solid components

Abstract

To provide a solid composition containing ibuprofen in which changes in properties are suppressed. [Solution] The following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, A solid composition comprising (C) at least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen, wherein the mass ratio of component (A) to (C) is 1:0.3 to 1:3 ((A):(C)) and the mass ratio of component (B) to (C) is 1:0.3 to 1:3 ((B):(C)).

Description

Technical Field

[0001] The present invention broadly relates to a solid composition comprising ibuprofen, at least one selected from the group consisting of tipepidine and its salts, and at least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen.

Background Art

[0002] Ibuprofen is widely used as a non-steroidal antipyretic and analgesic drug. However, solid compositions containing ibuprofen may undergo time-dependent property changes such as discoloration, melting, separation, solidification, wetting, and aggregation due to the formulation of other components, and thus suppression of such property changes has been studied.

[0003] For example, Patent Document 1 discloses a solid preparation containing granules containing ibuprofen, magnesium oxide, sodium lauryl sulfate, and a disintegrant.

[0004] Patent Document 2 discloses a solid preparation containing ibuprofen, scopolamine butylbromide, and a hygroscopic polymer.

[0005] Patent Document 3 discloses an ibuprofen-containing granule characterized in that an excipient is added to and granulated on a coated ibuprofen-containing granule obtained by coating an ibuprofen-containing mixture with an enteric polymer compound.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

[0007] Solid compositions containing ibuprofen still have room for improvement in terms of changes in properties over time. The present invention aims to provide a solid composition containing ibuprofen in which changes in properties are suppressed. [Means for solving the problem]

[0008] The inventors of the present invention have found that when ibuprofen is combined with at least one substance selected from the group consisting of tipepidine and its salts, a significant change in its properties occurs. Furthermore, they have found that this change in properties can be suppressed by combining it with glycine, silicon dioxide, and / or acetaminophen, and have completed the present invention.

[0009] In other words, this embodiment includes the following aspects. [1] A solid composition comprising the following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen. Solid composition containing (however, Excluding ibuprofen-containing granules prepared by coating an ibuprofen-containing mixture with an enteric-coated polymer compound and then adding an excipient to the coated ibuprofen-containing granules. [2] The solid composition according to [1], wherein the mass ratio of component (A) to (B) is 1:1 to 16:1 ((A):(B)). [3] The solid composition according to [1] or [2], wherein the mass ratio of component (A) to (C) is 1:0.01 to 1:3 ((A):(C)). [4] A solid composition according to any one of [1] or [3], wherein the mass ratio of component (B) to (C) is 1:0.1 to 1:25 ((B):(C)). Furthermore, this embodiment includes the following aspects. [1A] A solid composition comprising the following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen. Includes, The mass ratio of components (A) and (C) is 1:0.3 to 1:3 ((A):(C)), A solid composition in which the mass ratio of components (B) and (C) is 1:0.3 to 1:3 ((B):(C)) (however, (i) Ibuprofen-containing granules obtained by coating an ibuprofen-containing mixture with an enteric-coated polymer compound, and then adding an excipient and granulating the coated ibuprofen-containing granules, (ii) A solid composition containing mequitazine or a salt thereof, or thiamine or a salt thereof (iii) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of tipepidine hibenzate, 2.98 parts by weight of anhydrous caffeine, 64.06 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (iv) A solid composition comprising 17.86 parts by weight of ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 63.09 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (v) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of glycyrrhizic acid, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (vi) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 9.92 parts by weight of potassium cresol sulfonate, 2.98 parts by weight of anhydrous caffeine, 57.71 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (vii) A solid composition comprising 17.86 parts by weight of ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 7.14 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 59.52 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (viii) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate, and (ix) A solid composition containing 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methylephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 9.92 parts by weight of potassium cresolsulfonate, 2.98 parts by weight of anhydrous caffeine, 57.71 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 parts by weight of magnesium stearate Excluding.). [2A] The solid composition according to [1A], wherein the mass ratio of component (A) to (B) is 1:0.5 to 8:1 ((A):(B)), or 1:1 to 4.8:1 ((A):(B)). [3A] The solid composition according to [1A] or [2A], wherein the mass ratio of component (A) to (C) is 1:0.5 to 1:1 ((A):(C)). [4A] The solid composition according to [1A] or [2A], wherein the mass ratio of component (B) to (C) is 1:0.5 to 1:2.4 ((B):(C)). [Advantages of the Invention]

