Solid composition, agent for improving the sustained release of ibuprofen, and method for improving the sustained release of ibuprofen.

Abstract

To provide a solid composition containing ibuprofen and tranexamic acid with improved dissolution persistence. [Solution] A solid composition comprising (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and its salts, and (C) tranexamic acid.

Description

Technical Field

[0001] The present invention relates broadly to a solid composition comprising ibuprofen, at least one selected from the group consisting of dextromethorphan and its salts, and tranexamic acid, and to an agent for improving the sustained release of ibuprofen comprising at least one selected from the group consisting of dextromethorphan and its salts as an active ingredient.

Background Art

[0002] Ibuprofen is widely used as a non-steroidal antipyretic analgesic. Tranexamic acid is also widely used as an anti-inflammatory agent.

[0003] Patent Document 1 discloses a solid preparation containing ibuprofen and tranexamic acid.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present inventors have found that in a solid composition containing ibuprofen and tranexamic acid, the dissolution persistence or sustained release of ibuprofen may be insufficient. An object of the present invention is to provide a solid composition containing ibuprofen and tranexamic acid with improved dissolution persistence, or an agent for improving the sustained release of ibuprofen.

Means for Solving the Problems

[0006] The inventors of the present invention have discovered that when tranexamic acid is added to ibuprofen, the dissolution rate of ibuprofen is improved, which reduces the dissolution duration and sustained release properties, and that when at least one substance selected from the group consisting of dextromethorphan and its salts is added, the reduction in dissolution duration and sustained release properties is suppressed, thus completing the present invention.

[0007] In other words, this application encompasses the following inventions. [1] The following ingredients: (A) Ibuprofen and (B) At least one selected from the group consisting of dextromethorphan and its salts, (C) Tranexamic acid and, A solid composition containing the following: [2] The solid composition according to [1], comprising crystals consisting of (A) ibuprofen and (C) tranexamic acid. [3] The solid composition according to [2], wherein the molar ratio of (A) ibuprofen to (C) tranexamic acid in the crystal is 1:1. [4] A solid composition according to any one of [1] to [3], wherein the dissolution rate of ibuprofen 60 minutes after the start of the test, when performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, is 30-45%. [5] An agent for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, comprising at least one selected from the group consisting of dextromethorphan and salts thereof as an active ingredient. [6] The sustained-release improving agent according to [5], wherein the solid composition comprises crystals consisting of ibuprofen and tranexamic acid. [7] The sustained-release agent according to [6], wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:1. [8] A sustained-release agent according to any one of [5] to [7], which reduces the dissolution rate of ibuprofen 60 minutes after the start of a dissolution test, when an equal amount of ibuprofen is added to a solid composition containing ibuprofen and tranexamic acid, according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, to 0.85 times or less. [9] A method for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, comprising adding at least one selected from the group consisting of dextromethorphan and its salts to the solid composition. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a solid composition containing ibuprofen and tranexamic acid with improved dissolution persistence, or an agent for improving the sustained release properties of ibuprofen. [Brief explanation of the drawing]

[0009] [Figure 1] The results of differential scanning calorimetry (DSC) in crystals of ibuprofen and tranexamic acid are shown. [Figure 2] Measurement results of ibuprofen dissolution rate. [Modes for carrying out the invention]

[0010] The following describes embodiments of the present invention (hereinafter referred to as "these embodiments"), but the scope of the present invention is not limited to these embodiments. In these embodiments, each component may be included individually or in combination of two or more. In this specification, the "~" indicating a numerical range represents "greater than or equal to" and "less than or equal to," and includes both values ​​at either end.

[0011] (solid composition) In the first embodiment, the following components: (A) Ibuprofen and (B) At least one selected from the group consisting of dextromethorphan and its salts, (C) Tranexamic acid and, a solid composition is provided. The solid composition is specifically a solid pharmaceutical composition.

[0012] Each component contained in the solid composition according to this embodiment may be contained in the state of a pharmacologically acceptable salt, or may be contained as a complex with other components. That is, the solid composition according to this embodiment may contain salts of each component not only for component (B), but also for component (A), component (C), and other components. "Pharmacologically acceptable salts" include, for example, salts with bases or acids acceptable as pharmaceuticals. Non-limiting specific examples of pharmacologically acceptable salts include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids, etc. Pharmacologically acceptable salts may be hydrates or anhydrous salts.

[0013] (A) Ibuprofen As used herein, "ibuprofen" has a CAS registration number of 15687-27-1 and is a compound represented by the chemical formula C 13 H 18 O2. Ibuprofen is used as an active ingredient such as an anti-inflammatory, analgesic, and antipyretic agent. The salt of ibuprofen is not particularly limited as long as it is pharmacologically acceptable.

