solid components

Abstract

To provide a solid composition containing ibuprofen in which changes in properties are suppressed. [Solution] The following components: (A) A crystal composed 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 Seeds and, A solid composition containing the following:

Description

Technical Field

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

Background Art

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

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

[0004] Patent Document 2 discloses a crystal composed of ibuprofen and tranexamic acid.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] By the way, solid compositions containing ibuprofen may undergo changes in properties over time, such as moisture absorption, solidification, wetting, and aggregation, due to the blending of other components. Therefore, solid compositions containing ibuprofen still have room for improvement from the perspective of property changes. The present invention addresses property changes ​​​​The objective is to provide a solid composition containing ibuprofen in which chemical reactions are suppressed. [Means for solving the problem]

[0007] The inventors have found that ibuprofen contains a stomach-protective component and an α-amino acid or its salt. We found that a significant change in properties occurs when at least one species selected from the group is combined. Furthermore, this change in properties is achieved by crystallizing ibuprofen with tranexamic acid and combining them. We discovered that this could be suppressed, and thus completed the present invention.

[0008] In other words, this application encompasses the following inventions. [1] The following ingredients: (A) A crystal composed 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 Seeds and, A solid composition containing the following: [2] The aforementioned stomach-protecting component is glycine or its salt, magnesium aluminometasilicate, silica At least one selected from the group consisting of magnesium aluminate and aluminum silicate. It is also one type. The solid composition described in [1]. [3] The α-amino acid or its salt is glycine or its salt, carbocysteine ​​or its salt, A small amount selected from the group consisting of phenylalanine or its salts, and glutamic acid or its salts. At least one type. The solid composition described in [1] or [2]. [4] The above (B) is glycine or a salt thereof, magnesium aluminometasilicate, aluminometasilicate. Magnesium methyl phosphate, aluminum silicate, carbocysteine ​​or its salt, phenylalanine At least one selected from the group consisting of nimesulide or a salt thereof, and glutamic acid or a salt thereof which is the solid composition according to [1]. [5] where (B) is at least one selected from the group consisting of glycine or a salt thereof, magnesium aluminometasilicate, phenylalanine or a salt thereof, and glutamic acid or a salt thereof which is the solid composition according to [1]. [6] In the crystal, the molar ratio of ibuprofen to tranexamic acid is 1:1, the solid composition according to any one of [1 to [5]. [7] The mass ratio of component (A) to (B) is 1:0.01 to 1:10 ((A):(B)), the solid composition according to any one of 1] to [6]. [8] A method for suppressing the change in properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of a gastric protective component and α - amino acid or a salt thereof, which comprises crystallizing ibuprofen with tranexamic acid. A method. [9] Use of tranexamic acid for a method for suppressing the change in properties of a solid composition comprising ibuprofen and at least one selected from the group consisting of a gastric protective component and α - amino acid or a salt thereof, for a method. [Advantages of the Invention]

[0009] According to the present invention, it is possible to provide a solid composition containing ibuprofen with suppressed change in properties . [Brief Description of the Drawings]

[0010] [Figure 1]Figure 1 shows the differential scanning calorimetry (DSC) results of the crystals composed of ibuprofen and tranexamic acid obtained in Example 1. [Modes for carrying out the invention]

[0011] The following describes embodiments of the present invention (hereinafter referred to as "this embodiment"), but The scope of the invention is not limited to the following embodiments. In this embodiment, the composition is Each component may be included individually or in combination of two or more. The "~" symbol, which indicates a numerical range, represents "greater than or equal to" or "less than or equal to," and includes both numbers at either end.

[0012] (solid composition) In the first mode, (A) A crystal composed 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 Seeds and, Solid composition containing, It will be provided. The solid composition is specifically a solid pharmaceutical composition.

[0013] Each component contained in the solid composition according to this embodiment is included in a pharmaceutically acceptable salt state. It may be present on its own, or it may be included as a complex with other components. That is, in this embodiment In addition to components (A) and (B), the solid composition also contains salts of other components. It may contain. "Pharmacologically acceptable salts" means, for example, bases that are acceptable as medicines or It contains salts with acids. Non-specific examples of pharmacologically acceptable salts include inorganic acids (hydrochloric acid, hydrobromic acid, iodide). Addition salts of hydrogen acids, sulfuric acid, phosphoric acid, etc., organic acids (p-toluenesulfonic acid, methanesulfone Acids, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoate Addition salts of acetic acid (such as acetic acid), inorganic bases (ammonium hydroxide or alkali or alkali) Examples include addition salts of earth metal hydroxides, carbonates, bicarbonates, etc., and addition salts of amino acids. Pharmacologically acceptable salts may be hydrated or anhydrous.

[0014] In this embodiment, ibuprofen exists crystallized with tranexamic acid. Furthermore, the combination of ibuprofen and ingredient (B) results in a change in the properties of the solid composition, and special This suppresses changes in properties over time.

[0015] In this specification, "change in properties" includes at least aggregation, solidification, hygroscopicity, and wetting. , which means a change in properties and / or state. Therefore, the solid composition according to this embodiment is Any of the following changes that occur over time, such as aggregation, solidification, moisture absorption, and wetting, may be suppressed. Furthermore, "the change in properties is suppressed" means that the change in properties is unlikely to occur, for example. For example, when compared to a solid composition containing an equivalent amount of ibuprofen instead of the above component (A), Changes in properties may be suppressed.

[0016] The solid composition according to this embodiment may have its properties changed under high-temperature conditions. For example, the temperature range may be 30-100°C or 40-90°C.

[0017] Furthermore, "changes in properties over time" refers to changes in properties that occur over time, for example, during manufacturing. Afterwards, or after being exposed to a specific environment (e.g., a high temperature and / or high humidity environment), for 12 hours or less The above refers to a change in properties that occurs over a period of 18 hours or more, 24 hours or more, or 48 hours or more. The period during which changes in properties are suppressed in the solid composition according to this embodiment is not particularly limited. However, for example, it could be 12 hours or more, 18 hours or more, 24 hours or more, or 48 hours or more. stomach.

[0018] (A) Crystals composed of ibuprofen and tranexamic acid As used herein, "ibuprofen" refers to CAS Registry Number 15687-27 -1, C 13 H 18 It is a compound represented by the chemical formula O2 (molecular weight: 206.29g). ( / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic drugs. The ibuprofen salt is not particularly limited, as long as it is pharmacologically acceptable.

