组合物对于小鼠急性脑缺血缺氧存活时间的影响(X±S n=12)
实施例12:
采用所述组合物的酒精性肝损伤辅助保护功能试验
所述组合物的人体摄入量为每人每天2400mg。
实验动物:选择五十只体重18-22g的ICR种健康二级雌性小鼠,根据体重随意分成五组,每组10只小鼠。
剂量设计:设计三个样品剂量组,200mg/kg/日、400mg/kg/日(相当于对于成年人每千克体重每天推荐摄入量的十倍)和1200mg/kg/日,同时设计空白对照组和模型对照组。用重蒸馏水制备样品剂量组的试验物质,用重蒸馏水给药空白对照组和模型对照组中的试验物质,每天分别将20ml/kg体重的剂量灌服到每组小鼠的胃内,连续灌服30天。在最后一次给药试验物质之后两小时,分别将10ml/kg体重的65%酒精灌服到模型对照组和样品剂量组的小鼠的胃内,将重蒸馏水给药到空白对照组的小鼠内,在禁食六小时之后处死动物,进行各种生化指数测定和肝病理组织学检验。
试验方法
生化指数的测定:取0.2g的肝组织,制成肝匀浆。将肝匀浆以3000rpm的速度离心十分钟,然后除去上清液。用生物化学仪器测定所匀浆的上清液中甘油三酯含量,并根据试剂盒中提供的方法人工测定所述匀浆的上清液中的丙二醛、谷胱甘肽和蛋白水平。
肝病理组织学检验:取左侧肝叶,用4%的甲醛固定,采用石蜡和冰,将肝切成片,用苏木精-伊红和苏丹III染色,用显微镜检验,并评级。
数据处理:小鼠的体重、甘油三酯、丙二醛、谷胱甘肽及其它数据全部为测量数据,采用SPSS统计软件对原始资料进行正态检验和方差齐性检验,将丙二醛和甘油三酯数据进行对数转化,以确保其数据符合方差齐性的要求,然后,用单因素方差分析(ANOVA)进行溶剂分析,取许多实验组的平均数和对照组采用成对比较统计学进行数据的统计处理(P大于0.05)。采用秩和检验统计学处理病理组织学检验结果。
试验结果:将所述组合物对动物体重的影响显示在表14.1中。在所有组中,试验前后小鼠的体重没有任何实质性差异(P大于0.05)。这表明所述组合物对于小鼠的体重增加没有特别地影响。
表14.2显示了所述组合物对于小鼠的肝匀浆中丙二醛(MDA)含量的影响。如该表所显示的,模型对照组中小鼠肝匀浆的MDA含量增加,与空白对照组相比具有显著性差异(P低于0.01),这表明该模型是成功的。在所述组合物中,与模型对照组相比,高剂量组中小鼠的肝匀浆中的MDA降低,且具有重要的差异(P低于0.05),这表明采用本发明的组合物可以降低高剂量组中具有酒精性肝损伤的小鼠的肝匀浆中MDA含量。
表14.3显示了根据本发明的组合物对于小鼠的肝匀浆中谷胱甘肽(GSH)含量降低的影响。实际上,模型对照组中小鼠肝匀浆的GSH含量降低,且与空白对照组相比具有显著性差异(P低于0.01),这表明该模型是成功的。与模型对照组相比,通过采用本发明的组合物提高了所有剂量组中小鼠的肝匀浆中GSH含量,并且差异分别是显著的(P低于0.05、P低于0.01)。这表明本发明的组合物可以增加具有酒精性肝损伤的小鼠的肝组织中GSH含量。
表14.4显示了根据本发明的组合物对于小鼠的肝匀浆中三十二酸甘油酯(YG)含量的影响。
如表14.4所示,模型对照组中小鼠的肝匀浆中甘油三酯含量增加了,且与空白对照组相比具有显著性差异(P低于0.01),这表明该模型是成功的。与模型对照组相比,采用所述组合物降低了高剂量组中小鼠的肝匀浆中的甘油三酯含量,且具有显著性差异(P低于0.01),这表明采用所述组合物可以降低高剂量组中具有酒精性肝损伤的小鼠的肝匀浆中甘油三酯含量。
表14.5显示根据本发明的组合物对小鼠肝组织的病变的影响。在模型对照组中产生了不同程度的小鼠肝细胞脂肪变性,且与空白对照组相比具有显著性差异(P低于0.01),这表明该模型是成功的。与模型对照组相比,采用本发明的组合物降低了所有剂量组中小鼠的肝细胞脂肪变性程度,且具有显著性差异(P低于0.01)。这表明所述组合物可以降低所有剂量组中具有酒精性肝损伤的小鼠的肝细胞脂肪变性程度。
表14.3:所述组合物对小鼠肝匀浆中谷胱甘肽(GSH)含量的影响
表14.5:所述组合物对小鼠肝组织病变的影响
为了总结试验结果,选用采用本发明的组合物为阳性的四个指数肝丙二醛、谷胱甘肽和甘油三酯含量及病理组织学检验。这证实了本发明的组合物对于酒精性肝损伤存在辅助保护功能。
实施例13
还在患有复发性偏头痛的8名志愿者中检验了根据本发明的组合物,如受试者在每日服用所述组合物3个月之后报道的,表明偏头痛发作的频率、强度和持续时间都降低了。
Claims (24)
1.制剂,其包括包含由瓜氨酸和鸟氨酸盐酸盐和/或其衍生物组成的氨基酸组合物(a),和包含人参或人参提取物、银杏叶提取物和水飞蓟宾提取物的混合物的组合物(b),任选地与合适的赋形剂的组合。
2.权利要求1的制剂,其特征在于包含氨基酸的组合物(a)具有的瓜氨酸和鸟氨酸盐酸盐和/或其衍生物的重量比分别为0.1%-99%∶99%-0.1%。
3.权利要求1的制剂,其特征在于组合物(b)具有的人参或人参提取物、银杏叶提取物和水飞蓟宾提取物的重量比分别为0.01%-99%、0.01%-99%和0.01%-99%。
4.权利要求1-3中任一项的制剂,其特征在于包含氨基酸的组合物(a)进一步包含另外的选自精氨酸、鸟氨酸、苏氨酸、色氨酸或5-羟基色氨酸和/或其衍生物的氨基酸。
5.权利要求4的制剂,其特征在于所述添加的氨基酸和包含由瓜氨酸和鸟氨酸盐酸盐和/或其衍生物组成的氨基酸的组合物(a)之间的重量比分别为0.0001%-50%∶99.9999%-50%。
