Solid compositions and methods of manufacture

Abstract

To provide a solid composition containing at least one selected from the group consisting of loxoprofen, a salt thereof and a hydrate thereof, and other components, and having suppressed property change.SOLUTION: (A) at least one member selected from the group consisting of loxoprofen and salts and hydrates thereof, (B) fructose, and (C) one or more members selected from the group consisting of (C- 1) vitamin B1 and vitamin C, (C- 2) peony root, licorice, and valerian, (C- 3) bromhexine, ambroxol, tipepidine and salts and hydrates thereof, (C- 4) clemastine and salts and hydrates thereof, and (C- 5) dextromethorphan and salts and hydrates thereof; A solid composition comprising: SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid composition containing at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, fructose, and other ingredients, and a method for producing the same. [Background technology]

[0002] It is known that the properties of solid compositions prepared by mixing loxoprofen, its salts, and hydrates thereof with specific components change over time, and research has been conducted into the stabilization of loxoprofen.

[0003] Patent Document 1 discloses that when loxoprofen sodium and bromhexine hydrochloride are present together, changes in color and properties occur over time, and the content of bromhexine hydrochloride decreases, but that this decrease in content can be suppressed by adding synthetic hydrotalcite or hydrous silicon dioxide.

[0004] Patent Documents 2 to 4 disclose that when loxoprofen sodium and clemastine fumarate are present together, changes in color and properties occur over time, and the content of clemastine fumarate decreases, but that this decrease in content can be suppressed by adding hydrous silicon dioxide, light anhydrous silicic acid, or calcium silicate.

[0005] Patent Document 5 discloses that when loxoprofen sodium and ambroxol hydrochloride are present together, the color and properties change over time, but the stability can be improved by storing the mixture in the presence of a desiccant.

[0006] Furthermore, Non-Patent Document 1 discloses that loxoprofen sodium forms a salt co-crystal with fructose, and that the salt co-crystal of loxoprofen sodium with fructose maintains its anhydrous crystalline form even under high humidity conditions. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2012-140420 [Patent Document 2] Japanese Patent Application Laid-Open No. 2014-12661 [Patent Document 3] Japanese Patent Application Publication No. 2017-186384 [Patent Document 4] Japanese Patent Application Publication No. 2019-14760 [Patent Document 5] Japanese Patent Application Laid-Open No. 2016-155860 [Non-patent literature]

[0008] [Non-Patent Document 1] Doctoral thesis: "Elucidation of the mechanism of hydrate formation inhibition of loxoprofen sodium by salt co-crystal formation with sugars" (2022) by Takayuki Fujito (Graduate School of Pharmaceutical Sciences, Chiba University) Summary of the Invention [Problem to be solved by the invention]

[0009] The problem to be solved by the present invention is to provide a solid composition which contains at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof, and other ingredients, and which is inhibited from changing in properties. [Means for solving the problem]

[0010] The inventors surprisingly discovered that among components that are likely to undergo changes in properties when combined with at least one selected from the group consisting of rofecoxib, its salts, and hydrates thereof, the changes in properties of certain components can be suppressed when coexisting with fructose, and this discovery led to the completion of the present invention.

[0011] That is, the present application includes the following inventions. [1] A solid composition comprising: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) fructose, (C) The following: (C-1) Vitamin B1 and Vitamin C; (C-2) Peony, licorice, and valerian; (C-3) Bromhexine, ambroxol, tipepidine, their salts and their hydrates; (C-4) clemastine, its salts and hydrates thereof; and (C-5) Dextromethorphan, its salts and hydrates thereof; and one or more ingredients selected from the group consisting of: [2] The solid composition according to [1], comprising a complex in which components (A) and (B) are complexed. [3] The solid composition according to [2], wherein the molar ratio of components (A) and (B) in the complex is 1:1. [4] The solid composition according to any one of [1] to [3], which contains loxoprofen sodium as component (A). [5] The solid composition according to any one of [1] to [4], wherein the complex has diffraction peaks at diffraction angles 2θ=4.4±0.3° and 16.0±0.3° in a powder X-ray diffraction pattern. [6] The solid composition according to any one of [1] to [5], wherein the complex has diffraction peaks at diffraction angles 2θ=4.4±0.3°, 8.8±0.3°, 10.1±0.3°, and 16.0±0.3° in a powder X-ray diffraction pattern. [7] A method for producing the solid composition according to any one of [1] to [6], contacting components (A) and (B). [8] The method according to [7], wherein the contacting is carried out by at least one of the steps of mixing and grinding, heating and melting, crystallizing in the presence of a solvent, kneading, and spraying. [9] The method according to [8], further comprising the step of contacting the mixture of components (A) and (B) with component (C). [Effects of the Invention]

[0012] According to the present invention, a solid composition can be provided which contains at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and other ingredients, and which is inhibited from changing in properties. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows the diffraction patterns of the powder X-ray diffraction analysis of each sample measured in the examples. DETAILED DESCRIPTION OF THE INVENTION

[0014] Hereinafter, an embodiment of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not to be construed as being limited to the following embodiment. In the present embodiment, the composition may contain each component either alone or in combination of two or more. In this specification, the symbol "to" indicating a numerical range means "at least" or "at most", and includes both of the numerical values ​​at both ends.

[0015] (solid composition) In a first aspect, the following ingredients: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) fructose, (C) The following: (C-1) Vitamin B1 and Vitamin C; (C-2) Peony, licorice, and valerian; (C-3) Bromhexine, ambroxol, tipepidine, their salts and their hydrates; (C-4) clemastine, its salts and hydrates thereof; and (C-5) Dextromethorphan, its salts and hydrates thereof; One or more components selected from the group consisting of: A solid composition is provided comprising: Moreover, the solid composition is specifically a solid pharmaceutical composition.

[0016] In this embodiment, the component to be combined with at least one selected from the group consisting of rofecoxib, its salts, and their hydrates is the above-mentioned component (C), and the solid composition further contains the above-mentioned component (B), thereby suppressing changes in properties of the solid composition, particularly changes in properties over time.

[0017] As used herein, "change in properties" refers to a change in nature and / or state, including at least aggregation, discoloration, moisture absorption, and wetting. Therefore, the solid composition of this embodiment may be inhibited from undergoing any of aggregation, discoloration, moisture absorption, and wetting over time. Furthermore, "inhibited change in properties" means that the property change is unlikely to occur, and may be inhibited, for example, compared to a solid composition that does not contain the above-mentioned component (B).

[0018] For example, the solid composition of this embodiment has a color difference ΔE between before and after storage in a sealed container at 60° C. for 2 weeks, compared to a solid composition having the same composition except that it does not contain the above-mentioned component (B). * The color difference ΔE may be reduced by 5 or more, 7 or more, 8 or more, 10 or more, 12 or more, 15 or more, or 20 or more. * The change in may be 50 or less, 40 or less, or 30 or less.

[0019] The solid composition of this embodiment may be inhibited from changing in properties under high temperature and / or high humidity conditions. High temperature conditions may be, for example, 30 to 80° C., 35 to 75° C., or 50 to 70° C. High humidity conditions may be, for example, relative humidity of 50% or more, 60% or more, or 70% or more.

[0020] The period during which the property change is suppressed in the solid composition of this embodiment is not particularly limited, and may be, for example, one week or more, two weeks or more, four weeks or more, one month or more, or two months or more.

[0021] In the solid composition of this embodiment, it is preferable that component (A) and component (C) are not in contact in the absence of component (B). For example, it is preferable that they are contained as a granule containing all of component (A), component (B), and component (C). It is also preferable that a granule containing component (A) and component (B) and a granule containing component (C) are contained as separate granules.

