Ursodeoxycholic acid capsule and preparation method thereof

Abstract

The invention provides an ursodeoxycholic acid capsule and a preparation method thereof, and relates to the field of medical technology. The method comprises the following steps: crushing: mixing ursodeoxycholic acid raw material and diluent, and crushing; slurry preparation: heating water, keeping warm, adding starch, stirring, and obtaining starch slurry; premixing: adding the mixed material and the remaining starch in the prescription amount to a wet granulator, and premixing; granulation: adding water to the surface of the material, and performing the first granulation; adding starch slurry, and performing the second granulation; adding water, and performing the third granulation; discharging, granulation, and obtaining wet granules; drying: drying the wet granules; granulation and total mixing: mixing the dried granules with colloidal silicon dioxide and magnesium stearate; and capsule filling. The method solves the common problems of crushing difficulty and static electricity in the granulation process in the production process of ursodeoxycholic acid capsules. The method makes the process in the production process simpler, safer, and more efficient.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to an ursodeoxycholic acid capsule and a preparation method thereof. Background Art

[0002] Gallstones, also known as cholelithiasis, refer to a disease in which stones form in the biliary system, including the gallbladder or bile duct; bile duct infection is a common disease. According to the site of onset, they are divided into gallbladder stones and bile duct stones. After the stones form in the gallbladder, they can irritate the gallbladder mucosa, which can not only cause chronic inflammation of the gallbladder, but also cause secondary infection when the stones are lodged in the gallbladder neck or cystic duct, leading to acute inflammation of the gallbladder. Chronic irritation of the gallbladder mucosa by stones may also lead to the occurrence of gallbladder cancer. It has been reported that the incidence of this type of gallbladder cancer can reach 1%-2%.

[0003] Pharmacology of ursodeoxycholic acid: ursodeoxycholic acid is a free bile acid component in normal bile, which can increase the secretion of bile acid, leading to changes in the composition of bile acid, increasing the content of ursodeoxycholic acid in bile, and having a choleretic effect. Ursodeoxycholic acid can inhibit the synthesis of cholesterol in the liver, significantly reduce the number of cholesterol and cholesterol ester molecules in bile and the saturation index of cholesterol, thereby facilitating the gradual dissolution of cholesterol in stones, greatly reducing the stone formation index, and having a choleretic effect.

[0004] Ursodeoxycholic acid can also reduce liver fat, increase the activity of liver catalase, promote the accumulation of liver glycogen, improve the liver's anti-toxic and detoxification capabilities, and reduce the concentration of triglycerides in the liver and serum. Ursodeoxycholic acid is a hydrophilic bile acid that has important functions such as choleretic, cell protection, anti-oxidation and immunomodulation. It has been widely used in the clinical treatment of various liver diseases and has achieved good results.

[0005] Patent CN 109568288 A discloses an ursodeoxycholic acid capsule and its preparation method, belonging to the field of pharmaceutical preparation technology. An ursodeoxycholic acid capsule, the raw materials include by weight: 3-9 parts of ursodeoxycholic acid, 0.01-4 parts of pregelatinized starch, 0.02-4 parts of starch, 0.1-0.2 parts of magnesium stearate, 0.05-0.5 parts of colloidal silicon dioxide and 0.05-1 parts of hydroxypropyl methylcellulose, the ursodeoxycholic acid is micronized, and the particle size D90 is less than 40μm. The micronization treatment is achieved by an air flow mill, and the specific operation is: ursodeoxycholic acid is added to the crushing chamber, and the filtered and dried compressed air is sprayed into the crushing chamber through a Laval nozzle, and then the ursodeoxycholic acid is driven to collide and rub repeatedly at the intersection of the pressure airflow to achieve crushing.

[0006] Patent CN 111494333 B provides an ursodeoxycholic acid capsule and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. When preparing ursodeoxycholic acid capsules, the present invention uses only conventional pharmaceutical excipients corn starch, colloidal silicon dioxide and magnesium stearate as auxiliary materials, and the preparation process only uses an ordinary wet granulation process and no solubilizer is added during the preparation process, so that a robust dissolution effect can be achieved. However, the ursodeoxycholic acid raw material is hydrophobic and has certain adsorption properties, and there are static electricity and poor fluidity during the pulverization process. The production and preparation process of ursodeoxycholic acid capsules is mainly a wet granulation process, and static electricity is also generated during the granulation process. There has been no research on the problem of static electricity in the production and preparation process of ursodeoxycholic acid capsules, but solving the above problem is also crucial to improving the fluidity of the material after pulverization, which can reduce the difficulty of granulation.

