solid components

Abstract

To provide a solid composition containing crystals of ibuprofen and tranexamic acid, in which changes in properties are suppressed even under high-temperature conditions. [Solution] The following components: (A) A crystal consisting of ibuprofen and tranexamic acid, (B) At least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof, Includes, The mass ratio of (A) to (B) is 1:0.2 to 1:20 ((A):(B)). Solid composition.

Description

Technical Field

[0001] The present invention broadly relates to a solid composition comprising a crystal composed of ibuprofen and tranexamic acid, and at least one selected from the group consisting of a gastric protective component and an α-amino acid or a salt thereof.

Background Art

[0002] Ibuprofen is widely used as a non-steroidal antipyretic analgesic. In addition, a gastric protective component and an α-amino acid may be added to solid compositions such as cold medicines.

[0003] For example, Patent Document 1 discloses a solid preparation containing ibuprofen, tranexamic acid, and an inorganic salt containing magnesium.

[0004] Patent Document 2 discloses a crystal composed of ibuprofen and tranexamic acid. Patent Document 2 discloses that a crystal is formed by contacting ibuprofen and tranexamic acid, and by preparing a solid preparation from this crystal, expansion at high temperatures can be suppressed.

Prior Art Documents

Patent Documents

[0007] Therefore, the present invention aims to provide a solid composition containing ibuprofen and tranexamic acid crystals in which changes in properties are suppressed even under high-temperature conditions, by suppressing changes in properties that may occur in a solid composition containing ibuprofen and tranexamic acid crystals with a specific component, specifically, at least one selected from the group consisting of a gastric protective component and α-amino acids or salts thereof. [Means for solving the problem]

[0008] The present inventors have discovered that the above problem can be solved by combining a crystal composed of ibuprofen and tranexamic acid with at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt, such that the mass ratio of the crystal to at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt falls within a predetermined range, and have completed the present invention.

[0009] In other words, this application encompasses the following inventions. [1] The following ingredients: (A) A crystal consisting of ibuprofen and tranexamic acid, (B) At least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof, Includes, A solid composition in which the mass ratio of (A) to (B) is 1:0.2 to 1:20 ((A):(B)). [2] The aforementioned stomach-protective component is at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, magnesium aluminosilicate, and aluminum silicate. The solid composition described in [1]. [3] The α-amino acid or its salt is at least one selected from the group consisting of glycine or its salt, carbocysteine ​​or its salt, phenylalanine or its salt, and glutamic acid or its salt. The solid composition described in [1] or [2]. [4] The above (B) is at least one selected from the group consisting of glycine or a salt thereof, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, carbocysteine ​​or a salt thereof, phenylalanine or a salt thereof, and glutamic acid or a salt thereof. The solid composition described in [1]. [5] The above (B) is at least one selected from the group consisting of glycine or a salt thereof, magnesium aluminometasilicate, carbocysteine ​​or a salt thereof, and glutamic acid or a salt thereof. The solid composition described in [1]. [6] The solid composition according to any one of [1] to [5], wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:1. [7] A solid composition according to any one of items [1] to [6], wherein the mass ratio of component (A) to (B) is 1:0.2 to 1:10 ((A):(B)). [8] A method for suppressing changes in the properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of a gastric protective component and an α-amino acid or a salt thereof, A method comprising crystallizing ibuprofen with tranexamic acid. [9] Use of tranexamic acid for a method of suppressing changes in the properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of a gastric protective component and an α - amino acid or a salt thereof.

[10] [8] and [9], in the solid composition, the mass ratio of (A) a crystal composed of ibuprofen and tranexamic acid to (B) at least one selected from the group consisting of a gastric protective component and an α - amino acid or a salt thereof is 1:0.2 to 1:20 ((A):(B)). [Effects of the Invention]

[0010] According to the present invention, a solid composition containing crystals of ibuprofen and tranexamic acid, in which changes in properties under high - temperature conditions are suppressed, can be provided. [Brief Description of the Drawings]

[0011] [Figure 1] Figure 1 shows the results of differential scanning calorimetry (DSC) of the crystals composed of ibuprofen and tranexamic acid obtained in Example 1. [Modes for Carrying Out the Invention]

[0012] Hereinafter, embodiments of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not construed as being limited to the following embodiments. In the present embodiment, the composition can contain any of the components alone or in combination of two or more. In this specification, "~" indicating a numerical range represents "above" and "below", and includes both end values.

[0013] (Solid Composition) In a first aspect, (A) A crystal composed of ibuprofen and tranexamic acid, and (B) At least one selected from the group consisting of a gastric protective component and an α - amino acid or a salt thereof, Includes, A solid composition in which the mass ratio of (A) to (B) is 1:0.2 to 1:20 ((A):(B)), It will be provided. The solid composition is specifically a solid pharmaceutical composition.

