Pharmaceutical composition

Abstract

The object of the present invention is to provide a pharmaceutical composition that contains at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol, or a salt thereof, and has excellent storage stability. [Solution] To solve the above problems, methods such as incorporating (C) carbocysteine ​​are used.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing (A) ambroxol or a salt thereof, and at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof, and a pharmaceutical composition containing at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof.

Background Art

[0002] Ambroxol hydrochloride is a compound widely known as having a lubricating effect on airway mucosa and a mucolytic effect, and having an excellent expectorant effect. It has also been approved as a switched OTC drug and is formulated in general cold medicines and cough suppressants (Non-Patent Document 1). It has been known that ambroxol hydrochloride causes stability problems when formulated with certain components. For example, when 11 parts by mass or more of ibuprofen is formulated per 1 part by mass of ambroxol hydrochloride, a decrease in the content of ambroxol hydrochloride over time and a change in the appearance of the preparation occur. Therefore, in addition to pseudoephedrine hydrochloride, at least one selected from dihydrocodeine phosphate, dextromethorphan hydrobromide, and carbocysteine is formulated for improvement (Patent Document 1).

[0003] Methoxyphenamine and its salts are known to produce an antitussive effect due to a bronchodilator effect based on a sympathetic nerve excitatory effect. Therefore, as an antitussive component, it is formulated in antitussive and expectorant drugs, and is also a drug formulated in oral medications for rhinitis and the like for the purpose of relieving nasal congestion due to a vasoconstrictive effect (Non-Patent Document 2). Trimethoquinol, its salts or hydrates thereof are sympathomimetic and bronchodilator drugs classified as β2 receptor stimulants, and are drugs known to produce an antitussive effect due to a bronchodilator effect (Non-Patent Document 3).

[0004] Currently, solid pharmaceutical preparations containing multiple active ingredients are widely used in combination cold medicines and cough suppressants / expectorants. An example of such a solid pharmaceutical preparation is described in Patent Document 2. This document describes a pharmaceutical composition characterized by containing at least one selected from the group consisting of (a) ambroxol or a salt thereof, (b) Platycodon grandiflorus, (c) glycyrrhizic acid and its salt, dextromethorphan and its salt, phenylephrine and its salt, isopropamide iodide, methoxyphenamine and its salt, and ephedrines. The document also describes a solid preparation containing ambroxol hydrochloride and methoxyphenamine hydrochloride.

[0005] However, it is unknown whether an interaction occurs between ambroxol hydrochloride and methoxyphenamine hydrochloride that affects storage stability, and naturally, no way to resolve such an interaction is known. Similarly, no way to resolve interactions between ambroxol hydrochloride and trimethoquinol hydrochloride is known.

[0006] Furthermore, while products containing methoxyphenamine hydrochloride or trimethoquinol hydrochloride are known, no issues regarding storage stability in pharmaceutical formulations containing these active ingredients alone are known, nor is it known whether carbocysteine ​​is effective in addressing these issues. Similarly, in Patent Document 3, the storage stability of pharmaceutical formulations containing methoxyphenamine hydrochloride or trimethoquinol hydrochloride alone, and the effect of carbocysteine ​​on storage stability, have not been confirmed in test examples. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2021-195370 [Patent Document 2] Japanese Patent Publication No. 2023-10636 [Patent Document 3] Japanese Patent Publication No. 2006-96749 [Non-patent literature]

[0008] [Non-Patent Document 1] OTC Handbook 2008-09, p. 235, Academic Information Distribution Center Co., Ltd. (published in 2008) [Non-Patent Document 2] OTC Handbook 2006-07, p. 253, Academic Information Distribution Center Co., Ltd. (published in 2005) [Non-Patent Document 3] Package insert for Inolin Powder 1% (Revised April 2024 (3rd Edition)) Nipro ES Pharma Co., Ltd. [Overview of the project] [Problems that the invention aims to solve]

[0009] The inventors, in order to develop a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, investigated its storage stability and obtained the surprising finding that compositions containing these ingredients undergo changes in appearance over time, such as changes in color or caking. Furthermore, when the storage stability of a pharmaceutical composition containing (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, was investigated, the inventors obtained the surprising finding that even in the absence of component (A), changes in appearance such as changes in color or caking occur over time.

