Traditional Chinese medicine compound granules for treating chronic gastritis and preparation method thereof

Abstract

The present invention relates to the technical field of Chinese medicine preparations, and in particular to a Chinese medicine compound granule for treating chronic gastritis and a preparation method thereof. The formula of the Chinese medicine compound granule is: 3-7 parts of Astragalus, 3-6 parts of White Peony, 4-7 parts of Taraxacum, 2-5 parts of Angelica Dahurica, 1-4 parts of Tangerine Peel, 1-4 parts of Jianqu, 1-2 parts of Citron, and 1-2 parts of Licorice. It is prepared by the following method: the raw material of the medicinal material is impregnated, then the medicinal material is boiled and extracted, the medicinal residue obtained by the extraction is crushed, and the decoction is performed again. The extract is combined and concentrated into an extract, and the extract and auxiliary materials including lactose and microcrystalline cellulose are mixed for spray granulation to obtain the Chinese medicine compound granule for treating chronic gastritis. This technical scheme can solve the technical problem of the lack of Chinese medicine preparations for efficiently treating chronic gastritis in the prior art, and through process improvement, the particle formability, fluidity, solubility, hygroscopicity and stability are guaranteed, and it has an ideal application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of Chinese medicine preparations, and in particular to a Chinese medicine compound granule for treating chronic gastritis and a preparation method thereof. Background Art

[0002] Chronic gastritis is a chronic inflammation of the gastric mucosa caused by various reasons. It is a common clinical digestive system disease. According to its pathological changes, chronic gastritis can be divided into chronic non-atrophic gastritis, chronic atrophic gastritis and special types of gastritis. Although chronic gastritis is not an acute or difficult disease, it is also a major precancerous disease of the stomach because it is the basis of many stomach diseases or other organs. Therefore, active and effective prevention and treatment of chronic gastritis is a key step in intervening in precancerous lesions of the stomach.

[0003] Chronic gastritis has symptoms such as epigastric pain, upper abdominal distension, belching, acid reflux, heartburn, and decreased appetite. At present, Western medicine treatment is mainly based on the principle of removing the cause, relieving symptoms and improving the inflammatory reaction of gastric mucosa. It often uses anti-infection, gastric mucosa protection, acid suppression and other drugs for combined treatment, but its overall effect is not good. Traditional Chinese medicine points out that the disease is located in the stomach and is closely related to the liver and spleen. The cause is based on spleen and stomach weakness, and is accompanied by dampness, heat, blood stasis, and toxicity. The use of traditional Chinese medicine characteristics has obvious advantages in relieving the clinical symptoms of chronic gastritis, improving gastric mucosal lesions, and intervening in the "inflammation-cancer" transformation. Therefore, the treatment of gastritis should consider both the inflammation, heat syndrome, and excess syndrome, as well as the spleen and stomach weakness. It should consider both the organic aspect and the gastric dysfunction aspect. It should use both ancient prescriptions and the achievements of modern Chinese medicine pharmacology. The ancient prescriptions Shaoyao Gancao Decoction and Huangqi Jianzhong Decoction can both be used to treat chronic gastritis, but the clinical efficacy of the above ancient prescriptions is limited. In-depth research is needed on the formula and preparation process for the treatment of chronic gastritis in order to develop more effective Chinese medicine preparations for the treatment of chronic gastritis. Summary of the invention

[0004] The purpose of the present invention is to provide a Chinese medicine compound granule for treating chronic gastritis, so as to solve the technical problem of lack of Chinese medicine preparations for treating chronic gastritis with high efficiency in the prior art.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] A Chinese medicinal compound granule for treating chronic gastritis, wherein the medicinal raw materials include, by weight, 3-7 parts of astragalus, 3-6 parts of white peony root, 4-7 parts of dandelion, 2-5 parts of angelica dahurica, 1-4 parts of tangerine peel, 1-4 parts of jianqu, 1-2 parts of citron, and 1-2 parts of liquorice.

[0007] This study is based on the empirical prescriptions selected and optimized based on the ancient prescriptions of Shaoyao Gancao Decoction and Huangqi Jianzhong Decoction. This prescription not only follows the ancient teachings, according to the syndrome differentiation, strengthens the spleen and replenishes qi, clears away heat and detoxifies, softens the liver and nourishes blood, relieves spasms and relieves pain, but also adopts the results of modern pharmacological research, uses Huangqi to remove Guizhi to nourish without warming and drying, uses Dandelion to clear without hurting the spleen, and adds Angelica dahurica, which is also a feature of this prescription. It has the effects of strengthening the spleen and replenishing qi, soothing the liver and harmonizing the stomach, stopping vomiting and reducing adverse reactions, clearing away heat and relieving inflammation. It is used for epigastric pain, acid reflux, belching, upper abdominal distension, and stuffiness caused by chronic atrophic gastritis, gastritis, chronic superficial gastritis, erosive gastritis, and gastric diseases.

[0008] Furthermore, in parts by weight, the medicinal raw materials include: 4 parts of astragalus, 5 parts of white peony root, 6 parts of dandelion, 3 parts of angelica dahurica, 2 parts of tangerine peel, 2 parts of Jianqu, 1 part of citron, and 1 part of licorice.

[0009] The technical solution also provides a method for preparing Chinese medicine compound granules for treating chronic gastritis, which is characterized by comprising the following steps performed in sequence:

[0010] S1: soaking the raw materials of medicinal materials;

[0011] S2: adding water to the soaked medicinal material raw material, decoct and extract 2-3 times; combining the filtrate obtained from each extraction to obtain a first water extract; crushing the medicinal residue after decoction and extraction, adding water to decoct and extract, and obtaining the filtrate to obtain a second water extract; combining the first water extract and the second water extract to obtain a total extract;

[0012] S3: Concentrate the total extract into an extract;

[0013] S4: Mix the auxiliary materials and the extract, and spray granulate them with a boiling drying granulator to obtain Chinese medicine granules.

[0014] Furthermore, in S1, the temperature condition of the immersion treatment is room temperature, and the duration of the immersion treatment is 0-30 minutes; the duration of the immersion treatment is preferably 30 minutes.

[0015] Further, in S2, 4-6 times the volume of the raw material of the medicinal material is added to the raw material of the medicinal material after the immersion treatment, and the extraction is decocted for 1-3 times, each time for 30-60 minutes; the filtrate obtained from each extraction is combined to obtain a first water extract; the residue after decoction and extraction is crushed, and then 4 times the volume of the raw material of the medicinal material is added for decoction and extraction, and the filtrate is obtained to obtain a second water extract; the first water extract and the second water extract are combined to obtain a total extract.

[0016] Further, in S2, 6 times the volume of the medicinal raw material is added to the medicinal raw material after the immersion treatment, and the mixture is boiled and extracted for 60 minutes, and the filtrate is taken to obtain a first water extract; the medicinal residue after the decoction and extraction is crushed, and 4 times the volume of the medicinal raw material is added to decoct and extract for 45 minutes, and the filtrate is taken to obtain a second water extract; the first water extract and the second water extract are combined to obtain a total extract.

[0017] Furthermore, in S2, the particle size of the dregs after crushing is 1-4 mm.

[0018] Further, in S3, the total extract is concentrated into an extract by vacuum concentration at 65°C, and the relative density of the extract is 1.152-1.190.

[0019] Further, in S4, the auxiliary material includes at least one of lactose, dextrin, soluble starch, and microcrystalline cellulose;

[0020] The auxiliary materials and extract were mixed and added into a boiling drying granulator. The 30% ethanol solution was atomized and sprayed directly onto the fluidized material. After drying for 0.5 h, cooling, granulation and unloading, the Chinese medicine granules were obtained. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection rate 5 mL / min.

[0021] Furthermore, the auxiliary materials are composed of lactose and microcrystalline cellulose; the mass ratio of the extract, lactose and microcrystalline cellulose is 1-2:1-5:1-5; preferably, the mass ratio of the extract, lactose and microcrystalline cellulose is 1:2:1.

