Solid composition

Abstract

To provide a solid composition which suppresses decline in the content of loratadine over time even when containing ibuprofen and loratadine.SOLUTION: A solid composition comprises (a) ibuprofen and (b) loratadine and further (c) at least one kind selected from the group consisting of bromhexine and salts thereof, a tranexamic acid, a glycyrrhizic acid and salts thereof, tipepidine and salts thereof, and dextromethorphan and salts thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid composition containing ibuprofen and loratadine.

Background Art

[0002] Ibuprofen is effective for rheumatoid arthritis, arthralgia and arthritis, neuralgia and neuritis, low back pain, neck -arm syndrome, adnexitis, dysmenorrhea, erythema (erythema nodosum, polymorphic exudative erythema, centrifugal annular erythema), and in addition, is effective for antipyretic and analgesic effects of acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation accompanied by acute bronchitis), and is widely formulated as an antipyretic and analgesic component of a general cold medicine in addition to an antipyretic and analgesic drug (Non-Patent Document 1).

[0003] Loratadine is a second-generation histamine H1 receptor antagonist (second-generation antihistamine drug), and is effective for pruritus associated with allergic rhinitis, urticaria, skin diseases (eczema / dermatitis, skin pruritus), and has been approved as a switch OTC component (Non-Patent Document 2).

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

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

[0006] Bromhexine and its salts are known to have the effects of increasing serous secretion, dissolving and reducing the molecular weight of acidic glycoprotein, promoting the secretion of pulmonary surfactant, and enhancing ciliary movement, and thus have excellent expectorant effects on acute bronchitis , chronic bronchitis, pulmonary tuberculosis, pneumoconiosis, and after surgery, and are widely known as compounds with such effects, and are widely formulated in general cold medicines and cough and expectorant medicines (Non-Patent Document 5). (Non-Patent Document 5).

[0007] 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 nasal drugs, etc. (Non-Patent Document 6).

[0008] Glycyrrhizic acid and its salts are widely known as components contained in licorice, and have anti-inflammatory, anti-allergic, and cell repair effects, etc., and are known to have effects as digestive ulcers and expectorant medicines. Also, they are widely formulated as sweeteners and flavoring agents (Non-Patent Document 7). (Non-Patent Document 7).

[0009] Tipepidine and its salts show an antitussive effect by suppressing the cough center in the medulla oblongata and reducing the cough sensitivity, and at the same time show an expectorant effect by enhancing bronchial gland secretion and enhancing the movement of airway mucosal ciliated epithelium , and are widely used for cough and difficulty in expectorating phlegm associated with colds, upper respiratory tract infections (pharyngolaryngitis, rhinitis catarrhalis), acute bronchitis , chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 8). (Non-Patent Document 8). (Non-Patent Document 8)

[0010] Dextromethorphan and its salts directly act on the cough center in the medulla oblongata and exhibit an antitussive effect by suppressing the cough reflex. As a compound that exhibits an antitussive effect by doing so, it is widely used for coughs associated with colds, acute bronchitis, chronic bronchitis, tracheobronchiectasis, pneumonia, pulmonary tuberculosis, and upper respiratory tract infections (pharyngolaryngitis, rhinitis) (Non-Patent Document 9). (Non-Patent Document 9).

[0011] Hitherto, a capsule preparation in which ibuprofen, loratadine, 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 the crystallization of loratadine by the coexistence of cyclodextrin is shown. However, this technique requires a process of dissolving or dispersing loratadine in a base containing a special solvent and water, the available formulations are limited to soft capsules, and its manufacturing process is also limited.

[0012] Hitherto, it has not been known whether there is an interaction between ibuprofen and loratadine that directly affects the decrease in the content of loratadine.

Prior Art Documents

Non-Patent Documents

[0013]

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

Patent Document

[0014]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0015] When the present inventors produced a solid composition containing ibuprofen and loratadine, they obtained the surprising finding that the content of loratadine decreased over time. The present invention was made in view of the above circumstances and, even when containing ibuprofen and loratadine, the content of loratadine over time The object of the present invention is to provide a solid composition in which a decrease in the content is suppressed. [Means for solving the problem]

[0016] As a result of intensive research by the present inventors, carbocisteine, ambroxol and the like salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, chipe A small amount selected from the group consisting of pididine and its salts, and dextromethorphan and its salts. Surprisingly, the inclusion of at least one of these ingredients suppresses the decrease in loratadine content over time. Thus, the present invention has been completed.

