Solid preparation

Abstract

The solid preparation contains: component (A): at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; component (B): anhydrous calcium hydrogen phosphate; and component (C): granules containing silicon dioxide; and includes component (D): a disintegrant inside the granules and / or outside the granules.

Description

solid dosage forms

[0001] The present invention relates to a solid dosage form.

[0002] Loxoprofen is a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (NSAID). Patent documents 1 to 3 describe techniques for improving the disintegration and dissolution properties of formulations containing loxoprofen. Patent document 1 (JP 2016-190794 A) describes, as a technique aimed at providing a tablet with excellent disintegration properties and high strength, and a method for easily producing such tablets (paragraph 0006), a tablet having a drug layer containing at least one compound selected from the group consisting of loxoprofen and its salts, at least one compound selected from the group consisting of dried aluminum hydroxide gel, aluminum glycinate, magnesium carbonate, magnesium oxide, magnesium aluminometasilicate, and synthetic hydrotalcite, and a colorant, wherein the water content of the drug layer is 5% by mass or more (claim 1).

[0003] Patent Document 2 (JP 2015-98470 A) describes a tablet containing loxoprofen or a salt thereof, carmellose, and crospovidone (Claim 1), which is described as having a disintegration time of 1 to 60 seconds, a tablet hardness of 10 to 200 N, and a dissolution rate of 85% or more after 30 minutes according to the dissolution test method of the Japanese Pharmacopoeia, 16th Edition (Paragraph 0010). The same document also describes that a granulated product containing specific amounts of specific ingredients, such as loxoprofen sodium hydrate, polyvinylpyrrolidone, and hydrous silicon dioxide, is obtained, and then the obtained granulated product is mixed with specific ingredients, such as anhydrous calcium hydrogen phosphate, to obtain a mixed powder, which is then compressed into tablets having a diameter of 10 mm (Paragraph 0066).

[0004] Furthermore, Patent Document 3 (JP 2016-20329 A) describes a solid preparation that can be taken without water, which contains loxoprofen or a salt thereof and silicon dioxide in a specific blending ratio (Claim 1). It is stated that this makes it possible to produce a solid preparation that can be taken without water, which contains loxoprofen or a salt thereof, which disintegrates quickly in the oral cavity, has a desired appropriate hardness, and has excellent appearance stability (Paragraph 0010).

[0005] JP 2016-190794 A JP 2015-98470 A JP 2016-20329 A

[0006] However, the techniques described in the above patent documents require a certain amount of additives to obtain disintegration properties and tablet strength, which tends to increase the size of the tablets, leaving room for improvement.

[0007] Therefore, the present invention provides a solid preparation that has appropriate hardness and excellent disintegrability and can be made smaller.

[0008] As a result of intensive research to solve the above-mentioned problems, the inventors have found that the above-mentioned problems can be solved by configuring granules in which at least one selected from the group consisting of rofecoxib, its salts, and hydrates thereof is contained together with specific ingredients.

[0009] That is, aspects of the present invention are as follows. [1] A solid formulation comprising granules containing the following components (A) to (C), and comprising the following component (D) at least either inside or outside the granules: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) anhydrous calcium hydrogen phosphate; (C) silicon dioxide; and (D) a disintegrant. [2] The solid formulation according to [1], further comprising an extragranular component. [3] The solid formulation according to [2], wherein the extragranular component comprises one or more components selected from the group consisting of a phosphate compound, a sugar alcohol, and a sugar. [4] The solid formulation according to [3], wherein the sugar alcohol comprises one or more compounds selected from the group consisting of erythritol, sorbitol, mannitol, maltitol, and xylitol. [5] The solid formulation according to [3] or [4], wherein the phosphate compound comprises one or more compounds selected from the group consisting of potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, and sodium hydrogen phosphate. [6] The solid dosage form according to any one of [1] to [5], which is a tablet having a diameter of 7 mm or less. [7] The solid dosage form according to claim [6], wherein the content of component (A) in the solid dosage form is 45% by mass or more based on the total mass of the solid dosage form. [8] A solid dosage form having a volume of 350 mm 3The solid formulation according to any one of [1] to [7], which is a tablet as follows: [9] The solid formulation according to [8], wherein the content of component (A) in the solid formulation is 45% by mass or more relative to the total mass of the solid formulation.

[10] The solid formulation according to any one of [1] to [9], which is a tablet, and wherein the hardness of the solid formulation is 40 N or more.

[11] The solid formulation according to any one of [1] to

[10] , which is a tablet, and wherein the content of component (A) in one tablet is 30 mg or more.

[12] The solid formulation according to any one of [1] to

[11] , which is a tablet, and wherein the proportion of component (A) in the total mass of one tablet is 45% by mass or more.

[13] The solid formulation according to any one of [1] to

[12] , wherein the component (D) comprises one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, partially pregelatinized starch, crospovidone, and sodium starch glycolate.

