Solid composition

Abstract

Providing a novel solid composition. 【Solution means】The present invention provides a solid composition comprising a crystal composed of ibuprofen and tranexamic acid and licorice.

Description

Technical Field

[0001] The present invention broadly relates to a solid composition containing a crystal composed of ibuprofen and tranexamic acid and licorice, etc.

Background Art

[0002] Solid preparations such as tablets for oral administration disintegrate in the digestive tract, and then the active ingredients in the preparation are absorbed into the body. It is extremely important in the design of the preparation that the solid preparation disintegrates within a predetermined time under specified conditions. When the solid preparation is difficult to disintegrate, improvement of the disintegrability is often required by blending a disintegrant or the like.

[0003] Some active ingredients of pharmaceuticals reduce the disintegrability of solid preparations, and some of them further deteriorate the disintegrability in combination with other components than when alone. For example, ibuprofen causes a decrease in disintegrability even alone, but it is known that the disintegrability further decreases when combined with tranexamic acid (Patent Document 1).

[0004] It is also known that solid preparations containing licorice, which is one of the crude drugs, have low disintegrability (Non-Patent Document 1).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] A solid composition containing ibuprofen, tranexamic acid, and licorice, which is formulated as a cold medicine, may be required to disintegrate more quickly from the perspective of immediate efficacy.

[0008] It has been revealed that the disintegrability of a solid composition containing a combination of ibuprofen, tranexamic acid, and licorice is significantly lower than that of solid compositions containing each component alone.

Means for Solving the Problems

[0009] Regarding the poorly disintegrating solid composition containing the above three components, the inventors have found that the disintegrability can be improved by crystallizing ibuprofen and tranexamic acid, and have thus completed the present invention.

[0010] That is, the present application encompasses the following inventions. [1] (A) A crystal composed of ibuprofen and tranexamic acid, and (B) Licorice, and A solid composition containing the same. [2] The solid composition according to [1], wherein the mass ratio of component (A) to (B) is 75:25 to 15:85 ((A):(B)), and the mass of (B) is the amount in terms of crude drug. [3] The solid composition according to [1] or [2], further containing a disintegrant. [4] The solid composition according to [3], wherein the content of the disintegrant is less than 12% with respect to the total amount of the solid composition. [5] The solid composition according to [3], wherein the disintegrant is starches.

Effects of the Invention

[0011] By using ibuprofen crystallized with tranexamic acid in combination with licorice, a solid composition with improved disintegrability can be obtained compared to the case where tranexamic acid and ibuprofen are separately formulated. The improvement in the disintegrability of such a solid composition may exceed the improvement in disintegrability by a disintegrant.

Brief Description of the Drawings

[0012]

Figure 1

Modes for Carrying Out the Invention

[0013] (Solid Composition) In a first aspect, (A) a crystal composed of ibuprofen and tranexamic acid, and (B) licorice, and A solid composition containing is provided.

[0014] As used herein, "ibuprofen" has a CAS registration number of 15687 - 27 - 1 and is a compound represented by the chemical formula C 13 H 18 O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti - inflammatory, analgesic, antipyretic agents, etc. The salts of ibuprofen are not particularly limited as long as they are pharmaceutically acceptable.

[0015] The blending amount of ibuprofen or its salt is appropriately adjusted according to the use of ibuprofen or its salt in the composition, the symptoms, age, weight, gender, etc. of the subject to be administered. For example, when ibuprofen or its salt is blended as a non - steroidal anti - inflammatory drug, the amount of ibuprofen or its salt administered to an adult per day can be adjusted in the range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, more preferably 200 mg to 600 mg. In the present invention, "adult" means men and women 15 years of age or older. However, the composition of the present invention is not limited to those for adults to take, and may also be taken by children under 15 years of age. When children take it, it can be used after reducing the amount taken by an adult per day, such as 1 / 2 or 2 / 3, according to each age group.

[0016] The above dosage is an example, and the content of ibuprofen or a salt thereof per composition administered per day is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass, more preferably about 10% by mass to about 30% by mass.