[0014] Each component contained in the solid composition according to this embodiment may be included in the form of a pharmaceutically acceptable salt, or it may be included as a complex with other components. That is, in addition to components (A) and (B), the solid composition according to this embodiment may also contain salts of other components. "Pharmacologically acceptable salt" includes, for example, salts with pharmaceutically acceptable bases or acids. Non-specific examples of pharmacologically acceptable salts include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids. Pharmacologically acceptable salts may be hydrated or anhydrous.

[0015] In this embodiment, the mass ratio of the crystals consisting of ibuprofen and tranexamic acid to component (B) is within a predetermined range, thereby suppressing changes in the properties of the solid composition, particularly changes in properties over time.

[0016] In this specification, "change in properties" means a change in properties and / or state, including at least aggregation, solidification, moisture absorption, and wetting. Therefore, the solid composition according to this embodiment may have suppressed changes such as aggregation, solidification, moisture absorption, and wetting that occur over time. Furthermore, "suppression of changes in properties" means that changes in properties are less likely to occur, but for example, the suppression of changes in properties may be observed when compared to a solid composition containing an equal amount of ibuprofen instead of component (A). Alternatively, it may mean that the degree of change in properties is relatively low in the evaluation method described in the examples.

[0017] The solid composition according to this embodiment may have its properties suppressed under high-temperature conditions. High-temperature conditions may be, for example, 30 to 100°C or 40 to 90°C.

[0018] "Changes in properties over time" refers to changes in properties that occur over time, and may include changes in properties that occur over a period of 12 hours or more, 18 hours or more, 24 hours or more, or 48 hours or more after manufacturing or after being placed in a specific environment (e.g., a high-temperature environment). The period over which changes in properties are suppressed in the solid composition according to this embodiment is not particularly limited, but may be, for example, 12 hours or more, 18 hours or more, 24 hours or more, 48 hours or more, or 72 hours or more.

[0019] (A) Crystals composed of ibuprofen and tranexamic acid As used herein, "ibuprofen" refers to the CAS registry number 15687-27-1, C 13 H 18 Ibuprofen is a compound represented by the chemical formula O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic agents. The salts of ibuprofen are not particularly limited as long as they are pharmacologically acceptable.

[0020] The content of ibuprofen or its salt is appropriately adjusted according to the intended use of ibuprofen or its salt in the composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen or its salt is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen or its salt administered to adults can be adjusted to a range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In this embodiment, "adult" means males and females aged 15 years or older. However, the solid composition according to this embodiment is not limited to use by adults, but may also be used by children under 15 years of age. When used by children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount taken by adults per day, depending on the age group.

[0021] The above dosages are examples, and the ibuprofen or salt content per composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0022] The amount of ibuprofen or its salt contained in the composition administered daily may be 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0023] The weight and dosage in the above-mentioned compositions are daily doses (daily amounts), but the same amount may be administered to the subject multiple times a day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen or its salts. Furthermore, since each dosage is a total amount, the content of each component in the composition may vary depending on the single dose and the dosage form of the composition.

[0024] In certain embodiments, the composition is in tablet form, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0025] Unless otherwise specified, the amounts of ibuprofen described herein refer to the amount in crystalline form with tranexamic acid, but such amounts may also refer to the total amount of crystalline and uncrystallized ibuprofen.

[0026] The solid composition may contain both crystalline ibuprofen and non-crystalline ibuprofen.

[0027] The ibuprofen contained in the solid composition may be crystallized with tranexamic acid at a concentration of 90% by mass or more, for example, 90% by mass, 91% by mass, 92% by mass, 93% by mass, 94% by mass, 95% by mass, 96% by mass, 97% by mass, 98% by mass, 99% by mass, or 100% by mass.

[0028] As used herein, "tranexamic acid" refers to the C8H compound with CAS registry number 1197-18-8. 15 It is a compound represented by the chemical formula NO2 (molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs and other medications. The salts of tranexamic acid are not particularly limited as long as they are pharmacologically acceptable.

[0029] The content of tranexamic acid or its salt is adjusted as appropriate depending on the use of tranexamic acid or its salt in the composition. The dosage of tranexamic acid or its salt varies depending on the amount of ibuprofen, etc., but for example, the daily amount is in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0030] The content of tranexamic acid or its salt contained in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0031] The amount of tranexamic acid or a salt thereof contained in the composition administered daily is, for example, 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass, and more preferably 0.7 to 2.2 parts by mass, per 1 part by mass of ibuprofen.

[0032] Unless otherwise specified, the amounts of tranexamic acid described herein refer to the amount in crystalline form with ibuprofen, but such amounts may also refer to the total amount of crystalline and non-crystalline tranexamic acid.

[0033] The solid composition may contain both crystalline and non-crystalline tranexamic acid.

[0034] The tranexamic acid contained in the solid composition may be crystallized with ibuprofen at a concentration of 90% by mass or more, for example, 90% by mass, 91% by mass, 92% by mass, 93% by mass, 94% by mass, 95% by mass, 96% by mass, 97% by mass, 98% by mass, 99% by mass, or 100% by mass.

