formulation

Abstract

To solve the problem in which a preparation containing tranexamic acid and ibuprofen is unstable, so that the preparation expands in volume.SOLUTION: The present invention relates to a preparation containing ibuprofen and tranexamic acid, the preparation containing carbocysteine. In the preparation, the proportions of mixing of the ibuprofen and the tranexamic acid and the carbocysteine is 0.5-1.5:0.2-1.5:1.0 in weight. Thus, it becomes possible to prevent the expansion of the preparation.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] The present invention relates to formulations. [Background technology]

[0002] Ibuprofen (or its salts) and tranexamic acid (or its salts) are both known as active ingredients in anti-inflammatory, antipyretic and analgesic drugs, and preparations such as antipyretic and cold medicines that combine ibuprofen and tranexamic acid have already been manufactured.

[0003] However, formulations containing ibuprofen and tranexamic acid have the problem that, when bottled and stored, the volume of the formulation expands over time. To address this problem, for example, Japanese Patent Application Laid-Open No. 2007-284423 (Patent Document 1) discloses a formulation containing tranexamic acid (or a salt thereof) and ibuprofen, in which the tranexamic acid (or a salt thereof) and ibuprofen are blended so that they do not substantially come into contact with each other. Specifically, the formulation is produced by melt-granulating either tranexamic acid or ibuprofen, without melt-granulating both together. This prevents the volume expansion of the formulation containing tranexamic acid and ibuprofen, enabling the production of a stable formulation.

[0004] Japanese Patent Application Laid-Open Publication No. 2008-239554 (Patent Document 2) discloses a solid formulation containing ibuprofen and tranexamic acid, characterized in that it contains polyoxyethylene polyoxypropylene glycol. Japanese Patent Application Laid-Open Publication No. 2008-266270 (Patent Document 3) discloses the same solid formulation, characterized in that it contains a sugar alcohol. Japanese Patent Application Laid-Open Publication No. 2009-51795 (Patent Document 4) discloses the same solid formulation, characterized in that it contains one or more selected from the group consisting of cyclodextrins and their derivatives. Japanese Patent Application Laid-Open Publication No. 2009-179613 (Patent Document 5) discloses the same solid formulation, characterized in that it contains fumaric acid or its esters, or salts thereof. Japanese Patent Application Laid-Open Publication No. 2010-30903 (Patent Document 6) discloses the same solid formulation, characterized in that it contains calcium silicate. This makes it possible to obtain a stable solid preparation containing ibuprofen and tranexamic acid, in which swelling is suppressed even under high-temperature storage conditions.

[0005] Furthermore, Japanese Patent Laid-Open Publication No. 2007-91633 (Patent Document 7) discloses a pharmaceutical composition containing (i) mequitazine and / or a salt thereof, (ii) ibuprofen and / or a salt thereof, and (iii) tranexamic acid and / or a salt thereof, which is said to provide a pharmaceutical composition that not only prevents color change but also inhibits wetting and has excellent stability. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2007-284423 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-239554 [Patent Document 3] Japanese Patent Application Laid-Open No. 2008-266270 [Patent Document 4] Japanese Patent Application Laid-Open No. 2009-51795 [Patent Document 5] Japanese Patent Application Laid-Open No. 2009-179613 [Patent Document 6] Japanese Patent Application Laid-Open No. 2010-30903 [Patent Document 7] Japanese Patent Application Laid-Open No. 2007-91633 Summary of the Invention [Problem to be solved by the invention]

[0007] As described above, formulations containing ibuprofen and tranexamic acid have the problem of being unstable and of swelling in volume.

[0008] The technology described in Patent Document 1 has a problem in that it is necessary to melt-granulate either ibuprofen or tranexamic acid. Furthermore, the technologies described in Patent Documents 2-6 have a problem in that it is necessary to add an extra component to a fixed formulation containing ibuprofen and tranexamic acid. The technology described in Patent Document 7 has a problem in that it is necessary to add mequitazine, a phenothiazine antihistamine.

[0009] Therefore, there has been a need for a simple formulation that enhances the stability of a formulation containing ibuprofen and tranexamic acid.

