Solid composition

Abstract

The present invention provides a solid composition containing: crystals composed of ibuprofen and tranexamic acid; and a surfactant.

Description

solid composition

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

[0002] Ibuprofen or its salts are widely used as nonsteroidal antipyretics and 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 changing the pH and incorporating a water-soluble polymer base material and a nonionic 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.

[0004] Japanese Patent No. 3290970 Japanese Patent Laid-Open No. 2022-70674

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

[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 of ibuprofen, i.e., to rapidly dissolve the ibuprofen, and have thus completed the present invention.

[0007] Patent Document 2 reports that when ibuprofen and tranexamic acid, which have fluidity, are mixed together, the ibuprofen and tranexamic acid form crystals, but does not specifically mention the dissolution properties of ibuprofen in crystals consisting of ibuprofen and tranexamic acid.

[0008] That is, this application encompasses the following inventions. [1] A solid composition comprising a crystal of ibuprofen and tranexamic acid, and a surfactant. [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], wherein the surfactant is 0.0001 to 1 part by mass per part by mass of the crystal.

[0009] According to the present invention, by crystallizing ibuprofen with tranexamic acid and then blending the resulting crystals with a surfactant, rapid dissolution of ibuprofen is achieved, thereby providing a solid composition with improved dissolution and / or absorbability. 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 therefore the pharmacokinetic profile, such as the time to maximum blood concentration (Tmax), can also be improved.

[0010] Figure 1 shows the DSC curve of granules obtained by kneading, sizing, and drying the granule components 1 and 2 of the sample of Example 14. Figure 2 shows the DSC curve of the tableting powder mixture of the sample of Comparative Example 5. Figure 3 shows the DSC curve of the tableting powder mixture of the sample of Example 15. Figure 4 shows the DSC curves of the primary granules of the 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. Figure 5 shows the DSC curve of the primary granules of the sample of Example 17.

[0011] (Solid Composition) In a first aspect, there is provided a solid composition comprising the following components: a crystal consisting of ibuprofen and tranexamic acid; and a surfactant.

[0012] As used herein, "ibuprofen" is a compound having CAS registration number 15687-27-1 and １３ H １８ O ２(Molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, antipyretic, etc. There are no particular restrictions on the salt of ibuprofen, as long as it is pharmacologically acceptable.

[0013] The amount of ibuprofen or a salt thereof is adjusted appropriately depending on the intended use of ibuprofen or a salt thereof in the composition, the symptoms, age, weight, sex, etc. of the recipient. For example, when ibuprofen or a salt thereof is incorporated as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen or a salt thereof administered to an adult can be adjusted to within the range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In the present invention, "adult" refers to both men and women aged 15 years or older. However, the composition of the present invention is not limited to those intended for use by adults, and may also be intended for use by children under the age of 15. When administered to children, the amount can be reduced to, for example, half or two-thirds of the adult daily dose depending on the age group.

[0014] The above-mentioned 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% by mass to 70% by mass, preferably 5% by mass to 50% by mass, more preferably 10% by mass to 30% by mass.

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

[0017] In a specific embodiment, the composition is a tablet, and the dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient contained in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 tablets, and the single dose is 2, 3, or 4 tablets, preferably 3 tablets.

[0018] Unless otherwise specified, the amount of ibuprofen described herein refers 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 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 a compound having CAS Registry Number 1197-18-8 and C ８ H １５ NO ２ (Molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs and the like. There are no particular limitations on the salt of tranexamic acid, as long as it is pharmacologically acceptable.

[0022] The amount of tranexamic acid or a salt thereof to be added is adjusted appropriately depending on the intended use 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 or other properties of ibuprofen, the amount of tranexamic acid or a salt thereof to be added 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, and more preferably 400 mg to 750 mg.

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

[0024] The amount of tranexamic acid or a salt thereof contained in the composition to be 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, the amount of tranexamic acid described in this specification refers 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 crystals at 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 around 180° C. in differential scanning calorimetry (DSC). Around 180° C. may be, for example, in the range of 180° C.±20° C. or 180° C.±10° C. In DSC of the crystals, the heat of fusion peak around 75° C., which is characteristic of ibuprofen, may disappear.

