JP7742738B2 - Tablets containing ibuprofen and tranexamic acid and method for producing the same - Google Patents

Description

The present invention relates to a tablet containing ibuprofen or a salt thereof and tranexamic acid that is easy to manufacture.

Currently, pharmaceutical preparations containing multiple active ingredients are widely used in general cold medicines and antipyretic analgesics. For example, general cold medicines are widely sold as over-the-counter drugs containing multiple active ingredients, such as antipyretic analgesics, cough suppressants, expectorants, and rhinitis medications. However, because multiple ingredients are combined within a limited ingestible size, the concentration of the active ingredients becomes high, which can cause issues with the quality and manufacturability of the preparation.

In particular, many active ingredients in pharmaceutical preparations tend to adhere to the surface or sides of the punch during tableting, and it is known that preparations containing high concentrations of these active ingredients can cause punch adhesion or sticking during tableting.
Punch adhesion refers to the adhesion of medicinal ingredients or tablet powder to the tableting surface of the punch during tableting, which causes defects such as the formation of irregularities on the surface of the uncoated tablet. Even if such uncoated tablets are coated, the irregularities remain, which reduces the commercial value of the pharmaceutical preparation.
Punch sticking occurs when active ingredients or tablet powder adheres to the side of the punch during tableting, causing molding defects such as cracking of the uncoated tablet and capping. The lack of strength of such uncoated tablets can cause tablet cracking or chipping during coating, resulting in a decrease in production yield.

Punch adhesion and sticking can often be improved by increasing the amount of lubricant, but increasing the amount of lubricant is known to worsen disintegration and dissolution properties and reduce compression moldability during tableting.

Ibuprofen or its salts are widely used clinically as non-steroidal antipyretic analgesics. However, because it is a low-melting substance, it is known that blending it with various medicinal ingredients (e.g., ethenzamide) or additives (e.g., magnesium stearate, sucrose fatty acid esters, and other fatty acid-based lubricants) can cause a drop in the melting point, resulting in punch adhesion.
Tranexamic acid is also known as an anti-inflammatory drug and is used as an active ingredient in general cold medicines.

The combined use of ibuprofen or its salt with tranexamic acid, as well as pharmaceutical compositions combining these, have already been reported (Patent Document 1).

It has also been reported that by granulating ibuprofen separately from other active ingredients and adding fumaric acid or its esters or their salts, it was possible to improve appearance problems such as punch adhesion and poor flowability of the granulated product (Patent Document 2). It has also been reported that by adding crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, hydroxypropyl starch, and crystalline cellulose to granules containing ibuprofen or its salts and then tableting, it was possible to improve tableting problems such as punch adhesion and an irritating bitter taste (Patent Document 3).

As such, the combined use of ibuprofen or a salt thereof with tranexamic acid, and pharmaceutical compositions combining these, have already been reported. Methods known include separating ibuprofen-containing granules and tranexamic acid-containing granules to form a multi-granule formulation for stabilization purposes, and coating the granules to prevent aggregation. However, it was not fully known that punch sticking and adhesion can occur during tableting.

Patent Publication No. 6159268 Japanese Patent Application Laid-Open No. 2019-81757 Patent Publication No. 3836528

The inventors have discovered that when tablets containing a homogeneous mixture of ibuprofen or a salt thereof and tranexamic acid are produced, punch adhesion and punch sticking easily occur during tableting, and that even the addition of a lubricant makes it difficult to prevent punch adhesion and punch sticking, resulting in not only a manufacturing issue but also the inability to ensure formulation quality. Therefore, an object of the present invention is to provide tablets containing ibuprofen or a salt thereof and tranexamic acid that can be produced stably without punch adhesion and punch sticking.

The inventors conducted extensive research into formulations to solve the above-mentioned problems, and as a result, they discovered the surprising result that by incorporating granules containing ibuprofen or a salt thereof and tranexamic acid in a state coated with talc and a coating substrate, it is possible to produce high-quality tablets, even when the tablets contain ibuprofen or a salt thereof and tranexamic acid, without reducing compression moldability, punch adhesion, or punch sticking, and this led to the completion of the present invention.

That is, the present invention provides the following (1) to (13).
(1) A tablet comprising first granules containing ibuprofen or a salt thereof, second granules containing tranexamic acid, and talc,
The tablet hardness is 45N or more,
At least one of the first granules and the second granules is a coated granule in which at least a portion is coated with at least a portion of the talc.
tablet.
(2) The tablet according to (1), wherein the tablet contains 6.5% by mass or more of talc.
(3) The tablet according to (1) or (2), wherein the tablet has a hardness of 60 N or more.
(4) The tablet contains 7.5% by mass or more of talc,
a ratio X/Y of a mass ratio X of talc in the coated granules to a mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in the entire granules not coated with talc among the first granules and the second granules is 0.14 or more;
A tablet described in any one of (1) to (3).
(5) The tablet according to any one of (1) to (4), wherein the coating components of the coated granules include talc, a water-soluble polymer, and an anti-aggregating agent.
(6) The tablet according to (5), wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, povidone, polyvinyl alcohol (partially saponified), and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
(7) The tablet according to (5) or (6), wherein the anti-aggregating agent is one or more selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, and magnesium aluminometasilicate.
(8) forming the first granules containing ibuprofen or a salt thereof;
forming the second granules containing tranexamic acid;
and coating at least a portion of at least one of the first granules and the second granules with talc.
A method for producing a tablet according to any one of (1) to (7).
(9) forming coated granules by coating at least a portion of at least one of first granules containing ibuprofen or a salt thereof and second granules containing tranexamic acid with talc;
and preparing a tablet having a hardness of 45 N or more.
A method for producing a tablet containing ibuprofen or a salt thereof and tranexamic acid.
(10) The method for producing a tablet according to (9), wherein talc is blended so that the total amount of talc in the tablet is 6.5% by mass or more.
(11) The method for producing a tablet according to (9) or (10), wherein the tablet is prepared so that the tablet has a tablet hardness of 60 N or more.
(12) The method for producing a tablet according to any one of (9) to (11), wherein talc is blended so that the total amount of talc in the tablet is 7.5% by mass or more, and the ratio X/Y, which is the ratio of the mass ratio X of talc in the coated granules to the mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in all of the granules not coated with talc among the first granules and the second granules, is adjusted so that X/Y is 0.14 or more.
(13) The method for producing a tablet according to any one of (9) to (12), comprising, after the step of forming the coated granules, a step of mixing the first granules, the second granules, and the coated granules and compressing them into tablets.

