CN103370062A - 增强关节和/或姿势稳定性的组合物 - Google Patents
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Abstract
本发明涉及一种用于增强关节稳定性和/或姿势稳定性的组合物,其中,所述组合物包含支链氨基酸。本发明还涉及支链氨基酸用于制备预防和/或治疗关节和/或姿势不稳定的食品增补剂或药物的用途。
Description
本发明涉及一种用于增强关节稳定性或姿势稳定性的组合物,其中所述组合物包含支链氨基酸。本发明还涉及支链氨基酸用于制备预防和/或治疗关节和/或姿势不稳定的食品增补剂或药物的用途。2008年在德国八百万人患关节相关性疾病如骨关节炎(OA)、风湿性关节炎(RA)及其它疾病。
360000人已进行了关节置换,其中大多数涉及髋和膝关节(Pressrelease Endoprothetic clinic Ortenau(19.05.2010))。一般关节置换是在受损关节或关节炎关节中缓解疼痛和恢复关节有效活动范围的最后选择。
最初训炼,实施加强和拉伸技术以减少关节痛和增强关节活动范围。然而,如果不能获得明显的疼痛缓解和改善,那么关节置换是改善生命的功能和使人能身体活动的重要考虑。
根据WHO统计目前身体缺乏活动(physical inactivity)是全球死亡率的第四首要风险因素(全球6%的死因)。身体缺乏活动的水平在许多国家呈上升趋势,成为非传染性疾病(NCDs)患病率和全世界人口总体健康的主要因素。(WHO Brochure “GLOBALrecommendations on PHYSICAL ACTIVITY FOR HEALTH”2010)。
显然关节痛和关节僵直限制人们的身体活动。此外所感觉到的稳定性丧失(脆弱)增加了跌倒的恐惧,人就丧失身体活动的信心。
关节稳定性是运动性和身体活动的首要因素。关节稳定性可描述为两个骨头相互之间相对的位移或各自的半脱位并且是可测量的。半脱位是椎骨丧失其与上面的椎骨或下面的椎骨或丧失这两者的正常毗连至低于脱臼程度的病症,这影响神经并干扰精神冲动的传递。
关节稳定性的维系不能认为仅仅是韧带的结果,而应当被认为是骨骼、关节囊、韧带、肌肉、肌腱和感觉感受器及其脊骨和皮层神经投射与连接功能协调一致的协同功能。关节的生物力学排列不齐可促使OA发展。
关节不稳定指不能在没有受伤、移位或离位的情况下抵抗正常范围的冲击和运动。各种肌骨胳、或关节外的结构可能涉及如骨骼、肌腱、韧带、肌肉和软组织。关节内(关节腔内)的不完整性也可能导致关节不稳定。
关节软骨的主要机械功能之一是起低摩擦、载荷表面的作用。这些机械负荷被软骨细胞外基质(ECM)吸收,其中它们随后被消散并被传输到软骨细胞。由于其在关节表面上的独特位置,关节软骨经受一定范围的静态和动态作用力,包括剪切力、压缩和张力。
软骨细胞,是专门释放软骨成分的细胞,能感觉它们接收的机械信号并将其转换为生物化学信号,随后引导和调节合成代谢(基质建设)和分解代谢(基质降解)过程。这些过程包括基质蛋白(II型胶原蛋白和蛋白聚糖)、蛋白酶、蛋白酶抑制剂、转录因子、细胞因子和生长因子的合成。体内平衡受负荷类型、导致组织损伤的高应变率的强烈影响,结果造成降解和基质产生的减少以及细胞凋亡。
关节稳定性的缺乏导致软骨不平衡的机械负荷从而可能增加磨损。骨关节炎的特征是软骨缺失。
OA发展主要原因是
·年龄
·肥胖
·关节损伤或关节过度使用
·职业性紧张:在工作中重复和单调的动作以及
·缺乏活动
缺乏活动导致关节退化。考虑到关节内软骨只能通过扩散供给营养物(由于缺少血管)和这些扩散过程靠关节软骨的压缩或弯曲维持,因而运动的意义是显而易见的。
