solid components

Abstract

Selected from the group consisting of tipepidine and its salts, with improved tipepidine elution properties. At least one of the following is selected from the group consisting of tranexamic acid and its salts. To provide a solid composition containing seeds. [Solution] The following components: (A) At least one selected from the group consisting of tipepidine and its salts, (B) At least one selected from the group consisting of tranexamic acid and its salts, (C) At least one selected from the group consisting of ibuprofen and its salts Solid compositions containing (excluding solid compositions containing levocetirizine or loratadine). ).

Description

[Technical Field]

[0001] The present invention broadly comprises at least one selected from the group consisting of tipepidine and its salts, and At least one selected from the group consisting of ranexamic acid and its salts, and ibuprofen and This invention relates to a solid composition comprising at least one selected from the group consisting of bicarbonate salts. [Background technology]

[0002] Tipepidine is known to exhibit antitussive effects by suppressing the cough center, as well as expectorant effects. Tipepidine is used in cold medicines and cough suppressants / expectorants based on these effects. .

[0003] For example, Patent Document 1 contains (a) ibuprofen, (b) an amino group-containing compound or the A solid preparation containing salts, (c) a release control agent, and (d) an organic acid or an acidic amino acid It is disclosed. Patent Document 1 states that (b) tipepidine hibe as a salt of an amino group-containing compound. Alkaline salts are mentioned.

[0004] Patent Document 2 contains loxoprofen or its salts, tipepidine or its salts, and L-calcium. A pharmaceutical composition containing bocysteine ​​is disclosed.

[0005] Patent Document 3 includes (a) loxoprofen or a salt thereof, (b) tipepidine or a salt thereof, (c) a solid dosage form containing crospovidone and / or carmellose calcium is disclosed. It is being done.

[0006] Patent Document 4 contains ibuprofen, levocetirizine, carbocysteine, and ambro. Xol, tranexamic acid, glycyrrhizic acid, tipepidine, dextromethorphan, A small number of substances selected from the group consisting of bromhexine, dimemorphan, and methyl ephedrine A pharmaceutical composition containing at least one of the following is disclosed.

[0007] Patent Document 5 contains ibuprofen, loratadine, carbocysteine, and ambroxo , bromhexine, tranexamic acid, glycyrrhizic acid, tipepidine, and dextrin A solid composition containing at least one selected from the group consisting of lomethylphan is disclosed. It is being done.

[0008] Tranexamic acid has anti-plasmin activity, and therefore is effective against cold symptoms such as sore throat. It is being used. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2018-039792 [Patent Document 2] Japanese Patent Publication No. 2014-111565 [Patent Document 3] Japanese Patent Publication No. 2015-187095 [Patent Document 4] Japanese Patent Publication No. 2022-008041 [Patent Document 5] Japanese Patent Publication No. 2020-158487 [Overview of the project] [Problems that the invention aims to solve]

[0010] The present inventors have identified at least one selected from the group consisting of tipepidine and its salts, and tran In a solid composition comprising at least one selected from the group consisting of xamic acid and its salts, It was found that the elution of tipepidine may be insufficient in some cases. The present invention relates to tipepidine At least one selected from the group consisting of tipepidine and its salts, having improved dissolution properties, and a solid composition containing at least one selected from the group consisting of tranexamic acid and its salts are provided.

Means for Solving the Problems

[0011] The present inventor found that when 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 are blended with at least one selected from the group consisting of ibuprofen and its salts, the dissolution properties of tipepidine are improved, and thus the present invention was completed. That is, the present embodiment includes the following aspects. 、イブプロフェン及びその塩からなる群から選択される少なくとも1種を配合させるとチ ペピジンの溶出性が改善されることを見出し、本発明を完成させるに至った。

[0012] すなわち、本実施形態は以下の態様を包含する。 [1] The following components: (A) At least one selected from the group consisting of tipepidine and its salts, (B) At least one selected from the group consisting of tranexamic acid and its salts, and (C) At least one selected from the group consisting of ibuprofen and its salts are included in a solid composition (however, excluding solid compositions containing levocetirizine or loratadine. ). [2] 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)) The solid composition according to [1]. [3] The solid composition according to [1] or [2], containing crystals composed of ibuprofen and tranexamic acid . [4] The molar ratio of ibuprofen to tranexamic acid in the crystals is 1:1. The solid composition according to [3] . [5] (C) At least one selected from the group consisting of ibuprofen and its salts, (B) At least one selected from the group consisting of tranexamic acid and its salts forms crystals. The solid composition described in [1] or [2], which is included in the absence of the solid composition described in [1] or [2]. [6] The measurement is performed in accordance with the method described in the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, and the test begins. The tipepidine elution rate after 15 minutes is 30% or more, one of [1] to [5] The solid composition described. [7] (I) contains at least one selected from the group consisting of ibuprofen and its salts. (II) Tranexamic acid A solid composition comprising at least one selected from the group consisting of acids and salts thereof, An agent that improves the dissolution properties of tipepidine. [Effects of the Invention]

[0013] According to the present invention, a group comprising tipepidine and its salts, in which the elution properties of tipepidine have been improved. At least one selected from the group consisting of tranexamic acid and its salts, and a small A solid composition containing at least one of these ingredients can be provided. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 shows the differential scanning calorimetry (DSC) results of the crystals composed of ibuprofen and tranexamic acid obtained in Example 2. [Modes for carrying out the invention]

[0015] The following describes embodiments of the present invention (hereinafter referred to as "this embodiment"), but The scope of the invention is not limited to the following embodiments. In this embodiment, the composition is Each component may be included individually or in combination of two or more. The "~" symbol, which indicates a numerical range, represents "greater than or equal to" or "less than or equal to," and includes both numbers at either end.

