CN113230273A - 一种含有胆碱、b族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂 - Google Patents
一种含有胆碱、b族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂 Download PDFInfo
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- CN113230273A CN113230273A CN202110509217.5A CN202110509217A CN113230273A CN 113230273 A CN113230273 A CN 113230273A CN 202110509217 A CN202110509217 A CN 202110509217A CN 113230273 A CN113230273 A CN 113230273A
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Abstract
本发明公开了一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，涉及有效成分含氨基的医药配制品领域，其组分按重量份计包括：叶酸：300‑1300份、维生素B12：80‑280份、维生素B6：8000‑28000份、维生素B2：9000‑31000份、胆碱：190000‑610000份、锌：7000‑25000份、维生素B1：9000‑31000份、泛酸：4000‑16000份、烟酰胺：9000‑31000份、镁：900000‑3100000份、锰：1400‑4600份和维生素D：4‑16份。本复方制剂通过缓解ROS损伤和血管内皮细胞活力下降来消除当下机体的高Hcy状态的靶点损伤；还通过全面矫正叶酸代谢紊乱涉及的五大生化通路，达到快速降低血Hcy水平的目的；在实现有效稳定地抑制动脉粥样硬化病变的基础上，降脂、抗炎、消退软斑块，从根本上减少心脑血管事件的发生。
Description
技术领域
本申请涉及有效成分含氨基的医药配制品领域，尤其是一种含有胆碱和B族维生素、叶酸和锌的预防或治疗高同型半胱氨酸血症的复方制剂。
背景技术
动脉粥样硬化(atherosclerosis,AS)是与血管壁成分变化和血脂异常相关的最重要且最常见的动脉疾病之一。其为多种中老年常见疾病的发病基础，可导致多种临床心血管疾病，涉及全身各个器官，严重危害患者健康。[魏佳明,朱俊平,刘瑞连,郭志华,刘承鑫,罗莉,李玉莹,李佳玲,李雅.动脉粥样硬化的中医药研究进展[J].湖南中医杂志,2020,36(09):177-180.]
在人体中同型半胱氨酸(Hcy)的水平升高主要是由于以下两个原因:一为饮食,经食物摄入叶酸、维生素B12不足,引起体内还原性5-亚甲基四氢叶酸生成减少,造成Met循环障碍,导致Hcy蓄积；二为基因突变,亚甲基四氢叶酸还原酶(MTHFR)、甲硫氨酸合成还原酶基因突变,使其指导生成影响叶酸代谢的酶活性下降,阻碍Hcy代谢通路进程,导致其水平升高。[何景华,刘双,孙丽娟,辛世萌,殷雁.帕金森病与同型半胱氨酸关系的研究进展[J].中华老年心脑血管病杂志,2020,22(09):1001-1003.]而目前市面上的膳食补充剂往往是多维+矿物质，仅仅是单纯的补充人体所需，含量微不足道，几乎不能达到预防和治疗疾病的作用。同类国外产品各物质含量相对高一些，适合体内维生素和矿物质匮乏的人群，但是仍然不是针对同型半胱氨酸血症的对症治疗药物。
发明内容
本申请的目的是提供一种通过补充B族维生素、胆碱、叶酸和锌的预防或治疗同型半胱氨酸血症的复方制剂，在防病的基础上，进一步控制患者血清中同型半胱氨酸的水平。
为实现上述目的，采用的技术方案是：
