Preparation method of Fuganning tablet

Abstract

The invention relates to a preparation method of Fuganning tablets. The preparation method comprises the steps of raw material pretreatment, gradient extraction, composite purification, granulation, drying and granule finishing, tabletting and coating. The wall breaking rate of medicinal materials is increased by adopting low-temperature superfine grinding, the yield of effective components is increased by adopting a gradient extraction process combining microwave-ultrasonic synergistic extraction and constant-temperature reflux, impurities are reduced by virtue of acid precipitation-macroporous resin composite purification, and the disintegration performance and stability of the tablet are optimized in cooperation with fluidized bed granulation and functional coating technologies. The method can improve the purity and bioavailability of active ingredients, enhance the stability of the preparation and realize accurate quality control, and is suitable for industrial production of the Fuganning tablets.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of traditional Chinese medicine preparation, and particularly relates to a preparation method of Fuganning tablets. BACKGROUND

[0002] The Fuganning tablets have the effects of soothing liver and gallbladder and clearing heat and detoxifying, and are widely applied in the clinical treatment of chronic hepatitis, liver function abnormality and the like. However, the existing preparation process has many technical bottlenecks, which restricts the improvement of the preparation quality and the clinical curative effect.

[0003] In the raw material processing link, the traditional crushing technology mostly adopts normal temperature mechanical crushing, and the cell wall breaking rate of medicinal materials is less than 60%, so that the effective components are difficult to be fully released, and the subsequent extraction efficiency is affected. In the extraction process, the existing method mostly adopts single ethanol reflux extraction, and has the problems of long extraction time and low effective component extraction rate, and the high-temperature long-time extraction easily leads to the degradation of heat-sensitive components. The purification process mostly depends on single precipitation or resin adsorption, and the impurities are not completely removed, and the total impurity residual amount is too high, especially flavonoids and protein impurities, which can cause the decrease of the preparation stability.

[0004] Therefore, it is urgent to develop a new preparation process of Fuganning tablets which can improve the effective component utilization rate, optimize the preparation performance and enhance the quality stability. SUMMARY

[0005] The application provides a preparation method of Fuganning tablets aiming at the problems of the insufficient cell wall breaking rate of medicinal materials, the low effective component extraction rate and the incomplete impurity removal in the existing process.

[0006] The technical scheme adopted by the application is as follows.

[0007] A preparation method of Fuganning tablets, comprising the following steps:

[0008] S1, taking 6-10 parts of radix bupleuri, 13-17 parts of herba scutellariae, 3-7 parts of radix isatidis and 4-8 parts of fructus schisandrae by weight, respectively washing, drying and adopting low-temperature ultrafine crushing to 100-150 meshes;

[0009] S2, taking the medicinal material powders of radix bupleuri, herba scutellariae and radix isatidis, adding 6-10 times of 70% ethanol by mass, adopting microwave-ultrasonic synergistic extraction for 0.5-2 hours, filtering to obtain the first extraction liquid; adding 4-8 times of 50% ethanol by mass in the residue, adopting constant-temperature reflux extraction for 1-2 hours, filtering to obtain the second extraction liquid; combining the two extraction liquids, recovering ethanol under reduced pressure, and concentrating to a clear paste with a relative density of 1.05-1.15;

[0010] S3, slowly adding 2% citric acid solution to the clear paste obtained in step S2, adjusting pH to 5.0, standing for 2h to precipitate impurities, taking the supernatant, passing the supernatant through an AB-8 type macroporous resin column, first eluting with 3 times the column volume of deionized water, then eluting with 3-7 times the column volume of 60% ethanol, collecting the ethanol eluate and concentrating;

[0011] S4, mixing the concentrated solution obtained in step S3 with schisandra powder, adding a composite disintegrant, a temperature-sensitive binder and a drying aid, and adopting fluidized bed granulation to obtain wet granules;

[0012] S5, drying the wet granules obtained in step S4 at 45-55℃ to a water content of ≤3%, and sieving the dried granules through a 20 mesh sieve to obtain dry granules;

[0013] S6, mixing the dry granules obtained in step S5 with 0.8%-1.2% of a composite lubricant based on the total weight of the dry granules, and then compressing the mixture into tablets, and applying water-soluble film coating to the surface of the tablets.

