KR101492228B1 - Solid formulation containing ibuprofen and tranexamic acid - Google Patents

Abstract

A solid preparation containing ibuprofen and tranexamic acid, wherein the solid formulation is inhibited from swelling under high temperature storage conditions. A solid preparation containing ibuprofen and tranexamic acid, wherein the solid preparation contains an organic acid or an ester thereof or a salt thereof.

Ibuprofen, tranexamic acid, high temperature preservation, swelling inhibition, solid preparation

Description

SOLID FORMULATION CONTAINING IBUPROFEN AND TRANEXAMIC ACID < RTI ID = 0.0 >

The present invention relates to solid preparations containing ibuprofen and tranexamic acid, which are inhibited from swelling under high temperature preservation conditions.

Ibuprofen is effective for the treatment of diseases such as chronic arthritis, joint pain and arthritis, neuralgia and neuritis, chest lumbago, symptomatic inflammation and analgesia, as well as cold syndrome, acute bronchitis, acute respiratory syndrome of chronic bronchitis (NSAID), which is also effective in the treatment of inflammation, inflammation, and fever. However, ibuprofen has side effects such as gastrointestinal disorders, but the formulation with various drugs has been studied in view of the relatively low analgesic effect.

For example, a combination of an analgesic-induced analgesic agent such as ibuprofen and bacetin (see Patent Document 1), a combination of ibuprofen and caffeine (see Patent Document 2), ibuprofen and codeine (See Patent Documents 3 and 4), antipyretic analgesics comprising ibuprofen and acetaminophen (see Patent Documents 5 and 6), ibuprofen and acetaminophen and allyloisopropylacetylurea or bromvalerate (Refer to Patent Document 7), a cold medicine combined with ibuprofen and lysozyme (see Patent Document 8), an antipyretic analgesic including ibuprofen and tranexamic acid (see Patent Document 9), and the like Reported. In particular, Tranexamic acid has been widely used as a drug having anti-prasmin action, anti-allergic action, anti-inflammatory action, and many combinations of ibuprofen and tranexamic acid have been developed. For example, a combination of caffeine and caffeine in combination with ibuprofen and tranexamic acid (see Patent Document 10), antipyretic analgesic composition containing ascorbic acid (see Patent Document 11), bipyrin-based antipyretic analgesics such as acetaminophen (See Patent Document 12), a rhinitis medicinal composition containing pseudoephedrine and / or phenylpyridine (refer to Patent Document 13), an α receptor stimulant such as phenylpropanolamine or pseudoephedrine, and flavonoids (See Patent Document 14), and a pharmaceutical composition containing clemastine and / or bromhexine (see Patent Document 15).

[Patent Document 1] Japanese Patent Application Laid-Open No. 64-8602

[Patent Document 2] JP-A-01-24131

[Patent Document 3] JP-A-03-7218

[Patent Document 4] JP-A-05-194227

[Patent Document 5] JP-A-05-148139

[Patent Document 6] Japanese Patent Application Laid-Open No. 11-158066

[Patent Document 7] Japanese Patent Application Laid-Open No. 05-246845

[Patent Document 8] Japanese Patent Application Laid-Open No. 7-188004

[Patent Document 9] Japanese Laid-Open Patent Publication No. 09-48728

[Patent Document 10] Japanese Patent No. 3667381

[Patent Document 11] Japanese Patent Application Laid-Open No. 2006-1920

[Patent Document 12] Japanese Patent Application Laid-Open No. 2005-187328

[Patent Document 13] Japanese Patent Application Laid-Open No. 2005-232128

[Patent Document 14] Japanese Patent Application Laid-Open No. 2005-194269

[Patent Document 15] Japanese Patent Application Laid-Open No. 2006-124380

The present inventors have been conducting research and development of a solid preparation containing ibuprofen and tranexamic acid. When these solid preparations are stored at 1 to 25 占 폚, they can be stably stored for a long period of time. However, under high-temperature storage conditions, expansion may occur and cracks I found myself to be on my own.

The present inventors have explored this cause (expansion mechanism) in order to solve the problem of expansion under high temperature preservation conditions in a solid preparation containing ibuprofen and tranexamic acid. Solid formulations comprising ibuprofen and tranexamic acid expand under high temperature preservation conditions, but such expansion is not due to degradation of the components, but to moisture expansion, and to any expansion mechanism assumed from conventional knowledge And it is very difficult to elucidate the cause (expansion mechanism) sufficiently, and it is not clarified even now.

The present inventors have already found that expansion under high temperature preservation conditions occurs only when ibuprofen and tranexamic acid are simultaneously blended, and that they do not occur when each component is used as a single component. For this reason, for example, a solution for reducing the contact between ibuprofen and tranexamic acid by using a multi-layer tablet or a press-form tablet separately of both components can be considered. However, the multi-layered tablet or the press-molded tablet is troublesome to manufacture, and the cost and the production efficiency are lowered thereby, and the problem of expansion at the interface of each layer remains, which is not necessarily a preferable solution.

On the other hand, the present inventors tried to suppress the swelling of the preparation by coating such as a sugar film or a film coating as a direct solution deviating from the explanation of the mechanism. However, since the degree of swelling of the solid preparation is large, it has been difficult to prevent the solid preparation by coating only with a sugar film coating or the like.

There may also be means for sufficiently suppressing the expansion by preserving the solid preparation containing ibuprofen and tranexamic acid at 1 to 25 占 폚 as has been conventionally done, In addition, there is a great inconvenience in use.