[14] The solid formulation according to any one of [1] to

[13] , wherein the granules further comprise component (E): at least one selected from the group consisting of tranexamic acid and salts thereof.

[15] A packaged product, in which the solid formulation according to any one of [1] to

[14] is contained in a packaging container.

[0010] According to the present invention, it is possible to provide a solid preparation which has appropriate hardness and excellent disintegrability and can be made smaller.

[0011] Hereinafter, an embodiment of the present invention will be described. In this embodiment, the composition may contain each component alone or in combination of two or more. In this specification, the term "to" indicating a numerical range means "at least" or "at most," and both end values ​​are included.

[0012] First Embodiment (Solid Preparation) In this embodiment, the solid preparation comprises granules containing the following components (A) to (C), and the following component (D) is contained in at least one of the interior and exterior of the granules: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) anhydrous calcium hydrogen phosphate (C) silicon dioxide (D) a disintegrant In addition, the solid preparation is specifically a pharmaceutical composition.

[0013] In this embodiment, the granules in the solid formulation contain a combination of components (A) to (C), and component (D) is contained at least either inside or outside the granules. Therefore, a solid formulation having such a structure has appropriate hardness and excellent disintegrability, and can be made compact. More specifically, according to this embodiment, even when, for example, component (A) is blended in a high concentration in the solid formulation, the hardness and disintegrability of the solid formulation can be made preferable. Therefore, for example, it is possible to stably obtain a solid formulation that contains a desired amount of component (A), is compact, and has excellent hardness and disintegrability. Furthermore, according to this embodiment, it is possible to obtain, for example, a solid formulation that is compact and has excellent swallowability.

[0014] (Granules) Granules are specifically granulated products. The granules may be composed of components (A) to (C), or may be composed of components (A) to (D), or may further contain components other than components (A) to (D).

[0015] (Component (A)) Component (A) is at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. That is, loxoprofen and its salts may be hydrates (hydrated salts). Component (A) is preferably at least one selected from the group consisting of loxoprofen salts and hydrates thereof, and more preferably loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 18th Edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0016] The content of component (A) in the solid preparation is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, in terms of anhydrous basis, as the amount of the component contained in the solid preparation per dosage unit (single dose) for adults, and the frequency of administration is preferably 1 to 3 times a day.

[0017] When the solid preparation is a tablet, the content of component (A) in one tablet is preferably 30 mg or more, more preferably 50 mg or more, and even more preferably 60 mg or more, in terms of the anhydrous base, from the viewpoint of tablet size reduction. Also, from the viewpoint of obtaining more preferable tablet hardness and disintegrability, the content of component (A) in one tablet is preferably 180 mg or less, more preferably 120 mg or less, and even more preferably 90 mg or less, in terms of the anhydrous base.

[0018] From the viewpoint of miniaturization of the solid preparation, the content of component (A) in the solid preparation is preferably 45% by mass or more, more preferably 48% by mass or more, even more preferably 50% by mass or more, still more preferably 60% by mass or more, and even more preferably 65% ​​by mass or more, in terms of the anhydrous base, relative to the entire solid preparation. Also, from the viewpoint of improving the hardness and disintegrability of the solid preparation, the content of component (A) in the solid preparation is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, in terms of the anhydrous base, relative to the entire solid preparation.

[0019] When the solid preparation is a tablet, the proportion of component (A) in the total mass of one tablet is, from the viewpoint of tablet miniaturization, preferably 45% by mass or more, more preferably 48% by mass or more, even more preferably 50% by mass or more, still more preferably 60% by mass or more, and even more preferably 65% ​​by mass or more, calculated on an anhydrous basis. Also, from the viewpoint of improving tablet hardness and disintegrability, the proportion of component (A) in the total mass of one tablet is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, calculated on an anhydrous basis.

[0020] The content of component (A) in the granules is preferably 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, and may be 60 to 90 mg, in terms of the anhydrous amount, as the amount of the component contained in a solid preparation per dosage unit (single dose) for adults, and in this case too, the number of doses is preferably 1 to 3 times a day.

[0021] From the viewpoint of miniaturization of the solid preparation, the content of component (A) in the granules is preferably 50 parts by mass or more, more preferably 60 parts by mass or more, and even more preferably 65 parts by mass or more, in terms of anhydrous basis, per 100 parts by mass of the granules. From the viewpoint of improving the hardness and disintegrability of the solid preparation, the content of component (A) in the granules is preferably 90 parts by mass or less, more preferably 80 parts by mass or less, and even more preferably 70 parts by mass or less, in terms of anhydrous basis, per 100 parts by mass of the granules. The content of component (A) in the granules may be, for example, 65% by mass or less, in terms of anhydrous basis, per 100 parts by mass of the granules.

[0022] (Component (B)) Component (B) is anhydrous calcium hydrogen phosphate. Component (B) can be, for example, any of those listed in the Pharmaceutical Additives Dictionary. Examples of commercially available products that can be used as component (B) include anhydrous calcium hydrogen phosphate (heavy) manufactured by Kyowa Chemical Industry Co., Ltd. and anhydrous calcium hydrogen phosphate manufactured by Taihei Chemical Industry Co., Ltd.

