Pharmaceutical composition containing l-carbocysteine

Abstract

To provide a pharmaceutical composition containing L-carbocysteine that exhibits good formulation stability.SOLUTION: An oral pharmaceutical composition in a solid form contains (A) L-carbocysteine in an amount of 753 mg to 1,500 mg in terms of daily dose, (B) dextromethorphan, a pharmaceutically acceptable salt or a hydrate thereof, and (C) at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing L-carbocysteine. More specifically, it relates to an oral pharmaceutical composition in solid form containing L-carbocysteine as an expectorant and dextromethorphan (hereinafter sometimes abbreviated as "DXM"), its salts or their hydrates (hereinafter collectively also referred to as "DXMs") as an antitussive. Further, the present invention relates to a method for improving the formulation stability of a pharmaceutical composition containing L-carbocysteine and DXMs.

Background Art

[0002] In pharmaceutical preparations having the efficacy and effect of antitussive and expectoration (for example, antitussive and expectorant agents, cold medicines, etc.), usually, in addition to expectorants, antitussives, anti-inflammatory agents, allergy medicines and / or adjuvants are formulated. L-carbocysteine is a compound that has been used as an expectorant for a long time, and the maximum compounding amount per unit dose (unit dosage form) is set based on the upper limit of the daily dose of 750 mg determined by the manufacturing and sales approval standards (Non-Patent Documents 1 and 2).

[0003] Pharmaceutical preparations are products that are particularly strictly required to be stable over time not only during the manufacturing process but also under subsequent storage conditions. In particular, a decrease in the content of the active ingredient in a pharmaceutical preparation leads to a decrease in the drug efficacy of the pharmaceutical preparation, and coloring of the pharmaceutical preparation over time impairs the appearance quality, so both are problems to be avoided.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a pharmaceutical composition containing L-carbocysteine and DXM compounds having good formulation stability. Another object of the present invention is to provide a method for improving the formulation stability of a pharmaceutical composition containing L-carbocysteine and DXM compounds.

[0006] The inventors of the present invention have conducted intensive studies to provide a pharmaceutical composition containing L-carbocysteine having good formulation stability. As a result, in addition to L-carbocysteine, DXM compounds were added, and for a solid pharmaceutical composition with a blending amount of L-carbocysteine of 750 mg per daily dose, ambroxol salt (expectorant), chlorpheniramine salt (allergy drug, antihistamine), anhydrous caffeine (adjuvant), ibuprofen (analgesic), or tranexamic acid (anti-inflammatory drug) was added. It was found that the following problems occurred. (a) Blending of ambroxol salt: The content of ambroxol salt in the pharmaceutical composition decreases by an accelerated test at 40°C assuming long-term storage under room temperature conditions; (b) Blending of chlorpheniramine salt: The content of chlorpheniramine salt in the pharmaceutical composition decreases by an exposure test assuming storage under exposure conditions; (c) Blending of anhydrous caffeine: The content of anhydrous caffeine in the pharmaceutical composition decreases by an exposure test, and the pharmaceutical composition is colored by an accelerated test at 40°C; (d) Blending of ibuprofen: The pharmaceutical composition is colored by an exposure test; (e) Blending of tranexamic acid: The pharmaceutical composition is colored by an accelerated test at 40°C.

[0007] Therefore, a more specific problem of the present invention is to improve the problem of formulation stability (decrease in the content of active ingredients, coloring) in a solid pharmaceutical composition containing 750 mg of L-carbocysteine per daily dose, in addition to DXM drugs, and ambroxol or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, anhydrous caffeine, ibuprofen, and / or tranexamic acid or a pharmaceutically acceptable salt thereof. Another object is to provide an L-carbocysteine and DXM drug-containing pharmaceutical composition having good formulation stability improved by such a method.

Means for Solving the Problems

[0008] In order to solve the above problems, the present inventors conducted intensive studies and found that by increasing the blending amount of L-carbocysteine per daily dose to 753 mg or more, preferably 1000 mg or more, particularly up to 1500 mg, even when ambroxol or its salt, chlorpheniramine or its salt, anhydrous caffeine, ibuprofen, and / or tranexamic acid or its salt are blended in addition to DXM drugs, the above-mentioned problems of formulation stability do not occur. It was confirmed that the method is an effective method for improving and enhancing the formulation stability of a solid pharmaceutical composition containing ambroxol or its salt, chlorpheniramine or its salt, anhydrous caffeine, ibuprofen, and / or tranexamic acid or its salt in addition to L-carbocysteine and DXM drugs.

[0009] Based on such findings, the present invention was further studied and completed, and has the following embodiments.

[0010] (I) Pharmaceutical composition containing L-carbocysteine (I-1)(A) L-carbocysteine in an amount of 753 mg to 1500 mg in terms of the daily dose, (B) dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, and (C) At least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof An oral pharmaceutical composition in solid form containing (I-2) The oral pharmaceutical composition according to (I-1), wherein the ratio of the component (B) to 100 parts by mass of the component (A) is 1 to 10 parts by mass. (I-3) The oral pharmaceutical composition according to (I-1) or (I-2), which contains at least one of the components (C) in the following ratios with respect to 100 parts by mass of the component (A); (C1) Ambroxol or a pharmaceutically acceptable salt thereof: 0.5 to 5 parts by mass, (C2) Chlorpheniramine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass, (C3) Anhydrous caffeine: 1 to 30 parts by mass, (C4) Ibuprofen: 10 to 30 parts by mass, (C5) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 75 parts by mass. (I-4) The oral pharmaceutical composition according to any one of (I-1) to (I-3), wherein the solid form is in the form of powder, granule, tablet, or capsule. (I-5) The oral pharmaceutical composition according to any one of (I-1) to (I-4), wherein the amount (unit dose) of L-carbocysteine contained in one administration is 753 mg to 1500 mg when taken once a day; 753 / 2 mg to 1500 / 2 mg when taken twice a day; 753 / 3 mg to 1500 / 3 mg when taken three times a day.

[0011] (II) Method for stabilizing the formulation of a pharmaceutical composition containing L-carbocysteine (II-1) A method for improving the stability of a solid-form pharmaceutical composition containing the following components (A) to (C), characterized by setting the blending amount of the component (A) per daily dose to 753 mg to 1500 mg: (A) L-carbocysteine, (B) Dextromethorphan, a pharmaceutically acceptable salt thereof or hydrates thereof, and At least one selected from the group consisting of ambroxol, chlorpheniramine, caffeine anhydrous, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof. (II-2) The method for improving stability according to (II-1), wherein the pharmaceutical composition contains the component (B) in a ratio of 1 to 6 parts by mass with respect to 100 parts by mass of the component (A). (II-3) The method for improving stability according to (II-1) or (II-2), wherein at least one of the component (C) is blended in the following ratio with respect to 100 parts by mass of the component (A) in the pharmaceutical composition; (C1) Ambroxol or a salt thereof: 0.5 to 5 parts by mass, (C2) Chlorpheniramine or a salt thereof: 0.1 to 1.2 parts by mass, (C3) Caffeine anhydrous: 1 to 30 parts by mass, (C4) Ibuprofen: 10 to 30 parts by mass, (C5) Tranexamic acid or a salt thereof: 15 to 75 parts by mass. (II-4) The method for improving the stability of the pharmaceutical composition according to any one of (II-1) to (II-3), which is a method for suppressing a decrease in the content of the components (C1) to (C3) under exposure conditions, or a method for suppressing coloring of the pharmaceutical composition under 40°C and 75% RH. (II-5) The method for improving stability according to any one of (II-1) to (II-4), wherein the method for improving stability is a method for improving the stability of the pharmaceutical composition as compared with a pharmaceutical composition containing the components (A) to (C) and having a blending amount of the component (A) of 750 mg per daily dose. (II-6) The method for improving stability according to any one of (II-1) to (II-5), wherein the blending amount of the component (A) per single dose of the pharmaceutical composition is 753 mg to 1500 mg when taken once a day; 753 / 2 mg to 1500 / 2 mg when taken twice a day; 753 / 3 mg to 1500 / 3 mg when taken three times a day. [[Effect of the Invention]]

[0012] According to the present invention, it is possible to provide L-carbocysteine and a pharmaceutical composition containing the same having good formulation stability. More specifically, according to the present invention, in a solid pharmaceutical composition containing at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof, in addition to L-carbocysteine and DXM, when the daily dose of L-carbocysteine is adjusted to 750 mg, it is possible to provide an L-carbocysteine and DXM-containing pharmaceutical composition in which the following problems are suppressed and improved. (a) Blending of ambroxol salt: The content of ambroxol salt in the pharmaceutical composition decreases by an accelerated test at 40 °C assuming long-term storage under room temperature conditions; (b) Blending of chlorpheniramine salt: The content of chlorpheniramine salt in the pharmaceutical composition decreases by an exposure test assuming storage under exposure conditions; (c) Blending of anhydrous caffeine: The content of anhydrous caffeine in the pharmaceutical composition decreases by an exposure test, and the pharmaceutical composition is colored by an accelerated test at 40 °C; (d) Blending of ibuprofen: The pharmaceutical composition is colored by an exposure test; (e) Blending of tranexamic acid: The pharmaceutical composition is colored by an accelerated test at 40 °C.

