CN115835786A - 对映纯的R-β-羟基丁酸混合盐-酸组合物 - Google Patents
对映纯的R-β-羟基丁酸混合盐-酸组合物 Download PDFInfo
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- CN115835786A CN115835786A CN202180022721.0A CN202180022721A CN115835786A CN 115835786 A CN115835786 A CN 115835786A CN 202180022721 A CN202180022721 A CN 202180022721A CN 115835786 A CN115835786 A CN 115835786A
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- hydroxybutyrate
- enantiomerically pure
- beta
- composition
- mixed salt
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Abstract
生酮R‑β‑羟基丁酸混合盐‑酸组合物包括对映纯的R‑β‑羟基丁酸和一种或更多种对映纯的R‑β‑羟基丁酸盐。所述R‑β‑羟基丁酸比盐或酯更迅速地被身体吸收和利用,增强了味道,并降低了对柠檬酸或其他食用酸的需求。所述对映纯的R‑β‑羟基丁酸盐被身体更慢地吸收和利用,并且可以提供一种或更多种电解质。用于提高对象酮体水平的组合物可以含有饮食或药学上可接受的载体和R‑β‑羟基丁酸混合盐‑酸组合物。该组合物含有小于100%摩尔当量的总对映纯R‑β‑羟基丁酸盐和大于0%摩尔当量的对映纯R‑β‑羟基丁酸。
Description
1.技术领域
本文公开了R-β-羟基丁酸化合物、盐、酸以及组合物和使用方法。
2.背景技术
在禁食、剧烈运动和/或低碳水化合物消耗期间,体内储存的葡萄糖和糖原被迅速使用并且可快速耗尽。当葡萄糖储备耗尽时却未能补充葡萄糖会导致身体代谢转变为通过产生和使用酮体来获取能量(“酮症”)。酮体可以被身体的细胞用作燃料来满足身体的能量需求,包括脑和心脏。例如,在长时间禁食期间,血酮水平可提高到2-3mmol/L或更高。通常认为,当血酮浓度超过0.5mmol/L时,心脏、脑和外周组织会使用酮体(例如,β-羟基丁酸酯和乙酰乙酸酯)作为主要燃料来源。这种状况被称为酮症。血液浓度在1.0mmol/L和3.0mmol/L之间时,这种状况称为“营养性酮症”。
在转变为酮症时,或者换言之,在肝脏中的生酮代谢期间,身体将饮食的和身体的脂肪用作主要能源。因此,一旦发生酮症,其可以通过控制饮食的脂肪摄入,保持低碳水化合物摄入和血液水平来维持酮症,从而诱导体脂减少。
在酮症期间,身体处于生酮状态并且基本上燃烧脂肪作为其主要燃料。身体将脂肪分解为脂肪酸和甘油,并将脂肪酸转化为乙酰辅酶A分子,然后其通过生酮作用最终转化为水溶性酮体β-羟基丁酸(即“β-羟基丁酸”或“BHB”)、乙酰乙酸(也称为乙酰丙酮)和肝脏中的丙酮。β-羟基丁酸和乙酰乙酸是身体用来获取能量的主要酮体,而丙酮则作为生酮作用的副产物被除去和排出。
酮体的代谢与多种有益效果相关,包括抗惊厥作用、脑代谢增强、神经保护、肌肉保留特性以及认知和身体机能改善。通过补充酮进行管理,以科学为基础的细胞代谢效率的改善可以对身体健康、认知健康和心理健康产生有益影响,并对与常见的可避免的疾病(例如肥胖、心血管疾病、神经退行性疾病、糖尿病和癌症)有关的健康产生长期影响。
尽管追求生酮饮食或生活方式并维持营养性酮症状态有许多健康优势,但在追求和维持生酮状态上仍然存在显著障碍。这些障碍之一是难以过渡到生酮状态。通过耗尽体内葡萄糖储备进入酮症的最快的内源性方法是禁食与运动相结合。这对身体和情绪都有要求,且即使对于最有动力和最有纪律的人来说也是极具挑战性的。
此外,向酮症的转变通常伴随着低血糖,这可能导致许多人嗜睡和头晕,引起通常被称为“低碳水化合物流感(low-carb flu)”的不适的生理和精神状态。此外,随着身体自然进入“节能”模式,许多人的新陈代谢会下降。一些人认为这些短暂的症状可能会持续两到三周。在此过渡期间,如果对象食用含有超过限制量的碳水化合物的正餐或零食,则生酮作用立即终止,身体退出其酮症状态,这是因为身体转回利用葡萄糖作为其主要燃料,而向酮症的转变必须重新开始。
如果对象成功建立酮症,则维持酮症的行为同样困难(如果不是更困难的话),因为需要维持碳水化合物和蛋白质与脂肪的严格饮食比例。在过渡到和维持生酮状态时经常发生的正常电解质平衡的破坏会使情况变得更加复杂。消耗和降低肝脏和肌肉中的糖原储备会降低身体保留水分的能力,导致更频繁的排尿,从而导致更多的电解质流失。此外,由酮症引起的胰岛素水平下降会影响肾脏提取某些电解质的速度,从而进一步降低体内电解质水平。电解质失衡的负面影响包括肌肉酸痛、痉挛、抽搐和虚弱、烦躁不安、焦虑、经常头痛、口渴、失眠、发热、心悸或心律不齐、消化问题如痛性痉挛、便秘或腹泻、精神错乱和注意力不集中、骨骼疾病、关节疼痛、血压变化、食欲或体重变化、疲劳(包括慢性疲劳综合征)、关节麻木和头晕(尤其是突然站立时)。