[0010] Therefore, the present invention has been made to solve the above problems, and an object of the present invention is to provide a preparation that can suppress the swelling of the preparation. [Means for solving the problem]

[0011] The preparation according to the present invention is a preparation containing ibuprofen and tranexamic acid, and also contains carbocisteine. [Effects of the Invention]

[0012] According to the present invention, it is possible to suppress swelling of the preparation. [Brief explanation of the drawings]

[0013] [Figure 1] 1 is a table showing the formulations of Example 1 and Comparative Example 1. [Figure 2] 1 is a table showing the formulations of Example 2 and Comparative Example 2. [Figure 3] 1 is a table showing the formulations of Example 3 and Comparative Example 3. [Figure 4] 1 is a table showing the formulations of Example 4 and Comparative Example 4. [Figure 5] 1 is a table showing the formulations of Example 5 and Comparative Example 5. [Figure 6] 1 is a table showing the formulations of Example 6 and Comparative Example 6. [Figure 7] 1 is a table showing the formulations of Example 7 and Comparative Example 7. [Figure 8] 1 is a graph showing the evaluation results of the powders of Examples 1-3 and Comparative Examples 1-3. [Figure 9] 1 is a graph showing the evaluation results of tablets of Examples 4-7 and Comparative Examples 4-7. DETAILED DESCRIPTION OF THE INVENTION

[0014] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings to help understand the present invention. Note that the following embodiment is an example of the present invention and is not intended to limit the technical scope of the present invention.

[0015] The formulation of the present invention is a formulation containing ibuprofen and tranexamic acid, and also contains carbocisteine. When a formulation containing ibuprofen and tranexamic acid is produced according to a standard method, the combination of ibuprofen and tranexamic acid can be expected to provide additional effects such as enhanced efficacy and reduced side effects, but there is a problem that the formulation volume expands. When the formulation is a tablet, the expansion of the formulation can cause cracking of the tablet, and when the formulation is a powder, the bag containing the powder can be damaged.

[0016] Therefore, the present inventors have been searching for a formulation that suppresses the swelling of a preparation containing ibuprofin and tranexamic acid, and have unexpectedly discovered that the addition of carbocisteine ​​suppresses the swelling of the preparation. Based on these findings, the present invention has been completed based on the examples described below.

[0017] Here, ibuprofen is a non-steroidal anti-inflammatory analgesic classified as a propionic acid type, and examples thereof include ibuprofen itself as well as its pharmaceutically acceptable salts (alkali metal salts and alkaline earth metal salts such as sodium salt and calcium salt; organic acid salts such as arginine salt and lysine salt, etc.), and commercially available products can be used.

[0018] The proportion of ibuprofen contained in the formulation is not particularly limited, but is preferably 5% to 30% by weight, and more preferably 10% to 20% by weight, of the total formulation. Since ibuprofen includes its salts, when ibuprofen is a salt, the proportion of ibuprofen is calculated as the free form. The same applies hereinafter.

[0019] The amount of ibuprofen contained in the formulation is not particularly limited, but when the formulation is a tablet, the amount of ibuprofen is preferably 20 mg to 100 mg per formulation, and more preferably 40 mg to 80 mg. When the formulation is a powder, the amount of ibuprofen is preferably 300 mg to 600 mg per powder. When ibuprofin is administered orally, the daily dose of ibuprofin is preferably 300 mg to 600 mg.

[0020] Tranexamic acid is a type of hemostatic and anti-inflammatory agent, and examples thereof include tranexamic acid itself as well as its pharmaceutically acceptable salts (alkali metal salts such as potassium salt and magnesium salt, alkaline earth metal salts, mineral acid salts such as sulfate, etc.), and commercially available products can be used.

[0021] The proportion of tranexamic acid contained in the formulation is not particularly limited, but is preferably 3% to 40% by weight, and more preferably 5% to 30% by weight, of the total formulation. Since tranexamic acid includes its salts, when tranexamic acid is a salt, the proportion of tranexamic acid is calculated as the free form. The same applies below.

