Solid composition containing bromhexine

Abstract

The present invention provides a solid composition that contains: (a) bromhexine or a salt thereof; (b) a nonionic surfactant; and (c) a compound selected from the group consisting of a vitamin-based antioxidant, a phenolic antioxidant, meloxicam and acetaminophen (solid compositions containing ibuprofen, clemastine fumarate, dihydrocodeine phosphate, noscapin, dl-methylephedrine hydrochloride, anhydrous caffeine, bromhexine hydrochloride, tranexamic acid, riboflavin, benfotiamine, ascorbic acid, hesperidin, D-mannitol, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl cellulose, polyoxyethylene hardened castor oil 60, hypromellose, talc, hydroxypropyl cellulose, and light anhydrous silicic acid are excluded).

Description

Solid composition containing bromhexine

[0001] The present invention broadly relates to a solid composition containing bromhexine, a method for producing the same, and the like.

[0002] Bromhexine hydrochloride, known as an antitussive and expectorant, is an ingredient that is often incorporated into cold medicines and the like, but has the drawback of being prone to sublimation and dissipation when incorporated into a solid composition. In order to solve this problem, Japanese Patent Application Laid-Open No. 2007-119453 discloses a technique of incorporating a sugar alcohol into a solid preparation containing bromhexine hydrochloride.

[0003] The content of bromhexine hydrochloride may also be affected by other components present in the solid composition. JP 2022-155537 A discloses that the content of bromhexine hydrochloride in a solid composition decreases over time in the presence of ascorbic acid, and that such a decrease in content can be suppressed by incorporating at least one selected from the group consisting of dextromethorphan or a salt thereof, noscapine or a salt thereof, tipepidine or a salt thereof, carbocisteine, guaifenesin, guaiacol or a salt thereof, and dimemorfan or a salt thereof into the solid composition.

[0004] JP 2007-119453 A JP 2022-155537 A JP 2000-095682 A JP 2022-40057 A

[0005] The present inventors have found that the content of bromhexine is reduced in the presence of a nonionic surfactant such as polyoxyethylene hydrogenated castor oil.

[0006] Japanese Patent Laid-Open Publication No. 2000-095682 discloses that polyoxyethylene hydrogenated castor oil and other nonionic surfactants improve the solubility of poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in solid compositions. The publication describes various components that can be incorporated into the solid composition, including bromhexine, but does not disclose any results of actually allowing polyoxyethylene hydrogenated castor oil and bromhexine to coexist.

[0007] JP 2022-40057 A discloses a tablet containing ibuprofen or a salt thereof and tranexamic acid, which can be stably produced without punch adhesion or sticking, and which has a hardness of 45 N or more and at least one of the first granules and the second granules is at least partially coated with at least a portion of the talc. Formulation Example 14 of the same publication contains bromhexine and polyoxyethylene hydrogenated castor oil, but no consideration is given to reducing the bromhexine content.

[0008] In order to solve the above-mentioned problems, the inventors of the present invention have conducted extensive research into the formulation of solid compositions, and as a result have found that the decrease in bromhexine content caused by nonionic surfactants can be suppressed by incorporating a vitamin-based antioxidant, a phenol-based antioxidant, or meloxicam or acetaminophen into the solid composition, thereby completing the present invention.

[0009] That is, this application encompasses the following invention: [1] A solid composition containing the following ingredients: (a) bromhexine or a salt thereof, (b) a nonionic surfactant, and (c) a compound selected from the group consisting of a vitamin antioxidant, a phenolic antioxidant, meloxicam, and acetaminophen (excluding solid compositions containing ibuprofen, clemastine fumarate, dihydrocodeine phosphate, noscapine, dl-methylephedrine hydrochloride, anhydrous caffeine, bromhexine hydrochloride, tranexamic acid, riboflavin, benfotiamine, ascorbic acid, hesperidin, D-mannitol, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl cellulose, polyoxyethylene hydrogenated castor oil 60, hypromellose, talc, hydroxypropyl cellulose, and light anhydrous silicic acid). [2] The solid composition according to [1], wherein, when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant, the vitamin-based antioxidant is tocopherol or a derivative thereof or a salt thereof, or ascorbic acid or a derivative thereof or a salt thereof, and the phenol-based antioxidant is dibutylhydroxytoluene or a derivative thereof or a salt thereof. [3] The solid composition according to [1], wherein, when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant, the nonionic surfactant is an ethylene oxide condensation type or a polyhydric alcohol ester type, and the nonionic surfactant is an ethylene oxide condensation type. [4] The solid composition according to [3], wherein the ethylene oxide condensation type nonionic surfactant is a polyoxyethylene-based surfactant, and the polyhydric alcohol-based nonionic surfactant is a sucrose fatty acid ester-based surfactant. [5] The solid composition according to [4], wherein the average number of moles of polyoxyethylene added in the polyoxyethylene-based surfactant is 20 to 100. [6] The solid composition according to [4], wherein the constituent fatty acid of the sucrose fatty acid ester-based surfactant is stearic acid. [7] The solid composition according to any one of [1] to [6], further comprising ibuprofen or diclofenac when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant.[8] The solid composition according to any one of [1] to [7], wherein when component (c) is a vitamin-based antioxidant, bromhexine is a metabolite that retains its main skeleton, and the solid composition further contains ibuprofen. [9] The solid composition according to [8], wherein the metabolite is ambroxol or a salt thereof.