[0016] (solid composition) In the first embodiment, the following components: (A) At least one selected from the group consisting of tipepidine and its salts, (B) At least one selected from the group consisting of tranexamic acid and its salts, (C) At least one selected from the group consisting of ibuprofen and its salts Solid compositions containing (excluding solid compositions containing levocetirizine or loratadine). ) It will be provided. The solid composition is specifically a solid pharmaceutical composition.

[0017] Each component contained in the solid composition according to this embodiment is included in a pharmaceutically acceptable salt state. It may be present on its own, or it may be included as a complex with other components. That is, in this embodiment The solid composition in question is not only composed of components (A) to (C), but also of other components, and each component is... It may contain salt. "Pharmacologically acceptable salt" refers, for example, to a base that is acceptable as a medicine. It contains salts with acids. Non-specific examples of pharmacologically acceptable salts include inorganic acids (hydrochloric acid, hydrobromic acid, iodide). Addition salts of hydrogen acids, sulfuric acid, phosphoric acid, etc., organic acids (p-toluenesulfonic acid, methanesulfone Acids, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoate Addition salts of acetic acid (such as acetic acid), inorganic bases (ammonium hydroxide or alkali or alkali) Examples include addition salts of earth metal hydroxides, carbonates, bicarbonates, etc., and addition salts of amino acids. Pharmacologically acceptable salts may be hydrated or anhydrous.

[0018] In this embodiment, at least one selected from the group consisting of tipepidine and its salts In addition to the species, and at least one selected from the group consisting of tranexamic acid and its salts Because it contains the above component (C), the elution properties of tipepidine in the solid composition are improved.

[0019] In this specification, improved dissolution of tipepidine means that ibuprofen and so It does not contain at least one selected from the group consisting of salts of tipepidine and its salts. At least one selected from the group and selected from the group consisting of tranexamic acid and its salts A solid composition comprising at least one of the following; or selected from the group consisting of ibuprofen and its salts. It does not contain at least one of the following, or is selected from the group consisting of ibuprofen and its salts. Except for the inclusion of an equal amount of another control component in place of at least one of the specified components, the dissolution properties are not subject to evaluation. Compared to a solid composition containing the same components as the solid composition, the dissolution rate of tipepidine has been improved. This means that the dissolution rate of tipepidine is measured after a predetermined time has elapsed since the start of the dissolution test. It may be determined by the method, 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, but may be, for example, crystalline cellulose.

[0020] In this embodiment, the elution properties of tipepidine are, for example, defined in the "Elution" section of the 18th edition of the Japanese Pharmacopoeia. It may be measured by the method described in the "Test Methods." Specifically, the method described in the 18th edition of the Japanese Pharmacopoeia. Methods such as the paddle method, rotating basket method, and flow-through cell method described in "Dissolution Test Methods" It can be evaluated according to the following. In the dissolution test, tipepidine is dissolved in a specified test solution. This is quantified. More specifically, using the method for measuring the elution rate of tipepidine described in the examples. Just measure it.

[0021] In the solid composition according to this embodiment, when the above-described elution test was performed, the test results The elution rate of tipepidine after 15 minutes is preferably 30% or more, and more preferably 35%. % or more, more preferably 37% or more, and even more preferably 40% or more Yes. There is no particular upper limit to the dissolution rate, but the dissolution rate is, for example, 100% or less, 9% or less. 9% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less It may be 55% or less, or 50% or less.

[0022] In the solid composition according to this embodiment, when the above-described elution test was performed, the test results The elution rate of tipepidine 30 minutes after the start of the reaction is preferably 45% or more, and more preferably 50%. % or more, more preferably 53% or more, and even more preferably 55% or more Yes. There is no particular upper limit to the dissolution rate, but the dissolution rate is, for example, 100% or less, 9% or less. 9% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, or 60% The following is acceptable:

[0023] In addition, in the solid composition of this embodiment, "a solid containing levocetirizine or loratadine" "Composition" is excluded.

[0024] Here, "levocetirizine" refers to the chemical formula C 21 H 25 This compound is represented as ClN2O3. Levocetirizine is the R-enantifoliate, which is the more biologically active optical isomer of cetirizine. This is an optically resolved specimen of Omar only, with a CAS registry number of 130018-77-8. Furthermore, in this embodiment, solid compositions containing a salt of levocetirizine are also excluded. It is done. The salt of levocetirizine is not particularly limited as long as it is a pharmacologically acceptable salt. For example, salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and acetates and oxalates, Malonate, succinate, fumarate, maleate, lactate, malate, citrate Examples include organic acid salts such as tartrates and carbonates, with hydrochloride being particularly important.

[0025] Here, "loratadine" refers to the chemical formula C 22 H 23 It is a compound represented as ClN2O2, C The AS registration number is 79794-75-5.

[0026] Furthermore, in the solid composition of this embodiment, Japanese Patent Publication No. 2022-008041 and Japanese Patent Publication No. The solid compositions disclosed in Japanese Patent Publication No. 2020-158487 are excluded. The solid composition disclosed in Publication No. 22-008041 contains ibuprofen and levocetirizine. Or, even if it contains a salt thereof, the decrease in the content of levocetirizine or its salt over time is suppressed. The pharmaceutical composition, a solid composition disclosed in Japanese Patent Publication No. 2020-158487, is ibuprofen. Even when containing loratadine, the decrease in loratadine content over time is suppressed in the solid composition. The solid composition of this embodiment is selected from the group consisting of ibuprofen and its salts. For at least one selected, at least one selected from the group consisting of tipepidine and its salts ibuprofen and its salts, which suppress the changes in properties that may occur when one type is added to the mixture. It is a solid composition containing at least one selected from the group.