关节稳定性,尤其是膝关节稳定性一般通过Lachmann试验评价,其中参与者被要求仰卧并且膝关节弯曲大约30°(Torg J,Conrad W,Kalen V.Clinical diagnosis of anterior cruciate ligamentinstability in the athlete.Am J Sports Med4:84-93(1976))。然后检验人稳定股骨并在不限制轴向旋转的情况下对胫骨施加前方压力。在腿承受75%体重负荷并且弯曲30°时测量胫骨相对髌骨的偏转。
如上所述身体活动可用于增强关节稳定性和姿势的不稳定性。另外,为了减少软骨的缺失(特别是在骨关节炎中)可经常使用软骨保护剂,如葡糖胺和硫酸软骨素。尽管一些研究证实了OA的一些有益效果,但其它治疗的可能性也非常需要,尤其是使得增加关节稳定性和姿势的不稳定性。
本发明令人惊奇地发现有规律地摄取至少两种支链氨基酸(至少两个月)会导致关节稳定性和姿势稳定性增强并能因此提高生活质量。因此,本发明涉及一种用于增强关节稳定性和/或姿势稳定性的组合物,其中所述组合物包含至少两种支链氨基酸。
有利地,摄取包括与L-异亮氨酸和L-缬氨酸中的一种支链氨基酸一起的L-亮氨酸,如,例如,L-亮氨酸和L-异亮氨酸或L-亮氨酸和L-缬氨酸。因此,本发明的一个实施方案涉及用于增强关节稳定性和/或姿势不稳定性的组合物,其中该组合物包含L-亮氨酸以及L-异亮氨酸和L-缬氨酸中的至少一种支链氨基酸。
有利地,所述组合物含L-亮氨酸的量为基于所有支链氨基酸总重的约25至约80%重量,优选约35至约75%重量,更优选约45至约70%重量,最优选约64%重量。因此,本发明进一步涉及用于增强关节稳定性或姿势稳定性的组合物,其中L-亮氨酸以基于所有支链氨基酸总重的约25至约80%重量、优选约35至约75%重量、更优选约45至约70%重量、最优选约64%重量的量存在。
本发明进一步优选的实施方案涉及一种用于增强关节稳定性或姿势稳定性的组合物,其中L-亮氨酸以约35至约80%重量的量存在,L-异亮氨酸以约10至约30%重量的量存在且L-缬氨酸以约10至约30%重量的量存在。
本发明特别优选的实施方案涉及用于增强关节稳定性或姿势稳定性的组合物,其中L-亮氨酸、L-异亮氨酸和L-缬氨酸以约2~6:0.5~1.5:0.5~1.5的重量比、优选以3~5:0.75~1.25:0.75~1.25的重量比、更优选以约3.5:约1:约1的重量比存在。
根据本发明的另一优选实施方案,本发明的组合物可含一种或多种另外的活性成分。因此,本发明还涉及一种用于增强关节稳定性或姿势稳定性的组合物,其中所述组合物含一种或多种另外的活性成分。
原则上可存在于组合物中的活性成分,可以是任何药物或任何其它成分,其在摄入人体内之后具有有益的效果,如,例如,维生素、矿物质、痕量元素、粗食、酶类或植物提取物。可存在于组合物中的优选的活性成分,为疼痛缓解物质、软骨保护剂、维生素、植物提取物和/或矿物质。
优选的维生素为维生素D,优选的矿物质为无机或有机钙盐和/或镁盐,其适合于消费,优选为碳酸盐、碳酸氢盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、氯化物、氟化物、柠檬酸盐和/或乳酸盐的形式,优选的软骨保护剂为透明质酸和/或葡糖胺或其衍生物,如软骨素,和/或其盐,如硫酸盐或盐酸盐。
因此,本发明进一步涉及一种用于增强关节稳定性或姿势稳定性的组合物,其中活性成分为维生素,如维生素D,矿物质,如镁或钙盐和/或软骨保护剂,如透明质酸和/或葡糖胺或其衍生物,如软骨素,和/或其盐类,如硫酸盐或盐酸盐。
