Pharmaceutical preparation of triazole compound and preparation method therefor

Abstract

A pharmaceutical composition and preparation of a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, and a preparation method therefor. The pharmaceutical composition contains the compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition exhibits good drug stability and safety, and the preparation method is simple and convenient, and is applicable to industrial production.

Description

Pharmaceutical formulations of triazoles and methods of making the same

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411391209.5, filed September 30, 2024, in the State Intellectual Property Office of the People’s Republic of China, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application relates to the field of medicine, in particular to pharmaceutical compositions comprising triazoles, formulations, methods of making the same and uses thereof. BACKGROUND

[0004] Compound 1 is a urate transporter 1 (URAT1) inhibitor, which has the chemical formula of Formula (I) below, and its chemical name is 2-((5-bromo-4-(2-chloro-4-cyclopropyl naphthalenyl-1-yl)-4H-1,2,4-triazol-3-yl)-thio)acetic acid. The structure, crystal form and preparation method of Compound 1 can be found in WO2017215589A1, WO2019114838A1, WO2021249468A1, etc.

[0005] AstraZeneca’s first targeted URAT1 inhibitor, Lesinurad, was approved by FDA in December 2015, and its 200 mg / day dose was approved to be used in combination with xanthine oxidase inhibitors XOI (such as Febuxostat, etc.) for the treatment of hyperuricemia and gouty arthritis, but the additional effect of the combination drug compared with the use of xanthine oxidase inhibitors alone is not very significant. At the same time, the 400 mg / day dose of Lesinurad was not approved due to the significant increase in side effects observed at high doses (higher incidence of kidney-related adverse events, especially kidney stones), although the combination drug at high doses showed higher additional effects. Therefore, FDA required that the Lesinurad label add a black box warning to warn medical staff that Lesinurad can cause acute kidney failure, especially more common when not used in combination with XOI, and the risk of kidney failure is higher if Lesinurad is used at an unapproved dose. At the same time, the U.S. FDA required AstraZeneca to continue to investigate the safety of the kidneys and cardiovascular system after the marketing of Lesinurad.

[0006] CN112057429A discloses a controlled-release drug composition for retinal, overcoming the serious toxic side effects of existing retinal when used at high doses; CN107281108A discloses a solid dispersion containing retinal in an amorphous form, which increases dissolution and stability; CN108324695A discloses a retinal-coated tablet, wherein the retinal content in the coated tablet is 67 mg / tablet.

[0007] However, as a drug used for metabolic diseases, it requires long-term use, making drug safety particularly important. Therefore, developing a suitable dosage form for compound 1 that facilitates long-term administration and is suitable for monotherapy is essential. Summary of the Invention

[0008] In view of this, the technical problem to be solved by this application is to provide a suitable dosage form of compound 1 that achieves the purpose of treating hyperuricemia and gouty arthritis, has low toxicity, can meet the needs of long-term medication for patients, and can be used as a monotherapy without the need for combination with other drugs to achieve the therapeutic purpose.

[0009] In one aspect, this application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from one or more of the following: fillers, binders, disintegrants, flow aids, surfactants, and lubricants, etc.

[0010] In this invention, the pharmaceutical composition comprises, by weight percentage, 0.50 wt% to 50.00 wt%, preferably 1.00 wt% to 35.00 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof with a D90 particle size of 5-60 μm.

[0011] In a specific embodiment, the pharmaceutical composition comprises active pharmaceutical ingredient (API) particles and excipients. In a specific embodiment, in addition to a compound of formula (I) or a pharmaceutically acceptable salt thereof, the API particles may comprise one or more of a filler, a binder, and a disintegrant, and the excipients may comprise a disintegrant and a lubricant, and optionally a flow aid and a solubilizer.

[0012] In a preferred embodiment, the pharmaceutical composition is a dosage form for oral administration, such as a tablet.

[0013] In one aspect, the present invention also provides formulations of compounds of formula (I) or pharmaceutically acceptable salts thereof, said formulations comprising the pharmaceutical composition as described above.

[0014] In another aspect, the present application provides a method for preparing the pharmaceutical composition described herein.

[0015] In addition, the present application also provides the use of the pharmaceutical composition or preparation described in the present application in the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0016] The present application also provides the use of the pharmaceutical composition or preparation described in the present application in the preparation of a medicament for the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0017] In another aspect, the present application provides a method for inhibiting gout or treating or preventing hyperuricemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition or preparation described in the present application.

[0018] The present application provides the pharmaceutical composition or preparation described in the present application for inhibiting gout and treating or preventing hyperuricemia.

[0019] The present application also provides a kit comprising the pharmaceutical composition or preparation described in the present application and instructions for preparing a medicament for the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0020] The present application has the following advantages

[0021] ①The preparation of the present application is an oral preparation (preferably a tablet), which has simple prescription and production process, and in particular, the tablet has the advantages of accurate dosage, stable quality, convenient use, long storage time, etc., and is easy to take, carry and transport, and is convenient for clinical use and has high patient acceptance;

[0022] ②The preparation process of the active ingredient, i.e., the crystalline form A of Compound 1, is stable, has low impurity content, and slow increase in total impurities, which is beneficial to the production and storage of the product;

[0023] ③The pharmaceutical preparation composition provided in the present application has good stability and uniform content, improves the steady-state absorption and distribution of the drug in the body, and is confirmed to be effective through standardized clinical efficacy and pharmacokinetic studies, so that the drug has a broad clinical application prospect in the oral absorption pathway in the human body;

[0024] ④The preparation method of the pharmaceutical composition of the present application is simple and easy to operate, and can be applied to large-scale production; the prepared preparation has significantly improved dissolution under the same conditions, and solves the problem of unqualified content uniformity in the batch production process, and the related substances are stable, and the quality is effectively guaranteed. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is a comparison of the crystal pattern of the API that has been ground, sieved and untreated.

[0026] Figure 2 is a crystal pattern after micronization and wet granulation;

[0027] Figure 3 is a crystal pattern before and after tabletting;

[0028] Figure 4 is a graph of mean plasma drug concentration-time curve (Part 1 study);

[0029] Figure 5 is a graph of mean plasma drug concentration-time curve (Part 2 study). Note: The dotted line in the graph is the lower limit of quantification of blood drug concentration, which is 10 ng / mL. DETAILED DESCRIPTION

[0030] Next, the scheme of the present application will be described in detail in conjunction with examples, but the scope of protection of the present application is not limited thereto.

[0031] Unless otherwise specified, the reagents, materials and devices involved in the following examples are those commercially available in the art. It is particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they all belong to the scope of protection of the present application. The methods and applications of the present application have been described by the preferred embodiments, and the relevant personnel can obviously make modifications or appropriate changes and combinations to the methods and applications herein without departing from the content, spirit and scope of the present application, to realize and apply the technology of the present application.

[0032] In one aspect, the present application provides a pharmaceutical composition comprising a compound represented by formula (I) (hereinafter also referred to as "Compound 1") or a pharmaceutically acceptable salt thereof,

[0033] The chemical name of Compound 1 described in the present application is -((5-bromo-4-(2-chloro-4-cyclopropyl naphthalenyl-1-yl)-4H-1,2,4-triazol-3-yl)-thio)acetic acid, which is represented by the following formula (I):

[0034] In the present application, the pharmaceutical composition comprises 0.50wt%-50.00wt%, preferably 1.00wt%-35.00wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight percentage. Preferably, the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof with a D90 particle size of 5-60 μm, preferably 30-50 μm.

[0035] In the present application, the axially chiral isomers of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as the compounds represented by the following formula (I-a) and formula (I-b), can also be used:

[0036] In preferred embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be in an amorphous form and / or a crystalline form (including single or polycrystalline). For example, the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the present application can be selected from the group consisting of an amorphous form and / or a crystalline form of the compound of Formula (I); an amorphous form and / or a crystalline form of the compound of Formula (I-a) (hereinafter can also be referred to as “Compound la”); an amorphous form and / or a crystalline form of the compound of Formula (I-b) (hereinafter can also be referred to as “Compound lb”).

[0037] For example, the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the present application can be selected from the group consisting of: a crystalline Form A of the compound of Formula (I), a crystalline Form D of the compound of Formula (I), an amorphous Form I of the compound of Formula (I), a crystalline Form B of the compound of Formula (I-a), an amorphous Form II of the compound of Formula (I-a), a crystalline Form C of the compound of Formula (I-b), an amorphous Form III of the compound of Formula (I-b), or a combination thereof. The preparation of the above-mentioned specific crystalline forms and amorphous forms can be defined and confirmed by referring to the methods shown in WO2019114838A1.

[0038] In specific embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the present application is selected in the form of a single crystal. For example, in preferred embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be in the form of a crystalline Form A, a crystalline Form B or a crystalline Form C, in particular a crystalline Form A.

[0039] For the content of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present application, the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be selected from 1wt% to 50.00wt%, for example, preferably 1.00wt%, 2.50wt%, 5.00wt%, 7.50wt%, 10.00wt%, 12.50wt%, 15.00wt%, 20.00wt%, 25.00wt%, 30.00wt%, 35.00wt%, 40.00wt%, 50.00wt% by weight percentage for the purpose of facilitating administration and preparation.

