A pharmaceutical composition for treating cirrhotic ascites and a preparation method and application thereof

Abstract

The present application relates to the technical field of medicine, in particular to a kind of drug composition for treating cirrhosis ascites and its preparation method and application.The drug composition is composed of Radix Dipsaci, Radix Ilicis Rotundae, Peristrophe roxburghiana, Radix Potentillae Chinensis, Bidens pilosa and Eupatorium fortunei;The preparation method is to weigh Radix Dipsaci, Radix Ilicis Rotundae, Peristrophe roxburghiana, Radix Potentillae Chinensis, Bidens pilosa and Eupatorium fortunei according to the prescription amount, extract by heating with water;After water extraction, the residue is added with water and cellulase, and then extracted under certain conditions;After boiling, filter to obtain enzymatic extract;Combine the water extract and enzymatic extract, and concentrate to thick paste;Add appropriate amount of excipients to the thick paste for batching, and then prepare into corresponding dosage form to obtain the product.The drug has the effects of clearing heat and resolving toxins, soothing liver and gallbladder, dispelling wind and relieving pain, and is used for treating damp-heat jaundice, abdominal pain and diarrhea, etc.The drug composition is prepared into appropriate dosage form by modern pharmaceutical preparation technology, and the effect is more significant and faster.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a pharmaceutical composition for treating cirrhosis ascites and a preparation method and application thereof. BACKGROUND

[0002] Cirrhosis is a common chronic progressive liver disease in clinic, which is diffuse liver damage formed by one or more causes for a long time or repeated attacks. Its pathological characteristics are extensive liver cell repeated chronic degeneration and necrosis, regeneration nodule formation, followed by fibrous tissue proliferation and liver cell nodular regeneration, which destroys the normal liver lobule structure and changes the blood circulation pathway, causing the liver to deform, shrink, harden, and form nodular cirrhosis. The symptoms of compensated cirrhosis are relatively mild, often lack of characteristics, such as fatigue, loss of appetite, nausea and vomiting, indigestion, abdominal distension, right upper abdominal discomfort, and dull pain. When liver function is decompensated, loss of appetite, weight loss, fatigue, diarrhea, abdominal pain, abdominal distension, bleeding (including gum or nasal bleeding), skin and mucosa purpura, hematemesis and melena, and mental and neurological symptoms such as drowsiness, excitement, catalepsy, and coma may occur.

[0003] Ascites is one of the most common complications of decompensated cirrhosis, which usually has poor prognosis and seriously affects the quality of life of patients. If timely and effective intervention is not given, a large amount of ascites can lead to respiratory distress, acid-base disorder, hepatic encephalopathy, hepatorenal syndrome, and various complications, and even death in severe cases.

[0004] Currently, the routine treatment of cirrhosis ascites in Western medicine mainly adopts symptomatic supportive treatment such as liver protection, sodium restriction and diuresis, portal pressure reduction, albumin supplementation, and vasoactive drugs, which can achieve good short-term effect, but still has limitations such as poor long-term effect and obvious adverse reactions.

[0005] Traditional Chinese medicine believes that cirrhosis ascites belongs to the "distension" category in traditional Chinese medicine. Its etiology and pathogenesis are complex, so the clinical syndromes are varied, with virtual and actual intermingling and alternating cold and heat. The pathogenesis of this disease is considered by ancient physicians as the dysfunction of liver, spleen and kidney, and water accumulation and distension, so the treatment is mainly from liver, spleen and kidney.

[0006] Chuanjiaocang is the rhizome of Iris tectorum Maxim. of Iridaceae, also known as Iristectorum Maxim. It has the effects of eliminating accumulation, eliminating heat, and promoting defecation, and is used for treating food accumulation, ascites, and constipation.

[0007] Jiulongpan is the dried rhizome of Aspidistra tectorum Maxim. of Asparagaceae, which can be harvested all year round, removed from the mud and sand, and dried. It is slightly bitter and warm, and belongs to the liver, kidney and large intestine channels. It has the effects of activating blood and relieving pain, diuresis and relieving stranguria. It is used for treating contusions and injuries, abdominal distension and pain, and difficulty in urination.

[0008] Dried pericarp of Areca catehu L. is processed product of pericarp of Areca catehu L. in Palmaceae. It is pungent and warm in nature. It has the effects of activating qi, regulating middle energizer, removing water and reducing swelling. It is used for dampness and qi stagnation, abdominal distention, dyspepsia, edema, and so on.

[0009] Dichondra repens Forst. is dry whole grass of Dichondra repens Forst. in Convolvulaceae. It is bitter, pungent and cool in nature. It belongs to liver meridian. It has the effects of clearing heat and resolving toxin, promoting water and activating blood. It is used for jaundice, edema, stranguria, and so on.

[0010] Bidens pilosa L. is dry aboveground part of Bidens pilosa L. in Compositae. It is bitter and slightly cold in nature. It belongs to liver, lung and bladder meridians. It has the effects of promoting dampness and spleen, clearing heat and resolving toxin. It is used for jaundice, sore throat, cold and fever, and so on.

[0011] Halenia elliptica D.Don is dry whole grass of Halenia elliptica D.Don in Gentianaceae. It is bitter and cold in nature. It belongs to liver, gallbladder and lung meridians. It has the effects of clearing heat and resolving toxin, soothing liver and gallbladder, and relieving wind and pain. It is used for damp-heat jaundice, abdominal pain and diarrhea, and so on.

[0012] Therefore, the team of the present application develops a kind of drug composition for treating cirrhosis of liver ascites by long-term experiment repeatedly researching with traditional Chinese medicine as main component, the composition is composed of six medicinal materials such as earthy thunberg fritillary bulb, nine dragon disc, big belly skin, dichondra repens, bidens pilosa and halenia elliptica.The earthy thunberg fritillary bulb has the effects of eliminating accumulation, eliminating heat and promoting defecation, and is used for treating food accumulation and ascites, and is used as monarch drug when used in large amount;The nine dragon disc has the effects of activating blood and relieving pain, diuresis and stranguria, and the big belly skin has the effects of activating qi and regulating middle energizer, removing water and reducing swelling, and the two are co-used as ministerial drugs;The dichondra repens, bidens pilosa and halenia elliptica have the effects of clearing heat and resolving toxin, and are co-used as auxiliary drugs.The combination of the drugs has the effects of activating blood, regulating qi, promoting water and reducing swelling, and is used for treating cirrhosis of liver ascites.Under the guidance of traditional Chinese medicine theory, the team of the present application uses self-created traditional Chinese medicine composition decoction combined with conventional symptomatic treatment of western medicine to treat cirrhosis of liver ascites, and good curative effect is obtained.However, due to long course of cirrhosis of liver ascites, the self-created decoction of the present application has the inconvenience of decocting, carrying and storing in the long-term use process, therefore, the drug composition needs to be made into appropriate dosage form by modern pharmaceutical preparation technology, so that the treatment of cirrhosis of liver ascites has more significant curative effect, faster effect and more convenient use, and is convenient for patients to use and clinical popularization. SUMMARY

[0013] The present application aims at providing a kind of drug composition for treating cirrhosis of liver ascites;

[0014] Another object of the present application is to provide a kind of preparation method of drug composition for treating cirrhosis of liver ascites;

[0015] Another object of the present application is to provide the use of the pharmaceutical composition in the preparation of a medicament for treating cirrhotic ascites;

[0016] The pharmaceutical composition for treating cirrhotic ascites according to the present application is prepared from the following ingredients by weight: 10-15 parts of Radix Polygoni Multiflori, 10-15 parts of Radix Rubi Parvifolii, 6-10 parts of Pericarpium Citri Reticulatae Viride, 6-10 parts of Herba Hyperici Japonici, 4-8 parts of Herba Bidens Pilosa, and 4-8 parts of Herba Polygoni Orientalis.

[0017] Further, the pharmaceutical composition for treating cirrhotic ascites according to the present application is prepared from the following ingredients by weight: 12-15 parts of Radix Polygoni Multiflori, 12-15 parts of Radix Rubi Parvifolii, 8-10 parts of Pericarpium Citri Reticulatae Viride, 8-10 parts of Herba Hyperici Japonici, 6-8 parts of Herba Bidens Pilosa, and 6-8 parts of Herba Polygoni Orientalis.

[0018] Still further, the pharmaceutical composition for treating cirrhotic ascites according to the present application is prepared from the following ingredients by weight: 15 parts of Radix Polygoni Multiflori, 15 parts of Radix Rubi Parvifolii, 10 parts of Pericarpium Citri Reticulatae Viride, 10 parts of Herba Hyperici Japonici, 8 parts of Herba Bidens Pilosa, and 8 parts of Herba Polygoni Orientalis.