[0022] (Component (A)) Component (A) is at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. That is, loxoprofen and its salts may be hydrates (hydrated salts). Component (A) is preferably at least one selected from the group consisting of loxoprofen salts and hydrates thereof, more preferably at least one selected from the group consisting of loxoprofen sodium and hydrates thereof, and even more preferably loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 18th Edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0023] The content of component (A) in the solid composition is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, in anhydrous equivalent, per dosage unit (single dose) for adults, and is preferably administered 1 to 3 times a day.

[0024] The weight and dosage of component (A) above indicate one dosage unit (single dose) for adults, but as mentioned above, the same amount may be administered to a subject multiple times a day, for example, two or three times, preferably three times. The same applies to components other than component (A). Furthermore, since each dosage is a total amount, the content of each component contained in the composition may vary depending on the single dose, the dosage form of the composition, etc.

[0025] When the solid composition is in the form of a tablet, the content of component (A) in one tablet is preferably 30 to 180 mg, more preferably 50 to 120 mg, and even more preferably 60 to 90 mg, calculated as an anhydrous amount, when used as an antipyretic analgesic, etc. When used as a cold medicine, the content of ingredient (A) in one tablet is preferably 10 mg to 90 mg, more preferably 15 mg to 60 mg, and even more preferably 20 to 30 mg, calculated as the anhydrous substance. By setting the content of component (A) within the above range, the antipyretic, analgesic, or anti-inflammatory effects of the solid composition can be more effectively exhibited, the hardness and disintegration properties of the tablet can be more favorable, and changes in properties can be more effectively suppressed.

[0026] In this specification, the content of each ingredient in one tablet may be appropriately adjusted according to the number of tablets to be administered at one time. The content of each ingredient in one tablet described in this specification may be a constant multiple such as 3 times, 2 times, 1 / 2, 1 / 3, 1 / 4, 1 / 5, or 1 / 6, as long as it does not deviate from the range of the content of each ingredient per dosage unit.

[0027] When the solid composition is in the form of granules, the content of component (A) in the granules is, in terms of the amount of the component contained in one dosage unit (single dose) for adults, preferably 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, or may be 60 to 90 mg, calculated as an anhydrous amount.

[0028] From the viewpoint of increasing the amount of the active ingredient in the solid composition, the content of component (A) in the solid composition may be 0.01% by mass or more, 1% by mass or more, 5% by mass or more, 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 45% by mass or more, 48% by mass or more, 50% by mass or more, 60% by mass or more, or 65% by mass or more, calculated on an anhydrous basis, relative to the entire solid composition. Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the content of component (A) in the solid composition is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, calculated on an anhydrous basis, based on the total mass of the solid composition.

[0029] When used as an antipyretic analgesic, the content of component (A) in the solid composition may be 1 to 80 mass %, preferably 2 to 50 mass %, more preferably 5 to 30 mass %, and even more preferably 7 to 20 mass %, in anhydrous terms relative to the total solid composition. When used as a cold medicine, the content of component (A) in the solid composition may be 0.01% by mass to 20% by mass, preferably 0.03% by mass to 15% by mass, and more preferably 0.04% by mass to 10% by mass, calculated as the anhydrous base, relative to the total solid composition.

[0030] When the solid composition is a tablet, the proportion of component (A) in the total mass of one tablet may be 0.01% by mass or more, 1% by mass or more, 5% by mass or more, 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 45% by mass or more, 48% by mass or more, 50% by mass or more, 60% by mass or more, or 65% by mass or more, calculated on an anhydrous basis, from the viewpoint of increasing the amount of the active ingredient in the tablet. Furthermore, from the viewpoint of improving the hardness and disintegration properties of the tablet and suppressing changes in properties, the proportion of component (A) in the total mass of one tablet is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, calculated on an anhydrous basis.

[0031] When used as an antipyretic analgesic, the proportion of component (A) in the total mass of one tablet may be 1 to 80% by mass, preferably 2 to 50% by mass, more preferably 5 to 30% by mass, and even more preferably 7 to 20% by mass, calculated on an anhydrous basis. When used as a cold medicine, the proportion of component (A) in the total mass of one tablet may be 0.01% by mass to 20% by mass, preferably 0.03% by mass to 15% by mass, and more preferably 0.04% by mass to 10% by mass, calculated on an anhydrous basis.

[0032] When the solid composition is in the form of granules, the content of component (A) in the granules may be, in terms of anhydrous equivalent, 0.01 parts by mass or more, 1 part by mass or more, 5 parts by mass or more, 10 parts by mass or more, 20 parts by mass or more, 30 parts by mass or more, 40 parts by mass or more, 45 parts by mass or more, 48 parts by mass or more, 50 parts by mass or more, 60 parts by mass or more, or 65 parts by mass or more per 100 parts by mass of the granules, from the viewpoint of increasing the active ingredient in the solid composition. In addition, from the viewpoint of improving the hardness and disintegration properties of the granules and suppressing changes in properties, the content of component (A) in the granules is preferably 90 parts by mass or less, more preferably 80 parts by mass or less, and even more preferably 70 parts by mass or less, calculated on an anhydrous basis per 100 parts by mass of the granules.

[0033] (Component (B)) Component (B) is fructose. The fructose may be any of L-, D-, or a mixture thereof including a racemic form, but is preferably D-fructose.

[0034] In this embodiment, component (B) is preferably present in the solid composition as a complex with component (A). That is, the solid composition preferably contains a complex in which components (A) and (B) are complexed. In the complex, it is more preferable that components (A) and (B) are present as a complex at a molar ratio of 1:1. The complex may be a complex obtained by contacting components (A) and (B), or may be a complex obtained by kneading components (A) and (B). The complex may be a cocrystal of components (A) and (B), or may be a salt cocrystal of components (A) and (B). A method for producing the complex will be described later.

[0035] The term "complex of components (A) and (B)" refers to a state in which the component (A) molecules and the component (B) molecules are bonded together, resulting in a state in which the component (A) and (B) molecules exhibit properties different from those of the components (A) and (B) alone. For example, the complex of components (A) and (B) may have crystal structure characteristics different from those of the components (A) and (B) alone. Alternatively, the complex of components (A) and (B) may have a melting point measured by differential scanning calorimetry different from those of the components (A) and (B) alone. The complex of components (A) and (B) may be confirmed, for example, by powder X-ray diffraction and / or differential scanning calorimetry (DSC).

[0036] The composite of components (A) and (B) preferably has diffraction peaks at diffraction angles 2θ=4.4±0.3° and 16.0±0.3° in its powder X-ray diffraction pattern. The composite of components (A) and (B) more preferably has diffraction peaks at diffraction angles 2θ=4.4±0.3°, 8.8±0.3°, 10.1±0.3°, and 16.0±0.3° in its powder X-ray diffraction pattern. The composite of components (A) and (B) may have at least one, at least two, at least three, or four diffraction peaks among the diffraction peaks at diffraction angles 2θ=4.4±0.3°, 8.8±0.3°, 10.1±0.3°, and 16.0±0.3° in its powder X-ray diffraction pattern. The measurement conditions for powder X-ray diffraction may be the conditions described in the Examples.

[0037] The complex of components (A) and (B) may have a melting point in the range of, for example, 140 to 170°C, preferably 145 to 165°C, as measured by differential scanning calorimetry.

[0038] The content of component (B) in the solid composition may be adjusted depending on the content of component (A). In the solid composition, the molar ratio of component (A):component (B) may be, for example, 1:0.3 to 1:3.0, preferably 1:0.5 to 1:2, and more preferably 1:0.75 to 1:1.25.

