Solid pharmaceutical composition

Abstract

The present invention provides a solid pharmaceutical composition containing ibuprofen, alginic acid or a salt thereof, and a binder, while suppressing discoloration over time. [Solution] A solid pharmaceutical composition comprising (A) component: ibuprofen, (B) component: binder (excluding component (C) below), (C) component: at least one selected from the group consisting of alginic acid and its salts, and (D) component: acetaminophen.

Description

Technical Field

[0001] The present invention relates to a solid pharmaceutical composition.

Background Art

[0002] Among non-steroidal anti-inflammatory components, ibuprofen has excellent anti-inflammatory, analgesic, and antipyretic effects, and thus is widely used as an active ingredient in cold medicines and antipyretic analgesics. Since ibuprofen is a highly adhesive powder, when formulating a composition containing ibuprofen, it is likely to cause adhesion to the device and tableting problems. On the other hand, alginic acid or its salt has the characteristic of being less likely to cause adhesion inhibition and tableting problems, and thus is also used as an excipient in a solid pharmaceutical composition containing ibuprofen. Patent Document 1 describes an oral solid tablet containing ibuprofen and an alginate.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The inventors of the present invention found that in a solid pharmaceutical composition containing ibuprofen, when a water-soluble polymer such as hydroxypropyl cellulose was blended as a binder because the binding force between ibuprofen and only alginic acid or its salt was insufficient, discoloration occurred over time in these three-component systems. An object of the present invention is to provide a solid pharmaceutical composition containing ibuprofen, alginic acid or its salt, and a binder, while suppressing discoloration over time.

Means for Solving the Problems

[0005] As a result of diligent research to solve the above-mentioned problems, the present inventors have found that by incorporating acetaminophen into the above three-component system, discoloration over time can be suppressed, and that by incorporating acetaminophen into both layers of a two-layer tablet, changes in the color difference between the drug layers during storage can be suppressed.

[0006] The present invention has the following aspects. [1] A solid pharmaceutical composition comprising (A) component: ibuprofen, (B) component: binder (excluding component (C) below), (C) component: at least one selected from the group consisting of alginic acid and its salts, and (D) component: acetaminophen. [2] The solid pharmaceutical composition according to [1], wherein component (B) is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E. [3] The solid pharmaceutical composition according to [1] or [2], wherein the (C) component is sodium alginate. [4] The solid pharmaceutical composition according to any one of [1] to [3], wherein (D) / (A+B+C), which represents the mass ratio of the content of component (D) to the total content of component (A), component (B), and component (C), is 0.1 to 2. [5] A solid pharmaceutical composition according to any one of items [1] to [4], which is a tablet, capsule, pill, granule, or powder. [6] A solid pharmaceutical composition according to any one of [1] to [4], comprising a drug layer (X) containing component (A), component (B), component (C), and component (D), and a drug layer (Y) containing at least component (D) and having a different composition from drug layer (X). [Effects of the Invention]

[0007] According to the present invention, a solid pharmaceutical composition is obtained that contains ibuprofen, alginic acid or a salt thereof, and a binder, while suppressing discoloration over time. [Modes for carrying out the invention]

[0008] ≪Solid Pharmaceutical Compositions≫ The solid pharmaceutical composition of this embodiment (hereinafter also referred to as "solid pharmaceutical composition (Z)") comprises component (A), component (B), component (C), and component (D). The solid pharmaceutical composition (Z) may further contain optional components. In this specification, a numerical range represented by "~" means a numerical range whose lower limit and upper limit are the numbers before and after the "~". In this specification, a change in color difference between drug layers during storage means that the difference in b* between drug layer (X) and drug layer (Y) increases over time.

[0009] The solid pharmaceutical composition (Z) may be a pharmaceutical preparation such as a tablet, capsule, pill, granule, or powder. A tablet has a drug layer. In this specification, the "drug layer" contains an active ingredient and is compressed and molded by a tablet manufacturing method. A tablet may be a single-layer tablet consisting of only one drug layer, or it may have multiple drug layers in one tablet. Examples of tablets with multiple drug layers include laminated tablets and cored tablets. The tablets may be, for example, uncoated tablets, coated tablets (film-coated tablets, sugar-coated tablets, etc.). The tablets may also be, for example, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.

