JP2009235020A - Solid preparation containing ibuprofen and tranexamic acid - Google Patents

Abstract

An object of the present invention is to provide a solid preparation containing ibuprofen and tranexamic acid, in which swelling occurs even under high-temperature storage conditions and the preparation does not crack or the like.
A solid preparation containing ibuprofen and tranexamic acid, wherein (A) one or more selected from fumaric acid, tartaric acid, esters thereof or salts thereof and (B) citric acid, malic acid, tartaric acid A solid preparation containing at least one selected from gallic acid or edetic acid, or an ester or a salt thereof.
[Selection figure] None

Description

  The present invention relates to a solid preparation containing ibuprofen and tranexamic acid, in which swelling under high temperature storage conditions is suppressed.

  Ibuprofen is effective for diseases such as rheumatoid arthritis, arthralgia and arthritis, neuralgia and neuritis, spinal and lower back pain, symptomatic inflammation, and analgesia. It is a drug that is widely used as a non-steroidal anti-inflammatory drug (NSAID) that is also effective for exacerbation and antipyretic in exacerbations. However, since ibuprofen has side effects such as gastrointestinal disorders and its analgesic effect is relatively weak, preparations with various drugs have been studied.

For example, antipyretic analgesics (see Patent Document 1) containing ibuprofen and aniline derivative antipyretic analgesics such as busetine, preparations containing ibuprofen and caffeine (see Patent Document 2), and ibuprofen and codeine. Analgesic composition (see patent documents 3 and 4), antipyretic analgesic (see patent documents 5 and 6) containing ibuprofen and acetaminophen, antipyretic containing ibuprofen and acetaminophen and allylisopropylacetylurea or bromvalerylurea Analgesics (see Patent Document 7), cold medicines (see Patent Document 8) containing ibuprofen and lysozyme chloride, antipyretic analgesics containing ibuprofen and tranexamic acid (see Patent Document 9), and the like have been reported. In particular, tranexamic acid is widely used as a drug having an antiplasmin action, an antiallergic action, an anti-inflammatory action, and the like, and many combinations of ibuprofen and tranexamic acid have been developed. For example, an antipyretic analgesic (see Patent Document 10) further containing caffeine in ibuprofen and tranexamic acid, an antipyretic analgesic composition (see Patent Document 11) containing ascorbic acid, a non-pyrine antipyretic analgesic such as acetaminophen, Further combined with a combined pharmaceutical preparation (see Patent Document 12), a pharmaceutical composition for rhinitis containing pseudoephedrine and / or phenylephrine (see Patent Document 13), an alpha receptor stimulator such as phenylpropanolamine and pseudoephedrine, and a flavonoid A common cold medicinal composition (see Patent Document 14), a pharmaceutical composition containing clemastine and / or bromohexine (see Patent Document 15), and the like have been reported.
Japanese Patent Publication No. 64-8602 Japanese Patent Publication No. 1-24131 Japanese Patent Laid-Open No. 3-7218 JP-A-5-194227 JP-A-5-148139 Japanese Patent Laid-Open No. 11-158066 JP-A-5-246845 JP-A-7-188004 Japanese Patent Laid-Open No. 9-48728 Japanese Patent No. 3667381 JP 2006-1920 A JP 2005-187328 A JP-A-2005-232128 JP 2005-194269 A JP 2006-124380 A

  The inventors of the present invention have been intensively researching and developing a solid preparation containing ibuprofen and tranexamic acid. And when these preservatives and stability were examined, these solid preparations can be stored stably for a long period of time if stored at 1 to 25 ° C., but they expand under high temperature storage conditions. Occurring, it was found uniquely that the drug product cracks.

  And the present inventors have searched for this cause (swelling mechanism) in order to solve the problem of swelling under high-temperature storage conditions in a solid preparation containing ibuprofen and tranexamic acid. Solid formulations containing ibuprofen and tranexamic acid swell under high-temperature storage conditions, but such swelling is not due to decomposition of components, not due to moisture absorption, and any swelling mechanism assumed from conventional knowledge It is difficult to fully understand the cause (expansion mechanism), and it has not been elucidated yet.

