tablet

Abstract

The present invention provides tablets containing ibuprofen and at least one selected from the group consisting of acetaminophen and ethenzamide, exhibiting excellent disintegration stability over time. [Solution] A tablet having a drug layer comprising: (A) component: ibuprofen; (B) component: at least one selected from the group consisting of acetaminophen and ethenzamide; (C1) component: hypromellose; and (C2) component: at least one selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E.

Description

Technical Field

[0001] The present invention relates to tablets.

Background Art

[0002] In pharmaceuticals, it is very important to control the release of active ingredients to achieve a desired blood concentration. Among non-steroidal anti-inflammatory drugs, ibuprofen, acetaminophen, and ethenzamide have excellent anti-inflammatory, analgesic, and antipyretic effects, and are thus widely used as active ingredients in cold medicines and antipyretic analgesics. Patent Document 1 proposes a method of blending an organic acid or acidic amino acid to address the problem that the elution property of an amino group-containing compound is not affected by pH in a release control preparation containing ibuprofen, an amino group-containing compound, and a release control base agent. Patent Document 2 relates to a multilayer tablet having a release control layer, and proposes a method of forming each layer into a specific shape to address the problem of suppressing interlayer cracks and interlayer delamination when a multilayer tablet containing a low melting point drug such as ibuprofen and a release control base agent in the release control layer is stored for a long time.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Conventionally, solid dosage forms have been known that, for example, contain a release control agent in the drug layer to adjust the release rate, release time, and release site of the active ingredient from the formulation, with the aim of reducing the number of administrations or reducing side effects. In particular, since cold symptoms not only persist for a long time but are generally improved by rest (sleep, etc.) after administration, there is a strong need to reduce the number of administrations. The inventors have found that when ibuprofen and acetaminophen or ethenzamide are combined as active ingredients in a tablet, and hypromellose is added as a release control agent, the disintegration time of the tablet fluctuates during storage (disintegration is accelerated). This fluctuation in disintegration time may compromise the drug's efficacy and may also result in the inability to maintain the dissolution profile designed for the formulation. The present invention aims to provide a tablet containing ibuprofen and at least one of acetaminophen and ethenzamide, which exhibits excellent disintegration stability over time. [Means for solving the problem]

[0005] As a result of diligent research, the inventors have found that by including two or more specific water-soluble polymers, including hypromellose, in a drug layer containing ibuprofen and at least one of acetaminophen and ethenzamide, it is possible to suppress variations in the disintegration time of the drug layer over time. The present invention is based on the above findings and has the following embodiments.

[0006] [1] A tablet having a drug layer comprising: (A) component: ibuprofen; (B) component: at least one selected from the group consisting of acetaminophen and ethenzamide; (C1) component: hypromellose; and (C2) component: at least one selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, povidone and aminoalkyl methacrylate copolymer E. [2] The tablet according to [1], wherein the C1 / C2 ratio, which represents the mass ratio of component (C1) to component (C2) in the drug layer, is 1 to 20. [3] The tablet according to [1] or [2], wherein the drug layer comprises granules containing one or both of the components (A) and (B), and the content of the granules is 60% by mass or more of the total mass of the drug layer. [4] The tablet according to any one of [1] to [3], wherein the content of component (C1) is 1 to 30% by mass with respect to the total mass of the drug layer. [5] The tablet according to any one of [1] to [4], wherein the content of component (C2) is 1 to 10% by mass relative to the total mass of the drug layer. [6] The tablet according to any one of [1] to [5], wherein the drug layer does not contain component (D): crystalline cellulose, or if it does, the content of component (D) is less than 2% by mass relative to the total mass of the drug layer. [7] The tablet according to any one of [1] to [6], wherein the drug layer contains at least one selected from the group consisting of (E) component: hypromellose acetate succinate and alginic acid or a salt thereof. [8] A tablet according to any one of [1] to [7], having the drug layer and another layer different from the drug layer, wherein the other layer contains the component (A) and the component (B). [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a tablet containing ibuprofen and at least one of acetaminophen and ethenzamide, which exhibits excellent disintegration stability over time. [Modes for carrying out the invention]

[0008] The following definitions of terms apply throughout this specification and the claims. A numerical range represented by "~" means a range of numbers whose lower and upper limits are the numbers before and after the "~". "Water-soluble polymers" refer to high-molecular-weight compounds whose solubility in water at 20°C exceeds 1.3 g / 100 mL. "High-molecular-weight compounds" refer to compounds with a weight-average molecular weight of 1000 or more, as measured by GPC (gel permeation chromatography). "Volume-average particle size" refers to the value measured by laser diffraction and scattering, which can be measured by dry measurement using, for example, a laser diffraction and scattering particle size distribution analyzer (Beckman Coulter's "LS13320").

[0009] The "drug layer" contains the active ingredient and is compressed and molded using the tablet manufacturing method. In this invention, the layer containing component (A), component (B), component (C1), and component (C2) is referred to as the drug layer. From the viewpoint of improving stability and imparting functionality, multiple drug layers may be present in a single tablet. Examples of tablets with multiple drug layers include laminated tablets and core tablets.

[0010] Tablets The tablet of this embodiment has a drug layer (sometimes referred to as the X layer to distinguish it from other layers described later) containing at least component (A), component (B), component (C1), and component (C2). The drug layer may further contain any optional components.

[0011] ≪Drug Layer (Layer X)≫ <(A) component> (A) The component is ibuprofen (2-(4-isobutylphenyl)propionic acid). The presence of component (A) provides an antipyretic and analgesic effect. In the manufacture of a drug layer, when using a powder containing component (A) after granulation, the volume-average particle size of component (A) used in the granulation process is preferably 10 to 80 μm, and more preferably 20 to 60 μm. When the volume-average particle size of component (A) is within the above range, the fluidity is excellent, the degree of abrasion is reduced, and variations in content in the granulated material are less likely to occur. In the manufacture of the drug layer, when component (A) is used without granulation, the volume-average particle size of component (A) is preferably 30 to 100 μm, and more preferably 40 to 80 μm. When the volume-average particle size of component (A) is within the above range, it exhibits excellent fluidity and makes it easier to suppress adhesion to manufacturing equipment (dies, presses, etc.) during tableting.