一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，包括以下重量份的组分：叶酸：300-1300份、维生素B12：50-200份、维生素B6：6000-23000份、维生素B2：9000-31000份、胆碱：110000-390000份、锌：7000-25000份、维生素B1：9000-31000份、泛酸：4000-16000份、烟酰胺：9000-31000份、镁：90000-310000份、锰：1400-4600份和维生素D：4-16份。
优选地，一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，包括以下重量份的组分：叶酸：300-900份、维生素B12：50-130份、维生素B6：6000-17000份、维生素B2：9000-21000份、胆碱：110000-250000份、锌：7000-17000份、维生素B1：9000-24000份、泛酸：4000-11000份、烟酰胺：9000-21000份、镁：90000-210000份、锰：1400-2800份和维生素D：4-11份。
优选地，一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，包括以下重量份的组分：叶酸：800份、维生素B12：120份、维生素B6：14000份、维生素B2：20000份、胆碱：250000份、锌：16000份、维生素B1：20000份、泛酸：10000份、烟酰胺：20000份、镁：200000份、锰：2800份和维生素D：11份。
一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，所述的复方制剂含有医学上允许的辅料，所制成的片剂、丸剂、滴丸或颗粒剂。
优选地，一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，所述医学上允许的辅料为硬脂酸镁、糊精中的任一种或者组合。
一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，各个成分要求食药级纯度即可，例如制成片剂，将各成分装入搅拌机进行均质30-100分钟，上压片机进行压片；所需成分均为粉末无需进行粉碎，对制备方法无特殊要求。
一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂在制备高龄营养不良患者的膳食补充剂中的应用。
在本申请的有效组分中，叶酸在二氢叶酸还原酶的催化下，通过两步还原反应生成四氢叶酸。四氢叶酸是叶酸的活性形式。四氢叶酸是一碳单位转移酶的辅酶,是一碳单位的载体，其分子中的N5、N10两个氮原子可以携带一碳单位。一碳单位在体内参加多种物质的合成代谢，如蛋氨酸、同型半胱氨酸、嘌呤、胸腺嘧啶核苷酸等。叶酸是影响同型半胱氨酸水平的最主要因素，而维生素B12在人体内起辅酶作用，它主要参与两个代谢反应：催化同型半胱氨酸转变为甲硫氨酸以及L-甲基丙二酰辅酶A转变为琥玻酰4-磷酸泛酰巯基Z胺辅酶A(5'-脱氧腺苷钴胺素是L-甲基丙二酰辅酶A变构酶的辅酶)。若维生素B12缺乏，在前者使同型半胱氨酸、叶酸的代谢发生障碍，导致高同型半胱氨酸血症，并直接影响DNA的合成，从而使细胞核成熟受阻，出现细胞核发育落后于血浆内血红蛋白合成的速度，血红蛋白的含量增加，细胞体积增大，突出表现为巨幼细胞性贫血；在后者则使琥玻酰4-磷酸泛酰巯基乙胺辅酶A缺乏，并使L一甲基丙二酰辅酶A在体内蓄积，影响脂肪的正常合成，由于脂肪的合成异常而阻碍了神经髓鞘质的转换，结果导致髓鞘质变性退化，造成进行性脱髓鞘,使人体出现神经系统症状。此外，由于维生素B12是蛋氨酸合成酶的辅酶，同型半胱氨酸代谢依赖于叶酸及维生素B12，如果体内叶酸、维生素B12缺乏，使同型半胱氨酸再甲基化，并造成合成蛋氨酸发生障碍，则同型半胱氨酸代谢障碍，导致血浆同型半胱氨酸水平升高，引发高同型半胱氨酸血症。