CN100387236C - Pharmacetutical for treating cardiovascular and cerebrovascular disease and its preparing process - Google Patents
Pharmacetutical for treating cardiovascular and cerebrovascular disease and its preparing process Download PDFInfo
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- CN100387236C CN100387236C CNB2006100202352A CN200610020235A CN100387236C CN 100387236 C CN100387236 C CN 100387236C CN B2006100202352 A CNB2006100202352 A CN B2006100202352A CN 200610020235 A CN200610020235 A CN 200610020235A CN 100387236 C CN100387236 C CN 100387236C
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Abstract
The present invention discloses medicine which is used for injection and for treating cardiovascular and cerebrovascular diseases, and a preparation method. The medicine is composed of two raw materials of breviscapine and high-purity astragalus root saponin of which the purity is more than 80 %, the astragalus root saponin can be extracted from astragalus root, and the astragaloside content in the astragalus root saponin is from 20 to 30 %. The medicine used for injection has strong Qi-benefiting and blood-circulating function, can promote blood circulation, can dissipate stasis, can treat Qi and blood at the same time, and can obviously improve treating effect; compared with the effect of the medicine prepared from low-purity astragalus root saponin with the same content and breviscapine with the same content, the effect of the present invention can be greatly improved; furthermore, reliable security can exist.
Description
Affiliated technical field
The present invention relates to a kind of medicine for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof, relate in particular to injectable drug of a kind of treatment cardiovascular and cerebrovascular disease of forming by breviscapine and the Radix Astragali saponin that from the Radix Astragali, extracts and preparation method thereof.
Background technology
Motherland's medical science is thought, " qi being the governor of blood, blood being the material foundation of QI ", the capable then blood of gas is capable, and blood operation freely can not have influence on the biochemistry operation of gas yet, so when the treatment relevant disease, general opinion is used Qi-tonifying drug and blood circulation promoting medicine compatibility, to reach the effect that QI and blood is ruled together.
The Radix Astragali be a benefiting QI for strengthening the superficies, to heart have protective effect, can human body immunity improving the Chinese medicine of function.It mainly contains saponin, polysaccharide, contains compositions such as aminoacid, flavone in addition.Modern pharmacology and clinical research show: Radix Astragali saponin is an effective site main in the Radix Astragali, and its main onset composition is an astragaloside wherein.Radix Astragali saponin can pass through Na
+, K
+-ATP enzyme is realized heart tonifying; has positive inotropic action; blood vessel dilating; bring high blood pressure down; improve myocardial contractility, increase coronary flow, the protection cardiac muscle; alleviate myocardial ischemia reperfusion injury and heart failure resistance, antioxidant radical, protection brain cell, anticoagulant, microcirculation improvement, inhibition neuronal apoptosis or necrosis, protect effects such as half blanking bar.But existing Radix Astragali medicine, the impurity content in the Radix Astragali extract is many, Radix Astragali saponin purity is low, generally is lower than 30%, and the content of astragaloside is also very low, is about 0.04%, as the Radix Astragali injection of productions such as Chengdu buchu, Fuda, Shanghai.Because technological reason, generally adopt water to carry repeatedly alcohol deposition method, and that water is carried the extraction ratio of Radix Astragali saponin is lower, and filtration ratio difficulty, stop up filter cloth slowly and easily, not easy to operate; The loss of Radix Astragali saponin is also bigger during precipitate with ethanol, thereby the purity of Radix Astragali saponin is low in the preparation, and its purity is below 30%.In a word, the existing medicine that makes with Radix Astragali extract because the purity of Radix Astragali saponin is low in the extract, impurity is many, and main in the Radix Astragali saponin to play the content of effective constituent astragaloside also very low, make its weak curative effect, the QI invigorating effect has much room for improvement.
Breviscapine has function of promoting blood circulation to disperse blood clots preferably, cerebrovascular circulates to improving, the cerebral blood flow increasing amount has obvious effects, it is effective preparation of treatment cerebral infarction, in recent years find, breviscapine also has good dilating effect to cardiovascular, can reduce Peripheral resistance, reduce myocardial oxygen consumption, promote collateral circulation, suppress platelet aggregation, angina pectoris is had curative effect preferably.Existing Breviscapini injection has function of promoting blood circulation to disperse blood clots preferably, but its no QI invigorating effect.
Summary of the invention
Purpose of the present invention just provides a kind of injectable drug for the treatment of cardiovascular and cerebrovascular disease, this injectable drug have very strong replenishing qi and promoting blood flow effect, again can blood circulation promoting and blood stasis dispelling, QI and blood is ruled together, the curative effect height.
