Solid composition and dissolution improver

Abstract

To provide a solid composition containing crystals of ibuprofen and tranexamic acid with improved dissolution properties. [Solution] The following components: (A) A crystal consisting of ibuprofen and tranexamic acid, (B) Water-soluble polymer and A solid composition containing the following:

Description

[Technical Field]

[0001] The present invention generally relates to a solid composition comprising a crystal consisting of ibuprofen and tranexamic acid, and a water-soluble polymer. [Background Art]

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

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

[0004] Patent Document 2 discloses a solid preparation containing ibuprofen and an amino group-containing compound and having excellent controlled release properties. Patent Document 2 discloses that when ibuprofen and an amino group-containing compound such as ambroxol or dextromethorphan are blended together, the release property of these amino group-containing compounds may change depending on pH. [Prior Art Documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Unexamined Patent Publication No. 2022-070674 [Patent Document 2] Japanese Unexamined Patent Publication No. 2022-009553 [Brief Summary of the Invention] [Problem to be Solved by the Invention]

[0006] Patent Document 1 does not describe anything about the elution properties of crystals composed of ibuprofen and tranexamic acid. The present inventors have found that solid compositions containing crystals composed of ibuprofen and tranexamic acid may have insufficient ibuprofen elution properties in acidic environments. The present invention aims to provide a solid composition containing crystals composed of ibuprofen and tranexamic acid with improved elution properties. [Means for solving the problem]

[0007] The inventors of the present invention have discovered that when a water-soluble polymer is added to a solid composition containing crystals of ibuprofen and tranexamic acid, the dissolution of ibuprofen in an acidic environment is improved, and have completed the present invention.

[0008] In other words, this application encompasses the following inventions. [1] The following ingredients: (A) A crystal consisting of ibuprofen and tranexamic acid, (B) Water-soluble polymer and A solid composition containing the following: [2] The water-soluble polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropylcellulose. The solid composition described in [1]. [3] The water-soluble polymer has a viscosity of 0.1 to 4000 mPa·s when it is prepared as a 2.0% by mass aqueous solution at 20°C. The solid composition described in [1] or [2]. [4] The solid composition according to any one of [1] to [3], wherein the mass ratio of (A) to (B) is 1:0.01 to 1:1 ((A):(B)). [5] The solid composition according to any one of [1] to [4], wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:1. [6] Comprising a granulated product containing the aforementioned (A) and the aforementioned (B), The solid composition according to any one of [1] to [5]. [7] A tablet, Comprising the solid composition according to any one of [1] to [6], A coating film containing the aforementioned (B) is provided on the surface of the tablet, A tablet. [8] An agent for improving dissolution of a solid composition comprising a crystal consisting of (A) ibuprofen and tranexamic acid, comprising (B) a water-soluble polymer, the dissolution improving agent.

Advantageous Effects of Invention

[0009] According to the present invention, a solid composition comprising a crystal consisting of ibuprofen and tranexamic acid with improved dissolution can be provided.

Brief Description of Drawings

[0010] [Figure 1] Shows the results of differential scanning calorimetry (DSC) of the crystal consisting of ibuprofen and tranexamic acid obtained in an example. [Figure 2] Shows the measurement results of the dissolution rate of ibuprofen. "*" indicates that there was a significant difference relative to Comparative Example 1 at a significance level of p<0.05.

Mode for Carrying Out the Invention

[0011] Hereinafter, embodiments of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention should not be construed as being limited to the following embodiments. In the present embodiment, the composition may contain any of the components alone or in combination of two or more. In the present specification, "~" indicating a numerical range means "not less than" and "not more than", and includes both numerical values at both ends.

[0012] (Solid Composition) In the first aspect, The following components: (A) a crystal formed of ibuprofen and tranexamic acid, (B) a water-soluble polymer, and A solid composition comprising is provided. Specifically, the solid composition is a solid pharmaceutical composition.

