Regorafenib tablets and preparation method thereof

Abstract

The present invention relates to the technical field of medical, dental or cosmetic preparations, and in particular to a regorafenib tablet and a preparation method thereof. The regorafenib tablet comprises the following raw materials in parts by weight: 40 to 160 parts of coated regorafenib, 50 to 300 parts of a diluent, 50 to 200 parts of a disintegrant, 20 to 400 parts of an adhesive, 1 to 8 parts of a lubricant, and 1 to 50 parts of a coating material. The present invention also provides a preparation method thereof. Compared with the prior art, the regorafenib tablet prepared by the present invention has the advantages of stable properties, high bioavailability, and a sustained release effect.

Description

Technical Field

[0001] The present invention relates to the technical field of medical, dental or cosmetic preparations, and in particular to a regorafenib tablet and a preparation method thereof. Background Art

[0002] Cancer has a serious impact on human health. However, most traditional anti-tumor drugs have problems such as poor selectivity and strong side effects, while emerging single-target drugs are prone to drug resistance. In addition, since the biological behavior of most tumors is jointly exerted by multiple signal transduction pathways, it is generally believed that molecular targeted therapy targeting multiple targets will achieve better therapeutic effects. Regorafenib tablets are an oral multi-target phosphokinase inhibitor developed by Bayer Pharmaceuticals. Its targeting effects involve multiple protein kinases involved in tumor angiogenesis and tumor cell proliferation, including: (1) vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and tyrosine protein kinase receptor-2 (Tie-2) related to tumor angiogenesis; (2) proto-oncogene c-Kit, tyrosine protein kinase receptor RET, proto-oncogene c-RAF, serine / threonine protein kinase B (BRAF), and mitogen-activated protein (MAP) kinase p38 related to tumor cell proliferation; (3) platelet derived growth factor receptor-β (PDGFR-β) and fibroblast growth factor receptor-1 (FG-FR-1) related to the tumor microenvironment. Regorafenib blocks and inhibits the activity of the above-mentioned kinases, exerting multiple anti-tumor effects such as blocking tumor angiogenesis, inhibiting tumor cell proliferation, and anti-tumor immune escape.

[0003] Since multi-target kinase inhibitors can simultaneously inhibit or block multiple cell growth signal transduction pathways, they have become a hot spot for tumor treatment and new drug development. Star products of multi-target kinase inhibitors similar to regorafenib tablets include Novartis's Gleevec (imatinib), Zhengda Tianqing's Genike (imatinib), Pfizer's Sutent (sunitinib), Bayer's Nexavar (sorafenib), etc. However, the activity characteristics of regorafenib are significantly different from other multi-kinase inhibitors including sorafenib and axitinib. Its targets are more comprehensive and the range of targeted kinases is wider. At the same time, compared with other monoclonal antibody targeted therapeutic drugs for colorectal cancer, the small molecule structure of regorafenib can enter the cell membrane and exert an anti-tumor effect.

[0004] CN202010787157.9 discloses a cocrystal of regorafenib and maleic acid and a preparation method thereof. The molar ratio of regorafenib to maleic acid in the cocrystal is 1:1, and the X-ray powder diffraction pattern of the cocrystal has characteristic peaks at 2theta values ​​of 5.9±0.2°, 9.6±0.2°, 11.6±0.2°, 12.4±0.2°, 21.3±0.2°, and 25.6±0.2°. The cocrystal preparation method provided by the invention is simple in process, the crystallization process is easy to control, the reproducibility is good, and it is suitable for industrial production. This cocrystal has a higher apparent solubility than regorafenib monohydrate, which is beneficial to improve the oral absorption efficiency of regorafenib.

[0005] CN202110272946.3 relates to the field of nanopharmaceutical technology, and specifically discloses composite particles, preparation methods and applications thereof. Composite particles include regorafenib and amphiphilic molecules, and the two are combined by intermolecular forces. The method for preparing composite particles comprises the following steps: regorafenib is dissolved in dimethyl sulfoxide to obtain solution I; the amphiphilic molecule drug is dissolved in water to obtain solution II; solution I and solution II are mixed to obtain nanoparticles; the obtained nanoparticles are centrifuged and washed and then resuspended and freeze-dried. This invention does not require the introduction of external carriers, which greatly reduces potential toxic side effects; regorafenib nanomedicine can not only increase the circulation time of the drug in the blood, improve the utilization rate of the drug, but also increase the enrichment of the drug at the tumor site.