[0017] In one embodiment, the content of ibuprofen or a salt thereof contained in the composition administered per day is 1% by mass to 70% by mass, preferably 5 to 50% by mass, more preferably 10 to 30% by mass.

[0018] The weight and dosage of the above composition are the dosage per day (one-day dose), but the same amount may be divided into multiple times per day, for example, 2 times or 3 times, preferably 3 times, and administered to the subject. The same applies to components other than ibuprofen or a salt thereof. Also, since each dosage is the total amount, the content of each component contained in the composition may vary depending on the single dose, dosage form of the composition, etc.

[0019] In a specific embodiment, the composition is a tablet, and the above dosage is the amount of the component contained in 3 tablets, 6 tablets or 9 tablets, preferably the amount of the component in 9 tablets. In this embodiment, the number of times of taking for an adult (15 years old or above) is 3 times, the number of tablets taken at one time is 2 tablets, 3 tablets or 4 tablets, preferably the number of tablets taken at one time is 3 tablets.

[0020] Unless otherwise specified, the description regarding the amount of ibuprofen described in this specification is about the amount in the crystal with tranexamic acid, but the amount may be the total amount of crystallized ibuprofen and non-crystallized ibuprofen.

[0021] In one embodiment, the solid composition contains crystallized ibuprofen and non-crystallized ibuprofen.

[0022] In one embodiment, 90% by mass or more of the ibuprofen contained in the solid composition, 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, is crystallized.

[0023] As used in this specification, "tranexamic acid" has a CAS registration number of 1197-18-8 and is a compound represented by the chemical formula C8H 15 NO2 (molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs and the like. The salts of tranexamic acid are not particularly limited as long as they are pharmacologically acceptable.

[0024] The compounding amount of tranexamic acid or its salt is appropriately adjusted according to the use of tranexamic acid or its salt in the composition. The compounding amount of tranexamic acid or its salt varies depending on the amount of ibuprofen and the like. For example, the amount per day is in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, more preferably 400 mg to 750 mg.

[0025] The content of tranexamic acid or its salt contained in the composition administered daily is 1% by mass to 70% by mass, preferably 5% to 50% by mass, more preferably 10% to 30% by mass.

[0026] The tranexamic acid or its salt contained in the composition administered daily 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, more preferably 0.7 parts by mass to 2.2 parts by mass, relative to 1 part by mass of ibuprofen.

[0027] Unless otherwise specified, the description regarding the amount of tranexamic acid described in this specification is for the amount in the crystal with ibuprofen, but the amount may be the total amount of crystallized tranexamic acid and non-crystallized tranexamic acid.

[0028] In one embodiment, the solid composition contains crystallized tranexamic acid and non-crystallized tranexamic acid.

[0029] Ibuprofen and tranexamic acid exist as crystals in the composition. In the crystal, ibuprofen and tranexamic acid may be present in a molar ratio of 1:1. Further, in the crystal, ibuprofen and tranexamic acid may form a crystal unit cell of four molecules each.

[0030] In the crystal, a hydrogen bond may 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.

[0031] The crystal may have an endothermic peak near 180 °C in differential scanning calorimetry (DSC). Near 180 °C may be, for example, in the range of 180 °C ± 20 °C, or may be in the range of 180 °C ± 10 °C. Note that in the DSC of the crystal, the melting heat peak near 75 °C characteristic of ibuprofen may disappear.

[0032] The crystal may have, for example, the crystal structure shown in FIG. 1 of JP-A-2022-70674, and may have the X-ray diffraction pattern shown in FIG. 2 of the same publication. The crystal may have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in the X-ray diffraction pattern.

[0033] The crystal composed of ibuprofen and tranexamic acid can be produced, for example, by the method described in JP-A-2022-70674. Three typical production methods described in the same publication are shown below.

[0034] A method for producing a crystal composed of ibuprofen and tranexamic acid, (1) generating a fluid ibuprofen by adding or heating a solvent; (2) mixing the obtained fluid ibuprofen and tranexamic acid; and (3) generating crystals from the obtained mixture.

