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) at least one selected from the group consisting of tipepidine, bromhexine, and pharmaceutically acceptable salts thereof, and (C) dextromethorphan, a pharmaceutically acceptable salt or a hydrate 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. Further, the present invention relates to a method for improving the formulation stability of a pharmaceutical composition containing L-carbocysteine.

Background Art

[0002] In pharmaceutical preparations having the efficacy and effect of relieving cough and reducing phlegm (for example, cough expectorants, cold medicines, etc.), usually, in addition to an expectorant, a cough suppressant, an anti-inflammatory agent, and / or adjuvants are formulated. L-carbocysteine is a compound that has been used as an expectorant.

[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 coloration of the pharmaceutical preparation over time impairs the appearance quality, so both are problems to be avoided.

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a pharmaceutical composition containing L-carbocysteine 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.

[0005] In order to provide an L - carbocysteine - containing pharmaceutical composition with good formulation stability, the inventors have conducted intensive studies. As a result, for a solid - form pharmaceutical composition with a formulation amount of L - carbocysteine of 1500 mg per daily dose, when tipepidine hibenzate is formulated as an antitussive, there is a problem that the pharmaceutical composition becomes colored in an accelerated test at 40°C assuming long - term storage at room temperature; also, when bromhexine hydrochloride is formulated as an expectorant, there is a problem that the content of bromhexine hydrochloride in the pharmaceutical composition decreases in an exposure test assuming storage under exposure conditions.

[0006] Therefore, a more specific problem of the present invention is to improve the above - mentioned formulation stability problems (decrease in the content of the active ingredient, coloring) in a solid - form pharmaceutical composition containing 753 mg or more, preferably 753 mg to 1500 mg of L - carbocysteine in terms of the daily dose, in addition to tipepidine or a pharmaceutically acceptable salt thereof, and / or bromhexine or a pharmaceutically acceptable salt thereof, and to provide an L - carbocysteine - containing pharmaceutical composition having good formulation stability improved by such a method.

Means for Solving the Problems

[0007] In order to solve the above - mentioned problems, the inventors have conducted intensive studies. As a result, they have found that the above - mentioned problems that occur when the formulation amount of L - carbocysteine is increased to 753 mg or more, preferably about 1000 mg to 1500 mg in terms of the daily dose in the co - existence of tipepidine salt or bromhexine salt can be solved by formulating dextromethorphan, a salt thereof or a hydrate thereof (hereinafter, these are collectively also referred to as "DXM - related substances"), and have confirmed that the method is an effective method for improving and enhancing the formulation stability of a solid - form pharmaceutical composition containing tipepidine or a salt thereof, and / or bromhexine or a salt thereof in addition to L - carbocysteine at the above - mentioned dose.

[0008] Based on such findings, the present invention is an invention that has been further studied and completed, and has the following embodiments.

[0009] (I) L-Carbocisteine-containing pharmaceutical composition (I-1)(A) L-carbocysteine in an amount of 753 mg to 1500 mg, converted to a daily dose, (B) at least one selected from the group consisting of tipepidine, bromhexine, and pharmaceutically acceptable salts thereof, and (C) dextromethorphan, a pharmaceutically acceptable salt thereof, or a hydrate 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) tipepidine or a pharmaceutically acceptable salt thereof: 1 to 7 parts by mass, (B2) bromhexine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass. (I-3) The oral pharmaceutical composition according to (I-1) or (I-2), wherein the ratio of the component (C) to 100 parts by mass of the component (A) is 1 to 10 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 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-4).

