Pharmaceutical composition

Abstract

To provide a pharmaceutical composition which, despite containing ibuprofen and levocetirizine or a salt thereof, prevents a decline in levocetirizine content over time.SOLUTION: A pharmaceutical composition comprises at least one selected from the group consisting of (a) ibuprofen, (b) levocetirizine or a salt thereof, (c) (c1) carbocysteine, (c2) ambroxol and a salt thereof, (c3) tranexamic acid, (c4) glycyrrhizinic acid and a salt thereof, (C5) tipepidine and a salt thereof, (c6) dextromethorphan and a salt thereof, (c7) bromhexine and a salt thereof, (c8) dimemorfan and a salt thereof, and (c9) methylephedrine and a salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition containing ibuprofen and levocetirizine or a salt thereof. [Background technology]

[0002] Ibuprofen is effective in treating rheumatoid arthritis, joint pain and arthritis, neuralgia and neuritis, back and lower back pain, and cervical pain. Brachial syndrome, uterine adnexitis, dysmenorrhea, erythema (erythema nodosum, erythema exudativum multiforme, centrifugally It is also effective for treating acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation accompanied by acute bronchitis). It is also effective in reducing fever and pain, and is widely used as an antipyretic and analgesic ingredient in general cold medicines. It has been reported (Non-Patent Document 1).

[0003] Levocetirizine and its salts are second-generation histamine H1 receptor antagonists (second-generation antihistamines). As an anti-inflammatory drug, it is used to treat allergic rhinitis, urticaria, skin diseases (eczema, dermatitis, pruritus) ) is effective for itching associated with rheumatoid arthritis (Non-Patent Document 2). Levocetirizine is a derivative of cetirizine hydrochloride. It is a product of optical resolution of only the R-enantiomer, which has stronger biological activity among optical isomers. do.

[0004] Carbocysteine ​​regulates mucus components, inhibits goblet cell hyperplasia, and suppresses airway inflammation. It has a mucosal normalizing effect and is effective in treating upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, and bronchial asthma. As a compound with excellent expectorant properties against respiratory tract infections, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis It is widely known and is widely incorporated into general cold medicines and antitussives and expectorants (Non-Patent Document 3).

[0005] Ambroxol and its salts have the effect of promoting the secretion of pulmonary surfactant and secretion of airway fluid. It has an expectorant effect and a ciliary motility enhancing effect, and is well-known as a compound having excellent expectorant effects on acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, and difficulty in expectoration after surgery. It has also been approved as an OTC ingredient and is formulated in general cold medicines and cough and expectorant medicines (Non-Patent Document 4). Tranexamic acid has anti-allergic and anti-inflammatory effects, and shows excellent effects on symptoms such as sore throat, redness, congestion, and swelling in tonsillitis and pharyngolaryngitis. Therefore, it is widely formulated in general cold medicines, cough and expectorant medicines, and rhinitis medicines (Non-Patent Document 5). Glycyrrhizic acid and its salts are widely known as components contained in licorice. They have anti-inflammatory, anti-allergic, and cell repair effects, and are known to have effects as digestive ulcers and expectorant medicines. They are also used as sweeteners and flavoring agents (Non-Patent Document 6). Tipepidine and its salts show an antitussive effect by suppressing the cough center in the medulla oblongata and reducing the cough sensitivity, and also show an expectorant effect by enhancing bronchial gland secretion and enhancing the movement of airway mucosal ciliated epithelium. As a compound, it is widely used for cough and difficulty in expectoration associated with colds, upper respiratory tract infections (pharyngolaryngitis, rhinitis), acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 7).

[0006] Dextromethorphan and its salts directly act on the cough center in the medulla oblongata and suppress the cough reflex, thereby showing an antitussive effect. As a compound, it is widely used for coughs associated with colds, acute bronchitis, chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, and upper respiratory tract infections (pharyngolaryngitis, rhinitis).

[0007]

[0008]

[0009] ​​​​​​​​​​​​​​ is present (Non-Patent Document 8).

[0010] Bromhexine hydrochloride is widely known as a compound having an action of increasing serous secretion, an action of dissolving and reducing the molecular weight of acidic glycoprotein, an action of promoting the secretion of pulmonary surfactant, and an action of enhancing ciliary movement, and thus has an excellent expectorant action against acute bronchitis, chronic bronchitis, pulmonary tuberculosis, pneumoconiosis, and after surgery, and is widely formulated in general cold medicines and antitussive expectorants (Non-Patent Document 9). is present (Non-Patent Document 8). is present (Non-Patent Document 8). is present (Non-Patent Document 8).