[10] The solid composition according to any one of [1] to [9], wherein when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant, it does not contain anhydrous citric acid.

[11] The solid composition according to any one of [1] to

[10] , wherein when component (c) is meloxicam, the solid composition further contains tocopherol.

[12] A method for producing the solid composition according to any one of [1] to

[11] , comprising a step of contacting bromhexine or a salt thereof with a nonionic surfactant in the presence of component (c).

[0010] According to the present invention, it is possible to provide a stabilized composition containing bromhexine, particularly a cold remedy or an antipyretic analgesic, without avoiding the use of a nonionic surfactant, which has been required to improve the solubility of poorly water-soluble nonsteroidal anti-inflammatory drugs.

[0011] (Solid Composition) In a first aspect, there is provided a solid composition containing the following ingredients: (a) bromhexine or a salt thereof, (b) a nonionic surfactant, and (c) a compound selected from the group consisting of a vitamin antioxidant, a phenolic antioxidant, meloxicam, and acetaminophen (with the exception of solid compositions containing ibuprofen, clemastine fumarate, dihydrocodeine phosphate, noscapine, dl-methylephedrine hydrochloride, anhydrous caffeine, bromhexine hydrochloride, tranexamic acid, riboflavin, benfotiamine, ascorbic acid, hesperidin, D-mannitol, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl cellulose, polyoxyethylene hydrogenated castor oil 60, hypromellose, talc, hydroxypropyl cellulose, and light anhydrous silicic acid).

[0012] As used herein, "bromhexine" has CAS Registry Number 3572-43-8 and is １４ H ２０ Br２ N ２ Bromhexine is a compound represented by the chemical formula: Bromhexine is used as an active ingredient in antitussives and expectorants. There are no particular limitations on the salt of bromhexine as long as it is pharmacologically acceptable, and examples of salts of bromhexine include hydrochloride as an inorganic acid salt and fumarate as an organic acid salt. A preferred salt of bromhexine is hydrochloride.

[0013] Bromhexine may be a derivative thereof, as long as the decrease in its content can be suppressed by incorporating a vitamin-based antioxidant such as ascorbic acid or a phenol-based antioxidant into the solid composition, or into meloxicam or acetaminophen. Such derivatives include metabolites of bromhexine that retain the main structure of bromhexine, e.g., a dibromophenyl skeleton containing cyclohexylamine, such as ambroxol.

[0014] The amount of bromhexine or a salt thereof is adjusted appropriately depending on the intended use of bromhexine or a salt thereof in the composition, the symptoms, age, weight, sex, etc. of the subject to be administered. For example, when bromhexine or a salt thereof is formulated for the purpose of cough suppression and / or expectoration, the daily amount of bromhexine or a salt thereof administered to an adult can be adjusted to within the range of 1 mg to 36 mg, preferably 4 mg to 24 mg, and more preferably 8 mg to 12 mg. In the present invention, "adult" refers to both men and women aged 15 years or older. However, the composition of the present invention is not limited to those intended for administration by adults, and may also be for administration by children under 15 years of age. When administered to children, the amount can be reduced to, for example, 1 / 2 or 2 / 3 of the daily adult dose depending on the age group.

[0015] The above dosage is an example, and the content of bromhexine or a salt thereof per composition administered per day is, for example, about 0.025% by mass to about 0.975% by mass, preferably about 0.105% by mass to about 0.650% by mass, and more preferably about 0.210% by mass to about 0.325% by mass.

[0016] In one embodiment, the content of bromhexine or a salt thereof in the composition to be administered daily is 0.30% by weight to 0.45% by weight.

[0017] The weight and dosage of the composition described above are the daily dose (daily amount), but the same amount may be administered to a subject multiple times a day, for example, two or three times, preferably three times. The same applies to components other than bromhexine or a salt thereof. Furthermore, since each dosage is a total amount, the content of each component contained in the composition may vary depending on the single dose, the dosage form of the composition, etc.

[0018] In a specific embodiment, the composition is a tablet, and the dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient contained in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 tablets, and the single dose is 2, 3, or 4 tablets, preferably 3 tablets.

[0019] Nonionic surfactants are broadly classified into ethylene oxide condensation type and polyhydric alcohol ester type. As used herein, examples of "nonionic surfactants" include, but are not limited to, ethylene oxide condensation type and polyhydric alcohol ester type nonionic surfactants. Examples of ethylene oxide condensation type nonionic surfactants include polyoxyethylene surfactants, and examples of polyhydric alcohol ester type nonionic surfactants include sucrose fatty acid ester surfactants.

