CN100411653C - Chinese medicine composition for treating diabetes mellitus - Google Patents
Chinese medicine composition for treating diabetes mellitus Download PDFInfo
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- CN100411653C CN100411653C CNB2004100911379A CN200410091137A CN100411653C CN 100411653 C CN100411653 C CN 100411653C CN B2004100911379 A CNB2004100911379 A CN B2004100911379A CN 200410091137 A CN200410091137 A CN 200410091137A CN 100411653 C CN100411653 C CN 100411653C
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- radix paeoniae
- paeoniae rubra
- total glycosides
- rubra total
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Abstract
The present invention belongs to the research and development field of a new traditional Chinese medicine, particularly to a traditional Chinese medical composition for treating diabetes. The main component of the traditional Chinese medicine combination contains effective part of radices paeoniae rubra and total glycosides extracted from the radices paeoniae rubra of the traditional Chinese medicine (the main component is peoniflorin). The present invention is provided with a method for preparing the extract of radices paeoniae rubra and total glycosides, and also a preparation form of the traditional Chinese medicine combination. The effective component of radices paeoniae rubra and total glycosides extracted from the traditional Chinese medical composition is used for treating diabetes at the first time, which has good effect and no toxic side effect.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition for the treatment of diabetes, be specifically related to extract the effective ingredient of Radix Paeoniae Rubra total glycosides as this medicine from Chinese medicine Radix Paeoniae Rubra, this medicine produces effect to treatment of diabetes.The present invention also provides a kind of preparation method and the related dose forms and the purposes of this medicine.
Background technology
Diabetes are a kind of common endocrine---metabolic diseases, it distributes all in the whole world, and be the trend that increases gradually, the prevalence of China's diabetes has reached 10.50%, though it is higher than not with developed countries, but it is because populous, had second largest in the world diabetics crowd, be only second to the U.S., and just with per speed increment that doubled in 15 years, China's diabetics is based on the II type, but the many concealments of its morbidity, complication is often more serious, in carbohydrate metabolism disturbance often with lipometabolic disorder and hemorheological unusual, so atherosclerosis and microangiopathies take place in patient easily, early stage lose control or therapeutic effect bad, pathological changes can be involved health multisystem organ, has a strong impact on patient's life-span and life quality, therefore control is sugared, fat metabolic disturbance, what prevent complication is the emphasis for the treatment of diabetes.Therefore, seek effective blood sugar lowering, improve hemorheological medicine and become current urgent research topic.
Diabetes spp is in the traditional Chinese medical science category of " quenching one's thirst ".Theory of Chinese medical science is thought: the morbidity of quenching one's thirst mainly be because natural endowment deficiency, surfeit delicious food savoury, overaction of the five emotions, calentura fire be dry etc. multiple factor cause suffer from a deficiency of the kidney, due to the dryness of the lung, gastric heat.Because diabetic duration is with the passing of time, interior-heat caused by deficiency of YIN, consumption Tianjin liquid that burns is pointed out so the Ming Dynasty cures tame Li Zhongzi, " interior-heat is fried in shallow oil the bright liquid in Tianjin, body fluid deficiency insufficiency of blood and the hematogenous blockage that arrives, blood-vessel obstructive; Obstruction of collaterals by blood stasis, mechanism of qi operation is not smooth ", or disease goes into network for a long time, and the blood vessels stasis of blood stagnates, and causes the generation of all diseases, increases the weight of the state of an illness.Modern study shows, diabetics blood wrinkle microcirculation pathological changes is obvious, capillary basement membrane thickens, the capillary endothelium hypertrophy, cause the blood capillary form be distorted, the deformity, the knotting, antibacterial, Endothelin etc. can form microangioma to microvascular coup injury in addition, and meanwhile blood capillary is coarse, passage is narrow.In diabetic duration, there is tangible hemorheology unusual.The diabetic whole blood viscosity increases, the disorder of lipogenesis metabolic function, and lipoprotein lipase is active low, and free fatty acid and triglyceride concentration increase in the blood, and blood is in hypercoagulability.At middle and late stage, the heart, brain, kidney and limb pathological change often occur and cause complication.Therefore, blood stasis is through onset diabetes important pathogenesis all the time, and using the activating blood and resolving stasis and treating diabetes is one of clinical methods commonly used.
At present the main method of western medical treatment diabetes is insulinize and hypoglycemic drugs such as oral sulphanylureas, biguanides, but insulinize costs an arm and a leg, and other types of drug or curative effect are limited or toxic and side effects is obvious.
In recent years, studies show that in a large number, Chinese medicine demonstrates very big advantage in the clinical treatment of treatment diabetes, but the existing most effective ingredient of Chinese patent medicine is unclear, the mechanism of action is indeterminate, dosage form falls behind, and urgency waits to develop effective ingredient and the mechanism of action is clear, stable and controllable for quality, dosage form is advanced, take form of Chinese drug easy to carry.
