Solid composition and method of manufacture

Abstract

The invention relates to solid compositions and methods of manufacture. The present invention addresses the problem of providing a solid composition which contains at least one component selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, and another component, and in which changes in properties are suppressed. [Solution] A solid composition containing the following components: (A) at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; (B) fructose; and (C) one or more components selected from the group consisting of: (C-1) vitamin B1 and vitamin C; (C-2) Chinese herbaceous peony, liquorice and valerian; (C-3) bromhexine, ambroxol, tepiperidine, salts thereof, and hydrates thereof; (C-4) clomastine, salts thereof, and hydrates thereof; and (C-5) dextromethorphan, salts thereof, and hydrates thereof.

Description

Technical Field

[0001] The present invention relates to a solid composition comprising at least one of the groups selected from loxoprofen, its salts and their hydrates, fructose and other components, and a method thereof for manufacturing the same. Background Technology

[0002] It is known that solid compositions formed by mixing loxoprofen, its salts and their hydrates with certain ingredients can undergo changes in properties over time, and research is underway related to the stabilization of loxoprofen.

[0003] Patent document 1 discloses that if loxoprofen sodium coexists with bromhexine hydrochloride, the color and properties will change over time, and the content of bromhexine hydrochloride will decrease. However, this decrease in content can be suppressed by combining it with synthetic hydrotalcite or hydrated silica.

[0004] Patent documents 2-4 disclose that if loxoprofen sodium and chlormastine fumarate coexist, color and properties will change over time, and the content of chlormastine fumarate will decrease. However, this decrease in content can be suppressed by combining it with hydrated silica, light anhydrous silicic acid or calcium silicate.

[0005] Patent document 5 discloses that if loxoprofen sodium is coexisted with ambroxol hydrochloride, its color and properties will change over time, but its stability can be improved by storing the mixture in the presence of a desiccant.

[0006] In addition, Non-Patent Document 1 discloses that: Loxoprofen sodium forms a salt eutectic with fructose, and the salt eutectic of loxoprofen sodium and fructose maintains the anhydrous crystal form even under high humidity.

[0007] Existing technical documents

[0008] Patent documents

[0009] Patent Document 1: Japanese Patent Application Publication No. 2012-140420

[0010] Patent Document 2: Japanese Patent Application Publication No. 2014-12661

[0011] Patent Document 3: Japanese Patent Application Publication No. 2017-186384

[0012] Patent Document 4: Japanese Patent Application Publication No. 2019-14760

[0013] Patent Document 5: Japanese Patent Application Publication No. 2016-155860

[0014] Non-patent literature

[0015] Non-patent document 1: Doctoral thesis "Elucidation of the mechanism of inhibiting the formation of loxoprofen sodium hydrate by forming a salt co-crystal between loxoprofen sodium and sugar "Crystal Formation Inhibition of Crystal Formation" (2022) Takayuki Fujito (Chiba Daiin Pharmacy) Summary of the Invention

[0016] The problem that the invention aims to solve

[0017] The problem to be solved by the present invention is to provide a solid composition containing at least one of the following ingredients selected from the group consisting of loxoprofen, its salts and their hydrates, and other ingredients, wherein changes in properties are inhibited.

[0018] Methods for solving problems

[0019] The inventors of this application surprisingly discovered that, in components that are prone to morphological changes due to combination with at least one of the groups selected from loxoprofen, its salts and their hydrates, morphological changes can be suppressed by coexisting a specific component with fructose, thus completing the present invention.

[0020] That is, this application includes the following inventions.

[0021] [1] A solid composition comprising the following components:

[0022] (A) Select at least one from the group consisting of loxoprofen, its salts and their hydrates;

[0023] (B) Fructose; and

[0024] (C) Select one or more of the following components from the group consisting of:

[0025] (C-1) Vitamin B1 and Vitamin C;

[0026] (C-2) Peony, licorice, and valerian;

[0027] (C-3) Bromhexine, Ambroxol, Tiperidine, their salts and their hydrates;

[0028] (C-4) chlormastine, its salts, and their hydrates; and

[0029] (C-5) Dextromethorphan, its salts and their hydrates.

[0030] [2] The solid composition as described in [1] comprises a composite formed by combining components (A) and (B).

[0031] [3] The solid composition as described in [2], wherein the molar ratio of component (A) to (B) in the aforementioned composite is 1:1.

[0032] [4] The solid composition as described in any one of [1] to [3] contains loxoprofen sodium as component (A).

[0033] [5] The solid composition as described in any one of [1] to [4], wherein the aforementioned composite has diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3° and 16.0 ± 0.3° in an X-ray powder diffraction pattern.

[0034] [6] The solid composition as described in any one of [1] to [5], wherein the aforementioned composite has diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3° and 16.0 ± 0.3° in an X-ray powder diffraction pattern.

[0035] [7] A method for manufacturing a solid composition as described in any one of [1] to [6], comprising a step of contacting component (A) with (B).

[0036] [8] The method as described in [7], wherein the aforementioned contact is carried out by at least one of the steps of mixing and crushing, heating and melting, crystallization in the presence of a solvent, kneading and spraying.

[0037] [9] The method as described in [8] further includes the step of contacting component (C) with a mixture of components (A) and (B).

[0038] The effects of the invention

[0039] According to the present invention, it is possible to provide a solid composition containing at least one of the groups selected from loxoprofen, its salts and their hydrates, and other components, wherein changes in property are suppressed. Attached Figure Description

[0040] [ Figure 1 ] Figure 1 The diffraction patterns of the X-ray powder diffraction analysis of each specimen measured in the examples are shown. Detailed Implementation

[0041] Hereinafter, embodiments of the present invention (hereinafter referred to as "this embodiment") will be described, but the scope of the present invention is not to be construed as limited to the following embodiments. In this embodiment, the composition may contain each component individually or in combination of two or more components. In this specification, "~" indicating a numerical range means above or below, and the values ​​at both ends are inclusive.

[0042] (Solid composition)

[0043] In the first method, a solid composition is provided, comprising the following components:

[0044] (A) Select at least one from the group consisting of loxoprofen, its salts and their hydrates;

[0045] (B) Fructose; and

[0046] (C) Select one or more of the following components from the group consisting of:

[0047] (C-1) Vitamin B1 and Vitamin C;

[0048] (C-2) Peony, licorice and valerian;

[0049] (C-3) Bromhexine, Ambroxol, Tiperidine, their salts and their hydrates;

[0050] (C-4) chlormastine, its salts, and their hydrates; and

[0051] (C-5) Dextromethorphan, its salts and their hydrates.

[0052] In addition, specifically, the solid composition is a solid pharmaceutical composition.

[0053] In this embodiment, the component (C) is selected from at least one of the groups consisting of loxoprofen, its salts and their hydrates, and also includes the component (B). Therefore, changes in the properties of the solid composition, especially changes in properties over time, are suppressed.

[0054] In this specification, "change in properties" refers to changes in properties and / or state, including at least aggregation, discoloration, hygroscopicity, and wetting. Therefore, in the case of the solid composition of this embodiment, any one of aggregation, discoloration, hygroscopicity, and wetting that occurs over time is suppressed. Furthermore, "suppression of changes in properties" means that changes in properties are less likely to occur; for example, changes in properties are suppressed compared to a solid composition that does not contain component (B) described above.

[0055] For example, the solid composition of this embodiment, compared with a solid composition having the same composition except for the absence of component (B) described above, shows a color difference ΔE before and after storage at 60°C in a sealed container for 2 weeks. ＊ It can be reduced by 5, 7, 8, 10, 12, 15, or 20 or more. This color difference ΔE ＊ The change can be below 50, below 40, or below 30.

[0056] The solid composition of this embodiment can suppress changes in its properties under high temperature and / or high humidity conditions. High temperature conditions can be, for example, 30–80°C, 35–75°C, or 50–70°C. High humidity conditions can be, for example, a relative humidity of 50% or more, 60% or more, or 70% or more.

[0057] In the solid composition of this embodiment, the period during which property changes are suppressed is not particularly limited. For example, it can be more than 1 week, more than 2 weeks, more than 4 weeks, more than 1 month, or more than 2 months.

[0058] In the solid composition of this embodiment, component (A) and component (C) preferably do not come into contact when component (B) is absent. For example, it is preferable to contain them in the form of granules that include all of component (A), component (B) and component (C). It is also preferable that the granules containing component (A) and component (B) and the granules containing component (C) are contained in separate granules.