[0013] Also according to the present invention, it is possible to provide a method for improving the above-mentioned problems of formulation stability (decrease in the content of active ingredient, coloring) in a solid pharmaceutical composition containing 750 mg of L-carbocysteine in terms of the daily dose, and at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof, in addition to DXM.

Mode for Carrying Out the Invention

[0014] (I) Pharmaceutical composition containing L-carbocysteine and DXM analogs, and method for producing the same The L-carbocysteine and DXM-containing pharmaceutical composition of the present invention (hereinafter, also simply referred to as "the present pharmaceutical composition") is a solid pharmaceutical composition containing the following components (A), (B), and (C): (A) L-carbocysteine in an amount of 753 mg to 1500 mg in terms of the daily dose, (B) Dextromethorphan, its pharmaceutically acceptable salts or their hydrates, and (C) at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and their pharmaceutically acceptable salts.

[0015] These components will be described below. (A) Component L-carbocysteine is a compound having an airway mucus regulating action and a mucosal normalization action, and is used as an active ingredient of a pharmaceutical composition having an expectorant effect in diseases such as upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis; and an effect of discharging pus in chronic rhinosinusitis. As L-carbocysteine, any substance applicable to the human body may be used, for example, L-carbocysteine described in the Japanese Pharmacopoeia can be used.

[0016] The amount of L-carbocysteine contained in the present pharmaceutical composition is 753 mg or more in terms of the amount taken by one adult per day (daily dose), and it may be any amount that can exhibit at least the medicinal effect required for the L-carbocysteine-containing pharmaceutical composition and the effect of the present invention, and can be appropriately set and adjusted within that range. Preferably, the daily dose is 1000 mg or more, 1100 mg or more, more preferably 1200 mg or more, still more preferably 1300 mg or more, and particularly preferably 1400 mg or more. The upper limit value of the daily dose is not limited, but 1500 mg can be mentioned.

[0017] This pharmaceutical composition can be taken (orally administered) once a day or divided into 2 to 3 times a day so that the daily dosage of L-carbocysteine for one adult is 753 mg or more, preferably 753 mg to 1500 mg, more preferably 1000 mg to 1500 mg.

[0018] Here, "753 mg or more in terms of the amount taken by one adult per day (daily dosage)" means that when this pharmaceutical composition is designed for one adult to take once a day, the amount of L-carbocysteine (unit dosage) contained in one dose is 753 mg or more, preferably 753 to 1500 mg. Note that this dosage can be appropriately selected and set within the range of "753 to 1500 mg". Also, when it is designed to be taken in two divided doses a day, the amount of L-carbocysteine (unit dosage) contained in one dose means an amount corresponding to 1 / 2 of the above. Similarly, when it is designed to be taken in three divided doses a day, the amount of L-carbocysteine (unit dosage) contained in one dose means an amount corresponding to 1 / 3 of the above.

[0019] In the present invention, "adult" means men and women aged 15 or older. However, this pharmaceutical composition is not limited to a formulation for adults, and it may be taken by children under 15 years old. When taken by children, the daily dosage of L-carbocysteine per person may be the same as that of adults described above, or it can also be reduced, for example, to 1 / 2 or 2 / 3 of the amount taken by adults per day according to each age group.

[0020] Also, when the mass of this pharmaceutical composition is taken as 100% by mass, the proportion of L-carbocysteine contained therein can be appropriately set within the range that can exhibit the medicinal effects required for the L-carbocysteine-containing pharmaceutical composition and the effects of the present invention. For example, a range of 30 to 95% by mass can be exemplified. Preferably, it is in the range of 40 to 90% by mass, more preferably 50 to 90% by mass.

[0021] (B) Component Dextromethorphan is a compound that acts on the cough center of the brain, raises the cough reflex threshold, and has an effect of suppressing cough (antitussive effect). Usually, it is used as an active ingredient of a pharmaceutical composition with efficacy and effect for treating cough in colds, acute and chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, upper respiratory tract inflammation (pharyngolaryngitis, rhinitis), and during bronchography and bronchoscopy. Dextromethorphan (also simply referred to as "DXM" in this specification) can have a pharmaceutically acceptable salt (also referred to as "DXM salt") form and / or a hydrated form of these. In this specification, these may be collectively referred to as "(B) component" or "DXM compounds".

[0022] As the (B) component, any substance applicable to the human body may be used. For example, a hydrated DXM salt listed in the Japanese Pharmacopoeia can be used. Examples of DXM salts include hydrobromide salts of DXM.

[0023] The amount of the (B) component contained in this pharmaceutical composition may be any amount that can exhibit at least the medicinal efficacy required for the L-carbocysteine-containing pharmaceutical composition and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, in the case of DXM hydrobromide hydrate, it can be appropriately set and adjusted from the range of 15 to 150 mg in terms of the amount taken by one adult per day.

[0024] Here, the "range of 15 to 150 mg in terms of the amount taken by one adult per day" means that when this pharmaceutical composition is designed to be taken once a day by one adult, the amount of DXM hydrobromide hydrate contained in one dose (unit dose) is adjusted to the above range. When it is designed to be taken in two or three divided doses per day, the amount of DXM hydrobromide hydrate contained in one dose (unit dose) is adjusted to a range corresponding to 1 / 2 or 1 / 3 of the above. When children take it, it may be the same amount as that of the above-mentioned adults, or it can also be used in a reduced amount such as the same amount as or 1 / 2 or 2 / 3 of the amount taken by an adult per day according to each age group. Such a dosage design is similarly applicable to the (C) component described later.

[0025] Although the ratio of the component (B) to 100 parts by mass of the component (A) contained in the pharmaceutical composition is not limited, it can preferably be adjusted to be in the range of 1 to 6 parts by mass from the viewpoint of formulation stability. More preferably, it is in the range of 2 to 6 parts by mass, still more preferably in the range of 3 to 6 parts by mass, and particularly preferably in the range of 4 to 6 parts by mass.

[0026] (C) Component The component (C) used in combination with the above-mentioned components (A) and (B) is at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof.

[0027] (C1) Ambroxol or a pharmaceutically acceptable salt thereof Ambroxol or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "ambroxol salt") (hereinafter these are also collectively referred to as "(C1) component") is a compound having a respiratory lubricating and expectorant effect (expectorant), for example, expectoration during diseases such as acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, and difficulty in expectorating sputum after surgery, or it is used as an active ingredient of a pharmaceutical composition having efficacy and effect against purulent discharge during chronic rhinosinusitis. As the (C1) component, any one that can be applied to the human body may be used, for example, ambroxol salts listed in the Japanese Pharmacopoeia can be used.

[0028] Examples of ambroxol salts include inorganic acid salts such as hydrochloride, nitrate, and acetate of ambroxol; organic acid salts such as citrate, fumarate, and succinate. Inorganic acid salts such as ambroxol hydrochloride are preferred.

[0029] The amount of the component (C1) contained in the pharmaceutical composition may be any amount as long as it can exhibit at least the medicinal effects required for the L-carbocysteine- and DXM-containing pharmaceutical composition and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, in the case of ambroxol salts, it can be appropriately set and adjusted from the range of 15 to 75 mg in terms of the amount of ambroxol hydrochloride taken by one adult per day.

[0030] Here, the phrase "in the range of 15 to 75 mg in terms of the amount of ambroxol hydrochloride taken by one adult per day" means that when the pharmaceutical composition is designed for one adult to take once a day, the amount of ambroxol hydrochloride (unit dose) contained in one dose is adjusted to be within the above range. When it is designed to be taken in two or three divided doses per day, the amount of ambroxol hydrochloride (unit dose) contained in one dose is adjusted to be within the range corresponding to 1 / 2 or 1 / 3 of the above amount.

[0031] Although the ratio of the component (C1) to 100 parts by mass of the component (A) contained in the pharmaceutical composition is not limited, preferably, from the viewpoint of formulation stability, it can be adjusted to be in the range of 0.5 to 5 parts by mass. Preferably, it is in the range of 1 to 5 parts by mass, more preferably in the range of 2 to 5 parts by mass, and still more preferably in the range of 3 to 5 parts by mass.

