Solid composition

Abstract

Providing a solid composition. The present invention provides a solid composition comprising a crystal of ibuprofen and tranexamic acid, and a surfactant.

Description

[Technical field]

[0001] The present invention broadly relates to a solid composition comprising ibuprofen, tranexamic acid, and a surfactant. [Background technology]

[0002] Ibuprofen or its salts are widely used as non-steroidal antipyretic analgesics. However, since ibuprofen is a poorly water-soluble drug, improvements in its dissolution have been studied. Known methods for improving the dissolution of ibuprofen include, for example, changing the pH level and adding a water-soluble polymer base material and a non-ionic surfactant (Patent Document 1).

[0003] Patent Document 1 discloses an easily absorbable solid composition comprising 1 part by weight of ibuprofen, 0.01 to 10 parts by weight of one or more water-soluble polymer bases selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and methylcellulose, and 0.01 to 5 parts by weight of one or more nonionic surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, block polymer ethers, and sucrose fatty acid esters. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3290970 [Patent Document 2] JP 2022-70674 A Summary of the Invention [Problem to be solved by the invention]

[0005] The improvement in the solubility of ibuprofen is not sufficient, and there is still room for improvement. [Means for solving the problem]

[0006] The present inventors have discovered that by crystallizing ibuprofen with tranexamic acid and adding a surfactant to the resulting crystals, it is possible to improve the dissolution property of ibuprofen, i.e., to rapidly dissolve the ibuprofen, and have thus completed the present invention.

[0007] Patent Document 2 reports that by mixing ibuprofen and tranexamic acid, which have fluidity, the ibuprofen and tranexamic acid form crystals, but does not specifically mention the dissolution property of ibuprofen in the crystals composed of ibuprofen and tranexamic acid.

[0008] That is, the present application includes the following inventions. [1] A crystal consisting of ibuprofen and tranexamic acid, A surfactant, A solid composition comprising: [2] The solid composition according to [1], wherein the surfactant is one or more selected from the group consisting of sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyvinyl alcohol. [3] The solid composition according to [1] or [2], comprising 0.0001 to 1 part by mass of a surfactant per 1 part by mass of the crystals. Effect of the Invention

[0009] According to the present invention, by crystallizing ibuprofen with tranexamic acid and adding a surfactant to the obtained crystals, rapid dissolution of ibuprofen is achieved, and as a result, a solid composition with improved dissolution and / or absorbability can be provided. In particular, when the surfactant is sodium lauryl sulfate, an alkyl sulfate ester salt, even a small amount of the surfactant can improve dissolution, and thus the pharmacokinetic profile, such as the time to reach maximum blood concentration (Tmax), can also be improved. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the DSC curve of the granules obtained by kneading the granules containing components 1 and 2 of the sample of Example 14, sizing the granules, and drying them. [Diagram 2] FIG. 2 shows a DSC curve of the mixed powder for tableting of the sample of Comparative Example 5. [Diagram 3] FIG. 3 shows a DSC curve of the mixed powder for tableting of the sample of Example 15. [Figure 4] FIG. 4 shows DSC curves of primary granules of samples of Comparative Example 3, Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, Example 13, and Example 16. [Diagram 5] FIG. 5 shows the DSC curve of the primary granules of the sample of Example 17. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] (solid composition) In a first embodiment, the composition comprises the following ingredients: A crystal consisting of ibuprofen and tranexamic acid, A surfactant, A solid composition comprising: is provided.

[0012] As used herein, "ibuprofen" refers to the compound having the CAS Registry Number 15687-27-1 and C 13 H 18 It is a compound represented by the chemical formula O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic drugs. There are no particular limitations on the salt of ibuprofen as long as it is pharmacologically acceptable.

[0013] The amount of ibuprofen or a salt thereof is appropriately adjusted depending on the purpose of ibuprofen or a salt thereof in the composition, the symptoms, age, weight, sex, etc. of the subject to be administered. For example, when ibuprofen or a salt thereof is formulated as a nonsteroidal anti-inflammatory drug, the amount of ibuprofen or a salt thereof 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 males and females aged 15 years or older. However, the composition of the present invention is not limited to those for adults, and may be those for children under 15 years of age. When administered by children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount administered per day by adults according to each age group.

[0014] 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, and more preferably about 10% by mass to about 30% by mass.