[0010] The object of the present invention is to provide a pharmaceutical composition containing (A) ambroxol or a salt thereof, and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, and having excellent storage stability. Another object of the present invention is to provide a pharmaceutical composition containing (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, and having excellent storage stability. [Means for solving the problem]

[0011] The present inventors conducted various studies to solve the above problems and found that when (C) carbocysteine ​​or a salt thereof is added to a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, changes in appearance can be suppressed.

[0012] Furthermore, it was found that changes in appearance can be suppressed by including (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, in the pharmaceutical composition in such a way that they are not substantially in contact with each other.

[0013] Furthermore, it was found that adding (C) carbocysteine ​​or a salt thereof to a pharmaceutical composition containing (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, can suppress changes in appearance.

[0014] In other words, the present invention is (1) A pharmaceutical composition characterized by containing (A) ambroxol or a salt thereof, (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, and (C) carbocysteine ​​or a salt thereof. (2) A pharmaceutical composition containing (A) ambroxol or a salt thereof, and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, in such a manner that they are not substantially in contact with each other. (3) The pharmaceutical composition according to (1) or (2), wherein the content ratio of component (A) to component (B) is 0.25 to 35 parts by mass of component (B) per 1 part by mass of component (A) when component (B) is methoxyphenamine or a salt thereof, and 0.02 to 2.6 parts by mass of component (B) per 1 part by mass of component (A), (4) The amount of component (C) is 0.1 to 30 parts by mass per 1 part by mass of the total amount of component (A) and component (B) when component (B) is methoxyphenamine or a salt thereof, and 1.4 to 31 parts by mass per 1 part by mass of the total amount of component (A) and component (B) when component (B) is trimethoquinol or a salt thereof, as described in (1). (5) The pharmaceutical composition according to (1), wherein the content of component (A) is 2 to 17% by mass when component (B) is methoxyphenamine or a salt thereof, and 3 to 36% by mass when component (B) is trimethoquinol or a salt thereof. (6) The pharmaceutical composition described in (2), wherein the content of component (A) is 0.3 to 3.8% by mass. (7) The pharmaceutical composition according to (1), wherein the content of component (B) is 1 to 65% by mass when component (B) is methoxyphenamine or a salt thereof, and 0.1 to 13% by mass when component (B) is trimethoquinol or a salt thereof. (8) The pharmaceutical composition according to (2), wherein the content of component (B) is 1 to 9% by mass when component (B) is methoxyphenamine or a salt thereof. (9) The pharmaceutical composition according to (1), wherein the content of component (C) is 28 to 95% by mass when component (B) is methoxyphenamine or a salt thereof, and 60 to 96% by mass when component (B) is trimethoquinol or a salt thereof. (10) A method for suppressing changes in the appearance of a pharmaceutical composition, characterized by adding (C) carbocysteine ​​or a salt thereof to a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof. (11) A method for producing a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, characterized in that (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof are contained in such a manner that they are not substantially in contact with each other. (12) A pharmaceutical composition characterized by containing at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof, and (C) carbocisteine or a salt thereof. (13) When the content ratio of the (B) component to the (C) component is such that when the (B) component is methoxyphenamine or a salt thereof, the (C) component is 0.5 to 100 parts by mass with respect to 1 part by mass of the (B) component, and when the (B) component is trimethoquinol or a salt thereof, the (C) component is 6 to 1250 parts by mass with respect to 1 part by mass of the (B) component, the pharmaceutical composition according to (1) or (12). (14) When the content of the (B) component is such that when the (B) component is methoxyphenamine or a salt thereof, it is 1 to 66% by mass, and when the (B) component is trimethoquinol or a salt thereof, it is 0.08 to 13% by mass, the pharmaceutical composition according to (12). (15) When the content of the (C) component is such that when the (B) component is methoxyphenamine or a salt thereof, it is 34 to 99% by mass, and when the (B) component is trimethoquinol or a salt thereof, it is 87 to 99% by mass, the pharmaceutical composition according to (12). (16) The pharmaceutical composition according to (1) or (2) or (12), wherein the pharmaceutical composition is a solid preparation. (17) A method for suppressing the appearance change of the pharmaceutical composition, characterized by adding (C) carbocisteine or a salt thereof to a pharmaceutical composition containing at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof. Although it relates to these, it is not limited thereto.