[0013] Each component contained in the solid composition according to the present embodiment may be contained in the form of a pharmacologically acceptable salt, or may be contained as a complex with other components. The term "pharmacologically acceptable salt" includes, for example, salts with pharmaceutically acceptable bases or acids. 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. The pharmacologically acceptable salt may be a hydrate salt or an anhydrous salt.

[0014] The solid composition according to the present embodiment contains a water-soluble polymer in addition to the crystal formed of ibuprofen and tranexamic acid, whereby the elution property of ibuprofen, particularly the elution property in an acidic environment, is improved.

[0015] In this specification, improved ibuprofen dissolution means that the dissolution rate of ibuprofen is improved compared to a solid composition containing ibuprofen and tranexamic acid crystals alone; a solid composition containing ibuprofen and tranexamic acid crystals but without component (B); or a solid composition containing the same components as the solid composition being evaluated for dissolution, except that it does not contain component (B) or contains the same amount of another control component instead of component (B). 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 lactose, for example.

[0016] In this specification, an acidic environment means that the solid composition is present in an acidic solvent. The pH of the acidic solvent is, for example, 6.0 or less, preferably 0.5 to 5.0, more preferably 0.8 to 4.0, and even more preferably 1.0 to 3.0. The elution of ibuprofen in an acidic environment may be measured after a predetermined time has elapsed since the start of the elution test using an acidic solvent, for example, the elution rate of ibuprofen 60 minutes after the start of the test.

[0017] In this embodiment, the dissolution rate of ibuprofen may be measured, for example, by a method described in the "Dissolution Test Method" 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 Method" of the 18th Edition of the Japanese Pharmacopoeia. In the dissolution test, the amount of ibuprofen dissolved in a predetermined test solution is quantified. The test solution is preferably an acidic test solution, more preferably a test solution with a pH of 1.0 to 3.0, and particularly preferably the dissolution test solution No. 1 described in the 18th Edition of the Japanese Pharmacopoeia. More specifically, it can be measured using the method for measuring the dissolution rate of ibuprofen described in the examples.

[0018] In the solid composition according to this embodiment, the dissolution rate of ibuprofen 60 minutes after the start of the test when an dissolution test is performed, particularly when an dissolution test is performed using an acidic solvent, is preferably 25% or more, more preferably 28% or more, even more preferably 30% or more, even more preferably 35% or more, and particularly preferably 40% or more. The upper limit of the dissolution rate is not particularly limited, but the dissolution rate may be, for example, 100% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, or 50% or less.

[0019] (A) Crystals composed of ibuprofen and tranexamic acid 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.

[0020] The amount of ibuprofen or its salt included in the composition is adjusted as appropriate depending on the intended use of ibuprofen or its salt in the composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen or its salt is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen or its salt administered to adults can be adjusted to a range of 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 being taken by adults, but may also be taken by children under 15 years of age. When taken 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.

[0021] The above dosages are examples, and the ibuprofen or salt content per composition administered daily is, for example, 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0022] The weight and dosage in the above-mentioned compositions are daily doses (daily amounts), but the same amount may be administered to the subject multiple times a day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen or its salts. Furthermore, since each dosage is a total amount, the content of each component in the composition may vary depending on the single dose and the dosage form of the composition.

[0023] In certain embodiments, the composition is in tablet form, 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.

[0024] 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.

[0025] The solid composition may contain both crystalline ibuprofen and non-crystalline ibuprofen. Specifically, the solid composition may contain tranexamic acid and crystalline ibuprofen, and tranexamic acid and non-crystalline ibuprofen.

[0026] The ibuprofen contained in the solid composition may be crystallized with tranexamic acid at a concentration 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.

[0027] 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.

[0028] The amount of tranexamic acid or its salt is adjusted as appropriate depending on the intended use of tranexamic acid or its salt in the composition. The amount of tranexamic acid or its salt varies depending on the amount of ibuprofen, etc., but for example, the daily amount is in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The solid composition may contain both crystalline tranexamic acid and non-crystalline tranexamic acid. Specifically, the solid composition may contain ibuprofen and crystalline tranexamic acid, and ibuprofen and non-crystalline tranexamic acid.