[0010] If the solid pharmaceutical composition (Z) is a tablet, it is preferable to have a drug layer (X) containing components (A), (B), (C), and (D). Furthermore, it may also have a drug layer (Y) containing at least component (D) and having a different composition from the drug layer (X). The drug layer (Y) is preferably different from the drug layer (X) in that it does not contain one or more of the components (A), (B), and (C). It is more preferable that the drug layer (Y) does not contain component (C).

[0011] <(A) component> (A) The component is ibuprofen (2-(4-isobutylphenyl)propionic acid). Component (A) is an ingredient with excellent anti-inflammatory, analgesic, and antipyretic effects, and is used as one of the main ingredients in cold medicines and antipyretic analgesics that suppress symptoms such as fever and headache. In the solid pharmaceutical composition (Z), component (A) may exist as a component in the granules, as a non-granulated component, or both. If the solid pharmaceutical composition (Z) is a two-layer tablet consisting of the drug layer (X) and the drug layer (Y), it is preferable that component (A) is contained in both drug layers.

[0012] <(B) component> Component (B) is a binder (excluding component (C) below). The binder is used in the solid pharmaceutical composition (Z) as a binding medium between particles, and is added to impart cohesiveness of the powder and moldability of the formulation, thereby obtaining the desired hardness and drug solubility. A water-soluble polymer is preferred as the binder. A water-soluble polymer is defined as a polymer compound with a solubility in water at 20°C of more than 1.3 g / 100 mL. A "polymer compound" is defined as a compound with a weight-average molecular weight of 1000 or more, as measured by GPC (gel permeation chromatography).

[0013] Examples of component (B) include hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, povidone, aminoalkyl methacrylate copolymer E, gelatin, pullulan, dextrin, and carmellose sodium. Of these, hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E are preferred, and hydroxypropyl cellulose and polyvinyl alcohol are more preferred. (B) By incorporating component (B), the binding strength is increased, improving the cohesiveness of the powder and the moldability of the formulation.

[0014] Hydroxypropyl cellulose can preferably be that which is described in the 18th edition of the Japanese Pharmacopoeia. Polyvinyl alcohol can preferably use those described in the Pharmaceutical Additive Standards (2018). Partially saponified polyvinyl alcohol is preferred. The partially saponified polyvinyl alcohol is usually produced by partially saponifying polyvinyl acetate. The saponification degree is preferably 78 to 100 mol%, more preferably 78 to 96 mol%. Methylcellulose can preferably use those described in the Japanese Pharmacopoeia, Eighteenth Revision. Povidone (polyvinylpyrrolidone) can preferably use those described in the Japanese Pharmacopoeia, Eighteenth Revision. Povidone is grouped by the K value which is a characteristic value of viscosity, and is usually 10 to 120, preferably 25 to 90. The method for measuring the K value is described in "Povidone" in the Japanese Pharmacopoeia, Eighteenth Revision. Aminoalkyl methacrylate copolymer E has the chemical name: methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, and is a component described in the Pharmaceutical Additive Standards or the Specifications for Ingredients of Quasi-Drugs Other than the Japanese Pharmacopoeia.

[0015] In the solid pharmaceutical composition (Z), the component (B) may be present as a component in the granulated product, may be present as a non-granulated component, or may be both of them. When the solid pharmaceutical composition (Z) is a tablet containing a granulated product, from the viewpoints of homogeneity, reduction of the adhesion of the component (A) during tableting, and enhancement of the binding force of the component (D), it is preferable to use the component (B) as a granulating component, and particularly preferably to incorporate it into the granulated product by a method of spraying an aqueous solution of the component (B) as a binding liquid during granulation.

[0016] <(C) component> (C) component is at least one selected from the group consisting of alginic acid and its salts. Alginic acid is a carbohydrate obtained from brown algae (Phaeophyceae), and is a linear Glycuronoglycan mainly composed of the pyranose ring forms of β-1,4-D-mannuronic acid and α-1,4-L-guluronic acid. (C) Examples of components include alginic acid, sodium alginate, potassium alginate, and ammonium alginate. Among these, sodium alginate is preferred from the viewpoint of storage stability and odor of the solid pharmaceutical composition (Z).