[0022] The amount of tranexamic acid contained in the formulation is not particularly limited, but when the formulation is a tablet, the amount of tranexamic acid is preferably 20 mg to 120 mg per formulation, and more preferably 30 mg to 100 mg. When the formulation is a powder, the amount of tranexamic acid is preferably 280 mg to 750 mg per powder. When tranexamic acid is administered orally, the daily dose of tranexamic acid is preferably 280 mg to 750 mg.

[0023] Carbocisteine ​​is a type of expectorant, and examples thereof include carbocisteine ​​itself, as well as L-carbocistine and its pharmaceutically acceptable salts described in the Japanese Pharmacopoeia, and these can be commercially available products.

[0024] The proportion of carbocisteine ​​contained in the formulation is not particularly limited, but is preferably 5% to 40% by weight, and more preferably 10% to 30% by weight, based on the total weight of the formulation. Since carbocisteine ​​also includes its salts, when carbocisteine ​​is a salt, the proportion of carbocisteine ​​is calculated as the free form. The same applies hereinafter.

[0025] The amount of carbocisteine ​​contained in the formulation is not particularly limited, but when the formulation is a tablet, the amount of carbocisteine ​​is preferably 40 mg to 120 mg per formulation, and more preferably 60 mg to 100 mg. When the formulation is a powder, the amount of carbocisteine ​​is preferably 400 mg to 750 mg per powder. When carbocisteine ​​is administered orally, the daily dose of carbocisteine ​​is preferably 400 mg to 750 mg.

[0026] The mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the formulation is not particularly limited, but from the viewpoint of suppressing the swelling rate of the formulation, a weight ratio of 0.5-1.5:0.2-1.5:1.0 is preferred, and a weight ratio of 0.6-0.8:0.3-1.0:1.0 is even more preferred. When any one or all of ibuprofen, tranexamic acid, and carbocisteine ​​are salts thereof, the above-mentioned mixing ratio is calculated as the free form. The same applies hereinafter.

[0027] Furthermore, the formulation of the present invention may contain one or more drugs other than ibuprofen, tranexamic acid, and carbocisteine, such as antipyretics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents, herbal medicines, Chinese herbal medicines, caffeines, etc.

[0028] Examples of antipyretic analgesics include aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, and sodium salicylate.

[0029] Examples of antihistamines include azelastine hydrochloride, isothipendyl hydrochloride, clemastine fumarate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teoclate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, mequitazine, and difeterol phosphate.

[0030] Examples of antitussives include alloclamide hydrochloride, cloperastine hydrochloride, carbetapentane citrate, tipepidine citrate, dibunate sodium, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, tipepidine hibenzate, cloperastine fendizoate, codeine phosphate, and dihydrocodeine phosphate.

[0031] Examples of noscapines include noscapine hydrochloride and noscapine. Examples of bronchodilators include dl-methylephedrine hydrochloride and dl-methylephedrine saccharin salt. Examples of expectorants include potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, carbocisteine, and the like. Examples of hypnotics and sedatives include bromvalerylurea and allylisopropylacetylurea. Examples of vitamins include vitamin B1, vitamin B2, vitamin C, hesperidin and its derivatives and salts thereof. Examples of anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizic acid and its analogs.

[0032] Examples of gastric mucosa protective agents 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, co-precipitation product of aluminum hydroxide-sodium bicarbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, co-precipitation product of magnesium hydroxide-aluminum potassium sulfate, magnesium carbonate, and magnesium aluminometasilicate.

[0033] Examples of herbal medicines include oxoamide (processed garlic), ephedra (Ma Huang), Nantenjitsu (Nandina fruit), Ouhi (cherry bark), Onji (Peppermint), Glycyrrhiza (licorice), Platycodon grandiflorum (Platycodon root), Shazenshi (Plant psyllium), Shazensou (Plant psyllium), Sekisan (Garlic root), Senega, Fritillaria rosa (Fritillaria), Fennel (Anise), Phellodendron bark (Phellodendron bark), and Coptis japonica (Coptis Rhizome). ), Zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including bear gall), Shajin, Zingiber officinale, Atractylodes Root, Clove, Citrus Fruit Peel, Atractylodes Rhizome, Zirconia Root, Bamboo Root Ginseng, and Ginseng.

