Pharmaceutical composition

Abstract

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

Description

[Technical Field]

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

[0002] Ibuprofen is used for rheumatoid arthritis, joint pain and arthritis, neuralgia and neuritis, back and lower back pain, and neck pain. Arm syndrome, adnexitis, dysmenorrhea, erythema (erythema nodosum, erythema multiforme, centrifugal annular erythema) It is effective against erythema, as well as acute upper respiratory tract infections (including acute upper respiratory tract infections accompanied by acute bronchitis). It is also effective for fever and pain relief, and is widely used not only as an antipyretic and analgesic but also as an antipyretic and analgesic ingredient in combination cold medicines. (Non-patent document 1)

[0003] Levocetirizine and its salts are second-generation histamine H1 receptor antagonists (second-generation antihistamines) As a vitamin D drug, it is used for allergic rhinitis, urticaria, and skin diseases (eczema, dermatitis, pruritus). It is effective for itching associated with (Non-Patent Literature 2). Levocetirizine is cetirizine hydrochloride This is a method of optically resolving only the R-enantiomer, which has stronger biological activity, among the optical isomers. ru.

[0004] Carbocysteine ​​has mucus component regulating effects, inhibits goblet cell hyperplasia, and suppresses airway inflammation. It has both a normalizing effect on the mucous membranes and is used for upper respiratory tract infections (pharyngitis, laryngitis), acute bronchitis, and bronchial asthma. As a compound with excellent expectorant effects against respiratory problems, chronic bronchitis, bronchiectasis, and pulmonary tuberculosis. It is widely known and is commonly used in combination cold medicines and cough suppressants / expectorants (Non-Patent Literature 3).

[0005] Ambroxol and its salts promote the secretion of pulmonary surfactants and airway fluid. It has the effect of promoting ciliary movement and is used in acute bronchitis, bronchial asthma, chronic bronchitis, and bronchiectasis. Compounds that have excellent expectorant effects against sphincter syndrome, pulmonary tuberculosis, pneumoconiosis, and difficulty expectorating sputum after surgery. It is widely known as such, and is also approved as a switch OTC ingredient, used in general cold medicines and cough suppressants / expectorants. It is included in medicines (Non-Patent Document 4).

[0006] Tranexamic acid has anti-allergic and anti-inflammatory effects, and is used to relieve pharyngeal pain in tonsillitis and pharyngitis. Because it shows excellent efficacy against symptoms such as redness, congestion, and swelling, it is used as a general cold medicine and cough suppressant / expectorant. It is widely used in rhinitis medications and the like (Non-Patent Document 5).

[0007] Glycyrrhizic acid and its salts are widely known as components found in licorice. It has anti-inflammatory, anti-allergic, and cell repair effects, and is used as a remedy for peptic ulcers and as an expectorant. It is known to have the following effects. It is also used as a sweetener and flavoring agent (non-patent document). Reference 6).

[0008] Tipepidine and its salts suppress coughs by inhibiting the cough center in the medulla oblongata and reducing cough sensitivity. In addition to exerting its effects, it enhances bronchial gland secretion and increases the movement of ciliated epithelium in the airway mucosa. Compounds that exhibit expectorant effects include those used for the common cold, upper respiratory tract infections (pharyngitis, rhinitis), acute bronchitis, etc. It is widely used for cough and difficulty expectorating sputum associated with chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis. (Non-patent document 7)

[0009] Dextromethorphan and its salts act directly on the cough center in the medulla oblongata, suppressing the cough reflex. As a compound that exhibits antitussive effects, it is used for the common cold, acute bronchitis, chronic bronchitis, and trachea It is widely used for cough associated with bronchiectasis, pneumonia, pulmonary tuberculosis, and upper respiratory tract infections (pharyngitis, rhinitis). disclosed (Non-Patent Document 8).

[0010] Bromhexine hydrochloride has effects of increasing serous secretion, dissolving and reducing molecular weight of acid glycoprotein, and acting on pulmonary surface by promoting secretion of active substances and enhancing ciliary movement, it is widely known as a compound that has excellent expectorant effects for acute bronchitis, chronic bronchitis, pulmonary tuberculosis, pneumoconiosis and post-operative conditions, and is widely compounded in cold remedies and antitussive and expectorant drugs (Non-Patent Document 9).

[0011] Dimemorfan phosphate and salts thereof are compounds that directly act on the cough center in the medulla oblongata to exert antitussive effects and are widely used for antitussive treatment associated with upper respiratory tract inflammation, pneumonia, acute bronchitis, pulmonary tuberculosis, silicosis and silicotuberculosis, lung cancer, and chronic bronc hitis (Non-Patent Document 10).

