Therapeutic for gout or hyperuricemia

Abstract

To provide a pharmaceutical composition for treating gout or hyperuricemia, which reduces the induction of a gout attack.SOLUTION: The present invention provides a pharmaceutical composition for treating or preventing gout or hyperuricemia, the pharmaceutical composition including a compound represented by General Formula (I) (wherein R1 represents an unsubstituted or substituted phenyl group, R2 represents a cyano group or a nitro group, R3 represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or -S(O)n-, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for treating or preventing gout or hyperuricemia. This application claims priority based on Japanese Patent Application No. 2019-104534, filed on June 4, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] Hyperuricemia can lead to gout and renal failure, and is considered a risk factor for coronary artery disease. It has also been pointed out that it is closely related to the onset and progression of lifestyle-related diseases, including hypertension. Therefore, treating hyperuricemia not only treats gout, but also leads to the prevention of various lifestyle-related diseases associated with aging. Currently, xanthine oxidase inhibitors such as allopurinol and febuxostat are mainly used to treat hyperuricemia. These drugs are extremely effective in lowering uric acid levels and have been used for many years. On the other hand, one of the challenges in treating hyperuricemia is how to suppress gout attacks, which occur when there is an excess of uric acid in the blood, causing uric acid crystals to accumulate in the joints, resulting in severe inflammation and severe pain. Here, it is known that there is a relationship between uric acid lowering drugs and acute gout attacks, and a rapid decrease in serum uric acid causes transient localized precipitation of monosodium urate crystals in cartilage and soft tissue, leading to acute gout attacks. That is, it is known that conventional uric acid lowering drugs can induce gout attacks. Therefore, depending on the patient, gout attacks may require the discontinuation of treatment or a change in treatment plan (Non-Patent Document 1).

[0003] Regarding allopurinol, it has been reported that the incidence of gout attacks can be reduced by using colchicine in combination for the first 6 months of administration as a preventive measure against gout attacks (Non-Patent Document 2). However, colchicine has limitations on its use and is contraindicated for patients with liver or kidney disorders. It has also been reported to have side effects.

[0004] In the case of febuxostat, the usual adult dose is started at a low dose of 10 mg once a day, then gradually increased to 20 mg once a day and the usual maintenance dose of 40 mg once a day, gradually lowering the uric acid level and reducing the incidence of the attack. In addition, the gout guidelines state that rapid lowering of uric acid levels may induce gout attacks, so that uric acid levels should be lowered over a period of 3 to 6 months. Patent Document 1 discloses a method for preventing at least one gout attack or reducing the number of gout attacks by administering an effective amount of a xanthine oxidase inhibitor to a patient with hyperuricemia once a day in a modified release dosage form, or two or more times a day in an immediate release dosage form.

[0005] The compound described in WO 2005 / 121153 (Patent Document 2) has been reported as having a mechanism similar to that of the above-mentioned pharmaceuticals. Patent Document 2 discloses a comparative experiment on the suppression rate of plasma uric acid level between the compound of the invention and allopurinol or febuxostat in Pharmacological Experiment 2 of Example 51, and describes that the compound of the invention exhibits a xanthine oxidase inhibitory effect equal to or greater than that of the controls allopurinol or febuxostat. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2016-520133 [Patent Document 2] International Publication No. 2005 / 121153 [Non-patent literature]

[0007] [Non-Patent Document 1] Arthritis Res Ther. 2009;11:R46 [Non-Patent Document 2] J Rheumatol 2004;31;2429-2432 [Non-Patent Document 3] Feburic (registered trademark) Tablets Application Document Summary [January 2011]; 2.7.2 Clinical Pharmacology Study, P.30 Summary of the Invention [Problem to be solved by the invention]

[0008] The present inventors have investigated a treatment for gout or hyperuricemia that reduces the induction of gout attacks or the severity of attacks without using a drug having xanthine oxidase inhibitory activity in combination with colchicine and without gradually increasing the dosage of a drug having xanthine oxidase inhibitory activity from a low dose, and have found that there is still room for improvement in the treatment of gout or hyperuricemia with drugs having xanthine oxidase inhibitory activity.

[0009] The present invention aims to provide a pharmaceutical composition for treating or preventing gout or hyperuricemia, which reduces the induction of gout attacks or the severity of attacks without using a drug having xanthine oxidase inhibitory activity in combination with colchicine and without increasing the dosage of a drug having xanthine oxidase inhibitory activity stepwise from a low dose. [Means for solving the problem]

[0010] As a result of extensive investigations into pharmaceuticals having xanthine oxidase inhibitory activity, the present inventors have found that continuous administration of a specific amount of a pharmaceutical composition containing a compound represented by general formula (I) or a pharma- ceutical salt thereof is effective in treating gout or hyperuricemia by suppressing the induction of gout attacks or reducing the severity of attacks, without the need for combined use of the pharmaceutical composition with colchicine or without gradually increasing the dosage of the pharmaceutical composition, and have completed the present invention based on this finding.

[0011] That is, the present invention provides the following: [1] General formula (I)

[0012] [ka] (In the formula, R 1 represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, the substituent being at least one group selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a formyl group, a carboxyl group, a halogen atom, a phenyl group, and a phenoxy group; R 2 represents a cyano group or a nitro group, R 3 represents a hydrogen atom or a hydroxyl group, and X represents an oxygen atom or -S(O) n -, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom), or a pharma- ceutical composition for treating or preventing gout or hyperuricemia, comprising a compound represented by the following formula (I): [2] General formula (I)

[0013] [ka] (In the formula, R 1 represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, the substituent being at least one group selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a formyl group, a carboxyl group, a halogen atom, a phenyl group, and a phenoxy group; R 2 represents a cyano group or a nitro group, R 3 represents a hydrogen atom or a hydroxyl group, and X represents an oxygen atom or -S(O) n -, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom) or a pharma- ceutical acceptable salt thereof for treating hyperuricemia in a patient with gouty arthritis; [3] The pharmaceutical composition according to [1] or [2], which suppresses the onset of gout attacks associated with the initiation of uric acid-lowering therapy; [4] The pharmaceutical composition according to any one of [1] to [3], wherein the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is orally administered at 10 to 320 mg per day to a patient in need of treatment or prophylaxis, and the oral administration is continued for at least 7 days; [5] R 1 is an unsubstituted phenyl group or a phenyl group substituted with a halogen atom; [6] The pharmaceutical composition according to any one of [1] to [5], wherein X is an oxygen atom; [7] The pharmaceutical composition according to any one of [1] to [6], wherein Y is a sulfur atom; [8] The pharmaceutical composition according to any one of [1] to [7], wherein the compound or pharma- ceutical acceptable salt thereof according to any one of [1] to [7] contains an amorphous form, and the content of the amorphous form is 80 wt% or more based on the total weight of the compound or pharma-ceutical acceptable salt thereof according to any one of [1] to [7]; [9] The pharmaceutical composition according to any one of [1] to [8], which is an enteric formulation;

[10] The pharmaceutical composition according to [9], wherein the enteric formulation is a hard capsule;

[11] The pharmaceutical composition according to any one of [1] to

[10] , further comprising a solid dispersion containing a hypromellose derivative;

[12] The pharmaceutical composition according to

[11] , wherein the weight ratio of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:25;

[13] The pharmaceutical composition according to

[11] or

[12] , wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate;

[14] The pharmaceutical composition according to any one of [1] to

[13] , which is a solid formulation;

[15] The pharmaceutical composition according to any one of [1] to

[14] , wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is 10 mg to 320 mg;

[16] The pharmaceutical composition according to any one of [1] to

[15] , wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 320 mg;

[17] The pharmaceutical composition according to any one of [1] to

[16] , wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 160 mg;

[18] The pharmaceutical composition according to any one of [1] to

[17] , wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 80 mg;

[19] The pharmaceutical composition according to any one of [1] to

[18] , wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 20 mg to 80 mg;

[20] The pharmaceutical composition according to any one of [1] to

[19] , which reduces blood uric acid concentration by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration, as compared to before administration;

[21] The pharmaceutical composition according to any one of [1] to

[20] , wherein, by continuous administration once a day for 7 days, the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to the concentration before administration;

[22] The pharmaceutical composition according to any one of [1] to

[21] , wherein the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased within 3 weeks from the start of administration;

[23] The pharmaceutical composition according to any one of [1] to

[22] , wherein the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased or is increased once within 7 weeks from the start of administration;

[24] The pharmaceutical composition according to any one of [1] to

[23] , wherein the maximum reduction rate of blood uric acid level on the first day of administration ([(uric acid level before administration-minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is 10 to 25%;

[25] The pharmaceutical composition according to any one of [1] to

[24] , wherein the maximum reduction rate of blood uric acid level on the 7th day after administration ([(uric acid level before administration-minimum uric acid level after administration on the 7th day after administration) / uric acid level before administration]×100) is 20 to 45%;

[26] The pharmaceutical composition according to any one of [1] to

[25] , wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharma-ceutical acceptable salt thereof;

[27] A package comprising the pharmaceutical composition according to any one of [1] to

[26] , the package containing the pharmaceutical composition in the number of dosage units required for continuous administration for 5 to 15 days. Effect of the Invention

