JP2023103979A - Method for producing pharmaceutical solid composition - Google Patents

Abstract

To provide a technique for obtaining a composition having excellent stability of dextromethorphan or a salt thereof and uniform distribution of active ingredients.SOLUTION: A method for producing a pharmaceutical solid composition includes a first mixing step for providing a first mixture including powder of dextromethorphan or a salt thereof or granules thereof, and powder of acetaminophen, a fluidized bed granulation step for spraying the first mixture with purified water or liquid including a binder to provide granules, and a second mixing step for adding, to the granules obtained in the fluidized bed granulation step, a lubricant to provide a second mixture.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a solid pharmaceutical composition.

Currently, pharmaceutical formulations containing a plurality of medicinal ingredients are widely used in common cold medicines, antipyretic analgesics, and the like. Examples of such pharmaceutical formulations are those described in Patent Document 1 (Japanese Patent Application Laid-Open No. 2020-105108). In the same document, it has an uncoated tablet, a film coating layer covering the surface of the uncoated tablet, and a sugar-coating layer covering the surface of the film coating layer, and the uncoated tablet is acetaminophen, chlorpheniramine maleate or d-chlorpheniramine maleate, dextromethorphan hydrobromide hydrate or dextromethorphan phenolphthalate, dl-methylephedrine hydrochloride or dl-methylephedrine saccharin salt, potassium guaiacolsulfonate and anhydrous caffeine A dragee containing ine or caffeine hydrate and a film coating layer containing hypromellose is described (Claim 1). In addition, in the same document, in the production of sugar-coated tablets, acetaminophen, potassium guaiacolsulfonate, etc. are fluidized bed granulated to obtain granules, and then dextromethorphan hydrobromide is added to the obtained granules. It is described that a drug-containing powder was obtained by adding components such as salt hydrate (Example 1).

Japanese Patent Application Laid-Open No. 2020-105108

As a result of investigations by the present inventors, it has been found that when an attempt is made to produce a solid composition containing dextromethorphan such as dextromethorphan hydrobromide hydrate or a salt thereof and acetaminophen, the content of dextromethorphan increases. There is a concern that it will decrease, and there is room for improvement in terms of the stability of dextromethorphan in the composition.
In addition, as for Patent Document 1, as a result of studies by the present inventors, dextromethorphan hydrobromide hydrate and acetaminophen are separated to produce uncoated tablets. Since granules containing aminophen are obtained and then mixed with dextromethorphan hydrobromide hydrate, there is room for improvement in terms of uniformity of distribution of the active ingredient in tablets.

Accordingly, the present invention provides a technique for obtaining a composition having excellent stability of dextromethorphan or a salt thereof and excellent uniformity of active ingredient distribution.

According to the present invention, the following method for producing a solid pharmaceutical composition is provided.
[1] a first mixing step of producing a first mixture containing dextromethorphan or its salt powder or its granules and acetaminophen powder;
a fluid bed granulation step of spraying purified water or a liquid containing a binder to the first mixture to produce granules;
a second mixing step of adding a lubricant to the granules obtained in the fluidized bed granulation step to produce a second mixture;
A method for producing a pharmaceutical solid composition, comprising:
[2] a first mixing step of producing a first mixture containing dextromethorphan or its salt powder or its granules, acetaminophen powder, and an antioxidant;
a wet granulation step of spraying or dropping purified water or a liquid containing a binder to the first mixture to produce granules;
a second mixing step of adding a lubricant to the granules obtained in the wet granulation step to produce a second mixture;
A method for producing a pharmaceutical solid composition, comprising:
[3] The method for producing a pharmaceutical solid composition according to [2], wherein the antioxidant is ascorbic acid.
[4] the dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate;
The content of the antioxidant with respect to the total amount of the dextromethorphan hydrobromide hydrate and the acetaminophen in the first mixture is 0.002 or more and 0.35 or less by mass. A method for producing a pharmaceutical solid composition according to [2] or [3].
[5] The method for producing a solid pharmaceutical composition according to any one of [1] to [4], wherein the dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate.
[6] The method for producing a pharmaceutical solid composition according to any one of [1] to [5], wherein the first mixing step is a step of producing the first mixture further containing an excipient. .
[7] The method for producing a pharmaceutical solid composition according to [6], wherein the excipient contains crystalline cellulose.
[8] the dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate;
any one of [1] to [7], wherein the mass ratio of the acetaminophen to the dextromethorphan hydrobromide hydrate in the first mixture is 1 or more and 188 or less; A method for producing the described solid pharmaceutical composition.
[9] The pharmaceutical solid composition according to any one of [1] to [8], wherein the granules obtained in the step of producing the granules have an average particle size of 75 μm or more and 850 μm or less. Production method.
[10] The pharmaceutical composition according to any one of [1] to [9], wherein the solid pharmaceutical composition is a solid pharmaceutical preparation, and the dosage form of the solid pharmaceutical preparation is a sugar-coated tablet or a film-coated tablet. A method for producing a solid composition.
[11] any one of [1] to [9], wherein the solid pharmaceutical composition is a solid pharmaceutical preparation, and the dosage form of the solid pharmaceutical preparation is granules, fine granules or capsules; A method for producing the described solid pharmaceutical composition.