[0007] In view of the above situation, the present invention provides an ursodeoxycholic acid capsule and a preparation method thereof, which solves the static electricity problem in the pulverizing and granulating process by controlling the pulverizing process and wet granulation process of the ursodeoxycholic acid raw material, and also solves the fluidity problem of the pulverized material. Summary of the invention

[0008] The purpose of the present invention is to provide an ursodeoxycholic acid capsule and a preparation method thereof, and to solve the static electricity problem in the pulverizing and granulating process by controlling the pulverizing process and wet granulating process of the ursodeoxycholic acid raw material.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing ursodeoxycholic acid capsules comprises the following steps:

[0011] 1) Crushing: mixing the ursodeoxycholic acid raw material and the diluent, and crushing to obtain a mixed material;

[0012] 2) Slurry preparation: heat water to 75-95°C, keep warm, add starch, stir, cool to 60-73°C to obtain starch slurry;

[0013] 3) Premixing: Add the mixed material and the remaining starch in the prescription amount into the wet granulator for premixing;

[0014] 4) Granulation: adding water to the surface of the material to perform the first granulation; adding the starch slurry obtained in step 2) to perform the second granulation; adding purified water to perform the third granulation; discharging the material, granulating, and obtaining wet granules;

[0015] 5) Drying: Drying the wet granules;

[0016] 6) Granulation and total mixing: the dried granules are mixed with colloidal silicon dioxide and magnesium stearate;

[0017] 7) Capsule filling: Fill the granules into the capsule shell to obtain ursodeoxycholic acid capsules.

[0018] Preferably, the water in step 2) and step 4) is selected from at least one of purified water, distilled water and ultrapure water; more preferably, it is purified water.

[0019] Preferably, the mixing parameters in step 1) are: mixing time is 5-15 min, and mixing speed is 5-15 rpm.

[0020] Preferably, the pulverizing screen in step 1) is a 90-110 mesh screen; more preferably, it is a 100 mesh screen.

[0021] Preferably, the amount of water in step 2) is 84%-94% of the prescribed amount; more preferably, it is 90%.

[0022] Preferably, the amount of starch used in step 2) is 14.5-30% of the prescribed amount; more preferably, it is 21% of the prescribed amount.

[0023] Preferably, the specific parameters of the premixing in step 3) are: premixing time is 30-120s, stirring speed is 60-100rpm, and cutter speed is 1800-2200rpm; further preferably, the premixing time is 60s, the stirring speed is 80rpm, and the cutter speed is 2000rpm.

[0024] Preferably, the specific parameters of the first granulation in step 4) are: time 160-200s, stirring speed 100-150rpm, and cutter speed 1800-2200rpm; further preferably, time 180s, stirring speed 120rpm, and cutter speed 2000rpm.

[0025] Preferably, the specific parameters of the second granulation in step 4) are: time 160-200s, stirring speed 160-200rpm, and cutter speed 1800-2200rpm; more preferably, time 180s, stirring speed 180rpm, and cutter speed 2000rpm.

[0026] Preferably, the specific parameters of the third granulation in step 4) are: time 160-200s, stirring speed 100-150rpm, and cutter speed 1800-2200rpm; further preferably, time 180s, stirring speed 120rpm, and cutter speed 2000rpm.

[0027] Preferably, the water added in the first granulation in step 4) is 4.5%-12% of the prescribed amount, and the water added in the third granulation is 1.5%-4% of the prescribed amount; further preferably, the water added in the first granulation in step 4) is 8% of the prescribed amount, and the water added in the third granulation is 2.7%.

[0028] Preferably, the wet granules in step 4) are sieved through a 15-25 mesh sieve; preferably, sieved through a 20 mesh sieve.

[0029] Preferably, the specific parameters of the drying in step 5) are: inlet air temperature of 40-80°C, material temperature less than 50°C, and material moisture less than 5%; further preferably, the specific parameters of the drying are: inlet air temperature of 50-70°C, material temperature less than 45°C, and material moisture less than 2%.

[0030] Preferably, the specific parameters of the mixing in step 6) are: time 8-15 min, speed 5-15 rpm; further preferably, the specific parameters of the mixing are: time 10 min, speed 10 rpm.

[0031] Preferably, in step 7), the capsule shell is a size 0 capsule shell, and the filling amount is 330 mg±5%.

