solid components

Abstract

To provide an excellent solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof, wherein the decrease in the content of bromhexine or a salt thereof over time is suppressed. [Solution] We unexpectedly discovered that adding a specific component to a solid composition containing bromhexine or its salts, ascorbic acid or its derivatives, or their salts suppresses the time-dependent decrease in the content of bromhexine or its salts. In other words, the solid composition is characterized by containing (a) bromhexine or a salt thereof, (b) ascorbic acid or a derivative thereof or a salt thereof, and (c) at least one selected from the group consisting of dextromethorphan or a salt thereof, noscapine or a salt thereof, tipepidine or a salt thereof, carbocysteine, guaifenesin, guaiacol or a salt thereof, dimemorphan or a salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof. [Background technology]

[0002] In the field of over-the-counter (OTC) drugs, effectively eliminating the various symptoms of the common cold is crucial in drug development. Among the symptoms of the common cold, expectoration (coughing up phlegm) is particularly important as it reduces the burden on the patient.

[0003] Bromhexine hydrochloride is an expectorant that clears the airways through its mucolytic action, and is therefore included as an expectorant component in combination cold medicines (Non-Patent Document 1). It is also known that combining it with vitamin C enhances the mucolytic effect of bromhexine hydrochloride and strengthens its expectorant effect (Patent Document 1). Patent Document 1 describes a solid preparation containing bromhexine hydrochloride, ascorbic acid, and acetaminophen. Furthermore, a combination cold medicine formulation is known that includes a first combination cold medicine prescribed with an antihistamine in a first dose and a second combination cold medicine prescribed with the antihistamine in a second dose different from the first dose (Patent Document 2). Patent Document 2 describes a solid preparation containing bromhexine hydrochloride and dextromethorphan hydrobromide, and a solid preparation containing bromhexine hydrochloride, ascorbic acid, and acetaminophen.

[0004] However, these prior art documents do not mention the stability of bromhexine hydrochloride, and it is not known that the content of bromhexine or its salt decreases over time in compositions containing bromhexine or its salt and ascorbic acid or its derivatives or salts thereof. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Commentary on the Revised Japanese Pharmacopoeia, 17th Edition, Hirokawa Shoten Co., Ltd., page C-4878. [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2001-181206 [Patent Document 2] Japanese Patent Publication No. 2008-100924 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present inventors have found that when they prepare a solid composition containing bromhexine or a salt thereof, ascorbic acid or a derivative thereof, or a salt thereof, the content of bromhexine or a salt thereof decreases over time. The present invention has been made in view of the above-mentioned background circumstances, and aims to provide an excellent solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof, wherein the decrease in the content of bromhexine or a salt thereof over time is suppressed. [Means for solving the problem]

[0008] As a result of diligent research by the present inventors, it was unexpectedly discovered that when a solid composition containing bromhexine or its salt, ascorbic acid or its derivative, or its salt is infused with at least one substance selected from the group consisting of dextromethorphan or its salt, noscapine or its salt, tipepidine or its salt, carbocysteine, guaifenesin, guaiacol or its salt, or dimemorphan or its salt, the decrease in the content of bromhexine or its salt over time is suppressed. Furthermore, it was found that the decrease in the content of bromhexine or its salt over time is suppressed even more significantly when acetaminophen is added, leading to the completion of the present invention.

