Solid composition, ibuprofen dissolution improver, and method for improving dissolution.

Abstract

To provide a solid composition containing ibuprofen with improved dissolution properties. [Solution] A solid composition comprising (A) ibuprofen and (B) at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof (excluding (i) a solid composition that does not contain dextromethorphan or a salt thereof and in which ibuprofen and noscapine or a salt thereof exist as different granules, and (ii) a solid composition that does not contain noscapine or a salt thereof and in which ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid).

Description

[Technical Field]

[0001] The present invention broadly relates to a solid composition comprising ibuprofen and at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, and to an ibuprofen dissolution improver comprising at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof as an active ingredient. [Background technology]

[0002] Ibuprofen is widely used as a nonsteroidal antipyretic analgesic. However, because ibuprofen is poorly water-soluble, efforts are being made to improve its dissolution properties. Known methods for improving ibuprofen dissolution include, for example, altering the pH and incorporating water-soluble polymer bases and nonionic surfactants.

[0003] Patent Document 1 discloses an easily absorbable solid composition comprising 1 part by weight of ibuprofen, 0.01 to 10 parts by weight of a water-soluble polymer base, and 0.01 to 5 parts by weight of a nonionic surfactant.

[0004] Patent Document 2 discloses an ibuprofen-containing preparation comprising ibuprofen, polyvinylpyrrolidone or copovidone, sodium lauryl sulfate, and disodium hydrogen phosphate or smectite. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2000-095682 [Patent Document 2] Japanese Patent Publication No. 2011-136922 [Overview of the project] [Problems that the invention aims to solve]

[0006] Solid compositions containing ibuprofen still have room for improvement in terms of dissolution properties. The present invention aims to provide a solid composition containing ibuprofen with improved dissolution properties, or an ibuprofen dissolution improver. [Means for solving the problem]

[0007] The inventors of the present invention have discovered that the dissolution properties of ibuprofen are improved by combining it with at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof, and have completed the present invention.

[0008] In other words, this application encompasses the following inventions. [1] The following ingredients: (A) Ibuprofen and (B) At least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, Solid compositions containing (however, excluding (i) solid compositions that do not contain dextromethorphan or a salt thereof and in which ibuprofen and noscapine or a salt thereof exist as different granules, and (ii) solid compositions that do not contain noscapine or a salt thereof and in which ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid). [2] (C) Tranexamic acid The solid composition according to [1] further comprises: [3] The solid composition according to [2], comprising crystals consisting of (A) ibuprofen and (C) tranexamic acid. [4] The solid composition according to [3], wherein the molar ratio of (A) ibuprofen to (C) tranexamic acid in the crystal is 1:1. [5] A solid composition according to any one of [1] to [4], wherein the dissolution rate of ibuprofen 60 minutes after the start of the test, when an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, is 45% or more. [6] (D) At least one selected from the group consisting of glycine, talc, anhydrous caffeine, and tipepidine The solid composition according to any one of [1] to [5], further comprising [7] An elution improver for ibuprofen, comprising at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof as an active ingredient. [8] The elution improver according to [7], wherein the active ingredient is at least one selected from the group consisting of noscapine and salts thereof. [9] The elution improver according to [7], wherein the active ingredient is at least one selected from the group consisting of dextromethorphan and salts thereof.

[10] When ibuprofen is blended in an equal amount and an elution test is performed by the elution test method of the 18th revised Japanese Pharmacopoeia, the elution rate of ibuprofen 60 minutes after the start of the test is 1.2 times or more based on the elution rate of ibuprofen 60 minutes after the start of the test when ibuprofen and lactose are blended in an equal amount and the elution test is performed by the elution test method (the elution test method of the 18th revised Japanese Pharmacopoeia). The elution improver according to any one of [7] to [9].

[11] A method for improving the elution property of a solid composition containing ibuprofen, comprising adding at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof to the solid composition. [Effect of the Invention]

[0009] According to the present invention, a solid composition containing ibuprofen with improved elution property or an elution improver for ibuprofen can be provided. [Brief Description of the Drawings]

[0010] [Figure 1] Shows the results of differential scanning calorimetry (DSC) in the crystal of ibuprofen and tranexamic acid. [Figure 2] Measurement results of the dissolution rate of ibuprofen. "*" indicates that there was a significant difference at a significance level of p < 0.01 compared to Comparative Example 1. [Figure 3] Measurement results of the dissolution rate of ibuprofen. [Figure 4] Measurement results of the dissolution rate of ibuprofen.

Mode for Carrying Out the Invention

[0011] Hereinafter, embodiments of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not construed as being limited to the following embodiments. In the present embodiment, the composition can contain each component alone or in combination of two or more. In this specification, "~" indicating a numerical range represents above and below, and includes both end values.

[0012] (Solid composition) In a first aspect, the following components: (A) Ibuprofen and, (B) At least one selected from the group consisting of noscapine, dextromethorphan, and their salts, A solid composition containing (however, excluding (i) a solid composition in which dextromethorphan or its salt is not contained and ibuprofen and noscapine or its salt are present as different granules, and (ii) a solid composition containing noscapine or its salt and a polymer and an organic acid or acidic amino acid that form a hydrogel with ibuprofen and dextromethorphan or its salt). Is provided. The solid composition is specifically a solid pharmaceutical composition.

[0013] Each component contained in the solid composition according to this embodiment may be included in the form of a pharmaceutically acceptable salt, or it may be included as a complex with other components. That is, the solid composition according to this embodiment may contain salts of not only component (B), but also component (A) and other components. "Pharmacologically acceptable salt" includes, for example, salts with pharmaceutically acceptable bases or acids. Non-specific examples of pharmacologically acceptable salts include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids. Pharmacologically acceptable salts may be hydrated or anhydrous.

[0014] (A) Ibuprofen As used herein, "ibuprofen" refers to the CAS registry number 15687-27-1, C 13 H 18 It is a compound represented by the chemical formula O2. Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic drugs. The salts of ibuprofen are not particularly limited as long as they are pharmacologically acceptable.

[0015] The amount of ibuprofen included in the solid composition is adjusted as appropriate depending on the intended use of ibuprofen in the solid composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen administered to adults can be adjusted to a range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In this embodiment, "adult" means men and women aged 15 years or older. However, the solid composition according to this embodiment is not limited to use by adults, but may also be used by children under 15 years of age. When used by children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount taken by adults per day, depending on the age group. The same applies to ingredients other than ibuprofen.

[0016] The above dosages are examples, and the ibuprofen content per solid composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0017] In one embodiment, the ibuprofen content in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0018] The weight and dosage of the solid composition described above are for a day, but the same amount may be administered to the subject in one dose, or divided into multiple doses per day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose and the dosage form of the solid composition.

