CN100536868C - Powder injection contg high content tanshin polyphenolic acid salts, and its preparation method - Google Patents
Powder injection contg high content tanshin polyphenolic acid salts, and its preparation method Download PDFInfo
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- CN100536868C CN100536868C CNB2005100287407A CN200510028740A CN100536868C CN 100536868 C CN100536868 C CN 100536868C CN B2005100287407 A CNB2005100287407 A CN B2005100287407A CN 200510028740 A CN200510028740 A CN 200510028740A CN 100536868 C CN100536868 C CN 100536868C
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Abstract
A high-content powder injection of polydanshinolate for treating cardiovascular disease contains magnesium danshinoacetate (50-95%) and polydanshinolate (about 100%). Its preparing process is also disclosed.
Description
Technical field:
The invention belongs to technical field of Chinese medicines.Be specifically related to a kind of high content salvianolate injectable powder and preparation method thereof.
Background technology:
In recent years, the sickness rate of cardiovascular disease increases year by year, according to statistics at present in state-owned hyperpietic people more than 100,000,000, patients with coronary heart disease more than 1,000 ten thousand.Cardiovascular disease becomes " first killer " of harm people ' s health gradually.Seek and emphasis that to develop effective treating cardiovascular disease medicine be the drug research field always.Chinese medicine has shown very strong superiority in this area, wherein comparatively famous is Radix Salviae Miltiorrhizae and preparation thereof.Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge) is one of traditional blood-activating and stasis-removing, and secular clinical practice basis is arranged.Radix Salviae Miltiorrhizae Injection is the common drug for the treatment of diseases such as coronary heart disease, angina pectoris, myocardial infarction, cerebral infarction clinically, but existing injection is indeterminate because of effective ingredient, the not strict clinical efficacy instability that causes of quality control index, untoward reaction occurs often, has not met the modernization of Chinese medicine and has moved towards international requirement.The appearance of these problems, key are that the effective ingredient of Radix Salviae Miltiorrhizae fails to illustrate fully.
The inventor has carried out the systematic study of the water soluble ingredient of Radix Salviae Miltiorrhizae, the aqueous soluble active constituent of finding Radix Salviae Miltiorrhizae all is present in the raw medicinal herbs with the form of salt, and these compositions are mainly Radix Salviae Miltiorrhizae acetate magnesium and homologue thereof: alkannic acid magnesium, rosmarinic acid sodium, Radix Salviae Miltiorrhizae acetic acid dipotassium, different Radix Salviae Miltiorrhizae acetic acid dipotassium, danshensu potassium and alkannic acid dipotassium etc.Find by screening active ingredients and pharmaceutical research: Radix Salviae Miltiorrhizae acetate magnesium and its homologue are active component, wherein the strongest with the Radix Salviae Miltiorrhizae acetate magnesium pharmacological action, it is the main active of Radix Salviae Miltiorrhizae, and to illustrate first with the Radix Salviae Miltiorrhizae acetate magnesium be that the polyphenol hydrochlorate of main component is most important effective active position in the Radix Salviae Miltiorrhizae.
Summary of the invention:
Technical problem to be solved by this invention is to overcome the weak point of existing red sage formulation, the effective poly phenolic acid of Radix Salviae Miltiorrhizae salt pref that research design is new.
The invention provides a kind of high content salvianolate injectable powder.
The content of Radix Salviae Miltiorrhizae acetate magnesium is 50%-95% in many salvianolates of high-load injectable powder of the present invention, and salvianolate effective site content is near 100%.
Another purpose of the present invention provides the preparation method of high content salvianolate injectable powder.
For solving the preparation problem, the inventor has carried out the conceptual design of preparation method,
1, extracts the selected of solvent
The effective ingredient of salvianolate is Radix Salviae Miltiorrhizae acetate and homologue thereof, and the inventor is with the quality control index of Radix Salviae Miltiorrhizae acetate as raw material, and such polyphenol phosphate compounds is water soluble ingredient, and therefore, the most effective extraction solvent is water and aqueous alcohol.Select water, 70% aqueous methanol or ethanol extract respectively, and extracting solution is analyzed the content (as table 1) of contained Radix Salviae Miltiorrhizae acetate with HPLC
The extraction efficiency of the different solvents that extract of table 1
The crude drug amount is 20 grams, 100ml extracting solution reflux, extract, three times, and each 2 hours, after merge extractive liquid, is concentrated into organic solvent-free, after last macroporous resin is tentatively removed sugar, peptide class impurity, 50% ethanol elution, eluent is concentrated into dried, and extraction ratio is calculated in weighing.After being configured to the finite concentration sample solution, carry out the HPLC quantitative analysis respectively, calculate Radix Salviae Miltiorrhizae acetate content.
