Regorafenib coated tablet and preparation method thereof

Abstract

The invention relates to a regorafenib coated tablet, which is characterized in that the core of the regorafenib coated tablet is coated by a film coating material containing hydroxypropyl methylcellulose (HPMC), and the coating is obtained through a coating process. The film coating material containing hydroxypropyl methylcellulose (HPMC) is dispersed into a water-containing organic solvent in the coating process. The hydroxypropyl methylcellulose is added into the film coating material, so that the dissolution of the regorafenib coated tablet is improved, and the generation of mutagenic impurities is reduced.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a regorafenib coated tablet and a preparation method thereof. Background Art

[0002] Regorafenib tablets were developed and produced by Bayer in Germany. They were approved for marketing in the United States in September 2012 for the treatment of metastatic colorectal cancer (CRC) and locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST) that have previously received chemotherapy. In December 2017, they were approved by the CDE for the treatment of hepatocellular carcinoma that has previously received sorafenib treatment.

[0003] Patent CN111249247A discloses that the pharmaceutical composition of regorafenib tablets comprises regorafenib, its hydrate, solvate, metabolite or pharmaceutically acceptable salt or polymorph thereof, and the pharmaceutical composition is coated, wherein the coating can be obtained by a coating process, wherein the exhaust temperature during the coating process is equal to or lower than 42°C. When the film coating material HPMC is dissolved in water, the regorafenib tablet core is coated at an exhaust temperature of 60°C, and the impurity AFP-PMA increases by 0.0054% relative to regorafenib. The film prescription and process result in low safety of regorafenib tablets and low purity of the active ingredient regorafenib, thus limiting the application of the film coating material HPMC in regorafenib solid dispersions. Summary of the invention

[0004] The object of the present invention is to provide a regorafenib coated tablet, which has the characteristics of strong stability, high safety, and high solubility and purity of the active ingredient regorafenib.

[0005] Another object of the present invention is to provide a method for preparing regorafenib coated tablets, which is suitable for industrial production and ensures the qualified rate of finished products; at the same time, it makes the preparation process simpler and more reliable, and the industrial scale-up is controllable.

[0006] In order to achieve the above-mentioned object of the invention, the present invention is implemented by the following technical solutions:

[0007] In the research on the solid dispersion technology of regorafenib tablets, the inventors found that both the dispersing matrix agent polyvinyl pyrrolidone and the disintegrant cross-linked carboxymethyl cellulose sodium are hygroscopic, and the prepared preparations may absorb moisture during storage, thereby increasing the risk of impurities in the raw materials of regorafenib growing. Therefore, the water-proof performance of the film coating is crucial, and hydroxypropyl methylcellulose HPMC has better water-proof performance than polyvinyl alcohol PVA. Hydroxypropyl methylcellulose HPMC has good stability in both acidic and alkaline environments. When the pH value of the solution is in the range of 2-11, it can be stored for a long time, and its viscosity will not be affected by the acid-base environment of the solution. For unstable drugs such as those that are easy to absorb moisture, the use of hydroxypropyl methylcellulose HPMC to form a film can improve the stability of the drug and reduce the generation of impurities, especially the mutagenic impurity AFP-PMA. In addition, HPMC is a water-soluble cellulose derivative obtained by alkalization, etherification modification, neutralization reaction, washing and drying of natural cellulose. It has abundant sources and is renewable; it is environmentally friendly and biodegradable, and is more suitable for industrial production and use.