[0015] In one embodiment, the content of ibuprofen or a salt thereof in the composition to be administered daily is 1 to 70% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass.

[0016] The weight and dosage of the above composition are the dosage per day (daily amount), but the same amount may be administered to the subject multiple times a day, for example, twice or three times, preferably three times. The same applies to ingredients other than ibuprofen or its salt. In addition, since each dosage is the total amount, the content of each ingredient contained in the composition may vary depending on the dosage per time and the dosage form of the composition.

[0017] In a specific embodiment, the composition is a tablet, and the dosages given above are the amounts of ingredients contained in 3, 6 or 9 tablets, preferably 9 tablets. In this embodiment, the dosage for an adult (age 15 or older) is 3 tablets, and the dosage is 2, 3 or 4 tablets, preferably 3 tablets.

[0018] Unless otherwise specified, references to the amount of ibuprofen described herein are to the amount in crystals with tranexamic acid, but the amount may be the total amount of crystallized and non-crystallized ibuprofen.

[0019] In one embodiment, the solid composition comprises crystallized and non-crystallized ibuprofen.

[0020] In one embodiment, the ibuprofen contained in the solid composition is 90% by weight or more, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% by weight, crystallized.

[0021] As used herein, "tranexamic acid" refers to the compound having the CAS Registry Number 1197-18-8 and a C 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 of anti-inflammatory drugs, etc. There is no particular limitation on the salt of tranexamic acid as long as it is pharmacologically acceptable.

[0022] The amount of tranexamic acid or a salt thereof is appropriately adjusted depending on the application of tranexamic acid or a salt thereof in the composition. When tranexamic acid or a salt thereof is added for the purpose of improving the dissolution and / or absorbability of ibuprofen or other properties, the amount of tranexamic acid or a salt thereof varies depending on the amount of ibuprofen, etc., but 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.

[0023] The content of tranexamic acid or a salt thereof in the composition to be administered daily is 1 to 70% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass.

[0024] 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 part by mass of ibuprofen.

[0025] Unless otherwise specified, references to the amount of tranexamic acid described in this specification refer to the amount in crystals with ibuprofen, but the amount may be the total amount of crystallized and non-crystallized tranexamic acid.

[0026] In one embodiment, the solid composition comprises crystallized and non-crystallized tranexamic acid.

[0027] When ibuprofen and tranexamic acid are present as crystals in the composition, the ibuprofen and tranexamic acid may be present in the crystal in a molar ratio of 1:1. In addition, the ibuprofen and tranexamic acid may form a crystal unit cell of four molecules each.

[0028] 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.

[0029] The crystals may have an endothermic peak at about 180° C. in differential scanning calorimetry (DSC). The vicinity of 180° C. may be, for example, in the range of 180° C.±20° C. or in the range of 180° C.±10° C. In addition, in the DSC of the crystals, the heat of fusion peak at about 75° C., which is characteristic of ibuprofen, may disappear.

[0030] The crystal may have, for example, the crystal structure shown in FIG. 1 of JP 2022-70674 A 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.

[0031] Crystals consisting of ibuprofen and tranexamic acid can be produced, for example, by the method described in JP 2022-70674 A. Two representative production methods described in the publication are described below.

[0032] A method for producing a crystal of ibuprofen and tranexamic acid, comprising the steps of: The method includes: (1) forming a flowable fluid of ibuprofen by adding a solvent or by heating; (2) mixing the resulting flowable fluid of ibuprofen with tranexamic acid; and (3) forming crystals from the resulting mixture.

[0033] A method for producing a crystal of ibuprofen and tranexamic acid, comprising the steps of: A method comprising: (1) obtaining a free-flowing fluid of tranexamic acid; (2) mixing the free-flowing fluid of tranexamic acid with ibuprofen, or with a free-flowing fluid of ibuprofen obtained by adding a solvent or by heating; and (3) forming crystals from the mixture.

[0034] As used herein, "surfactant" refers to a substance that adsorbs to the interface between different phases and reduces the interfacial tension (surface tension). The surfactant may be either an ionic surfactant or a nonionic surfactant. Ionic surfactants are classified into anionic surfactants, cationic surfactants, and amphoteric surfactants. Among surfactants, anionic surfactants and nonionic surfactants are preferred, and anionic surfactants are more preferred.

[0035] The term "anionic surfactant" refers to a surfactant that has the effect of improving the dissolution and / or absorption of ibuprofen in combination with tranexamic acid. As such a surfactant, alkyl sulfate ester salts are preferred.

