CN113056206A - 维生素D在β-羟基-β-甲基丁酸(HMB)中的稳定性 - Google Patents
维生素D在β-羟基-β-甲基丁酸(HMB)中的稳定性 Download PDFInfo
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Abstract
本发明提供了一种包含酸性制剂的组合物,该酸性制剂含有β‑羟基‑β‑甲基丁酸(HMB)(优选地,其为游离酸形式)、维生素D和稳定化赋形剂,其中所述维生素D被稳定以防降解。
Description
发明背景
本申请要求于2018年6月25日提交的美国临时专利申请号62/689,305的优先权,并且通过引用将此临时申请合并于此。
1.发明领域
本发明涉及一种包含β-羟基-β-甲基丁酸(HMB)和维生素D的组合物。具体而言,本发明涉及含有HMB和维生素D的组合物以及当维生素D与酸性组合物组合时稳定维生素D的方法。
2.背景技术
维生素D通常与钙和磷的代谢以及骨骼强度有关。直到最近,使用维生素D缺乏症佝偻病定义了足够的维生素D水平。近年来发现维生素D除了具有对钙和骨骼结构的影响外,对新陈代谢也有更广泛的影响。低维生素D状态与以下有关:骨质疏松症,跌倒(falls),I型糖尿病,癌症,自身免疫性疾病,高血压,牙周疾病,多发性硬化,对感染的易感性/反应差1。
维生素D缺乏是一个全球性的问题,随着日晒减少和防晒霜使用的增加,这个问题只会更加严重。饮食和健康也可能是维生素D水平降低的因素。患有脂肪吸收不良综合征、慢性疾病、服用某些药物或肥胖症的受试者发生维生素D缺乏的风险较高2。肤色(Skintone)也会产生影响,因为肤色越深,产生相同量的维生素D所需的时间就越长。因此,补充是增加维生素D并减少缺乏的最佳方法2。胆钙化醇(维生素D3)可通过人皮肤中的7-脱氢胆固醇(7-dehydrochloesterol)经照射合成或从羊毛脂中提取得到。
很少有天然食物含有维生素D,而多脂鱼的肉和鱼肝油是最好的来源。在牛肝、乳制品和每个蛋黄中发现了少量的维生素D。一些蘑菇提供维生素D2,但量各不同。由于维生素D仅包含在很少的食物中,而且往往是少量的,因此必须对食物进行强化或通过膳食补充剂进行补充。自1930年以来,食物和饮料制造商开始强化食品,诸如牛奶、面包、热狗、苏打水以及甚至啤酒。维生素D也可通过膳食补充剂获得。
维生素D3是一种较大的疏水性固醇分子,其水溶性差,很容易被光和氧气降解。在没有水、光、酸性和低温的情况,维生素D的稳定性极佳3。当暴露于酸和光时,会形成5,6-反式异构体和异甾醇(isotachysterol)4。维生素比维生素A更不易被氧化,但维生素D的氧化可能是开环甾类化合物(secosteroid)结构的5,6和7,8位的共轭双键系统分解的主要途径3。维生素D在液态奶生产或脱脂奶粉(dry milk)生产的过程中非常稳定4。在95℃注入蒸汽时未观察到显著损失5。最近,发现维生素D在pH约为4的橙汁中稳定6。生物利用度与以胶囊形式服用时相同。但是,尚未确定维生素D3在pH为4或更低时的长期稳定性。
HMB
α-酮异己酸(KIC)是亮氨酸的第一种主要的活性代谢产物。KIC代谢的次要产物为β-羟基-β-甲基丁酸(HMB)。HMB已经被发现在不同申请的上下文中是有用的。具体地,在美国专利号5,360,613(Nissen)中,描述了HMB可用于降低总胆固醇和低密度脂蛋白胆固醇的血液水平。在美国专利号5,348,979(Nissen等人)中,描述了HMB可用于促进人体内的氮贮留。美国专利号5,028,440(Nissen)讨论了HMB对增加动物瘦组织发育的有用性。此外,在美国专利号4,992,470(Nissen)中,HMB被描述为有效增强哺乳动物的免疫应答。美国专利号6,031,000(Nissen等人)描述了HMB和至少一种氨基酸在治疗与疾病相关的消瘦(wasting)中的用途。
