JP7472540B2 - Solid Composition - Google Patents

Description

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

Ibuprofen is effective against rheumatoid arthritis, joint pain and arthritis, neuralgia and neuritis, back and lower back pain, cervicobrachial syndrome, uterine adnexitis, dysmenorrhea, and erythema (erythema nodosum, erythema multiforme, and erythema annulare centrifugally), as well as for reducing fever and relieving pain in acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation accompanied by acute bronchitis). In addition to being used as an antipyretic and analgesic, it is widely used as an antipyretic and analgesic ingredient in general cold medicines (Non-Patent Document 1).

Loratadine is a second-generation histamine H1 receptor antagonist (second-generation antihistamine) that is effective against allergic rhinitis, urticaria, and itching associated with skin diseases (eczema, dermatitis, and cutaneous pruritus), and has been approved as a switch OTC ingredient (Non-Patent Document 2).

Carbocysteine has effects of regulating mucus constituents, inhibiting goblet cell hyperplasia, inhibiting airway inflammation, and normalizing mucosa. It is widely known as a compound with excellent expectorant effects against upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis, and is widely incorporated into general cold medicines and antitussive and expectorant drugs (Non-Patent Document 3).

Ambroxol and its salts have the effects of promoting the secretion of pulmonary surfactant, promoting the secretion of airway fluid, and enhancing ciliary motility. They are widely known as compounds with excellent expectorant effects for acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, and difficulty in expectorating phlegm after surgery. They are also approved as switch OTC ingredients and are included in general cold medicines (Non-Patent Document 4).

Bromhexine and its salts are widely known as compounds with excellent expectorant effects for acute bronchitis, chronic bronchitis, pulmonary tuberculosis, pneumoconiosis, and post-surgery, due to their effects of increasing serous secretion, dissolving and depolymerizing acidic glycoproteins, promoting the secretion of pulmonary surfactant, and enhancing ciliary motility, and are widely incorporated into general cold medicines and antitussive and expectorant drugs (Non-Patent Document 5).

Tranexamic acid has anti-allergic and anti-inflammatory properties and is highly effective against symptoms such as sore throat, redness, congestion, and swelling associated with tonsillitis and pharyngitis, and is therefore widely used in general cold medicines, antitussives and expectorants, and rhinitis medicines (Non-Patent Document 6).

Glycyrrhizic acid and its salts are widely known as ingredients contained in licorice (liquorice), and are known to have anti-inflammatory, anti-allergic, and cell repairing effects, as well as to be effective against digestive ulcers and as an expectorant. They are also widely used as sweeteners and flavoring agents (Non-Patent Document 7).

Tipepidine and its salts have an antitussive effect by suppressing the cough center in the medulla oblongata and reducing cough sensitivity, and also have an expectorant effect by promoting bronchial gland secretion and promoting airway mucosal ciliary epithelial movement. They are widely used to treat cough and difficulty expectorating phlegm associated with colds, upper respiratory tract inflammation (pharyngitis, nasal catarrh), acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 8).

Dextromethorphan and its salts are compounds that directly act on the cough center in the medulla oblongata and have an antitussive effect by suppressing the cough reflex. They are widely used to treat coughs associated with the common cold, acute bronchitis, chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, and upper respiratory tract infections (pharyngitis, nasal catarrh) (Non-Patent Document 9).

Until now, capsules containing ibuprofen, loratadine, and cyclodextrin in a base containing POE sorbitan fatty acid ester, glycerin fatty acid ester macrogol, and water have been known (Patent Document 1). This document shows a method of solving the decrease in solubility of loratadine due to crystallization by the coexistence of cyclodextrin. However, this technology requires a process of dissolving or dispersing loratadine in a base containing a special solvent and water, so that the formulations that can be used are limited to soft capsules, and the manufacturing process is also limited.

To date, it is not known whether there is an interaction between ibuprofen and loratadine that would directly affect the reduction in loratadine content.