[0040] In the present application, the pharmaceutically acceptable excipient can be selected from one or more of the following: a filler, a binder, a disintegrant, a glidant, a surfactant, a lubricant, and the like.

[0041] In specific embodiments, the pharmaceutical composition comprises active pharmaceutical ingredient particles, and total mixed excipients. In preferred embodiments, the active pharmaceutical ingredient particles comprise the compound of Formula (I), and the particle size is 10-300pm, preferably 10-200pm, more preferably 10-50pm.

[0042] In a preferred embodiment, the active pharmaceutical ingredient is present in the form of microparticles in the active pharmaceutical ingredient particles, and the particle size of the active pharmaceutical ingredient in the form of microparticles is 5-60 μm.

[0043] In the pharmaceutical composition of the present application, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is included, together with one or more of a filler, a binder, a disintegrant, a solubilizer, a glidant, and a lubricant.

[0044] As an example, a filler used in the pharmaceutical field is mainly used to increase the weight and volume of a pharmaceutical composition or preparation (e.g., a tablet) for facilitating the division of a dose. A commonly used filler can be selected from one or more of the following: starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts (e.g., calcium carbonate, calcium phosphate), etc.

[0045] For example, a binder such as a tacky substance is required to be added when a drug itself (e.g., a powder) does not have tackiness or has low tackiness to make it adhere. A commonly used binder in the pharmaceutical field can be selected from one or more of the following: water (e.g., distilled water, purified water, or ultra-pure water), ethanol, starch paste, sugar powder and syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, etc.

[0046] For example, a disintegrant can be included to ensure that a preparation (e.g., an oral preparation) is rapidly disintegrated in a gastrointestinal fluid. A commonly used disintegrant can be selected from one or more of the following: dry starch and its derivatives (e.g., sodium carboxymethyl starch, hydroxypropyl starch), low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, etc.

[0047] As an example, a solubilizer can be selected from a surfactant, which can increase the wettability of a hydrophobic compound, accelerating the disintegration of a preparation and the dissolution of a drug. A commonly used solubilizer is polysorbate 80, sodium dodecyl sulfate, poloxamer 188, etc.

[0048] The addition of a glidant can reduce the angle of repose, thereby enhancing the flowability of a powder. A commonly used glidant is colloidal silicon dioxide, talc, etc.

[0049] In the art, a lubricant can be used to increase the flowability of granules (or powder), reducing the friction between the granules (or powder) and equipment. For example, a commonly used lubricant can be selected from one or more of the following: magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol (e.g., polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000), magnesium lauryl sulfate, sodium stearyl fumarate, etc.

[0050] In some embodiments, the pharmaceutical composition of the present application comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more of a filler, a binder, a disintegrant, a solubilizer, a glidant, and a lubricant.

[0051] In specific embodiments, the pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, a lubricant, a glidant, a binder.

[0052] For example, in specific embodiments, the pharmaceutical composition of the present application comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a filler, a disintegrant, a lubricant, a glidant, and a binder. For example, in preferred embodiments, the pharmaceutical composition of the present application comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a filler, a disintegrant, a lubricant, a glidant, and a binder. In another preferred embodiment, the pharmaceutical composition of the present application comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a filler, a disintegrant, a lubricant, and a binder.

[0053] In more preferred embodiments, the pharmaceutical composition of the present application comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; a lubricant; a binder; and optionally a glidant and / or a solubilizer.

[0054] In some embodiments, the filler comprises 50.00 wt% to 98.00 wt%, preferably 60.00 wt% to 70.00 wt%, by weight percentage, of the weight of the pharmaceutical composition. For example, the filler can be selected from one or more of starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts, and combinations thereof; preferably mannitol, microcrystalline cellulose, lactose, and combinations thereof, such as a combination of the three, or a combination of any two. In specific embodiments, the filler can be selected from a combination of the three of mannitol, microcrystalline cellulose, and lactose; a combination of the three of mannitol, microcrystalline cellulose, and lactose; a combination of microcrystalline cellulose and lactose; a combination of mannitol and microcrystalline cellulose. For cases where more than two fillers are used, the sum of the proportions of each filler is within the range of proportions of fillers defined herein.

[0055] For example, when two fillers (e.g., microcrystalline cellulose in combination with lactose / mannitol) are employed, the weight ratio of the two fillers can be in the range of 5: 1 to 1 :5, for example, 5: 1, 4: 1, 3: 1, 2: 1, 1 : 1, 1 :2, 1 :3, 1 :4, 1 :5, or any value in the range formed by any two of the foregoing. As an example, for a combination of microcrystalline cellulose and lactose or a combination of mannitol and microcrystalline cellulose as the filler, the weight ratio of microcrystalline cellulose to lactose / mannitol can be in the range of 5: 1 to 1 :5, for example, 5: 1, 4: 1, 3: 1, 2: 1, 1 : 1, 1 :2, 1 :3, 1 :4, 1 :5, or any value in the range formed by any two of the foregoing.

[0056] In some embodiments, the disintegrant comprises 0.50 wt% to 10.00 wt%, preferably 2.00 wt% to 7.50 wt%, of the pharmaceutical composition by weight percentage. For example, the disintegrant can be selected from one or more of the following: starch and its derivatives (e.g., sodium starch glycolate, hydroxypropyl starch), low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and cross-linked povidone, and combinations thereof; preferably cross-linked sodium carboxymethyl cellulose or cross-linked povidone.

[0057] In some embodiments, the lubricant comprises 0.10 wt% to 5.00 wt%, preferably 0.20 wt% to 2.00 wt%, of the pharmaceutical composition by weight percentage. As an example, the lubricant can be selected from one or more of the following: microfine silica, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, sodium stearyl fumarate, and combinations thereof; preferably magnesium stearate.

[0058] In some embodiments, the binder comprises 0.10 wt% to 5.00 wt%, preferably 0.50 wt% to 2.00 wt%, of the pharmaceutical composition by weight percentage. As an example, the binder can be selected from one or more of the following: water (e.g., distilled water, purified water, or ultra-pure water), ethanol, starch paste, sugar powder and syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, and combinations thereof; preferably hypromellose.

[0059] In some embodiments, the glidant comprises 0 to 2.50 wt%, preferably 0.10 wt% to 2.50 wt%, more preferably 0.50 wt% to 2.00 wt%, of the pharmaceutical composition by weight percentage. As an example, the glidant can be selected from colloidal silicon dioxide, talc.

[0060] In some embodiments, the co-solubilizer is present in an amount of 0-2.50 wt%, preferably 0.10 wt%-2.50 wt%, more preferably 0.50 wt%-2.00 wt% of the pharmaceutical composition by weight percentage. As an example, the co-solubilizer is selected from the group consisting of polysorbate 80, sodium dodecyl sulfate, poloxamer 188.

[0061] In a specific embodiment, the pharmaceutical composition comprises active pharmaceutical ingredient (API) granules, and extra excipients. In a specific embodiment, the API granules can comprise one or more of a filler, a binder, and a disintegrant, in addition to the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the extra excipients can comprise a disintegrant and a lubricant, and optionally a glidant and a solubilizer.

[0062] In a preferred embodiment, the active pharmaceutical ingredient granules comprise the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and have a particle size of 10-300 μιη, preferably 10-200 μιη, more preferably 10-50 μιη.

[0063] In a preferred embodiment, the active pharmaceutical ingredient in the active pharmaceutical ingredient granules is present in a particulate form, and the particulate active pharmaceutical ingredient has a particle size of 5-60 μιη.

[0064] In a preferred embodiment, the pharmaceutical composition of the present application is in a powder form, i.e., a powder form in which the API granules and the extra excipients are thoroughly mixed. In other embodiments, the pharmaceutical composition of the present application can be in a granule form, i.e., a form in which the pharmaceutical composition comprising the API granules and the extra excipients is granulated.

[0065] In the pharmaceutical composition of the present application, the disintegrant used in the API granules can be present in an amount of 40%-70%, preferably 45%-60%, more preferably 50% of the total weight of the disintegrant. In a preferred embodiment, the API granules comprise half of the disintegrant in the pharmaceutical composition.

[0066] As an optional embodiment, the disintegrant in the API of the pharmaceutical composition of the present application can be the same as or different from the disintegrant in the extra excipients, and the total amount of the disintegrant in both the API and the extra excipients is present in an amount of 2.00 wt%-7.50 wt% of the pharmaceutical composition. Preferably, the disintegrant in the API of the pharmaceutical composition of the present application can be the same as the disintegrant in the extra excipients, e.g., selected from the group consisting of croscarmellose sodium or crospovidone.