The technical solution adopted for the present invention to solve the technical problems is: a kind of injectable drug for the treatment of cardiovascular and cerebrovascular disease, it is that two kinds of raw materials of high-purity Radix Astragali saponin more than 80% are made by breviscapine and the purity that extracts from the Radix Astragali, and in the Radix Astragali saponin, the content of astragaloside is at 20%-30%.
The raw materials used weight proportion of medicine of the present invention can be 1 part of a high-purity Radix Astragali saponin more than 80% for: the purity that extracts from the Radix Astragali, breviscapine 0.1-10 part.
The raw materials used optimum ratio of medicine of the present invention is: 1 part of high-purity Radix Astragali saponin, breviscapine 0.2-5 part.Preferred proportioning is: 1 part of high-purity Radix Astragali saponin, breviscapine 0.5-2 part.Best proportioning then is: 1 part of high-purity Radix Astragali saponin, 1 part of breviscapine.
The dosage form of medicine of the present invention can be injection, transfusion, powder pin, etc. injecting and administering preparations dosage form dosage form.
The cardiovascular and cerebrovascular disease of being controlled mainly comprises cerebral thrombosis, cerebral ischemia, coronary heart disease, angina pectoris, myocardial ischemia, heart failure, arrhythmia etc.
Compared with prior art, the invention has the beneficial effects as follows:
This injectable drug contains breviscapine and high-purity Radix Astragali saponin, so its replenishing qi and promoting blood flow effect strengthens greatly, again can activating blood circulation to dissipate blood stasis, and QI and blood is ruled together, and produces synergism.Than low by purity, but the medicine that the breviscapine of identical Radix Astragali saponin of total saponin content and same amount is made, effect improves greatly; Simultaneously, in the high-purity Radix Astragali saponin, the effective constituent Astragaloside content that mainly contains of poorly water-soluble is controlled in the scope of 20%-30%, both made the curative effect of said preparation, preparation curative effect than low content astragaloside is higher, also make in the preparation particulate matter few, meet the injecting drug use requirement, guarantee drug safety.
The curative effect of medicine of the present invention improves greatly than with the low-purity Radix Astragali saponin of content with the effect of drugs that the content breviscapine is made, and can be proved by following pharmacology, pharmacodynamics test:
One, Radix Astragali saponin uses determining of purity
The Radix Astragali is as medicinal herbs most in use, and " Chinese pharmacopoeia has been stipulated oral crude drug amount.The Radix Astragali can obtain the Radix Astragali saponin of different purity and content through the extraction separation purification, and its best purity does not have bibliographical information, for determine to use the Radix Astragali saponin of what purity in this prescription, has carried out the pharmacological evaluation work of purity screening.Select the classical experimental project of QI invigorating experiment for use.
Experiment material:
Medicine: Radix Astragali saponin extract, purity: 20-80%.
Animal: Kunming mouse, male and female half and half, Mus 8 weeks of age, body weight 18～22g.
Experimental technique and result:
Get 60 of Kunming mouses, male and female half and half are divided into 6 groups at random, 10 every group.Except that the normal control group, all the other each groups all adopt starvation method (by Qi Chen's " herbal pharmacology research methodology " mice model of qi-asthenia method) preparation mice model of qi-asthenia, press medicine shown in the table 1 and the administration of dosage tail vein injection simultaneously, normal control group and model of qi-asthenia group injection isometric(al) normal saline, every day 1 time, successive administration 5 days, each organizes 30min after the last administration, in 25 ℃ of warm water, survey swimming time when respectively organizing mice and bearing a heavy burden (1/10 body weight) (with animal occur natural subsidence 10s do not refloat exceed), the results are shown in Table 2:
Table 1 dosage regimen
The Radix Astragali extract of table 2 different purity is to the influence of deficiency of vital energy mice swimming time
(each administration group all compares * P＜0.05 with model group, compares #P＜0.05 between * * P＜0.01 administration group mutually)
By table as seen: compare with the normal control group, the swimming time of model of qi-asthenia group obviously shortens, and shows the modeling success; Radix Astragali saponin different purity group all has prolongation to the swimming time of model of qi-asthenia group mice, and is the purity positive correlation, and purity is 80% experimental group, obviously is better than purity and is 20% experimental group, and P＜0.05 also is better than 40% purity group.
Two, high-purity Radix Astragali saponin consumption determines
Purity 80% or surpass 80% Radix Astragali saponin, its use amount does not have bibliographical information, for investigating whether science of its consumption, has carried out the pharmacological evaluation work that dosage is confirmed.Select the classical experimental project of QI invigorating experiment for use.
Experiment material:
Medicine: Radix Astragali saponin extract, purity 85%, concentration: during test extract is mixed with variable concentrations and uses.Radix Astragali injection, Heilongjiang Province Zhenbaodao Pharmaceutical Co., Ltd, lot number 20030106.
