A preparation method of high-quality spleen-strengthening and spleen-clearing granules

Abstract

The present invention discloses an industrial preparation method of high-quality Jianpi Qinghua granules, comprising the following steps: S1 preparation of extract; S2 preparation of precipitate; S3 preparation of precipitate; S4 preparation of concentrated powder; S5 preparation of granules. The present invention uses a neutral ethanol solution to reflux extract the Jianpi Qinghua medicinal material slices at a specific temperature, and the extract is successively acid-precipitated and alkaline-precipitated, thereby avoiding the compatibility reaction of active ingredients such as berberine and baicalin, and at the same time, appropriate process flow and parameters avoid chemical reactions between ingredients and changes in material basis caused by high temperature, thereby improving the quality of Jianpi Qinghua granules, ensuring their efficacy, and having the value of industrial promotion and application.

Description

Technical Field

[0001] The present invention specifically relates to a method for preparing high-quality spleen-strengthening and spleen-clearing granules. Background Art

[0002] Jianpi Qinghua Granule (formerly known as Jianpi Zhixie Ning Granule, abbreviated as JPZX) is a national protected Chinese medicine variety. Its main ingredients include Codonopsis pilosula, lotus seeds, white hyacinth bean, Coptis chinensis, Scutellaria baicalensis, honeysuckle, Jianqu, hawthorn, Plantago (salt-roasted), dried ginger, etc. It has the effects of clearing away heat and dampness, anti-inflammatory and analgesic, promoting digestion, promoting absorption, stopping diarrhea, enhancing immune function and improving intestinal microecological environment. It is included in the "National Compilation of Chinese Patent Medicine Standards Oral Tumor Pediatric Volume". It is clinically used to treat acute diarrhea of ​​spleen deficiency and damp-heat type in children, persistent diarrhea in children (spleen deficiency and damp-heat syndrome), and ulcerative colitis, and has achieved good results.

[0003] At present, Jianpiqinghua granules are prepared according to traditional processes, using high-temperature processes such as decoction, extraction, concentration, wet granulation, and boiling drying. During the process, berberine hydrochloride in Coptis chinensis and baicalin in Scutellaria baicalensis will have serious compatibility reactions, resulting in a very low transfer rate of berberine hydrochloride and baicalin to the finished product, and even causing their content to fail to meet quality standards. At the same time, since the process steps are divided into three units: decoction, extraction, concentration, and preparation; the preparation unit also includes wet granulation and boiling drying, the energy consumption in the production process is very large, the production cost is quite high, and the patient's medication cost is increased. Therefore, it is necessary to develop a new preparation method to increase the content of active ingredients, enhance its efficacy, and reduce production costs. Summary of the invention

[0004] The present invention aims to provide a modular preparation method for high-quality Jianpiqinghua granules to solve the technical problems in the existing process of low extraction transfer rate of berberine hydrochloride in Coptis chinensis and baicalin in Scutellaria baicalensis, as well as compatibility reaction, which leads to low content of ingredients such as berberine hydrochloride and baicalin in the medicine, thereby reducing the quality of the medicine.

[0005] To achieve the above-mentioned purpose, the present invention adopts the following technical scheme: a high-quality spleen-strengthening and spleen-clearing granule composition, whose medicinal raw materials include codonopsis pilosula, lotus seeds, white hyacinth bean, coptis chinensis, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seeds and dried ginger, and the mass ratio thereof is 100-110:100-110:150-200:50-60:100-110:100-110:100-110:100-110:100-110:50-60.

[0006] The medicinal raw materials are crushed, extracted by reflux of neutral ethanol solution, and volatile oil is collected. The extract is successively acid-precipitated and alkali-precipitated, and dried to obtain acid-precipitated and alkali-precipitated dry paste powders respectively. After the alkali-precipitated liquid is adjusted to a pH value, it is concentrated and dried to obtain a third dry paste powder. The acid-precipitated and alkali-precipitated dry paste powders, the third dry paste powder, a filler, a sweetener, an essence and volatile oil are mixed and dry granulated to obtain Jianpi Qinghua granules.