[0032] An ursodeoxycholic acid capsule prepared by the above preparation method comprises the following raw materials in parts by weight: 230-270 parts of ursodeoxycholic acid, 20-30 parts of diluent, 40-55 parts of starch, 4-6 parts of colloidal silicon dioxide, 1-3 parts of magnesium stearate, and 116-140 parts of purified water; preferably, the ursodeoxycholic acid capsule comprises the following raw materials in parts by weight: 240-260 parts of ursodeoxycholic acid, 23-27 parts of diluent, 42-50 parts of starch, 4-5 parts of colloidal silicon dioxide, 1-2 parts of magnesium stearate, and 118-130 parts of purified water; further preferably, the ursodeoxycholic acid capsule comprises the following raw materials in parts by weight: 250 parts of ursodeoxycholic acid, 25 parts of diluent, 48 parts of starch, 5 parts of colloidal silicon dioxide, 2 parts of magnesium stearate, and 128 parts of purified water.

[0033] Preferably, the diluent is selected from at least one of lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose; more preferably, it is microcrystalline cellulose.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The invention discloses an ursodeoxycholic acid capsule and a preparation method thereof. By improving two key steps of the preparation method, namely, a crushing process of ursodeoxycholic acid raw materials and a wet granulation process of ursodeoxycholic acid, the invention solves the common crushing difficulty problem in the production process of ursodeoxycholic acid capsules and the static electricity problem in the granulation process, making the process in the production process simpler, safer and more efficient. DETAILED DESCRIPTION

[0036] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0037] Example 1. Ursodeoxycholic acid prescription composition (specification: 250 mg), calculated as 1000 tablets.

[0038] Name of raw materials 1000 tablets / g Ursodeoxycholic acid 250.0 Microcrystalline Cellulose 25.0 starch 48.0 Colloidal Silica 5.0 Magnesium Stearate 2.0 Purified water 128.0

[0039] Preparation process:

[0040] Crushing: Add ursodeoxycholic acid raw material and microcrystalline cellulose into a mixer and premix for 10 minutes at a speed of 10 rpm. Mechanically crush the mixed materials using a 100-mesh sieve. Set aside.

[0041] Preparation of slurry: Take an appropriate amount of purified water (about 115g), heat it to 80-90℃ and keep it warm. Slowly add 10g of starch into the insulation bucket and stir until the temperature drops to 65-70℃. Set aside.

[0042] Premixing: Place the mixture after the raw materials are crushed into a wet granulator, add the remaining starch in the prescription into the wet granulator, start the machine, premix for 60 seconds, stir at 80 rpm, and cutter speed at 2000 rpm.

[0043] Granulation:

[0044] The first step is to open the feed port and spray 10g of purified water onto the surface of the material. The time is set to 180 seconds, the stirring speed is 120rpm, and the cutter speed is 2000rpm.

[0045] The second step is to open the feeding port and add the starch slurry into the material while it is hot. Set the time to 180 seconds, the stirring speed to 180 rpm, and the cutter speed to 2000 rpm.

[0046] Step 3: After the second step, add 3g of purified water through the feeding port, set the time to 180 seconds, the stirring speed to 120rpm, and the cutting speed to 2000rpm. After the granulation is completed, open the discharge valve to discharge the material. The obtained wet granules are granulated by a granulator with a mesh size of 20.

[0047] Drying: Add the wet granules into the fluidized bed for drying. Set the air inlet temperature to 50-70°C and control the material temperature below 45°C. When the moisture content of the material is dried to below 2.0%, stop drying and discharge the material.

[0048] Whole grain, total mixing:

[0049] The pulverizer was equipped with a 2.0 mm screen and the speed was set to 800 rpm. The dried granules were passed through the pulverizer and then transferred to a mixer. The prescribed amount of colloidal silicon dioxide and magnesium stearate were added and mixed for 10 minutes (the mixing speed was set to 10 rpm). After the mixing was completed, samples were taken and the intermediates were tested.

[0050] Capsule filling:

[0051] The granules were filled into No. 0 capsule shells in an amount of 330 mg ± 5%, thereby obtaining ursodeoxycholic acid capsules.

[0052] Example 2: Ursodeoxycholic acid prescription composition (specification: 250 mg), calculated as 1000 tablets.

[0053] Name of raw materials 1000 tablets / g Ursodeoxycholic acid 250.0 Low substituted hydroxypropyl cellulose 25.0 starch 48.0 Colloidal Silica 5.0 Magnesium Stearate 2.0 Purified water Moderate

[0054] Preparation process:

[0055] Crushing: Add ursodeoxycholic acid raw material and low-substituted hydroxypropyl cellulose into a mixer and premix for 10 minutes at a speed of 10 rpm. Mechanically crush the mixed materials using a 100-mesh sieve. Set aside.