叶酸缺乏，会引起血液中同型半胱氨酸大量蓄积，而后者会引起动脉粥样硬化、心脑血管病等疾病。孕妇细胞分裂速度增快，缺乏叶酸会引起胎儿神经管畸形。维生素B6是机体内许多重要酶系统的辅酶，参与多种代谢反应，尤其是和氨基酸代谢有密切关系，参与含硫氨基酸的代谢、氨基酸的脱羧、色氨酸及γ-氨基丁酸的合成，参与不饱和脂肪酸的代谢，也影响激素的代谢等生理过程，是人体正常发育所必需的营养物质。维生素B2是机体中许多酶系统的重要辅基的组成成分，参与物质和能量代谢。有助于皮肤、粘膜、毛囊系统的健康,缺乏维生素B2,会导致口角炎,唇炎,外阴瘙痒,口腔溃疡等多种皮肤粘膜问题；维生素B2的缺乏,也会影响维生素B6的吸收。缺乏维生素B2会出现充血、肿胀，主要原因在于：血管，构成血管壁的细胞离不开维生素B2，当缺乏维生素B2时，血管壁(主要是毛细血管)开始变薄，在血压的作用下，血管开始向外凸起，当局部的血管都开始鼓起时，就形成了肿块，最后血管开裂出血，如果恰恰发生在脑部，就是脑溢血。所以维生素B2的缺乏是脑卒中的“帮凶”之一。
众所周知，维生素之间是相互作用的，有时维生素的缺乏可引起一系列连锁反应。一方面，一种维生素的不足往往影响另一种维生素的补充，例如，缺乏叶酸可影响维生素B1的吸收，而维生素B1的缺乏又可影响到维生素B12和泛酸的利用，微量元素锰可以促进多种维生素的吸收。再如缺乏生物素可引起泛酸缺乏，而缺乏泛酸会影响肠道菌群，使其丧失合成肌醇的能力。因此当出现缺乏某种B族维生素的症状时，往往是反映多种B族维生素不足的共同结果，只不过缺乏程度有一些差异。如维生素B6不足常伴有烟酸缺乏。只凭临床表现，单用一种维生素去治疗，不但不能取得预期疗效，反而会促使其他维生素缺乏症状出现并导致病情加剧。因此补充维生素时需要考虑维生素之间的相互关系和全面平衡问题。另一方面，现代医学研究表明，人体必需的微量元素往往是维生素发挥生理作用的一把把钥匙，经由微量元素的参与，维生素的作用才会更加明显，某些维生素的作用甚至离不开微量元素的参与。
胆碱可促进脂肪代谢，因为胆碱对脂肪有亲合力，可促进脂肪以磷脂形式由肝脏通过血液输送出去或改善脂肪酸本身在肝中的利用，并防止脂肪在肝脏里的异常积聚。如果缺乏胆碱，脂肪聚积在肝中出现脂肪肝。临床上，应用胆碱治疗肝硬化、肝炎和其他肝疾病，效果良好。基于此，胆碱还可降低血清总胆固醇。随着老龄化社会的到来，高龄患者的新陈代谢变慢，胆固醇容易在血管内沉积引起动脉硬化，最终诱发心血管疾病。而胆碱和磷脂具有良好的乳化特性，能阻止胆固醇在血管内壁的沉积并清除部分沉积物，同时改善脂肪的吸收与利用，具有预防心血管疾病的作用。泛酸，即维生素B5，能够增加谷胱甘肽的生物合成，从而减缓细胞凋亡和损伤。锌是人体重要的微量元素，可以结合人体内约10％的蛋白质。两个锌转运蛋白家族的基因，即锌转运蛋白(Zn transporters，ZnT)和Zrt-，Irt-相关蛋白(Zin-regulated，Iron-regulated-like proteins，ZIP)基因共同调控锌在细胞内外及基质内的稳态，锌转运蛋白功能障碍可破坏细胞的锌稳态，导致糖尿病、心血管疾病和癌症等各种疾病的发生和发展。饮食锌摄入不佳促进血管炎症和动脉粥样硬化形成，且越来越多的研究发现锌有抗氧化和抗炎作用。现代药理学研究表明，高水平的血清镁可通过改善血管内皮功能,改善动脉硬化,减轻氧化应激等,降低脑梗死及梗死后出血转化(hemorrhagic transformation,HT)的风险。锰是人体必需的微量元素，促进骨骼的正常生长和发育；维持正常的糖代谢和脂肪代谢，锰还能刺激免疫细胞增殖，增强人体的免疫力；可以激活体内必要的酶的活性以充分利用维生素C、B族维生素、维生素H及生物素。