[0019] In a particular embodiment, the solid composition is a tablet, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0020] (B) At least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof. As used herein, "noscapine" refers to the noscapine with CAS Registry Number 128-62-1, C 22 H 23 It is a compound represented by the chemical formula NO7. Noscapine is used as an active ingredient in cough suppressants and other medications. The salts of noscapine are not particularly limited as long as they are pharmacologically acceptable, but noscapine hydrochloride is an example.

[0021] As used herein, "dextromethorphan" refers to the CAS registry number 125-71-3, C 18 H 25 It is a compound represented by the chemical formula NO. Dextromethorphan is used as an active ingredient in cough suppressants and other medications. Salts of dextromethorphan are not particularly limited as long as they are pharmacodynamically acceptable, but examples include dextromethorphan hydrobromide hydrate and dextromethorphan phenolphthalein salt.

[0022] The solid composition according to this embodiment has improved ibuprofen dissolution by including at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof. The solid composition according to this embodiment may include either at least one selected from the group consisting of noscapine and salts thereof, or at least one selected from the group consisting of dextromethorphan and salts thereof, or it may include both at least one selected from the group consisting of noscapine and salts thereof, and at least one selected from the group consisting of dextromethorphan and salts thereof.

[0023] In this specification, improved ibuprofen dissolution means that the dissolution rate of ibuprofen is improved compared to a solid composition containing ibuprofen alone; a solid composition containing ibuprofen but without at least one selected from the group consisting of component (B) noscapine, dextromethorphan, and their salts; or a solid composition containing the same components as the solid composition being evaluated for dissolution, except that it does not contain at least one selected from the group consisting of component (B) noscapine, dextromethorphan, and their salts, or contains the same amount of other control components instead of at least one selected from the group consisting of component (B) noscapine, dextromethorphan, and their salts. The dissolution rate of ibuprofen may be measured after a predetermined time has elapsed since the start of the dissolution test, for example, the dissolution rate of ibuprofen 60 minutes after the start of the test. The control component may be, for example, lactose.

[0024] In this embodiment, the dissolution of ibuprofen may be measured, for example, by a method described in the "Dissolution Test Methods" of the 18th edition of the Japanese Pharmacopoeia. Specifically, it can be evaluated according to methods such as the paddle method, rotating basket method, and flow-through cell method described in the "Dissolution Test Methods" of the 18th edition of the Japanese Pharmacopoeia. In the dissolution test, the amount of ibuprofen dissolved in a predetermined test solution is quantified. More specifically, it may be measured using the method for measuring the dissolution rate of ibuprofen described in the examples.

[0025] In the solid composition according to this embodiment, the dissolution rate of ibuprofen 60 minutes after the start of the dissolution test, when the above-described dissolution test is performed, is preferably 45% or more, more preferably 48% or more, even more preferably 50% or more, even more preferably 60% or more, and particularly preferably 70% or more. The upper limit of the dissolution rate is not particularly limited, but the dissolution rate may be, for example, 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 85% or less, or 80% or less.

[0026] From the viewpoint of further improving the dissolution of ibuprofen in the solid composition according to this embodiment, it is preferable that at least one selected from the group consisting of (B) noscapine, dextromethorphan, and salts thereof is included in the same granule as (A) ibuprofen. That is, it is preferable that the solid composition according to this embodiment includes granules obtained by granulating a mixed powder containing (A) ibuprofen and (B) noscapine, dextromethorphan, and salts thereof. The solid composition according to this embodiment may be a tablet obtained by compressing the granules said to be the granules. From a similar viewpoint, the solid composition according to this embodiment is preferably a tablet produced by a direct compression method in which a mixed powder containing (A) ibuprofen and (B) at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof is directly compressed into a tablet. Alternatively, it may be a powder obtained by dissolving (A) ibuprofen and (B) at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof in a solvent and drying off the solvent, and a tablet obtained by optionally granulating the powder and then compressing it into a tablet. In such embodiments, components (A) and (B) are in close proximity in the solid composition, and the dissolution of ibuprofen tends to be further improved.

[0027] Improved dissolution may also improve the pharmacokinetic profile of ibuprofen. Pharmacokinetics include blood dynamics such as absorption. As used herein, "blood dynamics" refers to pharmacokinetics in the blood circulation, i.e., the dynamics (absorption and distribution, etc.) and elimination (metabolism and excretion, etc.) of ibuprofen administered to an individual over time in the blood circulation, and is evaluated using indicators such as the change in blood drug concentration over time (PK) or blood exposure (AUC), drug elimination half-life (t1 / 2), peak blood concentration (Cmax), and time to reach peak blood concentration (Tmax). Such evaluations are performed by comparing the composition with a solid composition that is identical except that it does not contain at least one selected from the group consisting of component (B) noscapine, dextromethorphan, and their salts, or with a composition containing only ibuprofen.

[0028] Improvements in hemokinetics include shortening the time to reach peak blood concentration (time to peak concentration; Tmax), increasing the peak blood concentration of the drug (Cmax), suppressing the decrease in blood drug concentration over time (prolongation of PK), increasing blood exposure (AUC), and prolonging the drug elimination half-life (t1 / 2).

[0029] The amount of at least one component selected from the group consisting of component (B) noscapine, dextromethorphan, and their salts is appropriately adjusted according to the intended use of the solid composition, the required degree of antitussive effect, the required degree of dissolution, the symptoms of the recipient, age, weight, sex, etc. The amount and content of at least one component selected from the group consisting of noscapine and its salts, and at least one component selected from the group consisting of dextromethorphan and its salts, may be adjusted independently. The amount and content of at least one component selected from the group consisting of noscapine and its salts may be the amount and content in terms of noscapine equivalent of the total of noscapine and noscapine salts. Similarly, the amount and content of at least one component selected from the group consisting of dextromethorphan and its salts may be the amount and content in terms of dextromethorphan equivalent of the total of dextromethorphan and dextromethorphan salts.

[0030] The amount of at least one substance selected from the group consisting of noscapine and its salts varies depending on the amount of ibuprofen, etc., but the daily amount of noscapine can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0031] The amount of at least one substance selected from the group consisting of dextromethorphan and its salts varies depending on the amount of ibuprofen, etc., but the daily amount of dextromethorphan can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0032] At least one selected from the group consisting of noscapine and its salts contained in the solid composition administered daily is, for example, 0.0001 to 1 part by mass, preferably 0.0001 to 0.6 parts by mass, and more preferably 0.0003 to 0.3 parts by mass, per 1 part by mass of ibuprofen, in terms of noscapine.