[0014] Further, the low-temperature ultrafine grinding conditions in step S1 are: temperature -15 to -5℃.

[0015] Further, the microwave-ultrasound synergistic extraction conditions in step S2 are: microwave power 300-400W, ultrasonic frequency 25-35kHz.

[0016] Further, the composite disintegrant in step S4 is composed of 2% cross-linked povidone and 1% sodium carboxymethyl starch; the temperature-sensitive binder is a mixture of povidone K30 and hydroxypropyl methylcellulose in a mass ratio of 1:1; and the drying aid is a composite of microcrystalline cellulose and silicon dioxide in a mass ratio of 3:1.

[0017] Further, the fluidized bed granulation conditions in step S4 are: inlet air temperature 60-70℃, material temperature 40-45℃.

[0018] Further, the water-soluble film coating material in step S6 is composed of hydroxypropyl methylcellulose, β-cyclodextrin and polyethylene glycol 6000 in a mass ratio of 5:3:2.

[0019] Further, the key quality control indicators of the tablets after step S6 are: tablet hardness 80-100N, disintegration time ≤12 minutes.

[0020] Compared with the prior art, the present application has the following advantages:

[0021] (1) Improve the extraction efficiency of saikosaponin, reduce energy consumption: the present application adopts microwave-ultrasonic synergistic extraction process, compared with the traditional ethanol reflux extraction method, which can significantly improve the extraction efficiency of saikosaponin, shorten the extraction time, and reduce the energy consumption, effectively realize the efficient and energy-saving raw material extraction process.

[0022] (2) High impurity removal rate, significantly improve the purity of active ingredients: the present application introduces acid precipitation-macroporous resin composite purification process, which can remove total flavonoids and protein impurities at the same time, improve the purity of active ingredients, and significantly optimize the raw material purification effect, laying a high-quality foundation for subsequent preparation process.

[0023] (3) The disintegration performance of the tablet is significantly improved: the present application uses the synergistic effect of composite disintegrant and temperature-sensitive binder to make the compound liverning tablet start to disintegrate in 5 minutes in the simulated gastric juice environment, and completely disintegrate in 12 minutes, which improves the efficiency of using single disintegrant, thereby significantly improving the dissolution rate and bioavailability of the tablet.

[0024] (4) The stability of the preparation is significantly enhanced: the present application uses functional coating technology to form a molecular inclusion structure on the surface of the tablet, so that the final compound liverning tablet has a content change rate of less than 5% after being placed in high temperature and high humidity conditions for 12 months, the coating layer is intact, the stability is improved, and the shelf life of the preparation is significantly prolonged. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be described in detail next, and the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application. In the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from public commercial channels unless otherwise specified. Unless otherwise specified, the percentages mentioned in the present application are mass percentage contents.

[0026] Example 1

[0027] Raw material pretreatment: take 8 parts of bupleurum, 15 parts of coptis, 5 parts of isatis root and 6 parts of schisandra chinensis by weight. The above medicinal materials are washed with purified water for 3 times, and then dried in a 60℃ air drying oven to a water content of ≤8%. The dried medicinal materials are ground under the condition of-10℃ by using a low-temperature super micro grinder, and then sieved through a 120 mesh sieve to obtain medicinal powder with a cell wall breaking rate of ≥95%.

[0028] Gradient extraction: the powders of Bupleurum, Yinchen, Banlangen were mixed evenly, 8 times of 70% ethanol was added, and the mixture was put into a microwave-ultrasonic extraction device, set the microwave power to 350 W, ultrasonic frequency to 30 kHz, extracted for 1 hour, filtered, and the first extraction liquid was collected. The residue was transferred to a reflux extraction tank, 6 times of 50% ethanol was added, and extracted at 65°C for 1.5 hours, filtered to obtain the second extraction liquid. The two extraction liquids were combined, and the ethanol was recovered by rotary evaporation at 60°C, -0.08 MPa, and the clear extract with a relative density of 1.10 was obtained.