[0039] In one embodiment, the solid composition may include component (B) complexed with component (A) and component (B) not complexed with component (A). In one embodiment, the solid composition may be substantially free of component (B) not complexed with component (A). In one embodiment, the solid composition may include component (A) complexed with component (B) and component (A) not complexed with component (B). In one embodiment, the solid composition may be substantially free of component (A) not complexed with component (B).

[0040] In one embodiment, the content ratio of component (B) that does not form a complex with component (A) relative to component (B) contained in the solid composition may be 0 to 30 mass%, 0 to 10 mass%, 0 to 5 mass%, 0 to 3 mass%, 0 to 1 mass%, 0 to 0.5 mass%, or 0 to 0.1 mass%. In one embodiment, the content ratio of component (A) that does not form a complex with component (B) relative to component (A) contained in the solid composition may be 0 to 30 mass%, 0 to 10 mass%, 0 to 5 mass%, 0 to 3 mass%, 0 to 1 mass%, 0 to 0.5 mass%, or 0 to 0.1 mass%.

[0041] The content of component (B) in the solid composition is preferably 6 to 120 mg, more preferably 20 to 80 mg, and even more preferably 20 to 60 mg per dosage unit (single dose) for adults, and is preferably administered 1 to 3 times a day.

[0042] When the solid composition is in the form of a tablet, the content of component (B) in one tablet is preferably 20 to 120 mg, more preferably 30 to 80 mg, and more preferably 40 to 60 mg when used as an antipyretic analgesic. When used as a cold medicine, the content of ingredient (B) in one tablet is 6 mg to 60 mg, preferably 10 mg to 40 mg, and more preferably 13 to 20 mg. By setting the content of component (B) within the above range, the hardness and disintegration properties of the tablet can be made more preferable, and changes in properties can be further suppressed.

[0043] When the solid composition is in the form of granules, the content of component (B) in the granules is preferably 6 to 120 mg, more preferably 20 to 80 mg, and even more preferably 20 to 60 mg, in terms of the amount of the component contained in the solid composition per dosage unit (single dose) for adults.

[0044] From the viewpoint of suppressing changes in properties, the content of component (B) in the solid composition may be 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, 3% by mass or more, 6% by mass or more, 18% by mass or more, 20% by mass or more, 30% by mass or more, 32% by mass or more, 33% by mass or more, 40% by mass or more, or 43% by mass or more, based on the total mass of the solid composition. Furthermore, from the viewpoint of increasing the amount of the active ingredient in the solid composition, the content of component (B) in the solid composition is preferably 60% by mass or less, more preferably 55% by mass or less, and even more preferably 47% by mass or less, based on the total amount of the solid composition.

[0045] When used as an antipyretic analgesic, the content of component (B) in the solid composition may be 0.1 to 50% by mass, preferably 1 to 30% by mass, more preferably 3 to 20% by mass, and even more preferably 5 to 16% by mass, based on the total mass of the solid composition. When used as a cold medicine, the content of component (B) in the solid composition may be 0.005 to 15% by mass, preferably 0.02 to 10% by mass, and more preferably 2 to 7% by mass, based on the total mass of the solid composition.

[0046] When the solid composition is a tablet, the proportion of component (B) in the total mass of one tablet may be 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, 3% by mass or more, 6% by mass or more, 18% by mass or more, 20% by mass or more, 30% by mass or more, 32% by mass or more, 33% by mass or more, 40% by mass or more, or 43% by mass or more, from the viewpoint of suppressing changes in properties. Furthermore, from the viewpoint of increasing the amount of the active ingredient in the tablet, the proportion of ingredient (B) in the total mass of one tablet is preferably 60% by mass or less, more preferably 53% by mass or less, and even more preferably 47% by mass or less.

[0047] When used as an antipyretic analgesic, the proportion of component (B) in the total mass of one tablet may be 0.1 to 50% by mass, preferably 1 to 30% by mass, more preferably 3 to 20% by mass, and even more preferably 5 to 16% by mass. When used as a cold medicine, the proportion of component (B) in the total mass of one tablet may be 0.005% by mass to 15% by mass, preferably 0.02% by mass to 10% by mass, and more preferably 2 to 7% by mass.

[0048] When the solid composition is in the form of granules, the content of component (B) in the granules may be, from the viewpoint of suppressing changes in properties, 0.005 parts by mass or more, 0.01 parts by mass or more, 0.1 parts by mass or more, 1 part by mass or more, 3 parts by mass or more, 6 parts by mass or more, 18 parts by mass or more, 20 parts by mass or more, 30 parts by mass or more, 32% by mass or more, 33% by mass or more, 40 parts by mass or more, or 43 parts by mass or more per 100 parts by mass of the granules. In addition, from the viewpoint of increasing the active ingredient in the granules, the content of component (B) in the granules is preferably 60 parts by mass or less, more preferably 53 parts by mass or less, and even more preferably 47 parts by mass or less per 100 parts by mass of the granules.

[0049] (Component (C)) The component (C) is one or more selected from the group consisting of the following (C-1) to (C-5): (C-1) Vitamin B1 and Vitamin C (C-2) Peony, licorice, and valerian (C-3) Bromhexine, ambroxol, tipepidine, their salts and their hydrates (C-4) Clemastine, its salts and their hydrates (C-5) Dextromethorphan, its salts and their hydrates

[0050] Here, component (C-1) is a specific vitamin, component (C-2) is a specific herbal medicine, component (C-3) is a specific expectorant component, component (C-4) is a specific antihistamine, and component (C-5) is a specific antitussive component.

[0051] From the viewpoint of increasing the active ingredient in the solid composition, the total content of component (C) in the solid composition may be, for example, more than 0 mass%, 0.1 mass% or more, 0.5 mass% or more, 1.0 mass% or more, 5.0 mass% or more, 10 mass% or more, 15 mass% or more, 20 mass% or more, 30 mass% or more, 40 mass% or more, or 50 mass% or more, relative to the entire solid composition. Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the total content of component (C) in the solid composition may be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, relative to the entire solid composition. The total content of component (C) in the solid composition is, for example, 0.1 to 50 mass %, preferably 1 to 40 mass %, and more preferably 5 to 30 mass %, based on the total mass of the solid composition.

[0052] The total content of component (C) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C) to the total of components (A) and (B) may be, for example, 1:0.001 to 1:10, preferably 1:0.01 to 1:5, and more preferably 1:0.05 to 1:3.

[0053] When the solid composition is a tablet, the total proportion of component (C) in the total mass of one tablet may be the same as the above-mentioned proportion relative to the total mass of the solid composition. When the solid composition is in the form of granules, the total proportion of component (C) in the granules may be the same as the above-mentioned proportion relative to the entire solid composition.

[0054] The ranges described below as the preferred ranges of the content of each component refer to the preferred ranges of the content when each component is contained in the solid composition, and are not intended to exclude from the preferred embodiments cases where each component is not contained.

[0055] (Component (C-1)) Examples of vitamin B1 include compounds having vitamin B1 activity, and specifically include one or more compounds selected from the group consisting of thiamine, thiamine disulfide, fursultiamine, benfotiamine, and octotiamine.

[0056] Examples of vitamin C include one or more selected from the group consisting of ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, magnesium ascorbate, ascorbic acid palmitate, ascorbic acid 2-glucoside, ascorbic acid stearate, and ascorbic acid phosphate.

[0057] The content of component (C-1) vitamin B1 and vitamin C in the solid composition may be, for example, 0.5 to 100 mg and 10 to 1000 mg, respectively, as the amount of the components contained in one dosage unit (single dose) for adults. Preferably, the content is 1 to 60 mg and 50 to 600 mg.