与现有技术相比，本申请的有益效果在于：综合了对症和对因防治。在对症方面，通过缓解ROS损伤和血管内皮细胞活力下降来消除当下机体的高Hcy状态的靶点损伤；对因方面，通过全面矫正叶酸代谢紊乱涉及的五大生化通路，达到快速降低血Hcy水平的目的；与现有膳食补充剂相比，本复方制剂的各种有效成分之间的协同作用可提高产品的吸收率，并起到辅助降低血脂和血压的功效，例如B2可提高B6的利用率，胆碱可辅助降血脂，等等，而且本复方制剂针对中老年人群的体质特点而研发，防治效果突出，患者经过一定时期的治疗后，疗效显著，且安全性高，可以长期服用，达到扶正固本，并预防和辅助治疗动脉粥样硬化所致的心脑血管疾病的效果。
具体实施方式
下面将通过实施例对本申请做进一步详尽的解释和说明。
需要特别说明的是：各实施例所展示的各组分的用量并非制作过程中添加的物质，而是添加的物质中含有各组分的量。例如1000片本产品，添加一定量的碳酸镁(不局限于碳酸镁)，其中镁的含量为100g。
实施例1：本申请所述维生素组合物的片剂制备(1000片含量)
各组分的用量：
制备方法：取出聚维酮K30，用50％乙醇溶液配制成粘合剂，将主要液体成分加入粘合剂中搅拌均匀，备用。另取主要固体成分与预胶化淀粉混合、过筛，随后加入牛奶香精、羧甲淀粉钠、糊精混合，加入配制好的粘合剂制软材，然后24目筛制粒，55℃干燥2h，24目筛整粒，再加入硬脂酸镁混合，压片；最后将包衣预混剂配制成溶液，素片包衣，即得所需片剂。
实施例2：本申请所述维生素组合物的软胶囊制备(含量：1000粒)
各组分的用量：
| 成分 | 用量 |
| 叶酸 | 0.6g |
| 维生素B12 | 8mg |
| 维生素B6 | 10g |
| 维生素B2 | 11g |
| 胆碱 | 200g |
| 锌 | 7g |
| 维生素B1 | 9g |
| 泛酸 | 4g |
| 烟酰胺 | 9g |
| 镁 | 90g |
| 硫酸锰 | 3.8g |
| 维生素D | 4mg |
| 姜黄素 | 60g |
| 大豆油 | 365.8g |
| 蜂蜡 | 2.2g |
| 明胶 | 57.8g |
| 甘油 | 38.2g |
| 纯净水 | 55.3g |
| 焦糖色 | 0.5g |
| 对羟基苯甲酸酯 | 0.2g |
| 共制 | 1000粒 |
制备方法：将蜂蜡加入大豆油中，50℃加热，使蜂蜡溶解，放置至室温，取叶酸、维生素B12、维生素B6、维生素B2、胆碱、锌、维生素、泛酸、烟酰胺、镁、硫酸锰、维生素D和姜黄素加入大豆油中制成混悬液，备用。另取明胶、纯化水、焦糖色、对羟基苯甲酸酯配制成胶液，将制得的混悬物用压丸机压丸制成软胶囊，经定型，洗丸和干燥处理后，即制得本申请所述的保健食品的软胶囊剂。
实施例3：本申请所述维生素组合物硬胶囊剂制备(1000粒含量)
各组分的用量：
| 成分 | 用量 |
| 叶酸 | 0.4g |
| 维生素B12 | 6mg |
| 维生素B6 | 7g |
| 维生素B2 | 10g |
| 胆碱 | 150g |
| 锌 | 7g |
| 维生素B1 | 15g |
| 泛酸 | 6g |
| 烟酰胺 | 10g |
| 镁 | 130g |
| 硫酸锰 | 5.2g |
| 维生素D | 5mg |
| 姜黄素 | 70g |
| 乳糖 | 180g |
| 微晶纤维素 | 256g |
| 硬脂酸镁 | 2g |
| 共制 | 1000粒 |
制备方法：将叶酸、姜黄素与20％微晶纤维素混合，过筛，再加入维生素B12/B6/B2/D、胆碱、锌、泛酸、烟酰胺、镁和硫酸锰混合，将所得的原料混合物与剩余量的微晶纤维素等量递增混合，再加入乳糖、硬脂酸镁混合，然后采用全自动胶囊填充机进行填充，经抛光处理后即制得本申请所述保健食品的硬胶囊剂。
实施例4：本申请所述维生素组合物的片剂制备(1000片含量)
各组分的用量：
制备方法：取出交联聚维酮，用微晶纤维素溶液配制成粘合剂，将主要液体成分加入粘合剂中搅拌均匀，备用。另取主要固体成分与预胶化淀粉混合、过筛，随后加入羟丙基甲基纤维素、二氧化硅、羧甲淀粉钠，再加入配制好的粘合剂制软材，然后24目筛制粒，55℃干燥2h，24目筛整粒，再加入硬脂酸镁混合，压片，即得所需片剂。
实施例5：本申请所述维生素组合物的软胶囊制备(含量：1000粒)