Normalization method content in the table 1 can reflect the content of Radix Salviae Miltiorrhizae acetate in total polyphenol Barbiturates chemical compound, and actual measurement content then is the content of Radix Salviae Miltiorrhizae acetate in the extract that obtains.Although 70% ethanol extract, no matter normalization method content still is actual content all is better than other extraction method, but consider from economic angle, water extraction also has advantage as a kind of Chinese herbal medicine extracting method commonly used, in addition, aqueous extract can directly be adsorbed in next step macroporous resin, omitted the step of concentrating under reduced pressure, and the impurity that contains in the water extract mostly is impurity such as sugar that in next step macroporous resin chromatography water can eluting, protein greatly, and it is also better relatively to extract yield, therefore, the present invention is defined as water extraction with extracting method.
2, separation method is selected
Isolating purpose mainly is in order to obtain to conform with the product of injecting drug use prescription.The refining main alcohol deposition method that relies on of traditional medical herbs injection, alcohol deposition method can be removed resin, protein and the polysaccharide etc. of more macromolecule, but be difficult to remove micromolecular nucleotide and saccharide, this can only be a kind of thick extracted extract, its active constituent content is often not high, and its quality also can be subjected to about the quality institute of raw medicinal herbs.
Utilize modern chromatographic technique can obtain highly purified product, the existence form that can keep poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds organic salt, and the different salt of same polyphenol acid can be separated, it is refining to be fit to very much this product separation, but, the reversed phase chromatography carrier that adopts in laboratory research costs an arm and a leg mostly as MCI GEL CHP20P or Toyopearl HW40F etc., is not suitable for production extensive, economy.Macroporous resin is the more in recent years chromatography carrier that is used for industrialization plant component separation and purification, it is a kind of poly-divinylbenzene porous polymer, absorbability to the water solublity phenoloid is greater than the water solublity neutral compound, can be used for the initial gross separation and the desaccharide of plant component and takes off inorganic salt.And the inventor finds in test, the chromatography behavior of macroporous adsorbent resin and MCI GEL CHP20P similar (Fig. 1).
As shown in Figure 1, the absorbability of the different chemical compounds in the Radix Salviae Miltiorrhizae extract on 1300-I macroporous adsorption resin chromatography post has nothing in common with each other, and wherein sugar, protein and inorganic salt etc. can't be by resin absorptioies, and this is very beneficial for the removal of macromole class impurity; The relatively low chemical compound of TANSHINONES isopolarity is then adsorbed securely, needs they eluting can effectively to be removed equally with 100% ethanol; And the absorbability of poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds is by weak danshensu potassium, alkannic acid dipotassium, Radix Salviae Miltiorrhizae acetic acid dipotassium, alkannic acid magnesium, Radix Salviae Miltiorrhizae acetate magnesium and the rosmarinic acid sodium of extremely being followed successively by by force, especially Radix Salviae Miltiorrhizae acetic acid dipotassium is prior to Radix Salviae Miltiorrhizae acetate magnesium eluting from the chromatographic column, this is just for guaranteeing that final products are rich in the Radix Salviae Miltiorrhizae acetate, be mainly Radix Salviae Miltiorrhizae acetate magnesium, this just makes in the eluent collection process and detects according to thin layer, can on purpose collect the stream part of being rich in Radix Salviae Miltiorrhizae acetate (being mainly Radix Salviae Miltiorrhizae acetate magnesium), thereby the content that guarantees the Radix Salviae Miltiorrhizae acetate reaches prescription.
But, single carrying out the resin inspection regulation that product that separation and purification obtains does not meet injection with macroporous adsorbent resin, the inventor carries out concrete controlled trial and the results are shown in Table 2
The different separation method result of the tests of table 2
1) 200g crude drug powder, water extraction three times, filtering and concentrating is to 300ml, and it is refining according to each method to get 100ml respectively.
