solid components

Abstract

To provide a method for producing a novel solid composition. [Solution] The present invention provides a method for producing a solid composition, comprising the step of contacting (A) a crystal consisting of ibuprofen and tranexamic acid with (B) licorice.

Description

Technical Field

[0001] The present invention broadly relates to a solid composition containing crystals 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 hardly disintegratable, improvement in disintegratability is often required by blending a disintegrant or the like.

[0003] There are active ingredients of pharmaceuticals that reduce the disintegratability of solid preparations, and some of them further deteriorate the disintegratability in combination with other components than when alone. For example, ibuprofen causes a reduction in disintegratability even alone, but it is known that the disintegratability 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 disintegratability (Non-Patent Document 1).

Prior Art Documents

Patent Documents

[0008] It was found that the disintegration of a solid composition containing a combination of ibuprofen, tranexamic acid, and licorice was significantly lower than that of solid compositions containing each component individually. [Means for solving the problem]

[0009] Regarding a poorly disintegrating solid composition containing the three components mentioned above, the inventors discovered that the disintegration properties could be improved by crystallizing ibuprofen and tranexamic acid, thus completing the present invention.

[0010] In other words, this application encompasses the following inventions. [1] (A) A crystal composed of ibuprofen and tranexamic acid, (B) Licorice and, A solid composition containing the following: [2] The solid composition described in [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 equivalent amount of crude drug. [3] The solid composition according to [1] or [2], further comprising a disintegrant. [4] The solid composition according to [3], wherein the disintegrant content is less than 12% of the total amount of the solid composition. [5] The solid composition according to [3], wherein the disintegrant is a starch. [Effects of the Invention]

[0011] When used in combination with licorice, the use of tranexamic acid and crystallized ibuprofen yields a solid composition with improved disintegration properties compared to when tranexamic acid and ibuprofen are combined separately. This improvement in disintegration properties may even surpass the improvement achieved by disintegrants alone.

Brief Description of Drawings

[0012] [Figure 1] FIG. 1 shows the results of differential scanning calorimetry (DSC) of the sample of the embodiment.

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 such as an anti-inflammatory, analgesic, and antipyretic agent. The salt of ibuprofen is not particularly limited as long as it is pharmacologically acceptable.

[0015] The compounding 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 administered subject. For example, when ibuprofen or its salt is compounded as a non-steroidal anti-inflammatory drug, the amount of ibuprofen or its salt administered to an adult per day can be adjusted within 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 aged 15 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 old. When taken by children, it can be used after reducing the amount taken by an adult per day by 1 / 2, 2 / 3, etc. according to each age group.

[0016] The above dosage is an example, and the content of ibuprofen or its salt 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 its salt 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 and administered to the subject in multiple times per day, for example, 2 times or 3 times, preferably 3 times. The same applies to components other than ibuprofen or its salt. Also, since each dosage is the total amount, the content of each component contained in the composition may vary depending on the single-dose amount, 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 single dose for an adult (15 years old or above) is 3 times, and the single dose is 2 tablets, 3 tablets or 4 tablets, preferably the single dose is 3 tablets.

[0020] Unless otherwise specified, the description regarding the amount of ibuprofen described in this specification is for 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 is crystallized, 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.

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

[0024] The amount of tranexamic acid or its salt is adjusted as appropriate depending on the intended use of tranexamic acid or its salt in the composition. The amount of tranexamic acid or its salt varies depending on the amount of ibuprofen, etc., but for example, the daily amount is in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

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

[0026] The amount of tranexamic acid or a salt thereof contained in the composition administered daily is, for example, 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass, and more preferably 0.7 to 2.2 parts by mass, per 1 part by mass of ibuprofen.

[0027] Unless otherwise specified, the amounts of tranexamic acid described herein refer to the amount in crystalline form with ibuprofen, but such amounts may also refer to the total amount of crystalline and non-crystalline tranexamic acid.

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

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

[0030] In the crystal, hydrogen bonds 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 around 180°C in differential scanning calorimetry (DSC). "Around 180°C" may refer to a range such as 180°C ± 20°C or 180°C ± 10°C. Note that the fusion heat peak around 75°C, characteristic of ibuprofen, may disappear in the DSC of the crystal.