The Radix Paeoniae Rubra bitter in the mouth is gone into liver, spleen channel, is apt to away blood system, but both clearing away heat and cooling blood, but blood circulation promoting and blood stasis dispelling again is the activating blood and removing stasis drug of using always.Cure in early days in the nationality, Radix Paeoniae Rubra, the Radix Paeoniae Alba are regardless of, and are referred to as " Radix Paeoniae ".The Radix Paeoniae beginning is stated from Shennong's Herbal: " the Radix Paeoniae bitter in the mouth is flat, and main pathogen stomachache is removed arthralgia due to stagnation of blood, and is broken hard long-pending, cold and heat hernia abdominal mass, pain relieving, diuresis, QI invigorating ".From the TAO Hong-Jing beginning branch red, the Radix Paeoniae Alba is arranged.Radix Paeoniae Rubra is as the Chinese medicine of clearing away heat and cooling blood, blood circulation promoting and blood stasis dispelling, ancient Chinese medicine doctor whenever has application in the treatment of diabetes, as " Radix Aucklandiae soup ", Song in peaceful " Shengji Zonglu ". " Corticis Lycii Radicis Powder ", gold in the money second " the medicine card is straight determines ". the Herba Sidae Rhombifoliae soup in Liu's interchannel " the interchannel six scripts " adds Radix Paeoniae Rubra, and treating the equal compatibility of quenching one's thirst has Radix Paeoniae Rubra.In the modern treatment of diabetes, Zhu Chen gives the old docter of TCM with " blood sugar lowering blood circulation promoting recipe " (Radix Angelicae Sinensis, the Radix Aucklandiae, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Herba Leonuri) treatment diabetes, has obtained comparatively satisfied curative effect.Lin Shi uses " supplementing QI and nourishing YIN blood circulation promoting and blood stasis dispelling soup " (Radix Paeoniae Rubra, the Rhizoma Anemarrhenae, the Radix Rehmanniae, Radix Astragali Preparata, Herba Leonuri etc.) treatment diabetes 30 examples, Li Shi uses " blood circulation promoting and blood stasis dispelling soup " (Radix Paeoniae Rubra, Rhizoma Chuanxiong, Flos Carthami, Radix Angelicae Sinensis etc.) treatment diabetes 50 examples and all obtained comparatively satisfied curative effect.
Yet there are no the report of the effective site extracted in the relevant Radix Paeoniae Rubra material and effective ingredient treatment diabetes.
Radix Paeoniae Rubra total glycosides is the water soluble ingredient of Radix Paeoniae Rubra medical material, it is documented, the main paeoniflorin (Paeoniflorin) that contains in the Radix Paeoniae Rubra root, oxypaeoniflorin (Oxpaeoniflorin), peony lactone glycoside (albiflorin), benzoylpaeoniflorin (benzoylpaeoniflorin), disappointing basic paeoniflorin (oxypaeoniflorin), paeonol (paeonl), the former glycoside of paeonol (paeonolide), paeonol glycoside (paeoniside), paeoniflorin (paeonin), paeoniflorin unit (paeoniflorgenone) Galla Turcica (Galla Helepensis) acyl paeoniflorin (galloylpaeoniflorin), Lactiflorin. (lactiflorin), (Z)-(1S, 5R)-nopinene-10 bases-β-vicianoside [(Z) (1S, 5R)-β-pinen-10-y1-β-vicianoside].The preparation method of traditional Radix Paeoniae Rubra total glycosides of bibliographical information has water extraction, alcohol extracting method, decoction and alcohol sedimentation technique, because the complicated component of Radix Paeoniae Rubra medical material, contain non-glycoside composition, thus traditional method for making obtain shortcomings such as Radix Paeoniae Rubra total glycosides content is lower, impurity is high, quality is uncontrollable are arranged.Also have report to extract Radix Paeoniae Rubra total glycosides (referring to Chinese patent medicine, 1999,21 (12)) by macroreticular resin absorbing method, this method adopts 70% ethanol extraction, and after alcohol extract concentrated, reuse water dissolution upper prop adopted 20% ethanol elution.
Summary of the invention
The object of the present invention is to provide a kind of Chinese medicine composition for the treatment of diabetes, effective ingredient wherein is from the Radix Paeoniae Rubra total glycosides extract in the Chinese medicine Radix Paeoniae Rubra.
Having the present invention further provides with described Radix Paeoniae Rubra total glycosides extract is active component, is used for the treatment of the pure Chinese medicine pharmaceutical preparation and the related dose forms of diabetes.
Another object of the present invention is to be provided for to treat the preparation method of preparation method, particularly Radix Paeoniae Rubra total glycosides of this pure Chinese medicine medicine of diabetes.
Medical material of the present invention is for being the dry root of cohosh Radix Paeoniae Rubra (Paeonia lactiflora pall.).Summer, two season of autumn, bar dug, and removed rhizome, fibrous root and silt, dried.The Radix Paeoniae that Chinese Pharmacopoeia version in 2000 is recorded has two kinds: Radix Paeoniae (Paeonia lactiflora pall.), river Radix Paeoniae Rubra (Paeonia veitchii Lynch).Generally be born in patana and sylvan life, be distributed in northeast, North China, Shaanxi and Gansu, there is cultivation in each city and villages and small towns more.Radix Paeoniae Rubra is perennial herb, and main morphological characteristic is the former cylindricality of rhizome, and is crooked slightly, the leaf alternate, and the lower portion of the stem leaf is two times trifoliolate leaves, lobule ellipse, edge have the sclerotin serration.Spend greatly diameter 5.5-10cm, sepal 4, wide oval or subcircular; Petal white, pink or red, base portion tool darkviolet speckle sometimes.Gathering and processing this medical material of commonly using is root, cleans, and is cut into medical material.
Pulverize medical material before extracting, require by the 20-40 mesh sieve usually, being beneficial to wherein, effective ingredient is fully extracted.Consider peoniflorin (C in the Radix Paeoniae Rubra medical material that the present invention selects for use from the production angle
20H
18NO
4HCL) content should be not less than 1.8%.
Radix Paeoniae Rubra total glycosides extract provided by the invention can obtain by the following method:
Get the Radix Paeoniae Rubra medical material, be ground into coarse powder, extract three times each 1 hour with 50～70% alcoholic solution of 8～10 times of volume medical material weight.With alcohol extract decompression recycling ethanol to relative density is the concentrated solution of 1.08 (60 ℃), adding 1～5 times of water to crude drug weight stirs evenly, filter, filtrate is crossed the saponin adsorption resin column, wash remove impurity earlier with water, reuse 10～30% ethanol elutions, eluent are through the concentrating under reduced pressure drying, pulverize the Radix Paeoniae Rubra total glycosides extract.