[0011] Dimemorfanoline and its salts are compounds that act directly on the cough center in the medulla oblongata to exhibit an antitussive effect, and are widely used for antitussive in upper respiratory tract inflammation, pneumonia, acute bronchitis, pulmonary tuberculosis, silicosis and silicotuberculosis, lung cancer, and chronic bronchitis (Non-Patent Document 10). is present (Non-Patent Document 8). is present (Non-Patent Document 8).

[0012] Methylephedrine and its salts are sympathomimetic drugs, have a bronchodilating action by β2-receptor stimulation, and are widely formulated in general cold medicines and antitussive expectorants (Non-Patent Document 11). is present (Non-Patent Document 8). )

[0013] Heretofore, a capsule preparation in which ibuprofen, cetylidin hydrochloride, and cyclodextrin are formulated in a base containing a POE sorbitan fatty acid ester, a glycerin fatty acid ester, macrogol, and water has been known (Patent Document 1). In this document, a method for solving the decrease in solubility due to crystallization of cetylidin hydrochloride by the coexistence of cyclodextrin is shown. is present (Non-Patent Document 8). is present (Non-Patent Document 8). is present (Non-Patent Document 8). However, this technique requires a step of dissolving or dispersing cetylidin hydrochloride in a base containing a special solvent and water, the available preparations are limited to soft capsules, and its manufacturing process is also limited. is present (Non-Patent Document 8). is present (Non-Patent Document 8).

[0014] To date, it is unknown whether there is an interaction between ibuprofen and levocetirizine or a salt thereof that directly affects the decrease in the content of levocetirizine or its salt.

Prior Art Documents

Non-Patent Documents

[0015]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Patent Document

[0016]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0017] The inventors of the present invention have prepared a pharmaceutical composition containing ibuprofen and levocetirizine or a salt thereof, and surprisingly found that the content of levocetirizine or a salt thereof decreases over time. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a pharmaceutical composition in which the content reduction of levocetirizine or a salt thereof over time is suppressed even when ibuprofen and levocetirizine or a salt thereof are contained. or a salt thereof are contained. or a salt thereof are contained.

Means for Solving the Problems

[0018] As a result of intensive studies by the inventors, it has been found that when at least one selected from the group consisting of carbocisteine, ambroxol and salts thereof, tranexamic acid, glycyrrhizic acid and salts thereof, tipepidine and salts thereof, dextromethorphan and salts thereof, bromhexine and salts thereof, dimemorfan and salts thereof, and methyl ephedrine and salts thereof is contained, surprisingly, the content reduction of levocetirizine hydrochloride over time is suppressed. surprisingly, the content reduction of levocetirizine hydrochloride over time is suppressed. and the present invention has been completed.

