Pharmaceutical composition

Abstract

To provide a pharmaceutical composition in which a decrease of the content of levocetirizine over time is suppressed even if ibuprofen and levocetirizine or a salt thereof are contained.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 Art

[0002] Ibuprofen is effective for rheumatoid arthritis, arthralgia and arthritis, neuralgia and neuritis, low back pain, cervical spondylosis, adnexitis, dysmenorrhea, erythema (erythema nodosum, polymorphic exudative erythema, centrifugal annular erythema), and is also effective for antipyretic and analgesic effects of acute upper respiratory tract infection (including acute upper respiratory tract infection accompanied by acute bronchitis). In addition to antipyretic and analgesic drugs, it is widely formulated as an antipyretic and analgesic component of general cold medicines (Non-Patent Document 1).

[0003] Levocetirizine and its salts are effective for pruritus associated with allergic rhinitis, urticaria, and skin diseases (eczema / dermatitis, cutaneous pruritus) as second-generation histamine H1 receptor antagonists (second-generation antihistamines) (Non-Patent Document 2). Levocetirizine is an optically resolved product of only the more physiologically active R-enantiomer among the optical isomers of cetirizine hydrochloride.

[0004] Carbocisteine has an effect of adjusting mucus components, an effect of suppressing goblet cell hyperplasia, an effect of suppressing airway inflammation, and an effect of normalizing mucosa, and is widely known as a compound having excellent expectorant effects on upper respiratory tract infection (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis, and is widely formulated in general cold medicines and antitussive and expectorant drugs (Non-Patent Document 3).

[0005] Ambroxol and its salts have an effect of promoting the secretion of pulmonary surfactant, an effect of promoting the secretion of airway fluid, and an effect of enhancing ciliary movement, and are widely known as compounds having excellent expectorant effects on acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, and difficulty in expectorating sputum after surgery. It is also approved as a switch OTC component and is formulated in general cold medicines and antitussive and expectorant drugs (Non-Patent Document 4).

[0006] Tranexamic acid has anti-allergic and anti-inflammatory effects and exhibits excellent effects against symptoms such as sore throat, redness, congestion, and swelling in tonsillitis and pharyngitis. Therefore, it is widely formulated in general cold medicines, antitussive and expectorant medicines, and rhinitis medicines (Non-Patent Document 5).

[0007] Glycyrrhizic acid and its salts are widely known as components contained in licorice. They have anti-inflammatory effects, anti-allergic effects, cell repair effects, etc., and are known to have effects on peptic ulcers and as expectorant medicines. They are also used as sweeteners and flavoring agents (Non-Patent Document 6).

[0008] Tipepidine and its salts exhibit an antitussive effect by suppressing the cough center in the medulla oblongata and reducing the sensitivity to cough, and an expectorant effect by enhancing bronchial gland secretion and enhancing the movement of the ciliated epithelium of the airway mucosa. They are widely used for cough and difficulty in expectoration associated with colds, upper respiratory tract infections (pharyngitis, rhinitis), acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 7).

[0009] Dextromethorphan and its salts are compounds that directly act on the cough center in the medulla oblongata and exhibit an antitussive effect by suppressing the cough reflex. They are widely used for coughs associated with colds, acute bronchitis, chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, and upper respiratory tract infections (pharyngitis, rhinitis) (Non-Patent Document 8).

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

[0011] Dimemorfanrine and its salts are compounds that directly act on the cough center in the medulla oblongata and exhibit an antitussive effect. They are widely used for coughs associated with upper respiratory tract infections, pneumonia, acute bronchitis, pulmonary tuberculosis, silicosis and silicotuberculosis, lung cancer, and chronic bronchitis (Non-Patent Document 10).

[0012] Methylephedrine and its salts are sympathomimetic drugs, have a bronchodilating effect by stimulating β2 receptors, and are widely formulated in over-the-counter cold remedies and cough and expectorant medications (Non-Patent Document 11).

