A medicine for preventing and treating fatty liver and a preparation method thereof

Abstract

The application discloses a kind of prevention and cure medicine of fatty liver and preparation method thereof, and medicine includes effective component: Sanqi 0.1-100 parts;Artificial ox gall 0.1-100 parts;Radix Bupleuri 0.1-100 parts;Shaddock 0.1-100 parts;Danshen 0.1-100 parts and Yujin 0.1-100 parts;Preparation method includes initial preparation step: take the following weight parts of effective component: Radix Bupleuri 1-8 parts;Shaddock 1-6 parts;Danshen 1-8 parts;Yujin 1-8 parts;White Peony Root 1-8 parts;Buddha's hand 1-6 parts;Plumeria 1-5 parts;Yuzhu 1-10 parts;Lotus leaf 1-8 parts;Turmeric 1-5 parts;Alisma 1-8 parts;Yinchen 1-10 parts;Tianji Huang 1-10 parts and Licorice 1-4 parts;Water is soaked, decoct, filter and combine filtrate, and is concentrated into thick paste;Mixing step: Sanqi is crushed into coarse powder, and thick paste is mixed uniformly, dried, and after being crushed, it is fully ground, sieved, mixed uniformly with artificial ox gall, and obtained;Medicine is the treatment criterion with soothing liver and relieving depression, regulating qi and reducing phlegm, removing stasis and reducing turbidity, and dosage combination conforms to oral mode and is easily absorbed by human body.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of prevention and cure medicine of fatty liver and preparation method thereof, belong to the technical field of medicine. BACKGROUND

[0002] As a common disease, fatty liver has a certain morbidity in China, and there are new cases every year. The modern medical prevention and treatment scheme of fatty liver mainly includes changing unhealthy lifestyle, controlling metabolic syndrome and protecting liver, but there is still a lack of specific drugs for treating fatty liver. In terms of preparation technology: traditional treatment of fatty liver Chinese medicine compound is mainly based on TCM doctor's decoction prescription, which has the defects of long decoction time, inconvenient to take, poor taste, long medication time and high treatment cost. SUMMARY

[0003] In order to overcome the shortcomings of the prior art, the first object of the present application is to provide a kind of prevention and cure medicine of fatty liver, which is a compound traditional Chinese medicine formula, and the treatment criteria are soothing liver and relieving depression, regulating qi and resolving phlegm, removing blood stasis and reducing turbidity. The dosage combination conforms to the oral mode and is easily absorbed by the human body.

[0004] The second object of the present application is to provide a preparation method of the above-mentioned prevention and cure medicine of fatty liver, which is prepared by the method. The prepared medicine is convenient to carry, has good taste and is convenient to take.

[0005] The first object of the present application can be achieved by adopting the following technical scheme: a kind of prevention and cure medicine of fatty liver, characterized in that it comprises the following effective components by weight: Sanqi 0.1-100 parts; artificial ox gall 0.1-100 parts; Radix Bupleuri 0.1-100 parts; Fructus Aurantii 0.1-100 parts; Salvia miltiorrhiza 0.1-100 parts and Radix Curcumae 0.1-100 parts.

[0006] Further, the prevention and cure medicine of fatty liver further comprises: Radix Paeoniae Alba 0.1-100 parts; Bergamot 0.1-100 parts; Plumeria 0.1-100 parts; Semen Trichosanthis 0.1-100 parts; Lotus leaf 0.1-100 parts; Curcuma 0.1-100 parts; Alisma 0.1-100 parts; Yin Chen 0.1-100 parts; Gynura 0.1-100 parts and Licorice 0.1-100 parts.

[0007] Further, the prevention and cure medicine of fatty liver comprises: Sanqi 1-6 parts; artificial ox gall 0.5-2 parts; Radix Bupleuri 1-8 parts; Fructus Aurantii 1-6 parts; Salvia miltiorrhiza 1-8 parts; Radix Curcumae 1-8 parts; Radix Paeoniae Alba 1-8 parts; Bergamot 1-6 parts; Plumeria 1-5 parts; Semen Trichosanthis 1-10 parts; Lotus leaf 1-8 parts; Curcuma 1-5 parts; Alisma 1-8 parts; Yin Chen 1-10 parts; Gynura 1-10 parts and Licorice 1-4 parts.

[0008] Further, the fat liver prevention and treatment medicine comprises 4.5 parts of Sanqi, 1 part of artificial ox gall, 6 parts of Chaihu, 4.5 parts of Jisheng, 6 parts of Danshen, 6 parts of Yujin, 6 parts of Baishao, 4.5 parts of Foshou, 3 parts of Suxinghua, 8 parts of Bieqie, 6 parts of Heye, 3 parts of Jianghuang, 6 parts of Zexie, 8 parts of Yincheng, 8 parts of Tianjihuang and 2.5 parts of Gancao.

[0009] The second object of the present application can be achieved by adopting the following technical solution: a preparation method of a fat liver prevention and treatment medicine,

[0010] The initial preparation step is to take the following weight parts of effective components: 1-8 parts of Chaihu, 1-6 parts of Jisheng, 1-8 parts of Danshen, 1-8 parts of Yujin, 1-8 parts of Baishao, 1-6 parts of Foshou, 1-5 parts of Suxinghua, 1-10 parts of Bieqie, 1-8 parts of Heye, 1-5 parts of Jianghuang, 1-8 parts of Zexie, 1-10 parts of Yincheng, 1-10 parts of Tianjihuang and 1-4 parts of Gancao, soak them in water, decoct, filter and combine the filtrates, and concentrate into thick paste.

[0011] The mixing step is to crush 1-6 parts of Sanqi into coarse powder, mix the coarse powder with the thick paste, dry, and then grind, sieve and mix the powder with 0.5-2 parts of artificial ox gall, to obtain the fat liver prevention and treatment medicine.