[0067] In a specific embodiment, the pharmaceutical composition of the present application comprises, by weight percentage:

[0068] 1.00 wt% - 35.00 wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular crystalline A;

[0069] 60.00 wt% - 70.00 wt% of a filler, said filler being a combination of microcrystalline cellulose and lactose;

[0070] 2.00 wt% - 7.50 wt% of a disintegrant, said disintegrant being cross-linked polyplasdone;

[0071] 0.50 wt% - 2.00 wt% of a binder, said binder being hypromellose

[0072] 0.20 wt% - 2.00 wt% of a lubricant, said lubricant being magnesium stearate; and optionally

[0073] 0 - 2.50 wt%, preferably 0.10 wt% - 2.50 wt% of a glidant, said glidant being colloidal silicon dioxide; and

[0074] 0 - 2.50 wt%, preferably 0.10 wt% - 2.50 wt% of a solubilizer, said solubilizer being selected from a surfactant.

[0075] In a particular embodiment, the pharmaceutical composition of the application comprises, in percentage by weight:

[0076] 1.00 wt% - 35.00 wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular crystalline A;

[0077] 60.00 wt% - 70.00 wt% of a filler, said filler being a combination of microcrystalline cellulose and lactose, wherein the weight ratio of microcrystalline cellulose to lactose is between 5:1 and 1:5, in particular between 3:1 and 1:3;

[0078] 2.00 wt% - 7.50 wt% of a disintegrant, said disintegrant being cross-linked polyplasdone;

[0079] 0.50 wt% - 2.00 wt% of a binder, said binder being hypromellose

[0080] 0.20 wt% - 2.00 wt% of a lubricant, said lubricant being magnesium stearate

[0081] and, said pharmaceutical composition comprises API granules comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and 40% - 70% of the filler, the binder and the disintegrant, and said API granules have a particle size of 10 - 300 pm, preferably 10 - 200 pm, more preferably 10 - 50 pm.

[0082] In a further preferred embodiment, the pharmaceutical composition according to the present application comprises, by weight percentage:

[0083] 1.00 wt% - 35.00 wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0084] 60.00 wt% - 70.00 wt% of a filler, said filler being a combination of microcrystalline cellulose PH101 (MCC) and lactose 200, wherein the weight ratio of microcrystalline cellulose PH101 (MCC) and lactose 200 is 2: 1 - 1 : 2;

[0085] 2.00 wt% - 7.50 wt% of a disintegrant, said disintegrant being selected from the group consisting of croscarmellose sodium or crospovidone XL;

[0086] 0.20 wt% - 2.00 wt% of a lubricant, said lubricant being selected from the group consisting of magnesium stearate; and

[0087] 0.50 wt% - 2.00 wt% of a binder, said binder being selected from the group consisting of hypromellose E5 (HPMC).

[0088] It will also be appreciated by persons skilled in the art that, other than the active ingredient, the compound of formula (I), and the filler, the disintegrant, the lubricant, the binder, and the optional glidant and solubilizer, the pharmaceutical composition according to the present application can also include other pharmaceutically acceptable excipients or adjuvants as needed, such as but not limited to diluents, antioxidants, preservatives, colorants, flavoring agents, coating agents, etc., the selection and amount of which can be adjusted by persons skilled in the art according to actual needs. In a preferred embodiment, said coating agent can be selected from the group consisting of a gastroresistant coating agent, or an enteric coating agent.

[0089] In one aspect, the present application also provides a formulation of the compound of formula (I) or a pharmaceutically acceptable salt thereof, said formulation comprising the pharmaceutical composition as described above.

[0090] In some embodiments, the formulation is in the form of a unit dose. In some embodiments, the mass of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in each unit dose of the formulation is 1 mg to 200 mg. In some embodiments, the mass of the compound of Formula (I) in each unit dose of the composition is 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg; or a range formed by any of the foregoing values as endpoints. In some embodiments, the mass of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in each unit dose of the formulation is 10 mg to 50 mg, 20 mg to 50 mg, 100 mg to 200 mg, 50 mg to 200 mg, for example, 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg.

[0091] In some embodiments, the formulation is formulated as a unit dose. In some embodiments, the unit dose contains 10 mg to 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose contains 20 mg to 100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose contains 25 mg to 100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some particular embodiments, the unit dose contains 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0092] In the present application, the formulation is an oral formulation, in particular a solid formulation, for example selected from the group consisting of tablets, powders, pills, pellets, pastes, capsules (including soft capsules or hard capsules), granules, powders (flowable inhalable powders), and the like. In some embodiments, the formulation is formulated as an enteric formulation. In preferred embodiments, the formulation can be a sustained / controlled release formulation.

[0093] The pharmaceutical composition is in the form of a tablet; preferably, the tablet has a thickness of 1-10 mm, preferably 3 mm-5 mm.

[0094] It will also be appreciated by those skilled in the art that other pharmaceutically acceptable excipients or adjuvants can be included in the formulations of the present application as needed, such as but not limited to diluents, antioxidants, preservatives, colorants, flavoring agents, coating agents, and the like, the selection and amount of which can be adjusted by those skilled in the art as needed. In preferred embodiments, the coating agent can be selected from the group consisting of a gastric-soluble coating agent, or an enteric-soluble coating agent.

[0095] In another aspect, the present application provides a method for preparing the pharmaceutical composition described herein, comprising:

[0096] 1) granulating, preferably wet granulating, the compound of formula (I) or a pharmaceutically acceptable salt thereof with a filler, a binder, and a disintegrant, in an amount according to a formulation, to obtain API granules;

[0097] 2) mixing the API granules with the additional excipients, and optionally granulating, to obtain the pharmaceutical composition.

[0098] In step 1), the compound of formula (I) or a pharmaceutically acceptable salt thereof can be mixed with the filler and the disintegrant, and then the binder is added for granulation. In preferred embodiments, the binder is added in the form of a dry powder, or in the form of an aqueous solution (e.g. an aqueous solution) thereof. As an example, the aqueous solution of the binder contains 1wt%-5wt% of the binder, such as hypromellose.

[0099] In step 1), the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of microparticles of the compound of formula (I) or a pharmaceutically acceptable salt thereof, with a particle size of 5-60pm.

[0100] Before step 1), the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably subjected to micronization treatment.

[0101] After the wet granulation, drying and sizing are performed to obtain the API granules.

[0102] In one embodiment, the method for preparing comprises:

[0103] The raw material of the compound of formula (I) or a pharmaceutically acceptable salt thereof is sieved to 60 mesh;

[0104] The raw material is subjected to micronization treatment to obtain material ①;

[0105] Material ① is mixed with a filler and a disintegrant for internal addition to obtain mixture ①;

[0106] Mixture ① and a binder are mixed for granulation to obtain a uniform mixture ②;

[0107] drying (preferably to a final moisture content of < 3%), and sizing the dried granules to obtain a homogeneous mixture ③;

[0108] mixing the mixture ③ with the added disintegrant, and then adding the lubricant, at 10-30 rpm for 3-23 min to obtain a total mix mixture;

[0109] pressing the total mix mixture into a formulation, particularly a tablet.

[0110] In step 2), the added excipients can be first obtained according to the formulation amounts, and then mixed with the API granules, and optionally granulated; or the API granules can be mixed with the components of the added excipients in sequence. For example, the API granules can be mixed with the disintegrant, and then mixed with the lubricant.

[0111] In another aspect, the present application provides a method for preparing the formulation described above. The formulation described in the present application can be prepared according to the formulation methods in the art.

[0112] In addition, the present application also provides the use of the pharmaceutical composition or formulation described in the present application in the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0113] The present application also provides the use of the pharmaceutical composition or formulation described in the present application in the preparation of a medicament for the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0114] Another aspect of the present application provides a method for inhibiting gout or treating or preventing hyperuricemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition or formulation described above according to the present application.

[0115] The present application provides the pharmaceutical composition or formulation described in the present application for use in the inhibition of gout and the treatment or prevention of hyperuricemia.

[0116] The present application also provides a kit comprising the pharmaceutical composition or formulation described in the present application, and instructions for use in the preparation of a medicament for the treatment or prevention of diseases, for example, the inhibition of gout and the treatment or prevention of hyperuricemia.

[0117] For the purposes of the present application, the following terms used in the specification and claims have the meanings indicated below, unless stated otherwise.

[0118] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0119] The word "comprise" or "comprising" and its variations such as "comprises" or "comprising", are to be construed in an open, non-exclusive sense, i.e. in the sense of "including, but not limited to".

[0120] Unless specifically defined otherwise, all ratios (including percentages) or parts used herein are by weight.

[0121] The term "pharmaceutically acceptable" is used in reference to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0122] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to a subject.

[0123] In the present context, when referring to a compound of formula (I) or a pharmaceutically acceptable salt thereof, this is to be understood as meaning the amount of the compound of formula (I).

[0124] The compounds of formula (I) can be administered in the form of their free bases, but they can also be administered in the form of their salts, solvates and prodrugs, which are converted into the free base form of the compounds of formula (I) in the body. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present application and can be obtained from different organic and inorganic acids as is known in the art.

[0125] In some embodiments, the pharmaceutically acceptable salts of the compounds of Formula (I) of the present application refer to salts of the compounds of the present application, prepared from the compounds of the present application and either an acid or a base, which are not toxic to the subjects to which the compounds of the present application are administered. When the compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base to produce the salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid to produce the salt. Examples of pharmaceutically acceptable acid addition salts include salts of mineral acids, such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydrogensulfuric, hydroiodic, phosphorous, and the like; salts of organic acids, such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, and methanesulfonic acids, and the like; salts of amino acids, such as arginine and the like; and salts of organic acids, such as glucuronic, and the like (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, are capable of conversion into either base or acid addition salts.