[0010] According to the present invention, a solid composition containing ibuprofen with suppressed property changes can be provided. [Modes for Carrying Out the Invention]

[0011] Hereinafter, embodiments of the present invention (hereinafter referred to as "the present embodiments") will be described, but the scope of the present invention is not construed as being limited to the following embodiments. In the present embodiments, the composition can contain each component alone or in combination of two or more. In this specification, "~" indicating a numerical range represents above and below, and includes both end values.

[0012] (Solid Composition) In a first aspect, the following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen. Solid compositions containing (excluding ibuprofen-containing granules prepared by adding an excipient to coated ibuprofen-containing granules, which are made by coating an ibuprofen-containing mixture with an enteric-coated polymer compound). 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 may be included in the form of a pharmaceutically acceptable salt, or it may be included as a complex with other components. That is, the solid composition according to this embodiment may contain salts of each component, not only component (B), but also component (A) and / or component (C), and 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.

[0014] In this embodiment, in addition to ibuprofen and at least one selected from the group consisting of tipepidine and its salts, the above-mentioned component (C) is included, thereby suppressing changes in the properties of the solid composition, particularly changes in properties over time.

[0015] In this specification, "change in properties" means a change in properties and / or state, including at least aggregation, discoloration, moisture absorption, separation, and liquefaction. Therefore, the solid composition of this embodiment may have suppressed aggregation, discoloration, moisture absorption, separation, and liquefaction that occur over time. Furthermore, "suppression of changes in properties" means that changes in properties are less likely to occur, but for example, changes in properties may be suppressed when compared to a solid composition that does not contain component (C).

[0016] The solid composition of 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.

[0017] The period during which changes in properties are suppressed in the solid composition of this embodiment is not particularly limited, but may be, for example, 12 hours or more, 18 hours or more, or 24 hours or more.

[0018] In this embodiment, the solid composition excludes "ibuprofen-containing granules obtained by coating an ibuprofen-containing mixture with an enteric-coated polymer compound to form coated ibuprofen-containing granules, to which an excipient is added and granulated."

[0019] Here, in the phrase "ibuprofen-containing granules obtained by coating an ibuprofen-containing mixture with an enteric polymer compound to form coated ibuprofen-containing granules, to which an excipient is added and granulated," the enteric polymer compound refers to a polymer compound that does not dissolve for a relatively long time in the acidic environment of gastric juice (pH 1-3.5) but dissolves quickly in intestinal juice (pH 6-7). Enteric polymer compounds include polymer compounds commonly used for enteric coating in the pharmaceutical field, such as shellac (Nippon Shellac Industries), cellulose phthalate acetate (CAP, Wako Pure Chemical Industries), hydroxypropyl methylcellulose phthalate (HPMCP, Shin-Etsu Chemical), hydroxypropyl methylcellulose acetate succinate (AQOAT, Shin-Etsu Chemical), carboxymethyl ethylcellulose (CMEC, Freund Industrial), and methacrylic acid copolymer (Eudragit L, Eudragit S, etc., Higuchi Shokai). The amount of enteric-coated polymer compound used for coating may be 2-30% or 5-10% of the granular material to be coated. Here, known methods in the field of pharmaceutical formulation technology may be used for coating, such as coating methods using a fluidized bed, such as a fluidized bed granulator or a rolling fluidized bed granulator, or coating methods using a centrifugal rolling granulator or a pan coating device. The coating conditions are determined appropriately based on conventional methods. Furthermore, the particle size of the coated ibuprofen-containing granules may be 30 mesh or less, or 42 mesh or less.

