Pharmaceutical composition for gastroesophageal reflux disease and preparation method thereof

Abstract

The invention provides a composition for gastroesophageal reflux disease and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The composition provided by the invention comprises a tablet core and a coating layer, the tablet core comprises a plurality of components which are added in an internal adding mode and an external adding mode. The composition is uniform in active ingredient content, and has relatively good dissolution and extremely high stability; the problem of adhesion to a compression roller in the preparation process is avoided, and the process is simple and easy to implement and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition for gastroesophageal reflux disease and its preparation method, belonging to the field of pharmaceutical preparations. Background Technology

[0002] In the field of pharmaceutical formulations, drug formulations containing the same ingredients can exhibit significant differences in certain pharmaceutical properties, such as the dissolution characteristics and stability of the active ingredient contained in the formulation. These differences are related to the formulation's composition, content, impurities, and / or preparation process. Therefore, the research and development of drug formulations, including their formulations and processes, is extremely important.

[0003] Tigorafenib, chemically known as (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide, is a potassium-competitive acid blocker (P-CAB) used to treat diseases mediated by acid pump antagonism, such as gastroesophageal reflux disease, reflux esophagitis, duodenal ulcers, and Helicobacter pylori infection. Existing research indicates that tigorafenib is a poorly water-soluble drug, and its efficacy is easily destabilized over time. The method of obtaining tablets by wet granulation process is described in patent CN110121333B and other documents. However, due to the properties of tigorazine, this wet granulation process has extremely high requirements for the quality of tigorazine active pharmaceutical ingredient. For tigorazine active pharmaceutical ingredient that exists in metastable crystal form, amorphous form or other forms and has relatively low stability under high temperature or high humidity conditions, the wet granulation process is difficult to control and implement, which limits the selection of tigorazine active pharmaceutical ingredient and increases the difficulty and cost of formulation.

[0004] Tablets are a commonly used dosage form for oral medications. Therefore, developing an oral tablet of ticoraxen that can maintain stable drug action, is suitable for large-scale industrial production, and meets or exceeds the requirements in terms of dissolution behavior and other aspects remains both difficult and necessary. Summary of the Invention

[0005] The present invention provides a tablet composition for oral administration, which has good dissolution, stable drug action, and does not exhibit a bitter taste.

[0006] According to the present invention, an oral tablet comprises: a tablet core and a coating layer; the tablet core is composed of the following components: ticoraxan, microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropyl cellulose, silica, and magnesium stearate; the preparation method of the tablet core includes a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods.

[0007] According to the present invention, the core may be composed of the following components in parts by weight: 23 to 27 parts tegogasine, 35 to 41 parts microcrystalline cellulose, 23 to 27 parts mannitol, 6 to 8 parts croscarmellose sodium, 2.5 to 3.5 parts hydroxypropyl cellulose, 0.8 to 1.2 parts silica and 0.8 to 1.2 parts magnesium stearate.

[0008] In some preferred embodiments, the core is composed of the following components by weight: 24-26 parts tegogastric acid, 36-40 parts microcrystalline cellulose, 24-26 parts mannitol, 6-8 parts croscarmellose sodium, 2.7-3.3 parts hydroxypropyl cellulose, 0.9-1.1 parts silica, and 0.9-1.1 parts magnesium stearate.

[0009] In some preferred embodiments, the core is composed of the following components by weight: 25 parts tegogastric acid, 36 to 39 parts microcrystalline cellulose, 24 to 26 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica and 1 part magnesium stearate.

[0010] In some preferred embodiments, the core, by weight, comprises the following components: 25 parts ticoraxan, 38 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica, and 1 part magnesium stearate. In some preferred embodiments, the core, by weight, comprises the following components: 25 parts ticoraxan, 39 parts microcrystalline cellulose, 24 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica, and 1 part magnesium stearate. In some preferred embodiments, the core, by weight, comprises the following components: 25 parts ticoraxan, 39 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica, and 1 part magnesium stearate.

[0011] According to the present invention, the preparation method of the tablet core includes a dry granulation process, combined with the addition of some components by internal and external methods, and the internal and external components are controlled within a certain proportion range, which is more conducive to the preparation, stability and dissolution of the oral tablets to meet the quality requirements.

[0012] According to the present invention, the mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose can be 1:0.8 to 1:1. In some embodiments, the mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9. In some preferred embodiments, the mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.9.

[0013] According to the present invention, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium can be 1:0.6 to 1:1. In some preferred embodiments, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:1. In some preferred embodiments, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, or 1:1.

[0014] According to the present invention, the mass ratio of internally added silicon dioxide to externally added silicon dioxide can be 1:0.8 to 1:1.2. In some preferred embodiments, the mass ratio of internally added silicon dioxide to externally added silicon dioxide is 1:0.9 to 1:1.1. In some preferred embodiments, the mass ratio of internally added silicon dioxide to externally added silicon dioxide is 1:1.

[0015] In some embodiments, the silica is preferably colloidal silica.

[0016] According to the present invention, the mass ratio of internally added magnesium stearate to externally added magnesium stearate can be 1:0.8 to 1:1.2. In some preferred embodiments, the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:0.9 to 1:1.1. In some preferred embodiments, the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0017] The above-mentioned proportions of internal and external additives enable the resulting granules to be easily compressed during the tableting process, without problems such as sticking, roughness, or brittleness that do not meet quality requirements. The final tablets have good dissolution and stability and an attractive appearance.