Effects of the Invention

[0015] According to the present invention, it has become possible to provide a pharmaceutical composition containing (A) ambroxol or a salt thereof, which is excellent in storage stability, and at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof, and a pharmaceutical composition containing at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof, which is excellent in storage stability.

Modes for Carrying Out the Invention

[0016] The pharmaceutical composition of the present invention will be described in detail below. The compounds and salts of components (A), (B), and (C) described in relation to the present invention also include hydrates of the compounds or salts thereof. Therefore, when referring to the amounts of these compounds and salts, the amounts refer to the amount of the compound if only the compound is present, the amount of the salt if only the salt is present, the amount of the hydrate if only the hydrate is present, and the sum of the amounts if they are present in mixture.

[0017] <(A) component> The term "ambroxol" as used herein has the meaning commonly used in the industry, and is derived from the chemical formula C 13 H 18 The compound is represented by Br2N2O. In the present invention, ambroxol or a salt thereof may be used, either individually or in combination of two or more. Such ambroxol or a salt thereof can be produced by known methods or commercially available products can be used. Furthermore, ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of such salts include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred. The amount of component (A) in the pharmaceutical composition of the present invention (the total amount of ambroxol or its salts if two or more are included, the same applies hereinafter) is not limited and may be determined by appropriate consideration, for example, depending on the gender, age, symptoms, etc. of the person taking the medication. The daily dose is preferably 4.5 to 60 mg. The content of ambroxol or its salt in the pharmaceutical composition of the present invention, typically a solid composition, is not particularly limited as long as it is in an amount that exhibits its pharmacokinetic effect, but is usually 0.1 to 50% by mass, preferably 0.1 to 40% by mass, and more preferably 0.3 to 35% by mass. Other preferred content levels are 2 to 36% by mass, 3 to 17% by mass, 0.3 to 3.8% by mass, 0.5 to 25% by mass, and 1 to 25% by mass.

[0018] <(B) component> The term "methoxyphenamine" as used herein has the meaning commonly used in the industry, and is derived from the chemical formula C 11 H 17 The compound is represented by NO. In the present invention, methoxyphenamine or a salt thereof may be used, and one of these may be used alone or in combination of two or more. Such methoxyphenamine or a salt thereof can be produced by known methods, or commercially available products may be used. Furthermore, methoxyphenamine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, phenolphthalein salt, and carbonate, with hydrochloride being particularly preferred. The amount of methoxyphenamine or its salt contained in the pharmaceutical composition of the present invention (the total amount of methoxyphenamine or its salts if two or more are contained, the same applies hereinafter) is not limited and can be determined appropriately depending on the gender, age, symptoms, etc. of the user, and a daily dose of 15 to 150 mg is preferred. The number of times it is administered per day can be appropriately selected from 1 to 3 times. The content of methoxyphenamine or its salt in the pharmaceutical composition of the present invention is not particularly limited as long as it is in an amount that exhibits its pharmacokinetic effect, but is preferably 0.08 to 80% by mass, more preferably 0.1 to 80% by mass, more preferably 0.5 to 70% by mass, even more preferably 1 to 70% by mass, and particularly preferably 1 to 66% by mass, based on the total mass of the pharmaceutical composition. Other preferred content levels are 1 to 65% by mass, 0.08 to 13% by mass, 0.1 to 13% by mass, 1 to 9% by mass, 0.1 to 60% by mass, 1 to 60% by mass, and 2 to 56% by mass. The term "trimethoquinol" used in this invention has the meaning commonly used in the industry, C 19 H 23 This is a compound represented by NO5. In the present invention, trimethoquinol or a salt thereof may be used, and one of these may be used alone or in combination of two or more. Such trimethoquinol or a salt thereof can be produced by known methods, or commercially available products may be used. Furthermore, the trimethoquinol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, phenolphthalein salt, and carbonate, with hydrochloride being particularly preferred. The trimethoquinol or a salt thereof used in the present invention may be in hydrate or anhydrous form, and hydrate is preferred. The amount of trimethoquinol or its salt contained in the pharmaceutical composition of the present invention (the total amount if two or more of these are contained, the same applies hereinafter) is not limited and may be determined appropriately depending on the gender, age, symptoms, etc. of the person taking the medication. The daily dose is preferably 1.2 to 12 mg. The content of trimethoquinol or its salt in the pharmaceutical composition of the present invention is not particularly limited as long as it is in an amount that exhibits its pharmacokinetic effect, but is preferably 0.01 to 20% by mass, more preferably 0.01 to 15% by mass, even more preferably 0.05 to 15% by mass, and particularly preferably 0.08 to 13% by mass, based on the total mass of the pharmaceutical composition. Other preferred content levels are 0.1 to 13% by mass, 0.01 to 10% by mass, and 0.05 to 5% by mass.

