CN112089828A - 一种生物发酵型的复方三价铬的降血糖组合药的制备方法 - Google Patents
一种生物发酵型的复方三价铬的降血糖组合药的制备方法 Download PDFInfo
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Abstract
本发明公开了一种生物发酵型的复方三价铬的降血糖组合药的制备方法，所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法采用以下原料按重量比配制而成：富含三价铬酵母、灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳、蛹虫草和葛根。本发明运用有机三价铬在降糖的中药组合物中的特殊协同作用与生物发酵中药增效（4‑22倍）的机理，制备的复方三价铬的降血糖制剂，有高效的降低血糖、降血脂、降胆固醇效果，服用可以显著降低糖尿病人的血糖，治疗效果显著。
Description
技术领域
本发明涉及生物工程治疗糖尿病领域，特别是涉及中药发酵微生物工程领域中的一种生物发酵型的复方三价铬的降血糖组合药的制备方法。
背景技术
根据新发布的《中国糖尿病防治指南》显示糖尿病发病率已达10.4%。我国18岁以上成人2型糖尿病发病率已达10.4%，男性11.1%，女性9.6%。60岁以上的老年人糖尿病患病率均在20%以上。糖尿病的高发与体内微量元素铬的缺乏有直接关系。三价铬是葡萄糖耐量因子（GTF）的重要组成成分，它是通过GTF与机体胰岛素、膜受体之间形成三元配合物而发挥其重要的生理作用。人体细胞要靠胰岛素把血糖运到细胞内变成能量，缺少了铬的存在，就会使胰岛素的效能降低，糖不能正常顺利地进入细胞内，血糖就会持续升高。三价铬在体内参与糖代谢和脂肪代谢，其功能是维持机体正常的葡萄糖的耐受量，提高人体组织对胰岛素的敏感性和利用率，促进机体糖代谢的正常进行，有效地防治糖尿病地发生。
早在1959年之前，美国的医学家Schwarz和Mertz等提出微量元素的三价铬离子是葡萄糖耐量因子的主要组成部分之一，它具有调节脂质代谢、改善糖耐量的重要作用。人体摄入微量元素铬不足时，会导致自身胰岛素缺铬而工作效能降低，血糖升高，美国医生把糖尿病也叫做“三价铬缺乏症”。如果不及时补充铬元素，胰腺分泌的胰岛素代偿功能就可能发生衰竭，胰腺分泌胰岛素功能受损时，就会引发糖尿病。因此，专家们一致认为缺铬是引起糖尿病的主要原因之一。
人体根据年龄而不同对微量元素铬的需求，1～3岁每日，20～80微克，4～6岁是30～120微克，青少年和成人为50～200微克。富含铬元素的食物包括：燕麦、坚果、海藻、麦芽、全麦、绿菜花、黑胡椒、南瓜、玉米、胚芽米、米糖、苹果皮、动物肝脏、红糖、海产品、啤酒等。但由于含量少，通过普通食物获得微量铬元素，往往不能满足机体所需量。所以，最好摄入铬元素的补充剂。人体对不同来源三价铬的吸收利用的情况差异很大，对无机铬（例如三氯化铬）吸收率仅仅是0.5-2%，对有机铬吸收率比较高，可以达到10-25%。但是，由于人们在日常饮食中很难获得足够的三价有机铬，所以，还需要另外途径补充。特别对已经患有糖尿病的患者，补充微量元素铬显得更为重要。人体对不同来源三价铬的吸收利用的情况差异很大，临床上给糖尿病患者单纯补充三价铬元素用来降低血糖，效果并不明显，本发明攻克了微量元素铬吸收率低、糖尿病久治不愈等瓶颈技术，通过生物工程发酵，发明了一种高效复方三价铬的降血糖制剂。