[0017] Component (C) can be incorporated as an excipient in the solid pharmaceutical composition (Z). In particular, sodium alginate rapidly hydrates and dissolves in cold and hot water, exhibiting a neutral and smooth viscosity. As the pH decreases, it becomes alginic acid, which is insoluble in water, and gelation occurs. Therefore, tablets containing sodium alginate can extend the disintegration time of the tablet by gelling in the stomach, thereby providing sustained effects.

[0018] The viscosity of a 1% by mass aqueous solution of component (C) at 20°C is preferably 300 to 1000 mPa·s. In this invention, "viscosity" is the value measured using a rotational viscometer under the conditions of a liquid temperature of 20°C and a rotor speed of 30 rpm. In the solid pharmaceutical composition (Z), component (C) may exist as a component in the granules, as a non-granulated component, or both.

[0019] <(D) component> Component (D) is acetaminophen (N-(4-hydroxyphenyl)acetamide). Component (D) has the effect of suppressing discoloration of the solid pharmaceutical composition (Z) over time. In addition, component (D) is also an antipyretic and analgesic component. In the solid pharmaceutical composition (Z), component (D) may exist as a component in the granules, as a non-granulated component, or both. If the solid pharmaceutical composition (Z) is a two-layer tablet having the drug layer (X) and the drug layer (Y), it is preferable that component (D) is included in both the drug layer (X) and the drug layer (Y). When component (D) is included in both the drug layer (X) and the drug layer (Y), the difference in color between the drug layers after storage is more easily suppressed.

[0020] <Content> [(A) component] The content of component (A) relative to the total mass of the solid pharmaceutical composition (Z) is preferably 10 to 70% by mass, and more preferably 20 to 60% by mass. When the content of component (A) is above the lower limit, the therapeutic effects such as anti-inflammatory, analgesic, and antipyretic effects are further enhanced. When the content of component (A) is below the upper limit, discoloration over time is further suppressed. In addition, powder adhesion to the manufacturing equipment of the solid pharmaceutical composition (Z) is further suppressed, and in the case of tablets, adhesion to the rotating disc during tableting is further suppressed.

[0021] In particular, when the solid pharmaceutical composition (Z) is a tablet having the drug layer (X), the content of component (A) is preferably 10 to 70% by mass, and more preferably 15 to 60% by mass, relative to the total mass of the drug layer (X). When the content of component (A) is above the lower limit, the pharmacological effects such as anti-inflammatory, analgesic, and antipyretic effects are further enhanced. When the content of component (A) is below the upper limit, discoloration over time is further suppressed. In addition, adhesion to the rotating disc during tableting is further suppressed. For the same reasons as above, the content of component (A) in one tablet is preferably 20 to 300 mg, and more preferably 50 to 220 mg.

[0022] [(B) Component] The content of component (B) relative to the total mass of the solid pharmaceutical composition (Z) is preferably 1 to 30% by mass, and more preferably 2 to 25% by mass. When the content of component (B) is above the lower limit, the binding force between the powders constituting the solid pharmaceutical composition (Z) is easily maintained, and in the case of tablets, higher hardness is easily obtained. When the content of component (B) is below the upper limit, discoloration over time is further suppressed.

[0023] In particular, when the solid pharmaceutical composition (Z) is a tablet having the drug layer (X), the content of component (B) is preferably 1 to 15% by mass, and more preferably 2 to 14% by mass, relative to the total mass of the drug layer (X). When the content of component (B) is above the lower limit, higher hardness is more easily obtained. When the content of component (B) is below the upper limit, discoloration over time is more suppressed.

[0024] Component (B) preferably contains component (B1), which is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E. For example, the total content of component (B1) relative to the total mass of water-soluble polymers (excluding component (C)) contained in the solid pharmaceutical composition (Z) may be 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 100% by mass.

[0025] [(C) component] The content of component (C) relative to the total mass of the solid pharmaceutical composition (Z) is preferably 1 to 30% by mass, and more preferably 2 to 25% by mass. When the content of component (C) is above the lower limit, powder adhesion to the manufacturing equipment of the solid pharmaceutical composition (Z) is further suppressed, and in the case of tablets, adhesion to the rotating disc during tableting is further suppressed. In addition, a sustained-release effect is more easily obtained. When the content of component (C) is below the upper limit, discoloration over time is further suppressed.