[0019] <(C) component> The term "carbocysteine" as used in this invention has the meaning commonly used in this industry and refers to a compound represented by the chemical formula C5H9NO4S. In this invention, carbocysteine ​​or its salts may be used, either individually or in combination of two or more. Such carbocysteine ​​or its salts are not particularly limited as long as they are pharmaceutically acceptable, but examples of such salts include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, phenolphthalein salt, and carbonate; as well as amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, and inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt, and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, cyclohexylamine salt, and N-methyl-D-glucamine salt. In the present invention, L-carbocysteine ​​or its salts are usually used, and it is preferable to use free carbocysteine ​​or L-carbocysteine. Carbocysteine ​​or its salts can be produced by known methods, or commercially available products can be used. The amount of component (C) in the pharmaceutical composition of the present invention (the total amount of two or more of carbocysteine ​​or its salts if two or more are included, the same applies hereinafter) is not limited and may be determined by appropriate consideration, for example, depending on the gender, age, symptoms, etc. of the person taking the medication. The daily dose is preferably 75 to 1500 mg. The content of carbocysteine ​​or its salt in the pharmaceutical composition of the invention is not particularly limited as long as it is in an amount that exhibits its pharmacological effect, but is usually 1 to 99% by mass, preferably 10 to 99% by mass, more preferably 20 to 99% by mass, and more preferably 28 to 99% by mass. Other preferred content levels are 34 to 99% by mass, 87 to 99% by mass, 28 to 95% by mass, 60 to 96% by mass, 1 to 93% by mass, 20 to 93% by mass, and 25 to 93% by mass.

[0020] When using components (A) and (B), the mixing ratio of (A) ambroxol or its salt to (B) methoxyphenamine or its salt is preferably 0.1 to 50 parts by mass of (B) methoxyphenamine or its salt per 1 part by mass of (A) ambroxol or its salt, more preferably 0.5 to 40 parts by mass, even more preferably 0.3 to 40 parts by mass, particularly preferably 0.3 to 35 parts by mass, and most preferably 0.3 to 33 parts by mass. Another preferred mixing ratio is 0.25 to 35 parts by mass of (B) methoxyphenamine or its salt per 1 part by mass of (A) ambroxol or its salt. Furthermore, the mixing ratio of (A) ambroxol or its salt to (B) trimethoquinol or its salt is preferably such that (B) trimethoquinol or its salt is contained in an amount of 0.1 to 10 parts by mass per 1 part by mass of (A) ambroxol or its salt, more preferably 0.05 to 5 parts by mass, even more preferably 0.05 to 3 parts by mass, particularly preferably 0.02 to 3 parts by mass, and most preferably 0.02 to 2.6 parts by mass.

[0021] When using components (A), (B), and (C), the blending ratio of (A) ambroxol or its salt, (B) methoxyphenamine or its salt, and (C) carbocysteine ​​or its salt is preferably such that (C) carbocysteine ​​or its salt is contained in an amount of 0.1 parts by mass or more, more preferably 0.1 to 32 parts by mass, more preferably 0.1 to 30 parts by mass, more preferably 0.3 to 25 parts by mass, even more preferably 0.3 to 20 parts by mass, and most preferably 0.4 to 20 parts by mass. Furthermore, the blending ratio of (A) ambroxol or a salt thereof, (B) trimethoquinol or a salt thereof, and (C) carbocysteine ​​or a salt thereof is preferably such that (C) carbocysteine ​​or a salt is present in an amount of 0.1 parts by mass or more, more preferably 1 to 40 parts by mass, more preferably 1 to 35 parts by mass, even more preferably 1.4 to 31 parts by mass, and may also be present in amounts of 0.1 to 30 parts by mass, 0.3 to 25 parts by mass, or 0.3 to 20 parts by mass.