[0012] Methylephedrine and salts thereof are sympathomimetic excitatory drugs, and exert bronchodilatory effects via β2 receptor stimulation, and are widely compounded in cold remedies and antitussive and expectorant drugs (Non-Patent Document 11 ).

[0013] Heretofore, a capsule prepared by blending ibuprofen, cetirizine hydrochloride and cyclodextrin into a base containing POE sorbitan fatty acid ester, macrogol glycerol fatty acid ester and water is known (Patent Document 1). This document discloses a method for solving the problem of reduced solubility caused by crystallization of cetirizine hydrochloride by coexistence of cyclodextrin. A method for solving the reduction in solubility caused by crystallization via the coexistence of cyclodextrin is disclosed in this document. However, this technology requires a step of dissolving or dispersing cetirizine hydrochloride in a base containing a special solvent and water, available preparations are limited to soft capsules, and the manufacturing process was also limited.

[0014] To date, between ibuprofen and levocetirizine or its salts, levocetirizine or Whether or not an interaction occurs that directly affects the decrease in salt content is unknown. I haven't done that. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Package insert for Brufen Tablets 100mg / Brufen Tablets 200mg / Brufen Granules 20% (Revised April 2012 (14th Edition)) Kaken Pharmaceutical Co., Ltd. [Non-Patent Document 2] Package insert for Xyzal Tablets 5mg (Revised August 2019 (9th Edition)) GlaxoSmithKline K.K. [Non-Patent Document 3] Package insert for Mucodyne Tablets 250mg / Mucodyne Tablets 500mg (Revised December 2016 (16th Edition)) Kyorin Pharmaceutical Co., Ltd. [Non-Patent Document 4] Package insert for Mucosolvan Tablets 15mg (Revised November 2017 (9th Edition)) Teijin Pharma Limited [Non-Patent Document 5] Package insert for Transamin Tablets 250mg / Transamin Tablets 500mg / Transamin Capsules 250mg / Transamin Powder 50% (Revised April 2013 (10th Edition)) Daiichi Sankyo Co., Ltd. [Non-Patent Document 6] Dictionary of Pharmaceutical Additives 2016, edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo Co., Ltd. [Non-Patent Document 7] Package insert for Asvelin Tablets 10 / Asvelin Tablets 20 / Asvelin Powder 10% / Asvelin Dry Syrup 2% / Asvelin Syrup 0.5% / Asvelin Syrup "For Dispensing" 2% (Revised October 2017 (13th Edition)) Nipro ES Pharma Co., Ltd. [Non-Patent Document 8] Package insert for Mejicon Tablets 15mg / Mejicon Powder 10% (Revised April 2016 (11th Edition)) Shionogi & Co., Ltd. [Non-Patent Document 9] Package insert for Bisolvon Tablets 4mg (Revised July 2017 (7th Edition)) Sanofi K.K. [Non-Patent Document 10] Package insert for Astomin Tablets (Revised October 2015 (10th Edition)) Orphan Pacific Co., Ltd. [Non-Patent Document 11] Package insert for Fuscobron Combination Syrup (Revised July 2019 (13th Edition)) Takeda Teva Pharma Co., Ltd. [Patent Documents]

[0016] [Patent Document 1] Japanese Patent Publication No. 2008-143807 [Overview of the project] [Problems that the invention aims to solve]

[0017] The present inventors have developed a pharmaceutical composition containing ibuprofen and levocetirizine or a salt thereof. Upon manufacturing, a surprising finding was discovered: the content of levocetirizine or its salts decreases over time. The present invention was made in view of the above circumstances, and involves ibuprofen and levocetirizine. Or, even if it contains a salt thereof, the decrease in the content of levocetirizine or its salt over time is suppressed. The objective is to provide a pharmaceutical composition. [Means for solving the problem]

[0018] Therefore, as a result of diligent research by the present inventors, carbocysteine, ambroxol and so Salts of , tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, dextrose Lomethorphan and its salts, bromhexine and its salts, dimemorphan and its salts, and Furthermore, it contains at least one selected from the group consisting of methyl ephedrine and its salts. Surprisingly, we discovered that the time-dependent decrease in the content of levocetirizine hydrochloride was suppressed, and this is the first discovery. This led to the completion of the Ming Dynasty.