[0030] The crystal may have, for example, the crystal structure shown in Figure 1 of JP 2022-70674 A 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 the X-ray diffraction pattern.

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

[0032] A method for producing crystals of ibuprofen and tranexamic acid, comprising: (1) generating a free-flowing fluid of ibuprofen by adding a solvent or by heating; (2) mixing the free-flowing fluid of ibuprofen with tranexamic acid; and (3) generating crystals from the resulting mixture.

[0033] A method for producing crystals of ibuprofen and tranexamic acid, comprising: (1) obtaining a free-flowing fluid of tranexamic acid; (2) mixing the obtained free-flowing fluid of tranexamic acid with ibuprofen or a free-flowing fluid of ibuprofen obtained by adding a solvent or by heating; and (3) producing crystals from the obtained 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, when combined with tranexamic acid, has the effect of improving the dissolution and / or absorption of ibuprofen. Preferred examples of such surfactants include alkyl sulfates.

[0036] As used herein, "alkyl sulfate" refers to an R—O—SO ３ In the formula, 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 esters 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 absorption 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 surfactant to be added is adjusted appropriately depending on the intended use of the surfactant in the composition. When a surfactant is added for the purpose of improving the dissolution and / or absorption of ibuprofen or other properties, the amount of 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, and more preferably 0.2 mg to 200 mg.

[0040] The amount of surfactant contained in the composition to be administered daily 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 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 when added in small amounts compared to other surfactants. Dissolution can be evaluated by known dissolution tests such as the paddle method, rotating basket method, and flow-through cell method described in the "Dissolution Test Methods" of the Japanese Pharmacopoeia, 18th Edition. In dissolution tests, the amount of ibuprofen dissolved in a specified test solution is quantified.

[0043] The dissolution tests for each sample in the examples were conducted in accordance with the "Dissolution Test Method (Paddle Method)" of the Japanese Pharmacopoeia, 18th Edition, using a dissolution tester (NTR-6400AC or NTR-6400A, Toyama Sangyo Co., Ltd.) at 50 rpm using 800 mL of Japanese Pharmacopoeia-compliant dissolution test fluid No. 1 (Fujifilm Wako Pure Chemical Industries, Ltd.) at 50 rpm, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. The tests for capsules were conducted using a sinker exemplified in the Japanese Pharmacopoeia, 18th Edition. A dissolution rate of 36% or more at 30 minutes is defined as having an improved dissolution effect.

[0044] Improving dissolution may also improve the pharmacokinetic profile of ibuprofen. Pharmacokinetics also includes blood kinetics, such as absorption. As used herein, "blood kinetics" refers to pharmacokinetics in blood circulation, i.e., the kinetics (e.g., absorption, distribution, etc.) and elimination (e.g., metabolism, excretion, etc.) of ibuprofen administered to an individual in blood circulation over time. These kinetics are evaluated using indicators such as the change in blood drug concentration over time (PK) or blood exposure (AUC), drug elimination half-life (t1 / 2), maximum blood drug concentration (Cmax), and time to maximum blood concentration (Tmax). Such evaluations are performed in comparison with identical solid compositions except that they do not contain surfactants, or with compositions containing only ibuprofen.

[0045] Improvements in blood kinetics include shortening the time to reach the maximum blood concentration (time to reach maximum blood concentration; Tmax), increasing the maximum drug blood concentration (Cmax), suppressing the decrease in blood drug concentration over time (prolonging 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 compared to a composition comprising only ibuprofen or a composition comprising ibuprofen and tranexamic acid.

[0047] The composition may contain ingredients other than those mentioned above depending on its intended 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, the composition may contain active ingredients such as antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), or other pharmacologically acceptable ingredients.