[0019] The amount of ibuprofen or its salt included in the composition is determined by the use of ibuprofen or its salt in the composition. The dosage may be adjusted as appropriate depending on the symptoms, age, weight, sex, etc. of the recipient. For example, ibuprofen When profen or its salts are formulated as a nonsteroidal anti-inflammatory drug, they are administered to adults. The daily dose of ibuprofen or its salt is 30 mg to 2000 mg, preferably 1 It can be adjusted within the range of 00 mg to 1000 mg, more preferably 200 mg to 600 mg. In this embodiment, "adult" means males and females aged 15 or older. However, in this embodiment, These solid compositions are not limited to those intended for adult use, but also to children under 15 years of age. It may be taken by adults. When taken by children, the adult dose is daily according to the age group. It can be used in reduced doses, such as 1 / 2 or 2 / 3 of the normal dosage.

[0020] The above dosage is an example, and the amount of ibuprofen or its composition administered per day The salt content is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass. More preferably, it is about 10% by mass to about 30% by mass.

[0021] The ibuprofen or salt content in the composition administered daily is 1% by mass to 7%. It may be 0% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass.

[0022] The weight and dosage in the above composition are the daily dose (daily amount), however The dose may be administered to the subject multiple times a day, for example, two or three times, preferably in three divided doses. The same applies to ingredients other than ibuprofen or its salts. Also, each dose is calculated in total. Therefore, the content of each component in the composition can vary depending on the single dose and the dosage form of the composition. .

[0023] In certain embodiments, the composition is a tablet, and the above dosage is 3 tablets, 6 tablets, or 9 tablets. This refers to the amount of the ingredient contained within, preferably the amount of the ingredient in 9 tablets. In this embodiment, For adults (15 years and older), the single dose is three times a day, with each dose consisting of 2, 3, or 4 tablets. Preferably, the single dose is 3 tablets.

[0024] Unless otherwise specified, the amounts of ibuprofen described herein are subject to change. This concerns the amount of nexamic acid in the crystals, but the amount in question is the amount of crystallized ibuprofen. The total amount of rophene and uncrystallized ibuprofen may also be acceptable.

[0025] The solid composition contains crystalline ibuprofen and non-crystalline ibuprofen. It may be included.

[0026] The ibuprofen contained in the solid composition should be 90% by mass or more, for example, 90% by mass, 9 1% 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 may be crystallized with tranexamic acid.

[0027] As used herein, "tranexamic acid" refers to CAS Registry Number 1197-18- 8, C8H 15 It is a compound represented by the chemical formula NO2 (molecular weight: 157.21 g / (moles). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs, etc. Tranexamic acid The salt is not particularly limited as long as it is pharmacologically acceptable.

[0028] The amount of tranexamic acid or its salts used in the composition is determined by the use of tranexamic acid or its salts in the composition. The amount of tranexamic acid or its salt is adjusted as needed. Depending on the amount of ibuprofen, etc. The amount may vary, but for example, the daily amount is 10 mg to 3000 mg, preferably. The range is 100 mg to 1500 mg, more preferably 400 mg to 750 mg.

[0029] The content of tranexamic acid or its salt in the composition administered daily is 1% by mass to 7%. The mass is 0%, preferably 5-50%, and more preferably 10-30%.

[0030] The tranexamic acid or salt thereof contained in the composition administered daily is, for example, ibuprofen. 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass per 1 part by mass of the compound The amount is in parts by mass, more preferably 0.7 to 2.2 parts by mass.

[0031] Unless otherwise specified, the amounts of tranexamic acid described herein are as follows: This concerns the amount of profen in the crystal, but the amount is the amount of crystallized tranexamic acid. The total amount of xamic acid and uncrystallized tranexamic acid may also be used.

[0032] The solid composition contains crystalline tranexamic acid and non-crystalline tranexamic acid. It may be included.

[0033] The tranexamic acid contained in the solid composition shall be 90% by mass or more, for example, 90% by mass, 9 1% 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 may be crystallized with ibuprofen.

[0034] Ibuprofen and tranexamic acid exist as crystals in the composition. ibuprofen and tranexamic acid may be present in a 1:1 molar ratio. In this crystal, ibuprofen and tranexamic acid form a crystalline unit cell consisting of four molecules each. It's fine to leave it there.

[0035] In the crystal, the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid Between the ibuprofen carboxylic acid group and the tranexamic acid amino group, a hydrogen bond exists. It is acceptable for it to be formed.

[0036] The crystal exhibits an endothermic peak around 180°C in differential scanning calorimetry (DSC). It is acceptable to leave it as is. "Around 180°C" means, for example, a range of 180°C ± 20°C, and 180 The temperature may be within the range of ℃ ± 10℃. Furthermore, in the DSC of the crystal, ibuprofen is particularly The characteristic heat of fusion peak around 75°C may disappear.

[0037] The crystal in question has a crystal structure as shown in Figure 1 of Japanese Patent Publication No. 2022-070674, for example. The crystal may have the X-ray diffraction pattern shown in Figure 2 of the same publication. In the X-ray diffraction pattern, there are seven main peaks (2θ = 6.3, 8.4, 16.2) It may have (18.5, 19.1, 21.1, 25.6 ± 0.5°).

[0038] Crystals composed of ibuprofen and tranexamic acid are, for example, as described in Japanese Patent Publication No. 2022-07067. It can be manufactured by the method described in Publication No. 4. Three manufacturing methods are described below.

[0039] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) To produce ibuprofen in a fluid form by adding a solvent or heating, ( 2) Mix the resulting fluid ibuprofen with tranexamic acid, (3 A method comprising producing crystals from the obtained mixture.

[0040] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Obtain tranexamic acid in a fluid form, (2) the obtained fluid form Ranexamic acid and ibuprofen, or a fluidity obtained by adding or heating a solvent. (3) Mixing ibuprofen with the body, and (4) Producing crystals from the resulting mixture. Methods that include...

[0041] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Add ibuprofen and tranexamic acid to a solvent to obtain a solution or dispersion. (2) Spray and dry the obtained solution or dispersion, or (1) the solution obtained in step (1) A method comprising allowing the mixture to stand, filtering the product obtained after standing, and drying the product. Law.

[0042] (B) At least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof seed The solid composition according to this embodiment comprises (B) a stomach protective component and α-amino acids or salts thereof. It contains at least one selected from the group. These components may be one or two. The above may be included.

[0043] In this specification, a stomach-protective component may be a component that has a function of protecting the stomach. For example, it includes an ingredient added to a solid pharmaceutical composition to protect the stomach. The effects of gastric acid include neutralizing gastric acid, suppressing gastric acid secretion, assisting in the formation of the gastric mucosa, or repairing and protecting the gastric mucosa. It may protect the stomach, but the mechanism is not limited to these.