[0012] Further, in the initial preparation step, the soaking in water is performed twice, the first time is to add 10-12 times of the total solid mass of water, soak for 30-40 minutes, decoct for 2 hours, filter to obtain the filtrate; the second time is to add 8-10 times of the total solid mass of water, decoct for 2 hours, filter to obtain the filtrate; combine the two filtrates, and concentrate into thick paste.

[0013] Further, in the initial preparation step, the concentration into thick paste is performed under the conditions of 70-90℃, vacuum degree of-0.06MPa and steam pressure of less than 0.1MPa.

[0014] Further, the preparation method further comprises a pill making step: the medicine powder obtained after the mixing step is added with a solvent to make medicine pills, the medicine pills are dried under the condition of 70-90℃, the medicine powder is mixed with black oxidized iron as coating powder, and the water solution of ethanol and refined honey is used as adhesive, to coat the medicine pills, to obtain the fat liver prevention and treatment medicine.

[0015] Further, the medicine powder is mixed with black oxidized iron as coating powder, with the mass ratio of 0.5-3:0.1.

[0016] Further, the diameter of the medicine pills after coating is 3-4.2mm.

[0017] Compared with the prior art, the present application has the following beneficial effects:

[0018] 1. The prevention and treatment medicine for fatty liver of the present application is a compound traditional Chinese medicine formula, which takes relieving liver stagnation, regulating qi and reducing phlegm, and removing blood stasis and reducing turbidity as the treatment criteria, and the dosage is combined in compliance with the oral mode to be easily absorbed by human body; the main pathogenesis of fatty liver is considered in the theory of traditional Chinese medicine as improper diet, qi stagnation, wet accumulation into phlegm, and phlegm and blood stasis mutual knotting;

[0019] 2. The preparation method of the prevention and treatment medicine for fatty liver of the present application changes the original decoction into pills, which overcomes the shortcomings of poor taste and difficulty for patients to insist on taking medicine for a long time of the artificial bezoar in the formula, has the advantages of definite curative effect, no toxicity, no obvious side effects, convenient carrying, good taste, convenient taking, and reduction of overall treatment cost;

[0020] 3. Since the product is a medicine for treating fatty liver, it needs to be taken for a long time, and traditional dosage forms of pills and pills are usually used in the treatment of chronic diseases in traditional Chinese medicine, therefore, the present preparation adopts the traditional Chinese medicine dosage form of pills as the dosage form of the medicine; the dosage form has the advantages of simple and easy preparation process, suitability for medical institution preparation, easy dissolution, taking, carrying, and transportation, and is suitable for long-term taking. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The process flow chart for the preparation method;

[0022] Figure 2 The liver cells of normal (negative) control group rats;

[0023] Figure 3 The liver cells of model group rats;

[0024] Figure 4 The liver cells of low-dose group rats in Example 1;

[0025] Figure 5 The liver cells of medium-dose group rats in Example 1;

[0026] Figure 6 The liver cells of high-dose group rats in Example 1;

[0027] Figure 7 The liver cells of positive control group rats;

[0028] Figure 8 The effect curve diagram. DETAILED DESCRIPTION

[0029] The present application will be further described below in combination with the drawings and specific embodiments:

[0030] Prepare the ingredients by weight parts: 1-6 parts of Sanqi; 0.5-2 parts of artificial ox gall; 1-8 parts of Bupleurum; 1-6 parts of Shaddock; 1-8 parts of Salvia; 1-8 parts of White Peony Root; 1-6 parts of Bergamot; 1-5 parts of Gardenia; 1-10 parts of Turmeric; 1-8 parts of Alisma; 1-10 parts of Yin Chen; 1-10 parts of Tianji Huang and 1-4 parts of Licorice.

[0031] Primary preparation step: Bupleurum, Licorice, White Peony Root, Shaddock, Turmeric, Alisma, Bergamot, Gardenia, Salvia, Yin Chen, Tianji Huang and artificial ox gall are soaked twice with water, the first time with 10-12 times the total solid mass, soaked for 30 minutes, filtered after 2 hours of boiling to obtain the filtrate; the second time with 8-10 times the total solid mass, filtered after 2 hours of boiling to obtain the filtrate; the filtrates of the two times are combined and concentrated into thick paste under the conditions of temperature 70-90℃, vacuum degree -0.06MPa, vapor pressure <0.1MPa;

[0032] Mixing step: Sanqi is crushed into coarse powder, mixed with the thick paste, dried, and then fully ground, sieved and mixed with artificial ox gall to obtain the medicine powder;

[0033] Pellet preparation step: the medicine powder is added with solvent (water or ethanol) to prepare medicine pellets, which are dried under the condition of 70-90℃, coated with black iron oxide as coating powder at a mass ratio of 0.5-3:0.1, and coated with an aqueous solution of ethanol and refined honey as adhesive, to obtain the medicine pellets with a diameter of 3-4.2mm, which are the prevention and treatment medicine for fatty liver. The process flow is shown in Figure 1 .

[0034] In addition to the pellets, decoction, tablets, capsules, granules, oral liquid and other dosage forms can also be used as the medicine.