[0026] In particular, when the solid pharmaceutical composition (Z) is a tablet having the drug layer (X), the content of component (C) is preferably 3 to 30% by mass, and more preferably 5 to 22% by mass, relative to the total mass of the drug layer (X). If the content of component (C) is above the lower limit, adhesion to the rotating disc during tableting is further suppressed. If the content of component (C) is below the upper limit, discoloration over time is further suppressed.

[0027] Component (C) preferably contains sodium alginate. The amount of sodium alginate relative to the total mass of component (C) may be, for example, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 100% by mass.

[0028] [(D) component] The content of component (D) relative to the total mass of the solid pharmaceutical composition (Z) is preferably 10 to 70% by mass, and more preferably 10 to 50% by mass. When the content of component (D) is above the lower limit, the effect of suppressing discoloration over time is more easily obtained. When the content of component (D) is below the upper limit, the binding force between the powders constituting the solid pharmaceutical composition (Z) is more easily increased.

[0029] In particular, when the solid pharmaceutical composition (Z) is a tablet having the drug layer (X), the content of component (D) is preferably 10 to 70% by mass, and more preferably 12 to 50% by mass, relative to the total mass of the drug layer (X). If the content of component (D) is above the lower limit, the effect of suppressing discoloration over time is more easily obtained. If the content of component (D) is below the upper limit, the binding force between the powders constituting the drug layer (X) is more easily increased. Also, for the same reasons as above, the content of component (D) in one tablet is preferably 20 to 300 mg, and more preferably 50 to 220 mg.

[0030] Furthermore, if the solid pharmaceutical composition (Z) is a tablet having a drug layer (Y) in addition to the drug layer (X), the content of component (D) is preferably 5 to 70% by mass, and more preferably 7 to 50% by mass, relative to the total mass of the drug layer (Y). If the content of component (D) is above the lower limit, a greater effect of suppressing discoloration over time is more easily obtained. If the content of component (D) is below the upper limit, the binding force between the powders constituting the drug layer (Y) is more easily increased.

[0031] [ratio] In the solid pharmaceutical composition (Z), the mass ratio of the content of component (D) to the total content of components (A), (B), and (C), expressed as (D) / (A+B+C), is preferably 0.12 to 2, more preferably 0.2 to 1.7, and even more preferably 0.3 to 1.5. When (D) / (A+B+C) is above the lower limit, discoloration over time is further suppressed. When (D) / (A+B+C) is below the upper limit, the binding force between the powders constituting the solid pharmaceutical composition (Z) is more easily increased.

[0032] In particular, when the solid pharmaceutical composition (Z) is a tablet having the drug layer (X), the (D) / (A+B+C) ratio in the composition of the drug layer (X) is preferably 0.1 to 2, more preferably 0.15 to 1.5, and even more preferably 0.25 to 1.2. When the (D) / (A+B+C) ratio is above the lower limit, discoloration over time is further suppressed. When the (D) / (A+B+C) ratio is below the upper limit, the binding force between the powders constituting the drug layer (X) is more easily increased.

[0033] <Optional ingredients> The solid pharmaceutical composition (Z) may contain any components other than components (A) to (D). For example, other physiologically active components or additives may be added as desired, provided that they do not impair the physical properties or storage stability of the solid pharmaceutical composition (Z). The physiologically active ingredients include antipyretic and analgesic components (e.g., piroxicam, meloxicam, ampiroxicam, cerocoxib, rofecoxib, tiaramide, sulpyrine, etc.), sedative and hypnotic components (e.g., bromovalerylurea, 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 diphenyldisulfonic acid, and alimethrazine tartrate). (e.g., diphenhydramine tannate, diphenylpyraline theoclate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, chlorpheniramine maleate, d-chlorpheniramine maleate, dipheterol phosphate, etc.), central nervous system stimulants (e.g., sodium caffeine benzoate, caffeine, anhydrous caffeine, etc.), antitussive and expectorant ingredients (e.g., codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimetho Quinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), antacids (dried aluminum hydroxide gel, synthetic hydrotalcite, magnesium aluminometasilicate, magnesium oxide, glycine, magnesium silicate, 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, magnesium carbonate, aluminum hydroxide-sodium bicarbonate coprecipitate, synthetic aluminum silicate, dihydroxyaluminumaminoacetic acid, magnesium aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, precipitated calcium carbonate, anhydrous dicalcium phosphate, calcium hydrogen phosphate, 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,Examples include hesperidin and its derivatives and their salts. These physiologically active ingredients can be used individually or in appropriate combinations of two or more. The solid pharmaceutical composition (Z) preferably does not contain ethenzamide, an antipyretic and analgesic component, or contains only a small amount. For example, the ethenzamide content relative to the total mass of the solid pharmaceutical composition (Z) is preferably less than 5% by mass, more preferably less than 2% by mass, even more preferably 1% or less, and particularly preferably substantially absent. Substantially absent means below the detection limit.

