A preparation method of a lung-clearing and toxin-removing granule

Abstract

The application discloses a preparation method of a lung-clearing and toxin-removing granule, and specifically comprises the following steps: extracting, membrane separating, and high-efficiency preparation chromatography refining of asarum, so as to obtain an eluent 1; further removing aristolochic acid compounds by adopting ion exchange chromatography technology, so as to obtain an eluent 2; simultaneously, extracting, membrane separating, and high-efficiency preparation chromatography refining of other 20 kinds of medicines in the prescription except asarum, so as to obtain an eluent 3; combining the eluent 2 and the eluent 3, concentrating, drying, and adding accessories, so as to obtain the lung-clearing and toxin-removing granule. The lung-clearing and toxin-removing granule can effectively remove aristolochic acid compounds, retain main medicinal effect components of the medicines, realize the purpose of removing the crude and preserving the essence, increase the effect and reduce the toxicity, and significantly reduce the daily dosage.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine, and particularly relates to a preparation method of Qingfei Paidu granules. BACKGROUND

[0002] Qingfei Paidu granules are prepared by optimizing and combining four kinds of classical Chinese medicine prescriptions, namely Maxingshigan decoction, Shegan Mahuang decoction, Xiaochaihu decoction and Wuling powder. The drug components of Qingfei Paidu granules are Fuzi, Mahuang, Jiangbanxia, Zhigancao, Ganjiang, Xingren, Ziyuan, Shengshigao, Donghua, Guizhi, Shegan, Zexie, Shanyao, Ziling, Zhishi, Baizhu, Chenpi, Fuling, Huoxiang, Chaihu and Huangqi. The prescription is reasonable in composition and mild in nature and taste, and has the effects of clearing lung and detoxifying, dispersing cold and dampness, removing toxin and dampness and eliminating epidemic diseases. Modern research shows that Qingfei Paidu granules can achieve the effects of anti-inflammation, anti-virus, enhancing immunity, inhibiting pulmonary fibrosis, protecting heart and lung, treating asthma and regulating gastrointestinal tract by regulating relevant pathways such as interleukin signaling pathway, adrenoreceptor, CLEC7A / inflammation pathway and TP53 regulating transcription of DNA repair gene [Peng X J, Yang X J, Xu G, et al. Exploring the efficacy and mechanism of Qingfei Paidu decoction in treating COVID-19 based on integrative pharmacology [J]. Chinese Journal of Experimental Formulas, 2020, 26(16): 6-13.]. On February 6, 2020, the Office of the National Health Commission and the Office of the National Administration of Traditional Chinese Medicine jointly issued the Notice on Recommending Qingfei Paidu Decoction in the Treatment of COVID-19 in the Combination of Traditional Chinese and Western Medicine, which states that Qingfei Paidu Decoction is used to treat 214 confirmed cases in four pilot provinces, and clinical observation shows that the total effective rate of Qingfei Paidu Decoction treatment can reach more than 90%.

[0003] The traditional preparation process of Qingfei Paidu granules mainly adopts water decoction twice, filtration, combination of decoction, concentration of the filtrate to a clear paste under reduced pressure, addition of a proper amount of malt dextrin, drying or crushing, packaging, and then obtaining the product. The content of aristolochic acid I in the finished preparation reaches 1.49 μg / g. Aristolochic acid compounds are listed as class I carcinogens by the International Agency for Research on Cancer of the World Health Organization (WHO), which has a great safety risk. In addition, there are a large number of invalid components in Qingfei Paidu granules prepared by the traditional process, the granules are not easy to dissolve, the daily dosage is large, and the drug experience is poor.