According to the embodiment of comparative optimization of the present invention, the method for extracting the Radix Paeoniae Rubra total glycosides extract comprises the steps:
(1) with 70% alcohol reflux Radix Paeoniae Rubra crude drug 3 times, each 1 hour, filter ethanol extract;
This ethanol extract of concentrating under reduced pressure to relative density below (2) 60 ℃ is the thick paste of 1.08 (60 ℃ of mensuration);
(3) with above-mentioned thick paste with 2 times of dissolved in distilled water to crude drug weight, filter, filtrate is by the saponin resin column;
(4) remove partial impurities with the water elution of 10 times of resin volumes;
(5) Radix Paeoniae Rubra total glycosides that is adsorbed is 1.0mL/cm with 20% ethanol elution of 6 times of medical material weight, elution speed
2.min, get ethanol elution;
(6) ethanol elution is through concentrating under reduced pressure, and vacuum drying gets the Radix Paeoniae Rubra total glycosides extract.
The method for preparing the Radix Paeoniae Rubra total glycosides extract of above-mentioned employing is characterized in that used resin is the saponin resin, and further its resin model is ZTC-1.
In the said extracted step, concentration of ethanol is preferably 70%, can extract with the ethanol more than 50%, but from producing and the consideration of cost angle, the preferential ethanol of about 70% concentration that uses carries out the extraction of raw material, extracting method is for refluxing, or other feasible mode of operation, should keep bigger ratio between ethanol and the crude drug, complete with what guarantee to extract, can use about 8-10 alcoholic solution doubly of raw material weight to reflux (general reflux, extract, 3 times), available percolation and circumfluence method, the preferred employing refluxed.
Solvent method is generally adopted in the extraction of Radix Paeoniae Rubra total glycosides, common " glycoside composition " soluble in water and alcohols solvent, and water and alcohol are solvents cheap and easy to get, so at first consider to extract solvent with them.Because more with the impurity that hot water extraction goes out, therefore, we adopt ethanol is to extract solvent, extracts Radix Paeoniae Rubra total glycosides with circumfluence method.In order to investigate the factor that influences extraction ratio comprehensively, intend adopting four factors, the experiment of three horizontal quadratures, by to consumption of ethanol in the medicinal material extract process (A factor), the optimum condition of extraction process is determined in the investigation of extraction time (B factor) and extraction time (C factor).The result shows that extraction time has the greatest impact to must measuring of Radix Paeoniae Alba total glycosides in the extract, so extraction process is defined as each 70% ethanol with 8 times of amounts, heating and refluxing extraction 3 times, each 1 hour; Contain a large amount of oil-soluble impuritieses in the alcohol extract, so before chromatographic column on the extracting solution, will carry out remove impurity.Because peoniflorin is water-soluble, the insoluble method of oil-soluble impurities is removed oil-soluble impurities so adopt the water dissolution peoniflorin, and investigate amount of water to producing the sedimentary situation that influences, being defined as extracting solution is concentrated into relative density is 1.08, add 1～5 times of medical material volume distilled water and filter, removing insoluble matter (oil-soluble impurities), wherein to add the distilled water effect of 4 times of medical material volumes better.
The adsorption capacity of saponin resin has certain limit.Necessarily can not surpass its adsorption capacity so add sample size, otherwise a part of composition will spill and lose.Generation for fear of this phenomenon, we measure the carrying capacity of saponin absorption peoniflorin, take by weighing the saponin resin 200g chromatographic column of packing into, make medicinal liquid slowly by chromatographic column,, saponin is rinsed well (no peoniflorin outflow with deionized water up to the saponin supersaturation, till reuse 95% alcohol flushing to effluent does not have peoniflorin, alcohol washing liquid concentrate drying is measured peoniflorin weight, and the carrying capacity of peoniflorin is as a result: 40g medical material/100g saponin (1.44 peoniflorins/100 saponin).Used resin demand is generally 2.5 times～4 times of medical material weight, and preferable amount is 3.75 times.
The flow velocity of liquid was investigated when we also filtered the saponin resin column to medicinal liquid, get the Radix Paeoniae Rubra extract aqueous solution 490mL (promptly being equivalent to the 200g medical material) of remove impurity, totally 3 parts, cross 3 saponin resin columns of having handled well (internal diameter * saponin height: 55*300mm) respectively, the medicinal liquid consumption is equivalent to 70% of saponin adsorption capacity, regulate the speed of effluent, and whether containing the peoniflorin constituents in the inspection effluent, the flow velocity of liquid is that scope is: 0.1～0.5mL/cm when experimental result can be determined to go up sample
2.min, optimum flow rate is 0.2mL/cm
2.min.Can avoid the loss of sample like this, guarantee the stability of technology.
In order to investigate the optimum condition of desorbing peoniflorin from the saponin, select eluant strength, eluant consumption, three factors of effluent speed, each factor is respectively got three levels, adopts L
9(3
4) orthogonal table tests, the preferred for preparation technology of Radix Paeoniae Rubra total glycosides is defined as: add 8 times of amount 70% ethanol, reflux, extract, 3 times, each 1 hour; Extract is crossed the saponin resin column, makes eluant with 6 times of resin volume 20% ethanol, with 1.0mL/cm
2.min speed eluting.
Carry out isolation identification by the Radix Paeoniae Rubra total glycosides that said method is made, obtain following 4 kinds of chemical compounds, see the following form:
Chemical constituent in the Radix Paeoniae Rubra total glycosides
By the Radix Paeoniae Rubra total glycosides extract that said method makes, average yield will be higher than 5.4%, and the mean transferred rate of peoniflorin is higher than 87.53%, and wherein content of paeoniflorin is greater than 50%.
The present invention improves the preparation method of Radix Paeoniae Rubra total glycosides.Compared with prior art (referring to Chinese patent medicine, 1999,21 (12)) the invention discloses and adopt the saponin resin to extract Radix Paeoniae Rubra total glycosides, and the average yield of extract will be higher than above-mentioned prior art, and the mean transferred rate of peoniflorin is higher than 87.53%.With prior art (referring to: number of patent application is 03113126.3) compare, the concentration of alcohol that the present invention adopts is lower, thereby consumption is less, has reduced production cost, has saved energy consumption, and very is fit to suitability for industrialized production.The blood sugar lowering drug effect experiment showed, that the Radix Paeoniae Rubra total glycosides extract good effect, the toxic and side effects that make by this law extraction are little.