[0059] (ingredient (A))

[0060] Component (A) is selected from at least one of the groups consisting of loxoprofen, its salts and their hydrates. That is, loxoprofen and its salts can be hydrates (hydrated salts).

[0061] Component (A) is preferably at least one selected from the group consisting of loxoprofen salts and their hydrates, more preferably at least one selected from the group consisting of loxoprofen sodium salts and their hydrates, and even more preferably loxoprofen sodium salt dihydrate. Loxoprofen sodium dihydrate is included as loxoprofen sodium hydrate in the 18th edition of the Japanese Pharmacopoeia.

[0062] The amount of component (A) contained in each dose (one-time dose) of the solid composition for an adult is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, based on anhydrous equivalent. Furthermore, the frequency of administration is preferably 1 to 3 times per day.

[0063] The weight and dosage of component (A) described above represent one adult dose (single administration). However, as mentioned above, this amount can also be administered to the subject multiple times throughout the day, for example, two or three times, preferably three times. The same applies to components other than component (A). Furthermore, each administration amount is a total amount, therefore the content of each component contained in the composition may vary depending on the single administration amount, the dosage form of the composition, etc.

[0064] When the solid composition is in the form of a tablet, when used as an antipyretic analgesic, the content of component (A) in one tablet, calculated as anhydrous matter, is preferably 30 to 180 mg, more preferably 50 to 120 mg, and even more preferably 60 to 90 mg.

[0065] When used as a cold medicine, the content of ingredient (A) in one tablet, calculated as anhydrous matter, is preferably 10 mg to 90 mg, more preferably 15 mg to 60 mg, and even more preferably 20 to 30 mg.

[0066] By keeping the content of component (A) within the above range, the antipyretic, analgesic, or anti-inflammatory effects of the solid composition can be further enhanced, and the hardness and disintegration properties of the tablets can be made more satisfactory, further inhibiting changes in appearance.

[0067] It should be noted that, in this instruction manual, the content of each component in one tablet can be appropriately adjusted according to the number of tablets administered at one time. The content of each component in one tablet as described in this instruction manual can be appropriately set to a fixed multiple such as 3 times, 2 times, half, one-third times, one-quarter times, one-fifth times, or one-sixth times, within the range of the content of each component in each administered unit.

[0068] When the solid composition is in the form of granules, the amount of component (A) contained in each adult administration unit (one administration dose) of the solid composition is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, and can be 60 to 90 mg, as the amount of component (A) contained in the granules in anhydrous form.

[0069] From the viewpoint of increasing the effective components in the solid composition, the content of component (A) in the solid composition, relative to the solid composition as a whole, can 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.

[0070] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the content of component (A) in the solid composition as anhydrous is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, relative to the solid composition as a whole.

[0071] When used as an antipyretic and analgesic, the content of component (A) in the solid composition, relative to the solid composition as a whole, can be 1 to 80% by mass when converted to anhydrous matter, preferably 2 to 50% by mass, more preferably 5 to 30% by mass, and even more preferably 7 to 20% by mass.

[0072] When used as a cold medicine, the content of component (A) in the solid composition, relative to the solid composition as a whole, can be 0.01% to 20% by mass when converted to anhydrous form, preferably 0.03% to 15% by mass, and more preferably 0.04% to 10% by mass.

[0073] When the solid composition is in the form of a tablet, from the viewpoint of increasing the effective ingredient in the tablet, the proportion of ingredient (A) in the total mass of one tablet, converted to anhydrous matter, can 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.

[0074] Furthermore, from the viewpoint of making the tablet hardness and disintegration more satisfactory and inhibiting changes in properties, the proportion of component (A) in the total mass of one tablet, converted to anhydrous matter, is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less.

[0075] When used as an antipyretic and analgesic, the proportion of component (A) in the total mass of one tablet, converted to anhydrous matter, can 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.

[0076] When used as a cold medicine, the proportion of component (A) in the total weight of one tablet, converted to anhydrous form, can be 0.01% to 20% by mass, preferably 0.03% to 15% by mass, and more preferably 0.04% to 10% by mass.

[0077] When the solid composition is in the form of granules, from the viewpoint of increasing the effective components of the solid composition, the content of component (A) in the granules, in anhydrous form, can be 0.01 parts or more, 1 part or more, 5 parts or more, 10 parts or more, 20 parts or more, 30 parts or more, 40 parts or more, 45 parts or more, 48 parts or more, 50 parts or more, 60 parts or more, or 65 parts or more, relative to 100 parts by mass of the granules.

[0078] Furthermore, from the viewpoint of making the hardness and disintegration of the particles more satisfactory and suppressing changes in properties, the content of component (A) in the particles, calculated as anhydrous matter, 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, relative to 100 parts by mass of the particles.

[0079] (Ingredient (B))

[0080] Component (B) is fructose. The fructose can be any of the L-form, D-form, and mixtures thereof including racemic forms, preferably D-fructose.

[0081] In this embodiment, in the solid composition, component (B) is preferably present by complexing with component (A). That is, the solid composition preferably contains a composite formed by complexing components (A) and (B). More preferably, the composite is formed by complexing components (A) and (B) in a molar ratio of 1:1. This composite can be obtained by contacting components (A) and (B), or by kneading components (A) and (B). The composite can be a eutectic of components (A) and (B), or a salt eutectic of components (A) and (B). The method for manufacturing the composite will be described later.

[0082] The so-called complexation of components (A) and (B) refers to a state in which the molecules of component (A) combine with molecules of component (B) to exhibit properties different from those of the monomers of components (A) and (B). For example, the complex of components (A) and (B) may have crystal structure characteristics different from those of the monomers of components (A) and (B). Alternatively, the complex of components (A) and (B) may have a melting point different from that of the monomers of components (A) and (B) as determined by differential scanning calorimetry (DSC). The complexation of components (A) and (B) can be confirmed, for example, by X-ray powder diffraction and / or differential scanning calorimetry (DSC).

[0083] The composite of components (A) and (B) preferably exhibits diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3° and 16.0 ± 0.3° in the X-ray powder diffraction pattern. More preferably, the composite of components (A) and (B) exhibits diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3°, and 16.0 ± 0.3° in the X-ray powder diffraction pattern. The composite of components (A) and (B) may exhibit at least one, at least two, at least three, or four diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3°, and 16.0 ± 0.3° in the X-ray powder diffraction pattern. It should be noted that the X-ray powder diffraction measurement conditions can be those described in the examples.

[0084] In differential scanning calorimetry, the composite of components (A) and (B) can have a melting point in the range of, for example, 140–170 °C, preferably 145–165 °C.

[0085] The content of component (B) in the solid composition can be adjusted according to the content of component (A). In the solid composition, the molar ratio of component (A) to component (B) can 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.

[0086] In one embodiment, the solid composition may comprise: a component (B) that forms a complex with component (A); and a component (B) that does not form a complex with component (A). In another embodiment, the solid composition may substantially not comprise a component (B) that does not form a complex with component (A).

[0087] In one embodiment, the solid composition may comprise: a component (A) that forms a complex with component (B); and a component (A) that does not form a complex with component (B). In another embodiment, the solid composition may substantially not comprise the component (A) that does not form a complex with component (B).

[0088] 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 can be 0-30% by mass, 0-10% by mass, 0-5% by mass, 0-3% by mass, 0-1% by mass, 0-0.5% by mass, or 0-0.1% by mass.

[0089] 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 can be 0-30% by mass, 0-10% by mass, 0-5% by mass, 0-3% by mass, 0-1% by mass, 0-0.5% by mass, or 0-0.1% by mass.

[0090] The amount of component (B) contained in each administration unit (one administration dose) of the solid composition for an adult is preferably 6 to 120 mg, more preferably 20 to 80 mg, and even more preferably 20 to 60 mg. Furthermore, the administration frequency is preferably 1 to 3 times per day.

[0091] When the solid composition is in the form of a tablet, and is used as an antipyretic analgesic, the content of component (B) in one tablet is preferably 20 to 120 mg, more preferably 30 to 80 mg, and even more preferably 40 to 60 mg.

[0092] When used as a cold medicine, the content of ingredient (B) in one tablet is 6mg to 60mg, preferably 10mg to 40mg, and more preferably 13mg to 20mg.