[0014] The pharmaceutical composition provided by the present invention is useful for the treatment of gout or hyperuricemia, etc. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the particle size distribution of amorphous Compound 14 by wet laser diffraction method. [Diagram 2] FIG. 2 is a graph showing the plasma drug concentration-time curve when the capsule of Reference Example 1a and the capsule of Comparative Reference Example 1a were administered to dogs. [Diagram 3] FIG. 1 shows the crystalline powder X-ray diffraction pattern of compound 14. [Figure 4] FIG. 1 shows powder X-ray diffraction patterns of amorphous Compound 14, where (a) is the powder X-ray diffraction pattern before storage, (b) is the powder X-ray diffraction pattern after storage for 1 week under light-shielded, airtight and room temperature conditions, (c) is the powder X-ray diffraction pattern after storage for 2 weeks under light-shielded, airtight and room temperature conditions, and (d) is the powder X-ray diffraction pattern after storage for 4 weeks under light-shielded, airtight and room temperature conditions. [Diagram 5] FIG. 1 shows powder X-ray diffraction patterns of the solid dispersion of Reference Example 9b before storage and after storage for 1 week, 3 weeks, and 7 weeks under open conditions at 40° C. / 75% RH, respectively. [Figure 6]FIG. 1 shows powder X-ray diffraction patterns of the solid dispersion of Reference Example 10b before storage and after storage for 1 week, 3 weeks, and 7 weeks under open conditions at 40° C. / 75% RH, respectively. [Figure 7] FIG. 1 shows powder X-ray diffraction patterns of the solid dispersion of Reference Example 11b before storage and after storage for 1 week, 3 weeks, and 7 weeks under open conditions at 40° C. / 75% RH, respectively. [Figure 8] 1 is a graph showing the plasma uric acid level lowering effect in rats of the solid dispersion of Reference Example 11b. [Figure 9] FIG. 1 shows the decrease in serum uric acid level when compound 14 and febuxostat as a control drug were orally administered to healthy adult males in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] <Pharmaceutical Composition> The present invention will be described in more detail below. The pharmaceutical composition for treating or preventing gout or hyperuricemia of the present invention contains a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof as an active ingredient. In the compound represented by the general formula (I), R 1 represents an unsubstituted phenyl group or a phenyl group substituted with a substituent. R 1 Examples of the "alkyl group having 1 to 8 carbon atoms" as a substituent in the phenyl group represented by the following formula (1) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, and the like, and preferably include a methyl group, an ethyl group, and the like.

[0017] R 1 Examples of the "alkyl group having 1 to 8 carbon atoms substituted with a halogen atom" as a substituent in the phenyl group represented by the following formula (1) include a fluoromethyl group, a trifluoromethyl group, a 1,1-difluoroethyl group, a pentafluoroethyl group, and the like, and preferably a fluoromethyl group, a trifluoromethyl group, and the like.

[0018] R 1Examples of the "alkoxy group having 1 to 8 carbon atoms" as a substituent in the phenyl group represented by the following formula (1) include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, and the like, and preferably a methoxy group, and the like.

[0019] R 1 Examples of the "alkoxycarbonyl group having 2 to 8 carbon atoms" as a substituent in the phenyl group represented by the following formula (I) include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, and the like, and preferable examples include a methoxycarbonyl group, an ethoxycarbonyl group, and the like.

[0020] R 1 Examples of the "halogen atom" as a substituent in the phenyl group represented by the following formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferred examples include a fluorine atom, a chlorine atom, and the like.

[0021] R 1 As the aryl group, an unsubstituted phenyl group is preferable.

[0022] In the compound represented by the general formula (I), R 2 represents a cyano group or a nitro group, with a cyano group being preferred.

[0023] In the compound represented by the general formula (I), R 3 represents a hydrogen atom or a hydroxy group, with a hydrogen atom being preferred.

[0024] In the compound represented by the general formula (I), X is an oxygen atom or -S(O) n -, but an oxygen atom is preferred.

[0025] In the compound represented by formula (I), Y represents an oxygen atom or a sulfur atom, preferably a sulfur atom.

[0026] Examples of pharma- ceutically acceptable salts of the compound represented by general formula (I) include alkali metal salts such as sodium salts, potassium salts, and lithium salts, with potassium salts being preferred.

[0027] The compound of general formula (I) contained in the pharmaceutical composition for treating or preventing gout or hyperuricemia, which is one embodiment of the present invention, can be obtained, for example, by the synthesis method described in Patent Document 2 or the specification of International Application No. PCT / JP2019 / 17439.

[0028] Among the compounds of formula (I) contained in the pharmaceutical composition for treating or preventing gout or hyperuricemia of the present invention, preferred compounds include the compounds in Table 1. In the table, Me represents a methyl group.

[0029] [Table 1] Compounds 1 to 15 may form pharma- ceutically acceptable salts, and among these, Compounds 3 to 5, Compounds 8 to 10, Compounds 13 to 14, or pharma-ceutically acceptable salts of these compounds are preferred.

[0030] In the pharmaceutical composition for treating or preventing gout or hyperuricemia of the present invention, the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is preferably present in part or in whole as an amorphous substance, where the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof has a short-range order between atoms or molecules but does not have a long-range order as in crystals. In the present invention, an amorphous substance can be identified by the presence of a halo peak in X-ray diffraction. In the present invention, the compound represented by general formula (I) or its pharma- ceutically acceptable salt is preferably present as amorphous at 50% by weight or more, more preferably present as amorphous at 80% by weight or more, more preferably present as amorphous at 90% by weight or more, even more preferably present as amorphous at 95% by weight or more, and may be 100% by weight. The pharma-ceutically acceptable salt of the compound represented by general formula (I) may be crystalline, and in this case, the amorphous may be present at less than 50% by weight, 40% by weight or less, 30% by weight or less, 20% by weight or less, 10% by weight or less, or may not be present at all. The amorphous content can be determined by X-ray diffraction. In the amorphous content, the remainder is crystalline. That is, in the description of each content, the total content of the amorphous and crystalline is 100% by weight.

[0031] The amorphous compound represented by formula (I) or a pharma- ceutically acceptable salt thereof can be produced, for example, by subjecting the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof to a spray drying method (also called a spray-drying method). More specifically, the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof and, if desired, a pharma- cetically acceptable additive are added to a solvent described below to form a solution or suspension, and the solution or suspension is made into a fine mist by centrifugal spraying using a rotating disk or pressurized spraying using a pressure nozzle, and this is sprayed into a drying medium (for example, heated air or nitrogen gas), thereby obtaining an amorphous powdery dried product. In the spray drying method, the temperature of the drying medium is, for example, 50 to 120°C, preferably 50 to 90°C. The drying medium may be flowed in a certain direction, for example, at a speed of 0.1 to 0.6 m. 3 It can be made to flow at an air volume of 1 / min. Examples of solvents used in the spray drying method include alcohols containing alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol, ethers such as tetrahydrofuran (THF), acetonitrile, and water, and these solvents can be used alone or as a mixed solvent of two or more of them. Among them, ethanol, tetrahydrofuran, and mixed solvents of these solvents and water are preferred. Another method for producing the amorphous form of the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof is lyophilization. More specifically, the compound represented by formula (I) or a pharma-ceutically acceptable salt thereof is dissolved in a solvent, and the solution is then lyophilized to produce the amorphous form. Solvents used in the freeze-drying method include alcohols containing an alcohol having 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; and water. These solvents can be used alone or in combination of two or more. The particle size of the amorphous compound represented by formula (I) or a pharma- ceutically acceptable salt thereof is not particularly limited, but from the viewpoint of the effects of the invention and formulation, the volume average particle size (D50) is, for example, 20 μm or less, preferably 1 to 15 μm, more preferably 1 to 10 μm, even more preferably 1.5 to 5 μm, and most preferably 2 to 5 μm. The volume average particle diameter (D50) can usually be measured by dispersing a measurement sample in a solvent such as water or ethanol, and measuring the particle diameter distribution by a laser diffraction method. The measurement sample may be dispersed in a solvent by irradiating it with ultrasonic waves, etc. The particle diameter distribution can be measured by a particle diameter distribution measuring device (e.g., Shimadzu laser diffraction particle diameter distribution measuring device SALD-2200, etc.). The volume average particle diameter (D50) can be obtained from the obtained particle diameter distribution result. In addition, commercially available software (e.g., Shimadzu WingSALD-2200 version 1.02, etc.) can be used for data collection and analysis.

[0032] The pharmaceutical composition of the present invention can be blended with pharma- ceutical acceptable additives as necessary. For example, the pharmaceutical composition of the present invention can be produced by blending a binder, a disintegrant, an excipient, a lubricant, etc. in an appropriate combination in the required amounts.

[0033] Examples of the binder include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, xanthan gum, and powdered gum arabic. These may be used alone or in combination of two or more. Among these, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, and the like are preferred.

[0034] Examples of the disintegrant include crystalline cellulose, carboxymethylcellulose (also called carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partially pregelatinized starch, and sodium starch glycolate. These may be used alone or in a mixture of two or more. Among them, croscarmellose sodium, sodium starch glycolate, crospovidone, and the like are preferred, and crospovidone and the like are more preferred. The amount of the disintegrant used is, for example, preferably 5 to 30% by weight, more preferably 5 to 15% by weight, based on the total weight of the particles containing the active ingredient. When the disintegrant is added to a tablet, the amount is preferably 1 to 10% by weight, more preferably 2 to 6% by weight, based on the total weight of the granules for tableting containing the active ingredient.

[0035] The excipient can be added to any of the kneading process, granulation process, or post-granulation powder process of the pharmaceutical preparation. Examples of the excipient include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methylcellulose (also called hypromellose), starches such as corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, and hydroxypropyl starch, sugars such as glucose, lactose, white sugar, refined white sugar, powdered sugar, trehalose, dextran, and dextrin, sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol, inorganic salts such as glycerin fatty acid ester, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and sodium hydrogen carbonate, and the like, and crystalline cellulose and the like are preferred.

[0036] Examples of the lubricant include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hardened oil, glycerin fatty acid ester, and talc. These may be used alone or in combination of two or more. Among them, sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid ester are preferred.

[0037] In addition, in the pharmaceutical composition, the compound represented by the general formula (I) or its pharma- ceutically acceptable salt is mixed with an enteric polymer to suppress recrystallization from a supersaturated solution of the compound represented by the general formula (I) or its pharma- ceutically acceptable salt. When the compound represented by the general formula (I) or its pharma- ceutically acceptable salt is mixed with an enteric polymer, it is preferable that they are mixed uniformly. The weight ratio of the compound represented by the general formula (I) or its pharma- ceutically acceptable salt to the enteric polymer is 1:0.5 to 1:10, preferably 1:1 to 1:5, more preferably 1:2 to 1:5, and even more preferably 1:1 to 1:4. The enteric polymer includes the enteric polymers for coating described above, and is preferably a cellulose-based polymer, more preferably hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, or the like. When the compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof is mixed with the enteric polymer, the above-mentioned pharma- ceutically acceptable additives can be appropriately added.