一些用于促进哺乳动物酮症的组合物包括β-羟基丁酸(RS-β-羟基丁酸或DL-β-羟基丁酸)的外消旋混合物。US 2017/0296501和EP 1755743公开了R-β-羟基丁酸盐、酯和低聚物的用途。US 8,642,654公开了β-羟基丁酸酯:(3R)-羟基丁基(3R)-羟基丁酸酯的用途。US 2018/0057846公开了部分缓冲的β-羟基丁酸酯游离酸,其中酸是主要成分(参见第[0027]段,公开了51-99%的游离酸、1-25%的酮盐、-10%的1,3-丁二醇,和1-49%的酮酯)。US 2018/0055797公开了不含游离酸的β-羟基丁酸盐组合物。US 2018/0021274中酸和盐组分的范围非常宽,在较窄范围中酸是主要组分或主要的少数组分(例如,以摩尔计至少30%的酸)。
发明内容
本文公开了对映纯的R-β-羟基丁酸混合盐-酸组合物和使用方法。R-β-羟基丁酸混合盐-酸组合物可用于控制对象的酮体水平,包括在一段较长的时间内促进和/或维持对象的酮症。
R-β-羟基丁酸对映异构体是由哺乳动物在酮症期间内源性产生的。因此,给予对象的对映纯的R-β-羟基丁酸可以立即被身体利用,例如用于产生能量(例如,作为葡萄糖的替代能源)。
R-β-羟基丁酸混合盐-酸组合物包括一定量的游离R-β-羟基丁酸与一种或更多种R-β-羟基丁酸盐组合。这提供了与快速吸收相结合的优化的或可接受的电解质负荷,特别是当向对象施用较高量的组合物时。与在没有游离R-β-羟基丁酸的情况下施用的R-β-羟基丁酸盐和/或酯相比,这提供了更大和/或更快的生酮作用。
将R-β-羟基丁酸与一种或更多种R-β-羟基丁酸盐组合是非常有益的,因为它降低电解质负荷、提高吸收率、改善味道、有助于更简便的配制,并降低了添加柠檬酸或其他食用酸以获得具有中性或酸性pH的组合物的需要。
在一些实施方案中,本文公开的组合物可用于提高对象酮体水平的方法中,包括促进和/或维持对象酮症,包括向有此需要的对象施用营养上或药学上有效量的本文公开的一种或更多种组合物。对象中酮体水平提高的有益效果的实例包括食欲抑制、体重减轻、脂肪减少、血糖水平降低、精神警觉性提高、体能提高、认知功能改善、创伤性脑损伤减轻、糖尿病影响降低、神经系统疾病改善、癌症减轻、炎症减轻、抗衰老、抗糖化、癫痫发作减轻、情绪改善、力量增加、肌肉质量增加或身体成分组成中的一种或更多种。
在一些实施方案中,所述组合物可以包括营养学或药学上可接受的载体。
具体实施方式
I.定义
化合物“β-羟基丁酸根”,也称为β-羟基丁酸根、3-羟基丁酸根、βHB或BHB,是β-羟基丁酸(具有通式CH3CH2OHCH2COOH的羟基羧酸)的去质子化形式。在通常的生物pH水平下存在的去质子化形式是CH3CH2OHCH2COO-。下面所示的一般化学结构代表可用于所公开的组合物中的β-羟基丁酸化合物:
其中,
X可以是氢、金属离子、氨基阳离子(例如来自氨基酸)、烷基、烯基、芳基或酰基。
当X是氢时,化合物是β-羟基丁酸。当X是金属离子或氨基阳离子时,化合物是β-羟基丁酸盐。当X是烷基、烯基、芳基或酰基时,化合物是β-羟基丁酸酯。前述化合物可以是任何所需的物理形式,例如结晶、粉末、固体、液体、溶液、混悬液或凝胶。
术语“对映纯的R-β-羟基丁酸”是指其仅含有内源性产生的β-羟基丁酸的R-对映异构体并且不与S-β-羟基丁酸组合,后者在工业生产外源性R-β-羟基丁酸时通常被作为副产物产生。因为S-β-羟基丁酸不是由身体产生的,所以它被排除在所公开的组合物外。
术语“R-β-羟基丁酸混合盐-酸组合物”是指包含一种或更多种R-β-羟基丁酸盐和游离R-β-羟基丁酸的组合物。
术语“R-β-羟基丁酸盐”并不意指或暗示任何特定的物理状态,例如结晶、粉末、其他固体形式、及其溶解在水中形成的液体溶液、分散在液体中形成的混悬液,或凝胶。可以通过用强碱或弱碱如碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐、碱性氨基酸等中和β-羟基丁酸而在溶液中形成盐。
术语“游离R-β-羟基丁酸”是指未去质子化和去质子化的R-β-羟基丁酸分子的总和。去质子化的R-β-羟基丁酸分子通常是指已释放质子以形成水合氢离子(H3O+)和R-β-羟基丁酸根阴离子的分子(例如,溶解在水中)。
当游离的R-β-羟基丁酸分子被包含在干粉或其他固体形式的R-β-羟基丁酸混合盐-酸组合物中时,其通常不会去质子化至任何显著程度。在这种情况下,R-β-羟基丁酸混合盐-酸组合物中游离R-β-羟基丁酸以重量计的分数量是游离R-β-羟基丁酸的重量除以游离R-β-羟基丁酸和R-β-羟基丁酸盐的总重量。R-β-羟基丁酸混合盐-酸组合物中游离R-β-羟基丁酸以摩尔计的分数量是游离R-β-羟基丁酸的摩尔当量除以游离R-β-羟基丁酸和R-β-羟基丁酸盐提供的R-β-羟基丁酸根阴离子的摩尔当量之和。
当溶解在水中时,一部分R-β-羟基丁酸通常会解离成R-β-羟基丁酸根阴离子和水合氢离子(H3O+)。因此,R-β-羟基丁酸分子可以与溶解的R-β-羟基丁酸盐交换质子和阳离子。为了定义在R-β-羟基丁酸混合盐-酸组合物中R-β-羟基丁酸和R-β-羟基丁酸盐的相对量,R-β-羟基丁酸分子的解离和质子与阳离子的交换不被理解为会改变游离R-β-羟基丁酸相对于来自R-β-羟基丁酸盐的R-β-羟基丁酸根阴离子的摩尔比。溶液中游离R-β-羟基丁酸分子的总量是溶解的未去质子化的R-β-羟基丁酸分子和R-β-羟基丁酸分子去质子化形成的R-β-羟基丁酸根阴离子之和。