[0018] According to the present invention, the ticoraxen may be any suitable crystal form, such as crystal form A disclosed in patent CN107207478B, or crystal form B disclosed in patent application CN117222643A, or other forms, such as amorphous or solid dispersions.

[0019] In some preferred embodiments, the core, by weight, comprises the following components: 23-27 parts tegogasens, 35-41 parts microcrystalline cellulose, 23-27 parts mannitol, 6-8 parts croscarmellose sodium, 2.5-3.5 parts hydroxypropyl cellulose, 0.8-1.2 parts colloidal silica, and 0.8-1.2 parts magnesium stearate. The core is prepared using a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, colloidal silica, and magnesium stearate are added both internally and externally. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:1, and the mass ratio of internally added colloidal silica to externally added colloidal silica is 1:0.9 to 1:0.9. The mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:0.9 to 1:1.1.

[0020] In some preferred embodiments, the core, by weight, comprises the following components: 24-26 parts ticoraxan, 36-40 parts microcrystalline cellulose, 24-26 parts mannitol, 6-8 parts croscarmellose sodium, 2.7-3.3 parts hydroxypropyl cellulose, 0.9-1.1 parts colloidal silica, and 0.9-1.1 parts magnesium stearate. The core is prepared using a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added both internally and externally. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:1, and the mass ratio of internally added colloidal silica to externally added colloidal silica is 1:0.9 to 1:0.9. The mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:0.9 to 1:1.1.

[0021] In some preferred embodiments, the core, by weight, comprises the following components: 24-26 parts ticoraxan, 36-40 parts microcrystalline cellulose, 24-26 parts mannitol, 6-8 parts croscarmellose sodium, 2.7-3.3 parts hydroxypropyl cellulose, 0.9-1.1 parts colloidal silica, and 0.9-1.1 parts magnesium stearate. The core is prepared using a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added both internally and externally. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, and the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:0.9. The mass ratio of internally added colloidal silica to externally added colloidal silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0022] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 36-39 parts microcrystalline cellulose, 24-26 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:1, the mass ratio of internally added colloidal silica to externally added colloidal silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0023] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 36-39 parts microcrystalline cellulose, 24-26 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75 to 1:1, the mass ratio of internally added colloidal silica to externally added colloidal silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0024] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 38 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7 to 1:1, the mass ratio of internally added silica to externally added silica is 1:0.9 to 1:1.1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:0.9 to 1:1.1.

[0025] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 38 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75 to 1:1, the mass ratio of internally added silica to externally added silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0026] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 38 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75 to 1:1, the mass ratio of internally added silica to externally added silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0027] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 39 parts microcrystalline cellulose, 24 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75 to 1:1, the mass ratio of internally added silica to externally added silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0028] In some preferred embodiments, the core is composed of the following components by weight: 25 parts ticoraxan, 39 parts microcrystalline cellulose, 25 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part silica, and 1 part magnesium stearate. The core is prepared by a dry granulation process, wherein the microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:0.9, the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.75 to 1:1, the mass ratio of internally added silica to externally added silica is 1:1, and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:1.

[0029] According to some embodiments of the present invention, the preparation method of the tablet core includes: mixing internally added microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate with hydroxypropyl cellulose, mannitol and ticorazine, then performing dry granulation, granulation, adding externally added microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate, mixing, and compressing to obtain the tablet core.

[0030] According to the present invention, the coating material can be a gastrointestinal soluble film-coating premix. In some embodiments, the coating material is a gastrointestinal soluble film-coating premix.

[0031] The tablet core is coated and dried to obtain the oral tablet.

[0032] According to the present invention, the mass of the coating layer can be 2% to 8% of the mass of the core. In some embodiments, the mass of the coating layer is 2% to 5% or 2.5% to 4% of the core mass. In some preferred embodiments, the mass of the coating layer is 3% to 3.5% of the core mass.

[0033] In some implementations, a coating solution with a solid content of 10% to 15% is used to coat the tablet core until its weight gain is 2% to 8%, and then it is dried to obtain the oral tablet.

[0034] In some embodiments, water is mixed with a gastrointestinal film-coating premix, filtered through an 80-mesh sieve to obtain a coating solution with a solid content of 10% to 15%. The tablet core is then coated with the coating solution at a temperature of 35°C to 50°C until the weight gain is 2% to 5%. The tablet is then dried at 38°C to 45°C until the weight loss on drying does not exceed 3%, thus obtaining the oral tablet.

[0035] According to the present invention, a dry granulation process is adopted, and some components are added internally and externally, and the internal and external components are controlled within a certain proportion range, which is beneficial to the preparation of the tablet core and to obtaining stable oral tablets with dissolution meeting quality requirements.

[0036] On the other hand, the present invention provides a method for preparing an oral tablet, wherein the method can obtain the aforementioned oral tablet.

[0037] According to the present invention, a method for preparing an oral tablet includes: 1) Sieve the silica and set aside; 2) Hydroxypropyl cellulose, added microcrystalline cellulose, added croscarmellose sodium, added silica, mannitol and ticorazine are mixed to obtain premix 1 material; 3) Disperse and sieve the premix 1 material, mix it evenly, and obtain the premix 2 material; 4) Add magnesium stearate and mix well to obtain premixed material 3; 5) Dry granulate the premixed material 3, then granulate and mix it to obtain the granulated material; 6) Add the added microcrystalline cellulose, added croscarmellose sodium and added silica to the granulated material and mix well; then add the added magnesium stearate and mix well to obtain the total mixture. 7) Compress the total mixture into tablets to obtain tablet cores; 8) Coat the tablet core and dry it to obtain the tablet.