Accordingly, it is an object of the present invention to provide a solid preparation in which expansion of the solid preparation containing ibuprofen and tranexamic acid is suppressed, even when preserved at high temperature, not at 1 to 25 캜.

The present inventors have found that a stable solid preparation can be obtained which does not cause the problem of swelling even under high temperature preservation conditions by adding an organic acid or its ester or a salt thereof to ibuprofen and tranexamic acid to prepare a solid preparation, The present invention has been completed.

That is, the present invention relates to the following (1) and (2).

(1) Solid formulations containing solid, organic acids or esters thereof or salts thereof, containing ibuprofen and tranexamic acid.

(2) An expansion inhibitor for a solid preparation containing ibuprofen and tranexamic acid, which comprises an organic acid or an ester thereof or a salt thereof.

The present invention also relates to the following (3) to (9).

(3) A solid preparation containing ibuprofen and tranexamic acid, wherein the solid preparation contains an organic acid, an ester thereof, or a salt thereof as an expansion inhibiting component.

(4) A process for producing a solid preparation containing ibuprofen and tranexamic acid, which comprises the step of adding an organic acid or an ester thereof or a salt thereof.

(5) A process for producing a solid preparation containing ibuprofen and tranexamic acid, which comprises the step of adding an organic acid or an ester thereof or a salt thereof as an expansion inhibiting component.

(6) Use of an organic acid or an ester thereof or a salt thereof to prepare a solid preparation containing ibuprofen and tranexamic acid.

(7) Use of an organic acid or an ester thereof or a salt thereof to produce a solid preparation containing inflation-inhibited ibuprofen and tranexamic acid.

(8) Use of an organic acid or an ester thereof or a salt thereof to inhibit swelling of a solid preparation containing ibuprofen and tranexamic acid.

(9) A method for inhibiting swelling of a solid preparation containing ibuprofen and tranexamic acid by adding an organic acid or an ester thereof or a salt thereof.

In a preferred embodiment of the present invention, examples of the organic acid include a carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the present invention, a carboxylic acid having three carboxyl groups can be used. Preferred carboxylic acids are those having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 4 to 10 carbon atoms, still more preferably 4 to 7 carbon atoms And carboxylic acid having a carbon atom. In a preferred form of the invention, a carboxylic acid having six carbon atoms can be used. Preferred examples of the carboxylic acid include a carboxylic acid having a hydroxyl group (a hydroxyl group) (hydroxycarboxylic acid). Examples of the hydroxycarboxylic acid include a hydroxycarboxylic acid having 1 to 4 hydroxyl groups. In a preferred form of the present invention, a hydroxycarboxylic acid having one hydroxyl group may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred examples of the carboxylic acid include carboxylic acids (hydroxycarboxylic acid) having 4 to 7 carbon atoms, 1 to 4 carboxyl groups and 1 to 4 hydroxyl groups. In a preferred form of the invention, a carboxylic acid (hydroxycarboxylic acid) having six carbon atoms, three carboxyl groups and one hydroxyl group can be used.

In a preferred embodiment of the present invention, citric acid may be cited as the organic acid. In a preferred form of the present invention, one or two selected from the group consisting of citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, anhydrous citric acid, and anhydrous sodium citrate as citric acid or its ester or salt thereof More than species.

In another embodiment of the present invention, the organic acid includes, for example, carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the invention, a carboxylic acid having two carboxyl groups can be used. Preferred carboxylic acids are those having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 4 to 10 carbon atoms, still more preferably 4 to 7 carbon atoms And carboxylic acid having a carbon atom. In a preferred form of the invention, a carboxylic acid having four carbon atoms can be used. Preferred examples of the carboxylic acid include a carboxylic acid having a hydroxyl group (a hydroxyl group) (hydroxycarboxylic acid). Examples of the hydroxycarboxylic acid include a hydroxycarboxylic acid having 1 to 4 hydroxyl groups. In a preferred form of the present invention, a hydroxycarboxylic acid having one hydroxyl group may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred examples of the carboxylic acid include carboxylic acids (hydroxycarboxylic acid) having 4 to 7 carbon atoms, 1 to 4 carboxyl groups and 1 to 4 hydroxyl groups. In a preferred form of the invention, a carboxylic acid (hydroxycarboxylic acid) having four carbon atoms, two carboxyl groups and one hydroxyl group can be used.

In another embodiment of the customary embodiment of the present invention, the organic acid is suitably maleic acid. In a preferred form of the present invention, malic acid or its ester or a salt thereof may include malic acid and / or sodium malonic acid.

In another embodiment of the present invention, the organic acid includes, for example, carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the invention, a carboxylic acid having two carboxyl groups can be used. Preferred carboxylic acids are those having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 4 to 10 carbon atoms, still more preferably 4 to 7 carbon atoms And carboxylic acid having a carbon atom. In a preferred form of the invention, a carboxylic acid having seven carbon atoms can be used. As preferable carboxylic acid, a carboxylic acid having a hydroxyl group (hydroxyl group) (hydroxycarboxylic acid) can be mentioned. Examples of the hydroxycarboxylic acid include a hydroxycarboxylic acid having 1 to 4 hydroxyl groups. In a preferred form of the invention, a hydroxycarboxylic acid having three hydroxyl groups may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred examples of the carboxylic acid include carboxylic acids (hydroxycarboxylic acid) having 4 to 7 carbon atoms, 1 to 4 carboxyl groups and 1 to 4 hydroxyl groups. In a preferred form of the invention, an aromatic carboxylic acid (carboxylic acid) having 7 carbon atoms, 1 carboxyl group and 3 hydroxyl groups (hydroxycarboxylic acid), preferably 7 carbon atoms, 1 carboxyl group and 3 hydroxyl groups Aromatic hydroxycarboxylic acid) can be used.