[0014] The amount of ibuprofen included in the solid composition is adjusted as appropriate depending on the intended use of ibuprofen in the solid composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen administered to adults can be adjusted to a range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In this embodiment, "adult" means men and women aged 15 years or older. However, the solid composition according to this embodiment is not limited to use by adults, but may also be used by children under 15 years of age. When used by children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount taken by adults per day, depending on the age group. The same applies to ingredients other than ibuprofen.

[0015] The above dosages are examples, and the ibuprofen content per solid composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0016] In one embodiment, the ibuprofen content 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.

[0017] The weight and dosage of the solid composition described above are for a day, but the same amount may be administered to the subject in one dose, or divided into multiple doses per day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose and the dosage form of the solid composition.

[0018] In a particular embodiment, the solid composition is a tablet, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0019] (B) At least one selected from the group consisting of dextromethorphan and its salts As used herein, "dextromethorphan" refers to the CAS registry number 125-71-3, C 18 H 25 It is a compound represented by the chemical formula NO. Dextromethorphan is used as an active ingredient in cough suppressants and other medications. Salts of dextromethorphan are not particularly limited as long as they are pharmacodynamically acceptable, but examples include dextromethorphan hydrobromide hydrate and dextromethorphan phenolphthalein salt.

[0020] The solid composition according to this embodiment has improved ibuprofen dissolution persistence by containing at least one selected from the group consisting of dextromethorphan and its salts. In this specification, ibuprofen dissolution persistence means the degree of duration for which ibuprofen is dissolved from the solid composition, and can also be rephrased as ibuprofen sustained release. High, improved, and enhanced ibuprofen dissolution persistence all mean that the duration for which ibuprofen is dissolved from the solid composition is relatively long.

[0021] In this specification, improved ibuprofen dissolution persistence means that the dissolution persistence of ibuprofen is improved compared to a solid composition containing ibuprofen and tranexamic acid but without component (B) dextromethorphan; or a solid composition containing the same components as the solid composition being evaluated for dissolution persistence, except that it does not contain at least one selected from the group consisting of component (B) dextromethorphan and its salts, or contains the same amount of other control components in place of at least one selected from the group consisting of component (B) dextromethorphan and its salts. The dissolution rate of ibuprofen may be measured after a predetermined time has elapsed since the start of the dissolution test, for example, the dissolution rate of ibuprofen 60 minutes after the start of the test. The control component may be, for example, lactose.

[0022] In this embodiment, the persistence of ibuprofen dissolution may be measured, for example, by measuring the dissolution rate of ibuprofen from a solid composition over time, or by measuring the dissolution rate of ibuprofen after a predetermined period of time. The dissolution rate of ibuprofen may be measured, for example, by the method described in the "Dissolution Test Methods" of the 18th edition of the Japanese Pharmacopoeia. Specifically, it can be evaluated according to methods such as the paddle method, rotating basket method, and flow-through cell method 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 predetermined test solution is quantified. More specifically, it may be measured using the method for measuring the dissolution rate of ibuprofen described in the examples.

[0023] In the solid composition according to this embodiment, the dissolution rate of ibuprofen 60 minutes after the start of the dissolution test, when the above-described dissolution test is performed, is preferably 30-45%, more preferably 31-44%, and even more preferably 33-43%. When the above-described dissolution rate of ibuprofen is, for example, 30% or more, the immediate effect of the solid composition tends to improve. When the above-described dissolution rate of ibuprofen is, for example, 45% or less, the sustained dissolution of ibuprofen in the solid composition improves, and the sustained effect of the drug tends to improve.

[0024] From the viewpoint of further enhancing the sustained dissolution of ibuprofen in the solid composition according to this embodiment, it is preferable that at least one selected from the group consisting of (B) dextromethorphan and its salts is included in the same granules as (A) ibuprofen. That is, it is preferable that the solid composition according to this embodiment includes granules obtained by granulating a mixed powder containing at least (A) ibuprofen and at least one selected from the group consisting of (B) dextromethorphan and its salts. The solid composition according to this embodiment may be a tablet obtained by tableting the granules which are the granules. From a similar viewpoint, it is also preferable that the solid composition according to this embodiment is a tablet produced by a direct compression method in which a mixed powder containing at least (A) ibuprofen and at least one selected from the group consisting of (B) dextromethorphan and its salts is directly tableted, and it is also preferable that it is a tablet obtained by dissolving at least (A) ibuprofen and at least one selected from the group consisting of (B) dextromethorphan and its salts in a solvent, drying off the solvent, and optionally granulating the powder and then tableting it. In such embodiments, components (A) and (B) are located in close proximity in the solid composition, which tends to further improve the sustained dissolution of ibuprofen. Furthermore, in the above embodiments, (C) tranexamic acid may also be located in close proximity to at least one selected from the group consisting of (A) ibuprofen and (B) dextromethorphan and its salts, and (A) ibuprofen may form crystals together with (C) tranexamic acid.