[0019] That is, the present invention (1) (a) Ibuprofen, (b) Levofloxacin or a salt thereof, (c) (c1) Carbocysteine, (c2) Ambroxol and a salt thereof, (c3) Tranexamic acid, (c4) Glycyrrhizic acid and a salt thereof, (c5) Tipepidine and a salt thereof, (c6) Dextromethorphan and a salt thereof, (c7) Bromhexine and a salt thereof, (c8) Dimemorfan and a salt thereof, and (c9) Methylphenidate and a salt thereof, and contains at least one selected from the group consisting of, characterized in that it is a pharmaceutical composition, (2) The pharmaceutical composition according to (1), wherein the salt of (b) Levofloxacin is Levofloxacin hydrochloride. (3) The pharmaceutical composition according to (1), wherein the component (c) is (c1) Carbocysteine. (4) The pharmaceutical composition according to (1), wherein the component (c) is (c2) Ambroxol or a salt thereof. (5) The pharmaceutical composition according to (1) or (4), wherein the salt of Ambroxol is Ambroxol hydrochloride. (6) The pharmaceutical composition according to (1), wherein the component (c) is (c3) Tranexamic acid. (7) The pharmaceutical composition according to (1), wherein the component (c) is (c4) Glycyrrhizic acid or a salt thereof. (8) The pharmaceutical composition according to (1) or (7), wherein the salt of Glycyrrhizic acid is Dipotassium Glycyrrhizinate. (9) The pharmaceutical composition according to (1), wherein the component (c) is (c5) Tipepidine or a salt thereof. (10) The pharmaceutical composition according to (1) or (9), wherein the salt of Tipepidine is Tipepidine Hibenzate. (11) The pharmaceutical composition according to (1), wherein the component (c) is (c6) Dextromethorphan or a salt thereof. ​​​​​​​The pharmaceutical composition, (12) The salt of dextromethorphan is dextromethorphan hydrobromide hydrate, The pharmaceutical composition according to (1) or (11), (13) The pharmaceutical composition according to (1), wherein component (c) is bromhexine or a salt thereof, The pharmaceutical composition, (14) The salt of bromhexine is bromhexine hydrochloride, the pharmaceutical composition according to (1) or (13), The pharmaceutical composition, (15) The pharmaceutical composition according to (1), wherein component (c) is dimemorfan or a salt thereof, The pharmaceutical composition, (16) The salt of dimemorfan is dimemorfan phosphate hydrochloride, the pharmaceutical composition according to (1) or (15), The pharmaceutical composition, (17) The pharmaceutical composition according to (1), wherein component (c) is methylphenidate or a salt thereof, The pharmaceutical composition, (18) The salt of methylphenidate is dl-methylphenidate hydrochloride, the pharmaceutical composition according to (1) or (17), The pharmaceutical composition, (19) The pharmaceutical composition according to any one of (1) to (18), wherein the dosage form is tablets, powders, fine granules, granules, pills, capsules, oral liquids, or syrups, The pharmaceutical composition, (20) For producing a pharmaceutical composition containing (a) ibuprofen and (b) levocetirizine or a salt thereof, and (b) levocetirizine or a salt thereof is stabilized, (c) (c1) Carbocisteine, (c2) Ambroxol and its salts, (c3) Tranexamic acid, (c4 ) Glycyrrhizic acid and its salts, (c5) Tipepidine and its salts, (c6) Dextromethorphan and its salts, (c7) Bromhexine and its salts, (c8) Dimemorfan and its salts, and (c9) Methylphenidate and its salts, at least one use selected from the group consisting of, The pharmaceutical composition, The pharmaceutical composition, And at least one selected from the group consisting of (c9) methylphenidate and its salts, At least one use, (21) In a pharmaceutical composition comprising (a) ibuprofen and (b) levocetirizine or a salt thereof (b) (c) (c1) carbocysteine ​​for stabilizing levocetirizine or a salt thereof (c2) ambroxol and its salts, (c3) tranexamic acid, (c4) glycyrrhizin Litic acid and its salts, (c5) tipepidine and its salts, (c6) dextromethorphan and its salts, (c7) bromhexine and its salts, (c8) dimemorfan and its salts, and (c9) at least one selected from the group consisting of methylephedrine and its salts. use, It is. Effect of the Invention

[0020] According to the present invention, a pharmaceutical composition comprising ibuprofen and levocetirizine or a salt thereof is provided. It is now possible to provide a pharmaceutical composition containing an amine or a salt thereof having excellent stability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The ibuprofen used in the present invention has the chemical formula C 13 H 18 The compound represented by O2 There are no particular limitations as long as it is pharma- ceutical acceptable. Ibuprofen can be prepared by a known method. In addition, commercially available products can be used. The amount of ibuprofen contained is not particularly limited as long as it is an amount that shows its medicinal effect, but is usually 5 to 100 mg. 95% by mass, preferably 10 to 90% by mass, 15 to 85% by mass, 15 to 80% by mass, 20 % by mass or less, and 20 to 60% by mass.

[0022] The levocetirizine used in the present invention has the chemical formula C 21 H 25 ClN2O3The compound shown It is a substance and is not particularly limited as long as it is pharmaceutically acceptable. Also, the salt of levocetirizine is not particularly limited as long as it is pharmaceutically acceptable. For example, salts of inorganic acids such as hydrochloride, hydrobromide salt, phosphate, etc., and salts of organic acids such as acetate, oxalate, malonate, succinate, fuma rate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. are included, and hydrochloride is particularly preferred. Levocetirizine or its salt can be produced by known methods and commercially available products can also be used. The content of levocetirizine or its salt in the pharmaceutical composition of the present invention (when two or more of levocetirizine or its salts are contained, their total content, the same hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 0.001 to 50% by mass, 0.01 to 30% by mass, preferably 0. 1 to 10% by mass, 0.2 to 7% by mass. When contained, their total content, the same hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 0.001 to 50% by mass, 0.01 to 30% by mass, preferably 0. 1 to 10% by mass, 0.2 to 7% by mass. 1 to 10% by mass, 0.2 to 7% by mass.

[0023] The carbocisteine used in the present invention is a compound represented by the chemical formula C5H9NO4S and is not particularly limited as long as it is pharmaceutically acceptable. Usually, L-carbocisteine is used. Carbocisteine can be produced by known methods and commercially available products can also be used. The content of carbocisteine in the pharmaceutical composition of the present invention is not particularly limited, but is usually 1 to 95% by mass, 5 to 85% by mass, preferably 10 to 70% by mass is.

