Solid dosage form with excellent stability

Abstract

The present invention provides a solid preparation, which contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stabilizer, a sugar alcohol and / or a sugar, a water-soluble polymer, and an inorganic substance. The solid preparation has good stability, water suspension and fluidity.

Description

[Technical field]

[0001] The present invention relates to a preparation containing a polycyclic pyridone compound and having excellent stability and water suspension. That is, it relates to a solid preparation containing a stabilizer, a sugar alcohol and / or a sugar, a water-soluble polymer, and an inorganic substance. Specifically, it relates to a preparation containing a polycyclic pyridone compound, sodium chloride as a stabilizer, maltitol and mannitol as sugar alcohols and / or sugars, hydroxypropyl methylcellulose as a water-soluble polymer, and light anhydrous silicic acid and talc as inorganic substances, so as to improve the stability of the polycyclic pyridone compound, the suspension of the preparation in water, and the fluidity of the preparation.

[0002] [Prior Art]

[0003] Influenza is an acute respiratory infection caused by infection with influenza viruses. In Japan, there are reports of millions of people being suspected of being infected with influenza every winter, and influenza is associated with a high morbidity and mortality rate.

[0004] As for anti-influenza drugs, Symmetrel (trade name: Amantadine) and Flumadine (trade name: Rimantadine) are known to inhibit the denucleation process of the virus, and Oseltamivir (trade name: Tamiflu) and Zanamivir (trade name: Relenza) are neuraminidase inhibitors that inhibit the budding / release of the virus from cells. However, there are still concerns about the emergence of resistant strains and side effects, as well as the global pandemic of new influenza viruses with high pathogenicity and lethality, so the development of anti-influenza drugs with new mechanisms is desired.

[0005] Cap-dependent endonuclease is an enzyme derived from influenza virus. It is essential for viral proliferation and is a virus-specific enzymatic activity that the host does not have. Therefore, it is considered to be a suitable target for anti-influenza drugs.

[0006] Patent Document 1 describes that the compound represented by the following formula (II) is a compound that inhibits Cap-dependent endonuclease and is useful as a compound having an antiviral action (particularly, an activity to inhibit the proliferation of influenza virus).

[0007]

[0008] When the compound represented by formula (II) is administered to a living body (e.g., orally), it is necessary to provide a compound that is more efficiently absorbed in the body to exhibit a high pharmacological effect and at the same time shorten the duration of influenza. In order to achieve these purposes, a compound represented by formula (I) is provided, which is a prodrug of the compound represented by formula (II). The compound represented by formula (I) is also disclosed in Patent Document 1.

[0009]

[0010] However, Patent Document 1 does not disclose a specific formulation of the compound represented by formula (I).

[0011] Influenza is a disease that is particularly important for high-risk groups such as infants and the elderly. In particular, among the anti-influenza drugs currently on the market, the only oral preparation for children is Oseltamivir (trade name: Tamiflu), and it is hoped that an oral preparation for children of an anti-influenza drug can be developed.

[0012] As for oral preparations, there are dry syrup, granules, tablets, syrups, etc. If the drug concentration in the preparation is low, when the stability test over time is implemented, the amount of analogs may increase depending on the drug. In addition, when the oral preparation for children is to be taken by children, the preparation is suspended in water. If the suspension in water is not good, the drug will be stagnant at the bottom of the container. Furthermore, if the flowability of dry syrup or granules is not good, it will hinder its manufacture. Therefore, it is necessary to develop a kind of oral preparation for children, which has a small amount of analogs after the stability test over time, and has good suspension and flowability in water.

[0013] Patent Documents 2 to 4 disclose granules containing sodium chloride to suppress bitterness or improve drug absorption. However, the compounds used in Patent Documents 2 to 4 are chemically very different from the compound represented by Formula (I), and it is unknown whether the formulations disclosed in Patent Documents 2 to 4 can improve the stability of the compound represented by Formula (I), and there is no disclosure or suggestion in the documents.

[0014] In addition, a powder containing a specific compound, hydroxypropylmethylcellulose (hypromellose) and mannitol is disclosed in Patent Document 5. However, the compound used in Patent Document 5 is very different from the compound represented by Formula (I) in chemical structure, and it is not known whether the preparation formula described in Patent Document 5 can make the solid preparation containing the compound represented by Formula (I) obtain excellent water suspension properties, and there is no disclosure or suggestion in the document.

[0015] [Prior Technical Literature]

[0016] [Patent Document]

[0017] [Patent Document 1] International Publication No. 2016 / 175224 Pamphlet

[0018] [Patent Document 2] Japanese Patent Application Publication No. 2008-07420

[0019] [Patent Document 3] Japanese Patent Application Publication No. 2016-79102

[0020] [Patent Document 4] Japanese Patent Publication No. 2001-512433

[0021] [Patent Document 5] Japanese Patent Publication No. 2014-534215 [Summary of the invention]

[0022] [Problems to be solved by the invention]

[0023] An object of the present invention is to find a solid preparation which has excellent stability and excellent water suspension of the compound represented by formula (I).

[0024] [Methods to solve the problem]

[0025] The inventors of the present invention have made repeated studies to solve the above problems and have found that the stability of the polycyclic pyridone compound, the suspension of the preparation in water, and the fluidity of the preparation can be improved by containing one or more selected from the group consisting of alkali metal chlorides, organic acids, polyol esters, and fatty acid esters, sugar alcohols and / or sugars, water-soluble polymers, and inorganic substances as stabilizers, thereby completing the present invention. Hereinafter, the preparation completed by the present invention is sometimes referred to as the "preparation of the present invention".

[0026] Right now,

[0027] (1) A solid preparation comprising: a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of an alkali metal chloride, an organic acid, a polyol ester and a fatty acid ester;

[0028]

[0029] (2) The solid preparation according to (1) above, which contains an alkali metal chloride, and the alkali metal chloride is sodium chloride and / or potassium chloride.

[0030] (3) The solid preparation according to (1) above, which contains an organic acid, and the organic acid is ascorbic acid and / or fumaric acid.

[0031] (4) The solid preparation according to (1) above, comprising a polyol ester, wherein the polyol ester is at least one selected from the group consisting of Miglyol, triethyl citrate and polyoxyethylene sorbitan monooleate.

[0032] (5) The solid preparation according to (1) above, which contains a fatty acid ester, and the fatty acid ester is triacetin.

[0033] (6) The solid preparation according to any one of (1) to (5) above, further comprising a sugar alcohol and / or a sugar.

[0034] (7) A solid preparation as described in (6) above, wherein the sugar alcohol and / or sugar is one or more selected from the group consisting of isomalt, reduced maltose syrup (maltitol), mannitol, xylitol, erythritol, sorbitol, lactose, sucrose, fructose, maltose, refined white sugar and trehalose.

[0035] (8) The solid preparation according to any one of (1) to (7) above, further comprising a water-soluble polymer.

[0036] (9) The solid preparation according to (8) above, wherein the water-soluble polymer is a cellulose-based polymer.

[0037] (10) A solid preparation comprising: a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a cellulose polymer;

[0038]

[0039] However, the covering layer of the solid preparation does not contain a cellulose polymer.

[0040] (11) A solid preparation as described in (9) or (10) above, wherein the cellulose polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

[0041] (12) The solid preparation according to (11) above, wherein the cellulose-based polymer is hydroxypropylmethylcellulose.

[0042] (13) The solid preparation according to any one of (1) to (12) above, further comprising an inorganic substance, but the coating layer of the solid preparation does not contain the inorganic substance.

[0043] (14) The solid preparation according to (13) above, wherein the inorganic substance is one or more selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid and talc.

[0044] (15) A solid preparation as described in any one of (1) to (14) above, wherein the dissolution rate of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 80% or more 15 minutes after the start of the dissolution test in the dissolution test method (paddle method) specified in the 17th revision of the Japanese Pharmacopoeia.

[0045] (16) The solid preparation according to any one of (1) to (15), comprising 1 to 80 mg of the compound represented by formula (I);

[0046]

[0047] (17) The solid preparation according to any one of (1) to (16), which is a granule or a dry syrup.

[0048] [Effects of the Invention]

[0049] By containing one or more stabilizers selected from the group consisting of alkali metal chlorides, organic acids, polyol esters and fatty acid esters, sugar alcohols and / or sugars, water-soluble polymers and inorganic substances, the analogs of polycyclic pyridone compounds can be reduced, and the fluidity of the preparation and the suspension of the preparation in water can be improved. [Drawings]

[0050] Figure 1 This is a powder X-ray diffraction pattern of the crystals of the compound represented by formula (I).

[0051] Figure 2 It is the dissolution state of the compound represented by formula (I) at the start of the time storage test and after a certain period of time has passed since the start of the time storage test. [Specific implementation method]

[0052] The active ingredient in the preparation of the present invention is the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0053]

[0054] The preparation method of the compound represented by formula (I) and the pharmaceutically acceptable salt thereof is disclosed in Patent Document 1.