[0013] Heretofore, a capsule formulation containing ibuprofen, cetylpyridinium chloride, and cyclodextrin in a base containing a POE sorbitan fatty acid ester, a glycerin fatty acid ester, macrogol, and water has been known (Patent Document 1). This document discloses a method for solving the decrease in solubility due to crystallization of cetylpyridinium chloride by the coexistence of cyclodextrin. However, this technique requires a step of dissolving or dispersing cetylpyridinium chloride in a base containing a special solvent and water, the available formulations are limited to soft capsules, and the manufacturing process is also limited.

[0014] To date, it has not been known whether an interaction that directly affects the decrease in the content of levocetylpyridinium or its salt occurs between ibuprofen and levocetylpyridinium 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 Documents

[0016]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0017] The inventors of the present invention have produced a pharmaceutical composition containing ibuprofen and levofloxacin or a salt thereof, and obtained a surprising finding that the content of levofloxacin or a salt thereof decreases over time. The present invention has been made in view of the above circumstances, and an object thereof is to provide a pharmaceutical composition in which the content reduction of levofloxacin or a salt thereof over time is suppressed even when ibuprofen and levofloxacin or a salt thereof are contained. **Means for Solving the Problems**

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

[0019] That is, the present invention is (1) A pharmaceutical composition comprising: (a) ibuprofen; (b) levofloxacin or a salt thereof; and (c) at least one selected from the group consisting of (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) methyl ephedrine and its salts. (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) carbocisteine. (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. The pharmaceutical composition according to (1), wherein component (c) is tranexamic acid The pharmaceutical composition according to (1), wherein component (c) is glycyrrhizic acid or a salt thereof The pharmaceutical composition according to (1) or (7), wherein the salt of glycyrrhizic acid is dipotassium glycyrrhizate The pharmaceutical composition according to (1), wherein component (c) is tipepidine or a salt thereof The pharmaceutical composition according to (1) or (9), wherein the salt of tipepidine is tipepidine hibenzate The pharmaceutical composition according to (1), wherein component (c) is dextromethorphan or a salt thereof The pharmaceutical composition according to (1) or (11), wherein the salt of dextromethorphan is dextromethorphan hydrobromide hydrate The pharmaceutical composition according to (1), wherein component (c) is bromhexine or a salt thereof The pharmaceutical composition according to (1) or (13), wherein the salt of bromhexine is bromhexine hydrochloride The pharmaceutical composition according to (1), wherein component (c) is dimemorfan or a salt thereof The pharmaceutical composition according to (1) or (15), wherein the salt of dimemorfan is dimemorfan phosphate The pharmaceutical composition according to (1), wherein component (c) is methylephedrine or a salt thereof The pharmaceutical composition according to (1) or (17), wherein the salt of methylephedrine is dl-methylephedrine hydrochloride 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 (20)Use of at least one selected from the group consisting of (c1) carbocysteine, (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) methylephedrine and its salts for producing a pharmaceutical composition containing (a) ibuprofen and (b) levofloxacin or its salt, wherein (b) levofloxacin or its salt is stabilized. (21)Use of at least one selected from the group consisting of (c1) carbocysteine, (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) methylephedrine and its salts for stabilizing (b) levofloxacin or its salt in a pharmaceutical composition containing (a) ibuprofen and (b) levofloxacin or its salt. It is as follows. [Advantages of the Invention]

[0020] According to the present invention, it has become possible to provide a pharmaceutical composition containing ibuprofen and levofloxacin or its salt and having excellent stability of levofloxacin or its salt. [Embodiments for Carrying Out the Invention]

[0021] The ibuprofen used in the present invention is a compound represented by the chemical formula C 13 H 18 O2, and is not particularly limited as long as it is pharmaceutically acceptable. Ibuprofen can be produced by a known method, or a commercially available product can be used. The content of ibuprofen in the pharmaceutical composition of the present invention is not particularly limited as long as it exhibits its medicinal effect, but is usually 5 to 95% by mass, preferably 10 to 90% by mass, 15 to 85% by mass, 15 to 80% by mass, 20 to 70% by mass, 20 to 60% by mass.

[0022] The levocetirizine used in the present invention is a compound represented by the chemical formula C 21 H 25 ClN2O3, 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. Examples include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate. Particularly preferred is the hydrochloride. 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, the total content thereof, the same hereinafter) is not particularly limited as long as it exhibits 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.

