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, and (B) at least one selected from the group consisting of tipepidine, tranexamic acid, anhydrous caffeine, 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. The present invention also relates to a method for improving the formulation stability of a pharmaceutical composition containing L-carbocysteine.

Background Art

[0002] In pharmaceutical preparations having antitussive and expectorant effects (for example, antitussive and expectorant agents, cold medicines, etc.), usually, in addition to an expectorant, an antitussive agent, an anti-inflammatory agent, and / or adjuvants are formulated. L-carbocysteine is a compound that has been used as an expectorant conventionally, 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 defined in 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 an L-carbocysteine-containing pharmaceutical composition having good formulation stability. Another object of the present invention is to provide a method for improving the formulation stability of an L-carbocysteine-containing pharmaceutical composition.

[0006] The present inventors have conducted intensive studies to provide an L-carbocysteine-containing pharmaceutical composition having good formulation stability. As a result, when a tipepidine salt is formulated as an antitussive agent in a solid pharmaceutical composition containing 750 mg of L-carbocysteine per daily dose, the content of the tipepidine salt in the pharmaceutical composition decreases according to an exposure test assuming storage under exposure conditions; when tranexamic acid is formulated as an anti-inflammatory agent or anhydrous caffeine is formulated as an adjuvant, problems such as coloring of the pharmaceutical composition occur according to an accelerated stability test at 40°C assuming long-term storage under room temperature conditions.

[0007] Therefore, a more specific problem of the present invention is to provide a method for improving the above-mentioned formulation stability problems (decrease in the content of the active ingredient, coloring) in a solid pharmaceutical composition containing 750 mg of L-carbocysteine per daily dose, in addition to tipepidine or a pharmaceutically acceptable salt thereof, tranexamic acid or a pharmaceutically acceptable salt thereof, and / or anhydrous caffeine, and also to provide an L-carbocysteine-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 inventors of the present invention have conducted intensive studies. As a result, by increasing the compounding amount of L-carbocysteine per daily dose to 753 mg or more, preferably 1000 mg or more, particularly up to 1500 mg, even when combined with tepedine salt, tranexamic acid, and / or anhydrous caffeine, it has been found that the above-mentioned problems of formulation stability do not occur. It has been confirmed that the method is an effective method for improving and enhancing the formulation stability of a solid pharmaceutical composition containing tepedine salt, tranexamic acid, and / or anhydrous caffeine in addition to L-carbocysteine.

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

[0010] (I) L-Carbocisteine-containing pharmaceutical composition (I-1)(A) L-carbocysteine in an amount of 753 mg to 1500 mg in terms of the daily dose, and (B) at least one selected from the group consisting of tepedine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof A solid oral pharmaceutical composition containing the same. (I-2) The oral pharmaceutical composition according to (I-1), which contains at least one of the component (B) in the following ratios with respect to 100 parts by mass of the component (A); (B1) Tepedine or a pharmaceutically acceptable salt thereof: 1 to 8 parts by mass (B2) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 70 parts by mass, (B3) Anhydrous caffeine: 1 to 30 parts by mass. (I-3) The oral pharmaceutical composition according to (I-1) or (I-2), wherein the solid form is in the form of powder, granules, tablets, or capsules. (I-4) The amount of L-carbocysteine (unit dose) 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. The oral pharmaceutical composition according to any one of (I-1) to (I-3).

[0011] (II) Method for stabilizing the formulation of L-carbocisteine-containing pharmaceutical composition (II-1) A method for improving the stability of a solid pharmaceutical composition containing the following components (A) and (B), characterized in that the amount of component (A) per daily dose is set to 753 mg to 1500 mg: (A) L-Carbocysteine, and (B) At least one selected from the group consisting of tepipidine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof. (II-2) The method for improving stability according to (II-1), wherein at least one of the components (B) is blended in the following ratios with respect to 100 parts by mass of component (A) in the pharmaceutical composition; (B1) Tepipidine or a pharmaceutically acceptable salt thereof: 1 to 8 parts by mass, (B2) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 70 parts by mass, (B3) Anhydrous caffeine: 1 to 30 parts by mass. (II-3) The method for improving the stability according to (II-1) or (II-2), wherein the method for improving the stability of the pharmaceutical composition is a method for suppressing a decrease in the content of component (B1) under exposure conditions, or a method for suppressing coloring of the pharmaceutical composition under 40°C and 75% RH. (II-4) The method for improving stability according to any one of (II-1) to (II-3), wherein the method for improving stability is a method for improving the stability of a pharmaceutical composition containing components (A) and (B) and having a content of component (A) per daily dose of 750 mg as compared with the pharmaceutical composition. (II-5) The method for improving stability according to any one of (II-1) to (II-4), wherein the amount of 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.