[0038] According to the present invention, the silicon dioxide is preferably colloidal silicon dioxide.

[0039] According to the present invention, silicon dioxide can be passed through a 25-50 mesh sieve, preferably through a 28-40 mesh sieve, more preferably through a 28-35 mesh sieve, and even more preferably through a 30 mesh sieve.

[0040] According to the present invention, the premix 1 material can be dispersed and sieved using a sieve with an aperture of 0.5 mm to 1.5 mm. In some embodiments, a sieve with an aperture of 0.8 mm to 1.2 mm can be used to disperse and sieve the premix 1 material. In some preferred embodiments, a sieve with an aperture of 1.0 mm is used to disperse and sieve the premix 1 material.

[0041] According to the present invention, the dry granulation process can be carried out using any suitable instrument under suitable conditions.

[0042] According to the present invention, in some embodiments, the feeding speed during dry granulation can be 20 rpm to 100 rpm. According to the present invention, in some embodiments, the feeding speed during dry granulation can be 20 rpm to 80 rpm. In some embodiments, the feeding speed during dry granulation can be 20 rpm to 60 rpm.

[0043] In some implementations, the roller speed during dry granulation can be 5 rpm to 20 rpm. In other implementations, the roller speed during dry granulation can be 8 rpm to 15 rpm.

[0044] In some embodiments, the pressure of the pressure rollers during dry granulation can be 20 bar to 120 bar. In some embodiments, the pressure of the pressure rollers during dry granulation can be 20 bar to 100 bar. In some embodiments, the pressure of the pressure rollers during dry granulation can be 20 bar to 80 bar. In some embodiments, the pressure of the pressure rollers during dry granulation is 25 bar to 50 bar. In some embodiments, the pressure of the pressure rollers is 50 bar to 80 bar.

[0045] In some specific implementations, during the dry pelleting process, the feeding speed is 20 rpm to 60 rpm, the pressure roller speed is 8 rpm to 15 rpm, and the pressure roller pressure is 30 bar to 80 bar.

[0046] According to the present invention, the cooling temperature during the granulation process can be 15°C to 30°C or other suitable temperatures.

[0047] According to the present invention, granulation can be performed once or more as needed.

[0048] According to the present invention, granulation and sizing can be performed using a granulator, or granulation can be performed using a granulator followed by one or more sizing processes using a granulator.

[0049] According to the present invention, in some embodiments, the screen aperture does not exceed 2.0 mm during the granulation process. In some embodiments, the screen aperture can be 0.3 mm to 1.5 mm during the granulation process. In some embodiments, the screen aperture is 0.5 mm to 1.2 mm during the granulation process. In some embodiments, the screen aperture is 0.5 mm to 1.0 mm during the granulation process. In some embodiments, the screen aperture is 0.5 mm to 0.8 mm during the granulation process.

[0050] In some embodiments, the screen aperture is 1.0 mm during the pelleting process. In some embodiments, the screen aperture is 0.8 mm during the pelleting process. In some embodiments, the screen aperture is 0.5 mm during the pelleting process.

[0051] According to some embodiments of the present invention, the granulation speed can be 100 rpm to 900 rpm during the granulation process.

[0052] In some specific implementations, the granulation speed is 100 rpm to 150 rpm during the granulation process. In some specific implementations, the granulation speed is 100 rpm to 120 rpm during the granulation process.

[0053] In some specific implementations, the granulation speed is 100 rpm to 600 rpm during the granulation process. In other specific implementations, the granulation speed is 300 rpm to 600 rpm during the granulation process.

[0054] In some embodiments, granulation is performed using a sieve with an aperture not exceeding 2.0 mm and a granulation speed of 100 rpm to 900 rpm. In some embodiments, granulation is performed using a sieve with an aperture of 0.5 mm to 1.0 mm and a granulation speed of 100 rpm to 900 rpm. In some embodiments, granulation is performed using a sieve with an aperture of 0.5 mm to 0.8 mm and a granulation speed of 100 rpm to 900 rpm. In some embodiments, granulation is performed using a sieve with an aperture of 0.5 mm to 0.8 mm and a granulation speed of 100 rpm to 600 rpm.

[0055] In some embodiments, pelleting is performed once using a sieve with an aperture of no more than 1.0 mm and a pelleting speed of 100 rpm to 150 rpm, followed by a second pelleting using a sieve with an aperture of no more than 0.8 mm and a pelleting speed of 100 rpm to 900 rpm. In some embodiments, pelleting is performed once using a sieve with an aperture of 0.8 mm to 1.0 mm and a pelleting speed of 100 rpm to 150 rpm, followed by a second pelleting using a sieve with an aperture of 0.5 mm to 0.8 mm and a pelleting speed of 100 rpm to 900 rpm. In some embodiments, pelleting is performed once using a sieve with an aperture of 0.8 mm and a pelleting speed of 100 rpm to 150 rpm, followed by a second pelleting using a sieve with an aperture of 0.5 mm and a pelleting speed of 100 rpm to 900 rpm. In some embodiments, pelleting is performed once using a 0.8 mm aperture sieve and a pelleting speed of 100 rpm to 120 rpm, followed by a second pelleting using a 0.5 mm aperture sieve and a pelleting speed of 100 rpm to 600 rpm. In other embodiments, pelleting is performed once using a 0.8 mm aperture sieve and a pelleting speed of 100 rpm to 120 rpm, followed by a second pelleting using a 0.5 mm aperture sieve and a pelleting speed of 300 rpm to 600 rpm.

