solid components

Abstract

To provide a solid composition containing at least one selected from the group consisting of tipepidine and salts thereof and at least one selected from the group consisting of tranexamic acid and salts thereof, which has improved dissolution properties of tipepidine. The present invention relates to a composition comprising the following components: (A) at least one selected from the group consisting of tipepidine and salts thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of ibuprofen and salts thereof A solid composition comprising, but excluding a solid composition comprising levocetirizine or loratadine.

Description

[Technical Field]

[0001] The present invention broadly relates to a solid composition comprising at least one selected from the group consisting of tipepidine and salts thereof, at least one selected from the group consisting of tranexamic acid and salts thereof, and at least one selected from the group consisting of ibuprofen and salts thereof. [Background technology]

[0002] Tipepidine is known to have antitussive effects by suppressing the cough center, as well as expectorant effects, etc. Based on these effects, tipepidine is used in cold medicines and antitussive expectorants.

[0003] For example, Patent Document 1 discloses a solid preparation containing (a) ibuprofen, (b) an amino group-containing compound or a salt thereof, (c) a release-controlling agent, and (d) an organic acid or an acidic amino acid. Patent Document 1 also lists tipepidine hibenzate as a salt of (b) the amino group-containing compound.

[0004] Patent Document 2 discloses a pharmaceutical composition containing loxoprofen or a salt thereof, tipepidine or a salt thereof, and L-carbocysteine.

[0005] Patent Document 3 discloses a solid preparation containing (a) loxoprofen or a salt thereof, (b) tipepidine or a salt thereof, and (c) crospovidone and / or carmellose calcium.

[0006] Patent Document 4 discloses a pharmaceutical composition containing ibuprofen, levocetirizine, and at least one selected from the group consisting of carbocysteine, ambroxol, tranexamic acid, glycyrrhizinic acid, tipepidine, dextromethorphan, bromhexine, dimemorfan, and methylephedrine.

[0007] Patent Document 5 discloses a solid composition containing ibuprofen, loratadine, and at least one selected from the group consisting of carbocysteine, ambroxol, bromhexine, tranexamic acid, glycyrrhizinic acid, tipepidine, and dextromethorphan.

[0008] Tranexamic acid has an antiplasmin effect and is therefore used to treat cold symptoms such as sore throat. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Application Publication No. 2018-039792 [Patent Document 2] Japanese Patent Application Laid-Open No. 2014-111565 [Patent Document 3] Japanese Patent Application Laid-Open No. 2015-187095 [Patent Document 4] Japanese Patent Publication No. 2022-008041 [Patent Document 5] Japanese Patent Publication No. 2020-158487 Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have found that a solid composition containing at least one selected from the group consisting of tipepidine and its salts and at least one selected from the group consisting of tranexamic acid and its salts may have insufficient dissolution properties of tipepidine. An object of the present invention is to provide a solid composition containing at least one selected from the group consisting of tipepidine and its salts and at least one selected from the group consisting of tranexamic acid and its salts, which has improved dissolution properties of tipepidine. [Means for solving the problem]

[0011] The present inventors have found that the dissolution of tipepidine is improved when at least one selected from the group consisting of ibuprofen and its salts is added to a solid composition containing at least one selected from the group consisting of tipepidine and its salts and at least one selected from the group consisting of tranexamic acid and its salts, and have completed the present invention.

[0012] That is, this embodiment includes the following aspects. [1] Ingredients: (A) at least one selected from the group consisting of tipepidine and salts thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of ibuprofen and salts thereof A solid composition comprising, but excluding a solid composition comprising levocetirizine or loratadine. [2] The solid composition according to [1], wherein the mass ratio of the total amount of component (A) to the total amount of component (B) is 1:3 to 1:25 ((A):(B)). [3] The solid composition according to [1] or [2], comprising a crystal consisting of ibuprofen and tranexamic acid. [4] The solid composition according to [3], wherein the molar ratio of ibuprofen to tranexamic acid in the crystals is 1:1. [5] The solid composition according to [1] or [2], wherein (C) at least one selected from the group consisting of ibuprofen and salts thereof is contained in a state in which it does not form a crystal together with (B) at least one selected from the group consisting of tranexamic acid and salts thereof. [6] The solid composition according to any one of [1] to [5], wherein the dissolution rate of tipepidine 15 minutes after the start of the test, measured in accordance with the method described in the dissolution test method of the Japanese Pharmacopoeia, 18th Edition, is 30% or more. [7] An agent for improving the dissolution of tipepidine in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and salts thereof, and (II) at least one selected from the group consisting of tranexamic acid and salts thereof, and including at least one selected from the group consisting of ibuprofen and salts thereof. [Effects of the Invention]