[0056] Preparation of slurry: Take an appropriate amount of purified water (about 115g), heat it to 80-90℃ and keep it warm. Slowly add 10g of starch into the insulation bucket and stir until the temperature drops to 65-70℃. Set aside.

[0057] Premixing: Place the mixture after the raw materials are crushed into a wet granulator, add the remaining starch in the prescription into the wet granulator, start the machine, premix for 60 seconds, stir at 80 rpm, and cutter speed at 2000 rpm.

[0058] Granulation:

[0059] The first step is to open the feed port and spray 10g of purified water onto the surface of the material. The time is set to 180 seconds, the stirring speed is 120rpm, and the cutter speed is 2000rpm.

[0060] The second step is to open the feeding port and add the starch slurry into the material while it is hot. Set the time to 180 seconds, the stirring speed to 180 rpm, and the cutter speed to 2000 rpm.

[0061] Step 3: After the second step, add 3g of purified water through the feeding port, set the time to 180 seconds, the stirring speed to 120rpm, and the cutting speed to 2000rpm. After the granulation is completed, open the discharge valve to discharge the material. The obtained wet granules are granulated by a granulator with a mesh size of 20.

[0062] Drying: Add the wet granules into the fluidized bed for drying. Set the air inlet temperature to 50-70°C and control the material temperature below 45°C. When the moisture content of the material is dried to below 2.0%, stop drying and discharge the material.

[0063] Whole grain, total mixing:

[0064] The pulverizer was equipped with a 2.0 mm screen and the speed was set to 800 rpm. The dried granules were passed through the pulverizer and then transferred to a mixer. The prescribed amount of colloidal silicon dioxide and magnesium stearate were added and mixed for 10 minutes (the mixing speed was set to 10 rpm). After the mixing was completed, samples were taken and the intermediates were tested.

[0065] Capsule filling:

[0066] The granules were filled into No. 0 capsule shells in an amount of 330 mg ± 5%, thereby obtaining ursodeoxycholic acid capsules.

[0067] Comparative Example 1, ursodeoxycholic acid prescription composition (specification: 250 mg), calculated as 1000 tablets.

[0068] Name of raw materials 1000 tablets / g Ursodeoxycholic acid 250.0 Microcrystalline Cellulose 25.0 starch 48.0 Colloidal Silica 5.0 Magnesium Stearate 2.0 Purified water Moderate

[0069] Preparation process:

[0070] Crushing: Add ursodeoxycholic acid raw material and microcrystalline cellulose into a mixer and premix for 10 minutes at a speed of 10 rpm. Mechanically crush the mixed materials using a 100-mesh sieve. Set aside.

[0071] Preparation of slurry: Take an appropriate amount of purified water (about 115g), heat it to 80-90℃ and keep it warm. Slowly add 10g of starch into the insulation bucket and stir until the temperature drops to 65-70℃. Set aside.

[0072] Premixing: Place the mixture after the raw materials are crushed into a wet granulator, add the remaining starch in the prescription into the wet granulator, start the machine, premix for 60 seconds, stir at 80 rpm, and cutter speed at 2000 rpm.

[0073] Granulation:

[0074] The first step is to open the feed port and spray 10g of purified water onto the surface of the material. The time is set to 180 seconds, the stirring speed is 120rpm, and the cutter speed is 2000rpm.

[0075] The second step is to open the feeding port and add the starch slurry into the material while it is hot. Set the time to 180 seconds, the stirring speed to 180 rpm, and the cutter speed to 2000 rpm.

[0076] After granulation is completed, the discharge valve is opened to discharge the material. The obtained wet granules are granulated by a granulator with a screen having a mesh number of 20 meshes.

[0077] Drying: Add the wet granules into the fluidized bed for drying. Set the air inlet temperature to 50-70°C and control the material temperature below 45°C. When the moisture content of the material is dried to below 2.0%, stop drying and discharge the material.

[0078] Whole grain, total mixing:

[0079] The pulverizer was equipped with a 2.0 mm screen and the speed was set to 800 rpm. The dried granules were passed through the pulverizer and then transferred to a mixer. The prescribed amount of colloidal silicon dioxide and magnesium stearate were added and mixed for 10 minutes (the mixing speed was set to 10 rpm). After the mixing was completed, samples were taken and the intermediates were tested.