[0029] Complex purification: 2% citric acid solution was slowly added to the above clear extract, stirred, the pH was adjusted to 5.0, and the mixture was placed at room temperature for 2 hours, then centrifuged at 3000 r / min for 10 min, and the supernatant was collected. The supernatant was loaded onto an AB-8 type macroporous resin column with a column diameter ratio of 1:8, first eluted with 3 times the column volume of deionized water at a flow rate of 2 BV / h to remove impurities, then eluted with 5 times the column volume of 60% ethanol at a flow rate of 1.5 BV / h, and the ethanol eluate was collected and concentrated under reduced pressure to obtain a concentrated liquid with a relative density of 1.20.

[0030] Fluidized bed granulation: the above obtained concentrated liquid was mixed with Schisandra powder, and a composite disintegrating agent (2% crospovidone and 1% sodium carboxymethyl starch), a temperature-sensitive adhesive (povidone K30 and hydroxypropyl methyl cellulose mixed at a mass ratio of 1:1, prepared into a 10% aqueous solution), and a drying aid (microcrystalline cellulose and silicon dioxide mixed at a mass ratio of 3:1) were added, and then the mixture was put into a fluidized bed granulator. The inlet air temperature was set to 65°C, the material temperature was set to 42°C, the atomization pressure was set to 0.2 MPa, and the adhesive solution was sprayed for granulation to obtain uniform wet granules.

[0031] Drying and granulation: the wet granules were transferred to a vacuum drying oven and dried at 48°C, -0.07 MPa until the water content was 2.5%, then taken out and sieved through a 20 mesh sieve to obtain dry granules.

[0032] Tableting and coating: 1.0% of a composite lubricant (magnesium stearate and talc mixed at a mass ratio of 2:1) was added to the dry granules, and the mixture was mixed for 10 minutes, then pressed into tablets with a rotary tablet press to obtain tablets with a diameter of 8 mm and a weight of 0.3 g. The tablets were placed in a high-efficiency coating pot, and a coating solution (hydroxypropyl methyl cellulose, β-cyclodextrin, and polyethylene glycol 6000 mixed at a mass ratio of 5:3:2, prepared into a 15% aqueous solution) was sprayed, and the coating weight was controlled at 3% to obtain coated tablets.

[0033] Quality test results: the hardness of the obtained Fuganning tablets was 90 N. The physical properties met the preset quality requirements.

[0034] Example 2

[0035] Raw material pretreatment: Take Bupleurum falcatum L. 6 parts, Herba scurfpea 13 parts, Radix isatidis 3 parts, Schisandra chinensis (Turcz.) Baill. 6 parts by weight. The above-mentioned medicinal materials are washed with purified water for 3 times, and then dried in a 60°C air-drying oven to a water content of ≤8% after removing impurities. The dried medicinal materials are crushed at -15°C by using a low-temperature ultrafine grinder, and then sieved through a 100-mesh sieve to obtain medicinal powder with a cell wall breaking rate of ≥92%.

[0036] Gradient extraction: the Bupleurum falcatum L., Herba scurfpea and Radix isatidis powders are mixed evenly, 6 times the mass of 70% ethanol is added, and then placed in a microwave-ultrasonic synergistic extraction device. The microwave power is set to 300 W, and the ultrasonic frequency is set to 25 kHz. After 0.5 hours of extraction, the first extraction liquid is collected by filtration. 4 times the mass of 50% ethanol is added to the residue, and then transferred to a reflux extraction tank. The temperature is set to 65°C for constant temperature reflux extraction for 1 hour, and then the second extraction liquid is obtained by filtration. The two extraction liquids are combined, and then the ethanol is recovered by rotary evaporation at 60°C and -0.08 MPa under reduced pressure. The clear paste with a relative density of 1.05 is obtained by concentration.