In another embodiment of the customary embodiment of the present invention, the organic acid is suitably gallic acid (3,4,5-trihydroxybenzoic acid). In a preferred form of the present invention, galactic acid or its esters or salts thereof are selected from the group consisting of gallic acid, sodium glycyrrhizate, ethyl gallate, gallic acid propyl, gallic acid isoamyl, epicatechin gallate (gallic acid epicatechin) and / Epigallocatechin gallate (galic acid epigallocatechin), preferably galactic acid, ethyl gallate, gallic acid propyl and / or gallic acid isoamyl.

In another embodiment of the present invention, the organic acid includes, for example, carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the invention, a carboxylic acid having two carboxyl groups can be used. Preferred carboxylic acids are those having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 4 to 10 carbon atoms, still more preferably 4 to 7 carbon atoms And carboxylic acid having a carbon atom. In a preferred form of the invention, a carboxylic acid having four carbon atoms can be used. Preferred examples of the carboxylic acid include a carboxylic acid having a hydroxyl group (a hydroxyl group) (hydroxycarboxylic acid). Examples of the hydroxycarboxylic acid include a hydroxycarboxylic acid having 1 to 4 hydroxyl groups. In a preferred form of the invention, a hydroxycarboxylic acid having two hydroxyl groups may be used. In the present invention, a preferable carboxylic acid is a carboxylic acid having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred examples of the carboxylic acid include carboxylic acids (hydroxycarboxylic acid) having 4 to 7 carbon atoms, 1 to 4 carboxyl groups and 1 to 4 hydroxyl groups. In a preferred form of the invention, a carboxylic acid (hydroxycarboxylic acid) having four carbon atoms, two carboxyl groups and two hydroxyl groups can be used.

In another embodiment of the customary embodiment of the present invention, tartaric acid (2,3-dihydroxybutane diacid) is suitably used as the organic acid. In a preferred form of the present invention, tartaric acid, potassium hydrogen tartate, sodium tartrate, sodium potassium tartrate, monomethyl ester of tartaric acid, diethyl tartarate and the like can be mentioned as the tartaric acid or its ester or its salt, L-tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sodium L-tartrate and potassium sodium tartrate.

In another embodiment of the present invention, the organic acid includes, for example, carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the present invention, a carboxylic acid having four carboxyl groups can be used. Preferred carboxylic acids include carboxylic acids having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, and more preferably 4 to 10 carbon atoms. In a preferred form of the invention, a carboxylic acid having 10 carbon atoms can be used. A preferable carboxylic acid is a carboxylic acid having a tertiary amine structure. In a preferred form of the invention, a carboxylic acid having two tertiary amine structures may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred carboxylic acids are carboxylic acids having 4 to 10 carbon atoms, 1 to 4 carboxyl groups and 2 tertiary amine structures. In a preferred form of the invention, a carboxylic acid having 10 carbon atoms, 4 carboxyl groups and 2 tertiary amine structures can be used.

In another embodiment of the customary embodiment of the present invention, ethylenediamine tetraacetic acid (also referred to as "edetate") may be cited as an organic acid. In a preferred form of the present invention, ethylenediamine tetraacetic acid (edetic acid) or an ester thereof or salts thereof include ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate (also referred to as "sodium disodium edetate"), ethylene Dianhydride tetrasodium tetraacetate (also referred to as 'sodium edetate'), tetraethylenediaminetetraacetate tetrabromate (also referred to as 'tetra sodium edetate'), tetraethylenediaminetetraacetate tetrabromate Quot;), disodium ethylenediaminetetraacetate (III) trihydrate, dipotassium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate dihydrate, disodium ethylenediaminetetraacetate di-sodium zinc acetate, ethylenediaminetetraacetic acid 2 Sodium calcium n-hydrate, ethylenediamine tetraacetic acid disodium cobalt n-hydrate, ethylenediamine tetraacetate disodium copper (II) 4 hydrate, ethylenediamine tetraacetic acid Di-sodium n-hydrate, ethylenediaminetetraacetic acid disodium nickel n-hydrate, ethylenediamine tetraacetate magnesium disodium tetraacetate and / or ethylenediamine tetraacetate disodium manganese trihydrate, preferably ethylenediamine tetraacetic acid disodium And / or disodium ethylenediaminetetraacetate.

Therefore, the present invention also relates to the following (10) to (25).

(10) A solid preparation containing ibuprofen and tranexamic acid, wherein the solid preparation contains an organic acid or an ester thereof or a salt thereof.

(11) In the above (10), the organic acid is at least one selected from the group consisting of acetic acid, butyric acid, sorbic acid, benzoic acid, phthalic acid, salicylic acid, malonic acid, succinic acid, adipic acid, maleic acid, fumaric acid, citric acid, ethylenediaminetetraacetic acid, lactic acid, , Ascorbic acid, erythorbic acid, gallic acid, and amino acid.

(12) The solid preparation as described in (10) above, wherein the organic acid is at least one selected from the group consisting of citric acid, malic acid, gallic acid, tartaric acid and ethylenediaminetetraacetic acid.

(13) The solid preparation as described in (10), wherein the organic acid is citric acid.

(14) The solid preparation according to (10), wherein the organic acid is malic acid.

(15) The solid preparation according to (10), wherein the organic acid is gallic acid.

(16) The solid preparation according to (10), wherein the organic acid is ethylenediaminetetraacetic acid.