[0034] Examples of Chinese herbal medicine prescriptions include Kakkonto, Keishito, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekoubokuto, Maoto, etc. Examples of caffeine compounds include anhydrous caffeine, caffeine, sodium benzoate caffeine, etc.

[0035] Furthermore, the formulation according to the present invention may contain other additives (excipients, binders, disintegrants, lubricants, etc.) in addition to ibuprofen, tranexamic acid, and carbocisteine.

[0036] Examples of excipients include lactose, starches, crystalline cellulose, sucrose, mannitol, etc. Examples of binders include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, etc. Examples of disintegrants include carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, etc. Examples of lubricants include talc, stearic acid, silica, sucrose fatty acid esters, light anhydrous silicic acid, waxes (plant-derived waxes such as carnauba wax, Japan wax (cryptomeria japonica wax, lacquer wax), and castor wax; animal-derived waxes such as beeswax, white beeswax, spermaceti wax, and refined lanolin; petroleum-derived waxes such as paraffin and microcrystalline wax; and mineral-derived waxes such as montan wax and refined montan wax; and natural waxes and synthetic waxes), hydrogenated vegetable oils, macrogols, sodium lauryl sulfate, glycerin fatty acid esters, and hydrogenated castor oil.

[0037] The formulation of the present invention can be manufactured according to conventional methods. In the case of a powder formulation of the present invention, the powder of the present invention can be manufactured by mixing a powder of a desired drug and a powder of a desired additive. The powder of the present invention is sealed in a predetermined bag according to conventional methods. In the case of a tablet formulation of the present invention, the tablet of the present invention can be manufactured by mixing or granulating the desired drug and the desired additives according to conventional methods for tablet production, and then tableting. The form of mixing or granulation is not particularly limited, and examples thereof include a method of mixing (blending) ibuprofen, tranexamic acid, and carbocisteine ​​all at once and compressing the mixture into tablets (direct compression method), a method of mixing first granules of ibuprofen with tranexamic acid and carbocisteine ​​and compressing the mixture into tablets, a method of mixing first granules of ibuprofen with second granules obtained by mixing and granulating tranexamic acid and carbocisteine ​​and compressing the mixture into tablets, a method of mixing third granules of ibuprofen, tranexamic acid, and carbocisteine ​​with other additives and compressing the mixture into tablets, a method of mixing fourth granules of ibuprofen and carbocisteine ​​with fifth granules of tranexamic acid and compressing the mixture into tablets, and a method of granulating ibuprofen, tranexamic acid, and carbocisteine ​​separately, mixing them, and compressing the mixture into tablets. In addition, by adding a granulation step to the tablet manufacturing method according to the present invention, it is possible to further suppress the swelling of tablets containing L-carbocysteine. [Example]

[0038] The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited thereto.

[0039] Example 1 600 mg of ibuprofen (powder) (trade name "IBUPROFEN JP" manufactured by STRIDES SHASON), 750 mg of tranexamic acid (powder) (trade name "Tranexamic Acid" manufactured by Kyowa Pharma Chemical Co., Ltd.), 750 mg of L-carbocysteine ​​(powder) (trade name "L-Carbocysteine" manufactured by Ilshin Chemical Co., Ltd.), 1088 mg of lactose hydrate (powder) (trade name "Pharmatose" manufactured by DFE Pharma), 360 mg of crystalline cellulose (powder) (trade name "COMPRECEL" manufactured by Fushimi Seisakusho Co., Ltd.), 26 mg of light anhydrous silicic acid (powder) (trade name "Adsolider" manufactured by Fuji Silysia Chemical Ltd.), and 26 mg of magnesium stearate (powder) (trade name "Japanese Pharmacopoeia Magnesium Stearate" manufactured by Taihei Chemical Industry Co., Ltd.) were mixed by hand, and the resulting powder was designated as Example 1.

