CN101077364A - Traditional Chinese medicine composition for treating cardio cerebrovasculer disease and its preparations and preparation method - Google Patents
Traditional Chinese medicine composition for treating cardio cerebrovasculer disease and its preparations and preparation method Download PDFInfo
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Abstract
The present invention discloses one kind of Chinese medicine composition for treating cardiac and cerebral vascular diseases, and the Chinese medicine composition has total paeonoside extracted from tree peony bark as the effective component. The present invention also discloses the preparation process and preparation of the Chinese medicine composition. The preparation process has resin technology adopted and can reach high active component content. The Chinese medicine composition and its preparation havr high curative effect on cardiac and cerebral vascular diseases.
Description
Technical field
The invention belongs to new Chinese medicine research and development field.Relate to a kind of Chinese medicine composition for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof, be specifically related to the Cortex Moutan total glycosides and preparation and the preparation method that are contained in the Chinese medicine Cortex Moutan.
Background technology
Cardiovascular and cerebrovascular disease is the No.1 killer of human health, and according to the WTO incomplete statistics, the world has 1/3 people to suffer from cardiovascular and cerebrovascular disease, has every year 1500 ten thousand people to be devitalized by cardiovascular and cerebrovascular disease, accounts for more than 3/5 of death toll.China is the highest country of cardiovascular and cerebrovascular disease sickness rate in the world, and cardio-cerebral vascular disease patient more than 3,000 ten thousand is arranged, and the person that wherein is not paralyzed in bed reaches 1,200 ten thousand people, has every year 2600000 people to die from cardiovascular and cerebrovascular disease approximately, accounts for 40% of all disease death rates.At present, the medicine that is used for cardiovascular and cerebrovascular vessel both at home and abroad is a lot, but reasons such as, quality controllability difference indeterminate owing to the effective ingredient of the toxic and side effects of Western medicine and Chinese medicine compound recipe, still need to continually develop the Chinese medicine original new drug of the high-efficiency low-toxicity that meets modern social development, clear and definite material base improves drug safety and quality controllability.
Cortex Moutan has another name called moutan root bark (Compendium of Material Medica), Cortex Moutan (" book on Chinese herbal medicine just "), DANGEN (" Guizhou side's medicine among the people collection ").Regulation in the Pharmacopoeia of the People's Republic of China (an one), Cortex Moutan is the dry root bark of ranunculaceae peony Paeonia suffruticosa Andr..Excavate root autumn, remove radicula and silt, strip root bark, dry.Property hardship, suffering, flavor is slightly cold.GUIXIN, liver, kidney channel.Clearing away heat and cooling blood, blood circulation promoting and blood stasis dispelling.Be used for maculae caused by violent heat pathogen, hematemesis and epistaxis, night fever abating at dawn, lossless hectic fever due to YIN-deficiency, the amenorrhea dysmenorrhea, carbuncle sore tumefacting virus falls and pounces on the pain of injury, Chinese medicine for commonly used clinically is used in the Chinese medicine compound, as two red granule/cream/oral liquid, LIUWEI DIHUANG WAN, JIAWEI XIAOYAOWAN, QIJU DIHUANG WAN, nourishing YIN and clearing away lung-heat cream etc. more.
According to the literature, contain peoniflorin (paeoniflorin), Hydroxy peoniflorin (oxypaeoniflorin), benzoylpaeoniflorin (benzoylpaeoniflorin), benzoyl Hydroxy peoniflorin (benzoyl-oxypaeoniflorin), Galla Turcica (Galla Helepensis) acyloxylation peoniflorin A, B, C, D, E glycoside chemical components such as (suffruticosides A, B, C, D, E) in the Cortex Moutan, because its similar, be referred to as Cortex Moutan total glycosides, based on peoniflorin.Also contain phenols component, as paeonol (paeonol), paeonoside (paeonoside), the former glycosides of paeonol (paeonolide), the new glycosides of paeonol (apiopaeonoside) etc., wherein, claim paeonol again, be one of active component in the Cortex Moutan based on paeonol.In addition, also contain gallic acid, tannin, volatilization wet goods.
Modern pharmacological research shows, Cortex Moutan has antitumor, antiinflammatory, antibiotic, blood sugar lowering, blood pressure lowering, resists myocardial ischemia, arrhythmia, antithrombotic and effects such as arteriosclerosis, immunomodulating (" Cortex Moutan Pharmacological action study progress " " Chinese new medicine " rolled up the 8th phase p110-111 in 2004 the 3rd).Its main antitumor of bibliographical information and be paeonol (" paeonol Pharmacological action study progress " " Chinese patent medicine " rolled up the 7th phase p579-582 in 2004 the 26th) to the active component of cardiovascular and cerebrovascular vessel influences, but this composition is single, ignore the research of other active component in the Cortex Moutan, be unfavorable for the reasonable utilization and the exploitation of natural resources of Chinese medicinal materials.Other has Cortex Moutan polysaccharide for reducing blood sugar (" the extraction purification of Cortex Moutan polysaccharide and pharmacological action preliminary study " " Anhui agricultural sciences " nineteen ninety-five the 23rd volume the 4th volume p373-374), the research report of Cortex Moutan total glycosides treatment hepatitis B (" Cortex Moutan general glycoside treatment hepatitis B is effective " " medical information " 1997 the 10th volumes the 2nd its p3), immunomodulating, antiinflammatory (" antiinflammatory immunity function of Cortex Moutan total glycosides and part Mechanism Study " " 2002 the 18th volumes of Chinese Pharmacological Bulletin the 6th phase p656-660).Chinese patent, publication number is to disclose a kind of extracting method that is used for the treatment of the Cortex Moutan total glycosides of hepatitis among the CN1418673A " extracting method that is used for the treatment of the Cortex Moutan total glycosides of hepatitis class ", total glycosides content is more than 50%, this method adopts organic solvent extractionprocess, technical method is simple, but residual organic solvent (ethyl acetate in the Cortex Moutan total glycosides sample of preparation, second kind solvent that belongs to the ICH regulation) is difficult for removing, increased the difficulty of quality control, can affect the treatment, and the cost height does not meet the demand that the modernization of Chinese medicine develops.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of Chinese medicine composition for the treatment of cardiovascular and cerebrovascular disease, and active component wherein is the effective site that comes from the Cortex Moutan a---Cortex Moutan total glycosides.