[0008] The inventors have also found that in solid dispersion technology, when the drug and the carrier material (matrix) are completely compatible, the system is in a stable state and phase separation will not occur. If the system undergoes phase separation, the system's inhibitory force on drug recrystallization will be weakened, reducing physical stability, causing the drugs to aggregate with each other and be difficult to dissolve quickly. The phase separation process of solid dispersions depends on the compatibility between the drug and the carrier and the external conditions of the system, such as relative humidity, temperature, etc. For the present invention, the raw material regorafenib and the matrix polyvinyl pyrrolidone are mixed and dissolved in a mixed solvent of acetone and ethanol, and the drug exists in an amorphous form and is highly dispersed in the matrix. Amorphous drugs have a higher Gibbs free energy, and when dissolving, amorphous drugs do not need to overcome the lattice energy required for the dissolution of crystalline drugs, which accelerates dissolution. Amorphous drugs will spontaneously transform into crystalline drugs with lower thermodynamic energy and better stability. However, when the temperature rises, the thermal motion of molecules is accelerated, and the mobility of molecules is accelerated, resulting in reduced stability of solid dispersions, and the matrix is ​​difficult to play the role of encapsulating drugs, thereby affecting drug dissolution and stability. The polyvinyl pyrrolidone matrix is ​​hygroscopic. When the humidity is too high, the matrix forms a thick diffusion layer on the surface of the drug, resulting in phase separation of the drug and the matrix, making it difficult for the drug to contact the solvent and inhibiting the rapid dissolution of the drug. The inventor found that when using the film coating material hydroxypropyl methylcellulose HPMC, when water is used as a dispersing solvent, its solid content cannot be too high, otherwise there will be coating defects such as sticking to the tablet. In order to reduce the risk of sticking to the tablet, it is necessary to prepare a coating solution with a lower solid content, but the water content will increase. In order to remove excessive water, the coating must be carried out at high temperature, which will increase the amount of impurities generated. If the coating is applied at low temperature and high humidity, the phase separation of the drug and the matrix will occur. Although the phase separation is reversible, when the environmental conditions return to normal, the solid dispersion can return to an amorphous state, but the chemical and physical stability of the solid dispersion that has undergone phase separation will be reduced, and the dissolution rate and solubility of the drug will also be affected to a certain extent. In order to overcome the above problems, the present invention adopts hydroxypropyl methylcellulose HPMC as a film coating material and an aqueous organic solvent as a dispersing solvent, while reducing the tablet bed temperature and the humidity during the coating process, maintaining the amorphous steady state of the raw material drug, ensuring the stability of the solid dispersion system and improving the solubility and purity.

[0009] The specific technical solutions are as follows:

[0010] The first aspect of the present invention provides a regorafenib coated tablet, wherein the regorafenib coated tablet is a regorafenib tablet core coated with a film coating material containing hydroxypropyl methylcellulose (HPMC), wherein the coating is obtained through a coating process, and during the coating process, the film coating material containing hydroxypropyl methylcellulose (HPMC) is dispersed in an aqueous organic solvent.

[0011] In some embodiments of the present application, the tablet bed temperature during the coating process is ≤45°C, and preferably the tablet bed temperature during the coating process is 30-45°C. The tablet bed temperature can be selected from 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, and 45°C. This tablet bed temperature range can be industrialized and the production temperature can be controlled, ensuring that the tablets are not sticky during the coating process, quickly volatilizing water and inorganic solvents, reducing humidity, avoiding long-term coating under high humidity, low impurity generation, and safety and stability. At the same time, coating at this tablet bed temperature can also obtain a dense coating layer, and the edge of the film is not easy to crack.

[0012] In some embodiments of the present application, the organic solvent in the aqueous organic solvent includes but is not limited to one or more of ethanol, methanol, acetone, isopropanol, and diacetone alcohol, and the preferred organic solvent is ethanol or acetone.

[0013] In some embodiments of the present application, the volume concentration of the aqueous organic solvent can be selected from 20-95% (v / v), and the concentration of the organic solvent can be selected from 25% (v / v), 30% (v / v), 35% (v / v), 40% (v / v), 45% (v / v), 50% (v / v), 55% (v / v), 60% (v / v), 65% (v / v), 70% (v / v), 75% (v / v), 80% (v / v), 85% (v / v), 90% (v / v), 95% (v / v). The water content in this concentration range can remove moisture as soon as possible to avoid coating in a humid environment for a long time. The inventors found that when using anhydrous ethanol or different proportions of ethanol / water for coating, compared with plain tablets or core tablets, the coated tablets obtained with anhydrous ethanol have the lowest moisture content and the lowest mutagenic impurities, but the tablet surface is slightly rough; when using different proportions of ethanol / water for coating, as the ethanol concentration increases, the moisture content gradually decreases, and the mutagenic impurities also decrease accordingly. However, considering environmental issues, the alcohol content is reduced as much as possible. It is preferred to use 65-80% ethanol solution as the organic solvent for the coating dispersion of the present application, so that a preparation sample with good tablet surface and qualified moisture content can be obtained.

