Layered tablets

Abstract

The present invention provides a laminated tablet having a layer containing at least one of acetaminophen and ethenzamide, and hypromellose acetate succinate (HPMCAS), while suppressing the decrease in hardness during storage. [Solution] A laminated tablet comprising X layer and Y layer having different compositions, wherein the X layer contains (A) one or more selected from acetaminophen and ethenzamide, (B) hypromellose acetate succinate, and (C) ibuprofen.

Description

Technical Field

[0001] The present invention relates to multilayer tablets.

Background Art

[0002] Acetaminophen and ethenzamide, which are antipyretic and analgesic components, have excellent antipyretic and analgesic effects and cause few gastric disorders, so they are widely used as active ingredients in cold medicines and antipyretic and analgesic agents. On the other hand, it is known that they are powder raw materials with weak binding force, and in the formulation design of tablets, addition of a binder has generally been carried out.

[0003] Hypromellose acetate succinate (hereinafter also referred to as HPMCAS) is a mixed ester of hypromellose with acetic acid and monosuccinic acid, and is known to be used as a binder (Patent Document 1). In addition, it is also used in solid dispersion applications for improving the dissolution of water-insoluble drugs or in enteric coating applications (Patent Document 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] In the study of the formulation design of tablets containing acetaminophen or ethenzamide, the present inventors found that in single-layer tablets containing acetaminophen or ethenzamide and HPMCAS, the hardness hardly decreases during storage, but in multilayer tablets having a layer containing acetaminophen or ethenzamide and HPMCAS, the hardness may decrease during storage. This is a new problem, and no technology for solving it is known. The present invention aims to provide a laminated tablet having a layer containing at least one of acetaminophen and ethenzamide, and HPMCAS, while suppressing the decrease in hardness during storage. [Means for solving the problem]

[0006] As a result of diligent research to solve the above-mentioned problems, the present inventors have found that ibuprofen, which is generally known as an ingredient that has anti-inflammatory, analgesic, and antipyretic effects, contributes to suppressing the decrease in hardness in the laminated tablets having the above-mentioned specific layer.

[0007] The present invention has the following aspects. [1] A laminated tablet comprising X layer and Y layer having different compositions, wherein X layer contains the following component (A), component (B), and component (C). (A) Ingredients: One or more selected from acetaminophen and ethenzamide. (B) Ingredients: Hypromellose acetate succinate. (C) Ingredients: Ibuprofen. [2] The laminated tablet according to [1], wherein the content of component (B) is 1 to 50% by mass with respect to the total mass of the X layer. [3] The laminated tablet according to [1] or [2], wherein the content of component (C) is 5 to 70% by mass with respect to the total mass of the X layer. [4] The laminated tablet according to any one of [1] to [3], wherein the Y layer contains (C) component: ibuprofen. [5] The laminated tablet according to any one of [1] to [4], wherein the X layer further contains a component (D) which is one or both of the following components (D1) and (D2). (D1) Ingredient: Low-substituted hydroxypropyl cellulose. (D2) Components: One or more selected from silicon dioxide and calcium hydrogen phosphate. [6] The laminated tablet according to [5], wherein the content of component (D) is 0.1 to 30% by mass with respect to the total mass of the X layer. [Effects of the Invention]

[0008] According to the present invention, a laminated tablet is obtained that has a layer containing at least one of acetaminophen and ethenzamide and HPMCAS, while suppressing the decrease in hardness during storage. [Modes for carrying out the invention]

[0009] The laminated tablet of this embodiment is a two-layer tablet consisting of an X layer and a Y layer. Layer X is a drug layer containing component (A), component (B), and component (C). In this specification, "drug layer" means a layer containing an active ingredient that is compressed and molded by the tablet manufacturing process. In this specification, a numerical range represented by "~" means a numerical range whose lower limit and upper limit are the numbers before and after "~".

[0010] ≪X layer≫ <(A) component> (A) The component is one or more selected from acetaminophen and ethenzamide. (A) The component is an active ingredient that has antipyretic and analgesic effects.