[0012] <(B) component> (B) Component is at least one selected from the group consisting of acetaminophen (N-(4-hydroxyphenyl)acetamide) and ethenzamide (2-Ethoxybenzamide). By incorporating component (B), an antipyretic and analgesic effect is obtained. In the manufacture of a drug layer, when using a powder containing component (B) after granulation, the volume-average particle size of component (B) used in the granulation process is preferably 10 to 100 μm, and more preferably 20 to 60 μm. When the volume-average particle size of component (B) is within the above range, the fluidity is excellent, the degree of abrasion is reduced, and variations in content in the granulated material are less likely to occur. In the manufacture of the drug layer, when component (B) is used without granulation, acetaminophen and / or ethenzamide may be used individually as component (B), or a co-processed product obtained by co-processing acetaminophen and / or ethenzamide with other optional components may be used, or a combination thereof may be used. Commercially available co-processed products can be used. When component (B) is used without granulation, the volume average particle size of component (B) (acetaminophen or ethenzamide alone, or a co-processed product thereof) is preferably 50 to 300 μm, and more preferably 80 to 200 μm. When the volume average particle size of component (B) is within the above range, it has excellent fluidity and is less likely to adhere to manufacturing equipment (dies, turntables, etc.) during tableting.

[0013] <(C1) component> Component (C1) is hypromellose (hydroxypropyl methylcellulose). Component (C1) is a water-soluble polymer. By incorporating component (C1), the disintegration time of the drug layer can be controlled, and in a preferred example, the disintegration time can be extended. When the disintegration time is extended, the components contained in the drug layer are released slowly, providing sustained effects. Hypromellose is a nonionic cellulose derivative typically produced by reacting pulp with a mixture of chloromethane or propylene oxide. Various grades exist with different viscosities and degrees of substitution. Hypromellose can be used alone or in combination of two or more different grades. Specifically, there are several types of substitution degree types of hypromellose depending on the substitution degrees of methoxy groups and hydroxypropoxy groups. For example, type 1828, type 2208, type 2906, and type 2910 can be mentioned. From the viewpoint of excellent suppression effect of disintegration promotion over time, type 2208, type 2906, and type 2910 are preferable, and type 2208 is more preferable. (C1) component preferably has a viscosity of 3 to 100,000 mPa·s, and more preferably 50 to 8,000 mPa·s. The viscosity of hypromellose is the viscosity of a 2% by mass aqueous solution of hypromellose at 20°C, and is a value measured by a test according to Viscosity Measurement Method 1 <2.53> described in the Eighteenth Revised Japanese Pharmacopoeia.

[0014] <(C2) component> (C2) component is at least one selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E. (C2) component is a water-soluble polymer. Hydroxypropylcellulose described in the Eighteenth Revised Japanese Pharmacopoeia can be preferably used. Polyvinyl alcohol described in Pharmaceutical Additive Standards (2018) can be preferably used. Partially saponified polyvinyl alcohol is preferable. Partially saponified polyvinyl alcohol is usually produced by partially saponifying polyvinyl acetate. The saponification degree is preferably 78 to 100 mol%, and more preferably 78 to 96 mol%. Methylcellulose described in the Eighteenth Revised Japanese Pharmacopoeia can be preferably used. Povidone (polyvinylpyrrolidone) described in the Eighteenth Revised Japanese Pharmacopoeia can be preferably used. Aminoalkyl methacrylate copolymer E has the chemical name: methyl methacrylate·butyl methacrylate·dimethylaminoethyl methacrylate copolymer, and is a component described in Pharmaceutical Additive Standards or Non-Pharmacopoeial Pharmaceutical Ingredients Standards. By incorporating component (C2), the acceleration of the drug layer's disintegration over time can be suppressed, improving the long-term stability of its disintegration. Hydroxypropylcellulose, polyvinyl alcohol, and methylcellulose are preferred, and hydroxypropylcellulose and polyvinyl alcohol are more preferred, due to their excellent effect in suppressing changes in the disintegration properties of the drug layer over time.

[0015] <Content> The amount of component (A) contained in the tablets is not particularly limited, as long as it is within the permissible range for ingestion in oral medications (drug approval standard amount). For example, 200 to 600 mg of ibuprofen per day is preferred, and 390 to 500 mg is more preferred. Furthermore, the content of component (A) relative to the total mass of the tablets is preferably 15 to 70% by mass, and 20 to 70% by mass is more preferred.

[0016] The amount of component (B) contained in the tablets is not particularly limited, as long as it is within the permissible range for ingestion in oral medications (drug approval standard amount). For example, 100 to 1500 mg of acetaminophen per day is preferred, and 150 to 500 mg is more preferred. In addition, the content of component (B) relative to the total mass of the tablets is preferably 10 to 50% by mass, and 12 to 50% by mass is more preferred.

[0017] The A / B ratio, which represents the mass ratio of the content of component (A) to the content of component (B) in the tablet, is preferably 0.3 to 3, and more preferably 0.4 to 2.

[0018] The content of component (A) relative to the total mass of the drug layer is preferably 10 to 70% by mass, and more preferably 12 to 50% by mass. If the content of component (A) is above the lower limit, the tablets can be made smaller. In addition, the acceleration of disintegration of the drug layer over time is further suppressed, and the stability of disintegration over time is further improved. If the content of component (A) is below the upper limit, the degree of tablet wear is further reduced. In addition, indentations on the tablet surface due to the shedding of particles from the tablet surface (hereinafter also referred to as granule shedding indentations) are further suppressed, and adhesion to the rotating disc during tableting is further suppressed.

[0019] The content of component (B) relative to the total mass of the drug layer is preferably 5 to 60% by mass, and more preferably 10 to 50% by mass. If the content of component (B) is above the lower limit, the tablets can be made smaller. In addition, the acceleration of disintegration of the drug layer over time is further suppressed, and the stability of disintegration over time is further improved. If the content of component (B) is below the upper limit, the degree of tablet abrasion is further reduced. In addition, granule detachment indentations are further suppressed, and adhesion to the rotating disc during tableting is further suppressed.

[0020] The A / B ratio, which represents the mass ratio of the content of component (A) to the content of component (B) in the drug layer, is preferably 0.4 to 4, and more preferably 0.5 to 2.5. When A / B is above the lower limit, the degree of abrasion is further reduced. In addition, granule detachment is further suppressed, and adhesion to the rotating disc during tableting is further suppressed. When A / B is below the upper limit, the acceleration of disintegration of the drug layer over time is further suppressed, and the long-term stability of disintegration is further improved.

[0021] The content of component (C1) relative to the total mass of the drug layer is preferably 1 to 30% by mass, more preferably 3 to 25% by mass, and even more preferably 7 to 20% by mass. When the content of component (C1) is above the lower limit, the disintegration time of the drug layer becomes easier to control, the effect of controlling the release of components contained in the drug layer is enhanced, and the effect of sustained release of components contained in the drug layer is enhanced. When the content of component (C1) is below the upper limit, the acceleration of disintegration of the drug layer over time is further suppressed, and the time-dependent stability of disintegration can be further enhanced. In addition, the degree of abrasion is further reduced, and granule loss and depressions are further suppressed.