  The present inventors have already found that expansion under high temperature storage conditions occurs only when ibuprofen and tranexamic acid are blended simultaneously, and does not occur when each is a single component, as a condition for reproducing the expansion phenomenon. Yes. Therefore, for example, a solution means of reducing the contact between ibuprofen and tranexamic acid by using a multi-layered tablet or a dry-coated tablet in which both components are separated is also conceivable. However, multilayer tablets and dry-coated tablets are complicated to manufacture, which not only increases costs and decreases production efficiency, but also remains a problem of expansion at the interface of each layer, and is not necessarily a preferable solution. It was.

  On the other hand, the present inventors tried to suppress the expansion of the preparation by coating such as sugar coating or film coating as a direct solution away from the elucidation of the mechanism. However, the degree of expansion of the solid preparation is large, and it has been difficult to prevent it only by coating such as sugar coating or film coating.

  In addition, as has been done conventionally, there may be a means of sufficiently suppressing swelling by storing a solid preparation containing ibuprofen and tranexamic acid at 1 to 25 ° C. The inconvenience above is great.

  Therefore, the present invention is to provide a solid preparation containing ibuprofen and tranexamic acid, in which swelling is suppressed even when stored at a high temperature without storing at 1 to 25 ° C. And

  When the present inventors add two or more organic acids or their esters or their salts to ibuprofen and tranexamic acid to form a solid preparation, a stable solid preparation that does not swell even under high temperature storage conditions is obtained. The present invention has been found, and the present invention has been completed.

That is, the present invention relates to the following [1] to [2].
[1] A solid preparation containing ibuprofen and tranexamic acid, which contains two or more organic acids, esters thereof or salts thereof.
[2] An expansion inhibitor for solid preparations containing ibuprofen and tranexamic acid, comprising two or more organic acids or esters thereof or salts thereof.

  In a preferred embodiment, the expansion inhibitor for a solid preparation containing ibuprofen and tranexamic acid is an expansion suppression kit comprising two or more organic acids, esters thereof or salts thereof. In a preferred embodiment, two or more kinds of organic acids or esters or salts thereof contained in the expansion suppression kit can be separately added and used in different steps.

The present invention also relates to the following [3] to [9].
[3] A solid preparation containing ibuprofen and tranexamic acid, which contains two or more organic acids or esters thereof or salts thereof as an expansion inhibiting component.
[4] A method for producing a solid preparation containing ibuprofen and tranexamic acid,
Adding two or more organic acids or esters thereof or salts thereof;
The manufacturing method characterized by including.
[5] A method for producing a solid preparation containing ibuprofen and tranexamic acid,
A step of adding two or more organic acids or esters thereof or salts thereof as an expansion inhibiting component
The manufacturing method characterized by including.
[6] Use of two or more organic acids or esters thereof or salts thereof for producing a solid preparation containing ibuprofen and tranexamic acid.
[7] Use of two or more organic acids or esters thereof or salts thereof for producing a solid preparation containing ibuprofen and tranexamic acid which is suppressed in swelling.
[8] Use of two or more organic acids or esters thereof or salts thereof to suppress swelling of a solid preparation containing ibuprofen and tranexamic acid.
[9] A method for suppressing swelling of a solid preparation containing ibuprofen and tranexamic acid by adding two or more organic acids or esters thereof or a salt thereof.

The present invention also relates to the following [10] to [12].
[10] A solid preparation containing ibuprofen and tranexamic acid,
(A) one or more selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
(B) at least one selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or an ester or a salt thereof,
A solid preparation containing the components (A) and (B).
[11] The solid preparation according to [10], wherein the component (A) is one or more components selected from fumaric acid, sodium stearyl fumarate or potassium sodium tartrate.
[12] Component (B) is citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, malic acid, sodium malate, tartaric acid, potassium hydrogen tartrate The solid preparation according to [10] or [11], which is one or more components selected from sodium tartrate, propyl gallate, disodium calcium edetate or sodium edetate.