Advantages of the Invention

[0012] According to the present invention, it is possible to provide an L-carbocysteine-containing pharmaceutical composition having good formulation stability. More specifically, according to the present invention, in a solid pharmaceutical composition containing tipepidine or a pharmaceutically acceptable salt thereof in addition to L-carbocysteine, when the daily dose of L-carbocysteine is adjusted to 750 mg, it is possible to provide an L-carbocysteine-containing pharmaceutical composition in which the decrease in the content of tipepidine or its salt due to storage under exposure conditions that occur is suppressed and improved. Further, according to the present invention, in a solid pharmaceutical composition containing tranexamic acid or a pharmaceutically acceptable salt thereof and / or anhydrous caffeine in addition to L-carbocysteine, when the daily dose of L-carbocysteine is adjusted to 750 mg, it is possible to provide an L-carbocysteine-containing pharmaceutical composition in which the coloring over time due to storage under room temperature conditions that occur is suppressed and improved.

[0013] Further, according to the present invention, it is possible to provide a method for improving the above-mentioned formulation stability problems (decrease in the content of the active ingredient, coloring) in a solid pharmaceutical composition containing 750 mg of L-carbocysteine in terms of the daily dose, in addition to tipepidine or a pharmaceutically acceptable salt thereof, tranexamic acid or a pharmaceutically acceptable salt thereof, and / or anhydrous caffeine.

Mode for Carrying Out the Invention

[0014] (I) L-Carbocisteine-containing pharmaceutical composition and method for producing the same The L-carbocysteine-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) and (B): (A) 753 mg to 1500 mg of L-carbocysteine in terms of the daily dose, (B) At least one selected from the group consisting of tipepidine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof.

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

[0016] The amount of L-carbocisteine contained in this pharmaceutical composition, when converted to the amount taken by one adult per day (daily dose), is 753 mg or more, and it may be any amount that can exhibit at least the medicinal efficacy required for the L-carbocisteine-containing pharmaceutical composition and the effects 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 amount of L-carbocisteine taken by one adult per day is 753 mg or more, preferably 753 mg to 1500 mg, more preferably 1000 mg to 1500 mg.

[0018] Here, "753 mg or more when converted to the amount taken by one adult per day (daily dose)" means that when the pharmaceutical composition is designed for one adult to take once a day, the amount of L-carbocysteine contained in a single dose (unit dose) is 753 mg or more, preferably 753 to 1500 mg. Note that this dose can be appropriately selected and set within the range of "753 to 1500 mg". Also, when it is designed to be taken twice a day, the amount of L-carbocysteine contained in a single dose (unit dose) means an amount corresponding to 1 / 2 of the above. Similarly, when it is designed to be taken three times a day, the amount of L-carbocysteine contained in a single dose (unit 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, the pharmaceutical composition is not limited to a formulation for adults, and may be taken by children under 15 years old. When children take it, the daily dose of L-carbocysteine per person may be the same as that of the above-mentioned adults, or it can also be reduced, such as to 1 / 2 or 2 / 3 of the adult dose, according to each age group.

[0020] Also, when the mass of the 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 The component (B) used in combination with the above-mentioned component (A) is at least one selected from the group consisting of tepedine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof.

[0022] (B1) Thioperidine or a pharmaceutically acceptable salt thereof Chipepizin or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "chipepizin salt") (hereinafter collectively referred to as "(B1) component") is a compound having an antitussive effect (antitussive agent), and is used for cough and sputum associated with diseases such as cold, acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, upper respiratory tract inflammation (pharyngolaryngitis, rhinitis), and bronchiectasis. It is used as an active ingredient of a pharmaceutical composition having efficacy and effect against expectoration difficulty. As the (B1) component, any substance that can be applied to the human body may be used. For example, a chipepizin salt listed in the Japanese Pharmacopoeia can be used.

[0023] Examples of chipepizin salts include organic acid salts such as benzoate, citrate, fumarate, and succinate; and inorganic acid salts such as hydrochloride, nitrate, and acetate of chipepizin. Organic acid salts such as benzoate are preferred.

[0024] The amount of the (B1) component contained in this pharmaceutical composition may be at least an amount that exhibits the medicinal efficacy required for an 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 chipepizin benzoate, it can be appropriately set and adjusted within the range of 15 to 105 mg in terms of the amount of chipepizin benzoate taken by one adult per day; in the case of chipepizin citrate, it can be appropriately set and adjusted within the range of 30 to 120 mg in terms of the amount of chipepizin citrate taken by one adult per day.