[0017] That is, the present invention (1) (a) Ibuprofen, (b) Loratadine, (c) Carbocisteine, Ambrocin Sol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and and its salts, tipepidine and its salts, and dextromethorphan and its salts. A solid composition comprising at least one selected from the following: (2)(c) The solid composition according to (1), wherein the salt of ambroxol is ambroxol hydrochloride. composition, (3) (c) The solid composition according to (1), wherein the bromhexine salt is bromhexine hydrochloride. thing, (4) (c) The method according to (1), wherein the salt of glycyrrhizinic acid is dipotassium glycyrrhizinate. solid composition, (5) (c) The solid composition according to (1), wherein the salt of tipepidine is tipepidine hibenzate. , (6)(c) The salt of dextromethorphan is dextromethorphan hydrobromide hydrate. The solid composition according to (1), (7) The dosage form is a tablet, a powder, fine granules, granules, pills, or capsules (1) to (6 The solid composition according to any one of (8) containing (a) ibuprofen and (b) loratadine, and (b) loratadine being stabilized For the production of a solid composition, (c) carbocisteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and at least one selected from the group consisting of dextromethorphan and its salts Use, (9) For stabilizing (b) loratadine in a solid composition containing (a) ibuprofen and (b) loratadine, (c) carbocisteine, ambroxol and its salts, brom hexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and at least one selected from the group consisting of dextromethorphan and its salts Use, is. It is.

Advantages of the Invention

[0018] According to the present invention, a solid composition containing ibuprofen and loratadine and having excellent stability of loratadine can be provided.

Modes for Carrying Out the Invention

[0019] The ibuprofen used in the present invention has the chemical formula C 13 H 18 O 2 and is a compound represented by and is not particularly limited as long as it is pharmaceutically acceptable. Ibuprofen can be produced by known methods In addition, commercially available products can be used. The content of ibuprofen in the solid 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.

[0020] The loratadine used in the present invention has the chemical formula C 22 H 23 ClN 2 O 2 and is a compound represented by and is not particularly limited as long as it is pharmaceutically acceptable. Loratadine can be produced by known methods or commercially available products can be used. The content of loratadine in the solid composition of the present invention is not particularly limited as long as it exhibits the drug efficacy, 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 .

[0021] The carbocisteine used in the present invention has the chemical formula C 5 H 9 NO 4 S and is a compound represented by and is not particularly limited as long as it is pharmaceutically acceptable, but usually L-carbocisteine is used. Carbocisteine can be produced by known methods or commercially available products can be used. The content of carbocisteine in the solid 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 65% by mass .

[0022] The ambroxol used in the present invention has the chemical formula C 13 H 18 Br 2 N 2 O and is a compound or a salt thereof, and one of these may be used alone or two or more may be combined for use. Such ambroxol or a salt thereof can be produced by known methods In addition, commercially available products can be used. Ambroxol or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 solid 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. The bromhexine used in the present invention is a compound represented by the chemical formula C H Br N or its salt, and one of these can be used alone or two or more can be used in combination. Such bromhexine or its salts can be produced by known methods. In addition, commercially available products can be used. Bromhexine or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 bromhexine or its salts in the solid composition of the present invention (when two or more of bromhexine or its salts are included) 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.

[0023] In addition, commercially available products can be used. Ambroxol or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 solid 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 0.01~50 mass%, preferably 0.1~30 mass%. 14 H 20 Br 2 N 2 or its salt, and one of these can be used alone or two or more can be used in combination. Such bromhexine or its salts can be produced by known methods. In addition, commercially available products can be used. Bromhexine or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 bromhexine or its salts in the solid composition of the present invention (when two or more of bromhexine or its salts are included) 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. In addition, commercially available products can be used. Bromhexine or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 bromhexine or its salts in the solid composition of the present invention (when two or more of bromhexine or its salts are included) 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. In addition, commercially available products can be used. Bromhexine or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 bromhexine or its salts in the solid composition of the present invention (when two or more of bromhexine or its salts are included) 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. In addition, commercially available products can be used. Bromhexine or its salts are not particularly limited as long as they are pharmaceutically acceptable. The salts include, for example, 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 bromhexine or its salts in the solid composition of the present invention (when two or more of bromhexine or its salts are included) 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. Their total content (the same applies hereinafter) is not particularly limited as long as it shows the drug efficacy, but is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, 0.2 to 30% by mass. It is.