2) alcohol deposition method adopts twice sedimentation method of conventional 90% and 95% ethanol, and the macroporous resin rule adopts washing, and 20% and 50% ethanol elution is collected 50% ethanol elution.
3) the thin layer testing conditions is: benzene one Ethyl formate, one formic acid (8:7:2), silica gel plate, the colour developing of sulphuric acid one anisaldehyde.
4) be concentrated into dried sample ligand behind the precipitate with ethanol and make 5mg/ml solution, get one of 5ml enriching HCl, observe the situation that the resin-like thing is separated out after half an hour.
As seen, list is used alcohol deposition method from table 2, and solid must be measured higher, contains the saccharides that are the brownish black colour developing that are positioned at initial point in a large number in thin layer detects in the product, contains the more reddish brown mottle color of non-Radix Salviae Miltiorrhizae acetate in addition, i.e. the homologue of Radix Salviae Miltiorrhizae acetate; The product that Amberlyst process obtains, although the main Radix Salviae Miltiorrhizae acetate that contains, it is obvious that initial point shows henna macromolecule polyalcohol, resin is checked defective; The combination of two kinds of methods then can comprehensive two methods advantage, both removed neutral saccharide, removed macromole phenol polymer again, thin layer detects the main Radix Salviae Miltiorrhizae acetate speckle that shows, product purity is much better than the independent use of two methods, thereby determines that it is practicable that process for purification of the present invention adopts Amberlyst process ten alcohol deposition methods.
3, elution process research
The inventor has selected ethanol as eluant, carries out eluting with Different concentrations of alcohol respectively, and thin layer is followed the tracks of to detect and washed out situation, and concrete outcome sees Table 3
The eluting result of table 3 different concentration ethanol
1) 200g crude drug powder, hot water extraction filters, be condensed into 300ml solution, respectively get 30ml after the 60ml macroporous resin adsorption, use above-mentioned solvent elution, the control flow velocity is 2ml/min, and the cumulative volume of effluent volume to be effluent find in thin layer detects Radix Salviae Miltiorrhizae acetate speckle, solid must be measured to this eluent and be concentrated into weighing after doing.
2) water and 10%, 20% ethanol elution agent consumption are 120ml, and the Radix Salviae Miltiorrhizae acetate is not found in water and the thin-layered detection of 10% ethanol stream, and 20% flow point only contains a small amount of Radix Salviae Miltiorrhizae acetate, do not investigate so further add large volume.
3) thin layer testing conditions: benzene one Ethyl formate, one formic acid (8:7:2), the colour developing of sulphuric acid one anisaldehyde.
As seen from the above table, 0-10% ethanol can not elute the Radix Salviae Miltiorrhizae acetate; But the poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of sugar, protein, inorganic salt and non-Radix Salviae Miltiorrhizae acetate can be removed, though 20% ethanol elution contains the Radix Salviae Miltiorrhizae acetate, but based on the Radix Arnebiae (Radix Lithospermi) hydrochlorate, according to the chromatography behavior of poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds on 1300-I resin, this Radix Salviae Miltiorrhizae acetate is used Radix Salviae Miltiorrhizae acetic acid dipotassium, and 30-40% ethanol can eluting Radix Salviae Miltiorrhizae acetate, but it is serious to go out the peak hangover, cause collected volume to increase, and elution time is longer; 50-70% eluting then Radix Salviae Miltiorrhizae acetate flows out comparatively concentrated.Consider the plant produced cost, elution volume increases will be increased solvent-oil ratio and reclaim power cost, and the prolongation of elution time then makes the production cycle prolong, and increases production cost equally.The solid that this back of variable concentrations eluting obtains product must be measured not obviously difference.Take all factors into consideration, remove sugar, protein and inorganic salt with the water of 6 times of crude drug amounts earlier, 20% ethanol removal danshensu potassium, Radix Arnebiae (Radix Lithospermi) hydrochlorate with 6 times of crude drug amounts reaches the Radix Salviae Miltiorrhizae acetate of the amount of being (this salt should be Radix Salviae Miltiorrhizae acetic acid dipotassium) less again, 50% ethanol with 3 times of crude drug amounts obtains the main salvianolate flow point that contains the Radix Salviae Miltiorrhizae acetate as eluant at last, and practical operation can detect to follow the tracks of according to thin layer determines the consumption of eluant and the part that the Radix Salviae Miltiorrhizae acetate is rich in merging.