Animal: Kunming mouse, male and female half and half, Mus 8 weeks of age, body weight 18～22g.
Experimental technique and result:
Get 70 of Kunming mouses, male and female half and half are divided into 6 groups at random, 10 every group.Except that the normal control group, all the other each groups all adopt starvation method (by Qi Chen's " herbal pharmacology research methodology " mice model of qi-asthenia method) preparation mice model of qi-asthenia, press medicine shown in the table 3 and the administration of dosage tail vein injection simultaneously, normal control group and model of qi-asthenia group injection isometric(al) normal saline, every day 1 time, successive administration 5 days, each organizes 30min after the last administration, in 25 ℃ of warm water, survey swimming time when respectively organizing mice and bearing a heavy burden (1/10 body weight) (with animal occur natural subsidence 10s do not refloat exceed), the results are shown in Table 4:
Table 3 dosage regimen
The Radix Astragali total saponins of table 4 various dose is to the influence of deficiency of vital energy mice swimming time
(each administration group all compares *＜0.05, * * P＜0.01 with model group)
By table as seen: compare with the normal control group, the swimming time of model of qi-asthenia group obviously shortens, and shows the modeling success; The above dosage group of Radix Astragali extract group 3.33mg/kg is to the swimming time significant prolongation (P＜0.01) of model of qi-asthenia group mice, and the above dosage group of prompting Radix Astragali extract group 3.33mg/kg has remarkable QI invigorating effect.Amount to human dosage and be 0.16mg/kg and have significant QI invigorating effect when above, the consumption per day of being grown up should be about 10mg.
Three, the breviscapine consumption determines
At present, the consumption of the preparation intravenously administrable of breviscapine list marketing is 5mg-20mg/ day, and with reference to relevant document, the dosage of 10mg-20mg/ day is comparatively desirable.Be the optimal dose of investigating breviscapine and the dosage of verifying bibliographical information, at this index of blood circulation promoting and blood stasis dispelling, we have carried out following research.
Get 50 of Kunming mouses, be divided into 5 groups at random, 10 every group, male and female half and half.Lumbar injection 0.45% pentobarbital sodium 0.1ml/10g anesthesia is fixed on the mice ventricumbent position on the mice observation platform then during experiment, drips a little cedar oil in the auricle surface, and auricle is tiled in the ear holder, puts on the microscope carrier.Tail vein injection Adr10ml/kg (1mg/100ml), be administered once by medicine shown in the table and dosage tail vein injection simultaneously, then with before 40 times of sem observation administrations and after the administration 5,15min Auricle Microcirculation arteriole caliber and the open net number of blood capillary, the results are shown in Table 5-table 6.The result shows that breviscapine is with effect is preferably arranged more than the 1.67mg/kg, and according to relevant document, human dosage is effective in 8mg/ day.
Four, the proportion research of high-purity Radix Astragali saponin and breviscapine
Rat internal carotid artery injection thrombosis local cerebral ischemia model test: 80 of Wistar kind rats, male and female half and half, body weight 200～250g is divided into 8 groups at random, and 10 every group, press medicine shown in the table 7 and the administration of dosage tail vein injection, 1 time/day, continuous 7 days.30min after the last administration, animal is fixed the back heart extracting blood with chloral hydrate (350mg/kg) anesthesia, presses the light red thrombosis about 10 diameter 0.35mm of document preparation; Separating animal's left side neck is total, neck interior and external carotid artery, and temporary transient bulldog clamp folder closes common carotid artery, cuts an osculum from external carotid artery apart from the about 1cm of common carotid artery crotch, intubate is injected thrombosis, the ligation external carotid artery recovers the common carotid artery blood supply, and sham operated rats is only injected normal saline.After this after 24 hours the animal sacrificed by decapitation is got brain in injecting thrombosis, weigh ,-20 ℃ after freezing 30 minutes, section, infarcted region and non-infarcted region are carefully cut in 37 ℃ of dyeing of 2%TTC solution 15 minutes, weigh respectively, calculate infarcted region percentage ratio.Infarcted region percentage ratio=infarcted region weight ÷ brain gross weight * 100% the results are shown in Table 8.
Table 7 DENGHUANG ZHUSHEYE proportioning screening experiment dosage regimen
Table 8 DENGHUANG ZHUSHEYE is to the influence of rat suppository local cerebral ischemia model infarct
(model group and sham operated rats be △＜0.05 relatively, and each administration group of △ △＜0.01 all compares *＜0.05 with model group, compares #P＜0.05 between * * P＜0.01 administration group mutually))
Table 8 shows, compares with sham operated rats, and the infarcted region area had significance to change (P＜0.01) after the model group rat was injected thrombosis, showed the modeling success.All the have some improvement effect of infarcted region ratio of the independent use of high-purity Radix Astragali saponin and breviscapine, breviscapine is better than the high-purity Radix Astragali saponin, but both there was no significant differences.High-purity Radix Astragali saponin and breviscapine share, and can significantly improve infarcted region ratio (P＜0.01), and from the proportioning ratio as can be known, the two ratio the best of 1: 1 obviously is better than single Radix Astragali total saponins group of using.