The tablets and manufacturing method thereof of the present invention can suppress deterioration of compression moldability, the occurrence of punch adhesion, and the occurrence of punch sticking.

FIG. 1 shows an SEM photograph of the first granules of Example 6. FIG. 2 shows an SEM photograph of the first coated granules of Example 6.

The tablet of the present invention comprises first granules containing ibuprofen or a salt thereof, second granules containing tranexamic acid, and talc, and has a tablet hardness of 45N or more, and at least a portion of at least one of the first granules and the second granules is a coated granule in which at least a portion of the talc is coated.
In this specification, the coated granules coated with the first granules may be referred to as "first coated granules."
In addition, in this specification, coated granules coated with second granules may be referred to as "second coated granules."

The "tablets" in the present invention are described in the 17th edition of the Japanese Pharmacopoeia.
In addition, suitable embodiments of the tablet of the present invention include those in which the preparation is coated with a water-soluble polymer or the like, or those in which the tablet is coated with sugar, such as film-coated tablets and sugar-coated tablets.

Furthermore, powders or granules of different compositions can be stacked in two or more layers and compressed to form multilayer tablets.

In the present invention, "ibuprofen or a salt thereof" refers to ibuprofen or a pharmacologically acceptable salt thereof, including, for example, an alkali metal salt such as the sodium salt. Furthermore, when ibuprofen or a salt thereof is left in the air or recrystallized, it may absorb moisture, become absorbed, or become a hydrate; these various hydrates are also encompassed in the present invention. Ibuprofen is a preferred example. Ibuprofen is listed as "ibuprofen" in the 17th edition of the Japanese Pharmacopoeia.

The proportion of "ibuprofen or a salt thereof" in the tablet of the present invention is not particularly limited, but may be 1 to 70% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass of the entire tablet.
In the present invention, the granules containing "ibuprofen or a salt thereof" contained in the tablet may be referred to as "first granules."

The "tranexamic acid" used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia.

The proportion of "tranexamic acid" in the tablet of the present invention is not particularly limited, but may be 1 to 70% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass of the entire tablet.
In the present invention, the granules containing "tranexamic acid" contained in the tablet may be referred to as second granules.

The (c) "talc" used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia, and is not limited as long as it is usable as a pharmaceutical additive, and its average particle size is preferably within the range of 2 to 50 μm, more preferably 2 to 30 μm. Suitable examples include Crown Talc Pharmacopoeia PP and Hi-Filler #17 from Matsumura Sangyo Co., Ltd., PERTECK (registered trademark) LUB Talc from Merck, and Pharmacopoeia Talc SK-A, Victorlite SK-C, and Victorlite KST-W (registered trademark) from Shokoyama Mining Co., Ltd.
The "average particle size" in the present invention means the particle size at 50% of the cumulative value in the particle size distribution determined by a laser diffraction method (for example, model "MT3200II" manufactured by Microtrac Bell Co., Ltd.).
The proportion of "talc" in the tablet of the present invention is preferably 6.5% by mass or more of the entire tablet from the viewpoints of preventing punch adhesion (capping, cracking), preventing punch adhesion (sticking), and maintaining tablet hardness.
The proportion of "talc" in the tablet of the present invention is preferably 6.5% by mass or more of the entire tablet, more preferably 7.0% by mass or more, even more preferably 7.5% by mass or more, even more preferably 7.5% by mass to 20% by mass, and particularly preferably 7.5% by mass to 15% by mass.

In the present invention, "talc" is used as a granule coating agent to coat at least one of the first granules containing "ibuprofen or a salt thereof" and the second granules containing "tranexamic acid." It is sufficient that a portion of the "talc" is used as a granule coating agent, and talc other than the portion described above may be used as an additive such as a lubricant in tablets.

In the present invention, "mixing the first granules, the second granules, and the coated granules and compressing them into tablets" means, for example, that granules containing at least one of the total amount or a portion of the amount of ibuprofen or a salt thereof contained in a solid preparation, or the total amount or a portion of the amount of tranexamic acid contained in a solid preparation, are coated with talc and a coating base (a coating composition containing talc) and compressed into tablets.

The talc-containing granule coating composition is not particularly limited, but preferably contains a water-soluble polymer and an anti-agglomerating agent. That is, the talc-containing granule coating composition preferably contains talc, a water-soluble polymer, and an anti-agglomerating agent.

The water-soluble polymer is not particularly limited, but is preferably one or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, povidone, polyvinyl alcohol (partially saponified), and polyvinyl alcohol, acrylic acid, and methyl methacrylate copolymers.

The anti-agglomerating agent is not particularly limited, but is preferably one or more selected from hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, and magnesium aluminometasilicate.

