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CN101209975B - 左旋肉碱富马酸钙及其制备方法与用途 - Google Patents

左旋肉碱富马酸钙及其制备方法与用途 Download PDF

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CN101209975B
CN101209975B CN2007101486360A CN200710148636A CN101209975B CN 101209975 B CN101209975 B CN 101209975B CN 2007101486360 A CN2007101486360 A CN 2007101486360A CN 200710148636 A CN200710148636 A CN 200710148636A CN 101209975 B CN101209975 B CN 101209975B
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carnitine
levulorotation
calcium fumarate
calcium
fumarate
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CN101209975A (zh
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袁学亮
梅国庆
卿笃清
张薇薇
陈泠
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Liaoning Ke Shuo nutrition Polytron Technologies Inc
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SHENYANG KESHUO NUTRITION TECHNOLOGY Co Ltd
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Priority to US12/310,192 priority patent/US20090281183A1/en
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Priority to PCT/CN2007/003001 priority patent/WO2008080287A1/en
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Abstract

一种左旋肉碱富马酸钙及其制备方法和用途，该左旋肉碱富马酸钙具有适于口服、稳定、非吸潮性的特点，比相应的内盐具有更强及更多功能的营养及治疗作用，且水溶性好；其制备方法为：将富马酸溶于水中，加入含钙的碱，升温至70-90℃，反应2-8小时，减压蒸去水。将干燥所得固体加入乙醇中搅拌均匀，加入左旋肉碱，60-70℃反应1-6小时后，放入冰箱冷冻2-8小时，抽滤得到左旋肉碱富马酸钙；含有该左旋肉碱富马酸钙的组合物可制成一种或多种药理学上可接受的赋形剂，特别优选的是固液体口服制剂，如粉剂、颗粒剂、片剂、胶囊、口服液等，可用于人用饮食/营养增补剂，或兽用饲料增补剂，包括补钙用的增补剂。

