JP2023103978A - Pharmaceutical solid composition - Google Patents

Abstract

To provide a technique to stably blend a composition with belladonna total alkaloids, dextromethorphan hydrobromide hydrate and ambroxol hydrochloride.SOLUTION: A pharmaceutical solid composition contains component (A): belladonna total alkaloids, component (B): dextromethorphan hydrobromide hydrate, component (C): ambroxol hydrochloride, and component (D): at least one of tranexamic acid and crystalline cellulose.SELECTED DRAWING: None

Description

The present invention relates to solid pharmaceutical compositions.

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. 2020-158487). The same document describes the group consisting of ibuprofen, loratadine, carbocisteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts. A solid composition containing at least one selected from the above is described (claim 1). In addition, the document describes a formulation preparation example in which dextromethorphan hydrobromide hydrate and ambroxol hydrochloride are blended (formulation example 2).

JP 2020-158487 A

Here, Belladonna Total Alkaloids (BTA) has an anticholinergic effect that suppresses nasal discharge and is used as one of the components of general cold medicines. Dextromethorphan hydrobromide hydrate (DXM) has an antitussive effect, and ambroxol hydrochloride (AMB) has an expectorant effect, and these are also used as components of general cold medicines. It's being used.

However, when the present inventor attempted to formulate belladonna total alkaloids with dextromethorphan hydrobromide hydrate and ambroxol hydrochloride, compositions containing these may aggregate over time, resulting in poor stability. It was newly found that there is room for improvement in terms of

Accordingly, the present invention provides a technique for stably blending belladonna total alkaloids, dextromethorphan hydrobromide hydrate and ambroxol hydrochloride in a composition.

According to the present invention, the following solid pharmaceutical composition and method for improving the stability of the solid pharmaceutical composition are provided.
[1] Component (A): belladonna total alkaloid, component (B): dextromethorphan hydrobromide hydrate, component (C): ambroxol hydrochloride, component (D): tranexamic acid and and at least one of crystalline cellulose.
[2] The pharmaceutical solid composition of [1], wherein the component (D) is tranexamic acid.
[3] The content of the component (D) with respect to the total amount of the components (A) to (C) in the solid pharmaceutical composition ((D)/((A) + (B) + (C)) ) is 0.3 or more and 100 or less in mass ratio, the pharmaceutical solid composition according to [2].
[4] The pharmaceutical solid composition of [1], wherein the component (D) is crystalline cellulose.
[5] The content of the component (D) with respect to the total amount of the components (A) to (C) in the solid pharmaceutical composition ((D)/((A) + (B) + (C)) ) is 0.1 or more and 100 or less in mass ratio, the pharmaceutical solid composition according to [4].
[6] The pharmaceutical solid composition according to any one of [1] to [5], which is a solid formulation.
[7] The pharmaceutical solid composition of [6], wherein the dosage form of the solid preparation is granules, uncoated tablets, film-coated tablets or sugar-coated tablets.
[8] A method for improving the stability of a solid pharmaceutical composition, which comprises adding the following component (D) to a solid pharmaceutical composition containing the following components (A) to (C).
(A) belladonna total alkaloids (B) dextromethorphan hydrobromide hydrate (C) ambroxol hydrochloride (D) at least one of tranexamic acid and microcrystalline cellulose

It should be noted that arbitrary combinations of these configurations and conversion of expressions of the present invention between methods, apparatuses, and the like are also effective as aspects of the present invention.
For example, according to the present invention, it is also possible to provide a method for producing a solid pharmaceutical composition, which comprises the step of blending components (A) to (C) below and component (D) below. .
(A) belladonna total alkaloids (B) dextromethorphan hydrobromide hydrate (C) ambroxol hydrochloride (D) at least one of tranexamic acid and microcrystalline cellulose

According to the present invention, belladonna total alkaloids, dextromethorphan hydrobromide hydrate and ambroxol hydrochloride can be stably blended in the composition.

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.