[0023] From the viewpoint of improving the hardness of the solid preparation, the content of component (B) in the granules is preferably 0.1 parts by mass or more, more preferably 1 part by mass or more, even more preferably 3 parts by mass or more, and even more preferably 5 parts by mass or more per 100 parts by mass of the granules. From the viewpoint of reducing the size of the solid preparation, the content of component (B) in the granules is preferably 25 parts by mass or less, more preferably 20 parts by mass or less, even more preferably 15 parts by mass or less, and even more preferably 10 parts by mass or less per 100 parts by mass of the granules.

[0024] The mass ratio ((B) / (A)) of the content of component (B) to the content of component (A) (as anhydrous) in the granules is preferably 0.05 or more, more preferably 0.08 or more, and even more preferably 0.1 or more, from the viewpoint of improving the hardness of the solid preparation. Furthermore, from the viewpoint of reducing the size of the solid preparation, the mass ratio ((B) / (A)) is preferably 0.4 or less, more preferably 0.3 or less, and even more preferably 0.25 or less.

[0025] (Component (C)) Component (C) is silicon dioxide. From the viewpoint of improving the hardness and disintegrability of the solid preparation, component (C) preferably contains at least one of light anhydrous silicic acid and hydrous silicon dioxide, and more preferably contains hydrous silicon dioxide. Here, light anhydrous silicic acid is a known compound described in the 18th Edition of the Japanese Pharmacopoeia. Commercially available examples of light anhydrous silicic acid include the Aerosil series manufactured by Nippon Aerosil Co., Ltd., Adsolider 101 manufactured by Freund Corporation, and the Sylysia series manufactured by Fuji Silysia Chemical Ltd. Hydrous silicon dioxide is a known compound described in the Pharmaceutical Excipients Standards 2018. Commercially available examples of hydrous silicon dioxide include Adsolider 102 manufactured by Freund Corporation, and Sylysia 740 and Sylosphere C-1510 manufactured by Fuji Silysia Chemical Ltd.

[0026] From the viewpoint of improving the storage stability of the solid preparation, the specific surface area of ​​the component (C) is, for example, 1.5 × 10 2 m 2 / g or more, preferably 3.0 × 10 2 m 2 / g or more, more preferably 5.0 × 10 2 m 2 From the viewpoint of miniaturization of solid preparations, the specific surface area of ​​component (C) is preferably 1.0 × 10 3 m 2 / g or less, more preferably 8.5 × 10 2 m 2 / g or less, more preferably 6.5 × 10 2 m 2The specific surface area of ​​component (C) is specifically measured by the BET multipoint method (see General Test Method 3.02 "Specific Surface Area Measurement Method" of the 18th Edition of the Japanese Pharmacopoeia).

[0027] From the viewpoint of improving the hardness of the solid preparation, the content of component (C) in the granules is preferably 0.1 parts by mass or more, more preferably 1 part by mass or more, even more preferably 2 parts by mass or more, and even more preferably 3 parts by mass or more per 100 parts by mass of the granules. From the viewpoint of miniaturization of the solid preparation, the content of component (C) in the granules is preferably 10 parts by mass or less, more preferably 7 parts by mass or less, and even more preferably 5 parts by mass or less per 100 parts by mass of the granules.

[0028] The mass ratio ((C) / (A)) of the content of component (C) to the content of component (A) (as anhydrous) in the granules is preferably 0.01 or more, more preferably 0.03 or more, and even more preferably 0.05 or more, from the viewpoint of improving the hardness of the solid preparation. Furthermore, from the viewpoint of reducing the size of the solid preparation, the mass ratio ((C) / (A)) is preferably 0.5 or less, more preferably 0.3 or less, and even more preferably 0.2 or less.

[0029] (Component (D)) Component (D) is a disintegrant. In this embodiment, component (D) is contained in at least one of the interior and exterior of the granules. In other words, in this embodiment, component (D) may be contained only in the interior of the granules, only in the exterior of the granules, or both in the interior and exterior of the granules. Component (D) is, for example, one or more compounds selected from the group consisting of sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, and sodium starch glycolate.

[0030] From the viewpoint of obtaining more preferable hardness and disintegrability of the solid preparation, component (D) preferably comprises one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, partially pregelatinized starch, crospovidone, and sodium starch glycolate, more preferably at least one of croscarmellose sodium and low-substituted hydroxypropyl cellulose, and even more preferably croscarmellose sodium and low-substituted hydroxypropyl cellulose.