[0019] The preparation method of the pharmaceutical composition for treating cirrhotic ascites according to the present application comprises the following steps:

[0020] (1) Water extraction: the six medicinal materials of Radix Polygoni Multiflori, Radix Rubi Parvifolii, Pericarpium Citri Reticulatae Viride, Herba Hyperici Japonici, Herba Bidens Pilosa, and Herba Polygoni Orientalis are weighed according to the prescription amount, and 4-10 times the total amount of the medicinal materials of water is added, heated at 80-95℃ for 1-3 times of extraction, each time for 0.5-2h, filtered to obtain the water extract;

[0021] (2) Enzymatic extraction: the residue after water extraction is added with 8-12 times water, and 1.0-3.0% cellulase is added, and then soaked at 50℃ and PH 5.0 for 1-2h, boiled and filtered to obtain the enzymatic extract;

[0022] (3) Concentration: the water extract and the enzymatic extract are combined and concentrated to a thick paste;

[0023] (4) Forming into corresponding dosage forms: the thick paste is added with appropriate amount of excipients for compounding, and then formed into corresponding dosage forms to obtain the product.

[0024] Further, the preparation method of the pharmaceutical composition according to the present application comprises the following steps:

[0025] (1) Water extraction: the six medicinal materials of Radix Polygoni Multiflori, Radix Rubi Parvifolii, Pericarpium Citri Reticulatae Viride, Herba Hyperici Japonici, Herba Bidens Pilosa, and Herba Polygoni Orientalis are weighed according to the prescription amount, and 6 times the total amount of the medicinal materials of water is added, heated at 85℃ for 1 time of extraction for 0.5h, filtered to obtain the water extract;

[0026] (2) enzymatic extraction: add 10 times water to the residue after water extraction, add 1.0% cellulase, and extract at 50°C and pH 5.0 for 1.5h, then filter after boiling to obtain an enzymatic extraction solution;

[0027] (3) concentration: combine the water extraction solution and the enzymatic extraction solution, and concentrate to a thick paste;

[0028] (4) preparation of corresponding dosage forms: add appropriate amounts of excipients to the thick paste for compounding, and prepare corresponding dosage forms to obtain the product.

[0029] The excipient in the application is a pharmaceutically acceptable excipient.

[0030] The dosage form in the application is a solid preparation and a liquid preparation.

[0031] The solid preparation in the application is granules, capsules, tablets, and dripping pills.

[0032] The liquid preparation in the application is a mixture and a syrup.

[0033] The application of the pharmaceutical composition in the application in the preparation of a drug for treating cirrhosis ascites.

[0034] The application has the following beneficial effects:

[0035] 1. The product in the application has a significant treatment effect. The clinical efficacy test results show that the product prepared in the application has a total effective rate of 83.3% when combined with western medicine, which is significantly different from the total effective rate of 66.7% of the control group, indicating that the pharmaceutical composition prepared in the application can effectively improve the clinical symptoms of patients and improve the quality of life.

[0036] 2. The preparation method in the application has high extraction efficiency, low production cost, high safety, and a reasonable and feasible process. The extraction rate of total flavonoids in the prescription is used as an index for comparison. Through experiments, four different extraction processes, including water extraction, alcohol extraction, alcohol extraction and enzymatic extraction, and water extraction and enzymatic extraction, are compared. The results show that the extraction rate of total flavonoids is not high in water extraction and alcohol extraction alone, but the extraction rate of total flavonoids is significantly increased after enzymatic extraction of the residue. The extraction rate of total flavonoids is similar in water extraction and enzymatic extraction (53.6%) and alcohol extraction and enzymatic extraction (56.5%). Considering the lower production cost and higher safety of water extraction and enzymatic extraction, the preparation process in the application is determined to use water extraction and enzymatic extraction.

[0037] 3. The preparation method can enrich the effective components. The original use method of the prescription is the traditional water extraction method, that is, decocting with water. The extraction rate of the total flavonoids in the effective components in the prescription is only 21.2% by the method. The drug residue after water extraction is further extracted by the enzymatic method, so that the extraction rate of the total flavonoids is greatly increased to 62.3%, the effective components are enriched, and the product quality is improved and the efficiency is increased.

[0038] 4. The prepared product is convenient to use, safe and effective, and has few adverse reactions. After the pharmaceutical composition is prepared into a preparation (granules, oral liquid, etc.), compared with decoction, the patient is more convenient to take, carry and store.

[0039] 5. The prepared product has low cost, can reduce the economic burden of patients, and has wide market promotion value. The pharmaceutical composition has few medicinal materials, only 6 medicinal materials, and is cheap and easy to obtain. The prescription amount is small, and the preparation process is simple, so that the cost is very low, the economic burden of the patients using the product can be greatly reduced, and the product has wide market promotion and application value. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 : Liver cell images under light microscope of each group (among them, the N group is a control group; the M group is a model group; the G group is an experimental granule high-dose group; the Z group is an experimental granule medium-dose group; the D group is an experimental granule low-dose group; and the F group is a compound Biejia Ruangan tablet.) DETAILED DESCRIPTION

[0041] Example 1

[0042] Composition: Tuozhimu 15 g, Jiulongpan 15 g, Dafupiju 10 g, Matujin 10 g, Guizhencao 8 g, Hejiacai 8 g.

[0043] Example 2

[0044] Composition: Tuozhimu 10 g, Jiulongpan 10 g, Dafupiju 6 g, Matujin 6 g, Guizhencao 4 g, Hejiacai 4 g.

[0045] Example 3

[0046] Composition: Tuozhimu 15 g, Jiulongpan 15 g, Dafupiju 10 g, Matujin 10 g, Guizhencao 6 g, Hejiacai 6 g.

[0047] Example 4

[0048] Composition: Tuozhimu 10 g, Jiulongpan 10 g, Dafupiju 10 g, Matujin 10 g, Guizhencao 8 g, Hejiacai 8 g.

[0049] Example 5

[0050] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0051] Example 6

[0052] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0053] Example 7

[0054] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0055] Example 8

[0056] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0057] Example 9

[0058] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0059] Example 10

[0060] Composition: 15g of Radix Polygoni Multiflori, 10g of Radix Rubi, 8g of Pericarpium Citri Reticulatae Viride, 10g of Herba Hyperici, 6g of Herba Bidens, and 8g of Herba Rubi.

[0061] The pharmaceutical composition of Examples 1-10 is used in the following preparation method of Examples

[0062] Example 11

[0063] (1) Water extraction: according to the composition, Radix Polygoni Multiflori, Radix Rubi, Pericarpium Citri Reticulatae Viride, Herba Hyperici, Herba Bidens, and Herba Rubi are weighed, 6 times the total amount of water is added, heated at 85℃ for 1 time, extracted for 0.5h, filtered, and water extract is obtained;

[0064] (2) Enzymatic extraction: the water extracted residue is added with 10 times water, 1.0% cellulase is added, and extracted at 50℃, PH 5.0 for 1.5h, filtered after boiling, and enzyme extraction liquid is obtained;

[0065] (3) Concentration: water extraction liquid and enzyme extraction liquid are combined and concentrated to thick paste;

[0066] (4) Forming dosage form: appropriate amount of soluble starch is added to the thick paste, granulated, dried, and 30g granules are obtained, and granules are obtained.

[0067] Example 12

[0068] (1) Water extraction: six kinds of medicinal materials of Chuannuomu, Jiulongpan, Dafupiecong, Matujin, Guizhencao and Heijicao were weighed according to the prescription amount, and 4 times of water of the total amount of medicinal materials was added, and heated at 80℃ for 3 times of extraction, 0.5h of extraction, filtration, and water extraction liquid was obtained;

[0069] (2) Enzymatic extraction: the water-extracted residue was added with 8 times of water, and 1.0% of cellulase was added, and the mixture was extracted at 50℃ and PH 5.0 for 1h, and then filtered after boiling to obtain the enzymatic extraction liquid;

[0070] (3) Concentration: the water extraction liquid and the enzymatic extraction liquid were combined and concentrated to a thick paste;

[0071] (4) Preparation of dosage form: a suitable amount of soluble starch was added to the thick paste, granulated, dried, and 30g granules were prepared to obtain granules.

[0072] Example 13

[0073] (1) Water extraction: six kinds of medicinal materials of Chuannuomu, Jiulongpan, Dafupiecong, Matujin, Guizhencao and Heijicao were weighed according to the prescription amount, and 10 times of water of the total amount of medicinal materials was added, and heated at 95℃ for 1 time of extraction, 2h of extraction, filtration, and water extraction liquid was obtained;

[0074] (2) Enzymatic extraction: the water-extracted residue was added with 12 times of water, and 3.0% of cellulase was added, and the mixture was extracted at 50℃ and PH 5.0 for 2h, and then filtered after boiling to obtain the enzymatic extraction liquid;

[0075] (3) Concentration: the water extraction liquid and the enzymatic extraction liquid were combined and concentrated to a thick paste;

[0076] (4) Preparation of dosage form: a suitable amount of soluble starch was added to the thick paste, granulated, dried, and 30g granules were prepared to obtain granules.