[0024] The ambroxol used in the present invention is a compound represented by the chemical formula C 13 H 18 Br2N2O or a salt thereof, and one of these can be used alone or two or more can be combined compounds or salts thereof, and one of these can be used alone or two or more can be combined It may be used. Such ambroxol or its salts can be produced by known methods and commercially available products can also be used. Further, ambroxol or its salts are not particularly limited as long as they are pharmaceutically acceptable. Examples of the salts include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate , fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate. Particularly preferred is the hydrochloride. The content of ambroxol or its salts in the pharmaceutical composition of the present invention (when two or more of ambroxol or its salts are included, the total content thereof, the same applies hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass. , fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. of organic acids, etc. are mentioned, and particularly preferably the hydrochloride. The content of ambroxol or its salts in the pharmaceutical composition of the present invention is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass.

[0025] The tranexamic acid used in the present invention is a compound represented by the chemical formula C8H 15 NO2 and is not particularly limited as long as it is pharmaceutically acceptable. Tranexamic acid can be produced by known methods and commercially available products can also be used. The content of tranexamic acid in the pharmaceutical composition of the present invention is not particularly limited as long as it exhibits the medicinal effect, but is usually 1 to 95% by mass, 3 to 95% by mass, preferably 5 to 70% by mass, 8 to 85% by mass, 10 to 6 5% by mass.

[0026] Glycyrrhizic acid or its salts in the present invention are widely known as components contained in licorice (Glycyrrhiza glabra). They can be obtained commercially or produced by known production methods and may be derived from crude drugs. Glycyrrhizic acid or its salts may be the components themselves ​​​​​​It may also be contained in crude drugs or traditional Chinese medicines. In particular, as the crude drug containing glycyrrhizic acids, licorice (licorice extract or licorice powder) can be used. In licorice, glycyrrhizic acid exists in both the free acid and salt forms. The salt of glycyrrhizic acid is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, tripotassium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate can be mentioned. As glycyrrhizic acid and its salts, glycyrrhizic acid and dipotassium glycyrrhizate are preferable, and dipotassium glycyrrhizate is particularly preferable. The content of glycyrrhizic acid and its salts in the pharmaceutical composition of the present invention (when two or more kinds of glycyrrhizic acid and its salts are contained, the total amount thereof, the same hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.01 to 50% by mass as glycyrrhizic acid, preferably 0.1 to 30% by mass. As the crude drug, licorice (licorice extract or licorice powder) can be used. In licorice, glycyrrhizic acid exists in both the free acid and salt forms. The salt of glycyrrhizic acid is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, tripotassium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate can be mentioned. As glycyrrhizic acid and its salts, glycyrrhizic acid and dipotassium glycyrrhizate are preferable, and dipotassium glycyrrhizate is particularly preferable. The content of glycyrrhizic acid and its salts in the pharmaceutical composition of the present invention (when two or more kinds of glycyrrhizic acid and its salts are contained, the total amount thereof, the same hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.01 to 50% by mass as glycyrrhizic acid, preferably 0.1 to 30% by mass. As glycyrrhizic acid and its salts, glycyrrhizic acid and dipotassium glycyrrhizate are preferable, and dipotassium glycyrrhizate is particularly preferable. The content of glycyrrhizic acid and its salts in the pharmaceutical composition of the present invention (when two or more kinds of glycyrrhizic acid and its salts are contained, the total amount thereof, the same hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but is usually 0.01 to 50% by mass as glycyrrhizic acid, preferably 0.1 to 30% by mass. In licorice, glycyrrhizic acid exists in both the free acid and salt forms. The salt of glycyrrhizic acid is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, tripotassium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate can be mentioned.

[0027] The tipepidine used in the present invention is a compound represented by the chemical formula C 15 H 17 NS2 or a salt thereof, and one of these can be used alone or two or more thereof can be used in combination. Such tipepidine or a salt thereof can be produced by a known method, and commercially available products can also be used. The tipepidine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. The salt includes, for example, salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, and maleate. Such tipepidine or a salt thereof can be produced by a known method, and commercially available products can also be used. The tipepidine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. The salt includes, for example, salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, and maleate. For example, tripotassium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate can be mentioned. Organic acid salts such as salts, lactates, malates, citrates, tartrates, benzoates, carbonates, etc. are mentioned, and benzoate is particularly preferred. The content of tipepidine or its salt in the pharmaceutical composition of the present invention (when two or more of tipepidine or its salts are contained, the total content thereof, the same hereinafter) is not particularly limited as long as it shows the medicinal effect, but usually is 0.1 to 50% by mass, 0.1 to 30% by mass, preferably 1 to 30% by mass.