[0007] The principles and advantages of this solution are:

[0008] In this scheme, the medicinal raw materials are extracted by reflux extraction under a neutral ethanol solution of appropriate concentration to extract the medicinal ingredients of the medicinal materials, and then the extract is acidified and allowed to stand to precipitate baicalin and other insoluble substances under weak acidic conditions (to prevent baicalin from having a strong compatibility reaction in subsequent concentration, thereby improving the quality of the product), and the precipitate is dried and crushed to obtain a first medicinal powder; the above-mentioned filtrate is then alkalized, allowed to stand to precipitate berberine and other insoluble substances under weak alkaline conditions (to prevent berberine from having a strong compatibility reaction in subsequent concentration, thereby improving the quality of the product), and the precipitate is dried and crushed to obtain a second medicinal powder; the filtrate is adjusted to a weakly acidic pH value (pH value 5.5-6.5), and then concentrated, dried and crushed under reduced pressure to obtain a third medicinal powder, and the first medicinal powder, the second medicinal powder and the third medicinal powder, the filler, the sweetener and the flavor are roughly mixed, and the volatile oil obtained in S1 is sprayed, and dry granulation is performed to obtain Jianpi Qinghua granules.

[0009] Under this process condition, the total material basis remains unchanged. The reflux extraction of neutral ethanol and the simple process control solve the problems of drug component extraction transfer rate and compatibility reaction, greatly improving the quality of the product, especially solving the poor extraction transfer rate of berberine hydrochloride and baicalin. Then, weakly acidic insoluble components such as baicalin are first separated under normal temperature and acidic conditions, and then berberine and other insoluble substances under weakly alkaline conditions are separated and precipitated under weakly alkaline conditions. The other components are then prepared into dry paste powder by conventional pH adjustment, concentration, and drying methods to prevent the conventional concentration and drying methods from causing The process causes a strong compatibility reaction between berberine and baicalin and other ingredients, greatly increasing the content of medicinal ingredients in the finished product. The process also unexpectedly found that the spots of thin layer identification (including Codonopsis pilosula, Coptis chinensis, lotus seeds, and honeysuckle) were significantly larger than the spots of thin layer identification using the existing process, indicating that the transfer rates of these ingredients have also been greatly improved. Furthermore, the second drug powder obtained by alkali precipitation, drying and crushing in the process has a good hygroscopic sealing effect, which greatly reduces the hygroscopicity of the particles, solving the problem of hygroscopicity of the particles in the process and the problem of easy moisture absorption in the sub-packaging of the particles in the process.

[0010] After analysis and testing, the berberine hydrochloride content in the granules prepared by this scheme is as high as 29.2 mg / bag, which is significantly higher than the minimum standard of berberine hydrochloride content in the national drug standard for Jianpi Qinghua Granules (standard number WS-10941-(ZD-0941)-2002) (berberine hydrochloride is not less than 17 mg / bag); baicalin is as high as 21.5 mg / bag, which is higher than the internal control standard of 10 mg / bag, thereby effectively improving the quality and efficacy of the drug. Secondly, this scheme adopts dry granulation to reduce the loss of active ingredients and does not require large-scale energy consumption. The preparation method is green and environmentally friendly, and the production efficiency is greatly improved, which greatly reduces the production cost. In addition, the process has simple production conditions and strong practicality, and the moisture absorption rate of the total mixture produced is low, and the material is smoothly transmitted on the production line, which helps to improve the production efficiency of large-scale preparation.

[0011] The present invention discloses an industrial preparation method of high-quality Jianpiqinghua granules, comprising the following steps:

[0012] Preparation of S1 extract: Codonopsis pilosula, lotus seeds, white hyacinth bean, coptis root, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seeds, and dried ginger are extracted by reflux with a neutral ethanol solution, and volatile oil is collected to obtain an extract and volatile oil;

[0013] Preparation of S2 precipitate: Take the extract obtained from S1 and adjust the pH value to 1.0-2.0, let it stand, filter to obtain precipitate and filtrate, dry, crush and sieve the precipitate to obtain S2 powder;

[0014] Preparation of S3 precipitate: Take the filtrate obtained from S2 and adjust the pH value to 8.5-9.5, let it stand, filter to obtain precipitate and filtrate, dry, crush and sieve the precipitate to obtain S3 powder;

[0015] Preparation of S4 concentrate powder: Take the filtrate obtained from S3 and adjust the pH value to 5.5-6.5, recover the ethanol, concentrate and dry, and grind to obtain S4 powder;

[0016] Preparation of S5 granules: Mix S2, S3, S4 powders, fillers, sweeteners and flavors, spray the volatile oil obtained from S1, and granulate to obtain Jianpiqinghua granules.

[0017] Furthermore, the temperature of the reflux extraction in step S1 is 70-75° C.; and the ethanol concentration in the neutral ethanol solution is 55%-65%.

[0018] Furthermore, the reflux extraction is performed twice, and the amount of neutral ethanol solution used each time is 8 times and 6 times the amount of medicinal material respectively, and the extraction time each time is 3 hours.