[0019] In other words, the present invention (1) (a) ibuprofen, (b) levocetirizine or a salt thereof, (c) (c1) carbo (c2) Cysteine, (c3) Ambroxol and its salts, (c4) Tranexamic acid, (c4) Glycyrrhizic acid and its salts, (c5) Tipepidine and its salts, (c6) Dextromethorphan (c7) Ruphan and its salts, (c8) Bromhexine and its salts, (c8) Dimemorphan and At least one selected from the group consisting of (c9) methyl ephedrine and its salts A pharmaceutical composition characterized by containing one type, (2)(b) The pharmaceutical composition described in (1) where the salt of levocetirizine is levocetirizine hydrochloride. thing, (3) The pharmaceutical composition described in (1), wherein component (c) is (c1) carbocysteine. (4) The pharmaceutical compound described in (1) wherein component (c) is (c2) ambroxol or a salt thereof. finished product, (5) The salt of ambroxol is ambroxol hydrochloride as described in (1) or (4) Pharmaceutical compositions, (6) The pharmaceutical composition according to (1), wherein component (c) is (c3) tranexamic acid. (7) The pharmaceutical compound described in (1) wherein component (c) is (c4) glycyrrhizic acid or a salt thereof. finished product, (8) The salt of glycyrrhizic acid is dipotassium glycyrrhizinate as described in (1) or (7) The listed pharmaceutical composition, (9) The pharmaceutical composition according to (1), wherein component (c) is (c5) tipepidine or a salt thereof. (10) The pharmaceutical product described in (1) or (9) wherein the salt of tipepidine is tipepidine hibenzate. composition, (11) The component (c) is (c6) dextromethorphan or a salt thereof as described in (1) Pharmaceutical composition, (12) The salt of dextromethorphan is dextromethorphan hydrobromide hydrate. The pharmaceutical composition described in (1) or (11), (13) The pharmaceutical combination described in (1) wherein component (c) is (c7) bromhexine or a salt thereof. finished product, (14) The salt of bromhexine is bromhexine hydrochloride as described in (1) or (13). Pharmaceutical compositions, (15) The pharmaceutical combination described in (1) wherein component (c) is (c8) dimemorphan or a salt thereof. finished product, (16) Dimemorphan salt is dimemorphanline hydrochloride as described in (1) or (15) The listed pharmaceutical composition, (17) The medical (1) wherein component (c) is (c9) methyl ephedrine or a salt thereof. Pharmaceutical composition, (18) The salt of methyl ephedrine is dl-methyl ephedrine hydrochloride (1) or ( 17) The pharmaceutical composition described above, (19) The dosage form is a tablet, powder, fine granules, granules, pill, capsule, oral liquid, or syrup. A pharmaceutical composition described in any of (1) to (18), which is a suppository. (20) (a) ibuprofen and (b) levocetirizine or a salt thereof, (b) levocetirizine (c)(c1) for manufacturing a stabilized pharmaceutical composition of cetirizine or a salt thereof, Bocysteine, (c2) Ambroxol and its salts, (c3) Tranexamic acid, (c4 (c5) Glycyrrhizic acid and its salts, (c6) Tipepidine and its salts, (c6) Dextromethorrhea Turpan and its salts, (c7) Bromhexine and its salts, (c8) Dimemorphan and A minimum of the group consisting of (c9) methyl ephedrine and its salts Both use one type, (21) A pharmaceutical composition comprising (a) ibuprofen and (b) levocetirizine or a salt thereof (b) levocetirizine or a salt thereof for stabilizing (c) (c1) carbocyst (c2) Ambroxol and its salts, (c3) Tranexamic acid, (c4) Glycyrrhizic acid (c5) Rhizomezyl acid and its salts, (c6) Tipepidine and its salts, (c6) Dextromethorphan and its salts, (c7) bromhexine and its salts, (c8) dimemorphan and its salts, (c9) At least one selected from the group consisting of methyl ephedrine and its salts use, That is the case. [Effects of the Invention]

[0020] The present invention provides a product containing ibuprofen and levocetirizine or a salt thereof, and levocetirizine This makes it possible to provide pharmaceutical compositions with excellent stability of ions or their salts. [Modes for carrying out the invention]

[0021] The ibuprofen used in this invention has the chemical formula C 13 H 18 A compound represented by O2 There are no particular limitations as long as it is medically acceptable. Ibuprofen is administered by known methods. In addition to being manufactured by the present invention, commercially available products can also be used. The amount of ibuprofen contained is not particularly limited as long as it is in an amount that exhibits its medicinal effect, but is usually 5- 95% by mass, preferably 10-90% by mass, 15-85% by mass, 15-80% by mass, 20 The masses are approximately 70% and 20-60%.