[0036] As used herein, "alkyl sulfate" refers to an anionic surfactant represented by the formula RO-SO3M, in which R represents a linear or branched, saturated or unsaturated hydrocarbon group having 10 to 14 carbon atoms, and M represents an alkali metal such as sodium, an alkaline earth metal such as magnesium, or the like.

[0037] The physical properties of alkyl sulfate ester vary depending on the number of carbon atoms in the alkyl group. The number of carbon atoms in the alkyl group is appropriately selected from 10, 11, 12, 13, and 14 in order to improve the dissolution and / or absorbability of ibuprofen. The number of carbon atoms is preferably within the range of 11 to 13.

[0038] Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyvinyl alcohol. The average number of moles of ethylene oxide added in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is, for example, 5 to 100 moles, and preferably 20 to 100 moles.

[0039] The amount of the surfactant to be added is appropriately adjusted depending on the application of the surfactant in the composition. When the surfactant is added for the purpose of improving the dissolution and / or absorption of ibuprofen or other properties, the amount of the surfactant to be added varies depending on the amount of ibuprofen, etc., but for example, the amount per day is in the range of 0.01 mg to 400 mg, preferably 0.1 mg to 250 mg, more preferably 0.2 mg to 200 mg.

[0040] The amount of the surfactant contained in the composition administered per day is, for example, 0.0001 to 1 part by mass, preferably 0.0001 to 0.6 parts by mass, and more preferably 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0041] In one embodiment, the surfactant is one or more selected from the group consisting of sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyvinyl alcohol.

[0042] Sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyvinyl alcohol can improve the dissolution of ibuprofen by adding a small amount compared to other surfactants. The dissolution can be evaluated according to known dissolution tests such as the paddle method, rotating basket method, and flow-through cell method described in the Japanese Pharmacopoeia, 18th Edition, "Dissolution Test Method." In the dissolution test, the amount of ibuprofen dissolved in a specified test solution is quantified.

[0043] The dissolution test of each sample in the examples was performed in accordance with the "Dissolution Test Method (Paddle Method)" of the 18th Edition of the Japanese Pharmacopoeia, using 800 mL of the first dissolution test liquid (Fujifilm Wako Pure Chemical Industries, Ltd.) conforming to the Japanese Pharmacopoeia as the test liquid, at 50 rpm per minute, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. The test of the capsules was performed using a sinker exemplified in the 18th Edition of the Japanese Pharmacopoeia. A dissolution rate of 36% or more at 30 minutes is defined as having an effect of improving dissolution.

[0044] The improvement of dissolution may also improve the pharmacokinetic profile of ibuprofen. Pharmacokinetics includes blood kinetics such as absorbability. As used herein, "blood kinetics" refers to pharmacokinetics in blood circulation, i.e., the kinetics (absorption, distribution, etc.) and disappearance (metabolism, excretion, etc.) of ibuprofen administered to an individual in blood circulation over time, and is evaluated using the time course of the change in blood drug concentration (PK) or blood exposure (AUC), drug elimination half-life (t1 / 2), maximum blood drug concentration (Cmax), time to reach maximum blood concentration (Tmax), etc. as indicators. Such evaluation is performed in comparison with a solid composition that is the same except that it does not contain a surfactant, or a composition containing only ibuprofen.

[0045] Improvements in blood kinetics include shortening the time to reach the maximum blood concentration (time to maximum blood concentration; Tmax), increasing the maximum drug blood concentration (Cmax), suppressing the decrease in blood drug concentration over time (prolonged PK), increasing blood exposure (AUC), and prolonging the drug elimination half-life (t1 / 2).

[0046] In one embodiment, the composition has a time to maximum plasma concentration (Tmax) of less than 2 hours. The composition comprising ibuprofen, tranexamic acid and a surfactant may have an improved Tmax of less than 2 hours, as compared to a composition comprising only ibuprofen or a composition comprising ibuprofen and tranexamic acid.

[0047] The composition may contain ingredients other than the above-mentioned ingredients depending on its use. When the composition is intended to relieve cold symptoms such as runny nose, stuffy nose, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, active ingredients such as antipyretics and analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable ingredients may be blended.