[0033] The tranexamic acid contained in the solid composition may be crystallized with ibuprofen at a concentration 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.

[0034] Ibuprofen and tranexamic acid exist as crystals in the composition. In these crystals, ibuprofen and tranexamic acid may exist in a 1:1 molar ratio. In addition, in these crystals, ibuprofen and tranexamic acid may form a crystalline unit cell of four molecules each.

[0035] 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.

[0036] 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.

[0037] The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-070674, 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.

[0038] Crystals composed of ibuprofen and tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-070674. Three representative production methods described in the same publication are listed below.

[0039] 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.

[0040] 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.

[0041] A method for producing crystals consisting of ibuprofen and tranexamic acid, A method comprising: (1) adding ibuprofen and tranexamic acid to a solvent to obtain a solution or dispersion; (2) spraying and drying the obtained solution or dispersion; or (3) allowing the solution obtained in step (1) to stand, filtering the product obtained after standing, and drying the product.

[0042] (B) Water-soluble polymer The solid composition according to this embodiment contains (B) a water-soluble polymer. The water-soluble polymer may be one type alone or may contain two or more types.

[0043] In this specification, a water-soluble polymer is a polymer compound that can dissolve in water. In this embodiment, it is preferable that the amount of water required to dissolve 1 g of the water-soluble polymer in water within 30 minutes when the polymer is placed in powder form and shaken vigorously for 30 seconds every 5 minutes at 20±5°C is less than 100 mL.

[0044] Examples of water-soluble polymers include cellulose-based water-soluble polymers, polyvinyl alcohol (also known as "PVA"), polyvinylpyrrolidone (also known as "povidone"), polyethylene glycol (including macrogol), polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer vinyl acetate / vinylpyrrolidone copolymer (also known as "copolyvidone"), alginic acid, alkali metal alginates, ammonium alginates, carrageenan, xanthan gum, gum arabic, and polyethylene oxide.

[0045] Cellulose-based water-soluble polymers are obtained by modifying the hydroxyl groups of water-insoluble cellulose with methyl chloride, propylene oxide, ethylene oxide, etc., to make them water-soluble. For example, they are listed in the 2021 Dictionary of Pharmaceutical Additives and the 18th Revised Japanese Pharmacopoeia. Examples of cellulose-based water-soluble polymers include hydroxypropyl methylcellulose (also called "HPMC" or "hypromellose"), hydroxypropyl cellulose (also called "HPC"), methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, and sodium carboxymethylcellulose.

[0046] The water-soluble polymer is preferably at least one selected from the group consisting of cellulosic water-soluble polymers, PVA, and povidone, more preferably at least one selected from the group consisting of HPMC, HPC, PVA, and povidone, and even more preferably at least one selected from the group consisting of HPMC, PVA, and povidone.

[0047] HPMC is a cellulose derivative having a hydroxypropoxyl group and a methoxy group in its molecule. HPMC can be broadly classified into hypromellose 1828, hypromellose 2208, hypromellose 2906, and hypromellose 2910 depending on the degree of substitution, but any of these types may be used. The substitution ratios of the hydroxypropoxyl group and methoxy group in each type are described in the 18th edition of the Japanese Pharmacopoeia.

[0048] HPC is a cellulose derivative having a hydroxypropoxyl group in its molecule. In this embodiment, when quantifying HPC, it may contain 53.4 to 80.5% of hydroxypropoxyl groups (-OC3H6OH:75.09) relative to the converted dry product (see the 18th edition of the Japanese Pharmacopoeia). When the degree of substitution of the hydroxypropoxyl group is low, it is called low-substituted hydroxypropyl cellulose (also called "L-HPC") and is clearly distinguished. When quantifying L-HPC, it may contain 5.0 to 16.0% of hydroxypropoxyl groups (-OC3H6OH:75.09) relative to the converted dry product. L-HPC is not included in the water-soluble polymers defined above.