[0020] Furthermore, examples of excipients in "ibuprofen-containing granules obtained by coating an ibuprofen-containing mixture with an enteric-coated polymer compound to form coated ibuprofen-containing granules, and then adding an excipient and granulating them" include D-mannitol, xylitol, sorbitol, sucrose, lactose, reduced maltose, reduced lactose, L-HPC, carmellose derivatives, starches, etc.

[0021] Furthermore, the solid composition disclosed in Japanese Patent Publication No. 11-335279 is excluded from the solid composition of this embodiment. The solid composition disclosed in Japanese Patent Publication No. 11-335279 is an ibuprofen-containing granule that has suppressed bitterness and irritation, is easy to take, and is stable over time. However, the solid composition of this embodiment is a solid composition containing ibuprofen in which changes in properties that may occur by combining ibuprofen with at least one selected from the group consisting of tipepidine and its salts are suppressed.

[0022] Furthermore, in the solid composition of this embodiment, a solid composition containing an enteric-coated polymer compound may be excluded. Here, the enteric-coated polymer compound is as described above.

[0023] In the solid compositions of this embodiment, solid compositions containing mequitazine or a salt thereof, or thiamine or a salt thereof, may be excluded. In some cases, pharmaceutical compositions disclosed in Japanese Patent Application Publication No. 2007-091633 and Japanese Patent Application Publication No. 2009-109406 may be excluded in the solid compositions of this embodiment.

[0024] Furthermore, in the solid composition of this embodiment, a solid composition containing an alkaline drug that is an antihistamine may be excluded. Examples of antihistamines include those described later and those listed in Japanese Patent Publication No. 2007-091633. Alkaline antihistamines are antihistamines that have alkaline properties. In the solid composition of this embodiment, solid compositions containing phenothiazine compounds may be excluded. Examples of phenothiazine compounds include alimazine, isotipendyl, phenetazine, promethazine, and methidilazine.

[0025] In the solid compositions of this embodiment, solid compositions containing compounds or salts thereof having a structure and function similar to thiamine may be excluded. Examples of compounds having a structure and function similar to thiamine include derivatives of thiamine, but may also be vitamin B1 compounds, such as those listed in Japanese Patent Publication No. 2024-052654 and Japanese Patent Publication No. 2019-142860.

[0026] Furthermore, in the solid composition of this embodiment, the solid compositions disclosed in Japanese Patent Publication No. 2005-289904 and Japanese Patent Publication No. 2005-289906 may be excluded. More specifically, in the solid composition of this embodiment, A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of tipepidine hibenzate, 2.98 parts by weight of anhydrous caffeine, 64.06 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition comprising 17.86 parts by weight of ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 63.09 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of glycyrrhizic acid, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 9.92 parts by weight of potassium cresol sulfonate, 2.98 parts by weight of anhydrous caffeine, 57.71 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition comprising 17.86 parts by weight of ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 7.14 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 59.52 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition containing 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate, and A solid composition containing 17.86 parts by weight of ibuprofen, 0.02 parts by weight of total belladonna alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 9.92 parts by weight of potassium cresol sulfonate, 2.98 parts by weight of anhydrous caffeine, 57.71 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate may be excluded.

[0027] (A) Ibuprofen (ingredient (A)) As used herein, "ibuprofen" refers to the CAS registry number 15687-27-1, C 13H 18 It is a compound represented by the chemical formula O2. Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic drugs. The salts of ibuprofen are not particularly limited as long as they are pharmacologically acceptable.

[0028] The amount of ibuprofen included in the solid composition is adjusted as appropriate depending on the intended use of ibuprofen in the solid composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen administered to adults can be adjusted to a range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In this embodiment, "adult" means men and women 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. The same applies to ingredients other than ibuprofen. The amount of ibuprofen included may be 30mg to 2000mg per day, 100mg to 1000mg, 200mg to 600mg, or 300mg to 600mg.

[0029] The above dosages are examples, and the ibuprofen content per solid 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.