[0055] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is converted into the compound represented by formula (II) in vivo and has a Cap-dependent endonuclease inhibitory effect. Therefore, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent and / or preventive agent for influenza.

[0056] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is useful for treating symptoms and / or diseases induced by influenza virus. For example, it is effective for treating and / or preventing symptoms of flu-like symptoms accompanied by fever, aversion to cold, headache, muscle pain, general malaise, etc., as well as symptoms of airway inflammation such as pharyngeal headache, runny nose, nasal congestion, cough, sputum, abdominal pain, vomiting, diarrhea, gastrointestinal symptoms such as acute encephalopathy, pneumonia, and complications accompanied by secondary infection, and improving symptoms. That is, the compound used in the present invention can be used for treating and / or preventing influenza virus infection.

[0057] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is effective in shortening the duration of influenza. For example, the duration of influenza can be shortened by about 20 to 40 hours, or about 25 to 30 hours. Specifically, the time until "cough", "sore throat", "headache", "stuffy nose", "fever or chills", "muscle or joint pain", and "fatigue" are improved can be shortened. In particular, it is useful for shortening the time until "stuffy nose", "muscle or joint pain", "fatigue", "fever or chills", and "headache" are improved. Furthermore, it is useful for shortening the time until "stuffy nose" and "muscle or joint pain" are improved.

[0058] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is useful as a medicine. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a prodrug, has high oral absorption, exhibits good bioavailability and clearance, has advantages such as high lung migration, and can become an excellent medicine.

[0059] The compound shown in formula (I) or its pharmaceutically acceptable salt has high metabolic stability and oral absorbability, and shows good bioavailability and clearance. In addition, the compound shown in formula (I) or its pharmaceutically acceptable salt has high lung migration and long half-life. Furthermore, the compound shown in formula (I) or its pharmaceutically acceptable salt has, for example, high non-protein binding rate, low hERG channel inhibition and CYP inhibition, confirmed CPE (CytoPathic Effect, cytopathic effect) inhibitory effect, and / or shows negative in phototoxicity test, Ames test, genetic toxicity test, or has advantages such as no toxicity such as liver disorder. Therefore, the pharmaceutical composition of the compound used in the present invention can become an excellent drug.

[0060] The dosage of the compound shown in formula (I) or its pharmaceutically acceptable salt varies according to the method of administration, the age, weight, state and type of disease of the patient, but usually in the case of oral administration, the dosage for adults is about 0.05 mg to 3000 mg per day, preferably about 0.1 mg to 1000 mg, more preferably about 10 mg to 80 mg, and the dosage can be divided if necessary. In addition, in the case of parenteral administration, the dosage for adults is about 0.01 mg to 1000 mg per day, preferably about 0.05 mg to 500 mg, more preferably about 1 mg to 80 mg. It can be administered once a day or divided into several doses. Specifically, the content of the compound shown in formula (I) or its pharmaceutically acceptable salt is 10 mg, 20 mg, 40 mg or 80 mg. In this case, 10 mg means a range of 9.0 to 11.0 mg, preferably 9.5 to 10.5 mg, 20 mg means a range of 18.0 to 22.0 mg, preferably 19.0 to 21.0 mg, 40 mg means a range of 36.0 to 44.0 mg, preferably 38.0 to 42.0 mg, and 80 mg means 72.0 to 88.0 mg, preferably 76.0 to 84.0 mg.

[0061] The compound shown in formula (I) or its pharmaceutically acceptable salt can be used in combination with other drugs (hereinafter referred to as "combination drugs") for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. For example, for influenza diseases, it can be used in combination with neuraminidase inhibitors (such as oseltamivir, zanamivir, peramivir and Inavir, etc.), RNA-dependent RNA polymerase inhibitors (such as favipiravir), M2 protein inhibitors (such as amandazin), PB2 Cap binding inhibitors (such as VX-787), anti-HA antibodies (such as MHAA4549A), or immune drugs (such as nitazoxanide). At this time, the administration period of the compound and the combination drug used in the present invention is not limited, and these drugs can be administered to the subject at the same time, or they can be administered after a period of time. Furthermore, the combination drug with the compound shown in formula (I) or its pharmaceutically acceptable salt can be administered in the form of two or more preparations containing their respective active ingredients, or it can be administered in the form of a single preparation containing all active ingredients.

[0062] The dosage of the combined drug can be appropriately selected based on the dosage used clinically. In addition, the compound shown in formula (I) or its pharmaceutically acceptable salt and the combined drug are appropriately selected according to the drug object, drug administration route, target disease, symptoms, combination, etc. For example, when the drug object is a human, 0.01 to 100 parts by weight of the combined drug can be used relative to 1 part by weight of the compound shown in formula (I) or its pharmaceutically acceptable salt.

[0063] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof has high inhibitory activity against Cap-dependent endonucleases and has high selectivity because it is a virus-specific enzyme, and thus can be used as a drug for reducing side effects.

[0064] Hereinafter, a method for identifying the compound represented by formula (I) or its crystal, or the compound represented by formula (II) will be described.

[0065] Unless otherwise specified, the values ​​in this specification and the scope of patent applications are approximate values. The changes in values ​​are caused by device calibration, device error, material purity, crystal size, sample size or other factors.

[0066] As used in this specification, "crystal" refers to a structure in which atoms, ions, molecules, etc. constituting a solid are arranged in a regular manner, and as a result, has a periodic and anisotropic structure. Crystalline morphology and crystallinity can be measured by a variety of techniques including, for example, powder X-ray diffraction measurement, water adsorption and desorption measurement, differential scanning calorimetry, differential thermal and thermogravimetric simultaneous measurement, solution colorimetry, and solubility characteristics.

[0067] NMR analysis of the compound was performed at 300 MHz using DMSO-d6 and CDCl3.

[0068] Determination of powder X-ray diffraction patterns

[0069] The crystals obtained in each example were subjected to powder X-ray diffraction measurement in accordance with the powder X-ray diffraction measurement method described in the General Test Methods of the Japanese Pharmacopoeia. The measurement conditions are shown below.

[0070] (Device)

[0071] Rigaku MiniFlex600

[0072] (Operation method)

[0073] Detector: High-speed one-dimensional detector (D / TecUltra2) and variable knife edge

[0074] Measurement method: Reflectometer

[0075] Type of light source: Cu

[0076] Wavelength: CuKα line

[0077] Tube current: 15mA

[0078] Tube voltage: 40kV

[0079] Test plate: Silicon non-reflective test plate

[0080] X-ray incident angle (θ): 4-40°, sampling amplitude: 0.02°

[0081] Generally speaking, the diffraction angle (2θ) in powder X-ray diffraction may have an error within the range of ±0.2°, and the value of the diffraction angle also includes a numerical value within the range of about ±0.2°. Therefore, in the preparation of the present invention, not only crystals whose peak diffraction angles in powder X-ray diffraction are completely consistent, but also crystals whose peak diffraction angles are consistent with an error of about ±0.2° can be used.

[0082] The amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of the present invention is 0.1 to 80% by weight, preferably 0.5 to 8% by weight, and more preferably 1 to 4% by weight, relative to the total amount of the preparation.

[0083] The preparation of the present invention may contain a stabilizer. In this specification, as for the stabilizer, the stabilizer listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia External Drug Specifications, the Drug Additive Specifications and the Food Additives Public Book can be used, and in particular, the stabilizer that can stabilize the compound represented by formula (I) or its pharmaceutically acceptable salt under storage for a long time can be used.

[0084] The stabilizer may be any substance that can reduce the amount of the analog (particularly the compound represented by formula (II)), and specific examples thereof include alkali metal chlorides, organic acids, polyol esters, and fatty acid esters.

[0085] The alkali metal chloride refers to an inorganic compound represented by the chemical formula MX, in which M is an alkali metal and X is chlorine. Specifically, sodium chloride and potassium chloride are mentioned, and sodium chloride is preferred.

[0086] Organic acids refer to organic compounds having a carboxyl group (carboxylic acid), organic compounds having a sulfonic acid group (sulfonic acid), and organic compounds having a hydroxyl group, a thiol group, or an enol group as a characteristic group. Specifically, formic acid, oxalic acid, acetic acid, citric acid, ascorbic acid, and fumaric acid are listed, with ascorbic acid and fumaric acid being preferred, and fumaric acid being more preferred.

[0087] Polyol esters refer to esters of alcohols having two or more hydroxyl groups in the molecule, and in polyols, the hydroxyl groups are attached to different carbon atoms. Specifically, Miglyol (i.e., medium-chain fatty acid triglyceride), triethyl citrate, and polyoxyethylene sorbitan monooleate are exemplified, with Miglyol being preferred.