[0013] According to the present invention, a solid composition can be provided which contains at least one selected from the group consisting of tipepidine and salts thereof, and at least one selected from the group consisting of tranexamic acid and salts thereof, and which has improved dissolution properties of tipepidine. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows the results of differential scanning calorimetry (DSC) of the crystals composed of ibuprofen and tranexamic acid obtained in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, an embodiment of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not to be construed as being limited to the following embodiment. In the present embodiment, the composition may contain each component either alone or in combination of two or more. In this specification, the symbol "to" indicating a numerical range means "at least" or "at most", and includes both of the numerical values ​​at both ends.

[0016] (solid composition) In a first embodiment, the following ingredients: (A) at least one selected from the group consisting of tipepidine and salts thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of ibuprofen and salts thereof A solid composition containing (excluding solid compositions containing levocetirizine or loratadine). is provided. The solid composition is in particular a solid pharmaceutical composition.

[0017] Each component contained in the solid composition according to this embodiment may be contained in the form of a pharmacologically acceptable salt, or may be contained as a complex with another component. That is, the solid composition according to this embodiment may contain salts of not only components (A) to (C) but also other components. "Pharmacologically acceptable salts" include, 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 acids, 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 hydrated salt or an anhydrous salt.

[0018] In this embodiment, in addition to at least one selected from the group consisting of tipepidine and its salts, and at least one selected from the group consisting of tranexamic acid and its salts, the solid composition contains the above-mentioned component (C), thereby improving the dissolution of tipepidine in the solid composition.

[0019] As used herein, "improved dissolution of tipepidine" means that the dissolution rate of tipepidine is improved compared to a solid composition that does not contain at least one selected from the group consisting of ibuprofen and its salts, but contains at least one selected from the group consisting of tipepidine and its salts and at least one selected from the group consisting of tranexamic acid and its salts; or a solid composition that contains the same components as the solid composition being evaluated for dissolution, except that it does not contain at least one selected from the group consisting of ibuprofen and its salts, or contains the same amount of a control component instead of at least one selected from the group consisting of ibuprofen and its salts. The dissolution rate of tipepidine may be measured after a predetermined time has elapsed since the start of the dissolution test, and may be, for example, the dissolution rate of tipepidine 15 minutes or 30 minutes after the start of the test. The control component is not particularly limited, and may be, for example, crystalline cellulose.

[0020] In this embodiment, the dissolution property of tipepidine may be measured, for example, by the method described in the "Dissolution Test" of the Japanese Pharmacopoeia, 18th Edition. Specifically, it can be evaluated according to the paddle method, rotating basket method, flow-through cell method, etc. described in the "Dissolution Test" of the Japanese Pharmacopoeia, 18th Edition. In the dissolution test, the amount of tipepidine dissolved in a predetermined test solution is quantified. More specifically, the dissolution rate may be measured using the method for measuring the dissolution rate of tipepidine described in the Examples.

[0021] In the solid composition according to this embodiment, the dissolution rate of tipepidine 15 minutes after the start of the dissolution test is preferably 30% or more, more preferably 35% or more, even more preferably 37% or more, and even more preferably 40% or more. The upper limit of the dissolution rate is not particularly limited, and may be, for example, 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, 55% or less, or 50% or less.

[0022] In the solid composition according to this embodiment, the dissolution rate of tipepidine 30 minutes after the start of the dissolution test is preferably 45% or more, more preferably 50% or more, even more preferably 53% or more, and even more preferably 55% or more. The upper limit of the dissolution rate is not particularly limited, and the dissolution rate may be, for example, 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, or 60% or less.

[0023] The solid composition of this embodiment excludes "a solid composition containing levocetirizine or loratadine."

[0024] Here, "levocetirizine" means a compound having the chemical formula C 21 H 25 Levocetirizine is a compound represented by the formula ClN2O3. Levocetirizine is obtained by optical resolution of only the R-enantiomer, which has stronger physiological activity among the optical isomers of cetirizine, and its CAS registry number is 130018-77-8. Furthermore, the solid composition of this embodiment also excludes solid compositions containing salts of levocetirizine. The salt of levocetirizine is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred.

