CN102626438A - Antidiabetic medicament and preparation method - Google Patents
Antidiabetic medicament and preparation method Download PDFInfo
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Abstract
Disclosed are an antidiabetic medicament and a preparation method, which comprises the following steps of: extracting Caragana opulens medicinal material by an organic solvent thermal reflux extraction method to obtain an extract product, and further purifying the obtained medicinal active site and a pharmaceutically acceptable conventional excipient by an alkali-solution and acid-isolation method and macroporous resin separation process to prepare an oral preparation. The content of an effective component total organic acid contained in the medicinal active site reaches up to more than 50%. It is proved through pharmacological experiments that the antidiabetic medicament has a significant hyperglycemic function and can be used as a medicament to treat or prevent type 2 diabetes and its complication; the medicament takes action in gastrointestinal tract and is convenient to take; By the adoption of the organic solvent thermal reflux extraction method and the alkali-solution and acid-isolation method and with the combination of the macroporous resin separation technology, total organic acid of Caragana opulens with high content of effective component can be obtained, and the preparation method has advantages of good curative effect, small drug dosage and little side effect, convenient production, little pollution and the like.
Description
Technical field
The present invention relates to treat the Chinese medicine of diabetes.
Background technology
In recent years, diabetes prevalence and mortality rate have obvious ascendant trend, and according to estimates, there is diabetic 1.5 hundred million in the whole world at present, will reach 300,000,000 in 2025, and China has diabetics 3,000 ten thousand now, will reach 5,000 ten thousand in 2025.Along with the increase of diabetics prevalence, complication such as scheming infarction, renal failure, uremia, blind etc. sickness rate will seriously jeopardize patient's life also along with raising, and this disease has become the third commonly encountered diseases after cardiovascular disease, tumor in China.And the treatment of diabetes medicine is chemical synthetic drug mostly, though certain effect is arranged, exists action target spot single, is prone to bounce-back, the shortcoming that side effect is many after the drug withdrawal.Yet many Chinese medicines have good hypoglycemic activity equally, and its mechanism of action is many-sided.Special significant be to have many blood sugar lowering Chinese medicines to have dual regulation, and Chinese medicine is hypoglycemic also has blood fat reducing simultaneously concurrently, anticoagulant and reduce viscosity of blood improves multiple effects such as blood circulation.Therefore, Chinese medicine can not only blood sugar lowering and its complication is had significant specific aim and preventive and therapeutic effect, from Chinese medicine, filters out efficient, low toxicity, can prevent and treat the medicine of complication again, has very big advantage and is worth with exploitation.
Sweet illiteracy caragana (Caragana opulens) is a pulse family Caragana shrub, extensively originates in ground such as Gansu, the Inner Mongol, is that Tibetan medicine is looked into one of former plant of agate; Cool in nature, bitter in the mouth; Can be clear various muscle heat are hot with arteries and veins, can arrange disorders of meridian and emetic action is arranged, its stem branch micromicro expelling wind and activating blood circulation; The pain relieving diuresis, the QI invigorating kidney tonifying.Up to the present, do not see the modern study of and pharmacology chemical to this medical material.
Summary of the invention
The purpose of this invention is to provide a kind of medicine of treating diabetes.
Another object of the present invention provides the method for preparing of this antidiabetic medicine.
For the technical scheme that reaches the object of the invention employing is to get the sweet illiteracy caragana of pulse family population pattern change to obtain extract with the extraction of organic solvent water bath reflux method; Further with the medical active position of alkali extraction and acid precipitation method and macroporous resin partition method purification gained and the oral formulations that pharmaceutically acceptable conventional adjuvant is processed; By weight percentage, contain effective composition total organic acids in the dry product of said medical active position greater than 50%.