[0030] In one embodiment, the ibuprofen content 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 weight and dosage of the solid composition described above are for a day, but the same amount may be administered to the subject in one dose, or divided into multiple doses per day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose and the dosage form of the solid composition.

[0032] In a particular embodiment, the solid composition is a tablet, 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.

[0033] (B) Tipepidine and its salts (Component (B)) As used herein, "tipepidine" refers to the substance with CAS Registry Number 5169-78-8, C 15 H 17 It is a compound represented by the chemical formula NS2. The salts of tipepidine are not particularly limited as long as they are pharmacologically acceptable, but examples include tipepidine hibenzate and tipepidine citrate.

[0034] The amount of at least one substance selected from the group consisting of tipepidine and its salts is appropriately adjusted according to the intended use of the solid composition, the required degree of antitussive and expectorant effect, the required degree of stability, the symptoms of the recipient, age, weight, sex, etc. The amounts and contents of at least one substance selected from the group consisting of tipepidine and its salts described below are the amounts and contents for tipepidine and tipepidine salts respectively, but it is preferable that the total amount and content of tipepidine and tipepidine salts be within the range of the amounts and contents described below. The amount of at least one substance selected from the group consisting of tipepidine and its salts may be adjusted as appropriate, but the daily amount may be 30 mg to 100 mg, 60 mg to 100 mg, or 70 mg to 90 mg.

[0035] The amount of at least one selected from the group consisting of tipepidine and its salts may vary depending on the amount of ibuprofen, etc. For example, the mass ratio ((A):(B)) of components (A):(B) in the solid composition according to this embodiment may be 1:0.5 to 16:1, preferably 1:1 to 16:1, more preferably 1:1 to 14:1, and even more preferably 1:1 to 10:1 in the solid composition administered daily. The mass ratio ((A):(B)) of components (A):(B) in the solid composition according to this embodiment may be 1:0.5 to 8:1, 1:0.5 to 6:1, or 1:0.5 to 5:1 in the solid composition administered daily. Furthermore, the mass ratio ((A):(B)) of components (A):(B) in the solid composition according to this embodiment may be 1:1 to 8:1, 1:1 to 6:1, 1:1 to 5:1, or 1:1 to 4.8:1 in the solid composition administered daily. Including at least one selected from the group consisting of tipepidine and its salts in the above range relative to ibuprofen tends to further suppress changes in the properties of the solid composition.

[0036] The amount of at least one substance selected from the group consisting of tipepidine and its salts can be adjusted, for example, in the range of 8 mg to 120 mg per day, more preferably 16 mg to 72 mg.

[0037] (C) Glycine, silicon dioxide, and acetaminophen (component (C)) The solid composition according to this embodiment further comprises at least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen. These components may be present individually or in combination of two or more.

[0038] As used herein, "glycine" refers to the compound with CAS registry number 56-40-6 and the chemical formula C2H5NO2. Salts of glycine are not particularly limited, as long as they are pharmacodynamically acceptable.

[0039] As used herein, "silicon dioxide" refers to a compound represented by the chemical formula SiO2, and includes, for example, silica with CAS registry number 7631-86-9. In this embodiment, "silicon dioxide" may be a component mainly comprising a compound represented by the chemical formula SiO2, for example, light anhydrous silicic acid listed in the 18th edition of the Japanese Pharmacopoeia and / or hydrated silicon dioxide listed in the Japanese Standards for Pharmaceutical Additives 2018. Light anhydrous silicic acid contains 98.0% or more silicon dioxide (SiO2), and hydrated silicon dioxide contains 95.0% or more silicon dioxide (SiO2). In this embodiment, "silicon dioxide" may be light anhydrous silicic acid and / or hydrated silicon dioxide, and is preferably light anhydrous silicic acid.

[0040] In this embodiment, when light anhydrous silicic acid is used, the specific surface area of ​​the light anhydrous silicic acid is not particularly limited, but for example, 100 to 350 m². 2 It is preferable that the amount is / g. Here, the specific surface area of ​​light anhydrous silicic acid is measured by the BET multi-point method described in 3.02 Specific Surface Area Measurement Method of the 18th Edition of the Japanese Pharmacopoeia.