[0025] Improved dissolution persistence 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 in the blood circulation over time. 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 solid composition with a composition that is identical except for the absence of component (B) dextromethorphan, or with a composition containing only ibuprofen and tranexamic acid.

[0026] Improvements in hemokinetics include extending the time to reach peak blood concentration (time to peak blood concentration; Tmax), increasing the peak blood concentration of the drug (Cmax), suppressing the decrease in blood drug concentration over time (extension of PK), increasing blood exposure (AUC), and extending the drug elimination half-life (t1 / 2).

[0027] The amount of at least one component selected from the group consisting of component (B) dextromethorphan and its salts is appropriately adjusted according to the intended use of the solid composition, the required degree of antitussive effect, the required degree of dissolution persistence, the symptoms of the recipient, age, weight, sex, etc. The amount and content of at least one component selected from the group consisting of dextromethorphan and its salts may be the amount and content of the total of dextromethorphan and dextromethorphan salts in terms of dextromethorphan equivalent.

[0028] The amount of at least one substance selected from the group consisting of dextromethorphan and its salts varies depending on the amount of ibuprofen, etc., but the daily amount of dextromethorphan can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0029] At least one selected from the group consisting of dextromethorphan and its salts contained in the solid composition administered daily is, for example, 0.0001 parts by mass to 1 part by mass, preferably 0.0001 parts by mass to 0.6 parts by mass, and more preferably 0.0003 parts by mass to 0.3 parts by mass, per 1 part by mass of ibuprofen, in terms of dextromethorphan.

[0030] In this embodiment, solid compositions comprising ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid may be excluded from the present invention.

[0031] Specifically, the present invention may exclude solid compositions comprising ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid; solid formulations comprising ibuprofen, dextromethorphan or a salt thereof, a release control agent that controls the release of dextromethorphan or a salt thereof (for example, a polymer that forms a hydrophilic hydrogel), and an organic acid or an acidic amino acid; solid formulations comprising ibuprofen, dextromethorphan or a salt thereof, and an organic acid or an acidic amino acid; and the invention described in Japanese Patent Application Publication No. 2018-039792. Here, examples of organic acids include citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, and succinic acid, and examples of acidic amino acids include L-carbocysteine, aspartic acid, and glutamic acid.

[0032] (C) Tranexamic acid 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. 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.

[0033] The amount of tranexamic acid is appropriately adjusted according to the intended use of the solid composition, the required degree of anti-inflammatory effect, the required degree of dissolution persistence, the symptoms of the recipient, age, weight, sex, etc. The amount of tranexamic acid varies depending on the amount of ibuprofen, etc., but for example, the daily amount can be adjusted within the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0034] The tranexamic acid content in the solid composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass. The amount of tranexamic acid contained in the solid 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.

[0035] The solid composition according to this embodiment may contain crystals composed of (A) ibuprofen and (C) tranexamic acid. That is, if the solid composition according to this embodiment contains (C) tranexamic acid, (A) ibuprofen and (C) tranexamic acid may form crystals.

[0036] In a crystal composed of (A) ibuprofen and (C) tranexamic acid, (A) ibuprofen and (C) tranexamic acid may exist in a 1:1 molar ratio. Furthermore, in the crystal, ibuprofen and tranexamic acid may form a crystalline unit cell of four molecules each.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] Crystals comprising (A) ibuprofen and (C) tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-70674.

[0041] (Other ingredients) The solid composition according to this embodiment may contain components other than those described above, depending on its intended use. When the solid composition is used to alleviate various symptoms of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, or other pharmacologically acceptable components.

[0042] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into COX-2 nonselective inhibitors such as 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 (including a hydrated salt).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Examples of cough suppressants and expectorants include noscapine hydrochloride, bromhexine, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, tipepidine, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0047] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0048] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0049] 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.

[0050] 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.

[0051] Pharmaceutical additives may be added to the solid composition according to this embodiment 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 formulations can be used for the above purposes.

[0052] 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 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.

[0053] Examples of binders include gum arabic, gum arabic powder, kanbai flour, 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, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0054] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0055] 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.

[0056] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0057] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0058] Examples of moisture-proofing agents include 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, and magnesium aluminometasilicate.

[0059] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0060] 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.)Examples include 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.

[0061] 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.

[0062] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0063] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, and erythritol.

[0064] 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-tartaric acid Examples include sodium glycyrrhizate, ginger powder, 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, porcini 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.

[0065] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0066] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0067] 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, and rose oil.

[0068] Examples of coloring agents include 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.

[0069] The base ingredients include: acacia 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. Examples include hydroxypropylcellulose, 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.

[0070] 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 / Hypermethylcellulose Examples include droxypropyl 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 methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0071] Examples of sugar coating agents include 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, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.