[0020] In one embodiment, the nonionic surfactant is one or more ethylene oxide condensation type nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene steryl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyhydric alcohol fatty acid ester, and polyoxyethylene sorbitan fatty acid ester.

[0021] As the ethylene oxide condensation type nonionic surfactant, polyoxyethylene hydrogenated castor oil is preferred. Polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. The average number of moles of ethylene oxide added in the polyoxyethylene hydrogenated castor oil used in this specification is not particularly limited, but is, for example, 5 to 100 moles, preferably 20 to 100 moles.

[0022] In one embodiment, the polyoxyethylene hydrogenated castor oil is one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil 5 (average number of moles of ethylene oxide added: 5), polyoxyethylene hydrogenated castor oil 10 (average number of moles of ethylene oxide added: 10), polyoxyethylene hydrogenated castor oil 20 (average number of moles of ethylene oxide added: 20), polyoxyethylene hydrogenated castor oil 30 (average number of moles of ethylene oxide added: 30), polyoxyethylene hydrogenated castor oil 40 (average number of moles of ethylene oxide added: 40), polyoxyethylene hydrogenated castor oil 50 (average number of moles of ethylene oxide added: 50), polyoxyethylene hydrogenated castor oil 60 (average number of moles of ethylene oxide added: 60), polyoxyethylene hydrogenated castor oil 80 (average number of moles of ethylene oxide added: 80) and polyoxyethylene hydrogenated castor oil 100 (average number of moles of ethylene oxide added: 100).

[0023] In one embodiment, the nonionic surfactant is one or more polyhydric alcohol ester type surfactants selected from the group consisting of sucrose fatty acid esters, glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, and polyglycerin fatty acid esters.

[0024] As a polyhydric alcohol ester type nonionic surfactant, sucrose fatty acid ester is preferred. Sucrose fatty acid ester is a nonionic surfactant in which sucrose is the hydrophilic group and fatty acid is the lipophilic group. There are various types depending on the type of fatty acid, the degree of esterification, HLB (Hydrophilic-Lipophilic Balance), fatty acid purity, etc.

[0025] Examples of fatty acids include saturated or unsaturated fatty acids having 6 to 30 carbon atoms, preferably 10 to 20 carbon atoms. Examples of saturated fatty acids that constitute sucrose fatty acid esters include lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18), and behenic acid (C22). Among these saturated fatty acids, stearic acid is preferred.

[0026] The HLB value ranges from 0 to 20, with lipophilicity increasing as the value approaches 0 and hydrophilicity increasing as the value approaches 20. The HLB value of the sucrose fatty acid ester used herein is preferably about 3, about 4, about 5, about 6, or about 7, and more preferably about 5.

[0027] The fatty acid purity of the sucrose fatty acid ester is preferably about 50% by mass, about 60% by mass, about 70% by mass, about 80% by mass, or about 90% by mass, and more preferably about 70% by mass.

[0028] The ester composition of the sucrose fatty acid ester preferably has a monoester content of about 10% by mass, about 20% by mass, about 30% by mass, about 40% by mass, or about 50% by mass, and more preferably about 30% by mass.

[0029] The amount of the nonionic surfactant to be added is adjusted appropriately depending on the intended use of the nonionic surfactant in the composition. When the nonionic surfactant is added for the purpose of improving the solubility or other properties of the components to be added to the composition, the amount of the nonionic surfactant to be added varies depending on the amount of the target component, but for example, the amount per day is in the range of 1 mg to 240 mg, preferably 10 mg to 120 mg, and more preferably 30 mg to 90 mg.

[0030] The amount of the nonionic surfactant contained in the composition administered daily is, for example, 0.1 to 20 parts by mass, preferably 1.0 to 10 parts by mass, and more preferably 2.5 to 7.5 parts by mass per part by mass of bromhexine hydrochloride.

[0031] In one embodiment, the amount of the nonionic surfactant contained in the composition administered daily is 4.0 to 6.0 parts by weight per part by weight of bromhexine hydrochloride.

[0032] When the composition further contains a poorly water-soluble nonsteroidal anti-inflammatory drug, the amount of the nonionic surfactant can be determined based on the amount of the nonsteroidal anti-inflammatory drug. For example, the amount of the nonionic surfactant contained in the composition administered daily may be 0.01 to 5.00 parts by mass, preferably 0.05 to 2.0 parts by mass, and more preferably 0.05 to 1.0 part by mass, per part by mass of ibuprofen.

[0033] In one embodiment, the amount of the nonionic surfactant contained in the composition administered daily is 0.05 to 0.15 parts by weight per part by weight of bromhexine hydrochloride.

[0034] As used herein, the terms "vitamin-based antioxidant" and "phenol-based antioxidant" refer to substances that have antioxidant properties and that have the effect of suppressing the decrease in the content of bromhexine or its salts caused by nonionic surfactants.

[0035] In one embodiment, the vitamin-based antioxidant is a tocopherol selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, or a derivative thereof, or a salt thereof.