[0010] (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 (A) L-carbocysteine and at least one selected from the group consisting of (B) tipepidine, bromhexine, and pharmaceutically acceptable salts thereof, wherein the content of component (A) per daily dose is 753 mg to 1500 mg, The method is characterized in that (C) dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof is formulated in the pharmaceutical composition. (II-2) The method for improving stability according to (II-1), wherein the pharmaceutical composition contains at least one of the components (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 7 parts by mass, (B2) bromhexine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass. (II-3) The method for improving stability according to (II-1) or (II-2), wherein the component (C) is formulated in a ratio of 1 to 10 parts by mass with respect to 100 parts by mass of the component (A) in the pharmaceutical composition. (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 component (B2) 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 is A method for improving the stability of a pharmaceutical composition containing the components (A) and (B) and not containing the component (C), compared with a pharmaceutical composition having a content of the component (A) of 1500 mg per daily dose, according to any one of (II-1) to (II-4). (II-6) The method for improving stability according to any one of (II-1) to (II-5), wherein the 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]]

[0011] 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 L-carbocysteine in addition to tipepidine or a pharmaceutically acceptable salt thereof, when the daily dose of L-carbocysteine is adjusted to be 753 mg to 1500 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 is suppressed and improved. Further, according to the present invention, in a solid pharmaceutical composition containing L-carbocysteine in addition to bromhexine or a pharmaceutically acceptable salt thereof, when the daily dose of L-carbocysteine is adjusted to be 753 mg to 1500 mg, it is possible to provide an L-carbocysteine-containing pharmaceutical composition in which the decrease in the content of bromhexine or its salt due to storage under exposure conditions is suppressed and improved.

[0012] Further, according to the present invention, it is possible to provide a method for improving the above-mentioned formulation stability problems (coloring, decrease in the content of active ingredient) in a solid pharmaceutical composition containing 753 mg to 1500 mg of L-carbocysteine in terms of the daily dose, in addition to tipepidine or a pharmaceutically acceptable salt thereof, and / or bromhexine or a pharmaceutically acceptable salt thereof.

Mode for Carrying Out the Invention

[0013] (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) to (C): (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, bromhexine, and pharmaceutically acceptable salts thereof, and (C) dextromethorphan, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0014] These components will be described below. (A) component L-Carbocysteine 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 that has an expectorant effect in diseases such as upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis; and has an effect of discharging pus in chronic sinusitis. L-Carbocysteine may be any one that can be applied to the human body. For example, L-Carbocysteine listed in the Japanese Pharmacopoeia can be used.

[0015] The amount of L-carbocysteine contained in this 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.

[0016] 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-carbocysteine taken by one adult per day is 753 mg or more, preferably 753 mg to 1500 mg, more preferably 1000 mg to 1500 mg, and particularly preferably 1300 to 1500 mg.

[0017] 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 from the range of "753 to 1500 mg". Also, when it is designed to be taken twice a day, it means that the amount of L-carbocysteine contained in a single dose (unit dose) corresponds to 1 / 2 of the above amount. Similarly, when it is designed to be taken three times a day, it means that the amount of L-carbocysteine contained in a single dose (unit dose) corresponds to 1 / 3 of the above amount.

[0018] In the present invention, "adult" means men and women 15 years of age or older. However, the pharmaceutical composition is not limited to a formulation for adults to take, and it may be for children under 15 years of age to take. When children take it, the daily dose of L-carbocysteine per person may be the same as that of the aforementioned adults, or it can also be reduced to 1 / 2, 2 / 3, etc. of the adult dose according to each age group. This also applies to the following components (B) and (C) in the same manner.

[0019] Also, when the mass of the pharmaceutical composition is set to 100% by mass, the proportion of L-carbocysteine contained therein can be appropriately set within the range that exhibits 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.

[0020] (B) component The component (B) used in combination with the aforementioned component (A) is at least one selected from the group consisting of tepedine, bromhexine, and pharmaceutically acceptable salts thereof.

[0021] (B1) Cipemide or a pharmaceutically acceptable salt thereof Chipepidine or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "chipepidine salt") (hereinafter these are collectively also referred to as "(B1) component") is a compound having an antitussive effect (antitussive agent), and is used for cough and sputum expectoration difficulty 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. As the (B1) component, any substance that can be applied to the human body may be used, for example, a chipepidine salt listed in the Japanese Pharmacopoeia can be used.

[0022] Examples of chipepidine salts include organic acid salts such as benzoate, citrate, fumarate, and succinate; and inorganic acid salts such as hydrochloride, nitrate, and acetate of chipepidine. Preferably, they are organic acid salts such as benzoate.