[0072] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, 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, and liquid paraffin.

[0073] 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. Examples include 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, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0074] Examples of defoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid esters, silicone defoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0075] Examples of fluidizing agents include 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, and calcium hydrogen phosphate granules.

[0076] 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, Vitabase, 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 flakes powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0077] These components may be present individually or in combination of two or more types.

[0078] (Dosage form) The solid composition according to this embodiment can be in dosage forms described in the 18th edition of the Japanese Pharmacopoeia, General Provisions for Pharmaceutical Preparations, etc., such as oral preparations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders), or preparations applied orally (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition according to this embodiment is preferably an oral solid composition.

[0079] Dosage forms of the solid composition according to this embodiment include, for example, tablets, capsules, pills, granules, and fine granules. These solid compositions may be coated by known methods such as sugar coating or film coating as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets.

[0080] The solid composition according to this embodiment may be initially packaged in bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored airtight. Furthermore, they may be pillow-packaged, or stored in boxes or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, 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 packaging or pillow packaging.

[0081] The solid composition according to this embodiment may be contained in a packaging container to form a package. The solid composition according to this embodiment may be contained in, for example, an airtight package. By forming a package, the convenience of use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0082] As for the packaging form of the solid composition, the solid composition may be initially packaged in a bottle, PTP (Press Through Package), pouch, stick, or SP (Strip Package) and stored airtight. Furthermore, these may be pillow-packed, or stored in a box or similar container. In addition, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be stored simultaneously in the packaging container, such as the bottle or pillow packaging.

[0083] Materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as resin films to which aluminum foil is attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0084] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Examples of such packaging include packaging formed from at least one of a moisture-proof material and a gas barrier material.

[0085] Examples of moisture-proof materials include a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. Furthermore, when the solid composition is a tablet, PTP packaging with aluminum on both sides (Al-Al packaging) may be used as a moisture-proof material, considering factors such as suppressing the rise in moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0086] Known materials may be used as the gas barrier material, for example, a laminate film having a functional barrier layer, and may be used to serve the same purpose as the moisture barrier material, or in combination with the moisture barrier material.

[0087] Furthermore, the packaging containers may be made environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used in part or all of the packaging materials.

[0088] (Manufacturing method) In a second embodiment, a method for producing a solid composition is provided, comprising the step of contacting (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and salts thereof, and (C) tranexamic acid.

[0089] The production of the solid composition can be carried out using known techniques. Each component is added in 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 paste may be used as the solid composition.

[0090] Crystals comprising (A) ibuprofen and (C) tranexamic acid may be produced in accordance with a method for producing a mixture containing both components, as described in Japanese Patent Publication No. 2022-40057.

[0091] The resulting mixture can be further subjected to drying and granulation processes to produce granules. In this case, granules containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0092] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0093] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the section on "Tablets" in the General Provisions of the Japanese Pharmacopoeia. Specifically, for example, a mixed powder containing (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and its salts, and (C) tranexamic acid may be granulated to obtain granules, and then the obtained granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet. Alternatively, a mixed powder containing (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and its salts, and (C) at least one tranexamic acid may be granulated to obtain a first granule, a mixed powder containing (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and its salts, and (C) at least one tranexamic acid may be granulated to obtain a second granule, and then the two types of granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet. From the viewpoint of enhancing the sustained dissolution of ibuprofen, it is preferable to granulate a mixed powder containing (A) ibuprofen and (B) dextromethorphan and its salts to form granules, thereby containing both components in the same granule. Here, (A) ibuprofen and (C) tranexamic acid may be crystallized in advance by the method described above.

[0094] When the solid composition contains extragranular components, tablets may be manufactured by adding the extragranular components to the granulated granules to form an outer layer of granulated granules, and then compressing the mixture into tablets. The extragranular components may also be in granular form. For example, granulated granules containing at least one selected from the group consisting of (A) ibuprofen, (B) dextromethorphan and its salts, and (C) tranexamic acid may be manufactured as the first granules, and granulated granules containing other active ingredients may be manufactured as the second granules. In this case, the first granules containing (A) ibuprofen, (B) dextromethorphan and its salts, and (C) tranexamic acid, and the second granules containing other active ingredients may be prepared separately, and the solid composition may be manufactured so that the components in the first granules and the other active ingredients in the second granules do not substantially come into contact. Other active ingredients may be included in the first granule or in the second granule, in order to obtain a suitable formulation.

[0095] The granules obtained in the above process may be used as is as a granular material.