The present invention also relates to the following [13] to [14].
[13] An expansion inhibitor for solid preparations containing ibuprofen and tranexamic acid, comprising two or more organic acids or esters thereof or salts thereof.
[14] As two or more organic acids or esters thereof or salts thereof, the following components (A) and (B):
(A) one or more selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
(B) at least one selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or an ester or a salt thereof,
An expansion inhibitor for solid preparations containing ibuprofen and tranexamic acid.

  In a preferred embodiment, the expansion inhibitor for a solid preparation containing ibuprofen and tranexamic acid is an expansion suppression kit comprising components (A) and (B). In a preferred embodiment, the components (A) and (B) contained in the expansion suppression kit can be added and used separately in different steps.

The present invention also relates to the following [15] to [16].
[15] A method for producing a solid preparation containing ibuprofen and tranexamic acid, which is suppressed in swelling,
Next component (A):
(A) one or more selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
Adding,
And the following component (B):
(B) at least one selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or an ester or a salt thereof,
Adding,
Including methods.
[16] A method for suppressing swelling of a solid preparation containing ibuprofen and tranexamic acid,
Next component (A):
(A) one or more selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
Adding,
And the following component (B):
(B) at least one selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or an ester or a salt thereof,
Adding the step.

  According to the present invention, by adding two or more organic acids or esters thereof or salts thereof, the expansion of the solid preparation containing ibuprofen and tranexamic acid is suppressed even under high temperature storage conditions, and if transported and stored, Even if it is subjected to high-temperature storage conditions, expansion does not occur and cracks and the like do not occur in the preparation. Therefore, the value of the solid preparation as a product is maintained even under various distribution and storage conditions, and is also convenient for use.

  Hereinafter, the present invention will be described in detail with reference to embodiments. The present invention is not limited to the embodiments exemplified below.

  The present invention relates to a solid preparation containing ibuprofen and tranexamic acid, which contains two or more organic acids or esters thereof or salts thereof, and two or more organic acids or esters thereof or salts thereof. The present invention relates to an expansion inhibitor for solid preparations containing ibuprofen and tranexamic acid.

  The solid preparation of the present invention is one in which swelling under high temperature storage conditions is suppressed, and can be produced by adding two or more organic acids or esters thereof or salts thereof.

  In a preferred embodiment, the step of adding two or more organic acids or esters thereof or a salt thereof can be performed by adding each of two or more components in a separate step.

  In a preferred embodiment, the solid preparation of the present invention is prepared by adding one or more components of two or more organic acids or their esters or their salts to ibuprofen and / or tranexamic acid, and mixing or preparing them. If ibuprofen and tranexamic acid are not added together in the previous step to the granulating step, this mixture or granulated product (sized granulated product), the remaining components and two or more organic acids or their esters or their salts It can obtain by the manufacturing method including the process of adding the 1 or more types of component, mixing and tableting.

  As the ibuprofen contained in the solid preparation of the present invention, not only ibuprofen but also a pharmaceutically acceptable salt of ibuprofen can be used, and these can be used commercially. The proportion of ibuprofen contained in the solid preparation of the present invention is preferably 1 to 70% by weight, more preferably 5 to 60% by weight, and particularly preferably 7 to 50% by weight as ibuprofen with respect to the whole solid preparation.

  As the tranexamic acid contained in the solid preparation of the present invention, not only tranexamic acid but also pharmaceutically acceptable salts of tranexamic acid can be used, and commercially available ones can be used. The proportion of tranexamic acid 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 tranexamic acid with respect to the entire solid formulation.

  Two or more organic acids or esters thereof or salts thereof contained in the solid preparation of the present invention can be produced by a known method, respectively, and commercially available products can also be used.

  Examples of the organic acid used in the present invention 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, and maleic acid. Fumaric acid, citric acid, edetic acid (ethylenediaminetetraacetic acid), lactic acid, malic acid, tartaric acid, ascorbic acid, erythorbic acid, gallic acid, glycine, alanine, arginine, cystathione, cysteine, lanthionine, histidine, homoserine, leucine, isoleucine And various carboxylic acids that may have a hydroxyl group or tertiary amine structure such as amino acids such as norleucine, lysine, methionine, valine, norvaline, ornithine, proline, sarcosine, serine, threonine, thyronine and tyrosine. The organic acid used in the present invention includes an acid anhydride (for example, phthalic anhydride) of the organic acid that can be converted into an acid anhydride by intramolecular dehydration condensation.