The method for preparing of antidiabetic medicine provided by the present invention is that to get the sweet illiteracy caragana of pulse family population pattern change plant be raw material, adopts the organic solvent water bath reflux method, and the extraction solvent is an ethyl acetate; Extracted solid-to-liquid ratio 1: 15, and extracted temperature and be under 80 ℃ the condition and extracted 2～4 hours, evaporated under reduced pressure reclaims organic solvent and obtains extract; Further purify extract obtained with the alkali extraction and acid precipitation method; Be dissolved in earlier in the 0.5M sodium hydroxide solution of 10 times of amounts, the hold over night after-filtration, filtrating is with 1M hydrochloric acid solution adjust pH to 2～3; Use the ethyl acetate extraction 2 times of 2 times of amounts then; Evaporated under reduced pressure gets extractum, and reuse macroporous resin partition method is purified, earlier with washing with 30% alcoholic solution after the macroporous resin adsorption; Resolve with 70% ethanol then; Evaporated under reduced pressure, medical active position (be called for short MAS), getting it filled adds pharmaceutically acceptable conventional adjuvant with active site and processes oral formulations or the medical active position is processed oral formulations with adding pharmaceutically acceptable conventional adjuvant again after comprising agent and comprising with conventional method of Chinese medicinal with conventional method of Chinese medicinal.
Sweet illiteracy caragana medical active position involved in the present invention is fat-soluble material, so pharmaceutical dosage form is the best with the preparation soft capsule, the adjuvant commonly used during the preparation soft capsule has vegetable oil and Polyethylene Glycol-400; Earlier carry out enclose with the medical active position when preparation capsule, drop pill, tablet and process little rubber powder, add pharmaceutically acceptable conventional adjuvant then and be prepared into oral formulations with conventional method of Chinese medicinal with inclusion agents.As get when preparing capsule, tablet behind the enclose for the capsule powder adds adjuvant micropowder silica gel, starch, lactose, microcrystalline Cellulose etc., add adjuvant Polyethylene Glycol-400, Polyethylene Glycol-600, plant wet goods during the preparation drop pill.Inclusion agents is beta-schardinger dextrin-or modified starch, uses polishing when adopting beta-cyclodextrin inclusion compound, and concrete grammar is: get the beta-schardinger dextrin-that weight is 10 times of amounts of active site; Join in the beta-schardinger dextrin-water of 30 times of amounts, insert and grind in the colloid mill evenly, then active site is dissolved in 1 times of amount dehydrated alcohol; Add in the colloid mill, ground 30 minutes, inclining lapping liquid; Filter, filter cake is washed 3 times with a small amount of dehydrated alcohol, vacuum drying or spray drying.
Oral dose when product provided by the invention is used to treat diabetes is recommended in MAS (sweet illiteracy caragana extract is through the active site of alkali extraction and acid precipitation method and macroporous resin partition method purification gained) to take 60-240mg for each person every day.
The invention has the beneficial effects as follows: 1. the medicine that is provided has remarkable anti-diabetic function, can be used for treating diabetes; 2. medicine is with gastrointestinal administration, and product forms is conveniently taken; 3. method for preparing adopts organic solvent water bath reflux method and alkali extraction and acid precipitation method to have advantages such as convenient for production, that pollution is little.The present invention will provide new selection for the treatment of diabetes medication.On preparation technology, adopted the macroporous resin isolation technics, obtained the high sweet illiteracy caragana total organic acids of active constituent content, had good effect, dosage is little, the advantage that side effect is little.
Description of drawings
Fig. 1 is the potentiometric titration curve figure of vanillic acid reference substance, and vertical coordinate is the ratio of potential change amount (Δ E) and volume change (Δ V), and abscissa is the volume averaging value (V) of the sodium hydroxide solution that spent before and after the potential change.Potential change when having reacted sodium hydroxide solution titration vanillic acid among the figure.
Fig. 2 is the potentiometric titration curve figure of total organic acids in the sweet illiteracy caragana, and vertical coordinate is the ratio of potential change amount (Δ E) and volume change (Δ V), and abscissa is the volume averaging value (V) of the sodium hydroxide solution that spent before and after the potential change.Potential change when having reacted the sweet illiteracy caragana of sodium hydroxide solution titration extract among the figure.
Fig. 3 is the curve chart of sweet illiteracy caragana extract MAS to the alpha-glucosidase activity influence, and vertical coordinate is the enzymatic activity suppression ratio, and the abscissa representative sample suppresses the logarithm value of final concentration (μ g/ml).It is active to have compared the inhibition to alpha-glucosidase when variable concentrations of sweet illiteracy caragana extract MAS and acarbose among the figure.