[0058] When the solid composition is in the form of a tablet, the content of component (C-1) vitamin B1 and vitamin C in one tablet may be the same as the above-mentioned amounts of each of the components contained in the solid composition.

[0059] When the solid composition is in the form of granules, the content of component (C-1) vitamin B1 and vitamin C in the granules may be the same as the above-mentioned amounts of each of the components contained in the solid composition.

[0060] From the viewpoint of increasing the amount of active ingredient in the solid composition, the contents of component (C-1) vitamin B1 and vitamin C in the solid composition may each independently be, for example, 0% by mass or more, more than 0%, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 1.5% by mass or more, 3.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more relative to the entire solid composition. The total content of component (C-1) in the solid composition may also be, for example, 0% by mass or more, more than 0%, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 1.5% by mass or more, 3.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more.

[0061] Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the contents of the component (C-1) vitamin B1s and vitamin Cs in the solid composition may each independently be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, 4.5% by mass or less, or 1.0% by mass or less, relative to the entire solid composition. The total content of component (C-1) in the solid composition may also be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less.

[0062] In the case of an antipyretic analgesic, the content of vitamin B1 class relative to the total mass of the solid composition may be 3 to 8 mass%, preferably 2.5 to 5 mass%, more preferably 1.5 to 4.5 mass%. In the case of an antipyretic analgesic, the content of vitamin C relative to the total mass of the solid composition may be 1 to 40% by mass, preferably 2 to 35% by mass, and more preferably 3 to 30% by mass. In the case of a cold medicine, the content of vitamin B1 class relative to the total mass of the solid composition may be 0.1 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.7 to 1% by mass. In the case of a cold medicine, the content of vitamin C relative to the total mass of the solid composition may be 0.1 to 40 mass%, preferably 0.5 to 30 mass%, and more preferably 1 to 20 mass%.

[0063] The content of component (C-1) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C-1) to the total content of components (A) and (B) may be, for example, 1:0.001 to 1:10, preferably 1:0.01 to 1:5, and more preferably 1:0.05 to 1:3.

[0064] When the solid composition is in the form of a tablet, the proportion of component (C-1) vitamin B1 and vitamin C in the total mass of one tablet, as well as the total proportion of component (C-1), may be the same as the respective proportions described above relative to the total mass of the solid composition.

[0065] When the solid composition is in the form of granules, the proportions of component (C-1), vitamin B1 group, and vitamin C group in the granules, as well as the total proportion of component (C-1), may be the same as the above-mentioned proportions relative to the entire solid composition.

[0066] (Component (C-2)) Peony, licorice, and valerian have been used medicinally since ancient times, either alone or as traditional Chinese medicines, and the herbal powders or extract components obtained according to conventional methods can be used as they are. The herbal powders or extract components can be in the form of ordinary commercially available products or processed products thereof. For example, dried, chopped, processed products can be further pulverized into a powder (fine powder) for use as a dry powder. The form of the extract from the herbal medicine is not particularly limited, and any form, such as a dried extract, extract powder, soft extract, liquid extract, or tincture containing ethanol or ethanol and water, can be used. Preferred herbal medicines include extract components that offer a high degree of formulation flexibility, such as soft extracts and dried extract powders.

[0067] The extract can be obtained by conventional methods, for example, extracting the active ingredients having antibacterial activity from the herbal medicine using an extraction solvent. The extraction solvent is often water, a hydrophilic solvent, or a mixture thereof. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or in combination.

[0068] Peony, licorice, and valerian can preferably be those listed in the 18th revised Japanese Pharmacopoeia. Licorice extracts include those using water or 30% ethanol aqueous solution as the extraction solvent, and various extracts with different crude drug equivalent ratios can be used depending on the type of extract, such as licorice extract, licorice dry extract, licorice soft extract, licorice liquid extract, etc. In addition to these licorice extracts, licorice extracts, licorice extract liquids, etc. may also be used appropriately and are not particularly limited. Valerian is not particularly limited, and examples thereof include valerian powder and valerian extract (such as soft extract or dry extract). As the peony, for example, peony powder or peony extract (including, for example, dry extract or soft extract) can be used, and is not particularly limited.

[0069] The contents of peony, licorice, and valerian in the solid composition may be adjusted to an appropriate content in the solid composition, taking into consideration the ratio of the raw herbal medicines. The content of licorice (including licorice and licorice extract) in the solid composition per dosage unit (single dose) for adults is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, or may be 500 mg to 1500 mg, in terms of the amount of the ingredient contained in the solid composition per dosage unit (single dose) for adults, equivalent to the amount of the raw herbal medicine. The content of valerian (including valerian and valerian extract) may be 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, even more preferably 60 mg to 1000 mg, or may be 60 to 450 mg, in terms of the amount of ingredients contained in the solid composition per dosage unit (single dose) for adults, equivalent to the amount of the original herbal medicine. The content of peony (including peony and peony extract) in the solid composition per dosage unit (single dose) for adults may be 100 to 5000 mg, preferably 150 to 2000 mg, and more preferably 200 to 900 mg, in terms of the amount of the raw herbal medicine.

[0070] When the solid composition is in the form of a tablet, the content of component (C-2) peony, licorice, and valerian in one tablet may be the same as the above-mentioned amounts of each of the components contained in the solid composition. When the solid composition is in the form of granules, the content of component (C-2) peony, licorice, and valerian in the granules may be the same as the above-mentioned amounts of each of the components contained in the solid composition.

[0071] In order to increase the amount of active ingredient in the solid composition, the contents of component (C-2) peony, licorice, and valerian in the solid composition may each independently be, for example, 0% by mass or more, more than 0%, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more relative to the total solid composition, in terms of the amount of the herbal drug. The total content of component (C-2) in the solid composition may also be, for example, 0% by mass or more, more than 0%, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more relative to the total amount of the herbal drug. Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the contents of component (C-2) peony, licorice, and valerian in the solid composition may each independently be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, calculated as the amount of the crude drug relative to the entire solid composition. The total content of component (C-2) in the solid composition may also be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, calculated as the amount of the crude drug.

[0072] The content of peony in the solid composition may be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass, in terms of the amount of crude drug relative to the entire solid composition. The content of peony in the solid composition may be 1.5 to 4.5% by mass, in terms of the amount of crude drug relative to the entire solid composition. The content of valerian in the solid composition may be 1 to 50 mass %, preferably 2 to 40 mass %, more preferably 3 to 20 mass %, in terms of the amount of the crude drug relative to the entire solid composition. The content of licorice in the solid composition may be 0.1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass, in terms of the amount of the crude drug relative to the entire solid composition.

[0073] The content of component (C-2) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C-2) to the total content of components (A) and (B) may be, for example, 1:0.001 to 1:10, preferably 1:0.01 to 1:5, and more preferably 1:0.05 to 1:3.

[0074] When the solid composition is a tablet, the proportions of component (C-2) peony, licorice, and valerian in the total mass of one tablet, as well as the total proportion of component (C-2), may be the same as the respective proportions described above relative to the total mass of the solid composition.

[0075] When the solid composition is in the form of granules, the proportions of component (C-2) peony, licorice, and valerian in the granules, as well as the total proportion of component (C-2), may be the same as the respective proportions described above relative to the entire solid composition.

[0076] (Component (C-3)) Salts of bromhexine include bromhexine hydrochloride. Salts of ambroxol include ambroxol hydrochloride. Salts of tipepidine include tipepidine citrate and tipepidine hibenzate.