[0027] (A) At least one selected from the group consisting of tipepidine and its salts As used herein, "tipepidine" is the CAS registry number 5169-78-8 Yes, C 15 H 17 This compound is represented by the chemical formula NS2 (molecular weight: 275.43 g / molecular weight). Tipepidine is used as an active ingredient in cough suppressants and expectorants. Tipepidine salts are While not particularly limited as long as it is pharmacologically acceptable, tipepidine hibenzate and tipep Pidine citrates are an example. Furthermore, selection is made from the group consisting of tipepidine and its salts listed below. The amount and content of at least one of the compounds are determined for tipepidine and tipepidine salts respectively. The amounts and contents of the ingredients are as follows: the total amount and contents of tipepidine and tipepidine salts. The following blending amounts and content ranges are preferred.

[0028] The amount of at least one component selected from the group consisting of component (A) tipepidine and its salts , at least one selected from the group consisting of tipepidine and its salts in a solid composition The dosage is adjusted as appropriate depending on the intended use, the symptoms of the recipient, age, weight, sex, etc. For example, The daily dose of tipepidine administered to humans is, for example, 8 mg to 120 mg, and more preferably... Alternatively, it can be adjusted within the range of 16 mg to 100 mg. In this embodiment, "adult" means 1 This refers to men and women aged 5 years or older. However, the solid composition according to this embodiment is intended for adult consumption. It is not limited to those mentioned above, and may also be used by children under 15 years of age. When administered to children, the dosage should be reduced to 1 / 2 or 2 / 3 of the adult daily dose, depending on the age group. It can be used in any quantity. The same applies to ingredients other than tipepidine.

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

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

[0031] The weight and dosage of the above solid composition are the daily dose (daily amount), but the same amount The substance can be administered to the target in one dose, or multiple times a day, for example, two or three times, preferably in three separate doses. It may be administered. The same applies to components other than tipepidine. Also, the total amount of each dose is... Therefore, the content of each component in the solid composition varies depending on the single dose and the dosage form of the solid composition. It can be moved.

[0032] In certain embodiments, the solid composition is a tablet, and the above dosage is 3 tablets, 6 tablets, or This is the amount of the ingredient contained in 9 tablets, preferably the amount of the ingredient in 9 tablets. For adults (15 years and older), the single dose is three times a day, with each dose consisting of 2 tablets, 3 tablets, or The dosage is 4 tablets, preferably 3 tablets per dose.

[0033] (B) At least one selected from the group consisting of tranexamic acid and its salts As used herein, "tranexamic acid" refers to CAS Registry Number 1197-18- 8, C8H 15 It is a compound represented by the chemical formula NO2 (molecular weight: 157.21 g / (moles). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs, etc. Tranexamic acid The salt 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 tranexamic acid and its salts is tranexamic acid. The proportions and content of the acid and the tranexamic acid salt are as follows: The total amount and content of the tranexamic acid salt are within the range of the amounts and content described below. It is preferable to do so.

[0034] The amount of at least one substance selected from the group consisting of tranexamic acid and its salts is, In a substance, at least one use selected from the group consisting of tranexamic acid and its salts It is adjusted as appropriate. At least one selected from the group consisting of tranexamic acid and its salts. One type is formulated for the purpose of anti-plasmin activity, hemostatic activity, or anti-allergic / anti-inflammatory activity. If so, the amount of at least one selected from the group consisting of tipepidine and its salts, etc. The amount of at least one substance selected from the group consisting of tranexamic acid and its salts varies. However, for example, the daily amount is 10 mg to 3000 mg, preferably 100 mg to 2 The amount is 000 mg, more preferably in the range of 200 mg to 1000 mg.

[0035] The content of tranexamic acid and its salts in the composition administered daily is 1% by mass to 7%. The mass is 0%, preferably 5-50%, and more preferably 10-30%.

[0036] The amount of at least one substance selected from the group consisting of tranexamic acid and its salts is tippe The amount of at least one substance selected from the group consisting of pidins and their salts may vary. For example, the total amount of component (A) and the total amount of component (B) in the solid composition according to this embodiment. The ratio ((A):(B)) is preferably 1:3 to 1:25 in the solid composition administered daily. The ratio is 1:3.5 to 1:23, and more preferably 1:4 to 1:2 It is 0. At least one selected from the group consisting of tranexamic acid and its salts is tipep. At least one selected from the group consisting of gin and its salts is included within the above range. This tends to improve the elution properties of tipepidine in solid compositions.

[0037] For example, the mass ratio of components (A) and (B) in the solid composition according to this embodiment is ((A):(B) )) is preferred in terms of tranexamic acid and tipepidine in the solid composition administered daily. The ratio is 1:3 to 1:25, more preferably 1:4 to 1:23, and even more preferably The ratio is 1:5 to 1:20. Selected from the group consisting of tranexamic acid and its salts, with a minimum of Since one type is included in tipepidine within the above range, the solid composition The dissolution properties of tipepidine tend to improve.

[0038] For example, the mass ratio of components (A) and (B) in the solid composition according to this embodiment is ((A):(B) )) contains tranexamic acid and tipepidine hibenzate in the solid composition administered daily. In calculation, the ratio is preferably 1:3 to 1:25, and more preferably 1:3.5 to 1:20. More preferably 1:4 to 1:15. From the group consisting of tranexamic acid and its salts At least one of the selected types is included in the above range relative to tipepidine hibenzate. There is a tendency for the elution properties of tipepidine in solid compositions to be improved.

[0039] In one embodiment, tranexamic acid forms crystals with ibuprofen in the solid composition. It may be selected from the group consisting of tranexamic acid and its salts as described herein. The description regarding the amount of at least one of the following is ibuprofen and crystalline tranexamic acid. At least one selected from the group consisting of acids and uncrystallized tranexamic acid and its salts It can be the total amount of seeds.

[0040] In one embodiment, the solid composition is ibuprofen and crystalline tranexamic acid. and at least one selected from the group consisting of uncrystallized tranexamic acid and its salts. This includes.

