JP7752145B2 - Pharmaceutical solid composition - Google Patents

Description

The present invention relates to a pharmaceutical solid composition.

Currently, pharmaceutical preparations containing multiple medicinal ingredients are widely used in general cold remedies, antipyretics, analgesics, and other medicines. An example of such a pharmaceutical preparation is described in Patent Document 1 (JP 2020-158487 A). This document describes a solid composition containing ibuprofen, loratadine, and at least one selected from the group consisting of carbocysteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizinic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts (Claim 1). This document also describes an example of a formulation containing dextromethorphan hydrobromide hydrate and ambroxol hydrochloride (Formulation Example 2).

Japanese Patent Application Laid-Open No. 2020-158487

Belladonna Total Alkaloids (BTA) have an anticholinergic effect that suppresses nasal discharge, and are used as one of the ingredients in comprehensive cold medicines. Dextromethorphan hydrobromide hydrate (DXM) has an antitussive effect, and ambroxol hydrochloride (AMB) has an expectorant effect, and these are also used as ingredients in comprehensive cold medicines.

However, when the inventors attempted to combine total belladonna alkaloids with dextromethorphan hydrobromide hydrate and ambroxol hydrochloride, they discovered that compositions containing these compounds sometimes aggregated over time, indicating that there was room for improvement in terms of stability.

The present invention therefore provides a technology for stably blending total belladonna alkaloids, dextromethorphan hydrobromide hydrate, and ambroxol hydrochloride in a composition.

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

Any combination of these configurations and conversion of the present invention between methods, devices, etc. are also valid aspects of the present invention.
For example, the present invention can also provide a method for producing a pharmaceutical solid composition, which includes a step of blending the following components (A) to (C) and the following component (D):
(A) Total alkaloids of belladonna (B) Dextromethorphan hydrobromide hydrate (C) Ambroxol hydrochloride (D) At least one of tranexamic acid and crystalline cellulose

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

Hereinafter, an embodiment of the present invention will be described. In this embodiment, the composition may contain each component either alone or in combination of two or more.
In this specification, the term "to" indicating a range of values means "at least" or "at most", and includes both of the values on both ends.

(Solid pharmaceutical composition)
In this embodiment, the pharmaceutical solid composition contains the following components (A) to (D):
(A) Total belladonna alkaloids (B) Dextromethorphan hydrobromide hydrate (C) Ambroxol hydrochloride (D) At least one of tranexamic acid and crystalline cellulose Each component will be explained below.

(Component (A))
Component (A) is total alkaloids of belladonna. Component (A) is a known compound and can be produced by known methods, or commercially available products can be used.

The amount of component (A) contained in the pharmaceutical solid composition is not limited and may be determined appropriately based on factors such as the recipient's gender, age, and symptoms. The daily dose is typically 0.01 to 5 mg, and preferably 0.1 to 0.6 mg.

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

The amount of component (B) contained in the pharmaceutical solid composition is not limited and may be determined appropriately based on factors such as the user's gender, age, and symptoms. The daily dose is typically 8 to 120 mg, and preferably 16 to 48 mg.

(Component (C))
Component (C) is ambroxol hydrochloride. Component (C) is a known compound and can be produced by known methods, or commercially available products can be used.

The amount of component (C) contained in the pharmaceutical solid composition is not limited and may be determined appropriately based on factors such as the recipient's gender, age, and symptoms. The daily dose is typically 7.5 to 60 mg, and preferably 45 mg.

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

(tranexamic acid)
Tranexamic acid is a known compound and can be produced by known methods, or commercially available products can be used.

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

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

From the viewpoint of suppressing aggregation in the pharmaceutical solid composition, the average particle size of the crystalline cellulose is preferably 10 μm or more, more preferably 20 μm or more, even more preferably 30 μm or more, and is preferably 200 μm or less, more preferably 170 μm or less, even more preferably 100 μm or less.
Here, the average particle size of crystalline cellulose specifically means the volume-average diameter, which is the arithmetic mean value in the volume-based particle size distribution determined by a laser diffraction/scattering method. For example, it can be evaluated by dry measurement using a particle size distribution measuring device MT3300EX II (manufactured by Microtrac Bell).

From the viewpoint of suppressing aggregation in the pharmaceutical solid composition, the bulk density of the crystalline cellulose is preferably 0.05 ^cm3 or more, more preferably 0.09 ^cm3 or more, even more preferably 0.15 ^cm3 or more, and is preferably 0.6 ^cm3 or less, more preferably 0.5 ^cm3 or less, even more preferably 0.4 ^cm3 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 18th Edition of the Japanese Pharmacopoeia.