[0011] <(B) component> (B) The component is hypromellose acetate succinate (also known as hydroxypropyl cellulose acetate succinate). Component (B) acts as a binder. The coexistence of components (B) and (C) suppresses the decrease in hardness over time. In addition, the inclusion of component (B) allows for the sustained release of component (A).

[0012] Hypromellose acetate succinate is a compound produced by reacting hydroxypropyl cellulose with acetic anhydride and succinic anhydride, thereby introducing acetyl and succinyl groups to the hydroxyl groups of hydroxypropyl cellulose. Various grades exist with different proportions of acetyl and succinyl groups and particle sizes. Hydroxypropyl cellulose is usually produced by reacting pulp with a mixture of chloromethane or propylene oxide.

[0013] The solubility of component (B) has pH-dependence. At a measurement temperature of 37 ± 0.5°C, component (B) preferably dissolves in water at pH 5.5 or higher, and more preferably at pH 6 or higher. The average particle diameter of component (B) used in the production of the laminated tablets is preferably 1 to 1000 μm, more preferably 3 to 800 μm, and even more preferably 5 to 500 μm. In the case of fine powder with an average particle diameter of 10 μm or less, the 90% integrated particle diameter is preferably 20 μm or less. In this specification, the particle diameter of component (B) is a measured value by the dry laser diffraction method, and the average particle diameter and 90% integrated particle diameter are based on volume.

[0014] <Component (C)> Component (C) is ibuprofen (2-(4-isobutylphenyl)propionic acid). The coexistence of component (B) and component (C) can suppress the decrease in hardness over time.

[0015] <Component (D)> Component (D) is one or both of the following component (D1) and the following component (D2). [[ID=Z19]] Component (D1) is low-substituted hydroxypropyl cellulose. Component (D2) is one or more selected from silicon dioxide and calcium hydrogen phosphate. As the silicon dioxide, light anhydrous silicic acid, hydrous silicon dioxide, both can be preferably used. When component (B) and component (C) coexist, an increase in hardness over time may occur, but when component (D) is blended, the increase in hardness can be suppressed.

[0016] <Content> [Component (A)] With respect to the total mass of the X layer, the content of component (A) is preferably 5 to 70% by mass, and more preferably 8 to 30% by mass. When the content of component (A) is at least the lower limit value, it is easier to make the tablets smaller. When the content is at most the upper limit value, it is easier to suppress the decrease in hardness over time.

[0017] [(B) Component] The content of component (B) relative to the total mass of layer X is preferably 1 to 50% by mass, and more preferably 5 to 30% by mass. When the content of component (B) is above the lower limit, an appropriate tablet hardness is more easily obtained. In addition, the sustained release effect of components (A) and (C) is more easily obtained. When the content of component (B) is below the upper limit, adhesion to manufacturing equipment during tableting is more easily suppressed. In addition, the increase in hardness over time due to coexistence with component (C) is more easily suppressed.

[0018] [(C) component] The content of component (C) relative to the total mass of layer X is preferably 5 to 70% by mass, and more preferably 10 to 30% by mass. When the content of component (C) is above the lower limit, the effect of suppressing hardness reduction is more easily obtained. In addition, it is easier to make tablets smaller. When the content of component (C) is below the upper limit, it is easier to suppress adhesion to manufacturing equipment during tableting. In addition, it is easier to suppress the increase in hardness over time due to coexistence with component (B).

[0019] The total content of components (A), (B), and (C) relative to the total mass of layer X is preferably 11 to 85% by mass, and more preferably 23 to 75% by mass. In layer X, the mass ratio of the content of component (C) to the total content of component (A) and component (B), (C) / (A+B), is preferably 0.1 to 5, and more preferably 0.3 to 2.