[0004] The present application provides a preparation method, which removes insoluble particles by using membrane separation technology, then refines by using high-performance preparation chromatography technology, and finally removes aristolochic acid compounds by using ion exchange chromatography technology, so that the toxic components of aristolochic acid compounds can be effectively removed, the crude components can be removed to retain the fine components, the efficacy can be enhanced and the toxicity can be reduced, and the daily dosage can be significantly reduced. SUMMARY

[0005] In view of the above problems, the technical purpose of the present application is to provide a preparation method of lung detoxification granules. Through water extraction, membrane separation, high-efficiency preparation chromatography, ion exchange chromatography, insoluble impurities are removed, the aristolochic acid compounds are removed, the daily dosage is reduced, and the lung detoxification granules are obtained.

[0006] The specific technical scheme of the present application is:

[0007] A preparation method of lung detoxification granules, comprising the following steps:

[0008] The prescription components include: asarum, ephedra, pinellia, honey-fried licorice, dried ginger, apricot kernel, purple root, raw gypsum, winter flower, cassia twig, belamcanda, alisma, Chinese yam, polyporus, citrus, white atractylodes, dried tangerine or orange peel, poria cocos, agastache, bupleurum, scutellaria.

[0009] 1) Refine detoxification: asarum is extracted by water to obtain extract 1, the insoluble particles are removed from the extract 1 by membrane separation technology, the permeate 1 is collected, the permeate 1 is refined by high-efficiency preparation chromatography technology first, the eluate 1 is collected, and the aristolochic acid compounds are removed by ion exchange chromatography technology, the eluate 2 is collected, and is ready for use.

[0010] 2) Separation and refinement: the other 20 kinds of medicines contained in the prescription except asarum are extracted by water to obtain extract 2, the insoluble particles are removed from the extract 2 by membrane separation technology, the permeate 2 is collected, the permeate 2 is refined by high-efficiency preparation chromatography technology, the eluate 3 is collected, and is ready for use.

[0011] 3) Formulation molding: the eluate 2 of step 1) and the eluate 3 of step 2) are combined, concentrated, dried, and added with appropriate excipients to prepare lung detoxification granules.

[0012] Further, the prescription components include the following weight parts: asarum 4-8 parts, ephedra 8-10 parts, pinellia 8-10 parts, honey-fried licorice 4-8 parts, dried ginger 8-10 parts, apricot kernel 8-10 parts, purple root 8-10 parts, raw gypsum 14-16 parts, winter flower 8-10 parts, cassia twig 8-10 parts, belamcanda 8-10 parts, alisma 8-10 parts, Chinese yam 10-14 parts, polyporus 8-10 parts, citrus 4-8 parts, white atractylodes 8-10 parts, dried tangerine or orange peel 4-5 parts, poria cocos 14-16 parts, agastache 8-10 parts, bupleurum 14-18 parts, scutellaria 4-8 parts.

[0013] Further, in the step 1), take Xinxin, add 5-20 times of water by weight, extract at 90-100℃, solid-liquid separation, obtain the extract, extract for 2-3 times, each time for 10-30 minutes, combine the extract, get extract 1; in the step 2), take the 20 herbs contained in the prescription except Xinxin, add 5-20 times of water by weight, extract at 90-100℃, solid-liquid separation, obtain the extract, extract for 2-3 times, each time for 10-30 minutes, combine the extract, get extract 2.

[0014] Extract 2-3 times means: after the first extraction, the separated solid is soaked with water again for extraction, then solid-liquid separation, obtain the second extract, after the second extraction, the separated solid is soaked with water again for extraction, then solid-liquid separation, obtain the third extract;