[0096] (Sustained-release agent) In a third embodiment, an agent for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid is provided (hereinafter also simply referred to as the "sustained-release agent"), comprising at least one selected from the group consisting of dextromethorphan and its salts as an active ingredient. That is, the sustained-release agent according to this embodiment improves the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, and improves the sustained dissolution of ibuprofen. The ibuprofen sustained-release agent is added, for example, to a solid composition containing ibuprofen and tranexamic acid, specifically to a solid pharmaceutical composition containing ibuprofen and tranexamic acid.

[0097] In this embodiment, each component contained in the sustained-release agent, and each component contained in the solid composition to which the sustained-release agent is added, may be contained in the form of a pharmaceutically acceptable salt, or as a complex with other components. That is, in this embodiment, components other than dextromethorphan may also be contained as salts. "Pharmacologically acceptable salt" includes, for example, salts with pharmaceutically acceptable bases or acids. Non-limiting specific examples of pharmaceutically acceptable salts are as described above.

[0098] (At least one selected from the group consisting of dextromethorphan and its salts) The sustained-release improving agent according to this embodiment can improve the sustained-release properties of ibuprofen by including at least one selected from the group consisting of dextromethorphan and its salts. The sustained-release improving agent according to this embodiment includes at least one selected from the group consisting of dextromethorphan and its salts, and may be at least one selected from the group consisting of dextromethorphan and its salts, or it may be dextromethorphan. In this specification, the sustained-release properties of ibuprofen mean the degree of duration for which ibuprofen is eluted from the solid composition, and can also be rephrased as the duration of ibuprofen dissolution. High, improved, and enhanced sustained-release and dissolution duration of ibuprofen all mean that the duration for which ibuprofen is eluted from the solid composition is relatively long.

[0099] In this specification, "improving the sustained-release properties of ibuprofen" means that the sustained-release properties of ibuprofen are improved by adding the sustained-release properties of the sustained-release properties of the sustained-release properties of ibuprofen compared to a solid composition containing ibuprofen and tranexamic acid, but without at least one selected from the group consisting of dextromethorphan and its salts; or a solid composition containing the same components as the solid composition being evaluated for sustained-release properties, except that it does not contain at least one selected from the group consisting of dextromethorphan and its salts, or contains the same amount of other control components (e.g., lactose) instead of at least one selected from the group consisting of dextromethorphan and its salts. The dissolution rate of ibuprofen may be measured after a predetermined time has elapsed since the start of the dissolution test, for example, the dissolution rate of ibuprofen 60 minutes after the start of the test.

[0100] In this embodiment, the sustained-release properties of ibuprofen may be measured in the same way as the sustained dissolution properties of ibuprofen. For example, this may be done by measuring the dissolution rate of ibuprofen from a solid composition over time, or by measuring the dissolution rate of ibuprofen after a predetermined period of time. The method for measuring the dissolution rate of ibuprofen is as described above.

[0101] The sustained-release improving agent according to this embodiment, when combined with a solid composition containing ibuprofen and tranexamic acid in an equal amount of ibuprofen (by mass ratio) (when the sustained-release improving agent and ibuprofen are combined in equal amounts by mass ratio), can suppress the dissolution rate of ibuprofen 60 minutes after the start of the test, when an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, to, for example, 0.90 times or less, preferably 0.85 times or less, more preferably 0.82 times or less, even more preferably 0.80 times or less, and even more preferably 0.70 times or less. The sustained-release improving agent according to this embodiment may suppress the dissolution rate of ibuprofen 60 minutes after the start of a dissolution test, when performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, to, for example, 0.90 to 0.20 times, preferably 0.85 to 0.30 times, more preferably 0.82 to 0.35 times, even more preferably 0.80 to 0.40 times, and even more preferably 0.70 to 0.45 times, when an equivalent amount of ibuprofen (by mass ratio) is added to a solid composition containing ibuprofen and tranexamic acid. Here, the sustained-release improving agent may be blended with ibuprofen in an equivalent amount (by mass ratio) of an active ingredient selected from the group consisting of dextromethorphan and its salts.

[0102] When a solid composition containing ibuprofen and tranexamic acid is mixed with the sustained-release improving agent according to this embodiment in an equal amount (by mass ratio) with ibuprofen and an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of ibuprofen 60 minutes after the start of the test may be, for example, 0.90 times or less, preferably 0.85 times or less, more preferably 0.82 times or less, even more preferably 0.80 times or less, and even more preferably 0.70 times or less, based on the dissolution rate of ibuprofen when the same dissolution test is performed by mixing lactose in an equal amount (by mass ratio) with ibuprofen and a solid composition containing ibuprofen and tranexamic acid. When a solid composition containing ibuprofen and tranexamic acid is mixed with the sustained-release improving agent according to this embodiment in an equal amount (by mass ratio) with ibuprofen and subjected to an dissolution test according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of ibuprofen 60 minutes after the start of the test may be, for example, 0.90 to 0.20 times, preferably 0.85 to 0.30 times, more preferably 0.82 to 0.35 times, even more preferably 0.80 to 0.40 times, and even more preferably 0.70 to 0.45 times, based on the dissolution rate of ibuprofen when the same dissolution test is performed by mixing lactose in an equal amount (by mass ratio) with ibuprofen and subjected to an ibuprofen dissolution test. Here, the sustained-release improving agent may be formulated so that the active ingredient, which is at least one selected from the group consisting of dextromethorphan and its salts, is in an equal amount (by mass ratio) with ibuprofen.

