Solid composition

Abstract

The present invention relates to solid compositions. The present invention addresses the problem of providing a solid composition containing at least one substance selected from the group consisting of tepiperidine and salts thereof, and at least one substance selected from the group consisting of tranexamic acid and salts thereof, in which the dissolution of tepiperidine is improved. [Solution] A solid composition containing the following components: (A) at least one substance selected from the group consisting of tepiperidine and salts thereof; (B) at least one substance selected from the group consisting of tranexamic acid and salts thereof; and (C) at least one compound selected from the group consisting of ibuprofen and salts thereof, in which the solid composition does not include a solid composition comprising levocetirizine or loratadine.

Description

TECHNICAL FIELD

[0001] The present application 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

[0002] Tipepidine is known to exhibit an antitussive effect due to inhibition of a cough center, and to exhibit an expectorant effect, etc. Tipepidine is used for cold medicines, antitussive expectorants, based on these effects.

[0003] For example, Patent Literature 1 discloses a solid preparation containing (a) ibuprofen, (b) an amino group-containing compound or a salt thereof, (c) a controlled-release base, and (d) an organic acid or an acidic amino acid. In Patent Literature 1, tipepidine hemibenzoate is cited as the salt of the amino group-containing compound of (b).

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

[0005] Patent Literature 3 discloses a solid preparation containing (a) loxoprofen or a salt thereof, (b) tipepidine or a salt thereof, and (c) cross-linked povidone and / or carboxymethylcellulose calcium.

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

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

[0008] Tranexamic acid has an antifibrinolytic effect, and is therefore used for cold symptoms such as sore throat.

[0009] PRIOR ART DOCUMENTS

[0010] PATENT LITERATURE

[0011] Patent Literature 1: Japanese Patent Application Laid-Open (kokai) No. 2018-039792

[0012] Patent Literature 2: Japanese Patent Application Laid-Open (kokai) No. 2014-111565

[0013] Patent Literature 3: Japanese Patent Application Laid-Open (kokai) No. 2015-187095

[0014] Patent Literature 4: Japanese Patent Application Laid-Open No. 2022-008041

[0015] Patent Literature 5: Japanese Patent Application Laid-Open No. 2020-158487 SUMMARY

[0016] PROBLEMS TO BE SOLVED BY THE INVENTION

[0017] The present inventors found that, in a solid-state composition containing at least one selected from the group consisting of tipepidine and a salt thereof and at least one selected from the group consisting of tranexamic acid and a salt thereof, there is a case where the dissolution property of tipepidine is insufficient. An object of the present application is to provide a solid-state composition containing at least one selected from the group consisting of tipepidine and a salt thereof and at least one selected from the group consisting of tranexamic acid and a salt thereof, in which the dissolution property of tipepidine is improved.

[0018] MEANS FOR SOLVING THE PROBLEMS

[0019] The present inventors found that, in a solid-state composition containing at least one selected from the group consisting of tipepidine and a salt thereof and at least one selected from the group consisting of tranexamic acid and a salt thereof, the dissolution property of tipepidine is improved when at least one selected from the group consisting of ibuprofen and a salt thereof is combined, thereby completing the present application.

[0020] That is, the present embodiment contains the following modes.

[0021] [1] A solid-state composition (wherein a solid-state composition containing levocetirizine or montelukast is excluded) containing the following components:

[0022] (A) at least one selected from the group consisting of tipepidine and a salt thereof;

[0023] (B) at least one selected from the group consisting of tranexamic acid and a salt thereof; and

[0024] (C) at least one selected from the group consisting of ibuprofen and a salt thereof.

[0025] [2] The solid-state 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)).

[0026] [3] The solid-state composition according to [1] or [2], which contains a crystal formed from ibuprofen and tranexamic acid.

[0027] [4] The solid-state composition according to [3], wherein the molar ratio of ibuprofen to tranexamic acid in the aforementioned crystal is 1:1.

[0028] [5] The solid composition according to any one of [1] to [2], wherein (C) is at least one selected from the group consisting of ibuprofen and a salt thereof, is contained in a state not forming a crystal with (B) which is at least one selected from the group consisting of tranexamic acid and a salt thereof.

[0029] [6] The solid composition according to any one of [1] to [5], wherein the dissolution rate of tipepidine after 15 minutes from the start of the test is 30% or more as measured according to the method described in the dissolution test method of the Eighteenth Edition of the Japanese Pharmacopoeia.

[0030] [7] An agent for improving the dissolution property of tipepidine in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and a salt thereof, and (II) at least one selected from the group consisting of tranexamic acid and a salt thereof,

[0031] wherein the agent for improving the dissolution property comprises at least one selected from the group consisting of ibuprofen and a salt thereof.

[0032] Effects of the Invention

[0033] According to the present application, it is possible to provide a solid composition comprising at least one selected from the group consisting of tipepidine and a salt thereof and at least one selected from the group consisting of tranexamic acid and a salt thereof, in which the dissolution property of tipepidine is improved. BRIEF DESCRIPTION OF DRAWINGS

[0034] [ Figure 1 ] Figure 1 The results of differential scanning calorimetry (DSC) of the crystal formed from ibuprofen and tranexamic acid obtained in Example 2 are shown. DETAILED DESCRIPTION

[0035] Hereinafter, an embodiment of the present application (hereinafter, referred to as "the present embodiment") will be described, but the scope of the present application is not construed as being limited to the following embodiment. In the present embodiment, the composition can contain each component alone or contain two or more kinds of each component in combination. In the present specification, "~" indicating a numerical range indicates the above, the below, and both the numerical values are included.

