Solid composition

Abstract

The present invention relates to solid compositions. The present invention addresses the problem of providing a novel solid composition. The solution of the invention is to provide a solid composition containing crystals formed by ibuprofen and tranexamic acid, and licorice.

Description

TECHNICAL FIELD

[0001] The present application relates to a solid composition comprising a crystal formed from ibuprofen and tranexamic acid, and licorice, and the like. BACKGROUND

[0002] Solid preparations such as tablets administered orally disintegrate in the digestive tract, and then the effective ingredients in the preparation are absorbed in the body. In the design of the preparation, it is extremely important that the solid preparation disintegrates within a prescribed time under prescribed conditions, and in the case where the solid preparation is difficult to disintegrate, it is generally necessary to improve the disintegrability by the incorporation of a disintegrant or the like.

[0003] Among the effective ingredients of pharmaceutical products, there are ingredients that decrease the disintegrability of a solid preparation, and among them, there are ingredients that further deteriorate the disintegrability in combination with other ingredients than alone. For example, it is known that ibuprofen alone also causes a decrease in disintegrability, but further decreases the disintegrability in combination with tranexamic acid (Patent Literature 1).

[0004] It is also known that the disintegrability of a solid preparation containing licorice as one of crude drugs is low (Non-Patent Literature 1).

[0005] PRIOR ART DOCUMENTS

[0006] PATENT LITERATURE

[0007] Patent Literature 1: Japanese Patent Application Publication No. 2014-162743

[0008] NON-PATENT LITERATURE

[0009] Non-Patent Literature 1: Nagai, H. et al., "Study on the design of tablets containing Chinese medicine extracts" (Study on the design of tablets containing Chinese medicine extracts), Yakugaku Jissai Kenkyuho, No. 41, pp. 33-35 SUMMARY

[0010] PROBLEMS TO BE SOLVED BY THE INVENTION

[0011] From the viewpoint of the rapidity of the effect, it is sometimes required for a solid composition containing ibuprofen, tranexamic acid, and licorice incorporated in a cold medicine to disintegrate more quickly.

[0012] It has been clarified that the disintegrability of a solid composition containing a combination of ibuprofen, tranexamic acid, and licorice is significantly lower than the disintegrability of a solid composition containing each ingredient alone.

[0013] MEANS FOR SOLVING THE PROBLEMS

[0014] For a solid composition containing the above three ingredients which is difficult to disintegrate, the present inventors have found that the disintegrability is improved by crystallizing ibuprofen with tranexamic acid, and thus have completed the present application.

[0015] That is, the present application includes the following inventions.

[0016] [1] A solid composition comprising:

[0017] (A) a crystal formed from ibuprofen and tranexamic acid; and

[0018] (B) licorice.

[0019] [2] The solid composition according to [1], wherein the mass ratio of component (A) to component (B) is 75:25 to 15:85 ((A):(B)), and the mass of (B) is an amount of crude drug conversion.

[0020] [3] The solid composition according to [1] or [2], further comprising a disintegrant.

[0021] [4] The solid composition according to [3], wherein the content of the disintegrant is less than 12% relative to the total amount of the solid composition.

[0022] [5] The solid composition according to [3], wherein the disintegrant is a starch.

[0023] Effects of the Invention

[0024] In the combination with licorice, by using ibuprofen which has been crystallized with tranexamic acid, a solid composition having improved disintegrability is obtained as compared with the case where tranexamic acid and ibuprofen are separately formulated. The improvement in disintegrability of such a solid composition is sometimes beyond the improvement in disintegrability brought by a disintegrant. BRIEF DESCRIPTION OF DRAWINGS

[0025] [ Figure 1 ] Figure 1 Differential scanning calorimetry (DSC) results of samples of Examples are shown. DETAILED DESCRIPTION

[0026] (Solid composition)

[0027] In the first mode, a solid composition is provided, which comprises:

[0028] (A) a crystal formed from ibuprofen and tranexamic acid; and

[0029] (B) licorice.

[0030] In the present specification, "ibuprofen" is CAS No. 15687-27-1, and is a compound represented by the formula: 13 H 18A compound represented by the chemical formula of O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an effective ingredient of anti-inflammatory, analgesic, antipyretic agents, and the like. The salt of ibuprofen is not particularly limited as long as it is a pharmacologically acceptable salt.

