Pharmaceutical solid compositions

Abstract

To provide a technique for obtaining a composition having excellent storage stability of active ingredients.SOLUTION: A solid composition for medicine contains (A) dextromethorphan or salt thereof, and (C) acetaminophen, where a chart of high-performance liquid chromatography (HPLC) has a peak of the component (A) which appears in a region where the retention time is 7.2 minutes or more and 8.8 minutes or less, and a peak of an analogous substance which appears in a region where the relative retention time is 0.675 or more and 0.825 or less with respect to the retention time of component (A). When a peak area of component (A) is S1, and a peak area of the analogous substance is S2, an analogous substance ratio calculated by the following formula (I) is 0.005 or more and 0.3 or less. Analogous substance ratio [%]=100×(S2 / S1) (I)SELECTED DRAWING: None

Description

【Technical Field】 【0001】 The present invention relates to a solid pharmaceutical composition. 【Background Art】 【0002】 Currently, in over-the-counter cold medications, antipyretics, and analgesics, pharmaceutical preparations containing multiple medicinal components are widely used. As an example of such a pharmaceutical preparation, there is one described in Patent Document 1 (Japanese Patent Application Laid-Open No. 2020-105108). This document describes a sugar-coated tablet having a core tablet, a film coating layer covering the surface of the core tablet, and a sugar coating layer covering the surface of the film coating layer, wherein the core tablet contains acetaminophen, chlorpheniramine maleate or d-chlorpheniramine maleate, dextromethorphan hydrobromide hydrate or dextromethorphan phenolphthalein salt, dl-methyl ephedrine hydrochloride or dl-methyl ephedrine saccharin salt, potassium guaiacolsulfonate, and anhydrous caffeine or caffeine hydrate, and the film coating layer contains hypromellose (Claim 1). Further, this document describes that in the production of the sugar-coated tablet, after granulating acetaminophen, potassium guaiacolsulfonate, etc. by fluidized bed granulation to obtain a granulated product, components such as dextromethorphan hydrobromide hydrate are added to the obtained granulated product to obtain a drug-containing powder (Example 1). 【Prior Art Documents】 【Patent Documents】 [[ID=2(0]] 【0003】 【Patent Document 1】 Japanese Patent Application Laid-Open No. 2020-105108 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0004】 The inventors found that when attempting to manufacture a solid composition containing dextromethorphan or a salt thereof, such as dextromethorphan hydrobromide hydrate, and acetaminophen, there was a concern that the dextromethorphan would decompose during the manufacturing process or over time during storage, indicating that there was room for improvement in terms of the stability of dextromethorphan in the composition. 【0005】 This invention provides a technique for obtaining a composition with excellent storage stability of the active ingredient. [Means for solving the problem] 【0006】 The inventors have newly discovered that the above problem can be solved by evaluating related substances in pharmaceutical solid compositions. 【0007】 The present invention provides the following pharmaceutical solid compositions and evaluation methods. [1] (A) Dextromethorphan or a salt thereof, (C) acetaminophen A pharmaceutical solid composition containing, The chart obtained under the following measurement conditions is a high-performance liquid chromatography (HPLC) chart. The peak of component (A) appears in the region of retention time between 7.2 minutes and 8.8 minutes, The peak of a related substance that appears in the region where the relative retention time with respect to the retention time of component (A) is 0.675 or more and 0.825 or less, It has, When the peak area of ​​component (A) is denoted as S1 and the peak area of ​​the related substance as S2, A pharmaceutical solid composition having a related substance ratio of 0.005 or more and 0.3 or less, calculated by the following formula (I). Related substance ratio [%]=100×(S2 / S1) (I) (Measurement conditions) • Equipment: High-performance liquid chromatography • Detector: UV absorbance spectrophotometer • Detection wavelength: 280nm • Column: L-Column ODS manufactured by the Chemicals Evaluation and Research Institute (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) • Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: 80 μg / mL of component (A) • Sample injection volume: 10 μL [2] The pharmaceutical solid composition according to [1], wherein, after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months, the related substance ratio calculated by formula (I) in the HPLC chart obtained by the above measurement conditions is 0.005 or more and 3.0 or less. [3] A pharmaceutical solid composition according to [1] or [2], further comprising an antioxidant. [4] The pharmaceutical solid composition according to [3], wherein the antioxidant is ascorbic acid. [5] A pharmaceutical solid composition according to any one of [1] to [4], wherein component (A) is dextromethorphan hydrobromide hydrate. [6] The component (A) is dextromethorphan hydrobromide hydrate, A pharmaceutical solid composition according to any one of [1] to [5], wherein the mass ratio ((C) / (A)) of the content of component (C) to the content of component (A) in the pharmaceutical solid composition is 1 or more and 188 or less. [7] A pharmaceutical solid composition according to any one of [1] to [6], wherein the dosage form of the pharmaceutical solid preparation is a sugar-coated tablet or a film-coated tablet. [8] A pharmaceutical solid composition according to any one of [1] to [6], wherein the dosage form of the pharmaceutical solid preparation is a tablet, granules, fine granules, or capsule. [9] (A) Dextromethorphan or a salt thereof, (C) acetaminophen A method for evaluating a pharmaceutical solid composition containing, A step of obtaining a high performance liquid chromatography (HPLC) chart under the following measurement conditions, and In the said chart, Let the peak area of the peak of the said component (A) appearing in the region where the retention time is 7.2 minutes or more and 8.8 minutes or less be S1, Let the peak area of the peak of the said related substance appearing in the region where the relative retention time with respect to the retention time of the said component (A) is 0.675 or more and 0.825 or less be S2, A step of calculating the related substance ratio calculated by the following formula (I), An evaluation method comprising Related substance ratio [%]=100×(S2 / S1) (I) (Measurement conditions) · Apparatus: High performance liquid chromatography · Detector: Ultraviolet absorptiometer · Detection wavelength: 280 nm · Column: Manufactured by Chemical Substance Evaluation Research Institute, L-Column ODS (carrier particle diameter 5 μm, column inner diameter 4.6 mm, column length 250 mm) · Column temperature: 40 °C · Mobile phase: Methanol / Phosphate buffer solution mixture of pH 6.0 (17:3) · Mobile phase flow rate: Adjusted so that the retention time of the said component (A) becomes 8 minutes · Sample concentration: 80 μg / mL as the said component (A) · Sample injection volume: 10 μL 【0008】 Also, according to the present invention, for example, the following solid pharmaceutical compositions can also be provided. [X1] A solid pharmaceutical composition containing the following components (A) to (C), wherein the mass ratio ((B) / (A)) of the content of the said component (B) to the content of the said component (A) is 0.0004 or less. (A) Dextromethorphan or a salt thereof (B) 10-Keto dextromethorphan (C) Acetaminophen The solid pharmaceutical composition according to [X1], wherein the mass ratio of the content of the component (B) to the total content of the components (A) and (C) ((B) / ((A)+(C))) is 0.00002 or less. The solid pharmaceutical composition according to [X1] or [X2], wherein the mass ratio of the content of the component (B) to the content of the component (A) ((B) / (A)) after storing the solid pharmaceutical composition at 60 °C under open conditions for 2.5 months is 0.004 or less based on the whole solid pharmaceutical composition. [Advantages of the Invention] 【0009】 According to the present invention, a composition excellent in storage stability of an active ingredient can be obtained. [Modes for Carrying Out the Invention] 【0010】 Hereinafter, embodiments of the present invention will be described. In the present embodiment, the composition may contain each component alone or in combination of two or more. In the present specification, "~" indicating a numerical range represents "or more" and "or less", and includes both end numerical values. 【0011】 (Solid pharmaceutical composition) In the present embodiment, the solid pharmaceutical composition contains the following components (A) and (C). (A) Dextromethorphan or a salt thereof, and (C) Acetaminophen And, when the high performance liquid chromatography (HPLC) chart obtained under the following measurement conditions has a peak of the component (A) and a peak of an analog, and the peak area of the component (A) is S1 and the peak area of the analog is S2, the analog ratio calculated by the following formula (I) is 0.005 or more and 0.3 or less. Here, on the HPLC chart, the retention time of the peak of the component (A) is in the range of 7.2 minutes or more and 8.8 minutes or less, and the relative retention time of the peak of the analog to the peak of the component (A) is in the range of 0.675 or more and 0.825 or less. Analog ratio [%]=100×(S2 / S1) (I) (Measurement conditions) • Equipment: High-performance liquid chromatography (e.g., Shimadzu Corporation, Nexera series) • Detector: UV absorbance spectrophotometer • Detection wavelength: 280nm • Column: ODS column with a carrier particle size of 5 μm, column inner diameter of 4.6 mm, and column length of 250 mm. Specifically, L-Column ODS (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) manufactured by the Chemicals Evaluation and Research Institute. Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) • Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: 80 μg / mL as component (A) • Sample injection volume: 10 μL 【0012】 The pharmaceutical solid composition in this embodiment exhibits excellent storage stability because the related substance ratio calculated by formula (I) falls within a specific range, and can achieve a high level of stability for component (A), for example. Furthermore, this embodiment makes it possible to obtain a pharmaceutical solid composition with excellent manufacturing stability. Furthermore, in the aforementioned Patent Document 1, dextromethorphan hydrobromide hydrate and acetaminophen are separated to produce uncoated tablets. Specifically, granules containing acetaminophen are obtained and then mixed with dextromethorphan hydrobromide hydrate. In contrast, according to this embodiment, it is possible to obtain a pharmaceutical solid composition with superior flexibility in the manufacturing process. Moreover, according to this embodiment, it is possible to obtain a pharmaceutical solid composition with even greater uniformity in the distribution of the active ingredient within the tablet. 【0013】 More specifically, HPLC measurement of pharmaceutical solid compositions is performed with the pharmaceutical solid composition at room temperature (1-30°C). Furthermore, the sample concentration can be adjusted, for example, in the case of tablets, based on the amount of ingredient (A) per tablet as indicated in the product information or packaging, and the measured weight of the tablet. 【0014】 In such measurements, the related substance ratio calculated by formula (I) is 0.005 or higher, more preferably 0.008 or higher, and even more preferably 0.01 or higher, from the viewpoint of expanding the options for manufacturing conditions. From the viewpoint of improving the storage stability of the active ingredient, in the above measurement, the related substance ratio calculated by formula (I) is 0.3 or less, preferably 0.25 or less, more preferably 0.22 or less, even more preferably 0.2 or less, and even more preferably 0.15 or less. 【0015】 Furthermore, after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months, the related substance ratio calculated by formula (I) in the HPLC chart obtained under the above-described measurement conditions is preferably 0.005 or higher, more preferably 0.01 or higher, even more preferably 0.1 or higher, and even more preferably 0.2 or higher, from the viewpoint of expanding the options for manufacturing conditions. From the viewpoint of improving the storage stability of the active ingredient, in the above measurement, the ratio of related substances after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months is preferably 3.0 or less, more preferably 2.0 or less, even more preferably 1.0 or less, and even more preferably 0.8 or less. Here, the HPLC measurement of the pharmaceutical solid composition after storage at 60°C under open conditions for 2.5 months is more specifically performed with the pharmaceutical solid composition at room temperature (1-30°C) after storage. Next, we will describe each component in the pharmaceutical solid composition. 【0016】 (Component (A)) Component (A) is dextromethorphan or a salt thereof. Specific examples of component (A) include dextromethorphan; and dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, and other salts of dextromethorphan and their hydrates. These are known compounds and can be produced by known methods, or commercially available products can be used. Component (A) is preferably dextromethorphan hydrobromide hydrate, from the viewpoint of more reliably improving stability. 【0017】 The amount of component (A) to be incorporated into the pharmaceutical solid composition is not limited and should be determined appropriately based on the gender, age, symptoms, etc. of the user. For example, if component (A) is dextromethorphan hydrobromide hydrate, the daily dose is usually 8 to 120 mg, preferably 16 to 48 mg. If dextromethorphan or its salt is dextromethorphan phenolphthalein salt, the daily dose is usually 9 to 90 mg, preferably 24 to 72 mg. Furthermore, the amount of component (A) in the pharmaceutical solid composition is, for example, 1% by mass or more, preferably 3% by mass or more, and also, for example, 30% by mass or less, preferably 15% by mass or less, and more preferably 10% by mass or less, relative to the total composition of the pharmaceutical solid composition (in the case of film-coated tablets or sugar-coated tablets, the total composition of the uncoated tablet portion). 【0018】 (Related substances) In this embodiment, the pharmaceutical solid composition specifically includes a related substance of component (A). The related substance includes, for example, component (B): 10-Keto dextromethorphan. Related substances may include, for example, oxidized forms of dextromethorphan. In this case, if the frequency of contact between dextromethorphan and oxygen or radicals increases during the manufacturing process of the pharmaceutical solid composition, the amount of related substances produced will also increase. Factors that increase the frequency of contact include the dissolution and precipitation of dextromethorphan during operations such as granulation, or the formation of strain in the crystals, which increases the particle surface area of ​​dextromethorphan. Furthermore, related substances may include, for example, decomposition products of dextromethorphan. If the amount of related substances in the pharmaceutical solid composition is too high, the aforementioned contact frequency is high, raising concerns that dextromethorphan will decompose easily and storage stability will decrease. In contrast, in this embodiment, by keeping the ratio of related substances in the pharmaceutical solid composition within a certain range, the composition can be further stabilized. 【0019】 From the viewpoint of expanding the options for manufacturing conditions, the content of component (B) in the pharmaceutical solid composition is preferably 0.00004% by mass or more, and more preferably 0.00006% by mass or more, relative to the total pharmaceutical solid composition. Alternatively, the content of component (B) may be, for example, 0.000007% by mass or more, or for example, 0.00001% by mass or more. Furthermore, from the viewpoint of improving the storage stability of the active ingredient, the content of component (B) in the pharmaceutical solid composition is preferably 0.0025% by mass or less, more preferably 0.002% by mass or less, and even more preferably 0.0018% by mass or less, relative to the total pharmaceutical solid composition. Alternatively, the content of component (B) may be, for example, 0.0005% by mass or less, or for example 0.0004% by mass or less, or for example 0.00035% by mass or less. 【0020】 The mass ratio ((B) / (A)) of the content of component (B) to the content of component (A) in the pharmaceutical solid composition is preferably 0.000006 or higher, and more preferably 0.000009 or higher, from the viewpoint of expanding the options for manufacturing conditions. Furthermore, from the viewpoint of improving the storage stability of the active ingredient, the above mass ratio ((B) / (A)) is, for example, 0.0004 or lower, preferably 0.00035 or lower, and more preferably 0.0003 or lower. 【0021】 The mass ratio ((B) / ((A)+(C))) of the content of component (B) to the total content of component (A) and component (C) described below in the pharmaceutical solid composition is preferably 0.0000003 or more, and more preferably 0.0000004 or more, from the viewpoint of expanding the options for manufacturing conditions. Furthermore, from the viewpoint of improving the storage stability of the active ingredient, the above mass ratio ((B) / ((A)+(C))) is, for example, 0.00002 or less, preferably 0.000018 or less, and more preferably 0.000015 or less. 【0022】 After storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months, the mass ratio ((B) / (A)) of the content of component (B) to the content of component (A) in the pharmaceutical solid composition is preferably 0.000006 or higher, and more preferably 0.000012 or higher, from the viewpoint of expanding the options for manufacturing conditions. Furthermore, from the viewpoint of improving the storage stability of the active ingredient, the mass ratio ((B) / (A)) after storage is, for example, 0.004 or lower, preferably 0.0035 or lower, and more preferably 0.0025 or lower. 【0023】 (Component (C)) Component (C) is acetaminophen (also known as paracetamol). Component (C) is listed in the 18th edition of the Japanese Pharmacopoeia. Acetaminophen is a known compound and can be manufactured by known methods, or commercially available acetaminophen can be used. 