[0077] Example 14

[0078] (1) Water extraction: six kinds of medicinal materials of Chuannuomu, Jiulongpan, Dafupiecong, Matujin, Guizhencao and Heijicao were weighed according to the prescription amount, and 8 times of water of the total amount of medicinal materials was added, and heated at 85℃ for 2 times of extraction, 1h of extraction, filtration, and water extraction liquid was obtained;

[0079] (2) Enzymatic extraction: the water-extracted residue was added with 10 times of water, and 2.0% of cellulase was added, and the mixture was extracted at 50℃ and PH 5.0 for 1.5h, and then filtered after boiling to obtain the enzymatic extraction liquid;

[0080] (3) Concentration: the water extraction liquid and the enzymatic extraction liquid were combined and concentrated to a thick paste;

[0081] (4) Preparation of corresponding dosage form: a suitable amount of refined honey was added to the thick paste, mixed, and 30g of paste was prepared.

[0082] Example 15

[0083] (1) Water extraction: six kinds of medicinal materials of Tujiaomu, Jiulongpan, Dafupi Rong, Matujin, Guizhencao and Heijiacao were weighed according to the prescription amount, 6 times of water was added, and the mixture was heated at 80℃ for 2 times, 1.5h each time, and then filtered to obtain water extract;

[0084] (2) Enzymatic extraction: the residue after water extraction was added with 8 times of water and 1.0% cellulase, and then the mixture was extracted at 50℃ and pH 5.0 for 1h, and then filtered after boiling to obtain enzymatic extract;

[0085] (3) Concentration: the water extract and the enzymatic extract were combined and concentrated to a thick paste;

[0086] (4) Preparation of corresponding dosage form: the thick paste was mixed with appropriate amount of refined honey to prepare 30g of paste.

[0087] Example 16

[0088] (1) Water extraction: six kinds of medicinal materials of Tujiaomu, Jiulongpan, Dafupi Rong, Matujin, Guizhencao and Heijiacao were weighed according to the prescription amount, 6 times of water was added, and the mixture was heated at 85℃ for 3 times, 1h each time, and then filtered to obtain water extract;

[0089] (2) Enzymatic extraction: the residue after water extraction was added with 10 times of water and 1.0% cellulase, and then the mixture was extracted at 50℃ and pH 5.0 for 1h, and then filtered after boiling to obtain enzymatic extract;

[0090] (3) Concentration: the water extract and the enzymatic extract were combined and concentrated to a thick paste;

[0091] (4) Preparation of corresponding dosage form: the thick paste was mixed with appropriate amount of refined honey to prepare 30g of paste.

[0092] Example 17

[0093] (1) Water extraction: six kinds of medicinal materials of Tujiaomu, Jiulongpan, Dafupi Rong, Matujin, Guizhencao and Heijiacao were weighed according to the prescription amount, 6 times of water was added, and the mixture was heated at 85℃ for 1 time, 0.5h, and then filtered to obtain water extract;

[0094] (2) Enzymatic extraction: the residue after water extraction was added with 10 times of water and 1.0% cellulase, and then the mixture was extracted at 50℃ and pH 5.0 for 1.5h, and then filtered after boiling to obtain enzymatic extract;

[0095] (3) Concentration: the water extract and the enzymatic extract were combined and concentrated to a thick paste;

[0096] (4) Preparation of corresponding dosage form: the thick paste was mixed with appropriate amount of poly starch and dextrin to prepare 30g of tablets.

[0097] Example 18

[0098] (1) Water extraction: six kinds of medicinal materials of Chuannuomu, Jiulongpan, Dafupiecong, Matujin, Guizhencao and Heijiacao were weighed according to the prescription amount, 6 times of water was added, heated at 85℃ for extraction once, extracted for 0.5h, filtered, and water extract was obtained;

[0099] (2) Enzymatic extraction: the residue after water extraction was added with 10 times of water, 1.0 cellulase was added, and the mixture was extracted at 50℃ and pH 5.0 for 1.5h, then boiled and filtered, and enzymatic extract was obtained;

[0100] (3) Concentration: the water extract and the enzymatic extract were combined and concentrated to a thick paste;

[0101] (4) Preparation of corresponding dosage form: the thick paste was added with appropriate amount of polyethylene glycol 4000, and 30g pills were prepared by dropping.

[0102] Example 19

[0103] (1) Water extraction: six kinds of medicinal materials of Chuannuomu, Jiulongpan, Dafupiecong, Matujin, Guizhencao and Heijiacao were weighed according to the prescription amount, 6 times of water was added, heated at 85℃ for extraction once, extracted for 0.5h, filtered, and water extract was obtained;

[0104] (2) Enzymatic extraction: the residue after water extraction was added with 10 times of water, 1.0 cellulase was added, and the mixture was extracted at 50℃ and pH 5.0 for 1.5h, then boiled and filtered, and enzymatic extract was obtained;

[0105] (3) Concentration: the water extract and the enzymatic extract were combined and concentrated to a thick paste;

[0106] (4) Preparation of corresponding dosage form: the thick paste was added with appropriate amount of water, diluted, 1g of sodium benzoate was added, stirred and mixed uniformly, and then diluted to 50mL to prepare an oral solution.

[0107] In order to further verify the effectiveness of the present application, the inventors carried out a series of verification tests, as follows:

[0108] I. Preparation process optimization test

[0109] The prescription of the application is composed of 6 ingredients, including Radix Polygoni Multiflori, Radix Rubi Parvifolii, Pericarpium Citri Reticulatae Viride, Radix Rubi Parvifolii, Herba Bidens, and Herba Imperatae, wherein Radix Polygoni Multiflori is the monarch drug. The active ingredients, target points and action pathways of Radix Polygoni Multiflori for preventing and treating liver cirrhosis are analyzed by the network pharmacology and molecular docking technology applied by the previous team, and the research shows that the core active ingredients of Radix Polygoni Multiflori for preventing and treating liver cirrhosis include 23 kinds of isoflavones, other flavones, dipeptide compounds, volatile oils and other compounds. Through the analysis of the effective components of other ingredients in the prescription, it is found that flavonoids are the important material basis for the prescription to treat liver cirrhosis.

[0110] In order to seek the best extraction method, the extraction rate of total flavonoids in the prescription is taken as the index, and four different extraction processes, including water extraction, alcohol extraction, alcohol extraction and enzymatic hydrolysis, and water extraction and enzymatic hydrolysis, are compared through experiments, and the best extraction process is finally selected.

[0111] 1. Determination method of total flavonoid extraction rate

[0112] Determination is carried out by ultraviolet spectrophotometry.

[0113] (1) Determination of detection wavelength

[0114] 2 ml of rutin reference substance is accurately measured and placed in a 25 ml volumetric flask, and then 1 ml of 5% sodium nitrite solution is added to 6.0 ml of water, mixed, placed for 6 minutes, 1 ml of 10% aluminum nitrate solution is added, shaken, placed for 6 minutes, 10 ml of sodium hydroxide test solution is added, and then water is added to the mark, shaken, placed for 15 minutes, and the corresponding reagent is used as a blank to carry out spectral scanning at a wavelength of 400-800 nm. The reference solution has a large absorption at 500 nm, so the detection wavelength is determined to be 500 nm.

[0115] (2) Preparation of reference solution

[0116] 50 mg of rutin reference substance is accurately weighed and placed in a 25 ml volumetric flask, and then appropriate amount of methanol is added, heated in a water bath to dissolve, cooled, and then methanol is added to the mark, shaken, and 10 ml is accurately measured and placed in a 100 ml volumetric flask, and then water is added to the mark, shaken, and the rutin reference solution (0.2 mg of rutin per 1 ml) is obtained.

[0117] (3) Preparation of standard curve

[0118] Accurately take 1 ml, 2 ml, 3 ml, 4 ml, 5 ml and 6 ml of the reference solution, respectively, into 25-ml volumetric flasks, add water to 6.0 ml, add 1 ml of 5% sodium nitrite solution, mix well, stand for 6 minutes, add 1 ml of 10% aluminum nitrate solution, shake well, stand for 6 minutes, add 10 ml of sodium hydroxide test solution, then add water to the calibration mark, shake well, stand for 15 minutes, take the corresponding reagent as the blank, determine the absorbance at 500 nm by UV-visible spectrophotometry, take the absorbance as the vertical coordinate and the concentration as the horizontal coordinate to draw a standard curve.

[0119] (4) Determination method

[0120] A: Total flavone content before extraction

[0121] Take about 2 g of the coarse powder according to the prescription proportion, accurately weigh, place in a Soxhlet extractor, add appropriate amount of diethyl ether, heat to reflux until the extract is colorless, cool, discard the diethyl ether liquid. Add 90 ml of methanol, heat to reflux until the extract is colorless, transfer to a 100-ml volumetric flask, wash the container with a small amount of methanol, and add the washing liquid to the same volumetric flask, add methanol to the calibration mark, shake well. Accurately take 10 ml, place in a 100-ml volumetric flask, add water to the calibration mark, shake well. Accurately take 3 ml, place in a 25-ml volumetric flask, follow the method under the standard curve preparation item from "add water to 6.0 ml" to determine the absorbance according to the method, read the weight of rutin contained in the test solution from the standard curve (μg), calculate, and the total flavone content before extraction is obtained.

