JP7127329B2 - Pharmaceutical composition - Google Patents

Description

The present invention relates to pharmaceutical compositions containing ambroxol or salts thereof. More particularly, the present invention relates to a pharmaceutical composition in which the decrease in the content of ambroxol or a salt thereof over time is suppressed and which is excellent in administration.

In the field of over-the-counter drugs (OTC), how to effectively remove various symptoms of colds is important in drug development. Among cold syndromes, expectoration of sputum (expectoration) is particularly important because it reduces the burden on the patient.
Ambroxol hydrochloride, which is an expectorant, is known as an airway-lubricating expectorant, and has an expectorant effect for acute and chronic bronchitis, bronchial asthma, etc. as a medical drug (Non-Patent Document 1). .

Therefore, ambroxol hydrochloride is blended in many antitussive expectorants and common cold medicines due to its excellent effects. However, these active ingredients are known to have a bitter taste (Patent Documents 1 and 2), and since the bitter taste leads to a decrease in patient compliance, there is a demand for formulations that reduce the bitter taste and are easy to take.
Many methods have been proposed in the past for blocking or reducing the unpleasant taste of drugs. For example, in liquid formulations, syrups, powders, fine granules, granules, dry syrups, orally disintegrating tablets, etc., methods of adding sweeteners or flavoring agents are known. In some cases, microencapsulation, coating, spray drying, etc. are used (Patent Document 3). Also, as a way to improve the bitterness of bromhexine, it has been reported that vanillin, which is a flavor frequently used as the main aromatic component of vanilla seeds, is blended (Patent Document 4).

Japanese Non-Pharmacopoeia Pharmaceutical Standards 2002 p.158

Japanese Patent No. 5758552 JP 2008-260717 A Japanese Patent Application Laid-Open No. 2010-53048 Japanese Patent Application Laid-Open No. 2001-106639

The present inventors have tried to reduce the bitterness of formulations containing ambroxol or its salt by adding a flavor that is simple and reported to have an improvement effect. It was surprisingly found that the content of ambroxol or a salt thereof decreased over time by blending an additive containing a derivative thereof.

An object of the present invention is to provide a formulation containing ambroxol or a salt thereof and at least one selected from the group consisting of vanillin or a derivative thereof and cinnamaldehyde or a derivative thereof, and the content of ambroxol or a salt thereof over time The purpose of the present invention is to provide a pharmaceutical composition that suppresses the decrease in the drug content and is excellent in administration.

The present inventors conducted various investigations to solve the above problems, and found that at least one selected from the group consisting of ambroxol or a salt thereof, vanillin or a derivative thereof, and cinnamaldehyde or a derivative thereof. It was found that by adding an additive containing two or more amino groups to a formulation, the decrease in the content of ambroxol or a salt thereof is suppressed, and a formulation with reduced bitterness and excellent administration properties can be obtained. was completed.

That is, the present invention comprises (1) (a) ambroxol or a salt thereof, (b) at least one selected from the group consisting of vanillin or a derivative thereof and cinnamaldehyde or a derivative thereof, and (c) aspartame and neotame. A pharmaceutical composition characterized by containing at least one selected from the group,
(2) The pharmaceutical composition according to (1), wherein (a) ambroxol or a salt thereof is ambroxol hydrochloride;
is.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition excellent in stability and dosability by blending at least one selected from the group consisting of ambroxol or a salt thereof, vanillin or a derivative thereof, and cinnamaldehyde or a derivative thereof. became.

INDUSTRIAL APPLICABILITY The pharmaceutical composition of the present invention can be provided as a pharmaceutical composition which has a simple formulation process, is less bitter, is easy to take, and has excellent stability. Moreover, the pharmaceutical composition of the present invention means an orally administered formulation.

Ambroxol or a salt thereof used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ Br ₂ N ₂ O or a salt thereof. may be used. Such ambroxol or a salt thereof can be produced by a known method, or commercially available products can be used. In addition, ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. , and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate. , particularly preferably the hydrochloride. Content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention (when two or more of compounds represented by the chemical formula C ₁₃ H ₁₈ Br ₂ N ₂ O or salts thereof are contained, The total content, hereinafter the same) is not particularly limited as long as it is an amount that exhibits its efficacy, but usually 0.1 to 70% by mass, preferably 0.1 to 50% by mass, more than It is preferably 0.5 to 10% by mass.