【0024】 The amount of component (C) to be incorporated into the pharmaceutical solid composition is not limited and should be determined appropriately based on the gender, age, symptoms, etc. of the user. For example, the daily dose of acetaminophen is usually 150 to 1500 mg, preferably 300 to 900 mg. Furthermore, the amount of component (C) in the pharmaceutical solid composition is, for example, 40% by mass or more, preferably 55% by mass or more, and also, for example, 99% by mass or less, preferably 85% by mass or less, and more preferably 70% by mass or less, relative to the total composition of the pharmaceutical solid composition (in the case of film-coated tablets or sugar-coated tablets, the total composition of the uncoated tablet portion). 【0025】 Component (A) is preferably dextromethorphan hydrobromide hydrate, and the mass ratio of the content of component (C) to the content of component (A) in the pharmaceutical solid composition ((C) / (A)) is, for example, 1 or more, preferably 2 or more, and more preferably 6 or more, from the viewpoint of obtaining the desired pharmacological effect. Furthermore, from the viewpoint of improving the stability of component (A), the above mass ratio ((C) / (A)) is preferably 188 or less, more preferably 100 or less, and even more preferably 60 or less. Also, the above mass ratio ((C) / (A)) may be, for example, 30 or less, or for example, 20 or less. 【0026】 The pharmaceutical solid composition may further contain components other than component (A), its related substances, and component (C). 【0027】 (Antioxidant) From the viewpoint of improving the stability of component (A) during the manufacture of the pharmaceutical solid composition and from the viewpoint of improving the stability of component (A) during the storage of the pharmaceutical solid composition, the pharmaceutical solid composition preferably further contains an antioxidant. 【0028】 Specific examples of antioxidants include ascorbic acid, calcium ascorbate, ascorbic acid stearate or its salts, ascorbic acid derivatives and salts thereof; natural vitamin E, tocopherol (dl-α-tocopherol), d-α-tocopherol, β-tocopherol, γ-tocopherol, σ-tocopherol, tocopherol, tocopherol derivatives and salts thereof, such as tocopherol acetate, tocopherol nicotinate, tocopherol succinate calcium, concentrated mixed tocopherol; sodium edetate, erythorbic acid, cysteine ​​hydrochloride, anhydrous sodium sulfite, One or more components selected from the group consisting of citric acid, potassium dichloroisocyanurate, dibutylhydroxytoluene, soy lecithin, sodium thioglycolate, sodium thiomalate, ascorbic acid palmitate, butylhydroxyanisole, 1,3-butylene glycol, benzotriazole, propyl gallate, 2-mercaptobenzimidazole, pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], sodium pyrosulfite, sodium nitrite, sodium sulfite, sodium bisulfite, alpha-thioglycerin, and β-carotene. 【0029】 From the viewpoint of improving the stability of component (A) during the manufacture of the pharmaceutical solid composition, and from the viewpoint of improving the stability of component (A) during the storage of the pharmaceutical solid composition, the antioxidant is preferably ascorbic acid. The amount of ascorbic acid in the pharmaceutical solid composition is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, and also, for example, 5% by mass or less, and preferably 2% by mass or less, based on the total composition of the pharmaceutical solid composition (in the case of film-coated tablets or sugar-coated tablets, the total composition of the uncoated tablet portion). 【0030】 Furthermore, component (A) is preferably dextromethorphan hydrobromide hydrate, and the amount of antioxidant relative to the total amount of components (A) and (C) in the pharmaceutical solid composition is preferably 0.002 or more by mass ratio, more preferably 0.003 or more, and even more preferably 0.004 or more, from the viewpoint of obtaining antioxidant activity more stably. Furthermore, the amount of antioxidant relative to the total amount of components (A) and (C) in the pharmaceutical solid composition is, for example, 0.35 or less, preferably 0.25 or less, and more preferably 0.2 or less. 【0031】 (Excipients) From the viewpoint of improving its manufacturing stability, the pharmaceutical solid composition may further contain excipients. 【0032】 Excipients include, for example, syrup powder, pregelatinized starch, isomalt, cocoa butter, hydrolyzed starch dry product, caramel, carmellose, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrated amorphous silicon dioxide, dried aluminum hydroxide gel, dried potato starch, licorice powder, agar, agar powder, kanbai powder, xylitol, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, calcium silicate, magnesium silicate, and cinnamon powder. Crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, synthetic hydrotalcite, wheat starch, rice flour, rice starch, β-cyclodextrin, heavy anhydrous silicic acid, aluminum magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate, magnesium hydroxide, D-sorbitol, talc, Calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, corn starch granules, trehalose hydrate, silicon dioxide, lactose hydrate, lactose granules, sucrose, potato starch, microcrystalline cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose phthalate (200 731), hypromellose phthalate (220824), fine silicon dioxide, partially pregelatinized starch, pullulan, powdered sugar, powdered reduced maltose syrup, powdered cellulose, powdered cellulose (average degree of polymerization: 800~1100), povidone (K25), povidone (K30), povidone (K90), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate,One or more components selected from the group consisting of polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol / diethylene glycol mixture, maltitol, maltose hydrate, D-mannitol, D-mannitol / crospovidone / D-sorbitol / hydrated silicon dioxide mixture, anhydrous silicic acid hydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, methacrylate copolymer LD, magnesium aluminometasilicate, methyl acrylate / methacrylate copolymer, methyl acrylate / methyl methacrylate, methylcellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, and erythritol may be incorporated. 【0033】 The excipient preferably includes crystalline cellulose from the viewpoint of improving the moldability and strength of the formulation. From the viewpoint of improving fluidity in the granulation process, the amount of crystalline cellulose in the pharmaceutical solid composition is preferably 0.5% by mass or more, more preferably 0.7% by mass or more, and even more preferably 1% by mass or more, relative to the total composition of the pharmaceutical solid composition (or the total composition of the uncoated tablet portion in the case of film-coated tablets or sugar-coated tablets). Furthermore, from the viewpoint of improving the palatability of the formulation and making the size of the formulation more desirable, the amount of crystalline cellulose in the pharmaceutical solid composition is preferably 90% by mass or less, more preferably 50% by mass or less, and even more preferably 30% by mass or less, relative to the total composition of the pharmaceutical solid composition (or the total composition of the uncoated tablet portion in the case of film-coated tablets or sugar-coated tablets). 【0034】 (Disintegrant) The pharmaceutical solid composition may further contain a disintegrant, depending on the dosage form. This can improve the disintegration properties of pharmaceutical solid compositions, such as tablets or granules. As a disintegrant, one or more components selected from the group consisting of pregelatinized starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, potato starch, hydroxypropyl starch, crystalline cellulose, and partially pregelatinized starch may be incorporated. When a pharmaceutical solid composition contains carmellose, the amount of carmellose in the pharmaceutical solid composition is, for example, 1% by mass or more, preferably 3% by mass or more, and also, for example, 30% by mass or less, and preferably 15% by mass or less, relative to the total composition of the pharmaceutical solid composition (in the case of film-coated tablets or sugar-coated tablets, the total composition of the uncoated tablet portion). 【0035】 The solid pharmaceutical composition may contain other ingredients commonly used in general cold medicines, as needed. Furthermore, the solid pharmaceutical composition may contain ingredients listed in the General Use Drug Manufacturing and Marketing Approval Standards, for example. Specifically, such ingredients may include one or more selected from the group consisting of antipyretic analgesics other than ingredient (C), antihistamines, antitussives other than ingredient (A), noscapines, bronchodilators, expectorants, anticholinergics, anti-inflammatory agents, caffeines, vitamins, gastric mucosal protectants, herbal medicines, hypnotics / sedatives, and traditional Chinese medicine prescriptions. These ingredients may also be included as the antioxidants mentioned above. 【0036】 Other antipyretic analgesics besides component (C) may include, for example, one or more components selected from the group consisting of aspirin, aluminum aspirin, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, pranopufen, diclofenac sodium, mefenamic acid, indomethacin farnesil, acemetacin, etodolac, naproxen, meloxicam, celecoxib, and tiaramide hydrochloride. 