CN111295102A - 氨基酸补充剂在提高肌肉蛋白质合成中的用途 - Google Patents
氨基酸补充剂在提高肌肉蛋白质合成中的用途 Download PDFInfo
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Abstract
本发明包括用于刺激肌肉蛋白质合成的氨基酸组合物。进一步地,本公开总体上涉及合成代谢氨基酸组合物在刺激肌肉蛋白质合成中的用途。特别地,公开了组合物,以及使用所述组合物预防和/或治疗哺乳动物,尤其是成年哺乳动物中的肌肉质量、肌肉力量、肌肉功能和身体功能,或其任何组合中的任一种的损失的方法。还提供了试剂盒,所述试剂盒包括用于刺激肌肉蛋白质合成的组合物,并且在某些实施方案中包括施用说明书。
Description
相关申请的交叉引用
本申请要求2017年11月2日提交的美国临时申请号62/580,861的权益,所述临时申请的公开内容据此以引用方式整体并入本文。
政府权利
本发明是在由美国国家卫生研究院(National Institutes of Health)颁发的AR052293下借助政府资助进行的。政府享有本发明的某些权利。
发明领域
本公开总体上涉及合成代谢氨基酸组合物在刺激肌肉蛋白质合成中的用途。特别地,公开了组合物,以及使用所述组合物预防和/或治疗哺乳动物,尤其是成年哺乳动物的肌肉质量、肌肉力量、肌肉功能和身体功能,或其任何组合中的任一种的损失的方法。
背景技术
需要大剂量的膳食蛋白质来刺激肌肉蛋白质合成。营养物的合成代谢作用主要是由从膳食蛋白质来源捕获的氨基酸转移和并入到骨骼肌蛋白质中来驱动的。其目的是补偿在禁食(吸收后)期间由于例如用于肝脏糖异生的氨基酸氧化和/或碳贡献而损失的肌肉蛋白质。然而,随着人类年龄的增长,人体消化蛋白质的能力变得越来越差。肌肉质量损失从30岁开始,每十年损失3-8%,从60岁开始加速。这种损失在超过70岁的老年人中高达35-40%,因此,少肌症在老年人中尤为突出。因此,与年龄相关的肌肉质量的逐渐丧失增加了受伤和残疾的风险。
因此,需要这样的营养补充剂,其能使肌肉蛋白质合成速度加快到比根据摄取的膳食蛋白质预期的更大的程度。
发明内容
在本公开的各个方面中,有用于刺激肌肉蛋白质合成的方法和组合物。总的来说,本公开提供了包含有效量的氨基酸的营养组合物,所述有效量的氨基酸相对于未施用该组合物的受试者而言能刺激受试者肌肉蛋白质合成。
本公开的一个方面涉及提供包含以下的组合物:组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸、色氨酸和精氨酸。在一方面,本公开提供了包含以下以w/w%计的以下浓度的氨基酸的组合物:约1%至2%的组氨酸、约9%至11%的异亮氨酸、约35%至38%的亮氨酸、约14%至17%的赖氨酸、约2%至4%的甲硫氨酸、约5%至7%的苯丙氨酸、约8%至9%的苏氨酸、约9%至11%的缬氨酸、约0.005%至0.8%的色氨酸和约8%至11%的精氨酸。
在另一方面,肌肉蛋白质合成在3.6克的最小剂量下提高了大约50%。在又一方面,该组合物包含以w/w%计的以下浓度的氨基酸:1.5%的组氨酸、9.7%的异亮氨酸、36.4%的亮氨酸、15.2%的赖氨酸、3%的甲硫氨酸、6.1%的苯丙氨酸、8.5%的苏氨酸、10%的缬氨酸、0.6%的色氨酸和9%的精氨酸。
本公开的进一步方面涉及以一天一次12g剂量、一天三次3.6g剂量、一天一次3.6g剂量、一天两次3.6g剂量、一天一次6.7g剂量、一天两次6.7g剂量或一天三次6.7g剂量施用包含氨基酸的营养组合物的方法。
另一方面提供了包含下列氨基酸的组合物:组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸、色氨酸和精氨酸,该组合物以低于12克的剂量在锻炼或不锻炼的情况下刺激肌肉蛋白质合成超过50%。
在又一方面,本公开提供了组合物,以及使用该组合物利用小于12克的剂量来刺激肌肉蛋白质合成的方法。在一些实施方案中,该组合物包含以w/w%计的以下浓度的氨基酸:约1%至2%的组氨酸、约9%至11%的异亮氨酸、约35%至38%的亮氨酸、约14%至17%的赖氨酸、约2%至4%的甲硫氨酸、约5%至7%的苯丙氨酸、约8%至9%的苏氨酸、约9%至11%的缬氨酸、约0.005%至0.8%的色氨酸和约8%至11%的精氨酸。
虽然公开了多个实施方案,但对于本领域技术人员来说,根据示出并描述本发明的说明性实施方案的以下详述,本发明的另一些其他实施方案将变得显而易见。因此,所述详述应被视为在本质上是说明性的而不是限制性的。
具体实施方式
本公开总体上提供了包含能够刺激肌肉蛋白质合成速率的特定氨基酸制剂的方法和组合物。申请人已经发现本文所述的组合物令人惊讶地以高效方式刺激肌肉蛋白质合成。特别地,本文公开的组合物刺激比所摄入组分的总重量更多的肌肉蛋白质的产生。根据本发明,发现包含特定量的游离必需氨基酸(EAA)和精氨酸的制剂非常适合于刺激肌肉蛋白质合成。特别地,已经发现包含必需氨基酸和精氨酸的混合物(包括大量亮氨酸)的营养组合物有效地刺激肌肉蛋白质的合成。有利的是,发现该制剂在刺激肌肉蛋白质合成效率较低的成年人中是有效的。肌肉蛋白质合成相对于未接受所述氨基酸组合物的受试者得到提高,并且在锻炼或不锻炼的情况下均发生。
公开了用于制备所公开的组合物的组分以及在本文公开的方法中使用的组合物本身。本文公开了这些材料和其他材料,应当理解,当公开了这些材料的组合、子集、相互作用、群组等时,虽然可能没有明确地公开对这些化合物的各种单独和集体的组合以及排列中每一种的具体提及,但每一种均在本文中进行了特别考虑和描述。例如,如果公开并讨论了特定的化合物,并且讨论了可对该化合物的多个分子进行的多种修改,则特别考虑了所述化合物的每一种组合和排列以及可能的修改,除非有明确相反的说明。因此,如果公开了一类分子A、B和C以及一类分子D、E和F,并且公开了一个组合分子的例子A-D,那么即使没有单独列举每一个,也单独和集体地考虑了每一个,这意味着组合A-E、A-F、B-D、B-E、B-F、C-D、C-E和C-F被视为得到公开。同样地,这些的任何子集或组合也得到公开。因此,例如,A-E、B-F和C-E的亚组将被视为得到公开。这一概念适用于本申请的所有方面,包括但不限于制备和使用所公开组合物的方法中的步骤。因此,如果存在可以执行的各种另外的步骤,应当理解,这些另外的步骤中的每一个均可以与所公开方法的任何特定实施方案或实施方案的组合一起执行。
本发明的各个方面在以下章节中进一步详细描述。
(I)组分
本文提供了可用于刺激肌肉蛋白质合成的合成代谢氨基酸组合物。在一些实施方案中,组合物可以包含必需氨基酸组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸和色氨酸。在优选的实施方案中,除必需氨基酸组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸和色氨酸之外,组合物还可以包含氨基酸精氨酸。
通常,所述氨基酸可以是L-氨基酸、D-氨基酸或其混合物。在优选的实施方案中,氨基酸是L-氨基酸。本领域技术人员将理解,所述组合物中的氨基酸可以是游离氨基酸或氨基酸盐。本发明的氨基酸组合物也可以是完整的蛋白质或肽的形式,只要该蛋白质或肽包含相对于彼此的正确浓度的本发明氨基酸。在优选的实施方案中,本发明的氨基酸是游离氨基酸或氨基酸盐。如果不能从商业上获得,则可以通过包括化学合成或使用重组微生物在内的本领域公知的方法来生产单个氨基酸。
该氨基酸可以是规范氨基酸组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸、色氨酸和精氨酸,或者非规范氨基酸衍生物(例如氨基酸的前体)。可以用于本发明的非规范氨基酸的非限制性实例包括L-赖氨酸乙酸盐、L-酪氨酸衍生物、鸟氨酸、酮酸类似物、盐酸盐(L-半胱氨酸HCL.H2O),和各种氨基酸的N-乙酰基衍生物。在优选的实施方案中,用于本发明的组合物和溶液中的氨基酸可以是游离形式或盐形式。
在一方面,本公开的氨基酸组合物包含一种或多种必需氨基酸。必需氨基酸(EAA)是不能由受试者从头合成的氨基酸,因此必须在其饮食中提供。被视为人类必需的氨基酸有苯丙氨酸、缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸和组氨酸。在一些实施方案中,EEA的组合包含苯丙氨酸、缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸和组氨酸。在优选的实施方案中,氨基酸组合物还包含至少一种条件必需氨基酸。