[0044] Examples of stomach-protective components include glycine or its salts, and magnesium aluminometasilicate. Aluminum, aluminum silicate, magnesium aluminosilicate, magnesium silicate, synthetic Hydrotalcite, dihydroxyaluminum anoacetate (aluminum glycine (Aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide) Co-precipitation product of sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate Coprecipitate of aluminum hydroxide, magnesium carbonate, and calcium carbonate, magnesium carbonate Aldioxa, copper chlorophyllin sodium, copper chlorophyllin potassium, methylmeth Onin sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone , gefarnate, teprenone, rebamipide, magnesium aluminum silicate, hydroxide Alumina magnesium, bentonite, calcium silicate, calcium carbonate, precipitated carbonate Calcium, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous sodium carbonate, water Sodium oxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate solution Japanese sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate Oyster shell, pirenzepine hydrochloride hydrate, sodium azulene sulfonate, glycyrrhizin One or more selected from the group consisting of salts, L-glutamine, Mallotus japonicus, and aminoacetic acid Two or more components may be listed, but are not limited to these.

[0045] The stomach-protecting component is preferably glycine or its salt, magnesium aluminometasilicate. Selected from the group consisting of , magnesium aluminosilicate, and aluminum silicate. At least one, more preferably glycine, magnesium aluminometasilicate. A small amount selected from the group consisting of magnesium aluminosilicate and aluminum silicate. At least one type, and more preferably glycine and magnesium aluminometasilicate. It is at least one selected from the group consisting of , and aluminum silicate.

[0046] As used herein, "glycine" refers to the glycine with CAS Registry Number 56-40-6. It is a compound represented by the chemical formula C2H5NO2 (molecular weight: 75.07 g / mol). The salts of glycine are not particularly limited, as long as they are pharmacologically acceptable.

[0047] As used herein, "magnesium aluminometasilicate" is referred to by its CAS Registry Number It is 12408-47-8, and Al2Mg2O 11 The chemical formula of Si3·xH2O (for example, x It contains the compound represented in 1). Magnesium aluminometasilicate is converted to dry For the dry material, 29.1-35.5% aluminum oxide (Al2O3:101.96), acid Magnesium oxide (MgO:40.30) 11.4-14.0%, and silicon dioxide (S iO2:60.08) May contain 29.2-35.6%.

[0048] When used herein, "magnesium aluminosilicate" refers to CAS Registry Number 7 It is 1205-22-6 and contains a compound represented by the chemical formula Al2MgO8Si2. Magnesium aluminosilicate is equivalent to aluminum oxide (Al2) when converted to dry weight. O3:101.96) 27.0~34.3%, Magnesium oxide (MgO:40.30 ) 20.5~27.7%, and silicon dioxide (SiO2:60.08) 14.4~2 It may contain 1.7%.

[0049] As used herein, "aluminum silicate" refers to the CAS registry number 12141- 46-7 includes compounds represented by the chemical formula Al2O5Si. Um refers to natural aluminum silicate and synthetic aluminum silicate, which are listed in the 18th edition of the Japanese Pharmacopoeia. Any form of luminium may be used, but synthetic aluminum silicate is preferred.

[0050] In this specification, α-amino acids include not only naturally occurring α-amino acids but also artificial ones. This includes α-amino acid variants and derivatives of α-amino acids. The α-amino acids are not limited to those listed above. It is not defined, but for example, proteinogenic amino acids Examples include natural amino acids (containing 0 acids) and non-natural amino acids.

[0051] Protein amino acids, when represented using the three-letter abbreviations commonly used in this industry, are Arg, His, and L. ys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Gly, Pro, A la, Ile, Leu, Met, Phe, Trp, Tyr, and Val. Also, Ta Protein-containing amino acids, when represented by a single letter commonly used in this industry, are R, H, K, D, E, S. These are T, N, Q, C, G, P, A, I, L, M, F, W, Y, and V.

[0052] α-amino acids (excluding glycine) may be L-amino acids or D-amino acids, It is preferably an L-amino acid. Examples of non-proteinogenic α-amino acids include substitutions in the side chains of proteinogenic amino acids. Examples include compounds in which groups are bonded together, such as carbocysteine. The α-amino acid salts are not particularly limited, as long as they are pharmacologically acceptable.

[0053] In this embodiment, the α-amino acid or its salt is preferably glycine or its salt, Rubocysteine ​​or its salts, phenylalanine or its salts, and glutamic acid or its salts At least one selected from the group consisting of, more preferably, glycine or a salt thereof. Selected from the group consisting of phenylalanine or its salts, and glutamic acid or its salts. At least one, more preferably glycine, phenylalanine, and glutamic acid It is at least one selected from the group consisting of sodium glycans. These amino acids (glycans) (Excluding syn) is preferably an L-amino acid.

[0054] As used herein, "carbocysteine" refers to CAS Registry Number 638-23- It is a compound represented by the chemical formula C5H9NO4S (molecular weight: 179.19 g / molecular weight). (moles). The salt of carbocysteine ​​is not particularly limited as long as it is pharmacologically acceptable.

[0055] As used herein, "phenylalanine" refers to CAS Registry Number 63-91-2 Therefore, the chemical formula is C9H 11 This compound is represented by NO2 (molecular weight: 165.19 g / mol). The phenylalanine salt is not particularly limited, as long as it is pharmacologically acceptable.

[0056] As used herein, "glutamic acid" refers to the substance with CAS Registry Number 56-86-0. It is a compound represented by the chemical formula C5H9NO4 (molecular weight: 147.13 g / mol). The salt of glutamic acid is not particularly limited as long as it is pharmacodynamically acceptable, but preferably It is sodium glutamate. The salt of glutamic acid has CAS registry number 142-47-2 It is a compound represented by the chemical formula C5H8NNaO4·H2O (molecular weight: 187.1) (3 g / mol) or monosodium glutamate hydrate may also be used.

[0057] Component (B) is preferably glycine or a salt thereof, magnesium aluminometasilicate, Magnesium aluminosilicate, aluminum silicate, carbocysteine ​​or its salts, f A small number of compounds selected from the group consisting of phenylalanine or its salts, and glutamic acid or its salts. It is at least one type, more preferably glycine or a salt thereof, magnesium aluminometasilicate. Selected from the group consisting of um, phenylalanine or its salts, and glutamic acid or its salts. It is at least one of the following types.