【0037】 Examples of antihistamines include isotipendyl 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, and diphenhydride tannate. One or more components selected from the group consisting of lamin, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, ketotifen fumarate, promethazine hydrochloride, epinastine hydrochloride, emedastine fumarate, fexofenadine, azelastine hydrochloride, cetirizine hydrochloride, and olopatadine hydrochloride may be included. 【0038】 Other antitussives besides component (A) may include, for example, one or more components selected from the group consisting of alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dibnate sodium, tipepidine citrate, tipepidine hibenzate, dimemorphan phosphate, eprazinon hydrochloride, pentoxyverin cyanate, benproperine phosphate, and clofedanol hydrochloride. 【0039】 As for noscapines, for example, at least one component selected from the group consisting of noscapine and noscapine hydrochloride hydrate can be included. 【0040】 As a bronchodilator, one or more components selected from the group consisting of dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, aminophylline, diprophylline, theophylline, proxyphylline, dl-methyl ephedrine, l-methyl ephedrine hydrochloride, pseudoephedrine hydrochloride, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, and isoprenaline hydrochloride may be included. 【0041】 As an expectorant, one or more components selected from the group consisting of guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, l-carbocysteine, l-ethylcysteine ​​hydrochloride, l-methylcysteine ​​hydrochloride, ambroxol hydrochloride, ammonium chloride, l-menthol, ammonia fennel extract, cherry bark extract, methylcysteine ​​hydrochloride, and fudosteine ​​may be included. 【0042】 As an anticholinergic agent, for example, one or more components selected from the group consisting of total belladonna alkaloids, belladonna extract, datura extract, and isopropamide iodide may be included. 【0043】 As an anti-inflammatory agent, for example, one or more components selected from the group consisting of glycyrrhizic acid and its salts, tranexamic acid, serrapeptase, bromelain, semi-alkaline proteinase, pronase, cearprose, prodase, and lysozyme hydrochloride may be included. 【0044】 As for caffeine components, one or more components selected from the group consisting of sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine may be included. 【0045】 Examples of vitamins include vitamin B1 and its derivatives and their salts, such as thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, shikothiamine, thiamine disulfide, bis-ibthiamine, bisbentiamine, prosultiamine, and benfotiamine; vitamin B2 and its derivatives and their salts, such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate; pantothenic acid, panthenol, pantethine, pantothenic acid One or more components selected from the group consisting of vitamin B5 and its derivatives and salts, such as calcium thenate and sodium pantothenate; vitamin B6 and its derivatives and salts, such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 and its derivatives and salts, such as cyanocobalamin and mecobalamin; vitamin C and its derivatives and salts, such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and salts may be incorporated. 【0046】 As a gastric mucosal protective agent, one or more components selected from the group consisting of glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum alnoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel, coprecipitation product of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, magnesium aluminometasilicate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, solfalkone, gefarnate, teprenone, and rebamipide may be incorporated. 【0047】 Examples of crude drugs include ephedra, nandina fruit, oyster shell, yam, licorice, balloon flower, plant star, plant star, sekisan (stone garlic), senega, fritillary, fennel, phellodendron bark, cow's ren, turmeric, chamomile, cinnamon bark, gentian, ox gall, animal bile (including bear bile), adenophora, ginger, lanceolata, clove, citrus peel, atractylodes, zest, ginseng, ginseng, red oak, catechu, edamame, Corydalis, scutellaria, oleander, valerian, carotenoides, and apricot kernel. One or more ingredients selected from the group consisting of crude drugs such as Lycium barbarum, Lycium chinense, Schizonepeta tenuifolia, Cassia seed, Geranium thunbergii, Cyperus rotundus, Schisandra chinensis, Asarum sieboldii, Zanthoxylum piperitum, Aster tataricus, Paeonia lactiflora, Musk, Magnolia bark, Ligusticum chuanxiong, Zenia japonica, Swertia japonica, Morus alba bark, Perilla frutescens, Southern laurel, Angelica acutiloba, Gloucestershire bark, Pinellia ternata, Banka japonica, Angelica dahurica, Poria cocos, Stephania japonica, Paeonia lactiflora, Oyster shell, and Deer antler jasmine, as well as extracts (extracts, tinctures, dried extracts, etc.) of these, may be incorporated. 【0048】 As a hypnotic sedative, for example, at least one component selected from the group consisting of bromovalerylurea and allyl isopropylacetylurea may be included. 【0049】 Furthermore, as a Kampo prescription, for example, Kakkonto, Kakkonto-ka-kikyo, Keishito, Kososan, Saiko-keishito, Sho-saikoto, Sho-seiryuto, Bakumondoto, Hange-kobokuto, Maoto, and their extracts (extracts, tinctures, dried extracts, etc.) can be combined. 【0050】 Furthermore, the pharmaceutical solid composition may contain pharmaceutical additives necessary for manufacturing the formulation, to the extent that it does not impair the effects of the present invention. For example, pharmaceutical additives listed in Pharmaceutical and Food Safety Bureau Notification No. 1204-1 (Pharmaceutical Administration Laws and Regulations), Pharmaceutical Additives Dictionary 2021 (edited by the Japan Pharmaceutical Additives Association, Yakuji Nippo Co., Ltd.), and the 8th Edition of the Official Compendium of Food Additives (Japan Food Additives Association), etc., may be included. Specifically, in addition to the aforementioned excipients and disintegrants, one or more components selected from the group consisting of binders, disintegration aids, fluidizers, lubricants, plasticizers, coating agents, sugar coating agents, glossing agents, colorants, flavoring agents, sweeteners, fragrances, and flavoring agents / fragrances may be included in the pharmaceutical solid composition. 【0051】 Examples of binders include gum arabic, gum arabic powder, agar, agar powder, kanbai flour, copolividone, gelatin, shellac, low-substituted hydroxypropyl cellulose, corn starch, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropyl cellulose, vinylpyrrolidone / vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), and fumellose. One or more components selected from the group consisting of acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropylcellulose 2910 mixture, pullulan, povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), polyvinyl alcohol / polyethylene glycol / graft polymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate / methyl methacrylate copolymer, magnesium aluminometasilicate, and methylcellulose may be incorporated. When a pharmaceutical solid composition contains hydroxypropyl cellulose, the amount of hydroxypropyl cellulose in the pharmaceutical solid composition is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, and also, for example, 10% by mass or less, and preferably 5% by mass or less, relative to the total composition of the pharmaceutical solid composition (or, in the case of film-coated tablets or sugar-coated tablets, the total composition of the uncoated tablet portion). 【0052】 As disintegration aids, for example, one or more components selected from the group consisting of carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium starch glycolate, and hydroxypropyl starch may be included. 【0053】 As a fluidizing agent, one or more components selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, tricalcium phosphate, talc, corn starch, magnesium aluminometasilicate, and calcium hydrogen phosphate granules may be incorporated. 【0054】 As a lubricant, one or more components selected from the group consisting of hydrated silicon dioxide, hydrated amorphous silicon dioxide, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, heavy anhydrous silicic acid, sucrose fatty acid ester, stearyl alcohol, stearic acid, zinc stearate, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, hydrogenated soybean oil, talc, sodium stearyl fumarate, beeswax, anhydrous silicic acid hydrate, magnesium aluminometasilicate, and glyceryl monostearate may be incorporated. 【0055】 As plasticizers, one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, 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 may be incorporated. 