[0025] Here, "loratadine" means a compound having the chemical formula C 22 H 23 The compound is represented by ClN2O2 and has the CAS registration number 79794-75-5.

[0026] The solid composition of this embodiment excludes the solid compositions disclosed in Japanese Patent Application Laid-Open No. 2022-008041 and Japanese Patent Application Laid-Open No. 2020-158487. The solid composition disclosed in Japanese Patent Application Laid-Open No. 2022-008041 is a pharmaceutical composition containing ibuprofen and levocetirizine or a salt thereof, in which the decrease in the content of levocetirizine or a salt thereof over time is suppressed, and the solid composition disclosed in Japanese Patent Application Laid-Open No. 2020-158487 is a solid composition containing ibuprofen and loratadine, in which the decrease in the content of loratadine over time is suppressed. However, the solid composition of this embodiment is a solid composition containing at least one selected from the group consisting of ibuprofen and its salts, in which changes in properties that may occur when at least one selected from the group consisting of tipepidine and its salts is combined with at least one selected from the group consisting of ibuprofen and its salts are suppressed.

[0027] (A) at least one selected from the group consisting of tipepidine and salts thereof As used herein, "tipepidine" refers to the compound having the CAS Registry Number 5169-78-8 and C 15 H 17 It is a compound represented by the chemical formula NS2 (molecular weight: 275.43 g / mol). Tipepidine is used as an active ingredient in antitussives and expectorants, etc. Tipepidine salts are not particularly limited as long as they are pharmacologically acceptable, and examples include tipepidine hibenzate and tipepidine citrate. Note that the amount and content of at least one selected from the group consisting of tipepidine and its salts described below refer to the amount and content of each of tipepidine and tipepidine salt, but it is preferable that the total amount and content of tipepidine and tipepidine salt fall within the ranges of the amount and content described below.

[0028] The amount of component (A) at least one selected from the group consisting of tipepidine and salts thereof is adjusted appropriately depending on the intended use of the at least one selected from the group consisting of tipepidine and salts thereof in the solid composition, and the symptoms, age, weight, sex, etc. of the subject to be administered. For example, the daily amount of tipepidine administered to an adult can be adjusted within the range of, for example, 8 mg to 120 mg, more preferably 16 mg to 100 mg. In this embodiment, "adult" refers to both men and women aged 15 years or older. However, the solid composition according to this embodiment is not limited to that for adults, and may also be for children under 15 years of age. When administered to children, the amount can be reduced to, for example, 1 / 2 or 2 / 3 of the amount administered daily by adults depending on the age group. The same applies to components other than tipepidine.

[0029] The above dosage is an example, and the content of at least one selected from the group consisting of tipepidine and salts thereof per solid composition administered per day is, for example, about 0.1 to about 40% by mass, preferably about 0.3 to about 30% by mass, and more preferably about 0.5 to about 20% by mass.

[0030] In one embodiment, the content of tipepidine in the composition to be administered daily is 0.1 to 40% by mass, preferably 0.3 to 30% by mass, and more preferably 0.5 to 20% by mass.

[0031] The weight and dosage of the solid composition described above are the daily dosage (daily dose), but the same amount may be administered to a subject in a single dose or multiple times a day, for example, two or three times, preferably three times. The same applies to ingredients other than tipepidine. Furthermore, since each dosage is a total amount, the content of each ingredient contained in the solid composition may vary depending on the single dose, the dosage form of the solid composition, etc.

[0032] In a specific embodiment, the solid composition is a tablet, and the dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient contained in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3, and the single dose is 2, 3, or 4 tablets, preferably 3 tablets.

[0033] (B) at least one selected from the group consisting of tranexamic acid and salts thereof As used herein, "tranexamic acid" refers to the compound having the CAS Registry Number 1197-18-8 and C8H 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 the like. There are no particular limitations on the salt of tranexamic acid, as long as it is pharmacologically acceptable. Note that the amount and content of at least one selected from the group consisting of tranexamic acid and its salts described below refer to the amount and content of tranexamic acid and the salt of tranexamic acid, respectively, but it is preferable that the total amount and content of tranexamic acid and the salt of tranexamic acid fall within the ranges of the amount and content described below.