[0093] By keeping the content of component (B) within the above range, the hardness and disintegration of the tablets can be made more satisfactory, and changes in properties can be further inhibited.

[0094] When the solid composition is in the form of granules, the amount of component (B) contained in each adult administration unit (one administration dose) of the solid composition is preferably 6 to 120 mg, more preferably 20 to 80 mg, and even more preferably 20 to 60 mg.

[0095] From the viewpoint of inhibiting changes in properties, the content of component (B) in the solid composition, relative to the solid composition as a whole, can 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.

[0096] Furthermore, from the viewpoint of increasing the effective components 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, relative to the solid composition as a whole.

[0097] When used as an antipyretic and 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, relative to the solid composition as a whole.

[0098] 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, relative to the solid composition as a whole.

[0099] When the solid composition is in the form of tablets, from the viewpoint of inhibiting changes in properties, the proportion of component (B) in the total mass of one tablet can 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.

[0100] Furthermore, from the viewpoint of increasing the effective ingredients 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.

[0101] When used as an antipyretic and 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.

[0102] When used as a cold medicine, the proportion of component (B) in the total mass of one tablet can be 0.005% to 15% by mass, preferably 0.02% to 10% by mass, and more preferably 2% to 7% by mass.

[0103] When the solid composition is in the form of granules, from the viewpoint of suppressing changes in properties, the content of component (B) in the granules can be 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, relative to 100 parts by mass of the granules.

[0104] Furthermore, from the viewpoint of increasing the effective ingredients in the granules, the content of ingredient (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, relative to 100 parts by mass of the granules.

[0105] (Ingredient (C))

[0106] Component (C) is one or more selected from the group consisting of (C-1) to (C-5) below.

[0107] (C-1) Vitamin B1 and Vitamin C

[0108] (C-2) Peony, licorice and valerian

[0109] (C-3) Bromhexine, Ambroxol, Tiperidine, their salts and their hydrates

[0110] (C-4) Chlormastine, its salts and their hydrates

[0111] (C-5) Dextromethorphan, its salts and their hydrates

[0112] Here, component (C-1) is a specific vitamin, component (C-2) is a specific crude drug, component (C-3) is a specific expectorant, component (C-4) is a specific antihistamine, and component (C-5) is a specific antitussive.

[0113] From the viewpoint of increasing the effective components in the solid composition, the total content of component (C) in the solid composition, relative to the solid composition as a whole, may be greater than 0% by mass, or more than 0.1% by mass, more than 0.5% by mass, more than 1.0% by mass, more than 5.0% by mass, more than 10% by mass, more than 15% by mass, more than 20% by mass, more than 30% by mass, more than 40% by mass, or more than 50% by mass.

[0114] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the total content of component (C) in the solid composition relative to the solid composition as a whole can 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.

[0115] The total content of component (C) in the solid composition relative to the solid composition as a whole is, for example, 0.1 to 50% by mass, preferably 1 to 40% by mass, more preferably 5 to 30% by mass.

[0116] The total content of component (C) in the solid composition can 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) can 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.

[0117] 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 proportion described above relative to the solid composition as a whole.

[0118] When the solid composition is in the form of particles, the total proportion of component (C) in the particles can be the same as the proportion described above relative to the solid composition as a whole.

[0119] It should be noted that the ranges described as preferred ranges for the content of each component refer to preferred ranges for the content of each component when it is contained in the solid composition, and are not intended to exclude cases where the components are not contained from the preferred method.

[0120] (Component (C-1))

[0121] As a vitamin B1 class, for example, a compound having vitamin B1 activity, specifically, one or more compounds selected from the group consisting of thiamine, thiamine disulfide, furfural thiamine, phenylphosphine thiamine and thiamine lipoic acid can be cited.

[0122] As a type of vitamin C, examples include one or more selected from the group consisting of ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, magnesium ascorbate, ascorbate palmitate, ascorbate 2-glucoside, ascorbate stearate and ascorbate phosphate.

[0123] As for the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for adults, the content of vitamin B1 and vitamin C in the solid composition may be, for example, 0.5 to 100 mg and 10 to 1000 mg respectively, preferably 1 to 60 mg and 50 to 600 mg respectively.

[0124] 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 the components contained in the solid composition.

[0125] When the solid composition is in the form of granules, the content of component (C-1) vitamin B1 and vitamin C in the granules can be the same as the above-mentioned amounts of the components contained in the solid composition.

[0126] From the viewpoint of increasing the effective components in the solid composition, the content of vitamin B1 and vitamin C in the solid composition (C-1) can be, independently, for example, 0% or more by mass, greater than 0% by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 1.5% or more by mass, 3.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass, relative to the solid composition as a whole. The total content of component (C-1) in the solid composition can also be, for example, 0% or more by mass, greater than 0% by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 1.5% or more by mass, 3.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass.

[0127] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the content of vitamin B1 and vitamin C in the solid composition (C-1) can be individually, 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 solid composition as a whole. The total content of component (C-1) in the solid composition can 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.

[0128] In the case of antipyretic analgesics, the content of vitamin B1 relative to the solid composition as a whole can be 3 to 8% by mass, preferably 2.5 to 5% by mass, and more preferably 1.5 to 4.5% by mass.

[0129] In the case of antipyretic analgesics, the content of vitamin C relative to the solid composition as a whole can be 1 to 40% by mass, preferably 2 to 35% by mass, and more preferably 3 to 30% by mass.

[0130] In the case of cold medicine, the content of vitamin B1 relative to the solid composition as a whole can be 0.1 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.7 to 1% by mass.

[0131] In the case of cold medicine, the content of vitamin C relative to the solid composition as a whole can be 0.1 to 40% by mass, preferably 0.5 to 30% by mass, and more preferably 1 to 20% by mass.

[0132] The content of component (C-1) in the solid composition can 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 of components (A) and (B) can 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.

[0133] When the solid composition is a tablet, the proportions of vitamin B1 and vitamin C in the total mass of one tablet, as well as the total proportion of component (C-1), can be the same as the proportions mentioned above relative to the solid composition as a whole.

[0134] When the solid composition is in the form of granules, the proportions of vitamin B1 and vitamin C in component (C-1) and the total proportion of component (C-1) in the granules can be the same as the proportions mentioned above relative to the solid composition as a whole.

[0135] (Component (C-2))

[0136] Peony, licorice, and valerian have been used medicinally since ancient times, either as single herbs or in traditional Chinese medicine formulas. Crude herb powders or extracts obtained using their respective conventional methods can be used directly. The form of the crude herb powder or extract can also be a commonly available commercial product or its processed form. As a crude herb powder, it can be used, for example, as a powder (micronized powder) obtained by further finely pulverizing dried and chopped processed products. Furthermore, there are no particular limitations on the form of extracts from crude herbs; for example, they can be used as dried extracts, extract powders, soft extracts, fluid extracts, tinctures containing ethanol or ethanol and water, etc. Preferred crude herbs include extracts with high formulation flexibility, such as soft extracts and dried extract powders.

[0137] The active ingredients with antibacterial activity can be obtained from the aforementioned crude drugs using conventional methods, such as extraction solvents. Extraction solvents typically include, for example, water, hydrophilic solvents, or mixtures thereof. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, and tert-butanol; cellolytic agents such as methyl and ethyl cellolytic agents; 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 can be used individually or in mixtures of two or more.

[0138] Peony, licorice, and valerian can be used appropriately as substances listed in the 18th edition of the Japanese Pharmacopoeia.

[0139] As for licorice, there are extracts obtained using water, 30% ethanol aqueous solution, etc., as extraction solvents. For example, depending on the type of extract, such as licorice extract, dried licorice extract, soft licorice extract, licorice fluid extract, etc., various products can be made using the raw herb. In addition to these licorice extracts, licorice extract, licorice extract solution, etc., can also be used appropriately, without particular limitation.

[0140] Valerian can be used, for example, valerian powder, valerian extract (e.g., soft extract, dried extract, etc.), without particular limitation.

[0141] As for peony, for example, peony powder or peony extract (e.g., including dried extract, soft extract, etc.) can be used, without particular limitation.

[0142] Regarding the content of peony, licorice and valerian in the solid composition, the content can be adjusted in a way that makes the content in the solid composition appropriate, taking into account the conversion ratio of the raw herbs.