[0049] PVA is a polymer compound obtained by saponifying polyvinyl acetate, which is obtained by polymerizing vinyl acetate monomer. Depending on the degree of saponification, it can be broadly classified into polyvinyl alcohol (fully saponified) and polyvinyl alcohol (partially saponified), but either type is acceptable. In this embodiment, the PVA is preferably partially saponified, and the degree of saponification is preferably 50 to 95 mol%, more preferably 60 to 93 mol%, and even more preferably 80 to 90 mol%.

[0050] Povidone has a CAS registry number of 9003-39-8, (C6H9NO) n It is a compound represented by the chemical formula shown.

[0051] Water-soluble polymers may become viscous when dissolved in water. Including the water-soluble polymers described above, water-soluble polymers may have a viscosity of 0.1 to 5000 mPa·s at 20°C when prepared as an aqueous solution of 10% by mass or less. Water-soluble polymers have a viscosity of 0.01 to 10% by mass, preferably 0.1 to 8.0% by mass, more preferably 1.0 to 5.0% by mass, even more preferably 2.0 to 4.0% by mass, and particularly preferably 2.0% by mass, when prepared as an aqueous solution of 0.01 to 10% by mass, preferably 0.1 to 8.0% by mass, more preferably 1.0 to 5.0% by mass, even more preferably 2.0% by mass, at 20°C, preferably 0.1 to 4000 mPa·s, more preferably 0.5 to 2000 mPa·s, even more preferably 1.0 to 1000 mPa·s, even more preferably 1.5 to 500 mPa·s, and particularly preferably 2.0 to 100 mPa·s.

[0052] The viscosity of water-soluble polymers can be measured by the method described in the 18th edition of the Japanese Pharmacopoeia. For example, a water-soluble polymer can be dissolved in water, allowed to stand at 20°C for approximately 24 hours, and then measured using a rotational viscometer (RHEOMETER R / S plus, Brookfield) at a temperature of 20°C and a rotation speed of 10 rpm, with the viscosity measured 300 seconds after the start of measurement.

[0053] In this embodiment, the water-soluble polymer is preferably at least one selected from the group consisting of HPMC, HPC, PVA, and povidone, having a viscosity of 2.0 to 100 mPa·s at 20°C when prepared as a 2.0 to 4.0% by mass aqueous solution; more preferably at least one selected from the group consisting of HPMC, PVA, and povidone, having a viscosity of 2.0 to 100 mPa·s at 20°C when prepared as a 2.0 to 4.0% by mass aqueous solution; and particularly preferably at least one selected from the group consisting of HPMC and povidone, having a viscosity of 2.0 to 100 mPa·s at 20°C when prepared as a 2.0% by mass aqueous solution, and PVA, having a viscosity of 2.0 to 100 mPa·s at 20°C when prepared as a 4.0% by mass aqueous solution.

[0054] In this embodiment, the water-soluble polymer is preferably contained in the same granule as component (A). That is, the solid composition according to this embodiment preferably contains granules obtained by granulating a mixed powder containing (A) crystals of ibuprofen and tranexamic acid and (B) a water-soluble polymer. The solid composition according to this embodiment may be a tablet obtained by tableting the granules which are the granules. From a similar viewpoint, the solid composition according to this embodiment is also preferably a tablet produced by a direct compression method in which a mixed powder containing component (A) and component (B) is directly tableted, or it is also preferably a powder obtained by dissolving component (A) and component (B) in a solvent and drying off the solvent, and a tablet obtained by optionally granulating the powder and then tableting it. In such embodiments, component (A) and component (B) exist in close proximity in the solid composition, and the dissolution of ibuprofen tends to be further improved.

[0055] In this embodiment, the water-soluble polymer may be used as a coating agent. The dosage form of the solid composition according to this embodiment will be described later, but the solid formulation containing the solid composition according to this embodiment may be a tablet, and the water-soluble polymer may be contained in the coating film provided on the surface of the tablet.

