Solid preparation

Abstract

To provide a solid preparation in which temporal color tone change hard to occur when stored, despite that the preparation contains acetaminophen, ibuprofen or a salt thereof or their solvate, and one or more kinds of antacid selected from magnesium oxide and synthetic hydrotalcite.SOLUTION: A solid preparation contains the following components (a1), (a2), (a3) and (a4): (a1) acetaminophen; (a2) ibuprofen or a salt thereof or their solvate; (a3) one or more kinds of antacid selected from magnesium oxide and synthetic hydrotalcite; and (a4) one or more kinds of components selected from talc, light anhydrous silicic acid and mannitol.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a solid dosage form, more particularly to a solid dosage form comprising acetaminophen, ibuprofen and one or more antacids selected from magnesium oxide and synthetic hydrotalcite. [Background technology]

[0002] Acetaminophen is a type of antipyretic analgesic, but when it is mixed with an antacid to form a solid preparation, there is a problem that the color tends to change over time during storage (Patent Documents 1 to 4). It is also known that ibuprofen also changes color over time when it is mixed with an antacid to form a solid preparation and stored (Patent Document 5). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 02-286614 [Patent Document 2] Japanese Patent Application Publication No. 05-294829 [Patent Document 3] JP 2011-68584 A [Patent Document 4] JP 2011-111393 A [Patent Document 5] JP 2011-68645 A [Patent Document 6] JP 2017-226611 A Summary of the Invention [Problem to be solved by the invention]

[0004] For this reason, tablets have been proposed which are obtained by compressing a powder mixture of granules in which acetaminophen particles are coated with an antacid such as synthetic hydrotalcite, magnesium aluminometasilicate, or magnesium oxide, and ibuprofen together with crospovidone, sodium starch glycolate, or calcium carboxymethylcellulose (Patent Document 6). It has been reported that when tablets are produced in this manner, the change in color over time that occurs when acetaminophen is combined with the above-mentioned antacid is suppressed.

[0005] However, the tablet described in Patent Document 6 had insufficient storage stability, as the color tone of the tablet could change significantly over time when stored under harsh conditions or for a long period of time. In addition, although magnesium oxide is a type of antacid, it tends to change color more significantly over time when combined with acetaminophen to form a solid preparation and stored than other antacids such as dried aluminum hydroxide gel, magnesium aluminometasilicate, and synthetic hydrotalcite. An object of the present invention is to provide a solid preparation which is unlikely to undergo color change over time during storage, despite containing acetaminophen, ibuprofen or a salt thereof, or a solvate thereof, and one or more antacids selected from magnesium oxide and synthetic hydrotalcite. [Means for solving the problem]

[0006] The present inventors have found that by combining acetaminophen, ibuprofen or a salt thereof, or a solvate thereof, and one or more antacids selected from magnesium oxide and synthetic hydrotalcite, together with one or more components selected from talc, light anhydrous silicic acid and mannitol to form a solid preparation, the color tone is less likely to change over time during storage, and have completed the present invention.

[0007] That is, the present invention provides the following: <1> ~ <9> This provides: <1> A solid formulation (hereinafter also referred to as the solid formulation of the present invention) comprising the following components (a1), (a2), (a3) ​​and (a4). (a1) Acetaminophen (a2) Ibuprofen or a salt thereof or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

[0008] <2> A solid formulation comprising a granule containing the following components (a1), (a2), (a3) ​​and (a4). (a1) Acetaminophen (a2) Ibuprofen or a salt thereof or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

[0009] <3> A solid preparation comprising an additive layer and a granulated material dispersed in the additive layer, the granulated material containing the following components (a1), (a2), (a3) ​​and (a4): (a1) Acetaminophen (a2) Ibuprofen or a salt thereof or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

[0010] <4> Component (a3) ​​is magnesium oxide; <1> ~ <3> 2. The solid formulation according to claim 1 , <5> The component (a4) is one or more components selected from talc and light anhydrous silicic acid. <1> ~ <4> 2. The solid formulation according to claim 1 , <6> Component (a4) is talc; <1> ~ <4> 2. The solid formulation according to claim 1 , <7> Component (a3) ​​is magnesium oxide and component (a4) is talc; <1> ~ <3> 2. The solid formulation according to claim 1 ,

[0011] <8> the mass ratio of the component (a4) to the component (a1) [(a4) / (a1)] is 0.15 or more and 1 or less; <1> ~ <7> 2. The solid formulation according to claim 1 , <9> The dosage form is granules, fine granules, powders, tablets, pills, capsules or dry syrup. <1> ~ <8> 2. The solid formulation according to claim 1 , Effect of the Invention

[0012] According to the present invention, a solid preparation which is less likely to undergo color change over time during storage can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] <Solid preparations> The solid preparation of the present invention contains the above-mentioned components (a1), (a2), (a3) ​​and (a4). First, the components (a1) to (a4) will be described.