[0077] The content of bromhexine and its salts (including their respective hydrates) in the solid composition is, for example, 0.6 mg to 24 mg, and preferably 1.2 mg to 12 mg, in anhydrous terms, as the amount of components contained in the solid composition per dosage unit (single dose) for adults. The content of ambroxol and its salts (including their respective hydrates) in the solid composition is, for example, 2 to 90 mg, and preferably 4.5 to 45 mg, in anhydrous terms, of the components contained in one dosage unit (single dose) for adults. The content of tipepidine and its salts (including their respective hydrates) in the solid composition is, for example, 5 to 140 mg, and preferably 20 to 100 mg, in terms of anhydrous form, of the components contained in the solid composition per dosage unit (single dose) for adults.

[0078] When the solid composition is a tablet, the content of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in one tablet may be the same as the above-mentioned amounts of each component contained in the solid composition. When the solid composition is in the form of granules, the content of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in the granules may be the same as the above-mentioned amounts of each of the components contained in the solid composition.

[0079] In order to increase the amount of the active ingredient in the solid composition, the content of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in the solid composition may each independently be, for example, 0% by mass or more, more than 0% by mass, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more, calculated on an anhydrous basis, relative to the entire solid composition. The total content of component (C-3) in the solid composition, calculated on an anhydrous basis, may be, for example, 0% by mass or more, more than 0% by mass, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more.

[0080] Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the contents of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in the solid composition may each independently be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, calculated on an anhydrous basis, relative to the entire solid composition. The total content of component (C-3) in the solid composition may also be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, calculated on an anhydrous basis. The total content of component (C-3) in the solid composition is preferably 1.0 to 10 mass %, particularly preferably 3.5 to 6 mass %, based on the total mass of the solid composition.

[0081] The total content of bromhexine and its salts (including their respective hydrates) in the solid composition may be 0.01 to 10 mass%, preferably 0.1 to 1 mass%, and more preferably 0.3 to 0.5 mass%, calculated on an anhydrous basis, based on the total solid composition. The total content of ambroxol and its salts (including their respective hydrates) in the solid composition may be 0.01 to 10% by mass, preferably 0.1 to 5% by mass, and more preferably 1.0 to 2% by mass, calculated on an anhydrous basis based on the total solid composition. The total content of tipepidine and its salts (including their respective hydrates) in the solid composition may be 0.01 to 20% by mass, preferably 0.05 to 10% by mass, and more preferably 0.1 to 5% by mass, calculated on an anhydrous basis based on the total solid composition.

[0082] The content of component (C-3) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C-3) to the total of components (A) and (B) calculated on an anhydrous basis may be, for example, 1:0.0001 to 1:3, preferably 1:0.001 to 1:1.5, and more preferably 1:0.001 to 1:1.

[0083] When the solid composition is a tablet, the proportion of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in the total mass of one tablet, as well as the total proportion of component (C-3), may be the same as the respective proportions described above relative to the total solid composition.

[0084] When the solid composition is in the form of granules, the proportions of component (C-3) bromhexine, ambroxol, and tipepidine (including their respective salts and hydrates) in the granules, as well as the total proportion of component (C-3), may be the same as the respective proportions described above relative to the entire solid composition.

[0085] (Component (C-4)) Salts of clemastine include clemastine fumarate.

[0086] The content of clemastine and its salts (including their respective hydrates) in the solid composition is, for example, 0.1 mg to 8 mg, and preferably 0.3 mg to 4 mg, in terms of the anhydrous substance, of the components contained in the solid composition per dosage unit (single dose) for adults.

[0087] When the solid composition is in the form of a tablet, the content of component (C-4) clemastine and its salts (including their respective hydrates) in one tablet may be the same as the above-mentioned amounts of the components contained in the solid composition. When the solid composition is in the form of granules, the content of component (C-4) clemastine and its salts (including their respective hydrates) in the granules may be the same as the above-mentioned amounts of the components contained in the solid composition.

[0088] In order to increase the amount of the active ingredient in the solid composition, the content of component (C-4) clemastine and salts thereof (including their respective hydrates) in the solid composition may be, for example, 0% by mass or more, more than 0% by mass, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more, calculated on an anhydrous basis relative to the entire solid composition.

[0089] Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid composition and suppressing changes in properties, the content of component (C-4) clemastine and its salts (including their respective hydrates) in the solid composition may be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, calculated on an anhydrous basis, relative to the entire solid composition. The total content of component (C-4) in the solid composition may be, for example, 0.001 to 10 mass%, preferably 0.005 to 5 mass%, and more preferably 0.01 to 1 mass%, calculated on an anhydrous basis based on the entire solid composition.

[0090] The content of component (C-4) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C-4) to the total of components (A) and (B) calculated on an anhydrous basis may be, for example, 1:0.0001 to 1:3, preferably 1:0.001 to 1:1.5, and more preferably 1:0.001 to 1:1.

[0091] When the solid composition is a tablet, the proportion of component (C-4) clemastine and its salts (including their respective hydrates) in the total mass of one tablet may be the same as the above-mentioned proportion relative to the total mass of the solid composition.

[0092] When the solid composition is in the form of granules, the proportion of component (C-4) clemastine and salts thereof (including their respective hydrates) in the granules may be the same as the above-mentioned proportion relative to the entire solid composition.

[0093] (Component (C-5)) Salts of dextromethorphan include dextromethorphan hydrobromide hydrate and dextromethorphan phenolphthalin salt.

[0094] The content of dextromethorphan and its salts (including their respective hydrates) in the solid composition is, for example, 8 mg to 120 mg, and preferably 16 mg to 72 mg, in terms of the anhydrous substance, of the components contained in one dosage unit (single dose) for adults.

[0095] When the solid composition is in the form of a tablet, the content of component (C-5) dextromethorphan (including salts and hydrates) in one tablet may be the same as the above-mentioned amount of the component contained in the solid composition. When the solid composition is in the form of granules, the content of component (C-5) dextromethorphan (including salts and hydrates) in the granules may be the same as the above-mentioned amount of the component contained in the solid composition.

[0096] From the viewpoint of increasing the amount of the active ingredient in the solid composition, the content of component (C-5) dextromethorphan (including salts and hydrates) in the solid composition, calculated on an anhydrous basis relative to the entire solid composition, may be, for example, 0% by mass or more, more than 0% by mass, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1.0% by mass or more, 5.0% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more.

[0097] Furthermore, from the viewpoint of making the hardness and disintegrability of the solid composition more preferable and suppressing changes in properties, the content of component (C-5) dextromethorphan (including salts and hydrates) in the solid composition, calculated as the anhydrous substance relative to the entire solid composition, may be, for example, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, 3.0% by mass or less, or 1.0% by mass or less. The total content of component (C-5) in the solid composition may be, for example, 0.01 to 10 mass%, preferably 0.05 to 5 mass%, and more preferably 0.1 to 3 mass%, calculated on an anhydrous basis based on the entire solid composition.

[0098] The content of component (C-5) in the solid composition may be adjusted according to the total content of components (A) and (B). In the solid composition, the mass ratio of component (C-5) to the total of components (A) and (B) calculated on an anhydrous basis may be, for example, 1:0.001 to 1:3, preferably 1:0.001 to 1:1.5, and more preferably 1:0.001 to 1:1.

[0099] When the solid composition is a tablet, the proportion of component (C-5) dextromethorphan (including each salt thereof) in the total mass of one tablet, as well as the total proportion of component (C-5), may be the same as the above-mentioned respective proportions relative to the total mass of the solid composition.

[0100] When the solid composition is in the form of granules, the proportion of component (C-5) dextromethorphan (including each salt thereof) in the granules, as well as the total proportion of component (C-5), may be the same as the above-mentioned respective proportions relative to the entire solid composition.