[0126] Preferably, the salts are contacted with a base or an acid in a conventional manner to re-isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0127] As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the application wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, alkali or organic salts of acidic groups such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound which are formed, for example, from non-toxic inorganic or organic acids. The conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactose, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.

[0128] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acid or a base moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, among others, are preferred.

[0129] It is noted that the crystalline and amorphous forms of the compounds can be identified by conventional means, including X-ray diffraction spectroscopy (XRD), differential scanning calorimetry (DSC) measurements, and the like. In X-ray diffraction spectroscopy (XRD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal form, where the relative intensities of the bands can vary due to preferred orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of a particular crystal form, and it is the relative positions of the peaks, rather than their relative intensities, that should be noted in comparing a crystal form with a known crystal form. Furthermore, for any given crystal form, there can be slight errors in the position of the peaks, which are well known in the art of crystallography. For example, the position of the peaks can shift due to variations in temperature during sample analysis, sample movement, or instrument calibration, and the measurement error in 2Θ is typically ±0.2°. Thus, this error should be taken into account in determining each crystal structure. In XRD patterns, the position of the peaks is usually given in terms of the 2Θ angle or the interplanar spacing d, which are related by the simple conversion: d = λ / 2 sin Θ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-rays, and Θ is the diffraction angle.

[0130] Differential scanning calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat as its crystal structure changes or the crystal melts. For the same crystalline form of the same compound, the thermal transition temperature and melting point are typically within about 5°C, usually within about 3°C, in successive analyses, and when we say that a compound has a given DSC peak or melting point, we mean the DSC peak or melting point ± 5°C. DSC provides a useful method for distinguishing between different crystalline forms. Different crystalline forms can be identified by their different transition temperature profiles. It is noted that for mixtures, the DSC peak or melting point can vary over a larger range. In addition, because decomposition can occur during melting of a substance, the melting temperature is closely related to the rate of temperature increase.

[0131] The term "administering" or "administration" means physically introducing a composition comprising an active compound into a subject or patient or subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, oral administration is used.

[0132] "Unit dosage" or "unit dose" means the preparation of a formulation packaged in a single container, e.g., "a formulation in unit dosage form" means each tablet. "A pharmaceutical composition in unit dosage form contains 25 mg of a compound of Formula (I)" means that each tablet in the final preparation contains 25 mg of a compound of Formula (I).

[0133] "Patient," "subject," or "host" means a mammal, preferably a human.

[0134] "Therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment for that disease.

[0135] "Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

[0136] (1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and / or symptomatology), or

[0137] (2) effecting an improvement in the pathology and / or symptomatology of the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology).

[0138] For purposes of description and disclosure, all patents, patent applications, and other publications identified herein are expressly incorporated herein by reference. Any reference to such publications is not intended to limit the scope of the disclosure to the specific disclosure contained therein.

[0139] Examples

[0140] Next, the present application will be further described in detail by examples, but the present application is not limited to these examples.

[0141]

Content Determination

[0142] Preparation method of compound 1 and crystal form A of Preparation Example 1

[0143] The preparation process of compound 1 was obtained with reference to the preparation method of Example 3 in the prior art WO2017215589A1.

[0144] The preparation process of compound 1 crystal form A was obtained with reference to the preparation method of Example 7 in the prior art WO2019114838A1.

[0145] Among them, the raw material compound 1 and its crystal form A are white or white-like powders, and have low solubility.

[0146] Screening of crystal form

[0147] With reference to the prior art WO2019114838A1, compound 1 exists in amorphous form and crystal form A, and finally determines to develop crystal form A as the active ingredient of the preparation. The following experiments are all for crystal form A.

[0148] Determination of related physicochemical properties of crystal form A of compound 1

[0149] 1.1 Hygroscopicity investigation

[0150] The hygroscopicity of the compound was determined according to the method of Chinese Pharmacopoeia 2015 Edition Part IV General Rule. The determination was carried out in a repeated manner. The results are shown in Table 1.

[0151] Table 1 Hygroscopicity results

[0152] With reference to the 2015 Edition Chinese Pharmacopoeia Part IV General Rule 9103 "Guiding Principles for Drug Hygroscopicity Test", the hygroscopicity evaluation classification. The average hygroscopicity of the raw material compound is 0.46%, which indicates that the product has slight hygroscopicity.

[0153] 1.2 Particle size distribution

[0154] In order to understand the particle size distribution of crystal form A, the particle size distribution of the product was detected by using the S3500 type laser particle size analyzer of Microtrac Company. Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. The test uses wet method, and the test dispersion medium is Isopar G. The results are shown in the following table:

[0155] Table 2 Particle size distribution

[0156] Example 1

[0157] Prepared according to the following method:

[0158] Microcrystalline cellulose PH101, lactose and mannitol were selected as fillers, cross-linked polyplasdone as disintegrant, magnesium stearate as lubricant.

[0159] Prepared in 25 mg size.

[0160] Preparation method of prescription 1:

[0161] The active pharmaceutical ingredient was sieved through 60 mesh; mixing: prescription amount of active pharmaceutical ingredient, lactose, microcrystalline cellulose, cross-linked polyplasdone XL (internal) were mixed uniformly; granulation: hydroxypropyl methyl cellulose was added for granulation; whole mixing: dry granules were mixed with prescription proportion of cross-linked polyplasdone XL (external), and magnesium stearate was added for total mixing; tabletting.

[0162] Preparation method of prescription 2: The active pharmaceutical ingredient was sieved through 60 mesh; mixing: prescription amount of active pharmaceutical ingredient, lactose, mannitol, microcrystalline cellulose, cross-linked polyplasdone XL (internal) were mixed uniformly; granulation: 3wt% aqueous solution of hydroxypropyl methyl cellulose E5 was added for granulation; drying; whole mixing: dry granules were mixed with prescription proportion of cross-linked polyplasdone XL (external), and magnesium stearate was added for total mixing; tabletting.

[0163] The specific composition of prescription 1 and prescription 2 is shown in Table 3 below.

[0164] Table 3 Composition of prescription 1 and prescription 2

[0165] Prescription 1 and prescription 2 both use wet granulation process, and are tabletted after mixing with additional excipients. The active pharmaceutical ingredients (API) used are all sieved through 60 mesh. When prescription 1 is operated, the binder hydroxypropyl methyl cellulose E5 is dry added, and the granulation effect is loose. Prescription 2 uses the binder hydroxypropyl methyl cellulose E5 to prepare an aqueous solution before adding. The dissolution and stability of the two prescriptions are investigated.

[0166] The results of the content detected at 0 days are shown in Table 4 below:

[0167] Table 4 Research content results of prescription 1 and prescription 2

[0168] The related substance detection results are shown in Table 5 below:

[0169] Table 5 Related substance detection results of prescription 1 and prescription 2

[0170] The results of the related substance test showed that there was no significant difference between the two formulations at 0 days and 7 days of acceleration. From the results of the open and closed, moisture had no effect on the impurities.

[0171] Dissolution conditions: According to the solubility of the drug in different pH buffers, pH 4.5 acetate buffer that meets the sink conditions is selected as the dissolution medium for formulation screening. The dissolution method is to maintain 37 ± 0.5°C, pH 4.5 acetate buffer 900 mL as the medium, slurry method 50 rpm, 60 min 250 rpm, and the dissolution curve of the drug within 90 min is investigated. The dissolution results of 0 days and 7 days of acceleration are as follows:

[0172] Table 6 Dissolution results of 0 days of formulation study

[0173] Table 7 Dissolution results of 7 days of acceleration of formulation study

[0174] The dissolution results showed that there was no significant difference between the two formulations. Compared with 0 days, the dissolution of the samples of 7 days of acceleration open had a downward trend, and the samples of 7 days of acceleration closed with desiccant were improved.

[0175] Example 2

[0176] Preparation method of prescription 3: The raw drug was sieved to 60 mesh; mixing: the raw drug, lactose, microcrystalline cellulose, and cross-linked polyvinylpyrrolidone XL (added inside) were mixed according to the prescription amount; granulation: 3wt% aqueous solution of hydroxypropyl methyl cellulose E5 was added for granulation; drying; whole mixing: the dry granules were mixed with cross-linked polyvinylpyrrolidone XL (added outside) in the proportion of the prescription, and magnesium stearate was added for total mixing; tabletting.

[0177] Table 8 Composition of prescription 3

[0178] Compared with prescription 1, prescription 3 changed the disintegrant and used a wet granulation process. The binder hydroxypropyl methyl cellulose E5 was prepared into an aqueous solution and added. After mixing with the added excipients, the tablets were pressed. The API used was sieved to 60 mesh. The content, related substances, and dissolution were investigated.