Having the present invention further provides with above-mentioned Cortex Moutan total glycosides is active component, is used for the treatment of the pure Chinese medicine pharmaceutical preparation and the related dose forms of cardiovascular and cerebrovascular disease.
Another technical problem that the present invention will solve provides the preparation method of the preparation method, particularly Cortex Moutan total glycosides of the Chinese medicine composition that is used for the treatment of cardiovascular and cerebrovascular vessel.
For solving the problems of the technologies described above, the present invention has studied and defined following technical scheme.
The used Cortex Moutan of the present invention is the dry root bark of ranunculaceae peony Paeonia suffruticosa Andr..Chinese medicine composition provided by the invention, the Cortex Moutan total glycosides extract that obtains with ethanol extraction during it contains from the Cortex Moutan medical material, the main active of this extract is a Cortex Moutan total glycosides.From the pharmacodynamics angle, be used for the treatment of the Chinese medicine composition of cardiovascular and cerebrovascular disease as the present invention, the content of Cortex Moutan total glycosides wherein is more than 70%, and content of paeoniflorin is more than 60%.
The Cortex Moutan medical material generally is to excavate root autumn, removes radicula and silt, strips root bark, dries.Should pulverize earlier before being used for extracting, require by 20～40 mesh sieves usually, being beneficial to wherein, active component is fully extracted.
The embodiment of comparative optimization of the present invention, Cortex Moutan total glycosides prepares by following method:
(1) with 50～90% ethanol extraction Cortex Moutan medical material 3 times;
This ethanol extract of concentrating under reduced pressure below (2) 60 ℃ is 1.20 extractum to relative density;
(3) add water and make the extractum dissolving, centrifugal, get supernatant;
(4) supernatant is washed remove impurity by adsorption resin column;
(5) with 10～30% ethanol-eluting resin column remove impurity, again with 10～40% ethanol elutions, desorbing,
Collect stripping liquid, concentrating under reduced pressure, vacuum drying below 60 ℃ get Cortex Moutan total glycosides.
Extracting the concentration of alcohol of selecting for use in the preparation method of the present invention is 50～90%, from producing and the consideration of cost angle, preferably uses 80% ethanol to carry out raw material and extracts; Extracting method can be that percolation extracts or reflux, extract,, should keep bigger ratio between ethanol and the raw material, extracts fully guaranteeing, can use the ethanol extraction 2～3 times of 8～16 times of medical material weight.
Described adsorbent resin can in styrene, divinylbenzene, acrylate or the methacrylate any one or a few be framework material resin, specifically can comprise ZTC-1, D101, AB-8 or DM301 type resin.Be preferably the ZTC-1 resin.The consumption of resin is 2～3 times of medical material amount.
First in the process of described remove impurity with 8～12 times of water to resin volume (V/W), 10～30% ethanol of 2～5 times of resin volumes of reuse (V/W), the impurity that is not adsorbed in the flush away post uses this method can remove impurity effectively.
Described elution process is in order to obtain qualified samples, and the inventor gropes to determine to collect stripping liquid with 6～12 times of 10～40% alcohol desorptions to resin volume (V/W) through overtesting, concentrating under reduced pressure, and vacuum drying gets Cortex Moutan total glycosides.
In the process of remove impurity and desorbing, can monitor eluting or desorbing consumption of ethanol by detecting in the eluent content of Cortex Moutan total glycosides at any time, the time of control eluting and desorbing.The content assaying method of Cortex Moutan total glycosides can be measured by method well known in the art, and the present invention provides a cover feasible high-performance liquid chromatogram determination method at this.Specific as follows:
1, the about 3mg of benzoic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and puts in the 100mL measuring bottle, add an amount of supersound process of methanol (power 250W, frequency 33KHZ) and make dissolving, take out, put to room temperature, shake up to scale with methanol is fixed, precision is measured 1mL, put in the 10mL measuring bottle, add methanol and be diluted to scale, shake up, promptly get (containing benzoic acid 0.003mg among every 1mL).
2, the preparation of need testing solution is got the about 20mg of test sample with the dry test sample that gets of the eluent of Fractional Collections, and accurate the title decides, to the 10mL measuring bottle, add an amount of supersound process of 5% sodium hydroxide solution (power 250W, frequency 33KHZ) and made dissolving in 10 minutes, take out, put to room temperature, fixed with 5% sodium hydroxide solution to scale, shake up, filter, precision is measured subsequent filtrate 1mL, to 10mL tool plug test tube, boiling water bath hydrolysis 2 hours, take out, put, quantitatively be transferred in the 50mL measuring bottle to room temperature, transfer pH=6 with dilute hydrochloric acid, thin up shakes up to scale, filters with microporous filter membrane (0.22um), get subsequent filtrate, promptly.