优选的植物提取物为公知具有抗炎作用的植物提取物,如,例如,齿叶乳香树(Boswellia serrata)或南非钩麻(Harpagophytumprocumbens)的提取物。
原则上该组合物可通过所有适宜的途径施用,包括不限于口服和肠胃外应用途径。不过,优选口服途径。因此,本发明的优选实施方案涉及用于增强关节稳定性或姿势稳定性的组合物,其中所述组合物用于口服。
由于组合物可以各种形式服用,组合物的呈现形式不限于任何特定形式。用于组合物摄取的适宜形式的实例为饮食的方式,如饮食增补剂,食品,如医药或功能食物或饮料,例如以完整的进餐形式,以部分进餐的形式,以食品添加剂的形式或以用于溶解的粉末形式,或药物制剂,例如以片剂、囊剂(sachet)或胶囊的形式。优选本发明的组合物属于食品、饮食增补剂和/或药物制剂的一部分。因此,本发明进一步涉及一种用于增强关节稳定性或姿势稳定性的组合物,其中所述组合物为食品、饮食增补剂或药物制剂的形式。
术语“功能食品”和“医药食品”理解为任何食品,其富含活性成分使得它具有超出补充营养组合物基本功能的促进健康或预防疾病的性质。功能食品可以是加工食品(其为设计成便于消费的商业制造的食品)、以及“普通(normal)”食品。富含本发明组合物的食品理解为功能食品或医药食品,其可用于增强关节稳定性和姿势稳定性。
饮食增补剂和药物制剂可以固体、半固体或液体剂型的形式提供。固体剂型的实例为片剂、糖衣药丸(dragées)、胶囊、颗粒剂、粉末,半固体剂型的实例为霜剂或凝胶剂,液体剂型的实例为溶液或混悬剂。优选固体剂型如片剂、糖衣药丸、胶囊、颗粒剂或粉末。因此,本发明的优选实施方案涉及一种用于增强关节稳定性和姿势不稳定性的组合物,其中所述组合物为固体剂型,优选为片剂、糖衣药丸、胶囊或粉末的形式。
固体口服剂型通常是本领域已知的,它们可,例如,通过常规的混合、制粒、成型(confectioning)、溶解或冻干步骤制备。
例如,口服给药的组合物通过将活性成分与固体载体结合、任选地将所得混合物制粒和将混合物或颗粒加工(如果需要或必要的话在加入适宜的赋形剂之后)以形成片剂或糖衣药丸芯而获得。颗粒本身也可以不经进一步加工而使用。
适宜的生理学可接受的辅助剂为填料,如糖,例如乳糖、甘露醇或山梨醇,纤维素制备物和/或磷酸钙,例如磷酸三钙或磷酸氢钙,以及粘合剂,如使用淀粉糊,例如,玉米、小麦、大米或马铃薯淀粉,明胶,西黄蓍胶,甲基纤维素和/或聚乙烯吡咯烷酮,和(如果需要)崩解剂,如上述的淀粉、以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,如藻酸钠。本发明的一方面本发明的组合物不含乳糖。其它赋形剂可以特别是流动调节剂和润滑剂,例如硅酸,滑石粉,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。
糖衣药丸芯被提供适宜的包衣,尤其使用可含阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛的浓缩的糖溶液、或在适宜的有机溶剂或溶剂混合物中的包衣溶液。可将染料或颜料加入到片剂或糖衣药丸包衣中,例如出于标识的目的或指示活性成分的不同剂量。
粉末通过将组合物的物质粉碎成适宜的精细尺寸并将其与以类似的方式粉碎的生理学可接受的辅助剂(如,例如,可食用的碳水化合物,如,例如,淀粉或甘露醇)混合来制备。
调味剂、防腐剂、分散剂和染料同样可以存在。其它优选的口服给药的固体剂型为胶囊,包括硬胶囊和软胶囊,特别是硬明胶胶囊,由明胶和增塑剂如甘油或山梨醇构成的密封的胶囊。硬明胶胶囊可以包含颗粒形式的本发明组合物,例如与填料(如乳糖)、粘合剂(如淀粉)和/或助流剂(如滑石粉或硬脂酸镁)和(如果需要)稳定剂混合。在软胶囊中本发明的组合物优选溶解或混悬于适宜的液体,如脂肪油、石蜡油或液体聚乙二醇中,同样加入稳定剂是可能的。