When component (D) is crystalline cellulose, the content of component (D) relative 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 even more preferably 0.3 or more, in terms of mass ratio, from the viewpoint of suppressing aggregation in the pharmaceutical solid composition.
Furthermore, from the viewpoint of improving the ease of administration of the formulation and making the size of the formulation more suitable, the mass ratio ((D)/((A)+(B)+(C))) is, for example, 100 or less, preferably 45 or less, and more preferably 15 or less.

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

(Other ingredients)
The pharmaceutical solid composition may further contain ingredients other than components (A) to (D) to the extent that the effects of the present invention are not impaired. For example, other ingredients typically used in general cold medicines can be blended into the pharmaceutical solid composition as needed. Furthermore, the pharmaceutical solid composition can also blend ingredients listed in the OTC drug manufacturing and marketing approval standards. Specific examples of such ingredients include one or more selected from the group consisting of antipyretics, antihistamines, antitussives other than component (B), noscapines, bronchodilators, expectorants other than component (C), anticholinergics other than component (A), anti-inflammatory agents, caffeines, vitamins, gastric mucosa protectants, herbal medicines, hypnotics and sedatives, and herbal prescriptions.

Examples of antipyretic analgesics include one or more ingredients selected from the group consisting of aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, prazolam, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, and tiaramide hydrochloride.

Examples of antihistamines include isothipendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, and tannins. It may contain one or more ingredients selected from the group consisting of diphenhydramine phosphate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, ketotifen fumarate, promethazine hydrochloride, epinastine hydrochloride, emedastine fumarate, fexofenadine, azelastine hydrochloride, cetirizine hydrochloride, and olopatadine hydrochloride.

Antictussives other than ingredient (B) may include, for example, one or more ingredients selected from the group consisting of alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dibunate sodium, dextromethorphan, tipepidine citrate, tipepidine hibenzate, dimemorfan phosphate, eprazinone hydrochloride, pentoxyverine citrate, benproperine phosphate, and clofedanol hydrochloride.

Noscapine compounds may include, for example, one or more components selected from the group consisting of noscapine and noscapine hydrochloride hydrate.

The bronchodilator may contain, for example, one or more components selected from the group consisting of dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, aminophylline, diprophylline, theophylline, proxyphylline, dl-methylephedrine, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, and isoprenaline hydrochloride.

Expectorants other than component (C) may include, for example, one or more components selected from the group consisting of guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, l-carbocysteine, l-ethylcysteine hydrochloride, l-methylcysteine hydrochloride, ammonium chloride, l-menthol, ammonia-fennel extract, cherry bark extract, methylcysteine hydrochloride, and fudosteine.

Anticholinergic agents other than component (A) may include, for example, one or more components selected from the group consisting of Scopolia extract, Datura extract, and isopropamide iodide.

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

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

Vitamins include, for example, vitamin B1 and its derivatives and salts such as thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, sicotiamine, thiamine disulfide, bis-ibutiamine, bis-bentiamine, prosultiamine, and benfotiamine; vitamin B2 and its derivatives and salts such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate; pantothenic acid, panthenol, pantethine, pantothenic acid, panthenol ... It may contain one or more ingredients selected from the group consisting of vitamin B5 and its derivatives and salts such as calcium pantothenate and sodium pantothenate; vitamin B6 and its derivatives and salts such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 and its derivatives and salts such as cyanocobalamin and mecobalamin; vitamin C and its derivatives and salts such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and salts.

Gastric mucosal protectants may include, for example, one or more components selected from the group consisting of glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum alnoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium bicarbonate, dried mixed gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, magnesium aluminometasilicate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, teprenone, and rebamipide.

Examples of herbal medicines include ephedra, nandina, scutellaria, onji, licorice, bellflower, scutellaria, scutellaria, scutellaria (lily of the valley), senega, fritillary, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yutan), shanghai, ginger, atractylodes, clove, tangerine peel, atractylodes, scutellaria, ginseng, carrot, Mallotus japonicus, echinacea, corydalis, Scutellaria root, scutellaria, valerian, calonin, and apricot kernel. It can contain one or more ingredients selected from the group consisting of herbal medicines such as lycium berry, wolfberry, scutellaria, cassia, germanium, koji, kobushi, chinese pepper, sansho, schisandra, jiaozi, peony, musk, saffron, cnidium, zenko, swertia bristlecone, sophora rhizome, perilla, tang, angelica, ipecac, rhododendron, rhododendron bark, siamensis, angelica, peony, rhododendron rhizome, rhododendron bark, angelica tree, poria, rhododendron bark, rhododendron rhizome ... rhizome, and extracts thereof (extracts, tinctures, dried extracts, etc.).

