Topiroxostat pharmaceutical composition, preparation method and use

Abstract

A topiroxostat pharmaceutical composition, a preparation method and a use. The dissolution release profile of the topiroxostat pharmaceutical composition has the following characteristics: 1) dissolution of no more than 30% of a pharmaceutically active ingredient within 1 hour; 2) dissolution of 20%-70% of the pharmaceutically active ingredient within 8 hours; and 3) dissolution of no less than 70% of the pharmaceutically active ingredient within 24 hours. The topiroxostat pharmaceutical composition has good sustained-release performance and a 24-hour cumulative release rate of 70% or more; the drug exhibits stable plasma concentration, good stability and few adverse effects, requires less frequent administration, and has good patient compliance; and the preparation process is simple and stable, process parameters are adjustable and controllable, which is conducive to production scale-up, and the market prospect is good.

Description

Topiroxostat pharmaceutical composition, preparation method and application

[0001] The present application claims the priority of the prior application filed with the China National Intellectual Property Office on September 27, 2024, with the patent application number 2024113617959, and the invention name of "Topiroxostat pharmaceutical composition, preparation method and application"; the prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and relates to a topiroxostat pharmaceutical composition, a preparation method and application thereof. BACKGROUND

[0003] Hyperuricemia is a metabolic abnormality syndrome caused by purine metabolism disorder, and allopurinol is an effective uric acid-lowering drug. Hyperuricemia in China shows a trend of high prevalence, youth, higher in men than in women, and higher in coastal areas than in inland. According to estimates, 10% of the population in China suffers from hyperuricemia, and the prevalence of hyperuricemia in coastal and economically developed areas is even as high as 20% or more. The prevalence of hyperuricemia in China has already been higher than that of diabetes. The incidence is characterized by being mainly male, and the characteristics are "more men than women". Since patients have no clinical symptoms, they often do not pay attention to it and ignore treatment.

[0004] At present, there are few drugs for treating gout and hyperuricemia, and there are certain individual differences and treatment risks. For example, patients using allopurinol may have severe allergic reactions, one of the reasons is that these patients carry the HLA-B*5801 gene type which is prone to sensitization, and the proportion of people in Asian population carrying this gene is higher. Ethnic differences and genetic background differences are important factors affecting drug safety and effectiveness, which are often difficult to predict and need to be confirmed by early clinical trials. Topiroxostat (topiroxostat) developed by Fuji Pharmaceutical Company in Japan is a new uric acid-lowering drug, which can safely and effectively treat hyperuricemia and gout as a new xanthine enzyme inhibitor.

[0005] The currently marketed topiroxostat preparation is an ordinary tablet with specifications of 20mg, 40mg and 60mg, but the ordinary tablet has large peak-trough fluctuations in blood drug concentration, large side effects, and needs to be taken multiple times a day, with poor compliance.

[0006] Therefore, it is an urgent technical problem to be solved to find a topiroxostat dosage form with small side effects, stable blood drug concentration, good stability, convenient to take and good patient compliance. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a topropicast drug composition with good sustained-release effect, stable blood concentration, small side effects, good stability and good compliance, a preparation method and application thereof, which are different from the prior art.

[0008] The present application provides a topropicast drug composition, which has the following characteristics in the dissolution release curve:

[0009] 1) not more than 30% (for example, not more than 20%, and also not more than 15%) of the pharmaceutical active ingredient is dissolved within 1 hour;

[0010] 2) 20% to 70% (for example, 30%, 40%, 50% or 60%) of the pharmaceutical active ingredient is dissolved within 8 hours;

[0011] 3) not less than 70% (for example, 80%, 90%, 95% or 100%) of the pharmaceutical active ingredient is dissolved within 24 hours;

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

[0013] The present application provides a topropicast drug composition, which comprises a drug-containing tablet core and a coating; the drug-containing tablet core comprises a pharmaceutical active ingredient and pharmaceutical excipients; the pharmaceutical excipients are selected from one or more of a matrix material, a disintegrant, a pH regulator, a glidant, a lubricant and a matrix strength regulator; the pharmaceutical active ingredient is selected from one or more of topropicast, pharmaceutically acceptable salts, solvates and hydrates thereof.

[0014] According to an embodiment of the present application, the topropicast drug composition has a dissolution release curve as described above.

[0015] According to an embodiment of the present application, the content of the pharmaceutical active 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%, which is the percentage of the weight of the pharmaceutical active ingredient to the weight of the drug-containing tablet core.

[0016] According to some embodiments of the present application, the pharmaceutical excipients comprise or consist of a matrix material, a disintegrant, a glidant, a lubricant and a matrix strength regulator.

[0017] According to some embodiments of the present application, the pharmaceutical excipient comprises or consists of a matrix material, a disintegrant, a pH adjuster, a glidant, a lubricant, and a matrix strength adjuster.

[0018] According to embodiments of the present application, the matrix material refers to a substance that controls the speed and degree of drug release, maintains the good shape of the tablet, allows the drug to slowly enter the blood, reduces the blood drug concentration, and achieves the intended therapeutic effect, and is selected from one or more of sodium alginate, hydroxyethyl cellulose, hypromellose, a polyvinyl acetate povidone mixture (trade name Opadry® from BASF SE), carbomer, and polyoxyethylene, preferably one or more of sodium alginate, hydroxyethyl cellulose, hypromellose, and a polyvinyl acetate povidone mixture. According to embodiments of the present application, 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%, the content referring to the weight percentage of the matrix material in the weight of the tablet core.

[0019] According to embodiments of the present application, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and can also swell the tablet to form channels in the tablet core, promoting drug release, and is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carmellose calcium, and low-substituted hydroxypropyl cellulose, preferably crospovidone.

[0020] According to embodiments of the present application, 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%, the content referring to the weight percentage of the disintegrant in the weight of the tablet core.

[0021] According to embodiments of the present application, the pH adjuster refers to a substance dispersed in the tablet core to maintain or change the acid-base degree of the microenvironment in the tablet core, and is selected from one or more of fumaric acid, citric acid, potassium citrate, lactic acid, and tartaric acid, for example fumaric acid.