[0048] Nonsteroidal anti-inflammatory drugs are broadly classified into non-selective 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 non-selective 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, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmin agents, which are typically 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 teoclate, 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, sazapyrine, 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 (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

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

[0055] Vitamin preparations include vitamin B1 and its derivatives and salts thereof (e.g., benfotiamine), vitamin B2 and its derivatives and salts thereof (e.g., riboflavin), vitamin C and its derivatives and salts thereof (e.g., ascorbic acid), hesperidin and its derivatives and salts thereof, 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, Scopolia root extract, Scopolia root total alkaloid citrate, and the like.

[0057] Antiplasmin agents include tranexamic acid.

[0058] The composition of the present invention may further contain formulation additives, if necessary. Examples of formulation additives include pharmaceutically 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 flavoring agents / fragrances. Formulation additives that can be used in conventionally known solid formulations may be used for the above-mentioned purposes.

[0059] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa 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, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, 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.

[0060] The binder may be one or more components selected from gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0061] Examples of disintegrants include carboxymethyl starch sodium, 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 carboxymethyl starch sodium, 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, purified shellac, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, beeswax, etc.

[0064] The foaming agent may be one or more components selected from, for example, 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] The moisture-proofing agent may be one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, refined 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, and the like.

[0066] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, and calcium chloride. Stain, 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, sodium chondroitin 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, poly 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,One or more ingredients selected from 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. may be blended.

[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 add tocopherols as antioxidants or stabilizers.

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

[0069] The sweetener may be one or more components selected from, for example, aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, and the like.

[0070] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron bark 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, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and ginger. It is possible to blend 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, tangerine tincture, capsicum, capsicum powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, Ryuno, Ryuno 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 components selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, 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, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper 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, and rose oil.

[0074] Examples of colorants that can be blended include one or more components selected from yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium oxide, 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, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0075] The bases include gum arabic powder, pregelatinized starch, ethyl cellulose, cacao 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, hardened oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, and hydroxypropyl cellulose. The composition may contain 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, gum arabic powder, 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, hydroxypropyl methylcellulose 2910-titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydrogenated cellulose. Examples of suitable surfactants include hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Macrogol 20000, Macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[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] Examples of the plasticizer that can be blended include one or more components selected from 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 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0079] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene terephthalate, PEG-10 cellulose, PEG-10 cellulose, PEG-10 cellulose, PEG-10 cellulose ester ... One or more ingredients selected from the group consisting of 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, and sodium lauryl sulfate may be blended.

[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, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc.

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

[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 The composition may 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 dosage form described in the General Provisions of Preparations of the 17th Edition of the Japanese Pharmacopoeia, etc., such as solid preparations such as tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), troches, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, poultices, plasters, and caplets; semi-solid preparations such as lozenges, chewing gums, jellies, jelly drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; and liquid preparations such as syrups, drinks, suspensions, spirits, liquids, sprays, and aerosols. From the viewpoints of ease of administration and manufacturing, the composition of the present invention is preferably a solid preparation, 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 or capsule.

[0084] When the composition is a solid formulation, the composition may be temporarily 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 examples thereof include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. If moisture absorption is a concern, a desiccant or the like may be stored in the bottle or pillow packaging.

[0085] (Method of Production) In a second aspect, there is provided a method of producing a solid composition, comprising the step of contacting ibuprofen, tranexamic acid, and a surfactant.

[0086] The solid composition can be produced using known techniques. For example, contact between ibuprofen and 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 may be added at any step and finally brought into contact with each other. A solvent and a binder may be added to the contacted mixture, followed by kneading, and the resulting kneaded product may be used as a solid composition.

[0087] The kneaded mixture can be further subjected to a drying process or a granulation process to produce granules (granulated material). In this case, granules (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 used as they are or can be mixed with additives and compressed into tablets to produce plain tablets, which can then 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.

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

[0091] 1. Raw materials and solid dosage form preparation method

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

[0093] 2. Manufacturing Method Each sample listed in Table 2 was manufactured as follows.