[0080] Capsule filling:

[0081] The granules were filled into No. 0 capsule shells in an amount of 330 mg ± 5%, thereby obtaining ursodeoxycholic acid capsules.

[0082] Comparative Example 2, ursodeoxycholic acid prescription composition (specification: 250 mg), calculated as 1000 tablets.

[0083] Name of raw materials 1000 tablets / g Ursodeoxycholic acid 250.0 Microcrystalline Cellulose 25.0 starch 48.0 Colloidal Silica 5.0 Magnesium Stearate 2.0 Purified water Moderate

[0084] Preparation process:

[0085] Crushing: Add ursodeoxycholic acid raw material and microcrystalline cellulose into a mixer and premix for 10 minutes at a speed of 10 rpm. Mechanically crush the mixed materials using a 100-mesh sieve. Set aside.

[0086] Preparation of slurry: Take an appropriate amount of purified water (about 115g), heat it to 80-90℃ and keep it warm. Slowly add 10g of starch into the insulation bucket and stir until the temperature drops to 65-70℃. Set aside.

[0087] Premixing: Place the mixture after the raw materials are crushed into a wet granulator, add the remaining starch in the prescription into the wet granulator, start the machine, premix for 60 seconds, stir at 80 rpm, and cutter speed at 2000 rpm.

[0088] Granulation: Open the feeding port and add the starch slurry into the material while it is hot. Set the time to 180 seconds, the stirring speed to 180 rpm, and the cutter speed to 2000 rpm.

[0089] After granulation is completed, the discharge valve is opened to discharge the material. The obtained wet granules are granulated by a granulator with a screen having a mesh number of 20 meshes.

[0090] Drying: Add the wet granules into the fluidized bed for drying. Set the air inlet temperature to 50-70°C and control the material temperature below 45°C. When the moisture content of the material is dried to below 2.0%, stop drying and discharge the material.

[0091] Whole grain, total mixing:

[0092] The pulverizer was equipped with a 2.0 mm screen and the speed was set to 800 rpm. The dried granules were passed through the pulverizer and then transferred to a mixer. The prescribed amount of colloidal silicon dioxide and magnesium stearate were added and mixed for 10 minutes (the mixing speed was set to 10 rpm). After the mixing was completed, samples were taken and the intermediates were tested.

[0093] Capsule filling:

[0094] The granules were filled into No. 0 capsule shells in an amount of 330 mg ± 5%, thereby obtaining ursodeoxycholic acid capsules.

[0095] The dissolution was determined according to the dissolution and release method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition).

[0096] Dissolution conditions: Use 900 ml of phosphate buffer (mix equal amounts of 0.03 mol / L potassium dihydrogen phosphate solution and 0.12 mol / L disodium hydrogen phosphate solution, and adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution) as the dissolution medium, rotate at 75 revolutions per minute, operate according to the method, and take samples after 60 minutes.

[0097] Test solution: Take an appropriate amount of the dissolution solution, filter it, and take the filtrate to obtain the solution.

[0098] Reference solution: Take an appropriate amount of ursodeoxycholic acid reference substance, weigh accurately, add 1.4 ml of 1 mol / L sodium hydroxide solution to dissolve, and quantitatively dilute with dissolution medium to make a solution containing approximately 0.28 mg per 1 ml.

[0099] Chromatographic conditions: injection volume 50 μl, others see under content determination.

[0100] System suitability requirements: See under Assay.

[0101] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount of each particle by the peak area according to the external standard method.

[0102] Commercially available preparation: specification 250 mg; manufacturer: Losan Pharma GmbH; batch number: L20312A.

[0103] Table 1. Dissolution results

[0104]

[0105]

[0106] According to the experimental results, the ursodeoxycholic acid capsules obtained in Examples 1-2 of the present invention have the same in vitro dissolution behavior as the commercially available preparations. However, the dissolution behavior of Comparative Examples 1-2 is significantly lower than that of the commercially available preparations. It can be seen that qualified products can be produced by granulating three times, and the static electricity problem can be solved.

[0107] Evaluation of electrostatics during granulation

[0108] The static electricity in the granulation process is evaluated by visual inspection, and there are three static electricity states: strong, medium and weak. The weaker the static electricity, the safer it is in the production process.

[0109] Table 2. Electrostatic evaluation results

[0110] sample Electrostatic evaluation Example 1 weak Example 2 weak Comparative Example 1 middle Comparative Example 2 powerful

[0111] Conclusion: After the same pulverization process, Examples 1-2 used 3 granulation, and the static electricity during the granulation process was weak; while Comparative Examples 1 and 2, which used 2 granulation and 1 granulation, had neutral and strong static electricity evaluations, respectively. It can be seen that the use of three granulation processes can effectively eliminate the static electricity problem in the production process.