换言之,溶液中R-β-羟基丁酸的总摩尔当量,无论是否去质子化,都应理解为以下二者之间的差值:(i)溶液中未去质子化的R-β-羟基丁酸分子的摩尔当量与R-β-羟基丁酸根阴离子的总摩尔当量(来自所有来源)的总和,以及(ii)由来自R-β-羟基丁酸盐化合物的阳离子提供的阳离子电荷的总摩尔当量(其等于由R-β-羟基丁酸盐提供的R-β-羟基丁酸根阴离子的总摩尔当量)。碱金属阳离子如钠和钾为每摩尔金属阳离子提供1摩尔阳离子电荷。另一方面,碱土金属阳离子,如镁和钙,为每摩尔金属阳离子提供2摩尔阳离子电荷。1摩尔去质子化的R-β-羟基丁酸分子提供1摩尔阴离子电荷和1摩尔阳离子电荷。
鉴于前述,溶液中R-β-羟基丁酸的摩尔分数相对于溶液中R-β-羟基丁酸混合盐-酸组合物的R-β-羟基丁酸分子的总摩尔数是[(i)-(ii)÷(i)],溶液中R-β-羟基丁酸盐的R-β-羟基丁酸分子的摩尔分数为[(ii)÷(i)]。将每种物质的摩尔分数乘以100可得出每种物质在溶液中的百分比。
例如,如果100摩尔当量的干粉状R-β-羟基丁酸混合盐-酸组合物含有以摩尔计5%的游离非去质子化R-β-羟基丁酸和95%的R-β-羟基丁酸盐,则基本上有5摩尔当量的R-β-羟基丁酸分子和95摩尔当量的R-β-羟基丁酸根阴离子。当有足够的水溶解R-β-羟基丁酸盐时,如果一部分R-β-羟基丁酸分子被去质子化,则未去质子化的R-β-羟基丁酸的摩尔当量会少于5,且R-β-羟基丁酸根阴离子的摩尔当量会大于95。溶液中R-β-羟基丁酸的去质子化程度与溶液pH有关。
如本文所用,“生酮组合物”被配制成用于提高对象的酮体水平,包括在其所施用的对象中诱导和/或维持酮体升高至期望水平的状态,例如酮症。
如本文所用,“对象”或“患者”是指动物界的成员,包括哺乳动物,例如但不限于人类和其他灵长类动物;啮齿动物、鱼类、爬行动物和鸟类。对象可以是任何需要治疗、处理或预防的动物,或任何疑似需要治疗、处理或预防的动物。预防是指进行一些方案以防止可能发生的病症,例如确定高血糖或糖尿病的病症。“患者”和“对象”在本文中可互换使用。
本文所用的“酮症”是指在对象中血酮水平在约0.5mmol/L至约16mmol/L范围内。酮症可以改善线粒体功能,降低活性氧的产生,减轻炎症并提高神经营养因子的活性。如本文所用,“酮症适应”是指延长营养性酮症(>1周)以实现持续的非病理性“轻度酮症”或“治疗性酮症”。
在一些情况下,“升高的酮体水平”可以并不意味着对象处于“临床酮症”状态,但仍然具有升高的酮体供应用于产生能量和/或用于进行酮体的其他有益效果。例如,与未“适应酮”的对象相比,“适应酮”的对象不一定具有升高的血清酮体水平,但是能够更快地利用可用的酮体。在这种情况下,“升高的酮体水平”可以是指被对象利用的酮体的总量和/或比率,而不是血浆水平本身。
本文使用术语“给药”或“施用”来描述将所公开的组合物递送至对象的过程。该组合物可以多种方式施用,包括经口、胃内和肠胃外施用(指静脉内和动脉内以及其他适当的肠胃外途径)等。
II.R-β-羟基丁酸混合盐-酸组合物
本文公开的R-β-羟基丁酸混合盐-酸组合物包含一种或更多种对映纯的R-β-羟基丁酸盐和对映纯的R-β-羟基丁酸。提供一定量的R-β-羟基丁酸是有益的,因为与R-β-羟基丁酸盐形式相比,其吸收响应时间要快得多。此外,尽管游离的R-β-羟基丁酸通常是液体,当与水混合时会形成低pH值的酸性溶液并具有令人不快的味道,但当其与R-β-羟基丁酸盐形式结合且其中β-羟基丁酸的量相对于盐形式较小时,该组合物仍可形成固体、粉末或其他盐形式的典型形式。在这种情况下,R-BHB的盐和酸组合形式具有可接受的pH值和味道。R-β-羟基丁酸混合盐-酸组合物与纯R-β-羟基丁酸盐和酯相比具有显著优势,包括提高吸收率、提高生物利用度、降低电解质负荷、易于制造、显著改善味道和降低对用柠檬酸或其他食用酸以获得具有中性或酸性pH值的组合物的需求。
在一些实施方案中,R-β-羟基丁酸混合盐-酸组合物包含小于100%的一种或更多种对映纯的R-β-羟基丁酸盐和大于0%的对映纯的游离R-β-羟基丁酸。R-β-羟基丁酸混合盐-酸组合物可包含(以摩尔计)高达99.975%、99.95%、99.925%、99.90%、99.875%、99.85%、99.825%、99.80%、99.775%、99.75%、99.725%、99.70%、99.675%、99.65%、99.625%、99.60%、99.5%、99.4%、99.3%、99.2%、99.1%、99%、98.8%、98.65%、98.5%、98.35%、98.2%、98%、97.75%、97.5%、97.25%或97%,以及至少75%、80%、85%、90%、92%、94%、95%、96%、97%、98%、99%、99.2%、99.4%、99.60%、99.625%、99.65%、99.675%、99.70%、99.725%、99.75%、99.775%、99.80%、99.825%、99.85%、99.875%或99.9%的一种或更多种对映纯的R-β-羟基丁酸盐和至少0.025%、0.05%、0.075%、0.10%、0.125%、0.15%、0.175%、0.02%、0.225%、0.25%、0.275%、0.30%、0.325%、0.35%、0.375%、0.40%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、1.2%、1.35%、1.5%、1.65%、1.8%、2%、2.25%、2.5%、2.75%或3%,且小于25%、20%、15%、10%、8%、6%、5%、4%、3%、2%、1%、0.8%、0.6%、0.40%、0.375%、0.35%、0.325%、0.30%、0.275%、0.25%、0.225%、0.20%、0.175%、0.15%、0.125%或0.10%的对映纯的游离R-β-羟基丁酸。