[0058] At least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof is The composition is appropriately adjusted according to the intended use of the solid composition, the symptoms of the target patient, age, weight, sex, etc. At least one selected from the group consisting of stomach protective components and α-amino acids or salts thereof. The proportions of each ingredient can be adjusted independently.

[0059] At least one selected from the group consisting of gastric protective components and α-amino acids or salts thereof The total amount of ingredients will vary depending on the amount of crystals composed of ibuprofen and tranexamic acid. However, for example, the daily amount is 0.1 mg to 18,000 mg, preferably 1 mg to 6 000 mg, more preferably in the range of 10 mg to 1000 mg, or 100 mg to 400 mg. be.

[0060] From the gastric protective components and α-amino acids or their salts contained in the solid composition administered daily The total amount of at least one substance selected from the group is, for example, 0.01% by mass to 99% by mass. The amount is %, preferably 0.1% to 40% by mass, more preferably 1% to 10% by mass. ru.

[0061] The total amount of stomach-protective ingredients is the amount of crystals consisting of ibuprofen and tranexamic acid. The amount varies depending on factors such as, for example, the daily amount is 0.1 mg to 15,000 mg, preferred More preferably 1mg to 10000mg, more preferably 10mg to 1000mg, 100mg to The range is 300 mg.

[0062] The total amount of gastric protective components contained in the solid composition administered daily is, for example, 0.0 1% to 99% by mass, preferably 0.1% to 40% by mass, more preferably 1% by mass It is approximately 10% by mass.

[0063] The total amount of α-amino acids or their salts is derived from ibuprofen and tranexamic acid. The amount varies depending on the amount of crystals, but for example, the daily amount is 0.01 mg to 3000 mg. mg, preferably 0.1 mg to 2000 mg, more preferably 1 mg to 1000 mg, 1 The range is 00mg to 300mg.

[0064] The total amount of α-amino acids or their salts contained in the solid composition administered daily is, for example, If so, 0.01% to 99% by mass, preferably 0.1% to 40% by mass, more preferably It is between 1% and 10% by mass.

[0065] The amount of glycine or its salt is equal to the amount of crystals consisting of ibuprofen and tranexamic acid. The amount varies depending on various factors, but for example, the daily amount is preferably 10 mg to 1500 mg. The dosage is in the range of 80 mg to 1000 mg, more preferably 150 mg to 300 mg.

[0066] The amount of glycine or its salt contained in the solid composition administered daily is, for example, 0.01 by mass. %~99% by mass, preferably 0.1%~40% by mass, more preferably 1%~10% by mass It is expressed as mass percent.

[0067] The amount of magnesium aluminometasilicate included is similar to that of ibuprofen and tranexamic acid. The amount varies depending on the amount of crystals, but for example, the daily amount is 0.1 mg to 150 mg. 0 mg, preferably 1 mg to 800 mg, more preferably 10 mg to 500 mg be.

[0068] The magnesium aluminometasilicate contained in the solid composition administered daily is, for example, , 0.01% to 99% by mass, preferably 0.1% to 40% by mass, more preferably It is between 1% by mass and 10% by mass.

[0069] The amount of magnesium aluminosilicate included is different from that of ibuprofen and tranexamic acid. The amount varies depending on the amount of crystals used, but for example, the daily amount is 0.1 mg to 4000 mg. g, preferably in the range of 1 mg to 1200 mg, more preferably in the range of 10 mg to 800 mg. ru.

[0070] The amount of magnesium aluminosilicate contained in the solid composition administered daily is, for example, 0 0.01% to 99% by mass, preferably 0.1% to 40% by mass, more preferably 1% by mass It is between % by quantity and 10% by mass.

[0071] The amount of aluminum silicate is equal to the amount of crystals composed of ibuprofen and tranexamic acid. The amount varies depending on factors such as, for example, the daily amount is 0.1 mg to 12,000 mg, preferred The range is 1 mg to 3000 mg, more preferably 10 mg to 800 mg.

[0072] The amount of aluminum silicate contained in the solid composition administered daily is, for example, 0.01 by mass. %~99% by mass, preferably 0.1%~40% by mass, more preferably 1%~10% by mass It is expressed as mass percent.

[0073] The amount of carbocysteine ​​or its salt is equal to the amount of ibuprofen and tranexamic acid. The amount varies depending on the amount of crystals, but for example, the daily amount is 100mg to 1000mg. Preferably in the range of 400 mg to 900 mg, more preferably in the range of 700 mg to 800 mg. be.

[0074] The amount of carbocysteine ​​or its salt contained in the solid composition administered daily is, for example, 0. 0.1% to 99% by mass, preferably 1% to 50% by mass, more preferably 10% by mass It is approximately 30% by mass.

[0075] The amount of phenylalanine or its salt is equal to the amount of ibuprofen and tranexamic acid. The amount varies depending on the amount of crystals, but for example, the daily amount is 0.01 mg to 100 mg. Preferably, the amount is in the range of 0.1 mg to 85 mg, and more preferably, 1 mg to 70 mg.

[0076] The amount of phenylalanine or its salt contained in the solid composition administered daily is, for example, 0. 0.1% to 99% by mass, preferably 0.1% to 20% by mass, more preferably 1% by mass It is approximately % to 10% by mass.

[0077] The amount of glutamic acid or its salt is determined by the crystals composed of ibuprofen and tranexamic acid. The amount varies depending on the quantity, but for example, the daily amount is preferably 5 mg to 300 mg. The range is 10 mg to 210 mg, more preferably 20 mg to 120 mg.

[0078] The amount of glutamic acid or its salt contained in the solid composition administered daily is, for example, 0.01 Mass% to 99% by mass, preferably 0.1% to 20% by mass, more preferably 1% by mass It is 10% by mass.

[0079] In this embodiment, the mass ratio of components (A) and (B) contained in the solid composition is (component (A) The mass ratio of (1) to the total amount of component (B) is not particularly limited, but is preferably 1:0.01 to 1 :10((A):(B)), more preferably 1:0.05~1:5((A)):((B) ), more preferably 1:0.1 to 1:1 ((A)):((B)).