[0025] Here, the phrase "in the range of 15 to 105 mg in terms of the amount of chipepizin benzoate 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 chipepizin benzoate 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 chipepizin benzoate 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 can be used after reducing the dose according to each age group, such as 1 / 2 or 2 / 3 of the amount taken by an adult per day. Such a dosage design is similarly applicable to the following components (B2) and (B3).

[0026] Although the ratio of component (B1) to 100 parts by mass of 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 1 to 8 parts by mass. As the lower limit value of component (B1), 1 part by mass, preferably 2 parts by mass, more preferably 3 parts by mass, and particularly preferably 4 parts by mass can be mentioned. As the upper limit value of component (B1), 8 parts by mass, preferably 7.5 parts by mass, and more preferably 7 parts by mass can be mentioned. These lower limit values and upper limit values can be arbitrarily combined. Although not limited, for example, ranges such as 1 to 8 parts by mass, 2 to 8 parts by mass, 2 to 6 parts by mass, 2 to 5.5 parts by mass, 3 to 8 parts by mass, and 4 to 8 parts by mass can be exemplified.

[0027] By blending component (B1) with the pharmaceutical composition containing component (A) at the aforementioned ratio, as shown in Experimental Example 1 described later, it is possible to suppress and improve the decrease in the content of component (B1) due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and a pharmaceutical composition containing (A) and (B1) having good formulation stability can be provided. The effect can be obtained more effectively by adjusting the blending ratio of component (B1) to be in the above range.

[0028] (B2) Tranexamic acid or a pharmaceutically acceptable salt thereof Tranexamic acid or its pharmaceutically acceptable salts (hereinafter sometimes referred to as "tranexamic acid salts") (hereinafter collectively referred to as "ingredient (B2)") are compounds with antiplasmin activity and are used as the active ingredient of pharmaceutical compositions effective against bleeding tendency (e.g., leukemia, aplastic anemia, purpura, etc., and abnormal bleeding during and after surgery) thought to be associated with systemic hyperfibrinolysis; abnormal bleeding (e.g., pulmonary hemorrhage, epistaxis, genital bleeding, renal hemorrhage, abnormal bleeding during and after prostate surgery) thought to be associated with local hyperfibrinolysis; symptoms such as erythema, swelling, and itching in diseases such as eczema and its analogues, urticaria, drug eruption, and toxicosis; symptoms such as sore throat, redness, congestion, and swelling in diseases such as tonsillitis and pharyngolaryngitis; and oral pain and oral mucosal ulcers caused by stomatitis. Ingredient (B2) may be any compound that can be administered to the human body; for example, tranexamic acid listed in the Japanese Pharmacopoeia can be used.

[0029] Examples of tranexamic acid salts include alkali metal salts and alkaline earth metal salts of tranexamic acid, and tranexamic acid is preferred as component (B2).

[0030] The amount of component (B2) contained in this pharmaceutical composition may be an amount that at least achieves the desired efficacy of 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, the amount can be appropriately set and adjusted within a range of 225 to 1050 mg, calculated as the amount of tranexamic acid taken by an adult per day. When this amount is designed to be taken in two or three divided doses per day, the amount of tranexamic acid contained in a single dose (unit dose) is adjusted to be within a range equivalent to 1 / 2 or 1 / 3 of the above amount.

[0031] The ratio of component (B2) to 100 parts by mass of component (A) contained in the pharmaceutical composition is not limited, but is preferably adjusted to be in the range of 15 to 70 parts by mass from the viewpoint of formulation stability. The lower limit of component (B2) can be 15 parts by mass, preferably 25 parts by mass, more preferably 30 parts by mass, and particularly preferably 40 parts by mass. The upper limit of component (B2) can be 70 parts by mass, preferably 65 parts by mass, and more preferably 60 parts by mass. These lower and upper limits can be combined arbitrarily. Although not limited, examples of the range include 20 to 60 parts by mass, 30 to 60 parts by mass, and 40 to 60 parts by mass.

[0032] By incorporating the component (B2) into the present pharmaceutical composition containing the component (A) in the aforementioned ratio, coloration over time due to storage at room temperature can be suppressed and improved, as shown in Experimental Example 2 described below, and a pharmaceutical composition containing (A) and (B2) with good formulation stability can be provided. This effect can be more effectively achieved by adjusting the blending ratio of the component (B2) so that it is within the aforementioned range.