[0014] In some embodiments of the present application, the film coating material containing hydroxypropyl methylcellulose HPMC is dispersed in an aqueous organic solvent to obtain a coating solution, and the solid content or concentration of the coating solution is 5-15%. The solid content or concentration within this range can improve the strength and adhesion of the coating film. If the solid content or concentration is too large, it is easy to form larger droplets during spraying, the ability of the coating material to penetrate into the tablet core is weak, and the tablets are more aggregated and adhered. At the same time, the density of the coating film is poor and there are more bubbles. The solid content or coating material concentration described in the present application can be selected from 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%. The calculation method of the solid content or concentration of the coating solution is: liquid solid content (%) = (solid mass ÷ total mass) × 100%.

[0015] In some embodiments of the present application, the viscosity of the Hydroxypropyl Methylcellulose (HPMC) is 4-8 mPa·S.

[0016] In some embodiments of the present application, the mass of the Hydroxypropyl Methylcellulose (HPMC) in the film coating material is 30-80%, preferably 40-75%.

[0017] In some embodiments of the present application, the film coating material containing hydroxypropyl methylcellulose (HPMC) further includes one or more of a plasticizer, a colorant, a sunscreen, an anti-sticking agent or a pore-forming agent.

[0018] In some embodiments of the present application, the plasticizer includes but is not limited to one or more of polyethylene glycol, propylene glycol, glycerol, maltitol, xylitol, mannitol, erythritol, triolein, tributyl citrate, triethyl citrate, acetylcitrate triethyl, triacetin, stearic acid, triacetin, acetylated glyceryl ester, and phthalate; preferably, the plasticizer includes polyethylene glycol. The model of the polyethylene glycol includes but is not limited to polyethylene glycol 1000, polyethylene glycol 1450, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, etc.

[0019] In some embodiments of the present application, the plasticizer accounts for 5-25% by weight of the film coating material, preferably 10-20% by weight.

[0020] In some embodiments of the present application, the colorant includes but is not limited to one or more of red iron oxide, yellow iron oxide, black iron oxide, sunset yellow, and anthocyanin.

[0021] In some embodiments of the present application, the colorant accounts for 2-30% by weight of the film coating material, preferably 5-20% by weight.

[0022] In some embodiments of the present application, the sunscreen includes but is not limited to titanium dioxide and / or talc, preferably titanium dioxide.

[0023] In some embodiments of the present application, the sunscreen agent accounts for 5-30% by weight of the film coating material, preferably 15-25%.

[0024] In some embodiments of the present application, the anti-adhesive agent includes but is not limited to one or more of talc, magnesium stearate, stearic acid, lecithin, soybean lecithin, mineral oil, and polysorbate.

[0025] In some embodiments of the present application, the anti-sticking agent accounts for 0-25% by weight of the film coating material, preferably 0-20% by weight.

[0026] In some embodiments of the present application, the porogen of the present invention comprises one or more of polyethylene glycol, sucrose, sodium chloride and a surfactant, preferably polyethylene glycol.

[0027] In some embodiments of the present application, the pore-forming agent accounts for 0-25% by weight of the film coating material, preferably 0-20% by weight.

[0028] In some embodiments of the present application, the coating material can be prepared from the above ingredients, or commercially available products, such as film coating premix (gastric soluble), such as Opadry ○R QX, Opadry ○R ambll, Opady ○R SGR, Opady ○R fx, Opady ○R EZ et al.

[0029] In some embodiments of the present application, the weight gain of the coating is 1.0%-4.0%, and the coating weight gain can be selected from 1.0%, 2.0%, 3.0%, and 4.0%. The present application controls the coating weight gain within the range of 1.0%-4.0%, and the appearance of the sample after coating meets the requirements, ensuring the in vitro dissolution, effectively ensuring the stability of the product during storage, and reducing the risk of impurity growth.