在本发明的组合物中可包含常规的添加剂,包括选自下列的任何添加剂:防腐剂,螯合剂,渗透剂,缓冲剂或pH调节剂,泡腾剂,甜味剂,例如人造甜味剂,调味剂,着色剂,掩味剂,酸化剂,乳化剂,稳定剂,增稠剂,助悬剂,分散剂或润湿剂,抗氧化剂,酸化剂,组织形成剂(texturizer),消泡剂等。
除前述的内容之外本发明还提供一种生产组合物例如在上文中定义的营养或药物制剂的方法,步骤包括使其单独的组分进行密切的混合和(如果需要)将所得到的组合物配合成食品或饮料产品,例如即用的饮料,或在单位剂型中,例如将所述组合物填充到硬胶囊中。
有利地本发明的组合物适合于提供每日剂量的支链氨基酸,每日剂量范围为约1000至约5000mg L-亮氨酸、约300至约2000mg L-异亮氨酸和约300至约2000mg L-缬氨酸,优选约2000至约4000mgL-亮氨酸、约600至约1500mg L-异亮氨酸和约600至约1500mg L-缬氨酸,更优选约3200mg L-亮氨酸、约900mg L-异亮氨酸和约900mg L-缬氨酸。
为了提供每日剂量的支链氨基酸,组合物可以一个单剂量的形式施用,如,例如,如本文中定义的一餐或一种剂型形式,如固体剂型如一片、一个胶囊或一个囊剂(sachet),其含适量的颗粒或粉末。作为替代,每日剂量还可通过分配每日剂量到剂型中,如,例如,两个或更多的片剂、胶囊和/或囊剂中。
根据本发明的优选实施方案每日剂量以单一的组合物提供,如,例如,一餐、一片、一个胶囊或囊剂。
根据本发明的优选实施方案,使支链氨基酸的每日剂量适应于服用该组合物的人的体重。关于支链氨基酸L-亮氨酸,表1公开了摄取的典型的量,优选取决于体重使用。
表1:优选的L-亮氨酸的每日剂量
适应于重量的每日剂量的L-亮氨酸优选与其它支链氨基酸以上面确定的重量比组合,结果是各个量的L-亮氨酸与L-异亮氨酸和L-缬氨酸以2~6:0.5~1.5:0.5~1.5的重量比组合,优选以3~5:0.75~1.25:0.75~1.25的重量比组合,更优选以约3.5:约1:约1的重量比组合。
根据本发明的另一优选实施方案,该组合物可用于预防和/或治疗关节不稳定性和/或姿势不稳定性。因此本发明还涉及一种用于预防和/或治疗关节不稳定性和/或姿势不稳定性的组合物,其中此种组合物包含至少两种支链氨基酸。用于预防和/或治疗关节不稳定性和/或姿势不稳定性的组合物可以是之前本文中描述的任何组合物。
另外,本发明还涉及至少两种支链氨基酸用于制备预防和/或治疗关节不稳定性和/或姿势不稳定性的药物的用途。优选用于预防和/或治疗关节不稳定性和/或姿势不稳定性的组合物的所述用途伴随着身体活动。
实施例用于解释本发明而不是受其限制。
实施例
除了另外明确说明之外在下文中所公开的成分的量以毫克(mg)给出。
粉末组合物
制备
1.称量
2.过筛
3.掺混
4.包装
颗粒剂
制备
1.称量
2.过筛
3.掺混
4.制粒(例如流化床制粒,湿法制粒)
5.掺混
6.包装
奶粉(营养组合物)
制备
1.称量
2.过筛
3.掺混
4.包装
关节稳定性的测量
在有规律的摄取BCAA之后通过运用Lachmann试验的进一步发展的方法对膝关节稳定性进行评价。在斯图加特大学(University ofStuttgart)已经开发了用于测量在功能病症下的胫骨位移的具有瞬间和局部高分辨率的设备。测量的基础是通过10g加速计在两个不同作用力的动态作用力应用下测定胫骨相对髌骨的偏转。使腿承担75%的体重(通过秤控制)并弯曲30°(附图1)。
姿势稳定性的测量
