CN113616667A - 一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用 - Google Patents

一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用 Download PDF

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CN113616667A
CN113616667A CN202110853073.5A CN202110853073A CN113616667A CN 113616667 A CN113616667 A CN 113616667A CN 202110853073 A CN202110853073 A CN 202110853073A CN 113616667 A CN113616667 A CN 113616667A
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parts
nucleotide
vitamin
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nucleotide composition
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CN113616667B (zh
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陈玉松
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Chen Yusong
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Dalian Zhen Ao Biotechnology Co ltd
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Abstract

本发明公开了一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用。该复配核苷酸是由AMP、CMP、GMP、UMP四种单核苷酸组成的混合物。其可以与维生素、矿物质等营养素或其他功能性物质(成分)搭配应用于药品、特医食品、保健品和功能性食品，可以改善机体糖耐量，促进胰岛素分泌，起到降血糖的作用。

Description

一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用
技术领域
本发明属于医药保健领域，具体为一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用。
背景技术
糖尿病是一种以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损或两者兼有引起。胰岛素是由胰脏内的胰岛β细胞受内源性或外源性物质如葡萄糖、乳糖、核糖、精氨酸、胰高血糖素等的刺激而分泌的一种蛋白质激素，是机体内唯一降低血糖的激素，同时促进糖原、脂肪、蛋白质合成。
核苷酸是核糖核酸及脱氧核糖核酸的基本组成单位，是体内合成核酸的前身物。核苷酸随着核酸分布于生物体内各器官、组织、细胞的核及胞质中，具有重要的生物学功能，它们参与了生物体内几乎所有的生物化学反应过程。胰岛素分泌的调控与β细胞内的多种核苷酸代谢息息相关，胰岛素分泌时细胞质中多种核苷酸类物质同时对胰岛素分泌产生影响。三磷酸腺苷(ATP)在β细胞分泌胰岛素调控中起关键性作用。同时，腺苷酸还是几种重要辅酶，如辅酶Ⅰ(烟酰胺腺嘌呤二核苷酸，NAD+)、辅酶Ⅱ(磷酸烟酰胺腺嘌呤二核苷酸，NADP+)、黄素腺嘌呤二核苷酸(FAD)及辅酶A(CoA)的组成成分，NAD+可以促进胰岛素的分泌，从而补充糖尿病患者胰岛素分泌不足的情况。此外，核苷酸对于维持机体免疫功能，促进免疫细胞的增殖和细胞因子的分泌具有重要作用。补充核苷酸可以很好的改善机体免疫功能，提高机体免疫力。近二十年来，外源核苷酸已广泛应用于婴幼儿配方乳粉以及保健品中，其在人体中使用的安全性已得到科学试验的充分证明。