[0022] When using components (B) and (C), the mixing ratio of (B) methoxyphenamine or its salt to (C) carbocysteine ​​or its salt is preferably such that (C) carbocysteine ​​or its salt is present in an amount of 0.05 parts by mass or more per 1 part by mass of (B) methoxyphenamine or its salt, more preferably 0.05 to 200 parts by mass, even more preferably 0.05 to 150 parts by mass, even more preferably 0.1 to 150 parts by mass, particularly preferably 0.1 to 100 parts by mass, and most preferably 0.5 to 100 parts by mass. Furthermore, the mixing ratio of (B) trimethoquinol or its salt to (C) carbocysteine ​​or its salt is preferably such that (C) carbocysteine ​​or its salt is present in an amount of 0.05 parts by mass or more per 1 part by mass of (B) trimethoquinol or its salt, more preferably 1 to 1300 parts by mass, even more preferably 1 to 1250 parts by mass, even more preferably 6 to 1250 parts by mass, and most preferably 6.3 to 1250 parts by mass.

[0023] Furthermore, in the present invention, "containing so that they are substantially in contact with each other" means that in the pharmaceutical composition, the two target components, for example, (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, do not come into contact or come into contact to an extent that does not cause interaction. However, it is preferable that (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof do not come into contact. The means for "containing so that they are substantially in contact with each other" in the present invention are not particularly limited, and specific forms include the following.

[0024] 1. (A) Ambroxol or a salt thereof and (B) At least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, are granulated separately, and these are combined to obtain fine particles, granules, etc., and preparations coated therewith. 2. A solid preparation obtained by granulating (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, and blending the other ungranulated component (A) or (B) into the resulting granules, and a preparation obtained by coating the granules with the ungranulated component. 3. Tablets or capsules containing the above 1 or 2, and preparations obtained by coating such tablets or capsules. 4. Multilayer tablets containing the above 1 or 2, and preparations coated therewith 5. A core tablet containing the above 1 or 2, and a preparation coated therewith. 6. Powders, granules, and formulations coated with the above 1 or 2, which are laminated and coated. Furthermore, the dosage form of the pharmaceutical composition of the present invention is not particularly limited, but solid formulations are preferred. Examples include oral formulations such as powders, fine granules, granules, pills, tablets (including film-coated tablets, sugar-coated tablets, and laminated tablets), capsules, dry syrups, and lozenges, as well as parenteral formulations such as topical preparations. Oral formulations are preferred, and there is particular significance in using tablets, fine granules, granules, and capsules, which are affected by changes in appearance.

[0025] When manufacturing granules, etc., as described in 1 and 2 above, appropriate amounts of other pharmacoactive ingredients, excipients, disintegrants, and binders may be added as appropriate by methods such as agitation granulation, fluid bed granulation, extrusion granulation, rolling fluid bed granulation, and dry granulation. These can be manufactured using general pharmaceutical manufacturing equipment. Specifically, for example, component (A) and component (B) may be mixed and ground separately and granulated, and then the resulting granules may be mixed together. Alternatively, when granulating only component (A), component (A) may be mixed and ground, granulated, and then component (B) may be added to the resulting granules. Similarly, when granulating only component (B), component (B) may be mixed and ground, granulated, and then component (A) may be added to the resulting granules. Granules containing component (A) or component (B) obtained by granulation as described above may be coated. Alternatively, the obtained powders, granules, etc., may be directly filled into capsules.

[0026] Regarding the formulations described in item 3 above, tablets can be obtained by appropriately adding active ingredients and conventional pharmaceutical additives such as excipients to the powder or granules obtained by method 1 or 2, and then compressing the mixture into tablets. These tablets may then be coated with a film coating or sugar coating. Alternatively, the formulation obtained by this method can be encapsulated.