[0035] Ibuprofen and tranexamic acid exist as crystals in the composition. In these crystals, ibuprofen and tranexamic acid may exist in a 1:1 molar ratio. In addition, in these crystals, ibuprofen and tranexamic acid may form a crystalline unit cell of four molecules each.

[0036] In the crystal, hydrogen bonds may be formed between the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid, and between the carboxylic acid group of ibuprofen and the amino group of tranexamic acid.

[0037] The crystal may have an endothermic peak around 180°C in differential scanning calorimetry (DSC). "Around 180°C" may refer to a range such as 180°C ± 20°C or 180°C ± 10°C. Note that the fusion heat peak around 75°C, characteristic of ibuprofen, may disappear in the DSC of the crystal.

[0038] The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-070674, and may have the X-ray diffraction pattern shown in Figure 2 of the same publication. The crystal may have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in its X-ray diffraction pattern.

[0039] Crystals composed of ibuprofen and tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-070674. Three representative production methods described in the same publication are listed below.

[0040] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising: (1) producing ibuprofen in a fluid form by adding a solvent or heating; (2) mixing the obtained fluid ibuprofen with tranexamic acid; and (3) producing crystals from the obtained mixture.

[0041] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising (1) obtaining tranexamic acid in a fluid form, (2) mixing the obtained fluid tranexamic acid with ibuprofen, or ibuprofen in a fluid form obtained by adding a solvent or heating, and (3) generating crystals from the obtained mixture.

[0042] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising: (1) adding ibuprofen and tranexamic acid to a solvent to obtain a solution or dispersion; (2) spraying and drying the obtained solution or dispersion; or (3) allowing the solution obtained in step (1) to stand, filtering the product obtained after standing, and drying the product.

[0043] (B) At least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof. The solid composition according to this embodiment contains (B) a stomach protective component and at least one selected from the group consisting of α-amino acids or salts thereof. These components may be present individually or in combination of two or more.

[0044] In this specification, a gastric protective component may be a component that has a function of protecting the stomach, and includes, for example, components added to a solid pharmaceutical composition to protect the stomach. The gastric protective component may protect the stomach by neutralizing gastric acid, suppressing gastric acid secretion, assisting in the formation of the gastric mucosa, or repairing and protecting the gastric mucosa, but the mechanism is not limited to these.

[0045] Examples of stomach-protective ingredients include glycine or its salts, magnesium aluminometasilicate, aluminum silicate, magnesium aluminometasilicate, magnesium silicate, synthetic hydrotalcite, dihydroxyaluminum alnoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel, coprecipitation product of aluminum hydroxide and sodium bicarbonate, dried mixed gel of aluminum hydroxide and magnesium carbonate, coprecipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, magnesium carbonate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, and cetraxate hydrochloride. Examples of components include, but are not limited to, one or more selected from the group consisting of sofarcone, gefarnate, teprenone, rebamipide, magnesium aluminum silicate, magnesium aluminum hydroxide, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, oyster shell, pirenzepine hydrochloride hydrate, sodium azulene sulfonate, glycyrrhizinate, L-glutamine, Japanese oak, and aminoacetic acid. Note that α-amino acids or their salts may also be included as stomach protective components. Component (B) may be rephrased as at least one selected from the group consisting of stomach protective components (excluding those corresponding to α-amino acids or their salts) and α-amino acids or their salts.

[0046] The stomach-protective component is preferably at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, magnesium aluminomesilicate, and aluminum silicate; more preferably at least one selected from the group consisting of glycine, magnesium aluminometasilicate, magnesium aluminomesilicate, and aluminum silicate; and even more preferably at least one selected from the group consisting of glycine, magnesium aluminometasilicate, and aluminum silicate.

[0047] As used herein, "glycine" refers to the compound with CAS registry number 56-40-6 and the chemical formula C2H5NO2 (molecular weight: 75.07 g / mol). The salt of glycine is not particularly limited as long as it is pharmacodynamically acceptable.

[0048] As used herein, "magnesium aluminometasilicate" refers to the substance with CAS registry number 12408-47-8, Al2Mg2O 11 It contains compounds represented by the chemical formula Si3·xH2O (for example, x is 1). Magnesium aluminometasilicate may contain 29.1-35.5% aluminum oxide (Al2O3: 101.96), 11.4-14.0% magnesium oxide (MgO: 40.30), and 29.2-35.6% silicon dioxide (SiO2: 60.08) on a converted dry basis.

[0049] As used herein, "magnesium aluminosilicate" includes the compound with CAS registry number 71205-22-6 and the chemical formula Al2MgO8Si2. Magnesium aluminosilicate may contain, on an average dry basis, 27.0-34.3% aluminum oxide (Al2O3: 101.96), 20.5-27.7% magnesium oxide (MgO: 40.30), and 14.4-21.7% silicon dioxide (SiO2: 60.08).

[0050] As used herein, "aluminum silicate" includes the compound with CAS registry number 12141-46-7 and the chemical formula Al2O5Si. The aluminum silicate may be either natural aluminum silicate or synthetic aluminum silicate as listed in the 18th edition of the Japanese Pharmacopoeia, but synthetic aluminum silicate is preferred.