[0143] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for adults, the content of licorice (including licorice and licorice extract) is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, and can be 500 mg to 1500 mg.

[0144] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of valerian (including valerian and valerian extract) in the amount of raw drug can be 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, and even more preferably 60 mg to 1000 mg, and can be 60 to 450 mg.

[0145] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of peony (including peony and peony extract) can be 100 to 5000 mg, preferably 150 to 2000 mg, and more preferably 200 to 900 mg, based on the amount of the raw herb.

[0146] When the solid composition is in the form of tablets, the content of ingredient (C-2) peony, licorice and valerian in one tablet can be the same as the above-mentioned amounts of the ingredients contained in the solid composition.

[0147] When the solid composition is in the form of granules, the content of component (C-2) peony, licorice and valerian in the granules can be the same as the above-mentioned amounts of the components contained in the solid composition.

[0148] From the perspective of increasing the effective components in the solid composition, the content of components (C-2) peony, licorice, and valerian in the solid composition, relative to the solid composition as a whole, can be individually, for example, 0% or more by mass, greater than 0% by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass, based on the amount of raw medicinal materials. The total content of component (C-2) in the solid composition, based on the amount of raw medicinal materials, can also be, for example, 0% or more by mass, greater than 0% by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass.

[0149] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and inhibiting changes in properties, the content of component (C-2) peony, licorice, and valerian in the solid composition, in terms of the amount of raw medicinal materials, can be individually, 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, in terms of the amount of raw medicinal materials. The total content of component (C-2) in the solid composition, in terms of the amount of raw medicinal materials, can 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.

[0150] Relative to the entire solid composition, the content of peony root in the solid composition, calculated as raw medicinal material, can be 1-50% by mass, preferably 2-40% by mass, more preferably 3-20% by mass. Relative to the entire solid composition, the content of peony root in the solid composition, calculated as raw medicinal material, can be 1.5-4.5% by mass.

[0151] The content of valerian in the solid composition relative to the total solid composition, in terms of the amount of raw medicinal material, can be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0152] The content of licorice in the solid composition relative to the total solid composition, based on the amount of raw medicinal material, can be 0.1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0153] The content of component (C-2) in the solid composition can 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 of components (A) and (B) can 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.

[0154] When the solid composition is a tablet, the proportions of ingredient (C-2) peony, licorice and valerian in the total mass of one tablet, as well as the total proportion of ingredient (C-2), can be the same as the above proportions relative to the solid composition as a whole.

[0155] When the solid composition is in the form of granules, the proportions of peony, licorice and valerian in the granules, as well as the total proportion of the component (C-2), can be the same as the proportions mentioned above relative to the solid composition as a whole.

[0156] (Component (C-3))

[0157] Bromohexene salts include bromhexene hydrochloride.

[0158] Ambroxol hydrochloride is an example of a salt of ambroxol.

[0159] Examples of tepedidine salts include tepedidine citrate and tepedidine hypotonic acid.

[0160] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of bromhexine and its salts (including their respective hydrates) in the solid composition, when converted to anhydrous form, is, for example, 0.6 mg to 24 mg, preferably 1.2 mg to 12 mg.

[0161] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of ambroxol and its salts (including their respective hydrates) in the solid composition, when converted to anhydrous form, is, for example, 2 to 90 mg, preferably 4.5 to 45 mg.

[0162] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of teperidine and its salts (including their respective hydrates) in the solid composition, when converted to anhydrous form, is, for example, 5 to 140 mg, preferably 20 to 100 mg.

[0163] When the solid composition is in the form of tablets, the content of ingredient (C-3) bromhexine, ambroxol and tepedidine (which also include their respective salts and hydrates) in one tablet can be the same as the above-mentioned amounts of the ingredients contained in the solid composition.

[0164] When the solid composition is in the form of granules, the content of component (C-3) bromhexine, ambroxol and tepedidine (which also include their respective salts and hydrates) in the granules can be the same as the above-mentioned amounts of the components contained in the solid composition.

[0165] From the viewpoint of increasing the effective components in the solid composition, the content of component (C-3) bromhexine, ambroxol, and tepedidine (including their respective salts and hydrates) in the solid composition, relative to the solid composition as a whole, can be calculated independently in anhydrous form, for example, as 0% or more by mass, greater than 0% by mass, 0.001% or more by mass, 0.005% or more by mass, 0.01% or more by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass. The total content of component (C-3) in the solid composition can also be calculated in anhydrous form, for example, as 0% or more by mass, greater than 0% by mass, 0.001% or more by mass, 0.005% or more by mass, 0.01% or more by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass.

[0166] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the content of component (C-3) bromhexine, ambroxol, and tepedidine (including their respective salts and hydrates) in the solid composition, relative to the solid composition as a whole, can be individually calculated in anhydrous form as, 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. The total content of component (C-3) in the solid composition can also be calculated in anhydrous form as, 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. The total content of component (C-3) in the solid composition is preferably 1.0 to 10% by mass, and more preferably 3.5 to 6% by mass, relative to the solid composition as a whole.

[0167] The total content of bromhexine and its salts (including their respective hydrates) in the solid composition relative to the solid composition as a whole can be 0.01 to 10% by mass, preferably 0.1 to 1% by mass, and more preferably 0.3 to 0.5% by mass.

[0168] The total content of ambroxol and its salts (including their respective hydrates) in the solid composition relative to the solid composition as a whole can be 0.01 to 10% by mass, preferably 0.1 to 5% by mass, and more preferably 1.0 to 2% by mass, in anhydrous form.

[0169] The total content of teperidine and its salts (including their respective hydrates) in the solid composition relative to the solid composition as a whole can be 0.01 to 20% by mass, preferably 0.05 to 10% by mass, and more preferably 0.1 to 5% by mass.

[0170] The content of component (C-3) in the solid composition can 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 in anhydrous form, can 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.

[0171] When the solid composition is a tablet, the proportions of component (C-3) bromhexine, ambroxol and tepedidine (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 proportions described above relative to the solid composition as a whole.

[0172] When the solid composition is in the form of particles, the proportions of component (C-3) bromhexine, ambroxol and tepedidine (which also include their respective salts and hydrates) in the particles, as well as the total proportion of component (C-3), can be the same as the proportions mentioned above relative to the solid composition as a whole.

[0173] (Component (C-4))

[0174] As a salt of chlormastine, chlormastine fumarate can be cited as an example.

[0175] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of chlormastine and its salts (including their respective hydrates) in the solid composition, when converted to anhydrous form, is, for example, 0.1 mg to 8 mg, preferably 0.3 mg to 4 mg.

[0176] When the solid composition is a tablet, the content of ingredient (C-4) clomastine and its salt (including their respective hydrates) in one tablet may be the same as the above-mentioned amount of the ingredients contained in the solid composition.

[0177] When the solid composition is in the form of granules, the content of component (C-4) chlormastine 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.

[0178] From the viewpoint of increasing the effective components in the solid composition, the content of component (C-4) chlormastine and its salts (including their respective hydrates) in the solid composition, relative to the solid composition as a whole, can be, for example, 0% or more by mass, greater than 0% by mass, 0.001% or more by mass, 0.005% or more by mass, 0.01% or more by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass.

[0179] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the content of component (C-4) chlormastine and its salts (including their respective hydrates) in the solid composition, calculated in anhydrous form, can 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 solid composition as a whole. The total content of component (C-4) in the solid composition, calculated in anhydrous form, can be, for example, 0.001 to 10% by mass, preferably 0.005 to 5% by mass, more preferably 0.01 to 1% by mass.

[0180] The content of component (C-4) in the solid composition can 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 in anhydrous form, can 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.

[0181] When the solid composition is a tablet, the proportion of component (C-4) clomastine and its salts (including their respective hydrates) in the total mass of one tablet may be the same as the proportions described above relative to the solid composition as a whole.

[0182] When the solid composition is in the form of particles, the proportion of component (C-4) chlormastine and its salts (including their respective hydrates) in the particles can be the same as the proportions described above relative to the solid composition as a whole.

[0183] (Component (C-5))

[0184] Examples of salts of dextromethorphan include dextromethorphan hydrobromide hydrate and dextromethorphan phenolphthalein.

[0185] As the amount of ingredients contained in each administration unit (one administration dose) of the solid composition for an adult, the content of dextromethorphan and its salts (including their respective hydrates) in the solid composition, when converted to anhydrous form, is, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0186] When the solid composition is a tablet, the content of ingredient (C-5) dextromethorphan (which also includes salts and hydrates) in one tablet may be the same as the above-mentioned amount of the ingredients contained in the solid composition.