[0056] The water-soluble polymer is adjusted as appropriate depending on the intended use of the solid composition, the required ibuprofen dissolution, the symptoms of the recipient, age, weight, sex, etc. If multiple water-soluble polymers are included, the amount of each water-soluble polymer may be adjusted independently.

[0057] The total amount of water-soluble polymer varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 10 mg to 500 mg, preferably 20 mg to 200 mg, and more preferably 50 mg to 100 mg.

[0058] The total amount of water-soluble polymer contained in the solid composition administered daily is, for example, 0.01% to 99% by mass, preferably 0.1% to 50% by mass, and more preferably 1% to 20% by mass.

[0059] The amount of HPMC included varies depending on the amount of crystals consisting of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 10 mg to 500 mg, preferably 20 mg to 200 mg, and more preferably 50 mg to 100 mg.

[0060] The amount of HPMC contained in the solid composition administered daily is, for example, 0.01% to 99% by mass, preferably 0.1% to 50% by mass, and more preferably 1% to 20% by mass.

[0061] The amount of PVA included varies depending on the amount of crystals consisting of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 10 mg to 500 mg, preferably 20 mg to 200 mg, and more preferably 50 mg to 100 mg.

[0062] The amount of PVA contained in the solid composition administered daily is, for example, 0.01% to 99% by mass, preferably 0.1% to 50% by mass, and more preferably 1% to 20% by mass.

[0063] The amount of povidone varies depending on the amount of crystals composed of ibuprofen and tranexamic acid, but for example, the daily amount is in the range of 10 mg to 500 mg, preferably 20 mg to 200 mg, and more preferably 50 mg to 100 mg.

[0064] The amount of povidone contained in the solid composition administered daily is, for example, 0.01% to 99% by mass, preferably 0.1% to 50% by mass, and more preferably 1% to 20% by mass.

[0065] In this embodiment, the mass ratio of component (A) to component (B) contained in the solid composition (the mass ratio of the total amount of component (A) to component (B)) ((A):(B)) is not particularly limited, but is preferably 1:0.01 to 1:1, more preferably 1:0.1 to 1:0.8, and even more preferably 1:0.2 to 1:0.5. The mass ratio of each component corresponding to component (A) to component (B) may be within the above range. By having the mass ratio of component (A) to component (B) within the above range, the dissolution of ibuprofen can be further improved.

[0066] (Other ingredients) The solid composition according to this embodiment may contain components other than those listed above, depending on its intended use. When the solid composition is intended 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, antipyretic analgesics, particularly active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components may be added. The water-soluble polymer described above may be added, for example, as components described later, such as excipients, binders, disintegrants, disintegration aids, glossing agents, bases, coating agents, and sugar coating agents.

[0067] 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 salt form.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] Examples of cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, bromhexine, bromhexine hydrochloride, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0072] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0073] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, pullulan, 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.

[0079] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0080] 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.

[0081] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0082] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0083] 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.

[0084] 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.

[0085] 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 chloride. Ferric, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, hydrated silicon dioxide, carmellose sodium, 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, Sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.)Examples include polysorbate 20, polysorbate 60, polysorbate 80, 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, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.

[0086] 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.

[0087] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0088] 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.

[0089] 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.

[0090] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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 Examples include glycerin, potato starch, hydroxypropylcellulose, pullulan, pectin, polysorbate 60, polysorbate 80, 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.

[0095] 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, fumaric acid / stearic acid / polyvinyl acetal diethyl ammonium Examples include a mixture of 2910 hydroxypropyl methylcellulose, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, 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.

[0096] 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, pullulan, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0097] 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.

[0098] 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, 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] These components may be present individually or in combination of two or more types.

[0103] (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.

[0104] 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.

[0105] 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 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] (tablet) In the second mode, It is a tablet, The solid composition according to this embodiment includes, The surface of the tablet is provided with a coating film containing (B) a water-soluble polymer. tablet It will be provided.