[0041] In one embodiment, ibuprofen contained in the solid composition and non-crystallized tranexamic acid The content of at least one selected from the group consisting of xamic acid and its salts is tranexamic acid. For example, 0-100% by mass, 10-99% by mass, 20-95% by mass relative to the total amount of acid and its salts. It may be in mass%, or 30-90% by mass. It binds with ibuprofen contained in the solid composition. A compound containing at least one selected from the group consisting of uncrystallized tranexamic acid and its salts. The amount is, for example, 8% by mass or less, relative to the total amount of tranexamic acid and its salts, within the above range. It may be 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.1% by mass or less. Solid The composition consists of ibuprofen, non-crystallized tranexamic acid, and its salts. The content of at least one selected from the group is, relative to the total amount of tranexamic acid and its salts. Within the above range, for example, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more The above, or 80% by mass or more.

[0042] At least one selected from the group consisting of ibuprofen and its salts As used herein, "ibuprofen" has a CAS registration number of 15687-27 -1, and is a compound represented by the chemical formula C 13 H 18 O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, antipyretic agents, etc. The salts of ibuprofen are not particularly limited as long as they are pharmacologically acceptable. Note that the dosage and content of at least one selected from the group consisting of ibuprofen and its salts are the dosage and content for ibuprofen and its salts respectively, but the total dosage and content of ibuprofen and its salts are preferably within the range of the dosage and content described below

[0043] The dosage of at least one selected from the group consisting of ibuprofen and its salts is appropriately adjusted according to the use of at least one selected from the group consisting of ibuprofen and its salts in the solid composition[[ID=2!5]]

[0044] ​​​​​For example, the total amount of component (A) and the total amount of component (C) in the solid composition according to this embodiment. The ratio ((A):(C)) is preferably 1:2 to 1:30 in the solid composition administered daily. The ratio is, more preferably 1:3 to 1:25, and even more preferably 1:4 to 1:20. Yes. At least one selected from the group consisting of ibuprofen and its salts is tipepidine. The above range applies to at least one selected from the group consisting of salts thereof. There is a tendency for the elution properties of tipepidine in solid compositions to be improved.

[0045] For example, the mass ratio of components (A) and (C) in the solid composition according to this embodiment is ((A):(C) )) is preferred in terms of ibuprofen and tipepidine in the solid composition administered daily. The ratio is 1:2 to 1:30, more preferably 1:4 to 1:25, and even more preferably The ratio is 1:6 to 1:20. Selected from the group consisting of ibuprofen and its salts, with a minimum of 1. Each of the above applies to at least one selected from the group consisting of tipepidine and its salts. By including it within a certain range, the elution properties of tipepidine in solid compositions can be improved. It's across the street.

[0046] For example, the mass ratio of components (A) and (C) in the solid composition according to this embodiment is ((A):(C) )) contains ibuprofen and tipepidine hibenzate in the solid composition administered daily. In calculation, the ratio is preferably 1:2 to 1:30, more preferably 1:3 to 1:20, and More preferably, the ratio is 1:4 to 1:10. Selected from the group consisting of ibuprofen and its salts. At least one of the following is selected from the group consisting of tipepidine and its salts. By being included within the above range, the elution of tipepidine in the solid composition is improved. It tends to improve.

[0047] The above dosage is an example, and the amount of ibuprofen and ibuprofen per solid composition administered daily. The content of at least one salt selected from the group consisting of those salts is, for example, about 1% by mass to about 70% by mass. Amount in percent, preferably about 5% to about 50% by mass, more preferably about 10% to about 30% by mass It is a percentage.

[0048] In one embodiment, the composition administered daily contains ibuprofen and its salts. The content of at least one selected from the group is 1% by mass to 70% by mass, preferably 5% by mass. The percentage is approximately 50% by mass, more preferably 10-30% by mass.

[0049] Selected from the group consisting of ibuprofen and its salts as described herein The description regarding the amount of each type is that tranexamic acid and crystallized ibuprofen and crystallized The total amount of at least one selected from the group consisting of ibuprofen and its salts that have not been used It can be about that.

[0050] In one embodiment, the solid composition is tranexamic acid and crystallized ibuprofen. Selected from the group consisting of tranexamic acid, uncrystallized ibuprofen, and salts thereof. It includes at least one of the following.

[0051] In one embodiment, tranexamic acid contained in the solid composition and non-crystallized ibuprofen are used. The content of at least one selected from the group consisting of rophene and its salts is ibuprofen For example, 0-100% by mass, 10-99% by mass, 20-95% by mass relative to the total amount of ions and their salts. It may be in mass%, or 30-90% by mass. It combines with tranexamic acid contained in the solid composition. At least one substance selected from the group consisting of uncrystallized ibuprofen and its salts The amount is, for example, 8% by mass or less, relative to the total amount of ibuprofen and its salts, within the above range. It may be 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.1% by mass or less. Solid The composition consists of tranexamic acid, non-crystallized ibuprofen, and its salts. The content of at least one selected from the group is, relative to the total amount of ibuprofen and its salts. Within the above range, for example, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more The above, or 80% by mass or more.

[0052] If ibuprofen and tranexamic acid exist as crystals in the composition, then... Furthermore, ibuprofen and tranexamic acid may exist in a 1:1 molar ratio. In the crystal, ibuprofen and tranexamic acid form a crystalline unit cell of four molecules each. It's fine to have done it.

[0053] In the crystal, the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid Between the ibuprofen carboxylic acid group and the tranexamic acid amino group, a hydrogen bond exists. It is acceptable for it to be formed.

[0054] The crystal exhibits an endothermic peak around 180°C in differential scanning calorimetry (DSC). It is acceptable to leave it as is. "Around 180°C" means, for example, a range of 180°C ± 20°C, and 180 The temperature may be within the range of ℃ ± 10℃. Furthermore, in the DSC of the crystal, ibuprofen is particularly The characteristic heat of fusion peak around 75°C may disappear.