[0014] (Component (a1)) Acetaminophen can be produced by a known method, and commercially available products can also be used. The content of acetaminophen is preferably from 1% by mass to 50% by mass, more preferably from 5% by mass to 40% by mass, even more preferably from 10% by mass to 35% by mass, and particularly preferably from 15% by mass to 30% by mass, based on the total mass of the solid preparation, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, and the like.

[0015] When acetaminophen is contained in the granules, the content of acetaminophen in the granules is, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, etc., preferably from 5% by mass to 45% by mass, more preferably from 10% by mass to 40% by mass, even more preferably from 15% by mass to 35% by mass, and particularly preferably from 20% by mass to 30% by mass, relative to the total mass of the granules.

[0016] (ingredient (a2)) Examples of ibuprofen or a salt thereof or a solvate thereof include ibuprofen; alkali metal salts of ibuprofen such as sodium ibuprofen and potassium ibuprofen; and hydrates and alcohol solvates thereof. In addition, ibuprofen or a salt thereof, or a solvate thereof is preferably in a powder form. The average particle size of the powder is preferably 5 to 75 μm, more preferably 15 to 60 μm. The average particle size of the powder can be measured by a laser diffraction method. Ibuprofen or a salt thereof, or a solvate thereof can be produced by a known method, or a commercially available product can also be used.

[0017] The content of ibuprofen or a salt thereof, or a solvate thereof is preferably from 1% by mass to 50% by mass, more preferably from 5% by mass to 40% by mass, even more preferably from 10% by mass to 35% by mass, and particularly preferably from 15% by mass to 30% by mass, based on the total mass of the solid preparation, from the viewpoints of resistance to color change, disintegrability, ease of production, and the like.

[0018] When ibuprofen or a salt thereof, or a solvate thereof is contained in the granule, the content of ibuprofen or a salt thereof, or a solvate thereof in the granule is, from the viewpoints of resistance to color change, disintegrability, ease of production during tableting, etc., preferably from 5% by mass to 45% by mass, more preferably from 10% by mass to 40% by mass, even more preferably from 15% by mass to 35% by mass, and particularly preferably from 20% by mass to 30% by mass, relative to the total mass of the granule.

[0019] The mass ratio of component (a2) in the solid preparation (preferably in the granules) to component (a1) in the solid preparation (preferably in the granules) [(a2) / (a1)] is preferably from 0.05 to 10, more preferably from 0.1 to 5, even more preferably from 0.25 to 3, and particularly preferably from 0.5 to 1.5, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, and the like.

[0020] (ingredient (a3)) The solid preparation of the present invention contains (a3) ​​one or more antacids selected from magnesium oxide and synthetic hydrotalcite. The particle size and specific volume of the antacid of component (a3) ​​are not particularly limited, but the specific volume is preferably 1 to 12 mL / g, more preferably 2 to 10 mL / g. Magnesium oxide is preferred as component (a3). Magnesium oxide may be heavy magnesium oxide or light magnesium oxide. Magnesium oxide undergoes a large color change over time when combined with acetaminophen to form a solid preparation, but the solid preparation of the present invention, although it contains magnesium oxide together with acetaminophen, is less likely to undergo a color change over time during storage. The antacid of component (a3) ​​can be produced by a known method, and commercially available products can also be used.

[0021] The content of the antacid of component (a3) ​​is preferably from 0.1% by mass to 50% by mass, more preferably from 1% by mass to 30% by mass, even more preferably from 2% by mass to 20% by mass, and particularly preferably from 3% by mass to 10% by mass, based on the total mass of the solid preparation, from the viewpoints of resistance to color change, disintegrability, reduction of unpleasant taste, etc.

[0022] When the antacid of component (a3) ​​is contained in the granule, the content of the antacid of component (a3) ​​in the granule is, from the viewpoints of resistance to color change, disintegrability, reduction of unpleasant taste, etc., preferably from 0.5% by mass to 30% by mass, more preferably from 1% by mass to 25% by mass, even more preferably from 2.5% by mass to 20% by mass, and particularly preferably from 5% by mass to 15% by mass, based on the total mass of the granule.

[0023] The mass ratio of component (a3) ​​in the solid preparation (preferably in the granules) to component (a1) in the solid preparation (preferably in the granules) [(a3) / (a1)] is preferably from 0.005 to 5, more preferably from 0.01 to 2, even more preferably from 0.05 to 1, and particularly preferably from 0.1 to 0.75, from the viewpoints of resistance to color change, disintegrability, manufacturability, and the like.

[0024] (ingredient (a4)) The solid preparation of the present invention contains (a4) one or more components selected from talc, light anhydrous silicic acid, and mannitol. By including the component (a4) in the solid preparation, the color tone is less likely to change over time.