[0051] In this specification, α-amino acids include not only naturally occurring α-amino acids but also artificial α-amino acid variants and derivatives of α-amino acids. α-amino acids are not particularly limited, but examples include natural amino acids, including proteinogenic amino acids, and unnatural amino acids.

[0052] When protein amino acids are represented using the three-letter abbreviations commonly used in this industry, they are Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Gly, Pro, Ala, Ile, Leu, Met, Phe, Trp, Tyr, and Val. Alternatively, when protein amino acids are represented using the single-letter abbreviations commonly used in this industry, they are R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, and V.

[0053] α-amino acids (excluding glycine) may be L-amino acids or D-amino acids, but L-amino acids are preferred. Examples of non-proteinogenic α-amino acids include those in which substituents are attached to the side chains of proteinogenic amino acids, such as carbocysteine. The α-amino acid salts are not particularly limited, as long as they are pharmacologically acceptable.

[0054] In this embodiment, the α-amino acid or its salt is preferably at least one selected from the group consisting of glycine or its salt, carbocysteine ​​or its salt, phenylalanine or its salt, and glutamic acid or its salt; more preferably at least one selected from the group consisting of glycine or its salt, phenylalanine or its salt, and glutamic acid or its salt; and even more preferably at least one selected from the group consisting of glycine, phenylalanine, and sodium glutamate. These amino acids (excluding glycine) are preferably L-amino acids.

[0055] As used herein, "carbocysteine" refers to the compound with CAS registry number 638-23-3 and chemical formula C5H9NO4S (molecular weight: 179.19 g / mol). Salts of carbocysteine ​​are not particularly limited as long as they are pharmacodynamically acceptable.

[0056] As used herein, "phenylalanine" refers to a compound with CAS registry number 63-91-2 and chemical formula C9H 11 It is a compound represented by NO2 (molecular weight: 165.19 g / mol). The salt of phenylalanine is not particularly limited as long as it is pharmacologically acceptable.

[0057] As used herein, "glutamic acid" refers to the compound with CAS registry number 56-86-0 and chemical formula C5H9NO4 (molecular weight: 147.13 g / mol). The salt of glutamic acid is not particularly limited as long as it is pharmaceutically acceptable, but sodium glutamate is preferred. The salt of glutamic acid may also be sodium glutamate hydrate, which has CAS registry number 142-47-2 and chemical formula C5H8NNaO4·H2O (molecular weight: 187.13 g / mol).

[0058] Component (B) is preferably at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, carbocysteine ​​or its salt, phenylalanine or its salt, and glutamic acid or its salt, and more preferably at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, phenylalanine or its salt, and glutamic acid or its salt. Component (B) may also be at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, carbocysteine ​​or its salt, and glutamic acid or its salt.

[0059] In this embodiment, the mass ratio of components (A) and (B) contained in the solid composition (the mass ratio of the total amount of component (A) to component (B)) is 1:0.2 to 1:20 ((A):(B)), preferably 1:0.2 to 1:10 ((A):(B)), and more preferably 1:0.2 to 1:1.5 ((A):(B)). By having the mass ratio of components (A) and (B) contained in the solid composition within this range, it is possible to further suppress the changes in properties that may occur when at least one selected from the group consisting of a gastric protective component and α-amino acids or salts thereof is added to the crystals consisting of ibuprofen and tranexamic acid. The mass ratio of components (A) and (B) contained in the solid composition may be 1:0.57 to 1:20 ((A):(B)), 1:0.57 to 1:10 ((A):(B)), 1:0.57 to 1:5 ((A):(B)), or 1:0.57 to 1:1.5 ((A):(B)).

[0060] In this embodiment, the mass ratio of components (A) and (B) contained in the solid composition (the mass ratio of the total amount of component (A) to component (B)) may be 1:0.01 to 1:10 ((A):(B)), 1:0.05 to 1:5 ((A)):((B)), or 1:0.1 to 1:1 ((A)):((B)).

[0061] At least one component selected from the group consisting of gastric protective components and α-amino acids or their salts is appropriately adjusted according to the intended use of the solid composition, the symptoms of the recipient, age, weight, sex, etc. The content of at least one component selected from the group consisting of gastric protective components and α-amino acids or their salts may be adjusted independently of each other, within the range where the mass ratio of components (A) and (B) is within the above range.

[0062] The total dose of at least one component selected from the group consisting of a gastric protective component and α-amino acids or their salts varies depending on the amount of crystals consisting of ibuprofen and tranexamic acid, for example, the daily dose is in the range of 0.1 mg to 18000 mg, preferably 1 mg to 6000 mg, more preferably 10 mg to 1000 mg, or 100 mg to 400 mg.

[0063] The total amount of gastric protective components and at least one selected from the group consisting of α-amino acids or salts thereof contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0064] The total amount of gastric protective components administered varies depending on the amount of crystals consisting of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.1 mg to 15,000 mg, preferably 1 mg to 10,000 mg, more preferably 10 mg to 1,000 mg, or 100 mg to 300 mg.

