Topiromilast pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention discloses a topirolast pharmaceutical composition as well as a preparation method and application thereof. The invention provides a topiromilast pharmaceutical composition. A dissolution release curve of the topiromilast pharmaceutical composition has the following characteristics: 1) no more than 30% of active pharmaceutical ingredients are dissolved out within 1 hour; 2) dissolving out 20%-70% of active pharmaceutical ingredients within 8 hours; and 3) dissolving out not less than 70% of active pharmaceutical ingredients within 24 hours. The topiromilast pharmaceutical composition disclosed by the invention has good slow release performance, the 24-hour accumulative release rate can reach 70% or above, and the topiromilast pharmaceutical composition is stable in medicine plasma concentration, good in stability, small in adverse reaction, small in medicine taking frequency and good in patient compliance. The preparation process is simple and stable, process parameters are adjustable and controllable, production amplification is facilitated, and the market prospect is good.

Description

[0001] This application claims priority to an earlier application filed on September 27, 2024, with China National Intellectual Property Administration, patent application number 2024113617959, entitled "Topiraster Pharmaceutical Composition, Preparation Method Thereof and Application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field and relates to topiramate pharmaceutical compositions, their preparation methods, and applications. Background Technology

[0003] Hyperuricemia is a metabolic disorder syndrome caused by purine metabolism disorder, and allopurinol is an effective uric acid-lowering drug.

[0004] Currently, there are few drugs available for treating gout and hyperuricemia, and there are certain individual differences and treatment risks. For example, patients using allopurinol may experience severe allergic reactions, partly because these patients carry the sensitizing HLA-B*5801 genotype, a gene with a higher proportion carried by Asian populations. Racial and genetic differences are important factors affecting drug safety and efficacy, and are often difficult to predict, requiring confirmation through early clinical trials. Topiroxostat, a new uric acid-lowering drug developed by Fuji Pharmaceuticals in Japan, is a novel xanthine oxidase inhibitor that can safely and effectively treat hyperuricemia and gout.

[0005] Currently available topiramate formulations are in the form of regular tablets, available in strengths of 20mg, 40mg, and 60mg. However, regular tablets have large fluctuations in peak and trough blood drug concentrations, significant side effects, and require multiple daily doses, resulting in poor compliance.

[0006] Therefore, finding a topiramate formulation with fewer side effects, stable blood drug concentrations, good stability, convenient administration, and good patient compliance is an urgent technical problem to be solved. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a topiramate drug composition that has good sustained-release effect, stable blood drug concentration, few side effects, good stability and good compliance, which is different from the prior art, as well as its preparation method and application.

[0008] This invention provides a topiramate pharmaceutical composition whose dissolution-release profile has the following characteristics:

[0009] 1) No more than 30% (e.g., no more than 20%, or even no more than 15%) of the active pharmaceutical ingredient dissolves within 1 hour;

[0010] 2) Dissolves 20% to 70% (e.g., 30%, 40%, 50% or 60%) of the active pharmaceutical ingredient within 8 hours;

[0011] 3) The active pharmaceutical ingredient is dissolved in at least 70% (e.g., 80%, 90%, 95% or 100%) within 24 hours;

[0012] The active ingredient is selected from one or more of topiramate, its pharmaceutically acceptable salts, solvates and hydrates.

[0013] This invention provides a topiramate pharmaceutical composition comprising a tablet core and a coating; the tablet core comprises a pharmaceutical active ingredient and pharmaceutical excipients; the pharmaceutical excipients are selected from one or more of matrix materials, disintegrants, pH adjusters, flow aids, lubricants, and matrix strength modifiers; the pharmaceutical active ingredient is selected from one or more of topiramate, pharmaceutically acceptable salts thereof, solvates, and hydrates thereof.

[0014] According to an embodiment of the present invention, the topiramate pharmaceutical composition has a dissolution-release profile as described above.

[0015] According to an embodiment of the present invention, the content of the active pharmaceutical ingredient can be 2.00% to 25.00%, for example 2.00% to 20.00% or 5.00% to 25.00%, for example 5.0%, 6.0%, 7.0%, 7.27%, 8.0%, 9.0%, 10.0%, 10.91%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, 18.0%, 18.18%, 19.0%, 20.0%, or 21.82%, where the content refers to the percentage of the weight of the active pharmaceutical ingredient to the weight of the tablet core.

[0016] According to some embodiments of the present invention, the pharmaceutical excipient includes a matrix material, a disintegrant, a flow aid, a lubricant, and a matrix strength modifier, or is composed of a matrix material, a disintegrant, a flow aid, a lubricant, and a matrix strength modifier.

[0017] According to some embodiments of the present invention, the pharmaceutical excipient includes a matrix material, a disintegrant, a pH adjuster, a flow aid, a lubricant, and a matrix strength modifier, or is composed of a matrix material, a disintegrant, a pH adjuster, a flow aid, a lubricant, and a matrix strength modifier.

[0018] According to an embodiment of the present invention, the matrix material refers to a substance that controls the rate and extent of drug release, maintains the good shape of the tablet, allows the drug to slowly enter the bloodstream, reduces the blood drug concentration, and achieves the desired therapeutic effect. It is selected from sodium alginate, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and a mixture of polyvinyl acetate and povidone (trade name: SR (manufactured by BASF SE), carbomer and polyoxyethylene, preferably selected from one or more of sodium alginate, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl acetate-polyvinyl ketone mixture.