[0080] (Other ingredients) The solid composition according to this embodiment may contain components other than those listed above, depending on its intended use. The solid composition relieves various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, cough, and For the purpose of relieving chills, fever, headache, joint pain, muscle pain, etc., bromhexyl In addition to methamine, meloxicam, and acetaminophen, antipyretic analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs) It may contain active ingredients such as anti-inflammatory drugs (NSAIDs) and other pharmacologically acceptable ingredients. Furthermore, a small amount selected from the group consisting of the above-mentioned stomach-protecting components and α-amino acids or their salts. At the very least, one of the following components may be present: for example, anti-inflammatory drugs, anticholinergics, excipients, or disintegrating agents. Auxiliary agents, foaming agents, moisture-proofing agents, stabilizers, sweeteners, coloring agents, bases, coating agents, sugar coating agents, and It may be added as a fluidizing agent or the like.

[0081] Nonsteroidal anti-inflammatory drugs include diclofenac, loxoprofen, zaltoprofen, Pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam Ampiroxicam, Piroxicam, Nabumetone, Indomethacin, Sulindac, Mofe COX-2 nonselective inhibitors such as Zolac and mefenamic acid, and meloxicam, etodolac, ce They are broadly classified into COX-2 selective inhibitors such as recoxib. Meloxicam is a nonsteroidal anti-steroid. It may be incorporated into the composition as an anti-inflammatory agent. Nonsteroidal anti-inflammatory drugs are COX-2 nonselective. It is preferable that the agent be an inhibitor. Nonsteroidal anti-inflammatory drugs may also be in the form of a salt.

[0082] Other pharmacologically acceptable ingredients include those found in combination cold medicines, antipyretic analgesics, and rhinitis medications. Antihistamines, antipyretics and analgesics, cough suppressants and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins The drug may also be formulated with other agents such as anticholinergics and antiplasmins.

[0083] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, and triphosphate hydrochloride. Perenamin, tondiamine hydrochloride, phenetazine hydrochloride, methidilazine hydrochloride, dl-chlor Pheniramine maleate, d-chlorpheniramine maleate, diphenyl disulfone Carbinoxamine phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, Diphenhydramine hydrochloride, diphenhydramine salicylate, alimethazine tartrate, Diphenhydramine iodine, triprolidine hydrochloride hydrate, mebhydrolysine napadisylate N, promethazine methylene disalicylate, carbinoxamine maleate, diphosphate Examples include terol, clemastine fumarate, and mequitazine.

[0084] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin and acetamine. Nophen, ethenzamide, sazapyrine, salicylamide, lactylphenethidine, isop Examples include ropilantipyrine. Acetaminophen is included in the composition as an antipyretic and analgesic. They may be combined.

[0085] Cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, and tipepidine hibenzate. Dextromethorphan hydrobromide hydrate, bromhexine, bromhexine hydrochloride , dihydrocodeine phosphate, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine Examples include phosphate saccharin salt, pseudoephedrine hydrochloride, and ambroxol hydrochloride. ru.

[0086] Anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (for example, glycyrrhizic acid and its derivatives and salts). Examples include dipotassium lysyrrhizinate and monoammonium glycyrrhizinate.

[0087] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0088] Vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., Benf Othiamine, vitamin B2 and its derivatives and their salts (e.g., riboflavin) Vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin Examples include ions and their derivatives, as well as salts thereof.

[0089] Anticholinergic agents include scopolamine hydrobromide, datura extract, and methylscopolamine. Bromides, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine Bromides, belladonna alkaloids, belladonna extract, total belladonna alkaloids, iodine Isopropamide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, ro Examples include belladonna root, belladonna root total alkaloid citrate, etc.

[0090] The solid composition according to this embodiment may be further modified by adding a formulation additive as needed. Possible alternatives include pharmaceutically acceptable carriers, such as excipients, binders, and disintegrants. Disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, Sweeteners, flavoring agents, cooling agents, fragrances, air fresheners, coloring agents, bases, coating agents, sugar coating agents, etc. Examples include plasticizers, dispersants, defoamers, fluidizers, and flavorings / fragrances, and conventionally known solid compositions Pharmaceutical additives that can be used in materials may be used for the purposes described above.

[0091] Excipients include, for example, sugar powder, gum arabic, powdered gum arabic, cocoa butter, caramel. Sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, Xylitol, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose Sodium crystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose - (granules), powdered cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, Refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate Nesium, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, 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 Examples include D-mannitol, calcium sulfate, erythritol, glucose, and fructose. .

[0092] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, and ceramic. Hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, Lulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified) (Diluted methacrylate), methacrylate copolymer L, methacrylate copolymer LD, methacrylate Copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose Examples include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers.

[0093] Examples of disintegrants include sodium carboxymethyl starch, carmellose, and caramel. Mellose calcium, croscarmellose sodium, croscarmellose sodium, Crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch Examples include partially pregelatinized starch.

[0094] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, Carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose Sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch -ch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1 Examples include 500 and macrogol 4000.

[0095] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, and macromolecules. Goal 400, Macro Goal 1500, Macro Goal 4000, Macro Goal 6000, Examples include macrogol 6000NF and beeswax.

[0096] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, and carbonated water. Examples include sodium chloride and anhydrous citric acid.

[0097] Examples of moisture-proofing agents include ethylcellulose, olive oil, and 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, fumaric acid, stearic acid, polyvinyl acetal Diethylaminoacetate / hydroxypropylmethylcellulose 2910 mixture, poly Examples include vinyl acetal diethylaminoacetate.

[0098] Examples of surfactants include sucrose fatty acid esters and polyoxyethylene hydrogenated castor oil. 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 Poly(105)polyoxypropylene(5)glycol, polyoxyethylene(120) Polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene Polypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) Cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macro Logol 400, sorbitan monooleate, glyceryl monostearate, monostearate Examples include sorbitan phosphate, sorbitan monolaurate, and sodium lauryl sulfate. ru.

[0099] Examples of stabilizers include adipic acid, L-aspartic acid, and L-aspartic acid sodium. Thorium, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, A Sodium benzoate, propylene glycol alginate, benzoic acid, sodium benzoate Thorium, ethylenediamine, calcium disodium edetate, sodium edetate, Tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, salt Calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride Nesium, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer , carmellose calcium, hydrated silicon dioxide, carmellose sodium, dried sodium carbonate Glycerin, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, gluconate Sodium phosphate, magnesium gluconate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate Ingredients: chondroitin sulfate sodium, zinc oxide, 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, Vidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether , polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, Hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (6 7) Glycol, polyoxyethylene (54) polyoxypropylene (39) glycol Polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxy Ethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut Glyceryl oats (7E.O.), polysorbate 20, polysorbate 60, polysorbate Rubate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400mg of iodine, 4000mg of macrogol, anhydrous citric acid, anhydrous sodium citrate, anhydrous phosphorus. Sodium monohydrogen acid, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol Glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, ri Sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L - Examples include leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. It is possible.