4, the precipitate with ethanol condition is selected
The purpose of precipitate with ethanol is in order to remove residual macromolecular substances in the effective site such as resin etc., to reduce the zest of injection, to improve security of products.The main effective ingredient Radix Salviae Miltiorrhizae acetate water soluble and the aqueous alcohol of product, but can dissolubility be little in dehydrated alcohol, therefore considers to use aquiferous ethanol to carry out precipitate with ethanol, be the key that obtain qualified products and select the ethanol of suitable concn.
Result of study shows, 95% precipitate with ethanol product yield is than 90% precipitate with ethanol loss nearly 1/3, and 90% precipitate with ethanol final resin inspection shows, resin-like thing precipitated phase is to less, and when its loss was mainly 95% precipitate with ethanol, precipitate was too sticking, a large amount of filtrate double teams in precipitation due to.Therefore, consider to carry out fractional precipitation, at first remove most of resin with 90% ethanol precipitation, and leach more filtrate as far as possible, and reuse 95% ethanol is thoroughly removed resin, and result of the test shows, the secondary precipitate with ethanol can reduce the loss of effective components in the precipitate with ethanol process, improves product yield.
5, the selection of dosage form
Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate is the salvia-soluble active site, and its activity index composition is Radix Salviae Miltiorrhizae acetate (be mainly Radix Salviae Miltiorrhizae acetate magnesium, other comprises a small amount of Radix Salviae Miltiorrhizae acetic acid dipotassium), and the structure of Radix Salviae Miltiorrhizae acetate magnesium is as follows:
The chemical structural formula of Radix Salviae Miltiorrhizae acetate magnesium
This chemical compound is yellowish amorphous powder, and is soluble in water, is slightly soluble in alcohol, is insoluble in acetone.
Two ester bonds are arranged in its molecular structure, less stable in aqueous solution, easily degraded was placed 4 days at ambient temperature, and Radix Salviae Miltiorrhizae acetate magnesium (Rt 5.428) is degraded into Radix Arnebiae (Radix Lithospermi) hydrochlorate (Rt 1.828) and danshensu salt (Rt3.249) in aqueous solution; Phenolic hydroxyl group is at solution state also very easily oxidation, and therefore the raw material as aqueous injection is not too suitable.This also be on the market in the Radix Salviae Miltiorrhizae Injection Radix Salviae Miltiorrhizae acetate content lower, color is one of dark-brown reason.Because injection onset speed is fast far beyond oral formulations, therefore, injectable powder is ideal dosage form.
In addition, salvianolate is soluble in water, is difficult for the moisture absorption, and the powder of common drying and crushing or spray drying gained is when dissolving, be easy to cohere agglomerating, dissolving needs high degree of agitation fully, and consuming time longer, is unfavorable for clinical use, in addition, as previously mentioned, the activity index composition Radix Salviae Miltiorrhizae acetate of this product is unstable in aqueous solution, selects freeze drying process can reduce its degraded as much as possible.
Another object of the present invention has provided the preparation method of high content salvianolate injectable powder, and this method comprises the following steps:
(1) Radix Salviae Miltiorrhizae decocts and extracts:
After red rooted salvia was pulverized, the water with 4 times of amounts of Radix Salviae Miltiorrhizae crude drug weight, 2 times of amounts and 2 times of amounts successively decocted three times successively, and each 2 hours, merge three times extracting solution, be chilled to room temperature, centrifugal filtration, filtrate for later use;
(2) resin isolation:
Filtrate is slowly flow through 1300-I macroporous resin adsorption post of 3 times of amounts that Radix Salviae Miltiorrhizae crude drug weight is housed, after absorption finishes, earlier with 6 times of water gaging flush away sugar, protein and inorganic salts of Radix Salviae Miltiorrhizae crude drug weight; Remove the poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of non-Radix Salviae Miltiorrhizae acetate again with 6 times of amount 20% ethanol of Radix Salviae Miltiorrhizae crude drug weight, detect control with thin layer and collect 50% ethanol elution that is rich in the Radix Salviae Miltiorrhizae acetate;
(3) secondary precipitate with ethanol:
To be rich in 50% ethanol elution of Radix Salviae Miltiorrhizae acetate, be evaporated to 1/10 Radix Salviae Miltiorrhizae crude drug amount after, stir the dehydrated alcohol that adds 9/10 Radix Salviae Miltiorrhizae crude drug amount down slowly, leave standstill two hours after, the centrifugal precipitation that discards; After filtrate is concentrated into 1/20 Radix Salviae Miltiorrhizae crude drug amount, add the dehydrated alcohol of the 19/20 Radix Salviae Miltiorrhizae crude drug amount that is equivalent to, left standstill two hours, as the precipitate with ethanol second time, the centrifugal precipitation that discards, filtrate decompression is concentrated into dried, makes salvianolate;
(4) salvianolate injectable powder preparation:
The salvianolate powder is dissolved in 40 times of water gagings, and by the ultrafilter membrane of 0.2-0.4 μ m, the filtrate fill promptly gets product after the lyophilization in bottle.
