CN114699437B - Oral preparation containing breviscapine extract and preparation method thereof - Google Patents

Abstract

The invention relates to an oral preparation containing erigeron breviscapus extract and a preparation method and application thereof, wherein the preparation method comprises common oral dosage forms such as capsules, tablets, oral liquid, dripping pills or granules, and the like.

Description

Oral preparation containing breviscapine extract and preparation method thereof

technical field

In particular, it relates to a preparation method and application of breviscapine and caffeic acid ester extract or its salt, especially in the preparation and treatment of metabolic related diseases such as hyperlipidemia, hypertension, diabetes, obesity, non-alcoholic fatty liver disease and heart disease. The application in the medicine of cerebrovascular diseases, and the application in the preparation of medicines for platelet aggregation and abnormal blood coagulation function caused by metabolic related diseases.

Background technique

In recent years, with the acceleration of population aging, continuous deepening of urbanization, and gradual changes in lifestyle, the spectrum of diseases has also undergone major changes. Metabolism-related diseases such as hypertension, hyperlipidemia, obesity, and diabetes are widespread, and the resulting incidence of cardiovascular and cerebrovascular diseases is also showing an accelerated upward trend.

Erigeron breviscapus (Erigeron breviscapus) is the dry whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, a plant of the genus Asteraceae. The power of removing blood stasis, dredging collaterals and relieving pain is used for cold headache, rheumatism pain, paralysis caused by cerebrovascular accident, etc. ("National Chinese Herbal Medicine Compilation"). Asarum breviscapus can be made into medicine alone. The existing varieties on the market include Asarum breviscapus injection, Asarum breviscapus capsule, Asarum breviscapus soft capsule, Asarum breviscapus dripping pills, Yimaikang, Asarum breviscapus granules, etc.; Asarum breviscapus The active ingredients are flavonoid scutellarin and caffeic acid esters, while the existing products mainly emphasize scutellarin as the main component.

Breviscapine products include breviscapine injection, breviscapine for injection, breviscapine tablets, breviscapine dripping pills, etc. Even breviscapine capsules, Yimaikang and other breviscapine extract products do not set regulations on the content of caffeic acid esters, let alone enrichment. Erigeron breviscapitalis injection is the only product that enriches caffeic acid ester components technologically. But the ratio of caffeic acid ester content to flavonoids is only in the range of 1:1.2-1:5.5. Through the research on the caffeic acid esters in Erigeron breviscapus, it is found that the caffeic acid esters in Erigeron breviscapus are very rich, including monocaffeic acid esters and dicaffeic acid esters. There are many families and genera containing caffeic acid esters in plants, such as Compositae, Lonicera, Eucommiaceae, Dipsaceae, Rubiaceae, Convolvulaceae and other plants. It is known that Compositae plants are different from other plants containing caffeoyl quinate in that they also contain a class of caffeoyl octulose acid compounds, namely monocaffeoyl, dicaffeoyl and tricaffeoyl octulose acids class of substances. The caffeoyloctulose acids contained in Erigeron breviscapine are dicaffeoyloctulose acids, which include scutellarin and scutellarin. Scutellariae B is isolated from Asteraceae plants, and scutellaria is now only obtained from scutellaria. Jianping Zhao, et al. (J.Nat.Prod.2014,77,509-515) reported that the six caffeoyloctulose acids obtained from the chrysanthemum genus A. The content range of this special type of dicaffeic acid ester compounds is listed separately, which can better clearly classify and control the content of the caffeic acid ester components obtained from Erigeron breviscapine, so that the effective The content of ingredients is easier to control, which also makes the quality of such products more controllable. There is also a class of hepatotoxic substance γ-pyrone in Erigeron scutellaria, and the representative compound is pyromeconic acid. The previous patented method for removing pyromeconic acid is to adopt column chromatography, and the property used is Pyromeconic acid is highly polar and can be removed by washing with water in column chromatography, but the extraction solvent must be low-concentration alcohol or water extraction, otherwise impurities such as chlorophyll will easily solidify on the adsorption column, resulting in failure to elute Or cause difficulty in column regeneration. This patent adjusts the pH of the acidified supernatant to neutral and then performs microfiltration to remove insoluble macromolecular impurities, including most of chlorophyll, protein, tannin, etc., and then concentrates them through nanofiltration membranes. Molecular substances and water filtration, pyromeiconic acid can be dissolved in water, and the molecular weight is only 112Da, so 90% of pyromeiconic acid can be removed by this method. The concentrated solution after removing the pyromeconic acid is put on the column, so that the upper column solution can be separated and purified more effectively. And it can also be extracted with 50-80% ethanol in the first step of extraction to increase the extraction rate. The extracted and refined breviscapine and caffeic acid esters can be directly dried and used as medicine, or the pH of breviscapine and caffeic acid esters can be adjusted to neutral, and spray-dried after forming salts to increase their water solubility and increase Druggability of two classes of ingredients.

Contents of the invention

In view of the above technical problems, the object of the present invention is to provide an oral preparation containing breviscapine extract, wherein, the oral preparation contains caffeic acid ester or its salt and breviscapine or its salt and pharmaceutically acceptable auxiliary materials, coffee The weight ratio of the acid ester or its salt to scutellarin or its salt is 1:1-30:1.

The current oral preparations of Erigeron breviscapine are limited by the extraction method, usually the preparation is a mixture of caffeic acid esters, breviscapine, and other substances, which cannot be precisely mixed. The invention adopts a unique preparation method to extract the main components, especially the two main active component salts and make accurate ratios, which effectively improves the drug efficacy.

Preferably, the present invention further provides an oral preparation containing breviscapine extract, the caffeic acid ester or its salt includes dicaffeic acid ester or its salt and monocaffeic acid ester or its salt, wherein the dicaffeic acid ester The weight ratio of its salt to scutellarin or its salt is 1.25:1～6:1, (preferably 1.25:1～5.5:1, more preferably 1.5:1-5:1, most preferably 2:1-4.5: 1), the weight ratio of monocaffeic acid ester or its salt to dicaffeic acid ester or its salt is 1:1.2～1:6.2.

Preferably, the present invention further provides an oral preparation containing breviscapine extract, and the dicaffeic acid ester or its salt includes 1,3-O-dicaffeoylquinic acid or its salt, 3,4- O-dicaffeoylquinic acid or its salts, 3,5-O-dicaffeoylquinic acid or its salts, 4,5-O-dicaffeoylquinic acid or its salts, phenidyl ethyl or its salts , scutellarin or its salts; monocaffeic acid esters or their salts include 3-O-caffeoylquinic acid or its salts, 4-O-caffeoylquinic acid or its salts, 5-O-caffeoylquinic acid Nitric acid or its salt, scutellarin or its salt.