上述百分比以摩尔为基础表示(例如,对映纯的R-β-羟基丁酸盐或对映纯的游离R-β-羟基丁酸的摩尔数相对于盐和酸形式的对映纯的R-β-羟基丁酸化合物的总摩尔数)。
β-羟基丁酸是S-还是R-对映异构体取决于3-碳(β-碳)上的羟基(或在酯的情况下为氧基)相对于平面羧基的四面体取向。在本公开中,S-对映异构体形式被排除在外。R-β-羟基丁酸混合盐-酸组合物含有100%对映异构体当量的组合R-β-羟基丁酸盐和R-β-羟基丁酸,以及0%对映异构体当量的S-β-羟基丁酸盐和S-β-羟基丁酸。
R-β-羟基丁酸是由身体从脂肪产生的内源形式,并且可以在低葡萄糖水平的情况下或当对象的身体被补充可用形式的R-β-羟基丁酸时被对象用作燃料来源。R-β-羟基丁酸通常被称为“酮体”。
R-β-羟基丁酸混合盐-酸组合物可用于例如在对象中产生一种或更多种所需效果,包括但不限于食欲抑制、体重减轻、脂肪减少、降低血糖水平、提高精神警觉性、增加体能、改善认知功能、减轻创伤性脑损伤、减轻糖尿病影响、改善神经系统疾病、减轻癌症、减轻炎症、抗衰老、抗糖化、减轻癫痫发作、改善情绪、增加力量、提高肌肉质量或改善身体组成。
在一些实施方案中,R-β-羟基丁酸混合盐-酸组合物可以包括载体或与载体组合,例如饮食或药学上可接受的载体。组合物的载体或形式的实例包括粉末、液体、片剂、胶囊、食品、食品添加剂、饮料、维生素强化饮料、饮料添加剂、糖果、棒糖(sucker)、锭剂、食品补充剂、喷雾剂、注射剂和栓剂。
在一些实施方案中,R-β-羟基丁酸混合盐-酸组合物可以包括碱金属、碱土金属、过渡金属、氨基酸或氨基酸代谢物的一种或更多种盐。例子包括锂盐、钠盐、钾盐、镁盐、钙盐、锌盐、铁盐(如铁II和/或铁III)、铬盐、锰盐、钴盐、铜盐、钼盐、硒盐、精氨酸盐、赖氨酸盐、亮氨酸盐、异亮氨酸盐、组氨酸盐、鸟氨酸盐、瓜氨酸盐、谷氨酰胺盐和肌酸盐。
在一些实施方案中,所述组合物可以进一步包括或组合至少一种短链脂肪酸,或所述至少一种短链脂肪酸的甘油单酯、甘油二酯或甘油三酯,其中所述短链脂肪酸具有少于6个碳。示例性短链脂肪酸包括乙酸、丙酸、丁酸、异丁酸、戊酸和异戊酸。一个示例性短链甘油三酯是三丁酸甘油酯。这些分子可以为肠道提供保护并改善微生物组的健康。
所述组合物可包含或组合至少一种中链脂肪酸,或所述至少一种中链脂肪酸的甘油单酯、甘油二酯或甘油三酯,其中所述中链脂肪酸具有6至12个碳,优选8至10个碳。示例性中链脂肪酸是己酸、辛酸、癸酸和月桂酸。中链甘油三酯(Medium chain triglycerides,MCT)、中链脂肪酸和甘油单酯和甘油二酯是酮体前体,可为不依赖于R-β-羟基丁酸的酮体产生提供额外的来源。
组合物可以包括或组合至少一种长链脂肪酸,或所述至少一种长链脂肪酸的甘油单酯、甘油二酯或甘油三酯,其具有多于12个碳。长链脂肪酸的实例包括肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山嵛酸、二十二烷酸、蜡酸、ω-3脂肪酸、ω-6脂肪酸、ω-7脂肪酸和ω-9种脂肪酸。
中链脂肪酸或其酯(例如中链甘油三酯)的实例和来源包括椰子油、椰奶粉、分馏椰子油、棕榈油、棕榈仁油、辛酸、癸酸、分离的中链脂肪酸,例如分离的己酸、分离的辛酸、分离的癸酸、纯化的或天然形式的中链甘油三酯,例如椰子油,以及中链脂肪酸乙氧基化甘油三酯的酯衍生物、烯酮甘油三酯衍生物、醛甘油三酯衍生物、甘油单酯衍生物、甘油二酯衍生物和甘油三酯衍生物,以及中链甘油三酯的盐。酯衍生物任选地包括烷基酯衍生物,例如甲基、乙基、丙基、丁基、己基等。
R-β-羟基丁酸混合盐-酸组合物的施用导致酮体的血液水平升高,从而利用酮症的代谢和生理优势。与旨在仅基于饮食(例如,基于禁食和/或限制碳水化合物摄入)诱导和维持酮症的方法相比,提高血液中酮体的水平为对象提供了更大的饮食选择灵活性。例如,已被给予适量R-β-羟基丁酸混合盐-酸组合物的对象将能够偶尔食用碳水化合物或糖类食物,且不会危及生酮状态并转回以葡萄糖为基础的代谢状态。此外,这种施用有助于更容易地转变为生酮状态,同时减轻或消除通常与进入酮症相关的有害影响。
在一些实施方案中,生酮组合物另外包含治疗有效量的维生素D3。维生素D3被认为与镁和钙一起作用,以促进良好的骨骼健康并防止软组织发生不良钙化。在优选的实施方案中,生酮组合物的平均日剂量包含约200IU(“国际单位”)至约8000IU,或约400IU至约4000IU,或约600IU至约3000IU的维生素D3。在一些实施方案中,生酮组合物的平均日剂量包含约5μg至约200μg,或约10μg至约100μg,或约15μg至约75μg的维生素D3。