[0033] (B3) Caffeine anhydrous Anhydrous caffeine (hereinafter referred to as "ingredient (B3)") is a compound that stimulates the central nervous system, relieving drowsiness and fatigue and alleviating a feeling of heaviness in the head. It can be incorporated as an adjuvant in cough suppressants, expectorants, cold medicines, oral medications for rhinitis, antipyretics, analgesics, motion sickness medications, and energy drinks to enhance the effectiveness of the drug. Any ingredient that can be administered to the human body can be used as ingredient (B3). For example, anhydrous caffeine, which is listed in the Japanese Pharmacopoeia, can be used. The Japanese Pharmacopoeia specifies that anhydrous caffeine must contain at least 98.5% anhydrous caffeine when measured on a dried basis.

[0034] The amount of the component (B3) contained in the pharmaceutical composition may be any amount as long as it 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. For example, it can be appropriately set and adjusted from 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 each single dose (unit dose) is adjusted to be in the range corresponding to 1 / 2 or 1 / 3 of the above.

[0035] Although the ratio of the component (B3) 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. As the lower limit value of the component (B3), 1 part by mass, preferably 3 parts by mass, more preferably 5 parts by mass, and particularly preferably 10 parts by mass can be mentioned. As the upper limit value of the component (B2), 30 parts by mass, preferably 25 parts by mass can be mentioned. These lower limit values and upper limit values can be arbitrarily combined. Although not limited, for example, ranges such as 3 to 30 parts by mass, 5 to 30 parts by mass, 10 to 30 parts by mass, 3 to 25 parts by mass, and 5 to 25 parts by mass can be exemplified.

[0036] By blending the component (B3) 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 provide an (A)- and (B3)-containing pharmaceutical composition having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (B3) to be within the above range.

[0037] The aforementioned components (B1) to (B3) may each be used in combination with the component (A) alone, or two or more of them may be arbitrarily combined and used in combination with the component (A). Examples of the combination of the component (B) include (B1) and (B2), (B1) and (B3), (B2) and (B3), and (B1) to (B3).

[0038] (C) Optional pharmacologically active ingredient In addition to the above-mentioned components (A) and (B), 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, ibuprofen, isopropylantipyrine, loxoprofen, acetylsalicylic acid, diclofenac, and their salts; antihistamines such as chlorpheniramine, diphenhydramine, clemastine, promethazine, and their salts; anticholinergic drugs such as isopropamide iodide; adrenergic components such as pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, phenylephrine hydrochloride; antitussive components such as dihydrocodeine phosphate, dextromethorphan hydrobromide hydrate, noscapine; expectorant components such as ambroxol hydrochloride, bromhexine hydrochloride, potassium cresolsulfonate, guaifenesin; anti-inflammatory components such as glycyrrhizic acid, sodium azulenesulfonate hydrate; crude drug components such as Cnidium officinale, Cinnamomum cassia, Zingiber officinale, Platycodon grandiflorum, Glycyrrhiza glabra, Malva verticillata, Amomum kravanh, Zanthoxylum piperitum; antacid components such as sodium hydrogen carbonate, magnesium carbonate, magnesium aluminometasilicate; vitamin C; vitamin B1 such as thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate ester, fursultiamine hydrochloride, disethiamine hydrochloride, octotiamine, ciclotiamine, bisibuthiamine, 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 succinic acid d-α-tocopherol, succinic acid dl-α-tocopherol, calcium succinate dl-α-tocopherol, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol, and dl-α-tocopherol, etc. can be mentioned.

[0039] Among these, ethenzamide, acetaminophen, ibuprofen, loxoprofen, chlorpheniramine, dextromethorphan hydrobromide hydrate, ambroxol hydrochloride, and bromhexine hydrochloride are preferred, with dextromethorphan hydrobromide hydrate being more preferred. When dextromethorphan hydrobromide hydrate is incorporated into the present pharmaceutical composition, the amount of dextromethorphan hydrobromide hydrate incorporated can be, for example, 15 to 150 mg, calculated as the amount of dextromethorphan hydrobromide hydrate taken by an adult per day. Furthermore, when the mass of the present pharmaceutical composition is taken as 100% by mass, the proportion of dextromethorphan hydrobromide hydrate contained therein can be appropriately set within a range that achieves the desired efficacy of the L-carbocysteine-containing pharmaceutical composition and the effects of the present invention, and can be, for example, in the range of 1 to 30% by mass.

[0040] (D) Optional carrier / additive In preparing the pharmaceutical composition, conventionally known carriers and additives may be optionally blended in addition to the above-mentioned components, as long as the effects of the present invention are not impaired. Examples of such carriers and additives include, without limitation, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, solubilizers, fluidizing agents, glossing agents, flavoring agents, sweeteners, refreshing agents, coloring agents, odorants, flavoring agents, flavoring agents, adsorbents, sugar-coating agents, suspending agents, antistatic agents, plasticizers, and fragrances.

[0041] 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.

[0042] 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.