[0034] Examples of additives include excipients, disintegrants, flavorings, lubricants, sweeteners, and acidulants. Examples of excipients include crystalline cellulose, lactose, mannitol, erythritol, xylitol, lactitol, trehalose, maltitol, talc, silicon dioxide, corn starch, powdered sugar, carmellose, carmellose calcium, L-cysteine, sodium hydrogen phosphate, calcium hydrogen phosphate, and the like. Examples of disintegrants include adipic acid, methylcellulose, crospovitone, low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, partially pregelatinized starch, sodium starch glycolate, and calcium stearate. 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, dipotassium glycyrrhizinate, and acesulfame potassium. Examples of acidulants include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or salts thereof.

[0035] ≪Manufacturing method≫ The solid pharmaceutical composition (Z) can be manufactured using known methods. The process of mixing components (A), (B), (C), (D), and any optional components as needed can be carried out using a general-purpose mixer. 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.).

[0036] [Granulation process] The solid pharmaceutical composition (Z) may contain granules. The granulation process can be carried out using a known granulation method. Granulation methods include wet granulation and dry granulation, with wet granulation methods including 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.), in which a fluidized bed granulator is used to granulate while spraying an aqueous solution containing a water-soluble polymer compound (e.g., component (B)). 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.

[0037] The granules preferably contain component (B) and one or more components selected from components (A), (C), and (D). They may also contain any additional components. If two or more components selected from (A), (C), and (D) are included in the granules, they may be included in separate granules or in the same granule. For example, if components (A) and (D) are included in the granules, the granules may contain both components (A) and (D), or they may be a mixture of granules containing component (A) but not component (D) and granules containing component (D) but not component (A). If the solid pharmaceutical composition (Z) is a tablet, it is preferable that at least component (D) is included in the granules from the viewpoint of tablet moldability.

[0038] [Tableting process] When the solid pharmaceutical composition (Z) is a tablet, 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. If the solid pharmaceutical composition (Z) is a multilayer tablet having drug layers (X) and drug layers (Y), it 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. The powder mixture used for tableting preferably contains excipients and lubricants.

[0039] 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 the curved (R-shaped) surface being more preferable.

[0040] 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, particle shedding (granule shedding) and abrasion from the tablet surface are further reduced.

[0041] [Grinding process] (A) The component may be pulverized to reduce the particle size and used in the manufacture of the solid pharmaceutical composition (Z). From the viewpoint of productivity, an impact-type pulverization method is preferred. A disc-type pulverizer is more preferred. A hammer mill or a pin mill is preferred as the grinder, 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 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 component (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.

[0042] <Preferred embodiment> A preferred embodiment of the solid pharmaceutical composition (Z) is a tablet having a drug layer (X) containing component (A), component (B), component (C), and component (D), and a drug layer (Y) containing at least component (D) and having a different composition from drug layer (X). The drug layer (Y) preferably contains component (A), component (B), and component (D).

[0043] In this embodiment, the content of component (A) is preferably 10 to 70% by mass, and more preferably 15 to 60% by mass, relative to the total mass of the drug layer (X). The content of component (B) relative to the total mass of the drug layer (X) is preferably 1 to 15% by mass, and more preferably 2 to 14% by mass. The content of component (C) relative to the total mass of the drug layer (X) is preferably 3 to 30% by mass, and more preferably 5 to 22% by mass. The content of component (D) relative to the total mass of the drug layer (X) is preferably 5 to 70% by mass, and more preferably 7 to 50% by mass. The total content of components (A), (B), (C), and (D) relative to the total mass of the drug layer (X) is preferably 30 to 99.7% by mass, and more preferably 50 to 99% by mass.