[0040] In Example 1, the ratio of ibuprofen to the total powder was 16.7% by weight, the ratio of tranexamic acid to the total powder was 20.8% by weight, and the ratio of L-carbocysteine ​​to the total powder was 20.8% by weight. The mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the powder was 0.8:1.0:1.0 by weight.

[0041] <Comparative Example 1> A powder was produced in the same manner as in Example 1, except that 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 1,838 mg. The powder thus obtained was designated Comparative Example 1.

[0042] <Example 2> A powder was produced in the same manner as in Example 1, except that the amounts of ibuprofen, tranexamic acid, and lactose hydrate were changed to 450 mg, 280 mg, and 1708 mg, respectively, and the powder thus obtained was designated Example 2.

[0043] In Example 2, the ratio of ibuprofen to the total powder was 12.5% ​​by weight, the ratio of tranexamic acid to the total powder was 7.8% by weight, and the ratio of L-carbocysteine ​​to the total tablet was 20.8% by weight. The mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the powder was 0.6:0.4:1.0 by weight.

[0044] <Comparative Example 2> A powder was produced in the same manner as in Example 2, except that 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 2458 mg. The powder thus obtained was designated Comparative Example 2.

[0045] Example 3 A powder was produced in the same manner as in Example 1, except that the amount of tranexamic acid was 450 mg and the amount of lactose hydrate was 1388 mg. The powder thus obtained was designated Example 3.

[0046] In Example 3, the ratio of ibuprofen to the total powder was 16.7% by weight, the ratio of tranexamic acid to the total powder was 12.5% ​​by weight, and the ratio of L-carbocysteine ​​to the total tablet was 20.8% by weight. The mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the powder was 0.8:0.6:1.0 by weight.

[0047] <Comparative Example 3> A powder was produced in the same manner as in Example 3, except that 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 2138 mg. The powder thus obtained was designated Comparative Example 3.

[0048] Example 4 In Example 1, ibuprofen, tranexamic acid, L-carbocysteine, lactose hydrate, crystalline cellulose, light anhydrous silicic acid, and magnesium stearate were mixed by hand in the same amounts as in Example 1, and the mixture was compressed to a hardness of 7 kgf (trade name "Digital Hardness Tester KHT-40N", manufactured by Fujiwara Seisakusho Co., Ltd.) using a tablet press (product name "Collect 836 KAWC", manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a punch having a diameter of 9.0 mm to produce nine tablets, each weighing 400 mg. The resulting tablets were designated as Example 4.

[0049] In Example 4, the proportion of ibuprofen, the proportion of tranexamic acid, and the proportion of L-carbocysteine ​​relative to the total powder, and the mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the powder were the same as in Example 1.

[0050] <Comparative Example 4> Tablets were produced in the same manner as in Example 4, except that 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 1838 mg. The tablets thus obtained were designated as Comparative Example 4.

[0051] <Example 5> In Examples 1 and 4, 600 mg of ibuprofin, 321 mg of lactose hydrate, and 124 mg of crystalline cellulose were mixed by hand, and then 8 mg of hydroxypropyl cellulose (powder) (trade name "Japanese Pharmacopoeia HPC", manufactured by Nippon Soda Co., Ltd.) was added dropwise as an aqueous solution as a binder. Then, the mixture was granulated and dried using a granulation dryer (trade name "FD-MP-01D type", manufactured by Powrex Corporation) to obtain a first powder. Then, the first powder, 750 mg of tranexamic acid, 750 mg of L-carbocysteine, 66 mg of lactose hydrate, 950 mg of crystalline cellulose, and 31 mg of magnesium stearate were mixed by hand, and the mixture was tableted at a hardness of 7 kgf using a tablet press equipped with a pestle having a diameter of 9.0 mm. Nine tablets, each weighing 400 mg, were produced. The tablets obtained were designated as Example 5.

[0052] In Example 5, the proportion of ibuprofen, the proportion of tranexamic acid, and the proportion of L-carbocysteine ​​relative to the total powder, and the mixing ratio of ibuprofen, tranexamic acid, and carbocisteine ​​in the powder were the same as in Example 1.