[0022] The content of component (C2) relative to the total mass of the drug layer is preferably 1 to 10% by mass, and more preferably 1.5 to 6% by mass. If the content of component (C2) is above the lower limit, the acceleration of disintegration of the drug layer over time can be further suppressed, and the stability of disintegration over time can be further improved. If the content of component (C2) is below the upper limit, the tablets can be made smaller.

[0023] The C1 / C2 ratio, which represents the mass ratio of the content of component (C1) to the content of component (C2) in the drug layer, is preferably 1 to 20, more preferably 2 to 16, and even more preferably 4 to 13. When C1 / C2 is above the lower limit and below the upper limit, the acceleration of disintegration of the drug layer over time can be suppressed, and the time-dependent stability of disintegration can be further enhanced.

[0024] <(D) component> Component (D) is crystalline cellulose. Crystalline cellulose is obtained by partially depolymerizing α-cellulose, which is obtained as pulp from fibrous plants, with acid and then purifying it. If the drug layer contains component (D), the disintegration of the drug layer over time may be accelerated. For this reason, it is preferable that the drug layer does not contain component (D), or if it does, only a small amount. For example, the content of component (D) relative to the total mass of the drug layer is preferably less than 10% by mass, more preferably less than 2% by mass, even more preferably 1% or less, and particularly preferably not present at all. "Substantially absent" means below the detection limit.

[0025] <(E) component> (E) Component is at least one selected from the group consisting of hypromellose acetate succinate and alginic acid or its salts. Hypromellose acetate succinate is produced by reacting hydroxypropyl cellulose, which is normally made from pulp and reacted with a mixture of chloromethane or propylene oxide, with acetic anhydride and succinic anhydride to introduce acetyl groups and succinyl groups to the hydroxyl groups of hydroxypropyl cellulose. Alginic acid is a carbohydrate obtained from brown algae (Phaeophyceae) and is a linear glycoglycan mainly composed of pyranose rings of β-1,4-D-mannuronic acid and α-1,4-L-guluronic acid. Salts of alginic acid include sodium salt, potassium salt, and ammonium salt. If the drug layer contains component (E), it is possible to suppress the acceleration of the drug layer's disintegration over time and improve its stability over time. The content of component (E) relative to the total mass of the drug layer is preferably 1 to 15% by mass, and more preferably 2 to 10% by mass. If the content of component (E) is above the lower limit, the acceleration of disintegration of the drug layer over time can be further suppressed, and the stability of disintegration over time can be further improved. If the content of component (E) is below the upper limit, the tablets can be made smaller.

[0026] <Optional ingredients> The drug layer may contain any components other than components (A), (B), (C1), and (C2). Examples of optional components include physiologically active components other than components (A) and (B), and additives other than component (C). Known components can be used as optional components. Examples of physiologically active ingredients other than components (A) and (B) include antipyretic and analgesic ingredients (e.g., aspirin, aluminum aspirin, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, loxoprofen sodium hydrate, piroxicam, meloxicam, ampiroxicam, cerocoxib, lofecoxib, tiaramide, sulpyrine, etodolac, etc.), and antihistamine ingredients (e.g., isotipendyl hydrochloride, diphenylpyraline hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phene Tadine, Methidilazine Hydrochloride, Chlorpheniramine Maleate, d-Chlorpheniramine Maleate, Carbinoxamine Diphenyl Disulfonate, Diphenylpyraline Hydrochloride, Diphenylpyraline Theoclate, Diphenhydramine Hydrochloride, Diphenhydramine Salicylate, Alimemazine Tartrate, Diphenhydramine Tannate, Triprolidine Hydrochloride Hydrate, Diphenylpyraline Theoclate, Mebhydroline Napadisylate, Promethazine Methylene Disalicylate, Carbinoxamine Maleate, Diphenol Phosphate, Clemastine Fumarate, Me (e.g., chlorophyll), central nervous system stimulants (e.g., sodium benzoate caffeine), antitussives (e.g., alloclamide hydrochloride, tipepidine citrate, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate, sodium dibnate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, acetylcysteine, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophosphate) Phosphorus, etc.), bronchodilating components (e.g., dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, etc.), expectorant components (e.g., guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, L-carbocysteine, L-ethylcysteine ​​hydrochloride, etc.), anticholinergic components (e.g., total belladonna alkaloids, isopropamide iodide, etc.), anti-inflammatory components (e.g., tranexamic acid, glycyrrhizic acid and their salts), central nervous system stimulant components (e.g., sodium benzoate caffeine, caffeine hydrate,Anhydrous caffeine, etc.), vitamin components (e.g., vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, etc.), antacids (glycine, synthetic aluminum silicate, dihydroxyaluminum aminoacetate, aluminum hydroxide-sodium bicarbonate coprecipitate, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitate, magnesium hydroxide-potassium aluminum sulfate coprecipitate product, dried aluminum hydroxide gel (aluminum hydroxide gel), magnesium aluminometasilicate, aluminum silicate Examples include magnesium maltate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, magnesium silicate, sodium bicarbonate, etc., sedative and hypnotic components (e.g., allyl isopropylacetylurea, bromovalerylurea, etc.), and crude drugs (e.g., ephedra, nandina fruit, parsley, polygala, licorice, balloon flower, plantago-aquatica, plantago-aquatica, crepidinophylla, senega, fritillary, fennel, phellodendron bark, cow's rhizome, turmeric, chamomile, cinnamon bark, gentian, ox gall, animal bile, ginseng, ginger, atractylodes rhizome, clove, citrus peel, atractylodes rhizome, zest of ginseng, ginseng, kakkonto, kakkonto-ka-kikyo, keishito, kososan, saiko-keishito, shosaikoto, shoseiryuto, maimondoto, hanekobokuto, maoto, etc.). These physiologically active ingredients can be used individually or in appropriate combinations of two or more. Particularly from the viewpoint of efficacy, it is preferable to include one or more selected ingredients from the group consisting of clemastine fumarate, dextromethorphan hydrobromide hydrate, dl-methylephedrine hydrochloride, potassium guaiacolsulfonate, bromhexine hydrochloride, dihydrocodeine phosphate, anhydrous caffeine, ascorbic acid, and calcium ascorbate.

