CN112294820B - 一种减少高血压患者血管内皮损伤的组合物 - Google Patents
一种减少高血压患者血管内皮损伤的组合物 Download PDFInfo
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Abstract
本发明涉及一种含有姜黄素和B族维生的组合物，由姜黄色素类化合物及其活性代谢产物中的一种或多种、B族维生素中的一种或多种、和药学上可接受的载体组成；其中姜黄色素类化合物及其活性代谢产物的含量为150～500mg，B族维生素的含量为0.5～100mg。本发明可用于减少高血压患者血管内皮损伤，减少动脉粥样硬化、心肌梗死、脑卒中等重大心脑血管事件的发生风险。
Description
技术领域
本发明属于药学领域，特别涉及一种含有姜黄素和B族维生素的组合物，以及该组合物在预防及缓解高血压患者血管内皮损伤、动脉粥样硬化、心肌梗死、脑卒中等高血压密切相关疾病中的用途。
背景技术
我国是高血压大国，冠心病、心肌梗死、脑卒中发病率逐年攀升，已成为一个不容忽视的国民问题。由于MTHFR C677T基因在中国人群中突变率较高，中国高血压患者血压升高同时更容易并发Hcy升高，而Hcy升高引起血管内皮炎症加剧，是动脉粥样硬化、脑卒中的独立危险因素，因此，在血压水平、患病年限、患者年龄相近的情况下，中国患者比美国、欧洲患者更容易发生脑卒中、急性心肌梗死等重大心脑血管事件。为适应我国患者高血压疾病特点，有必要研发一种能针对性降低Hcy水平、保护血管内皮、减少内皮损伤的产品。
姜黄素是植物姜黄中的主要活性成分，研究表明，姜黄素能通过调节不同的信号分子产生抗氧化、抗炎、抗血小板聚集等药理特性，尤其可通过上调内皮型一氧化氮合酶(eNOS)的表达或磷酸化，提高内源性一氧化氮的生成，从而改善内皮功能。姜黄素的这些特性为其降低高血压患者血管内皮损伤、预防脑卒中提供了理论基础。叶酸和维生素B12、B6是影响Hcy浓度的重要营养因素，缺乏会引起高Hcy血症。叶酸转化为N6甲基叶酸后直接参与蛋氨酸的合成，从而降低血浆Hcy浓度，降低脑卒中的发病风险。
发明内容
本发明的目的在于提供一种姜黄素和B族维生素的组合物，用于减少高血压患者血管内皮损伤。
为了实现上述目的，本发明采用以下技术方案：
一种用于减少高血压患者血管内皮损伤的组合物，由姜黄色素类化合物及其活性代谢产物中的一种或多种、B族维生素中的一种或多种、和药学上可接受的载体组成；其中姜黄色素类化合物及其活性代谢产物的含量为150～500mg，B族维生素的含量为0.5～50mg。
在本发明中，姜黄色素类化合物及其活性代谢产物选自姜黄素、去甲氧基姜黄素、双去甲氧基姜黄素、四氢姜黄素及其活性代谢产物或盐类中的一种或多种。
通过实验研究，姜黄色素类化合物及其活性代谢产物含量分别为：姜黄素(150～300mg)、去甲氧基姜黄素(200～500mg)、双去甲氧基姜黄素(200～500mg)、四氢姜黄素(150～300mg)，上述物质的活性代谢产物或盐类含量与相应的上述物质含量等同。
在本发明中，B族维生素选自维生素B6、维生素B12、叶酸类物质中的一种或多种。
在本发明中，维生素B6包括吡哆醇、吡哆醛、吡哆胺、磷酸吡哆醛、磷酸吡哆胺及上述物质的衍生物和可在体内释放/生成该类化合物的物质。
在本发明中，维生素B12包括钴胺素、甲钴胺素、5’脱氧腺苷钴胺素、羟钴胺素、氰钴胺素及其他钴胺素的衍生物和可在体内释放/生成钴胺素的物质。
在本发明中，叶酸类物质包括叶酸、甲酰四氢叶酸盐、L-甲基叶酸、叶酸盐、叶酸或叶酸盐的活性代谢物和可在体内释放/生成叶酸的物质。
B族维生素类物质在本发明中的治疗有效量分别为：叶酸类物质的含量为0.2～10mg，维生素B12含量为0.1～2mg，维生素B6含量为0.5～50mg。
本发明优选由以下含量的组分作为活性成分的组合物：其中姜黄色素类化合物及其活性代谢产物选自姜黄素(150～300mg)、去甲氧基姜黄素(200～500mg)、双去甲氧基姜黄素(200～500mg)、四氢姜黄素(150～300mg)中的一种；B族维生素选自叶酸(0.2～5mg)、甲酰四氢叶酸钙(0.2～5mg)、维生素B12(0.25～2mg)和维生素B6(5～50mg)中的一种或几种。
作为一种优选，本发明提供的组合物中姜黄色素类化合物为姜黄素或四氢姜黄素，B族维生素为叶酸或甲酰四氢叶酸钙；其中姜黄色素类化合物含量为150～300mg，B族维生素的含量为0.2～5mg。
作为一种优选，本发明提供的组合物中姜黄色素类化合物为姜黄素或四氢姜黄素，B族维生素为维生素B6；其中姜黄色素类化合物含量为150～300mg，B族维生素的含量为5～50mg。
作为一种优选，本发明提供的组合物中姜黄色素类化合物选自姜黄素或四氢姜黄素，B族维生素为维生素B12；其中姜黄色素类化合物含量为150～300mg，B族维生素的含量为0.25～2mg。