[0037] Compound purification: 2% citric acid aqueous solution is slowly added to the above-mentioned clear paste while stirring, and the pH is adjusted to 4.0. After standing at room temperature for 2 hours, centrifugation is performed at 3000 r / min for 10 min, and the supernatant is collected. The supernatant is loaded onto an AB-8 type macroporous resin column with a column diameter ratio of 1:8. First, 3 times the column volume of deionized water is used for elution at a flow rate of 2 BV / h to remove impurities. Then, 3 times the column volume of 60% ethanol is used for elution at a flow rate of 1.5 BV / h, and the ethanol eluate is collected. The concentrated liquid with a relative density of 1.20 is obtained by concentration under reduced pressure.

[0038] Fluidized bed granulation: the above-mentioned concentrated liquid is mixed with Schisandra chinensis (Turcz.) Baill. powder, and then compound disintegrating agent (2% crospovidone and 1% sodium starch glycolate), temperature-sensitive adhesive (polyvinylpyrrolidone K30 and hydroxypropyl methyl cellulose mixed at a mass ratio of 1:1 to prepare a 10% aqueous solution), and drying aid (microcrystalline cellulose and silicon dioxide mixed at a mass ratio of 3:1) are added. The mixture is put into a fluidized bed granulator. The inlet air temperature is set to 60°C, the material temperature is set to 40°C, and the atomization pressure is set to 0.2 MPa. The adhesive solution is sprayed for granulation to obtain uniform wet granules.

[0039] Drying and granulation: the wet granules are transferred to a vacuum drying oven, and then dried at 45°C and -0.07 MPa until the water content is 2.8%. After taking out, the granules are sieved through a 20-mesh sieve for granulation to obtain dry granules.

[0040] Tableting and Coating: Add 0.8% of a composite lubricant (magnesium stearate and talc mixed at a mass ratio of 2:1) to the dried granules. After mixing for 10 minutes, compress the mixture into uncoated tablets with a diameter of 8 mm and a weight of 0.3 g using a rotary tablet press. Place the uncoated tablets in a high-efficiency coating pan and spray in a coating solution (hydroxypropyl methylcellulose, β-cyclodextrin, and polyethylene glycol 6000 mixed at a mass ratio of 5:3:2 to prepare a 15% aqueous solution). Control the coating weight gain to 3% to obtain coated tablets.

[0041] Quality inspection results: The hardness of the obtained Fuganning tablets is 85N. Its physical properties meet the preset quality requirements.

[0042] Example 3

[0043] Raw material pretreatment: Weigh out 10 parts of Bupleurum chinense, 17 parts of Artemisia capillaris, 7 parts of Isatis indigotica, and 8 parts of Schisandra chinensis by weight. Wash the above medicinal materials three times with purified water to remove impurities, and then dry them in a 60℃ forced-air drying oven until the moisture content is ≤8%. Use a low-temperature ultrafine pulverizer to pulverize the dried medicinal materials separately at -5℃, and pass them through a 150-mesh sieve to obtain medicinal powder with a cell wall breakage rate ≥96%.

[0044] Gradient extraction: Mix Bupleurum, Artemisia capillaris, and Isatis indigotica powders evenly, add 10 times their weight of 70% ethanol, and place in a microwave-ultrasound synergistic extraction device. Set the microwave power to 400W and the ultrasonic frequency to 35kHz, extract for 2 hours, then filter and collect the first extract. Add 8 times their weight of 50% ethanol to the residue, transfer to a reflux extraction tank, and reflux at 65℃ for 2 hours. Filter to obtain the second extract. Combine the two extracts, and use a rotary evaporator at 60℃ and -0.08MPa to recover ethanol under reduced pressure, concentrating to a clear extract with a relative density of 1.15.

[0045] Compound purification: Slowly add 2% citric acid aqueous solution dropwise to the above-mentioned extract while stirring, adjust the pH to 6.0, let stand at room temperature for 2 hours, centrifuge at 3000 r / min for 10 min, and collect the supernatant. Load the supernatant onto an AB-8 macroporous resin column with a column diameter ratio of 1:8. First, elute with 3 column volumes of deionized water at a flow rate of 2 BV / h to remove impurities, then elute with 7 column volumes of 60% ethanol at a flow rate of 1.5 BV / h. Collect the ethanol eluent and concentrate under reduced pressure to a concentrate with a relative density of 1.20.