[0027] Examples of additives other than component (C) include binders, excipients, disintegrants, lubricants, flavorings, sweeteners, acidifiers, etc. Examples of binders other than component (C) include, in addition to component (E) mentioned above, gelatin, pullulan, dextrin, etc. Examples of excipients include, in addition to the aforementioned component (D), lactose, mannitol, erythritol, xylitol, lactitol, trehalose, maltitol, talc, powdered sugar, dextrin, cyclodextrin, carboxymethylcellulose, carboxymethylcellulose calcium, L-cysteine, sodium hydrogen phosphate, calcium hydrogen phosphate, carmellose sodium, etc. Examples of disintegrants include adipic acid, calcium stearate, and low-substituted hydroxypropyl cellulose. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, and light anhydrous silicic acid. Examples of fragrances include menthol, limonene, and plant essential oils (such as peppermint oil, mint oil, lychee oil, orange oil, and lemon oil). Examples of sweeteners include saccharin, sodium saccharin, aspartame, stevia, sucralose, dipotassium glycyrrhizinate, and acesulfame potassium. Examples of acidulants include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or salts thereof.

[0028] <Granulated material> The drug layer preferably contains granules. The granules contain one or both of component (A) and component (B). The granules may further contain one or both of component (C1) and component (C2). They may also contain any other components. Granules (Pa) or (Pb) containing either component (A) or component (B) are a group of particles obtained by granulating a granular material containing either component (A) or component (B). Granules (Pab) containing both component (A) and component (B) are a group of particles obtained by granulating a granular material containing both component (A) and component (B). The granulation process will be described later.

[0029] In a granule (Pa) containing component (A) but not component (B), the content of component (A) is preferably 40 to 95% by mass, and more preferably 50 to 85% by mass, relative to the total mass of the granule (Pa). If the content of component (A) is above the lower limit, the tablets can be made smaller. In addition, the acceleration of disintegration of the drug layer over time can be further suppressed, and the long-term stability of disintegration can be further improved. If the content of component (A) is below the upper limit, granule detachment depressions are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed.

[0030] In a granule (Pb) containing component (B) but not component (A), the content of component (B) is preferably 40 to 98% by mass, and more preferably 50 to 96% by mass, relative to the total mass of the granule (Pb). When the content of component (B) is above the lower limit, the tablets can be made smaller. In addition, the acceleration of disintegration of the drug layer over time can be further suppressed, and the long-term stability of disintegration can be further improved. When the content of component (B) is below the upper limit, granule detachment depressions are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed.

[0031] In granules (Pab) containing components (A) and (B), the content of component (A) is preferably 10 to 70% by mass, and more preferably 30 to 60% by mass, relative to the total mass of the granules (Pab). If the content of component (A) is above the lower limit, the tablets can be made smaller. In addition, the acceleration of disintegration of the drug layer over time can be further suppressed, and the long-term stability of disintegration can be further improved. If the content of component (A) is below the upper limit, granule detachment and indentation are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed. The combined content of component (A) and component (B) relative to the total mass of the granules (Pab) is preferably 30 to 99% by mass, and more preferably 50 to 98% by mass. If the combined content is above the lower limit, the tablets can be made smaller. If the combined content is below the upper limit, the acceleration of disintegration over time can be further suppressed, and the stability of disintegration over time can be further improved.

[0032] Component (C1) may be added during granulation, or it may be added when preparing the powder mixture by mixing the granulated material and non-granulated components before tableting. From the viewpoint of improving manufacturing efficiency, it is preferable to add it when preparing the powder mixture before tableting.

[0033] Component (C2) may be added during granulation or during the preparation of the powder mixture before tableting. From the viewpoint of homogeneity of the granules, reduction of the adhesion of component (A) during tableting, and enhancement of the binding strength of component (B), it is preferable to add it during granulation, and in particular it is preferable to spray and blend component (C2) as a binding solution dissolved in water during granulation.

[0034] The volume-average particle size of the granules is preferably 50 to 1000 μm, more preferably 100 to 700 μm, and even more preferably 100 to 300 μm. If the volume-average particle size of the granules is above the lower limit, the filling of the die during tableting will be better, and if it is below the upper limit, the mass variation of the tablets will be smaller.

[0035] The granules in the drug layer may be granules (Pa), granules (Pb), or granules (Pab), or any combination thereof. The total content of granules relative to the total mass of the drug layer may be 15 to 100% by mass. A content of 30% or more is preferable, 45% or more is preferable, and 58% or more is even preferable, in order to further suppress the acceleration of disintegration of the drug layer over time and to further improve the stability of disintegration over time. The upper limit of the total content of granules is preferably 99% or less by mass and more preferably 85% or less by mass, in order to further suppress adhesion to manufacturing equipment during tableting and to further suppress discoloration of the drug layer over time. Furthermore, any components of the drug layer that are not included in the granules are added to the drug layer as non-granulated components.

[0036] ≪Other layers (Y layer)≫ The tablet of this embodiment may consist only of the drug layer (layer X) of this embodiment, or it may have other layers other than the drug layer (layer X) of this embodiment (sometimes referred to as the layer Y to distinguish it from the drug layer). The tablet of this embodiment may be a single-layer tablet consisting of only one drug layer of this embodiment, or a multi-layer tablet having at least one layer consisting of the drug layer of this embodiment. The multi-layer tablet may be, for example, a laminated tablet in which two or more layers are stacked, or a cored tablet in which an inner layer exists inside an outer layer. In a multilayer tablet, the other layers (Y layers) besides the drug layer (X layer) of this embodiment may be an immediate-release layer, a sustained-release layer, or a layer that is neither an immediate-release layer, or a sustained-release layer with a different composition from the drug layer of this embodiment. Combinations of these are also acceptable. If the multilayer tablet has two or more layers, two layers with the same composition may be present flanked by other layers.

[0037] In one example of this embodiment, it is preferable that the tablet includes a drug layer and another layer, wherein the drug layer is a sustained-release layer and the other layer is an immediate-release layer. That is, a tablet having a sustained-release layer and an immediate-release layer according to this embodiment is preferred. The "sustained-release layer" is a drug layer that has been given the added function of a sustained-release formulation as defined by the Japanese Pharmacopoeia, and therefore possesses sustained-release properties. In this specification, "having sustained-release properties" means that when the disintegration time is measured using a Bio-Dis sustained-release formulation dissolution tester (for example, ERWEKA product name "RRT10") under the conditions described in the test method described later, the disintegration time is 2 hours or more. Furthermore, "immediately disintegrating layer" refers to a layer that exhibits immediate disintegration properties. In this specification, "immediately disintegrating" means that when the disintegration time is measured under the conditions described in the test method described later, the disintegration time is 1 hour or less. Generally, an immediate-release layer is a drug layer in which the dissolution of the active ingredient has been enhanced through formulation improvements. Formulation improvements to enhance the dissolution of the active ingredient include the addition of water-soluble components, increasing the surface area of ​​the active ingredient, and granulation of the active ingredient.

