JP7740754B2 - formulation - Google Patents

Description

The present invention relates to a formulation.

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 combining ibuprofen and tranexamic acid, such as antipyretic and cold medicines, are already being manufactured.

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 issue, 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, making it possible to produce a stable formulation.

Furthermore, 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. Furthermore, 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. Furthermore, 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 members selected from the group consisting of cyclodextrins and their derivatives. And, 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. Furthermore, 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 formulation containing ibuprofen and tranexamic acid in which swelling is suppressed even under high-temperature storage conditions.

Furthermore, Japanese Patent Application Laid-Open No. 2007-91633 (Patent Document 7) discloses a pharmaceutical composition characterized by containing (i) mequitazine and/or a salt thereof, (ii) ibuprofen and/or a salt thereof, and (iii) tranexamic acid and/or a salt thereof. This is said to provide a pharmaceutical composition that not only suppresses color change but also moisturization, resulting in excellent stability.

Japanese Patent Application Laid-Open No. 2007-284423 Japanese Patent Application Laid-Open No. 2008-239554 JP 2008-266270 A JP 2009-51795 A JP 2009-179613 A JP 2010-30903 A Japanese Patent Application Laid-Open No. 2007-91633

As mentioned above, formulations containing ibuprofen and tranexamic acid have the problem of being unstable and causing the volume of the formulation to expand.

The technology described in Patent Document 1 has the problem of requiring melt granulation of either ibuprofen or tranexamic acid. Furthermore, the technologies described in Patent Documents 2-6 have the problem of requiring the addition of extra ingredients to a fixed formulation containing ibuprofen and tranexamic acid. The technology described in Patent Document 7 has the problem of requiring the addition of mequitazine, a phenothiazine antihistamine.

Therefore, a simple formulation that would improve the stability of formulations containing ibuprofen and tranexamic acid was needed.

The present invention was made to solve the above-mentioned problems, and aims to provide a formulation that can suppress swelling of the formulation.

The formulation of the present invention contains ibuprofen and tranexamic acid, and also contains carbocisteine.

The present invention makes it possible to suppress swelling of the formulation.

1 is a table showing the formulations of Example 1 and Comparative Example 1. 1 is a table showing the formulations of Example 2 and Comparative Example 2. 1 is a table showing the formulations of Example 3 and Comparative Example 3. 1 is a table showing the formulations of Example 4 and Comparative Example 4. 1 is a table showing the formulations of Example 5 and Comparative Example 5. 1 is a table showing the formulations of Example 6 and Comparative Example 6. 1 is a table showing the formulations of Example 7 and Comparative Example 7. 1 is a graph showing the evaluation results of the powders of Examples 1-3 and Comparative Examples 1-3. 1 is a graph showing the evaluation results of tablets of Examples 4-7 and Comparative Examples 4-7.

The following describes an embodiment of the present invention with reference to the accompanying drawings to aid in understanding the present invention. Note that the following embodiment is an example of a specific embodiment of the present invention and is not intended to limit the technical scope of the present invention.

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 manufactured according to standard methods, the combination of ibuprofen and tranexamic acid can be expected to provide additional effects such as enhanced efficacy and reduced side effects, but the formulation suffers from the problem of volume expansion. This expansion can cause cracks in tablets, or damage to the bag containing the powder, if the formulation is a powder.

The inventors therefore searched for a formula that would suppress the swelling of formulations containing ibuprofin and tranexamic acid, and unexpectedly discovered that the addition of carbocisteine suppressed the swelling of the formulation. This led to the completion of the present invention, based on the examples described below.

Here, ibuprofen is a non-steroidal anti-inflammatory analgesic classified as a propionic acid drug. In addition to ibuprofen itself, examples include 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); and commercially available products can be used.

The percentage 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 also contains its salts, when ibuprofen is a salt, the percentage of ibuprofen is calculated as the free form. The same applies below.

The amount of ibuprofen contained in the formulation is not particularly limited, but if 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. If the formulation is a powder, the amount of ibuprofen is preferably 300 mg to 600 mg per powder. If ibuprofin is administered orally, the daily dosage of ibuprofin is preferably 300 mg to 600 mg.