发明内容
人体对不同来源三价铬的吸收利用的情况差异很大，对无机铬（例如三氯化铬）吸收率仅仅是0.5-2%，对有机铬吸收率比较高，可以达到10-25%。糖尿病患者持续高血糖与长期代谢紊乱等原因，往往导致全身组织器官，如眼、肾、心血管及神经末梢系统的损害及其功能的障碍和衰竭。严重患者可引起失水，电解质的紊乱和酸碱平衡的失调、急性并发症酮症酸中毒和高渗昏迷等。然而，控制糖尿病患者血糖升高，从目前来看，还没有根本治疗的办法。为解决现有的糖尿病治疗技术的问题，本发明提供了一种生物发酵型的复方三价铬的降血糖组合药的制备方法，采取以下原料按照如下重量比例配制而成：富含三价铬酵母50～80份，灵芝40～60份，金耳30～50份，番石榴叶10～30份，枸杞子40～60份，地黄20～40份，金顶侧耳20～30份，蛹虫草30～40份，葛根50-100份和胰蛋白酶10-30份。
一种生物发酵型的复方三价铬的降血糖组合药的制备方法的制备方法，其制备方法按照以下步骤：
S01、洗涤离心：将灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳、蛹虫草和葛根按着规定比例放入温水池内，浸泡10分钟，清洗三遍，离心烘干；
S02、粉碎：将干燥的中药配料进行粉碎和过筛；
S03、煎药：将中药粉末到入反应釜中，按着比例加水煮沸（100℃），煮沸煎药时间60-120分钟；
S04、发酵：待反应釜物料降温，按比例加入富含三价铬酵母和胰蛋白酶混合，间隔6小时搅拌30分钟，发酵时间为24小时-48小时；
S05、灭菌：采用巴士灭菌，30分钟，
S06、装瓶：导入瓶中，充入惰性气体，封口制得复方有机三价铬的降血糖制剂。
优选的，所述中药配料进行粉碎和过筛的网眼为3-9mm；
优选的，所述的反应釜发酵温度为37-45℃；
优选的，所述巴氏消毒温度为62-86℃；
优选的，所述惰性气体为氮气或者氩气；
优选的，所述终端产品患者服用每日有机三价铬含量为200微克。
本发明复方三价铬的降血糖特殊功效：
一、糖尿病疗效评价
I、执行标准为WHO2019公布糖尿病诊断标准。
1)空腹血糖浓度≥7.0mmol/l（全血≥6.1mmol/l）；
2)两小时血糖浓度≥11.1mmol/l与75g两小时后无水葡萄糖在口服葡萄糖耐量试验(OGTT)。
3)没有症状的诊断不应该基于单一的血糖测定，而是需要确定的血浆静脉测定；
4)在另一天至少有一个血糖测试结果，其值在糖尿病范围内，这是必要的，从一个随机样品或两个小时后的血糖负荷禁食；
5)如果空腹随机值不能诊断，应使用两小时值。
II效果评价
表1、临床实验选择正常人群与糖尿病患者（N=6）测试
对照组为正常血糖人群，实验组分三个，每日服用含三价铬200微克本发明制剂，连续服用一个月，进行检测结果统计图3，结果表明，实验组与对照组比较P<0.01，差异有高度显著性。使用本发明的复方三价铬的降血糖组合药制剂，通过一个月的治疗后，患者的各组织器官活动时所需要的能量，如大脑思考、心脏跳动、肌肉收缩等活动能力明显增强，把血糖控制在正常范围或者接近正常数值。
典型的案例一位男性55岁糖尿病患者，血糖26.9mmol/L ，左眼裸眼视力0.1，右眼裸眼视力0.2，疼痛乏力，失去劳动力。服用本发明的药一个月好转，三个月血糖6.7mmol/L，眼底变化如图1和图2.