Myocardial infarction and ischemia model test due to the medicine method
70 of healthy careless dogs, body weight 8.5～12.5kg, the male and female dual-purpose is divided into 7 groups, 10 every group.Through with sodium pentobarbital 30mg/kg intravenous anesthesia, fixing back, back of the body position with the safe BL-420 of alliance type biological function signaling system according to the standard I I connection lead that leads, according to medicine shown in the table 9 and dosed administration.One section normal II of record ECG that leads behind the administration 15min, iv pituitrin 1u/kg then, 15s, 30s, 1min, 2min, 3min, 4min, 5min, 10min, 15min, 20min write down the II ECG that leads respectively after administration, and with the T ripple of any time wherein or ST section rising 0.1mv or decline 0.05mv as the positive number of animals of myocardial ischemia, result of the test is made the Fisher Precision Test with SPSS software and is organized a significant difference relatively, the results are shown in Table 10.
Table 9 DENGHUANG ZHUSHEYE proportioning screening experiment dosage regimen
Table 10 DENGHUANG ZHUSHEYE is to the influence of T ripple displacement
Table 10 shows that the independent use of high-purity Radix Astragali saponin and breviscapine all has the significant effect that improves the drug-induced myocardial ischemia to the electrocardiogram influence, and the high-purity Radix Astragali saponin is better than breviscapine, but both there was no significant differences.High-purity Radix Astragali saponin and breviscapine share, and can significantly improve T ripple displacement (P＜0.01), from the proportioning ratio as can be known, and the two ratio the best of 1: 1.
Injectable drug is in the form of administration of cardiovascular and cerebrovascular disease medication, intravenously administrable is the dosage form that suits, " Chinese Pharmacopoeia 2005 editions " regulation, intravenous administration formulation should carry out visible foreign matters, particulate matter, related substances such as tannin, protein, aseptic, pyrogen or bacterial endotoxin, the preparation security inspection, and should meet the pharmacopeia related request.
Under study for action, the purity of Radix Astragali saponin and the content of astragaloside are key technologies, and the purity of Radix Astragali saponin directly influences the security features of preparation.Behind the Radix Astragali saponin and breviscapine combination with different purity, the parallel safety evaluatio that carries out.Selecting index for use is the models of passive skin irritability of rats test.
Get 30 of the male rats of body weight 150～200g, be divided into 10 groups at random, promptly test product (corresponding Radix Astragali saponin+breviscapine composition solution), 3 every group are organized and be subjected to negative control (0.9% sodium chloride injection) group, positive control (1% ovalbumin).Respectively organize rat by group and inject said medicine 0.15ml respectively in two lower limbs, lumbar injection pertussis vaccine 0.1ml/ only simultaneously.Broken end is got blood after 14 days, collects 3 groups of antiserums respectively, and each organizes antiserum mixing respectively ,-20 ℃ of freezing preservations.
Choose 100 rats, Mus 6～8 weeks of age, body weight 150～200g, be divided into 10 groups at random, every group 10, male and female half and half, promptly 0.9% sodium chloride injection (dilution in 1: 5) is organized, ovalbumin (dilution in 1: 5) group, 20% Radix Astragali saponin+breviscapine (dilution in 1: 5) group, 20% Radix Astragali saponin+breviscapine (dilution in 1: 10) group, 40% Radix Astragali saponin+breviscapine (dilution in 1: 5) group, 40% Radix Astragali saponin+breviscapine (dilution in 1: 10) group, 60% Radix Astragali saponin+breviscapine (dilution in 1: 5) group, 60% Radix Astragali saponin+breviscapine (dilution in 1: 10) group, 80% Radix Astragali saponin+breviscapine (dilution in 1: 5) group, 80% Radix Astragali saponin+breviscapine (dilution in 1: 10) group.Get above-mentioned each medicine antiserum and be diluted to different dilution factors, organize every rat stomach wall intradermal injection 2 points, every some 0.03ml in each by group with 0.9% sodium chloride.
Each carries out the antigen attack after organizing sensitization 48h immediately.Promptly by group tail vein injection 0.9% sodium chloride injection, 1% ovalbumin, corresponding Radix Astragali saponin+breviscapine composition solution 0.2ml/ only, above solution is all prepared with 0.5% azovan blue-0.9% sodium chloride.Sacrificed by decapitation animal behind the 30min is cut blue speckle skin graft, shreds, and adds acetone-normal saline (7: 3) mixed liquor 5ml, soaks 48h, and is centrifugal, gets supernatant and surveys trap at wavelength 610nm place, the results are shown in Table 11.