一些实施方案还包括一种或更多种额外的酮前体或补充剂。这些额外的酮前体或补充剂可以包括乙酰乙酸酯、酮酯和/或其他化合物,它们会导致血酮水平升高,而不会向血流中加入更多的电解质。其他添加剂包括增强酮体作用或转运酮体到线粒体中的代谢物、咖啡因、可可碱和益智药,例如L-α甘油磷酸胆碱(“αGPC”)。
组合物可以包括有助于掩盖β-羟基丁酸化合物味道的调味剂。其包括精油,例如薄荷、天然和人造甜味剂,以及本领域已知的其他调味剂。
在一些实施方案中,生酮组合物可以进一步包括一种或更多种附加组分,其被用来降低组合物的吸湿性。例如,可以包括消耗安全的类型和数量的各种抗结块剂、流动剂和/或吸湿剂。此类附加组分可包括硅铝酸盐、亚铁氰化物、碳酸盐或碳酸氢盐、硅酸盐(例如硅酸钠或硅酸钙)、二氧化硅、磷酸盐(例如磷酸二钙或磷酸三钙)、滑石、粉状纤维素、碳酸钙等中的一种或更多种。
III.施用
在一些实施方案中,本文公开的组合物可用于提高对象的酮体水平,包括促进和/或维持酮症的方法,该方法包括向有此需要的对象施用营养或药学有效量的一种或更多种本文公开的组合物。在对象中提高酮体水平(包括促进和/或维持酮症)的有益效果的实例包括食欲抑制、体重减轻、脂肪减少、血糖水平降低、精神警觉性提高、体能增加、认知能力改善、减轻创伤性脑损伤、减轻糖尿病的影响、改善神经系统疾病、减轻癌症、减轻炎症、抗衰老、抗糖化、减轻癫痫发作、改善情绪、增加力量、提高肌肉质量、或改善身体组成中的一种或更多种。
本文所述的生酮组合物可以在对象中施用治疗有效剂量和/或以诱导或维持酮症的频率施用。在一些实施方案中,单次(或单位)剂量将包括R-β-羟基丁酸混合盐-酸组合物的量为约0.5克至约25克、或约0.75克至约20克、或约1克至约15克,或约1.5克至约12克。
术语“单位剂量”是指被配置为递送特定量或剂量的组合物或其组分的剂型。示例性剂型包括但不限于片剂、胶囊剂、粉剂、食品、食品添加剂、饮料(例如调味的、维生素强化的或非酒精的)、饮料添加剂(例如调味的、维生素强化的或非酒精的)、糖果、棒糖、锭剂、食品补充剂、饮食上可接受的喷雾剂(如调味口腔喷雾剂)、注射剂(如无酒精注射剂)和栓剂。此类剂型可以被用于提供完整的单位剂量或其部分(例如,单位剂量的1/2、1/3或1/4)。
可用于提供单位剂量的组合物或其组分的另一种剂型是单位剂量测量装置,例如杯子、量斗(scoop)、注射器、滴管、量匙(spoon)、刮勺(spatula)或结肠灌洗装置,其被用于在其中保持测量量等于完整单位剂量或其分数(例如,单位剂量的1/2、1/3或1/4)的组合物。例如,包含多个单位剂量的组合物(例如,5-250或10-150个单位剂量)的散装容器,例如箱(carton)、盒、罐、缸、袋、小包、瓶、壶或小桶,可以与用于提供单位剂量或其部分的组合物或其组分的单位剂量测量装置一起提供给用户。
用于以散装形式提供如本文所公开的组合物的试剂盒,在提供单位剂量的组合物的同时,可包括一个容纳有一定量的组合物的散装容器和一个被用于提供单位剂量或其部分的组合物或其组分的单位剂量测量装置。一个或更多个单位剂量测量装置可以在销售时被放置在散装容器内,或连到散装容器的外部,或与散装容器一起预先包装在一个更大的包装中,或由销售商或制造商提供与一个或更多个散装容器一起使用。
试剂盒可以包含关于单位剂量或其部分的大小以及施用方式和频率的说明书。说明书可以提供在散装容器上、或与散装容器一起预先包装、或放在与散装容器一起出售的包装材料上,或者由销售商或制造商以其他方式提供(例如,在网站、邮件、传单、产品资料等上)。使用说明可包括关于如何使用单位剂量测量装置以正确递送单位剂量或其部分的参考。说明书可以作为补充或替代地包括未随散装容器一同提供的常见单位剂量测量装置(例如,在所提供的单位剂量测量装置丢失或错放的情况下)的参考,例如量匙、刮勺、杯子等。在这种情况下,最终用户可以按照散装容器上或随散装容器提供的说明书或销售商提供的关于产品以及如何正确递送单位剂量的组合物或其部分的说明书来构建试剂盒。
在一些实施方案中,生酮组合物可以包括其他补充剂或与其他补充剂一起施用,例如维生素D3、维生素、矿物质、益智药和本领域已知的其他补充剂。可以添加到生酮组合物中的维生素、矿物质和草药补充剂的例子包括维生素A、维生素C、维生素E、烟酸、维生素B6、叶酸、5-MTHF、维生素B12、碘、锌、铜、锰、铬、咖啡因、可可碱、茶碱、甲基游离碱、石杉碱甲、表儿茶素和酶中的一种或更多种。
在一些实施方案中,对象优选地遵循在组合物施用期间限制碳水化合物和蛋白质摄入的生酮饮食。在一个示例性实施例中,对象可将饮食摄入限制为约65%的脂肪、约25%的蛋白质和约10%的碳水化合物的比例。由此产生的治疗性酮症提供了快速和持续的酮体适应,以此作为多种代谢紊乱的代谢疗法,并为治疗性禁食、体重减轻和性能增强提供营养支持。因此,该组合物通常每天一次、每天两次或每天三次给予希望促进和/或维持酮症状态的对象。
在一些实施方案中,生酮组合物以每天一个或更多个单位剂量通过固体和/或粉末形式(例如粉末混合物(例如,粉末填充的明胶胶囊)、硬压片剂)经口施用,或通过本领域技术人员已知的其他经口施用途径。
在一些实施方案中,在一段时间内施用多剂量组合物。组合物的施用频率可以根据多种因素中的任何一种而变化,例如从先前治疗开始的治疗时间、治疗目标等。组合物的施用持续时间(例如,施用药剂的时间段)可以根据多种因素中的任何一种而变化,包括对象反应、期望的治疗效果等。