[0035] The monarch drug in the medicine is ox gall and Sanqi, which is heart and liver meridian, has the effects of clearing heat and resolving toxins, and opening the orifices, and is combined with Sanqi to activate blood and resolve stasis, which is an excellent combination for resolving phlegm and removing stasis. Modern pharmacological research: natural ox gall, in vitro cultured ox gall and ursodeoxycholic acid can increase the secretion of bile acids, adjust the ratio of bile acids, effectively reduce the levels of serum bilirubin, total bile acid and cholesterol, and have improvement effect on liver cell and bile duct damage caused by various liver and gall diseases such as intrahepatic cholestasis of pregnancy and primary biliary cirrhosis. Ox gall and its derivatives (such as artificial ox gall and taurine) have protective effect on chemical liver injury (such as liver injury caused by carbon tetrachloride in mice) and non-alcoholic fatty liver. Panax notoginseng total saponins can significantly inhibit the expression of CYP2E1 in rats with fatty liver, reduce lipid peroxidation, and thus have the effect of preventing and treating fatty liver.

[0036] The ministerial medicine is used to smoothen the liver and regulate qi and activate blood with Radix Bupleuri, Fructus Aurantii, Radix Salviae Miltiorrhizae and Radix Anemarrhenae. Fatty liver patients often have right hypochondrium distending pain and discomfort, so the auxiliary medicine is used to smoothen the liver and regulate qi, soften the liver and relieve pain with Flos Jasmini, Fructus Citri Sarcodactylis and Radix Paeoniae Alba.

[0037] Curcuma longa, Folium Nelumbinis, Rhizoma Alismatis and Rhizoma Alpiniae Oxophyllae all have the effect of resolving turbidity and reducing fat, and have auxiliary effects on the treatment of fatty liver from the aspects of improving lipid metabolism, anti-inflammation, anti-oxidation, removing dampness and regulating glucose and lipid metabolism balance. The main active ingredient of Curcuma longa, curcumin, has strong anti-oxidation and anti-inflammation effects, and can effectively inhibit inflammatory reaction in the liver and reduce fatty degeneration and fibrosis process.

[0038] Radix et Rhizoma Hedysuri and Herba Artemisiae Scopariae have the effects of clearing heat and removing dampness, detoxifying and removing jaundice, and together reflect multiple effects of protecting liver, promoting bile secretion, anti-inflammation, antibiosis and anti-oxidation, and are used as auxiliary medicine.

[0039] Glycyrrhiza uralensis regulates all the medicines, and is the binder.

[0040] Example 1

[0041] Prepare the materials by mass: Panax notoginseng 180g, artificial ox gall 40g, Radix Bupleuri 240g, Glycyrrhiza uralensis 100g, Radix Paeoniae Alba 240g, Fructus Aurantii praeparatus 180g, Rhizoma Alismatis 360g, Radix Anemarrhenae 240g, Radix et Rhizoma Hedysuri 240g, Folium Nelumbinis 240g, Fructus Citri Sarcodactylis 180g, Curcuma longa 120g, Rhizoma Alpiniae Oxophyllae 240g, Radix Salviae Miltiorrhizae 240g, Herba Artemisiae Scopariae 360g and Radix et Rhizoma Hedysuri 360g.

[0042] Initial preparation step: Radix Bupleuri, Glycyrrhiza uralensis, Radix Paeoniae Alba, Fructus Aurantii, Rhizoma Alismatis, Radix Anemarrhenae, Folium Nelumbinis, Fructus Citri Sarcodactylis, Curcuma longa, Rhizoma Alpiniae Oxophyllae, Herba Artemisiae Scopariae, Radix et Rhizoma Hedysuri and Radix et Rhizoma Hedysuri are soaked with water twice, the first time with 10 times the total mass of solid, soaked for 30 minutes, and then filtered after 2 hours of boiling; the second time with 8 times the total mass of solid, and then filtered after 2 hours of boiling; the filtrates of the two times are combined, and concentrated into thick paste under the conditions of temperature 80℃, vacuum degree-0.06MPa and vapor pressure<0.1MPa;

[0043] Mixing step: Panax notoginseng is crushed into coarse powder, mixed with the thick paste, dried, and then ground, screened and mixed with artificial ox gall at a rotation speed of 10rpm for 30 minutes to obtain medicine powder.

[0044] Pill making step: the medicine powder is made into pills with 75% v / v ethanol as binder, dried at 80℃, and then coated with black oxidized iron powder as coating powder at a mass ratio of 3:0.1, and ethanol and honey solution as binder. After coating, the diameter of the prepared medicine pills is 3-4.2mm, and the fatty liver prevention and treatment medicine is obtained.

[0045] Table 1 Preparation process

[0046]

[0047]

[0048] 1 Experimental materials

[0049] 1.1 Experimental animals

[0050] SPF level male SD rats were 33, weighing 200±20g. Purchased from Guangzhou University of Chinese Medicine Experimental Animal Center.

[0051] 1.2 Experimental drugs and feed

[0052] 1.2.1 Experimental drugs

[0053] Example 1, the clinical adult dosage, 19g / time, 2 times / day.

[0054] Comparative example: Shui Feiji Capsules (abbreviation: Shui Lin Jia), Tianjin Tian Shi Li Shengte Pharmaceutical Co., Ltd. provided, specification is 35mg x 20 grains / box, the State Drug Standard number is H20040299. The clinical adult dosage is 2 grains / time, 3 times / day.

[0055] 1.2.2 Experimental feed

[0056] High-fat GD60 feed was purchased from Guangdong Medical Experimental Animal Center.

[0057] 1.3 Experimental reagents

[0058] Total cholesterol kit (TC), triglyceride kit (TG), free fatty acid kit (FFA), alanine aminotransferase kit (ALT), aspartate aminotransferase kit (AST), and γ-glutamyltransferase test kit (GGT) were purchased from Nanjing Jiancheng Biological Engineering Institute.