ADVANTAGE OF THE INVENTION According to this invention, the composition which is excellent in the stability of dextromethorphan or its salt, and is excellent in the uniformity of distribution of an active ingredient can be obtained.

Embodiments of the present invention will be described below. In this embodiment, the composition can contain each component alone or in combination of two or more.
In the present specification, "-" indicating a numerical range represents above and below, and includes both numerical values at both ends.

(First embodiment)
In this embodiment, the method for producing a solid pharmaceutical composition includes the following steps.
(First mixing step) step of producing a first mixture containing dextromethorphan or its salt powder or its granules and acetaminophen powder (granulation step) fluid bed granulation step There is a step of spraying purified water or a liquid containing a binder to the first mixture to produce granules (second mixing step), adding a lubricant to the granules obtained in the granulation step In addition, the step of generating the second mixture Each step will be specifically described below.

(First mixing step)
A first mixture is obtained in the first mixing step.
In the first mixing step, dextromethorphan or a salt thereof is blended into the first mixture as powder or granules thereof. On the other hand, acetaminophen is blended into the first mixture as a powder.

Here, the dextromethorphan or its salt and the acetaminophen powder described later are powders that are not granules of these bulk powders. It may be divided, pulverized, or pulverized.
The average particle size of the powder is specifically less than 300 μm, preferably less than 150 μm, and may be, for example, 1 μm or more.
Here, the average particle diameter of the powder specifically means the volume average diameter which is the arithmetic mean value in the volume-based particle size distribution determined by the laser diffraction/scattering method. For example, it can be evaluated by dry measurement using a particle size distribution analyzer MT3300EXII (manufactured by Microtrac Bell).

On the other hand, granules of dextromethorphan or a salt thereof and acetaminophen, which will be described later, are granules obtained by granulating these bulk powders together with other ingredients as appropriate. Further, the granules may be obtained by granulating the raw powder and then subjecting the granules to sizing, crushing, or pulverization.
Specifically, the average particle size of the granules is 75 μm or more, preferably 100 μm or more, and may be, for example, 850 μm or less.
Here, the average particle diameter of the granules specifically means the mass average diameter which is the arithmetic mean value in the mass-based particle size distribution determined by the sieving method. For example, a robot shifter RPS-105M (manufactured by Seishin Enterprise Co., Ltd.) can be used for evaluation.

Specific examples of dextromethorphan or salts thereof include dextromethorphan; and salts of dextromethorphan such as dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, and hydrates thereof. . These are known compounds and can be produced by known methods, or commercially available ones can be used.
Dextromethorphan or its salt is preferably dextromethorphan hydrobromide hydrate.

The amount of dextromethorphan or a salt thereof to be added to the first mixture and the solid pharmaceutical composition obtained in the present embodiment is not limited, and should be appropriately examined according to the sex, age, symptoms, etc. of the recipient. You just have to decide. For example, when the dextromethorphan or its salt is dextromethorphan hydrobromide hydrate, the daily dose is usually 8-120 mg, preferably 16-48 mg. When the dextromethorphan or its salt is dextromethorphan phenolphthalin salt, the daily dose is usually 9-90 mg, preferably 24-72 mg.

Acetaminophen (also known as paracetamol) is listed in the Japanese Pharmacopoeia 18th Edition. Acetaminophen is a known compound, can be produced by a known method, or can be commercially available.

The amount of acetaminophen to be added to the first mixture and the solid pharmaceutical composition obtained in the present embodiment is not limited, and can be determined by considering the gender, age, symptoms, etc. of the user as appropriate. good. For example, the daily dose of acetaminophen is usually 150-1500 mg, preferably 300-900 mg.

The mass ratio of acetaminophen to dextromethorphan hydrobromide hydrate in the first mixture is, for example, 1 or more, preferably 2 or more, and more preferably 6 or more.
In addition, from the viewpoint of improving the stability of dextromethorphan hydrobromide hydrate, the blending ratio is preferably 188 or less, more preferably 100 or less, and still more preferably 60 or less in mass ratio.

Alternatively, the first mixing step may be a step of producing a first mixture further comprising an excipient. Thereby, the fluidity in the granulation process can be further improved, and granulation can be made more preferable when obtaining a solid pharmaceutical composition in the form of granules.

Excipients include, for example, candy powder, pregelatinized starch, isomalt, cacao butter, dried hydrolyzed starch, caramel, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry water Aluminum oxide gel, dried potato starch, licorice powder, agar, agar powder, cold plum powder, xylitol, croscarmellose sodium, crospovidone, magnesium aluminate silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, silicic acid Calcium, magnesium silicate, cinnamon powder, crystalline cellulose, crystalline cellulose/carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (grains), synthetic aluminum silicate, synthetic aluminum silicate/hydroxypropyl starch/crystalline cellulose, synthetic hydro Talcite, wheat starch, rice flour, rice starch, β-cyclodextrin, heavy silicic anhydride, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide/sodium hydrogen carbonate coprecipitate, aluminum hydroxide/magnesium carbonate/ Calcium carbonate coprecipitate, magnesium hydroxide, D-sorbitol, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, 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 (200731), 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 to 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, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol/diethylene glycol mixture, maltitol, maltose hydrate, D-mannitol, D - Mannitol/crospovidone/D-sorbitol/hydrous silicon dioxide mixture, anhydrous silicic acid hydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, methacrylic acid copolymer LD, magnesium aluminometasilicate , methyl acrylate/methacrylic acid copolymer, methyl acrylate/methyl methacrylate, methyl cellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, dihydrogen phosphate One or two or more ingredients selected from the group consisting of calcium hydrate, sodium dihydrogen phosphate and erythritol can be blended.