[0043] 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 of low degree of substitution, calcium carmellose, hydroxypropyl cellulose of 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.

[0044] 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.

[0045] As flavoring agents, although not limited, examples include organic acids such as citric acid, tartaric acid, malic acid, sodium glutamate, sodium 5'-inosinate, sodium 5-guanylate, sodium aspartate, and caramel.

[0046] As sweeteners, although not limited, examples include high-intensity sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, lakanka, thaumatin, acesulfame potassium, sucralose, sucrose, fructose, glucose, lactose, maltose, sorbitol, maltitol, mannitol, xylitol, erythritol, glycerol, inositol, reduced maltose syrup, palatinose, coupling sugar, honey and the like.

[0047] This pharmaceutical composition has a solid form. Such preparations can include tablets, powders, granules, and pills. Granules and tablets are preferred. The tablets may be single-layer or have a multi-layer structure of two or more layers.

[0048] This pharmaceutical composition can be produced by mixing at least component (A) and component (B) selected from the group consisting of components (A), (B), (C), and (D) and shaping them into a desired form. Preferably, in addition to components (A) and (B), at least component (D) can be formulated and shaped to produce it.

[0049] More specifically, for example, in the production of granules, a method can be used in which at least component (A) and component (B) are mixed and granulated to prepare L-carbocysteine-containing granules. For granulation, a wet granulation method or a dry granulation method may be used. In the preparation of the granules, any additive used in the production of the granules can be formulated as component (D) as long as the effects of the present invention are not impaired. Examples of such additives include 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.

[0050] For the production of granules, known granulation apparatuses can be used without limitation. Specifically, a fluidized bed granulator, a stirring granulator, an extrusion granulator, a rolling granulator, a wurster granulator, or a granulator combining these can be mentioned. As described above, to a powder mixture obtained by adding and mixing additives ((D) component) such as excipients and binders, as necessary, to component (A) and component (B), a solution or suspension of a granulation binder is added, and granulation is carried out using the above-mentioned granulator. The obtained granulated product can be dried using, for example, a fluidized bed dryer, etc., to obtain an L-carbocysteine-containing granulated product. In addition, the obtained granulated product may be subjected to a sizing process to be adjusted to a desired average particle size. Although not limited, the average particle size can be exemplified in the range of 80 to 300 μm, preferably 100 to 250 μm (measurement by sieve).

[0051] For the production of tablets, a method can be used in which a lubricant is blended, as necessary, into the L-carbocysteine-containing granulated product 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 tableting machine, a single-shot tableting machine, 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.

[0052] 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 a pan coating method, a fluidized bed coating method, a rolling coating method, a 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.

[0053] The mass per single dose of this pharmaceutical composition can be appropriately set and adjusted from the daily dosage (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 dosage (unit dosage) per administration of this pharmaceutical composition can be selected from the range of 251 to 500 mg in terms of the unit dosage 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.

[0054] (II) Method for stabilizing the formulation of L-carbocisteine-containing pharmaceutical composition The present invention provides a method for improving the formulation stability of a solid pharmaceutical composition containing the following component (A) and component (B): (A) L-carbocysteine, and (B) at least one selected from the group consisting of tipepidine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof. This method (hereinafter also referred to as "the method of the present invention") can be implemented 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).

[0055] 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 dosage (unit dosage) corresponds to 1 / 2 of the above amount (376.5 mg or more, preferably 376.5 to 750 mg). The unit dosage (equivalent to 1 / 2) 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 dosage (unit dosage) corresponds to 1 / 3 of the above amount (251 mg or more, preferably 251 to 500 mg). The unit dosage (equivalent to 1 / 3) includes 300 to 500 mg, 350 to 500 mg, 400 to 500 mg, 450 to 500 mg.

[0056] The method of the present invention can be more preferably implemented by, in addition to the above means, blending at least one of the following components (B) with respect to 100 parts by mass of component (A) in the pharmaceutical composition in the following ratios; (B1) Tipiracil or a pharmaceutically acceptable salt thereof: 1 to 8 parts by mass, preferably 2 to 8 parts by mass, more preferably 3 to 8 parts by mass, particularly preferably 4 to 8 parts by mass, (B2) Tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 70 parts by mass, preferably 20 to 60 parts by mass, more preferably 30 to 60 parts by mass, particularly preferably 40 to 60 parts by mass, (B3) Caffeine anhydrous: 1 to 30 parts by mass, preferably 5 to 30 parts by mass, more preferably 10 to 30 parts by mass.

[0057] The above-mentioned components (B1) to (B3) may each be used alone in combination with the component (A), or two or more of them may be arbitrarily combined and used in combination with the component (A). Examples of the combination of the component (B) include (B1) and (B2), (B1) and (B3), (B2) and (B3), and (B1) to (B3).