[0022] The technical principle of this technical solution is:

[0023] The technical scheme discloses a Chinese medicine compound granule for treating chronic gastritis and a preparation method thereof, wherein the Chinese medicine compound comprises: astragalus, white peony root, dandelion, angelica dahurica, dried orange peel, Jianqu, bergamot, and liquorice. The above-mentioned medicinal materials are extracted with water, the residue after water extraction is crushed and extracted again, and the combined extract is concentrated to a thick paste. The method can obtain an extract rate of 30.37%, which is significantly better than the pure water extraction method. The preparation process is improved and optimized, and lactose and microcrystalline cellulose are selected as auxiliary materials for spray granulation, which can obtain more excellent granule forming property, fluidity, solubility, hygroscopicity and stability. The Chinese medicine granule of the present invention not only follows the ancient teachings, strengthens the spleen and replenishes qi according to syndrome differentiation, clears away heat and detoxifies, softens the liver and nourishes blood, relieves spasms and relieves pain, but also adopts the results of modern pharmacological research, uses astragalus to remove cinnamon twig to nourish without warming and drying, uses dandelion to clear without hurting the spleen, and adds angelica dahurica as a feature of this prescription. The granule dosage form not only maintains the characteristics of fast absorption and rapid action of decoction, but also overcomes the shortcomings of decoction, such as inconvenience of boiling, large dosage, and easy mildew, and significantly improves the efficacy. It has achieved good therapeutic effects in clinical use and has been recognized by the majority of patients.

[0024] The beneficial effects of this technical solution are:

[0025] (1) This program uses common Chinese medicinal materials as raw materials, has a scientific formula, is highly safe and has ideal therapeutic effects.

[0026] (2) The Chinese medicine compound granules of the present invention adopt the dosage form of granules, which have good dispersibility and fast absorption. The drugs reach the lesions quickly, thus significantly improving the therapeutic effect.

[0027] (3) The preparation method of the present invention is obtained through comparative experiments and process verification. The amount of extract can be greatly increased by crushing the drug residue and then extracting it again.

[0028] (4) In the granule forming process, when the ratio of extract: lactose: microcrystalline cellulose is 1:2:1, better forming properties, fluidity, solubility and hygroscopicity can be obtained. DETAILED DESCRIPTION

[0029] The present invention is further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following examples and experimental examples are conventional means well known to those skilled in the art, and the materials, reagents, etc. used can be obtained from commercial sources. The standards for the excipients used in this scheme refer to the 2020 edition of the Chinese Pharmacopoeia, Part IV, Pharmaceutical Excipients; the standards for the use of Chinese medicinal materials and decoction pieces refer to the 2020 edition of the Chinese Pharmacopoeia, Part I, Medicinal Materials and Decoction Pieces.

[0030] The following is further described in detail through specific implementation methods:

[0031] A Chinese medicine compound granule for treating chronic gastritis, the formula of which is, by weight, 3-7 parts of astragalus, 3-6 parts of white peony root, 4-7 parts of dandelion, 2-5 parts of angelica dahurica, 1-4 parts of tangerine peel, 1-4 parts of Jianqu, 1-2 parts of citron, and 1-2 parts of liquorice.

[0032] The Chinese medicine compound granules are prepared according to the following process (overall process):

[0033] S1: Weigh the Chinese medicinal materials astragalus, white peony root, dandelion, angelica dahurica, tangerine peel, Jianqu, citron, and liquorice according to the formula ratio, wash the medicinal materials, add purified water to immerse the medicinal materials (just immerse the medicinal materials fully), and immerse them at room temperature for 0-30 minutes (preferably 30 minutes).

[0034] S2: Transfer the medicinal materials to an extraction tank, add 4-6 times the volume of the medicinal materials, and heat the extraction for 30-60 minutes (decoction extraction). The above heating extraction process can be repeated 1-3 times. After each extraction, filter the filtrate, combine the filtrate obtained from each extraction, and obtain the first water extract, and at the same time retain the medicinal residue for subsequent processes. After the medicinal residue after water extraction is crushed into a particle size of 1-4mm, add 4 times the volume of the medicinal materials, heat and extract for 45 minutes, and obtain the second water extract after filtering.

[0035] The preferred operation method of this step is: add purified water 6 times the volume of the medicinal material, decoct and extract for 60 minutes, and then filter to obtain the first water extract. After the medicinal residue is crushed, add purified water 4 times the volume of the medicinal material, decoct and extract for 45 minutes to obtain the second water extract. The first water extract and the second water extract are combined to obtain the total extract.

[0036] S3: After the total extracts are combined, they are concentrated under reduced pressure at 65°C to a thick paste (vacuum degree is -0.04Mpa). The Baume degree of the thick paste is about 20 degrees (i.e., the relative density is 1.152-1.190).

[0037] S4: After spraying the auxiliary materials and the thick paste in a certain mass ratio, the granules are mixed and granulated. The auxiliary materials can be lactose, dextrin, soluble starch, microcrystalline cellulose (see "Chinese Pharmacopoeia" 2020 edition, Part IV, Pharmaceutical Excipients)

[0038] More specifically, the thick paste, lactose, and microcrystalline cellulose are preferably weighed according to the prescription ratio of 1-2:1-5:1-5 (further preferably 1:2:1), and a boiling drying granulator is used for spray granulation. The specific operation process is: the powder is introduced into the fluidized bed, and the 30% ethanol solution is atomized and sprayed directly onto the fluidized material (30% ethanol solution is used to wet the material, and the thick paste prepared from 1.2 kg of raw medicinal materials requires about 100 mL of 30% ethanol solution at the optimal ratio of thick paste and excipients). After drying for 0.5 hours, cooling, granulating, and unloading, the drug particles of this scheme are obtained. The parameters of the boiling drying granulator are set as follows: inlet temperature 60°C, air pressure adjusted to 0.6Mpa, and liquid injection speed 5mL / min.

[0039] Examples 1-8 are specific preparations of the above-mentioned Chinese medicine compound granules, and the specific conditions are as follows:

[0040] Example 1

[0041] Weigh 150g of Astragalus, 150g of White Peony, 200g of Taraxacum, 100g of Angelica Dahurica, 50g of Tangerine Peel, 50g of Jianqu, 50g of Citronella, and 50g of Licorice and put them into a thermal circulation multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to submerge the medicinal materials, decocted and extracted after immersion at room temperature for 30 minutes, and extract twice in total. For the first time, add 6 times the amount (volume of medicinal materials) of purified water after immersion and boil for 1 hour, and for the second time, add 4 times the amount of water and boil for 45 minutes, filter and combine the extracts, 65°C decompression concentration to 10 degrees Baume, stand for 6 hours and filter. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and dextrin were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0042] Example 2

[0043] Weigh 350g of Astragalus, 300g of White Peony, 350g of Taraxacum, 250g of Angelica Dahurica, 200g of Tangerine Peel, 200g of Jianqu, 100g of Citrus Hand, and 100g of Licorice and put them into a thermal circulation multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to submerge the medicinal materials, decocted and extracted after immersion at room temperature for 30 minutes, extract 2 times in total, add 6 times the amount (medicinal material volume) of purified water after immersion for the first time, decoct and boil for 1 hour, add 4 times the amount of water for the second time, decoct and boil for 45 minutes, merge the water extract after filtration, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and dextrin were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0044] Example 3

[0045] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice and put them into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to submerge the medicinal materials, decocted and extracted after immersion at room temperature for 30 minutes, and extract twice in total. For the first time, add 6 times the amount (medicinal material volume) of purified water after immersion and boil for 1 hour, and add 4 times the amount of water for the second time and boil for 45 minutes. After filtering, combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and dextrin were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0046] Example 4

[0047] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to immerse the medicinal materials, immerse at room temperature for 30 minutes, and then decoct and extract. Extract twice in total. For the first time, add 6 times (the volume of the medicinal materials) of purified water after immersion and boil for 1 hour. For the second time, crush the medicinal residue after water extraction and add 4 times the volume of the medicinal materials. Extract by heating for 45 minutes, and filter to obtain a water extract; combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and dextrin were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0048] Example 5