【CN 201880051788.5】公开了一种使用烟酰胺单核苷酸进行治疗的组合物和方法，其中包括含有烟酰胺单核苷酸的组合物可用于治疗、改善、减轻或逆转涉及NMN代谢的任何疾病或病症，例如，糖尿病、肥胖症、胰岛素敏感性的降低、葡萄糖刺激的胰岛素分泌的损伤等。
发明内容
本发明的目的在于提供一种辅助治疗糖尿病的核苷酸组合物及其制备方法和应用。该复配核苷酸是由AMP、CMP、GMP、UMP四种单核苷酸按一定比例组成的混合物，可再搭配维生素、矿物质等营养素或功能性物质(成分)，可以起到辅助治疗、改善糖尿病的作用。
为实现上述目的，本发明所采用的技术方案是：
一种辅助治疗糖尿病的核苷酸组合物，所述核苷酸组合物包括由AMP、CMP、GMP、UMP四种单核苷酸组成的复配核苷酸，其中复配核苷酸的重量配比为：AMP 15.0-25.0％、CMP15.0-45.0％、GMP 15.0-35.0％、UMP 15.0-30.0％。
进一步地，复配核苷酸的重量配比为：AMP 16.9％、CMP 43.2％、GMP 17.8％、UMP22.1％，或AMP 24.3％、CMP 28.3％、GMP 19.3％、UMP 28.1％。
进一步地，所述核苷酸组合物还包括维生素、矿物质等营养素或功能物质(成分)，将复配核苷酸与维生素、矿物质等营养素或功能物质(成分)搭配，制成组合物，发挥协同作用；
所述复配核苷酸与维生素、矿物质等营养素的配比为：复配核苷酸8-232份、维生素A0.16-0.9份、维生素D 0.003-0.012份、维生素E 3.18-7.15份、维生素K10.018-0.04份、维生素B10.34-0.76份、维生素B20.34-0.76份、维生素B60.34-0.76份、维生素B120.0005-0.0011份、烟酸0.84-1.89份、叶酸0.089-0.2份、泛酸1.17-2.63份、维生素C 21.76-48.96份、生物素0.008-0.019份、钠334.71-522.99份、钾451.86-706.04份、铜0.18-2份、镁73.64-115.06份、铁3.3-9.2份、锌1.67-8.36份、锰0.1-2.44份、钙217.56-339.94份、磷160.67-251.04份、碘0.027-0.042份、氯251.03-870.25份、硒0.013-0.089份，所述营养素还包括铬、牛磺酸、膳食纤维中的一种或多种，铬0.0067-0.2228份、牛磺酸32.2-80.4份、膳食纤维5023-18846份；
或所述复配核苷酸与功能性物质(成分)配比为：复配核苷酸1-3份、功能性物质(成分)5-15份，所述功能性物质为川陈皮提取物(川陈皮素)、亚麻酸微囊粉、抗性糊精中的一种或多种。
本发明的另一目的在于提供上述复配核苷酸组合物的制备方法，将各组分按配方进行称量，混合均匀后按照常规工艺制备成成品。
进一步地，所述成品状态包括粉剂、颗粒剂、片剂、丸剂、口服液、胶囊。
本发明的再一目的在于提供上述核苷酸组合物在制备辅助治疗糖尿病的产品上的应用。所述核苷酸组合物成品可以直接或经常规步骤处理后添加在药品、特医食品、保健品和功能性食品中，起到辅助治疗糖尿病的作用。
本发明的有益效果为：本发明提供了一种辅助治疗糖尿病的核苷酸组合物，包括由AMP、CMP、GMP、UMP四种单核苷酸组成的复配核苷酸，或复配核苷酸与维生素、矿物质等营养素或功能性物质(成分)配伍制成的混合物。该核苷酸组合物被人体摄入以后，在人体消化道内各种酶的作用下分解成各种游离核苷酸类物质，促进胰岛素的分泌，还可以增加人体的免疫力，从而达到辅助治疗糖尿病的作用。核苷酸是食品添加剂类物质，其在人体中使用的安全性已得到科学试验的充分证明。
具体实施方式
下面结合具体实施例对本发明的作进一步解释说明，这些实施例应被理解为仅是举例说明，而非以任何方式限制本发明的范围。