[0055] The crystal has, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674. The crystal may have the X-ray diffraction pattern shown in Figure 2 of the same publication. In the X-ray diffraction pattern, there are seven main peaks (2θ = 6.3, 8.4, 16.2, It may have angles of 18.5, 19.1, 21.1, and 25.6 ± 0.5°.

[0056] A crystal composed of ibuprofen and tranexamic acid is, for example, described in Japanese Patent Publication No. 2022-70674. It can be manufactured by the method described in the publication. The following are two manufacturing methods.

[0057] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) To produce ibuprofen in a fluid form by adding a solvent or heating, (2) Mix the obtained fluid ibuprofen and tranexamic acid, 3) A method comprising producing crystals from the obtained mixture.

[0058] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Obtain tranexamic acid in a fluid form, (2) the obtained fluid form Ranexamic acid and ibuprofen, or fluidity obtained by adding or heating a solvent. (3) Mixing the fluid ibuprofen with the mixture, and (4) Producing crystals from the resulting mixture. A method that includes doing so.

[0059] (Other ingredients) The solid composition according to this embodiment may contain components other than those described above, depending on its intended use. Good. The solid composition relieves various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, and cough. It is used to relieve symptoms such as phlegm, chills, fever, headache, joint pain, and muscle pain. In addition to bromhexine, meloxicam, and acetaminophen, antipyretic analgesics, especially, Other active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs) other than buprofen, and other Pharmacologically acceptable ingredients may be included.

[0060] Nonsteroidal anti-inflammatory drugs include diclofenac, loxoprofen, zaltoprofen, Pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam Ampiroxicam, Piroxicam, Nabumetone, Indomethacin, Sulindac, Mofe COX-2 nonselective inhibitors such as Zolac and mefenamic acid, and meloxicam, etodolac, ce They are broadly classified into COX-2 selective inhibitors such as recoxib. Meloxicam is a nonsteroidal anti-steroid. It may be incorporated into the composition as an anti-inflammatory agent. Nonsteroidal anti-inflammatory drugs are COX-2 nonselective. It is preferable that the agent be an inhibitor. Nonsteroidal anti-inflammatory drugs may also be in the form of a salt.

[0061] Other pharmacologically acceptable ingredients include those found in combination cold medicines, antipyretic analgesics, and rhinitis medications. Antihistamines, antipyretics and analgesics, cough suppressants and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins The drug may also be formulated with other agents such as anticholinergics and antiplasmins.

[0062] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, and triphosphate hydrochloride. Perenamin, tondiamine hydrochloride, phenetazine hydrochloride, methidilazine hydrochloride, dl-chlor Pheniramine maleate, d-chlorpheniramine maleate, diphenyl disulfone Carbinoxamine phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, Diphenhydramine hydrochloride, diphenhydramine salicylate, alimethazine tartrate, Diphenhydramine iodine, triprolidine hydrochloride hydrate, mebhydrolysine napadisylate N, promethazine methylene disalicylate, carbinoxamine maleate, diphosphate Examples include terol, clemastine fumarate, and mequitazine.

[0063] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin and acetamine. Nophen, ethenzamide, sazapyrine, salicylamide, lactylphenethidine, isop Examples include ropilantipyrine. Acetaminophen is included in the composition as an antipyretic and analgesic. They may be combined.

[0064] Cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, and dextromethorphan. Hydrobromide hydrate, bromhexine hydrochloride, dihydrocodeine phosphate, dl-methyl Ephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine salt Examples include salts, ambroxol hydrochloride, and L-carbocysteine.

[0065] Anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (for example, glycyrrhizic acid and its derivatives and salts). Examples include dipotassium lysyrrhizinate and monoammonium glycyrrhizinate.

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

[0067] Vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., Benf Othiamine, vitamin B2 and its derivatives and their salts (e.g., riboflavin) Vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin Examples include ions and their derivatives, as well as salts thereof.

[0068] Anticholinergic agents include scopolamine hydrobromide, datura extract, and methylscopolamine. Bromides, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine Bromides, belladonna alkaloids, belladonna extract, total belladonna alkaloids, iodine Isopropamide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, ro Examples include belladonna root, belladonna root total alkaloid citrate, etc.

[0069] The solid composition according to this embodiment may be further modified by adding a formulation additive as needed. Possible alternatives include pharmaceutically acceptable carriers, such as excipients, binders, and disintegrants. Disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, Sweeteners, flavoring agents, cooling agents, fragrances, air fresheners, coloring agents, bases, coating agents, sugar coating agents, etc. Examples include plasticizers, dispersants, defoamers, fluidizers, and flavoring agents / fragrances, etc., as well as conventionally known solid formulations. Pharmaceutical additives that can be used for the above purposes may be used for the above purposes.

[0070] Excipients include, for example, sugar powder, gum arabic, powdered gum arabic, cocoa butter, caramel. Sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, Xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate Light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose Lurose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate Synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, wheat cellulose Pun, 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, low degree of substitution Hydroxypropylcellulose, dextrin, corn starch, corn Starch granules, trehalose, lactose monohydrate, lactose granules, sucrose, potato starch, Hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup Powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene Castor oil 60%, maltitol, D-mannitol, magnesium aluminometasilicate Examples include calcium sulfate, erythritol, glucose, and fructose.

[0071] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, and ceramic. Hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, Lulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified) (Diluted methacrylate), methacrylate copolymer L, methacrylate copolymer LD, methacrylate Copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose Examples include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers.

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

[0073] Examples of disintegration aids include sodium carboxymethyl starch, carmellose, Carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose Sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch -ch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1 Examples include 500 and macrogol 4000.

[0074] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, and macromolecules. Goal 400, Macro Goal 1500, Macro Goal 4000, Macro Goal 6000, Examples include macrogol 6000NF and beeswax.

[0075] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, and carbonated water. Examples include sodium chloride and anhydrous citric acid.