[0049] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to immerse the medicinal materials, immerse at room temperature for 30 minutes, and then decoct and extract. Extract twice in total. For the first time, add 6 times (the volume of the medicinal materials) of purified water after immersion and boil for 1 hour. For the second time, crush the medicinal residue after water extraction and add 4 times the volume of the medicinal materials. Extract by heating for 45 minutes, and filter to obtain a water extract; combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and microcrystalline cellulose were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0050] Example 6

[0051] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to immerse the medicinal materials, immerse at room temperature for 30 minutes, and then decoct and extract. Extract twice in total. For the first time, add 6 times (the volume of the medicinal materials) of purified water after immersion and boil for 1 hour. For the second time, crush the medicinal residue after water extraction and add 4 times the volume of the medicinal materials. Extract by heating for 45 minutes, and filter to obtain a water extract; combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 1:2:1, 1000 g of thick paste, lactose powder and soluble starch were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0052] Example 7

[0053] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to immerse the medicinal materials, immerse at room temperature for 30 minutes, and then decoct and extract. Extract twice in total. For the first time, add 6 times (the volume of the medicinal materials) of purified water after immersion and boil for 1 hour. For the second time, crush the medicinal residue after water extraction and add 4 times the volume of the medicinal materials. Extract by heating for 45 minutes, and filter to obtain a water extract; combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 2:1:5, 1000 g of thick paste, lactose powder and microcrystalline cellulose were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0054] Example 8

[0055] Weigh 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice into a thermal cycle multifunctional extraction tank. Rinse with normal water for 1 minute to wash away dust. Add purified water to the extraction tank to immerse the medicinal materials, immerse at room temperature for 30 minutes, and then decoct and extract. Extract twice in total. For the first time, add 6 times (the volume of the medicinal materials) of purified water after immersion and boil for 1 hour. For the second time, crush the medicinal residue after water extraction and add 4 times the volume of the medicinal materials. Extract by heating for 45 minutes, and filter to obtain a water extract; combine the water extracts, concentrate under reduced pressure at 65°C to 10 degrees Baume, and filter after standing for 6 hours. The filtrate is concentrated under reduced pressure at 65°C to a thick paste of about 20 degrees Baume (relative density of 1.152-1.190), and weigh. According to the prescription ratio of 2:5:1, 1000 g of thick paste, lactose powder and microcrystalline cellulose were weighed, the powder was introduced into the fluidized bed, 30% ethanol solution was atomized and sprayed directly onto the fluidized material, and the drug granules of this scheme were obtained after drying for 0.5 h, cooling, granulation and unloading. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection speed 5 mL / min.

[0056] The above embodiments of the present invention are for description only and do not represent the advantages or disadvantages of the embodiments.

[0057] In order to further verify the feasibility of the present invention, the inventor conducted a series of tests as follows:

[0058] The following test items all use the formula: 4 parts of Astragalus, 5 parts of White Peony, 6 parts of Dandelion, 3 parts of Angelica Dahurica, 2 parts of Tangerine Peel, 2 parts of Jianqu, 1 part of Citron, and 1 part of Licorice. More specifically, the prescription is: 200g of Astragalus, 250g of White Peony, 300g of Dandelion, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice.

[0059] Experimental Example 1: Extraction Process Research

[0060] (1) Soaking time

[0061] According to the prescription ratio of 1 / 10 of 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice, 8 herbs including Astragalus and White Peony were weighed and 6 times the amount of water were added. Each herb was soaked separately, and the soaking condition was observed every 10 minutes until all the herbs were soaked and the dry core of the herbs became soft, and the soaking time was recorded. The results are shown in Table 1. The herbs were basically soaked in 30 minutes, so the soaking time of 30 minutes was selected.

[0062] Table 1: Results of investigations at different immersion times

[0063] time result 0min All 8 medicinal materials are not transparent 10min 8 kinds of medicinal materials, some of them are heart-penetrating 20min Most of the 8 medicinal materials are heart-penetrating 30min All 8 medicinal materials are thoroughly

[0064] (2) Investigation of decoction extraction process parameters

[0065] The decoction extraction method of S2 was tested, and the determination method was as follows: 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice were weighed and decocted (total medicinal material mass 120g), and the extracts were finally combined and filtered for testing. The decoction process was carried out with reference to the overall process S2 mentioned above, and the specific method and parameter selection were shown in Table 2. The volume V of the combined extract was measured, 20mL was accurately drawn into a dry and weighed evaporating dish and concentrated to a thick paste, moved into a 105℃ oven for drying for 3 hours, taken out, cooled to room temperature in a desiccator, and the weight W was taken out to calculate the amount of extract, and the amount of extract (g) = (W×V) / 20×100%. The test results are shown in Table 3. The results show that the extraction rate of the extract after crushing the residue and then boiling again (Experiment 6) increased by 16.14% compared with the same conditions (Experiment 4), and the amount of extract reached 36.34g, which was also better than the effect of three decoctions (Experiment 5). Therefore, the extraction process conditions determined were that the eight medicinal materials such as Astragalus and White Peony were soaked in water for 30 minutes and then boiled twice. The first time, 6 times the amount of water was added for 60 minutes, and the second time, the residue was crushed and 4 times the amount of water was added for 45 minutes.

[0066] In addition, it is necessary to further explain that the present scheme adopts the scheme of not crushing the medicinal materials in the first decoction extraction, and crushing the medicinal materials in the second decoction extraction, which achieves the following effects: the 30-minute soaking before decoction can ensure the effective components in the medicinal materials, which can be accelerated in the subsequent decoction process; if crushing is performed during the first decoction extraction, the volatile components inside will volatilize prematurely; in order to ensure the full extraction of the effective components of the medicinal materials, the medicinal materials cannot be crushed during the first decoction extraction, so that the first decoction extraction can fully extract most of the volatile and non-volatile effective components; in the process of the second decoction extraction, the medicinal materials are crushed again to ensure that the remaining effective components are also fully extracted. The inventor once tried to decoct and extract the medicinal materials with 6 times the amount of water after crushing the medicinal materials on the basis of Experiment 1 in Table 2, and then continued to decoct and extract with 4 times the amount of water, and found that the amount of extract obtained was about 5-8% less than the amount of extract in Experiment 6, indicating that if all the medicinal materials are crushed before decoction extraction, some volatile components will be lost, resulting in a low amount of extract.

[0067] Table 2: Extraction process parameters

[0068]

[0069] Table 3: Extraction test results (average results of 3 repeated experiments)

[0070]

[0071]

[0072] Experimental Example 2: Molding Process Research

[0073] (1) Investigation of excipient types and dosage

[0074] Lactose (powder), dextrin, microcrystalline cellulose, and soluble starch were selected as excipients for granules, and a comprehensive scoring method was used to examine the formability, fluidity, solubility, and hygroscopicity of granules made in different proportions (formability 25 points, fluidity 25 points, solubility 25 points, hygroscopicity 25 points, total score 100 points). At the same time, the appearance of the granules was visually evaluated to select appropriate excipients. The types of excipients and their ratios to the extract are detailed in Tables 4-8. In addition, the process was carried out in accordance with the optimal process route of the "overall process" mentioned above to prepare Chinese medicine granules. The obtained granules were subjected to formability tests, angle of repose tests (fluidity tests), solubility tests, hygroscopic tests, etc. The specific test methods are as follows:

[0075] A. Formability Determination

[0076] A certain proportion of extract and auxiliary materials are granulated in one step to form granules (the sum of the mass of extract and auxiliary materials is 1000g, and all moldability experiments are fixed), first through a No. 1 sieve, then through a No. 5 sieve, collect the granules that can pass through the No. 1 sieve but cannot pass through the No. 5 sieve, and weigh them. Molding rate = mass of granules after sieving / material weight × 100%, moldability score = molding rate value / maximum molding rate value × 25. Among them, material weight = auxiliary materials + dry extract; dry extract is calculated based on a collection rate of 30.37%. The experimental results are shown in Table 4. In this technical solution, on the basis of the combination of extract and lactose, microcrystalline cellulose is added to obtain a higher molding rate, and the effect is significant. There is no relevant report on the effect of dextrin, microcrystalline cellulose and soluble starch on granule moldability in the prior art. Moreover, in the preparation process of other granules, microcrystalline cellulose as an auxiliary material has not shown the effect of improving moldability. For example, when the inventor prepared Chinese medicine granules containing Artemisia capillaris, Salvia miltiorrhiza, Forsythia suspensa, Scutellaria baicalensis, Angelica sinensis, and Sanguisorba officinalis, soluble starch was used for spray granulation, and the granule molding properties were better than those using microcrystalline cellulose. It can be seen that the effective improvement of granule molding effect by microcrystalline cellulose only appeared in this formula, and there was no way to predict it through prior art reports. Therefore, lactose and microcrystalline cellulose were used as granulation excipients in this formula, and unexpected technical effects were obtained.