[0019] Furthermore, the pH value of the extract in step S2 and the filtrate in step S4 is adjusted with a hydrochloric acid solution; the concentration of the hydrochloric acid solution is 0.1 mol / L.

[0020] Furthermore, in step S3, the pH value of the filtrate is adjusted with a sodium hydroxide solution; the sodium hydroxide solution is 0.1 mol / L.

[0021] Furthermore, the standing time in step S2 and step S3 is 8 to 24 hours, preferably 12 hours; and the drying temperature is 40 to 60° C., preferably 50° C.

[0022] Furthermore, in step S4, the concentration is performed to a relative density of 1.20 to 1.25, and the drying is performed under reduced pressure at a temperature of 60 to 70° C. and a vacuum degree of not less than -0.09 MPa.

[0023] Furthermore, the granulation in step S5 is dry granulation.

[0024] Furthermore, the mass ratio of the codonopsis pilosula, lotus seed, white hyacinth bean, coptis chinensis, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seed and dried ginger is 100-110:100-110:150-200:50-60:100-110:100-110:100-110:100-110:100-110:100-110:50-60, preferably, the mass ratio is 108:108:162:54:108:108:108:108:108:54; the filler includes soluble starch and / or dextrin; the sweetener includes sucralose, steviol glycoside and / or saccharin sodium; the flavor includes pineapple flavor, strawberry flavor and / or lemon flavor.

[0025] Furthermore, the particle size of the Jianpi Qinghua granules is 16-20 meshes, and each 1g of Jianpi Qinghua granules contains 3-4g of the original drug.

[0026] Finally, the present invention provides a high-quality Jianpiqinghua granule, which is a granule prepared according to the above method.

[0027] The "neutral ethanol" described in the present invention is an ethanol solution prepared by adding 1 to 2 drops of phenolphthalein indicator solution and titrating with sodium hydroxide solution to a light pink ethanol solution.

[0028] The industrial preparation method of the Jianpi Qinghua granules of the present invention comprises the following steps: refluxing and extracting the Jianpi Qinghua medicinal material slices with a neutral ethanol solution at a specific temperature, and the extract is successively subjected to acid precipitation and alkali precipitation, thereby avoiding the compatibility reaction of the active ingredients such as berberine and baicalin, and at the same time, appropriate process flow and parameters are used to avoid the chemical reaction between the ingredients and the change of the material basis caused by high temperature, thereby improving the quality of the Jianpi Qinghua granules, ensuring the therapeutic effect thereof, and having the value of industrial promotion and application.

[0029] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0030] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0031] Example 1 Preparation of the spleen-strengthening and cleansing composition granules of the present invention

[0032] Recipe: Codonopsis pilosula 108g, lotus seeds 108g, white hyacinth bean 162g, Coptis chinensis 54g, Scutellaria baicalensis 108g, honeysuckle 108g, Jianqu 108g, hawthorn 108g, salt-roasted Plantago seed 108g, and dried ginger 54g.

[0033] Preparation method:

[0034] Preparation of S1 extract: Mix the above raw materials, add 60% neutral ethanol solution, reflux extraction twice (reflux temperature 70-75°C), the amount of neutral ethanol solution used each time is 8 times and 6 times the amount of medicinal materials, the extraction time each time is 3 hours, and the volatile oil is collected to obtain an extract and volatile oil;

[0035] Preparation of S2 precipitate: adjust the pH value of the extract obtained from S1 to 1.5 with 0.1 mol / l hydrochloric acid solution, let it stand for 12 hours, filter to obtain the precipitate and filtrate, dry the precipitate at 50°C, crush and sieve to obtain S2 precipitate powder;

[0036] Preparation of S3 precipitate: Take the filtrate obtained from S2, adjust the pH value of the filtrate to 8.5 with 0.1 mol / l sodium hydroxide solution, let it stand for 12 hours, filter to obtain the precipitate and filtrate, dry the precipitate at 50°C, crush and sieve to obtain S2 precipitate powder;

[0037] Preparation of S4 concentrate powder: Take the filtrate obtained from S3, adjust the pH value of the filtrate to 6.0 with 0.1 mol / l hydrochloric acid solution, then reduce pressure to recover ethanol, continue to concentrate to a relative density of 1.20-1.25 (60°C), dry under reduced pressure at 60-70°C with a vacuum degree of not less than -0.09 MPa, and grind to obtain S4 powder.

[0038] Preparation of S5 granules: Mix S2, S3, S4 powders, soluble starch, sucralose and strawberry essence, spray the volatile oil obtained in S1, mix for 10 to 20 minutes, add to a dry granulator, press into tablets, and use a granulator to granulate into 16 to 20 mesh granules to obtain 270 g of Jianpi Qinghua granules;

[0039] S6 packaging: Put S4 granules into aluminum-plastic composite bags, 3g of Jianpiqinghua granules per bag, 90 bags in total.