[0065] The total amount of gastric protective components contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0066] The total amount of α-amino acids or their salts administered varies depending on the amount of crystals consisting of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.01 mg to 3000 mg, preferably 0.1 mg to 2000 mg, more preferably 1 mg to 1000 mg, or 100 mg to 300 mg.

[0067] The total amount of α-amino acids or their salts contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0068] The dosage of glycine or its salt varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 10 mg to 1500 mg, preferably 80 mg to 1000 mg, and more preferably 150 mg to 300 mg.

[0069] The amount of glycine or its salt contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0070] The dosage of magnesium aluminometasilicate varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.1 mg to 1500 mg, preferably 1 mg to 800 mg, and more preferably 10 mg to 500 mg.

[0071] The amount of magnesium aluminometasilicate contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0072] The dosage of magnesium aluminosilicate varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.1 mg to 4000 mg, preferably 1 mg to 1200 mg, and more preferably 10 mg to 800 mg.

[0073] The amount of magnesium aluminosilicate contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0074] The dosage of aluminum silicate varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.1 mg to 12,000 mg, preferably 1 mg to 3,000 mg, and more preferably 10 mg to 800 mg.

[0075] The amount of aluminum silicate contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 40% by mass, and more preferably 1% to 10% by mass.

[0076] The dosage of carbocysteine ​​or its salt varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 100 mg to 1000 mg, preferably 400 mg to 900 mg, and more preferably 700 mg to 800 mg.

[0077] The amount of carbocysteine ​​or its salt contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 1% to 50% by mass, and more preferably 10% to 30% by mass.

[0078] The dosage of phenylalanine or its salt varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 0.01 mg to 100 mg, preferably 0.1 mg to 85 mg, and more preferably 1 mg to 70 mg.

[0079] The amount of phenylalanine or its salt contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 20% by mass, and more preferably 1% to 10% by mass.

[0080] The dosage of glutamic acid or its salt varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily dose is in the range of 5 mg to 300 mg, preferably 10 mg to 210 mg, and more preferably 20 mg to 120 mg.

[0081] The amount of glutamic acid or its salt contained in the solid composition administered daily is, for example, 0.01% to 95% by mass, preferably 0.1% to 20% by mass, and more preferably 1% to 10% by mass.

[0082] (Other ingredients) The solid composition according to this embodiment may contain components other than those listed above, depending on its intended use. When the solid composition is intended to alleviate various symptoms of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components. At least one selected from the group consisting of the above-mentioned gastric protective components and α-amino acids or their salts may be added as, for example, the components described later, such as anti-inflammatory agents, anticholinergics, excipients, disintegration aids, foaming agents, moisture-proofing agents, stabilizers, sweeteners, colorants, bases, coating agents, sugar coating agents, and fluidizing agents.

[0083] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into COX-2 nonselective inhibitors such as diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and COX-2 selective inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be included in the composition as a NSAID. It is preferable that the NSAID is a COX-2 nonselective inhibitor. The NSAID may also be in salt form.

[0084] Other pharmacologically acceptable ingredients that may be added include antihistamines, antipyretic analgesics, cough and expectorant agents, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly found in combination cold medicines, antipyretic analgesics, and rhinitis medicines.

[0085] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, and mequitazine.

[0086] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine. Acetaminophen may be included in the composition as an antipyretic analgesic.

[0087] Examples of cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, bromhexine, bromhexine hydrochloride, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, and ambroxol hydrochloride.

[0088] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0089] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0090] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, and so on.

[0091] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, and total belladonna root alkaloid citrate.

[0092] Pharmaceutical additives may be added to the solid composition according to this embodiment as needed. Examples of pharmaceutical additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents / fragrances. Pharmaceutical additives that are conventionally known and can be used in solid compositions can be used for the above purposes.

[0093] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose monohydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, calcium sulfate, erythritol, glucose, fructose, etc.

[0094] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0095] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0096] Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0097] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0098] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0099] Examples of moisture-proofing agents include ethylcellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined sucrose, 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.

[0100] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0101] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, disodium calcium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, hydrated silicon dioxide, carmellose sodium, anhydrous sodium carbonate, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, and L-cystine. L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.Examples include polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0102] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, and sodium pyrosulfite. In the case of a solid composition containing acetaminophen, it is preferable not to include tocopherols as antioxidants or stabilizers.

[0103] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0104] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, and erythritol.

[0105] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, and ginger. Examples of ingredients include lemon extract, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, porcini powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flake powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, rose oil, etc.

[0106] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0107] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0108] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili pepper powder, 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.

[0109] Examples of coloring agents include yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, dizazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc.

[0110] The base ingredients include acacia gum powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic magnesium sodium silicate, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer, concentrated glycerin, potato starch, and hydroxypropyl Examples include cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0111] As coating agents, for example, ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium dioxide / macrogol 400 mixture, hypromellose, fumaric acid / stearic acid / polyvinyl acetal diethyl Examples include a mixture of methylcellulose 2910 and hydroxypropyl methylcellulose, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S methyl acrylate / methacrylic acid / methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0112] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.