[0022] According to embodiments of the present application, the pH adjuster refers to a substance dispersed in the tablet core to maintain or change the acid-base degree of the microenvironment in the tablet core, 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 the embodiments of the present application, the content of the pH adjusting agent 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%, 1.10%, 1.20%, 1.30%, 1.36%, 1.40%, 1.50%, 2.00%, 3.00%, 4.00%, the content being the weight percentage of the pH adjusting agent to the weight of the drug-containing tablet core.

[0024] According to the embodiments of the present application, the particle size of the pH adjusting agent is 10 to 150 μm, for example, 20 to 110 μm, 20 to 40 μm, exemplarily 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm.

[0025] According to the embodiments of the present application, the glidant refers to a conventional auxiliary material in the art which can reduce the friction between particles and improve the flowability of powder or granules, and is selected from one or more of colloidal silicon dioxide, microfine silica and talc.

[0026] According to the embodiments of the present application, the content of the glidant 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%, the content being the weight percentage of the glidant to the weight of the drug-containing tablet core.

[0027] According to the embodiments of the present application, the lubricant refers to a conventional substance having lubricating effect in the art, and is selected from one or more of metal stearate, glycerin 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 and stearyl fumarate; the stearyl fumarate is selected from sodium stearyl fumarate.

[0028] According to the embodiments of the present application, 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%, the content being the weight percentage of the lubricant to the weight of the drug-containing tablet core.

[0029] According to embodiments of the present application, the backbone strength regulator refers to a material that is conventionally used to regulate the release strength of a backbone material in the art, and is selected from one or more of anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium chloride, calcium carbonate, and calcium silicate, for example anhydrous dibasic calcium phosphate.

[0030] According to embodiments of the present application, the backbone strength regulator can be present in an amount of 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%, the amount being the weight percentage of the backbone strength regulator to the weight of the drug-containing tablet core.

[0031] According to embodiments of the present application, the coating can be a film coating; the film coating can be a gastric-soluble film coating.

[0032] According to embodiments of the present application, the coating can be present in an amount of 1.00% to 5.00%, for example 1.00%, 2.00%, 3.00%, 4.00%, or 5.00%, the amount being the weight percentage of the coating to the weight of the drug-containing tablet core.

[0033] According to some embodiments of the present application, the drug-containing tablet core can comprise or consist of the following components in the following amounts: 2.00% to 25.00% of a pharmaceutically active ingredient, 40.00% to 80.00% of a backbone material, 10.00% to 40.00% of a disintegrant, 0.10% to 1.00% of a glidant, 0.10% to 5.00% of a lubricant, and 1.00% to 30.00% of a backbone strength regulator.

[0034] For example, the drug-containing tablet core can comprise or consist of the following components in the following amounts: 2.00% to 25.00% of topropisteril, 40.00% to 80.00% of a backbone material (selected from one or more of sodium alginate, hydroxyethyl cellulose, hypromellose, and a polyvinyl acetate povidone mixture), 10.00% to 40.00% of crospovidone, 0.10% to 1.00% of colloidal silicon dioxide, 0.10% to 5.00% of magnesium stearate, and 1.00% to 30.00% of anhydrous dibasic calcium phosphate.

[0035] According to some embodiments of the present application, the drug-containing tablet core can comprise or consist of the following components in the following amounts: 2.00% to 20.00% of a pharmaceutically active ingredient, 40.00% to 80.00% of a backbone material, 0.05% to 5.00% of a pH regulator, 10.00% to 40.00% of a disintegrant, 0.10% to 1.00% of a glidant, 0.10% to 5.00% of a lubricant, and 1.00% to 30.00% of a backbone strength regulator.

[0036] For example, the tablet comprises or consists of the following components: 2.00% to 20.00% of toptipost, 40.00% to 80.00% of a matrix material (selected from one or more of sodium alginate, hydroxyethyl cellulose, hypromellose, and a mixture of polyvinyl acetate povidone), 0.05% to 5.00% of fumaric acid, 10.00% to 40.00% of cross-linked povidone, 0.10% to 1.00% of colloidal silicon dioxide, 0.10% to 5.00% of magnesium stearate, and 1.00% to 30.00% of dibasic calcium phosphate.

[0037] According to an embodiment of the present application, the drug-containing tablet core has an inner layer and an outer layer;

[0038] The inner layer comprises or consists of the following components: a pharmaceutically active ingredient, a matrix material, a disintegrant, a glidant, and a lubricant, or comprises or consists of the following components: a pharmaceutically active ingredient, a matrix material, a disintegrant, a pH adjuster, a glidant, and a lubricant;

[0039] The outer layer comprises or consists of the following components: a matrix material, a matrix strength adjuster, and a lubricant.

[0040] According to an embodiment of the present application, the weight ratio of the inner layer matrix material to the outer layer matrix material is greater than 1 and not more than 3.0, preferably 1.05 to 2.5, exemplarily 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 application, the inner layer matrix material and the outer layer matrix material are the same or different, for example, the inner layer matrix material is sodium alginate and hydroxyethyl cellulose, and the outer layer matrix material is a mixture of hypromellose and polyvinyl acetate povidone.

[0042] According to an embodiment of the present application, 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 application, the inner layer lubricant and the outer layer lubricant are the same or different, for example, both are metal stearate salts.