The excipient preferably contains crystalline cellulose from the viewpoint of improving moldability and strength of the formulation.
From the viewpoint of improving fluidity in the granulation process, the amount of crystalline cellulose to be added to the first mixture is the total composition of the pharmaceutical solid composition (in the case of film-coated tablets and sugar-coated tablets, the total composition of the uncoated tablet). is preferably 0.5% by mass or more, more preferably 0.7% by mass or more, and still more preferably 1% by mass or more.
In addition, from the viewpoint of improving the ingestibility of the formulation and making the size of the formulation more preferable, the amount of crystalline cellulose in the first mixture is adjusted to the total composition of the pharmaceutical solid composition (film-coated tablets and sugar-coated tablets In the case of , it is preferably 90% by mass or less, more preferably 50% by mass or less, still more preferably 40% by mass or less, and even more preferably 30% by mass or less, based on the total composition of the uncoated tablet portion).

Alternatively, the first mixing step may be a step of producing a first mixture further comprising a disintegrant. Thereby, when obtaining a pharmaceutical solid composition such as a tablet or a granule, it is possible to improve their disintegration properties.
Examples of disintegrants include pregelatinized starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, corn. One or two or more ingredients selected from the group consisting of starch, potato starch, hydroxypropyl starch, the above-mentioned crystalline cellulose and partially pregelatinized starch can be blended.

(Granulation process)
In the present embodiment, the granulation step is a fluidized bed granulation step, in which the first mixture is sprayed with purified water or a liquid containing a binder to produce granules.
Fluidized bed granulation can be performed, for example, by a fluidized bed granulator dryer, a tumbling fluidized bed granulator, a swirling fluidized bed granulator, or the like.

The average particle size of the granules obtained in the granulation step is preferably 75 µm or more, more preferably 90 µm or more, and still more preferably 100 µm or more, from the viewpoint of improving the fluidity of the granules.
Moreover, from the viewpoint of improving the uniformity of the effective component, the average particle size of the granules obtained in the granulation step is preferably 850 µm or less, more preferably 500 µm or less, and even more preferably 400 µm or less.

Further, in the granulation step, the first mixture is sprayed with purified water or a liquid containing a binder (binding liquid). These are specifically atomized in the granulator.
The binding liquid specifically includes a binding agent and purified water. On the other hand, when granulating by spraying purified water, a binder can be added, for example, in the first mixing step.
Binders include, for example, gum arabic, gum arabic powder, agar, agar powder, kanbai powder, crystalline cellulose, copolyvidone, gelatin, shellac, low-substituted hydroxypropylcellulose, corn starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl Starch, hydroxypropylcellulose, vinylpyrrolidone/vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose Phthalates (220824), fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl cellulose 2910 mixture, pullulan, povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (fully saponified), polyvinyl Alcohol (partially saponified product), 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 methyl cellulose One or two or more ingredients selected from the group can be blended.

In the present embodiment, the granules obtained in the granulation step may be subjected to the second mixing step as they are, or after the granulation step, the granules may be subjected to drying, sizing, and other steps as appropriate. , may be subjected to the second mixing step.

(Second mixing step)
In the second mixing step, a lubricant is added to the granules obtained in the granulation step, that is, the fluidized bed granulation step to produce a second mixture.
Examples of lubricants include hydrous silicon dioxide, hydrous amorphous silicon oxide, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, heavy anhydrous silicic acid, sucrose fatty acid ester, stearyl alcohol, and stearic acid. , zinc stearate, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, hydrogenated soybean oil, talc, sodium stearyl fumarate, beeswax, anhydrous silicate hydrate, magnesium aluminometasilicate and monostearic acid. One or two or more ingredients selected from the group consisting of glycerin can be blended.

Magnesium stearate is preferable as the lubricant from the viewpoint of reducing metal adhesion in the process of compressing tablets and filling granules.
The amount of magnesium stearate is, for example, the total composition of the pharmaceutical solid composition obtained by the production method of the present embodiment (in the case of film-coated tablets and sugar-coated tablets, the total composition of the uncoated tablet portion). From the viewpoint of reduction, it is preferably 0.5% by mass or more, more preferably 0.8% by mass or more.
In addition, from the viewpoint of improving the disintegration and dissolution properties of tablets and granules, for example, the amount of magnesium stearate to be blended is, for example, the total composition of the solid pharmaceutical composition obtained by the production method of the present embodiment (film-coated tablets In the case of sugar-coated tablets, the content is preferably 5% by mass or less, more preferably 3% by mass or less, based on the total composition of the uncoated tablet portion.