[0040] Example 2

[0041] This embodiment is basically the same as Embodiment 1, except that in S1, the concentration of neutral ethanol is 55%, and the rest is the same as Embodiment 1.

[0042] Example 3

[0043] This embodiment is basically the same as Embodiment 1, except that in S1, the concentration of neutral ethanol is 65%, and the rest is the same as Embodiment 1.

[0044] Example 4

[0045] This embodiment is basically the same as Embodiment 1, except that in S2, the pH value of the extract is adjusted to be acidic to 1.0.

[0046] Example 5

[0047] This embodiment is basically the same as the embodiment 1, except that in S2, the pH value of the extract is adjusted to an acidic pH of 2.0, and the rest is the same as the embodiment 1.

[0048] Example 6

[0049] This embodiment is basically the same as the embodiment 1, except that in S3, the pH value of the extract is adjusted to a weakly alkaline pH of 9.0, and the rest is the same as the embodiment 1.

[0050] Example 7

[0051] This embodiment is basically the same as the embodiment 1, except that in S3, the pH value of the extract is adjusted to a weakly alkaline pH of 9.5, and the rest is the same as the embodiment 1.

[0052] Example 8

[0053] This embodiment is basically the same as the embodiment 1, except that in S4, the pH value of the extract is adjusted to a weakly acidic pH of 5.5, and the rest is the same as the embodiment 1.

[0054] Example 9

[0055] This embodiment is basically the same as the embodiment 1, except that in S4, the pH value of the extract is adjusted to a weakly acidic pH of 6.5. The rest is the same as the embodiment 1.

[0056] Comparative Example 1

[0057] This comparative example is basically the same as Example 1, except that in S1, the concentration of neutral ethanol is 45%, and the rest is the same as Example 1.

[0058] Comparative Example 2

[0059] This comparative example is basically the same as Example 1, except that in S1, the concentration of neutral ethanol is 70%, and the rest is the same as Example 1.

[0060] Comparative Example 3

[0061] This comparative example is basically the same as Example 1, except that in S2, the pH value of the extract is adjusted to an acidic pH of 0.5, and the rest is the same as Example 1.

[0062] Comparative Example 4

[0063] This comparative example is basically the same as Example 1, except that in S2, the pH value of the extract is adjusted to an acidic pH of 2.5, and the rest is the same as Example 1.

[0064] Comparative Example 5

[0065] This comparative example is basically the same as Example 1, except that in S3, the pH value of the extract is adjusted to a weakly alkaline pH of 7.5, and the rest is the same as Example 1.

[0066] Comparative Example 6

[0067] This comparative example is basically the same as Example 1, except that in S3, the extract is adjusted to a weakly alkaline pH value of 10.0, and the rest is the same as Example 1.

[0068] Comparative Example 7

[0069] This comparative example is basically the same as Example 1, except that, in S4, the alkali precipitation filtrate is directly concentrated under reduced pressure, and the rest is the same as Example 1.

[0070] Comparative Example 8

[0071] This comparative example is basically the same as Example 1, except that in S4, the pH value of the alkali precipitation filtrate is directly adjusted to 7.5, and then concentrated, dried, etc., and the rest is the same as Example 1.

[0072] Comparative Example 9

[0073] This comparative example is basically the same as Example 1, except that in S4, the pH value of the alkali precipitation filtrate is directly adjusted to 4.5, and then concentrated, dried, etc., and the rest is the same as Example 1.

[0074] Comparative Example 10

[0075] The current preparation process and the prescription amount are consistent with those in Example 1. The preparation method is to take all the medicinal materials, add 10 times the amount of water and decoct three times, each time for 1 hour, combine the decoctions, and filter. The filtrate is concentrated under reduced pressure to a clear paste (relative density 1.15-1.20 50-60°C), cooled, added with an equal amount of ethanol, mixed, allowed to stand, and filtered. The filtrate is recovered with ethanol, concentrated to a clear paste with a relative density of not less than 1.25 (50-60°C), starch, dextrin and steviol glycoside are added, mixed, granulated, and dried to obtain 270g, which is divided into aluminum-plastic composite bags, 3g per bag.