Package insert: Brufen Tablets 100/Brufen Tablets 200/Brufen Granules 20% (Revised April 2012 (14th edition)) Kaken Pharmaceutical Co., Ltd. Package insert Claritin Tablets 10 mg / Claritin RediTabs Tablets 10 mg (Revised January 2017 (16th edition)) Bayer Yakuhin, Ltd. Package insert Mucodyne Tablets 250 mg / Mucodyne Tablets 500 mg (Revised December 2016 (16th edition)) Kyorin Pharmaceutical Co., Ltd. Package insert Mucosolvan Tablets 15mg (Revised November 2017 (9th edition)) Teijin Pharma Limited Package insert Bisolvon Tablets 4mg (Revised July 2017 (7th edition)) Sanofi K.K. Package insert: Transamin Tablets 250 mg / Transamin Tablets 500 mg / Transamin Capsules 250 mg / Transamin Powder 50% (Revised April 2013 (10th edition)) Daiichi Sankyo Co., Ltd. Pharmaceutical Additives Dictionary 2016, edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha Package insert Asverin Tablets 10 / Asverin Tablets 20 / Asverin Powder 10% / Asverin Dry Syrup 2% / Asverin Syrup 0.5% / Asverin Syrup "for dispensing" 2% (revised October 2017 (13th edition)) Nipro ES Pharma Co., Ltd. Package insert: Mejicon Tablets 15mg/Mejicon Powder 10% (Revised April 2016 (11th edition)) Shionogi & Co., Ltd.

Patent Publication 2008-143807

The present inventors produced a solid composition containing ibuprofen and loratadine and made the surprising discovery that the loratadine content decreased over time. The present invention has been made in view of the above circumstances, and aims to provide a solid composition that contains ibuprofen and loratadine and in which the decrease in the loratadine content over time is suppressed.

As a result of extensive research, the inventors have unexpectedly found that the decrease in the loratadine content over time can be suppressed by adding at least one selected from the group consisting of 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, and have completed the present invention.

That is, the present invention relates to (1) a solid composition comprising at least one member selected from the group consisting of (a) ibuprofen, (b) loratadine, (c) carbocysteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts;
(2) (c) The solid composition according to (1), wherein the salt of ambroxol is ambroxol hydrochloride.
(3) (c) the solid composition according to (1), wherein the salt of bromhexine is bromhexine hydrochloride;
(4) (c) The solid composition according to (1), wherein the salt of glycyrrhizinic acid is dipotassium glycyrrhizinate;
(5) (c) The solid composition according to (1), wherein the salt of tipepidine is tipepidine hibenzate.
(6) (c) The solid composition according to (1), wherein the salt of dextromethorphan is dextromethorphan hydrobromide hydrate.
(7) The solid composition according to any one of (1) to (6), wherein the dosage form is a tablet, a powder, fine granules, granules, pills, or a capsule.
(8) Use of (c) at least one member selected from the group consisting of carbocysteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts for the production of a solid composition comprising (a) ibuprofen and (b) loratadine, in which the loratadine is stabilized;
(9) Use of (c) at least one member selected from the group consisting of carbocysteine, ambroxol and its salts, 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;
It is.

The present invention makes it possible to provide a solid composition that contains ibuprofen and loratadine and has excellent stability of loratadine.

The ibuprofen used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ O ₂ , and is not particularly limited as long as it is medicamentously acceptable. Ibuprofen can be produced by a known method, or a commercially available product can be used. The content of ibuprofen in the solid composition of the present invention is not particularly limited as long as it is an amount that 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, or 20 to 60% by mass.

The loratadine used in the present invention is a compound represented by _the chemical formula _{C22H23ClN2O2 , and} is not particularly limited as long as it is medicamentously acceptable. Loratadine can be produced by a known method, or a commercially available product can be used. The content of loratadine in the solid composition of the present invention is not particularly limited as long as it is an amount that exhibits its medicinal effect, but is usually 0.001 to 50 mass%, 0.01 to 30 mass%, preferably 0.1 to 10 mass%, 0.2 to 7 mass%.

The carbocysteine used in the present invention is a compound represented by the chemical formula C ₅ H ₉ NO ₄ S, and is not particularly limited as long as it is medicamentously acceptable, but L-carbocysteine is usually used. Carbocysteine can be produced by known methods, or a commercially available product can be used. The content of carbocysteine 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, and preferably 10 to 65% by mass.