[0113] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, and liquid paraffin.

[0114] The dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0115] Examples of defoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid esters, silicone defoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0116] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, calcium hydrogen phosphate granules, and the like.

[0117] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, Vitabase, cedarwood oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flakes powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0118] These components may be present individually or in combination of two or more types.

[0119] (Dosage form) The solid composition according to this embodiment can be in dosage forms described in the 18th edition of the Japanese Pharmacopoeia, General Provisions for Pharmaceutical Preparations, etc., such as oral preparations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders), or preparations applied orally (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition according to this embodiment is preferably an oral solid composition.

[0120] Examples of dosage forms for the solid composition according to this embodiment include tablets, capsules, pills, granules, and fine granules. These solid compositions may be coated by known methods such as sugar coating or film coating as needed. Since the solid composition according to this embodiment is susceptible to changes in properties due to the incorporation of components (A) and (B), it can maintain its powdered state for a long period of time. Therefore, from the viewpoint of effectively achieving the effects of the present invention, the dosage form of the solid composition according to this embodiment is preferably a tablet or a powder formulation. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets. Specific examples of powder formulations include capsules, granules, and fine granules.

[0121] The solid composition according to this embodiment may be initially packaged in bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored airtight. Furthermore, they may be pillow-packaged, or stored in boxes or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, polyethylene film, or resin films with aluminum foil attached can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle packaging or pillow packaging.

[0122] The solid composition according to this embodiment may be contained in a packaging container to form a package. The solid composition according to this embodiment may be contained in, for example, an airtight package. By forming a package, the convenience of use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0123] As for the packaging form of the solid composition, the solid composition may be initially packaged in a bottle, PTP (Press Through Package), pouch, stick, or SP (Strip Package) and stored airtight. Furthermore, these may be pillow-packed, or stored in a box or similar container. In addition, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be stored simultaneously in the packaging container, such as the bottle or pillow packaging.

[0124] Materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as resin films to which aluminum foil is attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0125] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Examples of such packaging include packaging formed from at least one of a moisture-proof material and a gas barrier material.

[0126] Examples of moisture-proof materials include a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. Furthermore, when the solid composition is a tablet, PTP packaging with aluminum on both sides (Al-Al packaging) may be used as a moisture-proof material, considering factors such as suppressing the rise in moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0127] Known materials may be used as the gas barrier material, for example, a laminate film having a functional barrier layer, and may be used to serve the same purpose as the moisture barrier material, or in combination with the moisture barrier material.

[0128] Furthermore, the packaging containers may be made environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used in part or all of the packaging materials.

[0129] (Manufacturing method) The solid composition can be manufactured using known techniques. Crystals comprising ibuprofen and tranexamic acid can be manufactured by the method described in Japanese Patent Application Publication No. 2022-070674 (listed above). At least one selected from the group consisting of a gastric protective component and α-amino acids or salts thereof can be commercially available.

[0130] A crystal consisting of ibuprofen and tranexamic acid, and at least one selected from the group consisting of a stomach-protective component and an α-amino acid or its salt, are each added in an optional step and finally brought into contact with each other. A solvent or binder may be added to the mixture after contact and kneaded, and the resulting paste may be a solid composition.

[0131] The resulting mixture can be further subjected to drying and granulation processes to produce granules. In this case, granules containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0132] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0133] (Methods to suppress changes in properties) In the second mode, A method for suppressing changes in the properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of a gastric protective component and an α-amino acid or a salt thereof, A method is provided which includes crystallizing ibuprofen with tranexamic acid. In the solid composition, the mass ratio of (A) crystals consisting of ibuprofen and tranexamic acid to (B) at least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof is preferably 1:0.2 to 1:20 ((A):(B)). The solid composition is preferably in powder form.

[0134] The method for suppressing changes in properties according to this embodiment can suppress changes in the properties of ibuprofen by combining ibuprofen with at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt. This method suppresses changes in the properties of ibuprofen by crystallizing ibuprofen with tranexamic acid and incorporating it into a solid composition. Furthermore, by setting the mass ratio of the crystals consisting of ibuprofen and tranexamic acid to at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt within the above range, changes in the properties of ibuprofen can be further suppressed.

[0135] In the method for suppressing changes in properties according to this embodiment, the method for crystallizing ibuprofen with tranexamic acid is as described above. Furthermore, the amounts of ibuprofen, at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt, and tranexamic acid should be adjusted to be the same as the content of the same components in the solid composition according to this embodiment.

[0136] (Use of tranexamic acid) In a third embodiment, the use of tranexamic acid is provided for a method of suppressing changes in the properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof. In the solid composition, the mass ratio of (A) crystals consisting of ibuprofen and tranexamic acid to (B) at least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof is preferably 1:0.2 to 1:20 ((A):(B)). The solid composition is preferably in powder form.