[0122] B: Total flavone content after extraction

[0123] Accurately take 5 ml of the extract liquid of each extraction method, place in a 25-ml volumetric flask, follow the method under the standard curve preparation item from "add 1 ml of 5% sodium nitrite solution" to determine the absorbance according to the method, read the weight of rutin contained in the test solution from the standard curve (μg), calculate, and the total flavone content after extraction is obtained.

[0124] (5) Total flavone extraction rate

[0125] Total flavone extraction rate = total flavone content after extraction ÷ total flavone content before extraction × 100%

[0126] 2. Preliminary selection of extraction method

[0127] (1) Water extraction method

[0128] Take the medicinal materials according to the prescription proportion, add 8 times the amount of water, heat to extract at 85°C for 2 times, each time for 1 hour, filter, concentrate and dilute the filtrate to an appropriate amount, and determine the total flavone extraction rate. The results are shown in Table 2.

[0129] (2) Water extraction and enzymatic hydrolysis extraction method

[0130] The residue after water extraction is added with 10 times water, 2.0% cellulase is added, and then the mixture is immersed for 90 minutes at 50°C and pH 5.0, boiled, filtered, the filtrate is concentrated and diluted to a proper volume, and the total flavone extraction rate is determined. The results are shown in Table 2.

[0131] (3) Alcohol extraction method

[0132] The medicinal materials are weighed according to the prescription proportion, 8 times 60% ethanol is added, and then the mixture is extracted twice, each time for 1 hour, filtered, the filtrate is concentrated and diluted to a proper volume, and the total flavone extraction rate is determined. The results are shown in Table 2.

[0133] (4) Alcohol extraction and enzymatic hydrolysis extraction method

[0134] The residue after alcohol extraction is added with 8 times water, 2.0% cellulase is added, and then the mixture is immersed for 60 minutes at 50°C and pH 5.0, boiled, filtered, the filtrate is concentrated and diluted to a proper volume, and the total flavone extraction rate is determined. The results are shown in Table 2.

[0135] Table 2 Total flavone extraction rate results of different extraction methods

[0136]

[0137] From the test results, it can be seen that the total flavone extraction rates of water extraction and alcohol extraction alone are not high, and the total flavone extraction rates of the residue after enzymatic hydrolysis extraction are greatly increased. Since the total flavone extraction rates of the water extraction and enzymatic hydrolysis extraction method and the alcohol extraction and enzymatic hydrolysis extraction method are equivalent, and considering that the water extraction and enzymatic hydrolysis extraction method has lower production cost and higher safety, the preparation process of the present application is determined to adopt the water extraction and enzymatic hydrolysis extraction method.

[0138] 3. Optimization of extraction method process parameters

[0139] (1) Water extraction process parameters

[0140] The water amount (factor A), extraction time (factor B) and extraction times (factor C) are selected as the observation factors, the orthogonal test is adopted to screen the optimal water extraction process parameters, the factors and levels are shown in Table 3, the orthogonal design and test results are shown in Table 4, and the variance analysis results are shown in Table 5.

[0141] Table 3 Orthogonal test factors and level table of water extraction process

[0142] Level Factor A (times) Factor B (hours) Factor C (times) 1 4 0.5 1 2 6 1 2 3 8 2 3

[0143] Table 4 Orthogonal test design and results table of water extraction process

[0144]

[0145]

[0146] Table 5 Variance analysis results of water extraction process

[0147] Source of variance Sum of squares of deviation Degree of freedom Mean square F value Significance A 57.66 2 28.83 14.14 Not significant B 44.29 2 22.15 10.86 Not significant C 12.36 2 6.18 3.03 Not significant D (error) 4.08 2 2.04

[0148] Note: F0.05(2,2) = 19

[0149] From the orthogonal test results in Table 4, the influence of each factor on the water extraction effect is A > B > C, and A2 > A3 > A1, B3 > B2 > B1, C3 > C2 > C1, the best water extraction process parameters are A2B3C3. As can be seen from the variance analysis in Table 5, among the three factors, A, B and C factors have no significant effect, but since A factor has no significant difference, but A2 is significantly higher than A1, therefore, from the perspective of cost saving, the best parameters of water extraction process can be adjusted to A2B1C1, that is, 6 times water decoction for 1 time, and the decoction time is 0.5 hours.

[0150] (2) Verification of the best parameters of water extraction process

[0151] According to the prescription proportion, take 3 parts of Tuozhi, Jiulongpan, Dafubingdou, Matujin, Guizhencao and Heijiacao, respectively, and perform water decoction extraction according to the best water extraction process parameters selected in the foregoing. After the extraction liquid is concentrated and constant volume is added, the total flavonoid extraction rate is determined, and the results are shown in Table 6.

[0152] Table 6 Verification results of the best water extraction process parameters

[0153]

[0154] The verification results show that the total flavonoid extraction rate in the prescription is 18.62% by using the best water extraction process parameters selected by orthogonal test.

[0155] (3) Water extraction and enzyme hydrolysis process parameters

[0156] The medicinal materials in the prescription are first extracted by the best water extraction process as described above, and the residues are extracted by enzyme hydrolysis extraction method for the second time. The water addition amount (factor A), cellulase dosage (factor B) and enzyme hydrolysis time (factor C) are selected as the observation factors, and the total flavonoid extraction rate by the two extraction methods is used as the index. The best enzyme hydrolysis extraction process conditions (50°C, PH value 5.0) are selected by orthogonal test. The factors and levels are shown in Table 7, the orthogonal design and test results are shown in Table 8, and the variance analysis results are shown in Table 9.

[0157] Table 7 Orthogonal test factors and levels table of enzyme hydrolysis process

[0158] Level Factor A (times) Factor B (%) Factor C (min) 1 8 1.0 60 2 10 2.0 90 3 12 3.0 120

[0159] Table 8 Orthogonal test design and results table of enzyme hydrolysis process

[0160] Number Factor A Factor B Factor C Error D Total flavonoids extraction rate (%) 1 1 1 1 1 27.54 2 1 2 2 2 47.28 3 1 3 3 3 52.21 4 2 1 2 3 62.98 5 2 2 3 1 64.14 6 2 3 1 2 57.27 7 3 1 3 2 64.06 8 3 2 1 3 53.43 9 3 3 2 1 68.01 K1 127.03 154.58 138.24 159.69 K2 184.39 164.85 178.27 168.61 K3 185.50 177.49 180.41 168.62 R 58.47 22.91 42.17 8.93

[0161] Table 9 variance analysis results of enzymatic hydrolysis process

[0162] Source of variance Sum of squares of deviation Degree of freedom Mean square F value Significance A 745.57 2 372.79 42.12 Significant B 87.79 2 43.90 4.96 Not significant C 376.14 2 188.07 21.25 Significant D (error) 17.70 2 8.85

[0163] Note: F0.05(2,2) = 19

[0164] From the orthogonal test results in Table 8, the influence of each factor on the extraction effect in the enzymatic extraction process is A > C > B, and A3 > A2 > A1, C3 > C2 > C1, B3 > B2 > B1. From the variance analysis in Table 9, it can be seen that factors A and C have a significant effect on the enzymatic extraction process, and factor B has no significant effect. Considering the production cycle and production cost, the optimal process parameters can be selected as A2B1C2, i.e. adding 10 times the amount of water to the total amount of medicinal materials, adding 1.0% cellulase, and extracting at 50°C and a pH of 5.0 for 90 minutes.

[0165] (4) Verification of the optimal parameters of the water extraction and enzymatic hydrolysis process

[0166] According to the prescription proportion, take 3 parts of Tuozhi Mother, Jiulongpan, Dafupie Rong, Matengjin, Guizhencao, and Heiji Cao, and extract them according to the optimal water extraction process parameters described above (add 6 times the amount of water and extract for 1 hour), filter, and reserve the filtrate; add 10 times the amount of water to the total amount of medicinal materials, and then add 1.0% cellulase, and extract at 50°C and a pH of 5.0 for 90 minutes. After boiling, filter, combine the filtrate with the water extraction filtrate, concentrate, and make up the volume. Determine the total flavonoid extraction rate, and the results are shown in Table 10.

[0167] Table 10 verification results of the optimal enzymatic extraction process parameters

[0168]

[0169] The verification results show that after the optimal water extraction and enzymatic hydrolysis process selected by the orthogonal test is used for extraction, the total flavonoid extraction rate in the prescription is 62.33%, the extraction efficiency is high, the process is reasonable and feasible, and can be used as the optimal extraction process for the prescription.

