CN101199647A - Medicament compound agent for treating II model diabetes and reversing insulin resistive and preparing method thereof - Google Patents
Medicament compound agent for treating II model diabetes and reversing insulin resistive and preparing method thereof Download PDFInfo
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- CN101199647A CN101199647A CNA2007101759743A CN200710175974A CN101199647A CN 101199647 A CN101199647 A CN 101199647A CN A2007101759743 A CNA2007101759743 A CN A2007101759743A CN 200710175974 A CN200710175974 A CN 200710175974A CN 101199647 A CN101199647 A CN 101199647A
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Abstract
The invention aims at providing a compound medical preparation for clinically curing type II diabetes mellitus and reversing insulin resistance. The compound medical preparation contains effective ingredients and medical auxiliary materials, which are the mixture of epigallocatechin-3-gallate, any kind of tea polyphenol and cyclocarya paliurus (Batal.) iljinsk water extracts. The invention also provides a method to prepare the compound medical preparation. The compound medical preparation of the invention can be effectively used to clinically cure type II diabetes mellitus and reverse insulin resistance.
Description
Technical field
The medicine compound preparation that the present invention relates to treat type ii diabetes and reverse insulin resistant.
Background technology
Type ii diabetes is a kind of metabolic syndrome, and is closely related with obesity, and it influences a plurality of organs, and metabolism and hormone confusion have caused diabetes gradually.Type ii diabetes is very serious international health problem.According to estimates, in the whole world, type ii diabetes will from 1995 1.35 hundred million rise to 2025 300,000,000, and this will mainly occur in developing country.Environmental factors plays a part very important to the formation of type ii diabetes with development.General Study person thinks that adipose cell overnutrition and glycolipid toxicity are the basic reasons that causes type ii diabetes.Along with the development of Chinese national economy and the raising of living standards of the people, the morbidity ratio of China's diabetes, particularly type ii diabetes is obvious ascendant trend, has a strong impact on the people's health.
The medicine that is used for the treatment of both at home and abroad type ii diabetes at present is parahormone medicine troglitazone (TZD) more effectively, and obviously blood sugar lowering mainly acts on periphery fat.Cause fat apparent side effect (Peter Arner:The adipocyte in insulin resistance:keymolecules and the impact of the thiazolidinediones but have.TRENDS inEndocrinology and Metabolism.14，137-136，2003)。The cause of disease at type ii diabetes, researcher has proposed the corresponding treatment scheme and has promptly kept on a diet, improves the patience of insulin, stimulates secretion of insulin and suppress the method such as synthetic of sugar, what all have has certain effect, but all can not really play the result of treatment type ii diabetes and reverse insulin resistant, still not have good solution at present both at home and abroad.
Up to now, also do not find to be used for the treatment of the report of type ii diabetes and reverse insulin resistant in the prior art by the pharmaceutical composition that tea polyphenols, epi-nutgall acid catechin and Cyclocarya paliurus Iljinskaja water extract are formed.
Summary of the invention
In view of the foregoing with prior art in the subject matter that exists, current pressing for sought a kind of new medicine or medicine composite for curing type ii diabetes.For this reason, the technical problem to be solved in the present invention provides the medicine compound preparation that is used for the clinical treatment type ii diabetes and reverses insulin resistant.The technical problem that the present invention further will solve provides the method for preparing the said medicine compound formulation.
Technical scheme of the present invention is summarized as follows.
The invention provides the medicine compound preparation that is used for the clinical treatment type ii diabetes and reverses insulin resistant, wherein, described medicine compound preparation comprises the pharmaceutical composition be made up of epi-nutgall acid catechin, optionally tea polyphenol and Cyclocarya paliurus Iljinskaja water extract (main component is a flavonoid) as effective ingredient and pharmaceutic adjuvant.
Medicine compound preparation of the present invention is characterised in that in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is 0～9 weight portion, and the content of epi-nutgall acid catechin is that the content of 1～7 weight portion and Cyclocarya paliurus Iljinskaja water extract is 0～3 weight portion.
Medicine compound preparation of the present invention is characterised in that in the described pharmaceutical composition of 10 weight portions, the content of preferred tea polyphenols is 4 weight portions, and the content of epi-nutgall acid catechin is that the content of 3 weight portions and Cyclocarya paliurus Iljinskaja water extract is 3 weight portions.
Medicine compound preparation of the present invention is characterised in that in the described pharmaceutical composition of 10 weight portions, also the content of preferred tea polyphenols is 5 weight portions, and the content of epi-nutgall acid catechin is that the content of 3 weight portions and Cyclocarya paliurus Iljinskaja water extract is 2 weight portions.
Medicine compound preparation of the present invention is characterised in that in the described pharmaceutical composition of 10 weight portions, also the content of preferred tea polyphenols is 8 weight portions, and the content of epi-nutgall acid catechin is that the content of 1 weight portion and Cyclocarya paliurus Iljinskaja water extract is 1 weight portion.
Medicine compound preparation of the present invention is characterised in that in the described pharmaceutical composition of 10 weight portions, also the content of preferred tea polyphenols is that the content of 9 weight portions and epi-nutgall acid catechin is 1 weight portion, can not contain the Cyclocarya paliurus Iljinskaja water extract.
In medicine compound preparation of the present invention, described pharmaceutic adjuvant is powder of Radix Puerariae, starch or aqueous solution.