[0032] In addition to the aforementioned component (B), by adding component (C1) to the pharmaceutical composition containing component (A) in the aforementioned ratio, as shown in Experimental Example 1 described below, it is possible to suppress and improve the decrease in the content of component (C1) during storage under room temperature conditions, and a pharmaceutical composition containing (A), (B) and (C1) having good formulation stability can be provided. This effect can be obtained more effectively by adjusting the blending ratio of component (C1) relative to 100 parts by mass of component (A) so as to be within the above range. Further, while adjusting the blending ratio of component (C1) relative to 100 parts by mass of component (A) to be within the above range, the ratio of component (B) relative to 100 parts by mass of component (A) is adjusted to be 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and still more preferably 4 to 6 parts by mass, whereby the above effect can be obtained more effectively.

[0033] (C2) Chlorpheniramine or a pharmaceutically acceptable salt thereof Chlorpheniramine or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as "chlorpheniramine salt") (hereinafter, these are also collectively referred to as "(C2) component") is a compound having an antihistamine action (allergy drug). For example, it is used as an active ingredient of a pharmaceutical composition having efficacy and effect against urticaria, angioedema, hay fever, pruritus associated with skin diseases (eczema / dermatitis, cutaneous pruritus, drug eruption), allergic rhinitis, vasomotor rhinitis, or sneezing / rhinorrhea / cough associated with upper respiratory tract inflammation such as cold. As the (C2) component, any substance that can be applied to the human body may be used. For example, chlorpheniramine salts listed in the Japanese Pharmacopoeia can be used.

[0034] Examples of the chlorpheniramine salt include organic acid salts such as maleate, citrate, fumarate and succinate of chlorpheniramine; or inorganic acid salts such as hydrochloride, nitrate and acetate. Organic acid salts such as chlorpheniramine maleate are preferred.

[0035] The amount of the component (C2) contained in the pharmaceutical composition may be any amount as long as it can exhibit at least the medicinal effects required for the L-carbocysteine and DXM-containing pharmaceutical composition and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, in the case of chlorpheniramine salt, it can be appropriately set and adjusted within the range of 1.5 to 18 mg in terms of the amount of chlorpheniramine maleate taken by one adult per day.

[0036] Here, the phrase "in the range of 1.5 to 18 mg in terms of the amount of chlorpheniramine maleate taken by one adult per day" means that when the pharmaceutical composition is designed for one adult to take once a day, the amount of chlorpheniramine maleate (unit dose) contained in one dose is adjusted to be within the above range. When it is designed to be taken in two or three divided doses per day, the amount of chlorpheniramine maleate (unit dose) contained in one dose is adjusted to be within the range corresponding to 1 / 2 or 1 / 3 of the above.

[0037] The ratio of the component (C2) to 100 parts by mass of the component (A) contained in the pharmaceutical composition is not limited, but preferably can be adjusted to be in the range of 0.1 to 1.2 parts by mass from the viewpoint of formulation stability. Preferably it is in the range of 0.2 to 1.2 parts by mass, more preferably in the range of 0.4 to 1.2 parts by mass, and still more preferably in the range of 0.6 to 1.2 parts by mass.

[0038] In addition to the aforementioned component (B), by blending component (C2) into the pharmaceutical composition containing component (A) at the aforementioned ratio, as shown in Experimental Example 2 described below, it is possible to suppress and improve the decrease in the content of component (C2) due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and a pharmaceutical composition containing (A), (B), and (C2) having good formulation stability can be provided. This effect can be obtained more effectively by adjusting the blending ratio of component (C2) with respect to 100 parts by mass of component (A) to be within the above range. Further, while adjusting the blending ratio of component (C2) with respect to 100 parts by mass of component (A) to be within the above range, and adjusting the ratio of component (B) with respect to 100 parts by mass of component (A) to be 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass, the above effect can be obtained more effectively.

[0039] (C3) Caffeine anhydrous Caffeine anhydrous (hereinafter, this is also referred to as "component (C3)") is a compound that has the effect of removing drowsiness and fatigue by stimulating the central nervous system and alleviating the feeling of a heavy head. It is a component that can be blended as an adjuvant in cough and expectorant drugs, cold remedies, oral medications for rhinitis, analgesics, motion sickness drugs, or drinks, etc. for the purpose of enhancing the efficacy of the drug. As component (C3), any substance that can be applied to the human body may be used, and for example, caffeine anhydrous listed in the Japanese Pharmacopoeia can be used. The standard for caffeine anhydrous is defined in the Japanese Pharmacopoeia as containing 98.5% or more of caffeine anhydrous when quantified in a dried state.

[0040] The amount of the component (C3) contained in the pharmaceutical composition may be any amount as long as it can exhibit at least the medicinal effects required for the L-carbocysteine and DXM-containing pharmaceutical composition and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, it can be appropriately set and adjusted within the range of 15 to 450 mg in terms of the amount of anhydrous caffeine taken by one adult per day. When designed to be taken in two or three divided doses per day, the amount of anhydrous caffeine contained in a single dose (unit dose) is adjusted to be in the range corresponding to 1 / 2 or 1 / 3 of the above.

[0041] Although the ratio of the component (C3) to 100 parts by mass of the component (A) contained in the pharmaceutical composition is not limited, preferably, from the viewpoint of formulation stability, it is preferably adjusted to be in the range of 1 to 30 parts by mass. Preferably, it is in the range of 5 to 30 parts by mass, more preferably in the range of 10 to 30 parts by mass, and even more preferably in the range of 20 to 30 parts by mass.

[0042] By blending the component (C3) with the pharmaceutical composition containing the component (A) at the aforementioned ratio, as shown in Experimental Example 3 described later, it is possible to suppress and improve the coloring over time during storage under room temperature conditions, and / or suppress and improve the decrease in the content of the component (C3) during storage under sunlight or lighting (exposure conditions) indoors and outdoors, and it is possible to provide a pharmaceutical composition containing (A), (B), and (C3) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (C3) to 100 parts by mass of the component (A) to be within the above range. Further, while adjusting the blending ratio of the component (C3) to 100 parts by mass of the component (A) to be within the above range, and adjusting the ratio of the component (B) to 100 parts by mass of the component (A) to be 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass, the above effect can be obtained more effectively.

[0043] (C4) Ibuprofen Ibuprofen (hereinafter also referred to as "(C4) component") is a non-steroidal compound having anti-inflammatory, analgesic and antipyretic effects. For example, it is used as an active ingredient in pharmaceutical compositions for anti-inflammatory and analgesic effects such as rheumatoid arthritis, arthralgia and arthritis, neuralgia and neuritis, low back pain, cervical spondylosis, adnexitis, dysmenorrhea, erythema (erythema nodosum, polymorphic exudative erythema, centrifugal annular erythema), etc.; anti-inflammatory and analgesic effects after surgery and trauma; antipyretic and analgesic effects during acute upper respiratory tract infection. As the (C4) component, any substance applicable to the human body can be used. For example, ibuprofen listed in the Japanese Pharmacopoeia can be used.

[0044] The amount of the (C4) component contained in this pharmaceutical composition may be any amount as long as it can exhibit at least the medicinal effects required for the L-carbocysteine and DXM-containing pharmaceutical compositions and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, it can be appropriately set and adjusted within the range of 150 to 600 mg in terms of the amount of ibuprofen taken by an adult per day. When designed to be taken in two or three divided doses per day, the amount of ibuprofen contained in each single dose is adjusted to be in the range corresponding to 1 / 2 or 1 / 3 of the above.

[0045] Although the ratio of the (C4) component to 100 parts by mass of the (A) component contained in this pharmaceutical composition is not limited, preferably, from the viewpoint of formulation stability, it is preferably adjusted to be in the range of 10 to 30 parts by mass. More preferably, it is in the range of 15 to 30 parts by mass, and particularly preferably, it is in the range of 20 to 30 parts by mass.

[0046] By blending the (C4) component into the pharmaceutical composition containing the (A) component in the aforementioned ratio, as shown in Experimental Example 4 described later, it is possible to suppress and improve the coloring over time due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and it is possible to provide a pharmaceutical composition containing (A), (B), and (C4) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the (C4) component with respect to 100 parts by mass of the (A) component so as to be within the above range. Further, while adjusting the blending ratio of the (C4) component with respect to 100 parts by mass of the (A) component to be within the above range, and adjusting the ratio of the (B) component with respect to 100 parts by mass of the (A) component to be 1 to 4 parts by mass, preferably 2 to 4 parts by mass, more preferably 3 to 4 parts by mass, the above effect can be obtained more effectively.

