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CN105497051B - A kind of hypoglycemic pharmaceutical formulation and its experimental method - Google Patents

  • ️Tue Jul 17 2018

CN105497051B - A kind of hypoglycemic pharmaceutical formulation and its experimental method - Google Patents

A kind of hypoglycemic pharmaceutical formulation and its experimental method Download PDF

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Publication number
CN105497051B
CN105497051B CN201510902706.1A CN201510902706A CN105497051B CN 105497051 B CN105497051 B CN 105497051B CN 201510902706 A CN201510902706 A CN 201510902706A CN 105497051 B CN105497051 B CN 105497051B Authority
CN
China
Prior art keywords
group
formula
blood glucose
groups
blood sugar
Prior art date
2015-12-09
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510902706.1A
Other languages
Chinese (zh)
Other versions
CN105497051A (en
Inventor
胡锐
张晓双
智冰清
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shaanxi University of Chinese Medicine
Original Assignee
Shaanxi University of Chinese Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2015-12-09
Filing date
2015-12-09
Publication date
2018-07-17
2015-12-09 Application filed by Shaanxi University of Chinese Medicine filed Critical Shaanxi University of Chinese Medicine
2015-12-09 Priority to CN201510902706.1A priority Critical patent/CN105497051B/en
2016-04-20 Publication of CN105497051A publication Critical patent/CN105497051A/en
2018-07-17 Application granted granted Critical
2018-07-17 Publication of CN105497051B publication Critical patent/CN105497051B/en
Status Expired - Fee Related legal-status Critical Current
2035-12-09 Anticipated expiration legal-status Critical

Links

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Classifications

    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
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Abstract

本发明涉及医药行业技术领域，具体涉及一种降血糖的药物配方及其实验方法。一种降血糖的药物配方，由按浓度配比的以下原料制备而成：葛根素100mg/kg.d、大豆苷元25mg/kg.d、黄芩苷100mg/kg.d、黄芩素10mg/kg.d、小檗碱10mg/kg.d、甘草酸5mg/kg.d、甘草苷50mg/kg.d；一种验证降血糖药物配方的实验方法，包括如下实验步骤：1)建立大鼠高血糖模型；2)筛选分组；3)检测指标；4)分析对比和得出结论。本发明中的配方是经过严密的科学实验得来，具有很好的降低血糖、改善胰岛素抵抗的作用，能够为此类经典方剂的二次开发提供研究基础，有着极强的创新性。

The invention relates to the technical field of the pharmaceutical industry, in particular to a drug formula for lowering blood sugar and an experimental method thereof. A drug formula for lowering blood sugar, which is prepared from the following raw materials according to the ratio of concentration: puerarin 100mg/kg.d, daidzein 25mg/kg.d, baicalin 100mg/kg.d, baicalein 10mg/kg .d, berberine 10mg/kg.d, glycyrrhizinic acid 5mg/kg.d, liquiritin 50mg/kg.d; an experimental method for verifying the formula of hypoglycemic drugs, including the following experimental steps: 1) establish rat hyperglycemia Blood glucose model; 2) screening and grouping; 3) detection indicators; 4) analysis and comparison and drawing conclusions. The formula in the present invention is obtained through rigorous scientific experiments, has good effects of lowering blood sugar and improving insulin resistance, can provide a research basis for the secondary development of such classic formulas, and has strong innovation.

Description

一种降血糖的药物配方及其实验方法A kind of drug formula and experimental method for lowering blood sugar

技术领域technical field

本发明涉及医药行业技术领域，具体涉及一种降血糖的药物配方及其实验方法。The invention relates to the technical field of the pharmaceutical industry, in particular to a drug formula for lowering blood sugar and an experimental method thereof.

背景技术Background technique

临床和实验研究报道葛根芩连汤对糖尿病具有治疗作用，其中，葛根芩连汤内含有不同极性的黄酮、异黄酮类、生物碱类、皂苷类等大量化合物，完全获得这些物质并进行全面研究非常困难，究竟是哪些化合物在起作用也不清楚。我们根据相关文献，从葛根芩连汤中选取了7个活性较强的化合物：①来源于葛根的黄酮类：葛根素、大豆苷；②来源于黄芩的黄酮类：黄芩苷、黄芩素；③来源于黄连的生物碱：小檗碱；④来源于甘草的甘草酸、甘草苷，我们研究了7个化合物不同配比对高血糖模型大鼠的降糖以及改善胰岛素抵抗的作用，并与原方剂进行比对研究，发现了最佳降血糖化合物的构成和比例。Clinical and experimental studies have reported that Gegen Qinlian Decoction has a therapeutic effect on diabetes. Among them, Gegen Qinlian Decoction contains a large number of compounds of different polarities such as flavonoids, isoflavones, alkaloids, saponins, etc. These substances are completely obtained and comprehensively treated Research has been difficult, and it's unclear exactly which compounds are at work. Based on relevant literature, we selected 7 compounds with strong activity from Gegen Qinlian Decoction: ①Flavonoids derived from Pueraria root: puerarin, daidzein; ②Flavonoids derived from Scutellaria baicalensis: baicalin, baicalein; ③ Alkaloids derived from Coptidis Rhizoma: berberine; ④ Glycyrrhizic acid and liquiritin derived from licorice. We studied the effects of 7 compounds on hypoglycemia and improving insulin resistance in hyperglycemia model rats with different ratios, and compared with the original The composition and ratio of the best hypoglycemic compounds were found through comparative research on prescriptions.