[0114] In other words, the tablet according to this embodiment comprises (A) a crystal composed of ibuprofen and tranexamic acid, and (B) a water-soluble polymer. Components (A) and (B) are as described in the description of the solid composition according to this embodiment. The preferred dosage and content of each component are also the same.

[0115] The tablets according to this embodiment contain (B) a water-soluble polymer in the coating film, but the water-soluble polymer (B) may also be contained in parts other than the coating film. Preferably, the tablets according to this embodiment contain granules containing component (A) and component (B). By compounding component (B) in close proximity to component (A), the dissolution of ibuprofen can be further improved.

[0116] (Manufacturing method) The solid composition according to this embodiment can be manufactured using known techniques. Crystals comprising ibuprofen and tranexamic acid can be manufactured by the method described in Japanese Patent Application Publication No. 2022-070674 (listed above). A commercially available water-soluble polymer can be used.

[0117] The crystals consisting of ibuprofen and tranexamic acid and the water-soluble polymer are added at any step and ultimately brought into contact with each other. A solvent and binder may be added to the mixture after contact and kneaded, and the resulting mixture may be a solid composition. It is preferable that components (A) and (B) are granulated so that they are contained in the same granule.

[0118] 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.

[0119] The obtained 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, or these can be further film-coated. The water-soluble polymer may also be added to the tablets as a coating film for the compressed uncoated tablets.

[0120] (Dissolution improving agent) In the third embodiment, (A) An agent for improving the dissolution properties of a solid composition containing crystals of ibuprofen and tranexamic acid, (B) Containing a water-soluble polymer, Dissolution improving agent It will be provided.

[0121] (B) The water-soluble polymer is as described in component (B) of the solid composition according to this embodiment, and the crystals consisting of (A) ibuprofen and tranexamic acid are as described in component (A) of the solid composition according to this embodiment. The dissolution improving agent according to this embodiment can improve the dissolution of ibuprofen in the solid composition containing the crystals consisting of (A) ibuprofen and tranexamic acid, and can particularly improve the dissolution of ibuprofen in an acidic environment.

[0122] The dissolution properties and improvements in dissolution properties are as described in the solid composition according to this embodiment.

[0123] The dissolution improver is preferably used in such an amount that the amount of water-soluble polymer (B) relative to component (A) falls within the range described as the preferred content of component (B) in the solid composition according to this embodiment. The form of each component and the order of addition are not particularly limited, but it is preferable that components (A) and (B) are granulated so that they are contained in the same granule.

[0124] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. [Examples]

[0125] 1.Raw materials In this example, the following raw materials were used. In the table, "HPMC," "L-HPC," and "PVA" are defined as specified herein. The degree of saponification of the PVA (Gosenol EG-05PW) used in this example was 86.5 to 89.0 mol%. [Table 1]

[0126] 2. Preparation of the solid composition (Reference example 1) Ibuprofen and lactose were weighed in a total of 1 g in the mass ratio shown in Table 1, and then uniformly mixed in a bottle to prepare the sample for Reference Example 1.

[0127] (Comparative Example 1) 240.0 g of ibuprofen and 182.9 g of tranexamic acid were charged into a stirring granulator (Vertical Granulator VG-5 (Powrec)) and mixed to obtain a mixed powder. 69 g of a mixture of ethanol (99.5% purity) (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 (Dalton) at low speed and 32 mesh. Subsequently, it was stored in a constant temperature bath at 70°C for 89 hours to obtain crystals consisting of ibuprofen and tranexamic acid.

[0128] Six mg of the obtained crystals were 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). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen around 75°C disappeared, and a peak derived from the crystal composed of ibuprofen and tranexamic acid appeared around 180°C, confirming that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained.

[0129] The obtained crystals and lactose were weighed in a total of 1 g in the mass ratio shown in Table 1, and uniformly mixed in a bottle to prepare the sample for Comparative Example 1.