[0038] <Enteric-coated preparations> The pharmaceutical composition according to the present invention is preferably an enteric formulation. The "enteric formulation" according to the present invention is a formulation designed to prevent the decomposition of an active ingredient in the stomach, or to release the active ingredient mainly in the small intestine without releasing it in the stomach. The enteric formulation itself is described in the Japanese Pharmacopoeia. As enteric formulations, dosage forms such as tablets, granules, fine granules, and capsules are known. The methods for producing these dosage forms include (i) a method of producing enteric granules in which an active ingredient, or an active ingredient and a pharma- ceutically acceptable additive are coated with an enteric polymer, and then preparing tablets, granules, fine granules, or capsules containing the enteric granules; (ii) a method of producing tablets, granules, fine granules, or capsules containing an active ingredient and a pharma-ceutically acceptable additive, and coating these preparations with an enteric polymer; or (iii) a method of accommodating an active ingredient, or an active ingredient and a pharma-ceutically acceptable additive, in a hard capsule made of an enteric base, and the like. That is, examples of the enteric preparation according to the present invention include (i) tablets, granules, fine granules, or capsules containing an active ingredient, or an active ingredient and a pharma- ceutically acceptable additive coated with an enteric polymer, (ii) tablets, granules, fine granules, or capsules containing an active ingredient and a pharma- ceutically acceptable additive coated with an enteric polymer, or (iii) hard capsules in which an active ingredient, or an active ingredient and a pharma- ceutically acceptable additive are accommodated in a hard capsule made of an enteric base. The enteric base means a base composed of a known enteric polymer, and examples of the enteric polymer include the enteric polymers exemplified below as enteric polymers for coating.

[0039] Examples of the enteric polymer for coating used in the present invention include enteric methacrylic acid copolymers such as methacrylic acid copolymer L, methacrylic acid copolymer S (e.g., Eudragit (registered trademark) L100, Eudragit (registered trademark) S100, manufactured by Evonik), methacrylic acid copolymer LD (e.g., Eudragit (registered trademark) L100-55, Eudragit (registered trademark) L30D-55, manufactured by Evonik), and methyl acrylate-methyl methacrylate-methacrylic acid copolymer (e.g., Eudragit (registered trademark) FS30D, manufactured by Evonik); Examples of such cellulose-based polymers include enteric cellulose polymers such as hydroxypropyl methylcellulose, hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCAS), hypromellose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCP), carboxymethylethylcellulose (manufactured by Freund Corporation, sometimes abbreviated as CMEC), and ceracephate (also called cellulose acetate phthalate), and enteric vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate (manufactured by Colorcon Co., Ltd.), but enteric cellulose polymers and the like are preferred. Among these, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate are preferred. The enteric granules can be produced according to a known method, for example, by producing granules by a fluidized bed granulation method such as tumbling fluidized bed granulation or fluidized bed granulation, a rolling granulation method such as centrifugal rolling granulation, or an agitation granulation method, and then coating the granules with an enteric coating liquid and drying the same. The enteric coating liquid can be prepared by adding the enteric polymer to a solvent and concentrating the solvent as necessary. Examples of the solvent used to prepare the enteric coating liquid include water, alcoholic solvents such as methanol and ethanol, or mixtures thereof. Pharmaceutically acceptable additives such as binders, plasticizers, coating bases, surfactants, and excipients can be appropriately blended as necessary. The amount of the solvent is not particularly limited, but it can be used in an amount 3 to 10 times the total weight of the dissolved matter (i.e., the total weight of the enteric polymer and the pharma- ceutical acceptable additives).

[0040] The tablets, granules, fine granules, or capsules containing an active ingredient and a pharma- ceutically acceptable additive and coated with the enteric polymer can be produced by producing tablets, granules, fine granules, or capsules containing an active ingredient and a pharma- ceutically acceptable additive according to a known method, and coating the resulting preparation with the enteric coating liquid and drying it.

[0041] As the hard capsule made of an enteric base, a commercially available product can be used, for example, a hard capsule made of an enteric base containing hydroxypropyl methylcellulose or hydroxypropyl methylcellulose acetate succinate can be used, more specifically, Vcaps (registered trademark) Enteric (manufactured by Capsugel), etc. can be used. The enteric formulation according to the present invention can be blended with pharma- ceutical acceptable additives as necessary, and the pharmaceutical composition of the present invention can be produced by blending, for example, a binder, a disintegrant, an excipient, a lubricant, etc. in an appropriate combination in the required amounts. Examples of the "pharma- ceutical acceptable additives" include the pharma- ceutical acceptable additives exemplified in the pharmaceutical composition. The enteric formulation provided by the present invention can exhibit high absorbability in the body.

[0042] <Solid dispersion> The pharmaceutical composition of the present invention may further comprise a solid dispersion containing a hypromellose derivative. The "hypromellose derivative" according to the present invention refers to hypromellose itself (sometimes abbreviated as HPMC) and organic acid esters of hypromellose. Hypromellose is also called hydroxypropyl methylcellulose, and is a mixed ether of cellulose methyl and hydroxypropyl groups. Examples of organic acids that form esters with hypromellose include acetic acid, succinic acid, and phthalic acid. Hypromellose according to the present invention may form esters with one or more organic acids selected from the above organic acids. Examples of hypromellose derivatives used in the present invention include hypromellose, hypromellose acetate succinate (sometimes abbreviated as HPMCAS), and hypromellose phthalate (sometimes abbreviated as HPMCP), of which hypromellose acetate succinate and hypromellose phthalate are preferred.

[0043] The hypromellose according to the present invention is exemplified by hypromellose having a substitution ratio per monomer unit of 28 to 30% for methoxy groups and 7 to 12% for hydroxypropoxy groups. The hypromellose acetate succinate of the present invention is exemplified by hypromellose acetate succinate having a substitution ratio per monomer unit of 20-26%, preferably 21-25%, for methoxy groups, 5-10%, preferably 5-9%, for hydroxypropoxyl groups, 5-14%, preferably 7-11%, for acetyl groups, and 4-18%, preferably 10-14%, for succinoyl groups. The hypromellose phthalate of the present invention is exemplified by hypromellose phthalate having a substitution ratio per monomer unit of 18-24% for methoxy groups, 5-10% for hydroxypropoxy groups, and 21-35% for carboxybenzoyl groups. The content of methoxy groups, hydroxypropoxy groups, acetyl groups, succinoyl groups, carboxybenzoyl groups, etc. in the above-mentioned hypromellose derivatives can be measured by a method conforming to the method for measuring the degree of substitution of hypromellose, hypromellose acetate succinate, and hypromellose phthalate specified in the 17th Edition of the Japanese Pharmacopoeia.

[0044] The viscosity of the hypromellose derivative according to the present invention is not particularly limited as long as it has the effects of the present invention, but may be, for example, 2.4 to 204 mPa·s, and preferably 2.4 to 3.6 mPa·s. The viscosity of the hypromellose derivative according to the present invention can be measured by a method conforming to the method for measuring the viscosity of hypromellose, hypromellose acetate succinate, and hypromellose phthalate specified in the 17th Edition of the Japanese Pharmacopoeia.

[0045] The weight ratio of the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof to the hypromellose derivative can be appropriately adjusted within the range of 1:0.1 to 1:25. One example of the weight ratio of the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:10, another example is 1:0.1 to 1:4, still another example is 1:1 to 1:10, still another example is 1:2 to 1:5, and still another example is 1:3 to 1:4. One embodiment of the present invention is a solid dispersion in which the weight ratio of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharma- ceutically acceptable salt thereof to a hypromellose derivative is 1:0.1 to 1:25, another embodiment is 1:0.1 to 1:10, yet another embodiment is 1:0.1 to 1:4, yet another embodiment is 1:1 to 1:10, yet another embodiment is 1:2 to 1:5, and yet another embodiment is 1:3 to 1:4.

[0046] The term "solid dispersion" refers to a solid composition that includes at least two components forming a homogeneously mixed system, and in the solid dispersion, at least one component is usually dispersed throughout the system. Therefore, one embodiment of the "solid dispersion" according to the present invention is a solid composition comprising a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, and a hypromellose derivative, forming a system in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and the hypromellose derivative are homogeneously mixed. Another embodiment of the "solid dispersion" according to the present invention is a solid composition in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is dispersed throughout a hypromellose derivative to form a system, in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof constitutes the dispersed phase as a dispersoid, and the hypromellose derivative constitutes the continuous phase as a dispersion medium.

[0047] The "solid dispersion" according to the present invention is composed of a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, a hypromellose derivative, and, if desired, a pharma- ceutically acceptable additive. Examples of the pharma- ceutically acceptable additive that may be included if desired include additives selected from surfactants, pH adjusters, sugars, plasticizers, and the like. These may be appropriately combined and incorporated in the solid dispersion according to the present invention in the required amount. Surfactants that can be used include cationic surfactants such as sodium bis-(2-ethylhexyl) sulfosuccinate (docusate sodium), alkyltrimethylammonium bromides (e.g., cetyltrimethylammonium bromide (cetrimide)), anionic surfactants such as sodium lauryl sulfate, polyoxyethylene sorbitan (e.g., Tween TM 20, 40, 60, 80 or 85), sorbitan fatty acid esters (e.g., Span TM 20, 40, 60, 80 or 85). Examples of pH adjusters that can be used include acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, and alkalis such as sodium hydroxide, magnesium oxide, silicon dioxide, sodium bicarbonate, and L-arginine. Examples of sugars that can be used include lactose, sucrose, glucose, fructose, sucrose, maltose (malt sugar), reduced maltose, maltitol, mannitol, erythritol, sorbitol, and xylitol. Plasticizers that can be used include triethyl citrate, polyethylene glycol, triacetin, and the like. The "solid dispersion" according to the present invention may not contain the pharma- ceutically acceptable additives. When the "solid dispersion" contains the pharma-ceutically acceptable additives, for example, the weight ratio of the compound represented by general formula (I) or a pharma-ceutically acceptable salt thereof to the surfactant is 1:0.01 to 1:2, more preferably 1:0.02 to 1:1.5, and even more preferably 1:0.03 to 1:1.2, and the weight ratio of the compound represented by general formula (I) or a pharma-ceutically acceptable salt thereof to the pH adjuster is 1: The weight ratio of the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof to the saccharide is 0.01 to 1:2, more preferably 1:0.02 to 1:1.5, and even more preferably 1:0.03 to 1:1.2; the weight ratio of the compound represented by general formula (I) or a pharma-ceutically acceptable salt thereof to the plasticizer is 1:0.02 to 1:20, more preferably 1:0.15 to 1:10. In the "solid dispersion" according to the present invention, the pharma- ceutical acceptable additive may constitute either the dispersed phase or the continuous phase of the solid dispersion.

