solid components

Abstract

Providing a solid composition. [Solution] The present invention provides a solid composition comprising crystals composed of ibuprofen and tranexamic acid, and a surfactant.

Description

Technical Field

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

Background Art

[0002] Ibuprofen or its salts are widely used as non-steroidal anti-inflammatory drugs. However, since ibuprofen is a poorly water-soluble drug, improving its dissolution has been studied conventionally. As methods for improving the dissolution of ibuprofen, for example, a method of changing the pH, a method of blending a water-soluble polymer base material and a nonionic surfactant (Patent Document 1), etc. are known.

[0003] Patent Document 1 discloses an easily absorbable solid composition characterized by containing 1 part by weight of ibuprofen, 0.01 to 10 parts by weight of one or more water-soluble polymer base materials 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 ester, block polymer type ether, and sucrose fatty acid ester.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

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

Means for Solving the Problems

[0006] The inventors of the present invention have discovered that by crystallizing ibuprofen with tranexamic acid and then adding a surfactant to the resulting crystals, the elution properties of ibuprofen can be improved, i.e., rapid dissolution can be achieved, thus completing the present invention.

[0007] Patent Document 2 reports that when fluid ibuprofen and tranexamic acid are mixed, ibuprofen and tranexamic acid form crystals, but it does not specifically mention the elution properties of ibuprofen in the crystals composed of ibuprofen and tranexamic acid.

[0008] In other words, this application encompasses the following inventions. [1] A crystal composed of ibuprofen and tranexamic acid, Surfactants and A solid composition containing the following: [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 parts by mass to 1 part by mass of the aforementioned crystal. [Effects of the Invention]

[0009] According to the present invention, by crystallizing ibuprofen with tranexamic acid and then compounding the resulting crystals with a surfactant, rapid dissolution of ibuprofen is achieved, and as a result, it becomes possible to provide a solid composition with improved dissolution and / or absorption. In particular, when the surfactant is an alkyl sulfate ester salt such as sodium lauryl sulfate, dissolution can be improved even with a small amount added, and consequently, the pharmacokinetic profile, such as the time to reach peak blood concentration (Tmax), can also be improved. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the DSC curve of granules obtained by kneading components 1 and 2 of the sample from Example 14, followed by sizing and drying. [Figure 2] Figure 2 shows the DSC curve of the tablet mixture powder for Comparative Example 5. [Figure 3] Figure 3 shows the DSC curve of the tablet mixture powder of the sample from Example 15. [Figure 4] Figure 4 shows the DSC curves of the primary granules of the samples from 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] Figure 5 shows the DSC curve of the primary granules of the sample from Example 17. [Modes for carrying out the invention]

[0011] (solid composition) In the first embodiment, the following components: A crystal composed of ibuprofen and tranexamic acid, Surfactants and Solid composition containing, It will be provided.

[0012] As used herein, "ibuprofen" refers to the CAS registry number 15687-27-1, C 13 H 18 Ibuprofen 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 agents. The salts of ibuprofen are not particularly limited as long as they are pharmacologically acceptable.

[0013] The dosage of ibuprofen or its salt is appropriately adjusted according to the use of ibuprofen or its salt in the composition, the symptoms, age, weight, gender, etc. of the subject to be administered. For example, when ibuprofen or its salt is formulated as a non-steroidal anti-inflammatory drug, the amount of ibuprofen or its salt administered to an adult per day can be adjusted within the range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, more preferably 200 mg to 600 mg. In the present invention, "adult" means men and women aged 15 or older. However, the composition of the present invention is not limited to those for adults to take, and may also be for children under 15 years old to take. When taken by children, it can be used in a reduced amount, such as 1 / 2 or 2 / 3 of the amount taken by an adult per day, according to each age group.

[0014] The above dosage is an example, and the content of ibuprofen or its salt per composition administered per day is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass, more preferably about 10% by mass to about 30% by mass.

[0015] In one embodiment, the content of ibuprofen or its salt contained in the composition administered per day is 1% by mass to 70% by mass, preferably 5 to 50% by mass, more preferably 10 to 30% by mass.

[0016] The weight and dosage of the above composition are the dosage per day (one-day dose), but the same amount may be divided into a plurality of times per day, for example, 2 times or 3 times, preferably 3 times, and administered to the subject. The same applies to components other than ibuprofen or its salt. Also, since each dosage is the total amount, the content of each component contained in the composition may vary depending on the single dose and the dosage form of the composition.