[0036] Examples of tocopherol derivatives include tocopherol organic acid esters such as tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol linoleate, etc. Examples of salts of tocopherol or its derivatives include organic acid salts such as acetate, nicotinate, succinate, etc.

[0037] In one embodiment, the vitamin-based antioxidant is ascorbic acid or a derivative thereof or a salt thereof.

[0038] Ascorbic acid may be in the L- or D-form (erythorbic acid). Examples of ascorbic acid derivatives include ascorbic acid 2-glucoside, ascorbic acid phosphate, 3-o-ethyl ascorbic acid, ascorbyl tetrahexyldecanoate, ascorbyl palmitate, ascorbyl stearate, ascorbic acid-2-phosphate-6 palmitate, and glyceryl octyl ascorbic acid. Examples of ascorbic acid salts include inorganic salts such as sodium salts, potassium salts, magnesium salts, and calcium salts.

[0039] In one embodiment, the phenolic antioxidant is dibutylhydroxytoluene or a derivative thereof or a salt thereof.

[0040] The IUPAC name for dibutylhydroxytoluene (BHT) is 2,6-di-tert-butyl-4-methylphenol.

[0041] When the vitamin-based antioxidant and phenol-based antioxidant are added for the purpose of suppressing a decrease in the content of bromhexine or a salt thereof due to a nonionic surfactant, the amount of the vitamin-based antioxidant and phenol-based antioxidant to be added will vary depending on the desired level of suppression effect, the type of antioxidant used, and the presence of other ingredients.

[0042] In the case of tocopherol or a derivative thereof or a salt thereof, for example, the daily amount ranges from 0.1 mg to 20 mg, preferably from 0.5 mg to 16 mg, more preferably from 2.5 mg to 10 mg.

[0043] In one embodiment, tocopherol is added in an amount of 0.2 parts by weight, 0.3 parts by weight, 0.4 parts by weight, 0.5 parts by weight, 0.6 parts by weight, 0.7 parts by weight, 0.8 parts by weight, or 0.9 parts by weight per part by weight of bromhexine.

[0044] In the case of ascorbic acid or a derivative thereof or a salt thereof, for example, the daily amount ranges from 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and more preferably from 10 mg to 50 mg.

[0045] In one embodiment, ascorbic acid is 0.8 parts by mass, 0.9 parts by mass, 1.0 parts by mass, 1.1 parts by mass, 1.2 parts by mass, 1.3 parts by mass, 1.4 parts by mass, 1.5 parts by mass, 1.6 parts by mass, 1.7 parts by mass, 1.8 parts by mass, 1.9 parts by mass, 2.0 parts by mass, 2.1 parts by mass, 2.2 parts by mass, 2.3 parts by mass, based on 1 part by mass of bromhexine. Parts by weight, 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight parts, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight or 4.2 parts by weight.

[0046] In the case of dibutylhydroxytoluene or a derivative thereof or a salt thereof, for example, the daily amount ranges from 0.01 mg to 10 mg, preferably from 0.1 mg to 5 mg, more preferably from 1 mg to 4 mg.

[0047] In one embodiment, dibutylhydroxytoluene is added in an amount of 0.3 parts by weight per 1 part by weight of bromhexine.

[0048] "Meloxicam" as used herein has CAS registration number 71125-38-7 and is １４ H １３ N ３ O ４ S ２ Meloxicam is a compound represented by the chemical formula: Meloxicam may be a derivative or a salt thereof. There are no particular limitations on the salt of meloxicam, as long as it is pharmacologically acceptable.

[0049] "Acetaminophen" as used herein has CAS Registry Number 103-90-2 and is ８ H ９ NO ２ Acetaminophen is a compound represented by the chemical formula: Acetaminophen is also known as paracetamol. Acetaminophen may be a derivative or a salt thereof. There are no particular limitations on the salt of acetaminophen, as long as it is pharmacologically acceptable.

[0050] When meloxicam or acetaminophen is added for the purpose of suppressing a decrease in the content of bromhexine or a salt thereof due to a nonionic surfactant, the amount of meloxicam or acetaminophen to be added varies depending on the degree of the desired suppressive effect and the presence of other ingredients.

[0051] The daily dose of acetaminophen ranges from 150 mg to 1200 mg, preferably from 450 mg to 1000 mg, more preferably from 750 mg to 900 mg.

[0052] The daily dose of meloxicam ranges from 5 mg to 20 mg, preferably from 8 mg to 17 mg, more preferably from 10 mg to 15 mg.

[0053] In one embodiment, meloxicam is added in an amount of 0.4 to 1.3 parts by weight, preferably 0.8 to 1.3 parts by weight, per 1 part by weight of bromhexine.

[0054] In one embodiment, acetaminophen is added in an amount of 62.5 to 75 parts by weight per part by weight of bromhexine.

[0055] The solid composition may further contain an antioxidant in combination with meloxicam or acetaminophen. The incorporation of an antioxidant can further suppress the decrease in bromhexine content. Examples of antioxidants that can be incorporated in combination with meloxicam include vitamin-based antioxidants such as tocopherols.

