Fumagilln composition and method of making same

Abstract

The application discloses a kind of fumarate vinorelbine tablet compositions and preparation method thereof, fumarate vinorelbine raw drug, excipient, first part low molecular weight low substitution hydroxypropyl cellulose and stabilizer are mixed into premix substrate;Granulation is sprayed in wet granulator second part low molecular weight low substitution hydroxypropyl cellulose aqueous solution;Pre-drying is passed through 20 mesh sieve, again drying is passed through 24 mesh sieve;Add disintegrating agent and lubricant mixture;Tabletting;Finally coating.The method is by internal and external addition method and three-step granulation process, ensure that in vitro dissolution property is equivalent to original research drug, use lipid plasticizer instead of polyethylene glycol, can reduce coating temperature, reduce drug thermal degradation.Fluidized bed one-step granulation is split into two independent steps of high-speed shearing granulation and fluidized bed drying, greatly simplify the production process process parameter control difficulty, more easily to scale-up production, make production process control more accurate, product quality is more stable, production cost is significantly reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmacy, in particular to a Vonoprazan fumarate tablet composition and a preparation method thereof. BACKGROUND

[0002] Vonoprazan fumarate (development code: TAK-438) is a new type of potassium-competitive acid blocker (P-CAB). Its chemical name is 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine fumarate. As an innovative drug, Vonoprazan fumarate is developed by Takeda Pharmaceutical Company Limited, Japan. Its clinical indications include: gastroesophageal reflux disease (GERD), erosive esophagitis, gastric ulcer, duodenal ulcer, and as a component of Helicobacter pylori eradication therapy. Its unique mechanism of action and excellent clinical efficacy provide a new choice for the treatment of acid-related diseases, especially in patients who do not respond well to traditional PPIs, showing important clinical application value.

[0003] Patent 201210251154.9 introduces a drug composition of Takeda Company, the main drug: Vonoprazan fumarate, the filler: mannitol, the disintegrant: cross-linked sodium carboxymethyl cellulose, the binder: hydroxypropyl cellulose, crystalline cellulose, the lubricant: magnesium stearate, the stabilizer: fumaric acid, the light shielding agent: titanium dioxide, the plasticizer: polyethylene glycol (PEG), which adopts the fluidized bed granulation process to prepare Vonoprazan fumarate tablets. The technical problem it solves is that although titanium dioxide has a light shielding effect, it can generate free radicals under UV light, which can cause the decomposition of coating reagents (such as PEG), and the decomposition products can further accelerate the decomposition of the drug. The patent adds a chain organic acid to the formulation containing titanium dioxide and plasticizer, without the need to add an intermediate layer or remove PEG, solving the problem of light stability caused by titanium dioxide. Therefore, changing the plasticizer to maintain the stability of Vonoprazan fumarate during light, high temperature and accelerated testing has become a research hotspot in the field. For example: patent 202211017190.9 Vonoprazan fumarate tablets, in which the stabilizing protective agent is an alkaline earth metal salt that provides an acidic environment for Vonoprazan fumarate.

[0004] However, the preparation process used in the preparation of fumaric acid vinorelbine reported in the current original research patent is fluidized bed technology. Fluidized bed granulation is a process of making granules from powder materials through a binder. The basic steps include: placing the mixed substrate in the cavity, spraying the binder solution, and drying, and finally sieving the particles. It is a process that integrates mixing, granulation and drying. In the granulation process, the height of the particle blown up is controlled by the air volume, the spray speed is controlled by the atomizing and flow pump speed, and the speed of water evaporation in the cavity is controlled by the inlet air temperature and humidity. Key process parameters and influencing factors:

[0005] Influencing factor 1: air volume

[0006] In the process of fluidized bed granulation, air volume is a key process parameter, which not only determines the fluidization state of the material, but also significantly affects the drying efficiency. During the operation, due to the continuous spraying of the binder solution, the particle quality changes dynamically, and the air volume needs to be adjusted in real time to maintain the best fluidization state. The control of air volume needs to be in a suitable range: too high air volume will cause the particles to be transported to the top of the equipment, causing the filter bag to be blocked, and then causing the airflow to be blocked, eventually leading to the collapse of the fluidization state (i.e. "bed collapse" phenomenon); while too low air volume cannot make the material reach the effective fluidization height, so that the particles cannot fully contact the atomized binder, affecting the granulation effect. Therefore, accurate control of the air volume parameter is crucial to ensure the stable operation of the fluidized bed granulation process.

[0007] Influencing factor 2: inlet air temperature and humidity

[0008] Inlet air temperature and humidity are important factors in the evaporation kinetics of water in the process of fluidized bed granulation. The control of these two parameters needs to be maintained within the best process window: if the water evaporation is too fast, the binder will solidify before it fully contacts the material, resulting in poor bonding effect; on the contrary, if the water evaporation is too slow, the material will agglomerate into blocks, destroying the fluidization state and causing the "bed collapse" phenomenon. In practical applications, since the inlet air comes from the environment, it needs to be adjusted by a rotary dehumidification and steam humidification system. However, due to the influence of equipment structure and environmental factors, especially the constraint of pipeline length, the control accuracy of temperature and humidity has obvious scale dependence: in the laboratory conditions with short pipeline, the temperature can be maintained within a fluctuation range of ±2℃; while in the industrial production environment, due to the significant extension of the pipeline distance, the temperature fluctuation range usually expands to ±10℃, which puts higher requirements on the stability of the process.

[0009] Influencing factor 3: spray rate

[0010] As one of the key process parameters of fluidized bed granulation, spray rate directly affects the distribution efficiency of the binder and the humidity balance in the cavity.

[0011] In summary, in the fluidized bed granulation process, there is a complex coupling relationship between various process parameters, forming a highly correlated dynamic system. Any adjustment of a single parameter will trigger a chain reaction, requiring corresponding adjustment of other parameters to maintain the steady-state operation of the process. However, due to the inherent characteristics of the equipment (such as air pipe transmission delay), there is a significant lag period from adjustment to reaching the set value. This tardiness of system response leads to large fluctuations in process parameters, increasing the difficulty of process control. In addition, environmental factors (especially seasonal changes in temperature and humidity) can significantly affect the initial conditions of the granulation process, resulting in the need for differentiated adjustment of process parameters between batches, which further exacerbates the variability between batches. Therefore, the precise control of the fluidized bed granulation process needs to consider the effects of multi-parameter coupling, system response characteristics, and environmental factors.