In medicine compound preparation of the present invention, described medicine compound preparation is capsule, tablet or oral liquid.When medicine compound preparation of the present invention is capsule, pharmaceutic adjuvant powder of Radix Puerariae preferably wherein.When medicine compound preparation of the present invention is tablet, pharmaceutic adjuvant starch preferably wherein.When medicine compound preparation of the present invention is oral liquid, pharmaceutic adjuvant aqueous citric acid solution preferably wherein.
The invention provides the preparation method of described medicine compound preparation, the described pharmaceutical composition that this method comprises effective dose mixes with proper proportion with described pharmaceutic adjuvant, preferably the pharmaceutical composition with 10 weight % mixes with the pharmaceutic adjuvant of 90 weight %, with prepare clinical in required dosage form.
The present invention also provides described medicine compound preparation to be used for the application of the medicine of clinical treatment type ii diabetes and reverse insulin resistant in preparation.
Those skilled in the art are to be understood that, it is preferred ratio between each component of the present invention that above-mentioned part by weight is formed, those skilled in the art suitably adjust by conventional method and the ratio that changes between each component of described pharmaceutical composition also can reach purpose of the present invention, therefore are intended to this adjustment and change are also included within the content of the present invention.The component of the above-mentioned medicine compound preparation that relates to is the pharmaceutical grade product that market can be purchased.
Above-mentioned treatment type ii diabetes provided by the present invention and reverse insulin resistant medicine compound preparation, process cell and zoopery in the specific embodiment, verified the mechanism of action, described medicine compound preparation has following functional character and beneficial effect: medicine compound preparation of the present invention is to hydroxyl, ultra-oxygen anion free radical has obvious scavenging action, induce blood sugar increasing that obvious reduction effect is arranged to high lipid food, rising has obvious inhibitory action to high lipid food induced lipolysis cytoactive oxygen, induce blood sugar increasing that obvious reduction effect is arranged to chain urase element, induce lipid peroxidation to raise to chain urase element obvious inhibitory action is arranged, the fat type ii diabetes transgenic mouse of yellow (KKAY) blood sugar increasing there is obvious reduction effect, rising has obvious inhibitory action to the fat type ii diabetes transgenic mouse of yellow (KKAY) adipose cell active oxygen, the adipose cell active oxygen that dexamethasone (DEX) and tumor necrosis factor (TNF-α) are caused raises obvious inhibitory action is arranged, cause the rising of adipose cell active oxygen that obvious inhibitory action is arranged to dexamethasone (DEX) and tumor necrosis factor (TNF-α), causing the adipose cell insulin resistance factor to raise to dexamethasone (DEX) has obvious inhibitory action.
Description of drawings
Fig. 1 shows the figure of medicine compound preparation of the present invention to the scavenging action of hydroxyl and ultra-oxygen anion free radical.
Fig. 2 shows that medicine compound preparation of the present invention induces rat blood sugar to raise to high lipid food the figure of obvious reduction effect is arranged.
Fig. 3 shows that medicine compound preparation of the present invention induces rat fat cell active oxygen (ROS) to raise to high lipid food obvious inhibiting figure is arranged.
Fig. 4 shows that medicine compound preparation of the present invention induces rat blood sugar to raise to chain urase element the figure of obvious reduction effect is arranged.
Fig. 5 shows that medicine compound preparation of the present invention induces rat lipid peroxidation (TBARS, thiobarbituricacid (TBA, Thiobarbituric acid) reactive substance) to raise to chain urase element obvious inhibiting figure is arranged.
Fig. 6 shows that medicine compound preparation of the present invention has the figure of obvious reduction effect to the fat type ii diabetes transgenic mouse of yellow (KKAY) blood sugar increasing.
Fig. 7 shows that rising has obvious inhibiting figure to medicine compound preparation of the present invention to the fat type ii diabetes transgenic mouse of yellow (KKAY) adipose cell active oxygen.
Fig. 8 shows that medicine compound preparation of the present invention causes the rising of adipose cell active oxygen that obvious inhibiting figure is arranged to dexamethasone (DEX) and tumor necrosis factor (TNF-α), and wherein "+" expression is added with respective substance, the no respective substance of "-" expression.
Fig. 9 shows that medicine compound preparation of the present invention causes the rising of adipose cell active oxygen that obvious inhibiting figure is arranged to dexamethasone (DEX) and tumor necrosis factor (TNF-α), and wherein "+" expression is added with respective substance, the no respective substance of "-" expression.
Figure 10 shows that medicine compound preparation of the present invention causes the adipose cell insulin resistance factor to raise to dexamethasone (DEX) obvious inhibiting figure is arranged, and wherein "+" expression is added with respective substance, the no respective substance of "-" expression.
In accompanying drawing 2 to 10, " * " expression compares with normal control that there were significant differences (P＜0.05), and " # " expression compares with the damage contrast that there were significant differences (P＜0.05).
The specific embodiment
Come further to illustrate the preparation method of medicine compound preparation of the present invention by the following examples.The preparation of embodiment 1. medicine compound preparations of the present invention---capsular preparation
300 milligrams every, effective ingredient is 80%, and other adds powder of Radix Puerariae (available from Sichuan Fuguiren Bioengineering Co., Ltd.).Tea polyphenols (available from Sichuan Fuguiren Bioengineering Co., Ltd.): epi-nutgall acid catechin (available from Zhejiang University's Tea department): the part by weight and the weight separately of Cyclocarya paliurus Iljinskaja water extract (available from Longyan, Fujian Province Mantidis tea company limited) see Table 1 respectively.