[0076] Examples of moisture-proofing agents include ethylcellulose, olive oil, and dried aluminum hydroxide gel. Glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, Refined sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid, stearin Acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose -2910 mixture, polyvinyl acetal diethylaminoacetate, aluminum metasilicate Examples include magnesium methyl phosphate.

[0077] Examples of surfactants include sucrose fatty acid esters and polyoxyethylene hydrogenated castor oil. 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 Poly(105)polyoxypropylene(5)glycol, polyoxyethylene(120) Polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene Polypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) Cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macro Logol 400, sorbitan monooleate, glyceryl monostearate, monostearate Examples include sorbitan phosphate, sorbitan monolaurate, and sodium lauryl sulfate. ru.

[0078] Examples of stabilizers include adipic acid, L-aspartic acid, and L-aspartic acid sodium. Thorium, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, A Sodium benzoate, propylene glycol alginate, benzoic acid, sodium benzoate Thorium, ethylenediamine, calcium disodium edetate, sodium edetate, Tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, salt Calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride Nesium, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer , carmellose calcium, carmellose sodium, anhydrous sodium carbonate, glycine, Glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate L-Glutamate, Magnesium Gluconate, Potassium L-Glutamate, Sodium L-Glutamate Um, L-glutamic acid L-lysine, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, ko Sodium rhoidin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sodium phosphate Sugar fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin Hydrolyzed cellulose, sorbitan fatty acid ester, taurine, talc, calcium carbonate, carbonated water Potassium phosphate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin Min E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone Polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, poly Oxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxy Hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) Recall, polyoxyethylene (54) polyoxypropylene (39) glycol, poly Oxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) Polyoxypropylene (67) Glycol, Polyoxyethylene Coconut Oil Fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate T80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 4 00, Macrogol 4000, Anhydrous Citric Acid, Anhydrous Sodium Citrate, Anhydrous Phosphate Monohydrate Sodium phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methyl Cellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate Malic acid hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, phosphorus Calcium dihydrogen hydrate, L-leucine, polyvinyl alcohol, acrylic acid, metha Examples include methyl lylate copolymers.

[0079] Examples of antioxidants include ascorbic acid, L-ascorbic acid, and steate. Ingredients: Citric acid hydrate, soy lecithin, natural vitamin E, tocopherol tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. Examples include: In the case of a solid composition containing acetaminophen, an antioxidant or stabilizer. It is preferable not to include tocopherols.

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

[0081] Examples of sweeteners include aspartame, acesulfame potassium, amacha, and ama. Tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, Dipotassium lycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin Thorium hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose Examples include sucrose, maltitol, D-mannitol, and erythritol.

[0082] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, and others. Uren powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract Ingredients: licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate L-hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract Brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper Powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, ginger Powder, sucralose, stevia extract, stevia extract refined product, Swertia japonica, D-sorbitol Tannic acid, clove oil, dried tangerine peel tincture, chili pepper, chili pepper powder, spruce powder, trefoil Halos hydrate, senna powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder - D-mannitol, dl-menthol, l-menthol, menthol powder, ryu Uno, Ophiopogon powder, green tea powder, DL-malic acid, DL-malate sodium, lemon oil Examples include rose oil.

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

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

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

[0086] Examples of coloring agents include yellow iron oxide, yellow iron(III) oxide, orange essence, and brown iron oxide. Iron, carbon black, caramel, beta-carotene, licorice extract, gold leaf, black iron oxide, acid Titanium oxide, iron(III) oxide, dizuazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5 Food-grade Blue No. 2 aluminum lake, Food-grade Yellow No. 4 aluminum lake, Food-grade Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin Thorium, copper chlorophyll, phenol red, malachite green, methylene blue, Medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate Examples include um, green tea powder, and rose oil.

[0087] The base ingredients are acacia powder, pregelatinized starch, ethylcellulose, and cocoa butter. Carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium Reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, can Ten powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous Silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium silicate Thorium, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, sucrose Magnesium thearate, gelatin, D-sorbitol, talc, calcium carbonate, tofu Sorghum starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer Combined ingredients, concentrated glycerin, potato starch, hydroxypropylcellulose, hypromello Polysorbate 60, Polysorbate 80, Poly Vinyl alcohol (partially saponified), microcrystalline wax, macrogol 20 0, Macrogol 300, Macrogol 400, Macrogol 1000, Macrogol 1 500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macro Gol 6000NF, Macrogol 20000, D-mannitol, Monostearate Lycerin, sorbitan monostearate, batyl monostearate, pryl monostearate Polyethylene glycol, polyethylene glycol monostearate, sodium lauryl sulfate Examples include polyvinyl alcohol, acrylic acid, and methyl methacrylate copolymers.

[0088] Examples of coating agents include ethyl acrylate / methyl methacrylate copolymer. Dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate Polymer RS, gum arabic, gum arabic powder, ethylcellulose, ethylcellulose water Dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate Glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester , stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, Shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate Gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose Rose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl Pyrmethylcellulose 2910, titanium dioxide, macrogol 400 mixture, hypromellol S, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydro Xypropylmethylcellulose 2910 mixture, pullulan, polysorbate 80, polypropylmethylcellulose Nylacetal diethylaminoacetate, povidone, polyvinyl alcohol (partially hydrated) (Monster), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Mac Logol 6000NF, Macrogol 20000, Macrogol 35000, Methacrylic Acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, metasilicic acid Magnesium aluminate, methyl acrylate, methacrylic acid, methyl methacrylate Tocopolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate • Methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate N, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl sulfate Examples include a copolymer of methyl methacrylate, acrylic acid, and methyl alcohol.

[0089] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, and carnauba. Uva wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxy stearate Sil-40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitate Calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose Pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500 Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Hydrophosphate Calcium hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol, acrylic Examples include acid-methyl methacrylate copolymers.