[0056] In some preferred embodiments, the second granulation is performed using a granulator.

[0057] According to the present invention, the amount of material not passing through a 50-mesh sieve in the resulting aggregate does not exceed 25 wt%, which is beneficial for obtaining qualified wafer cores. In some preferred embodiments, the amount of material not passing through a 50-mesh sieve in the resulting aggregate does not exceed 20 wt%. In some preferred embodiments, the amount of material not passing through a 50-mesh sieve in the resulting aggregate does not exceed 15 wt%. In some preferred embodiments, the amount of material not passing through a 50-mesh sieve in the resulting aggregate does not exceed 10 wt%. In some preferred embodiments, the amount of material not passing through a 50-mesh sieve in the resulting aggregate does not exceed 5 wt%.

[0058] According to the present invention, during the tableting process, the core hardness can be controlled to be 60N~120N, preferably 70N~115N, and more preferably 80N~110N.

[0059] According to the present invention, the speed of the tablet press can be controlled to be 19 rpm to 50 rpm during the tableting process.

[0060] According to the present invention, a coating solution with a solid content of 10% to 15% can be prepared by mixing water or a mixture of water and ethanol as a solvent with a gastric-soluble film-coating premix. In some preferred embodiments, water is used as a solvent, and the mixture is mixed with a gastric-soluble film-coating premix and filtered through a sieve of not less than 80 mesh to prepare a coating solution with a solid content of 10% to 15%. In some preferred embodiments, water is used as a solvent, and the mixture is mixed with a gastric-soluble film-coating premix and filtered through an 80-mesh sieve to prepare a coating solution with a solid content of 10% to 15%.

[0061] According to the present invention, the temperature of the wafer core can be controlled at 35°C to 50°C before coating. In some specific embodiments, the temperature of the wafer core is controlled at 38°C to 45°C before coating.

[0062] In some specific embodiments, the tablet core is coated with a coating solution to achieve a weight gain of 2% to 5%. In some specific embodiments, the tablet core is coated with a coating solution to achieve a weight gain of 2% to 4%. In some preferred embodiments, the tablet core is coated with a coating solution to achieve a weight gain of 2.5% to 3.5%.

[0063] According to the present invention, tablets can be obtained by drying at 35°C to 50°C. In some specific embodiments, tablets are obtained by drying at 38°C to 45°C.

[0064] According to the present invention, tablets can be obtained by drying until the loss on drying is no more than 3.5%. In some embodiments, tablets are obtained by drying until the loss on drying is no more than 3%.

[0065] In some embodiments, the tablets are obtained by drying at 35°C to 50°C until the loss on drying is no more than 3%. In some preferred embodiments, the tablets are obtained by drying at 38°C to 45°C until the loss on drying is no more than 3%.

[0066] In some preferred embodiments, a method for preparing an oral tablet includes: 1) Pass the silica through a 28-35 mesh sieve and set aside; 2) Mix hydroxypropyl cellulose, added microcrystalline cellulose, added croscarmellose sodium, added silica, mannitol and ticorazine to obtain premix 1 material. 3) Disperse and sieve the premix 1 material through a 0.8mm~1.2mm sieve, mix well, and obtain the premix 2 material; 4) Add magnesium stearate and mix well to obtain premixed material 3; 5) Dry granulation of premixed material 3, followed by granulation and mixing to obtain granulated material; wherein the sieve aperture is 0.3mm~2.0mm, and the granulation speed is 100rpm~900rpm; the granulation process may optionally include a second granulation under the conditions of a sieve aperture of 0.5mm~0.8mm and a granulation speed of 100rpm~900rpm; 6) Add the added microcrystalline cellulose, added croscarmellose sodium and added silica to the granulated material and mix well; then add the added magnesium stearate and mix well to obtain the total mixture. 7) Add the total mixture to the tablet press, compress the tablets, and control the hardness to 60N~120N to obtain tablet cores; 8) Mix water with a gastrointestinal film coating premix, filter through an 80-mesh sieve to obtain a coating solution with a solid content of 10% to 15%, use the coating solution to coat tablet cores at a temperature of 35°C to 50°C until the weight gain is 2% to 5%, and then dry at 38°C to 45°C until the weight loss of the tablets does not exceed 3% to obtain oral tablets.

[0067] In some preferred embodiments, a method for preparing an oral tablet includes: 1) Pass the silica through a 30-mesh sieve and set aside; 2) Mix hydroxypropyl cellulose, added microcrystalline cellulose, added croscarmellose sodium, added silica, mannitol and ticorazine to obtain premix 1 material. 3) Disperse and sieve the premix 1 material through a 1.0mm sieve, mix well, and obtain the premix 2 material; 4) Add the added magnesium stearate, mix well, and obtain premixed material 3; 5) Dry granulation of premixed material 3, followed by granulation and mixing to obtain granulated material; wherein, the sieve aperture of the first granulation is 0.8mm and the granulation speed is 100rpm~150rpm, and the sieve aperture of the second granulation is 0.5mm and the granulation speed is 100rpm~600rpm. 6) Add the added microcrystalline cellulose, added croscarmellose sodium, and added silica to the granulated material and mix well; then add the added magnesium stearate and mix well to obtain the total mixture; in the total mixture, the material that does not pass through a 50-mesh sieve does not exceed 25 wt%; 7) Add the total mixture to the tablet press and press it into tablets. The hardness is controlled at 60N~120N or 70N~115N to obtain tablet cores. 8) Mix water with a gastrointestinal film coating premix, filter through an 80-mesh sieve to obtain a coating solution with a solid content of 10% to 15%; use the coating solution to coat tablet cores at a temperature of 38°C to 45°C until the weight gain is 2% to 4%, and then dry at 38°C to 45°C until the weight loss of the tablets does not exceed 3% to obtain oral tablets.

