CN1778337B - A kind of preparation method of compound salvia miltiorrhiza tablet - Google Patents

Abstract

A composite Danshen tablet is prepared from red sage root, notoginseng and borneol through extracting the liquid extract from red sage root and notoginseng in water or alcohol, clarifying, ultrafiltering, concentrating, adding borneol and tabletting.

Description

A kind of preparation method of compound salvia miltiorrhiza tablet

technical field

The invention relates to a traditional Chinese medicine tablet prepared by an ultrafiltration process. Specifically, the invention relates to a compound Danshen tablet prepared by an ultrafiltration process.

Background technique

Compound Danshen Tablet is a variety recorded in the Chinese Pharmacopoeia. It has the effects of promoting blood circulation and removing blood stasis, regulating qi and relieving pain. It is commonly used clinically for chest tightness and angina pectoris. The traditional process is: take Salvia miltiorrhiza and extract 3 times, add ethanol to reflux for 1.5 hours for the first time, filter, recover ethanol from the filtrate, concentrate to a relative density of 1.30 (55-60°C); add 50% ethanol for the second time and reflux for 1.5 hours , filtered. For the third time, add water and reflux for 2 hours, filter, combine the second and third filtrates, recover ethanol, concentrate to a relative density of 1.40 (55-60°C), combine with the first concentrated solution, and mix well to prepare It forms an extract with a relative density of 1.35 to 1.39 (55°C). Crush Panax notoginseng into fine powder, mix with salvia miltiorrhiza extract, dry and make granules. Grind the borneol finely, mix it with the above granules, press it into 1000 pieces, or coat it with sugar.

Although the above-mentioned process can retain most of the active ingredients and remove a considerable amount of impurities, recent studies have found that many polysaccharides and many trace elements related to immunity have great Large loss; and the production cycle of this production process is long, the process is complicated, the production cost is high, the stability of the finished product is poor, and it is easy to produce environmental pollution.

Membrane separation technology (Membrane Separation Technique) is a new high-efficiency separation technology, which has been internationally recognized as the most promising high-tech production technology from the end of the 20th century to the middle of the 21st century. Ultrafiltration (UF) technology is a membrane separation technology whose basic principle is to use the selective screening performance of membrane pores to separate, purify and concentrate substances. The ultrafiltration method uses an anisotropic membrane (that is, an asymmetric membrane) made of polymer materials as the filter medium. Under normal temperature conditions, relying on a certain pressure and flow rate, the solution flows through the membrane surface, forcing low molecular weight substances to permeate. Through the membrane, the polymer substances are intercepted.