In this embodiment, the second mixture obtained in the second mixing step may be used as it is as a solid pharmaceutical composition, or depending on the form of the solid pharmaceutical composition, etc., after the second mixing step, A step of molding or filling may be further included. For example, the production method in the present embodiment may further include a step of tableting the second mixture obtained in the second mixing step to obtain uncoated tablets.
In addition, the pharmaceutical solid composition can be prepared according to the dosage form according to the method described in the Japanese Pharmacopoeia 18th Edition, etc., and can be made into a formulation.
For example, when the dosage form of the solid pharmaceutical composition is a tablet, it can be produced according to the Japanese Pharmacopoeia General Rules for Preparations, Section "Tablet". In addition, when the dosage form of the solid pharmaceutical composition is granules, it can be produced according to the Japanese Pharmacopoeia General Rules for Preparations, “Granules”.
In addition, from the viewpoint of avoiding contraindications for ingredients and additives mixed in the solid pharmaceutical composition, and from the viewpoint of further improving the storage stability of the composition, the prescribed may be formulated so that the components of are not in contact with each other.

As described above, the pharmaceutical solid composition of the present embodiment can be obtained.
In the present embodiment, in the first mixing step, a first mixture containing dextromethorphan or its salt powder or its granules and acetaminophen powder is produced and granulated by fluidized bed granulation. By producing granules, it is possible to produce a solid pharmaceutical composition in which dextromethorphan or a salt thereof is excellent in stability and in which the active ingredient is uniformly distributed.
The reason why the production method of the present embodiment can provide excellent stability of dextromethorphan or a salt thereof is that the production method of the present embodiment suitably suppresses oxidation of dextromethorphan or a salt thereof. can be considered.

The solid pharmaceutical composition obtained in this embodiment is specifically a solid pharmaceutical preparation.
The dosage forms of solid pharmaceutical preparations are not limited, and examples include capsules, pills, granules, fine granules, powders, and tablets. These solid preparations may be coated with sugar coating, film coating, or the like by a known method, if necessary. From the viewpoint of further improving the stability of dextromethorphan or a salt thereof, the dosage form of the solid preparation is preferably sugar-coated tablets, film-coated tablets, granules, fine granules or capsules, more preferably sugar-coated tablets or granules. is.
Also, the solid formulation is preferably an orally administered formulation.

The packaging form of the solid pharmaceutical composition, specifically the solid preparation, can be suitably bottle packaging, SP (Strip Package) packaging, stick packaging, PTP (Press Through Package), pouch packaging, or the like. They may be once packaged and airtightly preserved. Furthermore, they may be pillow-wrapped. Alternatively, they may be stored in a box or the like. The material used for SP packaging, stick packaging, PTP packaging, and pillow packaging is not limited. A resin film, a multi-layer film obtained by combining these resin films, or a film obtained by attaching an aluminum foil to these resin films can be used. A multilayer film may be, for example, a laminate film. Furthermore, it can be enclosed together with a desiccant, an oxygen absorber, and a deodorant, if necessary.

In addition, the pharmaceutical solid composition obtained in this embodiment can be suitably used, for example, as a general cold medicine. For example, by adding various ingredients, patients who have cold symptoms, especially fever, chills, headache, sore throat, runny nose, stuffy nose, cough, phlegm, joint pain, muscle pain, sneezing, etc. can be administered to alleviate these symptoms.

In addition, in the production method of the present embodiment, in each step, components other than the components described above may be further blended within a range that does not impair the effects of the present invention. For example, the solid pharmaceutical composition obtained by the production method of the present embodiment may optionally contain other ingredients that are commonly used in common cold remedies. In addition, the pharmaceutical solid composition may contain, for example, components described in the Standards for Approval for Manufacturing and Marketing of OTC Drugs. Specific examples of such ingredients include antipyretic analgesics other than acetaminophen, antihistamines, antitussives other than dextromethorphan or its salts, noscapines, bronchodilators, expectorants, anticholinergics, anti-inflammatory agents, and caffeine. , vitamins, gastric mucosa protective agents, herbal medicines, hypnotics and sedatives, and Chinese herbal formulations.

Examples of antipyretic analgesics other than acetaminophen include aspirin, aspirin aluminum, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesil , acemethacin, etodolac, naproxen, meloxicam and celecoxib, and tiaramide hydrochloride.

Examples of antihistamines include isothipendyl hydrochloride, diferol hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, chlorpheniramine maleate, d-chlorpheniramine maleate, diphenyl Carbinoxamine disulfonate, diphenylpyraline hydrochloride, diphenylpyraline teocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, maleic acid Carbinoxamine, diferol phosphate, clemastine fumarate, mequitazine, ketotifen fumarate, promethazine hydrochloride, epinastine hydrochloride, emedastine fumarate, fexofenadine, azelastine hydrochloride, cetirizine hydrochloride and olopatadine hydrochloride One or two or more ingredients selected from the group can be blended.

Antitussives other than dextromethorphan or salts thereof include, for example, aloclamid hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dibunate sodium, tipepidine citrate, tipepidine Blending one or two or more ingredients selected from the group consisting of hibenzate, dimemorphan phosphate, eprazinone hydrochloride, pentoxyverine citrate, benproperine phosphate and clofedanol hydrochloride can be done.