[0019] According to an embodiment of the present invention, the content of the matrix material can be 40.00% to 80.00%, preferably 50.00% to 65.00%, for example 40.00%, 45.00%, 50.00%, 51.83%, 52.28%, 54.10%, 54.11%, 55.00%, 56.83%, 57.74%, 60.00%, 60.47%, 65.00%, 70.00%, 75.00%, or 80.00%, where the content refers to the percentage of the weight of the matrix material to the weight of the tablet core.

[0020] According to an embodiment of the present invention, the disintegrant is an excipient that causes the drug to rapidly disintegrate into small particles in the gastrointestinal tract, and can also cause the tablet to expand, forming channels in the tablet core to promote drug release. It is selected from one or more of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, preferably crospovidone.

[0021] According to an embodiment of the present invention, the content of the disintegrant can be 10.00% to 40.00%, preferably 15.00% to 25.00%, for example 10.00%, 15.00%, 16.36%, 19.09%, 20.00%, 21.82%, 25.00%, 30.00%, 35.00%, or 40.00%, where the content refers to the percentage of the weight of the disintegrant to the weight of the tablet core.

[0022] According to an embodiment of the present invention, the pH adjuster refers to a substance dispersed in the core of a drug tablet to maintain or change the pH of the microenvironment in the core of the drug tablet, and is selected from one or more of fumaric acid, citric acid, potassium citrate, lactic acid and tartaric acid, for example, fumaric acid.

[0023] According to an embodiment of the present invention, the content of the pH adjuster can be 0.05% to 5.00%, preferably 0.5% to 2.00%, for example 0.7%, 0.8%, 0.9%, 0.91%, 1.00%, 110%, 1.20%, 1.30%, 1.36%, 1.40%, 1.50%, 2.00%, 3.00%, 4.00%, where the content is the percentage of the weight of the pH adjuster to the weight of the tablet core.

[0024] According to an embodiment of the present invention, the particle size of the pH adjuster is 10-150 μm, for example 20-110 μm, 20-40 μm, and exemplary values ​​are 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, and 110 μm.

[0025] According to an embodiment of the present invention, the flow aid refers to a conventional excipient in the art that can reduce the friction between particles and improve the flowability of powder or granules, selected from one or more of colloidal silica, micronized silica gel and talc.

[0026] According to an embodiment of the present invention, the content of the gliding agent can be 0.10% to 1.00%, for example 0.10%, 0.20%, 0.30%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90% or 1.00%, where the content refers to the percentage of the weight of the gliding agent to the weight of the tablet core.

[0027] According to an embodiment of the present invention, the lubricant refers to a conventional lubricating substance in the art, selected from one or more of metal stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and mineral oil; further, the metal stearate is selected from one or more of magnesium stearate, stearic acid, stearate ester, and stearoyl fumarate; the stearoyl fumarate is selected from sodium stearate.

[0028] According to an embodiment of the present invention, the content of the lubricant can be 0.10% to 5.00%, preferably 0.50% to 2.50%, for example 0.20%, 0.30%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.50%, 1.81%, 2.00%, 2.50%, 3.00%, 3.50%, 4.00%, 4.50%, or 5.00%, where the content refers to the percentage of the weight of the lubricant to the weight of the tablet core.

[0029] According to an embodiment of the present invention, the skeleton strength modifier refers to a material conventionally used in the art to adjust the release strength of skeleton materials, selected from one or more of anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, calcium chloride, calcium carbonate and calcium silicate, for example, anhydrous dicalcium phosphate.

[0030] According to an embodiment of the present invention, the content of the matrix strength modifier can be 1.00% to 30.00%, preferably 5.00% to 20.00%, for example 1.00%, 5.00%, 9.09%, 10.00%, 10.91%, 13.64%, 14.55%, 15.00%, 20.00%, 25.00%, or 30.00%, where the content refers to the percentage of the weight of the matrix strength modifier to the weight of the tablet core.

[0031] According to an embodiment of the present invention, the coating can be a film coating; the film coating can be a gastrosoluble film coating.

[0032] According to an embodiment of the present invention, the coating content can be 1.00% to 5.00%, for example 1.00%, 2.00%, 3.00%, 4.00% or 5.00%, where the content refers to the percentage of the weight of the coating to the weight of the tablet core.

[0033] According to some embodiments of the present invention, the medicated tablet core may include or be composed of the following components in the following proportions: 2.00% to 25.00% active pharmaceutical ingredient, 40.00% to 80.00% matrix material, 10.00% to 40.00% disintegrant, 0.10% to 1.00% flow aid, 0.10% to 5.00% lubricant, and 1.00% to 30.00% matrix strength modifier;

[0034] For example, it may include or consist of the following components in the following amounts: 2.00% to 25.00% topiramate, 40.00% to 80.00% skeleton material (selected from one or more of sodium alginate, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinyl acetate polyvinyl ketone mixture), 10.00% to 40.00% cross-linked polyvinyl ketone, 0.10% to 1.00% colloidal silica, 0.10% to 5.00% magnesium stearate and 1.00% to 30.00% anhydrous dicalcium phosphate.

[0035] According to some embodiments of the present invention, the medicated tablet core may include or be composed of the following components in the following proportions: 2.00% to 20.00% active pharmaceutical ingredient, 40.00% to 80.00% matrix material, 0.05% to 5.00% pH adjuster, 10.00% to 40.00% disintegrant, 0.10% to 1.00% flow aid, 0.10% to 5.00% lubricant, and 1.00% to 30.00% matrix strength modifier;

[0036] For example, it may include or consist of the following components in the following amounts: 2.00% to 20.00% topiramate, 40.00% to 80.00% skeleton material (selected from one or more of sodium alginate, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinyl acetate polyvinyl ketone mixture), 0.05% to 5.00% fumaric acid, 10.00% to 40.00% crospovidone, 0.10% to 1.00% colloidal silica, 0.10% to 5.00% magnesium stearate and 1.00% to 30.00% dicalcium phosphate.