Among these, it is preferable to use, as the granule coating base material, for example, hydroxypropyl cellulose, which is a water-soluble polymer, and light anhydrous silicic acid, which is an anti-aggregation agent.
That is, the talc-containing granule coating composition is preferably composed of, for example, talc, hydroxypropyl cellulose, and light anhydrous silicic acid.

The proportions of each component in the talc-containing granule coating composition are not particularly limited, but may be 20 to 80% by mass of talc, 10 to 40% by mass of hydroxypropyl cellulose, and 10 to 40% by mass of light anhydrous silicic acid.

Furthermore, when coating first granules containing "ibuprofen or a salt thereof" with a granule coating composition containing talc, it is preferable to use a composition containing 40 to 60% by mass of talc, 10 to 30% by mass of hydroxypropyl cellulose, and 10 to 30% by mass of light anhydrous silicic acid.
Furthermore, when the second granules containing "tranexamic acid" are coated with a granule coating composition containing talc, it is preferable to use a composition containing 40 to 60% by mass of talc, 10 to 30% by mass of hydroxypropyl cellulose, and 10 to 30% by mass of light anhydrous silicic acid.

The tablet of the present invention comprises first granules containing ibuprofen or a salt thereof, second granules containing tranexamic acid, and talc, has a hardness of 45N or greater, and at least one of the first granules and the second granules is at least partially coated with at least a portion of the talc, thereby improving the way the tablets break and the degree of adhesion of the tableting powder to the punches when compressed.

Furthermore, if the proportion of "talc" in the tablet of the present invention is 6.5% by mass or more of the entire tablet, the tablet hardness will be 45 N or more, and when the tablet is compressed, the way the tablet breaks and the degree of adhesion of the tablet powder to the punches will be suitably improved.

Furthermore, in the tablet of the present invention, talc is blended in an amount of 7.5% by mass or more in the tablet, and the ratio X/Y, where X is the mass ratio of talc in the coated granules and Y is the mass ratio of ibuprofen or a salt thereof and tranexamic acid in all of the granules not coated with talc among the first granules and the second granules, is 0.14 or more. This ensures a higher tablet hardness, for example, a tablet hardness of 60 N or more, and enables stable tablet production.

In the tablet of the present invention, the coated granules coated with talc may be composed of first granules containing ibuprofen or a salt thereof and talc (a granule coating composition containing talc), or may be composed of second granules containing tranexamic acid and talc (a granule coating composition containing talc), or may be composed of first granules containing ibuprofen or a salt thereof, second granules containing tranexamic acid and talc (a granule coating composition containing talc).

Furthermore, in the tablet of the present invention, the ratio of the "mass of talc in the talc-coated granules" to the "mass of the tablet (plain tablet)" is not particularly limited, but may be 2.0% by mass or more, or 3.0% by mass or more.
Furthermore, in the tablet of the present invention, the proportion of talc added to the powder is not particularly limited, but may be 3.0% by mass or more in the tablet (uncoated tablet).

The above-mentioned "talc mass ratio X in the coated granules" means the ratio of "the mass of talc contained in the coated granules coated with talc" to "the mass of the coated granules coated with talc."
Furthermore, the above-mentioned "mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in the granules not coated with talc among the first and second granules" means the ratio of "the mass of ibuprofen or a salt thereof and tranexamic acid in the uncoated granules" to "the mass of the granules not coated with talc among the first and second granules (uncoated granules)."
In the tablet of the present invention, X/Y, which is the ratio of the mass ratio X of talc in the coated granules to the mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in the granules that are not coated with talc among the first granules and the second granules, is 0.14 or more, and may be 0.15 or more, 0.14 to 0.20, 0.15 to 0.20, or 0.15 to 0.17.

The mass ratio X of talc (talc used to coat the granules) in the coated granules is not particularly limited, but may be 0.065 or more, 0.070 or more, 0.065 to 0.100, 0.070 to 0.100, or 0.070 to 0.090.

The proportion of ibuprofen and its salts in the first granules is not particularly limited, but may be 40% by mass or more.
The proportion of ibuprofen and its salts in the first coated granules may be 35% by mass or more.

The proportion of tranexamic acid in the second granules is not particularly limited, but may be 40% by mass or more.
The proportion of tranexamic acid in the second coated granules may be 35% by mass or more.

The method for producing the granules of the present invention is not particularly limited, as long as it includes a step of granulating ibuprofen or a salt thereof and tranexamic acid using a commonly used granulator, such as an extrusion granulator, agitator granulator, a fluidized bed dryer granulator, or a tumbling granulator.

Furthermore, the coating manufacturing method of the present invention is not particularly limited as long as it includes a step of coating granules containing at least one of ibuprofen or a salt thereof, or tranexamic acid, with talc and a coating base material using a commonly used coating machine, such as a fluidized bed granulator/coator, a tumbling fluidized bed granulator/coator, a centrifugal fluidized bed granulator/coator, or a Wurster fluidized bed granulator/coator. In the present invention, the granules obtained by the granulation are preferably compressed to form tablets.

The method for manufacturing the tablet of the present invention may include, for example, a step of forming a first granule containing ibuprofen or a salt thereof, a step of forming a second granule containing tranexamic acid, and a step of coating at least a portion of at least one of the first granule and the second granule with talc.
The method for producing a tablet of the present invention is, for example, a method for producing a tablet containing ibuprofen or a salt thereof and tranexamic acid, and includes a step of coating at least a portion of at least one of a first granule containing ibuprofen or a salt thereof and a second granule containing tranexamic acid with talc to form a coated granule, and preparing a tablet so that the hardness is 45 N or more.