[0088] Fatty acid esters refer to compounds formed by esterification of a carboxyl group of a fatty acid and an alcohol, and specifically include triacetin (glyceryl triacetate), fatty acid glycerides, acylglycerols, monoglyceride derivatives, and fatty acid polyglycerol esters, preferably triacetin.

[0089] The stabilizer of the preparation of the present invention can be formulated in the preparation or covered on the surface of the preparation, preferably formulated in the preparation. If formulated in the preparation, the stability of the compound represented by formula (I) contained in the preparation can be improved, and the amount of analogs (especially the compound represented by formula (II)) can be reduced.

[0090] The amount of the stabilizer in the preparation of the present invention is 0.01 to 10% by weight, preferably 0.05 to 7.5% by weight, and more preferably 0.1 to 5% by weight relative to the total amount of the preparation. When the amount is less than this, the amount of analogs may increase.

[0091] The preparation of the present invention may contain an excipient. In this specification, the excipient is an excipient that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications, the drug additive specifications and the food additive official book. Preferably, it is an excipient that can make the preparation have good suspension in water, the preparation has little attachment to the container, and the fine particle yield of the preparation is high, and the bulk density is small. Specifically, sugar alcohols and sugars can be listed.

[0092] Sugar alcohol is a sugar equivalent to the food labeling standard announced by the Consumer Affairs Agency of Japan, and is a type of sugar produced by reducing the carbonyl group of an aldose or ketose. Specifically, examples thereof include isomalt, erythritol, D-mannitol, xylitol, sorbitol, reduced maltose syrup (maltitol), lactitol, oligosaccharide alcohol, etc., preferably D-mannitol and reduced maltose syrup (maltitol).

[0093] The sugar is a sugar equivalent to the food labeling standard announced by the Consumer Affairs Agency of Japan. Specifically, monosaccharides and disaccharides are listed, and more specifically, xylose, glucose, fructose, maltose, lactose, sucrose, fructose, trehalose, isomerized sugar, maltose, refined white sugar, white sugar, refined white sugar spherical granules, anhydrous lactose, white sugar / starch spherical granules, etc. are preferred. Refined white sugar and white sugar are preferred.

[0094] The excipients in the preparation of the present invention are sugar alcohols and sugars that can be mixed and used. In this case, sugar alcohols and sugars can be combined, sugar alcohols and other sugar alcohols can be combined, and sugars and other sugars can be combined. The types and blending ratios of the combined sugar alcohols and sugars can be any type and blending ratio that can improve the water suspension of the preparation, the adhesion of the preparation to the container, and make the fine particle yield of the preparation high and the bulk density small. Regarding specific combinations, there are refined white sugar and reduced maltose maltose (maltitol), refined white sugar and D-mannitol, reduced maltose maltose (maltitol) and D-mannitol, etc., preferably reduced maltose maltose (maltitol) and D-mannitol. In addition, the blending ratio is 99:1 to 1:99 by weight, preferably 90:10 to 10:90, more preferably 80:20 to 20:80, and particularly preferably 75:25 to 25:75. More specifically, the ratio of reduced maltose starch syrup (maltitol) to D-mannitol is 30:70 to 50:50.

[0095] The preparation of the present invention may also contain excipients other than sugar alcohols and sugars. Specifically, examples thereof include oligosaccharides, dextrins, polysaccharides such as starch, semi-digested starch, glucose hydrate, crystalline cellulose, microcrystalline cellulose, pullulan, β-cyclodextrin, aminoethylsulfonic acid, maltose, sodium chloride, citric acid, sodium citrate, glycine, calcium gluconate, L-glutamine, tartaric acid, potassium hydrogen tartrate, ammonium carbonate, dextran 40, dextrin, calcium lactate, povidone, Macrogol (polyethylene glycol) 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, anhydrous citric acid, DL-malic acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, L-aspartic acid, alginic acid, carmellose sodium sodium), hydrated silicon dioxide, crospovidone, calcium glycerophosphate, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, wheat flour, wheat starch, wheat germ flour, wheat germ oil, rice flour, rice starch, cellulose acetate phthalate, titanium oxide, magnesium oxide, dihydroxyaluminum aminoacetate, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, natural aluminum silicate, corn starch, corn starch granules, potato starch, hydroxypropyl cellulose, hydroxypropyl starch, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, monocalcium phosphate, etc.

[0096] The amount of the excipient in the preparation of the present invention is 1 to 99.5% by weight, preferably 5 to 99% by weight, and more preferably 10 to 98.5% by weight relative to the total amount of the preparation. If the amount is greater than this, there is a risk that other ingredients cannot be mixed; if the amount is less than this, there is a possibility that the appearance of the preparation is affected.

[0097] The preparation of the present invention can be suspended in water and the suspension can be taken. In particular, when the medicine is administered to children, such a method of administration can be implemented. However, it is difficult to suspend the preparation of the present invention without a suspending agent. Therefore, a suspending agent can be prepared in the preparation of the present invention. The suspending agent is a suspending agent that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia External Drug Specifications, the Drug Additive Specifications, and the Food Additives Public Book. Specifically, there are cellulose polymers such as carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose, i.e., hydroxy propyl methyl cellulose), methyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, and a mixture of fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose; ethyl acrylate / methyl methacrylate copolymer dispersions, methacrylate aminoalkyl copolymers, methacrylic acid copolymers, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymers, dry methacrylic acid copolymers, and acrylic acid polymers such as dimethylaminoethyl methacrylate / methyl methacrylate copolymers; and polyvinyl pyrrolidone (polyvinyl pyrrolidone). The present invention can be prepared from ethylene-based polymers such as polyvinyl alcohol, polyvinyl alcohol / methyl methacrylate / acrylic acid copolymer, polyvinyl alcohol copolymer, sodium alginate, carrageenan, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, magnesium aluminum silicate, sodium polyphosphate, Macrogol 4000, Macrogol 6000, etc., preferably carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and more preferably hydroxypropyl methyl cellulose. In addition, the suspending agent also has the role of a dispersant for dispersing the preparation of the present invention in water. However, when the solid preparation has a covering layer, the covering layer of the solid preparation does not contain a cellulose-based polymer.

[0098] The amount of the suspending agent in the preparation of the present invention is 0.01 to 10% by weight, preferably 0.05 to 7.5% by weight, and more preferably 0.1 to 5% by weight relative to the total amount of the preparation. When the amount is greater than this, there is a possibility of foaming in water; when the amount is less than this, the preparation may not be suspended in water.

[0099] In the preparation of the present invention, in order to improve the fluidity of the preparation, a fluidizer can be prepared. In addition, there is a possibility of increasing impurities or the like according to the fluidizer, so the fluidizer that does not increase impurities or the like must be selected. The fluidizer is a fluidizer that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications, the drug additive specifications and the food additive official book, mainly to select inorganic substances or fatty acids, and in many cases select their salts. Specifically, there are light anhydrous silicic acid, hydrous silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, etc., preferably light anhydrous silicic acid, hydrous silicon dioxide, more preferably light anhydrous silicic acid. But when the fluidizer is an inorganic substance and a covering layer is formed in the solid preparation, the covering layer of the solid preparation does not contain inorganic substances.

[0100] The amount of the fluidizing agent in the preparation of the present invention is 0.01 to 10% by weight, preferably 0.05 to 7.5% by weight, and more preferably 0.1 to 5% by weight relative to the total amount of the preparation. When the amount is greater than this, the analogs may increase; when the amount is less than this, the preparation may not flow and cause trouble during manufacturing.

[0101] In the preparation of the present invention, in order to improve the lubricity of the preparation, a lubricant can be prepared. The index of the selection of the lubricant includes the angle of repose, and the smaller the angle of repose, the better the fluidity. The lubricant is a lubricant that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications, the drug additive specifications and the food additive official book, mainly to select inorganic substances or fatty acids, and select its salt in many cases. Specifically, there are light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate (sodium stearyl fumarate), talcum, etc., preferably light anhydrous silicic acid, hydrous silicon dioxide, talcum, more preferably talcum. But when the lubricant is an inorganic substance and has a cover layer formed in the solid preparation, the cover layer of the solid preparation does not contain inorganic substances.

[0102] The amount of lubricant in the preparation of the present invention is 0.001 to 1% by weight, preferably 0.005 to 0.75% by weight, and more preferably 0.01 to 0.5% by weight relative to the total amount of the preparation. If the amount is greater than this, analogs may increase; if the amount is less than this, the preparation may not flow and cause trouble during manufacturing.

[0103] In the preparation of the present invention, in order to add to the medicine with bad taste such as bitter taste and correct its taste, correctives can be prepared.Correctives are correctives that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications, drug additive specifications and food additives official book.Specifically, there are ascorbic acid, aspartic acid, aspartame (aspartame), sucralose (sucralose), glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt, anhydrous citric acid, L-glutamic acid and its salt, succinic acid and its salt, acetic acid, tartaric acid and its salt, sodium bicarbonate, fumaric acid and its salt, malic acid and its salt, glacial acetic acid, disodium inosinate, honey, reduced maltose syrup (maltitol), liquorice powder etc., preferably sodium chloride.