3, accurate respectively reference substance solution and each the 10 μ L of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
Advantage of the present invention: the Cortex Moutan total glycosides compositions that the present invention makes, owing to adopted the resin technology in the modernization of Chinese medicine technology, not only making wherein, the content of active component improves, thereby improved curative effect, simultaneously also remove a large amount of impurity, compared with prior art, both solved the problem of organic solvent residual, improved the content (Cortex Moutan total glycosides content is more than 70%) of active component again, curative effect is more definite.
On this basis, the present invention has has also researched and proposed a kind of pure Chinese medicine pharmaceutical preparation for the treatment of cardiovascular and cerebrovascular disease, and this Chinese medicine medicine is the effective active composition with above-mentioned Cortex Moutan total glycosides, and has comprised acceptable auxiliary component on the pharmaceutics.
According to technical scheme of the present invention, this Chinese medicine preparation dosage form can be oral formulations or injection preparation, and wherein oral formulations comprises capsule, oral liquid, tablet, granule etc.Injection type is injection or lyophilized injectable powder.Used adjuvant comprises: conventional adjuvants such as starch, sucrose, lactose, Icing Sugar, glucose, mannitol, xylitol, Polyethylene Glycol, isopropyl alcohol, soil temperature-80, glycerol, propylene glycol, microcrystalline Cellulose sodium, dextrin, cyclodextrin, sodium chloride, vitamin C, cysteine, citric acid, sodium thiosulfate, sodium sulfite, stearate and gelatin, 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.
Observe Chinese medicine composition of the present invention by research cardiovascular and cerebrovascular disease is had better therapeutic effect.For the ease of understanding the therapeutic effect of this Chinese medicine composition, the inventor has carried out following pharmacodynamics test:
Test example 1 Chinese medicine composition Cortex Moutan total glycosides is to the therapeutical effect of dog experimental myocardial infarction due to the coronary ligation
Chinese medicine composition: Cortex Moutan total glycosides, content 75%, wherein content of paeoniflorin is 65%.
Experiment is divided into 6 groups, is respectively sham operated rats (only opening not ligation of breast arteria coronaria), model group, positive drug diltiazem group (5mg/kg), Cortex Moutan total glycosides 10mg/kg dosage group, Cortex Moutan total glycosides 20mg/kg dosage group, three dosage groups of Cortex Moutan total glycosides 40mg/kg.The method that the model preparation is described by " pharmacological experiment method " corresponding chapters and sections is carried out.After the dog open chest anesthetized,, cause the acute preceding inferior wall myocardial infarction of dog with the anterior descending coronary ligation.The record dog before ligation, after the ligation, before the administration, after the administration 10,20,30,60,90,120,150,180,240,360min electrocardiogram (EECG), leave and take before the medicine and behind the medicine 60,150,240,360min time femoral vein blood examination thought-read creatase CK-MB, the dirty section statining of coring behind the administration 360min, the calculating myocardium infarct size.All numerical value are represented with x ± s, relatively adopt the t check between group.
Every group of 6 dogs, the male and female dual-purpose.Each dosage group of Cortex Moutan total glycosides and positive drug all adopt normal saline to be mixed with solution, and the administration volume is 1mL/kg, and blank group and model group are given the normal saline with volume, and each group is all stablized 15min behind coronary ligation, through the duodenum single-dose.
The degree of myocardial ischemia of the 1 pair of dog (influence of ∑-ST): see Table 1
Compare with sham operated rats, model group myocardial infarction degree ∑-ST amplitude that each time point raises behind coronary ligation all increases, and difference has significance (P＜0.01), and the modeling success is described; Each organizes dog after ligation, with before self ligation relatively, the millivolt number that the myocardial infarction degree that all obviously raises ∑-ST increases, difference has significance (P＜0.01 and P＜0.05), has statistical significance, illustrate respectively to organize the equal modeling of dog successfully;
Compare with model group, positive drug diltiazem group all can obviously reduce the millivolt number that myocardial infarction degree ∑-ST increases at each time point, after administration 30,60,90,120,150,180, a 240min7 time point difference has significance (P＜0.01), consistent with bibliographical information, also verified the reliability of this kind method;
Cortex Moutan total glycosides 10mg/kg dosage group can obviously reduce the millivolt number that myocardial infarction degree ∑-ST increases behind medicine 180, during 240min, difference has significance (P＜0.05); Cortex Moutan total glycosides 20mg/kg dosage group each time point behind medicine all can obviously reduce the millivolt number that myocardial infarction degree ∑-ST increases, behind medicine 120,150,180min has three time point differences to have significance (P＜0.05); Cortex Moutan total glycosides 40mg/kg dosage group each time point behind medicine all can obviously reduce the millivolt number that myocardial infarction degree ∑-ST increases, behind medicine 30,120,150,180,240min has five time point differences to have significance (P＜0.05), demonstrate and improve myocardial ischemia dose dependent preferably.
The influence of the myocardial ischemia scope (N-ST) of 2 pairs of dogs: see Table 2
Compare with sham operated rats, model group myocardial infarct size N-ST obviously increases, and difference has significance (P＜0.01), proves the modeling success; Each organizes dog after ligation, with before self ligation relatively, the number that the myocardial ischemia scope that all obviously raises N-ST section increases, difference has significance (P＜0.01 and P＜0.05), has statistical significance, illustrate respectively to organize the equal modeling of dog successfully;
Positive drug diltiazem group and model group are relatively, myocardial ischemia scope (N-ST) all has the trend of reducing, behind medicine 30,60,90,120,150,180,240min has seven time points significant difference (P＜0.05) to occur, consistent with bibliographical information, verified the function of resisting myocardial ischemia of diltiazem, the method for justification function simultaneously is reliable;
Cortex Moutan total glycosides 10mg/kg dosage group reduces the number of leading (number of N-ST) of electrocardiogram risings＞2mv during 240min behind medicine, learn processing by statistics, and difference has significance (P＜0.5); Cortex Moutan total glycosides 20mg/kg dosage group behind medicine during 180min difference have significance (P＜0.05); Cortex Moutan total glycosides 40mg/kg dosage group behind medicine 60,90,120,150,180,240min has six time points the effect of myocardial ischemia scope to occur dwindling, difference has significance (P＜0.01 or P＜0.05).