[0068] According to the aforementioned method and the range of control conditions, the oral tablets of the present invention can be prepared, and the obtained tablets meet the quality requirements.

[0069] The oral tablets provided by this invention have stable quality, uniform content of active ingredients, good disintegration and dissolution uniformity among different batches, and dissolution in the dissolution medium meets quality requirements.

[0070] The tablet preparation method provided by this invention uses a combination of internal and external addition of multiple components and a dry granulation process. This ensures the uniformity of the raw materials and excipients, avoids uneven tablet content caused by poor flowability and compressibility, and prevents defects such as hardness, brittleness, disintegration time, weight differences, and appearance during the tableting process. It also avoids the instability caused by water affecting the components during the preparation process. The resulting tablets are stable and meet quality requirements. Attached Figure Description

[0071] Figure 1 Dissolution curves of the products obtained from each formulation in Example 2 and the reference formulation in acetic acid solution at pH 4.5 (paddle method, 50 rpm, 900 mL); Figure 2 Dissolution profiles of the products obtained from each formulation in Example 2 and the reference formulation in a phosphate solution (containing 0.1% SDS, w / v) at pH 6.8 (paddle method, 50 rpm, 900 mL). Detailed Implementation

[0072] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0073] In this invention, the phrase "composed of..." may include unavoidable impurities and / or water.

[0074] Unless otherwise specified, the raw materials, reagents or devices used in this invention can be obtained from conventional commercial sources or by existing known methods. For example, ticoraxan can be prepared using the methods disclosed in patent applications CN107207478A or CN117222643A.

[0075] SDS refers to sodium dodecyl sulfate.

[0076] In this invention, the reference preparation (hereinafter referred to as the reference) is produced by Shandong Luoxin Pharmaceutical Group Co., Ltd., with batch number 625041030.

[0077] In this invention, relevant testing items such as particle size distribution, mixing uniformity, tablet weight, hardness, content uniformity and dissolution are conducted in accordance with the relevant methods / regulations of the Chinese Pharmacopoeia (2020 edition). The dissolution curve is determined by the paddle method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, Method II).

[0078] In the following preliminary experimental examples and embodiments: ticoraxan uses crystal form A as described in CN107207478A (or can be directly replaced by crystal form B as described in CN117222643A).

[0079] Preliminary Experiment Example 1 Prescription form:

[0080] Preparation method: Prepare all raw materials and excipients according to the prescription, at a rate of 1000 tablets per batch. Add one-third of the total amount of mannitol, microcrystalline cellulose and ticorazine to the hopper of a square cone mixer and mix well to obtain premix 1 material; The premix 1 material, the remaining mannitol, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose and colloidal silica are dispersed and sieved through a granulator using a 1.0 mm sieve; the dispersed and sieved material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain premix 2 material; Magnesium stearate was added to the hopper of a square cone mixer and mixed thoroughly to obtain a total mixture (white powder). The total mixture was transferred to a tablet press and tableted. The tablet press speed was set to 17-18 rpm, and the tablet hardness was controlled at 90N±30N to obtain tablet cores. (During the tableting process, it was found that cracked tablets appeared in all formulations, with more cracked tablets appearing in formulations 1-D). Mix water with a film coating premix (gastric-soluble type), pass through an 80-mesh sieve, and prepare a coating solution with a solid content of 12% (mass fraction) for later use; control the temperature of the obtained tablet core at 38℃~48℃, coat the tablet core with the coating solution until the tablet core gains 3% in weight, and stop spraying; dry the coated tablets at 40℃~45℃ until the weight loss during drying does not exceed 3%, and cool to room temperature to obtain the coated tablets.

[0081] The intermediates obtained from the above prescriptions were subjected to relevant tests, and the test results are shown in the table below.

[0082]

[0083] The results show that the tablet cores obtained from different formulations have certain differences in terms of content uniformity, hardness and / or tablet weight. Among them, the hardness and tablet weight deviations of formulation 1-D are relatively excessive.

[0084] Dissolution profiles of the tablets obtained from formulations 1-A, 1-B, and 1-C were analyzed. It was found that the dissolution profiles of the tablets obtained from the three formulations at pH 4.5 (50 rpm, 900 mL) were not similar to those of the reference formulation.