In addition, in the tablet manufacturing method of the present invention, it is preferable to blend talc so that the total amount of talc in the tablet is 6.5 mass% or more.
Furthermore, in the tablet manufacturing method of the present invention, it is preferable that talc is blended so that the total amount of talc in the tablet is 7.5% by mass or more, and that X/Y, which is the ratio of the mass ratio X of talc in the coated granules to the mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in all of the granules not coated with talc among the first granules and the second granules, is adjusted so that X/Y is 0.14 or more.
Furthermore, the tablet manufacturing method of the present invention may include, for example, a step of mixing the first granules, the second granules, the coated granules, and optionally a disintegrant, a lubricant, and other additives, followed by tableting, after the step of forming the coated granules. The mixing is carried out, for example, using a tumble mixer or a convection mixer. Tableting is carried out, for example, using a rotary tablet press.

The tablet of the present invention may have a hardness of 45 N or more, preferably 60 N or more. For example, the hardness when compressed under 2000 kgf is preferably 60 N or more.
If the tablet of the present invention has a hardness of 45 N or more, it can be used as a tablet in various forms, such as an orally disintegrating tablet (OD) while maintaining a certain tablet hardness.
If the hardness of the tablet of the present invention is 60 N or more, this is a preferred hardness from the viewpoint of avoiding wear and tear of the tablet when film-coating on a production scale, for example.

The solid formulation of the present invention may optionally contain other medicinal ingredients, such as antihistamines, antipyretics, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly used in general cold medicines, antipyretics, and rhinitis medicines.

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

Examples of antipyretic analgesics include aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine.
Antitussive and expectorant drugs include dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocysteine, tipepidine hibenzate, dextromethorphan hydrobromide hydrate and the like.

Anti-inflammatory drugs include glycyrrhizinic acid, dipotassium glycyrrhizinate, and the like.
Examples of central nervous system stimulants include caffeine and anhydrous caffeine.
Vitamin preparations include vitamin B1 and its derivatives and salts thereof (e.g., benfotiamine), vitamin B2 and its derivatives and salts thereof (e.g., riboflavin), vitamin C and its derivatives and salts thereof (e.g., ascorbic acid), hesperidin and its derivatives and salts thereof, etc.
Anticholinergic agents include belladonna total alkaloids, isopropamide iodide, and the like.

Among these, preferred additional ingredients include one or more selected from the group consisting of dl-chlorpheniramine maleate, d-chlorpheniramine maleate, clemastine fumarate, dihydrocodeine phosphate, noscapine, dl-methylephedrine hydrochloride, bromhexine hydrochloride, ambroxol hydrochloride, L-carbocysteine, glycyrrhizic acid, anhydrous caffeine, benfotiamine, riboflavin, ascorbic acid, hesperidin, belladonna total alkaloids, and isopropamide iodide. Because the solid formulation of the present invention does not exhibit a decrease in content even when ibuprofen or a salt thereof and tranexamic acid are homogeneously mixed, these additional ingredients can also be homogeneously mixed therewith.

The tablets of the present invention may further contain formulation additives, if necessary. Examples of formulation additives used to formulate the tablets of the present invention include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glazing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, flavors, aromas, colorants, bases, coating agents, sugar-coating agents, plasticizers, dispersants, antifoaming agents, fluidizing agents, and flavoring agents/fragrances. Formulation additives that can be used in conventional solid formulations can also be used for the above purposes.

Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose/carmellose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate/hydroxypropyl starch/crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

Binders that can be blended include, for example, one or more components selected from gum arabic, gum arabic powder, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

Disintegrants include, for example, carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, etc.

Examples of disintegration aids include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

The glossing agent may be one or more components selected from, for example, carnauba wax, white beeswax, purified shellac, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, beeswax, etc.

The foaming agent may be one or more components selected from, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc.

The moisture-proofing agent may be one or more components selected from the group consisting of ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

The surfactant may be one or more components selected from, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium Ingredients: hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, Natural Vitamin E, Tocopherol, Tocopheryl Acetate, Lactose, Concentrated Glycerin, Povidone, Polyoxyethylene Hydrogenated Castor Oil 60, Polyoxyethylene Stearyl Ether, Polyoxyethylene Cetyl Ether, Polyoxyethylene Nonylphenyl Ether, Polyoxyethylene Hydrogenated Castor Oil, Polyoxyethylene (42) Polyoxypropylene (67) Glycol, Polyoxyethylene (54) Polyoxypropylene (39) Glycol, Polyoxyethylene (160) Polyoxypropylene (30) Glycol, Polyoxyethylene (196) Polyoxypropylene (67) Glycol, Polyoxyethylene Coconut Fatty Glyceryl (7E.O.), Polysol It can contain one or more ingredients selected from the group consisting of polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium metabisulfite.

Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

Sweeteners that can be blended include, for example, one or more ingredients selected from aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc.

Flavoring agents include, for example, sodium chloride, Phellodendron bark powder, Phellodendron bark extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and ginger. It can contain one or more ingredients selected from the following: powdered sorghum, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

Flavors that can be blended include, for example, one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc.

Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

Coloring agents may include one or more components selected from the group consisting of yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, beta-carotene, licorice extract, gold leaf, black iron oxide, titanium oxide, ferric oxide, dizazo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide/glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

The base ingredients include: gum arabic powder, pregelatinized starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid/glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropyl cellulose It can contain one or more ingredients selected from the group consisting of sucrose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2910, titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2910, titanium oxide-macrogol 400 mixture, hydroxypropyl methylcellulose 2910, titanium oxide-macrogol 400 mixture, hydroxypropyl methylcellulose 2910, titanium oxide-macrogol 400 mixture, hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose acetate succinate- ... Examples of suitable surfactants include hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Macrogol 20000, Macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

The sugar-coating agent may be one or more ingredients selected from the group consisting of gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, refined sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like can be blended in one or more ingredients.