[0077] Table 4: Formability test results (average value of 3 repeated tests)

[0078]

[0079]

[0080] B. Determination of the angle of repose

[0081] Using the fixed funnel method, three funnels are connected in series and fixed at a height of 1.5 cm on the horizontal coordinate paper. The particles are carefully poured into the uppermost funnel along the funnel wall until the tip of the particle cone formed on the coordinate paper touches the funnel mouth. The diameter of the cone bottom is measured by the coordinate paper (2r), and the angle of repose tgα=H / r is calculated. Do it 5 times and calculate the average value. The formula for calculating the angle of repose score is: minimum angle of repose value / angle of repose value×25. The experimental results are shown in Table 5. The size of the angle of repose reflects the friction and adhesion between particles. It is an important indicator for evaluating the fluidity of granular materials. A small angle of repose means that the friction between particles is small and the fluidity is good. A large angle of repose means that the friction between particles is large and the fluidity is poor. Materials with an angle of repose between 30° and 40° have good fluidity. Materials with an angle of repose greater than 40° have poor fluidity. In the production process of granules, if granules with poor fluidity are used, the material flow is likely to be poor during the packaging process, resulting in material accumulation, which leads to too little or too much in some small packages, which does not meet product requirements. Therefore, granule preparations need to maintain a small angle of repose to facilitate the smoothness of the preparation process.

[0082] Table 5: Results of angle of repose (average value of 3 repeated experiments)

[0083]

[0084]

[0085] C. Determination of dissolution rate

[0086] Add precisely weighed particles to a 10mL centrifuge tube (minimum scale 0.1mL) of dry constant weight, accurately add 10mL of boiling water, stir and shake for 5min, centrifuge at 3000rpm / min for 10min, discard the supernatant, dry the residue at 90℃ to constant weight, accurately weigh, and calculate the dissolution rate. Dissolution rate = (particle mass - residue mass) / particle mass 100%, dissolution rate score calculation formula: dissolution rate value / maximum dissolution rate value × 25. The experimental results are shown in Table 6.

[0087] Table 6: Melting rate determination results (average value of 3 repeated experiments)

[0088]

[0089] D. Determination of hygroscopicity

[0090] Place the sample in a flat weighing bottle of known weight, weigh it accurately, store it in a constant temperature incubator at 25°C and 75% relative humidity for 48 hours away from light, and then take it out and weigh it accurately. Moisture absorption rate = (hygroscopic particles - original particles) / original particles × 100%; the formula for calculating the hygroscopicity score is: minimum moisture absorption rate / moisture absorption rate value 25. The experimental results are shown in Table 7.

[0091] Table 7: Hygroscopicity test results (average value of 3 repeated experiments)

[0092]

[0093] The results of comprehensive formability determination, angle of repose determination, dissolution rate determination, and hygroscopicity determination are shown in Table 8. It can be seen from the comprehensive scoring results that the effects of formability, fluidity, solubility, and hygroscopicity of granules obtained by granulating with different excipients in different proportions are completely different. The granules obtained with extract: lactose: microcrystalline cellulose = 2:1:5 have the highest comprehensive score, ideal formability and fluidity, good solubility, and low hygroscopicity. Lactose and microcrystalline cellulose are used in combination with extracts in a certain mass ratio. Compared with lactose and other excipients, the obtained Chinese medicine granules have obvious advantages in formability, fluidity, solubility, and hygroscopicity under the same preparation process.

[0094] For example, the forming rate of the particles obtained by the condition of "extract: lactose: microcrystalline cellulose = 1:2:1" is 93.17%, while the forming rate of the particles obtained by the condition of "extract: lactose: dextrin = 1:2:1" is only 81.24%, and the forming rate of the particles obtained by the condition of "extract: lactose: soluble starch = 1:2:1" is only 84.2%. It can be seen that the use of this technical solution can increase the forming rate of the product by about 9-12%, which is a relatively large increase. Microcrystalline cellulose, dextrin and soluble starch are all conventional auxiliary materials for preparing granules in the prior art. In theory, there is no great difference in the particle forming rate using these three substances. However, the extract prepared by the formula of this solution actually shows a significant improvement effect of microcrystalline cellulose, which was not expected by the inventor before the experimental study. Similarly, the angle of repose of the particles obtained using the condition of "extract: lactose: microcrystalline cellulose = 1:2:1" is 30.3°, while the angle of repose of the particles obtained using the condition of "extract: lactose: dextrin = 1:2:1" is 36.5°, and the angle of repose of the particles obtained using the condition of "extract: lactose: soluble starch = 1:2:1" is 35.3°. The use of microcrystalline cellulose plays a very significant role in improving the fluidity of the particles, reducing the angle of repose of the product by about 15-20%, which is also something that the inventors could not have anticipated before the experimental research.

[0095] The moisture absorption rate of the particles obtained by the condition of "extract: lactose: microcrystalline cellulose = 1:2:1" is 2.16%, while the angle of repose of the particles obtained by the condition of "extract: lactose: dextrin = 1:2:1" is 10.68%, and the angle of repose of the particles obtained by the condition of "extract: lactose: soluble starch = 1:2:1" is 4.91%. "Extract: lactose: microcrystalline cellulose = 1:2:1" plays a very significant role in reducing the moisture absorption rate compared with other conditions, and the moisture absorption rate is about one-half or one-fifth of the other two conditions. When the particles are dissolved (dissolution rate determination), microcrystalline cellulose can quickly absorb water and swell after encountering water, destroying the particle structure, thereby accelerating the disintegration process and having good solubility. The solubility of particles using microcrystalline cellulose as an excipient is equivalent to that using dextrin and soluble starch, that is, the affinity of these excipients with water is roughly equivalent. However, under the storage conditions of granules (non-dissolving conditions), the condition of "extract: lactose: microcrystalline cellulose = 1:2:1" (especially using microcrystalline cellulose as an excipient) can maintain a very low moisture absorption rate, which has significant advantages over dextrin and soluble starch. This shows that the use of the excipient combination of lactose and microcrystalline cellulose has achieved unexpected technical effects compared to other excipient forms. The inventor analyzed the reasons as follows: the nature of lactose is relatively stable and non-hygroscopic. Microcrystalline cellulose is used in an environment composed of extract and lactose in this scheme, which can greatly reduce the hygroscopicity of the particles and increase the stability of the drug. However, other Chinese medicine granule excipients such as dextrin and soluble starch cannot achieve the effect of microcrystalline cellulose.

[0096] In addition, the inventors also tried the schemes of "extract: lactose = 1:3" and "extract: microcrystalline cellulose = 1:3", and prepared the granules with reference to the optimal process parameters of the overall process described above. It was found that when "extract: lactose = 1:3", the anti-hygroscopicity of the obtained Chinese medicine granules was very excellent, but the fluidity of the granules was not very ideal, the average angle of repose was greater than 40°, and the formability was not ideal, with a forming rate of less than 82%. When "extract: microcrystalline cellulose = 1:3", the anti-hygroscopicity of the obtained Chinese medicine granules was significantly lower than that of the optimal method of the present technical solution, and the formability was not ideal, with a forming rate of less than 85%. However, this scheme adopts the form of "extract: lactose: microcrystalline cellulose = 1:2:1", and the angle of repose of the obtained Chinese medicine granules is 30.3°, and the formability can reach 93.7%. This shows that for the specific Chinese medicine extract of this solution, the combination of the auxiliary materials lactose and microcrystalline cellulose can effectively ensure the formability and fluidity of the Chinese medicine granules, and the combination of the two auxiliary materials has achieved unexpected technical effects. The synergistic effect of the combined use of lactose and microcrystalline cellulose mentioned above has not been reported in other Chinese medicine extracts. The effects of lactose and microcrystalline cellulose on the extract of this formula were discovered by the inventor for the first time, and the above effects were used to prepare Chinese medicine granules with ideal performance.