Description

左旋肉碱富马酸钙及其制备方法与用途 
技术领域
本发明涉及一种稳定的、不易吸潮的左旋肉碱药用可接受盐，特别是涉及一种左旋肉碱富马酸钙及其制备方法与用途，属于医药中间体与食品添加剂的制备技术，适于制备人用或兽用的营养增补剂，包括补钙用营养增补剂组合物。 
背景技术
左旋肉碱的功效已有很多报道，左旋肉碱是一种重要的食品营养强化剂，已广泛应用于食品工业，如婴儿奶粉，减肥食品，运动员营养品和中老年营养补剂中以及饲料加工业中，此外还有医药方面的疗效，心血管疾病、肝脏疾病、肾脏疾病、高脂血症、糖尿病、神经肌肉疾病等均可通过服用左旋肉碱及其系列产品而使病症得到改善，有报道说左旋肉碱还可以提高生殖能力。 
还已知左旋肉碱的药学可接受盐和其内盐一样具有同样的治疗或营养作用，即没有毒性或副作用。且这些药学可接受盐能改善内盐的稳定性及易吸潮性，以广泛用于实际中，包括现在市场上已经非常普遍的左旋肉碱酒石酸盐(US 4,602,039，Lonza)和左旋肉碱富马酸盐(US 5,703,376，Sigma-Tau)，以及较新一点的左旋肉碱粘酸盐(US 5,952,379，Sigma-Tau)。 
但是左旋肉碱酒石酸盐仍有较大的吸潮性，相对湿度超过60％会潮解，且其中的阴离子部分酒石酸本身并无任何营养或治疗作用，而左旋肉碱富马 酸盐很不易吸潮，比左旋肉碱酒石酸盐能经受更高的相对湿度，且富马酸本身也是生物体代谢中，柠檬酸循环中的底物，食用后，可以很快的参加到人体代谢中去，作为能量物质发挥作用。 
镁、钙等微量金属元素是人体所必需的，因此作为营养品它们的需求很广泛。流行病学研究表明，日常饮食和饮用水中钙、镁离子的比率与心脏局部缺血的发病率成明显的相关性。Goodman和Gilman所著的《治疗学药理基础》(1990)中对于镁和钙的药理及生理活性及治疗应用作了详细的评论。此外，《当今药物诊断与治疗》(1999)中对于钙、镁离子功能紊乱也有论述。 
将左旋肉碱与这些金属离子结合，形成具有良好水溶性，易于被人体吸收的盐，增强左旋肉碱的营养及治疗作用，这一领域已有一些成果，但主要集中在含镁的复盐，如左旋肉碱富马酸镁和烷酰基左旋肉碱富马酸镁(US6,051,608，Sigma-Tau)；左旋肉碱酒石酸镁和烷酰基左旋肉碱酒石酸镁(WO98/45250，Sigma-Tau)；左旋肉碱柠檬酸(US 5,071,874，Lonza)和烷酰基L-肉碱柠檬酸镁(WO 98/44918，Sigma-Tau)。对于与钙离子形成的复盐，迄今为止，只有左旋肉碱半乳糖二酸钙有专利报道，但半乳糖二酸国内没有大批量生产，价格较昂贵。而最为常用的左旋肉碱富马酸盐没有形成与钙的复盐的报道。 
发明内容
本发明的目的就在于克服现有技术存在的上述不足，提供新的左旋肉碱药学可接受盐--左旋肉碱富马酸钙，及左旋肉碱富马酸钙的制备方法与用途。本发明给出的这种左旋肉碱富马酸钙具有适于口服、稳定、不易吸潮的特点，而且比相应的内盐具有更强及更多功能的营养及治疗作用。 
本发明给出的技术解决方案是：这种左旋肉碱富马酸钙的结构式为： 
其中R＝H或含有2-6个碳原子的直链或支链烷酰基 
m＝1或2； 
n＝1或2； 
而且当m＝1，且COOX＝COO-时，n＝1，则COOY＝COO-或n＝2，则COOY＝COOH； 
当m＝2，且COOX＝COOH时，n＝2，则COOY＝COO-
当m＝2，且COOX＝COO-时，n＝1，则COOY＝COO-
特别优选的结构式包含 
还包括 
本发明提供的左旋肉碱富马酸钙，是因为钙除了对牙齿和骨头有至关重要的作用外，还能维持细胞的生存和功能，对神经传导、维持免疫系统、帮助血液凝固、新陈代谢、肌肉收缩、以及心脏细胞有着重要的帮助。钙对维持体内酸碱平衡，维持和调节体内许多生化过程是必需的，它能促进体内多种酶的活动，为凝血酶起到催化作用。钙缺乏容易引起软骨瘤质、骨质疏松、佝偻病、坐骨神经痛、龋齿、白发；容易引起肌肉痉挛，心肌功能下降，心脏病，生殖能力下降，经痛；会导致神经兴奋性增强，精神失调、记忆力下降，易于疲劳，过敏反应，增加肠癌患病率，高血压，骨骼畸形，痉挛等。因此，钙是人体不可或缺的元素，是人体的生命之源，成为各种营养补剂中的常见元素。但绝大多数的天然钙和合成钙制剂都不易溶解于水，故都不是活性钙，吃进胃里都必须先由胃酸活解转变成活性钙即离子钙后，才能吸收，进而发挥生理功能。因此将钙制成水溶性的盐即活性钙用于食品添加剂或营养补剂中具有重大的意义。大量摄取乳酸钙会引起疲劳，葡萄糖酸钙、氯化钙过多对糖尿病不利，本发明所提供的左旋肉碱富马酸钙无该类副作用，适合替代这些补钙剂并具有更有益的营养作用。 
本发明给出的这种左旋肉碱富马酸钙的制备方法为： 
将富马酸溶于水中，加入含钙的碱，升温至70-90℃，剧烈搅拌至溶液澄清， 反应2-8小时，减压蒸去水，干燥，将干燥所得富马酸钙加入乙醇或甲醇中搅拌均匀，加入左旋肉碱内盐，60-70℃反应1-6小时后，放入冰箱冷冻2-8小时，抽滤得到左旋肉碱富马酸钙，再进行干燥，经检测合格即为产品，所得的盐具有良好的流动性和抗吸潮性，水溶性良好。 
在本发明给出的上述技术方案中，所述的含钙的碱为Ca(OH)2、CaO、CaCO3中的一种。由于富马酸以及含钙无机碱水溶性较差，制备富马酸钙时对应于每克含钙碱所用溶剂水的量为80-140mL。 
在本发明给出的上述技术方案中，由于以水为溶剂，富马酸钙与左旋肉碱反应不易析晶得到目标产物，因此，不选择水为溶剂，而以乙醇或甲醇为溶剂。 