Antifoaming agents can be one or more selected from ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silicon dioxide mixtures, sucrose fatty acid esters, silicone antifoaming agents, silicone oils, sorbitan fatty acid esters, polysorbate 80, etc.

The fluidizing agent may be one or more components selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

Flavoring agents and fragrances include, for example, fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, vitabe It can contain one or more ingredients selected from the following: rose, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

These additives are not limited to those listed above, and one of these may be used alone or in combination of two or more.

The tablets of the present invention may be temporarily packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and then stored in an airtight container. They may also be pillow-packaged, and may be stored in a box or the like.
The materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples thereof include resin films such as polyethylene, polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached thereto.

To explain the present invention in more detail, the following test examples and examples are provided, but the present invention is not limited to these.

Test Example 1: Evaluation of tableting properties of granules uncoated with talc and a coating substrate

1. Tablet Production The formulations (tablets) used in the tests of Comparative Examples 1 to 8 were produced by the following method. The formulations (per 9 tablets) of Comparative Examples 1 to 4 are shown in Table 1. The formulations (per 9 tablets) of Comparative Examples 5 to 8 are shown in Table 2. Note that the percentages in Table 1 and the following tables refer to mass % unless otherwise specified.

(Comparative Example 1)
1,400.0 g of ibuprofen, 58.3 g of benfotiamine, 14.0 g of riboflavin, 280 g of hypromellose, 767.7 g of crystalline cellulose, and 490.0 g of D-mannitol were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, followed by the addition of a mixture of 140 g of polyoxyethylene hydrogenated castor oil 60 in an 80% by mass aqueous solution of ethanol and kneading. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3,150.0 g of first granules.

Furthermore, 1,750 g of tranexamic acid, 8.2 g of d-chlorpheniramine maleate hydrochloride, 140.0 g of dl-methylephedrine hydrochloride, 105.0 g of ambroxol hydrochloride, 175.0 g of anhydrous caffeine, 14.0 g of riboflavin, 1,662.5 g of low-substituted hydroxypropyl cellulose, 32.7 g of D-mannitol, and 228.7 g of hydroxypropyl cellulose were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, and then ethanol was added and kneaded. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 4,116.0 g of a second granule.
1,350.0 g of the first granules, 1,764.0 g of the second granules, 27.0 g of light anhydrous silicic acid, 36.0 g of croscarmellose sodium, and 153.0 g of talc were mixed in a plastic bag, and then compressed into tablets using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho).

For Comparative Examples 2 to 8, tablets were manufactured in the same manner as Comparative Example 1, except that the composition was changed to the compositions shown in Tables 1 and 2.

2. Test Methods The formulations of Comparative Examples 1 to 8 were compressed into 30 tablets each at 1600, 1800, and 2000 kgf using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho), and the tablet hardness and cracking behavior were measured. In addition, the tablets were compressed for 10 minutes at 1800 kgf, and the degree of adhesion of the tablet powder to the punches was confirmed.
The evaluation items in Tables 3 and 4 were judged according to the following criteria.
- Degree of adhesion of tableting powder to punch (sticking)
○: No sticking (caused by adhesion of punch) was observed.
×: Sticking (caused by adhesion of punch) was observed.
- Tablet breaking (sticking to punch (capping, cracking))
○: No capping or cracking (caused by sticking of the punch) was observed.
×: Capping and cracking (caused by sticking of punch) were observed.
Tablet hardness: Excellent: When tablets were compressed at 2000 kgf, the tablet hardness was 60 N or more.
○: When tablets were compressed at 1600 kgf, 1800 kgf, and 2000 kgf, the tablet hardness was 45 N or more in all cases (tablet hardness was 45 N or more but less than 60 N).
×: The tablet hardness was less than 45 N at any of 1600 kgf, 1800 kgf, and 2000 kgf.

3. Test Results Tables 3 and 4 show the tablet hardness, cracking pattern, and degree of adhesion of tableting powder to the punch of the samples obtained by tableting Comparative Examples 1 to 8.
As shown in Tables 3 and 4, even when talc was mixed with the granular material and compressed into tablets, the results of the three evaluation items of tablet hardness, cracking, and degree of adhesion of tableting powder to the punch were good, and no product was found that was likely to enable stable tablet production.

Test Example 2: Evaluation of tableting properties of granules coated with talc and a coating substrate

2. Production of Solid Preparations The preparations (tablets) used in the tests in Comparative Examples 9 and 10 and Examples 1 to 10 were produced by the following method. The formulations (per 9 tablets) of Comparative Examples 9 to 10 are shown in Table 5. The formulations (per 9 tablets) of Examples 1 to 3 are shown in Table 6. The formulations (per 9 tablets) of Examples 4 to 6 are shown in Table 7. The formulations (per 9 tablets) of Examples 7 to 10 are shown in Table 8.

(Comparative Example 9)
1,400.0 g of ibuprofen, 58.3 g of benfotiamine, 14.0 g of riboflavin, 280 g of hypromellose, 767.7 g of crystalline cellulose, and 490.0 g of D-mannitol were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, followed by the addition of a mixture of 140 g of polyoxyethylene hydrogenated castor oil 60 in an 80% by mass aqueous solution of ethanol and kneading. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3,150.0 g of first granules.

2100.0 g of the first granules were placed in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), and a coating solution was prepared by mixing 210.0 g of crystalline cellulose, 147.0 g of hydroxypropyl cellulose, and 147.0 g of light anhydrous silicic acid with an 80% by mass aqueous solution of ethanol. The resulting coating solution was then applied in the desired amount to the first granules using a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), thereby producing first coated granules.