[0037] According to an embodiment of the present invention, the medicated tablet core has an inner layer and an outer layer;

[0038] The inner layer includes or is composed of the following components: active pharmaceutical ingredient, matrix material, disintegrant, flow aid, and lubricant; or includes or is composed of the following components: active pharmaceutical ingredient, matrix material, disintegrant, pH adjuster, flow aid, and lubricant.

[0039] The outer layer includes or is composed of the following components: skeleton material, skeleton strength modifier, and lubricant.

[0040] According to an embodiment of the present invention, the weight ratio of the inner skeleton material to the outer skeleton material is greater than 1 and does not exceed 3.0, preferably 1.05 to 2.5, and exemplary ratios are 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3 or 2.4.

[0041] According to an embodiment of the present invention, the inner skeleton material may be the same as or different from the outer skeleton material. For example, the inner skeleton material may be sodium alginate and hydroxyethyl cellulose, and the outer skeleton material may be a mixture of hydroxypropyl methylcellulose and polyvinyl acetate polyvinyl ketone.

[0042] According to an embodiment of the present invention, the weight ratio of the inner layer lubricant to the outer layer lubricant is 1:(1 to 10), preferably 1:(1 to 5), for example 1:1, 1:2, 1:3, 1:4.

[0043] According to an embodiment of the present invention, the inner layer lubricant may be the same as or different from the outer layer lubricant, for example, both may be metal stearate salts.

[0044] According to an embodiment of the present invention, the medicated tablet core can be any of the following formulations:

[0045] Formula 1: 10.91% Topiramate (added internally), 25.92% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0046] Prescription 2: 7.27% Topiramate (added internally), 29.56% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0047] Prescription 3: 10.91% Topiramate (added internally), 26.00% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 18.56% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally);

[0048] Prescription 4: 10.91% Topiramate (added internally), 29.74% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 14.82% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally);

[0049] Prescription 5: 10.91% Topiramate (added internally), 23.19% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 13.64% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0050] Prescription 6: 10.91% Topiramate (added internally), 28.19% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 10.91% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally);

[0051] Prescription 7: 7.27% Topiramate (added internally), 25.92% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 14.55% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0052] Prescription 8: 7.27% Topiramate (added internally), 29.56% Sodium Alginate (added internally), 21.82% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 10.00% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0053] Prescription 9: 18.18% Topiramate (added internally), 25.47% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0054] Formula 10: 18.18% Topiramate (added internally), 23.65% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0055] Formula 11: 21.82% Topiramate (added internally), 23.19% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 7.73% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0056] Prescription 12: 21.82% Topiramate (added internally), 25.91% Sodium Alginate (added internally), 14.55% Crospovidone (added internally), 4.55% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 7.27% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally);

[0057] Prescription 13: 10.91% Topiramate (added internally), 0.91% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous dicalcium phosphate (added externally), and 1.36% Magnesium stearate (added externally);

[0058] The fumaric acid has a particle size greater than 10 μm and not more than 150 μm, for example, 20 to 110 μm, with exemplary sizes of 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, and 110 μm.

[0059] Prescription 14: 10.91% Topiramate (added internally), 0.91% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium stearate (added externally);

[0060] The particle size of the fumaric acid is 20–40 μm;

[0061] Prescription 15: 10.91% Topiramate (added internally), 1.37% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.41% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.41% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium stearate (added externally);

[0062] The particle size of the fumaric acid is 20–40 μm;

[0063] Formula 16: 7.27% Topiramate (added internally), 0.91% Fumaric acid (added internally), 29.55% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous dicalcium phosphate (added externally), and 1.36% Magnesium stearate (added externally).

[0064] In the above formulations, the internal components form the inner layer, and the external components form the outer layer.

[0065] According to an embodiment of the invention, the topiramate pharmaceutical composition comprises 40 mg to 240 mg of topiramate, such as 40 mg, 80 mg, 120 mg, 200 mg or 240 mg.

[0066] The present invention also provides a method for preparing the topiramate pharmaceutical composition, including but not limited to dry granulation, wet granulation, fluidized bed granulation, tableting, and film coating.

[0067] The present invention also provides a topiramate pharmaceutical composition prepared by the aforementioned method.

[0068] The present invention also provides a pharmaceutical formulation comprising the aforementioned topiramate pharmaceutical composition.

[0069] The present invention also provides the use of the aforementioned topiramate pharmaceutical composition in the preparation of pharmaceutical formulations, preferably the pharmaceutical formulations for the treatment and / or prevention of hyperuricemia and / or gout.

[0070] According to embodiments of the present invention, the pharmaceutical preparation may be an oral pharmaceutical preparation, such as a tablet; the oral pharmaceutical preparation may be an oral sustained-release pharmaceutical preparation; the oral sustained-release pharmaceutical preparation may be, for example, a sustained-release tablet.

[0071] According to an embodiment of the invention, the pharmaceutical preparation comprises 40 mg to 240 mg of topiramate, for example 40 mg, 80 mg, 120 mg, 200 mg or 240 mg.