姿势稳定性(全部、前后的,和中侧的姿势稳定性)按照Myer等人(Myer G,Brunner H,Meldon P,Peterno M,Ford K,and HewettT Specialised neuromuscular training to improve neuromuscularfunction and biomechanics in a patient with quiescent juvenilerheumatoid arthritis Phys Ther85:791-802(2005))描述的平衡试验进行评价。在此种方法中稳定测量仪平衡-协调系统(例如GK1000IMM Elektronik GmbH)用于在40秒双足站立试验中测量压力中心(COP)的摇摆振幅。人必须用双腿站立在不稳定的平台上,然后可用电子测量恢复平衡的所有动作从而测量姿势稳定性。
研究
在双盲随机的安慰剂对照的临床研究中测试本发明的组合物对关节稳定性的效果。在电流试验中包括48名健康的受试者,年龄在54至72岁之间,BMI在22至30之间(男女比例为1:1)且活动水平低。总共45名受试者完成研究的主要部分。参与者必须适度地锻炼,用允许根据个体体重训练和通过增加重复而增加成绩的设备锻炼每周3次30分钟。在研究期间(3个月)参与者必须每天一次服用如上所述的含支链氨基酸的粉末组合物(verum)或安慰剂,靠近于身体活动的最高水平。在研究开始时(访问1)对身体活动能力的基准值和软骨合成和降解的生物标志物进行评价,并每个月间歇地进行进一步的测量,在研究结束时结束(访问4)。在进行规定的身体工作负荷之前(预先)、之后立刻(之后0h)、和之后三小时(之后3h)进行测量(参见附图2)。
身体的工作负荷通过采用“身体工作负荷模型”操练。在此种身体工作负荷模型中,参与者必须在跑步机(treadmill)上进行偏心的向下25%梯度的步行。受试者另外负荷其体重的10%(以铅加重的夹克的形式)。女性必须以4km/h行走,男子必须以5km/h行走。在访问1中要求参与者根据其个人能力在不超过40分钟的情况下尽可能长时间地行走。在访问4中重复访问1的个体方案。在跑步机之前(预先)和在跑步机之后立刻(0h之后)和在3小时时(之后3h)采用David Back概念评价腿的伸展(David Health Solutions LTD)(WydraG.Zur Problematik von Normen in der BewegungstherapieKrankengymnastik2004)。腿伸展的测量代表一种评价肌肉强度并由此评价强度损失的有效方法(Saris W.et al,PASSCLAIM-Physicalperformance and fitness Eur J Nutr2003)。
评价作为软骨合成和降解生物标志物的CP2和C2C(Bijlsma J etal Osteoarthritis:an update with relevance for clinicalpractice Lancet2011),CP2(两种类型胶原蛋白CP2的C-前肽,同义词CII CP)是反映新胶原蛋白合成的标记物,C2C(两种类型胶原蛋白胶原酶裂解抗体结合位(neoepitop))是反映血样中的胶原蛋白降解的标记物。运用此类生物标志物的基本原理是关节的身体工作负荷导致必须被新胶原蛋白的合成置换的软骨中胶原蛋白的结构片断的释放。身体工作负荷诱导的此种增加的代谢导致软骨降解和合成生物标志物(C2C/CP2)之比降低。因此,工作负荷诱导的降低的C2C/CP2比的下降可理解为关节稳定性的改进。
结果
与安慰剂相比,在关节的身体紧张状态下(在身体工作负荷模型中)verum的摄取导致关节稳定性的额外改进。