治疗原理与机制
1）人体的细胞靠胰岛素把血糖送到细胞内转化能量，缺少铬元素，就会使胰岛素功能下降，葡萄糖不能顺利地进入细胞内，血糖就可能升高。三价铬是葡萄糖耐量因子（GTF）的重要组成成分，通过GTF与膜受体、胰岛素之间形成三维配合体而发挥生理作用。铬元素参与体内糖代谢，维持身体正常葡萄糖耐量，提高机体细胞对胰岛素敏感性，促进细胞糖代谢正常进行，有预防和治疗糖尿病的功效。美国科学家报道，适当补充三价铬元素，能改善机体对葡萄糖利用，而且，降低对外源性胰岛素需求量，有降低血糖，降低血中的胆固醇和甘油三脂的功效，对降低糖尿病患者的血糖水平、改善糖尿病症状和促进血糖回复正常有显著的作用。一般人每天摄入50-200微克的三价铬可满足需要，中老年人特别是糖尿病人对三价铬的需要量高于正常人。但是，人体对不同来源三价铬的吸收利用的情况差异很大，对无机铬（例如三氯化铬）吸收率仅仅是0.5-2%，对有机铬吸收率比较高，可以达到10-25%。本发明通过生物工程微生物发酵，使药效与三价铬，高度协调融合与互相增效，创造出显著的新效果。
2) 灵芝主要成分是灵芝多糖、腺苷、灵芝酸以及10余种碱、纤维素、油酸、氨基酸、微量元素等，其应用的范围，对心、肝、肺、脾、肾脏等都有治疗效果。灵芝能起到很好的调节免疫力作用，预防各种疾病发生。还具有双向调节血压作用，预防癌症和肿瘤。灵芝可以起到一定预防过敏作用。大量研究报道，灵芝可以使机体细胞对于糖的利用代谢有很大程度提升，因此，适合血糖高的人使用。使用了灵芝后，起到抑制脂肪酸释放作用，改善血糖高的症状。
3）黄芪含有胆碱、叶酸、豆香素、皂甙、氨基酸、蛋白质、甜菜碱、核黄素、糖类、蛋白质、黄烷化合钙、物、铁、磷及硒、铜、锌、锰等多种元素。由于黄芪能防止肝脏糖元减少，对肝脏有保护功能，并且能够促进人体血液的白细胞增加，有显著提高单核巨噬细胞的系统和白细胞吞噬功能。黄芪对治疗抗糖尿病上有特殊功效，该药材具有双向调节身体血糖的功效，既可降低血糖的作用，也具备升高血糖的功效，患上了高血糖的人，如果长期服用黄芪，就可以降低血糖。
4）山药可为普通蔬菜的食用，也可入药用作一些疾病的预防和治疗，有良好的降低血糖的功效，血糖高的人群多吃山药可以降低血糖。在山药里含有的黏液蛋白，在血糖的降低上面有着明显的效果，成为许多糖尿病患者的食物。在临床上的使用自然很多，经常用来降低血糖的中药物里都有山药，比如参芪消渴胶囊等。
5）番石榴叶是生活中常见的植物叶子，从药理的角度分析发现，番石榴叶里的一些成分对于消渴症的治疗有很好的效果。含不挥发性油6％，树脂3．15％，挥发性油0．365％，丹宁8．5％及大量的填充性物质。主要药理活性的成分有黄酮类，挥发油和三萜皂苷类等。挥发油化学组分为蒎烯，柠檬油精，蒎烯，薄荷醇等。现代科学证明，番石榴叶具有明显的降低血糖功效。
6）蛹虫草富含虫草素、腺苷、虫草酸等活性成分和多种氨基酸、维生素、微量元素等营养成分,虫草属真菌类，有抗肿瘤、抗氧化、抗病原、以及增强人体免疫功能等多种药理的作用。蛹虫草 (C. militaris)得到广泛的研究和利用。1951年,德国科学家Cuningham等观察到被蛹虫草寄生的昆虫组织不易腐烂，虫草素是第一个从真菌中分离出来的核苷类抗生素。从中分离到一种腺苷类活性物质, 确定其结构式为3’-脱氧腺苷，命名为虫草菌素,又称虫草素，1960年已经实现了全化学合成。蛹虫草中含有丰富的虫草素、多糖、虫草酸、腺苷、SOD酶等物质，其中，核心的成分虫草素就可说明一切。有显著的降低血糖的功效。
7）枸杞子：枸杞能补肾养肝，治肝肾阴虚、消渴等。枸杞子提取物能促进人体血糖下降，糖尿病患者服用后，血糖持久下降，对糖尿性血脂升高、视力不佳有改善功能。
8）葛根：为豆科植物野葛或粉葛的根，具有升阳透疹、发表解肌、解热的生津等功效，从干燥的葛根中萃取的葛根素，有直接降低血糖功效。90年代初，广泛应用于糖尿病患者及其并发症的治疗上，葛根素有降血糖、提高胰岛素受体、抑制糖基化作用。对II型糖尿病及糖尿病周围神经病变、糖尿病视网膜病变、糖尿病肾病、糖尿病合并冠心病和高脂血症等有显著的疗效。
附图
图1是糖尿病患者的眼底病变；