葛根芩连汤经过临床实践验证，对2型糖尿病和胰岛素抵抗有干预治疗作用，但复方汤剂缺乏对药效物质的微观分析和质量控制，影响临床疗效，本发明对葛根芩连汤的主要活性成分进行配比研究，发现并优化葛根芩连汤干预治疗2型糖尿病最佳有效组分配比，为此类经典方剂的二次开发提供研究基础。Gegen Qinlian Decoction has been verified by clinical practice to have an intervention treatment effect on type 2 diabetes and insulin resistance, but the compound decoction lacks microscopic analysis and quality control of medicinal substances, which affects clinical efficacy. The ratio of active ingredients was studied to discover and optimize the ratio of the best effective components of Gegen Qinlian Decoction for the intervention and treatment of type 2 diabetes, providing a research basis for the secondary development of such classic prescriptions.

发明内容Contents of the invention

本发明所要解决的技术问题是提供一种降血糖的药物配方及其实验方法。The technical problem to be solved by the present invention is to provide a drug formula for lowering blood sugar and an experimental method thereof.

为解决上述技术问题，本发明提供以下技术方案：一种降血糖的药物配方，所述药物配方包括葛根素、大豆苷元、黄芩苷、黄芩素、小檗碱、甘草酸、甘草苷七种药物，所述葛根素的剂量浓度为50-500mg/kg.d、大豆苷元的剂量浓度为10-100mg/kg.d、黄芩苷的剂量浓度为10-100mg/kg.d、黄芩素的剂量浓度为10-100mg/kg.d、小檗碱的剂量浓度为10-100mg/kg.d、甘草酸的剂量浓度为5-50mg/kg.d、甘草苷的剂量浓度为10-100mg/kg.d。In order to solve the above-mentioned technical problems, the present invention provides the following technical solutions: a drug formulation for lowering blood sugar, which includes seven kinds of puerarin, daidzein, baicalin, baicalein, berberine, glycyrrhizic acid, and liquiritin Medicine, the dosage concentration of described puerarin is 50-500mg/kg.d, the dosage concentration of daidzein is 10-100mg/kg.d, the dosage concentration of baicalin is 10-100mg/kg.d, the dosage concentration of baicalein The dosage concentration is 10-100mg/kg.d, the dosage concentration of berberine is 10-100mg/kg.d, the dosage concentration of glycyrrhizic acid is 5-50mg/kg.d, and the dosage concentration of liquiritin is 10-100mg/kg. kg.d.

优选的，所述药物配方由如下配比浓度的原料药组成：葛根素100mg/kg.d、大豆苷元25mg/kg.d、黄芩苷的剂量浓度为100mg/kg.d、黄芩素的剂量浓度为10mg/kg.d、小檗碱的剂量浓度为10mg/kg.d、甘草酸的剂量浓度为5mg/kg.d、甘草苷的剂量浓度为50mg/kg.d。Preferably, the pharmaceutical formula is composed of raw materials with the following proportioning concentrations: 100 mg/kg.d of puerarin, 25 mg/kg.d of daidzein, 100 mg/kg.d of baicalin, and 100 mg/kg.d of baicalein. The concentration is 10mg/kg.d, the dosage concentration of berberine is 10mg/kg.d, the dosage concentration of glycyrrhizic acid is 5mg/kg.d, and the dosage concentration of liquiritin is 50mg/kg.d.

一种验证降血糖药物配方的实验方法：包括如下实验步骤：1)建立大鼠高血糖模型；2)筛选分组；3)检测指标；4)分析对比和得出结论。An experimental method for verifying the formula of a hypoglycemic drug comprises the following experimental steps: 1) establishing a rat hyperglycemia model; 2) screening and grouping; 3) detecting indicators; 4) analyzing and comparing and drawing conclusions.

优选的，所述步骤1)中建立大鼠高血糖模型的大鼠数为110只，且都为雄性大鼠，上述110只雄性大鼠被随机的分为11组，每组10只。Preferably, the number of rats for establishing the rat hyperglycemia model in step 1) is 110, and all of them are male rats. The above-mentioned 110 male rats are randomly divided into 11 groups, with 10 rats in each group.

优选的，所述步骤2)中筛选分组共分为十二个组，分别为按照葛根芩连汤各提取物组分配比的八个组合N1-N8、葛根芩连汤原方组N9、二甲双胍组N10、模型组N11、原有空白组N12。Preferably, the screening group in step 2) is divided into twelve groups, which are eight combinations N1-N8 according to the distribution ratio of each extract component of Gegen Qinlian Decoction, Gegen Qinlian Decoction original prescription group N9, metformin group N10 , model group N11, and original blank group N12.

优选的，所述步骤3)中检测的指标为体重、空腹血糖、餐后2h血糖、葡萄糖灌注率、血清胰岛素。Preferably, the indicators detected in step 3) are body weight, fasting blood glucose, 2h postprandial blood glucose, glucose perfusion rate, and serum insulin.