Table 1
| Numbering | Tea polyphenols: epi-nutgall acid catechin: Cyclocarya paliurus Iljinskaja water extract (weight ratio) | Tea polyphenols (mg) | Epi-nutgall acid catechin (mg) | Cyclocarya paliurus Iljinskaja water extract (mg) | Powder of Radix Puerariae (mg) |
| 1 | 6∶1∶3 | 144 | 24 | 72 | 60 |
| 2 | 7∶1∶2 | 168 | 24 | 48 | 60 |
| 3 | 8∶1∶1 | 192 | 24 | 24 | 60 |
| 4 | 9∶1∶0 | 216 | 24 | 0 | 60 |
| 5 | 5∶2∶3 | 120 | 48 | 72 | 60 |
| 6 | 6∶2∶2 | 144 | 48 | 48 | 60 |
| 7 | 7∶2∶1 | 268 | 48 | 24 | 60 |
| 8 | 8∶2∶0 | 192 | 48 | 0 | 60 |
| 9 | 4∶3∶3 | 96 | 72 | 72 | 60 |
| 10 | 5∶3∶2 | 120 | 72 | 48 | 60 |
| 11 | 6∶3∶1 | 144 | 72 | 24 | 60 |
| 12 | 7∶3∶0 | 168 | 72 | 0 | 60 |
| 13 | 3∶4∶3 | 72 | 96 | 72 | 60 |
| 14 | 4∶4∶2 | 96 | 96 | 48 | 60 |
| 15 | 5∶4∶1 | 120 | 96 | 24 | 60 |
| 16 | 6∶4∶0 | 144 | 96 | 0 | 60 |
| 17 | 2∶5∶3 | 48 | 120 | 72 | 60 |
| 18 | 3∶5∶2 | 72 | 120 | 48 | 60 |
| 19 | 4∶5∶1 | 96 | 120 | 24 | 60 |
| 20 | 5∶5∶0 | 120 | 120 | 0 | 60 |
| 21 | 1∶6∶3 | 24 | 144 | 72 | 60 |
| 22 | 2∶6∶2 | 48 | 144 | 48 | 60 |
| 23 | 3∶6∶1 | 72 | 144 | 24 | 60 |
| 24 | 4∶6∶0 | 96 | 144 | 0 | 60 |
| 25 | 0∶7∶3 | 0 | 168 | 72 | 60 |
| 26 | 1∶7∶2 | 24 | 168 | 48 | 60 |
| 27 | 2∶7∶1 | 48 | 168 | 24 | 60 |
| 28 | 3∶7∶0 | 72 | 168 | 0 | 60 |
In the GMP workshop, with tea polyphenols, epi-nutgall acid catechin and Cyclocarya paliurus Iljinskaja water extract and additive powder of Radix Puerariae ratio on request are at agitator (the small-sized mixer of CH-10, Zhongnan (South Contral) Pharmacentical Machinery Fectory) fully mixes (1 hour) in, at capsule machine (semi-automatic capsule filler, Shandong Province's Qingzhou City absolute sincerity machine-building company limited) goes up encapsulated (A type enteric coated capsule, Chaozhou City Qiangji Pharmaceutical Factory), adopt the ultraviolet technology bluepoint 4 economical ultraviolet sterilizer sterilizations of good happy joint-stock company, packing (YLE-500+YLH-500L packer, Yue Loong Coating Equipment Co., Ltd).
The preparation of embodiment 2. medicine compound preparations of the present invention---the preparation of oral liquid
10 milliliters every bottle, composition of medicine is dissolved in the distilled water, effective ingredient is 80%, other adds citric acid (food grade, available from Jinan, Shandong Yunxiang chemical industry Co., Ltd), tea polyphenols (available from Sichuan Fuguiren Bioengineering Co., Ltd.) wherein: epi-nutgall acid catechin (available from Zhejiang University's Tea department): the part by weight and the weight separately of Cyclocarya paliurus Iljinskaja water extract (available from Longyan, Fujian Province Mantidis tea company limited) see Table 2 respectively.