[0076] Comparative Example 11

[0077] The extraction process in the current preparation process remains unchanged, and the subsequent preparation process is changed: the prescription amount is consistent with Example 1, and the preparation method is to take all the medicinal materials, add 10 times the amount of water and boil three times, each time for 1 hour, combine the decoction, and filter. The filtrate is concentrated under reduced pressure to a clear paste (relative density 1.15-1.20 50-60°C), cooled, added with an equal amount of ethanol, mixed, allowed to stand, and filtered. The filtrate is recovered with ethanol, concentrated to a clear paste with a relative density of not less than 1.25 (50-60°C), dried under reduced pressure, crushed to obtain a dry paste powder, added starch, dextrin and stevioside, mixed, dry granulated, and 270g was obtained, which was divided into aluminum-plastic composite bags, 3g per bag.

[0078] Comparative Example 12

[0079] This embodiment is basically the same as the embodiment 1, except that, in S1, a 60% acidic ethanol solution (pH value of about 1.0) with a pH value of 1.0 is used as the extracting solution, and the rest is the same as the embodiment 1.

[0080] Comparative Example 13

[0081] This embodiment is basically the same as the embodiment 1, except that, in S1, a 60% alkaline ethanol solution (pH value of about 9.0) with a pH value of 9.0 is used as the extracting solution, and the rest is the same as the embodiment 1.

[0082] Comparative Example 14

[0083] This embodiment is basically the same as the embodiment 1, except that in S1, a 60% acidic ethanol solution with a pH value of 4.5 is used as the extracting solution, and the rest is the same as the embodiment 1.

[0084] Comparative Example 15

[0085] This embodiment is basically the same as the embodiment 1, except that in S1, a 60% ethanol solution is used as the extracting solution, and the rest is the same as the embodiment 1.

[0086] Note: The ethanol solution in this comparative example is the raw material for preparing neutral ethanol.

[0087] Comparative Example 16

[0088] This embodiment is basically the same as the embodiment 1, except that in S2, alkali precipitation is performed first, and then acid precipitation is performed in S3. The rest is the same as the embodiment 1.

[0089] The beneficial effects of the present invention are further illustrated by experimental examples below.

[0090] Experimental Example 1: Study on the effects of different preparation methods on the quality of Jianpiqinghua granules

[0091] 1. Quality testing standards for Jianpiqinghua granules

[0092] [Properties] This product is yellow to brown granules; bitter and slightly sweet.

[0093] [Identification] (1) Take 3g of this product, grind it into powder, add 40ml of methanol, extract under reflux for 1 hour, filter, evaporate the filtrate, dissolve the residue in 30ml of water, extract twice with chloroform by shaking, 30ml each time, combine the chloroform extracts, evaporate to dryness, dissolve the residue in 1ml of methanol, and use this as the test solution. Take 1g of Codonopsis pilosula as a control medicinal material, add 30ml of methanol, extract under reflux for 1 hour, filter, evaporate the filtrate, dissolve the residue in 20ml of water, extract twice with chloroform by shaking, 20ml each time, combine the chloroform extracts, evaporate to dryness, dissolve the residue in 1ml of methanol, and use this as the control medicinal material solution. According to the thin layer chromatography method (General Rule 0502), 15 μl of each of the above two solutions were taken and spotted on the same silica gel G thin layer plate, and toluene-acetone (9:1) was used as the developing solvent. After development, the plate was taken out, dried, sprayed with a freshly prepared 20% perchloric acid ethanol solution, and heated at 105°C until the spots were clearly colored. In the chromatogram of the test sample, spots of the same color appeared at the corresponding positions of the chromatogram of the control medicinal material.

[0094] (2) Take 3g of this product, add 30ml of water, heat to dissolve, cool, add 1ml of hydrochloric acid, shake and extract with ether 3 times, 25ml each time, discard the ether solution, add ammonia test solution to adjust the pH value of the water solution to 9-11, shake and extract with ether 3 times, 25ml each time, combine the ether solutions, evaporate to dryness, add 0.5ml of methanol to the residue to dissolve, and use it as the test solution. Take 1g of lotus seed control medicinal material, add 100ml of water, decoct for 30 minutes, cool, filter, and use the filtrate from "add 1ml of hydrochloric acid" to prepare the control medicinal material solution in the same way. According to the thin layer chromatography method (General Rule 0502), 10 μl of the test solution and 5 μl of the control medicinal material solution are respectively spotted on the same silica gel G thin layer plate, and chloroform-acetone-diethylamine (5:4:0.4) is used as the developing agent. After development, the plate is taken out, dried, left overnight, and examined under ultraviolet light (365 nm). In the chromatogram of the test sample, two or more main fluorescent spots of the same color appear at the corresponding positions of the chromatogram of the control medicinal material.