[0056] In one embodiment, the solid composition further comprises a tocopherol in combination with meloxicam.

[0057] As used herein, "tocopherols" refers to tocopherols selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, or derivatives thereof, or salts thereof. Among tocopherols, α-tocopherol is preferred, and dl-α-tocopherol is particularly preferred.

[0058] Examples of tocopherol derivatives include tocopherol organic acid esters such as tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol linoleate, etc. Examples of salts of tocopherol or its derivatives include organic acid salts such as acetate, nicotinate, succinate, etc.

[0059] In the case of tocopherol or a derivative thereof or a salt thereof, for example, the daily amount ranges from 0.1 mg to 20 mg, preferably from 0.5 mg to 16 mg, more preferably from 2.5 mg to 10 mg.

[0060] In one embodiment, tocopherol is added in an amount of 0.2 to 0.9 parts by weight per 1 part by weight of bromhexine.

[0061] In one embodiment, tocopherol is added in an amount of 0.2 to 1.0 part by weight, preferably 0.5 to 1.0 part by weight, per 1 part by weight of meloxicam.

[0062] The composition may contain ingredients other than those mentioned above depending on its intended use. When the composition is intended to relieve cold symptoms such as runny nose, stuffy nose, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine, meloxicam, and acetaminophen, the composition may contain active ingredients such as antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), or other pharmacologically acceptable ingredients.

[0063] Nonsteroidal anti-inflammatory drugs are broadly classified into non-selective COX-2 inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and selective COX-2 inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be incorporated into the composition as a nonsteroidal anti-inflammatory drug. The nonsteroidal anti-inflammatory drug is preferably a non-selective COX-2 inhibitor. The nonsteroidal anti-inflammatory drug may be in the form of a salt.

[0064] In one embodiment, the nonsteroidal anti-inflammatory drug is ibuprofen or diclofenac.

[0065] When ibuprofen is incorporated into the composition, any compound selected from the group consisting of vitamin-based antioxidants, phenol-based antioxidants, meloxicam, and acetaminophen may be incorporated into the composition, but among these, it is preferable to select vitamin-based antioxidants, particularly tocopherol.

[0066] In one embodiment, when ibuprofen and a vitamin-based antioxidant are combined in a composition, bromhexine is a metabolite that retains its primary skeleton.

[0067] Examples of such metabolites include ambroxol or a salt thereof, preferably ambroxol hydrochloride.

[0068] In one embodiment, when meloxicam is included in the composition, the nonsteroidal anti-inflammatory drug included in the composition other than meloxicam is ibuprofen or diclofenac.

[0069] Other pharmacologically acceptable ingredients may be added, such as antihistamines, antipyretics, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmin agents, which are typically added to general cold medicines, antipyretics, and rhinitis medicines.

[0070] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, and the like.

[0071] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, etc. Acetaminophen may be incorporated into the composition as an antipyretic analgesic.

[0072] Examples of antitussive and expectorant drugs other than bromhexine include dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, and dextromethorphan hydrobromide hydrate.

[0073] Anti-inflammatory drugs include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

[0074] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0075] Vitamin preparations include vitamin B1 and its derivatives and salts thereof (e.g., benfotiamine), vitamin B2 and its derivatives and salts thereof (e.g., riboflavin), vitamin C and its derivatives and salts thereof (e.g., ascorbic acid), hesperidin and its derivatives and salts thereof, etc.

[0076] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia root extract, Scopolia root total alkaloid citrate, and the like.

[0077] Antiplasmin agents include tranexamic acid.

[0078] The composition of the present invention may further contain formulation additives, if necessary. Examples of formulation additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, refreshing agents, flavorings, aromas, coloring agents, bases, coating agents, sugar-coating agents, plasticizers, dispersants, antifoaming agents, fluidizing agents, and flavoring agents / fragrances. Formulation additives that can be used in conventionally known solid formulations may be used for the above-mentioned purposes.

[0079] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0080] The binder may be one or more components selected from gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0081] Examples of disintegrants include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, and the like.

[0082] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0083] The glossing agent may be, for example, one or more components selected from carnauba wax, white beeswax, purified shellac, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, beeswax, etc.

[0084] The foaming agent may be one or more components selected from, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc. However, it is preferred that the composition does not contain anhydrous citric acid.

[0085] The moisture-proofing agent may be one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, refined sucrose, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, magnesium aluminometasilicate, and the like.

[0086] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene One or more ingredients selected from the group consisting of polyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate can be blended.

[0087] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, and calcium chloride. Stain, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester Stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, poly Polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid,One or more ingredients selected from anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc. may be blended.

[0088] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. In the case of a solid composition containing acetaminophen, it is preferable not to add tocopherols as antioxidants or stabilizers.

[0089] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

[0090] The sweetener may be one or more components selected from, for example, aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, and the like.