[0041] As used herein, "acetaminophen" refers to the compound with CAS registry number 103-90-2 and the chemical formula C8H9NO2. Salts of acetaminophen are not particularly limited, as long as they are pharmacodynamically acceptable.

[0042] The amount of at least one substance selected from the group consisting of glycine, silicon dioxide, and acetaminophen is appropriately adjusted according to the intended use of the solid composition, the required degree of stability, the symptoms of the recipient, age, weight, sex, etc. The amounts of glycine, silicon dioxide, and acetaminophen may be adjusted independently of each other.

[0043] The total amount of glycine, silicon dioxide, and acetaminophen may vary depending on the amount of ibuprofen, etc. The mass ratio ((A):(C)) of components (A):(C) in the solid composition according to this embodiment is preferably 1:0.01 to 1:3, more preferably 1:0.1 to 1:3, and even more preferably 1:0.3 to 1:3 in the solid composition administered daily. The mass ratio ((A):(C)) of components (A):(C) in the solid composition according to this embodiment may be 1:0.5 to 1:3, 1:0.5 to 1:2, or 1:0.5 to 1:1 in the solid composition administered daily. Here, the mass of component (C) is the total amount of glycine, silicon dioxide, and acetaminophen combined or administered.

[0044] The mass ratio of each component (A) to each component (C) in the solid composition administered daily ((A):each component of (C)) is preferably 1:0.01 to 1:3, independently of each other, as the ratio of component (A):glycine, silicon dioxide, or acetaminophen. More specifically, the mass ratio of ibuprofen to glycine (ibuprofen:glycine) is preferably 1:0.01 to 1:3, more preferably 1:0.1 to 1:2.5, and preferably 1:0.3 to 1:2. The mass ratio of ibuprofen to silicic acid dioxide (ibuprofen:silicic acid dioxide) is preferably 1:0.01 to 1:3, more preferably 1:0.05 to 1:2, and even more preferably 1:0.1 to 1:1. The mass ratio of ibuprofen to acetaminophen (ibuprofen:acetaminophen) is preferably 1:0.01 to 1:3, more preferably 1:0.1 to 1:3, and more preferably 1:0.3 to 1:2.5.

[0045] The total amount of glycine, silicon dioxide, and acetaminophen may vary depending on the amount of at least one selected from the group consisting of tipepidine and its salts. The mass ratio of components (B) to (C) in the solid composition according to this embodiment ((B):(C)) is preferably 1:0.1 to 1:25 in the solid composition administered daily. The mass ratio of components (B) to (C) in the solid composition according to this embodiment ((B):(C)) is preferably 1:0.1 to 1:3, more preferably 1:0.1 to 1:3, and even more preferably 1:0.3 to 1:3 in the solid composition administered daily. The mass ratio of components (B) to (C) in the solid composition according to this embodiment ((B):(C)) may be 1:0.5 to 1:3 or 1:0.5 to 1:2.4 in the solid composition administered daily.

[0046] The mass ratio of each component (B):component (C) in the solid composition administered daily is preferably 1:0.1 to 1:25, where component (B):glycine, silicon dioxide, or acetaminophen is the ratio of each component independently. More specifically, the mass ratio of the total amount of tipepidine and its salts to glycine (total amount of tipepidine and its salts: glycine) is preferably 1:0.1 to 1:25, more preferably 1:0.8 to 1:25, more preferably 1:1 to 1:20, and even more preferably 1:2 to 1:15. The mass ratio of tipepidine and its salts to silicate (total amount of tipepidine and its salts: silicate) is preferably 1:0.1 to 1:25, more preferably 1:0.2 to 1:23, and even more preferably 1:0.3 to 1:20. The mass ratio of the total amount of tipepidine and its salts to acetaminophen (total amount of tipepidine and its salts: acetaminophen) is preferably 1:0.1 to 1:25, more preferably 1:1 to 1:24, and more preferably 1:2 to 1:24.