[0027] The preparations described in items 4 and 5 above are tablets prepared so that component (A) and component (B) are not substantially in contact with each other. For multilayer tablets, it is preferable that component (A) and component (B) are arranged in different layers, and these can be manufactured using commercially available laminating tablets. Alternatively, they may be coated with a film coating or sugar coating. For core tablets, component (A) or component (B) may be used as the inner core, and the other as the outer core. In this case, a preparation may be made by coating a tablet containing either component (A) or component (B) with the other component.

[0028] When manufacturing the granules etc. described in item 6 above, they are obtained by coating a core granule with either component (A) or component (B), and then coating it with the other component. The obtained granules etc. may be further coated with a film coating or sugar coating. Alternatively, the granules etc. obtained in this way may be compressed into tablets or filled directly into capsules.

[0029] The pharmaceutical composition of the present invention may optionally contain other active ingredients, excipients, binders, disintegrants, film coating agents, lubricants, antioxidants, fragrances, and colorants in appropriate amounts, as needed.

[0030] Furthermore, the storage container for the pharmaceutical composition of the invention is not particularly limited as long as it is an airtight container, and a desiccant may be used. Preferably, glass bottles, SP packaging, PTP packaging, and stick packaging are used. In one embodiment, the present invention is not limited to a pharmaceutical composition for treating the common cold containing ibuprofen, an antitussive component, a bronchodilator component, an antihistamine component, and carbocysteine. In another embodiment, the present invention is not limited to pharmaceutical compositions containing ibuprofen, an antitussive component, a bronchodilator component, an antihistamine component, and carbocysteine. In another embodiment, the present invention is not limited to pharmaceutical compositions containing ibuprofen, an antihistamine component, and carbocysteine. In another embodiment, the present invention excludes pharmaceutical compositions containing ibuprofen and carbocysteine. [Examples]

[0031] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0032] (Preparation of solid dosage forms) (Reference Examples 1-4, Comparative Examples 1-5, Comparative Examples 8-12, Comparative Examples 14-19, Examples 1-5, Examples 10-14, Examples 16-21) After weighing each raw material component according to the formulations described in Tables 1, 3, 5, 7, and 8, they were uniformly mixed. The mixture was then granulated in a mortar to obtain a solid preparation. (Comparative Examples 6-7, 13, 6-9, 15) After weighing the raw materials for Granule A according to the formulations shown in Tables 2, 4, and 6, they were uniformly mixed. An appropriate amount of water was added to the resulting mixture and granulated in a mortar. Next, after weighing the raw materials for Granule B, they were uniformly mixed. An appropriate amount of water was added to the resulting mixture and granulated in a mortar. These granules were weighed and mixed in the ratios shown in Tables 2 and 6 to obtain solid formulations. (Example test) <Evaluation Method> The storage stability of the solid dosage forms of Reference Examples 1-4, Comparative Examples 1-19, and Examples 1-21 was evaluated using the following test methods. Storage stability (appearance evaluation) The obtained formulations were stored in tightly sealed glass bottles (PS2K bottles), and the state of the solid formulations was visually observed after storage at 65°C for 3 days. The evaluation method involved a relative comparison between the sample stored at 65°C for 3 days and the sample immediately after storage began. The degree of color change and caking of the formulations were evaluated on an 11-point scale from 0 to 10 (0 representing no color change or caking, and 10 representing the most significant change or caking), and the average value of two evaluators was calculated. The sample immediately after storage was all in a white powder state, and a degree of color change and caking of 3 or less after storage was considered acceptable.

[0033] [Table 1]

[0034] As shown in Table 1, color change and caking were observed in Reference Example 1. In Comparative Examples 1-5, which contained lactose, a common excipient, color change and caking were observed, and no sufficient improvement was seen. On the other hand, in Examples 1-5, which contained carbocysteine, color change and caking were sufficiently improved.

[0035] [Table 2]

[0036] As shown in Table 2, color changes and caking were observed in Comparative Examples 4, 6, and 7. In Examples 6-9, where ambroxol hydrochloride and methoxyphenamine hydrochloride were granulated separately so that they were not substantially in contact with each other, the color changes and caking were significantly improved.