[0030] In some embodiments of the present application, during the coating process, the inlet air temperature is 40-70°C. The inlet air temperature can be selected from 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C. The temperature within this range can ensure that the tablet bed temperature is always maintained below 45°C, and it is easy to control the temperature in industrialization and has strong operability. If the inlet air temperature is too high, the coating liquid will form atomization, and if the temperature is too low, it will cause poor flow, material agglomeration, or water cannot be discharged to form adhesion.

[0031] In some embodiments of the present application, the regorafenib core tablet comprises regorafenib and pharmaceutically acceptable excipients. Preferably, the excipients comprise one or more of a dispersing matrix agent, a disintegrant, a filler, a binder, a lubricant, and a glidant.

[0032] In some embodiments of the present application, the regorafenib in the regorafenib core tablet includes regorafenib, regorafenib anhydrate, hydrate, solvate, metabolite or pharmaceutically acceptable salt, or a polymorph thereof.

[0033] In some embodiments of the present application, the regorafenib hydrate includes anhydrate, hemihydrate, monohydrate, and dihydrate, preferably regorafenib monohydrate.

[0034] In some embodiments of the present application, the regorafenib in the regorafenib tablet core refers to one or more of regorafenib, regorafenib monohydrate, and regorafenib anhydrate as the active ingredient in the regorafenib coated tablet.

[0035] In some embodiments of the present application, the regorafenib tablet core contains 5.0-15.0% by weight of regorafenib, 18.0-30.0% by weight of filler, 30.0-40.0% by weight of disintegrant, 30.0-40.0% by weight of dispersant matrix agent, 0.1-1.0% by weight of glidant, and 0.1-1.0% by weight of lubricant; preferably, the regorafenib tablet core contains 8.70% by weight of regorafenib, 21.74% by weight of filler, 33.48% by weight of disintegrant, 34.78% by weight of dispersant matrix agent, 0.52% by weight of lubricant.

[0036] In some embodiments of the present application, the dispersing matrix agent in the regorafenib tablet core includes, but is not limited to, one or more of polyvinyl pyrrolidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide, preferably polyvinyl pyrrolidone as the dispersing matrix agent.

[0037] In some embodiments of the present application, the disintegrant described in the regorafenib tablet core includes but is not limited to one or more of cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and starch; preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0038] In some embodiments of the present application, the disintegrant is added by internal or external addition.

[0039] In some embodiments of the present application, the filler in the regorafenib tablet core includes but is not limited to one or more of microcrystalline cellulose, lactose, dextrin, and pregelatinized starch; preferably, the filler is microcrystalline cellulose.

[0040] In some embodiments of the present application, the lubricant described in the regorafenib tablet core includes, but is not limited to, one or more of magnesium stearate, stearic acid, sodium fumarate stearate, and hydrogenated vegetable oil, and the preferred lubricant is magnesium stearate.

[0041] In some embodiments of the present application, the glidant in the regorafenib tablet core includes but is not limited to one or more of colloidal silicon dioxide, silicon dioxide, and talc, and the preferred glidant is colloidal silicon dioxide.

[0042] The second aspect of the present invention provides a method for preparing regorafenib coated tablets, wherein the coating process comprises the following steps:

[0043] (1) dispersing a film coating material containing hydroxypropyl methylcellulose (HPMC) into an aqueous organic solvent to prepare a coating solution with a certain solid content;

[0044] (2) Use coating pan for coating, with air inlet temperature of 40-70℃ and air volume of 50-90m 3 / h, peristaltic pump speed 1-15rpm, coating pan speed 5-25rpm;

[0045] (3) controlling the tablet bed temperature to ≤45°C, more preferably 35-45°C, and coating the regorafenib tablet cores;

[0046] (4) Stop coating when the coating weight gain is 1.0%-4.0%.

[0047] In some embodiments of the present application, the aqueous organic solvent in step (1) refers to adding the organic solvent into water according to a volume ratio.

[0048] In some embodiments of the present application, the organic solvent in the aqueous organic solvent includes but is not limited to one or more of ethanol, methanol, acetone, isopropanol or diacetone alcohol, and the preferred organic solvent is ethanol or acetone.