[0094] Comparative Example 1 The ingredients of Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (manufactured by Caleva), 20% ethanol was added to the mixture in an amount of 12.1%, and the mixture was kneaded. The ingredients of Granule 3 in Table 2 were then added in the ratios shown, and 20% ethanol was added to the mixture in an amount of 13%, and the mixture was kneaded. The resulting wet granules were sieved through a 12-mesh sieve and dried in an incubator (manufactured by AS ONE) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0095] 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 (manufactured by Caleva), 20% ethanol was added to the mixture in an amount of 12.0%, and the mixture was kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown, and 20% ethanol was added to the mixture in an amount of 4.6%, and the resulting wet granules were sieved through a 12-mesh sieve and dried in an incubator (manufactured by AS ONE) to obtain final granules. 270 mg of the final granules were filled into No. 1 hypromellose capsules to obtain capsules.

[0096] Reference Example 1 The ingredients of Granule 1 and Granule 2 in Table 2 were mixed in the ratios shown in the table using a mixer torque rheometer 3 (manufactured by Caleva), 20% ethanol was added to the mixture in an amount of 11.6% based on the mixture, and kneaded. The ingredients of Granule 3 in Table 2 were then added in the ratios shown, and 20% ethanol was added to the mixture in an amount of 7.3% based on the mixture, and kneaded. The resulting wet granules were sieved through a 12-mesh sieve and dried in an incubator (manufactured by AS ONE) to obtain 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 a VG-25 (Powrex Corporation). Purified water was added at 11.2% of the mixture and kneaded. Then, 99% ethanol was added at 20.8% and kneaded. The resulting granules were dried using an MP-01 (Powrex Corporation) and crushed using a sample mill (Nara Machinery Works, Ltd.) to obtain primary granules. The ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (Caleva Corporation). 20% ethanol was added at 12.1% of the mixture and kneaded. The ingredients in Granule 3 in Table 2 were added at the ratios shown and kneaded with 20% ethanol at 7.3% of the mixture. The resulting wet granules were dried in a thermostatic oven (As One Corporation) 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 (manufactured by Caleva), and 20% ethanol was added at 11.5% based on the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added at the indicated ratio, and 20% ethanol was added at 7.0% based on the mixture and kneaded. The resulting wet granules were sieved through a 12-mesh sieve and dried in an incubator (manufactured by AS ONE) to obtain final granules. 187 mg of the final granules and 83 mg of tranexamic acid (270 mg in total) 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 (manufactured by Caleva), and 20% ethanol was added at 22.8% of the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added at the indicated ratio, and 20% ethanol was added at 10.6% of the mixture and kneaded. The resulting wet granules were sieved through a 12-mesh sieve and dried in an incubator (manufactured by AS ONE) to obtain final granules. 187 mg of the final granules and 83 mg of tranexamic acid (270 mg in total) 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added at 12.1% of the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added at the ratios shown and 20% ethanol was added at 11.0% of the mixture and kneaded. The resulting wet granules were dried in a thermostatic oven (manufactured by 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 8.4% of 50% ethanol was added to the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then 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 (manufactured by 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 Comparative Example 3. The ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added to the mixture in an amount of 14.0% and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 20% ethanol was added to the mixture in an amount of 7.2% and kneaded. The resulting wet granules were dried in a thermostatic oven (manufactured by 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added to the mixture in an amount of 14.0% and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 20% ethanol was added to the mixture in an amount of 8.8% and kneaded. The resulting wet granules were dried in an incubator (manufactured by 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added to the mixture in an amount of 14.6% and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 20% ethanol was added to the mixture in an amount of 10.8% and kneaded. The resulting wet granules were dried in an incubator (manufactured by 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 9.9% 80% ethanol was added to the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 12.0% 80% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a thermostatic oven (manufactured by 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 Comparative Example 3. The ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 11.9% 50% ethanol was added to the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 17.5% 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in an incubator (manufactured by 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 using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added at 12.1% of the mixture and kneaded. The components in Granule 3 in Table 2 were then added at the ratios shown and 20% ethanol was added at 11.0% of the mixture and kneaded. The resulting wet granules were dried in an incubator (manufactured by 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 ingredients in Granule 2 in Table 2 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 7.7% of 50% ethanol was added to the mixture and kneaded. The ingredients in Granule 3 in Table 2 were then added in the ratios shown and 12.0% of 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in an incubator (manufactured by 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 Comparative Example 3. The components of Granule 2 in Table 4 were added to the primary granules in the ratios shown and mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added at 13.2% of the mixture and kneaded, and the resulting wet granules were dried in a thermostatic oven (manufactured by 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 Φ9.5 mm, double-R mortar and pestle in a hydraulic press (manufactured by Riken Seiki) to obtain tablets.