氨基酸精氨酸、半胱氨酸、甘氨酸、谷氨酰胺、脯氨酸、丝氨酸和酪氨酸被认为是条件必需的,这意味着它们正常情况下在饮食中是不需要的,但必须外源性地提供给不能足够量合成它们的特定人群。例如,人体产生足够的精氨酸来满足正常条件下的代谢要求。因此,对于许多受试者来说,精氨酸补充剂并不是刺激肌肉蛋白质合成所必需的。然而,在包括患有心力衰竭的老年人在内的某些临床情况中,内源性精氨酸的生产不足以满足所有需求。对于这样的群体,本发明的组合包含精氨酸或氨基酸精氨酸的前体是有利的。术语“氨基酸前体”是指氨基酸的代谢前体。例如,丝氨酸是半胱氨酸和甘氨酸的代谢前体;而3-磷酸甘油酸盐是丝氨酸的代谢前体,因此也是半胱氨酸和甘氨酸的代谢前体。作为第二个实例,瓜氨酸是精氨酸的代谢前体。合成氨基酸的代谢途径在本领域中是众所周知的,技术人员可以参考这些途径来鉴定其他氨基酸的代谢前体。在一些实施方案中,本发明的组合包含苯丙氨酸、缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸、组氨酸和至少一种条件必需氨基酸。例如,所述组合可以包含1、2、3、4、5、6、7、8、9或10种条件必需氨基酸。在其他实施方案中,本发明的组合包含苯丙氨酸、缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸、组氨酸和至少一种条件必需氨基酸前体。例如,组合可以包含1、2、3、4、5、6、7、8、9或10种条件必需氨基酸前体。在另一些其他实施方案中,本发明的组合包含苯丙氨酸、缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸、组氨酸、至少一种非必需氨基酸和至少一种条件必需氨基酸前体。
在一些实施方案中,组合物可以包含以w/w%计的以下浓度的组氨酸:约1%至约2%、约1.1%至约2%、约1.2%至约2%、约1.3%至约2%、约1.4%至约2%、约1.5%至约2%、约1.6%至约2%、约1.7%至约2%、约1.8%至约2%、约1.9%至约2%、约1%至约1.9%、约1%至约1.8%、约1%至约1.7%、约1%至约1.6%、约1%至约1.5%、约1%至约1.4%、约1%至约1.3%、约1%至约1.2%,或约1%至约1.1%的组氨酸。
在一些实施方案中,组合物可以包含以w/w%计的以下浓度的异亮氨酸:约9%至约11%、约9.1%至约11%、约9.2%至约11%、约9.3%至约11%、约9.4%至约11%、约9.4%至约11%、约9.4%至约11%、约9.5%至约11%、约9.6%至约11%、约9.7%至约11%、约9.8%至约11%、约9.9%至约11%、约10%至约11%、约10.1%至约11%、约10.2%至约11%、约10.3%至约11%、约10.4%至约11%、约10.5%至约11%、约10.6%至约11%、约10.7%至约11%、约10.8%至约11%、约10.9%至约11%、约9%至约10.9%、约9%至约10.8%、约9%至约10.7%、约9%至约10.6%、约9%至约10.5%、约9%至约10.4%、约9%至约10.3%、约9%至约10.2%、约9%至约10.1%、约9%至约10%、约9%至约9.9%、约9%至约9.8%、约9%至约9.7%、约9%至约9.6%、约9%至约9.5%、约9%至约9.4%、约9%至约9.3%、约9%至约9.2%,或约9%至约9.1%的异亮氨酸。
在一些实施方案中,组合物可以包含以w/w%计的以下浓度的亮氨酸:约35%至约38%、约35.2%至约38%、约35.4%至约38%、约35.6%至约38%、约35.8%至约38%、约36%至约38%、约36.2%至约38%、约36.4%至约38%、约36.6%至约38%、约36.8%至约38%、约37%至约38%、约37.2%至约38%、约37.4%至约38%、约37.6%至约38%、约37.8%至约38%、约35%至约37.8%、约35%至约37.6%、约35%至约37.4%、约35%至约37.2%、约35%至约37%、约35%至约36.8%、约35%至约36.6%、约35%至约36.4%、约35%至约36.2%、约35%至约36%、约35%至约35.8%、约35%至约35.6%、约35%至约35.4%,或约35%至约35.2%的亮氨酸。
在一些实施方案中,组合物可以包含以w/w%计以下浓度的赖氨酸:约14%至约17%、约14.2%至约17%、约14.4%至约17%、约14.6%至约17%、约14.8%至约17%、约15%至约17%、约15.2%至约17%、约15.4%至约17%、约15.6%至约17%、约15.8%至约17%、约16%至约17%、约16.2%至约17%、约16.4%至约17%、约16.6%至约17%、约16.8%至约17%、约14%至约16.8%、约14%至约16.6%、约14%至约16.4%、约14%至约16.2%、约14%至约16%、约14%至约15.8%、约14%至约15.6%、约14%至约15.4%,或约14%至约15.2%的赖氨酸。
在一些实施方案中,组合物可以包含以w/w%计以下浓度的甲硫氨酸:约2%至约4%、约2.1%至约4%、约2.2%至约4%、约2.3%至约4%、约2.4%至约4%、约2.5%至约4%、约2.6%至约4%、约2.7%至约4%、约2.8%至约4%、约2.9%至约4%、约3%至约4%、约3.1%至约4%、约3.2%至约4%、约3.3%至约4%、约3.4%至约4%、约3.5%至约4%、约3.6%至约4%、约3.7%至约4%、约3.8%至约4%、约3.9%至约4%、约2%至约3.9%、约2%至约3.8%、约2%至约3.7%、约2%至约3.6%、约2%至约3.5%、约2%至约3.4%、约2%至约3.3%、约2%至约3.2%、约2%至约3.1%、约2%至约3%、约2%至约2.9%、约2%至约2.8%、约2%至约2.7%、约2%至约2.6%、约2%至约2.5%、约2%至约2.4%、约2%至约2.3%、约2%至约2.2%,或约2%至约2.1%的甲硫氨酸。
在一些实施方案中,组合物可以包含以w/w%计以下浓度的苯丙氨酸:约5%至约7%、约5.1%至约7%、约5.2%至约7%、约5.3%至约7%、约5.4%至约7%、约5.5%至约7%、约5.6%至约7%、约5.7%至约7%、约5.8%至约7%、约5.9%至约7%、约6%至约7%、约6.1%至约7%、约6.2%至约7%、约6.3%至约7%、约6.4%至约7%、约6.5%至约7%、约6.6%至约7%、约6.7%至约7%、约6.8%至约7%、约6.9%至约7%、约5%至约6.9%、约5%至约6.8%、约5%至约6.7%、约5%至约6.6%、约5%至约6.5%、约5%至约6.4%、约5%至约6.3%、约5%至约6.2%、约5%至约6.1%、约5%至约6%、约5%至约5.9%、约5%至约5.8%、约5%至约5.7%、约5%至约5.6%、约5%至约5.5%、约5%至约5.4%、约5%至约5.3%、约5%至约5.2%,或约5%至约5.1%的苯丙氨酸
在一些实施方案中,组合物可以包含以w/w%计以下浓度的苏氨酸:约8%至约9%、约8.1%至约9%、约8.2%至约9%、约8.3%至约9%、约8.4%至约9%、约8.5%至约9%、约8.6%至约9%、约8.7%至约9%、约8.8%至约9%、约8.9%至约9%、约8%至约8.9%、约8%至约8.8%、约8%至约8.7%、约8%至约8.6%、约8%至约8.5%、约8%至约8.4%、约8%至约8.3%、约8%至约8.2%,或约8%至约8.1%的苏氨酸
在一些实施方案中,组合物可以包含以w/w%计以下浓度的缬氨酸:约9%至约11%、约9.1%至约11%、约9.2%至约11%、约9.3%至约11%、约9.4%至约11%、约9.4%至约11%、约9.4%至约11%、约9.5%至约11%、约9.6%至约11%、约9.7%至约11%、约9.8%至约11%、约9.9%至约11%、约10%至约11%、约10.1%至约11%、约10.2%至约11%、约10.3%至约11%、约10.4%至约11%、约10.5%至约11%、约10.6%至约11%、约10.7%至约11%、约10.8%至约11%、约10.9%至约11%、约9%至约10.9%、约9%至约10.8%、约9%至约10.7%、约9%至约10.6%、约9%至约10.5%、约9%至约10.4%、约9%至约10.3%、约9%至约10.2%、约9%至约10.1%、约9%至约10%、约9%至约9.9%、约9%至约9.8%、约9%至约9.7%、约9%至约9.6%、约9%至约9.5%、约9%至约9.4%、约9%至约9.3%、约9%至约9.2%,或约9%至约9.1%的缬氨酸。