[0104] The amount of the flavoring agent in the preparation of the present invention is 0.01 to 10% by weight, preferably 0.05 to 7.5% by weight, and more preferably 0.1 to 5% by weight relative to the total amount of the preparation. If the amount is more or less than this, there is a risk of producing an unpleasant taste when the preparation is taken.

[0105] Preparation of the present invention can contain adhesive. Adhesive is the adhesive that can be used in Japanese Pharmacopoeia, Japanese Pharmacopoeia external drug specifications, drug additive specifications and food additives official book etc.. Specifically, can list as hydroxypropyl cellulose, corn starch, alpha starch, part alpha starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, polytriglucose, polyvinyl pyrrolidone, polyvinyl alcohol, crystalline cellulose, methyl cellulose, ethyl cellulose, carboxymethyl ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc., preferably polyvinyl pyrrolidone.

[0106] The content of the binder in the preparation of the present invention is 0.1 to 20% by weight, preferably 0.25 to 15% by weight, and more preferably 0.5 to 10% by weight relative to the total amount of the preparation. When the amount is greater than this, the particle size of the preparation may become too large; when the amount is less than this, the particle size of the preparation may become too small.

[0107] The preparation of the present invention may contain a disintegrant. The disintegrant may be a disintegrant listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia External Drug Specifications, the Drug Additive Specifications, and the Food Additives Public Regulations. Specifically, examples thereof include crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, carboxymethylcellulose calcium, sodium carboxymethyl starch, and low exchange degree hydroxypropyl cellulose.

[0108] The content of the disintegrant in the preparation of the present invention is 0.5 to 20% by weight, preferably 0.75 to 15% by weight, more preferably 1 to 10% by weight, relative to the total weight of the preparation.

[0109] The preparation of the present invention may contain a polymer. The polymer may be a polymer listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Other Drug Specifications, the Drug Additive Specifications, and the Official Food Additives Regulations. Specifically, examples thereof include cellulose-based polymers such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, and a mixture of fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose; ethyl acrylate / methyl methacrylate copolymer dispersions, methacrylate aminoalkyl copolymers, methacrylic acid copolymers, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymers, dry methacrylic acid copolymers, and acrylic acid-based polymers such as dimethylaminoethyl methacrylate / methyl methacrylate copolymers; polyvinyl pyrrolidone, cross-linked polyvinylpyrrolidone, carboxyvinyl polymers, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, polyvinyl alcohol / methyl methacrylate / acrylic acid copolymers, and polyvinyl alcohol copolymers; carnauba wax (carnauba wax), stearyl alcohol, shellac, cetyl alcohol, and the like; preferably, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) is used.

[0110] The preparation of the present invention may contain a colorant. The colorant is a colorant that can be used in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications or the drug additive specifications. Specifically, iron oxide, tar pigments and natural pigments can be cited. As for iron oxide, there are ferric oxide, yellow iron oxide, yellow ferric oxide, black iron oxide, etc. As for tar pigments, there are edible yellow No. 4 aluminum lake, edible blue No. 1 aluminum lake, edible red No. 3 aluminum lake, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible red No. 102, edible red No. 2, edible red No. 3, etc. As for natural pigments, there are turmeric extract, β-carotene, carotene liquid, sodium copperchlorophyllin, copper chlorophyllin, highland barley (naked barley) green leaf extract powder, highland barley green leaf green juice dry powder, highland barley green leaf extract, titanium oxide, talc, etc. Pigments also include pigments used as light stabilizers.

[0111] The preparation of the present invention may also contain additives other than the above as needed, and may use additives recorded in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia external drug specifications, the drug additive specifications and the food additive official book. In addition, the content of these additives may be any ratio. The additives other than the above specifically include spices, sweeteners, etc.

[0112] Specific examples of the flavor include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, orange peel oil, pine oil, mint oil, vanilla flavor, strawberry flavor, bitter essence, fruit flavor, peppermint essence, mix flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, etc., and strawberry flavor is preferred.

[0113] Specific examples of the sweetener include aspartame, reduced maltose syrup (maltitol), licorice, xylitol, glycerin, saccharin, sucralose, D-sorbitol, acesulfame potassium, stevia, thamatin, and advantame, and sucralose is preferred.

[0114] The preparation of the present invention may be any solid preparation, specifically, any granule, dry syrup, fine granule, tablet, powder, capsule, pill, etc., preferably granule, dry syrup, fine granule, more preferably granule.

[0115] The method for producing the granules in the preparation of the present invention is not particularly limited. Specifically, the method is a method in which the active ingredient, the binder, the excipient and other additives are mixed to produce a mixed powder and then the mixed powder is granulated. Preferably, a wet granulation method in which water, water containing a binder, a solvent and the like are added to granulate, and a dry granulation method and a melt granulation method in which water is not used by compression molding are used. The machine used to mix the active ingredient and the additive, etc., can use a crushing granulator (powermill), a V-type mixer, a container blender (container blender) and the like. In addition, the machine for granulation can use a wet extrusion granulator, a fluidized bed granulator, a stirring granulator, a dry crushing granulator and a melt extrusion granulator and the like.

[0116] When the preparation of the present invention is a granule, the average particle size of the granule is in the range of 1 to 1000 μm.

[0117] Preferred aspects are described below.

[0118] (1) A solid preparation is provided, comprising: a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and (2) at least one selected from the group consisting of alkali metal chlorides, organic acids, polyol esters and fatty acid esters. Specifically, the alkali metal chlorides include sodium chloride and / or potassium chloride, preferably sodium chloride; specifically, the organic acids include ascorbic acid and / or fumaric acid, preferably fumaric acid; specifically, the polyol esters include Miglyol, triethyl citrate, polyoxyethylene sorbitan monooleate; and specifically, the fatty acid esters include triacetin.

[0119] On the other hand, a solid preparation is provided, which contains: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (2) one or more selected from the group consisting of alkali metal chlorides, organic acids, polyol esters and fatty acid esters, and (3) sugar alcohols and / or sugars. The alkali metal chlorides specifically include sodium chloride and / or potassium chloride, preferably sodium chloride, the organic acids specifically include ascorbic acid and / or fumaric acid, preferably fumaric acid, the polyol esters specifically include Miglyol, triethyl citrate, polyoxyethylene sorbitan monooleate, and the fatty acid esters specifically include triacetin. The sugar alcohol and / or sugar is specifically one or more selected from the group consisting of isomalt, reduced maltose syrup (maltitol), mannitol, xylitol, erythritol, sorbitol, lactose, sucrose, fructose, maltose, refined white sugar and trehalose, preferably one or more selected from the group consisting of refined white sugar, reduced maltose syrup and D-mannitol, more preferably reduced maltose syrup and D-mannitol, and particularly preferably a mixture of reduced maltose syrup and D-mannitol.

[0120] On the other hand, a solid preparation is provided, which contains: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (2) one or more selected from the group consisting of alkali metal chlorides, organic acids, polyol esters and fatty acid esters, (3) sugar alcohols and / or sugars, and (4) a water-soluble polymer. The alkali metal chlorides specifically include sodium chloride and / or potassium chloride, preferably sodium chloride, the organic acids specifically include ascorbic acid and / or fumaric acid, preferably fumaric acid, the polyol esters specifically include Miglyol, triethyl citrate, polyoxyethylene sorbitan monooleate, and the fatty acid esters specifically include triacetin. The sugar alcohol and / or sugar is specifically selected from one or more of the group consisting of isomalt, reduced maltose syrup (maltitol), mannitol, xylitol, erythritol, sorbitol, lactose, sucrose, fructose, maltose, refined white sugar and trehalose, preferably selected from one or more of the group consisting of refined white sugar, reduced maltose syrup (maltitol) and D-mannitol, more preferably reduced maltose syrup, D-mannitol, and particularly preferably a mixture of reduced maltose syrup (maltitol) and D-mannitol. The water-soluble polymer is specifically selected from a cellulose polymer, an acrylic polymer, and a polyethylene polymer, preferably a cellulose polymer. More specifically, the cellulose polymer includes carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, and a mixture of fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose. Preferred examples include hydroxypropyl methyl cellulose.