Table 11 models of passive skin irritability of rats result of the test
Annotate: each administration group and 0.9% sodium chloride injection group be * P＜0.05 * P＜0.05 * * * P＜0.001 relatively
Table 11 shows that the purity of Radix Astragali saponin becomes negative correlativing relation with locus coeruleus leachate absorbance, shows that purity is high more, and it is low more that medicine causes taking place the irritated degree that reflects.For the safety of pharmaceutical preparation, should select the high-purity Radix Astragali saponin for use.
In Radix Astragali saponin, contain the monomeric substance of at least 5 kinds of Radix Astragali saponins, wherein astragaloside is most important a kind of, the dissolubility of astragaloside in water is relatively poor.Therefore, in the control Radix Astragali saponin content of astragaloside can be prepared as intravenous administration formulation to said composition most important.In the research, will contain the Radix Astragali saponin and the breviscapine compatibility of different content astragaloside, carry out the inspection of insoluble matter microgranule, to determine the content of astragaloside.
80% high-purity Radix Astragali saponin that table 12 Astragaloside content is different and breviscapine compatibility particulate matter and curative effect are investigated, pharmacodynamics selects for use rat internal carotid artery injection thrombosis local cerebral ischemia model test to screen, and measures the change of zymetology index in the mass percent of respectively organizing infarct and the brain homogenate.
Annotate: each administration group of pharmacodynamic study and model group be * P＜0.05 * * P＜0.01 * * * P＜0.001 relatively
Table 12 shows that the drug effect dissolubility of the content of astragaloside and this injectable drug is closely related in the Radix Astragali saponin, and Astragaloside content is high more, and curative effect is good more, but dissolubility is poor more; When Astragaloside content surpasses 30%, particulate matter does not reach the pharmacopeia requirement; Content is lower than 20%, and curative effect is undesirable, and after content surpassed 20%, curative effect of medication increased not obvious, had reached maximum usefulness substantially, so the suitable content of astragaloside is 20-30%
In a word, Radix Astragali first soap content had both made the therapeutic effect of medicine best when 20%-30%, again preparation during injection its solubility best, meet the pharmacopeia requirement, can be directly effectively in being injected into body, play a role.
Another object of the present invention provides a kind of method for preparing the injectable drug of the described treatment cardiovascular and cerebrovascular disease of claim 1 of preparation method of the injectable drug of above-mentioned treatment cardiovascular and cerebrovascular disease, and its concrete practice is:
(1), from Milkvetch Root, extract the high-purity Radix Astragali saponin:
A, alcohol extraction: cut into the thick oblique sheet of 2～3mm, add the 60-80% ethanol of 3-5 times of medical material amount, circulating reflux leaches to be extracted 4-6 hour, and extraction temperature is 40～50 ℃, merges ethanol, gets extracting solution;
B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, add ethanol again and be 70-85%, leave standstill, filter to containing the alcohol amount; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, Milkvetch Root weight 0.5-2 water doubly when adding alcohol extraction again, cold preservation is left standstill, filter filtrate;
C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post (film) ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion;
D, extraction: the Na that the extractum in c step is added 2-4%
2CO
3, penetrate with water-saturated n-butanol that to be extracted to no Liebermann reaction be acetic anhydride-strong sulfuric acid response;
E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds an amount of calcium carbonate, stirs, and there not to be obvious agglomerate degree of being, gets the titanium pillaring solution thing;
F: washing: e is gone on foot acetone-ether that gained titanium pillaring solution thing doubly measures with 2-4, and (0.5-2: 1) water-bath refluxes 3 times, each 20-40 minute, filters; The titanium pillaring solution thing, reclaims ethanol, and in 50-70 ℃ of vacuum drying, collects dry solid content to colourless with alcohol reflux.
Radix Astragali saponin purity by this method preparation is not less than 80%, and Radix Astragali saponin also is that the content of astragaloside in the total saponins is at 20-30%.
(2), preparation: behind the high-purity Radix Astragali saponin uniform mixing that breviscapine and (1) step is extracted, add auxiliary agent, preparation, promptly.