[0097] In summary, the combination of extract, lactose and microcrystalline cellulose excipients and drug raw materials can comprehensively improve the quality of particles in terms of formability, fluidity, solubility and hygroscopicity, and achieve unexpected technical effects.

[0098] Table 8: Comprehensive scoring results

[0099]

[0100] Experimental Example 3: Hygroscopicity Test

[0101] The hygroscopicity test method was used to determine whether the moisture absorption resistance of the extract after adding excipients met the process requirements. 2g of pure extract (see the optimal preparation process above) and granules made according to the ratio of extract: lactose: microcrystalline cellulose = 1:2:1 were accurately weighed and placed in flat weighing bottles, respectively, and stored in a constant temperature incubator at a temperature of 25°C and a relative humidity of 75%. The moisture absorption was measured after 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, and 96 hours, respectively, to examine the moisture absorption percentage of pure extract powder and granules with excipients added. The experimental results are detailed in Table 9. The results show that the extract powder has better moisture absorption resistance after adding excipients than the pure extract powder.

[0102] Table 9: Hygroscopicity test results (average value of 3 repeated experiments)

[0103]

[0104] Experimental Example 4: Small-scale trial production

[0105] The optimal process method of this scheme was used to carry out three batches of small-scale production, and the prescription used was: 200g of Astragalus, 250g of White Peony, 300g of Taraxacum, 150g of Angelica Dahurica, 100g of Tangerine Peel, 100g of Jianqu, 50g of Citron, and 50g of Licorice. The prepared Chinese medicine compound granules were mixed and packaged, with 10 grams per bag. The results are shown in Table 10.

[0106] Table 10: Small-scale test results (average results of 3 repeated experiments)

[0107] batch number 1 2 3 Extracted medicinal materials (kg) 1.2 1.2 1.2 Extract weight (kg) 0.36 0.35 0.33 Amount of microcrystalline cellulose (kg) 0.25 0.25 0.25 Lactose dosage (kg) 0.50 0.50 0.50 Theoretical output (bag) 100 100 100 Actual output (bags) 95 93 93 Yield rate (%) 95 93 93

[0108] Experimental Example 5: Pilot Production

[0109] Three batches of small-scale production were carried out using the optimal process method of this scheme. The prescription used was: 2000g of Astragalus, 2500g of White Peony, 3000g of Taraxacum, 1500g of Angelica Dahurica, 1000g of Tangerine Peel, 1000g of Jianqu, 500g of Citrus Hand, and 500g of Licorice. The prepared Chinese medicine compound granules were mixed and granulated and then packaged, with 10 grams per bag. The results are shown in Table 11.

[0110] Table 11: Pilot test results (average value of 3 repeated experiments)

[0111] batch number 1 2 3 Extracted medicinal materials (kg) 12 12 12 Extract weight (kg) 3.56 3.53 3.62 Amount of microcrystalline cellulose (kg) 2.5 2.5 2.5 Lactose dosage (kg) 5.0 5.0 5.0 Theoretical output (bag) 1000 1000 1000 Actual output (bags) 980 969 973 Yield rate (%) 98.0 96.9 97.3

[0112] Experimental Example 6: Quality Standard Identification

[0113] (1) Identification of Astragaloside IV

[0114] According to the preferred process of this scheme, Chinese medicine granules are prepared. After obtaining the extract, take an appropriate amount of granules prepared according to the ratio of extract: lactose: microcrystalline cellulose = 1:2:1, grind it, accurately weigh 10g and place it in a stoppered conical bottle, add 50mL of methanol, treat it with ultrasound (frequency 60kHz) in warm water (40-50°C) for 30 minutes, filter, evaporate the filtrate in a water bath, dissolve the residue in 20mL of warm water (40-50°C), extract it twice with water-saturated n-butanol, 30mL each time, combine the n-butanol solution, wash it twice with ammonia test solution, 30mL each time, discard the ammonia test solution, wash it twice with water, 30ml each time, discard the water solution, evaporate the n-butanol solution in a water bath, and dissolve the residue in 1mL of methanol as the test solution. Take another reference substance of astragaloside IV, add methanol to make a solution containing 0.5mg per 1mL as the reference substance solution. According to the thin layer chromatography test (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0502), 10 μL of each of the above solutions were taken and spotted on the same silica gel G thin layer plate, and the lower layer solution of chloroform: methanol: water (13: 7: 2) was placed below 10°C as the developing agent, developed, taken out, dried, sprayed with 10% sulfuric acid ethanol solution, heated at 105°C until the spots were clearly colored, and inspected under sunlight. In the test sample chromatogram, at the corresponding position of the control chromatogram, spots of the same color appeared under sunlight; under ultraviolet light (365nm), fluorescent spots of the same color appeared. The Chinese medicine compound granules of the present invention show the same fluorescent spots at the corresponding position of astragaloside IV in the control chromatogram, and the spots are clear, and there is no interference with the negative control.

[0115] (2) Identification of paeoniflorin

[0116] According to the preferred process of this scheme, Chinese medicine granules are prepared. After obtaining the extract, take an appropriate amount of granules made according to the ratio of extract: lactose: microcrystalline cellulose = 1:2:1, grind, accurately weigh 10g and place in a stoppered flask, add 50mL of anhydrous ethanol, shake, seal, ultrasonic (60kHz) treatment for 10min, let stand for stratification, filter, collect the filtrate, evaporate to dryness, and dissolve the residue in 1mL of anhydrous ethanol to obtain the test solution. Separately take the paeoniflorin reference substance, add anhydrous ethanol to make a solution containing 1mg per 1mL as the reference substance solution. According to the thin layer chromatography test (Chinese Pharmacopoeia 2020 Edition Four General Rules 0502), take 10μL of each of the above solutions, spot them on the same silica gel G thin layer plate, use chloroform: methanol: formic acid (20:4:0.05) as the developing agent, develop, take out, dry, spray with 10% sulfuric acid ethanol solution, heat at 105°C until the spots are clear, and inspect under sunlight. In the chromatogram of the test product, the same color spot is displayed at the corresponding position of the chromatogram of the reference product. The Chinese medicine compound granules of the present invention show the same fluorescent spot at the corresponding position of the peony glycoside in the reference chromatogram, and the half spot is clear, and there is no interference with the negative control.

[0117] Experimental Example 7: Particle Size Determination

[0118] According to the particle size determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0982, Second Method, Double Screening Method), the sum of the granules that cannot pass through the No. 1 sieve and can pass through the No. 5 sieve according to the extract: lactose: microcrystalline cellulose = 1:2:1 and the optimal process shall not exceed 15%. The experimental results are shown in Table 12, and the results show that the Chinese medicine compound granules of the present invention meet the regulations and do not exceed the specified limit.

[0119] Table 12: Particle size determination results (average value of 3 repeated experiments)

[0120]

[0121] Experimental Example 8: Moisture Determination

[0122] According to the moisture determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0832), the moisture content of the granules prepared according to the extract: lactose: microcrystalline cellulose = 1:2:1 and the optimal process shall not exceed 8.0%. The experimental results are shown in Table 13, and the results show that the Chinese medicine compound granules of the present invention meet the regulations and do not exceed the prescribed limit.

[0123] Table 13: Moisture determination results (average value of 3 repeated experiments)

[0124]

[0125] Experimental Example 9: Solubility Determination

[0126] According to the solubility test method under the granule item (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0104), accurately weigh 10g of granules made according to the extract: lactose: microcrystalline cellulose = 1:2:1 and the optimal process, add 200mL of hot water and stir for 5 minutes. Immediately observe that all should be dissolved, and slight turbidity is allowed. The experimental results are shown in Table 14. The results show that this product meets the requirements and is completely dissolved within 5 minutes.