The Chinese medicine composition of treatment diabetes provided by the invention, it contains the Radix Paeoniae Rubra total glycosides extract that adopts above-mentioned preparation method gained, comprised Radix Paeoniae Rubra total glycosides in the composition of this extract, main active wherein is a peoniflorin, from the pharmacodynamics angle, be used for the treatment of the Chinese medicine composition of diabetes as the present invention, the content of paeoniflorin in the described Radix Paeoniae Rubra total glycosides is more than 50%.
On this basis, the present invention has has also researched and proposed a kind of pure Chinese medicine pharmaceutical preparation for the treatment of diabetes, and this Chinese medicine medicine is the effective active composition with above-mentioned Radix Paeoniae Rubra total glycosides, and has comprised acceptable auxiliary component on the pharmaceutics.The present invention also provides a kind of preparation method of this pure Chinese medicine pharmaceutical preparation, and it comprises: be raw material with Radix Paeoniae Rubra, use ethanol extraction, and purified separation produces Radix Paeoniae Rubra total glycosides, make in the Radix Paeoniae Rubra total glycosides content of paeoniflorin more than 50%; With this Radix Paeoniae Rubra total glycosides is effective ingredient, is prepared into the pharmaceutical preparation of requirement according to practice of pharmacy.
Pharmaceutical preparation of the present invention comprises injection and oral agents; wherein oral agents comprises capsule, oral liquid, tablet, granule etc.; particularly capsule requires the content of the Radix Paeoniae Alba total glycosides in the Radix Paeoniae Rubra total glycosides extract more than 55%; paeoniflorin content is more than 50%, and it is 10～100mg that every or sheet contain the Radix Paeoniae Rubra total glycosides extract.When the preparation oral formulations, it is characterized in that the auxiliary type agent of selecting for use can be conventional fillers such as starch, dextrin or cyclodextrin, sucrose, stearate.Injection type comprises injection and freeze-dried powder.When the preparation injection type, the content that requires the Radix Paeoniae Alba total glycosides in the described Radix Paeoniae Rubra total glycosides extract is more than 80%, and containing the Radix Paeoniae Rubra total glycosides extract is 1～5mg/mL, and the amount of peoniflorin is not less than 50%.Lyophilized injectable powder can prepare by methods such as aseptic spray drying, low-temperature vacuum drying, lyophilizations.Each preparation later stage preparation technology and equipment all belong to the routine techniques of pharmaceutical field, the present invention does not limit this, so will not describe in detail at this.
For guaranteeing the quality of medicine, need in process of production the active constituent content in the final extract is detected at any time.The method that is used to detect described glycosides compound can be by any feasible detection means and known method, and the present invention has proposed the feasible detection method of a cover at this.
At first, by efficient liquid phase chromatographic analysis,, proved that containing with the peoniflorin is the Radix Paeoniae Rubra total glycosides of main component in extract with the contrast of peoniflorin standard substance spectrogram.Therefore, we adopt the high performance liquid chromatogram external standard method, detect the paeoniflorin content of controlling in the Radix Paeoniae Rubra extract by standard curve, prove through actual detected, and the favorable reproducibility of testing result, highly sensitive.Should be noted that this method only on the quality control method as product of the present invention, should not get rid of other any method that meets the demands and operation.Particularly peoniflorin extraction ratio assay is easy to realize for those skilled in the art, can record by the HPLC external standard method, therefore is fit to very much the industrialized great production requirement.The HPLC assay method of peoniflorin is as follows in the Radix Paeoniae Rubra total glycosides extract:
The HPLC condition:
Immobile phase: octadecylsilane chemically bonded silica 250 * 4.6mm 5um
Mobile phase: acetonitrile-0.02mol/L sodium dihydrogen phosphate (20: 80)
Detect wavelength: 230nm
Flow velocity: 1mL/ minute
Column temperature: room temperature
Sample size: 10ul
1, standard curve
Precision takes by weighing 36 hours peoniflorin reference substance 11.16mg of drying under reduced pressure in the phosphorus pentoxide vacuum drying apparatus, put in the 10mL measuring bottle, the methanol ultrasonic dissolution also is settled to scale, shake up, therefrom accurate absorption 0.2,0.4,0.6,0.8,1.0mL split in the 10mL measuring bottle, methanol is diluted to scale, shake up, the therefrom accurate respectively 10u of absorption l injects high performance liquid chromatograph, measures by above-mentioned chromatographic condition.With peoniflorin amount (ug) is abscissa, and peak area is the vertical coordinate mapping, the drawing standard curve.See accompanying drawing 1.
The standard curve determination data are as follows:
| Numbering | Peoniflorin amount (ug) | |
| 1 | 0.4592 | 565516 |
| 2 | 0.9184 | 1171490 |
| 3 | 1.3776 | 1783885 |
| 4 | 1.8368 | 2344300 |
| 5 | 2.2960 | 2895713 |
Regression equation is y=1E+06x+2219.6 R
2=0.9994
Peoniflorin is good in 0.4592～2.2960ug scope internal linear.
2, the mensuration of peoniflorin in the Radix Paeoniae Rubra total glycosides extract
The preparation precision of reference substance solution takes by weighing 36 hours peoniflorin reference substance 5mg of drying under reduced pressure in the phosphorus pentoxide vacuum drying apparatus, put in the 10mL measuring bottle, the methanol ultrasonic dissolution also is settled to scale, shake up, the therefrom accurate 1.0mL that draws puts in the 10mL measuring bottle, and methanol is diluted to scale, shake up, promptly.
Radix Paeoniae Rubra total glycosides 25mg is got in the preparation of need testing solution, and accurate the title decides, and puts in the 25mL measuring bottle, and the methanol ultrasonic dissolution is also decided to shake up to scale, and the therefrom accurate 1.0mL that draws puts in the 10mL measuring bottle, and methanol is diluted to scale, shakes up, promptly.
Accurate reference substance solution, each 10ul of need testing solution of drawing of algoscopy injects chromatograph of liquid, measures, promptly.
This product contains peoniflorin (C
23H
28O
11), must not be less than 50.0%.