[0047] The total amount of glycine, silicon dioxide, and acetaminophen may vary depending on the amount of at least one selected from the group consisting of ibuprofen and / or tipepidine and its salts. The mass ratio of (A) and (B) to (C) in the solid composition according to this embodiment ({(A)+(B)}:(C)) is preferably 1:0.01 to 1:12.5, more preferably 1:0.03 to 1:10, even more preferably 1:0.05 to 1:5, even more preferably 1:0.1 to 1:3, and even more preferably 1:0.2 to 1:1 in the solid composition administered daily.

[0048] The amount of glycine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to a range of, for example, 10 mg to 1000 mg, preferably 30 mg to 950 mg, more preferably 100 mg to 900 mg, and even more preferably 180 mg to 900 mg. The amount of glycine included may be 120 mg to 200 mg or 160 mg to 200 mg per day.

[0049] When light anhydrous silicic acid is included as silicon dioxide, the amount will vary depending on the amount of ibuprofen, etc., but the amount per day can be adjusted to, for example, preferably 1 mg to 300 mg, more preferably 5 mg to 200 mg, and even more preferably 15 mg to 160 mg. When light anhydrous silicic acid is included as silicon dioxide, the amount per day may be 15 mg to 100 mg.

[0050] When hydrated silicon dioxide is included as silicon dioxide, the amount to be included will vary depending on the amount of ibuprofen, etc., but the amount per day can be adjusted to, for example, preferably 1 mg to 300 mg, more preferably 5 mg to 200 mg, and even more preferably 15 mg to 160 mg. When hydrated silicon dioxide is included as silicon dioxide, the amount to be included may be 15 mg to 100 mg per day.

[0051] The amount of acetaminophen included will vary depending on the amount of ibuprofen, etc., but can be adjusted to a daily amount of 120 mg to 1200 mg, preferably 150 mg to 900 mg, and more preferably 180 mg to 600 mg. The amount of acetaminophen included may be 120 mg to 200 mg, or 160 mg to 200 mg, as a daily amount.

[0052] (Other ingredients) The solid composition according to this embodiment may contain components other than those described above, depending on its intended use. When the solid composition is used 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 and meloxicam, antipyretic analgesics, in particular nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, and other pharmacologically acceptable components may be included.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine.

[0057] Examples of cough suppressants and expectorants include noscapine hydrochloride, dextromethorphan hydrobromide hydrate, bromhexine, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0058] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), and tranexamic acid.

[0059] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0060] 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.

[0061] 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.

[0062] 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 formulations can be used for the above purposes.

[0063] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, corn starch granules, trehalose, 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, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0064] 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.

[0065] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0066] Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0067] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0068] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0069] Examples of moisture-proofing agents include ethylcellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hydrogenated oil, synthetic aluminum silicate, 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, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

[0070] 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.

[0071] 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, and cetylpyridinyl chloride. Ingredients: ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, anhydrous sodium carbonate, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, sodium dihydrogen phosphate, sodium chondroitin sulfate 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, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearic acid 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, magnesium aluminometasilicate, 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.

[0072] 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.

[0073] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, titanium dioxide, and calcium monohydrogen phosphate.

[0074] 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.

[0075] 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, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-tartaric acid Examples include sodium glycyrrhizate, ginger powder, 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 flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0076] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] The base ingredients include: acacia gum powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycerin, glycerin fatty acid ester, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, 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, hydroxypropyl cellulose. Examples include rose, 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.

[0081] Examples of coating agents include: 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 diethylaminoacetate / Hypermethylcellulose Examples include droxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, 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.

[0082] 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.

[0083] 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.

[0084] 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, 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, magnesium aluminometasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0085] 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.

[0086] Examples of fluidizing agents include synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0087] 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.

[0088] These components may be present individually or in combination of two or more types.