[0053] <Comparative Example 5> In Example 5, tablets were produced in the same manner as in Example 5, except that when mixing with the first powder, 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 816 mg.The tablets obtained in this manner were designated as Comparative Example 5.

[0054] Example 6 In Example 5, 600 mg of ibuprofin, 321 mg of lactose hydrate, and 124 mg of crystalline cellulose were mixed by hand, and then 8 mg of hydroxypropyl cellulose as a binder was added dropwise as an aqueous solution, and then granulated and dried using a granulator dryer to obtain a first powder. Meanwhile, 750 mg of tranexamic acid, 750 mg of L-carbocysteine, 46 mg of lactose hydrate, and 378 mg of crystalline cellulose were mixed by hand, and then 20 mg of hydroxypropyl cellulose as a binder was added dropwise as an aqueous solution, and then granulated and dried using a granulator dryer to obtain a second powder. Then, the first powder, the second powder, 32 mg of crystalline cellulose, and 31 mg of magnesium stearate were mixed by hand, and then the mixture was tableted using a tablet press equipped with a 9.0 mm diameter punch at a hardness of 5 kgf to produce 9 tablets of 340 mg each.

[0055] In Example 6, the ratio of ibuprofen to the total powder was 19.6% by weight, the ratio of tranexamic acid to the total powder was 24.5% by weight, and the ratio of L-carbocysteine ​​to the total powder was 24.5% by weight. The mixing ratio of ibuprofen to tranexamic acid to carbocisteine ​​in the powder was 0.8:1.0:1.0 by weight.

[0056] <Comparative Example 6> In Example 6, tablets were produced in the same manner as in Example 6, except that when mixing with the second powder, 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 796 mg.The tablets obtained in this manner were designated as Comparative Example 6.

[0057] Example 7 In Example 5, 600 mg of ibuprofin, 450 mg of tranexamic acid, 750 mg of L-carbocysteine, 740 mg of lactose hydrate, and 1314 mg of crystalline cellulose were mixed by hand, and then 8 mg of hydroxypropyl cellulose as a binder was added dropwise as an aqueous solution, and then the mixture was granulated and dried using a granulator to obtain a first powder.Then, the first powder, 40 mg of lactose hydrate, 29 mg of light anhydrous silicic acid, and 29 mg of magnesium stearate were mixed by hand, and the mixture was tableted using a tablet press equipped with a pestle with a diameter of 9.0 mm at a hardness of 11 kgf to produce 9 tablets, each 440 mg.

[0058] In Example 7, the ratio of ibuprofen to the total powder was 15.2% by weight, the ratio of tranexamic acid to the total powder was 11.4% by weight, and the ratio of L-carbocysteine ​​to the total powder was 18.9% by weight. The mixing ratio of ibuprofen to tranexamic acid to carbocisteine ​​in the powder was 0.8:0.6:1.0 by weight.

[0059] <Comparative Example 7> In Example 7, tablets were produced in the same manner as in Example 7, except that when mixing with the first powder, 750 mg of L-carbocysteine ​​was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 1,490 mg.The tablets obtained in this manner were designated as Comparative Example 7.

[0060] 1 to 7 show tables showing the formulations of Examples 1 to 7 and Comparative Examples 1 to 7.

[0061] <Evaluation method> The powder expansion was evaluated as follows: First, the powders of Examples 1-3 and Comparative Examples 1-3 were placed in a glass bottle, and the surface height of the powder in the glass bottle was measured at three points, the average value was calculated, and the height H0 (mm) of the powder immediately after production was measured.

[0062] The vial was then sealed and stored in a constant temperature bath at 50°C for one week. The surface height of the powder in the vial after storage was calculated in the same manner, and the height H1 (mm) of the powder after storage was measured. The powder height H0 immediately after production and the powder height H1 after storage were substituted into the following equation (1) to calculate the expansion coefficient E (%).

