Oral solid preparation

Abstract

The present invention provides an oral solid preparation containing, as an active ingredient, 1-((1R, 2R)-2-hydroxy-4, 4-dimethyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl)-3-(2-phenylpyridin-3-yl) urea, a pharmaceutically acceptable salt thereof, or a solvate of the 1-((1R, 2R)-2-hydroxy-4, 4-dimethyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl)-3-(2-phenylpyridin-3-yl) urea or the pharmaceutically acceptable salt thereof. The present invention relates to an oral solid preparation containing 1-((1R, 2R)-2-hydroxy-4, 4-dimethyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl)-3-(2-phenylpyridin-3-yl) urea or a pharmaceutically acceptable salt thereof, or a solvate of the same.

Description

Technical Field

[0001] The present invention relates to an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof. Background Art

[0002] 1-((1R,2R)-2-Hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea is a compound represented by the chemical structural formula of formula (I) (hereinafter, sometimes also referred to as compound (I)).

[0003] It is known that 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof is a compound having excellent TrkA (Tropomyosin receptor kinase A) inhibitory activity and is useful for preventing or / and treating diseases related to TrkA (for example, pain, pruritus, etc.) (Patent Document 1: International Publication No. 2018 / 199166 pamphlet).

[0004] Formula (I):

[0005]

[0006] In Patent Document 1, it is disclosed that a pharmaceutical composition of compound (I) can be optionally made into various dosage forms (for example, tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, extracts, elixirs, etc.) by appropriately combining with pharmaceutically acceptable additives (for example, excipients, binders, lubricants, disintegrants, surfactants, flow promoters, film formers, plasticizers, masking agents, colorants, flavoring agents, preservatives, isotonic agents, pH regulators, stabilizers, dispersants, antioxidants, buffers, preservatives, fragrances, cosolvents, absorption promoters, gelling agents, suspending agents, emulsifiers, commonly used appropriate additives or solvents). However, specific formulation recipes and preparations made using specific additives, solvents, etc. are not disclosed.

[0007] For the purpose of improving patient compliance with taking medicine and providing economical medical treatment, for example, in the medical field, etc., oral administration preparations such as tablets and capsules that are easy to take or preparations that can achieve drug efficacy with fewer daily doses of taking medicine are required.

[0008] Prior Art Documents

[0009] Patent Document

[0010] Patent Document 1: Pamphlet of International Publication No. 2018 / 199166 Summary of the Invention

[0011] An object of the present invention is to provide an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea (Compound (I)) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient

[0012] Another object of the present invention is to provide an oral solid preparation that can suppress a sharp increase in the blood concentration of the compound of the active ingredient at an early stage after the preparation is administered to a subject

[0013] It is known that Compound (I) is a compound having the following properties: when orally administered to a subject, it rapidly dissolves and is absorbed in the stomach (under acidic conditions with a pH of about 1 to about 2), and at an early stage after administration, the blood concentration of this Compound (I) shows a sharp increase and rapidly disappears

[0014] In the case of Compound (I) having a large fluctuation in blood concentration that shows a sharp increase in blood concentration at an early stage after administration and rapidly disappears before the next administration, there is a concern that adverse effects such as the occurrence of toxicity associated with a temporarily high blood concentration of Compound (I) may occur

[0015] In such a situation, it is urgent to provide a preparation containing Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient that can suppress the occurrence of toxicity

[0016] To achieve the above object, the present inventors repeatedly conducted in-depth studies. As a result, when designing a preparation with a core containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea (Compound (I)) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient and coated with a specific coating agent, and administering the preparation produced according to the design to a subject, an oral solid preparation that can suppress a sharp increase in the blood concentration of Compound (I) at an early stage after administration was found

[0017] The present inventors have also found that an oral solid preparation with excellent persistence of the blood concentration of compound (I) can be obtained by using a coating agent that starts to dissolve the preparation at a specific pH. As a specific example, it is an oral solid preparation obtained by coating a core containing 50 mg or 150 mg of compound (I) with a coating agent that starts to dissolve the preparation at pH = about 5.0 to about 6.5 or pH = about 5.0 to about 7.0. After 12 hours or 24 hours of administering this preparation to a subject, the blood concentration of compound (I) is about 100 nM (preferably 90 - 110 nM) or more.

[0018] In summary, the present inventors have found the following oral solid preparations, thus completing the present invention: (i) an oral solid preparation containing compound (I) and considered to be highly safe; and (ii) an oral solid preparation in which the blood concentration of compound (I) persists for a long time when a preparation containing compound (I) is administered to a subject, especially an oral solid preparation in which the medicinal effect can be expected to persist for a long time by taking the medicine once or twice a day.

[0019] Compound (I) contained in the oral solid preparation of the present invention has TrkA inhibitory activity. Therefore, by administering this preparation, it can have an improving effect on diseases related to TrkA (for example, pain, pruritus, etc.).

[0020] The present invention is an oral solid preparation containing 1 - ((1R,2R)-2 - hydroxy - 4,4 - dimethyl - 1,2,3,4 - tetrahydronaphthalen - 1 - yl) - 3 - (2 - phenylpyridin - 3 - yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof, and more specifically, it can be as shown in the following [1] to [21 - 3].

[0021] [1] An oral solid preparation which is an oral solid preparation containing 1 - ((1R,2R)-2 - hydroxy - 4,4 - dimethyl - 1,2,3,4 - tetrahydronaphthalen - 1 - yl) - 3 - (2 - phenylpyridin - 3 - yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and this preparation is characterized by having the following (1) and (2):

[0022] (1) A core containing the above - mentioned active ingredient; and

[0023] (2) A coating layer covering the above - mentioned core, and this coating layer contains at least 1 kind of coating agent selected from the following, such as hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethylethylcellulose, etc.

[0024] [1-1] In the above-mentioned solution [1], the coating agent preferably used for coating the core is at least one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, and hydroxypropyl methylcellulose acetate succinate; more preferably, it is one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, and hydroxypropyl methylcellulose acetate succinate.

[0025] [1-2] In the above-mentioned solution [1], the coating agent preferably used for coating the core is at least one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose; more preferably, it is one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose.

[0026] [1-3] In the above-mentioned solutions [1] to [1-2], the methacrylic acid copolymer is, for example, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc.; preferably, the methacrylic acid copolymer is at least one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dry methacrylic acid copolymer LD; more preferably, it is one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dry methacrylic acid copolymer LD.

[0027] [2] The oral solid preparation described in the above-mentioned solutions [1] to [1-3], wherein the coating layer further contains at least one additive selected from the following, for example: plasticizer, excipient, binder, disintegrant, wetting agent, surfactant, pH regulator, solubilizer, stabilizer, antioxidant, adsorbent, flavoring agent, sweetener, colorant, perfume, fluidizing agent, lubricant, coating agent other than the coating agent described in the above-mentioned solution [1] (including the second coating agent), etc.

[0028] [2-1] In the above-mentioned solution [2], as the plasticizer, it is, for example, at least one selected from triethyl citrate, tributyl citrate, Macrogol (registered trademark) (polyethylene glycol), propylene glycol, sodium lauryl sulfate ethanol, triacetin, polysorbate 80, etc.; preferably, it is at least one selected from triethyl citrate, Macrogol (registered trademark) (polyethylene glycol), propylene glycol, triacetin, and polysorbate 80; more preferably, it is triethyl citrate.

[0029] [2-2] In the above-mentioned solution [2], as the second coating agent, for example, it is at least one selected from titanium oxide, talc, crystalline cellulose, calcium carbonate, shellac, etc.; preferably, it is at least one or more selected from titanium oxide, talc, crystalline cellulose, calcium carbonate and shellac; more preferably, it is titanium oxide and / or talc.

[0030] [3] The oral solid preparation according to any one of the above-mentioned solutions [1] to [2-2], wherein the components that can be contained in the core are at least one selected from additives such as excipients, fluidizing agents, disintegrants, lubricants, etc.

[0031] [3-1] The oral solid preparation according to any one of the above-mentioned solutions [1] to [2-2], wherein the components that can be contained in the core are at least one additive selected from excipients, fluidizing agents, disintegrants and lubricants.

[0032] [3-2] The oral solid preparation according to any one of the above-mentioned solutions [1] to [2-2], wherein the core contains an excipient, a fluidizing agent, a disintegrant and a lubricant.

[0033] [4] The oral solid preparation according to any one of the above-mentioned solutions [3] to [3-2], wherein the excipient is at least one selected from the following: for example, glucose, lactose (lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, etc.), granulated lactose, sucrose, white sugar, mannitol (D-mannitol), mannitol, xylitol, sorbitol (D-sorbitol), crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, calcium hydrogen phosphate dihydrate, isomaltitol, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch, partially pregelatinized starch, light anhydrous silicic acid, titanium oxide, etc.

[0034] [4-1] In the above-mentioned solution [4], preferably, the excipient is at least one selected from lactose (lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, etc.), granulated lactose, white sugar, mannitol (D-mannitol), crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch and partially pregelatinized starch; more preferably, it is at least one selected from crystalline cellulose, mannitol (D-mannitol) and granulated lactose; further preferably, it is one selected from mannitol, crystalline cellulose, a mixture of mannitol and crystalline cellulose, and a mixture of crystalline cellulose and granulated lactose.

[0035] [5] The oral solid preparation according to any one of the above-mentioned solutions [3] to [3-2], wherein the fluidizing agent is, for example, at least one selected from the following: silicon dioxide (light anhydrous silicic acid, silica gel), talc, hydrated silicon dioxide, magnesium aluminum metasilicate and calcium hydrogen phosphate granules, etc.

[0036] In the solution [5] described above [5], it is preferred that the fluidizing agent is at least one selected from light anhydrous silicic acid, talc, and magnesium aluminometasilicate; more preferably, it is one selected from light anhydrous silicic acid, a mixture of light anhydrous silicic acid and talc, talc, and magnesium aluminometasilicate.

[0037] The oral solid preparation according to any one of the solutions [3] to [3-2] described above [6], wherein the disintegrant is at least one selected from the following: for example, starches (corn starch, potato starch, starch, pregelatinized starch, partially pregelatinized starch), sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose, CMC), calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone (PVPP), methyl cellulose, microcrystalline cellulose, crystalline cellulose, low alkyl-substituted hydroxypropyl cellulose (L-HPC), sodium alginate, corn starch, sodium carboxymethyl starch, etc.

[0038] In the solution [6] described above [6-1], it is preferred that the disintegrant is at least one selected from sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose, CMC), croscarmellose sodium, crospovidone, sodium starch glycolate, calcium carboxymethyl cellulose, polyvinylpyrrolidone (PVPP), microcrystalline cellulose (crystalline cellulose), low alkyl-substituted hydroxypropyl cellulose (L-HPC), and sodium carboxymethyl starch; more preferably, it is at least one selected from croscarmellose sodium and sodium starch glycolate; further preferably, it is croscarmellose sodium or sodium starch glycolate.

[0039] The oral solid preparation according to any one of the solutions [3] to [3-2] described above [7], wherein the lubricant is at least one selected from the following: for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium dodecyl sulfate, talc, carboxymethyl cellulose, stearic acid, sodium dodecyl sulfate, carnauba wax, sucrose fatty acid ester, polyethylene glycol, glycerol, monoglyceryl stearate, castor oil, hydrogenated castor oil, etc.

[0040] In the solution [7] described above [7-1], it is preferred that the lubricant is at least one selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium dodecyl sulfate, talc, stearic acid, sodium dodecyl sulfate, and carnauba wax; more preferably, it is at least one selected from magnesium stearate and sodium stearyl fumarate; further preferably, it is magnesium stearate or sodium stearyl fumarate.

[0041] [8] The oral solid preparation according to any one of [1] to [7-1] (excluding the oral solid preparation with the coating agent being methacrylic acid copolymer S), characterized in that, when the dissolution test is carried out using the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia with dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 13.0% or more after 1 hour from the start of the dissolution test.

[0042] [8A] The oral solid preparation according to any one of [1] to [7-1] (excluding the oral solid preparation with the coating agent being methacrylic acid copolymer S), wherein, when the dissolution test is carried out using the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia with dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, about 15.0% or more, about 18.0% or more, or about 20.0% or more after 1 hour from the start of the dissolution test.

[0043] [8B] The oral solid preparation according to any one of [1] to [7-1], wherein, when the dissolution test is carried out using the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia with dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more after 6 hours from the start of the dissolution test.

[0044] [8C] The oral solid preparation according to any one of [1] to [7-1], wherein, when the dissolution test is carried out using the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia with dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more after 1 hour or 6 hours from the start of the dissolution test.

[0045] The oral solid preparation according to any one of the above-mentioned [1] to [8C], characterized in that, when performing a dissolution test using dissolution test solution No. 1 according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 2.5% or less after 1 hour from the start of the dissolution test.

[0046] [9-1] In the above-mentioned [9], preferably the dissolution rate is about 2.0% or less; more preferably about 1.0% or less; still more preferably about 0.5% or less.

[0047]

[10] The oral solid preparation according to any one of the above-mentioned [1] to [9-1], wherein the coating layer starts to dissolve in a solution within the range of pH = about 5.0 to about 7.0, and the active ingredient in the preparation is dissolved.

[0048] [10-1] In the above-mentioned

[10] , the pH at which the coating layer starts to dissolve is, for example, a range having a pH value of about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0 as the upper limit value and / or the lower limit value (for example, a range of about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0), preferably pH = about 5.0 to about 7.0; more preferably pH = about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0.