[0170] II. Pharmacodynamic study

[0171] 1. Purpose of the experiment

[0172] In order to verify the efficacy of the preparation prepared by the water extraction and enzymatic hydrolysis process, the prescription is prepared into granules according to the optimal water extraction and enzymatic hydrolysis process described above, and then test research is carried out according to the relevant technical requirements.

[0173] 2. Experimental method

[0174] The clean level male Wistar rats are randomly divided into blank control group (N group), model group (M group), high, medium and low dose groups of the granule of the application (G, Z, D groups), compound Biejia Ruangan tablet group (F group). The cirrhosis ascitic rat model is prepared by using the improved CCl4-ethanol comprehensive method, the model is intervened and treated by giving the granule of the application and the compound Biejia Ruangan tablet, and the general situation, abdominal fluid volume, liver function, liver fibrosis index, NO, ET-1, AQP8 and liver pathological changes of the rats in each group are observed.

[0175] Results:

[0176] (1) General situation

[0177] The rats in the N group have good mental state, normal activity, no obvious change in fur, diet and excretion, and gradually increasing body weight. The rats in the M group have obvious abdominal distension, listless spirit, easy to frighten, reduced activity, dry and itchy yellow fur, reduced diet, reduced urine volume, grayish white stool, and reduced body weight. The body weight of the rats in the first to fourth week group gradually decreases by 10 to 30 g, no obvious change in the fifth week, the body weight of individual rats decreases by about 10 g, and the body weight of about 80% of the rats gradually increases by 20 to 60 g in the sixth to tenth week. After treatment, the above-mentioned conditions of the rats in the G, Z, D and F groups are improved to different degrees, and the body weight increases. Among them, the rats in the G group are improved most obviously, followed by the Z group, and there is no obvious difference between the D group and the F group.

[0178] (2) Comparison of liver tissue appearance

[0179] The rat liver tissue is observed by naked eye. The liver of the rats in the N group has good texture, bright red color, smooth surface and sharp edge. The liver of the rats in the M group is brittle, dark red or brown in color, uneven in surface, and has different sizes of nodules, blunt edge and small volume. The liver of the rats in the D group is enlarged, brittle, brown in color, and has rough surface and blunt edge. The liver of the rats in the G, Z and F groups is enlarged, dark red in color, smooth in surface, and has different degrees of small granular area and sharp edge.

[0180] (3) Comparison of ascites volume of rats in each group

[0181] See Table 11.

[0182] Table 11 Comparison of ascites volume of rats in each group

[0183] Group Rat (only) Ascites volume (mL) N group 8 0 M group 8 5.10±0.41 G group 8 0.42±0.12* Z group 8 1.04±0.32* D group 8 2.46±0.35* F group 8 4.06±0.40

[0184] Note: compared with the M group, *P<0.05

[0185] (4) Liver function index of rats in each group

[0186] See Table 12.

[0187] Table 12 Comparison of liver function of rats in each group

[0188] Group Rat (only) Alb (g / L) AST (U / L) ALT (U / L) N group 8 40.23±5.07 54.37±34.38 70.32±8.37 M group 8 14.35±3.31 459.86±154.65 172.36±12.48 G group 8 36.24±4.05*# 72.30±38.42*# 75.58±8.69*# Z group 8 26.51±3.15* 84.66±39.97*# 90.75±9.38*# D group 8 20.78±2.26 164.33±63.35* 110.76±11.31* F group 8 21.58±3.04 186.95±84.84* 122.70±14.88*

[0189] Note: compared with M group, *P<0.05; compared with F group, #P<0.05

[0190] (5) Liver fibrosis index of rats in each group

[0191] See Table 13.

[0192] Table 13 Comparison of liver fibrosis index of rats in each group

[0193] Group Rat (only) Ⅳ-C PC III LN HA N group 8 68.2±10.5 84.3±10.8 64.2±7.4 98.5±9.7 M group 8 171.2±18.3 254.5±90.5 182.1±47.3 268.3±43.3 G group 8 73.4±9.05* 95.7±12.2* 71.3±11.6* 106.2±9.9* Z group 8 96.1±10.1* 134.3±18.2* 95.6±17.6* 126.5±13.15* D group 8 120.7±12.2* 128.5±20.1* 114.1±28.7* 170.7±22.2 F group 8 93.5±10.0* 84.3±10.8* 84.2±17.6* 121.5±3.4

[0194] Note: compared with M group, *P<0.05

[0195] (6) Effect of each group on NO, ET-1 and AQP8 IOD value

[0196] See Table 14.

[0197] Table 14 Comparison of NO, ET-1 and AQP8 IOD value of rats in each group

[0198]

[0199]

[0200] Note: compared with M group, *P<0.05

[0201] (7) Observation under light microscope

[0202] See Figure 1 . The liver lobule structure of N group rats was clear, the hepatocyte morphology was normal, and the central vein was arranged in a radial and neat manner, and no pathological changes such as inflammation, degeneration or necrosis were observed. The normal liver lobule structure of most M group rats was obviously destroyed, and extensive pathological changes such as degeneration, hemorrhage and inflammation were observed, and typical pseudolobules were widely formed. Compared with M group, the liver structure of each treatment group was reduced to different degrees, and G group was the most obvious. The liver lobule structure of G group was slightly damaged, fibrous tissue hyperplasia was observed, no pseudolobule was observed, fatty degeneration disappeared, hepatocytes were slightly congested and swollen, and less inflammatory cell infiltration was observed. In Z group, the fibrous septum was reduced, a small amount of pseudolobule was formed, fatty degeneration basically disappeared, and a small amount of inflammatory cell infiltration was observed. In D group, the liver lobule structure was destroyed, pseudolobule formation was obvious, a large amount of inflammatory cell infiltration was observed, and pathological changes such as degeneration and hemorrhage were observed, which was improved compared with M group, but the degree was not obvious. In F group, the liver lobule structure was moderately damaged, and part of the pseudolobule was formed, and inflammatory cell infiltration was observed.

[0203] III. Verification of clinical efficacy

[0204] In order to verify the clinical curative effect of the preparation prepared by the water extraction enzyme hydrolysis process, the team of the present application further carried out a clinical curative effect verification experiment.

[0205] 1. Data and methods

[0206] (1) Clinical data

[0207] Select 120 cases of cirrhosis ascites patients treated in the outpatient department of the hospital from September 2020 to November 2023 as the research object, generate a random number table by SAS statistical software package, and randomly divide the 120 cases of cirrhosis ascites patients into treatment group and control group according to the ratio of 1:1, 60 cases in each group. There was no statistically significant difference in age, disease duration and other general data between the two groups of patients, and they were comparable.

[0208] (2) Diagnostic criteria

[0209] According to the "Guidelines for Diagnosis and Treatment of Cirrhosis Ascites and Related Complications" published by the Chinese Medical Association in 2018 and the "Expert Consensus Opinion on TCM Diagnosis and Treatment of Cirrhosis Ascites" published by the Chinese Medical Association in 2017, the diagnostic criteria for "distension" in TCM are met, and clinical evaluation is carried out according to clinical symptoms and laboratory examination. The TCM syndrome score mainly refers to the TCM symptom grading and quantification standard for cirrhosis ascites in "Guiding Principles for Clinical Research of New Drugs of Traditional Chinese Medicine", and the main symptoms include: ① abdominal distension and fullness; ② abdominal fullness; ③ lower extremity edema; ④ oliguria; ⑤ drowsiness and inactivity; ⑥ sallow and yellow; ⑦ poor appetite and loose stools. The above 7 symptoms are divided into 4 grades of no, mild, moderate and severe, corresponding to 0, 1, 2 and 4 points, and the sum of the above 7 items is the TCM syndrome score.

[0210] (3) Inclusion criteria

[0211] ① At the same time, meet the above diagnostic criteria for cirrhosis ascites in TCM and Western medicine; ② Age 18-75 years old, regardless of gender; ③ Quantitative evaluation of liver reserve function grading (Child-Pugh grading) rating B or C; ④ No other serious systemic organic diseases other than cirrhosis; ⑤ Patients voluntarily participate in the test and sign the informed consent form.

[0212] (4) Exclusion criteria

[0213] ① Patients with decompensated cirrhosis accompanied by bleeding, gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, etc. serious complications; ② Combined with serious cardiovascular, pulmonary, renal, neuronal and blood circulation system diseases and other serious diseases, such as mental illness or tumor; ③ Pregnant or lactating women; ④ Received TCM preparation treatment within 1 month; ⑤ Allergic constitution or allergic to drugs in this research program or not cooperative.