  Examples of the organic acid ester include esters of an organic acid and a monovalent or polyhydric alcohol. The monovalent alcohol generally has 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. Can be mentioned. In the present invention, monohydric alcohols preferably used for forming an ester of an organic acid include, for example, methanol, ethanol, propanol (propan-1-ol), isopropanol (propan-2-ol), butyl Alcohol (butan-1-ol), s-butyl alcohol (butan-2-ol), isobutyl alcohol (2-methylpropan-1-ol), t-butyl alcohol (2-methylpropan-2-ol), amyl Alcohol (pentan-1-ol, pentyl alcohol), 3-methylbutan-1-ol (isopentyl alcohol, isoamyl alcohol), 2-methylbutan-1-ol, pentane-3-ol, pentan-2-ol, 3- Methylbutan-2-ol, 2-methylbutane-2-o (T-pentyl alcohol), 2,2-dimethylpropan-1-ol (neopentyl alcohol), etc., preferably methanol, ethanol, propanol (propan-1-ol), isopropanol (propane-2) -Ol), butyl alcohol (butan-1-ol), s-butyl alcohol (butan-2-ol), isobutyl alcohol (2-methylpropan-1-ol), t-butyl alcohol (2-methylpropane-2) -Ol), 3-methylbutan-1-ol (isopentyl alcohol, isoamyl alcohol) and the like, particularly preferably methanol, ethanol, propanol (propan-1-ol), isopropanol (propan-2-ol). , 3-Methylbutane-1-o It can be mentioned (isopentyl alcohol, isoamyl alcohol), and the like. Examples of the polyhydric alcohol include pentavalent or hexavalent alcohol. In the present invention, examples of the polyhydric alcohol suitably used for forming an ester of an organic acid include catechin and derivatives thereof, preferably epicatechin and epigallocatechin. . The ester of an organic acid and an alcohol may be a monoester of an organic acid, and may be an organic acid ester having two or more ester bonds, up to the number of carboxyl groups of the organic acid. Organic acid diesters, organic acid triesters, and the like can be used. As preferable monoesters of organic acids, monoesters of organic acids with the above alcohols can be mentioned. As particularly preferred monoesters of organic acids, there can be mentioned, for example, monomethyl esters of organic acids and monoethyl esters of organic acids. Preferred diesters of organic acids include diesters of organic acids with the above alcohols. Examples of particularly preferable 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 alcohols. In a preferred embodiment, the organic acid ester having two or more ester bonds is such that each ester bond is formed by the same alcohol.

  Organic acid salts, specifically pharmaceutically acceptable salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, transitions such as manganese, iron, cobalt, nickel and copper Inorganic salts such as metal salts (inorganic salts of organic acids) can be mentioned. Esters include those derived from alcohols and those derived from phenols.

  In the present invention, preferred organic acids include, for example, 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 (edeto Acid), lactic acid, malic acid, tartaric acid, ascorbic acid, erythorbic acid, gallic acid, and amino acids. Fumaric acid, citric acid, edetic acid, malic acid, tartaric acid, and gallic acid are particularly preferable.

  Examples of organic acids or esters thereof or salts thereof include acetic acid, calcium acetate, cellulose acetate, tocopherol acetate, ethyl butyrate, riboflavin butyrate, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, benzyl benzoate, phthalate Diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, phthalic anhydride, salicylic acid, sodium salicylate, phenyl salicylate, malonic acid, succinic acid, monosodium succinate, disodium succinate hexahydrate, adipic acid, maleic Acid, fumaric acid, monosodium fumarate, sodium stearyl fumarate, dimethyl fumarate, diethyl fumarate, citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, sodium dihydrogen citrate Lithium, anhydrous citric acid, anhydrous sodium citrate, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate (also called calcium disodium edetate), disodium ethylenediaminetetraacetate (also referred to as sodium edetate), tetrasodium ethylenediaminetetraacetate Water salt (also called edetate tetrasodium), ethylenediaminetetraacetic acid tetrasodium tetrahydrate (also called edetate tetrasodium tetrahydrate), lactic acid, calcium lactate, malic acid, sodium malate, potassium malate, magnesium malate , Calcium malate, barium malate, malic acid dimethyl ester, malic acid diethyl ester, tartaric acid, potassium hydrogen tartrate, sodium tartrate, sodium potassium tartrate, monomethyl tartrate, ditartrate Tilester, ascorbic acid, erythorbic acid, sodium erythorbate, gallic acid, sodium gallate, ethyl gallate, propyl gallate, isoamyl gallate, epicatechin gallate (epicatechin gallate), epigallocatechin gallate (epigallo gallate) Catechin), amino acids and amino acid salts are preferred.