[0047] (C5) Tranexamic acid or a pharmaceutically acceptable salt thereof Tranexamic acid or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as "tranexamate") (hereinafter, these are also collectively referred to as "(C2) component") is a compound having an antiplasmin action, and bleeding tendency considered to be involved in systemic hyperfibrinolysis (leukemia, aplastic anemia, purpura, etc., and abnormal bleeding during and after surgery); abnormal bleeding considered to be involved in local hyperfibrinolysis (pulmonary hemorrhage, epistaxis, genital bleeding, renal hemorrhage, abnormal bleeding during and after prostate surgery); symptoms such as erythema, swelling, and itching in diseases such as eczema and its similar diseases, urticaria, drug rash, and toxic rash; symptoms such as sore throat, redness, congestion, and swelling in diseases such as tonsillitis and pharyngitis; oral pain and oral mucosal aphthae in stomatitis. It is used as an active ingredient of a pharmaceutical composition having efficacy and effect. As the (C5) component, any substance that can be applied to the human body may be used, and for example, tranexamic acid listed in the Japanese Pharmacopoeia can be used.

[0048] Examples of tranexamate include alkali metal salts and alkaline earth metal salts of tranexamic acid, but tranexamic acid is preferably used as the (C5) component.

[0049] The amount of the (C5) component contained in the pharmaceutical composition may be any amount that can exhibit at least the medicinal effects required for the L-carbocysteine and DXM-containing pharmaceutical composition and the effects of the present invention, and can be appropriately set and adjusted within that range. For example, it can be appropriately set and adjusted within the range of 225 to 1050 mg in terms of the amount of tranexamic acid taken by one adult per day. When designed to be taken in two or three divided doses per day, the amount of tranexamic acid (unit dose) contained in each dose is adjusted to be in the range corresponding to 1 / 2 or 1 / 3 of the above.

[0050] Although the ratio of the (C5) component to 100 parts by mass of the (A) component contained in the pharmaceutical composition is not limited, preferably, from the viewpoint of formulation stability, it can be adjusted to be in the range of 15 to 75 parts by mass. More preferably, it is in the range of 20 to 75 parts by mass, still more preferably in the range of 30 to 75 parts by mass, and particularly preferably in the range of 40 to 75 parts by mass.

[0051] In addition to the aforementioned (B) component, by blending the (C5) component with the pharmaceutical composition containing the (A) component in the aforementioned ratio, as shown in Experimental Example 5 described later, it is possible to suppress and improve the coloring over time due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and provide a pharmaceutical composition containing (A), (B), and (C5) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the (C5) component to 100 parts by mass of the (A) component to be within the above range. Further, while adjusting the blending ratio of the (C5) component to 100 parts by mass of the (A) component to be within the above range, and adjusting the ratio of the (B) component to 100 parts by mass of the (A) component to be 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and still more preferably 4 to 6 parts by mass, the above effect can be obtained more effectively.

[0052] The above-described components (C1) to (C5) may each be used alone or in combination with the components (A) and (B), or two or more of them may be arbitrarily combined and used in combination with the components (A) and (B). Examples of combinations of the component (C) include, for example, a mode in which at least one selected from the group consisting of (C2) to (C5) is combined with (C1); a mode in which at least one selected from the group consisting of (C1), (C3) to (C5) is combined with (C2); a mode in which at least one selected from the group consisting of (C1), (C2), (C4), and (C5) is combined with (C3); a mode in which at least one selected from the group consisting of (C1) to (C3) and (C5) is combined with (C4); and a mode in which at least one selected from the group consisting of (C1) to (C4) is combined with (C5).

[0053] (D) Optional pharmacologically active ingredient In addition to the aforementioned components (A) to (C), the pharmaceutical composition may further contain other pharmacologically active ingredients, provided that the effects of the present invention are not impaired. Although not limited, for example, analgesics and antipyretics such as aspirin, ethenzamide, acetaminophen, isopropylantipyrine, loxoprofen, acetylsalicylic acid, diclofenac, and salts thereof; antihistamines such as diphenhydramine, clemastine, promethazine, and salts thereof; anticholinergic drugs such as isopropylamide iodide; adrenergic components such as pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, phenylephrine hydrochloride, etc.; antitussive components such as dihydrocodeine phosphate, tipepidine hibenzate, noscapine, etc.; expectorant components such as bromhexine hydrochloride, potassium cresolsulfonate, guaifenesin, etc.; anti-inflammatory components such as glycyrrhizic acid, sodium azulenesulfonate hydrate, etc.; crude drug components such as Glycyrrhizae Radix, Cinnamomi Ramulus, Zingiberis Rhizoma, Platycodonis Radix, Glycyrrhizae Radix, Mori Cortex, Zanthoxyli Pericarpium, Citri Reticulatae Pericarpium, etc.; antacid components such as sodium hydrogen carbonate, magnesium carbonate, magnesium aluminometasilicate, etc.; vitamin C; vitamin B1 such as thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate ester, fursultiamine hydrochloride, disulthiame hydrochloride, octothiamine, ciclotiamine, bisibutiamine, bisbentiamine, and benfotiamine; vitamin B2 such as riboflavin, riboflavin butyrate, and sodium riboflavin phosphate; vitamin B6 such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 such as cyanocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, and mecobalamin; nicotinic acids such as nicotinic acid and nicotinamide; vitamin E such as d-α-tocopherol succinate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol, and dl-α-tocopherol, etc. can be mentioned.

[0054] Among them, preferably, they are tepedine hibenzate, acetaminophen, loxoprofen, diphenhydramine, and bromhexine hydrochloride, and more preferably acetaminophen. For example, when acetaminophen is formulated in the pharmaceutical composition, the amount thereof can be exemplified as 450 to 900 mg in terms of the daily dose. Further, when tepedine hibenzate is formulated in the pharmaceutical composition, for example, the ratio can be appropriately set within the range that exhibits the medicinal effects required for the L-carbocysteine and DXM-containing pharmaceutical composition and the effects of the present invention. For example, a ratio of 20 to 70 parts by mass can be exemplified with respect to 100 parts by mass of the component (A).

[0055] (E) Optional carrier / additive In the production of the pharmaceutical composition, in addition to the components described above, conventional well-known carriers and additives can be arbitrarily blended as long as the effects of the present invention are not impaired. Examples of these carriers and additives include, for example, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusting agents, dispersants, solubilizers, fluidizing agents, glazing agents, flavoring agents, sweetening agents, cooling agents, coloring agents, odor correctors, fragrances, adsorbents, sugar coatings, suspending agents, antistatic agents, plasticizers, and fragrances, etc., can be exemplified without limitation.

[0056] As excipients, although not limited as long as the effects of the present invention are not impaired, for example, lactose, refined sugar, glucose, powdered sugar, fructose, maltose, reduced maltose syrup, crystalline cellulose, powdered cellulose, corn starch, potato starch, sugar alcohols (mannitol, xylitol, sorbitol, erythritol, etc.), trehalose, inorganic salts, dextran, dextrin, β-cyclodextrin, sucrose fatty acid ester, soybean lecithin, tragacanth powder, gum arabic, pullulan, kaolin, etc. can be mentioned. These can be used alone or in any combination of two or more. When the mass of the pharmaceutical composition is 100% by mass, the proportion of the excipient contained therein is not limited as long as it does not adversely affect the effects of the present invention. For example, a range of 0.1 to 70% by mass can be exemplified. Preferably, it is in the range of 0.5 to 50% by mass, more preferably in the range of 1 to 40% by mass.

[0057] As binders, although not limited as long as the effects of the present invention are not impaired, for example, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, carnauba wax, beeswax, gum arabic, powdered gum arabic, gelatin, pregelatinized starch, alginic acid, sodium alginate, carboxyvinyl polymer, agar, pullulan, dextrin, shellac, sucrose, tragacanth, tragacanth powder, xanthan gum, pectin, sodium polyacrylate, guar gum, etc. can be mentioned. When the mass of the pharmaceutical composition is 100% by mass, the proportion of the binder contained therein is not limited as long as it does not adversely affect the effects of the present invention. For example, a range of 0.1 to 5% by mass can be exemplified. Preferably, it is in the range of 0.5 to 4% by mass, more preferably in the range of 1 to 3% by mass.

[0058] As disintegrants, although not limited as long as the effects of the present invention are not impaired, examples include corn starch, potato starch, pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl starch with low degree of substitution, calcium carmellose, hydroxypropyl cellulose with low degree of substitution, croscarmellose sodium, crystalline cellulose, powdered cellulose, crospovidone, sodium carmellose, agar powder, tricalcium phosphate, sodium hydrogen carbonate, and the like. When the mass of the pharmaceutical composition is 100% by mass, the proportion of the disintegrant contained therein is not limited as long as it does not adversely affect the effects of the present invention, and for example, a range of 0.1 to 20% by mass can be exemplified. Preferably, it is in the range of 0.5 to 15% by mass, more preferably in the range of 1 to 10% by mass.