Effective site Radix Paeoniae Rubra total glycosides of the present invention especially has good curative effect for the blood stasis type diabetes by the effect that the serial experiment proof has the treatment diabetes.For ease of understanding the present composition at the medical value aspect treatment and the prevent diabetes, the inventor uses Radix Paeoniae Rubra total glycosides extract that the above method makes and related dose forms to comprise that capsule medicament and injection finished the following pharmacology and the test of pesticide effectiveness.
The present invention has carried out the general pharmacology experiment of Radix Paeoniae Rubra total glycosides, comprises spontaneous activity in mice and other systematic influence; To the neural influence of mice (pentobarbital sodium sub-threshold dose hypnosis experiment); To anesthetized cat breathing, blood pressure, cardiac electrical influence experiment.Experimental result shows: give mouse stomach Radix Paeoniae Rubra total glycosides (200mg/kg, 400mg/kg and 800mg/kg), mice is probed into and influence is not seen by spontaneous activity, nervous system and other system; Anesthetized cat after duodenum gives Radix Paeoniae Rubra total glycosides (60mg/kg, 120mg/kg, 240mg/kg), is not seen that to its blood pressure, ECG, heart rate, the rhythm of the heart, respiratory frequency and respiratory depth are influential yet.
The present invention has also carried out the anxious poison experiment of Radix Paeoniae Rubra total glycosides.Radix Paeoniae Rubra total glycosides is irritated the stomach Kunming mouse and is measured LD with the Bliss method
50Be 10.50 ± 0.02 (g/kg), 95% credible 9.50～11.63 (g/kg) that are limited to, the internal organs that become celestial are not seen obvious pathological changes.
The present invention has also carried out the long poison experiment of Radix Paeoniae Rubra total glycosides, comprising:
(1) Radix Paeoniae Rubra total glycosides is irritated stomach rat long term toxicity test: Radix Paeoniae Rubra total glycosides little (600mg/kg), in (1400mg/kg), big (3200mg/kg) three dosage irritate stomach (ig) Wistar rat respectively, every day 1 time, 6 times weekly, in continuous 26 weeks, continue after the drug withdrawal to observe for 4 weeks.Body weight and food ration (recovery voluntarily before the drug withdrawal) administration appearance in mid-term reduces except that heavy dose of group, the ordinary circumstance of each administration group, food ration, body weight, urine analysis of blood, hematological indices, blood parameters, organ weights, organ coefficient, system become celestial and histopathologic examination, with matched group relatively there are no significant difference, do not see the overt toxicity reaction.
(2) the oral Radix Paeoniae Rubra total glycosides long term toxicity test of Beagle dog: the oral Radix Paeoniae Rubra total glycosides of Beagle dog three kinds of dosage 200mg/kg, 450mg/kg, 1000mg/kg, every day 1 time, 6 days weekly, in 39 weeks of successive administration, drug withdrawal observed for 9 weeks.The body weight of the big or middle dosage treated animal of Radix Paeoniae Rubra total glycosides lowered to some extent in administration 17-26 week, and heavy dose of group relatively has significant difference with matched group, in, small dose group body weight unknown significance difference.The ordinary circumstance of 3 dosage treated animals between whole administration and withdrawal time, electrocardiogram detect, every hematology and serum biochemistry index, urine analysis of blood, system become celestial, organ coefficient, histopathologic examination, with the relatively equal not statistically significant of matched group.
Above-mentioned general pharmacology and toxicity result show that the toxicity of Radix Paeoniae Rubra total glycosides is less.
The effect experiment that the present invention carries out comprises:
One, Radix Paeoniae Rubra total glycosides is to the influence of streptozotocin diabetes model rat blood sugar
This experiment causes diabetes model by giving rats by intraperitoneal injection streptozotocin 80mg/kg, irritate the stomach Radix Paeoniae Rubra total glycosides little, in, heavy dose of 40mg/kg, 80mg/kg, 160mg/kg, every day 1 time, continuous 12 days, observe the influence of Radix Paeoniae Rubra total glycosides to the 3rd, 7,12 days blood glucose of streptozotocin diabetes model rat administration.The results are shown in Table 1 and Fig. 2:
Table 1 Radix Paeoniae Rubra total glycosides causes the influence (X ± SD) of diabetes model rat blood sugar to streptozotocin
Annotate: 1. compare with the normal control group
△ △ △* p＜0.05, * * p＜0.01 are compared with model control group in p＜0.001; 2.n for irritating the 12nd day number of animals of stomach.
By table 1 as seen, learn by statistics and handle, model control group and normal control group relatively have significant difference (P＜0.001); The 3rd, 7,12 days each dosage groups of Radix Paeoniae Rubra total glycosides of administration all can obviously reduce streptozotocin and cause the diabetes model rat blood sugar, and certain dose-effect relationship is arranged, and compare with model control group, and significant difference (all P＜0.05 or P＜0.01) is arranged; Positive controls can obviously reduce streptozotocin and cause the diabetes model rat blood sugar, compares with model control group, and significant difference (all P＜0.05 or P＜0.01) is arranged.The result shows: three dosage groups of Radix Paeoniae Rubra total glycosides all can obviously reduce the blood glucose that streptozotocin causes diabetes rat.
Two, Radix Paeoniae Rubra total glycosides is to the influence of streptozotocin diabetic mice blood glucose
This experiment is by causing diabetes model to mouse peritoneal injection streptozotocin 200mg/kg, irritate the stomach Radix Paeoniae Rubra total glycosides little, in, heavy dose of 50mg/kg, 100mg/kg, 200mg/kg, every day 1 time, continuous 12 days, observe the influence of Radix Paeoniae Rubra total glycosides to the 3rd, 7,12 days blood glucose of streptozotocin diabetic mice administration.The results are shown in Table 2 and Fig. 3:
Table 2 Radix Paeoniae Rubra total glycosides is to the influence of streptozotocin diabetic mice blood glucose (X ± SD)
Annotate: 1. compare with the normal control group
△ △ △* p＜0.05, * * p＜0.01, * * * p＜0.001 are compared with model control group in p＜0.001; 2.n for irritating the 12nd day number of animals of stomach.
