CN1778334B - Chinese Medicine Dropping Pills for Treating Angina Pectoris of Coronary Heart Disease - Google Patents

Abstract

A Chinese medicine in the form of dripping pill for treating coronary heart disease and angina pectoris is prepared from red sage root, Chuang-xiong rhizome and borneol through extracting the liquid extract from red sage root and Chuan-xiong rhizome in water or alcohol, clarifying, ultrafiltering, concentrating, adding borneol and preparing dripping pills.

Description

Chinese Medicine Dropping Pills for Treating Angina Pectoris of Coronary Heart Disease

technical field

The invention relates to a traditional Chinese medicine prepared by an ultrafiltration process. Specifically, the invention relates to a traditional Chinese medicine dripping pill prepared by an ultrafiltration process.

Background technique

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 It is becoming more and more active, and some products have moved from laboratory research to industrial production. Wang Shiling and others in the PLA 304 Hospital used ultrafiltration to extract the active ingredient baicalin in Scutellaria baicalensis. The results showed that the ultrafiltration method was better than the conventional method in terms of yield and purity. And once ultrafiltration can meet the requirement of injection, no further refinement is needed, the process is simple, and the production cycle can be shortened by 1 to 2 times (Wang Shiling, Zheng Dianbao "Preliminary investigation of extracting 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 ultrafiltration membrane with suitable pore size (molecular weight cut-off is 6000～10000) is the best way to improve the yield and quality of baicalin. The key is to increase the temperature of the liquid medicine or reduce the concentration at the same time, and strictly control the pH value (pH=1.5 during acidification, pH=7.0 during alkali dissolution), which can significantly increase the ultrafiltration speed and obtain the best output effect (Wang Shiling, "Ultrafiltration A study on the process of extracting baicalin at one time", Chinese patent medicine, 1994, 16 (3): 2). Xu Jinlin et al. used ultrafiltration (polysulfone membrane, molecular weight cut-off 6000) in the preparation of phytic acid, and the yield of phytic acid It is 86.4%, 12.6% higher than the conventional phytate method, and the phytic acid obtained by the ultrafiltration method almost does not contain inorganic phosphorus, and the appearance is transparent and almost colorless (Xu Jinlin, Xu Jie, Wang Yuanjin "Research on the Preparation of Phytic Acid by Membrane Separation Technology" , Chinese Journal of Pharmaceutical Industry, 1994, 25 (4): 150). He Changsheng and other applications of ultrafiltration technology to separate and refine stevioside, using ultra-thin plate ultrafilter and cellulose acetate membrane (CA membrane) with a molecular weight cut-off of 10000 ) field experiments on stevioside purification, 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, and it can better solve the precipitation and potting that often occur in the production of stevioside. Foaming problem (He Changsheng, Wang Bingnan, Zhu Shanshan "Research on the application of stevioside ultrafiltration", Water Treatment Technology, 1994, 20(2): 89). Huang Ziqiang used ultrafiltration membranes (molecular weight cut-offs of 4000 and 10000 Compared with the bleaching method, recrystallization method, alcohol ether precipitation method and basic salt precipitation method that are mostly used in China, the ultrafiltration process is simple, efficient, and low in cost. Oils, pigments, sugars and other highly hydrophilic impurities in the water can achieve the desired effect (Huang Ziqiang, "Preliminary Study on the Purification of Camellia Camellia Saponin by Ultrafiltration Membrane Method", Water Treatment 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. The ultrafiltration membrane has no obvious effect on loganin (molecular weight is 384), but the membrane with a molecular weight cut-off of 1000 makes loganin lose about 50% Right (Guo Liwei, Peng Guoping, Pan Yang, etc. "Comparative research on refining traditional Chinese medicine preparations containing Cornus officinalis by water-alcohol method and membrane separation method", Chinese Patent Medicine, 1999, 21 (2): 59). Wang Chengzhang et al. Sulfone membrane, molecular weight cut-off 30000) and polyamide resin adsorption and elution method are used to separate and purify the ethanol extract of Ginkgo biloba leaves. After detection by high performance liquid chromatography (HPLC), the content of glycosides in Ginkgo biloba is about 45%, and the yield is 0.5% %～0.7%, compared with conventional steam distillation and organic solvent extraction, it is superior, and can reduce wastewater 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 flavonoid glycosides from Ginkgo biloba leaves", 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.