[0009] In other words, the present invention (1) A solid composition characterized by containing (a) bromhexine or a salt thereof, (b) ascorbic acid or a derivative thereof or a salt thereof, and (c) at least one selected from the group consisting of dextromethorphan or a salt thereof, noscapine or a salt thereof, tipepidine or a salt thereof, carbocysteine, guaifenesin, guaiacol or a salt thereof, dimemorphan or a salt thereof. (2) Furthermore, (d) the solid composition according to (1) containing acetaminophen, (3)(a) The solid composition according to (1) or (2), wherein the bromhexine or salt thereof is bromhexine hydrochloride. (4)(b) A solid composition according to any one of (1) to (3), wherein the ascorbic acid or its derivative or a salt thereof is ascorbic acid or calcium ascorbate. (5)(c) A solid composition according to any one of (1) to (4), wherein the dextromethorphan or salt thereof is dextromethorphan hydrobromide hydrate. (6)(c) A solid composition according to any one of (1) to (5) wherein noscapine or a salt thereof is noscapine. (7)(c) A solid composition according to any one of (1) to (6), wherein tipepidine or a salt thereof is tipepidine hibenzate. (8)(c) A solid composition according to any one of (1) to (7) wherein guaiacol or a salt thereof is potassium guaiacolsulfonate. (9)(c) A solid composition according to any one of (1) to (8), wherein dimemorphan or a salt thereof is dimemorphan phosphate. (10) A solid composition according to any of (1) to (9), which is a tablet, powder, fine granule, granule, pill, or capsule. (11) A method for suppressing the decrease in the content of (a) bromhexine or its salt in a solid composition containing (a) bromhexine or its salt and (b) ascorbic acid or its derivative or its salt, by incorporating (c) at least one selected from the group consisting of dextromethorphan or its salt, noscapine or its salt, tipepidine or its salt, carbocysteine, guaifenesin, guaiacol or its salt, dimemorphan or its salt. (12) A method for suppressing the decrease in the content of (a) bromhexine or its salt in a solid composition containing (a) bromhexine or its salt and (b) ascorbic acid or its derivative or its salt, wherein (c) at least one selected from the group consisting of dextromethorphan or its salt, noscapine or its salt, tipepidine or its salt, carbocysteine, guaifenesin, guaiacol or its salt, dimemorphan or its salt and (d) acetaminophen, That is the case. [Effects of the Invention]

[0010] The present invention makes it possible to provide a solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof, which exhibits excellent stability of bromhexine or a salt thereof. [Modes for carrying out the invention]

[0011] The bromhexine or salt thereof used in the present invention has the chemical formula C 14 H 20The compound is represented by Br2N2 or a salt thereof, and one of these may be used alone or in combination of two or more. Such bromhexine or salt thereof can be produced by known methods or commercially available products can be used. Furthermore, the bromhexine or salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred. The content of bromhexine or salt thereof in the solid composition of the present invention (the total content of two or more bromhexine or salt thereof if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that shows its pharmaceutically effective, but is usually 0.005 to 20% by mass, preferably 0.01 to 10% by mass, and more preferably 0.05 to 5% by mass.

[0012] The ascorbic acid, its derivative or their salts used in the present invention are compounds represented by the chemical formula C6H8O6, their derivatives or their salts, and one of these may be used alone or two or more of them may be used in combination. Such ascorbic acid, its derivative or their salts can be produced by known methods and commercially available products can also be used. Further, the ascorbic acid, its derivative or their salts are not particularly limited as long as they are pharmaceutically acceptable. The derivatives include ascorbic acid 2-glucoside, ascorbyl phosphate, 3-o-ethylascorbic acid, ascorbyl tetrahexyldecanoate, ascorbyl palmitate, ascorbyl stearate, ascorbic acid-2-phosphate-6-palmitate, glyceryl octyl ascorbate, etc. The salts include, for example, metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt, etc., and particularly preferably calcium salt. The content of ascorbic acid or its salt in the solid composition of the present invention (when two or more of ascorbic acid or its salts are contained, their total content, the same shall apply hereinafter) is not particularly limited as long as it is an amount showing its medicinal effect, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass, more preferably 1 to 20% by mass.

[0013] The dextromethorphan or its salt used in the present invention has the chemical formula C 18 H 25The compound represented by NO or a salt thereof may be used alone or in combination of two or more. Such dextromethorphan or salt thereof can be produced by known methods or commercially available products can be used. Furthermore, the dextromethorphan or salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthalate, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrobromide or phenolphthalate being particularly preferred. The content of dextromethorphan or salt thereof in the solid composition of the present invention (the total content of two or more of dextromethorphan or salt thereof if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that shows its pharmaceutically active effect, but is usually 0.001 to 30% by mass, preferably 0.01 to 20% by mass, and more preferably 0.1 to 10% by mass.

[0014] The noscapine or salt thereof used in this invention has the chemical formula C 22 H 23 The compound represented by NO7 or a salt thereof may be used alone or in combination of two or more. Such noscapine or salt thereof can be produced by known methods or commercially available products can be used. Furthermore, noscapine or its salt is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthalate, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred. The content of noscapine or its salt in the solid composition of the present invention (the total content of two or more of noscapine or its salts if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that shows its pharmacokinetic effect, but is usually 0.001 to 30% by mass, preferably 0.01 to 20% by mass, and more preferably 0.1 to 10% by mass.