[0025] The average particle size of talc is preferably 0.1 to 20 μm, and more preferably 1 to 12 μm. The average particle size of talc can be measured by a measurement method in accordance with JIS M8016. As the mannitol, D-mannitol is preferred. Talc, light anhydrous silicic acid and mannitol can be produced by known methods, or commercially available products can also be used. As the component (a4), from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, etc., one or more components selected from talc and light anhydrous silicic acid are preferred, and talc is particularly preferred. When one or more components selected from talc and light anhydrous silicic acid are used as component (a4) (preferably when the granules contain one or more components selected from talc and light anhydrous silicic acid as component (a4)), the color tone is further prevented from changing over time, and the disintegration property of the solid preparation is improved. In particular, when talc is used as component (a4) (preferably when the granules contain talc as component (a4)), the disintegration property of the solid preparation is further improved.

[0026] The content of one or more components selected from talc, light anhydrous silicic acid and mannitol is, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, etc., preferably from 0.05% by mass to 35% by mass, more preferably from 0.1% by mass to 30% by mass, even more preferably from 0.5% by mass to 25% by mass, and particularly preferably from 1% by mass to 20% by mass, based on the total mass of the solid preparation.

[0027] When the granulated product contains one or more components selected from talc, light anhydrous silicic acid, and mannitol, the content of the one or more components selected from talc, light anhydrous silicic acid, and mannitol in the granulated product is, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, etc., preferably 1% by mass or more and 30% by mass or less, more preferably 2% by mass or more and 25% by mass or less, even more preferably 3% by mass or more and 20% by mass or less, and particularly preferably 4% by mass or more and 18% by mass or less, based on the total mass of the granulated product.

[0028] The mass ratio of component (a4) in the solid preparation (preferably in the granules) to component (a1) in the solid preparation (preferably in the granules) [(a4) / (a1)] is, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, and the like, preferably from 0.1 to 3, more preferably from 0.15 to 1.5, even more preferably from 0.15 to 1, still more preferably from 0.175 to 1, and particularly preferably from 0.2 to 0.85. When the content mass ratio [(a4) / (a1)] is 0.15 or more or 0.2 or more, color tone change over time is particularly unlikely to occur.

[0029] The solid preparation of the present invention may contain, in addition to the above components (a1) to (a4), a drug other than the components (a1) to (a3). Examples of drugs other than the components (a1) to (a3) ​​include (a5) caffeines and drugs other than the components (a1) to (a3) ​​and (a5) (hereinafter also referred to as other drugs). From the viewpoints of disintegration, moldability, ease of manufacture, etc., the solid preparation of the present invention preferably further contains the component (a5) in addition to the components (a1) to (a4).

[0030] (ingredient (a5)) Examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0031] From the viewpoints of resistance to color change, disintegrability, moldability, ease of manufacture, etc., the caffeine content is preferably from 0.1% by mass to 30% by mass, more preferably from 0.5% by mass to 25% by mass, even more preferably from 1% by mass to 20% by mass, and particularly preferably from 3% by mass to 10% by mass, based on the total mass of the solid preparation.

[0032] When caffeine is contained in the granulated product, the content of caffeine in the granulated product is preferably from 1% by mass to 25% by mass, more preferably from 2.5% by mass to 20% by mass, even more preferably from 2.5% by mass to 15% by mass, and particularly preferably from 5% by mass to 10% by mass, based on the total mass of the granulated product, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, etc.

[0033] The mass ratio of the component (a5) in the solid preparation (preferably in the granules) to the component (a1) in the solid preparation (preferably in the granules) [(a5) / (a1)] is preferably from 0.01 to 2, more preferably from 0.05 to 1.5, even more preferably from 0.075 to 1, and particularly preferably from 0.1 to 0.75, from the viewpoints of resistance to color change, disintegrability, moldability, ease of production, and the like.

[0034] Examples of other drugs include antipyretics and analgesics other than the components (a1) and (a2), antacids other than the component (a3), hypnotics and sedatives, anti-inflammatory drugs, antitussives and expectorants, antihistamines, antiallergic drugs, anticholinergic drugs, vitamins, muscle relaxants, herbal medicines, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination.

[0035] Examples of antipyretic analgesics other than the components (a1) and (a2) include aspirin, acetaminophen, isopropylantipyrine, salicylamide, ethenzamide, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination. The content of the antipyretic analgesic other than the components (a1) and (a2) is usually from 0% to 5% by mass, preferably from 0% to 0.1% by mass, and more preferably from 0% to 0.01% by mass, based on the total mass of the solid preparation.

[0036] Examples of antacids other than component (a3) ​​include sodium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, calcium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-sodium hydrogen carbonate co-precipitation product, aluminum hydroxide-magnesium carbonate mixed dry gel, aluminum hydroxide-magnesium carbonate-calcium carbonate co-precipitation product, magnesium hydroxide-aluminum potassium sulfate co-precipitation product, glycine, magnesium silicate, dihydroxyaluminum aminoacetate, magnesium hydroxide, magnesium carbonate, etc. Among these, one type may be used alone, or two or more types may be used in combination. The content of the antacid other than component (a3) ​​is usually 0% by mass or more and 5% by mass or less, preferably 0% by mass or more and 0.1% by mass or less, and more preferably 0% by mass or more and 0.01% by mass or less, based on the total mass of the solid preparation.

