CN1778343B - A drug drop pill for treating coronary heart disease - Google Patents

Abstract

The invention discloses a traditional Chinese medicine dripping pill for treating angina pectoris of coronary heart disease, which uses salvia miltiorrhiza, notoginseng, safflower and borneol as raw materials, and the preparation process steps are: (1) mixing salvia miltiorrhiza, notoginseng and safflower or separately water extract or ethanol extract; (2) carry out preliminary clarification treatment to described extract; (3) further carry out ultrafiltration treatment to described extract; (4) concentrate ultrafiltrate, add borneol, prepare into dripping pills.

Description

A drug drop pill for treating 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 method, organic solvent extraction method is superior, and can reduce waste water discharge in ultrafiltration process, protect environment, reduce production cost, improve economic benefit (Wang Chengzhang etc. " ultrafiltration is in purifying ginkgo The application of lutein 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.

After long-term and unremitting efforts, the inventor determined the appropriate process operating conditions by analyzing a large number of experimental data, and provided a specific solution for the industrial production of the drug of the present invention by ultrafiltration.

Contents of the invention

The object of the present invention is to provide a kind of traditional Chinese medicine dripping pill for treating coronary heart disease.

The present invention is implemented through the following schemes:

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

(1) Mix Salvia Miltiorrhiza, Panax notoginseng, and safflower separately or 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 ratio of the above-mentioned raw materials is calculated in parts by weight: Salvia miltiorrhiza 20-97, Panax notoginseng 2-79, Borneol 0.2-3, Safflower 3-15; Preferably: Danshen 63.0-94.0, Panax notoginseng 4.0-35.0, Borneol 0.5 ～2.0, safflower 4～10; more preferably: salvia miltiorrhiza 75.2～90, Sanqi 9～23.5, borneol 0.5～1.3, safflower 5～8.

In the technical step (1) of the present invention, the alcohol extract can be an extract of different concentrations of lower alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or a mixture thereof. The alcohol extract can be subjected to the next step of preliminary clarification after being not concentrated or properly concentrated.

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 cleaning agent, rinse with water until it is 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 Clinical curative effect observation of drug treatment of coronary heart disease angina pectoris according to the present invention

1. Materials and methods

1.1 General information According to the diagnostic standard of WHO coronary heart disease in 1979, 52 cases of coronary heart disease were randomly selected, including 35 males and 17 females, aged 44 to 72 years, with an average age of 56.4 years, including 30 cases of stable angina pectoris and unstable heart system. Bear 13 cases, 8 cases of angina after myocardial infarction. All cases had myocardial ischemic changes in the electrocardiogram, T wave flat, inverted and or ST segment depression ≥ 1mv. Another 40 patients with angina pectoris were selected as the control group, including 25 males and 15 females, aged 45 to 74 years, with an average age of 58.2 years.

1.2 Medication method The treatment group adopts the medicine of the present invention, 10 capsules each time, orally 3 times a day, and the course of treatment is 2 months. The control group was given Xiaoxintong, 10 mg each time, 3 times a day, and the course of treatment was 2 months. Stop taking other anti-anginal drugs before treatment. All patients had hematuria, blood lipid, liver function, kidney function, serum potassium, uranium, chlorine, blood sugar, and electrocardiogram examinations before treatment, after one month of treatment and after the course of treatment. Observe the number of angina pectoris attacks, detect blood pressure, heart rate and inquire about adverse reactions during the medication.

1.3 Judgment criteria for curative effect: (1) If the number of angina pectoris symptoms is reduced by more than 80%, it is markedly effective, if it is reduced by more than 50%, it is effective, and if it is less than 50%, it is invalid. In the past, it was exacerbated; (2) The curative effect of electrocardiogram was markedly effective when the resting electrocardiogram returned to normal, and it was effective when the ST segment recovered or the T wave in the main lead became shallower by more than 50%. Decline > 0.5mv, T wave inversion deepened > 50% from upright to inverted to aggravated.

2. Results

2.1 Curative effect of angina symptoms (see Table 1)

Table 1 Comparison of curative effect of angina pectoris in two groups

The total effective rate of the treatment group was 94.2%, and that of the Xiaoxintong group was 82.5%. There was no significant difference between the two groups (P>0.05). However, the effective rate was 73% in the treatment group and 52.5% in the Xiaoxintong group, and there was a significant difference between the two groups (P<0.05). Show that the drug treatment of the present invention is superior to Xiaoxintong in the aspect of effective rate.

2.2 Efficacy of electrocardiogram improvement

In the treatment group, there were 52 cases, 37 cases were effective, the effective rate was 71.1%, 15 cases were ineffective, and the ineffective rate was 28.9%; in the Xiaoxintong group, 40 cases were effective, 16 cases were effective, the effective rate was 40%, 24 cases were ineffective, and the ineffective rate was 60%, showing a significant difference (P<0.01). It shows that the drug of the present invention improves myocardial ischemia better than Xiaoxintong in terms of electrocardiogram changes.