[0034] The amount of at least one selected from the group consisting of tranexamic acid and its salts is adjusted appropriately depending on the intended use of the at least one selected from the group consisting of tranexamic acid and its salts in the composition. When at least one selected from the group consisting of tranexamic acid and its salts is added for the purpose of antiplasmin activity, hemostatic activity, or antiallergic / anti-inflammatory activity, the amount of at least one selected from the group consisting of tranexamic acid and its salts varies depending on the amount of at least one selected from the group consisting of tipepidine and its salts, but the amount per day is, for example, in the range of 10 mg to 3000 mg, preferably 100 mg to 2000 mg, and more preferably 200 mg to 1000 mg.

[0035] The content of tranexamic acid and salts thereof 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.

[0036] The amount of at least one component selected from the group consisting of tranexamic acid and its salts may vary depending on the amount of at least one component selected from the group consisting of tipepidine and its salts. For example, the mass ratio ((A):(B)) of the total amount of component (A) to the total amount of component (B) in the solid composition according to this embodiment is preferably 1:3 to 1:25, more preferably 1:3.5 to 1:23, and even more preferably 1:4 to 1:20, in the solid composition administered daily. By including at least one component selected from the group consisting of tranexamic acid and its salts in the above range relative to at least one component selected from the group consisting of tipepidine and its salts, the dissolution of tipepidine in the solid composition tends to be further improved.

[0037] For example, the mass ratio ((A):(B)) of components (A) to (B) in the solid composition according to this embodiment is preferably 1:3 to 1:25, more preferably 1:4 to 1:23, and even more preferably 1:5 to 1:20, calculated as tranexamic acid and tipepidine in a solid composition administered daily. By including at least one selected from the group consisting of tranexamic acid and salts thereof in the above range relative to tipepidine, the dissolution properties of tipepidine in the solid composition tend to be further improved.

[0038] For example, the mass ratio ((A):(B)) of components (A) to (B) in the solid composition according to this embodiment, calculated as tranexamic acid and tipepidine hibenzate in a solid composition administered daily, is preferably 1:3 to 1:25, more preferably 1:3.5 to 1:20, and even more preferably 1:4 to 1:15. By including at least one selected from the group consisting of tranexamic acid and salts thereof in the above range relative to tipepidine hibenzate, the dissolution of tipepidine in the solid composition tends to be further improved.

[0039] In one embodiment, in the solid composition, tranexamic acid may form a crystal with ibuprofen. The amount of at least one selected from the group consisting of tranexamic acid and a salt thereof described herein may refer to the total amount of tranexamic acid crystallized with ibuprofen and at least one selected from the group consisting of tranexamic acid and a salt thereof that is not crystallized.

[0040] In one embodiment, the solid composition comprises ibuprofen and at least one member selected from the group consisting of crystallized tranexamic acid and non-crystallized tranexamic acid and salts thereof.

[0041] In one embodiment, the content of at least one selected from the group consisting of ibuprofen and non-crystallized tranexamic acid and salts thereof in the solid composition may be, for example, 0 to 100% by mass, 10 to 99% by mass, 20 to 95% by mass, or 30 to 90% by mass, relative to the total amount of tranexamic acid and salts thereof. The content of at least one selected from the group consisting of ibuprofen and non-crystallized tranexamic acid and salts thereof in the solid composition may be within the above-mentioned ranges, for example, 8% by mass or less, 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.1% by mass or less, relative to the total amount of tranexamic acid and salts thereof. The content of at least one selected from the group consisting of ibuprofen and non-crystallized tranexamic acid and salts thereof in the solid composition may be, for example, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, or 80% by mass or more, relative to the total amount of tranexamic acid and salts thereof.

[0042] (C) at least one selected from the group consisting of ibuprofen and salts thereof As used herein, "ibuprofen" refers to ibuprofen having CAS Registry Number 15687-27-1 and C 13 H 18Ibuprofen 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, antipyretic, etc. The salt of ibuprofen is not particularly limited as long as it is pharmacologically acceptable. The amount and content of at least one selected from the group consisting of ibuprofen and its salts refers to the amount and content of ibuprofen and the ibuprofen salt, respectively, but it is preferable that the total amount and content of ibuprofen and the ibuprofen salt fall within the ranges of the amount and content described below.