[0028] The dextromethorphan used in the present invention is a compound represented by the chemical formula C 18 H 25 NO or a salt thereof, and one of these may be used alone or two or more may be used in combination. As such dextromethorphan or its salt, it can be produced by a known method, and commercially available products can also be used. Further, dextromethorphan or its salt is not particularly limited as long as it is pharmaceutically acceptable, but the salts include, for example, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hydrobromide, phenolphthalein salt, carbonate, etc. Benzoate is particularly preferred. The content of dextromethorphan or its salt in the pharmaceutical composition of the present invention (when two or more of dextromethorphan or its salts are contained, the total content thereof, the same hereinafter) is not particularly limited as long as it shows the medicinal effect, but usually is 0.1 to 50% by mass, preferably 0.5 to 30% by mass.

[0029] The bromhexine used in the present invention has the chemical formula C 14 H20 A compound represented by Br2N2 or a salt thereof, and one of these may be used alone or two or more of them may be used in combination. Such bromhexine or a salt thereof can be produced by a known method, and in addition, commercially available products can be used. Further, bromhexine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but the salt includes, for example, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc., and particularly preferably hydrochloride. The content of bromhexine or a salt thereof in the solid composition of the present invention (when two or more of bromhexine or a salt thereof are contained, the total content thereof, the same applies hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, 0.2 to 30% by mass. Dextromethorphan used in the present invention is a compound represented by the chemical formula H NC, and is not particularly limited as long as it is pharmaceutically acceptable. Further, the salt of dextromethorphan is not particularly limited as long as it is pharmaceutically acceptable, but includes, for example, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate,

[0030] maleate, lactate, malate, citrate, tartrate, benzoate, carbonate, etc., and particularly preferably phosphate. Dextromethorphan or a salt thereof can be produced by a known method, 18 H 25 and in addition, commercially available products can be used. In the pharmaceutical composition of the present invention, the content of dextromethorphan or a salt thereof (when two or more of dextromethorphan or a salt thereof are contained, the total content thereof, the same applies hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, 0.2 to 30% by mass. maleate, lactate, malate, citrate, tartrate, hibenzate, carbonate, etc., and particularly preferably phosphate. Dextromethorphan or a salt thereof can be produced by a known method, and in addition, commercially available products can be used. In the pharmaceutical composition of the present invention, ​The content of dimemorfan or its salt in it (when two or more of dimemorfan or its salts are contained, their total content, the same applies hereinafter) is not particularly limited as long as it is an amount that exhibits its medicinal effect, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass.

[0031] Methylephedrine used in the present invention is a compound represented by the chemical formula C 11 H 17 NO, and is not particularly limited as long as it is pharmaceutically acceptable. Also, the salt of methylephedrine is not particularly limited as long as it is pharmaceutically acceptable. For example, salts of inorganic acids such as hydrochloride, hydrobromide salt, phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate salt, maleate, lactate, malate, citrate, tartrate, benzoate, carbonate salt, etc. are mentioned, and hydrochloride is particularly preferred. Methylephedrine or its salt can be produced by known methods, and commercially available products can also be used. The content of methylephedrine or its salt in the pharmaceutical composition of the present invention (when two or more of methylephedrine or its salts are contained, their total content, the same applies hereinafter) is not particularly limited as long as it is an amount that exhibits its medicinal effect, but is usually 0.01 to 50% by mass, preferably 0 ...05 to 10% by mass.

[0032] Also, the mixing ratio of (a) ibuprofen and (b) levocetirizine or its salt is not particularly limited, but 10 parts by mass or more of ibuprofen is preferred per 1 part by mass of levocetirizine and its salt. This is because the decrease in the content of levocetirizine and its salt over time becomes significant. The upper limit is not particularly limited, but may be 120 parts by mass, 60 parts by mass, or may also be 20 parts by mass, 40 parts by mass ​​​​​​​​ It may also be a part.

[0033] Moreover, the mixing ratio of (a) levocetirizine and its salts and (c) carbocisteine is, from the viewpoint of the effect of the invention, 4 parts by mass or more of carbocisteine is preferable with respect to 1 part by mass of levocetirizine and its salts, 25 parts by mass or more and 50 parts by mass or more may also be used. The upper limit is not particularly limited, and it may be 75 parts by mass or 150 parts by mass.

[0034] The mixing ratio of (a) levocetirizine and its salts and (c) ambroxol and its salts is, from the viewpoint of the effect of the invention, 1.5 parts by mass or more and preferably 3 parts by mass or more of ambroxol and its salts with respect to 1 part by mass of levocetirizine and its salts, and 4 parts by mass or more may also be used. The upper limit is not particularly limited, and it may be 9 parts by mass or 4.5 parts by mass.