[0059] As lubricants, although not limited as long as the effects of the present invention are not impaired, examples include magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid ester, sodium stearyl fumarate, light anhydrous silicic acid, silicon dioxide, carnauba wax, glycerin fatty acid ester, hydrogenated oil, and the like.

[0060] As flavoring agents, although not limited, examples include organic acids such as citric acid, tartaric acid, and malic acid, sodium glutamate, sodium 5'-inosinate, sodium 5-guanylate, sodium aspartate, and caramel.

[0061] As sweeteners, although not limited, examples include high-intensity sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, lo han guo, thaumatin, acesulfame potassium, sucralose, sucrose, fructose, glucose, lactose, maltose, sorbitol, maltitol, mannitol, xylitol, erythritol, glycerol, inositol, reduced maltose syrup, palatinose, coupling sugar, and honey.

[0062] This pharmaceutical composition has a solid form. Examples of such preparations include tablets, powders, granules, and pills. Granules and tablets are preferred. The tablets may be composed of a single layer or may have a multi-layer structure of two or more layers.

[0063] This pharmaceutical composition can be produced by mixing at least components (A), (B), and (C) selected from the group consisting of the aforementioned components (A) to (E) and shaping them into a desired form. Preferably, in addition to components (A) to (C), at least component (E) can be blended and shaped to produce it.

[0064] More specifically, for example, in the production of granules, at least components (A) to (C) can be mixed and granulated to prepare a granulated product containing L-carbocysteine and DXM analogs A method can be used. For granulation, either a wet granulation method or a dry granulation method may be used. In the preparation of the granulated product, any additive used in the production of the granulated product can be further blended as component (E) as long as the effects of the present invention are not impaired. Examples of such additives include, for example, excipients, binders, disintegrants, disintegration aids, adsorbents, fluidizing agents, lubricants, sweeteners, flavoring agents, cooling agents, coloring agents, pH adjusters, surfactants, and antioxidants. Although not limited, excipients, binders, disintegrants, and fluidizing agents are preferred.

[0065] For the production of granules, known granulation apparatuses can be used without limitation. Specifically, fluidized bed granulators, stirring granulators, extrusion granulators, rolling granulators, wurster granulators, or granulators combining these can be mentioned. As described above, to a powder mixture obtained by adding and mixing additives ((E) component) such as excipients and binders, as necessary, to components (A) to (C), a solution or suspension of a granulation binder is added, and granulation is carried out using the above-mentioned granulator, and the obtained granulated product is dried using, for example, a fluidized bed dryer or the like, whereby a granulated product containing L-carbocysteine and DXM can be obtained. The obtained granulated product may then be subjected to a sizing process to be adjusted to a desired average particle size. Although not limited, examples of the average particle size can include a range of 80 to 300 μm, preferably 100 to 250 μm (measurement by sieve).

[0066] For the production of tablets, a method can be used in which a lubricant is blended, as necessary, with the granulated product containing L-carbocysteine and DXM prepared as described above, and this is compression molded. Compression molding can be carried out according to a conventional method and is not particularly limited. For example, compression molding using a rotary tablet press, a single-shot tablet press, etc. can be used. Also, regarding the pressure during compression molding, although not particularly limited as long as it is a condition under which a compression molded body having a desired hardness and not cracking or chipping during production or transportation can be produced, usually, a pressure of 50 MPa to 500 MPa can be mentioned. Preferably, it is 100 MPa to 400 MPa.

[0067] After compression molding, a coating process may be performed as necessary to prepare a coated preparation. The coated preparation includes a sugar-coated preparation in which the surface of the tablet is coated with sugar, and a film coating preparation in which the surface is coated with a film or the like. The film includes films having properties such as immediate solubility, delayed solubility, gastric solubility, and enteric solubility. Coating with sugar or a film can be carried out, for example, by the pan coating method, the fluidized bed coating method, the rolling coating method, the dry coating method, or a combination of these methods. At this time, according to a conventional method, a sugar coating component or a film component can be dissolved or dispersed in water or an organic solvent (such as ethanol) and spray-coated, or the film component can be directly sprayed and dry-coated by applying heat or pressure.

[0068] The mass per single dose of this pharmaceutical composition can be appropriately set and adjusted from the daily dose (753 mg to 1500 mg) of L-carbocysteine and the number of daily administrations. For example, although not limited, when designed to be administered 3 times a day to one adult, the dose (unit dose) per administration of this pharmaceutical composition can be selected from the range of 251 to 500 mg in terms of the unit dose of L-carbocysteine. This range can be appropriately set, for example, to be 300 to 500 mg, 350 to 500 mg, 400 to 500 mg, and 450 to 500 mg. In addition, when this pharmaceutical composition is prepared in tablet form and designed to be taken 2 tablets at a time, 3 times a day for one adult, the mass of one tablet of this pharmaceutical composition can be selected from the range of 125.5 to 250 mg in terms of the amount of L-carbocysteine.

[0069] (II) Method for stabilizing the formulation of a pharmaceutical composition containing L-carbocysteine and DXM analogs The present invention provides a method for improving the formulation stability of a solid pharmaceutical composition containing the following components (A) to (C): (A) L-carbocysteine, (B) Dextromethorphan, its pharmaceutically acceptable salts or their hydrates, and At least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof. The method (hereinafter also referred to as "the method of the present invention") can be carried out by setting the blending amount of component (A) in the pharmaceutical composition to 753 mg or more, preferably 753 mg to 1500 mg, more preferably 1000 mg to 1500 mg, in terms of the amount taken by one adult per day (daily dosage).

[0070] In the above, "753 mg or more in terms of the amount taken by one adult per day" means that the amount of component (A) contained in the daily dosage of this pharmaceutical composition is 753 mg or more. Therefore, when this pharmaceutical composition is designed to be taken twice a day, the amount of component (A) contained in one dose (unit dose) corresponds to 1 / 2 of the above amount (376.5 mg or more, preferably 376.5 to 750 mg). The unit dose (1 / 2 equivalent amount) includes 400 to 750 mg, 500 to 750 mg, 600 to 750 mg, 700 to 750 mg. Also, when this pharmaceutical composition is designed to be taken three times a day, the amount of component (A) contained in one dose (unit dose) corresponds to 1 / 3 of the above amount (251 mg or more, preferably 251 to 500 mg). The unit dose (1 / 3 equivalent amount) includes 300 to 500 mg, 350 to 500 mg, 400 to 500 mg, 450 to 500 mg.

[0071] The method of the present invention can be more preferably carried out by, in addition to the above means, blending the component (B) in a ratio of 1 to 6 parts by mass with respect to 100 parts by mass of the component (A) in the pharmaceutical composition. The blending ratio of the component (B) is preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and still more preferably 4 to 6 parts by mass.

[0072] The method of the present invention can be more preferably carried out by, in addition to the means described above, blending at least one of the component (C) in the following ratios with respect to 100 parts by mass of the component (A) in the pharmaceutical composition; (C1) Ambroxol or a pharmaceutically acceptable salt thereof: 0.5 to 5 parts by mass, preferably 1 to 5 parts by mass, more preferably 2 to 5 parts by mass, still more preferably 3 to 5 parts by mass. (C2) Chlorpheniramine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass, preferably 0.2 to 1.2 parts by mass, more preferably 0.4 to 1.2 parts by mass, still more preferably 0.6 to 1.2 parts by mass. (C3) Caffeine anhydrous: 1 to 30 parts by mass, preferably 5 to 30 parts by mass, more preferably 10 to 30 parts by mass, still more preferably 20 to 30 parts by mass. (C4) Ibuprofen: 10 to 30 parts by mass, preferably 15 to 30 parts by mass, more preferably 20 to 30 parts by mass, (C5) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 75 parts by mass, preferably 20 to 75 parts by mass, more preferably 30 to 75 parts by mass, still more preferably 40 to 75 parts by mass.

[0073] The above-described components (C1) to (C5) may each be used alone in combination with the components (A) and (B), or two or more of them may be arbitrarily combined and used in combination with the components (A) and (B). Examples of the combination of the component (C) include a mode of combining (C1) with at least one selected from the group consisting of (C2) to (C5); a mode of combining (C2) with at least one selected from the group consisting of (C1) and (C3) to (C5); a mode of combining (C3) with at least one selected from the group consisting of (C1), (C2), (C4) and (C5); a mode of combining (C4) with at least one selected from the group consisting of (C1) to (C3) and (C5); and a mode of combining (C5) with at least one selected from the group consisting of (C1) to (C4). Regarding the types, blending ratios, and blending methods of the components (A), (B), (C1), (C2), (C3), (C4), and (C5), the description in the aforementioned (I) can be referred to, and the description can be incorporated herein by reference.