选择健康雄性8-9周龄SD大鼠140只，由第四军医大学动物实验中心提供，体重在280～300g之间，适应性喂养7天，按随机数字表法分为空白组和模型组，空白组10只，模型组130只，空白组喂食普通饲料，其中，普通饲料为常规的啮齿类动物饲料，成分为脂肪10％、蛋白22％、碳水化合物68％、盐0.5％，模型组喂食高脂高糖高胆固醇饲料，其中，高脂高糖高胆固醇饲料配方为：基础饲料73.8％、猪油10％、蔗糖5％、鸡蛋黄10％、胆固醇1％、胆盐0.2％，模型组和空白组均予以普通饮水，按上述条件连续喂养6周，每周测体重及空腹血糖，6周末测体重，禁食12小时后测空腹血糖、空腹血清胰岛素，计算胰岛素抵抗指数和胰岛素敏感指数，使用SPSS19.0统计软件进行数据分析，试验结果中计量资料用均数±标准差，多组之间比较采用单因素方差分析，两组比较采用t检验进行统计学处理，P＜0.05为差异具有显著性。Select 140 healthy male SD rats aged 8-9 weeks, provided by the Animal Experiment Center of the Fourth Military Medical University, with a body weight of 280-300g, and adaptive feeding for 7 days, and divided them into blank group and model group according to the random number table method , 10 rats in the blank group, 130 rats in the model group, the blank group was fed with common feed, wherein, the common feed was conventional rodent feed, the ingredients were 10% fat, 22% protein, 68% carbohydrates, 0.5% salt, and the model group Feed high-fat, high-sugar and high-cholesterol feed, wherein, the formula of high-fat, high-sugar and high-cholesterol feed is: basal feed 73.8%, lard 10%, sucrose 5%, egg yolk 10%, cholesterol 1%, bile salt 0.2%, model Both the control group and the blank group were given normal drinking water, fed continuously for 6 weeks according to the above conditions, measured body weight and fasting blood glucose every week, measured body weight at the end of 6 weeks, measured fasting blood glucose and fasting serum insulin after fasting for 12 hours, and calculated insulin resistance index and insulin sensitivity. Index, using SPSS19.0 statistical software for data analysis, measurement data in the test results using mean ± standard deviation, comparison between multiple groups using one-way analysis of variance, two groups using t test for statistical processing, P<0.05 is The difference is significant.

本发明的有益效果是：本发明中的配方是经过严密的科学实验得来，具有很好的降低血糖、改善胰岛素抵抗的作用，能够为此类经典方剂的二次开发提供研究基础，有着极强的创新性。The beneficial effects of the present invention are: the formula in the present invention is obtained through rigorous scientific experiments, has a good effect of lowering blood sugar and improving insulin resistance, and can provide a research basis for the secondary development of such classic prescriptions, and has great Strong innovation.

附图说明Description of drawings

图1为本发明中实验方法的步骤图；Fig. 1 is the step diagram of experimental method among the present invention;

图2为均匀实验设计图；Fig. 2 is uniform experimental design drawing;

图3为均匀设计的优化方案图。Figure 3 is a diagram of the optimization scheme of the uniform design.

具体实施方式Detailed ways

为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明，应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be described in further detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention and are not intended to limit the invention.

从图1可以看出本发明中的实验方案如下：As can be seen from Fig. 1, the experimental scheme among the present invention is as follows:

1.高血糖大鼠模型的建立1. Establishment of hyperglycemia rat model

1.1实验动物分组及造模1.1 Experimental animal grouping and modeling

健康雄性8-9周龄SD大鼠140只第四军医大学动物实验中心提供，体重在280～300g之间，适应性喂养7天，按随机数字表法分为空白组和模型组，空白组10只，模型组130只，空白组喂食普通饲料，模型组喂食高脂高糖高胆固醇饲料，模型组(RI)和空白组(Normol)均予以普通饮水，按上述条件连续喂养6周，每周测体重及空腹血糖，6周末测体重，禁食12小时后测空腹血糖，空腹血清胰岛素，计算胰岛素抵抗指数和胰岛素敏感指数。140 healthy male SD rats aged 8-9 weeks were provided by the Animal Experiment Center of the Fourth Military Medical University, with a body weight of 280-300 g, and were fed adaptively for 7 days. They were divided into blank group and model group according to the random number table method, and blank group 10 rats, 130 rats in the model group, the blank group was fed with common feed, the model group was fed with high-fat, high-sugar, and high-cholesterol feed, the model group (RI) and the blank group (Normol) were given ordinary drinking water, and were continuously fed for 6 weeks according to the above conditions. Body weight and fasting blood glucose were measured weekly, body weight was measured at the end of 6 weeks, fasting blood glucose and fasting serum insulin were measured after 12 hours of fasting, and insulin resistance index and insulin sensitivity index were calculated.

1.2观察指标1.2 Observation indicators

1.2.1一般情况观察1.2.1 General observation

观察各组大鼠精神、活动状态、毛发及动物死亡情况，每周用电子天平称量大鼠体重1次，记录并分析体重变化。Observe the mental state, activity state, hair and animal death of the rats in each group, weigh the rats' body weight with an electronic balance once a week, record and analyze the body weight changes.

1.2.2血糖1.2.2 Blood sugar

给药第6周末，禁食12小时后，用血糖仪测尾静脉血糖。At the end of the 6th week of administration, after fasting for 12 hours, blood glucose in the tail vein was measured with a blood glucose meter.