[0090] Examples of plasticizers include triethyl citrate, glycerin, and glycerin fatty acid ester. Ingredients: D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil Castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polysorbate 80, Macroglucose Lu 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macro Gol 6000, Macrogol 6000NF, Glyceryl Monostearate, Linoleic Acid Examples include isopropyl alcohol and liquid paraffin.

[0091] Dispersants include aminoalkyl methacrylate polymer RS, acacia gum, and arabic Agumon powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar Powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester Magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, acid Titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sol Bitol, soy lecithin, low-substituted hydroxypropyl cellulose, dextrin, Corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethyl Cellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromene Rose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, Polyoxyethylene hydrogenated castor oil 50, Polyoxyethylene hydrogenated castor oil 60, Resorbate 20, Polysorbate 60, Polysorbate 80, Microcrystalline Macrogol, Macrogol 300, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methyl Cellulose, glyceryl monooleate, sorbitan monooleate, monostearin Aluminum phosphate, glyceryl monostearate, sorbitan monostearate, monopal Examples include sorbitan mitinate, sorbitan monolaurate, and sodium lauryl sulfate. ru.

[0092] Antifoaming agents include ethanol, glycerin fatty acid ester, and dimethylpolysiloxane. (For oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, sil Examples include antifoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80. ru.

[0093] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, and synthetic aluminum silicate. Um, heavy anhydrous silicic acid, aluminum magnesium hydroxide, stearic acid, calcium stearate Cium, magnesium stearate, tricalcium phosphate, talc, aluminum metasilicate Examples include magnesium phosphate and calcium hydrogen phosphate granules.

[0094] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, and oleo. Orange, orange extract, orange essence, orange oil, chamomile oil, caramel, can Elephant 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, Hess Peridine peppermint essence, bergamot oil, vermouth flavor, d-borneol All, dl-borneol, matcha, mixed flavor, mint flavor, dl -Menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder Examples include lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0095] These components may be present individually or in combination of two or more types.

[0096] (Dosage form) The solid composition of this embodiment is, for example, an orally administered preparation (tablet (orally disintegrating tablet, tubular disintegrating tablet, tubular disintegrating tablet)). (Including Abul tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders, etc.) Preparations for oral application (oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums) This includes, etc. ) and other dosage forms as described in the General Provisions for Preparations of the 18th Revised Japanese Pharmacopoeia, etc. The solid composition of this embodiment is preferably an oral solid composition.

[0097] The dosage forms of the solid composition in this embodiment include, for example, tablets, capsules, pills, granules, and Examples include fine granules. These solid compositions may be sugar-coated or by known methods as needed. It may be coated with a film coating or the like. The dosage form of the solid composition is preferably It is a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets. It can be done.

[0098] The solid composition of this embodiment is packaged in bottles, PTP packaging, pouches, sticks, and SPs. They can be packaged and stored airtight. They can also be pillow-wrapped. These may be stored in boxes or the like. The materials used for pillow packaging are not particularly limited. For example, polypropylene film, polyethylene terephthalate film, polyethylene The materials used include resin films such as film, and resin films to which aluminum foil has been attached. It can be placed inside the bottle packaging or pillow packaging if moisture absorption is a concern. It may also be saved internally at the same time.

[0099] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition may be contained, for example, in an airtight package. By using a package, For example, it can improve the convenience of using solid compositions. Packaging in this embodiment Specifically, these are pharmaceuticals.

[0100] As for the packaging form of solid dosage forms, the solid composition can be packaged in bottles, PTP packaging (Press Through Packaging). Once packaged, it is packaged in a pouch, stick, or strip package. They may be stored in an airtight container. Furthermore, they may be pillow-wrapped and stored in a box or similar container. Alternatively, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be placed inside the bottle packaging, pillow packaging, etc. They may be stored together in the same packaging container.

[0101] Examples of materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include: For example, polypropylene film, polyethylene terephthalate film, polyethylene film Examples include resin films such as acrylic, and those made by attaching aluminum foil to these resin films. It can be made from either a single-layer film or a multi-layer film (e.g., laminate film). You may use it.

[0102] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Such packaging is formed of at least one of a moisture-proof material and a gas barrier material. Examples of packaging include [mention specific packaging].

[0103] For example, PTP (polypropylene) and polyethylene aluminum pillow - A combination of packaging is an example. Also, when the solid composition is a tablet, Considering the suppression of moisture content increase, the storage stability of tablets, and the stability of tablets after opening, as a moisture-proof material Alternatively, PTP packaging (Al-Al packaging) using aluminum on both sides may be used.

[0104] As the gas barrier material, known materials may be used, for example, materials having a functional barrier layer It may also be a laminate film, which serves the same function as the above moisture-proof material, or in combination with the above moisture-proof material. They may be used together.

[0105] Furthermore, packaging containers may be made with environmentally friendly materials. For example, recycled plastics or bio-based materials. Environmentally friendly materials such as mass plastics and biodegradable plastics are used as part of the packaging material or It can be used for all of them.

[0106] (Manufacturing method) In a second aspect, at least one selected from the group consisting of (A) tipepidine and its salts, and at least one selected from the group consisting of (B) tranexamic acid and its salts are contacted with at least one selected from the group consisting of (C) ibuprofen and its salts, to provide a method for producing a solid composition.

[0107] The production of the solid composition can be carried out using known techniques. Each component can be added in any step and finally brought into contact with each other. A solvent or binder can be added to the mixture after contact and kneaded , and the resulting kneaded product can be used as the solid composition. Crystals composed of ibuprofen and tranexamic acid can be produced by the method described in JP-A-2022-70674 (supra). After forming crystals composed of ibuprofen and tranexamic acid, the crystals are contacted or kneaded with at least one selected from the group consisting of (A) tipepidine and its salts. Alternatively, each component can be contacted appropriately, sequentially or simultaneously.