In the method for the invention, resin also can be used resins such as D101 type, AB-8 type and RA type except 1300-I macroporous resin.
High content salvianolate injectable powder of the present invention is in preparation process, there is strict quality standard to detect, adopt fingerprint pattern technology that the quality of red rooted salvia, crude drug and preparation is controlled comprehensively, thereby guaranteed the steady quality of product, overcome the shortcoming of existing injection.Method of the present invention has obtained high content salvianolate, and Radix Salviae Miltiorrhizae acetate magnesium content is 50%-95% after testing, and all the other compositions are alkannic acid magnesium, rosmarinic acid sodium and a small amount of danshensu, polyphenol hydrochlorate effective site content nearly 100%.
The present invention is according to the pharmacodynamic study result of salvianolate, the effective dose 1,3 of Canis familiaris L., 10mg/kg, convert corresponding human body agent reason amount and be respectively 0.53,1.59,5.31mg/kg, corresponding clinical consumption (by body weight for humans 70kg) is difference 37,111,371mg is so we get the each 50-100mg of this product intravenous injection, every day 1-2 time is as recommending the clinical therapeutic dose of using; Or this product 200mg adds 5% normal saline 500ml (or 5% glucose solution 500ml) intravenous drip, and every day 1 time is as recommending the clinical therapeutic dose of using.Based on this, the specification of determining this product is 50mg/ bottle, 100mg/ bottle, 200mg/ bottle, 300mg/ bottle, 400mg/ bottle.
Because the intravenous injection concentration of this product is 5.0mg/ml, thus office preparation bottle at least capacity be at least 10ml.
The preclinical pharmacology and the clinical effectiveness of high content salvianolate of the present invention are as follows:
The salvianolate preclinical pharmacology studies show that: poly phenolic acid of Radix Salviae Miltiorrhizae salt pair Canis familiaris L. coronary artery ligation causes myocardial infarction model and isolated rat heart reperfusion injury, degree of myocardial ischemia is significantly descended, the myocardial ischemia scope is dwindled, primary cellular defect when alleviating myocardial ischemia has significant function of resisting myocardial ischemia.Salvianolate can reduce the heart oxygen consumption simultaneously, and can resist the inductive platelet aggregation of ADP and suppress thrombosis.Be characterized in the therapeutic dose scope, not influencing the cardiac hemodynamics function.
Salvianolate injectable powder I, II, III clinical trial phase result of study show:
In the I clinical trial phase, the single-dose group reaches repeatedly (accumulation) administration group totally 30 routine health volunteers, in 2 times of scopes of predose and clinical recommended dose, does not all occur untoward reaction in the observation process, and follows up a case by regular visits to after drug withdrawal and also do not see untoward reaction in 3 days;
In the II clinical trial phase, adopt multicenter, antithetic experimental program carries out clinical research to salvianolate injectable powder treatment coronary heart disease, angina pectoris at random.The result shows: Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate reagent group angina pectoris total effective rate is 92.2%, ECG curative effect total effective rate 61.2%; Tcm symptom curative effect total effective rate is 92.2%.The disease comprehensive therapeutic effect: Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate reagent group total effective rate is 86.2%, and the positive controls Radix Salviae Miltiorrhizae Injection is 55.3%.Statistical significance (P＜0.01) is relatively arranged between two groups.The II clinical trial phase is the result show: Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate treatment coronary heart disease, angina pectoris (stagnation of heart-blood disease) determined curative effect are safe.