The ambroxol used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ Br ₂ N ₂ O or a salt thereof, and one of these may be used alone or two or more may be used in combination. Such ambroxol or a salt thereof may be produced by a known method, or may be a commercially available product. In addition, ambroxol or a salt thereof is not particularly limited as long as it is pharmacologic acceptable, and 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, and the like, and hydrochloride is particularly preferred. The content of ambroxol or a salt thereof in the solid composition of the present invention (when two or more of ambroxol or a salt thereof are contained, the total content thereof, the same applies below) is not particularly limited as long as it is an amount that exhibits its medicinal effect, and 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 _C14H20Br2N2 or a _salt thereof _, and one of these may be used alone or two or more may be used in combination. Such bromhexine or a salt thereof may be produced by a known method, or a commercially available product may be used. In addition, bromhexine or a salt thereof is not particularly limited as long as it is medicamentously acceptable, and 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, and the like, and hydrochloride is particularly preferred. 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 is an amount that exhibits its medicinal effect, but is usually 0.01 to 30 mass%, preferably 0.1 to 30 mass%, and 0.2 to 30 mass%.

The tranexamic acid used in the present invention is a compound represented by the chemical formula C ₈ H ₁₅ NO ₂ , and is not particularly limited as long as it is pharma- ceutical acceptable. Tranexamic acid can be produced by known methods, or commercially available products can be used. The content of tranexamic acid in the formulation of the present invention is not particularly limited as long as it is an amount that exhibits its pharmacological effect, but is usually 1-95% by mass, 3-95% by mass, preferably 5-70% by mass, 8-85% by mass, or 10-65% by mass.

The glycyrrhizic acid or a salt thereof in the present invention is widely known as a component contained in licorice (liquorice) and can be obtained as a commercially available product or produced by a known production method, and may be derived from a herbal medicine.
Glycyrrhizic acid or its salt may be the ingredient itself, or may be contained in herbal medicine or herbal medicine. In particular, licorice (licorice extract or licorice powder) can be used as a herbal medicine containing glycyrrhizic acids, and glycyrrhizic acid exists in licorice in both the form of free acid and salt.
The salt of glycyrrhizinic acid is not particularly limited as long as it is a pharma- ceutically acceptable salt, and examples thereof include trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, and monopotassium glycyrrhizinate. As glycyrrhizinic acid and its salts, preferred are glycyrrhizinic acid and dipotassium glycyrrhizinate, and particularly preferred is dipotassium glycyrrhizinate.
The content of glycyrrhizinic acid and salts thereof in the solid composition of the present invention (when two or more types of glycyrrhizinic acid and salts thereof are contained, the total amount thereof, the same applies below) 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 in terms of glycyrrhizinic acid.

The tipepidine used in the present invention is a compound represented by the chemical formula C ₁₅ H ₁₇ NS ₂ or its salt, and one of these may be used alone or two or more may be used in combination. Such tipepidine or its salt can be produced by a known method or can be commercially available. In addition, the tipepidine or its salt is not particularly limited as long as it is medicamentously acceptable, and examples of the salt include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hybenzate, and carbonate, and the like, and hybenzate is particularly preferred. The content of tipepidine or a salt thereof in the solid composition of the present invention (when two or more of tipepidine or a salt thereof are contained, the total content thereof, the same applies below) is not particularly limited as long as it is an amount that exhibits its medicinal effect, but is usually 0.1 to 50% by mass, 0.1 to 30% by mass, and preferably 1 to 30% by mass.

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. Such dextromethorphan or a salt thereof may be produced by a known method or may be a commercially available product. In addition, dextromethorphan or a salt thereof is not particularly limited as long as it is medicamentously acceptable, and 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, hydrobromide, phenolphthalein salt, and carbonate, and the like, and hydrobromide is particularly preferred. 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 applies hereinafter) is not particularly limited as long as it is an amount that exhibits its medicinal effect, but is usually 0.1 to 50% by mass, preferably 0.5 to 30% by mass.

The compounding ratio of (a) ibuprofen and (b) loratadine is not particularly limited, but is preferably 10 parts by mass or more of ibuprofen per 1 part by mass of loratadine. This is because the content of loratadine decreases significantly over time. The upper limit is not particularly limited, but may be 60 parts by mass or 20 parts by mass.