[0110] Example 12 Primary granules were obtained using the same manufacturing method as Comparative Example 3. The components listed in Granule 2 in Table 4 were added to the primary granules in the ratios shown, and the mixture was mixed using a mixer torque rheometer 3 (manufactured by Caleva). 50% ethanol was added to the mixture in an amount of 8.4% and kneaded. The components listed in Granule 3 in Table 4 were then added in the ratios shown, and 50% ethanol was added to the mixture in an amount of 6.3% and kneaded. The resulting wet granules were dried in a thermostatic oven (manufactured by 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 mixture was tableted using a 9.5 mm diameter, double-R mortar and pestle in a hydraulic press (manufactured by Riken Seiki) 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 the mixture was mixed using a mixer torque rheometer 3 (manufactured by Caleva). 20% ethanol was added at 18.0% of the mixture, and the mixture was kneaded. The resulting wet granules were dried in a thermostatic oven (manufactured by 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 Φ9.5 mm, double-R mortar and pestle in a hydraulic press (manufactured by Riken Seiki) 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 (manufactured by Caleva), and 80% ethanol was added at 12.0% based on the mixture and kneaded, and then the ingredients in Granule 2 in Table 6 were added at the indicated ratios, and 20% ethanol was added at 35.0% based on the mixture and kneaded, and the resulting wet granules were sized using a 12-mesh sieve and dried in a thermostatic oven (manufactured by 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 Φ9.5 mm, double-R mortar and pestle in a hydraulic press (manufactured by Riken Seiki) 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 listed in Granule 2 in Table 6 were added to the primary granules in the ratios shown, and the mixture was mixed using a mixer torque rheometer 3 (Caleva). 20% ethanol was added at 16.0% of the mixture, and the mixture was kneaded. The resulting wet granules were sieved through 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 9.5 mm diameter, double-R mortar and pestle in a hydraulic press (Riken Seiki) to obtain tablets.

[0115] 3. Evaluation of Crystals Composed of Ibuprofen and Tranexamic Acid The fact that the crystals were composed of ibuprofen and tranexamic acid was confirmed by the following measurements.

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

[0117] <Measurements for Comparative Example 5 and Example 15> 6 mg of the obtained mixed powder for tableting was placed in an aluminum pan and measured using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo) at a rate of 60°C per minute over the range of 25 to 350°C. As shown in Figure 2 for Comparative Example 5 and Figure 3 for Example 15, 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.

[0118] <Measurements in 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 was placed in an aluminum pan, and measurement was performed in the range of 25 to 350°C at a rate of 60°C per minute using a differential scanning calorimeter DSC1 (manufactured by Mettler Toledo). As shown in Figure 4, 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 appeared near 180°C.

[0119] 4. Evaluation of dissolution of solid dosage forms The dissolution of each sample was evaluated in accordance with 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 using 800 mL of Japanese Pharmacopoeia-compliant dissolution test first fluid (Fujifilm Wako Pure Chemical Industries, Ltd.) as the test fluid, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. Tests for capsules were conducted using a sinker exemplified in the Japanese Pharmacopoeia, 18th Edition.

[0120] The dissolution rate at 30 minutes is shown in Table 3.