[0214] (5) Treatment method

[0215] The control group was given symptomatic and supportive treatment including sodium and water intake restriction, bed rest. Reduced glutathione (Biomedica Foscama Industria Chimico Farmaceutica S.p.A., approval number H20181207) 1.8 g was added to 5% glucose injection 100 mL, intravenous injection, once a day; furosemide tablets (Tianfang Pharmaceutical Co., Ltd., drug standard number H41020435) 20 mg, oral, once a day; spironolactone tablets (Jiangsu Lianshui Pharmaceutical Co., Ltd., drug standard number H32023932) 100 mg, oral, once a day. Continuous treatment for 1 month.

[0216] The treatment group was treated with the product granules prepared according to the preparation method of Example 11 on the basis of symptomatic and supportive treatment, 30 g each time, 3 times a day, and taken with boiling water. Continuous treatment for 1 month.

[0217] (6) Observation index

[0218] ① The body weight and abdominal circumference of the patients in the two groups after morning empty stomach urination were detected before and after treatment, and the 24 h urine volume was recorded. ② The TCM syndrome score was statistically analyzed. The total score of 7 syndromes was 28 points at most and 0 point at least. The lower the score, the better the TCM syndrome effect.

[0219] (7) Efficacy determination

[0220] According to the relevant standards of “Expert Consensus Opinion on Chinese Medicine Diagnosis and Treatment of Ascites due to Cirrhosis”, clinical remission: ascites and limb edema completely disappeared, B-ultrasound detection was negative; main symptoms disappeared, daily urine volume > 1200 mL, body weight and abdominal circumference returned to the level before ascites appeared, and could be stable for > 3 months; marked effect: ascites and limb edema mostly disappeared, B-ultrasound detection showed that ascites was reduced by ≥ 50%, symptoms were obviously improved, abdominal distension was obviously relieved, daily urine volume was > 1000 mL, body weight was reduced by > 2 kg, or abdominal circumference was reduced by > 5 cm; effective: ascites and limb edema were relieved, B-ultrasound detection showed that ascites was reduced by < 50%; symptoms were slightly improved, abdominal distension was slightly relieved, 24 h urine volume was < 1000 mL, body weight was reduced but < 2 kg, or abdominal circumference was reduced by > 3 cm but < 5 cm; ineffective: ascites, body weight, abdominal circumference and symptoms were not improved or aggravated.

[0221] 2、Results

[0222] (1) Body weight, abdominal circumference, 24 h urine volume and TCM syndrome score of the patients in the two groups before and after treatment

[0223] The body mass, abdominal circumference and TCM syndrome scores of the two groups were significantly reduced after treatment(P<0.05), and the 24h urine volume was significantly increased(P<0.05); after treatment, the body mass, abdominal circumference and TCM syndrome scores of the treatment group were significantly lower than those of the control group(P<0.05), and the 24h urine volume was significantly higher than that of the control group(P<0.05). See Table 15.

[0224] Table 15 Comparison of body mass, abdominal circumference, 24h urine volume and TCM syndrome scores of patients in the two groups before and after treatment

[0225]

[0226]

[0227] Note: Compared with the control group after treatment * P<0.05; compared with the same group before treatment △ P<0.05.

[0228] (2) Comparison of abdominal B-ultrasound of the two groups before and after treatment

[0229] Compared with before treatment, the ascites dark area, splenic vein blood flow and portal vein blood flow of the two groups were significantly reduced after treatment(P<0.05); after treatment, the ascites dark area, splenic vein blood flow and portal vein blood flow of the treatment group were significantly lower than those of the control group(P<0.05). See Table 16.

[0230] Table 16 Comparison of abdominal B-ultrasound of the two groups before and after treatment

[0231]

[0232] Note: Compared with the control group after treatment * P<0.05; compared with the same group before treatment △ P<0.05.

[0233] (3) Comparison of liver and kidney function of the two groups before and after treatment

[0234] Compared with before treatment, the ALT, AST activity, TBIL and BUN content of the two groups were significantly reduced after treatment(P<0.05), and the ALB content was significantly increased(P<0.05), and the Cr content of the treatment group was significantly reduced(P<0.05); after treatment, the ALT, AST activity, TBIL and Cr content of the treatment group were significantly lower than those of the control group(P<0.05), and the ALB content was significantly higher than that of the control group(P<0.05). See Table 17.

[0235] Table 17 Comparison of liver and kidney function of the two groups before and after treatment

[0236]

[0237] Note: Compared with the control group after treatment *P<0.05; compared with the same group before treatment △ P<0.05.

[0238] (4) Comparison of four items of liver fibrosis in two groups of patients before and after treatment

[0239] Compared with before treatment, the contents of HA, IV-C, LN and PⅢNP in two groups of patients after treatment were significantly reduced (P<0.05); after treatment, the contents of HA and LN in the treatment group were significantly lower than those in the control group (P<0.05). See Table 18.

[0240] Table 18 Comparison of four items of liver fibrosis in two groups of patients before and after treatment

[0241]

[0242] Note: Compared with the control group after treatment * P<0.05; compared with the same group before treatment △ P<0.05.

[0243] (5) Detection of serum CHI3L1 and inflammatory factors before and after treatment

[0244] Compared with before treatment, the contents of serum CHI3L1, TGF-β1, IL-6, IL-22 and TNF-α in two groups of patients after treatment were significantly reduced (P<0.05); after treatment, the contents of serum CHI3L1, IL-6 and TNF-α in the treatment group were significantly lower than those in the control group (P<0.05). See Table 19.

[0245] Table 19 Detection of serum CHI3L1, TGF-β1, IL-6, IL-22 and TNF-α in two groups of patients before and after treatment

[0246]

[0247] Note: Compared with the control group after treatment * P<0.05; compared with the same group before treatment △ P<0.05.

[0248] (6) Clinical efficacy of two groups of patients

[0249] The total effective rates of the treatment group and the control group were 83.3% and 66.7%, respectively, and the total effective rate of the treatment group was significantly higher than that of the control group (P<0.05). See Table 20.

[0250] Table 20 Comparison of clinical efficacy of two groups of patients

[0251] Group Example Relief Effective Effective Ineffective Total effective rate (%) Control group 60 8 19 13 20 66.7 Treatment group 60 10 25 15 10 83.3 * ]]>

[0252] Note: Compared with the control group *P < 0.05;

[0253] 3. Conclusion

[0254] In summary, the drug combination of the present invention, after being prepared into granules through water extraction and enzymatic hydrolysis, has significant therapeutic effects in treating ascites due to liver cirrhosis.

[0255] IV. Collection of Typical Cases

[0256] 1. Li XX, male, 65 years old, XX Traditional Chinese Medicine Hospital

[0257] Admission status: Admitted on October 2, 2023 at 12:05 PM due to "abdominal distension for 3+ months." Symptoms included abdominal distension, moderate pitting edema in both lower extremities, early satiety after meals, cough with copious white sputum that was difficult to expectorate, clear consciousness, lethargy, weakness in limbs, poor appetite, normal sleep, dysuria, and normal bowel movements. Tongue was pale red with a yellow, greasy coating, and pulse was wiry and slippery. Physical examination: Temperature: 36.6℃, Pulse: 82 bpm, Respiration: 20 bpm, Blood Pressure: 133 / 67 mmHg.

[0258] Specialist examination: The abdomen was distended upon inspection, but no visible gastrointestinal shape or peristaltic waves were observed. Abdominal breathing was present, and no varicose veins were seen on the abdominal wall. Palpation revealed tenderness in the left upper quadrant, but no rebound tenderness or muscle guarding. Thrusting splash and fluid wave sensation were absent. The liver was palpable below the costal margin at the level of the umbilicus, with mild tenderness but no percussion pain. The gallbladder was not palpable, and Murphy's sign was absent. The spleen was palpable 5 cm below the costal margin, soft in texture, and without tenderness. The kidneys were not palpable, and there was no ureteral tenderness. There was no percussion tenderness in the liver area. The liver dullness was located at the fifth intercostal space along the right midclavicular line. There was no significant percussion tenderness in the bilateral renal areas, but shifting dullness was positive. Auscultation revealed bowel sounds at 4 times / min, without metallic or high-pitched tones, and no vascular murmurs were heard.

[0259] Traditional Chinese Medicine (TCM) diagnosis: The patient's main symptom is "abdominal distension for 3+ months," falling under the TCM category of "abdominal distension." The patient habitually consumes rich and fatty foods, damaging the spleen and stomach, leading to liver dysfunction, stagnation of Qi, and the generation of blood stasis. Liver Qi stagnation further affects the spleen, and prolonged illness can also impact the kidneys, resulting in deficiency of vital energy, imbalance of the liver, spleen, and kidneys. This leads to Qi stagnation, blood stasis, and fluid retention in the abdomen, causing abdominal distension and fullness. Deficiency of vital energy and liver and kidney essence and blood also contribute to weakness and fatigue. The tongue is red with little coating, and the pulse is floating and rapid—all signs of deficiency of vital energy, blood stasis, Qi stagnation, and fluid retention. In summary, the disease location is in the liver and spleen, related to the kidneys; the nature of the disease is deficiency in the root and excess in the branches, with deficiency of vital energy as the root and Qi stagnation, blood stasis, and fluid retention as the branches.