[0127] Table 14: Solubility test results (average value of 3 repeated experiments)

[0128]

[0129] Experimental Example 10: Difference in Filling Volume

[0130] According to the test method for the difference in filling quantity under the 0104 granule item of the 2020 edition of the Chinese Pharmacopoeia, 10 bags (10g / bag) of granules made with extract: lactose: microcrystalline cellulose = 1:2:1 and the optimal process were weighed, and the weight of each bag was compared with the labeled amount. No more than 2 bags of granules exceeded the limit of filling quantity difference (±5%), and no bag exceeded the limit by 1 times. The experimental results are shown in Table 15, and the results show that the difference in filling quantity per bag meets the regulations.

[0131] Table 15: Results of the measurement of the difference in loading (average value of 3 repeated experiments)

[0132]

[0133] Experimental Example 11: Content Determination

[0134] Paeoniflorin: Determined by high performance liquid chromatography according to General Chapter 0512 of Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China.

[0135] Chromatographic column: octadecylsilane bonded silica gel as filler; mobile phase: acetonitrile-methanol-0.1% phosphoric acid solution (7:13:80); detection wavelength: 230nm; column temperature: 30°C; theoretical plate number based on paeoniflorin is not less than 3000; separation degree: R>1.5.

[0136] Preparation of reference solution: Take an appropriate amount of paeoniflorin reference substance, weigh accurately, add methanol to make 1 ml of solution containing 50 μg, shake well, and obtain.

[0137] Preparation of test solution: Take an appropriate amount of Chinese medicine compound granules, grind them into powder, weigh 1g, accurately weigh, place in a stoppered conical bottle, accurately add 50mL of methanol, seal, and weigh. Ultrasonic (60kHz) treatment for 30min, cool, wipe dry, weigh, make up the lost weight with methanol, shake well, filter with a microporous filter membrane (0.45μm), and obtain.

[0138] Determination method: Accurately pipette 10 μL of reference substance and test substance solution respectively, inject into liquid chromatograph, and determine.

[0139] ① Exclusiveness

[0140] According to the prescription ratio, the remaining medicinal materials except white peony root were accurately weighed, and a negative control without white peony root was prepared according to the preparation method, and a negative control solution was prepared by the same preparation method as the "test solution". The peony inoside reference solution, test solution, and negative control solution were measured under the above chromatographic conditions. Under this chromatographic condition, peony inoside can be well separated, with a good peak shape and a moderate retention time. The negative control solution has no chromatographic peak at the retention time of peony inoside, and there is no interference.

[0141] ②Linear range

[0142] Take 26.62 mg of paeoniflorin reference substance, place it in a 25 mL volumetric flask, add methanol to dilute to the scale, and make a paeoniflorin reference substance solution with a concentration of 1.010 mg / mL. Take 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL, 1 mL, and 1.2 mL respectively and dilute to 10 mL to make solutions with concentrations of 20.21 μg / mL, 40.42 μg / mL, 60.63 μg / mL, 80.84 μg / mL, 101.05 μg / mL, and 121.26 μg / mL. Inject 10 μL, measure and record the chromatogram.

[0143] The measurement results are shown in Table 16. The results show that the concentration of paeoniflorin is in the range of 20.21 to 121.3 μg / mL, and the concentration and peak area have a good linear relationship.

[0144] Table 16: Results of linear range determination of paeoniflorin

[0145] serial number 1 2 3 4 5 6 Concentration C (μg / mL) 20.21 40.42 60.63 80.84 101.0 121.3 Peak area A 261.52 532.05 793.57 1048.09 1322.62 1587.14

[0146] ③Repeatability test

[0147] Accurately weigh 6 portions of Chinese herbal compound granules, prepare the test solution according to the preparation method of the test solution, inject the sample, record the chromatogram, and the RSD value of the six measurement results shall not exceed 3.0%.

[0148] ④Intermediate precision test

[0149] Accurately weigh 10.29 mg of paeoniflorin reference substance, place it in a 50 mL volumetric flask, add methanol to dilute the solution, take 1 mL of this solution, dilute and dissolve it to 10 mL with methanol, and prepare a paeoniflorin reference substance solution with a concentration of 19.53 μg / mL. According to different experimenters at different times, the sample is injected and measured (n=3), the peak area is recorded, and the calculated RSD shall not be greater than 3.0%. The experimental results are shown in Table 17. The results show that: different experimenters inject samples at different times, and the RSD value is less than 3.0%, and the precision is good.

[0150] Table 17: Intermediate precision determination results (average value of 3 repeated experiments)

[0151]

[0152]

[0153] ⑤Accuracy

[0154] Sample recovery test: Take 0.5g of a sample with a known content, weigh it accurately, take six portions in total, add the paeoniflorin reference solution to each portion, dilute it to 50mL with methanol, shake well, take 2mL of the above solution accurately, add it to the above 6 samples, make the reference amount added to each portion a fixed value, prepare the test solution according to the sample processing method, inject the sample, record the chromatogram, calculate its recovery rate and relative average deviation. The results show that the average recovery rate is within the range of 90.0-108.0%, the RSD is less than 2.0%, and the accuracy meets the requirements.

[0155] ⑥ Sample content determination and content limit establishment

[0156] Six samples from different batches were accurately weighed respectively, and the content of paeoniflorin in each bag (10 g / bag) of the Chinese medicine compound granules was determined and calculated according to the content determination method (the content of paeoniflorin reference substance was calculated as 94.9%). The experimental results are shown in Table 18.

[0157] Table 18: Results of determination of paeoniflorin content in samples (average value of 3 repeated experiments)

[0158]

[0159] Experimental Example 12: Pharmacodynamics Study

[0160] ①Establishment of rat chronic atrophic gastritis model

[0161] Healthy SD rats were selected, half male and half female, and gavaged with 2% sodium salicylate solution, once a day, 2 mL / rat, for 6 weeks. No food or water was allowed for 1 hour before and after gavage. Sufficient food was allowed for the first 3 weeks, and no food or water was allowed for the next 3 weeks. Sufficient food was allowed for the odd-day fasting but no water restriction, and sufficient food was allowed for the even-day fasting. The rats were also allowed to swim for 10 minutes in warm water at 28°C every day after meals.

[0162] ② Experimental grouping and drug administration

[0163] 84 SD rats were randomly divided into the following 6 groups according to gender and weight, with 14 rats in each group. ① Normal control group: ② Model group: ③ High-dose group of granules of this scheme (6g / kg); ④ Medium-dose group of granules of this scheme (3g / kg); ⑤ Granule dose group of this scheme (1.5g / kg); ⑧ Sanjiu Weitai group (4g / kg); After 6 weeks of modeling, fasting and swimming were stopped and experimental treatment began. The drugs in each administration group were dissolved in normal saline, and the animal administration volume was 1mL / 100g, once a day; Normal control group and model group were given 1mL / 100g of normal saline. And groups 2-6 were changed to oral administration of 2mL of 2% sodium salicylate solution every other day, and sufficient food was eaten during the treatment period. Gastric juice analysis and gastric mucosal pathology examination were performed after one month of treatment.

[0164] ③ Gastric acid and pepsin activity determination

[0165] Gastric juice collection: After fasting for 24 hours, rats were anesthetized by intraperitoneal injection of 1.5% pentobarbital, 30 mg / kg, and the stomach was exposed by midline incision in the upper abdomen, and the pylorus was ligated. After 4-6 hours, the cardia was ligated again, and the lower end of the esophagus and the proximal end of the duodenum were cut off, and the gastric juice was collected in a container, centrifuged and the supernatant was taken for gastric acid determination and pepsin activity determination.

[0166] Gastric acidity determination: Take the gastric juice after centrifugation and use an acidity meter to determine the pH value. Use p-dimethylazoaniline and phenolphthalein ethanol as free acid and total acid indicators, respectively, and titrate with NaOH to measure the free acid and total acid content, respectively.

[0167] Pepsin activity assay: Cut a capillary glass tube with an inner diameter of 2 mm and uniform thickness into 10 cm long sections. Take an appropriate amount of egg white and stir it, then fill the capillary glass tube with egg white and immediately place it in a water bath above 85°C to solidify it. Seal both ends with wax and refrigerate at 4°C for later use. Place the solidified glass tube filled with egg white into 1 mL of gastric juice, digest it at 37°C for 8 hours, and accurately measure the length of the transparent part at the end of the capillary tube. The length of the transparent part is used to represent the level of pepsin activity.