[0012] For laboratory scale-up to process production, due to the large difference in batch size (laboratory 500g or so, workshop several hundred kilograms) and equipment (scale, air pipe length, dehumidification and humidification efficiency, heating and cooling efficiency), and the fact that the parameter settings of the fluidized bed are closely related to the batch size and equipment, therefore, in process scale-up, the parameters of the laboratory usually do not have the meaning of scale-up. Process scale-up usually needs to be reevaluated.

[0013] In view of the above process, especially the coupling effect of various influencing factors of the fluidized bed in the production process, the parameters need to be adjusted in real time, and the operation is complex, with significant differences between batches, the stable operation of the fluidized bed granulation process is highly dependent on the experience and skill level of the operator. This excessive reliance on human experience not only increases the uncertainty of the production process, but also brings challenges to the standardization of process parameters and the consistent control of product quality. SUMMARY

[0014] To solve the above technical problems, the first aspect of the present application provides a preparation method of fumarate volorasen tablet, comprising the following steps:

[0015] Step 1: weigh fumarate volorasen raw material, excipient, first part of binder and stabilizer as premix substrate;

[0016] Step 2: put the premix substrate in a wet granulator, spray the second part of the binder aqueous solution in a state of stirring and chopping, to obtain wet material;

[0017] Step 3: pre-dry the wet material and pass through a 20-mesh screen to obtain coarse granules after screening;

[0018] Step 4: re-dry the coarse granules and pass them through a 24-mesh screen again to obtain dried intermediate granules;

[0019] Step 5: total mixing of intermediate granules, added disintegrant and lubricant to obtain tabletting granules;

[0020] Step 6: compression of tabletting granules to obtain tablets;

[0021] Step 7: coating of tablets with coating liquid prepared by mixing colorant, film- forming agent, plasticizer and opacifier with water to obtain fumaderm tablets;

[0022] The first part of the binder and the second part of the binder are both low molecular weight low-substituted hydroxypropyl cellulose, the hydroxypropyl cellulose has a hydroxypropoxy substitution degree of 7.0%-16.0% and a molecular weight of 80-120 thousand;

[0023] wherein, in terms of weight percentage,

[0024] The fumaderm raw material accounts for 11.68wt% of the total prescription amount,

[0025] The excipient accounts for 73-75wt% of the total prescription amount,

[0026] The first part of the binder accounts for 0.2-0.58wt% of the total prescription amount,

[0027] The second part of the binder accounts for 1.3-2.8wt% of the total prescription amount,

[0028] The stabilizer accounts for 2.4-3wt% of the total prescription amount,

[0029] The disintegrant accounts for 4.8-5.0wt% of the total prescription amount,

[0030] The lubricant accounts for 0.5-1.0wt% of the total prescription amount,

[0031] The opacifier accounts for 1.0-1.2wt% of the total prescription amount,

[0032] The film-forming agent accounts for 2.15-2.5wt% of the total prescription amount,

[0033] The colorant accounts for 0.04-0.24wt% of the total prescription amount,

[0034] The plasticizer accounts for 0.3-0.6wt% of the total prescription amount,

[0035] The water in the aqueous solution of the second part of the binder accounts for 11.9-23.6wt% of the premix substrate.

[0036] Further, the excipient is mannitol and / or microcrystalline cellulose, the stabilizer is fumaric acid, the disintegrant is croscarmellose sodium, the lubricant is magnesium stearate, the opacifier is titanium dioxide, the film-forming agent is hypromellose, and the colorant is iron oxide red or iron oxide yellow.

[0037] The excipient is mannitol and / or microcrystalline cellulose, preferably a mixture of mannitol and microcrystalline cellulose.

[0038] The stabilizer is one or more of fumaric acid, malonic acid, citric anhydride, maleic anhydride, succinic acid or tartaric acid. The highly nucleophilic primary or secondary amino group in the molecular structure of vorinostat fumarate makes it prone to chemical reactions under certain conditions. In particular, when the formulation contains basic excipients, these basic components can act as catalysts to promote the Michael addition reaction of vorinostat fumarate. In order to inhibit the above degradation pathway, the present application specifically adds a stabilizer system in the prescription. Thus effectively prevent it from Michael addition reaction with α, β-unsaturated carbonyl compounds. In this way, the chemical stability of the formulation is significantly improved, and the storage period of the drug is prolonged.

[0039] Further, the plasticizer is one or two or more combinations of glyceryl triacetate, triethyl citrate or dibutyl sebacate.

[0040] The present application belongs to the optimization of generic drugs. The original research company of vorinostat fumarate tablets is Takeda Pharmaceutical Company Limited, Hikari Plant, which uses high molecular weight low-substituted hydroxypropyl cellulose, fluidized bed process, and polyethylene glycol as a plasticizer coating to make vorinostat fumarate tablets. While the present application uses low molecular weight low-substituted hydroxypropyl cellulose as a binder, adds low molecular weight low-substituted hydroxypropyl cellulose by internal and external methods, and uses high-speed shear granulation method, three-step granulation and two-step drying process, and uses esters containing C1-C6 straight-chain or branched-chain alcohol and C1-C10 straight-chain or branched-chain carboxylic acid as a plasticizer for coating.

[0041] Through the dual breakthroughs of process innovation and prescription optimization, the present application ensures that the pharmaceutical composition and the original drug have high similarity in in vitro dissolution, and under the premise of equivalent light stability, the production cost is significantly reduced, and has obvious industrialization advantages.