[0038] The immediate-release layer preferably contains component (A) and component (B). The amount of component (A) in the slow-release layer and the amount of component (A) in the immediate-release layer are preferably the same. The amount of component (B) in the slow-release layer and the amount of component (B) in the immediate-release layer are preferably the same. When components (A) and (B) are included in both the sustained-release layer and the immediate-release layer, it is possible to create a tablet that provides an effective blood concentration immediately after administration and sustains its effects for a long period of time. For example, it is possible to create a tablet that maintains an effective blood concentration and provides antipyretic and analgesic effects for more than 8 hours with just two doses per day.

[0039] [(A) component] In the manufacture of other layers, when using a powder containing component (A) after granulation, the volume-average particle size of component (A) used in the granulation process is preferably 1 to 50 μm, and more preferably 5 to 30 μm. When the volume-average particle size of component (A) is within the above range, the fluidity is excellent, the degree of abrasion is reduced, and variations in content in the granulated material are less likely to occur. When component (A) is used without granulation in the production of other layers, the volume-average particle size of component (A) is preferably 10 to 100 μm, and more preferably 20 to 80 μm. When the volume-average particle size of component (A) is within the above range, it exhibits excellent fluidity and makes it easier to prevent adhesion to manufacturing equipment (dies, turntables, etc.) during tableting. In addition, it is easy to obtain sufficient hardness even at low tableting pressure and excellent disintegration properties. The (A) component of the other layers may be a commercially available (A) component (for example, one with a volume-average particle size of about 10 to 100 μm) that has been ground to a volume-average particle size of 5 to 30 μm. The grinding process will be described later.

[0040] The content of component (A) relative to the total mass of the other layers is preferably 10 to 50% by mass, and more preferably 20 to 40% by mass. If the content of component (A) is above the lower limit, the tablets can be made smaller. If the content of component (A) is below the upper limit, the degree of tablet wear is further reduced. In addition, granule detachment is further suppressed, and adhesion to the rotating disc during tableting is further suppressed.

[0041] [(B) Component] When using a powder containing component (B) in the production of other layers, the volume-average particle size of component (B) used in the granulation process is preferably 10 to 100 μm, and more preferably 15 to 60 μm. When the volume-average particle size of component (B) is within the above range, the fluidity is excellent, the degree of abrasion is reduced, and variations in content in the granulated material are less likely to occur. When component (B) is used without granulation in the manufacture of other layers, the volume-average particle size of component (B) (acetaminophen or ethenzamide alone, or a co-processed product thereof) is preferably 50 to 300 μm, and more preferably 80 to 200 μm. When the volume-average particle size of component (B) is within the above range, it exhibits excellent fluidity and makes it easier to suppress adhesion to manufacturing equipment (dies and punches, turntables, etc.) during tableting.

[0042] The content of component (B) relative to the total mass of the other layers is preferably 10 to 50% by mass, and more preferably 12 to 40% by mass. If the content of component (B) is above the lower limit, the tablets can be made smaller. If the content of component (B) is below the upper limit, the degree of wear of the tablets is further reduced. In addition, granule detachment is further suppressed, and adhesion to the rotating disc during tableting is further suppressed.

[0043] [(C1) component] The other layers preferably do not contain the (C1) component, or if they do, the (C1) component is present in a smaller quantity than in the drug layer, or has a lower viscosity than the drug layer. For example, the content of component (C1) relative to the total mass of the other layers is preferably 10% by mass or less, and more preferably 6% by mass or less. It may be substantially absent. When the content of component (C1) is below the upper limit, the degree of wear is further reduced and granule detachment depressions are further suppressed. The proportion of the (C1) component contained in the drug layer of the total mass of the (C1) component contained in the entire tablet may be more than 50% by mass, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 100% by mass. The viscosity of component (C1) used in the production of other layers is preferably 3 to 50 mPa·s, and more preferably 3 to 15 mPa·s.

[0044] [(C2) component] The other layers preferably contain the (C2) component. The amount of the (C2) component in the drug layer and the amount of the (C2) component in the other layers may be the same or different. The content of component (C2) relative to the total mass of the other layers is preferably 1 to 10% by mass, and more preferably 1.5 to 6% by mass. When the content of component (C2) is above the lower limit, the degree of abrasion is further reduced. In addition, granule detachment depressions are further suppressed. When the content of component (C2) is below the upper limit, the tablets can be made smaller.

[0045] <Other optional components> Other layers may contain other optional components besides components (A), (B), (C1), and (C2). Examples of other optional components include physiologically active components other than components (A) and (B), and additives other than component (C). Other optional components can be known components. Examples of other optional components in other layers include those similar to those of the drug layer. In addition, other layers may contain component (D) as an additive. Component (D) contributes to the disintegration of other layers. When component (D) is added to other layers, the content of component (D) relative to the total mass of other layers is preferably 1 to 30% by mass, and more preferably 3 to 20% by mass.

[0046] The other layers preferably contain the antacid as another optional component. The antacid can enhance the disintegration of the other layers immediately after manufacturing and suppress the delay of disintegration over time. From the viewpoint of preventing the disintegration of other layers immediately after manufacturing and suppressing the delay of disintegration over time, among antacids, dried aluminum hydroxide and magnesium aluminometasilicate are particularly preferred, and as components other than antacids, it is preferable to include at least one selected from anhydrous caffeine, clemastine fumarate, dextromethorphan hydrobromide hydrate, potassium guaiacolsulfonate, bromhexine hydrochloride, anhydrous caffeine, ascorbic acid, and calcium ascorbate. When adding antacids, caffeine, or other components to other layers, the content of these components relative to the total mass of the other layers is preferably 5 to 40% by mass, and more preferably 10 to 30% by mass. If the content of the antacid is above the lower limit, the disintegration of the other layers immediately after manufacturing can be improved. In addition, the delay in the disintegration of the other layers over time can be suppressed. If the content of the antacid is below the upper limit, the tablets can be made smaller.

[0047] [Granulated material] The other layers preferably contain granules. The granules in the other layers preferably contain either or both of component (A) and component (B). The granules may contain component (C1) or component (C2), and it is preferable that they contain component (C2). They may also contain other optional components. The granules in the other layers may be granules (Pa), granules (Pb), or granules (Pab), or any combination thereof.

[0048] In a granule (Pa) containing component (A) but not component (B), the content of component (A) is preferably 40 to 95% by mass, and more preferably 50 to 80% by mass, relative to the total mass of the granule (Pa). If the content of component (A) is above the lower limit, the tablets can be made smaller. If the content of component (A) is below the upper limit, granule detachment indentations are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed.

[0049] In a granule (Pb) containing component (B) but not component (A), the content of component (B) is preferably 40 to 95% by mass, and more preferably 50 to 80% by mass, relative to the total mass of the granule (Pb). If the content of component (B) is above the lower limit, the tablets can be made smaller. If the content of component (B) is below the upper limit, granule detachment indentations are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed.