[0031] The following describes in detail a preferred configuration in the first embodiment, in which component (D) is contained inside granules. From the viewpoint of improving the hardness and disintegrability of the solid preparation, the content of component (D) in the granules is preferably 1 part by mass or more, more preferably 3 parts by mass or more, even more preferably 5 parts by mass or more, and even more preferably 10 parts by mass or more per 100 parts by mass of granules. Furthermore, from the viewpoint of reducing the size of the solid preparation, the content of component (D) in the granules is preferably 30 parts by mass or less, more preferably 25 parts by mass or less, even more preferably 20 parts by mass or less, and even more preferably 15 parts by mass or less per 100 parts by mass of granules.

[0032] The mass ratio ((D) / (A)) of the content of component (D) to the content of component (A) (as anhydrous) in the granules is preferably 0.1 or more, more preferably 0.15 or more, and even more preferably 0.2 or more, from the viewpoint of improving the hardness and disintegrability of the solid preparation. Furthermore, from the viewpoint of miniaturizing the solid preparation, the mass ratio ((D) / (A)) is preferably 0.8 or less, more preferably 0.7 or less, and even more preferably 0.6 or less.

[0033] The mass ratio of the total content of components (B) to (D) to the content of component (A) (as an anhydrate) in the granules (((B)+(C)+(D)) / (A)) is preferably 0.1 or more, more preferably 0.2 or more, and even more preferably 0.3 or more, from the viewpoint of improving the hardness and disintegrability of the solid preparation. Furthermore, from the viewpoint of reducing the size of the solid preparation, the mass ratio (((B)+(C)+(D)) / (A)) is preferably 1.2 or less, more preferably 1.0 or less, and even more preferably 0.9 or less.

[0034] The granules may contain components other than components (A) to (D). For example, the granules may further contain at least one selected from the group consisting of tranexamic acid and its salts (component (E) described below). Furthermore, components other than components (A) to (D) contained in the granules include, for example, excipients and binders (both of which exclude those corresponding to components (B) to (D)). Examples of such excipients include one or more selected from the group consisting of crystalline cellulose, powdered cellulose, potato starch, corn starch, precipitated calcium carbonate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, and fructose. From the viewpoint of improving the production stability of the granules, the excipient preferably includes lactose, crystalline cellulose, or D-mannitol.

[0035] From the viewpoint of improving the hardness of the solid preparation, the content of the other excipients in the granules is preferably 0.1 parts by mass or more, more preferably 1 part by mass or more, and even more preferably 3 parts by mass or more per 100 parts by mass of the granules. From the viewpoint of miniaturization of the solid preparation, the content of the other excipients in the granules is preferably 15 parts by mass or less, more preferably 10 parts by mass or less, even more preferably 8 parts by mass or less, and may be, for example, 5 parts by mass or less per 100 parts by mass of the granules.

[0036] The binder can be selected from the extragranular components described below, and is preferably hydroxypropyl cellulose. From the viewpoint of improving the hardness of the solid preparation, the content of the binder in the granules is preferably 0.1 parts by mass or more, more preferably 1 part by mass or more, and even more preferably 1.2 parts by mass or more per 100 parts by mass of the granules. From the viewpoint of reducing the size of the solid preparation, the content of the binder in the granules is preferably 5 parts by mass or less, more preferably 3 parts by mass or less, and even more preferably 2 parts by mass or less per 100 parts by mass of the granules.

[0037] (Moisture) From the viewpoint of improving the storage stability of the solid preparation, the moisture value (moisture content) of the granules is preferably less than 5% by mass, more preferably 4% by mass or less, even more preferably 3% by mass or less, and even more preferably 2% by mass or less, based on the total mass of the granules. Specifically, the moisture value of the granules is 0% by mass or 0% by mass or more, and may be, for example, 0.01% by mass or 0.05% by mass or more, based on the total mass of the granules. Specifically, the moisture value of the granules can be obtained by measuring the loss on drying (LOD) when heated at 80°C until the mass change is 1 mg / 50 seconds using a halogen moisture meter.

[0038] (Extragranular Component) The solid preparation preferably further comprises an extragranular component. This can impart desired properties to the solid preparation, such as further improving the strength of the solid preparation. Specifically, the extragranular component is a component contained outside the granules (outside the granules), and is, for example, a component (powders) that is added outside the granules during the production process of the solid preparation. The extragranular component also constitutes the extragranular portion of the solid preparation.

[0039] For example, when the solid preparation is a tablet, the extragranular portion is a portion that constitutes the exterior of a granulated granule in the tablet, and may be a portion configured to cover one granulated granule in the tablet, or may be a portion configured to cover multiple granulated granules.Furthermore, it may be a portion that covers at least one granulated granule in the tablet and also constitutes the outer surface of the tablet.

[0040] The extragranular component is one or more components selected from the group consisting of components (A) to (D) and other components. That is, components (A) to (C) are at least contained in the granules, and components (A) to (D) may also be contained extragranularly. Furthermore, extragranular components other than components (A) to (D) need only be contained extragranularly, and may be contained both extragranularly and in the granules.