[0020] [(D) component] The content of component (D) relative to the total mass of layer X is preferably 0.1 to 30% by mass, and more preferably 0.5 to 15% by mass. When the content of component (D) is above the lower limit, the effect of suppressing the increase in hardness over time due to the coexistence of components (B) and (C) is more easily obtained. When the content of component (D) is below the upper limit, the effect of suppressing the decrease in hardness is more easily obtained. The content of component (D1) relative to the total mass of layer X is preferably 1 to 20% by mass, and more preferably 3 to 10% by mass. The content of component (D2) relative to the total mass of layer X is preferably 0.1 to 10% by mass, and more preferably 0.5 to 8% by mass. The total content of components (A), (B), (C), and (D) relative to the total mass of layer X is preferably 11.1 to 90% by mass, and more preferably 23.5 to 80% by mass. Furthermore, the total amount of all components contained in layer X does not exceed 100% by mass.

[0021] <Optional ingredients> Layer X may contain any components other than components (A), (B), (C), and (D). These optional components may include physiologically active ingredients, additives, etc. The physiologically active ingredients include antipyretic and analgesic components (e.g., piroxicam, meloxicam, ampiroxicam, cerocoxib, lofecoxib, tiaramide, sulpyrine, etc.), sedative and hypnotic components (e.g., bromovalerylurea, (anhydrous) caffeine, etc.), and antihistamine components (e.g., isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimazine tartrate, diphenhydramine tannate, diphenylpyraline theoclate, mebhydrolin napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, chlorpheniramine maleate, d-chlorpheniramine Examples of physiologically active ingredients include: dimethyl maleate, diphenol phosphate, etc.; central nervous system stimulants (e.g., sodium caffeine benzoate); antitussive and expectorant ingredients (e.g., potassium guaiacolsulfonate, codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline); and vitamins (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.). These physiologically active ingredients can be used individually or in appropriate combinations of two or more.

[0022] Examples of additives include binders, excipients, disintegrants, flavorings, lubricants, sweeteners, acidulants, and antacids. Examples of binders include hydroxypropylcellulose, carmellose sodium, gelatin, pullulan, polyvinylpyrrolidone, pullulan, and dextrin. Examples of excipients include lactose, mannitol, erythritol, xylitol, lactitol, trehalose, maltitol, talc, powdered sugar, dextrin, cyclodextrin, carboxymethylcellulose (carmellose), carboxymethylcellulose calcium, L-cysteine, sodium hydrogen phosphate, carmellose sodium, and crystalline cellulose. Examples of disintegrants include adipic acid, methylcellulose, povidone, crospovidone, and calcium stearate. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid esters. 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. Examples of antacids include dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium aluminosilicate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, magnesium silicate, and sodium bicarbonate.

[0023] ≪Y layer≫ The Y layer is a layer with a different composition from the X layer. The components contained in layer Y are not particularly limited. Layer Y may also be a drug layer containing an active ingredient. The Y layer may contain, for example, one or more selected from the components (A), (B), and (C). It may also contain the component (D). In particular, the inclusion of component (C) in the Y layer is preferable because it can further suppress the decrease in hardness over time.

[0024] When the Y layer contains component (A), the content of component (A) is preferably 5 to 70% by mass, and more preferably 8 to 30% by mass, relative to the total mass of the Y layer. If the content of component (A) is above the lower limit, it is easier to make the tablets smaller. If the Y layer contains component (B), the content of component (B) is preferably 0.1 to 10% by mass, and more preferably 0.5 to 5% by mass, relative to the total mass of the Y layer. When the Y layer contains component (C), the content of component (C) is preferably 5 to 70% by mass, and more preferably 10 to 30% by mass, relative to the total mass of the Y layer. When the content of component (C) is above the lower limit, the effect of suppressing hardness reduction is more easily obtained. In addition, it is easier to make the tablets smaller. When the content of component (C) is below the upper limit, it is easier to suppress adhesion to manufacturing equipment during tableting. In addition, it is easier to suppress the increase in hardness over time. The total content of components (A), (B), and (C) relative to the total mass of the Y layer is preferably 10.1 to 70% by mass, and more preferably 18.5 to 65% by mass.