  In the present invention, the organic acid or ester thereof or a salt thereof includes fumaric acid, fumaric acid, monosodium fumarate, sodium stearyl fumarate, an ester thereof or a salt thereof, citric acid, calcium citrate, triethyl citrate. Citric acid such as sodium citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, esters thereof or salts thereof, disodium calcium ethylenediaminetetraacetate (disodium calcium edetate), disodium ethylenediaminetetraacetate ( Edetic acid such as sodium edetate), its esters or their salts, malic acid such as malic acid, sodium malate, its esters or their salts, tartaric acid, potassium hydrogen tartrate, sodium tartrate, sodium potassium tartrate Gallic acid such as tartaric acid, its esters or salts thereof, gallic acid, ethyl gallate, propyl gallate, isoamyl gallate, its esters or their salts, particularly fumaric acid, monosodium fumarate, fumaric acid Sodium stearyl, citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, calcium disodium edetate, sodium edetate, malic acid, sodium malate, tartaric acid Potassium hydrogen tartrate, sodium tartrate, sodium potassium tartrate and propyl gallate are preferred.

  The proportion of the organic acid or ester thereof or salt thereof contained in the solid preparation of the present invention is preferably 0.01 to 30% by weight, more preferably 0.1 to 20% by weight as the organic acid with respect to the whole solid preparation. preferable. Moreover, when an organic acid is fumaric acid, 0.1-10 mass% is preferable as fumaric acid with respect to the whole solid formulation, 0.5-5 mass% is still more preferable, 1-3 mass% is preferable. Particularly preferred. When the organic acid is citric acid, the ratio is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass as citric acid with respect to the entire solid preparation. . When the organic acid is edetic acid, the proportion thereof is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, particularly preferably 1 to 3% by weight as edetic acid with respect to the whole solid preparation. . When the organic acid is malic acid, the ratio is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass as malic acid with respect to the whole solid preparation. . When the organic acid is tartaric acid, the proportion thereof is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass as tartaric acid with respect to the whole solid preparation. When the organic acid is gallic acid, the ratio is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass as gallic acid with respect to the entire solid preparation. .

The solid preparation of the present invention contains two or more organic acids or esters thereof or salts thereof. In a preferred embodiment, the solid preparation of the present invention contains ibuprofen and tranexamic acid,
(A) One or more components selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
(B) one or more components selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or esters or salts thereof;
A solid preparation containing the components (A) and (B) is preferred.

In a preferred embodiment, the solid preparation of the present invention comprises
A step of adding the above component (B) to ibuprofen and / or tranexamic acid and mixing or granulating;
In the case where ibuprofen and tranexamic acid are not added together in the previous step, the remaining component and the component (A) are added to the mixture or granulated product (sized granulated product), mixed and tableted. It can obtain by the manufacturing method containing.

  In a preferred embodiment, an excellent expansion suppressing effect can be achieved by a combination of the addition of the component (A) and the addition of the component (B) in such a process.

  Among them, the component (A) is preferably selected from fumaric acid, sodium stearyl fumarate, and potassium sodium tartrate. In addition, the component (B) is citric acid, calcium citrate, triethyl citrate, sodium citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, disodium calcium edetate, sodium edetate, malic acid, Those selected from sodium malate, tartaric acid, potassium hydrogen tartrate, sodium tartrate and propyl gallate are preferred.

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

  In the solid preparation of the present invention, drugs other than ibuprofen and tranexamic acid, such as antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents , One or more selected from the group consisting of gastric mucosal protective agents, herbal medicines, Chinese herbal formulas, caffeine and the like may be included.

  Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, sodium salicylate, and the like.

Antihistamines include, for example, azelastine hydrochloride, isothipentyl hydrochloride, clemastine fumarate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolyzine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, Phenetadine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebhydroline napadisylate, promethazine methylene disalicylate , Carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, mequitazine, difeterol phosphate Etc.
Antitussives include, for example, aloclamide hydrochloride, cloperastine hydrochloride, carbetapentane citrate, tipepidine citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorphan / phenolphthaline salt, tipepidine hibenz Acid salt, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate and the like.

  Examples of noscapine include noscapine hydrochloride and noscapine.

  Examples of bronchodilators include dl-methylephedrine hydrochloride and dl-methylephedrine saccharin salt.

  Examples of expectorants include potassium guaiacol sulfonate, guaifenesin, bromohexine hydrochloride, ambroxol hydrochloride, carbocysteine and the like.

  Examples of the hypnotic sedative include bromvalerylurea and allylisopropylacetylurea.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof.

  Examples of the anti-inflammatory agent include lysozyme chloride, serrapase, glycyrrhizic acid and related substances.

  As gastric mucosa protective agents, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate Mixed dry gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, metasilicic acid Examples include magnesium aluminate.

  Herbal medicines include oxoamidin (processed garlic), mao (mao), nantenjitsu (nantenji), ohi (sakura), onji (dianthus), licorice (licorice), yellow bell (kikyo), shazenshi (carrot) , Shazenso (carcass), Sexan (Sardine carp), Senega, Baimo (shellfish mother), Fennel (clover), Oubak (yellow coral), Auren (yellow ream), Gajutsu, Chamomile, Keihi (cinnamon), Gentian, Gouo (cow yellow) ), Beast (including Yutan (bear gall)), Shajin (Ginseng), Syougyo (Ginger), Sojutsu (Coffee), Clove (Chen), Chimpi (Chen), Sandalwood (Bird), Giryu (Earth Dragon) ), Chixetsu carrot (bamboo carrot), carrot (carrot) and the like.

  The Kampo prescriptions include Kakkon-yu, Katsue-yu, Kososan, Saiko-Kei-yu, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-koboku-yu, Mao-to, and the like.

  Examples of caffeine include anhydrous caffeine, caffeine, and sodium benzoate caffeine.

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

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

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

Examples of the disintegrant include carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone, and croscarmellose sodium.
Examples of the lubricant include glycerin fatty acid ester, sucrose fatty acid ester, hydrogenated oil, talc and the like.

  Applicants have found that in solid formulations already containing ibuprofen and tranexamic acid, the swelling during storage at high temperatures is due to metal stearates such as magnesium stearate, calcium stearate, aluminum stearate. (See PCT / JP2007 / 001080 specification). Therefore, in the solid preparation of the present invention, those which do not substantially contain these metal stearates are preferable.

  Examples of the dosage form of the solid preparation of the present invention include capsules, pills, granules, tablets, powders and the like, and tablets are particularly preferable. The solid preparation may be coated with sugar coating, film coating, or the like.

  The solid preparation of the present invention can be produced according to a conventional method. For example, when the dosage form is a tablet, ibuprofen, tranexamic acid, two or more organic acids or esters thereof, salts thereof, various drugs, and various commonly used additives are used in conventional methods such as the Japanese Pharmacopoeia General Rules for Preparations. Based on this, the solid preparation of the present invention can be produced by tableting after mixing or granulating and mixing the resulting mixture or granulated product with a lubricant if desired.

  In addition, mixing or granulating, using ibuprofen, tranexamic acid, a kind of organic acid or ester thereof or salts thereof, various drugs and various commonly used additives based on conventional methods such as the Japanese Pharmacopoeia General Rules Tableting after mixing the obtained mixture or granulated product with another organic acid or an ester thereof or a salt thereof, and optionally further mixing an organic acid or an ester thereof or a salt thereof, and / or a lubricant, The solid preparation of the present invention can be produced.