[0074] As shown in Experimental Example 1 described later, by blending the component (C1) with the pharmaceutical composition containing the component (A) at the aforementioned ratio in addition to the component (B), it is possible to suppress and improve the decrease in the content of the component (C1) due to storage at 40°C and 75% RH, and a pharmaceutical composition containing (A), (B), and (C1) with improved formulation stability can be provided. This effect can be obtained more effectively by adjusting the blending ratios of the component (B) and / or the component (C1) to be within the aforementioned range. The presence or absence of the improvement in formulation stability can be evaluated according to the method described in Experimental Example 1. In this case, compared with a pharmaceutical composition (control composition) containing the components (A), (B), and (C1) and having a content of the component (A) of 750 mg (for example, when converted to the unit dose of the component (A) for three times a day administration, it is 250 mg) when converted to the daily dose, when the decrease in the content of the component (C1) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0075] As shown in Experimental Example 2 described below, by adding the component (C2) to the pharmaceutical composition containing the component (A) at the ratio described above in addition to the component (B), it is possible to suppress and improve the decrease in the content of the component (C2) due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and it is possible to provide a pharmaceutical composition containing (A), (B), and (C2) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (B) and / or the component (C2) so as to be within the above range. The presence or absence of the improvement in formulation stability can be evaluated according to the method described in Experimental Example 2. In this case, compared with a pharmaceutical composition (control composition) containing the above (A), (B), and (C2) components and having a content of the component (A) of 750 mg when converted to the daily dose (when converted to the unit dose of the component (A) in the case of administering three times a day, it is 250 mg), when the decrease in the content of the component (C2) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0076] As shown in Experimental Example 3 described below, by adding the component (C3) to the pharmaceutical composition containing the component (A) at the ratio described above in addition to the component (B), it is possible to suppress and improve the decrease in the content of the component (C3) due to storage at 40 °C and 75% RH and / or storage under sunlight or lighting (exposure conditions) indoors and outdoors, and it is possible to provide a pharmaceutical composition containing (A), (B), and (C3) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (B) and / or the component (C3) so as to be within the above range. The presence or absence of the improvement in formulation stability can be evaluated according to the method described in Experimental Example 3. In this case, compared with a pharmaceutical composition (control composition) containing the above (A), (B), and (C3) components and having a content of the component (A) of 750 mg when converted to the daily dose (when converted to the unit dose of the component (A) in the case of administering three times a day, it is 250 mg), when the decrease in the content of the component (C3) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0077] As shown in Experimental Example 4 described below, by adding component (C4) to the pharmaceutical composition containing component (A) at the aforementioned ratio in addition to component (B), the coloring over time of the pharmaceutical composition due to storage under sunlight or lighting (exposure conditions) indoors and outdoors can be suppressed and improved, and a pharmaceutical composition containing (A), (B), and (C4) having good formulation stability can be provided. This effect can be obtained more effectively by adjusting the blending ratio of component (B) and / or component (C4) to be within the aforementioned range. The presence or absence of the improvement in formulation stability can be evaluated according to the method described in Experimental Example 4. In this case, compared with a pharmaceutical composition (control composition) containing the aforementioned (A), (B), and (C4) components and having a content of component (A) of 750 mg when converted to the daily dose (when converted to the unit dose of component (A) for administration three times a day, it is 250 mg), when the decrease in the content of component (C4) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0078] As shown in Experimental Example 5 described below, by adding component (C5) to the pharmaceutical composition containing component (A) at the aforementioned ratio in addition to component (B), the coloring over time of the pharmaceutical composition due to storage under sunlight or lighting (exposure conditions) indoors and outdoors can be suppressed and improved, and a pharmaceutical composition containing (A), (B), and (C5) having good formulation stability can be provided. This effect can be obtained more effectively by adjusting the blending ratio of component (B) and / or component (C5) to be within the aforementioned range. The presence or absence of the improvement in formulation stability can be evaluated according to the method described in Experimental Example 5. In this case, compared with a pharmaceutical composition (control composition) containing the aforementioned (A), (B), and (C5) components and having a content of component (A) of 750 mg when converted to the daily dose (when converted to the unit dose of component (A) for administration three times a day, it is 250 mg), when the decrease in the content of component (C5) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0079] As described above, in this specification, the terms "comprising" and "containing" include the meanings of "consisting of" and "substantially consisting of".

Examples

[0080] Hereinafter, in order to assist the understanding of the configuration and effects of the present invention, the present invention will be described using experimental examples. However, the present invention is not limited by these experimental examples in any way. The following experiments were carried out under room temperature (25 ± 5°C) and atmospheric pressure conditions unless otherwise specified. Unless otherwise specified, the "%" described below means "mass %" and the "parts" means "parts by mass".

[0081] The compounds used in the following experimental examples are as follows. L-Carbocysteine: Obtained from Alfaresa Pharma Co., Ltd. DXM hydrate: Dextromethorphan hydrobromide hydrate (obtained from Alps Pharmaceutical Co., Ltd.). Ambroxol salt: Ambroxol hydrochloride (obtained from Cambrex Profarmaco Milano S.r.L). Chlorpheniramine salt: Chlorpheniramine maleate (obtained from Kongang Chemical Co., Ltd.). Caffeine anhydrous: Obtained from Shizuoka Caffeine Industry Co., Ltd. Ibuprofen: Obtained from Yatsushiro Pharmaceutical Co., Ltd. Tranexamic acid: Obtained from Jiangsu Tianhe Pharmaceutical Co., Ltd.

[0082] The test methods adopted in the following experimental examples are as follows. (1) Exposure test (photo-stability evaluation test) The test preparation (granulated product) was placed in an unpacked glass petri dish and placed in the chamber of a photostability test apparatus (LTL-200A-15WCD, manufactured by Nagano Science Co., Ltd.) with the internal environment set to 25°C and 60% relative humidity (RH). The illuminance of the light source (D65 lamp) was set to 4000 lux, and the light was irradiated so that the total illuminance reached 1.2 million lux·hr.

[0083] (2) Accelerated test (storage stability evaluation test under room temperature conditions) The test preparation (granules) was filled into a brown glass bottle and placed in a constant temperature and humidity chamber (H21-13M, manufactured by Nagano Science Co., Ltd.) with the internal environment set to 40°C and 75% RH in the open-capped state, and allowed to stand and store for 1 month or 2 months.

[0084] The analysis methods and evaluation criteria adopted in the following experimental examples are as follows. (A) Method for quantifying the active ingredient and evaluation criteria (1) Quantitative method The test preparation containing the active ingredient to be measured (ambroxol salt, chlorpheniramine salt, or anhydrous caffeine) (test preparation before exposure or accelerated test, test preparation after exposure or accelerated test) was dissolved in a phosphoric acid ethanol solution and then filtered through a 0.45 μm filter, which was used as a sample for quantification. The phosphoric acid ethanol solution was prepared by mixing an aqueous phosphoric acid solution (phosphoric acid (1→500)) in which phosphoric acid was diluted 500-fold with water with ethanol at a ratio of 1:1 (volume ratio). This sample for quantification was subjected to HPLC under the following conditions to determine the area of the peak generated at the retention time corresponding to each active ingredient. The content of each active ingredient (ambroxol, chlorpheniramine, or anhydrous caffeine) contained in the sample for quantification was calculated from the ratio to the peak area of the standard solution prepared with the standard product (ambroxol, chlorpheniramine, or anhydrous caffeine) corresponding to each active ingredient.

[0085] [HPLC conditions] Measuring device: Alliance 2695 (manufactured by Waters Japan K.K.) Stationary phase: L-column2 4.6×100 mm, 3 μm (manufactured by Shimadzu GL Sciences Inc.) Mobile phase A: 0.1% trifluoroacetic acid Mobile phase B: methanol Gradient conditions:

[0086] [Table 1] Detector: W2489 UV / Vis detector (manufactured by Waters Japan K.K.) Measurement wavelength: 260 nm

[0087] (2) Evaluation criteria When the content (initial value) of each active ingredient in the test preparation (control preparation) (specifically, the sample for quantification) before exposure or accelerated testing is set to 100%, the percentage reduction in the content of each active ingredient in the test preparation (specifically, the sample for quantification) after exposure or accelerated testing is determined, and the formulation stability is evaluated according to the criteria described in Table 2.

[0088]

Table 2

[0089] (B) Method for measuring the coloring of the test formulation and evaluation criteria (1) Color measurement method The test preparation (test preparation before exposure or accelerated testing, test preparation after exposure or accelerated testing) was placed in a measurement cell (φ30 mm cell) of a spectrocolorimeter, and color digitization was performed using a colorimetric system (L*a*b color space).