[0112] Particle flowability

[0113] The flow properties of the dried granules after wet granulation were evaluated and the angle of repose was measured.

[0114] Table 3. Angle of repose results

[0115] sample Angle of repose(°) Example 1 34.6° Example 2 35.1° Comparative Example 1 40.3° Comparative Example 2 41.2°

[0116] Conclusion: The dry granules obtained in Example 1-2 have a small angle of repose and good fluidity, while the dry granules obtained in Comparative Example 1-2 have a large angle of repose and poor fluidity.

[0117] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing ursodeoxycholic acid capsules, characterized in that: The invention comprises the following raw materials in parts by weight: 230-270 parts of ursodeoxycholic acid, 20-30 parts of diluent, 40-55 parts of starch, 4-6 parts of colloidal silicon dioxide, 1-3 parts of magnesium stearate, and 116-140 parts of purified water; The following steps are involved: 1) Grinding: ursodeoxycholic acid raw material and diluent are mixed and pulverized to obtain a mixed material; the mixing parameters are: mixing time is 5-15min, mixing speed is 5-15rpm; the diluent is microcrystalline cellulose and low-substituted hydroxypropyl cellulose; 2) Slurry preparation: heat water to 75-95°C, keep warm, add starch, stir, cool to 60-73°C to obtain starch slurry; 3) Premixing: Add the mixed material and starch into the wet granulator and premix; 4) Granulation: adding water to the surface of the material to perform the first granulation; adding the starch slurry obtained in step 2) to perform the second granulation; adding water to perform the third granulation; discharging the material, granulating, and obtaining wet granules; the specific parameters of the first granulation are: time 160-200s, stirring speed 100-150rpm, and cutter speed 1800-2200rpm; the specific parameters of the second granulation are: time 160-200s, stirring speed 160-200rpm, and cutter speed 1800-2200rpm; the specific parameters of the third granulation are: time 160-200s, stirring speed 100-150rpm, and cutter speed 1800-2200rpm; 5) Drying: Drying the wet granules; 6) Granulation and total mixing: the dried granules are mixed with colloidal silicon dioxide and magnesium stearate; 7) Capsule filling: Fill the granules into the capsule shell to obtain ursodeoxycholic acid capsules.

2. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The water in step 2) and step 4) is selected from at least one of purified water, distilled water and ultrapure water.

3. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The pulverizing screen in step 1) is a 90-110 mesh screen.

4. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The amount of water used in step 2) is 84%-94% of the prescribed amount.

5. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The amount of starch used in step 2) is 14.5-30% of the prescribed amount; the amount of starch used in step 3) is 70%-85.5% of the prescribed amount.

6. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The specific parameters of the premixing in step 3) are: premixing time is 30-120s, stirring speed is 60-100rpm, and cutter speed is 1800-2200rpm.

7. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: In step 4), the water added in the first granulation is 4.5%-12% of the prescribed amount, and the water added in the third granulation is 1.5%-4% of the prescribed amount.

8. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The wet granules in step 4) are passed through a 15-25 mesh sieve.

9. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: The specific parameters of the drying in step 5) are: the air inlet temperature is 40-80°C, the material temperature is less than 50°C, and the material moisture is less than 5%.

10. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: Step 6) The specific parameters of the mixing are: time 8-15 min, speed 5-15 rpm.

11. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: Step 7) The capsule shell is a No. 0 capsule shell, and the filling amount is 330 mg ± 5%.

12. Ursodeoxycholic acid capsules prepared according to the method for preparing ursodeoxycholic acid capsules according to any one of claims 1 to 11, characterized in that: The ursodeoxycholic acid capsule comprises the following raw materials in parts by weight: 240-260 parts of ursodeoxycholic acid, 23-27 parts of diluent, 42-50 parts of starch, 4-5 parts of colloidal silicon dioxide, 1-2 parts of magnesium stearate and 118-130 parts of purified water.

13. The ursodeoxycholic acid capsule according to claim 12, characterized in that: The ursodeoxycholic acid capsule comprises the following raw materials in parts by weight: 250 parts of ursodeoxycholic acid, 25 parts of diluent, 48 parts of starch, 5 parts of colloidal silicon dioxide, 2 parts of magnesium stearate, and 128 parts of purified water.

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