[0260] Initial diagnosis: Traditional Chinese Medicine diagnosis: 1. Abdominal distension. 2. Deficiency of vital energy and blood stasis, qi stagnation and water retention. Western Medicine diagnosis: 1. Decompensated cirrhosis.

[0261] 2. Stage 5 chronic renal failure (CKD). 3. Type 2 diabetes mellitus. 4. Grade 3 primary hypertension (very high risk). The patient also has cirrhosis with ascites.

[0262] Treatment: on the basis of giving symptomatic support treatment, combined with the application, the product granules prepared according to the preparation method of Example 11 were used for treatment, 30 g each time, 3 times a day, and taken with boiling water. Continuous treatment for 1 month, and then re-examination.

[0263] Re-examination results: After the combination of traditional Chinese and western medicine system treatment, the patient's condition improved significantly compared with before. The patient complained that the abdominal distension improved significantly, the appetite was good, the abdomen was flat, the abdominal circumference was reduced, and there was no edema in the lower extremities, and the urination and defecation were normal.

[0264] 2. Wu XX, female, 65 years old, XX Hospital of Traditional Chinese Medicine

[0265] Admission: On October 28, 2023, 08:14, admitted to hospital due to "abdominal distension with anorexia for 11+ months, aggravated for 2+ weeks." Abdominal distension, anorexia, reduced food intake by about 1 / 2, shortness of breath and fatigue, dry mouth and bitter taste, 1 time / day of soft yellow stool, spirit is acceptable, sleep is poor, urine is acceptable. Red tongue, thin white fur, pulse is thin and astringent. Physical examination: T: 36.5℃, P: 104 times / min, R: 20 times / min, BP: 107 / 61 mmHg.

[0266] Special examination: Visual examination of the abdomen is swollen, no gastrointestinal shape and peristalsis wave is found, abdominal breathing exists, the navel is normal, no abdominal wall varices is found, abdominal palpation is soft, no rebound pain and muscle tension is found, liquid wave feeling is found, no water hammer sound is heard.{{No abdominal mass is found}}.{{No subcostal liver is found, no tenderness is found}}. No gallbladder is found, Murphy sign is negative, spleen is found under the rib. No kidney is found, no tenderness is found in each ureter point. The liver dullness boundary is normal, the liver upper boundary is located at the right clavicular midline 5 intercostal, the shifting dullness is positive. No obvious percussion pain is found in the bilateral kidney area, the bowel sound is normal, no blood vessel murmur is heard.

[0267] TCM syndrome differentiation: The patient's main symptoms are "abdominal distension with anorexia for 10+ months, aggravated for 2 months.", which belongs to the "distension" category in TCM. The patient is old and weak, and the diet is not good, which leads to spleen deficiency over time, which cannot promote blood circulation, leading to blood stasis, abnormal qi movement, qi stagnation, water retention, and blood stasis. The swelling is more and more severe, and the more the evil is, the more the normal is. Therefore, it is virtual and real. Red tongue, thin white fur, and pulse are thin and astringent, which are all signs of blood stasis, qi stagnation, and water retention. The nature of the disease is virtual and real, the basic pathogenesis is blood stasis, qi stagnation, and water retention.

[0268] Initial diagnosis: TCM diagnosis: 1. Distension. 2. Blood stasis due to deficiency of qi and water retention. Western medical diagnosis: 1. Decompensated primary cirrhosis. 2. Primary hypertension 2 high-risk group. 3. Sleep disorder.

[0269] Treatment: on the basis of giving symptomatic support treatment, combined with the application, the product granules prepared according to the preparation method of Example 11 were used for treatment, 30 g each time, 3 times a day, and taken with boiling water. Continuous treatment for 1 month, and then two follow-up visits.

[0270] The second diagnosis result: After the combination of traditional Chinese and western medicine system treatment, the patient's condition improved significantly. The patient complained that the abdominal distension was significantly improved, the weight loss, and the normal bowel movement.

[0271] 3. Huang XX, male, 61 years old, XX Hospital of Traditional Chinese Medicine

[0272] Admission: On 2022-06-19 0856, the patient was admitted to the hospital due to "abdominal distension for 2 weeks, aggravated for 1 week." The abdomen was distended like a drum, accompanied by loss of appetite, diarrhea, occasional palpitations and dizziness, no nausea, vomiting, abdominal pain, hematemesis, melena, chest pain, etc., spirit and sleep normal, tongue dull, thin white fur, pulse thin. Physical examination: T: 36.3℃, P: 75 times / min, R: 20 times / min, BP: 115 / 75mmHg.

[0273] Special examination: visual examination of the abdomen was swollen, no gastrointestinal shape and peristalsis wave was found, abdominal breathing existed, the navel was normal, no abdominal wall varices was found, the abdomen was soft, the subxiphoid and periumbilical light tenderness, no rebound tenderness and muscle tension, liquid wave and water sound were found.{{No abdominal mass was found}}.{{No liver was found under the ribs, no tenderness was found}}. The gallbladder was not palpable, Murphy's sign was negative, the spleen was not palpable under the ribs. The kidney was not palpable, and there was no tenderness in the ureter points. The liver dullness boundary was normal, the liver superior border was located at the right clavicular midline 5th intercostal space, and the shifting dullness was positive. There was no obvious percussion pain in the bilateral kidney area, the bowel sounds were normal, and no blood vessel murmur was heard.

[0274] TCM syndrome differentiation: "abdominal distension for 2 weeks, aggravated for 1 week" is the main symptom, which belongs to the category of "distension" in TCM. The patient has a history of chronic bronchitis, and the qi movement is not smooth, which leads to liver stagnation, qi stagnation, blood stasis, liver stagnation, spleen dysfunction, and kidney disease over time. Deficiency of vital qi, liver and kidney deficiency of essence and blood, and fatigue, loss of appetite. In summary, the disease is located in the lung, liver and spleen, and is related to the kidney. The nature of the disease is deficiency of the root and excess of the branch, and the blood stasis is the branch. The basic pathogenesis is deficiency of vital qi, blood stasis, and qi stagnation.

[0275] Initial diagnosis result: TCM diagnosis: 1. Distension. 2. Deficiency of vital qi, blood stasis, qi stagnation and water retention. Western medical diagnosis: 1. Cause of abdominal distension: cirrhosis? 2. Abnormal liver function. 3. Chronic bronchial asthma. The patient belongs to cirrhosis and ascites.

[0276] Treatment: on the basis of giving symptomatic support treatment, combined with the application, the product granules prepared according to the preparation method of Example 11 were used for treatment, 30 g each time, 3 times a day, and taken with boiling water. Continuous treatment for 1 month, and then two diagnoses.

[0277] Second diagnosis result: after the combination of traditional Chinese and western medicine system treatment, the patient's condition improved significantly. The patient complained that the abdominal distension was significantly improved, the abdomen was flatter, the abdominal circumference was smaller, the body weight was reduced, most of the ascites was resolved, and the bowel movement was normal.

[0278] 4. Long X, male, 60 years old, XX Chinese medicine hospital

[0279] Admission: admitted on 2023-07-06 15:54 due to "diagnosed primary hepatocellular carcinoma 2+ months, abdominal distension with right flank pain 1+ week." The spirit is clear, the spirit is weak, the abdomen is full and uncomfortable, and it is aggravated after eating, accompanied by right flank pain and discomfort, affecting rest and sleep, feeling limb weakness, shortness of breath after exercise, no chill, fever, cough, sputum, nausea, vomiting, palpitation, chest tightness and other discomfort, poor sleep, stool, small amount of urine, yellow. Physical examination: T: 36.5℃, P: 75 times / min, R: 20 times / min, BP: 102 / 67mmHg.

[0280] Special examination: sclera and skin moderate yellow staining, no palpable enlargement of superficial lymph nodes all over the body, auscultation of both lungs with clear breath sounds, no dry and wet rales and wheezing sounds in both lower lungs. Heart rate 75 times / min, regular, normal heart sound, no pathological murmur was heard in each valve listening area. Visual inspection of the abdomen is swollen, frog-like abdomen, no gastrointestinal shape and peristalsis wave, right upper quadrant dull pain, no tenderness, no rebound tenderness and muscle tension, fluid wave positive, no shock sound. Mobile dullness positive, auscultation of intestinal sounds 4 times / min, mild pitting edema of both lower extremities.