[0006] Due to the limited solubility of regorafenib, the existing drug delivery forms have low dissolution of active ingredients, low bioavailability, and difficult dosage form preparation. Therefore, from the perspective of formulation, developing a regorafenib tablet with high dissolution of active ingredients and good bioavailability will further improve product quality and reduce production costs, which will have greater market value. Summary of the invention

[0007] In view of the above-mentioned defects in the prior art, the technical problem to be solved by the present invention is to provide a regorafenib tablet and a preparation method thereof.

[0008] The chemical structure of Regorafenib is a fat-soluble macromolecule, with no hydrophilic group in the structure, almost insoluble in water, and belongs to BCSII class drugs, i.e. low solubility and high permeability. The solubility of such drugs is low, and the dissolution of drugs is the rate-limiting process of absorption. The oral bioavailability of generally poorly soluble drugs is low, so it will greatly affect the efficacy of the drug. The structure of Regorafenib mainly includes urea, benzene ring, pyridine ring, ether bond, amide bond, and the molecular structure is very stable, but the nitrogen on the pyridine ring may generate nitrogen oxide degradation impurities under oxidation conditions, so it is necessary to pay attention to its stability. The present invention provides an amphiphilic cyclic macromolecule having both hydrophilic and lipophilic groups, the hydrophobic cavity having which can fix the drug in the ring through hydrophobic and van der Waals forces, and the outermost lipophilic group can give the cyclic molecule good membrane permeability, so the cyclic macromolecule is used to coat Regorafenib, which can achieve sustained release of the drug, and improve the membrane permeability and molecular stability of the drug, thereby solving the defect of low bioavailability and controlling the risk of degradation. In addition, when the cyclic macromolecule provided by the present invention mainly uses biological raw materials protocatechuic aldehyde and catechol, since the raw materials have good biocompatibility, no additional side effects will be generated.

[0009] To achieve the above-mentioned object, the present invention provides a regorafenib tablet, comprising the following raw materials in parts by weight: 40 to 160 parts of coated regorafenib, 50 to 300 parts of a diluent, 50 to 200 parts of a disintegrant, 20 to 400 parts of a binder, 1 to 8 parts of a lubricant and 1 to 50 parts of a coating material.

[0010] Furthermore, the diluent is selected from one of starch, cyclodextrin and microcrystalline cellulose.

[0011] Furthermore, the disintegrant is selected from sodium carboxymethyl starch, sodium starch glycolate, and sodium carboxymethyl cellulose.

[0012] Furthermore, the adhesive is polyvinyl pyrrolidone.

[0013] Furthermore, the lubricant is selected from one of magnesium stearate, talc and stearic acid.

[0014] Furthermore, the coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution, and the mass ratio is 1-80:0.5-15:0.1-20:1-5:1-3:1-3:500-1000.

[0015] The method for preparing the coated regorafenib comprises the following steps:

[0016] X1. Add benzaldehyde compounds and potassium carbonate to N,N-dimethylformamide, heat to 50-60°C, stir for 0.5-1h, then add 1-chlorodecane, the molar ratio of benzaldehyde compounds to potassium carbonate and 1-chlorodecane is 1:1-1.5:1-3, heat to 70-80°C and stir for 8-12h, cool to room temperature after stirring, add water and then extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and then purify it by column for the next step;

[0017] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1-2:0.01-0.02. Heat to 70-80°C and stir for 18-28 hours, then cool to room temperature. A precipitate is precipitated. Filter it, wash the residue with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry it for the next step.

[0018] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step to regorafenib and cholesterol is 2-3:1:1, and the volume ratio of methanol and chloroform is 4-5:6. After rotating the mixture until dry, add buffer solution, hydrate at 35-45°C for 0.5-1h, and obtain the mixture by ultrasonic dispersion and freeze-drying.

[0019] Preferably, the benzaldehyde compound is at least one of protocatechuic aldehyde, p-hydroxybenzaldehyde and 3-methyl-4-hydroxybenzaldehyde.