HMB抑制蛋白水解的用途源自以下事实:亮氨酸具有蛋白质节约(protein-sparing)特性。必需氨基酸亮氨酸可以用于蛋白质合成,也可以转氨为α-酮酸(α-酮异己酸,KIC)。在一种途径中,KIC可被氧化为HMB,这约占亮氨酸氧化的5%。HMB在增强肌肉质量和强度方面优于亮氨酸。以HMB钙盐的形式每天服用3.0克,或每天0.038g/kg体重,可获得HMB的最佳效果,而亮氨酸需要超过每天30.0克。
一旦产生或摄入,HMB似乎有两种命运。第一种命运为简单的尿中排泄。摄入HMB后,尿浓度增加,导致约20-50%HMB损失到尿。另一种命运与HMB活化为HMB-CoA有关。一旦转化为HMB-CoA,就可能发生进一步的代谢,将HMB-CoA脱水为MC-CoA,或将HMB-CoA直接转化为HMG-CoA,其为细胞内胆固醇合成提供底物。多项研究表明,HMB被整合至胆固醇合成途径中,并且可能是新细胞膜的来源,这些新细胞膜可用于受损细胞膜的再生。人体研究表明,剧烈运动后的肌肉损伤(通过血浆CPK(肌酸磷酸激酶)升高来测量)在开始的48小时内通过补充HMB得以减轻。每天持续使用HMB的保护作用可持续长达三周。大量研究表明,HMB的有效剂量为CaHMB(HMB钙)每天3.0克(~38mg·kg体重-1·天-1)。HMB已测试过安全性,在健康的年轻或老年成人中显示无副作用。HMB与L-精氨酸和L-谷氨酰胺联合补充还被证明对AIDS和癌症患者是安全的。
已经开发出HMB游离酸(”HMBFA”),一种HMB的递送形式。与CaHMB相比,这种递送形式已被证明吸收更快,且具有更高的组织清除率。这种递送形式描述于美国专利公开序列号20120053240,其通过引用整体并入本文。
HMB已显示出在增加肌肉质量、提高强度和改善肌肉功能方面是有效的。当血液中的维生素D水平充足时,这些作用最为显著,该水平进一步定义为至少25ng/ml左右或更高。
因此,期望将HMB与维生素D组合以将HMB对肌肉质量、强度和功能的影响最大化。然而,发现当与包括游离酸形式的HMB(HMBFA)的酸性组合物组合时,维生素D且尤其是维生素D3不稳定。维生素D在仅包含HMBFA和维生素D的组合物中的水平随着时间的推移显著降解。由于就对肌肉的影响而言,HMBFA可能是HMB的更有效的递送形式,因此期望将HMBFA与维生素D组合以将HMB的功效最大化。因此,需要开发一种含有HMBFA和维生素D的稳定制剂。为此,发现维生素D在酸性制剂中针对降解是稳定的,该酸性制剂包括含有HMB、包含至少一种稳定化赋形剂的制剂。
发明内容
本发明的一个目的为提供一种稳定的含有HMBFA和维生素D的组合物。
本发明的另一个目的为提供一种含HMBFA和维生素D的组合物,其中维生素D不会随时间显著减少。
通过参考以下说明书、附图和权利要求,本发明的这些和其他目的对于本领域技术人员将变得明显。
本发明旨在克服迄今为止遇到的困难。为此,提供了一种包含HMBFA和维生素D的组合物。
附图说明
图1描述了配方7中维生素D的稳定性。
图2描述了配方10中维生素D的稳定性。
图3描述了配方11中维生素D的稳定性。
具体实施方式
本文公开了当维生素D与HMB组合时用于改善维生素D的稳定性的制剂。发现在HMB和维生素D的制剂中包含充当稳定化赋形剂的其他组分可改善维生素D的稳定性。稳定化赋形剂的代表性实例包括但不限于EDTA、丁羟甲苯(BHT)、肉碱、迷迭香提取物、卡诺酸(carnosolic acid)和/或山梨酸。在包含HMB和维生素D的制剂中至少包含这些添加剂中的一种,可产生制剂中的维生素D随时间的最小损失。将添加剂添加到含有与酸性组分(诸如HMBFA)组合的维生素D的制剂中,稳定维生素D防止其随时间推移而降解。