[0187] When the solid composition is in the form of granules, the content of component (C-5) dextromethorphan (which also includes salt and hydrate) in the granules can be the same as the above-mentioned amount of the component contained in the solid composition.

[0188] From the viewpoint of increasing the effective components in the solid composition, the content of component (C-5) dextromethorphan (including salt and hydrate) in the solid composition relative to the solid composition as a whole, when converted to anhydrous form, can be, for example, 0% or more by mass, greater than 0% by mass, 0.001% or more by mass, 0.005% or more by mass, 0.01% or more by mass, 0.1% or more by mass, 0.5% or more by mass, 1.0% or more by mass, 5.0% or more by mass, 10% or more by mass, 15% or more by mass, 20% or more by mass, 30% or more by mass, 40% or more by mass, or 50% or more by mass.

[0189] Furthermore, from the viewpoint of making the hardness and disintegration of the solid composition more satisfactory and suppressing changes in properties, the content of component (C-5) dextromethorphan (which also includes salt and hydrate) in the solid composition, relative to the solid composition as a whole, can 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.

[0190] The total content of component (C-5) in the solid composition relative to the solid composition as a whole can be, for example, 0.01 to 10% by mass, preferably 0.05 to 5% by mass, and more preferably 0.1 to 3% by mass.

[0191] The content of component (C-5) in the solid composition can 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 in anhydrous form, can 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.

[0192] When the solid composition is a tablet, the proportion of component (C-5) dextromethorphan (including its respective salt) in the total mass of one tablet, and the total proportion of component (C-5), may be the same as the above proportions relative to the solid composition as a whole.

[0193] When the solid composition is in the form of granules, the proportion of component (C-5) dextromethorphan (also including its respective salt) in the granules and the total proportion of component (C-5) can be the same as the above proportions relative to the solid composition as a whole.

[0194] (Other ingredients)

[0195] From the viewpoint of improving the storage stability of the solid composition, the moisture content (moisture content) in the solid composition is preferably less than 5% by mass, more preferably less than 4% by mass, even more preferably less than 3% by mass, and even more preferably less than 2% by mass, relative to the solid composition as a whole.

[0196] The moisture content of the solid composition is specifically 0% by mass or more, relative to the solid composition as a whole, and may be, for example, 0.01% by mass or more, 0.05% by mass or more.

[0197] Specifically, the moisture content of the solid composition can be obtained by measuring the loss on drying (LOD) when heated to 80°C until the mass change is 1 mg / 50 seconds using a halogen moisture meter.

[0198] In addition, the solid composition may also contain components other than those mentioned above.

[0199] Examples of such additives include one or more selected from the group consisting of pharmaceutically permissible carriers, such as excipients, binders, disintegrants (as extragranular components), disintegration aids, lubricants, flow agents, gloss enhancers, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, flavorings, aromatics, colorants, matrices, coating agents, sugar coatings, plasticizers, dispersants, and defoamers. These may be, for example, pharmaceutical additives previously known for use in solid compositions.

[0200] Examples of excipients include, for example, powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, anhydrous amorphous silica, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, anhydrous calcium hydrogen phosphate (as an in-particle component), anhydrous calcium hydrogen phosphate granules (as an in-particle component), monocalcium 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·sodium carboxymethyl cellulose, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate·hydroxypropyl starch·crystalline cellulose The group consisting of one or more of the following: vitamin B, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, purified white sugar, purified white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose (as an off-granule component), dextrin, corn starch, corn starch granules, trehalose, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, powdered sugar, powdered sugar, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminum metasilicate, calcium sulfate, erythritol, glucose, and fructose.

[0201] As a binder, examples include one or more selected from the group consisting of gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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.

[0202] Examples of disintegrants include carboxymethyl ethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. These can be used alone or in combination of two or more.

[0203] Examples of disintegration aids include, for example, one or more selected from the group consisting of sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0204] As a lubricant, for example, one or more of the following can be selected from the group consisting of magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, fatty acid glyceride, polyethylene glycol, hydrogenated oil and sodium stearate fumarate.

[0205] As a flow agent, examples include one or more selected from the group consisting of synthetic aluminum silicate, heavy anhydrous silicate, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and dicalcium phosphate granules.

[0206] As a glossing agent, examples include one or more selected from the group consisting of carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF and beeswax.

[0207] As a foaming agent, for example, one or more of the following can be selected from the group consisting of dry sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate and citric anhydride.

[0208] As a desiccant, examples include one or more selected from the group consisting of ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified 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.

[0209] Examples of surfactants include, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate, polyoxyethylene cetyl ether, polyoxyethylene dehydrated sorbitol monolaurate, polyoxyethylene sorbitol beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20)polyoxypropylene (20) diol, polyoxyethylene (105)polyoxypropylene (5) diol, and polyoxyethylene (12) 0) One or more of the following groups: polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, sorbitol monooleate, glyceryl monostearate, sorbitol monostearate, sorbitol monolaurate, and sodium dodecyl sulfate.

[0210] Examples of stabilizers include, for instance, 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, hexadecylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymers, and carboxylic acid. Calcium methylcellulose, sodium carboxymethylcellulose, dried sodium carbonate, glycine, glycerol, fatty acid glycerides, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamate, L-lysine, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, dehydrated sorbitol fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate Sodium carbonate hydrate, magnesium carbonate, tocopherol, tocopheryl acetate, lactose, concentrated glycerol, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate, 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 glyceride (7E.O.), polyoxin The group consisting of one or more of the following: 20 sorbitol, 60 polysorbate, 80 polysorbate, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, citric anhydride, sodium citric anhydride, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0211] Examples of emulsifiers include, for example, one or more selected from the group consisting of fatty acid glycerides, fatty acid propylene glycol esters, polyoxyethylene glycerides, polyglycerol fatty acid esters, sucrose fatty acid esters, dehydrated sorbitol fatty acid esters, polyoxyethylene dehydrated sorbitol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean lecithin.

[0212] As antioxidants, examples include one or more selected from the group consisting of citric acid hydrate, soybean lecithin, tocopherol, tocopheryl acetate, and sodium metabisulfite.

[0213] As a filler, for example, one or more can be selected from the group consisting of RSS No.1 raw rubber, acrylic starch 1000, titanium dioxide and dicalcium phosphate.

[0214] As a preservative, examples include one or more selected from the group consisting of benzoic acid, sodium benzoate, ethylparaben, propylparaben, methylparaben, dehydroacetic acid, sodium dehydroacetate, sorbic acid and phenoxyethanol.

[0215] As a sweetener, examples include one or more selected from the group consisting of aspartame, acesulfame potassium, gancha, gancha powder, reduced malt syrup, xylitol, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, purified white sugar, fructose, white sugar, maltitol, D-mannitol and erythritol.

[0216] As a flavoring agent, examples include one or more selected from the group consisting of sodium chloride, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, monosodium L-glutamate, grapefruit extract, brown sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sucralose, stevia extract, purified stevia extract, senna, 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, sodium DL-malate, lemon oil, and rose oil.

[0217] As a cooling agent, for example, one or more of the following can be selected from the group consisting of fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil and l-menthol.

[0218] As a flavoring agent, for example, one or more of the following can be selected from the group consisting of orange flavoring, guarana extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach essence, fruit flavoring, mint, melon powder flavoring, l-menthol and peppermint oil.

[0219] As a fragrance agent, for example, one or more of the following can be selected from the group consisting of anise powder, anise oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water and rose oil.

[0220] As a coloring agent, examples include one or more selected from the group consisting of yellow iron oxide, yellow ferric oxide, orange flavoring, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium dioxide, ferric oxide, diazo 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 / glycerol suspension, sodium copper chlorophyllin, copper chlorophyllin, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, and rose oil.