各组分的用量：
| 成分 | 用量 |
| 叶酸 | 0.8g |
| 维生素B12 | 12mg |
| 维生素B6 | 14g |
| 维生素B2 | 20g |
| 胆碱 | 250g |
| 锌 | 16g |
| 维生素B1 | 20g |
| 泛酸 | 10g |
| 烟酰胺 | 20g |
| 镁 | 200g |
| 硫酸锰 | 8.2g |
| 维生素D | 5mg |
| 姜黄素 | 100g |
| 大豆油 | 327.5g |
| 蜂蜡 | 2g |
| 明胶 | 52.2g |
| 甘油 | 35.2g |
| 纯净水 | 50.3g |
| 焦糖色 | 0.5g |
| 对羟基苯甲酸酯 | 0.2g |
| 共制 | 1000粒 |
制备方法：将蜂蜡加入大豆油中，50℃加热，使蜂蜡溶解，放置至室温，取叶酸、维生素B12、维生素B6、维生素B2、胆碱、锌、维生素、泛酸、烟酰胺、镁、硫酸锰、维生素D和姜黄素加入大豆油中制成混悬液，备用。另取明胶、纯化水、焦糖色、对羟基苯甲酸酯配制成胶液，将制得的混悬物用压丸机压丸制成软胶囊，经定型、洗丸和干燥处理后，即制得本申请所述的保健食品的软胶囊剂。
动物实验
取实施例3制得的复方制剂，按照卫生部《保健食品检验与评价技术规范》的评价方法进行动物功能试验和安全性毒理学评价试验。
1、实验动物：大鼠
采用健康的成年大鼠模拟高血脂情况，从心脑血管病预防方面进行实验验证：预防心血管疾病，降低血浆低密度脂蛋白、Hcy及丙二醛。
实验过程：将100只成年大鼠(体重280～320g)随机分为模型组、维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组。模型组、维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组，通过对大鼠常规饲养4周后，对两组大鼠分别给予以下灌胃处理：模型组给予0.9％氯化钠注射液10ml/kg，维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组则是给予维生素B12+维生素B6+维生素B2+维生素B1+维生素D+叶酸+胆碱+锌+泛酸+烟酰胺+镁+锰+姜黄素(0.000018+0.00036+0.48+0.54+0.54+0.00024+0.018+9+0.42+0.24+0.54+5.5+0.084+4.2)mg/kg，8周后对血清总胆固醇(TC)、低密度脂蛋白(LDL)及同型半胱氨酸(Hcy)的含量进行测定。
实验结果：如表1、2所示，同模型组相比，维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组能显著降低Hcy水平(P<0.05)。维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组有降低血浆氧化低密度脂蛋白的趋势，且维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组的组合物降低效果具有统计学意义(P<0.05)。
血清和动脉壁上的脂质过氧化物(LPO)与动脉粥硬化呈平行关系，脂质过氧化物代谢产物是丙二醛(MDA)，检测MDA的含量可反映血管脂质过氧化程度，即动脉粥样硬化程度。如表3所示，灌胃8周后，同模型组相比，维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组血清和动脉壁丙二醛显著降低(P<0.05),维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组具有降低效果更好的趋势，可以说明维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组合物对实验大鼠有积极的干预效果，具有较强的预防动脉硬化、保护心血管功能的功效。