[0031] The amount of ibuprofen or the salt thereof to be compounded can be appropriately adjusted depending on the use of ibuprofen or the salt thereof in the composition, the symptoms, age, body weight, gender, and the like of the subject to be administered. For example, in the case where ibuprofen or the salt thereof is compounded as a non-steroidal anti-inflammatory drug, the amount of ibuprofen or the salt thereof to be administered per 1 day to an adult can be adjusted within the range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In the present application, "adult" means men and women of 15 years of age or older. However, the composition of the present application is not limited to be used for adults, and can be used for children of less than 15 years of age. In the case of children, the amount can be reduced to 1 / 2, 2 / 3, or the like of the amount to be administered per 1 day to an adult.

[0032] The above-mentioned administration amount is an example, and the content of ibuprofen or the salt thereof in the composition to be administered per 1 day is, for example, about 1 mass% to about 70 mass%, preferably about 5 mass% to about 50 mass%, and more preferably about 10 mass% to about 30 mass%.

[0033] In one embodiment, the content of ibuprofen or the salt thereof in the composition to be administered per 1 day is 1 mass% to 70 mass%, preferably 5 to 50 mass%, and more preferably 10 to 30 mass%.

[0034] The above-mentioned weight and administration amount of the composition are the administration amount per 1 day (1-day dose), and the amount can be administered to the subject in multiple times (for example, 2 or 3 times, and preferably 3 times) per 1 day. The same applies to the components other than ibuprofen or the salt thereof. In addition, each administration amount is a total amount, and thus the content of each component contained in the composition can vary depending on the amount per 1 time, the dosage form of the composition, and the like.

[0035] In a specific embodiment, the composition is a tablet, and the above-mentioned administration amount is the amount of the components contained in 3 tablets, 6 tablets, or 9 tablets, and preferably the amount of the components in 9 tablets. In this embodiment, the administration amount per 1 time for an adult (15 years of age or older) is 3 times, and the administration amount per 1 time is 2 tablets, 3 tablets, or 4 tablets, and preferably the administration amount per 1 time is 3 tablets.

[0036] Unless otherwise specified, the amount of ibuprofen described in the present specification is the amount in the crystal formed with tranexamic acid, but the amount can also be the total amount of ibuprofen subjected to crystallization and ibuprofen not subjected to crystallization.

[0037] In one embodiment, the solid-state composition contains ibuprofen subjected to crystallization and ibuprofen not subjected to crystallization.

[0038] In one embodiment, 90% by mass or more, for example, 90% by mass, 91% by mass, 92% by mass, 93% by mass, 94% by mass, 95% by mass, 96% by mass, 97% by mass, 98% by mass, 99% by mass, or 100% by mass of the ibuprofen contained in the solid composition is crystallized.

[0039] As used in the present specification, "tranexamic acid" is a compound represented by the chemical formula of C8H 15 NO2(CAS No. 1197-18-8) having a molecular weight of 157.21 g / mol. Tranexamic acid is used as an effective ingredient of an anti-inflammatory drug or the like. The salt of tranexamic acid is not particularly limited as long as it is a pharmacologically acceptable salt.

[0040] The amount of tranexamic acid or a salt thereof to be incorporated can be appropriately adjusted depending on the use of the tranexamic acid or a salt thereof in the composition. The amount of tranexamic acid or a salt thereof to be incorporated varies depending on the amount of ibuprofen or the like, and is, for example, in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg per 1 day.

[0041] The content of tranexamic acid or a salt thereof contained in the composition to be administered in one day is 1% by mass to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0042] The content of tranexamic acid or a salt thereof contained in the composition to be administered in one day is, for example, 0.5 parts by mass to 3.5 parts by mass, preferably 0.6 parts by mass to 3.0 parts by mass, and more preferably 0.7 parts by mass to 2.2 parts by mass, relative to 1 part by mass of ibuprofen.

[0043] Unless otherwise specified, the amount of tranexamic acid described in the present specification is described as the amount in the crystal formed with ibuprofen, but the amount can also be the total amount of tranexamic acid that has been crystallized and tranexamic acid that has not been crystallized.

[0044] In one embodiment, the solid composition contains: tranexamic acid that has been crystallized; and tranexamic acid that has not been crystallized.

[0045] Ibuprofen and tranexamic acid exist as a crystal in the composition. In the crystal, ibuprofen and tranexamic acid can exist at a molar ratio of 1:1. In addition, in the crystal, ibuprofen and tranexamic acid can form a crystal cell of 4 molecules each.