[0121] On the other hand, a solid preparation is provided, which contains: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (2) one or more selected from the group consisting of alkali metal chlorides, organic acids, polyol esters and fatty acid esters, (3) sugar alcohols and / or sugars, (4) water-soluble polymers, and (5) inorganic substances. The alkali metal chlorides specifically include sodium chloride and / or potassium chloride, preferably sodium chloride, the organic acids specifically include ascorbic acid and / or fumaric acid, preferably fumaric acid, the preferred examples of polyol esters include Miglyol, triethyl citrate, and polyoxyethylene sorbitan monooleate, and the fatty acid esters specifically include triacetin. The sugar alcohol and / or sugar is specifically selected from the group consisting of isomalt, reduced maltose syrup (maltitol), mannitol, xylitol, erythritol, sorbitol, lactose, sucrose, fructose, maltose, refined white sugar and trehalose. It is preferably selected from the group consisting of refined white sugar, reduced maltose syrup (maltitol) and D-mannitol. More preferably, reduced maltose syrup (maltitol) and D-mannitol are listed. In particular, a mixture of reduced maltose syrup (maltitol) and D-mannitol is particularly preferred. The water-soluble polymer is specifically selected from a cellulose polymer, an acrylic polymer, and a polyethylene polymer. Preferably, a cellulose polymer is listed. As the cellulose polymer, more specifically, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose mixture, etc., preferably hydroxypropyl methyl cellulose. Specifically, inorganic substances include light anhydrous silicic acid, hydrated silicon dioxide, sodium stearyl fumarate, and talc, preferably light anhydrous silicic acid and talc.

[0122] On the other hand, a solid preparation is provided, which contains: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and (2) a cellulose polymer. However, when the solid preparation forms a covering layer, the covering layer does not contain a cellulose polymer. The cellulose polymer is specifically carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose mixture, etc., and preferably hydroxypropyl methyl cellulose can be cited.

[0123] On the other hand, a solid preparation is provided, which contains: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (2) a cellulose polymer, and (3) an inorganic substance. However, when the solid preparation forms a covering layer, the covering layer does not contain a cellulose polymer and an inorganic substance. The cellulose polymer is specifically carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose / sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methyl cellulose mixture, and the preferred one is hydroxypropyl methyl cellulose. The inorganic substance is specifically light anhydrous silicic acid, hydrated silicon dioxide, sodium stearyl fumarate, talc, and the preferred one is light anhydrous silicic acid and talc.

[0124] The preparation of the present invention can maintain suspension in water even if water is added during use and the preparation is left for a long time. For example, the suspension can be prepared by mixing the preparation of the present invention with water. In another aspect, the suspension can be prepared by adding 20 ml of water to 2 g of the preparation of the present invention and mixing. In addition, in another aspect, the suspension can be prepared by adding 20 ml of water to the preparation of the present invention placed in a bottle and gently shaking and mixing so that the preparation of the present invention and water are mixed.

[0125] Suspensibility in water means that when 9.5 mL of water is added to about 1 g of the preparation of the present invention, a uniform suspension is visually confirmed. In this specification, these physical properties may be collectively referred to as "uniform dispersibility".

[0126] The preparation of the present invention hardly adheres to the surface of the container when it is put into the container.

[0127] The preparation of the present invention can prevent the preparations from sticking to each other after storage. As an indicator of the sticking of the preparation, the preparation can be filled in a container and confirmed by the fluidity of the preparation after turning it over.

[0128] The preparation of the present invention can improve fluidity and increase the production efficiency. The angle of repose can be used as an indicator of the fluidity of the preparation.

[0129] In the preparation of the present invention, the dissolution rate of the compound represented by formula (I) or its pharmaceutically acceptable salt 15 minutes after the start of the dissolution test according to the 17th revised Japanese Pharmacopoeia (paddle method) is 75% or more, preferably 80% or more, and more preferably 85% or more.

[0130] The preparation of the present invention can be taken orally directly, or the preparation of the present invention can be suspended in water or boiled water and then the suspension of the preparation of the present invention can be taken. The preparation of the present invention can be taken not only by adults but also by children. In particular, for children, the suspension of the preparation of the present invention can be taken after the preparation of the present invention is suspended in water or boiled water.

[0131] [Example]

[0132] The present invention is described in detail below with reference to Examples, Comparative Examples and Reference Examples, but the present invention is not limited to these Examples. Compound II can be prepared according to the method disclosed in WO 2016 / 175224.

[0133] Example A Preparation Method of Compound I

[0134]

[0135] Potassium carbonate (1483.4 mg, 10.7 mmol) and potassium iodide (549.5 mg, 3.3 mmol), tetrahydrofuran (33.1 g), N,N-dimethylacetamide (3.8 g) and water (80.3 mg) were added to compound II (4.0 g, 8.3 mmol) and stirred. The temperature was raised to 60°C, and methyl chloromethyl carbonate (1758.9 mg, 14.2 mmol) was added. Stir at 60°C for 9 hours and cooled to 20°C. Acetic acid (822.0 mg), 2-propanol (3.1 g) and water (20.0 g) were added, and extracted twice with tetrahydrofuran (1.8 g, 8.9 g). The solvent was distilled off by concentrating under reduced pressure until the liquid weight became about 32 g. After heating to 45°C, 2-propanol (1.6 g) was added and cooled to 20°C. After adding an aqueous sodium acetate solution prepared from sodium acetate (339.0 mg) and water (46.0 g), the mixture was cooled to 5°C. After stirring at 5°C for 3 hours, the generated pale yellowish white precipitate was filtered out. After washing the obtained solid with a mixed solution of 2-propanol (4.7 g) and water (6.0 g), the solid was washed again with 2-propanol (6.3 g). Dimethyl sulfoxide (30.9 g) was added to the obtained pale yellowish white solid and stirred. The temperature was raised to 60°C, and a mixed solution of dimethyl sulfoxide (2.2 g) and water (4.8 g) was added. A mixed solution of dimethyl sulfoxide (19.9 g) and water (28.4 g) was further added, and the mixture was cooled to 20°C. After stirring at 20°C for 3 hours, the generated white precipitate was filtered out. After washing the obtained solid with a mixed solution of dimethyl sulfoxide (8.0 g) and water (4.8 g), the solid was washed again with water (12.0 g). The obtained solid was dried to obtain Compound I (4.21 g) as white crystals.

[0136] 1H-NMR(DMSO-D6)δ:2.91-2.98(1H,m),3.24-3.31(1H,m),3.44(1H,t,J=10.4Hz),3.69(1H,dd,J=11.5,2.8H z),3.73(3H,s),4.00(1H,dd,J=10.8,2.9Hz),4.06(1H,d,J=14.3Hz),4.40(1H,d,J=11.8Hz),4.45(1H,dd,J =9.9,2.9Hz),5.42(1H,dd,J=14.4,1.8Hz),5.67(1H,d,J=6.5Hz),5.72-5.75(3H,m),6.83-6.87(1H,m),7. 01(1H,d,J=6.9Hz),7.09(1H,dd,J=8.0,1.1Hz),7.14-7.18(1H,m),7.23(1H,d,J=7.8Hz),7.37-7.44(2H,m)

[0137] Powder X-ray diffraction 2θ(°): characteristic peaks at 8.6°±0.2°, 14.1°±0.2°, 17.4°±0.2°, 20.0°±0.2°, 24.0°±0.2°, 26.3°±0.2°, 29.6°±0.2° and 35.4°±0.2°.

[0138] The powder X-ray diffraction pattern of compound I is shown in Figure 1 .

[0139] (1) Discussion of stabilizers

[0140] In order to investigate the stabilizer, the stabilizers shown in Tables 2 to 4 and the compound represented by formula (I) were wet granulated, and the increase in the compound represented by formula (II) as an analog was evaluated after the time-dependent stability test of the manufactured granules. The preparation of the prescription shown in Table 1 was manufactured by the stirring granulation method.

[0141] [Table 1]

[0142] Preparation amount (mg) Compound represented by formula (I) 2.0 Refined white sugar 488.0 Reduced maltose syrup (maltitol) 500.0 Stabilizer 30.0 Hydroxypropyl Cellulose 10.0 total 1030.0

[0143] (Manufacturing method of preparation)

[0144] The compound represented by formula (I) shown in Table 1, refined white sugar, powdered reduced maltose syrup (maltitol), stabilizer and hydroxypropyl cellulose are mixed with a high speed mixer (FS-GS SJT 10 high speed mixer, Fukae Powtech Co.), water is added, and granulation is carried out by stirring. Thereafter, the granulated material is granulated with a crushing type granulator (P-3S type, Showa Chemical Machinery Works) and dried at 65 to 70°C with a fluidized bed granulator (WSG2&5fluid bed dryer granulator, Okawara Seisakusho). After drying, granulation is carried out with a crushing type granulator (P-3S type, Showa Chemical Machinery Works) to obtain granules. The granulation conditions of the high speed mixer are as follows.

[0145] (Granulation conditions)

[0146] Granulator: FS-GS SJT 10 high speed mixer

[0147] Agitator speed: 250 rpm

[0148] Chopper speed: 2500 rpm

[0149] Liquid injection acceleration: 21±2g / min

[0150] Water content: 4 to 6.5% by weight

[0151] Massing time: 1 minute ± 5 seconds

[0152] (Study on the stability of preparations over time)

[0153] The prepared preparation was stored at 60°C for 2 weeks, and the increased amount of the compound represented by formula (II) as an analog was measured.