[0137] In this embodiment, tranexamic acid is crystallized with ibuprofen and added to the solid composition together with at least one selected from the group consisting of a gastric protective component and an α-amino acid or a salt thereof. The amount of tranexamic acid used may be such that it can crystallize with ibuprofen. The amount of tranexamic acid used may be adjusted so that the content of tranexamic acid in the resulting solid composition is similar to that of the component in the solid composition according to this embodiment.

[0138] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. [Examples]

[0139] 1.Raw materials In this example, the following raw materials were used. [Table 1]

[0140] 2. Preparation of the solid composition (Comparative Example 1) 2.5g of ibuprofen (manufactured by SI Group) and 2.5g of glycine were weighed into a 5K standard bottle, mixed 100 times, sieved through a 42-mesh sieve, and then mixed 100 more times in the 5K standard bottle to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and then adjusted to a uniform thickness to prepare the sample for Comparative Example 1.

[0141] (Comparative Examples 2-4) 2.5g of ibuprofen (manufactured by SI Group) and 2.5g each of magnesium aluminometasilicate, L-carbocysteine, or L-phenylalanine were weighed into a 5K standard bottle, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in the 5K standard bottle to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and then adjusted to a uniform thickness to obtain the samples for Comparative Examples 2 to 4.

[0142] (Comparative Example 5) Approximately 7 g of L-sodium glutamate was weighed into a mortar, ground with a pestle, and then sieved through a 22-mesh sieve to obtain the sieved L-sodium glutamate product. 2.5g of ibuprofen (manufactured by SI Group) and 2.5g of sieved L-sodium glutamate were weighed into an 8K standard bottle, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in the 8K standard bottle to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to obtain the sample for Comparative Example 5.

[0143] (Example 1) 240.0 g of ibuprofen (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd.) and 182.9 g of tranexamic acid were charged into a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Powrec)) and mixed to obtain a mixed powder. 69 g of a mixture of ethanol (purity 99.5%) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was added to this mixed powder and kneaded and granulated to obtain a paste. The paste was wet-milled using a power mill (manufactured by Dalton) at low speed and 32 mesh. Subsequently, it was stored in a constant temperature bath at 70°C for 89 hours to obtain crystals consisting of ibuprofen and tranexamic acid.

[0144] Six mg of the obtained crystals were placed in an aluminum pan, and the temperature range of 25 to 350°C was measured at a rate of 60°C per minute using a differential scanning calorimeter DSC3+ (Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen around 75°C disappeared, and a peak derived from the crystal composed of ibuprofen and tranexamic acid appeared around 180°C, confirming that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained.

[0145] The obtained crystals (4.4g) and glycine (2.5g) were weighed into a 5K standard bottle, mixed 100 times, sieved through a 42-mesh sieve, and then mixed again 100 times in the 5K standard bottle to obtain the physical mixture powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to obtain the sample for Example 1.

[0146] (Examples 2-4) 4.4 g of the ibuprofen and tranexamic acid crystals obtained in Example 1, along with 2.5 g each of magnesium aluminometasilicate, L-carbocysteine, or L-phenylalanine, were weighed into a 5K standard bottle, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in the 5K standard bottle to obtain a physical mixture powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to obtain the samples for Examples 2-4.

[0147] (Example 5) 4.4 g of the ibuprofen and tranexamic acid crystals obtained in Example 1 and 2.5 g of the sieved L-sodium glutamate product obtained in Comparative Example 5 were weighed into an 8K standard bottle, mixed 100 times, sieved through a 22-mesh sieve, and then mixed 100 more times in the 8K standard bottle to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to obtain the sample for Example 5.

[0148] The mixing ratios (mass ratios) of each sample are shown in the table below. In the table below, "IB-TXA crystals" refers to crystals composed of ibuprofen and tranexamic acid.

[0149] [Table 2]

[0150] [Table 3]

[0151] (Samples A-1 to A-6) The crystals consisting of ibuprofen and tranexamic acid obtained in Example 1, along with glycine, were weighed into 5K standard bottles according to the formulations shown in Table 4, mixed 100 times, sieved through a 22-mesh sieve (42-mesh in the case of sample A-4), and then mixed 100 more times in a 5K standard bottle to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to produce samples A-1 to A-6.

[0152] (Samples B-1 to B-3) The ibuprofen and tranexamic acid crystals obtained in Example 1 and magnesium aluminometasilicate were weighed into 5K standard bottles according to the formulations shown in Table 4, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in the 5K standard bottle to obtain a physically mixed powder. Two g (0.5 g for samples B-2 and B-3) of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to produce samples B-1 to B-3.

[0153] (Sample C-1) The crystals consisting of ibuprofen and tranexamic acid obtained in Example 1, along with L-phenylalanine, were weighed into 5K standard bottles according to the formulations shown in Table 4, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in the 5K standard bottle to obtain a physically mixed powder. Two grams of the obtained physical mixture powder were weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to obtain sample C-1.