[0044] In this embodiment, the content of component (A) relative to the total mass of the drug layer (Y) is preferably 10 to 70% by mass, and more preferably 12 to 60% by mass. The content of component (B) relative to the total mass of the drug layer (Y) is preferably 1 to 15% by mass, and more preferably 2 to 10% by mass. The content of component (D) relative to the total mass of the drug layer (Y) is preferably 5 to 70% by mass, and more preferably 7 to 50% by mass. It is preferable that the drug layer (Y) does not contain component (C). The absence of component (C) in the drug layer (Y) is preferable because it makes it easier to make the disintegration rate of the drug layer (Y) faster than that of the drug layer (X).

[0045] The solid pharmaceutical composition (Z) in this embodiment may be a two-layer tablet consisting of a drug layer (X) and a drug layer (Y). In the two-layer tablet, the proportion of the drug layer (X) to the total mass of the solid pharmaceutical composition (Z), i.e., the combined mass of the drug layer (X) and the drug layer (Y), is preferably 20 to 80% by mass, more preferably 30 to 70% by mass, and even more preferably 40 to 60% by mass. When the proportion of the drug layer (X) is above the lower limit and below the upper limit, the moldability as a laminated tablet is further improved. Furthermore, if the drug layer (Y) contains component (D), when it is below the upper limit, the difference in color of the drug layer after storage is further suppressed.

[0046] In the aforementioned two-layer tablet, the drug layer (X) may contain granules and non-granulated components, and the drug layer (Y) may consist only of non-granulated components, or both the drug layer (X) and the drug layer (Y) may consist only of non-granulated components. When the drug layer (X) contains granules and non-granulated components, the proportion of granules relative to the total mass of the drug layer (X) is preferably 20 to 99% by mass, more preferably 25 to 95% by mass, and even more preferably 30 to 90% by mass. If the proportion of granules is above the lower limit, the moldability of the tablets is further improved. If the proportion of granules is below the upper limit, adhesion during tableting can be further suppressed. When the drug layer (X) contains granules and non-granulated components, it is preferable that the entire amounts of components (A), (B), and (D) are contained in the granules and the entire amount of component (C) is contained in the non-granulated components, or that the entire amounts of components (A), (B), and (D) are contained in the granules and component (C) is contained in both the granules and the non-granulated components. When component (C) is present in both granules and non-granules in the drug layer (X), the proportion of component (C) in the granules relative to the total amount of component (C) in the drug layer (X) is preferably, for example, 20 to 80% by mass. If the proportion of component (C) is above the lower limit, higher hardness is more likely to be obtained. If the proportion of component (C) is below the upper limit, adhesion to the rotating disc during tableting is further suppressed. [Examples]

[0047] 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 18th revised Japanese Pharmacopoeia standards. The indication "compliant with the Pharmaceutical Additives Standards," means that the raw materials conform to the Pharmaceutical Additives Standards (2018).

[0048] ≪Raw materials used≫ <(A) component> Ibuprofen: Product name "Ibuprofen 25", manufactured by BASF, compliant with the Japanese Pharmacopoeia. <(B) component> Hydroxypropylcellulose (L): Product name "HPC-L", manufactured by Nippon Soda Co., Ltd., compliant with the Japanese Pharmacopoeia. Hydroxypropylcellulose (SSL): Product name "HPC-SSL", manufactured by Nippon Soda Co., Ltd., compliant with the Japanese Pharmacopoeia. Hypromellose: Product name "TC-5 E", manufactured by Shin-Etsu Chemical Co., Ltd., compliant with the Japanese Pharmacopoeia. 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. <(C) component> Sodium alginate: Product name "Snow Algin SSH", manufactured by Fuji Chemical Industry Co., Ltd., compliant with pharmaceutical additive regulations. <(D) component> Acetaminophen: Product name "Acetaminophen (powder)", manufactured by SperaNexus, compliant with the Japanese Pharmacopoeia. <(D') component: Comparison component> Ethenzamide: Product name "Ethenzamide", manufactured by SperaNexus, compliant with the Japanese Pharmacopoeia.