[0049]

[11] An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2):

[0050] (1) A core containing the following components (a) to (e):

[0051] (a) The above-mentioned active ingredient,

[0052] (b) At least one excipient selected from crystalline cellulose, granulated lactose and crystalline cellulose,

[0053] (c) At least one fluidizing agent selected from light anhydrous silicic acid, talc and magnesium aluminometasilicate,

[0054] (d) At least one disintegrant selected from croscarmellose sodium and sodium starch glycolate, and

[0055] (e) At least one lubricant selected from magnesium stearate and sodium stearyl fumarate; and

[0056] (2) A coating layer that coats the above core, and the coating layer contains at least one coating agent selected from the following: hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose.

[0057] [11-X1] In the above-mentioned solution

[11] , preferably, the coating agent used for coating the core is more preferably one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose.

[0058] [11-X2] In the above-mentioned solution

[11] or [11-X1], the methacrylic acid copolymer is, for example, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, dried methacrylic acid copolymer LD, etc. Preferably, the methacrylic acid copolymer is, for example, at least one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dried methacrylic acid copolymer LD; more preferably, it is one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dried methacrylic acid copolymer LD.

[0059] [11-1] The oral solid preparation according to any one of the above-mentioned solutions

[11] to [11-X2], wherein triethyl citrate is further contained in the coating layer.

[0060] [11-2] The oral solid preparation according to any one of the above-mentioned solutions

[11] to [11-X2], wherein titanium oxide and / or talc is further contained in the coating layer.

[0061] [11-3] The oral solid preparation according to any one of the above-mentioned solutions

[11] to [11-X2], wherein triethyl citrate, titanium oxide, and talc are further contained in the coating layer.

[0062] The oral solid preparation according to any one of the above-mentioned

[11] to [11-3] (excluding the oral solid preparation with methacrylic acid copolymer S as the coating agent), characterized in that, when the dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 13.0% or more after 1 hour from the start of the dissolution test.

[0063] [11-4A] The oral solid preparation according to any one of the above-mentioned

[11] to [11-3] (excluding the oral solid preparation with methacrylic acid copolymer S as the coating agent), wherein, when the dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, about 15.0% or more, about 18.0% or more, or about 20.0% or more after 1 hour from the start of the dissolution test.

[0064] [11-4B] The oral solid preparation according to any one of the above-mentioned

[11] to [11-3], wherein, when the dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more after 6 hours from the start of the dissolution test.

[0065] [11-4C] The oral solid preparation according to any one of the above-mentioned

[11] to [11-3], wherein, when the dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more after 1 hour or 6 hours from the start of the dissolution test.

[0066] The oral solid preparation according to any one of the aspects

[11] to [11-4C], characterized in that, when a dissolution test is carried out using dissolution test solution 1 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 2.5% or less after 1 hour from the start of the dissolution test.

[0067] [11-6] In the aspect [11-5], it is preferred that the dissolution rate is about 2.0% or less; more preferably about 1.0% or less; still more preferably about 0.5% or less.

[0068] [11-7] The oral solid preparation according to any one of the aspects

[11] to [11-6], wherein the coating layer starts to dissolve in a solution within the range of pH = about 5.0 to about 7.0, and the active ingredient in the preparation is dissolved out.

[0069] [11-8] In the aspect [11-7], the pH at which the coating layer starts to dissolve is, for example, a range with the pH values of pH = about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0 as the upper limit value and / or the lower limit value (for example, a range of about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0), preferably pH = about 5.0 to about 7.0; more preferably pH = about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0.

[0070] [11A] An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2):

[0071] (1) A core containing the following components (a) to (e):

[0072] (a) The above active ingredient,

[0073] (b) At least 1 excipient selected from crystalline cellulose, granulated lactose and crystalline cellulose,

[0074] (c) At least 1 fluidizing agent selected from light anhydrous silicic acid, talc and magnesium aluminometasilicate;

[0075] (d) At least one disintegrant selected from croscarmellose sodium and sodium starch glycolate, and

[0076] (e) At least one lubricant selected from magnesium stearate and sodium stearyl fumarate; and

[0077] (2) A coating layer that coats the above core, and the coating layer contains the following coating agent: a coating agent in which the coating layer of the above preparation containing at least one starts to dissolve in a solution in the range of pH = about 5.0 to about 7.0.

[0078] [11A-1] In the above-mentioned solution [11A], the coating agent used to coat the core is, for example, a range with a pH value of about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0 as the upper limit value and / or the lower limit value (for example, about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0), preferably a coating agent in which the coating layer of the above preparation starts to dissolve in a solution in the range of pH = about 5.0 to about 7.0; more preferably a coating agent in which the coating layer of the above preparation starts to dissolve in a solution of pH = about 5.0, about 5.5, about 6.0, about 6.5 or about 7.0.

[0079] [11A-2] In the above-mentioned solution [11A] or [11A-1], the coating agent used to coat the core is, for example, at least one coating agent selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate and carboxymethyl ethylcellulose.

[0080] [11A-3] In the above-mentioned solution [11A-2], the coating agent used to coat the core is preferably one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate and carboxymethyl ethylcellulose.

[0081] [11A-3A] In the above-mentioned solutions [11A-1] to [11A-3], the methacrylic acid copolymer is, for example, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc., preferably the methacrylic acid copolymer is, for example, at least one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S and dry methacrylic acid copolymer LD; more preferably one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S and dry methacrylic acid copolymer LD.

[0082] [11A-4] The oral solid preparation according to any one of the solutions [11A] to [11A-3A], wherein triethyl citrate is further contained in the coating layer.

[0083] [11A-5] The oral solid preparation according to any one of the solutions [11A] to [11A-3], wherein titanium oxide and / or talc is further contained in the coating layer.

[0084] [11A-6] The oral solid preparation according to any one of the solutions [11A] to [11A-3A], wherein triethyl citrate, titanium oxide and talc are further contained in the coating layer.

[0085] [11A-7] The oral solid preparation according to any one of the solutions [11A] to [11A-6] (excluding the oral solid preparation with the coating agent being methacrylic acid copolymer S), characterized in that when the dissolution test is carried out using dissolution test solution 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 13.0% or more after 1 hour from the start of the dissolution test.

[0086] [11A-7A] The oral solid preparation according to any one of the solutions [11A] to [11A-6] (excluding the oral solid preparation with the coating agent being methacrylic acid copolymer S), wherein when the dissolution test is carried out using dissolution test solution 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, about 15.0% or more, about 18.0% or more or about 20.0% or more after 1 hour from the start of the dissolution test.

[0087] [11A-7B] The oral solid preparation according to any one of the solutions [11A] to [11A-6], wherein when the dissolution test is carried out using dissolution test solution 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more or 15.0% or more after 6 hours from the start of the dissolution test.

[0088] [11A-7C] The oral solid preparation according to any one of the schemes [11A] to [11A-6], wherein, when performing a dissolution test using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, after 1 hour or 6 hours from the start of the dissolution test, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or 15.0% or more.

[0089] [11A-8] The oral solid preparation according to any one of the schemes [11A] to [11A-7C], characterized in that, when performing a dissolution test using dissolution test solution No. 1 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, after 1 hour from the start of the dissolution test, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 2.5% or less.

[0090] [11A-9] In the scheme [11A-8], preferably the dissolution rate is about 2.0% or less; more preferably about 1.0% or less; still more preferably about 0.5% or less.

[0091] [11B] An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2):

[0092] (1) A core containing the following components (a) and (b):

[0093] (a) The above active ingredient,

[0094] (b) At least one additive selected from excipients, fluidizing agents, disintegrants, and lubricants; and

[0095] (2) A coating layer covering the above core, and the coating layer contains the following coating agent: a coating agent in which the coating layer of at least one of the above preparations starts to dissolve in a solution in the range of pH = about 5.0 to about 7.0.

[0096] [11B-1]In the said solution [11B], the preferred excipients are at least one component selected from lactose (lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, etc.), granulated lactose, white sugar, mannitol (D-mannitol), crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch, and partially pregelatinized starch; more preferably at least one selected from crystalline cellulose, mannitol (D-mannitol), and granulated lactose; further preferably one selected from mannitol, crystalline cellulose, a mixture of mannitol and crystalline cellulose, and a mixture of crystalline cellulose and granulated lactose.

[0097] [11B-2]In the said solution [11B], the preferred fluidizing agents are at least one selected from light anhydrous silicic acid, talc, and magnesium aluminum metasilicate; more preferably one selected from light anhydrous silicic acid, a mixture of light anhydrous silicic acid and talc, talc, and magnesium aluminum metasilicate.

[0098] [11B-3]In the said solution [11B], the preferred disintegrants are at least one selected from sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose, CMC), sodium cross-linked carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, calcium carboxymethyl cellulose, polyvinylpyrrolidone (PVPP), microcrystalline cellulose (crystalline cellulose), low alkyl-substituted hydroxypropyl cellulose (L-HPC), and sodium carboxymethyl starch; more preferably at least one selected from sodium cross-linked carboxymethyl cellulose and sodium starch glycolate; further preferably sodium cross-linked carboxymethyl cellulose or sodium starch glycolate.

[0099] [11B-4]In the said solution [11B], the preferred lubricants are at least one selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, talc, stearic acid, sodium lauryl sulfate, and carnauba wax; more preferably at least one selected from magnesium stearate and sodium stearyl fumarate; further preferably magnesium stearate or sodium stearyl fumarate.

[0100] [11B-5] In the above-described solution [11B], the coating agent for coating the core is, for example, in a range where the upper limit value and / or the lower limit value is a pH value of about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0 (for example, a range of about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0), preferably a coating agent in which the coating layer of the preparation starts to dissolve in a solution within the range of pH = about 5.0 to about 7.0; more preferably a coating agent in which the coating layer of the above-mentioned preparation starts to dissolve in a solution of pH = about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0.

[0101] [11B-6] In the above-described solutions [11B] to [11B-5], the coating agent for coating the core is at least one coating agent selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose.

[0102] [11B-7] In the above-described solution [11B-6], preferably, the coating agent for coating the core is one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose.

[0103] [11B-7A] In the above-described solution [11B-6] or [11B-7], the methacrylic acid copolymer is, for example, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc. Preferably, the methacrylic acid copolymer is at least one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dry methacrylic acid copolymer LD; more preferably, it is one selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dry methacrylic acid copolymer LD.

[0104] [11B-8] The oral solid preparation according to any one of the above-described solutions [11B] to [11B-7A], wherein triethyl citrate is further contained in the coating layer.

[0105] [11B-9] The oral solid preparation according to any one of the above-described solutions [11B] to [11B-7A], wherein titanium oxide and / or talc is further contained in the coating layer.

[0106] [11B-10] The oral solid preparation according to any one of the schemes [11B] to [11B-7A], wherein triethyl citrate, titanium oxide and talc are further contained in the coating layer.

[0107] [11B-11] The oral solid preparation according to any one of the schemes [11B] to [11B-10] (excluding the oral solid preparation with methacrylic acid copolymer S as the coating agent), characterized in that when the dissolution test is carried out with dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 13.0% or more after 1 hour from the start of the dissolution test.

[0108] [11B-11A] The oral solid preparation according to any one of the schemes [11B] to [11B-10] (excluding the oral solid preparation with methacrylic acid copolymer S as the coating agent), wherein when the dissolution test is carried out with dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, about 15.0% or more, about 18.0% or more or about 20.0% or more after 1 hour from the start of the dissolution test.

[0109] [11B-11B] The oral solid preparation according to any one of the schemes [11B] to [11B-10], wherein when the dissolution test is carried out with dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more or about 15.0% or more after 6 hours from the start of the dissolution test.

[0110] [11B-11C] The oral solid preparation according to any one of the schemes [11B] to [11B-10], wherein, when a dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more after 1 hour or 6 hours from the start of the dissolution test.

[0111] [11B-12] The oral solid preparation according to any one of the schemes [11B] to [11B-11C], characterized in that, when a dissolution test is carried out using dissolution test solution No. 1 according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is about 2.5% or less after 1 hour from the start of the dissolution test.

[0112] [11B-13] In the scheme [11B-12], preferably the dissolution rate is about 2.0% or less; more preferably about 1.0% or less; still more preferably about 0.5% or less.

[0113]

[12] The oral solid preparation according to any one of the schemes [1] to [11B-13], which contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount, and the oral solid preparation is characterized in that the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 100 nM or more 12 hours after the first administration of the preparation to the subject.

[0114] [12A] The oral solid preparation according to any one of the schemes [1] to [11B-13] contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that 12 hours after the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 90 nM or more, about 95 nM or more, about 100 nM or more, about 105 nM or more, or about 110 nM or more.

[0115] [12-1] The oral solid preparation according to any one of the schemes [1] to [11B-13] contains: 150 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that 12 hours after the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 100 nM or more.

[0116] [12-1A] The oral solid preparation according to any one of the schemes [1] to [11B-13] contains: 150 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that 12 hours after the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 90 nM or more, about 95 nM or more, about 100 nM or more, about 105 nM or more, or about 110 nM or more.

[0117] [12-2] The oral solid preparation according to any one of [1] to [11B-13] contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that at any time after 12 hours or 24 hours from the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 100 nM or more.

[0118] [12-2A] The oral solid preparation according to any one of [1] to [11B-13] contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that at any time after 12 hours or 24 hours from the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 90 nM or more, about 95 nM or more, about 100 nM or more, about 105 nM or more, or about 110 nM or more.

[0119] [12-3] The oral solid preparation according to any one of [1] to [11B-13] contains: 150 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that at any time after 12 hours or 24 hours from the first administration of the preparation to the subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 100 nM or more.

[0120] [12-3A] The oral solid preparation according to any one of the [1] to [11B-13], which contains: 150 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount. The oral solid preparation is characterized in that at any time 12 hours or 24 hours after the first administration of the preparation to a subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is about 90 nM or more, about 95 nM or more, about 100 nM or more, about 105 nM or more, or about 110 nM or more.