So far, the application of ultrafiltration technology in (compound) Danshen preparations is limited to the report that it is used to prepare Danshen injection. A kind of traditional Chinese medicine injection (Chinese People's Liberation Army Air Force Beijing Hospital Pharmacy, "Experimental Research on Preparation of Compound Chinese Medicine Injection by Ultrafiltration", Chinese Herbal Medicine, 1981, 12(12): 8-12). Hao Li of Sichuan Ya'an Pharmaceutical Factory prepared Danshen Injection by ultrafiltration (ultrafiltration membrane with a molecular weight cut-off of 20,000) (Hao Li, "Technology Improvement for Preparation of Danshen Injection by Ultrafiltration", Journal of Chengdu University of Traditional Chinese Medicine, 1996, 27( 8): 7). Wang Dan et al reported the preparation of Danshen injection by micellar ultrafiltration (Wang Dan, "Preparation of Danshen injection by micellar ultrafiltration", Chinese Patent Medicine, 2003, 25(6): 441-443). However, these reports are all derived from laboratory research, and have not proposed the feasibility of industrial production and its specific process operating conditions.

After long-term and unremitting efforts, the present inventor verified the feasibility of preparing the drug of the present invention by the ultrafiltration method by analyzing a large amount of experimental data, and determined the appropriate process operating conditions.

Contents of the invention

The purpose of the present invention is to provide a medicine for treating coronary heart disease and angina pectoris prepared by an ultrafiltration preparation process with less impurities, less active ingredient loss and low cost. It overcomes the deficiencies in the prior art and solves the industrial production ultrafiltration process conditions operability problem.

The present invention is realized through the following technical steps: using salvia miltiorrhiza, chuanxiong and borneol as raw materials, it is prepared according to the following steps:

(1) Mix Salvia Miltiorrhiza and Rhizoma Chuanxiong or separately make water extract or alcohol extract;

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

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

(4) Concentrate the ultrafiltrate into an extract, mix the obtained extract with borneol and auxiliary materials evenly, and make a drop pill preparation.

The weight percentages of the above-mentioned raw materials are: Salvia miltiorrhiza 20%-97%, Chuanxiong 2%-79%, Borneol 0.2%-3%; Preferably Danshen 63.0%-94%, Chuanxiong 4.0%-35.0%, Borneol 0.5%- 2.0%; more preferably 75.2% to 90% of Danshen, 9% to 23.5% of Chuanxiong, and 0.5% to 1.3% of borneol. The sum of the weight percentages of salvia miltiorrhiza, chuanxiong 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 cycle is 0.5 months to 2 months. 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 The mixed solution of 2% sodium hypochlorite, 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, after mixing evenly with borneol and auxiliary materials, the chemical material is heated, moved into the dropping tank of the dropping pill machine, and the medicinal liquid is dropped into low-temperature liquid paraffin to remove the liquid Paraffin, choose pills.

Among them: the auxiliary material is polyethylene glycol-6000, its freezing point is 53-58 °C, and the addition amount is 2-6 times the weight of the extract and borneol; the temperature of the chemical material is 60-100 °C; the temperature of the liquid paraffin is 0-10 °C. ℃ (optimally 5-10 ℃); pellet weight 5-50mg/granule, diameter 1.95-4.29mm.

Experimental example The present invention medicine treats clinical observation of coronary heart disease

1 Materials and methods

1.1 General information Among 200 patients with coronary heart disease and angina pectoris, there were 130 males and 70 females, 64 cases aged 35-55 years, and 136 cases aged 56-70 years. The course of the disease ranged from 2 to 6 years, including 86 cases with hypertension and 7 cases with type II diabetes. All patients were in line with WHO's nomenclature and criteria for the diagnosis of ischemic heart disease, including 96 cases of stable angina pectoris and 104 cases of unstable angina pectoris. They were randomly divided into a treatment group and a control group, 100 cases in each group, and there was no significant difference in gender, medical history, and age between the two groups.

1.2 Method of administration Except those with primary diseases (hypertension, routinely used antihypertensive drugs), diabetes (routinely used hypoglycemic drugs for diet control). All selected cases stopped using other drugs for the treatment of coronary heart disease. The treatment group was given orally the medicine of the present invention, 10 capsules each time, 3 times a day, and sublingual nitroglycerin was taken if necessary, and the course of treatment was 28 days. The control group was given Compound Danshen Tablets, 3 tablets each time, 3 times a day, and sublingual nitroglycerin if necessary, for 28 days.

1.3 Observation content Inquire about clinical symptoms and adverse reactions before and after adding the medicine of the present invention. Record blood pressure, do routine 12-lead electrocardiogram, and blood, urine routine and liver and kidney function tests.