[0046] Fluidized bed granulation: The concentrated liquid obtained above is mixed evenly with Schisandra chinensis powder, and a composite disintegrant (2% crospovidone and 1% sodium carboxymethyl starch by mass percentage), a temperature-sensitive binder (povidone K30 and hydroxypropyl methylcellulose mixed at a mass ratio of 1:1 to prepare a 10% aqueous solution), and a drying aid (microcrystalline cellulose and silica mixed at a mass ratio of 3:1) are added to a fluidized bed granulator. The inlet air temperature is set to 70℃, the material temperature to 45℃, and the atomization pressure to 0.2MPa. The binder solution is sprayed in for granulation to obtain uniform wet granules.

[0047] Drying and granulation: The wet granules are transferred to a vacuum drying oven and dried at 55℃ and -0.07MPa until the moisture content is 2.2%. After drying, the granules are sieved through a 20-mesh sieve to obtain dried granules.

[0048] Tableting and Coating: Add 1.2% by weight of a composite lubricant (magnesium stearate and talc mixed at a mass ratio of 2:1) to the dried granules. After mixing for 10 minutes, compress the mixture into uncoated tablets with a diameter of 8 mm and a tablet weight of 0.3 g using a rotary tablet press. Place the uncoated tablets in a high-efficiency coating pan and spray in a coating solution (hydroxypropyl methylcellulose, β-cyclodextrin, and polyethylene glycol 6000 mixed at a mass ratio of 5:3:2 to prepare a 15% aqueous solution). Control the coating weight gain to 3% to obtain coated tablets.

[0049] Quality inspection results: The hardness of the obtained Fuganning tablets is 95N. Its physical properties meet the preset quality requirements.

[0050] Comparative Example 1

[0051] Raw material pretreatment: Weigh out 8 parts of Bupleurum chinense, 15 parts of Artemisia capillaris, 5 parts of Isatis indigotica, and 6 parts of Schisandra chinensis by weight. Wash the above medicinal materials three times with purified water to remove impurities, and then dry them in a 60℃ forced-air drying oven until the moisture content is ≤8%. Grind them using a room-temperature mechanical pulverizer and pass them through an 80-mesh sieve to obtain medicinal powder with a cell wall breakage rate of 55%.

[0052] Extraction: Mix Bupleurum, Artemisia capillaris and Isatis indigotica powder evenly, add 10 times the mass of 80% ethanol, transfer to a reflux extraction tank, reflux at 80℃ for 2 hours, filter to obtain the extract, use a rotary evaporator to recover ethanol under reduced pressure at 60℃ and -0.08MPa, concentrate to a clear extract with a relative density of 1.10.

[0053] Purification: The above-mentioned extract was directly loaded onto an AB-8 macroporous resin column (column diameter ratio 1:8). First, it was eluted with 3 column volumes of deionized water at a flow rate of 2 BV / h to remove impurities. Then, it was eluted with 5 column volumes of 60% ethanol at a flow rate of 1.5 BV / h. The ethanol eluent was collected and concentrated under reduced pressure to a concentrate with a relative density of 1.20.

[0054] Granulation: The concentrated liquid obtained above is mixed evenly with Schisandra chinensis powder, and a single disintegrant (sodium carboxymethyl starch at a mass percentage of 3%) and a binder (starch paste at a mass percentage of 5%) are added. Wet granulation is then performed to obtain wet granules.

[0055] Drying and granulation: The wet granules are transferred to a hot air circulating drying oven and dried at 60°C until the moisture content is ≤3%. After drying, they are granulated by passing them through a 20-mesh sieve to obtain dried granules.

[0056] Tableting: Add 1.0% magnesium stearate as a lubricant to the dry granules as a total weight, mix for 10 minutes, and then compress into unprocessed tablets with a diameter of 8 mm and a tablet weight of 0.3 g using a rotary tablet press.

[0057] Quality inspection results: The hardness of the obtained Fuganning tablets was 65N. Its physical properties did not meet the preset quality requirements.