Because the ultrafiltration method is a physical method, it has the characteristics of no need for repeated heating, no "phase state" change, less possibility of destroying active ingredients than other general methods, and short process flow, so it is applied to the research of extracting active ingredients of traditional Chinese medicine Increasingly active, some products have moved from laboratory research to industrial production. People's Liberation Army 304 Hospital Wang Shiling and others used ultrafiltration to extract the active ingredient baicalin in Scutellaria baicalensis. The results showed that the ultrafiltration method was superior to the conventional method in terms of yield and purity, and one ultrafiltration can meet the requirements of injections without further steps. Refined, simple process, the production cycle can be shortened by 1 to 2 times (Wang Shiling, Zheng Dianbao "A Preliminary Investigation on the Extraction of Baicalin by Ultrafiltration", Chinese Patent Medicine Research, 1988 (3): 5). Wang Shiling and others have further studied the optimal process conditions for extracting baicalin by ultrafiltration. The experimental results prove that the selection of an ultrafiltration membrane with a suitable pore size (molecular weight cut-off is 6000-10000) is the key to improving the yield and quality of baicalin. Liquid temperature or lower concentration, strictly control the pH value (pH=1.5 during acidification, pH=7.0 during alkali dissolution), can significantly improve the ultrafiltration speed, and obtain the best output effect (Wang Shiling, "One-time extraction of baicalin by ultrafiltration Technology Research", Chinese Patent Medicine, 1994, 16(3): 2). Xu Jinlin and others used the ultrafiltration method (polysulfone membrane, molecular weight cut-off 6000) in the preparation of phytic acid, and the yield of phytic acid was 86.4%, which was 12.6% higher than the conventional phytate method, and the phytic acid obtained by the ultrafiltration method was almost It does not contain inorganic phosphorus, and its appearance is transparent and almost colorless (Xu Jinlin, Xu Jie, Wang Yuanjin "Research on Preparation of Phytic Acid by Membrane Separation Technology", China Journal of Pharmaceutical Industry, 1994, 25(4): 150). He Changsheng and others applied ultrafiltration technology to separate and refine stevioside, and used ultra-thin plate ultrafilter and cellulose acetate membrane (CA membrane) with a molecular weight cut-off of 10,000 to carry out field experiments on the purification of stevioside. The process flow is reasonable and feasible. The performance of the ultrafilter is stable, the decolorization performance of the membrane and the effect of removing impurities are good, which can better solve the problems of precipitation and foaming during potting that often occur in the production of stevioside (He Changsheng, Wang Bingnan, Zhu Shanshan "Stevioside Application Research of Ultrafiltration", Water Treatment Technology, 1994, 20(2): 89). Huang Ziqiang used ultrafiltration membranes (polysulfone membranes with a molecular weight cut-off of 4000 and 10000) to refine camellia oleifera saponin, compared with the bleaching method, recrystallization method, alcohol ether precipitation method and alkaline salt precipitation method mostly used in China, the ultrafiltration process flow Simple, efficient, low cost, to remove grease, pigments, sugars and other highly hydrophilic impurities in the crude camellia saponin, all can achieve the expected effect (Huang Ziqiang, "Ultrafiltration membrane method refining camellia saponin preliminary research" water Process Technology, 1995, 21(2):99). Guo Liwei from Nanjing University of Traditional Chinese Medicine compared and studied the effects of water-alcohol method and ultrafiltration method on the clarification of Cornus officinalis preparations on the ingredients contained in the preparations. Ultrafiltration membrane has no obvious effect on loganin (molecular weight is 384), but the film with molecular weight cut-off is 1000 makes loganin loss about 50% (Guo Liwei, Peng Guoping, Pan Yang et al. A Comparative Study of Chinese Medicine Preparations from Cornus officinalis", Chinese Patent Medicine, 1999, 21(2): 59). Wang Chengzhang et al. used ultrafiltration (polysulfone membrane, molecular weight cut-off 30000) and polyamide resin adsorption elution method to separate and purify the ethanol extract of Ginkgo biloba leaves, and the content of ginkgo flavonoid glycosides was detected by high performance liquid chromatography (HPLC). At about 45%, the yield is 0.5% to 0.7%, which is superior to conventional steam distillation and organic solvent extraction, and can reduce waste water discharge in the ultrafiltration process, protect the environment, reduce production costs, and improve economic benefits ( Wang Chengzhang, Yu Qing, Tan Weihong, etc. "Application of Ultrafiltration in the Purification of Ginkgo Flavonoid Glycosides", Forestry Science and Technology Communication, 1997, (2): 21).

Although the application of ultrafiltration technology in the production of traditional Chinese medicine preparations has its unique advantages, the extent of its application is still very limited. The reason is that there are still the following problems:

(1) The composition of Chinese herbal medicine is complex, especially in many compound preparations, the active ingredients have not been fully understood, so it needs to be thoroughly studied before applying ultrafiltration technology to Chinese herbal medicine preparations. For example, due to the complexity of the components, it is impossible to apply ultrafiltration to the production of most traditional Chinese medicine preparations before a large number of pharmacological and clinical research tests are conducted to fully evaluate the effect of ultrafiltration on the efficacy of each component in traditional Chinese medicine preparations.

(2) There are few types of membrane materials, the membrane pore size distribution is wide, and the performance is not stable. The ultrafiltration membrane materials used in the production of traditional Chinese medicine preparations include cellulose acetate, polyacrylonitrile, polysulfone, sulfonated polysulfone, polysulfone amide, etc. According to its affinity to water, it can be roughly divided into two categories: hydrophobic membrane materials and hydrophilic membrane materials. Hydrophilic membrane materials such as cellulose acetate and sulfonated polysulfone have less adsorption of solutes and a smaller molecular weight cut-off, but poor thermal stability, mechanical strength, chemical resistance, and bacterial erosion resistance are usually not high; polysulfone and other hydrophobic Membrane material has high mechanical strength, high temperature resistance, solvent resistance, and biodegradation resistance, but because the molecular chain contains a large number of hydrophobic genes or chain links, and has a lot of electrostatic charges, the membrane has a low water permeability and low anti-pollution ability .