[0046] In the crystal, a hydrogen bond can be formed between the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid, and between the carboxylic acid group of ibuprofen and the amino group of tranexamic acid.

[0047] The crystal can have an endothermic peak around 180°C in differential scanning calorimetry (DSC). By "around 180°C", for example, it can be a range of 180°C ± 20°C, or a range of 180°C ± 10°C. Note that in the DSC of the crystal, the characteristic melting heat peak of ibuprofen around 75°C can disappear.

[0048] The crystal, for example, can have the crystal structure shown in Japanese Patent Application Publication No. 2022-70674 Figure 1 The crystal can have the X-ray diffraction pattern shown in Fig. 2 of the above publication. The crystal can have mainly 7 peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in the X-ray diffraction pattern.

[0049] The crystal formed from ibuprofen and tranexamic acid, for example, can be manufactured using the method described in Japanese Patent Application Publication No. 2022-70674. Three representative manufacturing methods described in the above publication are described below.

[0050] A method for manufacturing a crystal formed from ibuprofen and tranexamic acid, comprising:

[0051] (1) generating ibuprofen having fluidity by adding a solvent or heating;

[0052] (2) mixing the obtained ibuprofen having fluidity with tranexamic acid;

[0053] (3) generating a crystal from the obtained mixture.

[0054] A method for manufacturing a crystal formed from ibuprofen and tranexamic acid, comprising:

[0055] (1) obtaining tranexamic acid having fluidity;

[0056] (2) mixing the obtained tranexamic acid having fluidity with ibuprofen or ibuprofen having fluidity obtained by adding a solvent or heating;

[0057] (3) generating a crystal from the obtained mixture.

[0058] A method for manufacturing a crystal formed from ibuprofen and tranexamic acid, comprising:

[0059] (1) adding ibuprofen and tranexamic acid to a solvent to obtain a solution or dispersion;

[0060] (2) spraying and drying the obtained solution or dispersion, or leaving the solution obtained in (1) to stand, filtering the product obtained after standing, and drying the product.

[0061] In the present specification, "licorice" can use a substance described in the 18th edition of the Japanese Pharmacopoeia. As licorice, for example, there are products obtained using water, 30% ethanol aqueous solution, or the like as an extraction solvent, and for example, depending on the kind of extract such as licorice extract, licorice dry extract, licorice soft extract, licorice fluid extract, and the like, various products are sold as crude drugs. Unless otherwise specified, the amount described in the present specification in relation to licorice is a value converted to crude drugs. For example, in the case of licorice soft extract, about 4 parts by mass of licorice is contained in 1 part by mass of extraction solvent, on a crude drug conversion basis. In addition, in addition to these licorice extracts, a substance (extract powder) obtained by powdering an extract obtained by extracting licorice with water, 30% ethanol aqueous solution, or the like, and licorice extract, licorice extract solution, and the like can also be appropriately used, and there is no particular limitation. However, an extract powder in which about 5 parts by mass to about 9 parts by mass, for example, about 7 parts by mass to about 8 parts by mass, of licorice is contained in 1 part by mass of extraction solvent, on a crude drug conversion basis, is preferably dried.

[0062] The extract component can be obtained by a conventional method, for example, by extracting the active component from the aforementioned crude drugs using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is used. Among the aforementioned hydrophilic solvents, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, and the like; cellosolves such as methyl cellosolve, ethyl cellosolve, and the like; ketones such as acetone and the like; ethers such as dioxane, tetrahydrofuran, and the like; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and the like, and the like can be used. These hydrophilic solvents can be used alone or as a mixed solvent of two or more.

[0063] The amount of licorice to be compounded is appropriately adjusted depending on the use of licorice in the composition. The amount of licorice to be compounded per day is, for example, in the range of 100 mg to 5,000 mg, preferably in the range of 200 mg to 2,000 mg, and more preferably in the range of 500 mg to 1,200 mg.

[0064] The content of licorice contained in the composition to be administered in a day is 1% by mass to 80% by mass, preferably 5% by mass to 60% by mass, and more preferably 10% by mass to 40% by mass.

[0065] The mass ratio of the crystal formed of ibuprofen and tranexamic acid to licorice contained in the composition to be administered in a day is 75:25 to 15:85, preferably 60:40 to 20:80, and more preferably 50:50 to 30:70.