[0058] Comparative Example 2

[0059] Raw material pretreatment: Weigh out 8 parts of Bupleurum chinense, 15 parts of Artemisia capillaris, 5 parts of Isatis indigotica, and 6 parts of Schisandra chinensis by weight. Use a low-temperature ultrafine pulverizer to pulverize the dried medicinal materials separately at -10℃, and pass them through a 120-mesh sieve to obtain medicinal powder.

[0060] Extraction: Mix Bupleurum chinense, Artemisia capillaris, and Isatis indigotica powder evenly, add 8 times their weight of 70% ethanol, and place in a microwave-ultrasound synergistic extraction device. Set the microwave power to 350W and the ultrasonic frequency to 30kHz, extract for 1 hour, filter, and collect the extract. Use a rotary evaporator to recover ethanol under reduced pressure at 60℃ and -0.08MPa, and concentrate to a clear extract with a relative density of 1.10.

[0061] Purification: Slowly add 2% citric acid aqueous solution to the above clear extract, adjust the pH to 5.0, let stand at room temperature for 2 hours, centrifuge at 3000 r / min for 10 minutes, take the supernatant, and concentrate under reduced pressure to a concentrate with a relative density of 1.20.

[0062] Fluidized bed granulation: The concentrated liquid obtained above is mixed evenly with Schisandra chinensis powder, and a composite disintegrant (2% by mass of crospovidone and 1% by mass of sodium carboxymethyl starch), a single binder (10% by mass of crospovidone K30 aqueous solution), and a drying aid (microcrystalline cellulose and silica mixed at a mass ratio of 3:1) are added to a fluidized bed granulator to obtain wet granules. The wet granules are dried at 60°C to obtain dry granules, which are used for subsequent tableting. The coating material is hydroxypropyl methylcellulose.

[0063] Drying and granulation: The wet granules are vacuum dried at 48℃ until the moisture content is ≤2.5%, and then granulated by passing them through a 20-mesh sieve to obtain dried granules.

[0064] Tableting and Coating: Add 1.0% by weight of a composite lubricant (magnesium stearate and talc mixed at a mass ratio of 2:1) to the dried granules, mix thoroughly, and then compress into uncoated tablets. Place the uncoated tablets in a high-efficiency coating pan and spray in the coating solution (single hydroxypropyl methylcellulose, prepared as a 15% aqueous solution by mass), controlling the coating weight gain to 3%.

[0065] Quality inspection results: The hardness of the obtained Fuganning tablets was 70N. Its physical properties did not meet the preset quality requirements.

[0066] Test Example 1: Disintegration Time Determination

[0067] The test samples included Fuganning tablets (all coated tablets, each weighing 0.3g) prepared in Examples 1, 2, and 3, as well as Fuganning tablets (plain tablets, uncoated, each weighing 0.3g) prepared in Comparative Example 1 and Fuganning tablets (coated tablets, each weighing 0.3g) prepared in Comparative Example 2.

[0068] The basket method was used. The test samples were placed in the baskets of the disintegration apparatus, and artificial gastric fluid (pH=1.2) at 37℃±1℃ was added. The instrument was started, and the time for complete disintegration of each tablet (all disintegrating particles passed through the sieve) was recorded. The test results are shown in Table 1.

[0069] Table 1. Disintegration time limit test results

[0070] Group Disintegration Time (min) Example 1 10 Example 2 11 Example 3 9 Comparative Example 1 28 Comparative Example 2 20

[0071] As shown in Table 1, the tablet disintegration time of Examples 1-3 of the present invention is significantly shorter than that of Comparative Examples 1-2. The composite disintegrant and the gradient extraction process synergistically improve the disintegration performance.

[0072] Experiment Example 2 Stability Test

[0073] The test samples included Fuganning tablets (all coated tablets, each weighing 0.3g) prepared in Examples 1, 2, and 3, as well as Fuganning tablets (plain tablets, uncoated, each weighing 0.3g) prepared in Comparative Example 1 and Fuganning tablets (coated tablets, each weighing 0.3g) prepared in Comparative Example 2.