Preferably, the present invention further provides an oral preparation containing Erigeron breviscapine extract, 1,3-O-dicaffeoylquinic acid or its salt, 3,4- O-dicaffeoylquinic acid or its salt, 3,5-O-dicaffeoylquinic acid or its salt, 4,5-O-dicaffeoylquinic acid or its salt, the above four are the same Isomers; said scutellarin or its salts and scutellarin or its salts are isomers, which are dicaffeoyloctulose acid or its class, wherein the dicaffeoyl ester or its salt is simply substituted The ratio of salt to dicaffeoyloctulose acid or its salt is 2:1-0.9:1.

The above-mentioned oral preparations are preferably hard capsules, soft capsules, tablets, granules, oral liquids, dripping pills, water pills, powders, and pills.

The scutellarin or its salts of the above-mentioned oral preparations include scutellarin or its salts, scutellarin or its salts, scutellarein and its salts, etc. scutellarin or its salts related flavonoids isolated from scutellaria or its salt.

In the above preparation, caffeic acid ester or its salt and scutellarin or its salt account for 80-99% by weight of the preparation, and the balance is auxiliary materials. The oral preparation is preferably capsules, tablets, such as hard capsules.

Further, both the dicaffeate salt and the scutellarin salt are sodium salt or potassium salt or other pharmaceutically acceptable and water-soluble salts; sodium salt is preferred, and the weight ratio thereof is 1:1-6:1. That is, other products should also be sodium salts or potassium salts or other medicinal and water-soluble salts, and similarly, other products should also preferably be sodium salts.

The present invention further provides a preparation method of oral preparations, the preparation method is as follows:

Take Erigeron breviscapine and add 10-90% concentration of aqueous ethanol to extract, the extract is concentrated under reduced pressure to form an extract; add water to dissolve the extract, adjust pH 7-9, filter, add acid to adjust pH 1-3, leave overnight, filter , collect the filtrate and precipitate, refine the precipitate with water and ethanol, and obtain scutellarin after drying; add alkali to adjust the pH value to 7-8 after the precipitation is refined, and spray dry to obtain scutellarin salt; the acidified filtrate adjusts the pH value to 7 ～9, clarification with ceramic microfiltration membrane, the clarified liquid obtained after clarification is concentrated with organic nanofiltration membrane, and the concentrated solution passes through a polyamide chromatography column, and after elution with water, it is eluted with 50-80% ethanol and collected Concentrate the ethanol eluent and dry to obtain caffeic acid ester; adjust the pH value to 7-9 after concentrating the ethanol eluent, filter, and spray-dry the filtrate to obtain caffeic acid ester salt. Mix dicaffeic acid ester or its salt and scutellaria or its plain salt at a ratio of 1:1 to 6:1 (preferably 1.25:1 to 5.5:1, more preferably 1.5:1 to 5:1, most preferably 2:1 to 4.5 :1) ratio compatibility, adding appropriate auxiliary materials, can be made into tablets, capsules, soft capsules, dripping pills, granules and oral liquid preparations.

In the preparation method of the above-mentioned oral preparation, the pH value of the alkali adjustment solution is NaOH, Na ₂ CO ₃ , NaHCO ₃ , KOH, K ₂ CO ₃ or KHCO ₃ , or other alkali solutions that can be used to adjust the pH value ; The acid used to adjust the pH of the solution is HCl, H ₂ SO ₄ or H ₃ PO ₄ , or other acid solutions that can be used to adjust the pH. The alkali to adjust the pH of the solution is preferably NaOH, Na ₂ CO ₃ , NaHCO ₃ , KOH, K ₂ CO ₃ or KHCO ₃ ; the acid to adjust the pH of the solution is preferably HCl, H ₂ SO ₄ Or H ₃ PO ₄ .

The concentration of ethanol used for ethanol elution in the polyamide chromatography column is 50-95%.

The present invention provides the application of the above-mentioned pharmaceutical composition in the preparation of drugs for treating hypertension, hyperlipidemia, diabetes, obesity, non-alcoholic fatty liver disease and other metabolic related diseases and cardiovascular and cerebrovascular diseases. More creatively, the present invention According to the invention, the pharmaceutical composition obtained by screening the above ratio has the effect of regulating metabolism-related diseases and resulting platelet aggregation and coagulation disorders, and is more pleased to obtain an unexpected effect, that is, compared with aspirin and clopidogrel, The composition of the present invention not only has an anti-platelet aggregation effect equivalent to that of the active drug, but also has a better anti-coagulant effect, which is a medical and pharmaceutical advantage that aspirin and clopidogrel do not possess, and more importantly, The composition of the present invention is administered beyond the doctor's prescription and will not cause bleeding symptoms, which is very important for preventing atherosclerosis and cardiovascular and cerebrovascular diseases caused by it.

The single oral preparation of breviscapine currently on the market does not have the step of removing the hepatotoxic component pyromeconic acid, nor does it have the step or process of refining caffeic acid ester or its salt components, especially dicaffeic acid ester or its salt components. For example, the existing process of Erigeron breviscapus capsules is to take 2000g of Asarum breviscapus, heat and reflux with 80% ethanol to extract twice for 1.5 hours for the first time, and 1 hour for the second time, combine the extracts, add about 640g of activated carbon, boil, filter, and filtrate Concentrate under reduced pressure to a thick paste, add appropriate amount of starch, dry under reduced pressure, pulverize, sieve, coat with 3% polyvinyl alcohol solution, add 0.5g of magnesium stearate, mix well, put into capsules, and prepare Make 1000 capsules, and you get it.

It has been reported in the literature that caffeoylquinic acid ester compounds have anti-oxidation, anti-inflammatory, anti-bacterial, anti-viral, hypoglycemic, hypolipidemic, and immunomodulatory effects, and are a class of active ingredients. Therefore, refining such active substances and comparing the two components to quantitative regulations is a necessary work to make Erigeron breviscapus products better serve clinical services. Breviscapine and caffeic acid esters have poor water solubility and fat solubility, resulting in low bioavailability and weak druggability. The present invention adopts alkali-soluble acid precipitation in the preparation method, and firstly precipitates the flavonoid component scutellarin, and then refines it; at the same time, the acidified supernatant part is retained, and the acidified supernatant part is another type of active ingredient caffeic acid esters. Through membrane separation technology, microfiltration is used to remove macromolecular insoluble substances, and then nanofiltration membrane is used to concentrate and remove most pyromeconic acid, and then column chromatography is carried out to enrich dicaffeic acid ester components and remove hepatotoxic substances again. Pyromeiaconic acid. After nanofiltration membrane and column chromatography, more than 99% of pyromeiconic acid can be removed.

This result was confirmed experimentally:

Table 1. Changes in component content of the acidified supernatant of Erigeron breviscapine after pH adjustment after membrane filtration

It can be seen from Table 1 that the effective substance dicaffeate was better retained after the acidified supernatant of breviscapine was adjusted to be close to neutral after passing through the clarification membrane and the nanofiltration concentration membrane, while the harmful substance pyroconic acid was removed. rate reached 84%. After column chromatography, the content of dicaffeic acid ester was well retained, and pyromeiconic acid was further removed.