[0059] 2. Experimental method

[0060] 2.1 Establishment of rat model and grouping and administration

[0061] 33 SPF male SD rats were selected and randomly divided into normal control group (n=6) and experimental group (n=27). The normal control group was fed with ordinary feed, and the experimental group was fed with high-fat feed to construct a fatty liver rat model, and the modeling time lasted for 10 weeks. After 3 rats were randomly selected for pathological examination to confirm the success of modeling, the remaining 30 model rats were randomly divided into 6 groups (n=5). Group A: normal control group, normal saline gavage, 1 mL / 100 g / d; Group B: model group, normal saline gavage, 1 mL / 100 g / d; Group C: low-dose group of Example 1: 630 mg / kg / d; Group D: medium-dose group of Example 1: 1260 mg / kg / d; Group E: high-dose group of Example 1: 2520 mg / kg / d; Group F: positive control group of Shuifei Bini Capsule group: 22.05 mg / kg / d. From the 11th week, the experimental groups were changed to normal diet, and ordinary feed was fed. Continuous 4 weeks of gavage administration, once a day. At the end of the 14th week, all animals were anesthetized and sacrificed after fasting for 12 h, and serum and liver tissue were rapidly separated according to the conventional method.

[0062] 2.2 Detection items

[0063] After sampling, the indicators were detected:

[0064] a. Observe the general situation, take the liver tissue, and calculate the liver index.

[0065] b. Histopathological observation of liver tissue, evaluation of steatosis and inflammatory activity.

[0066] c. Serum biochemical determination: determination of serum ALT, AST, GGT, TG, TC, FFA expression levels before and after treatment.

[0067] 3 Results

[0068] 3.1 Example 1 can improve liver steatosis and reduce liver index

[0069] The liver cells (as shown in Figure 2 ) of the normal (negative) control group of rats were complete and clear in structure, and no pathological changes such as fatty degeneration and inflammatory infiltration were observed. The liver cells (as shown in Figure 3 ) of the model group of rats were destroyed, fatty degeneration appeared, accompanied by a small amount of inflammatory cell infiltration. The diffuse area of fatty degeneration and the degree of pathological changes of the liver cells (as shown in Figure 4-6 ) of the low, medium and high dose groups of Example 1 (as shown in Figure 7 ) and the positive control group were significantly reduced.

[0070] The liver index of the model group was significantly higher than that of the normal (negative) control group (P<0.001); after treatment with Example 1 and Shui Fei Ji capsules, the liver index was decreased, indicating that the intervention of Example 1 and the positive control drug Shui Fei Ji on fatty liver can effectively reduce the weight of the liver, and the low, medium and high dose groups were all decreased but the difference was not significant, indicating the effectiveness of Example 1 in reducing the weight of the liver, as shown in Table 2.

[0071] Table 2 Comparison of liver index of rats in each group n = 5

[0072] Group n Liver index (%) Normal control group 5 2.26±0.25 Model group 5 3.03 ± 0.10 ** ]] Low-dose Example 1 group 5 2.70 ± 0.06 # ]] Medium-dose Example 1 group 5 2.61 ± 0.05 ## ]] High-dose Example 1 group 5 2.51 ± 0.06 ## ]] Positive control group 5 2.58 ± 0.13 ## ]]

[0073] Note: compared with the control group, ***P<0.001; compared with the model group, #P<0.05, ##P<0.01.

[0074] 3.2 Example 1 improves liver function and reduces blood lipid level

[0075] Compared with the normal (negative) control group, the serum ALT, AST and GGT levels, TG, TC and FFA levels of the model group were significantly increased (P<0.001). After treatment with low, medium and high dose Example 1 groups and the positive control group, the serum ALT, AST and GGT levels, TG, TC and FFA levels were significantly decreased (P<0.001);

[0076] Compared with the low dose Example 1 group, the medium and high dose Example 1 groups had advantages in reducing all except ALT, among which the medium dose had a significant advantage in GGT (P<0.01) level, and the high dose had a significant advantage in reducing AST, TG, TC (P<0.01) and GGT (P<0.001) levels; compared with the medium dose Example 1 group, the high dose Example 1 group had an advantage in reducing GGT level (P<0.05) and a significant advantage in reducing TC level (P<0.01); Example 1 had a certain dose dependence;

[0077] Compared with the high dose Example 1 group, the positive control group had no advantage in reducing AST (P<0.01) and GGT (P<0.05) levels, and was equivalent to the Example 1 group in improving other indicators.

[0078] Table 3 Comparison of serum ALT, AST and GGT levels of rats in each group n = 5

[0079]

[0080] Note: compared with the control group, ***P<0.001; compared with the model group, ###P<0.001; compared with the low-dose Tian Niwan group, ΔP<0.05, ΔΔP<0.01, ΔΔΔP<0.001; compared with the medium-dose Tian Niwan group, P<0.05; compared with the high-dose Tian Niwan group, °P<0.05, °°P<0.01.

[0081] Table 4 Comparison of serum TG, TC and FFA levels of rats in each group n=5

[0082]

[0083]

[0084] Note: compared with the control group, ***P<0.001; compared with the model group, ###P<0.001; compared with the low-dose Tian Niwan group, ΔP<0.05, ΔΔP<0.01; compared with the medium-dose Tian Niwan group, P<0.05, P<0.01; compared with the high-dose Tian Niwan group, °P<0.05.

[0085] 4 Results

[0086] The above results show that Example 1 has the effect of treating fatty liver.

[0087] Example 2:

[0088] Process stability investigation

[0089] According to the preparation method of Example 1, three batches of production verification samples (20221101, 20221102, 20221103) were subjected to stability investigation according to the stability investigation scheme. The results show that the preparation method used is suitable for industrial production, the process is stable, and the product is qualified.