[0023] The amount of the (B1) component contained in this pharmaceutical composition may be an amount that exhibits at least 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 chipepidine benzoate, it can be appropriately set and adjusted within the range of 15 to 105 mg in terms of the amount of chipepidine benzoate taken by one adult per day; in the case of chipepidine citrate, it can be appropriately set and adjusted within the range of 30 to 120 mg in terms of the amount of chipepidine citrate taken by one adult per day.

[0024] Here, the phrase "in the range of 15 to 105 mg in terms of the amount of chipepidine 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 chipepidine 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 chipepidine benzoate contained in one dose (unit dose) is adjusted to a range corresponding to 1 / 2 or 1 / 3 of the above.

[0025] Although the ratio of the component (B1) to 100 parts by mass of the component (A) contained in the present pharmaceutical composition is not limited, it is preferably adjusted to be in the range of 1 to 7 parts by mass from the viewpoint of the formulation stability obtained by using it in combination with the component (C) described later. More preferably, it is in the range of 2 to 6 parts by mass, and particularly preferably in the range of 2 to 5.5 parts by mass or 3 to 6 parts by mass.

[0026] (B2) Bromhexine or a pharmaceutically acceptable salt thereof Bromhexine or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as "bromhexine salt") (hereinafter, these are collectively also referred to as "(B2) component") is a compound having a mucolytic action on the respiratory tract. For example, it is used as an active ingredient of a pharmaceutical composition having efficacy and effect in expectoration during diseases such as acute bronchitis, chronic bronchitis, pulmonary tuberculosis, and pneumoconiosis, and expectoration after surgery. As the (B2) component, any substance that can be applied to the human body may be used. For example, bromhexine salts listed in the Japanese Pharmacopoeia can be used.

[0027] Examples of bromhexine salts include inorganic acid salts such as hydrochloride, nitrate, and acetate of bromhexine; organic acid salts such as maleate, citrate, fumarate, and succinate. Inorganic acid salts such as hydrochloride of bromhexine are preferred.

[0028] The amount of the (B2) component contained in the present pharmaceutical composition may be an amount that exhibits 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 1.5 to 18 mg in terms of the amount of bromhexine hydrochloride taken by one adult per day. When it is designed to be taken in 2 or 3 divided doses per day, the amount of bromhexine hydrochloride contained in one dose (unit dose) is adjusted to be in the range corresponding to 1 / 2 or 1 / 3 of the above.

[0029] Although the ratio of the component (B2) to 100 parts by mass of the component (A) contained in the present pharmaceutical composition is not limited, preferably, from the viewpoint of the formulation stability obtained by using in combination with the component (C) described later, it can be adjusted to be in the range of 0.1 to 1.2 parts by mass. More preferably, it is in the range of 0.2 to 1.0 parts by mass, and particularly preferably, it is in the range of 0.3 to 1.0 parts by mass or 0.5 to 0.9 parts by mass.

[0030] The aforementioned components (B1) and (B2) may each be used in combination with the component (A) alone, or both of them may be combined and used in combination with the component (A).

[0031] (C) component Dextromethorphan is a compound that acts on the cough center in the brain, increases 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 for the efficacy and effect of treating cough (antitussive) 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 hydrate form of these. In this specification, these may be collectively referred to as "(C) component" or "DXMs".

[0032] As the component (C), any substance applicable to the human body may be used. For example, a hydrate of DXM salt listed in the Japanese Pharmacopoeia can be used. Examples of DXM salts include hydrobromide salt of DXM.

[0033] The amount of the component (C) contained in the present pharmaceutical composition may be an amount that exhibits at least the medicinal effect 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 salt, 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.

[0034] Here, the phrase "in 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 dextromethorphan hydrobromide (unit dose) contained in a single 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 dextromethorphan hydrobromide (unit dose) contained in a single dose is adjusted to be in a range corresponding to 1 / 2 or 1 / 3 of the above amount.