1.4 Efficacy evaluation standards are evaluated in accordance with the "Guiding Principles for Clinical Research of Cardiovascular and Cerebrovascular Drugs" designated by the Pharmaceutical Administration of the Ministry of Health of the People's Republic of China.

1.4.1 Symptom efficacy evaluation criteria Significantly effective: the same labor capacity does not cause the occurrence of angina pectoris or the number of attacks is reduced by more than 70%, and there is no chest tightness in general activities; effective: the number of angina pectoris and chest tightness are reduced by 50% to 70%; invalid: more than 70% after medication The situation has not changed significantly.

1.4.2 ECG curative effect evaluation criteria Markedly effective: resting ECG ischemic manifestations return to normal; effective: resting ECG ischemic ST-segment decline, after treatment, the recovery is more than 1 mm, but not normal, the inferior wall and left chest leads are inverted, T The wave became shallower up to 1mm group. Invalid: the resting electrocardiogram was basically the same as before treatment.

2 results

2.1 Comparison of curative effect between the treatment group and the control group (see Table I, Table II).

Table 1 Angina pectoris symptom curative effect comparison

Table II ECG curative effect comparison

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 55.8g of Danshen, 3.4g of Chuanxiong, and 0.8g of borneol.

Extract Danshen and Chuanxiong with ethanol to obtain ethanol extracts of Danshen and Chuanxiong, 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 an extract with a relative density of 1.35-1.39 (55° C.). Take the extract and borneol, mix evenly with polyethylene glycol-6000018g, heat to a temperature of 85°C, and after 20-120 minutes to make the material, move it to a dropping tank of a dripping machine whose tank temperature is kept at 85-90°C. Drop the drug solution into liquid paraffin at 7-8°C, take out the dropping pills, remove the oil, select the pills through a sieve, and make 1000 dropping pills.

Embodiment two

The raw materials are 59.3g of Danshen, 6.38g of Chuanxiong, and 0.34g of borneol.

Decoct the coarsely crushed Salvia miltiorrhiza in 5 times the amount of water 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, discard the filter residue, and combine the filtrates to obtain the salvia miltiorrhiza extract . Extract Rhizoma Chuanxiong with 70% ethanol to obtain Ligusticum Chuanxiong extract. The above-mentioned Danshen extract and Chuanxiong extract were combined, allowed to stand, and filtered. 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 1.35-1.39 (55° C.). Take the extract and borneol, mix evenly with 20g of polyethylene glycol-6000, heat to a temperature of 85°C, and after 20-120 minutes of compounding, move to a dropping tank of a dripping machine whose tank temperature is kept at 85-90°C. Drop the drug solution into liquid paraffin at 7-8°C, take out the dropping pills, remove the oil, select the pills through a sieve, and make 1000 dropping pills.

Embodiment three

The raw materials are 36.0g of Danshen, 23.2g of Chuanxiong, and 0.8g of borneol.

Extracting Danshen and Chuanxiong with 80% ethanol to obtain ethanol extracts of Danshen and Chuanxiong, centrifuging the extract at high speed and separating supernatant. 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.

Concentrating the ultrafiltrate to obtain an extract with a relative density of 1.35-1.39 (55° C.). Take the extract and borneol, mix evenly with 20g of polyethylene glycol-6000, heat to a temperature of 60°C, and after 20 to 120 minutes, transfer to a dropping tank of a dripping machine with a tank temperature of 90°C. Put it in methyl silicone oil at 7-8°C, take out the dripping pills, remove the oil, select the pills with a screen, and make 1000 dropping pills, that is.

Embodiment four

The raw materials are 41.1g of Salvia miltiorrhiza, 8.0g of Chuanxiong, and 0.46g of borneol.

Put the coarsely crushed Danshen and Chuanxiong herbs 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 , combined 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 an extract with a relative density of 1.35-1.39 (55° C.). Take the extract and borneol, mix evenly with 21g of polyethylene glycol-6000, heat to a temperature of 60°C, and after 20 to 120 minutes of compounding, move to a dropping tank of a dropping pill machine whose tank temperature is kept at 90°C. Drop the drug solution into liquid paraffin at 7-8°C, take out the dropping pills, remove the oil, select the pills through a sieve, and make 1000 dropping pills.

Embodiment five

The raw materials are 29.0g of Salvia miltiorrhiza, 30.6g of Chuanxiong, and 0.6g of borneol.

Put the coarsely crushed Danshen and Chuanxiong herbs 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 , combined 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.