[0015] The thioperidine or its salt used in the present invention is a compound represented by the chemical formula C 15 H 17 NS2 or a salt thereof, and one of these may be used alone or two or more thereof may be used in combination. Such thioperidine or its salt can be produced by a known method, and commercially available products can also be used. Further, the thioperidine or its salt is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthaleinate, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, and hibenzate. Particularly preferred is hibenzate. The content of thioperidine or its salt in the solid composition of the present invention (when two or more of thioperidine or its salts are contained, the total content thereof, the same hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.05 to 30% by mass, preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass.

[0016] The carbocysteine used in the present invention is a compound represented by the chemical formula C5H9NO4S. Such carbocysteine can be produced by a known method, and commercially available products can also be used. Further, carbocysteine is not particularly limited as long as it is pharmaceutically acceptable, but particularly preferred is L-carbocysteine. The content of carbocysteine in the solid composition of the present invention is not particularly limited as long as it exhibits the medicinal effect, but is usually 1 to 95% by mass, preferably 5 to 85% by mass, more preferably 10 to 65% by mass.

[0017] The guaifenesin used in the present invention has the chemical formula C 10 H 14The compound is represented by O4. Such guaifenesin can be produced by known methods, or commercially available guaifenesin can be used. Furthermore, the carbocysteine ​​is not particularly limited as long as it is pharmaceutically acceptable. The amount of guaifenesin in the solid composition of the present invention is not particularly limited as long as it is in an amount that exhibits its pharmacokinetic effect, but is usually 0.1 to 50% by mass, preferably 0.5 to 30% by mass, and more preferably 1 to 15% by mass.

[0018] The guaiacol or salt thereof used in the present invention is a compound represented by the chemical formula C7H8O2 or a salt thereof, and one of these may be used alone or in combination of two or more. Such guaiacol or salt thereof can be produced by known methods or commercially available products can be used. Furthermore, the guaiacol or salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthalate, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, and sulfonate, with sulfonate being particularly preferred. The content of guaiacol or salt thereof in the solid composition of the present invention (the total content of two or more of the guaiacol or salt thereof if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that shows its medicinal effect, but is usually 0.1 to 50% by mass, preferably 0.5 to 30% by mass, and more preferably 1 to 15% by mass.

[0019] The dimemorphan or salt thereof used in this invention has the chemical formula C 18 H 25The compound is represented by NC or a salt thereof, and one of these may be used alone or in combination of two or more. Such dimemorphan or salt thereof can be produced by known methods or commercially available products can be used. Furthermore, dimemorphan or salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthalate, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with phosphate being particularly preferred. The content of dimemorphan or salt thereof in the solid composition of the present invention (the total content of two or more dimemorphan or salt thereof if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that shows its pharmaceutically effective, but is usually 0.001 to 30% by mass, preferably 0.01 to 20% by mass, and more preferably 0.1 to 10% by mass.

[0020] The mixing ratio of (a) bromhexine or a salt thereof to (b) ascorbic acid or a derivative thereof or a salt thereof is 0.001 to 10 parts by mass, preferably 0.005 to 1 part by mass, and more preferably 0.01 to 0.1 parts by mass of (a) bromhexine or a salt thereof per 1 part by mass of (b) ascorbic acid or a derivative thereof or a salt thereof.

[0021] The mixing ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) dextromethorphan or its salts is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) dextromethorphan or its salts is not particularly limited, but is 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, and more preferably 0.05 to 1 part by mass.

[0022] The mixing ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) noscapine or its salts is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) noscapine or its salts is 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, and more preferably 0.05 to 1 part by mass.

[0023] The mixing ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) tipepidine or its salts is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) tipepidine or its salts is 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, and more preferably 0.05 to 2 parts by mass.

[0024] The blending ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) carbocysteine ​​is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) carbocysteine ​​is 0.01 to 30 parts by mass, preferably 0.05 to 20 parts by mass, and more preferably 0.1 to 10 parts by mass.

[0025] (b) ascorbic acid or a derivative thereof or a salt thereof and (c) guaifenesin, with respect to 1 part by mass of (b) ascorbic acid or a derivative thereof or a salt thereof, the amount of (c) guaifenesin is not particularly limited, but is 0.001 to 15 parts by mass, preferably 0.01 to 10 parts by mass, and more preferably 0.1 to 5 parts by mass.