[0035] A method for producing crystals composed of ibuprofen and tranexamic acid, comprising: (1) obtaining tranexamic acid in a fluid having fluidity; (2) mixing the obtained tranexamic acid in a fluid having fluidity with ibuprofen or ibuprofen in a fluid having fluidity obtained by adding or heating a solvent; and (3) generating crystals from the obtained mixture.

[0036] A method for producing crystals composed of ibuprofen and tranexamic acid, comprising: (1) adding ibuprofen and tranexamic acid into a solvent to obtain a solution or dispersion; (2) spraying and drying the obtained solution or dispersion, or allowing the solution obtained in step (1) to stand, filtering the product obtained after standing, and drying the product.

[0037] As used herein, "Licorice" can be the one listed in the 18th Revised Japanese Pharmacopoeia. As Licorice, for example, there are those obtained by using water or a 30% aqueous ethanol solution as an extraction solvent. For example, depending on the type of extract such as Licorice extract, Licorice dry extract, Licorice soft extract, Licorice fluid extract, etc., various products with different crude drug conversion ratios are sold. The amounts of Licorice described in this specification are values converted to crude drugs unless otherwise specified. For example, Licorice soft extract contains about 4 parts by mass of Licorice in terms of crude drug conversion ratio per 1 part by mass of the extraction solvent. In addition to these Licorice extracts, powders of extracts obtained by extracting Licorice with water or a 30% aqueous ethanol solution (extract powder), Licorice extracts, Licorice extract solutions, etc. may be used as appropriate and are not particularly limited. However, an extract powder obtained by drying a Licorice dry extract containing 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 in terms of crude drug conversion ratio per 1 part by mass of the extraction solvent is preferred.

[0038] The extract component can be obtained by a conventional method, for example, by extracting the active ingredient from the crude drug with an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or as a mixed solvent of two or more kinds.

[0039] The blending amount of licorice is appropriately adjusted according to the use of licorice in the composition. The blending amount of licorice is, for example, in the range of 100 mg to 5,000 mg, preferably 200 mg to 2,000 mg, more preferably 500 mg to 1,200 mg per day.

[0040] The content of licorice contained in the composition administered per day is 1% by mass to 80% by mass, preferably 5% by mass to 60% by mass, more preferably 10% by mass to 40% by mass.

[0041] The mass ratio of the crystal composed of ibuprofen and tranexamic acid to licorice contained in the composition administered per day is 75:25 to 15:85, preferably 60:40 to 20:80, more preferably 50:50 to 30:70.

[0042] In one embodiment, the mass ratio of the crystal composed of ibuprofen and tranexamic acid to licorice is 75:25 to 15:85.

[0043] The composition may contain components other than the above components depending on its use. When the composition is intended to relieve various symptoms of a cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, antipyretic analgesics, particularly active ingredients such as non-steroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components may be formulated.

[0044] Non-steroidal anti-inflammatory drugs are broadly classified into COX-2 non-selective inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, mefenamic acid, etc., and COX-2 selective inhibitors such as meloxicam, etodolac, celecoxib, etc. Meloxicam may be formulated in the composition as a non-steroidal anti-inflammatory drug. The non-steroidal anti-inflammatory drug is preferably a COX-2 non-selective inhibitor. The non-steroidal anti-inflammatory drug may be in the form of a salt.

[0045] As other pharmacologically acceptable components, antihistamines, antipyretic analgesics, antitussive expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, antiplasmin agents, etc., which are formulated in over-the-counter cold medicines, antipyretic analgesics, rhinitis medicines, etc., may be additionally formulated.

[0046] For example, antihistamines include isopentyl hydrochloride, dipheteol hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, phenetidine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyl disulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dipheteol phosphate, clemastine fumarate, mequitazine, and the like.

[0047] Examples of antipyretics and analgesics other than non-steroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, salsalate, salicylamide, lactylphenetidine, isopropylantipyrine, and the like. Acetaminophen may be formulated in the composition as an antipyretic and analgesic.

[0048] Examples of antitussive and expectorant drugs include bromhexine, dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylphenidate hydrochloride, dl-methylphenidate saccharinate, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, and the like.

[0049] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), tranexamic acid, and the like.

[0050] Examples of central nervous system stimulants include caffeine, anhydrous caffeine, and the like.