[0085] Preliminary Experiment Example 2 Prescription form:

[0086] Preparation method: According to the prescription, prepare all raw and excipient materials in batches of 1000 tablets. Pass the colloidal silica through a 24-mesh sieve and set aside. Weigh out hydroxypropyl cellulose, microcrystalline cellulose (added internally), croscarmellose sodium (added internally), colloidal silica (added internally), mannitol and ticorazine, add them to the hopper of a square cone mixer, mix well, and obtain premix 1 material; The premix 1 material is passed through a granulator and dispersed through a 1.0mm sieve; the dispersed and sieved material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain premix 2 material; Add magnesium stearate (added internally), mix well, and obtain premixed material 3; Add the premixed material 3 to the dry granulator and perform dry granulation according to the parameters in the table below;

[0087] After granulation, the granulated material is transferred to the hopper of a square cone mixer and mixed evenly to obtain dry granulated material. Add microcrystalline cellulose (additive, if present), croscarmellose sodium (additive), and colloidal silica (additive) to the dry granulation material and mix well; then add magnesium stearate (additive) and mix well to obtain the total mixture (white powder). The total mixture was transferred to a tablet press and tableted. The tablet hardness was controlled at 90N±30N to obtain tablet cores. (During the tableting process, it was found that formulation 2-D had sticking and punching issues, while no sticking and punching issues were observed in other formulations.) Mix water with a film coating premix (gastric-soluble type), pass through an 80-mesh sieve, and prepare a coating solution with a solid content of 12% (mass fraction) for later use; control the temperature of the obtained tablet core at 38℃~48℃, coat the tablet core with the coating solution until the tablet core gains 3% in weight, and stop spraying; dry the coated tablets at 40℃~45℃ until the weight loss during drying does not exceed 3%, and cool to room temperature to obtain the coated tablets.

[0088] The intermediates obtained from the above prescriptions were subjected to relevant tests, and the test results are shown in the table below.

[0089]

[0090] The results show that prescription 2-A produced too many coarse particles, prescription 2-D resulted in sticking during tablet compression, and the tablet weights of the resulting tablet cores differed relatively greatly.

[0091] Dissolution profiles of tablets derived from formulations 2-A, 2-B, and 2-C were analyzed. The results showed that the dissolution profiles of the three formulations at pH 4.5 (50 rpm, 500 mL) were similar to the reference formulation. The dissolution profiles of tablets derived from formulation 2-A at pH 4.5 (50 rpm, 900 mL) were not similar to the reference formulation. The dissolution profiles of tablets derived from formulations 2-B and 2-C at pH 4.5 (50 rpm, 900 mL) were similar to the reference formulation, but the dissolution profiles at pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were not similar to the reference formulation.

[0092] Preliminary Experiment Example 3: Prescription form:

[0093] Preparation method: According to the prescription, prepare each raw and auxiliary material in batches, and pass the colloidal silica through a 30-mesh sieve for later use; Weigh out hydroxypropyl cellulose, microcrystalline cellulose (added internally), croscarmellose sodium (added internally), colloidal silica (added internally), mannitol and ticorazine, add them to the hopper of a square cone mixer, mix well, and obtain premix 1 material; The premix 1 material is passed through a granulator and dispersed through a 1.0mm sieve; the dispersed and sieved material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain premix 2 material; Add magnesium stearate (added internally), mix well, and obtain premixed material 3; Add the premixed material 3 to a dry granulator, set the feeding motor to 10rpm~30rpm, the tableting motor to 3rpm, and the pressure to 60bar~110bar for dry granulation to obtain flake material; pass the obtained flake material through a pulverizer and granulator, first using a 0.8mm round hole screen, setting the speed to 500rpm to obtain material I; pass the obtained material I through the pulverizer and granulator again, using a 0.5mm round hole screen, setting the speed to 500rpm, and transfer the obtained material to the hopper of a square cone mixer for mixing to obtain dry granulated material; Microcrystalline cellulose (added), croscarmellose sodium (added), and colloidal silica (added) are added to the dry granulation material and mixed well; then magnesium stearate (added) is added and mixed well to obtain the total mixture (white powder); The total mixture was transferred to a tablet press and tableted. The tablet press speed was set to 17-18 rpm, and the tablet hardness was controlled at 90N±30N to obtain tablet cores (no broken / fractured tablets were observed). Mix water with a film coating premix (gastric-soluble type), pass through an 80-mesh sieve, and prepare a coating solution with a solid content of 12% (mass fraction) for later use; control the temperature of the obtained tablet core at 40℃~45℃, coat the tablet core with the coating solution until the tablet core gains 3% in weight, and stop spraying; dry the coated tablets at 40℃~45℃ until the weight loss during drying does not exceed 3%, and cool to room temperature to obtain the coated tablets.

[0094] The intermediates obtained from the above prescriptions were subjected to relevant tests, and the test results are shown in the table below.

[0095]

[0096] Dissolution profiles were analyzed for tablet cores or coated tablets obtained from each formulation. The results showed that the uncoated tablets (tablet cores) from formulations 3-A and 3-B, and the coated tablets from formulation 3-C, exhibited dissolution profiles similar to the reference formulation at pH 4.5 (50 rpm, 500 mL) and pH 4.5 (50 rpm, 900 mL). Their dissolution profiles at pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were also largely similar to the reference formulation. However, the coated tablets from formulation 3-D showed a dissolution profile dissimilar to the reference formulation at pH 4.5 (50 rpm, 900 mL). Based on these dissolution profile results, it is concluded that the formulation and / or preparation process of formulation 3-D deviated significantly from expectations. Formulations 3-A, 3-B, or 3-C are expected to meet expectations, but further adjustments and / or confirmation of the formulation and preparation process are necessary.