[0048] Nonsteroidal anti-inflammatory drugs are broadly classified into nonselective COX-2 inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and selective COX-2 inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be incorporated into the composition as a nonsteroidal anti-inflammatory drug. The nonsteroidal anti-inflammatory drug is preferably a nonselective COX-2 inhibitor. The nonsteroidal anti-inflammatory drug may be in the form of a salt.

[0049] Other pharmacologically acceptable ingredients may be added, such as antihistamines, antipyretics, antitussives, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmin agents, which are added to general cold medicines, antipyretics, and rhinitis medicines.

[0050] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, and the like.

[0051] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, isopropylantipyrine, etc. Acetaminophen may be incorporated into the composition as an antipyretic analgesic.

[0052] Antitussive and expectorant drugs include bromhexine, dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, dextromethorphan hydrobromide hydrate and the like.

[0053] Anti-inflammatory drugs include glycyrrhizinic acid and its derivatives and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, and the like.

[0054] Examples of central nervous system stimulants include caffeine, anhydrous caffeine, and the like.

[0055] Vitamin preparations 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, etc.

[0056] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scolytsum extract, Scolytsum root, and Scolytsum root total alkaloid citrate.

[0057] Antiplasmin agents include tranexamic acid.

[0058] The composition of the present invention may further contain formulation additives as necessary. Examples of the formulation additives include pharma- ceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, refreshing agents, flavorings, aromas, coloring agents, bases, coating agents, sugar-coating agents, plasticizers, dispersants, antifoaming agents, fluidizing agents, and flavorings and aromas, and formulation additives that can be used in conventionally known solid preparations may be used for the above-mentioned purposes.

[0059] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cacao butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, 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 white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially gelatinized 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.

[0060] The binder may be one or more components selected from the group consisting of gum arabic, powdered gum arabic, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (completely 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, and the like.

[0061] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, and the like.

[0062] 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 hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0063] The glossing agent may be, for example, one or more components selected from carnauba wax, white beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, and the like.

[0064] The foaming agent may be, for example, one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc. However, it is preferred that the composition does not contain anhydrous citric acid.

[0065] As the moisture-proofing agent, one or more components selected from, for example, 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, refined shellac, refined 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 aluminometasilicate, etc. may be blended.

[0066] Examples of the stabilizer 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, dichloromethane, and the like. Iron, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, condo Sodium leucine 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 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 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, 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. can be blended with one or more ingredients selected from the following.

[0067] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean 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 preferable not to incorporate tocopherols as antioxidants or stabilizers.

[0068] Examples of the filler include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, calcium hydrogen phosphate, and the like.

[0069] As the sweetener, for example, one or more components selected from 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, purified stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc. may be blended.

[0070] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron hirsutum extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cacao 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 hydrogen tartrate, DL-sodium tartrate, and ginger. It can contain one or more ingredients selected from the group consisting of powdered sorghum, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0071] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0072] As the flavoring, for example, one or more ingredients 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, 1-menthol, peppermint oil, etc. can be blended.

[0073] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginseng powder, spearmint oil, clove oil, turpentine, chili powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, and the like.

[0074] As the colorant, for example, one or more components selected from yellow iron oxide, yellow iron sesquioxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium oxide, iron sesquioxide, diaz azo 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, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil, etc. may be blended.

[0075] Bases include: powdered acacia, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid esters, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid esters, silicon 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, and hydroxypropyl cellulose. It is possible to blend one or more ingredients selected from the group consisting of 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, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0076] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, 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 leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydrochloride, and the like. Examples of the surfactants include dimethyl ether, ...

[0077] Examples of sugar-coating agents that can be blended include one or more components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, 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, and the like.

[0078] The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, 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, and liquid paraffin.

[0079] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, powdered agar, 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, soybean lecithin, and 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, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0080] The antifoaming agent may be one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane-silicon dioxide mixture, sucrose fatty acid ester, silicon antifoaming agent, silicon oil, sorbitan fatty acid ester, polysorbate 80, etc.

[0081] The fluidizing agent may be, for example, one or more components selected from hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, and the like.