Table 2
| Numbering | Tea polyphenols: epi-nutgall acid catechin: Cyclocarya paliurus Iljinskaja water extract (weight ratio) | Tea polyphenols (mg) | Epi-nutgall acid catechin (mg) | Cyclocarya paliurus Iljinskaja water extract (mg) | Citric acid (mg) |
| 1 | 6∶1∶3 | 144 | 24 | 72 | 60 |
| 2 | 7∶1∶2 | 168 | 24 | 48 | 60 |
| 3 | 8∶1∶1 | 192 | 24 | 24 | 60 |
| 4 | 9∶1∶0 | 216 | 24 | 0 | 60 |
| 5 | 5∶2∶3 | 120 | 48 | 72 | 60 |
| 6 | 6∶2∶2 | 144 | 48 | 48 | 60 |
| 7 | 7∶2∶1 | 268 | 48 | 24 | 60 |
| 8 | 8∶2∶0 | 192 | 48 | 0 | 60 |
| 9 | 4∶3∶3 | 96 | 72 | 72 | 60 |
| 10 | 5∶3∶2 | 120 | 72 | 48 | 60 |
| 11 | 6∶3∶1 | 144 | 72 | 24 | 60 |
| 12 | 7∶3∶0 | 168 | 72 | 0 | 60 |
| 13 | 3∶4∶3 | 72 | 96 | 72 | 60 |
| 14 | 4∶4∶2 | 96 | 96 | 48 | 60 |
| 15 | 5∶4∶1 | 120 | 96 | 24 | 60 |
| 16 | 6∶4∶0 | 144 | 96 | 0 | 60 |
| 17 | 2∶5∶3 | 48 | 120 | 72 | 60 |
| 18 | 3∶5∶2 | 72 | 120 | 48 | 60 |
| 19 | 4∶5∶1 | 96 | 120 | 24 | 60 |
| 20 | 5∶5∶0 | 120 | 120 | 0 | 60 |
| 21 | 1∶6∶3 | 24 | 144 | 72 | 60 |
| 22 | 2∶6∶2 | 48 | 144 | 48 | 60 |
| 23 | 3∶6∶1 | 72 | 144 | 24 | 60 |
| 24 | 4∶6∶0 | 96 | 144 | 0 | 60 |
| 25 | 0∶7∶3 | 0 | 168 | 72 | 60 |
| 26 | 1∶7∶2 | 24 | 168 | 48 | 60 |
| 27 | 2∶7∶1 | 48 | 168 | 24 | 60 |
| 28 | 3∶7∶0 | 72 | 168 | 0 | 60 |
In the GMP workshop, with tea polyphenols, epi-nutgall acid catechin and Cyclocarya paliurus Iljinskaja water extract and additive citric acid ratio on request at agitator (RW 20 DZM.n overhead type mechanical agitators, Shanghai beautiful degree electronics technology Development Co., Ltd) fully mixes in, at can packing machine (the desk-top liquid-filling machine of DGDG series, Zhongnan (South Contral) Pharmacentical Machinery Fectory) goes up the dress bottling, adopt the ultraviolet technology bluepoint 4 economical ultraviolet sterilizer sterilizations of good happy joint-stock company, packing (YLE-500+YLH-500L packer, Yue Loong Coating Equipment Co., Ltd).
The preparation of embodiment 3. medicine compound preparations of the present invention---the preparation of tablet
Every 300 milligrams, effective ingredient is 80%, and other additive is starch (Tianjin gloomy many commerce and trade company).Tea polyphenols: epi-nutgall acid catechin: the part by weight of Cyclocarya paliurus Iljinskaja water extract and weight separately see Table 3 respectively.
Table 3
| Numbering | Tea polyphenols: epi-nutgall acid catechin: Cyclocarya paliurus Iljinskaja water extract (weight ratio) | Tea polyphenols (mg) | Epi-nutgall acid catechin (mg) | Cyclocarya paliurus Iljinskaja water extract (mg) | Starch (mg) |
| 1 | 6∶1∶3 | 144 | 24 | 72 | 60 |
| 2 | 7∶1∶2 | 168 | 24 | 48 | 60 |
| 3 | 8∶1∶1 | 192 | 24 | 24 | 60 |
| 4 | 9∶1∶0 | 216 | 24 | 0 | 60 |
| 5 | 5∶2∶3 | 120 | 48 | 72 | 60 |
| 6 | 6∶2∶2 | 144 | 48 | 48 | 60 |
| 7 | 7∶2∶1 | 268 | 48 | 24 | 60 |
| 8 | 8∶2∶0 | 192 | 48 | 0 | 60 |
| 9 | 4∶3∶3 | 96 | 72 | 72 | 60 |
| 10 | 5∶3∶2 | 120 | 72 | 48 | 60 |
| 11 | 6∶3∶1 | 144 | 72 | 24 | 60 |
| 12 | 7∶3∶0 | 168 | 72 | 0 | 60 |
| 13 | 3∶4∶3 | 72 | 96 | 72 | 60 |
| 14 | 4∶4∶2 | 96 | 96 | 48 | 60 |
| 15 | 5∶4∶1 | 120 | 96 | 24 | 60 |
| 16 | 6∶4∶0 | 144 | 96 | 0 | 60 |
| 17 | 2∶5∶3 | 48 | 120 | 72 | 60 |
| 18 | 3∶5∶2 | 72 | 120 | 48 | 60 |
| 19 | 4∶5∶1 | 96 | 120 | 24 | 60 |
| 20 | 5∶5∶0 | 120 | 120 | 0 | 60 |
| 21 | 1∶6∶3 | 24 | 144 | 72 | 60 |
| 22 | 2∶6∶2 | 48 | 144 | 48 | 60 |
| 23 | 3∶6∶1 | 72 | 144 | 24 | 60 |
| 24 | 4∶6∶0 | 96 | 144 | 0 | 60 |
| 25 | 0∶7∶3 | 0 | 168 | 72 | 60 |
| 26 | 1∶7∶2 | 24 | 168 | 48 | 60 |
| 27 | 2∶7∶1 | 48 | 168 | 24 | 60 |
| 28 | 3∶7∶0 | 72 | 168 | 0 | 60 |
In the GMP workshop, with tea polyphenols, epi-nutgall acid catechin and Cyclocarya paliurus Iljinskaja water extract and additive starch ratio on request at agitator (RW 20 DZM.n overhead type mechanical agitators, Shanghai beautiful degree electronics technology Development Co., Ltd) fully mixes in, at pelleter (TDP-1.5 single punch tablet machine, Zhongnan (South Contral) Pharmacentical Machinery Fectory) goes up the dress film-making, adopt the ultraviolet technology bluepoint 4 economical ultraviolet sterilizer sterilizations of good happy joint-stock company, packing (YLE-500+YLH-500L packer, Yue Loong Coating Equipment Co., Ltd).