[0035] The mixing ratio of (a) levocetirizine and its salts and (c) tranexamic acid is, with respect to 1 part by mass of levocetirizine and its salts, from the viewpoint of the effect of the invention, 4 parts by mass or more of tranexamic acid is preferable, and it may be 9.3 parts by mass or more and 18.6 parts by mass or more. The upper limit is not particularly limited, and it may be 150 parts by mass or 100 parts by mass, 75 parts by mass, or 56 parts by mass.

[0036] The mixing ratio of (a) levocetirizine and its salts and (c) glycyrrhizic acid and its salts is, from the viewpoint of the effect of the invention, 0.12 parts by mass or more and preferably 0.2 parts by mass or more of glycyrrhizic acid with respect to 1 part by mass of levocetirizine and its salts, more preferably 1.2 parts by mass or more, and it may be 2.4 parts by mass or more. The upper limit is not particularly limited, and it may be 12 parts by mass or 10 parts by mass, or 8 parts by mass.

[0037] (a) Levocetirizine and its salts, and (c) tipepidine and its salts, the mixing ratio is, from the viewpoint of the effects of the invention, for 1 part by mass of levocetirizine and its salts, tipepidine and its salts are preferably 1 part by mass or more, more preferably 2 parts by mass or more from the viewpoint of the effects of the invention, and even more preferably 2.5 parts by mass or more, 4 parts by mass or more, 5 parts by mass or more. Also, the upper limit is not particularly limited and may be 15 parts by mass, 10 parts by mass, or 7.5 parts by mass.

[0038] (a) Levocetirizine and its salts, and (c) dextromethorphan and its salts, the mixing ratio is, from the viewpoint of the effects of the invention, for 1 part by mass of levocetirizine and its salts, dextromethorphan and its salts are preferably 0.5 part by mass or more, more preferably 0.8 part by mass or more, even more preferably 1 part by mass or more, and even more preferably 1.6 parts by mass or more, 3.2 parts by mass or more. Also, the upper limit is not particularly limited and may be 10 parts by mass, or 5 parts by mass.

[0039] (a) Levocetirizine and its salts, and (c) bromhexine and its salts, the mixing ratio is, from the viewpoint of the effects of the invention, for 1 part by mass of levocetirizine and its salts, bromhexine and its salts are preferably 0.1 part by mass or more, more preferably 0.2 part by mass or more, even more preferably 0.8 part by mass or more, and even more preferably 1.2 parts by mass or more, and may also be 2.4 parts by mass or more. The upper limit is not particularly limited and may be 12 parts by mass, or 10 parts by mass, or 8 parts by mass.

[0040] (a) Levocetirizine and its salts, and (c) dimemorfan and its salts, the mixing ratio is, from the viewpoint of the effects of the invention, for 1 part by mass of levocetirizine and its salts, dimemorfan and its salts are preferably 0.5 part by mass or more, 1 part by mass or more, 2 parts by mass or more, 4 parts by mass or more, and also, the upper ​​​There is no particular limitation, and it may be 10 parts by mass, or may be 9.6 parts by mass or 4 parts by mass.

[0041] (a) The mixing ratio of levocetirizine and its salts and (c) methylphenidate and its salts is , from the viewpoint of the effects of the invention, for 1 part by mass of levocetirizine and its salts, methylphenidate and its salts are preferably 0.5 part by mass or more, 1 part by mass or more, 2 parts by mass or more, 4 parts by mass or more, and the upper limit is not particularly limited, and may be 15 parts by mass, 7.5 parts by mass, 3.75 parts by mass. .

[0042] In the pharmaceutical composition of the present invention, other active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants, cooling agents, coloring agents, sweetening agents, adsorbents, suspending agents, antioxidants, stabilizers, surfactants, plasticizers, solubilizers, emulsifiers, pH regulators, buffers, flavoring and deodorizing agents, cooling agents, fragrances, coating agents, etc. that are usually used can be blended within a qualitative and quantitative range that does not impair the effects of the present invention.

[0043] Examples of other active ingredients that can be incorporated into the pharmaceutical composition of the present invention include, for example, antipyretics, antihistamines, cough suppressants, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosal protectants, crude drugs, traditional Chinese medicine prescriptions, caffeine, etc., and one or more selected from the group consisting of these may be contained.

[0044] Examples of excipients that can be incorporated into the pharmaceutical composition of the present invention include, for example, lactose, starches, crystalline cellulose, sucrose, sugar alcohols, etc. Examples of disintegrants include low-substituted hydroxypropylcellulose, sodium starch glycolate, crospovidone, carmellose, ​​​​​​​​​Examples include sodium carboxymethylcellulose, calcium carboxymethylcellulose, pregelatinized starch, etc. , Examples of the binder include hydroxypropylcellulose, hypromellose, gelatin, alpha- pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, etc. Examples of the lubricant include sucrose fatty acid ester , hydrogenated oil, stearic acid, magnesium stearate, calcium stearate, etc. Examples of the cooling agent include menthol, peppermint oil, eucalyptus oil, etc.