1.2.3空腹血清胰岛素1.2.3 Fasting serum insulin

用酶联免疫法(ELISA)测空腹血清胰岛素，造模第六周末，禁食12h后，10％水合氯醛腹腔注射麻醉，眶静脉丛采血，取抗凝血，4000r/min，离心5min，获得血浆。酶联免疫吸附法(Enzyme一linked immunosorbent assay，ELISA)测定空腹血清胰岛素(Fasting seruminsulin，FINS)含量。Fasting serum insulin was measured by enzyme-linked immunosorbent assay (ELISA). At the end of the sixth week of modeling, after fasting for 12 hours, 10% chloral hydrate was injected intraperitoneally for anesthesia, and blood was collected from the orbital venous plexus. Anticoagulant blood was collected and centrifuged at 4000r/min for 5min. Get plasma. Enzyme-linked immunosorbent assay (ELISA) was used to measure fasting serum insulin (Fasting serum insulin, FINS) content.

1.2.4胰岛素抵抗指数1.2.4 Insulin resistance index

用HOMA模型公式：IRI＝GLU×INS÷22.5计算胰岛素抵抗指数。Insulin resistance index was calculated with HOMA model formula: IRI=GLU×INS÷22.5.

1.2.5胰岛素敏感指数1.2.5 Insulin sensitivity index

测定空腹血糖(FPG)和空腹胰岛素(FINS)浓度后，进行计算:胰岛素敏感指数(ISI)＝Ln[1/(FPGxFINS)]After measuring fasting blood glucose (FPG) and fasting insulin (FINS) concentration, calculate: insulin sensitivity index (ISI)=Ln[1/(FPGxFINS)]

1.3实验仪器1.3 Experimental Instruments

ACS-30电子计价秤 永康市华鹰衡器有限公司ACS-30 electronic pricing scale Yongkang Huaying Weighing Apparatus Co., Ltd.

胰岛素测试试剂盒 北京北方生物技术研究所产品Insulin Test Kit Product of Beijing North Institute of Biotechnology

KQ2200DE型数控超声波清洗器 昆山市超声仪器有限公司KQ2200DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd.

TGL-16M台式高速冷冻离心机 长沙湘仪离心机仪器有限公司TGL-16M Desktop High Speed Refrigerated Centrifuge Changsha Xiangyi Centrifuge Instrument Co., Ltd.

磁力加热搅拌器 常州国华电器有限公司Magnetic Heating Stirrer Changzhou Guohua Electric Co., Ltd.

电热鼓风干燥机 上海一恒科学仪器有限公司Electric Blast Dryer Shanghai Yiheng Scientific Instrument Co., Ltd.

电子恒温水浴锅 北京科伟永兴仪器有限公司Electronic constant temperature water bath Beijing Kewei Yongxing Instrument Co., Ltd.

HH-S6型电子天平 上海民桥精密科学仪器有限公司HH-S6 Electronic Balance Shanghai Minqiao Precision Scientific Instrument Co., Ltd.

4℃冰箱 合肥美菱股份有限公司4℃ Refrigerator Hefei Meiling Co., Ltd.

胰岛素测试试剂盒 北京北方生物技术研究所产品Insulin Test Kit Product of Beijing North Institute of Biotechnology

移液器20一200ul，100一1000ul 德国EPPendorf公司Pipette 20-200ul, 100-1000ul German EPPendorf company

三诺牌血糖仪 长沙三诺生物传感技术有限公司Sannuo Blood Glucose Meter Changsha Sannuo Biosensor Technology Co., Ltd.

1.4统计学处理1.4 Statistical processing

使用SPSS19.0统计软件进行数据分析，试验结果中计量资料用均数±标准差表示。多组之间比较采用单因素方差分析(ANOVA)，两组比较采用t检验进行统计学处理，P＜0.05为差异具有显著性。SPSS19.0 statistical software was used for data analysis, and the measurement data in the test results were used as mean ± standard deviation express. One-way analysis of variance (ANOVA) was used for comparison among multiple groups, and t-test was used for statistical processing for comparison between two groups, and P<0.05 was considered a significant difference.

1.5实验结果1.5 Experimental results

一般情况造模过程中，对照组大鼠毛色光滑、柔顺，模型组大鼠活动量明显减少，精神萎靡，体毛无光泽，造模6周后，根据检测指标，剔除造模未成功和死亡的大鼠。两组动物体重比较，在第2-5周，两组体重均在稳步上升，模型组比空白组体重增长的更为迅速，但在第1周，第2周，两组体重比较，P>0.05，差异无统计学意义；动物饲养至第3周、第4周、5周，两组体重比较，P<0.05，差异有统计学意义，至第6周，两组体重比较，P<0.01，差异显著，有统计学意义，见表1。In general, during the modeling process, the coat color of the rats in the control group was smooth and supple, while the activity of the rats in the model group was significantly reduced, the spirit was listless, and the body hair was dull. rat. Compared with the weight of the two groups of animals, in the 2nd to 5th week, the weight of the two groups was steadily increasing, and the weight of the model group increased more rapidly than that of the blank group, but in the first week and the second week, the weight of the two groups was compared, P> 0.05, the difference was not statistically significant; the animals were fed to the 3rd week, 4th week, 5th week, P<0.05, the difference was statistically significant, until the 6th week, the weight comparison of the two groups, P<0.01 , the difference is significant and statistically significant, as shown in Table 1.

表1给药前两组体重变化比较(单位：g)Table 1 Comparison of body weight changes between the two groups before administration (unit: g)

注：与空白组比较*P<0.05,**P<0.01Note: Compared with blank group * P<0.05, ** P<0.01

造模第6周末，模型组的空腹血糖，空腹胰岛素，胰岛素抵抗指数均升高，与空白组比较，P<0.05，差异显著，有统计学意义，胰岛素敏感指数下降，P<0.05，与空白组比较，差异显著，有统计学意义，见表2和表3。At the end of the 6th week of modeling, the fasting blood glucose, fasting insulin, and insulin resistance index of the model group all increased, compared with the blank group, P<0.05, the difference was significant and statistically significant, and the insulin sensitivity index decreased, P<0.05, compared with the blank group Group comparison, significant difference, statistically significant, see Table 2 and Table 3.