[0130] (Comparative Examples 2-3 and Examples 1-4) The crystals obtained in Comparative Example 1, lactose, and the components listed in Table 1 were weighed in a total of 1 g in the mass ratios listed in Table 1, and uniformly mixed in a bottle to obtain the samples for Comparative Examples 2-3 and Examples 1-4, respectively.

[0131] The mixing ratios (mass ratios) of each sample are shown in the table below. In the table below, "IB" means ibuprofen, and "IB-TXA" means the crystal consisting of ibuprofen and tranexamic acid obtained in Comparative Example 1. Furthermore, "IB content" refers to the amount of ibuprofen contained in the crystal obtained in Comparative Example 1, assuming that the molar ratio of ibuprofen to tranexamic acid is 1:1.

[0132] [Table 2]

[0133] 3. Measurement of elution properties of solid compositions For each sample prepared as described above, the dissolution rate of ibuprofen was measured according to the "Dissolution Test Method (Paddle Method)" of the 18th edition of the Japanese Pharmacopoeia, as follows. Equipment used: Toyama Sangyo NTR-6400AC elution tester Dissolution test solution: Dissolution test solution 1 (Fujifilm Wako Pure Chemical Industries, Ltd., pH 1.2) 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. Of the taken test solution, the first 7 mL was discarded, and the remaining 3 mL was filtered through a membrane filter (Millex-GV, material: PVDF, pore size: 0.22 μm, diameter: 33 mm) and used for the quantification of ibuprofen. The quantification of ibuprofen 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 150 mm (Manufactured by Shimadzu GLC Co., Ltd.) Mobile phase: Phosphate / Water / Acetonitrile = 2:400:600 mixture Test procedure: The ibuprofen concentration in the samples obtained from the dissolution test was measured, and the ibuprofen dissolution rate at each time point was calculated.

[0135] Figure 2 shows the ibuprofen dissolution rates for each example. From Figure 2, it can be seen that the solid composition of Comparative Example 1, which contains ibuprofen and tranexamic acid crystals, has a lower ibuprofen dissolution rate under acidic conditions compared to the solid composition of Reference Example 1, which contains ibuprofen. Furthermore, it was found that Examples 1-4, which contain water-soluble polymers, have significantly higher ibuprofen dissolution rates compared to Comparative Example 1. For statistical comparisons, one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test were used, and a p-value of less than 0.05 was considered statistically significant.

[0136] Furthermore, when measuring the elution properties described above, using 900 mL of water (37°C) instead of the first elution test solution, the elution rate of ibuprofen was measured for Reference Example 1 and Comparative Example 1. The elution rate was approximately 41% for Reference Example 1 and approximately 65% ​​for Comparative Example 1. This indicates that the decrease in ibuprofen elution in solid compositions containing ibuprofen and tranexamic acid crystals is particularly pronounced under acidic conditions.

[0137] From the above, it was shown that by incorporating a water-soluble polymer into a solid composition containing crystals of ibuprofen and tranexamic acid, the dissolution properties of ibuprofen, particularly under acidic conditions, are improved.

[0138] 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) A crystal composed of ibuprofen and tranexamic acid, (B) Water-soluble polymer and A solid composition containing the following:

2. The water-soluble polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropylcellulose. The solid composition according to claim 1.

3. The water-soluble polymer has a viscosity of 0.1 to 4000 mPa·s when it is prepared as a 2.0% by mass aqueous solution at 20°C. The solid composition according to claim 1.

4. The solid composition according to claim 1, wherein the mass ratio of (A) to (B) is 1:0.01 to 1:1 ((A):(B)).

5. The solid composition according to claim 1, wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:

1.

6. A granulated product comprising the above (A) and the above (B), The solid composition according to any one of claims 1 to 5.

7. It is a tablet, The solid composition comprises the solid composition according to any one of claims 1 to 5, A coating film containing (B) is provided on the surface of the tablet. tablet.

8. (A) An agent for improving the dissolution properties of a solid composition containing crystals of ibuprofen and tranexamic acid, (B) Containing a water-soluble polymer, Dissolution improving agent.

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