[0024] The tranexamic acid used in the present invention has the chemical formula C 8 H 15 NO 2 and is a compound represented by, and is not particularly limited as long as it is pharmaceutically acceptable. Tranexamic acid can be produced by known methods In addition, commercially available products can be used. The content of tranexamic acid in the preparation of the present invention is not particularly limited as long as it shows the drug efficacy, 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. It is. It is. It is.

[0025] Glycyrrhizic acid or its salt in the present invention is widely known as a component contained in licorice, and can be obtained from commercially available products or produced by known production methods It can be produced, and may be derived from crude drugs. It can be. Glycyrrhizic acid or its salt may be the component itself, or may be contained in crude drugs or traditional Chinese medicines. In particular, as crude drugs 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. and salt forms. It 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, trisodium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, g and so on. Examples include monopotassium lithocholate. As glycyrrhizic acid and its salts, preferably glycyrrhizic acid or dipotassium glycyrrhizate, and particularly preferably dipotassium glycyrrhizate. The content of glycyrrhizic acid and its salts in the solid composition of the present invention (when two or more kinds of glycyrrhizic acid and its salts are included, the total amount thereof, the same applies hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but usually 0.01 to 50% by mass as glycyrrhizic acid, preferably 0.1 to 30% by mass.

[0026] The tipepidine used in the present invention is a compound represented by the chemical formula C 15 H 17 NS 2 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 its salt can be produced by a known method, and commercially available products can also be used. The tipepidine or its salt is not particularly limited as long as it is pharmaceutically acceptable, but the above-mentioned salts include, for example, salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate salt, lactate, malate, citrate, tartrate, benzoate, carbonate, etc., and particularly preferably benzoate. The content of tipepidine or its salt in the solid composition of the present invention (when two or more of tipepidine or its salts are contained, the total content thereof, the same applies hereinafter) is not particularly limited as long as it exhibits the medicinal effect, but usually 0.1 to 50% by mass, 0.1 to 30% by mass, preferably 1 to 30% by mass.

[0027] 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 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, the 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, and phosphate, and acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hydrobromide, phenolphthalein salt, carbonate and other organic acid salts, etc., and particularly preferably hydrobromide. The content of dextromethorphan or a salt thereof in the solid 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 its medicinal effect, but usually it is 0.1 to 50% by mass, preferably 0.5 to 30% by mass. In addition, the mixing ratio of (a) ibuprofen and (b) loratadine is not particularly limited, but preferably 10 parts by mass or more of ibuprofen with respect to 1 part by mass of loratadine. This is because the decrease in the content of loratadine over time becomes remarkable. The upper limit is not particularly limited, and it may be 60 parts by mass or well 20 parts by mass. Furthermore, from the viewpoint of the effects of the invention, the mixing ratio of (a) loratadine and (c) carbocisteine is preferably 4 parts by mass or more of carbocisteine with respect to 1 part by mass of loratadine, and 25 parts by mass or more succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hydrobromide, phenolphthalein salt, carbonate and other organic acid salts, etc., and particularly preferably hydrobromide. The content of dextromethorphan or a salt thereof in the solid 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 its medicinal effect, but usually it is 0.1 to 50% by mass, preferably 0.5 to 30% by mass. salt of loratadine 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, and phosphate, and acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hydrobromide, phenolphthalein salt, carbonate and other organic acid salts, etc., and particularly preferably

[0028] In addition, the mixing ratio of (a) ibuprofen and (b) loratadine is not particularly limited, but preferably 10 parts by mass or more of ibuprofen with respect to 1 part by mass of loratadine. This is because the decrease in the content of loratadine over time becomes remarkable. The upper limit is not particularly limited, and it may be 60 parts by mass or well 20 parts by mass. Furthermore, from the viewpoint of the effects of the invention, the mixing ratio of (a) loratadine and (c) carbocisteine is preferably 4 parts by mass or more of carbocisteine with respect to 1 part by mass of loratadine, and 25 parts by mass or more is also good. The upper limit is not particularly limited, and it may be 60 parts by mass or well 20 parts by mass. is also good.