[0049] In some embodiments of the present application, the concentration of the aqueous organic solvent is 20-95% (v / v), and the concentration of the organic solvent can be selected from 25% (v / v), 30% (v / v), 35% (v / v), 40% (v / v), 45% (v / v), 50% (v / v), 55% (v / v), 60% (v / v), 65% (v / v), 70% (v / v), 75% (v / v), 80% (v / v), 85% (v / v), 90% (v / v), 95% (v / v). The water content in this concentration range can avoid long-term coating in a high humidity environment, and the speed of spraying and drying is balanced, thereby reducing the risk of coating defects and the generation of impurities.

[0050] The film coating material containing hydroxypropyl methylcellulose (HPMC) is dispersed in an aqueous organic solvent to obtain a coating agent solvent, and the solid content or concentration of the coating agent solution is 5-15%.

[0051] In some embodiments of the present application, the air volume in step (2) is 50-90m 3 / h, the air volume can be selected from 50m3 / h、55m 3 / h、60m 3 / h、65m 3 / h、70m 3 / h、75m 3 / h、80m 3 / h、85m 3 / h、90m 3 / h.

[0052] The peristaltic pump speed is 1-15rpm, and the peristaltic pump speed can be selected from 1rpm, 2rpm, 3rpm, 4rpm, 5rpm, 6rpm, 7rpm, 8rpm, 9rpm, 10rpm, 11rpm, 12rpm, 13rpm, 14rpm, and 15rpm.

[0053] The coating pan has a rotation speed of 5-25 rpm; the coating pan has a rotation speed of 5 rpm, 7 rpm, 9 rpm, 11 rpm, 13 rpm, 15 rpm, 17 rpm, 19 rpm, 21 rpm, 23 rpm, and 25 rpm.

[0054] The inventor found that after the HPMC material was water-coated, the obtained coated tablets had a high moisture content and the coating layer gained weight quickly. This is because the excipients in the regorafenib tablet core are highly hygroscopic. During the water coating process, the regorafenib API and excipients absorbed more moisture in the coating agent, resulting in significant coating weight gain. When the weight gain standard was reached, it was found that the coating film was over-coated, and there was a risk of coating defects, such as unevenness, cracking, etc., and the yield rate was difficult to control. In order to control the moisture content, it is also necessary to add a drying and dehydration step after coating to achieve a moisture content of less than 3%. The coating prescription of the present application does not require an additional drying and dehydration step, and the moisture content of the coated tablets obtained after coating can be controlled to less than 3%, or even less than 2%, further reducing the risk of moisture growth during storage. In the coating process of the present application, excessive air intake or excessively high air intake temperature will lead to excessive drying speed, slow film formation of the tablet core, and long idling time and wear time of the tablet core in the coating pan, resulting in uneven coating film after coating and poor appearance. The perfect combination of air volume, peristaltic pump speed, coating pan rotation range and tablet bed temperature or concentration of aqueous organic solvent within the scope of the present invention can achieve an optimal combination state, reduce friction between tablet cores, and reduce wear.

[0055] In some embodiments of the present application, the core preparation process includes the following steps:

[0056] Step A: Fluidized bed granulation: dissolve the regorafenib API and the dispersing matrix in a dispersing solvent, stir until a clear solution is obtained; spray the solution onto a mixture of a filler and a portion of a disintegrant in a fluidized bed granulator, control the material temperature at 20-40° C., dry until the moisture content is less than 3.0%, and discharge the material to obtain granules;

[0057] Step B: Dry granulation: The granules in step A are sieved at multiple stages, crushed to obtain dry granules, and mixed with the remaining disintegrant, glidant and lubricant;

[0058] Step C: compressing regorafenib tablet cores.

[0059] In some embodiments of the present application, the dispersing solvent in step A includes but is not limited to one or more of ethanol, methanol, propanol, butanol, acetone, ethyl acetate, and propyl acetate, preferably a mixed solution of ethanol and acetone, and more preferably a mixed solution of acetone to ethanol in a volume ratio of (2-6:1).

[0060] The mutagenic impurity mentioned in the present application refers to 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid amide, referred to as AFP-PMA.