[0101] (Other ingredients) From the viewpoint of improving the storage stability of the solid composition, the moisture value (moisture content) of the solid composition is preferably less than 5% by mass, more preferably 4% by mass or less, even more preferably 3% by mass or less, and even more preferably 2% by mass or less, based on the total mass of the solid composition. The water content of the solid composition is specifically 0% by mass or 0% by mass or more, and may be, for example, 0.01% by mass or 0.05% by mass or more, based on the total mass of the solid composition. Specifically, the moisture content of the solid composition can be obtained by measuring the loss on drying (LOD) when heated at 80°C until the mass fluctuation is 1 mg / 50 seconds using a halogen moisture meter.

[0102] The solid composition may further contain components other than those described above. Such additives include one or more selected from the group consisting of pharmaceutically acceptable carriers, such as excipients, binders, disintegrants (as extragranular components), disintegration aids, lubricants, fluidizing agents, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, refreshing agents, flavors, fragrances, colorants, bases, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. These may be, for example, formulation additives that can be used in conventionally known solid compositions.

[0103] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, anhydrous calcium hydrogen phosphate (as an extragranular component), anhydrous calcium hydrogen phosphate granules (as an extragranular component), calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-silica gel Examples of the sugar-soluble starch include one or more selected from the group consisting of crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose (as an extragranular component), dextrin, corn starch, corn starch granules, trehalose, lactose hydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, and fructose.

[0104] Examples of binders include one or more selected from the group consisting of gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0105] Examples of disintegrants include carboxymethylethyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, etc. These may be used alone or in combination of two or more.

[0106] Examples of disintegration aids include one or more selected from the group consisting of carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, and macrogol 4000.

[0107] Examples of lubricants include one or more selected from the group consisting of magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oils, and sodium stearyl fumarate.

[0108] Examples of the fluidizing agent include one or more selected from the group consisting of synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, calcium triphosphate, talc, and calcium hydrogen phosphate granules.

[0109] Examples of glossing agents include one or more selected from the group consisting of carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0110] Examples of the foaming agent include one or more selected from the group consisting of dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, and anhydrous citric acid.

[0111] Examples of moisture-proofing agents include one or more selected from the group consisting of ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, and polyvinyl acetal diethylaminoacetate.

[0112] Examples of surfactants include one or more selected from the group consisting of sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0113] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, and cetylpyridinyl chloride. Ingredients: ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-lysine glutamate, crystalline sodium dihydrogen phosphate, chondroitin Sodium sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and one or more selected from the group consisting of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0114] Examples of the emulsifier include one or more selected from the group consisting of glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids.

[0115] Examples of antioxidants include one or more selected from the group consisting of citric acid hydrate, soybean lecithin, tocopherol, tocopherol acetate, and sodium pyrosulfite.

[0116] Examples of the filler include one or more selected from the group consisting of RSS No. 1 crude rubber, starch acrylate 1000, titanium oxide, and calcium hydrogen phosphate.

[0117] Examples of preservatives include one or more selected from the group consisting of benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0118] Examples of sweeteners include one or more selected from the group consisting of aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, xylitol, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, and erythritol.

[0119] Examples of flavoring agents include one or more selected from the group consisting of sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil.

[0120] Examples of the cooling agent include one or more selected from the group consisting of fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0121] Examples of flavorings include one or more selected from the group consisting of orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0122] Examples of fragrances include one or more selected from the group consisting of fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0123] Examples of colorants include one or more selected from the group consisting of yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, ferric oxide, diaz azo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide-glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0124] Examples of bases include powdered acacia, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropyl cellulose, hypromellose, hydroxypropyl cellulose ... Examples of the surfactant include one or more selected from the group consisting of romerose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0125] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, aqueous ethyl cellulose dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. and one or more selected from the group consisting of cellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0126] Examples of sugar-coating agents include one or more selected from the group consisting of gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0127] Examples of the plasticizer include one or more selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0128] Examples of dispersing agents include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose (as an extragranular component), dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, Examples of the surfactant include one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, and sodium lauryl sulfate.

[0129] Examples of the antifoaming agent include one or more selected from the group consisting of ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, and polysorbate 80.

[0130] The solid composition may further contain other active ingredients as needed. However, the content of vitamins, herbal medicines, expectorant ingredients, antihistamines, antitussive ingredients, and anti-inflammatory ingredients that do not fall under component (C) is preferably adjusted within a range that does not impair the effects of the present invention, and it is preferable that these ingredients are not included. Specifically, the total content of vitamins, herbal medicines, expectorant ingredients, antihistamines, antitussive ingredients, and anti-inflammatory ingredients that do not fall under component (C) is preferably 20 parts by mass or less, 10 parts by mass or less, 5 parts by mass or less, 1 part by mass or less, 0.5 parts by mass or less, or 0.1 parts by mass or less per 100 parts by mass of the total content of component (C). However, even if such ingredients are included, they may be appropriately blended as long as they do not cause any change in properties when combined with at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. Furthermore, they may be appropriately blended if the change in properties can be suppressed by other formulation techniques, such as granulation.

[0131] Other active ingredients that may be contained in the solid composition include, for example, one or more selected from the group consisting of antipyretic analgesics, xanthine derivatives, sedatives, and anticholinergic agents. These ingredients may be blended as appropriate within a range that does not impair the effects of the present invention. If there are any contraindications for blending, they may be formulated by granulating them as appropriate. The total content of the antipyretic analgesics, xanthine derivatives, sedatives, and anticholinergic agents is preferably 200 parts by weight or less, 100 parts by weight or less, 50 parts by weight or less, 40 parts by weight or less, 30 parts by weight or less, 20 parts by weight or less, 15 parts by weight or less, 10 parts by weight or less, 5 parts by weight or less, 1 part by weight or less, 0.5 parts by weight or less, or 0.1 parts by weight or less, per 100 parts by weight of the total content of component (A).

[0132] Examples of antipyretic analgesics include one or more selected from the group consisting of aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, prazolophen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate, and tiaramide hydrochloride.

[0133] Examples of xanthine derivatives include one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.

[0134] The sedative may include, for example, at least one selected from the group consisting of allylisopropylacetylurea and bromvalerylurea.

[0135] Examples of anticholinergic agents include one or more selected from the group consisting of scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia extract, Scopolia root, and Scopolia root total alkaloid citrate.

[0136] Examples of antitussives and expectorants other than component (C) include one or more selected from the group consisting of codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, noscapine, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, and L-ethylcysteine ​​hydrochloride.

[0137] Examples of antihistamines other than component (C) include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine ... Examples include one or more selected from the group consisting of phenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, difeterol hydrochloride, methdilazine hydrochloride, mebhydroline napadisilate, promethazine methylenedisalicylate, and difeterol phosphate.

[0138] Examples of anti-inflammatory agents other than component (C) include one or more selected from the group consisting of glycyrrhizinic acid, its derivatives and salts thereof (e.g., dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, its derivatives and salts thereof (e.g., potassium glycyrrhetinate, sodium glycyrrhetinate, ammonium glycyrrhetinate, etc.), and tranexamic acid.

[0139] Examples of vitamins other than component (C) include one or more selected from the group consisting of vitamin A, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, an equal mixture of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine.

[0140] The solid composition of this embodiment can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient, ingredient (A), has antipyretic, analgesic, and anti-inflammatory effects, it can be suitably used as an antipyretic analgesic, specifically for the pain relief of headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, fracture pain, sprain pain, and trauma pain, as well as for the fever reduction associated with chills and fever. It can also be suitably used as a cold remedy for the relief of cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0141] (Dosage form) The solid composition of this embodiment can be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as preparations for oral administration (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, powders, etc.), preparations for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition of this embodiment is preferably an oral solid composition.