[0017] In a specific embodiment, the composition is a tablet, and the above dosage is the amount of the component contained in 3 tablets, 6 tablets or 9 tablets, preferably the amount of the component in 9 tablets. In this embodiment, the number of times an adult (15 years old or older) takes the medicine once a day is 3 times, and the amount taken once is 2 tablets, 3 tablets or 4 tablets, preferably the amount taken once is 3 tablets.

[0018] Unless otherwise specified, the amounts of ibuprofen described herein refer to the amount in crystalline form with tranexamic acid, but such amounts may also refer to the total amount of crystalline and uncrystallized ibuprofen.

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

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

[0021] As used herein, "tranexamic acid" refers to the C8H compound with CAS registry number 1197-18-8. 15 It is a compound represented by the chemical formula NO2 (molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs and other medications. The salts of tranexamic acid are not particularly limited as long as they are pharmacologically acceptable.

[0022] The amount of tranexamic acid or its salt included in the composition is adjusted as appropriate depending on the intended use of the tranexamic acid or its salt in the composition. When tranexamic acid or its salt is included for the purpose of improving the dissolution and / or absorption of ibuprofen, or other properties, the amount of tranexamic acid or its salt included will vary depending on the amount of ibuprofen, etc., but for example, the daily amount is in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

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

[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 1 part by mass of ibuprofen.

[0025] Unless otherwise specified, the amounts of tranexamic acid described herein refer to the amount in crystalline form with ibuprofen, but such amounts may also refer to the total amount of crystalline and non-crystalline tranexamic acid.

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

[0027] If ibuprofen and tranexamic acid exist as crystals in the composition, they may exist in a 1:1 molar ratio within the crystals. Furthermore, ibuprofen and tranexamic acid may form a crystalline unit cell of four molecules each within the crystals.

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

[0030] The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674, and may have the X-ray diffraction pattern shown in Figure 2 of the same publication. The crystal may have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in its X-ray diffraction pattern.

[0031] Crystals composed of ibuprofen and tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-70674. Two representative production methods described in the same publication are listed below.

[0032] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising (1) producing ibuprofen in a fluid form by adding a solvent or heating, (2) mixing the obtained fluid ibuprofen with tranexamic acid, and (3) producing crystals from the obtained mixture.

[0033] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising (1) obtaining tranexamic acid in a fluid form, (2) mixing the obtained fluid tranexamic acid with ibuprofen, or ibuprofen in a fluid form obtained by adding a solvent or heating, and (3) generating crystals from the obtained mixture.

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

[0035] An "anionic surfactant" refers to a surfactant that, in combination with tranexamic acid, has the effect of improving the elution and / or absorption of ibuprofen. Alkyl sulfate salts are preferred as such surfactants.

[0036] As used herein, "alkyl sulfate salt" refers to an anionic surfactant represented by the formula RO-SO3M, where 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, etc.

[0037] The physical properties of alkyl sulfate esters change 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 from the viewpoint of improving the elution and / or absorption of ibuprofen. The number of carbon atoms is preferably in 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 to polyoxyethylene hydrogenated castor oil is not particularly limited, but is, for example, 5 to 100 moles, preferably 20 to 100 moles.

[0039] The amount of surfactant added is adjusted as appropriate depending on the intended use of the surfactant in the composition. When the surfactant is added for the purpose of improving the elution and / or absorption of ibuprofen, or other properties, the amount of surfactant added will vary 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 surfactant contained in the composition 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 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 with small amounts compared to other surfactants. Dissolution can be evaluated according to known dissolution tests such as the paddle method, rotating basket method, and flow-through cell method, as described in the "Dissolution Test Methods" of the 18th edition of the Japanese Pharmacopoeia. In the dissolution test, 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 18th Edition of the Japanese Pharmacopoeia, using a dissolution test machine (NTR-6400AC or NTR-6400A, Toyama Sangyo Co., Ltd.), with 800 mL of the Japanese Pharmacopoeia-compliant Dissolution Test Solution 1 (Fujifilm Wako Pure Chemical Industries, Ltd.) as the test solution, at a speed of 50 rpm, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. The capsule test was conducted using a sinker as exemplified in the 18th Edition of the Japanese Pharmacopoeia. A dissolution rate of 36% or higher at 30 minutes was defined as having an improved dissolution effect.