The test example
Below further illustrate the beneficial effect of composition of medicine compound formulation of the present invention by concrete test example.
1. pairs of measured by esr technique of test example
Free radical, particularly reactive oxygen free radical as hydroxyl, ultra-oxygen anion free radical, are the key factors that causes insulin resistant.Adopt electronic self-rotary resonant technology (ESR) test, condition is as follows: when measuring on Brucker ER200 D-SRC type ESR spectrometer (German Brucker company), X-band, microwave power 10mW, modulating frequency 100kHz, amplitude modulation 1G, central magnetic field 3385G sweeps wide 200G, detect under the room temperature (referring to, Zhao, B-L, Li, X-J, He, R-G, Cheng, S-J, Xin, W-J:Scavenging effect of extracts of green tea and natural antioxidants onactive oxygen radicals.Cell Biophys.14:175.1989).Test result shows that medicine compound preparation of the present invention has obvious scavenging action to hydroxyl, ultra-oxygen anion free radical.As seen from Figure 1, medicine compound preparation of the present invention is to the IC of the scavenging action of hydroxyl and ultra-oxygen anion free radical
50Almost be the same, be approximately 7 μ M.From general trend, treatment type ii diabetes and reverse insulin resistant compound formulation are to the scavenging action slightly strong (referring to Fig. 1) of the scavenging action comparison hydroxyl of ultra-oxygen anion free radical.
The reduction effect that 2. pairs of high lipid foods of test example induce rat blood sugar to raise
The SD rat of male 30 days ages in days (body weight 180-200g is available from dimension tonneau China company) is raised under SPF (specific pathogen free microorganism) environment, and room temperature is 22 ℃, 12 hours day-night cycle.Rat is divided into two groups at random after growth feedstuff in feeding basis conformed three days.One group of feeding basis growth feedstuff (CHOW), one group of feeding high lipid food.Weigh after 30 days, judge the foundation of fat model.High fat and base set respectively are divided into two groups at random, i.e. composition of medicine compound formulation group and matched group.Animal every day of composition of medicine compound formulation group with No. 4 oral liquid formulations of table 2 irritate stomaches (1 milliliter/kg), the base set animal is irritated stomach with the distilled water of equal volume every day.Write down the weight of animals every day.Irritate stomach after 45 days, with urethane (Sigma company, the U.S.) anesthetized animal, get blood on an empty stomach, adopt SUPERGLUCOCARDII glucose detection instrument (the northern control of middle life company product) test blood glucose, test condition is as follows: wash 3-4 time with KRBH buffer (Sigma company, the U.S.), guaranteeing does not have residual glucose in the hole; Every hole adds 1ml KRBH buffer, needs the every hole of the cell insulin working concentration of insulin stimulating to be generally 100nM, hatches 20min for 37 ℃; Every hole adding KRBH buffer is made into
3The deoxyglucose of H labelling (
3H-2DG, deoxyglugose) with the mixed solution (Sigma company, the U.S.) of 2-deoxyglucose (2DG),
3H-2DG work unit is 0.5 μ Ci/ hole, and the final concentration of 2DG is 50 μ M, hatches 5min for 37 ℃; Suction goes to contain
3The solution of H-2DG, with the KRBH buffer give a baby a bath on the third day after its birth all over more than; Every hole adds 300 μ l 1%triton X-100 (Sigma company, the U.S.), or 1% sodium lauryl sulphate (SDS) (Sigma company, the U.S.), makes cell rupture; Liquid in every hole all transferred to measure in the bottle, each liquid dodges and 3ml liquid is housed in the bottle dodges liquid, ie in solution with measure the liquid volume ratio can not be above 1: 10; To measure bottle takes instrument to and detects.Then with its execution, it is frozen at-80 ℃ to get fatty tissue.Long fed with high (30+45 days) blood glucose (39.4%) of rat that can raise significantly.Can reduce rat blood sugar (base set reduces by 18.8%, and high fat group has reduced by 31.7%) significantly and irritate stomach tea polyphenols (45 days).Result of the test is seen Fig. 2.
The inhibitory action that 3. pairs of high lipid foods of test example induce the rat fat cell active oxygen to raise
The SD rat of male 30 days ages in days (body weight 180-200g is available from dimension tonneau China company) is raised under SPF (specific pathogen free microorganism) environment, and room temperature is 22 ℃, 12 hours day-night cycle.Rat is divided into two groups at random after growth feedstuff in feeding basis conformed three days.One group of feeding basis growth feedstuff (CHOW), one group of feeding high lipid food.Weigh after 30 days, judge the foundation of fat model.High fat and base set respectively are divided into two groups at random, i.e. composition of medicine compound formulation group and matched group.The composition of medicine compound formulation adopts No. 8 oral liquid formulations of table 2, animal irritate every day stomach (1 milliliter/kg), the base set animal is irritated stomach with the distilled water of equal volume every day.Write down the weight of animals every day.Irritate stomach after 45 days, use the urethane anesthetized animal, get blood on an empty stomach, execution then, it is frozen at-80 ℃ to get fatty tissue.When adopting electronic self-rotary resonant technology (ESR) test to measure on Brucker ER200 D-SRC type ESR spectrometer, condition is as follows: X-band, microwave power 10mW, modulating frequency 100kHz, amplitude modulation 1G, central magnetic field 3385G, sweep wide 200G, detect under the room temperature.Long fed with high active oxygen classification (ROS) level (52.3%) of rat fat tissue that can raise significantly.Irritate stomach tea polyphenols (45 days) and can reduce the ROS level (base set reduces by 28.4%, and high fat group has reduced by 26.2%) of rat fat tissue significantly.Result of the test is seen Fig. 3.