[0048] In the "solid dispersion" according to the present invention, the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is preferably present in part or in whole as an amorphous substance.

[0049] The solid dispersion according to the present invention can be produced by a method known per se, for example, a mixing and grinding method (mechanochemical method), a solvent method, a melting method, a heat-kneading and melting method, or the like. Here, the mixed grinding method can be carried out by a conventional method using a mixer and grinder such as a ball mill or a hammer mill after mixing the compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof, the hypromellose derivative, and optionally a pharma- ceutically acceptable additive. The solvent method refers to a method in which the compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof, the hypromellose derivative, and optionally a pharma- ceutically acceptable additive are dissolved or suspended in a solvent (organic solvent, water, or a mixture thereof), and then the solvent is removed to precipitate a solid dispersion, or a solid dispersion is precipitated in the solvent. The solvent can be removed by a method such as a spray method (which can be classified into a fluidized bed method, a spray drying method (also called a spray-drying method), a rolling bed method, a stirring method, or a supercritical method, depending on the embodiment), a filtration method, an evaporation method, or a freeze-drying method, of which the spray method is preferred, and the spray drying method is particularly preferred. The solvent that can be used in producing the solid dispersion according to the present invention is preferably a pharma- ceutically acceptable solvent, and examples thereof include ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, toluene, acetonitrile, methylene chloride, chloroform, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. In these solvents, it is preferable that the compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof, and pharma- ceutically acceptable additives, which are optionally blended, are dissolved. In the spray drying method, a solid dispersion can be produced by a method known per se. For example, the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, a hypromellose derivative, and optionally a pharma- ceutically acceptable additive are added to the solvent to form a solution or suspension, and the solution or suspension is turned into a fine mist by centrifugal spraying using a rotating disk or pressurized spraying using a pressure nozzle, and this is sprayed into a drying medium (heated air or nitrogen gas) to obtain a powdery dried product, thereby obtaining a solid dispersion. In the spray drying method, the temperature of the drying medium is, for example, 50 to 120° C., and preferably 50 to 90° C. The drying medium may be flowed in a certain direction, for example, at a rate of 0.1 to 0.6 m 3 It can be made to flow at an air volume of 1 / min. In the solvent method, the precipitation method is preferably a coprecipitation method, in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a hypromellose derivative, as well as optionally pharma- ceutically acceptable additives, are dissolved or suspended in a solvent, and the dissolved compound (I) or a pharma- ceutically acceptable salt thereof and a hypromellose derivative, as well as optionally pharma- ceutically acceptable additives, are precipitated by lowering the dissolution concentration by adding a solvent in which the dissolved compound (I) or a pharma- ceutically acceptable salt thereof and a hypromellose derivative, as well as optionally pharma- ceutically acceptable additives, are insoluble, or by lowering the temperature, etc., to obtain a solid dispersion. The melting method refers to a method in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, the hypromellose derivative, and optionally pharma- ceutically acceptable additives are heated to a temperature above the melting point or softening point of the hypromellose derivative, and stirred, etc., to dissolve or disperse the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, and optionally pharma- ceutically acceptable additives, in the hypromellose derivative, and then rapidly cooled. In this case, additives such as plasticizers, such as triethyl citrate, polyethylene glycol, triacetin, and surfactants, can be further added, if desired. The preparation can be carried out using an agitating granulator equipped with a heating device. The heat-kneading melting method refers to a method in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, a hypromellose derivative, and, if desired, a pharma- ceutically acceptable additive are mixed under heat and pressure using an extruder equipped with a heating device, such as a twin-screw extruder, to obtain a solid dispersion, and the obtained plastic-like solid dispersion can be pulverized using a pulverizer to obtain a powder of the solid dispersion.

[0050] The solid dispersion according to the present invention produced by the above-mentioned production method can be made into solid dispersion particles having any particle size by a known method, and the solid dispersion particles can be used as they are as a powder or granules.

[0051] The pharmaceutical composition containing the solid dispersion according to the present invention contains the solid dispersion and a pharma- ceutical acceptable additive, and the pharmaceutical composition of the present invention can be produced by blending a required amount of an appropriate combination of, for example, a binder, a disintegrant, an excipient, a lubricant, etc. As the pharma- ceutical acceptable additive, the pharma- ceutical composition of the present invention can be produced by blending, for example, a binder, a disintegrant, an excipient, a lubricant, etc. As the "pharma- ceutical acceptable additive", the pharma- ceutical acceptable additives exemplified in the pharmaceutical composition can be exemplified.

[0052] The pharmaceutical composition containing the solid dispersion according to the present invention can be provided by subjecting it to a formulation process known per se to be formulated into solid preparations such as tablets, capsules, granules, powders, etc., or liquid preparations such as injections, etc. The injections may be in a form in which the pharmaceutical composition of the present invention is provided as a solid preparation and then prepared into an injection at the time of use. Since the present invention also has an effect of suppressing tableting trouble, it is particularly preferable for the solid preparation to be a tablet. Furthermore, these solid preparations can be coated as desired.

[0053] The content of the solid dispersion in the pharmaceutical composition containing the solid dispersion according to the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, based on the total weight of the pharmaceutical composition. The solid dispersion provided by the present invention can exhibit high in vivo absorbability and storage stability.

[0054] The pharmaceutical composition provided by the present invention can be administered orally or parenterally, more preferably orally, to a patient in need of treatment or prevention, more specifically to a human or other mammal. Preferably, the pharmaceutical composition provided by the present invention is administered to a human. The pharmaceutical composition provided by the present invention is useful as a therapeutic or prophylactic agent for hyperuricemia or gout.

[0055] One embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0056] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, which contains enteric granules in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day to a patient in need of such treatment or prevention, and the oral administration is continued for at least 7 days.

[0057] Another embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof in the enteric granules is further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0058] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof in the enteric granules is further mixed with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention in an amount of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days. The tablet, granule, fine granule, or capsule is used.

[0059] Another embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable additive are coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0060] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, comprising a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and enteric granules in which a pharma- ceutically acceptable additive is coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0061] Another embodiment of the present invention is a pharmaceutical composition for treating or preventing gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable additive are coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and the pharma- ceutical acceptable additive in the enteric granules are further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of treatment or prevention in an amount of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0062] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, comprising enteric granules in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable additive are coated with an enteric polymer, and the compound represented by general formula (I) or a pharma-ceutically acceptable salt thereof and the pharma-ceutically acceptable additive in the enteric granules are further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharma-ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention in an amount of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0063] Another embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of gout or hyperuricemia, which contains a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof coated with an enteric polymer, and a pharma- ceutical acceptable additive, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0064] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, which is coated with an enteric polymer and contains a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable additive, wherein the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0065] Another embodiment of the present invention is a pharmaceutical composition for treating or preventing gout or hyperuricemia, comprising a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable additive coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and the pharma- ceutical acceptable additive are further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0066] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for treating or preventing gout or hyperuricemia, which contains a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable additive coated with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and the pharma- ceutically acceptable additive are further mixed with an enteric polymer, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day to a patient in need of treatment or prevention, and the oral administration is continued for at least 7 days. The tablet, granule, fine granule, or capsule is used.

[0067] Another embodiment of the present invention is a hard capsule preparation for treating or preventing gout or hyperuricemia, comprising a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof housed in a hard capsule made of an enteric base, wherein the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0068] Another embodiment of the present invention is a hard capsule preparation for treating or preventing gout or hyperuricemia, comprising a hard capsule made of an enteric base, a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable additive contained therein, wherein the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days. Another embodiment of the present invention is a hard capsule preparation for treating or preventing gout or hyperuricemia, in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is contained in a hard capsule made of an enteric base, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is further mixed with an enteric polymer, in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0069] Another embodiment of the present invention is a hard capsule preparation for treating or preventing gout or hyperuricemia, in which a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable additive are contained in a hard capsule made of an enteric base, and the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable additive are further mixed with an enteric polymer, in which the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered to a patient in need of treatment or prevention at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0070] Another embodiment of the present invention is a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of gout or hyperuricemia, wherein the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof is orally administered at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day to a patient in need of such treatment or prevention, and the oral administration is continued for at least 7 days.

[0071] Another embodiment of the present invention is a pharmaceutical composition for use in the treatment or prevention of gout or hyperuricemia, comprising a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable additive, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0072] Another embodiment of the present invention is a solid dispersion according to the present invention or a pharmaceutical composition comprising the solid dispersion for use in the treatment or prevention of gout or hyperuricemia, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered at 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day to a patient in need of such treatment or prevention, and the oral administration is continued for at least 7 days.

[0073] Another embodiment of the present invention is use of a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof for the manufacture of a drug for the treatment or prevention of gout or hyperuricemia, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of such treatment or prevention at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is continued for at least 7 days.