(3) Membrane fouling is the biggest obstacle preventing ultrafiltration technology from laboratory research to industrial application. In the ultrafiltration process of traditional Chinese medicine preparations, if the pretreatment effect of the liquid medicine is not good, the membrane surface will be easily polluted and the membrane pores will be blocked, which will reduce the permeation flux, that is, the productivity, or even fail to work normally, reduce the production efficiency, and increase the cost, resulting in membrane shortened service life.

(4) The selection method of membrane modules has not been established yet, and the operating parameters of ultrafiltration still need to be optimized. There are many factors that affect the effect of ultrafiltration, including the selection of membrane components, the determination of process parameters and the cleaning method of the ultrafilter after use. Therefore, the ultrafiltration equipment and operating technology suitable for ultrafiltration of traditional Chinese medicine systems need further research.

Regarding the practical application of compound Danshen tablets prepared by ultrafiltration, there are no reports in the current literature. In particular, the use of ultrafiltration for industrial production has always been a technical problem in this field.

The inventor has made unremitting efforts for a long time, and verified the feasibility of ultrafiltration to prepare Compound Danshen Tablets by analyzing a large amount of experimental data, and determined suitable process operating conditions, in order to utilize ultrafiltration to carry out the industrialized production of Compound Danshen Tablets Specific solutions are provided.

Contents of the invention

The purpose of the present invention is to provide a preparation method of Compound Danshen Tablets. The compound Danshen Tablets prepared by the method has little loss of active ingredients and solves the difficult problem of operability of industrial production ultrafiltration process conditions.

The preparation method of the compound Danshen tablet of the present invention is realized through the following technical steps: taking Danshen, Radix Notoginseng and Borneolum as raw materials, the preparation is carried out according to the following steps:

(1) Mix Salvia Miltiorrhiza and Panax notoginseng or make water extract or alcohol extract separately;

(2) Carry out preliminary clarification treatment to described extract;

(3) further carry out ultrafiltration treatment to described extract;

(4) Concentrate the ultrafiltrate, add borneol, and make tablets according to conventional methods.

The proportion by weight of the above-mentioned crude drug is 20%-97% of salvia miltiorrhiza, 2%-79% of notoginseng, 0.2%-3% of borneol; preferably 63.0%-94% of salvia miltiorrhiza, 4.0%-35.0% of notoginseng, and 0.5% of borneol. % to 2.0%; more preferably 75.2% to 90% of Danshen, 9% to 23.5% of Radix Notoginseng, and 0.5% to 1.3% of Borneol; the best are 82.87% of Salvia Miltiorrhiza, 16.21% of Radix Notoginseng, and 0.92% of Borneol. The sum of the percentages by weight of salvia miltiorrhiza, notoginseng and borneol is 100%.

In the technical step (1) of the present invention, the alcohol extract can be lower alcohols of different concentrations such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc., or extracts of their mixtures. The alcohol extract can be subjected to the next preliminary clarification treatment without concentration or after proper concentration.

In the technical step (2) of the present invention, preliminary clarification treatment can carry out rough filtration with general material such as gauze, silk silk etc., also can carry out microfiltration with more professional material such as ceramic membrane, also can get supernatant after high-speed centrifugation Liquid, also can use flocculant such as chitosan flocculation clarifier, 101 fruit juice clarifier, ZTC1+1 natural clarifier, egg white flocculant etc. Some impurities. The above clarification methods can be used alone or in combination, such as coarse filtration-adsorption clarification, adsorption clarification-high-speed centrifugation, coarse filtration-microfiltration, coarse filtration-alcohol precipitation, etc. The solution that has been preliminarily clarified can be subjected to the next step of ultrafiltration without concentration or after being properly concentrated; preferably, the next step of ultrafiltration is performed without concentration.