[0091] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron bark extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cacao powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and ginger. It is possible to blend one or more ingredients selected from the group consisting of powdered sorghum, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, capsicum, capsicum powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, Ryuno, Ryuno powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0092] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0093] As the flavoring, for example, one or more components selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, 1-menthol, peppermint oil, etc. can be blended.

[0094] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0095] Examples of colorants that can be blended include one or more components selected from yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium oxide, ferric oxide, dizazo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide / glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0096] The bases include gum arabic powder, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, and hydroxypropyl cellulose. The composition may contain one or more ingredients selected from the group consisting of cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0097] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hardened oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydrogenated cellulose. Examples of suitable surfactants include hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Macrogol 20000, Macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0098] Examples of sugar-coating agents that can be blended include one or more components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0099] Examples of the plasticizer that can be blended include one or more components selected from triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0100] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, powdered agar, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0101] The antifoaming agent may be one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc.

[0102] The fluidizing agent may be one or more components selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0103] Examples of flavoring agents and fragrances include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, vitabe The composition may contain one or more ingredients selected from the group consisting of rose, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0104] The composition may be in the dosage form described in the General Provisions of Preparations of the 17th Edition of the Japanese Pharmacopoeia, etc., such as solid preparations such as tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), troches, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, poultices, plasters, and caplets; semi-solid preparations such as lozenges, chewing gums, jellies, jelly drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; and liquid preparations such as syrups, drinks, suspensions, spirits, liquids, sprays, and aerosols. From the viewpoints of ease of administration and manufacturing, the composition of the present invention is preferably a solid preparation, more preferably an orally administered composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules, and particularly preferably a tablet or capsule.

[0105] When the composition is a solid formulation, the composition may be temporarily packaged in a bottle, PTP, pouch, stick, or SP package and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and examples include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. If moisture absorption is a concern, a desiccant or the like may be stored in the bottle or pillow packaging.

[0106] (Method of Production) In a second aspect, there is provided a method of producing a solid composition, comprising the step of contacting bromhexine or a salt thereof with a nonionic surfactant in the presence of a compound selected from the group consisting of a vitamin-based antioxidant, a phenolic antioxidant, meloxicam, and acetaminophen.

[0107] The solid composition can be produced using known techniques. For example, contact of bromhexine or a salt thereof with a nonionic surfactant may be carried out in accordance with the method for producing a bromhexine-containing formulation as described in JP 2015-137238 A. Bromhexine, the nonionic surfactant, and the antioxidant may each be added at any step and then finally contacted with each other. After contact, a solvent and a binder may be added to the mixture and kneaded, and the resulting kneaded product may be used as a solid composition.

[0108] The kneaded mixture can be further subjected to a drying process or a granulation process to produce granules (granules). In this case, the granules (granules) containing bromhexine or a salt thereof and the granules (granules) containing a nonionic surfactant may be prepared separately. Granulation may be performed by either a wet method or a dry method.

[0109] The obtained granules (granulated product) can be used as they are or can be mixed with additives and compressed into tablets to produce plain tablets, which can then be further film-coated.

[0110] In one embodiment, a granule (granulation product) containing bromhexine or a salt thereof is contacted with a granule (granulation product) containing a nonionic surfactant.

[0111] (Method for inhibiting discoloration) In a third aspect, there is provided a method for inhibiting discoloration of a solid composition, the method comprising the step of contacting bromhexine or a salt thereof with a nonionic surfactant in the presence of a compound selected from the group consisting of a vitamin-based antioxidant, a phenolic antioxidant, meloxicam, and acetaminophen.

[0112] The amount of vitamin-based antioxidant or phenol-based antioxidant added may also vary depending on the amount of bromhexine.

[0113] In one embodiment, the tocopherol is added in an amount of 0.2 parts by weight, 0.3 parts by weight, 0.4 parts by weight, 0.5 parts by weight, 0.6 parts by weight, 0.7 parts by weight, or 0.8 parts by weight per part by weight of bromhexine.

[0114] In one embodiment, ascorbic acid is 0.8 parts by mass, 0.9 parts by mass, 1.0 parts by mass, 1.1 parts by mass, 1.2 parts by mass, 1.3 parts by mass, 1.4 parts by mass, 1.5 parts by mass, 1.6 parts by mass, 1.7 parts by mass, 1.8 parts by mass, 1.9 parts by mass, 2.0 parts by mass, 2.1 parts by mass, 2.2 parts by mass, 2.3 parts by mass, based on 1 part by mass of bromhexine. Parts by weight, 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight parts, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight or 4.2 parts by weight.

[0115] In one embodiment, dibutylhydroxytoluene is added in an amount of 0.3 parts by weight per 1 part by weight of bromhexine.

[0116] The amount of meloxicam or acetaminophen added may also vary depending on the amount of bromhexine.

[0117] In one embodiment, meloxicam is added in an amount of 0.4 to 1.3 parts by weight, preferably 0.8 to 1.3 parts by weight, per 1 part by weight of bromhexine.