[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.

[0024] The ambroxol used in the present invention is a chemical formula C 13 H 18A compound represented by Br2N2O or a salt thereof, and one of these may be used alone or two or more thereof may be used in combination. Such ambroxol or a salt thereof can be produced by a known method, and commercially available products can also be used. Further, ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate. Particularly preferred is hydrochloride. The content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention (when two or more of ambroxol or a salt thereof are contained, the total content thereof, the same shall apply 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.

[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 a known method, 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 65% by mass.

[0026] Glycyrrhizic acid or its salt in the present invention is widely known as a component contained in licorice, and can be obtained as a commercially available product or produced by a known production method, and may be derived from crude drugs. Glycyrrhizic acid or its salt may be the component itself or may be contained in crude drugs or Kampo medicines. In particular, as the crude drug containing glycyrrhizic acids, licorice (licorice extract or licorice powder) can be used, and 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. Examples thereof include trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, and monopotassium glycyrrhizinate. As glycyrrhizic acid and its salt, glycyrrhizic acid and dipotassium glycyrrhizinate are preferable, and dipotassium glycyrrhizinate is particularly preferable. The content of glycyrrhizic acid and its salt in the pharmaceutical composition of the present invention (when two or more kinds of glycyrrhizic acid and its salt are included, the total amount thereof, the same shall apply hereinafter) is not particularly limited as long as it is an amount showing its pharmaceutical effect, but usually 0.01 to 50% by mass as glycyrrhizic acid, preferably 0.1 to 30% by mass.

[0027] The tipepidine used in the present invention has the chemical formula C 15 H 17A compound represented by NS2 or a salt thereof, and one of these may be used alone or two or more thereof may 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. Further, tipepidine 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, hibenzate, carbonate, etc. Particularly preferred is hibenzate. The content of tipepidine or a salt thereof in the pharmaceutical composition of the present invention (when two or more of tipepidine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 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 has the chemical formula C 18 H 25 A compound represented by NO or a salt thereof, and one of these may be used alone or two or more thereof may be used in combination. Such dextromethorphan or a salt thereof can be produced by a known method, and commercially available products can also be used. Further, dextromethorphan 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, hydrobromide, phenolphthalein salt, carbonate, etc. Particularly preferred is hydrobromide. The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention (when two or more of dextromethorphan or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is not particularly limited as long as it shows the medicinal effect, but is usually 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 C14 H 20 A compound represented by Br2N2 or a salt thereof, and one of these may be used alone or two or more thereof may be used in combination. Such bromhexine or a salt thereof can be produced by a known method, and commercially available products can also be used. Further, bromhexine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt 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 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 shall apply hereinafter) is not particularly limited as long as it is an amount showing the drug effect, but is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, 0.2 to 30% by mass.

[0030] Dextromethorphan used in the present invention has the chemical formula 18 H 25 It is a compound represented by 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. Examples thereof 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, benzoate, and carbonate. Particularly preferred is phosphate. Dextromethorphan or a salt thereof can be produced by a known method, and commercially available products can also be used. The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention (when two or more of dextromethorphan or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is not particularly limited as long as it is an amount showing the drug effect, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass.

[0031] Methylephedrine used in the present invention has the chemical formula C 11 H 17It is a compound represented by NO, and is not particularly limited as long as it is pharmaceutically acceptable. The salts of methylphentermine are not particularly limited as long as they are pharmaceutically acceptable. Examples 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, benzoate, and carbonate. Particularly preferred is the hydrochloride. Methylphentermine or its salts can be produced by known methods, and commercially available products can also be used. The content of methylphentermine or its salts in the pharmaceutical composition of the present invention (when two or more of methylphentermine or its salts are contained, the total content thereof, the same applies hereinafter) is not particularly limited as long as it is an amount that exhibits the medicinal effect, but is usually 0.01 to 50% by mass, preferably 0.05 to 10% by mass.

[0032] In addition, the mixing ratio of (a) ibuprofen and (b) levocetirizine or its salt is not particularly limited, but preferably 10 parts by mass or more of ibuprofen with respect to 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, and may be 120 parts by mass, 60 parts by mass, or may be 20 parts by mass, 40 parts by mass.

