CN108785381B - Preparation method of pharmaceutical composition for treating cardiovascular diseases - Google Patents
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Abstract
The invention relates to a preparation method of a salvia miltiorrhiza extract for treating cardiovascular diseases, which uses an improved clarifying agent method to treat salvia miltiorrhiza medicinal materials after water extraction, adopts an acid method and activated carbon to remove impurities such as protein, tannin and the like in the extract, and prepares a salvia miltiorrhiza extract containing high-concentration tanshinol by conversion under an alkaline condition. The invention also relates to a method for recycling, rectifying and reusing ethanol used in the process of preparing the salvia miltiorrhiza extract, the salvia miltiorrhiza extract prepared by ethanol recovered for four times still meets the market standard of medicines, and the aims of environmental protection and energy conservation are achieved while the preparation cost is saved. The invention also relates to a method for preparing the salvia miltiorrhiza-ligustrazine injection by using the salvia miltiorrhiza extract, and provides application of the salvia miltiorrhiza-ligustrazine injection in preparing cardiovascular treatment medicines.
Description
Technical Field
The invention belongs to the technical field of preparation of traditional Chinese medicine compositions, and particularly relates to a preparation method of a traditional Chinese medicine composition containing a red sage root extracting solution.
Background
Cardiovascular and cerebrovascular diseases, typically including coronary heart disease, angina pectoris, myocardial infarction, cerebral dementia and cerebral hemorrhage, are common diseases that seriously threaten the health of human beings, especially the middle-aged and elderly people. According to the record of 'Chinese cardiovascular disease report 2017', the prevalence and mortality of Chinese cardiovascular diseases are still in the rising stage. The number of patients suffering from cardiovascular diseases is 2.9 million, wherein 1300 million stroke, 1100 million coronary heart disease, 500 million pulmonary heart disease, 450 million heart failure, 250 million rheumatic heart disease, 200 million congenital heart disease and 2.7 million hypertension are calculated. Cardiovascular death accounts for more than 40% of the deaths of resident diseases, and is the first place higher than tumors and other diseases.
Salvianic acid A is a water-soluble component of the traditional Chinese medicine Salvia miltiorrhiza (Salvia militari Bge.) and is one of the main active components of Salvia miltiorrhiza. The natural danshensu is a dextro-isomer and has pharmacological actions of expanding coronary artery, controlling platelet aggregation, improving microcirculation and the like (Shanghai second medical university, 1990, 10, 3 rd phase: page 208 and 211; J. Med. in 1983, 3, 5 th phase: page 297 and 299; Chinese pharmacological report, 2000, 16, 6 th phase: page 682 and 685). Salvianic acid A has a prominent effect in treating cardiovascular and cerebrovascular diseases, is widely applied to treating cardiovascular diseases clinically, and can improve cardiac function, coronary circulation, anticoagulation and microcirculation, so as to treat ischemic heart diseases such as coronary heart disease and angina pectoris (China pathophysiology journal, No. 5, No. 2: pages 65-69 in 1989). The danshensu has quick effect, high bioavailability, and high clinical value.
Ligustrazine, also called Tetramethylpyrazine (TMP), is an alkaloid extracted from ligusticum wallichii, a traditional Chinese medicine of the family of Umbelliferae, and is an active ingredient of ligusticum wallichii. TMP is widely used in the field of cardiovascular and cerebrovascular therapy because of its ability to treat ischemic stroke. The treatment mechanism is as follows: the anticoagulation effect. TMP can significantly inhibit the expression of PAI-1 protein and its mRNA induced by LPS in endothelial cells (Song, et al, Chinese Medical J.113:136, 2000); the low dose of TMP can inhibit decomposition of phosphatidylinositol and TXA2At high doses, platelet aggregation is inhibited by binding to glycoprotein IIb/IIIa (Sheu, et. al., Thromb Res.88:259,1997). ② TMP can also be directly thrombolytic (Liu and Sylvester, Thromb Res.58:129,1990; Liu and Sylvester, Thromb Res.75:51,1994). TMP has the function of protecting nerve cells, can obviously improve the ischemia injury of brain cells of rats and obviously clear free radicals generated by human neutrophils (Hsiao, et al, Planta Med.72: 411. Easter 417, 2006; Kao, et al, neurohem int.48:166, 2006). TMP also acts as a calcium channel blocker, promoting potassium channel development, thereby inhibiting free radical production, inhibiting inflammatory responses (Zhu, et al, eur.j. pharmacol.510:187, 2005).
Because the danshensu and the ligustrazine have the effects of promoting blood circulation, removing blood stasis, dissolving thrombus and promoting circulation, and have synergistic effect, the danshensu and the ligustrazine are clinically used for treating ischemic encephalopathy, coronary heart disease, angina pectoris, myocardial infarction and other diseases by matching. One of the key steps for preparing the composition of danshensu and ligustrazine is the extraction of danshensu. The tanshinol is mainly derived from a botanical drug, namely salvia miltiorrhiza, and in the prior art, the tanshinol is extracted by a water decoction method, an ethanol reflux method, an ultrasonic method, a water extraction and alcohol precipitation method and the like. The most common water extraction and alcohol precipitation method is divided into a clarifier method and a lime sulphur method, and compared with the current clarifier method and lime sulphur method, the advantages and the disadvantages of the clarifier method and the lime sulphur method are obvious: (1) the clarifier method has simple process operation, simple and convenient alcohol precipitation process and relatively high extraction rate. However, the impurity components of the salvia miltiorrhiza extract obtained by the clarifying agent method are not completely removed, and the medication safety is possibly influenced. (2) The lime sulfur method has complex operation process, long time consumption and low yield, and the obtained salvia miltiorrhiza extract has high content of salvianolic acid B impurities and strong irritation, and can stimulate the medicine application part in clinic to cause irritation to patients.