[0022] The levocetirizine used in this invention has the chemical formula C 21 H 25 The compound represented by ClN2O3 It is a substance, and there are no particular limitations as long as it is medically acceptable. Also, levocetirizine The salt is not particularly limited as long as it is medicinally acceptable, but examples include hydrochloride salts and hydrobromic acid. Salts of inorganic acids such as salts and phosphates, as well as acetates, oxalates, malons, succinates, and fumes. Organic acids such as malates, maleates, lactates, citrates, tartrates, and carbonates. Examples include salts, and hydrochloride salts are particularly preferred. Levocetirizine or its salts are known. In addition to being manufactured by law, commercially available products can be used. The content of levocetirizine or its salts (two or more of levocetirizine or its salts) If present, the total amount of those substances (the same applies hereinafter) is particularly important as long as it is in an amount that demonstrates its medicinal effect. Not limited to, but typically 0.001 to 50% by mass, 0.01 to 30% by mass, preferably 0. The amounts are 1-10% by mass and 0.2-7% by mass.

[0023] The carbocysteine ​​used in this invention is a compound represented by the chemical formula C5H9NO4S. Yes, and there are no particular limitations as long as it is medically acceptable, but usually L-carbocyste Carbocysteine ​​is used. Carbocysteine ​​can be produced by known methods, or commercially available. It can be used. The content of carbocysteine ​​in the pharmaceutical composition of the present invention is particularly Not limited to, but usually 1-95% by mass, 5-85% by mass, preferably 10-70% by mass. be.

[0024] The ambroxol used in this invention has the chemical formula C 13 H 18 Represented by Br2N2O These are compounds or salts thereof, and can be used individually or in combination of two or more. It may be used. Such ambroxol or its salts can be prepared by known methods. In addition, commercially available products can be used. Also, ambroxol or its salts are used in medicine. The salt is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include hydrochloride salts and bromide salts. Salts of inorganic acids such as hydrogenates and phosphates, and acetates, oxalates, malons, and succinates. fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Examples include organic salts, and hydrochloride salts are particularly preferred. Ambroxol content or the content of its salts (containing two or more of the following: ambroxol or its salts) If present, the total amount of those substances (hereinafter the same) is not limited to the amount that demonstrates the medicinal effect. Although not fixed, it is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass.

[0025] The tranexamic acid used in this invention has the chemical formula C8H 15 The compound represented by NO2 There are no particular limitations as long as it is medically acceptable. Tranexamic acid is administered by known methods. In addition to being manufactured by the present invention, commercially available products can also be used. The amount of itranexamic acid contained is not particularly limited as long as it is in an amount that exhibits its medicinal effect, but usually 1 ~95% by mass, 3~95% by mass, preferably 5~70% by mass, 8~85% by mass, 10~6% by mass It is 5% by mass.

[0026] In this invention, glycyrrhizic acid or its salt is a component contained in licorice. It is widely known and can be obtained commercially or manufactured by known manufacturing methods. It may be derived from herbal medicine. Glycyrrhizic acid or its salt is the component itself. may be present, or may be contained in crude drugs or traditional Chinese medicines. In particular, crude drugs containing glycyrrhizic acids can use Glycyrrhiza (Glycyrrhiza extract or Glycyrrhiza powder), and in Glycyrrhiza , glycyrrhizic acid exists in both free acid and salt forms. There is no particular limitation on salts of glycyrrhizic acid as long as they are pharmaceutically acceptable salts, and examples include trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, monopotassium glycyrrhizinate monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, monopotassium glycyrrhizinate can be mentioned. As glycyrrhizic acid and salts thereof, preferred are glycyrrhizic acid and dipotassium glycyrrhizinate, and particularly preferred is dipotassium glycyrrhizinate . The content of glycyrrhizic acid and salts thereof in the pharmaceutical composition of the present invention (when two or more types of glycyrrhizic acid and salts thereof are included, it refers to the total amount 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 as glycyrrhizic acid , preferably 0.1 to 30% by mass.

[0027] Tipecpidine used in the present invention is a compound represented by the chemical formula C 15 H 17 NS2 or a salt thereof, and one of these may be used alone or two or more may be used in combination or a salt thereof, and one of these may be used alone or two or more may be used in combination . Such tipecpidine or a salt thereof can be produced by a known method, and a commercially available product can be used. There is no particular limitation on tipecpidine or a salt thereof as long as it is pharmaceutically acceptable , and examples of the salt include inorganic acid salts such as hydrochloride, hydrobromide and phosphate, and acetates, oxalates, malonates, succinates, fumarates, maleic acid inorganic acid salts, and acetates, oxalates, malonates, succinates, fumarates, maleic acid Organic salts such as salts, lactates, malates, citrates, tartrates, hibenzates, and carbonates. Examples include hibenzates, and particularly preferred are hibenzates. Tipep in the pharmaceutical composition of the present invention Content of din or its salts (if two or more of tipepidine or its salts are included) The total amount of these substances (hereinafter the same) is not particularly limited as long as it is in an amount that exhibits its medicinal effect, The amount is typically 0.1 to 50% by mass, 0.1 to 30% by mass, preferably 1 to 30% by mass.