In the technical step (3) of the present invention, the ultrafiltration membrane used for ultrafiltration can be cellulose diacetate membrane (CA), cellulose triacetate membrane (CTA), cyanoethyl cellulose acetate membrane (CN-CA), polyester Sulfone membrane (PS), sulfonated polysulfone membrane (SPS), polyethersulfone membrane (PES), sulfonated polyethersulfone membrane (SPES), polysulfone amide membrane (PSA), phenolphthalein side group polyarylsulfone membrane (PDS) ), polyvinylidene fluoride film (PVDF), polyacrylonitrile film (PAN), polyimide film (N), cellulose film, methyl methacrylate-acrylonitrile copolymer film (MMA-AN), poly Acrylonitrile/cellulose diacetate (PAN/CA) blend membranes, dynamically formed ultrafiltration membranes, and modified membranes of the above membranes. Preferably cellulose diacetate membrane (CA), cellulose triacetate membrane (CTA), polysulfone membrane (PS), sulfonated polysulfone membrane (SPS), polyethersulfone membrane (PES), sulfonated polyethersulfone membrane (SPES), polysulfoneamide membrane (PSA), polyvinylidene fluoride membrane (PVDF), polyacrylonitrile membrane (PAN).

The molecular weight cut-off of the ultrafiltration membrane is generally 6000-80000, preferably 10000-70000, most preferably 20000-50000.

Ultrafiltration can be either cross-flow filtration or dead-end filtration, but cross-flow filtration is preferred.

The operating conditions of the ultrafiltration process are as follows:

(1) The inlet pressure of the ultrafiltration is 0.1-0.5MPa, preferably 0.1-0.35Mpa, and most preferably 0.25-0.35Mpa; the outlet pressure of the ultrafiltration is 0.5-0.25kPa lower than the inlet pressure. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are adopted, and the pressure fluctuation difference is 0.1-0.2Mpa.

(2) The flow rate of the feed liquid is 1.0-4.0 m/s, preferably 2.0-3.0 m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating flow or unsteady flow in the membrane channel, and the flow velocity fluctuation difference is 1.0-2.0m/s.

(3) In the ultrafiltration system, high-pressure inert gas such as nitrogen is fed intermittently to form a gas-liquid pulse flow, and the cycle is 0.5h-2h to ventilate once, each time for 1 minute.

(3) The feed liquid temperature is 15-50°C, preferably 20-40°C.

(4) When the stock solution is concentrated by 1/15 to 1/5, add water or dilute alcohol solution for ultrafiltration 1 to 2 times; preferably when the stock solution is concentrated by 1/12 to 1/8, add water Or dilute alcohol solution ultrafiltration 1 to 2 times.

(5) The pH value of the feed liquid is controlled at 5 to 9, preferably 6.0 to 7.5;

(6) Backwashing conditions: Backwashing pressure is 0.15-2.5MPa, backwashing cycle is 0.5-1.5h, and backwashing time is 1min-10min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time To carry out, generally work for 10 to 20 minutes, and recoil for 30 seconds to 3 minutes.

(7) The chemical cleaning period is 0.5 months to February. The chemical cleaning agents are generally dilute acids, dilute alkalis, and surfactants, preferably dilute alkalis, such as 0.5% to 4.0% sodium hydroxide, 1.5% sodium hydroxide and 2 % sodium hypochlorite mixed solution, etc., the pH value is 10-12, and the cleaning working pressure is 0.05-1.0MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

In the ultrafiltration process, periodic pressure fluctuations or periodic flow fluctuations or periodic inert gas injections can be used alone, or in combination, that is, periodic pressure fluctuations and periodic flow fluctuations are used in combination, or periodic pressure fluctuations It is used in combination with periodic inert gas injection, or in combination with periodic flow fluctuations and inert gas injection, or in combination with the three.

In the technical step (4) of the present invention, after the ultrafiltrate is concentrated into an extractum, it is made into tablets according to a conventional method. For example, it can be mixed with any one or more pharmaceutical excipients such as starch, dextrin, lactose, microcrystalline cellulose, hydroxypropylmethylcellulose, polyethylene glycol, magnesium stearate, micronized silica gel, xylose Alcohol, lactitol, glucose, glycine, mannitol, glycine, etc. are mixed to form tablets.

The medicine of the invention has a good therapeutic effect in treating angina pectoris of coronary heart disease.

Experimental Example Clinical Observation on the Treatment of Coronary Heart Disease Angina Pectoris by Compound Danshen Tablets of the Present Invention

1. General information: According to the 1976 WHO diagnostic criteria for coronary heart disease, 30 cases were selected as the treatment group to take the compound Danshen tablet of the present invention, and 30 cases were taken as the control group for observation. In the treatment group, there were 24 males and 6 females, aged 55 to 80 years, with a course of 1 to 10 years, including 24 cases of stable angina, 6 cases of unstable angina, 7 cases of hypertension and 3 cases of diabetes. In the control group, there were 23 males and 7 females, aged 52-78 years, with a course of 1-9 years, including 25 cases of stable angina, 5 cases of unstable angina, 8 cases of hypertension and 2 cases of diabetes.