[0037] Examples of hypnotic sedatives include allylisopropylacetylurea, bromovalerylurea, etc. Among these, one kind may be used alone, or two kinds may be used in combination. The content of the hypnotic sedative is usually from 0 to 5% by mass, preferably from 0 to 0.1% by mass, and more preferably from 0 to 0.01% by mass, based on the total mass of the solid preparation. Examples of anti-inflammatory agents include glycyrrhizic acid and its salts, tranexamic acid, glycyrrhetinic acid, sodium azulene sulfonate, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination. The content of the anti-inflammatory agent is generally from 0% to 5% by mass, preferably from 0% to 0.1% by mass, and more preferably from 0% to 0.01% by mass, based on the total mass of the solid preparation.

[0038] Examples of the antitussive and expectorant drugs include ambroxol hydrochloride, L-ethylcysteine ​​hydrochloride, potassium guaiacolsulfonate, potassium cresolsulfonate, guaifenesin, bromhexine hydrochloride, L-carbocysteine, codeine phosphate hydrate, dihydrocodeine phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, dimemorphan phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, etc. One of these may be used alone, or two or more may be used in combination. The content of the antitussive and expectorant is generally from 0 to 5% by mass, preferably from 0 to 0.1% by mass, and more preferably from 0 to 0.01% by mass, based on the total mass of the solid preparation.

[0039] Examples of antihistamines and antiallergic agents include mequitazine, azelastine hydrochloride, fexofenadine hydrochloride, epinastine hydrochloride, loratadine, cetirizine hydrochloride, olopatadine hydrochloride, alimemazine tartrate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, diphenhydramine hydrochloride, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination.

[0040] Examples of anticholinergic drugs include isopropamide iodide, Scopolia extract, Scopolia root, total belladonna alkaloids, scopolamine hydrobromide, scopolamine butylbromide, benactidium methyl bromide, timepidium bromide, pirenzepine, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0041] Examples of vitamins include vitamin B1, vitamin B1 derivatives, vitamin B2, vitamin B2 derivatives, vitamin C, vitamin C derivatives, hesperidin, hesperidin derivatives, salts thereof, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination.

[0042] Examples of muscle relaxants include methocarbamol, chlorzoxazone, pridinol mesylate, chlorphenesin carbamate, eperisone hydrochloride, afloqualone, tizanidine hydrochloride, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination.

[0043] Examples of herbal medicines include radish root, cinnamon bark, licorice, peony root, moutan peel, tangerine peel, ginger, Japanese pepper, bellflower, ephedra, apricot kernel, Pinellia gracilis, radish, Senega, Bupleurum falcatum, and Xinjiang, etc. One of these may be used alone, or two or more may be used in combination.

[0044] The total content of other drugs is usually 0% by mass or more and 60% by mass or less, preferably 0% by mass or more and 30% by mass or less, more preferably 0% by mass or more and 20% by mass or less, and particularly preferably 0% by mass, based on the total mass of the solid formulation.

[0045] The solid preparation of the present invention may contain, in addition to the above-mentioned components (a1) to (a4), a pharmaceutical additive other than component (a4). Also, the solid preparation of the present invention may contain both a drug other than components (a1) to (a3) ​​and a pharmaceutical additive other than component (a4). Examples of pharmaceutical additives other than component (a4) include surfactants such as sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, and sodium lauryl sulfate; disintegrants such as sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, alginic acid, bentonite, and partially pregelatinized starch; excipients other than mannitol such as low-substituted hydroxypropyl cellulose, corn starch, crystalline cellulose, lactose, lactose hydrate, sucrose, glucose, sorbitol, and xylitol; binders such as gelatin, sodium alginate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and carmellose sodium; lubricants other than talc such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and glycerin fatty acid esters; and flow agents other than light anhydrous silicic acid such as hydrated silicon dioxide. One of these may be used alone, or two or more may be used in combination. Furthermore, solubilizing agents, buffering agents, preservatives, flavorings, colorings, highly sensitive sweeteners, flavoring agents, etc. may be used as necessary.

[0046] The total content of pharmaceutical additives other than component (a4) in the solid formulation is preferably from 5% by mass to 50% by mass, more preferably from 10% by mass to 45% by mass, even more preferably from 15% by mass to 40% by mass, and particularly preferably from 20% by mass to 35% by mass, based on the total mass of the solid formulation.

[0047] The dosage form of the solid preparation of the present invention may be granules, fine granules, powders, tablets, pills, capsules, dry syrups, etc., with granules, tablets and capsules being preferred, and tablets being particularly preferred. Specific examples of the tablet include plain tablets, film-coated tablets, sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc. Among these, plain tablets, film-coated tablets, and orally disintegrating tablets are preferred.