[0029] In addition, the mixing ratio of (a) loratadine and (c) carbocisteine is preferably 4 parts by mass or more of carbocisteine with respect to 1 part by mass of loratadine, and 25 parts by mass or more is also good. The upper limit is not particularly limited, and it may be 60 parts by mass or well 20 parts by mass. It may also be the above. Also, the upper limit is not particularly limited and may be 75 parts by mass.

[0030] (a) The mixing ratio of loratadine and (c) ambroxol and its salts, from the viewpoint of the effects of the invention is preferably 1.5 parts by mass or more, and may be 4 parts by mass or more of ambroxol and its salts with respect to 1 part by mass of loratadine. Also, the upper limit is not particularly limited and may be 10 parts by mass, and may also be 4.5 parts by mass.

[0031] (a) The mixing ratio of loratadine and (c) bromhexine and its salts is preferably 0.2 parts by mass or more of bromhexine and its salts with respect to 1 part by mass of loratadine from the viewpoint of the effects of the invention and preferably 0.26 parts by mass or more, and may be 0.4 parts by mass or more. The upper limit is not particularly limited and may be 4 parts by mass, and may also be 1.2 parts by mass.

[0032] (a) The mixing ratio of loratadine and (c) tranexamic acid is preferably 4 parts by mass or more of tranexamic acid with respect to 1 part by mass of loratadine from the viewpoint of the effects of the invention and may be 9.3 parts by mass or more. The upper limit is not particularly limited and may be 100 parts by mass, and may also be 75 parts by mass.

[0033] (a) The mixing ratio of loratadine and (c) glycyrrhizic acid and its salts is preferably 0.1 parts by mass or more of glycyrrhizic acid with respect to 1 part by mass of loratadine from the viewpoint of the effects of the invention and more preferably 1.2 parts by mass or more, and may be 2.4 parts by mass. The upper limit is not particularly limited and may be 10 parts by mass, and may also be 6 parts by mass.

[0034] (a) The mixing ratio of loratadine and (c) tipepidine and its salts is preferably 1 part by mass or more of tipepidine and its salts with respect to 1 part by mass of loratadine from the viewpoint of the effects of the invention and preferably 2.5 parts by mass Two or more parts by mass are more preferable, and 4 parts by mass or more may be used. The upper limit is not particularly limited, and it may be 10 parts by mass, or may be 7.5 parts by mass.

[0035] (a) The mixing ratio of loratadine and (c) dextromethorphan and its salts is, from the viewpoint of the effects of the invention, 0.5 part by mass of dextromethorphan and its salts per 1 part by mass of loratadine or more is preferable, and 1.6 parts by mass or more is more preferable. The upper limit is not particularly limited, and it may be 10 parts by mass, or may be 4 parts by mass, 5 parts by mass.

[0036] In the solid composition of the present invention, other active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants, cooling agents, coloring agents, flavoring correcting agents, flavoring agents, fragrances, coating agents, etc. can be blended within a qualitative and quantitative range that does not impair the effects of the present invention.

[0037] Examples of other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretic analgesics, antihistamines agents, antitussives, noscapines, bronchodilators, expectorants, hypnotic 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.

[0038] Examples of excipients that can be incorporated into the solid composition of the present invention include, for example, 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, alpha ​​​​ Examples include dextrin, 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.

[0039] The solid composition 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) loratadine (hereinafter also referred to as component (b)), (c) carbocisteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts. At least one selected from the group consisting of (hereinafter also referred to as component (c)) may be simply mixed, granulated after mixing, or the obtained granulated product may be coated. Further, 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 component (a) and component (c), component (b) is mixed, or after producing a granulated product containing component (a) and component (b), component (c) is mixed, or after producing a granulated product containing component (a) and component (c) and a granulated product containing component (b) and component (c), the two granulated products are mixed, etc.