[0033] At least one selected from the group consisting of dextromethorphan and its salts contained in the solid composition administered daily is, for example, 0.0001 parts by mass to 1 part by mass, preferably 0.0001 parts by mass to 0.6 parts by mass, and more preferably 0.0003 parts by mass to 0.3 parts by mass, per 1 part by mass of ibuprofen, in terms of dextromethorphan.

[0034] In this embodiment, (i) solid compositions that do not contain dextromethorphan or a salt thereof and in which ibuprofen and noscapine or a salt thereof exist as different granules, and (ii) solid compositions that do not contain noscapine or a salt thereof and in which ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid are excluded from the present invention.

[0035] For example, solid compositions in which ibuprofen and noscapine or a salt thereof exist as different granules may be excluded from the present invention, oral formulations containing ibuprofen particles and particles containing noscapine or a salt thereof may be excluded, more specifically oral formulations manufactured by the following methods may be excluded, and the invention described in International Publication No. 1996 / 033704 may be excluded. (1) A method of separately manufacturing particles containing ibuprofen and particles containing noscapine or a salt thereof, and then mixing these particles. (2) A method of compressing the mixture obtained by the method of (1) above into tablets. (3) A method of forming two-layer or multi-layer tablets by alternately stacking each particle obtained by the method in (1) above using a tablet stacking machine. (4) A method of forming a sandwich-type tablet in which a thin buffer layer is provided between each particle layer of a multi-layer tablet manufactured by the method of (3) above.

[0036] The invention described in International Publication No. 1996 / 033704 aims to improve the dissolution of bromhexine hydrochloride, ambroxol hydrochloride, and noscapine by compounding a mixture of particles containing ibuprofen and particles containing one or more of bromhexine hydrochloride, ambroxol hydrochloride, and noscapine. The solid composition according to this embodiment aims to improve the dissolution of ibuprofen, and it is preferable that ibuprofen and at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof are in close proximity.

[0037] Furthermore, the present invention may exclude solid compositions comprising ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid; solid formulations comprising ibuprofen, dextromethorphan or a salt thereof, a release control agent that controls the release of dextromethorphan or a salt thereof (for example, a polymer that forms a hydrophilic hydrogel), and an organic acid or an acidic amino acid; solid formulations comprising ibuprofen, dextromethorphan or a salt thereof, and an organic acid or an acidic amino acid; and the invention described in Japanese Patent Application Publication No. 2018-039792. Here, examples of organic acids include citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, and succinic acid, and examples of acidic amino acids include L-carbocysteine, aspartic acid, and glutamic acid.

[0038] The invention described in Japanese Patent Publication No. 2018-039792 aims to control the release of an amino group-containing compound so that it does not depend on pH by incorporating an organic acid or an acidic amino acid, assuming that the compound contains a release control base. The solid composition according to this embodiment can provide a solid composition containing ibuprofen with improved elution properties even without including such a release control base or an organic acid or an acidic amino acid.

[0039] (C) Tranexamic acid The solid composition according to this embodiment may further contain (C) tranexamic acid. When the solid composition according to this embodiment contains (C) tranexamic acid, the dissolution of ibuprofen tends to be further improved. In other words, in this embodiment, even when (C) tranexamic acid is included, the dissolution of ibuprofen is further improved by including at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof.

[0040] When the solid composition according to this embodiment contains (C) tranexamic acid, the dissolution rate of ibuprofen 60 minutes after the start of the dissolution test performed as described above is preferably 50% or more, more preferably 60% or more, even more preferably 70% or more, and even more preferably 75% or more. The upper limit of the dissolution rate is not particularly limited, but the dissolution rate may be, for example, 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 85% or less, or 80% or less.

[0041] As used herein, "tranexamic acid" refers to the C8H compound with CAS registry number 1197-18-8. 15 It is a compound represented by the chemical formula NO2. Tranexamic acid is used as an active ingredient in anti-inflammatory drugs and other medications. The salts of tranexamic acid are not particularly limited as long as they are pharmacologically acceptable.

[0042] The amount of tranexamic acid is appropriately adjusted according to the intended use of the solid composition, the required degree of anti-inflammatory effect, the required degree of dissolution, the symptoms of the recipient, age, weight, sex, etc. The amount of tranexamic acid varies depending on the amount of ibuprofen, etc., but for example, the daily amount can be adjusted in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0043] The tranexamic acid content in the solid composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass. The amount of tranexamic acid contained in the solid composition administered daily is, for example, 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass, and more preferably 0.7 to 2.2 parts by mass, per 1 part by mass of ibuprofen.

[0044] The solid composition according to this embodiment may contain crystals composed of (A) ibuprofen and (C) tranexamic acid. That is, if the solid composition according to this embodiment contains (C) tranexamic acid, (A) ibuprofen and (C) tranexamic acid may form crystals.

[0045] In a crystal composed of (A) ibuprofen and (C) tranexamic acid, (A) ibuprofen and (C) tranexamic acid may exist in a 1:1 molar ratio. Furthermore, in the crystal, ibuprofen and tranexamic acid may form a crystalline unit cell of four molecules each.

[0046] In the crystal, hydrogen bonds may be formed between the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid, and between the carboxylic acid group of ibuprofen and the amino group of tranexamic acid.

[0047] The crystal may have an endothermic peak around 180°C in differential scanning calorimetry (DSC). "Around 180°C" may refer to a range such as 180°C ± 20°C or 180°C ± 10°C. Note that the fusion heat peak around 75°C, characteristic of ibuprofen, may disappear in the DSC of the crystal.

[0048] The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674, and may have the X-ray diffraction pattern shown in Figure 2 of the same publication. The crystal may have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in its X-ray diffraction pattern.

[0049] Crystals comprising (A) ibuprofen and (C) tranexamic acid can be produced, for example, by the method described in Japanese Patent Publication No. 2022-70674.

[0050] The solid composition according to this embodiment tends to have improved ibuprofen dissolution properties by including crystals consisting of (A) ibuprofen and (C) tranexamic acid.

[0051] In one embodiment, the solid composition according to this embodiment comprises (A) ibuprofen, (B) at least one selected from the group consisting of noscapine and its salts, and (C) tranexamic acid. In another embodiment, the solid composition according to this embodiment comprises (A) ibuprofen, (B) at least one selected from the group consisting of noscapine and its salts, and (C) tranexamic acid, but does not contain at least one selected from the group consisting of dextromethorphan and its salts. In these embodiments, (A) ibuprofen and (C) tranexamic acid may form crystals as described above.