The influence of the myocardial infarction area of 3 pairs of dogs (MIS): see Table 3
Compare with model group, positive drug diltiazem group can obviously be dwindled myocardial infarction area, and difference has significance (P＜0.05), and is consistent with bibliographical information; Other each dosage groups are all obviously dwindled myocardial infarction area, learn by statistics and handle, and difference all has significance (P＜0.05).
4. to myocardial infarction dogs CK-MB influence due to the coronary ligation: see Table 4
With sham operated rats relatively, model group behind medicine 60,240, three time point risings of 360min myocardium enzyme CK-MB, learn by statistics and handle difference and have significance (P＜0.05); Compare with model group, diltiazem hydrochloride group CK-MB value is obviously low, and difference has significance (P＜0.05); Cortex Moutan total glycosides 10mg/kg dosage group behind medicine 150,240,360min has three time points significantly to reduce the value of CK-MB, learn by statistics to handle difference and have significance (P＜0.05); Cortex Moutan total glycosides 20mg/kg dosage group each time point behind medicine significantly reduces the value of CK-MB, learns processing difference by statistics and has significance (P＜0.05); Cortex Moutan total glycosides 40mg/kg dosage group each time point behind medicine significantly reduces the value of CK-MB, learns processing difference by statistics and has significance (P＜0.05).
In a word, Cortex Moutan total glycosides can alleviate the degree and the scope of myocardial infarction, reduces the release of myocardium enzyme, obviously dwindles myocardial infarction area, points out it to have the effect that resists myocardial ischemia preferably.
Table 1: Cortex Moutan total glycosides is to the influence (unit: mv) of experimental myocardial infarction dog ∑-ST
| Group | Number of animals n | Dosage mg/kg | Before the ligation | After the ligation before the administration | Behind the medicine (min) | |||||||||
| 10 | 20 | 30 | 60 | 90 | 120 | 150 | 180 | 240 | 360 | |||||
| The heavy dose of diltiazem hydrochloride of dosage Cortex Moutan total glycosides in the low dose of Cortex Moutan total glycosides of sham-operation group model group Cortex Moutan total glycosides | 6 8 6 6 6 8 | - - 10 20 40 5 | 16.05± 8.50 8.31± 2.76 8.96± 4.76 11.40± 4.92 10.53± 2.77 11.64± 4.16 | 13.97± 9.36 38.98± 14.67 ▲▲##34.92± 19.26 # 32.82± 14.01 # 34.22± 9.71 ## 29.59± 18.81 # | 14.71± 8.78 44.11± 18.04 ▲▲##34.06± 14.12 # 31.83± 14.50 # 33.45± 9.66 ## 32.26± 18.49 # | 13.39± 7.36 46.02± 15.71 ▲▲##36.65± 16.72 # 33.29± 17.81 # 31.02± 10.36 ## 29.76± 20.93 # | 12.54± 4.24 49.01± 15.59 ▲▲##37.39± 17.13 # 36.52± 19.40 # 29.83± 6.42 ##* 28.16± 18.83 #* | 14.49± 10.04 48.11± 16.09 ▲▲##40.00± 19.86 # 34.35± 16.85 # 33.57± 10.39 ## 27.07± 18.51 #* | 13.68± 9.22 53.88± 19.32 ▲▲##42.21± 22.82 # 35.76± 12.63 # 36.15± 12.47 ## 29.92± 23.67 #* | 16.15± 12.63 54.74± 11.03 ▲▲##38.94± 22.43 # 38.10± 15.80 #* 36.93± 17.21 ##* 25.02± 19.03 #** | 15.40± 8.61 52.72± 11.54 ▲▲##40.50± 27.75 # 34.70± 13.25 #* 35.49± 16.89 ##* 25.46± 20.39 #** | 13.53± 7.54 50.49± 8.49 ▲▲##34.68± 17.93 #* 32.04± 17.05 #* 30.03± 17.67 ##* 26.65± 19.42 #* | 14.08± 6.61 46.04± 9.45 ▲▲##30.89± 11.35 #* 31.55± 17.42 # 30.02± 14.10 ##* 27.10± 19.11 #* | 12.73± 6.51 37.13± 9.97 ▲▲##25.33± 14.84 # 31.90± 15.89 # 28.93± 13.34 ## 27.19± 16.89 # |
▲Compare p＜0.05 with the normal control group
▲ ▲Compare p＜0.01 with the normal control group;
*Compare p＜0.05 with model group;
*Compare p＜0.01 with model group;
Compare p＜0.05 before # and self medicine; Compare p＜0.01 before ## and self medicine
Table 2: Cortex Moutan total glycosides is to the influence (unit: mv) of experimental myocardial infarction dog N-ST