Adopt multicenter, at random, the positive drug contrast, three groups of parallel test methods, III clinical trial phase result of study shows: (1) Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate reagent group 1 angina pectoris total effective rate is 88.085%, test group 2 total effective rates are 89.744%, matched group Radix Salviae Miltiorrhizae Injection total effective rate is 67.257%, test group 1, test group 2 has height statistical significance (P＜0.01) (2) tcm symptom curative effect with matched group total effective rate comparing difference: test group 1 total effective rate is 80.426%, test group 2 total effective rates are 80.342%, matched group Radix Salviae Miltiorrhizae Injection total effective rate is 58.407%, test group 1, test group 2 all has height statistical significance (P＜0.01) with the matched group comparing difference; (3) ECG curative effect: test group 1 total effective rate is 44.444%, test group 2 total effective rates are 53.086%, matched group Radix Salviae Miltiorrhizae Injection total effective rate is 32.530%, test group 2 and matched group electrocardiogram total effects, the total effective rate comparing difference has statistical significance (P＜0.01 or P＜0.05) (4) exercise ECG curative effect: the clinical recommended dose group of Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate (200mg) test front and back are in levels of motion, the motion equivalent, 2 minutes and 4 minutes 12 indexs such as the ST section fall sum of leading have clear improvement after the off-test, relatively, difference has statistical significance (P＜0.01 or P＜0.05) before and after self.
Show by I, II, III clinical trial phase result of study and preclinical pharmacology toxicological study: Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate and powder pin thereof are a safety, cardiovascular drugs efficient, stable and controllable for quality, have good development and application prospect.
Description of drawings:
The chromatography behavior of the different poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of Fig. 1 on 1300-I macroporous adsorbent resin.
The specific embodiment:
Example 1:
After 1 part of red rooted salvia is pulverized, successively with 4 times of water gagings, 2 times of water gagings, 2 times of water gagings decoct and extract three times, and each extraction time is 2 hours.Merge three times extracting solution, be chilled to room temperature after, centrifugal filtration, filtrate is slowly flow through 1300-I macroporous resin absorption post that 3 times of amounts are housed.After absorption finishes, with 6 times of water gaging flush away sugar, protein and inorganic salts, remove the poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of non-Radix Salviae Miltiorrhizae acetate again with 6 times of amount 20% ethanol, at last with 3 times of amount 50% ethanol elution salvianolates.Detect to collect the 50% ethanol eluate that is rich in the Radix Salviae Miltiorrhizae acetate according to thin layer, be evaporated to 1/10 crude drug amount after, after stirring the dehydrated alcohol that adds 9/10 crude drug amount down slowly, leaving standstill two hours, the centrifugal precipitation that discards; Filtrate is concentrated into 1/20 crude drug amount, adds the dehydrated alcohol of 19/20 crude drug amount, left standstill two hours, and centrifugal filtration, filtrate decompression is concentrated into dried, and pulverizing can obtain finished product.Yield by the raw medicinal herbs salvianolate is 1%, and Radix Salviae Miltiorrhizae acetate magnesium content can reach 82% in the finished product.The salvianolate powder is dissolved in 40 times of water gagings, and by the ultrafilter membrane of 0.2-0.4 μ m, the filtrate fill promptly gets Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate injectable powder after the lyophilization in bottle.
Example 2:
After 1 part of red rooted salvia is pulverized, successively with 4 times of water gagings, 2 times of water gagings, 2 times of water gagings decoct and extract three times, and each extraction time is 2 hours.Merge three times extracting solution, be chilled to room temperature after, centrifugal filtration, filtrate is slowly flow through the D101 type macroporous resin absorption post that 3 times of amounts are housed.After absorption finishes, with 6 times of water gaging flush away sugar, protein and inorganic salts, remove the poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of non-Radix Salviae Miltiorrhizae acetate again with 6 times of amount 20% ethanol, at last with 3 times of amount 50% ethanol elution salvianolates.Detect to collect the 50% ethanol eluate that is rich in the Radix Salviae Miltiorrhizae acetate according to thin layer, be evaporated to 1/10 crude drug amount after, after stirring the dehydrated alcohol that adds 9/10 crude drug amount down slowly, leaving standstill two hours, the centrifugal precipitation that discards; Filtrate is concentrated into 1/20 crude drug amount, adds the dehydrated alcohol of 19/20 crude drug amount, left standstill two hours, and centrifugal filtration, filtrate decompression is concentrated into dried, and pulverizing can obtain finished product.Yield by the raw medicinal herbs salvianolate is 2%, and Radix Salviae Miltiorrhizae acetate magnesium content can reach 90% in the finished product.The salvianolate powder is dissolved in 40 times of water gagings, and by the ultrafilter membrane of 0.2-0.4 μ m, the filtrate fill promptly gets Radix Salviae Miltiorrhizae for injection polyphenol hydrochlorate injectable powder after the lyophilization in bottle.