[0097] Example 1 Prescription form:

[0098] Preparation method: According to the prescription, prepare all raw and excipient materials in batches of 2000 tablets. Pass the colloidal silica through a 30-mesh sieve and set aside. Weigh out hydroxypropyl cellulose, microcrystalline cellulose (added internally), croscarmellose sodium (added internally), colloidal silica (added internally), mannitol and ticorazine, add them to the hopper of a square cone mixer, mix well, and obtain premix 1 material; The premix 1 material is passed through a granulator and dispersed through a 1.0mm sieve; the dispersed and sieved material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain premix 2 material; Add magnesium stearate (added internally), mix well, and obtain premixed material 3; Add the premixed material 3 to the dry granulator, set the feeding motor to 10rpm~30rpm, the tableting motor to 3rpm, and the pressure to 60bar~110bar for dry granulation; after granulation, transfer the material to the granulator, use a 0.8mm screen and 500rpm for the first granulation, and then use a 0.5mm screen and 500rpm for the second granulation; transfer the granulated material to the hopper of the square cone mixer, mix evenly, and obtain the granulated material; Microcrystalline cellulose (added), croscarmellose sodium (added), and colloidal silica (added) are added to the granulated material and mixed well; then magnesium stearate (added) is added and mixed well to obtain the total mixture. The total mixture was transferred to a tablet press and tableted. The tablet press speed was set to 17 rpm to 18 rpm, and the tablet core hardness was controlled at 90 N ± 30 N to obtain tablet cores (no broken / fractured tablets were observed). Mix water with a film coating premix (gastric-soluble type), pass through an 80-mesh sieve, and prepare a coating solution with a solid content of 12% (mass fraction) for later use; control the temperature of the obtained tablet core at 40℃~45℃, coat the tablet core with the coating solution until the tablet core gains 3% in weight, and stop spraying; dry the coated tablets at 40℃~45℃ until the weight loss during drying does not exceed 3%, and cool to room temperature to obtain the coated tablets.

[0099] The intermediates obtained from each prescription were subjected to relevant tests, and the results are shown in the table below.

[0100]

[0101] According to the test results, the particle size distribution, mixing uniformity, content uniformity, hardness and tablet weight of the intermediates obtained from prescriptions 5 to 7 meet the requirements.

[0102] The dissolution curve test results are as follows: (1) The dissolution profiles of the coated tablets obtained from Formula 5 were similar to those of the reference formulation under pH 4.5 (50 rpm, 500 mL) and pH 4.5 (50 rpm, 900 mL) conditions, but not similar to those of the reference formulation under pH 6.8 + 0.1% SDS (50 rpm, 900 mL) conditions. (2) The dissolution curves of the coated tablets obtained from Formulation 6 under the conditions of pH 4.5 (50 rpm, 500 mL), pH 4.5 (50 rpm, 900 mL) and pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were similar to those of the reference formulation. (3) The dissolution curves of the coated tablets obtained from Formulation 7 under the conditions of pH 4.5 (50 rpm, 500 mL), pH 4.5 (50 rpm, 900 mL) and pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were similar to those of the reference formulation.

[0103] The dissolution curve results show that the dissolution curve of the coated tablets obtained from Formula 5 still deviates from the expectation, while the test results of the coated tablets obtained from Formulas 6 and 7 meet the expectations.

[0104] Example 2 Prescription form:

[0105] Preparation method: According to the prescription, prepare all raw and excipient materials in batches of 10,000 tablets. Pass the colloidal silica through a 30-mesh sieve and set aside. Weigh out hydroxypropyl cellulose, microcrystalline cellulose (added internally), croscarmellose sodium (added internally), colloidal silica (added internally), mannitol and ticorazine, add them to the hopper of a square cone mixer, mix well, and obtain premix 1 material; The premix 1 material is passed through a granulator and dispersed through a 1.0mm sieve; the dispersed and sieved material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain premix 2 material; Add magnesium stearate (added internally), mix well, and obtain premixed material 3; Add the premixed material 3 into the dry granulator and perform dry granulation according to the parameters in the table below, and collect the dry granulated material.

[0106] The obtained dry granulated material is then subjected to a second granulation under a 0.5mm sieve and a granulation speed of 300rpm~600rpm; the granulated material is then transferred to the hopper of a square cone mixer and mixed evenly to obtain the granulated material. Microcrystalline cellulose (added), croscarmellose sodium (added), and colloidal silica (added) are added to the granulated material and mixed well; then magnesium stearate (added) is added and mixed well to obtain the total mixture (white powder); The total mixture was transferred to a tablet press and tableted. The hardness was controlled at 90N±30N. The tablet press speed was set to 30rpm to obtain tablet cores (no broken / fractured tablets were observed). Mix water with a film coating premix (gastric-soluble type), pass through an 80-mesh sieve, and prepare a coating solution with a solid content of 12% (mass fraction) for later use; control the temperature of the obtained tablet core at 38℃~45℃, coat the tablet core with the coating solution until the tablet core gains 3% in weight, and stop spraying; dry the coated tablets at 40℃~45℃ until the weight loss during drying does not exceed 3%, and cool to room temperature to obtain the coated tablets.

[0107] The intermediates obtained from each prescription were subjected to relevant tests, and the results are shown in the table below.

[0108]

[0109] Dissolution profiles of the coated tablets obtained from formulations 7-9 were analyzed. The dissolution profiles at pH 4.5 (50 rpm, 500 mL), pH 4.5 (50 rpm, 900 mL), and pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were similar to those of the reference formulation (hereinafter referred to as the reference). See Appendix. Figure 1 and attached Figure 2 Based on the results, the coated tablets obtained from prescriptions 7 to 9 are considered to meet the expected requirements.

[0110] Example 3 According to the prescription of prescription 7 in Example 2, but with a batch size of 100,000 tablets / batch, coated tablets were prepared using the preparation method of Example 2.