表1维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素对高血脂大鼠氧化低密度脂蛋白(oxLDL)的影响
(与模型组比较，aP<0.05)
表2维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素对高血脂大鼠同型半胱氨酸(Hcy)的影响
注：与模型组比较，aP<0.05。
表3维生素K/B12/B6/B2/B1/D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰、和姜黄素对高血脂大鼠丙二醛(MDA)水平的影响
注：与模型组比较，aP<0.05。
临床试验
实验对象：2019年1-12月于大连市中心医院选取血清Hcy水平≥15μmol/L的脑卒中者120例，随机分为两组，各60例。观察组男30例，女30例，年龄52～84岁，平均73.6岁。对照组男28例，女32例，年龄52～84岁，平均72.3岁。所有患者均签署知情同意书，本研究经医院医学伦理委员会批准。两组患者一般资料比较，差异无统计学意义(P>0.05)，具有可比性。并排除以下患者：(1)正常压力性脑积水、糖尿病患者血糖控制不达标、使用抗精神病药物；(2)合并恶性肿瘤；(3)头部严重外伤史；(4)重要脏器功能不全；(5)阿尔茨海默病；(6)语言/听力障碍者。
分别对两组患者进行临床试验，(1)对照组口服A片(叶酸0.4mg、维生素B12 6μg、维生素B6 7mg)，1片/次/天，口服。(2)观察组口服B片(叶酸0.4mg、维生素B12 6μg、维生素B6 7mg、维生素B2 10mg、锌8mg、维生素B1 10mg、泛酸5mg、烟酰胺10mg、胆碱125mg、维生素D5μg、镁100mg、锰1.5mg)，1片/次/天，口服。两组患者均治疗半年。
半年后观察两组患者临床疗效和血清Hcy水平。临床疗效根据血清Hcy水平改善情况进行评定。血清Hcy水平通过循环菌法进行测定，在清晨空腹状态下抽取患者肘静脉血2ml。置于抗凝管内，通过系列化学检测，计算Hcy含量，≥15μmol/L即为高同型半胱氨酸血症。分别对比两组患者治疔前和治疗半年后的血清Hcy水平。
疗效判定标准为(1)显效：患者治疗后血清Hcy水平降低70％以上；(2)有效：患者治疗后血清Hcy水平降低40％～69％；(3)无效：患者治疗后血清Hcy水平降低未达到39％以上。
总有效率＝(显效+有效)例数/总例数×100％。
采用SPSS 20.0统计学软件分析数据，计量资料以
表示，采用t检验；计数资料以[n(％)]表示，采用x2检验；P<0.05为差异有统计学意义。
两组患者血清Hcy水平比较：两组治疗前血清Hcy水平比较，差异无统计学意义(P>0.05)。观察组治疗半年后血清Hcy水平显著低于对照组，差异有统计学意义(P<0.05)。见表4。
两组患者临床疗效比较：观察组治疗总有效率显著高于对照组，差异有统计学意义(P<0.05)。见表5。
表4两组患者血清Hcy水平比较
| 组别 | n | 治疗前 | 治疗后 |
| 对照组 | 60 | 23.02±2.76 | 18.21±2.12 |
| 观察组 | 60 | 23.11±2.79 | 9.32±1.46<sup>a</sup> |
| r值 | 0.039 | 27.987 | |
| P值 | 0.975 | 0.000 |
注：与对照组比较，Pa<0.05。
表5两组患者临床疗效比较[n(％)]
注：与对照组比较，Pa<0.05。
综上所述，对脑卒中Hcy水平偏高患者实施叶酸、维生素B12、维生素B6、维生素B2、锌、维生素B1、泛酸、烟酰胺、胆碱、维生素D、镁、锰治疗可有效降低患者的血清Hcy水平，提高治疗效果，具有较高的临床应用价值。
2、实验对象：全胃切除患者和大部分胃切除患者。
实验要求：志愿者服药依从性强，处于手术后的康复期初期，术后恢复正常。