[0179] The content results are shown in Table 9 below:

[0180] Table 9 Content test results of prescription 3 study

[0181] Dissolution condition: According to the solubility of the drug in different pH buffer, pH 4.5 acetate buffer which met the sink condition was selected as the medium for prescription screening dissolution. The dissolution method was to keep 37 ± 0.5℃, pH 4.5 acetate buffer 900 mL as the medium, slurry method 50 rpm, 60 min at 250 rpm, and the dissolution curve of the drug was investigated within 90 min. The accelerated dissolution results of 0 days and 7 days are shown in the following table:

[0182] Table 10 Dissolution results of prescription 3 study 0 days and accelerated 7 days

[0183] The dissolution results show that there is no significant difference in the dissolution results of the first three prescriptions. Compared with prescription 1 and prescription 2, the dissolution of prescription 3 which replaced the disintegrating agent did not improve.

[0184] Example 3

[0185] Preparation method of prescription 4: The raw material was sieved to 60 mesh; mixing: the prescription amount of micronized raw material, lactose, microcrystalline cellulose, crosslinked polyvinylpyrrolidone XL (internal) were mixed uniformly; granulation: 3wt% water solution of hydroxypropyl methyl cellulose E5 was added for granulation; drying; whole granulation; total mixing: the dry granules were mixed with crosslinked polyvinylpyrrolidone XL (external) in the prescription proportion, and magnesium stearate was added for total mixing; tabletting.

[0186] Table 11 Composition of prescription 4

[0187] The wet granulation and tabletting process of prescription 4 was selected as the same as prescription 3, and micronized API was used. At the same time, the influence of the process on the crystal form, content, related substances and dissolution were investigated.

[0188] The samples of sieving, grinding and micronization of API were detected for crystal form to investigate the influence on the crystal form of API. The samples of crushed material after granulation and total mixing and the finished product after tabletting were detected for crystal form to investigate the influence of the granulation and tabletting process on the crystal form of API. The results are shown in Figures 1-3.

[0189] The results show that the processes of grinding, sieving, micronization and wet granulation and tabletting do not affect the crystal form of the drug.

[0190] The results of content detection are shown in the following table 12:

[0191] Table 12 Content detection results of prescription 4 study

[0192] The results of related substance detection of prescription 3 and prescription 4 are shown in the following table 13:

[0193] Table 13 Related substance detection results of prescription 3 and prescription 4 study

[0194] The results of related substance detection showed that there was no significant difference between the two formulations of 0 days and accelerated 7 days, and the open, sealed and sealed with desiccant conditions had no effect on the related substances.

[0195] Dissolution conditions: According to the solubility of the drug in different pH buffers, pH 4.5 acetate buffer that meets the sink conditions is selected as the dissolution medium for formulation screening. The dissolution method is to maintain 37 ± 0.5℃, pH 4.5 acetate buffer 900mL as medium, slurry method 50rpm, 60min 250rpm, to investigate the dissolution curve of the drug within 90min. The dissolution results of 0 days and 7 days accelerated are shown in the following table:

[0196] Table 14 Dissolution results of formulation research at room temperature for 0 days and 7 days accelerated

[0197] The dissolution results showed that the dissolution without desiccant was slightly decreased, and there was no difference between 0 days and desiccant samples, and there was no significant difference compared with the first three formulations, and API micronization could not improve the in vitro dissolution.

[0198] Example 4

[0199] The preparation method of prescription 5 and prescription 6 is the same as prescription 4.

[0200] Table 15 Composition of prescription 5 and prescription 6

[0201] Prescription 5 and prescription 6 are 25mg and 100mg specifications respectively. The two specifications are enlarged in equal proportion. The prescription process is wet granulation drying and then mixed with additional excipients and pressed into tablets. The content uniformity, dissolution and stability of the samples are investigated.

[0202] The detection results of content uniformity are as follows in table 16:

[0203] Table 16 Determination results of content uniformity of different formulations

[0204] The results of related substance detection of pre-stability samples are shown in the following table 17:

[0205] Table 17 Results of related substance detection

[0206] The results of related substances showed that there was no significant difference in related substances between the two formulations under the conditions of 0 days sealing and accelerated conditions.

[0207] Dissolution condition: According to the solubility of the drug in different pH buffer, pH 5.5 acetate buffer was selected as the dissolution medium for 100 mg sample to meet the sink condition. In order to unify the dissolution medium and facilitate comparison with small sample, pH 4.5 acetate buffer was selected as the medium for 25 mg sample at 0 day and pH 5.5 acetate buffer was selected as the medium. The dissolution method was as follows: 900 mL of pH 5.5 (pH 4.5) acetate buffer was used as the dissolution medium, the slurry method was used at 50 rpm, and the speed was increased to 250 rpm after 60 min. The dissolution curve of the drug within 90 min was investigated. The dissolution results are shown in the following table:

[0208] Table 18 Dissolution results of prescription 5 room temperature 0 day and accelerated sample

[0209] Table 19 Dissolution results of prescription 6 0 day and accelerated sample

[0210] The dissolution results show that when pH 5.5 acetate buffer is used as the dissolution medium, the dissolution of the 25 mg sample is significantly accelerated and completely dissolved. The dissolution of the 100 mg sample is still significantly improved after the speed is increased at 60 min, and the dissolution degree is improved. Therefore, the dissolution medium is considered to be replaced.

[0211] Dissolution condition: 900 mL of pH 6.0 phosphate buffer was selected as the medium, 37±0.5℃ was maintained, the slurry method was used at 50 rpm, and the speed was increased to 250 rpm after 60 min. The dissolution curve of the drug within 90 min was investigated. The dissolution results are shown in the following table:

[0212] Table 20 Dissolution results of prescription 6 0 day

[0213] The dissolution results show that after the dissolution medium is replaced, the dissolution rate of the 100 mg sample is significantly accelerated and completely dissolved. Therefore, the unified dissolution condition for different sizes is determined as follows: 900 mL of pH 6.0 phosphate buffer is used as the medium, 37±0.5℃ is maintained, the slurry method is used at 50 rpm, and the speed is increased to 250 rpm after 60 min. The dissolution curve of the drug within 90 min is investigated.

[0214] Based on the above results, wet granulation and boiling drying are selected. The related substances basically meet the requirements, and pH 6.0 phosphate buffer is selected as the dissolution medium, which can be completely dissolved.

[0215] Example 5 Prescription 7 and prescription 8

[0216] Table 21 Composition of prescription 7 and prescription 8

[0217] The preparation process is as follows:

[0218] ① Raw material pretreatment

[0219] The raw material was sieved to 60 mesh.

[0220] ② Mixing

[0221] The micronized raw material, lactose, microcrystalline cellulose and crospovidone XL (added inside) were weighed according to the prescription and added into the P1 / 6 type high shear wet granulator kettle. The pre-mixing was carried out for 10 minutes, the stirring speed was 270 rpm, and the shearing speed was 1000 rpm.

[0222] ③ Granulation

[0223] The prescription proportion of 3wt% hydroxypropyl methyl cellulose E5 aqueous solution was added to the running high-speed mixing granulator for granulation, which was completed within 3 minutes. The stirring speed of the mixer was 270 rpm, and the shearing speed was 1200 rpm.

[0224] The wet granules were transferred out of the mixing granulator and sieved through an 18-mesh sieve.

[0225] ④ Drying

[0226] The drying was carried out using a fluidized bed dryer, with a set air volume of 60 L / min and a temperature of 60°C. The moisture content at the end of drying was ≤3%.

[0227] ⑤ Granulation

[0228] The dried granules were sieved through an 18-mesh sieve for granulation.

[0229] ⑥ Total mixing

[0230] The dried granules and the prescription proportion of crospovidone XL (added outside) were placed in the mixer for mixing, with a mixing speed of 20 rpm and a mixing time of 30 minutes.

[0231] Magnesium stearate was further added to the mixer for total mixing, with a mixing speed of 20 rpm and a total mixing time of 3 minutes.

[0232] The intermediate was sampled and tested for mixing uniformity.

[0233] ⑦ Tabletting

[0234] 25mg specification: punch: shallow arc-shaped round punch, diameter: 6mm, tablet weight difference: ±7.5%, tablet hardness: 6-8Kp (1Kp≈10N);

[0235] 100mg specification punch: shallow arc-shaped round punch, diameter: 10mm, tablet weight difference: ±5%, tablet hardness: 10-13Kp (1Kp≈10N).

[0236] ⑧ Packaging

[0237] The finished product and 1 gram of desiccant are packaged in a high-density polyethylene bottle for oral solid drugs, and the bottle is sealed with an induction sealing machine.

[0238] Example 6 scale-up experiment

[0239] According to the determined prescription process, the samples of two specifications are scaled up, the 25 mg specification is scaled up to 4000 tablets / batch, prescription 9; the 100 mg specification is scaled up to 3000 tablets / batch, prescription 10.

[0240] Table 22 Prescription Composition Summary (25 mg Specification)

[0241] (1) Preparation process is:

[0242] ① Pretreatment of raw and auxiliary materials

[0243] The raw drug is sieved to 60 mesh.

[0244] ② Mixing

[0245] The prescription amount of micronized raw drug, lactose, microcrystalline cellulose, and cross-linked polyvinylpyrrolidone XL (added inside) are weighed and added to the P1 / 6 type high-shear wet granulator kettle, pre-mixed for 10 minutes, stirring speed 270 rpm, shear speed 1000 rpm.