实施例1
一种复配核苷酸的制备方法如下：
复配核苷酸按照AMP 16.9wt％、CMP 43.2wt％、GMP 17.8wt％、UMP 22.1wt％配比，换算后称取原料，用混合机混合均匀，制得粉剂。以上操作均在洁净区进行操作，按质量标准的规定取样进行各项指标的检验。
实施例2
一种复配核苷酸的制备方法如下：
复配核苷酸按照AMP 24.3wt％、CMP 28.3wt％、GMP 19.3wt％、UMP 28.1wt％配比，换算后称取原料，用混合机混合均匀，制得粉剂。以上操作均在洁净区进行操作，按质量标准的规定取样进行各项指标的检验。
实施例3
一种复配核苷酸组合物的制备方法如下：
Figure BDA0003183171680000031
Figure BDA0003183171680000041
本实施例中的复配核苷酸为实施例2中制得的复配核苷酸。
按照以上复配核苷酸与营养素、矿物质等营养素的配比，换算后称取一定量的原料，用混合机混合均匀，制得粉剂。以上操作均在洁净区进行操作，成品按质量标准的规定取样进行各项指标的检验。
实施例4
一种复配核苷酸组合物的制备方法如下：
Figure BDA0003183171680000042
Figure BDA0003183171680000051
本实施例中的复配核苷酸为实施例2中制得的复配核苷酸。
按照以上复配核苷酸与营养素、矿物质等营养素的配比，换算后称取一定量的原料，用混合机混合均匀，制得粉剂、片剂或胶囊。以上操作均在洁净区进行操作，成品按质量标准的规定取样进行各项指标的检验。
实施例5
一种复配核苷酸组合物的制备方法如下：
Figure BDA0003183171680000052
Figure BDA0003183171680000061
本实施例中的复配核苷酸为实施例1中制备得到的复配核苷酸。
按照以上复配核苷酸与营养素、矿物质等营养素的配比，换算后称取一定量的原料，用混合机混合均匀，制得粉剂。以上操作均在洁净区进行操作，成品按质量标准的规定取样进行各项指标的检验。
实施例6
一种复配核苷酸组合物的制备方法如下：
按照复配核苷酸(实施例2中制备得到的复配核苷酸)1.2g、抗性糊精6.5g、原亚麻酸微囊粉(亚麻籽油微囊粉)6g、牛磺酸0.5g的配比，称取原料，用混合机混合均匀，制成片剂。以上操作均在洁净区进行操作，成品按质量标准的规定取样进行各项指标的检验。
实施例7
一种复配核苷酸组合物的制备方法如下：
按照复配核苷酸(实施例2中制备得到复配核苷酸)2.4g、抗性糊精6.5g、牛磺酸0.5份、川陈皮提取物(川陈皮素)0.034g的配比，称取原料，用混合机混合均匀，装成胶囊。以上操作均在洁净区进行操作，成品按质量标准的规定取样进行各项指标的检验。
实施例8效果实验例
一、材料与方法
1、样品：上述实施例1-7中所得的核苷酸混合物样品。
2、实验动物
SPF级昆明种小鼠，20g左右，实验温度：24-26℃，湿度65-70％。
3、实验剂量：核苷酸低剂量组45mg/kgBW、核苷酸中剂量组90mg/kgBW和核苷酸高剂量组135mg/kgBW，用蒸馏水配至所需浓度；联合用药剂量0.1U/kg加上核苷酸低剂量组45mg/kgBW、核苷酸中剂量组90mg/kgBW和核苷酸高剂量组135mg/kgBW。
4、实验方法
(1)核苷酸混合物对正常小鼠降糖试验
选用健康雄性小鼠，禁食不禁水12h，取尾血测血糖值，按血糖水平随机分为两组，1个对照组和1个核苷酸高剂量组，每组10只，核苷酸高剂量组给予135mg/kgBW，对照组给予蒸馏水，连续灌胃30天，禁食同前，测空腹血糖值，观察受试物对正常动物空腹血糖的影响。
(2)核苷酸混合物对四氧嘧啶高血糖模型小鼠降糖试验及糖耐量试验
利用四氧嘧啶诱导胰岛素抵抗糖代谢紊乱模型对小鼠进行高血糖模型降糖实验(四氧嘧啶是一种胰岛β细胞毒剂，能够产生自由基，并选择性的攻击胰岛β细胞，造成胰岛素分泌降低，从而导致血糖升高，而且还能影响到其他脏器，比如肝脏，使肝脏糖原合成及葡萄糖利用等功能受到抑制，从而引起实验性糖尿病)。采用小鼠空腹血糖以及糖耐量为判断指标。