在一些实施方案中,组合物可以包含以w/w%计以下浓度的色氨酸:约0.005%至约0.8%、约0.006%至约0.8%、约0.007%至约0.8%、约0.008%至约0.8%、约0.009%至约0.8%、约0.01%至约0.8%、约0.02%至约0.8%、约0.03%至约0.8%、约0.04%至约0.8%、约0.05%至约0.8%、约0.06%至约0.8%、约0.07%至约0.8%、约0.08%至约0.8%、约0.09%至约0.8%、约0.1%至约0.8%、约0.2%至约0.8%、约0.3%至约0.8%、约0.4%至约0.8%、约0.5%至约0.8%、约0.6%至约0.8%、约0.7%至约0.8%、约0.005%至约0.7%、约0.005%至约0.6%、约0.005%至约0.5%、约0.005%至约0.4%、约0.005%至约0.3%、约0.005%至约0.2%、约0.005%至约0.1%、约0.005%至约0.09%、约0.005%至约0.08%、约0.005%至约0.07%、约0.005%至约0.06%、约0.005%至约0.05%、约0.005%至约0.04%、约0.005%至约0.03%、约0.005%至约0.02%、约0.005%至约0.01%、约0.005%至约0.009%、约0.005%至约0.008%、约0.005%至约0.007%,或约0.005%至约0.006%的色氨酸
在一些实施方案中,组合物可以包含以w/w%计以下浓度的精氨酸:约8%至约11%、约8.1%至约11%、约8.2%至约11%、约8.3%至约11%、约8.4%至约11%、约8.5%至约11%、约8.6%至约11%、约8.7%至约11%、约8.8%至约11%、约8.9%至约11%、约9%至约11%、约9.1%至约11%、约9.2%至约11%、约9.3%至约11%、约9.4%至约11%、约9.4%至约11%、约9.4%至约11%、约9.5%至约11%、约9.6%至约11%、约9.7%至约11%、约9.8%至约11%、约9.9%至约11%、约10%至约11%、约10.1%至约11%、约10.2%至约11%、约10.3%至约11%、约10.4%至约11%、约10.5%至约11%、约10.6%至约11%、约10.7%至约11%、约10.8%至约11%、约10.9%至约11%、约8%至约10.8%、约8%至约10.7%、约8%至约10.6%、约8%至约10.5%、约8%至约10.4%、约8%至约10.3%、约8%至约10.2%、约8%至约10.1%、约8%至约10%、约8%至约9.9%、约8%至约9.8%、约8%至约9.7%、约8%至约9.6%、约8%至约9.5%、约8%至约9.4%、约8%至约9.3%、约8%至约9.2%、约8%至约9.1%、约8%至约9%、约8%至约8.9%、约8%至约8.8%、约8%至约8.7%、约8%至约8.6%、约8%至约8.5%、约8%至约8.4%、约8%至约8.3%、约8%至约8.2%,或约8%至约8.1%的精氨酸
在一些实施方案中,组合物可以包含以w/w%计的以下浓度的氨基酸:约1%至约2%的组氨酸、约9%至约11%的异亮氨酸、约35%至约38%的亮氨酸、约14%至约17%的赖氨酸、约2%至约4%的甲硫氨酸、约5%至约7%的苯丙氨酸、约8%至约9%的苏氨酸、约9%至约11%的缬氨酸、约0.005%至约0.8%的色氨酸和约8%至约11%的精氨酸。在示例性实施方案中,组合物可以包含以下,基本上由以下组成或由以下组成:1.5%的组氨酸、9.7%的异亮氨酸、36.4%的亮氨酸、15.2%的赖氨酸、3%的甲硫氨酸、6.1%的苯丙氨酸、8.5%的苏氨酸、10%的缬氨酸、0.6%的色氨酸和9%的精氨酸。
在另一方面,本发明的组合可以进一步包含一种或多种另外的营养素。本文中所用的术语“营养素”是指益生元、维生素、碳水化合物、纤维、脂肪酸、硫酸盐、矿物质、抗氧化剂以及用于受试者新陈代谢中的从新陈代谢环境中获取的其他食物成分。合适的维生素可以包括但不限于:维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B9、维生素B12、硫辛酸、维生素A、生物素、维生素K、维生素C、维生素D和维生素E。合适的矿物质可以包括但不限于含有以下的化合物:铁、铜、镁、锰、钼、镍和锌。合适的酶辅因子可包括但不限于:三磷酸腺苷(ATP)、S-腺苷甲硫氨酸(SAM)、辅酶B、辅酶M、辅酶Q、谷胱甘肽、血红素、甲烷呋喃和核苷酸糖。合适的脂质可包括但不限于:脂肪酸、甘油脂、甘油磷脂、鞘脂、固醇脂、异戊烯醇脂(prenol lipid)、糖脂和聚酮。脂肪酸的非限制性实例包括十四碳烯酸、棕榈油酸、十六碳烯酸(sapienic acid)、油酸、反油酸、异油酸、亚油酸、反式亚油酸、花生四烯酸、二十碳五烯酸、芥酸、二十二碳六烯酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、蜡酸、十六碳三烯酸、α-亚麻酸、十八碳四烯酸(stearidonic acid)、二十碳四烯酸、二十碳五烯酸、二十一碳五烯酸、二十二碳五烯酸(docosapentaenoic acid)、鰶鱼酸(clupanodonic acid)、二十二碳六烯酸(docasehaenoic acid)、二十四碳五烯酸和二十四碳六烯酸。营养素的另外的非限制性实例可以包括硫胺素、核黄素、烟酸、叶酸、泛酸、钙、磷、镁、锰、铁、锌、铜、硒、钠、钾、β-胡萝卜素、视黄醇、α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、α-生育三烯酚、β-生育三烯酚、γ-生育三烯酚、δ-生育三烯酚、apo-8-胡萝卜素醛、反式番茄红素、顺式番茄红素、反式-β-胡萝卜素和顺式-β-胡萝卜素、咖啡因。在一些实施方案中,本发明的组合还包含一种营养素。在其他实施方案中,本发明的组合还包含至少一种营养素。例如,本发明的组合可以包含1、2、3、4、5、6、7、8、9、10或更多种营养素。在其他实施方案中,本发明的组合还包含两种或更多种营养素。在优选的实施方案中,本发明的组合还包含至少一种选自由ω-3脂肪酸和生物素组成的组的营养素。在其他优选的实施方案中,本发明的组合还包含两种选自由ω-3脂肪酸和生物素组成的组的营养素。一种或多种营养素对所述组合的总重量的总贡献显著小于多种氨基酸的贡献。通常,一种或多种营养素占所述组合的不超过约10重量%,优选不超过约5重量%,更优选不超过约3重量%。在优选的实施方案中,一种或多种营养素是生物素。在其他优选的实施方案中,一种或多种营养素是一种或多种ω-3脂肪酸。在其他优选的实施方案中,一种或多种营养素是生物素和一种或多种ω-3脂肪酸。
(II)制剂
在上述每个实施方案中,可以配制氨基酸和营养素(当存在时)以供动物或人使用。在一些实施方案中,每种氨基酸和营养素(当存在时)分开配制。在其他实施方案中,两种或更多种氨基酸和营养素(当存在时)一起配制。在另一些其他实施方案中,构成本发明的组合的所有氨基酸和营养素一起配制。然后可以将一种或多种制剂加工成一种或多种剂量形式,这些剂量形式可以一起、依顺序或在一段时间内施用(例如,1分钟内、10分钟内、30分钟内、1小时内、3小时内、6小时内、9小时内、12小时内、18小时内、24小时内或更长时间内)。可以使用包括口服、肠胃外(例如静脉内、腹膜内、皮下、肌肉内)、口腔、舌下或栓剂施用在内的标准有效技术进行施用。本文中所用的术语口服是指任何形式的经口施用,包括向动物饲料或其他食品中添加组合物。药物组合物的配制在,例如,Hoover,John E.,Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.(1975)以及Liberman,H.A.和Lachman,L.编辑,Pharmaceutical Dosage Forms,Marcel Decker,NewYork,N.Y.(1980)中有论述。