[0020] A method for preparing regorafenib tablets comprises the following steps:

[0021] S1. After the diluent and disintegrant are evenly mixed, the coated regorafenib is added and mixed to obtain a mixture;

[0022] S2, mixing the mixed material with the binder, performing wet granulation, and drying at 50-60° C. until the moisture content is less than 5%;

[0023] S3, mixing the granules obtained after granulation with a lubricant, and tableting to obtain a tablet core;

[0024] S4. Mix the raw materials in the coating material to obtain a coating solution, and then coat the tablet core to obtain regorafenib tablets.

[0025] Furthermore, the coating material is added in an amount of 1 to 4 wt % of the tablet core.

[0026] Furthermore, the coating temperature is 40-60°C.

[0027] Beneficial effects of the present invention:

[0028] 1. Compared with the prior art, the regorafenib tablets prepared by the present invention have the advantages of stable properties, high bioavailability, and sustained release effect.

[0029] 2. The present invention coats regorafenib with cyclic macromolecules to achieve sustained release of the drug and improve the membrane permeability and molecular stability of the drug, thereby solving the defect of low bioavailability and controlling the risk of degradation. DETAILED DESCRIPTION

[0030] Microcrystalline cellulose, 200 mesh.

[0031] Sodium carboxymethyl cellulose, 100 mesh.

[0032] Polyvinyl pyrrolidone, model: K25, Chongqing Steckreidenmeier Materials.

[0033] PBS buffer, pH=7.

[0034] Polyethylene glycol, model: PEG-6000, Zhengzhou Yanheng Chemical.

[0035] Concentrated sulfuric acid, 98wt%.

[0036] A method for preparing coated regorafenib comprises the following steps:

[0037] X1. Add benzaldehyde compounds and potassium carbonate to N,N-dimethylformamide, heat to 50-60°C, stir for 0.5-1h, then add 1-chlorodecane, the molar ratio of benzaldehyde compounds to potassium carbonate and 1-chlorodecane is 1:1-1.5:1-3, heat to 70-80°C and stir for 8-12h, cool to room temperature after stirring, add water and then extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and then purify it by column for the next step;

[0038] During the preparation process, a heating mixing reaction is first carried out, and benzaldehyde compounds and potassium carbonate are added to N,N-dimethylformamide. The heating reaction is not only conducive to the dissolution of potassium carbonate, but also promotes the reaction. Under the conditions of heating and stirring, the reaction produces intermediates, which form precursors of regorafenib when reacting with 1-chlorodecane. Next, the unreacted residues and target products in the organic phase are extracted by extraction with n-hexane. After separation and concentration of the organic phase, a reaction product with higher purity is obtained by column purification;

[0039] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1-2:0.01-0.02. Heat to 70-80°C and stir for 18-28 hours, then cool to room temperature. A precipitate is precipitated. Filter it, wash the residue with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry it for the next step.

[0040] The product obtained in the previous step reacts with catechol and concentrated sulfuric acid to form a precipitate, which is then separated by filtration and then washed with water, a saturated sodium bicarbonate aqueous solution and brine to remove reaction residues and impure substances and improve the purity of the product;

[0041] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform, wherein the mass ratio of the product of the previous step to regorafenib and cholesterol is 2-3:1:1, and the volume ratio of methanol to chloroform is 4-5:6. After the mixture is rotated to dryness, a buffer solution is added, and the mixture is hydrated at 35-45°C for 0.5-1h. After ultrasonic dispersion, the mixture is freeze-dried to obtain the mixture.

[0042] The product obtained in the previous step is mixed with regorafenib and cholesterol to form coated regorafenib, which plays an important role in the subsequent drug release and stability. Next, after hydration and ultrasonic dispersion in a mixture of methanol and chloroform, a freeze-drying step is performed. This process helps to form a uniformly coated regorafenib and improve the stability and efficacy of subsequent tablets. During the freeze-drying process, the water is frozen and removed, which helps to maintain the integrity and stability of the coating while retaining the active ingredients of regorafenib and other drugs;

[0043] The benzaldehyde compound is at least one of protocatechuic aldehyde, p-hydroxybenzaldehyde and 3-methyl-4-hydroxybenzaldehyde. The benzaldehyde compound reacts with potassium carbonate in N,N-dimethylformamide to form a carboxylate intermediate. This intermediate then undergoes a nucleophilic substitution reaction with 1-chlorodecane to produce an alkylated product. These alkylated products play a key role in the subsequent formation of a precursor coated with regorafenib.