【0056】 Examples of coating agents include ethyl acrylate / methyl methacrylate copolymer dispersion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, gum arabic, gum arabic powder, ammoniaalkyl methacrylate copolymer, ethyl cellulose, ethyl cellulose aqueous dispersion, octyldecyl triglyceride, Opadry OY-6950, Opadry OY-L-28900, Opadry OY-LS-20291, Opadry OY-LS-23016, Opadry OY-S-7135, Opadry OY-S-8471, OpaDry OY-S-9607, OpaDry OY-S-22829, OpaDry OY-S-22835, OpaDry OY-S-22961, OpaDry OY-S-28924, OpaDry YS-1-7003 White, OpaDry YS-1-12524-A, OpaDry YS-1-14762-A, OpaDry YS-1-15585-A, OpaDry YS-1-19025A, OpaDry YS-2-19114-A, OpaDry II Yellow, OpaDry Clear (YS-2-19114-A), OpaDry II Gray 85F17659, OpaDry White 03K28 0000, OpaDry Pink (02F34337), OpaDry II Pink, OpaDry II Pink 85F97191, OpaDry II Blue (85G20427), OpaDry II Beige 85F17438, OpaDry White (15B180002), OpaDry White OY-LS-28914, OpaDry White YS-1-18177-A, OpaDry White (YS-1-18202-A), OpaDry II White (33G28523), OpaDry II White (85F28751), OpaDry II White (OY-LS-2891 4) OpaDry II Light Blue (85G20426), OpaDry II Light Beige 85F17498, OpaDry II Red (32K15441), Carnauba wax, Carmellose calcium, Carmellose sodium, Hydrated silicon dioxide, Dried aluminum hydroxide gel, Dried methacrylate copolymer LD, Triethyl citrate, Glycerin, Glycerin fatty acid ester, Magnesium silicate, Light anhydrous silicic acid, Light anhydrous silicic acid-containing hydroxypropyl cellulose, Crystalline cellulose, Synthetic aluminum silicate, Synthetic hydrotalcite, Titanium dioxide,Magnesium oxide, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, D-sorbitol, D-sorbitol solution, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, concentrated glycerin, white shellac, sucrose Paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, titanium dioxide, macrogol mixture, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (type 200731), hypromellose phthalate (type 220824), fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose 2910 mixture, pullulan, premix additive Opadry White, Bentonite, Polyoxyethylene Hydrogenated Castor Oil 40, Polyoxyethylene Hydrogenated Castor Oil 60, Polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polyoxyethylene (160) Polyoxypropylene (30) Glycol, Sodium Polystyrene Sulfonate, Polysorbate 80, Polyvinyl Acetal Diethylaminoacetate, Polyvinyl Alcohol (Partially Saponified), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 40 00, Macrogol 6000, Macrogol 6000EP, Macrogol 20000, Macrogol 35000, D-mannitol, Anhydrous citric acid, Anhydrous silicic acid hydrate, Anhydrous phthalic acid, Anhydrous calcium hydrogen phosphate, Methacrylic acid copolymer L, Methacrylic acid copolymer LD, Methacrylic acid copolymer S, Magnesium aluminometasilicate, Methyl methacrylate / methacrylic acid / methyl methacrylate copolymer, Aluminum monostearate, Glyceryl monostearate, Sorbitan monostearate, Sorbitan monolaurate,One or more components selected from the group consisting of calcium sulfate, fumaric acid, and DL-malic acid may be included. 【0057】 As a sugar coating agent, one or more components selected from the group consisting of, for example, gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, crystalline cellulose, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose (2208), hypromellose (2910), pullulan, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene (105) polyoxypropylene (5) glycol, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, and D-mannitol may be incorporated. 【0058】 As a glossing agent, one or more components selected from the group consisting of carnauba wax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, and beeswax may be incorporated. 【0059】 As colorants, for example, one or more components selected from the group consisting of yellow iron oxide, Yellow No. 5 premix, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium dioxide, ferric oxide, ferric oxide / glycerin suspension, Food Blue No. 1, Food Blue No. 2 aluminum lake, Food Yellow No. 4, Food Yellow No. 4 aluminum lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, copper chlorophyllin sodium, copper chlorophyll, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, and rose oil may be incorporated. 【0060】 As flavoring agents, for example, erythritol, sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, Ononis root dry extract, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, crude licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, glycyrrhizic acid, trisodium glycyrrhizate, diammonium glycyrrhizate, disodium glycyrrhizate, monoammonium glycyrrhizate, L-glutamic acid, L-arginine glutamate, L-glutamate salt, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon tincture, cinnamon powder, cinnamon oil, kelp powder, saccharin, sodium saccharin hydrate, saffron, saffron tincture, sansho tincture, sansho powder, tartaric acid, It may contain one or more ingredients selected from the group consisting of D-tartaric acid, potassium bitartrate, DL-sodium tartrate, ginger tincture, ginger powder, sucralose, stevia extract, stevia extract, refined licorice extract powder, refined sucrose, swertia japonica, hibiscus powder, D-sorbitol, jujube powder, taurine, taraxacum root / grass dry extract, tannic acid, clove tincture, clove oil, citrus peel tincture, chili pepper, chili pepper tincture, chili pepper powder, spruce tincture, spruce powder, trehalose hydrate, pisulphureus powder, plum extract, sucrose, fructooligosaccharides, powdered sugar, peppermint powder, maltose hydrate, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil. 【0061】 As a sweetener, one or more ingredients selected from the group consisting of aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, refined sucrose granules, sucrose, powdered reduced maltose syrup, maltitol, D-mannitol, and erythritol may be included. 【0062】 As for the flavorings, one or more ingredients selected from the group consisting of, for example, orange flavor, orange flavor powder SH-1171-A, orange micron H-800092, guarana extract, sweet orange flavor, strawberry flavor, lemon flavor, brown sugar flavor, strawberry essence, strawberry flavor B86173, cherry flavor 181612, dentmint 1148J, banana powder flavor, peach essence, cypress 6E-84211, blackcurrant flavor 290012SYM, fruit essence, peppermint NAEFCOPO551957685, peppermint micron H-81550, mixed flavor powder, melon powder flavor, l-menthol, and menthol L163592SYM may be incorporated. 【0063】 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, and Himalayan. One or more ingredients selected from the group consisting of cedar 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 flake powder, lemon powder, lemon oil, rose water, rose oil, belladonna oil, and Roman chamomile oil may be incorporated. 【0064】 (Solid dosage form) Furthermore, pharmaceutical solid compositions are specifically pharmaceutical solid dosage forms. The dosage form of a solid pharmaceutical preparation is not limited and includes, for example, capsules, pills, granules, fine granules, powders, and tablets. These solid preparations may be coated by known methods such as sugar coating or film coating as needed. From the viewpoint of further improving the stability of component (A), the dosage form of the solid preparation is preferably a tablet such as a sugar-coated tablet or film-coated tablet, granules, fine granules, or capsule, and more preferably a sugar-coated tablet or granule. Furthermore, the solid dosage form is preferably an orally administered formulation. 【0065】 The packaging form for pharmaceutical solid compositions, specifically solid dosage forms, can be bottle packaging, SP (Strip Package) packaging, stick packaging, PTP (Press Through Package), pouch packaging, etc., as appropriate. They may be packaged in these forms and stored airtight. In other words, pharmaceutical solid compositions may be contained in airtight packaging. Furthermore, they may be pillow-packaged. They may also be stored in boxes or the like. The materials used for SP packaging, stick packaging, PTP packaging, and pillow packaging are not limited and include, for example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polyethylene, polypropylene film, polyethylene terephthalate film, and polyethylene film, multi-layer films combining these resin films, and resin films with aluminum foil attached. Multi-layer films may be laminate films, for example. Furthermore, they may be sealed together with a desiccant, oxygen absorber, and deodorizer as needed. 【0066】 Furthermore, the pharmaceutical solid composition can be suitably used, for example, as a combination cold medicine. For instance, by adding various components, it can be administered to patients suffering from various cold symptoms, particularly fever, chills, headache, sore throat, runny nose, nasal congestion, cough, phlegm, joint pain, muscle pain, and sneezing, in order to alleviate these symptoms. 【0067】 (Manufacturing method) In this embodiment, the pharmaceutical solid composition includes a step of blending, for example, components (A), (C), and other components as appropriate. More specifically, solid pharmaceutical compositions can be manufactured and prepared according to the methods described in the 18th edition of the Japanese Pharmacopoeia, etc., depending on their dosage form. For example, if the dosage form of a solid pharmaceutical composition is a tablet, it can be manufactured in accordance with the "Tablets" section of the General Provisions for Pharmaceutical Preparations in the Japanese Pharmacopoeia. Similarly, if the dosage form of a solid pharmaceutical composition is a granule, it can be manufactured in accordance with the "Granules" section of the General Provisions for Pharmaceutical Preparations in the Japanese Pharmacopoeia. Furthermore, from the viewpoint of avoiding contraindications for the ingredients and additives incorporated into the pharmaceutical solid composition, and from the viewpoint of further improving the storage stability of the composition, the composition may be formulated in such a way that the specified ingredients do not come into contact with each other, such as by granulation or multilayering. 