[0100] Examples of antioxidants include ascorbic acid, L-ascorbic acid, and steate. Ingredients: Citric acid hydrate, soy lecithin, natural vitamin E, tocopherol tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. Examples include: In the case of a solid composition containing acetaminophen, an antioxidant or stabilizer. It is preferable not to include tocopherols.

[0101] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, and Examples include silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0102] Examples of sweeteners include aspartame, acesulfame potassium, amacha, and ama. Tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, Dipotassium lycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin Thorium hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose Examples include sucrose, maltitol, D-mannitol, and erythritol.

[0103] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, and others. Uren powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract Ingredients: licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate Umum hydrate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sucrose Sodium quince hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, D Sodium L-tartrate, ginger powder, sucralose, stevia extract, stevia extract Refined product, Swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, tomato leaf extract Ingredients: Rashi, chili pepper powder, spruce powder, trehalose hydrate, pisiflora powder, plum extract, fructose Oligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l- Menthol, menthol powder, bonito flakes, bonito flake powder, green tea powder, DL-malic acid, Examples include DL-sodium malate, lemon oil, and rose oil.

[0104] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, and cinnamon oil. Examples include peppermint water, peppermint oil, and l-menthol.

[0105] Flavorings include, for example, orange flavor, guarana extract, sweet orange, and Strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder Dark flavor, peach essence, fruit essence, peppermint, melon powder Examples include flavorings, l-menthol, and peppermint oil.

[0106] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, and d-camphor. dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint Oil, clove oil, turpentine oil, chili pepper powder, pineapple powder, flavoring 51357, pineapple Apple powder flavoring 59492, peppermint water, peppermint oil, vanilla powder flavoring 54286, vanillin Bergamot oil, d-borneol, dl-borneol, dl-menthol, l- Examples include ethanol, eucalyptus oil, rose water, and rose oil.

[0107] Examples of coloring agents include yellow iron oxide, yellow iron(III) oxide, orange essence, and brown iron oxide. Iron, carbon black, caramel, beta-carotene, licorice extract, gold leaf, black iron oxide, acid Titanium oxide, iron(III) oxide, dizuazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5 Food-grade Blue No. 2 aluminum lake, Food-grade Yellow No. 4 aluminum lake, Food-grade Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin Thorium, copper chlorophyll, phenol red, malachite green, methylene blue, Medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate Examples include um, green tea powder, and rose oil.

[0108] The base ingredients are acacia powder, pregelatinized starch, ethylcellulose, and cocoa butter. Carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium Reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, can Marbled powder, xanthan gum, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, knot Crystalline cellulose, hydrogenated oil, synthetic magnesium sodium silicate, titanium dioxide, tartaric acid, sodium Sugar 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 sudden Pyropropylcellulose, hypromellose, pullulan, pectin, povidone Polysorbate 60, Polysorbate 80, Polyvinyl alcohol (partially saponified), Microcrystalline wax, Macrogol 200, Macrogol 300, Macrogol Lu 400, Macrogol 1000, Macrogol 1500, Macrogol 1540, Mac Logol 4000, Macrogol 6000, Macrogol 6000NF, Macrogol 2 0000, D-mannitol, glyceryl monostearate, sorbita monostearate N, batyl monostearate, propylene glycol monostearate, monostearin Polyethylene glycol acid, sodium lauryl sulfate, polyvinyl alcohol, acrylic Examples include acid-methyl methacrylate copolymers.

[0109] Examples of coating agents include ethyl acrylate / methyl methacrylate copolymer. Dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate Polymer RS, gum arabic, gum arabic powder, ethylcellulose, ethylcellulose water 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, refined gelatin, Shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate Gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose Rose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl Pyrmethylcellulose 2910, titanium dioxide, macrogol 400 mixture, hypromellol S, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydro Xypropylmethylcellulose 2910 mixture, pullulan, polysorbate 80, polypropylmethylcellulose Nylacetal diethylaminoacetate, povidone, polyvinyl alcohol (partially hydrated) (Monster), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Mac Logol 6000NF, Macrogol 20000, Macrogol 35000, Methacrylic Acid copolymer L, methacrylate copolymer LD, methacrylate copolymer S methyl acrylate methacrylate copolymer, methyl methacrylate copolymer, methylcellulose, 2- Methyl-5-vinylpyridinemethyl acrylate / methacrylate copolymer, monostea Aluminum phosphate, glyceryl monostearate, sorbitan monostearate, mono Sorbitan laurate, calcium sulfate, polyvinyl alcohol, acrylic acid, methacrylate Examples include methyl methyl phosphate copolymers.

[0110] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, and carnauba. Uva wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxy stearate Sil-40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitate Calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose Pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500 Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Hydrophosphate Calcium hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol, acrylic Examples include acid-methyl methacrylate copolymers.

[0111] Examples of plasticizers include triethyl citrate, glycerin, and glycerin fatty acid ester. Lu, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil Castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polysorbate 80, Macroglucose Lu 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macro Gol 6000, Macrogol 6000NF, Glyceryl Monostearate, Linoleic Acid Examples include isopropyl alcohol and liquid paraffin.

[0112] Dispersants include aminoalkyl methacrylate polymer RS, acacia gum, and arabic Agumon 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, acid Titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sol Bitol, soy lecithin, low-substituted hydroxypropyl cellulose, dextrin, Corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethyl Cellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromene Rose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, Polyoxyethylene hydrogenated castor oil 50, Polyoxyethylene hydrogenated castor oil 60, Resorbate 20, Polysorbate 60, Polysorbate 80, Microcrystalline Macrogol, Macrogol 300, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, anhydrous sodium citrate, methylcellulose, glyceryl monooleate Phosphorus, sorbitan monooleate, aluminum monostearate, glyceryl monostearate Ricelin, sorbitan monostearate, sorbitan monopalmitate, monolauric acid Examples include sorbitan and sodium lauryl sulfate.

[0113] Antifoaming agents include ethanol, glycerin fatty acid ester, and dimethylpolysiloxane. (For oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, sil Examples include antifoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80. ru.

[0114] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, and water. Aluminum magnesium oxide, stearic acid, calcium stearate, magnesium stearate Examples include nesium, tricalcium phosphate, talc, and calcium hydrogen phosphate granules. .