维生素D旨在包括维生素D2、D3和D4及相关类似物。
本发明包括的稳定化赋形剂包括EDTA或抗氧化剂(包括BHT、BHA、抗坏血酸棕榈酸酯、没食子酸丙酯、维生素E、抗坏血酸、半胱氨酸、蛋氨酸、单硫代甘油(monothiogylcerol)、硫代硫酸钠或亚硫酸盐类)。
发现当维生素D被包括在酸性制剂中时,维生素D会随时间推移而显著降解。由于期望在低pH的酸性制剂中将维生素D与HMBFA组合,因此需要稳定的HMB和维生素D的制剂。出乎意料地发现,包括稳定化赋形剂(诸如EDTA、BHT、肉碱、迷迭香提取物、卡诺酸和/或山梨酸),可得到制剂,其中维生素D随时间推移是稳定的而不会降解。
在大多数情况下,临床研究中使用的HMB以及作为强化助剂(ergogenic aid)销售的HMB是钙盐形式。最近的进展使得HMB可以以游离酸的形式被生产用于人类和动物用途,并且优选作为营养补充剂或被掺入食品中。已开发出游离酸形式的HMB(HMBFA),其显示比CaHMB吸收更快,从而导致更快、更高的峰值血清HMB水平,并改善对组织的血清清除率。HMBFA的pH<3。
因此,HMB游离酸可能是一种比钙盐形式更有效的HMB施用方法,尤其是在剧烈运动前直接施用时。但是,本领域普通技术人员将认识到,本发明包括任何形式的HMB。
可以以某种方式将任何形式的HMB掺入递送和/或施用形式中,从而导致典型的剂量范围为约0.5克HMB至约30克HMB。
在本发明的上下文中可以使用任何合适剂量的HMB。计算适当剂量的方法是本领域众所周知的。
当该组合物以可食用形式口服施用时,该组合物优选为膳食补充剂、食品或药物介质的形式,更优选为膳食补充剂或食品的形式。包含该组合物的任何合适的膳食补充剂或食品都可以在本发明的范围内使用。本领域普通技术人员将理解,该组合物,无论形式(诸如膳食补充剂、食品或药物介质),可包括氨基酸、维生素、蛋白质、肽、碳水化合物、脂肪、糖、矿物质和/或微量元素。
为了将该组合物制备为膳食补充剂或食品,通常将该组合物以这种方法组合或混合使得该组合物基本上均匀地分布在膳食补充剂或食品中。或者,可以将组合物溶解在液体(诸如水)中。
膳食补充剂的组合物可为粉末、凝胶、液体,或者可被制成平板状(tabulated)或封装在例如软凝胶制剂中。以下实施例考察了维生素D当与HMB以软胶囊或胶囊递送形式结合时的稳定性。本发明不限于任何特定的递送形式,并且可以包括在液体制剂、凝胶和食品中的HMB和维生素D的组合。
尽管可以在本发明的范围内使用包含该组合物的任何合适的药物介质,但是优选地,该组合物与合适的药物载体(诸如右旋糖或蔗糖)组合。
此外,该药物介质的组合物可以以任何合适的方式静脉内施用。为了通过静脉输注施用,该组合物优选为水溶性无毒形式。静脉内施用尤其适用于正在接受静脉(IV)治疗的住院患者。例如,可以将组合物溶解在施用于患者的IV溶液(例如,盐水或葡萄糖溶液)中。而且,可以将组合物添加到营养IV溶液中,其可包括氨基酸、葡萄糖、肽、蛋白质和/或脂质。静脉内施用的组合物的量可以类似于口服施用中使用的水平。静脉输注可能比口服施用更为可控和精确。
计算组合物的施用频率的方法是本领域众所周知的,并且在本发明的上下文中,可以使用任何合适的施用频率(例如,每天一次6g剂量或每天两次3g剂量)并在任何合适的时间段使用(例如,可以在五分钟的时间段或在一小时的时间段施用单个剂量,或者,作为一种选择,可以在延长的时间段内施用多个剂量)。该组合物可以在延长的时间段(诸如多周、多月或多年)施用。
在本发明的上下文中可以使用任何合适剂量的HMB和维生素D。计算适当剂量的方法是本领域众所周知的。
术语施用(administering)或施用(administration)包括向哺乳动物提供组合物、食用该组合物及其组合。
实验实施例