[0121] [12-4] In the

[12] to [12-3A], the subject is a human or a non-human mammal (such as a dog, a cat, a rat, a mouse, a monkey, a cow, a horse, a pig, a sheep, etc.).

[0122]

[13] The oral solid preparation according to any one of the [1] to [12-4], wherein the content of the coating agent for coating the core is, for example, in the range of about 1.0 to about 25.0% by mass, preferably in the range of about 2.0 to about 20.0% by mass, more preferably in the range of about 3.5 to about 15.0% by mass or about 5.0 to about 15.0% by mass, based on the total mass of the oral solid preparation.

[0123]

[14] The oral solid preparation according to any one of the [1] to

[13] , wherein the content of the plasticizer that can be contained in the coating layer is, for example, in the range of 0.0 to about 10.0% by mass, preferably in the range of about 0.1 to about 5.0% by mass, more preferably in the range of about 0.5 to about 3.0% by mass, based on the total mass of the oral solid preparation.

[0124]

[15] The oral solid preparation according to any one of the [1] to

[14] , wherein the content of the second coating agent that can be further contained in the coating layer is, for example, in the range of 0.0 to about 25.0% by mass, preferably in the range of about 1.0 to about 20.0% by mass, more preferably in the range of about 1.0 to about 6.0% by mass, based on the total mass of the oral solid preparation.

[0125]

[16] The oral solid preparation according to any one of the [1] to

[15] , wherein the content of the excipient is, for example, in the range of about 20.0 to about 90.0% by mass, preferably in the range of about 30.0 to about 80.0% by mass, more preferably in the range of about 40.0 to about 75.0% by mass, based on the total mass of the oral solid preparation.

[0126]

[17] The oral solid preparation according to any one of [1] to

[16] above, wherein the content of the fluidizing agent is, for example, in the range of 0.0 to about 15.0% by mass, preferably in the range of about 0.1 to about 10.0% by weight, and more preferably in the range of about 0.5 to about 5.0% by mass, based on the total mass of the oral solid preparation.

[0127]

[18] The oral solid preparation according to any one of [1] to

[17] above, wherein the content of the disintegrant is, for example, in the range of 0.0 to about 30.0% by mass, preferably in the range of about 1.0 to about 20.0% by mass, and more preferably in the range of about 2.0 to about 8.0% by mass, based on the total mass of the oral solid preparation.

[0128]

[19] The oral solid preparation according to any one of [1] to

[18] above, wherein the content of the lubricant is, for example, in the range of 0.0 to about 10.0% by mass, preferably in the range of about 0.1 to about 5.0% by mass, and more preferably in the range of about 0.5 to about 3.0% by mass, based on the total mass of the oral solid preparation.

[0129]

[20] The oral solid preparation according to any one of [1] to

[19] above, wherein the release property of the active ingredient is rapid release in the intestine.

[0130] [20-1] The oral solid preparation according to any one of [1] to

[19] above, wherein the release property of the active ingredient is sustained release or insoluble in the stomach.

[0131] [20-2] The oral solid preparation according to any one of [1] to

[19] above, wherein the release property of the active ingredient is sustained release or insoluble in the stomach and rapid release in the intestine.

[0132]

[21] The oral solid preparation according to any one of [1] to [20-2] above, which is used for preventing and / or treating diseases related to TrkA.

[0133] [21-1] In

[21] above, the diseases related to TrkA are at least one or more diseases selected from the following: pain, cancer, inflammation / inflammatory diseases, allergic diseases, skin diseases, pruritus, neurodegenerative diseases, infectious diseases, Sjogren's syndrome, endometriosis, kidney diseases, osteoporosis, etc.

[0134] In the above-mentioned solution [21-1], preferably, the diseases related to TrkA are at least one or more diseases selected from the following: pain (arthrosis deformans, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis, pain associated with prostatitis, chronic low back pain, painful diabetic peripheral neuropathy, postoperative pain, pelvic pain, nociceptive pain represented by cancer pain, neuropathic pain, acute pain, chronic pain, inflammatory pain, etc.) and pruritus (generalized pruritus, localized pruritus, widespread pruritus, etc.).

[0135] In the above-described solution

[21] , the diseases related to TrkA are at least one or more diseases selected from the following: osteoarthritis pain, arthralgia, neuropathic pain, postoperative pain, low back pain, diabetic neuropathy, intraoperative pain, cancer pain, chemotherapy-induced pain, headache (including cluster headache, tension headache, migraine pain), trigeminal neuralgia, herpes zoster pain, postherpetic neuralgia, carpal tunnel syndrome, inflammatory pain, pain caused by rheumatoid arthritis, colitis, pain of interstitial cystitis, visceral pain, pain caused by kidney stones, pain caused by gallstones, sore throat, fibromyalgia, chronic pain syndrome, thalamic pain syndrome, pain caused by stroke, phantom limb pain, sunburn, radiculopathy, complex regional pain syndrome, HIV-related sensory neuropathy, central nervous disorder pain syndrome, pain of multiple sclerosis, pain of Parkinson's disease, pain of spinal cord injury, dysmenorrhea, toothache, pain caused by bone metastasis, pain caused by endometriosis, pain caused by uterine fibroids, nociceptive pain, hyperalgesia, temporomandibular joint pain, neuroblastoma, ovarian cancer, endometrial cancer, glioblastoma multiforme, cervical cancer, pancreatic cancer, colon cancer, rectal cancer, prostate cancer, melanoma, myeloma, thyroid cancer, lung cancer (small cell lung cancer, non-small cell lung cancer), brain tumor, esophageal cancer, kidney tumor, bone tumor, blood cancer (chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML)), squamous cell carcinoma, glioma, gastrointestinal cancer, ovarian cancer, liver cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, head and neck cancer, germ cell tumor, pediatric sarcoma, natural killer cell tumor of the paranasal sinuses, multiple myeloma, interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, inflammatory cystitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, joint swelling, asthma, atopic dermatitis, psoriasis, psoriatic arthritis, rhinitis, generalized pruritus, localized pruritus, widespread pruritus, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, Sjogren's syndrome, endometriosis, diabetic nephropathy, renal fibrosis, chronic kidney disease, and osteoporosis, etc.

[0136] The present invention has the following effects: When an oral solid preparation containing compound (I) is administered to a subject, (1) a sharp increase in the blood concentration of compound (I) can be controlled, and (2) the blood concentration of compound (I) can be maintained for a long time. BRIEF DESCRIPTION OF THE DRAWINGS

[0137] Figure 1 are the result data of the dissolution test of Test Example 1. ​

[0138] Figure 2 are the result data of the dissolution test in Test Example 2.

[0139] Figure 3 are the result data of the dissolution test in Test Example 3.

[0140] Figure 4 are the result data of the dissolution test in Test Example 4.

[0141] Figure 5 are the result data of the dissolution test in Test Example 5.

[0142] Figure 6 are the result data of the dissolution test in Test Example 6.

[0143] Figure 7 are the result data of the dissolution test in Test Example 7.

[0144] Figure 8 are the result data of the dissolution test in Test Example 8.

[0145] Figure 9 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the control beagle dog oral administration (Comparative Example 1) is orally administered.

[0146] Figure 10 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the beagle dog oral administration (Example 1-1) is orally administered.

[0147] Figure 11 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the beagle dog oral administration (Example 1-2) is orally administered.

[0148] Figure 12 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the beagle dog oral administration (Example 2-1) is orally administered.

[0149] Figure 13 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the beagle dog oral administration (Example 2-2) is orally administered.

[0150] Figure 14 is a graph showing the change in plasma concentration of Compound (I) over time when an oral solid preparation manufactured with the formulation of the beagle dog oral administration (Example 2-3) is orally administered.

[0151] ​​​​​​​​​​​​​Figure 15 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Examples 2-4) is orally administered to beagle dogs.

[0152] Figure 16 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Example 2-5) is orally administered to beagle dogs.

[0153] Figure 17 is the result data of the dissolution test in Test Example 9.

[0154] Figure 18 is the result data of the dissolution test in Test Example 10.

[0155] Figure 19 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Example 5-1) is orally administered to beagle dogs.

[0156] Figure 20 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Example 5-2-1) is orally administered to beagle dogs.

[0157] Figure 21 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Example 5-3) is orally administered to beagle dogs.

[0158] Figure 22 is a graph showing the change in plasma concentration of compound (I) over time when an oral solid preparation prepared with the formulation (Example 5-4) is orally administered to beagle dogs. Detailed Description of the Invention

[0159] The present invention relates to an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

[0160] ​​​​​​​​Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments and can be implemented in any manner without departing from the gist of the present invention. In addition, the preferred or more preferred embodiments shown below can be used in appropriate combinations regardless of expressions such as "for example", "preferably", and "more preferably". In addition, the description of the numerical range is for example, and a range obtained by appropriately combining the upper and lower limits of each range and the numerical values of the examples can also be preferably used. Moreover, terms such as "containing" or "comprising" are interpreted as inclusive open transitional phrases, rather than exclusive closed transitional phrases. Terms such as "containing" or "comprising" can be replaced by "substantially consisting of" or "consisting only of".

[0161] In the present invention, the "core" refers to a solid obtained by compression molding 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof together with a pharmaceutically acceptable additive, and is preferably a tablet or its central part. There is no particular limitation on the shape or size of the core. For example, it is preferable that the surface of the core has a curved surface that can be coated with a coating agent. In addition, examples of the shape of the solid preparation having a coating layer obtained by coating the coating agent on the core include shapes that are easy to handle as a preparation and easy for the subject to take, such as circular, triangular, and elliptical shapes.

[0162] In the present invention, there is no particular limitation on the method for manufacturing a core containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and methods commonly used for manufacturing cores or tablets for preparations, such as direct compression method, dry granulation method, wet granulation method, and fluidized bed granulation method, can be selected.

[0163] As the pharmaceutically acceptable additive, as long as it is an additive that can be used for formulation, there is no particular limitation, and additives described in reference books for formulation research such as "Dictionary of Pharmaceutical Excipients 2021, edited by the Japanese Pharmaceutical Excipients Association, February 2021" (the content of this reference book is incorporated herein by reference) can be used. For example, as components for ensuring functions such as manufacturability of the preparation, appropriate hardness of the preparation, disintegration property, and dissolution property, additives such as excipients, disintegrants, fluidizing agents, lubricants, binders, stabilizers, and colorants can be used.

[0164] As the additive contained in the core of the present invention, it is at least one selected from excipients, fluidizing agents, disintegrants, and lubricants, preferably excipients, fluidizing agents, disintegrants, and lubricants. The core of the present invention may further contain additives such as binders, stabilizers, surfactants, pH regulators, solubilizers, antioxidants, adsorbents, flavoring agents, sweeteners, colorants, fragrances, etc.

[0165] In the present invention, the "coating layer" refers to a layer containing the coating agents (including the second coating agent) described below for coating the core (for example, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, aminoalkyl methacrylate copolymer, cellulose acetate phthalate, carboxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium oxide, talc, etc.), and laminated or coated on the surface of the core.

[0166] The surface of the core of the present invention is coated with the above coating layer on the entire surface. The oral solid preparation of the present invention has the following properties: for example, it dissolves when contacted with a solution in the range of pH = about 5.0 to about 7.0 or a range with the pH values of about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0 as the upper limit value and / or the lower limit value (for example, in the ranges of about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0), preferably a solution in the range of pH = about 5.0 to about 7.0, and more preferably a solution with pH = about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0, and releases the active ingredient contained in the core.

[0167] The coating layer may further contain additives such as plasticizers, excipients, binders, disintegrants, emollients, surfactants, pH regulators, solubilizers, stabilizers, antioxidants, adsorbents, flavoring agents, sweeteners, colorants, fragrances, fluidizing agents, lubricants, etc.

[0168] The additives that can be additionally contained in the core or the coating layer (for example, binders, stabilizers, surfactants, pH regulators, solubilizers, antioxidants, adsorbents, flavoring agents, sweeteners, colorants, fragrances, etc.) can be appropriately selected from the additives described in reference books for pharmaceutical research such as "Dictionary of Pharmaceutical Excipients 2021, edited by the Japanese Pharmaceutical Excipients Association, February 2021". Here, the additives that can be additionally contained in the exemplified core or coating layer can also be added to either the core or the coating layer. In addition, one compound can play multiple roles (for example, excipients and binders, etc.).

[0169] In the present invention, the "solution" includes liquids such as aqueous solutions and body fluids. A solution with a pH of about 1 to about 2 becomes a solution with a pH equivalent to that of gastric juice, and a solution with a pH of about 4 to about 8 becomes a solution with a pH equivalent to that of intestinal fluid.

[0170] Coating can be carried out by coating methods commonly used in this technical field. Specifically, the following methods can be cited: pan coating method, fluidized bed coating method, vented drying pan coating method, rolling coating method, spray coating method, etc. Coating can be performed using coating devices corresponding to various coating methods.

[0171] Coating can also, if necessary, use a coating solution in which additives such as colorants, flavoring agents, sweetening agents, and fragrances are blended in the above-listed coating agents to coat the surface of the core.

[0172] There is no particular limitation on the usage ratio of the solvents (water, organic solvents, etc.) used in the manufacture of the coating agent, and they can be used in any ratio. There is no particular limitation on the type of organic solvent. For example, alcohol-based solvents (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.) can be used.

[0173] In the present invention, the "oral solid preparation" refers to a solid dosage form for oral administration. As such oral solid preparations, for example, tablets, powders, granules, capsules, lozenges, pills, etc. can be cited. The oral solid preparation of the present invention is preferably a tablet. As tablets, there is no particular limitation. For example, the following types of tablets can be cited: orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, sugar-coated tablets, film-coated tablets, etc. The oral solid preparation of the present invention is preferably a film-coated tablet.