作为一种优选，本发明提供的组合物中姜黄色素类化合物为去甲氧基姜黄素或双去甲氧基姜黄素，B族维生素为叶酸或甲酰四氢叶酸钙；其中姜黄色素类化合物含量为200～500mg，B族维生素的含量为0.2～5mg。
作为一种优选，本发明提供的组合物中姜黄色素类化合物为去甲氧基姜黄素或双去甲氧基姜黄素，B族维生素为维生素B6；其中姜黄色素类化合物含量为200～500mg，B族维生素的含量为5～50mg。
作为一种优选，本发明提供的组合物中姜黄色素类化合物为去甲氧基姜黄素或双去甲氧基姜黄素，B族维生素为维生素B12；其中姜黄色素类化合物含量为200～500mg，B族维生素的含量为0.25～2mg。
本组合物可以制成普通片剂、普通胶囊、颗粒剂、缓释片剂、舌下含片、口腔速崩片、分散片、肠溶片、肠溶胶囊、延迟释放片、定时/位释放片、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊、颗粒剂、口服液、膜剂、贴剂等剂型。
本组合物中还含有药剂学可接受的载体，可制成普通口服制剂、包括普通片剂、普通胶囊、颗粒剂、缓释控释剂型等，制成片剂时所述药学上可接受的载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅料等，如淀粉、微晶纤维素、无机盐类、蔗糖、糊精、乳糖、糖粉、葡萄糖、氯化钠、半胱氨酸、柠檬酸、亚硫酸钠、二氧化硅、山嵛酸甘油酯、滑石粉、硬脂酸、硬脂酸镁等的一种或几种物质的组合物，虫胶、乙基纤维素、羟丙甲基纤维素、丙烯酸树脂、聚醋酸乙烯苯二甲酸酯中的一种或几种物质的组合物等，属于本领域常识。
本组合物还可含有药剂学可接受的载体，可制成缓释片剂，包括赋形剂和辅料等。
本发明用于制备预防及缓解高血压患者血管内皮损伤、眼底出血、动脉粥样硬化、心肌梗死、脑卒中等高血压密切相关疾病和症状。本发明筛选具有协同作用的姜黄色素类化合物与B族维生素进行科学组方，通过对组合物组分最佳剂量的选择，达到预防及缓解高血压患者血管内皮损伤的目的。与现有产品相比，本发明是一种更加安全有效的组合物产品，其作用效果亦显著强于组成成分的单一应用效果，改善高血压患者血管内皮损伤的状况具有意想不到的协同增效作用。可用于高血压患者的日常保健，安全无副作用，兼具有治疗预防眼底出血、动脉粥样硬化、心肌梗死、脑卒中等高血压密切相关疾病的功能。
以下所述是本发明实施例的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明实施例原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明实施例的保护范围。
实施例1：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取姜黄素、30％处方量的微晶纤维素和50％处方量的二氧化硅混合10分钟，过0.5mm筛网3次，得混粉1，备用；取叶酸、剩余处方量的微晶纤维素和剩余处方量的二氧化硅、预胶化淀粉混合10分钟，过0.3mm筛网3次，得混粉2，备用；取得混粉1、混粉2和羧甲淀粉钠混合；加入硬脂酸镁混合，得混粉，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例2：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取PVP-K30、姜黄素、30％处方量的二氧化硅和乳糖，用适量乙醇使其完全溶解，置高速剪切制粒机混合与制粒，挥干乙醇后置烘箱干燥，整粒，得颗粒备用；另取5甲基四氢叶酸、微晶纤维素、剩余处方量的二氧化硅和预胶化淀粉混合，过筛，得混粉备用；取颗粒和混粉和硬脂酸镁混合，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例3：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取姜黄素、30％处方量的微晶纤维素和50％处方量的二氧化硅混合10分钟，过0.5mm筛网3次，得混粉1，备用；取叶酸、剩余处方量的微晶纤维素和剩余处方量的二氧化硅、预胶化淀粉混合10分钟，过0.3mm筛网3次，得混粉2，备用；取得混粉1、混粉2和羧甲淀粉钠混合；加入硬脂酸镁混合，得混粉，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例4：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取四氢姜黄素、磷酸氢钙和50％处方量的二氧化硅混合，过筛，得混粉1，备用；取叶酸、微晶纤维素、预胶化淀粉和剩余处方量的二氧化硅混合，过筛，得混粉2，备用；将混粉1和混粉2置高速剪切制粒机加水制粒，30目筛网整粒，干燥，得颗粒；取颗粒和硬脂酸镁混合