The specific embodiment
The preparation of embodiment 1, plant extract
1 potentiometric titration is surveyed the foundation of total organic acids content
(1) constant-current titration of vanillic acid reference substance
Vanillic acid 95% alcoholic solution of accurately drawing 25mL 0.0103mol/L adds 95% ethanol 15mL and shakes up in the 100mL beaker, connects potentiometer, magnetic stirring apparatus and solution to be measured, with the titration of 25mL burette splendid attire 0.051mol/L sodium hydroxide solution.The sodium hydroxide volume and the corresponding potential changing value thereof that spend in the record titration process during titration carry out blank correction simultaneously.Ratio with potential change amount (Δ E) and volume change (Δ V) is vertical coordinate, and the volume averaging value (V) of the sodium hydroxide solution that is spent before and after the potential change is abscissa, and the result sees Fig. 1.Can be known that by Fig. 1 the maximum of curve is exactly titration end-point, the consumption alkali number is 5.05mL.By formula (V
Alkali=C
AcidV
Acid/ C
Alkali) the calculation consumption alkali number is 5.05mL, the two matches, and the curve display titration end-point is very obvious, explains that potentiometric titration surveys total organic acids content and have accuracy and susceptiveness.
(2) constant-current titration of total organic acids in the sweet illiteracy caragana
Total organic acids content is in vanillic acid in the sweet illiteracy caragana.Accurately take by weighing the about 240mg of sweet illiteracy caragana total acid extract in the 100mL beaker, with 95% dissolve with ethanol solution system test liquid, the making of titration curve is identical with the making of vanillic acid titration curve, and the result sees Fig. 2.Can be known that by Fig. 2 the maximum of curve is exactly titration end-point, the consumption alkali number is 4.35mL.The curve display titration end-point is very obvious, explains that potentiometric titration surveys that total organic acids content is feasible in the sweet illiteracy caragana.
(3) calculating of total organic acids (vanillic acid meter) yield in the sweet illiteracy caragana:
V---the volume of the sodium hydroxide that titration consumed, unit is: L
C---the used concentration sodium hydroxide of titration, unit is: mol/L
W---organic acid yield, unit is: %
The quality of M---medical material, unit is: g
2, the preparation of sweet illiteracy caragana crude extract
Choosing ethyl acetate is solvent, according to the influence factor who extracts, selected solvent extraction consumption 12-18 doubly, extraction time 2.5-3.5 hour, 1-3 3 factors of extraction time, each factor is got 3 levels, the fixed extraction temperature is 80 ℃, employing L
9(3
4) orthogonal table optimization extraction process condition, gauge outfit designs like table 1, and experimental data is seen table 2.Through analytical calculation, the process conditions of selected optimum extraction.
Table 1 factor level table
Table 2 orthogonal experiments table
Experimental result by last (table 2) can be found out, at L
9(3
4) total organic acids extraction time in orthogonal experiment three factors is more obvious to the experimental result influence; It is the principal element that influences the total organic acids yield; Extraction ratio to chrysophanic acid has a significant effect; And other factors are less relatively to the influence of total organic acids yield in test. so the primary and secondary of each factor affecting total organic acids extraction ratio relation is C＞A＞B, optimised process is A
2B
3C
3The optimised process concrete operations: sweet illiteracy caragana coarse powder 10Kg, to extract 80 ℃ of refluxed with 15 times of volumes of acetic acid ethyl esters, extraction time is 3.5 hours, and extraction time is 3 times, and merge extractive liquid, is evaporated to the dried extractum 1 that obtains with Rotary Evaporators.
3, the preparation of sweet illiteracy caragana total organic acids
Gained extractum 1 is used of the sodium hydroxide solution dissolving of the molar concentration of 20 times of amounts as 0.5M, the hold over night after-filtration, filtrating is with 1M hydrochloric acid solution adjust pH to 2～3; Use the ethyl acetate extraction 2 times of 2 times of amounts then, evaporated under reduced pressure gets extractum 2, with crossing the HPD-100 macroporous resin behind gained extractum 2 usefulness 30% dissolve with ethanol; Absorption back is fully resolved with 70% ethanol, with the desorbed solution evaporated under reduced pressure, gets extractum 3; Be medical active position (being called for short MAS), yield is 0.21%.Detect with potentiometric titration, wherein total organic acids content is 64.5%.
(1) enclose of MAS
1, adds 30L water in the 1Kg beta-schardinger dextrin-, insert in the colloid mill and grind evenly.Then MAS 100g is dissolved in the 100ml dehydrated alcohol, adds in the colloid mill, ground 30 minutes.Incline and lapping liquid, sucking filtration.Filter cake is washed 3 times with a small amount of dehydrated alcohol, and vacuum drying or spray drying get 1098g MAS clathrate.