[0103] This embodiment includes the following inventions. Use of at least one substance selected from the group consisting of dextromethorphan and its salts to improve the sustained release of ibuprofen; Use of at least one substance selected from the group consisting of dextromethorphan and its salts to improve the sustained release of a solid composition containing ibuprofen and tranexamic acid; In a solid composition containing ibuprofen and tranexamic acid, the use of at least one substance selected from the group consisting of dextromethorphan and its salts to improve the sustained release of ibuprofen; Use of at least one substance selected from the group consisting of dextromethorphan and its salts in the production of a solid composition containing ibuprofen and tranexamic acid with improved sustained-release properties; Use of at least one substance selected from the group consisting of dextromethorphan and its salts in the production of a solid composition containing ibuprofen and tranexamic acid with improved sustained-release properties of ibuprofen; A method for improving the sustained release properties of a solid composition containing ibuprofen and tranexamic acid, comprising adding at least one selected from the group consisting of dextromethorphan and its salts to the solid composition; A method for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, comprising adding at least one selected from the group consisting of dextromethorphan and its salts to the solid composition; At least one selected from the group consisting of dextromethorphan and its salts for use in improving the sustained release of ibuprofen; At least one selected from the group consisting of dextromethorphan and its salts for use in improving the sustained release of a solid composition containing ibuprofen and tranexamic acid; A solid composition containing ibuprofen and tranexamic acid, wherein at least one selected from the group consisting of dextromethorphan and its salts is used to improve the sustained release properties of ibuprofen.

[0104] When adding the sustained-release improving agent according to this embodiment to a solid composition containing ibuprofen and tranexamic acid, the amount of the sustained-release improving agent added is determined based on the amount of at least one substance selected from the group consisting of dextromethorphan and its salts. The amount of the sustained-release improving agent added is appropriately adjusted according to the use of the solid composition, the required degree of sustained release, the symptoms of the person being administered to, age, weight, sex, etc. The amount of at least one substance selected from the group consisting of dextromethorphan and its salts added may be the amount of dextromethorphan equivalent of the total of dextromethorphan and dextromethorphan salts added.

[0105] The amount of at least one additive selected from the group consisting of dextromethorphan and its salts varies depending on the amount of ibuprofen contained in the solid composition to which it is added, but the daily amount of dextromethorphan can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0106] The amount of at least one additive selected from the group consisting of dextromethorphan and its salts is, based on the amount administered per day, 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, in terms of dextromethorphan.

[0107] (solid composition) The sustained-release improving agent according to this embodiment is added to a solid composition containing ibuprofen and tranexamic acid. The following describes solid compositions containing ibuprofen and tranexamic acid to which the sustained-release improving agent according to this embodiment may be added. It goes without saying that the sustained-release improving agent according to this embodiment can also be added to compositions other than those described below.

[0108] (Ibuprofen) The amount of ibuprofen in a solid composition is adjusted as appropriate depending on the intended use of the solid composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen administered to an adult may be adjusted to a range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg.

[0109] The above dosages are examples, and the ibuprofen content per solid composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0110] In one embodiment, the ibuprofen content 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.

[0111] The weight and dosage of the solid composition described above are for a day, but the same amount may be administered to the subject in one dose, or divided into multiple doses per day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose and the dosage form of the solid composition.

[0112] In a particular embodiment, the solid composition is a tablet, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0113] (Tranexamic acid) The amount of tranexamic acid is appropriately adjusted according to the intended use of the solid composition, the required degree of anti-inflammatory effect, the required degree of sustained release, the symptoms of the recipient, age, weight, sex, etc. The amount of tranexamic acid varies depending on the amount of ibuprofen, etc., but for example, the daily amount can be adjusted within the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0114] The tranexamic acid content in the solid composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass. The amount of tranexamic acid contained in the solid 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.

[0115] The solid composition may contain crystals composed of ibuprofen and tranexamic acid. The crystals composed of ibuprofen and tranexamic acid, their characteristics, and the method of producing them are as described above.

[0116] (Other ingredients) The solid composition may contain ingredients other than ibuprofen and tranexamic acid, depending on its intended use. When the solid composition is used to alleviate various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, and muscle pain, in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, and other pharmacologically acceptable ingredients. Specific examples of ingredients that may be included in the solid composition, including these ingredients, are as described above. Other ingredients may be included individually or in combination of two or more. Furthermore, the dosage form of the solid composition to which the sustained-release improving agent according to this embodiment is added is the same as that of the solid composition described above.