In addition, ibuprofen, tranexamic acid, two or more organic acids or their esters or their salts, various drugs, and various commonly used additives are used in accordance with conventional methods such as the Japanese Pharmacopoeia General Rules for Preparation of Ibuprofen and tranexamic acid. By separately granulating each of these two granulated products, and optionally mixing an organic acid or an ester thereof or a salt thereof, and / or a lubricant, tableting is performed. It is possible to produce a solid preparation.
The solid preparation only needs to contain two or more organic acids or their esters or their salts, and both of the two types of granulated products contain organic acids or their esters or their salts. It may be. Further, when granulating separately, the organic acid or its ester or their salt may be the same or different.

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

[Example 1]
1350 g of ibuprofen (manufactured by Ritsu Yonezawa, trade name: Japanese Pharmacopoeia ibuprofen), 1260 g of tranexamic acid (manufactured by Daiichi Sankyo Propharma Co., Ltd .: trade name, Japanese Pharmacopoeia tranexamic acid), 106.2 g of citric acid anhydride (commercially manufactured by Komatsuya Chemical: Commodity) Name Japanese Pharmacopoeia Anhydrous Citric Acid), 486 g of croscarmellose sodium and 1560.6 g of D-mannitol were added to a high speed agitation granulator (Fukae Kogyo Co., Ltd .: FS-10 type) and mixed, and then 466 g of purified water was added. Kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). This sized product 4762.8 g and sodium stearyl fumarate 97.2 g (manufactured by JRS PHARMA, trade name: PROB) were put into a mixer (manufactured by Kotobuki: model PM50) and mixed, and then a bowl having a diameter of 8.5 mm was added. Tableting was performed using the attached tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) to obtain 18000 tablets each having a mass of 270 mg.

[Comparative example]
900 g of ibuprofen (manufactured by Riyone Yonezawa, trade name: Japanese Pharmacopoeia ibuprofen), 1499.4 g of tranexamic acid (manufactured by Daiichi Sankyo Propharma: trade name, Japanese Pharmacopoeia tranexamic acid), 106.2 g of hydroxypropyl cellulose (manufactured by Nippon Soda: (Trade name HPC-L), croscarmellose sodium 360 g (manufactured by Nichirin Kagaku Kogyo: trade name Kikkolate ND-2HS), and crystalline cellulose 1897.2 g (manufactured by Asahi Kasei Chemicals: trade name Seolus PH-101) Fukae Kogyo Co., Ltd .: FS-10 type) was added and mixed, and then 466 g of purified water was added and kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). The sized powder 4762.8 g and magnesium stearate 97.2 g were put into a mixer (Kotobuki: PM50 type) and mixed, and then a tableting machine (made by Hata Iron Works: 8.5 mm diameter) was attached. HT-AP18SS type) was used to obtain 18000 tablets each having a mass of 270 mg.

[Test Example] Expansion Evaluation One tablet obtained in Example 1 and Comparative Example was put in a glass bottle (2K standard), sealed, and then placed in a thermostatic container at 40 ° C. for 1 month, 2 months and 3 months. Saved for a while. The expansion rate (%) defined by the following formula (1) was calculated from the thickness of the tablet immediately after production measured with a digital micrometer and the thickness of the tablet after storage.

Expansion rate (%) = (D−D0) / D0 × 100 (1)

In the formula, D is the thickness of the tablet after storage, and D0 is the thickness of the tablet immediately after production.
The results are shown in Table 1.

  As is apparent from Table 1, the tablet containing no organic acid or its ester or salt thereof (Comparative Example) has a high expansion rate after storage at 40 ° C. for 1 month, 2 months, 3 months. Cracking and chipping were likely to occur. In the comparative example, the tablet was clearly unsuitable as a product after storage at 40 ° C. for 3 months, and it was judged that the storage test over the subsequent storage period was meaningless, and the subsequent test was not performed. On the other hand, in the tablet (Example 1) of the present invention containing two or more organic acids or esters thereof or salts thereof (citric acid and sodium stearyl fumarate), 40 ° C. for 1 month, 2 months, Expansion rates after storage for 3 months, 4 months, 5 months, and 6 months are 0.5%, 0.4%, 0.5%, 0.6%, 0.5%, and 0.6%, respectively. %, And a remarkable expansion suppressing effect was recognized. In addition, the tablet of the present invention (Example 1) was found to be an extremely stable tablet with no cracking or chipping of the tablet even after storage under the severe conditions described above.