[0052] In one embodiment, the solid composition according to this embodiment contains (A) ibuprofen, at least one selected from the group consisting of (B) dextromethorphan and its salts, and (C) tranexamic acid. In one embodiment, the solid composition according to this embodiment contains (A) ibuprofen, at least one selected from the group consisting of (B) dextromethorphan and its salts, and (C) tranexamic acid, and may not contain at least one selected from the group consisting of noscapine and its salts. In these embodiments, (A) ibuprofen and (C) tranexamic acid may form crystals as described above.

[0053] (D) Glycine, talc, anhydrous caffeine, and tipepidine The solid composition according to this embodiment may further contain at least one selected from the group consisting of (D) glycine, talc, anhydrous caffeine, and tipepidine. These components may be included singly or in combination of two or more.

[0054] As used herein, "glycine" is a compound having a CAS registration number of 56-40-6 and represented by the chemical formula C2H5NO2. The salts of glycine are not particularly limited as long as they are pharmaceutically acceptable.

[0055] As used herein, "talc" has a CAS registration number of 14807-96-6 and is a compound represented by the chemical formula Mg3Si4O 10 (OH)2.

[0056] As used herein, "anhydrous caffeine" has a CAS registration number of 58-08-2 and is a compound represented by the chemical formula C8H 10 N4O2. The salts of anhydrous caffeine are not particularly limited as long as they are pharmaceutically acceptable.

[0057] As used herein, "tipepidine" has a CAS registration number of 5169-78-8 and is C 15 H 17It is a compound represented by the chemical formula NS2. The salts of tipepidine are not particularly limited as long as they are pharmacologically acceptable, but examples include tipepidine hibenzate and tipepidine citrate.

[0058] The amounts of component (D) glycine, talc, anhydrous caffeine, and tipepidine are adjusted as appropriate depending on the intended use of the solid composition, the symptoms of the recipient, age, weight, sex, etc. The amounts of glycine, talc, anhydrous caffeine, and tipepidine may be adjusted independently of each other.

[0059] The amount of glycine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 900 mg, preferably 16 mg to 300 mg.

[0060] The amount of talc included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0061] The amount of anhydrous caffeine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 150 mg, preferably 16 mg to 80 mg.

[0062] The amount of tipepidine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0063] The amount of glycine contained in the solid composition administered daily is, for example, 0 to 10 parts by mass, 0.0001 to 1 part by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0064] The amount of talc contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0065] The amount of anhydrous caffeine contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0066] The amount of tipepidine contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0067] In one embodiment, the solid composition according to this embodiment comprises (A) ibuprofen, (B) at least one selected from the group consisting of noscapine and its salts, (C) tranexamic acid, and (D) talc. In this embodiment, (A) ibuprofen and (C) tranexamic acid may form crystals as described above.

[0068] In one embodiment, the solid composition according to this embodiment comprises (A) ibuprofen, (B) at least one selected from the group consisting of dextromethorphan and its salts, (C) tranexamic acid, and (D) glycine. In this embodiment, (A) ibuprofen and (C) tranexamic acid may form crystals as described above.

[0069] (Other ingredients) The solid composition according to this embodiment may contain components other than those described above, depending on its intended use. When the solid composition is used to alleviate various symptoms of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, or other pharmacologically acceptable components.

[0070] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into COX-2 nonselective inhibitors such as diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and COX-2 selective inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be included in the composition as a NSAID. It is preferable that the NSAID is a COX-2 nonselective inhibitor. The NSAID may also be in the form of a salt (including a hydrated salt).

[0071] Other pharmacologically acceptable ingredients that may be added include antihistamines, antipyretic analgesics, cough and expectorant agents, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly found in combination cold medicines, antipyretic analgesics, and rhinitis medicines.

[0072] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, and mequitazine.

[0073] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine. Acetaminophen may be included in the composition as an antipyretic analgesic.

[0074] Examples of cough suppressants and expectorants include bromhexine, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0075] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0076] Examples of central nervous system stimulants include caffeine.

[0077] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, and so on.

[0078] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, and total belladonna root alkaloid citrate.

[0079] Pharmaceutical additives may be added to the solid composition according to this embodiment as needed. Examples of pharmaceutical additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents / fragrances. Pharmaceutical additives that are conventionally known and can be used in solid formulations can be used for the above purposes.

[0080] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose monohydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0081] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0082] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0083] Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0084] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0085] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0086] Examples of moisture-proofing agents include ethylcellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined sucrose, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

[0087] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0088] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, disodium calcium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and salts. Ferric acid, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, anhydrous sodium carbonate, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, chondrone Sodium leutin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, 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 Tearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.)Examples include polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0089] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, and sodium pyrosulfite. In the case of a solid composition containing acetaminophen, it is preferable not to include tocopherols as antioxidants or stabilizers.

[0090] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0091] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, and erythritol.

[0092] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-tartaric acid Examples include sodium glycyrrhizate, ginger powder, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, porcini powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0093] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0094] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0095] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili pepper powder, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0096] Examples of coloring agents include yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, dizazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc.

[0097] The base ingredients include acacia gum powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer, concentrated glycerin, potato starch, hydroxy Examples include propylcellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0098] Examples of coating agents include: ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium dioxide / macrogol 400 mixture, hypromellose, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydro Examples include oxypropylmethylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0099] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0100] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, and liquid paraffin.

[0101] The dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0102] Examples of defoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid esters, silicone defoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0103] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0104] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, Vitabase, cedarwood oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flakes powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0105] These components may be present individually or in combination of two or more types.

[0106] (Dosage form) The solid composition according to this embodiment can be in dosage forms described in the 18th edition of the Japanese Pharmacopoeia, General Provisions for Pharmaceutical Preparations, etc., such as oral preparations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders), or preparations applied orally (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition according to this embodiment is preferably an oral solid composition.

[0107] Dosage forms of the solid composition according to this embodiment include, for example, tablets, capsules, pills, granules, and fine granules. These solid compositions may be coated by known methods such as sugar coating or film coating as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets.

[0108] The solid composition according to this embodiment may be initially packaged in bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored airtight. Furthermore, they may be pillow-packaged, or stored in boxes or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, polyethylene film, or these resin films with aluminum foil attached can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle packaging or pillow packaging.

[0109] The solid composition according to this embodiment may be contained in a packaging container to form a package. The solid composition according to this embodiment may be contained in, for example, an airtight package. By forming a package, the convenience of use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0110] As for the packaging form of the solid composition, the solid composition may be initially packaged in a bottle, PTP (Press Through Package), pouch, stick, or SP (Strip Package) and stored airtight. Furthermore, these may be pillow-packed, or stored in a box or similar container. In addition, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be stored simultaneously in the packaging container, such as the bottle or pillow packaging.