2, add 15L water among the 500g distortion starch N-LOK, implant in the colloid mill and grind evenly.Then MAS 50g is dissolved in the 50ml dehydrated alcohol, adds in the colloid mill, ground 30 minutes.Incline and lapping liquid, sucking filtration.Filter cake is washed 3 times with a small amount of dehydrated alcohol, and vacuum drying or spray drying get 547g MAS clathrate.
(2) preparation of medicine
1, preparation of soft capsule
Content: get MAS 60g, vegetable oil: 300g, glycerol: 20g, Tween 80: 0.1g mix homogeneously.
Get content and be pressed into 1000 soft capsules with the rotation rolling capsule machine.
2, capsular preparation
Get MAS clathrate 220g, cross 80 mesh sieves, add an amount of 10% starch slurry and process soft material, cross 14 order nylon mesh and granulate, 60 ℃ of dry granules that get are inserted capsulae vacuus, process 1000 of hard capsules altogether.
3, the preparation of tablet
Get MAS clathrate 220g and starch 85g, dextrin 66g, sucrose 10g mixing is processed granule.Dry below 60 ℃, add Pulvis Talci 5g and magnesium stearate 1g mixing, be pressed into 1000.
4, the preparation of drop pill
Get 180g PEG-4000 heating and make into molten condition, add 60g MAS, mixing splashes in the refrigerative liquid paraffin, and routine is processed 1000 drop pill.
Below use according to the sweet illiteracy caragana of embodiment 1 gained extract MAS and carry out in vitro tests, pharmacodynamics test and toxicologic study
One, sweet illiteracy caragana extract MAS is to the inhibiting in vitro tests of alpha-glucosidase
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation), acarbose (Bayer medicines and health protection company limited), 4-Nitrobenzol-α-D-pyranglucoside (pNPG, Sigma company), alpha-D-glucose glycosides enzyme (Sigma company).
2, method
Sweet illiteracy caragana extract MAS and acarbose are dissolved in DMSO respectively, and being made into concentration is the appearance liquid of 5mg/ml, uses phosphate buffer (10mmol/L then; PH=6.8) dilution is the liquid to be measured of variable concentrations (10-500 μ g/ml); Get 120 μ l phosphate buffers and 20 μ l appearance liquid and 0.75U/ml glucosidase 10 μ l mixings, cultivate 20min, adding 10mmol/L pNPG (phosphate buffer dissolving) 50 μ l in 4 ℃; In 37 ℃ of incubation 20min; Under the 405nm wavelength, measure the OD value, more than be reflected on 96 orifice plates and accomplish, the reaction cumulative volume is 200 μ l.Each test sample is done 3 multiple holes simultaneously, averages, and repeats 3 experiments.Acarbose is set blank and negative control simultaneously as the positive control of this law.Calculate the suppression ratio of enzymatic activity: suppression ratio=((sample-feminine gender)/(blank-feminine gender)) * 100%.Logarithm with sample final concentration (μ g/ml) is done abscissa, and suppression ratio is done the vertical coordinate mapping, and the result is as shown in Figure 3.
Can find out that by Fig. 3 result sweet illiteracy caragana extract MAS has remarkable inhibitory action external to alpha-glucosidase, and effect is suitable with acarbose.
Two, the Pharmacodynamic test of active extract of sweet illiteracy caragana extract MAS
(1) sweet illiteracy caragana extract MAS is to the influence of normal mouse starch-bearing carbohydrate tolerance
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation); Acarbose (production of Bayer medicines and health protection limit company); Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides); Blood glucose monitoring system (the happy one-tenth in Beijing Bioisystech Co., Ltd), blood glucose strip (the happy one-tenth in Beijing Bioisystech Co., Ltd).