[0044] A regorafenib tablet, comprising the following raw materials in parts by weight: 40 to 160 parts of the coated regorafenib, 50 to 300 parts of a diluent, 50 to 200 parts of a disintegrant, 20 to 400 parts of a binder, 1 to 8 parts of a lubricant, and 1 to 50 parts of a coating material;

[0045] The diluent is selected from one of starch, cyclodextrin and microcrystalline cellulose;

[0046] The disintegrant is selected from sodium carboxymethyl starch, sodium starch glycolate, and sodium carboxymethyl cellulose;

[0047] The adhesive is polyvinyl pyrrolidone;

[0048] The lubricant is selected from one of magnesium stearate, talc and stearic acid;

[0049] The coating material comprises hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution, and the mass ratio is 1-80:0.5-15:0.1-20:1-5:1-3:1-3:500-1000.

[0050] In the process of preparing regorafenib tablets, each raw material plays a different role. First of all, as a drug ingredient, the coated regorafenib undertakes the important task of providing drug efficacy. The diluent is used to adjust the concentration of the drug so that it is suitable for tablet making, thereby ensuring the safe and effective use of the drug. The role of the disintegrant is to help the tablets disintegrate rapidly in the gastrointestinal tract and release the drug for absorption in the body. The binder plays the role of bonding the various components in the tablet to ensure the integrity of the shape and structure of the tablet. The addition of lubricants can reduce the friction of the tablets during the preparation and packaging process and maintain the smoothness of the tablet surface. The coating material is used to coat the tablets, which not only protects the drug from the influence of the external environment and improves the taste, but also slows down the release rate of the drug, improves the stability of the tablets, and ensures the durability of the drug effect.

[0051] The preparation method of the regorafenib tablets comprises the following steps:

[0052] S1. After the diluent and disintegrant are evenly mixed, the coated regorafenib is added and mixed to obtain a mixture;

[0053] S2, mixing the mixed material with the binder, performing wet granulation, and drying at 50-60° C. until the moisture content is less than 5%;

[0054] S3, mixing the granules obtained after granulation with a lubricant, and tableting to obtain a tablet core;

[0055] S4, mixing the raw materials in the coating material to obtain a coating solution, and then coating the tablet core to obtain regorafenib tablets;

[0056] The coating material is added in an amount of 1 to 4 wt % of the tablet core.

[0057] The coating temperature is 40-60°C.

[0058] Benzaldehyde compounds are used as starting materials. They are carboxylated in the presence of N,N-dimethylformamide as a medium and potassium carbonate. The resulting carboxylates undergo nucleophilic substitution with 1-chlorodecane to obtain the corresponding alkylated products. After extraction with n-hexane and further separation, they are used in the next step. In the next step, acetic acid is used as a solvent and a medium, and concentrated sulfuric acid is used as a catalyst to promote the reaction. Catechol is another raw material. It is more nucleophilic under the activation of concentrated sulfuric acid and thus replaces the product of the previous step to finally obtain a cyclic product. Water and saturated sodium bicarbonate aqueous solution are used to wash the solid product after the reaction in post-treatment. Sodium bicarbonate can neutralize the residual acid, and water helps dissolve and remove impurities. Regorafenib is used as the target compound. It forms a coating structure with the cyclic product of the previous step and cholesterol in the presence of methanol and chloroform as a medium. Cholesterol, as a stabilizer or auxiliary component, may help form a stable coating structure. PBS buffer is used as a hydration medium for further hydration, and then ultrasonic dispersion is used to help form a uniform dispersion system to improve the coating efficiency. Freeze drying is the process of removing the solvent from the solution to obtain dry coated regorafenib.

[0059] Comparative Example 1

[0060] A method for preparing regorafenib tablets comprises the following steps:

[0061] S1. Mix 100 g of microcrystalline cellulose and 150 g of sodium carboxymethyl cellulose evenly, and then add 40 g of regorafenib to obtain a mixture;

[0062] S2, mixing the mixture with 150 g of polyvinyl pyrrolidone, performing wet granulation, and drying at 55° C. to a moisture content of 4%;

[0063] S3, mixing the granules obtained after granulation with 5 g of magnesium stearate, and tableting to obtain a tablet core;

[0064] S4. After mixing the raw materials in the coating material to obtain the coating solution, the tablet core is coated at a coating temperature of 40°C to obtain regorafenib tablets. The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution in a mass ratio of 5:10:2:1:1:1:500. The amount of coating material added is 4wt% of the tablet core.