[0036] (Solid composition)

[0037] In the first mode, a solid composition (wherein a solid composition containing levocetirizine or montelukast is excluded) is provided, which contains the following components:

[0038] (A) at least one selected from the group consisting of tipepidine and a salt thereof;

[0039] (B) at least one selected from the group consisting of tranexamic acid and a salt thereof; and

[0040] (C) at least one selected from the group consisting of ibuprofen and salts thereof.

[0041] The solid composition is specifically a solid pharmaceutical composition.

[0042] Each component included in the solid composition according to the present embodiment can be included in a state of a pharmacologically acceptable salt, or can be included as a complex with other components. That is, not only components (A) to (C), but also as to other components, a salt of each component can be included in the solid composition according to the present embodiment. The "pharmacologically acceptable salt" includes, for example, a salt with a base or an acid which is pharmacologically acceptable.

[0043] As non-limiting specific examples of the pharmacologically acceptable salt, an addition salt of an inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), an addition salt of an organic acid (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.), an addition salt of an inorganic base (ammonium hydroxide, or an alkali metal hydroxide or an alkaline earth metal hydroxide, carbonate, bicarbonate, etc.), and an addition salt of an amino acid, etc. can be given. The pharmacologically acceptable salt can be a hydrate salt, or an anhydrous salt.

[0044] In the present embodiment, in addition to including 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, the above component (C) is also included, and thus the dissolution property of tipepidine in the solid composition is improved.

[0045] In the present specification, the "dissolution property of tipepidine is improved" means that the dissolution rate of tipepidine is increased compared to a solid composition which does not include at least one selected from the group consisting of ibuprofen and salts thereof, but includes 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, or a solid composition which, in addition to not including at least one selected from the group consisting of ibuprofen and salts thereof, includes the same components as the solid composition which is the evaluation target of the dissolution property, or a solid composition which, in addition to including the same amount of other control components instead of at least one selected from the group consisting of ibuprofen and salts thereof, includes the same components as the solid composition which is the evaluation target of the dissolution property. The dissolution rate of tipepidine can be measured after a prescribed time has passed after the start of the dissolution test, and for example, can be the dissolution rate of tipepidine after 15 minutes or 30 minutes from the start of the test. The control component is not particularly limited, and for example, can be crystalline cellulose.

[0046] In the present embodiment, the dissolution rate of tipepidine can be measured, for example, using the method described in the "Dissolution Test Method" of the seventeenth edition of the Japanese Pharmacopoeia. Specifically, the dissolution rate can be evaluated according to the paddle method, the rotating basket method, the flow-through cell method, or the like described in the "Dissolution Test Method" of the seventeenth edition of the Japanese Pharmacopoeia. In the dissolution test, tipepidine dissolved in a prescribed test solution is quantified. More specifically, the dissolution rate can be measured using the method described in the examples.

[0047] In the solid composition according to the present embodiment, the dissolution rate of tipepidine 15 minutes after the start of the test in the dissolution test described above is preferably 30% or greater, more preferably 35% or greater, further preferably 37% or greater, and further more preferably 40% or greater. The upper limit of the dissolution rate is not particularly limited, and the dissolution rate can 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.

[0048] In the solid composition according to the present embodiment, the dissolution rate of tipepidine 30 minutes after the start of the test in the dissolution test described above is preferably 45% or greater, more preferably 50% or greater, further preferably 53% or greater, and further more preferably 55% or greater. The upper limit of the dissolution rate is not particularly limited, and the dissolution rate can 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.

[0049] Note that the "solid composition containing levocetirizine or montelukast" is not included in the solid composition according to the present embodiment.

[0050] Here, "levocetirizine" refers to a compound represented by the chemical formula C 21 H 25 ClN2O3. Levocetirizine is a substance obtained by optically resolving only the R-enantiomer, which is an optically active isomer of cetirizine, and has a CAS registration number of 130018-77-8. In addition, the solid composition containing a salt of levocetirizine is not included in the solid composition according to the present embodiment. As the salt of levocetirizine, there is no particular limitation as long as it is a pharmacologically acceptable salt, and examples include a salt of an inorganic acid such as hydrochloride, hydrobromide, and phosphate, and a salt of an organic acid such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, and particularly, hydrochloride.

[0051] Here, "montelukast" refers to a compound represented by the chemical formula C 22 H 23A compound represented by ClN2O2, CAS No. 79794-75-5.

[0052] In addition, in the solid composition of the present embodiment, each of the solid compositions disclosed in Japanese Patent Application Publication No. 2022-008041 and Japanese Patent Application Publication No. 2020-158487 is excluded. The solid composition disclosed in Japanese Patent Application Publication No. 2022-008041 is a pharmaceutical composition in which the content of the levocetirizine or a salt thereof is inhibited from decreasing over time even if the solid composition contains ibuprofen and the levocetirizine or a salt thereof, and the solid composition disclosed in Japanese Patent Application Publication No. 2020-158487 is a solid composition in which the content of the loratadine is inhibited from decreasing over time even if the solid composition contains ibuprofen and the loratadine, but the solid composition of the present embodiment is a solid composition containing at least one selected from the group consisting of ibuprofen and a salt thereof, in which a change in properties that can occur due to the combination of at least one selected from the group consisting of tipepidine and a salt thereof with at least one selected from the group consisting of ibuprofen and a salt thereof is inhibited.