[0089] (Dosage form) The solid composition of this embodiment can be in dosage forms described in the General Provisions for Formulations of the 18th Edition of the Japanese Pharmacopoeia, such as oral formulations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders), or formulations applied orally (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition of this embodiment is preferably an oral solid composition.

[0090] Examples of dosage forms for the solid composition in 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. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets.

[0091] The solid composition of 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 these 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.

[0092] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition of this embodiment may be contained in, for example, an airtight package. By forming a package, the convenience of use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0093] As for the packaging of solid dosage forms, 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 inside the packaging container, such as the bottle or pillow packaging.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] (Manufacturing method) In a second embodiment, a method for producing a solid composition is provided, comprising the step of contacting (A) ibuprofen, (B) at least one selected from the group consisting of tipepidine and its salts, and (C) glycine, silicon dioxide, and / or acetaminophen.

[0100] The production of the solid composition can be carried out using known techniques. Each component is added in any step and finally brought into contact with each other. A solvent and a binder may be added to the mixture after contact and kneaded, and the resulting paste may be used as the solid composition.

[0101] 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.

[0102] 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.

[0103] (Property change inhibitor) In a third embodiment, a property change inhibitor for solid compositions is provided, comprising (I) ibuprofen, which includes at least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen, and (II) at least one selected from the group consisting of tipepidine and its salts.

[0104] Glycine, silicon dioxide, and acetaminophen are as described in component (C) of the solid composition according to this embodiment, and components (I) and (II) are as described in components (A) and (B) of the solid composition according to this embodiment.

[0105] The property change inhibitor is preferably used in such an amount that the amount of glycine, silicon dioxide, and / or acetaminophen relative to component (I) or (II) falls within the range described as the preferred content of component (C) of the solid composition according to this embodiment.

[0106] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. [Examples]

[0107] 1. Raw materials In this example, the following raw materials were used. [Table 1]

[0108] 2. Preparation of the solid composition 50 g of ibuprofen and 50 g of tipepidine hibenzate were placed in a plastic bag and mixed 100 times. After sieving with a 42-mesh sieve, the mixture was mixed 100 more times to obtain the mixture. 2 g of the resulting mixture was weighed into a 1K standard bottle, sealed tightly, and then prepared to ensure uniform thickness to serve as the sample for Comparative Example 1.

[0109] 5 g of a mixture of ibuprofen and tipepidine hibenzate, obtained in the same manner as in Comparative Example 1, and 2.5 g of either glycine or acetaminophen were added to a plastic bag and mixed 100 times. 2 g of the resulting mixture was weighed into a 1K standard bottle, sealed tightly, and then prepared to ensure uniform thickness to obtain the samples for Examples 1 and 3.

[0110] 5 g of a mixture of ibuprofen and tipepidine hibenzate, obtained in the same manner as in Comparative Example 1, and 2.5 g of either tartaric acid, sodium bicarbonate, or noscapine were added to a plastic bag and mixed 100 times. 2 g of the resulting mixture was weighed into a 1K standard bottle, sealed tightly, and then prepared to ensure uniform thickness to obtain the samples for Comparative Examples 2-4.

[0111] To 5 g of a mixture of ibuprofen and tipepidine hibenzate obtained in the same manner as in Comparative Example 1, 1.25 g of silicon dioxide was added, and the mixture was sieved through a 42-mesh sieve, followed by 100 bag mixings. 1 g of the resulting mixture was weighed into a 1K standard bottle, sealed tightly, and then prepared to ensure uniform thickness to serve as the sample for Example 2.

[0112] The mixing ratios (mass ratios) of each sample are shown below. [Table 2]

[0113] 3. Evaluation of changes in the properties of the solid composition Each sample from Examples 1-3 and Comparative Examples 1-4 was stored at 80°C for 24 hours, and changes in properties were evaluated. Changes in properties included changes in color and state. For changes in color, it was confirmed whether a change in color was observed visually before and after storage. For changes in state, it was confirmed visually before and after storage whether any of the following occurred: aggregation of powder, moisture absorption, separation, or liquefaction.