The vanillin or derivative thereof used in the present invention is not particularly limited in terms of its origin, as long as it can be orally ingested, and can be extracted from natural products, synthetic products, or commercially available products.
Vanillin (4-hydroxy-3-methoxybenzaldehyde, chemical formula C ₈ H ₈ O ₃ ) is a vanilla-like fragrance component or fruit-like fragrance component, and is used as an additive or flavoring agent in the fields of pharmaceuticals, quasi-drugs, and foods. can be obtained commercially as Fruit-like scents include, for example, apple-like, strawberry-like, berry-like, pineapple-like, banana-like, peach-like, melon-like, apricot-like, cherry-like, grape-like, and muscat-like. It is also used as a chocolate-like, milk-like, cocoa-like, and jasmine-like fragrance component.
In addition, vanillin derivatives include those in which the methoxy group of vanillin is substituted with an alkoxy group, those in which a hydroxyl group is etherified (alkoxy group) or esterified, those in which an aldehyde is oxidized or acetalized, and those in which vanillin is halogenated. , nitrated products, structural isomers of vanillin, and the like, and those used as additives or fragrances in the fields of pharmaceuticals, quasi-drugs, and foods are preferred. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy groups. Specifically, those in which a methoxy group is substituted with an alkoxy group include ethyl vanillin, propyl vanillin, isopropyl vanillin, butyl vanillin, isobutyl vanillin, tert-butyl vanillin and the like. Etherified hydroxyl groups include methyl vanillin (3,4-dimethoxybenzaldehyde), 4-ethoxy-3-methoxybenzaldehyde, 4-propoxy-3-methoxybenzaldehyde, 4-isopropoxy-3-methoxybenzaldehyde, 4 -butoxy-3-methoxybenzaldehyde, 4-isobutoxy-3-methoxybenzaldehyde, 4-tert-butoxy-3-methoxybenzaldehyde, glucovanillin and the like. Examples of esterified hydroxy groups include vanillin acetate, vanillin propylate, vanillin isopropylate, vanillin butyrate, and vanillin isobutyrate. Examples of oxidized aldehydes include vanilla acid, and examples of acetalized aldehydes include vanillin propylene glycol acetal. Halogenated or nitrated vanillin includes vanillin 2-chlorovanillin, 5-chlorovanillin, 6-chlorovanillin, 2-bromovanillin, 5-bromovanillin, 6-bromovanillin, 2-iodovanillin, 5 -iodovanillin, 6-iodovanillin, 2-nitrovanillin, 5-nitrovanillin, 6-nitrovanillin and the like. Structural isomers of vanillin include isovanillin and o-vanillin, and other vanillin derivatives include dehydroisovanillin (anisaldehyde), eugenol, vanillylacetone (gingerone), homovanillin, homovanillic acid, apocynin, and capsaicin. , capsiate, vanilla mandelic acid, Ethamivan, Metanephrine, Normeranephrine and the like. Among them, vanillin derivatives are preferably ethyl vanillin, propyl vanillin, isopropyl vanillin, butyl vanillin, isobutyl vanillin, methyl vanillin, glucovanillin, vanillin acetate, vanillin propylate, vanillin isopropylate, vanillin butyrate, vanillin isobutyrate, isovanillin, o-vanillin, dehydroisovanillin, eugenol, vanillylacetone, homovanillin, capsaicin, capsiate, particularly preferably ethyl vanillin, glucovanillin, vanillin acetate, vanillin isobutyrate, isovanillin, o-vanillin, dehydroisovanillin , eugenol, vanillylacetone, capsaicin, capsiate. Although the vanillin or derivative thereof used in the present invention is not particularly limited, it is preferably vanillin.
The content of vanillin or a derivative thereof in the pharmaceutical composition of the present invention is not particularly limited, but is usually 0.001 to 10% by mass, preferably 0.01 to 5% by mass in the formulation. .

The origin of the cinnamaldehyde or its derivative used in the present invention is not particularly limited as long as it can be orally ingested, and those extracted from natural products, synthetic products, and commercially available products can be used.
Cinnamaldehyde, also called cinnamaldehyde, is a kind of known aromatic aldehyde represented by the chemical formula C ₉ H ₈ O (molecular weight 132.16). It is a cinnamon-like fragrance component, available as a fragrance preparation, and is also known as a component contained in the crude drug cinnamon bark. The herbal medicine, cinnamon bark, is the dried bark of cinnamon in the Lauraceae family and its congeners. It is Cinnamon bark is known to contain 1 to 3.5% of essential oil, and cinnamaldehyde is the main component of the essential oil contained in cinnamon bark, and is usually contained in the essential oil by about 75% or more. In the present invention, the pulverized product or extract of cinnamon bark (including extract powder) can be used.
The cinnamaldehyde derivative is not particularly limited, and examples thereof include 4-ethoxycinnamaldehyde, 4-propoxycinnamaldehyde, 4-isopropoxycinnamaldehyde, 4-(2-propenyloxy)cinnamaldehyde, 4-butoxycinnamaldehyde, 4-isobutoxycinnamaldehyde, 4-(sec-butoxy)cinnamaldehyde, 4-(tert-butoxy)cinnamaldehyde, 4-(3-butenyloxy)cinnamaldehyde. Cinnamaldehyde or a derivative thereof is preferably cinnamaldehyde that is commercially available as an additive or fragrance in the fields of pharmaceuticals, quasi-drugs, or foods.
The content of cinnamaldehyde or a derivative thereof in the pharmaceutical composition of the present invention is not particularly limited. More preferably 0.01 to 5%.