2020年1-12月在大连医科大学附属第一医院选取符合实验要求的志愿者100人，年龄在50-75岁之间，平均年龄64.3岁，根据实际病情分为两组，即全胃切除后康复期的患者组和胃大部切除患者组，每组50人，在此基础上将两组患者再分为两组，一组为普通营养支持组，一组为服用维生素K/B12/B6/B2/B1/D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组。也就是说将志愿者分为A、B、C、D四组，每组25人。所有患者均签署知情同意书，本研究经医院医学伦理委员会批准。两组患者一般资料比较，差异无统计学意义(P>0.05)，具有可比性。并排除以下患者：(1)正常压力性脑积水、糖尿病患者血糖控制不达标、使用抗精神病药物；(2)合并恶性肿瘤；(3)头部严重外伤史；(4)重要脏器功能不全；(5)阿尔茨海默病；(6)语言/听力障碍者。
实验过程：四组人员的采用不同治疗方案为：用本产品治疗组(模型组)、仅使用叶酸和B组维生素治疗组、维生素K/B12/B6/B2/B1/D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素组，空白对照组，首先对四组志愿者进行常规营养治疗四周，然后同时分别给药，空白对照组给予葡萄糖等普通营养支持治疗。模型组服用剂量为1片/次/天，口服。建模方法即常规医院的营养支持治疗和日常饮食相结合的方法。实验跟踪一年时间。
具体的观察指标：轻度高同型半胱氨酸血症：血清同型半胱氨酸(Hcy)水平10-15μmol/L；中度高同型半胱氨酸血症：血清同型半胱氨酸(Hcy)水平15-30μmol/L；重度高同型半胱氨酸血症：血清同型半胱氨酸(Hcy)水平30μmol/L以上。
实验结果：
表6胃大部切除患者的统计结果(表中指标含义：显效：Hcy＜6μmol/L,有效：6μmol/L＜Hcy＜10μmol/L)
表7全胃切除患者的统计结果(表中指标含义：显效：Hcy＜6μmol/L,有效：6μmol/L＜Hcy＜10μmol/L)
从表6和表7的实验统计结果可知，无论对于全胃切除的志愿者还是胃大部切除的志愿者，本产品治疗组的治疗效果最佳，远高于单纯叶酸和B族维生素干预组。由上述实验结果推而广之，即使对于健康人群，补充本复方制剂也对高同型半胱氨酸血症的预防具有积极作用。上述实验同时也证明本复方制剂对于中老年人早期预防同型半胱氨酸血症的发生和发展有重要作用。
实验对象：2019年1-12月，大连市中心医院营养科75岁～90岁的营养不良患者30人，平均年龄81.9岁。
实验要求：患者及家属自愿参与实验；老人精神状态正常；患者的实验依从性较强。
实验过程：将老年患者随机分成两组，分别采血测量血液的生化指标，一组采用叶酸+B组维生素的常规营养支持治疗，称为模型组，另一组服用如实施例1所述的片剂，一日三次，一次一片，所有患者均签署知情同意书，本研究经医院医学伦理委员会批准。两组患者一般资料比较，差异无统计学意义(P>0.05)，具有可比性。并排除以下患者：(1)正常压力性脑积水、糖尿病患者血糖控制不达标、使用抗精神病药物；(2)合并恶性肿瘤；(3)头部严重外伤史；(4)重要脏器功能不全；(5)阿尔茨海默病；(6)语言/听力障碍者。
连续观察八周后采集血样后得出患者的生化指标，从而得到治疗效果的比较结果。最后两组患者各选取10例数据进行比较，结果如表8所示。
表8维生素K/维生素B12/维生素B6/维生素B2/维生素B1/维生素D、叶酸、胆碱、锌、泛酸、烟酰胺、镁、锰和姜黄素对营养不良患者丙二醛(MDA)水平的影响
实验结果表明，本复方制剂对于降低同型半胱氨酸水平和血脂水平都有明显的积极意义，相对于普通的营养支持治疗效果更明显。
本发明的产品主要针对高同型半胱氨酸人群(或高血脂高血压等人群)，而起主要辅助治疗作用的成分是叶酸、维生素B12、维生素B6，改善国内外同类产品较少且配方单一的情况。本产品区别于其他同类产品之处在于添加其他多种维生素及矿物质，主要原因是各种物质之间存在相互作用可提高产品的吸收率，并起到辅助降低血脂和血压的功效，例如B2可提高B6的利用率，胆碱可辅助降血脂等等，而且本产品针对中老年人群，适当的膳食补充对身体健康起到关键作用。