Preparation method of the present invention, it is extracted as the 60-80% ethanol extraction, and purification process is precipitate with ethanol, ultrafiltration, extraction, absorption, washing etc.And existing Radix Astragali extracting method is a water extract-alcohol precipitation, because technology is too simple, makes that impurity contents such as flavone in the extract of gained and the related preparations, polysaccharide are more, and Radix Astragali saponin purity is all below 30%; And this method is at the physicochemical properties of Radix Astragali saponin, the extraction and purification process of design: 1, through the low concentration alcohol extraction, the impurity of proposing proposition than water lacks; 2, higher concentration precipitate with ethanol can effectively be removed impurity such as polysaccharide; 3, ultrafiltration: can effectively remove macromole impurity; 4, extraction can be removed low polar impurity; 5, absorption, washing are to remove meta-alkalescence impurity.These steps are committed step such as ultrafiltration, extraction especially, has removed all kinds of impurity to greatest extent, makes that the purity of Radix Astragali saponin is brought up to more than 80% in the extract, reaches as high as 95%; Avoid the highly basic processing simultaneously, made Astragaloside content be controlled in the 20-30% scope.
The specific embodiment
The present invention is described in further detail below in conjunction with the specific embodiment.
Embodiment one:
The concrete practice of this example is:
(1), extract the high-purity Radix Astragali saponin:
A, alcohol extraction: Milkvetch Root is cut into the thick oblique sheet of 2～3mm, add 70% ethanol of 4 times of medical material amounts, circulating reflux leaches to be extracted 5 hours, and extraction temperature is 45 ℃, merges ethanol, gets extracting solution.B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, and adding ethanol again is 80% to containing the alcohol amount, leaves standstill, and filters; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, the water of 2 times of Milkvetch Root weight when adding alcohol extraction again, cold preservation is left standstill, filter filtrate.C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post (film) ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion.D, extraction: the Na that the extractum in c step is added extractum amount 3%
2CO
3, penetrate with water saturated n-butyl alcohol that to be extracted to no Liebermann reaction be acetic anhydride-strong sulfuric acid response.E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds calcium carbonate, stirs, and the addition of calcium carbonate gets the titanium pillaring solution thing there not to be obvious agglomerate degree of being.F: washing: e is gone on foot gained titanium pillaring solution thing reflux 3 times with acetone-ether (1: 1) water-bath of 3 times of amounts, each 30 minutes, filtration; The titanium pillaring solution thing, reclaims ethanol, and in 60 ℃ of vacuum dryings, collects dry solid content to colourless with alcohol reflux, promptly makes purity and be the high-purity Radix Astragali saponin more than 80%, and wherein the content of astragaloside is 22-25%.
(2), preparation: behind the high-purity Radix Astragali saponin uniform mixing more than 80% that the above step of 1 part of heavy breviscapine and 1 part heavy is extracted, add ejection preparation and carry out preparation with adjuvant, the existing injection technology of employing, promptly getting weight proportion is: 1 part of high-purity Radix Astragali saponin, the injection that breviscapine is 1 part.
Embodiment two
The concrete practice of this example is:
(1), extract the high-purity Radix Astragali saponin:
A, alcohol extraction: Milkvetch Root is cut into the thick oblique sheet of 2～3mm, add 80% ethanol of 5 times of medical material amounts, circulating reflux leaches to be extracted 6 hours, and extraction temperature is 50 ℃, merges ethanol, gets extracting solution; B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, and adding ethanol again is 85% to containing the alcohol amount, leaves standstill, and filters; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, the water of 2 times of Milkvetch Root weight when adding alcohol extraction again, cold preservation is left standstill, filter filtrate; C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post (film) ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion; D, extraction: the Na that the extractum in c step is added extractum amount 4%
2CO
3, penetrate with water saturated n-butyl alcohol and to be extracted to no Liebermann reaction; E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds calcium carbonate, stirs, and the addition of calcium carbonate gets the titanium pillaring solution thing there not to be obvious agglomerate degree of being; F: washing: e is gone on foot gained titanium pillaring solution thing reflux 4 times with acetone-ether (2: 1) water-bath of 4 times of amounts, each 40 minutes, filtration; The titanium pillaring solution thing, reclaims ethanol, and in 70 ℃ of vacuum dryings, collects dry solid content to colourless with alcohol reflux, promptly makes purity and be the high-purity Radix Astragali saponin more than 80%, and wherein the content of astragaloside is 20-26%.
(2), preparation: behind the high-purity Radix Astragali saponin uniform mixing that above (1) of 1.5 parts of heavy breviscapines and 1 part of weight step is extracted, the existing powder injection formulation technology of adjuvant commonly used, employing that adds the preparation powder injection formulation is carried out preparation, promptly getting weight proportion is: 1 part of high-purity Radix Astragali saponin, the injectable powder that breviscapine is 1.5 parts.