[0043] The amount of at least one selected from the group consisting of ibuprofen and salts thereof is adjusted appropriately depending on the use of the at least one selected from the group consisting of ibuprofen and salts thereof in the solid composition, the required degree of dissolution of tipepidine, and the symptoms, age, weight, sex, etc. of the subject to be administered. For example, the daily amount of at least one selected from the group consisting of ibuprofen and salts thereof administered to an adult can be adjusted within the range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg.

[0044] The amount of at least one component selected from the group consisting of ibuprofen and salts thereof may vary depending on the amount of at least one component selected from the group consisting of tipepidine and salts thereof. For example, the mass ratio ((A):(C)) of the total amount of component (A) to the total amount of component (C) in the solid composition according to this embodiment is preferably 1:2 to 1:30, more preferably 1:3 to 1:25, and even more preferably 1:4 to 1:20, in the solid composition administered daily. By including at least one component selected from the group consisting of ibuprofen and salts thereof in the above range relative to at least one component selected from the group consisting of tipepidine and salts thereof, the dissolution of tipepidine in the solid composition tends to be further improved.

[0045] For example, the mass ratio of components (A) to (C) ((A):(C)) in the solid composition according to this embodiment is preferably 1:2 to 1:30, more preferably 1:4 to 1:25, and even more preferably 1:6 to 1:20, calculated as ibuprofen and tipepidine in a solid composition administered daily. By including at least one selected from the group consisting of ibuprofen and salts thereof relative to at least one selected from the group consisting of tipepidine and salts thereof in the above ranges, the dissolution of tipepidine in the solid composition tends to be further improved.

[0046] For example, the mass ratio of components (A) to (C) ((A):(C)) in the solid composition according to this embodiment is preferably 1:2 to 1:30, more preferably 1:3 to 1:20, and even more preferably 1:4 to 1:10, calculated as ibuprofen and tipepidine hibenzate in a solid composition administered daily. By including at least one selected from the group consisting of ibuprofen and salts thereof relative to at least one selected from the group consisting of tipepidine and salts thereof in the above range, the dissolution of tipepidine in the solid composition tends to be further improved.

[0047] The above dosage is an example, and the content of at least one selected from the group consisting of ibuprofen and salts thereof per solid composition administered per day is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass, and more preferably about 10% by mass to about 30% by mass.

[0048] In one embodiment, the content of at least one selected from the group consisting of ibuprofen and salts thereof in the composition to be administered daily is 1% by mass to 70% by mass, preferably 5% by mass to 50% by mass, and more preferably 10% by mass to 30% by mass.

[0049] Any description in this specification of the amount of at least one selected from the group consisting of ibuprofen and a salt thereof may refer to the total amount of tranexamic acid, crystallized ibuprofen, and non-crystallized ibuprofen and a salt thereof.

[0050] In one embodiment, the solid composition comprises at least one selected from the group consisting of tranexamic acid and crystallized ibuprofen, and tranexamic acid and non-crystallized ibuprofen and salts thereof.

[0051] In one embodiment, the content of at least one selected from the group consisting of tranexamic acid, non-crystallized ibuprofen, and salts thereof in the solid composition may be, for example, 0 to 100% by mass, 10 to 99% by mass, 20 to 95% by mass, or 30 to 90% by mass, relative to the total amount of ibuprofen and salts thereof. The content of at least one selected from the group consisting of tranexamic acid, non-crystallized ibuprofen, and salts thereof in the solid composition may be within the above-mentioned ranges, for example, 8% by mass or less, 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.1% by mass or less, relative to the total amount of ibuprofen and salts thereof. The content of at least one selected from the group consisting of tranexamic acid, non-crystallized ibuprofen, and salts thereof in the solid composition may be, for example, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, or 80% by mass or more, relative to the total amount of ibuprofen and salts thereof.

[0052] When ibuprofen and tranexamic acid are present as crystals in the composition, the ibuprofen and tranexamic acid may be present in the crystals at a molar ratio of 1:1. In addition, the ibuprofen and tranexamic acid may form a crystal unit cell of four molecules each.

[0053] 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.

[0054] The crystals may have an endothermic peak around 180° C. in differential scanning calorimetry (DSC). Around 180° C. may be, for example, in the range of 180° C.±20° C. or 180° C.±10° C. In DSC of the crystals, the heat of fusion peak around 75° C., which is characteristic of ibuprofen, may disappear.