[0154] (Stabilizer)

[0155] As for the stabilizer, as shown in Tables 2 to 4, sodium chloride (Kanto Chemical), potassium chloride (Wako Pure Chemical Industries, Ltd.), ascorbic acid (Nacalai Tesque), fumaric acid (Merck), medium-chain fatty acid triglyceride Miglyol (Sanye Trading), triethyl citrate (Merck), sodium nitrite (Nacalai Tesque), glycerin (Kanto Chemical), and vitamin E (Merck) were used.

[0156] [Table 2]

[0157] Example 1 Example 2 Example 3 Example 4 Stabilizer Sodium chloride Potassium chloride ascorbic acid Fumaric Acid

[0158] [Table 3]

[0159] Example 5 Example 6 Comparative Example 1 Comparative Example 2 Stabilizer Medium chain triglyceride Miglyol Triethyl citrate Sodium Nitrite glycerin

[0160] [Table 4]

[0161] Comparative Example 3 Comparative Example 4 Stabilizer Vitamin E none

[0162] (Determination method of the compound represented by formula (II))

[0163] The amount of the compound represented by formula (II) was measured by liquid chromatography according to the following method and conditions.

[0164] Detector: UV spectrophotometer (measurement wavelength 260nm)

[0165] Column: XBridge C18, 3.5μm, 3.0×150mm

[0166] Column temperature: a certain temperature around 35°C

[0167] Mobile phase A: 0.1% trifluoroacetic acid / 0.2 mM EDTA solution, mobile phase B: acetonitrile

[0168] · Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 5 to control the concentration gradient.

[0169] [Table 5]

[0170]

[0171] Flow rate: about 0.6mL / min

[0172] Injection volume: 5μL

[0173] Sample cooler temperature: about 5°C

[0174] Automatic syringe cleaning solution: acetonitrile / methanol mixture (1:3)

[0175] Area measurement range: 50 minutes after sample solution injection

[0176] · Calculation formula for the amount of the compound represented by formula (II)

[0177] The amount of the compound represented by formula (II) (%) = (ATII / ΣA T )×100

[0178] ATII: Peak area of ​​the compound represented by formula (II) in the sample solution

[0179] ΣA T : Total peak area of ​​sample solution (excluding blank and system peaks)

[0180] (result)

[0181] The increase (%) of the compound represented by formula (II) when the formulations of Examples 1 to 6 and Comparative Examples 1 to 4 were subjected to a time stability test is shown in Tables 6 to 8. As a result, the increase (%) of the compound represented by formula (II) in the granules of Examples 1 to 6 was lower than that in the granules without stabilizer of Comparative Example 4. In particular, the granules containing sodium chloride of Example 1, the granules containing ascorbic acid of Example 3, the granules containing fumaric acid of Example 4, and the granules containing medium-chain fatty acid triglyceride Miglyol of Example 5 showed a much smaller increase in the compound represented by formula (II) than that in the granules without stabilizer of Comparative Example 4.

[0182] [Table 6]

[0183]

[0184] [Table 7]

[0185]

[0186] [Table 8]

[0187] Comparative Example 3 Comparative Example 4 Stabilizer Vitamin E none Increased amount of the compound represented by formula (II) (%) 3.56 1.35

[0188] (2) Discussion of excipients

[0189] In order to investigate the excipients, the excipients shown in Tables 9 to 11 and the compound represented by formula (I) were wet granulated, and after the temporal stability test of the produced granules, the increase in the compound represented by formula (II) as an analog was evaluated.

[0190] (Manufacturing method of preparation)

[0191] After mixing the excipients shown in Tables 9 to 11 and the compound represented by formula (I) in a bag at a ratio of 1:1, sieve through a 30-mesh (wire diameter 0.22 mm) sieve. After mixing the sieved mixed powder in a mortar, slowly add purified water so that the granulation moisture content becomes about 5% by weight relative to the loading amount of the raw materials, and knead with a pestle. The kneaded material is squeezed by hand on a 16-mesh (wire diameter 0.55 mm) metal mesh and wet granulated. The granulated material is dried in a ventilated dryer, squeezed by hand on a 20-mesh (wire diameter 0.40 mm) metal mesh and granulated.

[0192] (Study on the stability of preparations over time)

[0193] The prepared preparation was stored at 60°C for 2 weeks, and the increased amount of the compound represented by formula (II) as an analog was measured.

[0194] (excipient)

[0195] As for excipients, as shown in Tables 9 to 11, refined white sugar (Merck), reduced maltose syrup (maltitol, ROQUETTE), D-mannitol (ROQUETTE), lactose hydrate (DMV-Fonterra), sorbitol (Merck), erythritol (ROQUETTE), xylitol (ROQUETTE), and isomalt (Beneo palatinit) were used.

[0196] [Table 9]

[0197]

[0198] [Table 10]

[0199] Reference Example 1 Reference Example 2 Reference Example 3 excipient Lactose hydrate Sorbitol Erythritol

[0200] [Table 11]

[0201] Reference Example 4 Reference Example 5 excipient Xylitol Isomalt

[0202] (result)

[0203] The increase (%) of the compound represented by formula (II) and the melting point of each excipient when the preparations of Examples 7 to 9 and Reference Examples 1 to 5 were subjected to a time stability test are shown in Tables 12 to 14. As a result, the increase (%) of the compound represented by formula (II) of the granules of Examples 7 to 9 was slightly lower than that of the granules of Reference Examples 1, 2 and 5. In addition, the increase (%) of the compound represented by formula (II) of the granules of Reference Examples 3 and 4 was almost the same as that of the granules of Examples 7 to 9, but the melting point was lower than that of Examples 7 to 9, and there was a possibility of fixation. Therefore, it is considered that refined white sugar, reduced maltose syrup (maltitol) and D-mannitol are preferable as excipients.

[0204] [Table 12]

[0205]

[0206] [Table 13]

[0207] Reference Example 1 Reference Example 2 Reference Example 3 excipient Lactose hydrate Sorbitol Erythritol Melting point(℃) 160 to 186 145 166 to 168 Increased amount of the compound represented by formula (II) (%) 0.17 0.15 0.08

[0208] [Table 14]

[0209] Reference Example 4 Reference Example 5 excipient Xylitol Isomalt Melting point(℃) 92 to 96 141 to 161 Increased amount of the compound represented by formula (II) (%) 0.04 0.38

[0210] (3) Discussion on the combination of excipients

[0211] Although refined white sugar, reduced maltose syrup (maltitol) and D-mannitol were selected as preferred excipients, in order to explore the combination of these excipients, the combination of excipients shown in Table 15 and Table 16 and the compound represented by formula (I) were wet granulated, and the (a) increase in the amount of the compound represented by formula (II) as an analog, (b) water suspensibility, (c) container adhesion, (d) fine particle yield, and (e) bulk density of the manufactured granules were evaluated. The preparations of the prescriptions shown in Table 15 and Table 16 were manufactured by the stirring granulation method.

[0212] [Table 15]

[0213]

[0214] [Table 16]

[0215]

[0216] (Manufacturing method of preparation)

[0217] The compound represented by formula (I) shown in Table 15 and Table 16, excipients and polyvinyl pyrrolidone were mixed with a high-speed mixer (LFS-GS-2J high-speed mixer, Powtech Fukae), and water was added to stir and granulate. Thereafter, the granulated material was granulated with a crushing granulator (P-3S type, Showa Machinery Works) and dried at 65 to 70°C with a fluidized bed granulator (MP-01 Fluid bed dryer granulator, Powrex). After drying, the granulated material was granulated with a crushing granulator (P-3S type, Showa Machinery Works) to obtain granules. The granulation conditions of the high-speed mixer are as follows.

[0218] (Granulation conditions)

[0219] Granulator: LFS-GS-2J high speed mixer

[0220] Mixer speed: 333 rpm

[0221] Chopper speed: 2500 rpm

[0222] Liquid injection acceleration: 20±3.5g / min

[0223] Water content: 3 to 7.5% by weight

[0224] Blocking time: 1 to 2 minutes ± 5 seconds

[0225] (Water Suspensibility Test of Preparations)

[0226] The number of times of inversion mixing required to visually confirm that a uniform suspension was achieved when 9.5 mL of water was added to about 1 g of the preparation of the present invention was recorded.

[0227] (Container adhesion of preparations)

[0228] During the preparation of the present invention, the amount of granulated material adhering to the inner wall of the stirring granulator after granulation was visually confirmed. The container adhesion index was evaluated based on the presence or absence of adhesion after scraping.

[0229] (Determination of fine particle yield of preparation)

[0230] 100 g of the preparation of the present invention was sieved with No. 30 and No. 140 sieves, and the ratio of "the amount of granules that passed through the No. 30 sieve but remained on the No. 140 sieve" to "the total amount of granules sieved" was calculated.