本发明要求保护的范围还应涉及到这种左旋肉碱富马酸钙的用途，即以组合物形式作为人用饮食/营养增补剂或作为兽用营养增补剂，其中所述的组合物中包含有结构式1-3所述的任意一种左旋肉碱富马酸钙作为活性成分，包含上述适于口服、非吸潮性的、稳定的药学可接受盐--左旋肉碱富马酸钙的组合物，和该组合物可选的一种或多种药理学上可接受的赋形剂，以及药学和食品工艺学专家熟知的活性成分。 
特别优选的是固体或液体口服制剂，如片剂、胶囊、颗粒剂、粉剂、口服液等，该组合物包含结构式所示的任意一种左旋肉碱富马酸钙，单位剂量中其量相当于50-2000mg，优选100-1000mg左旋肉碱内盐或烷酰基左旋肉碱内盐。 
例如，以下是制备片剂的一种组合物： 
左旋肉碱富马酸钙：500mg 
淀粉：      20mg 
滑石粉：    5mg 
微晶纤维素：30mg 
硬脂酸镁：  2mg 
            557mg 
本发明的组合物可用于人用饮食/营养增补剂，或兽用饲料增补剂，包括补钙用的增补剂。 
与现有技术相比，本发明的有益效果为：给出的这种左旋肉碱富马酸钙具有适于口服、稳定、不易吸潮的特点，便于储藏和运输，以及制备固体制剂；而且比相应的内盐具有更强及更多功能的营养及治疗作用，尤其是增加了补钙的作用。 
具体实施方式
下面的实施例旨在进一步说明本发明给出的这种稳定的、非吸潮性的左旋肉碱富马酸钙及其制备方法和用途： 
实施例一左旋肉碱富马酸钙(2∶2∶1)的制备 
Figure G071E8636020070911D000061
将富马酸(11.6g，0.1mol)加入200mL水中搅拌溶解，隔半小时分两次加入研磨成细粉的氢氧化钙(3.7g，0.05mol)，升温至70-90℃，剧烈搅拌至溶液澄清，反应两小时，减压蒸去水。加入左旋肉碱(16.12g，0.1mol)以及乙醇200mL，60-70℃反应3h后，降至室温后，在-5～5℃下冷冻 2小时，抽滤得到左旋肉碱富马酸钙，再进行干燥得产品28g，收率95％。 
所得左旋肉碱富马酸钙具有良好的流动性，粉末均匀，98％以上小于40目。水溶性良好，溶解度为1.8g/100mL水。25℃相对湿度60±5％时暴露24小时，无结团发粘现象，抗吸潮性良好，钙含量为6.76％。 
DSC：160℃开始分解，但不熔化。 
[α]D 20＝11.37(1％H2O) 
pH：3.98 
元素分析C22H36N2O16Ca 
                     C％    N％    H％    Ca％ 
计算值(有7.5％的水)：44.5   4.7    6.1    6.7 
测定值：             41.8   4.3    6.33   6.7 
HPLC： 
柱：APS-2HYPERSIL(NH2)(5μm)250×4.6mm 
温度：30℃ 
流动相：KH2PO4/乙腈(70/30)(v/v) 
pH：4.0H3PO4
检测波长：205nm 
流速：1.0毫升/分钟 
肉碱：Rt＝5.3分钟 
富马酸：Rt＝12.2分钟 
实施例二左旋肉碱富马酸钙(1∶2∶1)的制备 
Figure G071E8636020070911D000081
将富马酸(23.2g，0.2mol)溶于740mL水中，加入Ca(OH)2(7.4g，0.1mol)升温至70℃，剧烈搅拌至溶液澄清，反应两小时，减压蒸去水，干燥。将干燥所得固体加入200mL乙醇中搅拌均匀，加入左旋肉碱(16.12g，0.1mol)，60-70℃反应3h后，在-5～5℃下冷冻5小时，抽滤得到左旋肉碱富马酸钙，再进行干燥，得39.5g，收率91.6％。该化合物水溶性小于40目粉末的水溶性为3.5g/100mL(冷水)，钙含量9.28％。 
所得左旋肉碱富马酸钙具有良好的流动性，粉末均匀，98％以上小于40目。水溶性良好，溶解度为3.5g/100mL水。25℃相对湿度60±5％时暴露24小时，无结团发粘现象，抗吸潮性良好，钙含量为9.28％。 
DSC：136℃开始分解，但不熔化。 
[α]D 20＝-10.2(1％H2O) 
pH：3.82 
元素分析C15H21NO11Ca 
                     C％     N％     H％    Ca％ 
计算值(有7.5％的水)：38.62   3.00    5.36   9.28 
测定值：             37.06   3.10    5.13   9.22 
HPLC： 
柱：Bonchrom-C18(5μm)250×4.6mm 
温度：30℃ 
流动相：0.05MKH2PO4/乙腈(60/40)(v/v) 
pH：3.0 H3PO4
检测波长：205nm 
流速：0.6毫升/分钟 
左旋肉碱：Rt＝5.6分钟 
富马酸：Rt＝12.3分钟 
本发明以组合物形式作为人用饮食/营养增补剂或作为兽用营养增补剂，其中所述的组合物中包含有结构式1-3所述的任意一种左旋肉碱富马酸钙作为活性成分。其组合物可制成一种或多种药理学上可接受的赋形剂，例如固体口服制剂，如片剂、胶囊、咀嚼片，或液体制剂如口服液。该组合物包含结构式I所示的其中一种结构的左旋肉碱富马酸钙，每单位剂量中其量相当于50-2000mg、优选100-1000mg左旋肉碱内盐或烷酰基左旋肉碱内盐，其中的一种片剂的组分为： 
左旋肉碱富马酸钙：500mg 
淀粉：            20mg 
滑石粉：          5cm 
微晶纤维素：      30mg 
硬脂酸镁：        2mg 
                  557mg。 