[0028] The dextromethorphan used in this invention has the chemical formula C 18 H 25 NO is indicated These are compounds or salts thereof, and can be used individually or in combination of two or more. It may be present. Such dextromethorphan or a salt thereof may be prepared by known methods. It can be manufactured, or commercially available products can be used. Also, dextromethorphan or The salt is not particularly limited as long as it is medicinally acceptable, but the salt mentioned above is, for example, salt Salts of inorganic acids such as acid salts, hydrobromide salts, and phosphate salts, as well as acetate salts, oxalates, malonates, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, Examples include hydrobromide salts, phenolphthalein salts, and organic acid salts such as carbonates, and are particularly preferred. It is a hydrobromide salt. Dextromethorphan or its in the pharmaceutical composition of the present invention Salt content (if two or more of dextromethorphan or its salts are present) The total amount of these substances (hereinafter the same) is not particularly limited as long as it is in an amount that exhibits its medicinal effect, The amount is usually 0.1 to 50% by mass, preferably 0.5 to 30% by mass.

[0029] The bromhexine used in this invention has the chemical formula C 14 H20 The compound represented by Br2N2 A substance or its salt, which can be used individually or in combination of two or more. It is also possible to produce such bromhexine or its salts by known methods. In addition, commercially available products can be used. Furthermore, bromhexine or its salts are pharmaceutically permitted. The salt is not particularly limited as long as it is acceptable, but examples of salts include hydrochloride salts and hydrobromide salts. , phosphates and other inorganic acid salts, as well as acetates, oxalates, malons, succinates, fumarates Organic acid salts such as salts, maleates, lactates, malates, citrates, tartrates, and carbonates. Examples include the above, and particularly preferably a hydrochloride salt. Bromhexyl Content of bromhexine or its salts (when two or more of bromhexine or its salts are present) The total amount of these substances (hereinafter the same) is not particularly limited as long as it is in an amount that demonstrates its medicinal effect. Typically 0.01 to 30% by mass, preferably 0.1 to 30% by mass, or 0.2 to 30% by mass. ru.

[0030] The dimemorphan used in this invention has the chemical formula 18 H 25 This is a compound represented by NC, There are no particular limitations as long as it is medically acceptable. Also, dimemorphan salt is medically acceptable. While not particularly limited as long as it is permissible, examples include hydrochloride salts, hydrobromide salts, and phosphoric acid. Salts of inorganic acids such as salts, and acetates, oxalates, malonates, succinates, fumarates, ma Laitates, lactates, malates, citrates, tartrates, hibenzates, carbonates, etc. Examples include methyl salts, and phosphates are particularly preferred. Dimemorphan or its salts are public It can be manufactured by the methods described in the present invention, or commercially available products can be used. Content of dimemorphan or its salts in (two of dimemorphan or its salts) If any of the above are present, their total content (hereinafter the same) is the amount that demonstrates the medicinal effect. However, it is not particularly limited, but is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass. ru.

[0031] The methyl ephedrine used in this invention has the chemical formula C 11 H 17 Compounds indicated by NO Yes, and there are no particular limitations as long as it is medically acceptable. Also, methyl ephedrine The salt is not particularly limited as long as it is medicinally acceptable, but examples include hydrochloride salts and hydrobromic acid. Salts of inorganic acids such as salts and phosphates, as well as acetates, oxalates, malons, succinates, and fumes. Malates, maleates, lactates, citrates, tartrates, hibenzates, charcoal Examples include organic salts such as salts, and hydrochloride salts are particularly preferred. Methyl ephedrine or The salt can be produced by known methods, or a commercially available salt can be used. The amount of methyl ephedrine or its salt in the pharmaceutical composition (methyl ephedrine or If two or more of those salts are included, the total amount of those salts (the same applies hereinafter) is... The amount is not particularly limited as long as it shows the medicinal effect, but is usually 0.01 to 50% by mass, preferably 0 It is 0.05-10% by mass.

[0032] Furthermore, the ratio of (a) ibuprofen to (b) levocetirizine or its salt is not particularly limited. However, if 1 part by mass of levocetirizine or its salt is used, then 10 parts by mass or more of ibuprofen should be used. This is preferable because it leads to a significant decrease in the content of levocetirizine and its salts over time. There are no particular limitations, but 120 parts by mass, 60 parts by mass, 20 parts by mass, 40 parts by mass are also acceptable. It could also be a department.