As noscapines, for example, one or two or more ingredients selected from the group consisting of noscapine and noscapine hydrochloride hydrate can be blended.

Bronchodilators include, for example, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, aminophylline, diprophylline, theophylline, proxyphylline, dl-methylephedrine, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, trimetoquinol One or two or more components selected from the group consisting of hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and isoprenaline hydrochloride can be blended.

Expectorants include, for example, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, l-carbocysteine, l-ethylcysteine hydrochloride, l-methylcysteine hydrochloride, ambroxol hydrochloride, ammonium chloride , l-menthol, ammonia/fennel essence, cherry bark extract, methylcysteine hydrochloride and fudosteine.

As anticholinergic agents, for example, one or two or more ingredients selected from the group consisting of belladonna total alkaloids, Rohto extract, Datura extract and isopropamide iodide can be blended.

As the anti-inflammatory agent, for example, one or more ingredients selected from the group consisting of glycyrrhizic acid and its salts, tranexamic acid, serrapeptase, bromelain, semi-alkaline proteinase, pronase, seaprose, proctase and lysozyme hydrochloride are blended. be able to.

As caffeine, for example, one or two or more ingredients selected from the group consisting of sodium caffeine benzoate, caffeine hydrate and anhydrous caffeine can be blended.

Vitamins include, for example, thiamine, thiamine chloride hydrochloride, thiamine nitrate, disetiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, sicothiamine, thiamine disulfide, bis-butiamine, bis vitamin B1 and its derivatives and their salts such as bentiamine, prosultiamine and benfotiamine; vitamin B2 and its derivatives and their salts such as riboflavin, riboflavin phosphate, riboflavin butyrate and riboflavin sodium phosphate; pantothene vitamin B5 and its derivatives and their salts such as acid, panthenol, pantethine, calcium pantothenate and sodium pantothenate; vitamin B6 and its derivatives and their salts such as pyridoxine hydrochloride and pyridoxal phosphate; cyanocobalamin and mecobalamin and the like vitamin B12 and its derivatives and their salts; vitamin C and its derivatives and their salts such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and their salts One or more ingredients can be blended.

Gastric mucosa protective agents include, for example, glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum arnoacetate (aluminum glycinate), aluminum hydroxide gel, dry aluminum hydroxide gel, water Aluminum oxide/sodium bicarbonate coprecipitate, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide/aluminum potassium sulfate coprecipitate, carbonate One or more ingredients selected from the group consisting of magnesium, magnesium aluminometasilicate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, teprenone and rebamipide can be blended.

Examples of herbal medicines include Ephedra, Nantenjitsu, Peppermint, Onji, Glycyrrhiza, Bellflower, Shazenshii, Shazensou, Seksan (Stone garlic), Senega, Fritillaria, Fennel, Phellodendron bark, Japanese coptis, Cedar, Chamomile, Cinnamon, Gentian, Chinese gourd, animal Bile (including gall), shoji, ginger, sojutsu, clove, chimpi, bayakujutsu, jiryu, chiksettsu carrot, carrot, red-clawed wrinkle, asenyak, inyoukaku, corydalis, scutellaria root, Chinese walnut, valerian, caronin, kyounin, wolfberry, kukoyo . One or two or more ingredients selected from the group consisting of herbal medicines such as hampi, juniper, bukuryo, bowie, botanpi, borey, and rokujo and their extracts (extracts, tinctures, dried extracts, etc.) can be blended.

As a hypnotic sedative, for example, one or two or more ingredients selected from the group consisting of bromvalerylurea and allylisopropylacetylurea can be blended.

Kampo prescriptions include, for example, Kakkonto, Kakkonto Kakikyo, Keishito, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekobokuto, Maoto, and these. extracts (extracts, tinctures, dry extracts, etc.) can be blended.

Furthermore, the pharmaceutical solid composition obtained by the production method of the present embodiment can be blended with pharmaceutical additives necessary for producing the formulation within a range that does not impair the effects of the present invention. For example, as a pharmaceutical additive, PFSB/ELD Notification No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), Pharmaceutical Additives Dictionary 2021 (edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo) and the 8th Edition Food Additives Official Code (Japanese Food Additives Additives Association), etc. can be blended. Specifically, disintegrants, disintegration aids, flow agents, lubricants, plasticizers, coating agents, sugar coating agents, glossing agents, coloring agents, flavoring agents, sweetening agents, flavors, and flavoring agents One or two or more ingredients selected from the group consisting of fragrances can be blended into the solid pharmaceutical composition.
Moreover, when the excipient is not blended in the first mixing step, the excipient may be further blended in another step. Specific examples of excipients include those described above.
Moreover, when a binder is not used in the granulation step, a binder may be added in another step. Specific examples of binders include those described above.
Disintegrants also include, for example, the components described above.

Examples of disintegrating aids include one or more 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. can be blended.