[0055] The crystal may have, for example, the crystal structure shown in Figure 1 of JP 2022-70674 A and the X-ray diffraction pattern shown in Figure 2 of the same publication. The crystal may have seven major peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5 °) in the X-ray diffraction pattern.

[0056] Crystals consisting of ibuprofen and tranexamic acid can be produced, for example, by the method described in JP 2022-70674 A. Two representative production methods described in the publication are described below.

[0057] A method for producing a crystal of ibuprofen and tranexamic acid, comprising: The method includes: (1) generating a flowable fluid of ibuprofen by adding a solvent or by heating; (2) mixing the resulting flowable fluid of ibuprofen with tranexamic acid; and (3) generating crystals from the resulting mixture.

[0058] A method for producing a crystal of ibuprofen and tranexamic acid, comprising: A method comprising: (1) obtaining a free-flowing fluid of tranexamic acid; (2) mixing the obtained free-flowing fluid of tranexamic acid with ibuprofen, or a free-flowing fluid of ibuprofen obtained by adding a solvent or by heating; and (3) forming crystals from the obtained mixture.

[0059] (Other ingredients) The solid composition according to this embodiment may contain ingredients other than those described above depending on its intended use. When the solid composition is used for the purpose of relieving cold symptoms, such as runny nose, stuffy nose, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, the solid composition may contain active ingredients such as antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, or other pharmacologically acceptable ingredients.

[0060] Nonsteroidal anti-inflammatory drugs are broadly classified into non-selective COX-2 inhibitors such as diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and selective COX-2 inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be incorporated into the composition as a nonsteroidal anti-inflammatory drug. The nonsteroidal anti-inflammatory drug is preferably a non-selective COX-2 inhibitor. The nonsteroidal anti-inflammatory drug may be in the form of a salt.

[0061] Other pharmacologically acceptable ingredients may be added, such as antihistamines, antipyretics, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmin agents, which are typically added to general cold medicines, antipyretics, and rhinitis medicines.

[0062] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, and the like.

[0063] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, etc. Acetaminophen may be incorporated into the composition as an antipyretic analgesic.

[0064] Antitussive and expectorant drugs include noscapine, noscapine hydrochloride hydrate, dextromethorphan hydrobromide hydrate, bromhexine hydrochloride, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0065] Anti-inflammatory drugs include glycyrrhizinic acid and its derivatives, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0066] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0067] Vitamin preparations include vitamin B1 and its derivatives and salts thereof (e.g., benfotiamine), vitamin B2 and its derivatives and salts thereof (e.g., riboflavin), vitamin C and its derivatives and salts thereof (e.g., ascorbic acid), hesperidin and its derivatives and salts thereof, etc.

[0068] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia extract, Scopolia root, and Scopolia root total alkaloid citrate.

[0069] If necessary, formulation additives may be added to the solid composition according to this embodiment. Examples of formulation additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, flavorings, aromas, coloring agents, bases, coating agents, sugar-coating agents, plasticizers, dispersants, antifoaming agents, fluidizing agents, and flavorings and fragrances. Formulation additives that can be used in conventionally known solid formulations may be used for the above purposes.

[0070] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, corn starch granules, trehalose, lactose hydrate, lactose granules, white sugar, 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 aluminum metasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0071] Examples of binders include gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0072] Examples of disintegrants include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0073] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

[0074] Examples of glossing agents include carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0075] Examples of foaming agents include dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, and anhydrous citric acid.

[0076] Examples of moisture-proofing agents include ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid esters, stearic acid, magnesium stearate, refined shellac, refined white sugar, 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.

[0077] 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.

[0078] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and salts. Ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, chondroitin Sodium sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified 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, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate Tearyl 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 Fatty Glyceryl (7E.O.)), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0079] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. In the case of a solid composition containing acetaminophen, it is preferable not to add tocopherols as antioxidants or stabilizers.

[0080] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, and calcium hydrogen phosphate.

[0081] Examples of sweeteners include aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucralose, maltitol, D-mannitol, and erythritol.