表2两组空腹血糖变化比较(单位：mmol/L)Table 2 Comparison of changes in fasting blood glucose between the two groups (unit: mmol/L)

注：与空白组比较*P<0.05,**P<0.01Note: Compared with blank group * P<0.05, ** P<0.01

表36周末两组胰岛素、胰岛素敏感指数、胰岛素抵抗指数比较Table 36 Comparison of insulin, insulin sensitivity index, and insulin resistance index between the two groups at the weekend

注：与空白组比较，*P<0.05，有统计学意义Note: Compared with the blank group, *P<0.05, statistically significant

2.葛根芩连汤组分对高血糖模型大鼠糖代谢的影响2. Effect of components of Gegen Qinlian Decoction on glucose metabolism in hyperglycemia model rats

2.1动物分组2.1 Animal grouping

将造模成功的110只SD雄性大鼠，根据体重编号按随机数字表法分为11组:葛根芩连汤各提取物组分配比的八个组合(N1、N2、N3、N4、N5、N6、N7、N8)，葛根芩连汤原方组(N9)、二甲双胍组(N10)、模型组(N11)。各组继续予以高脂高糖高胆固醇饲料，原有空白组(N12)继续予以普通饲料，共12组动物，每组各10只，均予以普通饮水。The 110 SD male rats with successful modeling were divided into 11 groups according to the body weight number by the random number table method: eight combinations (N1, N2, N3, N4, N5, N6, N7, N8), Gegen Qinlian decoction original prescription group (N9), metformin group (N10), model group (N11). Each group continued to receive high-fat, high-sugar and high-cholesterol feed, and the original blank group (N12) continued to receive normal feed. A total of 12 groups of animals, 10 animals in each group, were given normal drinking water.

2.2药物及试剂来源2.2 Sources of drugs and reagents

葛根素(Pue)：西安辉煌植物科技有限公司，纯度:90％Puerarin (Pue): Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

大豆苷元：西安辉煌植物科技有限公司，纯度:90％Daidzein: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

黄芩苷：西安辉煌植物科技有限公司，纯度:90％Baicalin: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

黄芩素：西安辉煌植物科技有限公司，纯度:90％Baicalein: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

小檗碱：西安辉煌植物科技有限公司，纯度:90％Berberine: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

甘草酸：西安辉煌植物科技有限公司，纯度:90％Glycyrrhizic acid: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

甘草苷：西安辉煌植物科技有限公司，纯度:90％Liquiritin: Xi'an Brilliant Plant Technology Co., Ltd., purity: 90%

葛根芩连汤：各味中药购自陕西中医药大学校医院。Gegen Qinlian Decoction: Various Chinese medicines were purchased from the School Hospital of Shaanxi University of Traditional Chinese Medicine.

胆固醇：平顶山市慧源生物制品有限公司Cholesterol: Pingdingshan Huiyuan Biological Products Co., Ltd.

胆盐：平顶山市慧源生物制品有限公司Bile salt: Pingdingshan Huiyuan Biological Products Co., Ltd.

CMC(羧甲基纤维素钠):湖北新河原料有限公司CMC (Sodium Carboxymethyl Cellulose): Hubei Xinhe Raw Materials Co., Ltd.

盐酸二甲双胍(Met):上海医药(集团)有限公司信谊制药总厂Metformin Hydrochloride (Met): Shanghai Pharmaceutical (Group) Co., Ltd. Xinyi Pharmaceutical General Factory

10％葡萄糖注射液:华裕(无锡)制药有限公司10% Glucose Injection: Huayu (Wuxi) Pharmaceutical Co., Ltd.

水合氯醛:中国医药集团上海化学试验公司Chloral hydrate: China Pharmaceutical Group Shanghai Chemical Testing Company

2.3药品、试剂的配置2.3 Configuration of drugs and reagents

葛根芩连汤中有效且活性较强的有以下7个化合物：①来源于葛根的黄酮类：葛根素、大豆苷；②来源于黄芩的黄酮类：黄芩苷、黄芩素；③来源于黄连的生物碱：小檗碱；④来源于甘草的甘草酸、甘草苷。浓度及配比方案如下：葛根素的四个剂量浓度为50，100，250，500(mg/kg)，大豆苷元10，25，50，100(mg/kg)，黄芩苷10，25，50，100(mg/kg)，黄芩素10，25，50，100(mg/kg)，小檗碱10，25，50，100(mg/kg)，甘草酸10，25，50，100(mg/kg)，甘草苷10，25，50，100(mg/kg)。按照均匀设计原则，将葛根芩连汤的七个有效成分，参照每个成分四个浓度范围，原则上水平数应大于因素数，故采用DPS数据处理系统，按照7个因素8个水平进行均匀设计，根据均匀设计方案得出优化的方案，如图2和图3所示。The following seven compounds are effective and active in Gegen Qinlian Decoction: ①Flavonoids derived from Pueraria root: puerarin, daidzin; ②Flavonoids derived from Scutellaria baicalensis: baicalin, baicalein; ③Flavonoids derived from Coptidis Alkaloids: berberine; ④ glycyrrhizic acid and liquiritin derived from licorice. The concentration and proportioning scheme are as follows: the four dosage concentrations of puerarin are 50, 100, 250, 500 (mg/kg), daidzein 10, 25, 50, 100 (mg/kg), baicalin 10, 25, 50, 100 (mg/kg), baicalein 10, 25, 50, 100 (mg/kg), berberine 10, 25, 50, 100 (mg/kg), glycyrrhizic acid 10, 25, 50, 100 ( mg/kg), Liquiritin 10, 25, 50, 100 (mg/kg). According to the principle of uniform design, the seven active ingredients of Gegen Qinlian Decoction are referred to the four concentration ranges of each ingredient. In principle, the number of levels should be greater than the number of factors. Therefore, the DPS data processing system is used to perform uniform According to the uniform design scheme, the optimized scheme is obtained, as shown in Figure 2 and Figure 3.