[0154] (Samples D-1 to D-5) The crystals consisting of ibuprofen and tranexamic acid obtained in Example 1, along with L-carbocysteine, were weighed into 5K standard bottles according to the formulations shown in Table 5, mixed 100 times, sieved through a 22-mesh sieve, and then mixed again 100 times in a 5K standard bottle to obtain a physically mixed powder. Two g each of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to produce samples D-1 to D-5.

[0155] (Samples E-1 to E-5) The crystals consisting of ibuprofen and tranexamic acid obtained in Example 1 and the sieved L-sodium glutamate product obtained in Comparative Example 5 were weighed into 5K standard bottles (8K standard bottles in the case of sample E-3) according to the formulations shown in Table 5, mixed 100 times, sieved through a 22-mesh sieve, and then mixed 100 times again in 5K standard bottles (8K standard bottles in the case of sample E-3) to obtain a physically mixed powder. Two g of the obtained physical mixture powder was weighed into a 1K standard bottle, sealed tightly, and adjusted to ensure uniform thickness to produce samples E-1 to E-5.

[0156] [Table 4]

[0157] [Table 5]

[0158] 3. Evaluation of changes in the properties of the solid composition (Examples 1-5 and Comparative Examples 1-5) First, each sample from Examples 1-5 and Comparative Examples 1-5 was left to stand at 80°C for 48 hours, and changes in properties were evaluated. Changes in properties observed included aggregation, solidification, moisture absorption, and wetting. Changes in properties were confirmed visually before and after standing to determine whether aggregation, solidification, moisture absorption, and wetting of the powder had occurred.

[0159] As a result, while Comparative Examples 1 to 5 showed significant changes in properties compared to the start of high-temperature storage, these changes were suppressed in Examples 1 to 5, in which ibuprofen was crystallized and blended with tranexamic acid. Specifically, Comparative Example 1 became wet, and Comparative Example 5 became partially wet and aggregated, but in Examples 1 and 5, changes in properties were significantly suppressed, and the powder remained in a powder state even after 48 hours of standing. Furthermore, while Comparative Examples 2 and 3 solidified, and Comparative Example 4 solidified and aggregated, changes in properties were significantly suppressed in Examples 2, 3, and 4, and the powder remained in a powder state even after 48 hours of standing.

[0160] (Samples A-E) Next, samples A-1 to A-6, B-1 to B-3, C-1, D-1 to D-5, and E-1 to E-5 were left to stand at 80°C for 48 hours, and changes in properties were evaluated. Changes in properties observed included aggregation, solidification, moisture absorption, and wetting. Changes in properties were confirmed visually before and after standing to see if aggregation, solidification, moisture absorption, and wetting of the powder had occurred. The results are shown in Table 6. As shown in Table 6, comparative examples (A-1 to A-2, D-1 to D-2, and E-1 to E-2) in which the mass ratio of component (A) ibuprofen and tranexamic acid crystals to component (B) at least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof was outside the range of 1:0.2 to 1:20 ((A):(B)) partially solidified or completely solidified. On the other hand, the samples in the examples (A-3 to A-6, B-1 to B-3, C-1, D-3 to D-5, and E-3 to E-5) with a mass ratio in the range of 1:0.2 to 1:20 ((A):(B)) showed significantly suppressed changes in properties and maintained their powdery state even after 48 hours of standing. Sample D-3 showed some clouding on the wall of the standard bottle, but maintained its powdery state.

[0161] [Table 6]

[0162] From the above, it was shown that by crystallizing ibuprofen with tranexamic acid and combining it with at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt, and by combining the crystals consisting of ibuprofen and tranexamic acid with at least one selected from the group consisting of a gastric protective component and an α-amino acid or its salt within a predetermined range, changes in properties under high-temperature conditions are significantly suppressed.

[0163] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

Claims

1. The following ingredients: (A) A crystal composed of ibuprofen and tranexamic acid, (B) At least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof, Includes, The mass ratio of (A) to (B) is 1:0.2 to 1:20 ((A):(B)). Solid composition.

2. The aforementioned stomach-protective component is at least one selected from the group consisting of glycine or its salt, magnesium aluminometasilicate, magnesium aluminosilicate, and aluminum silicate. The solid composition according to claim 1.

3. The α-amino acid or its salt is at least one selected from the group consisting of glycine or its salt, carbocysteine ​​or its salt, phenylalanine or its salt, and glutamic acid or its salt. The solid composition according to claim 1.

4. The above (B) is at least one selected from the group consisting of glycine or a salt thereof, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, carbocysteine ​​or a salt thereof, phenylalanine or a salt thereof, and glutamic acid or a salt thereof. The solid composition according to claim 1.

5. The above (B) is at least one selected from the group consisting of glycine or a salt thereof, magnesium aluminometasilicate, carbocysteine ​​or a salt thereof, and glutamic acid or a salt thereof. The solid composition according to claim 1.

6. The solid composition according to any one of claims 1 to 5, wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:

1.

7. A solid composition according to any one of claims 1 to 5, wherein the mass ratio of component (A) to (B) is 1:0.2 to 1:10 ((A):(B)).

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