2, method
Get 50 of healthy adult male mices, fasting 2 hours is divided into 5 groups at random: high, normal, basic three dose groups (50mg/Kg of normal control group, acarbose group and sweet illiteracy caragana extract MAS; 100mg/Kg; 200mg/Kg), 10 every group, the blood glucose there was no significant difference that each is organized.Respectively give corresponding dosage once after, irritate stomach with 5g/kg dosage starch, give starch after 3 hours, mouse blood sugar is surveyed in the eye socket blood sampling.The result is as shown in table 3:
The sweet illiteracy caragana of table 3 extract MAS is to the influence of normal mouse blood sugar
| Group | Dosage (mg/Kg) | Blood glucose value (mmol/L) |
| The normal control group | - | 6.92±1.13 |
| MAS organizes (low) | 50 | 6.76±1.32 |
| The MAS group (in) | 100 | 5.98±0.82 * |
| MAS organizes (height) | 200 | 5.72±0.53 ** |
| The |
20 | 5.16±0.64 ** |
Annotate: compare with the normal control group,
*P＜0.05,
*P＜0.01.
Can be found out by table 3: the post-prandial glycemia that sweet illiteracy caragana extract MAS is high, middle dose groups all can significantly suppress normal mouse raises (p＜0.05 or p＜0.01), and the effect and the acarbose of its high dose group are suitable.
(2) sweet illiteracy caragana extract MAS induces diabetic mice starch-bearing carbohydrate tolerance influence test to alloxan
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation); Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides); Alloxan (production of Sigma company); Glibenclamide (Shaanxi Sen Fu Bioisystech Co., Ltd), blood glucose monitoring system (the happy one-tenth in Beijing Bioisystech Co., Ltd), blood glucose strip (the happy one-tenth in Beijing Bioisystech Co., Ltd).
2, method
Get body weight 22-26g Kunming mouse; Lumbar injection 200mg/kg alloxan; Measure blood glucose after 72 hours, choose the mice of blood glucose value more than 11.1mmol/L, by 10 every group; Male and female half and half are divided into 6 groups; Be diabetic model group, acarbose group, sweet illiteracy caragana extract MAS high dose group, middle dose groups, low dose group, acarbose dosage is 20mg/kg (body weight), and sweet illiteracy caragana extract MAS high dose group is that 200mg/kg, middle dose groups are that 100mg/kg, low dose group are 50mg/kg; Measure fasting glucose (0min); Administration is (model group is irritated stomach with normal saline) after ten minutes, and each group is all irritated stomach with starch 5g/kg, gets eye socket rear vein beard blood respectively at 30min, 60min, 90min, 120min; Measure blood sugar content with the blood glucose strip, the result sees table 4.
The sweet illiteracy caragana of table 4 extract MAS induces the influence of diabetic mice starch-bearing carbohydrate tolerance to alloxan
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
Can be found out by table 4: diabetic mice is after giving starch, and blood glucose value (model group) obviously raises.Sweet illiteracy caragana extract MAS high dose group all significantly suppresses the blood sugar increasing of diabetic mice at each time point, and its effect is suitable with acarbose; Compare with model group, among the MAS, low dose group all has certain inhibitory action to the blood sugar increasing of each time point diabetic mice, but effect is not as good as the MAS high dose group.
(3) sweet illiteracy caragana extract MAS is to the influence of the blood glucose of diabetic mice due to the streptozotocin
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation); Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides); Glibenclamide (Shaanxi Sen Fu Bioisystech Co., Ltd); Streptozotocin (production of Sigma company), blood glucose monitoring system (the happy one-tenth in Beijing Bioisystech Co., Ltd), blood glucose strip (the happy one-tenth in Beijing Bioisystech Co., Ltd).
2, method
Get 80 of healthy male mices; 10 of picked at random are as the normal control group; The dosage lumbar injection streptozotocin of 60mg/kg body weight is pressed in all the other 70 fasting 12 hours, normal control group injection citrate buffer solution; 1 week was measured fasting blood sugar after modeling, and the mice that the screening blood glucose value surpasses 11.1mmol/L is the experimental model Mus.50 diabetes experimental model Mus are divided into diabetic model group at random, glibenclamide (irritating stomach 20mg/kg), the basic, normal, high dose groups of sweet illiteracy caragana extract MAS (is respectively 50,100,200mg/kg).Normal control group and diabetic model group are irritated stomach normal saline, 3 weeks of successive administration.Fasting is 12 hours after the last administration, and eye socket is got blood, surveys the change of blood sugar value, and the result sees table 5.