[0035] Although the ratio of the component (C) to 100 parts by mass of the component (A) contained in this pharmaceutical composition is not limited, preferably, from the viewpoint of the formulation stability of the pharmaceutical composition containing the component (B) described above in addition to the component (A) in an amount of 753 to 1500 mg in terms of the daily dose, it can be adjusted to be in the range of 1 to 10 parts by mass. More preferably, it is in the range of 2 to 8 parts by mass, and particularly preferably, it is in the range of 3 to 7 parts by mass or 3 to 6 parts by mass.

[0036] For example, by blending the component (C) with the pharmaceutical composition containing the component (B1) described above, in addition to the component (A) in an amount of 753 to 1500 mg, preferably 1000 to 1500 mg in terms of the daily dose, as shown in Experimental Example 1 described below, the coloring over time during storage at room temperature, which occurs in the pharmaceutical composition not containing the component (C), can be suppressed and improved, and a pharmaceutical composition containing (A), (B1), and (C) having good formulation stability can be provided. The above effect can be obtained more effectively by adjusting the blending ratios of the components (B1) and / or (C) to be within the ranges described above, respectively.

[0037] For example, by adding component (C) to the pharmaceutical composition containing 753 to 1500 mg, preferably 1000 to 1500 mg of component (A) in terms of the daily dose and the aforementioned component (B2), as shown in Experimental Example 2 described below, it is possible to suppress and improve the decrease in the content of component (B2) caused by storage under sunlight or lighting (exposure conditions) indoors and outdoors in the pharmaceutical composition not containing component (C), and to provide a pharmaceutical composition containing (A), (B2) and (C) having good formulation stability. The effect can be obtained more effectively by adjusting the blending ratios of components (B2) and / or (C) so as to be within the aforementioned ranges, respectively.

[0038] (D) Optional pharmacologically active ingredient In addition to the aforementioned components (A) to (C), other pharmacologically active ingredients may be included in the pharmaceutical composition, 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 salts thereof; antihistamines such as chlorpheniramine, diphenhydramine, clemastine, promethazine, and salts thereof; anticholinergic drugs such as isopropylamide iodide; adrenergic components such as pseudoephedrine hydrochloride, dl-methylphedrine hydrochloride, phenylephrine hydrochloride, etc.; antiplasmin components such as tranexamic acid; antitussive components such as dihydrocodeine phosphate, noscapine, etc.; expectorant components such as ambroxol hydrochloride, potassium cresolsulfonate, guaifenesin, etc.; anti-inflammatory components such as glycyrrhizic acid, sodium azulenesulfonate hydrate, etc.; crude drug components such as Cnidium officinale, Cinnamomum cassia, Zingiber officinale, Platycodon grandiflorum, Glycyrrhiza glabra, Malva verticillata, Amomum kravanh, Zanthoxylum piperitum, 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, disethiamine hydrochloride, octothiamine, 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 them, preferably are ethoxamide, acetaminophen, ibuprofen, loxoprofen, chlorpheniramine, and ambroxol hydrochloride, and more preferably is chlorpheniramine maleate. When chlorpheniramine maleate is formulated in this pharmaceutical composition, its formulation amount can be exemplified as 1.5 to 18 mg in terms of the amount of chlorpheniramine maleate taken by one adult per day. Further, when the mass in this pharmaceutical composition is taken as 100% by mass, the proportion of chlorpheniramine maleate contained therein can be appropriately set within the range that exerts the medicinal effects required for the L-carbocysteine-containing pharmaceutical composition and the effects of the present invention, and for example, a range of 0.1 to 10% by mass can be exemplified.

[0040] (E) Optional carrier / additive In the production of this pharmaceutical composition, in addition to the components described above, conventional well-known carriers and additives can be arbitrarily formulated as appropriate within the limit of not impairing the effects of the present invention. Examples of these carriers and additives include, without limitation, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, solubilizers, fluidizing agents, brighteners, flavoring agents, sweeteners, cooling agents, coloring agents, odor correctors, fragrances, adsorbents, sugar coating agents, suspending agents, antistatic agents, plasticizers, and fragrances, etc.

[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, gum arabic powder, 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, 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, honey and the like.

[0047] This pharmaceutical composition has a solid form. Examples of such preparations include tablets, powders, granules, and pills. Granules and tablets are preferred. Note that 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 components (A), (B), and (C) selected from the group consisting of components (A), (B), (C), (D), and (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.