[0025] When the Y layer contains component (D), the content of component (D) relative to the total mass of the Y layer is not particularly limited, but for example, 0.1 to 30% by mass is preferred. When the Y layer contains component (D1), the content of component (D1) relative to the total mass of the Y layer is not particularly limited, but for example, 1 to 20% by mass is preferred. When the Y layer contains component (D2), the content of component (D2) relative to the total mass of the Y layer is not particularly limited, but for example, 0.1 to 10% by mass is preferred. The total content of components (A), (B), (C), and (D) relative to the total mass of the Y layer is preferably 10.2 to 75% by mass, and more preferably 20 to 70% by mass. Furthermore, the total content of all components contained in the Y layer does not exceed 100% by mass.

[0026] <Optional ingredients> The Y layer may include any components other than components (A), (B), (C), and (D). Examples of the arbitrary components of the Y layer are the same as those of the arbitrary components of the X layer.

[0027] <Preferred embodiment> For example, it is preferable that the Y layer is a drug layer containing component (A) and component (C). Furthermore, it is more preferable that the Y layer contains components (A) and (C) and does not contain component (B), or contains component (B) in a smaller amount than the X layer. Component (B) is a component that contributes to the sustained release of the active ingredient in the layer, and by increasing the content of component (B) in the X layer compared to the content of component (B) in the Y layer, the dissolution rate of the active ingredient in the Y layer can be made faster than the dissolution rate of the active ingredient in the X layer. For example, if the content of component (B) relative to the total mass of layer X is (bx) mass%, and the content of component (B) relative to the total mass of layer Y is (by) mass%, then the ratio of (by) / (bx) may be 80 / 100 or less, 60 / 100 or less, 40 / 100 or less, or 20 / 100 or less, or it may even be 0 / 100.

[0028] For example, layer X may be a slow-release layer containing components (A) and (C), and layer Y may be a fast-release layer containing components (A) and (C). Generally, a sustained-release layer refers to a drug layer in which the release rate, release time, and release site of the active ingredient from the formulation are adjusted for purposes such as reducing the number of administrations or minimizing side effects. An immediate-release layer refers to a drug layer in which the active ingredient dissolves quickly due to formulation modifications. Known techniques can be used to accelerate the dissolution of the active ingredient, and include the addition of water-soluble components, increasing the surface area of ​​the active ingredient, and granulation of the active ingredient.

[0029] For example, by incorporating an antacid into the immediate disintegration layer, the disintegration properties immediately after production can be enhanced. From the viewpoint of improving disintegration properties immediately after production and suppressing the delay of disintegration over time, the antacid is preferably at least one selected from the group consisting of dried aluminum hydroxide gel, magnesium aluminometasilicate, synthetic hydrotalcite, and magnesium oxide, with dried aluminum hydroxide and magnesium aluminometasilicate being particularly preferred. When the above antacid is incorporated into the Y layer, the content of the antacid relative to the total mass of the Y layer is preferably 10 to 80% by mass, and more preferably 20 to 60% by mass. Furthermore, the content of the antacid relative to the total mass of the laminated tablet is preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0030] ≪Stackable Locks≫ <Content> In the stacked tablets, the content of component (A) is preferably 20 to 300 mg, and more preferably 50 to 220 mg. In the stacked tablets, the content of component (C) is preferably 20 to 300 mg, and more preferably 50 to 220 mg. The preferred content is as described above.

[0031] In this specification, the definitions of a slow-release layer and a rapid-release layer are as follows: The sustained-release layer is a drug layer that has been given the added function of a sustained-release formulation as defined in the Japanese Pharmacopoeia (JP), and thus possesses sustained-release properties. In this specification, "possesses sustained-release properties" means that, using a JP disintegration test machine, it does not disintegrate within 2 hours in a test solution with a pH of 1.2, and disintegrates within 1 hour in a test solution with a pH of 6.8 or higher. The immediate-release layer is a layer that is immediately released. In this specification, "immediately released" means that it disintegrates within 30 minutes using a pH 1.2 test solution with a disintegration test machine according to the Japanese Pharmacopoeia method.