[0015] Further, the filter membrane in the membrane separation technology in the step 1) and step 2) is one or more of organic membrane or inorganic membrane, the membrane is one or more of tubular membrane, hollow fiber membrane, roll membrane, or flat membrane or ceramic membrane, the pore size of the tubular membrane, hollow fiber membrane or roll membrane is 50kD-1000kD; the pore size of the flat membrane or ceramic membrane is 50-800nm. Further, the filler matrix in the high-performance preparative chromatography technology in the step 1) and step 2) is silica gel or high molecular polymer; the filler matrix is bonded with a bonded phase, the bonded phase is one or more of n-alkyl with carbon number 1-30 (preferably 8-18); the inner diameter of the chromatographic column is 20mm-1600mm, the bed height of the chromatographic column is 100mm-1000mm; the chromatographic column is equilibrated with the equilibration liquid before sample loading and elution, the organic solvent concentration in the equilibration liquid is 0-20% (preferably 0-10%, the rest is water); the sample loading and elution flow rate of the chromatography is 10mL / min-20L / min (preferably 10-50mL / min in step 1, preferably 1-20L / min in step 2); the elution solvent concentration of the chromatography target component is 30-90% (preferably 50-70%), the elution mode can be isocratic or linear gradient or step gradient.

[0016] Further, the elution solvent in the high-performance preparative chromatography technology in the step 1) and step 2) is one or two or three organic solvents mixed with water, the organic solvent concentration is 50%-90%.

[0017] Further, the filler matrix in the ion exchange chromatography technology in the step 1) is one or more of macroporous resin with styrene-divinylbenzene copolymer structure or silica gel, the elution solvent is one or two or three organic solvents mixed with water, the elution mode can be isocratic or linear gradient or step gradient.

[0018] Further, the packing matrix of the ion exchange chromatography technique in the step 1) is characterized in that the macroporous resin with styrene-divinylbenzene copolymer structure comprises one or more than two of D201, PA408, PA308, etc.; the silica gel comprises one or two of SAX, QA, etc.

[0019] Further, the elution solvent in the ion exchange chromatography technique in the step 1) is one or two or three of acetonitrile, methanol or ethanol mixed with water, and the volume concentration of the organic solvent is 50% to 90% (preferably 50 to 70%).

[0020] Further, the concentration mode in the step 3) can be one or more than two of vacuum concentration, thin film concentration or pressure concentration; the drying mode can be one or more than two of freeze drying, vacuum drying, spray drying or belt drying; the auxiliary material can be the ratio of 1-1.2:1, preferably 1:1, 1.1:1 or 1.2:1 of the raw material to the auxiliary material; the auxiliary material is a pharmaceutically acceptable solid carrier or solid auxiliary material, and the granulation mode is dry granulation.

[0021] The beneficial effects of the present application are: 1) the ion exchange chromatography separation technology can effectively remove the aristolochic acid compounds in the Qingfei Paidu Granules, ensuring the safety of clinical medication. 2) The membrane separation technology and high-efficiency preparation chromatography technology can effectively remove the suspended particles, realize the enrichment and purification of the main active ingredients, solve the problems of Qingfei Paidu Granules, such as a large amount of invalid components, difficulty in dissolving the granules, large daily dosage, poor medication experience, etc. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is a process flow chart;

[0023] Figure 2 is a comparison chart of the contents of ephedrine hydrochloride, pseudoephedrine hydrochloride, baicalin and glycyrrhizic acid in the prior art and the present application;

[0024] Figure 3 is a comparison chart of the contents of aristolochic acid compounds in the prior art and the present application. DETAILED DESCRIPTION

[0025] In order to be able to understand the features and technical contents of the present application more thoroughly, the implementation of the present application is described in detail below.

[0026] Example 1

[0027] Refining of Asarum and removal of aristolochic acid compounds

[0028] Step 1: Take 360g of Radix et Rhizoma Asari, put it into a 20L decoction machine, add 3.6L of pure water, soak for 30 minutes, heat to boiling at 100℃, extract for 20 minutes, filter with 200 mesh gauze, collect the filtrate; add 2.88L of pure water to the solid residue, heat to boiling at 100℃, extract for 15 minutes, filter with 200 mesh gauze, collect the filtrate, combine the filtrates of the two times, and obtain the extract 1.