[0231] (Determination of bulk density of preparations)

[0232] The preparation of the present invention was poured into a container with a capacity of 100 mL until it overflowed, and the excess preparation was carefully wiped off from the upper surface of the container. The bulk density was calculated using the following formula using the weight of the preparation in the container deducted from the weight of the container.

[0233] Bulk density = weight of preparation in container / 100

[0234] (excipient)

[0235] As shown in Tables 15 and 16, excipients were used in combination of purified white sugar (Merck), reduced maltose starch syrup (maltitol, ROQUETTE), and D-mannitol (ROQUETTE).

[0236] (result)

[0237] The water suspension, container adhesion, fine particle yield and bulk density of the preparations of Examples 10 to 12 and Comparative Examples 5 and 6 are shown in Tables 17 and 18. As a result, the preparations of Examples 10 to 12, in which the excipient is a mixture of reduced maltose syrup (maltitol) and D-mannitol, have excellent water suspension, less adhesion to the container, and a bulk density of more than 0.5 g / mL. In particular, Examples 10 and 11 have a fine particle yield as high as more than 90%. On the other hand, Comparative Examples 5 and 6, in which the excipient is a mixture of refined white sugar and reduced maltose syrup (maltitol) or refined white sugar and D-mannitol, have poor water suspension than the examples and large container adhesion. In particular, Comparative Example 6 has a low fine particle yield.

[0238] [Table 17]

[0239]

[0240] [Table 18]

[0241]

[0242] (4) Discussion on adhesives

[0243] In order to investigate the binder, the binder shown in Table 19 and the compound shown in formula (I) were wet granulated, and the (a) increase in the compound shown in formula (II) as an analog after the time stability test and (b) the bulk density of the prepared preparations were evaluated. The preparations of the prescriptions shown in Table 19 were prepared by a stirring granulation method. The binder used was polyvinyl pyrrolidone K25 (BASF) and hydroxypropyl cellulose SL (Shin-Etsu Chemical Co., Ltd.).

[0244] [Table 19]

[0245]

[0246] (Manufacturing method of preparation)

[0247] The compound represented by formula (I) shown in Table 19, refined white sugar, reduced maltose syrup (maltitol), and hydroxypropylcellulose SL (Nippon Soda) or polyvinylpyrrolidone K25 as a binder were mixed with a high-speed mixer (LFS-GS-2J high-speed mixer, Powtech Fukae), and water was added to stir and granulate. Thereafter, the granulated product was granulated with a crushing granulator (P-3S type, Showa Chemical Machinery Works) and dried at 65 to 70°C with a fluidized bed granulator (MP-01 Fluid bed dryer granulator, Powrex). After drying, the product was granulated with a crushing granulator (P-3S type, Showa Chemical Machinery Works) to obtain granules. The granulation conditions of the high-speed mixer are as follows.

[0248] (Granulation conditions)

[0249] Granulator: LFS-GS-2J high speed mixer

[0250] Mixer speed: 333 rpm

[0251] Chopper speed: 2500 rpm

[0252] Liquid injection acceleration: 20±3.5g / min

[0253] Water content: 3 to 7.5% by weight

[0254] Blocking time: 1 to 2 minutes ± 5 seconds

[0255] (Study on the stability of preparations over time)

[0256] The prepared preparation was stored at 60°C for 2 weeks, and the increased amount of the compound represented by formula (II) as an analog was measured.

[0257] (Determination of bulk density of preparations)

[0258] The preparation of the present invention was poured into a container with a capacity of 100 mL until it overflowed, and the excess preparation was carefully wiped off from the upper surface of the container. The bulk density was calculated using the following formula using the weight of the preparation in the container deducted from the weight of the container.

[0259] Bulk density = weight of preparation in container / 100

[0260] (result)

[0261] The increase (%) of the compound represented by formula (II) and the bulk density of the preparations of Examples 13, 14 and Reference Example 6 during the time stability test are shown in Table 20. As a result, the increase (%) of the compound represented by formula (II) of the preparations of Examples 12 and 13 containing polyvinyl pyrrolidone was lower than that of the preparation of Reference Example 6 containing hydroxypropyl cellulose. In addition, compared with the preparation of Example 13 in which the amount of polyvinyl pyrrolidone was 3% by weight, the preparation of Example 12 in which the amount of polyvinyl pyrrolidone was 1% by weight had a lower increase (%) of the compound represented by formula (II) during the time stability test and a lower bulk density.

[0262] [Table 20]

[0263] Example 13 Embodiment 14 Reference Example 6 Increased amount of the compound represented by formula (II) (%) 0.12 0.15 0.20 Bulk density (g / mL) 0.72 0.77 -

[0264] (5) Discussion on fluidizing agent

[0265] In order to investigate the fluidizer, (a) the amount of analogs after the preparations were stored for a period of time, and (b) the adhesion between the preparations were evaluated. The preparations of the prescriptions shown in Table 21 and Table 22 were prepared by a stirring granulation method. The fluidizers used were 1% and 3% of light anhydrous silicic acid (Cab-o-sil, CABOT), 1% and 3% of hydrated silicon dioxide (RxCIPIENTS), and 1% and 3% of sodium stearyl fumarate (PRUV, JRS PHARMA).

[0266] [Table 21]

[0267]

[0268] [Table 22]

[0269]

[0270] (Manufacturing method of preparation)

[0271] The compound represented by formula (I) shown in Table 21 and Table 22, reduced maltose syrup (maltitol), D-mannitol, polyvinylpyrrolidone K25, sucralose, a fluidizer (any one of light anhydrous silicic acid, hydrous silicon dioxide, sodium stearyl fumarate) and strawberry flavor were mixed with a high-speed mixer (LFS-GS-2J high-speed mixer, Powtech Fukae), and water was added to stir and granulate. Thereafter, the granulated product was granulated with a crushing type granulator (P-3S type, Showa Chemical Machinery Works) and dried at 65 to 70°C with a fluidized bed granulator (MP-01 Fluid bed dryer granulator, Powrex). After drying, the product was granulated with a crushing type granulator (P-3S type, Showa Chemical Machinery Works) to obtain granules. The granulation conditions of the high-speed mixer are as follows.

[0272] (Granulation conditions)

[0273] Granulator: LFS-GS-2J high speed mixer

[0274] Mixer speed: 333 rpm

[0275] Chopper speed: 2500 rpm

[0276] Liquid injection acceleration: 20±3.5g / min

[0277] Water content: 3 to 7.5% by weight

[0278] Blocking time: 1 to 2 minutes ± 5 seconds

[0279] (Study on the stability of preparations over time)

[0280] The prepared preparation of the present invention was stored at 60°C for 2 weeks, and the increased amount of the compound represented by formula (II) as an analog was measured.

[0281] (Adhesion test of preparations)

[0282] A 4 mL brown bottle was filled with 1 g of the preparation. When the bottle was turned over 3 times, the case where the preparation at the bottom flowed was rated as ○, the case where the preparation at the top flowed was rated as △, and the case where the preparation did not flow at all was rated as ×.

[0283] (result)

[0284] The increase (%) of the compound represented by formula (II) and the fixation properties of the formulations of Examples 15 to 18 and Comparative Examples 7 and 8 when subjected to a time stability test are shown in Tables 23 and 24. As a result, the increase (%) of the compound represented by formula (II) in the formulations of Examples 15 to 18 was almost the same as that in the formulations of Comparative Examples 7 and 8 containing sodium stearyl fumarate, and the results were almost the same even when the amount of the fluidizer was changed.

[0285] On the other hand, the results of investigating the fixation properties of the preparations of Examples 15 to 18 and Comparative Examples 7 and 8 showed that the fixation properties of the preparations of Examples 15 to 18 were lower than those of the preparations of Comparative Examples 7 and 8.

[0286] [Table 23]

[0287] Embodiment 15 Example 16 Embodiment 17 Increased amount of the compound represented by formula (II) (%) 0.64 0.51 0.34 fixation △ ○ ○

[0288] [Table 24]

[0289] Embodiment 18 Comparative Example 7 Comparative Example 8 Increased amount of the compound represented by formula (II) (%) 0.58 0.51 0.45 fixation ○ × ×

[0290] (6) Discussion on suspension concentrate

[0291] In order to explore the suspension, the water suspension of the preparation was evaluated. The preparation of the present invention of the prescription shown in Table 25 was manufactured by a stirring granulation method. The suspension was made of hydroxypropyl methylcellulose (TC-5, Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (HPC-L, Nippon Soda), and methylcellulose (SM-4, Shin-Etsu Chemical Co., Ltd.).