In terms of the effects of the invention, the compounding ratio of (a) loratadine and (c) carbocisteine is preferably 4 parts by mass or more of carbocisteine per 1 part by mass of loratadine, and may be 25 parts by mass or more. There is no particular upper limit, and it may be 75 parts by mass.

The compounding ratio of (a) loratadine and (c) ambroxol and its salts is preferably 1.5 parts by mass or more of ambroxol and its salts per 1 part by mass of loratadine in terms of the effects of the invention, and may be 4 parts by mass or more. There is no particular upper limit, and it may be 10 parts by mass or 4.5 parts by mass.

The compounding ratio of (a) loratadine and (c) bromhexine and its salts is preferably 0.2 parts by mass or more, more preferably 0.26 parts by mass or more, and may be 0.4 parts by mass or more per 1 part by mass of loratadine in terms of the effects of the invention. There is no particular upper limit, and it may be 4 parts by mass or 1.2 parts by mass.

The compounding ratio of (a) loratadine and (c) tranexamic acid is preferably 4 parts by mass or more of tranexamic acid per 1 part by mass of loratadine in terms of the effects of the invention, and may be 9.3 parts by mass or more. There is no particular upper limit, and it may be 100 parts by mass or 75 parts by mass.

The compounding ratio of (a) loratadine and (c) glycyrrhizinic acid and its salts is preferably 0.1 parts by mass or more, more preferably 1.2 parts by mass or more, and may be 2.4 parts by mass, of glycyrrhizinic acid per 1 part by mass of loratadine in terms of the effects of the invention. There is no particular upper limit, and it may be 10 parts by mass or 6 parts by mass.

The compounding ratio of (a) loratadine and (c) tipepidine and its salts is preferably 1 part by mass or more, more preferably 2.5 parts by mass or more, and may be 4 parts by mass or more, of tipepidine and its salts per 1 part by mass of loratadine in terms of the effects of the invention. There is no particular upper limit, and it may be 10 parts by mass or 7.5 parts by mass.

The compounding ratio of (a) loratadine and (c) dextromethorphan and its salts is preferably 0.5 parts by mass or more, and more preferably 1.6 parts by mass or more, of dextromethorphan and its salts per 1 part by mass of loratadine in terms of the effects of the invention. There is no particular upper limit, and it may be 10 parts by mass, 4 parts by mass, or 5 parts by mass.

The solid composition of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, flow agents, lubricants, cooling agents, colorants, flavorings, fragrances, coating agents, etc., within the qualitative and quantitative ranges that do not impair the effects of the present invention.

Other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretics, analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics, sedatives, vitamins, anti-inflammatory agents, gastric mucosa protectants, herbal medicines, Chinese herbal medicines, caffeines, etc., and the solid composition may contain one or more selected from the group consisting of these.

Examples of excipients that can be incorporated into the solid composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, etc.; disintegrants include low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone, carmellose, carmellose sodium, carmellose calcium, pregelatinized starch, etc.; binders include hydroxypropyl cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc.; flow agents include light anhydrous silicic acid, hydrated silicon dioxide, etc.; lubricants include sucrose fatty acid esters, hardened oils, stearic acid, magnesium stearate, calcium stearate, etc.; and cooling agents include menthol, peppermint oil, eucalyptus oil, etc.

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)), and (c) at least one selected from the group consisting of carbocysteine, ambroxol and its salts, bromhexine and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, and dextromethorphan and its salts (hereinafter also referred to as component (c)) may be simply mixed, or may be granulated after mixing, or the resulting granulated product may be coated. In addition, component (a), component (b), and component (c) do not necessarily have to be contained in the same granulated product. For example, a granulated material containing components (a) and (c) is produced and then mixed with component (b); a granulated material containing components (a) and (b) is produced and then mixed with component (c); a granulated material containing components (a) and (c) and a granulated material containing components (b) and (c) are produced and then the two granulated materials are mixed together; etc.

The granulation method is not particularly limited, and can be produced by wet granulation, dry granulation, melt granulation, etc., but wet granulation is preferred. Wet granulation methods include, for example, stirring granulation, fluidized bed granulation, kneading granulation, extrusion granulation, and rolling fluidized granulation. Conventional formulation additives such as the above-mentioned active ingredients and excipients may be appropriately blended with the obtained granules. The mixture thus obtained can also be compressed into tablets. When producing tablets, they may be produced by direct compression.