身体紧张之后强度下降的结果呈现在附图3中。如该图所示,在verum组中服用verum3个月之后身体紧张强度下降明显比安慰剂组较不显著,其中在两个时间点强度下降几乎相同。在verum组中强度下降不显著表明其强度耐力上的有益提高。在日常活动如爬楼梯和长距离步行中强度耐力的提高是有益的,可促进特别是老年人保持身体活性。身体活动对维持健康的关节是必需的。
身体紧张的软骨降解和合成生物标志物之比的结果呈现在附图4中。如该图所示在verum组中软骨降解和合成生物标志物之比(C2C/CP2)的降低较不显著,如通过在身体紧张之前(预先)的值和在身体紧张之后立刻(0h)的值和在身体紧张之后三小时(3h)的值之间的Δ指示。另外,与安慰剂组不同,在摄取研究药物3个月之后(访问4)verum组显示C2C/CP2比在身体紧张之后零时刻(0h)和三小时(3h)对比开始(访问1)的下降较不显著。
总之这些结果明确地证实用含至少两种支链氨基酸的组合物治疗导致身体负荷诱导的关节结构紧张减轻和关节稳定性改进。
Claims (15)
1.用于增强关节稳定性和/或姿势稳定性的组合物,其中所述组合物包含至少两种支链氨基酸。
2.根据权利要求1的组合物,其中所述组合物包含L-亮氨酸,以及支链氨基酸L-异亮氨酸和L-缬氨酸中的至少一种。
3.根据权利要求1或2组合物,其中L-亮氨酸以基于所有支链氨基酸总重的约25至约80%重量、优选约35至约75%重量、更优选约45至约70%重量、最优选约64%重量的量存在。
4.根据权利要求1至3中一项或多项的组合物,其中L-亮氨酸以约35至约80%重量的量存在,L-异亮氨酸以约10至约30%重量的量存在,以及L-缬氨酸以约10至约30%重量的量存在。
5.根据权利要求1至4中一项或多项的组合物,其中L-亮氨酸、L-异亮氨酸和L-缬氨酸以2~6:0.5~1.5:0.5~1.5的重量比、优选以3~5:0.75~1.25:0.75~1.25的重量比、更优选以约3.5:约1:约1的重量比存在。
6.根据权利要求1至3中一项或多项的组合物,其中所述组合物含一种或多种其它活性成分。
7.根据权利要求6的组合物,其中所述活性成分为维生素,如维生素D,矿物质,如镁或钙盐和/或软骨保护剂,如透明质酸和/或葡糖胺或其衍生物,如软骨素,和/或其盐类,如硫酸盐或盐酸盐。
8.根据权利要求1至7中一项或多项的组合物,其中所述组合物用于口服。
9.根据权利要求1至8中一项或多项的组合物,其中使所述组合物适于提供每日剂量的支链氨基酸,每日剂量范围为约1000至约5000mg L-亮氨酸、约300至约2000mg L-异亮氨酸和约300至约2000mg L-缬氨酸,优选约2000至约4000mg L-亮氨酸、约600至约1500mg L-异亮氨酸和约600至约1500mg L-缬氨酸,更优选约3200mg L-亮氨酸、约900mg L-异亮氨酸和约900mg L-缬氨酸。
10.根据权利要求1至9中一项或多项的组合物,其中所述组合物为食品、饮食增补剂或药物制剂的形式。
11.根据权利要求10的组合物,其中所述组合物为固体剂型的形式,优选为片剂、胶囊、颗粒或粉末的形式。
12.用于预防和/或治疗关节不稳定性和/或姿势不稳定性的组合物,其中此种组合物包含至少两种支链氨基酸。
13.根据权利要求12的组合物,其中所述组合物与权利要求2至11中一项或多项描述的组合物相同。
14.至少两种支链氨基酸用于制备预防和/或治疗关节不稳定性和/或姿势不稳定性的药物的用途。
15.根据权利要求14的用途,其中所述药物包含权利要求2至11中一项或多项的组合物。
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