The sweet illiteracy caragana of table 5 extract MAS is to the influence of the blood glucose of diabetic mice due to the streptozotocin
| Group | Dosage (mg/kg) | Blood glucose value (mmol/L) |
| The normal control group | - | 4.7±0.9 ** |
| Model control group | - | 15.4±3.8 |
| The |
20 | 9.1±4.9 ** |
| MAS organizes (height) | 200 | 9.3±4.5 ** |
| The MAS group (in) | 100 | 10.6±5.3 ** |
| MAS organizes (low) | 50 | 12.4±6.1 * |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01.
Can be found out by table 5: compare with model group, the high, medium and low dose groups of sweet illiteracy caragana extract MAS all can significantly reduce the blood glucose value (p＜0.05 or p＜0.01) of diabetic mice, and effect and acarbose high, middle dose groups are suitable.
(4) sweet illiteracy caragana extract MAS is to the influence of the blood glucose of alloxan diabetes mice
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation); Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides); Glibenclamide (Shaanxi Sen Fu Bioisystech Co., Ltd); Alloxan (production of Sigma company), blood glucose monitoring system (the happy one-tenth in Beijing Bioisystech Co., Ltd), blood glucose strip (the happy one-tenth in Beijing Bioisystech Co., Ltd).
2, method
80 of male mice in kunming, fasting 12 hours before the experiment, all the other lumbar injection 200mg/kg alloxan were surveyed blood glucose value after 72 hours to 10 of picked at random as the normal control group, choosing wherein 50 blood glucose value＞11.1mmol/L persons as diabetic mice.Diabetic mice be divided at random high, medium and low three dose groups of Rhizoma Anemarrhenae extract (50mg/Kg, 100mg/Kg, 200mg/Kg); Model control group; Glibenclamide positive controls (20mg/Kg) makes there was no significant difference between each blood glucose value mean of organizing, 10 every group.Each organizes gastric infusion or normal saline every day, continuous 3 weeks, got blood from mouse orbit in 1 hour after the administration again in last fasting 12 hours, and measure blood sugar content with the blood glucose strip, the result sees table 6.
The sweet illiteracy caragana of table 6 extract MAS is to the blood sugar influence of model induced by alloxan diabetic mice
| Group | Dosage (mg/kg) | Blood glucose value (mmol/L) |
| The normal control group | - | 5.4±0.8 ** |
| Model control group | - | 19.3±2.6 |
| The |
20 | 13.1±1.9 ** |
| MAS organizes (height) | 200 | 14.3±2.5 ** |
| The MAS group (in) | 100 | 15.6±3.3 ** |
| MAS organizes (low) | 50 | 17.4±3.8 * |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01.
Can be known that by table 6 administration group blood glucose is compared remarkable reduction (P＜0.01) with model control group, and blood glucose descends and sweet illiteracy caragana extract MAS is dose dependent, the effect and the acarbose of high dose group are suitable.
(5) sweet illiteracy caragana extract MAS is to the influence of the liver glycogen content of alloxan diabetes mice
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation), Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides), glibenclamide (Shaanxi Sen Fu Bioisystech Co., Ltd), alloxan (production of Sigma company).
2, method
80 of male mice in kunming, fasting 12 hours before the experiment, 10 of picked at random are as the normal control group, all the other lumbar injection 200mg/kg alloxan, 72 hours rear side blood glucose values, choosing wherein 50 blood glucose value＞11.1mmol/L as diabetic mice.Diabetic mice be divided at random high, medium and low three dose groups of sweet illiteracy caragana extract MAS (50mg/Kg, 100mg/Kg, 200mg/Kg); Model control group; And glibenclamide positive controls (20mg/Kg), make there was no significant difference between each blood glucose value mean of organizing, 10 every group.Each organizes gastric infusion or normal saline every day, continuous 21 days, in the last administration after 1 hour disconnected marrow put to death, by sulphuric acid-fear the ketone method, measure liver glycogen content, the result is as shown in table 7:
The sweet illiteracy caragana of table 7 extract MAS is to the influence of the liver glycogen content of alloxan diabetes mice
| Group | Dosage (mg/kg) | Blood glucose value (mg/g) |
| The normal control group | - | 35.3±1.8 ** |
| Model control group | - | 17.6±1.6 |
| The |
20 | 25.1±4.7 ** |
| MAS organizes (height) | 200 | 24.3±3.5 ** |
| The MAS group (in) | 100 | 23.6±3.3 ** |
| MAS organizes (low) | 50 | 21.4±2.1 * |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01.