【0068】 In order to obtain a pharmaceutical solid composition in which the related substance ratio calculated by formula (I) falls within the above range, it is important to pay attention to the following points in the manufacturing process. Specifically, it is preferable to select and use raw materials of components (A) and (C) that have predetermined properties, and to carry out granulation by a fluid bed granulation process. Alternatively, it is also preferable to use antioxidants in combination with the raw materials of components (A) and (C). Below, we will further describe in detail an example of a manufacturing method that is effective for obtaining a pharmaceutical solid composition in which the related substance ratio calculated by formula (I) falls within the above-mentioned range. 【0069】 (First method) A method for producing a pharmaceutical solid composition includes, for example, the following steps: (First mixing step) A step to produce a first mixture containing the powder or granules of component (A) and the powder of component (C). (Granulation process) This is a fluid bed granulation process in which purified water or a liquid containing a binder is sprayed onto the first mixture to produce granules. (Second mixing step) A step in which a lubricant is added to the granules obtained in the granulation step to produce a second mixture. The following describes each step in detail. 【0070】 (First mixing process) In the first mixing step, a first mixture is obtained. In the first mixing step, component (A) is incorporated into the first mixture as a powder or granules thereof. Meanwhile, component (C) is incorporated into the first mixture as a powder. 【0071】 Here, the powders of component (A) and component (C) refer to powders that are not granulated products of these raw materials, and may be, for example, the raw materials themselves, or they may be obtained by sieving, crushing, or grinding the raw materials. The average particle size of the powder is specifically less than 300 μm, preferably less than 150 μm, and may also be, for example, 1 μm or more. Here, the average particle size of the powder specifically refers to the volume-average diameter, which is the arithmetic mean of the volume-based particle size distribution obtained by laser diffraction / scattering. For example, it can be evaluated by dry measurement using a particle size distribution analyzer MT3300EXII (manufactured by Microtrac-Bel). 【0072】 On the other hand, the granulated material of component (A) and component (C) is a granular material obtained by granulating these raw powders together with other components as appropriate. Furthermore, the granulated material may be obtained by sizing, crushing, or pulverizing the raw powder after granulation. The average particle size of the granules is specifically 75 μm or more, preferably 100 μm or more, and may also be, for example, 850 μm or less. Here, the average particle size of the granulated material specifically refers to the mass-average diameter, which is the arithmetic mean of the mass-based particle size distribution obtained by the sieving method. For example, this can be evaluated using a robot shifter RPS-105M (manufactured by Seishin Corporation). 【0073】 The first mixing step may be a step of producing a first mixture further containing excipients. This can further improve the fluidity in the granulation step and make granulation more preferable when obtaining a pharmaceutical solid composition in granular form. For example, the aforementioned components can be incorporated as excipients. 【0074】 Furthermore, the first mixing step may be a step to produce a first mixture further containing a disintegrant. This can improve the disintegration properties when obtaining pharmaceutical solid compositions such as tablets or granules. As a disintegrant, for example, the aforementioned components can be incorporated. 【0075】 (granulation process) The granulation process is a fluidized bed granulation process, in which purified water or a liquid containing a binder is sprayed onto the first mixture to produce granules. Fluidized bed granulation can be carried out using, for example, a fluidized bed granulator / dryer, a rolling fluidized bed granulator, or a swirling fluidized bed granulator. 【0076】 From the viewpoint of improving the fluidity of the granules, the average particle size of the granules obtained in the granulation process is preferably 75 μm or more, more preferably 90 μm or more, and even more preferably 100 μm or more. Furthermore, from the viewpoint of improving the uniformity of the effective ingredients, the average particle size of the granules obtained in the granulation process is preferably 850 μm or less, more preferably 500 μm or less, and even more preferably 400 μm or less. 【0077】 Furthermore, in the granulation process, purified water or a liquid containing a binder (binding solution) is sprayed onto the first mixture. Specifically, these are sprayed inside the granulator. The binding solution specifically includes a binder and purified water. On the other hand, when granulation is performed by spraying purified water, the binder can be added, for example, in the first mixing step. For example, the aforementioned components can be incorporated as binders. 【0078】 In this embodiment, the granules obtained in the granulation step may be used directly in the second mixing step, or, after the granulation step, the granules may be subjected to appropriate processes such as drying and sizing before being used in the second mixing step. 【0079】 (Second mixing process) In the second mixing step, a lubricant is added to the granules obtained in the granulation step, i.e., the fluidized bed granulation step, to produce a second mixture. 【0080】 The aforementioned components can be used as lubricants. Furthermore, magnesium stearate is preferred as a lubricant from the viewpoint of reducing metal adhesion during the tableting process and the granule filling process. The amount of magnesium stearate added is preferably 0.5% by mass or more, and more preferably 0.8% by mass or more, relative to the total composition of the pharmaceutical solid composition (or the total composition of the uncoated tablet portion in the case of film-coated tablets or sugar-coated tablets), from the viewpoint of reducing metal adhesion. Furthermore, from the viewpoint of improving the disintegration and dissolution properties of tablets and granules, for example, the amount of magnesium stearate added is preferably 5% by mass or less, and more preferably 3% by mass or less, relative to the total composition of the pharmaceutical solid composition (or the total composition of the uncoated tablet portion in the case of film-coated tablets or sugar-coated tablets). 【0081】 The second mixture obtained in the second mixing step may be used as is as a pharmaceutical solid composition, or, depending on the form of the pharmaceutical solid composition, the process may further include molding or filling steps after the second mixing step. For example, the manufacturing method in this embodiment may further include a step of compressing the second mixture obtained in the second mixing step into tablets to obtain uncoated tablets. Furthermore, solid pharmaceutical compositions can be manufactured and prepared in accordance with the methods described in the 18th edition of the Japanese Pharmacopoeia, etc., depending on their dosage form. For example, if the dosage form of a solid pharmaceutical composition is a tablet, it can be manufactured in accordance with the "Tablets" section of the General Provisions for Pharmaceutical Preparations in the Japanese Pharmacopoeia. Similarly, if the dosage form of a solid pharmaceutical composition is a granule, it can be manufactured in accordance with the "Granules" section of the General Provisions for Pharmaceutical Preparations in the Japanese Pharmacopoeia. Furthermore, from the viewpoint of avoiding contraindications for the ingredients and additives incorporated into the pharmaceutical solid composition, and from the viewpoint of further improving the storage stability of the composition, the composition may be formulated in such a way that the specified ingredients do not come into contact with each other, such as by granulation or multilayering. 【0082】 As a result, the pharmaceutical solid composition according to this embodiment can be obtained. In the first method, a first mixture containing a powder or granules thereof of component (A) and a powder of component (C) is produced in the first mixing step, and granules are produced by fluid bed granulation, thereby obtaining a pharmaceutical composition with excellent manufacturing stability and storage stability. More specifically, a pharmaceutical solid composition with excellent stability of component (A) and excellent uniformity of the distribution of the active ingredient can be produced. This is thought to be because the oxidation of component (A) is suitably suppressed by the first method. 【0083】 (Second method) In the second method, the method for producing a pharmaceutical solid composition includes the following steps: (First mixing step) A step to produce a first mixture containing a powder or granules of component (A), a powder of component (C), and an antioxidant. (Granulation process) This is a wet granulation process in which purified water or a liquid containing a binder is sprayed or dropped onto a first mixture to produce granules. (Second mixing step) A step in which a lubricant is added to the granules obtained in the granulation step to produce a second mixture. The second method differs from the first method in that, in the first mixing step, a first mixture further containing an antioxidant is obtained, and the granulation step is a wet granulation step. Aside from these points, each step can be carried out in accordance with the first method, and the aforementioned configuration can be used appropriately in the first method. 