[0037] Examples of formulations Tables 3 and 4 below show examples of formulations 1 to 11.

[0038] [Table 3]

[0039] [Table 4]

[0040] [Table 5]

[0041] As shown in Table 5, a change in color was observed in Reference Example 2. In Comparative Examples 8-12, where lactose, a common excipient, was added, a change in color and caking were observed, indicating insufficient improvement. On the other hand, in Examples 10-14, where carbocysteine ​​was added, no change in color or caking was observed, indicating sufficient improvement.

[0042] [Table 6]

[0043] As shown in Table 6, color change and caking were observed in Comparative Example 13. In Example 15, where ambroxol hydrochloride and trimethoquinol hydrochloride hydrate were granulated separately so that they were not substantially in contact with each other, a significant improvement in color change and caking was observed.

[0044] [Table 7]

[0045] As shown in Table 7, in Reference Example 3, where methoxyphenamine hydrochloride was present alone, color changes and caking were observed. In Comparative Examples 14-16, where lactose, a common excipient, was added, color changes and caking were observed, and no sufficient improvement was seen. On the other hand, in Examples 16-18, where carbocysteine ​​was added, sufficient improvement was observed.

[0046] [Table 8]

[0047] As shown in Table 8, in Reference Example 4, where trimethoquinol hydrochloride hydrate was present alone, color changes and caking were observed. In Comparative Examples 17-19, where lactose, a common excipient, was added, color changes and caking were observed, and no sufficient improvement was seen. On the other hand, in Examples 19-21, where carbocysteine ​​was added, no color changes or caking were observed, and sufficient improvement was seen. [Industrial applicability]

[0048] According to the present invention, it is possible to provide a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, which has excellent storage stability, and a pharmaceutical composition containing at least one selected from the group consisting of (B) methoxyphenamine and trimethoquinol or a salt thereof, which has excellent storage stability.

Claims

1. A pharmaceutical composition characterized by containing (A) ambroxol or a salt thereof, (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, and (C) carbocysteine ​​or a salt thereof.

2. A pharmaceutical composition comprising (A) ambroxol or a salt thereof, and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, in such a manner that they are not substantially in contact with each other.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content ratio of component (A) to component (B) is 0.25 to 35 parts by mass of component (B) per 1 part by mass of component (A) when component (B) is methoxyphenamine or a salt thereof, and 0.02 to 2.6 parts by mass of component (B) per 1 part by mass of component (A) when component (B) is trimethoquinol or a salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the content of component (C) is 0.1 to 30 parts by mass per 1 part by mass of the total amount of component (A) and component (B) when component (B) is methoxyphenamine or a salt thereof, and 1.4 to 31 parts by mass per 1 part by mass of the total amount of component (A) and component (B) when component (B) is trimethoquinol or a salt thereof.

5. A method for suppressing changes in the appearance of a pharmaceutical composition, characterized by adding (C) carbocysteine ​​or a salt thereof to a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof.

6. A method for producing a pharmaceutical composition containing (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof, characterized in that (A) ambroxol or a salt thereof and (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof are contained in such a way that they are not substantially in contact with each other.

7. A pharmaceutical composition characterized by containing (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol, or a salt thereof, and (C) carbocysteine ​​or a salt thereof.

8. The pharmaceutical composition according to claim 1 or 7, wherein the content ratio of component (B) to component (C) is 0.5 to 100 parts by mass of component (C) per 1 part by mass of component (B) when component (B) is methoxyphenamine or a salt thereof, and 6 to 1250 parts by mass of component (C) per 1 part by mass of component (B) when component (B) is trimethoquinol or a salt thereof.

9. The pharmaceutical composition according to claim 1, 2, or 7, wherein the pharmaceutical composition is a solid dosage form.

10. A method for suppressing changes in the appearance of a pharmaceutical composition, characterized by adding (C) carbocysteine ​​or a salt thereof to a pharmaceutical composition containing (B) at least one selected from the group consisting of methoxyphenamine and trimethoquinol or a salt thereof.

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