[0032] The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674, and may have the X-ray diffraction pattern shown in Figure 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 its X-ray diffraction pattern.

[0033] Crystals composed of ibuprofen and tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-70674. Three representative production methods described in the same publication are listed below.

[0034] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising (1) producing ibuprofen in a fluid form by adding a solvent or heating, (2) mixing the obtained fluid ibuprofen with tranexamic acid, and (3) producing crystals from the obtained mixture.

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

[0036] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising: (1) adding ibuprofen and tranexamic acid to 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] In this specification, "licorice" refers to the licorice listed in the 18th edition of the Japanese Pharmacopoeia. Examples of licorice include those extracted using water or a 30% ethanol aqueous solution as the extraction solvent. Depending on the type of extract, such as licorice extract, dried licorice extract, soft licorice extract, or fluid licorice extract, various crude drug equivalent ratios are available. Unless otherwise specified, the amounts of licorice described herein are converted to crude drug equivalents. For example, soft licorice extract contains approximately 4 parts by mass of licorice per 1 part by mass of extraction solvent. In addition to these licorice extracts, powdered extracts obtained by extracting licorice with water or a 30% ethanol aqueous solution (extract powder), licorice extract, licorice extract solution, etc., may also be used as appropriate, and are not particularly limited. However, a dried extract powder of licorice containing approximately 5 to 9 parts by mass of licorice per 1 part by mass of extraction solvent, for example, approximately 7 to 8 parts by mass of licorice in terms of crude drug equivalent, is preferred.

[0038] The extracted components can be obtained by conventional methods, for example, by extracting the active ingredients from the crude drug using an extraction solvent. Commonly used extraction solvents include water, hydrophilic solvents, or mixtures thereof. Examples of hydrophilic solvents 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; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used individually or as a mixture of two or more.

[0039] The amount of licorice included is adjusted as appropriate depending on the use of licorice in the composition. For example, the amount of licorice included is in the range of 100 mg to 5,000 mg per day, preferably 200 mg to 2,000 mg, and more preferably 500 mg to 1,200 mg.

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

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

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

[0043] The composition may contain components other than those listed above, depending on its intended use. If the composition is intended to alleviate various cold symptoms, 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, it may contain antipyretic analgesics, particularly active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components.

[0044] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into COX-2 nonselective inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and COX-2 selective inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be included in the composition as a NSAID. It is preferable that the NSAID is a COX-2 nonselective inhibitor. The NSAID may also be in the form of a salt.

[0045] Other pharmacologically acceptable ingredients that may be added include antihistamines, antipyretic analgesics, cough and expectorant agents, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly found in combination cold medicines, antipyretic analgesics, and rhinitis medicines.

[0046] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, and mequitazine.

[0047] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine. Acetaminophen may be included in the composition as an antipyretic analgesic.

[0048] Examples of cough suppressants and expectorants include bromhexine, dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, and dextromethorphan hydrobromide hydrate.

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

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

[0051] Examples of vitamin supplements 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 so on.

[0052] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, and total belladonna root alkaloid citrate.

[0053] Tranexamic acid is an example of an antiplasmin agent.

[0054] Examples of disintegrants include starches, adipic acid, alginic acid, sodium carboxymethyl starch, carmellose, calcium carmellose, sodium carmellose (hereinafter sometimes referred to as CMC-Na), hydrated silicon dioxide, calcium citrate, sodium croscarmellose, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, cellulose phthalate acetate, calcium stearate, low-substituted hydroxypropyl cellulose, tragacanth powder, hydroxyethyl methylcellulose, hydroxypropyl starch, monosodium fumarate, povidone, anhydrous citric acid, methylcellulose, calcium dihydrogen phosphate, etc., and these can be blended individually or in combination of two or more. Preferably, the disintegrant is 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, partially pregelatinized starch, and pregelatinized starch. Corn starch is preferred.

[0056] The amount of the above-mentioned disintegrant is not particularly limited as long as it does not impair the effects of the present invention, 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 formulation.

[0057] Pharmaceutical additives may be added to the composition of the present invention as needed. Examples of pharmaceutical additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents / fragrances. Pharmaceutical additives that are conventionally known and can be used in solid dosage forms can be used for the above purposes.