[0029] Step 2: Connect a ceramic membrane with a pore size of 500nm to a membrane filtration system (model: CeraMem0100-01), and perform clarification filtration of the extract 1 under the conditions of a membrane filtration temperature of 25℃, a membrane inlet pressure of 0.7MPa, and a membrane outlet pressure of 0.6MPa, collect the membrane permeate, take 2L of pure water, and add 500mL every 5 minutes to wash the membrane, collect the membrane washing filtrate, combine the membrane permeate and the membrane washing filtrate to obtain the permeate 1.

[0030] Step 3: Connect a chromatographic column (filler type: C18YE, specifications: 50x250mm, filler weight about 350g, particle size 30μm, column volume about 490mL) to a high-pressure liquid chromatography system, set the flow rate to 25mL / min, first activate the preparative liquid chromatography column with 3 column volumes of ethanol, then rinse the chromatographic column with 3 column volumes of pure water, pass the Radix et Rhizoma Asari permeate 1 through the chromatographic column, wash away impurities with 3 column volumes of pure water, elute the target with 3 column volumes of 60%(v / v) ethanol, and collect the 60% ethanol eluate as the eluate 1.

[0031] Step 4: Connect a chromatographic column (filler type: PA308 resin, specifications: 30x250mm, filler weight about 108g, particle size 300μm, column volume about 150mL) to a high-pressure liquid chromatography system, set the flow rate to 25mL / min, first activate the preparative liquid chromatography column with 3 column volumes of ethanol, then rinse the chromatographic column with 3 column volumes of pure water, pass the Radix et Rhizoma Asari eluate 1 through the chromatographic column, collect the flow-through liquid, elute with 3 column volumes of 60%(v / v) ethanol, collect the 60%(v / v) ethanol eluate, combine the flow-through liquid and the 60%(v / v) ethanol eluate to obtain the eluate 2.

[0032] Example 2

[0033] Separation and purification of other 20 medicinal herbs in the prescription except Radix et Rhizoma Asari

[0034] Prescription composition:

[0035] Decoction pieces Weight (g) Decoction pieces Weight (g) Ephedra 540 Pinellia 540 Radix Glycyrrhizae Praeparata cum Melle 360 Rhizoma Zingiberis Recens 540 Almond 540 Radix Paeoniae Alba 540 Gypsum Fibrosum 900 Radix Ledebouriellae 540 Ramulus Cinnamomi 540 Radix Adenophorae 540 Alisma 540 Radix Dioscoreae 720 Radix Phellodendri 540 Fructus Aurantii Immaturus 360 Radix Paeoniae Alba 540 Figure 2 360 ​ 900 ​ 540 ​ 960 ​ 360

[0036] Step 1: Put other 20 herbs in the prescription except for Xinxin together into a 150L multifunctional extraction tank, add 114L purified water, soak for 30 minutes, heat to boiling at 100℃, extract for 20 minutes, filter with 200 mesh gauze, collect the filtrate; add another 84L purified water, heat to boiling at 100℃, extract for 15 minutes, filter with 200 mesh gauze, combine the filtrates of the two times, and the extraction liquid 2 is obtained.

[0037] Step 2: Connect a 500nm ceramic membrane to a membrane filtration system (model: CeraMem0100-01), and perform clarification filtration under the conditions of a membrane filtration temperature of 25℃, a membrane inlet pressure of 0.7MPa, and a membrane outlet pressure of 0.6MPa, collect the membrane permeate, take 40L purified water, and add 500mL every 5 minutes to wash the membrane, collect the membrane washing permeate, and combine the membrane permeate and the membrane washing permeate to obtain the permeate 2.

[0038] Step 3: Connect a chromatographic column (filler type: C18YE, size: 500x350mm, filler weight: 40kg, particle size: 30μm, column volume: about 40L) to a high-pressure liquid chromatography system, set the flow rate to 10L / min, first activate the preparative liquid chromatography column with 3 column volumes of ethanol, then rinse the chromatographic column with 3 column volumes of purified water, pass the permeate 2 through the system pump and through the chromatographic column for purification, wash away impurities with 3 column volumes of purified water, elute the target with 3 column volumes of 60%(v / v) ethanol, and collect the 60% ethanol eluate as the eluate 3.