Embodiment three
The concrete practice of this example is:
(1), extract the high-purity Radix Astragali saponin:
A, alcohol extraction: Milkvetch Root is cut into the thick oblique sheet of 2～3mm, add 60% ethanol of 3 times of medical material amounts, circulating reflux leaches to be extracted 4 hours, and extraction temperature is 40 ℃, merges ethanol, gets extracting solution;
B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, and adding ethanol again is 70% to containing the alcohol amount, leaves standstill, and filters; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, the water of 0.5 times of Milkvetch Root weight when adding alcohol extraction again, cold preservation is left standstill, filter filtrate;
C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post (film) ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion;
D, extraction: the Na that the extractum in c step is added extractum amount 2%
2CO
3, penetrate with water saturated n-butyl alcohol and to be extracted to no Liebermann reaction;
E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds calcium carbonate, stirs, and the addition of calcium carbonate gets the titanium pillaring solution thing there not to be obvious agglomerate degree of being;
F: washing: e is gone on foot gained titanium pillaring solution thing reflux 2 times with acetone-ether (0.5: 1) water-bath of 2 times of amounts, each 20 minutes, filtration; The titanium pillaring solution thing, reclaims ethanol, and in 50 ℃ of vacuum dryings, collects dry solid content to colourless with alcohol reflux, promptly makes purity and be the high-purity Radix Astragali saponin more than 80%, and wherein the content of astragaloside is 24-30%.
(2), preparation: behind the high-purity Radix Astragali saponin uniform mixing that above (1) of 5 parts of heavy breviscapines and 1 part of weight step is extracted, the existing preparation process of adjuvant, employing that adds transfusion carries out preparation, promptly getting weight proportion is: 1 part of high-purity Radix Astragali saponin, the flow of infusate that breviscapine is 5 parts.
Embodiment four
The concrete practice of this example is:
(1), extract the high-purity Radix Astragali saponin:
A, alcohol extraction: Milkvetch Root is cut into the thick oblique sheet of 2～3mm, add 75% ethanol of 4 times of medical material amounts, circulating reflux leaches to be extracted 4.5 hours, and extraction temperature is 50 ℃, merges ethanol, gets extracting solution;
B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, and adding ethanol again is 75% to containing the alcohol amount, leaves standstill, and filters; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, the water of 1.5 times of Milkvetch Root weight when adding alcohol extraction again, cold preservation is left standstill, filter filtrate;
C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post (film) ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion;
D, extraction: the Na that the extractum in c step is added extractum amount 3.5%
2CO
3, penetrate with water saturated n-butyl alcohol and to be extracted to no Liebermann reaction;
E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds calcium carbonate, stirs, and the addition of calcium carbonate gets the titanium pillaring solution thing there not to be obvious agglomerate degree of being;
F: washing: e is gone on foot gained titanium pillaring solution thing reflux 3 times with acetone-ether (1.5: 1) water-bath of 3 times of amounts, each 40 minutes, filtration; The titanium pillaring solution thing, reclaims ethanol, and in 65 ℃ of vacuum dryings, collects dry solid content to colourless with alcohol reflux, promptly makes purity and be the high-purity Radix Astragali saponin more than 80%, and wherein the content of astragaloside is 24-28%.
(2), preparation: behind the high-purity Radix Astragali saponin uniform mixing that above (1) of 0.5 part of heavy breviscapine and 1 part of weight step is extracted, add the infusion preparation adjuvant, adopt existing infusion preparation technology to carry out preparation, promptly getting weight proportion is: 1 part of high-purity Radix Astragali saponin, the flow of infusate that breviscapine is 0.5 part.
Embodiment five
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 0.2.
Embodiment six
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 2.
Embodiment seven
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 0.1.
Embodiment eight
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 10.
Embodiment eight
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 4.
Embodiment nine
The concrete practice and the embodiment one of this example are basic identical, and different only is: the weight proportion of high-purity Radix Astragali saponin and breviscapine is: 1: 8.
Obviously, the purity of the high-purity Radix Astragali saponin of indication of the present invention is more than 80%, comprises 80% this endpoint value.
The Reinheitszahl of the high-purity Radix Astragali saponin that extracts from Milkvetch Root with method of the present invention can differently because of the quality of Milkvetch Root change to some extent; But as long as the quality of Milkvetch Root meets the Chinese Pharmacopoeia requirement, the purity of the high-purity Radix Astragali saponin that extracts promptly is not less than 80%, and the content of astragaloside also should be controlled at 20-30% in the total saponins.
Claims (7)
1. injectable drug for the treatment of cardiovascular and cerebrovascular disease, it is that two kinds of raw materials of high-purity Radix Astragali saponin more than 80% are made by breviscapine and the purity that extracts from the Radix Astragali, and the content of astragaloside is 20-30% in the high-purity Radix Astragali saponin.
2. the injectable drug of treatment cardiovascular and cerebrovascular disease according to claim 1 is characterized in that: the weight proportion of described two kinds of raw materials is: 1 part of high-purity Radix Astragali saponin, breviscapine 0.1-10 part.