[0045] The pharmaceutical composition of the present invention is not particularly limited as long as it is a dosage form defined in the Pharmaceutical Excipients of the Japanese Pharmacopoeia, and can take any commonly used dosage form. For example, solid preparations such as tablets, powders, fine granules, granules, pills, capsules, etc., or liquid preparations such as oral liquids, syrups, etc. are mentioned. Preferably, they are tablets, powders, fine granules, granules, pills, capsules (preferably hard capsules). Tablets defined in the Pharmaceutical Excipients of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and soluble tablets, film-coated tablets, sugar-coated tablets, nucleated tablets, multi-layer tablets, etc. In addition, the tablets can be provided with score lines, marks, or imprints for improving identification. Furthermore, the tablets of the present preparation may be round tablets or shaped tablets. Moreover, the tablets of the present preparation may be round tablets or shaped tablets.

[0046] The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. For example, (a) ibuprofen (hereinafter also referred to as component (a)), (b) levocetirizine or a salt thereof (hereinafter also referred to as component (b)), (c) carbocisteine, ambroxol ​and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, de kistromethorphan and its salts, bromhexine and its salts, dimemorfan and its salts, and at least one selected from the group consisting of methylephedrine and its salts (hereinafter , also referred to as component (c)) may be simply mixed, or may be granulated after mixing, and the obtained granulated product may be coated. Further, the component (a), component (b) or component (c) does not necessarily have to be contained in the same granulated product. For example, after producing a granulated product containing the component (a) and the component (c), the component (b) is mixed, or after producing a granulated product containing the component (a) and the component (b), the component (c) is mixed, or after producing a granulated product containing the component (a) and the component (c) and a granulated product containing the component (b) and the component (c), the two granulated products are mixed , etc.

[0047] The granulation method is not particularly limited, and it can be produced by a wet granulation method, a dry granulation method, a melt granulation method, etc., but preferably a wet granulation method. Examples of the wet granulation method include a stirring granulation method, a fluidized bed granulation method, a kneading granulation method, an extrusion granulation method, and a rolling fluidized granulation method. Further, conventional pharmaceutical additives such as the above active ingredients and excipients may be appropriately blended into the obtained granulated product. Further, the mixture thus obtained can be tableted into tablets. When producing tablets, it may be produced by a direct tableting method .

Examples

[0048] Examples, control examples, and comparative examples are given below to explain the present invention in more detail, but the present invention is not limited to these examples and the like. (Control Example 1) (Control Example 1) (Control Example 1) An appropriate amount of a water / alcohol mixture was added to levocetirizine hydrochloride, mixed, and then dried to obtain a composition. obtained. (Comparative Example 1) 10 parts by mass of ibuprofen was weighed and mixed with 1 part by mass of levocetirizine hydrochloride, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 2) 4 parts by mass of pranlukast hydrate was weighed and mixed with 1 part by mass of levocetirizine hydrochloride and 10 parts by mass of ibuprofen, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 1) 4 parts by mass of L-carnosine was weighed and mixed with 1 part by mass of levocetirizine hydrochloride and 10 parts by mass of ibuprofen, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 2) 4 parts by mass of ambroxol hydrochloride was weighed and mixed with 1 part by mass of levocetirizine hydrochloride and 10 parts by mass of ibuprofen, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 3) 4 parts by mass of tranexamic acid was weighed and mixed with 1 part by mass of levocetirizine hydrochloride and 10 parts by mass of ibuprofen, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 4) 4 parts by mass of dipotassium glycyrrhizinate (2.4 parts by mass as glycyrrhizic acid) was weighed and mixed with 1 part by mass of levocetirizine hydrochloride and 10 parts by mass of ibuprofen, An appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 5) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and tipepidine hibenzate Weighed and mixed 4 parts by mass of cinnamate, added an appropriate amount of water / alcohol mixture thereto and mixed, and then dried to obtain a composition. (Example 6) To 1 part by mass of levocetirizine hydrochloride, weighed and mixed 10 parts by mass of ibuprofen and 4 parts by mass of dextromethorphan hydrobromide hydrate, added an appropriate amount of water / alcohol mixture thereto and mixed, and then dried to obtain a composition.

[0049] (Test method) The compositions of the control example, comparative examples and examples were stored at 65 °C for 14 days, and the residual rate of levocetirizine hydrochloride in the composition after 14 days was evaluated by HPLC method. Table 1 shows the residual rate (%) of levocetirizine hydrochloride after storage at 65 °C for 14 days.