The microfiltration clarification membrane is preferably 100nm or 200nm, and the nanofiltration concentration membrane is preferably 300D-400D.

When the flavonoids and caffeic acid esters are salted, the in vitro dissolution test proves that the dissolution is higher than that of the prototype, so it is better than the prototype in terms of druggability. The dissolution profiles of breviscapine tablets and breviscapine sodium tablets in different dissolution media were evaluated. The results of the study showed that the dissolution rates of the two tablets in 0.1M HCl were all low, reaching saturation in 5 minutes, and the cumulative dissolution percentage was less than 15%; The release amount basically reached saturation in 30 minutes, and the cumulative dissolution percentage of breviscapine sodium salt tablets was higher than that of the prototype tablet, both less than 60%. The salt tablets were completely dissolved at 15 minutes, while the cumulative dissolution rate of Erigeron breviscapine tablets was greater than 85% at 45 minutes; at 30 minutes, the cumulative dissolution rate of Erigeron breviscapus sodium salt tablets was greater than that of Asarum breviscapine tablets.

C57 mice were fed with MCD (Methionine and Choline Deficient L-Amino Acid Diet) methionine and choline-deficient diet to construct a non-alcoholic steatohepatitis (NASH) model, and to explore the existing Erigeron capsules and the invention process Erigeron breviscapus Therapeutic effect of capsules on NASH.

1. Test reagent

MCD feed, article number A02082002BR, manufacturer: Research Diets (USA)

2. Test process

(1) Animal grouping and treatment Twenty C57BL/6J male mice were randomly divided into 4 groups after adaptive feeding for 1 week, with 5 mice in each group. The control group was a normal maintenance feed, the model group was fed MCD feed, the existing Erigeron breviscapus capsule powder group and the invented process Erigeron breviscens capsule powder group (see Example 6 for prescription), oral liquid administration (100mg/kg body weight ), once a day. The experimental animals were given free access to food and water, and were intervened for 4 weeks.

(2) Determination of mouse body weight and liver weight The body weight and liver wet weight of mice in each group were weighed, and the liver index was calculated.

3. Test results

(1) Effects on mouse body weight, liver weight and liver index

After feeding for 4 weeks, the body weight, liver weight and liver index of the mice in the model group, the existing Erigeron Capsules powder group, and the inventive process Erigerons Capsules powder group were significantly lower than those in the control group, indicating that the tested drugs could not effectively improve the MCD diet-induced reduction in body weight, liver weight. In addition, there was no significant difference in body weight, liver weight and liver index between the two tested drugs and the model group, as shown in Table 2.

Table 2. Effects of Erigeron Capsules Powder on Body Weight, Liver Weight, and Liver Index of Mice

(2), the influence on mouse liver function index

Compared with the control group, the serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels of the mice in the model group were significantly increased ( ^### P<0.001). The levels of serum AST and ALT in mice in the inventive process Erigeron Capsules powder group were higher than those in the control group, but compared with the model group, the inventive process Erigeron Capsules powder significantly reduced the levels of serum AST and ALT induced by the MCD diet. High; the scutellaria scutellaria group with existing technology (such as Yunnan Haobang Pharmaceutical) can significantly reduce the ALT level, and there is a tendency to reduce AST, but there is no statistical significance, see Table 3.

Table 3. Influence of the inventive process Dengzhan Xixin capsule powder and the existing Dengzhan Shengmai capsule powder on liver function indicators in NASH mice

group Alanine aminotransferase (U/L) Aspartate aminotransferase (U/L) control group 37.2±6.57 103.2±22.9 model group 160.8±49.2^### 181.2±34.1^### Invention Process Erigeron Erigeron 101.6±28.2*^# 132.1±22.1* Existing craft Erigeron asarum group 100.1±22.4*^# 162.2±21.6^##

^### P<0.005vs control group; ^## P<0.01vs control group; ^# P<0.05vs control group; ^* P<0.05vs model group

4. Analysis and conclusion

(1) Effect on body weight The weight loss of NASH mice induced by MCD diet is a disease characterization of this diet model. In this study, it was found that the invented process of Erigeron breviscapus capsule powder and the existing process of Erigeron breviscapus capsule powder could not inhibit the weight loss induced by the MCD diet, which may be related to the structure of the MCD diet.

(2) Effects on liver function The levels of serum ALT and AST in mice fed with MCD diet were significantly increased, indicating that the NASH model induced by MCD diet was successfully established. This study found that both the invented process of Eriganthorus capsule powder and the existing process of Eriganthorus capsule powder can improve the liver function damage induced by MCD diet, and the inventive process of Eriganthorn capsule powder has a down-regulation effect on ALT and AST, although Existing literature has found that scutellarin (scutellarin, usually by injection) may have a protective effect on the liver, but this experiment shows that compared with scutellaria obtained by the existing process, scutellaria scutellaria obtained by the inventive process is more effective when administered orally. Drug (100mg/Kg) has better hepatoprotective effect.

The existing breviscapine capsule powder is prepared from scutellarin salt and caffeic acid ester salt at a ratio within the scope of claims.

Description of drawings:

Fig. 1 Body weight change of golden hamster;

Fig. 2 plasma total cholesterol content of golden hamster;

Fig. 3 golden hamster plasma low-density lipoprotein-cholesterol (LDL-c) content;

Fig. 4 golden hamster plasma triglyceride (TG) content;

Fig. 5 golden hamster plasma alanine aminotransferase (ALT) content;

Fig. 6 golden hamster plasma aspartate aminotransferase (AST) content;

Fig. 7 golden hamster liver index (%);

Fig. 8 golden hamster fat index (%);

Fig. 9 Triglyceride content in golden hamster liver;

Figure 10 platelet aggregation rate (%);

Figure 11 Activated partial thromboplastin time;

Figure 12 Prothrombin time;

Figure 13 plasma thrombin time;

Figure 14. Plasma fibrinogen levels.

The purpose of this experiment is to study the curative effect of different ratios of the main components of calendula on metabolism-related diseases caused by high-fat diet, as well as on platelet aggregation and coagulation disorders, and provide experimental data support for the new clinical application of the drug.

It was found from the aforementioned experiments that the new technology Erigeron breviscapus Capsules can effectively reduce ALT and AST in the non-alcoholic steatohepatitis model, and then further use the existing technology (Yunnan Haobang Pharmaceutical Co., Ltd.) and this product technology Example 6 to carry out Comparing, while comparing, calculate the dicaffeate salt and scutellarin salt in the embodiment, and carry out precise proportioning, so as to achieve the most suitable ratio of dicaffeate salt and scutellarin salt. Aspirin and clopidogrel were used as positive control drugs in the study. Since there was no significant difference in the test results of the two drugs, the following experiments only show the test results of aspirin.