[0082] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron bark extract, Coptis chinensis, Coptis chinensis 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, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-tartar Examples of ingredients include sodium menthol, ginger powder, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, Ryuno, Ryuno powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0083] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0084] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0085] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0086] Examples of colorants 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 oxide, ferric oxide, diaz azo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide-glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0087] Bases include: gum arabic powder, pregelatinized starch, ethyl cellulose, 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, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, Hydroxypropyl cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0088] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, aqueous ethyl cellulose dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hypromellose. Hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0089] Examples of sugar-coating agents include gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, refined sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0090] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0091] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0092] Antifoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane-silicon dioxide mixtures, sucrose fatty acid esters, silicone antifoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0093] Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0094] Examples of flavoring agents and fragrances include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, vitabase, Himalayan cedar oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0095] These components may be contained alone or in combination of two or more.

[0096] (Dosage form) The solid composition of this embodiment can be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as preparations for oral administration (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, powders, etc.), preparations for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition of this embodiment is preferably an oral solid composition.

[0097] The dosage form of the solid composition of this embodiment may be, for example, a tablet, a capsule, a pill, a granule, or a fine granule. These solid compositions may be coated with sugar coating, film coating, or the like by a known method, as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0098] The solid composition of this embodiment may be temporarily packaged in a bottle, PTP, pouch, stick, or SP package and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and examples include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. If moisture absorption is a concern, a desiccant or the like may be stored simultaneously in the bottle packaging or pillow packaging.

[0099] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition of this embodiment may be contained in, for example, an airtight package. By forming the solid composition into a package, for example, convenience during use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0100] As for the packaging form of the solid preparation, the solid composition may be temporarily packaged and stored airtight in a bottle, PTP (Press-Through Package), pouch, stick, or SP (Strip Package) or the like. These may also be pillow-packaged, or may be stored in a box or the like. Furthermore, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant or the like may be stored in the packaging container, such as the bottle or pillow package, at the same time.

[0101] Materials used for SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0102] Furthermore, it is preferable that the material constituting the packaging container contains a material that is resistant to the effects of moisture. Examples of such packaging include packaging made of at least one of a moisture-proof material and a gas barrier material.

[0103] An example of a moisture-proof material is a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. When the solid composition is a tablet, PTP packaging (Al-Al packaging) with aluminum on both sides may be used as the moisture-proof material, taking into consideration the prevention of an increase in the moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0104] Any known gas barrier material may be used, for example, a laminate film having a functional barrier layer, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material.

[0105] Furthermore, the packaging container may be environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material.

[0106] (Manufacturing method) In a second aspect, there is provided a method for producing a solid composition, comprising the steps of contacting (A) at least one selected from the group consisting of tipepidine and salts thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of ibuprofen and salts thereof.

[0107] The solid composition can be produced using known techniques. Each component is added at any step and finally contacted with each other. A solvent or binder may be added to the contacted mixture and kneaded, and the resulting kneaded product may be used as a solid composition. Crystals consisting of ibuprofen and tranexamic acid can be produced by the method described in JP 2022-70674 A (cited above). After forming a crystal consisting of ibuprofen and tranexamic acid, the crystal may be contacted or kneaded with (A) at least one selected from the group consisting of tipepidine and salts thereof. Alternatively, the components may be contacted sequentially or simultaneously, as appropriate.

[0108] The resulting kneaded mixture can be further subjected to a drying process and a granulation process to produce granules (granulated material). In this case, granules (granulated material) containing each component may be prepared separately. Granulation may be performed by either a wet method or a dry method.

[0109] The obtained granules (granulated product) can be used as they are or can be mixed with additives and compressed into tablets to produce plain tablets, which can then be further film-coated.

[0110] (Dissolution improver) In a third aspect, there is provided an agent for improving the dissolution of tipepidine in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and salts thereof, and (II) at least one selected from the group consisting of tranexamic acid and salts thereof, which comprises at least one selected from the group consisting of ibuprofen and salts thereof.

[0111] The at least one member selected from the group consisting of ibuprofen and salts thereof is as described in component (C) of the solid composition of this embodiment, and the above components (I) and (II) are as described in components (A) and (B) of the solid composition of this embodiment.

[0112] The dissolution improver is preferably used in an amount such that the amount of ibuprofen relative to component (I) or (II) falls within the range described as the preferred content of component (C) in the solid composition of this embodiment. In addition, ibuprofen may be added to the solid composition without crystallizing with tranexamic acid (in an uncrystallized state).