选用健康雄性小鼠，实验小鼠分为三大组，空白对照组(用于判断模型是否建立成功)、对照组及试验组。首先构建小鼠糖尿病模型，将后两组小鼠禁食不禁水12h，腹腔注射45mg/kgBW四氧嘧啶生理盐水溶液，连续数日，5天后当小鼠空腹血糖达到大于10mmol/L时，模型构建成功。将构建成功的四氧嘧啶高血糖模型分为1个模型对照组及7个试验组，，每个试验组分为三个小组，分别为核苷酸低剂量组、核苷酸中剂量组和核苷酸高剂量组，模型对照组以及每小组分别10只。将试验组小鼠每日灌胃一定剂量的实施例1-7配方的复配核苷酸的生理盐水溶液，分别为核苷酸低剂量组45mg/kgBW、核苷酸中剂量组90mg/kgBW和核苷酸高剂量组135mg/kgBW。其余两组(空白对照组、模型对照组)每日灌胃等量的生理盐水溶液，30d后，取尾血测定小鼠的空腹血糖和胰岛素含量，并给各组小鼠灌胃2.0g/kgBW葡萄糖溶液，分别于0.5h、2h后取尾血测定小鼠的空腹血糖进行糖耐量实验。
(3)联合用药对四氧嘧啶高血糖模型小鼠降糖试验
选用健康雄性小鼠，实验小鼠分为四大组，空白对照组(用于判断模型是否建立成功)、模型对照组、胰岛素治疗组及核苷酸混合物与胰岛素联合用药的试验组。首先构建小鼠糖尿病模型，将后两组小鼠禁食不禁水12h，腹腔注射45mg/kgBW四氧嘧啶生理盐水溶液，连续数日，5天后当小鼠空腹血糖达到大于10mmol/L时，模型构建成功。将构建成功的四氧嘧啶高血糖模型分为1个模型对照组、1个胰岛素治疗组及4个核苷酸混合物与胰岛素联合用药组的试验组，每个试验组分为三个小组，分别为核苷酸低剂量组、核苷酸中剂量组和核苷酸高剂量组，模型对照组、胰岛素治疗组、以及每小组分别10只。将试验组小鼠每日灌胃一定剂量的实施例2、4、6、7配方的复配核苷酸的生理盐水溶液+胰岛素，分别为核苷酸低剂量组45mg/kgBW+胰岛素联合用药、核苷酸中剂量组90mg/kgBW+胰岛素联合用药，和核苷酸高剂量组135mg/kgBW+胰岛素联合用药。空白对照组、模型对照组每日灌胃等量的生理盐水溶液，胰岛素治疗组每日灌胃与核苷酸混合物+胰岛素联合用药中相同剂量的胰岛素(仅加入胰岛素，无核苷酸混合物)，30d后，取尾血测定小鼠的空腹血糖和胰岛素含量。
二、实施例1-7实验结果
1、核苷酸混合物对正常小鼠空腹血糖的影响
由表1结果可见，与对照组比较，实施例1-7中核苷酸混合物对正常小鼠空腹血糖差异无显著性，说明核苷酸混合物对正常小鼠空腹血糖无影响。
表1实施例1-7中核苷酸混合物对正常小鼠空腹血糖的影响(
Figure BDA0003183171680000081
n＝10)
Figure BDA0003183171680000082
2、核苷酸混合物对四氧嘧啶高血糖模型小鼠空腹血糖的影响
由表2结果可见，与空白对照组比较，模型对照组空腹血糖值显著升高(P＜0.05)，说明高血糖模型成立；与模型对照组比较，实施例1-7中各剂量核苷酸混合物对高血糖模型小鼠空腹血清胰岛素含量显著升高，血糖值显著降低(P＜0.05)，说明核苷酸混合物可以促进胰岛素的分泌，起到降低血糖的作用。
表2实施例1-7中核苷酸混合物对四氧嘧啶高血糖模型小鼠空腹血糖的影响(
Figure BDA0003183171680000083
n＝10)
Figure BDA0003183171680000084
Figure BDA0003183171680000091
注：#表示与空白对照组比较，差异有统计学意义；*表示与模型对照组比较，差异有统计学意义。
3、核苷酸混合物对四氧嘧啶高血糖模型小鼠糖耐量的影响
由表3结果可见，与模型对照组比较，实施例1-7中各剂量核苷酸混合物对给葡萄糖后0.5h、2h血糖值显著降低(P＜0.05)，说明核苷酸混合物对糖尿病小鼠有升高糖耐量的作用。
表3实施例1-7中核苷酸混合物对小鼠空腹糖耐量的影响(
Figure BDA0003183171680000092
n＝10)