2) Experimental method:

2.1) Experimental animals: LVG Syrian golden hamster, male, 6 weeks old, weighing 90-110 g, adapted to the breeding environment for 2 weeks. Animals were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

2.2) Experimental feed: basic feed (Normal chow diet, NC group); high fat feed (High fat diet model group, HFD group: 1.0% cholesterol, 0.2% sodium cholate, 10.0% lard, 5.0% egg yolk powder and 83.8 % basal feed). The feed was purchased from Beijing Keao Xieli Feed Co., Ltd.

2.3) Dosing method: Animals were given medicated feed based on high-fat feed for 8 weeks, in which 4 g/kg of drug was contained in the feed containing breviscapine, equivalent to the animal food intake equivalent to 200 mg/kg body weight/day; The aspirin-containing feed contains 0.4g/kg of the drug, which is equivalent to an administration amount of 20mg/kg body weight/day. In addition, the same batch of golden hamsters fed the basal diet served as the normal control group (NC group).

2.4) Experimental grouping and administration

Table 4. Experimental grouping and administration

The control scutellaria was prepared by using the existing technology; the scutellaria groups A-F were prepared by the inventive technology.

2.5) Detection indicators and methods:

a. Weight determination

During the experiment period, the body weight of the animals was recorded once a week.

b. Blood biochemical test

After the experiment, the animals were fasted for 12 hours, and blood (0.5 ml) was collected from the orbital venous plexus in an anticoagulant tube, centrifuged at 3500 rpm and 4°C for 10 minutes, and 100 μL of the supernatant was taken and stored in a -80°C refrigerator. Then use an automatic biochemical analyzer to detect the levels of total cholesterol (CHO), low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in plasma . The detection kit was purchased from Zhongsheng Beikong Biotechnology Co., Ltd.

c. Liver wet weight ratio and epididymis fat wet weight ratio

After the experiment, the liver tissue and epididymis fat were taken from the animals, weighed, and the liver wet weight, epididymis fat weight and their body weight percentages of each animal were calculated respectively.

d. Determination of liver tissue lipid content

After the experiment, each hamster in each group weighed 20 mg of liver tissue, and added 20 times the volume of T-PER (containing 1/100 protease phosphate Enzyme inhibitors), homogenate mechanically (42HZ, 4-6min) in an ice-water bath, then centrifuge at 2500rpm for 10min, take 2.5μL of the upper layer and dilute 5 times to prepare the sample to be tested, and perform the test according to the TG test kit instructions. The remaining liver tissue homogenate was centrifuged at 12,000 rpm at 4°C for 30 min, and the supernatant was aspirated for BCA protein quantification. The obtained results are further calculated according to the following formula.

e. Determination of platelet aggregation and coagulation indicators

After the experiment, anesthetize with 5% chloral hydrate (1ml/100g), collect blood from the heart with a syringe, add anticoagulant in the ratio of sodium citrate (4%) solution to blood 1:9, and centrifuge at 200g for 10min to take the upper Platelet-rich plasma (PRP) was obtained from the supernatant, and the remaining plasma was centrifuged at 800 g for 10 min to obtain the supernatant to obtain platelet-poor plasma (PPP). In the platelet maximum aggregation rate detection experiment, first use PPP to calibrate, PRP is pre-warmed at 37°C for 180 seconds, then put it in the detection tank and quickly click start while adding 10ul adenosine diphosphate (ADP, 10nM), and read the platelets within 300s Maximum aggregation ratio (MAR) value. In the four tests of blood coagulation, PPP was pre-warmed at 37°C for 180s and placed in the test tank, and quantitative activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time ( TT) Fibrinogen (FIB) Detection Reagent Quickly click to start, and read the clotting time and fibrinogen content.

2.6) Data Analysis

All data were entered into an Excel file and expressed as Mean ± SEM. Statistical analysis of data using Graphpad Prism 8.0 software, one-way or two-factor analysis of variance comparison method, with *P<0.05 as the criterion of significant difference.

3) In vivo test results

3.1) Weight change

The body weight of the animals was measured once a week during the administration period, and the results are shown in Figure 1. Compared with the normal diet control group (NC), the body weight of the animals in the high-fat diet model group (HFD) was significantly increased. The antiplatelet drug aspirin has no effect on reducing the weight gain induced by high-fat diet. The control drug (Yunnan Haobang, existing technology) and Erigeron breviscapus (invention technology) each ratio group can reduce the weight gain caused by high-fat diet; each ratio group Erigeron breviscapus (invention technology) reduces body weight better than the control Erigeron breviscapus (Yunnan Haobang, existing technology); among them, the effect of two ratios of dicaffeate salt: scutellarin salt 3:1 and 4.5:1 is the best.

3.2) Blood biochemical testing

a. The results of plasma total cholesterol content are shown in FIG. 2 and Table 5.

Table 5. Total Plasma Cholesterol Content

The results showed that the plasma total cholesterol content of the high-fat diet model animals was significantly higher than that of the healthy control group (***P<0.001); aspirin and control Erigeron breviscapus (Yunnan Haobang, existing technology) had no effect on lowering plasma total cholesterol; Experimental Erigeron breviscapus (invention process) has a tendency to reduce plasma total cholesterol, but there is no significant difference compared with the HFD group.

b. The results of plasma low-density lipoprotein-cholesterol (LDL-c) content are shown in FIG. 3 and Table 6.

Table 6. Plasma low-density lipoprotein-cholesterol (LDL-c) content

The results showed that the plasma LDL-cholesterol content of the high-fat diet model animals was significantly higher than that of the healthy control group (***P<0.001); -Cholesterol effect; experimental breviscapine (invention process) has the effect of lowering plasma low-density lipoprotein-cholesterol, and the two ratio groups of dicaffeate salt: breviscapine salt 4:1 and 4.5:1 can significantly reduce LDL- c effect (**P<0.01), 3:1 (P=0.085) and 6:1 (P=0.071) ratio groups also had a certain effect of lowering plasma LDL-cholesterol.

c. Results for plasma triglyceride (TG) levels are shown in FIG. 4 and Table 7.

Table 7. Plasma Triglyceride (TG) Levels

The results showed that the plasma triglyceride (TG) content of the high-fat diet model animals was significantly higher than that of the healthy control group (***P<0.001); aspirin and the control breviscapine (existing technology) had no plasma triglyceride-lowering effect ;Experimental scutellaria (invention process) dicaffeate salt: breviscapine salt 4.5:1 ratio group has a significant effect on reducing plasma triglycerides (*P<0.05), 3:1 (P=0.0548) ratio Group also has a certain role in lowering plasma triglycerides.

d. The results of plasma alanine aminotransferase (ALT) levels are shown in FIG. 5 and Table 8.