Separately, 1500 g of tranexamic acid, 7.0 g of d-chlorpheniramine maleate hydrochloride, 120.0 g of dl-methylephedrine hydrochloride, 90.0 g of ambroxol hydrochloride, 150.0 g of anhydrous caffeine, 12.0 g of riboflavin, 1155.0 g of low-substituted hydroxypropyl cellulose, 28.0 g of D-mannitol, and 196.0 g of hydroxypropyl cellulose were charged into a high-speed agitating granulator (FM-VG-25; manufactured by Powrex) and mixed. After that, ethanol was added and kneaded. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3258.0 g of second granules.

1566.0 g of the first coated granules, 1629.0 g of the second granules, 27.0 g of light anhydrous silicic acid, 36.0 g of croscarmellose sodium, and 153.0 g of talc were mixed in a plastic bag, and then compressed into tablets using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho).
The composition of Comparative Example 9 is shown in Table 5.

In addition, for Comparative Example 10, tablets were produced in the same manner as in Comparative Example 9, except that the composition was changed to the composition shown in Table 5.

Example 1
1,400.0 g of ibuprofen, 58.3 g of benfotiamine, 14.0 g of riboflavin, 280.0 g of hypromellose, 767.7 g of crystalline cellulose, and 490.0 g of D-mannitol were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, and then a mixture of 140.0 g of polyoxyethylene hydrogenated castor oil 60 in an 80% by mass aqueous solution of ethanol was added and kneaded. The resulting kneaded mixture was granulated using a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3,150.0 g of first granules.

2,100.0 g of the first granules were placed in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), and a coating liquid was prepared by mixing 105.0 g of talc, 63.0 g of hydroxypropyl cellulose, and 42.0 g of light anhydrous silicic acid with an 80% by mass aqueous solution of ethanol. The resulting coating liquid was then applied in the desired amount to the first granules using a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), thereby producing first coated granules.

Separately, 1,500 g of tranexamic acid, 7.0 g of d-chlorpheniramine maleate hydrochloride, 120.0 g of dl-methylephedrine hydrochloride, 90.0 g of ambroxol hydrochloride, 150.0 g of anhydrous caffeine, 12.0 g of riboflavin, 28.0 g of D-mannitol, 885.0 g of low-substituted hydroxypropyl cellulose, and 196.0 g of hydroxypropyl cellulose were charged into a high-speed agitating granulator (FM-VG-25; manufactured by Powrex) and mixed. After that, ethanol was added and kneaded. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3,528.0 g of second granules.

1585.4 g of the first coated granules, 1595.0 g of the second granules, 28.8 g of light anhydrous silicic acid, 38.4 g of croscarmellose sodium, and 163.3 g of talc were mixed in a plastic bag and then compressed into tablets using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho).
The composition of Example 1 is shown in Table 6.

In addition, in Examples 2 to 10, tablets were manufactured in the same manner as in Example 1, except that the compositions were changed to those shown in Tables 6 to 8.

Furthermore, for Comparative Example 9, Comparative Example 10, Example 9, and Example 10, 750.0 g of tablets (uncoated tablets) were placed in a film coating machine (HC-FZ-Labo; manufactured by Freund Corporation), and a film coating solution was prepared by mixing 39.3 g of polyvinyl alcohol (partially saponified), 13.1 g of hypromellose, 4.4 g of triethyl citrate, 17.5 g of talc, and 13.1 g of titanium oxide with water. The desired amount of the resulting coating solution was then applied to the tablets (uncoated tablets) using a film coating machine (HC-FZ-Labo; manufactured by Freund Corporation), and then 0.39 g of carnauba wax was added to the film coating machine (HC-FZ-Labo; manufactured by Freund Corporation) for polishing, producing film-coated tablets.

In Examples 6 and 10, particle diameters were measured by SEM before and after granule coating to confirm whether the granules were properly coated.
The procedure for producing tablets in Example 6 is shown below.

Example 6 (including manufacturing method and particle size measurement)
1400.0 g of ibuprofen, 58.3 g of benfotiamine, 14.0 g of riboflavin, 280.0 g of hypromellose, 767.7 g of crystalline cellulose, and 490.0 g of D-mannitol were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed. Then, a mixture of 140.0 g of polyoxyethylene hydrogenated castor oil 60 in an 80% by mass aqueous solution of ethanol was added and kneaded. The resulting mixture was granulated using a flash mill (FL-200G; manufactured by Fuji Paudal). The resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3150.0 g of first granules. The SEM photograph shown in FIG. 1 was obtained, and the average particle size was 313 μm.

2100.0 g of the first granules were placed in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), and 210.0 g of talc, 126.0 g of hydroxypropyl cellulose, and 84.0 g of light anhydrous silicic acid were mixed with an 80% by mass aqueous solution of ethanol to prepare a coating solution. The resulting coating solution was then applied in a desired amount to the first granules in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), producing a first coated granule. The SEM photograph shown in Figure 2 was obtained, showing an average particle size of 355 μm, and an increase in the average particle size of about 40 μm was confirmed by coating. It was observed from the SEM photograph that small particles were incorporated into larger particles by coating.
Furthermore, 1500 g of tranexamic acid, 7.0 g of d-chlorpheniramine maleate hydrochloride, 120.0 g of dl-methylephedrine hydrochloride, 90.0 g of ambroxol hydrochloride, 150.0 g of anhydrous caffeine, 12.0 g of riboflavin, 28.0 g of D-mannitol, 1425.0 g of low-substituted hydroxypropyl cellulose, and 196.0 g of hydroxypropyl cellulose were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, followed by addition of ethanol and kneading. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3528.0 g of second granules, the average particle size of which was 276 μm.
1535.0 g of the first coated granules, 1671.4 g of the second granules, 25.6 g of light anhydrous silicic acid, 34.1 g of croscarmellose sodium, and 145.0 g of talc were mixed in a plastic bag and then compressed into tablets using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho).