Fluidizing agents include, for example, hydrous silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminate hydroxide, tribasic calcium phosphate, talc, corn starch, and alumina metasilicate. One or two or more components selected from the group consisting of magnesium and calcium hydrogen phosphate granules can be blended.

Lubricants include, for example, the components described above.

Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid ester, medium-chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, Contains one or more ingredients selected from the group consisting of Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, glyceryl monostearate, isopropyl linoleate and liquid paraffin. can do.

Coating agents include, for example, ethyl acrylate/methyl methacrylate copolymer dispersion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer E, gum arabic, gum arabic powder, ammonioalkyl methacrylate copolymer, ethyl cellulose, ethyl cellulose aqueous dispersion, octyl Decyl 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 03K280000, 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 Dry White YS-1-18177-A, Opadry White (YS-1-18202-A), Opadry II White (33G28523), Opadry II White (85F28751), Opadry II White (OY-LS-28914), Opadry II Light Blue (85G20426), Opadry II Light Beige 85F17498, Opadry II Red (32K15441), Carnauba Wax, Carmellose Calcium, Carmellose Sodium, Hydrous Silicon Dioxide, Dry Aluminum Hydroxide Gel, Dry Methacrylic Acid Copolymer LD, Triethyl Citrate, Glycerin , glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydroxypropyl cellulose containing light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, magnesium oxide, dimethylaminoethyl methacrylate/methyl meta Acrylates copolymer, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, refined gelatin, refined shellac, refined sucrose, gelatin, shellac, D- Sorbitol, D-sorbitol liquid, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, concentrated glycerin, white shellac, sucrose, paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, titanium oxide, macrogol Mixture, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (type 200731), hypromellose phthalate (type 220824), fumarate stearin Acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 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 product), macrogol 300, macrogol 400, macrogol 600 , Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000EP, Macrogol 20000, Macrogol 35000, D-mannitol, Anhydrous citric acid, Anhydrous silicic acid hydrate, Phthalic anhydride, Phosphorus anhydride Calcium hydrogen oxide, 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, monostearic acid One or two or more ingredients selected from the group consisting of sorbitan, sorbitan monolaurate, calcium sulfate, fumaric acid, DL-malic acid, erythritol and crystalline cellulose can be blended.

Sugar coating agents include, for example, gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, crystalline cellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined sucrose, gelatin, shellac, and talc. , precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose (2208), hypromellose (2910), pullulan, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene (105) polyoxypropylene (5) Blending one or more components selected from the group consisting of glycol, polyvinyl alcohol (partially saponified product), macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol, erythritol and crystalline cellulose. can be done.

As the brightening agent, for example, one or two or more components selected from the group consisting of carnauba wax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000 and beeswax can be blended.

Coloring agents include, for example, yellow iron oxide, yellow No. 5 premix, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium oxide, iron sesquioxide, iron sesquioxide/glycerol suspension Turbidity, 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, Sodium Copper Chlorophyllin , copper chlorophyll, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder and rose oil.

Flavoring agents include, for example, erythritol, sodium chloride, Phellodendron bark powder, Peppermint extract, coptis, Coptis powder, dried ononis root extract, orange, orange oil, cacao powder, fructose, caramel, licorice, licorice extract, licorice crude extract, licorice powder , xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, glycyrrhizic acid, trisodium glycyrrhizinate, diammonium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, L-glutamic acid, L-glutamic acid L-arginine, L-glutamic acid hydrochloride, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon tincture, cinnamon powder, cinnamon oil, kelp powder, saccharin, sodium saccharin hydrate, saffron, saffron tincture, Japanese pepper tincture, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, ginger tincture, ginger powder, sucralose, stevia extract, purified stevia extract, refined licorice extract powder, refined sucrose, assembly, soy sauce powder, D- Sorbitol, turmeric powder, taurine, taraxa root/grass dried extract, tannic acid, clove tincture, clove oil, chimp tincture, red pepper, red pepper tincture, red pepper powder, spruce tincture, spruce powder, trehalose hydrate, bittersweet powder, plum extract, White sugar, fructo-oligosaccharide, powdered sugar, peppermint powder, maltose hydrate, D-mannitol, dl-menthol, l-menthol, menthol powder, ryuno, ryuno powder, green tea powder, DL-malic acid, DL-sodium malate, One or two or more ingredients selected from the group consisting of lemon oil and rose oil can be blended.

Sweeteners include, for example, aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose starch syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monoglycyrrhizinate Selected from the group consisting of potassium, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, refined sucrose spherical granules, sucrose, powdered reduced maltose starch syrup, maltitol, D-mannitol and erythritol One or more ingredients can be blended.

Flavors include, for example, orange flavor, orange flavor powder SH-1171-A, orange micron H-800092, guarana extract, flavor (sweet orange), flavor (strawberry), flavor (lemon), brown sugar flavor, strawberry essence, strawberry Flavor B86173, cherry flavor 181612, dent mint 1148J, banana powder flavor, peach essence, cypress 6E-84211, black current flavor 290012SYM, fruit essence, peppermint NAEFCOPO551957685, peppermint micron H-81550, mix flavor powder, melon powder flavor, l- One or two or more components selected from the group consisting of menthol and menthol L163592SYM can be blended.