[0044] Improved dissolution properties may also improve the pharmacokinetic profile of ibuprofen. Pharmacokinetics include blood dynamics such as absorption. As used herein, "blood dynamics" refers to pharmacokinetics in the blood circulation, that is, the dynamics (absorption and distribution, etc.) and elimination (metabolism and excretion, etc.) of ibuprofen administered to an individual over time in the blood circulation. This is evaluated using indicators such as the change in blood drug concentration over time (PK) or blood exposure (AUC), drug elimination half-life (t1 / 2), peak blood concentration (Cmax), and time to reach peak blood concentration (Tmax). Such evaluations are performed by comparing the composition with a solid composition that is identical except for the absence of surfactants, or with a composition containing only ibuprofen.

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

[0046] In one embodiment, the time to reach peak blood concentration (Tmax) of the composition is less than 2 hours. Compared to compositions containing ibuprofen alone or compositions containing ibuprofen and tranexamic acid, a composition containing ibuprofen, tranexamic acid, and a surfactant can improve the Tmax to less than 2 hours.

[0047] The composition may contain components other than those listed above, depending on its intended use. If the composition is intended to alleviate various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components.

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

[0049] Other pharmacologically acceptable ingredients that may be added include antihistamines, antipyretic analgesics, cough and expectorant agents, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly found in combination cold medicines, antipyretic analgesics, and rhinitis medicines.

[0050] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, and mequitazine.

[0051] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine. Acetaminophen may be included in the composition as an antipyretic analgesic.

[0052] Examples of cough suppressants and expectorants include bromhexine, dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, and dextromethorphan hydrobromide hydrate.

[0053] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), and tranexamic acid.

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

[0055] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, and so on.

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

[0057] Tranexamic acid is an example of an antiplasmin agent.

[0058] Pharmaceutical additives may be added to the composition of the present invention as needed. Examples of pharmaceutical additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents / fragrances. Pharmaceutical additives that are conventionally known and can be used in solid dosage forms can be used for the above purposes.

[0059] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. Examples of ingredients include dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose monohydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0060] As a binder, one or more components selected from, for example, gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylate copolymer L, methacrylate copolymer LD, methacrylate copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc., may be incorporated.

[0061] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, 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 monohydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0063] As a glossing agent, one or more components selected from, for example, carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, etc., can be incorporated.

[0064] As a foaming agent, one or more components selected from, for example, anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid can be included. However, it is preferable that the composition does not contain anhydrous citric acid.

[0065] As a moisture-proofing agent, one or more components selected from, for example, ethylcellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined sucrose, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, magnesium aluminometasilicate, etc., can be incorporated.

[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, disodium calcium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and dichloride. Iron, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine L-hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, anhydrous sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, chondrone Sodium leutin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Nonstearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.)), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. may be included in the formulation.

[0067] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, and sodium pyrosulfite. In the case of a solid composition containing acetaminophen, it is preferable not to include tocopherols as antioxidants or stabilizers.

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

[0069] As a sweetener, one or more ingredients selected from, for example, aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. may be included.

[0070] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, and ginger. One or more ingredients selected from the following may be included: lemon extract, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, pisiflora powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

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

[0072] As for the flavoring, one or more ingredients selected from, for example, orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc., may be included.

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

[0074] As coloring agents, one or more ingredients selected from, for example, yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, dizazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc. may be included.

[0075] The base ingredients include: acacia gum powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropyl cellulose. One or more ingredients selected from the following may be included: rose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[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, hydrogenated oil, titanium dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium dioxide / macrogol 400 mixture, hypromellose, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydro Examples include oxypropylmethylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0077] As a sugar coating agent, one or more components selected from, for example, gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc., may be incorporated.

[0078] As plasticizers, one or more components selected from, for example, triethyl citrate, glycerin, glycerin fatty acid ester, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc., may be incorporated.

[0079] The dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, and low-substituted hydroxypropyl cellulose. One or more ingredients selected from dextrin, corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, 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, etc. may be included.

[0080] As an antifoaming agent, one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc., may be included.

[0081] As a fluidizing agent, one or more components selected from, for example, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, etc., can be blended.