Tranexamic acid is a type of hemostatic and anti-inflammatory agent, and in addition to tranexamic acid itself, its pharmaceutically acceptable salts (alkali metal salts and alkaline earth metal salts such as potassium salt and magnesium salt; mineral acid salts such as sulfate, etc.) can be used, and commercially available products can be used.

The percentage 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 also includes its salts, when tranexamic acid is a salt, the percentage of tranexamic acid is calculated as the free form. The same applies below.

The amount of tranexamic acid contained in the formulation is not particularly limited, but if 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. If the formulation is a powder, the amount of tranexamic acid is preferably 280 mg to 750 mg per powder. If tranexamic acid is administered orally, the daily dose of tranexamic acid is preferably 280 mg to 750 mg.

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

Furthermore, the percentage of carbocisteine contained in the formulation is not particularly limited, but is preferably 5% to 40% by weight of the total formulation, and more preferably 10% to 30% by weight. Note that since carbocisteine also includes its salts, when carbocisteine is a salt, the percentage of carbocisteine is calculated as the free form. The same applies below.

The amount of carbocisteine contained in the formulation is not particularly limited, but if 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. If the formulation is a powder, the amount of carbocisteine is preferably 400 mg to 750 mg per powder. If carbocisteine is administered orally, the daily dosage of carbocisteine is preferably 400 mg to 750 mg.

The mixing ratio of ibuprofen, tranexamic acid, and carbocisteine in the formulation is not particularly limited, but from the perspective 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. Note that when one or all of ibuprofen, tranexamic acid, and carbocisteine are salts thereof, the above-mentioned mixing ratio is calculated on a free-form basis. The same applies hereinafter.

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

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

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.

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.

Examples of noscapines include noscapine hydrochloride and noscapine. Bronchodilators include dl-methylephedrine hydrochloride and dl-methylephedrine saccharin salt. Expectorants include potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, and carbocisteine. Hypnotics and sedatives include bromvalerylurea and allylisopropylacetylurea. Vitamins include vitamin B1, vitamin B2, vitamin C, hesperidin and its derivatives and salts. Anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizinic acid and its analogs.

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.

Herbal medicines include, for example, oxoamide (processed garlic), ephedra (Ma Huang), Nantenjitsu (Nandina fruit), Cherry bark, Onji (Peppermint), Glycyrrhiza Root, Platycodon grandiflorum (Platycodon Root), Shazenshi (Plantaria root), Shazensou (Plantaria root), Garlic, Senega, Fritillaria (Fritillaria), Fennel (Anise), Phellodendron Bark (Phellodendron bark), and Coptis Rhizome (Coptis japonica). ), Zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including bear gall), Shajin, Zingiber officinale, Atractylodes Root, Clove, Citrus Fruit, Atractylodes Root, Jiryu, Bamboo Root Ginseng, and Ginseng.

Examples of herbal prescriptions include Kakkonto, Keishito, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekoubokuto, and Maoto. Examples of caffeine compounds include anhydrous caffeine, caffeine sodium benzoate, and the like.

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

Examples of excipients include lactose, starches, crystalline cellulose, sucrose, mannitol, etc. Binders include hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, etc. Disintegrants include carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, 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 (clover 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, as well as natural and synthetic waxes), hydrogenated vegetable oils, macrogols, sodium lauryl sulfate, glycerin fatty acid esters, and hydrogenated castor oil.

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 the desired drug and a powder of the desired additives. The powder of the present invention is sealed in a specified 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 desired additives according to conventional methods to manufacture the tablet. 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. Furthermore, by adding a granulation process to the tablet manufacturing method of the present invention, it is possible to further suppress swelling of tablets containing L-carbocysteine.

The present invention will be explained in detail below using examples and comparative examples, but the present invention is not limited to these.

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 The powder thus obtained was designated as Example 1.

In Example 1, the proportion of ibuprofen in the total powder was 16.7% by weight, the proportion of tranexamic acid in the total powder was 20.8% by weight, and the proportion of L-carbocysteine in 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.

<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.

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.

In Example 2, the proportion of ibuprofen in the powder was 12.5% by weight, the proportion of tranexamic acid in the powder was 7.8% by weight, and the proportion of L-carbocysteine in the 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.