[0051] Examples of vitamins include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), 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, and the like.

[0052] Examples of anticholinergics include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyl dioxolane iodide, rhubarb extract, rhubarb root, total rhubarb root alkaloids citrate, and the like.

[0053] An example of an antifibrinolytic agent is tranexamic acid.

[0054] Examples of disintegrants include starches, adipic acid, alginic acid, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium (hereinafter sometimes referred to as CMC-Na), hydrous silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, tragacanth powder, hydroxyethyl methyl cellulose, hydroxypropyl starch, sodium fumarate, povidone, anhydrous citric acid, methyl cellulose, calcium dihydrogen phosphate, and the like. These can be formulated by combining one or more of them. Preferred disintegrants are crospovidone and / or sodium carboxymethyl starch, and more preferably crospovidone.

[0055] Examples of starches include one or more combinations selected from corn starch, potato starch, rice starch, pregelatinized starch, and gelatinized starch. Corn starch is preferred.

[0056] The blending amount of the disintegrant is not particularly limited as long as the effects of the present invention are not impaired, but is preferably 0.1 to 12% by mass, more preferably 0.3 to 10% by mass, and even more preferably 3 to 7% by mass based on the total weight of the preparation.

[0057] For the composition of the present invention, pharmaceutical additives may be further added as necessary. Examples of pharmaceutical additives include pharmaceutically acceptable carriers such as excipients, binders, disintegration aids, glazing agents, foaming agents, moisture-proof agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, flavoring agents, coloring agents, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents and fragrances, etc. Pharmaceutical additives that can be used in conventionally known solid preparations can be used for the above purposes.

[0058] Examples of excipients include, for example, starch syrup, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose - sodium carboxymethyl cellulose, crystalline cellulose (fine particles), 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, refined sugar, refined sugar spherical granules, gelatin, D - sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low - substituted hydroxypropyl cellulose, dextrin, corn starch, granulated corn starch, trehalose, silicon dioxide, lactose hydrate, granulated lactose, sucrose, potato starch, hydroxypropyl starch, partially pre - gelatinized starch, powdered sugar, powdered maltose, powdered reduced maltose syrup starch, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D - mannitol, magnesium aluminum metasilicate, calcium sulfate, erythritol, glucose, fructose, and the like.

[0059] Examples of binders include, for example, gum arabic, powdered gum arabic, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, 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, methyl cellulose, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, and one or more components selected from these can be blended.

[0060] Examples of the disintegrating agent include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium hydrogen carbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0061] Examples of the brightening agent include one or more components selected from carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, and the like.

[0062] Examples of the foaming agent include one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, and the like. However, it is preferable that the composition does not contain anhydrous citric acid.

[0063] Examples of the moisture-proof agent include one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, refined sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid·stearic acid·polyvinyl acetal diethylaminoacetate·hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylaminoacetate, magnesium aluminometasilicate, and the like.

[0064] Examples of stabilizers include adipic 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, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cacao butter, carboxyvinyl polymer, calcium carmellose, sodium carmellose, hydrated silicon dioxide, anhydrous sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soy lecithin, gelatin, gelatin hydrolyzate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, 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 acid glyceryl (7 E.O.) Polysorbate 20, Polysorbate 60, Polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, sodium anhydrous citrate, sodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate anhydrous, magnesium aluminum metasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc., and one or more components selected therefrom can be formulated.

[0065] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. In the case of a solid composition containing acetaminophen, it is preferably not formulated with tocopherols as an antioxidant or stabilizer.

[0066] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, calcium hydrogen phosphate, etc.

[0067] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia purified extract, refined sugar, fructose, sucrose, maltitol, D-mannitol, erythritol, etc., and one or more components selected therefrom can be formulated.

[0068] As flavoring agents, for example, one or more components selected from sodium chloride, cinnamon powder, aconite extract, Chinese magnoliavine, Chinese magnoliavine powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, monosodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, sansho powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, ginger powder, sucralose, stevia extract, purified stevia extract, cinnamon, D-sorbitol, tannic acid, clove oil, Chinese prickly ash, capsicum, capsicum powder, torreya powder, trehalose hydrate, bitter orange powder, ume flesh extract, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, borneol, borneol powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, rose oil, etc. can be blended.