[0142] The dosage form of the solid composition of this embodiment may be, for example, a tablet, a capsule, a pill, a granule, or a fine granule. These solid compositions may be coated with sugar coating, film coating, or the like by a known method, as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0143] The solid composition of this embodiment may be temporarily packaged in a bottle, PTP, pouch, stick, or SP package and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and examples include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. If moisture absorption is a concern, a desiccant or the like may be stored in the bottle or pillow packaging.

[0144] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition of this embodiment may be contained in, for example, an airtight package. By forming the solid composition into a package, for example, convenience during use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0145] As for the packaging form of the solid preparation, the solid composition may be temporarily packaged and stored airtight in a bottle, PTP (Press-Through Package), pouch, stick, or SP (Strip Package) or the like. These may also be pillow-packaged, or may be stored in a box or the like. Furthermore, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant or the like may be stored in the packaging container, such as the bottle or pillow package, at the same time.

[0146] Materials used for SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0147] Furthermore, it is preferable that the material constituting the packaging container contains a material that is resistant to the effects of moisture. Examples of such packaging include packaging made of at least one of a moisture-proof material and a gas barrier material. An example of a moisture-proof material is a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. When the solid composition is a tablet, PTP packaging (Al-Al packaging) with aluminum on both sides may be used as the moisture-proof material, taking into consideration the prevention of an increase in the moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening. Any known gas barrier material may be used, for example, a laminate film having a functional barrier layer, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material.

[0148] Furthermore, the packaging container may be environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material.

[0149] (Manufacturing method) In a second aspect, there is provided a method for producing the solid composition of the present embodiment, which includes the step of contacting components (A) and (B). In the production method of the present embodiment, preferably, after the step of contacting components (A) and (B), component (C) is further added to produce a solid composition containing components (A) to (C).

[0150] However, the solid composition of this embodiment can be produced by mixing components (A) to (C). The order of mixing the components is not particularly limited, and the components may be mixed in any conceivable order, such as mixing components (A) and (B) and then mixing component (C), or mixing components (A) to (C) simultaneously.

[0151] The step of contacting components (A) and (B) may be, for example, a step of mixing powders of components (A) and (B). Alternatively, the step of contacting components (A) and (B) may be a step of contacting the two components more strongly, such as a step of mixing powders of components (A) and (B) while applying an impact force, or a step of mixing while heating until either component (A) or (B) melts, or a step of mixing in the presence of a suitable solvent. Examples of such a step include at least one of mixing and grinding, heating and melting, crystallization in the presence of a solvent, kneading, and spraying.

[0152] The step of contacting components (A) and (B) preferably includes a step of contacting components (A) and (B) in the presence of a suitable solvent. In such a step, components (A) and (B) may be dissolved in a suitable solvent, followed by precipitation of a composite. Examples of methods for precipitating the composite include crystallization and spraying. The step of contacting components (A) and (B) in the presence of a suitable solvent may involve adding a suitable solvent before or during mixing of the powders of components (A) and (B), dissolving one of components (A) and (B) in a solvent and then adding the other powder, or dissolving components (A) and (B) separately in a solvent and then mixing the two components. Alternatively, the amount of solvent may be appropriately adjusted to contact components (A) and (B) in the presence of a suitable solvent, while simultaneously continuously precipitating the composite. Examples of such a step include a kneading step. Contacting components (A) and (B) in the presence of a solvent in this way tends to produce a composite that is less susceptible to property changes in the solid composition.

[0153] The solvent used in the step of contacting components (A) and (B) in the presence of a suitable solvent is not particularly limited, and may be water, methanol, ethanol, acetone, dimethyl sulfoxide, or a mixture of one or more of these. The contact of components (A) and (B) may be carried out while heating, and the heating temperature may be, for example, 30 to 110°C. A method for forming a composite of components (A) and (B) may be, for example, a step of kneading components (A) and (B) in the presence of a suitable solvent.

[0154] Component (C) is preferably blended with the mixture obtained in the above step. In this case, the manufacturing method of this embodiment includes a step of contacting the mixture with component (C). After the mixing step, the mixture may be pulverized in a mortar or the like before being contacted with component (C), or may be pulverized and then sieved with an appropriate size before being contacted with component (C). The mixture and component (C) may be mixed in a powder state, or a uniform mixed powder may be obtained by performing mixing and sieving once or twice or more times.

[0155] In the production method of this embodiment, subsequent steps can be carried out using steps used in general production methods for solid compositions. Such production methods include granulation, examples of which include wet granulation methods such as high-speed stirring granulation and fluidized bed granulation.

[0156] In this embodiment, the method for producing the solid composition may include, for example, forming granules using the mixed powder of components (A) to (C) obtained as described above, and then forming a solid preparation from the granules. In this way, the solid composition of this embodiment can be formulated according to the dosage form in accordance with a conventional method.

[0157] For example, when the solid preparation is a tablet, the tablet can be manufactured in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations. Specifically, the mixed powder containing components (A) to (C) is granulated to obtain granules, and then the obtained granules and any extragranular components are compressed into tablets.

[0158] When a solid formulation contains an extragranular component, a final component may be added to the granulated granules to form the granulated granule outer layer, and the mixture may be compressed to produce a tablet. The extragranular component may also be in the form of granules. For example, granulated granules containing components (A) to (C) may be produced as the first granules, and granulated granules containing the other active ingredient(s) may be produced as the second granules. That is, the solid formulation may be constructed such that the first granules containing components (A) to (C) and the second granules containing the other active ingredient(s) are separately prepared, and the components (A) to (C) in the first granules and the other active ingredient(s) in the second granules are not substantially in contact with each other. The other active ingredient(s) may be contained in either the first granules or the second granules, so as to obtain a suitable formulation.

[0159] The granules obtained in the above steps may be used as a granule formulation as they are.

[0160] (Property change inhibitor) In a third embodiment, a property change inhibitor for a solid composition, the property change inhibitor comprising fructose, and the solid composition comprising: (I) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (II) The following: (II-1) Vitamin B1 and vitamin C; (II-2) Peony, licorice, and valerian; (II-3) Bromhexine, ambroxol, tipepidine, their salts and their hydrates; (II-4) Clemastine, its salts and hydrates thereof; and (II-5) Dextromethorphan, its salts and hydrates thereof; One or more components selected from the group consisting of: The property change inhibitor of this embodiment contains fructose, and therefore can suppress property change of a solid composition containing components (I) and (II).

[0161] Fructose is as described for component (B) of the solid composition of this embodiment, and components (I) and (II) are as described for components (A) and (C) of the solid composition of this embodiment. Fructose is preferably blended in an amount as described for component (B) of the solid composition of this embodiment, and components (I) and (II) are preferably blended in an amount as described for components (A) and (C) of the solid composition of this embodiment.

[0162] Fructose is preferably complexed with component (I), specifically, fructose and component (I) are complexed in a molar ratio of 1:1. The complexation method is as described above.

[0163] The present invention will be explained in more detail below with reference to examples and comparative examples, but the present invention is not limited to these. [Example]

[0164] [Preparation Example 1] A 50 mL vial for mixing and grinding was charged with 0.2827 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE), 0.1674 g of D-fructose (Kato Kagaku), and eight 7.9 mm diameter stainless steel beads, so that the molar ratio of loxoprofen to fructose was 1:1. 10 μL of ethanol was then added. The mixture was then ground (50 Hz) for 10 minutes using a mixer mill (8000D MXER / MILL, SPEX Corporation) to obtain a sample. The sample was then dried under reduced pressure overnight at room temperature to obtain a specimen.

[0165] [Preparation Example 2] Preparation was carried out in the same manner as in Preparation Example 1, except that the added solvent was changed to 10 μL of water, to obtain a sample.