，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例5：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取四氢姜黄素、磷酸氢钙和50％处方量的二氧化硅混合，过筛，得混粉1，备用；取叶酸、微晶纤维素、预胶化淀粉和剩余处方量的二氧化硅混合，过筛，得混粉2，备用；将混粉1和混粉2置高速剪切制粒机加水制粒，30目筛网整粒，干燥，得颗粒；取颗粒和硬脂酸镁混合，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例6：本发明所述组合物的片剂制备(1000片量)
配方：
制备方法：取去甲氧基姜黄素、30％处方量的微晶纤维素和50％处方量的二氧化硅混合10分钟，过0.5mm筛网3次，得混粉1，备用；取四氢叶酸、剩余处方量的微晶纤维素和剩余处方量的二氧化硅、预胶化淀粉混合10分钟，过0.3mm筛网3次，得混粉2，备用；取得混粉1、混粉2和羧甲淀粉钠混合；加入硬脂酸镁混合，得混粉，压片。将包衣预混剂配制成溶液，素片包衣，即制得本发明所述组合物的片剂。
实施例7：本发明所述组合物的胶囊制备(1000粒量)
配方：
制备方法：取去甲氧基姜黄素、磷酸氢钙和25％处方量的二氧化硅混合，过筛，得混粉1，备用；取维生素B6、微晶纤维素和剩余处方量的二氧化硅混合，过筛，得混粉2，备用；将混粉1、混粉2和预胶化淀粉置高速剪切制粒机加水制粒，24目筛网湿整粒，干燥，24目筛网干整粒，得颗粒；取颗粒和硬脂酸镁混合，灌装胶囊。
实施例8：本发明所述组合物的胶囊制备(1000粒量)
配方：
制备方法：取双去甲氧基姜黄素、磷酸氢钙和25％处方量的二氧化硅混合，过筛，得混粉1，备用；取维生素B12、微晶纤维素和剩余处方量的二氧化硅混合，过筛，得混粉2，备用；将混粉1、混粉2和预胶化淀粉置高速剪切制粒机加水制粒，24目筛网湿整粒，干燥，24目筛网干整粒，得颗粒；取颗粒和硬脂酸镁混合，灌装胶囊。
实施例9：本发明所述组合物对H型高血压大鼠炎症因子、Hcy水平影响研究
50只12周龄SHR大鼠(雄性，体重220～240g，SP级)与10只12周龄WKY大鼠饲养于标准实验条件(室温21～25℃，相对湿度40～60％，12h/12h光暗交替)。适应性喂养1周后，将SHR大鼠随机分成模型组、姜黄素组(30mg/kg/d)、叶酸组(0.08mg/kg/d)、叶酸+姜黄素组(30mg/kg/d姜黄素+0.08mg/kg/d叶酸)，每组10只，WKY大鼠作为空白对照。模型组、姜黄素组、叶酸组、叶酸+姜黄素组给予0.5％蛋氨酸溶液作为饮用水，其他各组标准饮食饮水。姜黄素组、叶酸组、姜黄素+叶酸组每天按剂量灌胃，模型组和WKY组灌胃同等溶剂，12周后检测相关指标。
表1各组大鼠Hcy、NO、ET-1水平(n＝10)
注：与WKY组比较*P<0.05，**P<0.01；与模型组比较，#P<0.05,##P<0.01；与叶酸组比较，ΔP<0.05，ΔΔP<0.01；与姜黄素组比较，■■P<0.01
如表1结果所示，与模型组相比，叶酸单用可降低大鼠血浆hcy水平，升高NO，表现出血管内皮保护的作用，叶酸对降低ET-1(内皮素-1)有一定降低作用，但无统计学差异(P>0.05)；姜黄素单用对血管内皮的保护作用不显著；两者联用在降低Hcy水平，升高NO和降低ET-1等指标上表现出意想不到的协同增效的作用，与单药相比差异现在(P>0.05或P>0.01),结果表面叶酸+姜黄素联用具有显著保护血管内皮的功能，且改善效果较单用叶酸或姜黄素单用效果更加显著。
表2各组大鼠MCP-1、hs-CRP水平(n＝10)
注：与WKY组比较*P<0.05，**P<0.01；与模型组比较，#P<0.05,##P<0.01；与叶酸组比较，ΔP<0.05，ΔΔP<0.01；与姜黄素组比较，■■P<0.01.
如表2结果所示，叶酸+姜黄素组联合应用能显著降低大鼠MCP-1(单核细胞趋化因子)和Hs-CRP(超敏C-反应蛋白)水平，且降低效果比叶酸或姜黄素单用均更加显著，表现出显著的协同增效的作用。超敏C-反应蛋白已被证实是由慢性炎症引发心血管疾病的独立危险因素，MCP-1是内皮炎症始动因子，并参与动脉粥样硬化斑块生成中的炎症扩大反应，本研究结果提示了姜黄素+叶酸连用能通过减少炎症反应，改善高血压大鼠血管内皮损伤，从而起到保护的作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种减少H型高血压患者血管内皮损伤的组合物，组成成分为：（ 1 ） .药用剂量的姜黄素；（ 2） .药用剂量的叶酸；（ 3） .可药用载体或赋形剂，其中姜黄素与叶酸的含量比为30：0.08。
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