[0221] Examples of matrices selected from sources include gum arabic powder, α-starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymers, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced malt syrup, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, fatty acid glycerides, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium silicate sodium, titanium dioxide, tartaric acid, sucrose fatty acid esters, 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 glycerol, potato starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. The following are one or more of the following: pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitol monostearate, squalene monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium dodecyl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0222] Examples of coating agents include, for instance, dispersions of ethyl acrylate and methyl methacrylate copolymers, aminoalkyl methacrylate copolymers E and RS, gum arabic, gum arabic powder, ethyl cellulose, aqueous dispersions of ethyl cellulose, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, fatty acid glycerides, hydrogenated oil, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium dioxide, and polyethylene glycol 400, hydroxypropyl methylcellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910. The group consisting of one or more of the following: pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, methyl 2-methyl-5-vinylpyridine acrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, dehydrated sorbitol monostearate, dehydrated sorbitol monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0223] As a sugar coating agent, examples include one or more selected from the group consisting of gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyoxyethylene stearate 40, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0224] Examples of plasticizers include, for example, one or more selected from the group consisting of triethyl citrate, glycerol, fatty acid glycerides, D-sorbitol, medium-chain fatty acid triglycerides, glyceryl triacetate, concentrated glycerol, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, and liquid paraffin.

[0225] Examples of dispersants selected from aminoalkyl methacrylate polymers (RS), gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, fatty acid glycerides, magnesium silicate, light alumina, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose (as an in-particulate component), dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and poly(hydroxypropyl methylcellulose) are also available. The group consisting of one or more of the following: ethylene-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, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, sodium citric anhydride, magnesium aluminum metasilicate, methylcellulose, glyceryl monooleate, sorbitol monooleate, aluminum monostearate, glyceryl monostearate, sorbitol monostearate, sorbitol monopalmitate, sorbitol monolaurate, and sodium dodecyl sulfate.

[0226] Examples of defoaming agents include, for example, one or more selected from the group consisting of ethanol, fatty acid glycerides, dimethyl polysiloxane (for internal use), sucrose fatty acid esters, silicone defoamers, silicone oil, dehydrated sorbitol fatty acid esters, and polysorbate 80.

[0227] In addition, the solid composition may also contain other active ingredients as needed. The content of components not belonging to component (C) among vitamins, medicinal herbs, expectorants, antihistamines, antitussives, and anti-inflammatory components is preferably adjusted within a range that does not impair the effects of the present invention, and preferably does not contain these components. Specifically, relative to the total content of 100 parts by weight of component (C), the total content of components not belonging to component (C) among vitamins, medicinal herbs, expectorants, antihistamines, antitussives, and anti-inflammatory components is preferably 20 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. However, even with these components, as long as they do not undergo a change in properties when combined with at least one of the groups selected from loxoprofen, its salts, and their hydrates, they may be appropriately incorporated. In addition, where changes in properties can be suppressed by other formulation methods such as particle separation, they may also be appropriately incorporated.

[0228] Other active ingredients that may be included in the solid composition include, for example, one or more selected from the group consisting of antipyretic analgesics, xanthine derivatives, sedatives, and anticholinergic drugs. These ingredients may be appropriately combined without impairing the effects of the present invention; if there are incompatibilities, appropriate particle separation or formulation can be performed. The total content of the antipyretic analgesic, xanthine derivative, sedative, and anticholinergic drug 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, relative to the total content of component (A) of 100 parts by weight.

[0229] As an antipyretic and analgesic, examples include one or more of the following: aspirin, aspirin aluminum, acetaminophen, ethylsalicylate, salicylate, salicylamide, lactoylphenethylamine, ibuprofen, isopropylantipyrine, pranoprofen, diclofenac sodium, mefenamic acid, indomethacin farnesyl ester, acemetacin, etodoxacin, naproxen, meloxicam, celecoxib, sodium salicylate, and thiamide hydrochloride.

[0230] As xanthine derivatives, examples include one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate and caffeine citrate.

[0231] As a sedative, for example, at least one selected from the group consisting of allyl isopropyl acetylurea and bromovalerylurea can be mentioned.

[0232] As an anticholinergic drug, examples include one or more selected from the group consisting of scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isoproiodine, diphenylpiperidine methyldioxolane iodide, hyoscyamine extract, hyoscyamine root, and citrate of total hyoscyamine root alkaloids.

[0233] As an antitussive and expectorant other than ingredient (C), examples include one or more of the following: codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium debufenozide, dimethylphenidate, alloramine hydrochloride, clopidogrel hydrochloride, clopidogrel fendifloxacin, pentoxyverine citrate, noscarbene, noscarbene hydrochloride, trimequinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine hydrochloride, racemic methylephedrine hydrochloride, racemic methylephedrine saccharin salt, guaiacol glyceryl ether, potassium guaiacol sulfonate, potassium cresol sulfonate, L-carboxymethylcysteine, and L-cysteine ​​ethyl ester hydrochloride.

[0234] As antihistamines other than component (C), examples include, for example, azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emesmetine fumarate, oxamide, olopatadine hydrochloride, carbixamine, diphenyl disulfonate, carbixamine maleate, d-chlorpheniramine maleate, racemic chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripiramine hydrochloride, pyrimidine diamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequinatazine hydrochloride, loratadine, isoamyl ester, and Difeterol. One or more of the following groups: Hydrochloride, Methionine Hydrochloride, Methionine Naphthalene Disulfonate, Methylene Disalicylic Acid Promethazine, and Difeterol Phosphate.

[0235] As an anti-inflammatory agent other than component (C), examples include one or more selected from the group consisting of glycyrrhizic acid, its derivatives and their salts (e.g., dipotassium glycyrrhizate, disodium glycyrrhizate, trisodium glycyrrhizate and monoammonium glycyrrhizate), glycyrrhetinic acid, its derivatives and their salts (e.g., potassium glycyrrhetinate, sodium glycyrrhetinate and ammonium glycyrrhetinate), and tranexamic acid.

[0236] As a vitamin other than component (C), examples 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, niacin, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, an equal mixture of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronide, sodium chondroitin sulfate, carrot, coix seed, and iodic acid.

[0237] The solid composition of this embodiment can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since component (A), as the active ingredient, has antipyretic, analgesic, and anti-inflammatory effects, it can be used as an antipyretic and analgesic agent, specifically, for the relief of headache, menstrual pain (menstrual pain), toothache, post-extraction pain, sore throat, back pain, joint pain, muscle pain, shoulder pain, earache, bruise pain, fracture pain, sprain pain, traumatic pain, etc., and for the relief of fever and chills. In addition, it can be used as a cold treatment agent to relieve various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0238] (Dosage Form)

[0239] The solid composition of this embodiment can be formulated into dosage forms such as those described in the 18th edition of the Japanese Pharmacopoeia, including oral administration formulations (tablets (including intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, and powders), and oral formulations (including oral tablets, lozenges, sublingual tablets, oral lozenges, adhesive tablets, and gels). The solid composition of this embodiment is preferably an oral solid composition.

[0240] Examples of dosage forms for the solid compositions of this embodiment include tablets, capsules, pills, granules, and fine granules. These solid compositions can be coated using known methods, such as sugar coating or film coating, as needed. Tablets are preferred as the dosage form of the solid composition. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0241] The solid composition of this embodiment can be temporarily packaged and airtightly stored in bottles, PTP packages, bags, strips, or SP packages. It can also be further packaged in pillow-like containers or stored in boxes. There are no particular limitations on the materials used in pillow-like packaging; for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, or materials made by attaching aluminum foil to these resin films, can be used. It should be noted that, if there are concerns about moisture absorption, desiccants or similar substances can be stored simultaneously inside the bottle packaging or the pillow-like packaging.

[0242] The solid composition of this embodiment can be contained within a packaging container to form a package. For example, the solid composition of this embodiment can be contained in an airtight package. By forming a package, for example, the convenience of using the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0243] As packaging forms for solid dosage forms, solid compositions can be temporarily packaged and airtightly preserved using bottles, PTP (Press Through Package), pouches, strips, and SP (Strip Package). They can also be further packaged in pillow-like containers or stored in boxes. Furthermore, from the viewpoint of reducing moisture absorption by the solid composition, desiccants can be stored simultaneously within the bottle or pillow-like packaging container.

[0244] Materials used in SP packaging, PTP packaging, strip packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and materials made by attaching aluminum foil to these resin films. Any of single-layer films and multi-layer films (e.g., laminated films) can be used.

[0245] Furthermore, the materials constituting the packaging container preferably include materials that are not easily affected by moisture. Examples of such packaging include packaging formed from at least one of moisture-proof materials and gas-barrier materials.