[0111] The intermediates were subjected to relevant tests, and the results are shown in the table below.

[0112]

[0113] Dissolution curves of the obtained coated tablets were analyzed, and the dissolution curves under the conditions of pH 4.5 (50 rpm, 500 mL), pH 4.5 (50 rpm, 900 mL) and pH 6.8 + 0.1% SDS (50 rpm, 900 mL) were similar to those of the reference formulation.

[0114] Stability study: The obtained coated tablets were tested according to the methods specified in the 2020 edition of the Chinese Pharmacopoeia. The stability of the obtained coated tablets (naked samples, without packaging) was investigated under high temperature (60℃), high humidity (25℃, 75%±5% RH) and light exposure (25℃±2℃, 4500±500 Lx, near-UV 0.9w / m 2 The stability under the specified conditions was assessed by sampling on day 5 and day 10, and relevant items were tested; the results are shown in the table below.

[0115]

[0116]

[0117]

[0118] The results show that the obtained coated tablets meet the requirements of the Chinese Pharmacopoeia in terms of shape, related substances, dissolution, content, and whether the crystal form (form) has changed.

[0119] The solutions of this invention have been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the solutions or applications described herein within the scope and content of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein and appropriately improve the conditions / parameters to implement and / or apply the technology of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within this invention.

Claims

1. An oral tablet comprising: Core and coating layer; The core is composed of the following components: ticoraxan, microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropyl cellulose, silica, and magnesium stearate; the preparation method of the core includes a dry granulation process, wherein microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added by both internal and external methods.

2. The oral tablet according to claim 1, wherein the tablet core comprises, by weight, the following components: Tigorafenib 23-27 parts, microcrystalline cellulose 35-41 parts, mannitol 23-27 parts, croscarmellose sodium 6-8 parts, hydroxypropyl cellulose 2.5-3.5 parts, colloidal silica 0.8-1.2 parts, and magnesium stearate 0.8-1.2 parts.

3. In the oral tablet according to claim 1 or 2, the mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8 to 1:

1.

4. In the oral tablet according to claim 1 or 2, the mass ratio of internally added sodium croscarmellose to externally added sodium croscarmellose is 1:0.6 to 1:

1.

5. The oral tablet according to claim 1 or 2, wherein the mass ratio of internally added silica to externally added silica is 1:0.8 to 1:1.2, and / or the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:0.8 to 1:1.

2.

6. The oral tablet according to claim 1 or 2, wherein the coating layer material is a gastrosoluble film coating premix, and the mass of the coating layer is 2% to 8% of the mass of the tablet core.

7. The oral tablet according to claim 1, wherein the tablet core comprises, by weight, the following components: The tablet contains 25 parts tegorasen, 36-39 parts microcrystalline cellulose, 24-26 parts mannitol, 7 parts croscarmellose sodium, 3 parts hydroxypropyl cellulose, 1 part colloidal silica, and 1 part magnesium stearate. The mass ratio of internally added microcrystalline cellulose to externally added microcrystalline cellulose is 1:0.8-1:0.9; the mass ratio of internally added croscarmellose sodium to externally added croscarmellose sodium is 1:0.7-1:1; the mass ratio of internally added colloidal silica to externally added colloidal silica is 1:1; and the mass ratio of internally added magnesium stearate to externally added magnesium stearate is 1:

1. The coating material is a gastrointestinal soluble film coating premix, and the mass of the coating layer is 2%-4% of the core mass.

8. The oral tablet according to any one of claims 1 to 7, wherein the method for preparing the tablet core comprises: The internally added microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are mixed with hydroxypropyl cellulose, mannitol, and ticoraxan, and then dry-granulated and sized. The externally added microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate are added, mixed, and compressed into tablets to obtain tablet cores.

9. A method for preparing an oral tablet according to any one of claims 1 to 7, comprising: 1) Sieve the silica and set aside; 2) Hydroxypropyl cellulose, added microcrystalline cellulose, added croscarmellose sodium, added silica, mannitol and ticorazine are mixed to obtain premix 1 material; 3) Disperse and sieve the premix 1 material, mix it evenly, and obtain the premix 2 material; 4) Add the added magnesium stearate, mix well, and obtain premixed material 3; 5) Dry granulate the premixed material 3, then granulate and mix it to obtain the granulated material; 6) Add the added microcrystalline cellulose, added croscarmellose sodium and added silica to the granulated material and mix well; then add the added magnesium stearate and mix well to obtain the total mixture. 7) Compress the total mixture into tablets to obtain tablet cores; 8) Using a coating solution with a solid content of 10%~15%, the tablet core is coated until its weight gain is 2%~8%, and then dried to obtain the tablet.

10. The preparation method according to claim 9, comprising at least one of the following conditions: In step 1), the silica is passed through a 25-50 mesh sieve; In step 3), disperse and sieve using a 0.5mm~1.5mm sieve; In step 5), during the granulation process, the mesh size of the sieve is 0.3mm~1.5mm; In step 6), the amount of material in the total mixture that does not pass through a 50-mesh sieve does not exceed 25 wt%; and In step 8), water and a gastrointestinal film coating premix are mixed and filtered through an 80-mesh sieve to obtain a coating solution with a solid content of 10% to 15%. The tablet cores are coated with the coating solution at a temperature of 35°C to 50°C until the weight gain is 2% to 5%, and then dried at 38°C to 45°C until the weight loss during drying does not exceed 3% to obtain the oral tablets.

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