2. Practical method: the treatment group took two tablets of Compound Danshen Tablets orally 1 time, 3 times a day; the control group took Xiaoxintong 10 mg 1 time, 3 times a day. The course of treatment for the two groups was 4 weeks. Patients with high blood pressure and diabetes continued to take antihypertensive and hypoglycemic drugs for treatment. If angina pectoris occurs during the medication, take nitroglycerin temporarily. Before treatment, during treatment and after treatment, the number of angina pectoris attacks, pain conditions, times of nitroglycerin, blood sugar, liver function, BUN and electrocardiogram, blood pressure were recorded, and adverse reactions after taking the medicine were recorded.

3. Judgment criteria for curative effect:

3.1 Significantly effective symptoms of angina pectoris: angina pectoris basically disappears without nitroglycerin; effective: the number of angina pectoris attacks and the dosage of nitroglycerin are halved; ineffective: angina pectoris is basically not relieved or the number of attacks is reduced by less than half; exacerbation: the number of angina pectoris attacks and the dosage of nitroglycerin are increased.

3.2 Electrocardiogram Significantly effective: resting ischemic electrocardiogram returned to normal or roughly normal after treatment; effective: S-T segment rebounded by about 0.05mv, T wave inversion became shallower by more than 50% or turned from flat to upright; invalid; S-T segment, T wave Changes without improvement; aggravated: S-T segment, T wave changes aggravated.

4. Results:

4.1 The total effective rate of treatment of angina pectoris symptoms in the two groups (marked effect plus effective)

The treatment group was 83.33%, and the control group was 80%. The P value of the curative effect of the two groups was tested by ^X2 , and there was no significant difference.

4.2 The total effective rate of resting ischemic electrocardiogram improvement in the two groups of patients (marked effect plus effective)

The treatment group was 60%, and the control group was 56.67%. The curative effect of the two groups was P>0.05 by ^X2 test, and there was no significant difference. The heart rate, liver function, and BUN of the two groups were normal before and after treatment, and had no effect on blood pressure and blood sugar. The treatment group had no adverse reactions during the treatment period.

Table 1 Analysis of curative effect of 30 cases of coronary heart disease with angina pectoris

Table 2 Analysis of the curative effect of resting ischemic electrocardiogram in 30 patients with coronary heart disease and angina pectoris

As we all know, Xiaoxintong has a positive effect on treating angina pectoris of coronary heart disease. In this paper, the total effective rate of Xiaoxintong in the control group is 80%, and the effective rate of electrocardiogram improvement is 56.67%, while the compound danshen tablet treatment group of the present invention reaches 83.33% in the relief rate of coronary heart disease angina pectoris, and the electrocardiogram improvement rate is 60%. There was no significant difference, P>0.05.

Detailed ways

The present invention will be further elaborated below in conjunction with embodiment. These examples are for illustrative purposes only and do not limit the invention in any way.

Embodiment one

The raw materials are 558g of Danshen, 34g of Radix Notoginseng and 8g of Borneol.

Extract Danshen with ethanol to obtain ethanol extract of Danshen, filter the extract with gauze, and collect the filtrate. The filtrate was ultrafiltered with a cellulose diacetate membrane with a molecular weight cut-off of 6000, and the filtration method was cross-flow filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.1Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.5kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are used, and the pressure fluctuation difference is 0.1Mpa. The flow rate of the feed liquid is 1.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating flow or unstable flow in the membrane channel. The difference in flow rate fluctuations is 1.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 0.5h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 15°C. When the original feed liquid is concentrated by 1/15, add water or dilute alcohol solution for ultrafiltration once, and the pH value of the feed liquid is controlled at 5. The backwash pressure is 0.15MPa, the backwash cycle is 0.5h, and the backwash time is 1min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 10min, recoil for 30sec. The chemical cleaning cycle is 0.5 months, the chemical cleaning agent is a mixed solution of 0.5%-4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10-12, and the cleaning working pressure is 0.05MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrating the ultrafiltrate to obtain the salvia miltiorrhiza extract with a relative density of 1.35-1.39 (55° C.). Crush Panax notoginseng into fine powder, mix with salvia miltiorrhiza extract, dry and make granules. Grind the borneol finely, mix it with the above granules, press it into 1000 pieces, or coat it with sugar.