(17) The method for producing a fermentation product according to (10) above, wherein the organic acid or its ester or a salt thereof is at least one selected from the group consisting of citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, citric anhydride, sodium citrate anhydrous, At least one member selected from the group consisting of potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, gallic acid, gallic acid ethyl, gallic acid propyl, gallic acid isoamyl, disodium ethylenediamine tetraacetate and disodium ethylenediaminetetraacetate ≪ / RTI >

(18) An expansion inhibitor for a solid preparation containing ibuprofen and tranexamic acid, which comprises an organic acid or an ester thereof or a salt thereof.

(19) In the above-mentioned (18), the organic acid is at least one selected from the group consisting of acetic acid, butyric acid, sorbic acid, benzoic acid, phthalic acid, salicylic acid, malonic acid, succinic acid, adipic acid, maleic acid, fumaric acid, citric acid, ethylenediaminetetraacetic acid, , Ascorbic acid, erythorbic acid, gallic acid, and amino acid.

(20) The swelling inhibitor according to (18), wherein the organic acid is at least one selected from the group consisting of citric acid, malic acid, gallic acid, tartaric acid and ethylenediaminetetraacetic acid.

(21) The expansion inhibitor according to (18), wherein the organic acid is citric acid.

(22) The swelling inhibitor according to (18), wherein the organic acid is malic acid.

(23) The expansion inhibitor according to (18), wherein the organic acid is gallic acid.

(24) The swelling inhibitor according to (18), wherein the organic acid is ethylenediaminetetraacetic acid.

(25) The process for producing a fermentation product according to (18), wherein the organic acid or its ester or a salt thereof is at least one selected from the group consisting of citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, citric anhydride, sodium citrate anhydrous, At least one member selected from the group consisting of potassium hydrogen tartrate, sodium tartrate, potassium sodium tartrate, gallic acid, gallic acid ethyl, gallic acid propyl, gallic acid isoamyl, disodium ethylenediamine tetraacetate and disodium ethylenediaminetetraacetate ≪ / RTI >

According to the present invention, the addition of an organic acid or an ester thereof or a salt thereof inhibits swelling of a solid preparation including ibuprofen and tranexamic acid even under high-temperature preservation conditions, and, at the time of transportation and storage, Even if it is passed through the storage conditions, there is no occurrence of cracking or the like due to no expansion. Therefore, the value of a solid preparation as a product is maintained under various distribution and storage conditions, and is convenient to use.

The present invention relates to a solid preparation containing ibuprofen and tranexamic acid, which comprises a solid preparation containing an organic acid or an ester thereof or a salt thereof, and ibuprofen and tranexa comprising an organic acid or an ester thereof or a salt thereof, Lt; RTI ID = 0.0 > a < / RTI >

The ibuprofen contained in the solid preparation of the present invention may use not only ibuprofen but also pharmaceutically acceptable salts of ibuprofen, and those commercially available can be used. The proportion of ibuprofen contained in the solid preparation of the present invention is preferably 1 to 70% by mass, more preferably 5 to 60% by mass, and particularly preferably 7 to 50% by mass as ibuprofen for the entire solid preparation Do.

Tranexamic acid contained in the solid preparation of the present invention may be not only tranexamic acid but also pharmaceutically acceptable salts of tranexamic acid, and commercially available ones can be used. The ratio of tranexamic acid contained in the solid preparation of the present invention is preferably from 1 to 70 mass%, more preferably from 5 to 60 mass%, and particularly preferably from 7 to 50 mass%, as tranexamic acid, Do.

The organic acid or ester thereof or the salt thereof contained in the solid preparation of the present invention may be prepared by a known method or a commercially available one.

The organic acid used in the present invention includes, for example, carboxylic acid. Preferred examples of the carboxylic acid include carboxylic acids having 1 to 5 carboxyl groups, preferably 1 to 4 carboxyl groups. In a preferred form of the present invention, a carboxylic acid having three carboxyl groups can be used. In another preferred embodiment of the present invention, a carboxylic acid having two carboxyl groups can be used. In another preferred embodiment of the present invention, a carboxylic acid having one carboxyl group can be used. In another preferred embodiment of the present invention, a carboxylic acid having four carboxyl groups can be used. Preferred carboxylic acids are those having 1 to 15 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 4 to 10 carbon atoms, still more preferably 4 to 7 carbon atoms And carboxylic acid having a carbon atom. In a preferred form of the invention, a carboxylic acid having six carbon atoms can be used. In another preferred embodiment of the present invention, a carboxylic acid having four carbon atoms can be used. In another preferred embodiment of the present invention, a carboxylic acid having 7 carbon atoms, preferably an aromatic carboxylic acid having 7 carbon atoms, can be used. In another preferred embodiment of the present invention, a carboxylic acid having 10 carbon atoms can be used. As preferable carboxylic acid, a carboxylic acid having a hydroxyl group (hydroxyl group) (hydroxycarboxylic acid) can be mentioned. Examples of the hydroxycarboxylic acid include a hydroxycarboxylic acid having 1 to 4 hydroxyl groups. In a preferred form of the present invention, a hydroxycarboxylic acid having one hydroxyl group may be used. In another preferred embodiment of the present invention, a hydroxycarboxylic acid having three acid groups can be used. In another preferred embodiment of the present invention, a hydroxycarboxylic acid having two hydroxyl groups may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred examples of the carboxylic acid include carboxylic acids (hydroxycarboxylic acid) having 4 to 7 carbon atoms, 1 to 4 carboxyl groups and 1 to 4 hydroxyl groups. In a preferred form of the invention, a carboxylic acid (hydroxycarboxylic acid) having six carbon atoms, three carboxyl groups and one hydroxyl group can be used. In another preferred embodiment of the present invention, a carboxylic acid (hydroxycarboxylic acid) having four carbon atoms, two carboxyl groups and one hydroxyl group can be used. In another preferred embodiment of the present invention, an aromatic carboxylic acid having 7 carbon atoms, 1 carboxyl group and 3 hydroxyl groups (hydroxycarboxylic acid), preferably 7 carbon atoms, 1 carboxyl group and 3 hydroxyl groups ( Aromatic hydroxycarboxylic acid) can be used. In another preferred embodiment of the present invention, a carboxylic acid (hydroxycarboxylic acid) having four carbon atoms, two carboxyl groups and two hydroxyl groups can be used. A preferable carboxylic acid is a carboxylic acid having a tertiary amine structure. In a preferred form of the invention, a carboxylic acid having two tertiary amine structures may be used. In the present invention, preferred carboxylic acids include carboxylic acids having 4 to 10 carbon atoms and 1 to 4 carboxyl groups. Particularly preferred carboxylic acids are carboxylic acids having 4 to 10 carbon atoms, 1 to 4 carboxyl groups and 2 tertiary amine structures. In a preferred form of the invention, a carboxylic acid having 10 carbon atoms, 4 carboxyl groups and 2 tertiary amine structures can be used.