[0053] (A) at least one selected from the group consisting of tipepidine and a salt thereof

[0054] In the present specification, “tipepidine” is CAS No. 5169-78-8, and is a compound represented by the following formula (I): 15 H 17 A compound represented by the chemical formula of NS2 (molecular weight: 275.43 g / mol). Tipepidine is used as an effective ingredient for antitussive and expectorant, and the like. The salt of tipepidine is not particularly limited as long as it is pharmacologically acceptable, and tipepidine hybenzoate and tipepidine citrate can be mentioned. Note that the combination amount and content of at least one selected from the group consisting of tipepidine and a salt thereof below are the combination amount and content for each of tipepidine and the salt of tipepidine, and it is preferable to adjust the combination amount and content of the total of tipepidine and the salt of tipepidine within the range of the combination amount and content described below.

[0055] The combination amount of the ingredient (A) of at least one selected from the group consisting of tipepidine and a salt thereof can be appropriately adjusted according to the use of at least one selected from the group consisting of tipepidine and a salt thereof in the solid composition, the symptoms, age, body weight, gender, and the like of the subject to be administered. For example, the amount of tipepidine per day to be administered to an adult can be adjusted within the range of, for example, 8 mg to 120 mg, further preferably 16 mg to 100 mg. In the present embodiment, “adult” means men and women of 15 years of age or older. However, the solid composition related to the present embodiment is not limited to be used for adults, and can be used for children less than 15 years of age. In the case of children, the amount can be reduced to, for example, 1 / 2, 2 / 3, or the like of the amount to be administered to an adult per day, according to each age group. The same applies to ingredients other than tipepidine.

[0056] The above-mentioned administration amount is an example, and the content of at least one selected from the group consisting of tipepidine and salts thereof is, for example, about 0.1 to about 40 mass% with respect to the solid composition to be administered in 1 day, preferably about 0.3 to about 30 mass%, and more preferably about 0.5 to about 20 mass%.

[0057] In one embodiment, the content of tipepidine contained in the composition to be administered in 1 day is 0.1 to 40 mass%, preferably 0.3 to 30 mass%, and more preferably 0.5 to 20 mass%.

[0058] The above-mentioned weight of the solid composition and the administration amount are the administration amount per day (1-day dose), and the amount can be administered to the subject at a time, or the amount can be administered to the subject in multiple times (for example, 2 or 3 times, and preferably 3 times) in 1 day. The same applies to the components other than tipepidine. In addition, each administration amount is a total amount, and thus the content of each component contained in the solid composition can vary depending on the amount at a time, the dosage form of the solid composition, and the like.

[0059] In a particular embodiment, the solid composition is a tablet, and the above-mentioned administration amount is the amount of the components contained in 3 tablets, 6 tablets, or 9 tablets, and preferably the amount of the components in 9 tablets. In this embodiment, the amount to be taken at a time for an adult (15 years old or older) is 3 times, and the amount to be taken at a time is 2 tablets, 3 tablets, or 4 tablets, and preferably the amount to be taken at a time is 3 tablets.

[0060] (B) at least one selected from the group consisting of tranexamic acid and salts thereof

[0061] In the present specification, "tranexamic acid" is a compound represented by the chemical formula of C8H 15 NO2(CAS No. 1197-18-8) (molecular weight: 157.21 g / mol). Tranexamic acid is used as an effective ingredient of an anti-inflammatory drug or the like. The salt of tranexamic acid is not particularly limited as long as it is pharmacologically acceptable. Note that the following combined amount and content of at least one selected from the group consisting of tranexamic acid and salts thereof are the combined amount and content of tranexamic acid and the salt of tranexamic acid, respectively, and it is preferable that the combined amount and content of tranexamic acid and the salt of tranexamic acid be within the range of the combined amount and content described below.

[0062] The amount of the at least one selected from the group consisting of tranexamic acid and salts thereof to be contained can be appropriately adjusted depending on the use of the at least one selected from the group consisting of tranexamic acid and salts thereof in the composition. In the case where the at least one selected from the group consisting of tranexamic acid and salts thereof is contained for the purpose of antifibrinolytic action, hemostatic action, or antiallergic / antiinflammatory action, the amount of the at least one selected from the group consisting of tranexamic acid and salts thereof to be contained varies depending on the amount of the at least one selected from the group consisting of tipepidine and salts thereof, for example, and is in the range of 10 mg to 3000 mg, preferably 100 mg to 2000 mg, more preferably 200 mg to 1000 mg per day.

[0063] The content of tranexamic acid and salts thereof contained in the composition to be administered within one day is in the range of 1 mass% to 70 mass%, preferably 5 to 50 mass%, more preferably 10 to 30 mass%.

[0064] The amount of the at least one selected from the group consisting of tranexamic acid and salts thereof to be contained can vary depending on the amount of the at least one selected from the group consisting of tipepidine and salts thereof, for example. For example, in the solid-state composition to be administered within one day, the mass ratio of the total amount of component (A) to the total amount of component (B) ((A):(B)) in the solid-state composition according to the present embodiment is preferably 1:3 to 1:25, more preferably 1:3.5 to 1:23, further preferably 1:4 to 1:20. By containing the at least one selected from the group consisting of tranexamic acid and salts thereof in the above range with respect to the at least one selected from the group consisting of tipepidine and salts thereof, there is a tendency that the dissolution property of tipepidine in the solid-state composition can be further improved.

[0065] For example, in the solid-state composition to be administered within one day, the mass ratio of component (A) to component (B) ((A):(B)) in the solid-state composition according to the present embodiment is preferably 1:3 to 1:25, more preferably 1:4 to 1:23, further preferably 1:5 to 1:20, in terms of tranexamic acid and tipepidine. By containing the at least one selected from the group consisting of tranexamic acid and salts thereof in the above range with respect to tipepidine, there is a tendency that the dissolution property of tipepidine in the solid-state composition can be further improved.