【0084】 Specific examples of antioxidants incorporated into the first mixture in the first mixing step include, for example, the aforementioned components. 【0085】 Furthermore, the wet granulation in the granulation process may be any method used in the manufacture of pharmaceutical compositions, for example, the fluidized bed granulation described above in the first method, or other wet granulation methods such as high-speed stirring granulation, extrusion granulation, or rolling granulation. 【0086】 In the second method, an antioxidant is further added to the first mixture in the first mixing step, and the granulation step is a wet granulation step, thereby obtaining a pharmaceutical composition with excellent manufacturing stability and storage stability. More specifically, a pharmaceutical solid composition can be produced that has excellent stability of component (A) and excellent uniformity of the distribution of the active ingredient. 【0087】 (Evaluation method) The evaluation method in this embodiment is a method for evaluating a pharmaceutical solid composition containing components (A) and (C), and includes the following steps. (Step 10) A step to obtain a high-performance liquid chromatography (HPLC) chart using the measurement conditions described above. (Step 20) A step to calculate the related substance ratio using the following formula (I), where S1 is the peak area of ​​the peak of component (A) that appears in the region of retention time between 7.2 minutes and 8.8 minutes in the chart above, and S2 is the peak area of ​​the peak of the related substance that appears in the region of relative retention time between 0.675 and 0.825 with respect to the retention time of component (A). Related substance ratio [%]=100×(S2 / S1) (I) 【0088】 This method allows for accurate evaluation of the storage stability of a pharmaceutical solid composition. In this embodiment, the evaluation method further includes the step of evaluating the pharmaceutical solid composition based on the ratio of related substances of (A) in the pharmaceutical solid composition. This method can be suitably used, for example, to evaluate the storage stability of a pharmaceutical solid composition. In this case, the evaluation method may further include the step of determining the storage stability of the pharmaceutical solid composition based on the ratio of related substances. In the process of evaluating the above-mentioned storage stability, specifically, if the ratio of related substances calculated by formula (I) is 0.005 or more and 0.3 or less, it may be determined that the storage stability meets the required level. Furthermore, the storage period for the above-mentioned storage stability is, for example, a period of 12 months or less, preferably a period of more than 12 months but within 24 months, and more preferably a period of more than 24 months but within 36 months. In addition, it is preferable to store the product under sealed conditions such as tightly sealed packaging. 【0089】 The embodiments of the present invention have been described above, but these are merely examples, and various other configurations can also be adopted. Examples of reference formats are provided below. 1. (A) Dextromethorphan or its salts, and (C) acetaminophen A pharmaceutical solid composition containing, The chart obtained under the following measurement conditions is a high-performance liquid chromatography (HPLC) chart. The peak of component (A) appears in the region of retention time between 7.2 minutes and 8.8 minutes, The peak of a related substance that appears in the region where the relative retention time with respect to the retention time of component (A) is 0.675 or more and 0.825 or less, It has, When the peak area of ​​component (A) is denoted as S1 and the peak area of ​​the related substance as S2, A pharmaceutical solid composition having a related substance ratio of 0.005 or more and 0.3 or less, calculated by the following formula (I). Related substance ratio [%]=100×(S2 / S1) (I) (Measurement conditions) • Equipment: High-performance liquid chromatography • Detector: UV absorbance spectrophotometer • Detection wavelength: 280nm • Column: L-Column ODS manufactured by the Chemicals Evaluation and Research Institute (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) • Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: 80 μg / mL of component (A) • Sample injection volume: 10 μL 2. The pharmaceutical solid composition according to 1, wherein, after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months, the related substance ratio calculated by formula (I) in the HPLC chart obtained under the above measurement conditions is 0.005 or more and 3.0 or less. 3. A pharmaceutical solid composition according to 1. or 2., further comprising an antioxidant. 4. The pharmaceutical solid composition according to 3, wherein the antioxidant is ascorbic acid. 5. The pharmaceutical solid composition according to 1. or 2., wherein component (A) is dextromethorphan hydrobromide hydrate. 6. The above component (A) is dextromethorphan hydrobromide hydrate, The pharmaceutical solid composition according to 1. or 2., wherein the mass ratio ((C) / (A)) of the content of component (C) to the content of component (A) in the pharmaceutical solid composition is 1 or more and 188 or less. 7. A pharmaceutical solid composition according to 1. or 2., wherein the dosage form of the pharmaceutical solid preparation is a sugar-coated tablet or a film-coated tablet. 8. A pharmaceutical solid composition according to 1. or 2., wherein the dosage form of the pharmaceutical solid preparation is a tablet, granules, fine granules, or capsule. 9. (A) Dextromethorphan or its salts, and (C) acetaminophen A method for evaluating a pharmaceutical solid composition containing, The following steps involve obtaining a high-performance liquid chromatography (HPLC) chart under the following measurement conditions, In the aforementioned chart, Let S1 be the peak area of ​​the peak of component (A) that appears in the region of retention time between 7.2 minutes and 8.8 minutes. Let S2 be the peak area of ​​the peak of the related substance that appears in the region where the relative retention time with respect to the retention time of component (A) is 0.675 or more and 0.825 or less. The process involves calculating the ratio of related substances using the following formula (I), An evaluation method that includes this. Related substance ratio [%]=100×(S2 / S1) (I) (Measurement conditions) • Equipment: High-performance liquid chromatography • Detector: UV absorbance spectrophotometer • Detection wavelength: 280nm • Column: L-Column ODS manufactured by the Chemicals Evaluation and Research Institute (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) • Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: 80 μg / mL of component (A) • Sample injection volume: 10 μL [Examples] 【0090】 The embodiment will be described in detail below with reference to examples and comparative examples, but this embodiment is not limited to these examples. 【0091】 (Examples 1 and 2 and Comparative Example 1) Each component was formulated according to the composition shown in Table 1, and tablets for each example were prepared using the following procedure. Note that "DXM" in Table 1 refers to dextromethorphan hydrobromide hydrate. 【0092】 (Example 1) Fluidized bed granulation According to the ratios shown in Table 1, acetaminophen (manufactured by Yamamoto Chemical Industry Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Industry Co., Ltd.), crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Corporation), and carmellose (NS-300: manufactured by Gotoku Pharmaceutical Co., Ltd.) were mixed in a fluidized bed granulator (FD-MP-01: manufactured by Pawrec Co., Ltd.). A 5% by mass aqueous solution of hydroxypropyl cellulose (HPC-L: manufactured by Nippon Soda Co., Ltd.) was sprayed as a binding agent until the amount of hydroxypropyl cellulose in the granules reached the values ​​shown in Table 1, and then the mixture was dried until the product temperature reached 65°C to obtain the granules. Magnesium stearate (manufactured by Taihei Chemical Co., Ltd.), weighed according to the ratios shown in Table 1, was mixed with the granulated material in a plastic bag, and then compressed into tablets using a tablet press (VIRGO: manufactured by Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets. 