[0042] The process innovation: the original research process uses fluidized bed one-step granulation. Process characteristics: the process of mixing, granulation and drying is integrated, and the binder spraying and drying are carried out simultaneously in the fluidized bed. This method has the advantages of small particle hardness, small bulk density and good fluidity. However, it is necessary to accurately control multiple key process parameters, which can be seen from the introduction of the background art. Key parameter control difficulties: (1) air volume control: real-time adjustment is required to maintain the material fluidization state, and too high air volume will cause filter bag blockage and bed collapse, and too low air volume will cause poor granulation effect. (2) Inlet air temperature and humidity: affecting the evaporation kinetics of water, it is difficult to accurately control. (3) Difficulty in water balance: the system has high water content (continuous spraying of binder aqueous solution), and it is necessary to ensure material fluidization and moderate drying at the same time. Improper humidity control will easily lead to poor drying effect, particle sticking and bed collapse. The coupling effect of these complex parameters makes the fluidized bed one-step granulation process face greater control difficulty in actual production.

[0043] Prescription optimization: 1. The original research uses high molecular weight low-substituted hydroxypropyl cellulose as a binder, while the present application uses low molecular weight low-substituted hydroxypropyl cellulose as a binder, and uses an internal and external addition method. According to the currently published literature reports, in order to achieve the greatest similarity with the original research, the current generic drugs basically continue to use the high molecular weight low-substituted hydroxypropyl cellulose in the original research. However, due to the high viscosity and large molecular weight of high molecular weight low-substituted hydroxypropyl cellulose, if it is still used in high-speed shear granulation, the dissolution effect is poor due to its high viscosity. The present inventors tried to reduce the amount of high-substituted hydroxypropyl cellulose and adjust the concentration of smaller high molecular weight low-substituted hydroxypropyl cellulose binder and other methods, but found that the dissolution degree was not ideal. When low molecular weight low-substituted hydroxypropyl cellulose is used, the granulation effect is better, the particles are softer and more elastic, and the internal and external addition method needs to be used during the addition process. In addition, the price of low molecular weight low-substituted hydroxypropyl cellulose is significantly lower than that of high molecular weight low-substituted hydroxypropyl cellulose, and under the same amount, the unit formulation auxiliary material cost can be greatly reduced.

[0044] 2. The original research uses polyethylene glycol as a plasticizer coating to make fumarate vorolanib tablets, while the present application uses an ester formed by C1-C6 straight-chain or branched-chain alcohol and C1-C10 straight-chain or branched-chain carboxylic acid as a plasticizer for coating, which can specifically select one or two or more combinations of triacetin, triethyl citrate or dibutyl sebacate. The inventors found that, compared with polyethylene glycol, the ester plasticizer reduces the thermal degradation of the drug during production by relatively lower coating temperature, improves the stability of product quality, enhances the tolerance of products at different storage temperatures, and is more conducive to long-term storage.

[0045] The present application adopts high-speed shearing granulation in wet granulation and fluidized bed drying. That is, the one-step granulation process is split into two relatively independent steps, which significantly reduces the process difficulty. Although the granule hardness of high-speed shearing granulation is higher than that of fluidized bed, the present application uses: 1. The binder is changed from high molecular weight low-substituted hydroxypropyl cellulose of the original drug to low molecular weight low-substituted hydroxypropyl cellulose, which makes the granulation softer, more elastic and better in adhesion. 2. The internal and external addition method is used, that is, the binder (low molecular weight low-substituted hydroxypropyl cellulose) is divided into two parts, the first part and the second part, which are added respectively when preparing the premix substrate and spraying the binder aqueous solution to prepare the wet material. 3. The three-step granulation process, the first step of high-speed shearing wet granulation to obtain the wet material, the second step of pre-drying through a 20-mesh screen, and the third step of re-drying and passing through a 24-mesh screen again to obtain the intermediate granules. The process flow makes the fumaric acid volorasib tablets of the present application have comparable in-vitro dissolution properties to the original drug.

[0046] Further, the humidity of the pre-dried granules in step 3 should be 1.5%-3.0%, and the humidity of the re-dried granules in step 4 should be 0.5%-1.0%.

[0047] Further, the pre-drying and re-drying in step 3 are both completed in a fluidized bed granulator.

[0048] Further, the stirring in step 2 is carried out in a wet granulator, the stirring paddle is set to 300-500 rpm, and the shearing paddle is set to 300-1000 rpm. When spraying the second part of the binder aqueous solution, the peristaltic pump is set to 15 rpm-30 rpm.

[0049] Further, the tabletting in step 6 uses a rotary tablet press, and the main pressure is 2-5 KN.

[0050] Further, the coating in step 7 uses a film coating machine, and the inlet air temperature of the coating liquid is 48-55℃. As mentioned earlier, the original process uses fluidized bed one-step granulation, which requires a higher inlet air temperature to ensure the fluidization state of the material and maintain sufficient drying effect. However, fumaric acid volorasib is sensitive to temperature, and high temperature may cause drug degradation. The present application uses an ester formed by C1-C6 straight-chain or branched-chain alcohol and C1-C10 straight-chain or branched-chain carboxylic acid as a plasticizer for coating, which can be one or two or more combinations of triacetin, triethyl citrate or dibutyl sebacate. Therefore, the coating can be completed at 48-55℃, which is a temperature range suitable for the performance of lipid plasticizers, conducive to the formation of uniform and dense coating film, and also conducive to maintaining the chemical stability of fumaric acid volorasib, reducing the generation of impurities.

[0051] Another aspect of the present application provides a vornolafex fumarate tablet, comprising vornolafex fumarate drug substance, excipient mannitol and microcrystalline cellulose, binder low molecular weight low-substituted hydroxypropyl cellulose, stabilizer fumaric acid, disintegrant croscarmellose sodium, lubricant magnesium stearate, opacifier titanium dioxide, plasticizer ester compound formed by C1-C6 straight chain or branched alcohol and C1-C10 straight chain or branched carboxylic acid, film-forming agent hydroxypropyl methyl cellulose, pigment iron oxide red or iron oxide yellow and water; wherein, in terms of weight percentage,

[0052] The vornolafex fumarate drug substance accounts for 11.68wt% of the total prescription amount,

[0053] The excipient mannitol and microcrystalline cellulose account for 73-75wt% of the total prescription amount,

[0054] The stabilizer fumaric acid accounts for 2.4-3wt% of the total prescription amount,

[0055] The disintegrant croscarmellose sodium accounts for 4.8-5.0wt% of the total prescription amount,