The clarifying agent method and the lime sulphur method in the prior art have the defects of long time consumption, complex steps, low yield and high cost. The preparation method of the salvia miltiorrhiza extract disclosed in the patent application CN106995369A previously filed by the inventor is a lime-sulfur method, the lime-sulfur method used by the inventor needs to adopt lime liquid and sulfuric acid with strong irritation for treatment, and needs to be decocted and extracted with water for more than two times and subjected to alcohol precipitation for two times, the process is complex, the consumed time is long, the dosage of ethanol is high, and the yield is low.
CN104721260A discloses an injection pharmaceutical composition containing Salvia miltiorrhiza and ligustrazine, which adopts a clarifying agent with less irritation to separate impurities from tanshinol. However, the time for soaking and boiling the medicinal materials and the time for treating the medicinal materials by the clarifying agent are both as long as 24 hours, so that the extraction process is very time-consuming, and the medicinal materials are not subjected to secondary impurity removal treatment after being precipitated by alcohol precipitation and water, and are not converted into the salvianolic acids, so that the prepared salvia miltiorrhiza extract has high impurity content and low content of active ingredients (tanshinol).
In the salvia miltiorrhiza and ligustrazine injection and the preparation method thereof disclosed in CN1775233A, the medicinal materials are soaked for 8-16 hours during the extraction of tanshinol, three times of long-time water decoction are needed, the operation is complex, and the extraction rate is not high. Moreover, the alcohol precipitation times are two, and ultrafiltration treatment is needed after water precipitation, so the steps are complicated and the extraction cost is high.
The preparation of the salvia miltiorrhiza extract by using a clarifying agent method or a lime sulphur method involves the step of carrying out alcohol precipitation on a sample by using a large amount of ethanol, and the process inevitably consumes a large amount of ethanol. Alcohol precipitation is a necessary step for extracting tanshinol, at present, after alcohol precipitation, used ethanol is generally removed by evaporation, which is not environment-friendly and causes solvent waste, and if the ethanol recovered by evaporation is directly used for other purposes, the residual traditional Chinese medicine components can also cause potential safety hazards.
Therefore, the current situation of the extraction and production of salvia miltiorrhiza is as follows: (1) the method for converting tanshinol in the process of extracting the salvia miltiorrhiza medicinal material is complex and has long extraction time; (2) the impurity removal is incomplete, the active substance conversion is incomplete, and the extraction rate is low; (3) the ethanol consumption is large, the ethanol cannot be directly discharged or reused, and the energy consumption is high.
Disclosure of Invention
Aiming at the problems, the invention provides an improved preparation method of a tanshinol extracting solution, which adopts a clarifying agent method with an optimized process to prepare the tanshinol extracting solution. The preparation method also comprises the steps of recovering, rectifying and recycling the ethanol used in the extraction process for multiple times so as to save the cost and reduce the energy consumption.
The invention also relates to a salvia miltiorrhiza extract prepared by the improved method, a tanshinol-ligustrazine injection containing the salvia miltiorrhiza extract, and application of the salvia miltiorrhiza extract and the salvia miltiorrhiza-ligustrazine injection in preparing medicaments for preventing or treating cardiovascular and cerebrovascular diseases.
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FIG. 1: process flow chart for preparing salvia miltiorrhiza extract
Detailed Description
The invention provides an improved preparation method of a salvia miltiorrhiza extract, which takes danshensu as a final product and uses a clarifying agent preparation process, thus having the advantages of short time consumption, simple and convenient operation and low cost, and can well solve the problems of long extraction time, complicated step operation, waste of consumables and low yield of a target product of the danshensu in the extraction process of the salvia miltiorrhiza medicinal material by the existing clarifying agent method.
The clarifying agent method extraction process comprises the following steps:
(I) extracting. Decocting Saviae Miltiorrhizae radix with water twice. For the first time: decocting Saviae Miltiorrhizae radix with 8-12 times of water for 1-3 hr; and (3) for the second time: extracting the raw materials with 6-10 times of water for 1-3 hr. Then filtering the two extracting solutions, concentrating and mixing.
Preferably, the first extraction in the step (I) is carried out for 2 hours by decocting with 10 times of water; the second extraction was carried out with 8 times the amount of water for 1.5 h. Filtering the decoction with 200 mesh filter cloth, and mixing at 65 + -5 deg.C. The Saviae Miltiorrhizae radix is not soaked in advance.
And (II) removing impurities. Adding clarifier into the extractive solution, clarifying, standing, centrifuging, and collecting filtrate.
Preferably, the clarifying agent is selected from ZTC1+1 clarifying agent, which comprises A, B components. The specific operation is as follows: sequentially adding clarifying agent B with a weight of 0.03-0.1% of the medicinal materials, standing for 1.5-3h, adding clarifying agent A with a weight of 0.01-0.05%, standing for 3-5h, centrifuging at 10000rmp/min (centrifuging time is 1h per 300L of liquid according to the volume of the centrifugate), filtering, and collecting filtrate.
The clarifying agent of the invention can use the ZTC1+1 clarifying agent which is commercially available at present. More preferably, a natural clarifier of type ZTC1+1III is used, and even more preferably, a natural clarifier of type ZTC1+1III available from Tianjin Zhengtian scientific Co. The ZTC1+1 natural clarifier is natural food extract, and is natural high molecular substance extracted from food. The ZTC1+1III type clarifier A, B component used in the invention is nontoxic after being detected by a health and disease prevention center to have LD50 more than 15g/kg, and according to food safety toxicology evaluation procedures, acute toxicity dose grading detection.
More preferably, the clarifying agent B with the proportion of 0.05 percent of the medicinal material is added in a stirring way, after the mixture is kept stand for 2 hours, the clarifying agent A with the proportion of 0.025 percent is added in a stirring way, the mixture is kept stand for 4 hours, the obtained treatment solution is centrifuged for two times (10000rmp/min, the centrifugation time is 1 hour per 300L of liquid according to the volume of the centrifugate), the supernatant is taken, 8 layers of filter paper are passed, and the supernatant is collected.