[0039] Example 3

[0040] Preparation of Qingfei Paidu Granules

[0041] Step 1: Combine the "eluate 2" under Example 1 and the "eluate 3" under Example 2, and concentrate under reduced pressure at 50℃, concentrate to a clear paste with a relative density of 1.10-1.15(60℃), spray dry to obtain a dry paste powder, add malt dextrin in a ratio of dry paste powder: excipient = 1.1:1, dry granulation, and Qingfei Paidu Granules are obtained.

[0042] Step 2: Take the prepared Qingfei Paidu Granules and commercially available Qingfei Paidu Granules, analyze and check for aristolochic acid compounds by liquid chromatography. The results show that the contents of ephedrine hydrochloride, pseudoephedrine hydrochloride, baicalin, and glycyrrhizic acid in the prepared Qingfei Paidu Granules are higher than those in the commercially available Qingfei Paidu Granules, and no aristolochic acid compounds are detected.

[0043] The LC-MS conditions are as follows:

[0044] (1) Preparation of the control solution: Take the ephedrine hydrochloride control, pseudoephedrine hydrochloride, baicalin, and ammonium glycyrrhizate control, accurately weigh, add methanol to prepare a mixture solution containing 40 μg per 1 mL, and then obtain. Take aristolochic acid I and aristolochic acid D, accurately weigh, add methanol to prepare a control solution containing 4.0 ng of aristolochic acid I and aristolochic acid D per 1 mL.

[0045] (2) Preparation of the test solution: Take about 0.3 g of commercially available Qingfei Paidu Granules or self-made Qingfei Paidu Granules, accurately weigh, place in a conical flask with a plug, accurately add 25 mL of 75% methanol, weigh, ultrasonically treat (power 400 W, frequency 40 kHz) for 30 minutes, cool, re-weigh, make up the weight loss with 75% methanol, shake well, filter, and then obtain the filtrate.

[0046] (3) Determination: Inject the test solution and the control solution into the LC-MS for analysis, and the chromatographic conditions are as follows:

[0047] Instrument: Waters Acquity UPLC

[0048] Chromatographic column: ACQUITY UPLC BEH C18 column (2.1 x 100 mm, 1.7 μm)

[0049] Mobile phase: A: 0.1% formic acid water B: acetonitrile;

[0050] Elution conditions:

[0051]

[0052]

[0053] Flow rate: 0.4 mL / min;

[0054] Column temperature: 30°C;

[0055] Injection volume: 0.5 μL

[0056] Detection wavelength: 254 nm

[0057] Ion source: ESI ion source; positive ion mode, negative ion mode; gas curtain gas: 35 psi; Gas 1: 55 psi; Gas 2: 55 psi; temperature: 350°C; ionization pressure: 5500 V (positive), -5500 V (negative); de-clustering voltage: 75 V; full scan range: m / z 50-1700; MS / MS scan range: m / z 50-1700; fragmentation voltage: 40 V (positive, negative).

[0058] (4) Content calculation: external standard method Wherein A x represents the peak area of the to-be-tested component in the to-be-tested sample, Rf represents a correction factor, m represents the sample mass of the to-be-tested sample, and the dilution multiple is 25 (i.e. the amount of solvent added per mL) The content of ephedrine hydrochloride, pseudoephedrine hydrochloride, baicalin and ammonium glycyrrhizinate in the to-be-tested sample is calculated.

[0059] (5) Limitation inspection of aristolochic acid: under a negative ion mode, mass-to-charge ratio (m / z) 355.95 and 356.04 are selected for detection, and an external standard method is adopted Wherein A x represents the peak area of the to-be-tested component in the to-be-tested sample, Rf represents a correction factor, m represents the sample mass of the to-be-tested sample, and the dilution multiple is 25 (i.e. the amount of solvent added per mL) The content of aristolochic acid I and aristolochic acid D in the to-be-tested sample is calculated. The content of aristolochic acid in the to-be-tested sample is the sum of the content of aristolochic acid I and the content of aristolochic acid D.