[0074] Another embodiment of the present invention is a method for treating or preventing gout or hyperuricemia, comprising orally administering 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, of the pharmaceutical composition of the present invention per day to a subject in need of treatment or prevention of gout or hyperuricemia, and continuously administering the oral administration for at least 7 days. Yet another embodiment of the present invention is a method for treating or preventing gout or hyperuricemia, comprising orally administering 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day of the solid dispersion according to the present invention or a pharmaceutical composition comprising the solid dispersion to a subject in need of treatment or prevention of gout or hyperuricemia, and continuously administering the oral administration for at least 7 days.

[0075] The dosage of the pharmaceutical composition of the present invention can be adjusted according to the content of the compound represented by general formula (I) or its pharma- ceutical acceptable salt in the pharmaceutical composition of the present invention. It is also determined appropriately according to the administration method, age, weight, sex, symptoms, drug sensitivity, etc. of the subject, and the dosage may be adjusted according to the state of symptom improvement. In the present invention, it is preferable to continuously administer a certain dosage. The dosage of the enteric formulation of the present invention is, for example, in an adult, usually 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, even more preferably 60 to 120 mg, and particularly preferably 60 to 100 mg per day, calculated as the content of the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof, and the oral administration can be continued for at least 7 days, but can be increased or decreased depending on age, symptoms, etc. The number of times of administration can be, for example, 1 to 3 times, preferably 1 to 2 times, more preferably 1 time per day.

[0076] Hyperuricemia is a condition in which the uric acid level in the blood is abnormally high. In hyperuricemia, some of the uric acid cannot be dissolved and crystallizes. When this crystallized uric acid accumulates in the joints and causes inflammation, it becomes gouty arthritis, and symptoms called gout attacks accompanied by severe pain are presented. There are two types of hyperuricemia: hyperuricemia that presents with clinical symptoms such as gouty arthritis, and asymptomatic hyperuricemia that does not have clinical symptoms such as gouty arthritis. The subject of administration of the pharmaceutical composition provided by the present invention may be a gouty arthritis patient (e.g., a gouty arthritis patient who has developed hyperuricemia), or a hyperuricemia patient who has developed a gout attack, or even an asymptomatic hyperuricemia patient.Preferably, the pharmaceutical composition provided by the present invention may be used to treat hyperuricemia in a gouty arthritis patient. As used herein, the terms "suppression of gout attacks," "suppression of the induction of gout attacks," and "suppression of the occurrence of gout attacks" mean, for example, a reduction in the frequency or severity (e.g., degree of pain) of "gout attacks," preferably the frequency, compared to a group administered conventional uric acid-lowering drugs such as allopurinol or febuxostat or a placebo group, and preferably include the absence of the occurrence of "gout attacks." In general, when treating patients with gouty arthritis to lower blood uric acid levels, uric acid lowering drugs are administered after the gout attack has gone into remission (after the pain has subsided), but the administration should be started at a low dose and gradually increased so that blood uric acid levels gradually drop to the target level. This is because if blood uric acid levels are suddenly lowered by administering uric acid lowering drugs, the re-dissolution of urate crystals attached to the joints will progress rapidly, making them more likely to peel off, and inducing a gout attack. Gout attacks caused by a sudden drop in uric acid levels due to uric acid lowering drugs are known as mobilization flare-ups. The pharmaceutical composition provided by the present invention can gradually lower the blood uric acid concentration, and therefore can suppress acute gout attacks such as mobilization flare-ups of uric acid without or with less gradual increase. Meanwhile, in Japan, it is recommended that the xanthine oxidase inhibitor febuxostat be administered at a starting dose of 10 mg once daily to suppress the induction of gout attacks (mobilization flare-ups of uric acid) caused by a sudden drop in blood uric acid levels, and then gradually increased to 20 mg once daily after two weeks from the start of administration, and 40 mg once daily after six weeks from the start of administration. In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in daily dose to suppress the onset of gout attacks (mobilization flare-ups of uric acid) associated with the initiation of uric acid-lowering therapy, and the daily dose does not need to be increased for three weeks after the initiation of administration. In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in daily dose to suppress the occurrence of gout attacks (mobilization flare-ups of uric acid) associated with the initiation of uric acid-lowering therapy, and the daily dose may not be increased or may be increased no more than once during the first 7 weeks of administration. The effect of gradually lowering blood uric acid levels which can be achieved by administering the pharmaceutical composition provided by the present invention can be achieved, for example, by orally administering 10 to 320 mg (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg) of a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per day. Furthermore, the blood uric acid level may be gradually lowered by daily administration of 10 to 320 mg (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg) of a compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof, for example, by daily administration for 7 days or more (e.g., 1 month, 2 months, or 3 months). In one embodiment, the pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharma- ceutical acceptable salt thereof is orally administered to a patient in need of treatment at 10-320 mg per day, and the oral administration is continued for at least 7 days. In this embodiment, the uric acid level of the patient is gradually lowered without being abruptly lowered, and therefore it may be useful for the treatment of gout or hyperuricemia, which reduces the induction or severity of gout attacks. The effect of gradually lowering blood uric acid levels achieved by administering the pharmaceutical composition provided by the present invention can be achieved, for example, by administering the pharmaceutical composition provided by the present invention to a healthy adult (e.g., a male) for 7 consecutive days, measuring blood uric acid levels before and after administration, and determining that the maximum rate of decrease in blood uric acid levels on the first day of administration ([(uric acid level before administration-minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is about 35% or less (e.g., a decrease of 1 to 35%, 10 to 30%). and / or the maximum rate of decrease in blood uric acid level on the 7th day after administration ([(pre-administration uric acid level-minimum post-administration uric acid level on the 7th day after administration) / pre-administration uric acid level]×100) is about 55% or less (e.g., 1-55% decrease, 10-50% decrease, 15-45% decrease, 20-45% decrease, 20-40% decrease, 20-35% decrease). The blood uric acid level (blood uric acid concentration) may be measured by the known uricase-peroxidase method. In this specification, the time or period expressed as "from the start of administration" can be calculated, for example, from the first administration of the compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof in one treatment plan. Thus, for example, "3 weeks after the start of administration" means the corresponding time 3 weeks after the first administration, and "7 weeks after the start of administration" means the corresponding time 3 weeks after the first administration. When the term "administration" is followed by a time or period, it means the time point after the passage of a subsequent time or period from the time of administration. For example, "12 hours after administration" means the time point 12 hours after administration, and "7 days after administration" means the time point 7 days after administration. In this specification, the term "period" is usually used to refer to a time defined by "days," "months," or "years." In the present specification, when "day X of administration" is expressed, its meaning can be judged in the context. For example, "day 1 of administration" may mean the time point one day (24 hours) after the first administration in one treatment plan, or may mean the period from the first administration to the time point immediately before the time point one day (24 hours) after the first administration, or may mean the time before or after the time point one day (24 hours) after the first administration, for example, ±12 hours, preferably ±6 hours, more preferably ±2 hours. In this specification, "minimum uric acid value after administration on the first day of administration" means, for example, the minimum uric acid value among blood samples taken from a subject every hour from the time of first administration to one day (after 24 hours) in one treatment plan, and the uric acid value is measured by a method known per se. In addition, "minimum uric acid value after administration on the seventh day of administration" means, for example, the minimum uric acid value among blood samples taken from a subject every hour from the time of first administration to 6 days (after 144 hours) to 7 days in one treatment plan, and the uric acid value is measured by a method known per se. As for "before administration", 12 hours before the first administration is preferable, 6 hours before the first administration is more preferable, 2 hours before the first administration is even more preferable, and 1 hour before the first administration is particularly preferable in one treatment plan. Therefore, "pre-dose uric acid level" means, for example, the uric acid level measured by a method known per se in blood taken from a subject 12 hours, preferably 6 hours, more preferably 2 hours, and even more preferably 1 hour before the first administration in a single treatment plan. The content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof contained in the pharmaceutical composition provided by the present invention can be appropriately determined by those skilled in the art. For example, the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof contained in the pharmaceutical composition provided by the present invention can be 10 to 320 mg (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg). The pharmaceutical composition provided by the present invention may be one dosage unit. The content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit may be, for example, 10 to 320 mg (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg). The packaging form of the pharmaceutical composition provided by the present invention can be appropriately determined by those skilled in the art. Examples of packaging forms include plastic containers, glass containers, and PTP sheets. The pharmaceutical composition provided by the present invention may be provided as a package containing the pharmaceutical composition in the number of dosage units required for continuous administration for 5 to 15 days. For example, the pharmaceutical composition provided by the present invention may be provided as a PTP sheet containing 5 to 15 (e.g., 6, 7, 8, 10, 12, or 14) dosage units.

[0077] In this specification, "dosage unit" refers to a unit of a formulation, and "one dosage unit" refers to the smallest unit of a formulation. Thus, for example, in the case of a tablet, the dosage unit is each tablet, and one dosage unit refers to one tablet. In the case of an injection, the dosage unit is an injection placed in a sealed container such as an ampoule or vial, and one dosage unit refers to an injection placed in a sealed container such as an ampoule or vial. When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the dosage units may be administered per time, or one dosage unit may be divided and administered.