[0048] As the solid preparation of the present invention, from the viewpoint of small variation during tableting and disintegration property, a solid preparation containing a granulated material containing components (a1) to (a4) is preferable. The solid preparation may be composed of a granulated material containing components (a1) to (a4) or may contain the granulated material and a component other than the granulated material (additive layer or film coating layer). However, from the viewpoint of small variation during tableting and disintegration property, a solid preparation containing an additive layer and a granulated material dispersed in the additive layer, the granulated material containing components (a1) to (a4) (hereinafter, this solid preparation is also referred to as "solid preparation (α)") is preferable, and a tablet containing an additive layer and a granulated material dispersed in the additive layer, the granulated material containing components (a1) to (a4) is particularly preferable. The additive layer is preferably in a solid state. In addition, as the solid preparation (α), one in which the additive layer is the outermost layer is preferable. When the component (a4) is thus incorporated into the granules together with the components (a1) to (a3), variation during tableting is less likely to occur, and disintegration properties are also improved. In addition, it is sufficient that at least a part of the granulated material contained in the solid preparation (α) is dispersed in the additive layer, and multiple granulated materials in the additive layer may be in contact with each other as long as at least a part of the granulated material is dispersed in the additive layer.

[0049] When the solid preparation of the present invention contains a granulated product, the granulated product preferably contains, in addition to the components (a1) to (a4), a drug other than the components (a1) to (a3) ​​and / or a pharmaceutical additive other than the component (a4), and is particularly preferably a drug other than the components (a1) to (a3) ​​and a pharmaceutical additive other than the component (a4). Examples of the drug other than the components (a1) to (a3) ​​and the pharmaceutical additive other than the component (a4) include the same as those mentioned above, and the drug other than the components (a1) to (a3) ​​is preferably (a5) caffeine. In addition, the pharmaceutical additive other than the component (a4) is preferably an excipient, and is particularly preferably low-substituted hydroxypropylcellulose.

[0050] In this specification, low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose described in the 18th revised Japanese Pharmacopoeia. Specifically, it refers to hydroxypropyl cellulose in which the hydroxypropoxy group is quantified at 5.0 to 16.0% when dried. The content of the hydroxypropoxy group is preferably 6 to 13% by mass, particularly preferably 7 to 11% by mass. Low-substituted hydroxypropyl cellulose can be produced by known methods, and commercially available products can also be used. Commercially available low-substituted hydroxypropyl cellulose products include Shin-Etsu Chemical Co., Ltd.'s L-HPC (LH31), Shin-Etsu Chemical Co., Ltd.'s L-HPC (LH21), Shin-Etsu Chemical Co., Ltd.'s L-HPC (LH11), Shin-Etsu Chemical Co., Ltd.'s L-HPC (LH32), Shin-Etsu Chemical Co., Ltd.'s L-HPC (NBD-020), etc.

[0051] The total content of pharmaceutical additives other than component (a4) (hereinafter also referred to as component (a6)) in the granule is preferably from 10% by mass to 50% by mass, more preferably from 15% by mass to 45% by mass, and particularly preferably from 20% by mass to 40% by mass, based on the total mass of the granule.

[0052] The mass ratio of the component (a6) in the granules to the component (a1) in the granules [(a6) / (a1)] is preferably 0.05 or more and 10 or less, more preferably 0.1 or more and 5 or less, and particularly preferably 0.5 or more and 2 or less.

[0053] The granulated material is preferably in the form of granules. The average particle size of the granulated material is usually 100 to 1000 μm, preferably 150 to 750 μm. The average particle size can be measured by a sieving method.

[0054] When the solid preparation of the present invention is the solid preparation (α), the additive layer preferably contains a pharmaceutical additive, which may include, in addition to the above-mentioned component (a4), one or more components selected from talc, light anhydrous silicic acid, and mannitol, as in the component (a4). From the viewpoints of tableting properties, filling properties, disintegration properties, fluidity, and the like, the additive layer preferably contains one or more selected from (b1) a lubricant, (b2) a disintegrant, (b3) an excipient, (b4) a flow agent, and (b5) a surfactant, more preferably contains one or more selected from (b1) a lubricant, (b2) a disintegrant, (b3) an excipient, and (b4) a flow agent, and particularly preferably contains one or more selected from (b1) a lubricant, (b2) a disintegrant, and (b3) an excipient.

[0055] (Component (b1)) Examples of the lubricant of component (b1) include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerin fatty acid esters, etc. Among these, one type may be used alone, or two or more types may be used in combination. From the viewpoints of tableting and filling properties, the content of component (b1) in the additive layer is preferably from 0.1% by mass to 25% by mass, more preferably from 0.5% by mass to 20% by mass, and particularly preferably from 1% by mass to 15% by mass, based on the total mass of the additive layer.