[0032] The present invention is not limited to the embodiments described above. The dissolution and disintegration properties of the Y layer are not particularly limited and may be an immediate-release layer, a sustained-release layer different from the X layer, or a layer with other purposes. Examples of drug layers other than the immediate-release and sustained-release layers include drug layers that typically exhibit dissolution behavior in accordance with the solubility of the active ingredient, such as immediate-release or sustained-release formulations of the Japanese Pharmacopoeia, in which the release of the active ingredient from the formulation is not particularly controlled.

[0033] <Manufacturing method> The laminated tablets of this embodiment can be manufactured using known methods. Specifically, the product can be manufactured by a method comprising: a first mixing step of mixing all the components constituting the X layer to obtain a powder mixture for the X layer; a second mixing step of mixing all the components constituting the Y layer to obtain a powder mixture for the Y layer; and a tableting step of sequentially filling the X layer powder mixture and the Y layer powder mixture and compressing them in a stacked state to obtain a stacked tablet.

[0034] [Mixing process] It is preferable to incorporate an excipient and a lubricant into the powder mixture for layer X and the powder mixture for layer Y, respectively. In the mixing process, general-purpose mixers can be used as needed. 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.).

[0035] [Mixing process] In the tableting process, there are no particular limitations on whether the powder mixture for the X layer or the powder mixture for the Y layer is filled first before tableting. However, from the viewpoint of suppressing the decrease in hardness over time, it is preferable to fill the powder mixture for the X layer first. Alternatively, after filling with one powder mixture, a pre-compression step may be performed on only one of the powder mixtures before filling with the other powder mixture. Pre-compression of the interlayer is preferable because it tends to reduce the boundary area between the two layers.

[0036] Tablet compression can be carried out using a known tablet press. Examples of tablet presses include single-shot tablet presses such as CRUX (manufactured by Kikusui Seisakusho Co., Ltd.) and HANDTAB (manufactured by Ichihashi Seiki Co., Ltd.). The tableting conditions can be set appropriately, taking into account the tablet hardness and other factors, depending on the tablet press used. 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.

[0037] 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 periphery 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 further reduced.

[0038] According to this embodiment, a laminated tablet is obtained in which the decrease in hardness during storage is suppressed. The hardness of the laminated tablets is preferably 4.5 to 15 kgf, and more preferably 6 to 12 kgf, both before and after storage. If the hardness of the laminated tablets is above the lower limit, abrasion during tablet manufacturing is more easily suppressed, and if it is below the upper limit, the delay in disintegration time is more easily suppressed. The hardness of tablets in this specification is the average value of five samples, measured by applying pressure in the direction of diametrical compression to the tablet hardness, in accordance with the Japanese Pharmacopoeia's method of tablet hardness measurement, as described in the examples below.

[0039] Furthermore, when stored using the storage test method described in the examples below, it is preferable that the decrease in hardness after storage is small compared to the hardness before storage, but the hardness after storage may be higher than the hardness before storage. For example, if the hardness before storage is 7 kgf, and the hardness after storage is lower than the hardness before storage, the absolute value of the difference between the hardness before storage and the hardness after storage is preferably 0 to 2.5 kgf, and more preferably 0 to 1.0 kgf. Furthermore, if the hardness before storage is 7 kgf and the hardness after storage is higher than the hardness before storage, the absolute value of the difference between the hardness before storage and the hardness after storage is preferably 0 to 4 kgf, and more preferably 0 to 2 kgf. [Examples]

[0040] 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 indication of "compliant with the Japanese Pharmacopoeia" means that the raw materials conform to the standards of the 18th revised Japanese Pharmacopoeia.