The reduction effect that 4. pairs of chain urases of test example element induces rat blood sugar to raise
Male SD rat (280-320g is available from dimension tonneau China company) is raised in all in check room of temperature and humidity, can free pickuping food and water.After the environmental adaptation through a week, animal hunger is spent the night (greater than 15 hours), and lumbar injection is dissolved in the streptozotocin (STZ) (Sigma company, the U.S.) in the citric acid solution, 0.2ml, (50 μ M).The citric acid solution of corresponding volumes such as matched group injection.The STZ injection detects 12 hours animal's whole blood sugar of fasting two days later.Adopt SUPER GLUCOCARDII glucose detection instrument (the northern control of middle life company product) test blood glucose, test condition is as follows: wash 3-4 time with the KRBH buffer, guaranteeing does not have residual glucose in the hole; Every hole adds 1ml KRBH buffer, needs insulin (Sigma company, the U.S.) the every hole of stimulated cells insulin working concentration to be generally 100nM, hatches 20min for 37 ℃; Every hole adding KRBH buffer is made into
3The deoxyglucose of H labelling (
3H-2DG is 0.5 μ Ci/ hole with 2-deoxyglucose (2DG) (Sigma company, the U.S.) work unit deoxyglugose), and the final concentration of 2DG is 50 μ M, hatches 5min for 37 ℃; Suction goes to contain
3The solution of H-2DG, with the KRBH buffer give a baby a bath on the third day after its birth all over more than; Every hole adds 300 μ l 1%tritonX-100, or 1%SDS, makes cell rupture; Liquid in every hole all transferred to measure in the bottle, each liquid dodges and 3ml liquid is housed in the bottle dodges liquid, ie in solution with measure the liquid volume ratio can not be above 1: 10; To measure bottle takes instrument to and detects.Blood sugar concentration is a diabetic mice greater than the animal of 16.6mM.Handled preceding 6 days at STZ, the composition of medicine compound formulation adopts No. 12 oral liquid formulations of table 2, animal irritate every day stomach (1 milliliter/kg), once a day, animal is condemned to death after three months.Detection blood glucose finds that the animal's whole blood sugar of tea polyphenols composition of medicine compound formulation processed group is reduced to about 2.5mM from about 22.5mM of diabetic groups.Result of the test is seen Fig. 4.
The inhibitory action that 5. pairs of chain urases of test example element induces the rat lipid peroxidation to raise
Male SD rat (280-320g is available from dimension tonneau China company) is raised in all in check room of temperature and humidity, can free pickuping food and water.After the environmental adaptation through a week, animal hunger is spent the night (greater than 15 hours), is dissolved in streptozotocin (STZ) in the citric acid solution as lumbar injection as described in the test example 4.The citric acid solution of corresponding volumes such as matched group injection.The STZ injection detects 12 hours animal's whole blood sugar of fasting two days later.Adopt SUPER GLUCOCARDII glucose detection instrument (the northern control of middle life company product) test blood glucose, condition is as follows: wash 3-4 time with the KRBH buffer, guaranteeing does not have residual glucose in the hole; Every hole adds 1ml KRBH buffer, needs the every hole of the cell insulin working concentration of insulin stimulating to be generally 100nM, hatches 20min for 37 ℃; The deoxyglucose of the 3H labelling that every hole adding KRBH buffer is made into (
3H-2DG, deoxyglugose) work unit is 0.5 μ Ci/ hole, the final concentration of 2-deoxyglucose (2DG) (Sigma company, the U.S.) is 50 μ M, hatches 5min for 37 ℃; Suction goes to contain
3The solution of H-2DG, with the KRBH buffer give a baby a bath on the third day after its birth all over more than; Every hole adds 300 μ l1% surfactants (triton X-100) (Sigma company, the U.S.), or 1%SDS, makes cell rupture; Liquid in every hole all transferred to measure in the bottle, each liquid dodges and 3ml liquid is housed in the bottle dodges liquid, ie in solution with measure the liquid volume ratio can not be above 1: 10; To measure bottle takes instrument to and detects.Blood sugar concentration is a diabetic mice greater than the animal of 16.6mM.Handled preceding 6 days at STZ, No. 16 oral liquid formulations filling stomaches of usefulness table 2 (1 milliliter/kg), once a day, animal is condemned to death after three months.Be increased to the about 300% of contrast at the diabetic mice lipid peroxidation, in the tea polyphenols processed group, it is about 20% that lipid peroxidation reduces, and all there were significant differences for the two.Result of the test is seen Fig. 5.