The hypnotic sedative may contain, for example, one or more components selected from the group consisting of bromvalerylurea and allylisopropylacetylurea.

In addition, Kampo prescriptions can include, for example, Kakkonto, Kakkonto-ka-kikyo, Keishito, Kososan, Saiko-keishito, Sho-saikoto, Sho-seiryuto, Bakumondo-to, Hange-kouboku-to, Ma-oto, and extracts thereof (extracts, tinctures, dried extracts, etc.).

Furthermore, pharmaceutical additives necessary for producing the formulation can be blended into the pharmaceutical solid composition, as long as they do not impair the effects of the present invention. For example, pharmaceutical additives listed in Yakushoku Shindan-Hatsu 1204-1 (Pharmaceutical Administration Law), Pharmaceutical Additives Dictionary 2021 (Edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha), and the 8th Edition of the Official Specification of Food Additives (Japan Food Additives Association) can be blended. Specifically, the pharmaceutical solid composition can be blended with one or more components selected from the group consisting of excipients, binders, disintegrants, disintegration aids, flow agents, lubricants, plasticizers, coating agents, sugar-coating agents, glazing agents, colorants, flavoring agents, sweeteners, flavoring agents, and flavoring agents/flavorings.

Examples of excipients include candy powder, pregelatinized starch, isomalt, cocoa butter, dried hydrolyzed starch, caramel, carmellose, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrated amorphous silicon oxide, dried aluminum hydroxide gel, dried potato starch, licorice powder, agar, agar powder, winter plum powder, xylitol, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, calcium silicate, magnesium silicate, cinnamon powder, synthetic aluminum silicate, synthetic hydrotalcite, wheat starch, rice flour, rice starch, β-cyclodextrin, heavy anhydrous silicic acid, alumina hydroxide Magnesium, aluminum hydroxide gel, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide, D-sorbitol, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, corn starch granules, trehalose hydrate, silicon dioxide, lactose hydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hyp Romellose 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 It may contain one or more ingredients selected from the group consisting of choline mixture, maltitol, maltose hydrate, D-mannitol, a mixture of D-mannitol, crospovidone, D-sorbitol, and hydrated silicon dioxide, 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, methylcellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, and erythritol.

Examples of binders include gum arabic, powdered gum arabic, agar, powdered agar, kanbai powder, copolyvidone, gelatin, shellac, low-substituted hydroxypropyl cellulose, corn starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, vinylpyrrolidone-vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731), hypromellose phthalate (220824), fumaric acid, It can contain one or more ingredients selected from the group consisting of a mixture of acetic acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl cellulose 2910, pullulan, povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol graft polymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, magnesium aluminometasilicate, and methylcellulose.

As disintegrants, for example, one or more components selected from the group consisting of pregelatinized starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, potato starch, hydroxypropyl starch, and partially pregelatinized starch can be blended.

Disintegration aids that can be used include, for example, 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.

The fluidizing agent may be, for example, one or more components selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, tricalcium phosphate, talc, corn starch, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

Lubricants that can be blended include, for example, one or more components selected from the group consisting of hydrous silicon dioxide, hydrous amorphous silicon oxide, glycerin fatty acid esters, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, heavy anhydrous silicic acid, sucrose fatty acid esters, stearyl alcohol, stearic acid, zinc stearate, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, hydrogenated soybean oil, talc, sodium stearyl fumarate, beeswax, anhydrous silicic acid hydrate, magnesium aluminum metasilicate, and glycerin monostearate.