2.3 Curative effect of hyperlipidemia

Table 2 Blood lipid changes before and after treatment

There were 30 cases of hyperlipidemia in the treatment group, and 26 cases of hyperlipidemia in the Xiaoxintong group. After two months of treatment, the results showed that the blood lipids in the treatment group decreased significantly, while the blood lipid changes in the Xiaoxintong group had no obvious therapeutic significance.

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 Danshen 45.0g, Panax notoginseng 14.1g, Borneol 0.8g and Safflower 5.0g.

Extract the salvia miltiorrhiza, notoginseng and safflower with ethanol to obtain ethanol extracts of the salvia miltiorrhiza, notoginseng and safflower, 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 them evenly with 18g of polyethylene glycol-6000, 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 55.8g of Salvia miltiorrhiza, 3.4g of notoginseng, 0.8g of borneol, and 7.2g of safflower.

Add 5 times the amount of water to the coarsely crushed Danshen and Panax notoginseng, 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, discard the filter residue, combine the filtrate, Obtain the extract of Salvia miltiorrhiza and Panax notoginseng. Extract the safflower with 70% ethanol to obtain the extract of safflower. Combine the above extracts of Danshen and Sanqi and the extract of safflower, let it stand, perform microfiltration with a ceramic membrane, and collect the filtrate. The filtrate is ultra-filtered with a polysulfone membrane with a molecular weight cut-off of 80,000, and the filtration method adopts dead-end filtration. The operating conditions of the ultra-filtration process are: the pressure of the ultra-filtration liquid inlet is 0.5Mpa, and the pressure of the ultra-filtration liquid outlet is higher than that of the liquid inlet. The outlet pressure is 0.25kPa lower. The initial ultrafiltration adopts a lower pressure, and then gradually increases the pressure; in the ultrafiltration process, it adopts periodic pressure fluctuations, and the pressure fluctuation difference is 0.2Mpa. The flow rate of the feed liquid is 4.0m/s, and the ultrafiltration During the process, periodic flow fluctuations are used to generate pulsating flow or unstable flow in the membrane channel. The difference in flow velocity fluctuation is 2.0m/s. Nitrogen is intermittently fed into the ultrafiltration system to form a gas-liquid pulse flow. The cycle is 2h. Once, 1 minute each time. 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. The pH value of the feed liquid is controlled at 9. The backwash pressure is 2.5 MPa, the backwash period is 1.5h, and the backwash time is 10min. When the ultrafiltration components are connected in parallel to use the alternate backflush method, one or several sets of them perform normal ultrafiltration and split out a part of the filtrate to backwash the other One set or several sets of ultrafiltration membranes should be exchanged after a period of time, work for 20 minutes, and backwash for 3 minutes. The chemical cleaning cycle is 2 months, and the chemical cleaning agent is 0.5% to 4.0% sodium hydroxide and 1.5% sodium hydroxide The mixed solution with 2% sodium hypochlorite, the pH value is 10-12, and the cleaning working pressure is 1.0MPa. After cleaning with chemical cleaning agent, rinse with water until it is 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 them evenly with 20g of polyethylene glycol-6000, 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 three

The raw materials are 36.0g of Salvia miltiorrhiza, 23.2g of Sanqi, 0.8g of borneol, and 2.4g of safflower.

Extract the salvia miltiorrhiza, notoginseng and safflower with 80% ethanol to obtain a mixed ethanol extract, centrifuge the extract at high speed and separate the 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 of compounding, move to a dropping tank of a dripping machine whose tank temperature is kept at 90°C. Drop the drug solution into methyl silicone oil at 7-8°C, take out the dropping pills, remove the oil, select the pills through a screen, and make 1000 dropping pills, to get ready.

Embodiment four

The raw materials are 50.0 grams of Danshen, 9.4 grams of Sanqi, 0.6 grams of borneol, and 4.2 grams of safflower.

Add coarsely crushed salvia miltiorrhiza, notoginseng and safflower to 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 After filtration, the filter residue was discarded, and the filtrates were combined. 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

29.0 grams of salvia miltiorrhiza, 30.6 grams of notoginseng, 0.6 grams of borneol, and 2.0 grams of safflower were used as raw materials.

Add coarsely crushed salvia miltiorrhiza, notoginseng and safflower to 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 After filtration, 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 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 where the tank temperature is maintained 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 six

21.0 grams of salvia miltiorrhiza, 38.0 grams of notoginseng, 0.4 grams of borneol, and 3.0 grams of safflower were used as raw materials.