制备供动物或人使用的组合物的方法是本领域众所周知的。例如,组合物通常可以配制成液体组合物、固体组合物或半固体组合物。液体组合物包括但不限于水性悬浮液、溶液、乳液、酏剂或糖浆。液体组合物通常将包含选自极性溶剂、非极性溶剂或两者的组合的溶剂载体。溶剂的选择将受到组合物组分的性质的影响。例如,如果组分是水溶性的,则可以使用极性溶剂。或者,如果组合物的组分是脂溶性的,则可以使用非极性溶剂。合适的极性和非极性溶剂是本领域已知的。半固体组合物包括冲洗剂(douches)、栓剂、霜剂和外用剂。干组合物包括但不限于可复原粉末、咀嚼片、速溶片、泡腾片、多层片、双层片、胶囊、软明胶胶囊、硬明胶胶囊、囊片、锭剂、可咀嚼锭剂、珠粒剂、粉末、颗粒剂(granule)、颗粒(particle)、微粒和可分散颗粒剂。制剂可包含与赋形剂在一起的本发明的组合。赋形剂的非限制性实例包括粘合剂、稀释剂(填充剂)、崩解剂、泡腾崩解剂、防腐剂(抗氧化剂)、风味改良剂、润滑剂和助流剂、分散剂、着色剂、pH调节剂、螯合剂、抗微生物剂、控释聚合物,以及任何这些剂的组合。
适用于各种实施方案的制剂的粘合剂的非限制性实例包括淀粉、预胶化淀粉、明胶、聚乙烯吡咯烷酮、纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚丙烯酰胺、聚乙烯噁唑烷酮、聚乙烯醇、C12-C18脂肪酸醇、聚乙二醇、多元醇、糖、寡糖、多肽、寡肽以及其组合。多肽可以是在约100至约300,000道尔顿范围内的氨基酸的任何排列。在一个实施方案中,粘合剂可以以固体形式引入到待造粒的混合物中,该固体形式包括但不限于晶体、颗粒、粉末或本领域已知的任何其他细分的固体形式。在另一实施方案中,可将粘合剂溶解或悬浮在溶剂中,并在造粒过程中作为粘合剂流体喷洒到造粒装置中的混合物上。
稀释剂(也称为“填充剂”或“冲淡剂”)的非限制性实例包括碳水化合物、无机化合物和生物相容性聚合物,诸如聚乙烯吡咯烷酮(PVP)。稀释剂的其他非限制性实例包括二碱式硫酸钙;三碱式硫酸钙;淀粉;碳酸钙;碳酸镁;微晶纤维素;二碱式磷酸钙;三碱式磷酸钙;碳酸镁;氧化镁;硅酸钙;滑石;改性淀粉;糖类诸如蔗糖、右旋糖、乳糖、微晶纤维素、果糖、木糖醇和山梨糖醇、多羟基醇;淀粉;预制直接压缩稀释剂;以及上述任一种的混合物。
崩解剂可以是泡腾性的或非泡腾性的。非泡腾崩解剂的非限制性实例包括淀粉(诸如玉米淀粉、马铃薯淀粉、其预胶化和改性淀粉)、甜味剂、粘土(诸如膨润土)、微晶纤维素、海藻酸盐、淀粉乙醇酸钠、树胶(诸如琼脂)、瓜尔胶、刺槐豆胶、刺梧桐胶、果胶(pecitin)和黄蓍胶。合适的泡腾崩解剂包括但不限于碳酸氢钠与柠檬酸的组合,以及碳酸氢钠与酒石酸的组合。
防腐剂的非限制性实例包括但不限于抗坏血酸及其盐、抗坏血酸棕榈酸酯、抗坏血酸硬脂酸酯、阿诺克索默、N-乙酰半胱氨酸、异硫氰酸苄酯、间氨基苯甲酸、邻氨基苯甲酸、对氨基苯甲酸(PABA)、丁基化羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)、咖啡酸、角黄素、α-胡萝卜素、β-胡萝卜素、beta-caraotene、β-阿扑-胡萝卜酸、鼠尾草酚、香芹酚、儿茶素、没食子酸十六烷基酯、绿原酸、柠檬酸及其盐、丁香提取物、咖啡豆提取物、对香豆酸、3,4-二羟基苯甲酸、N,N'-二苯基-对苯二胺(DPPD)、硫代二丙酸二月桂酯、硫代二丙酸双十八酯、2,6-二-叔丁基苯酚、没食子酸十二烷基酯、依地酸、鞣花酸、异抗坏血酸、异抗坏血酸钠、七叶亭、七叶灵、6-乙氧基-1,2-二氢-2,2,4-三甲基喹啉、没食子酸乙酯、乙基麦芽酚、乙二胺四乙酸(EDTA)、桉树提取物、丁香酚、阿魏酸、类黄酮(如儿茶素、表儿茶素、表儿茶素没食子酸酯、表没食子儿茶素(EGC)、表没食子儿茶素没食子酸酯(EGCG)、多酚表没食子儿茶素-3-没食子酸酯)、黄酮类(如芹菜素、柯因、木樨草素)、黄酮醇类(如橡精、杨梅酮、daemfero)、黄烷酮类、秦皮素、富马酸、没食子酸、龙胆提取物、葡萄糖酸、甘氨酸、愈创木脂(gum guaiacum)、橙皮素、α-羟基苄基次膦酸、羟基肉桂酸、羟基戊二酸、对苯二酚、N-羟基琥珀酸、羟基酪醇、羟基脲、米糠提取物、乳酸及其盐、卵磷脂、柠檬酸卵磷脂;R-α-硫辛酸、叶黄素、番茄红素、苹果酸、麦芽酚、5-甲氧基色胺、没食子酸甲酯、柠檬酸单甘油酯;柠檬酸单异丙酯、桑色素、β-萘黄酮、去甲二氢愈创木酸(NDGA)、没食子酸辛酯、草酸、柠檬酸棕榈酯、吩噻嗪、磷脂酰胆碱、磷酸、磷酸酯、植酸、植基泛色烯醇(phytylubichromel)、甘椒提取物、没食子酸丙酯、多磷酸酯、槲皮素、反式-白藜芦醇、迷迭香提取物、迷迭香酸、鼠尾草提取物、芝麻酚、水飞蓟素、芥子酸、琥珀酸、柠檬酸硬脂酰酯、丁香酸、酒石酸、百里香酚、生育酚(即α-、β-、γ-和δ-生育酚)、生育三烯酚(即α-、β-、γ-和δ-生育三烯酚)、酪醇、香草酸、2,6-二-叔丁基-4-羟甲基苯酚(即Ionox 100)、2,4-(三-3',5'-双-叔丁基-4'-羟基苄基)-均三甲苯(即Ionox 330)、2,4,5-三羟基丁酰苯、泛醌、叔丁基氢醌(TBHQ)、硫代二丙酸、三羟基丁酰苯、色胺、酪胺、尿酸、维生素K和衍生物、维生素Q10、小麦胚芽油、玉米黄质或其组合。在示例性实施方案中,防腐剂是抗氧化剂,诸如α-生育酚或抗坏血酸盐,以及抗微生物剂,诸如对羟基苯甲酸酯、氯丁醇或苯酚。
合适的风味改良剂剂包括调味剂、掩味剂、甜味剂等。调味剂包括但不限于合成风味油和调味芳香剂和/或天然油,来自植物、叶子、花、果实的提取物,及其组合。风味剂的其他非限制性实例包括肉桂油、冬青油、薄荷油、三叶草油、干草油、茴香油、桉树油、香草油、柑橘油诸如柠檬油、橙油、葡萄和葡萄柚油、水果香精(包括苹果香精、桃子香精、梨香精、草莓香精、树莓香精、樱桃香精、李子香精、菠萝香精和杏香精)。
掩味剂包括但不限于纤维素羟丙基醚(HPC),诸如Nisswo HPC和PrimaFlo HP22;低取代羟丙基醚(L-HPC);纤维素羟丙基甲基醚(HPMC),诸如Seppifilm-LC、Metolose SR、Opadry YS、PrimaFlo、MP3295A、Benecel MP824和Benecel MP843;甲基纤维素聚合物,诸如和乙基纤维素(EC)及其混合物,诸如E461、Surelease;聚乙烯醇(PVA),诸如Opadry AMB;羟乙基纤维素,诸如羧甲基纤维素以及羧甲基纤维素(CMC)的盐,诸如聚乙烯醇和聚乙二醇共聚物,诸如Kollicoat甘油单酯(Myverol),甘油三酯(KLX),聚乙二醇,改性食品淀粉,丙烯酸类聚合物以及丙烯酸类聚合物与纤维素醚(诸如EPO、RD100和E100)的混合物;邻苯二甲酸醋酸纤维素;sepifilms,诸如HPMC和硬脂酸的混合物,环糊精以及这些材料的混合物。在其他实施方案中,所考虑的另外的掩味剂是在美国专利号4,851,226、5,075,114和5,876,759中描述的那些,其中每一篇的全部内容都据此通过引用整体并入。
甜味剂的非限制性实例包括葡萄糖(玉米糖浆)、右旋糖、转化糖、果糖及其混合物(当不用作载体时);糖精及其各种盐,诸如钠盐;二肽甜味剂,诸如阿斯巴甜;二氢查尔酮化合物,甘草甜素;甜叶菊(甜菊苷);蔗糖的氯代衍生物,诸如三氯蔗糖;糖醇,诸如山梨糖醇、甘露糖醇、木糖醇(sylitol),氢化淀粉水解物和合成甜味剂3,6-二氢-6-甲基-1,2,3-氧杂噻嗪-4-酮-2,2-二氧化物,特别是其钾盐(乙酰磺胺酸钾)及钠盐和钙盐。
润滑剂可用于润滑形成本发明组合物的成分。作为助流剂,润滑剂有助于在制造过程中移出固体剂量形式。润滑剂和助流剂的非限制性实例包括硬脂酸镁、硬脂酸钙、硬脂酸锌、氢化植物油、氢化植物油(sterotex)、聚氧乙烯单硬脂酸酯、滑石、聚乙二醇、苯甲酸钠、月桂醇硫酸酯钠、月桂醇硫酸酯镁和轻质矿物油。组合物通常将包含约0.01重量%至约10重量%的润滑剂。在一些实施方案中,组合物将包含约0.1重量%至约5重量%的润滑剂。在另一实施方案中,组合物将包含约0.5重量%至约2重量%的润滑剂。
分散剂可包括但不限于作为高亲水-亲油平衡(HLB)乳化剂表面活性剂的淀粉、海藻酸、聚乙烯吡咯烷酮、瓜尔胶、高岭土、膨润土、纯化木纤维素、淀粉乙醇酸钠、同晶硅酸盐和微晶纤维素。