[0066] In one embodiment, the mass ratio of the crystals formed from ibuprofen and tranexamic acid to licorice is 75:25 to 15:85.

[0067] The composition may contain ingredients other than those listed above, depending on its intended use. When intended to relieve various symptoms of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, and muscle pain, the composition may contain, in addition to bromhexine, meloxicam, and acetaminophen, antipyretic analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically permissible ingredients.

[0068] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into: non-selective COX-2 inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprazin, tiprofenicol, naproxen, lornoxicam, ampicillin, piroxicam, nabumetone, indomethacin, sulindac, mofuzolic acid, and mefenamic acid; and selective COX-2 inhibitors such as meloxicam, etodoxacin, and celecoxib. Meloxicillin can be incorporated into compositions as an NSAID. Non-selective COX-2 inhibitors are preferred. NSAIDs can be in salt form.

[0069] As other pharmacologically permissible ingredients, it can be added in combination with compound cold medicines, antipyretic analgesics, rhinitis medicines, etc., as well as antihistamines, antipyretic analgesics, antitussives and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, antifibrinolytics, etc.

[0070] For example, antihistamines include isoxependyne hydrochloride, difeterol hydrochloride, trapyrimidine diamine hydrochloride, fenethazine hydrochloride, methaqualone hydrochloride, racemic chlorpheniramine maleate, d-chlorpheniramine maleate, carbixamine diphenyl disulfonic acid, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, methaqualone naphthalene disulfonic acid, methylene disalicylic acid promethazine, carbixamine maleate, difeterol phosphate, chlormastine fumarate, and mequinatazine.

[0071] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, acetaminophen, ethylsalicylate, salicylate, salicylamide, lactylphenylethylamine, and isopropylantipyrine. Acetaminophen can be incorporated into compositions as an antipyretic analgesic.

[0072] Examples of antitussive and expectorant drugs include bromhexine, codeine dihydrophosphate, noscarbene, noscarbene hydrochloride hydrate, racemic methylephedrine hydrochloride, racemic methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carboxycysteine, teperidine hydrochloride, and dextromethorphan hydrobromide hydrate.

[0073] As anti-inflammatory drugs, glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), tranexamic acid, etc. can be cited.

[0074] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0075] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., phenylphosphine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, etc.

[0076] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isoproiodine, diphenylpiperidine methyldioxolane iodide, hyoscyamine extract, hyoscyamine root, and total hyoscyamine root alkaloids citrate.

[0077] Tranexamic acid is an example of an antifibrinolytic agent.

[0078] Examples of disintegrants include starches, adipic acid, alginate, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (hereinafter sometimes referred to as CMC-Na), hydrated silica, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silica, crystalline cellulose, synthetic aluminum silicate, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, tragacanth gum powder, hydroxyethyl methyl cellulose, hydroxypropyl starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose, and calcium dihydrogen phosphate. These can be combined in combination with one or more of these substances. Crospovidone and / or sodium carboxymethyl starch are preferred disintegrants, and crospovidone is more preferred.

[0079] Examples of starches include, for instance, one or more combinations selected from corn starch, potato starch, rice starch, partially α-starch, and α-starch. Corn starch is preferred.

[0080] The amount of the disintegrant is not particularly limited as long as it does not impair the effect of the present invention. Preferably, it is 0.1 to 12% by mass relative to the total weight of the preparation, more preferably 0.3 to 10% by mass, and even more preferably 3 to 7% by mass.

[0081] For the compositions of the present invention, formulation additives may be further added as needed. Examples of pharmaceutically permissible carriers include excipients, binders, disintegration aids, gloss enhancers, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromas, colorants, matrices, coating agents, sugar coatings, plasticizers, dispersants, defoamers, flow agents, and flavoring agents. For the purposes described above, formulation additives conventionally known for use in solid dosage forms may be used.

[0082] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate·hydroxypropyl starch·crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, purified white sugar, purified white sugar spheres. Granular components, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially α-substituted starch, powdered sugar, powdered sugar, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminum metasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0083] As a binder, for example, it may be combined with one or more components selected from gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0084] Examples of disintegration aids include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, light anhydrous silica, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0085] As a glossing agent, it may be combined with one or more ingredients selected from carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc.

[0086] As a foaming agent, one or more components selected from dried sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, anhydrous citric acid, etc., may be incorporated. However, the composition preferably does not contain anhydrous citric acid.