Can be found out by table 7: compare with model group, the high, medium and low dose groups of sweet illiteracy caragana extract MAS all can significantly reduce the liver glycogen consumption of diabetic mice, and effect and acarbose high, middle dose groups are suitable.
(6) sweet illiteracy caragana extract MAS is to blood insulin and the morphologic influence of islet tissue of alloxan diabetes mice
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation), Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides), alloxan (production of Sigma company) is feared ketone reagent (5-linked chemical plant, Shanghai).
2, method
60 of male mice in kunming, fasting 12 hours before the experiment, 10 of picked at random are as the normal control group, all the other lumbar injection 200mg/kg alloxan, 72 hours rear side blood glucose values, choosing wherein 30 blood glucose value＞11.1mmol/L persons as diabetic mice.Diabetic mice be divided at random two dose groups of sweet illiteracy caragana extract MAS height (50mg/Kg, 200mg/Kg) and model control group, 10 every group.Each organizes gastric infusion or normal saline every day, continuous 21 days, in the last administration after 1 hour disconnected marrow put to death, from each group, get 3 mice pancreatic afterbody tissues at random respectively, use Gormori aldehyde-fuchsin and H.E colouring method, the observation islet tissue.Observed result is seen table 8:
The morphological change of table 8 islet tissue
Can be found out by table 7: sweet illiteracy caragana extract MAS high dose group is to being had significant repair by the destructive insulin secreting cells of alloxan, and increased the secretory granule of beta Cell of islet.Compare with model group, the MAS low dose group is to being had the certain repairing effect by the destructive insulin secreting cells of alloxan, but effect is not as good as the MAS high dose group.
(7) sweet illiteracy caragana extract MAS is to the influence of normal mouse blood sugar
1, material
Sweet illiteracy caragana extract MAS (pressing embodiment 1 preparation), Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides), blood glucose monitoring system (the happy one-tenth in Beijing Bioisystech Co., Ltd), blood glucose strip (the happy one-tenth in Beijing Bioisystech Co., Ltd).
2, method
40 of normal mouses, male and female half and half are divided into 4 groups at random: the normal control group, irritate the stomach normal saline; (50mg/Kg, 100mg/Kg 200mg/Kg) irritate the stomach Rhizoma Anemarrhenae extract respectively to high, medium and low dose groups, 1 Id, 3 weeks of continuous use.3 hours posterior orbits of last administration are got blood, survey the change of blood sugar value, and the result sees table 9.
The sweet illiteracy caragana of table 9 extract MAS is to the influence of normal mouse blood sugar
| Group | Dosage (mg/kg) | Blood glucose value (mg/g) |
| The normal control group | - | 5.3±1.8 |
| MAS organizes (height) | 200 | 4.3±1.5 * |
| The MAS group (in) | 100 | 4.6±1.3 * |
| MAS organizes (low) | 50 | 5.1±2.1 |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01.
Can be found out by table 9: compare with the normal control group, the high, medium and low dose groups of sweet illiteracy caragana extract MAS all can make the blood glucose value of normal mouse reduce, and effect remarkable (p＜0.05) high, middle dose groups.
Three, acute toxicity testing
1, material
Sweet illiteracy caragana extract MAS (press embodiment 1 preparation), Kunming mouse (preclinical medicine institute of Lanzhou University Experimental Animal Center provides), 0.5% methylcellulose receive (medicine dissolution diluent).
2, method
Respectively get 20 of normal mouses; Male and female half and half are received sweet illiteracy caragana extract MAS is made into 0.5% methylcellulose and can be irritated concentration 0.5g/mL, with the administration of every mice 20mL/kg body weight; Disposable filling stomach is observed after the administration poisoning and the death condition of mice in 14 days.Toxic reaction primary part observation symptom, degree are cutd open the dead white mice of inspection at toxic reaction zero-time, persistent period and recovery time, record dead mouse reason.Cutd open inspection, main organs such as perusal heart, liver, spleen, lungs, kidney after putting to death whole white mice on the 14th day.