[0072] The present invention also provides the use of the described topiramate pharmaceutical composition in the preparation of pharmaceutical formulations for the treatment and / or prevention of hyperuricemia and / or gout, said pharmaceutical formulation having the limitations shown above.

[0073] The present invention also provides a method for treating and / or preventing hyperuricemia and / or gout, which provides a therapeutically effective amount of the aforementioned topiramate pharmaceutical composition or pharmaceutical preparation to patients in need (e.g., patients with dysphagia).

[0074] Terminology Definitions and Explanations

[0075] The term "multiple" refers to two or more kinds, such as two, three or more kinds.

[0076] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0077] The term "therapeutic effective amount" refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are looking for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response.

[0078] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0079] The reagents and raw materials used in this invention are all commercially available.

[0080] The beneficial effects of this invention are as follows: The topiramate pharmaceutical composition of this invention has excellent sustained-release properties. During in vitro dissolution, the tablet size rapidly expands, exhibiting good rigidity and elasticity after expansion, resulting in a significant gastric retention effect. The cumulative release rate over 24 hours can reach over 70%. It reduces the peak-and-trough phenomenon in blood drug concentration observed in conventional dosage forms, maintaining a relatively stable blood drug concentration for sustained efficacy and reducing adverse reactions. It is suitable for patients with swallowing difficulties, improving medication compliance; it has a good taste, improving patient adherence; it is convenient to carry and has good stability. The preparation process of this invention is simple and significantly improves problems such as poor flowability of the active pharmaceutical ingredient and low bulk density leading to filling difficulties and unstable tablet weight during tableting. The process is stable, and the process parameters are adjustable and controllable, which is conducive to the scale-up of this product's production and has good market prospects. Detailed Implementation

[0081] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples described herein. For the experimental methods without specific conditions indicated in the following examples, they shall be carried out according to conventional methods and conditions, or selected according to the product specifications.

[0082] Example 1

[0083] Table 1 Prescription of Example 1

[0084]

[0085] Preparation process: [[ID=…]]

[0086] ① Weigh the internal added raw and auxiliary materials in the prescription amount, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone together for standby.

[0087] ② Place the sodium alginate, tolterodine tartrate, and the mixture of sieved hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone in a suitable mixing hopper, mix for 15 minutes, and after the mixing is completed, use a granulator for granulation and dispersion.

[0088] ③ Place the material granulated and dispersed in step ② in the mixing hopper, add magnesium stearate, and continue to mix for 10 minutes.

[0089] ④ Use a dry granulator to perform dry granulation on the material mixed in step ③. After pressing the material into tablets, use the granulating equipment配套 with the dry granulator for granulation. After the granulation is completed, collect the material for weighing.

[0090] ⑤ Calculate the added amount of external added materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate according to the prescription ratio, and weigh them.

[0091] ⑥ Place the material granulated in step ④ in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 minutes, and continue to mix for 10 minutes after adding magnesium stearate.

[0092] ⑦ Use a rotary tablet press to press the material mixed in step ⑥ into tablets. After the tableting is completed, use a high-efficiency coating machine and a film coating premix to coat the tablet cores.

[0093] Example 2

[0094] Table 2 Prescription of Example 2

[0095]

[0096] Preparation process:

[0097] ① Weigh the internal added raw and auxiliary materials in the prescription amount, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone together for standby.

[0098] ② Place the mixture of sodium alginate, tropisetron, and the sieved hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone in a suitable mixing hopper, mix for 15 min, and after mixing, use a granulator to granulate and disperse.

[0099] ③ Place the granulated and dispersed material from step ② in a mixing hopper, add magnesium stearate, and continue to mix for 10 min.

[0100] ④ Use a dry granulator to dry granulate the material mixed in step ③. After pressing the material into tablets, use the granulating equipment配套 with the dry granulator to granulate. After granulation is completed, collect the material for weighing.

[0101] ⑤ Calculate and weigh the additional materials added externally according to the prescription ratio: the addition amounts of hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate.

[0102] ⑥ Place the granulated material from step ④ in a mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 min, and continue to mix for 10 min after adding magnesium stearate.

[0103] ⑦ Use a rotary tablet press to press the material mixed in step ⑥ into tablets. After tableting is completed, use a high - efficiency coating machine and a film - coating premix to coat the tablet cores.

[0104] Example 3

[0105] Table 3 Prescription of Example 3

[0106]

[0107] Preparation process:

[0108] ① Weigh the internally added raw and auxiliary materials in the prescription amount, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone together for standby.

[0109] ② Place the mixture of sodium alginate, tropisetron, and the sieved hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone in a suitable mixing hopper, mix for 15 min, and after mixing, use a granulator to granulate and disperse.

[0110] ③ Place the granulated and dispersed material from step ② in a mixing hopper, add magnesium stearate, and continue to mix for 10 min.

[0111] ④ Use a dry granulator to dry granulate the material mixed in step ③. After pressing the material into large tablets, use the granulating equipment配套 with the dry granulator to granulate. After granulation is completed, collect the material for weighing.

[0112] ⑤ Calculate and convert the added materials according to the prescription ratio: the addition amounts of hypromellose, polyvinyl acetate-polyvinylpyrrolidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate, and weigh them.

[0113] ⑥ Place the granulated materials from step ④ into a mixing hopper, add the hypromellose, polyvinyl acetate-polyvinylpyrrolidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 min, and continue to mix for 10 min after adding magnesium stearate.