[0063] E = (H1 - H0) / H0 × 100 (1)

[0064] FIG. 8 is a graph showing the evaluation results of the powders of Examples 1-3 and Comparative Examples 1-3. As shown in FIG. 8, the expansion coefficient of Comparative Example 1 was 7.8%, while that of Example 1 was 3.6%. The expansion coefficient of Comparative Example 2 was 3.3%, while that of Example 2 was 1.7%. The expansion coefficient of Comparative Example 3 was 6.0%, while that of Example 3 was 5.5%. In other words, at the component concentrations (proportions, mixing ratios) of Examples 1-3, the expansion coefficient of the powder containing L-carbocysteine ​​was surprisingly significantly lower than that of the powder not containing L-carbocysteine. Therefore, it was found that the expansion coefficient of the powder can be suppressed by adding L-carbocysteine ​​to ibuprofen and tranexamic acid, even if the component concentrations vary slightly.

[0065] Next, the expansion of the tablets was evaluated as follows. First, for the tablets of Examples 4-7 and Comparative Examples 4-7, the thickness D0 (mm) of the tablets immediately after production was measured using a digital micrometer. Next, the produced tablets were placed in a glass bottle, sealed, and then stored in a constant temperature bath at 50°C for 1 week. Then, the thickness D1 (mm) of the tablets after storage was measured using a digital micrometer. The thickness D0 of the tablets immediately after production and the thickness D1 of the tablets after storage were substituted into the following formula (2) to calculate the expansion coefficient E (%).

[0066] E = (D1 - D0) / D0 × 100 (2)

[0067] 9 is a graph showing the evaluation results of the tablets of Examples 4-7 and Comparative Examples 4-7. As shown in FIG. 9, the expansion rate of Comparative Example 4 was 29.6%, while that of Example 4 was 26.6%; the expansion rate of Comparative Example 5 was 15.5% while that of Example 5 was 13.3%; the expansion rate of Comparative Example 6 was 20.9% while that of Example 6 was 18.1%; and the expansion rate of Comparative Example 7 was 9.0% while that of Example 7 was 7.8%. In other words, it can be seen that, in each of the manufacturing methods of Examples 4-7, the expansion rate of the tablets containing L-carbocysteine ​​was surprisingly significantly lower than that of the tablets not containing L-carbocysteine. Therefore, it was found that the expansion rate of the tablets can be suppressed by adding L-carbocysteine ​​to ibuprofen and tranexamic acid, regardless of the type of manufacturing method. It was also found that the expansion rate of tablets containing L-carbocysteine ​​can be further reduced by adding a granulation process. [Industrial Applicability]

[0068] As described above, the preparation according to the present invention is useful as a preparation that can be stably stored for a long period of time, and is effective as a preparation that can suppress swelling of the preparation.

Claims

1. A method for producing a formulation containing ibuprofen and tranexamic acid and containing carbocisteine, comprising: (1) A method for producing tablets, which comprises mixing first granules obtained by granulating the ibuprofen and the carbocisteine ​​with second granules obtained by granulating the tranexamic acid, and compressing the mixture into tablets; (2) A method for producing a formulation (excluding formulations containing both noscapine and dihydrocodeine phosphate, and ambroxol or a salt thereof) by any one of the methods for producing tablets, in which the ibuprofen, the tranexamic acid, and the carbocisteine ​​are separately granulated, mixed, and compressed into tablets, The mixing ratio of the ibuprofen, the tranexamic acid, and the carbocisteine ​​in the preparation is 0.5 to 1.5:0.2 to 1.5:1.0 by weight. Method of manufacturing the formulation.

2. A method for producing a formulation containing ibuprofen and tranexamic acid and containing carbocisteine, comprising: (1) A method for producing a powder, which comprises mixing first granules obtained by granulating the ibuprofen and the carbocisteine ​​with second granules obtained by granulating the tranexamic acid; (2) A method for producing a formulation (excluding formulations containing both noscapine and dihydrocodeine phosphate, and ambroxol or a salt thereof) using any of the methods for producing powders in which the ibuprofen, tranexamic acid, and carbocisteine ​​are separately granulated and mixed, The mixing ratio of the ibuprofen, the tranexamic acid, and the carbocisteine ​​in the preparation is 0.5 to 1.5:0.2 to 1.5:1.0 by weight. Method of manufacturing the formulation.

Images