[0050]

Table 1

[0051] As shown in Table 1, in Comparative Examples 1-2 in which ibuprofen and levocetirizine hydrochloride were formulated, a decrease in the content of levocetirizine hydrochloride was confirmed. On the other hand, in Examples 1-6 in which L-carbocysteine, ambroxol hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were formulated, the decrease in the content of levocetirizine hydrochloride could be suppressed.

[0052] (Example 7) To 1 part by mass of levocetirizine hydrochloride, weighed and mixed 10 parts by mass of ibuprofen and 0.2 part by mass of bromhexine hydrochloride, added an appropriate amount of water / alcohol mixture thereto and mixed, and then dried to obtain a composition. (Example 8) For each part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and ambroxol 1.5 parts by mass of ethylhexyl hydrochloride was weighed out and mixed, and an appropriate amount of water / alcohol mixture was added and mixed. Then, it was dried to obtain a composition. Example 9 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and glycyrrhizin 0.2 parts by mass of dipotassium phosphate (0.12 parts by mass of glycyrrhizinic acid) was weighed out and mixed. An appropriate amount of a water / alcohol mixture was added to this, mixed, and then dried to obtain a composition. Example 10 For each part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and tipepidine hibe Weigh out 1 part by mass of benzoate, mix, add an appropriate amount of water / alcohol mixture, and then mix. After drying, a composition was obtained. Example 11 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dextromethorphan Weigh out 0.8 parts by mass of Fan hydrobromide hydrate and mix it, then add an appropriate amount of water / alcohol. The mixture was added, mixed, and then dried to obtain a composition. Example 12 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dimemorfan Weigh out 1 part by mass of phosphate, mix it, add an appropriate amount of water / alcohol mixture, and then mix. After drying, a composition was obtained. (Example 13) For each part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dl-methylethyl ether Weigh out 1 part by mass of Fedrine hydrochloride and mix it, then add an appropriate amount of water / alcohol mixture and mix. The mixture was mixed and then dried to obtain a composition.

[0053] (Test Method) The composition of the example was stored at 65° C. for 14 days, and the amount of levocetirizine in the composition after 14 days was The residual rate of levocetirizine hydrochloride was evaluated by HPLC method. Table 2 shows the residual rate (%) of levocetirizine hydrochloride after storage at 65°C for 14 days.

[0054] [Table 2]

[0055] The decrease in the content of levocetirizine hydrochloride confirmed in Comparative Examples 1 to 2 of Table 1 was suppressed in Examples 7 to 13 containing bromhexine hydrochloride, ambroxol hydrochloride, dipotassium glycyrrhizinate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, dimemorfan phosphate, and dl-methylephedrine hydrochloride. It was clarified that

[0056] Formulation preparation examples are given below. Formulation Examples 1 to 12 Regarding the formulation examples described in Tables 3 and 4, tablets, powders, or granules are produced using known techniques. The obtained powders or granules are filled into hard capsules using known techniques to produce hard capsule preparations.

[0057] [Table 3]

[0058] [Table 4] [Industrial Applicability]

[0059] According to the present invention, it has become possible to provide a pharmaceutical composition containing ibuprofen and levocetirizine or a salt thereof, which has excellent stability of levocetirizine and its salt. ​​​​​

Claims

1. A pharmaceutical composition comprising at least one selected from the group consisting of (a) ibuprofen, (b) levocetirizine or a salt thereof, and (c) (c2) ambroxol and a salt thereof, (c3) tranexamic acid, (c4) glycyrrhizic acid and a salt thereof, and (c9) methyl ephedrine and a salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the salt of (b) levocetirizine is levocetirizine hydrochloride. 。

3. The pharmaceutical composition according to claim 1, wherein component (c) is (c2) ambroxol or a salt thereof. composition.

4. The pharmaceutical composition according to claim 1 or 3, wherein the salt of ambroxol is ambroxol hydrochloride. composition.

5. The pharmaceutical composition according to claim 1, wherein component (c) is (c3) tranexamic acid.

6. The pharmaceutical composition according to claim 1, wherein component (c) is (c4) glycyrrhizic acid or a salt thereof. composition.

7. The pharmaceutical composition according to claim 1 or 6, wherein the salt of glycyrrhizic acid is dipotassium glycyrrhizinate. composition.

8. The pharmaceutical composition according to claim 1, wherein component (c) is (c9) methyl ephedrine or a salt thereof. composition.

9. The pharmaceutical composition according to claim 1 or 8, wherein the salt of methyl ephedrine is dl-methyl ephedrine hydrochloride. composition.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the dosage form is tablets, powders, fine granules, granules, pills, capsules, oral liquids, or syrups. composition.

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