[0041] From the viewpoint of achieving a more preferable balance between hardness and disintegrability of the solid preparation, the extragranular component preferably contains one or more components selected from the group consisting of phosphate compounds, sugar alcohols and sugars.

[0042] Of these, the phosphate compound preferably includes one or more compounds selected from the group consisting of potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, and sodium hydrogen phosphate, from the viewpoint of achieving a more preferable balance between hardness and disintegrability of the solid preparation. The phosphate compound may be a hydrate.

[0043] From the same viewpoint, the content of the phosphate compound contained as an extragranular component is preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 10% by mass or more, based on the total mass of the solid preparation. From the viewpoint of miniaturization of the solid preparation, the content of the phosphate compound contained as an extragranular component is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, based on the total mass of the solid preparation. Furthermore, the total content of the phosphate compound in the solid preparation can be, for example, 1 to 30% by mass.

[0044] From the viewpoint of achieving a more preferable balance between hardness and disintegrability of the solid preparation, the sugar alcohol preferably contains one or more compounds selected from the group consisting of erythritol, sorbitol, mannitol, maltitol and xylitol.

[0045] From the same viewpoint, the content of the sugar alcohol contained as an extragranular component is preferably 1% by mass or more, more preferably 3% by mass or more, and even more preferably 5% by mass or more, based on the total mass of the solid preparation. From the viewpoint of miniaturization of the solid preparation, the content of the sugar alcohol contained as an extragranular component is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, based on the total mass of the solid preparation. Furthermore, the total content of the sugar alcohol in the solid preparation can be, for example, 1 to 80% by mass, more preferably 1 to 50% by mass, and even more preferably 1 to 30% by mass.

[0046] The sugar preferably includes lactose from the viewpoint of achieving a more preferable balance between hardness and disintegrability of the solid preparation.

[0047] From the same viewpoint, the content of sugar contained as an extragranular component is preferably 1% by mass or more, more preferably 3% by mass or more, and even more preferably 5% by mass or more, based on the total mass of the solid preparation. From the viewpoint of miniaturization of the solid preparation, the content of sugar contained as an extragranular component is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, based on the total mass of the solid preparation. Furthermore, the total content of sugar in the solid preparation can be, for example, 1 to 80% by mass, more preferably 1 to 50% by mass, and even more preferably 1 to 30% by mass.

[0048] From the viewpoint of improving the production stability of the solid preparation, the extragranular component preferably further contains a lubricant as described below, more preferably magnesium stearate.

[0049] From the same viewpoint, the content of the lubricant contained as an extragranular component is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1% by mass or more, based on the total mass of the solid preparation. From the viewpoint of miniaturization of the solid preparation, the content of the lubricant contained as an extragranular component is preferably 5% by mass or less, more preferably 3% by mass or less, and even more preferably 2% by mass or less, based on the total mass of the solid preparation. The total content of the lubricant in the solid preparation can be, for example, 0.1 to 5% by mass.

[0050] From the viewpoint of improving the disintegration property of the solid preparation, the extragranular component preferably further contains a disintegrant. Specific examples of the disintegrant include the components used as component (D) above, and preferably at least one of croscarmellose sodium and low-substituted hydroxypropyl cellulose.

[0051] From the same viewpoint, the content of the disintegrant contained as an extragranular component is preferably 1% by mass or more, more preferably 2% by mass or more, and even more preferably 4% by mass or more, based on the total mass of the solid preparation. From the viewpoint of miniaturization of the solid preparation, the content of the disintegrant contained as an extragranular component is preferably 15% by mass or less, more preferably 10% by mass or less, and even more preferably 7% by mass or less, based on the total mass of the solid preparation. The total content of the disintegrant in the solid preparation can be, for example, 1 to 45% by mass.

[0052] Specifically, the total content of extragranular components in a solid preparation can be the remainder excluding the amount of granules contained in the solid preparation. From the viewpoint of achieving a more favorable balance between hardness and disintegrability of the solid preparation, the total content of extragranular components is preferably 0.1% by mass or more, more preferably 1% by mass or more, and even more preferably 10% by mass or more, based on the total solid preparation. From the viewpoint of miniaturization of the solid preparation, the total content of extragranular components is preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less, based on the total solid preparation.

[0053] The solid preparation may further contain components other than those described above. Such additives include one or more selected from the group consisting of pharmaceutically acceptable carriers, such as excipients, binders, disintegrants (as extragranular components), disintegration aids, lubricants, fluidizing agents, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, refreshing agents, flavors, fragrances, colorants, bases, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. These may be, for example, formulation additives that can be used in conventionally known solid preparations.

[0054] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, anhydrous calcium hydrogen phosphate (as an extragranular component), anhydrous calcium hydrogen phosphate granules (as an extragranular component), calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-crystalline Examples of the sugar additive include one or more selected from the group consisting of cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose (as an extragranular component), dextrin, corn starch, corn starch granules, trehalose, lactose hydrate, lactose granules, sucrose, potato starch, hydroxypropyl starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, and fructose.