[0246] ③ Granulation

[0247] Add 3 wt% of hydroxypropyl methyl cellulose E5 aqueous solution in the prescription ratio to the running high-speed mixing granulator, complete within 3 minutes, mixing machine stirring speed 270 rpm, shear speed 1200 rpm.

[0248] The wet granules are transferred out of the mixing granulator and sieved through an 18-mesh sieve.

[0249] ④ Drying

[0250] Use a fluidized bed dryer to dry, set the air volume to 60 L / min, the temperature to 60°C, and the final moisture content to ≤3%.

[0251] ⑤ Granulation

[0252] The dried granules are sieved through an 18-mesh sieve for granulation.

[0253] ⑥ Total mixing

[0254] The dry granules are mixed with cross-linked polyvinylpyrrolidone XL (added outside) in the prescription ratio in the mixer, mixing speed 20 rpm, mixing time 30 minutes.

[0255] Add magnesium stearate to the mixer for total mixing, mixing speed 20 rpm, total mixing time 3 minutes.

[0256] Sampling the intermediate to check the uniformity of mixing.

[0257] Tablet compression

[0258] 25mg specification: punch: shallow arc-shaped round punch, diameter: 6mm, tablet weight difference: ±7.5%, tablet hardness: 6-8Kp (1Kp≈10N);

[0259] 100mg specification punch: shallow arc-shaped round punch, diameter: 10mm, tablet weight difference: ±5%, tablet hardness: 10-13Kp (1Kp≈10N).

[0260] Packaging

[0261] The finished product and 1 gram of full white moisture-proof Zhaitaiwei paper or oral solid drug bagging silica gel desiccant are packaged together in an oral solid drug high-density polyethylene bottle, and an induction sealing machine is used for sealing.

[0262] The related properties of the obtained preparation obtained by scale-up preparation: the physicochemical properties related to the performance of the preparation mainly include dissolution rate and stability. The accelerated test and long-term test of the stability of the preparation sample have been conducted for 9 months. The preparation of the application is placed at 25℃±2℃ / 60%RH±5%RH for 9 months, and there is no obvious change in the properties, content and dissolution rate, and there is no obvious change in other impurities, which all meet the limit requirements; placed at 2-8℃ for 6 months, there is no obvious change in the properties, content, dissolution rate and related substances, which all meet the limit requirements. Based on the above analysis, the above properties of the preparation of the application are relatively stable.

[0263] A comprehensive quality research is conducted on the scale-up samples of each specification, including properties, related substances, dissolution rate, content, etc., and the relevant summary is shown in the following table.

[0264] Table 23 Quality research results of scale-up samples

[0265] Table 24 Dissolution results of scale-up samples

[0266] The quality research results show that the properties, related substances, tablet weight difference, dissolution rate and content of the product are within the limit requirements.

[0267] Effect example 1 Stability research of compound 1 tablet

[0268] 1. Research conclusion

[0269] The forced degradation test results show that the 100mg specification tablet of the product is relatively stable to acid and light, and is relatively sensitive to alkali, high temperature and oxidation conditions.

[0270] The results of the influencing factor test show that the 100 mg specification tablet of the product has no obvious changes in appearance, content, related substances and dissolution under the conditions of light [5000 ± 500 lux (visible light) and 90 μw / cm 2 (ultraviolet light) for 10 days; under the condition of high temperature (60 °C) for 30 days, the appearance, content and dissolution have no obvious changes, and the impurities have no obvious changes; under the condition of high temperature (40 °C) for 30 days, the appearance, content, dissolution and related substances have no obvious changes, and all meet the limit requirements; the 100 mg tablet of the product has an increase in moisture absorption of more than 5% under the condition of high humidity (25 °C / 92.5% RH) for 5 days; under the condition of high humidity (25 °C / 75% RH) for 30 days, the increase in moisture absorption meets the requirements, and the appearance, content, related substances and dissolution have no obvious changes, all of which meet the requirements. Therefore, the product is relatively stable to light, high temperature (40 °C) and high humidity (25 °C / 75% RH), and is slightly sensitive to high humidity (25 °C / 92.5% RH) and high temperature (60 °C).

[0271] The proposed inner packaging condition of the product is: oral solid pharmaceutical high-density polyethylene bottle plus 1 gram of white moisture-proof pearl Tivik paper packaging 10K / C (C137). Under the proposed packaging condition, the accelerated and long-term stability is investigated, and the preliminary stability study data show that the product has no obvious changes in appearance, content and dissolution under the condition of 40 °C ± 2 °C / 75% RH ± 5% RH for 6 months, and the impurities have no obvious changes, all of which meet the limit requirements; the product has no obvious changes in appearance, content and dissolution under the condition of 30 °C ± 2 °C / 65% RH ± 5% RH for 6 months, and the impurities have no obvious changes, all of which meet the limit requirements; the product has no obvious changes in appearance, content and dissolution under the condition of 25 °C ± 2 °C / 60% RH ± 5% RH for 9 months, and the impurities have no obvious changes, all of which meet the limit requirements; the product has no obvious changes in appearance, content, dissolution and related substances under the condition of 2-8 °C for 6 months, all of which meet the limit requirements.

[0272] Therefore, storage under the proposed packaging can ensure that the product remains stable within the proposed effective period.

[0273] Effect Example 2: Pharmacokinetic determination

[0274] Formulation 3 and Formulation 4 are selected for canine PK experiment to investigate the influence of different API particle sizes on the in-vivo bioavailability.

[0275] First batch of beagle dog pharmacokinetic test scheme:

[0276] Male beagle dogs were randomly divided into A, B, C, D groups, 2 in group A, 3 in group B, 3 in group C, and 2 in group D. Groups A, B, and C were single gavage administration, and group D was single intravenous bolus administration. Group A was single gavage administration of 5 mg / kg of compound 1 (API), group B was single gavage administration of 20 mg / dog of tablets containing API prescription 3 (tablet sample batch number 1902FP0116-03), group C was single gavage administration of 20 mg / dog of tablets containing API prescription 4 (tablet sample batch number 1902FP0116-04), and group D was single intravenous injection of 1 mg / kg of API.

[0277] Groups A, B, and C of single gavage administration were taken 1 mL of blood from the limbs before administration and at 0.25 (15 minutes), 0.5 (30 minutes), 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and placed in EDTA-K2 anticoagulant test tubes. Centrifugation was performed at 3500 rpm for 10 min (4°C), and plasma was separated within 2 h and stored at -70°C for testing. The blood sampling to centrifugation process was operated under ice bath conditions.

[0278] Group D of single intravenous bolus administration was taken 1 mL of blood from the limbs before administration and at 0.083 (5 minutes), 0.25 (15 minutes), 0.5 (30 minutes), 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration, and placed in EDTA-K2 anticoagulant test tubes. The sample was treated in the same way as above. LC-MS / MS method was used to determine the concentration of compound 1 in the plasma of beagle dogs at different time points after administration.

[0279] Second batch of beagle dogs pharmacokinetic test scheme:

[0280] Male beagle dogs were randomly divided into A, B, C groups, 2 in group A, 3 in group B, and 3 in group C. All three groups were single gavage administration. Group A was single gavage administration of 5 mg / kg of compound 1 (API), group B was single gavage administration of 50 mg / dog of tablets containing API prescription 5 (tablet sample batch number F-1903FP0119-04), and group C was single gavage administration of 50 mg / dog of tablets containing API prescription 6 (tablet sample batch number F-1903FP0119-02).

[0281] Groups A, B, and C of single gavage administration were taken 1 mL of blood from the limbs before administration and at 0.25 (15 minutes), 0.5 (30 minutes), 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, and 48 hours after administration, and placed in EDTA-K2 anticoagulant test tubes. Centrifugation was performed at 3500 rpm for 10 min (4°C), and plasma was separated within 2 h and stored at -70°C for testing. The blood sampling to centrifugation process was operated under ice bath conditions. LC-MS / MS method was used to determine the concentration of compound 1 in the plasma of beagle dogs at different time points after administration.

[0282] Table 2.1 Oral bioavailability parameters of the first batch of tablets

[0283] Table 2.2 Oral bioavailability parameters of the second batch of tablets

[0284] By investigating the dog PK experiment of prescription 3 and prescription 4, it is determined that the API particle size difference has little effect on the bioavailability in vivo, and the bioavailability measured is 122% and 100% respectively, that is, the bioavailability of the two prescriptions in vivo is good, and the 60 mesh screening is slightly better, so the prescription 3 of API screening treatment is selected for process verification, and the in vitro dissolution is detected by changing the dissolution medium.

[0285] Safety, tolerability and pharmacokinetics study of single, multiple dosing and food effect of the tablets of Example 3

[0286] Objective: To evaluate the safety and tolerability and pharmacokinetics of single and multiple oral administration of Compound 1 tablets in healthy adults under fasting conditions, and to explore the effect of food on the pharmacokinetics of Compound 1 tablets.

[0287] Methods: A randomized, double-blind, placebo-controlled, single and multiple ascending dose study design was adopted.