[0044] According to an embodiment of the present application, the drug-containing tablet core can be any of the following formulations:

[0045] Formulation 1 : 10.91% toptipost (internal), 25.92% sodium alginate (internal), 19.09% crospovidone (internal), 9.09% hydroxyethyl cellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone blend (external), 10.91% anhydrous dibasic calcium phosphate (external), and 1.36% magnesium stearate (external);

[0046] Formulation 2: 7.27% toptipost (internal), 29.56% sodium alginate (internal), 19.09% crospovidone (internal), 9.09% hydroxyethyl cellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone blend (external), 10.91% anhydrous dibasic calcium phosphate (external), and 1.36% magnesium stearate (external);

[0047] Formulation 3: 10.91% toptipost (internal), 26.00% sodium alginate (internal), 16.36% crospovidone (internal), 6.82% hydroxyethyl cellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 18.56% polyvinyl acetate povidone blend (external), 10.91% anhydrous dibasic calcium phosphate (external), and 0.45% magnesium stearate (external);

[0048] Formulation 4: 10.91% toptipost (internal), 29.74% sodium alginate (internal), 16.36% crospovidone (internal), 6.82% hydroxyethyl cellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 14.82% polyvinyl acetate povidone blend (external), 10.91% anhydrous dibasic calcium phosphate (external), and 0.45% magnesium stearate (external);

[0049] Formulation 5: 10.91% toptipost (internal), 23.19% sodium alginate (internal), 19.09% crospovidone (internal), 9.09% hydroxyethyl cellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone blend (external), 13.64% anhydrous dibasic calcium phosphate (external), and 1.36% magnesium stearate (external);

[0050] Formulation 6: 10.91% toripristat (ing), 28.19% sodium alginate (ing), 16.36% crospovidone (ing), 6.82% hydroxyethylcellulose (ing), 0.45% colloidal silicon dioxide (ing), 0.45% magnesium stearate (ing), 10.91% hypromellose (eg), 14.55% polyvinyl acetate povidone mixture (eg), 10.91% anhydrous dibasic calcium phosphate (eg), and 0.45% magnesium stearate (eg);

[0051] Formulation 7: 7.27% toripristat (ing), 25.92% sodium alginate (ing), 19.09% crospovidone (ing), 9.09% hydroxyethylcellulose (ing), 0.45% colloidal silicon dioxide (ing), 0.45% magnesium stearate (ing), 9.09% hypromellose (eg), 12.73% polyvinyl acetate povidone mixture (eg), 14.55% anhydrous dibasic calcium phosphate (eg), and 1.36% magnesium stearate (eg);

[0052] Formulation 8: 7.27% toripristat (ing), 29.56% sodium alginate (ing), 21.82% crospovidone (ing), 9.09% hydroxyethylcellulose (ing), 0.45% colloidal silicon dioxide (ing), 0.45% magnesium stearate (ing), 9.09% hypromellose (eg), 10.00% polyvinyl acetate povidone mixture (eg), 10.91% anhydrous dibasic calcium phosphate (eg), and 1.36% magnesium stearate (eg);

[0053] Formulation 9: 18.18% toripristat (ing), 25.47% sodium alginate (ing), 16.36% crospovidone (ing), 6.82% hydroxyethylcellulose (ing), 0.45% colloidal silicon dioxide (ing), 0.45% magnesium stearate (ing), 9.09% hypromellose (eg), 12.73% polyvinyl acetate povidone mixture (eg), 9.09% anhydrous dibasic calcium phosphate (eg), and 1.36% magnesium stearate (eg);

[0054] Formulation 10: 18.18% toripristat (ing), 23.65% sodium alginate (ing), 16.36% crospovidone (ing), 6.82% hydroxyethylcellulose (ing), 0.45% colloidal silicon dioxide (ing), 0.45% magnesium stearate (ing), 9.09% hypromellose (eg), 14.55% polyvinyl acetate povidone mixture (eg), 9.09% anhydrous dibasic calcium phosphate (eg), and 1.36% magnesium stearate (eg);

[0055] Formulation 11 : 21.82% of toptiprolate (internal), 23.19% of sodium alginate (internal), 16.36% of cross-linked povidone (internal), 6.82% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 9.09% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 7.73% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external);

[0056] Formulation 12: 21.82% of toptiprolate (internal), 25.91% of sodium alginate (internal), 14.55% of cross-linked povidone (internal), 4.55% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 7.27% of hypromellose (external), 14.55% of polyvinyl acetate povidone mixture (external), 9.09% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external);

[0057] Formulation 13: 10.91% of toptiprolate (internal), 0.91% of fumaric acid (internal), 25.91% of sodium alginate (internal), 19.09% of cross-linked povidone (internal), 8.64% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 8.64% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 10.91% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external);

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

[0059] Formulation 14: 10.91% of toptiprolate (internal), 0.91% of fumaric acid (internal), 25.91% of sodium alginate (internal), 19.09% of cross-linked povidone (internal), 8.64% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 8.64% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 10.91% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external);

[0060] The fumaric acid has a particle size of 20-40 μm;

[0061] Prescription 15: 10.91% of topropidostat (internal addition), 1.37% of fumaric acid (internal addition), 25.91% of sodium alginate (internal addition), 19.09% of cross-linked povidone (internal addition), 8.41% of hydroxyethyl cellulose (internal addition), 0.45% of colloidal silicon dioxide (internal addition), 0.45% of magnesium stearate (internal addition), 8.41% of hypromellose (external addition), 12.73% of polyvinyl acetate povidone mixture (external addition), 10.91% of anhydrous calcium hydrogen phosphate (external addition), and 1.36% of magnesium stearate (external addition);

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

[0063] Prescription 16: 7.27% of topropidostat (internal addition), 0.91% of fumaric acid (internal addition), 29.55% of sodium alginate (internal addition), 19.09% of cross-linked povidone (internal addition), 8.64% of hydroxyethyl cellulose (internal addition), 0.45% of colloidal silicon dioxide (internal addition), 0.45% of magnesium stearate (internal addition), 8.64% of hypromellose (external addition), 12.73% of polyvinyl acetate povidone mixture (external addition), 10.91% of anhydrous calcium hydrogen phosphate (external addition), and 1.36% of magnesium stearate (external addition).

[0064] In each of the above prescriptions, the internal addition components form an inner layer, and the external addition components form an outer layer.

[0065] According to an embodiment of the present application, the topropidostat pharmaceutical composition comprises 40 mg to 240 mg of topropidostat, for example, 40 mg, 80 mg, 120 mg, 200 mg, or 240 mg.

[0066] The present application also provides a preparation method of the topropidostat pharmaceutical composition, which includes, but is not limited to, dry granulation method, wet granulation method, fluidized granulation method, tablet compression method, and film coating method.