[0074] For initial sample testing (0 months), three batches of each test sample were taken, and 10 tablets were randomly selected from each batch. The content of saikosaponins was first determined using high-performance liquid chromatography (HPLC). The chromatographic conditions were: Agilent ZORBAX SB-C18 column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile-water (30:70, v / v); detection wavelength: 210 nm; flow rate: 1.0 mL / min; column temperature: 30 ℃; injection volume: 10 μL. The average saikosaponin content per tablet was calculated.

[0075] Next, visually inspect the coated tablets for cracks, peeling, discoloration, or other defects in the coating, and calculate the coating integrity rate. Then, place each test sample in a constant temperature and humidity chamber (temperature 25℃, relative humidity 60%) according to the above packaging method. Samples are taken at 1 month, 3 months, and 6 months, with 3 batches of 10 tablets each at each time point. The content of saikosaponin and the coating integrity rate are repeatedly tested using the same initial testing method as described above.

[0076] The content change rate was calculated as follows: (content at 0 months - content at each time point) / content at 0 months × 100%; a positive value indicates a decrease in content, and the larger the absolute value, the more significant the degradation. The coating integrity rate was calculated as: number of intact tablets / total number of tablets tested × 100%. The test results are shown in Table 2.

[0077] Table 2 Stability test results

[0078]

[0079]

[0080] In the stability test, the change rate of saikosaponin content in the Fuganning tablets of Examples 1-3 of this invention was ≤2.5%, and the coating integrity rate was ≥98%, showing significantly better stability than the comparative example. This indicates that the compound purification process and functional coating technology can effectively delay the degradation of active ingredients and maintain the integrity of the coating, significantly improving the stability of the formulation. The results meet the conventional requirements of the stability test cycle for the invention patent.

[0081] Experimental Example 3: Liver Function Test

[0082] The test samples included Fuganning tablets prepared in Examples 1, 2, 3, and Comparative Examples 1 and 2 (all crushed and prepared into a 0.1 g / mL suspension with 0.5% sodium carboxymethyl cellulose solution); the positive control drug was biphenyl diester pellets (crushed and prepared into a 0.02 g / mL suspension); the modeling reagent was carbon tetrachloride solution diluted with olive oil to 0.1% (v / v); and the detection reagents were serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) kits (purchased from Nanjing Jiancheng Bioengineering Institute).

[0083] Eighty SPF-grade BALB / c mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 22±2g, were used as experimental animals. They were not treated with any drugs before the experiment and had free access to food and water. The mice were randomly divided into 8 groups of 10 mice each:

[0084] Normal control group: Intraperitoneal injection of an equal volume of olive oil, and daily gavage administration of 0.2 mL / 10 g body weight of 0.5% sodium carboxymethyl cellulose solution;

[0085] Model control group: Intraperitoneal injection of 0.1% CCl4 olive oil solution 0.1mL / 10g body weight (once daily for 3 consecutive days), and at the same time, oral administration of an equal volume of 0.5% carboxymethyl cellulose sodium solution;

[0086] Example 1 group: The modeling method was the same as that of the model control group. From the first day of modeling, 0.2 mL of the Example 1 suspension per 10 g body weight was administered by gavage daily (dosage dose 0.5 g / kg).

[0087] Example 2 group: The modeling method was the same as the model control group, and the suspension of Example 2 was administered by gavage (dose 0.5g / kg);

[0088] Example 3 group: The modeling method was the same as the model control group, and the suspension of Example 3 was administered by gavage (dosage dose 0.5g / kg);

[0089] Comparative Example 1: The modeling method was the same as that of the model control group, and the Comparative Example 1 suspension was administered by gavage (dose of 0.5 g / kg);

[0090] Comparative Example 2: The modeling method was the same as that of the model control group, and the Comparative Example 2 suspension was administered by gavage (dose of 0.5 g / kg);

[0091] Positive drug control group: The modeling method was the same as that of the model control group, and the biphenyl diester suspension was administered by gavage at a rate of 0.2 mL / 10 g body weight (dose of 0.1 g / kg).

[0092] All groups were treated for 5 consecutive days, and after the last administration, fasting was allowed but water was permitted for 12 hours.