[0111] Materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as resin films to which aluminum foil is attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0112] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Examples of such packaging include packaging formed from at least one of a moisture-proof material and a gas barrier material.

[0113] Examples of moisture-proof materials include a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. Furthermore, when the solid composition is a tablet, PTP packaging with aluminum on both sides (Al-Al packaging) may be used as a moisture-proof material, considering factors such as suppressing the rise in moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0114] Known materials may be used as the gas barrier material, for example, a laminate film having a functional barrier layer, and may be used to serve the same purpose as the moisture barrier material, or in combination with the moisture barrier material.

[0115] Furthermore, the packaging containers may be made environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used in part or all of the packaging materials.

[0116] (Manufacturing method) In a second embodiment, a method for producing a solid composition is provided, comprising the step of contacting (A) ibuprofen with (B) at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof.

[0117] A method for producing a solid composition may further include the steps of contacting (C) tranexamic acid with at least one selected from the group consisting of (A) ibuprofen and (B) noscapine, dextromethorphan, and salts thereof, or contacting at least one selected from the group consisting of (A) ibuprofen and (B) noscapine, dextromethorphan, and salts thereof with at least one selected from the group consisting of (D) glycine, talc, anhydrous caffeine, and tipepidine.

[0118] The production of the solid composition can be carried out using known techniques. Each component is added in any step and finally brought into contact with each other. A solvent and a binder may be added to the mixture after contact and kneaded, and the resulting paste may be used as the solid composition.

[0119] Crystals comprising (A) ibuprofen and (C) tranexamic acid may be produced in accordance with a method for producing a mixture containing both components, as described in Japanese Patent Publication No. 2022-40057.

[0120] The resulting mixture can be further subjected to drying and granulation processes to produce granules (granulated material). In this case, granules (granulated material) containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0121] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0122] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the section on "Tablets" in the General Provisions of the Japanese Pharmacopoeia. Specifically, a mixed powder containing at least (A) ibuprofen and (B) noscapine, dextromethorphan, and their salts may be granulated to obtain granules, and then tablets may be manufactured by compressing the obtained granules and appropriate extragranular components into tablets. Alternatively, a mixed powder containing (A) ibuprofen may be granulated to obtain a first granule, a mixed powder containing at least one selected from the group consisting of (B) dextromethorphan and its salts may be granulated to obtain a second granule, and then tablets may be manufactured by compressing these two types of granules and appropriate extragranular components into tablets. From the viewpoint of improving the dissolution of ibuprofen, it is preferable to form granules by granulating a mixed powder containing (A) ibuprofen and (B) noscapine, dextromethorphan, and their salts, and to include both components in the same granule.

[0123] When the solid composition contains extragranular components, tablets may be manufactured by adding the final components to the granulated granules so as to form an outer layer of granulated granules, and then compressing the mixture into tablets. The extragranular components may also be in granular form. For example, a first granule may be manufactured containing (A) ibuprofen and (B) noscapine, dextromethorphan, and their salts, and a second granule may be manufactured containing other active ingredients. In this case, the first granule containing (A) ibuprofen and (B) noscapine, dextromethorphan, and their salts, and the second granule containing other active ingredients may be prepared separately, and the solid composition may be manufactured so that the components in the first granule and the other active ingredients in the second granule do not substantially come into contact. The other active ingredients may be included in the first granule or in the second granule so as to obtain a suitable formulation.

[0124] The granules obtained in the above process may be used as is as a granular material.

[0125] (Dissolution improving agent) In a third embodiment, an ibuprofen dissolution enhancer (hereinafter also simply referred to as "dissolution enhancer") is provided, comprising at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, as an active ingredient. Ibuprofen dissolution improvers are added, for example, to ibuprofen or a solid composition containing ibuprofen, and more specifically, to a solid pharmaceutical composition containing ibuprofen. From this perspective, in this specification, ibuprofen dissolution improvers may also be described as agents for improving the dissolution of ibuprofen in a solid composition containing ibuprofen, and agents for improving the dissolution of a solid composition containing ibuprofen.

[0126] In this embodiment, each component contained in the dissolution improver, and each component contained in the solid composition to which the dissolution improver is added, may be contained in the form of a pharmaceutically acceptable salt, or as a complex with other components. That is, in this embodiment, components other than noscapine and dextromethorphan may also be contained as salts. "Pharmacologically acceptable salt" includes, for example, salts with pharmaceutically acceptable bases or acids. Non-limiting specific examples of pharmaceutically acceptable salts are as described above.

[0127] (At least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof) The dissolution improving agent according to this embodiment can improve the dissolution of ibuprofen in a solid composition containing ibuprofen by including at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof. The dissolution improving agent according to this embodiment may include either at least one selected from the group consisting of noscapine and salts thereof, or at least one selected from the group consisting of dextromethorphan and salts thereof, or it may include both at least one selected from the group consisting of noscapine and salts thereof, and at least one selected from the group consisting of dextromethorphan and salts thereof.

[0128] In one embodiment, the dissolution improving agent according to this embodiment may include at least one selected from the group consisting of noscapine and its salts, and may be at least one selected from the group consisting of noscapine and its salts. In another embodiment, the dissolution improving agent according to this embodiment may include at least one selected from the group consisting of dextromethorphan and its salts, and may be at least one selected from the group consisting of dextromethorphan and its salts. In yet another embodiment, the dissolution improving agent according to this embodiment may include at least one selected from the group consisting of noscapine, dextromethorphan, and their salts, and may be at least one selected from the group consisting of noscapine, dextromethorphan, and their salts.

[0129] In this specification, when we say that the dissolution improving agent according to this embodiment improves the dissolution of ibuprofen, we mean that the dissolution rate of ibuprofen is improved by adding the dissolution improving agent according to this embodiment compared to a solid composition containing ibuprofen but without at least one selected from the group consisting of noscapine, dextromethorphan, and their salts; or a solid composition containing the same components as the solid composition whose dissolution is being evaluated, except that it does not contain at least one selected from the group consisting of noscapine, dextromethorphan, and their salts, or contains the same amount of other control components instead of at least one selected from the group consisting of noscapine, dextromethorphan, and their salts. The dissolution rate of ibuprofen may be measured after a predetermined time has elapsed since the start of the dissolution test, for example, the dissolution rate of ibuprofen 60 minutes after the start of the test. The control component may be, for example, lactose. In this embodiment, the dissolution of ibuprofen may be measured as described above.