[0061] Beneficial Effects

[0062] The use of hydroxypropyl methylcellulose as the coating material for regorafenib tablets in this application greatly improves the shortcomings of the water resistance, mechanical properties and thermal stability of the PVA coating film when exposed to water. The coating solvent is replaced by a certain proportion of water-containing organic solvents from water, which reduces the tablet bed temperature, reduces the risk of impurity growth and raw material crystal transformation, and ensures that the dissolution of the active ingredient in the preparation reaches more than 99% in 45 minutes. At the same time, it makes the preparation process simpler and more reliable, and the industrial scale-up is controllable. The use of hydroxypropyl methylcellulose as a coating material, combined with a specific solvent and tablet bed temperature, significantly reduces the mutagenic impurities compared to using only pure water as a dispersion solvent, regardless of whether the tablet bed is at high or low temperatures.

[0063] Of course, implementing any product or method of the present application does not necessarily require achieving all of the advantages described above at the same time. DETAILED DESCRIPTION

[0064] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those skilled in the art based on the present application belong to the scope of protection of the present application.

[0065] Example 1 Tablet preparation

[0066] (1) Tablet prescription:

[0067]

[0068] (2) Fluidized bed granulation: Dissolve regorafenib API and povidone K25 in acetone / ethanol solution and stir until clear. Spray the solution onto the mixture of microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose in a fluidized bed granulator and control the material temperature at 20-40°C. Dry until the moisture content is less than 3.0% and discharge.

[0069] (3) Dry granulation: The granules prepared in step (1) are subjected to primary sieving (mesh size: 3.0 mm) and secondary sieving (mesh size: 1.0 mm), and then crushed to obtain dry granules, which are then mixed with the remaining cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and magnesium stearate.

[0070] (4) Qualified regorafenib tablet cores were pressed on a rotary tablet press, using a 16*7 mm angular punch, setting a tableting speed of 30,000 to 150,000 tablets / h, a main pressure of 10.0 to 26.0 kN, a controlled hardness range of 100 to 260 N, and a weight difference of ±5%.

[0071] (5) Study on key quality attributes of chip core

[0072] Moisture 2.00％ Mutagenic impurity AFP-PMA 0.0054％

[0073] The content of AFP-PMA is calculated based on the amount of regorafenib.

[0074] Example 2 Film Coating

[0075] The regorafenib core tablets prepared in Example 1 were used.

[0076] (1) Preparation of coating solution: Pour coating powder into 70% ethanol solution. The coating powder is commercially available. 03B640020-CN, which comprises hydroxypropyl methylcellulose E6, viscosity 6mPa·S accounting for 50-70% of the coating powder, polyethylene glycol accounting for 5-15% of the coating powder, colorant accounting for 5-15% of the coating powder, titanium dioxide accounting for 10-30% of the coating powder), and a coating solution with a certain solid content of 10% is prepared.

[0077] (2) Use a coating pan for coating, set the air inlet temperature to 60-70°C and the air volume to 50-60m 3 / h, peristaltic pump speed 10-12rpm, coating pan speed 12-15rpm.

[0078] (3) Control the tablet bed temperature at 35-45°C

[0079] (4) Stop coating when the coating weight gain exceeds the target weight gain by about 2.0-3.0%.

[0080] Embodiment 3-8

[0081] Except for the coating solvent, air inlet temperature, air volume, peristaltic pump speed, tablet bed temperature, coating pan speed and coating weight gain, everything else was prepared according to the method of Example 2.

[0082]

[0083] Note: “ / ” indicates that the test was not performed.

[0084] Examples 9-11

[0085] Except for the organic solvent for coating dispersion, air inlet temperature, air volume, peristaltic pump speed, tablet bed temperature, coating pan speed and coating weight gain, everything else was prepared according to the method of Example 2.