[0118] In one embodiment, acetaminophen is added in an amount of 62.5 to 75 parts by weight per part by weight of bromhexine.

[0119] The above amounts are merely examples, and the amount of active ingredient added can be increased or decreased to achieve the desired discoloration suppression effect.

[0120] The timing of adding each component is not particularly limited. For example, the active ingredient may be added before the onset of discoloration, or at an appropriate time after the onset of discoloration.

[0121] The discoloration suppression method may further include an optional step. For example, from the viewpoint of maintaining the discoloration suppression effect, it is preferable to store the granulated material in an airtight container with reduced moisture permeability at a temperature below room temperature. Here, as defined in the General Rules of the Japanese Pharmacopoeia, 18th Edition, an "airtight container" means a container that prevents the intrusion of solid or liquid foreign matter during transportation or storage and can prevent the loss, efflorescence, deliquescence, or evaporation of the contained pharmaceutical. An example of such an airtight container is a general tablet bottle.

[0122] In order to explain the present invention in more detail, test examples and examples are described below, but the present invention is not limited to these.

[0123] 1. Method for preparing a solid preparation containing raw materials and antioxidants The following raw materials were used in this experiment. A solid preparation was prepared by mixing the raw materials in the specified amounts.

[0124] 2. Stability of Bromhexine (BH) in the Presence of Polyoxyethylene Hydrogenated Castor Oil 60 (HCO) Approximately 130 g of a solid preparation prepared with the ingredients other than HCO and tocopherol listed in Table 2 was placed in a plastic bag, mixed for 1 minute, sieved through No. 26-30 sieves, and mixed for 30 seconds. A 30 g portion of the preparation was granulated in a mortar with 80% ethanol in which HCO and tocopherol had been dissolved. The granulation conditions were consistent, and the amounts added were adjusted appropriately. After the granulation process, the resulting granules were sieved through No. 12-14 sieves. After shelf-drying at 40°C, 2 g of each granule was filled into a 1K standard bottle, sealed, and stored at 60°C for 2 weeks, 1 month, and 2 months. The bromhexine hydrochloride content of the samples before and after storage was evaluated. The results are shown in Table 3.

[0125]

[0126] * Three measurements were taken from one bottle (same below).

[0127] The content of bromhexine was significantly reduced in the presence of polyoxyethylene hydrogenated castor oil.

[0128] 3. Study on the effect of antioxidants on bromhexine content Next, the effect of antioxidants on bromhexine content in the presence of polyoxyethylene hydrogenated castor oil was studied. Tocopherol and ascorbic acid (VC) were used as antioxidants. Solid preparations prepared in the amounts listed in Table 4 were stored at 60°C, and the bromhexine content was quantified. The results are shown in Table 5.

[0129]

[0130] Both tocopherol and ascorbic acid suppressed the decrease in bromhexine content.

[0131] 4. Effect of Antioxidants in the Presence of Ibuprofen The effect of antioxidants in the presence of poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs) was examined. Ibuprofen was used as the NSAID. Dibutylhydroxytoluene (BHT) was used as the antioxidant in addition to tocopherol and ascorbic acid (VC). Solid preparations prepared in the amounts listed in Table 6 were stored at 60°C, and the bromhexine content was quantified. The results are shown in Table 7.

[0132]

[0133] Tocopherol, ascorbic acid (VC), and dibutylhydroxytoluene (BHT) all inhibited the reduction of bromhexine content even in the presence of ibuprofen, whereas anhydrous citric acid and sodium bisulfite accelerated the reduction of bromhexine content.

[0134] 5. Stability of bromhexine (BH) in the presence of sucrose fatty acid esters The stability of bromhexine (BH) was evaluated when sucrose fatty acid esters were used instead of polyoxyethylene hydrogenated castor oil 60 (HCO). Solid preparations prepared in the amounts shown in Table 8 were stored at 60°C, and the bromhexine content was quantified. The results are shown in Table 9.

[0135]

[0136] Sucrose fatty acid esters also reduced the bromhexine content, but the reduction in content was suppressed in solid preparations containing tocopherol.

[0137] 6. Effect of Antioxidants in the Presence of Diclofenac Sodium The effect of antioxidants in the presence of poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs) was investigated. Diclofenac sodium was used as the NSAID. Tocopherol was used as the antioxidant. Solid preparations prepared in the amounts listed in Table 10 were subjected to a light exposure test, and the bromhexine content was quantified. The results are shown in Table 11.

[0138]

[0139] Tocopherol suppressed the decrease in bromhexine content even in the presence of diclofenac sodium.

[0140] 7. Formulation Examples Formulation examples of solid compositions are shown in the table below.

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] 8. Method for preparing raw materials and solid preparations containing meloxicam or acetaminophen The following raw materials were used in this experiment. Solid preparations were prepared by mixing the specified amounts of each raw material.