[0067] The present application also provides a topropidostat pharmaceutical composition prepared by the preparation method.

[0068] The present application also provides a pharmaceutical preparation comprising the topropidostat pharmaceutical composition.

[0069] The present application also provides an application of the topropidostat pharmaceutical composition in the preparation of a pharmaceutical preparation, preferably the pharmaceutical preparation is used for treating and / or preventing hyperuricemia and / or gout.

[0070] According to an embodiment of the present application, the pharmaceutical preparation can be an oral pharmaceutical preparation, for example, a tablet; the oral pharmaceutical preparation can be an oral sustained-release pharmaceutical preparation; the oral sustained-release pharmaceutical preparation is, for example, a sustained-release tablet.

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

[0072] The present application also provides the use of the toptipirate pharmaceutical composition in the preparation of a pharmaceutical preparation for treating and / or preventing hyperuricemia and / or gout, which has the limitations as shown above.

[0073] The present application also provides a method for treating and / or preventing hyperuricemia and / or gout, which provides a therapeutically effective amount of the toptipirate pharmaceutical composition or pharmaceutical preparation to a patient in need (for example a patient with difficulty in swallowing).

[0074] Definitions and explanations of terms

[0075] The term "plurality" means two or more, for example two, three or more.

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

[0077] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0078] On the basis of not violating the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining each preferred example of the present application.

[0079] The reagents and raw materials used in the present application are commercially available.

[0080] Advantages of the present application: The toptipirate pharmaceutical composition of the present application has good sustained-release performance, the tablet size can expand rapidly during in vitro dissolution, and after expansion, it has good rigidity and elasticity, has a significant gastric retention effect, and the 24-hour cumulative release rate can reach more than 70%. The peak-trough phenomenon of blood drug concentration presented by ordinary dosage forms is reduced, the blood drug concentration of the drug is maintained at a relatively stable concentration for continuous effect, and the adverse reactions are reduced; it is suitable for patients with difficulty in swallowing, improves the compliance of drug taking, has good taste, and improves the patient's compliance; it is convenient to carry and has good stability. The preparation process of the present application is simple, significantly improves the problems of filling difficulty, tablet weight instability and the like in the tabletting process caused by poor flowability and low bulk density of the raw material drug, the process is stable, the process parameters are adjustable and controllable, is conducive to the production of the product, and has good market prospect. DETAILED DESCRIPTION

[0081] The application will be further described in the following by way of examples without thereby limiting the application to the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are selected in accordance with the usual methods and conditions, or in accordance with the instructions of the commercial suppliers.

[0082] Example 1

[0083] Table 1 Formulation of Example 1

[0084] Preparation process:

[0085] ① Take the prescription amount of internal added raw and auxiliary materials, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone together for use.

[0086] ② Place the mixture of sodium alginate, topropisate, and sieved hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone in a suitable mixing hopper, mix for 15 min, and after mixing, use a whole granulator to whole granulate and scatter.

[0087] ③ Place the whole granulated and scattered material of step ② in a mixing hopper, add magnesium stearate, and continue mixing for 10 min.

[0088] ④ Use a dry granulator to dry granulate the mixed material of step ③, press the material into tablets, use the whole granulation equipment matched with the dry granulator to whole granulate, and after whole granulation, collect the material for weighing.

[0089] ⑤ According to the prescription proportion, convert the addition of materials: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate and magnesium stearate, and weigh.

[0090] ⑥ Place the whole granulated material of step ④ in a mixing hopper, add the weighed hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture and anhydrous calcium hydrogen phosphate of step ⑤, mix for 15 min, and after adding magnesium stearate, continue mixing for 10 min.

[0091] ⑦ Use a rotary tablet press to press the mixed material of step ⑥ into tablets, and after tablet pressing, use a high-efficiency coating machine and a film coating premix to coat the tablet core.

[0092] Example 2

[0093] Table 2 Formulation of Example 2

[0094] Preparation process:

[0095] ① Take the prescription amount of internal added raw and auxiliary materials, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone together for use.

[0096] ② Put the mixture of sodium alginate, toptiprist, and sieved hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone into the matching mixing hopper, mix for 15 min, and after mixing is completed, use the whole granulator to whole granulate and scatter.

[0097] ③ Put the material after whole granulation and scattering in step ② into the mixing hopper, add magnesium stearate, and continue to mix for 10 min.

[0098] ④ Use the dry granulator to dry granulate the mixed material in step ③, press the material into tablets, and after that, use the whole granulation equipment matched with the dry granulator to whole granulate, and after whole granulation is completed, collect the material for weighing.

[0099] ⑤ Add and weigh the material according to the prescription proportion: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate.

[0100] ⑥ Put the material after whole granulation in step ④ into the mixing hopper, add the hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step ⑤, mix for 15 min, and after adding magnesium stearate, continue to mix for 10 min.

[0101] ⑦ Use the rotary tablet press to press the mixed material in step ⑥ into tablets, and after tablet pressing is completed, use the high-efficiency coating machine and film coating premix to coat the tablet core.

[0102] Example 3

[0103] Table 3 Prescription of Example 3

[0104] Preparation process:

[0105] ① Weigh the prescription amount of internal additive raw materials, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone together for use.

[0106] ② Put the mixture of sodium alginate, toptiprist, and sieved hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone into the matching mixing hopper, mix for 15 min, and after mixing is completed, use the whole granulator to whole granulate and scatter.

[0107] ③ Put the material after whole granulation and scattering in step ② into the mixing hopper, add magnesium stearate, and continue to mix for 10 min.

[0108] ④ Use the dry granulator to dry granulate the mixed material in step ③, press the material into tablets, and after that, use the whole granulation equipment matched with the dry granulator to whole granulate, and after whole granulation is completed, collect the material for weighing.

[0109] 5. Add the additional materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous dibasic calcium phosphate, and magnesium stearate, according to the prescription proportion, and weigh.

[0110] 6. Place the granulated material of step 4 in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous dibasic calcium phosphate weighed in step 5, and mix for 15 min. After adding magnesium stearate, continue mixing for 10 min.