[0056] The lubricant magnesium stearate accounts for 0.5-1.0wt% of the total prescription amount,

[0057] The opacifier titanium dioxide accounts for 1.0-1.2wt% of the total prescription amount,

[0058] The film-forming agent hydroxypropyl methyl cellulose accounts for 2.15-2.5wt% of the total prescription amount,

[0059] The pigment iron oxide red or iron oxide yellow accounts for 0.04-0.24wt% of the total prescription amount,

[0060] The plasticizer ester compound formed by C1-C6 straight chain or branched alcohol and C1-C10 straight chain or branched carboxylic acid accounts for 0.3-0.6wt% of the total prescription amount,

[0061] The binder is low molecular weight low-substituted hydroxypropyl cellulose, the hydroxypropoxy content of which is 7.0%-16.0%, and the molecular weight is 80-120 thousand, and the binder is composed of a first part of the binder accounting for 0.2-0.58wt% of the total prescription amount and a second part of the binder accounting for 1.3-2.8wt% of the total prescription amount;

[0062] The vornolafex fumarate drug substance, the excipient, the first part of the binder and the stabilizer are mixed into a premixed base, the second part of the binder is mixed with water into a second part of the binder aqueous solution, and the water in the second part of the binder aqueous solution accounts for 11.9-23.6wt% of the premixed base.

[0063] Further, the plasticizer is one or two or more combinations of glyceryl triacetate, triethyl citrate or dibutyl sebacate.

[0064] Further, the stability and in-vitro dissolution of the volorinase fumarate tablet are equivalent to those of the reference preparation.

[0065] The present application has the following advantages over the prior art:

[0066] 1. Product quality advantage: By replacing high molecular weight low-substituted hydroxypropyl cellulose with low molecular weight low-substituted hydroxypropyl cellulose, internal and external addition method and three-step granulation process, the in-vitro dissolution properties equivalent to those of the original drug are ensured, and ester plasticizers (such as glyceryl triacetate, triethyl citrate or dibutyl sebacate) are used to replace polyethylene glycol: reduce the coating temperature, reduce the thermal degradation of the drug, improve the product stability, enhance the tolerance at different storage temperatures, and improve the long-term storage performance.

[0067] 2. The fluidized bed one-step granulation is divided into two independent steps of high-speed shearing granulation and fluidized bed drying, which greatly simplifies the process parameter control and avoids the complex multi-parameter coupling control problems of air volume, temperature and humidity in the fluidized bed one-step granulation. The process has higher repeatability, better production stability, is easier to scale up, has more accurate process control, and has more stable product quality.

[0068] 3. Cost advantage: By using low molecular weight low-substituted hydroxypropyl cellulose to replace high molecular weight low-substituted hydroxypropyl cellulose, the cost of excipients is significantly reduced, and the labor cost per unit product is reduced. BRIEF DESCRIPTION OF DRAWINGS

[0069] Figure 1 is the dissolution curve of Example 2, 4, 9 and reference preparation in pH 1.2 hydrochloric acid solution medium.

[0070] Figure 2 is the dissolution curve of Example 2, 4, 9 and reference preparation in pH 4.5 acetic acid solution medium.

[0071] Figure 3 is the dissolution curve of Example 2, 4, 9 and reference preparation in pH 6.8 hydrochloric acid solution medium.

[0072] Figure 4 is the dissolution curve of Example 2, 4, 9 and reference preparation in water medium. DETAILED DESCRIPTION

[0073] The present application will be further described below in conjunction with the drawings and examples.

[0074] Example 1:

[0075] Coated tablets containing active substance, Venofer, were prepared in the composition ratio shown in Table 1. Venofer raw material (59.79 g), i.e., active substance A, mannitol (325.23 g), microcrystalline cellulose (51.20 g), low molecular weight low-substituted hydroxypropyl cellulose (hereinafter: hydroxypropyl cellulose), hydroxypropyl cellulose (2.24 g), and pulverized fumaric acid (15.36 g) were placed in a wet granulator (MINI-CG, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Subsequently, with the stirring (400 rpm) and chopping (1000 rpm) turned on, a peristaltic pump was set to 30 rpm to spray an aqueous solution (119.5 g) containing hydroxypropyl cellulose (12.1 g), i.e., water accounted for 23.66% of the pre-mixed substrate. After the spraying was completed, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (3.0% moisture) were sieved through a 20-mesh sieve using a swing granulator. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to 1.0% moisture and then sieved through a 24-mesh sieve. Crosscarmellose sodium (24.62 g) and magnesium stearate (2.56 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, manufactured by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 2 KN to obtain the tablet core tablets (220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, sunscreen, and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet core was placed in a coating machine (LABCOATING Type I high-efficiency coating machine, manufactured by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 55°C to spray the coating liquid to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil to obtain inner packaging preparation products, which were placed in light for 5 days or stored at 40°C, 75% RH for 4 weeks.

[0076]

[0077] Example 2:

[0078] Table 2 shows the composition ratio for preparing the coated tablet containing the active substance, Vornosatub, raw material drug. Briefly, the Vornosatub raw material drug (58.39 g), mannitol (325.94 g), microcrystalline cellulose (48.08 g), hydroxypropyl cellulose (1.0 g), and crushed fumaric acid (12.02 g) were placed in a wet granulator (MINI-CG, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Subsequently, the peristaltic pump was set to 15 rpm to spray 65 (g) of an aqueous solution containing hydroxypropyl cellulose (6.5 g) under the condition of open stirring (400 rpm) and chopping (1000 rpm), i.e., water accounted for 13.13% of the pre-mixed substrate. After the spraying was completed, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.5% moisture) were sieved through a 20-mesh sieve using a swing granulator. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to a moisture content of 0.5% and then sieved through a 24-mesh sieve. Crosscarmellose sodium (24.04 g) and magnesium stearate (4.81 g) were added to the sieved powder, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, manufactured by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 5 KN to obtain the tablet core tablets (220 mg per tablet). Before coating, the mixed powder of the plasticizer, pigment, sunscreen agent, and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet core was placed in a coating machine (LABCOATING type I high-efficiency coating machine, manufactured by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 52°C to spray the coating liquid to obtain the film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil to obtain the inner packaging preparation product, which was placed in the light for 5 days or stored at 40°C and 75% RH for 4 weeks. Table 2:

[0079]

[0080] Example 3:

[0081] Table 3 shows the composition ratio for preparing the coated tablet containing the active substance, Vornosatub, raw material drug. Briefly, the Vornosatub raw material drug (59.79 g), mannitol (326.67 g), microcrystalline cellulose (49.23 g), hydroxypropyl cellulose (2.5 g), and crushed fumaric acid (12.31 g) were placed in a wet granulator (MINI-CG, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Subsequently, the peristaltic pump was set to 20 rpm to spray an aqueous solution containing hydroxypropyl cellulose (12.27 g) 81.8 (g) of water, which accounted for 15.43% of the pre-mixed substrate, under the conditions of open stirring (300 rpm) and chopping (800 rpm). After the spraying was completed, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.91% moisture) were sieved through a 20-mesh sieve using a swing granulator. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, manufactured by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to a moisture content of 0.72% and then sieved through a 24-mesh sieve. Crosscarmellose sodium (24.62 g) and magnesium stearate (4.92 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, manufactured by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 3 KN to obtain the tablet core tablets (220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, sunscreen, and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet core was placed in a coating machine (LABCOATING type I high-efficiency coating machine, manufactured by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 48°C to spray the coating liquid, obtaining the film-coated tablet. The obtained film-coated tablet was packaged using PVC and aluminum foil to obtain the inner packaging preparation product, which was placed in the light for 5 days or stored at 40°C, 75% RH for 4 weeks. Table 3:

[0082]

[0083] Example 4:

[0084] Coated tablets containing active substance Vornosaric acid fumarate drug substance were prepared in the composition ratio shown in Table 4. Briefly, Vornosaric acid fumarate drug substance (59.79 g), mannitol (326.67 g), microcrystalline cellulose (49.23 g), hydroxypropyl cellulose (1.57 g) and pulverized fumaric acid (12.31 g) were placed in a wet granulator (MINI-CG, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Subsequently, a peristaltic pump was set to 30 rpm to spray an aqueous solution (110 g) containing hydroxypropyl cellulose (13.2 g) under the condition of open stirring (300 rpm) and chopping (1000 rpm), i.e. water accounted for 21.53% of the pre-mixed substrate. After spraying was completed, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (2.12% moisture) were sieved by a 20-mesh sieve using a swing granulator to obtain sieved coarse granules. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to a moisture content of 0.51% and then sieved again through a 24-mesh sieve. Crosscarmellose sodium (24.62 g) and magnesium stearate (4.92 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, made by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 3 KN to obtain the tablet core tablets (220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, sunscreen agent and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet core was placed in a coating machine (LABCOATING type I high-efficiency coating machine, made by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 50°C to spray the coating liquid to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil by an aluminum plastic packaging machine to obtain inner packaging preparation products, which were placed in light for 5 days or stored at 40°C, 75% RH for 4 weeks. Table 4:

[0085]

[0086] Example 5:

[0087] Coated tablets containing active substance Vornosat alfabex raw material were prepared in the composition ratio shown in Table 5. Briefly, vornosat alfabex raw material (58.39 g), mannitol (320.88 g), microcrystalline cellulose (48.08 g), hydroxypropyl cellulose (2.89 g) and crushed fumaric acid (10.00 g) were placed in a wet granulator (MINI-CG, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Then, under the condition of opening the stirring (300 rpm) and chopping (1000 rpm), the peristaltic pump was set to 18 rpm to spray an aqueous solution (72.06 g) containing hydroxypropyl cellulose (11.53 g), i.e. water accounted for 13.75% of the pre-mixed substrate. After spraying, the wet material was obtained by continuing granulation for one minute. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.5% moisture) were sieved by a 20-mesh sieve using a swing granulator to obtain sieved coarse granules. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to 0.53% moisture and then sieved by a 24-mesh sieve again. Crosscarmellose sodium (24.04 g) and magnesium stearate (500 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, made by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 3 KN to obtain the tablet cores (tablet core tablets, 220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, sunscreen agent and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet cores were placed in a coating machine (LABCOATING type I high-efficiency coating machine, made by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 54°C to spray the coating liquid to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil by an aluminum plastic packaging machine to obtain the inner packaging preparation product, which was placed in light for 5 days or stored at 40°C, 75% RH for 4 weeks. Table 5:

[0088]

[0089] Example 6:

[0090] Coated tablets containing active substance Vornosat alfabex raw material were prepared in the composition ratio shown in Table 6. Briefly, vornosat alfabex raw material (59.79 g), mannitol (326.68 g), microcrystalline cellulose (49.23 g), hydroxypropyl cellulose (1.57 g) and crushed fumaric acid (12.31 g) were placed in a wet granulator (MINI-CG, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.), the stirring paddle was set to 300 rpm, the shearing paddle was set to 300 rpm, and the mixture was first pre-mixed. Then, under the condition of opening the stirring (300 rpm) and chopping (1000 rpm), the peristaltic pump was set to 30 rpm to spray an aqueous solution (110 g) containing hydroxypropyl cellulose (13.2 g), i.e. water accounted for 21.53% of the pre-mixed substrate. After spraying, the wet material was obtained by continuing granulation for one minute. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.89% moisture) were sieved by a 20-mesh sieve using a swing granulator to obtain sieved coarse granules. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to 0.66% moisture and then sieved by a 24-mesh sieve again. Crosscarmellose sodium (24.62 g) and magnesium stearate (4.92 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, made by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.), using an 11*5.95 mm irregular double-inking punch, and the main pressure was 3 KN to obtain the tablet cores (tablet core tablets, 220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, sunscreen agent and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet cores were placed in a coating machine (LABCOATING type I high-efficiency coating machine, made by Shenzhen Xinyite Technology Co., Ltd.), and the inlet air temperature was set to 50°C to spray the coating liquid to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil by an aluminum plastic packaging machine to obtain the inner packaging preparation product, which was placed in light for 5 days or stored at 40°C, 75% RH for 4 weeks. Table 6:

[0091]

[0092] Example 7:

[0093] Coated tablets containing the active substance, Vornosatub, were prepared in the proportions shown in Table 7. Briefly, Vornosatub (59.79 g), mannitol (326.44 g), microcrystalline cellulose (49.23 g), hydroxypropyl cellulose (1.0 g) and powdered fumaric acid (12.31 g) were placed in a wet granulator (MINI-CG, Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) with the stirring paddle set at 300 rpm and the shear paddle set at 300 rpm. The mixture was then premixed. Subsequently, a peristaltic pump was set to 30 rpm to spray an aqueous solution (140 g) containing hydroxypropyl cellulose (14.0 g) (i.e. water accounted for 28.08% of the premixed substrate) with stirring (500 rpm) and chopping (1000 rpm) turned on. After spraying was complete, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluid bed granulator (FLZB-30, Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (2.97% moisture) were sieved using a swing granulator through a 20 mesh sieve to obtain sieved coarse granules. The sieved coarse granules were again placed in a fluid bed granulator (FLZB-30, Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to a moisture content of 0.98% and then sieved again through a 24 mesh sieve. Crosscarmellose sodium (25.0 g) and magnesium stearate (5.0 g) were added to the sieved granules and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.) with 11*5.95 mm irregular double- scoring punches and a main pressure of 4 KN to obtain the tablet cores (core tablets, 220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, opacifier and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet cores were placed in a coating machine (LABCOATING Type I high-efficiency coating machine, Shenzhen Xinyite Technology Co., Ltd.) and the coating liquid was sprayed at an inlet air temperature of 49°C to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil by an aluminum plastic packaging machine to obtain the inner packaging preparation product, which was placed in light for 5 days or stored at 40°C, 75% RH for 4 weeks. Table 7:

[0094]

[0095] Example 8:

[0096] Coated tablets containing the active substance, Vornosarafumate, were prepared in the following composition ratio shown in Table 8. Briefly, Vornosarafumate drug substance (58.39 g), mannitol (34.36 g), microcrystalline cellulose (25.00 g), hydroxypropyl cellulose (2 g) and pulverized fumaric acid (12.02 g) were placed in a wet granulator (MINI-CG, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) with the stirring paddle set at 300 rpm and the shearing paddle set at 300 rpm, and the mixture was first pre-mixed. Then, a peristaltic pump was set to 15 rpm to spray an aqueous solution (65 g) containing hydroxypropyl cellulose (13 g) under the condition of open stirring (500 rpm) and chopping (1000 rpm), i.e. water accounted for 11.88% of the pre-mixed substrate. After the spraying was completed, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.5% moisture) were sieved through a 20-mesh screen using a swing granulator. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to a moisture content of 0.61% and then sieved through a 24-mesh screen. Crosscarmellose sodium (25.00 g) and magnesium stearate (5.00 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, made by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.) with 11*5.95 mm irregular double-inking punches and a main pressure of 2 KN to obtain the tablet cores (core tablets, 220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, opacifier and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet cores were placed in a coating machine (LABCOATING Type I high-efficiency coating machine, made by Shenzhen Xinyite Technology Co., Ltd.) and sprayed with the coating liquid at an inlet air temperature of 53°C to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil by an aluminum plastic packaging machine to obtain the inner packaging preparation product, which was placed in light for 5 days or stored at 40°C and 75% RH for 4 weeks.

[0097]

[0098] Example 9;

[0099] Coated tablets containing the active substance, Vornosatub, were prepared in the proportions shown in Table 9. Briefly, the Vornosatub raw material (58.39 g), mannitol (325.94 g), microcrystalline cellulose (48.08 g), hydroxypropyl cellulose (1.0 g) and powdered fumaric acid (12.02 g) were placed in a wet granulator (MINI-CG, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) with the stirring paddle set at 300 rpm and the shearing paddle set at 300 rpm, and the mixture was first premixed. Then, with the stirring (300 rpm) and shearing (1000 rpm) turned on, a peristaltic pump was set to 15 rpm to spray a solution of hydroxypropyl cellulose (6.5 g) in water (65 g), i.e. 13.13% water based on the premixed substrate. After spraying was complete, the granulation was continued for one minute to obtain wet material. The obtained wet material was placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for pre-drying. The pre-dried granules (1.7% moisture) were sieved using a swing granulator through a 20-mesh screen to obtain sieved coarse granules. The sieved coarse granules were again placed in a fluidized bed granulator (FLZB-30, made by Chuangzhi Electromechanical Technology Development (Jiangsu) Co., Ltd.) for re-drying to 0.8% moisture and then sieved again through a 24-mesh screen. Crosscarmellose sodium (24.04 g) and magnesium stearate (4.81 g) were added to the sieved granules, and the mixture was mixed in a three-dimensional mixer to obtain the total mixed granules. The mixed granules were tableted using a rotary tablet press (ZP-S008, made by Shanghai Tianxiangjian Pharmaceutical Machinery Co., Ltd.) with 11*5.95 mm irregular double-inking punches and a main pressure of 5 KN to obtain the tablet cores (core tablets, 220 mg per tablet). Before coating, the mixed powder of plasticizer, pigment, opacifier and film-forming agent was stirred with purified water for not less than 45 minutes to prepare a coating liquid. The tablet cores were placed in a coating machine (LABCOATING Type I high-efficiency coating machine, made by Shenzhen Xinyite Technology Co., Ltd.) and sprayed with the coating liquid at an inlet air temperature of 50°C to obtain film-coated tablets. The obtained film-coated tablets were packaged using PVC and aluminum foil to obtain inner packaging of the preparation product, which was placed in light for 5 days or stored at 40°C and 75% RH for 4 weeks. Table 9:

[0100]

[0101] Experimental Example 1 (Method for measuring decomposition products):

[0102] To evaluate the stability of the preparation, the present study compared the changes in the content of degradation products in fumarate vorolanib tablets (batch number: 11848645) produced by the Hikari factory of Takeda Pharmaceutical Co., Ltd., and the film-coated tablets of Examples 2, 8, and 9 of the present application before and after storage. During sample preparation, strict light-avoiding operations were performed. Three tablets of the sample were placed in a 200 mL volumetric flask, about 120 mL of solvent I [water-acetonitrile (3:1, v / v)] was added, and the tablets were completely dissolved after shaking for 30 minutes. Then, solvent I was diluted to the calibration mark to complete the sample extraction.