[0174] The oral solid preparation of the present invention is preferably an oral solid preparation (tablet) in which 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient is blended with formulation carriers (additives such as excipients, disintegrants, fluidizing agents, lubricants, etc.), granulated, tabletted, and coated with a coating agent (which may contain a plasticizer, etc.), and the active ingredient has a uniform content (e.g., 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 100 mg, 150 mg, etc.).

[0175] 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea is described in International Publication Pamphlet No. 2018 / 199166 or International Publication Pamphlet No. 2019 / 189717, and can be manufactured by the manufacturing methods described in these pamphlets.

[0176] As a pharmaceutically acceptable salt of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea (Compound (I)), there is no particular limitation as long as it is a pharmaceutically acceptable salt. For example, acid addition salts with the following acids can be mentioned: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, heptanoic acid, decanoic acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid, aromatic monocarboxylic acids such as benzoic acid, salicylic acid, aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aliphatic tricarboxylic acids such as citric acid, etc. organic carboxylic acids; aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, etc. organic sulfonic acids, etc., and inorganic base addition salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, calcium, etc., organic base addition salts such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, ornithine, etc. These salts can be obtained by conventional methods. For example, an equivalent amount of Compound (I) can be mixed with a solution containing the required acid or base, etc., and the required salt can be filtered or the solvent can be distilled off and collected.

[0177] In the present invention, "solvate" refers to a molecular complex containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (such as water, ethanol, etc.). When the solvent molecule is water, it is particularly called "hydrate".

[0178] With respect to the total mass of the oral solid preparation, the content of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or their solvate used in the present invention is, for example, in the range of about 5.0 to about 70.0% by mass, preferably in the range of about 10.0 to about 50.0% by mass, more preferably in the range of about 10.0 to about 30.0% by mass.

[0179] In the present invention, the "excipient" refers to an additive described in a reference book for formulation research such as "Pharmaceutical Excipient Dictionary 2021, edited by the Japanese Pharmaceutical Excipient Society, February 2021", and is a component added to achieve a certain size or concentration in the formulation of tablets and the like. The excipient is not particularly limited, and examples thereof include: glucose, lactose (lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, etc.), granulated lactose, sucrose, white sugar, mannitol (D-mannitol), mannitol, xylitol, sorbitol (D-sorbitol), crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, calcium hydrogen phosphate dihydrate, isomaltulose, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch, partially pregelatinized starch, light anhydrous silicic acid, titanium oxide, and mixtures thereof. Preferred excipients are at least one selected from lactose (lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, etc.), granulated lactose, white sugar, mannitol (D-mannitol), crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch, and partially pregelatinized starch; more preferably at least one selected from mannitol, crystalline cellulose, and granulated lactose; and further preferably one selected from mannitol, crystalline cellulose, a mixture of mannitol and crystalline cellulose, and a mixture of crystalline cellulose and granulated lactose.

[0180] In the present invention, the content of the excipient used is, for example, in the range of about 20.0 to about 90.0% by mass, preferably in the range of about 30.0 to about 80.0% by mass, and more preferably in the range of about 40.0 to about 75.0% by mass, based on the total mass of the oral solid preparation.

[0181] In the present invention, a "disintegrant" refers to an additive described in a reference book for preparation research such as "Dictionary of Pharmaceutical Excipients 2021, edited by the Japanese Pharmaceutical Excipients Association, February 2021", etc., and is an ingredient added to absorb moisture in the body and expand, etc., so as to disintegrate the preparation (tablet) and easily release the active ingredient. There is no particular limitation on the disintegrant. For example, examples thereof include: starches (corn starch, potato starch, starch, pregelatinized starch, partially pregelatinized starch), sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose, CMC), calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone (PVPP), methyl cellulose, microcrystalline cellulose (crystalline cellulose), low alkyl-substituted hydroxypropyl cellulose (L-HPC), sodium alginate, corn starch, sodium carboxymethyl starch, mixtures thereof, etc. Preferred disintegrants are at least one or more selected from sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose, CMC), croscarmellose sodium, crospovidone, sodium starch glycolate, calcium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), microcrystalline cellulose (crystalline cellulose), low alkyl-substituted hydroxypropyl cellulose (L-HPC), and sodium carboxymethyl starch; more preferably at least one or more selected from croscarmellose sodium and sodium starch glycolate; still more preferably croscarmellose sodium or sodium starch glycolate.

[0182] With respect to the total mass of the oral solid preparation, the content of the disintegrant used in the present invention is, for example, in the range of 0.0 to about 30.0% by mass, preferably in the range of about 1.0 to about 20.0% by mass, more preferably in the range of about 2.0 to about 8.0% by mass.

[0183] In the present invention, a "fluidizing agent" refers to an additive described in a reference book for preparation research such as "Dictionary of Pharmaceutical Excipients 2021, edited by the Japanese Pharmaceutical Excipients Association, February 2021", etc., and is an ingredient added to improve the fluidity of the powder before tableting. There is no particular limitation on the fluidizing agent. For example, examples thereof include: silica (light anhydrous silicic acid, silica gel), talc, hydrated silica, magnesium aluminum metasilicate aluminate, calcium hydrogen phosphate granules, mixtures thereof, etc. Preferred fluidizing agents are at least one or more selected from light anhydrous silicic acid, talc, and magnesium aluminum metasilicate aluminate; more preferably one selected from light anhydrous silicic acid, a mixture of light anhydrous silicic acid and talc, talc, and magnesium aluminum metasilicate aluminate.

[0184] With respect to the total mass of the oral solid preparation, the content of the fluidizing agent used in the present invention is, for example, in the range of 0.0 to about 15.0% by mass, preferably in the range of about 0.1 to about 10.0% by weight, more preferably in the range of about 0.5 to about 5.0% by mass.

[0185] In the present invention, the "lubricant" refers to an additive described in a reference book for formulation research such as "Pharmaceutical Additive Dictionary 2021, edited by the Japan Pharmaceutical Additive Association, February 2021", and is a component appropriately added in the process of making cores by tableting to eliminate insufficient hardness (core defect) of the cores caused by adhesion of the active ingredient to the compression device, compression force, etc. The lubricant is not particularly limited, and examples thereof include: magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate (alias: sodium stearyl fumarate), a mixture of magnesium stearate and sodium lauryl sulfate, talc, carboxymethyl cellulose, stearic acid, sodium lauryl sulfate, carnauba wax, sucrose fatty acid ester, polyethylene glycol, glycerin, monoglyceryl stearate, castor oil, hydrogenated castor oil, and mixtures thereof. Preferred lubricants are at least one or more selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, talc, stearic acid, sodium lauryl sulfate, and carnauba wax; more preferably at least one or more selected from magnesium stearate and sodium stearyl fumarate; and still more preferably magnesium stearate or sodium stearyl fumarate.

[0186] With respect to the total mass of the oral solid preparation, the content of the lubricant used in the present invention is, for example, in the range of 0.0 to about 10.0% by mass, preferably in the range of about 0.1 to about 5.0% by mass, and more preferably in the range of about 0.5 to about 3.0% by mass.

[0187] In the present invention, the "plasticizer" refers to an additive described in a reference book for formulation research such as "Pharmaceutical Additive Dictionary 2021, edited by the Japan Pharmaceutical Additive Association, February 2021", and is a component added to interact with the polymer used to make the polymer into a flexible structure so that the active ingredient can be constantly released from the preparation. The plasticizer is not particularly limited, and examples thereof include: triethyl citrate, tributyl citrate, Macrogol (polyethylene glycol), propylene glycol, sodium lauryl sulfate ethanol, triacetin, polysorbate 80, and mixtures thereof. Preferred plasticizers are at least one or more selected from triethyl citrate, Macrogol (polyethylene glycol), propylene glycol, triacetin, and polysorbate 80; and more preferably triethyl citrate.

[0188] With respect to the total mass of the oral solid preparation, the content of the plasticizer used in the present invention is, for example, in the range of 0.0 to about 10.0% by mass, preferably in the range of about 0.1 to about 5.0% by mass, and more preferably in the range of about 0.5 to about 3.0% by mass.

[0189] "Coating agent" refers to an additive described in reference books for preparation research such as "Dictionary of Pharmaceutical Excipients 2021, edited by the Pharmaceutical Excipients Society of Japan, February 2021", etc., and is a component that can be added to coat the surface of solid preparations (solid pharmaceuticals). There is no particular limitation on the coating agent, and a fat-soluble coating is preferred. For example, examples include: hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, aminoalkyl methacrylate copolymer, cellulose acetate phthalate, carboxymethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylcellulose, titanium oxide, talc, etc. or a mixture thereof.

[0190] In the present invention, examples of the coating agent that can be contained in the coating layer include: hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, carboxymethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, or a mixture thereof. The preferred coating agent contained in the coating layer is at least one or more selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose; more preferably, it is one selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose.

[0191] Examples of the second coating agent that can be contained in the coating layer include: titanium oxide, talc, crystalline cellulose, calcium carbonate, shellac, and a mixture thereof. The preferred second coating agent is at least one or more selected from titanium oxide, talc, crystalline cellulose, calcium carbonate, and shellac; more preferably, it is titanium oxide and / or talc.

[0192] In the present invention, the content of the coating agent contained in the coating layer is, for example, in the range of about 1.0 to about 25.0% by mass, preferably in the range of about 2.0 to about 20.0% by mass, and more preferably in the range of about 3.5 to about 15.0% by mass.

[0193] With respect to the total mass of the oral solid preparation, the content of the second coating agent used in the present invention is, for example, in the range of 0.0 to about 25.0% by mass, preferably in the range of about 1.0 to about 20.0% by mass.

[0194] In the present invention, an oral solid preparation prepared by using a coating agent contained in a coating layer selected from hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose is a preparation that is substantially insoluble in the acidic region but at least partially soluble in the weakly acidic to alkaline region. In the present invention, unless otherwise specified, the acidic region means a pH of about 0.5 to about 4.5, preferably about 1.0 to about 2.0, and unless otherwise specified, the weakly acidic to alkaline region means a pH of about 5.0 to 9.0, and may preferably be about 5.0 to about 6.5 or about 5.0 to about 7.0.

[0195] In the present invention, the pH of a solution in which the coating layer of an oral solid preparation starts to dissolve and the active ingredient in the preparation dissolves is also referred to as the "dissolution pH". For example, regarding the dissolution pH, in the case of mimicking the pH of intestinal fluid, for example, a range of pH = about 4.0 to about 8.0 can be cited.

[0196] In the present invention, the dissolution pH of an oral solid preparation is, for example, in the range of pH = about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, about 5.0 to about 5.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.0 to about 7.0, about 6.0 to about 6.5, about 6.5 to about 7.0. As a method of setting the dissolution pH to a range such as about 5.0 to about 7.0, for example, using a commercially available coating agent can be cited. For example, by using the coating agents described in Table 1 alone or in combination of multiple kinds for the coating agent contained in the coating layer, an oral solid preparation capable of controlling the dissolution pH can be prepared.

[0197] [Table 1]

[0198]

[0199] In addition, multiple coating agents can also be combined to adjust the dissolution pH. It should be noted that the method of adjusting the dissolution pH is not limited to these.

[0200] The methacrylic acid copolymer includes methacrylic acid copolymer LD (for example, EUDRAGIT L30D-55 (molecular weight: ~320,000 g / mol), etc.), methacrylic acid copolymer L (for example, EUDRAGIT L100 (molecular weight: ~125,000 g / mol), etc.), methacrylic acid copolymer S (for example, EUDRAGIT S100 (molecular weight: ~125,000 g / mol), etc.), etc., and also includes dry methacrylic acid copolymer LD obtained by drying methacrylic acid copolymer LD (for example, EUDRAGIT L100-55 (molecular weight: ~320,000 g / mol), etc.).

[0201] Here, the methacrylic acid copolymer LD is a copolymer of methacrylic acid and ethyl acrylate (ratio 1:1) (the following structural formula):

[0202]

[0203] [In the formula, n1, x1, and y1 are arbitrary numbers determined according to the molecular weight]. Usually, the methacrylic acid copolymer LD has an emulsion form obtained by using methacrylic acid and ethyl acrylate in an aqueous solution of polysorbate 80 and sodium lauryl sulfate. It is usually dissolved in a solution with a pH of 5.5 or higher.

[0204] The methacrylic acid copolymer L is a copolymer of methacrylic acid and methyl methacrylate (ratio 1:1) (the following structural formula):

[0205]

[0206] [In the formula, n2, x2, and y2 are arbitrary numbers determined according to the molecular weight]. Usually, it has a powder form that is dissolved in a solution with a pH of 6.0 or higher.

[0207] The methacrylic acid copolymer S is a copolymer of methacrylic acid and methyl methacrylate (ratio 1:2) (the following structural formula):

[0208]

[0209] [In the formula, n3, x3, and y3 are arbitrary numbers determined according to the molecular weight]. Usually, it has a powder form that is dissolved in a solution with a pH of 7.0 or higher.

[0210] The amount of the coating agent used can also be appropriately adjusted. For example, the amounts of the coating agent (dry methacrylic acid copolymer LD) for the tablets (oral solid preparations) prepared in Examples 3-1 and 3-2 described below are 2 times and 3 times the amount of the coating agent used in Example 2-1, respectively. For example, the amount of the coating agent (methacrylic acid copolymer L) for the tablets (oral solid preparations) prepared in Example 5-2-2 described below is about 0.7 times the amount of the coating agent used in Example 5-2-1.

[0211] In the present invention, the dissolution rate of the active ingredient contained in the oral solid preparation can be measured by dissolution test methods such as the basket method and the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia.