[0090] [Measuring device and measurement conditions] Measuring device: Spectrocolorimeter SE-7700 (manufactured by Nippon Denshoku Industries Co., Ltd.) Reflection measurement diameter: 6 mmφ

[0091] For each measured value (L*, a*, b*) obtained for each test preparation before exposure or accelerated testing and after exposure or accelerated testing, the difference between the two values (ΔL*, Δa*, Δb*) is determined, and the color difference (ΔE) is calculated based on the following formula (JIS Z8730).

[0092]

Equation

[0093] (2) Evaluation criteria From the color difference (ΔE) of the test preparation before and after the obtained exposure or accelerated test, the degree of coloring by the accelerated test was evaluated according to the criteria shown in Table 3. This criterion is based on "Color difference ΔE - A survey" by Mokrzycki W.S. et al (April 2011, Machine Graphics and Vision 20(4):383-411).

[0094]

Table 3

[0095] According to this criterion, when the color difference (ΔE) is 2.0 or more, the general public notices the color change. Therefore, the preparation stability is evaluated according to the criteria described in Table 4.

[0096]

Table 4

[0097] Experimental Example 1 Preparation of pharmaceutical formulation and its stability evaluation (Part 1) (1) Preparation of pharmaceutical preparation L-Carbocisteine, DXM hydrate, and Ambroxol salt were placed in an agate mortar and mixed at the ratios described in Table 5 as the amounts per daily dose, and then water was added little by little and kneaded. The obtained kneaded product was sized using a 10-mesh sieve, and the sized product was dried using a ventilated dryer at 60 °C for 30 minutes to prepare a granular pharmaceutical preparation (granular preparation) (Examples 1-1 to 1-4, Control Example 1, and Comparative Example 1: see Table 5).

[0098] (2) Experimental method 1 g of each of the prepared granular preparations (Examples 1-1 to 1-4, Control Example 1, and Comparative Example 1) was used as a test preparation and subjected to the above-described accelerated test (storage period: 1 month). Then, for each test preparation, the content of ambroxol salt was measured before and after the accelerated test according to the above-described quantitative method, the content reduction rate of ambroxol salt by the accelerated test was calculated, and the preparation stability (room temperature storage stability) was evaluated.

[0099] (3) Experimental results The results are shown in accordance with Table 5.

[0100]

Table 5

[0101] As can be seen by comparing the control example 1 and the comparative example 1 in Table 5, when DXM hydrate is formulated in a pharmaceutical composition containing 750 mg of L-carbocysteine and 45 mg of ambroxol salt per daily dose, it was confirmed by the accelerated test that there is a problem that the content of ambroxol salt in the pharmaceutical composition decreases. In addition, when the above daily dose is administered in three divided doses, the dose per administration (unit dose) of L-carbocysteine is 250 mg. The decrease in the content of ambroxol salt by the accelerated test (40 °C, 75% RH, for 1 month) means that the efficacy of the pharmaceutical preparation decreases due to storage and use under room temperature conditions.

[0102] From the results of Examples 1-1 to 1-4, it was confirmed that this problem can be solved by increasing the blending amount of L-carbocysteine per daily dose (or unit dose), preferably to 1000 mg to 1500 mg (when administered three times a day, the unit dose is 1000 / 3 mg to 500 mg). In addition, this problem can be more effectively solved by increasing the blending amount of L-carbocysteine per daily dose (unit dose) as described above, and setting the ratio of DXM salt to 100 parts by mass of L-carbocysteine to 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass; and the ratio of ambroxol salt to 0.5 to 5 parts by mass, preferably 1 to 5 parts by mass, more preferably 2 to 5 parts by mass, and even more preferably 3 to 5 parts by mass.

[0103] Experimental Example 2 Preparation of pharmaceutical formulation and its stability evaluation (Part 2) (1) Preparation of pharmaceutical preparation L-Carbocisteine, DXM hydrate, and chlorpheniramine salt were placed in an agate mortar and mixed at the ratios shown in Table 6 as the amounts per unit dose (daily dose), and then water was added little by little and kneaded. The obtained kneaded product was sized using a 10-mesh sieve, and the sized product was dried using a ventilated dryer at 60 °C for 30 minutes to prepare a granular pharmaceutical preparation (granular preparation) (Examples 2-1 to 2-4, Control Example 2, Comparative Example 2: see Table 6).

[0104] (2) Experimental method Using 2 g of the prepared granular preparations (Examples 2-1 to 2-4, Control Example 2, Comparative Example 2) as test preparations, each was subjected to the above-described exposure test. Next, for each test preparation, the content of chlorpheniramine salt was measured before and after the exposure test according to the above-described quantification method, and the content reduction rate of chlorpheniramine salt due to the exposure test was calculated to evaluate the preparation stability (photo stability).

[0105] (3) Experimental results The results are shown in accordance with Table 6.

[0106]

Table 6

[0107] As can be seen by comparing Control Example 2 and Comparative Example 2 in Table 6, when DXM hydrate is blended into a pharmaceutical composition containing 750 mg of L-carbocisteine and 12 mg of chlorpheniramine salt per daily dose, it was confirmed that there is a problem that the content of chlorpheniramine salt in the pharmaceutical composition decreases due to the exposure test. When the above daily dose is administered in three divided doses, the dose per administration (unit dose) of L-carbocisteine is 250 mg. The decrease in the content of chlorpheniramine salt due to the exposure test (total illuminance 120,000 lux·hr) means that the efficacy of the pharmaceutical preparation decreases due to storage and use under non-shielded conditions under sunlight and lighting indoors and outdoors.

[0108] <unk> From the results of Examples 2-1 to 1-4, it was confirmed that this problem can be solved by increasing the compounding amount of L-carbocysteine per daily dose (unit dose), preferably to 1000 mg to 1500 mg (when administered three times a day, the unit dose is 1000 / 3 mg to 500 mg). Further, this problem can be more effectively solved by increasing the compounding amount of L-carbocysteine per daily dose (or unit dose) as described above, and setting the ratio of the DXM salt to 100 parts by mass of L-carbocysteine to 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass; and setting the ratio of the chlorpheniramine salt to 0.1 to 1.2 parts by mass, preferably 0.2 to 1.2 parts by mass, more preferably 0.4 to 1.2 parts by mass, and even more preferably 0.6 to 1.2 parts by mass.

[0109] Experimental Example 3 Preparation of pharmaceutical formulation and its stability evaluation (Part 3) (1) Preparation of pharmaceutical preparations L-carbocysteine, DXM hydrate, and anhydrous caffeine were placed in an agate mortar and mixed at the ratios shown in Tables 7 and 8 as the amounts per daily dose, and then a small amount of water was added little by little and kneaded. The obtained kneaded product was sized using a 10-mesh sieve, and the sized product was dried at 60 °C for 30 minutes using a through-air dryer to prepare a granular pharmaceutical preparation (granule preparation) (Examples 3-1 to 3-4, Control Example 3, Comparative Example 3: see Tables 7 and 8).

[0110] (2) Experimental method 1 g of each of the prepared granule preparations (Examples 3-1 to 3-4, Control Example 3, and Comparative Example 3) was used as a test preparation and subjected to the above-described accelerated test (storage period: 2 months) and exposure test, respectively. Then, for the test preparations subjected to the accelerated test, the above-described coloring measurement method was carried out before and after the accelerated test to calculate the color difference (ΔE) and evaluate the preparation stability (coloring resistance). For the test preparations subjected to the exposure test, the content of anhydrous caffeine was measured according to the above-described quantitative method before and after the exposure test, the content reduction rate of anhydrous caffeine due to the exposure test was calculated, and the preparation stability (room temperature storage stability) was evaluated.

[0111] (3) Experimental results The results of the accelerated test are shown in Table 7, and the results of the exposure test are shown in Table 8.

[0112]

Table 7

[0113]

Table 8

[0114] As can be seen by comparing Control Example 3 and Comparative Example 3 in Table 8, when DXM hydrate is formulated in a pharmaceutical composition containing 750 mg of L-carbocysteine and 300 mg of anhydrous caffeine per daily dose, it was confirmed by the exposure test that there is a problem that the content of anhydrous caffeine in the pharmaceutical composition decreases. Further, as shown in Comparative Example 3 of Table 7, it was confirmed that the pharmaceutical composition has a problem of coloring to such an extent that it can be distinguished even by ordinary people by the accelerated test (40 °C, 75% RH, for 2 months). When the above daily dose is administered in three divided doses, the dose (unit dose) of L-carbocysteine per administration is 250 mg. The decrease in the content of anhydrous caffeine by the exposure test (total illuminance 120,000 lux·hr) means that the drug efficacy of the pharmaceutical preparation decreases due to storage and use under non-shielded conditions under sunlight and lighting indoors and outdoors. Further, the coloring by the above accelerated test means that the appearance quality is impaired because the pharmaceutical preparation may be colored under the influence of temperature and / or humidity, or may be colored when stored at room temperature for one year.