[0095] (3) Take 3g of this product, add 10ml of water, heat to dissolve, add dilute hydrochloric acid to adjust the pH to 1-2, and centrifuge for 10min. Take the supernatant, shake and extract with 15ml of ethyl acetate, evaporate the ethyl acetate solution, and dissolve the residue in 2ml of ethyl acetate as the test solution. Take another chlorogenic acid reference substance, add methanol to make a solution containing 1mg per 1ml, and use it as the reference solution. According to the thin layer chromatography method (General Rule 0502), take 2μl of the above test solution and 0.5μl of the reference solution, and spot them on the same polyamide film respectively, use the upper layer solution of butyl acetate-formic acid-water (7:2.5:2.5) as the developing agent, develop, take out, dry, and examine under ultraviolet light (365nm). In the chromatogram of the test product, at the corresponding position of the chromatogram of the reference substance, a fluorescent spot of the same color appears.

[0096] (4) Take 1g of this product, grind it into powder, add 10ml of methanol, ultrasonically treat it for 10 minutes, filter it, and use the filtrate as the test solution. Take 0.03g of Rhizoma Coptidis as the reference medicinal material, add 10ml of methanol, ultrasonically treat it for 10 minutes, filter it, and use the filtrate as the reference medicinal material solution. Take berberine hydrochloride as the reference material, add methanol to make a solution containing 0.1mg per 1ml, and use it as the reference material solution. According to the thin layer chromatography method (General Rule 0502), take 1μl of each of the above three solutions and spot them on the same silica gel G thin layer plate, use cyclohexane-ethyl acetate-isopropanol-methanol-water-triethylamine (3:3.5:1:1.5:0.5:1) as the developing agent, place it in a developing cylinder pre-saturated with concentrated ammonia test solution for 20 minutes, develop it, take it out, dry it, and examine it under ultraviolet light (365nm). In the test sample chromatogram, four fluorescent spots of the same color appear at the corresponding positions in the reference medicinal material chromatogram; and a fluorescent spot of the same color appears at the corresponding positions in the reference sample chromatogram.

[0097] [Inspection] The relevant provisions under granules should be met (General Rule 0104).

[0098] [Content Determination] Scutellaria baicalensis and Coptis chinensis were determined by HPLC (General Rule 0512).

[0099] Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as filler; acetonitrile was used as mobile phase A, 0.02 mol / L potassium dihydrogen phosphate solution was used as mobile phase B, and gradient elution was performed according to the provisions in the following table; the detection wavelength was 275 nm; the column temperature was 30°C. The theoretical plate number calculated based on the berberine hydrochloride peak should be no less than 2000.

[0100]

[0101] Preparation of reference solution Take an appropriate amount of baicalin reference substance, weigh it accurately, and add 70% ethanol to prepare a solution containing 70 μg of baicalin per 1 ml. Take an appropriate amount of berberine hydrochloride reference substance, weigh it accurately, and add 70% ethanol to prepare a reference solution containing 20 μg of berberine hydrochloride per 1 ml.

[0102] Preparation of test solution: Take the contents under the item of dosage difference of this product, grind it into powder, take about 1 g, weigh it accurately, put it in a stoppered conical flask, accurately add 50 ml of 70% ethanol, weigh it, treat it with ultrasound (power 300 W, frequency 40 kHz) for 30 minutes, let it cool, weigh it again, make up the lost weight with 70% ethanol, shake it well, filter it, and take the filtrate to obtain it.

[0103] Determination method: Accurately pipette 10μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0104] Each bag of this product contains baicalin (C 21 H 18 O 11 ) shall not be less than 10.0mg; containing berberine hydrochloride (C 20 H 17 NO4·HCl), shall not be less than 17.0 mg.

[0105] 2. Results

[0106] The results of the Jianpi Qinghua granules obtained in the examples and comparative examples are shown in the following tables (Tables 1-5):

[0107] Table 1: Test results of Examples 1 to 5 with reference to quality standards

[0108]

[0109]

[0110] Table 2: Test results of Examples 6 to 9 with reference to quality standards

[0111]

[0112] Table 3: Comparative Examples 1 to 6 Test Results with Reference to Quality Standards

[0113]

[0114]

[0115] Table 4: Comparative Examples 7 to 11 Test Results with Reference to Quality Standards

[0116]

[0117]

[0118] Table 5: Comparative Examples 12 to 15 Test Results with Reference to Quality Standards

[0119]

[0120] From the above test results, it can be seen that: ① Compared with the preparation method in the embodiment, in Comparative Example 1, the concentration of neutral ethanol was reduced to 45%, and the contents of berberine hydrochloride and baicalin in the obtained finished product decreased; in Comparative Example 2, the concentration of neutral ethanol was increased from 45% to 70%, and the contents of berberine hydrochloride and baicalin in the obtained finished product were still low; in Comparative Examples 12 to 15, neutral ethanol was replaced with acidic ethanol, alkaline ethanol and ethanol solution of different pH values, respectively, and the obtained finished products either had a very low content of berberine hydrochloride, and the thin layer identification of honeysuckle was not obvious, or the contents of berberine hydrochloride and baicalin were both reduced, and the thin layer identification of lotus seeds was not obvious; from these comparative experiments, it can be seen that the type and concentration of the extraction solvent in the extraction process have a significant effect on the active ingredients of the preparation, baicalin and berberine hydrochloride.