[0212] In the present invention, the dissolution rate (dissolution percentage) of the active ingredient contained in the oral solid preparation in vitro can be measured, for example, according to the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia. This test method measures the time and proportion of the active ingredient dissolved in the test solution in vitro. Examples of the test solution for measurement include: Dissolution Test Solution 1 (a liquid with a pH of approximately 1.2 that mimics gastric juice prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL, also known as JP1 solution), or Dissolution Test Solution 2 (a liquid with a pH of approximately 6.8 that mimics intestinal fluid obtained by adding 1 volume of water to 1 volume of phosphate buffer solution with a pH of 6.8, also known as JP2 solution), etc., but it is not limited thereto. As the measurement method, for example, the basket method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the paddle method of this method, and other dissolution test methods can be cited.

[0213] In the present invention, when measuring the dissolution rate of the active ingredient contained in the oral solid preparation in vitro according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, using Dissolution Test Solution 1 of the Japanese Pharmacopoeia by the method described in the test examples below, the dissolution percentage of the active ingredient (compound (I)) after 1 hour can be cited as: for example, about 2.5% or less. When measured according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, using Dissolution Test Solution 1 of the Japanese Pharmacopoeia by the method described in the test examples below, after 1 hour from the start of the dissolution test, the dissolution percentage of the active ingredient (compound (I)) is preferably about 2.0% or less, more preferably about 1.0% or less, and further preferably about 0.5% or less.

[0214] In the present invention, when measuring the dissolution rate of the active ingredient contained in the oral solid preparation in vitro according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, using Dissolution Test Solution 2 of the Japanese Pharmacopoeia by the method described in the test examples below, after 1 hour from the start of the dissolution test, the dissolution percentage of the active ingredient (compound (I)) can be cited as: for example, about 10.0% or more, about 13.0% or more, about 15.0% or more, about 18.0% or more, about 20.0% or more, etc.

[0215] In the present invention, when measuring the dissolution rate of the active ingredient contained in the oral solid preparation in vitro according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, using Dissolution Test Solution 2 of the Japanese Pharmacopoeia by the method described in the test examples below, after 6 hours from the start of the dissolution test, the dissolution percentage of the active ingredient (compound (I)) can be, for example, about 10.0% or more, about 13.0% or more, or about 15.0% or more, etc.

[0216] In the present invention, "the first dissolution test solution of the Japanese Pharmacopoeia" is sometimes referred to as "the first dissolution test solution". Additionally, "the second dissolution test solution of the Japanese Pharmacopoeia" is sometimes referred to as "the second dissolution test solution".

[0217] When applying the in vitro pH to the in vivo (inside the body) situation, it is known that the pH in the digestive tract is in the range of about 1 to about 2 in the stomach, in the range of about 4 to about 7 in the small intestine, and in the range of about 7 to about 8 in the large intestine, and the pH increases as it enters the lower digestive tract. Therefore, when performing a dissolution test with the first dissolution test solution according to the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, it is equivalent to measuring the dissolution rate of the active ingredient contained in the oral solid preparation in the test solution simulating the fasting stomach. When performing a dissolution test with the second dissolution test solution according to the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, it is equivalent to measuring the dissolution rate of the active ingredient contained in the oral solid preparation in the test solution simulating the intestine.

[0218] In the present invention, "release property" refers to the release amount, release rate, etc. of the active ingredient contained in the oral solid preparation. The release rate refers to the amount of the active ingredient released from the preparation within a certain period of time.

[0219] In the present invention, "rapid intestinal release property" means that when performing a dissolution test on the dissolution rate of an oral solid preparation with the second dissolution test solution according to the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the active ingredient (compound (I)) contained in the preparation shows a dissolution rate of about 13.0% or more relative to the total mass of the active ingredient (compound (I)) originally contained in the preparation 1 hour after the start of the dissolution test.

[0220] In the present invention, "slow release or insoluble in the stomach" means that when performing a dissolution test with the first dissolution test solution according to the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, the active ingredient (compound (I)) contained in the preparation shows a dissolution rate of about 2.5% or less relative to the total mass of the active ingredient (compound (I)) originally contained in the preparation 1 hour after the start of the dissolution test. In particular, when the dissolution rate is about 0.5% or less, it becomes insoluble.

[0221] In the present invention, when it is described as "about", values within ±20% of this value, preferably within ±10% of this value, may be included.

[0222] In the present invention, examples of diseases related to TrkA include: pain, cancer, inflammation / inflammatory diseases, allergic diseases, skin diseases, pruritus, neurodegenerative diseases, infectious diseases, Sjögren's syndrome, endometriosis, kidney diseases, osteoporosis, and other diseases.

[0223] More specifically, examples include: osteoarthritis pain, arthralgia, neuropathic pain, postoperative pain, low back pain, diabetic neuropathy, intraoperative pain, cancer pain, chemotherapy-induced pain, headache (including cluster headache, tension headache, migraine pain), trigeminal neuralgia, herpes zoster pain, postherpetic neuralgia, carpal tunnel syndrome, inflammatory pain, pain caused by rheumatoid arthritis, colitis, pain of interstitial cystitis, visceral pain, pain caused by kidney stones, pain caused by gallstones, sore throat, fibromyalgia, chronic pain syndrome, thalamic pain syndrome, pain caused by stroke, phantom limb pain, sunburn, radiculopathy, complex regional pain syndrome, HIV-related sensory neuropathy, central nervous disorder pain syndrome, pain in multiple sclerosis, pain in Parkinson's disease, pain in spinal cord injury, dysmenorrhea, toothache, pain caused by bone metastasis, pain caused by endometriosis, pain caused by uterine fibroids, nociceptive pain, hyperalgesia, temporomandibular joint pain, neuroblastoma, ovarian cancer, endometrial cancer, glioblastoma multiforme, cervical cancer, pancreatic cancer, colon cancer, rectal cancer, prostate cancer, melanoma, myeloma, thyroid cancer, lung cancer (small cell lung cancer, non-small cell lung cancer), brain tumor, esophageal cancer, kidney cancer, osteoma, blood cancer (chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML)), squamous cell carcinoma, glioma, gastrointestinal cancer, ovarian cancer, liver cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, head and neck cancer, germ cell tumor, pediatric sarcoma, natural killer cell tumor of the paranasal sinuses, multiple myeloma, interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, inflammatory cystitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, joint swelling, asthma, atopic dermatitis, psoriasis, psoriatic arthritis, rhinitis, generalized pruritus, localized pruritus, universal pruritus, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, Sjogren's syndrome, endometriosis, diabetic nephropathy, renal fibrosis, chronic kidney disease, and osteoporosis and other diseases.

[0224] The oral solid preparation of the present invention can be used for subjects in need of preventing and / or treating diseases related to TrkA. The subjects are human or non-human mammals (dogs, cats, rats, mice, monkeys, cows, horses, pigs, sheep, etc.).

[0225] In the present invention, the content of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea (Compound (I)), or a pharmaceutically acceptable salt thereof, or a solvate thereof, is not particularly limited as long as it is an amount effective for the prevention and / or treatment of diseases related to TrkA. For example, in the case of containing Compound (I), examples include: 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 100 mg, 150 mg, etc., and amounts within the ranges with these as the upper or lower limits. In addition, in the case of containing a pharmaceutically acceptable salt of Compound (I), a solvate of Compound (I), or a solvate of a pharmaceutically acceptable salt of Compound (I), their respective contents are, for example, equivalent amounts of the salt, solvate, or solvate of the salt corresponding to the amount of the said Compound (I).

[0226] In the present invention, for example, when an oral solid preparation containing 50 mg or 150 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an equivalent amount, or a solvate thereof in an equivalent amount is administered to a subject, the concentration of Compound (I) in the plasma of the subject is about 90 nM or more, about 95 nM or more, about 100 nM or more, about 105 nM or more, or about 110 nM or more 12 hours or 24 hours after the first administration.

[0227] The oral solid preparation of the present invention can also be a preparation for preventing cracks in the preparation. Generally, tablets or cores are manufactured by compression molding of pharmaceutical powders, but depending on the manufacturing conditions, the types and contents of additives contained, etc., cracks may sometimes occur inside the tablets or cores during molding (this phenomenon is sometimes also referred to as cracking, lamination, capping, etc.). For example, in the following examples, the preparation of the formulation of Example 1-2 containing 50 mg of Compound (I) does not produce cracks during its manufacturing process, but in the case of preparing a preparation containing 150 mg of Compound (I) using this formulation composition (Reference Example 1), cracks were confirmed at the core manufacturing stage. Considering insufficient adhesion of the pharmaceutical powder and poor demolding property from the mortar as the causes of crack generation, in the formulation of Example 2-1, the excipient was changed to a mixture of mannitol and crystalline cellulose to improve the adhesion of the pharmaceutical powder, and the fluidizing agent was changed to a mixture of light anhydrous silicic acid and talc to improve the demolding property, so that even when the content of Compound (I) in the preparation is up to 150 mg, tablets or cores with a hardness such that no cracks are confirmed can be molded.

[0228] Hereinafter, the manufacturing method of the oral solid preparation of the present invention will be described, which also includes known methods including, for example, the following steps: pulverization, mixing, granulation, drying, sieving, sizing, molding (tabletting), coating, crystallization, etc.

[0229] In the pulverization step, as long as it is a method that can generally pulverize drugs and appropriate additives in pharmacy, there are no particular restrictions on the device and means. As pulverization devices, for example, impact pulverizers, hammer mills, ball mills, jet pulverizers, colloid mills, etc. can be cited. The pulverization conditions can be appropriately selected and there are no particular restrictions. For the mixing step of each component consecutive to pulverization, as long as it is a method that can generally mix each component uniformly in pharmacy, there are no particular restrictions on the device and means.

[0230] As the manufacturing method of the oral solid preparation of the present invention, granulation can also be used. In the granulation step, as long as it is a method that can generally granulate drugs and appropriate pharmaceutical additives in pharmacy, there are no particular restrictions on the device and means. As granulation methods and devices used in wet granulation using a binding liquid obtained by dispersing or dissolving in water or the like a solvent such as water or an appropriate amount of binder, for example, high-speed stirring granulation method, crushing (pulverization) granulation method, fluidized bed granulation method, extrusion granulation method, rolling granulation method, spray granulation method, or devices used by these methods, etc. can be cited, but it is not limited thereto. As a method that does not use water in granulation, a wet granulation method using a non-aqueous solvent or a dry granulation method without using a solvent can also be selected.

[0231] In the drying step, as long as it is a method that can generally perform drying in pharmacy, there are no particular restrictions on the device and means. As devices, for example, ventilation dryers, vacuum dryers, vacuum drying machines, fluidized bed granulation dryers, etc. can be cited, but it is not limited thereto.

[0232] In the sieving and sizing steps, as long as it is a method that can generally perform sieving or sizing in pharmacy, there are no particular restrictions on the device and means. As devices, for example, sieves, colloid mills, power mills, etc. can be cited, but it is not limited thereto.

[0233] In the compression molding step (tabletting step), as long as it is a method for molding the preparation or core of the present invention, there are no particular restrictions on the device and means. For example, methods can be cited such as directly compressing and molding a pharmaceutical composition after mixing drugs and appropriate pharmaceutical additives without performing granulation and drying steps; manufacturing a pharmaceutical composition by compressing and molding after granulation and drying; manufacturing a pharmaceutical composition (for example, a plain tablet or a core) by mixing a lubricant after granulation and then compressing and molding, etc., but it is not limited thereto.

[0234] As tabletting devices, for example, rotary tablet presses, single punch tablet presses, hydraulic presses, etc. can be cited.

[0235] As the tableting conditions such as tableting pressure, there are no particular limitations as long as the pressure can form the core and the core will not break during the manufacturing process. For example, it can be cited that when compression molding is carried out using a bench-top rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.), the tableting pressure (main pressure) is 0.5 to 20.0 kN, preferably 1.0 to 10.0 kN, and more preferably 3.0 to 8.0 kN. It should be noted that the upper and lower limits described above can be arbitrarily combined as needed.

[0236] In addition, as the hardness of the core, there are no particular limitations as long as the hardness is such that the core will not break during the coating process. For example, it can be cited that when measuring the hardness of the tableted product using a bench-top rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.), the hardness is 30 N or more, preferably 40 N or more, and more preferably 50 N or more.

[0237] As the coating process, the surface of the core can be coated after appropriate tableting.

[0238] As the method, there are no particular limitations as long as it is a method commonly used in pharmacy for coating. For example, it can be cited that pan coating, dip coating, etc.

[0239] One or more coating agents can be combined and appropriately added in an appropriate amount. The coating rate has no particular limitations as long as it is the ratio of forming a film on the core. For example, it is 1% to 20% by mass, preferably 2% to 18% by mass, and more preferably 3% to 16% by mass, etc., relative to the total mass of the tablets.

[0240] Drying can be carried out after coating. As the method, there are no particular limitations as long as it is a method commonly used in pharmacy for drying.

[0241] Examples

[0242] Hereinafter, examples, comparative examples, reference examples, and test examples are listed to explain the present invention in more detail, but the present invention is not limited to these examples for interpretation.

[0243] The 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea described in this example and the like used a substance manufactured by the method described in International Publication No. 2018 / 199166 pamphlet (Patent Document 1) or International Publication No. 2019 / 189717 pamphlet or a method based on this method. Here, as a part of this specification, the contents described in International Publication No. 2018 / 199166 pamphlet and International Publication No. 2019 / 189717 pamphlet are incorporated by reference.

[0244] In this embodiment and the like, the additives described were respectively the additives described in Table 2.

[0245] [Table 2]

[0246]

[0247] <Manufacture of the preparation (tablet) of Comparative Example 1>

[0248] According to the formulation described in Table 3 below, 4.00 g of light anhydrous silicic acid was added to 22.18 g of 1 - ((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 163.82 g of mannitol and 8.00 g of croscarmellose sodium were added, and after manual mixing using a polyethylene bag, sieving was carried out to break up agglomerates, and then 2.00 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tabletted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain the preparation (tablet) of Comparative Example 1.