[0082] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, and bitter bean paste. One or more ingredients selected from the following may be included: cereal, cedarwood oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0083] The composition may be in the form of a solid preparation such as tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), lozenges, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, poultices, plasters, and caplets; a semi-solid preparation such as licks, chewing gums, jellies, jelly drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; or a liquid preparation such as syrups, drinks, suspensions, alcoholic preparations, liquids, sprays, and aerosols, as described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia. The composition of the present invention is preferably a solid preparation in terms of ease of administration and ease of manufacture, more preferably an orally administered composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules, and particularly preferably a tablet or capsule.

[0084] If the composition is a solid dosage form, it may be initially packaged in a bottle, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored airtight. Furthermore, these may be pillow-packaged, and then stored in a box or similar container. The material used for the pillow packaging is not particularly limited; for example, resin films such as polypropylene film, polyethylene terephthalate film, or polyethylene film, or these resin films with aluminum foil attached, can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle or pillow packaging.

[0085] (Manufacturing method) In a second embodiment, a method for producing a solid composition is provided, comprising the step of contacting ibuprofen with tranexamic acid and a surfactant.

[0086] The production of the solid composition can be carried out using known techniques. For example, the contact between ibuprofen and tranexamic acid may be carried out in accordance with the method for producing a mixture containing both, as described in Japanese Patent Application Publication No. 2022-40057. Ibuprofen, tranexamic acid, and a surfactant may each be added at any step and finally brought into contact with each other. A solvent and a binder may be added to the mixture after contact and kneaded, and the resulting kneaded product may be used as the solid composition.

[0087] The mixture can also be subjected to further drying and granulation processes to produce granules. In this case, the granules containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0088] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be further coated with a film.

[0089] To illustrate the present invention in more detail, test examples and embodiments are described below, but the present invention is not limited thereto. [Examples]

[0090] The dissolution properties of ibuprofen were evaluated as follows.

[0091] 1. Method for preparing 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 components of Granule 1 and Granule 2 in Table 2 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva). 12.1% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions shown, and 13% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve, and then dried in a constant temperature 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 components of Granule 1 and Granule 2 in Table 2 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva). 12.0% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions shown, and 4.6% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve, and then dried in a constant temperature 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 components of Granule 1 and Granule 2 in Table 2 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva). 11.6% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions shown, and 7.3% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve, and then dried in a constant temperature 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 components of Granule 1 in Table 2 were mixed in the proportions shown in the table using VG-25 (manufactured by Powrec), 11.2% purified water was added to the mixture and kneaded, then 20.8% 99% ethanol was added and kneaded, and the granules obtained by drying with MP-01 (manufactured by Powrec) were crushed in a sample mill (manufactured by Nara Machine Works) to obtain primary granules. The components of Granule 2 in Table 2 were added to the primary granules in the proportions shown and mixed with a mixer torque rheometer 3 (manufactured by Caleva), 12.1% 20% ethanol was added to the mixture and kneaded, and then the components of Granule 3 in Table 2 were added in the proportions shown, and 7.3% 20% ethanol was added to the mixture and kneaded, and the resulting wet granules were dried in a constant temperature 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.

[0098] (Comparative Example 4) The components of Granule 1 and Granule 2 in Table 2 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva). 11.5% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions shown, and 7.0% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve, and then dried in a constant temperature oven (AS ONE) to obtain the final granules. 187 mg of the final granules and 83 mg of tranexamic acid, totaling 270 mg, were filled into No. 1 hypromellose capsules to obtain capsules.

[0099] (Reference example 2) The components of Granule 1 and Granule 2 in Table 2 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva). 22.8% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions shown, and 10.6% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve, and then dried in a constant temperature oven (AS ONE) to obtain the final granules. 187 mg of the final granules and 83 mg of tranexamic acid, totaling 270 mg, were filled into No. 1 hypromellose capsules to obtain capsules.

[0100] (Example 1) Primary granules were obtained using the same method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 12.1% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 11.0% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 8.4% of 50% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 6.3% of 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 14.0% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 7.2% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 14.0% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 8.8% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 14.6% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 10.8% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 9.9% of 80% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 12.0% of 80% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 11.9% of 50% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 17.5% of 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 12.1% of 20% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 11.0% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 2 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 7.7% of 50% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 2 were added in the proportions indicated and 12.0% of 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature 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 method as in Comparative Example 3. The components of Granule 2 in Table 4 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 13.2% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature oven (AS ONE) to obtain granules. The granules and extragranule components were mixed in the proportions shown in Table 4 to prepare a tableting mixture. 340 mg of this mixture was compressed into tablets using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double-R die to obtain tablets.