[0148] 9. Stability of Bromhexine (BH) in the Presence of Polyoxyethylene Hydrogenated Castor Oil 60 (HCO) Approximately 130 g of a solid preparation prepared with the blending amounts of ingredients other than HCO and tocopherol listed in Table 20 was placed in a plastic bag, mixed for 1 minute, sieved through No. 26-30 sieves, and mixed for 30 seconds. A 30 g portion of the preparation was granulated in a mortar with 80% ethanol in which HCO and tocopherol had been dissolved. The granulation conditions were consistent, and the amounts added were adjusted appropriately. After the granulation process, the resulting granules were sieved through No. 12-14 sieves. After shelf-drying at 40°C, 2 g of each granule was filled into a 1K standard bottle, sealed, and stored at 60°C for 1 month. The bromhexine hydrochloride content of the samples before and after storage was evaluated. The results are shown in Table 21.

[0149]

[0150] * Three measurements were taken from one bottle (same below).

[0151] The content of bromhexine was significantly reduced in the presence of polyoxyethylene hydrogenated castor oil.

[0152] 10. Study on the effect of meloxicam on bromhexine content Next, the effect of meloxicam in the presence of polyoxyethylene hydrogenated castor oil on bromhexine content was studied. Solid preparations prepared in the amounts listed in Table 22 were stored at 60°C, and the bromhexine content was quantified. The results are shown in Table 23.

[0153]

[0154] Meloxicam suppressed the decrease in bromhexine content, and the presence of tocopherol further suppressed the decrease in bromhexine content.

[0155] 11. Study on the effect of acetaminophen on bromhexine content Next, the effect of acetaminophen in the presence of polyoxyethylene hydrogenated castor oil on bromhexine content was studied. Solid preparations prepared in the amounts listed in Table 24 were stored at 60°C, and the bromhexine content was quantified. The results are shown in Table 25.

[0156]

[0157] Acetaminophen inhibited the decrease in bromhexine content.

[0158] 12. Ambroxol Stability Bromhexine was replaced with ambroxol hydrochloride (Yoshindou), and the effect of tocopherol as an antioxidant on ambroxol content was examined. Tocopherol was used as the antioxidant. Solid preparations prepared in the amounts listed in Table 26 were stored at 60°C, and the ambroxol content was quantified. The results are shown in Table 27.

[0159]

[0160]

[0161] By adding tocopherol to a solid formulation containing ibuprofen, the decrease in ambroxol content was suppressed.

Claims

1. A solid composition containing the following ingredients: (a) bromhexine or a salt thereof; (b) a nonionic surfactant; and (c) a compound selected from the group consisting of vitamin antioxidants, phenolic antioxidants, meloxicam, and acetaminophen (excluding solid compositions containing ibuprofen, clemastine fumarate, dihydrocodeine phosphate, noscapine, dl-methylephedrine hydrochloride, anhydrous caffeine, bromhexine hydrochloride, tranexamic acid, riboflavin, benfotiamine, ascorbic acid, hesperidin, D-mannitol, low-substituted hydroxypropylcellulose, crystalline cellulose, hydroxypropylcellulose, polyoxyethylene hydrogenated castor oil 60, hypromellose, talc, hydroxypropylcellulose, and light anhydrous silicic acid).

2. The solid composition according to claim 1, wherein when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant, the vitamin-based antioxidant is tocopherol or a derivative thereof or a salt thereof, or ascorbic acid or a derivative thereof or a salt thereof, and the phenol-based antioxidant is dibutylhydroxytoluene or a derivative thereof or a salt thereof.

3. The solid composition according to claim 1, wherein when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant, the nonionic surfactant is an ethylene oxide condensation type or a polyhydric alcohol ester type, and the nonionic surfactant is an ethylene oxide condensation type.

4. The solid composition according to claim 3, wherein the ethylene oxide condensation type nonionic surfactant is a polyoxyethylene type surfactant, and the polyhydric alcohol type nonionic surfactant is a sucrose fatty acid ester type surfactant.

5. The solid composition according to claim 4, wherein the average number of moles of polyoxyethylene added in the polyoxyethylene surfactant is 20 to 100.

6. The solid composition according to claim 4, wherein the constituent fatty acid of the sucrose fatty acid ester surfactant is stearic acid.

7. A solid composition according to claim 1 or 2, further comprising ibuprofen or diclofenac when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant.

8. A solid composition according to claim 1 or 2, wherein when component (c) is a vitamin-based antioxidant, bromhexine is a metabolite thereof retaining its main skeleton, and the solid composition further comprises ibuprofen.

9. The solid composition according to claim 8, wherein the metabolite is ambroxol or a salt thereof.

10. A solid composition according to claim 1 or 2, which does not contain anhydrous citric acid when component (c) is a vitamin-based antioxidant or a phenol-based antioxidant.

11. The solid composition of claim 1, wherein when component (c) is meloxicam, the solid composition further comprises tocopherol.

12. A method for preparing the solid composition of claim 1, comprising the step of contacting bromhexine or a salt thereof with a nonionic surfactant in the presence of component (c).