JP2009179613A - Solid preparation comprising ibuprofen and tranexamic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation containing ibuprofen and tranexamic acid and exhibiting suppressed expansion by the storage at a high temperature. <P>SOLUTION: The solid preparation comprising ibuprofen and tranexamic acid further comprises fumaric acid, its ester or their salts. <P>COPYRIGHT: (C)2009,JPO&INPIT

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), 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 bromvalenylurea 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, 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 medicinal composition for cold (see Patent Document 14), a pharmaceutical composition containing clemastine and / or bromohexine (see Patent Document 15), and the like have been reported.

  On the other hand, there is a method of formulating a narcotic analgesic such as morphine and codeine and a non-steroidal anti-inflammatory carboxylic acid such as diclofenac, naproxen, ketoprofen and ibuprofen as a multilayer tablet without containing stearic acid and stearate. It has been proposed (see Patent Document 16). This is because the compatibility of these components is very poor, the compressibility is low, the disintegration time is long, and the colorability is high, so that these components cannot be formulated as a single-layer tablet. Yes. For this reason, a method of using hydrogenated vegetable oil instead of stearic acid as a lubricant has also been proposed (see Patent Document 17).

However, such a case has not been reported in combination with drugs other than narcotic analgesics such as codeine. For example, in Patent Document 9, a component containing ibuprofen, tranexamic acid, etc. is added using magnesium stearate. It was described that tablets of 370 mg were tableted (Patent Document 9, Paragraph [0032]). In Patent Document 11, a known method described in the General Rules for Preparation of Pharmacopoeia with ingredients containing ibuprofen and tranexamic acid together with magnesium stearate (Patent Document 11, paragraphs [0047] and [0048]). Also in Patent Document 15, magnesium stearate is used as a component containing tranexamic acid and ibuprofen. It is described that it was tableted by a conventional method. (Patent Document 15, Paragraph [0039]), and also in JP-A-2006-104186 (Patent Document 18), it was similarly tableted by the method described in the section of tablets in the Japanese Pharmacopoeia General Rules for Preparations. (Patent Document 18, paragraph [0012]). Thus, it was believed that the undesirable effects of stearic acid and stearate in formulations containing ibuprofen were limited to combinations with narcotic analgesics such as codeine.
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 JP-A-62-51625 Japanese National Patent Publication No. 10-504557 JP 2006-104186 A

  The present inventors have studied solid preparations containing ibuprofen and tranexamic acid, and these solid preparations can be stably stored for a long period of time if stored at 1 to 25 ° C. Then, it discovered that expansion | swelling occurred and a crack etc. generate | occur | produced in a formulation.

  Therefore, an object of the present invention is to provide a solid preparation containing ibuprofen and tranexamic acid in which swelling is suppressed even when stored under high temperature storage conditions.

  The inventors have sought this cause to solve the problem of swelling under high temperature storage conditions in solid formulations containing ibuprofen and tranexamic acid. A solid preparation containing ibuprofen and tranexamic acid swells under high-temperature storage conditions, but can be tableted and does not cause coloration. Formulation such as codeine described in Patent Document 16 and Patent Document 17 It was completely different from the tableting problem. Further, such expansion is not accompanied by generation of gas due to decomposition of components, and is not due to moisture absorption, and it has been very difficult to fully elucidate the cause.

  Swelling under high-temperature storage conditions occurs only when ibuprofen and tranexamic acid are blended at the same time, and not when each is a single component. For example, a multilayer tablet or a dry-coated tablet with both components separated. It is also possible to reduce the contact between ibuprofen and tranexamic acid. 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. Furthermore, it is conceivable to suppress the expansion of the preparation by covering with a sugar coating or a film coating, but the degree of expansion of the solid preparation is large, and it was difficult to prevent it by only the sugar coating or the film coating. Moreover, although it can also be said that expansion | swelling is suppressed by storing the solid formulation containing ibuprofen and tranexamic acid at 1-25 degreeC like before, there existed inconvenience on distribution, storage, and use. .