[0058] Regarding the types, compounding ratios, compounding methods, etc. of the above-mentioned components (A), (B1), (B2), and (B3), the description in the above-mentioned (I) can be referred to, and the description can be incorporated herein by reference.

[0059] As shown in Experimental Example 1 described below, by adding the component (B1) to the pharmaceutical composition containing the component (A) at the above-mentioned ratio, it is possible to suppress and improve the decrease in the content of the component (B1) due to storage under sunlight or lighting (exposure conditions) indoors and outdoors, and it is possible to provide a pharmaceutical composition containing (A) and (B1) with improved formulation stability. The effect can be obtained more effectively by adjusting the compounding ratio of the component (B1) to be within the above-mentioned 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 above-mentioned components (A) and (B1) 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, it is 250 mg) when converted to the daily dose, when the decrease in the content of the component (B1) in the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0060] As shown in Experimental Example 2 described below, by blending the component (B2) with the pharmaceutical composition containing the component (A) at the ratio described above, it is possible to suppress and improve the coloring over time due to storage at 40°C and 75% RH, and it is possible to provide a pharmaceutical composition containing (A) and (B2) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (B2) 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 component (A) and the component (B2) and having a content of the component (A) of 750 mg in terms of 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 coloring of the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0061] As shown in Experimental Example 3 described below, by blending the component (B3) with the pharmaceutical composition containing the component (A) at the ratio described above, it is possible to suppress and improve the coloring over time due to storage at 40°C and 75% RH, and it is possible to provide a pharmaceutical composition containing (A) and (B3) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratio of the component (B3) 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 component (A) and the component (B3) and having a content of the component (A) of 750 mg in terms of 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 coloring of the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved.

[0062] As described above, in this specification, the terms "comprising" and "containing" include the meanings of "consisting of" and "substantially consisting of".

Examples

[0063] Hereinafter, in order to facilitate 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 in any way by these experimental examples. The following experiments were carried out under room temperature (25 ± 5°C) and atmospheric pressure conditions unless otherwise specified. Unless otherwise specified, “%” described below means “mass %” and “parts” means “parts by mass”.

[0064] The compounds used in the following experimental examples are as follows. L-Carbocysteine: Obtained from Astellas Pharma Inc. Tipenidine salt: Tipenidine hibenzate (obtained from Fujifilm Wako Pure Chemical Corporation). Tranexamic acid: Obtained from Jiangsu Tianhe Pharmaceutical Co., Ltd. Caffeine anhydrous: Obtained from Shizuoka Caffeine Industry Co., Ltd.

[0065] 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 unpackaged 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.

[0066] (2) Accelerated test (storage stability evaluation test under room temperature conditions) The test preparation (granulated product) was filled into a brown glass bottle and placed in the chamber of a thermo-hygrostat (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 2 months.

[0067] The analysis methods and evaluation criteria adopted in the following experimental examples are as follows. (A) Quantitative method and evaluation criteria for thioperidine salt (1) Quantitative method The test preparations containing tipiperidine salt (the test preparation before the exposure test and the test preparation after the exposure test) are dissolved in a phosphoric acid ethanol solution and then filtered through a 0.45 μm filter, which is used as the sample for quantification. The phosphoric acid ethanol solution is prepared by mixing an aqueous phosphoric acid solution (phosphoric acid (1→500)) obtained by diluting phosphoric acid 500-fold with water with ethanol at a ratio of 1:1 (volume ratio). This sample for quantification is subjected to HPLC under the following conditions to determine the area of the peak corresponding to tipiperidine, and the content of tipiperidine contained in the sample for quantification is calculated from the ratio to the peak area of the standard solution prepared using a tipiperidine standard product.

[0068] [HPLC Conditions] Measuring device: Alliance 2695 (manufactured by Waters K.K., Japan) Stationary phase: L-column2 4.6×100 mm, 3 μm (manufactured by Shimadzu GL Corporation) Mobile phase A: 0.1% trifluoroacetic acid Mobile phase B: methanol Gradient conditions:

[0069]

Table 1

[0070] (2) Evaluation criteria When the content (initial value) of tipiperidine salt in the test preparation (control preparation) before the exposure test is taken as 100%, the percentage reduction in the content of tipiperidine salt in the test preparation after the exposure test is determined, and the formulation stability is evaluated according to the criteria described in Table 2.