By table 2 as seen, learn by statistics and handle, model control group and normal control group relatively have significant difference (P＜0.001); The 3rd, 7,12 days each dosage groups of Radix Paeoniae Rubra total glycosides of administration all can obviously reduce streptozotocin and cause diabetic mice blood glucose, dosage is big more, blood sugar lowering is obvious more, compares with model control group, and significant difference (all P＜0.05, P＜0.01 or P＜0.001) is arranged; Positive controls can obviously reduce streptozotocin and cause diabetic mice blood glucose, compares with model control group, and significant difference (all P＜0.05 or P＜0.01) is arranged.The result shows: three dosage groups of Radix Paeoniae Rubra total glycosides all can obviously reduce the blood glucose that streptozotocin causes diabetic mice.
Three, Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes rat model blood glucose
This experiment is passed through to rats by intraperitoneal injection alloxan 190mg/kg, cause diabetes animal model, irritate the stomach Radix Paeoniae Rubra total glycosides little, in, heavy dose of 40mg/kg, 80mg/kg, 160mg/kg, every day 1 time, continuous 12 days, observe the influence of Radix Paeoniae Rubra total glycosides to the 3rd, 7,12 days blood glucose of alloxan diabetes rat model administration.The results are shown in Table 3 and Fig. 4:
Table 3 Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes rat model blood glucose (X ± SD)
Annotate: 1. compare with the normal control group
△ △ △* P＜0.05 is compared in p＜0.001 with model control group, * * P＜0.01, * * * P＜0.001; 2.n for irritating 12 days animal numbers of elements of stomach.
By table 3 as seen, learn by statistics and handle, model control group and normal control group relatively have significant difference (P＜0.001); The 3rd, 7,12 days each dosage groups of Radix Paeoniae Rubra total glycosides of administration all can obviously reduce alloxan and cause the diabetes model rat blood sugar, and certain dose-effect relationship is arranged, and compare with model control group, and significant difference (all P＜0.05, P＜0.01 or P＜0.001) is arranged; Positive controls can obviously reduce alloxan and cause the diabetes model rat blood sugar, compares with model control group, and significant difference (all P＜0.05 or P＜0.01) is arranged.The result shows: three dosage groups of Radix Paeoniae Rubra total glycosides all can obviously reduce the blood glucose that alloxan causes diabetes rat.
Four, Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes model mice blood glucose
This experiment is by injecting alloxan 100mg/kg to mouse peritoneal, cause the diabetic mice model, irritate the stomach Radix Paeoniae Rubra total glycosides little, in, heavy dose of 50mg/kg, 100mg/kg, 200mg/kg, every day 1 time, continuous 12 days, measure the blood glucose value of the 3rd, 7,12 days mices of administration, observe the therapeutical effect of Radix Paeoniae Rubra total glycosides the alloxan diabetes mice.The results are shown in Table 4 and Fig. 5:
Table 4 Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes model mice blood glucose (X ± SD)
Annotate: 1. compare with the normal control group
△ △ △P＜0.001; Compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001; 2.n for irritating 12 days animal numbers of elements of stomach.
By table 4 as seen, learn by statistics and handle, model control group and normal control group relatively have significant difference (P＜0.001); The 3rd, 7,12 days each dosage groups of Radix Paeoniae Rubra total glycosides of administration all can obviously reduce alloxan and cause diabetic mice blood glucose, and certain dose-effect relationship is arranged, and compare with model control group, and significant difference (all P＜0.05, P＜0.01 or P＜0.001) is arranged; Positive controls can obviously reduce alloxan and cause diabetic mice blood glucose, compares with model control group, and significant difference (equal P＜0.05, P＜0.01 or P＜0.001) is arranged.
The result shows: three dosage groups of Radix Paeoniae Rubra total glycosides all can obviously reduce the blood glucose of alloxan diabetes mice.
Five, Radix Paeoniae Rubra total glycosides is to the influence of insulin resistant model rat insulin sensitivity
This experiment is by giving the rat high fat diet 4 weeks, cause Insulin Resistance Animal Model, modeling press simultaneously Radix Paeoniae Rubra total glycosides little, in, heavy dose of 40mg/kg, 80mg/kg, 160mg/kg gastric infusion, every day 1 time, in continuous 4 weeks, observe Radix Paeoniae Rubra total glycosides to insulin resistance rat fasting glucose, the influence of serum insulin levels, serum cholesterol (T-CHO), serum levels of triglyceride (TG), serum low-density LP cholesterol (LDL), insulin sensitivity on an empty stomach.The result is as follows:
One, ordinary circumstance:
Table 5 Radix Paeoniae Rubra total glycosides is to the influence of insulin resistance rat body weight (X ± SD)
Annotate: compare with the normal control group
△P＜0.05; Compare * P＜0.05 with model control group.
As seen from the above table, administration 2 week back model group the weight of animals compared with normal group and Radix Paeoniae Rubra total glycosides small dose group to a certain degree and raise (P＜0.05), 3 week each group of back with model control group relatively there are no significant difference.
Two, Radix Paeoniae Rubra total glycosides the results are shown in Table 6 to the influence of insulin resistance rat fasting glucose and serum insulin levels:
Table 6 Radix Paeoniae Rubra total glycosides is to the influence of insulin resistance rat fasting glucose and serum insulin levels (X ± SD)
Annotate: compare with the normal control group
△P＜0.05,
△ △ △P＜0.001; Compare * P＜0.05, * * P＜0.01 or * * * P＜0.001 with model control group.
As seen from the above table, model group animal fasting glucose is apparently higher than intact animal's blood glucose (P＜0.001), positive controls, each administration treated animal blood glucose value of Radix Paeoniae Rubra total glycosides obviously reduce, with model control group significant difference (P＜0.01 or P＜0.001) is arranged more all, model group serum insulin levels and normal control group relatively have obvious rising (P＜0.05), the heavy dose of group of positive controls and Radix Paeoniae Rubra total glycosides serum insulin levels descends to some extent, with model control group significant difference (P＜0.05 or P＜0.01) is arranged relatively.