[0069] As cooling agents, for example, perilla oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, l-menthol, etc. can be mentioned.

[0070] As fragrances, for example, one or more components selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc. can be blended.

[0071] Examples of fragrances include, for example, star anise powder, star anise oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginseng powder, spearmint oil, clove oil, turpentine oil, capsicum powder, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanilla, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0072] Examples of colorants include, for example, iron oxide yellow, yellow iron sesquioxide, orange essence, iron oxide brown, carbon black, caramel, β-carotene, licorice extract, gold leaf, iron oxide black, titanium oxide, iron sesquioxide, disazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, iron sesquioxide-glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc. One or more components selected therefrom can be blended.

[0073] As the base, one or more components selected from gum arabic powder, α - starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, sodium carmellose, reduced maltose syrup, hydrous silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, 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 glycerin, potato starch, hydroxypropyl cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D - mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, etc. can be blended. Crystalline cellulose is preferred as the base material.

[0074] Examples of coating agents include, for example, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold foil, silver foil, triethyl citrate, glycerin, glycerin fatty acid ester, hardened oil, titanium oxide, sucrose fatty acid ester, 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 glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 - titanium oxide - macrogol 400 mixture, hypromellose, fumaric acid - stearic acid - polyvinyl acetal diethylaminoacetate - hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate - methacrylic acid - methyl methacrylate copolymer, methyl cellulose, 2-methyl-5-vinylpyridine methyl acrylate - methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, etc.

[0075] Examples of sugar coating agents include one or more components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, etc.

[0076] Examples of plasticizers include one or more components selected from triethyl citrate, glycerin, glycerin fatty acid ester, D - sorbitol, medium - chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, 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, liquid paraffin, etc.

[0077] As the dispersant, one or more components selected from aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated 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, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, sodium anhydrous citrate, magnesium aluminum metasilicate, methyl cellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc. can be blended.

[0078] As the antifoaming agent, one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for oral use), dimethylpolysiloxane - silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc. can be blended.

[0079] As the fluidizing agent, for example, one or more components selected from hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, etc. can be blended.

[0080] As the perfume and flavoring agent, for example, one or more components selected from star anise powder, star anise 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, torreya tincture, torreya oil, pine oil, peppermint oil, vanilla flavor, vanilla, bitter essence, vitabase, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, bergamot flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, dragon's blood, dragon's blood powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc. can be blended.

[0081] The composition can be in dosage forms described in the General Rules for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as solid preparations like tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), troches, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, cataplasms, plasters, caplets, etc.; semi-solid preparations like lozenges, chewing gums, jellies, jelly drops, whips, ointments, creams, foams, inhalants, nasal gels, etc.; liquid preparations like syrups, drinks, suspensions, spirits, solutions, aerosols, sprays, etc. The composition of the present invention is preferably a solid preparation in terms of ease of administration and manufacturing aspects, more preferably an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules, and particularly preferably a tablet.

[0082] When the composition is a solid preparation, the composition may be once packaged by bottle packaging, PTP packaging, pouch packaging, stick packaging, SP packaging and stored airtightly. Further, they may be pillow-packaged, and they may be stored in a box or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene films, polyethylene terephthalate films, and polyethylene films, or those with an aluminum foil attached to these resin films can be used. In addition, when there is concern about hygroscopicity, a desiccant or the like may be stored simultaneously in the bottle packaging or the pillow packaging.

[0083] The composition is preferably prepared by compression molding so as to disintegrate and dissolve at an appropriate time. Compression molding can be carried out using an ordinary tableting machine. The molding pressure by the tableting machine may be similar to that of ordinary tablets.

[0084] The disintegration property can be determined by a method known to those skilled in the art, for example, in the tablet disintegration test according to the "Disintegration Test Method" of the Japanese Pharmacopoeia, 18th Edition. The conditions for the disintegration test are, for example, when the composition is a tablet, the disintegration time is within 60 minutes, preferably within 30 minutes, when tableting is carried out with a pressure that gives a predetermined hardness. The tablet hardness is, for example, 105 ± 5 N.