[0090] Table 5 Accelerated stability test report of Example 1 (batch number: 20221101)

[0091]

[0092] Table 6 Accelerated stability test report of Example 1 (batch number: 20221102)

[0093]

[0094]

[0095] Table 7 Accelerated stability test report of Example 1 (Batch No.: 20221103)

[0096]

[0097]

[0098] Example 3:

[0099] 1. Verification of the number of extractions selected in the initial preparation step of the preparation method:

[0100] Take the prescribed amount of 14 herbs including Bupleurum chinense, Radix Trichosanthis, etc. (except Panax notoginseng and artificial bezoar), add 10 times the amount of water, extract for 2 hours, and determine the dry paste yield and paeoniflorin content of the first, second and third extractions.

[0101] Table 8 Selection test of extraction times

[0102]

[0103]

[0104] The test results show that, taking the dry paste yield as the evaluation index, the third extraction accounts for 9.6%; taking the paeoniflorin content as the evaluation index, the third extraction accounts for 6.91%, indicating that the two extractions have been basically complete, so the two-extraction process is adopted.

[0105] 2. Orthogonal test to optimize the extraction process:

[0106] a. The factor level settings of the orthogonal experiment are as follows:

[0107] Table 9 Orthogonal test factor level table

[0108]

[0109] b. Sample preparation: L9(3 4 ) Arrange the experiment according to the orthogonal table. Weigh an appropriate amount of medicinal materials according to the prescription ratio, extract according to the orthogonal table, filter through 200-mesh filter cloth, combine the two filtrates, concentrate under vacuum, and make the concentrate to 250 mL. Determine the dry paste yield and paeoniflorin content.

[0110] Table 10 Orthogonal test table of extraction conditions

[0111]

[0112]

[0113] c. Determination of dry cream yield:

[0114] Precisely pipette 10 mL of the concentrated solution into an evaporating dish which has been dried to a constant weight, weigh, evaporate to dryness in a water bath, place in an oven at 105°C for 3 hours, cool in a desiccator for 30 minutes, and weigh. Calculate the yield of dry extract, using the following formula:

[0115]

[0116] W is the weight of dry extract in 10 mL of the concentrated solution, V is the constant volume, and Wt is the weight of medicinal material.

[0117] d. Paeoniflorin content:

[0118] The chromatographic conditions and system suitability test were as follows: octadecylsilane-bonded silica gel as the filler; acetonitrile-0.1% formic acid (15:85) as the mobile phase; detection wavelength 230 nm; column temperature 30°C; flow rate 1.0 mL / min.

[0119] Preparation of the reference solution: accurately weigh an appropriate amount of paeoniflorin reference substance, add methanol / dilute ethanol to make a solution containing 40 μg per 1 mL, and obtain the solution.

[0120] Preparation of the test solution: finely grind about 1 g of the product, accurately weigh, place in a conical flask with a stopper, add 20 mL of methanol, weigh, ultrasonically treat for 30 minutes, cool, weigh, make up the weight loss with methanol, take the supernatant, pass through a 0.22 μm microporous filter membrane, and take the filtrate, and obtain the solution.

[0121] Determination: accurately pipette 10 μl of the reference solution and the test solution, respectively, into the liquid chromatograph, and determine, and obtain the results.

[0122] e. Visual analysis

[0123] Table 11 Analysis of orthogonal test results

[0124]

[0125] Comprehensive score = yield of dry extract (%) * 0.5 + paeoniflorin content % * 0.5.

[0126] f. Analysis of variance

[0127] Table 12 Analysis of variance table

[0128] Factor Sum of squares of deviation Degree of freedom F ratio F critical value Significance A (water amount) 2.018 2 26.553 19 * B (soaking time) 0.076 2 1 19 C (extraction time) 0.63 2 8.289 19 Error 0.08 2

[0129] F 0.1 (2,2) = 9.0, F 0.05 (2,2) = 19.0, F 0.01 (2,2) = 99.0

[0130] g. Effect curve diagram

[0131] AsFigure 8 The results are shown in Table 2.

[0132] h. Analysis of orthogonal test results:

[0133] The results of the orthogonal test are shown in Table 3. The primary and secondary factors are A (water amount) > C (extraction time) > B (soaking time) according to the range size in the direct analysis. The variance analysis results show that the factor A (water amount) has significant meaning, while the other two factors B (soaking time) and C (extraction time) have no significant influence. That is, the water amount is a significant influencing factor, while the soaking time and the extraction time are not significant influencing factors in the selected range, which can be adjusted according to the actual situation. From the effect curve graph, it can be seen that with the increase of the water amount, the dry extract yield and the paeoniflorin content increase continuously, and when the water amount exceeds 10 times, the dry extract yield and the paeoniflorin content increase slowly. The water amount factor is a significant influencing factor, and the water amount is re-optimized. From the effect curve graph, it can be seen that with the increase of the soaking time, the dry extract yield and the paeoniflorin content increase slowly, and there is no significant difference. However, the present prescription contains lotus leaf and radix scutellariae, which are easy to float on the water surface. Soaking for half an hour can make the medicinal materials fully infiltrate, which is beneficial to improve the extraction efficiency. Therefore, the soaking time is determined to be 0.5 hours. From the effect curve graph, it can be seen that with the increase of the extraction time, the dry extract yield and the paeoniflorin content increase slowly, but the extraction time factor has no significant influence. Considering the actual production, the extraction efficiency and the need to save costs, the extraction time is determined to be 2 hours.

[0134] i. Preferred optimal industrial extraction route

[0135] According to the process optimized by the orthogonal experiment, the optimal extraction conditions are that the medicinal materials are soaked for 0.5 hours, and the extraction time is 2 hours each time. The water extraction amount needs to be compared and tested, so the following three routes are designed for comparison.

[0136] Preparation of test sample: The medicinal materials are weighed according to the prescription amount ratio, extracted according to different extraction conditions, filtered with 200 mesh filter cloth, the filtrates are combined, vacuum reduced pressure concentrated, and the concentrated solution is diluted to 250 mL for standby. The dry extract yield and the paeoniflorin content are determined.