[0049] <Optional ingredients> Crystalline cellulose: Product name "Ceolus UF-702", manufactured by Asahi Kasei Corporation, compliant with the Japanese Pharmacopoeia. D-Mannitol (granules): Product name "Granitol F", manufactured by Freund Industrial 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. Anhydrous caffeine; Product name: "Anhydrous Caffeine," manufactured by Shizuoka Caffeine Industry Co., Ltd., compliant with the Japanese Pharmacopoeia. Chlorpheniramine maleate: Product name "Chlorpheniramine maleate", manufactured by Kongo Chemical 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. Dried aluminum hydroxide: Product name "S-100", manufactured by Kyowa Chemical Industry Co., Ltd., compliant with the Japanese Pharmacopoeia.

[0050] ≪Evaluation Method≫ <Method for evaluating the discoloration suppression effect> [Method for measuring Δb* value] For each example, the solid pharmaceutical composition (10 g of powder or one tablet) was placed in a screw-cap vial (50 mL capacity) and stored at 60°C and 75% RH for 6 hours in a storage test. The b* value of the solid pharmaceutical composition at the start of the storage test was measured using a spectrophotometer CM-700d (manufactured by Konica Minolta Sensing, Inc., measurement conditions: *L*a*b system), and this value was defined as "b* value: A". Similarly, the b* value of the solid pharmaceutical composition at the end of the storage test was measured, and this value was defined as "b* value: B". The "Δb* value" was calculated from each of the obtained b* values ​​using the formula (1) below. Δb*value = [b*value: B] - [b*value: A] ... (1) The discoloration suppression effect was evaluated based on the calculated Δb* value. A smaller Δb* value indicates less discoloration during storage of the solid pharmaceutical composition. A Δb* value of 2.0 or higher was considered to indicate significant discoloration. In other words, a Δb* value of less than 2.0 was judged to indicate excellent discoloration suppression.

[0051] [Method for measuring the difference in *b of the drug layer after storage] In the case of a two-layer tablet consisting of a drug layer (X) and a drug layer (Y), the two-layer tablet was placed in the screw-cap vial and a storage test was conducted. The b* value (b* value: B) at the end of the storage test was measured for each of the drug layers (X) and (Y). The absolute difference between the "b* value: B" of drug layer (X) and drug layer (Y) after the storage test was evaluated as the "difference in *b of the drug layers after storage." A smaller difference in *b of the drug layers after storage means that the color difference between drug layer (X) and drug layer (Y) after the storage test is small. Note that a difference in *b of the drug layers after storage of less than 2.0 indicates that the color difference of the drug layers is sufficiently small.

[0052] <Examples 1-4, Reference Examples 1-6, Comparative Examples 1-2> Powders (solid pharmaceutical compositions) with the compositions shown in Tables 1 and 2 were manufactured. The tables show the content of each component relative to the total mass of the powder (unit: mass%), and the mass ratio of (D) / (A+B+C). Unless otherwise specified, the amounts of each component in the tables are on a pure content basis. Specifically, all components were mixed to obtain the desired powder (solid pharmaceutical composition) according to the composition ratios shown in the table. The discoloration suppression effect was evaluated for the powders obtained in each example using the method described above. The results are shown in Table 1.

[0053] [Table 1]

[0054] [Table 2]

[0055] As shown in Table 1, Reference Examples 1-6, which contained one or two of the three components (A), (B), and (C), showed minimal discoloration over time even without component (D). As shown in Table 2, Comparative Example 1, which contained components (A), (B), and (C) but not (D), had a significantly higher Δb* value compared to Reference Examples 1-6, and showed clear discoloration during storage. This indicates that the combination of components (A), (B), and (C) is the cause of the discoloration. In contrast, Examples 1-4, which contained components (A), (B), and (C), and also included component (D), showed a significantly lower Δb* value compared to Comparative Example 1. This indicates that component (D) has the effect of suppressing discoloration over time, and is particularly effective in suppressing discoloration caused by the combination of components (A), (B), and (C). Comparative Example 2, which contained three components (A), (B), and (C), and substituted component (D') for component (D), did not show a discoloration suppression effect.