  In order to solve these problems, the present inventors have conducted a detailed study on all the components blended in the solid preparation, and this problem is not due to only the two components ibuprofen and tranexamic acid, but ibuprofen, It was found that it was caused by a combination of three components of tranexamic acid and magnesium stearate. As a result of further investigation, it was found that the same swelling problem occurs when calcium stearate or aluminum stearate is used in place of magnesium stearate. Surprisingly, this is the case with stearic acid or magnesium silicate. It was also found that no problem occurred. This was found to be due to a compound such as magnesium stearate, calcium stearate, and aluminum stearate, and not a problem with stearic acid itself or a metal ion itself such as magnesium or calcium.

  In producing a solid preparation containing ibuprofen and tranexamic acid, the present inventors do not combine magnesium stearate, calcium stearate or aluminum stearate, but use fumaric acid or an ester thereof or a salt thereof in combination. The inventors have found that a stable solid preparation that does not cause the problem of swelling under high-temperature storage conditions can be obtained, and the present invention has been completed.

  That is, the present invention relates to a solid preparation containing ibuprofen and tranexamic acid, wherein the solid preparation contains fumaric acid or an ester thereof or a salt thereof.

  Further, the present invention is a solid preparation containing ibuprofen and tranexamic acid, wherein a lubricant other than a metal stearate, preferably a lubricant other than magnesium stearate, calcium stearate or aluminum stearate is used as a lubricant. It relates to a featured solid formulation.

More specifically, the present invention relates to the following items.
(1) A solid preparation containing ibuprofen and tranexamic acid,
A solid preparation containing fumaric acid or an ester thereof or a salt thereof.
(2) An expansion inhibitor for a solid preparation containing ibuprofen and tranexamic acid, comprising fumaric acid or an ester thereof or a salt thereof.

Furthermore, the present invention relates to the following matters.
(3) The solid preparation of (1), wherein the solid preparation does not contain magnesium stearate, calcium stearate and aluminum stearate.
(4) The solid preparation of (1) or (3), wherein the solid preparation is a tablet.
(5) The expansion inhibitor according to (2) for use in a solid preparation not containing magnesium stearate, calcium stearate and aluminum stearate.
(6) The expansion inhibitor according to (2) or (5), wherein the solid preparation is a tablet.
(7) A method for inhibiting swelling of a solid preparation containing ibuprofen and tranexamic acid, comprising a step of containing fumaric acid or an ester thereof or a salt thereof.
(8) The method according to (7), wherein the solid preparation does not contain magnesium stearate, calcium stearate and aluminum stearate.
(9) The method according to (7) or (8), wherein the solid preparation is a tablet.
(10) A method for producing a solid preparation containing ibuprofen and tranexamic acid, comprising a step of containing fumaric acid or an ester thereof or a salt thereof.
(11) The method according to (10), wherein the solid preparation does not contain magnesium stearate, calcium stearate and aluminum stearate.
(12) The method according to (10) or (11), wherein the solid preparation is a tablet.

  According to the present invention, a stable solid preparation in which the expansion of a solid preparation containing ibuprofen and tranexamic acid is suppressed even under high-temperature storage conditions can be obtained.

  The solid preparation of the present invention contains ibuprofen and tranexamic acid, and contains fumaric acid or an ester thereof or a salt thereof.

  The ibuprofen contained in the solid preparation of the present invention is not only ibuprofen itself but also pharmaceutically acceptable salts (alkali metal salts such as sodium salt and calcium salt and alkaline earth metal salts; organic acids such as arginine salt and lysine salt). Salt, etc.) can also be used, and these can be used commercially. The proportion of ibuprofen contained in the solid preparation of the present invention is not particularly limited, but from the viewpoint of the pharmacological effect, 1 to 70% by mass in terms of free form of ibuprofen is preferable with respect to the entire solid preparation, 5-60 mass% is still more preferable, and 7-50 mass% is especially preferable.

  In addition to tranexamic acid itself, tranexamic acid contained in the solid preparation of the present invention includes pharmaceutically acceptable salts thereof (alkali metal salts such as potassium salt and magnesium salt and alkaline earth metal salts; mineral salts such as sulfates). Etc.) can also be used, and these can be used commercially. The proportion of tranexamic acid contained in the solid preparation of the present invention is not particularly limited, but from the viewpoint of pharmacological effects, 1 to 70 mass% in terms of free form of tranexamic acid is used relative to the entire solid preparation. Preferably, 5-60 mass% is further more preferable, and 7-50 mass% is especially preferable.