[0111] 7. Use a rotary tablet press to compress the mixed material of step 6 into tablets. After tablet compression, use a high-efficiency coating machine and film coating premix to coat the tablet core.

[0112] Example 4

[0113] Table 4 Prescription of Example 4

[0114] Preparation process:

[0115] 1. Weigh the prescribed amount of internal additives, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone together for use.

[0116] 2. Place the mixture of sodium alginate, topropisate, and sieved hydroxyethyl cellulose, colloidal silicon dioxide, and cross-linked povidone in a suitable mixing hopper, mix for 15 min, and then use a granulator to granulate and scatter.

[0117] 3. Place the granulated and scattered material of step 2 in the mixing hopper, add magnesium stearate, and continue mixing for 10 min.

[0118] 4. Use a dry granulator to dry granulate the mixed material of step 3. After compressing the material into tablets, use the granulating equipment of the dry granulator to granulate. After granulation, collect the material for weighing.

[0119] 5. Add the additional materials: hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, anhydrous dibasic calcium phosphate, and magnesium stearate, according to the prescription proportion, and weigh.

[0120] 6. Place the granulated material of step 4 in the mixing hopper, add the hydroxypropyl methylcellulose, polyvinyl acetate povidone mixture, and anhydrous dibasic calcium phosphate weighed in step 5, and mix for 15 min. After adding magnesium stearate, continue mixing for 10 min.

[0121] 7. Use a rotary tablet press to compress the mixed material of step 6 into tablets. After tablet compression, use a high-efficiency coating machine and film coating premix to coat the tablet core.

[0122] Example 5

[0123] Table 5 Formulation of Example 5

[0124] Preparation process:

[0125] ① Take the prescription amount of internal additives, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone together for use.

[0126] ② Place the mixture of sodium alginate, topropister and sieved hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone in a suitable mixing hopper, mix for 15 min, and after mixing, use a granulator to granulate and scatter.

[0127] ③ Place the granulated and scattered material of step ② in the mixing hopper, add magnesium stearate, and continue mixing for 10 min.

[0128] ④ Use a dry granulator to dry granulate the mixed material of step ③, press the material into large pieces, and then use the granulating equipment of the dry granulator to granulate. After granulation, collect the material for weighing.

[0129] ⑤ According to the prescription proportion, calculate the addition amount of the external materials: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate and magnesium stearate, and weigh them.

[0130] ⑥ Place the granulated material of step ④ in the mixing hopper, add the weighed hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture and anhydrous calcium hydrogen phosphate of step ⑤, mix for 15 min, and continue mixing for 10 min after adding magnesium stearate.

[0131] ⑦ Use a rotary tablet press to compress the mixed material of step ⑥ into tablets, and then use a high-efficiency coating machine and a film coating premix to coat the tablet cores.

[0132] Example 6

[0133] Table 6 Formulation of Example 6

[0134] Preparation process:

[0135] ① Take the prescription amount of internal additives, and sieve the hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone together for use.

[0136] ② Place the mixture of sodium alginate, topropister, sieved hydroxyethyl cellulose, colloidal silicon dioxide and cross-linked povidone in a suitable mixing hopper, mix for 15 min, and after mixing, use a granulator to granulate and scatter.

[0137] ③ Put the material after step 2 into the mixing hopper, add magnesium stearate, and continue mixing for 10 min.

[0138] ④ Use dry granulator to granulate the mixed material of step 3, and then press the material into tablets. After that, use the granulating equipment matched with the dry granulator to granulate the material. After the granulation is completed, collect the material for weighing.

[0139] ⑤ Add the materials according to the prescription proportion: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate, and weigh them.

[0140] ⑥ Put the material after step 4 into the mixing hopper, add the hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step 5, and mix for 15 min. Then add magnesium stearate and continue mixing for 10 min.

[0141] ⑦ Use rotary tablet press to press the mixed material of step 6 into tablets. After that, use high-efficiency coating machine and film coating premix to coat the tablet core.

[0142] Example 7

[0143] The samples of Examples 1-4 were tested by USP Method 2 (900 ml, pH 1.2 hydrochloric acid solution, 50 rpm). The in vitro release results and the tablet core size and rigidity after dissolution are shown in Table 7.

[0144] Table 7

[0145] Example 8

[0146] The samples of Examples 1-4 were tested by USP Method 2 (900 ml, pH 4.5 acetate buffer, 50 rpm). The tablet core size and rigidity after dissolution (24 h) were measured, and the results are shown in Table 8.

[0147] Table 8

[0148] Example 9

[0149] Based on the above examples, the pH regulator was added to improve the tablet core microenvironment and improve the dissolution and release speed.

[0150] Table 9 Prescription of Example 9

[0151] 120mg-7 example fumaric acid particle size is 110 μm, 120mg-8 example fumaric acid particle size is 20-40 μm, 120mg-9 example fumaric acid particle size is 20-40 μm.

[0152] Preparation process:

[0153] ① Take the prescription amount of internal additives, hydroxyethyl cellulose, colloidal silicon dioxide, sieve for use.

[0154] ② The mixture of sodium alginate, fumaric acid, toptirum, and sieved hydroxyethyl cellulose, colloidal silicon dioxide is placed in the appropriate mixing hopper, mixed for 15 min, after mixing, the whole granulator is used for whole granulation and sieving.

[0155] ③ The material after whole granulation and sieving in step ② is placed in the mixing hopper, and magnesium stearate is added, and the mixing is continued for 10 min.

[0156] ④ The mixed material in step ③ is used for dry granulation by using dry granulator, and the material is pressed into tablets, and the whole granulation equipment matched with the dry granulator is used for whole granulation, and after whole granulation, the material is collected and weighed.

[0157] ⑤ The added material is converted according to the prescription proportion: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate and magnesium stearate, and weighed.

[0158] ⑥ The whole granulated material in step ④ is placed in the mixing hopper, and the hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate weighed in step ⑤ is added, mixed for 15 min, and magnesium stearate is added and mixed for 10 min.