【0093】 (Example 2) Stirring granulation Acetaminophen (manufactured by Yamamoto Chemical Industry Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Industry Co., Ltd.), crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Corporation), carmellose (NS-300: manufactured by Gotoku Pharmaceutical Co., Ltd.), and ascorbic acid (manufactured by DSM Corporation) were mixed in a high-speed stirring granulator (VG-05: manufactured by Powrec Co., Ltd.) (first mixing step). Then, a 10% by mass aqueous solution of hydroxypropyl cellulose (HPC-L: manufactured by Nippon Soda Co., Ltd.) was added dropwise as a binding solution until the amount of hydroxypropyl cellulose in the granules reached the values ​​shown in Table 1. After kneading, the mixture was dried in a fluid bed granulator (FD-MP-01: manufactured by Powrec Co., Ltd.) until the product temperature reached 65°C, and granules were obtained by sieving with an 850 μm round sieve. Magnesium stearate (manufactured by Taihei Chemical Co., Ltd.), weighed according to the ratios shown in Table 1, was mixed with the granulated material in a plastic bag, and then compressed into tablets using a tablet press (VIRGO: manufactured by Kikusui Seisakusho Co., Ltd.) to obtain uncoated tablets. 【0094】 (Comparative Example 1) Agitated Granulation In Example 2, tablets were obtained in accordance with the procedure described in Example 2, except that ascorbic acid was not added during the first mixing step. 【0095】 [Table 1] 【0096】 (HPLC measurement) HPLC analysis of the tablets obtained in each example was performed according to the following procedure to determine the analogous substance ratios. The analogous substance ratios for each example are shown in Table 2. 【0097】 (Condition 1) Approximately 110 mg of the crushed tablets obtained in each example (equivalent to 8 mg of dextromethorphan hydrobromide hydrate) was mixed with 7 mL of water, and methanol was added to make a total volume of 100 mL. Dextromethorphan was extracted, and the supernatant liquid separated from the insoluble matter by centrifugation was used as the sample solution. The solution was measured using the liquid chromatography method of the 18th edition of the Japanese Pharmacopoeia. The measurement conditions are shown below. (Measurement conditions) • HPLC model: Shimadzu Corporation, Nexera series • Detector: UV absorbance spectrophotometer • Detection wavelength: 280nm • Column: L-Column ODS manufactured by the Chemicals Evaluation and Research Institute (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) • Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: As described above • Sample injection volume: 10 μL 【0098】 For each example of tablet, the peak area of ​​component (A) with a retention time in the range of 7.2 minutes to 8.8 minutes was defined as S1 from the obtained HPLC chart, and the peak area of ​​related substances with a relative retention time to the peak of component (A) in the range of 0.675 to 0.825 minutes was defined as S2, and the ratio of related substances was calculated using the following formula (I). Related substance ratio [%]=100×(S2 / S1) (I) Measurements were performed three times for each sample, and the average of the related substance ratios from the three measurements was calculated. 【0099】 (Condition 2) The tablets obtained in each example were stored at 60°C under open conditions for 2.5 months, then allowed to reach room temperature (1-30°C) for measurement. The measurement conditions and the method for calculating the ratio of related substances were the same as in Condition 1 above. 【0100】 (evaluation) The storage stability and manufacturing stability of the tablets obtained in each case were evaluated using the following method. 【0101】 (Storage stability) To evaluate the storage stability obtained in each case, the following tests were conducted. The tablets from Examples 1 and 2, and the tablet from Comparative Example 1 were filled into glass bottles (6K standard bottles) and stored at 25°C in a tightly sealed state for 12 months, 24 months, or 36 months. HPLC measurements were performed on each tablet before and after storage for each period, and the ratio of related substances was calculated. This was used as an indicator of the storage stability of dextromethorphan hydrobromide hydrate. The measurement conditions and the method for calculating the ratio of related substances are the same as in Condition 1 above. The results for each example are shown in Table 2. 【0102】 [Table 2] 【0103】 (manufacturing stability) The tablets obtained in each case were used as samples, and a tablet hardness test was performed on 10 tablets from each sample. The number of tablets showing capping cracks was then counted. A Dr. Schleuniger 8M (manufactured by Freund Industrial Co., Ltd.) was used as the hardness tester. The evaluation results are shown in Table 3. 【0104】 [Table 3] 【0105】 Tables 2 and 3 show that, compared to Comparative Example 1, each example had lower levels of dextromethorphan-related substances after storage at 25°C for 12, 24, and 36 months, demonstrating superior storage stability and effectively suppressing capping cracking. Furthermore, the manufacturing methods used in each example allow for excellent uniformity in the distribution of the active ingredients, dextromethorphan hydrobromide hydrate and acetaminophen, within the uncoated tablets.

Claims

[Claim 1] (A) Dextromethorphan or a salt thereof, (C) Acetaminophen, Binder, and Antioxidants A pharmaceutical solid composition containing, The above component (A) is a powder or granules, The above component (C) is in powder form, The amount of component (A) in the pharmaceutical solid composition is 1% by mass or more and 10% by mass or less relative to the total composition of the pharmaceutical solid composition. The mass ratio ((C) / (A)) of the content of component (C) to the content of component (A) in the pharmaceutical solid composition is 1 or more and 188 or less. The binder comprises hydroxypropyl cellulose, The aforementioned antioxidant is ascorbic acid, The amount of hydroxypropyl cellulose in the pharmaceutical solid composition is 0.1% by mass or more and 10% by mass or less relative to the total composition of the pharmaceutical solid composition. The chart obtained under the following measurement conditions is a high-performance liquid chromatography (HPLC) chart. The peak of component (A) appears in the region of retention time between 7.2 minutes and 8.8 minutes, The peak of a related substance that appears in the region where the relative retention time with respect to the retention time of component (A) is 0.675 or more and 0.825 or less, It has, The aforementioned related substance is component (B): 10-Keto dextromethorphan, When the peak area of ​​component (A) is denoted as S1 and the peak area of ​​the related substance as S2, A pharmaceutical solid composition having a related substance ratio of 0.005 or more and 0.3 or less, calculated by the following formula (I). Related substance ratio [%] = 100 x (S2 / S1) (I) (Measurement conditions) • Equipment: High-performance liquid chromatography Detector: UV absorbance spectrophotometer Detection wavelength: 280 nm • Column: L-Column ODS manufactured by the Chemicals Evaluation and Research Institute (carrier particle size 5 μm, column inner diameter 4.6 mm, column length 250 mm) Column temperature: 40°C Mobile phase: Methanol / phosphate buffer mixture at pH 6.0 (17:3) - Mobile phase velocity: Adjusted so that the retention time of component (A) is 8 minutes. • Sample concentration: 80 μg / mL of component (A) Sample injection volume: 10 μL [Claim 2] The pharmaceutical solid composition according to claim 1, wherein, after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months, the related substance ratio calculated by formula (I) in the HPLC chart obtained by the measurement conditions is 0.005 or more and 3.0 or less. [Claim 3] The pharmaceutical solid composition according to claim 1 or 2, wherein the component (A) is dextromethorphan hydrobromide hydrate. [Claim 4] A pharmaceutical solid composition according to claim 1 or 2, wherein the dosage form of the pharmaceutical solid preparation is a sugar-coated tablet or a film-coated tablet. [Claim 5] A pharmaceutical solid composition according to claim 1 or 2, wherein the dosage form of the pharmaceutical solid preparation is a tablet, granules, fine granules, or capsule. [Claim 6] The pharmaceutical solid composition according to claim 1 or 2, wherein the mass ratio ((B) / (A)) of the content of component (B) to the content of component (A) in the pharmaceutical solid composition is 0.000006 or more and 0.0004 or less. [Claim 7] The pharmaceutical solid composition according to claim 1 or 2, wherein the mass ratio of the content of component (B) to the total content of components (A) and (C) in the pharmaceutical solid composition ((B) / ((A)+(C))) is 0.0000003 or more and 0.00002 or less. [Claim 8] The pharmaceutical solid composition according to claim 1 or 2, wherein the mass ratio ((B) / (A)) of the content of component (B) to the content of component (A) in the pharmaceutical solid composition after storing the pharmaceutical solid composition at 60°C under open conditions for 2.5 months is 0.000006 or more and 0.004 or less. [Claim 9] The pharmaceutical solid composition according to claim 1 or 2, wherein the amount of ascorbic acid in the pharmaceutical solid composition is 0.1% by mass or more and 5% by mass or less relative to the total composition of the pharmaceutical solid composition. [Claim 10] The pharmaceutical solid composition according to claim 1 or 2, wherein the content of the antioxidant relative to the total amount of components (A) and (C) in the pharmaceutical solid composition is 0.002 or more and 0.35 or less by mass ratio. [Claim 11] A pharmaceutical solid composition according to claim 1 or 2, further comprising an excipient. [Claim 12] A pharmaceutical solid composition according to claim 1 or 2, further comprising a disintegrant.

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