[0166] [Preparation Example 3] 502.6 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE) and 297.4 g of D-fructose (Kato Kagaku) ​​were placed in a stirring mixer / granulator (VG-25, Powrex) so that the molar ratio of loxoprofen sodium to fructose was 1:1. After mixing, 32 g of purified water was added and kneaded. The mixture was then granulated using a Power Mill (Dalton) and dried in a fluidized bed apparatus (MP-01, Powrex) to obtain the sample.

[0167] [Test Example 1] Powder X-ray diffraction analysis was carried out on loxoprofen sodium dihydrate (KOLON LIFE SCIENCE), D-fructose (Kato Kagaku), the sample prepared in Preparation Example 1, the sample prepared in Preparation Example 2, and the sample prepared in Preparation Example 3. Powder X-ray diffraction was measured using the Empyrean multipurpose X-ray diffractometer (PANalytical) by the reflection method after pulverizing each sample in a mortar. The measurement conditions were as follows: (Measurement conditions) X-ray generation conditions: 45kV, 40mA ·Wavelength: 1.54Å (CuKα ray) ·Measurement temperature: room temperature Sample holder: Non-reflective sample holder Scan range: 3~40° Scan step size: 0.0131303° Time per step: 43.095 seconds

[0168] The powder X-ray diffraction patterns of each sample are shown in Figure 1. The powder X-ray diffraction patterns of the samples prepared in Preparation Examples 1, 2, and 3 showed characteristic diffraction peaks not observed in the powder X-ray diffraction patterns of loxoprofen sodium dihydrate and D-fructose. As shown in Figure 1, the powder X-ray diffraction patterns of the samples prepared in Preparation Examples 1 to 3 contained diffraction peaks in the diffraction angle ranges 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3°, and 16.0 ± 0.3°. These measurement results indicated that the preparation procedures in Preparation Examples 1, 2, and 3 all produced complexes of loxoprofen sodium and fructose with the same crystalline structure.

[0169] [Preparation Example 4] The sample prepared in Preparation Example 3 was mixed with powders of the components listed in Table 1 and sieved to obtain a solid composition. The components listed in Table 1 were blended so that the molar ratio of the components to the complex of loxoprofen sodium and fructose was 1:1. The molecular weight of the complex of loxoprofen sodium and fructose was calculated as 448.47. However, because the molecular weights of the dried peony extract and valerian extract are not constant, they were mixed with the complex of loxoprofen sodium and fructose in equal amounts. Valerian extract was mixed with an equal amount of crystalline cellulose PH-101 before incorporation.

[0170] [Table 1]

[0171] [Preparation Example 5] Solid compositions containing the components listed in Table 1 were prepared in the same manner as in Preparation Example 4, except that loxoprofen sodium dihydrate was used instead of the sample prepared in Preparation Example 3.

[0172] [Test Example 2] Approximately 2 g of each of the solid compositions prepared in Preparation Examples 4 and 5 was placed in a glass bottle, and the bottle was sealed and stored at 60°C for 2 weeks.

[0173] After two weeks, the changes in the properties of each solid composition were evaluated according to the following criteria, and the results are shown in Table 2. (Color change) A: No discoloration, B: Slight discoloration, C: Discoloration, D: Significant discoloration (Agglomeration and wetting) A: No agglomeration or wetting, B: Slight agglomeration or wetting, C: Agglomeration or wetting, D: Significant agglomeration or wetting

[0174] In addition, a spectrophotometer (SE7700: manufactured by Nippon Denshoku Industries Co., Ltd.) was used to measure the brightness (L * ), and chromaticity (a * , b * ) was measured, and the color difference (ΔE * ab The results are shown in Table 2.

number

[0175] ΔL * : The brightness (L * ) difference Δa * : Color intensity (a) of the sample at each time point of storage and the sample at the start of storage * ) difference Δb * : Color intensity (b) of the sample at each time point and the sample at the start of storage * ) difference

[0176] [Table 2]

[0177] [Test Example 3] The following test was conducted to confirm the effectiveness of fructose-induced suppression of property changes in both the case of containing loxoprofen sodium dihydrate and the case of containing loxoprofen sodium anhydrous. The solid compositions prepared in Preparation Examples 4 and 5 were dried at 60°C for 3 hours, and approximately 1 g of each was placed in glass bottles to ensure uniform thickness. The glass bottles were sealed and stored at 60°C for 2 weeks, after which property changes were evaluated in the same manner as in Experimental Example 1. Color difference was not measured. The results are shown in Table 3.

[0178] [Table 3]

[0179] [Test Example 4] Approximately 1 to 2 g of each of the solid compositions prepared in Preparation Examples 4 and 5 was placed in a plastic petri dish so that the thickness was uniform. The sample was stored in an open system at 40°C and a relative humidity of 75% for 2 weeks.

[0180] After two weeks, the changes in the properties of each solid composition were evaluated according to the following criteria, and the results are shown in Table 4. (Color change) A: No discoloration, B: Slight discoloration, C: Discoloration, D: Significant discoloration (Agglomeration and wetting) A: No agglomeration or wetting, B: Slight agglomeration or wetting, C: Agglomeration or wetting, D: Significant agglomeration or wetting

[0181] Approximately 0.1 g of each of the solid compositions prepared in Preparation Examples 4 and 5 was weighed into a plastic petri dish and stored in an open system at 40°C and a relative humidity of 75% for 24 hours. The change in mass before and after 24 hours of storage was calculated, and the hygroscopicity was evaluated as the mass increase (%). The results are shown in Table 4. In Table 4, the hygroscopicity is negative, especially when valerian extract is included, which is thought to be due to the evaporation of water from the valerian extract.

[0182] [Table 4]

[0183] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention. [Industrial Applicability]

[0184] In this embodiment, the solid composition has excellent storage stability and is therefore extremely useful in terms of quality. The solid composition of this embodiment is suitable for use as an antipyretic analgesic, specifically for relieving pain from headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, fracture pain, sprain pain, and trauma pain, as well as for reducing fever during chills and fever, and is also suitable for use as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims

1. 1. A solid composition comprising: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) fructose, (C) the following: (C-1) Vitamin B1 and vitamin C; (C-2) Peony, licorice, and valerian; (C-3) bromhexine, ambroxol, tipepidine, salts thereof, and hydrates thereof; (C-4) clemastine, its salts and hydrates thereof; and (C-5) dextromethorphan, its salts, and hydrates thereof; and one or more ingredients selected from the group consisting of:

2. 10. The solid composition of claim 1, comprising a complex in which components (A) and (B) are complexed.

3. 3. The solid composition of claim 2, wherein the molar ratio of components (A) and (B) in the composite is 1:

1.

4. The solid composition according to any one of claims 1 to 3, comprising loxoprofen sodium as component (A).

5. The solid composition according to claim 2 or 3, wherein the complex has diffraction peaks at diffraction angles 2θ=4.4±0.3° and 16.0±0.3° in a powder X-ray diffraction pattern.

6. 4. The solid composition according to claim 2 or 3, wherein the complex has diffraction peaks at diffraction angles 2θ=4.4±0.3°, 8.8±0.3°, 10.1±0.3°, and 16.0±0.3° in a powder X-ray diffraction pattern.

7. A method for producing the solid composition according to any one of claims 1 to 3, comprising the steps of: contacting components (A) and (B).

8. 8. The method of claim 7, wherein the contacting is carried out by at least one of the following processes: co-grinding, heating and melting, crystallizing in the presence of a solvent, kneading, and spraying.

9. 9. The method of claim 8, further comprising contacting the mixture of components (A) and (B) with component (C).

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