[0065] Example 1

[0066] A method for preparing regorafenib tablets comprises the following steps:

[0067] S1. Mix 100 g of microcrystalline cellulose and 150 g of sodium carboxymethyl cellulose evenly, and then add 160 g of the coated regorafenib to obtain a mixture;

[0068] S2, mixing the mixture with 150 g of polyvinyl pyrrolidone, performing wet granulation, and drying at 55° C. to a moisture content of 4%;

[0069] S3, mixing the granules obtained after granulation with 5 g of magnesium stearate, and tableting to obtain a tablet core;

[0070] S4. After mixing the raw materials in the coating material to obtain the coating solution, the tablet core is coated at a coating temperature of 40°C to obtain regorafenib tablets. The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution in a mass ratio of 5:10:2:1:1:1:500. The amount of coating material added is 4wt% of the tablet core.

[0071] The method for preparing the coated regorafenib comprises the following steps:

[0072] X1. Add protocatechuic aldehyde and potassium carbonate to N,N-dimethylformamide, heat to 50°C, stir for 0.5h, then add 1-chlorodecane, the molar ratio of protocatechuic aldehyde to potassium carbonate and 1-chlorodecane is 1:1:2, heat to 80°C and stir for 10h, cool to room temperature after stirring, add water and extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and purify it by column for the next step;

[0073] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1:0.01. Heat to 80°C and stir for 20 hours, then cool to room temperature. A precipitate is precipitated. Filter the residue, wash with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry for the next step.

[0074] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step, regorafenib and cholesterol is 2:1:1, and the volume ratio of methanol and chloroform is 4:6. After rotating the mixture until dry, add PBS buffer, hydrate at 40°C for 0.5h, and obtain the mixture by ultrasonic dispersion at 400W and 45kHz, followed by freeze-drying.

[0075] Example 2

[0076] A method for preparing regorafenib tablets comprises the following steps:

[0077] S1. Mix 100 g of microcrystalline cellulose and 150 g of sodium carboxymethyl cellulose evenly, and then add 160 g of the coated regorafenib to obtain a mixture;

[0078] S2, mixing the mixture with 150 g of polyvinyl pyrrolidone, performing wet granulation, and drying at 55° C. to a moisture content of 4%;

[0079] S3, mixing the granules obtained after granulation with 5 g of magnesium stearate, and tableting to obtain a tablet core;

[0080] S4. After mixing the raw materials in the coating material to obtain the coating solution, the tablet core is coated at a coating temperature of 40°C to obtain regorafenib tablets. The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution in a mass ratio of 5:10:2:1:1:1:500. The amount of coating material added is 4wt% of the tablet core.

[0081] The method for preparing the coated regorafenib comprises the following steps:

[0082] X1. Add p-hydroxybenzaldehyde and potassium carbonate to N,N-dimethylformamide, heat to 50°C, stir for 0.5h, then add 1-chlorodecane, the molar ratio of p-hydroxybenzaldehyde to potassium carbonate and 1-chlorodecane is 1:1:2, heat to 80°C and stir for 10h, cool to room temperature after stirring, add water and extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and purify it by column for the next step;

[0083] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1:0.01. Heat to 80°C and stir for 20 hours, then cool to room temperature. A precipitate is precipitated. Filter the residue, wash with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry for the next step.

[0084] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step, regorafenib and cholesterol is 2:1:1, and the volume ratio of methanol and chloroform is 4:6. After rotating the mixture until dry, add PBS buffer, hydrate at 40°C for 0.5h, and obtain the mixture by ultrasonic dispersion at 400W and 45kHz, followed by freeze-drying.

[0085] Example 3

[0086] A method for preparing regorafenib tablets comprises the following steps:

[0087] S1. Mix 100 g of microcrystalline cellulose and 150 g of sodium carboxymethyl cellulose evenly, and then add 160 g of the coated regorafenib to obtain a mixture;

[0088] S2, mixing the mixture with 150 g of polyvinyl pyrrolidone, performing wet granulation, and drying at 55° C. to a moisture content of 4%;

[0089] S3, mixing the granules obtained after granulation with 5 g of magnesium stearate, and tableting to obtain a tablet core;

[0090] S4. After mixing the raw materials in the coating material to obtain the coating solution, the tablet core is coated at a coating temperature of 40°C to obtain regorafenib tablets. The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution in a mass ratio of 5:10:2:1:1:1:500. The amount of coating material added is 4wt% of the tablet core.