待施用的组合物的量可以根据例如个体的易感程度、个体的年龄、性别和体重、个体的特异反应等因素而变化。“治疗有效量”是促进体内治疗有效结果(即治疗性酮症)所必需的量。根据本公开,合适的单剂量大小是当在合适的时间段内施用一次或更多次时能够预防或减轻(减轻或消除)患者症状的剂量。
所施用的组合物的量将取决于未使用的酮体的效力、吸收、分布、代谢和排出速率、电解质、施用方法和正在治疗的特定疾病,以及本领域技术人员已知的其他因素。考虑到要减轻的病症的严重性,该剂量应该足以造成期望的反应,例如针对特定疾病或病症的治疗或预防响应。化合物可以一次施用,或者可以分开并间隔时间施用。应当理解,施用可以根据个人需要和根据施用或监督组合物施用的人的专业判断进行调整。
IV.实施例
以下是对用于提高对象酮水平的示例性R-β-羟基丁酸混合盐-酸组合物的描述,包括诱导和/或调节被施用对象的生酮状态。组合物可以包括R-β-羟基丁酸盐和游离R-β-羟基丁酸的混合物,以提供所需的电解质平衡、味道和/或药代动力学反应。组合物还可与本文公开的短链、中链或长链脂肪酸、酯、甘油酯和其他补充剂组合,以提供升高至期望水平的酮体和其他效果。
实施例1
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供99%摩尔当量的R-β-羟基丁酸盐和1%摩尔当量的R-β-羟基丁酸。因为与R-β-羟基丁酸盐相比,该组合物包含较少量的R-β-羟基丁酸,所以该组合物的吸收速度只比仅包含BHB盐形式的组合物稍快(尽管显著),但比R-β-羟基丁酸酯形式快得多。
将R-β-羟基丁酸混合盐-酸组合物作为生酮组合物施用,例如以粉末形式作为与食物或饮料混合的饮食补充剂,或以一种或更多种胶囊或片剂的形式,或以液体形式如口腔喷雾剂。
实施例2
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供98%摩尔当量的R-β-羟基丁酸盐和2%摩尔当量的R-β-羟基丁酸。因为与实施例1相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1的组合物吸收得更快。另一方面,包含相当大百分比的量的R-β-羟基丁酸盐仍然使吸收延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平较慢提高。
实施例3
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供97%摩尔当量的R-β-羟基丁酸盐和3%摩尔当量的R-β-羟基丁酸。因为与实施例1和2相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1和2的组合物吸收得更快。另一方面,包含相当大百分比的量的R-β-羟基丁酸盐仍然使吸收延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平较慢提高。
实施例4
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供96%摩尔当量的R-β-羟基丁酸盐和4%摩尔当量的R-β-羟基丁酸。因为与实施例1-3相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-3的组合物吸收得更快。另一方面,包含相当大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例5
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供95%摩尔当量的R-β-羟基丁酸盐和5%摩尔当量的R-β-羟基丁酸。因为与实施例1-4相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-4的组合物吸收得更快。另一方面,包含相当大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例6
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供94%摩尔当量的R-β-羟基丁酸盐和6%摩尔当量的R-β-羟基丁酸。因为与实施例1-5相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-5的组合物吸收得更快。另一方面,包含相当大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例7
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供92%摩尔当量的R-β-羟基丁酸盐和8%摩尔当量的R-β-羟基丁酸。因为与实施例1-6相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-6的组合物吸收得更快。另一方面,包含大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例8