[0137] Table 13 Results of process optimization test

[0138]

[0139] Conclusion: Process one is the best process optimized by orthogonal test, process two and process three are comparative processes designed by combining actual production situation and comprehensively considering energy saving and efficiency improvement. According to the results, there is no significant difference in the dry extract yield and paeoniflorin content obtained by the three processes. Therefore, according to the actual production experience, the water amount of the second time is adjusted, that is, the final process of the variety is as follows: after the prescription amount of 14 kinds of medicinal materials (except for notoginseng and artificial cow-bezoar) is washed with fast water, the medicinal materials are extracted twice, the water amount of the first time is 10 times of the medicinal material amount, the medicinal materials are soaked for half an hour, then boiled for 2 hours, the water amount of the second time is 8 times of the medicinal material amount, boiled for 2 hours, filtered through a 200 mesh sieve, and the filtrates are combined.

[0140] j. Verification of the optimal industrial extraction

[0141] Three batches of small-scale tests are conducted to verify the optimal industrial extraction route: after the prescription amount of 14 kinds of medicinal materials (except for notoginseng and artificial cow-bezoar) is washed with fast water, the medicinal materials are extracted twice, the water amount of the first time is 10 times of the medicinal material amount, the medicinal materials are soaked for half an hour, then boiled for 2 hours, the water amount of the second time is 8 times of the medicinal material amount, boiled for 2 hours, filtered through a 200 mesh sieve, and the filtrates are combined, vacuum reduced pressure concentrated, the concentrated liquid is made up to 250 mL in a volumetric flask, and the dry extract yield and paeoniflorin content are determined.

[0142] Table 14 Analysis of the results of small-scale test verification

[0143] Test Dry extract yield (%) Paeoniflorin content (%) Verification 1 25.80 2.14 Verification 2 25.45 2.07 Verification 3 25.45 2.08

[0144] Conclusion: There is no significant difference in the dry extract yield and paeoniflorin content obtained by the three batches of small-scale test verification, and the extraction process is stable and feasible.

[0145] 3 Concentration and drying process research

[0146] 3.1 Concentration process research

[0147] According to the properties of the medicinal material components in the prescription, in order to prevent the effective components from being damaged by heat for a long time, a reduced pressure concentration device is used for concentration, and the concentration temperature is ≤80℃. In order to determine the process parameters such as the relative density of thick paste and the dry solid content, combined with the 200L extraction tank in the laboratory, 4 times of the prescription amount is selected for scale-up trial of 3 batches, and it is preliminarily determined that the relative density of thick paste of the variety is in the range of 1.10-1.20 (60℃), the dry solid content is 41%-43%, and the paeoniflorin content of thick paste is 1.5%-1.8%.

[0148] Table 15 Laboratory pilot scale-up record

[0149]

[0150]

[0151] 3.2 Drying process research

[0152] Select hot air circulation oven for drying, with paeoniflorin content as evaluation index, combined with drying time and material appearance, the suitable drying temperature is optimized for drying.

[0153] Method: about 300 g thick paste was weighed and placed in a hot air drying oven (paving layer thickness 1 cm), the heating temperature was set at 70℃, 80℃, 90℃, 100℃, 110℃, respectively, and dried until the material moisture was ≤6.0%. Each sample was prepared in triplicate and placed in the upper, middle and lower layers of the oven. The drying time was recorded, the appearance of the dried paste was observed, the moisture and paeoniflorin content of the dried paste were measured, and the suitable drying temperature was optimized.

[0154] Table 16 Optimal results of thick paste drying temperature

[0155]

[0156]

[0157] The above results show that the appearance and paeoniflorin content of the dried paste powder are stable when the thick paste is dried at ≤80℃. With the increase of drying temperature, the paeoniflorin content decreases. When the drying temperature is 100-110℃, there may be differences in local temperature in the oven, resulting in different degrees of charring phenomenon and large content difference. Therefore, the drying temperature of the thick paste is determined to be ≤80℃.

[0158] 4 Preparation process research

[0159] 4.1 Basis for determining the preparation process

[0160] Water pills, as a traditional Chinese medicine preparation, have a relatively simple preparation process. We have two methods for producing water pills. One is the most traditional hand pan pill, which mainly uses a coating machine to flip and increase the size of the pill mold to prepare. The other is mechanical pill preparation, which involves preparing soft material, cutting after pressing, and then rolling. Both methods have their advantages. The first method has low requirements for equipment and drug powder, has a wide range of applications, but requires experienced personnel for operation. The second method produces uniform-sized pellets, but has strict requirements for equipment and drug powder adhesion, and has a narrow range of applications. Although mechanical pill preparation is efficient and easy to control the hygiene standard, its dissolution time limit and drug roundness are not as good as hand pan pill. In summary, Example 1 plans to use the hand pan pill preparation method.

[0161] 4.2 Investigation of powder fineness

[0162] The fineness of the powder affects the appearance of the water pill, and the particle size of the powder affects the viscosity of the powder, which determines the difficulty of the pan pill process. According to traditional experience, water pills generally use 80 mesh fine powder or 100 mesh finest powder. In this study, the difficulty of the pan pill process and the appearance of the finished product were used as indicators to select the appropriate mesh size of the drug. The results showed that 100 mesh drug powder was fine and easy to shape, and the pill surface was smooth.