[0050] In a granule (Pab) containing component (A) and component (B), the content of component (A) is preferably 10 to 60% by mass, and more preferably 20 to 45% by mass, relative to the total mass of the granule (Pab). If the content of component (A) is above the lower limit, the tablets can be made smaller. If the content of component (A) is below the upper limit, granule detachment and indentation are further suppressed, and adhesion to manufacturing equipment during tableting is further suppressed. The combined content of component (A) and component (B) relative to the total mass of the granules (Pab) is preferably 30 to 90% by mass, and more preferably 40 to 80% by mass. If the combined content is above the lower limit, the tablets can be made smaller. If the combined content is below the upper limit, the adhesion during tableting can be reduced.

[0051] In other layers, component (C2) may be added during granulation or during the preparation of the powder mixture before tableting. From the viewpoint of homogeneity of the granules, reduction of the adhesion of component (A) during tableting, and enhancement of the binding strength of component (B), it is preferable to add it during granulation, and in particular, it is preferable to spray and blend component (C2) as a binding solution dissolved in water during granulation.

[0052] In other layers, the volume-average particle size of the granules is preferably 50 to 1000 μm, more preferably 100 to 700 μm, and even more preferably 100 to 300 μm. If the volume-average particle size of the granules is above the lower limit, the filling of the die during tableting will be better, and if it is below the upper limit, the mass variation of the tablets will be smaller.

[0053] The granules in the other layers may be granules (Pa), granules (Pb), or granules (Pab), or any combination thereof. The total content of granules relative to the total mass of the other layers may be 30 to 100% by mass. From the viewpoint of stability, a content of 40% by mass or more is preferable, 50% by mass or more is more preferable, and 55% by mass or more is even preferable, in order to suppress reactivity with the drug layer and suppress content decrease over time and discoloration of the layer interface. The upper limit of the total content of granules is preferably 90% by mass or less, and more preferably 80% by mass or less, in order to further suppress adhesion to manufacturing equipment during tableting. Furthermore, any components from the other layers that are not included in the granulated material are added to the other layers as non-granulated components.

[0054] ≪Manufacturing method≫ The tablets of this embodiment can be manufactured using known methods. Specifically, it can be manufactured by a method comprising a mixing step of mixing all the components constituting the drug layer to obtain a powder mixture, and a tableting step of compressing the powder mixture into tablets to obtain tablets. In the case of multilayer tablets having layers other than the drug layer, they can be manufactured, for example, by mixing all the components constituting each layer in a mixing step to obtain powder mixtures for each layer, and then stacking them in a tableting step and compressing them into tablets.

[0055] <Mixing process> Mixers can be selected from a range of general-purpose mixers. Examples of mixers include the Bohle container mixer (manufactured by Hiroshima Metal & Machinery Co., Ltd.), the V-type mixer (manufactured by Dalton Co., Ltd.), and the ribbon mixer (manufactured by Dalton Co., Ltd.).

[0056] <Tableting process> Tablet compression can be carried out using a known tablet press. Examples of tablet presses include rotary-type tablet presses such as the Libra (manufactured by Kikusui Seisakusho Co., Ltd.) and the L-41 (manufactured by Hata Iron Works Co., Ltd.). The tableting conditions can be appropriately set depending on the tablet press used, taking into account factors such as tablet hardness. For example, in the case of a rotary tablet press, the rotation speed of the rotary disc is preferably 10 to 90 rpm, and more preferably 20 to 60 rpm. The punch shape of the tablet press is preferably smooth or curved (R-shaped) on the tablet pressing surface, with a curved (R-shaped) surface being more preferable.

[0057] The tablet diameter is preferably 7 mm to 12 mm, and more preferably 8.5 mm to 10 mm. When using oval tablets or caplet tablets (oblong tablets), the long diameter is preferably 9 mm to 18 mm, more preferably 10 mm to 14 mm, and the short diameter is preferably 5 mm to 12 mm, and more preferably 6 mm to 9 mm. For single R tablets, the radius of curvature is preferably 8 to 15 mm, and more preferably 11 to 13 mm. For double R tablets, the radius of curvature r1 of the peripheral edge is preferably 2 to 6 mm, and more preferably 3 to 4 mm. The radius of curvature r2 of the apex is preferably 8 to 13 mm, and more preferably 9 to 11 mm. By using the above preferred ranges, the degree of granule detachment and abrasion of the tablet is reduced.

[0058] In the case of a two-layer tablet having a drug layer and another layer, there is no particular limit to which layer's powder mixture is filled first during tableting. However, if the drug layer is a sustained-release layer, it is preferable to fill the drug layer (sustained-release layer) first, from the viewpoint of maintaining sustained release properties and suppressing accelerated disintegration over time. In the case of a core tablet having a drug layer and other layers, it is preferable to have a drug layer (sustained-release layer) inside from the viewpoint of drug release in the body.

[0059] <Granulation process> If the tablets contain granules, the granulation process can be carried out using known granulation methods. Examples of granulation methods include wet granulation and dry granulation, and examples of wet granulation include fluidized bed granulation, agitated granulation, and extrusion granulation. Wet granulation can be performed using, for example, a fluidized bed granulator such as Multiplex (product name, manufactured by Powrec Co., Ltd.) or Spiraflow (product name, manufactured by Freund Industrial Co., Ltd.), which granulates while spraying an aqueous solution containing a water-soluble polymer compound (e.g., component (C2)). Alternatively, wet granulation may be performed using a stirring granulator such as a High-Speed ​​Mixer (product name, manufactured by Fukae Powtec Co., Ltd.) or a High-Speed ​​Agitator Granulator (product name, manufactured by Dalton Co., Ltd.), or an extrusion granulator such as Dome Gran (product name, manufactured by Dalton Co., Ltd.). Wet granulation is preferred from the viewpoint of uniformity of the active ingredients in the granulated material, and fluidized bed granulation is particularly preferred from the viewpoint of suppressing adhesion to manufacturing equipment.