[0085] (Disintegration improver) In a second aspect, there is provided a disintegration improver for a solid composition containing crystals composed of ibuprofen and tranexamic acid, which contains glycyrrhiza as an active ingredient.

[0086] The disintegration improver may further contain a disintegrant. As such a disintegrant, starches are preferable.

[0087] (Production method) In a third aspect, there is provided a method for producing a solid composition, which includes a step of bringing crystals composed of ibuprofen and tranexamic acid into contact with glycyrrhiza.

[0088] The production of the solid composition can be carried out using known techniques. Commercially available glycyrrhiza can be used. Crystals composed of ibuprofen and tranexamic acid can be produced by the method described in JP 2022-70674 A (supra).

[0089] The crystals composed of ibuprofen and tranexamic acid and glycyrrhiza are each added in an arbitrary step and finally brought into contact with each other. A solvent or a binder may be added to the mixture after contact and kneaded, and the obtained kneaded product may be used as the solid composition.

[0090] The kneaded product can also be subjected to a further drying step or granulation step to produce granules (granulated products). In this case, the granules (granulated products) containing each component may be prepared separately. The granulation may be wet or dry.

[0091] The obtained granules (granulated products) as they are, or additives are blended with the granules, and these can be tabletted to produce tablets, and further, these can be film-coated.

[0092] In order to explain the present invention in more detail, test examples and examples are described below, but the present invention is not limited thereto.

Example

[0093] The elution property evaluation of ibuprofen was carried out as follows.

[0094] 1. Preparation method of raw materials and solid preparations

[0095] The raw materials used are shown in Table 1. Raw materials used

Table 1

[0096] 2. Method for producing a crystal composed of ibuprofen and tranexamic acid 240.0 g of ibuprofen (manufactured by Yonezawa Hamari) and 182.9 g of tranexamic acid (manufactured by AMI) were charged into a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Pauleck)) and mixed to obtain a mixed powder. 69 g of a mixed solution of ethanol (purity 99.5%) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was poured into this mixed powder and kneaded and granulated to obtain a kneaded product. The kneaded product was wet-crushed under the conditions of a power mill (manufactured by Dalton), low speed, and 32 mesh, and stored for 89 hours under the condition of a constant temperature bath at 70°C.

[0097] As a result of subjecting the obtained sample to a differential scanning calorimeter, a DSC curve as shown in Figure 1 was obtained. In the DSC curve, an endothermic peak around 180°C, which is specific to the crystal composed of ibuprofen and tranexamic acid, was confirmed.

[0098] 3. Method for producing tablets Each raw material was weighed so as to total 5 g according to the blending ratios shown in Tables 1 and 2 below, and uniformly mixed in a bottle to prepare each tableting powder. Each tableting powder was used with a 9φ, 10.8R pestle and tableted at a tableting pressure such that the tablet hardness became 105 ± 5 N using a hand press tableting machine (manufactured by Riken Seiki) to prepare tablets of 300 mg per tablet. For samples with a tablet hardness less than 105 N, tablets were prepared by tableting at a pressure of 10 kN.

[0099] 4. Disintegration property evaluation The disintegration test was performed on the tablets prepared in 3 above using a disintegration tester NT-2HSF (Toyama Sangyo). The disintegration test was carried out based on the 18th revised Japanese Pharmacopoeia.

[0100]

Table 2

[0101]

Table 3

[0102] As shown in Tables 2 and 3, the crystal composed of ibuprofen and tranexamic acid was superior in disintegration property to the mixture of ibuprofen and tranexamic acid at the same mixing ratio.

Claims

Claim 1 (A) a crystal comprising ibuprofen and tranexamic acid, and (B) licorice, A solid composition comprising the same. Claim 2 The solid composition according to 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 amount in terms of crude drug. Claim 3 The solid composition according to claim 1 or 2, further comprising a disintegrant. Claim 4 The solid composition according to claim 3, wherein the content of the disintegrant is less than 12% of the total amount of the solid composition. Claim 5 The solid composition according to claim 3, wherein the disintegrant is starches.

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