The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

Examples of coating agents include 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, octyldecyl triglyceride, Opadry OY-6950, Opadry OY-L-28900, Padry 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-1-1 4762-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 White YS-1-18177-A, Opadry White (YS-1-18202-A), Opadry II White (33G28523), Opadry II White (85F28751), Opadry II White (OY-LS-289 14), Opadry II Light Blue (85G20426), Opadry II Light Beige 85F17498, Opadry II Red (32K15441), carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried aluminum hydroxide gel, dried methacrylic acid copolymer LD, triethyl citrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropyl cellulose, 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, stearin Magnesium carbonate, purified gelatin, purified shellac, refined sucrose, gelatin, shellac, D-sorbitol, D-sorbitol liquid, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, concentrated glycerin, white shellac, sucrose, paraffin, hydroxypropyl cellulose, hydroxypropyl methylcellulose 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 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), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000EP, macrogol 20000, macrogol 300, macrogol 4 ... One or more ingredients selected from the group consisting of Logol 35000, D-mannitol, anhydrous citric acid, anhydrous silicic acid hydrate, phthalic anhydride, anhydrous calcium hydrogen phosphate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl methacrylate-methacrylic acid-methyl methacrylate copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, fumaric acid, DL-malic acid, erythritol, and crystalline cellulose (the aforementioned ingredient (D)) can be blended.

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

The glossing agent may be, for example, one or more components selected from the group consisting of carnauba wax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, and beeswax.

Coloring agents that can be blended include, for example, one or more components selected from the group consisting of yellow iron oxide, Yellow No. 5 premix, brown iron oxide, carbon black, caramel, beta-carotene, licorice extract, black iron oxide, titanium oxide, iron sesquioxide, iron sesquioxide/glycerin suspension, Food Blue No. 1, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, copper chlorophyllin sodium, copper chlorophyll, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

Flavoring agents include, for example, erythritol, sodium chloride, Phellodendron Bark Powder, Phellodendron Bark Extract, Coptis Rhizome, Coptis Rhizome Powder, Ononis Root Dried Extract, Orange, Orange Oil, Cocoa Powder, Fructose, Caramel, Licorice, Licorice Extract, Crude Licorice Extract, Licorice Powder, Xylitol, Calcium Citrate, Citric Acid Hydrate, Sodium Citrate Hydrate, Glycyrrhizic Acid, Trisodium Glycyrrhizate, Diammonium Glycyrrhizate, Disodium Glycyrrhizate, Monoammonium Glycyrrhizate, L-Glutamic Acid, L-Arginine Glycyrrhizate, L-Glutamate 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, purified licorice extract powder, refined white sugar, Swertia japonica, Perilla frutescens powder, D-sorbitol, ginseng powder, taurine, dried extract of Arakuraku root and grass, tannic acid, clove tincture, clove oil, tangerine tincture, capsicum, capsicum tincture, capsicum powder, spruce It can contain one or more ingredients selected from the group consisting of tincture, spruce powder, trehalose hydrate, bitter persimmon powder, plum extract, white sugar, fructooligosaccharide, powdered sugar, peppermint powder, maltose hydrate, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil.

Sweetening agents that can be blended include, for example, one or more ingredients selected from the group consisting of aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose starch syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, 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.

Flavors may include, for example, one or more ingredients selected from the group consisting of 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 NAEFCOPO 551957685, peppermint micron H-81550, mixed flavor powder, melon powder flavor, l-menthol, and menthol L163592SYM.

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, Vitabase, Himalayan It can contain one or more ingredients selected from the group consisting of cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, turmeric oil, and Roman chamomile oil.

(Solid preparations)
Moreover, the pharmaceutical solid composition is specifically a solid preparation.
The dosage form of the solid preparation is not limited, and examples thereof include capsules, pills, granules, fine granules, powders, and tablets. These solid preparations may be coated with sugar coating, film coating, or the like by known methods, if necessary. The dosage form of the solid preparation is preferably plain tablets, film-coated tablets, sugar-coated tablets, granules, fine granules, or capsules, and more preferably granules, plain tablets, film-coated tablets, or sugar-coated tablets.
The solid preparation is preferably an oral administration preparation.
When the solid preparation has a coating layer, component (D) is preferably incorporated into the core tablet together with components (A) to (C). Alternatively, component (D) may be incorporated into the core tablet and the coating layer.

(Manufacturing method)
In this embodiment, the pharmaceutical solid composition includes, for example, a step of blending components (A) to (C), component (D), and, if necessary, other components.
More specifically, the pharmaceutical solid composition can be produced according to the method described in the 18th edition of the Japanese Pharmacopoeia and the like depending on the dosage form, and can be made into a formulation.
For example, when the pharmaceutical solid composition is in the form of a tablet, it can be produced in accordance with the section on "tablets" in the General Rules for Preparations of the Japanese Pharmacopoeia. When the pharmaceutical solid composition is in the form of granules, it can be produced in accordance with the section on "granules" in the General Rules for Preparations of the Japanese Pharmacopoeia.
In addition, from the viewpoint of avoiding incompatibility of ingredients and additives to be blended in the pharmaceutical solid composition, and from the viewpoint of further improving the storage stability of the composition, the composition may be formulated so that the predetermined ingredients do not come into contact with each other by, for example, dividing the composition into granules or forming multiple layers.