The preparation method of the clarifying agent comprises the following steps:
the component A comprises: weighing 0.01-0.05% (w/w) of clarifier A, stirring with small amount of deionized water (distilled water) to obtain paste, adding required amount of deionized water, and swelling for 24 hr to obtain 1% viscose solution.
The component B comprises: a1% (v/v) acetic acid solution was prepared with glacial acetic acid and deionized water. Weighing 0.03% -0.1% (w/w) of clarifier B, dissolving component B with small amount of 1% (v/v) acetic acid solution, stirring to paste, adding sufficient 1% (v/v) acetic acid solution, and swelling for 24 hr to obtain 1% component B viscose.
Optionally, before the step (two), a pretreatment step is included, wherein the pretreatment step is as follows: controlling the temperature of the concentrated solution at 80 + -10 deg.C, adding 0.5-3kg of pretreating agent A per 1000kg of medicinal materials, boiling for 20min, adding 0.5-3kg of pretreating agent B per 1000kg of medicinal materials when the temperature is reduced to 55 + -5 deg.C, keeping the temperature, heating for 4 hr, boiling for 20min, and cooling to 80 + -10 deg.C for performing step (II).
The pretreating agent A mainly comprises amylase, and the pretreating agent B mainly comprises complex enzyme of the amylase. The clarifier pretreatment agent of the invention can use the current commercial pretreatment agent. Preferably, the pretreatment agent used in the present invention is available from Tianjin Zhentian science and technology limited.
And (III) precipitating with ethanol. Concentrating the supernatant, adding 95% ethanol to make ethanol content not less than 80%, stirring, standing, and cooling the supernatant.
Preferably, the supernatant is concentrated to the specific gravity of 1.22 +/-0.02, 95% ethanol is added at the temperature of 45 +/-5 ℃ to ensure that the ethanol content is not less than 80%, the mixture is stirred for 20 minutes, the mixture is kept stand for 20 minutes, and the supernatant is cooled for more than 24 hours at the temperature of 0-5 ℃.
(IV) water precipitation. Filtering the cooled alcohol precipitation solution, recovering ethanol, concentrating, adding injection water with volume of 8-12 times of the solution, stirring, standing, and cooling the water precipitation solution.
As a preferred scheme, filtering the cooled alcohol precipitation solution by adopting an 8-layer filter board frame, concentrating the filtrate to the specific gravity of 1.22 +/-0.02 by using a single-effect concentrator at the temperature of 45 +/-5 ℃, and recovering ethanol;
more preferably, the injection water is added in an amount which is 10 times the volume of the liquid medicine, the mixture is stirred for 20 minutes and kept stand for 20 minutes, and the water-precipitated liquid is cooled for more than 36 hours at the temperature of 0-5 ℃.
And (V) collecting the paste. And (3) filtering the cooled water precipitation solution again, adjusting the pH of the filtrate to 2-2.5 by using hydrochloric acid, standing, and centrifuging and filtering at 10000rpm/min (centrifuging for 1h per 300L of the liquid according to the volume of the centrifugate). Adjusting pH of the filtrate to 8-9.5 with sodium hydroxide, boiling, cooling to 70-80 deg.C, adjusting pH to 5.5-6, adding active carbon, boiling, and filtering. Concentrating the filtrate, collecting the extract, and refrigerating.
Preferably, after cooling the water precipitation solution, centrifuging (10000rmp/min, centrifuging time according to the volume of the centrifugate, centrifuging for 1h every 300L of the liquid) and filtering through an 8-layer filter board frame, adjusting the pH value of the filtrate to 2.08-2.13 by using a 10% hydrochloric acid solution, standing for 1h, and centrifuging and filtering (10000rmp/min, centrifuging time according to the volume of the centrifugate, centrifuging for 1h every 300L of the liquid). And adjusting the pH value of the filtrate to 8.95-9.0 by using 10% sodium hydroxide solution, and boiling for 60 minutes at 20 ℃. And then cooling to 70-80 ℃, adjusting the pH value to 5.5-6.0, adding 0.1% of activated carbon, continuously boiling for 30 minutes, and filtering by using 8 layers of filter paper and 1 layer of 0.22 mu m filter membrane. Concentrating the filtrate to relative density of 1.15 + -0.05, collecting the extract, and refrigerating to obtain Saviae Miltiorrhizae radix extract.
The second technical problem to be solved by the invention is to provide a method for recovering and rectifying ethanol, which is to recover and rectify the ethanol used in the ethanol precipitation step in the salvia miltiorrhiza extraction process and recycle the ethanol for the ethanol precipitation step again, so as to reduce waste, pollution and cost.
The ethanol recovery and rectification method comprises the following steps:
1. and (5) recovering the ethanol. Heating and evaporating the alcohol precipitation solution in the step (IV) in the preparation process of the salvia miltiorrhiza extract through a single-effect concentrator, recovering ethanol in a gas form, cooling to obtain recovered ethanol, separating the liquid medicine from the ethanol at the bottom of the concentrator, wherein the ethanol concentration is about 80%, the recovered ethanol has light brown red, and possible impurities are tanshinol, tanshinone IIA and salvianolic acid B.
2. And (5) rectifying the ethanol. And (3) feeding the recovered ethanol into a rectifying tower, heating by steam, rectifying at the tower top temperature of 75-80 ℃, recovering the ethanol in a gas form, and cooling to obtain the rectified ethanol.
The specific rectification steps are as follows:
(1) and the recovered ethanol enters an evaporation chamber of the recovery tower, the feeding is stopped when the volume of 2/3 is reached, and the conveying pump and the feeding valve are closed.