Flavoring agents and fragrances include, for example, 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, vita base, cedar oil, fruit flavor, flavor G1 , hesperidin peppermint extract, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryuno, ryuno powder, lemon powder, lemon One or two or more ingredients selected from the group consisting of oil, rose water, rose oil, funnel oil and Roman chamomile oil can be blended.

Hereinafter, an embodiment of a method for producing a solid pharmaceutical composition will be described, focusing on points different from the first embodiment. Also, in the following embodiments, the configuration described above in the first embodiment can be appropriately used.

(Second embodiment)
In this embodiment, the method for producing a solid pharmaceutical composition includes the following steps.
(First mixing step) A step of producing a first mixture containing dextromethorphan or its salt powder or its granules, acetaminophen powder, and an antioxidant (granulation step) wet A granulation step in which purified water or a liquid containing a binder is sprayed or dropped onto the first mixture to produce granules (second mixing step) granules obtained in the granulation step Step of adding a lubricant to the product to produce a second mixture The production method in the present embodiment is characterized in that in the first mixing step, a first mixture further containing an antioxidant is obtained, and a granulation step is a wet granulation step, which is different from the production method described above in the first embodiment. Except for these points, each step can be performed according to the first embodiment.

Specific examples of antioxidants to be blended in the first mixture in the first mixing step include ascorbic acid, calcium ascorbate, ascorbic acid such as ascorbic acid stearate or salts thereof, ascorbic acid derivatives and salts thereof; Tocopherols, tocopherols such as natural vitamin E, tocopherol (dl-α-tocopherol), β-tocopherol, γ-tocopherol, σ-tocopherol, tocopherol acetate, tocopherol nicotinate, tocopherol succinate calcium, concentrated mixed tocopherols Derivatives and their salts; sodium edetate, erythorbic acid, cysteine hydrochloride, dry sodium sulfite, citric acid, potassium dichloroisocyanurate, dibutylhydroxytoluene, soybean lecithin, sodium thioglycolate, sodium thiomalate, ascorbic acid palmitate. , butyl hydroxyanisole, 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 hydrogensulfite, alpha thioglycerin and β-carotene.

From the viewpoint of further improving the stability of dextromethorphan or a salt thereof, the antioxidant is preferably ascorbic acid.

Also in this embodiment, the dextromethorphan or salt thereof is preferably dextromethorphan hydrobromide hydrate, and the combination of dextromethorphan hydrobromide hydrate and acetaminophen in the first mixture The content of the antioxidant with respect to the total amount is preferably 0.002 or more, more preferably 0.003 or more, and still more preferably 0.004 or more in terms of mass ratio from the viewpoint of obtaining antioxidant action more stably. is.
In addition, the content of the antioxidant with respect to the total amount of dextromethorphan hydrobromide hydrate and acetaminophen in the first mixture is, for example, 0.35 or less, preferably 0.25 or less, more It is preferably 0.2 or less.

In addition, the wet granulation in the granulation step may be, for example, a method used in the production of pharmaceutical compositions, and may be the fluidized bed granulation described above in the first embodiment, or high-speed stirring granulation. , extrusion granulation, rolling granulation, or other wet granulation.

In the present embodiment, the antioxidant is further blended into the first mixture in the first mixing step, and the granulation step is a wet granulation step, so that dextromethorphan or a salt thereof is excellent in stability. , it is possible to produce a pharmaceutical solid composition with excellent uniformity of distribution of the active ingredient.

Although the embodiments of the present invention have been described above, these are examples of the present invention, and various configurations other than those described above can also be adopted.

EXAMPLES The present embodiment will be specifically described below with reference to examples and comparative examples, but the present embodiment is not limited to these examples.

(Examples 1 and 2 and Comparative Example 1)
Each component was blended according to the composition shown in Table 1, and a tablet of each example was produced by the following procedure. "DXM" in Table 1 is dextromethorphan hydrobromide hydrate.

(Example 1) Fluid bed granulation According to the ratio shown in Table 1, acetaminophen (manufactured by Yamamoto Chemical Industry Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), crystalline cellulose (Seolus PH-101) : Asahi Kasei Co., Ltd.) and carmellose (NS-300: Gotoku Yakuhin Kogyo Co., Ltd.) are mixed in a fluidized bed granulator dryer (FD-MP-01: Powrex Co., Ltd.), and 5% by mass of hydroxy is added as a binding liquid. After spraying an aqueous solution of propyl cellulose (HPC-L: manufactured by Nippon Soda Co., Ltd.) until the amount of hydroxypropyl cellulose in the granule reaches the value shown in Table 1, granulate by drying until the product temperature reaches 65 ° C. got stuff
Magnesium stearate (manufactured by Taihei Kagaku Co., Ltd.) weighed according to the ratio shown in Table 1 was mixed with the granules in a plastic bag, and then tableted with a tableting machine (VIRGO: manufactured by Kikusui Seisakusho) to obtain uncoated tablets. Obtained.