[0113] In order to explain the present invention in more detail, examples are described below, but the present invention is not limited to these examples. [Example]

[0114] 1.Raw materials In this example, the following raw materials were used: [Table 1]

[0115] 2. Preparation of Solid Composition (Reference example 1) Tipepidine hibenzate and crystalline cellulose were weighed out in the amounts shown in Table 1, sieved through a 30 mesh, and then mixed 100 times in a 4K standard bottle to obtain a mixture.

[0116] (Reference Example 2, Comparative Example 1, Example 1) A mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used in the weighed amounts shown in Table 1.

[0117] Example 2 Using a Mixer Torque Rheometer 3 (manufactured by Caleva), 11.1 g of ibuprofen and 13.9 g of tranexamic acid were mixed in a stirring vessel, and then 3.0 ml of 90% ethanol was added and kneaded for 10 minutes. The resulting wet granules were dried at 60°C for 1 hour to obtain crystalline granules consisting of ibuprofen and tranexamic acid. A mixture was obtained in the same manner as in Reference Example 1, except that the granules obtained in the weighed amounts shown in Table 1 were used.

[0118] Six mg of the resulting granules were placed in an aluminum pan and measured at a rate of 10°C per minute over the temperature range of 25 to 250°C using a differential scanning calorimeter DSC3+ (Mettler-Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak at around 75°C attributed to ibuprofen disappears, and a peak at around 180°C attributed to crystals of ibuprofen and tranexamic acid appears, confirming that the produced granules contain crystals in which the molar ratio of ibuprofen to tranexamic acid is 1:1.

[0119] The amount (g) of each sample is shown in the table below: In the table below, the granules produced in Example 2 contain crystals consisting of ibuprofen and tranexamic acid. [Table 2]

[0120] 3. Measurement of dissolution of solid compositions The dissolution properties of tipepidine in the prepared samples were evaluated as follows. Specifically, the test was performed using a dissolution tester (NTR-6400AC, Toyama Sangyo Co., Ltd.) in accordance with the "Dissolution Test Method (Paddle Method)" described in the 18th Edition of the Japanese Pharmacopoeia. Each mixture of prepared samples was weighed out in the amount of test sample shown in Table 1. The weighed test sample was placed in a test solution of 900 mL of water and tested at 100 rpm by the paddle method. The dissolution rates of tipepidine were evaluated 15 minutes and 30 minutes after the start of the test. The results are shown in Table 3. As shown in Table 3, the dissolution properties of tipepidine were improved by adding ibuprofen to tipepidine hibenzate and tranexamic acid.

[0121] The dissolution rate of tipepidine was measured by spectrophotometry using standard solutions of known concentrations. The absorbance at wavelengths of 286 nm and 360 nm was measured, and the concentration was calculated by subtracting the absorbance at 360 nm from the absorbance at 286 nm to remove background signals.

[0122] [Table 3]

[0123] Examples of solid formulations are shown below.

[0124] [Table 4]

[0125] [Table 5]

[0126] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible within the scope of the present invention.

Claims

1. Ingredients: (A) at least one selected from the group consisting of tipepidine and salts thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of ibuprofen and salts thereof A solid composition comprising, but excluding a solid composition comprising levocetirizine or loratadine.

2. 2. The solid composition according to claim 1, wherein the mass ratio of the total amount of component (A) to the total amount of component (B) is 1:3 to 1:25 ((A):(B)).

3. The solid composition according to claim 1 or 2, comprising a crystal consisting of ibuprofen and tranexamic acid.

4. 4. The solid composition of claim 3, wherein the molar ratio of ibuprofen to tranexamic acid in the crystals is 1:

1.

5. 3. The solid composition according to claim 1, wherein (C) at least one selected from the group consisting of ibuprofen and salts thereof is contained in a state in which it does not form a crystal together with (B) at least one selected from the group consisting of tranexamic acid and salts thereof.

6. 3. The solid composition according to claim 1, wherein the dissolution rate of tipepidine 15 minutes after the start of the test, measured in accordance with the dissolution test method described in the 18th edition of the Japanese Pharmacopoeia, is 30% or more.

7. An agent for improving the dissolution of tipepidine in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and salts thereof, and (II) at least one selected from the group consisting of tranexamic acid and salts thereof, and including at least one selected from the group consisting of ibuprofen and salts thereof.

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