And starting heating, controlling the gauge pressure of a steam valve in the evaporation chamber to be 0.12MPa, and controlling the gauge pressure of the steam valve to be 0.05-0.15 MPa when the temperature reaches 75-80 ℃. And after running for 50-70min, opening a reflux sampling valve for sampling, and detecting the concentration of the ethanol. Opening a reflux sampling valve for sampling, and detecting the concentration of ethanol;
(2) and collecting: when the concentration of the ethanol is detected to be more than 95% by sampling, a reflux metering valve is opened, the ethanol is collected to a rectification ethanol tank, and if the concentration of the detected ethanol is lower than 95%, the reflux metering valve is closed to continue refluxing; and (6) detecting the concentration. The sampling is to detect the concentration of the ethanol by an alcohol meter at the temperature of less than or equal to 30 ℃, detect the temperature of the ethanol at the moment by a thermometer, read the value, refer to an alcohol concentration and temperature conversion table, and search the ethanol concentration.
Preferably, when the amount of the recovered ethanol pumped into the evaporation chamber is less than 1/2, the recovered ethanol needs to be continuously supplemented to 2/3 volume, and the reflux flow is adjusted after the addition.
And as a more preferable scheme, controlling the reflux flow to be 500-1500L/H, detecting the concentration of ethanol recovered by rectification by using an alcohol meter every 10-30 minutes in the collection process, if the concentration of the ethanol is lower than 95%, adjusting the flow meter, and otherwise, adjusting the flow meter to be small.
(3) And rectifying ethanol for inspection.
And (3) inspecting the rectified ethanol in the step (2), wherein specific detection items and standards are as follows.
Detection standard:
relative density: not greater than 0.8129, corresponding to C2H6O is not less than 95.0% (ml/ml)
The characteristics are as follows: colorless clear liquid with little odor; is easy to volatilize and burn, and shows light blue flame when burning; heating to 78 deg.C and boiling.
And (3) residual detection: the residual amount of tanshinol in the rectified ethanol is not more than 10 ug/ml.
As one of the preferable schemes, the ethanol detection standard is in accordance with Chinese pharmacopoeia (2015), and the detection of related substances (tanshinol, tanshinone IIA and salvianolic acid B) of the salvia miltiorrhiza extract is added.
The method for identifying related substances in the salvia miltiorrhiza extract comprises the following steps:
adding ethanol into Saviae Miltiorrhizae radix control, ultrasonic treating, centrifuging, and collecting supernatant as control solution.
And adding ethanol into tanshinone IIA reference substance and salvianolic acid B reference substance to obtain mixed solution containing 0.5mg and 1.5mg as reference substance solution.
And (3) taking the rectified ethanol stock solution as a test solution, operating according to a test of thin-layer chromatography standard operating procedures, and detecting whether spots or fluorescent spots with the same color are displayed at corresponding positions of a rectified ethanol chromatogram and a reference substance chromatogram, wherein if the spots or the fluorescent spots do not develop the color, the red sage root related substances are not contained, and if the spots or the fluorescent spots do not develop the color, the red sage root related substances are contained.
(4) And recovering ethanol for recycling. And (3) applying the qualified and qualified rectified ethanol to the alcohol precipitation step (III) of the preparation of the salvia miltiorrhiza extract. And (3) subjecting the obtained alcohol precipitation liquid to a water precipitation step (IV), recovering and rectifying the ethanol again, and performing alcohol precipitation in the step (III), so that the ethanol precipitation liquid can be repeatedly recovered and recycled for four times.
The third technical problem to be solved by the invention is to provide a method for further preparing the salvia miltiorrhiza-ligustrazine injection by using the salvia miltiorrhiza extract.
The salvia miltiorrhiza extracting solution prepared by the method is prepared by mixing 5-110 parts of salvia miltiorrhiza and ligustrazine as raw materials: 1 to prepare the injection.
As one of the preferred technical schemes, the salvia miltiorrhiza extract is prepared by mixing the salvia miltiorrhiza raw material and the ligustrazine raw material 10: 1-100: 1;
as another preferred technical scheme, the ligustrazine raw material medicine is selected from ligustrazine phosphate or ligustrazine hydrochloride.
The salvia miltiorrhiza-ligustrazine injection is prepared by the following steps:
preparing the Saviae Miltiorrhizae radix extractive solution into clear liquid containing 4g medicinal materials per ml, and adjusting pH to 5.0-6.0 to obtain medicinal liquid. Mixing ligustrazine hydrochloride, adjuvants and the above medicinal liquid uniformly, adding water for injection, adjusting pH to 3.5, making into 1000ml, filtering, packaging into ampoule bottle, and sterilizing. Preferably, the adjuvant is glycerol.
The fourth technical problem to be solved by the invention is to provide the application of the salvia miltiorrhiza extract or the salvia miltiorrhiza-ligustrazine injection in preparing the cardiovascular and cerebrovascular treatment medicines.
The invention has the following beneficial effects after being implemented:
1. the extraction steps are simplified, the extraction time is saved, and the extraction rate is high.
The preparation of the salvia miltiorrhiza extracting solution is carried out by utilizing a natural clarifying agent ZTC1+1 and optimizing the conditions. Compared with the lime sulphur method, firstly, the pretreatment of the medicinal materials is not needed; alcohol precipitation is carried out only once; and the extraction and pretreatment time is obviously reduced, so that the extraction time of the salvia miltiorrhiza is greatly reduced. Compared with the lime sulphur method, the extraction rate is increased by multiple levels;
compared with the clarifying agent method known in the prior art, the times of water decoction and extraction are reduced, the time of water decoction is reduced from 24h to 3.5h, the time of clarifying agent treatment is reduced from 24h to at most 8h, the extraction time is greatly reduced, the extraction times are reduced, and finally the content of the tanshinol in the extracting solution is high;
2. the steps of improving, removing impurities and purifying are added, and the proportion of active ingredients is improved.