[0093] During the test, blood was collected from the orbital cavity of mice, and serum was separated by centrifugation at 3000 r / min for 10 min. Serum ALT and AST activities were measured according to the kit instructions. At the same time, the mice were sacrificed and their livers were dissected to observe the color, texture, and degree of swelling of the livers in each group. The experimental results are shown in Table 3.

[0094] Table 3 Results of Liver Function Tests

[0095]

[0096]

[0097] The serum ALT and AST activities of mice in the model control group were significantly increased (compared to the normal control group), indicating that the liver injury model was successfully established. The ALT and AST activities of groups 1-3 of this invention were significantly lower than those of groups 1-2 of the comparative examples, and the appearance of the liver tissue was also closer to that of a normal state. This indicates that the Fuganning tablets prepared by the process of this invention can more effectively improve the liver function of mice with liver injury, and its hepatoprotective efficacy is superior to that of preparations prepared by traditional and simplified processes.

Claims

1. A method for preparing Fuganning tablets, characterized in that, Includes the following steps: S1. Take 6-10 parts of Bupleurum chinense, 13-17 parts of Artemisia capillaris, 3-7 parts of Isatis indigotica, and 4-8 parts of Schisandra chinensis by weight, wash and dry them separately, and then pulverize them to 100-150 mesh using low-temperature ultrafine grinding. S2. Take powdered Bupleurum, Artemisia capillaris, and Isatis indigotica, add 6-10 times their weight of 70% ethanol, and extract using microwave-ultrasound combined extraction for 0.5-2 hours. Filter to obtain the first extract. Add 4-8 times their weight of 50% ethanol to the residue, and extract using constant temperature reflux for 1-2 hours. Filter to obtain the second extract. Combine the two extracts, recover the ethanol under reduced pressure, and concentrate to a clear extract with a relative density of 1.05-1.

15. S3. Slowly add 2% citric acid aqueous solution to the clear paste obtained in step S2, adjust the pH to 4.0-6.0, let stand for 2 hours to precipitate impurities, take the supernatant, pass the supernatant through an AB-8 macroporous resin column, first elute with 3 column volumes of deionized water, then elute with 3-7 column volumes of 60% ethanol, collect the ethanol eluent and concentrate it. S4. Mix the concentrated liquid obtained in step S3 with Schisandra chinensis powder, add a composite disintegrant, a temperature-sensitive binder and a drying aid, and granulate using a fluidized bed to obtain wet granules. S5. Dry the wet granules obtained in step S4 at 45-55℃ until the moisture content is ≤3%, and then granulate them through a 20-mesh sieve to obtain dried granules. S6. After mixing the dried granules obtained in step S5 with a composite lubricant accounting for 0.8% to 1.2% of the total weight of the dried granules, compress the mixture into tablets and apply a water-soluble film coating to the surface of the tablets.

2. The preparation method according to claim 1, characterized in that, The conditions for low-temperature ultrafine pulverization in step S1 are: temperature -15 to -5℃.

3. The preparation method according to claim 1, characterized in that, The conditions for microwave-ultrasound synergistic extraction in step S2 are: microwave power 300-400W, ultrasonic frequency 25-35kHz.

4. The preparation method according to claim 1, characterized in that, The composite disintegrant in step S4 is composed of 2% crosslinked polyvinylpyrrolidone and 1% sodium carboxymethyl starch by mass percentage; the temperature-sensitive adhesive is a mixture of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose by mass ratio of 1:1; and the drying aid is a composite of microcrystalline cellulose and silica by mass ratio of 3:

1.

5. The preparation method according to claim 1, characterized in that, The fluidized bed granulation conditions described in step S4 are: inlet air temperature 60-70℃, material temperature 40-45℃.

6. The preparation method according to claim 1, characterized in that, The water-soluble film coating material mentioned in step S6 is composed of hydroxypropyl methylcellulose, β-cyclodextrin, and polyethylene glycol 6000 in a mass ratio of 5:3:

2.

7. The preparation method according to claim 1, characterized in that, The key quality control indicators for tablets after step S6 are: tablet hardness 80-100N, disintegration time ≤12 minutes.

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