[0115] From the results of Examples 3-1 to 3-4 shown in Tables 7 and 8, it was confirmed that all of these problems can be solved by increasing the amount of L-carbocysteine per daily dose (or unit dose), preferably to 1000 mg to 1500 mg (when administered three times a day, the unit dose is 1000 / 3 mg to 500 mg). Further, this problem can be more effectively solved by increasing the amount of L-carbocysteine per daily dose (unit dose) as described above, and setting the ratio of the DXM salt to 100 parts by mass of L-carbocysteine to 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass; and setting the ratio of anhydrous caffeine to 1 to 30 parts by mass, preferably 5 to 30 parts by mass, more preferably 10 to 30 parts by mass, and even more preferably 20 to 30 parts by mass.

[0116] Experimental Example 4 Preparation of pharmaceutical formulation and its stability evaluation (Part 4) (1) Preparation of pharmaceutical preparation L-carbocysteine, DXM hydrate, and ibuprofen were placed in an agate mortar and mixed at the ratios described in Table 8 as the amounts per daily dose, and then water was added little by little and kneaded. The obtained kneaded product was sized using a 10-mesh sieve, and the sized product was dried using a through-air dryer at 60 °C for 30 minutes to prepare a granular pharmaceutical preparation (granule preparation) (Example 4, Control Examples 4-1 to 4-4, Comparative Example 4: see Table 9).

[0117] (2) Experimental method Using 2 g of the prepared granule preparation (Example 4, Control Examples 4-1 to 4-4, and Comparative Example 4) as the test preparation, each was subjected to the above-described exposure test. Then, before and after the exposure test, the above-described coloring measurement method was carried out to calculate the color difference (ΔE) and evaluate the preparation stability (color resistance).

[0118] (3) Experimental results The results of the exposure test are shown in Table 9.

[0119]

Table 9

[0120] As can be seen by comparing Comparative Example 4 with Control Example 4-4 in Table 9, when DXM hydrate is blended with a pharmaceutical composition containing 750 mg of L-carbocysteine and 450 mg of ibuprofen per daily dose, it was confirmed by the exposure test that there is a problem of coloring to such an extent that it can be distinguished even by ordinary people. When the above daily dose is administered in three divided doses, the dose (unit dose) of L-carbocysteine per administration is 250 mg. Coloring by the exposure test (total illuminance of 120,000 lux·hr) means coloring due to storage and use under non-shielded conditions under sunlight or lighting indoors and outdoors, which impairs the appearance quality.

[0121] From the results of Example 4 shown in Table 9, it was confirmed that this problem is solved by increasing the blending amount of L-carbocysteine per daily dose (unit dose), preferably to 1500 mg (unit dose of 500 mg when administered three times a day). Further, this problem is solved more effectively by increasing the blending amount of L-carbocysteine per daily dose (unit dose) as described above, and setting the ratio of the DXM salt to 100 parts by mass of L-carbocysteine to ɪ~6 parts by mass, particularly ɪ~4 parts by mass, preferably 2~4 parts by mass, more preferably 3~4 parts by mass; and the ratio of ibuprofen to 10~30 parts by mass, preferably 15~30 parts by mass, more preferably 20~30 parts by mass.

[0122] Experimental Example 5 Preparation of pharmaceutical formulation and its stability evaluation (Part 5) (1) Preparation of pharmaceutical preparation L-carbocysteine, DXM hydrate, and tranexamic acid were placed in an agate mortar and mixed at the ratios shown in Table 10 as the amount per single dose, and then water was added little by little and kneaded. The obtained kneaded product was sized using a 10-mesh sieve, and the sized product was dried using a through-air dryer at 60°C for 30 minutes to prepare a granular pharmaceutical preparation (granule preparation) (Example 5, Comparative Example 5: see Table 10).

[0123] (2) Experimental method 1 g of the prepared granule preparations (Example 5 and Comparative Example 5) was used as the test preparation, and each was subjected to the accelerated test described above. Then, before and after the accelerated test, the coloring measurement method described above was carried out, the color difference (ΔE) was calculated, and the formulation stability (color resistance) was evaluated.

[0124] (3) Experimental results The results of the accelerated test are shown in Table 10.

[0125] [Table 10]

[0126] As can be seen from Comparative Example 5 in Table 10, when dexamethasone hydrate is formulated in a pharmaceutical composition containing 750 mg of L-carbocysteine and 750 mg of tranexamic acid per daily dose, it was confirmed by the accelerated test (40 °C, 75% RH, for 2 months) that there is a problem of coloring to such an extent that it can be distinguished even by ordinary people. When the above daily dose is administered in three divided doses, the dose per administration (unit dose) of L-carbocysteine is 250 mg. The coloring by the above accelerated test means that the pharmaceutical preparation is colored under the influence of temperature and / or humidity, or may be colored when stored at room temperature for one year, which impairs the appearance quality. Since it may be colored when stored for one year under room temperature conditions, it means that the appearance quality is impaired.

[0127] From the results of Examples 5-1 to 5-4 shown in Table 10, it was confirmed that this problem can be solved by increasing the amount of L-carbocysteine per daily dose (or unit dose), preferably to 1000 mg to 1500 mg (when administered three times a day, the unit dose is 1000 / 3 mg to 500 mg). Further, this problem can be more effectively solved by increasing the amount of L-carbocysteine per daily dose (or unit dose) as described above, and setting the ratio of the DXM salt to 100 parts by mass of L-carbocysteine to 1 to 6 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and even more preferably 4 to 6 parts by mass; and setting the ratio of tranexamic acid to 15 to 75 parts by mass, preferably 20 to 75 parts by mass, more preferably 30 to 75 parts by mass, and even more preferably 40 to 75 parts by mass.

[0128] Formulation Examples 1 to 56 By mixing each component in the ratios described in Tables 11 to 14, an oral pharmaceutical composition in solid form having the effects of the present invention can be prepared.

Table 11

Table 12

Table 13

Table 14

Claims

1. An oral pharmaceutical composition in solid form, containing: (A) 753 mg to 1500 mg of L-carbocysteine in terms of the daily dose, (B) dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, and (C) at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof.

2. The oral pharmaceutical composition according to Claim 1, wherein the ratio of the component (B) to 100 parts by mass of the component (A) is 1 to 6 parts by mass.

3. The oral pharmaceutical composition according to Claim 1 or 2, wherein, based on 100 parts by mass of the component (A), at least one of the components (C) is contained in each of the following ratios: (C1) Ambroxol or a pharmaceutically acceptable salt thereof: 0.5 to 5 parts by mass, (C2) Chlorpheniramine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass, (C3) Anhydrous caffeine: 1 to 30 parts by mass, (C4) Ibuprofen: 10 to 30 parts by mass, (C5) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 75 parts by mass.

4. The oral pharmaceutical composition according to Claim 1 or 2, wherein the solid form is in the form of powder, granules, tablets, or capsules.

5. A method for improving the stability of a pharmaceutical composition in solid form containing the following components (A) to (C), characterized in that the blending amount of the component (A) per daily dose is set to 753 mg to 1500 mg: (A) L-carbocysteine, (B) dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, and (C) at least one selected from the group consisting of ambroxol, chlorpheniramine, anhydrous caffeine, ibuprofen, tranexamic acid, and pharmaceutically acceptable salts thereof.

6. The method for improving stability according to Claim 5, wherein the pharmaceutical composition contains the component (B) in a ratio of 1 to 6 parts by mass with respect to 100 parts by mass of the component (A).

7. The method for improving stability according to Claim 5 or 6, wherein, based on 100 parts by mass of the component (A) in the pharmaceutical composition, at least one of the components (C) is blended in each of the following ratios: (C1) Ambroxol or a pharmaceutically acceptable salt thereof: 0.5 to 5 parts by mass, (C2) Chlorpheniramine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass, (C3)Caffeine anhydrous: 1 to 30 parts by mass, (C4)Ibuprofen: 10 to 30 parts by mass, (C5)Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 75 parts by mass.

8. The method for improving the stability of the pharmaceutical composition according to claim 5 or 6, wherein the method for improving the stability of the pharmaceutical composition is a method for suppressing a decrease in the content of component (C) under exposure conditions or a method for suppressing coloring of the pharmaceutical composition under 40°C and 75% RH.

9. The method for improving the stability according to claim 8, wherein the method for improving the stability is a method for improving the stability of the pharmaceutical composition as compared with a pharmaceutical composition containing the components (A) to (C) and having a blending amount of component (A) of 750 mg per daily dose.

Images