[0121] ② Compared with the preparation method in the embodiment, in Comparative Example 3, the acid precipitation solution acidity is reduced to pH 0.5, and the contents of baicalin and berberine hydrochloride in the finished product are both reduced; in Comparative Example 4, the acid precipitation solution acidity is increased from pH 0.5 to 2.5, and the contents of baicalin and berberine hydrochloride in the finished product are still reduced; in Comparative Example 5, the alkalinity of the alkali precipitation solution is reduced to pH 7.5, and the baicalin content in the finished product is significantly reduced; in Comparative Example 6, the alkalinity of the alkali precipitation solution is increased to pH 10.0, and the baicalin content in the finished product is still significantly reduced. It can be seen from these comparative experiments that the pH values ​​of acid precipitation and alkali precipitation need to be accurately controlled during the purification process, otherwise it will cause the compatibility reaction of baicalin and berberine hydrochloride, which will ultimately affect the quality of the preparation.

[0122] ③ Compared with the preparation method in the embodiment, Comparative Example 7 directly concentrated the alkali precipitation filtrate, and the thin layer identification of honeysuckle in the finished product was not obvious; Comparative Example 8 lowered the alkalinity of the alkali precipitation filtrate, and the thin layer identification of honeysuckle in the finished product was still not obvious; Comparative Example 9 directly adjusted the alkali precipitation filtrate to an acidic pH value of 4.5, and the thin layer identification of Codonopsis pilosula in the finished product was not obvious, and the contents of baicalin and berberine hydrochloride were reduced; Comparative Example 16 adjusted the order of alkali precipitation and acid precipitation processes, and the active ingredients in the prepared Jianpi Qinghua granules changed, and the content was reduced. It can be seen from these comparative experiments that the various process links in the preparation method are closely related and complementary. The omission of any process step and the change of the process sequence will affect the change of the content of the ingredients in the preparation, resulting in preparation quality problems.

[0123] ④ The content of baicalin in the Jianpi Qinghua granules prepared by the current process is 17.2 mg / bag, and the content of berberine hydrochloride is 11.0 mg / bag, which are significantly lower than the content in the embodiment, and the thin layer identification of lotus seeds is not obvious, indicating that the traditional process makes the transfer rate of active ingredients low. The content of baicalin in the Jianpi Qinghua granules prepared by the current process is improved to 21.4 mg / bag, and the content of berberine hydrochloride is 14.2 mg / bag. Dry granulation can effectively increase the content of the characteristic ingredients in the finished product, but there is still no obvious thin layer identification of lotus seeds, indicating that the transfer rate is still low.

[0124] The above experimental comparison reflects the technical problems encountered in the production of Jianpi Qinghua granules: the content of the characteristic components in the granules is low, and the identification fluorescent spots are not obvious. At the same time, the comparative experiment is also a microcosm of trying to improve the process to solve the granule quality problem:

[0125] First, from the extraction solvent, water or 60% ethanol solution was considered as the reflux extraction solution, but the extraction effect on the characteristic components baicalin and berberine hydrochloride was not very obvious; later, the physical and chemical properties of baicalin and berberine hydrochloride were analyzed, and it was found that pH value and ethanol concentration had a greater impact on the two components, so a series of ethanol solutions with a pH value range were studied, and it was found that acidic or alkaline had a great influence on the extraction. The solubility of each substance near neutral ethanol almost reached the maximum limit, which effectively took into account the dissolution of each component. In order to prevent the compatibility reaction of berberine hydrochloride with baicalin and other components, the acid-base double precipitation method was adopted according to the physical and chemical properties of the two important components. The research results showed that acid precipitation first and then alkaline precipitation would not affect the content of the two characteristic components, while alkaline precipitation first and then acid precipitation had a greater impact on the content of the two characteristic components. In addition, the pH value of acid precipitation has a greater impact on berberine hydrochloride, and its precipitation is most complete when the pH value is between 1.0 and 2.0. The pH value of alkaline precipitation also has a greater impact on baicalin, and its precipitation is most complete when the pH value is between 8.5 and 9.5. When the alkaline precipitation filtrate returns to a pH value between 5.5 and 6.5, high-temperature concentration will not cause compatibility reactions with other components.