以下实施例将更详细地说明本发明。容易理解的是,如本文的实施例中一般描述和说明的,本发明的组合物可以各种制剂和剂型合成。因此,本发明的方法、制剂和组合物的当前优选实施方案的以下更详细的描述并非旨在限制所要求的本发明的范围,而仅仅是本发明的当前优选实施方案的代表。
以下实验的目的为测试不同配方的HMBFA中维生素D3的稳定性。维生素D3的损失少于10%被认为是可以接受的。
方法:测试了11种不同的HMBFA/维生素D3配方。测试了这些配方的维生素D3随时间推移的稳定性。配方如下:
1.HMBFA+维生素D3(100HP,BASF,Denmark)
2.HMB FA加氯化胆碱(Acros Organics)中的维生素D3(100HP,BASF,Denmark)
3.HMB FA加甜菜碱(Sigma-Aldrich)中的维生素D3(100HP,BASF,Denmark)
4.缓冲的HMBFA+维生素D3(100HP,BASF,Denmark)
5.缓冲的HMBFA+BASF保护的维生素D3(100GFP/HP,BASF,Denmark)
9.缓冲的HMBFA+维生素D3(Sigma-Aldrich),用60ppm EDTA二钠(VerseneTM NA螯合剂,Dow Chemical,Midland,MI)稳定
维生素D3通过Heartland分析通过HPLC测定。
结果:在测试的11个配方中,含有缓冲的HMBFA加NovaSol D保护的维生素D3(用60ppm EDTA二钠(VerseneTM NA)稳定)的配方7、含有HMBFA加NovaSol D保护的维生素D3(用BHT稳定)的配方10以及缓冲HMBFA+NovaSol D维生素D3(用NovaSol Rosmary、NovaSol DS/4和BHT稳定)的配方11是稳定的。下表列出了维生素D3的变化百分比:
表1
图1、2和3分别说明了配方7、10和11中维生素D3的稳定性。总之,这些研究表明,维生素D3当与缓冲的HMBFA和EDTA二钠配制时或当BHT代替EDTA二钠时是稳定的。还需要受保护的维生素D3,诸如NovaSol D。
制备游离酸形式的缓冲的HMB(HMBFA)
简而言之,将400g HMBFA(TSI批号12111036)称入一升烧杯中,并然后将37.8g碳酸钾(K2CO3)加入到HMBFA中。加入搅拌棒,并将混合物搅拌60h。所得的pH约为4.5。或者,可通过将水(35g)与碳酸钾(37)g混合,然后添加HMBFA(400g)来加速反应。
配方7中的维生素D3来自AquaNova,并被称为NovaSOL D。维生素D3产品受聚山梨酯80保护。该产品溶于水和油,形成透明溶液。为了计算所需成分的量,使用了以下方法:使用每粒胶囊250IU维生素D3(计算1μg=40IU),意味着6.25μg,基于这种0.25%NovaSOL D产品,需要每粒胶囊2.5mg NovaSOL D。
配方7和配方8中使用的EDTA为Dow的EDTA二钠(VerseneTM NA螯合剂,DowChemical,Midland,MI)。在配方10和11中,用防腐剂BHT代替EDTA二钠。此外,配方11还含有抗氧化剂NovaSol迷迭香提取物,其卡诺酸和防腐剂NovaSol DS/4(山梨酸)含量高。
以上的描述和附图包含本发明的说明性实施方案。本文描述的前述实施方案和方法可基于本领域技术人员的能力、经验和偏好而变化。仅以一定顺序列出方法的步骤并不构成对方法步骤的顺序的任何限制。以上描述和附图仅解释和说明了本发明,而本发明不限于此,除非权利要求如此限制。具有其之前披露内容的本领域技术人员将能够在不脱离本发明范围的情况下对其进行修改和变化。
参考文献
1.Heaney,R.P.Vitamin D in Health and Disease.Clin.J.Am.Soc.Nephrol 3,1535-1541(2008).