取决于实施方案,可能期望包括着色剂。合适的色彩添加剂包括但不限于食物、药物和化妆品着色剂(FD&C)、药物和化妆品着色剂(D&C),或外用药物和化妆品着色剂(Ext.d&C)。这些着色剂或染料,连同它们相应的色淀,以及某些天然的和衍生的染色剂可适用于各种实施方案。
pH调节剂的非限制性实例包括柠檬酸、乙酸、酒石酸、苹果酸、富马酸、乳酸、磷酸、山梨酸、苯甲酸、碳酸钠和碳酸氢钠。
可以包含螯合剂作为赋形剂来固定包括但不限于金属离子的氧化基团,以抑制这些氧化基团对***喃的氧化降解。螯合剂的非限制性实例包括赖氨酸、甲硫氨酸、甘氨酸、葡糖酸盐、多糖、谷氨酸盐、天冬氨酸盐和乙二胺四乙酸二钠(Na2EDTA)。
可以包含抗微生物剂作为赋形剂,以使包括但不限于细菌和真菌的微生物剂对根据本公开的化合物的降解最小化。抗微生物剂的非限制性实例包括对羟基苯甲酸酯、氯丁醇、苯酚、丙酸钙、硝酸钠、亚硝酸钠、Na2EDTA和亚硫酸盐(包括但不限于二氧化硫、亚硫酸氢钠和亚硫酸氢钾)。
控释聚合物可包含在掺有根据本公开的化合物的固体剂型组合物的各种实施方案中。在一个实施方案中,控释聚合物可用作片剂包衣。在包括但不限于双层片剂的其他实施方案中,可以将控释聚合物与颗粒剂和其他赋形剂混合在一起,之后通过包括但不限于在片剂模具中压制的已知工艺来形成片剂。合适的控释聚合物包括但不限于亲水聚合物和疏水聚合物。
合适的亲水控释聚合物包括但不限于乙酸纤维素、二乙酸纤维素、三乙酸纤维素、纤维素醚、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、硝化纤维素、交联淀粉、琼脂、酪蛋白、甲壳质、胶原蛋白、明胶、麦芽糖、甘露醇、麦芽糊精、果胶、普鲁兰多糖、山梨糖醇、木糖醇、多糖、海藻酸铵、海藻酸钠、海藻酸钙、海藻酸钾、海藻酸丙二醇酯、海藻酸羧甲基纤维素钠(alginate sodium carmellose)、羧甲基纤维素钙、角叉菜胶、岩藻依聚糖、叉红藻胶、***胶、角叉菜胶(carrageensgum)、印度树胶(ghaftigum)、瓜尔胶、刺梧桐胶、槐豆胶、秋葵荚胶(okra gum)、黄芪胶、硬葡聚糖胶(scleroglucangum)、黄原胶、卡拉胶(hypnea)、海带淀粉(laminaran)、丙烯酸类聚合物、丙烯酸酯聚合物、羧乙烯基聚合物、马来酸酐和苯乙烯的共聚物、马来酸酐和乙烯的共聚物、马来酸酐和丙烯的共聚物或马来酸酐和异丁烯的共聚物)、交联聚乙烯醇和聚N-乙烯基-2-吡咯烷酮、聚葡聚糖的二酯、聚丙烯酰胺、聚丙烯酸、聚酰胺、聚乙二醇、聚环氧乙烷、聚甲基丙烯酸羟烷基酯、聚乙酸乙烯酯、聚乙烯醇、聚氯乙烯、聚苯乙烯、聚乙烯吡咯烷酮、阴离子和阳离子水凝胶,及其组合。
本文所公开的氨基酸组合物还可包括可以被制成可添加到食品中的粉末、制成烘焙食品(例如饼干和巧克力蛋糕),以及制成浓缩物的组合物。可以将浓缩物添加到水或另一种可摄入液体中制成营养饮料。营养补充剂通常包含在单份或多份容器,诸如包装、盒子、纸箱、包装纸、瓶或罐中。当营养补充剂以浓缩物的形式制备时,可以将其添加到饮料、瓶子中并与之混合,或者可以用于包装浓缩物。营养补充剂还可以包括水。
(a)氨基酸剂量
如本领域技术人员将理解的,本发明的氨基酸组合物的剂量可以并且将根据受试者的体重、性别、年龄和/或医学疾患、受试者的体育锻炼强度、施用方法而变化。物种的非限制性实例可以包括人、伴侣动物、实验室动物、动物园动物或农业动物。常规实验可以很容易地确定所需剂量。口服施用的典型氨基酸剂量可以是每剂约7g。在一些实施方案中,可以施用约3、4、5、10或12g氨基酸组合物的氨基酸剂量。在其他实施方案中,可以施用约3、4、5、6、7、8、9、10、11或12g氨基酸组合物的氨基酸剂量。在示例性实施方案中,氨基酸剂量可以是每剂约7g。
根据需要,也可以每天施用多剂氨基酸组合物,以提供肌肉蛋白质合成的所需刺激。例如,每天可以施用一、二、三、四剂或更多剂氨基酸组合物。在一个优选的实施方案中,每天可以施用一剂氨基酸组合物。在另一优选的实施方案中,每天可以施用两剂氨基酸组合物。在又一优选的实施方案中,每天可以施用三剂氨基酸组合物。
本发明组合物的施用时间安排和持续时间可以并且将变化。例如,当在锻炼或不锻炼的情况下施用组合物以刺激肌肉蛋白质合成时,可以在没有日常锻炼的情况下、在开始日常锻炼之前、日常锻炼期间或日常锻炼之后施用组合物。或者,当施用该组合物以提高易出现肌肉问题的受试者如老年受试者的肌肉蛋白质合成时,可以定期施用该组合物。
在示例性实施方案中,当受试者是人时,每天可施用三剂、每剂3g的氨基酸组合物。在另一示例性实施方案中,每天可以施用两剂,每剂7g氨基酸组合物。在又一示例性实施方案中,每天可以施用单剂、每剂7g的氨基酸组合物。
(b)施用
本发明组合物可以通过静脉内、肌内、皮下注射或肠胃外途径施用。在一些实施方案中,组合物可被配制用于通过注射(例如,腹膜内、静脉内、皮下、肌内注射,等)施用。因此,优选将这些组合物与药学上可接受的媒介物诸如盐水、林格氏溶液、右旋糖溶液等组合在一起。
本发明的氨基酸组合物可以包含药物载体(或赋形剂)。此类载体可以是无毒的用于封装的任何溶剂或固体材料。载体可以赋予形态或稠度,或充当稀释剂。合适的药物载体可以包括液体载体,诸如生理盐水以及生理浓度或接近生理浓度的其他无毒盐,以及不用于人的固体载体,诸如滑石或蔗糖,或动物饲料。载体还可以包括稳定剂、润湿剂和乳化剂、用于改变渗透压的盐、包封剂、缓冲剂和皮肤渗透促进剂。载体和赋形剂以及用于肠胃外和非肠胃外药物递送的制剂阐述于Remington's Pharmaceutical Sciences,第19版,MackPublishing(1995)中。
对于肠胃外施用(包括皮下、皮内、静脉内、肌内和腹膜内施用),组合物可以是水性溶液或油基溶液。水性溶液可包括无菌稀释剂,诸如水,盐溶液,药学上可接受的多元醇,诸如甘油、丙二醇或其他合成溶剂;抗细菌剂和/或抗真菌剂,诸如苯甲醇、对羟基苯甲酸甲酯、氯丁醇、苯酚、硫柳汞等;抗氧化剂,诸如抗坏血酸或亚硫酸氢钠;螯合剂,诸如乙二胺四乙酸;缓冲剂,诸如醋酸盐、柠檬酸盐或磷酸盐;和/或用于调节张力的剂,诸如氯化钠、右旋糖或多元醇,诸如甘露醇或山梨糖醇。水溶液的pH可以用酸或碱,诸如盐酸或氢氧化钠来调节。油基溶液或悬浮液可进一步包含芝麻油、花生油、橄榄油或矿物油。
在优选实施方案中,本发明的氨基酸组合物可以口服施用。可用于施用本发明氨基酸组合物的口服制剂的非限制性实例可以是营养制剂、医疗食品、医疗饮料,其呈现为全餐、部分餐的形式;作为用于溶解的粉末的食品添加剂的形式;药物制剂的形式,诸如片剂、丸剂、囊剂或胶囊剂的形式,或通过管饲,诸如通过鼻饲、鼻十二指肠、食管造口术、胃造口术或空肠造口术施用的形式,或外周或全胃肠外营养品的形式。在示例性实施方案中,本发明的组合物可以作为膳食补充剂口服施用。
除组合物的氨基酸成分外,用于口服施用的组合物通常还包含有惰性赋形剂。口服制品可以封装在明胶胶囊中或压制成片剂。在此类制品中使用的常见赋形剂包括药学上相容的填充剂/稀释剂,诸如微晶纤维素、羟丙基甲基纤维素、淀粉、乳糖、蔗糖、葡萄糖、甘露醇、山梨糖醇、二碱式磷酸钙或碳酸钙;粘合剂,诸如海藻酸、羧甲基纤维素、微晶纤维素、明胶、黄芪胶或聚乙烯吡咯烷酮;崩解剂,诸如海藻酸、纤维素、淀粉或聚乙烯吡咯烷酮;润滑剂,诸如硬脂酸钙、硬脂酸镁、滑石、二氧化硅或硬脂酰富马酸钠;助流剂,诸如胶体二氧化硅;甜味剂,诸如蔗糖或糖精;调味剂,诸如薄荷、水杨酸甲酯或柑橘调味剂;着色剂;以及防腐剂,诸如抗氧化剂(例如维生素A、维生素C、维生素E或棕榈酸视黄酯)、柠檬酸或柠檬酸钠。口服制品还可以以水性悬浮液、酏剂或糖浆的形式施用。为此,可将活性成分与各种甜味剂或调味剂、着色剂,以及如果需要的话与乳化剂和/或悬浮剂以及稀释剂诸如水、乙醇、甘油及其组合组合在一起。
根据本发明的组合物可以是营养全面的,即可以包含维生素、矿物质、微量元素以及氮、碳水化合物和脂肪和/或脂肪酸来源,因此它们可以用作唯一的营养源,提供基本上所有每日需要的量的维生素、矿物质、碳水化合物、脂肪和/或脂肪酸、蛋白质等。
(II)方法
本发明还提供了用于增加肌肉蛋白质合成,预防和/或治疗肌肉质量、肌肉力量、肌肉功能和身体功能,或其任何组合中的任一种的损失的方法。该方法包括向受试者施用包含多种必需氨基酸和任选非必需氨基酸和/或营养素的组合物。用于施用的合适的组合和制剂分别在上文的第I节和第II节中有描述。