[0082] Examples of flavoring agents and fragrances 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, vitabe It can contain one or more ingredients selected from the group consisting of rose, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0083] The composition may be in the form of a solid preparation such as a tablet (including a chewable tablet, an effervescent tablet, an orally disintegrating tablet, etc.), a troche, a drop, a capsule (hard capsule, soft capsule, etc.), a granule, a fine granule, a powder, a pill, a dry syrup, a suppository, a cataplasm, a plaster, a caplet, etc.; a semi-solid preparation such as a lozenge, a chewing gum, a jelly, a jelly drop, a whipped cream, an ointment, a cream, a foam, an inhaler, a nasal gel, etc.; a liquid preparation such as a syrup, a drink, a suspension, an alcohol, a liquid, a spray, a spray, etc., as described in the General Provisions of Preparations of the 17th Revised Japanese Pharmacopoeia, etc. In terms of convenience of taking and manufacturing, etc., the composition of the present invention is preferably a solid preparation, more preferably an oral administration composition selected from the group consisting of a tablet, a capsule, a pill, a granule, a powder, and a fine granule, and particularly preferably a tablet or a capsule.

[0084] When the composition is a solid preparation, the composition may be once packaged in a bottle, PTP, pouch, stick, or SP package and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and may be, for example, a resin film such as a polypropylene film, a polyethylene terephthalate film, or a polyethylene film, or a resin film with aluminum foil attached thereto. If hygroscopicity is a concern, a desiccant or the like may be stored in the bottle packaging or pillow packaging at the same time.

[0085] (Manufacturing method) In a second aspect, there is provided a method of making a solid composition comprising the steps of contacting ibuprofen, tranexamic acid, and a surfactant.

[0086] The solid composition can be produced using known techniques. For example, the contact of ibuprofen with tranexamic acid may be carried out in accordance with the method for producing a mixture containing both, as described in JP 2022-40057 A. Ibuprofen, tranexamic acid, and a surfactant are each added at any step and finally contacted with each other. A solvent or a binder may be added to the mixture after contact and kneaded, and the resulting kneaded product may be used as a solid composition.

[0087] The kneaded mixture can be further subjected to a drying process and a granulation process to produce a granule (granulated material). In this case, the granule (granulated material) containing each component may be prepared separately. Granulation may be performed by either a wet method or a dry method.

[0088] The obtained granules (granulated product) can be directly used or can be mixed with additives and compressed into tablets to produce plain tablets, or can be further film-coated.

[0089] In order to explain the present invention in more detail, test examples and examples are described below, but the present invention is not limited to these. EXAMPLES

[0090] The dissolution evaluation of ibuprofen was carried out as follows.

[0091] 1. Preparation of raw materials and solid dosage forms

[0092] The raw materials used are shown in Table 1. [Table 1]

[0093] 2. Manufacturing method Each sample listed in Table 2 was prepared as follows. [Table 2]

[0094] Comparative Example 1 The ingredients in Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 12.1% and kneaded, and then the ingredients in Granule 3 in Table 2 were added in the ratios shown, and 20% ethanol was added to the mixture at 13% and kneaded, and the resulting wet granules were sized using a 12 mesh sieve and dried in a thermostatic oven (As One) to obtain the final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0095] Comparative Example 2 The ingredients in Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 12.0% and kneaded, and then the ingredients in Granule 3 in Table 2 were added in the ratios shown, and 20% ethanol was added to the mixture at 4.6% and kneaded, and the resulting wet granules were sized using a 12 mesh sieve and dried in a thermostatic oven (As One) to obtain the final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0096] (Reference example 1) The ingredients in Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 11.6% and kneaded, and then the ingredients in Granule 3 in Table 2 were added in the ratios shown, and 20% ethanol was added to the mixture at 7.3% and kneaded, and the resulting wet granules were sized using a 12 mesh sieve and dried in a thermostatic oven (As One) to obtain the final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0097] Comparative Example 3 The ingredients in granule 1 in Table 2 were mixed in the ratios shown in the table using VG-25 (Powrex), purified water was added to the mixture at 11.2% and kneaded, then 99% ethanol was added at 20.8% and kneaded, and the granules obtained by drying with MP-01 (Powrex) were crushed with a sample mill (Nara Machinery Works) to obtain primary granules. The ingredients in granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed with a mixer torque rheometer 3 (Caleva), 20% ethanol was added at 12.1% and kneaded with the mixture, and further the ingredients in granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added at 7.3% and kneaded with the mixture, and the obtained wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0098] Comparative Example 4 The ingredients in Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 11.5% and kneaded, and then the ingredients in Granule 3 in Table 2 were added in the ratios shown, and 20% ethanol was added to the mixture at 7.0% and kneaded, and the resulting wet granules were sized using a 12 mesh sieve and dried in a thermostatic oven (As One) to obtain the final granules. 187 mg of the final granules and 83 mg of tranexamic acid (total of 270 mg) were filled into No. 1 hypromellose capsules to obtain capsules.