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供90%摩尔当量的R-β-羟基丁酸盐和10%摩尔当量的R-β-羟基丁酸。因为与实施例1-7相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-7的组合物吸收得更快。另一方面,包含大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例9
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供85%摩尔当量的R-β-羟基丁酸盐和15%摩尔当量的R-β-羟基丁酸。因为与实施例1-8相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-8的组合物吸收得更快。另一方面,包含大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例10
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供80%摩尔当量的R-β-羟基丁酸盐和20%摩尔当量的R-β-羟基丁酸。因为与实施例1-9相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-9的组合物吸收得更快。另一方面,包含大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例11
R-β-羟基丁酸混合盐-酸组合物通过将一种或更多种对映纯的R-β-羟基丁酸盐与对映纯的R-β-羟基丁酸组合以提供75%摩尔当量的R-β-羟基丁酸盐和25%摩尔当量的R-β-羟基丁酸。因为与实施例1-10相比,该组合物包含更高百分比的R-β-羟基丁酸,所以该组合物比实施例1-10的组合物吸收得更快。另一方面,包含大百分比的量的R-β-羟基丁酸盐仍然使吸收有些延迟,使得与含有更高量的R-β-羟基丁酸的组合物相比,其可以使对象血酮水平更慢提高。
实施例12
将实施例1-11的任何前述R-β-羟基丁酸混合盐-酸组合物或其变体与饮食(即,营养学)或药学上可接受的载体混合。
实施例13
将R-β-羟基丁酸混合盐-酸组合物与一种或更多种短链脂肪酸和/或其一种或更多种甘油单酯、甘油二酯或甘油三酯(例如三丁酸甘油酯)组合来修改任一前述实施例。
实施例14
将R-β-羟基丁酸混合盐-酸组合物与一种或更多种中链脂肪酸和/或其一种或更多种甘油单酯、甘油二酯或甘油三酯(例如MCT油)组合来修改任一前述实施例。
实施例15
将R-β-羟基丁酸混合盐-酸组合物与一种或更多种长链脂肪酸和/或其一种或更多种甘油单酯、甘油二酯或甘油三酯组合来修改任一前述实施例。
实施例16
将R-β-羟基丁酸混合盐-酸组合物与一种或更多种补充剂,例如维生素D3、维生素、矿物质和本领域已知的其他物质组合,以修改任一前述实施例。
实施例17
将R-β-羟基丁酸混合盐-酸组合物与一种或更多种增强酮体效果或促进酮体向线粒体转运的添加剂或代谢物、咖啡因、可可碱或益智药(例如L-α甘油基磷酸胆碱)组合,以修改任一前述实施例。
实施例18
制造一种R-β-羟基丁酸混合盐-酸组合物,其含有高达99.975%、99.95%、99.925%、99.90%、99.875%、99.85%、99.825%、99.80%、99.775%、99.75%、99.725%、99.70%、99.675%、99.65%、99.625%、99.60%、99.5%、99.4%、99.3%、99.2%、99.1%、99%、98.8%、98.65%、98.5%、98.35%、98.2%、98%、97.75%、97.5%、97.25%或97%的一种或更多种对映纯的R-β-羟基丁酸盐,以及至少0.025%、0.05%、0.075%、0.10%、0.125%、0.15%、0.175%、0.02%、0.225%、0.25%、0.275%、0.30%、0.325%、0.35%、0.375%、0.40%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、1.2%、1.35%、1.5%、1.65%、1.8%、2%、2.25%、2.5%、2.75%或3%的游离对映纯R-β-羟基丁酸。
Claims (20)
1.用于提高对象酮水平的R-β-羟基丁酸混合盐-酸组合物,其包含:
对映纯的R-β-羟基丁酸;和
一种或更多种对映纯的R-β-羟基丁酸盐,其选自:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;和
对映纯的R-β-羟基丁酸镁;
其中所述组合物为固体和/或粉末形式。
2.根据权利要求1所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含以下中的至少两种:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;或者
对映纯的R-β-羟基丁酸镁。
3.根据权利要求1或2所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含以下中的至少三种:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;或者
对映纯的R-β-羟基丁酸镁。