[0066] For example, in the solid-state composition to be administered within one day, the mass ratio of component (A) to component (B) ((A):(B)) in the solid-state composition according to the present embodiment is preferably 1:3 to 1:25, more preferably 1:3.5 to 1:20, further preferably 1:4 to 1:15, in terms of tranexamic acid and tipepidine hemibenzoate. By containing the at least one selected from the group consisting of tranexamic acid and salts thereof in the above range with respect to tipepidine hemibenzoate, there is a tendency that the dissolution property of tipepidine in the solid-state composition can be further improved.

[0067] In one embodiment, in the solid-state composition, the tranexamic acid can form crystals with ibuprofen. The amount described in the present specification in relation to at least one selected from the group consisting of tranexamic acid and a salt thereof can be the total amount of the tranexamic acid crystallized with ibuprofen and the at least one selected from the group consisting of tranexamic acid and a salt thereof that is not crystallized with ibuprofen.

[0068] In one embodiment, the solid-state composition contains: 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 with ibuprofen.

[0069] In one embodiment, the content of the at least one selected from the group consisting of tranexamic acid and a salt thereof that is not crystallized with ibuprofen contained in the solid-state composition can be, for example, 0 to 100 mass%, 10 to 99 mass%, 20 to 95 mass%, or 30 to 90 mass%, relative to the total amount of tranexamic acid and a salt thereof. The content of the at least one selected from the group consisting of tranexamic acid and a salt thereof that is not crystallized with ibuprofen contained in the solid-state composition can be, for example, 8 mass% or less, 5 mass% or less, 3 mass% or less, 1 mass% or less, or 0.1 mass% or less, within the above range, relative to the total amount of tranexamic acid and a salt thereof. The content of the at least one selected from the group consisting of tranexamic acid and a salt thereof that is not crystallized with ibuprofen contained in the solid-state composition can be, for example, 40 mass% or more, 50 mass% or more, 60 mass% or more, 70 mass% or more, or 80 mass% or more, within the above range, relative to the total amount of tranexamic acid and a salt thereof.

[0070] (C) at least one selected from the group consisting of ibuprofen and a salt thereof

[0071] In the present specification, "ibuprofen" is a compound represented by the chemical formula of C 13 H 18 O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an effective ingredient of anti-inflammatory, analgesic, antipyretic agents, and the like. The salt of ibuprofen is not particularly limited as long as it is pharmacologically tolerable. Note that the compounding amount and content of at least one selected from the group consisting of ibuprofen and a salt thereof are the compounding amount and content of ibuprofen and the salt of ibuprofen respectively, and it is preferable to make the compounding amount and content of ibuprofen and the salt of ibuprofen in total within the range of the compounding amount and content described below.

[0072] The blending amount of at least one selected from the group consisting of ibuprofen and salts thereof can be appropriately adjusted depending on the use of at least one selected from the group consisting of ibuprofen and salts thereof in the solid composition, the degree of dissolution of the required tipepidine, the symptoms, age, body weight, sex, and the like of the subject to be administered. For example, the amount of at least one selected from the group consisting of ibuprofen and salts thereof administered to an adult per day can be adjusted, for example, in the range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, more preferably 200 mg to 600 mg.

[0073] The blending amount of at least one selected from the group consisting of ibuprofen and salts thereof can be varied depending on the amount of at least one selected from the group consisting of tipepidine and salts thereof, and the like. For example, in the solid composition administered within one day, the mass ratio of the total amount of component (A) to the total amount of component (C) ((A):(C)) in the solid composition according to the present embodiment is preferably 1:2 to 1:30, more preferably 1:3 to 1:25, and further preferably 1:4 to 1:20. By containing at least one selected from the group consisting of ibuprofen and salts thereof in the above range with respect to at least one selected from the group consisting of tipepidine and salts thereof, there is a tendency that the dissolution of tipepidine in the solid composition can be further improved.

[0074] For example, in the solid composition administered within one day, the mass ratio of component (A) to (C) ((A):(C)) in the solid composition according to the present embodiment is preferably 1:2 to 1:30, more preferably 1:4 to 1:25, and further preferably 1:6 to 1:20, in terms of ibuprofen and tipepidine. By containing at least one selected from the group consisting of ibuprofen and salts thereof in the above range with respect to at least one selected from the group consisting of tipepidine and salts thereof, there is a tendency that the dissolution of tipepidine in the solid composition can be further improved.

[0075] For example, in the solid composition administered within one day, the mass ratio of component (A) to (C) ((A):(C)) in the solid composition according to the present embodiment is preferably 1:2 to 1:30, more preferably 1:3 to 1:20, and further preferably 1:4 to 1:10, in terms of ibuprofen and tipepidine hemibenzoate. By containing at least one selected from the group consisting of ibuprofen and salts thereof in the above range with respect to at least one selected from the group consisting of tipepidine and salts thereof, there is a tendency that the dissolution of tipepidine in the solid composition can be further improved.

[0076] The above-mentioned administration amount is an example, and the content of at least one selected from the group consisting of ibuprofen and salts thereof is, for example, about 1 mass% to about 70 mass%, preferably about 5 mass% to about 50 mass%, and more preferably about 10 mass% to about 30 mass%, with respect to the solid composition administered within one day.

[0077] In one embodiment, the content of at least one selected from the group consisting of ibuprofen and salts thereof contained in the composition administered within a day is 1 to 70 mass%, preferably 5 to 50 mass%, more preferably 10 to 30 mass%.