[0110] (Example 12) Primary granules were obtained using the same method as in Comparative Example 3. The components of Granule 2 in Table 4 were added to the primary granules in the proportions indicated and mixed in a mixer torque rheometer 3 (Caleva). 8.4% of 50% ethanol was added to the mixture and kneaded. Then, the components of Granule 3 in Table 4 were added in the proportions indicated and 6.3% of 50% ethanol was added to the mixture and kneaded. The resulting wet granules were dried in a constant temperature oven (AS ONE) to obtain granules. The granules and extragranule components were mixed in the proportions indicated in Table 4 to prepare a tableting mixture. 340 mg of this mixture was compressed into tablets using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double-R die to obtain tablets.

[0111] (Example 13) Primary granules were obtained using the same method as in Comparative Example 3. Components 2 and 3 of the granules shown in Table 4 were added to the primary granules in the proportions indicated and mixed using a mixer torque rheometer 3 (Caleva). 18.0% of 20% ethanol was added to the mixture and kneaded, and the resulting wet granules were dried in a constant temperature oven (AS ONE) to obtain granules. The granules and extragranule components were mixed in the proportions shown in Table 4 to prepare a tableting mixture, and 340 mg of this mixture was compressed into tablets using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double-R die to obtain tablets.

[0112] (Comparative Example 5, Example 15) The components of Granule 1 in Table 6 were mixed in the proportions shown in the table using a mixer torque rheometer 3 (Caleva), and 12.0% of 80% ethanol was added to the mixture and kneaded. Then, the components of Granule 2 in Table 6 were added in the proportions shown, and 35.0% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve and then dried in a constant temperature oven (AS ONE) to obtain granules. The granules and extragranule components were mixed in the proportions shown in Table 6 to prepare a tableting mixture, and 340 mg of this mixture was compressed into tablets using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double-R die to obtain tablets.

[0113] (Example 14) Granules were obtained using the same 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 No. 1 hypromellose capsules to obtain capsules.

[0114] (Example 16) Primary granules were obtained using the same manufacturing method as in Comparative Example 3. The components of Granule 2 in Table 6 were added to the primary granules in the proportions indicated and mixed using a mixer torque rheometer 3 (Caleva). 16.0% of 20% ethanol was added to the mixture and kneaded. The resulting wet granules were sized using a 12-mesh sieve and then dried in a constant temperature oven (AS ONE) to obtain granules. The granules and extragranule components were mixed in the proportions shown in Table 6 to prepare a tableting mixture. 340 mg of this mixture was compressed into tablets using a hydraulic press (Riken Seiki) with a Φ9.5 mm, double-R die to obtain tablets.

[0115] 3. Evaluation of crystals composed of ibuprofen and tranexamic acid The crystal was confirmed to be composed of ibuprofen and tranexamic acid through the following measurements.

[0116] <Measurement of Example 14> When 6 mg of the granules obtained by kneading components 1 and 2 of the granules, sizing, and drying them was placed in an aluminum pan, the temperature range of 25 to 280°C was measured 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 originating from ibuprofen around 75°C was very small, and that there was a peak originating from crystals composed of ibuprofen and tranexamic acid around 180°C.

[0117] <Measurements for Comparative Example 5 and Example 15> The resulting tablet mixture of 6 mg was placed in an aluminum pan, and the temperature range of 25 to 350°C was measured at a rate of 60°C per minute 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 around 75°C disappeared, and a peak derived from crystals composed of ibuprofen and tranexamic acid was present around 180°C.

[0118] <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, Example 16 Measurement> The obtained 6 mg of primary granules was placed in an aluminum pan, and the temperature range of 25 to 350°C was measured at a rate of 60°C per minute using a differential scanning calorimeter DSC1 (Mettler Toledo). As shown in Figure 4, it was confirmed that the peak derived from ibuprofen around 75°C disappeared, and a peak derived from crystals composed of ibuprofen and tranexamic acid was present around 180°C.

[0119] 4. Evaluation of the dissolution properties of solid dosage forms The dissolution properties of each sample were evaluated according to the dissolution test method (paddle method) described in the 18th edition of the Japanese Pharmacopoeia. The dissolution test was performed using a dissolution test machine (NTR-6400AC or NTR-6400A, Toyama Sangyo Co., Ltd.) with 800 mL of the Japanese Pharmacopoeia-compliant dissolution test solution No. 1 (Fujifilm Wako Pure Chemical Industries, Ltd.) as the test solution at 50 rpm, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. The capsule test was performed using a sinker as exemplified in the 18th edition of the Japanese Pharmacopoeia.