Examples of such organic acids include formic acid; Acetic acid; Propionic acid; Butyric acid; Sorbic acid; Benzoic acid; Phthalic acid; Salicylic acid; Oxalic acid; Malonic acid; Succinic acid; Glutaric acid; Adipic acid; Maleic acid; Fumaric acid; Citric acid; Edetate (ethylenediamine-4-acetic acid); Lactic acid; Malic acid; Tartaric acid; Ascorbic acid; Erythorbic acid; Gallic acid; But are not limited to, glycine, alanine, arginine, cystathion, cysteine, lanthionine, histidine, homoserine, leucine, isoleucine, norleucine, lysine, methionine, valine, norvaline, ornithine, proline, sarcosine, serine, threonine, Amino acids such as ronin and tyrosine, and the like. The organic acid used in the present invention also includes an acid anhydride of an organic acid (for example, phthalic anhydride) for an organic acid which can be an acid anhydride by intramolecular dehydration condensation.

Examples of the ester of an organic acid include an ester with an organic acid and a monohydric or polyhydric alcohol. The monohydric alcohols generally include monovalent alcohols having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. . In a preferred embodiment of the present invention, an organic acid ester of a monovalent alcohol having three carbon atoms is used. Examples of monohydric alcohols conventionally used for forming esters of organic acids in the present invention include alcohols such as methanol, ethanol, propanol (propan-1-ol), isopropanol (propan- 1-ol), s-butyl alcohol (butan-2-ol), isobutyl alcohol (2-methylpropan- 1-ol, pentyl alcohol, 3-methylbutan-1-ol (isopentyl alcohol, isoamyl alcohol) 2-methylbutan-2-ol (t-pentyl alcohol), 2,2-dimethylpropan-1-ol (neopentyl alcohol), and the like, preferably methanol, ethanol, Propanol (propan-1-ol), isopropanol (propan-2-ol), butyl alcohol (butan-1-ol), s- -Ol), t-butyl alcohol (2-methylpropan-2-ol), 3-methylbutan-1-ol (isopentyl alcohol Propanol (propane-1-ol), isopropanol (propane-2-ol), 3-methylbutan-1-ol (isopentyl alcohol, Isoamyl alcohol), and the like. The polyvalent alcohol includes, for example, a pentavalent or hexavalent alcohol. In the present invention, examples of polyhydric alcohols conventionally used for forming an ester of an organic acid include catechins and derivatives thereof, preferably epicatechin, epigallocatechin and the like. The ester by the organic acid and the alcohol may be a monoester of an organic acid or may be an organic acid ester having two or more ester bonds in the upper limit of the number of carboxyl groups of the organic acid. Examples thereof include diesters of organic acids, Ester and the like. Preferred monoesters of organic acids include monoesters of organic acids with the above-mentioned alcohols. Particularly preferred examples of monoesters of organic acids include monomethyl esters of organic acids and monoethyl esters of organic acids. Preferred diesters of organic acids include diesters of organic acids with the above-mentioned alcohols. Particularly preferred diesters of organic acids include dimethyl esters of organic acids, diethyl esters of organic acids, and ethyl methyl esters of organic acids. In the organic acid ester having two or more ester bonds, the alcohol forming each ester bond may be the same alcohol or different alcohol. In one embodiment of the present invention, the organic acid ester having two or more ester bonds has the ester bond formed by the same alcohol.

Examples of salts of organic acids, specifically, pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and transition metal salts such as manganese, iron, cobalt, nickel and copper. Examples of esters include those derived from alcohol and those derived from phenol. In the present invention, preferable examples of the organic acid include acetic acid, butyric acid, sorbic acid, benzoic acid, phthalic acid, salicylic acid, malonic acid, succinic acid, adipic acid, maleic acid, fumaric acid, citric acid, edetic acid (ethylenediaminetetraacetic acid) Acid, tartaric acid, ascorbic acid, erythorbic acid, gallic acid, and amino acid. Particularly, citric acid, edetic acid, malic acid, tartaric acid and gallic acid are preferable.