<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 2,458 mg. The powder thus obtained was designated Comparative Example 2.

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 1,388 mg. The powder thus obtained was designated Example 3.

In Example 3, the proportion of ibuprofen in the powder was 16.7% by weight, the proportion of tranexamic acid in the powder was 12.5% by weight, and the proportion of L-carbocysteine in the 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.

<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.

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 tablets obtained were designated as Example 4.

Here, in Example 4, the proportions of ibuprofen, tranexamic acid, and L-carbocysteine relative to the total powder, as well as the mixing ratios of ibuprofen, tranexamic acid, and carbocisteine in the powder, are the same as in Example 1.

<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 1,838 mg. The tablets thus obtained were designated as Comparative Example 4.

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. The mixture was then 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 compressed 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 resulting tablets were designated as Example 5.

Here, in Example 5, the proportions of ibuprofen, tranexamic acid, and L-carbocysteine relative to the total powder, as well as the mixing ratios of ibuprofen, tranexamic acid, and carbocisteine in the powder, are the same as in Example 1.

Comparative Example 5
In Example 5, a tablet was 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 tablet thus obtained was designated as Comparative Example 5.

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 compressed at a hardness of 5 kgf using a tablet press equipped with a punch having a diameter of 9.0 mm, and 9 tablets of 340 mg each were produced.

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

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

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 1,314 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. The mixture was then granulated and dried using a granulator dryer to obtain a first powder. The first powder, 40 mg of lactose hydrate, 29 mg of light anhydrous silicic acid, and 29 mg of magnesium stearate were then mixed by hand, and the mixture was tableted at a hardness of 11 kgf using a tablet press equipped with a pestle with a diameter of 9.0 mm to produce nine tablets, each 440 mg.

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

Comparative Example 7
Tablets were produced in the same manner as in Example 7, except that when mixing with the first powder in Example 7, 750 mg of L-carbocysteine was replaced with 750 mg of lactose hydrate, making the amount of lactose hydrate 1,490 mg. The tablets thus obtained were designated as Comparative Example 7.

Figures 1-7 show tables showing the formulations of Examples 1-7 and Comparative Examples 1-7.

<Evaluation method>
The expansion of the powder was evaluated as follows: First, the powders of Examples 1 to 3 and Comparative Examples 1 to 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.

Next, the vial was sealed and stored in a 50°C thermostatic chamber for one week. The surface height of the powder inside the vial after storage was then 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 formula (1) to calculate the expansion coefficient E (%).

E=(H1-H0)/H0×100...(1)

Figure 8 is a graph showing the evaluation results of the powders of Examples 1-3 and Comparative Examples 1-3. As shown in Figure 8, the expansion rate of Comparative Example 1 was 7.8%, while that of Example 1 was 3.6%; the expansion rate of Comparative Example 2 was 3.3%, while that of Example 2 was 1.7%; and the expansion rate 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 rate 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 rate of the powder can be suppressed by adding L-carbocysteine to ibuprofen and tranexamic acid, even if the component concentrations vary slightly.

Next, the expansion of the tablets was evaluated as follows. First, the thickness D0 (mm) of the tablets of Examples 4-7 and Comparative Examples 4-7 immediately after production was measured using a digital micrometer. Next, the manufactured tablets were placed in glass bottles, sealed, and stored in a constant temperature bath at 50°C for one week. The thickness D1 (mm) of the tablets after storage was then 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 rate E (%).

E=(D1-D0)/D0×100...(2)

Figure 9 is a graph showing the evaluation results of tablets from Examples 4-7 and Comparative Examples 4-7. As shown in Figure 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, surprisingly, in each of the manufacturing methods of Examples 4-7, the expansion rate of tablets containing L-carbocysteine was significantly lower than that of tablets not containing L-carbocysteine. Therefore, it was found that regardless of the type of manufacturing method, the expansion rate of tablets can be reduced by adding L-carbocysteine to ibuprofen and tranexamic acid. It was also found that the expansion rate of tablets containing L-carbocysteine can be further reduced by adding a granulation process.

As described above, the formulation of the present invention is useful as a formulation that can be stored stably for a long period of time, and is effective as a formulation that can suppress swelling of the formulation.

Claims (2)

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. 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.