Table 8. Plasma alanine aminotransferase (ALT) content

The results show that the plasma alanine aminotransferase (ALT) content of the high-fat diet model animal is significantly higher than that of the healthy control group (*P<0.05); aspirin and contrast breviscapine (existing technology) have no effect on reducing plasma alanine aminotransferase; the experiment Erigeron breviscapine (invention process) dicaffeate salt: breviscapine salt 3:1 ratio group and 4.5:1 ratio group have a significant effect on reducing plasma ALT (*P<0.05); 4:1 (P=0.0573 ) ratio group also has a certain effect of lowering plasma alanine aminotransferase.

e. The results of plasma aspartate aminotransferase (AST) content are shown in FIG. 6 and Table 9.

Table 9. Plasma aspartate aminotransferase (AST) content

The results showed that the plasma aspartate aminotransferase (AST) content of the high-fat diet model animals was significantly higher than that of the healthy control group (*P<0.05); each experimental group had no effect on reducing plasma aspartate aminotransferase.

3.3) Detection of liver and fat index

a. The results of liver index are shown in FIG. 7 and Table 10.

Table 10. Liver Index

Liver index refers to the ratio of liver wet weight to body weight. The results show that compared with the healthy control group, the liver index of the high-fat diet model animal significantly increases (***P<0.001); aspirin and contrast breviscapine (existing technology) do not have the effect of reducing the liver index; the experimental breviscapine (invention) Process) dicaffeic acid ester salt: breviscapine salt 4.5:1 ratio group has a certain effect on reducing liver index (P=0.0529), suggesting that it has a certain preventive effect on non-alcoholic fatty liver disease caused by high-fat diet.

b. The results of fat index are shown in Figure 8 and Table 11

Table 11. Fat Index

Fat index refers to the ratio of epididymis fat wet weight to body weight. The results showed that compared with the healthy control group, the animal fat index of the high-fat diet model increased significantly (*P<0.05); aspirin and control breviscapine (existing technology) had no effect on reducing the fat index; experimental breviscapine (invention technology) Dicaffeic acid ester salt: breviscapine salt 4.5:1 ratio group has a certain effect of reducing fat index.

3.4) Test results of liver tissue lipid content

The results of liver lipid content expressed as liver triglycerides are shown in FIG. 9 and Table 12.

Table 12. Liver Triglyceride Content

The results showed that the TG content in the liver tissue of the high-fat diet model animals was significantly higher than that in the healthy control group (***P<0.001); (Invention process) can significantly reduce the TG of liver tissue, among which the dicaffeate salt: breviscapine salt 3:1 and 4.5:1 two ratio groups have the most significant effect (**P<0.01), 1.25:1, 2: 1. The 4:1 and 6:1 groups can also significantly reduce TG in liver tissue (*P<0.05), suggesting that they have a better effect on preventing and treating non-alcoholic fatty liver disease.

3.5) Platelet aggregation and coagulation test results

a. Platelet aggregation results are shown in FIG. 10 and Table 13.

Table 13. Platelet aggregation rate

Increased platelet aggregation rate is easy to form thrombus and block blood vessels. It is also one of the factors of coronary heart disease and may lead to the formation of atherosclerosis. The results showed that the platelet aggregation rate of the high-fat diet model animals was significantly higher than that of the healthy control group (***P<0.001); aspirin significantly reduced the platelet aggregation induced by the high-fat diet (***P<0.001); Xin (existing technology) and experimental groups Erigeron breviscapine (invented technology) in each ratio group can significantly reduce the platelet aggregation caused by high-fat diet, in which dicaffeate salt: breviscapine salt 3:1 and 4.5:1 The two ratio groups had the most significant effect (**P<0.01), and the 1.25:1, 2:1, 4:1 and 6:1 groups could also significantly reduce platelet aggregation caused by high-fat diet (*P<0.05) and the effect All are better than the reference Erigeron breviscapus (existing technology).

b. Activated partial thromboplastin time (APTT) results are shown in Figure 11 and Table 14.

Table 14. Activated partial thromboplastin time

Activated partial thromboplastin time (APTT) is a coagulation function test index that reflects the comprehensive activity of the endogenous coagulation pathway, especially the coagulation factors in the first stage. The shortened time can be seen in hypercoagulable states and thromboembolic diseases. The results showed that the APTT of the high-fat diet model animals was significantly lower than that of the healthy control group (*P<0.05); Ester salt: Breviscapine salt 4:1 (P=0.052) and 4.5:1 (P=0.089) two ratio groups have a certain effect of increasing APTT, suggesting that it may prevent thrombotic diseases caused by high-fat diet.

c. Prothrombin time (PT) results are shown in Figure 12 and Table 15.

Table 15. Prothrombin Time (PT)

Prothrombin time is an index reflecting the activity of coagulation factors Ⅰ, Ⅱ, Ⅴ, Ⅶ, and Ⅹ in plasma. Low prothrombin time is common in hypercoagulable state of blood, for example, prothrombin time will be low in myocardial infarction or cerebral thrombosis. The results showed that the PT of high-fat diet model animals was significantly lower than that of the healthy control group (***P<0.001); aspirin and control scutellaria (existing technology) had no effect on increasing PT; Dicaffeate salt: breviscapine salt 4.5:1 ratio group can significantly increase the PT reduction caused by high-fat diet (*P<0.05), suggesting that it may prevent thrombotic diseases caused by high-fat diet.

d. Thrombin time (TT) results are shown in Figure 13 and Table 16.

Table 16. Thrombin Time

Plasma thrombin time refers to the time required for plasma fibrinogen to convert into fibrin after adding "standardized" thrombin to the tested plasma. The low thrombin time may be related to the hyperlipidemia in the patient's own blood. May be due to thromboembolic disease. The results showed that the TT of the high-fat diet model animals was significantly lower than that of the healthy control group (***P<0.001); Dicaffeate salt: breviscapine salt 4.5:1 ratio group can significantly increase the TT reduction caused by high-fat diet (*P<0.05), suggesting that it may prevent thrombotic diseases caused by high-fat diet.

d. Fibrinogen (FIB) Results are shown in Figure 14 and Table 17.

Table 17. Fibrinogen

Fibrinogen (FIB) is a protein with coagulation function mainly synthesized by liver cells, and is the coagulation factor with the highest content in plasma. Clinical data show that: in patients with elevated fibrinogen levels, most patients may suffer from myocardial infarction or sudden death, and the higher the fibrinogen level, the greater the risk; Factors; fibrinogen rises, blood is in a hypercoagulable state, blood flow slows down, blood viscosity increases, and thrombosis is prone to occur; hypertension is often accompanied by increased fibrinogen levels, which is the cause of inducing and aggravating hypertension An important reason; fibrinogen is closely related to fat metabolism; in addition, old age, smoking, obesity, stress and diabetes can promote the increase of fibrinogen levels in the body. The results showed that the plasma fibrinogen of the high-fat diet model animals was significantly higher than that of the healthy control group (***P<0.001); High effect; experimental group breviscapine (invention process) dicaffeate salt: breviscapine salt 4.5:1 ratio group can significantly reduce the increase of fibrinogen caused by high-fat diet (*P<0.05), dicoffee Ester salt: breviscapine salt 2:1 (P=0.064), 3:1 (P=0.058), 6:1 (P=0.057) groups also had a certain effect of reducing plasma fibrinogen.