Claims (8)

1.一种左旋肉碱富马酸钙，其特征在于所述的左旋肉碱富马酸钙的结构式为：
Figure FSB00000058526500011
其中R＝H或含有2-6个碳原子的直链或支链烷酰基
m＝1或2；
n＝1或2；
而且当m＝1，且COOX＝COO-时，
n＝1，则COOY＝COO-或
n＝2，则COOY＝COOH；
当m＝2，且COOX＝COOH时，n＝2，则COOY＝COO-
当m＝2，且COOX＝COO-时，n＝1，则COOY＝COO-。
2.根据权利要求1所述的左旋肉碱富马酸钙，其特征在于优选的左旋肉碱富马酸钙结构式为 
Figure FSB00000058526500021
3.根据权利要求1所述的左旋肉碱富马酸钙，其特征在于优选的左旋肉碱富马酸钙结构式为
Figure FSB00000058526500022
4.制备权利要求1所述的左旋肉碱富马酸钙的方法，其特征在于将富马酸溶于水中，加入含钙的碱，升温至70-90℃，剧烈搅拌至溶液澄清，反应2-8小时，减压蒸去水，干燥得富马酸钙，将干燥所得富马酸钙加入乙醇或甲醇中搅拌均匀，加入左旋肉碱内盐，60-70℃反应1-6小时后，放入冰箱冷冻2-8小时，抽滤得到左旋肉碱富马酸钙。
5.根据权利要求4所述的左旋肉碱富马酸钙的制备方法，其特征在于所述的含钙的碱为Ca(OH)2、CaO、CaCO3中的一种。
6.根据权利要求4所述的左旋肉碱富马酸钙的制备方法，其特征在于制备富马酸钙时对应于每克含钙碱所用溶剂水的量为80-140mL。
7.权利要求1所述的左旋肉碱富马酸钙的用途，其特征在于以组合物形式作为人用饮食/营养增补剂或作为兽用营养增补剂，其中所述的组合物中包含有权利要求1所述的左旋肉碱富马酸钙作为活性成分。
8.根据权利要求7所述的左旋肉碱富马酸钙的用途，其特征在于所述的组合物为固、液体口服制剂中的粉剂、颗粒剂、片剂、胶囊、口服液中的一种 。
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