(Pharmaceutical solid composition)
In this embodiment, the pharmaceutical solid composition contains the following components (A) to (D).
(A) belladonna total alkaloids (B) dextromethorphan hydrobromide hydrate (C) ambroxol hydrochloride (D) at least one of tranexamic acid and crystalline cellulose Each component will be described below.

(Component (A))
Component (A) is a belladonna total alkaloid. Component (A) is a known compound, can be produced by a known method, or can be commercially available.

The content of the component (A) in the solid pharmaceutical composition is not limited, and may be determined by appropriate examination according to, for example, the sex, age and symptoms of the recipient. The daily dose is usually 0.01-5 mg, preferably 0.1-0.6 mg.

(Component (B))
Component (B) is dextromethorphan hydrobromide hydrate. Component (B) is a known compound, can be produced by a known method, or can be commercially available.

The content of the component (B) in the solid pharmaceutical composition is not limited, and may be determined by appropriate examination according to, for example, the sex, age and symptoms of the recipient. The daily dose is usually 8-120 mg, preferably 16-48 mg.

(Component (C))
Component (C) is ambroxol hydrochloride. Component (C) is a known compound, can be produced by a known method, or can be commercially available.

The content of the component (C) in the solid pharmaceutical composition is not limited, and may be determined by appropriate examination according to, for example, the sex, age and symptoms of the recipient. The daily dose is usually 7.5-60 mg, preferably 45 mg.

(Component (D))
Component (D) is at least one of tranexamic acid and crystalline cellulose. The pharmaceutical solid composition may contain either one of tranexamic acid and microcrystalline cellulose, or both.

(tranexamic acid)
Tranexamic acid is a known compound, can be produced by a known method, or can be commercially available.

When component (D) is tranexamic acid, the content of component (D) relative to the total amount of components (A) to (C) in the solid pharmaceutical composition ((D)/((A) + (B) +(C))) preferably has a mass ratio of 0.3 or more, more preferably 0.9 or more, and still more preferably 2.5 or more, from the viewpoint of suppressing aggregation in the solid pharmaceutical composition. .
In addition, from the viewpoint of improving the ease of administration of the formulation and from the viewpoint of making the size of the formulation more suitable, the mass ratio ((D) / ((A) + (B) + (C))) is It is preferably 100 or less, more preferably 45 or less, still more preferably 15 or less.

(crystalline cellulose)
Crystalline cellulose is a known component, can be produced by a known method, or can be commercially available.

The average particle size of crystalline cellulose is preferably 10 µm or more, more preferably 20 µm or more, still more preferably 30 µm or more, and preferably 200 µm or less, from the viewpoint of suppressing aggregation in the solid pharmaceutical composition. , more preferably 170 μm or less, still more preferably 100 μm or less.
Here, the average particle diameter of crystalline cellulose 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 MT3300EX II (manufactured by Microtrac Bell).

The bulk density of crystalline cellulose is preferably 0.05 cm 3 or more, more preferably 0.09 cm ^{3 or} more, and still more preferably 0.15 cm ³ or more, from the viewpoint of suppressing aggregation in the solid pharmaceutical composition. It is preferably 0.6 cm ³ or less, more preferably 0.5 cm ³ or less, and still more preferably 0.4 cm ³ or less.
Here, the bulk density of crystalline cellulose is specifically measured by the method for measuring bulk density described in the section on crystalline cellulose in the Japanese Pharmacopoeia 18th Edition.

When component (D) is crystalline cellulose, the content of component (D) with respect to the total amount of components (A) to (C) in the pharmaceutical solid composition ((D)/((A) + (B) +(C))) is preferably 0.1 or more, more preferably 0.15 or more, and still more preferably 0.3 or more in mass ratio from the viewpoint of suppressing aggregation in the solid pharmaceutical composition. .
In addition, from the viewpoint of improving the ease of administration of the formulation and from the viewpoint of making the size of the formulation more suitable, the mass ratio ((D) / ((A) + (B) + (C))) is For example, it is 100 or less, preferably 45 or less, more preferably 15 or less.