[0078] The description in the present specification regarding the amount of at least one selected from the group consisting of ibuprofen and salts thereof can be a description of the total amount of ibuprofen crystallized with tranexamic acid and at least one selected from the group consisting of ibuprofen and salts thereof not crystallized with tranexamic acid.

[0079] In one embodiment, the solid composition contains: ibuprofen crystallized with tranexamic acid; and at least one selected from the group consisting of ibuprofen and salts thereof not crystallized with tranexamic acid.

[0080] In one embodiment, the content of at least one selected from the group consisting of ibuprofen and salts thereof not crystallized with tranexamic acid contained in the solid composition can be, for example, 0 to 100 mass%, 10 to 99 mass%, 20 to 95 mass%, or 30 to 90 mass%, relative to the total amount of ibuprofen and salts thereof. The content of at least one selected from the group consisting of ibuprofen and salts thereof not crystallized with tranexamic acid contained in the solid composition can be, for example, 8 mass% or less, 5 mass% or less, 3 mass% or less, 1 mass% or less, or 0.1 mass% or less, relative to the total amount of ibuprofen and salts thereof, within the above range. The content of at least one selected from the group consisting of ibuprofen and salts thereof not crystallized with tranexamic acid contained in the solid composition can be, for example, 40 mass% or more, 50 mass% or more, 60 mass% or more, 70 mass% or more, or 80 mass% or more, relative to the total amount of ibuprofen and salts thereof, within the above range.

[0081] In the case where ibuprofen and tranexamic acid exist as crystals in the composition, ibuprofen and tranexamic acid can exist in a molar ratio of 1:1 in the crystals. In addition, ibuprofen and tranexamic acid can form respective unit cells of 4 molecules in the crystals.

[0082] In the crystals, a hydrogen bond can 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.

[0083] The crystals can have an endothermic peak around 180°C in differential scanning calorimetry (DSC). By "around 180°C", for example, it can be a range of 180°C ± 20°C, or a range of 180°C ± 10°C. Note that in the DSC of the crystals, the characteristic melting heat peak of ibuprofen around 75°C can disappear.

[0084] The crystal may, for example, have the crystal structure shown in Japanese Patent Application Publication No. 2022-70674 Figure 1 The crystal structure shown in Japanese Patent Application Publication No. 2022-70674, and can have the X-ray diffraction pattern shown in FIG. 2 of the publication. The crystal can have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in the X-ray diffraction pattern.

[0085] The crystal formed from ibuprofen and tranexamic acid may, for example, be manufactured using the method described in Japanese Patent Application Publication No. 2022-70674. Two representative manufacturing methods described in the publication are described below.

[0086] A method of manufacturing a crystal formed from ibuprofen and tranexamic acid, comprising:

[0087] (1) generating ibuprofen having fluidity by adding a solvent or heating; (2) mixing the resulting ibuprofen having fluidity with tranexamic acid;

[0088] (3) generating a crystal from the resulting mixture.

[0089] A method of manufacturing a crystal formed from ibuprofen and tranexamic acid, comprising:

[0090] (1) obtaining tranexamic acid having fluidity;

[0091] (2) mixing the resulting tranexamic acid having fluidity with ibuprofen or ibuprofen having fluidity obtained by adding a solvent or heating;

[0092] (3) generating a crystal from the resulting mixture.

[0093] (Other ingredients)

[0094] The solid composition to which the present embodiment relates can contain ingredients other than the above-mentioned ingredients depending on its use. In the case where the solid composition is used with the aim of alleviating various symptoms of a cold, such as runny nose, stuffy nose, sneezing, sore throat, cough, sputum, chills, fever, headache, joint pain, muscle pain, and the like, in addition to bromhexine, meloxicam, and acetaminophen, an effective ingredient such as an antipyretic analgesic, in particular, a non-steroidal anti-inflammatory drug (NSAID) other than ibuprofen, and other pharmacologically acceptable ingredients can be added.

[0095] The non-steroidal anti-inflammatory drugs are roughly classified into: non-selective COX-2 inhibitors such as diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nalfamotum, indomethacin, sulindac, mofezolac, and mefenamic acid; and selective COX-2 inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam can be incorporated as a non-steroidal anti-inflammatory drug in the composition. The non-steroidal anti-inflammatory drug is preferably a non-selective COX-2 inhibitor. The non-steroidal anti-inflammatory drug can be in the form of a salt.

[0096] As other pharmacologically acceptable ingredients, antihistamines, analgesics, antitussives, antiinflammatories, central nervous stimulants, vitamin agents, anticholin agents, antifibrinolytic agents, and the like, which are incorporated in cold medicines, antipyretic analgesics, rhinitis medicines, and the like, can be additionally incorporated.

[0097] For example, as the antihistamines, isoxsuprine hydrochloride, Difeterol Hydrochloride, tripelennamine hydrochloride, pyrilamine maleate, fenethazine hydrochloride, methdilazine hydrochloride, chlorpheniramine maleate, d-chlorpheniramine maleate, carebastine, diphenylpyraline teoclate, benztropine hydrochloride, benztropine salicylate, alimemazine tartrate, benztropine gallate, triprolidine hydrochloride hydrate, methapyrilene napsylate, promethazine methanesulfonate, Difeterol Phosphate, clemastine fumarate, mequitazine, and the like can be mentioned.

[0098] As the analgesics other than the non-steroidal anti-inflammatory drugs, for example, aspirin, acetaminophen, benorylate, sasapyrine, salicylamide, lactylphenetamine, propyphenazone, and the like can be mentioned. Acetaminophen can be incorporated as an analgesic in the composition.