Embodiment two

The raw materials are 593g of Danshen, 64g of Radix Notoginseng and 4g of Borneol.

Extracting Danshen with ethanol to obtain the ethanol extract of Danshen, microfiltration with ceramic membrane, and collecting the filtrate. The filtrate was ultrafiltered with a polysulfone membrane with a molecular weight cut-off of 80,000, and the filtration method was dead-end filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.5Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.25kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are adopted, and the pressure fluctuation difference is 0.2Mpa. The flow rate of the feed liquid is 4.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating flow or unstable flow in the membrane channel. The difference in flow rate fluctuations is 2.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 2h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 50°C. When the raw liquid of the feed liquid is concentrated by 1/5, add water or dilute alcohol solution for ultrafiltration twice, and the pH value of the feed liquid is controlled at 9. The backwash pressure is 2.5MPa, the backwash cycle is 1.5h, and the backwash time is 10min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 20 minutes, recoil for 3 minutes. The chemical cleaning cycle is 2 months, the chemical cleaning agent is a mixed solution of 0.5% to 4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10 to 12, and the cleaning working pressure is 1.0MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrating the ultrafiltrate to obtain the salvia miltiorrhiza extract with a relative density of 1.35-1.39 (55° C.). Crush Panax notoginseng into fine powder, mix with salvia miltiorrhiza extract, dry and make granules. Grind the borneol finely, mix it with the above granules, press it into 1000 pieces, or coat it with sugar.

Embodiment three:

The raw materials are 360g of Danshen, 232g of Radix Notoginseng and 8g of Borneol.

The salvia miltiorrhiza and notoginseng are extracted with 80% ethanol to obtain the ethanol extract of the salvia miltiorrhiza and notoginseng, the extract is centrifuged at high speed and the supernatant is collected. The liquid is ultrafiltered with a polysulfone membrane with a molecular weight cut-off of 50,000, and the filtration method adopts cross-flow filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.35Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.20kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are adopted, and the pressure fluctuation difference is 0.2Mpa. The flow rate of the feed liquid is 3.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating or unstable flows in the membrane channel. The difference in flow rate fluctuations is 2.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 2h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 40°C. When the original feed liquid is concentrated by 1/8, add water or dilute alcohol solution for ultrafiltration twice, and the pH value of the feed liquid is controlled at 7.5. The backwash pressure is 2.5MPa, the backwash cycle is 1.5h, and the backwash time is 10min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 20 minutes, recoil for 3 minutes. The chemical cleaning cycle is 2 months, the chemical cleaning agent is a mixed solution of 0.5% to 4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10 to 12, and the cleaning working pressure is 1.0MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrate the ultrafiltrate to obtain the salvia miltiorrhiza extract with a relative density of 1.35-1.39 (55° C.), mix the extract evenly with borneol and an appropriate amount of magnesium stearate, press it into 1000 tablets, or coat it with sugar, that is, have to.

Embodiment four

The raw materials are Danshen 411g, Sanqi 80g, and Borneol 4.6g.

Put the coarsely crushed Danshen and Panax notoginseng into the extraction tank, add 5 times the amount of water, decoct for 2 hours, filter, and extract the filter residue for the second time, add 4 times the amount of water, fry for 1 hour, filter, and discard the filter residue To, combine the filtrates. The filtrate was ultrafiltered with a cellulose diacetate membrane with a molecular weight cut-off of 6000, and the filtration method was cross-flow filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.1Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.5kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are used, and the pressure fluctuation difference is 0.1Mpa. The flow rate of the feed liquid is 1.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating flow or unstable flow in the membrane channel. The difference in flow rate fluctuations is 1.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 0.5h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 15°C. When the original feed liquid is concentrated by 1/15, add water or dilute alcohol solution for ultrafiltration once, and the pH value of the feed liquid is controlled at 5. The backwash pressure is 0.15MPa, the backwash cycle is 0.5h, and the backwash time is 1min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 10min, recoil for 30sec. The chemical cleaning cycle is 0.5 months, the chemical cleaning agent is a mixed solution of 0.5%-4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10-12, and the cleaning working pressure is 0.05MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrating the ultrafiltrate to obtain an extract with a relative density of 1.32-1.40 (55° C.), mixing the extract with borneol and an appropriate amount of microcrystalline cellulose, and pressing it into tablets.