The solid composition of the present invention is not particularly limited as long as it is in a dosage form specified in the General Rules for Preparations in the Japanese Pharmacopoeia, but is preferably a tablet, powder, fine granules, granules, pills, or capsule (preferably a hard capsule). Tablets specified in the General Rules for Preparations in the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible and dissolving tablets, film-coated tablets, sugar-coated tablets, dry-coated tablets, and layered tablets. In addition, the tablets may be provided with a score line, or a mark or stamp for improved identification. Furthermore, the tablets of the present preparation may be round or irregularly shaped.

The present invention will be described in more detail below with reference to examples, control examples and comparative examples, but the present invention is not limited to these examples.
(Control Example 1)
A suitable 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 were weighed out and mixed with 1 part by mass of loratadine, and 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 loratadine, 10 parts by mass of ibuprofen and 4 parts by mass of lactose were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.
(Comparative Example 3)
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, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, 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 glycyrrhizinic acid) were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.
(Example 7)
To 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, mixed, and then dried to obtain a composition.

(Test method)
The compositions of the control example, comparative example and examples were stored at 65° C. for 14 days, and the remaining percentage of loratadine in the composition after 14 days was evaluated by HPLC.
Table 1 shows the remaining percentage (%) of loratadine after storage at 65° C. for 14 days.

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

The present invention will be described in more detail below with reference to examples, control examples and comparative examples, but the present invention is not limited to these examples.
(Comparative Example 4)
20 parts by mass of ibuprofen was weighed out and mixed with 1 part by mass of loratadine, and an appropriate amount of a water/alcohol mixture was added thereto, mixed, and then dried to obtain a composition.
(Example 8)
To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 25 parts by mass of L-carbocysteine were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.
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, and an appropriate amount of a water/alcohol mixture was added, 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 parts by mass of bromhexine hydrochloride were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.
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 glycyrrhizinic acid) were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, 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, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.

(Test method)
The compositions of the Comparative Examples and Examples were stored at 65° C. for 14 days, and the remaining percentage of loratadine in the compositions after 14 days was evaluated by HPLC.
Table 2 shows the remaining percentage (%) of loratadine after storage at 65° C. for 14 days.

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

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
(Example 15)
To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 0.2 parts by mass of bromhexine hydrochloride were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.
(Example 16)
To 1 part by mass of loratadine, 20 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, mixed, and then dried to obtain a composition.
(Example 17)
To 1 part by mass of loratadine, 20 parts by mass of ibuprofen and 0.5 parts by mass of dextromethorphan hydrobromide hydrate were weighed and mixed, and an appropriate amount of a water/alcohol mixture was added, mixed, and then dried to obtain a composition.

(Test method)
The compositions of the examples were stored at 65° C. for 14 days, and the remaining percentage of loratadine in the compositions after 14 days was evaluated by HPLC.
Table 3 shows the remaining percentage of loratadine after storage at 65° C. for 14 days.

As shown in Table 3, the decrease in loratadine content observed when ibuprofen and loratadine were combined (Comparative Example 4) was suppressed in Examples 15 to 17, which combined bromhexine hydrochloride, tipepidine hibenzate, and dextromethorphan hydrobromide hydrate.

The following are examples of formulation preparations.
Formulation Examples 1 to 12
Tablets, powders or granules are produced using known techniques for the formulation examples shown in Tables 4 and 5. The resulting powders or granules are filled into hard capsules using known techniques to produce hard capsules.

The present invention makes it possible to provide a solid composition that contains ibuprofen and loratadine and has excellent stability of loratadine.

Claims (4)

A solid composition comprising : (a) ibuprofen; (b) loratadine; and (c) carbocisteine. 2. The solid composition according to claim 1, which is in the form of a tablet, a powder, fine granules, granules, pills, or a capsule. 1. Use of (c) carbocisteine to prepare a solid composition comprising (a) ibuprofen and (b) loratadine, wherein the (b) loratadine is stabilized. 2. Use of (c) carbocisteine to stabilize (b) loratadine in a solid composition comprising (a) ibuprofen and (b) loratadine.