[0292] [Table 25]

[0293]

[0294] (Manufacturing method of preparation)

[0295] The compound represented by formula (I) shown in Table 25, D-mannitol, reduced maltose starch syrup (maltitol), sodium chloride and polyvinylpyrrolidone K25 were mixed with a vertical granulator (VG-50 type, Powrex), and water was added to perform stirring granulation. Thereafter, the granulated product was granulated with a crushing type granulator (P-3S type, Showa Chemical Machinery Works) and dried at 65 to 70° C. with a fluidized bed granulator (GPGC-15&30fluid bed dryer granulator, Powrex). After drying, the granulated product was granulated with a crushing type granulator (P-3S type, Showa Chemical Machinery Works). The sized granules, sucralose, a suspending agent (any one of hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose), light anhydrous silicic acid and strawberry flavor are mixed with a V-type blender (130L V-type blender, manufactured by Tokuju Kosho Co., Ltd.) to prepare granules.

[0296] (Granulation conditions)

[0297] Granulator: Vertical Granulator VG-50

[0298] Mixer speed: 200 rpm

[0299] Chopper speed: 2500 rpm

[0300] Liquid injection acceleration: 105±3g / min

[0301] Water content: 4.5 to 7.5% by weight

[0302] Blocking time: 1 to 3 minutes ± 5 seconds

[0303] (Water Suspensibility Test of Preparations)

[0304] 1 g of the preparation of the present invention was placed in a covered container containing 9.5 mL of water. The covered container was flipped back and forth 40 times, and liquid was immediately collected from the upper and lower parts of the container. After the container was flipped, it was left at room temperature for 10 minutes, and liquid was collected from the center of the container. The concentration of the compound represented by formula (I) in the collected liquid was measured.

[0305] (Determination method of the compound represented by formula (I))

[0306] The amount of the compound represented by formula (I) was measured by liquid chromatography according to the following method and conditions.

[0307] Detector: UV spectrophotometer (measurement wavelength 260nm)

[0308] ·Column: ACQUITY UPLC BEH C18 1.7μm, 2.1×50mm (Waters)

[0309] Column temperature: a certain temperature around 35°C

[0310] Mobile phase A: 0.1% trifluoroacetic acid / 0.2 mM EDTA solution, mobile phase B: acetonitrile

[0311] · Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 26 to control the concentration gradient.

[0312] [Table 26]

[0313] Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%) 0 to 2.3 62 38 2.3 to 3 62→20 38→80 3 to 4 20 80

[0314] Flow rate: about 0.6mL / min

[0315] Injection volume: 4μL

[0316] Sample cooler temperature: about 5°C

[0317] Automatic syringe cleaning fluid: acetonitrile

[0318] Area measurement range: 8 minutes after sample solution injection

[0319] · Calculation formula for the amount of the compound represented by formula (I)

[0320] The amount of the compound represented by formula (I) (%) = MS / C×A T / A S ×100

[0321] MS: mass (mg)

[0322] C: Amount in the preparation (mg / mL)

[0323] A S : Peak area obtained from the standard solution

[0324] A T : Peak area obtained from the sample solution

[0325] (Assessment of Suspension in Water)

[0326] The suspensibility of the formulation was evaluated according to the following formula.

[0327] Ratio of the amount of the compound represented by formula (I) in the suspension located in the center of the container 10 minutes after the container is inverted (%) = (concentration of the compound represented by formula (I) in the suspension located in the center of the container 10 minutes after the container is inverted / concentration of the compound represented by formula (I) in the suspension located in the center of the container immediately after the container is inverted) × 100 (%)

[0328] (result)

[0329] The water suspension properties of the preparations of Example 19, Reference Examples 7, 8 and Comparative Example 9 are shown in Table 27. As a result, the ratio of the amount of the compound represented by formula (I) in the suspensions of Example 19 and Reference Examples 7 and 8 was higher than that of Comparative Example 9 which did not contain a suspending agent. In particular, the ratio of the amount of the compound represented by formula (I) in the suspension of the preparation of Example 19 containing hydroxypropyl methylcellulose was high, and the water suspension property was good.

[0330] [Table 27]

[0331]

[0332] (7) Discussion on lubricants

[0333] In order to investigate the lubricant, the angle of repose, which is an index of the fluidity of the preparation, was evaluated. The preparations of the formulations shown in Table 28 were prepared by a stirring granulation method. Talc (Merck, LUB) was used as the lubricant.

[0334] [Table 28]

[0335]

[0336] (Manufacturing method of preparation)

[0337] The compound represented by formula (I) shown in Table 28, D-mannitol, reduced maltose starch syrup (maltitol), sodium chloride, polyvinylpyrrolidone K25 and hydroxypropylmethylcellulose were mixed in a vertical granulator (FM-VG50 model, Powrex), and water was added to perform stirring granulation. Thereafter, the granulated product was granulated in a crushing type granulator (P-3S model, Showa Chemical Machinery Works) and dried in a fluidized bed granulator (GPGC-15&30fluid bed dryer granulator, Powrex) at 65 to 70°C. After drying, the granulated product was granulated in a crushing type granulator (P-3S model, Showa Chemical Machinery Works). The granulated product after granulation was mixed with talc, sucralose, light anhydrous silicic acid and strawberry flavor in a V-type blender (130L V type blender, Tokuju Works) to obtain granules.

[0338] (Granulation conditions)

[0339] Granulator: Vertical Granulator VG-50

[0340] Mixer speed: 200 rpm

[0341] Chopper speed: 2500 rpm

[0342] Liquid injection acceleration: 105±3g / min

[0343] Water content: 4.5 to 7.5% by weight

[0344] Blocking time: 1 to 3 minutes ± 5 seconds

[0345] (Determination of the angle of repose of preparations)

[0346] The angle of repose of the prepared preparation was measured using a powder tester (Hosokawa Micron) under the following conditions.

[0347] Action time: 170 seconds, slow down: 10 seconds, amplitude: 1.5 mm

[0348] (result)

[0349] The angles of repose of the preparations of Example 20 and Comparative Example 10 are shown in Table 29. As a result, the angle of repose of the preparation of Example 20 containing talc was smaller than that of the preparation of Comparative Example 10 not containing talc, which shows that the fluidity of the preparation can be improved when talc is contained.

[0350] [Table 29]

[0351] Embodiment 20 Comparative Example 10 Angle of repose(°) 33.7 36.2

[0352] (8) Determination of dissolution rate

[0353] The preparation of Example 20 shown in Table 28 was packaged in SP (aluminum), stored at 25°C and a relative humidity of 60% for 3, 6, 9 and 12 months, and the dissolution rate of the compound represented by formula (I) was measured.

[0354] (Dissolution test of preparations)

[0355] After the prepared preparation was stored at 25°C and a relative humidity of 60% for a certain period of time, the dissolution rate of the compound represented by formula (I) was measured according to the dissolution test method (method 2, paddle method) of the Japanese Pharmacopoeia. The solution used in the dissolution test method was the dissolution solution 2 (containing cetyltrimethylammonium bromide), and the paddle rotation speed was set to 50 rpm.

[0356] (result)

[0357] like Figure 2 As shown, regarding the dissolution rate of the preparation of Example 20, there was almost no difference between the dissolution rate of the preparation immediately after preparation and the dissolution rate of the preparation after storage at 25°C and a relative humidity of 60% for 3, 6, 9, and 12 months.

[0358] (9) Preparations containing different amounts of compounds

[0359] As another aspect, the preparation of Example 21 shown in Table 29 was prepared. Example 21 was produced in the same manner as Example 20 by the stirring granulation method.

[0360] [Table 30]

[0361]

[0362]

[0363] [Industrial Applicability]

[0364] The preparation of the present invention containing the compound represented by formula (I) has improved stability, water suspension, fluidity, etc. in various studies. Therefore, the preparation of the present invention can be suspended in water and can be easily taken by children.

Claims

1. A solid preparation comprising: a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more selected from the group consisting of alkali metal chlorides, organic acids and polyol esters; in, The alkali metal chloride is sodium chloride, The organic acid is ascorbic acid and / or fumaric acid, The polyol ester is Miglyol, The solid preparation further contains sugar alcohol and / or sugars, The sugar alcohol and / or sugar are: a. Reduced maltose syrup and refined white sugar, or b. Reduced maltose syrup and D-mannitol, The solid preparation further contains a water-soluble polymer, The water-soluble polymer is a cellulose polymer, The cellulose polymer is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

2. The solid preparation according to claim 1, comprising sodium chloride.

3. The solid preparation according to claim 1 or 2, wherein the sugar alcohol and / or sugar is reduced maltose syrup and refined white sugar.

4. The solid preparation according to claim 1 or 2, wherein the sugar alcohol and / or sugar is reduced maltose syrup and D-mannitol. The solid preparation according to claim 1 or 2, wherein the cellulose polymer is hydroxypropyl methylcellulose. The solid preparation according to claim 3 , wherein the cellulose polymer is hydroxypropyl cellulose. The solid preparation according to claim 4 , wherein the cellulose polymer is hydroxypropyl methylcellulose.

8. The solid preparation according to claim 1, comprising 1 to 80 mg of the compound represented by formula (I),

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