Concentrate the ultrafiltrate to obtain an extract with a relative density of 1.32 to 1.40 (55° C.), take the extract and borneol, mix with 20 g of polyethylene glycol-6000, heat to a temperature of 60° C. After 120 minutes, move to the dripping tank of the dropping pill machine with the tank temperature kept at 90°C. Drop the drug liquid into the liquid paraffin at 7-8°C, take out the dropping pills, remove the oil, and select the pills with a screen to make 1000 dropping pills , that is.

Embodiment six

The raw materials are 21.0g of Danshen, 38.0g of Chuanxiong, and 0.4g of borneol.

Take the coarsely crushed medicinal materials of Salvia miltiorrhiza and Chuanxiong into the extraction tank, add 0.89g of sodium bicarbonate, add 4 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.

Concentrate the ultrafiltrate to obtain an extract with a relative density of 1.32 to 1.40 (55° C.), take the extract and borneol, mix it with polyethylene glycol-6000 18 g, heat to a temperature of 85° C. After 120 minutes, move to the dropping tank of the dropping pill machine whose tank temperature is kept at 85-90°C. Drop the drug solution into liquid paraffin at 7-8°C, take out the dropping pills, remove the oil, select the pills through a sieve, and make 1000 dropping pills.

Claims (12)

1. a Chinese medicine dripping pill for the treatment of coronary heart disease angina pectoris, it is made with salvia miltiorrhiza, Rhizoma Chuanxiong and Borneolum as raw materials, it is characterized in that, the weight percent ratio of described raw materials is: 20%～97% of salvia miltiorrhiza, 20%～97% of chuanxiong 2%～79%, borneol 0.2%～3%; The process steps of its preparation are: (1) Mix Salvia Miltiorrhiza and Rhizoma Chuanxiong 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, mix the obtained extract with borneol and auxiliary materials, and make dropping pills; 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. Chinese medicine dripping pill according to claim 1, is characterized in that, the weight percentage of described raw material is: Salvia miltiorrhiza 63.0%～94%, Chuanxiong 4.0%～35.0%, Borneol 0.5% ~ 2.0%. 3. Chinese medicine dripping pill according to claim 2, is characterized in that, the weight percent of described raw material is: Danshen 75.2% ~ 90%, Chuanxiong 9%～23.5%, Borneol 0.5% ~ 1.3%. 4. according to the arbitrary described Chinese medicine dripping pill of claim 1～3, it is characterized in that, described ethanol extract is the extract that is selected from following lower alcohol or its mixture: methanol, ethanol, n-propanol, isopropanol, Propanol, n-butanol, isobutanol. 5. The Chinese medicine dripping pill according to any one of claims 1 to 3, characterized in that the alcohol extract is an ethanol extract. 6. The Chinese medicine dripping pill according to any one of claims 1 to 3, characterized in that, what is obtained in the step (1) is an ethanol extract prepared by mixing Salvia miltiorrhiza and Rhizoma Chuanxiong. 7. The Chinese medicine dripping pill according to any one of claims 1 to 3, characterized in that, what is obtained in the step (1) is a water extract prepared by mixing Salvia miltiorrhiza and Rhizoma Chuanxiong. 8. According to the Chinese medicine dripping pill described in any one of claims 1 to 3, it is characterized in that the step (1) is: take the coarsely crushed medicinal materials of Salvia Miltiorrhiza and Rhizoma Chuanxiong into the extraction tank, add 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 Chinese medicine dripping pill according to any one of claims 1 to 3, characterized in that, the preliminary clarification treatment is coarse filtration-adsorption clarification, adsorption clarification-high-speed centrifugation, coarse filtration-microfiltration or coarse filtration- Alcoholic. 10. according to the arbitrary described Chinese medicine dripping pill of claim 1～3, it is characterized in that, the used ultrafiltration membrane of described ultrafiltration treatment is selected from: cellulose diacetate film, cellulose triacetate film, cyanoethyl acetic acid Cellulose membrane, polysulfone membrane, sulfonated polysulfone membrane, polyethersulfone membrane, sulfonated polyethersulfone membrane, polysulfone amide membrane, polyarylsulfone membrane with phenolphthalein side group, polyvinylidene fluoride membrane, polyacrylonitrile membrane, Polyimide 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 ultrafiltration membrane is 6000-80000. 11. The Chinese medicine dripping pill 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 10000-70000. 12. The Chinese medicine dripping pill according to claim 1, characterized in that, in the process of the ultrafiltration, the following methods are adopted alone or in combination: periodic pressure fluctuations, periodic flow fluctuations, intermittently feeding inert gas; Among them, 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 once every 0.5-2 hours, each time for 1 minute .