[0086]

[0087]

[0088]

[0089] Conclusion: From the above table, it can be seen that after the PVA purified water coating and HMPC water coating were applied at 40-45°C on the tablet bed, the coating agent had good properties, but the dissolution of the two coating agents was about 97% at 45min, and they were not completely dissolved. After the HMPC 75% ethanol water coating was applied at 40-45°C on the tablet bed, the coating agent had good properties, and its dissolution reached 99.5% and approached 100% at 45min. Comparative Example 2, HMPC water coating, had the problem of sticking to the tablet at 30-35°C; Comparative Example 4 used anhydrous ethanol coating, resulting in uneven tablet surface; Comparative Example 5 used anhydrous propanol coating, the coating material could not be dissolved, blocked the nozzle, and could not be coated smoothly; Comparative Example 6 used anhydrous isopropanol coating, resulting in uneven tablet surface; Comparative Example 7 used anhydrous methanol coating, and the viscosity of the coating liquid was too high, resulting in uneven tablet surface. At the same time, the inventor reduced the concentration of the solid content, such as Comparative Example 8, which still did not solve the problem of rough tablet surface. Therefore, for the present invention, the influence of solid content is small, and whether the organic solvent contains water has a greater influence on the properties of the tablet. The use of a water-containing organic solvent in Example 6 of the present application can solve the problems of low solubility and uneven tablet surface.

[0090] Test Example 2 Investigation of Factors Affecting Stability

[0091] By conducting influencing factor tests (high temperature 60°C, high humidity 75% RH, high temperature and high humidity 60°C + 72.5% RH) on the bare chip of the comparative example 1 sample, the related substances, mutagenic impurity AFP-PMA, moisture, and solubility were used as evaluation indicators.

[0092]

[0093] Results: The study showed that the key quality attributes (related substances, AFP-PMA impurities, moisture, and solubility) of the formulation samples of Comparative Example 1 changed significantly under high temperature and high humidity conditions. Regorafenib coated tablets containing PVA film coating premix were unstable under high temperature and high humidity conditions.

[0094] Test Example 3 Stability Test

[0095] The sample bare chips prepared in Comparative Example 2 and Example 6 were placed in a constant temperature and humidity chamber (60±2°C, 75±5%RH) for 12h, 24h, and 48h to investigate the influencing factors and investigate the growth of key indicators of mutagenic impurities.

[0096]

[0097]

[0098] Conclusion: Through the investigation of influencing factors, compared with HPMC water coating, the growth of mutagenic impurities in products obtained by HPMC 75% ethanol coating is more advantageous in the short term, especially with the extension of storage time, the growth rate of mutagenic impurities in the process of HPMC water coating is faster than that of aqueous organic solvent coating.

Claims

1. A regorafenib coated tablet, characterized in that: The regorafenib coated tablets are regorafenib tablet cores coated with a film coating material containing hydroxypropyl methylcellulose (HPMC), wherein the coating is obtained through a coating process, during which the film coating material containing hydroxypropyl methylcellulose (HPMC) is dispersed in an aqueous organic solvent.

2. The regorafenib coated tablet according to claim 1, characterized in that: The tablet bed temperature during the coating process is ≤45°C.

3. The regorafenib coated tablet according to claim 1, characterized in that: The organic solvent comprises ethanol, methanol, acetone, isopropanol, diacetone alcohol, and preferably the organic solvent is ethanol or acetone.

4. The regorafenib coated tablet according to claim 1, characterized in that: The concentration of the aqueous organic solvent is 20-95% (v / v).

5. The regorafenib coated tablet according to claim 1, characterized in that: The viscosity of the HPMC is 4-8 mPa·S, or the mass of the HPMC in the film coating material is 30-80%, preferably 40-75%.

6. The regorafenib coated tablet according to claim 1, characterized in that: The film coating material containing hydroxypropyl methylcellulose (HPMC) is dispersed in an aqueous organic solvent to obtain a coating solution, wherein the solid content or concentration of the coating solution is 5-15%.