Furthermore, in Example 10, using the same method as in Example 6, the average particle size of the first granules was measured using an SEM before and after coating.The average particle size of the first granules before granule coating was 315 μm, and the average particle size of the first coated granules after granule coating was 367 μm.

In Example 10, it was confirmed that coating the granules increased the average particle size by approximately 40 μm, and it was observed from the SEM photographs that coating caused the smaller particles to be incorporated into larger particles in the coating liquid.
From the results of particle size measurement and SEM observation in Examples 6 and 10, it was confirmed that the tablet manufacturing method of the present invention enables granule coating to be carried out appropriately.

2. Test Methods The preparations obtained in Comparative Examples 9 and 10 and Examples 1 to 10 were compressed into 30 tablets each at 1600, 1800, and 2000 kgf using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho), and the tablet hardness and cracking behavior were measured. Tablets were also compressed for 10 minutes at 1800 kgf, and the degree of adhesion of the tablet powder to the punches was confirmed.
The evaluation items in Tables 9 to 12 were judged according to the following criteria, similar to those in Tables 3 and 4.
- Degree of adhesion of tableting powder to punch (sticking)
○: No sticking (caused by adhesion of punch) was observed.
×: Sticking (caused by adhesion of punch) was observed.
- Tablet breaking (sticking to punch (capping, cracking))
○: No capping or cracking (caused by sticking of the punch) was observed.
×: Capping and cracking (caused by sticking of punch) were observed.
Tablet hardness: Excellent: When tablets were compressed at 2000 kgf, the tablet hardness was 60 N or more.
○: When tablets were compressed at 1600 kgf, 1800 kgf, and 2000 kgf, the tablet hardness was 45 N or more in all cases (tablet hardness was 45 N or more but less than 60 N).
×: The tablet hardness was less than 45 N at any of 1600 kgf, 1800 kgf, and 2000 kgf.

3. Test Results Tables 9 to 12 show the tablet hardness, cracking pattern, and degree of adhesion of tableting powder to the punch of the samples obtained by tableting Comparative Examples 9 to 10 and Examples 1 to 10.
As shown in Comparative Examples 9 and 10, when the coating composition in the first coated granules did not contain talc, sticking occurred even when talc was used as the final component.
As shown in Comparative Example 10, when magnesium stearate, a common stearic acid-based lubricant, was used as the final component, a tendency for the melting point to decrease was observed, and the decrease in melting point caused the tablets to stick to the punch.

On the other hand, as shown in Examples 1 to 3, when the first granules were coated with a composition containing talc to form the first coated granules and the tablet hardness was 45 N or higher, sticking, capping, and cracking were not observed. In addition, in these cases, the proportion of talc in the entire tablet (plain tablet) was 6.5% by mass or higher in all cases.

Furthermore, as shown in Examples 4 to 7 and 9, when talc was blended in an amount of 7.5% by mass or more throughout the tablet (plain tablet), and the ratio X/Y ((1)/(2) in Tables 11 and 12), which is the ratio of the mass ratio X of talc in the talc-coated first coated granules (talc ratio (1) in the coated granules in Tables 11 and 12) to the mass ratio Y of tranexamic acid in the untalc-coated second granules (tranexamic acid ratio (2) in the uncoated granules in Tables 11 and 12), was 0.14 or greater, no punch adhesion (sticking) or punch fixation (capping, cracking) was observed, and a desirable tablet hardness (60 N or greater at 2000 kgf) was obtained.

Furthermore, as shown in Example 8, when talc was blended in an amount of 7.5% by mass or more throughout the tablet (plain tablet), and the ratio X/Y ((1)/(2) in Tables 11 and 12) of the mass ratio X of the talc-coated second coated granules (talc ratio (1) in the coated granules in Tables 11 and 12) to the mass ratio Y of ibuprofen in the first granules not coated with talc (ibuprofen ratio (2) in the uncoated granules in Tables 11 and 12) was 0.14 or greater, no punch adhesion (sticking) or punch fixation (capping, cracking) was observed, and a desirable tablet hardness (60 N or greater at 2000 kgf) was obtained.

In this way, when talc is blended in at least 6.5% by mass of the entire tablet (uncoated tablet) and the tablet hardness is 45 N or greater, it has been found that by mixing granules coated with a coating composition containing talc and granules containing at least one of ibuprofen or a salt thereof and tranexamic acid before compressing the tablets, it is possible to improve the degree of cracking and adhesion of the tableting powder to the punches.

Furthermore, it was found that when talc is blended in at least 7.5% by mass of the entire tablet (plain tablet), and the ratio X/Y, where X is the mass ratio of talc in the talc-coated granules (coated granules) of granules A and B, and Y is the mass ratio of ibuprofen or a salt thereof and tranexamic acid in the entire talc-uncoated granules (granules) of granules A (first granules) and granules B (the second granules), is 0.14 or greater, a desirable tablet hardness (for example, a tablet hardness of 60 N or greater when compressed at 2000 kgf) can be ensured, enabling stable production.

<Formulation example>
The formulations of Formulation Examples 1 to 24 (per 6 or 9 tablets) are shown in Tables 13 to 24.