  In the fumaric acid or an ester thereof or a salt thereof contained in the solid preparation of the present invention, examples of the alcohol that forms an ester with fumaric acid include alcohols having an alkyl group or an alkenyl group. 22 (C1-C22 straight chain, C3-C22 branched or cyclic) alkyl group, or C2-C22 (C2-C22 linear, or C3-C3) (22 branched or cyclic) alcohol having an alkenyl group, and examples of the alkyl group and alkenyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, an allyl group, a butyl group, and a pentyl group. Group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, isodecyl group, undecyl group, dodecyl group (lauryl group), tridecyl group, teto Decyl group (myristyl group), a pentadecyl group, a hexadecyl group (cetyl group, palmityl group), a heptadecyl group, an octadecyl group (stearyl group), isostearyl group, oleyl group, a nonadecyl group, eicosyl group, behenyl group and the like. Examples of these alcohols and fumaric acid esters, alkyl fumarate and alkenyl fumarate include, for example, methyl fumarate, ethyl fumarate, propyl fumarate, isopropyl fumarate, cyclopropyl fumarate, allyl fumarate, butyl fumarate , Pentyl fumarate, hexyl fumarate, heptyl fumarate, octyl fumarate, nonyl fumarate, decyl fumarate, isodecyl fumarate, undecyl fumarate, dodecyl fumarate (lauryl fumarate), tridecyl fumarate, tetradecyl fumarate ( Myristyl fumarate), pentadecyl fumarate, hexadecyl fumarate (cetyl fumarate, palmityl fumarate), heptadecyl fumarate, octadecyl fumarate (stearyl fumarate), isostearyl fumarate, oleyl fumarate, fumarate Le acid nonadecyl, eicosyl fumarate, behenyl fumarate and the like. Preferable ester includes octadecyl fumarate (stearyl fumarate).

  Specific examples of the salt of fumaric acid or its ester include pharmaceutically acceptable salts, such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, manganese, iron and the like. And transition metal salts. Preferable salts include alkali metal salts such as sodium and potassium, particularly preferably sodium salts.

  In the embodiment of the present invention, as fumaric acid or an ester thereof or a salt thereof that can be suitably used, specifically, fumaric acid, dimethyl fumarate, diethyl fumarate, dibutyl fumarate, dioctyl fumarate, fumaric acid Monosodium, sodium fumarate, ferrous fumarate, sodium stearyl fumarate, etc., and more preferable examples include fumaric acid, monosodium fumarate, sodium stearyl fumarate, and particularly fumaric acid, fumaric acid. Sodium stearyl is preferred.

  The ratio of fumaric acid or an ester thereof or a salt thereof contained in the solid preparation of the present invention is preferably from 0.1 to 20% by weight, more preferably from 0.5 to 10% by weight, based on the whole solid preparation. 1-5 mass% is especially preferable.

  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 a preferred embodiment, the solid preparation of the present invention does not contain magnesium stearate, calcium stearate and aluminum stearate, which causes expansion of the solid preparation when stored at high temperature, and fumaric acid or its esters or their It contains the salt of. Further, a solid preparation containing fumaric acid or an ester thereof or a salt thereof and containing substantially no magnesium stearate, calcium stearate and aluminum stearate, and having suppressed swelling during storage at high temperature, It is included in the present invention.

  The solid preparation of the present invention comprises drugs other than ibuprofen and tranexamic acid, such as antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents , One or more selected from the group consisting of 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 maleic acid, mequitazine, difeterol phosphate, etc. Is mentioned.

  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, dl-methylephedrine saccharin salt, and the like.

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

  Examples of the hypnotic sedative include bromvalerylurea and allyl isopropyl acetyl urea.

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

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

  Examples of the gastric mucosa protective agent include 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, Examples thereof include magnesium aluminate metasilicate.