7. The regorafenib coated tablet according to any one of claims 1 to 6, characterized in that: The film coating material containing hydroxypropyl methylcellulose (HPMC) further comprises one or more of a plasticizer, a colorant, a sunscreen, an anti-adhesive agent, and a pore-forming agent; Or preferably, the plasticizer includes one or more of polyethylene glycol, propylene glycol, glycerol, maltitol, xylitol, mannitol, erythritol, triolein, tributyl citrate, triethyl citrate, acetylcitrate triethyl, triacetin, stearic acid, triacetin, acetylated glyceride, and phthalate; preferably, the plasticizer includes polyethylene glycol, and preferably the plasticizer accounts for 5-25% of the mass of the film coating material, preferably 10-20%; Or preferably, the colorant accounts for 2-30% by mass of the film coating material, preferably 5-20%; preferably, the colorant comprises one or more of red iron oxide, yellow iron oxide, black iron oxide, sunset yellow, anthocyanin, preferably one or more of red iron oxide, yellow iron oxide, black iron oxide; Or preferably, the sunscreen agent accounts for 5-30% by mass of the film coating material, preferably 15-25%; preferably, the sunscreen agent comprises titanium dioxide and / or talc, preferably titanium dioxide; Or preferably, the anti-adhesive agent comprises one or more of talc, magnesium stearate, stearic acid, lecithin, soybean lecithin, mineral oil, polysorbate, which accounts for 0-25% by weight of the film coating material, preferably 0-20%; Alternatively, the porogen preferably comprises one or more of polyethylene glycol, sucrose, sodium chloride and a surfactant, preferably polyethylene glycol.

8. The regorafenib coated tablet according to claim 7, characterized in that: The regorafenib core tablet contains regorafenib and pharmaceutically acceptable excipients; Preferably, the excipients include one or more of a dispersing matrix agent, a disintegrant, a filler, a binder, a lubricant, and a glidant; Preferably, the regorafenib tablet core contains 5.0-15.0% by weight of regorafenib, 18.0-30.0% by weight of filler, 30.0-40.0% by weight of disintegrant, 30.0-40.0% by weight of dispersant, 0.1-1.0% by weight of glidant, and 0.1-1.0% by weight of lubricant; preferably, the regorafenib tablet core contains 8.70% by weight of regorafenib, 21.74% by weight of filler, 33.48% by weight of disintegrant, 34.78% by weight of dispersant, 0.52% by weight of glidant, and 0.78% by weight of lubricant; Preferably, the dispersing matrix comprises polyvinyl pyrrolidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyoxyethylene, etc., and polyvinyl pyrrolidone is preferably used as the dispersing matrix; Preferably, the disintegrant comprises one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and starch; preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose; Preferably, the filler comprises one or more of microcrystalline cellulose, lactose, dextrin, and pregelatinized starch; preferably, the filler is microcrystalline cellulose; Preferably, the lubricant comprises one or more of magnesium stearate, sodium fumarate stearate, and hydrogenated vegetable oil, and preferably the lubricant is magnesium stearate; Preferably, the glidant comprises one or more of colloidal silicon dioxide, silicon dioxide, and talc, and preferably the glidant is colloidal silicon dioxide.

9. The regorafenib coated tablet according to claim 8, characterized in that: The weight gain of the coating is 1.0%-4.0%, preferably 2.0-3.0%.

10. The method for preparing the regorafenib coated tablets according to any one of claims 1 to 9, characterized in that: The coating process comprises the following steps: (1) dispersing a film coating material containing hydroxypropyl methylcellulose (HPMC) into an aqueous organic solvent to prepare a coating solution with a certain solid content; (2) Coating pan coating, air inlet temperature 40~70℃, air volume 50~90m 3 / h, peristaltic pump speed 1~15rpm, coating pan speed 5~25rpm; (3) controlling the tablet bed temperature to ≤45°C, more preferably 35-45°C, and coating the regorafenib tablet cores; (4) Stop coating when the coating weight gain is 1.0% to 4.0%; Preferably, the invention also includes a method for preparing a tablet core, wherein the tablet core preparation process comprises the following steps: Step A: fluidized bed granulation: dissolving the regorafenib API and the dispersing matrix in a dispersing solvent, stirring until a clear solution is obtained; spraying the solution onto a mixture of a filler and a portion of a disintegrant in a fluidized bed granulator, controlling the material temperature at 20-40° C.; drying until the moisture content is less than 3.0%, and discharging the material to obtain granules; Step B: Dry granulation: The granules in step A are sieved at multiple stages, crushed to obtain dry granules, and mixed with the remaining disintegrant, glidant and lubricant; Step C: compressing regorafenib tablet cores; Preferably, the dispersing solvent in step A is a mixed solution of acetone and ethanol, and preferably the volume ratio of acetone to ethanol is 2-6:1.

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