[0246] As a moisture-proof material, a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging can be cited as an example. Furthermore, when the solid composition is a tablet, considering factors such as inhibiting the rise in moisture content of the tablet, tablet storage stability, and tablet stability after opening, PTP packaging (Al-Al packaging) using aluminum on both sides can be used as a moisture-proof material.

[0247] As a gas barrier material, known materials can be used, such as laminates with functional barrier layers, or materials that also function as moisture-proof materials, or materials that are used together with moisture-proof materials.

[0248] In addition, packaging containers can be made in an environmentally conscious way. For example, environmentally friendly raw materials such as recycled plastics, biomass plastics, and biodegradable plastics can be used in part or all of the packaging materials.

[0249] (Manufacturing method)

[0250] In a second approach, a method for manufacturing the solid composition of this embodiment is provided, which includes a step of contacting component (A) with (B). Preferably, the manufacturing method of this embodiment involves further adding component (C) after the step of contacting component (A) with (B) to manufacture a solid composition comprising components (A) to (C).

[0251] However, the solid composition of this embodiment can be manufactured by mixing components (A) to (C). The mixing order of the components is not particularly limited, and can be any conceivable order, such as mixing components (A) and (B) and then mixing component (C), or mixing components (A) to (C) simultaneously.

[0252] The process of contacting component (A) with (B) can be, for example, a process of mixing powders of components (A) and (B). Alternatively, the process of contacting component (A) with (B) can be a process of mixing powders of components (A) and (B) while applying impact force, or a process of mixing while heating to the point that either component (A) or (B) melts, or a process of mixing in the presence of a suitable solvent. Examples of such processes include, for instance, at least one of the following: mixing and pulverizing, heating and melting, crystallization in the presence of a solvent, kneading, and spraying.

[0253] The process of contacting components (A) and (B) more preferably includes a process of contacting components (A) and (B) in the presence of a suitable solvent. In such a process, components (A) and (B) can be dissolved in a solvent in the presence of a suitable solvent, and then the composite can be precipitated. Examples of methods for precipitating the composite include crystallization and spraying. For the process of contacting components (A) and (B) in the presence of a suitable solvent, a suitable solvent can be added before or during mixing of the powders of components (A) and (B), or either component (A) or (B) can be dissolved in a solvent and the other powder can be added, or components (A) and (B) can be dissolved separately in a solvent and the two components can be mixed. Alternatively, the amount of solvent can be appropriately adjusted so that the composite can be continuously precipitated while components (A) and (B) are contacted in the presence of a suitable solvent. A kneading process is an example of such a process. Thus, by contacting components (A) and (B) in the presence of a solvent, there is a tendency to obtain a composite that is less prone to changes in properties in a solid composition.

[0254] The solvent used in the process 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 thereof. The contact of components (A) and (B) may be carried out while heating, for example, at a temperature of 30–110°C. The method for forming a composite of components (A) and (B) may be, for example, a process of kneading components (A) and (B) together in the presence of a suitable solvent.

[0255] Preferably, the mixture obtained in the above-described process is combined with component (C). In this case, the manufacturing method of this embodiment includes a step of contacting the mixture with component (C). The mixture can be pulverized using a mortar and pestle or the like after the mixing step, and then contacted with component (C), or it can be pulverized and then passed through a sieve of an appropriate size before contacting with component (C). The mixture and component (C) can be mixed in powder form, or a uniform mixed powder can be obtained by performing mixing and sieving once or twice or more.

[0256] In the manufacturing method of this embodiment, subsequent processes can be performed using processes in conventional solid composition manufacturing methods. As such a manufacturing method, granulation is employed; examples include wet granulation methods such as high-speed stirring granulation and fluidized bed granulation.

[0257] In this embodiment, the method for manufacturing the solid composition may include, for example, the following steps: forming particles using a mixed powder of components (A) to (C) obtained as described above, and forming a solid formulation from these particles. Thus, the solid composition of this embodiment can be formulated according to its dosage form using conventional methods.

[0258] For example, when the solid dosage form is a tablet, it can be manufactured in accordance with the "Tablets" section of the General Principles of Pharmaceutical Preparations in the Japanese Pharmacopoeia. Specifically, tablets can be manufactured by granulating a mixed powder containing ingredients (A) to (C) to obtain granules, and then compressing the obtained granules and appropriate extragranule ingredients into tablets.

[0259] When a solid dosage form contains an extragranular component, subsequent components can be added to the granulated granules in a manner that forms the exterior of the granules, and the mixture is compressed into a tablet, thereby manufacturing a tablet. Alternatively, the extragranular component can be formed into granules. For example, granules containing components (A) to (C) can be manufactured as a first particle, and granules containing other active ingredients can be configured as a second particle. That is, a first particle containing components (A) to (C) and a second particle containing other active ingredients can be separately provided, and a solid dosage form can be constructed in such a manner that components (A) to (C) in the first particle and other active ingredients in the second particle do not substantially come into contact. Other active ingredients can be contained in the first particle or in the second particle in a manner that yields a suitable formulation.

[0260] It should be noted that the granules obtained in the above process can be used directly as granules.

[0261] (Inhibitor of trait change)

[0262] In the third method, a phenotypic change inhibitor is provided, which is a phenotypic change inhibitor of a solid composition. The phenotypic change inhibitor contains fructose, and the solid composition contains:

[0263] (I) Select at least one from the group consisting of loxoprofen, its salts and their hydrates; and

[0264] (II) Select one or more of the following components from the group consisting of:

[0265] (II-1) Vitamin B1 and Vitamin C;

[0266] (II-2) Peony, licorice and valerian;

[0267] (II-3) Bromhexine, Ambroxol, Tiperidine, their salts and their hydrates;

[0268] (II-4) Chlomastine, its salts, and their hydrates; and

[0269] (II-5) Dextromethorphan, its salts and their hydrates.

[0270] The property change inhibitor of this embodiment contains fructose, and therefore can inhibit property changes in the solid composition containing components (I) and (II).

[0271] Regarding fructose, it is as described in component (B) of the solid composition of this embodiment; regarding components (I) and (II), it is as described in components (A) and (C) of the solid composition of this embodiment. Furthermore, fructose is preferably formulated in the amount described in component (B) of the solid composition of this embodiment, and components (I) and (II) are also preferably formulated in the amounts described in components (A) and (C) of the solid composition of this embodiment.

[0272] Fructose is preferably complexed with component (I), specifically, fructose is complexed with component (I) in a 1:1 molar ratio. The method of complexation is as described above.

[0273] The present invention is illustrated in more detail by the following examples and comparative examples, but the present invention is not limited thereto.

[0274] Example

[0275] [Preparation Example 1]

[0276] To a 50 mL mixing vial, add 0.2827 g of loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE), 0.1674 g of D-fructose (manufactured by Kato Chemical), and eight Φ7.9 mm stainless steel beads in a 1:1 molar ratio of loxoprofen to fructose, followed by 10 μL of ethanol. Then, grind the sample using a mixing mill (8000D MXER / MILL, SPEX Corporation) for 10 minutes (50 Hz) to obtain the sample. The obtained sample was then dried under reduced pressure overnight at room temperature to obtain the specimen.

[0277] [Preparation Example 2]

[0278] The solvent added in Preparation Example 1 was changed to 10 μL of water to prepare the sample.

[0279] [Preparation Example 3]

[0280] 502.6 g of loxoprofen sodium dihydrate (manufactured by KOLONLIFE SCIENCE) and 297.4 g of D-fructose (manufactured by Kato Chemical) were added to a stirred mixing granulator (manufactured by VG-25 Powrex) at a molar ratio of 1:1 to fructose. After mixing, 32 g of purified water was added and kneaded. Then, the mixture was granulated using a power mill (manufactured by Dalton) and dried using a fluidized bed apparatus (manufactured by MP-01 Powrex) to obtain the sample.

[0281] [Experimental Example 1]

[0282] X-ray powder diffraction analysis was performed on loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE), D-fructose (manufactured by Kato Chemical), and the samples prepared in Preparation Example 1, Preparation Example 2, and Preparation Example 3, respectively. X-ray powder diffraction was performed using the Empyrean (PANalytical) multi-functional X-ray diffractometer, employing the reflection method to determine the substances obtained by pulverizing each sample in a mortar. The measurement conditions are described below.