[0056] (component (b2)) As the disintegrant of component (b2), those listed as the pharmaceutical additives other than component (a4) can be used. One of them may be used alone, or two or more of them may be used in combination. The content of component (b2) in the additive layer is preferably from 5% by mass to 55% by mass, more preferably from 10% by mass to 50% by mass, and particularly preferably from 15% by mass to 45% by mass, based on the total mass of the additive layer, from the viewpoint of disintegration property of the solid preparation, etc.

[0057] (Component (b3)) Examples of the excipient of component (b3) include mannitol, low-substituted hydroxypropylcellulose, corn starch, crystalline cellulose, lactose, lactose hydrate, sucrose, glucose, sorbitol, xylitol, etc. Among these, one kind may be used alone, or two or more kinds may be used in combination. The content of component (b3) in the additive layer is preferably from 30% by mass to 80% by mass, more preferably from 35% by mass to 75% by mass, and particularly preferably from 40% by mass to 70% by mass, based on the total mass of the additive layer, from the viewpoints of disintegration property, moldability, etc. of the solid preparation.

[0058] (component (b4)) Examples of the fluidizing agent of component (b4) include hydrous silicon dioxide, light anhydrous silicic acid, etc. Among these, one type may be used alone, or two or more types may be used in combination. The content of component (b4) in the additive layer is preferably 0.01% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 10% by mass or less, and particularly preferably 3% by mass or more and 7% by mass or less, based on the total mass of the additive layer.

[0059] (component (b5)) Examples of the surfactant of component (b5) include sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, sodium lauryl sulfate, etc. Among these, one type may be used alone, or two or more types may be used in combination.

[0060] When the solid preparation of the present invention is a solid preparation (α), the total content of the above-mentioned granules and the additive layer is preferably from 80% by mass to 100% by mass, more preferably from 90% by mass to 100% by mass, even more preferably from 95% by mass to 100% by mass, and particularly preferably from 99.9% by mass to 100% by mass, based on the total mass of the solid preparation (α).

[0061] The mass ratio of the (B) additive layer to the (A) granules in the solid preparation (α) [(B) / (A)] is preferably 0.001 or more and 2 or less, more preferably 0.01 or more and 1 or less, and particularly preferably 0.1 or more and 0.5 or less.

[0062] The solid formulation of the present invention is preferably for oral administration. The dosage of the solid preparation of the present invention is preferably 100 to 1500 mg of component (a1) per day, more preferably 300 to 500 mg per day, and more preferably 100 to 500 mg of component (a1) per dose, more preferably 120 to 210 mg per dose.

[0063] The solid preparation of the present invention can be produced by appropriately combining known methods described in the General Provisions for Preparations in the 18th Edition of the Japanese Pharmacopoeia and the like.

[0064] The solid preparation of the present invention is also unlikely to undergo color change over time during storage, and is therefore extremely useful as an antipyretic analgesic, cold remedy, etc. EXAMPLES

[0065] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0066] [Test Example 1] Samples 1 to 4 were prepared by mixing the ingredients listed in Table 1 except for purified water, adding 1 g of purified water, and mixing. After storing the samples for one week under conditions of 60°C and 75% relative humidity (RH), the change in color tone from before storage (initial) was measured using a spectrophotometer (SE 7700: manufactured by Nippon Denshoku Industries Co., Ltd.), and ΔE * The results are shown in Table 1.

[0067] [Table 1]

[0068] The symbols in the table indicate the following: *1: Acetaminophen manufactured by SpecGX *2: Magnesium oxide manufactured by Kyowa Chemical Industry Co., Ltd. *3: Dried aluminum hydroxide gel manufactured by Tomita Pharmaceutical Co., Ltd. *4: Magnesium aluminometasilicate manufactured by Fuji Chemical Co., Ltd. *5: Synthetic hydrotalcite manufactured by Tomita Pharmaceutical Co., Ltd.

[0069] As shown in Table 1, magnesium oxide caused a greater color change over time when combined with acetaminophen than did dried aluminum hydroxide gel, magnesium aluminometasilicate, or synthetic hydrotalcite.

[0070] [Test Example 2] Each component was weighed according to each granule formulation shown in Table 2, and mixed for 3 minutes in a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). Then, an appropriate amount of purified water was added to the mixed powder of the obtained granule formulation components, and kneaded for 3 minutes in a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). The kneaded product was extrusion-granulated in an extrusion granulator (Twin Dome Gran TDG-80A, manufactured by Dalton Corporation) to obtain wet granules A. Then, the mixture was dried in a fluidized bed dryer (FLO-2, manufactured by Freund Corporation) to obtain dried granules B. Furthermore, the granules were sized in a sieving machine (Comil QC-U10, manufactured by Powrex Corporation) to obtain sized granules C. Granule C was stored for 3 weeks under conditions of 60°C and 75% relative humidity (RH), and the change in color from before storage (initial) was measured using a spectrophotometer (SE 7700: manufactured by Nippon Denshoku Industries Co., Ltd.) to obtain ΔE * The color difference (ΔE * ) and the color difference (ΔE * ) was subtracted to obtain the relative value of the rate of color change of the granules of each Example and Comparative Example (ratio to Reference Example 1 (control)), which was then evaluated according to the following criteria. The results are shown in Table 2.