[0114] ⑦ Press the mixed materials from step ⑥ using a rotary tablet press. After tablet pressing, coat the tablet cores using a high-efficiency coating machine and a film coating premix.

[0115] Example 4

[0116] Table 4 Prescription of Example 4

[0117]

[0118]

[0119] Preparation process:

[0120] ① Weigh the internal added raw and auxiliary materials in the prescription amount, and sieve hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked polyvinylpyrrolidone together for standby.

[0121] ② Place sodium alginate, tolterodine, and the mixture of sieved hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked polyvinylpyrrolidone into a suitable mixing hopper, mix for 15 min. After mixing, use a granulator to granulate and disperse.

[0122] ③ Place the granulated and dispersed materials from step ② into a mixing hopper, add magnesium stearate, and continue to mix for 10 min.

[0123] ④ Use a dry granulator to perform dry granulation on the mixed materials from step ③. After pressing the materials into tablets, use the granulating equipment配套 with the dry granulator to granulate. After granulation is completed, collect the materials for weighing.

[0124] ⑤ Calculate and convert the added materials according to the prescription ratio: the addition amounts of hypromellose, polyvinyl acetate-polyvinylpyrrolidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate, and weigh them.

[0125] ⑥ Place the granulated materials from step ④ into a mixing hopper, add the hypromellose, polyvinyl acetate-polyvinylpyrrolidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 min, and continue to mix for 10 min after adding magnesium stearate.

[0126] ⑦ Press the materials mixed in step ⑥ into tablets using a rotary tablet press. After tablet pressing is completed, coat the tablet cores using a high-efficiency coating machine and a film coating premix.

[0127] Example 5

[0128] Table 5 Prescription of Example 5

[0129]

[0130]

[0131] Preparation process:

[0132] ① Weigh the internal added raw and auxiliary materials in the prescription amount, and sieve hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone together for standby.

[0133] ② Place sodium alginate, tolterodine, and the mixture of sieved hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone in a suitable mixing hopper, mix for 15 minutes. After mixing is completed, use a granulator to granulate and disperse.

[0134] ③ Place the materials granulated and dispersed in step ② in a mixing hopper, add magnesium stearate, and continue to mix for 10 minutes.

[0135] ④ Use a dry granulator to granulate the materials mixed in step ③. After pressing the materials into large tablets, use the granulating equipment配套 with the dry granulator to granulate. After granulation is completed, collect the materials for weighing.

[0136] ⑤ Calculate the added amount of external added materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate according to the prescription ratio, and weigh them.

[0137] ⑥ Place the materials granulated in step ④ in a mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 minutes, and continue to mix for 10 minutes after adding magnesium stearate.

[0138] ⑦ Press the materials mixed in step ⑥ into tablets using a rotary tablet press. After tablet pressing is completed, coat the tablet cores using a high-efficiency coating machine and a film coating premix.

[0139] Example 6

[0140] Table 6 Prescription of Example 6

[0141]

[0142]

[0143] Preparation process:

[0144] ① Weigh the internal added raw and auxiliary materials in the prescription amount. Sieve hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone together and reserve for use.

[0145] ② Place sodium alginate, tolterodine tartrate, and the mixture of sieved hydroxyethyl cellulose, colloidal silicon dioxide, and crospovidone in a suitable mixing hopper, mix for 15 minutes. After mixing, use a granulator to break up the granules.

[0146] ③ Place the material after breaking up the granules in step ② in the mixing hopper, add magnesium stearate, and continue to mix for 10 minutes.

[0147] ④ Use a dry granulator to perform dry granulation on the material mixed in step ③. After pressing the material into tablets, use the granulating equipment配套 with the dry granulator to break up the granules. After granulation is completed, collect the material and weigh it.

[0148] ⑤ Calculate the added amount of external added materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate according to the prescription ratio, and weigh them.

[0149] ⑥ Place the material after granulation in step ④ in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 minutes, and continue to mix for 10 minutes after adding magnesium stearate.

[0150] ⑦ Use a rotary tablet press to press the material mixed in step ⑥ into tablets. After tableting is completed, use a high - efficiency coating machine and a film - coating premix to coat the tablet cores.

[0151] Example 7

[0152] The samples of Examples 1 - 4 were detected by USP Method 2 (900 ml, hydrochloric acid solution with pH 1.2, 50 rpm). The in - vitro release results, as well as the tablet core size and rigidity results after dissolution, are shown in Table 7 below.

[0153] Table 7

[0154]

[0155]

[0156] Example 8

[0157] The samples of Examples 1 - 4 were subjected to a dissolution test by USP Dissolution Method 2 (900 ml, acetate buffer solution with pH 4.5, 50 rpm). The tablet core size and rigidity after dissolution (24 h) were measured, and the results are shown in Table 8 below.

[0158] Table 8

[0159]

[0160] Example 9

[0161] Based on the above examples, optimization is carried out by adding a pH regulator to improve the microenvironment of the tablet core and the dissolution and release rate.

[0162] Table 9 Prescription of Example 9

[0163]

[0164]

[0165] In Example 120mg-7, the particle size of fumaric acid is 110μm; in Example 120mg-8, the particle size of fumaric acid is 20-40μm; in Example 120mg-9, the particle size of fumaric acid is 20-40μm.

[0166] Preparation process:

[0167] ① Weigh the internal added raw and auxiliary materials, and reserve the hydroxyethyl cellulose, colloidal silicon dioxide after sieving.