| Group | Number of animals n | Dosage mg/kg | Before the ligation | After the ligation before the administration | Behind the medicine (min) | |||||||||
| 10 | 20 | 30 | 60 | 90 | 120 | 150 | 180 | 240 | 360 | |||||
| The heavy dose of diltiazem hydrochloride of dosage Cortex Moutan total glycosides in the low dose of Cortex Moutan total glycosides of sham-operation group model group Cortex Moutan total glycosides | 6 8 6 6 6 8 | - - 10 20 40 5 | 2.50± 3.01 0.50± 0.76 0.66± 1.63 1.00± 1.26 1.17± 0.75 ## 2.00± 1.77 | 2.83± 3.71 7.25± 2.60 ▲## 7.00± 4.04 ## 8.00± 3.16 ## 7.83± 2.31 ## 6.25± 4.46 # | 3.00± 3.28 8.38± 1.76 ▲▲## 7.66± 3.26 ## 7.50± 3.27 ## 8.17± 1.33 ## 6.50± 3.96 # | 2.50± 3.01 8.38± 2.19 ▲▲## 7.5± 3.08 ##7.33± 4.03 # 7.50± 1.64 ##5.62± 3.70 # | 1.83± 2.13 9.25± 1.49 ▲▲## 7.33± 3.07 ## 7.66± 3.44 ## 7.50± 2.07 ## 5.62± 3.58 #* | 2.33± 3.61 9.13± 1.46 ▲▲## 7.83± 3.25 ## 7.16± 3.76 ## 7.50± 1.05 ##* 5.25± 3.95 #* | 2.33± 3.93 9.75± 1.04 ▲▲## 7.83± 2.99 ## 8.33± 2.80 ## 8.33± 0.52 ##** 5.12± 3.94 #* | 2.33± 3.61 9.63± 1.19 ▲▲## 7.16± 3.18 ## 8.16± 3.06 ## 7.83± 1.60 ##* 5.12± 4.08 #* | 2.16± 3.06 9.88± 1.36 ▲▲## 6.83± 3.25 ## 7.50± 3.20 ## 7.17± 2.71 ##* 5.12± 4.12 #* | 2.33± 3.61 9.75± 1.28 ▲▲## 6.83± 3.43 ## 7.00± 2.89 ##* 7.17± 2.86 ##* 4.75± 3.88 #* | 2.50± 2.88 9.13± 1.64 ▲▲## 6.33± 2.05 ##* 7.33± 3.01 ## 6.01± 2.66 ##* 5.25± 3.69 #* | 2.00± 2.68 9.00± 1.85 ▲▲## 5.66± 4.13 ## 7.16 ±4.07 # 6.50± 4.37 5.37± 4.43 # |
▲Compare p＜0.05 with the normal control group
▲ ▲Compare p＜0.01 with the normal control group;
*Compare p＜0.05 with model group;
*Compare p＜0.01 with model group;
Compare p＜0.05 before # and the self administration; Compare p＜0.01 before ## and the self administration
Table 3: Cortex Moutan total glycosides is to the influence (accounting for the left ventricle ratio) of dog myocardial infarction area
| Group | Dosage (mg/kg) | 6h after the administration |
| The heavy dose of group of dosage group Cortex Moutan total glycosides in the model group diltiazem hydrochloride Cortex Moutan total glycosides small dose group Cortex Moutan total glycosides | 5 10 20 40 | 0.080±0.050 0.017±0.029 * 0.020±0.021 * 0.018±0.010 * 0.012±0.012 * |
Compare with model group:
*P＜0.05
Table 4: Cortex Moutan total glycosides is to the influence of experimental myocardial infarction dog myocardium enzyme CK-MB (x ± S)
| Group | Quantity n | Unit: U/L before the administration | Unit after the administration: U/L | |||
| 60min | 150min | 240min | 360min | |||
| Normal group model group diltiazem group Cortex Moutan total glycosides 10mg/kg dosage group Cortex Moutan total glycosides 20mg/kg dosage group Cortex Moutan total glycosides 40mg/kg dosage group | 6 6 6 6 6 6 | 104.2± 50.9 188.9± 60.4 184.8± 61.4 163.2± 60.8 209.1± 153.7 176.0± 51.2 | 278.7± 180.0 660.9± 243.5 ▲ 282.4± 239.7 * 609.2± 98.7 369.1± 89.9 * 360.6± 105.3 * | 544.3± 259.8 534.3± 372.9 228.4± 404.5 * 312.3± 109.3 * 404.3± 93.5 * 234.6± 131.2 * | 610.0± 496.4 1006.5± 507.5 ▲ 535.2± 478.2 * 562.7± 367.6 * 576.3± 239.4 * 238.6± 203.6 * | 711.5± 409.9 1079.1± 667.2 ▲ 441.4± 524.1 * 735.7± 217.8 * 468.7± 248.2 * 378.6± 277.7 * |
Compare with normal group,
▲P＜0.05; Compare with model group,
*P＜0.05
Test example 2 Chinese medicine composition Cortex Moutan total glycosides are to the protective effect of cerebral ischemia
Test used Chinese medicine composition: Cortex Moutan total glycosides, content 82%, wherein content of paeoniflorin is 71%.
The SD rat is divided into sham operated rats, model group, Cortex Moutan total glycosides 20mg/kg, 40mg/kg, 80mg/kg group, nimodipine 15mg/kg group at random.Adopt gastric infusion, 1 feed ration to divide and give continuous 2 days for 2 times.1h, the 6h difference administration of operation back are 1 time before the operation on the 3rd, and sham operated rats and model group gavage the equivalent distilled water.