Aspartame used in the present invention is N-(L-α-aspartyl)-L-phenylalanine 1-methyl ester (dipeptide in which methyl ester of L-aspartic acid and phenylalanine are linked). The compounding ratio of aspartame and ambroxol or a salt thereof is preferably 0.01 to 20 parts by mass, particularly preferably 0.1 to 10 parts by mass, per 1 part by mass of ambroxol or a salt thereof. .
The neotame used in the present invention is N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.
The blending ratio of neotame and ambroxol or a salt thereof is preferably 0.01 to 20 parts by mass, particularly preferably 0.1 to 10 parts by mass, per 1 part by mass of ambroxol or a salt thereof. .

The pharmaceutical composition of the present invention is not particularly limited as long as it is in the dosage form specified in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia, and can take any commonly used dosage form. Examples include solid formulations such as tablets, powders, fine granules, granules, pills and capsules, or liquid formulations such as oral liquids and syrups. Tablets defined in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, laminated tablets and the like. The pharmaceutical composition of the present invention is preferably a solid formulation, more preferably tablets, powders, fine granules, granules, pills and capsules. In addition, the tablet can be provided with a score line, a mark for improving identification, or an engraving. Furthermore, the tablet of this preparation may be a round tablet or an irregularly shaped tablet.

The pharmaceutical composition of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, lubricants, coloring agents, and flavoring agents within qualitative and quantitative ranges that do not impair the effects of the present invention. Flavoring agents, fragrances, coating agents and the like can be blended.

Other active ingredients that can be incorporated into the pharmaceutical composition of the present invention include, for example, antipyretic analgesics, antihistamines, antiallergic agents, anticholinergics, antitussives, noscapines, bronchodilators, expectorants, sedative hypnotics, and vitamins. anti-inflammatory agents, gastric mucosa protective agents, herbal medicines, Chinese herbal medicines, caffeines, vitamins, etc., and may contain one or more selected from the group consisting of these.
Examples of active ingredients that can be incorporated into the pharmaceutical composition of the present invention include acetaminophen, ibuprofen, loxoprofen or its salts, ethenzamide, aspirin or its salts, chlorpheniramine or its salts, carbinoxamine or its salts, mequitazine, and fexofenadine. or salts thereof, loratadine, ketotifen or its salts, azelastine or its salts, epinastine or its salts, ebastine, cetirizine or its salts, olopatadine or its salts, levocetirizine or its salts, belladonna total alkaloids, isopropamide iodide, pranlukast, montelukast, gromoglycate sodium, tranilast, pemirolast, repirinast, ibudilast, tazanolast, diphenhydramine or its salts, diphenhydramine or its salts, dihydrocodeine phosphate, codeine phosphate, dextromethorphan or its salts, tipepidine or its salts, cloperastine or its salt, noscapine or its salts, ephedrine or its salts, guaifenesin, guaiacolsulfonate sodium, trimetoquinol or its salts, methoxyphenamine or its salts, theophylline, aminophylline, diprophylline, proxyphylline, clemastine, l-menthol, caffeine or salts thereof, aminoacetic acid, magnesium silicate, aluminum silicate, magnesium oxide, synthetic hydrotalcite, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, vitamin E and derivatives thereof, salts thereof, and the like.

Examples of excipients that can be incorporated into the pharmaceutical composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, calcium hydrogen phosphate, etc. Binders include hydroxypropyl cellulose and hypromellose. , pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Fluidizers include light anhydrous silicic acid, hydrous silicon dioxide, aluminum silicate, etc. Lubricants include stearic acid, magnesium stearate, calcium stearate, Talc, sucrose fatty acid ester, sodium stearyl fumarate, sucrose fatty acid ester, hardened oil and the like. Disintegrants include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylstarch and the like.