[0126] In summary, Examples 1 to 9 prove that the content and identification of the characteristic components of the Jianpi Qinghua composition granules prepared by the present invention meet the requirements of relevant standards. In addition, the content of berberine hydrochloride in the granules prepared by the present invention is 29.0 to 29.4 mg / bag, and the content of baicalin is 20.1 to 22.1 mg / bag, which are significantly higher than the minimum internal control standard for the content of the characteristic components of Jianpi Qinghua granules (berberine hydrochloride is not less than 17 mg / bag, baicalin is not less than 10 mg / bag), thereby effectively improving the quality and efficacy of the drug, and solving the problem that the thin layer identification spots of lotus seeds have long been not very obvious.

Claims

1. An industrial preparation method of Jianpi Qinghua granules, characterized in that: The following steps are involved: Preparation of S1 extract: Codonopsis pilosula, lotus seeds, white hyacinth bean, coptis root, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seeds, and dried ginger are mixed, extracted by reflux with a neutral ethanol solution, and volatile oil is collected to obtain an extract and volatile oil; Preparation of S2 precipitate: Take the extract obtained from S1 and adjust the pH value to 1.0-2.0, let it stand, filter to obtain precipitate and filtrate, dry, crush and sieve the precipitate to obtain S2 powder; Preparation of S3 precipitate: Take the filtrate obtained from S2 and adjust the pH value to 8.5-9.5, let it stand, filter to obtain precipitate and filtrate, dry, crush and sieve the precipitate to obtain S3 powder; Preparation of S4 concentrate powder: Take the filtrate obtained from S3 and adjust the pH value to 5.5-6.5, recover the ethanol, concentrate and dry, and grind to obtain S4 powder; Preparation of S5 granules: Mix S2, S3, S4 powders, fillers, sweeteners and flavors, spray the volatile oil obtained from S1, and granulate to obtain Jianpi Qinghua granules; The mass ratio of the codonopsis pilosula, lotus seed, white hyacinth bean, coptis root, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seed and dried ginger is 100-110:100-110:150-200:50-60:100-110:100-110:100-110:100-110:100-110:50-60; The neutral ethanol is an ethanol solution with 1-2 drops of phenolphthalein indicator solution added thereto, and the solution is titrated with sodium hydroxide solution to a light pink ethanol solution; The ethanol concentration in the neutral ethanol solution is 55% to 65%; The particle size of the Jianpi Qinghua granules is 16-20 meshes, and each 1g of Jianpi Qinghua granules contains 3-4g of the original drug.

2. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: The temperature of the reflux extraction in step S1 is 70-75°C.

3. The industrial preparation method of the spleen-strengthening and spleen-clearing granules according to claim 2 is characterized in that: The reflux extraction was performed twice, the amount of neutral ethanol solution used was 8 times and 6 times the amount of medicinal material respectively, and the extraction time for each time was 3 hours.

4. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: The pH value of the extract in step S2 and the filtrate in step S4 is adjusted with 0.1 mol / L hydrochloric acid solution.

5. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: In step S3, the pH value of the filtrate is adjusted with 0.1 mol / L sodium hydroxide solution.

6. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: The standing time in step S2 and step S3 is 8 to 24 hours; and the drying temperature is 40 to 60°C.

7. The industrial preparation method of Jianpiqinghua granules according to claim 6 is characterized in that: The standing time in step S2 and step S3 is 12 hours; the drying temperature is 50°C.

8. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: The concentration operation in step S4 is: concentrating to a relative density of 1.20-1.25 at 60° C.; the drying operation is: drying under reduced pressure at 60-70° C. and a vacuum degree not lower than -0.09 MPa; and the granulation in step S5 is dry granulation.

9. The industrial preparation method of Jianpiqinghua granules according to claim 1, characterized in that: The mass ratio of the codonopsis pilosula, lotus seed, white hyacinth bean, coptis chinensis, scutellaria baicalensis, honeysuckle, jianqu, hawthorn, salt-roasted plantain seed and dried ginger is 108:108:162:54:108:108:108:108:108:54; the filler includes soluble starch and / or dextrin; the sweetener includes sucralose, steviol glycoside and / or saccharin sodium; the flavor includes pineapple flavor, strawberry flavor and / or lemon flavor.

10. A spleen-strengthening and spleen-clearing granule, characterized in that: The invention is prepared according to the preparation method described in any one of claims 1 to 9.

Images