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

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

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

[0036] (a) Levocetirizine and its salts, and (c) glycyrrhizic acid and its salts, the mixing ratio is preferably 0.12 parts by mass or more, 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 may be 2.4 parts by mass or more from the viewpoint of the effects of the invention. The upper limit is not particularly limited, and may be 12 parts by mass, and may also be 10 parts by mass, 8 parts by mass.

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

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

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

[0040] (a) Levocetirizine and its salts, and (c) dimemorfan and its salts, the mixing ratio thereof is 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 of dimemorfan and its salts with respect to 1 part by mass of levocetirizine and its salts from the viewpoint of the effect of the invention. Also, the upper limit is not particularly limited, and may be 10 parts by mass, may be 9.6 parts by mass, or may be 4 parts by mass.

[0041] (a) Levocetirizine and its salts, and (c) methylphenidate and its salts, the mixing ratio thereof is 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 of methylphenidate and its salts with respect to 1 part by mass of levocetirizine and its salts from the viewpoint of the effect of the invention. Also, the upper limit is not particularly limited, and may be 15 parts by mass, may be 7.5 parts by mass, or may be 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, sweeteners, adsorbents, suspending agents, antioxidants, stabilizers, surfactants, plasticizers, solubilizers, emulsifiers, pH adjusters, buffers, flavoring and deodorizing agents, cooling agents, fragrances, coating agents, etc. 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 blended in the pharmaceutical composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosal protectants, crude drugs, traditional Chinese medicine prescriptions, caffeine, etc., and may contain one or more selected from the group consisting of these.

[0044] Examples of excipients that can be formulated in the pharmaceutical composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, etc. Examples of disintegrants include low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone, carmellose, sodium carmellose, calcium carmellose, pregelatinized starch, etc. Examples of binders include hydroxypropyl cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Examples of fluidizing agents include light anhydrous silicic acid, hydrous silicon dioxide, etc. Examples of lubricants include sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, calcium stearate, etc. Examples of cooling agents include menthol, peppermint oil, eucalyptus oil, etc.

[0045] The pharmaceutical composition of the present invention is not particularly limited as long as it is in a dosage form defined in the Japanese Pharmacopoeia's general rules for preparations, and can take any dosage form that can be commonly used. 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. Tablets, powders, fine granules, granules, pills, and capsules (preferably hard capsules) are preferred. Tablets defined in the Japanese Pharmacopoeia's general rules for preparations include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, film-coated tablets, sugar-coated tablets, nucleated tablets, multilayer tablets, etc. In addition, tablets can be provided with score lines and marks or imprints for improving identification. Furthermore, the tablets of this 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, it is also possible to simply mix at least one selected from the group consisting of (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, dextromethorphan and its salts, bromhexine and its salts, dimemorfan and its salts, and methyl ephedrine and its salts (hereinafter also referred to as component (c)). After mixing, granulation may be carried out, or the obtained granulated product may be coated. Further, components (a), (b), or (c) do not necessarily have to be contained in the same granulated product. For example, after producing a granulated product containing components (a) and (c), component (b) is mixed, or after producing a granulated product containing components (a) and (b), component (c) is mixed, or after producing a granulated product containing components (a) and (c) and a granulated product containing components (b) and (c), the two granulated products are mixed, and so on.

[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-mentioned active ingredients and excipients may be appropriately blended into the obtained granulated product. In addition, the mixture thus obtained can be tabletted into tablets. When producing tablets, it may be produced by a direct tabletting 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) An appropriate amount of a water / alcohol mixture was added to levocetirizine hydrochloride, mixed, and then dried to obtain a composition. (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) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of pranlukast hydrate were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 1) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of L-carbocysteine were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 2) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of ambroxol hydrochloride were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 3) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of tranexamic acid were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 4) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of dipotassium glycyrrhizinate (2.4 parts by mass as glycyrrhizic acid) were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 5) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of tipepidine hibenzate were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was dried to obtain a composition. (Example 6) To 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and 4 parts by mass of dextromethorphan hydrobromide hydrate were weighed and mixed. An appropriate amount of a water / alcohol mixture was added thereto, and after mixing, the mixture was 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, a decrease in the content of levocetirizine hydrochloride was confirmed in Comparative Examples 1-2 in which ibuprofen and levocetirizine hydrochloride were blended. 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 blended, a decrease in the content of levocetirizine hydrochloride could be suppressed.