[0249] <Manufacture of the preparation (tablet) of Example 1-1>

[0250] According to the formulation described in Table 3 below, a solid preparation was prepared using 220 g of the preparation of Comparative Example 1 as the core. Specifically, the above core was placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, and talc in absolute ethanol and purified water to obtain the preparation (tablet) of Example 1-1.

[0251] <Manufacture of the preparation (tablet) of Example 1-2>

[0252] According to the formulation described in Table 3 below, 22.0 g of light anhydrous silicic acid was added to 260.6 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. 762.5 g of mannitol and 44.00 g of croscarmellose sodium were added to the obtained mixture, and after manual mixing using a polyethylene bag, sieving was carried out to break up agglomerates, and then 2.00 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tabletted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores. 219.8 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, and talc in absolute ethanol and purified water to obtain the preparation (tablet) of Example 1-2.

[0253] <Manufacture of the preparation of Reference Example 1>

[0254] According to the formulation described in Table 3 below, the preparation of Reference Example 1 was obtained according to the method of Example 1-2.

[0255] [Table 3]

[0256]

[0257] (The unit of the value is mg)

[0258] <Test Example 1> Dissolution test (1)

[0259] For each of the preparations produced in Comparative Example 1, Example 1-1, and Example 1-2, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 1 (JP1 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. For Comparative Example 1, after 5, 10, 15, 30, and 60 minutes from the start of the test, for Example 1-1, after 30 and 60 minutes from the start of the test, and for Example 1-2, after 5, 10, 15, 30, 60, and 120 minutes, the absorbance of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using ultraviolet-visible spectrophotometry (UV method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained absorbance, and then the dissolution rate was calculated (the start of the test was set as the dissolution rate of 0%. Hereinafter, the results of the dissolution rate are the same). The UV method was measured using an ultraviolet-visible spectrophotometer (V-660, manufactured by JASCO Corporation) (wavelength: 210 nm). The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 4 and Figure 1 in.

[0260] [Table 4]

[0261]

[0262] <Test Example 2> Dissolution Test (2)

[0263] For each of the preparations produced in Comparative Example 1, Example 1-1, and Example 1-2, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 2 (JP2 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. For Comparative Example 1 and Example 1-1, after 5, 10, 15, 30, 60, and 120 minutes from the start of the test, and for Example 1-2, after 5, 10, 15, 30, 60, 120, 180, 240, 300, and 360 minutes, the absorbance of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using ultraviolet-visible spectrophotometry (UV method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained absorbance, and thus the dissolution rate was calculated. The UV method was carried out using an ultraviolet-visible spectrophotometer (V-660, manufactured by JASCO Corporation) for measurement (wavelength: 210 nm). The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 5 and Figure 2 in.

[0264] [Table 5]

[0265]

[0266] <Manufacture of the preparation (tablet) of Example 2-1>

[0267] According to the formulation described in Table 6 below, 22.0 g of light anhydrous silicic acid was added to 255.00 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 707.51 g of mannitol, 5.50 g of talc, 44.00 g of croscarmellose sodium, and 55.00 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 11.00 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tabletted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores. 500.10 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 2-1.

[0268] <Manufacture of the preparation (tablet) of Example 2-2>

[0269] According to the formulation described in Table 6 below, 66.00 g of light anhydrous silicic acid was added to 767.50 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 2120.00 g of mannitol, 16.50 g of talc, 132.00 g of croscarmellose sodium, and 165.00 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 33.00 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tabletted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores. 600.56 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 2-2.

[0270] <Manufacture of the cores of Examples 2-3, 2-4, and 2-5>

[0271] According to the formulation described in Table 6 below, 66.0 g of light anhydrous silicic acid was added to 779.8 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 2107.7 g of mannitol, 16.5 g of talc, 132.0 g of croscarmellose sodium, and 165.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 33.0 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores.

[0272] <Manufacture of the preparations (tablets) of Examples 2-3, 2-4 and 2-5>

[0273] 600 g of the cores obtained in <Manufacture of the tablet cores of Examples 2-3, 2-4 and 2-5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex). For Example 2-3, film coating was carried out using a liquid obtained by dispersing or dissolving hypromellose phthalate, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water. For Examples 2-4 and 2-5, film coating was carried out using a liquid obtained by dispersing or dissolving hypromellose acetate succinate, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparations (tablets) of Examples 2-3, 2-4 and 2-5.

[0274] [Table 6]

[0275]

[0276] (The unit of the values is mg)

[0277] <Test Example 3> Dissolution test (3)

[0278] For each of the preparations (tablets) produced in Examples 2-1, 2-3, 2-4, and 2-5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 1 (JP1 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. After 5, 10, 15, 30, 60, and 120 minutes from the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 7 and Figure 3 in.

[0279] [Table 7]

[0280]

[0281] <Test Example 4> Dissolution Test (4)

[0282] For each of the preparations (tablets) manufactured in Examples 2-1, 2-3, 2-4, and 2-5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method in the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 2 (JP2 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 8 and Figure 4 in.

[0283] [Table 8]

[0284]

[0285] <Manufacture of the preparations (tablets) of Examples 3-1 and 3-2>

[0286] According to the formulation described in Table 9 below, 17.6 g of light anhydrous silicic acid was added to 207.9 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 562.1 g of mannitol, 4.4 g of talc, 35.2 g of croscarmellose sodium, and 44.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 8.8 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLANOVA, manufactured by RIVA S.A.) to obtain cores. 600.1 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was performed using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparations (tablets) of Examples 3-1 and 3-2.

[0287] [Table 9]

[0288] Component Example 3-1 Example 3-2 Compound (I) 50.0 50.0 Mannitol (Parteck M100) 142.5 142.5 Crystalline cellulose (Ceolus KG-1000) 11 11 Light anhydrous silicic acid 4.4 4.4 Talc 1.1 1.1 Croscarmellose sodium (Ac-Di-Sol) 8.8 8.8 Magnesium stearate 2.2 2.2 Core subtotal 220 220 Dry methacrylic acid copolymer LD (EUDRAGIT L100-55) 15.8 23.7 Triethyl citrate 3.2 4.8 Talc 3.2 4.8 Titanium oxide 3.8 5.7 Absolute ethanol 0 0 Purified water 0 0 Coating subtotal 26 39 Total 246 259

[0289] (The unit of the value is mg)

[0290] <Test Example 5>Dissolution Test (5)

[0291] For each of the preparations (tablets) manufactured in Examples 3-1 and 3-2, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 1 (JP1 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60, and 120 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 10 and Figure 5 in.

[0292] [Table 10]

[0293]

[0294] <Test Example 6> Dissolution Test (6)

[0295] For each of the preparations (tablets) produced in Examples 3-1 and 3-2, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 2 (JP2 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated based on the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 11 and Figure 6 in.

[0296] [Table 11]

[0297]

[0298] <Manufacture of the preparation (tablet) of Example 4-1>

[0299] According to the formulation described in Table 12 below, 4.4 g of light anhydrous silicic acid was added to 51.1 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 141.4 g of lactose hydrate, 1.10 g of talc, 8.8 g of croscarmellose sodium, and 11.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 2.2 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLANOVA, manufactured by RIVA S.A.) to obtain cores. 130.0 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 4-1.

[0300] <Manufacture of the Preparation (Tablet) of Example 4-2>

[0301] According to the formulation described in Table 12 below, 4.4 g of light anhydrous silicic acid was added to 51.1 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 141.4 g of crystalline cellulose, 1.10 g of talc, 8.8 g of croscarmellose sodium, and 11.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 2.2 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLANOVA, manufactured by RIVA S.A.) to obtain cores. 150.1 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 4-2.

[0302] <Manufacture of the Preparation (Tablet) of Example 4-3>

[0303] According to the formulation described in Table 12 below, 4.4 g of magnesium aluminum metasilicate was added to 51.1 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 141.4 g of mannitol, 1.10 g of talc, 8.8 g of croscarmellose sodium, and 11.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 2.2 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLANOVA, manufactured by RIVA S.A.) to obtain cores. 140.1 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 4-3.

[0304] <Manufacture of the Preparation (Tablet) of Example 4-4>

[0305] According to the formulation described in Table 12 below, 4.4 g of light anhydrous silicic acid was added to 51.1 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 141.4 g of mannitol, 1.10 g of talc, 8.8 g of sodium starch glycolate, and 11.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 2.2 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores. 150.0 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 4-4.

[0306] <Manufacture of the Preparation (Tablet) of Example 4-5>

[0307] According to the formulation described in Table 12 below, 4.4 g of light anhydrous silicic acid was added to 51.1 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 139.2 g of mannitol, 1.10 g of talc, 8.8 g of croscarmellose sodium, and 11.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 4.4 g of sodium stearyl fumarate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tabletted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores. 150.1 g of the obtained cores were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was performed using a liquid obtained by dispersing or dissolving EUDRAGIT L100-55, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 4-5.

[0308] [Table 12]

[0309]

[0310] (The unit of the value is mg)

[0311] <Test Example 7> Dissolution Test (7)

[0312] For each of the preparations (tablets) manufactured in Examples 4-1, 4-2, 4-3, 4-4, and 4-5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 1 (JP1 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. After 5, 10, 15, 30, 60, and 120 minutes from the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 13 and Figure 7 in.

[0313] [Table 13]

[0314]

[0315] <Test Example 8> Dissolution Test (8)

[0316] For each of the preparations (tablets) manufactured in Examples 4-1, 4-2, 4-3, 4-4, and 4-5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 2 (JP2 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated based on the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 14 and Figure 8 in.

[0317] [Table 14]

[0318]

[0319] Pharmacokinetics (PK) test:

[0320] Hereinafter, the pharmacokinetics (PK) test of the tablets (oral solid preparations) manufactured in Example 1-1, Example 1-2, Example 2-1, Example 2-2, Example 2-3, Example 2-4, Example 2-5, and Comparative Example 1 will be described.

[0321] Figures 9 to 16 The vertical axis of the curve graph represents the plasma concentration (blood concentration) (nM) of compound (I), and the horizontal axis represents the time (hours) after administration of compound (I).

[0322] (Comparative Example PK1)

[0323] (1) Administration and blood sampling of the test preparation

[0324] An oral solid preparation (Compound (I): containing 23.4 mg) prepared with the formulation of Comparative Example 1 was orally administered once (n = 3: 11.80 kg (5 years old), 11.00 kg (2 years old), 13.25 kg (2 years old)) to beagle dogs (male, 2 - 5 years old, 11.00 - 13.25 kg) at a dose of 23.4 mg / kg body weight in a non - fasting state with water (30 mL). After administration, blood (0.5 mL) was collected from the radial vein on the anterior wrist of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 22, and 24 hours. The collected blood was centrifuged (micro high - speed cooling centrifuge MX - 201, manufactured by TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C), and plasma was collected.

[0325] (2) Determination of the concentration of Compound (I) in plasma

[0326] To the plasma (0.02 mL) collected in (1) above, an internal standard solution (0.18 mL) in which buspirone (manufactured by Sigma - Aldrich) was dissolved in methanol at 50 nmol / L was added and stirred well, and then left standing on ice for 30 minutes. The mixed solution was centrifuged at 540 G for 5 minutes (Hitachi multi - tube rack cooling centrifuge CF - 9RX, manufactured by Hitachi Koki Co., Ltd.), and the supernatant was aliquoted. Using LC - MS / MS (Triple Quad 4500, manufactured by AB Sciex), the concentration of Compound (I) in plasma was determined. Using a standard plasma sample prepared by step - wise dilution of a 1 mg / mL solution of Compound (I) in plasma, a standard curve was made, and from this, the plasma concentration of Compound (I) was calculated, obtaining Figure 9 the plasma concentration change data shown.

[0327] According to Figure 9 , when an oral solid preparation prepared with the formulation of (Comparative Example PK1) was orally administered, due to good absorbability, the maximum plasma concentration (662 nM) was reached 2 hours after administration and then rapidly declined from the plasma. Most of Compound (I) disappeared from the plasma 24 hours after administration (plasma concentration 12 hours after administration: 91.6 nM, plasma concentration 24 hours after administration: 18.6 nM). In addition, it is considered that the maximum plasma concentration of this preparation increases in a dose - dependent manner, and it is expected to show a maximum plasma concentration of about 1410 nM at a dose of 50 mg / kg body weight and about 4240 nM at a dose of 150 mg / kg body weight.

[0328] (Example PK1 - 1)

[0329] (1) Administration of the test preparation and blood collection

[0330] An oral solid preparation (Compound (I): containing 23.4 mg) prepared with the formulation of Example 1-1 was orally administered as a single dose (n = 3: 12.50 kg (5 years old), 12.00 kg (2 years old), 10.95 kg (2 years old)) to beagle dogs (male, 2-5 years old, 10.95-12.50 kg) at a dose of 23.4 mg / kg of body weight with water (30 mL) in the non-fasted state. After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 22, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C) to collect plasma.

[0331] (2) Determination of the concentration of Compound (I) in plasma

[0332] The same operation as in the concentration determination of (2) in Comparative Example PK1 was carried out to calculate the plasma concentration of Compound (I), and the plasma concentration change data shown below were obtained. Figure 10 The plasma concentration change data shown

[0333] According to Figure 10 , when an oral solid preparation prepared with the formulation of (Example 1-1) was orally administered, the highest plasma concentration (374 nM) was reached 4 hours after administration, and the plasma concentration of Compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 114 nM, plasma concentration 24 hours after administration: 116 nM).