[0026] The mixing ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) guaiacol or its salts is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) guaiacol or its salts is 0.001 to 15 parts by mass, preferably 0.01 to 10 parts by mass, and more preferably 0.1 to 5 parts by mass.

[0027] The blending ratio of (b) ascorbic acid or its derivatives or salts thereof to (c) dimemorphan or its salts is such that, for every 1 part by mass of (b) ascorbic acid or its derivatives or salts thereof, (c) dimemorphan or its salts is 0.001 to 5 parts by mass, preferably 0.005 to 3 parts by mass, and more preferably 0.01 to 1 part by mass.

[0028] The mixing ratio of (a) bromhexine or a salt thereof to (c) dextromethorphan or a salt thereof is such that, for every 1 part by mass of (a) bromhexine or a salt thereof, (c) dextromethorphan or a salt thereof is 0.01 to 30 parts by mass, preferably 0.1 to 20 parts by mass, and more preferably 1 to 10 parts by mass.

[0029] The mixing ratio of (a) bromhexine or a salt thereof to (c) noscapine or a salt thereof is such that, for every 1 part by mass of (a) bromhexine or a salt thereof, (c) noscapine or a salt thereof is 0.01 to 30 parts by mass, preferably 0.1 to 20 parts by mass, and more preferably 1 to 10 parts by mass.

[0030] The mixing ratio of (a) bromhexine or a salt thereof to (c) tipepidine or a salt thereof is such that, for every 1 part by mass of (a) bromhexine or a salt thereof, (c) tipepidine or a salt thereof is 0.01 to 40 parts by mass, preferably 0.1 to 30 parts by mass, and more preferably 1 to 15 parts by mass.

[0031] The mixing ratio of (a) bromhexine or a salt thereof to (c) carbocysteine ​​is, with a minimum of 1 part by mass of (a) bromhexine or a salt thereof, of (c) carbocysteine, which is not particularly limited, but is 1 to 100 parts by mass, preferably 10 to 98 parts by mass, and more preferably 20 to 95 parts by mass.

[0032] The mixing ratio of (a) bromhexine or a salt thereof to (c) guaifenesin is, with a minimum of 1 part by mass of (a) bromhexine or a salt thereof, 0.1 to 60 parts by mass, preferably 1 to 50 parts by mass, and more preferably 5 to 40 parts by mass of (c) guaifenesin, although this ratio is not particularly limited.

[0033] The mixing ratio of (a) bromhexine or a salt thereof to (c) guaiacol or a salt thereof is, with a minimum of 1 part by mass of (a) bromhexine or a salt thereof, of (c) guaiacol or a salt thereof, which is not particularly limited, but is 0.1 to 60 parts by mass, preferably 1 to 50 parts by mass, and more preferably 5 to 40 parts by mass.

[0034] The mixing ratio of (a) bromhexine or a salt thereof to (c) dimemorphan or a salt thereof is such that, for every 1 part by mass of (a) bromhexine or a salt thereof, (c) dimemorphan or a salt thereof is 0.01 to 20 parts by mass, preferably 0.1 to 10 parts by mass, and more preferably 1 to 5 parts by mass.

[0035] The solid composition of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, cooling agents, colorants, flavoring agents, fragrances, coating agents, etc., within a qualitative and quantitative range that does not impair the effects of the present invention. Other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosal protectants, herbal medicines, Kampo prescriptions, caffeines, etc., and may contain one or more selected from the group consisting of these.

[0036] Examples of excipients that can be incorporated into the solid composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, etc. Examples of disintegrants include low-substituted hydroxypropylcellulose, sodium starch glycolate, crospovidone, carmellose, sodium carmellose, calcium carmellose, pregelatinized starch, etc. Examples of binders include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Examples of fluidizers include light anhydrous silicic acid, hydrated silicon dioxide, etc. Examples of lubricants include sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, calcium stearate, talc, etc. Examples of cooling agents include menthol, peppermint oil, eucalyptus oil, etc.