[0040] The granulation method is not particularly limited either, 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 Examples thereof include the method of fusion granulation, extrusion granulation, and rolling fluidized granulation. Further, the obtained granulated product may be appropriately blended with conventional pharmaceutical additives such as the above-mentioned active ingredient and excipient. Further, the mixture thus obtained can be tabletted into tablets. When producing tablets, they may be produced by the direct tabletting method. The solid composition of the present invention is not particularly limited as long as it is a dosage form defined in the general rules for pharmaceutical preparations of the Japanese Pharmacopoeia, but is preferably tablets, powders, fine granules, granules, pills, or capsules (preferably hard capsules). Tablets defined in the general rules for pharmaceutical preparations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, film-coated tablets, sugar-coated tablets, core tablets, multilayer tablets, and the like. Further, a scored line, a mark for improving distinguishability, or an imprint can be provided on the tablets. Furthermore, the tablets of the present preparation may be round tablets or shaped tablets.

Examples

[0041] (Control Example 1) An appropriate amount of a water / alcohol mixture was added to loratadine, 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 loratadine, an appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 2) 10 parts by mass of ibuprofen and 4 parts by mass of lactose were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 3) Examples thereof include the fusion granulation method, extrusion granulation method, and rolling fluidized granulation method. Further, the obtained granulated product may be appropriately blended with conventional pharmaceutical additives such as the above active ingredient and excipient. Further, the mixture thus obtained can be tabletted into tablets. When producing tablets, they may be produced by the direct tabletting method.

[0042] Hereinafter, examples, control examples, and comparative examples will be given to explain the present invention in more detail, but the present invention is not limited to these examples. (Control Example 1) An appropriate amount of a water / alcohol mixture was added to loratadine, 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 loratadine, an appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 2) 10 parts by mass of ibuprofen and 4 parts by mass of lactose were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 3) 10 parts by mass of ibuprofen and 4 parts by mass of lactose were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Comparative Example 4) (Comparative Example 5) To 1 part by mass of loratadine, 10 parts by mass of ibuprofen and 4 parts by mass of crystalline cellulose 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 1) To 1 part by mass of loratadine, 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 mixed, and then dried to obtain a composition. (Example 2) To 1 part by mass of loratadine, 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 mixed, and then dried to obtain a composition. (Example 3) To 1 part by mass of loratadine, 10 parts by mass of ibuprofen and 4 parts by mass of bromhexine 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. (Example 4) To 1 part by mass of loratadine, 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 mixed, and then dried to obtain a composition. (Example 5) To 1 part by mass of loratadine, 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 water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition. (Example 6) To 1 part by mass of loratadine, 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 mixed, and then dried to obtain a composition. (Example 7) For 1 part by mass of loratadine, 10 parts by mass of ibuprofen and 4 parts by mass of dextromethorphan hydrobromide hydrate were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto and mixed and then dried to obtain a composition.

[0043] (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 loratadine in the composition after 14 days was evaluated by HPLC method. Table 1 shows the residual rate (%) of loratadine after storage at 65 °C for 14 days.

[0044]

Table 1

[0045] As shown in Table 1, in Comparative Examples 1 to 3 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 1 to 7 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, the decrease in the content of loratadine could be suppressed.

[0046] 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 etc. (Comparative Example 4) For 1 part by mass of loratadine, 20 parts by mass of ibuprofen were weighed and mixed, and an appropriate amount of a water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition. (Example 8) For 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 25 ​​​​Weighed and mixed the mass parts, added an appropriate amount of water / alcohol mixture thereto, mixed, and then dried to obtain a composition. The product was obtained. (Example 9) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 1 .5 parts by mass of ambroxol hydrochloride were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 10) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 0. 4 part by mass of bromhexine hydrochloride were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 11) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 9.3 parts by mass of tranexamic acid were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition thereof. (Example 12) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 2 parts by mass of dipotassium glycyrrhizinate (1.2 parts by mass as glycyrrhizic acid) were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 13) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 2 .5 parts by mass of tipepidine hibenzate were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto, mixed, and then dried to obtain a composition. (Example 14) To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 1.6 parts by mass of dextromethorphan hydrobromide hydrate were weighed and mixed, an appropriate amount of water / alcohol mixture was added thereto and mixed, and then dried to obtain a composition.