根据葛根芩连汤各药物提取物的七个成分，四个浓度范围，N1-N8组成分配比如下表4：According to the seven components of each drug extract of Gegen Qinlian Decoction, four concentration ranges, the N1-N8 composition distribution ratio is as follows in Table 4:

表4葛根芩连汤各组分配伍浓度表(单位：mg/kg·d)Table 4 Composite concentration of each component of Gegen Qinlian Decoction (unit: mg/kg·d)

N9：葛根芩连汤原方组(葛根：黄芩：黄连：甘草)：葛根芩连汤，9.0(4.5：1.69：1.69：1.12)g/kg·d，将葛根芩连汤90(45：16.9：16.9：11.2)g的各味中药，分别加水浸泡20min，先煎葛根，加热回流20min，再加入其余药，加热回流30min，后将药液倒出，加入水二次回流30min，合并药液，将汤药浓缩至100ml(按照10ml/kg·d浓缩中药)，备用。N9: Gegen Qinlian Decoction original prescription group (Gegen: Scutellaria: Coptidis: Licorice): Gegen Qinlian Decoction, 9.0 (4.5: 1.69: 1.69: 1.12) g/kg·d, Gegen Qinlian Decoction 90 (45: 16.9: 16.9 : 11.2) g of each flavor of traditional Chinese medicine, soaked in water for 20 minutes respectively, decocted kudzu root, heated and refluxed for 20 minutes, then added the rest of the medicine, heated and refluxed for 30 minutes, then poured out the medicinal solution, added water for a second reflux for 30 minutes, combined the medicinal solution, and Concentrate the decoction to 100ml (according to 10ml/kg·d concentrated traditional Chinese medicine), set aside.

N10：二甲双胍组，200mg/kg·d.按照10ml/kg·d配置二甲双胍溶液，将二甲双胍片2000mg，加5‰羧甲基纤维素钠(CMC)溶液至100ml，搅拌均匀。N10: metformin group, 200mg/kg·d. Prepare metformin solution according to 10ml/kg·d, add 5‰ carboxymethylcellulose sodium (CMC) solution to 2000mg metformin tablets to 100ml, and stir well.

N11：5g/L的羧甲基纤维素钠溶液，10ml/kg灌胃。N11: 5g/L sodium carboxymethylcellulose solution, 10ml/kg orally.

N12：5g/L的羧甲基纤维素钠溶液，10ml/kg灌胃。N12: 5g/L sodium carboxymethylcellulose solution, 10ml/kg orally.

5‰的羧甲基纤维素钠溶液的配制：将5g羧甲基纤维素钠缓慢加入至1000ml纯净水中，边加边用玻璃棒搅拌，使羧甲基纤维素钠充分溶解，静置1天后使用。Preparation of 5‰ sodium carboxymethylcellulose solution: Slowly add 5g sodium carboxymethylcellulose into 1000ml of pure water, stir with a glass rod while adding to fully dissolve sodium carboxymethylcellulose, and let stand for 1 day use.

10％水合氯醛的配制：称取10克水合氯醛，用纯净水溶解，再用纯净水稀释到100毫升。Preparation of 10% chloral hydrate: Weigh 10 grams of chloral hydrate, dissolve it with pure water, and then dilute to 100 ml with pure water.

2.4检测指标2.4 Detection indicators

2.4.1一般情况观察大鼠的食欲，体重，行为，毛发及死亡情况，实验结束时各大鼠称重后麻醉动物。2.4.1 General conditions Observe the rats' appetite, body weight, behavior, hair and death. At the end of the experiment, each rat is weighed and the animal is anesthetized.

2.4.2空腹血葡萄糖(FPG)及餐后2h葡萄糖(PG-2h)动物禁食12h后，剪尾取血，用血糖仪测空腹血糖，测完后，以25％葡萄糖水按2.5g/kg剂量灌胃，用血糖仪测餐后(2h)血糖。2.4.2 Fasting blood glucose (FPG) and postprandial 2h glucose (PG-2h) After the animal fasted for 12 hours, cut the tail to take blood, and measure the fasting blood glucose with a blood glucose meter. The dose of kg was gavaged, and the postprandial (2h) blood glucose was measured with a blood glucose meter.