[0071]

Table 2

[0072] (B) Method for measuring the coloring of the test formulation and evaluation criteria (1) Color measurement method The test preparations (test preparation before accelerated test, test preparation after accelerated test) were placed in a measuring cell (φ30 mm cell) of a spectrocolorimeter, and color digitization was performed using a color system (L*a*b color space). [Measuring Device and Measuring Conditions] Measuring device: Spectrocolorimeter SE-7700 (manufactured by Nippon Denshoku Industries Co., Ltd.) Reflection measurement diameter: 6 mmφ

[0073] For each measurement value (L*, a*, b*) obtained for each test preparation before and after the accelerated test, the difference between the two values (ΔL*, Δa*, Δb*) was determined, and the color difference (ΔE) was calculated based on the following formula (JIS Z8730).

[0074] [Number]

[0075] (2) Evaluation Criteria From the color difference (ΔE) of the test preparations before and after the accelerated test thus obtained, 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).

[0076] [Table 3]

[0077] According to this criterion, since the color difference (ΔE) is 2.0 or more and the general public can notice the color change, the preparation stability is evaluated according to the criteria described in Table 4.

[0078] [Table 4]

[0079] Experimental Example 1 Preparation of pharmaceutical formulation and evaluation of its stability (Part 1) (1) Preparation of Pharmaceutical Preparation L-carbocysteine and tipepidine hibenzate were mixed in an agate mortar in the proportions shown in Table 5 as the amount per daily dose, and then water was added little by little to knead the mixture. The resulting mixture was sieved through a 10-mesh sieve, and the sieved product was dried at 60°C for 30 minutes in a ventilated dryer to prepare a granular pharmaceutical preparation (granule preparation) (see Examples 1-1, 1-2, 1-2, and Comparative Example 1: Table 5).

[0080] (2) Experimental method Approximately 2 g of the prepared granule formulations (Examples 1-1 to 1-3, Comparative Example 1) were used as test formulations and subjected to the above-mentioned light exposure test. Next, for each test formulation, the tipepidine salt content was measured before and after the light exposure test according to the above-mentioned quantification method, and the reduction rate of the tipepidine salt content due to the light exposure test was calculated to evaluate the formulation stability (photostability).

[0081] (3) Experimental results The results are also shown in Table 5.

[0082] [Table 5]

[0083] As shown in Comparative Example 1 in Table 5, when the amount of L-carbocysteine per daily dose was set to 750 mg, a light exposure test confirmed that the content of the incorporated tipepidine salt decreased. When the daily dose was divided into three doses, the L-carbocysteine dose per dose (unit dose) was 250 mg. The decrease in the content of tipepidine salt due to light exposure means that the efficacy of the pharmaceutical preparation decreases when stored or used under unprotected conditions, such as indoors or outdoors, under sunlight or lighting.

[0084] The results of Examples 1-1 to 1-3 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 (1000 / 3 mg to 500 mg unit dose in the case of administration three times a day). It was also confirmed that 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 tipepidine salt to 100 parts by mass of L-carbocysteine to 1 to 8 parts by mass, preferably 2 to 8 parts by mass, more preferably 3 to 8 parts by mass, and particularly preferably 4 to 8 parts by mass.

[0085] Experimental Example 2 Preparation of pharmaceutical formulation and evaluation of its stability (Part 2) (1) Preparation of pharmaceutical preparations L-carbocysteine and tranexamic acid were mixed in an agate mortar in the proportions shown in Table 6 as the amount per daily dose, and then water was added little by little to knead the mixture. The resulting mixture was sieved through a 10-mesh sieve, and the sieved product was dried at 60°C for 30 minutes in a ventilated dryer to prepare a granular pharmaceutical preparation (granule preparation) (see Examples 2-1, 2-2, and Comparative Example 2: Table 6).

[0086] (2) Experimental method The entire amount of the prepared granule formulations (Examples 2-1 to 2-2, Comparative Example 2) was used as test formulations and subjected to the accelerated test described above. Next, for each test formulation, the coloration measurement method described above was carried out before and after the accelerated test, and the color difference (ΔE) was calculated to evaluate the formulation stability (coloration resistance).

[0087] (3) Experimental results The results are also shown in Table 6.

[0088] [Table 6]

[0089] As shown in Comparative Example 2 of Table 6, when the compounding amount of L-carbocysteine per daily dose was set to 750 mg, it was confirmed that there was a problem that the pharmaceutical preparation was colored to such an extent that it could be distinguished even by ordinary people by the accelerated test. When the above daily dose is administered in three divided doses, the unit dose of L-carbocysteine becomes 250 mg. The coloring by the accelerated test (40 °C, 75% RH, for 2 months) 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, thus impairing the appearance quality.