4.根据权利要求1至3中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;和
对映纯的R-β-羟基丁酸镁。
5.根据权利要求1至4中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含75%至99.975%摩尔当量的总对映纯R-β-羟基丁酸盐和25%至0.025%摩尔当量的对映纯R-β-羟基丁酸。
6.根据权利要求1至5中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含80%至99.95%摩尔当量的总对映纯的R-β-羟基丁酸盐和20%至0.05%摩尔当量的对映纯R-β-羟基丁酸。
7.根据权利要求1至6中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含85%至99.925%摩尔当量的总对映纯的R-β-羟基丁酸盐和15%至0.075%摩尔当量的对映纯R-β-羟基丁酸。
8.根据权利要求1至5中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含99.60%至99.975%摩尔当量的总对映纯的R-β-羟基丁酸盐和0.40%至0.025%摩尔当量的对映纯R-β-羟基丁酸。
9.根据权利要求1至8中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其还包含至少一种具有少于6个碳的短链脂肪酸,或所述至少一种短链脂肪酸的甘油单酯、甘油二酯或甘油三酯。
10.根据权利要求1至9中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其还包含至少一种具有6至12个碳的中链脂肪酸,或所述至少一种中链脂肪酸的甘油单酯、甘油二酯或甘油三酯。
11.根据权利要求1至10中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其还包含具有阳离子的R-β-羟基丁酸盐,所述阳离子选自其他碱金属、其他碱土金属、过渡金属、氨基酸或氨基酸代谢物。
12.根据权利要求11所述的R-β-羟基丁酸混合盐-酸组合物,其中所述R-β-羟基丁酸盐选自锂盐、锌盐、铁盐、铬盐、锰盐、钴盐、铜盐、钼盐、硒盐、精氨酸盐、赖氨酸盐、亮氨酸盐、异亮氨酸盐、组氨酸盐、鸟氨酸盐、瓜氨酸盐、谷氨酰胺盐和肌酸盐。
13.根据权利要求1至12中任一项所述的R-β-羟基丁酸混合盐-酸组合物,其还包含至少一种选自维生素、矿物质、益智药和草药补充剂的补充剂。
14.一种用于提高对象酮水平的R-β-羟基丁酸混合盐-酸组合物,其包含:
对映纯的R-β-羟基丁酸;和
一种或更多种对映纯的R-β-羟基丁酸盐,其选自:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;和
对映纯的R-β-羟基丁酸镁,
其中所述组合物作为以下形式或在以下形式中提供:片剂、胶囊、粉末、食品、食品添加剂、调味饮料、维生素强化饮料、非酒精饮料、调味饮料添加剂、维生素强化饮料添加剂、非酒精饮料添加剂、糖果、棒糖、锭剂、食品补充剂、调味口腔喷雾剂或栓剂。
15.根据权利要求14所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含75%至99.975%摩尔当量的总对映纯的R-β-羟基丁酸盐和25%至0.025%摩尔当量的对映纯R-β-羟基丁酸。
16.一种用于提高对象酮水平的R-β-羟基丁酸混合盐-酸组合物,其包含:
饮食或药学上可接受的载体,其选自片剂、胶囊、粉末、食品、食品添加剂、调味饮料、维生素强化饮料、非酒精饮料、调味饮料添加剂、维生素强化饮料添加剂、非酒精饮料添加剂、糖果、棒糖、锭剂、食品补充剂、调味口腔喷雾剂和栓剂;
对映纯的R-β-羟基丁酸;和
一种或更多种对映纯的R-β-羟基丁酸盐,其选自:
对映纯的R-β-羟基丁酸钠;
对映纯的R-β-羟基丁酸钾;
对映纯的R-β-羟基丁酸钙;和
对映纯的R-β-羟基丁酸镁。
17.根据权利要求16所述的R-β-羟基丁酸混合盐-酸组合物,其中所述组合物包含75%至99.975%摩尔当量的总对映纯R-β-羟基丁酸盐和25%至0.025%摩尔当量的对映纯R-β-羟基丁酸。
18.一种用于向对象施用酮体的试剂盒,其包含:
根据权利要求1至17中任一项所述的R-β-羟基丁酸混合盐-酸组合物;
放置所述组合物的容器;和
测量装置,其设置成在其中容纳单位剂量或其部分的所述组合物,其中单位剂量的所述组合物含有约0.5g至约25g的R-β-羟基丁酸化合物。
19.根据权利要求18所述的试剂盒,其中所述容器选自箱、盒、罐、缸、袋、小包、瓶、壶和小桶。
20.根据权利要求18或19所述的试剂盒,其中所述测量装置选自杯、量斗、注射器、滴管、刮勺、量匙和结肠灌洗装置。
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CA3166226C (en) | 2023-09-12 |
WO2021159070A1 (en) | 2021-08-12 |
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