2.4.3空腹血清胰岛素2.4.3 Fasting serum insulin

用酶联免疫法(ELISA)测空腹血清胰岛素，造模第六周末，禁食12h后，10％水合氯醛腹腔注射麻醉，眶静脉丛采血，取抗凝血，4000r/min，离心5min，获得血浆。酶联免疫吸附法(Enzyme一linked immunosorbent assay，ELISA)测定空腹血清胰岛素(Fasting seruminsulin，FINS)含量。Fasting serum insulin was measured by enzyme-linked immunosorbent assay (ELISA). At the end of the sixth week of modeling, after fasting for 12 hours, 10% chloral hydrate was injected intraperitoneally for anesthesia, and blood was collected from the orbital venous plexus. Anticoagulant blood was collected and centrifuged at 4000r/min for 5min. Get plasma. Enzyme-linked immunosorbent assay (ELISA) was used to measure fasting serum insulin (Fasting serum insulin, FINS) content.

2.4.4葡萄糖输注率(GIR)采用正糖钳技术[28]，大鼠禁食不禁水12h后，称重，以10％水合氯醛溶液(0.3ml/100g)腹腔麻醉。将大鼠仰位固定于手术台上，保持体温在37℃左右，剪开右颈部皮肤，手术分离右颈外静脉，结扎远心端，切口，向近心端方向插入胶管(管中预先注入5U/ml肝素生理盐水溶液)，结扎固定插管。从此插管中按0.lml/l00g体重注入1000u/ml肝素生理盐水溶液抗凝，封住插管。另剪开左颈部(近中线)皮肤，分离出左侧颈总动脉，结扎远心端，用动脉夹夹住近心端，切口，往近心端方向插入胶管，结扎固定插管，开放动脉夹。2.4.4 Glucose infusion rate (GIR) Using the glucose clamp technique [28] , the rats were fasted for 12 hours, weighed, and anesthetized intraperitoneally with 10% chloral hydrate solution (0.3ml/100g). The rat was fixed on the operating table in a supine position, and the body temperature was kept at about 37°C. The skin of the right neck was cut open, the right external jugular vein was surgically separated, the distal end was ligated, the incision was made, and a rubber tube was inserted toward the proximal end (pre-prepared in the tube). Inject 5U/ml heparin saline solution), ligate and fix the cannula. Inject 1000u/ml heparinized saline solution into the cannula for anticoagulation at 0.1ml/l00g body weight, and seal the cannula. Cut the skin of the left neck (near the midline), separate the left common carotid artery, ligate the distal end, clamp the proximal end with an arterial clip, make an incision, insert a rubber tube toward the proximal end, ligate and fix the cannula, and open arterial clamp.

取一小三通，出口端与静脉插管相连，一进口端与输注胰岛素的恒流泵相接，另一进口端与蠕动泵相连接，蠕动泵的进口端连接盛有10％葡萄糖溶液的微量滴定管，待插管手术和输注装置安装完毕，开始实验。测定基础血糖值(BBG)后，从静脉以每分钟4mu/kg恒速输注胰岛素溶液(用生理盐水配置，胰岛素的浓度根据大鼠体重调整)，同时输注10％葡萄糖溶液，每隔5min从动脉取血，用血糖仪测定血糖，根据血糖值调节GIR以维持血糖水平在BBG士0.5mmol/L的范围内，当连续3次血糖值均在上述范围时，即达到稳定状态，记录稳态下最后6次GIR的平均值用于统计对照。Take a small three-way connection, the outlet end is connected with the venous cannula, one inlet end is connected with the constant flow pump for insulin infusion, and the other inlet end is connected with the peristaltic pump, and the inlet end of the peristaltic pump is connected with a bottle filled with 10% glucose solution. Microburette, after the intubation operation and the infusion set are installed, start the experiment. After measuring the basal blood glucose level (BBG), infuse the insulin solution (prepared with normal saline, the concentration of insulin according to the body weight of the rat) from the vein at a constant rate of 4mu/kg per minute, and at the same time infuse the 10% glucose solution every 5min Take blood from the artery, measure blood glucose with a blood glucose meter, adjust the GIR according to the blood glucose value to maintain the blood glucose level within the range of BBG±0.5mmol/L, when the blood glucose value is within the above range for 3 consecutive times, it will reach a stable state, and record the stable state. The average value of the last 6 GIRs under the state was used for statistical control.

2.5实验结果2.5 Experimental results

2.5.1一般情况给药28天后，各组大鼠正常活动、进食和饮水，无食量减少，模型组(N11组)动物体重增长明显快于空白对照组(N12组)，动物毛色加深，行动反应迟缓，出现明显的肥胖。各组体重变化如下表5：2.5.1 General situation After 28 days of administration, the rats in each group moved normally, ate and drank water, and there was no reduction in food intake. The weight of the animals in the model group (N11 group) increased significantly faster than that of the blank control group (N12 group), and the coat color of the animals deepened. Slow response, obvious obesity. The body weight changes of each group are shown in Table 5:

表5各组体重变化比较(单位：g)Table 5 Comparison of body weight changes in each group (unit: g)

注：与N11组比较*P<0.05,**P<0.01Note: Compared with N11 group * P<0.05, ** P<0.01

第6周末(给药前)，各组体重比较，N1至N10组各组间比较，P>0.05，各组间比较无差异，无统计学意义，N1至N10组与N11组(模型组)比较，P<0.05，有显著差异，说明给药前，高糖动物模型分组均衡性好，给药治疗后，各组体重数据的差异主要由药物因素引起。给药治疗28天后，N1组至N10组体重均有降低，与N11组(模型组)比较有明显差异，P<0.05，各组体重组间比较无明显差异(P>0.05)。At the end of the 6th week (before administration), the weight comparison of each group, the comparison between the N1 to N10 groups, P>0.05, no difference between the groups, no statistical significance, the N1 to N10 group and the N11 group (model group) Compared, P<0.05, there is a significant difference, indicating that before administration, the high-glucose animal model grouping is well balanced, and after administration, the differences in body weight data of each group are mainly caused by drug factors. After 28 days of drug treatment, the body weights of groups N1 to N10 all decreased, which was significantly different from that of group N11 (model group), P<0.05, and there was no significant difference in body weight among the groups (P>0.05).