[0033] Furthermore, the ratio of (a) levocetirizine and its salts to (c) carbocysteine ​​is as described in the invention. From the standpoint of effectiveness, 1 part by mass of levocetirizine and its salt is mixed with 4 parts by mass of carbocysteine. The above is preferable, but it may be 25 parts by mass or more, or 50 parts by mass or more. Furthermore, the upper limit is not particularly limited. Alternatively, it may be 75 parts by mass or 150 parts by mass.

[0034] (a) Levocetirizine and its salts, and (c) Ambroxol and its salts, are in the following proportions: From the viewpoint of the effects of the invention, 1 part by mass of levocetirizine and its salt, ambroxol and so The amount of salt is 1.5 parts by mass or more, preferably 3 parts by mass or more, and may be 4 parts by mass or more. Also, the upper limit The amount is not particularly limited and may be 9 parts by mass or 4.5 parts by mass.

[0035] (a) Levocetirizine and its salts, and (c) Tranexamic acid are in the following proportions: For 1 part by mass of benzoyl peroxide and its salt, 4 parts by mass or more of tranexamic acid is preferred from the viewpoint of the effects of the invention. Furthermore, it may be 9.3 parts by mass or more, or 18.6 parts by mass or more. There is no particular upper limit, The amount may be 50 parts by mass, or 100 parts by mass, 75 parts by mass, or 56 parts by mass.

[0036] (a) Levocetirizine and its salts, and (c) Glycyrrhizic acid and its salts, are in the following proportions: To 1 part by mass of levocetirizine and its salt, glycyrrhizic acid is used from the viewpoint of the effects of the invention. Preferably 0.12 parts by mass or more, 0.2 parts by mass or more, and more preferably 1.2 parts by mass or more. It may be 2.4 parts by mass or more. There is no particular upper limit, and it may be 12 parts by mass, and 10 Parts by mass, or 8 parts by mass may also be used.

[0037] (a) Levocetirizine and its salts and (c) Tipepidine and its salts are in the following proportions: For 1 part by mass of tyridine and its salt, 1 part by mass of tipepidine and its salt is added in order to achieve the effects of the invention. Parts or more, preferably 2 parts by mass or more, and preferably 2.5 parts by mass or more, 4 parts by mass or more, or 5 parts by mass or more. It is preferable. Furthermore, the upper limit is not particularly limited and may be 15 parts by mass, 10 parts by mass, 7. It may be 5 parts by mass.

[0038] (a) Levocetirizine and its salts, and (c) Dextromethorphan and its salts The ratio is 1 part by mass of levocetirizine and its salt, with dextromethorhynchol used in order to achieve the effects of the invention. Fan and its salt are preferably in amounts of 0.5 parts by mass or more, 0.8 parts by mass or more, or 1 part by mass or more, 0.6 parts by mass or more, more preferably 3.2 parts by mass or more. Furthermore, there is no particular upper limit, 10 It may be expressed as parts by mass, or as 5 parts by mass.

[0039] (a) Levocetirizine and its salts, and (c) Bromhexine and its salts are in the following proportions: To 1 part by mass of bosetirizine and its salt, bromhexine and its salt are used in order to achieve the effects of the invention. Preferably, the amount is 0.1 parts by mass or more, 0.2 parts by mass or more, 0.8 parts by mass or more, and 1.2 parts by mass or less. The above is more preferable, and may be 2.4 parts by mass or more. The upper limit is not particularly limited, and is 12 parts by mass. It may also be 10 parts by mass or 8 parts by mass.

[0040] (a) Levocetirizine and its salts, and (c) Dimemorphan and its salts are in the following proportions: To 1 part by mass of bosetiridine and its salt, dimemorphan and its salt are used in order to achieve the effects of the invention. Preferably, the amount is 0.5 parts by mass or more, 1 part by mass or more, 2 parts by mass or more, or 4 parts by mass or more. The limit is not particularly limited; it may be 10 parts by mass, 9.6 parts by mass, or 4 parts by mass.

[0041] (a) The ratio of levocetirizine and its salts to (c) methyl ephedrine and its salts is , 1 part by mass of levocetirizine and its salt, methyl ephedrine and The amount of bisono salt is preferably 0.5 parts by mass or more, 1 part by mass or more, 2 parts by mass or more, or 4 parts by mass or more. Furthermore, there is no particular upper limit; it may be 15 parts by mass, 7.5 parts by mass, or 3.75 parts by mass. .

[0042] The pharmaceutical composition of the present invention contains, within a qualitative and quantitative range that does not impair the effects of the present invention, commonly used Other active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, cooling agents, colorants, sweeteners Agents, adsorbents, suspending agents, antioxidants, stabilizers, surfactants, plasticizers, solubilizers, emulsifiers, p This may involve the incorporation of H adjusters, buffering agents, flavoring and deodorizing agents, cooling agents, fragrances, coating agents, etc. can.