Further, when the component (D) contains tranexamic acid and crystalline cellulose, the total content of the component (D) with respect to the total amount of the components (A) to (C) in the pharmaceutical solid composition ((D)/(( A) + (B) + (C))) preferably has a mass ratio of 0.4 or more, more preferably 1 or more, and still more preferably 2 or more, from the viewpoint of suppressing aggregation in the solid pharmaceutical composition. , and more preferably 5 or more.
In addition, from the viewpoint of improving the ease of administration of the formulation and from the viewpoint of making the size of the formulation more suitable, the mass ratio ((D) / ((A) + (B) + (C))) is It is preferably 200 or less, more preferably 85 or less, still more preferably 30 or less.

(Other ingredients)
The pharmaceutical solid composition may further contain components other than components (A) to (D) within a range that does not impair the effects of the present invention. For example, the solid pharmaceutical composition can 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 components include antipyretic analgesics, antihistamines, antitussives other than component (B), noscapines, bronchodilators, expectorants other than component (C), anticholinergics other than component (A), One or more selected from the group consisting of inflammatory agents, caffeines, vitamins, gastric mucosa protective agents, herbal medicines, hypnotics and sedatives, and Chinese medicine formulations can be blended.

Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, One or two or more ingredients selected from the group consisting of acemethacin, etodolac, naproxen, meloxicam, celecoxib and tiaramide hydrochloride can be blended.

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 component (B) include, for example, aloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dibunate sodium, dextromethorphan, and tipepidine citrate. , tipepidine hibenzate, dimemorphan phosphate, eprazinone hydrochloride, pentoxyverine citrate, benproperine phosphate and clofedanol hydrochloride. can do.

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 other than component (C) include, for example, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, l-carbocysteine, l-ethylcysteine hydrochloride, l-methylcysteine hydrochloride, and ammonium chloride. , l-menthol, ammonia/fennel essence, cherry bark extract, methylcysteine hydrochloride and fudosteine.

As an anticholinergic agent other than component (A), for example, one or two or more components selected from the group consisting of Rohto extract, Datura extract and isopropamide iodide can be blended.

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

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 may contain pharmaceutical additives necessary for producing the formulation as long as they do 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, excipients, binders, disintegrants, disintegration aids, fluidizers, lubricants, plasticizers, coating agents, sugar coating agents, glossing agents, coloring agents, flavoring agents, sweetening agents, flavoring agents , and one or more components selected from the group consisting of flavoring agents and fragrances can be blended into the solid pharmaceutical composition.

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, synthetic aluminum silicate, synthetic hydrotalcite, wheat starch, rice flour, rice starch, β-cyclodextrin, heavy silicic anhydride, magnesium alumina hydroxide, aluminum hydroxide gel, hydroxide Aluminum/sodium bicarbonate coprecipitate, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide, D-sorbitol, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, sodium carboxymethyl starch with low substitution, Low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, corn starch granules, trehalose hydrate, silicon dioxide, lactose hydrate, lactose granules, sucrose, potato starch, 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: 800-1100), 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, multi Tall, 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 granulation 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 One or two or more ingredients selected from the group consisting of a substance, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate and erythritol can be blended.

Binders include, for example, gum arabic, gum arabic powder, agar, agar powder, kanbai powder, copolyvidone, gelatin, shellac, low-substituted hydroxypropyl cellulose, corn starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxy Propyl cellulose, vinylpyrrolidone-vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (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 (partial) 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 can be blended.

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 more ingredients selected from the group consisting of starch, potato starch, hydroxypropyl starch and partially pregelatinized starch can be blended.

Examples of disintegration aids include one or more components selected from the group consisting of carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, sodium starch glycolate and hydroxypropyl starch. can be compounded.

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

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.