[0049] More specifically, for example, in the production of granules, a method of mixing at least components (A) to (C) and granulating them to prepare L-carbocisteine-containing granules can be used. 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 blended as component (E) to the extent that 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 granulating 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 performed using the above-mentioned granulator. The obtained granulated product can be dried using, for example, a fluidized bed dryer or the like to obtain an L-carbocysteine-containing granulated product. The obtained granulated product may then 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, with the L-carbocysteine-containing granulated product prepared as described above, and this is compression molded. The 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 manufactured, 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 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.

[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, in terms of the daily dose, is 753 mg or more, preferably 1000 mg to 1500 mg, and (B) At least one selected from the group consisting of tipepidine, bromhexine, and pharmaceutically acceptable salts thereof. The method (hereinafter also referred to as "the method of the present invention") can be carried out by formulating (C) dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof in the pharmaceutical composition.

[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 dose 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 (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 dose (unit dose) corresponds to 1 / 3 of the above amount (251 mg or more, preferably 251 to 500 mg). The unit dose (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 carried out by formulating at least one of the above (B) components in the following ratios with respect to 100 parts by mass of component (A) in the pharmaceutical composition; (B1) Tipepidine or a pharmaceutically acceptable salt thereof: 1 to 7 parts by mass, preferably 2 to 6 parts by mass, more preferably 2 to 5.5 or 3 to 6 parts by mass. (B2) Bromhexine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass, preferably 0.2 to 1.0 parts by mass, more preferably 0.3 to 1.9 or 0.5 to 0.9 parts by mass.

[0057] The above-mentioned components (B1) and (B2) may be used in combination with components (A) and (C) individually, or two of them may be arbitrarily combined and used in combination with components (A) and (C).

[0058] Furthermore, the method of the present invention can be implemented by blending the component (C) in a ratio of 1 to 10 parts by mass with respect to 100 parts by mass of the component (A) in the pharmaceutical composition. The blending ratio of the component (C) is preferably 2 to 8 parts by mass, more preferably 3 to 7 or 3 to 6 parts by mass.

[0059] Regarding the types, blending ratios, and blending methods of the above-mentioned components (A), (B1), (B2), and (C), reference can be made to the description in the above-mentioned (I), and the description can be incorporated herein by reference.

[0060] As shown in Experimental Example 1 described later, by blending the component (C) with the pharmaceutical composition containing the component (A) and the component (B1) at the above-mentioned ratios, the coloring over time due to storage under room temperature conditions that occurs in the pharmaceutical composition not containing the component (C) can be suppressed and improved, and a pharmaceutical composition containing (A), (B1), and (C) with improved formulation stability can be provided. The effect can be obtained more effectively by adjusting the blending ratios of the components (B1) and / or (C) 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) that does not contain the component (C), contains the component (A) and the component (B1), and has a content of the component (A) of 1500 mg (for example, 500 mg when converted to the unit dose of the component (A) in the case of administering three times a day), when the coloring of the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved. When the coloring of the pharmaceutical composition is suppressed, it can be determined that the stability of the pharmaceutical composition is improved as compared with a pharmaceutical composition (control composition) that does not contain the component (C), contains the component (A) and the component (B1), and has a content of the component (A) of 1500 mg (for example, 500 mg when converted to the unit dose of the component (A) in the case of administering three times a day) when converted to the daily dose.

[0061] Furthermore, as shown in Experimental Example 2 below, by incorporating component (C) into the present pharmaceutical composition containing components (A) and (B2) in the aforementioned ratios, the decrease in the content of component (B2) that occurs in pharmaceutical compositions that do not contain component (C) during storage indoors or outdoors under sunlight or lighting (exposure conditions) can be suppressed and improved, thereby providing a pharmaceutical composition containing (A), (B2), and (C) with improved formulation stability. This effect can be more effectively achieved by adjusting the blending ratio of components (B2) and / or (C) to fall within the above-mentioned range. The presence or absence of such improved formulation stability can be evaluated according to the method described in Experimental Example 2. In this case, when a decrease in the content of component (B2) in the pharmaceutical composition is suppressed compared to a pharmaceutical composition (control composition) that does not contain component (C) but contains component (A) and component (B2), and has a content of component (A) of 1500 mg when converted to a daily dose (e.g., 500 mg when converted to a unit dose of component (A) when administered three times a day), the stability of the pharmaceutical composition can be determined to be improved.