[0099] As the antitussives, noscapine, noscapine hydrochloride hydrate, dextromethorphan hydrobromide hydrate, bromhexine hydrochloride, codeine phosphate, racemic ephedrine hydrochloride, racemic ephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, and the like can be mentioned.

[0100] As the antiinflammatories, glycyrrhizinic acid and its derivatives and salts thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, and the like), and the like can be mentioned.

[0101] As the central nervous stimulants, caffeine, anhydrous caffeine, and the like can be mentioned.

[0102] As the vitamin agent, 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, and the like can be exemplified.

[0103] As the anticholinergic agent, hyoscine hydrobromide, stramonium extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, isopropyl iodoamide, diphenylpiperidylmethyl dioxolane iodide, scopolia extract, scopolia root, scopolia root total alkaloid citrate, and the like can be exemplified.

[0104] As the formulation additive, a pharmaceutically acceptable carrier such as an excipient, a binder, a disintegrant, a disintegrant aid, a glossing agent, a foaming agent, a moisture-proof agent, a surfactant, a stabilizer, an antioxidant, a filler, a sweetener, a flavoring agent, a cooling agent, a perfume, an aromatic agent, a coloring agent, a base, a coating agent, a sugar coating agent, a plasticizer, a dispersant, an antifoaming agent, a fluidizing agent, and a perfuming agent, a flavoring agent, and the like can be exemplified, and a formulation additive usable in a conventional solid formulation can be used for the above-mentioned purposes.

[0105] As the excipient, for example, powdered sugar, acacia, acacia powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrous silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose · sodium carboxymethyl cellulose, crystalline cellulose (microgranules), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate · hydroxypropyl starch · crystalline cellulose, wheat starch, rice powder, rice starch, heavy anhydrous silicic acid, purified white sugar, purified white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially alpha starch, powdered sugar, powdered sugar, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium metasilicate aluminate, calcium sulfate, erythritol, glucose, fructose, and the like can be exemplified.

[0106] As the binder, for example, gum arabic, gum arabic powder, cold plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (complete saponification), polyvinyl alcohol (partial saponification), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like can be given.

[0107] As the disintegrant, for example, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially alpha starch, and the like can be given.

[0108] As the disintegration aid, for example, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, polyethylene glycol 4000, and the like can be given.

[0109] As the lusterizing agent, for example, carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, beeswax, and the like can be given.

[0110] As the foaming agent, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium bicarbonate, anhydrous citric acid, and the like can be given.

[0111] As the moisture-proof agent, for example, ethyl cellulose, olive oil, dry aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetalate-hydroxypropyl methyl cellulose 2910 mixture, polyvinyl acetal diethylaminoacetalate, magnesium metasilicate, and the like can be given.

[0112] As the surfactant, for example, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol beeswax, polyoxyethylene nonyl phenyl 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, polyethylene glycol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium dodecyl sulfate, etc. can be mentioned.

[0113] As stabilizing agents, for example, adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dried sodium carbonate, glycine, glycerin, fatty acid glycerides, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, L-potassium glutamate, L-sodium glutamate, L-glutamic acid L-lysine, 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, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceride (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminum metasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium phosphate dibasic hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0114] As antioxidants, for example, ascorbic acid, L-ascorbyl stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbyl palmitate, sodium pyrosulfite, and the like can be mentioned. In the case of a solid composition containing acetaminophen, it is preferable not to incorporate tocopherols as antioxidants or stabilizing agents.

[0115] As fillers, for example, RSS No. 1 raw rubber, acryl starch 1000, hydrous silicon dioxide, titanium oxide, calcium monohydrogen phosphate, and the like can be mentioned.

[0116] As a sweetener, for example, aspartame, acesulfame potassium, stevia, stevia powder, maltitol syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract purified, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, and the like can be given.

[0117] As a flavoring agent, for example, sodium chloride, phellodendron powder, cherry bark extract, coptis, coptis 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, sodium saccharin hydrate, sansho powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, ginger powder, sucralose, stevia extract, stevia extract purified, swertia, D-sorbitol, tannic acid, clove oil, dried tangerine peel tincture, chili, chili powder, spruce powder, trehalose hydrate, quassia powder, plum extract, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, borneol, borneol powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, rose oil, and the like can be given.

[0118] As a cooling agent, for example, anise oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, l-menthol, and the like can be given.

[0119] As a flavor, for example, orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, and the like can be given.

[0120] As a fragrance, for example, anise powder, anise oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, linaloe powder, spearmint oil, clove oil, turpentine oil, chili 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, rose oil, and the like can be given.

[0121] As the coloring agent, for example, yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold foil, black iron oxide, titanium oxide, ferric oxide, disazo 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 phosphate sodium, green tea powder, rose oil, and the like can be given.

[0122] As the base, for example, gum arabic powder, alpha starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrous silicon dioxide, dry aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, fatty acid glycerin ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, polyethylene glycol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, squalane monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium dodecyl sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like can be given.

[0123] As a coating agent, for example, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, acacia, acacia powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold foil, silver foil, triethyl citrate, glycerin, fatty acid glycerin 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, gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose 2910-titanium oxide-polyethylene glycol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methyl cellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium metasilicate aluminum, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, 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, and the like can be given.

[0124] As a sugar coating agent, for example, acacia, acacia powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium oxide, stearic acid, stearic acid polyoxyl 40 ester, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, dicalcium phosphate hydrate, monobasic calcium phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like can be given.