Examples of the organic acid or its ester or a salt thereof include acetic acid, calcium acetate, cellulose acetate, tocopherol acetate, ethyl butyrate, riboflavin butyrate, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, benzyl benzoate, diethyl phthalate, Butyl phthalate, butyl phthalate, phthalic anhydride, salicylic acid, sodium salicylate, phenyl salicylate, malonic acid, succinic acid, monosodium succinate, disodium dihydrogenphosphate, adipic acid, maleic acid, fumaric acid, monosodium fumarate, stearyl fumarate Sodium citrate, sodium citrate, sodium citrate anhydrous, ethylenediamine tetraacetic acid, ethylenediamine tetraacetate disodium (also referred to as 'sodium disodium edetate'), sodium citrate, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, , Disodium ethylenediaminetetraacetate (" sodium edetate " (Also called tetrasodium ethylenediaminetetraacetate), tetrasodium ethylenediaminetetraacetate tetraacetate (also referred to as tetrasodium edetate), tetraethylenediaminetetraacetate tetraacetate (also referred to as tetraethylenetetraacetate tetraacetate), ethylenediamine tetraacetate monosodium iron (III) trihydrate, dipotassium ethylenediamine tetraacetate, triethylenediaminetetraacetate dihydrate, ethylenediaminetetraacetate di-sodium zinc n-hydrate, ethylenediaminetetraacetate di-sodium calcium acetate n-hydrate, ethylenediamine tetraacetate di- Cobalt n-hydrate, disodium ethylenediaminetetraacetate (II) tetra-hydrate, ethylenediamine tetraacetate disodium n-hydrate, ethylenediamine tetraacetate di-sodium nickel n-hydrate, ethylenediamine tetraacetate disodium magnesium dihydrate, Ethylenediaminetetraacetic acid disodium manganese trihydrate, lactic acid, calcium lactate, malic acid, sodium malic acid, potassium malic acid, magnesium malic acid, calcium malic acid, barium malonic acid, Wherein the organic acid is at least one selected from the group consisting of esters, maleic acid diethyl ester, tartaric acid, potassium hydrogen tartrate, sodium tartarate, sodium potassium tartrate, monomethylstarch tartrate, diethyl stearate, ascorbic acid, erythorbic acid, sodium erythorbate, (Gallic acid epigallocatechin), salts of amino acids and amino acids, and the like can be given as examples of the salts of glycyrrhizic acid. Particularly, it is preferable to use at least one selected from the group consisting of citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, calcium disodium edetate, sodium edetate, malic acid, sodium malic acid, , Sodium potassium tartrate, gallic acid, ethyl gallate, propyl gallate, and gallic acid isoamyl are preferable. Among them, citric acid, citric anhydride, sodium edetate, malic acid, tartaric acid and gallic acid propyl are particularly preferable.

The proportion of the organic acid or its ester or salt thereof contained in the solid preparation of the present invention is preferably 0.01 to 30% by mass, more preferably 0.1 to 20% by mass as an organic acid with respect to the whole solid preparation. When the organic acid is citric acid, the proportion thereof is preferably 0.1 to 10 mass%, more preferably 0.5 to 5 mass%, and particularly preferably 1 to 3 mass% as citric acid with respect to the whole solid preparation. When the organic acid is an edetic acid, the proportion thereof is preferably from 0.1 to 10 mass%, more preferably from 0.5 to 5 mass%, and particularly preferably from 1 to 3 mass%, as edetic acid with respect to the whole solid preparation. When the organic acid is malic acid, the proportion thereof is preferably 0.1 to 10 mass%, more preferably 0.5 to 5 mass%, and particularly preferably 1 to 3 mass%, based on the whole solid preparation, as malic acid. When the organic acid is stannic acid, the proportion thereof is preferably from 0.1 to 10 mass%, more preferably from 0.5 to 5 mass%, and particularly preferably from 1 to 3 mass%, based on the whole solid preparation, as tartaric acid. When the organic acid is galactic acid, the proportion thereof is preferably 0.1 to 10 mass%, more preferably 0.5 to 5 mass%, and particularly preferably 1 to 3 mass% as gallic acid to the whole solid preparation.

In the solid preparation of the present invention, the blending ratio of ibuprofen and tranexamic acid is preferably 0.1 to 10 parts by mass, more preferably 0.2 to 2.5 parts by mass, of tranexamic acid relative to 1 part by mass of ibuprofen. In the case of oral administration, the dosage of the solid preparation of the present invention is preferably 300 to 600 mg as ibuprofen per day, and preferably 400 to 750 mg per day as tranexamic acid.

The solid preparation of the present invention may contain, as medicinal ingredients, drugs other than ibuprofen and tranexamic acid, for example, antipyretic analgesics, antihistamines, antiinflammatory agents, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti- A preservative, an herbal medicine, a herbal medicine, a caffeine, and the like.

Examples of the antipyretic analgesic agent include aspirin, aspirin aluminum, acetaminophen, ethenamicide, sasapyrin, salicylamide, lactylphenididine, sodium salicylate and the like.

Examples of the antihistamine agent include azelastine hydrochloride, isodiphenyldihydrochloride, clemastine fumarate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triproolidine hydrochloride , Triperenylamine hydrochloride, thonzylamine hydrochloride, phenetadine hydrochloride, methadylazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemarginate tartrate, diphenhydramine tannate, di Di-chlorophenamine maleate, d-chlorpenilamine maleate, mequitrazine, dipeterol (diphenylmethane diisocyanate, diphenylmethane diisocyanate, ) Phosphate, and the like.