[0130] The dissolution improving agent according to this embodiment, when combined with ibuprofen in an equal amount (by mass ratio), may improve the dissolution rate of ibuprofen 60 minutes after the start of the dissolution test, when performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, by, for example, 1.1 times or more, preferably 1.2 times or more, more preferably 1.3 times or more, even more preferably 1.4 times or more, and even more preferably 1.5 times or more. Here, the dissolution improving agent may be combined with ibuprofen in an amount (by mass ratio) equal to that of an active ingredient selected from the group consisting of noscapine, dextromethorphan, and salts thereof.

[0131] The dissolution improving agent according to this embodiment may improve the dissolution rate of ibuprofen 60 minutes after the start of a dissolution test, when an equivalent amount (by mass ratio) of ibuprofen is added to a solid composition containing ibuprofen, by, for example, 1.1 times or more, preferably 1.2 times or more, more preferably 1.3 times or more, even more preferably 1.4 times or more, and even more preferably 1.5 times or more, when an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia. Here, the dissolution improving agent may be formulated so that the active ingredient, which is at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, is equivalent (by mass ratio) to ibuprofen.

[0132] When the dissolution improving agent according to this embodiment is mixed with ibuprofen in an equal amount (by mass ratio) and an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of ibuprofen 60 minutes after the start of the test may be, for example, 1.1 times or more, preferably 1.2 times or more, more preferably 1.3 times or more, even more preferably 1.4 times or more, and even more preferably 1.5 times or more, based on the dissolution rate of ibuprofen when ibuprofen and lactose are mixed in an equal amount (by mass ratio) and a similar dissolution test is performed. Here, the dissolution improving agent may be mixed with ibuprofen in an amount (by mass ratio) equal to that of an active ingredient selected from the group consisting of noscapine, dextromethorphan, and salts thereof.

[0133] When an ibuprofen-containing solid composition is mixed with the dissolution-improving agent according to this embodiment in an equal amount (by mass ratio) with ibuprofen and an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of ibuprofen 60 minutes after the start of the test may be, for example, 1.1 times or more, preferably 1.2 times or more, more preferably 1.3 times or more, even more preferably 1.4 times or more, and even more preferably 1.5 times or more, based on the dissolution rate of ibuprofen when the ibuprofen-containing solid composition is mixed with lactose in an equal amount (by mass ratio) with ibuprofen and a similar dissolution test is performed. Here, the dissolution-improving agent may be formulated so that the active ingredient, which is at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, is in an equal amount (by mass ratio) with ibuprofen.

[0134] This embodiment includes the following inventions. Use of at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof to improve the dissolution of ibuprofen; Use of at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof to improve the dissolution of a solid composition containing ibuprofen; In a solid composition containing ibuprofen, use of at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof to improve the dissolution of ibuprofen; Use of at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof in the preparation of a solid composition containing ibuprofen with improved dissolution properties; Use of at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof in the manufacture of a solid composition containing ibuprofen with improved ibuprofen dissolution; A method for improving the dissolution of a solid composition containing ibuprofen, comprising adding at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof to the solid composition; A method for improving the dissolution of ibuprofen in a solid composition containing ibuprofen, comprising adding at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof to the solid composition; At least one selected from the group consisting of noscapine and its salts, or at least one selected from the group consisting of dextromethorphan and its salts, for use in improving the dissolution of ibuprofen; At least one selected from the group consisting of noscapine and its salts, or at least one selected from the group consisting of dextromethorphan and its salts, for use in improving the dissolution of solid compositions containing ibuprofen; A solid composition containing ibuprofen, wherein at least one selected from the group consisting of noscapine and its salts, or at least one selected from the group consisting of dextromethorphan and its salts, is used to improve the dissolution of ibuprofen.

[0135] When adding the dissolution-improving agent according to this embodiment to ibuprofen or a solid composition containing ibuprofen, the amount of dissolution-improving agent added is based on the amount of at least one selected from the group consisting of noscapine and its salts, and at least one selected from the group consisting of dextromethorphan and its salts. The amount of dissolution-improving agent added is appropriately adjusted according to the use of the solid composition, the required degree of dissolution, the symptoms of the person being administered to, age, weight, sex, etc. The amounts of at least one selected from the group consisting of noscapine and its salts, and at least one selected from the group consisting of dextromethorphan and its salts, may be adjusted independently. The amount of at least one selected from the group consisting of noscapine and its salts may be the amount added in terms of noscapine equivalent of the total of noscapine and noscapine salts. The amount of at least one selected from the group consisting of dextromethorphan and its salts may be the amount added in terms of dextromethorphan equivalent of the total of dextromethorphan and dextromethorphan salts.

[0136] The amount of at least one substance selected from the group consisting of noscapine and its salts added varies depending on the amount of ibuprofen contained in the solid composition to which it is added, but the daily amount of noscapine can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0137] The amount of at least one additive selected from the group consisting of dextromethorphan and its salts varies depending on the amount of ibuprofen contained in the solid composition to which it is added, but the daily amount of dextromethorphan can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0138] The amount of at least one substance selected from the group consisting of noscapine and its salts added is, based on the amount administered per day, for example, 0.0001 to 1 part by mass, preferably 0.0001 to 0.6 parts by mass, and more preferably 0.0003 to 0.3 parts by mass, in terms of noscapine, per 1 part by mass of ibuprofen.

[0139] The amount of at least one additive selected from the group consisting of dextromethorphan and its salts is, based on the amount administered per day, 0.0001 to 1 part by mass, preferably 0.0001 to 0.6 parts by mass, and more preferably 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen, in terms of dextromethorphan.

[0140] The total amount of at least one substance selected from the group consisting of noscapine, dextromethorphan, and salts thereof added is, based on the daily dose, 0.0001 to 1 part by mass, preferably 0.0001 to 0.6 parts by mass, and more preferably 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen, in terms of noscapine and dextromethorphan.

[0141] (solid composition) The dissolution improving agent according to this embodiment is added to ibuprofen or a solid composition containing ibuprofen. The following describes solid compositions containing ibuprofen to which the dissolution improving agent according to this embodiment may be added; however, it goes without saying that the dissolution improving agent according to this embodiment can also be added to compositions other than those described below.

[0142] (Ibuprofen) The amount of ibuprofen in a solid composition is adjusted as appropriate depending on the intended use of the solid composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen administered to an adult may be adjusted to a range of, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg.

[0143] The above dosages are examples, and the ibuprofen content per solid composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0144] In one embodiment, the ibuprofen content in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0145] The weight and dosage of the solid composition described above are for a day, but the same amount may be administered to the subject in one dose, or divided into multiple doses per day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose and the dosage form of the solid composition.

[0146] In a particular embodiment, the solid composition is a tablet, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0147] (Other ingredients) The solid composition may contain ingredients other than ibuprofen, depending on its intended use.