Embodiment five

The raw materials are 290g of Danshen, 306g of Radix Notoginseng and 6g of Borneol.

Put the coarsely crushed Danshen and Panax notoginseng into the extraction tank, add 5 times the amount of water, decoct for 2 hours, filter, and extract the filter residue for the second time, add 4 times the amount of water, fry for 1 hour, filter, and discard the filter residue To, combine the filtrates. The filtrate was ultrafiltered with a polysulfone membrane with a molecular weight cut-off of 80,000, and the filtration method was dead-end filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.5Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.25kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are adopted, and the pressure fluctuation difference is 0.2Mpa. The flow rate of the feed liquid is 4.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating flow or unstable flow in the membrane channel. The difference in flow rate fluctuations is 2.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 2h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 50°C. When the raw liquid of the feed liquid is concentrated by 1/5, add water or dilute alcohol solution for ultrafiltration twice, and the pH value of the feed liquid is controlled at 9. The backwash pressure is 2.5MPa, the backwash cycle is 1.5h, and the backwash time is 10min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 20 minutes, recoil for 3 minutes. The chemical cleaning cycle is 2 months, the chemical cleaning agent is a mixed solution of 0.5% to 4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10 to 12, and the cleaning working pressure is 1.0MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrating the ultrafiltrate to obtain an extract with a relative density of 1.32-1.40 (55° C.), mixing the extract with borneol, an appropriate amount of lactitol and starch, and pressing it into tablets.

Embodiment six

210g of salvia miltiorrhiza, 380g of notoginseng and 4g of borneol were used as raw materials.

Put the coarsely crushed salvia miltiorrhiza and Panax notoginseng into the extraction tank, add 0.89g sodium bicarbonate, add 5 times the amount of water, decoct for 2 hours, filter, and extract the filter residue for the second time, add 4 times the amount of water, decoct for 1 hours, filtered, the filter residue was discarded, and the filtrates were combined. The filtrate was ultrafiltered with a polysulfone membrane with a molecular weight cut-off of 50,000, and the filtration method was cross-flow filtration. The operating conditions of the ultrafiltration process are: the pressure of the liquid inlet of the ultrafiltration is 0.35Mpa, and the pressure of the liquid outlet of the ultrafiltration is 0.20kPa lower than the pressure of the liquid inlet. In the initial stage of ultrafiltration, a lower pressure is used, and then the pressure is gradually increased; in the process of ultrafiltration, periodic pressure fluctuations are adopted, and the pressure fluctuation difference is 0.2Mpa. The flow rate of the feed liquid is 3.0m/s. During the ultrafiltration process, periodic flow fluctuations are used to generate pulsating or unstable flows in the membrane channel. The difference in flow rate fluctuations is 2.0m/s. Nitrogen is intermittently fed into the ultrafiltration system , to form a gas-liquid pulse flow, and the period is 2h to ventilate once, each time for 1 minute. The temperature of the feed liquid is 40°C. When the original feed liquid is concentrated by 1/8, add water or dilute alcohol solution for ultrafiltration twice, and the pH value of the feed liquid is controlled at 7.5. The backwash pressure is 2.5MPa, the backwash cycle is 1.5h, and the backwash time is 10min. When the ultrafiltration modules are connected in parallel to use the method of alternate backflushing, one or several sets perform normal ultrafiltration and part of the filtrate is flowed out to backwash the ultrafiltration membrane of another set or several sets of components, and exchange after a period of time Carry out, work for 20 minutes, recoil for 3 minutes. The chemical cleaning cycle is 2 months, the chemical cleaning agent is a mixed solution of 0.5% to 4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, the pH value is 10 to 12, and the cleaning working pressure is 1.0MPa. After cleaning with chemical cleaners, rinse with water until nearly neutral.

Concentrating the ultrafiltrate to obtain an extract with a relative density of 1.32-1.40 (55° C.), mixing the extract with borneol and an appropriate amount of magnesium stearate, and pressing it into tablets.