[0043] Other active ingredients that can be incorporated into the pharmaceutical composition of the present invention include, for example, antipyretic analgesics and antihistamines. Vitamins, cough suppressants, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti Examples include anti-inflammatory agents, gastric mucosal protectants, herbal medicines, traditional Chinese medicine prescriptions, caffeine, etc., and consist of these. It may contain one or more types selected from the group.

[0044] Excipients that can be incorporated into the pharmaceutical composition of the present invention include, for example, lactose, starches, and crystalline sugars. Examples include lurose, sucrose, sugar alcohols, etc., and as a disintegrant, low-substituted hydroxypluripotency. Pyrocellulose, sodium starch glycolate, crospovidone, carmellose, Examples include carmellose sodium, carmellose calcium, and pregelatinized starch. As binders, hydroxypropylcellulose, hypromellose, gelatin, and alpha are used. Examples include fermented starch, polyvinylpyrrolidone, pullulan, etc., and as a fluidizing agent, light Examples include anhydrous silicic acid and hydrated silicon dioxide, and as a lubricant, sucrose fatty acid esters. Examples include hydrogenated oils, stearic acid, magnesium stearate, and calcium stearate. Examples of cooling agents include menthol, peppermint oil, and eucalyptus oil.

[0045] The pharmaceutical composition of the present invention is not particularly limited as long as it is in a dosage form as defined in the General Rules for Formulations of the Japanese Pharmacopoeia. It is not prescribed and can take any dosage form that is normally available. For example, tablets, powders, granules. Examples include solid preparations such as granules, pills, and capsules, or liquid preparations such as oral solutions and syrups. It can be produced. Preferably in the form of tablets, powders, granules, pills, or capsules (preferably hard capsules). It is a capsule. Tablets specified in the general rules of the Japanese Pharmacopoeia include orally disintegrating tablets and chrysoprazole tablets. Dubible tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, core tablets, stacked tablets This includes layered tablets, etc. It also includes tablets with score lines, marks for improved identification, or engravings. This is possible. Furthermore, the tablets of this preparation may be round tablets or irregularly shaped tablets.

[0046] The solid dosage form of the present invention can be manufactured by conventional methods, and the method is not particularly limited. isn't it. For example, (a) ibuprofen (hereinafter also referred to as component (a)), (b) levocetirizine or its salt (hereinafter also referred to as component (b)), (c) carbocysteine, ambroxol and its salts, tranexamic acid, glycyrrhizic acid and its salts, tipepidine and its salts, Xistromethorphan and its salts, bromhexine and its salts, dimemorphan and its Salt, and at least one selected from the group consisting of methyl ephedrine and its salts (hereinafter (c) It is also possible to simply mix the two components, or to granulate them after mixing, and obtain The granules may be coated. Also, component (a), component (b), or component (c) are not necessarily the same. It is not necessary for them to be contained in a single granule. For example, a granule containing component (a) and component (c) The granular material is manufactured by mixing in component (b), or by containing both component (a) and component (b). After manufacturing the granules, component (c) is mixed in, or the product contains both component (a) and component (c). After producing granules containing (b) and (c), the two granules are mixed. These are examples.

[0047] The granulation method is not particularly limited and can be manufactured using wet granulation, dry granulation, or melt granulation methods. However, a wet granulation method is preferred. Wet granulation methods include, for example, agitated granulation and fluidized bed granulation. Examples include the mixing granulation method, the extrusion granulation method, and the rolling flow granulation method. Furthermore, the obtained granules are The above-mentioned active ingredients and conventional pharmaceutical additives such as excipients may be added as appropriate. The mixture obtained can also be compressed into tablets. When manufacturing tablets, the direct compression method is used. It may be manufactured by [method]. [Examples]