The preparation of intraluminal middle cerebral artery occlusion in rats ischemia-reperfusion injury model: rat anesthesia, dorsal position is fixed.Separate right carotid, internal carotid artery and external carotid artery, threading is standby, ligation external carotid artery and common carotid artery, after closing the internal carotid artery distal end with bulldog clamp folder, make a kerf in external carotid artery and internal carotid artery crotch, insert head end from incision and wear into spheric smooth nylon wire (diameter 0.285mm), stop inlet wire when resistance sense is arranged and write down Ischemia Time, about insertion depth 18mm, realize that middle cerebral artery occlusion causes cerebral ischemia.The ligation incision, skin suture.Behind the 3h nylon wire is extracted into nearly incision gently, realizes perfusion again.A sham operated rats ligation right carotid.Detect the neurological's scoring and the cerebral infarction scope of each treated animal respectively, concrete grammar is as follows:
Neurological scoring: press 5 grades of point systems of Zea Longa, respectively at postoperative 3h with pour into 21h again and evaluate, 0 minute and the person's of remaining unconscious rejecting.Standards of grading: do not have obvious neurological's symptom, 0 minute; Can not full extension the left side fore paw, 1 minute; Rotation to the left, 2 minutes; Topple over 3 fens during walking to the left; Can not walk 4 fens voluntarily.
The cerebral infarction scope is measured: broken end is got brain in postoperative 24h scoring back, and the remainder that removes behind olfactory bulb, cerebellum and the low brain stem crownly is cut to 6 at 4 ℃, and (every 5mL dye liquor contains 4%TTC 1.5mL, 1M K rapidly the brain sheet to be placed the TTC dye liquor
2HPO
40.1mL all the other adding distil waters are to scale), 37 ℃ of lucifuge temperature were incubated 30 minutes, took out to be placed on the 24h that keeps in Dark Place in 10% formalin.The non-ischemic region in dyed back is a rose, and infarcted region is a white.White organized carefully to dig down weigh, the percentage ratio that accounts for full brain weight with infarction tissue's weight is as the cerebral infarction scope.
All index values are represented with x ± s, relatively adopt the t check between group.
Experimental result:
(1) Cortex Moutan total glycosides is to the influence of middle cerebral artery ischemia-reperfusion rat nervous symptoms scoring
The sham operated rats rat does not have the neurologic impairment performance, has occurred neurologic impairment symptom in various degree after the modeling.Each administration group can obviously be improved rat model neurologic defect symptom, improves the most remarkable with Cortex Moutan total glycosides 80mg/kg group and nimodipine 15mg/kg group especially.The results are shown in Table 5.
The influence that table 5 Cortex Moutan total glycosides is marked to tMCAO rat nervous symptoms (x ± s)
| Group | Dosage (mg/kg) | Number of animals (n) | Ischemia 3h | Number of animals (n) | Irritate 21h again |
| Sham-operation model nimodipine Cortex Moutan total glycosides | - - 15 20 40 80 | 15 18 20 18 19 19 | 0±0 2.67±0.69 △△ 2.05±0.76 * 2.17±0.51 2.11±0.57 * 2.00±0.82 * | 15 12 14 12 13 12 | 0±0 2.33±0.65 △△ 1.57±0.64 ** 1.83±0.83 1.69±0.63 * 1.50±0.67 ** |
Annotate: compare with model group,
*P＜0.01,
*P＜0.05; Compare with sham operated rats,
△ △P＜0.01.
(2) Cortex Moutan total glycosides is to the influence of middle cerebral artery ischemia-reperfusion rat cerebral infarction scope
TTC dyeing shows that model group cerebral infarction scope reaches 13.7%, and each administration group all can reduce tMCAO rat cerebral infarction scope.Compare with model group, Cortex Moutan total glycosides 80mg/kg group, Cortex Moutan total glycosides 40mg/kg group and nimodipine 15mg/kg group difference have significance.The results are shown in Table 6.
Table 6 Cortex Moutan total glycosides is to the influence of tMCAO rat cerebral infarction scope (x ± s)
| Group | Dosage (mg/kg) | Number of animals (n) | Infarct size (%) |
| Sham-operation model nimodipine Cortex Moutan total glycosides | - - 15 20 | 15 12 14 12 | 0±0 13.70±3.84 △△ 9.05±2.56 * 11.53±4.93 |
| 40 80 | 13 12 | 10.35±3.49 * 9.86±2.62 ** |
Annotate: compare with model group,
*P＜0.01,
*P＜0.05; Compare with sham operated rats,
△ △P＜0.01.
Test example 3 Chinese medicine composition Cortex Moutan total glycosides are to the thrombotic influence of rat arteriovenous shut
Test used Chinese medicine composition: Cortex Moutan total glycosides, content 85%, wherein content of paeoniflorin is 76%.
The SD rat is divided into 5 groups at random, and promptly blank group, aspirin 40mg/kg group, Cortex Moutan total glycosides 20mg/kg, 40mg/kg, 80mg/kg group adopt gastric infusion, and 1 feed ration divides and gives continuous 3 days for 2 times.The 1h administration is 1 time before the operation on the 4th, and the blank group gives the isometric(al) distilled water.
The arteriovenous shut thrombosis is made: rat is anaesthetized with 10% chloral hydrate solution (0.35g/kg), dorsal position is fixed, separate right carotid and left side external jugular vein, three sections polyethylene tubes are linked to each other, and an end inserts right common carotid artery, and the other end inserts left external jugular vein, middle segment length 10cm, put into one and longly be No. 0 surgical thread (weighing) of 8cm, fill with normal saline in the pipe, set up arteriovenous shut.Take off sleeve pipe behind the 20min, removal of thromboses is removed unnecessary floating blood, puts on the template of having weighed and takes by weighing wet weight of thrombus.Place the interior 60 ℃ of baking 1h of baking oven to constant weight then, cooling back weighing thrombosis dry weight.