[0078] Examples of other embodiments of the present invention include the following. <1-1> A pharmaceutical composition comprising a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof for use in the treatment of gout or hyperuricemia. <1-2> A pharmaceutical composition comprising a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof for use in treating hyperuricemia in a patient with gouty arthritis. <1-3> A pharmaceutical composition for use according to <1-1> or <1-2>, which suppresses the onset of gout attacks associated with the initiation of uric acid-lowering therapy. <1-4> The pharmaceutical composition for use according to any one of <1-1> to <1-3>, wherein the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is orally administered in an amount of 10 to 320 mg per day to a patient in need of treatment or prophylaxis, and the oral administration is continued for at least 7 days. <1-5>R 1 The pharmaceutical composition for use according to any one of <1-1> to <1-4>, wherein is an unsubstituted phenyl group, or a phenyl group substituted with a halogen atom. <1-6> The pharmaceutical composition for use according to any one of <1-1> to <1-5>, wherein X is an oxygen atom. <1-7> The pharmaceutical composition for use according to any one of <1-1> to <1-6>, wherein Y is a sulfur atom. <1-8> The pharmaceutical composition for use according to any one of <1-1> to <1-7>, wherein the compound or the pharma- ceutical acceptable salt thereof according to any one of <1-1> to <1-7> contains an amorphous form thereof, and the content of the amorphous form is 80 wt% or more based on the total weight of the compound or the pharma-ceutical acceptable salt thereof according to any one of <1-1> to <1-7>. <1-9> The pharmaceutical composition for use according to any one of <1-1> to <1-8>, which is an enteric formulation. <1-10> The pharmaceutical composition for use according to <1-9>, wherein the enteric formulation is a hard capsule. <1-11> The pharmaceutical composition for use according to any one of <1-1> to <1-10>, further comprising a solid dispersion containing a hypromellose derivative. <1-12> The pharmaceutical composition for use according to <1-11>, wherein the weight ratio of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:25. <1-13> The pharmaceutical composition for use according to <1-11> or <1-12>, wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate. <1-14> The pharmaceutical composition for use according to any one of <1-1> to <1-13>, which is a solid formulation. <1-15> The pharmaceutical composition for use according to any one of <1-1> to <1-14>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is 10 mg to 320 mg. <1-16> The pharmaceutical composition for use according to any one of <1-1> to <1-15>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 320 mg. <1-17> The pharmaceutical composition for use according to any one of <1-1> to <1-16>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 160 mg. <1-18> The pharmaceutical composition for use according to any one of <1-1> to <1-17>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 10 mg to 80 mg. <1-19> The pharmaceutical composition for use according to any one of <1-1> to <1-18>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit is 20 mg to 80 mg. <1-20> The pharmaceutical composition for use according to any one of <1-1> to <1-19>, which reduces blood uric acid concentration by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration, as compared to before administration. <1-21> The pharmaceutical composition for use according to any one of <1-1> to <1-20>, wherein, by continuous administration once a day for 7 days, the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to before administration. <1-22> The pharmaceutical composition for use according to any one of <1-1> to <1-21>, wherein the pharmaceutical composition is continuously administered once a day, and the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased from the start of administration until 3 weeks after the administration. <1-23> The pharmaceutical composition for use according to any one of <1-1> to <1-22>, wherein the pharmaceutical composition is continuously administered once a day, and the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased or is increased once from the start of administration until 7 weeks after the administration. <1-24> The pharmaceutical composition for use according to any one of <1-1> to <1-23>, wherein the pharmaceutical composition is continuously administered once a day, and the maximum reduction rate of blood uric acid level on the first day of administration ([(uric acid level before administration-minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is 10 to 25%. <1-25> The pharmaceutical composition for use according to any one of <1-1> to <1-24>, wherein the pharmaceutical composition is continuously administered once a day, and the maximum reduction rate of blood uric acid level on the 7th day after administration ([(uric acid level before administration-minimum uric acid level after administration on the 7th day after administration) / uric acid level before administration]×100) is 20 to 45%. <1-26> The pharmaceutical composition for use according to any one of <1-1> to <1-25>, wherein the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharma-ceutical acceptable salt thereof. <1-27> A package containing a pharmaceutical composition for use according to any one of <1-1> to <1-26>, the package containing the pharmaceutical composition in the number of dosage units required for continuous administration for 5 to 15 days.

[0079] <2-1> Use of a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof for producing a pharmaceutical composition for the treatment of gout or hyperuricemia. <2-2> Use of a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof for producing a pharmaceutical composition for treating hyperuricemia in a patient with gouty arthritis. <2-3> The use described in <2-1> or <2-2>, which suppresses the onset of gout attacks associated with the initiation of uric acid-lowering therapy. <2-4> The use according to any one of <2-1> to <2-3>, in which the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is orally administered at 10 to 320 mg per day to a patient in need of treatment or prophylaxis, and the oral administration is continued for at least 7 days. <2-5>R 1 The use according to any one of <2-1> to <2-4>, wherein is an unsubstituted phenyl group or a phenyl group substituted with a halogen atom. <2-6> The use according to any one of <2-1> to <2-5>, wherein X is an oxygen atom. <2-7> The use according to any one of <2-1> to <2-6>, wherein Y is a sulfur atom. <2-8> The use according to any one of <2-1> to <2-7>, wherein the compound or the pharma- ceutically acceptable salt thereof according to any one of <2-1> to <2-7> contains an amorphous form thereof, and the content of the amorphous form is 80% by weight or more based on the total weight of the compound or the pharma-ceutically acceptable salt thereof according to any one of <2-1> to <2-7>. <2-9> The use according to any one of <2-1> to <2-8>, wherein the pharmaceutical composition is an enteric formulation. <2-10> The use according to <2-9>, wherein the enteric formulation is a hard capsule. <2-11> The use according to any one of <2-1> to <2-10>, wherein the pharmaceutical composition further comprises a solid dispersion containing a hypromellose derivative. <2-12> The use according to <2-11>, wherein the weight ratio of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:25. <2-13> The use according to <2-11> or <2-12>, wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate. <2-14> The use according to any one of <2-1> to <2-13>, wherein the pharmaceutical composition is a solid formulation. <2-15> The use according to any one of <2-1> to <2-14>, wherein the content of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof is 10 mg to 320 mg. <2-16> The use according to any one of <2-1> to <2-15>, wherein the content of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit of the pharmaceutical composition is 10 mg to 320 mg. <2-17> The use according to any one of <2-1> to <2-16>, wherein the content of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit of the pharmaceutical composition is 10 mg to 160 mg. <2-18> The use according to any one of <2-1> to <2-17>, wherein the content of the compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit of the pharmaceutical composition is 10 mg to 80 mg. <2-19> The use according to any one of <2-1> to <2-18>, wherein the content of the compound represented by the general formula (I) or a pharma- ceutical acceptable salt thereof per dosage unit of the pharmaceutical composition is 20 mg to 80 mg. <2-20> The use according to any one of <2-1> to <2-19>, wherein the pharmaceutical composition reduces the blood uric acid concentration by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration, compared to before administration. <2-21> The use according to any one of <2-1> to <2-20>, wherein the pharmaceutical composition is administered once a day for 7 consecutive days, and the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to before administration. <2-22> The use according to any one of <2-1> to <2-21>, wherein the pharmaceutical composition is administered continuously once a day, and the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased from the start of administration until 3 weeks after the administration. <2-23> The use according to any one of <2-1> to <2-22>, wherein the pharmaceutical composition is continuously administered once a day, and the daily dose of the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof is not increased or is increased once from the start of administration until 7 weeks after the administration. <2-24> The use according to any one of <2-1> to <2-23>, wherein the pharmaceutical composition is continuously administered once a day, and the maximum reduction rate of blood uric acid level on the first day of administration ([(uric acid level before administration-minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is 10 to 25%. <2-25> The use according to any one of <2-1> to <2-24>, wherein the pharmaceutical composition is continuously administered once a day, and the maximum reduction rate of blood uric acid level on the 7th day after administration ([(uric acid level before administration-minimum uric acid level after administration on the 7th day after administration) / uric acid level before administration]×100) is 20 to 45%. <2-26> The use according to any one of <2-1> to <2-25>, wherein the compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharma-ceutically acceptable salt thereof. <2-27> Use of a compound represented by general formula (I) or a pharma- ceutical acceptable salt thereof for producing a package comprising the pharmaceutical composition according to any one of <2-1> to <2-26>, the package comprising the pharmaceutical composition in the number of dosage units required for continuous administration for 5 to 15 days. EXAMPLES

[0080] The present invention will be described in more detail below with reference to Examples, Reference Examples, Comparative Reference Examples, Test Examples, etc., but the present invention is not limited to these. <Reference Example 1a and Comparative Reference Example 1a, Preparation of Enteric Capsules> 9 g of compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine) was dissolved in 1936 g of a mixed solvent of tetrahydrofuran (sometimes abbreviated as THF), ethanol, and water (weight ratio: THF / ethanol / water = 1600.5 / 254.5 / 81) (warmed slightly to dissolve), then pumped into a spray dryer at a rate of approximately 5 mL / min via a peristaltic pump and sprayed from a two-fluid nozzle (diameter 508 μm) with an inlet temperature of 80°C, an outlet temperature of approximately 60°C, and a drying air flow rate of 0.30 m. 3 / min, and nozzle spray air pressure 1.0kgf / cm 2 The resulting dried product was left at room temperature overnight to obtain Compound 14, which was 100% amorphous. The volume average particle size (D50) of the amorphous compound 14 obtained was measured by adding about 2 mg of the sample to a 0.2% Aerosol OT aqueous solution, dispersing it by ultrasonic irradiation for 30 seconds, and using this dispersion liquid, using a Shimadzu laser diffraction particle size distribution analyzer SALD-2200. Shimadzu WingSALD-2200 version 1.02 software was used for data collection and analysis. The results of the particle size distribution of the amorphous compound 14 are shown in Figure 1. The volume average particle size (D50) of the amorphous compound 14 calculated from the particle size distribution was 2.949 μm. The obtained amorphous compound 14 was filled into capsules shown in Table 2A in an amount of 40 mg each, to obtain capsule preparations of amorphous compound 14. [Table 2A]

[0081] <Test Example 1a, Absorption of Amorphous Compound 14 in Dogs> Beagle dogs (1-5 years old, Kitayama Labes Co., Ltd.) were fasted from the evening of the day before administration, and the capsules of Reference Example 1a and Comparative Reference Example 1a were orally administered in a single dose (40 mg / body as compound 14) in a crossover method with a one-week administration interval. Blood was collected from the lateral vein at 0.5, 1, 3, 5, 8, and 24 hours before administration and 0.5, 1, 3, 5, 8, and 24 hours after administration. The blood obtained was centrifuged at 10,000×g and 4° C. for 5 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Osaka Soda Co., Ltd.). Since dogs generally have a high intragastric pH, a gastric acid secretion stimulant, pentagastrin, was intramuscularly injected at a dose of 0.01 mg / kg 30 minutes and immediately before administration of the capsules. The pH of the intragastric solution was then measured, and the capsule sample was administered after confirming that the intragastric pH was low. A plasma drug concentration-time curve was created from the measured values ​​obtained. The results are shown in Figure 2. The drug concentrations in the figure show the average value ± standard deviation of four cases. When the enteric-coated capsule of Reference Example 1a was used, a higher drug concentration was observed compared to when the normal gastric-soluble capsule of Comparative Reference Example 1a, which does not have enteric coating, was used, indicating that the absorbability of amorphous Compound 14 is improved by making it enteric-coated.