(Example 2) Stirring granulation according to the ratio shown in Table 1 Acetaminophen (manufactured by Yamamoto Chemical Industry Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), crystalline cellulose (Seolus PH-101: Asahi Kasei Co., Ltd.), carmellose (NS-300: Gotoku Yakuhin Kogyo Co., Ltd.) and ascorbic acid (DSM Co., Ltd.) are mixed with a high-speed stirring granulator (VG-05: Powrex Co., Ltd.) (first mixing step). After that, a 10% by weight hydroxypropylcellulose (HPC-L: manufactured by Nippon Soda Co., Ltd.) aqueous solution as a binding liquid was added dropwise so that the amount of hydroxypropylcellulose in the granules was the value shown in Table 1, and kneaded. After that, the product is dried with a fluid bed granulator dryer (FD-MP-01: manufactured by Powrex Corporation) until the product temperature reaches 65 ° C., and the granules are obtained by sizing with a round sieve of 850 μm. rice field.
Magnesium stearate (manufactured by Taihei Kagaku Co., Ltd.) weighed according to the ratio shown in Table 1 was mixed with the granules in a plastic bag, and then tableted with a tableting machine (VIRGO: manufactured by Kikusui Seisakusho) to obtain uncoated tablets. Obtained.

(Comparative example 1)
Tablets were obtained in the same manner as in Example 2, except that ascorbic acid was not added in the first mixing step.

(evaluation)
In order to evaluate the storage stability of dextromethorphan hydrobromide hydrate (DXM), the residual rate of dextromethorphan hydrobromide hydrate in the tablets obtained in each example was measured by the following procedure. bottom. Table 2 shows the results.
The tablets of Examples 1 and 2 and the tablets of Comparative Example 1 were filled in a glass bottle (6K standard bottle) and stored in an open state at 60°C for 2.5 months.
Dextromethorphan hydrobromide hydrate in each tablet before and after storage was quantified three times for each sample, and the ratio of the average content after storage to the average content before storage was calculated, It was defined as the residual rate of dextromethorphan hydrobromide hydrate in the tablet.
Quantification is performed by adding 5 mL of diluted phosphoric acid (1 → 50), an appropriate amount of methanol, and 2 mL of sodium hydroxide test solution to about 110 mg of the pulverized specimen to make 100 mL, extracting dextromethorphan, and centrifuging. Using the supernatant separated from the insolubles as a sample solution, liquid Using a column packed with octadecylsilylated silica gel for chromatography, measurement was performed at a measurement wavelength of 280 nm.

As shown in Table 2, in each example, compared to Comparative Example 1, the residual ratio of dextromethorphan hydrobromide hydrate was high and the storage stability was excellent. In addition, the manufacturing method described in each example can provide excellent uniformity of distribution of the active ingredients, dextromethorphan hydrobromide hydrate and acetaminophen, in the uncoated tablet.

(Formulation Examples 1-63)
Examples of solid formulations are shown in Tables 3-11.

Claims (11)

a first mixing step of producing a first mixture containing dextromethorphan or its salt powder or granules thereof and acetaminophen powder;
a fluid bed granulation step of spraying purified water or a liquid containing a binder to the first mixture to produce granules;
a second mixing step of adding a lubricant to the granules obtained in the fluidized bed granulation step to produce a second mixture;
A method for producing a pharmaceutical solid composition, comprising: a first mixing step of producing a first mixture comprising dextromethorphan or its salt powder or granules thereof, acetaminophen powder, and an antioxidant;
a wet granulation step of spraying or dropping purified water or a liquid containing a binder to the first mixture to produce granules;
a second mixing step of adding a lubricant to the granules obtained in the wet granulation step to produce a second mixture;
A method for producing a pharmaceutical solid composition, comprising: 3. The method for producing a pharmaceutical solid composition according to claim 2, wherein the antioxidant is ascorbic acid. the dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate,
The content of the antioxidant with respect to the total amount of the dextromethorphan hydrobromide hydrate and the acetaminophen in the first mixture is 0.002 or more and 0.35 or less by mass. A method for producing the solid pharmaceutical composition according to claim 2 or 3. 3. The method for producing a solid pharmaceutical composition according to claim 1, wherein said dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate. 3. The method for producing a solid pharmaceutical composition according to claim 1 or 2, wherein said first mixing step is a step of producing said first mixture further comprising an excipient. 7. The method for producing a pharmaceutical solid composition according to claim 6, wherein said excipient comprises crystalline cellulose. the dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate,
3. The pharmaceutical solid composition according to claim 1, wherein the mass ratio of said acetaminophen to said dextromethorphan hydrobromide hydrate in said first mixture is 1 or more and 188 or less. A method of making things. 3. The method for producing a pharmaceutical solid composition according to claim 1, wherein the granules obtained in the step of producing the granules have an average particle size of 75 [mu]m or more and 850 [mu]m or less. 3. The method for producing a solid pharmaceutical composition according to claim 1, wherein said solid pharmaceutical composition is a solid pharmaceutical preparation, and the dosage form of said solid pharmaceutical preparation is a sugar-coated tablet or a film-coated tablet. The production of the solid pharmaceutical composition according to claim 1 or 2, wherein the solid pharmaceutical composition is a solid pharmaceutical preparation, and the dosage form of the solid pharmaceutical preparation is granules, fine granules or capsules. Method.