Three, Radix Paeoniae Rubra total glycosides the results are shown in Table 7 to insulin resistance rat serum T-CHO, TG, LDL level affects:
Table 7 Radix Paeoniae Rubra total glycosides is to the influence of insulin resistance rat blood fat (X ± SD)
Annotate: compare with the normal control group
△ △ △P＜0.001; Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group.
As seen from the above table, model control group serum T-CHO and LDL level obviously raise, with the normal control group significant difference (P＜0.001) is arranged relatively, positive controls, Radix Paeoniae Rubra total glycosides each dosage group serum T-CHO, TG, LDL level obviously reduce, with model control group significant difference (P＜0.05, P＜0.01 or P＜0.001) is arranged more all.
Four, Radix Paeoniae Rubra total glycosides the results are shown in Table 8 to the influence of insulin resistance rat insulin sensitivity:
Table 8 Radix Paeoniae Rubra total glycosides is to the influence of insulin resistance rat insulin sensitivity (X ± SD)
Annotate: compare with the normal control group
△ △P＜0.01,
△ △ △P＜0.001; Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group
As seen from the above table, model control group blood glucose after giving glucose obviously raises, and same time point and normal control group relatively have significant difference (P＜0.01 or P＜0.001); Be starkly lower than model control group to positive controls, each dosage group blood glucose of Radix Paeoniae Rubra total glycosides behind the glucose, with model control group significant difference (P＜0.05 or P＜0.01) arranged more all, the insulin resistance rat carbohydrate tolerance is strengthened; Show that Radix Paeoniae Rubra total glycosides has the effect that similar increase insulin sensitivity is arranged to phenformin hydrochloride.
The result shows: Radix Paeoniae Rubra total glycosides can obviously reduce the insulin resistance rat animal fasting glucose that high fat diet is brought out, reduce T-CHO, TG, LDL, increase the sensitivity of insulin resistance rat to insulin, wherein the heavy dose of group of Radix Paeoniae Rubra can reduce serum insulin levels on an empty stomach.
This shows that Radix Paeoniae Rubra total glycosides can obviously reduce the blood sugar level of diabetes model rat and mice due to streptozotocin or the alloxan; And can improve the mice carbohydrate tolerance; Increase the sensitivity of insulin resistance rat to insulin.
Creativeness of the present invention is that extraction separation has gone out Radix Paeoniae Rubra total glycosides as the application of effective ingredient in preparation treatment and prevent diabetes medicine from Radix Paeoniae Rubra Chinese medicine, and further this extract is prepared into the Chinese medicine preparation that is used for the treatment of diabetes as effective ingredient.As previously described, the effect composition that medicine provided by the invention has is the Radix Paeoniae Rubra total glycosides that comprises peoniflorin, for reaching goal of the invention, and should be to peoniflorin extraction ratio in the crude drug more than 50%.Pharmaceutical composition of the present invention has following outstanding feature: (1) high-efficiency low-toxicity; (2) effective ingredient is clear and definite, and is quality controllable; (3) plant material is cheap and easy to get; (4) indication is wide, and market capacity is big; (5) with low cost, technology is easy, is easy to industrialization.
Description of drawings
The standard curve of Fig. 1 peoniflorin reference substance
Vertical coordinate: peak area; Abscissa: peoniflorin amount (ug)
Fig. 2 Radix Paeoniae Rubra total glycosides is to the influence of streptozotocin diabetes model rat blood sugar
Fig. 3 Radix Paeoniae Rubra total glycosides is to the influence of streptozotocin diabetic mice blood glucose
Fig. 4 Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes rat model blood glucose
Fig. 5 Radix Paeoniae Rubra total glycosides is to the influence of alloxan diabetes model mice blood glucose
In Fig. 2,3,4,5:
Vertical coordinate: blood glucose value (mmol/L); Abscissa: the time (my god); A: normal control group; B: model control group; C: positive controls; D: Radix Paeoniae Rubra total glycosides small dose group; E: dosage group in the Radix Paeoniae Rubra total glycosides; F: the heavy dose of group of Radix Paeoniae Rubra total glycosides
Specific embodiment
The present invention is further elaborated with following embodiment, but the present invention is not limited to the content that the following example comprises.
The preferred for preparation method of [embodiment 1] Radix Paeoniae Rubra total glycosides
Get Radix Paeoniae Rubra medical material 200g (the peoniflorin content of monomer is 3.61%), be ground into coarse powder,, each 1 hour, add 8 times of amounts of medical material bulking value at every turn with 70% alcohol reflux three times.With alcohol extract decompression recycling ethanol to relative density is the concentrated solution of 1.08 (60 ℃), adds 2 times of water to crude drug weight and stirs evenly, and filters, and filtrate is with 0.2mL/cm
2.min by ZTC-1 saponin adsorption resin column (resin ratio of height to diameter 8: 1, resin demand are 3.75 times of medical material weight), earlier with the washing of 10 times of resin volumes, 6 times of reuse to 20% ethanol of weight resin with 1mL/cm
2.min speed eluting, alcohol eluen be through concentrating under reduced pressure, drying under reduced pressure, pulverize Radix Paeoniae Rubra total glycosides extract 11.36g, yield is 5.7%, peoniflorin 6.46g, the peoniflorin rate of transform is 89.47%.
The preferred for preparation method of [embodiment 2] Radix Paeoniae Rubra total glycosides
Get Radix Paeoniae Rubra medical material 120kg (the peoniflorin content of monomer is 3.61%),, extracted 1 hour at every turn with the alcohol reflux of the solvent 70% of 8 times of amounts (v/w) 3 times.The extracting solution concentrating under reduced pressure gets ethanol extract (60 ℃ time relative density 1.08).Add 2 times of water to medical material weight and make the extractum dissolving, filter, filtrate is slowly by Saponin resin column (weight of Saponin resin is 3.75 times of medical material), and the control flow velocity is
Logical finishing, with 8 times of water to the Saponin weight resin, remaining impurities in the flush away post is then with 6 times of 20% alcohol desorptions to Saponin resin volume.Collect stripping liquid, concentrating under reduced pressure and drying under reduced pressure promptly get Radix Paeoniae Rubra total glycosides extract 6.53kg, and yield is 5.44%, get peoniflorin 3.86kg, and the peoniflorin rate of transform is 89.10%.