[0099] (Reference example 2) The ingredients in Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 20% ethanol was added at 22.8% of the mixture and kneaded, and then the ingredients in Granule 3 in Table 2 were added in the ratios shown, and 20% ethanol was added at 10.6% of the mixture and kneaded, and the resulting wet granules were sized using a 12 mesh sieve and dried in a thermostatic oven (As One) to obtain the final granules. 187 mg of the final granules and 83 mg of tranexamic acid (total of 270 mg) were filled into No. 1 hypromellose capsules to obtain capsules.

[0100] Example 1 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 12.1% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added to the mixture at 11.0% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0101] Example 2 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 50% ethanol was added to the mixture in an amount of 8.4% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 50% ethanol was added to the mixture in an amount of 6.3% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0102] Example 3 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 14.0% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added to the mixture at 7.2% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0103] Example 4 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 14.0% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added to the mixture at 8.8% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0104] Example 5 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 14.6% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added to the mixture at 10.8% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0105] Example 6 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 9.9% 80% ethanol was added to the mixture and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 12.0% 80% ethanol was added to the mixture and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0106] Example 7 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 50% ethanol was added to the mixture at 11.9% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 50% ethanol was added to the mixture at 17.5% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0107] (Examples 8 and 9) Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 12.1% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 20% ethanol was added to the mixture at 11.0% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0108] Example 10 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 50% ethanol was added to the mixture at 7.7% and kneaded, and the components in Granule 3 in Table 2 were added in the ratios shown and 50% ethanol was added to the mixture at 12.0% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0109] Example 11 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in granule 2 in Table 4 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture in an amount of 13.2% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain granules. The granules and extragranular components were mixed in the ratios shown in Table 4 to prepare a mixed powder for tableting, and 340 mg of this was tableted using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double R mortar and pestle to obtain tablets.

[0110] Example 12 Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in Granule 2 in Table 4 were added to the primary granules in the ratios shown, and mixed using a mixer torque rheometer 3 (Caleva). 8.4% of 50% ethanol was added to the mixture, and kneaded. The components in Granule 3 in Table 4 were added in the ratios shown, and 6.3% of 50% ethanol was added to the mixture, and kneaded. The resulting wet granules were dried in a thermostatic oven (As One) to obtain granules. The granules and extragranular components were mixed in the ratios shown in Table 4 to prepare a mixed powder for tableting, and 340 mg of the powder was tableted using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double R mortar and pestle to obtain tablets.

[0111] (Example 13) Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in granules 2 and 3 in Table 4 were added to the primary granules in the ratios shown and mixed in a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture at 18.0% and kneaded, and the resulting wet granules were dried in a thermostatic oven (As One) to obtain granules. The granules and extragranular components were mixed in the ratios shown in Table 4 to prepare a mixed powder for tableting, and 340 mg of this was tableted using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double R mortar and pestle to obtain tablets.

[0112] (Comparative Example 5, Example 15) The ingredients in granule 1 in Table 6 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (Caleva), 80% ethanol was added to the mixture at 12.0% and kneaded, then the ingredients in granule 2 in Table 6 were added in the ratios shown, 20% ethanol was added to the mixture at 35.0% and kneaded, the resulting wet granules were sized using a 12 mesh sieve and then dried in a thermostatic oven (As One) to obtain granules. The granules and extragranular ingredients were mixed in the ratios shown in Table 6 to prepare a mixed powder for tableting, and 340 mg of this was tableted using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double R mortar and pestle to obtain tablets.

[0113] Example 14 Granules were obtained by the same manufacturing method as in Comparative Example 5. The obtained granules and extragranular components were mixed in the ratios shown in Table 6, and 277 mg of the mixed powder was filled into a No. 1 hypromellose capsule to obtain a capsule preparation.

[0114] (Example 16) Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components in granule 2 in Table 6 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (Caleva), 20% ethanol was added to the mixture in an amount of 16.0% and kneaded, the resulting wet granules were sized using a 12 mesh sieve and then dried in a thermostatic oven (AS ONE) to obtain granules. The granules and extragranular components were mixed in the ratios shown in Table 6 to prepare a mixed powder for tableting, and 340 mg of this was tableted using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double R mortar and pestle to obtain tablets.