[0087] As a desiccant, it may be combined with one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylaminoacetate, magnesium aluminum metasilicate, etc.

[0088] As a stabilizer, it can be combined with, for example, acetic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, hexadecylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymer, calcium carboxymethyl cellulose, carboxylic acid, etc. Sodium methylcellulose, hydrated silica, dried sodium carbonate, glycine, glycerol, fatty acid glycerides, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamic acid, L-lysine, light anhydrous silica, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, dehydrated sorbitol fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, carbon Sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54)polyoxypropylene (39) glycol, polyoxyethylene (160)polyoxypropylene (30) glycol, polyoxyethylene (196)polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceride (7E.O.), polysorbate The following are one or more components selected from the following: ester 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminum metasilicate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0089] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, ascorbic acid palmitate, and sodium metabisulfite. In the case of a solid composition containing acetaminophen, it is preferable to omit tocopherols as antioxidants or stabilizers.

[0090] Examples of fillers include RSS No.1 raw rubber, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0091] As a sweetener, it may be combined with one or more ingredients selected from aspartame, acesulfame potassium, gancha, gancha powder, reduced malt syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0092] As a flavoring agent, it can be combined with, for example, sodium chloride, phellodendron bark powder, cherry bark extract, coptis root, coptis root powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citrate hydrate, sodium citrate hydrate, L-glutamic acid, monosodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Sichuan pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate. The ingredients include one or more of the following: ginger powder, sucralose, stevia extract, purified stevia extract, angelica, D-sorbitol, tannic acid, clove oil, tangerine peel tincture, chili pepper, chili powder, spruce powder, trehalose hydrate, bitterwood powder, plum pulp extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, borneol, borneol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0093] Examples of cooling agents include, for example, fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0094] As a flavoring agent, it may be combined with one or more ingredients selected from orange flavoring, guarana extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach essence, fruit flavoring, mint, melon powder flavoring, L-menthol, peppermint oil, etc.

[0095] Examples of aromatic agents include, for example, anise powder, anise oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili powder, pineapple powder spice 51357, pineapple powder spice 59492, peppermint water, peppermint oil, vanilla powder spice 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0096] As a coloring agent, it may be combined with one or more ingredients selected from the following: yellow iron oxide, yellow ferric oxide, orange flavor, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, diazo yellow, edible blue 1, edible yellow 4, edible yellow 5, edible blue 2 aluminum lake, edible yellow 4 aluminum lake, edible red 2, edible red 3, edible red 102, ferric oxide / glycerol suspension, sodium copper chlorophyllin, copper chlorophyllin, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc.

[0097] As a matrix, it can be formulated with ingredients selected from gum arabic powder, α-starch, ethyl cellulose, cocoa butter, carbamate wax, carboxyvinyl polymers, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced malt syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, fatty acid glycerides, light anhydrous silicate, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium silicate sodium, titanium dioxide, tartaric acid, sucrose fatty acid esters, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerol, potato starch, hydroxypropyl cellulose, and hydroxyl... The product contains one or more of the following components: propyl methylcellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitol monostearate, squalene monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylate-methyl methacrylate copolymer. Crystalline cellulose is preferred as the base material.

[0098] Examples of coating agents include, for instance, ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers E, aminoalkyl methacrylate copolymers RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersions, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, fatty acid glycerides, hydrogenated oil, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methylcellulose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2 Mixture 910, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, methyl 2-methyl-5-vinylpyridine acrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, dehydrated sorbitol monostearate, dehydrated sorbitol monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0099] As a sugar coating agent, for example, it may be combined with one or more components selected from gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyoxyethylene stearate 40, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0100] As a plasticizer, it may be combined with one or more components selected from triethyl citrate, glycerol, fatty acid glycerides, D-sorbitol, medium-chain fatty acid triglycerides, glyceryl triacetate, concentrated glycerol, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc.

[0101] As a dispersant, it can be formulated with a selection of aminoalkyl methacrylate polymers (RS), gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, fatty acid glycerides, magnesium silicate, light alumina, light anhydrous silicate, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and polyoxyethylene hydrogen. The ingredients include one or more of the following: castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glyceryl monooleate, sorbitol monooleate, aluminum monostearate, glyceryl monostearate, sorbitol monostearate, sorbitol monopalmitate, sorbitol monolaurate, and sodium lauryl sulfate.