[0168] ② Place the sodium alginate, fumaric acid, tropisetron, and the mixture of sieved hydroxyethyl cellulose and colloidal silicon dioxide in a suitable mixing hopper, mix for 15 minutes. After mixing, use a granulator to granulate and sieve.

[0169] ③ Place the material after granulating and sieving in step ② in the mixing hopper, add magnesium stearate, and continue to mix for 10 minutes.

[0170] ④ Use a dry granulator to dry granulate the material mixed in step ③. After pressing the material into tablets, use the granulating equipment配套 with the dry granulator to granulate. After granulating, collect the material for weighing.

[0171] ⑤ Calculate the added amount of external added materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate and magnesium stearate according to the prescription ratio, and weigh them.

[0172] ⑥ Place the material after granulating in step ④ in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 minutes, and continue to mix for 10 minutes after adding magnesium stearate.

[0173] ⑦ Use a rotary tablet press to press the material mixed in step ⑥ into tablets. After pressing, use a high-efficiency coating machine and a film coating premix to coat the tablet core.

[0174] Example 1 O

[0175] Table 10 Prescription of Example 10

[0176]

[0177] Preparation process:

[0178] ① Weigh the internal added raw and auxiliary materials in the prescription amount, and reserve the hydroxyethyl cellulose, colloidal silicon dioxide after sieving.

[0179] ② Place the mixture of sodium alginate, fumaric acid, tolterodine tartrate, and the sieved hydroxyethyl cellulose and colloidal silicon dioxide in a suitable mixing hopper, mix for 15 minutes. After mixing, use a granulating machine for granulation and sieving.

[0180] ③ Place the materials after granulation and sieving in step ② in the mixing hopper, add magnesium stearate, and continue to mix for 10 minutes.

[0181] ④ Use a dry granulator to granulate the materials mixed in step ③. After pressing the materials into large tablets, use the granulating equipment配套 with the dry granulator for granulation. After granulation, collect the materials for weighing.

[0182] ⑤ Calculate the added amount of external added materials: hydroxypropyl methylcellulose, polyvinyl acetate polyvinylpyrrolidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate according to the prescription ratio, and weigh them.

[0183] ⑥ Place the materials after granulation in step ④ in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate polyvinylpyrrolidone mixture, anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 minutes, and continue to mix for 10 minutes after adding magnesium stearate.

[0184] ⑦ Use a rotary tablet press to press the materials mixed in step ⑥ into tablets. After tableting, use a high - efficiency coating machine and film coating premix to coat the tablet cores.

[0185] Example 11

[0186] The samples in Examples 9 - 10 were detected for in vitro release using USP Method 2 (900 ml, pH 1.2 hydrochloric acid solution, 50 rpm), and the results are shown in Table 11 below.

[0187] Table 11

[0188]

[0189] After adding a pH regulator to the formula, the dissolution rate of the product was significantly improved.

[0190] Example 12

[0191] The in vitro release of the samples from Examples 9 to 10 was detected using the USP Method 1 (900 ml, pH 1.2 hydrochloric acid solution, basket method at 100 rpm), and the results are shown in Table 12 below.

[0192] Table 12

[0193]

[0194]

[0195] By adding a pH adjuster, the product dissolution rate is improved, the sustained-release effect is better, the product manufacturing process is simple, and the process stability is good.

[0196] Example 13

[0197] In Example 9, the 120mg-8 product was subjected to a stability test. The test method was as follows: using 0.1mol / L hydrochloric acid-methanol (50:50) as solvent, the test was performed by high performance liquid chromatography. The test results showed that the related substances were almost the same as before the test, indicating that the product has good stability.

[0198] Table 13 Stability Test Results

[0199]

[0200] *TPST-1 impurity chemical name: 4-[5-(pyridin-4-yl)-1H-[1,2,4]-triazol-3-yl]pyridin-2-carboxamide, chemical name: C 13 H 10 N6O, molecular weight: 266.26.

[0201] Example 14

[0202] The test sample group (the 120mg-1 product in Example 1 and the 120mg-8 product in Example 9) and the control group (original topiramate tablets, trade name) were used. A pharmacokinetic (PK) study was conducted in healthy subjects using a 60mg formulation.

[0203] Test sample group: Topiramate extended-release tablets of 120 mg-1 in Example 1 and Topiramate extended-release tablets of 120 mg-8 in Example 9, with a dose of 240 mg / day, administered as a single dose of 2 tablets;

[0204] The control group received 240 mg / day, two tablets every 12 hours, for a total of two doses.

[0205] Blood samples were collected at different time points in both the original drug control group and the test drug group to determine the drug concentration. The blood sampling times were 0.5h, 1h, 1.33h, 1.67h, 2h, 2.33h, 2.67h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 12.5h, 13h, 13.33h, 13.67h, 14h, 14.33h, 14.67h, 15h, 15.5h, 16h, 17h, 18h, 20h, 22h, 24h, 28h, 36h, and 48h. The pharmacokinetic parameters are shown in Table 14.

[0206] Table 14 In vivo PK results

[0207]

[0208]

[0209] The results showed that the geometric mean ratios of Cmax and AUC in the test group (120 mg-1 topiramate extended-release tablets in Example 1) were both far below 80%. However, with the addition of the pH adjuster sodium fumarate, the geometric mean ratios of Cmax and AUC in the test group (120 mg-8 topiramate extended-release tablets in Example 9) were significantly improved, with the AUC geometric mean ratio approaching 80%. Therefore, through optimization, the AUC of topiramate extended-release tablets was significantly improved, becoming comparable to that of topiramate tablets. Furthermore, the extended-release tablets have a slower release rate and more stable blood drug concentration, achieving therapeutic efficacy while reducing the occurrence of adverse reactions, resulting in better patient efficacy, compliance, and safety.