[0159] ⑦ The mixed material in step ⑥ is used for tabletting by using rotary tablet press, and after tabletting, the tablet core is coated by using high efficiency coating machine and film coating premix.

[0160] Example 10

[0161] Table 10 prescription of example 10

[0162] Preparation process:

[0163] ① Take the prescription amount of internal additives, hydroxyethyl cellulose, colloidal silicon dioxide, sieve for use.

[0164] ② The mixture of sodium alginate, fumaric acid, toptirum, and sieved hydroxyethyl cellulose, colloidal silicon dioxide is placed in the appropriate mixing hopper, mixed for 15 min, after mixing, the whole granulator is used for whole granulation and sieving.

[0165] ③ Put the material sieved in step 2 into the mixing hopper, add magnesium stearate, and continue mixing for 10 min.

[0166] ④ Use the dry granulator to dry-granulate the mixed material in step 3, press the material into large pieces, and then use the granulating equipment matched with the dry granulator to granulate. After granulation, collect the material for weighing.

[0167] ⑤ Add the material according to the prescription proportion: hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, anhydrous calcium hydrogen phosphate, and magnesium stearate, and weigh them.

[0168] ⑥ Put the granulated material in step 4 into the mixing hopper, add the hydroxypropyl methyl cellulose, polyvinyl acetate povidone mixture, and anhydrous calcium hydrogen phosphate weighed in step 5, mix for 15 min, and then add magnesium stearate and continue mixing for 10 min.

[0169] ⑦ Use the rotary tablet press to compress the mixed material in step 6 into tablets, and then use the high-efficiency coating machine and film coating premix to coat the tablet cores.

[0170] Example 11

[0171] The samples in Examples 9-10 were tested 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.

[0172] Table 11

[0173] The addition of the pH adjuster in the formula significantly improves the dissolution rate of the product.

[0174] Example 12

[0175] The samples in Examples 9-10 were tested for in-vitro release using USP Method 1 (900 ml, pH 1.2 hydrochloric acid solution, basket method 100 rpm), and the results are shown in Table 12 below.

[0176] Table 12

[0177] The addition of the pH adjuster improves the dissolution rate of the product, the sustained-release effect is good, the production process of the product is simple, and the process stability is good.

[0178] Example 13

[0179] The 120mg-8 product in Example 9 was subjected to a stability test, and the test method was as follows: high performance liquid chromatography was used for testing, with 0.1 mol / L hydrochloric acid-methanol (50:50) as the solvent. The test results showed that the related substances were almost the same as before the test, and the product had good stability.

[0180] Table 13 Stability test results

[0181] The TPST-1 impurity chemical name: 4-[5-(pyridin-4-yl)-1H-[1,2,4]-triazol-3-yl]pyridine-2-carboxamide, chemical name: C 13 H 10 N6O, molecular weight: 266.26.

[0182] Example 14

[0183] A PK study was carried out in healthy subjects using the test product group (120mg-1 product in Example 1 and 120mg-8 product in Example 9) and the control group (original research Tomiptik tablet, trade name 60mg specification).

[0184] Test product group: 120mg-1 Tomiptik sustained-release tablets in Example 1 and 120mg-8 Tomiptik sustained-release tablets in Example 9, with a dose of 240mg / day, single administration, 2 tablets at a time;

[0185] The control group was administered at a dose of 240mg / day, 2 tablets every 12h, for a total of 2 times.

[0186] The original research control group and the test product group were subjected to phase blood sampling for blood concentration detection, with blood sampling time points of 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, 48h, and the pharmacokinetic parameter results are shown in Table 14:

[0187] Table 14 In vivo PK results

[0188] The results show that the geometric mean ratios of Cmax and AUC of the test product group (120 mg-1 of the sustained-release tablet of toptipirate in Example 1) are far lower than 80%, and the geometric mean ratios of Cmax and AUC of the test product group (120 mg-8 of the sustained-release tablet of toptipirate in Example 9) are greatly improved by adding the pH adjuster sodium fumarate, and the geometric mean ratio of AUC is close to 80%. Therefore, by optimizing adjustment, the AUC of the sustained-release tablet of toptipirate is obviously improved, is equivalent to the AUC of the tablet of toptipirate, and the sustained-release tablet of toptipirate has a slower release speed, a more stable blood drug concentration, reduces the occurrence of adverse reactions while achieving curative effect, and brings better curative effect, compliance and safety to patients.

[0189] The sustained-release tablet of toptipirate obtained in Example 10 also has the same or similar pharmacokinetic effect as the 120 mg-8 sustained-release tablet of toptipirate in Example 9.

[0190] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A toipsumide pharmaceutical composition, characterized by: The toptiprazate pharmaceutical composition comprises a drug-containing tablet core and a coating; the drug-containing tablet core comprises a pharmaceutical active ingredient and pharmaceutical excipients; the pharmaceutical excipients are selected from one or more of a matrix material, a disintegrant, a pH regulator, a glidant, a lubricant and a matrix strength regulator; the pharmaceutical active ingredient is selected from one or more of toptiprazate, pharmaceutically acceptable salts, solvates and hydrates thereof; Preferably, the pharmaceutical excipients comprise or consist of a matrix material, a disintegrant, a glidant, a lubricant and a matrix strength regulator; Preferably, the pharmaceutical excipients comprise or consist of a matrix material, a disintegrant, a pH regulator, a glidant, a lubricant and a matrix strength regulator; Preferably, the toptiprazate pharmaceutical composition comprises 40 mg to 240 mg of toptiprazate.

2. A tolfenpirad drug composition, characterized by: The dissolution release profile of the toptiprazate pharmaceutical composition has the following characteristics: 1) not more than 30% of the pharmaceutical active ingredient is dissolved within 1 hour; 2) 20% to 70% of the pharmaceutical active ingredient is dissolved within 8 hours; 3) not less than 70% of the pharmaceutical active ingredient is dissolved within 24 hours; Preferably, the toptiprazate pharmaceutical composition is the toptiprazate pharmaceutical composition of claim 1.