[0288] 1 Case selection

[0289] 1.1 Inclusion criteria Age ≥ 18 and ≤ 45 years old, body mass index (BMI) 19.0-26.0 kg / m 2 (including both ends); serum uric acid test value in screening period: 240-420 μmol / L; female: 210-360 μmol / L; normal or abnormal results of vital signs, physical examination, 12-lead electrocardiogram, laboratory tests, chest X-ray, etc. have no clinical significance.

[0290] 1.2 Exclusion criteria Pregnant or lactating women; history of hyperuricemia and / or gout and kidney stone disease; history of cardiovascular, respiratory, digestive, endocrine, infectious and other mental diseases or abnormalities; past or current surgery that may affect the results of the clinical trial; taking any drugs within 4 weeks or 7 drug half-lives before administration; loss of blood or blood donation of more than 400 mL within 2 months before screening; participation in other clinical trials within 3 months before screening; history of allergy, alcohol abuse, smoking, drug abuse; any condition that the investigator considers to pose a safety risk to the subject during the trial or may interfere with the conduct of the study, etc.

[0291] This study was a randomized, double-blind, placebo-controlled, single and multiple ascending dose clinical trial. A total of 376 subjects were screened, 298 subjects failed the screening, and 78 subjects were successfully screened and randomized (48 subjects were randomized in Part 1, and 30 subjects were randomized in Part 2). In Part 1 study, 1 subject (Group 200 mg / B) was withdrawn from the study due to the fluctuation of blood pressure before the first dose after randomization, and the investigator judged that it was not suitable to continue the study. All subjects in Part 1 and Part 2 received all the study drugs according to the protocol, and the treatment compliance was 100%.

[0292] 2 Test drug

[0293] Test drug: Compound 1 tablets (Jiangsu Kanion Pharmaceutical Co., Ltd., specifications: 25 mg / tablet, 100 mg / tablet, prepared according to Prescription 5 and Prescription 6). Placebo: Compound 1 placebo (Jiangsu Kanion Pharmaceutical Co., Ltd., batch number: 25 mg / tablet: 211101; 100 mg / tablet: 211102). The placebo looks the same as the test drug and meets the requirements for simulating tablet preparation.

[0294] 3 Treatment regimen

[0295] Part 1: Standard group subjects should take the prescribed dose of test drug orally under fasting conditions. Combined group subjects should take the prescribed dose of test drug orally under fasting or 30 minutes after starting to eat high-fat high-calorie meals.

[0296] Part 2: Subjects should take the prescribed dose of test drug orally under fasting conditions.

[0297] Each subject should take 240 mL of warm water to swallow each time. If vomiting occurs after taking the medicine, it will not be supplemented. The subjects should not consume food within 2 hours after taking the medicine and should not drink extra water within 1 hour. In this study protocol, fasting means fasting for at least 4 hours and water for at least 1 hour before administration. See Table 3.1 for details.

[0298] Table 3.1 Treatment regimen

[0299] 4 Pharmacokinetic study

[0300] Part 1 study: The following pharmacokinetic parameters were determined: peak time (T max ), peak concentration (C max ), area under the blood concentration-time curve (AUC 0-24h , AUC 0-t , AUC 0-∞ ), apparent distribution volume (Vd / F), plasma clearance (CL / F), and plasma elimination half-life (T 1 / 2), mean residence time (MRT).

[0301] Part 2 study: Steady-state time to peak (T max,ss ), steady-state peak concentration (C max,ss) , steady-state trough concentration (C min,ss ), mean steady-state concentration (C av,ss ), area under the steady-state concentration-time curve (AUC ss ), coefficient of fluctuation between drug trough and peak concentrations (DF), accumulation ratio R ac : C max , R ac : AUC.

[0302] 5 Safety Evaluation

[0303] The safety evaluation index used in this study is a widely accepted evaluation index, such as vital signs, physical examination, 12-lead electrocardiogram, laboratory examination, recording adverse events, etc.

[0304] 6 Statistical Analysis

[0305] Adverse events, laboratory examination indexes, vital signs, electrocardiogram, etc. were analyzed by descriptive statistics. The incidence of adverse events and serious adverse events was summarized according to the enrollment queue. AE and SAE were summarized using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

[0306] A validated LC / MS method was used to determine plasma and estimate the main plasma PK parameters. Pharmacokinetic analysis was calculated using a non-compartment model, and pharmacokinetic analysis was performed using WinNonlin 8.2 software. Other statistical analysis will be calculated using SAS Enterprise Guide 9.4.

[0307] 7 Results

[0308] (1) Safety and tolerability

[0309] In Part 1 study, 22 AEs occurred in 14 subjects (36.8%) of Compound 1 group, all were TEAEs, among which 17 AEs occurred in 12 subjects (31.6%) were related to study drug; 5 TEAEs occurred in 4 subjects (44.4%) of placebo group, among which 4 AEs occurred in 4 subjects (44.4%) were related to study drug. The common (incidence ≥5.0%) TEAEs in Compound 1 group included: elevated urine beta 2 microglobulin (4 subjects 4 events, 10.5%), decreased blood pressure (3 subjects 5 events, 7.9%), positive urine leukocyte (2 subjects 2 events, 5.3%), rash (2 subjects 2 events, 5.3%), mouth sores (2 subjects 2 events, 5.3%), diarrhea (2 subjects 2 events, 5.3%).

[0310] In Part 2 study, 32 AEs occurred in 18 subjects (75.0%) of Compound 1 group, all were TEAEs, among which 31 AEs occurred in 18 subjects (75.0%) were related to study drug; 2 TEAEs occurred in 2 subjects (33.3%) of placebo group, among which 2 AEs occurred in 2 subjects (33.3%) were related to study drug. The most common (incidence ≥5.0%) TEAEs in Compound 1 group included: positive urine leukocyte (5 subjects 7 events, 45.8%), elevated urine beta 2 microglobulin (3 subjects 3 events, 12.5%), elevated serum creatinine (3 subjects 3 events, 12.5%), elevated pulse in arms (3 subjects 3 events, 12.5%), mouth ulcers (3 subjects 3 events, 12.5%), diarrhea (2 subjects 2 events, 8.3%).

[0311] (2) Pharmacokinetic results

[0312] The mean plasma concentration-time curves of Compound 1 in each dose group of Part 1 study were shown in Figure 4. As can be seen from the plasma concentration-time curve, after single oral administration, Compound 1 was rapidly absorbed in human body, and the peak time was about 1.5-3.5 h, and then the plasma concentration value rapidly decreased. With the increase of the dose, the plasma drug concentration increased. Compared with fasting administration, the peak time was later and the peak concentration was higher after meal administration. The pharmacokinetic parameters were shown in Table 3.2.

[0313] Power model analysis, AUC 0-24h The 90% CI was (1.0255, 1.1885), which was out of the linear reference interval (0.9298, 1.0702), indicating that the plasma AUC was not linearly proportional to the dose in the dose range. According to the slope 1.1070, the proportion of increase in plasma exposure level was slightly higher than that of dose increase. In addition, C maxThe 90% CI of (0.9469, 1.0636) of AUC max The increase ratio was linear to the dose. The non-parametric test (Kruskal-Wallis test) showed that there was no significant difference in T max There was no significant difference.

[0314] The variance analysis of the effect of food on pharmacokinetics showed that the AUC 0-∞ , AUC 0-t , and C max of the fasting group and the postprandial group had statistical significance. It was proved that food had an effect on the plasma drug exposure level of Compound 1. The T max of the postprandial group was slightly longer than that of the fasting group, which showed that the postprandial administration might delay the peak time of the plasma drug concentration. max

[0315] In the Part 2 study, the average plasma drug concentration-time curve of each dose group is shown in the following Figure 5. After the first administration, Compound 1 was quickly absorbed in the human body, and the peak time was about 2.28-3.06 h, and then the plasma concentration value rapidly decreased. With the increase of the dose, the plasma drug concentration increased. The plasma concentration curve after the oral administration once a day for 7 consecutive days was similar to that of the first administration. After the first oral administration, the data were basically consistent with the plasma pharmacokinetic parameter data of the corresponding respective dose groups in the Part 1 study. The specific information is shown in Table 3.3.

[0316] Table 3.3 Summary of pharmacokinetic parameters (Mean ± SD) (Part 2 study)

[0317] The above data showed that the pharmacokinetic parameters of each dose group after 7 days of continuous administration were similar to those of the first day. The non-parametric test (Kruskal-Wallis test) showed that there was no significant difference in T max . The Power model analysis showed that the 90% CI of AUC 0-24h，ss , C max , ss was (1.1649, 1.5030) and (1.1147, 1.5284), respectively, both of which fell outside the linear reference interval (0.8390, 1.1610), which indicated that the C max and AUC were not in proportion to the dose in the dose range. According to the slopes 1.3340 and 1.3216, it was suggested that the increase ratio of the plasma exposure and the peak concentration level was more than the increase ratio of the dose.