[0115] 3. Evaluation of crystals composed of ibuprofen and tranexamic acid The fact that the crystals consisted of ibuprofen and tranexamic acid was confirmed by the following measurements.

[0116] <Measurement of Example 14> Granule components 1 and 2 were mixed, sized, and dried to obtain 6 mg of granules, which were then placed in an aluminum pan and measured over the range of 25 to 280°C at a rate of 10°C per minute using a differential scanning calorimeter DSC1 (Mettler Toledo). As shown in Figure 1, it was confirmed that the peak derived from ibuprofen near 75°C was very small, and that there was a peak derived from crystals consisting of ibuprofen and tranexamic acid near 180°C.

[0117] <Measurements of Comparative Example 5 and Example 15> 6 mg of the obtained mixed powder for tableting was placed in an aluminum pan and measured at a rate of 60°C per minute over the range of 25 to 350°C using a differential scanning calorimeter DSC3+ (Mettler Toledo). As shown in Figure 2 for Comparative Example 5 and Figure 3 for Example 15, it was confirmed that the peak derived from ibuprofen near 75°C disappeared and a peak derived from crystals consisting of ibuprofen and tranexamic acid was observed near 180°C.

[0118] <Measurements of Comparative Example 3, Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, Example 13, and Example 16> 6 mg of the obtained primary granules were placed in an aluminum pan and measured using a differential scanning calorimeter DSC1 (Mettler Toledo) at a rate of 60°C per minute over the range of 25 to 350°C. As shown in Figure 4, it was confirmed that the peak derived from ibuprofen around 75°C disappeared, and a peak derived from crystals consisting of ibuprofen and tranexamic acid appeared around 180°C.

[0119] 4. Evaluation of dissolution properties of solid dosage forms The dissolution of each sample was evaluated according to the dissolution test method (paddle method) described in the Japanese Pharmacopoeia, 18th Edition, using a dissolution tester (NTR-6400AC or NTR-6400A, Toyama Sangyo Co., Ltd.) at 50 rpm per minute, using 800 mL of the first dissolution test fluid (Fujifilm Wako Pure Chemical Industries, Ltd.) in accordance with the Japanese Pharmacopoeia, and evaluating the dissolution rate of ibuprofen 30 minutes after the start of the test. The test for capsules was performed using a sinker exemplified in the Japanese Pharmacopoeia, 18th Edition.

[0120] The dissolution rates at 30 minutes are shown in Table 3. [Table 3]

[0121] <Results of Examples 1 to 10> Comparison of Comparative Examples 1, 2, 3, and 4 with Examples 1, 2, and 7 in Table 3 revealed that the use of crystals consisting of ibuprofen and tranexamic acid in the formulation and the addition of sodium lauryl sulfate to the formulation increased the ibuprofen dissolution rate and improved the dissolution of ibuprofen. In addition, the improvement in the dissolution of ibuprofen was also confirmed when the surfactants shown in Examples 3 to 6 were added in place of the sodium lauryl sulfate used in Example 1. Among them, polyoxyethylene ethylene hydrogenated castor oil (Example 6) and polyoxyethylene (196) polyoxypropylene (67) glycol (Example 4) were particularly excellent in improving the dissolution.

[0122] From the above, it was shown that the dissolution rate of ibuprofen can be improved by adding a surfactant to crystals composed of ibuprofen and tranexamic acid. Furthermore, since a high dissolution rate of ibuprofen was confirmed even when the amount of sodium lauryl sulfate was changed in Examples 8 to 10, it was shown that the dissolution rate of ibuprofen is improved regardless of the amount of surfactant.

[0123] [Table 4]

[0124] [Table 5]

[0125] <Results of Examples 11 to 13> From the results of the dissolution tests of Examples 11 to 13 shown in Table 5, it was confirmed that the dissolution of ibuprofen was improved even when the formulation was in the form of a tablet. It was also shown that the dissolution of ibuprofen can be improved by changing the method of adding additive components during granule preparation as in Example 11 or the method of adding a surfactant as in Example 13.