Examples of the diluting agent include allocamid hydrochloride, cloferastine hydrochloride, carbbeta pentane citrate, dipeptin citrate, dibnat sodium, dextromethorphan hydrobromide, dextromethorphan phenol phthalate , Dipropyldihydrobenzoate, clopherastine fendiate, cordine phosphate, dihydrocodeine phosphate, and the like.

Examples of the noscapine include noscapine hydrochloride and noscapine.

Examples of bronchodilators include dl-methyl ephedrine hydrochloride and dl-methyl ephedrine saccharin salts.

Examples of the expectorant include potassium guaiacosylphonate, guanifenesin, bromhexine hydrochloride, ambroxol hydrochloride, carbostein, and the like.

Examples of the hypnotic sedative agent include bromovaleryl component and allyl isopropyl acetal component.

Examples of vitamins include vitamin B1, vitamin B2, vitamin C, hesperidin and its derivatives, and salts thereof.

Examples of the anti-inflammatory agent include lysozyme chloride, cerapeptide, glycyrrhizin acid, and the like.

Examples of gastric mucosal protective agents include aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxy aluminum / aminoacetic acid salt (aluminum glycinate), aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, A coprecipitation product of aluminum hydroxide and sodium hydrogencarbonate, a coprecipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, a coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate and magnesium metasilicate aluminate.

As medicinal herbs, garlic (Daesan), Maehyang, Namcheon room, Anpye, raw paper, licorice, bellflower, (tinctures, dried ginseng, etc.), herbal medicines such as gentian, bamboo, livestock gut (including umbrella), ginseng, ginger, creation, sperm, dermis, X, etc.).

Herbal remedies include Galgengtang, Gui Ji Tang, Fragrant Xiao, Shiho Gui Jiang Tang, Soshiho Tang, Sochyong Rong Tang, McMundong Tang, Banha Hubang Tang, Mahhang Tang.

Examples of caffeine humans include anhydrous caffeine, caffeine, sodium benzoate caffeine, and the like.

The solid preparation of the present invention may further contain, as additives, excipients, binders, disintegrants, lubricants and the like.

Examples of the excipient include lactose, starch, crystalline cellulose, sucrose, sugar alcohol and the like.

Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, alpha starch, polyvinylpyrrolidone, polyvinyl alcohol, and pullulan.

Examples of the disintegrant include camelose, camelose calcium, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium and the like.

Examples of lubricants include glycerin fatty acid esters, sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, calcium stearate and talc.

Examples of the formulations of the solid preparation of the present invention include capsules, pills, granules, tablets and powders, and particularly tablets are preferred. The solid preparation may also be coated with a sugar film or the like.

The solid preparation of the present invention can be prepared by a conventional method. For example, when the formulation is tablets, it is possible to use tablets containing ibuprofen, tranexamic acid, organic acids or esters thereof, salts thereof and various drugs or various additives which can be generally used according to a conventional method , Mixing or granulating the mixture, and mixing the resultant mixture or granule with a lubricant, if desired, followed by tableting, to prepare the solid preparation of the present invention. In addition, based on conventional methods such as the Japanese Pharmacopoeia General Provisions such as ibuprofen, tranexamic acid, organic acids, esters or salts thereof, various drugs and various additives which can be used in general, ibuprofen and tranexamic acid And then granulating these granules and mixing the lubricant with the desired lubricant, followed by tableting, the solid preparation according to the present invention can be produced. The organic acid or its ester or a salt thereof may be contained in one of the granules when the granule is divided into ibuprofen and tranexamic acid, or it may be mixed at the time of tabletting.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

( Example  One)

(Trade name: Nippon Yakusen Traxexamic acid), and anhydrous citric acid (106.2 g, manufactured by Komatsu Chemical Co., Ltd.) (FS-10, manufactured by Fukae Kyogyo Co., Ltd.), 1869.2 g of lactose hydrate (manufactured by DMV INTERNATIONA; trade name: Lactose 200M) was added to a high-speed stirring granulator After mixing and mixing, 466 g of purified water was added and kneaded. The granules were put into a fluidized bed dryer (FLO-5 type manufactured by Furonto Industrial Co., Ltd.), dried and then granulated using a granulator (ND-10 type manufactured by Okada Seiko). 4,762.8 g of this granule and 97.2 g of magnesium stearate were put into a mixer (manufactured by Gotobukiya Co., Ltd., PM50 type) and mixed. Thereafter, using a tableting machine (HT-AP18SS type) equipped with a punch having a diameter of 8.5 mm And 18,000 tablets having a defined mass of 270 mg were obtained.

( Comparative Example  One)

(Manufactured by Yonezawa Pharmaceutical Co., Ltd., trade name: Nippon Pharmaceutical Co., Ltd., ibuprofen), 1,499.4 g of tranexamic acid (manufactured by Daiichi Sankyo KK; trade name: Nippon Yakusen tranexamic acid), and hydroxypropylcellulose (Trade name: HPC-L), 360 g of croscarmellose sodium salt (Nichirin Chemical Industry: Kickcore ND-2HS) and 1897.2 g of crystalline cellulose (Asahi Chemical Industry Co., Ltd .: Seiolus PH-101) (Fukae Kyogyo Co., Ltd .: FS-10 type), mixed, and then 466 g of purified water was added and kneaded. The granules were put into a fluidized bed dryer (FLO-5 type manufactured by Furonto Industrial Co., Ltd.), dried and then granulated using a granulator (ND-10 type manufactured by Okada Seiko). 4,762.8 g of this granule and 97.2 g of magnesium stearate were put into a mixer (manufactured by Gotobukiya Co., Ltd., PM50 type) and mixed. Thereafter, using a tableting machine (HT-AP18SS type) equipped with a punch having a diameter of 8.5 mm And 18,000 tablets having a defined mass of 270 mg were obtained.