[0210] The topiramate extended-release tablets obtained in Example 10 also have the same or similar pharmacokinetic effects as the 120mg-8 topiramate extended-release tablets in Example 9.

[0211] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A topiramate pharmaceutical composition, characterized in that: The topirafil pharmaceutical composition comprises a tablet core and a coating; the tablet core comprises an active pharmaceutical ingredient and pharmaceutical excipients; the pharmaceutical excipients are selected from one or more of matrix materials, disintegrants, pH adjusters, flow aids, lubricants, and matrix strength modifiers; the active pharmaceutical ingredient is selected from one or more of topirafil, its pharmaceutically acceptable salts, solvates, and hydrates. Preferably, the pharmaceutical excipients include a matrix material, a disintegrant, a flow aid, a lubricant, and a matrix strength modifier, or are composed of a matrix material, a disintegrant, a flow aid, a lubricant, and a matrix strength modifier; Preferably, the pharmaceutical excipients include a matrix material, a disintegrant, a pH adjuster, a flow aid, a lubricant, and a matrix strength modifier, or are composed of a matrix material, a disintegrant, a pH adjuster, a flow aid, a lubricant, and a matrix strength modifier; Preferably, the topiramate pharmaceutical composition comprises 40 mg to 240 mg of topiramate.

2. A topiramate pharmaceutical composition, characterized in that: The dissolution-release profile of the topiramate pharmaceutical composition has the following characteristics: 1) No more than 30% of the active pharmaceutical ingredient dissolves within 1 hour; 2) 20%–70% of the active pharmaceutical ingredient dissolves within 8 hours; 3) At least 70% of the active pharmaceutical ingredient dissolves within 24 hours; Preferably, the topirafil pharmaceutical composition is the topirafil pharmaceutical composition of claim 1.

3. The topiramate pharmaceutical composition according to claim 1 or 2, characterized in that: The content of the active pharmaceutical ingredient is 2.00% to 25.00%, preferably 2.00% to 20.00%, whereby the content refers to the percentage of the weight of the active pharmaceutical ingredient to the weight of the tablet core; and / or, The skeleton material is selected from one or more of sodium alginate, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate-polyvinyl ketone mixture, carbomer, and polyoxyethylene. And / or, The disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; And / or, The pH adjuster is selected from one or more of fumaric acid, citric acid, potassium citrate, lactic acid, and tartaric acid; And / or, The flow aid is selected from one or more of colloidal silica, micronized silica gel, and talc. And / or, The lubricant is selected from one or more of metal stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and mineral oil; preferably, the metal stearate is selected from one or more of magnesium stearate, stearic acid, stearate ester, and stearoyl fumarate; preferably, the stearoyl fumarate is selected from sodium stearate. And / or, The skeleton strength modifier is selected from one or more of anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, calcium chloride, calcium carbonate, and calcium silicate; And / or, The coating is a film coating; preferably, the coating is a gastrosoluble film coating.

4. The topiramate pharmaceutical composition according to claim 1 or 2, characterized in that: The content of the matrix material is 40.00% to 80.00%, preferably 50.00% to 65.00%, where the content refers to the percentage of the weight of the matrix material to the weight of the tablet core. And / or, The content of the disintegrant is 10.00% to 40.00%, preferably 15.00% to 25.00%, and the content refers to the percentage of the weight of the disintegrant to the weight of the tablet core; And / or, The content of the pH adjuster can be 0.05% to 5.00%, preferably 0.5% to 2.00%, and the content is the percentage of the weight of the pH adjuster to the weight of the tablet core; And / or, The pH adjuster has a particle size of 10–150 μm; And / or, The content of the gliding agent is 0.10% to 1.00%, and the content refers to the percentage of the weight of the gliding agent to the weight of the tablet core. And / or, The content of the lubricant is 0.10% to 5.00%, and the content refers to the percentage of the weight of the lubricant to the weight of the tablet core. And / or, The content of the matrix strength modifier is 1.00% to 30.00%, preferably 5.00% to 20.00%, and the content refers to the percentage of the weight of the matrix strength modifier to the weight of the tablet core. And / or, The coating content is 1.00% to 5.00%, and the content refers to the percentage of the weight of the coating to the weight of the tablet core.

5. The topiramate pharmaceutical composition according to claim 1 or 2, characterized in that: The medicated tablet core comprises or is composed of the following components in the following proportions: 2.00%–25.00% active pharmaceutical ingredient, 40.00%–80.00% matrix material, 10.00%–40.00% disintegrant, 0.10%–1.00% flow aid, 0.10%–5.00% lubricant, and 1.00%–30.00% matrix strength modifier; Preferably, the medicated tablet core comprises or is composed of the following components in the following proportions: 2.00%–25.00% topiramate, 40.00%–80.00% matrix material, 10.00%–40.00% crospovidone, 0.10%–1.00% colloidal silica, 0.10%–5.00% magnesium stearate, and 1.00%–30.00% anhydrous calcium hydrogen phosphate; Alternatively, the medicated tablet core may comprise or consist of the following components in the following proportions: 2.00%–20.00% active pharmaceutical ingredient, 40.00%–80.00% matrix material, 0.05%–5.00% pH adjuster, 10.00%–40.00% disintegrant, 0.10%–1.00% flow aid, 0.10%–5.00% lubricant, and 1.00%–30.00% matrix strength modifier; Preferably, the medicated tablet core comprises or is composed of the following components in the following proportions: 2.00%–20.00% topiramate, 40.00%–80.00% matrix material, 0.05%–5.00% fumaric acid, 10.00%–40.00% crospovidone, 0.10%–1.00% colloidal silica, 0.10%–5.00% magnesium stearate, and 1.00%–30.00% dicalcium phosphate.