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

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

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

[0123] [Table 4]

[0124] [Table 5]

[0125] <Results of Examples 11-13> The dissolution test results for Examples 11-13, shown in Table 5, demonstrate that the dissolution of ibuprofen improves even when the formulation is in tablet form. Furthermore, it was shown that improving ibuprofen dissolution is possible by changing the method of adding additive components during granule preparation, as in Example 11, or by changing the method of adding surfactants, as in Example 13.

[0126] [Table 6]

[0127] [Table 7]

[0128] <Results of Examples 14-16> As shown in Table 7, the results of Example 14 confirm that even when the formulation was manufactured by mixing ibuprofen and tranexamic acid with the components of granule 2 without going through the drying process after mixing, a high ibuprofen dissolution rate was confirmed. Improved ibuprofen dissolution was observed in both Example 15, which involved mixing in the same manner as in Example 14 to produce tablets, and Example 16, in which active ingredients other than ibuprofen and tranexamic acid were added during mixing. The above findings indicate that the improvement in ibuprofen dissolution is independent of the method of producing the crystals composed of ibuprofen and tranexamic acid, or the presence or absence of other active ingredients.

[0129] The absorption of ibuprofen was evaluated 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 (Caleva), ibuprofen and D-mannitol were added to a stirring vessel in the ratios shown in Table 8 to a total of 11.4 g and mixed. 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 in the ratios shown in Table 8 to a total of 25.0 g and mixed. Then, 3.0 mL of 50% ethanol was added and kneaded for 10 minutes. The resulting wet granules were dried at 60°C for 1 hour to obtain granules. Croscarmellose sodium, light anhydrous silicic acid (Adsolider 101, Freund Industrial Co., Ltd.), and magnesium stearate were added to the granules as a finishing powder in the ratios shown in Table 8. The resulting mixture was compressed into tablets at 10 kN using a hydraulic pump tablet press (Riken Seiki Co., Ltd.) to obtain tablets of the masses shown in Table 8.

[0132] (Comparative Example 7) In Comparative Example 6, the tablets were manufactured in accordance with Comparative Example 6, except that D-mannitol in the granulation section was replaced with tranexamic acid, using the ratios shown in Table 8.

[0133] (Comparative Example 8) In Comparative Example 6, tablets were manufactured in accordance with Comparative Example 6, except that sodium lauryl sulfate was added at the end of the mixture, using the proportions shown in Table 8.

[0134] (Example 17) In Comparative Example 7, tablets were manufactured in the same manner as in Comparative Example 6, except that sodium lauryl sulfate was added at the end of the mixture, using the proportions shown in Table 8.

[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 the temperature range of 25 to 250°C was measured 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 granules of Example 17 showed no peak originating from ibuprofen around 75°C, and a peak originating from crystals composed of ibuprofen and tranexamic acid around 180°C.

[0136] 3. Evaluation of ibuprofen absorption in solid dosage forms (canine PK study) Four male beagle dogs weighing approximately 10 kg were fasted from the day before administration. Pentagastrin was administered intramuscularly into the thigh at a dose of 0.01 mg / 0.1 mL / kg / dose twice, 30 minutes before administration and 3 minutes before administration of the test product. Each dog was orally administered two tablets per body (150 mg as ibuprofen) of the tablets from Comparative Examples 6-8 and Example 17, respectively. After administration, approximately 50 mL of distilled water was placed in the mouth and swallowed, and then 100 mL of distilled water was force-administered orally using a catheter. Approximately 1 mL of blood was collected over time from the cephalic vein (non-administration site) using a heparin sodium-treated syringe and needle. The collected blood was transferred to a PP tube and centrifuged at 2330 × g, 10 minutes, and 4°C (Model 3740, Kubota Manufacturing Co., Ltd.) 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, the Cmax was significantly improved and the Tmax was remarkably shortened. These results indicate that the solid composition of the present invention improves the absorption of ibuprofen and can be expected to have a rapid effect.

Claims

1. A crystal composed of ibuprofen and tranexamic acid, Surfactants and A solid composition containing the following:

2. The solid composition according to 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 parts by mass to 1 part by mass of a surfactant per 1 part by mass of the crystal.

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