[0125] As a plasticizer, for example, triethyl citrate, glycerin, fatty acid glycerin ester, D-sorbitol, medium-chain fatty acid triglyceride, glycerin triacetate, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, glycerin monostearate, isopropyl linoleate, liquid paraffin, and the like can be given.

[0126] As a dispersing agent, for example, aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, fatty acid glycerin ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, 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, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000 NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methyl cellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like can be given.

[0127] As an antifoaming agent, for example, ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane·silica mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, and the like can be given.

[0128] As a fluidizing agent, for example, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, aluminum magnesium hydroxide, stearic acid, calcium stearate, magnesium stearate, calcium phosphate, talc, magnesium aluminum metasilicate, calcium hydrogen phosphate granules, and the like can be given.

[0129] As the incense and flavor, for example, aniseed, anise 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 flavor, vitamin base, Himalayan cedar oil, fruit flavor, G1 flavor, orange peel glycoside peppermint essence, bergamot oil, bergamot flavor, d-limonene, dl-limonene, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, borneol, borneol powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, and the like can be given.

[0130] These components can be contained singly or two or more kinds.

[0131] (Dosage form)

[0132] The solid composition of the present embodiment can be, for example, a preparation for oral administration (tablets (including intraoral disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, and powders, etc.), a preparation for intraoral use (including oral tablets, lozenges, sublingual tablets, buccal tablets, adherent tablets, gums, etc.), and the like described in the General Rules for Preparations of the Eighteenth Edition of the Japanese Pharmacopoeia, etc. The solid composition of the present embodiment is preferably an oral solid composition.

[0133] As the dosage form of the solid composition of the present embodiment, for example, tablets, capsules, pills, granules, and fine granules can be given. These solid compositions can be coated with sugar coating, film coating, or the like as needed by using a known method. The dosage form of the solid composition is preferably a tablet. As specific examples of the tablet, plain tablets, film-coated tablets, and sugar-coated tablets can be given.

[0134] The solid composition of the present embodiment can be temporarily packaged by bottle packaging, PTP packaging, bag-like packaging, strip packaging, SP packaging, and hermetically stored. They can be further pillow-packaged, and they can be housed in a case or the like. As the material used in the pillow packaging, there is no particular limitation, and for example, a resin film such as a polypropylene film, a polyethylene terephthalate film, a polyethylene film, or the like, a material in which an aluminum foil is attached to these resin films can be used. Note that in the case where hygroscopicity is a concern, a desiccant or the like can be stored in the bottle packaging or the pillow packaging.

[0135] The solid composition of the present embodiment can be housed in a packaging container to be a packaged body. The solid composition of the present embodiment can be, for example, housed in a hermetically packaged body. By being a packaged body, for example, the convenience when using the solid composition can be improved. The packaged body in the present embodiment is specifically a pharmaceutical product.

[0136] As a packaging form of the solid preparation, the solid composition can be temporarily packaged and hermetically stored by bottle packaging, PTP packaging (Press Through Package), bag-like packaging, strip-like packaging, SP packaging (Strip Package), and the like. They can be further pillow-packaged, and they can be housed in a case or the like. In addition, from the viewpoint of reducing the hygroscopicity of the solid composition, a desiccant or the like can be stored in the packaging container, such as in the bottle packaging, the pillow packaging, and the like.

[0137] As a material used in the SP packaging, the PTP packaging, the strip-like packaging, the pillow packaging, and the like, for example, a resin film such as a polypropylene film, a polyethylene terephthalate film, a polyethylene film, or the like, a material in which an aluminum foil is attached to these resin films can be cited. Either a single layer film or a multilayer film (for example, a laminated film) can be used.

[0138] In addition, the material constituting the packaging container preferably contains a material that is not easily affected by moisture. As the packaging, a packaging formed of at least one of a moisture-proof material and a gas-barrier material can be cited.

[0139] As the moisture-proof material, for example, a combination packaging of PTP (polypropylene) and a polyethylene aluminum pillow can be cited. In addition, when the solid composition is a tablet, in consideration of the suppression of the increase in the moisture value in the tablet, the storage stability of the tablet, the stability of the tablet after opening, and the like, as the moisture-proof material, a PTP packaging using aluminum on both sides (Al-Al packaging) can be used.

[0140] As the gas-barrier material, a known material can be used, for example, it can be a laminated film having a functional barrier layer, or it can have the function of the above-described moisture-proof material or be used together with the above-described moisture-proof material.

[0141] In addition, the packaging container can be made into an article that takes the environment into consideration. For example, a raw material that takes the environment into consideration, such as a recycled plastic, a biomass plastic, a biodegradable plastic, or the like, can be used for a part or all of the packaging material.

[0142] (Method for manufacturing)

[0143] In the second aspect, a method for manufacturing a solid composition is provided, which includes a step of bringing (A) at least one selected from the group consisting of tipepidine and a salt thereof, (B) at least one selected from the group consisting of tranexamic acid and a salt thereof, and (C) at least one selected from the group consisting of ibuprofen and a salt thereof into contact.

[0144] The manufacture of the solid composition can be carried out using known techniques. The components are added in any order, and finally brought into contact with each other. A solvent, a binder can be added to the mixture after the contact, and kneading is carried out, and the resulting kneaded product is used as the solid composition. The crystals formed from ibuprofen and tranexamic acid can be manufactured using the method described in Japanese Patent Application Publication No. 2022-70674 (described above). After the crystals formed from ibuprofen and tranexamic acid are formed, the crystals can be brought into contact with, or kneaded with, (A) at least one selected from the group consisting of tipepidine and salts thereof. Alternatively, the components can be brought into contact with each other sequentially or simultaneously, as appropriate.