[0041] (Raw materials used) <(A) component> Acetaminophen: Product name "Acetaminophen (powder)", manufactured by SperaNexus, compliant with the Japanese Pharmacopoeia. Ethenzamide: Product name "Ethoxybenzamide A", manufactured by Yoshitomi Pharmaceutical Co., Ltd., compliant with the Japanese Pharmacopoeia.

[0042] <(B) component> AS-HF: Hypromellose acetate succinate, pH solubility "≧6.5", form "fine powder", product name "Shin-Etsu AQOAT, AS-HF", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. AS-MF: Hypromellose acetate succinate, pH solubility "≧6.0", form "fine powder", product name "Shin-Etsu AQOAT, AS-MF", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. AS-HMP: Hypromellose acetate succinate, pH solubility "≧6.5", shape "medium particle size", product name "Shin-Etsu AQOAT, AS-HMP", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. AS-LMP: Hypromellose acetate succinate, pH solubility "≧5.5", shape "medium particle size", product name "Shin-Etsu AQOAT, AS-LMP", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. The "fine powder" mentioned above refers to powder with a volume-average particle size of 10 μm or less and a 90% integrated particle size of 20 μm or less, as determined by dry laser diffraction. The above-mentioned "intermediate particle size" refers to powders with a volume-average particle diameter of 70 μm or more and 300 μm or less, as determined by dry laser diffraction. Regarding pH solubility, "≧(x)" indicates that the substance dissolves in water (measurement temperature 37.0±0.5℃) at a pH of (x) or higher. For example, the above AS-HF dissolves in water at a pH of 6.5 or higher.

[0043] <(C) component> Ibuprofen: Product name "Ibuprofen 50", manufactured by BASF, compliant with the Japanese Pharmacopoeia.

[0044] <(D1) component> LH-21: Low-substituted hydroxypropyl cellulose, product name "LH-21", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. <(D2) component> Hydrated silicon dioxide: Product name "Fujisil", manufactured by Fuji Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. Anhydrous calcium hydrogen phosphate: Product name "GSH", manufactured by Kyowa Chemical Industry Co., Ltd., conforms to the Japanese Pharmacopoeia.

[0045] <Optional ingredients> Carmellose: Product name "NS-300", manufactured by Nichirin Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. Crystalline cellulose: Product name "Ceolus UF-702", manufactured by Asahi Kasei Corporation, compliant with the Japanese Pharmacopoeia. Mannitol: Product name "Granitol F", manufactured by Freund Industrial Co., Ltd., compliant with the Japanese Pharmacopoeia. Hydroxypropylcellulose (HPC): Product name "HPC-L", manufactured by Nippon Soda Co., Ltd., compliant with the Japanese Pharmacopoeia. Anhydrous caffeine: Product name "Anhydrous Caffeine", manufactured by Shizuoka Caffeine Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. Potassium guaiacolsulfonate: Product name "Potassium guaiacolsulfonate", manufactured by SperaNexus 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. Chlorpheniramine maleate: Product name "Chlorpheniramine maleate", manufactured by Kongo 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. Magnesium stearate: Product name "Magnesium stearate, plant-derived, light type", manufactured by Taihei Chemical Industry Co., Ltd., conforms to the Japanese Pharmacopoeia.

[0046] ≪Method for evaluating hardness≫ <Storage Test Method> 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 and 75% RH for one week. The hardness was measured before (initial) storage and after storage. The hardness was measured using a Pharma Test product called "PTB-502," following the Japanese Pharmacopoeia's method for measuring tablet hardness. Specifically, a tablet was placed between two pressure plates in a direction that compressed it in the diametrical direction, and one of the pressure plates was moved at a constant speed to measure the force (in kgf) just before the tablet broke. The average value of five samples (tablets) was used as the hardness (in kgf).

[0047] <Examples 1-24, Comparative Examples 1-4> Laminated tablets (two-layer tablets) with the compositions shown in Tables 1-4 were manufactured. A powder mixture for layer X was prepared by mixing all the components to achieve the composition ratio of layer X shown in the table. Separately, a powder mixture for layer Y was prepared by mixing all the components to achieve the composition ratio of layer Y shown in the table.