[0108] The resulting kneaded product can be further subjected to a drying process or a granulation process to produce granules (granulated products). In this case, the granules (granulated products) containing each component can be prepared separately. Granulation can be either wet or dry.

[0109] As the obtained granules (granulated products) or by blending additives into the granules, tablets can be produced by tableting and molding, and these can be further film-coated.

[0110] (Dissolution improver) In a third embodiment, at least selected from the group consisting of ibuprofen and its salts (I) At least one selected from the group consisting of tipepidine and its salts, including one of the following: (II) comprising at least one selected from the group consisting of tranexamic acid and its salts, An agent for improving the dissolution properties of tipepidine in solid compositions is provided.

[0111] For at least one selected from the group consisting of ibuprofen and its salts, As explained in component (C) of the solid composition relating to the application form, the above component (I) and Regarding (II), see components (A) and (B) of the solid composition according to this embodiment. As I have explained.

[0112] The dissolution improving agent is defined as the amount of ibuprofen added to component (I) or (II) as follows: The preferred content of component (C) of the solid composition relating to the application form is within the range described. It is preferable to use it in a certain amount. Also, ibuprofen does not crystallize with tranexamic acid. It may be added to a solid composition (in a non-crystallized state).

[0113] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. It is not something that should be done. [Examples]

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

[0115] 2. Preparation of the solid composition (Reference example 1) Weighed out tipiprazine hibenzate and crystalline cellulose according to the weighed amounts in Table 1, and sieved them through a 30-mesh sieve. Then, they were mixed 100 times in a 4K standard bottle to obtain a mixture. After sieving, the mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts in Table 1.

[0116] (Reference Example 2, Comparative Example 1, Example 1) After sieving, the mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts in Table 1. A mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts 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 placed in a stirring container and mixed. Then, 3.0 ml of 90% ethanol was added and kneaded for 10 minutes. The obtained wet granules were dried at 60°C for 1 hour to obtain granules of crystals composed of ibuprofen and tranexamic acid. A mixture was obtained in the same manner as in Reference Example 1, except that the granules obtained according to the weighed amounts in Table 1 were used. After sieving, the mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts in Table 1. After sieving, the mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts in Table 1. After sieving, the mixture was obtained in the same manner as in Reference Example 1, except that ibuprofen and / or tranexamic acid were used according to the weighed amounts in Table 1. A mixture was obtained in the same manner as in Reference Example 1, except that the granules obtained according to the weighed amounts in Table 1 were used.

[0118] In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1. In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1. In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1. In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1. In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1. In addition, the obtained 6 mg of granules were placed in an aluminum pan, and measured in the range of 25 to 250°C at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (manufactured by Mettler Toledo). The results are shown in Figure 1. As shown in Figure 1, the peak derived from ibuprofen near 75°C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid near 180°C. Therefore, it was confirmed that the prepared granules contained crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1.

[0119] The compounding amounts (g) of each sample are shown in the following table. In the following table, the granules produced in Example 2 contain crystals composed of ibuprofen and tranexamic acid. The compounding amounts (g) of each sample are shown in the following table. In the following table, the granules produced in Example 2 contain crystals composed of ibuprofen and tranexamic acid.

Table 2

[0120] 3. Measurement of elution properties of solid compositions The elution properties of tipepidine in the prepared samples were evaluated as follows. Specifically, In accordance with the "Dissolution Test Method (Paddle Method)" described in the 18th Revised Japanese Pharmacopoeia, a dissolution tester (NTR) was used. The tests were conducted at a 6400AC (Toyama Sangyo Co., Ltd.). The various mixtures of the prepared samples are listed in Table 1. The test sample was weighed out in the specified volume. The weighed test sample was added to 900 mL of water test solution, and then padded. The test was performed at 100 revolutions per minute using the method, and the solution of tipepidine was measured 15 minutes and 30 minutes after the start of the test. The discharge rate was evaluated. The results are shown in Table 3. As shown in Table 3, tipepidine hibenzate and By combining ibuprofen with ranexamic acid, the dissolution rate of tipepidine was improved.

[0121] The elution rate of tipepidine was measured by spectrophotometric analysis using a standard solution of known concentration. Absorbance was measured at wavelengths of 286 nm and 360 nm, and background signals were removed. To do this, the concentration was calculated using the value obtained by subtracting the absorbance at 360 nm from the absorbance at 286 nm. Ta.

[0122] [Table 3]

[0123] Examples of solid dosage forms are shown below.

[0124] [Table 4]

[0125] [Table 5]

[0126] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. This does not mean adding, omitting, substituting, or otherwise modifying the configuration without departing from the spirit of the present invention. It is possible to change this.

Claims

1. A tipepidine dissolution improver in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and its salts, and (II) at least one selected from the group consisting of tranexamic acid and its salts, A dissolution-improving agent comprising at least one selected from the group consisting of ibuprofen and its salts.

2. The dissolution improving agent according to claim 1, wherein the mass ratio of the total amount of component (I) to the total amount of component (II) in the solid composition is 1:3 to 1:25 ((I):(II)).

3. The dissolution improving agent according to claim 1 or 2, wherein the solid composition comprises crystals composed of ibuprofen and tranexamic acid.

4. The dissolution improving agent according to claim 3, wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:

1.

5. The dissolution improving agent according to claim 1 or 2, wherein at least one selected from the group consisting of ibuprofen and its salts is contained in a state that does not form crystals with at least one selected from the group consisting of tranexamic acid and its salts.

6. The dissolution improving agent according to claim 1 or 2, 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 18th edition of the Japanese Pharmacopoeia, is 30% or more.

7. A method for improving the elution properties of tipepidine in a solid composition comprising (I) at least one selected from the group consisting of tipepidine and its salts, and (II) at least one selected from the group consisting of tranexamic acid and its salts, A method comprising adding at least one selected from the group consisting of ibuprofen and its salts to the solid composition.

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