3. The toptiprazate pharmaceutical composition of claim 1 or 2, wherein: the content of the pharmaceutical active ingredient is 2.00% to 25.00%, preferably 2.00% to 20.00%, the content referring to the weight percentage of the pharmaceutical active ingredient in the drug-containing tablet core; and / or, the matrix material is selected from one or more of sodium alginate, hydroxyethyl cellulose, hypromellose, polyvinyl acetate povidone mixture, carbomer and polyoxyethylene; and / or, the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carboxymethyl cellulose calcium and low-substituted hydroxypropyl cellulose; and / or, the pH regulator is selected from one or more of fumaric acid, citric acid, potassium citrate, lactic acid and tartaric acid; and / or, the glidant is selected from one or more of colloidal silicon dioxide, micro-powder 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 and stearyl fumarate; preferably, the stearyl fumarate is sodium stearyl fumarate; and / or, the matrix strength regulator is selected from one or more of anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, calcium chloride, calcium carbonate and calcium silicate; and / or, the coating is a film coating; preferably, the coating is a gastro-soluble film coating.

4. The toptiprazate pharmaceutical composition of claim 1 or 2, wherein: The content of the said skeleton material is 40.00% to 80.00%, preferably 50.00% to 65.00%, the content refers to the weight percentage of the skeleton material in the weight of the tablet core; and / or, The content of the said disintegrant is 10.00% to 40.00%, preferably 15.00% to 25.00%, the content refers to the weight percentage of the disintegrant in the weight of the tablet core; and / or, The content of the said pH regulator can be 0.05% to 5.00%, preferably 0.5% to 2.00%, the content refers to the weight percentage of the pH regulator in the weight of the tablet core; and / or, The particle size of the said pH regulator is 10 to 150 μm; and / or, The content of the said glidant is 0.10% to 1.00%, the content refers to the weight percentage of the glidant in the weight of the tablet core; and / or, The content of the said lubricant is 0.10% to 5.00%, the content refers to the weight percentage of the lubricant in the weight of the tablet core; and / or, The content of the said skeleton strength regulator is 1.00% to 30.00%, preferably 5.00% to 20.00%, the content refers to the weight percentage of the skeleton strength regulator in the weight of the tablet core; and / or, The content of the said coating is 1.00% to 5.00%, the content refers to the weight percentage of the coating in the weight of the tablet core.

5. The topropirimate pharmaceutical composition of claim 1 or 2, wherein: The said tablet core comprises or consists of the following components in the following content: 2.00% to 25.00% of the pharmaceutical active ingredient, 40.00% to 80.00% of the skeleton material, 10.00% to 40.00% of the disintegrant, 0.10% to 1.00% of the glidant, 0.10% to 5.00% of the lubricant and 1.00% to 30.00% of the skeleton strength regulator; Preferably, the said tablet core comprises or consists of the following components in the following content: 2.00% to 25.00% of topropirimate, 40.00% to 80.00% of the skeleton material, 10.00% to 40.00% of crosslinked polyvinylpyrrolidone, 0.10% to 1.00% of colloidal silicon dioxide, 0.10% to 5.00% of magnesium stearate and 1.00% to 30.00% of anhydrous calcium hydrogen phosphate; Alternatively, the said tablet core comprises or consists of the following components in the following content: 2.00% to 20.00% of the pharmaceutical active ingredient, 40.00% to 80.00% of the skeleton material, 0.05% to 5.00% of the pH regulator, 10.00% to 40.00% of the disintegrant, 0.10% to 1.00% of the glidant, 0.10% to 5.00% of the lubricant and 1.00% to 30.00% of the skeleton strength regulator; Preferably, the drug-containing tablet core comprises or consists of the following components in the following amounts: 2.00% to 20.00% of toptiprol, 40.00% to 80.00% of a matrix material, 0.05% to 5.00% of fumaric acid, 10.00% to 40.00% of cross-linked povidone, 0.10% to 1.00% of colloidal silicon dioxide, 0.10% to 5.00% of magnesium stearate, and 1.00% to 30.00% of dibasic calcium phosphate anhydrous.

6. The tolfenpyrad pharmaceutical composition according to claim 1 or 2, wherein: The drug-containing tablet core has an inner layer and an outer layer; The inner layer comprises or consists of a pharmaceutically active ingredient, a matrix material, a disintegrant, a glidant, and a lubricant, or comprises or consists of a pharmaceutically active ingredient, a matrix material, a disintegrant, a pH adjuster, a glidant, and a lubricant; The outer layer comprises or consists of a matrix material, a matrix strength adjuster, and a lubricant; Preferably, the weight ratio of the inner layer matrix material to the outer layer matrix material is greater than 1 and not more than 3.0, preferably 1.05 to 2.5; And / or, the inner layer matrix material and the outer layer matrix material are the same or different, for example, the inner layer matrix material is sodium alginate and hydroxyethyl cellulose, and the outer layer matrix material is hypromellose and a polyvinyl acetate povidone mixture; And / or, the weight ratio of the inner layer lubricant to the outer layer lubricant is 1: (1 to 10).