[0121] <Results of Examples 1 to 10> A comparison of Comparative Examples 1, 2, 3, and 4 with Examples 1, 2, and 7 in Table 3 revealed that using crystals of ibuprofen and tranexamic acid in a formulation and further adding sodium lauryl sulfate increased the ibuprofen dissolution rate and improved the dissolution of ibuprofen. Furthermore, when the surfactants shown in Examples 3 to 6 were added instead of the sodium lauryl sulfate used in Example 1, improvements in the dissolution of ibuprofen were also confirmed. Among these, polyoxyethylene ethylene hydrogenated castor oil (Example 6) and polyoxyethylene (196) polyoxypropylene (67) glycol (Example 4) were particularly effective in improving dissolution.

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

[0123]

[0124]

[0125] <Results of Examples 11 to 13> The results of the dissolution tests of Examples 11 to 13 shown in Table 5 demonstrate that the dissolution of ibuprofen is improved even when the formulation is in the form of a tablet. It was also demonstrated 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]

[0127]

[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 a formulation was produced by kneading ibuprofen and tranexamic acid with the components of Granule 2 without going through a drying step after kneading. Improved ibuprofen dissolution was observed in both Example 15, in which tablets were produced by kneading in the same manner as in Example 14, and Example 16, in which an active ingredient other than ibuprofen and tranexamic acid was added during kneading. These results demonstrate that the improvement in ibuprofen dissolution is not dependent on the method for producing crystals consisting of ibuprofen and tranexamic acid or the presence or absence of other active ingredients.

[0129] The absorbability of ibuprofen was evaluated as follows.

[0130] 1. Manufacturing method The manufacturing method for each specimen 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 total weight of 11.4 g in the ratio shown in Table 8, followed by kneading for 10 minutes with 2.3 mL of 50% ethanol. Furthermore, microcrystalline cellulose, D-mannitol, hydroxypropyl cellulose, and croscarmellose sodium were mixed at a total weight of 25.0 g in the ratio shown in Table 8, followed by kneading for 10 minutes with 3.0 mL of 50% ethanol. The resulting 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 powder in the ratios shown in Table 8. The resulting mixture was compressed 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 the same manner as in Comparative Example 6 using the proportions shown 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 proportions shown in Table 8, except that sodium lauryl sulfate was added to the powder.

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

[0135] 2. Evaluation of Crystals Composed 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 measurements were taken over the range of 25 to 250°C at a rate of 60°C per minute using a differential scanning calorimeter DSC3+ (Mettler Toledo). As shown in Figure 5, it was confirmed that the peak derived from ibuprofen near 75°C disappeared for the granules of Example 17, and a peak derived from crystals composed of ibuprofen and tranexamic acid was present near 180°C.

[0136] 3. Evaluation of Ibuprofen Absorption from Solid Formulations (Canine PK Study) Four male beagle dogs weighing approximately 10 kg were fasted the day before administration and administered pentagastrin intramuscularly in the thigh at a dose of 0.01 mg / 0.1 mL / kg twice, 30 minutes before administration and 3 minutes before administration of the test formulation. Two tablets per body (150 mg of ibuprofen) of each of Comparative Examples 6 to 8 and Example 17 were orally administered per dog. After administration, approximately 50 mL of distilled water was placed in the oral cavity and swallowed thoroughly. Subsequently, 100 mL of distilled water was orally administered by force using a catheter. Approximately 1 mL of blood was collected periodically from the cephalic vein (non-administration site) using a heparin sodium-treated syringe and injection needle. The collected blood was transferred to a PP tube and centrifuged (Model 3740, Kubota Seisakusho Co., Ltd.) at 2330 × g for 10 minutes at 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]

[0138] As shown in Table 8, by blending ibuprofen with a surfactant and tranexamic acid, Cmax was significantly improved and Tmax was significantly shortened. These results demonstrate 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 solid composition comprising a crystal of ibuprofen and tranexamic acid, and a surfactant.

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, which contains 0.0001 to 1 part by mass of a surfactant per 1 part by mass of the crystals.

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