The reduction effect of the test example fat type ii diabetes transgenic mouses of 6. pairs of yellow (KKAY) blood sugar increasing
Yellow fat type ii diabetes transgenic mouse (KKAY) (28-32g is available from Chinese Academy of Medical Sciences's animal center) is raised in all in check room of temperature and humidity, can free pickuping food and water.After the environmental adaptation through a week, animal hunger is spent the night.Adopt SUPER GLUCOCARDII glucose detection instrument (the northern control of middle life company product) test blood glucose, test condition is as follows: wash 3-4 time with the KRBH buffer, guaranteeing does not have residual glucose in the hole; Every hole adds 1ml KRBH buffer, needs the every hole of the cell insulin working concentration of insulin stimulating to be generally 100nM, hatches 20min for 37 ℃; Every hole adding KRBH buffer is made into
3The deoxyglucose of H labelling (
3H-2DG, deoxyglugose) with the mixed solution of 2-deoxyglucose (2DG) (Sigma company, the U.S.),
3H-2DG work unit is 0.5 μ Ci/ hole, and the final concentration of 2DG is 50 μ M, hatches 5min for 37 ℃; Suction goes to contain
3The solution of H-2DG, with the KRBH buffer give a baby a bath on the third day after its birth all over more than; Every hole adds 300 μ l, 1% surfactant (triton X-100) (Sigma company, the U.S.), or 1%SDS, makes cell rupture; Liquid in every hole all transferred to measure in the bottle, each liquid dodges and 3ml liquid is housed in the bottle dodges liquid, ie in solution with measure the liquid volume ratio can not be above 1: 10; To measure bottle takes instrument to and detects.The detection blood sugar concentration is a diabetic mice greater than the animal of 16.6mM.With No. 20 oral liquid formulations of table 2 be animal irritate stomach (1 milliliter/kg), once a day, animal is condemned to death behind one and a half months.Detection blood glucose is found, long fed with high (30+45 days) blood glucose (39.4%) of type ii diabetes transgenic mouse that can raise significantly, (base set reduces by 18.8%, and high fat group has reduced by 31.7% and filling stomach tea polyphenols (45 days) can reduce type ii diabetes transgenic mouse blood glucose significantly.Result of the test is seen Fig. 6.
The inhibitory action that the test example fat type ii diabetes transgenic mouses of 7. pairs of yellow (KKAY) adipose cell active oxygen raises
Yellow fat type ii diabetes transgenic mouse (KKAY) (28-32g, available from Chinese Academy of Medical Sciences's animal center) (Houstis N, Rosen ED, Lander ES.Reactive oxygen species havea causal role in multiple forms of insulin resistance.Nature 2006; 440:944-8.) raise in all in check room of temperature and humidity, can free pickuping food and water.After the environmental adaptation through a week, animal hunger is spent the night.The detection blood sugar concentration is a diabetic mice greater than the animal of 16.6mM.The composition of medicine compound formulation adopts No. 24 oral liquid formulations, animal irritate every day stomach (1 milliliter/kg), once a day, animal is condemned to death behind one and a half months.Adopt electronic self-rotary resonant technology (ESR) test, for a long time the fed with high ROS level (52.3%) of rat fat tissue that can raise significantly.Irritate stomach tea polyphenols (45 days) and can reduce the ROS level (base set reduces by 28.4%, and high fat group has reduced by 26.2%) of rat fat tissue significantly.Result of the test is seen Fig. 7.
The inductive restitution that glucose absorption behind the adipose cell insulin stimulating is suppressed of test 8. couples of dexamethasone DEX of example or TNF-α
Glucose absorption behind the insulin stimulating is reflection adipose cell function and the adipose cell important indicator to the ability of insulin response.With dexamethasone (dexameson, DEX) (Sigma company, the U.S.) (20nM) or tumor necrosis factor TNF-alpha (turmor necrosis factor-α, 15nM) (Sigma company, the U.S.) processing induced the adipose cell 3T3-L1 of ripe differentiation (available from Chinese Academy of Medical Sciences's cell centre in 6 days, referring to Houstis N, Rosen ED, Lander ES.Reactive oxygen species have a causal role in multiple forms of insulinresistance.Nature 2006; 440:944-8.) oxidative stress, and handle jointly with No. 28 oral liquid formulations of the table 2 of 0.5 milliliter composition of medicine compound formulation and DEX or TNF-α.DEX and TNF-α can both reduce behind the adipose cell insulin stimulating absorption to glucose significantly, the glucose absorption function of the recovery adipose cell that type ii diabetes tea polyphenols composition of medicine compound formulation can part.Result of the test is seen Fig. 8.
The inhibitory action that test 9. pairs of dexamethasone of example (DEX) and tumor necrosis factor (TNF-α) cause the adipose cell active oxygen to raise
Dexamethasone DEX (dexameson) (20nM) or tumor necrosis factor TNF-alpha (turmornecrosis factor-α) and epi-nutgall acid catechin handle adipose cell 3T3-L1 (available from Chinese Academy of Medical Sciences's cell centre) jointly after 6 days, directly measure intracellular at that time ROS level with fluorescent probe, intracellular reactive oxygen level is by fluorescent probe 2 ', 7 '-dichlorofluorescein diacetate esters (2 ', 7 '-dichlorofluorescin diacetate, be called for short 2 ', 7 '-DCF-DA) (Sigma company, the U.S.) measures.DCF-DA itself is fluorescence not, but it enters after the cell, under the effect of hydrogen peroxide, can take off ester group and become the DCF that has fluorescence.Hanks balanced salt solution (Sigma company, the U.S.) and the DCF-DA of 10ml 0.5mM are dissolved in N, and (N N-dimethyl-formamide) in (Sigma company, the U.S.), adds in 6 orifice plates dinethylformamide.DCF-DA and cell were hatched 50 minutes altogether, hatched when finishing, and cell is washed off Incubating Solution at once, and detection in the fluorescent sub-photometer of packing into (485nm excites, and 535nm absorbs).The fluorescent value of measuring is characterized the percent with respect to contrast, and DEX and TNF-α can both increase the ROS level of adipose cell significantly, and No. 4 medicine compound preparations of type ii diabetes tea polyphenols combination table 2 can reduce the ROS level.Result of the test is seen Fig. 9.