( Test Example  1) Evaluation of swelling

One tablets obtained in Example 1 and Comparative Example 1 were each placed in a glass bottle (2K standard) and air-tightly closed, and then stored in a constant-temperature container at 40 ° C for 1 month, 2 months, and 3 months. The expansion ratio (%) defined by the following formula (1) was calculated from the thickness of the tablet immediately after preparation and the thickness of the tablet after storage measured with a digital micrometer.

Expansion ratio (%) = (D-D0) / D0 100

In the above formula, "D" is the thickness of the tablet after storage, and "D0" is the thickness of the tablet immediately after preparation.

The results of the tablets obtained in Example 1 and Comparative Example 1 are shown in Table 1 below.

Example 1 Comparative Example 1 Expansion ratio (%) after storage at 40 占 폚 for 1 month 0 7.5 Expansion ratio (%) after storage at 40 占 폚 for 2 months 0.4 9.7 Expansion ratio (%) after storage at 40 占 폚 for 3 months 0.8 10.7

As is evident from Table 1, the expansion ratios after storage at 40 ° C for 1 month, 2 months and 3 months were 7.5%, 9.7% and 10.7%, respectively, in tablets (Comparative Example 1) containing no organic acids or esters or salts thereof And high expansion rate was recognized. On the other hand, in the tablets of the present invention (Example 1) containing citric acid as the organic acid or its ester or a salt thereof, the expansion ratios after storage at 40 ° C for 1 month, 2 months, and 3 months were 0%, 0.4%, and 0.8% , A remarkable expansion inhibiting effect was recognized. In addition, the tablets of Comparative Example 1 were liable to be cracked or scratched due to their high expansion ratio, but the tablets of the present invention (Example 1) had cracks in tablets even after storage at the above- And no scratches were observed, indicating that the tablets were stable.

( Example  2)

Tablets were obtained in the same manner as in Example 1, except that the anhydrous citric acid was changed to malic acid (manufactured by Kawasaki Kasei Corporation: 40M for the addition of malic acid).

( Test Example  2)

The tablets obtained in Example 2 were tested in the same manner as in Test Example 1 with a storage period of one month. As a result, the expansion rate after storage at 40 占 폚 for 1 month was 0.1%, and remarkable expansion inhibiting effect was recognized. Further, it was found that the tablets of the present invention (Example 2) had no cracks or flaws in tablets even after storage and were stable tablets.

( Example  3)

Tablets were obtained in the same manner as in Example 1 except that anhydrous citric acid was replaced by gallic acid propylate (manufactured by Wako Pure Chemical Industries Ltd., trade name: gallic acid propylate).

( Test Example  3)

The tablets obtained in Example 3 were tested in the same manner as in Test Example 1 with a storage period of one month. As a result, the expansion rate after storage at 40 占 폚 for 1 month was 0.1%, and remarkable expansion inhibiting effect was recognized. It was also found that the tablets of the present invention (Example 3) had no cracks or flaws in tablets even after storage, and were stable tablets.

( Example  4)

Tablets were obtained in the same manner as in Example 1 except that citric acid anhydride was changed to tartaric acid (Kanto Kagaku: trade name: L (+) - tartaric acid).

( Test Example  4)

The tablets obtained in Example 4 were tested in the same manner as in Test Example 1 except that the storage period was one month. As a result, the expansion rate after storage at 40 占 폚 for 1 month was 0.5%, and a remarkable expansion inhibiting effect was recognized. In addition, it was found that the tablets of the present invention (Example 4) had no cracks or flaws in tablets even after storage, and were stable tablets.

( Example  5)

Tablets were obtained in the same manner as in Example 1 except that anhydrous citric acid was changed to sodium edetate (Kanto Chemical Co., trade name: EDTA2Na).

( Test Example  5)

The tablets obtained in Example 5 were tested in the same manner as in Test Example 1 except that the storage period was one month. As a result, the expansion rate after storage for one month at 40 占 폚 was 0.6%, and the remarkable expansion inhibition effect was recognized. In addition, it was found that the tablets of the present invention (Example 5) had no cracks or scratches of tablets even after storage, and were stable tablets.

The present invention is a solid preparation containing ibuprofen and tranexamic acid, which contains an organic acid or an ester thereof or a salt thereof, thereby providing a stable solid preparation free from swelling under high temperature storage conditions. It is also known that medicinal preparations containing ibuprofen and tranexamic acid can obtain not only the medicinal effects possessed by these components, but also the additional effects of medicinal enhancement and side effect reduction. The present invention makes it possible to stably provide such a useful pharmaceutical preparation. The use of the solid preparation obtained in the present invention enables long-term storage and use under high-temperature conditions, and is very useful in the pharmaceutical industry.

Claims (6)

As solid preparations containing ibuprofen and tranexamic acid, A solid preparation containing at least one organic acid or a salt thereof selected from the group consisting of citric acid, maleic acid, gallic acid, tartaric acid and ethylenediaminetetraacetic acid. The method according to claim 1, Wherein the content of the organic acid or its salt in the solid preparation is 0.01 to 30% by weight as an organic acid. The method according to claim 1, Wherein the daily dosage of ibuprofen is 300 to 600 mg as ibuprofen. The method according to claim 1, Wherein the daily dose of tranexamic acid is 400 to 750 mg as tranexamic acid. 5. The method according to any one of claims 1 to 4, Solid formulations are capsules, pills, granules, tablets or powders. delete