[0114] Next, the changes in color tone and condition were evaluated according to the following criteria. Color change: A: No discoloration, B: Slight discoloration, C: Discoloration present, D: Significant discoloration State change A: No change, B: Slight change, C: Change present, D: Significant change

[0115] The following table shows the results of color and condition changes compared to the start of high-temperature storage. In Comparative Example 1, significant changes were observed in both color and condition. In Examples 1, 2, and 3, changes were suppressed in both color and condition. In Comparative Examples 2, 3, and 4, changes were not suppressed in either color or condition, and significant changes were observed. [Table 3]

[0116] These results demonstrate that the glycine, silicon dioxide, and acetaminophen added in Examples 1-3 can suppress changes in the properties of a solid composition containing at least one selected from the group consisting of ibuprofen and tipepidine and its salts, particularly changes in properties under high-temperature conditions.

[0117] The following ingredients: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen. Examples of formulations of solid compositions containing the following are shown in the table below.

[0118] [Table 4]

[0119] [Table 5]

[0120] [Table 6]

[0121] 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. A solid composition comprising the following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of glycine, silicon dioxide, and acetaminophen Includes, The mass ratio of components (A) to (C) is 1:0.3 to 1:3 ((A):(C)), A solid composition in which the mass ratio of components (B) to (C) is 1:0.3 to 1:3 ((B):(C)) (however, (i) Ibuprofen-containing granules obtained by coating an ibuprofen-containing mixture with an enteric-coated polymer compound, and then adding an excipient and granulating the coated ibuprofen-containing granules, (ii) A solid composition containing mequitazine or a salt thereof, or thiamine or a salt thereof. (iii) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of belladonna total alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of tipepidine hibenzate, 2.98 parts by weight of anhydrous caffeine, 64.06 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. A solid composition comprising 17.86 parts by weight of (iv) ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 3.57 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 63.09 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (v) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of belladonna total alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of glycyrrhizic acid, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (vi) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of belladonna total alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 9.92 parts by weight of potassium cresol sulfonate, 2.98 parts by weight of anhydrous caffeine, 57.71 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (vii) A solid composition comprising 17.86 parts by weight of ibuprofen, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 3.97 parts by weight of tipepidine hibenzate, 7.14 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 59.52 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate. (viiii) A solid composition comprising 17.86 parts by weight of ibuprofen, 0.02 parts by weight of belladonna total alkaloids, 2.98 parts by weight of dl-methyl ephedrine hydrochloride, 0.05 parts by weight of clemastine fumarate, 2.98 parts by weight of tipepidine hibenzate, 5.56 parts by weight of lysozyme chloride, 2.98 parts by weight of anhydrous caffeine, 62.07 parts by weight of crystalline cellulose, 4.00 parts by weight of croscarmellose sodium, 0.50 parts by weight of light anhydrous silicic acid, and 1.00 part by weight of magnesium stearate, and A solid composition containing (ix) ibuprofen 17.86 parts by weight, belladonna total alkaloids 0.02 parts by weight, dl-methyl ephedrine hydrochloride 2.98 parts by weight, clemastine fumarate 0.05 parts by weight, tipepidine hibenzate 2.98 parts by weight, potassium cresol sulfonate 9.92 parts by weight, anhydrous caffeine 2.98 parts by weight, crystalline cellulose 57.71 parts by weight, croscarmellose sodium 4.00 parts by weight, light anhydrous silicic acid 0.50 parts by weight, and magnesium stearate 1.00 part by weight. (Excluding...)

2. The solid composition according to claim 1, wherein the mass ratio of component (A) to (B) is 1:0.5 to 8:1 ((A):(B)) or 1:1 to 4.8:1 ((A):(B)).

3. The solid composition according to claim 1 or 2, wherein the mass ratio of component (A) to (C) is 1:0.5 to 1:1 ((A):(C)).

4. The solid composition according to claim 1 or 2, wherein the mass ratio of component (B) to (C) is 1:0.5 to 1:2.4 ((B):(C)).

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