以片剂为例，说明本复方制剂的服用方法：
健康人群保健与预防：每日1次，每次1片；
中高风险治疗剂量：每日2次，每次1片；
高同型半胱氨酸血症治疗剂量：每日3次，每次1片。
注：中高风险治疗剂量所对应人群为：同型半胱氨酸水平6-10μmol/L；轻度高同型半胱氨酸血症：血清同型半胱氨酸水平10-15μmol/L；中度高同型半胱氨酸血症：血清同型半胱氨酸水平15-30μmol/L；重度高同型半胱氨酸血症：血清同型半胱氨酸水平30μmol/L以上。本领域公知的是，未在安全范围内的同型半胱氨酸水平6μmol/L以下，均可引发心脑血管疾病，损伤动脉、脑部甚至是DNA。
后三种指标的对应人群都属于高同型半胱氨酸血症患者，需每日3次，每次1片或者遵医嘱，并在服药期间密切关注血液生化指标。
Claims (7)
1.一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，其特征在于包括以下重量份的组分：叶酸：300-1300份、维生素B12：50-200份、维生素B6：6000-23000份、维生素B2：9000-31000份、胆碱：110000-390000份、锌：7000-25000份、维生素B1：9000-31000份、泛酸：4000-16000份、烟酰胺：9000-31000份、镁：900000-3100000份、锰：1400-4600份和维生素D：4-16份。
2.根据权利要求1所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，其特征在于包括以下重量份的组分：叶酸：300-900份、维生素B12：50-130份、维生素B6：6000-17000份、维生素B2：9000-21000份、胆碱：110000-250000份、锌：7000-17000份、维生素B1：9000-24000份、泛酸：4000-11000份、烟酰胺：9000-21000份、镁：90000-210000份、锰：1400-2800份和维生素D：4-11份。
3.根据权利要求1所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，其特征在于包括以下重量份的组分：叶酸：800份、维生素B12：120份、维生素B6：14000份、维生素B2：20000份、胆碱：250000份、锌：16000份、维生素B1：20000份、泛酸：10000份、烟酰胺：20000份、镁：200000份、锰：2800份和维生素D：11份。
4.根据权利要求1-3任一项所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，其特征在于：所述的复方制剂含有医学上允许的辅料，所制成的片剂、丸剂、滴丸或颗粒剂。
5.根据权利要求4所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂，其特征在于：所述医学上允许的辅料为硬脂酸镁、糊精中的任一种或者组合。
6.根据权利要求1-3任一项所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂的制备方法，其特征在于：各个成分要求食药级纯度即可，片剂的制备方法为：将各成分装入搅拌机进行均质30-100分钟，上压片机进行压片；所需成分均为粉末无需进行粉碎。
7.如权利要求1所述的一种含有胆碱、B族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂在制备高龄营养不良患者的膳食补充剂中的应用。
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