[0082] <Test Example 2a, Evaluation of the amorphous state of Compound 14 (Powder X-ray diffraction)> Since it is very important that the amorphous properties are maintained even after storage over time, the amorphous form of compound 14 of Reference Example 1a was stored at room temperature in a light-shielded, airtight condition, and the change in the amorphous state of compound 14 was evaluated using an X-ray diffractometer (D2 Phaser, Bruker). The results are shown in Figures 4(a) to (d). For comparison, the powder X-ray diffraction of crystals of compound 14 is shown in Figure 3. When the capsule preparation of Reference Example 1a was stored at room temperature in a light-shielded, airtight condition, no change in the powder X-ray diffraction pattern of Compound 14 was observed over time during storage up to 4 weeks.

[0083] <Reference Example 1b and Comparative Reference Examples 1b to 9b. Preparation of solid dispersion (polymer, 25 times amount)> 250 mg of compound 14 was dissolved in tetrahydrofuran to make 100 mL. 5 mL of the mixed solution (dichloromethane / methanol = 50 / 15) was added to 125 mg of each of the polymers shown in Table 2B to dissolve them. 2 mL of the solution of compound 14 was placed in a test tube, 5 mL of the above polymer solution was added, and the mixture was mixed homogenously with a vortex mixer. A sample without adding a polymer was also prepared (Comparative Reference Example 9b). The solvent was removed by blowing a nitrogen stream onto these samples, and then the samples were dried under reduced pressure overnight to obtain solid dispersion samples of compound 14. The HPMCAS used in Reference Example 1b was of the MF type (i.e., the substitution ratios per monomer unit were 21.0-25.0% methoxy group, 5.0-9.0% hydroxypropoxyl group, 7.0-11.0% acetyl group, 10.0-14.0% succinoyl group, and viscosity: 2.4-3.6 mPa s).

[0084] [Table 2B]

[0085] <Test Example 1b. Solubility test> 5mL of the first solution (pH 1.2) or 5mL of the second solution (pH 6.8) in the Japanese Pharmacopoeia dissolution test was added to the solid dispersions of Reference Example 1b and Comparative Reference Examples 1b to 8b and the sample of Comparative Reference Example 9b, and the solid dispersions were crushed with a glass rod or spatula, and then shaken at 37°C for 2 hours. 400μL of a mixed solution (acetonitrile / water = 3 / 2) was immediately added to 600μL of the sample solution filtered through a 0.45μm filter, and the concentration of Compound 14 in the sample solution was measured by HPLC (Shimadzu Corporation). The results are shown in Table 3B. The values ​​in the table are the average values ​​of two repeated measurements.

[0086] [Table 3B] The solubility of compound 14 in Comparative Reference Example 9b was 0.39 μg / mL in the first solution and 0.49 μg / mL in the second solution, but the solubility increased to 5.0 μg / mL or more in Reference Examples 1b, 3b, and 4b. In particular, the basic polymer Eudragit E-100 of Comparative Reference Example 3b was highly effective in improving the solubility of compound 14 in the first solution under acidic conditions, and the acidic polymer HPMCAS of Reference Example 1b was highly effective in improving the solubility of compound 14 in the second solution under neutral conditions.

[0087] <Reference Example 2b, Comparative Reference Examples 10b and 11b. Preparation of solid dispersion (polymer, 25 times amount)> Compound 14 was dissolved in tetrahydrofuran and adjusted to 2.5 mg / mL. Each polymer shown in Table 4B was dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) and adjusted to about 45 mg / mL. The compound 14 solution was added to the above polymer solution while stirring so that the weight ratio of compound 14 to polymer was 1:25. A sample without adding a polymer was also prepared. The mixture was immediately transferred to an eggplant flask, and the organic solvent was distilled off using a rotary evaporator (N-1100, Tokyo Rikakikai Co., Ltd.). The eggplant flask was transferred to a desiccator and dried under reduced pressure for about 16 hours using a vacuum pump to obtain a solid dispersion of compound 14. After drying, the solid dispersion was crushed in an agate mortar or crushed with a portable high-speed crusher (LM-PLUS, Osaka Chemical Co., Ltd.), and then sieved (mesh size: 150 μm).

[0088] [Table 4B]

[0089] <Test Example 2b. Absorption of solid dispersion of Compound 14 in rats> The solid dispersions of Reference Example 2b and Comparative Reference Example 10b, and the sample of Comparative Reference Example 11b suspended in a 1% aqueous carboxymethylcellulose solution were orally administered in a single dose of 10 mg / kg or 30 mg / kg as compound 14 to male rats (8 weeks old, Crl:CD(SD), Charles River Japan, Inc.) under fasting conditions. As a control, the crystalline drug substance of compound 14 was used (Comparative Reference Example 12b). The blood samples were collected 0.5, 1, 2, 4, 8, and 24 hours after administration, and about 300 μL of blood was collected from the tail vein at each time point (n=3). The blood was centrifuged at 1500×g and 4° C. for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Co., Ltd.). The time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) were calculated. The results are shown in Table 5B. The values ​​in the table are the mean value of three cases ± standard deviation. The solid dispersions of Reference Example 2b and Comparative Reference Example 10b, and the sample of Comparative Reference Example 11b had a higher C max The results showed that compound 14 can be absorbed more efficiently by amorphizing it and dispersing it in a solid form. The solid dispersion with HPMCAS showed a higher absorption improvement effect than the solid dispersion with Eudragit.

[0090] [Table 5B]

[0091] <Reference Examples 3b, 4 and 5. Preparation of solid dispersions (polymer, 25 times amount)> Compound 14 was dissolved in tetrahydrofuran and adjusted to 2.5 mg / mL. Each polymer shown in Table 6B was dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) and adjusted to about 45 mg / mL. After mixing compound 14 and the polymer so that the weight ratio was 1:25, the solvent was distilled off at about 50 ° C. under reduced pressure using a rotary evaporator (N-1100, Tokyo Rikakikai Co., Ltd.). The obtained primary dried product was further subjected to secondary drying (room temperature / overnight) using a vacuum pump, and the secondary dried product was appropriately pulverized using a portable high-speed pulverizer (LM-PLUS, Osaka Chemical Co., Ltd.) and then sieved (mesh size: 300 μm). The HPMCAS used in Reference Example 3b was of the LG type (i.e., the substitution ratios per monomer unit were 20.0-24.0% methoxy group, 5.0-9.0% hydroxypropoxyl group, 5.0-9.0% acetyl group, 14.0-18.0% succinoyl group, and viscosity: 2.4-3.6 mPa·s). The HPMCAS used in Reference Example 4b was of the MG type (i.e., the substitution ratios per monomer unit were 21.0 to 25.0% methoxy group, 5.0 to 9.0% hydroxypropoxyl group, 7.0 to 11.0% acetyl group, 10.0 to 14.0% succinoyl group, and viscosity: 2.4 to 3.6 mPa s). The HPMCAS used in Reference Example 5b was of the HG type (i.e., the substitution ratios per monomer unit were 22.0-26.0% methoxy group, 6.0-10.0% hydroxypropoxyl group, 10.0-14.0% acetyl group, 4.0-8.0% succinoyl group, and viscosity: 2.4-3.6 mPa·s).

[0092] [Table 6B]

[0093] <Test Example 3b. Absorption of solid dispersion of Compound 14 in rats> The solid dispersions of Reference Examples 3b, 4b and 5b suspended in 1% aqueous carboxymethylcellulose solution were orally administered in a single dose of 10 mg / kg of compound 14 to male rats (7-9 weeks old, Crl:CD(SD), Charles River Laboratories Japan, Ltd.) under fasting conditions. Blood was collected from the tail vein at 0.5, 1, 2, 4, 8 and 24 hours after administration, and approximately 300 μL of blood was collected per time point (n=3). The blood was centrifuged at 1500×g and 4° C. for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). The time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) were calculated. The results are shown in Table 7B. The values ​​in the table are the mean value of three cases ± standard deviation. In the solid dispersion of Reference Example 4b, C max The plasma concentration and AUC were both the highest.

[0094] [Table 7B]

[0095] <Reference Examples 6b to 12b. Preparation of solid dispersions (HPMCAS-MG, 1 to 10 times the amount)> Compound 14 was dissolved in tetrahydrofuran and adjusted to 2.5 mg / mL. HPMCAS-MG was dissolved in a mixed solvent (ethanol / water = 4 / 1) and adjusted to about 45 mg / mL. Compound 14 was mixed with the polymer shown in Table 8B in a weight ratio of 1:1 to 1:10, and then pumped into a spray dryer (GB22, Yamato Scientific Co., Ltd.) at a rate of about 5 mL / min via a peristaltic pump, and dried from a two-fluid nozzle (diameter 406 or 508 μm) with an inlet temperature of 80 °C, an outlet temperature of about 60 °C, and a dry air flow rate of 0.32 to 0.47 m 3 / min, nozzle atomizing air pressure 1.0 to 3.1kgf / cm 2 Spray drying and granulation were started under the conditions. The obtained primary dried material was further subjected to secondary drying using a vacuum pump (room temperature / overnight or room temperature / overnight-40°C / 1 day) and sieved (mesh opening: 300 μm).