[0037] The solid composition of the present invention can be manufactured by conventional methods, and the method is not particularly limited. For example, (a) bromhexine or a salt thereof (hereinafter also referred to as component (a)), (b) ascorbic acid or a derivative thereof or a salt thereof (hereinafter also referred to as component (b)), and (c) dextromethorphan or a salt thereof, noscapine or a salt thereof, tipepidine or a salt thereof, carbocysteine, guaifenesin, guaiacol or a salt thereof, dimemorphan or a salt thereof (hereinafter also referred to as component (c)) may be simply mixed, or granulated after mixing, and the resulting granules may be coated. Furthermore, components (a), (b), and (c) do not necessarily have to be contained in the same granule. For example, this could involve manufacturing granules containing components (a) and (c), then mixing in component (b), or manufacturing granules containing components (a) and (b), then mixing in component (c), or manufacturing granules containing components (a) and (c) and granules containing components (b) and (c), then mixing the two granules together.

[0038] The granulation method is not particularly limited and can be manufactured by wet granulation, dry granulation, or melt granulation, but wet granulation is preferred. Examples of wet granulation methods include agitation granulation, fluid bed granulation, kneading granulation, extrusion granulation, and rolling fluid granulation. The obtained granules may also be appropriately blended with the above-mentioned active ingredients and conventional pharmaceutical additives such as excipients. The mixture obtained in this way can also be compressed into tablets. When manufacturing tablets, direct compression may be used.

[0039] The solid composition of the present invention is not particularly limited as long as it is in a dosage form as specified in the General Rules for Formulations of the Japanese Pharmacopoeia, but is preferably a tablet, powder, fine granule, granule, pill, or capsule. Tablets specified in the General Rules for Formulations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, core tablets, and laminated tablets. Furthermore, the tablets may be scored, marked, or engraved to improve identification. In addition, the tablets of this formulation may be round or irregularly shaped. [Examples]

[0040] The present invention will be described in more detail below with reference to examples, control examples, and comparative examples, but the present invention is not limited to these examples.

[0041] (Control Example 1, Comparative Examples 1-3, Examples 1-17) According to the formulations shown in Tables 1-3, each component was measured out, mixed, and an appropriate amount of water was added and mixed to obtain the preparation.

[0042] (Test Example 1) The preparations of Control Example 1, Comparative Examples 1-3, and Examples 1-17 were stored at 65°C for 3 days. The content of bromhexine hydrochloride in each solid composition after storage was measured, and the remaining percentage (%) was determined. The results are shown in Tables 1-3.

[0043] [Table 1]

[0044] As shown in Table 1, a decrease in the bromhexine hydrochloride content was observed in Comparative Example 1 compared to Control Example 1, while the decrease in the bromhexine hydrochloride content was suppressed in Examples 1 to 8 compared to Comparative Example 1.

[0045] [Table 2]

[0046] As shown in Table 2, a decrease in the bromhexine hydrochloride content was observed in Comparative Example 2 compared to Control Example 1, while the decrease in the bromhexine hydrochloride content was suppressed in Example 9 compared to Comparative Example 2.

[0047] [Table 3]

[0048] Furthermore, in Examples 10-17 shown in Table 3, the decrease in bromhexine hydrochloride content was even more suppressed compared to Examples 2-8 shown in Table 1 and Comparative Example 3 shown in Table 3.

[0049] (Control Example 2, Comparative Example 4, Examples 18-19) According to the formulation shown in Table 4, each component was measured out, mixed, and an appropriate amount of ethanol was added and mixed to obtain the prepared product.

[0050] (Test Example 2) The preparations of Control Example 2, Comparative Example 4, and Examples 18-19 were stored at 65°C for 7 days. The content of bromhexine hydrochloride in each solid composition after storage was measured, and the remaining percentage was determined. The results are shown in Table 4.

[0051] [Table 4]

[0052] As shown in Table 4, Comparative Example 4 showed a decrease in the bromhexine hydrochloride content compared to Control Example 2, and Example 18 showed a suppressed decrease in the bromhexine hydrochloride content compared to Comparative Example 4. Furthermore, Example 19 showed an even greater suppression of the decrease in the bromhexine hydrochloride content compared to Example 18.

[0053] Examples of formulation preparations are given below. (Example of formulation 1) Based on the quantities shown in Table 5, the granular components were mixed and wet-granulated. The resulting granular components were then mixed with the added end-of-day components to prepare a granular preparation of approximately 1.23 g per sachet, resulting in a formulation to be taken at a rate of 3 sachets per day.