6. The topiramate pharmaceutical composition according to claim 1 or 2, characterized in that: The medicated tablet core has an inner layer and an outer layer; The inner layer includes or is composed of the following components: active pharmaceutical ingredient, matrix material, disintegrant, flow aid, and lubricant; or includes or is composed of the following components: active pharmaceutical ingredient, matrix material, disintegrant, pH adjuster, flow aid, and lubricant. The outer layer includes or is composed of the following components: skeleton material, skeleton strength modifier, and lubricant; Preferably, the weight ratio of the inner skeleton material to the outer skeleton material is greater than 1 and does not exceed 3.0, more preferably 1.05 to 2.5; And / or, the inner skeleton material is the same as or different from the outer skeleton material, for example, the inner skeleton material is sodium alginate and hydroxyethyl cellulose, and the outer skeleton material is a mixture of hydroxypropyl methyl cellulose and polyvinyl acetate polyvinyl ketone; And / or, the weight ratio of the inner layer lubricant to the outer layer lubricant is 1:(1 to 10).

7. The topiramate pharmaceutical composition according to claim 1 or 2, characterized in that: The topiramate pharmaceutical composition is any of the following formulations: Formula 1: 10.91% Topiramate (added internally), 25.92% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 2: 7.27% Topiramate (added internally), 29.56% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 3: 10.91% Topiramate (added internally), 26.00% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 18.56% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally); Prescription 4: 10.91% Topiramate (added internally), 29.74% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 14.82% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally); Prescription 5: 10.91% Topiramate (added internally), 23.19% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 13.64% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 6: 10.91% Topiramate (added internally), 28.19% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 10.91% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 0.45% Magnesium Stearate (added externally); Prescription 7: 7.27% Topiramate (added internally), 25.92% Sodium Alginate (added internally), 19.09% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 14.55% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 8: 7.27% Topiramate (added internally), 29.56% Sodium Alginate (added internally), 21.82% Crospovidone (added internally), 9.09% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 10.00% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 9: 18.18% Topiramate (added internally), 25.47% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Formula 10: 18.18% Topiramate (added internally), 23.65% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Formula 11: 21.82% Topiramate (added internally), 23.19% Sodium Alginate (added internally), 16.36% Crospovidone (added internally), 6.82% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 9.09% Hydroxypropyl Methylcellulose (added externally), 12.73% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 7.73% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 12: 21.82% Topiramate (added internally), 25.91% Sodium Alginate (added internally), 14.55% Crospovidone (added internally), 4.55% Hydroxyethylcellulose (added internally), 0.45% Colloidal Silica (added internally), 0.45% Magnesium Stearate (added internally), 7.27% Hydroxypropyl Methylcellulose (added externally), 14.55% Polyvinyl Acetate-Polyvinyl Acetate Mixture (added externally), 9.09% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium Stearate (added externally); Prescription 13: 10.91% Topiramate (added internally), 0.91% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous dicalcium phosphate (added externally), and 1.36% Magnesium stearate (added externally); The particle size of the fumaric acid is greater than 10 μm and does not exceed 150 μm; Prescription 14: 10.91% Topiramate (added internally), 0.91% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium stearate (added externally); The particle size of the fumaric acid is 20–40 μm; Prescription 15: 10.91% Topiramate (added internally), 1.37% Fumaric acid (added internally), 25.91% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.41% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.41% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous Dicalcium Phosphate (added externally), and 1.36% Magnesium stearate (added externally); The particle size of the fumaric acid is 20–40 μm; Formula 16: 7.27% Topiramate (added internally), 0.91% Fumaric acid (added internally), 29.55% Sodium alginate (added internally), 19.09% Crospovidone (added internally), 8.64% Hydroxyethyl cellulose (added internally), 0.45% Colloidal silica (added internally), 0.45% Magnesium stearate (added internally), 8.64% Hydroxypropyl methylcellulose (added externally), 12.73% Polyvinyl acetate-Povidone mixture (added externally), 10.91% Anhydrous dicalcium phosphate (added externally), and 1.36% Magnesium stearate (added externally).

8. The method for preparing the topiramate pharmaceutical composition according to any one of claims 1 to 7, characterized in that: This includes, but is not limited to, dry granulation, wet granulation, vulcanization granulation, tableting, and film coating.

9. The use of the topiramate pharmaceutical composition according to any one of claims 1 to 7 in the preparation of pharmaceutical formulations for the treatment and / or prevention of hyperuricemia and / or gout; Preferably, the pharmaceutical preparation is an oral pharmaceutical preparation; Preferably, the pharmaceutical preparation is an oral sustained-release pharmaceutical preparation; Preferably, the pharmaceutical preparation is a sustained-release tablet.

10. A pharmaceutical formulation comprising the topiramate pharmaceutical composition according to any one of claims 1 to 7; Preferably, the pharmaceutical preparation is an oral pharmaceutical preparation; Preferably, the pharmaceutical preparation is an oral sustained-release pharmaceutical preparation; Preferably, the pharmaceutical preparation is a sustained-release tablet.

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