Experimental result
Cortex Moutan total glycosides 40mg/kg, 80mg/kg can obviously reduce the weight in wet base and the dry weight of arteriovenous shut thrombosis, thereby antithrombotic forms.The results are shown in Table 7.
Table 7 Cortex Moutan total glycosides is to the thrombotic influence of rat artery-vein bypass (n=12, x ± s)
| Group | Dosage (mg/kg) | Wet weight of thrombus (mg) | Thrombosis dry weight (mg) |
| Blank group aspirin Cortex Moutan total glycosides | - 40 20 40 80 | 221.6±54.0 154.4±35.0 ** 198.3±53.6 172.6±41.6 * 161.1±45.9 ** | 48.7±11.7 32.7±5.5 ** 40.8±11.0 38.1±8.9 * 32.0±9.3 ** |
Annotate: compare with the blank group,
*P＜0.01,
*P＜0.05.
Middle cerebral artery is the common site that apoplexy takes place, and its blocking-up model is generally believed it is the representative animal model of focal cerebral ischemia.This part is adopted line bolt method to cause the temporary middle cerebral artery occlusion model of rat and is observed the influence of Cortex Moutan total glycosides to cerebral ischemia re-pouring rat neurological scoring, cerebral infarction scope.The result tangible neurologic defect symptom and large tracts of land cerebral infarction have occurred after showing the rat modeling.Cortex Moutan total glycosides 80mg/kg, 40mg/kg can obviously improve rat model neurologic defect symptom, reduce the cerebral infarction scope, demonstrate certain cerebral ischemia protective effect.
Thrombosis is one of important pathological process of ischemic cerebrovascular.The thrombosis similar that the rat carotid artery that this experiment is adopted-external jugular vein blood flow the method for bypass forms is in platelet thrombus.Platelet in the artery blood flow adheres to wire surface when touching the matsurface of silk thread and forms thrombosis, so can predict hematoblastic adhesion and aggregation function from the weight of thrombosis.Result of study shows that Cortex Moutan total glycosides has tangible antithrombotic effect, and this effect may be that the Cortex Moutan total glycosides performance improves one of mechanism of cerebral ischemia effect.
Specific embodiment
Describe the enforcement of technical solution of the present invention by the following examples in detail, but should not limit practical range of the present invention with this.
Embodiment 1: the preferred for preparation method of Chinese medicine composition
Get the Cortex Moutan medicinal powder, extract 2 times each 1 hour with 10 times of medical material amount 80% alcohol heating reflux.Filter, with 60 ℃ of decompression recycling ethanols of ethanol extract, extracting solution is concentrated into the extractum of relative density 1.20 (25 ℃ of mensuration), add 5.5 times of water (60 ℃) and make the extractum dissolving to medical material weight, centrifugal, supernatant is the ZTC-1 resin column by 2.5 times of medical material amounts slowly, with 8 times to the water of resin volume (V/W) and 15% ethanol of 2.5 times of resin volumes (V/W), the impurity that is not adsorbed in the flush away post is then with 8 times of 20% alcohol desorptions to resin volume (V/W).Collect stripping liquid, concentrating under reduced pressure, vacuum drying gets Chinese medicine composition, and wherein the content of Cortex Moutan total glycosides counts 75% with peoniflorin, and content of paeoniflorin is 69%.
Embodiment 2: the preferred for preparation method of Chinese medicine composition
Get the Cortex Moutan medicinal powder, extract 3 times each 1 hour with 8 times of medical material amount 90% alcohol heating reflux.Filter, with 60 ℃ of decompression recycling ethanols of ethanol extract, extracting solution is concentrated into the extractum of relative density 1.20 (25 ℃ of mensuration), add 5 times of water (60 ℃) and make the extractum dissolving to medical material weight, centrifugal, supernatant is the D101 resin column by 2 times of medical material amounts slowly, with 10 times to the water of resin volume (V/W) and 30% ethanol of 2 times of resin volumes (V/W), the impurity that is not adsorbed in the flush away post is then with 6 times of 40% alcohol desorptions to resin volume (V/W).Collect stripping liquid, concentrating under reduced pressure, vacuum drying gets Chinese medicine composition, and wherein the content of Cortex Moutan total glycosides counts 72% with peoniflorin, and content of paeoniflorin is 67%.
Embodiment 3: the preferred for preparation method of Chinese medicine composition
Get the Cortex Moutan medicinal powder, extract 2 times each 1 hour with 12 times of medical material amount 60% alcohol heating reflux.Filter, with 60 ℃ of decompression recycling ethanols of ethanol extract, extracting solution is concentrated into the extractum of relative density 1.20 (25 ℃ of mensuration), add 6 times of water (60 ℃) and make the extractum dissolving to medical material weight, centrifugal, supernatant is the AB-8 resin column by 3 times of medical material amounts slowly, with 12 times to the water of resin volume (V/W) and 10% ethanol of 4 times of resin volumes (V/W), the impurity that is not adsorbed in the flush away post is then with 12 times of 30% alcohol desorptions to resin volume (V/W).Collect stripping liquid, concentrating under reduced pressure, vacuum drying gets Chinese medicine composition, and wherein the content of Cortex Moutan total glycosides counts 76% with peoniflorin, and content of paeoniflorin is 69%.