[0048] The present invention will be described in more detail below with reference to examples, control examples, and comparative examples, but the present invention is These examples are not the only ones that can be implemented. (Contrast example 1) A suitable amount of water / alcohol mixture is added to levocetirizine hydrochloride, mixed, and then dried to obtain the composition. Ta. (Comparative Example 1) Mix 1 part by mass of levocetirizine hydrochloride with 10 parts by mass of ibuprofen. An appropriate amount of water / alcohol mixture was added to this, mixed, and then dried to obtain the composition. (Comparative Example 2) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and pranlukast Weigh out 4 parts by mass of hydrate and mix it, then add an appropriate amount of water / alcohol mixture and mix, then dry. A dried composition was obtained. (Example 1) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and L-carbosis Weigh out 4 parts by mass of tein and mix it, then add an appropriate amount of water / alcohol mixture and mix, then dry. A dried composition was obtained. (Example 2) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and ambroxol Weigh out 4 parts by mass of uric acid hydrochloride and mix it, then add an appropriate amount of water / alcohol mixture and mix. The composition was dried to obtain the desired result. (Example 3) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and tranexamic acid Weigh out 4 parts by mass and mix, then add an appropriate amount of water / alcohol mixture and mix, then dry and assemble. We obtained the finished product. (Example 4) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and glycyrrhizin Weigh out 4 parts by mass of dipotassium acid (2.4 parts by mass as glycyrrhizic acid) and mix it, An appropriate amount of water / alcohol mixture was added and mixed, then dried to obtain the composition. (Example 5) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and tipepidine hibe Weigh out 4 parts by mass of sodium salt and mix it, then add an appropriate amount of water / alcohol mixture and mix. The composition was dried to obtain the desired result. (Example 6) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dextromethor Weigh out 4 parts by mass of fan hydrobromide hydrate and mix it with an appropriate amount of water / alcohol mixture. After adding and mixing, the mixture was dried to obtain the composition.

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

[0050] [Table 1]

[0051] As shown in Table 1, in Comparative Examples 1-2, which combined ibuprofen and levocetirizine hydrochloride... A decrease in the content of levocetirizine hydrochloride was observed. On the other hand, L-carbocysteine ​​and Broxol hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tipepidine hibe In Examples 1-6, which contained sodium salt and dextromethorphan hydrobromide hydrate, We were able to suppress the decrease in the content of bosetirizine hydrochloride.

[0052] (Example 7) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and bromhexine 0.2 parts by mass of hydrochloride was weighed out and mixed, and an appropriate amount of water / alcohol mixture was added and mixed. The composition was then dried to obtain the result. (Example 8) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and ambroxol Weigh out 1.5 parts by mass of uric acid hydrochloride and mix it, then add an appropriate amount of water / alcohol mixture and mix. The composition was then dried to obtain the result. (Example 9) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and glycyrrhizin Weigh out 0.2 parts by mass of dipotassium acid (0.12 parts by mass as glycyrrhizic acid) and mix. Then, an appropriate amount of water / alcohol mixture was added and mixed, and then dried to obtain the composition. (Example 10) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and tipepidine hibe Weigh out 1 part by mass of sodium salt and mix it, then add an appropriate amount of water / alcohol mixture and mix. The composition was dried to obtain the desired result. (Example 11) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dextromethor Weigh out 0.8 parts by mass of phan hydrobromide hydrate and mix it with an appropriate amount of water / alcohol. The mixture was added and mixed, then dried to obtain the composition. (Example 12) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dimemorphan Weigh out 1 part by mass of phosphate and mix it, then add an appropriate amount of water / alcohol mixture and mix. The composition was dried to obtain the desired result. (Example 13) 1 part by mass of levocetirizine hydrochloride, 10 parts by mass of ibuprofen and dl-methyl ester Weigh out 1 part by mass of fedrine hydrochloride and mix it, then add an appropriate amount of water / alcohol mixture and mix. The mixture was then dried to obtain the composition.

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

[0054] [Table 2]

[0055] The decrease in levocetirizine hydrochloride content observed in Comparative Examples 1-2 of Table 1 is due to the bromhexyl Ambroxol hydrochloride, dipotassium glycyrrhizinate, tipepidine hibenz Salts, dextromethorphan hydrobromide hydrate, dimemorphan phosphate and dl- Examples 7-13, which contained methyl ephedrine hydrochloride, clearly showed suppression. It happened.

[0056] Examples of formulation preparations are given below. Formulation Examples 1-12 Tablets, powders, or granules are manufactured using known techniques for the formulation examples listed in Tables 3 and 4. The resulting powder or granules are filled into hard capsules using known techniques. Manufactures a drug.

[0057] [Table 3]

[0058] [Table 4] [Industrial applicability]

[0059] The present invention provides a product containing ibuprofen and levocetirizine or a salt thereof, and levocetirizine This makes it possible to provide pharmaceutical compositions with excellent stability of ions and their salts.

Claims

1. A pharmaceutical composition characterized by containing (a) ibuprofen, (b) levocetirizine or a salt thereof, and (c)(c2) ambroxol and a salt thereof, (c3) tranexamic acid, and (c4) glycyrrhizic acid and a salt thereof.

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

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

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

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

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

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

8. A pharmaceutical composition comprising (a) ibuprofen, (b) levocetirizine or a salt thereof, and (c9) methyl ephedrine or a salt thereof, wherein the dosage form is a tablet, powder, fine granules, granules, or pill.

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

10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the dosage form is a tablet, powder, fine granules, granules, pill, capsule, oral liquid, or syrup.

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