[0281] TCM syndrome differentiation: the patient was admitted with "diagnosed primary hepatocellular carcinoma 2+ months, abdominal distension with right flank pain 1+ week", which belongs to the category of "liver accumulation" in TCM. The patient has a history of smoking and drinking, alcohol damages the liver, and the patient has a history of hepatitis B virus infection, which further damages the liver. The liver loses its function of regulating and controlling, the qi movement is disorder, the liver cannot store blood, so there is qi stagnation and blood stasis, qi deficiency and blood stasis, and deficiency of qi and blood, so there is spirit weakness, limb weakness; the liver loses its function of regulating and controlling, the qi movement is disorder, so there is right upper quadrant dull pain, poor sleep, and yellow urine. Liver disease and spleen, spleen loses its function of transportation and transformation, water and dampness lose their distribution, so there is edema of both lower extremities; the patient's tongue is dark red, the fur is thin yellow, and the pulse is thin, which is the manifestation of liver stagnation and liver accumulation. The nature of the disease is deficiency in the root and excess in the branches.

[0282] Initial diagnosis: TCM diagnosis: 1. Liver accumulation. 2. Liver stagnation and spleen deficiency. Western medicine diagnosis: 1. Decompensated cirrhosis. 2. Primary liver cancer (CNLC IV, BCLC D, Child-Pugh C). 3. Type 2 diabetes. 4. Chronic hepatitis B. 5. Cancer pain. 6. Severe malnutrition. 7. High-risk group of grade 2 essential hypertension. 8. Type 2 diabetes. The patient belongs to cirrhosis ascites.

[0283] Treatment: On the basis of symptomatic and supportive treatment, the product granules prepared according to the preparation method of Example 11 were used in combination with the application, 30g each time, 3 times a day, and taken with boiling water. Continuous treatment for 1 month, and then the second diagnosis.

[0284] Second diagnosis: After the combination of traditional Chinese and western medicine treatment, the patient's condition improved. The patient complained that the abdominal distension improved significantly, the appetite improved, the spirit improved, the abdomen was flatter, the mild pitting edema of the lower extremities disappeared, and the bowel movements were normal.

[0285] 5. Shi XX, male, 71 years old, XX TCM Hospital

[0286] Admission: On September 18, 2023, 09:16, the patient was admitted to the hospital due to "3+ years of comprehensive treatment after liver cancer resection, 2+ weeks of low back pain". The patient was conscious, spirit was weak, limbs were weak and weak, especially after exercise, appetite and sleep were poor, no chills, fever, nausea, vomiting, palpitation, chest tightness, diarrhea, etc. The stool was 3-4 times a day, the tongue was pale red, the fur was thin white, and the pulse was thin. Physical examination: T: 36.6℃, P: 76 times / min, R: 20 times / min, BP: 98 / 70mmHg.

[0287] Special examination: No enlarged superficial lymph nodes were found in the whole body, the skin and sclera were yellow, percussion was performed on both lungs, auscultation was performed on both lungs, and no dry and wet rales were heard, no abnormal protrusions or depressions were found in the precordial area, no tremors were felt, the heart border was not large, the heart apex was 0.5cm inside the left clavicular line at the 5th intercostal space, the heart rate was 76 times / min, the rhythm was regular, the heart sound was forceful, and no murmur was heard. Visual inspection of the abdomen showed a long 30cm surgical scar in the midline to the right upper abdomen, a PTCD drainage tube was fixed in place in the right upper abdomen, no gastrointestinal shape and peristalsis wave was found, abdominal breathing existed, the navel was normal, no abdominal wall varices were found, the abdomen was soft, no tenderness, rebound tenderness and muscle tension, no liquid wave and water sound were felt. No abdominal mass was felt. The liver was palpable 5cm below the rib, the quality was hard, and the mobility was good.

[0288] TCM syndrome differentiation: The patient's main symptoms are "abdominal distension for 3+ months", which belongs to the category of "distension" in TCM. The patient usually likes to eat rich and sweet food, which damages the spleen and stomach, and causes the liver to be out of order, with unsmooth qi movement. Blood stasis is caused by qi stagnation, and the liver qi stagnation attacks the spleen. Long-term illness affects the kidney, and the healthy qi is deficient, with liver-spleen-kidney disorder, qi stagnation, blood stasis, and water retention in the abdomen, leading to distension and abdominal distension. The deficiency of healthy qi, deficiency of liver-kidney essence and blood, and soft limbs and lack of strength are caused by the deficiency of healthy qi. Red tongue, little moss, and floating pulse are all manifestations of deficiency of healthy qi, blood stasis, and qi stagnation and water retention. In summary, the disease is located in the liver and spleen, and is related to the kidney. The nature of the disease is deficiency in the root and excess in the branch, and the deficiency of healthy qi is the root, and qi stagnation, blood stasis, and water retention are the branch.

[0289] Initial diagnosis: TCM diagnosis: 1. Liver accumulation. 2. Liver stagnation and spleen deficiency. Western medicine diagnosis: 1. Decompensated cirrhosis (splenomegaly, ascites). 2. Chronic liver failure. 3. Biliary obstruction. 4. Postoperative recurrence of hepatocellular carcinoma (CNLC III BCLC C Child-pugh B). 5. Cancer pain. 6. Severe malnutrition. 7. Chronic hepatitis B. The patient belongs to cirrhosis and ascites.

[0290] Treatment: On the basis of symptomatic and supportive treatment, the product granules obtained by using the formulation of Example 1 and the preparation method of Example 11 are used for treatment, 30 g each time, 3 times a day, and decocted with boiling water. Continuous treatment for 1 month, and then the second diagnosis.

[0291] Second diagnosis: After the combination of traditional Chinese and western medicine treatment, the patient's condition improved significantly. The patient complained that the abdominal distension improved significantly, the abdomen was relatively flat, most of the ascites subsided, the abdominal circumference decreased, the limbs were less weak than before, the activity tolerance increased, the mind was clear, and the bowel movements were normal.

[0292] Although the invention has been described in detail in the foregoing description with general general description, specific embodiments and experiments, some modifications or improvements can be made on the basis of the invention, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the invention, all belong to the scope of protection required by the invention.

Claims

1. A pharmaceutical composition for treating cirrhotic ascites, characterized by comprising, It is prepared by the following drugs in parts by weight: Tuozhimu 10-15 parts, Jiulongpan 10-15 parts, Dafupiju 6-10 parts, Matujin 6-10 parts, Guizhencao 4-8 parts, Heijiacao 4-8 parts.

2. The pharmaceutical composition for treating cirrhotic ascites according to claim 1, wherein It is prepared by the following drugs in parts by weight: Tuozhimu 12-15 parts, Jiulongpan 12-15 parts, Dafupiju 8-10 parts, Matujin 8-10 parts, Guizhencao 6-8 parts, Heijiacao 6-8 parts.

3. The pharmaceutical composition for treating cirrhotic ascites according to claim 2, wherein It is prepared by the following drugs in parts by weight: Tuozhimu 15 parts, Jiulongpan 15 parts, Dafupiju 10 parts, Matujin 10 parts, Guizhencao 8 parts, Heijiacao 8 parts.

4. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 3, characterized in that, It comprises the following steps: (1) water extraction: Tuozhimu, Jiulongpan, Dafupiju, Matujin, Guizhencao and Heijiacao are weighed according to the prescription amount, and 4-10 times the total amount of water is added, heated at 80-95 ℃ for 1-3 times, each time for 0.5-2 h, filtered, and the water extract is obtained; (2) enzyme extraction: the water extracted residue is added with 8-12 times water, 1.0-3.0% cellulase is added, and the mixture is extracted at 50 ℃ and pH 5.0 for 1-2 h, then boiled and filtered, and the enzyme extract is obtained; (3) concentration: the water extract and the enzyme extract are combined and concentrated to a thick paste; (4) preparation of corresponding dosage forms: the thick paste is added with appropriate excipients for compounding, and the corresponding dosage forms are prepared.

5. The method of claim 4, wherein the pharmaceutical composition is prepared by, It comprises the following steps: (1) water extraction: Tuozhimu, Jiulongpan, Dafupiju, Matujin, Guizhencao and Heijiacao are weighed according to the prescription amount, and 6 times the total amount of water is added, heated at 85 ℃ for 0.5 h, filtered, and the water extract is obtained; (2) enzyme extraction: the water extracted residue is added with 10 times water, 1.0% cellulase is added, and the mixture is extracted at 50 ℃ and pH 5.0 for 1.5 h, then boiled and filtered, and the enzyme extract is obtained; (3) concentration: the water extract and the enzyme extract are combined and concentrated to a thick paste; (4) preparation of corresponding dosage forms: the thick paste is added with appropriate excipients for compounding, and the corresponding dosage forms are prepared.

6. The method of claim 4, wherein the pharmaceutical composition is prepared by, The excipient is a pharmaceutically acceptable excipient.

7. The method of claim 4, wherein the pharmaceutical composition is prepared by, The dosage forms are: solid preparations and liquid preparations.

8. The production method according to claim 7, wherein The solid preparations are: granules, capsules, tablets, and drop pills.

9. The preparation method according to claim 7, characterized in that, The liquid preparations are: mixtures and syrups.

10. The use of the pharmaceutical composition according to any one of claims 1-3 in the preparation of a medicament for treating liver cirrhosis ascites.

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