Embodiment 4: the preferred for preparation method of Chinese medicine composition
Get the Cortex Moutan medicinal powder, extract 2 times each 1 hour with 16 times of medical material amount 50% alcohol heating reflux.Filter, with 60 ℃ of decompression recycling ethanols of ethanol extract, extracting solution is concentrated into the extractum of relative density 1.20 (25 ℃ of mensuration), add 5 times of water (60 ℃) and make the extractum dissolving to medical material weight, centrifugal, supernatant is the DM301 resin column by 2.5 times of medical material amounts slowly, with 10 times to the water of resin volume (V/W) and 10% ethanol of 5 times of resin volumes (V/W), the impurity that is not adsorbed in the flush away post is then with 12 times of 15% alcohol desorptions to resin volume (V/W).Collect stripping liquid, concentrating under reduced pressure, vacuum drying gets Chinese medicine composition, and wherein the content of Cortex Moutan total glycosides counts 70% with peoniflorin, and content of paeoniflorin is 62%.
Embodiment 5: the preferred dosage form capsule of Cortex Moutan total glycosides
Get the Cortex Moutan total glycosides 100g of embodiment 1 method preparation, 60 ℃ of dryings grind, and cross 80 mesh sieves, the medical starch 98g and the magnesium stearate 2g that added 80 mesh sieves, mix homogeneously is made soft material in right amount with 85% ethanol, crosses 30 mesh sieve system granules, oven dry, make moisture less than 5%, cross 40 orders and shine granulate, be sub-packed in No. 3 capsules.Every capsules contains Cortex Moutan total glycosides extract extract 0.1g, uses aluminium plastic composite packaging, promptly.
Embodiment 6: the preferred dosage form tablet of Cortex Moutan total glycosides
Get the Cortex Moutan total glycosides 30g of embodiment 1 method preparation, add starch 30g, microcrystalline Cellulose 10g granulates with 12 mesh sieves in right amount with 10% starch slurry, and dry below 55 ℃, dry granular adds magnesium stearate, granulate, and mixing, tabletting, promptly.
Claims (10)
1. Chinese medicine composition for the treatment of cardiovascular and cerebrovascular disease, it is to make solvent with ethanol, extracts the Cortex Moutan total glycosides that obtains from the Cortex Moutan medical material, it is characterized in that it being to prepare by the following method:
(1) with 50%～90% ethanol extraction Cortex Moutan medical material 3 times;
This ethanol extract of concentrating under reduced pressure below (2) 60 ℃ is 1.20 extractum to relative density;
(3) add water and make the extractum dissolving, centrifugal, get supernatant;
(4) supernatant is washed remove impurity by adsorption resin column;
(5) with 10～30% ethanol-eluting resin column remove impurity, again with 10～40% alcohol desorptions, collect stripping liquid, concentrating under reduced pressure, vacuum drying below 60 ℃ get Cortex Moutan total glycosides.
2. Chinese medicine composition according to claim 1, the content that it is characterized in that Cortex Moutan total glycosides in the said composition is more than 70%, and content of paeoniflorin is more than 60%.
3. Chinese medicine composition according to claim 1 is characterized in that being extracted as percolation and extracts or reflux, extract.
4. Chinese medicine composition according to claim 1, it is characterized in that described resin be in styrene, divinylbenzene, acrylate or the methacrylate any one or a few for framework material resin.
5. Chinese medicine composition according to claim 4 is characterized in that the adsorbent resin that is adopted can be ZTC-1, D101, AB-8 or DM301 type resin.
6. Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease is characterized in that it is made by acceptable adjuvant on described Chinese medicine composition of the arbitrary claim of claim 1～6 and the pharmaceutics.
7. Chinese medicine preparation according to claim 6 is characterized in that described adjuvant is selected from any one or a few in starch, sucrose, lactose, Icing Sugar, glucose, mannitol, xylitol, Polyethylene Glycol, isopropyl alcohol, soil temperature-80, glycerol, propylene glycol, microcrystalline Cellulose sodium, dextrin, cyclodextrin, sodium chloride, vitamin C, cysteine, citric acid, sodium thiosulfate, sodium sulfite, stearate and the gelatin.
8. Chinese medicine preparation according to claim 6 is characterized in that dosage form comprises oral formulations or ejection preparation.
9. Chinese medicine preparation according to claim 8 is characterized in that oral formulations is capsule, granule, oral liquid or tablet.
10. described Chinese medicine composition of the arbitrary claim of claim 1～9 or the Chinese medicine preparation application in preparation treatment cardiovascular and cerebrovascular diseases medicament.
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| CN102283911A (en) * | 2011-09-16 | 2011-12-21 | 河南省中医药研究院 | Capsule with functions of supplementing qi, activating blood circulation and calming for treating ischemic stroke |
| CN108451965A (en) * | 2018-05-03 | 2018-08-28 | 黄山学院 | A kind of radix paeoniae rubra terpene glycoside composition and preparation method thereof with function of resisting myocardial ischemia |
| CN115645464A (en) * | 2022-11-11 | 2023-01-31 | 广州中医药大学(广州中医药研究院) | Traditional Chinese medicine composition for treating atherosclerosis and fatty liver and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102283911A (en) * | 2011-09-16 | 2011-12-21 | 河南省中医药研究院 | Capsule with functions of supplementing qi, activating blood circulation and calming for treating ischemic stroke |
| CN108451965A (en) * | 2018-05-03 | 2018-08-28 | 黄山学院 | A kind of radix paeoniae rubra terpene glycoside composition and preparation method thereof with function of resisting myocardial ischemia |
| CN115645464A (en) * | 2022-11-11 | 2023-01-31 | 广州中医药大学(广州中医药研究院) | Traditional Chinese medicine composition for treating atherosclerosis and fatty liver and application thereof |
| CN115645464B (en) * | 2022-11-11 | 2024-04-12 | 广州中医药大学(广州中医药研究院) | Traditional Chinese medicine composition for treating atherosclerosis and fatty liver and application thereof |
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