[0056] <Examples 5-14> Tablets (two-layer tablets) with the compositions shown in Tables 3 and 4 were manufactured. This example does not use granules. Tables 3 and 4 show the composition (in parts by mass) of all raw materials used in the manufacture of the tablets. Furthermore, the mass ratio of (D) / (A+B+C) in the drug layer (X) and the mass ratio of (D) / (A+B+C) in the entire two-layer tablet are shown. Unless otherwise specified, the amounts of each component in the table are calculated on a pure content basis. The same applies below.

[0057] [Preparation of powder mixture for drug layer (X)] A powder mixture for the drug layer (X) was obtained by mixing all of the non-granulated components to achieve the composition ratio of the drug layer (X) shown in the table. [Preparation of powder mixture for drug layer (Y)] A powder mixture for the drug layer (Y) was obtained by mixing all of the non-granulated components to achieve the composition ratio of the drug layer (Y) shown in the table. Using the obtained powder mixtures for drug layer (X) and drug layer (Y), tablets (two-layer tablets) were manufactured using the tableting method described later.

[0058] <Examples 15-22> Tablets (two-layer tablets) with the compositions shown in Tables 5 and 6 were manufactured. In this example, the drug layer (X) contains granules. [Preparation of powder mixture for drug layer (X)] A powder mixture for the drug layer (X) was prepared so that it matched the composition ratio of the drug layer (X) shown in the table. First, powder (a1) was prepared by mixing all components except component (B) from the granulation components shown in the table. Separately, among the granulation components shown in the table, component (B) 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 (X).

[0059] [Preparation of powder mixture for drug layer (Y)] A powder mixture for the drug layer (Y) was obtained by mixing all of the non-granulated components to achieve the composition ratio of the drug layer (Y) shown in the table. Using the obtained powder mixtures for drug layer (X) and drug layer (Y), tablets (two-layer tablets) were manufactured using the tableting method described later.

[0060] [Tableting method] In each example, tablets (two-layer tablets) were manufactured using the powder mixture for drug layer (X) and the powder mixture for drug layer (Y) so that the composition ratios of drug layer (X) and drug layer (Y) 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 approximately 7 kgf. 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 tableting. The first layer was filled with the powder mixture for the drug layer (X) in the amount shown in the table (unit: mg), and after compression, the second layer was filled with the powder mixture for the drug layer (Y) in the amount shown in the table (unit: mg), and compressed to obtain a two-layer tablet. The discoloration-inhibiting effect of the obtained two-layer tablets was evaluated using the method described above. The results are shown in the table.

[0061] [Table 3]

[0062] [Table 4]

[0063] [Table 5]

[0064] [Table 6]

[0065] As shown in Tables 3-6, the drug layer (X) of Examples 5-22 contained components (A), (B), (C), and (D), and the Δb* value was small, indicating that discoloration during storage was well suppressed. The drug layer (Y) in Examples 5-22 did not contain component (C) but contained component (D), the Δb* value was very small, and there was almost no discoloration during storage. In the two-layer tablets of Examples 5-22, component (D) was present in both the drug layer (X) and the drug layer (Y), resulting in a small difference in *b of the drug layer after storage.

Claims

1. (A) Ingredients: Ibuprofen, (B) Component: Binder (excluding component (C) below), (C) Component: At least one selected from the group consisting of alginic acid and its salts, (D) A solid pharmaceutical composition containing acetaminophen.

2. The solid pharmaceutical composition according to claim 1, wherein component (B) is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, povidone, and aminoalkyl methacrylate copolymer E.

3. The solid pharmaceutical composition according to claim 1, wherein the (C) component is sodium alginate.

4. The solid pharmaceutical composition according to claim 1, wherein the mass ratio of the content of component (D) to the total content of component (A), component (B), and component (C), is (D) / (A+B+C), which is 0.1 to 2.

5. A solid pharmaceutical composition according to any one of claims 1 to 4, which is a tablet, capsule, pill, granule, or powder.

6. A drug layer (X) comprising the aforementioned component (A), the aforementioned component (B), the aforementioned component (C), and the aforementioned component (D), A solid pharmaceutical composition according to any one of claims 1 to 4, comprising a tablet containing at least the component (D) and having a drug layer (Y) with a composition different from the drug layer (X).

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