4 Conclusion

4.1) Eight weeks of high-fat diet modeling can significantly increase the body weight, liver index, fat index, liver lipids, blood lipids and liver enzyme levels of golden hamsters, and the model is successful.

4.2) The antiplatelet drug aspirin has no effect on reducing the weight gain caused by high-fat diet (the test result of another positive drug clopidogrel is the same as that of aspirin); the invention process Erigeron breviscapine can reduce the weight gain caused by high-fat diet; And the effect of reducing body weight is better than that of the control scutellaria breviscapine (Haobang Pharmaceutical, existing technology); among them, the effect of two ratios of dicaffeate salt: breviscapine salt 3:1 and 4.5:1 is the best.

4.3) The antiplatelet drug aspirin and the control Erigeron breviscapine (Haobang Pharmaceuticals, existing technology) have no effect on lowering blood lipids, including plasma total cholesterol, low-density lipoprotein-cholesterol, triglycerides (the test result of another positive drug clopidogrel Same as aspirin); experimental scutellaria breviscapine (invented process) has blood lipid-lowering effect, and the dicaffeate salt: breviscapine salt 4.5:1 ratio group is the best.

4.4) Aspirin and control breviscapine (Haobang pharmaceutical, existing technology) have no effect on lowering plasma liver enzymes (another positive drug, clopidogrel, has the same test result as aspirin); Transaminase effect, and dicaffeate salt: scutellarin salt 4.5:1 ratio group is the best.

4.5) Aspirin and control breviscapine (Haobang Pharmaceutical, existing technology) had no effect on reducing liver index, fat index and lipid accumulation in liver tissue (the test result of another positive drug clopidogrel was the same as that of aspirin); breviscapine ( New technology) each proportioning drug has the effect of regulating the above-mentioned indicators, and the dicaffeate salt:breviscapine salt 4.5:1 proportioning group is the best.

4.6) Erigeron breviscapine (invention process) can significantly improve platelet aggregation and coagulation disorders induced by high-fat diet, including four indicators of platelet aggregation rate and coagulation; its effect is better than that of the control breviscapine (existing process ); Among them, the comprehensive effect of dicaffeate salt: breviscapine salt ratio of 4.5:1 is the best; aspirin can effectively reduce platelet aggregation but has no anticoagulant effect (the test result of another positive drug clopidogrel is the same as that of aspirin ).

7. Based on the above results, the experimental Erigeron breviscapus (invention process) has a good effect on the prevention and treatment of hyperlipidemia, non-alcoholic fatty liver disease, obesity and other metabolic-related diseases, and can effectively prevent and treat platelet aggregation and abnormal coagulation function caused by metabolic-related diseases , has the effect of preventing and treating cardiovascular and cerebrovascular diseases; its effect is related to the preparation process and the proportion of main components.

The existing breviscapine capsule powder is prepared from scutellarin salt and caffeic acid ester salt at a ratio within the scope of claims.

detailed description:

Embodiment 1: preparation of crude drug extract

Take 2000g Erigeron breviscapine and add 50% ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to obtain extract (relative density 1.15-1.25, 75°C); add 5 times the amount of extract Dissolve in water, add 5% sodium hydroxide solution under stirring, adjust pH 7.5 to 8.5, filter, add 10% sulfuric acid solution to adjust pH 1 to 3, leave overnight, filter, collect filtrate and precipitate, precipitate ethanol refining, and then Add 5% sodium hydroxide to adjust the pH value to 7-8, spray dry to obtain powder 1; adjust the pH value of the acidified filtrate to 7-9, use a 100nm ceramic membrane to clarify, and then use a 350D organic membrane to clarify the clarified liquid obtained after clarification. Concentrate, the concentrated solution is passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio 1:4), after elution of 3 column volumes with water, 4 column volumes of elution with 65% ethanol, and the ethanol eluate is collected, After concentrating, adjust the pH value to 7-9 and spray-dry to obtain powder 2; mix powder 1 and powder 2 in proportion to obtain a 1:4 mixture of scutellarin sodium salt powder and caffeic acid ester sodium salt powder, and obtain the medicinal product of the present invention. Composition ingredients of the drug substance of the composition. Wherein the powder 1 contains 36.3% of scutellarin sodium salt, 5.4g in total. Powder 2 contains 21.0% dicaffeate salt, a total of 30.9g, and monocaffeate salt 9.1g. Among them, the simple substituted dicaffeate salt was 19.0g, and the dicaffeoyloctulone salt was 11.9g. The total mixed powder of Erigeron breviscapus obtained was 162g.

Embodiment 2: preparation of crude drug extract

Take 2000g Erigeron breviscapine and add 50% ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to obtain extract (relative density 1.15-1.25, 75°C); add 5 times the amount of extract Dissolve in water, add 5% sodium hydroxide solution under stirring, adjust pH 7.5-8.5, filter, add 10% sulfuric acid solution to adjust pH 1-3, leave overnight, filter, collect filtrate and precipitate, precipitate ethanol refining, reduce Press and dry to obtain powder 1; adjust the pH value of the acidified filtrate to 7-9, and clarify it with a 100nm ceramic membrane. (diameter to length ratio 1:4), after elution of 3 column volumes with water, 4 column volumes were eluted with 65% ethanol, the ethanol eluate was collected, concentrated and dried under reduced pressure to obtain powder 2; powder 1 and powder 2. Mix in proportion to obtain a 1:4 mixture of scutellarin powder and caffeic acid ester powder, and obtain the raw material composition component of the pharmaceutical composition of the present invention. Wherein powder 1 contains scutellarin 35.7%, totally 5.6g. Powder 2 contains 21.5% dicaffeate, 31.4g in total, and 9.1g monocaffeate. Among them, the simple substituted dicaffeic acid ester was 18.5g, and the dicaffeoyloctulonic acid was 12.9g. The total mixed powder of Erigeron breviscapus obtained was 161.7g.

Embodiment 3: preparation of crude drug extract

Take 3000g of Erigeron breviscapine and add 60% ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to obtain extract (relative density 1.15-1.25, 75°C); add 5 times the amount of extract Dissolve in water, add 5% sodium hydroxide solution under stirring, adjust pH 7-9, filter, add 10% hydrochloric acid solution to adjust pH 1-3, leave overnight, filter, collect filtrate and precipitate, precipitate ethanol for refining, add Adjust the pH value to 7-8 with 5% sodium hydroxide, and spray-dry to obtain powder 1;

The acidified filtrate is adjusted to a pH value of 7-9, clarified with a 200nm ceramic membrane, and the clarified solution obtained after clarification is concentrated with a 400D organic membrane, and the concentrated solution passes through a 30-60 mesh polyamide chromatography column (diameter to length ratio of 1 :4), after elution with water of 3 column volumes, elution with 70% ethanol of 3 column volumes, collecting the ethanol eluent, concentrating and adjusting the pH value to 7～9 and spray drying to obtain powder 2; to obtain powder 1 is about 18.7g, and powder 2 is about 208.3g. Mix powder 1 and powder 2 in proportion to obtain a 1:3 mixture of scutellarin sodium salt powder and caffeic acid ester sodium salt powder, and obtain the pharmaceutical composition of the present invention. API Composition Components.