(1) During the preparation process of the salvia miltiorrhiza extract, activated carbon is used for replacing ultrafiltration for purification and impurity removal after water precipitation, and a 0.22 mu m filter membrane is used for filtration and sterilization, so that the impurity removal and sterile effects are enhanced;
(2) when the paste is collected, the tannin is further removed by adopting hydrochloric acid treatment, and the danshenic acid B in the extracting solution is converted into an active ingredient of sodium danshensu by using sodium hydroxide, so that the quality of the extracting solution of the salvia miltiorrhiza is further improved, the irritant side effect is reduced, and the pharmacodynamic activity is improved.
3. The ethanol solvent is recycled, and the method is green, environment-friendly and energy-saving.
The ethanol used in alcohol precipitation is recycled, rectified, concentrated and purified, so that the cost is saved. The ethanol after being recovered and rectified for 4 times can still reach the pharmacopoeia standard, and does not contain related substances of the salvia miltiorrhiza extract, and the salvia miltiorrhiza extract prepared by the recovered ethanol has no difference in drug effect and purity compared with the extract prepared by new ethanol, and completely meets the marketing standard.
Example 1 preparation of Salvia miltiorrhiza Bunge extract example 1
1. Extraction: 480kg of clean salvia miltiorrhiza medicinal material is added with purified water and decocted for two times; adding 10 times of purified water for the first time, and decocting for 2 hours; adding 8 times of purified water for the second time, and decocting for 1.5 hr. The two extracting solutions pass through a 200-mesh filter screen, the two extracting solutions are concentrated to 450L and then discharged, and then the extracting solutions are mixed in a pretreatment tank. The mixture had a specific gravity of 1.10, a volume of 900L and a temperature of 65 ℃.
2. Pretreatment: controlling the temperature of the concentrated solution, adding 1kg of ZTC pretreating agent A at 80 ℃, boiling for 20 minutes, adding 1kg of ZTC pretreating agent B when the temperature is reduced to 55 ℃, keeping warm, heating for 4 hours, boiling for 20 minutes, adding ZTC1+1III clarifying agent B which is 0.05% (w/w) relative to the weight of the medicinal material while stirring when the temperature is reduced to 80 ℃, standing for 2 hours, adding ZTC1+1III clarifying agent A which is 0.025% (w/w) relative to the weight of the medicinal material while stirring, standing for 4 hours, centrifuging the pretreating solution twice (10000rpm/min, 1.5 hours), taking the supernatant, filtering by 8 layers of filter paper, and collecting the supernatant. The ZTC pretreatment agent and ZTC1+1III clarifier are both available from Tianjin Zhentian science and technology Co.
3. Alcohol precipitation: the supernatant was placed in a single effect concentrator and concentrated to a specific gravity of 1.22 and a volume of 325L. Adding 95% ethanol to make the final alcohol content not less than 81%, stirring for 20min, standing for 20min, collecting supernatant, adding into another ethanol precipitation tank, and cooling at 4 deg.C for 24 hr.
4. Water precipitation: cooling, filtering the ethanol precipitation solution with 8 layers of filter paper plate frames, passing the filtrate through a single-effect concentrator, collecting ethanol, recovering ethanol, and concentrating the filtrate to specific gravity of 1.22, volume of 87.5L, and temperature of 45 deg.C. Adding injection water 10 times the volume of the medicinal liquid, stirring for 20min, standing for 20min, storing the water precipitate in a tank, and cooling at 4 deg.C for 36 hr.
5. Collecting paste: cooling the water precipitation solution, centrifuging at 10000rmp/min for 20min, filtering with 8 layers of filter paper board frames, adjusting pH of the filtrate to 2.1 with 10% (v/v) hydrochloric acid solution, standing for 1 hr, and centrifuging at 10000rpm for 20 min. The supernatant was adjusted to pH 9.0 with 10% sodium hydroxide (w/w) solution and boiled for 60 minutes. Cooling to 70 deg.C, adjusting pH to 6.0, adding 0.1% (w/w) active carbon, boiling for 30 min, and filtering with 8 layers of filter paper and 1 layer of 0.22 filter membrane. Concentrating the filtrate to specific gravity of 1.15, refrigerating, collecting the extract, and refrigerating the extract to obtain Saviae Miltiorrhizae radix extract.
Example 2 preparation of Salvia miltiorrhiza Bunge extract example 2
1. Extraction: 480kg of clean salvia miltiorrhiza medicinal material is added with purified water and decocted for two times; 9 times of purified water is added for the first time, and the decoction is carried out for 2.5 hours; adding 10 times of purified water for the second time, decocting for 2 hr, filtering the extractive solution with 200 mesh filter screen, concentrating the extractive solutions to about 450L, discharging, and mixing the concentrated solutions in a pretreatment tank. The mixture had a specific gravity of 1.0, a volume of 900L and a temperature of 68 ℃.
2. Pretreatment: controlling the temperature of the concentrated solution to be 75 ℃, adding 0.5kg of ZTC pretreating agent A to boil for 20 minutes, adding 0.5kg of pretreating agent B with final concentration when the temperature is reduced to 55 ℃, keeping the temperature and heating for 4 hours, then boiling for 20 minutes, stirring and adding ZTC1+1III clarifying agent B with 0.08% (w/w) relative to the weight of the medicinal material when the temperature is reduced to 75 ℃, standing for 1.5 hours, stirring and adding ZTC1+1III clarifying agent A with 0.04% (w/w) relative to the weight of the medicinal material, standing for 3 hours, secondarily centrifuging the pretreating solution (10000rpm/min, 1.5 hours), taking the supernatant, filtering by 8 layers of filter paper, and collecting the supernatant. The ZTC pretreating agent and the clarifying agent are purchased from Tianjin Zhentian science and technology limited.