[0117] (Addition method) The sustained-release improving agent according to this embodiment is added to a solid composition containing ibuprofen and tranexamic acid to improve the sustained-release properties of ibuprofen. The sustained-release improving agent according to this embodiment is added to a solid composition, for example, in the production of a solid composition containing ibuprofen and tranexamic acid. The method for producing the solid composition may include a step of contacting at least one of ibuprofen and tranexamic acid with the sustained-release improving agent according to this embodiment.

[0118] The production of the solid composition can be carried out using known techniques. Each component is added in 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. Crystals consisting of ibuprofen and tranexamic acid may be produced in accordance with the method for producing a mixture containing both components, as described in Japanese Patent Application Publication No. 2022-40057.

[0119] The resulting mixture can be further subjected to drying and granulation processes to produce granules. In this case, granules containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0120] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0121] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the section on "Tablets" in the General Provisions of the Japanese Pharmacopoeia. Specifically, a mixed powder containing at least ibuprofen, tranexamic acid, and the sustained-release agent according to this embodiment may be granulated to obtain granules, and then the obtained granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet. Alternatively, a mixed powder containing ibuprofen, tranexamic acid, and at least one of the sustained-release agent according to this embodiment may be granulated to obtain a first granule, a mixed powder containing ibuprofen, tranexamic acid, and at least one of the sustained-release agent according to this embodiment may be granulated to obtain a second granule, and then the two types of granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet. From the viewpoint of enhancing the sustained-release properties of ibuprofen, it is preferable to granulate a mixed powder containing at least ibuprofen and the sustained-release agent according to this embodiment to form granules, and to include both components in the same granule. Here, ibuprofen and tranexamic acid may be crystallized in advance by the method described above.

[0122] When the solid composition contains extragranular components, tablets may be manufactured by adding the final components to the granulated granules to form an outer layer of granulated granules, and then compressing the mixture into tablets. The extragranular components may also be in granular form. For example, granulated granules containing ibuprofen, tranexamic acid, and the sustained-release agent according to this embodiment may be manufactured as the first granules, and granulated granules containing other active ingredients may be manufactured as the second granules. In this case, the first granules containing ibuprofen, tranexamic acid, and the sustained-release agent according to this embodiment and the second granules containing other active ingredients may be provided separately, and the solid composition may be manufactured so that the components in the first granules and the other active ingredients in the second granules do not substantially come into contact. The other active ingredients may be included in the first granules or in the second granules so as to obtain a suitable formulation.

[0123] The granules obtained in the above process may be used as is as a granular material.

[0124] From the viewpoint of further enhancing the effect of the sustained-release improving agent according to this embodiment, it is preferable that the sustained-release improving agent according to this embodiment be included in the same granule as ibuprofen. That is, it is preferable that the sustained-release improving agent according to this embodiment be granulated together with the mixed powder containing ibuprofen. The granules may be further compressed into tablets to produce tablets. From a similar viewpoint, it is also preferable that the sustained-release improving agent according to this embodiment be added to the mixed powder containing ibuprofen and tablets be produced by direct compression, or that ibuprofen and the sustained-release improving agent according to this embodiment be dissolved in a solvent, the solvent be dried off to obtain a powder, and then the powder be optionally granulated and compressed into tablets to produce tablets. When the sustained-release improving agent according to this embodiment is added in this way, ibuprofen and at least one selected from the group consisting of dextromethorphan and its salts are present in close proximity in the solid composition, and the sustained-release properties of ibuprofen tend to be further improved.

[0125] To illustrate the present invention in more detail, test examples and embodiments are described below, but the present invention is not limited thereto. [Examples]

[0126] 1.Raw materials In this example, unless otherwise specified, the following raw materials were used. [Table 1]

[0127] Crystals of ibuprofen and tranexamic acid were prepared as follows: 240.0 g of ibuprofen (manufactured by Yonezawa Hamari) and 182.9 g of tranexamic acid (manufactured by AMI) were charged into a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Powrec)) and mixed to obtain a mixed powder. 69 g of a mixture of ethanol (purity 99.5%) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was added to this mixed powder and kneaded and granulated to obtain a paste. The paste was wet-milled using a power mill (manufactured by Dalton) at low speed and 32 mesh, and stored in a constant temperature bath at 70°C for 89 hours to obtain crystals of ibuprofen and tranexamic acid.

[0128] Furthermore, differential scanning calorimetry (DSC) was performed on the obtained ibuprofen and tranexamic acid crystals, and the DSC curve shown in Figure 1 was obtained. From Figure 1, it was found that there is a peak around 186°C. It was also confirmed that the endothermic peak around 75°C related to the melting of ibuprofen had disappeared.