The pharmaceutical composition of the present invention comprises (a) ambroquil or a salt thereof (hereinafter also referred to as component (a)), (b) vanillins or cinnamaldehydes (hereinafter also referred to as component (b)), and (c ) As long as it contains an additive containing two or more amino groups (hereinafter also referred to as component (c)), the production method is not particularly limited, and is based on the known method described in the Japanese Pharmacopoeia General Rules for Preparations. It can be manufactured and formulated.
For example, in the case of granulation, the granulation method is not particularly limited. Raw materials containing agents are mixed and granulated by dry granulation, wet granulation, or hot melt granulation, preferably wet granulation. Wet granulation methods include, for example, extrusion granulation, fluid bed granulation, stirring granulation, kneading granulation, spray drying granulation, etc. Fluid bed granulation, stirring granulation, and kneading are preferred. Synthetic granules.
The granules may be a single granule containing components (a), (b), and (c), or a combination of two or more granules with different compositions. It is good also as a granule by combining the granule containing and the granule containing (b) component. At this time, the component (c) may be blended with each granule or may be added later. The granules may also be coated. Furthermore, using this granule, capsules or tablets can be produced by a conventional method. Moreover, when the present invention is a tablet, it can also be produced by a direct compression method.
In the case of a liquid formulation, for example, components (a), (b), (c) and, if necessary, other additives can be dissolved in purified water.

EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.
(Comparative example 1)
34% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 62% by mass of mannitol, and 2.3% by mass of hydroxypropylcellulose were mixed with the entire formulation using a polyethylene bag. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Comparative example 2)
33% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 61% by mass of mannitol, 2.2% by mass of hydroxypropylcellulose, and 1.7% by mass of sucralose were added to the entire formulation using a polyethylene bag. mixed. After adding the mixture and an appropriate amount of water and kneading with a mortar and granulation, the mixture was sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Comparative Example 3)
33% by weight of acetaminophen, 1.7% by weight of ambroxol hydrochloride, 61% by weight of mannitol, 2.2% by weight of hydroxypropyl cellulose, and 1.7% by weight of dipotassium glycyrrhizinate are added to the entire formulation. A bag was used to mix. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Example 1)
33% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 61% by mass of mannitol, 2.2% by mass of hydroxypropylcellulose, and 1.7% by mass of aspartame were added to the entire formulation using a polyethylene bag. mixed. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Example 2)
34% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 62% by mass of mannitol, 2.2% by mass of hydroxypropylcellulose, and 0.6% by mass of aspartame were added to the entire formulation using a polyethylene bag. mixed. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Example 3)
32% by mass of acetaminophen, 1.6% by mass of ambroxol hydrochloride, 58% by mass of mannitol, 2.1% by mass of hydroxypropylcellulose, and 7% by mass of aspartame were mixed with the entire formulation using a polyethylene bag. did. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of a cinnamon-like fragrance having a cinnamaldehyde content of about 70% and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Comparative Example 4)
34% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 62% by mass of mannitol, and 2.3% by mass of hydroxypropylcellulose were mixed with the entire formulation using a polyethylene bag. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of vanillin and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Example 4)
33% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 61% by mass of mannitol, 2.2% by mass of hydroxypropylcellulose, and 1.7% by mass of aspartame were added to the entire formulation using a polyethylene bag. mixed. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of vanillin and 0.1% by mass of light anhydrous silicic acid were added to the granules.
(Comparative Example 5)
34% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 62% by mass of mannitol, and 2.3% by mass of hydroxypropylcellulose were mixed with the entire formulation using a polyethylene bag. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of herb-like fragrance (free of vanillins and cinnamaldehydes) and 0.1% by mass of light anhydrous silicic acid were added to the granules. The herb-like fragrances used consist of cuminal, cumin alcohol, γ-terpinene, and α-pinene.
(Comparative Example 6)
34% by mass of acetaminophen, 1.7% by mass of ambroxol hydrochloride, 62% by mass of mannitol, and 2.3% by mass of hydroxypropylcellulose were mixed with the entire formulation using a polyethylene bag. The mixture and an appropriate amount of water were added, kneaded in a mortar, granulated, and then sufficiently dried. After that, the whole amount was passed through a sieve (500 μm mesh size) to obtain granules. Furthermore, 0.1% by mass of an anise-like fragrance (free of vanillins and cinnamaldehydes) and 0.1% by mass of light silicic anhydride were added to the granules. The anise-like fragrance used consists of anethole, aniseketone, limonene and anise alcohol.