[0102] As an antifoaming agent, it can be combined with one or more ingredients selected from ethanol, glycerol fatty acid esters, dimethyl polysiloxane (for internal use), dimethyl polysiloxane-silica mixture, sucrose fatty acid esters, silicone defoamers, silicone oil, dehydrated sorbitol fatty acid esters, polysorbate 80, etc.

[0103] As a flow agent, it may be combined with one or more components selected from hydrated silica, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, calcium phosphate, talc, magnesium aluminum metasilicate, and dicalcium phosphate granules.

[0104] As a flavoring agent or fragrance, it may be combined with one or more ingredients selected from the following: anise powder, anise oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, lemongrass oil, sugar flavoring, spearmint oil, cherry flavoring, clove oil, chili flavoring, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavoring, vanillin, bittering essence, vitamin base, Himalayan cedar oil, fruit flavoring, G1 flavoring, hesperidin peppermint extract, bergamot oil, bergamot flavoring, d-borneol, dl-borneol, matcha, mixed flavorings, peppermint flavoring, dl-menthol, l-menthol, eucalyptus oil, lavender oil, borneol, borneol powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0105] The composition can be formulated into, for example, solid dosage forms such as tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), lozenges, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, poultices, plasters, and caplets; semi-solid dosage forms such as licks, chewing gum, gels, gel drops, whips, ointments, creams, foams, inhalers, and nasal gels; and liquid dosage forms such as syrups, decoctions, suspensions, tinctures, liquids, sprays, and nebulizers, as described in the 18th edition of the Japanese Pharmacopoeia's General Principles of Preparations. Considering ease of administration and manufacturing, the composition of the present invention is preferably a solid dosage form, more preferably an orally administered composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules, and especially preferably a tablet.

[0106] When the composition is a solid dosage form, it can be temporarily packaged and airtightly preserved using bottle packaging, PTP packaging, bag packaging, strip packaging, or SP packaging. It can also be further packaged in pillow-like containers or stored in boxes. There are no particular limitations on the materials used in pillow-like packaging; for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, or materials made by attaching aluminum foil to these resin films, can be used. It should be noted that, if there are concerns about moisture absorption, desiccants can be stored simultaneously inside the bottle packaging or the pillow-like packaging.

[0107] The composition is preferably prepared by compression molding in a manner that causes disintegration and dissolution within an appropriate time. Compression molding can be performed using a conventional tableting machine. The molding pressure of the tableting machine can be comparable to that of a conventional tablet.

[0108] Disintegration can be determined in a tablet disintegration test according to methods known to those skilled in the art, such as the "Disintegration Test Method" of the 18th Revision of the Japanese Pharmacopoeia. The conditions for the disintegration test are, for example, in the case of a tablet composition, a disintegration time of less than 60 minutes, preferably less than 30 minutes, when compressed to a specified hardness. The tablet hardness is, for example, 105 ± 5 N.

[0109] (Disintegration modifier)

[0110] In the second approach, a disintegration modifier is provided for a solid composition comprising crystals formed from ibuprofen and tranexamic acid.

[0111] The disintegration improver contains licorice as an active ingredient.

[0112] The disintegrity improver may also contain a disintegrant. Starch-based disintegrants are preferred.

[0113] (Manufacturing method)

[0114] In a third approach, a method for manufacturing a solid composition is provided, the method comprising the step of contacting crystals formed from ibuprofen and tranexamic acid with licorice.

[0115] The solid composition can be manufactured using known techniques. Licorice can be a commercially available substance. Crystals formed from ibuprofen and tranexamic acid can be manufactured using the method described in Japanese Patent Application Publication No. 2022-70674 (as described above).

[0116] Crystals formed from ibuprofen and tranexamic acid, along with licorice, are added individually in any step of the process, ultimately bringing them into contact. Solvents and binders can be added to the resulting mixture, and the mixture can be kneaded to obtain a solid composition.

[0117] The kneaded mixture can also be further dried and granulated to produce granules. In this case, granules containing each component can be prepared separately. Granulation can be wet or dry.

[0118] The resulting granules can be used directly, or additives can be added to the granules and compressed into tablets to produce uncoated tablets, or they can be further coated with a film.

[0119] To illustrate the invention in more detail, experimental examples and embodiments are described below, but the invention is not limited to these.

[0120] Example

[0121] The solubility evaluation of ibuprofen was carried out as follows.