[0115] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, and oleo. Orange, orange extract, orange essence, orange oil, chamomile oil, caramel, can Elephant 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, Himalayan cedar oil, fruit flavor, Flavor G1, Hess Peridine peppermint essence, bergamot oil, vermouth flavor, d-borneol All, dl-borneol, matcha, mixed flavor, mint flavor, dl -Menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder Examples include lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0116] These components may be present individually or in combination of two or more types.

[0117] (Dosage form) The solid composition according to this embodiment is, for example, an orally administered preparation (tablet (orally disintegrating tablet), Chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders, etc. ), preparations applied orally (oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gas This includes formulations such as iodine preparations.) Yes, it is possible. The solid composition according to this embodiment is preferably an oral solid composition.

[0118] Examples of the dosage forms of the solid composition according to the present embodiment include tablets, capsules, pills, granules agents, and fine granules. These solid compositions may be coated with sugar coats, film coatings, etc. by known methods if necessary. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets .

[0119] The solid composition according to the present embodiment may be once packaged by bottle packaging, PTP packaging, pouch packaging, stick packaging, SP packaging and stored airtightly. Further, they may be pillow-packaged , and they may be stored in a box or the like. The material used for pillow packaging is not particularly limited , and for example, resin films such as polypropylene films, polyethylene terephthalate films, polyethylene films, or those obtained by attaching aluminum foil to these resin films can be used . When there is concern about hygroscopicity, a desiccant or the like may be stored simultaneously in the bottle packaging or the pillow packaging.

[0120] The solid composition according to the present embodiment may be contained in a packaging container and used as a package. In the present embodiment, the solid composition may be contained in, for example, an airtight package. By making it into a package , for example, the convenience during the use of the solid composition can be improved. The package in the present embodiment is specifically a pharmaceutical product.

[0121] As the packaging form of the solid composition, the solid composition is once packaged by bottle packaging, PTP packaging (Press Through Package), pouch packaging, stick packaging, SP packaging (Strip Package), etc. They may be stored in an airtight container. Furthermore, they may be pillow-wrapped and stored in a box or similar container. It is also possible to use a desiccant inside the bottle packaging or pillow packaging from the viewpoint of reducing moisture absorption of the solid composition. They may be stored together in the same packaging container.

[0122] Examples of materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include: For example, polypropylene film, polyethylene terephthalate film, polyethylene film Examples include resin films such as acrylic, and those made by attaching aluminum foil to these resin films. It can be made from either a single-layer film or a multi-layer film (e.g., laminate film). You may use it.

[0123] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Such packaging is formed of at least one of a moisture-proof material and a gas barrier material. Examples of packaging include:

[0124] For example, PTP (polypropylene) and polyethylene aluminum pillow - A combination of packaging is an example. Also, when the solid composition is a tablet, Considering the suppression of moisture content increase, the storage stability of tablets, and the stability of tablets after opening, as a moisture-proof material Alternatively, PTP packaging (Al-Al packaging) using aluminum on both sides may be used.

[0125] As the gas barrier material, known materials may be used, for example, materials having a functional barrier layer It may also be a laminate film, which serves the same function as the above moisture-proof material, or in combination with the above moisture-proof material. They may be used together.

[0126] Also, the packaging container may be environmentally friendly. For example, materials that consider the environment such as recycled plastics, bio mass plastics, biodegradable plastics, etc. may be used as part or all of the packaging material.

[0127] (Manufacturing method) The solid composition can be manufactured using known techniques. Crystals composed of ibuprofen and tranexamic acid can be manufactured by the method described in Japanese Patent Laid-Open No. 2022-070674 (supra). At least one selected from the group consisting of the gastric protective component and α-amino acid or its salt can be a commercially available product. [[ID=I5]]

[0128] <OMID=19>Crystals composed of ibuprofen and tranexamic acid, and at least one selected from the group consisting of the gastric protective component and α-amino acid or its salt are each added in an arbitrary step and finally brought into contact with each other. A solvent or binder is added to the mixture after contact and kneaded, and the obtained kneaded product may be used as the solid composition.

[0129] The obtained kneaded product may be further subjected to a drying process or a granulation process to produce a granule (granulated product). In this case, the granule (granulated product) containing each component may be prepared separately. Granulation may be wet or dry. <00OO969>

[0130] As it is, the obtained granule (granulated product), or an additive is blended with the granule, and this is compression-molded to produce a tablet, and this may be further film-coated.

[0131] " (Method for suppressing property change) In the second aspect, ibuprofen, and at least one selected from the group consisting of the gastric protective component and α-amino acid or its salt are selected​ A method for suppressing changes in the properties of a solid composition containing at least one of the following: A method is provided which includes crystallizing ibuprofen with tranexamic acid.

[0132] The method for suppressing changes in properties according to this embodiment involves ibuprofen, a gastric protective component, and α -By incorporating at least one selected from the group consisting of amino acids or salts thereof. This method can suppress the occurrence of changes in the properties of ibuprofen. By crystallizing ibuprofen with tranexamic acid and incorporating it into a solid composition, the properties of ibuprofen are altered. It suppresses the occurrence of chemical changes.

[0133] In the method for suppressing changes in properties according to this embodiment, ibuprofen is replaced with tranexamic acid The method of crystallization is as described above. In addition, ibuprofen, a stomach protective component and α- At least one selected from the group consisting of amino acids or salts thereof, and tranexamic acid The total amount should be adjusted to have the same content as the same component in the solid composition according to this embodiment. Yes.

[0134] (Use of tranexamic acid) In a third aspect, ibuprofen, a gastric protective component, and an α-amino acid or a salt thereof. A method for suppressing changes in the properties of a solid composition comprising at least one selected from the group. The use of tranexamic acid is provided for this purpose.

[0135] In this embodiment, tranexamic acid is crystallized with ibuprofen, and the stomach protective component and A solid composition together with at least one selected from the group consisting of α-amino acids or salts thereof. It is added. Tranexamic acid can be used in an amount that can crystallize with ibuprofen. The amount of xamic acid used determines the tranexamic acid content in the resulting solid composition. The content of the component can be adjusted to be similar to that of the solid composition in this embodiment.

[0136] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. It is not something that should be done. [Examples]

[0137] 1. Raw materials In this example, the following raw materials were used. [Table 1]

[0138] 2. Preparation of the solid composition (Comparative Example 1) Dissolve 2.5g of ibuprofen (SI Group) and 2.5g of glycine in a 5kg standard bottle. After removing the contents and mixing 100 times, sift through a 42-mesh sieve, and then transfer to a 5K standard bottle. The mixture was mixed 00 times to obtain a physical mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and then adjust it to ensure uniform thickness. This was used as the sample for Comparative Example 1.