[0062] As described above, in this specification, the terms "comprise" and "contain" encompass the meanings of "consist of" and "consist essentially of." [Example]

[0063] The present invention will be explained below using experimental examples to aid in understanding the configuration and effects of the present invention. However, the present invention is not limited by these experimental examples. Unless otherwise specified, the following experiments were carried out at room temperature (25±5°C) and atmospheric pressure. Unless otherwise specified, "%" and "parts" in the following descriptions mean "% by mass" and "parts by mass," respectively.

[0064] The compounds used in the following experimental examples are as follows: L-carbocisteine: Obtained from Alfresa Pharma Corporation. DXM salt hydrate: dextromethorphan hydrobromide hydrate (obtained from Alps Pharmaceutical Co., Ltd.). Tipepidine salt: Tipepidine hibenzate (obtained from Fujifilm Wako Pure Chemical Industries, Ltd.). Bromhexine salt: bromhexine hydrochloride (obtained from Yamamoto Chemical Industry Co., Ltd.).

[0065] The test methods used in the following experimental examples are as follows. (1) Exposure test (photo-stability evaluation test) The test formulation (granulated product) was placed unpackaged in a glass petri dish and placed in the compartment of a photostability testing device (LTL-200A-15WCD, 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 light was irradiated so that the total illuminance was 1.2 million lux·hr.

[0066] (2) Accelerated test 1 (storage stability evaluation test under room temperature conditions) The test formulation (sized product) is filled into a brown glass bottle, sealed, and then placed in a thermo-hygrostat (CH21-13M, Nagano Science Co., Ltd.) with the internal environment set at 40°C and 75% RH, and left to stand for 2 months.

[0067] (3) Accelerated test 2 (storage stability evaluation test under room temperature conditions) The test formulation (sized product) is filled into a brown glass bottle, and the bottle is placed in an open thermo-hygrostat (CH21-13M, Nagano Science Co., Ltd.) with the internal environment set to 40°C and 75% RH, and left to stand for 2 months.

[0068] The analytical methods and evaluation criteria used in the following experimental examples are as follows: (A) Quantitative method and evaluation criteria for the active ingredient (1) Quantification method The test preparations containing the active ingredient to be measured (bromhexine salt) (the test preparations before and after the light exposure test) were dissolved in a phosphoric acid ethanol solution and then filtered through a 0.45 μm filter to prepare the quantitative sample. The phosphoric acid ethanol solution was prepared by mixing a phosphoric acid aqueous solution (phosphoric acid (1→500)) in which phosphoric acid was diluted 500 times with water with ethanol in a 1:1 (volume ratio).

[0069] This sample for quantification is subjected to HPLC under the conditions below to determine the area of the peak occurring at the retention time corresponding to each active ingredient. The content of each active ingredient (bromhexine) contained in the sample for quantification is calculated from the ratio to the peak area of a standard solution prepared using a standard (bromhexine) corresponding to each active ingredient.

[0070] [HPLC conditions] Measurement device: Alliance 2695 (manufactured by Nihon Waters Co., Ltd.) Stationary phase: L-column 2 4.6 x 100 mm, 3 μm (Shimadzu GLC Corporation) Mobile phase A: 0.1% trifluoroacetic acid Mobile phase B: methanol Gradient conditions:

[0071] [Table 1] Detector: W2489 UV / Vis detector (manufactured by Nihon Waters Co., Ltd.) Measurement wavelength: 260nm

[0072] (2) Evaluation criteria The content (initial value) of each active ingredient in the test formulation (control formulation) (more precisely, the sample for quantification) before the light exposure test is taken as 100%, and the percentage decrease in the content of each active ingredient in the test formulation (more precisely, the sample for quantification) after the light exposure test is calculated, and the stability of the formulation is evaluated according to the criteria listed in Table 2.