Packaging of pharmaceutical solid compositions, specifically solid formulations, can be appropriately done in bottle packaging, SP packaging (Strip Package), stick packaging, PTP (Press-Through Package), pouch packaging, etc. They may be packaged in these and then stored airtight. They may then be pillow-packaged. They may also be stored in boxes, etc. Materials used for SP packaging, stick packaging, PTP packaging, and pillow packaging are not limited, and include, for example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polyethylene, polypropylene film, polyethylene terephthalate film, and polyethylene film; multi-layer films combining these resin films; and resin films with aluminum foil attached. Multi-layer films may be, for example, laminate films. Furthermore, desiccants, oxygen absorbers, and deodorizers may be enclosed as needed.

The pharmaceutical solid composition obtained in this embodiment contains components (A) to (C) as well as component (D), and therefore can effectively suppress aggregation that occurs when components (A) to (C) are blended into the composition, resulting in excellent storage stability. Furthermore, this embodiment also makes it possible to reduce, for example, the decrease in disintegrability of the pharmaceutical solid composition, deterioration in appearance, or deterioration in ease of administration.
In addition, in this embodiment, the method for improving the stability of a pharmaceutical solid composition includes adding component (D) to the pharmaceutical solid composition containing components (A) to (C).

Furthermore, in this embodiment, the pharmaceutical solid composition can be suitably used, for example, as a comprehensive cold medicine. For example, by adding various ingredients, it can be administered to patients with cold symptoms, particularly fever, chills, headache, sore throat, runny nose, nasal congestion, cough, phlegm, joint pain, muscle pain, sneezing, etc., to alleviate these symptoms.

The above describes embodiments of the present invention, but these are merely examples of the present invention, and various other configurations may also be adopted.

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.
The following abbreviations will also be used as appropriate (Table 1).
AMB: Ambroxol hydrochloride BTA: Belladonna total alkaloids DXM: Dextromethorphan hydrobromide hydrate TXA: Tranexamic acid MCC: Microcrystalline cellulose

(Test Example 1) Confirmation of the degree of aggregation of mixed powders of ambroxol hydrochloride, belladonna total alkaloids, and dextromethorphan hydrobromide hydrate Samples of the mixtures shown in the following examples were prepared, placed in glass bottles (1K standard bottles), and stored at 60°C with a tight stopper. The state of the mixtures after one week was evaluated to confirm the presence or absence of any changes in properties (interactions).

Changes in properties were evaluated using a four-point scale: -: no change (powder: flowable), +: slight change (light agglomeration: crumbles into powder with light vibration), ++: change (agglomeration: does not crumble with vibration, but crumbles into powder with light crushing), +++: significant change (strong agglomeration: crumbles into small agglomerations and powder with strong crushing). The evaluation results for each example are shown in Table 1.

(Control Example 1)
The test was carried out by placing only ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) in a glass bottle (1K standard bottle).

(Control Example 2)
The test was conducted by placing only belladonna total alkaloids (manufactured by Alps Pharmaceutical Co., Ltd.) in a glass bottle (1K standard bottle).

(Control Example 3)
The test was carried out by placing only dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Co., Ltd.) in a glass bottle (1K standard bottle).

(Control Example 4)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) and belladonna total alkaloids (manufactured by Alps Pharmaceutical Industries Co., Ltd.) were mixed in a mass ratio of 45:0.6 to prepare a sample.

(Control Example 5)
Ambroxol hydrochloride (manufactured by Yoshindo Co., Ltd.) and dextromethorphan hydrobromide hydrate (manufactured by Alps Pharmaceutical Industries Co., Ltd.) were mixed in 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.) were mixed in a mass ratio of 45:0.6:48 to prepare 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 in 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 in 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 in 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 (Ceolus PH-101: manufactured by Asahi Kasei Corporation) were mixed in a mass ratio of 45:0.6:48:420 to prepare a sample. The Ceolus PH-101 (manufactured by Asahi Kasei Corporation) used as the crystalline cellulose had an average particle size of 50 μm and a bulk density of 0.26 to 0.31 g/cm.

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

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

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

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

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

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

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

Table 1 confirms that in each example, sample aggregation was suppressed and stability was superior compared to the comparative example.

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

Claims (8)

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