Wherein powder 1 contains scutellarin sodium salt 45% in total 8.4g. Powder 2 contains 18.6% of dicaffeate salt, a total of 38.7g, and 7.3g of monocaffeate salt. Among them, the simple substituted dicaffeate salt was 18.3g, and the dicaffeoyloctulone salt was 20.4g.

Embodiment 4: preparation of crude drug extract

Take 3000g of Erigeron breviscapine and add 65% ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to obtain extract (relative density 1.15-1.25, 75°C); add 5 times the amount of extract Dissolve in water, add 5% sodium hydroxide solution under stirring, adjust pH 7-9, filter, add 10% hydrochloric acid solution to adjust pH 1-3, leave overnight, filter, collect filtrate and precipitate, precipitate ethanol refining, reduce Press to get powder 1; the acidified filtrate is adjusted to a pH value of 7 to 9, clarified with a 200nm ceramic membrane, and the clarified liquid obtained after clarification is concentrated with a 400D organic membrane, and the concentrated solution passes through a 30-60 mesh polyamide chromatography column ( The ratio of diameter to length is 1:4), after elution with 3 column volumes of water, then elution with 3 column volumes of 70% ethanol, collecting the ethanol eluate, concentrating, adjusting the pH value to 7-9 and spray drying to obtain Powder 2: obtain about 25.3g of powder 1 and about 223g of powder 2, mix powder 1 and powder 2 in proportion to obtain a mixture of breviscapine and dicaffeate sodium salt powder 1:3.5, and obtain the medicinal combination of the present invention The ingredients of the drug substance composition.

Wherein powder 1 contains scutellarin 32%, totally 8.1g. Powder 2 contains 12.7% of dicaffeate salt, a total of 28.4g, and 7.3g of monocaffeate salt. Among them, the simple substituted dicaffeoate salt was 13.4g, and the dicaffeoyloctulone salt was 15g.

Embodiment 5: preparation of crude drug extract

Take 2500g of Erigeron breviscapine and add 75% concentration of ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to obtain extract (relative density 1.15-1.25, 75°C); add 5 times the amount of extract Dissolve in water, add 5% sodium hydroxide solution under stirring, adjust pH 7.5-9.0, filter, add 10% sulfuric acid solution to adjust pH 1-3, leave overnight, filter, collect filtrate and precipitate, precipitate ethanol for refining, add Adjust the pH value to 7-8 with 5% sodium hydroxide, and spray-dry to obtain powder 1;

The acidified filtrate is adjusted to a pH value of 7 to 9, clarified with a 100nm ceramic membrane, and the clarified liquid obtained after clarification is concentrated with a 300D organic membrane, and the concentrated solution is passed through a 30-60 mesh polyamide chromatography column (diameter and length ratio 1: 4), eluted with 3.5 column volumes of water, then eluted with 3 column volumes of 75% ethanol, collected the ethanol eluate, concentrated and adjusted the pH value to 7-9 to obtain powder 2; obtained 13.5g of Powder 1 and 164g of powder 2 were mixed with the obtained breviscapine sodium salt powder and caffeic acid ester sodium salt powder at a ratio of 1:2 to obtain the raw material composition components of the pharmaceutical composition of the present invention. Wherein powder 1 contains scutellarin sodium salt 51%, 6.9g in total. Powder 2 contains 19.5% dicaffeate salt, 32.0 g in total, and 9.7 g monocaffeate salt. Among them, the simple substituted dicaffeate salt was 19.6g, and the dicaffeoyloctulone salt was 12.4g.

The inventor also used 10%, 30%, 40%, 45%, 50%, 55%, 60%, 75%, and 90% of different concentrations of ethanol to extract Erigeron breviscapine at the same time, and the other steps were the same as in Example 1 , after being acidified and concentrated through the membrane, the spray dry powder is obtained. Experiments have proved that 10-90% ethanol extraction can obtain the extract of the lampshade, but from the yield, the membrane passing rate, the impurity content, the bulk density and the uniformity of the powder, the industrial Indicators such as production cost are measured, and the extract obtained by more than 40% ethanol is relatively better than the ethanol extract below 40%, and the ethanol extract of 40-75% is obviously better and more suitable for the technology of the present invention, wherein the most preferably adopts 50% ethanol extract. % ethanol to extract Erigeron breviscapine.

Embodiment 6: The difference between the content of active ingredients in the inventive process and the existing process

Invention process: Take 2000g of Erigeron breviscapine and add 50% ethanol to decoct twice, each time for 2 hours, filter, combine the filtrate, concentrate under reduced pressure to form extract (relative density 1.15-1.25, 75°C); Dissolve 5 times the amount of water, add 5% sodium hydroxide solution under stirring, adjust the pH to 7.5-8.5, filter, add 10% sulfuric acid solution to adjust the pH to 1-3, leave it overnight, filter, collect the filtrate and precipitate, and precipitate ethanol After refining, add 5% sodium hydroxide to adjust the pH value to 7-8, spray dry to obtain powder 1; adjust the pH value of the acidified filtrate to 7-9, use 100nm ceramic membrane for clarification, and then use 350D The organic membrane is concentrated, and the concentrated solution is passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio 1:4), and after elution of 3 column volumes with water, 4 column volumes are eluted with 65% ethanol, and the ethanol wash is collected. Deliquoring, concentrating, adjusting the pH value to 7-9 and spray-drying to obtain powder 2; mixing 15g of powder 1 and 147g of powder 2 to obtain scutellarin sodium salt powder and caffeic acid ester sodium salt powder.

Existing process: Take 2000g of Erigeron breviscapine, extract twice with 80% ethanol under reflux, the first time is 1.5 hours, the second time is 1 hour, combine the extracts, add about 640g of activated carbon, boil, filter, and concentrate the filtrate under reduced pressure to Thick paste, add appropriate amount of starch, dry under reduced pressure, crush, and sieve. The extract powder of breviscapine was obtained.

Take the weight of the total mixed powder as the denominator, and the weight of each type of ingredient as the numerator to calculate the content Table 18

Table 18. Comparison of each component between the existing technology and the inventive technology

Scutellarin is an extract specified in the Pharmacopoeia, and its main components are scutellarin and other substances, such as scutellarin, apigenin, scutellarein, etc., but the content is expressed as scutellarin.