[0060] As shown in ​ , 3 LC-MS analysis results show that the content of ephedrine hydrochloride, pseudoephedrine hydrochloride, baicalin and glycyrrhizic acid in the Qingfei Paidu granules prepared by using the advanced manufacturing process is significantly improved, the aristolochic acid compounds are effectively removed, and the daily dosage is significantly reduced. The Qingfei Paidu granules prepared by using the preparation method of the Qingfei Paidu granules have the advantages of removing the coarse and retaining the fine, increasing the efficacy and reducing the toxicity, and significantly reducing the daily dosage.

[0061] The above merely describes preferred embodiments of the present application and is not intended to limit the protection scope of the present application, and thus equivalent changes or modifications made according to the patent scope of the present application shall fall within the patent claim scope of the present application.

[0062] Table 4 Comparison between the technical scheme provided by the present application and the prior art is as follows:

[0063]

[0064]

[0065] As shown in Table 4, compared with other technologies, the preparation method provided by the application can obviously improve the content of ephedrine hydrochloride, pseudoephedrine hydrochloride, baicalin and glycyrrhizic acid, effectively remove aristolochic acid compounds, significantly reduce the dosage, and improve the compliance of patients. Obviously, the preparation method provided by the application can obtain better products and better technical effects. For those skilled in the art, it is obvious that the application is not limited to the details of the above exemplary embodiments, and the application can be implemented in other specific forms without departing from the spirit or essential characteristics of the application. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting, and the scope of the application is defined by the appended claims rather than the above description, and therefore all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the application. Any reference signs in the claims should not be regarded as limiting the claims involved.

Claims

1. A method for preparing lung-clearing and detoxifying granules, characterized in that: The formula for Qingfei Paidu Granules consists of: Asarum, Ephedra, Pinellia ternata, Glycyrrhiza uralensis (processed), Zingiber officinale (dried), Prunus armeniaca, Aster tataricus, Gypsum fibrosum, Tussilago farfara, Cinnamomum cassia, Belamcanda chinensis, Alisma plantago-aquatica, Dioscorea opposita, Polyporus umbellatus, Citrus aurantium, Atractylodes macrocephala, Citrus reticulata peel, Poria cocos, Pogostemon cablin, Bupleurum chinense, and Scutellaria baicalensis. The prescription consists of the following parts by weight: Asarum 4-8 parts, Ephedra 8-10 parts, Pinellia ternata 8-10 parts, Glycyrrhiza uralensis (processed) 4-8 parts, Zingiber officinale (dried) 8-10 parts, Prunus armeniaca (apricot kernel) 8-10 parts, Aster tataricus 8-10 parts, Gypsum fibrosum 14-16 parts, Tussilago farfara 8-10 parts, Cinnamomum cassia 8-10 parts, Belamcanda chinensis 8-10 parts, Alisma plantago-aquatica 8-10 parts, Dioscorea opposita 10-14 parts, Polyporus umbellatus 8-10 parts, Citrus aurantium 4-8 parts, Atractylodes macrocephala 8-10 parts, Citrus reticulata 4-5 parts, Poria cocos 14-16 parts, Pogostemon cablin 8-10 parts, Bupleurum chinense 14-18 parts, Scutellaria baicalensis 4-8 parts. 1) Refining and detoxification: Asarum is extracted with water to obtain extract 1. Insoluble particulate matter is removed from extract 1 using membrane separation technology. Permeate 1 is collected. Permeate 1 is first refined using high efficiency preparative chromatography technology. Eluent 1 is collected. Then, aristolochic acid compounds are removed using ion exchange chromatography technology. Eluent 2 is collected and set aside. 2) Separation and purification: The other 20 medicinal ingredients in the prescription, excluding Asarum, are extracted with water to obtain extract 2. Insoluble particulate matter in extract 2 is removed by membrane separation technology, and permeate 2 is collected. Permeate 2 is purified by high performance preparative chromatography, and eluent 3 is collected for later use. 3) Formulation: The eluent 2 obtained in step 1) and the eluent 3 obtained in step 2) are combined, concentrated, dried, and excipients are added to prepare lung-clearing and detoxifying granules; In the membrane separation technology described in steps 1) and 2), the filter membrane is a ceramic membrane with a pore size of 50~800 nm; In the high-efficiency preparative chromatography techniques described in steps 1) and 2), the packing matrix is ​​silica gel; a bonded phase is bonded to the packing matrix, and the bonded phase is one or more of a positive-chain alkyl group with 1 to 30 carbon atoms; the inner diameter of the chromatographic column is 20 mm to 1600 mm, and the column bed height is 100 mm to 1000 mm; the chromatographic column is equilibrated with an equilibration buffer before sample loading and elution, and the organic solvent volume concentration in the equilibration buffer is 0 to 20%, with the remainder being water; the sample loading and elution flow rate is 10 mL / min to 20 L / min; the elution solvent for the target component is an aqueous ethanol solution with a volume concentration of 50% to 90%, and the elution method is isocratic, linear gradient, or step gradient. In step 1), the packing matrix of the ion exchange chromatography technique is one or more of a macroporous resin with a styrene-divinylbenzene copolymer structure or silica gel. The macroporous resin with the styrene-divinylbenzene copolymer structure is one or more of D201, PA408, and PA308; the silica gel is one or two of SAX and QA. In step 1), the elution solvent in the ion exchange chromatography technique is an aqueous ethanol solution with a volume concentration of 50-70%.