[0047] (Test method) The compositions of the comparative examples and the examples were stored at 65 °C for 14 days, and the residual ratio of loratadine in the compositions after 14 days was evaluated by HPLC method. The residual ratio of loratadine in the compositions after 14 days was evaluated by HPLC method. Table 2 shows the residual ratio (%) of loratadine after storage at 65 °C for 14 days.

[0048]

Table 2

[0049] As shown in Table 2, in Comparative Example 4 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 8 to 14 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, a decrease in the content of loratadine could be suppressed. As shown in Table 2, in Comparative Example 4 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 8 to 14 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, a decrease in the content of loratadine could be suppressed. As shown in Table 2, in Comparative Example 4 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 8 to 14 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, a decrease in the content of loratadine could be suppressed. As shown in Table 2, in Comparative Example 4 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 8 to 14 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, a decrease in the content of loratadine could be suppressed. As shown in Table 2, in Comparative Example 4 in which ibuprofen and loratadine were blended, a decrease in the content of loratadine was confirmed. On the other hand, in Examples 8 to 14 in which L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibenzate and dextromethorphan hydrobromide hydrate were blended, a decrease in the content of loratadine could be suppressed.

[0050] 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. 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. (Example 15) 20 parts by mass of ibuprofen and 0.2 parts by mass of bromhexine hydrochloride were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. 20 parts by mass of ibuprofen and 0.2 parts by mass of bromhexine hydrochloride were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. 20 parts by mass of ibuprofen and 0.2 parts by mass of bromhexine hydrochloride were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. (Example 16) 20 parts by mass of ibuprofen and 1 part by mass of tipepidine hibenzate were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. 20 parts by mass of ibuprofen and 1 part by mass of tipepidine hibenzate were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. 20 parts by mass of ibuprofen and 1 part by mass of tipepidine hibenzate were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. (Example 17) 20 parts by mass of ibuprofen and dextromethorphan hydrobromide were weighed and mixed with 1 part by mass of loratadine, an appropriate amount of a water / alcohol mixture was added thereto, and the mixture was dried to obtain a composition. Weighed and mixed 0.5 parts by mass of the hydrogen acid salt hydrate, and added an appropriate amount of a water / alcohol mixture thereto. After mixing, it was dried to obtain a composition.

[0051] (Test method) The composition of the example was stored at 65°C for 14 days, and the residual rate of loratadine in the composition after 14 days was evaluated by the HPLC method. Table 3 shows the loratadine residual rate (%) after storage at 65°C for 14 days.

[0052]

Table 3

[0053] As shown in Table 3, the decrease in the content of loratadine confirmed when ibuprofen and loratadine were formulated (Comparative Example 4 ) was suppressed in Examples 15 to 17 formulated with bromhexine hydrochloride, tipepidine hibenzate, and dextromethorphan hydrobromide hydrate.

[0054] The following are formulation preparation examples. Formulation Examples 1 to 12 For the formulation examples described in Tables 4 and 5, tablets, powders, or granules were manufactured using known techniques. The obtained powder or granule was filled into hard capsules using known techniques to manufacture hard capsule preparations.

[0055]

Table 4

[0056]

Table 5

Industrial Applicability

[0057] According to the present invention, there is provided a solid composition containing ibuprofen and loratadine and having excellent stability of loratadine. ​

Claims

1. A solid composition comprising at least one member selected from the group consisting of (a) ibuprofen, (b) loratadine, (c) bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts.

2. 2. The solid composition according to claim 1, wherein the salt of bromhexine is bromhexine hydrochloride. 。

3. (c) The solid composition according to claim 1, wherein the salt of glycyrrhizinic acid is dipotassium glycyrrhizinate. Form composition.

4. 2. The solid composition according to claim 1, wherein (c) the salt of tipepidine is tipepidine hibenzate.

5. (c) The salt of dextromethorphan is dextromethorphan hydrobromide hydrate. The solid composition according to claim 1 .

6. 6. The solid composition according to claim 1, which is in the form of a tablet, a powder, fine granules, granules, a pill, or a capsule.

7. 1. Use of (c) at least one member selected from the group consisting of bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts, for producing a solid composition containing (a) ibuprofen and (b) loratadine, in which the loratadine is stabilized.

8. 1. Use of (c) at least one member selected from the group consisting of bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts, for stabilizing (b) loratadine in a solid composition comprising (a) ibuprofen and (b) loratadine.

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