3. the injectable drug of treatment cardiovascular and cerebrovascular disease according to claim 2 is characterized in that: the weight proportion of described two kinds of raw materials is: 1 part of high-purity Radix Astragali saponin, breviscapine 0.2-5 part.
4. the injectable drug of treatment cardiovascular and cerebrovascular disease according to claim 3 is characterized in that: the weight proportion of described two kinds of raw materials is: 1 part of high-purity Radix Astragali saponin, breviscapine 0.5-2 part.
5. the injectable drug of treatment cardiovascular and cerebrovascular disease according to claim 4 is characterized in that: the weight proportion of described two kinds of raw materials is: 1 part of high-purity Radix Astragali saponin, 1 part of breviscapine.
6. according to claim 1 or 2 or 3 or the injectable drug of 4 or 5 described treatment cardiovascular and cerebrovascular disease, it is characterized in that: its dosage form is injection, transfusion, powder pin.
7. one kind prepares claim 1 or 2 or 3 or the method for the injectable drug of 4 or 5 described treatment cardiovascular and cerebrovascular disease, and its concrete practice is:
(1), extract the high-purity Radix Astragali saponin:
A, alcohol extraction: Milkvetch Root is cut into the thick oblique sheet of 2～3mm, add the 60-80% ethanol of 3-5 times of medical material amount, circulating reflux leaches to be extracted 4-6 hour, and extraction temperature is 40～50 ℃, merges ethanol, gets extracting solution;
B, precipitate with ethanol: the extracting solution decompression recycling ethanol in a step is not distinguished the flavor of to there being alcohol, add ethanol again and be 70-85%, leave standstill, filter to containing the alcohol amount; Filtrate once more decompression recycling ethanol to there not being the alcohol flavor, Milkvetch Root weight 0.5-2 water doubly when adding alcohol extraction again, cold preservation is left standstill, filter filtrate;
C, ultrafiltration: the filtrate in b step is carried out 〉=20000 rev/mins high speed centrifugation filtration with tube centrifuge, and the clear liquid molecular cut off is ultrafiltration post or the ultrafilter membrane ultrafiltration of 6000-10000; Ultrafiltration concentration liquid is 1.0～1.1 extractum to proportion;
D, extraction: the Na that the extractum in c step is added extractum amount 2-4%
2CO
3, penetrate with water saturated n-butyl alcohol and to be extracted to no acetic anhydride-strong sulfuric acid response;
E, absorption: concentrating under reduced pressure n-butyl alcohol liquid is done near, adds calcium carbonate, stirs, and the addition of calcium carbonate gets the titanium pillaring solution thing there not to be obvious agglomerate degree of being;
F: washing: e is gone on foot the acetone that gained titanium pillaring solution thing doubly measures with 2-4-ether water-bath backflow 2-4 time, and each 20-40 minute, wherein the ratio of acetone-ether was 0.5-2: 1, and filtration; The titanium pillaring solution thing, reclaims ethanol, and in 50-70 ℃ of vacuum drying, collects dry solid content to colourless with alcohol reflux, promptly makes purity and be the high-purity Radix Astragali saponin more than 80%, and in the Radix Astragali saponin content of astragaloside at 20%-30%.
(2), preparation: the high-purity Radix Astragali saponin that breviscapine and (1) step is extracted in described ratio uniform mixing after, preparation, promptly.
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| CN1528325A (en) * | 2003-09-29 | 2004-09-15 | 成都和康药业有限责任公司 | Medicinal composition for treating cardio-cerebro-vascular diseases |
| CN1569884A (en) * | 2004-04-29 | 2005-01-26 | 南京医科大学 | Method for preparing astragaloside and its use in preparation of drug for preventing and treating diabetic nephropathy |
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| CN1528325A (en) * | 2003-09-29 | 2004-09-15 | 成都和康药业有限责任公司 | Medicinal composition for treating cardio-cerebro-vascular diseases |
| CN1569884A (en) * | 2004-04-29 | 2005-01-26 | 南京医科大学 | Method for preparing astragaloside and its use in preparation of drug for preventing and treating diabetic nephropathy |
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| Title |
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| 黄芪和灯盏花素注射液治疗充血性心力衰竭临床观察. 詹克学.河南中医学院学报，第19卷第113期. 2004 |
| 黄芪和灯盏花素注射液治疗充血性心力衰竭临床观察. 詹克学.河南中医学院学报，第19卷第113期. 2004 * |
| 黄芪注射液与灯盏花素注射液合用治疗脑梗死. 刘君等.现代中西医结合杂志，第12卷第20期. 2003 |
| 黄芪注射液与灯盏花素注射液合用治疗脑梗死. 刘君等.现代中西医结合杂志，第12卷第20期. 2003 * |
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