Figure BDA0003183171680000093
Figure BDA0003183171680000101
注：#表示与空白对照组比较，差异有统计学意义；*表示与模型对照组比较，差异有统计学意义。
4、联合用药对四氧嘧啶高血糖模型小鼠降糖试验
由表4结果可见，与空白对照组比较，模型对照组空腹血糖值显著升高(P＜0.05)，说明高血糖模型成立；与模型对照组比较，胰岛素治疗组对高血糖模型小鼠空腹胰岛素含量显著升高，血糖值显著降低(P＜0.05)；与胰岛素治疗组比较，实施例2、4、6、7中各剂量核苷酸混合物与胰岛素联合用药对高血糖模型小鼠空腹胰岛素含量显著升高，血糖值降低(P＜0.05)；说明在注射的胰岛素降低血糖的同时，核苷酸混合物还可以促进胰岛素的分泌，核苷酸混合物与胰岛素起到协同降低血糖的作用。
表4实施例2、4、6、7中核苷酸混合物+胰岛素联合用药对四氧嘧啶高血糖模型小鼠空腹血糖的影响(
Figure BDA0003183171680000111
n＝10)
Figure BDA0003183171680000112
注：#表示与空白对照组比较，差异有统计学意义；*表示与模型对照组比较，差异有统计学意义。
实验结果表明：摄入复配核苷酸的小鼠空腹血糖值比模型对照组小鼠降低，血清胰岛素含量比模型对照组升高，并且复配核苷酸能够在一定程度上改善糖尿病小鼠的糖耐量。说明复配核苷酸及混合物可以改善机体糖耐量，促进胰岛素分泌，具有辅助治疗糖尿病的作用。

Claims (7)

1.一种辅助治疗糖尿病的核苷酸组合物，其特征在于，所述核苷酸组合物包括复配核苷酸，其中复配核苷酸的重量配比为：AMP 15.0-25.0％、CMP 15.0-45.0％、GMP 15.0-35.0％、UMP 15.0-30.0％。
2.根据权利要求1所述的核苷酸组合物，其特征在于，复配核苷酸的重量配比为：AMP16.9％、CMP 43.2％、GMP 17.8％、UMP 22.1％，或AMP 24.3％、CMP 28.3％、GMP 19.3％、UMP 28.1％。
3.根据权利要求1或2所述的核苷酸组合物，其特征在于，还包括营养素或功能性物质；
所述复配核苷酸与营养素的重量配比为：复配核苷酸8-232份、维生素A 0.16-0.9份、维生素D 0.003-0.012份、维生素E 3.18-7.15份、维生素K1 0.018-0.04份、维生素B1 0.34-0.76份、维生素B2 0.34-0.76份、维生素B6 0.34-0.76份、维生素B12 0.0005-0.0011份、烟酸0.84-1.89份、叶酸0.09-0.2份、泛酸1.17-2.63份、维生素C 21.76-48.96份、生物素0.008-0.019份、钠334.71-522.99份、钾451.86-706.04份、铜0.18-2份、镁73.64-115.06份、铁3.3-9.2份、锌1.67-8.36份、锰0.1-2.4份、钙217.56-339.94份、磷160.67-251.04份、碘0.027-0.042份、氯251.03-870.25份、硒0.013-0.089份，所述营养素还包括铬、牛磺酸、膳食纤维中的一种或多种，铬0.0067-0.2228份、牛磺酸32.2-80.4份、膳食纤维5023-18846份；
所述复配核苷酸与功能性物质的重量配比为：复配核苷酸1-3份、功能性物质5-15份，所述功能性物质为抗性糊精、牛磺酸、亚麻酸微囊粉、川陈皮素中的一种或多种。
4.如权利要求1-3任一项所述的核苷酸组合物的制备方法，其特征在于，将各组分按配方进行称量，混合均匀后制成成品。
5.根据权利要求4所述的制备方法，其特征在于，所述成品状态包括粉剂、颗粒剂、片剂、丸剂、口服液、胶囊。
6.如权利要求1-3任一项所述的核苷酸组合物在制备辅助治疗糖尿病的产品中的应用。
7.根据权利要求6所述的应用，其特征在于，所述产品为药品、特医食品、保健品和功能性食品。
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