[0091] The method for preparing the coated regorafenib comprises the following steps:

[0092] X1. Add 3-methyl-4-hydroxybenzaldehyde and potassium carbonate to N,N-dimethylformamide, heat to 50°C, stir for 0.5h, then add 1-chlorodecane, the molar ratio of 3-methyl-4-hydroxybenzaldehyde to potassium carbonate and 1-chlorodecane is 1:1:2, heat to 80°C and stir for 10h, cool to room temperature after stirring, add water and extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and then purify it by column for the next step;

[0093] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1:0.01. Heat to 80°C and stir for 20 hours, then cool to room temperature. A precipitate is precipitated. Filter the residue, wash with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry for the next step.

[0094] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step, regorafenib and cholesterol is 2:1:1, and the volume ratio of methanol and chloroform is 4:6. After rotating the mixture until dry, add PBS buffer, hydrate at 40°C for 0.5h, and obtain the mixture by ultrasonic dispersion at 400W and 45kHz, followed by freeze-drying.

[0095] Example 4

[0096] A method for preparing regorafenib tablets comprises the following steps:

[0097] S1. Mix 100 g of microcrystalline cellulose and 150 g of sodium carboxymethyl cellulose evenly, and then add 160 g of the coated regorafenib to obtain a mixture;

[0098] S2, mixing the mixture with 150 g of polyvinyl pyrrolidone, performing wet granulation, and drying at 55° C. to a moisture content of 4%;

[0099] S3, mixing the granules obtained after granulation with 5 g of magnesium stearate, and tableting to obtain a tablet core;

[0100] S4. After mixing the raw materials in the coating material to obtain the coating solution, the tablet core is coated at a coating temperature of 40°C to obtain regorafenib tablets. The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution in a mass ratio of 5:10:2:1:1:1:500. The amount of coating material added is 4wt% of the tablet core.

[0101] The method for preparing the coated regorafenib comprises the following steps:

[0102] X1. Add p-hydroxybenzaldehyde and potassium carbonate to N,N-dimethylformamide, heat to 50°C, stir for 0.5h, then add tetradecane bromide, the molar ratio of p-hydroxybenzaldehyde to potassium carbonate and tetradecane bromide is 1:1:2, heat to 80°C and stir for 10h, cool to room temperature after stirring, add water and extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and purify it by column for the next step;

[0103] X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1:0.01. Heat to 80°C and stir for 20 hours, then cool to room temperature. A precipitate is precipitated. Filter the residue, wash with water, saturated sodium bicarbonate aqueous solution, and brine, and then dry for the next step.

[0104] X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step, regorafenib and cholesterol is 2:1:1, and the volume ratio of methanol and chloroform is 4:6. After rotating the mixture until dry, add PBS buffer, hydrate at 40°C for 0.5h, and obtain the mixture by ultrasonic dispersion at 400W and 45kHz, followed by freeze-drying.

[0105] Test Example 1

[0106] After mixing 50 mL of PBS buffer with 20 mg of regorafenib tablets prepared in the control example and the example, shake at 37°C. Take another 50 mL of PBS buffer and shake under the same conditions. After the sample is dissolved, take out the sample at 1, 4, 8, 10, and 14 hours, respectively, and detect the samples taken out at different times with a UV spectrophotometer, and calculate the cumulative release rate (%) of regorafenib. The experiment sets 3 parallel tests and takes the average value.

[0107] Table 1 Results of in vitro release experiment of regorafenib

[0108]

[0109]

[0110] It can be seen from the in vitro release test that compared with the uncoated regorafenib tablets in Control Example 1, the examples all have better sustained-release effects. This is because the hydrophobic cavity of the amphiphilic cyclic macromolecule prepared in the examples fixes regorafenib in the ring through hydrophobic and van der Waals forces, thereby achieving sustained release of the drug. This sustained-release effect can maintain the efficacy of the drug for a longer time, thereby improving the therapeutic effect of the drug.