[0054] [Table 5]

[0055] (Formulation Example 2) Based on the quantities shown in Table 6, the granular components were mixed and wet-granulated. The resulting granular components were then mixed with the added end-of-day components to prepare a granular preparation of approximately 0.89 g per sachet, resulting in a formulation to be taken three sachets per day.

[0056] [Table 6]

[0057] (Formulation Example 3) Based on the quantities shown in Table 7, the granular components were mixed and wet-granulated. The resulting granular components were then mixed with the added end-of-day components to prepare a granular preparation of approximately 1.2 g per sachet, resulting in a formulation to be taken three sachets per day.

[0058] [Table 7]

[0059] (Formulation example 4) Based on the quantities shown in Table 8, the granulation components were mixed and wet-granulated. The resulting granulation components were then mixed with the post-addition components to obtain tablet granules. From these tablet granules, tablets were manufactured using a rotary tablet press, with each tablet containing approximately 0.26 g and a daily dosage of 9 tablets.

[0060] [Table 8]

[0061] (Formulation example 5) Based on the quantities shown in Table 9, the granulation components were mixed and wet-granulated. The resulting granulation components were then mixed with the post-addition components to obtain tablet granules. From these tablet granules, tablets were manufactured using a rotary tablet press, with each tablet containing approximately 0.24 g and a daily dosage of 9 tablets.

[0062] [Table 9]

[0063] (Formulation example 6) Based on the quantities shown in Table 10, the granulation components were mixed and wet-granulated. The resulting granulation components were then mixed with the post-addition components to obtain tablet granules. From these tablet granules, tablets were manufactured using a rotary tablet press, with each tablet containing approximately 0.24 g and a daily dosage of 9 tablets.

[0064] [Table 10] [Industrial applicability]

[0065] The present invention makes it possible to provide a solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof, which exhibits excellent stability of bromhexine or a salt thereof. Furthermore, the present invention makes it possible to maintain the formulation stability of a solid composition containing bromhexine or a salt thereof and ascorbic acid or a derivative thereof or a salt thereof by a simple method.

Claims

1. A solid composition characterized by containing (a) bromhexine or a salt thereof, (b) ascorbic acid or a derivative thereof or a salt thereof, and (c) at least one selected from the group consisting of noscapine or a salt thereof, tipepidine or a salt thereof, carbocysteine, guaifenesin, guaiacol or a salt thereof, and dimemorphan or a salt thereof.

2. Furthermore, the solid composition according to claim 1, further comprising (d) acetaminophen.

3. (a) The solid composition according to claim 1 or 2, wherein the bromhexine or salt thereof is bromhexine hydrochloride.

4. (b) The solid composition according to any one of claims 1 to 3, wherein the ascorbic acid or its derivative or salt thereof is ascorbic acid or calcium ascorbate.

5. (c) The solid composition according to any one of claims 1 to 4, wherein noscapine or a salt thereof is noscapine.

6. (c) The solid composition according to any one of claims 1 to 5, wherein tipepidine or a salt thereof is tipepidine hibenzate.

7. (c) The solid composition according to any one of claims 1 to 6, wherein guaiacol or a salt thereof is potassium guaiacolsulfonate.

8. (c) The solid composition according to any one of claims 1 to 7, wherein dimemorphan or a salt thereof is dimemorphan phosphate.

9. The solid composition according to any one of claims 1 to 8, which is a tablet, powder, fine granules, granules, pill, or capsule.

10. A method for suppressing the decrease in the content of (a) bromhexine or its salt in a solid composition containing (a) bromhexine or its salt and (b) ascorbic acid or its derivative or its salt, by incorporating (c) at least one selected from the group consisting of noscapine or its salt, tipepidine or its salt, carbocysteine, guaifenesin, guaiacol or its salt, and dimemorphan or its salt.

11. A method for suppressing the decrease in the content of (a) bromhexine or its salt in a solid composition containing (a) bromhexine or its salt and (b) ascorbic acid or its derivative or its salt, by incorporating (c) at least one selected from the group consisting of noscapine or its salt, tipepidine or its salt, carbocysteine, guaifenesin, guaiacol or its salt, and dimemorphan or its salt, and (d) acetaminophen.

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