根据本公开的营养组合物可有利地用于制造用于预防或治疗哺乳动物,特别是成年哺乳动物中涉及肌肉衰退的疾病或疾患的药物。或者,根据本发明的营养组合物可有利地用于制造用于预防或治疗选自以下的组的疾病或疾患的药物:少肌症、肌肉损失、肌肉蛋白质合成不足、肌肉降解、肌肉蛋白质水解、肌肉萎缩、肌肉营养不良、肌肉分解代谢、肌肉消耗、肌肉力量损失、肌肉质量损失、肌肉功能损失、身体能力损失、身体机能损失、活动能力受损、虚弱、外科手术、残疾、跌倒风险和跌倒相关骨折风险。合适的受试者可以包括人、家畜动物、伴侣动物、实验室动物或动物园动物。在优选实施方案中,受试者为人。反应的幅度可部分取决于所给的剂量、氨基酸的确切组合、受试者的生理状况和/或年龄,和/或与锻炼进行有关的施用时间安排。
优选地,所述受试者是老年人。在这方面,本申请的上下文中提出,老年人是年龄为50岁或更大,特别是55岁或更大,更特别是60岁或更大,更特别是65岁或更大的人。这一相当宽泛的定义考虑到了这样一个事实,即平均年龄在不同人群、不同大洲等之间是不同的。大多数发达世界国家都接受65岁的实足年龄作为“老年人”或较年老的人的定义(与一个人可能开始领取养恤金的年龄相关联),但像许多西方化的概念一样,这并不适合例如非洲的状况。目前,没有***(UN)标准的数字标准,但UN同意西方世界老年人口的截止年龄为60岁以上。非洲对较年老的人或“老年人”的更为传统的定义对应于50至65岁的实足年龄,这取决于环境、地区和国家。
根据本公开的营养组合物可有利地用于在体重维持期间或之后、在能量限制期间或之后、在卧床休息期间或之后或在身体创伤后恢复期间预防或治疗肌肉衰退,特别是肌肉质量损失。在特别优选的实施方案中,本发明的组合物用于治疗受试者,例如患有超重或肥胖症的受试者,所述受试者遵循减肥计划、能量限制计划和/或锻炼计划。所述受试者可以是儿童、青少年、成人或老年受试者。在实施方案中,所述受试者是儿童、青少年或成人。
随着年龄的增长,肌肉质量和功能逐渐丧失,因此,到60岁时,许多其他方面健康的人受试者已经达到功能开始受到影响的阈值。一方面,给任何健康受试者施用本发明的组合物可以获得以下功效:增加肌肉蛋白质合成,增加肌肉力量,增加肌肉功能,或其组合,尽管反应的幅度可根据受试者的年龄和/或生理状况而变化。
身体蛋白质的损失经常伴随疾病,无论该疾病是短期还是长期的。在另一方面,向因疾病而损失身体蛋白质的受试者施用本发明的组合可以获得以下功效:增加受试者中的肌肉蛋白质合成,增加受试者中的肌肉力量,增加受试者中的肌肉功能,或其组合。在另一方面,向处于肌肉萎缩风险或患有肌肉萎缩的受试者施用本发明的组合可获得以下功效:增加肌肉蛋白质合成,增加肌肉力量,增加肌肉功能,或其组合。处于肌肉萎缩风险或患有肌肉萎缩的受试者的非限制性实例包括有久坐生活方式的人、从事坐着的工作的人、患有限制运动的医学疾患的人、卧床不起的受试者、远离地球引力的受试者、连接肌肉的神经受到损伤的受试者,以及处于影响控制肌肉的神经的疾病的风险或被诊断患有影响控制肌肉的神经的疾病的受试者。其中发生肌肉萎缩的疾病、病症或疾患的非限制性实例包括小儿麻痹症、格林-巴利综合征、慢性阻塞性肺疾病、充血性心力衰竭、急性冠状动脉综合征、慢性心力衰竭、心脏性恶病质、癌症、少肌症、脊髓损伤、骨关节炎、关节炎、中风、营养不良、肌肉营养不良(例如贝克型肌肉营养不良、先天性肌肉营养不良、杜氏营养不良症、远端型肌肉营养不良、德型肌肉营养不良、面肩胛肱型肌肉营养不良、肢节型肌肉营养不良、眼咽型肌肉营养不良)、脊髓性肌肉萎缩(例如ALS、运动神经元病、婴儿进行性脊髓性肌萎缩、中间型脊髓性肌肉萎缩、青少年脊髓性肌肉萎缩、成人脊髓性肌肉萎缩)、炎性肌肉病变(例如皮肌炎、多发性肌炎)、周围神经疾病(例如进行性神经性腓骨肌萎缩症(Carcot-Marie toothdisease)、德-索氏病(Dejerine-Sottas disease)、弗里德赖希共济失调(Friedreich’sataxia))、神经肌肉接头疾病(重症肌无力、兰伯特-伊顿综合征)、肌肉的代谢性疾病(酸性麦芽糖酶缺乏症、肉毒碱缺乏症、肉毒碱棕榈酰转移酶缺乏症、脱支酶缺乏症(DebrancherEnzyme Deficiency)、乳酸脱氢酶缺乏症、线粒体脱氨酶缺乏症、磷酸化酶缺乏症、磷酸果糖激酶缺乏症、磷酸甘油酸激酶缺乏症)、其他肌肉病变(中央轴突症、甲状腺机能亢进性肌病、先天性肌强直症、肌小管性肌病、先天性类肌强直、周期性麻痹-低钾血症-高钾血症),或需要使受试者固定不动或卧床休息的任何其他疾病或疾患,尤其是慢性心力衰竭和心脏性恶病质。
本发明的方法通常包括将氨基酸组合物施用于受试者。合适的受试者包括动物,诸如哺乳动物和人。合适的动物的非限制性实例包括陪伴动物,诸如猫、狗、啮齿动物和马;研究动物,诸如小鼠、大鼠和其他啮齿动物;农业动物,诸如奶牛、牛、猪、山羊、绵羊、马、鹿、鸡和其他家禽;动物园动物;和灵长类动物,诸如黑猩猩、猴子和大猩猩。在优选实施方案中,受试者是人。在另一优选实施方案中,受试者是哺乳动物。
根据需要,施用频率可以是每天一次、两次、三次或更多次,或者每周或每月一次、两次、三次或更多次,以产生期望的效果。施用于受试者的量可以并且将根据受试者(例如年龄、体重、健康状况)和特定的施用方式而变化。本领域技术人员将理解,剂量还可以在Goodman&Goldman's The Pharmacological Basis of Therapeutics,第十版(2001),附录II,第475-493页,和the Physicians'Desk Reference的指导下确定。
人受试者可以是任何年龄的。在一些实施方案中,人受试者可以是约30、40、45、50、55、60、65、70、75、80、85、90、95岁或更老。在一些优选实施方案中,人受试者的年龄是40岁或更老。在其他优选实施方案中,人受试者的年龄是45岁或更老。在又一些其他优选实施方案中,人受试者的年龄是50岁或更老。在另一些其他优选实施方案中,人受试者的年龄是55岁或更老。在其他优选实施方案中,人受试者的年龄是60岁或更老。在又一些其他优选实施方案中,人受试者的年龄是65岁或更老。在另一些其他优选实施方案中,人受试者的年龄是70岁或更老。在其他优选实施方案中,人受试者的年龄是75岁或更老。在另一些其他优选实施方案中,人受试者的年龄是80岁或更老。在又一些其他优选实施方案中,人受试者是85岁或更老。在另一些其他优选实施方案中,人受试者的年龄是90岁或更老。
在一些实施方案中,受试者可以是针对缺乏日常锻炼的受试者的实施方案的替代。
在其他实施方案中,受试者可以是针对缺乏有效刺激肌肉蛋白质合成的能力的受试者的实施方案的替代。
在其他实施方案中,受试者可能正在从缺乏体育锻炼中恢复。在高强度的肌肉体育锻炼期间,正在进行的肌肉活动的速度可能超过血液供应输送氧的能力,从而造成在肌肉细胞中诱发压力减小的状况,并可能导致肌肉损伤、功能受损、受伤倾向以及恢复期延长。可能导致肌肉损伤、功能受损、受伤倾向以及恢复期延长的体育锻炼的非限制性实例可包括柔韧性运动,诸如伸展运动,有氧运动,诸如骑自行车、游泳、散步、跳绳、划船、跑步、远足或打网球,无氧运动,诸如举重训练、功能训练、离心训练或短跑、力量训练、敏捷性训练或离心训练。
(a)肌肉蛋白质合成的提高
相对于不接受所述氨基酸组合物的受试者,本发明的方法提高了接受所述氨基酸组合物的受试者的肌肉蛋白质合成。
肌肉蛋白质合成的增加可以通过本领域已知的任何方法来测量。例如,多年来已经使用放射性标记的氨基酸或用稳定同位素标记的氨基酸来测量肌肉和血液中蛋白质合成和分解的速率。参见,例如,Yale J Biol Med 1997;70(1):65-76,其通过引用并入本文。尿液中3-甲基组氨酸的***量或3-甲基组氨酸的动静脉差异的测量被用作肌肉蛋白质分解的单向速率的测量。全身骨骼质量可以使用双能X射线(DEXA)吸收测定法或通过CT进行测量;参见,例如,Am J Clin Nutr 2002;76:378-83和J Appl Physiol 1985,其通过引用并入本文。测量肌肉力量或功能的方法也是本领域众所周知的。例如,肌肉力量和功能的变化可以使用如以下文献中所述的基本的标准化测试来评估:B J Nutr 2012;108:S88-93或Lu等人(2012)“Strength and Functional Measurement for Patients with MuscularDystrophy”Muscular Dystrophy,Madhuri Hegde博士(编辑),每一篇均在此通过引用并入。