[0318] 9CONCLUSION​

[0319] The severity of all TEAEs in Compound 1 group and placebo group was grade 1. No TEAEs leading to study drug discontinuation, TEAEs leading to subject withdrawal, and SAEs occurred. Compound 1 was well tolerated and safe. The plasma pharmacokinetic parameters showed that Compound 1 was rapidly absorbed after single dose, and the time to peak concentration occurred at about 1.50-3.59 h after administration. Within the dose range of 25-600 mg, the plasma drug exposure increased with the dose, and no absorption saturation occurred at the highest dose. The clearance rate of Compound 1 was moderate, and the elimination half-life was about 6.46-9.03 h. No accumulation occurred after once-daily, 7-day consecutive oral administration of Compound 1 at 100-400 mg in the fasted state. The accumulation index was about 0.99-1.10; the AUC 1 / 2 The accumulation index was about 0.99-1.10; the AUC max The accumulation index was about 0.99-1.10; the AUC 0-24h The accumulation index was about 0.99-1.10; the AUC max The accumulation index was about 0.99-1.10; the AUC

[0320] Compound 1 was safe and well tolerated at the study dose, and 100-400 mg / day can be used as the dose range for further study.

[0321] The above only is the preferred embodiment of the present application, it should be pointed out that, for the ordinary skilled in the technical field, without departing from the principles of the present application, can also make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A pharmaceutical composition comprising a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient, 2. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises 0.50wt%-50.00wt%, preferably 1.00wt%-35.00wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, by weight percentage; preferably, the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof with a D90 particle size of 5-60μm.

3. The pharmaceutical composition of claim 1 or 2, wherein, The compound of formula (I) is in crystalline form A, crystalline form B or crystalline form C, preferably crystalline form A.

4. The pharmaceutical composition of any one of claims 1-3, wherein, The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1wt%-50.00wt%, by weight percentage; Preferably, the pharmaceutically acceptable excipients can be selected from one or more of the following: fillers, binders, disintegrants, glidants, surfactants and lubricants.

5. The pharmaceutical composition of any one of claims 1-4, wherein, The pharmaceutical composition comprises active pharmaceutical ingredient particles, and additional excipients; Preferably, the active pharmaceutical ingredient particles comprise the compound of formula (I), and have a D90 particle size of 10-300μm.

6. The pharmaceutical composition of any one of claims 1-5, wherein, The pharmaceutically acceptable excipients are selected from one or more of the following: fillers, disintegrants, lubricants, glidants, binders; Preferably, the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fillers, disintegrants, lubricants, glidants and binders; or, The pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fillers, disintegrants, lubricants, glidants and binders; or The pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fillers, disintegrants, lubricants and binders.

7. The pharmaceutical composition of any one of claims 1-6, wherein, The fillers account for 50.00wt%-98.00wt%, preferably 60.00wt%-70.00wt% of the weight of the pharmaceutical composition, by weight percentage, and are selected from one or more of the following: starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts, and combinations thereof; preferably mannitol, microcrystalline cellulose, lactose, most preferably microcrystalline cellulose in combination with lactose; The disintegrants account for 0.50wt%-10.00wt%, preferably 2.00wt%-7.50wt% of the weight of the pharmaceutical composition, by weight percentage, and are selected from one or more of the following: starch and its derivatives, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and cross-linked povidone, and combinations thereof; preferably cross-linked sodium carboxymethyl cellulose or cross-linked povidone; The lubricants account for 0.10wt%-5.00wt%, preferably 0.20wt%-2.00wt% of the weight of the pharmaceutical composition, by weight percentage, and are selected from one or more of the following: microfine silica, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, sodium stearyl fumarate, and combinations thereof; preferably magnesium stearate; The binder is present in the pharmaceutical composition in an amount of 0.10-5.00 wt%, preferably 0.50-2.00 wt% by weight percentage, and the binder is selected from one or more of the following: water, ethanol, starch paste, sugar paste and syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, and combinations thereof; preferably hypromellose; The glidant is present in the pharmaceutical composition in an amount of 0-2.50 wt%, preferably 0.10-2.50 wt%, more preferably 0.50-2.00 wt% by weight percentage, and the glidant is selected from colloidal silicon dioxide, talc; or The solubilizer is present in the pharmaceutical composition in an amount of 0-2.50 wt%, preferably 0.10-2.50 wt%, more preferably 0.50-2.00 wt% by weight percentage, and the solubilizer is selected from polysorbate 80, sodium lauryl sulfate, poloxamer 188.

8. The pharmaceutical composition of any one of claims 1-7, wherein, In addition to the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the active pharmaceutical ingredient granules comprise one or more of a filler, a binder, and a disintegrant, and the additional excipients can comprise a disintegrant and a lubricant, and optionally a glidant and a solubilizer; Preferably, the disintegrant used in the active pharmaceutical ingredient granules can be present in an amount of 40-70%, preferably 45-60%, more preferably 50% by weight of the total disintegrant.

9. The pharmaceutical composition of any one of claims 1-8, wherein, The pharmaceutical composition comprises, by weight percentage: 1.00-35.00 wt% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, in particular crystalline Form A; 60.00-70.00 wt% of a filler, the filler being a combination of microcrystalline cellulose and lactose; 2.00-7.50 wt% of a disintegrant, the disintegrant being crospovidone; 0.50-2.00 wt% of a binder, the binder being hypromellose 0.20-2.00 wt% of a lubricant, the lubricant being magnesium stearate; and optionally 0-2.50 wt%, preferably 0.10-2.50 wt% of a glidant, the glidant being colloidal silicon dioxide; and 0-2.50 wt%, preferably 0.10-2.50 wt% of a solubilizer, the solubilizer being selected from a surfactant; Preferably, the pharmaceutical composition comprises, by weight percentage: 1.00-35.00 wt% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, in particular crystalline Form A; 60.00-70.00 wt% of a filler, the filler being a combination of microcrystalline cellulose and lactose, wherein the weight ratio of microcrystalline cellulose to lactose is in the range of 5:1 to 1:5, in particular 3:1 to 1:3; 2.00-7.50 wt% of a disintegrant, the disintegrant being crospovidone; 0.50-2.00 wt% of a binder, the binder being hypromellose 0.20-2.00 wt% of a lubricant, the lubricant being magnesium stearate; and optionally 0-2.50 wt%, preferably 0.10-2.50 wt% of a glidant, the glidant being colloidal silicon dioxide; and 0-2.50 wt%, preferably 0.10-2.50 wt% of a solubilizer, the solubilizer being selected from a surfactant; 0.20wt%-2.00wt% of a lubricant, the lubricant being magnesium stearate; and the pharmaceutical composition comprises active pharmaceutical ingredient particles comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a filler, a binder and 40%-70% of the disintegrant, and the D90 particle size of the API particles is 10-300 μm, preferably 10-200 μm, more preferably 10-50 μm; More preferably, the pharmaceutical composition comprises, by weight percentage: 1.00wt%-35.00wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof; 60.00wt%-70.00wt% of a filler, the filler being a combination of microcrystalline cellulose PH101 (MCC) and lactose 200, wherein the weight ratio of microcrystalline cellulose PH101 (MCC) and lactose 200 is 2:1-1:2; 2.00wt%-7.50wt% of a disintegrant, the disintegrant being selected from croscarmellose sodium or crospovidone XL; 0.20wt%-2.00wt% of a lubricant, the lubricant being selected from magnesium stearate; and 0.50wt%-2.00wt% of a binder, the binder being selected from hypromellose E5 (HPMC).

10. A preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the preparation comprising the pharmaceutical composition of any one of claims 1-9.

11. The formulation of claim 10, wherein, The preparation is in the form of a unit dose; preferably, the mass of the compound of formula (I) or a pharmaceutically acceptable salt thereof in each unit dose of the preparation is 1 mg-200 mg.

12. The formulation of claim 10 or 11, wherein, The preparation is an oral preparation, in particular a solid preparation, preferably selected from tablets, powders, pills, pellets, pastes, capsules, granules, powders.

13. A method for preparing the pharmaceutical composition of any one of claims 1-9, comprising: 1) granulating, preferably wet granulating, the compound of formula (I) or a pharmaceutically acceptable salt thereof with a filler, a binder and a disintegrant according to the formulation amount, to obtain active pharmaceutical ingredient particles; 2) mixing the active pharmaceutical ingredient particles with the additional excipients, and optionally granulating, to obtain the pharmaceutical composition.

14. The method for preparing of claim 13, comprising: sifting the raw material of the compound of formula (I) or a pharmaceutically acceptable salt thereof to 60 mesh; micronizing the raw material to obtain material ①; mixing material ① with a filler and a disintegrant for internal addition to obtain mixture ①; mixing granulation of mixture ① and a binder to obtain uniform mixture ②; drying (preferably to a final moisture content of ≤3%) mixture ② and sizing the dried granules to obtain uniform mixture ③; mixing mixture ③ with an additional disintegrant, and then adding a lubricant at 10 rpm-30 rpm for 3 min-23 min to obtain a total mixing mixture; molding the total mixing mixture to prepare a preparation, in particular a tablet.

15. Use of a pharmaceutical composition according to any one of claims 1 to 9 or a formulation according to any one of claims 10 to 12 for the manufacture of a medicament for the treatment or prevention of a disease, preferably the medicament is for the inhibition of gout and the treatment or prevention of hyperuricemia.

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