[0103] The determination was performed by high performance liquid chromatography (HPLC) with the following specific chromatographic conditions:

[0104] The detection was performed by ultraviolet absorption spectrophotometry with a detection wavelength of 230 nm.

[0105] The chromatographic column was an octadecylsilane-bonded silica gel (Hypersil GOLD 250x4.6mm, 5μm).

[0106] The column temperature was constant at 25°C.

[0107] The mobile phase system included mobile phase A [0.025 mol / L phosphate buffer (pH 6.8)-methanol-acetonitrile (14:5:1, v / v / v)]

[0108] mobile phase B [acetonitrile-0.025 mol / L phosphate buffer (pH 6.8) (7:3, v / v)],

[0109] The flow rate was 1.0 mL per minute. The detection conditions are shown in Table 10, and the detected impurities are shown in Table 11:

[0110] Table 10 Detection conditions

[0111] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 10 100 0 30 50 50 40 0 100 45 0 100 45.1 100 0 55 100 0

[0112] Table 11 Detected impurities

[0113]

[0114]

[0115] The results of the determination of the decomposition products after storage (light for 5 days and at 40°C, storage for 4 weeks) are shown in Table 12. Example 8, Example 2 and Example 9 showed no significant increase in impurities under the condition of storage for 5 days of light and were comparable to the reference formulation (Batch No: 11848645, manufactured by Takeda Pharmaceutical Company Limited, Hikari Plant) under the condition of storage for 5 days of light. In addition, the impurity 9 in the product produced according to the present application was not detected before and after storage, which is due to the relatively low temperature drop of the inlet air during the coating process, which reduces the extent of the degradation of the drug substance by temperature. In addition, Example 8 and Example 2 exhibited better stability than Batch No 11848645 under the condition of storage for 4 weeks at 40°C.

[0116] Table 12: Results of determination of decomposition products

[0117]

[0118]

[0119] Experimental Example 2 (In-vitro dissolution determination method)

[0120] After preparation, in-vitro dissolution tests were performed on the film-coated tablets of the pharmaceutical product manufactured by Takeda Pharmaceutical Company Limited, Hikari Plant (Batch No: 11848645) and Example 2, Example 4 and Example 9. Each time, 6 pieces of the sample to be tested were placed in an automatic sampling dissolution tester (FAD F1202, manufactured by Fuke Technology) and tested in pH 1.2, pH 4.5, pH 6.8 and water environments, respectively. The experimental method is as follows:

[0121] Dissolution method: Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0931 Dissolution and Release Determination Method;

[0122] Rotation speed: 50 revolutions;

[0123] Dissolution medium volume: 900 ml

[0124] Sampling points: 7 (5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes)

[0125] The samples taken by the dissolution tester were detected for concentration by HPLC, so as to measure the dissolution at each time point. The HPLC test conditions are as follows:

[0126] Detector: ultraviolet absorption spectrophotometer (detection wavelength: 230 nm)

[0127] C18 MGII 4.6 mm I.D. * 150 mm, 3 μm) with octadecylsilane-bonded silica as the excipient (C18, PECELL P, Vilonasertib fumarate drug substance K, Vilonasertib fumarate drug substance C)

[0128] Column temperature: fixed temperature of about 25°C

[0129] Mobile phase C: 0.05 mol / L phosphate buffer (pH 6.8) - methanol - acetonitrile (17:6:7),

[0130] Flow rate: 1.0 ml per minute.

[0131] The results of the experiment showed that the dissolution profile at pH 1.2 of the medium was as shown in Tables 13-16, and Figure 1 ;

[0132] Table 13 Dissolution values for pH 1.2 hydrochloride solution Reference Example 1 8 4 8 6 4 5

[0133]

[0134] Table 14 Dissolution values for pH 1.2 hydrochloride solution Example 2

[0135]

[0136] Table 15 Dissolution values for pH 1.2 hydrochloride solution Example 4

[0137]

[0138] Table 16 Dissolution values for pH 1.2 hydrochloride solution Example 9

[0139]

[0140] The dissolution profile at pH 4.5 of the medium was as shown in Tables 17-20, and Figure 2 ;

[0141] Table 17 Dissolution values for pH 4.5 acetate solution Reference Example 1 8 4 8 6 4 5

[0142]

[0143] Table 18 Dissolution values for pH 4.5 acetate solution Example 2

[0144]

[0145]

[0146] Table 19 Dissolution values for pH 4.5 acetate solution Example 4

[0147]

[0148] Table 20 pH 4.5 Acetate Solution Reference 11848645 Example 9 Dissolution Values

[0149]

[0150] Dissolution profiles for medium pH 6.8 are Tables 21-24, and Figure 3 ;

[0151] Table 21 pH 6.8 Acetate Solution Reference 11848645 Dissolution Values

[0152]

[0153]

[0154] Table 22 pH 6.8 Acetate Solution Example 2 Dissolution Values

[0155]

[0156] Table 23 pH 6.8 Acetate Solution Example 4 Dissolution Values

[0157]

[0158] Table 24 pH 6.8 Acetate Solution Example 9 Dissolution Values

[0159]

[0160]

[0161] Dissolution profiles for medium water are Tables 25-28, and Figure 4 Time (min) Mobile phase A (%) Mobile phase B (%) .

[0162] Table 25 Water Reference 11848645 Dissolution Values

[0163]

[0164] Table 26 Water Example 2 Dissolution Values

[0165]

[0166] Table 27 Water Example 4 Dissolution Values

[0167]

[0168] Table 28 Water Example 9 Dissolution Values

[0169]

[0170] As can be seen from the above table, the pharmaceutical compositions of batch no. 11848645, Example 2, Example 4 and Example 9 all exhibit a high degree of similarity in that the dissolution of each is greater than 85% at 15 minutes in the media pH 1.2 hydrochloride solution, pH 4.5 acetate solution, water and pH 6.8 acetate solution.