[0055] Examples of binders include one or more selected from the group consisting of gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0056] The disintegrant (as an extragranular component) can be selected, for example, from the components used as component (D) above.

[0057] Examples of disintegration aids include one or more selected from the group consisting of carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, and macrogol 4000.

[0058] Examples of lubricants include one or more selected from the group consisting of magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oils, and sodium stearyl fumarate.

[0059] Examples of the fluidizing agent include one or more selected from the group consisting of synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and calcium hydrogen phosphate granules.

[0060] Examples of glossing agents include one or more selected from the group consisting of carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF and beeswax.

[0061] Examples of the foaming agent include one or more selected from the group consisting of dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, and anhydrous citric acid.

[0062] Examples of moisture-proofing agents include one or more selected from the group consisting of ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, and polyvinyl acetal diethylaminoacetate.

[0063] Examples of surfactants include one or more selected from the group consisting of sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0064] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cis hydrochloride, Ingredients: tein, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soybeans Lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42), polyoxypropylene (6) 7) Glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate,Examples of the additives include one or more selected from the group consisting of anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0065] Examples of the emulsifier include one or more selected from the group consisting of glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids.

[0066] Examples of antioxidants include one or more selected from the group consisting of ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium pyrosulfite.

[0067] Examples of the filler include one or more selected from the group consisting of RSS No. 1 crude rubber, starch acrylate 1000, titanium oxide, and calcium hydrogen phosphate.

[0068] Examples of preservatives include one or more selected from the group consisting of benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0069] Examples of sweeteners include one or more selected from the group consisting of aspartame, acesulfame potassium, hydrangea, hydrangea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, and erythritol.

[0070] Examples of flavoring agents include one or more selected from the group consisting of sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0071] The cooling agent may, for example, be one or more selected from the group consisting of fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil and l-menthol.

[0072] Examples of flavorings include one or more selected from the group consisting of orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, 1-menthol, and peppermint oil.

[0073] Examples of the fragrance include one or more selected from the group consisting of fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0074] Examples of colorants include one or more selected from the group consisting of yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, ferric oxide, diazo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0075] Examples of bases include powdered gum arabic, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropyl cellulose, hypromellose, hydroxypropyl cellulose ... Examples of the surfactant include one or more selected from the group consisting of romerose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0076] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, aqueous ethyl cellulose dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hardened oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. Cellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0077] Examples of sugar-coating agents include one or more selected from the group consisting of gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0078] Examples of the plasticizer include one or more selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0079] Examples of dispersing agents include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, powdered agar, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose (as an extragranular component), dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, Examples of the surfactant include one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, and sodium lauryl sulfate.

[0080] Examples of the antifoaming agent include one or more selected from the group consisting of ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, and polysorbate 80.

[0081] Furthermore, the solid preparation may further contain, as necessary, one or more other active ingredients selected from the group consisting of antipyretic analgesics, antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives and sedatives, as long as the effects of the present invention are not impaired. If there are any contraindications for the incorporation of these ingredients, the solid preparation may be formulated after appropriate granulation or the like.

[0082] Examples of antipyretic analgesics include one or more selected from the group consisting of aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, prazolophen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate, and tiaramide hydrochloride.

[0083] Examples of antitussives / expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, noscapine, and noscapine hydrochloride. , trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine ​​hydrochloride.

[0084] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyldisulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, Examples thereof include one or more selected from the group consisting of diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, difeterol hydrochloride, methdilazine hydrochloride, mebhydroline napadisilate, promethazine methylenedisalicylate, and difeterol phosphate.

[0085] Examples of anti-inflammatory agents include one or more selected from the group consisting of glycyrrhizinic acid and its derivatives and salts thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.) and tranexamic acid.

[0086] Examples of anticholinergic agents include one or more selected from the group consisting of scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia extract, Scopolia root, and Scopolia root total alkaloid citrate.

[0087] Examples of vitamins include one or more selected from the group consisting of vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, an equal mixture of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine.

[0088] Examples of xanthine derivatives include one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate. Examples of sedatives include at least one selected from the group consisting of allylisopropylacetylurea and bromvalerylurea.

[0089] (Production Method) In this embodiment, the production method of a solid preparation includes, for example, a step of preparing granules containing components (A) to (C) or granules containing components (A) to (D), and a step of obtaining a solid preparation containing such granules. It also includes a step of blending other components as appropriate. The solid preparation can be formulated according to a conventional method depending on the dosage form.