The inhibitory action that test 10. pairs of dexamethasone of example (DEX) and tumor necrosis factor (TNF-α) cause the adipose cell insulin resistance factor to raise
Dexamethasone DEX (20nM) or tumor necrosis factor TNF-alpha (turmor necrosis factor-α) can both (the jun activating area connects albumen by increasing JNK, c-jun N-terminal Kinase) phosphorylation and activate the JNK path, and type ii diabetes tea polyphenols composition of medicine compound formulation can suppress phosphorylation (the Houstis N of JNK, Rosen ED, Lander ES.Reactive oxygen species have acausal role in multiple forms of insulin resistance.Nature 2006; 440:944-8.).DEX handles adipose cell 3T3-L1 (available from Chinese Academy of Medical Sciences's cell centre) can make the release of the useful factor adiponectin of adipose cell (adiponectin) reduce, and increase impels the release of the factor phylaxin of insulin resistance generation, and the release that the part that No. 4 medicine compound preparations energy concentration of type ii diabetes tea polyphenols combination table 2 rely on is recovered adiponectin, and the release of minimizing phylaxin.(useful factor adiponectin and resistance factor be inverse relation each other, so only represented the comparison of resistance factor among Figure 10).Result of the test is seen Figure 10.
Claims (10)
1. be used for the clinical treatment type ii diabetes and reverse the medicine compound preparation of insulin resistant, wherein said medicine compound preparation comprises the pharmaceutical composition be made up of epi-nutgall acid catechin, optionally tea polyphenol and Cyclocarya paliurus Iljinskaja water extract as effective ingredient and pharmaceutic adjuvant.
2. the described medicine compound preparation of claim 1, wherein, in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is 0～9 weight portion, the content of epi-nutgall acid catechin is that the content of 1～7 weight portion and Cyclocarya paliurus Iljinskaja water extract is 0～3 weight portion.
3. claim 1 or 2 any one medicine compound preparations, wherein, in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is 4 weight portions, the content of epi-nutgall acid catechin is that the content of 3 weight portions and Cyclocarya paliurus Iljinskaja water extract is 3 weight portions.
4. claim 1 or 2 any one medicine compound preparations, wherein, in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is 5 weight portions, the content of epi-nutgall acid catechin is that the content of 3 weight portions and Cyclocarya paliurus Iljinskaja water extract is 2 weight portions.
5. claim 1 or 2 any one medicine compound preparations, wherein, in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is 8 weight portions, the content of epi-nutgall acid catechin is that the content of 1 weight portion and Cyclocarya paliurus Iljinskaja water extract is 1 weight portion.
6. claim 1 or 2 any one medicine compound preparations, wherein, in the described pharmaceutical composition of 10 weight portions, the content of tea polyphenols is that the content of 9 weight portions and epi-nutgall acid catechin is 1 weight portion.
7. the medicine compound preparation of claim 1, wherein, described medicine compound preparation is capsule, tablet or oral liquid.
8. the medicine compound preparation of claim 7, wherein, when described medicine compound preparation was capsule, wherein pharmaceutic adjuvant was a powder of Radix Puerariae; When described medicine compound preparation was tablet, wherein pharmaceutic adjuvant was a starch; When described medicine compound preparation was oral liquid, wherein pharmaceutic adjuvant was an aqueous citric acid solution.
9. the preparation method of the medicine compound preparation of claim 1, the described pharmaceutical composition that described method comprises effective dose mixes with described pharmaceutic adjuvant.
10. any one medicine compound preparation of the claim 1-8 application that is used for the clinical treatment type ii diabetes and reverses the medicine of insulin resistant in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101759743A CN101199647A (en) | 2007-10-17 | 2007-10-17 | Medicament compound agent for treating II model diabetes and reversing insulin resistive and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101759743A CN101199647A (en) | 2007-10-17 | 2007-10-17 | Medicament compound agent for treating II model diabetes and reversing insulin resistive and preparing method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104138469A (en) * | 2013-05-12 | 2014-11-12 | 许昌市百药草园生物科技有限公司 | Medicinal composite preparation for treating type 2 diabetes and reversing insulin resistance, and preparation method thereof |
| CN111568945A (en) * | 2020-04-02 | 2020-08-25 | 湖南清雅健康服务有限公司 | Compound cyclocarya paliurus preparation |
-
2007
- 2007-10-17 CN CNA2007101759743A patent/CN101199647A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104138469A (en) * | 2013-05-12 | 2014-11-12 | 许昌市百药草园生物科技有限公司 | Medicinal composite preparation for treating type 2 diabetes and reversing insulin resistance, and preparation method thereof |
| CN111568945A (en) * | 2020-04-02 | 2020-08-25 | 湖南清雅健康服务有限公司 | Compound cyclocarya paliurus preparation |
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