[0111] Test Example 2

[0112] Five-week-old female BABL / c mice were selected to construct the CT26 tumor-bearing mouse model, with a tumor volume of 300 mm 3 At 10 days, there were 3 mice in each group. Each group was orally treated with 10 mg / kg of regorafenib tablets. The survival status of the mice was observed on day 0 and 10 days. The mice were killed on day 10, and the tumor weight was measured. The tumor inhibition rate was calculated. Tumor inhibition rate = (1-average tumor weight of the treatment group / average tumor weight of the control group) × 100%.

[0113] Table 2 Anti-tumor test results of Regorafenib tablets

[0114] Experimental protocol Tumor inhibition rate / % Comparative Example 1 36.85 Example 1 75.13 Example 2 60.81 Example 3 61.07 Example 4 60.94

[0115] The chemical structure of Regorafenib is a fat-soluble macromolecule, with no hydrophilic group in the structure, and is almost insoluble in water. It belongs to BCS II class drugs, i.e., low solubility and high permeability. The solubility of such drugs is low, and the dissolution of the drug is the rate-limiting process of absorption. The oral bioavailability of generally poorly soluble drugs is low, so it will greatly affect the efficacy of the drug. From the anti-tumor test, it can be seen that the Regorafenib tablets prepared by the present invention have a certain inhibitory effect on tumors, and the anti-tumor effect of the embodiment is better than that of the control example 1. Due to the poor water solubility of Regorafenib, its bioavailability is low, resulting in poor anti-tumor effect, while the effect of inhibiting tumors in the embodiment is significantly better, which may be due to the fact that compared with the uncoated Regorafenib, the coated Regorafenib has a longer release time, so the anti-tumor effect is longer. The embodiment provides an amphiphilic cyclic macromolecule having both hydrophilic and lipophilic groups, the hydrophobic cavity of which can fix the drug in the ring through hydrophobic and van der Waals forces, and the outermost lipophilic group can give the cyclic molecule good membrane permeability, so the cyclic macromolecule is used to coat regorafenib, which can achieve sustained release of the drug and improve the membrane permeability and molecular stability of the drug, thereby solving the defect of low bioavailability, and thus achieving a better effect of controlling tumor growth. The biological raw materials used in Example 1 include protocatechuic aldehyde and catechol, among which protocatechuic aldehyde has more hydroxyl groups than p-hydroxybenzaldehyde in Examples 2 and 4 and 3-methyl-4-hydroxybenzaldehyde in Example 3, so more hydrophobic alkyl chains can be grafted during alkylation, which is beneficial to improving the lipophilicity of the cyclic carrier, resulting in the obtained cyclic macromolecule having better lipophilicity, so the membrane permeability of the coated regorafenib is improved, and the efficacy is better than that of other embodiments. In addition, the cyclic macromolecule provided in Example 1 mainly uses biological raw materials including protocatechuic aldehyde and catechol, etc., so it has good biocompatibility and will not cause additional side effects.

[0116] Test Example 3

[0117] The regorafenib tablets obtained in this example were placed at 40° C. and under light for 7 days for stability study. The specific data are shown in Table 3.

[0118] Table 3 Stability test of regorafenib tablets

[0119]

[0120]

[0121] The structure of Regorafenib mainly includes urea, benzene ring, pyridine ring, ether bond, and amide bond. The molecular structure is very stable, but the nitrogen on the pyridine ring may generate nitrogen oxide degradation impurities under oxidation conditions, so its stability needs to be paid attention to. Under light, Regorafenib may be excited under ultraviolet light to undergo photochemical reactions to produce oxidative degradation. High temperature can also increase molecular motion, thereby increasing the possibility of oxidation reactions. It can be seen from the stability test that compared with the uncoated Regorafenib tablets in Control Example 1, the embodiment obviously has better stability, indicating that the Regorafenib tablets prepared by the present invention are stable to light and heat temperatures, and the resulting tablets are stable and conducive to storage and transportation. Compared with other embodiments, Example 1 has the lowest nitrogen oxides, single impurities and total impurities. This may be because the protocatechuic aldehyde used in Example 1 has more hydroxyl groups than p-hydroxybenzaldehyde in Examples 2 and 4 and 3-methyl-4-hydroxybenzaldehyde in Example 3. Therefore, more hydrophobic alkyl chains can be grafted during alkylation. These hydrophobic alkyl chains on the surface of the cyclic macromolecule can not only improve the membrane permeability, but also well inhibit the aggregation between the coated regorafenib. Aggregation may not only cause leakage of the coated drug but also affect its sustained release effect, and provide more interaction points for the drug, thereby increasing the risk of drug degradation. In Example 1, since the aggregation between the coated regorafenib is well avoided, the stability is relatively better and the impurities are therefore less. It can be seen from the results of the test examples of the present invention that protocatechuic aldehyde shows obvious advantages over p-hydroxybenzaldehyde and 3-methyl-4-hydroxybenzaldehyde, which is related to the characteristics of its chemical structure. The structure of protocatechuic aldehyde contains two hydroxyl groups (-OH), which play an important role in the subsequent alkylation. When there are more hydroxyl groups, there will be more alkyl chains grafted to it. The grafted alkyl chains, as lipophilic groups, can greatly improve the membrane permeability of the coating, thereby improving the bioavailability of regorafenib.