图2是糖尿病患者经过一个月治疗后眼底的病变好转照片；
图3是应用本发明制剂治疗糖尿病患者的统计图。
实施案例
案例一
本发明提供了一种生物发酵型的复方三价铬的降血糖组合药的制备方法，采取以下原料按照如下重量比例配制而成：富含三价铬酵母50份，灵芝40份，金耳30份，番石榴叶10份，枸杞子40份，地黄20份，金顶侧耳20份，蛹虫草30份和胰蛋白酶10份。
一种生物发酵型的复方三价铬的降血糖组合药的制备方法的制备方法，其制备方法按照以下步骤：
S01、洗涤离心：将灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳和蛹虫草按着规定比例放入温水池内，浸泡10分钟，清洗三遍，离心烘干；
S02、粉碎：将干燥的中药配料进行粉碎和过筛；
S03、煎药：将中药粉末到入反应釜中，按着比例加水煮沸（100℃），煮沸煎药时间60分钟；
S04、发酵：待反应釜物料降温，按比例加入富含三价铬酵母和胰蛋白酶混合，间隔6小时搅拌30分钟，发酵时间为24小时；
S05、灭菌：采用巴士灭菌，30分钟，
S06、装瓶：导入瓶中，充入惰性气体，封口制得复方有机三价铬的降血糖制剂。
优选的，所述中药配料进行粉碎和过筛的网眼为3mm；
优选的，所述的反应釜发酵温度为37℃；
优选的，所述巴氏消毒温度为62℃；
优选的，所述惰性气体为氮气或者氩气；
优选的，所述终端产品患者服用每日有机三价铬含量为200微克。
案例二
本发明提供了一种生物发酵型的复方三价铬的降血糖组合药的制备方法，采取以下原料按照如下重量比例配制而成：富含三价铬酵母80份，灵芝60份，金耳50份，番石榴叶30份，枸杞子60份，地黄40份，金顶侧耳30份，蛹虫草40份和胰蛋白酶30份。
一种生物发酵型的复方三价铬的降血糖组合药的制备方法的制备方法，其制备方法按照以下步骤：
S01、洗涤离心：将灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳和蛹虫草按着规定比例放入温水池内，浸泡10分钟，清洗三遍，离心烘干；
S02、粉碎：将干燥的中药配料进行粉碎和过筛；
S03、煎药：将中药粉末到入反应釜中，按着比例加水煮沸（100℃），煮沸煎药时间120分钟；
S04、发酵：待反应釜物料降温，按比例加入富含三价铬酵母和胰蛋白酶混合，间隔6小时搅拌30分钟，发酵时间为48小时；
S05、灭菌：采用巴士灭菌，时间30分钟，
S06、装瓶：导入瓶中，充入惰性气体，封口制得复方有机三价铬的降血糖制剂。
优选的，所述中药配料进行粉碎和过筛的网眼为3-9mm；
优选的，所述的反应釜发酵温度为45℃；
优选的，所述巴氏消毒温度为86℃；
优选的，所述惰性气体为氮气或者氩气；
优选的，所述终端产品患者服用每日有机三价铬含量为200微克。
案例三
本发明提供了一种生物发酵型的复方三价铬的降血糖组合药的制备方法，采取以下原料按照如下重量比例配制而成：富含三价铬酵母60份，灵芝50份，金耳40份，番石榴叶20份，枸杞子50份，地黄30份，金顶侧耳25份，蛹虫草35份和胰蛋白酶20份。
一种生物发酵型的复方三价铬的降血糖组合药的制备方法的制备方法，其制备方法按照以下步骤：
S01、洗涤离心：将灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳和蛹虫草按着规定比例放入温水池内，浸泡10分钟，清洗三遍，离心烘干；
S02、粉碎：将干燥的中药配料进行粉碎和过筛；
S03、煎药：将中药粉末到入反应釜中，按着比例加水煮沸（100℃），煮沸煎药时间90分钟；
S04、发酵：待反应釜物料降温，按比例加入富含三价铬酵母和胰蛋白酶混合，间隔6小时搅拌30分钟，发酵时间为36小时；
S05、灭菌：采用巴士灭菌，30分钟，
S06、装瓶：导入瓶中，充入惰性气体，封口制得复方有机三价铬的降血糖制剂。
优选的，所述中药配料进行粉碎和过筛的网眼为6mm；
优选的，所述的反应釜发酵温度为40℃；
优选的，所述巴氏消毒温度为75℃；
优选的，所述惰性气体为氮气或者氩气；