(Test example 1)
After the powders of Comparative Examples and Examples were stored at 65° C. for 1 week, the residual amount of ambroxol was measured by HPLC to obtain the residual rate (%).
Tables 1 and 3 show daily dosages for the compositions obtained by the methods described in Examples and Comparative Examples. Tables 2 and 4 show residual rates of ambroxol hydrochloride.

As shown in Table 2, in the preparation containing ambroxol hydrochloride and cinnamon-like flavor with a cinnamaldehyde content of about 70%, the content of ambroxol hydrochloride decreased by 5% after being stored at 65°C for 1 week. % or more (Comparative Example 1). On the other hand, in preparations containing ambroxol hydrochloride and cinnamon-like fragrance and aspartame, the decrease in ambroxol hydrochloride content was suppressed (Examples 1 to 3). Preparations containing sucralose or dipotassium glycyrrhizinate, which are the same sweeteners or sweetening agents as aspartame, did not improve the decrease in ambroxol hydrochloride content (Comparative Examples 2 and 3).

As shown in Table 4, in the preparation containing vanillin, storage at 65°C for 1 week reduced the content of ambroxol hydrochloride in the same manner as the cinnamaldehyde-containing perfume (Comparative Example 4). On the other hand, the formulation containing vanillin and aspartame inhibited the decrease in ambroxol hydrochloride content (Example 4). In addition, no decrease in the content of ambroxol hydrochloride was observed in preparations containing herb-like fragrances or anise-like fragrances that did not contain cinnamaldehydes and vanillins (Comparative Examples 4 and 5).

(Test example 2)
Flavor Evaluation Flavor evaluation was carried out according to the evaluation criteria in Table 5 for the preparations obtained in Comparative Examples and Examples in Tables 1 and 2. Flavor evaluation was carried out by four expert panelists, and Table 6 shows the average values of the obtained results.

As shown in Table 6, formulations containing ambroxol hydrochloride, cinnamaldehyde or vanillin, and aspartame were found to be less bitter and easier to take.

(Formulation example)
Based on the amounts of Formulation Example 1 in Table 7, each component was mixed and granulated with stirring, and then powders of 1005 mg per packet were prepared. In addition, after stirring and granulating, tableting was performed to prepare tablets of 335 mg per tablet, and 9 tablets were administered per day.
Based on the amount of Formulation Example 2 in Table 7, 843 mg of powder per package was prepared using a mixture of each component. In addition, the mixture was directly compressed into tablets of 281 mg per tablet, and 9 tablets were taken daily. Furthermore, tablets of 421 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 3 in Table 7, a powder of 843 mg per package was prepared using a mixture in which each component was mixed. In addition, the mixture was directly compressed into tablets of 281 mg per tablet, and 9 tablets were taken daily. In addition, tablets of 422 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 4 in Table 7, a powder of 845 mg per package was prepared using a mixture in which each component was mixed. In addition, the mixture was directly compressed into tablets of 282 mg per tablet to prepare 9 tablets per day. In addition, tablets of 422 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 5 in Table 7, a powder of 858 mg per package was prepared using a mixture in which each component was mixed. Furthermore, the mixture was directly compressed into tablets of 286 mg per tablet, and 9 tablets were taken daily. In addition, tablets of 429 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 6 in Table 7, a powder of 730 mg per package was prepared using a mixture of each component. Furthermore, the mixture was directly compressed into tablets of 243 mg per tablet, and 9 tablets were taken daily. Tablets of 365 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 7, a powder of 857 mg per package was prepared using a mixture in which each component was mixed. In addition, the mixture was directly compressed into tablets of 286 mg per tablet to prepare 9 tablets per day. Furthermore, tablets of 428 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 8, a powder of 1000 mg per package was prepared using a mixture of each component. In addition, the mixture was directly compressed to prepare tablets of 333 mg per tablet, and 9 tablets were taken per day. Furthermore, tablets of 500 mg per tablet were also prepared, and 6 tablets were taken per day.

Based on the amount of Formulation Example 9, a powder of 870 mg per package was prepared using a mixture of each component. In addition, the mixture was directly compressed into tablets of 290 mg per tablet, and 9 tablets were administered per day. Furthermore, tablets of 435 mg per tablet were also prepared, and 6 tablets were taken per day.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition containing ambroxol and cinnamaldehydes or vanillins and having improved stability and administration properties by a simple method.

Claims (2)

(a) ambroxol or a salt thereof, (b) at least one selected from the group consisting of vanillin and cinnamaldehyde , and (c) at least one selected from the group consisting of aspartame and neotame. A pharmaceutical composition for 2. The pharmaceutical composition according to claim 1, wherein (a) ambroxol or a salt thereof is ambroxol hydrochloride.