  Herbal medicines include, for example, oxoamidin (processed garlic), mao (mao), nantenjitsu (nantenji), ohi (cherry bark), onji (dianthus), licorice (licorice), kyokyo (kikyoroot), shazenshi (car) Maeko, Shazenso (carcass), Sexan (Sardine moth), Senega, Baimo (shellfish mother), Fennel (cage), Aubergine (Yellow), Ouren (Yellow), Gajutsu, Chamomile, Keihi (cinnamon), Gentian, Gooh (beef yellow), beast gall (including yuutan (bear gall)), shajin (shasan), ginger, sojutsu (cage), clove (clove), chimpi (skin), sandalwood (white birch), giryu (Earth dragon), Chikutsutsu carrot (Bamboo carrot), Carrot (carrot)

  Examples of Kampo prescriptions include Kakkon-to, Katsue-yu, Kosou-san, Saiko-Kei-to, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, 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 additives (excipients, binders, disintegrants, lubricants, etc.) other than magnesium stearate, calcium stearate and aluminum stearate within the range not impeding the effects of the present invention. It may be included.

  Examples of the excipient include lactose, starches, crystalline cellulose, sucrose, mannitol and the like. Examples of the binder include hydroxypropyl methylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol, pullulan and the like. Examples of the disintegrant include carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium and the like. As the lubricant, for example, talc, stearic acid, silica, sucrose fatty acid ester, light anhydrous silicic acid, wax (carnauba wax, wood wax (goose wax, urushi wax), castor wax, etc., plant-derived wax, beeswax, honey beeswax, etc. Animal waxes such as whale wax and refined lanolin, petroleum-derived waxes such as paraffin and microcrystalline wax, natural waxes such as montan wax and mineral-derived waxes such as refined montan wax, synthetic waxes, etc.), hydrogenated vegetable oils, macro Examples include galls, sodium lauryl sulfate, glycerin fatty acid ester, hydrogenated castor oil, and the like.

  Examples of the dosage form of the solid preparation capable of obtaining the effects 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 or film coating.

  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, fumaric acid or an ester thereof or a salt thereof, various additives usually used in the manufacture of tablets, and optionally various drugs are mixed according to a conventional method. The solid preparation of the present invention can be produced by granulating and tableting. In addition, ibuprofen, tranexamic acid, fumaric acid or its ester or their salts, and various additives usually used in the manufacture of tablets and, if necessary, various drugs, granulate ibuprofen and tranexamic acid separately according to conventional methods. The solid preparation of the present invention can be produced by mixing and tableting. Fumaric acid or an ester thereof or a salt thereof can be contained in an appropriate step during the production of a tablet.

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

[Reference Example 1]
900 g of ibuprofen (trade name: Japanese Pharmacopoeia ibuprofen), tranexamic acid 840 g (Daiichi Pharmatech: Japan Pharmacopoeia tranexamic acid), hydroxypropylcellulose 96 g, crystalline cellulose 1104 g, croscarmellose sodium 200 g The mixture was put into a high-speed agitation granulator (Fukae Kogyo: FS-10 type) and mixed, and then 1000 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). 3140 g of this sized product and 40 g of magnesium stearate were put into a mixer (Kotobuki: PM50 type) and mixed, and then a tableting machine (made by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch. ) Was used to obtain 12000 tablets each having a mass of 265 mg.
[Reference Example 2]
A tablet was obtained in the same manner as in Reference Example 1 except that 40 g of calcium stearate was blended instead of blending magnesium stearate of Reference Example 1.
[Reference Example 3]
Instead of blending magnesium stearate of Reference Example 1, 40 g of aluminum stearate was blended, and the rest was obtained in the same manner as Reference Example 1 except that tablets were obtained.
[Reference Example 4]
A tablet was obtained in the same manner as in Reference Example 1 except that 60 g of stearic acid was added instead of magnesium stearate of Reference Example 1 and crystalline cellulose was changed to 1084 g.