2. The method according to claim 1, characterized in that: Step 1) Extract 1 is obtained by adding 5 to 20 times its weight of water to Asarum, extracting at 90-100℃, separating solid and liquid, and obtaining the extract. The extraction is repeated 2 to 3 times, with each extraction time being 10 to 30 minutes. The extracts are combined to obtain extract 1. Step 2) Extract 2 is a mixture of the other 20 medicinal ingredients in the prescription (excluding Asarum) with 5 to 20 times their total weight of water. It is extracted at 90-100℃, and the solid and liquid are separated to obtain the extract. The extraction is repeated 2 to 3 times, with each extraction lasting 10 to 30 minutes. The extracts are then combined to obtain extract 2.

3. The method according to claim 1, characterized in that, In the high-efficiency preparative chromatography techniques described in steps 1) and 2), the packing matrix is ​​either silica gel or a polymer; a bonded phase is bonded to the packing matrix, which is one or more of a positive-chain alkyl group with 8 to 18 carbon atoms; the inner diameter of the chromatographic column is 20 mm to 1600 mm, and the column bed height is 100 mm to 1000 mm; the chromatographic column is equilibrated with an equilibration solution before sample loading and elution, and the volume concentration of the organic solvent in the equilibration solution is 0 to 10%, with the remainder being water; the sample loading and elution flow rates are 10 to 50 mL / min in step 1 and 1 to 20 L / min in step 2; the volume concentration of the organic solvent in the elution solvent for the target component is 50 to 70%, and the elution method is isocratic, linear gradient, or step gradient.

4. The method according to claim 1, characterized in that: Step 3) The concentration method can be one or more of vacuum concentration, thin film concentration or pressurized concentration; the drying method can be one or more of freeze drying, vacuum drying, spray drying or belt drying; the added excipients are in a weight ratio of 1-1.2:1 between the dried raw material and the excipients, the excipients are pharmaceutically acceptable solid carriers, and the granulation method is dry granulation.

5. The method according to claim 4, characterized in that: The auxiliary materials mentioned in step 3) are dry raw materials and auxiliary materials in a weight ratio of 1:1, 1.1:1 or 1.2:1.

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