[0126] [Table 6]

[0127] [Table 7]

[0128] <Results of Examples 14 to 16> From the results of Example 14 shown in Table 7, a high ibuprofen dissolution rate was confirmed even when the formulation was produced by kneading ibuprofen and tranexamic acid with the component of granule 2 without going through a drying process after kneading. Improvement in the dissolution rate of ibuprofen was observed both in Example 15, in which tablets were prepared by kneading in the same manner as in Example 14, and in Example 16, in which an active ingredient other than ibuprofen and tranexamic acid was added during kneading. These results demonstrate that the improvement in the dissolution property of ibuprofen is not dependent on the manufacturing method for crystals consisting of ibuprofen and tranexamic acid or on the presence or absence of other active ingredients.

[0129] The absorbability evaluation of ibuprofen was carried out as follows.

[0130] 1. Manufacturing method The manufacturing method for each sample is as follows.

[0131] Comparative Example 6 Using a mixer torque rheometer 3 (manufactured by Caleva), ibuprofen and D-mannitol were mixed in a stirring vessel at a ratio shown in Table 8 to a total of 11.4 g, and then 2.3 mL of 50% ethanol was added and kneaded for 10 minutes. Furthermore, crystalline cellulose, D-mannitol, hydroxypropyl cellulose, and croscarmellose sodium were added at a ratio shown in Table 8 to a total of 25.0 g and mixed, and 3.0 mL of 50% ethanol was added and kneaded for 10 minutes. The obtained wet granules were dried at 60°C for 1 hour to obtain granules. Croscarmellose sodium, light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation), and magnesium stearate were mixed with the granules as a post-powder at the ratio shown in Table 8. The obtained mixture was tableted at 10 kN using a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) to obtain tablets with the mass shown in Table 8.

[0132] Comparative Example 7 Tablets were produced in accordance with Comparative Example 6 using the ratios in Table 8, except that D-mannitol in the granulation section was changed to tranexamic acid.

[0133] Comparative Example 8 Tablets were produced in the same manner as in Comparative Example 6 using the ratios in Table 8, except that sodium lauryl sulfate was added to the exfoliant.

[0134] (Example 17) In Comparative Example 7, tablets were produced in the same manner as in Comparative Example 6 using the ratios in Table 8, except that sodium lauryl sulfate was added to the powder.

[0135] 2. Evaluation of crystals consisting of ibuprofen and tranexamic acid Approximately 6 mg of the granules prepared in Comparative Example 7 and Example 17 were placed in an aluminum pan and measured using a differential scanning calorimeter DSC3+ (Mettler Toledo) at a rate of 60°C per minute over the range of 25 to 250°C. As shown in Figure 5, it was confirmed that the peak derived from ibuprofen at around 75°C for the granules of Example 17 disappeared, and a peak derived from crystals consisting of ibuprofen and tranexamic acid was present at around 180°C.

[0136] 3. Evaluation of ibuprofen absorption from solid preparations (PK study in dogs) Four male beagle dogs weighing about 10 kg were fasted from the day before administration, and pentagastrin was administered twice, 30 minutes before administration and 3 minutes before administration of the test preparation, at a dose of 0.01 mg / 0.1 mL / kg / administration into the thigh muscle. Two tablets / body (150 mg as ibuprofen) of each of the tablets of Comparative Examples 6 to 8 and Example 17 were orally administered per dog. After administration, about 50 mL of distilled water was placed in the oral cavity and swallowed, and then 100 mL of distilled water was forcibly administered orally using a catheter. About 1 mL of blood was collected from the cephalic vein (non-administration site) over time using a syringe and injection needle treated with heparin sodium. The collected blood was transferred to a PP tube and centrifuged (3740 type, Kubota Manufacturing Co., Ltd.) at 2330×g, 10 minutes, and 4°C to obtain plasma. The ibuprofen concentration in this plasma was measured by LC-MS / MS. The results are shown in Table 8.

[0137] [Table 8]

[0138] As shown in Table 8, by combining ibuprofen with a surfactant and tranexamic acid, Cmax was significantly improved and Tmax was significantly shortened. This result shows that the solid composition of the present invention improves the absorbability of ibuprofen and can be expected to have an immediate effect.

Claims

1. A crystal consisting of ibuprofen and tranexamic acid, A surfactant, A solid composition comprising:

2. 2. The solid composition of claim 1, wherein the surfactant is one or more selected from the group consisting of sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyvinyl alcohol.

3. The solid composition according to claim 1 or 2, comprising 0.0001 to 1 part by mass of a surfactant per 1 part by mass of the crystals.

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