3. Alcohol precipitation: the supernatant was concentrated in a single effect concentrator to a specific gravity of 1.2 and a volume of 350L. Adding 95% ethanol to make alcohol content not less than 81%, stirring for 20min, standing for 20min, adding supernatant into another alcohol precipitation tank, and cooling at 4 deg.C for 24 hr.
4. Water precipitation: after cooling, the alcohol precipitation solution is filtered by a plate frame 8-layer filter plate frame, the filtrate passes through a single-effect concentrator, ethanol is collected and enters a recovery process, and the filtrate is concentrated to the specific gravity of 1.2, the volume of 85L and the temperature of 45 ℃. Adding injection water 10 times the volume of the medicinal liquid, stirring for 20min, standing for 20min, storing the water precipitate in a tank, and cooling at 4 deg.C for 36 hr.
5. Collecting paste: cooling the water precipitation solution, centrifuging (10000rpm/min, 25min), filtering with 8 layers of filter paper board frames, adjusting pH of the filtrate to 2.08 with 10% (v/v) hydrochloric acid solution, standing for 1 hr, and centrifuging at 10000rpm for 25 min. The supernatant was adjusted to pH 8.95 with 10% (w/w) sodium hydroxide solution and boiled for 60 minutes. Cooling to 75 deg.C, adjusting pH to 5.5, adding 0.1% (w/w) active carbon, boiling for 30 min, and filtering with 8 layers of filter paper and 1 layer of 0.22 filter membrane. Concentrating the filtrate to specific gravity of 1.1, refrigerating, collecting the extract, and refrigerating the extract to obtain Saviae Miltiorrhizae radix extract.
Example 3 preparation of Salvia miltiorrhiza Bunge extract
1. Extraction: 480kg of clean salvia miltiorrhiza medicinal material is added with purified water and decocted for two times; adding 10 times of purified water for the first time, and decocting for 2 hours; adding 12 times of purified water for the second time, decocting for 3 hr, filtering the extractive solution with 200 mesh filter screen, concentrating the extractive solutions to about 450L, and mixing the concentrated extractive solutions in a pretreatment tank. The mixture had a specific gravity of 1.2, a volume of 900L and a temperature of 65 ℃.
2. Pretreatment: controlling the temperature of the concentrated solution to 80 ℃, adding 1kg of ZTC pretreating agent A, boiling for 20 minutes, adding 1kg of ZTC pretreating agent B when the temperature is reduced to 60 ℃, keeping the temperature, heating for 4 hours, boiling for 20 minutes, adding ZTC1+1III clarifying agent B with the final concentration of 0.06% (w/w) while stirring when the temperature is reduced to 70 ℃, standing for 2 hours, adding ZTC1+1III clarifying agent A with the final concentration of 0.03% (w/w) while stirring, standing for 4 hours, centrifuging the pretreated solution for two times (10000rpm/min, 1.5 hours), taking supernatant, filtering by 8 layers of filter paper, and collecting the supernatant. The ZTC pretreating agent and the clarifying agent are purchased from Tianjin Zhentian science and technology limited.
3. Alcohol precipitation: the supernatant was concentrated in a single effect concentrator to a specific gravity of 1.24 and a volume of 350L. Adding 95% ethanol to make alcohol content not less than 81%, stirring for 20min, standing for 20min, adding the supernatant into another alcohol precipitation tank, and cooling at 4 deg.C for 24 hr.
4. Water precipitation: after cooling, the alcohol precipitation solution is filtered by a plate frame 8-layer filter plate frame, the filtrate passes through a single-effect concentrator, ethanol is collected and enters a recovery process, and the filtrate is concentrated to the specific gravity of 1.22, the volume of 85L and the temperature of 45 ℃. Adding injection water 10 times the volume of the medicinal liquid, stirring for 20min after adding a predetermined amount of injection water, standing for 20min, storing the water precipitate in a tank, and cooling at 4 deg.C for 36 hr.
5. Collecting paste: cooling the water precipitation solution, centrifuging (10000rpm/min, 25min), filtering with 8 layers of filter paper board frame, adjusting pH of the filtrate to 2.13 with 10% (v/v) hydrochloric acid solution, standing for 1 hr, and centrifuging at 10000rpm for 25 min. The supernatant was adjusted to pH 9.0 with 10% (w/w) sodium hydroxide solution and boiled for 60 minutes. Cooling to 70 deg.C, adjusting pH to 6.0, adding 0.1% (w/w) active carbon, boiling for 30 min, and filtering with 8 layers of filter paper and 1 layer of 0.22 filter membrane. Concentrating the filtrate to specific gravity of 1.17, refrigerating, collecting the extract, and refrigerating the extract to obtain Saviae Miltiorrhizae radix extract.
Example 4 comparison of different extraction methods
The danshen root extract prepared by the clarifier method disclosed in CN104721260A (example 1) was used as comparative example 1, the danshen root extract prepared by the two-step lime-precipitation lime-sulfide method in CN106995369A (clear examples) was used as comparative example 2, and the danshensu content in the danshen root extract prepared in comparative examples 1-2 and examples 1-3 was examined.
The improved fining agent extraction methods used in examples 1-3 were compared to the extraction methods of comparative examples 1-2, such as those shown in table 1:
table 1: comparison of extraction Process steps
From the comparison of table 1, examples 1 to 3 are much shorter in extraction time than comparative example 1, and at the time of collecting paste, tannin was removed by adding hydrochloric acid, and salvianolic acids were converted into tanshinol, which is an active substance, by adding sodium hydroxide. Compared with the comparative example 2, the method has the advantages that the steps are simple, the pretreatment time is greatly reduced, only one-time alcohol precipitation is carried out, the using amount of ethanol is greatly reduced, the alcohol precipitation time is reduced by half, the yield of the extracted tanshinol is high, and the purity and the quality of the extracting solution are further improved by filtering the extract through active carbon and a 0.22 filter membrane in the last paste collecting step.