3, result
Behind the gastric infusion mice occur in various degree few moving, do not take food or phenomenon such as few feed, but after 2 hours, promptly recover successively, mice does not see obvious abnormal response, draws together freely, diet, feces and other clear conditions are all no abnormal, hair color light next to the shin.7 days and 14 days animal subject body weight are not all seen significant change after the administration, cut open inspection after putting to death whole white mice on the 14th day, and main organs no abnormality seens such as perusal heart, liver, spleen, lungs, kidney change.The result show the mouse stomach administration to the maximum tolerated dose of sweet illiteracy caragana extract MAS greater than the 10g/Kg body weight, explain that this plant extract toxicity is extremely low or nontoxic.
Through above-mentioned in vitro tests and pharmacodynamics test; Prove that sweet illiteracy caragana and extract thereof have the effect that reduces post-prandial glycemia; The activity that can suppress alpha-glucosidase, and basic avirulence have characteristics such as evident in efficacy, cheap, safe and convenient to use.
Claims (5)
1. antidiabetic medicine; It is characterized in that: get the sweet illiteracy caragana of pulse family population pattern change and obtain extract with the extraction of organic solvent water bath reflux method; Further with the medical active position of alkali extraction and acid precipitation method and macroporous resin partition method purification gained and the oral formulations that pharmaceutically acceptable conventional adjuvant is processed; By weight percentage, contain effective composition total organic acids in the dry product of said medical active position greater than 50%.
2. antidiabetic medicine according to claim 1 is characterized in that: said oral formulations is a capsule, perhaps soft capsule, perhaps drop pill, perhaps tablet.
3. the method for preparing of the described antidiabetic medicine of claim 1 the steps include:
(1) getting the sweet illiteracy caragana of pulse family population pattern change plant is raw material; Use the organic solvent water bath reflux method, the extraction solvent is an ethyl acetate, extracts solid-to-liquid ratio 1: 15; Extract temperature and be under 80 ℃ the condition and extracted 2～4 hours, evaporated under reduced pressure reclaims organic solvent and obtains extract;
(2) further purify extract obtained, be dissolved in earlier in the 0.5M sodium hydroxide solution of 10 times of amounts with the alkali extraction and acid precipitation method, the hold over night after-filtration, filtrating is with 1M hydrochloric acid solution adjust pH to 2～3, uses the ethyl acetate extraction 2 times of 2 times of amounts then, and evaporated under reduced pressure gets extractum,
(3) purify with the macroporous resin partition method; Earlier with washing with 30% alcoholic solution after the macroporous resin adsorption; Resolve with 70% ethanol then; Evaporated under reduced pressure, the medical active position, getting it filled adds pharmaceutically acceptable conventional adjuvant with active site and processes oral formulations or the medical active position is processed oral formulations with adding pharmaceutically acceptable conventional adjuvant again after comprising agent and comprising with conventional method of Chinese medicinal with conventional method of Chinese medicinal.
4. the method for preparing of antidiabetic medicine according to claim 3, it is characterized in that: described inclusion agents is beta-schardinger dextrin-or modified starch.
5. the method for preparing of antidiabetic medicine according to claim 4, it is characterized in that: the method that described active site uses inclusion agents to satisfy and closes is: get the beta-schardinger dextrin-of weight as 10 times of amounts of active site, join in the water of beta-schardinger dextrin-consumption of 30 times of amounts; Insert and grind in the colloid mill evenly; Then active site is dissolved in one times of amount dehydrated alcohol, adds in the colloid mill, ground 30 minutes; Incline and lapping liquid; Filter, filter cake is with a spot of absolute ethanol washing 3 times, vacuum drying or spray drying.
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| CN1554626A (en) * | 2003-12-22 | 2004-12-15 | 复旦大学 | Eudesmane compounds, preparing method and use in preparing medicinal composition |
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| CN1554626A (en) * | 2003-12-22 | 2004-12-15 | 复旦大学 | Eudesmane compounds, preparing method and use in preparing medicinal composition |
Non-Patent Citations (3)
| Title |
|---|
| 杨中铎等: "锦鸡儿属植物化学成分及生物活性研究进展", 《中成药》, vol. 30, no. 11, 30 November 2008 (2008-11-30), pages 1678 - 1681 * |
| 肖岸容: "甘蒙锦鸡儿化学成分研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, no. 11, 30 November 2009 (2009-11-30), pages 057 - 89 * |
| 蒙秋霞: "小叶锦鸡儿黄酮类化合物研究", 《中国优秀博硕士学位论文全文数据库（硕士）农业科技辑》, no. 2, 28 February 2006 (2006-02-28), pages 049 - 41 * |
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