[0090] For example, when the solid preparation is a tablet, the tablet can be manufactured in accordance with the "Tablets" section of the Japanese Pharmacopoeia's General Provisions for Preparations. More specifically, when components (A) to (D) are contained in granules, a mixture containing components (A) to (D) and, if desired, other components is granulated to obtain granules, and the resulting granules and any appropriate extragranular components are then compressed to produce tablets. When the solid preparation contains extragranular components, for example, granulated granules containing components (A) to (D) and, if desired, other components are produced, and then final components are added to the resulting granulated granules so as to form the outer granules, and the mixture is compressed to produce tablets. Alternatively, the extragranular components may be in the form of granules. For example, granulated granules containing components (A) to (D) may be prepared as first granules, and granulated granules containing other active ingredients (e.g., one or more selected from the group consisting of antipyretics, analgesics, antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergics, other vitamins, xanthine derivatives, and sedatives) may be prepared as second granules. That is, a solid formulation may be constructed such that the first granules containing components (A) to (D) and the second granules containing the other active ingredients are separately prepared, and the components (A) to (D) in the first granules and the other active ingredients in the second granules are not substantially in contact with each other. The other active ingredients may be contained in either the first granules or the second granules, so as to obtain a suitable formulation. Furthermore, when the granules contain at least one component selected from the group consisting of tranexamic acid and salts thereof (component (E) described below) as a component other than components (A) to (D), a solid preparation may be constructed using, for example, first granules containing components (A) to (D) and second granules containing tranexamic acid. Furthermore, when components (A) to (C) are contained in the granules and component (D) is contained extragranularly, a mixture containing components (A) to (C) and, if desired, other components may be granulated to obtain granules, and the obtained granules and any extragranular components (such as component (D)) may then be compressed to produce tablets. The detailed configuration may be the same as that when the first granules containing components (A) to (D) described above are used.

[0091] The solid preparation obtained in this embodiment can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient, ingredient (A), has antipyretic, analgesic, and anti-inflammatory effects, it can be suitably used as an antipyretic analgesic, specifically for the pain relief of headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, fracture pain, sprain pain, trauma pain, etc., and for the fever reduction during chills and fever. It can also be suitably used as a cold treatment agent for the purpose of alleviating various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0092] (Dosage Form) The solid preparation may be in a dosage form described in the General Provisions for Preparations of the 18th Edition of the Japanese Pharmacopoeia, etc., such as a preparation for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), a preparation for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.), etc. The solid preparation is preferably an oral composition.

[0093] In addition, examples of the dosage form of the solid preparation include tablets, capsules, pills, granules, and fine granules. These solid preparations may be coated with sugar coating, film coating, or the like by known methods as needed. The dosage form of the solid preparation is preferably a tablet. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0094] From the viewpoint of increasing the amount of component (A) and improving ease of administration, the diameter of the tablet is, for example, 9 mm or less, preferably 7 mm or less, and also preferably 6 mm or less or 5 mm or less. The diameter of the tablet may also be, for example, 3 mm or more. From the same viewpoint, it is even more preferable that the tablet diameter is within the above range and the content of component (A) in the solid formulation is 45 mass% or more (in terms of anhydrous base) of the entire solid formulation.

[0095] The volume of the tablet is preferably 350 mm from the viewpoint of increasing the amount of component (A) and improving ease of administration. 3 More preferably, it is 300 mm or less. 3Less than 270 mm, more preferably 3 Less than or equal to 200 mm, and even more preferably 3 Below, more preferably 160 mm 3 The volume of the tablet is, for example, 50 mm 3 From the same viewpoint, it is even more preferable that the tablet volume is within the above-mentioned range and the content of component (A) in the solid preparation is 45% by mass or more (on an anhydrous basis) based on the total mass of the solid preparation.

[0096] From the viewpoint of improving strength, the tablet hardness is preferably 40 N or more, more preferably 45 N or more, even more preferably 60 N or more, and even more preferably 70 N or more. From the viewpoint of improving disintegrability, the tablet hardness is preferably 250 N or less, more preferably 200 N or less, even more preferably 180 N or less, and may be 120 N or less. In the solid preparation of this embodiment, even if the tablet hardness is high, the effect on the disintegration time is small, and the balance between hardness and disintegrability is excellent.

[0097] (Packaging) The packaging is a packaging container in which the solid formulation of the present embodiment is accommodated, and for example, the solid formulation of the present embodiment may be accommodated in an airtight packaging. By forming the solid formulation into a packaging, for example, convenience during use of the solid formulation can be improved. Specifically, the packaging of the present embodiment is a pharmaceutical product.

[0098] Regarding the packaging form of solid preparations, the solid preparations may be temporarily packaged in a bottle, a PTP (Press-Through Package), a pouch, a stick package, a SP (Strip Package), or the like, and then stored in an airtight container. Furthermore, these may be pillow-packaged, and these may be stored in a box or the like. Furthermore, from the viewpoint of reducing moisture absorption of the solid preparation, a desiccant or the like may be simultaneously stored in the bottle package, the pillow package, or the like. Examples of materials used for SP packages, PTP packages, stick packages, pillow packages, and the like include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and these resin films with aluminum foil attached. Either a single-layer film or a multi-layer film (e.g., a laminate film) may be used.