[0073] [Table 2]

[0074] (B) Method for measuring the coloring of the test formulation and evaluation criteria (1) Color measurement method The test formulations (test formulations before and after the accelerated test) were placed in the measurement cell (φ30 mm cell) of the spectrophotometer, and the color was quantified using a color system (L*a*b color space). [Measurement equipment and conditions] Measuring device: Spectrophotometric color difference meter SE-7700 (manufactured by Nippon Denshoku Industries Co., Ltd.) Reflection measurement diameter: 6 mm φ

[0075] For each test preparation before and after the acceleration test, the differences (ΔL*, Δa*, Δb*) between the two values are obtained from the respective measured values (L*, a*, b*), and the color difference (ΔE) is calculated based on the following formula (JIS Z8730).

[0076]

Equation

[0077] (2) Evaluation criteria From the color difference (ΔE) of the test preparations before and after the acceleration test obtained in this way, the degree of coloring by the acceleration 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).

[0078]

Table 3

[0079] 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.

[0080]

Table 4

[0081] Experimental example 1 Preparation of pharmaceutical formulation and its stability evaluation (Part 1) (1) Preparation of pharmaceutical preparations L-carbocysteine, DXM salt hydrate, and tipepidine salt were mixed in an agate mortar in the proportions shown in Table 5 as the amount per unit dose (single administration), and then water was added little by little to knead. The resulting kneaded mixture was sieved using a 10-mesh sieve, and the sieved product was dried at 60°C for 30 minutes using a ventilated dryer to prepare a granular pharmaceutical preparation (granule preparation) (see Examples 1-1 to 1-3, Control Example 1, and Comparative Example 1: Table 5).

[0082] (2) Experimental method 1 g of the prepared granule formulations (Examples 1-1 to 1-3, Control Example 1, and Comparative Example 1) was used as test formulations and subjected to the above-described accelerated tests 1 and 2. Next, for each test formulation, the above-described coloration measurement method was carried out before and after the accelerated test, and the color difference (ΔE) was calculated to evaluate the formulation stability (coloration resistance).

[0083] (3) Experimental results The results are also shown in Table 5.

[0084] [Table 5]

[0085] As can be seen from Control Example 1 and Comparative Example 1 in Table 5, a pharmaceutical composition containing 750 mg to 1500 mg of L-carbocysteine per daily dose in addition to a tipepidine salt was found to have a problem of discoloration that was discernible even to the average person in an accelerated test (40°C, 75% RH, sealed and opened). When the daily dose is administered in three divided doses, the L-carbocysteine dose per dose (unit dose) is 250 mg to 500 mg. Discoloration observed in the accelerated test indicates that the pharmaceutical preparation may discolor due to the influence of temperature and / or humidity, or may discolor after storage at room temperature for one year, impairing the appearance quality.

[0086] From the results of Examples 1-1 to 1-3 shown in Table 5, it was confirmed that this problem can be solved by formulating DXM, its salts or their hydrates (DXM compounds) in addition to L-carbocysteine and tipepidine salts. In particular, this problem can be more effectively solved by using a pharmaceutical composition in which the amount of L-carbocysteine per daily dose is 753 mg to 1500 mg, preferably 1000 mg to 1500 mg, and the mixing ratio of tipepidine salt to 100 parts by mass of L-carbocysteine is 1 to 7 parts by mass, preferably 2 to 6 parts by mass, more preferably 3 to 6 parts by mass, and the DXM compounds are 1 to 10 parts by mass, preferably 2 to 8 parts by mass, more preferably 3 to 7 parts by mass with respect to 100 parts by mass of L-carbocysteine.

[0087] Experimental example 2 Preparation of pharmaceutical formulation and its stability evaluation (Part 2) (1) Preparation of pharmaceutical preparations L-carbocysteine, DXM salt hydrate, and bromhexine salt were placed in an agate mortar and mixed at the ratios shown in Table 6 as the amounts per unit dose (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) (Examples 2-1 to 2-3, Control Example 2, Comparative Example 2: see Table 6).