[0148] Examples of such ingredients include tranexamic acid, glycine, talc, anhydrous caffeine, and tipepidine. These ingredients may be present individually or in combination of two or more.

[0149] When the solid composition contains tranexamic acid, the dissolution of ibuprofen tends to be further improved. In other words, the dissolution improving agent according to this embodiment can further improve the dissolution of ibuprofen even when the solid composition contains tranexamic acid in addition to ibuprofen.

[0150] The amount of tranexamic acid is appropriately adjusted according to the intended use of the solid composition, the required degree of anti-inflammatory effect, the required degree of dissolution, the symptoms of the recipient, age, weight, sex, etc. The amount of tranexamic acid varies depending on the amount of ibuprofen, etc., but for example, the daily amount can be adjusted in the range of 10 mg to 3000 mg, preferably 100 mg to 1500 mg, and more preferably 400 mg to 750 mg.

[0151] The tranexamic acid content in the solid composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass. The amount of tranexamic acid contained in the solid composition administered daily is, for example, 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass, and more preferably 0.7 to 2.2 parts by mass, per 1 part by mass of ibuprofen.

[0152] If the solid composition contains tranexamic acid, ibuprofen may form crystals together with tranexamic acid. That is, the solid composition may contain crystals composed of ibuprofen and tranexamic acid.

[0153] The crystals composed of ibuprofen and tranexamic acid, their characteristics, and the method of producing them are as described above.

[0154] The solid composition tends to have improved ibuprofen dissolution properties when it contains crystals composed of ibuprofen and tranexamic acid.

[0155] The amounts of glycine, talc, anhydrous caffeine, and tipepidine are adjusted as appropriate depending on the intended use of the solid composition, the symptoms of the recipient, age, weight, sex, etc. The amounts of glycine, talc, anhydrous caffeine, and tipepidine may be adjusted independently of each other.

[0156] The amount of glycine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 900 mg, preferably 16 mg to 300 mg.

[0157] The amount of talc included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0158] The amount of anhydrous caffeine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 150 mg, preferably 16 mg to 80 mg.

[0159] The amount of tipepidine included will vary depending on the amount of ibuprofen, etc., but the daily amount can be adjusted to, for example, 8 mg to 120 mg, preferably 16 mg to 72 mg.

[0160] The amount of glycine contained in the solid composition administered daily is, for example, 0 to 10 parts by mass, 0.0001 to 1 part by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0161] The amount of talc contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0162] The amount of anhydrous caffeine contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0163] The amount of tipepidine contained in the solid composition administered daily is, for example, 0 to 1 part by mass, 0.0001 to 0.6 parts by mass, or 0.0003 to 0.3 parts by mass per 1 part by mass of ibuprofen.

[0164] When a solid composition is used to alleviate various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, and muscle pain, in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, and other pharmacologically acceptable components. Specific examples of components that may be included in a solid composition containing these components are as described above. Other components may be included individually or in combination of two or more. Furthermore, the dosage form of the solid composition to which the dissolution-improving agent according to this embodiment is added is the same as that of the solid composition described above.

[0165] (Addition method) The dissolution improving agent according to this embodiment is added to ibuprofen or a solid composition containing ibuprofen to improve the dissolution of ibuprofen. The dissolution improving agent according to this embodiment is added to a solid composition, for example, in the production of a solid composition containing ibuprofen. The method for producing the solid composition may include a step of bringing ibuprofen into contact with the dissolution improving agent according to this embodiment.

[0166] The production of the solid composition can be carried out using known techniques. Each component is added in any step and finally brought into contact with each other. A solvent and a binder may be added to the mixture after contact and kneaded, and the resulting kneaded product may be used as the solid composition. Crystals consisting of ibuprofen and tranexamic acid may be produced in accordance with the method for producing a mixture containing both components, as described in Japanese Patent Application Publication No. 2022-40057.

[0167] The resulting mixture can be further subjected to drying and granulation processes to produce granules (granulated material). In this case, granules (granulated material) containing each component may be prepared separately. Granulation can be carried out wet or dry.

[0168] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0169] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the section on "Tablets" in the General Provisions of the Japanese Pharmacopoeia. Specifically, a mixed powder containing at least ibuprofen and the dissolution-improving agent according to this embodiment may be granulated to obtain granules, and then the obtained granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet. Alternatively, a mixed powder containing ibuprofen may be granulated to obtain a first granule, a mixed powder containing the dissolution-improving agent according to this embodiment may be granulated to obtain a second granule, and then these two types of granules and appropriate extragranular components may be compressed into tablets to manufacture the tablet.

[0170] When the solid composition contains extragranular components, tablets may be manufactured by adding the final components to the granulated granules so as to form an outer layer of granulated granules, and then compressing the mixture into tablets. The extragranular components may also be in granular form. For example, granulated granules containing ibuprofen and the dissolution-improving agent according to this embodiment may be manufactured as the first granules, and granulated granules containing other active ingredients may be manufactured as the second granules. In this case, the first granules containing ibuprofen and the dissolution-improving agent according to this embodiment and the second granules containing other active ingredients may be provided separately, and the solid composition may be manufactured so that the components in the first granules and the other active ingredients in the second granules do not substantially come into contact. The other active ingredients may be included in the first granules or in the second granules so as to obtain a suitable formulation.

[0171] The granules obtained in the above process may be used as is as a granular material.

[0172] From the viewpoint of further enhancing the effect of the dissolution improving agent according to this embodiment, it is preferable that the dissolution improving agent according to this embodiment (at least one selected from the group consisting of noscapine, dextromethorphan, and their salts) be included in the same granule as ibuprofen. That is, it is preferable that the dissolution improving agent according to this embodiment (at least one selected from the group consisting of noscapine, dextromethorphan, and their salts) be granulated together with the mixed powder containing ibuprofen. The granules may be further compressed into tablets to produce tablets. From a similar viewpoint, it is also preferable to manufacture tablets by direct compression after adding the dissolution improving agent according to this embodiment (at least one selected from the group consisting of noscapine, dextromethorphan, and their salts) to a mixed powder containing ibuprofen. Alternatively, it is also preferable to dissolve ibuprofen and the dissolution improving agent according to this embodiment (at least one selected from the group consisting of noscapine, dextromethorphan, and their salts) in a solvent, dry the solvent to obtain a powder, and then optionally granulate the powder before compressing it to manufacture tablets. When the dissolution improving agent according to this embodiment is added in this way, ibuprofen and at least one selected from the group consisting of noscapine, dextromethorphan, and their salts are in close proximity in the solid composition, and the dissolution of ibuprofen tends to be further improved.