[0168] Pathological examination of gastric tissue: Two cases were randomly selected from each experimental group, and tissues from the gastric fundus, gastric body, and gastric antrum were removed, fixed with formalin, embedded in paraffin, stained with HE, and examined and photographed under a light microscope.

[0169] The results showed that after each group of rats were modeled, 2 cases were randomly selected from each group for gastric mucosal pathological examination. Obvious pathological changes were found in each case, with thinning of the gastric mucosa, reduction in cell number and vacuolar changes, glandular atrophy, and a large number of inflammatory cells infiltrating the mucosal layer and submucosal layer. After confirming that the model was established, experimental treatment was carried out with the granules of this scheme of the present invention, and gastric function and morphological examination were carried out after 8 weeks of treatment. The experimental results are shown in Table 19.

[0170] Table 19: Effects of the granules of this regimen on gastric acidity and protein activity in rats with salicylic acid-induced atrophic gastritis

[0171]

[0172] Note: # indicates P<0.05 compared with the normal group; * indicates P<0.05 compared with the model group.

[0173] As shown in Table 19, compared with the normal control group, the model group had a significantly increased gastric juice pH value, a reduced gastric free acid, and a reduced pepsin activity, which was consistent with the clinical manifestations of chronic atrophic gastritis. Combined with pathological findings, it was proved that this model was successfully established. Compared with the model group, the gastric acidity of each treatment group of the granules of this scheme was significantly improved, and the pepsin activity was significantly increased. It is shown that the granules of this scheme have the effect of promoting gastric acid secretion and increasing pepsin activity, and have a significant therapeutic effect on the rat model of chronic atrophic gastritis caused by salicylic acid. Although there is no statistical significance compared with the Sanjiu Weitai group, it can be seen that there is no significant difference in free acid and pepsin activity between the Sanjiu Weitai group and the model group. It is shown that the granules of this scheme prepared by the present invention have a good therapeutic effect on the rat model of chronic atrophic gastritis caused by sodium salicylate solution, and its therapeutic effect may be better than that of the Sanjiu Weitai group.

[0174] The results showed that the granules of this regimen had a significant therapeutic effect on the salicylic acid-induced chronic atrophic gastritis model in rats.

[0175] Experimental Example 13: Acute toxicity test

[0176] According to the preliminary test results, the total lethal dose of the granules in this scheme for a single daily administration is 450g crude drug / kg, and the total non-lethal dose is 276g crude drug / kg. Therefore, 450g crude drug / kg is used as the total lethal dose, and four groups (398g crude drug / kg, 352g crude drug / kg, 311g crude drug / kg, and 276g crude drug / kg / kg) are set downward with a coefficient of 0.885 to carry out LD50 determination.

[0177] 60 Kunming mice were randomly divided into 6 groups according to body weight, fasted for 12 hours but not water, and given different amounts of the granules of this scheme according to the table below: the control group was given an equal volume of 0.5% CMC solution.

[0178] See Table 20 and Table 21 for the grouping method and experimental results. The animals were observed continuously for 4 hours after administration. From the next day to 14 days after administration, the toxic reactions and deaths of the animals were observed and recorded once every morning. The results showed that 5-20 minutes after the administration of the granules of this regimen, the animals had symptoms of toxic reactions such as watery stools, erect hair, decreased spontaneous activity, prone position, difficulty breathing, slower and deeper breathing, and the severity of the symptoms was positively correlated with the dose. The time of death of the animals ranged from 30 minutes to 1 day after administration, mostly concentrated within 2 hours, and breathing stopped before the heartbeat at the time of death. Autopsy observation revealed that the intestines of the animals were mostly congested with effusion and cardiac congestion. The surviving animals gradually returned to normal 4 hours after administration and began to eat. After the 14-day test, the surviving animals were killed by cervical vertebrae and anatomical observation showed that there were no obvious abnormalities in various tissues and organs. The LD50 was calculated using the median effective dose method 50 It is 347.43 g crude drug / kg, and its 95% confidence limit is 312.69-371.75 g crude drug / kg.

[0179] Table 20: Experimental groups and administration methods

[0180]

[0181]

[0182] Table 21: Death of animals in single-dose toxicity test in mice

[0183]

[0184] Experimental Example 14: Clinical Efficacy Verification

[0185] In order to verify the therapeutic effect of Chinese herbal compound granules on chronic gastritis, the inventor's team conducted a clinical verification study at the Southwest Hospital of the First Affiliated Hospital of Army Medical University.

[0186] ① General information

[0187] The plan enrolled 120 patients, and 118 patients were actually enrolled, including 65 males and 53 females, aged 22-65 years (mean age 42±6.12 years). Among them, 93 patients had chronic superficial gastritis and 25 patients had chronic atrophic antral gastritis.

[0188] ②Inclusion, exclusion and elimination criteria

[0189] All patients participating in this study met the Western medical diagnostic criteria for chronic gastritis and TCM meridian differentiation, and were aged between 18 and 65 years old. Patients under 18 or over 65 years old, pregnant or lactating women, allergic conditions, and allergic to this drug were excluded. Patients with gastric or duodenal ulcers, severe dysplasia of the gastric mucosa, or suspected malignant changes in pathological diagnosis were excluded. Patients with serious primary diseases such as cardiovascular, cerebrovascular, liver, kidney, and hematopoietic systems, and mental illness were excluded. Patients with poor compliance, failure to use medication as prescribed, inability to judge efficacy, and need to terminate the trial due to adverse reactions and other reasons were excluded; those who added other similar drugs during the trial or drugs that affect the judgment of efficacy and safety; and those with incomplete data that affect the judgment of efficacy and safety were excluded.

[0190] ④Diagnostic criteria

[0191] Western medicine diagnostic criteria for chronic gastritis: Refer to the diagnostic criteria for chronic atrophic gastritis in the "Chinese Consensus on Chronic Gastritis" and make a clear diagnosis through medical history, clinical symptoms and signs, and gastroscopy.

[0192] TCM syndrome differentiation criteria: refer to the "Expert Consensus on TCM Diagnosis and Treatment of Chronic Gastritis (2017)".

[0193] ⑤Case grouping

[0194] A randomized, parallel controlled trial design was adopted, the indication was chronic gastritis, and Sanjiu Weitai Granules were selected as the control drug. According to the random principle, 118 patients were divided into a trial group of 60 cases, who took the granules of this regimen orally; and a control group of 58 cases, who took Sanjiu Weitai Granules orally. There were 46 cases of chronic superficial gastritis and 14 cases of chronic atrophic antral gastritis in the trial group. There were 47 cases of chronic superficial gastritis and 11 cases of chronic atrophic antral gastritis in the trial group.

[0195] ⑥Treatment methods

[0196] The experimental group was given 10g / bag of this granule, three times a day; the control group was given 20g / bag of Sanjiu Weitai Granule, three times a day. Both were taken with warm water 30 minutes before meals, with a course of three months. The above patients stopped taking other drugs for treating gastritis during the treatment period.

[0197] ⑦Observation indicators

[0198] Safety observation: general physical examination items; routine blood, urine and stool tests; heart, liver and kidney function tests.

[0199] Efficacy observation: related symptoms and signs; gastroscopy and biopsy; basic gastric acid test or pentagastrin analysis; pepsinogen determination (blood pepsinogen Ⅰ, Ⅰ / Ⅰ ratio); serum gastrin determination; serum gastrin cell antibody (GCA), parietal cell antibody (PCA) determination; blood routine; Helicobacter pylori test. Among them, related symptoms and signs, gastroscopy and biopsy are mandatory, and others can be selected according to the condition and clinical research needs.

[0200] ⑧Basis for judging efficacy

[0201] Chronic superficial gastritis:

[0202] Clinical recovery: symptoms and signs disappear; gastroscopy and biopsy show that acute inflammation disappears, chronic inflammation becomes mild, and bile reflux disappears.