In view of the high content of the above-mentioned effective substances, the proportion of the experimental group is based on the test results, using powder 1 and powder 2 for deployment.

Embodiment 5: the preparation of capsule

Take 162g of the extraction mixture prepared in Example 1, add 18g of starch, mix well, fill in capsules, and obtain final product.

Embodiment 6: the preparation of capsule

Take 151 g of the extraction mixture prepared in Example 2, add 29 g of starch, mix well, fill in capsules, and obtain.

Embodiment 7: the preparation of capsule

Take 142g of the extraction mixture prepared in Example 1, add 34g of starch and 4g of magnesium stearate, mix well, fill in capsules, and obtain.

Embodiment 8: the preparation of tablet

Take 151 g of the extraction mixture prepared in Example 2, 100 g of starch, and 10 g of dextrin, granulate through a 14-mesh sieve, ventilate and dry at 60-70° C., and add 3 g of magnesium stearate. Compressed into tablets and coated.

Embodiment 9: the preparation of dropping pill

Take 15g of the extraction mixture prepared in Example 3, put in 45g, polyethylene glycol 4000, mix evenly, melt, drop into low-temperature liquid paraffin, select pellets, and remove the liquid paraffin to obtain final product.

Embodiment 10: the preparation of oral liquid

Take 20g of the extraction mixture prepared in Example 1, mix it with 300g of honey, 50g of sucrose, 2g of sodium benzoate and 300ml of distilled water, heat to dissolve, heat-preserve and filter, to obtain.

Embodiment 11: the preparation of granule

Take 9 g of the extraction mixture prepared in Example 3, mix it with 40 g of microcrystalline cellulose, add 3% povidone ethanol solution to make a soft material, pass through a 18-mesh sieve to make granules, dry at 600 ° C for 30 to 45 minutes, granulate, add 4g of talcum powder, mixed evenly, granulated, packed into bags, and ready to use.

Embodiment 12: the preparation of soft capsule

Take 120 g of the extraction mixture prepared in Example 3, add 5% glycerin, 1% glycine, add 400 to 400 g of polyethylene glycol, mix well, and press into 1000 soft capsules.

Claims (8)

1. An oral preparation containing erigeron breviscapus extract is characterized by comprising caffeic acid ester salt, breviscapine salt and pharmaceutically acceptable auxiliary materials, wherein the caffeic acid ester salt comprises dicaffeonate salt and monocffeonate salt, the weight ratio of the dicaffeonate salt to the breviscapine salt is 3:1-4.5, the weight ratio of the monocffeonate salt to the dicaffeonate salt is 1.2-1; the oral preparation is prepared by the following method:

extracting herba Erigerontis with 50-75% aqueous ethanol, and concentrating the extractive solution under reduced pressure to obtain extract; dissolving the extract in water, adjusting pH to 7-9, filtering, adjusting pH to 1-3 with acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with water and ethanol, adjusting pH to 7-8 with alkali, and spray drying to obtain breviscapine salt; adjusting the pH value of the acidified filtrate to 7-9, clarifying with a ceramic microfiltration membrane, concentrating the clarified liquid obtained after clarification with an organic nanofiltration membrane, passing the concentrated liquid through a polyamide chromatographic column, eluting with water, eluting with 50-80% ethanol, collecting ethanol eluate, adjusting the pH value to 7-9 after concentration, filtering, and spray-drying the filtrate to obtain caffeic acid ester salt; the weight ratio of the dicaffeonate to the breviscapine salt is 3:1-4.5, the weight ratio of the monocffeonate to the dicaffeonate is 1:1.2-1: 6.2, the erigeron breviscapus oral preparation is obtained, and proper auxiliary materials are added, so that the erigeron breviscapus oral preparation can be prepared into tablets, capsules, dripping pills, granules and oral liquid preparations.

2. The oral formulation of claim 1, wherein the dicaffeonate salt comprises 1,3-O-dicaffeoylquinate, 3,4-O-dicaffeoylquinate, 3,5-O-dicaffeoylquinate, 4,5-O-dicaffeoylquinate, erigeron ester salt; the monocaffeate salt includes 3-O-caffeoylquinic acid salt, 4-O-caffeoylquinic acid salt, 5-O-caffeoylquinic acid salt, and breviscapine salt.

3. The oral preparation according to claim 2, wherein the dicaffeonate salt is 1,3-O-dicaffeoylquininate, 3,4-O-dicaffeoylquininate, 3,5-O-dicaffeoylquininate, 4,5-O-dicaffeoylquininate, or simply substituted dicaffeoylate salt; the erigeron ester ethyl salt and the erigeron breviscapus ester salt are isomers, and are called dicaffeoyloctacosonate, wherein the ratio of the simple substituted dicaffeoyloctacosonate to the dicaffeoyloctacosonate is 2:1-0.9.

4. The oral preparation according to any one of claims 1 to 3, which is a hard capsule, a soft capsule, a tablet, a granule, an oral liquid, a drop pill, a water-paste pill, a powder, a pill.

5. A method for preparing an oral formulation according to claim 1, wherein: extracting herba Erigerontis with 50-75% aqueous ethanol, and concentrating the extractive solution under reduced pressure to obtain extract; dissolving the extract in water, adjusting pH to 7-9, filtering, adjusting pH to 1-3 with acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with water and ethanol, adjusting pH to 7-8 with alkali, and spray drying to obtain breviscapine salt; adjusting the pH value of the acidified filtrate to 7-9, clarifying with a ceramic microfiltration membrane, concentrating a clarified solution obtained after clarification with an organic nanofiltration membrane, passing the concentrated solution through a polyamide chromatographic column, eluting with water, eluting with 50-80% ethanol, collecting an ethanol eluent, adjusting the pH value to 7-9 after concentration, filtering, and spray-drying the filtrate to obtain caffeic acid ester salt; the weight ratio of the dicaffeonate to the breviscapine salt is 3:1-4.5, the weight ratio of the monocffeonate to the dicaffeonate is 1:1.2-1: 6.2, the erigeron breviscapus oral preparation is obtained, and proper auxiliary materials are added, so that the erigeron breviscapus oral preparation can be prepared into tablets, capsules, dripping pills, granules and oral liquid preparations.

6. The method of claim 5, wherein: the pH value of the alkali adjusting solution is NaOH or Na ₂ CO ₃ ,NaHCO ₃ ,KOH,K ₂ CO ₃ Or KHCO ₃ Or other alkali solutions useful for adjusting pH; the pH value of the acid adjusting solution is HCl and H ₂ SO ₄ Or H ₃ PO ₄ Or other acid solutions that may be used to adjust the pH.

7. The use of the oral formulation of claim 1 in the preparation of a medicament for the treatment of non-alcoholic fatty liver disease and cardiovascular and cerebrovascular diseases.

8. The use of the oral formulation of claim 1 for the preparation of a medicament for inhibiting or treating platelet aggregation and coagulation disorders associated with metabolic disorders.

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