[0173] To illustrate the present invention in more detail, test examples and embodiments are described below, but the present invention is not limited thereto. [Examples]

[0174] 1.Raw materials In this example, unless otherwise specified, the following raw materials were used. [Table 1]

[0175] Crystals of ibuprofen and tranexamic acid were prepared as follows: 240.0 g of ibuprofen (manufactured by Yonezawa Hamari) and 182.9 g of tranexamic acid (manufactured by AMI) were charged into a stirring and mixing granulator (Vertical Granulator VG-5 (manufactured by Powrec)) and mixed to obtain a mixed powder. 69 g of a mixture of ethanol (purity 99.5%) (manufactured by Kanto Chemical) and purified water (mass ratio 8:2) was added to this mixed powder and kneaded and granulated to obtain a paste. The paste was wet-milled using a power mill (manufactured by Dalton) at low speed and 32 mesh, and stored in a constant temperature bath at 70°C for 89 hours to obtain crystals of ibuprofen and tranexamic acid.

[0176] Furthermore, differential scanning calorimetry (DSC) was performed on the obtained ibuprofen and tranexamic acid crystals, and the DSC curve shown in Figure 1 was obtained. From Figure 1, it was found that there is a peak around 186°C. It was also confirmed that the endothermic peak around 75°C related to the melting of ibuprofen had disappeared.

[0177] Differential scanning calorimetry was performed as follows: The obtained single crystals were weighed into an aluminum cell and measured using a differential scanning calorimeter (METTLER TOLEDO, DSC 3+) under nitrogen conditions, with a heating rate of 60°C / min and a measurement temperature of 25–350°C.

[0178] 2. Measurement of elution properties of solid compositions The components shown in Tables 2 and 3 were uniformly mixed using a mortar and pestle to obtain samples for dissolution testing. In each example, the amount of tranexamic acid was equal to the molar ratio of ibuprofen. The other raw materials were also equal in mass ratio to ibuprofen. In Tables 2 and 3, the amount of each component is shown in grams. In the example using ibuprofen and tranexamic acid crystals, the amount of each component was calculated assuming that ibuprofen and tranexamic acid were present in a 1:1 molar ratio.

[0179] In Tables 2 and 3 below, "DX" refers to dextromethorphan hydrobromide, and "IB-TXA" refers to the crystals of ibuprofen and tranexamic acid formed as described above.

[0180] [Table 2]

[0181] [Table 3]

[0182] For each sample prepared as described above, the dissolution rate of ibuprofen was measured according to the "Dissolution Test Method (Paddle Method)" of the 18th edition of the Japanese Pharmacopoeia, as follows. Equipment used: Toyama Sangyo NTR-6400AC elution tester Dissolution test solution: Water 900 mL (37℃) Test method: Paddle method, 50 rpm Test Procedure: The prepared sample was weighed to contain 50 mg of ibuprofen and placed in an elution test vessel. After 60 minutes, 10 mL of the test solution was taken. The collected test solution was filtered through a membrane filter (Millex-GV, material: PVDF, pore size: 0.22 μm, diameter: 33 mm). The first 7 mL was discarded, and the remaining 3 mL was used for the quantification of ibuprofen. Ibuprofen quantification was performed by high-performance liquid chromatography (HPLC).

[0183] High-performance liquid chromatography measurements were performed as follows. Equipment used: High-performance liquid chromatography (manufactured by Agilent Technology) Column: L-Column2 ODS, Particle size: 5 μm, Size: 4.6 x 250 mm (Manufactured by Shimadzu GLC Co., Ltd.) Mobile phase: 0.05M sodium dihydrogen phosphate (pH 2.6) / acetonitrile mixture Test procedure: The ibuprofen concentration in each sample was measured, and the ibuprofen dissolution rate at each time point was calculated.

[0184] The ibuprofen dissolution rates for each example are shown in Figures 2 to 4. From Figure 2, it can be seen that Examples 1 and 2, which contained noscapine and dextromethorphan, respectively, had significantly higher ibuprofen dissolution rates compared to Comparative Examples 1 to 5. Compared to the dissolution rate of Comparative Example 1, the dissolution rates of Examples 1 and 2 were 1.49 times and 1.21 times, respectively.

[0185] Furthermore, Figure 3 shows that, as in Reference Examples 1-4, combining ibuprofen with tranexamic acid or crystallizing ibuprofen and tranexamic acid improves the dissolution rate of ibuprofen. Additionally, the addition of noscapine and dextromethorphan further improves the dissolution rate, even when tranexamic acid has already improved it. Note that, compared to the dissolution rate of Reference Example 2, the dissolution rate of Example 3 was 1.53 times higher. Also, compared to the dissolution rate of Reference Example 4, the dissolution rate of Example 4 was 1.17 times higher.

[0186] Furthermore, Figure 4 shows that even when components other than (A) ibuprofen, (B) noscapine and / or dextromethorphan, and (C) tranexamic acid are included, the effect of noscapine and dextromethorphan in improving the dissolution rate of ibuprofen is maintained.

[0187] Examples of solid compositions are shown below.

[0188] [Table 4]

[0189] [Table 5]

[0190] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

Claims

1. The following ingredients: (A) Ibuprofen and, (B) At least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof, Solid compositions containing (however, excluding (i) solid compositions that do not contain dextromethorphan or a salt thereof and in which ibuprofen and noscapine or a salt thereof exist as different granules, and (ii) solid compositions that do not contain noscapine or a salt thereof and in which ibuprofen, dextromethorphan or a salt thereof, a polymer that forms a hydrogel, and an organic acid or an acidic amino acid).

2. (C) Tranexamic acid The solid composition according to claim 1, further comprising:

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

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

1.

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

6. (D) At least one selected from the group consisting of glycine, talc, anhydrous caffeine, and tipepidine. A solid composition according to any one of claims 1 to 4, further comprising:

7. An ibuprofen dissolution enhancer comprising at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof as an active ingredient.

8. The dissolution improving agent according to claim 7, wherein the active ingredient is at least one selected from the group consisting of noscapine and its salts.

9. The dissolution improving agent according to claim 7, wherein the active ingredient is at least one selected from the group consisting of dextromethorphan and salts thereof.

10. The dissolution improving agent according to any one of claims 7 to 9, wherein when an equal amount of ibuprofen is mixed with the agent and an dissolution test is performed according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of ibuprofen 60 minutes after the start of the test is 1.2 times or more than the dissolution rate of ibuprofen 60 minutes after the start of the test when an equal amount of ibuprofen and lactose is mixed and an dissolution test is performed according to the same dissolution test method.

11. A method for improving the dissolution of a solid composition containing ibuprofen, comprising adding at least one selected from the group consisting of noscapine, dextromethorphan, and salts thereof to the solid composition.

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