[0203] Markedly effective: symptoms and signs improved by more than 2 levels; acute inflammation in gastroscopy and biopsy basically disappeared, the degree of chronic inflammation improved by 1 degree, and bile reflux decreased by more than 2 / 3.

[0204] Effective: symptoms and signs improved by more than 1 grade; endoscopy and biopsy showed that the range of mucosal lesions was reduced by more than 1 / 2, the degree of acute and chronic inflammation was reduced by 1 degree, and bile reflux was reduced by more than 1 / 2.

[0205] Ineffective: Failure to meet effectiveness standards or worsening.

[0206] Chronic atrophic antral gastritis:

[0207] Clinical cure: clinical symptoms and signs disappear, endoscopic examination shows significant improvement in chronic mucosal inflammation, and biopsy shows that glandular atrophy, intestinal metaplasia and dysplasia return to normal or disappear.

[0208] Markedly effective: The main clinical symptoms and signs disappeared, endoscopic examination showed improvement in chronic mucosal inflammation, and pathological examination of living tissue confirmed that glandular atrophy, cerebral metaplasia and dysplasia returned to normal or were reduced by 2 degrees.

[0209] Effective: The main symptoms and signs were significantly alleviated. Endoscopic examination showed that the scope of mucosal lesions was reduced by more than 1 / 2, and the inflammation was alleviated. Biopsy of the tissues confirmed that the chronic inflammation was reduced, and glandular atrophy, intestinal metaplasia and dysplasia were alleviated.

[0210] Invalid: Failure to meet the validity criteria or deterioration.

[0211] ⑨Results

[0212] Clinical symptoms: In the experimental group, 28 cases were cured (all symptoms disappeared), 19 cases were markedly effective (symptoms basically disappeared, with occasional upper abdominal discomfort), 7 cases were effective (symptoms improved significantly), 6 cases were ineffective (symptoms did not improve), and the total clinical effective rate was 90%. In the control group, 30 cases were cured, 15 cases were markedly effective, 4 cases were effective, 9 cases were ineffective, and the total clinical effective rate was 84%. The two groups were tested by Ridit test, P>0.05.

[0213] Gastroscopy: 56 patients in the experimental group underwent gastroscopy within 3 days after the end of the treatment. Among them, 8 cases (healing of gastric mucosal erosion or disappearance of congestion and edema), 19 cases were markedly effective (significant improvement of gastric mucosal congestion and edema, increased mucus spots and enhanced reflection), 13 cases were effective (improvement of gastric mucosal congestion and edema, increased mucus spots and enhanced reflection), 16 cases were ineffective (same as before taking the medicine, no improvement), and the total effective rate of gastroscopy was 71%. 53 cases in the control group underwent gastroscopy, among which 6 cases were cured, 9 cases were markedly effective, 16 cases were effective, 22 cases were ineffective, and the total effective rate of gastroscopy was 53%. The comparison between the two groups was tested, P>0.05.

[0214] Pathological examination: Among the 56 cases in the experimental group, 6 were cured (pathological examination returned to normal), 15 were markedly effective (the degree of inflammation and cell infiltration of the gastric angle and gastric antrum mucosa was significantly improved), 11 were effective (the degree of inflammation and cell infiltration of the gastric mucosa was improved compared with before taking the medicine), 24 were ineffective (the same as before taking the medicine, no improvement), and the total effective rate of pathological examination was 57%. Among the 53 cases in the control group, 6 were cured, 8 were markedly effective, 13 were effective, and 26 were ineffective, and the total effective rate of pathological examination was 51%. The comparison between the two groups was P>0.05.

[0215] Adverse reactions: 4 patients in the experimental group experienced looser stools and increased frequency of stools within 1 week of taking the medicine, but the symptoms disappeared on their own after continuing to take the medicine.

[0216] This experiment shows that after treatment with the granules of this scheme, the symptoms such as upper abdominal pain, fullness, and poor appetite caused by gastritis disappear or improve quickly, and the total clinical effective rate reaches 90%, which is slightly better than Sanjiu Weitai. The total effective rate is also higher than Sanjiu Weitai through gastroscopy and pathological examination results, indicating that the drug has reliable efficacy. No obvious adverse reactions were found in the clinical application process of the Chinese medicine compound granules of the present invention. Therefore, it is believed that the Chinese medicine compound granules of the present invention are effective and safe drugs for treating chronic superficial gastritis and chronic atrophic antral gastritis.

[0217] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A Chinese medicine compound granule for treating chronic gastritis, characterized in that: Calculated by weight, the medicinal raw materials include: 3-7 parts of astragalus, 3-6 parts of white peony root, 4-7 parts of dandelion, 2-5 parts of angelica, 1-4 parts of tangerine peel, 1-4 parts of Jianqu, 1-2 parts of citron, and 1-2 parts of licorice.

2. A Chinese medicine compound granule for treating chronic gastritis according to claim 1, characterized in that: Calculated by weight, the medicinal raw materials include: 4 parts of astragalus, 5 parts of white peony root, 6 parts of dandelion, 3 parts of angelica, 2 parts of tangerine peel, 2 parts of Jianqu, 1 part of bergamot, and 1 part of licorice.

3. A method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 1 or 2, characterized in that: The method includes the following steps in sequence: S1: soaking the raw materials of medicinal materials; S2: adding water to the soaked medicinal material raw material, decoct and extract 2-3 times; combining the filtrate obtained from each extraction to obtain a first water extract; crushing the medicinal residue after decoction and extraction, adding water to decoct and extract, and taking the filtrate to obtain a second water extract; combining the first water extract and the second water extract to obtain a total extract; S3: Concentrate the total extract into an extract; S4: Mix the auxiliary materials and the extract, and spray granulate them with a boiling drying granulator to obtain Chinese medicine granules.

4. A method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 3, characterized in that: In S1, the temperature condition of the immersion treatment is room temperature, and the duration of the immersion treatment is 0-30 minutes; the duration of the immersion treatment is preferably 30 minutes.

5. The method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 3, characterized in that: In S2, water 4 to 6 times the volume of the raw material is added to the soaked raw material, and the raw material is boiled and extracted 1 to 3 times, each time for 30 to 60 minutes; the filtrate obtained from each extraction is combined to obtain a first water extract; the residue after the decoction and extraction is crushed, and water 4 times the volume of the raw material is added to decoct and extract, and the filtrate is obtained to obtain a second water extract; The first water extract and the second water extract are combined to obtain a total extract.

6. A method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 5, characterized in that: In S2, water of 6 times the volume of the medicinal raw material is added to the medicinal raw material after the immersion treatment, and the mixture is boiled and extracted for 60 minutes, and the filtrate is taken to obtain a first water extract; the medicinal residue after the decoction and extraction is crushed, and water of 4 times the volume of the medicinal raw material is added to decoct and extract for 45 minutes, and the filtrate is taken to obtain a second water extract; the first water extract and the second water extract are combined to obtain a total extract.

7. A method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 6, characterized in that: In S2, the particle size of the dregs after crushing is 1-4 mm.

8. The method for preparing the Chinese medicinal compound granules for treating chronic gastritis according to claim 3, characterized in that: In S3, the total extract is concentrated into an extract by vacuum concentration at 65°C, and the relative density of the extract is 1.152-1.

190.

9. The method for preparing a Chinese medicine compound granule for treating chronic gastritis according to claim 3, characterized in that: In S4, the auxiliary material includes at least one of lactose, dextrin, soluble starch, and microcrystalline cellulose; The auxiliary materials and extract were mixed and added into a boiling drying granulator. The 30% ethanol solution was atomized and sprayed directly onto the fluidized material. After drying for 0.5 h, cooling, granulation and unloading, the Chinese medicine granules were obtained. The parameters of the boiling drying granulator were set as follows: inlet temperature 60°C, air pressure adjusted to 0.6 MPa, and liquid injection rate 5 mL / min.

10. The method for preparing the Chinese medicine compound granules for treating chronic gastritis according to claim 9, characterized in that: The auxiliary materials are composed of lactose and microcrystalline cellulose; the mass ratio of the extract, lactose and microcrystalline cellulose is 1-2:1-5:1-5; preferably, the mass ratio of the extract, lactose and microcrystalline cellulose is 1:2:1.

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