[0060] <Grinding process> If other layers are immediate-release layers, it is preferable to reduce the average volume particle size of component (A) contained in the other layers through a grinding process, as this makes it easier to obtain immediate-release properties. When using a pulverized material as component (A) of the immediate-release layer, an impact-type grinding method is preferred from the viewpoint of productivity. A disc-type grinder is even more preferred. For the grinder, a hammer mill or a pin mill is preferred, with a pin mill being particularly preferred because it can reduce the particle size even further. When using a pin mill, the grinding conditions are preferably a peripheral speed of 1000 m / min or more, and more preferably 1600 m / min to 2240 m / min. When using the readily available component (A) after pulverization, it is preferable to co-pulverize it with an additive from the viewpoint of suppressing adhesion. Examples of additives include, but are not limited to, low-substituted hydroxypropyl cellulose, crystalline cellulose, and corn starch. The ratio of (A) to the additive in the pulverization process is preferably 1:0.01 to 1:10, more preferably 1:0.05 to 1:2, and even more preferably 1:0.2 to 1:1. If the ratio of the additive is above the lower limit of the above range, the adhesion of component (A) to the pulverizer, etc., is further suppressed, and the mixing efficiency and pulverization performance are further improved. If the ratio of the additive is below the upper limit, the tablets can be made smaller. [Examples]

[0061] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following description. The raw materials and evaluation methods used in each example are as follows. The following indications, "compliant with the Japanese Pharmacopoeia," mean that the raw materials conform to the standards of the 18th revised Japanese Pharmacopoeia. The indication "compliant with the standards for pharmaceutical additives," means that the raw materials conform to the standards for pharmaceutical additives (2018).

[0062] ≪Measurement method≫ The volume-average particle size was measured using a laser diffraction / scattering particle size distribution analyzer (Beckman Coulter "LS13320").

[0063] ≪Raw materials used≫ <(A) component> Ibuprofen (granulation component): Product name "Ibuprofen 25", manufactured by BASF, compliant with the Japanese Pharmacopoeia, volume average particle size: approximately 25 μm. • Ibuprofen (non-granular component): Product name "Ibuprofen 50", manufactured by BASF, compliant with the Japanese Pharmacopoeia, volume average particle size: approximately 50 μm. The volume-average particle size of ibuprofen was measured using a laser diffraction / scattering particle size distribution analyzer (Beckman Coulter, Ltd., product name "LS13320") by manual flow cell measurement. <(B) component> • Acetaminophen: Product name "Acetaminophen (powder)", manufactured by SperaNexus, compliant with Japanese Pharmacopoeia, volume average particle size: approximately 20 μm. • Ethenzamide: Product name "Ethenzamide", manufactured by SperaNexus, compliant with the Japanese Pharmacopoeia. Volume average particle size: approximately 30 μm.

[0064] <(C1) component> • Hypromellose Type 2208 100 mPa·s: Product name "90SH-100SR", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Hypromellose Type 2208 4000 mPa·s: Product name "90SH-4000SR", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Hypromellose Type 2906 4000 mPa·s: Product name "65SH-4000", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Hypromellose Type 2910 4000 mPa·s: Product name "60SH-4000", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Hypromellose Type 2208 15000 mPa·s: Product name "90SH-15000SR", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. <(C2) component> • Polyvinyl alcohol: Partially saponified, product name "Gosenol EG-05PW", manufactured by Mitsubishi Chemical Corporation, degree of saponification 86.5-89.0 mol%, compliant with pharmaceutical additive regulations. • Hydroxypropylcellulose: Product name "HPC-SSL", manufactured by Nippon Soda Co., Ltd., compliant with the Japanese Pharmacopoeia. • Methylcellulose: Product name "SM-4", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia.

[0065] <(D) component> • Crystalline cellulose: Product name "Ceolus UF-702", manufactured by Asahi Kasei Corporation, compliant with the Japanese Pharmacopoeia.

[0066] <(E) component> • Hypromellose acetate succinate: Product name "Shin-Etsu AQOAT, AS-LMP", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Sodium alginate: Product name "Snow Algin SSH", manufactured by Fuji Chemical Industry Co., Ltd., compliant with pharmaceutical additive regulations.

[0067] <Optional ingredients> • D-mannitol (powder): Product name "PEARLITOL 50C", manufactured by ROQUETTE, compliant with the Japanese Pharmacopoeia. • D-mannitol (granules): Product name "Granitol F", manufactured by Freund Industrial Co., Ltd., compliant with the Japanese Pharmacopoeia. • Corn starch: Product name "Matsutani Corn Starch", manufactured by Matsutani Chemical Industry Co., Ltd., conforms to the Japanese Pharmacopoeia. • Low-substituted hydroxypropyl cellulose: Product name "LH-31", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Clemastine fumarate: Product name "Clemastine fumarate", manufactured by Daito Co., Ltd., compliant with the Japanese Pharmacopoeia. • d-Chlorpheniramine maleate: Product name "d-Chlorpheniramine maleate", manufactured by Kongo Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Bromhexine hydrochloride: Product name "Bromhexine hydrochloride", manufactured by Shiratori Pharmaceutical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Anhydrous caffeine: Product name "Anhydrous Caffeine", manufactured by Shiratori Pharmaceutical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Dextromethorphan hydrobromide hydrate: Product name "Dextromethorphan hydrobromide hydrate", manufactured by Alps Pharmaceutical Co., Ltd., compliant with the Japanese Pharmacopoeia. • Magnesium aluminometasilicate: Product name "Neusilin NFL2N", manufactured by Fuji Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. • Dried aluminum hydroxide gel: Product name "S-100", manufactured by Kyowa Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. • Hydrated silicon dioxide: Product name "Fujisil", manufactured by Fuji Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. • Magnesium stearate: Product name "Magnesium stearate, plant-derived, light type", manufactured by Taihei Chemical Industry Co., Ltd., conforms to the Japanese Pharmacopoeia.

[0068] ≪Evaluation Method≫ <Evaluation of the temporal stability of disintegration> (Storage conditions) A resin sheet (TAS-230, manufactured by Taisei Chemical Co., Ltd.) with multiple pockets for holding tablets was prepared. The tablets manufactured in each example were placed in each pocket of the resin sheet, and aluminum foil was attached to the pocket opening side to obtain a PTP (press-through packaging). This PTP was stored at 50°C for 3 weeks. The tablets before storage (immediately after manufacturing) and the tablets after storage (stored products) were subjected to the following tests. (Test method) The test machine used was the "BioDis RRT10" manufactured by ERWEKA, and, following the example of USP's Apparatus 7, a jig with a sinker attached to the tip was used. The tablets were placed in a sinker and shaken in the first vessel 1 containing the test solution (I) described below. After 1 hour, the sinker was transferred to the second vessel 2 containing the test solution (II) described below and shaken for 1 hour in the same manner. This procedure was repeated for a total of 8 hours, until the sinker was transferred to the eighth vessel 8 and shaken for 1 hour. The second through eighth vessels each contained the test solution (II). All test solutions were 50 mL at 37°C ± 0.5°C, and the sinker was moved up and down 2 cm at a rate of 5 reciprocations per minute during shaking. When transferring the vessel, the sinker was observed to check if the tablet had disintegrated, and the time the sinker was empty was recorded as the disintegration time (time from the start of the test until disintegration). If disintegration did not occur after 8 hours, the disintegration time was recorded as 8 hours. The following evaluation criteria were used, based on the absolute value of the difference in disintegration time before and after storage. A smaller difference in disintegration time indicates better temporal stability of the disintegration property. (Evaluation Criteria) A: The difference in collapse time is less than 1 hour. B: The difference in collapse time is between 1 hour and less than 2 hours. C: The difference in collapse time is between 2 hours and less than 3 hours. D: The difference in collapse time is between 3 hours and less than 4 hours. E: The difference in collapse time is 4 hours or more.