[0334] (Example PK1-2)

[0335] (1) Administration of the test preparation and blood collection

[0336] An oral solid preparation (Compound (I): containing 50 mg) prepared with the formulation of Example 1-2 was orally administered as a single dose (n = 6: 12.3 kg (5 years old), 10.1 kg (2 years old), 12.8 kg (2 years old), 12.8 kg (5 years old), 12.2 kg (2 years old), 10.6 kg (2 years old)) to beagle dogs (male, 2-5 years old, 10.1-12.8 kg) at a dose of 50 mg / kg of body weight with water (30 mL) in the non-fasted state. After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C) to collect plasma.

[0337] (2) Determination of the concentration of compound (I) in plasma

[0338] The same operation as the concentration determination in (2) of Comparative Example PK1 was carried out to calculate the plasma concentration of compound (I), and the plasma concentration change data shown in Figure 11 were obtained.

[0339] According to Figure 11 , when an oral solid preparation manufactured with the formulation of (Example 1-2) was orally administered, the highest plasma concentration (634 nM) was reached 2 hours after administration, and the plasma concentration of compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 202 nM, plasma concentration 24 hours after administration: 581 nM).

[0340] (Example PK2-1)

[0341] (1) Administration of the test preparation and blood sampling

[0342] An oral solid preparation (compound (I): containing 50 mg) manufactured with the formulation of Example 2-1 was orally administered once to beagle dogs (male, 4 years old, 12.3 - 13.8 kg) at a dose of 50 mg / kg body weight with water (30 mL) in a non-fasting state (n = 4: 12.8 kg (4 years old), 13.8 kg (4 years old), 13.3 kg (4 years old), 12.3 kg (4 years old)). After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C), and plasma was collected.

[0343] (2) Determination of the concentration of compound (I) in plasma

[0344] The same operation as the concentration determination in (2) of Comparative Example PK1 was carried out to calculate the plasma concentration of compound (I), and the plasma concentration change data shown in Figure 12 were obtained.

[0345] According to Figure 12 , when an oral solid preparation manufactured with the formulation of (Example 2-1) was orally administered, the highest plasma concentration (440 nM) was reached 2 hours after administration, and the plasma concentration of compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 195 nM, plasma concentration 24 hours after administration: 46.3 nM).

[0346] (Example PK2-2)

[0347] (1) Administration and blood sampling of the test preparation

[0348] An oral solid preparation (Compound (I): containing 150 mg) prepared with the formulation of Example 2-2 was orally administered once to beagle dogs (male, 4 years old, 12.4 - 14.0 kg) at a dose of 150 mg / kg body weight in a non-fasted state with water (30 mL) (n = 4: 12.5 kg (4 years old), 14.0 kg (4 years old), 13.4 kg (4 years old), 12.4 kg (4 years old)). After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4 °C), and plasma was collected.

[0349] (2) Determination of the concentration of Compound (I) in plasma

[0350] The same operation as in the concentration determination of (2) of Comparative Example PK1 was carried out to calculate the plasma concentration of Compound (I), and the plasma concentration change data shown in Figure 13 were obtained.

[0351] According to Figure 13 , when the oral solid preparation prepared with the formulation of (Example 2-2) was orally administered, the highest plasma concentration (735 nM) was reached 4 hours after administration, and the plasma concentration of Compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 258 nM, plasma concentration 24 hours after administration: 689 nM). The content of Compound (I) in this preparation was 6.1 times more than that of the oral solid preparation prepared with the formulation of Comparative Example 1, but the highest plasma concentration after administration was approximately 1.1 times. For the oral solid preparation prepared with the formulation of Example 2-2, it showed an inhibition of the sharp rise in plasma concentration.

[0352] (Example PK2-3)

[0353] (1) Administration and blood sampling of the test preparation

[0354] The oral solid preparation (Compound (I): containing 50 mg) prepared with the formulation of Example 2-3 was orally administered once to beagle dogs (male, 4 years old, 12.3 - 13.4 kg) at a dose of 50 mg / kg body weight with water (30 mL) in the non-fasted state (n = 4: 12.3 kg (4 years old), 13.4 kg (4 years old), 12.6 kg (4 years old), 12.8 kg (4 years old)). After administration, blood samples (0.5 mL) were collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4 °C) to collect plasma.

[0355] (2) Determination of the concentration of Compound (I) in plasma

[0356] The same operation as in the concentration determination of (2) in Comparative Example PK1 was carried out to calculate the plasma concentration of Compound (I), and the Figure 14 plasma concentration change data shown were obtained.

[0357] According to Figure 14 , when the oral solid preparation prepared with the formulation of (Example 2-3) was orally administered, the highest plasma concentration (664 nM) was reached 2 hours after administration, and the plasma concentration of Compound (I) also maintained a high level after 12 hours of administration (plasma concentration 12 hours after administration: 184 nM, plasma concentration 24 hours after administration: 552 nM).

[0358] (Example PK2-4)

[0359] (1) Administration of the test preparation and blood collection

[0360] The oral solid preparation (Compound (I): containing 50 mg) prepared with the formulation of Example 2-4 was orally administered once to beagle dogs (male, 5 years old, 12.15 - 13.00 kg) at a dose of 50 mg / kg body weight with water (30 mL) in the non-fasted state (n = 4: 12.15 kg (5 years old), 13.00 kg (5 years old), 12.40 kg (5 years old), 12.95 kg (5 years old)). After administration, blood samples (0.5 mL) were collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4 °C) to collect plasma.

[0361] (2) Determination of the concentration of Compound (I) in plasma

[0362] The same operation as the concentration measurement of (2) in Comparative Example PK1 was carried out to calculate the plasma concentration of Compound (I), and Figure 15 the plasma concentration change data shown below were obtained.

[0363] According to Figure 15 , when an oral solid preparation prepared with the formulation of (Examples 2-4) was orally administered, the maximum plasma concentration (577 nM) was reached 2 hours after administration, and the plasma concentration of Compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 189 nM, plasma concentration 24 hours after administration: 41.7 nM).

[0364] (Example PK2-5)

[0365] (1) Administration of the test preparation and blood sampling

[0366] An oral solid preparation (Compound (I): containing 50 mg) prepared with the formulation of Example 2-5 was orally administered once (n = 4: 11.90 kg (4 years old), 13.10 kg (4 years old), 12.20 kg (4 years old), 12.80 kg (4 years old)) to beagle dogs (male, 4 years old, 11.90 - 13.10 kg) at a dose of 50 mg / kg body weight with water (30 mL) in a non-fasting state. After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed cooling centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4 °C), and plasma was collected.

[0367] (2) Determination of the concentration of Compound (I) in plasma

[0368] The same operation as the concentration measurement of (2) in Comparative Example PK1 was carried out to calculate the plasma concentration of Compound (I), and Figure 16 the plasma concentration change data shown below were obtained.

[0369] According to Figure 16 , when an oral solid preparation prepared with the formulation of (Example 2-5) was orally administered, the maximum plasma concentration (397 nM) was reached 4 hours after administration, and the plasma concentration of Compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 135 nM, plasma concentration 24 hours after administration: 38.2 nM).

[0370] <Manufacture of the cores of Examples 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5>

[0371] According to the formulation described in Table 15 below, 44.0 g of light anhydrous silicic acid was added to 517.0 g of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, and manual mixing was carried out using a polyethylene bag to obtain a mixture. To the obtained mixture, 1408.0 g of mannitol, 11.0 g of talc, 88.0 g of croscarmellose sodium, and 110.0 g of crystalline cellulose were added. After manual mixing using a polyethylene bag, sieving was performed to break up agglomerates, and then 22.0 g of magnesium stearate was added for manual mixing to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a tabletop rotary tablet press (PICCOLA NOVA, manufactured by RIVA S.A.) to obtain cores.

[0372] <Manufacture of the preparation (tablet) of Example 5-1>

[0373] 200 g of the cores obtained in <Manufacture of the cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving carboxymethylethyl cellulose, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 5-1.

[0374] <Manufacture of the preparation (tablet) of Example 5-2-1>

[0375] 200 g of the cores obtained in <Manufacture of the cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving methacrylic acid copolymer L, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 5-2-1.

[0376] <Manufacture of the preparation (tablet) of Example 5-2-2>

[0377] 200 g of the cores obtained in <Manufacture of the cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film coating was carried out using a liquid obtained by dispersing or dissolving methacrylic acid copolymer L, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 5-2-2.

[0378] <Manufacture of the preparation (tablet) of Example 5-3>

[0379] 200 g of the cores obtained in <Manufacture of the Cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film-coated with a liquid obtained by dispersing or dissolving cellulose acetate phthalate, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Example 5-3.

[0380] <Manufacture of the Preparation (Tablet) of Example 5-4>

[0381] 200 g of the cores obtained in <Manufacture of the Cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film-coated with a liquid obtained by dispersing or dissolving methacrylic acid copolymer S, triethyl citrate, talc, and titanium oxide in absolute ethanol and acetone to obtain the preparation (tablet) of Example 5-4.

[0382] <Manufacture of the Preparation (Tablet) of Reference Example 5>

[0383] 200 g of the cores obtained in <Manufacture of the Cores of Example 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5> above were placed in a film coating machine (PRC-GTX-mini, manufactured by Powrex), and film-coated with a liquid obtained by dispersing or dissolving aminoalkyl methacrylate copolymer E, triethyl citrate, talc, and titanium oxide in absolute ethanol and purified water to obtain the preparation (tablet) of Reference Example 5.

[0384] [Table 15]

[0385]

[0386] (The unit of the values is mg)

[0387] <Test Example 9> Dissolution Test (9)

[0388] For each of the preparations (tablets) produced in Examples 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the 18th edition of the Japanese Pharmacopoeia dissolution test method, dissolution test solution No. 1 (JP1 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60 and 120 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was used for measurement using an HPLC system (manufactured by Shimadzu Corporation) (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, with an inner diameter of 4.6 mm, a length of 150 mm, and a particle size of 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 16 and Figure 17 in.

[0389] [Table 16]

[0390]

[0391] <Test Example 10>Dissolution test (10)

[0392] For each of the preparations (tablets) produced in Examples 5-1, 5-2-1, 5-2-2, 5-3, 5-4 and Reference Example 5, a dissolution test was carried out using a dissolution tester (NTR-8000AC series, NTR-8400AC series, NTR-8600AS series, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of the paddle method of the dissolution test method in the 18th edition of the Japanese Pharmacopoeia, dissolution test solution No. 2 (JP2 solution) as the dissolution test solution, and a paddle rotation speed of 50 revolutions per minute. At 5, 10, 15, 30, 60, 120, 180, 240, 300 and 360 minutes after the start of the test, the peak area of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the dissolution test solution was measured using high performance liquid chromatography (HPLC method), and the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea was calculated from the obtained peak area, and thus the dissolution rate was calculated. The HPLC method was carried out using an HPLC system (manufactured by Shimadzu Corporation) for measurement (wavelength: 210 nm). The column used in the HPLC method was ZORBAX SB-Aq, inner diameter 4.6 mm, length 150 mm, particle size 3.5 μm (manufactured by Agilent), maintained at 40 °C for use, and the mobile phase used was a mixed solution of 0.02 mol / L phosphate buffer (pH 2.0) / acetonitrile = 1 / 1. The dissolution rates of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea are shown in Table 17 and Figure 18 in.

[0393] The dissolution test conditions for JP2 solution (pH = 6.8) were near the dissolution pH boundary of Example 5-4 using the enteric coating agent methacrylic acid copolymer S that dissolves near pH 7.0. Compared with other examples using enteric coating agents that dissolve below pH 6.5, the dissolution of Example 5-4 was slightly slower.

[0394] [Table 17]

[0395]

[0396] Pharmacokinetics (PK) test:

[0397] Hereinafter, the pharmacokinetics (PK) test using the tablets (oral solid preparations) produced in the above-mentioned Examples 5-1, Example 5-2-1, Example 5-3 and Example 5-4 will be described.

[0398] Figures 19 to 22The vertical axis of the curve graph represents the plasma concentration (blood concentration) (nM) of compound (I), and the horizontal axis represents the time (Time after administration) (hours) after administration of compound (I).

[0399] (Example PK5-1)

[0400] (1) Administration of the test preparation and blood sampling

[0401] An oral solid preparation (compound (I): containing 50.0 mg) manufactured using the formulation of Example 5-1 was orally administered once to beagle dogs (male, 5 years old, 11.5 - 13.1 kg) at a dose of 50.0 mg / kg body weight in a non-fasting state with water (30 mL) (n = 4: 11.5 kg (5 years old), 12.7 kg (5 years old), 12.1 kg (5 years old), 13.1 kg (5 years old)). After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed cooling centrifuge MX-201, manufactured by TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C), and plasma was collected.

[0402] (2) Determination of the concentration of compound (I) in plasma

[0403] An internal standard solution (0.18 mL) in which buspirone (manufactured by Sigma-Aldrich) was dissolved in methanol at 50 nmol / L was added to the plasma (0.02 mL) collected in the above (1) and stirred well, and then left standing on ice for 30 minutes. The mixed solution was centrifuged at 540G for 5 minutes (Hitachi multi-tube rack cooling centrifuge CF-9RX, manufactured by Hitachi Koki Co., Ltd.), the supernatant was separated, and the concentration of compound (I) in plasma was measured using LC-MS / MS (Triple Quad 4500, manufactured by AB Sciex). Using a standard plasma sample obtained by serially diluting a 1 mg / mL solution of compound (I) in plasma, a standard curve was made, and from this, the plasma concentration of compound (I) was calculated, and the plasma concentration change data shown in Figure 19 were obtained.

[0404] According to Figure 19When an oral solid preparation prepared with the formulation of (Example 5-1) was orally administered, the maximum plasma concentration (491 nM) was reached 2 hours after administration, and the plasma concentration of Compound (I) remained high even after 12 hours of administration (plasma concentration at 12 hours after administration: 303 nM, plasma concentration at 24 hours after administration: 61.5 nM).