The preparation method of [embodiment 3] preferred dosage form capsule of the present invention
Get the Radix Paeoniae Rubra total glycosides extract 100g that above-mentioned drying (60 ℃) handled and grind, cross 80 mesh sieves.The starch 98g and the magnesium stearate 2g that added 80 mesh sieves, mix homogeneously is sub-packed in 1000 3# capsules (every of 200mg/), aluminium plastic composite packaging, that is, the every capsules of this product contains peoniflorin (C
23H
28O
11), should be less than 50.0mg.Oral, one time 2, every day three times.
The preparation method of [embodiment 4] preferred dosage form Radix Paeoniae Rubra total glycosides tablet of the present invention
Get the Radix Paeoniae Rubra total glycosides extract 100g that above-mentioned drying (60 ℃) handled and grind, cross 80 mesh sieves, added the starch 98g and the magnesium stearate 2g of 80 mesh sieves, mix homogeneously, be pressed into 1000 (every of 200mg/) after the drying, that is, every tablet of this product contains peoniflorin (C
23H
28O
11), should be less than 50.0mg.Oral, one time 2, every day three times.
The preparation method of [embodiment 5] preferred dosage form Radix Paeoniae Rubra total glycosides injection of the present invention
Get above-mentioned Radix Paeoniae Rubra total glycosides extract 6.0g, add the about 2800mL of water for injection, 65 ℃ of water-baths make dissolving, add total amount of preparation 2.0 ‰ active carbons (6.0g), stir half an hour, filter, add water to 3000mL on filter, continue with 0.45 μ m, 0.22 μ m microporous filter membrane classified filtering, filtrate is sub-packed in quantitatively with every bottle of 10mL that (10mL/ props up in the cillin bottle, 2mg/mL), lyophilization recharges high-purity nitrogen, jump a queue, roll lid, packing, promptly.Usage and consumption: every day 1 time, each 20～40mg intravenous injection.
Claims (14)
1. Radix Paeoniae Rubra total glycosides compositions for the treatment of diabetes is characterized in that obtaining by the following method:
Get the Radix Paeoniae Rubra medical material, be ground into coarse powder, extract three times with 50～70% alcoholic solution of 8～10 times of volume medical material weight, relative density is 1.08 concentrated solution during with alcohol extract decompression recycling ethanol to 60 ℃, adding 1～5 times of water to crude drug weight stirs evenly, filter, filtrate is crossed ZTC-1 Saponin adsorption resin column, washes remove impurity earlier with water, reuse 10～30% ethanol elutions, eluent is pulverized through the concentrating under reduced pressure drying, gets the Radix Paeoniae Rubra total glycosides extract; Mainly contain peoniflorin, gallic acid, catechin and five galloyl glucoses in the wherein said Radix Paeoniae Rubra total glycosides extract.
2. Radix Paeoniae Rubra total glycosides compositions according to claim 1 is characterized in that the percolation that is extracted as wherein extracts or reflux, extract.
3. Radix Paeoniae Rubra total glycosides compositions according to claim 1, resin demand wherein are 2.5 times～4 times of medical material weight.
4. Radix Paeoniae Rubra total glycosides compositions according to claim 3, resin demand wherein are 3.75 times of medical material weight.
5. Radix Paeoniae Rubra total glycosides compositions according to claim 1 is characterized in that filtrate is with 0.1～0.5mL/cm
2.min by ZTC-1 saponin adsorption resin column.
6. Radix Paeoniae Rubra total glycosides compositions according to claim 5 is characterized in that the speed of passing through of filtrate is 0.2mL/cm
2.min.
7. Radix Paeoniae Rubra total glycosides compositions according to claim 1 is characterized in that with 6 times of volume 20% ethanol with 1.0mL/cm
2.min speed eluting.
8. Radix Paeoniae Rubra total glycosides compositions according to claim 1 is characterized in that content of paeoniflorin is higher than 50% in this extract.
9. a Chinese medicine preparation for the treatment of diabetes is characterized in that wherein containing each Radix Paeoniae Rubra total glycosides compositions and acceptable accessories component in the claim 1-8 item.
10. Chinese medicine preparation according to claim 10, its dosage form are injection or oral agents.
11. Chinese medicine preparation according to claim 11, oral formulations wherein are oral capsule or tablet, and the content of Radix Paeoniae Rubra total glycosides is more than 5 5% in the described Radix Paeoniae Rubra total glycosides extract, paeoniflorin content is more than 50%.
12. Chinese medicine preparation according to claim 11, its dosage form are the Radix Paeoniae Rubra total glycosides injection, the content of the Radix Paeoniae Rubra total glycosides in the described Radix Paeoniae Rubra total glycosides extract is more than 80%, and containing the Radix Paeoniae Rubra total glycosides extract is 1～5mg/mL.
13. the application of the arbitrary described Radix Paeoniae Rubra total glycosides compositions of claim 1～8 in preparation treatment diabetes medicament.
14. the application of the arbitrary described Chinese medicine preparation of claim 9～12 in preparation treatment diabetes medicament.
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| CN103263486A (en) * | 2013-06-13 | 2013-08-28 | 陈曦 | Application of paeoniae radix extract with hypoglycemic activity |
| CN104337884A (en) * | 2013-08-06 | 2015-02-11 | 颜明 | Medicine composition for preventing and/or treating diabetes and complication of diabetes |
| CN105232641B (en) * | 2015-10-21 | 2019-10-25 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Total paeony glycoside causes purposes and pharmaceutical composition in neural cell injury drug in preparation prevention or treatment microwave radiation |
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| CN1778355A (en) | 2006-05-31 |
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