[0122] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A regorafenib tablet, characterized in that: The invention comprises the following raw materials in parts by weight: 40 to 160 parts of coated regorafenib, 50 to 300 parts of diluent, 50 to 200 parts of disintegrant, 20 to 400 parts of binder, 1 to 8 parts of lubricant and 1 to 50 parts of coating material; the preparation method of the coated regorafenib comprises the following steps: X1. Add benzaldehyde compounds and potassium carbonate to N,N-dimethylformamide, heat to 50-60°C, stir for 0.5-1h, then add 1-chlorodecane, the molar ratio of benzaldehyde compounds to potassium carbonate and 1-chlorodecane is 1:1-1.5:1-3, heat to 70-80°C and stir for 8-12h, cool to room temperature after stirring, add water and then extract with n-hexane, separate the liquids, concentrate the organic phase to remove the solvent and then purify it by column for the next step; X2. Add the product of the previous step and catechol to acetic acid, and then add concentrated sulfuric acid. The molar ratio of the product of the previous step to catechol and concentrated sulfuric acid is 1:1~2:0.01~0.

02. Heat to 70~80°C and stir for 18~28h, then cool to room temperature. A precipitate is precipitated. Filter it, wash the residue with water, saturated sodium bicarbonate aqueous solution and brine, and then dry it for the next step. X3. Add the product of the previous step, regorafenib and cholesterol to a mixture of methanol and chloroform. The mass ratio of the product of the previous step, regorafenib and cholesterol is 2-3:1:1, and the volume ratio of methanol and chloroform is 4-5:

6. After rotating the mixture until dry, add buffer solution, hydrate at 35-45°C for 0.5-1h, and obtain the mixture by ultrasonic dispersion and freeze-drying.

2. The regorafenib tablet according to claim 1, characterized in that: The diluent is selected from one of starch, cyclodextrin and microcrystalline cellulose.

3. The regorafenib tablet according to claim 1, characterized in that: The disintegrant is selected from sodium carboxymethyl starch, sodium starch glycolate, and sodium carboxymethyl cellulose.

4. The regorafenib tablet according to claim 1, characterized in that: The adhesive is polyvinyl pyrrolidone.

5. The regorafenib tablet according to claim 1, characterized in that: The lubricant is selected from one of magnesium stearate, talc and stearic acid.

6. The regorafenib tablet according to claim 1, characterized in that: The coating material includes hydroxypropyl cellulose, ethyl cellulose, triacetin, titanium dioxide, talc, polyethylene glycol and 70wt% ethanol aqueous solution, and the mass ratio is 1~80:0.5~15:0.1~20:1~5:1~3:1~3:500~1000.

7. A method for preparing the regorafenib tablet according to any one of claims 1 to 6, characterized in that: The steps include: S1. After the diluent and disintegrant are evenly mixed, the coated regorafenib is added and mixed to obtain a mixture; S2, mixing the mixture with the binder, performing wet granulation and drying at 50-60°C until the moisture content is less than 5%; S3, mixing the granules obtained after granulation with a lubricant, and tableting to obtain a tablet core; S4. Mix the raw materials in the coating material to obtain a coating solution, and then coat the tablet core to obtain regorafenib tablets.

8. The method for preparing the regorafenib tablet according to claim 7, characterized in that: The coating material is added in an amount of 1-4 wt % of the tablet core.

9. The method for preparing the regorafenib tablet according to claim 7, characterized in that: The coating temperature is 40-60°C.

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