[0071] (Evaluation criteria for color tone change suppression effect) AA: The relative value of the color tone change rate is less than 30 and the color difference (ΔE * ) is less than 5 A: The relative value of the color tone change rate is less than 30 and the color difference (ΔE * ) is between 5 and 5.3 B: Relative value of color tone change rate is 30 or more

[0072] [Table 2]

[0073] The symbols in the table indicate the following: *1: Acetaminophen manufactured by SpecGX *2: Magnesium oxide manufactured by Kyowa Chemical Industry Co., Ltd. *6: Ibuprofen manufactured by BASF *7: Anhydrous caffeine made by CSPC *8: Lactose hydrate manufactured by DFE Pharma *9: Talc manufactured by Nippon Talc Co., Ltd. *10: Light anhydrous silicic acid manufactured by Nippon Aerosil Co., Ltd. *11: Mannitol manufactured by Mitsubishi Corporation Life Sciences *12: Glycine manufactured by Kyowa Hakko Bio Co., Ltd. *13: Sodium starch glycolate manufactured by DFE Pharma *14: Sodium citrate hydrate manufactured by Fuso Chemical Co., Ltd. *15: Crospovidone manufactured by BASF *16: Carmellose manufactured by Nichirin Chemical Co., Ltd. *17: Carboxymethylcellulose Ca manufactured by Gotoku Pharmaceutical Co., Ltd. *18: Low-substitution HPC manufactured by Shin-Etsu Chemical Co., Ltd.

[0074] As shown in Table 2, the granules of Examples 1 to 3 were less likely to change in color over time when stored.

[0075] [Test Example 3] Granules of Examples 4 to 9 were produced in the same manner as in Test Example 2, except that the amount of component (a4) was changed to that shown in Table 3. The obtained granules were stored and evaluated in the same manner as in Test Example 2. The results are shown in Table 3.

[0076] [Table 3]

[0077] In Table 3, *1, *2, *6 to *11, and *18 have the same meanings as above. As shown in Table 3, the granules of Examples 4 to 9 also did not easily undergo color change over time during storage.

[0078] [Test Example 4] To the granules of Reference Example 1, Examples 1 to 9, and Comparative Examples 2, 4, and 6, 30 parts by mass of a post-powder additive consisting of crystalline cellulose (manufactured by Asahi Kasei Corporation), crospovidone (manufactured by BASF), light anhydrous silicic acid (manufactured by Nippon Aerosil Co., Ltd.), and magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed with the granules, and the mixture was compressed using a rotary tablet press (VIRG0512 type, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 4 to 8 kN to obtain the plain tablets of Examples 10 to 22. The disintegration time of the obtained uncoated tablets was measured according to the disintegration test method of the 18th revised Japanese Pharmacopoeia. The shorter the disintegration time, the better the disintegration property. The results are shown in Table 4.

[0079] [Table 4]

[0080] As shown in Table 4, the solid preparations (Examples 11 to 16) containing granules in which talc or light anhydrous silicic acid (particularly talc) was combined with components (a1) to (a3) ​​had good disintegration properties.

[0081] [Test Example 5] The uncoated tablets of Example 23 were produced in the same manner as in Example 12 of Test Example 4, except that talc was added during mixing rather than in the granule formulation. The uncoated tablets obtained were evaluated in the same manner as in Test Example 4. The results are shown in Table 5. Examples 10 and 12 in Table 5 are synonymous with Examples 10 and 12 in Table 4.

[0082] [Table 5]

[0083] In Table 5, *1, *2, *6 to *11, and *18 have the same meanings as above. As shown in Table 5, like the uncoated tablets of Example 12, the uncoated tablets of Example 23 were also found to have excellent disintegratability.

[0084] [Test Example 6] For the uncoated tablets of Examples 12 and 23, the variation during tableting was confirmed by the tableting pressure CV value of the tablet press. As a result, the CV value of the uncoated tablets of Example 23 was 6% or more, but the CV value of the uncoated tablets of Example 12 was 4% or less, which was not a large variation. Thus, it was found that the uncoated tablets of Example 12 had significantly smaller variation during tableting than the uncoated tablets of Example 23 and were also superior in production efficiency.

[0085] [Test Example 7] Each component was weighed according to each granule formulation shown in Table 6, and mixed for 3 minutes in a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). Then, an appropriate amount of purified water was added to the mixed powder of the obtained granule formulation components, and kneaded for 3 minutes in a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). The kneaded product was dried in a fluidized bed dryer (FLO-2, manufactured by Freund Corporation) to obtain dried granules. Further, granules of Reference Example 2 and Example 24 were obtained by sizing using a sizing machine (Comil QC-U10, manufactured by Powrex Corporation). The granules of Reference Example 2 and Example 24 were stored for 3 weeks under conditions of 60° C. and 75% relative humidity (RH), and the change in color tone from before storage (initial) was measured using a spectrophotometer (SE 7700: manufactured by Nippon Denshoku Industries Co., Ltd.). * The results are shown in Table 6.