[0096] [Table 8B]

[0097] <Test Example 4b. Absorption of solid dispersion of Compound 14 in rats> The solid dispersions of Reference Examples 6b to 8b and 10b to 12b suspended in 1% aqueous carboxymethylcellulose solution were orally administered in a single dose of 10 mg / kg of compound 14 to male rats (7-9 weeks old, Crl:CD(SD), Charles River Laboratories Japan, Ltd.) under fasting conditions. Blood was collected from the tail vein at 0.5, 1, 2, 4, 8, and 24 hours after administration, and approximately 300 μL of blood was collected per time point (n=3). The blood was centrifuged at 1500×g and 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Co., Ltd.). The time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) were calculated. The results are shown in Table 9B. The values ​​in the table are the mean value of three cases ± standard deviation. In the solid dispersions of Reference Examples 6b to 8b and 10b to 12b, when the weight ratio of HPMCAS-MG to compound 14 was 1, 2, and 3 times, the plasma concentration increased depending on the weight ratio, but when the weight ratio was in the range of 3, 4, 5, and 10 times, no difference depending on the weight ratio was observed in the plasma concentration.

[0098] [Table 9B]

[0099] <Test Example 5b. Evaluation of the amorphous state of a solid dispersion of Compound 14 (powder X-ray diffraction)> Since it is very important that the solid dispersion maintains its amorphous properties even after storage over time, the solid dispersions of Reference Examples 9b to 11b were stored under open conditions at 40°C / 75% RH, and the changes in the amorphous state were evaluated using an X-ray diffractometer (D2 Phaser, Bruker). The results are shown in Figures 5 to 7. When the solid dispersions of Reference Examples 9b to 11b were stored in the open at 40° C. / 75% RH, no change in the powder X-ray diffraction pattern was observed over time during storage up to 7 weeks.

[0100] <Test Example 6b. Evaluation of the amorphous state of solid dispersion of Compound 14 (absorbability in rats)> The solid dispersions of Reference Examples 9b to 11b were stored under open conditions at 40° C. / 75% RH, and the change in the amorphous state was evaluated by rat absorbency. The solid dispersions of Reference Examples 9b to 11b suspended in 1% aqueous carboxymethylcellulose solution were orally administered in a single dose of 10 or 30 mg / kg of compound 14 to male rats (7-9 weeks old, Crl:CD(SD), Charles River Laboratories Japan, Ltd.) under fasting conditions. Blood was collected from the tail vein at 0.5, 1, 2, 4, 8, and 24 hours after administration, and approximately 300 μL of blood was collected per time point (n=3). The collected blood was centrifuged at 1500×g and 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Co., Ltd.). The time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) were calculated. The results are shown in Table 10B. The values ​​in the table are the average value of three cases ± standard deviation. When the solid dispersions of Reference Examples 9b to 11b were stored open at 40°C / 75% RH, no decrease in plasma concentration over time was observed during storage up to 7 weeks.

[0101] [Table 10B]

[0102] <Test Example 7b. Effect of solid dispersion of compound 14 on plasma uric acid level in rats> The solid dispersion of Reference Example 11b suspended in a 1% carboxymethylcellulose aqueous solution was orally administered once at a dose of 30 mg / kg as compound 14 to male rats (8 weeks old, Crl:CD(SD), Charles River Japan, Inc.) under fasting conditions. A 1% carboxymethylcellulose aqueous solution was used as a control. Blood was collected from the tail vein at approximately 300 μL per time point (n=5), before administration (0), and 2, 6, 12, and 24 hours after administration. The blood obtained was centrifuged at 1500×g and 4° C. for 15 minutes to obtain plasma. The concentration of uric acid in this plasma was measured by HPLC (Hitachi High-Technologies Corporation). A Welch's t-test was performed on the plasma uric acid values ​​of the control group and Reference Example 11b at each time point. The significance level was set to p<0.05 (two-sided). The results are shown in FIG. 8. The plasma uric acid level after administration of the solid dispersion of Reference Example 11b was significantly lower than that of the control group, and the uric acid level lowering effect was sustained.

[0103] <Reference Examples 13b and 14b. Preparation of solid dispersions (HPMCAS-MG 3 times amount, surfactant 0.03 times amount)> Compound 14 was dissolved in tetrahydrofuran and adjusted to 2.5 mg / mL. HPMCAS-MG was dissolved in a mixed solvent (ethanol / water = 4 / 1) and adjusted to about 45 mg / mL. Compound 14 was mixed with the polymer and surfactant (polysorbate 80: Tween 80, sodium lauryl sulfate: SLS) shown in Table 11B in a weight ratio of 1:3:0.03, and then pumped into a spray dryer (GB22, Yamato Scientific Co., Ltd.) at a rate of about 5 mL / min via a peristaltic pump, and dried from a two-fluid nozzle (diameter 406 or 508 μm) with an inlet temperature of 80 ° C, an outlet temperature of about 60 ° C, and a drying air flow rate of 0.32 to 0.47 m 3 / min, nozzle atomizing air pressure 1.0 to 3.1kgf / cm 2 Spray drying and granulation were started under the conditions. The obtained primary dried material was further subjected to secondary drying using a vacuum pump (room temperature / overnight or room temperature / overnight-40°C / 1 day) and sieved (mesh opening: 300 μm).

[0104] [Table 11B]

[0105] <Test Example 8b. Absorption of solid dispersion of Compound 14 in rats> The solid dispersions of Reference Examples 13b and 14b suspended in a 1% aqueous carboxymethylcellulose solution were orally administered in a single dose of 10 mg / kg of compound 14 to male rats (7-9 weeks old, Crl:CD(SD), Charles River Laboratories Japan, Ltd.) under fasting conditions. Blood was collected from the tail vein at 0.5, 1, 2, 4, 8, and 24 hours after administration, and approximately 300 μL of blood was collected per time point (n=3). The collected blood was centrifuged at 1500×g and 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Co., Ltd.). The time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) were calculated. The results are shown in Table 12B together with Reference Example 8b. The values ​​in the table are the average value of three cases ± standard deviation. In the solid dispersions of Reference Examples 13b and 14b, no difference was observed in the plasma concentration compared to Reference Example 8b, which did not contain a surfactant.

[0106] [Table 12B]

[0107] <Example 1> Compound 14 was repeatedly administered to 6 healthy adult males at 80 mg once a day for 7 days using the solid dispersion capsule of Formulation Example 1, and the effect of lowering uric acid levels in serum was examined. The results are shown in Figure 9 together with the example of using febuxostat (40 mg) described in Non-Patent Document 3 for comparison. As a result, in the case of febuxostat, the maximum reduction rate of blood uric acid level reached about 35% (about 15 hours after administration) on the first day of administration, showing a rapid reduction in serum uric acid level. In contrast, the maximum reduction rate of blood uric acid level of compound 14 on the first day of administration was about 17% (12 hours after administration), showing a mild reduction in serum uric acid level. Thereafter, serum uric acid level gradually decreased over time throughout the administration period, and on the 7th day, the maximum reduction rate of blood uric acid level reached about 30% (about 8 hours after administration). From these results, compound 14 is expected to prevent gout attacks or reduce the number of gout attacks. In addition, when compound 14 was repeatedly administered at 20 mg once daily for 7 days using the solid dispersion capsules of Formulation Example 1, the serum uric acid level gradually decreased over time throughout the administration period, similar to the results for the 80 mg once daily administration, and the serum uric acid level 24 hours after the final administration was reduced by approximately 10 to 20% compared to the serum uric acid level before administration (initial value). In addition, when capsules containing finely powdered compound 14 (not solid dispersion capsules) were used, compound 14 was repeatedly administered at 40 mg once a day for 7 days. As a result, serum uric acid levels gradually decreased over time throughout the administration period, similar to the results when the solid dispersion capsules were used.

[0108] <Formulation Example 1, Production of Solid Dispersion Capsules> 0.18 kg of compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine) was dissolved in 38.72 kg of a mixed solvent (weight ratio: 32.01 / 5.09 / 1.62) of tetrahydrofuran (sometimes abbreviated as THF), anhydrous ethanol, and purified water while heating, and then 0.72 kg of HPMCAS-MG was added and stirred to prepare a feed liquid. Then, the mixture was spray-dried using a spray dryer under the conditions of a heat input temperature of 100°C, a heat exhaust temperature of 60°C, a feed liquid amount of 100g / min, and a two-fluid nozzle nitrogen spray pressure of 0.30MPa. The obtained spray-dried product was vacuum-dried at a drying temperature of 25°C for 16 hours and at 40°C for 24 hours. Then, the mixture was naturally dried at room temperature for 24 hours to obtain a solid dispersion of compound 14. The obtained solid dispersion of compound 14 was sieved through a sieve (mesh size: 300 μm), and then 50 g of sodium starch glycolate was added to and mixed with 250 g of the sieve to obtain a solid dispersion mixed powder of compound 14. The obtained solid dispersion mixed powder of Compound 14 was filled into No. 2 white gelatin capsules in an amount of 60 mg or 120 mg to obtain solid dispersion capsules of Compound 14. [Industrial Applicability]

[0109] The pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharma- ceutical acceptable salt thereof gradually reduces the uric acid level of a patient without abruptly lowering it, and therefore may be useful for the treatment or prevention of gout or hyperuricemia, which reduces the induction or severity of gout attacks. The pharmaceutical composition provided by the present invention may be orally administered at 10 to 320 mg per day to a patient in need of treatment or prevention, and the oral administration may be continued for at least 7 days. In addition, when the pharmaceutical composition is an enteric preparation, it shows high absorbability in the body, and therefore may be useful for the treatment or prevention of gout or hyperuricemia. In addition, when the pharmaceutical composition contains a solid dispersion, it shows high absorbability in the body and storage stability, and therefore may be useful for the treatment or prevention of gout or hyperuricemia.

Claims

【Request 1】 General formula (I) 【Chemistry 1】 (In the formula, R １ represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, the substituent being at least one group selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a formyl group, a carboxyl group, a halogen atom, a phenyl group, and a phenoxy group; R ２ represents a cyano group or a nitro group, R ３ represents a hydrogen atom or a hydroxyl group, and X represents an oxygen atom or -S(O) ｎ -, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom) or a pharma- ceutical composition for treating gout or hyperuricemia, comprising a compound represented by the following formula (I):

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