[0145] The resulting kneaded product can be further subjected to a drying step, a granulation step to manufacture granules (granulated products). In this case, granules (granulated products) containing each component can be prepared separately. The granulation can be wet type or dry type.

[0146] The resulting granules (granulated products) can be used as they are, or an additive can be incorporated in the granules, and they can be subjected to tableting to manufacture tablets, and they can be further subjected to film coating.

[0147] (Dissolution improver)

[0148] In the third aspect, a dissolution improver for tipepidine in a solid composition containing (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 is provided, the dissolution improver containing at least one selected from the group consisting of ibuprofen and salts thereof.

[0149] As for the at least one selected from the group consisting of ibuprofen and salts thereof, as described in component (C) of the solid composition according to the present embodiment, as for the above-mentioned components (I) and (II), as described in components (A) and (B) of the solid composition according to the present embodiment.

[0150] As for the dissolution improver, the amount of ibuprofen incorporated with respect to the components (I) or (II) is preferably used in an amount within the range described as the preferable content of component (C) of the solid composition according to the present embodiment. In addition, ibuprofen can be added to the solid composition without being crystallized with tranexamic acid (in a state without being crystallized).

[0151] In order to describe the present application in more detail, the following examples are described, but the present application is not limited to these.

[0152] Example

[0153] 1. Raw materials

[0154] In the present example, the following raw materials were used.

[0155] [Table 1]

[0156]

[0157] 2. Preparation of solid composition

[0158] (Reference Example 1)

[0159] Heparanthine and crystalline cellulose were weighed in the amounts shown in Table 1, sieved with a 30-mesh sieve, and mixed for 100 times in a 4K size bottle to obtain a mixture.

[0160] (Reference Example 2, Comparative Example 1, Example 1)

[0161] The same operation as in Reference Example 1 was performed except that ibuprofen and / or tranexamic acid were used in the amounts shown in Table 1 to obtain a mixture.

[0162] (Example 2)

[0163] A kneader 3 (manufactured by caleva) was used to add ibuprofen 11.1 g and tranexamic acid 13.9 g to a stirring vessel and mix, 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 granules of crystals formed from ibuprofen and tranexamic acid. The same operation as in Reference Example 1 was performed except that the resulting granules were used in the amounts shown in Table 1 to obtain a mixture.

[0164] Note that 6 mg of the resulting granules were placed in an aluminum pan, and a differential scanning calorimeter DSC 3+ (manufactured by Mettler-Toledo) was used to measure the range from 25 to 250°C at a rate of 10°C / minute. The results are shown in Figure 1 . As shown in Figure 1 , a peak from ibuprofen disappeared around 75°C, and a peak from crystals formed from ibuprofen and tranexamic acid was present around 180°C, thereby confirming that crystals having a molar ratio of 1:1 between ibuprofen and tranexamic acid were contained in the manufactured granules.

[0165] The amounts (g) of each sample are shown in the following table. In the following table, the granules manufactured in Example 2 contained crystals formed from ibuprofen and tranexamic acid.

[0166] [Table 2]

[0167]

[0168] 3. Dissolution test of solid composition

[0169] The dissolution of the prepared test sample was evaluated in the following manner. Specifically, the dissolution test machine (NTR-6400AC, Takara Shiken Co., Ltd.) was used in accordance with the "Dissolution Test Method (Paddle Method)" described in the seventeenth edition of the Japanese Pharmacopoeia. Each mixture of the prepared test sample was weighed in the amount described in Table 1. The weighed test sample was put into 900 mL of a test solution of water, and the test was performed using the paddle method at 100 rotations per minute. The dissolution rate of the test sample was 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 of the test sample was improved by adding ibuprofen to the test sample of tapentadol hydrobromide and tranexamic acid.

[0170] Note that the dissolution rate of tapentadol was determined using an absorbance method using a standard solution of a known concentration. The absorbance at wavelengths of 286 nm and 360 nm was measured, and the value obtained by subtracting the absorbance at 360 nm from the absorbance at 286 nm was used to calculate the concentration in order to remove the background signal.

[0171] [Table 3]

[0172] Tipepidine dissolution rate Reference Example 1 Reference Example 2 Comparative Example 1 Example 1 Example 2 15-minute time point (%) 35.7 31.2 26.2 40.2 37.1 30-minute time point (%) 50.2 51.1 40.7 56.5 54.3

[0173] Examples of the solid preparation are shown below.

[0174] [Table 4]

[0175]

[0176] [Table 5]

[0177]

[0178] The preferred embodiments and examples of the present application have been described above, but the present application is not limited to these. Additions, omissions, substitutions, and other modifications of the constitution can be made within the scope of the gist of the present application.

Claims

1. A solid 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, wherein which does not include a solid composition comprising levocetirizine or montelukast.

2. The solid state composition of 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, which comprises a crystal formed from ibuprofen and tranexamic acid.

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

1.

5. The solid state composition of claim 1 or 2, wherein, (C) at least one selected from the group consisting of ibuprofen and salts thereof is contained in a state not forming a crystal with (B) at least one selected from the group consisting of tranexamic acid and salts thereof.

6. The solid state composition of claim 1 or 2, wherein, The dissolution rate of tipepidine after 15 minutes from the start of the test is 30% or more as determined according to the method described in the dissolution test method of the Eighteenth Edition of the Japanese Pharmacopoeia.

7. An improvement agent for the dissolution property 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, wherein, which comprises at least one selected from the group consisting of ibuprofen and salts thereof.

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