[0171] The above is the preferred embodiment of the present application, but the embodiments of the present application are not limited by the above, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application should be equivalent replacement methods, and are included in the protection scope of the present application.

Claims

1. A method for preparing vonoprazan fumarate tablets, characterized in that: Includes the following steps: Step 1: Weigh out vonoprazan fumarate raw material, excipients, first-part binder and stabilizer as premixed substrate; Step 2: Place the premixed substrate in a wet granulator, and spray the aqueous solution of the second part of the adhesive while stirring and chopping to obtain a wet material; Step 3: After pre-drying the wet material, pass it through a 20-mesh sieve to obtain coarse particles after sieving; Step 4: Dry the coarse particles again and pass them through a 24-mesh sieve to obtain dried intermediate particles. Step 5: Mix the intermediate particles, added disintegrant and lubricant together to obtain tablet granules; Step 6: Compress the tablet granules into uncoated tablets; Step 7: Coat the uncoated tablets with a coating solution to prepare vonoprazan fumarate tablets. The coating solution is prepared by mixing pigments, film-forming agents, plasticizers, and opacifiers with water. Both the first and second adhesive components are low molecular weight, low-substituted hydroxypropyl cellulose, with a hydroxypropyl cellulose degree of substitution of 7.0%-16.0% and a molecular weight of 80,000-120,000. Of which, in weight percentage, The vonoprazan fumarate raw material accounted for 11.68 wt% of the total prescription. The excipients comprise 73-75 wt% of the total formulation. The first portion of the adhesive accounts for 0.2-0.58 wt% of the total formulation. The second part, the adhesive, accounts for 1.3-2.8 wt% of the total formulation. The stabilizer accounts for 2.4-3 wt% of the total prescription. The disintegrant constitutes 4.8-5.0 wt% of the total formulation. The lubricant accounts for 0.5-1.0 wt% of the total prescription. The light-blocking agent accounts for 1.0-1.2 wt% of the total formulation. The film-forming agent accounts for 2.15-2.5 wt% of the total formulation. The pigment accounts for 0.04-0.24 wt% of the total prescription. The plasticizer accounts for 0.3-0.6 wt% of the total formulation. In the second part of the adhesive aqueous solution, water accounts for 11.9-23.6 wt% of the premixed substrate; The excipient is mannitol and / or microcrystalline cellulose.

2. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that, The stabilizer is fumaric acid, the disintegrant is croscarmellose sodium cellulose, the lubricant is magnesium stearate, the opacifier is titanium dioxide, the film-forming agent is hydroxypropyl methylcellulose, and the pigment is iron oxide red or iron oxide yellow.

3. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: The plasticizer is one or a combination of two or more of triacetin, triethyl citrate, or dibutyl sebacate.

4. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: In step 3, the moisture content of the pre-dried particles is 1.5%-3.0%, and in step 4, the moisture content of the particles after further drying is 0.5%-1.0%.

5. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: In step 3, both pre-drying and re-drying are completed in a fluidized bed granulator.

6. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: In step 2, the stirring is carried out in a wet granulator, with the stirring paddle set to 300-500 rpm and the shearing paddle set to 300-1000 rpm. When spraying the aqueous solution of the second part of the adhesive, the peristaltic pump is set to 15-30 rpm.

7. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: In step 6, tableting is performed using a rotary tablet press with a main pressure of 2-5 kN.

8. The method for preparing vonoprazan fumarate tablets according to claim 1, characterized in that: In step 7, the coating is performed using a film coating machine, and the inlet air temperature of the coating solution is 48-55℃.

9. A vonoprazan fumarate tablet, characterized in that, The product comprises vonoprazan fumarate active pharmaceutical ingredient, mannitol and microcrystalline cellulose as excipients, low molecular weight, low-substituted hydroxypropyl cellulose as a binder, fumaric acid as a stabilizer, sodium croscarmellose as a disintegrant, magnesium stearate as a lubricant, titanium dioxide as a light-blocking agent, ester compounds formed from C1-C6 straight-chain or branched alcohols and C1-C10 straight-chain or branched carboxylic acids as plasticizers, hydroxypropyl methylcellulose as a film-forming agent, iron oxide red or iron oxide yellow as a pigment, and water; wherein, by weight percentage... The vonoprazan fumarate raw material accounted for 11.68 wt% of the total prescription. The excipients mannitol and microcrystalline cellulose account for 73-75% of the total formulation. The stabilizer fumaric acid accounts for 2.4-3 wt% of the total formulation. The disintegrant, croscarmellose sodium, accounts for 4.8-5.0 wt% of the total formulation. The lubricant, magnesium stearate, accounts for 0.5-1.0 wt% of the total formulation. The light-blocking agent, titanium dioxide, accounts for 1.0-1.2 wt% of the total formulation. The film-forming agent, hydroxypropyl methylcellulose, accounts for 2.15-2.5 wt% of the total formulation. The pigment iron oxide red or iron oxide yellow accounts for 0.04-0.24 wt% of the total formulation. The ester compounds formed by the plasticizer C1-C6 straight-chain or branched alcohol and C1-C10 straight-chain or branched carboxylic acid account for 0.3-0.6 wt% of the total formulation. The adhesive is low molecular weight, low-substituted hydroxypropyl cellulose, with a hydroxypropyl cellulose hydroxypropoxy content of 7.0%-16.0% and a molecular weight of 80,000-120,000. The adhesive consists of a first part of the adhesive accounting for 0.2-0.58 wt% of the total formulation and a second part of the adhesive accounting for 1.3-2.8 wt% of the total formulation. The vonoprazan fumarate active pharmaceutical ingredient, excipient, first-part binder and stabilizer are mixed to form a premixed substrate, and the second-part binder is mixed with water to form an aqueous solution of the second-part binder, wherein water accounts for 11.9-23.6 wt% of the premixed substrate in the aqueous solution of the second-part binder.

10. The vonoprazan fumarate tablets according to claim 9, characterized in that, The plasticizer is one or a combination of two or more of triacetin, triethyl citrate, or dibutyl sebacate.

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