[0129] Differential scanning calorimetry was performed as follows: The obtained single crystals were weighed into an aluminum cell and measured using a differential scanning calorimeter (METTLER TOLEDO, DSC 3+) under nitrogen conditions, with a heating rate of 60°C / min and a measurement temperature of 25–350°C.

[0130] 2. Measurement of the sustained release (dissolution duration) of solid compositions The components shown in Table 2 were uniformly mixed using a mortar and pestle to obtain samples for dissolution testing. In each example, tranexamic acid was added in a molar ratio equivalent to ibuprofen. Dextromethorphan hydrobromide was added in a mass ratio equivalent to ibuprofen. In Table 2, the amount of each component is shown in grams. In the example using ibuprofen and tranexamic acid crystals, the amount of each component was calculated assuming that ibuprofen and tranexamic acid were present in a 1:1 molar ratio.

[0131] In Table 2 below, "DX" refers to dextromethorphan hydrobromide, and "IB-TXA" refers to the crystals of ibuprofen and tranexamic acid formed as described above.

[0132] [Table 2]

[0133] For each sample prepared as described above, the dissolution rate of ibuprofen was measured as follows, in accordance with the "Dissolution Test Method (Paddle Method)" of the 18th edition of the Japanese Pharmacopoeia. Equipment used: Toyama Sangyo NTR-6400AC elution tester Dissolution test solution: Water 900 mL (37℃) Test method: Paddle method, 50 rpm Test Procedure: The prepared sample was weighed to contain 50 mg of ibuprofen and placed in an elution test vessel. After 60 minutes, 10 mL of the test solution was taken. The collected test solution was filtered through a membrane filter (Millex-GV, material: PVDF, pore size: 0.22 μm, diameter: 33 mm). The first 7 mL was discarded, and the remaining 3 mL was used for the quantification of ibuprofen. Ibuprofen quantification was performed by high-performance liquid chromatography (HPLC).

[0134] High-performance liquid chromatography measurements were performed as follows. Equipment used: High-performance liquid chromatography (manufactured by Agilent Technology) Column: L-Column2 ODS, Particle size: 5 μm, Size: 4.6 x 250 mm (Manufactured by Shimadzu GLC Co., Ltd.) Mobile phase: 0.05M sodium dihydrogen phosphate (pH 2.6) / acetonitrile mixture Test procedure: The ibuprofen concentration in each sample was measured, and the ibuprofen dissolution rate at each time point was calculated.

[0135] Figure 2 shows the ibuprofen dissolution rates in each example. From Figure 2, it can be seen that in Comparative Examples 1 and 2, which contain ibuprofen and tranexamic acid, the ibuprofen dissolution rate was higher compared to Reference Example 1, which contains ibuprofen alone. However, in Examples 1 and 2, which also contain dextromethorphan, the effect of tranexamic acid on increasing the ibuprofen dissolution rate was suppressed, and the dissolution persistence and sustained release properties were improved. Furthermore, in Reference Example 2, which contains ibuprofen and dextromethorphan, the ibuprofen dissolution rate was actually higher compared to Reference Example 1, which does not contain dextromethorphan. Compared to the dissolution rate of Comparative Example 1, the dissolution rate of Example 1 was 0.81 times. Compared to the dissolution rate of Comparative Example 2, the dissolution rate of Example 2 was 0.52 times.

[0136] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

Claims

1. The following ingredients: (A) Ibuprofen and, (B) At least one selected from the group consisting of dextromethorphan and its salts, (C) Tranexamic acid and A solid composition containing the following:

2. The solid composition according to claim 1, comprising crystals consisting of (A) ibuprofen and (C) tranexamic acid.

3. The solid composition according to claim 2, wherein the molar ratio of (A) ibuprofen to (C) tranexamic acid in the crystal is 1:

1.

4. The solid composition according to any one of claims 1 to 3, wherein the dissolution rate of ibuprofen 60 minutes after the start of the test, when performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, is 30 to 45%.

5. An agent for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, comprising at least one selected from the group consisting of dextromethorphan and salts thereof as an active ingredient.

6. The sustained-release improving agent according to claim 5, wherein the solid composition comprises crystals composed of ibuprofen and tranexamic acid.

7. The sustained-release agent according to claim 6, wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:

1.

8. A sustained-release agent according to any one of claims 5 to 7, which reduces the dissolution rate of ibuprofen 60 minutes after the start of a dissolution test, when an equal amount of ibuprofen is added to a solid composition containing ibuprofen and tranexamic acid, to 0.85 times or less, when a dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia.

9. A method for improving the sustained release of ibuprofen in a solid composition containing ibuprofen and tranexamic acid, comprising adding at least one selected from the group consisting of dextromethorphan and its salts to the solid composition.

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