Claims (12)

1. A preparation method of compound danshen tablet, which is made of salvia miltiorrhiza, notoginseng and borneol as raw materials, and the weight percentage proportion of said raw materials is: 20%～97% of salvia miltiorrhiza, 2%～79% of notoginseng %, borneol 0.2%～3%; it is characterized in that, the technological step of its preparation is: (1) Mix Salvia Miltiorrhiza and Panax notoginseng or make water extract or alcohol extract separately; (2) Carry out preliminary clarification treatment to described extract; (3) further carry out ultrafiltration treatment to described extract; (4) Concentrate the ultrafiltrate, add borneol, and make tablets according to conventional methods; The operation process condition of described ultrafiltration treatment is as follows: The liquid inlet pressure of ultrafiltration is 0.1-0.5MPa, and the liquid outlet pressure of ultrafiltration is 0.25-0.5kPa lower than the liquid inlet pressure; the temperature of the feed liquid is 15-50°C; the pH value of the feed liquid is controlled at 5-9 ; When the stock solution is concentrated by 1/15 to 1/5, add water or dilute alcohol solution for ultrafiltration 1 or 2 times. 2. preparation method according to claim 1 is characterized in that, the weight percent of described raw material is: Salvia miltiorrhiza 63.0%～94%, Panax notoginseng 4.0%～35.0%, Borneol 0.5% ~ 2.0%. 3. preparation method according to claim 2 is characterized in that, the weight percent of described raw material is: Danshen 75.2% ~ 90%, Notoginseng 9%～23.5%, Borneol 0.5% ~ 1.3%. 4. The preparation method according to any one of claims 1 to 3, characterized in that, the alcohol extract is an extract selected from the following lower alcohols or mixtures thereof: methanol, ethanol, n-propanol, isopropanol alcohol, n-butanol, isobutanol. 5. The preparation method according to claim 4, characterized in that, the alcohol extract is an ethanol extract. 6. The preparation method according to any one of claims 1-3, characterized in that, what is obtained in the step (1) is the ethanol extract of Salvia miltiorrhiza. 7. The preparation method according to any one of claims 1-3, characterized in that, what is obtained in the step (1) is a water extract prepared by mixing Danshen and Panax notoginseng. 8. The preparation method according to any one of claims 1 to 3, characterized in that the step (1) is: take the coarsely crushed Danshen and Panax notoginseng medicinal materials into the extraction tank, add an appropriate amount of sodium bicarbonate, add water to decoct Boil twice, filter, discard the filter residue, combine the filtrate to obtain the extract. 9. The preparation method according to any one of claims 1-3, characterized in that, the preliminary clarification treatment is coarse filtration-adsorption clarification, adsorption clarification-high-speed centrifugation, coarse filtration-microfiltration or coarse filtration-alcohol precipitation . 10. The preparation method according to any one of claims 1 to 3, wherein the ultrafiltration membrane used in the ultrafiltration treatment is selected from the group consisting of: cellulose diacetate membrane, cellulose triacetate membrane, cellulose cyanoethyl acetate Plain membrane, polysulfone membrane, sulfonated polysulfone membrane, polyethersulfone membrane, sulfonated polyethersulfone membrane, polysulfone amide membrane, polyarylsulfone membrane with phenolphthalein side groups, polyvinylidene fluoride membrane, polyacrylonitrile membrane, poly Imide membranes, cellulose membranes, methyl methacrylate-acrylonitrile copolymer membranes, polyacrylonitrile/cellulose diacetate blend membranes, dynamically formed ultrafiltration membranes, and modified membranes of the above membranes; The molecular weight cut-off of the filter membrane is 6000-80000. 11. The preparation method according to claim 10, wherein the ultrafiltration membrane is selected from: cellulose diacetate membrane, cellulose triacetate membrane, polysulfone membrane, sulfonated polysulfone membrane, polyethersulfone membrane , Sulfonated polyethersulfone membrane, polysulfoneamide membrane, polyvinylidene fluoride membrane, polyacrylonitrile membrane; the molecular weight cut-off of the ultrafiltration membrane is 10,000-70,000. 12. The preparation method according to claim 1, characterized in that, in the process of the ultrafiltration, the following methods are used alone or in combination: periodic pressure fluctuations, periodic flow fluctuations, intermittently feeding inert gas; wherein The pressure fluctuation difference of the periodic pressure fluctuation is 0.1-0.2Mpa, the flow velocity fluctuation difference of the periodic flow fluctuation is 1.0-2.0 m/s, and the inert gas is intermittently injected every 0.5-2 hours for 1 minute each time.