2.Holick,M.F.et al.Evaluation,treatment,and prevention of vitamin Ddeficiency:an Endocrine Society clinical practice guideline.J Clin EndocrinolMetab 96,1911-1930,doi:10.1210/jc.2011-0385(2011).
3.Eitenmiller,R.R.L.J.,W.O.;.in Vitamin Analysis for the Health ofFood Sciences77-107(CRC Press,1998).
4.Renken,S.A.W.,J.J.Vitamin stability in milk.Food Sci 58,552-556(1993).
5.Indyk,H.E.L.,V.;Woollard,d.C.Solubility of vitamin D3 during spray-dying of milk.Food Chem 57,283-286(1996).
6.Biancuzzo,R.M.et al.Fortification of orange juice with vitamin D(2)or vitamin D(3)is as effective as an oral supplement in maintaining vitamin Dstatus in adults.Am J Clin Nutr91,1621-1626,doi:10.3945/ajcn.2009.27972(2010).
Claims (10)
1.一种稳定制剂,其包含游离酸形式的β-羟基-β-甲基丁酸(HMB)、维生素D以及至少一种稳定化赋形剂。
2.权利要求1的制剂,其中所述稳定化赋形剂选自:EDTA、丁羟甲苯(BHT)、肉碱、迷迭香提取物、卡诺酸和山梨酸。
3.权利要求1的制剂,其中所述稳定化赋形剂选自:EDTA和丁羟甲苯(BHT)。
4.权利要求1的制剂,其中所述制剂包含在递送形式内,所述递送形式选自:胶囊、软凝胶、液体和食品。
5.一种在酸性制剂中稳定维生素D的方法,其包含在含有维生素D和β-羟基-β-甲基丁酸(HMB)的制剂中包括至少一种稳定化赋形剂的步骤。
6.权利要求5的方法,其中所述HMB为游离酸形式。
7.权利要求5的方法,其中所述稳定化赋形剂选自:EDTA、丁羟甲苯(BHT)、肉碱、迷迭香提取物、卡诺酸和山梨酸。
8.一种在含有β-羟基-β-甲基丁酸(HMB)和维生素D的酸性制剂中使维生素D降解最小化的方法,其包含在所述制剂中包括至少一种稳定化赋形剂的步骤。
9.权利要求8的方法,其中所述HMB为游离酸形式。
10.权利要求8的方法,其中所述稳定化赋形剂选自:EDTA、丁羟甲苯(BHT)、肉碱、迷迭香提取物、卡诺酸和山梨酸。
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US20100178369A1 (en) * | 2009-01-15 | 2010-07-15 | Nicole Lee Arledge | Antioxidant-stabilized concentrated fish oil |
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CN109862875A (zh) * | 2016-03-30 | 2019-06-07 | 西姆莱斯股份公司 | 一种活性混合物 |
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US20030147996A1 (en) * | 2001-08-29 | 2003-08-07 | Prasad Kedar N. | Multiple antioxidant micronutrients |
US20060019933A1 (en) * | 2004-07-22 | 2006-01-26 | David Boardman | Process for preparing stabilized vitamin D |
US20100178369A1 (en) * | 2009-01-15 | 2010-07-15 | Nicole Lee Arledge | Antioxidant-stabilized concentrated fish oil |
CN103442593A (zh) * | 2011-02-07 | 2013-12-11 | 雅培制药有限公司 | 包含β-羟基-β-甲基丁酸盐的营养产品 |
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