[0086] [Table 6]

[0087] *1, *2, *6, *8, *9, and *18 in Table 6 have the same meanings as above. As shown in Table 6, the granules of Example 24 were less likely to change in color over time when stored.

[0088] [Formulation Examples 1 to 3: Granules] Each component was weighed according to the granule recipe shown in Table 7 and put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation) and mixed for 3 minutes. Then, purified water was added and kneaded for 3 minutes with a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). The kneaded product was extrusion granulated using an extrusion granulator (TDG-80 type, manufactured by Dalton Corporation). Furthermore, the obtained extrusion granules were put into a fluidized bed dryer (FLO-5 type, manufactured by Freund Corporation) and dried, and then granulated with a granulator (Comil QC-U10) to obtain granules of Formulation Example 1, Formulation Example 2, and Formulation Example 3.

[0089] [Table 7]

[0090] [Formulation Example 4: Hard Capsule] 24 g of magnesium stearate was added to 3500 g of the granules obtained in Formulation Example 1, and mixed in a V-type mixer (TCV-20, manufactured by Tokuju Co., Ltd.) to obtain 3524 g of mixed powder. This was filled into a gelatin capsule to obtain a hard capsule of Formulation Example 4 (capsule content amount of 440.5 mg, corresponding to acetaminophen content of 97.5 mg).

[0091] [Formulation Example 5: Film-coated tablets] To 3500 g of the granules obtained in Formulation Example 1, 700 g of crystalline cellulose, 200 g of crospovidone, 72 g of light anhydrous silicic acid, and 72 g of magnesium stearate were added and mixed in a V-type mixer (TCV-20, manufactured by Tokuju Co., Ltd.) to obtain 4544 g of tablet powder. Next, tableting was performed using a rotary tableting machine (VIRG0512, manufactured by Kikusui Seisakusho Co., Ltd.) to produce plain tablets with a diameter of 11.0 mm and a tablet mass of 568 mg (acetaminophen content 97.5 mg). Next, 30 g of hypromellose and 5 g of macrogol 6000 were dissolved in purified water, and then 2.5 g of talc and 2.5 g of titanium oxide were dispersed therein to prepare 520 g of a film coating solution with a solid content of 8%. Next, 500 g of plain tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Corporation), and the prepared film coating solution was sprayed onto the tablets to coat them, thereby obtaining film-coated tablets of Formulation Example 5 (tablet mass 588 mg, white).

[0092] [Formulation Example 6: Orally Disintegrating Tablet] To 3500 g of the granules obtained in Preparation Example 2, 420 g of crystalline cellulose, 400 g of corn starch, 20 g of acesulfame potassium, 20 g of aspartame, 20 g of light anhydrous silicic acid, and 20 g of magnesium stearate were added and mixed in a V-type mixer (TCV-20 type, manufactured by Tokuju Co., Ltd.) to obtain 4400 g of tablet powder. Next, tableting was performed using a rotary tableting machine (VIRG0512 type, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets with a diameter of 11 mm and a tablet mass of 550 mg (acetaminophen content 97.5 mg).

Claims

1. A solid formulation comprising the following components (a1), (a2), (a3) ​​and (a4): (a1) Acetaminophen (a2) Ibuprofen or a salt thereof, or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

2. A solid formulation comprising a granule containing the following components (a1), (a2), (a3) ​​and (a4): (a1) Acetaminophen (a2) Ibuprofen or a salt thereof, or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

3. A solid preparation comprising an additive layer and a granulated material dispersed in the additive layer, the granulated material containing the following components (a1), (a2), (a3) ​​and (a4): (a1) Acetaminophen (a2) Ibuprofen or a salt thereof, or a solvate thereof (a3) one or more antacids selected from magnesium oxide and synthetic hydrotalcite (a4) One or more components selected from talc, light anhydrous silicic acid, and mannitol

4. The solid formulation according to any one of claims 1 to 3, wherein the component (a3) ​​is magnesium oxide.

5. The solid formulation according to any one of claims 1 to 3, wherein the component (a4) is one or more components selected from talc and light anhydrous silicic acid.

6. The solid formulation according to any one of claims 1 to 3, wherein the component (a4) is talc.

7. The solid formulation according to any one of claims 1 to 3, wherein the component (a3) ​​is magnesium oxide and the component (a4) is talc.

8. The solid preparation according to any one of claims 1 to 3, wherein the mass ratio of the component (a4) to the component (a1) [(a4) / (a1)] is 0.15 or more and 1 or less.

9. The solid preparation according to any one of claims 1 to 3, which is in the form of granules, fine granules, powder, tablets, pills, capsules or dry syrup.

Images