[0088] (2) Experimental method 2 g of the prepared granule preparations (Examples 2-1 to 2-3, Control Example 2, Comparative Example 2) were used as test preparations and subjected to the above-described exposure test, respectively. Then, for each test preparation, the content of bromhexine salt was measured according to the above-described quantification method before and after the exposure test, the content reduction rate of bromhexine salt due to the exposure test was calculated, and the preparation stability (photo stability) was evaluated.

[0089] (3) Experimental results The results are shown in accordance with Table 6.

[0090]

Table 6

[0091] As can be seen from Comparative Example 2 in Table 6, in addition to bromhexine salt, a pharmaceutical composition containing 1500 mg of the blending amount of L-carbocysteine per daily dose was confirmed to have a problem that the content of bromhexine salt in the pharmaceutical composition decreased due to the exposure test. When the above daily dose is divided into three administrations, the administration amount (unit dose) per administration of L-carbocysteine is 500 mg. The decrease in the content of bromhexine salt due to the exposure test (total illuminance 120,000 lux·hr) means that the medicinal efficacy of the pharmaceutical preparation decreases due to storage and use under non-shielded conditions under sunlight and lighting indoors and outdoors.

[0092] From the results of Examples 2-1 to 2-3 shown in Table 6, it was confirmed that this problem can be solved by blending DXM, its salt or their hydrates (DXM compounds) in addition to L-carbocysteine and bromhexine salt. In particular, this problem is a pharmaceutical composition in which the blending amount of L-carbocysteine per daily dose is 753 mg to 1500 mg, preferably 1000 mg to 1500 mg, and the blending ratio of bromhexine salt to 100 parts by mass of L-carbocysteine is 0.1 to 1.2 parts by mass, preferably 0.2 to 1.0 parts by mass, more preferably 0.5 to 1.0 parts by mass. In this pharmaceutical composition, when DXM compounds are 1 to 10 parts by mass, preferably 2 to 8 parts by mass, more preferably 3 to 7 parts by mass with respect to 100 parts by mass of L-carbocysteine, it was confirmed that the problem can be more effectively solved.

[0093] Formulation examples 1 to 32 By mixing each component at the ratios described in Tables 7 and 8, an oral pharmaceutical composition in solid form having the effects of the present invention can be prepared.

Table 7

Table 8

Claims

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

2. The oral pharmaceutical composition according to Claim 1, containing at least one of the component (B) in each of the following ratios with respect to 100 parts by mass of the component (A); (B1) tipepidine or a pharmaceutically acceptable salt thereof: 1 to 7 parts by mass, (B2) bromhexine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass.

3. The oral pharmaceutical composition according to Claim 1 or 2, wherein the ratio of the component (C) with respect to 100 parts by mass of the component (A) is 1 to 10 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 solid-form pharmaceutical composition containing (A) L-carbocysteine and at least one selected from the group consisting of (B) tipepidine, bromhexine, and pharmaceutically acceptable salts thereof, and having a content of the component (A) of 753 mg to 1500 mg per daily dose, characterized in that (C) dextromethorphan, a pharmaceutically acceptable salt thereof, or a hydrate thereof is blended into the pharmaceutical composition.

6. The method for improving stability according to Claim 5, wherein the pharmaceutical composition contains at least one of the component (B) in each of the following ratios with respect to 100 parts by mass of the component (A); (B1) tipepidine or a pharmaceutically acceptable salt thereof: 1 to 7 parts by mass, (B2) bromhexine or a pharmaceutically acceptable salt thereof: 0.1 to 1.2 parts by mass.

7. The method for improving stability according to Claim 5 or 6, wherein the component (C) is blended in a ratio of 1 to 10 parts by mass with respect to 100 parts by mass of the component (A) in the pharmaceutical composition.

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

9. The method for improving stability according to claim 8, wherein the method for improving stability is a pharmaceutical composition containing the components (A) and (B) and not containing the component (C), and the content of the component (A) per daily dose is 1500 mg, and the stability of the pharmaceutical composition is improved as compared with a pharmaceutical composition having the same components.

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