[0048] [Tablet compression] Tablets (two-layer tablets) were manufactured using the powder mixture for layer X and the powder mixture for layer Y, so that the composition ratios of layer X and layer Y were as shown in the table. Tablets were compressed using a single-shot tablet press (manufactured by Kikusui Seisakusho Co., Ltd., product name "CRUX03L"). The compression pressure was adjusted so that the average hardness of 5 tablets was approximately 7 kgf. For Examples 1-21, 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, while for Examples 22-24, 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. The powder mixture for layer X was filled into the first layer in the amount shown in the table (unit: mg), and after compression, the powder mixture for layer Y was filled into the second layer in the amount shown in the table (unit: mg), and compressed to obtain a two-layer tablet. The obtained tablets were subjected to a storage test using the method described above, and their hardness was measured before (initial) storage and after storage. The results are shown in the table. The table also shows the absolute value of the difference between the hardness before storage and the hardness after storage (the same applies below). In all of the laminated tablets in Examples 1-24 and Comparative Examples 1-4, the X layer was a sustained-release layer and the Y layer was an immediate-release layer.

[0049] <Reference example 1> In this example, a single-layer tablet containing component (A) and component (B) but not component (C) was manufactured. Specifically, a powder mixture for the X layer was prepared by mixing all the components to achieve the composition ratio of the X layer shown in Table 1, and single-layer tablets were manufactured using this mixture. The tablets were compressed using the single-shot tablet press described above, with the compression pressure adjusted so that the average hardness of 5 tablets was approximately 7 kgf. 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, and the powder mixture for the X layer was filled and compressed to obtain single-layer tablets.

[0050] [Table 1]

[0051] [Table 2]

[0052] [Table 3]

[0053] [Table 4]

[0054] As shown in Tables 1-4, the laminated tablets of Examples 1-24, in which the X layer contained components (A), (B), and (C), showed suppressed hardness reduction during storage. In particular, Examples 8, 10, and 12 showed no change in hardness before and after storage. In Examples 1-5, 7, 9, 11, and 13-24, hardness increased slightly during storage. On the other hand, the laminated tablets of Comparative Examples 1 and 2, in which the X layer did not contain component (C), and the laminated tablet of Comparative Example 3, in which the X layer did not contain component (B), showed a significant decrease in hardness during storage. Furthermore, the laminated tablet of Comparative Example 4, in which hydroxypropyl cellulose was used instead of component (B) in the X layer, also showed a significant decrease in hardness during storage. Comparing Reference Example 1 with Comparative Example 1, Reference Example 1 is a single-layer tablet containing components (A) and (B), but not component (C), similar to the X layer of Comparative Example 1. This single-layer tablet showed minimal hardness reduction during storage.

Claims

1. A laminated tablet consisting of X and Y layers with different compositions, A laminated tablet in which the X layer contains the following component (A), component (B), and component (C). (A) Ingredients: One or more selected from acetaminophen and ethenzamide. (B) Ingredients: Hypromellose acetate succinate. (C) Ingredients: Ibuprofen.

2. The laminated tablet according to claim 1, wherein the content of component (B) is 1 to 50% by mass with respect to the total mass of the X layer.

3. The laminated tablet according to claim 1, wherein the content of component (C) is 5 to 70% by mass with respect to the total mass of the X layer.

4. The laminated tablet according to claim 1, wherein the Y layer contains component (C): ibuprofen.

5. The laminated tablet according to any one of claims 1 to 4, wherein the X layer further contains a component (D) which is one or both of the following components (D1) and (D2). (D1) Ingredient: Low-substituted hydroxypropyl cellulose. (D2) Components: One or more selected from silicon dioxide and calcium hydrogen phosphate.

6. The laminated tablet according to claim 5, wherein the content of component (D) is 0.1 to 30% by mass with respect to the total mass of the X layer.

Images