在一些实施方案中,本发明的方法可使肌肉蛋白质合成增加至少2倍。例如,在施用本发明的组合后,肌肉蛋白质合成可以增加至少2倍、至少3倍、至少4倍、至少5倍、至少6倍、至少7倍、至少8倍、至少9倍、至少10倍或更多倍。在一些实施方案中,本发明的方法可以使肌肉力量增加至少2倍。例如,在施用本发明的组合后,肌肉力量可以增加至少2倍、至少3倍、至少4倍、至少5倍、至少6倍、至少7倍、至少8倍、至少9倍、至少10倍或更多倍。在一些实施方案中,本发明的方法可使肌肉功能增加至少2倍。例如,在施用本发明的组合后,肌肉功能合成可以增加至少2倍、至少3倍、至少4倍、至少5倍、至少6倍、至少7倍、至少8倍、至少9倍、至少10倍或更多倍。在其他实施方案中,本发明的方法可增加肌肉蛋白质合成、肌肉力量和肌肉功能,或其组合。测量肌肉蛋白质合成、肌肉力量和肌肉功能的方法是本领域已知的,并且在实施例中进一步详述。
(III)试剂盒
还提供了试剂盒。此类试剂盒可以包括本文所述的组合物,并且在某些实施方案中包括施用说明书。此类试剂盒可以促进本文所述方法的执行。当以试剂盒形式提供时,组合物的不同组分可以包装在单独的容器中,并在临使用前进行混合。如本文所述,组分包括但不限于氨基酸组合物。如果需要,组分的此种单独包装可以提供在这样的包装或分配器装置中,所述包装或分配器装置可以含有一种或多种含有组合物的单位剂量形式。所述包装可以例如包括金属或塑料箔,诸如泡罩包装。在某些情况下,组分的此种单独包装还可允许长期储存而不损失组分的活性。
试剂盒还可以包括在单独容器中的试剂,诸如无菌水或盐水,以添加到单独包装的冻干活性组分中。例如,密封的玻璃安瓿瓶可含有冻干的组分,以及在单独安瓿瓶中的无菌水、无菌盐水或无菌物质,其中的每一种都在中性非反应气体(诸如氮气)下进行包装。安瓿瓶可以由任何合适的材料,诸如玻璃、有机聚合物(诸如聚碳酸酯、聚苯乙烯)、陶瓷、金属或通常用于容纳试剂的任何其他材料组成。合适的容器的其他实例包括可以由与安瓿类似的物质制成的瓶子,以及可以由衬有铝箔的内部材料(诸如铝或合金)组成的封套。其他容器包括试管、小瓶、烧瓶、瓶子、注射器等。容器可以具有无菌进入口,诸如具有可被皮下注射针头刺穿的塞子的瓶子。其他容器可以有两个隔室,这两个隔室由可容易移除的膜隔开,该膜在移除后允许组分混合。可移除的膜可以是玻璃、塑料、橡胶等。
在某些实施方案中,试剂盒可以提供说明材料。说明书可以打印在纸或其他基材上,和/或可以作为电子可读介质,诸如软盘、小型CD-ROM、CD-ROM、DVD-ROM、Zip光盘、录像带、录音带等来提供。详细说明可能与试剂盒没有实际关联;而是可将用户引导到该试剂盒的制造商或经销商指定的Internet网站。
定义
应当理解,本文所用的所有术语仅用于描述特定实施方案的目的,并不旨在以任何方式或范围进行限制。例如,如在本说明书和所附权利要求书中所使用的,单数形式“一个/种(a/an)”和“所述”可以包括复数指代物,除非内容另外明确指出。术语“包括”、“包含”和“具有”旨在是包含性的,并且意味着可能存在除所列元素之外的另外的元素。进一步地,所有的单位、前缀和符号都可以用国际单位制接受的形式来表示。
除非另有说明,否则如本文所用的以下定义都将适用。为了本发明的目的,根据CAS版本的元素周期表和Handbook of Chemistry and Physics,第75版,1994年,来识别化学元素。此外,有机化学的一般原理描述于“Organic Chemistry,”Thomas Sorrell,University Science Books,Sausalito:1999,和“March’s Advanced OrganicChemistry,”第5版,Smith,M.B.and March,J.编辑,John Wiley&Sons,New York:2001中,所述文献的全部内容通过引用合并于此。
本文中所用的术语“mmol”旨在表示毫摩尔。本文中所用的术语“equiv”旨在表示当量。本文中所用的术语“mL”旨在表示毫升。本文中所用的术语“g”旨在表示克。本文中所用的术语“kg”旨在表示千克。本文中所用的术语“μg”旨在表示微克。本文中所用的术语“h”旨在表示小时。本文中所用的术语“min”旨在表示分钟。本文中所用的术语“M”旨在表示摩尔。本文中所用的术语“μL”旨在表示微升。本文中所用的术语“μM”旨在表示微摩尔。本文中所用的术语“nM”旨在表示纳摩尔。本文中所用的术语“N”旨在表示正常。本文中所用的术语“amu”旨在表示原子质量单位。本文中所用的术语“℃”旨在表示摄氏度。本文中所用的术语“wt/wt”旨在表示重量/重量。本文中所用的术语“v/v”旨在表示体积/体积。本文中所用的术语“MS”旨在表示质谱分析。本文中所用的术语“HPLC”旨在表示高效液相色谱分析。本文中所用的术语“RT”旨在表示室温。本文中所用的术语“e.g.”旨在表示示例。本文中所用的术语“N/A”旨在表示未测试。
说明书中列举的数字范围包括限定范围的数字,并且包括所限定范围内的每个整数。在整个本公开中,本发明的各个方面以范围形式呈现。应当理解,呈范围形式的描述仅仅是为了方便和简洁,而不应被解释为对本发明范围的硬性限制。因此,范围的描述应当被认为已经明确地公开了该范围内所有可能的子范围、分数和单个数值。例如,对范围诸如1至6的描述应被认为已经明确公开了子范围诸如1至3、1至4、1至5、2至4、2至6、3至6等,以及该范围内的单个数字,例如1、2、3、4、5和6,和小数和分数,例如1.2、3.8、11/2和43/4。无论范围有多宽,这都适用。在本申请的上下文中,术语“至少”还包括开放范围的起点。例如,“至少95重量%”的量指的是等于或大于95重量%的任何量。
本文中所用的术语“重量百分比(weight percent/percent by weight)”、“wt-%”、“重量%”及其变体是指物质的浓度,即该物质的重量除以组合物的总重量,再乘以100。应当理解,如本文所用,“百分比”、“%”等旨在与“重量百分比”、“wt-%”等同义。
本文中所用的术语“约”是指例如可由典型的测量技术和设备而产生的相对于任何可量化的变量(包括但不限于质量和体积)的数值量的变化。进一步地,考虑到现实世界中使用的固体和液体处理程序,可能会由于用于制备组合物或实施所述方法等的成分的制造、来源或纯度不同而产生某些无意的误差和变化。
本发明的方法和组合物可以包括以下、基本上由或由以下组成:本发明的组分和成分以及本文所述的其他成分。如本文所用,“基本上由...组成”是指所述方法和组合物可包括另外的步骤、组分或成分,但是仅在所述另外的步骤、组分或成分不实质上改变所要求保护的方法和组合物的基本和新颖特征的情况下。
由于在不脱离本发明的范围的情况下,可以对上述组合物和方法进行各种改变,因此上述描述和下面给出的实施例中包含的所有内容应被解释为说明性的,而不是限制性的。
实施例
包括以下实施例以说明本公开的各种实施方案。本领域技术人员应理解以下实施例中公开的技术代表了发明人发现的在本发明的实践中发挥良好作用的技术,并且因此可被认为构成本发明实践的优选方式。然而,根据本公开,本领域的技术人员应该理解,在不脱离本发明的精神和范围的情况下,可以对所公开的具体实施方案进行许多改变,并且仍然获得相似或类似的结果。
实施例1.3.6g EAA与精氨酸的混合物的作用的实验证据。
进行下面的研究以量化对两剂以下氨基酸制剂的反应:
·1-2%组氨酸
·9-11%异亮氨酸
·35-38%亮氨酸
·14-17%赖氨酸
·2-4%甲硫氨酸
·5-7%苯丙氨酸
·8-9%苏氨酸
·9-11%缬氨酸
·0.002-0.8%色氨酸
·8-11%的精氨酸
在一组老年受试者中确定了由摄入3.6或10.8g上述氨基酸制剂引起的肌肉蛋白质合成的急性刺激(参见表1)。之所以选择3.6g的剂量,是因为基于成本和口味,该剂量具有商业可行性。将对3.6g的反应与对10.8g剂量的反应进行比较,因为更高的剂量已被证明不仅刺激肌肉蛋白质FSR,而且在力量和身体功能方面带来长期的结果益处(13)。在口服摄入氨基酸制剂之前和之后确定肌肉蛋白质合成。
表1受试者特征