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, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, 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, 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, white sugar, paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910/titanium oxide/macrogol mixture, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), fumaric acid/stearic acid/polyvinyl acetal diethylamino Acetate-Hydroxypropyl Methylcellulose 2910 Mixture, Pullulan, Premixed Additive Opadry White, Bentonite, Polyoxyethylene Hydrogenated Castor Oil 40, Polyoxyethylene Hydrogenated Castor Oil 60, Polyoxyethylene (105) Polyoxypropylene (5) Glycol, Poly Oxyethylene (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, anhydrous calcium hydrogen phosphate, methacryl 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 , calcium sulfate, fumaric acid, DL-malic acid, erythritol and crystalline cellulose (component (D) described above).

Sugar coating agents include, for example, gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined sucrose, gelatin, shellac, talc, precipitated carbonic acid. Calcium, White Shellac, Sucrose, Hydroxypropyl Cellulose, Hypromellose (2208), Hypromellose (2910), Pullulan, Povidone (K25), Povidone (K30), Povidone (K90), Polyoxyethylene (105) Polyoxypropylene (5) One or more selected from the group consisting of glycol, polyvinyl alcohol (partially saponified product), macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol, erythritol and crystalline cellulose (component (D) described above) Ingredients can be blended.

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.

(Solid formulation)
Moreover, the pharmaceutical solid composition is specifically a solid preparation.
Solid dosage forms are not limited and 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. The dosage form of the solid preparation is preferably uncoated tablets, film-coated tablets, sugar-coated tablets, granules, fine granules or capsules, more preferably granules, uncoated tablets, film-coated tablets or sugar-coated tablets.
Also, the solid formulation is preferably an orally administered formulation.
When the solid preparation has a coating layer, component (D) is preferably incorporated into the uncoated tablet together with components (A) to (C). Also, the component (D) may be blended in the uncoated tablet and the coating layer.

(Production method)
In this embodiment, the pharmaceutical solid composition includes steps of blending components (A) to (C), component (D), and optionally other components, for example.
More specifically, the solid pharmaceutical composition can be produced 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.

The packaging form of a solid pharmaceutical composition, specifically a solid preparation, can be suitably bottle packaging, SP packaging (Strip Package), 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.

Since the pharmaceutical solid composition obtained in the present embodiment contains components (A) to (C) and also contains component (D), when blending components (A) to (C) into the composition, Aggregation can be effectively suppressed, and storage stability is excellent. In addition, according to the present embodiment, for example, it is possible to reduce deterioration in disintegration of the solid pharmaceutical composition, deterioration in appearance, or deterioration in ease of administration.
Further, in the present embodiment, the method for improving the stability of a solid pharmaceutical composition includes adding component (D) to a solid pharmaceutical composition containing components (A) to (C).

In addition, in the present embodiment, the solid pharmaceutical composition 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.

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.
Also, the following abbreviations are used as appropriate (Table 1).
AMB: ambroxol hydrochloride BTA: belladonna total alkaloid DXM: dextromethorphan hydrobromide hydrate TXA: tranexamic acid MCC: microcrystalline cellulose

(Test Example 1) Confirmation of degree of agglomeration of mixed powder of ambroxol hydrochloride, belladonna total alkaloids and dextromethorphan hydrobromide hydrate. The mixture was placed in a standard bottle) and stored in a sealed stopper at 60°C.

Evaluation of property change is as follows: -: no change (powder: fluid), +: slight change (light aggregation: crumbles into powder with light vibration), ++: change (aggregation: does not crumble with vibration, When lightly crushed, it crumbles into powder), +++: significant change (strongly aggregated: when strongly crushed, it crumbles into small aggregates and powder). Table 1 shows the evaluation results of each example.

(Control Example 1)
Only ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) was placed in a glass bottle (1K standard bottle) and tested.

(Control Example 2)
Belladonna total alkaloid (manufactured by Alps Yakuhin Kogyo Co., Ltd.) alone was placed in a glass bottle (1K standard bottle) and tested.

(Control Example 3)
Dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) alone was placed in a glass bottle (1K standard bottle) and tested.

(Control Example 4)
A sample was prepared by mixing ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) and belladonna total alkaloid (manufactured by Alps Yakuhin Kogyo Co., Ltd.) at a mass ratio of 45:0.6.