[0058] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carmellose sodium, 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 sucrose, refined sucrose spherical granules, gelatin, D Examples of ingredients include sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose monohydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0059] As a binder, one or more components selected from, for example, gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylate copolymer L, methacrylate copolymer LD, methacrylate copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc., may be incorporated.

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

[0061] As a glossing agent, one or more components selected from, for example, carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, etc., can be incorporated.

[0062] As a foaming agent, one or more components selected from, for example, anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid can be included. However, it is preferable that the composition does not contain anhydrous citric acid.

[0063] As a moisture-proofing agent, one or more components selected from, for example, ethylcellulose, 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, refined shellac, refined sucrose, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, magnesium aluminometasilicate, etc., can be incorporated.

[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, disodium calcium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and dichloride. Iron, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine L-hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, 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, chondrone Sodium leutin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Nonstearyl 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 fat glyceryl (7E.O.)), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glyceryl 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. may be included in the formulation.

[0065] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, and sodium pyrosulfite. In the case of a solid composition containing acetaminophen, it is preferable not to include tocopherols as antioxidants or stabilizers.

[0066] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0067] As a sweetener, one or more ingredients selected from, for example, 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 extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. may be included.

[0068] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica 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, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, and ginger. One or more ingredients selected from the following may be included: lemon extract, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, pisiflora powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0069] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0070] As for the flavoring, one or more ingredients selected from, for example, 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., may be included.

[0071] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili pepper powder, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0072] As coloring agents, one or more ingredients selected from, for example, yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, dizazo 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, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc. may be included.

[0073] The base ingredients include: acacia gum powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated 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 dioxide, 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. One or more components selected from the following can be incorporated: rose, 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, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. Crystalline cellulose is preferred as the base material.

[0074] Examples of coating agents include: 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 leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium dioxide / macrogol 400 mixture, hypromellose, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydro Examples include oxypropylmethylcellulose 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, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0075] As a sugar coating agent, one or more components selected from, for example, gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, 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., may be incorporated.

[0076] As plasticizers, one or more components selected from, for example, triethyl citrate, glycerin, glycerin fatty acid ester, D-sorbitol, medium-chain 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, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc., may be incorporated.

[0077] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, 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 dioxide, 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, and polyoxypropyl cellulose. One or more ingredients selected from the following may be included: hydrogenated ethylene castor oil, hydrogenated polyoxyethylene castor oil 40, hydrogenated polyoxyethylene castor oil 50, hydrogenated polyoxyethylene castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0078] As an 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., may be included.

[0079] As a fluidizing agent, one or more components selected from, for example, 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] Examples of fragrances and scentings include 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, and bitter bean paste. One or more ingredients selected from the following may be included: cereal, cedarwood 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, bonito flakes, bonito flake powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0081] The composition may be in the form of a solid preparation 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; a semi-solid preparation such as licks, chewing gums, jellies, jelly drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; or a liquid preparation such as syrups, drinks, suspensions, alcoholic preparations, liquids, sprays, and aerosols, as described in the General Provisions for Preparations of the 18th Edition of the Japanese Pharmacopoeia. The composition of the present invention is preferably a solid preparation in terms of ease of administration and ease of manufacture, more preferably an orally administered composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules, and particularly preferably a tablet.

[0082] If the composition is a solid dosage form, it may be initially packaged in a bottle, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored airtight. Furthermore, these may be pillow-packaged, and then stored in a box or similar container. The material used for the pillow packaging is not particularly limited; for example, resin films such as polypropylene film, polyethylene terephthalate film, or polyethylene film, or these resin films with aluminum foil attached, can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle or pillow packaging.

[0083] The composition is preferably prepared by compression molding so that it disintegrates and dissolves over an appropriate period of time. Compression molding can be performed using a standard tablet press. The molding pressure using the tablet press can be similar to that of a normal tablet.

[0084] The disintegration properties can be determined by methods known to those skilled in the art, for example, by a tablet disintegration test according to the "Disintegration Test Method" of the 18th edition of the Japanese Pharmacopoeia. The conditions for the disintegration test are, for example, that when the composition is a tablet, the disintegration time when the tablet is compressed with a pressure that results in a predetermined hardness is 60 minutes or less, preferably 30 minutes or less. The tablet hardness is, for example, 105 ± 5 N.