The improved clarifier method used in examples 1-3 is compared to the extraction results of comparative examples 1-3 as shown in Table 2:
table 2: comparison of extraction results by different methods
From the results in table 2, the content of danshensu in examples 1-3 is greatly increased (the comparative reference cream yield of comparative example 2) compared with that in comparative example 1 and comparative example 2, so that the extraction rate of the danshensu extract obtained by the preparation method of the present invention is greatly increased.
EXAMPLE 5 recovery of ethanol
1. And (5) evaporating and recovering the ethanol.
(1) Filtering the alcohol precipitation solution obtained in the step 4 of the embodiment 1 by using 8 layers of filter paper;
(2) heating and evaporating the filtrate by a single-effect concentrator, recovering ethanol in a gas form, cooling, and recovering ethanol;
(3) the liquid medicine is at the bottom of the concentrator and separated from the ethanol. The recovered ethanol is detected to have a concentration of about 80% and light red brown, and the possible impurities are tanshinol, tanshinone IIA and salvianolic acid B.
2. And (5) rectifying the ethanol.
(1) And the recovered ethanol enters an evaporation chamber of the recovery tower, the feeding is stopped when the volume of 2/3 is reached, and the conveying pump and the feeding valve are closed.
And starting heating, controlling the gauge pressure of a steam valve in the evaporation chamber to be 0.12MPa, and controlling the gauge pressure of the steam valve to be 0.05-0.15 MPa when the temperature reaches 75-80 ℃. And after running for 50-70min, opening a reflux sampling valve for sampling, and detecting the concentration of the ethanol. Opening a reflux sampling valve for sampling, and detecting the concentration of ethanol;
(2) and collecting: and (3) when the concentration of the ethanol is detected to be more than 95% by sampling, starting a reflux metering valve, controlling the reflux flow to be 500-1500L/H, collecting the ethanol to a rectification ethanol tank, detecting the concentration of the ethanol recovered by rectification by using an alcohol meter every 10-30 minutes in the collection process, adjusting the flow meter if the concentration of the ethanol is lower than 95%, and otherwise, adjusting the flow meter to be small. When the amount of the recovered ethanol pumped into the evaporation chamber is lower than 1/2 volumes, the recovered ethanol needs to be continuously supplemented to 2/3 volumes.
3. And (5) detecting ethanol.
(1) And (5) detecting the concentration yield.
In the preparation process, the impurities which may be introduced are clarificant, tanshinol, tanshinone IIA and salvianolic acid B. And detecting the concentration of the rectified ethanol obtained in the step and calculating the yield.
Yield:
(amount of distilled ethanol. times. degree of distilled ethanol)/(amount of recovered ethanol)
(2) And (5) detecting the relative density. It is required to be not more than 0.8129, corresponding to C2H6O is not less than 95 percent
(3) And (5) detecting the characters. Colorless clear liquid with little odor; is easy to volatilize and burn, and shows light blue flame when burning; heating to 78 deg.C and boiling.
(4) And (3) residual detection: the residual amount of tanshinol in the rectified ethanol is not more than 10 mug/ml.
4. The result of the detection
The ethanol recovered and rectified after the primary use is called the ethanol recovered for the 1 st time; the ethanol recovered from the 1 st time is used for extracting the salvia miltiorrhiza, and the ethanol obtained by recovering and rectifying the ethanol is called as the ethanol recovered from the 2 nd time, and so on. The ethanol recovered and rectified for four times is subjected to the quality detection, and compared with 3 batches of commercial ethanol samples, and the detection results are shown in table 3.
TABLE 3 comparison of quality test of four times recovered rectified ethanol and commercial ethanol
From the results, even if the ethanol is recovered and rectified for four times, the quality of the ethanol completely meets the indexes of national alcohol-related quality detection, and is not different from the quality of commercial ethanol.
Further, the quality of the tanshinol extract prepared from the rectified ethanol recovered 1 to 4 times was examined, and the results are shown in table 4.
Table 4: quality data of Saviae Miltiorrhizae radix extract prepared with recovered ethanol
From the results, the quality of the rectified ethanol is strictly controlled, so that the salvia miltiorrhiza extract prepared from the obtained rectified ethanol can completely reach the quality same as that of commercial ethanol even if the rectified ethanol is recycled for up to 4 times, and the salvia miltiorrhiza extract can reach the standard of the use of the medicines on the market.
Example 6 preparation of Salvia miltiorrhiza Chuanxiongzine injection
According to the national standard of injection of salvia miltiorrhiza and ligustrazine: WS-10001- (HD-1138) -2002-2017, the formula of the injection is as follows:
the preparation method comprises the following steps: taking the Saviae Miltiorrhizae radix extractive solution prepared in examples 1-3, making into clear liquid containing 4g medicinal materials per ml, and adjusting pH to 5.0-6.0 to obtain medicinal liquid. Mixing ligustrazine hydrochloride, adjuvants and the above medicinal liquid, adding water for injection, adjusting pH to 3.5, making into 1000ml, filtering, bottling after product inspection is qualified in 5ml ampoule bottle, and sterilizing at 115 deg.C for 30 min. The auxiliary material is glycerol.