[0163] Table 17 Investigation results of powder fineness

[0164]

[0165] 4.3 Investigation of the binder

[0166] The 100 mesh drug powder was poured into the pill-making cylinder, and glycerol, water, 50% ethanol, and 75% ethanol were added as binders. The pill mold was observed. After screening the qualified standard pill mold, it was poured into the pill-making cylinder, and the amount of drug powder and binder was increased until the wet pill size was 3.0-3.5 mm. The difficulty of the pan pill process and the appearance of the wet pill were used as indicators to select the appropriate binder. The results showed that using 75% ethanol as the binder for the pill mold, the pill mold did not form a cluster, the appearance was smooth, the pan pill was easy, and the wet pill was round and smooth.

[0167] Table 18 Investigation results of the binder

[0168]

[0169] 4.4 Investigation of the pill diameter

[0170] The 100 mesh drug powder was poured into the pill-making cylinder, and 75% ethanol was used as the binder. After screening the appropriate standard pill mold, it was poured into the pill-making cylinder, and the amount of drug powder and binder was increased until the wet pill size was 2.5-3.5 mm, 3.5-4.0 mm, and 4.0-4.5 mm. The wet pill was dried in a 80°C hot air drying box. The appearance of the dry pill and the dissolution time were used as indicators to select the appropriate pill diameter. The results showed that when the wet pill size was 4.0-4.5 mm, a small amount of irregular pill shape appeared after drying. When the wet pill size was 2.5-3.5 mm and 3.5-4.0 mm, the pill shape was round and uniform in size, and the dissolution time was qualified. Based on the experience of the pill mold, the smaller the pill diameter, the more the number of pill molds needed, and the more the material loss. Considering the saving of material, the wet pill size of the pill was initially determined to be 3.5-4.0 mm.

[0171] Table 19 Investigation results of the pill diameter

[0172] Wet pellet diameter Appearance Dissolution time (min) 2.5-3.5 mm Pellet round and uniform in size 9 3.5-4.0 mm Pellet round and uniform in size 13 4.0-4.5 mm Pellet slightly irregular in shape 16

[0173] 4.5 Investigation of wet pill drying method

[0174] Select 3.5-4.0 mm wet pills, 70°C, 80°C, 90°C hot air oven, with moisture, paeoniflorin content, and dissolution time as indicators, and optimize the best drying temperature of the wet pill.

[0175] Table 20 Investigation results of wet pill drying method

[0176] Drying temperature (°C) Drying duration (h) Moisture (%) Dissolution time (min) Paeoniflorin (%) Batch 70 21 6.20 15 2.86 80 16 4.95 15 2.83 90 8 5.95 15 2.47

[0177] The results show that the wet pill is dried at 70-90°C, and there is no significant difference in the dissolution time, and it meets the legal requirements of the dissolution time of the pill. The paeoniflorin content is stable when the wet pill is dried at ≤80°C, and the paeoniflorin content decreases slightly when the wet pill is dried at 90°C. Therefore, the drying temperature of the wet pill is set to ≤80°C.

[0178] 4.6 Investigation of coating process

[0179] According to our experience of pan-coating, there are two ways to collect pills after pan-coating, dry and wet. The pan-coated pills can be collected by dry or wet, and the non-coated pills are generally collected by wet, which makes the appearance color uniform. After small-scale trial, the pills collected by wet still have some pills with uneven color after drying, so the coating process is selected to improve the appearance of the pills. Therefore, the amount of raw powder and black iron oxide coating powder is optimized by taking the appearance of the coated pills as the indicator and using ethanol and honey solution as the adhesive. The results show that the coated pills are round, uniform in color, and smooth in appearance when 3% raw powder and 0.1% black iron oxide are used as coating powder.

[0180] Table 21 Investigation results of coating process

[0181]

[0182]

[0183] The results show that the coated pills appear to be raw powder color when only raw powder is used for coating, and the coating effect is not obvious. When the amount of raw powder increases from 1% to 3%, the coating effect is better and the color is more uniform. To ensure the coating effect, the amount of raw powder coating powder is determined to be 3%. When the amount of black iron oxide increases from 0.1% to 0.2%, the pill color becomes black, but it has no significant effect on the roundness of the pill. Therefore, from the perspective of reducing auxiliary materials, the amount of black iron oxide is determined to be 0.1%.

[0184] 5. Pilot study

[0185] Pilot unit: Guangzhou Baiyunshan Zhongyi Pharmaceutical Co., Ltd.

[0186] Pilot plant site: No. 4, Entrepreneurship Avenue, Mingzhu Industrial Park, Conghua District, Guangzhou (pre-treatment), No. 32, Yunpu Road 1, Huangpu District, Guangzhou (preparation).

[0187] GMP certification scope of enterprise: bolus (water-moon pill, water pill, honey pill, concentrated pill, paste pill), tablet, hard capsule, granule, powder, mixture, traditional Chinese medicine pre-treatment workshop, shared traditional Chinese medicine pre-treatment and extraction workshop.

[0188] The pilot test is based on the laboratory test, combined with the minimum capacity of the pilot production enterprise equipment, and 125 times the prescription amount is selected for production, and three batches of pilot scale production (20221101, 20221102, 20221103) are carried out according to the same process flow. The relevant data results are as follows:

[0189] 5.1 Drug extraction and concentration process trial production:

[0190] Table 22 Summary of drug extraction and concentration process trial production

[0191]

[0192] Note: Concentration uses double-effect circulating vacuum concentrator

[0193] 5.2 Mixing and drying process trial production:

[0194] Table 23 Summary of mixing and drying process trial production

[0195]

[0196] 5.3 Dry paste crushing process trial production:

[0197] Table 24 Crushing process trial production summary

[0198]

[0199] 5.4 Drug powder mixing process trial production

[0200] Table 25 Drug powder mixing process trial production summary

[0201]

[0202] 5.5 Pill making process trial production

[0203] Table 26 Pill making process trial production summary

[0204]

[0205] 5.6 Coating process trial production

[0206] Table 27 Coating process trial production summary

[0207]

[0208] 5.7 Formulation and yield summary

[0209] Table 28 Formulation and yield summary

[0210]

[0211] 5.8 Finished product test results

[0212] Table 29 Paeoniflorin content of three batches of pilot finished product

[0213] Paeoniflorin content (mg / g) Moisture (%) ​ 20221101 2.58 7.7 20221102 2.57 7.2 20221103 2.70 7.2

[0214] For those skilled in the art, other various corresponding changes and modifications can be made according to the technical solutions and concepts described above, and all these changes and modifications shall belong to the protection scope of the claims of the present application.