(Control Example 5)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) and dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) were mixed at a mass ratio of 45:48 to prepare a sample.

(Comparative example 1)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.) and dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) at a mass ratio of 45:0.6 :48 to make a sample.

(Example 1)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) were mixed at a mass ratio of 45:0.6:48:420 to prepare a sample.

(Example 2)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) were mixed at a mass ratio of 45:0.6:48:750 to prepare a sample.

(Example 3)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) were mixed at a mass ratio of 45:0.6:48:1500 to prepare a sample.

(Example 4)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) and crystalline cellulose (Seolus PH-101: Asahi Kasei Corporation) were mixed at a mass ratio of 45:0.6:48:420 to prepare a sample. Ceolus PH-101 (manufactured by Asahi Kasei Co., Ltd.) used as crystalline cellulose has an average particle size of 50 μm and a bulk density of 0.26 to 0.31 g/cm.

(Example 5)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) and crystalline cellulose (Seolus PH-101: Asahi Kasei Corp.) were mixed at a mass ratio of 45:0.6:48:750 to prepare a sample.

(Comparative example 2)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and lactose hydrate (Pharmatose 200M: DFE) Pharma) were mixed at a mass ratio of 45:0.6:48:420 to prepare a sample.

(Comparative Example 3)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and lactose hydrate (Pharmatose 200M: DFE) Pharma) were mixed at a mass ratio of 45:0.6:48:750 to prepare a sample.

(Example 6)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) and crystalline cellulose (Seolus PH-101: Asahi Kasei Corporation) were mixed at a mass ratio of 45:0.6:48:1500 to prepare a sample.

(Example 7)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) and crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Corporation) were mixed at a mass ratio of 45:0.6:48:140:1500 to prepare a sample.

(Example 8)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) and crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Co., Ltd.) were mixed at a mass ratio of 45:0.6:48:1500:20 to prepare a sample.

(Example 9)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.), belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.), dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.), and tranexamic acid (manufactured by Hunan Dongting Pharmaceutical Co., Ltd.) ) and crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Co., Ltd.) were mixed at a mass ratio of 45:0.6:48:1500:1500 to prepare a sample.

From Table 1, it was confirmed that in each example, aggregation of the sample was suppressed and the stability was superior to that in the comparative example.

(Formulation Examples 1-51)
Examples of solid formulations are shown in Tables 2-8 below.

Claims (8)

Component (A): belladonna total alkaloids, component (B): dextromethorphan hydrobromide hydrate, component (C): ambroxol hydrochloride, component (D): tranexamic acid and crystalline cellulose A pharmaceutical solid composition comprising at least one of 2. The pharmaceutical solid composition according to claim 1, wherein said component (D) is tranexamic acid. The content of the component (D) with respect to the total amount of the components (A) to (C) in the solid pharmaceutical composition ((D)/((A) + (B) + (C))) is 3. The pharmaceutical solid composition according to claim 2, wherein the mass ratio is 0.3 or more and 100 or less. 2. The pharmaceutical solid composition according to claim 1, wherein said component (D) is crystalline cellulose. The content of the component (D) with respect to the total amount of the components (A) to (C) in the solid pharmaceutical composition ((D)/((A) + (B) + (C))) is 5. The pharmaceutical solid composition according to claim 4, wherein the mass ratio is 0.1 or more and 100 or less. 6. The solid pharmaceutical composition according to any one of claims 1 to 5, which is a solid formulation. 7. The pharmaceutical solid composition according to claim 6, wherein the dosage form of said solid preparation is granules, uncoated tablets, film-coated tablets or sugar-coated tablets. A method for improving the stability of a solid pharmaceutical composition, comprising adding the following component (D) to a solid pharmaceutical composition containing the following components (A) to (C).
(A) belladonna total alkaloids (B) dextromethorphan hydrobromide hydrate (C) ambroxol hydrochloride (D) at least one of tranexamic acid and microcrystalline cellulose