[0283] (Measurement conditions)

[0284] X-ray generation conditions: 45kV, 40mA

[0285] wavelength: (CuKα line)

[0286] Measurement temperature: room temperature

[0287] Sample holder: Non-reflective sample holder

[0288] Scan range: 3–40°

[0289] Scan step size: 0.0131303°

[0290] Time per step: 43.095 seconds

[0291] The diffraction patterns of each sample obtained by X-ray powder diffraction analysis are shown below. Figure 1 In the X-ray powder diffraction patterns of the samples prepared in Preparation Example 1, Preparation Example 2, and Preparation Example 3, patterns with characteristic diffraction peaks not found in the X-ray powder diffraction patterns of loxoprofen sodium dihydrate and D-fructose were identified. Figure 1 As shown, the X-ray powder diffraction patterns of the samples prepared in Preparation Examples 1-3 exhibit diffraction peaks in the range of diffraction angles 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3°, and 16.0 ± 0.3°. These results indicate that the preparation operations in Preparation Examples 1, 2, and 3 all produced complexes of loxoprofen sodium and fructose with the same crystal structure.

[0292] [Preparation Example 4]

[0293] The sample prepared in Preparation Example 3 was mixed with the powders of the components listed in Table 1 and sieved to obtain a solid composition. It should be noted that the components listed in Table 1 are formulated in a 1:1 molar ratio relative to the loxoprofen sodium and fructose complex. The molecular weight of the loxoprofen sodium and fructose complex is calculated to be 448.47.

[0294] However, since the molecular weights of the dried peony extract and valerian extract are not fixed, they are mixed with the loxoprofen sodium and fructose complex in equal weight. Additionally, the valerian extract is formulated with an equivalent amount of crystalline cellulose PH-101.

[0295] [Table 1]

[0296] Classification Ingredient Name Manufacturer Remark (C-1) Vitamin ascorbic acid DSM Vitamin C (C-1) Vitamin Benzylphosphide Hamari Yonezawa Vitamin (B1) (C-2) Crude Drugs Licorice dried extract Alps Pharmaceutical Co., Ltd. anti-inflammatory (C-2) Crude Drugs Peony dried extract Japanese powder Antispasmodic and relieves muscle tension (C-2) Crude Drugs Valerian extract Japanese powder calm (C-3) expectorant ingredients bromhexine hydrochloride Ven Petrochem & Pharma expectorant (C-3) expectorant ingredients Ambroxol Hydrochloride Shizuoka Caffeine expectorant (C-3) expectorant ingredients Tiperidine hypotridine San Chemical expectorant (C-4) Antihistamines chlormastine fumarate SEKISUI MEDICAL antihistamine (C-5) Cough-suppressing ingredient Dextromethorphan hydrobromide hydrate Alps Pharmaceutical Co., Ltd. cough suppressant iodide Isopropyliodine Nippon Bulk anticholinergic

[0297] [Preparation Example 5]

[0298] Except for using loxoprofen sodium dihydrate instead of the sample prepared in Preparation Example 3, solid compositions containing the components listed in Table 1 were prepared in the same manner as in Preparation Example 4.

[0299] [Experimental Example 2]

[0300] Approximately 2 g of each of the solid compositions prepared in Examples 4 and 5 were placed in glass bottles to achieve a uniform thickness. The glass bottles were then sealed and stored at 60°C for 2 weeks.

[0301] Two weeks later, the changes in properties of each solid composition were evaluated according to the following criteria. The results are shown in Table 2.

[0302] (Color change) A: No color change, B: Slight color change, C: Color change, D: Significant color change

[0303] (Agglomeration / Wetting) A: No agglomeration or wetting; B: Slight agglomeration or wetting; C: Agglomeration or wetting; D: Significant agglomeration or wetting.

[0304] In addition, using a spectrophotometer (SE7700: manufactured by Nippon Denko Co., Ltd.), the lightness (L) of the samples at each time point during storage was measured, with the initial sample used as a comparison control. ＊ ) and chromaticity (a ＊ b ＊ The color difference (ΔE) before and after preservation is calculated using the following formula (1). ＊ ab (In the table, it is abbreviated as "ΔE"). The results are shown in Table 2.

[0305] [Mathematical Expression 1]

[0306]

[0307] ΔL ＊ Lightness (L) of samples at each time point of preservation compared to the sample at the beginning of preservation. ＊ ) difference

[0308] Δa ＊ : Colorimetric values ​​(a) of samples at each time point during storage compared to the sample at the start of storage. ＊ ) difference

[0309] Δb ＊ : Colorimetric values ​​(b) of samples at each time point of preservation compared to the samples at the beginning of preservation. ＊ ) difference

[0310] [Table 2]

[0311]

[0312] [Experimental Example 3]

[0313] To confirm the effect of fructose in inhibiting morphological changes not only in the presence of loxoprofen sodium dihydrate but also in the presence of anhydrous loxoprofen sodium, the following experiment was conducted. 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 separate glass bottles to achieve uniform thickness. The bottles were sealed and stored at 60°C for 2 weeks, and the morphological changes were evaluated in the same manner as in Experimental Example 1. It should be noted that color difference was not measured. The results are shown in Table 3.

[0314] [Table 3]

[0315]

[0316] [Experimental Example 4]

[0317] Approximately 1–2 g of each of the solid compositions prepared in Examples 4 and 5 were placed in plastic petri dishes to achieve uniform thickness. The samples were then stored in an open system at 40°C and 75% relative humidity for two weeks.

[0318] Two weeks later, the changes in properties of each solid composition were evaluated according to the following criteria. The results are shown in Table 4.

[0319] (Color change) A: No color change, B: Slight color change, C: Color change, D: Significant color change

[0320] (Agglomeration / Wetting) A: No agglomeration or wetting; B: Slight agglomeration or wetting; C: Agglomeration or wetting; D: Significant agglomeration or wetting.

[0321] In addition, approximately 0.1 g of each of the solid compositions prepared in Preparation Examples 4 and 5 were weighed and placed in plastic petri dishes, and stored in an open system at 40°C and 75% relative humidity for 24 hours. The mass change before and after 24 hours of storage was calculated, and the hygroscopicity was evaluated as the increase in mass (%). The results are shown in Table 4. In Table 4, especially in the case of valerian extract, the hygroscopicity became negative, which is considered to be caused by the evaporation of water from the valerian extract.

[0322] [Table 4]

[0323]

[0324] The preferred embodiments and examples of the present invention have been described above, but the present invention is not limited thereto. Additional, omitted, substituted, and other modifications can be made to the structure without departing from the spirit of the present invention.

[0325] Industrial availability

[0326] In this embodiment, the solid composition exhibits excellent storage stability, making it extremely useful in terms of quality. Specifically, the solid composition of this embodiment is suitable as an antipyretic and analgesic for relieving headaches, menstrual pain (menstrual cramps), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, shoulder pain, earaches, bruise pain, fracture pain, sprain pain, and traumatic pain, as well as for reducing fever and chills. In addition, it is suitable as a cold treatment for relieving various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims

1. A solid composition comprising the following components: (A) Select at least one from the group consisting of loxoprofen, its salts and their hydrates; (B) Fructose; and (C) Select one or more of the following components from the group consisting of: (C-1) Vitamin B1 and Vitamin C; (C-2) Peony, licorice, and valerian; (C-3) Bromhexine, Ambroxol, Tiperidine, their salts and their hydrates; (C-4) chlormastine, its salts, and their hydrates; and (C-5) Dextromethorphan, its salts and their hydrates.

2. The solid composition of claim 1, comprising a composite formed by combining components (A) and (B).

3. The solid composition according to claim 2, wherein, The molar ratio of component (A) to (B) in the aforementioned complex 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 aforementioned composite exhibits diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3° and 16.0 ± 0.3° in the X-ray powder diffraction pattern.

6. The solid composition according to claim 2 or 3, wherein, The aforementioned composite exhibits diffraction peaks with diffraction angles of 2θ = 4.4 ± 0.3°, 8.8 ± 0.3°, 10.1 ± 0.3°, and 16.0 ± 0.3° in X-ray powder diffraction patterns.

7. A method for manufacturing a solid composition according to any one of claims 1 to 3, comprising a step of contacting component (A) with (B).

8. The method of claim 7, wherein, The contact is carried out through at least one of the following steps: mixing and crushing, heating and melting, crystallization in the presence of solvent, kneading, and spraying.

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

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