Claims

1. A drug for preventing and treating fatty liver, characterized in that The invention is prepared from the following raw materials in parts by weight: 1-6 parts of Panax notoginseng; 0.5-2 parts of artificial bezoar; 1-8 parts of bupleurum; 1-6 parts of fructus aurantii; 1-8 parts of salvia miltiorrhiza; 1-8 parts of turmeric; 1-8 parts of white peony root; 1-6 parts of bergamot; 1-5 parts of frangipani flower; 1-10 parts of radix polygoni multiflori; 1-8 parts of lotus leaf; 1-5 parts of turmeric; 1-8 parts of oriental water plantain; 1-10 parts of capillaris; 1-10 parts of rhizoma scutellariae and 1-4 parts of liquorice.

2. The drug for preventing and treating fatty liver according to claim 1, wherein The drug for preventing and treating fatty liver is prepared from the following raw materials in parts by weight: 4.5 parts of Panax notoginseng; Artificial bezoar 1 part; Bupleurum 6 parts; Fructus Aurantii 4.5 parts; Salvia miltiorrhiza 6 parts; Curcuma 6 parts; White peony root 6 parts; Citron 4.5 parts; 3 parts of Flos Frangipani; 8 parts of Herba Dioscoreae; 6 parts of Lotus Leaves; 3 parts of Curcuma; 6 parts of Rhizoma Alismatis; 8 parts of Herba Artemisiae Scopariae; 8 parts of Radix Achyranthis Bidentatae and 2.5 parts of Radix Glycyrrhizae.

3. A method for preparing a drug for preventing and treating fatty liver, characterized in that: include: Preliminary preparation steps: Take the following raw materials in parts by weight: 1-8 parts of Bupleurum root; 1-6 parts of Citrus aurantium; 1-8 parts of Salvia miltiorrhiza; 1-8 parts of Curcuma zedoariae; 1-8 parts of White Peony Root; 1-6 parts of Citron; 1-5 parts of Jasmine Flowers; 1-10 parts of Dipterocarpus radix; 1-8 parts of Lotus Leaf; 1-5 parts of Curcuma Longa; 1-8 parts of Alisma Orientalis; 1-10 parts of Artemisia Capillaris; 1-10 parts of Radix Achyranthis Bidentatae and 1-4 parts of Licorice, soak in water, decoct, filter and combine the filtrates, and concentrate into a thick paste; Mixing steps: grind 1-6 parts of Panax notoginseng into coarse powder, mix it with the thick paste, dry it, grind it with 0.5-2 parts of artificial bezoar, sieve it, and mix it evenly to obtain the product.

4. The method for preparing the drug for preventing and treating fatty liver according to claim 3, wherein: In the initial preparation step, water is added and soaked twice. The first time, the amount of water added is 10-12 times the total mass of the solid, and the mixture is soaked for 30-40 minutes. After boiling for 2 hours, the filtrate is filtered and taken. The second time, the amount of water added is 8-10 times the total mass of the solid, and after boiling for 2 hours, the filtrate is filtered and taken. The two filtrates are combined and concentrated into a thick paste.

5. The method for preparing the drug for preventing and treating fatty liver according to claim 3, wherein: In the primary preparation step, the mixture is concentrated into a thick paste under the conditions of a temperature of 70-90°C, a vacuum degree of -0.06MPa, and a steam pressure of <0.1MPa.

6. A method for preparing a medicinal pill for preventing and treating fatty liver, characterized in that: include: Preliminary preparation steps: Take the following raw materials in parts by weight: 1-8 parts of Bupleurum root; 1-6 parts of Citrus aurantium; 1-8 parts of Salvia miltiorrhiza; 1-8 parts of Curcuma zedoariae; 1-8 parts of White Peony Root; 1-6 parts of Citron; 1-5 parts of Jasmine Flowers; 1-10 parts of Dipterocarpus radix; 1-8 parts of Lotus Leaf; 1-5 parts of Curcuma Longa; 1-8 parts of Alisma Orientalis; 1-10 parts of Artemisia Capillaris; 1-10 parts of Radix Achyranthis Bidentatae and 1-4 parts of Licorice, soak in water, decoct, filter and combine the filtrates, and concentrate into a thick paste; Mixing step: crush 1-6 parts of Panax notoginseng into coarse powder, mix with the thick paste, dry, grind and sieve, and mix evenly with 0.5-2 parts of artificial bezoar after crushing; Pill making step: adding a solvent to the medicinal powder obtained after the mixing step to make pills, drying at 70-90° C., using a mixture of medicinal powder and black iron oxide as coating powder, and an aqueous solution of ethanol and refined honey as a binder to coat the pills, thereby obtaining medicinal pills for preventing and treating fatty liver.

7. The method for preparing the medicinal pill for preventing and treating fatty liver according to claim 6, characterized in that: The drug powder and black iron oxide are mixed in a mass ratio of 0.5-3:0.1 to form the coating powder.

8. The method for preparing the medicinal pill for preventing and treating fatty liver according to claim 6, characterized in that: The diameter of the coated pellets was 3-4.2 mm.

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