2.5.2对空腹血糖和餐后2h血糖的影响2.5.2 Effects on fasting blood glucose and 2h postprandial blood glucose

表6各组空腹血糖(单位：mmol/L)Table 6 Fasting blood glucose of each group (unit: mmol/L)

注：*与N11(模型组)比较，P<0.05，**与N11(模型组)比较，P<0.01。Note: *Compared with N11 (model group), P<0.05, **Compared with N11 (model group), P<0.01.

表7各组餐后2h血糖(单位：mmol/L)Table 7 2h postprandial blood glucose in each group (unit: mmol/L)

注：*与N11(模型组)比较，P<0.05，**与N11(模型组)比较，P<0.01。Note: *Compared with N11 (model group), P<0.05, **Compared with N11 (model group), P<0.01.

实验结果表明：N11组空腹血糖升高，与N12组比较，有极显著性差异(P<0.01)；N1至N10各组与N11比较，均有显著性差异(P<0.05)；N1至N10组各组与N12组比较，无显著性差异(P>0.05)；N1至N10各组间比较，N4组降低空腹血糖疗效优于其他各组，其次是N3组，N9组、N10组疗效优于其他各组(P<0.05)。The experimental results showed that: the fasting blood sugar in the N11 group increased significantly compared with the N12 group (P<0.01); the N1 to N10 groups had significant differences compared with the N11 (P<0.05); the N1 to N10 There was no significant difference between each group of N12 group and N12 group (P>0.05); among N1 to N10 groups, N4 group was better than other groups in reducing fasting blood sugar, followed by N3 group, N9 group and N10 group had better curative effect. in other groups (P<0.05).

各组灌糖后2h血糖比较，N11组2hPh高于N12组，有极显著差异(P<0.01)，N1至N10各组与N11(模型组)比较，均有显著性差异(P<0.05)；各治疗组与空白组比较，无显著性差异；N1至N10各组间比较，以N4组在降低餐后血糖疗效优于其他各组，其次是N3组，N9组、N10组疗效优于其他各组(P<0.05)。Comparison of 2h blood glucose after glucose injection in each group showed that the 2hPh of N11 group was higher than that of N12 group, and there was a very significant difference (P<0.01), and there were significant differences between N1 to N10 groups and N11 (model group) (P<0.05) There was no significant difference between each treatment group and the blank group; compared among N1 to N10 groups, N4 group was better than other groups in reducing postprandial blood sugar, followed by N3 group, N9 group, N10 group were better than other groups. Other groups (P<0.05).

2.5.3对葡萄糖输注率和胰岛素的影响2.5.3 Effects on glucose infusion rate and insulin

对葡萄糖输注率和胰岛素的影响详见表8和表9。The effects on glucose infusion rate and insulin are detailed in Tables 8 and 9.

表8各组血清胰岛素水平(mmol/L)Table 8 Serum insulin levels in each group (mmol/L)

注：*与N11(模型组)比较，P<0.05，**与N11(模型组)比较，P<0.01。Note: *Compared with N11 (model group), P<0.05, **Compared with N11 (model group), P<0.01.

表9各组葡萄糖输注率(ul/min)Table 9 Glucose infusion rate (ul/min) in each group

注：*与N11(模型组)比较，*P<0.05，#与N3(模型组)比较，#P<0.05，Δ与N1、N2组比较，ΔP<0.05。Note: * compared with N11 (model group), * P<0.05, # compared with N3 (model group), # P<0.05, Δ compared with N1 and N2 groups, Δ P<0.05.

表5-表9的数据对比可以得出，最佳的降血糖药物的配方为按浓度配比葛根素100mg/kg.d、大豆苷元25mg/kg.d、黄芩苷100mg/kg.d、黄芩素10mg/kg.d、小檗碱10mg/kg.d、甘草酸5mg/kg.d、甘草苷50mg/kg.d。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。From the comparison of the data in Table 5-Table 9, it can be concluded that the optimal formulation of hypoglycemic drugs is puerarin 100mg/kg.d, daidzein 25mg/kg.d, baicalin 100mg/kg.d, Baicalein 10mg/kg.d, berberine 10mg/kg.d, glycyrrhizic acid 5mg/kg.d, liquiritin 50mg/kg.d. The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. within range.

Claims (1)

1.一种降血糖的药物，其特征在于，由葛根素、大豆苷元、黄芩苷、 黄芩素、小檗碱、甘草酸、甘草苷七种药物组成，所述七种药物的重量配比为：葛根素：大豆苷元：黄芩苷：黄芩素：小檗碱：甘草酸：甘草苷=100:25:100:10:10:5:50。1. a hypoglycemic medicine, is characterized in that, is made up of seven kinds of medicines of puerarin, daidzein, baicalin, baicalein, berberine, glycyrrhizic acid, liquiritin, the weight proportion of described seven kinds of medicines For: puerarin: daidzein: baicalin: baicalein: berberine: glycyrrhizic acid: liquiritin = 100:25:100:10:10:5:50.

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