6.权利要求1-5中任一项的制剂,其特征在于组合物(b)进一步包含另外的选自枸杞子提取物和茶多酚的植物提取物。
7.权利要求6的制剂,其特征在于重量比为:人参或人参提取物的混合物为0.001%-99%,银杏叶提取物为0.001%-99%,水飞蓟宾提取物为0.001%-99%,枸杞子提取物为0.0001%-70%,茶多酚分别为0.0001%-60%。
8.权利要求1-7中任一项的制剂,其中所述合适的赋形剂为可药用赋形剂。
9.权利要求8的制剂,其特征在于所述可药用赋形剂选自:羟丙基纤维素、甲基纤维素、甲基纤维素、交联羧甲纤维素钠、各种淀粉衍生物、二氧化硅、硬脂酸镁、法国白、山萮酸甘油酯和防潮剂。
10.食品制剂,其包含根据权利要求1-7中任一项的制剂。
11.食品补充剂,其包含根据权利要求1-7中任一项的制剂。
12.营养制品,其包含根据权利要求1-7中任一项的制剂。
13.饮料,其包含根据权利要求1-7中任一项的制剂。
14.药物,其包含根据权利要求1-9中任一项的制剂。
15.权利要求14的药物或权利要求11的食品补充剂,其特征在于所述药物或食品补充剂的给药剂量为0.1mg/kg/日-1g/kg/日。
16.根据权利要求1-7中任一项的制剂在如下中的用途。
-防护化学肝损伤,
-增强低氧耐受性,
-加快清除体内酒精量,和
-减少缺氧环境和增强缺氧环境中的生存力。
17.根据权利要求1-9中任一项的制剂,用于治疗或预防酒精中毒的方法中。
18.一种治疗或预防酒精中毒、化学肝损伤、低氧耐受性、体内酒精量及减少缺氧环境和增强缺氧环境中的生存力的方法,其包括向需要其的受试者给药有效量的根据权利要求1-9中任一项的制剂或根据权利要求14的药物。
19.权利要求18的方法,其中所述制剂或药物是口服、肠胃外或局部给药的。
20.权利要求18-19中任一项的方法,其中根据权利要求1-9中任一项的制剂或根据权利要求14的药物的给药剂量为0.1mg/kg/日-1g/kg/日。
21.权利要求18-20中任一项的方法,其中需要其的受试者为哺乳动物,优选人类。
22.根据权利要求1-7中任一项的制剂,其为固体制剂比如胶囊或片剂的形式或液体或油溶液的形式。
23.根据权利要求22的制剂,其中所述制备的胶囊或片剂的每剂量单位包含:
80mg-816mg的瓜氨酸或等同量的其衍生物,
50mg-512mg的鸟氨酸或等同量的其盐或衍生物,
0.0001mg-430mg的精氨酸或等同量的其衍生物,
0.0001mg-310mg的色氨酸或等同量的其衍生物,
0.0001mg-450mg的5-羟基色氨酸或等同量的其衍生物,
0001mg-500mg的苏氨酸或等同量的其衍生物,
1mg-500mg的人参提取物、银杏叶提取物、水飞蓟宾提取物或枸杞子提取物,和
0.0001mg-250mg的茶多酚。
24.根据权利要求1-9中任一项的制剂,用于治疗或预防头痛或偏头痛的方法中。
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PCT/IB2010/054885 WO2011051900A1 (en) | 2009-10-28 | 2010-10-28 | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
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CN108175807A (zh) * | 2018-02-22 | 2018-06-19 | 可贝熊(武汉)健康科技股份有限公司 | 一种治疗化学性肝损伤的药片 |
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MX2012004876A (es) | 2012-08-23 |
CN102711780B (zh) | 2014-11-12 |
BR112012009806A2 (pt) | 2020-08-25 |
ES2458353T3 (es) | 2014-05-05 |
CA2778884A1 (en) | 2011-05-05 |
EP2493488A1 (en) | 2012-09-05 |
US20140220162A1 (en) | 2014-08-07 |
US9526753B2 (en) | 2016-12-27 |
PL2493488T3 (pl) | 2014-10-31 |
US20120269909A1 (en) | 2012-10-25 |
WO2011051742A1 (en) | 2011-05-05 |
US9192638B2 (en) | 2015-11-24 |
BR112012009806B1 (pt) | 2021-11-16 |
EP2493488B1 (en) | 2014-01-15 |
JP2013509395A (ja) | 2013-03-14 |
RU2573990C2 (ru) | 2016-01-27 |
AR078812A1 (es) | 2011-12-07 |
RU2012119714A (ru) | 2013-12-10 |
JP6077305B2 (ja) | 2017-02-08 |
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