[0069] (Test solution) • Test solution (I): Disintegration test solution 1 of the 18th edition of the Japanese Pharmacopoeia, 50 mL. • Test solution (II): Disintegration test solution 2 of the 18th edition of the Japanese Pharmacopoeia, 50 mL. The state in which the tablet is immersed in test solution (I) simulates the state in which the tablet remains in the stomach, while the state in which the tablet is transferred from test solution (I) to test solution (II) and immersed there simulates the state in which the tablet moves from the stomach to the intestines and remains in the intestines.

[0070] <Examples 1-31, Comparative Example 1> Tablets (two-layer tablets) with the compositions shown in Tables 1-8 were manufactured. Tables 1-8 show the composition (in parts by mass) of all raw materials used in the manufacture of the tablets. They also show the mass ratio of C1 / C2 and A / B in the drug layer, as well as the mass ratio of A / B in the entire tablet.

[0071] [Preparation of powder mixture for drug layer] A powder mixture for the drug layer was prepared to match the composition ratio of the drug layer shown in the table. First, powder (a1) was prepared by mixing component A, component B, and an optional component from the granulation components shown in the table. Separately, among the granulation components shown in the table, component (C2) was dissolved in water to prepare aqueous solution (a2). The amount of water used to prepare aqueous solution (a2) was set so that the viscosity of aqueous solution (a2) at 20°C was in the range of 60 to 100 mPa·s. The powder (a1) is placed in a fluidized bed granulator (manufactured by Freund Industrial Co., Ltd., product name "FLO-5"), and the aqueous solution (a2) is sprayed at a liquid velocity such that the volume average particle size of the granulated material after drying is 150-350 μm, with an intake air volume of 2.5 m³. 3 Granulation was performed at a rate of / min and an intake air temperature of 60°C. After the spraying of the aqueous solution (a2) was completed, the mixture was dried until the exhaust temperature reached 40°C to obtain granules (a3). The obtained granules (a3) ​​were mixed with the non-granulated components shown in the table to obtain a powder mixture for the drug layer.

[0072] [Preparation of powder mixtures for other layers] Powder mixtures for other layers were prepared so that they matched the composition ratios of the other layers shown in the table. First, powder (b1) was prepared by mixing component A, component B, and an optional component from the granulation components shown in the table. Separately, among the granulation components shown in the table, component (C2) was dissolved in water to prepare aqueous solution (b2). The amount of water used to prepare aqueous solution (b2) was set so that the viscosity of aqueous solution (b2) at 20°C was in the range of 60 to 100 mPa·s. The powder (b1) is placed in the same fluidized bed granulator as described above, and the aqueous solution (b2) is sprayed at a liquid velocity such that the volume average particle size of the granulated material after drying is 150-350 μm, with an intake air volume of 2.5 m³. 3 Granulation was performed at a rate of / min and an intake air temperature of 60°C. After the spraying of the aqueous solution (b2) was completed, the mixture was dried until the exhaust temperature reached 40°C to obtain granules (b3). The obtained granules (b3) were mixed with the non-granulated components shown in the table to obtain a powder mixture for other layers.

[0073] [Tablet compression] Tablets (two-layer tablets) were manufactured using the drug layer powder mixture and the other layer powder mixture so that the composition ratios of the drug layer and the other layers were as shown in the table. Tablets were compressed using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., product name "AQUARIUS GJ") at a rotation speed of 30 rpm. The compression pressure was adjusted so that the average hardness of 10 tablets was 7.0 to 10.0 kgf. For Examples 1-6, 9-10, 17-18, and 26-27, a die with a diameter of φ8.5 mm and a two-stage R-shaped punch (radius of curvature R1=3.4 mm, radius of curvature R2=10.0 mm) were used. For Examples 21 and 30-31, a die with a diameter of φ9.5 mm and a two-stage R-shaped punch (radius of curvature R1=3.8 mm, radius of curvature R2=10.0 mm) were used. For the other tablets, a die with a diameter of φ9.0 mm and a two-stage R-shaped punch (radius of curvature R1=3.6 mm, radius of curvature R2=10.5 mm) were used. A two-layer tablet was obtained by filling the first layer with the amount of drug layer powder mixture shown in the table (unit: mg), compressing it, and then filling the second layer with the amount of other layer powder mixture shown in the table (unit: mg), and compressing it. The disintegration stability over time of the obtained tablets was evaluated using the method described above. The results are shown in the table.

[0074] [Table 1]

[0075] [Table 2]

[0076] [Table 3]

[0077] [Table 4]

[0078] [Table 5]

[0079] [Table 6]

[0080] [Table 7]

[0081] [Table 8]

[0082] As shown in Tables 1-8, the tablets of Examples 1-31 exhibited excellent long-term stability in terms of disintegration. On the other hand, Comparative Example 1, in which the drug layer did not contain component (C2), showed inferior stability over time in terms of disintegration.

Claims

1. (A) Ingredients: Ibuprofen, (B) Components: At least one selected from the group consisting of acetaminophen and ethenzamide. (C1) Components: Hypromellose, and (C2) A tablet having a drug layer containing at least one selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E.

2. The tablet according to claim 1, wherein the C1 / C2 ratio, which represents the mass ratio of component (C1) to component (C2) in the drug layer, is 1 to 20.

3. The tablet according to claim 1, wherein the drug layer comprises granules containing one or both of the components (A) and (B), and the content of the granules is 15% by mass or more relative to the total mass of the drug layer.

4. The tablet according to claim 1, wherein the content of component (C1) is 1 to 30% by mass relative to the total mass of the drug layer.

5. The tablet according to claim 1, wherein the content of component (C2) is 1 to 10% by mass relative to the total mass of the drug layer.

6. The tablet according to claim 1, wherein the drug layer does not contain component (D): crystalline cellulose, or if it does, the content of component (D) is less than 2% by mass relative to the total mass of the drug layer.

7. The tablet according to claim 1, wherein the drug layer contains at least one selected from the group consisting of (E) component: hypromellose acetate succinate and alginic acid or a salt thereof.

8. A tablet according to any one of claims 1 to 7, comprising the drug layer and another layer different from the drug layer, wherein the other layer contains the component (A) and the component (B).

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