[0139] (Comparative Examples 2-5) 2.5g of ibuprofen (manufactured by SI Group) and 2.5g each of metasilicate Magnesium luminate, synthetic aluminum silicate, L-carbocysteine, or L-phosphate Weigh out nyalanine and other ingredients into a 5K standard bottle, mix 100 times, and then sift through a 22-mesh sieve. The mixture was sieved and then mixed 100 times in a 5K standard bottle to obtain a physically mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and then adjust it to ensure uniform thickness. These samples were then used as comparative examples 2 to 5.

[0140] (Comparative Example 6) Approximately 7g of L-sodium glutamate was weighed into a mortar and ground with a pestle, then 22 mins of L-sodium glutamate was added. The mixture was sieved through a sieve to obtain the L-sodium glutamate sieved product. Ibuprofen (SI Group) 2.5g and sieved L-glutamate sodium Measure 2.5g into an 8K standard bottle, mix 100 times, and then sift through a 22-mesh sieve. Furthermore, the mixture was mixed 100 times in an 8K standard bottle to obtain a physically mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and adjust it so that the thickness is uniform. This was used as the sample for Comparative Example 6.

[0141] (Example 1) Ibuprofen (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd.) 240.0g, and tranexamic acid 1 82.9g was placed in a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Powrec)). The mixture was prepared and mixed to form a powder. Ethanol (99.5% purity) was added to this powder (Kanto Chemical Co., Ltd.) A mixture of (processed) and purified water (mass ratio 8:2) was poured in 69 g and kneaded and granulated to obtain a paste. The mixture was wet-milled using a Power Mill (Dalton) at low speed and 32 mesh. The mixture was stored in a constant temperature bath at 70°C for 89 hours, and then the ibuprofen and tranexamic acid were separated. We obtained the crystal.

[0142] Place 6 mg of the obtained crystals into an aluminum pan and use a differential scanning calorimeter DSC3+ (Mettler). A Toledo (Toledo) was used to measure temperatures in the range of 25 to 350°C at a rate of 60°C per minute. The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen around 75°C disappears at 180°C. The presence of a peak in the vicinity originating from crystals composed of ibuprofen and tranexamic acid. From this, it was found that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained. I confirmed it.

[0143] The obtained crystals (4.4g) and glycine (2.5g) were weighed into a 5K standard bottle and mixed 100 times. The mixture was then sieved through a 42-mesh sieve and further mixed 100 times in a 5K standard bottle before being physically processed. It was made into a mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and adjust it so that the thickness is uniform. This was used as the sample for Example 1.

[0144] (Examples 2-5) 4.4 g of crystals consisting of ibuprofen and tranexamic acid obtained in Example 1, and Each contains 2.5g of magnesium aluminometasilicate, synthetic aluminum silicate, and L-calcium dioxide. Measure out bocysteine ​​or L-phenylalanine into a 5K standard bottle and mix 100 times. After that, it was sieved through a 22-mesh sieve, and then mixed 100 times in a 5K standard bottle. It was prepared as a mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and adjust it so that the thickness is uniform. These were used as samples for Examples 2-5.

[0145] (Example 6) 4.4 g of crystals consisting of ibuprofen and tranexamic acid obtained in Example 1, and a comparison 2.5g of the sieved L-sodium glutamate obtained in Example 6 was weighed into an 8K standard bottle. After mixing 100 times, sift through a 22-mesh sieve, and then mix 100 more times in an 8K standard bottle. The combined substance was referred to as a physical mixed powder. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle, seal it tightly, and adjust it so that the thickness is uniform. This was used as the sample for Example 6.

[0146] The mixing ratio (mass ratio) of each sample is shown in the table below. In the table below, "IB-TXA crystal" refers to I This refers to a crystal composed of buprofen and tranexamic acid.

[0147] [Table 2]

[0148] [Table 3]

[0149] 3. Evaluation of changes in the properties of the solid composition Each sample from Examples 1-6 and Comparative Examples 1-6 was left to stand at 80°C for 48 hours to determine its properties. Changes were evaluated. Changes in properties observed included aggregation, solidification, moisture absorption, and wetting. Changes in properties can be visually inspected before and after standing to check for aggregation, solidification, moisture absorption, and wetting of the powder. I checked to see if that was the case.

[0150] As a result, compared to the start of high-temperature storage, significant changes in properties were observed in Comparative Examples 1-6. In Examples 1-6, ibuprofen was crystallized and combined with tranexamic acid, respectively. The change in properties was suppressed. Specifically, comparative example 1 experienced wetting, while comparative example 6 experienced partial wetting. Although aggregation occurred, the change in properties was significantly suppressed in Examples 1 and 6, and after 48 hours The powdery state was maintained even after standing. In addition, solidification occurred in Comparative Examples 2 and 4, and in Comparative Example 5, solidification occurred. Although aggregation occurred, the change in properties was significantly suppressed in Examples 2, 4, and 5, and 48 The powder remained in a powdery state even after standing for a period of time. Furthermore, solidification occurred in Comparative Example 3, but not in Example 3. Although some solidification occurred, it was significantly suppressed compared to Comparative Example 3.

[0151] Based on the above, ibuprofen is crystallized with tranexamic acid to provide a stomach protective component and α -By combining with at least one selected from the group consisting of amino acids or salts thereof, A small amount selected from the group consisting of ibuprofen, a gastric protective component, and α-amino acids or their salts. At the very least, the change in properties under high-temperature conditions should be suppressed compared to a mixture containing equal amounts of one type. This was shown.

[0152] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. This does not mean adding, omitting, substituting, or otherwise modifying the configuration without departing from the spirit of the present invention. It is possible to change this.

Claims

1. The following ingredients: (A) A crystal composed 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 Seeds and, A solid composition containing the following:

2. The aforementioned stomach-protecting component is glycine or its salt, magnesium aluminometasilicate, silica At least one selected from the group consisting of magnesium aluminate and aluminum silicate. It is also one type. The solid composition according to claim 1.

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

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

5. The above (B) is glycine or a salt thereof, magnesium aluminometasilicate, phenylalanine At least one selected from the group consisting of ranine or its salts, and glutamic acid or its salts. It is a species. The solid composition according to claim 1.

6. The claim is that the molar ratio of ibuprofen to tranexamic acid in the aforementioned crystal is 1:

1. A solid composition according to any one of items 1 to 5.

7. The mass ratio of component (A) to (B) is 1:0.01 to 1:10 ((A):(B)). A solid composition according to any one of the requests 1 to 5.

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