[Example 2]
A tablet was obtained in the same manner as in Example 1 except that the anhydrous citric acid was changed to malic acid (product name: Kawasaki Kasei Kogyo Co., Ltd .: trade name: malic acid, 40M for food additive).

[Example 3]
Tablets were obtained in the same manner as in Example 1 except that anhydrous citric acid was changed to propyl gallate (trade name: propyl gallate manufactured by Wako Pure Chemical Industries, Ltd.).

[Example 4]
Tablets were obtained in the same manner as in Example 1 except that the anhydrous citric acid was changed to tartaric acid (manufactured by Kanto Chemical Co., Ltd .: trade name L (+)-tartaric acid).

[Example 5]
Tablets were obtained in the same manner as in Example 1 except that anhydrous citrate was changed to sodium edetate (trade name: EDTA2Na manufactured by Kanto Chemical Co., Inc.).

[Production Example 1]
A film-coated tablet was produced according to the following prescription in accordance with the “Tablet” section of the General Rules for Preparations of the 15th revised Japanese Pharmacopoeia.
Ibuprofen 900.0g
Tranexamic acid 1500.0g
Anhydrous caffeine 150.0g
d-Chlorpheniramine maleate 7.0 g
Dihydrocodeine phosphate 48.0g
dl-Methylephedrine hydrochloride 120.0 g
Guayphenesin 500.0g
Carmellose calcium 200.0g
100.0 g of anhydrous citric acid
Sodium stearyl fumarate 100.0g
Light anhydrous silicic acid 130.0g
Lactose hydrate 945.0g
Calcium silicate 100.0g
Hypromellose 200.0g
Triacetin 20.0g
Titanium oxide 20.0g
Yellow No. 5 Trace amount carnauba wax Total amount 5040.0 g

[Production Example 2]
A film-coated tablet was produced according to the following prescription in accordance with the “Tablet” section of the General Rules for Preparations of the 15th revised Japanese Pharmacopoeia.
Ibuprofen 1350.0g
Tranexamic acid 1260.0g
Anhydrous caffeine 720.0g
Light anhydrous silicic acid 200.0g
Citric anhydride 150.0g
Sodium stearyl fumarate 100.0g
Croscarmellose sodium 500.0g
D-mannitol 190.0g
Crystalline cellulose 300.0g
Hypromellose 300.0g
Triacetin 30.0g
Titanium oxide 30.0g
Carnauba wax Trace amount 5130.0g

  The present invention relates to a solid preparation containing ibuprofen and tranexamic acid, which contains two or more organic acids or esters thereof, or salts thereof, and thereby a stable solid preparation that does not swell even under high temperature storage conditions. It is to provide. It is known that pharmaceutical preparations containing ibuprofen and tranexamic acid can obtain not only the medicinal effects of these components but also additional effects such as enhanced efficacy and reduced side effects. It makes it possible to provide the preparation stably. If the solid preparation obtained in the present invention is used, it can be stored for a long period of time or used under high temperature conditions, and is extremely useful in the pharmaceutical industry.

Claims (5)

A solid formulation containing ibuprofen and tranexamic acid,
A solid preparation containing two or more organic acids or esters thereof or salts thereof. A solid formulation containing ibuprofen and tranexamic acid,
(A) one or more selected from fumaric acid or tartaric acid, or an ester or a salt thereof,
(B) at least one selected from citric acid, malic acid, tartaric acid, gallic acid or edetic acid, or an ester or a salt thereof,
A solid preparation containing the components (A) and (B).   The solid preparation according to claim 2, wherein the component (A) is selected from fumaric acid, sodium stearyl fumarate or potassium sodium tartrate.   A swelling inhibitor for solid preparations containing ibuprofen and tranexamic acid, comprising two or more organic acids or esters thereof or salts thereof.   A method for suppressing swelling of a solid preparation containing ibuprofen and tranexamic acid by adding two or more organic acids or esters thereof or a salt thereof.