Claims (3)
1, a kind of high content salvianolate injectable powder, the content that it is characterized in that Radix Salviae Miltiorrhizae acetate magnesium in this injectable powder is 50%-95%, and polyphenol hydrochlorate effective site content is nearly 100%, and it makes by following method:
(1) Radix Salviae Miltiorrhizae decocts and extracts:
After red rooted salvia was pulverized, the water with 4 times of amounts of Radix Salviae Miltiorrhizae crude drug weight, 2 times of amounts and 2 times of amounts successively decocted three times successively, and each 2 hours, merge three times extracting solution, be chilled to room temperature, centrifugal filtration, filtrate for later use;
(2) resin isolation:
Filtrate is slowly flow through 1300-I macroporous resin adsorption post of 3 times of amounts that Radix Salviae Miltiorrhizae crude drug weight is housed, after absorption finishes, earlier with 6 times of water gaging flush away sugar, protein and inorganic salts of Radix Salviae Miltiorrhizae crude drug weight; Remove the poly phenolic acid of Radix Salviae Miltiorrhizae salt compounds of non-Radix Salviae Miltiorrhizae acetate again with 6 times of amount 20% ethanol of Radix Salviae Miltiorrhizae crude drug weight, detect control with thin layer and collect 50% ethanol elution that is rich in the Radix Salviae Miltiorrhizae acetate;
(3) secondary precipitate with ethanol:
To be rich in 50% ethanol elution of Radix Salviae Miltiorrhizae acetate, be evaporated to 1/10 Radix Salviae Miltiorrhizae crude drug amount after, stir the dehydrated alcohol that adds 9/10 Radix Salviae Miltiorrhizae crude drug amount down slowly, leave standstill two hours after, the centrifugal precipitation that discards; After filtrate is concentrated into 1/20 Radix Salviae Miltiorrhizae crude drug amount, add the dehydrated alcohol of the 19/20 Radix Salviae Miltiorrhizae crude drug amount that is equivalent to, left standstill two hours, as the precipitate with ethanol second time, the centrifugal precipitation that discards, filtrate decompression is concentrated into dried, makes salvianolate;
(4) salvianolate injectable powder preparation:
The salvianolate powder is dissolved in 40 times of water gagings, and by the ultrafilter membrane of 0.2-0.4 μ m, the filtrate fill promptly gets product after the lyophilization in bottle.
2,, it is characterized in that the preparation specification is 50mg/ bottle, 100mg/ bottle, 200mg/ bottle, 300mg/ bottle or 400mg/ bottle according to claims 1 described a kind of high content salvianolate injectable powder.
3, a kind of high content salvianolate injectable powder according to claim 1, the resin that it is characterized in that the step (2) of wherein said preparation method are D101 type, AB-8 type or RA type resin.
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|---|---|---|---|---|
| CN102058599A (en) * | 2009-11-17 | 2011-05-18 | 中国科学院上海药物研究所 | Salvianolate, and preparation method and application thereof |
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| CN103980236B (en) * | 2009-11-17 | 2017-10-03 | 中国科学院上海药物研究所 | Polydanshinolate and its production and use |
| CN104974119B (en) * | 2014-04-01 | 2018-10-19 | 中国科学院上海药物研究所 | A kind of high-purity danshinolic acid B magnesium and preparation method thereof |
| CN105311965A (en) * | 2014-07-04 | 2016-02-10 | 上海绿谷生命园医药有限公司 | Ultra-filtration method and ultra-filtration device for salvianolate extract liquid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058599A (en) * | 2009-11-17 | 2011-05-18 | 中国科学院上海药物研究所 | Salvianolate, and preparation method and application thereof |
| CN102058599B (en) * | 2009-11-17 | 2014-06-04 | 中国科学院上海药物研究所 | Salvianolate, and preparation method and application thereof |
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| CN1911272A (en) | 2007-02-14 |
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