(Formulation Example 1)
1,418.9 g of ibuprofen, 3.2 g of clemastine fumarate, 23.6 g of dihydrocodeine phosphate, 59.1 g of benfotiamine, 14.2 g of riboflavin, 283.8 g of hypromellose, 740.2 g of crystalline cellulose, and 465.1 g of D-mannitol were charged into a high-speed stirring granulator (FM-VG-25; manufactured by Powrex) and mixed, followed by the addition of a mixture of 141.9 g of polyoxyethylene hydrogenated castor oil 60 in an 80% by mass aqueous solution of ethanol and kneading. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3,150.0 g of first granules.

2,100.0 g of granules A were placed in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), and a coating solution was prepared by mixing 255.4 g of talc, 149.0 g of hydroxypropyl cellulose, and 106.4 g of light anhydrous silicic acid with an 80% by mass aqueous solution of ethanol. The resulting coating solution was then applied in the desired amount to granules A using a fluidized bed dryer (FLO-5; manufactured by Freund Corporation), producing first coated granules.

Separately, 1500 g of tranexamic acid, 28.0 g of dihydrocodeine phosphate, 120.0 g of dl-methylephedrine hydrochloride, 150.0 g of anhydrous caffeine, 12.0 g of riboflavin, 1155.0 g of low-substituted hydroxypropyl cellulose, 102.0 g of microcrystalline cellulose, and 196.0 g of hydroxypropyl cellulose were charged into a high-speed agitating granulator (FM-VG-25; manufactured by Powrex) and mixed. After that, ethanol was added and kneaded. The resulting kneaded mixture was granulated in a flash mill (FL-200G; manufactured by Fuji Paudal), and the resulting sized powder was dried in a fluidized bed dryer (FLO-5; manufactured by Freund Corporation) to produce 3258.0 g of second granules.

1548.0 g of the first coated granules, 1629.0 g of the second granules, 27.0 g of light anhydrous silicic acid, 45.0 g of croscarmellose sodium, and 153.0 g of talc were mixed in a plastic bag, and then compressed into tablets (plain tablets) using a rotary tablet press (CORRECT19; manufactured by Kikusui Seisakusho).
750.0 g of tablets (plain tablets) were charged into a film coating machine (HC-FZ-Labo; manufactured by Freund Corporation), and further, 39.3 g of polyvinyl alcohol (partially saponified), 13.1 g of hypromellose, 4.4 g of triethyl citrate, 17.5 g of talc, and 13.1 g of titanium oxide were mixed with water to prepare a film coating solution. Next, the resulting coating solution was applied to the tablets (plain tablets) in the desired amount using a film coating machine (HC-FZ-Labo; manufactured by Freund Corporation), and then 0.39 g of carnauba wax was added to the film coating machine (HC-FZ-Labo; manufactured by Freund Corporation) and polished to produce film-coated tablets.

Formulation Examples 2 to 24 can be manufactured in the same manner as Formulation Example 1.

The above describes preferred embodiments and examples of the present invention, but the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

The present invention enables the simple and cost-effective production of tablets containing ibuprofen or a salt thereof and tranexamic acid. The tablets of the present invention are useful for treating illnesses such as the common cold.

Claims (11)

A tablet comprising first granules containing ibuprofen or a salt thereof, second granules containing tranexamic acid, and talc,
The tablet hardness is 45N or more,
At least one of the first granules and the second granules is a coated granule coated with a coating component so that at least a portion of the first granules and the second granules is coated with at least a portion of the talc,
The coating composition comprises:
talc,
Water-soluble polymers, and
one or more selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, and magnesium aluminometasilicate;
Including,
tablet. The tablet according to claim 1, wherein the tablet contains 6.5% by mass or more of talc. The tablet according to claim 1 or 2, wherein the tablet has a hardness of 60 N or more. The tablet contains 7.5% by mass or more of talc,
a ratio X/Y of a mass ratio X of talc in the coated granules to a mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in the entire granules not coated with talc among the first granules and the second granules is 0.14 or more;
A tablet according to any one of claims 1 to 3. 3. The tablet according to claim 1, wherein the water-soluble polymer is one or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, povidone, polyvinyl alcohol (partially saponified), and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. forming said first granules comprising ibuprofen or a salt thereof;
forming the second granules containing tranexamic acid;
and coating at least a portion of at least one of the first granules and the second granules with talc.
A method for producing a tablet according to any one of claims 1 to 5 . a step of coating at least one of first granules containing ibuprofen or a salt thereof and second granules containing tranexamic acid with a coating component so as to coat at least a portion of the first granules with talc to form coated granules;
and preparing a tablet having a hardness of 45 N or more ;
The coating composition comprises:
talc,
Water-soluble polymers, and
one or more selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, and magnesium aluminometasilicate;
Including,
A method for producing a tablet containing ibuprofen or a salt thereof and tranexamic acid. A method for producing a tablet as described in claim 7 , wherein talc is blended so that the total amount of talc in the tablet is 6.5 mass% or more. The method for producing a tablet according to claim 7 or 8 , wherein the tablet is prepared so that the tablet has a tablet hardness of 60 N or more. 10. The method for producing a tablet according to claim 7, wherein talc is blended so that the total amount of talc in the tablet is 7.5% by mass or more, and X/Y, which is the ratio of the mass ratio X of talc in the coated granules to the mass ratio Y of ibuprofen or a salt thereof and tranexamic acid in all of the granules not coated with talc among the first granules and the second granules, is adjusted so that X/Y is 0.14 or more. 11. The method for producing a tablet according to claim 7 , further comprising, after the step of forming the coated granules, a step of mixing the first granules, the second granules, and the coated granules and compressing them into tablets.