[0085] (Disintegration-improving agent) In a second embodiment, a disintegration-improving agent for a solid composition comprising crystals of ibuprofen and tranexamic acid, with licorice as an active ingredient, is provided.

[0086] The disintegration modifier may further contain a disintegrant. Starches are preferred as such disintegrants.

[0087] (Manufacturing method) In a third embodiment, a method for producing a solid composition is provided, comprising the step of contacting crystals comprising ibuprofen and tranexamic acid with licorice.

[0088] The solid composition can be manufactured using known techniques. Commercially available licorice can be used. Crystals consisting of ibuprofen and tranexamic acid can be manufactured by the method described in Japanese Patent Application Publication No. 2022-70674 (listed above).

[0089] The crystals consisting of ibuprofen and tranexamic acid, and licorice, are added at any stage and finally brought into contact with each other. A solvent or binder may be added to the mixture after contact and kneaded, and the resulting paste may be a solid composition.

[0090] The mixture can also be subjected to further drying and granulation processes to produce granules. In this case, the granules containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0091] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0092] To illustrate the present invention in more detail, test examples and embodiments are described below, but the present invention is not limited thereto. [Examples]

[0093] The dissolution properties of ibuprofen were evaluated as follows.

[0094] 1. Method for preparing raw materials and solid dosage forms

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

[0096] 2. Method for producing crystals consisting of ibuprofen and tranexamic acid 240.0g of ibuprofen (manufactured by Yonezawa Hamari) and 182.9g of tranexamic acid (manufactured by AMI) were charged into a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Powrec)) and mixed to form a mixed powder. 69g of a mixture of ethanol (purity 99.5%) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was added to this mixed powder and kneaded and granulated to form a paste. The paste was wet-crushed using a power mill (manufactured by Dalton) at low speed and 32 mesh, and stored in a constant temperature bath at 70°C for 89 hours.

[0097] When the obtained sample was subjected to differential scanning calorimeter analysis, the DSC curve shown in Figure 1 was obtained. The DSC curve revealed an endothermic peak around 180°C, which is characteristic of crystals composed of ibuprofen and tranexamic acid.

[0098] 3. Method for manufacturing tablets Each raw material was weighed to a total of 5g according to the mixing ratios shown in Tables 1 and 2 below, and then uniformly mixed in a bottle to prepare each tablet powder. Each tablet powder was compressed using a hand press tablet press (manufactured by Riken Seiki) with a 9φ, 10.8R punch at a compression pressure that resulted in a tablet hardness of 105±5N to produce 300mg tablets. For samples with a tablet hardness less than 105N, tablets were prepared by compression at a pressure of 10kN.

[0099] 4. Assessment of disintegration potential The tablets prepared in step 3 above were subjected to a disintegration test using the NT-2HSF disintegration tester (Toyama Sangyo). The disintegration test was conducted in accordance with the 18th edition of the Japanese Pharmacopoeia.

[0100] [Table 2] In this embodiment, a mixture of ibuprofen and tranexamic acid may be referred to as "IB+TXA," and crystals consisting of ibuprofen and tranexamic acid may be referred to as "IB-TXA" or "IB-TXA crystals" in this specification.

[0101] [Table 3]

[0102] As shown in Tables 2 and 3, crystals composed of ibuprofen and tranexamic acid exhibited superior disintegration properties compared to a mixture of ibuprofen and tranexamic acid in the same proportions.

Claims

1. A method for producing a solid composition, comprising the step of contacting (A) crystals consisting of ibuprofen and tranexamic acid with (B) licorice.

2. A method for producing a solid composition, comprising the step of contacting (A) crystals consisting of ibuprofen and tranexamic acid with (B) licorice and (C) a disintegrant.

3. The method according to claim 1 or 2, further comprising the steps of drying and / or granulating a paste of component (A) and component (B).

4. The method according to claim 3, further comprising the step of blending an additive into the granules obtained in the granulation step and forming them into tablets.

5. The method according to claim 1 or 2, 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 equivalent to a crude drug.

6. The method according to claim 1, further comprising the step of blending a disintegrant into a mixture of component (A) and component (B).

7. The method according to claim 2 or 6, wherein the content of the disintegrant is less than 12% of the total amount of the solid composition.

8. The method according to claim 2 or 6, wherein the disintegrant is a starch.

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