Claims (11)
1. A preparation method of a salvia miltiorrhiza extract comprises the following steps: (1) decocting with water for the second time, and concentrating the extractive solution; (2) clarifying the extracting solution; (3) carrying out primary alcohol precipitation on the clarified liquid; (4) carrying out primary water precipitation on the alcohol precipitation solution; (5) further removing impurities with hydrochloric acid and sodium hydroxide, collecting paste, and concentrating to obtain Saviae Miltiorrhizae radix extract; the method is characterized in that the clarifying agent in the step (2) is a ZTC1+1 clarifying agent, and the clarifying treatment step comprises the following steps: adding clarifier B with a medicinal material proportion of 0.03-0.1% into the extractive solution, standing for 1.5-3h, adding clarifier A with a proportion of 0.01-0.05%, standing for 3-5h, centrifuging, filtering, collecting filtrate, adjusting pH to 2-2.5 with hydrochloric acid, adjusting pH to 8-9.5 with sodium hydroxide, and adjusting pH to 5.5-6 with hydrochloric acid in step (5).
2. The method of claim 1, wherein prior to step (2), a pretreatment step is performed, the pretreatment being: controlling the temperature of the concentrated solution at 80 +/-10 ℃, adding the pretreating agent A according to the proportion that 0.5-3kg of the pretreating agent A is added into each 1000kg of medicinal materials, boiling for 20 minutes, adding the pretreating agent B according to the proportion that 0.5-3kg of the pretreating agent B is added into each 1000kg of medicinal materials when the temperature is reduced to 55 +/-5 ℃, keeping the temperature, heating for 4 hours, boiling for 20 minutes, and performing the step (2) when the temperature is reduced to 80 +/-10 ℃.
3. The method according to any one of claims 1 to 2, wherein the alcohol precipitation step in step (3) comprises: heating and concentrating the supernatant, adding 95% ethanol to make the alcohol content not less than 80%, stirring, standing, and cooling the supernatant.
4. The method according to claim 3, wherein the alcohol precipitation step in step (3) comprises: heating and concentrating the supernatant to a specific gravity of 1.22 +/-0.02, adding 95% ethanol at 45 +/-5 ℃ to ensure that the alcohol content is not less than 80%, stirring for 20 minutes, standing for 20 minutes, and cooling the supernatant for more than 24 hours at 0-5 ℃.
5. The production method according to any one of claims 1 to 4, wherein the water-precipitation step in the step (4) comprises: filtering the cooled alcohol precipitation solution, recovering ethanol, concentrating, adding 8-12 times of injection water, stirring, standing, and cooling the water precipitation solution.
6. The method according to claim 5, wherein the water-settling step in the step (4) comprises: and filtering the cooled alcohol precipitation liquid by adopting an 8-layer filter board frame, concentrating the filtrate to the specific gravity of 1.22 +/-0.02 by using a single-effect concentrator at the temperature of 45 +/-5 ℃, simultaneously recovering ethanol, adding injection water with the volume being 10 times that of the concentrated liquid medicine, stirring for 20 minutes, standing for 20 minutes, and cooling the water precipitation liquid for over 36 hours at the temperature of 0-5 ℃.
7. The production method according to any one of claims 1 to 6, wherein the step (5) comprises: filtering the water precipitation solution again, adjusting pH of the filtrate to 2-2.5 with hydrochloric acid, standing, centrifuging, filtering, adjusting pH of the filtrate to 8-9.5 with sodium hydroxide, boiling, cooling to 70-80 deg.C, adjusting pH to 5.5-6, adding active carbon, boiling, filtering, concentrating the filtrate, collecting the extract, and refrigerating.
8. The method according to any one of claims 1 to 7, wherein the alcohol precipitation solution obtained in step (4) is subjected to ethanol recovery treatment and recycled for use in the alcohol precipitation in step (3).
9. The method of claim 8, wherein the ethanol recovery process comprises the steps of:
(1) and (3) recovering ethanol: heating and evaporating the alcohol precipitation solution in the step (4) of claims 1 to 8 by using a single-effect concentrator, recovering the ethanol in a gas form, and cooling to obtain recovered ethanol; (2) ethanol rectification: feeding the recovered ethanol into a rectifying tower, heating by steam, rectifying at the tower top temperature of 75-80 ℃, recovering the ethanol in a gas form, and cooling to obtain rectified ethanol; optionally, the ethanol rectified in the step (2) is sampled to detect the concentration, and the ethanol is collected when the concentration reaches more than 95%.
10. The extract of Salvia miltiorrhiza as prepared by the method of any one of claims 1 to 9.
11. An injection of red sage root and ligustrazine, characterized in that the injection comprises the red sage root extract prepared according to the method of claim 10, ligustrazine and a proper amount of glycerol, wherein the red sage root extract and the ligustrazine are prepared according to the weight ratio of 5-110:1 of the red sage root and the ligustrazine.
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| CN1559469A (en) * | 2004-02-27 | 2005-01-05 | 北京乾露春科技有限公司 | Prepn. method for freezing-drying powder injection for treating cardiovascular disease |
| CN1775233B (en) * | 2005-11-18 | 2011-06-22 | 万生联合制药有限公司 | Red-rooted-salvia-root chuanxiong-rhizome azine injecta, its preparation method and use |
| CN101332227B (en) * | 2008-07-04 | 2011-06-22 | 湖北清大康迪药业有限公司 | Preparation method of Clary injection |
| CN101985417B (en) * | 2010-11-02 | 2013-06-05 | 贵州景峰注射剂有限公司 | Process for extracting salvianic acid A |
| CN104974033A (en) * | 2013-12-22 | 2015-10-14 | 贵州景峰注射剂有限公司 | Method for extracting tanshinol |
| CN104721260A (en) * | 2013-12-22 | 2015-06-24 | 贵州景峰注射剂有限公司 | Pharmaceutical composition used for treating cardiovascular diseases, and preparation method thereof |
| CN106995369B (en) * | 2017-03-31 | 2019-06-14 | 吉林四长制药有限公司 | It is a kind of using danshensu as the preparation method of the red sage root extract of object |
| CN107260803A (en) * | 2017-06-19 | 2017-10-20 | 上海华源安徽锦辉制药有限公司 | The preparation method of Sodium Danshensu content in a kind of raising red sage roo drip liquid |
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