[0052] (Example 7) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 0.2 part by mass of bromhexine hydrochloride were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto, followed by mixing and drying to obtain a composition. (Example 8) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 1.5 parts by mass of ambroxol hydrochloride were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto, followed by mixing and drying to obtain a composition. (Example 9) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 0.2 part by mass of dipotassium glycyrrhizinate (0.12 part by mass as glycyrrhizic acid) were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto, followed by mixing and drying to obtain a composition. (Example 10) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 1 part by mass of tipepidine hibenzate were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto, followed by mixing and drying to obtain a composition. (Example 11) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 0.8 part by mass of dextromethorphan hydrobromide hydrate were weighed and mixed, an appropriate amount of a water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition. (Example 12) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 1 part by mass of dimemorfan phosphate were weighed and mixed, an appropriate amount of a water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition. (Example 13) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen, and 1 part by mass of dl-methyl ephedrine hydrochloride were weighed and mixed, an appropriate amount of a water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition.

[0053] (Test method) The compositions of the examples were stored at 65°C for 14 days, and the residual ratio of levocetirizine hydrochloride in the compositions after 14 days was evaluated by HPLC. Table 2 shows the residual ratio (%) of levocetirizine hydrochloride after storage at 65°C for 14 days.

[0054]

Table 2

[0055] It was clarified that the decrease in the content of levocetirizine hydrochloride confirmed in Comparative Examples 1 to 2 in 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-methyl ephedrine hydrochloride.

[0056] The following are formulation preparation examples. 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 levofloxacin or a salt thereof, which has excellent stability of levofloxacin 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) (c1) carbocisteine, (c5) tipepidine and a salt thereof, (c6) dextromethorphan and a salt thereof, (c7) bromhexine and a salt thereof, and (c8) dimemorfan 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 the component (c) is (c1) carbocisteine.

4. The pharmaceutical composition according to claim 1, wherein the component (c) is (c5) tipepidine or a salt thereof.

5. The pharmaceutical composition according to claim 1 or 4, wherein the salt of tipepidine is tipepidine hibenzate.

6. The pharmaceutical composition according to claim 1, wherein the component (c) is (c6) dextromethorphan or a salt thereof.

7. The pharmaceutical composition according to claim 1 or 6, wherein the salt of dextromethorphan is dextromethorphan hydrobromide hydrate.

8. The pharmaceutical composition according to claim 1, wherein the component (c) is (c7) bromhexine or a salt thereof. 。

9. The pharmaceutical composition according to claim 1 or 8, wherein the salt of bromhexine is bromhexine hydrochloride.

10. The pharmaceutical composition according to claim 1, wherein the component (c) is (c8) dimemorfan or a salt thereof. 。

11. The pharmaceutical composition according to claim 1 or 10, wherein the salt of dimemorfan is dimemorfan phosphate hydrochloride.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the dosage form is tablets, powders, fine granules, granules, pills, capsules, oral liquids, or syrups.

13. Use of at least one selected from the group consisting of (c) (c1) carbocisteine, (c2) ambroxol and a salt thereof, (c3) tranexamic acid, (c4) glutethimide 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 for producing a pharmaceutical composition containing (a) ibuprofen and (b) levocetirizine or a salt thereof, wherein (b) levocetirizine or a salt thereof is stabilized.

14. (a) Ibuprofen and (b) levocetirizine or a salt thereof in a pharmaceutical composition, for stabilizing (b ) levocetirizine or a salt thereof, (c) at least one use selected from the group consisting of (c1) carbocysteine, ( c2) ambroxol and salts thereof, (c3) tranexamic acid, (c4) glycyrrhizic acid and salts thereof, (c5) tipepidine and salts thereof, (c6) dextromethorphan and salts thereof, (c7) bromhexine and salts thereof, (c8) dimemorfan and salts thereof, and (c9) methamphetamine and salts thereof.

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