[0122] 1. Raw materials and preparation method of solid preparation

[0123] The raw materials used are shown in Table 1.

[0124] [Table 1]

[0125] Use raw materials

[0126] Raw materials Preparation name Manufacturer Ibuprofen Ibuprofen Albemarle Licorice extract powder Licorice extract powder-A Nippon Powder Medicine Co., Ltd. Tranexamic acid Tranexamic acid Kyowa Pharma Chemical Crystalline cellulose Ceolus UF-702 Asahi Kasei Corporation Corn starch Corn starch Matsutani Chemical Industry D-mannitol D-mannitol Bussan Food Science Co., Ltd. Magnesium stearate Magnesium stearate Taihe Chemical Industry

[0127] 2. Method for manufacturing crystals formed from ibuprofen and tranexamic acid

[0128] 240.0 g of ibuprofen (manufactured by R. Yonezawa) and 182.9 g of tranexamic acid (manufactured by AMI) were added to a vertical granulator (Vertical Granulator VG-5, manufactured by Powrex) and mixed to form a powder. 69 g of a mixture of ethanol (99.5% purity) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was added to the powder and kneaded to form a granulated compound. The compound was then wet-milled using a PowerMill (manufactured by Dalton) at low speed and 32 mesh conditions, and stored at 70°C for 89 hours.

[0129] The obtained sample was placed in a differential scanning calorimeter, and the results were obtained. Figure 1 The DSC curve is shown. The DSC curve reveals an endothermic peak near 180°C characteristic of crystals formed from ibuprofen and tranexamic acid.

[0130] 3. Tablet manufacturing method

[0131] Weigh each ingredient according to the proportions in Tables 1 and 2 below to make a total of 5g, mix them evenly in a bottle, and prepare each tablet powder. For each tablet powder, use... Using a 10.8R tablet press (Riken Seiki), tablets were produced at a pressure of 105 ± 5 N to produce 300 mg tablets. For samples with a tablet hardness of less than 105 N, tablets were produced by compression at a pressure of 10 kN.

[0132] 4. Disintegration assessment

[0133] For the tablets prepared in the above three methods, disintegration tests were conducted using an NT-2HSF disintegration testing machine (Toyama Sangyo). The disintegration tests were performed based on the 18th revision of the Japanese Pharmacopoeia.

[0134] [Table 2]

[0135]

[0136] In this embodiment, the mixture of ibuprofen and tranexamic acid is sometimes referred to as "IB+TXA", and the crystals formed by ibuprofen and tranexamic acid are sometimes referred to as "IB-TXA" or "IB-TXA crystals".

[0137] [Table 3]

[0138] Comparative Example 4 Example 4 Comparative Example 1 Example 1 Comparative Example 5 Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Ibuprofen 27.0 18.2 15.6 14.2 7.1 Licorice extract powder 2.5 2.5 18.0 18.0 22.5 22.5 25.0 25.0 37.5 37.5 Tranexamic acid 20.5 13.8 11.9 10.8 5.4 IB-TXA crystal 47.5 32.0 27.5 25.0 12.5 D-mannitol 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Crystalline cellulose 39.0 39.0 39.0 39.0 39.0 39.0 39.0 39.0 39.0 39.0 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Licorice (converted from crude drug) 17.5 17.5 126.0 126.0 157.5 157.5 175.0 175.0 262.5 262.5 IB-TXA crystal: licorice (converted from crude drug) ratio - 73：27 - 20：80 - 15：85 - 13：87 - 5：95 Disintegration time (min) ＞60 4.6 ＞60 32.8 42.8 29.2 35.0 32.5 24.7 26.6

[0139] As shown in Tables 2 and 3, the crystals formed from ibuprofen and tranexamic acid exhibit superior disintegration properties compared to a mixture of ibuprofen and tranexamic acid in the same proportion.

Claims

1. A solid composition comprising: (A) crystals formed from ibuprofen and tranexamic acid; and (B) licorice.

2. The solid state composition of claim 1, wherein, The mass ratio of component (A) to component (B) is 75:25 to 15:85 ((A):(B)), and the mass of (B) is the crude drug conversion amount.

3. The solid composition according to claim 1 or 2, further comprising a disintegrant.

4. The solid state composition of claim 3, wherein, The content of the disintegrant is less than 12% relative to the total amount of the solid composition.

5. The solid state composition of claim 3, wherein, The disintegrant is a starch.

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