[Test Example 1]
Evaluation of Expansion Six tablets prepared in Reference Examples 1 to 4 were put into glass bottles (5K standard), sealed, and stored in a thermostatic container at 60 ° C. for 3 days. 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−D ₀ ) / D ₀ × 100 (1)
In the formula, D is the thickness of the tablet after storage, and D ₀ is the thickness of the tablet immediately after production.
Table 1 below shows the formulation (unit: mg / 6 tablets) per tablet obtained in Reference Examples 1 to 4 and the test results.

  The swelling rate of a tablet containing ibuprofen and tranexamic acid and containing magnesium stearate (Reference Example 1), calcium stearate (Reference Example 2) or aluminum stearate (Reference Example 3)) at 60 ° C. for 3 days is A large expansion coefficient of 32% was observed for Reference Example 1, 26% for Reference Example 2, and 30% for Reference Example 3. Moreover, since these tablets had a large expansion rate, they became brittle and the tablets were easily cracked or chipped. On the other hand, the expansion rate of the tablet containing stearic acid was as extremely small as 6%.

[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: trade name, Japanese Pharmacopoeia, tranexamic acid), 145.8 g of hydroxypropylcellulose, 486 g of croscarmellose sodium, After 1521 g of D-mannitol was put into a high-speed stirring granulator (Fukae Kogyo Co., Ltd .: FS-10 type) and mixed, 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). 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 1]
Instead of compounding sodium stearyl fumarate of Example 1, 97.2 g of magnesium stearate (trade name: Magnesium stearate vegetable) manufactured by Taihei Chemical Co., Ltd. was added, and tablets were obtained in the same manner as Example 1 except for that. It was.

[Comparative Example 2]
Instead of blending sodium stearyl fumarate of Example 1, 97.2 g of calcium stearate (trade name: calcium stearate vegetable) manufactured by Taihei Chemical Co., Ltd. was blended in the same manner as in Example 1, and tablets were obtained.

[Test Example 2]
Evaluation of expansion After putting the tablets produced in Example 1 and Comparative Examples 1 and 2 into glass bottles (2K standard) one by one and sealing them, they are placed in a thermostatic container at 50 ° C. for 2 weeks and in a thermostatic container at 60 ° C. for 1 day. saved. The expansion rate (%) was calculated in the same manner as in Test Example 1.
The formulation (unit: mg / tablet) per tablet obtained in Example 1 and Comparative Examples 1 and 2 and the test results are shown in Table 2 below.

In the preparation containing magnesium stearate (Comparative Example 1), the expansion rates after storage at 60 ° C. for 1 day and 50 ° C. for 2 weeks were 22.8% and 29.6%, respectively, which were high. In addition, in the preparation containing calcium stearate (Comparative Example 2), the expansion rates after storage at 60 ° C. for 1 day and 50 ° C. for 2 weeks were 20.9% and 19.8%, respectively. On the other hand, the solid preparation (Example 1) of the present invention containing ibuprofen and tranexamic acid and containing sodium stearyl fumarate has an expansion rate of 2.6% after storage at 60 ° C. for 1 day, 50 ° C. for 2 weeks. The expansion rate after storage was as extremely small as 2.1%, and a remarkable expansion suppression effect was recognized.
In addition, Comparative Examples 1 and 2 were brittle and easily cracked or chipped due to the large expansion coefficient. However, the solid preparation of the present invention (Example 1) was subjected to the above severe high temperature conditions. Even after storage, the tablet was not broken or chipped, and was found to be a stable tablet.

  The present invention provides a stable preparation containing ibuprofen and tranexamic acid that does not swell even when stored at high temperatures. It is known that a preparation containing ibuprofen and tranexamic acid can obtain not only the medicinal effects of these components but also additional effects such as enhanced medicinal effects and reduced side effects. Therefore, the present invention makes it possible to provide useful pharmaceutical preparations in a stable dosage form, and further enables long-term storage and safe distribution under normal climatic conditions, which are extremely useful industrially. It is a thing.

Claims (2)

A solid formulation containing ibuprofen and tranexamic acid,
A solid preparation containing fumaric acid or an ester thereof or a salt thereof.   An expansion inhibitor for solid preparations containing ibuprofen and tranexamic acid, comprising fumaric acid or an ester thereof or a salt thereof.