7. The tolfenpyrad pharmaceutical composition according to claim 1 or 2, wherein the tolfenpyrad is tolfenpyrad. The toptiprol pharmaceutical composition is any one of the following formulations: Formulation 1: 10.91% toptiprol (added inside), 25.92% sodium alginate (added inside), 19.09% cross-linked povidone (added inside), 9.09% hydroxyethyl cellulose (added inside), 0.45% colloidal silicon dioxide (added inside), 0.45% magnesium stearate (added inside), 9.09% hypromellose (added outside), 12.73% polyvinyl acetate povidone mixture (added outside), 10.91% dibasic calcium phosphate anhydrous (added outside), and 1.36% magnesium stearate (added outside); Formulation 2: 7.27% toptiprol (added inside), 29.56% sodium alginate (added inside), 19.09% cross-linked povidone (added inside), 9.09% hydroxyethyl cellulose (added inside), 0.45% colloidal silicon dioxide (added inside), 0.45% magnesium stearate (added inside), 9.09% hypromellose (added outside), 12.73% polyvinyl acetate povidone mixture (added outside), 10.91% dibasic calcium phosphate anhydrous (added outside), and 1.36% magnesium stearate (added outside); Formulation 3: 10.91% toptiprol (added inside), 26.00% sodium alginate (added inside), 16.36% cross-linked povidone (added inside), 6.82% hydroxyethyl cellulose (added inside), 0.45% colloidal silicon dioxide (added inside), 0.45% magnesium stearate (added inside), 9.09% hypromellose (added outside), 18.56% polyvinyl acetate povidone mixture (added outside), 10.91% dibasic calcium phosphate anhydrous (added outside), and 0.45% magnesium stearate (added outside); Formulation 4: 10.91% toripastat (internal), 29.74% sodium alginate (internal), 16.36% cross-linked povidone (internal), 6.82% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 14.82% polyvinyl acetate povidone mixture (external), 10.91% anhydrous dibasic calcium phosphate (external) and 0.45% magnesium stearate (external); Formulation 5: 10.91% toripastat (internal), 23.19% sodium alginate (internal), 19.09% cross-linked povidone (internal), 9.09% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone mixture (external), 13.64% anhydrous dibasic calcium phosphate (external) and 1.36% magnesium stearate (external); Formulation 6: 10.91% toripastat (internal), 28.19% sodium alginate (internal), 16.36% cross-linked povidone (internal), 6.82% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 10.91% hypromellose (external), 14.55% polyvinyl acetate povidone mixture (external), 10.91% anhydrous dibasic calcium phosphate (external) and 0.45% magnesium stearate (external); Formulation 7: 7.27% toripastat (internal), 25.92% sodium alginate (internal), 19.09% cross-linked povidone (internal), 9.09% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone mixture (external), 14.55% anhydrous dibasic calcium phosphate (external) and 1.36% magnesium stearate (external); Formulation 8: 7.27% toripastat (internal), 29.56% sodium alginate (internal), 21.82% cross-linked povidone (internal), 9.09% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 10.00% polyvinyl acetate povidone mixture (external), 10.91% anhydrous dibasic calcium phosphate (external) and 1.36% magnesium stearate (external); Formulation 9: 18.18% toripastat (internal), 25.47% sodium alginate (internal), 16.36% cross-linked povidone (internal), 6.82% hydroxyethylcellulose (internal), 0.45% colloidal silicon dioxide (internal), 0.45% magnesium stearate (internal), 9.09% hypromellose (external), 12.73% polyvinyl acetate povidone mixture (external), 9.09% anhydrous dibasic calcium phosphate (external) and 1.36% magnesium stearate (external); Formulation 10: 18.18% of toptiprolate (internal), 23.65% of sodium alginate (internal), 16.36% of cross-linked povidone (internal), 6.82% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 9.09% of hypromellose (external), 14.55% of polyvinyl acetate povidone mixture (external), 9.09% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external); Formulation 11: 21.82% of toptiprolate (internal), 23.19% of sodium alginate (internal), 16.36% of cross-linked povidone (internal), 6.82% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 9.09% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 7.73% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external); Formulation 12: 21.82% of toptiprolate (internal), 25.91% of sodium alginate (internal), 14.55% of cross-linked povidone (internal), 4.55% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 7.27% of hypromellose (external), 14.55% of polyvinyl acetate povidone mixture (external), 9.09% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external); Formulation 13: 10.91% of toptiprolate (internal), 0.91% of fumaric acid (internal), 25.91% of sodium alginate (internal), 19.09% of cross-linked povidone (internal), 8.64% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 8.64% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 10.91% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external); the fumaric acid has a particle size of greater than 10 μm and not more than 150 μm; Formulation 14: 10.91% of toptiprolate (internal), 0.91% of fumaric acid (internal), 25.91% of sodium alginate (internal), 19.09% of cross-linked povidone (internal), 8.64% of hydroxyethyl cellulose (internal), 0.45% of colloidal silicon dioxide (internal), 0.45% of magnesium stearate (internal), 8.64% of hypromellose (external), 12.73% of polyvinyl acetate povidone mixture (external), 10.91% of anhydrous dibasic calcium phosphate (external) and 1.36% of magnesium stearate (external); the fumaric acid has a particle size of 20-40 μm; Prescription 15: 10.91% torisemide (internal addition), 1.37% fumaric acid (internal addition), 25.91% sodium alginate (internal addition), 19.09% cross-linked povidone (internal addition), 8.41% hydroxyethyl cellulose (internal addition), 0.45% colloidal silicon dioxide (internal addition), 0.45% magnesium stearate (internal addition), 8.41% hypromellose (external addition), 12.73% polyvinyl acetate povidone mixture (external addition), 10.91% anhydrous calcium hydrogen phosphate (external addition) and 1.36% magnesium stearate (external addition); The particle size of the fumaric acid is 20-40 μm; Prescription 16: 7.27% torisemide (internal addition), 0.91% fumaric acid (internal addition), 29.55% sodium alginate (internal addition), 19.09% cross-linked povidone (internal addition), 8.64% hydroxyethyl cellulose (internal addition), 0.45% colloidal silicon dioxide (internal addition), 0.45% magnesium stearate (internal addition), 8.64% hypromellose (external addition), 12.73% polyvinyl acetate povidone mixture (external addition), 10.91% anhydrous calcium hydrogen phosphate (external addition) and 1.36% magnesium stearate (external addition).

8. The method of preparing a topropide pharmaceutical composition according to any one of claims 1 to 7, wherein: The methods include, but are not limited to, dry granulation, wet granulation, sulfuration granulation, tabletting and film coating.

9. Use of the torisemide pharmaceutical composition according to any one of claims 1-7 in the preparation of a pharmaceutical preparation for treating and / or preventing 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 preparation comprising the torisemide pharmaceutical composition according to any one of claims 1-7. 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.

11. A method for the treatment and / or prophylaxis of hyperuricemia and / or gout, characterized in that: Providing a therapeutically effective amount of the torisemide pharmaceutical composition according to any one of claims 1-7 or the pharmaceutical preparation according to claim 10 to a patient in need.

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