Add coarsely crushed salvia miltiorrhiza, notoginseng and safflower to the extraction tank, add 0.89g sodium bicarbonate, add 5 times the amount of water, decoct for 2 hours, filter, and carry out the second extraction of the filter residue, add 4 times the amount water, fry for 1 hour, filter, discard the filter residue, and combine the filtrate. 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. medicinal dropping ball for the treatment of coronary heart disease, it is that crude drug is made with Radix Salviae Miltiorrhizae, Radix Notoginseng, Flos Carthami and Borneolum Syntheticum, it is characterized in that the weight proportion of described crude drug is: Radix Salviae Miltiorrhizae 20～97, Radix Notoginseng 2～79, Borneolum Syntheticum 0.2～3, Flos Carthami 3～15;

The processing step of its preparation is:

(1) Radix Salviae Miltiorrhizae, Radix Notoginseng, Flos Carthami are mixed or make water extract or alcohol extract separately;

(2) described extracting solution being carried out predefecation handles;

(3) further described extracting solution is carried out hyperfiltration treatment;

(4) ultrafiltrate is concentrated, with gained extractum and Borneolum Syntheticum and adjuvant mixed even after, make drop pill;

The operating procedure condition of described hyperfiltration treatment is as follows:

The inlet pressure of ultrafiltration is 0.1～0.5MPa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.25～0.5kPa; Feed temperature is 15～50 ℃; The pH value of feed liquid is controlled at 5～9; When feed liquid stock solution is concentrated 1/15～1/5, add water or dilute alcohol solution ultrafiltration 1～2 time again.

2. medicinal dropping ball according to claim 1 is characterized in that, the weight proportion of described raw material is:

Radix Salviae Miltiorrhizae 63.0～94.0,

Radix Notoginseng 4.0～35.0,

Borneolum Syntheticum 0.5～2.0,

Flos Carthami 4～10.

3. medicinal dropping ball according to claim 2 is characterized in that, the weight proportion of described raw material is:

Radix Salviae Miltiorrhizae 75.2～90,

Radix Notoginseng 9～23.5,

Borneolum Syntheticum 0.5～1.3,

Flos Carthami 5～8.

4. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that described alcohol extract is to be selected from the following lower alcohol or the extracting solution of its mixture: methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol.

5. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that described alcohol extract is an ethanol extract.

6. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that what described step (1) obtained is the ethanol extract that Radix Salviae Miltiorrhizae, Radix Notoginseng and Flos Carthami are mixed and made into.

7. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that what described step (1) obtained is the aqueous extract that Radix Salviae Miltiorrhizae, Radix Notoginseng and Flos Carthami are mixed and made into.

8. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that described step (1) is: the Radix Salviae Miltiorrhizae of the coarse pulverization of learning from else's experience, Radix Notoginseng and Flos Carthami medical material are to extraction pot, add an amount of sodium bicarbonate, decoct with water secondary, filter, filtering residue discards, and merging filtrate gets extracting solution.

9. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that described predefecation is treated to coarse filtration-adsorption clarification, adsorption clarification-high speed centrifugation, coarse filtration-microfiltration or coarse filtration-precipitate with ethanol.

10. according to the arbitrary described medicinal dropping ball of claim 1～3, it is characterized in that, the used ultrafilter membrane of described hyperfiltration treatment is selected from: the cellulose diacetate film, three cellulose acetate membrane, the cyanoethyl cellulose film, polysulfone membrane, sulfonated polysulfone membrane, poly (ether sulfone) film, the sulfonated polyether sulfone film, the polysulfonamides film, phenolphthalein side group polyarylsulfone (PAS) film, polyvinylidene fluoride film, polyacrylonitrile film, polyimide film, cellulose membrane, methyl methacrylate-acrylonitrile copolymer film, polyacrylonitrile/cellulose diacetate blend film, the dynamically ultrafilter membrane that forms, and the Modified Membrane of above-mentioned film; The molecular cut off of its ultrafilter membrane is 6000～80000.

11. medicinal dropping ball according to claim 10, it is characterized in that, described ultrafilter membrane is selected from: cellulose diacetate film, three cellulose acetate membrane, polysulfone membrane, sulfonated polysulfone membrane, poly (ether sulfone) film, sulfonated polyether sulfone film, polysulfonamides film, polyvinylidene fluoride film, polyacrylonitrile film; The molecular cut off of its ultrafilter membrane is 10000～70000.

12. medicinal dropping ball according to claim 1 is characterized in that, in the process of described ultrafiltration separately or unite the following method that adopts: periodic pressure fluctuation, periodically flow fluctuation, feed noble gas off and on; Wherein the pressure wave moment of periodic pressure fluctuation is 0.1～0.2Mpa, and periodically the flow speed wave moment of flow fluctuation is 1.0～2.0 meter per seconds, feeds noble gas off and on and be ventilation in 0.5 hour～2 hours once, each 1 minute.