[0405] (Example PK5-2-1)

[0406] (1) Administration of the test preparation and blood sampling

[0407] An oral solid preparation prepared with the formulation of Example 5-2-1 (Compound (I): containing 50.0 mg) was orally administered as a single dose (n = 4: 11.35 kg (5 years old), 12.75 kg (5 years old), 12.20 kg (5 years old), 13.25 kg (5 years old)) to beagle dogs (male, 5 years old, 11.35 - 13.25 kg) at a dose of 50.0 mg / kg body weight in a non-fasted state with water (30 mL). After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed cooling centrifuge MX-201, TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C) to collect plasma.

[0408] (2) Determination of the concentration of Compound (I) in plasma

[0409] The same operation as in the concentration determination of (2) in Example PK5-1 was performed to calculate the plasma concentration of Compound (I), and the plasma concentration change data shown in Figure 20 were obtained.

[0410] According to Figure 20 , when an oral solid preparation prepared with the formulation of (Example 5-2-1) was orally administered, the maximum plasma concentration (581 nM) was reached 6 hours after administration, and the plasma concentration of Compound (I) remained high even after 12 hours of administration (plasma concentration at 12 hours after administration: 163 nM, plasma concentration at 24 hours after administration: 26.7 nM).

[0411] (Example PK5-3)

[0412] (1) Administration of the test preparation and blood sampling

[0413] An oral solid preparation (Compound (I): containing 50 mg) prepared with the formulation of Example 5-3 was orally administered as a single dose (n = 4: 11.5 kg (5 years old), 12.8 kg (5 years old), 12.2 kg (5 years old), 13.0 kg (5 years old)) to beagle dogs (male, 5 years old, 11.5 - 13.0 kg) at a dose of 50 mg / kg body weight with water (30 mL) in the non-fasted state. After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, manufactured by TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C) to collect plasma.

[0414] (2) Determination of the concentration of Compound (I) in plasma

[0415] The same operation as in the concentration determination of (2) in Example PK5-1 was performed to calculate the plasma concentration of Compound (I), and the Figure 21 plasma concentration change data shown were obtained.

[0416] According to Figure 21 , when the oral solid preparation prepared with the formulation of (Example 5-3) was orally administered, the highest plasma concentration (381 nM) was reached 2 hours after administration, and the plasma concentration of Compound (I) also maintained a high level after 12 hours of administration (plasma concentration 12 hours after administration: 98.6 nM, plasma concentration 24 hours after administration: 17.9 nM).

[0417] (Example PK5-4)

[0418] (1) Administration of the test preparation and blood collection

[0419] An oral solid preparation (Compound (I): containing 50.0 mg) prepared with the formulation of Example 5-4 was orally administered as a single dose (n = 4: 11.5 kg (5 years old), 12.7 kg (5 years old), 12.0 kg (5 years old), 13.1 kg (5 years old)) to beagle dogs (male, 5 years old, 11.5 - 13.1 kg) at a dose of 50.0 mg / kg body weight with water (30 mL) in the non-fasted state. After administration, blood (0.5 mL) was collected from the cephalic vein on the radial side of the forelimb of the beagle dogs at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours. The collected blood was centrifuged (micro high-speed refrigerated centrifuge MX-201, manufactured by TOMY SEIKO CO., LTD., 10000×g, 5 minutes, 4°C) to collect plasma.

[0420] (2) Determination of the concentration of Compound (I) in plasma

[0421] The same operation as the concentration measurement in (2) of Example PK5-1 was carried out to calculate the plasma concentration of Compound (I), and Figure 22 the plasma concentration change data shown below were obtained.

[0422] According to Figure 22 , when an oral solid preparation manufactured with the formulation of (Example 5-4) was orally administered, the maximum plasma concentration (243 nM) was reached 4 hours after administration, and the plasma concentration of Compound (I) also maintained a high concentration after 12 hours of administration (plasma concentration 12 hours after administration: 116 nM, plasma concentration 24 hours after administration: 25.6 nM).

[0423] Another aspect of the present invention can be shown as follows.

[0424] [1] An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2):

[0425] (1) A core containing the active ingredient; and

[0426] (2) A coating layer covering the core, and the coating layer contains at least 1 kind of coating agent selected from the following: hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose.

[0427] [2] The oral solid preparation according to [1] above, wherein the methacrylic acid copolymer is at least 1 kind selected from the following: methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dried methacrylic acid copolymer LD.

[0428] [3] The oral solid preparation according to [1] or [2] above, wherein the coating layer further contains at least 1 kind of plasticizer selected from the following: triethyl citrate, tributyl citrate, polyethylene glycol, propylene glycol, sodium dodecyl sulfate ethanol, triacetin, and polysorbate 80.

[0429] [4] The oral solid preparation according to any one of [1] to [3] above, wherein the coating layer further contains at least 1 kind of additive selected from the following: titanium oxide, talc, crystalline cellulose, calcium carbonate, and shellac.

[0430] [5] The oral solid preparation according to any one of [1] to [4] above, wherein the core further contains at least one additive selected from the following: excipients, fluidizing agents, disintegrants, and lubricants.

[0431] [6] The oral solid preparation according to [5] above, wherein the excipient is at least one selected from the following: glucose, lactose, granulated lactose, sucrose, white sugar, mannitol, mannitol, xylitol, sorbitol, crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, calcium hydrogen phosphate dihydrate, isomaltitol, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, corn starch, pregelatinized starch, partially pregelatinized starch, light anhydrous silicic acid, and titanium oxide.

[0432] [7] The oral solid preparation according to [5] above, wherein the fluidizing agent is at least one selected from the following: silica, talc, hydrated silica, magnesium metasilicate aluminate, and calcium hydrogen phosphate granules.

[0433] [8] The oral solid preparation according to [5] above, wherein the disintegrant is at least one selected from the following: starches, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, crystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, sodium alginate, corn starch, and sodium carboxymethyl starch.

[0434] [9] The oral solid preparation according to [5] above, wherein the lubricant is at least one selected from the following: magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium dodecyl sulfate, talc, carboxymethyl cellulose, stearic acid, sodium dodecyl sulfate, carnauba wax, sucrose fatty acid ester, polyethylene glycol, glycerol, monoglyceride stearate, castor oil, and hydrogenated castor oil.

[0435]

[10] The oral solid preparation according to any one of [1] to [9] above, wherein, when a dissolution test is carried out using dissolution test solution No. 2 according to the paddle method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 13% or more after 1 hour from the start of the dissolution test.

[0436]

[11] The oral solid preparation according to any one of [1] to [9] above, wherein, when a dissolution test is carried out using dissolution test solution No. 2 according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 13% or more after 6 hours from the start of the dissolution test.

[0437]

[12] The oral solid preparation according to any one of [1] to

[11] above, wherein, when a dissolution test is carried out using dissolution test solution No. 1 according to the paddle method of the dissolution test method described in the 18th Edition of the Japanese Pharmacopoeia, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 2.5% or less after 1 hour from the start of the dissolution test.

[0438]

[13] The oral solid preparation according to any one of [1] to

[12] above, wherein the coating layer dissolves in a solution in the range of pH = 5.0 to 7.0.

[0439]

[14] An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2):

[0440] (1) A core containing the following components (a) to (e):

[0441] (a) The active ingredient,

[0442] (b) At least 1 excipient selected from crystalline cellulose, granulated lactose, and crystalline cellulose,

[0443] (c) At least 1 fluidizing agent selected from light anhydrous silicic acid, talc, and magnesium aluminometasilicate,

[0444] (d) At least 1 disintegrant selected from croscarmellose sodium and sodium starch glycolate, and

[0445] (e) At least 1 lubricant selected from magnesium stearate and sodium stearyl fumarate; and

[0446] (2) A coating layer covering the core, the coating layer containing at least 1 coating agent selected from the following: hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethylethylcellulose.

[0447]

[15] The oral solid preparation according to any one of [1] to

[14] above, which contains: 50 mg of 1 - ((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount, and the above amount or equivalent amount is the following amount: 12 hours after the first administration of the preparation to the administration subject, the concentration of 1 - ((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is 90 nM or more.

[0448]

[16] The oral solid preparation according to any one of [1] to

[14] above, which contains: 50 mg of 1 - ((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to the above amount, or a solvate thereof in an equivalent amount to the above amount, and the above amount or equivalent amount is the following amount: at any time after 12 hours or 24 hours from the first administration of the preparation to the administration subject, the concentration of 1 - ((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is 90 nM or more.

[0449]

[17] The oral solid preparation according to

[15] or

[16] above, wherein the administration subject is a human or a non-human mammal.

[0450]

[18] The oral solid preparation according to any one of [1] to

[17] above, which is used for preventing and / or treating diseases related to TrkA.

[0451]

[19] The oral solid preparation according to

[18] above, wherein the disease related to TrkA is pain or pruritus.

Claims

1. An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2): (1) A core containing the active ingredient; and (2) A coating layer coating the core, the coating layer containing at least 1 kind of coating agent selected from the following: hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose.

2. The oral solid preparation according to claim 1, wherein, The methacrylic acid copolymer is at least 1 kind selected from the following: methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and dried methacrylic acid copolymer LD.

3. The oral solid preparation according to claim 1 or 2, wherein The coating layer further contains at least 1 kind of plasticizer selected from the following: triethyl citrate, tributyl citrate, polyethylene glycol, propylene glycol, sodium lauryl sulfate ethanol, triacetin, and polysorbate 80.

4. The oral solid preparation according to any one of claims 1 to 3, wherein, The coating layer further contains at least 1 kind of additive selected from the following: titanium oxide, talc, crystalline cellulose, calcium carbonate, and shellac.

5. The oral solid preparation according to any one of claims 1 to 4, wherein, The core further contains at least 1 kind of additive selected from the following: excipient, fluidizing agent, disintegrant, and lubricant.

6. The oral solid preparation according to claim 5, wherein, The excipient is at least 1 kind selected from the following: glucose, lactose, granulated lactose, sucrose, white sugar, mannitol, mannitol, xylitol, sorbitol, crystalline cellulose, microcrystalline cellulose, silicic acid, starch, corn starch, potato starch, dibasic calcium phosphate dihydrate, isomaltulose, anhydrous calcium phosphate, anhydrous dibasic calcium phosphate, corn starch, pregelatinized starch, partially pregelatinized starch, light anhydrous silicic acid, and titanium oxide.

7. The oral solid preparation according to claim 5, wherein, The fluidizing agent is at least 1 kind selected from the following: silica, talc, hydrated silica, magnesium metasilicate aluminate, and calcium hydrogen phosphate granulate.

8. The oral solid preparation according to claim 5, wherein, The disintegrant is at least 1 kind selected from the following: starches, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, crystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, sodium alginate, corn starch, and sodium carboxymethyl starch.

9. The oral solid preparation according to claim 5, wherein, The lubricant is at least 1 kind selected from the following: magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, talc, carboxymethyl cellulose, stearic acid, sodium lauryl sulfate, carnauba wax, sucrose fatty acid ester, polyethylene glycol, glycerol, monoglyceride stearate, castor oil, and hydrogenated castor oil.

10. The oral solid preparation according to any one of claims 1 to 9, wherein, When the dissolution test is carried out using the paddle method described in the 18th Edition of the Japanese Pharmacopoeia and dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 13% or more after 1 hour from the start of the dissolution test.

11. The oral solid preparation according to any one of claims 1 to 9, wherein, When the dissolution test is carried out using the paddle method described in the 18th Edition of the Japanese Pharmacopoeia and dissolution test solution No. 2, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 13% or more after 6 hours from the start of the dissolution test.

12. The oral solid preparation according to any one of claims 1 to 9, wherein, When the dissolution test is carried out using the paddle method described in the 18th Edition of the Japanese Pharmacopoeia and dissolution test solution No. 1, the dissolution rate of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea contained in the preparation is 2.5% or less after 1 hour from the start of the dissolution test.

13. The oral solid preparation according to any one of claims 1 to 12, wherein, The coating layer dissolves in a solution in the range of pH = 5.0 to 7.

0.

14. An oral solid preparation, which is an oral solid preparation containing 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, and the preparation is characterized by having the following (1) and (2): (1) A core containing the following components (a) to (e): (a) The active ingredient, (b) At least one excipient selected from crystalline cellulose, granulated lactose, and crystalline cellulose, (c) At least one fluidizing agent selected from light anhydrous silicic acid, talc, and magnesium aluminometasilicate, (d) At least one disintegrant selected from sodium carboxymethylcellulose cross-linked and sodium starch glycolate, and (e) At least one lubricant selected from magnesium stearate and sodium stearyl fumarate; and (2) A coating layer covering the core, the coating layer containing at least one coating agent selected from the following: hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethylethylcellulose.

15. The oral solid preparation according to any one of claims 1 to 14, which contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to said amount, or a solvate thereof in an equivalent amount to said amount, and said amount or equivalent amount is the following amount: 12 hours after the first administration of said preparation to a subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is 90 nM or more.

16. The oral solid preparation according to any one of claims 1 to 14, which contains: 50 mg of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof in an equivalent amount to said amount, or a solvate thereof in an equivalent amount to said amount, and said amount or equivalent amount is the following amount: at any time 12 hours or 24 hours after the first administration of said preparation to a subject, the concentration of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea in the plasma of the subject is 90 nM or more.

17. The oral solid preparation according to claim 15 or 16, wherein, The subject is a human or non-human mammal.

18. The oral solid preparation according to any one of claims 1 to 17, which is used for preventing and / or treating a disease related to TrkA.

19. The oral solid preparation according to claim 18, wherein, The disease related to TrkA is pain or pruritus.

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