优选的，所述终端产品患者服用每日有机三价铬含量为200微克。
以上所述，仅是本发明的较佳的实施案例而已，并不是对本发明作所有形式上限制。熟悉本专业的技术人员，在发明技术方案范围情况下，都可能利用上述的方法和技术内容对本发明进行变动和修饰，或修改为等同变化的等效实施案例。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何修改、等同变化及修饰，均仍属于本发明技术方案保护的范围内。
Claims (10)
1.一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，采取以下原料按照如下重量比例配制而成：富含三价铬酵母50-80份，灵芝40-60份，金耳30-50份，番石榴叶10-30份，枸杞子40-60份，地黄20-40份，金顶侧耳20-30份，蛹虫草30-40份，葛根50-100 份和胰蛋白酶10-30份。
2.根据权利要求1 所述的一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，采用以下原料按照如下重量比例配制而成：富含三价铬酵母30-50份，灵芝40-50份，金耳30-40份，番石榴叶10-20份，枸杞子40-50份，地黄20-30份，金顶側耳20-25份，蛹虫草30-35份，葛根 50-100 份和胰蛋白酶 10-25份。
3.根据权利要求 1和2 所述的一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，优选地，采用以下原料按照如下重量份配制而成::富含三价铬酵母40份，灵芝45份，金耳35份，番石榴叶15份，枸杞子45份，地黄 25份，金顶侧耳25份，蛹虫草 30份，葛根50份和胰蛋白酶25份。
4.根据权利要求1、2或3 任意一项所述的一种生物发酵型的复方三价铬的降血糖组合药的制备方法的制备方法，其特征在于，制备方法按照以下步骤：
S01、洗涤离心:将灵芝、金耳、番石榴叶、枸杞子、地黄、金顶侧耳和蛹虫草按着规定比例放入温水池内，浸泡 10 分钟，清洗三遍，离心烘干；
S02、粉碎:将干燥的中药配料进行粉碎和过筛的药粉倒入反应釜中，按着比例加水煮沸(100℃)，煮沸煎药时间60-120分钟；
S04、发酵:待反应釜物料降温，按比例加入富含三价铬酵母和胰蛋白酶混合，间隔6 小时搅拌30 分钟，发酵时间为24-48 小时；
S05、灭菌：采用巴士灭菌，30 分钟；
S06、装瓶:导入瓶中，充入惰性气体，封口制得复方有机三价铬的降血糖制剂。
5.根据权利要求4 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，步骤 S01中所述清水温度为 37-45℃；所述离心速度为 700-1000R/min，所述的烘干温度为 75-85℃。
6.根据权利要求4 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，步骤 S2 中所述中药配料进行粉碎和过筛的网眼为 3-9mm。
7.根据权利要求4 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，步骤 S4 中所述的反应釜温度为 37-45℃。
8.根据权利要求4 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，步骤 S5 所述 62-86℃。
9.根据权利要求6 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，步骤 S5 所述惰性气体为氮气或者氩气。
10.根据权利要求 1-9 所述一种生物发酵型的复方三价铬的降血糖组合药的制备方法，其特征在于，糖尿病患者日服复方三价铬的降血糖组合药中有效的有机三价铬含量为200 微克。
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Application publication date: 20201218 |