[0090] From the results of Examples 2-1 and 2-2, it was confirmed that this problem can be solved by increasing the compounding amount of L-carbocysteine per daily dose (or unit dose), preferably to 1250 mg to 1500 mg (when administered three times a day, the unit dose is 1250 / 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 tranexamic acid to 100 parts by mass of L-carbocysteine to 15 to 70 parts by mass, preferably 20 to 60 parts by mass, more preferably 30 to 60 parts by mass, and particularly preferably 40 to 60 parts by mass.

[0091] Experimental Example 3 Preparation of pharmaceutical formulation and evaluation of its stability (Part 3) (1) Preparation of pharmaceutical preparation L-carbocysteine and anhydrous caffeine were placed in an agate mortar and mixed at the ratios shown in Table 7 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 an air-type dryer at 60 °C for 30 minutes to prepare a granular pharmaceutical preparation (granule preparation) (Examples 3-1, 3-2, 3-3, Comparative Example 3: see Table 7).

[0092] (2) Experimental method 1 g of the prepared granule formulations (Examples 3-1 to 3-3, Comparative Example 3) was used as test formulations and subjected to the accelerated test described above. Next, for each test formulation, the coloration measurement method described above was carried out before and after the accelerated test, and the color difference (ΔE) was calculated to evaluate the formulation stability (coloration resistance).

[0093] (3) Experimental results The results are also shown in Table 7.

[0094] [Table 7]

[0095] As shown in Comparative Example 3 in Table 7, when the amount of L-carbocysteine per daily dose was set to 750 mg, an accelerated test confirmed that the pharmaceutical formulation became discolored to a degree that even an average person could see. If the daily dose were administered in three divided doses, the unit dose of L-carbocysteine would be 250 mg. Discoloration observed in the accelerated test (40°C, 75% RH, 2 months) indicates that the pharmaceutical formulation may discolor due to the effects of temperature and / or humidity, or may discolor after storage at room temperature for one year, resulting in a loss of appearance quality.

[0096] The results of Examples 3-1 to 3-3 confirmed that this problem can be solved by increasing the amount of L-carbocysteine per daily dose (unit dose), preferably to 1000 mg to 1500 mg (1000 / 3 mg to 500 mg unit dose when administered three times a day). It was also confirmed that this problem can be more effectively solved by increasing the amount of L-carbocysteine per daily dose (unit dose) as described above and adjusting the ratio of anhydrous caffeine to 100 parts by mass of L-carbocysteine to 1 to 30 parts by mass, preferably 5 to 30 parts by mass, and more preferably 10 to 30 parts by mass.

[0097] Prescription examples 1-28 By mixing the components in the proportions shown in Tables 8 and 9, a solid oral pharmaceutical composition having the effects of the present invention can be prepared. [Table 8] [Table 9]

Claims

1. (A)L-carbocisteine in an amount of 753 mg to 1500 mg in terms of the daily dose, and (B)at least one selected from the group consisting of tipepidine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof A solid oral pharmaceutical composition containing the same.

2. The oral pharmaceutical composition according to Claim 1, which contains at least one of the component (B) in the following ratios with respect to 100 parts by mass of the component (A); (B1)tipepidine or a pharmaceutically acceptable salt thereof: 1 to 8 parts by mass, (B2)tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 70 parts by mass, (B3)anhydrous caffeine: 1 to 30 parts by mass.

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

4. A method for improving the stability of a solid pharmaceutical composition containing the following components (A) and (B), characterized in that the blending amount of the component (A) per daily dose is set to 753 mg to 1500 mg: (A)L-carbocisteine, and (B)at least one selected from the group consisting of tipepidine, tranexamic acid, anhydrous caffeine, and pharmaceutically acceptable salts thereof.

5. The method for improving stability according to Claim 4, wherein at least one of the component (B) is blended in the following ratios with respect to 100 parts by mass of the component (A) in the pharmaceutical composition; (B1)tipepidine or a pharmaceutically acceptable salt thereof: 1 to 8 parts by mass, (B2)tranexamic acid or a pharmaceutically acceptable salt thereof: 15 to 70 parts by mass, (B3)anhydrous caffeine: 1 to 30 parts by mass.

6. The method for improving the stability of the pharmaceutical composition according to Claim 4 or 5, wherein the method for improving the stability of the pharmaceutical composition is a method for suppressing a decrease in the content of (B) tipepidine or a pharmaceutically acceptable salt thereof under exposure conditions, or a method for suppressing coloring of the pharmaceutical composition under 40 °C and 75% RH.

7. The method for improving stability according to Claim 6, wherein the method for improving stability is a method for improving the stability of a pharmaceutical composition containing the component (A) and the component (B), as compared with a pharmaceutical composition in which the blending amount of the component (A) per daily dose is 750 mg.

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