受试者在禁食一夜后接受研究。研究程序涉及禁食5小时时段和摄入EAA配方后3小时时段。在整个实验期间,持续给受试者输注示踪量的2H5-苯丙氨酸。在基础阶段注入示踪剂2小时和5小时后,以及摄入氨基酸配方3小时后,进行肌肉活检。在每个活检样品上确定无肌肉和蛋白质结合的苯丙氨酸富集度,并在基础状态和摄入配方后3小时内计算肌肉蛋白质的分数合成比率(FSR)。肌肉蛋白质FSR反映了单位时间内(在此实验中为每小时)产生的全部肌肉的分数。由于在该实验这样短的时间内,从研究的开始到结束,肌肉蛋白质的数量不可能改变,因此肌肉蛋白质FSR直接反映了肌肉蛋白质合成的绝对速率。值被计算为后值-前值。以这种方式,每个受试者充当自己的对照,正如在各种研究中已证明的,在本研究的时间范围内,禁食情况下肌肉蛋白质合成没有改变(例如,14)。摄入后的值代表摄入氨基酸制剂后整个3小时的综合反应。
摄入3.6g剂量后,肌肉FSR增加0.0568%/h。这比基础FSR增加了57%。相应的值增加了0.0692%/h,比基础值增加了76%。还测量了血浆EAA水平(表2)。
表2氨基酸浓度(mol/L/3hr)*
*超过相应基础值的增加,曲线下面积
**BCAA是支链氨基酸亮氨酸、缬氨酸和异亮氨酸
虽然在较高的剂量下给予了3倍的氨基酸,但是在较高剂量下肌肉蛋白质FSR的增加仅比对3.6g剂量的反应稍大。对较低剂量的不成比例的较大反应的部分解释是,表2中所给出的氨基酸浓度没有反映所摄入的氨基酸量的差异的大小。这可能反映了当以较高剂量提供时,EAA加速氧化,因此给定剂量的利用效率较低。换句话说,在肌肉水平上增加合成的信号对低剂量的反应不成比例地更大。这也表明3.6g的剂量足以激活肌肉中的合成反应。对3.6g剂量的不成比例的大反应的另一个可能的解释是,3.6g制剂中亮氨酸的量足以引发起始因子的最大激活,并且在较高剂量下FSR相对较小的增加完全反映出所供应的合成的前体的增加。
新合成的蛋白质包含所有20种氨基酸,但制剂中仅包含9种氨基酸。其余的氨基酸来源于对蛋白质分解产生的氨基酸更有效的再利用。因此,包括丙氨酸在内的一部分氨基酸反而被重新用于蛋白质合成,这些氨基酸通常是作为将氮转运到肝脏以结合到氨和尿素中以最终***到尿中的主要手段而从肌肉中释放出来。与这种解释一致,在较早的研究中观察到,摄入EAA混合物后,丙氨酸浓度下降(15),反映出蛋白质合成过程的再利用增强。因此,与摄入包含丙氨酸和其他NEAA的氨基酸混合物相比,EAA摄入后尿素产量没有增加(15)。
该结果是出乎意料的,因为用于刺激肌肉蛋白质合成的这一优化比例的EAA+精氨酸的剂量低下。典型的含氨基酸的蛋白质将需要远远超过20克的剂量才能产生比3.6克这种组合物低得多的效果。
Claims (17)
1.一种用于刺激肌肉蛋白质合成的方法,所述方法包括向受试者施用包含以下以w/w%计的以下浓度的氨基酸的组合物:约1%至2%的组氨酸、约9%至11%的异亮氨酸、约35%至38%的亮氨酸、约14%至17%的赖氨酸、约2%至4%的甲硫氨酸、约5%至7%的苯丙氨酸、约8%至9%的苏氨酸、约9%至11%的缬氨酸、约0.005至0.8%的色氨酸和约8%至11%的精氨酸,其中刺激肌肉蛋白质合成与未施用所述氨基酸组合物的受试者相比增加。
2.如权利要求1所述的方法,其中肌肉蛋白质合成在没有体育锻炼的情况下得到提高。
3.如权利要求1所述的方法,其中所述受试者是哺乳动物。
4.如权利要求1所述的方法,其中所述受试者是人。
5.如权利要求1所述的方法,其中所述受试者是年龄为40岁或更老的人。
6.如权利要求1所述的方法,其中肌肉蛋白质合成在3.6克的最小剂量下提高了大约50%。
7.如权利要求1所述的方法,其中所述组合物包含以w/w%计的以下浓度的氨基酸:1.5%的组氨酸、9.7%的异亮氨酸、36.4%的亮氨酸、15.2%的赖氨酸、3%的甲硫氨酸、6.1%的苯丙氨酸、8.5%的苏氨酸、10%的缬氨酸、0.6%的色氨酸和9%的精氨酸。
8.如权利要求6所述的方法,其中将12g剂量的所述组合物一天一次施用于人受试者。
9.如权利要求6所述的方法,其中将3.6g剂量的所述组合物一天三次给予人受试者。
10.如权利要求6所述的方法,其中将3.6g剂量的所述组合物一天一次给予人受试者。
11.如权利要求6所述的方法,其中将3.6g剂量的所述组合物一天两次给予人受试者。
12.如权利要求6所述的方法,其中将6.7g剂量的所述组合物一天一次给予人受试者。
13.如权利要求6所述的方法,其中将6.7g剂量的所述组合物一天两次给予人受试者。
14.如权利要求6所述的方法,其中将6.7g剂量的所述组合物一天三次给予人受试者。
15.一种包含下列氨基酸的组合物:组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、缬氨酸、色氨酸和精氨酸,所述组合物以小于12克的剂量在锻炼或不锻炼的情况下刺激肌肉蛋白质合成超过50%。
16.一种利用小于12克的剂量刺激肌肉蛋白质合成的方法,所述方法包括向受试者施用包含以下以w/w%计的以下浓度的氨基酸的组合物:约1%至2%的组氨酸、约9%至11%的异亮氨酸、约35%至38%的亮氨酸、约14%至17%的赖氨酸、约2%至4%的甲硫氨酸、约5%至7%的苯丙氨酸、约8%至9%的苏氨酸、约9%至11%的缬氨酸、约0.005%至0.8%的色氨酸和约8%至11%的精氨酸,其中在未施用所述氨基酸组合物的受试者中刺激肌肉蛋白质合成。
17.一种利用小于12克的剂量刺激肌肉蛋白质合成的方法,所述方法包括向受试者施用包含以下以w/w%计的以下浓度的氨基酸的组合物:约1%至2%的组氨酸、约9%至11%的异亮氨酸、约35%至38%的亮氨酸、约14%至17%的赖氨酸、约2%至4%的甲硫氨酸、约5%至7%的苯丙氨酸、约8%至9%的苏氨酸、约9%至11%的缬氨酸、约0.005%至0.8%的色氨酸和约8%至11%的精氨酸,其中在未锻炼的情况下在未施用所述氨基酸组合物的受试者中刺激肌肉蛋白质合成。
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- 2018-11-02 CA CA3079518A patent/CA3079518A1/en active Pending
- 2018-11-02 CN CN201880070954.6A patent/CN111295102A/zh active Pending
- 2018-11-02 CN CN202311374241.8A patent/CN118178404A/zh active Pending
- 2018-11-02 KR KR1020207011303A patent/KR20200083977A/ko not_active Application Discontinuation
- 2018-11-02 US US16/761,175 patent/US11273138B2/en active Active
- 2018-11-02 BR BR112020007447-0A patent/BR112020007447A2/pt unknown
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CO2020004801A2 (es) | 2020-05-05 |
BR112020007447A2 (pt) | 2020-12-08 |
CN118178404A (zh) | 2024-06-14 |
EP3703516A1 (en) | 2020-09-09 |
US11273138B2 (en) | 2022-03-15 |
SG11202003370VA (en) | 2020-05-28 |
KR20200083977A (ko) | 2020-07-09 |
US20200253908A1 (en) | 2020-08-13 |
CA3079518A1 (en) | 2019-05-09 |
RU2020117917A (ru) | 2021-12-02 |
WO2019090061A1 (en) | 2019-05-09 |
RU2020117917A3 (zh) | 2022-02-04 |
JP2021501746A (ja) | 2021-01-21 |
EP3703516A4 (en) | 2021-08-18 |
JP2023154042A (ja) | 2023-10-18 |
MX2020004397A (es) | 2020-08-06 |
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