[0099] Furthermore, the packaging material for the solid formulation preferably contains a material that is resistant to the effects of moisture. Examples of such packaging include packaging formed from at least one of a moisture-proof material and a gas barrier material. Examples of moisture-proof materials include packaging that combines a press-through pack (PPP) with a polyethylene aluminum pillow. Furthermore, when the solid formulation is a tablet, taking into consideration factors such as suppressing an increase in the moisture content of the tablet, its storage stability, and its stability after opening, press-through pack packaging (Al-Al packaging) with aluminum on both sides may be used as the moisture-proof material. Known gas barrier materials may be used, such as a laminate film having a functional barrier layer, which may also function as the moisture-proof material or may be used in combination with the moisture-proof material.

[0100] Furthermore, the packaging container may be environmentally friendly. For example, environmentally friendly materials such as recycled plastic, biomass plastic, and biodegradable plastic may be used for part or all of the packaging material.

[0101] In the following embodiments, differences from the first embodiment will be mainly described. The configurations described in the first embodiment can also be used appropriately in the following embodiments.

[0102] Second Embodiment (Solid Preparation) A solid preparation according to a second embodiment includes granules containing the following components (A) to (E): (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) anhydrous calcium hydrogen phosphate (C) silicon dioxide (D) a disintegrant (E) at least one selected from the group consisting of tranexamic acid and a salt thereof. Specifically, the solid preparation is a pharmaceutical composition.

[0103] In this embodiment, components (A), (E), and (B) to (D) are combined in granules. In this case, the same effects as in the first embodiment can be obtained. Furthermore, according to this embodiment, even when components (A) and (E) are combined in a solid preparation to achieve a high total concentration, the hardness and disintegration properties of the solid preparation can be made favorable.

[0104] The solid preparation of the second embodiment can have the same basic structure as the first embodiment in which the granules contain component (D), except that the granules further contain component (E). In this embodiment, the content of component (A) is preferably as described below. Differences between the second embodiment and the first embodiment are described in detail below.

[0105] (Component (E)) Component (E) is at least one selected from the group consisting of tranexamic acid and its salts. Component (E) is a known compound and can be produced by known methods, or a commercially available product can be used. Tranexamic acid is listed in the 18th edition of the Japanese Pharmacopoeia.

[0106] From the viewpoint of improving the antipyretic effect, the content of component (E) is preferably 10% by mass or more, more preferably 12.5% ​​by mass or more, based on the total mass of the solid preparation. From the viewpoint of improving the physical properties of the preparation, the content of component (E) is preferably 80% by mass or less, more preferably 65% ​​by mass or less, based on the total mass of the solid preparation. The amount of component (E) blended may be, for example, 100 to 1000 mg, or 120 to 700 mg, in terms of the amount of component contained in the solid preparation per daily dose, and the number of administrations is preferably 1 to 3 times per day.

[0107] In this embodiment, from the viewpoint of miniaturization of the solid preparation, the total content of component (A) (as the anhydride) and component (E) in the solid preparation is preferably 45% by mass or more, more preferably 48% by mass or more, even more preferably 50% by mass or more, still more preferably 60% by mass or more, and even more preferably 65% ​​by mass or more, based on the total solid preparation. Furthermore, from the viewpoint of improving the hardness and disintegrability of the solid preparation in this embodiment, the total content of component (A) (as the anhydride) and component (E) in the solid preparation is preferably 90% by mass or less, more preferably 80% by mass or less, based on the total solid preparation.

[0108] In this embodiment, when the solid preparation is a tablet, the total proportion of component (A) (as the anhydride) and component (E) relative to the total mass of one tablet is, from the viewpoint of tablet miniaturization, preferably 45% by mass or more, more preferably 48% by mass or more, even more preferably 50% by mass or more, still more preferably 60% by mass or more, and even more preferably 65% ​​by mass or more. Furthermore, in this embodiment, from the viewpoint of obtaining more preferable tablet hardness and disintegrability, the total proportion of component (A) (as the anhydride) and component (E) relative to the total mass of one tablet is preferably 90% by mass or less, more preferably 80% by mass or less.

[0109] In this embodiment, the content of component (A) in the solid formulation is preferably 15% by mass or more, more preferably 20% by mass or more, in terms of anhydrous base, based on the total mass of the solid formulation, from the viewpoint of miniaturization of the solid formulation. Also, from the viewpoint of improving the hardness and disintegrability of the solid formulation, the content of component (A) in the solid formulation is preferably 80% by mass or less, more preferably 50% by mass or less, and even more preferably 30% by mass or less, in terms of anhydrous base, based on the total mass of the solid formulation.

[0110] The mass ratio ((E) / (A)) of the content of component (E) to the content of component (A) (as anhydrous form) in the solid preparation is, for example, 0.1 or more and 10 or less, preferably 0.5 or more and 10 or less, more preferably 1 or more and 10 or less, and even more preferably 1 or more and 5 or less. This enables the solid preparation to have an improved balance between storage stability and other efficacy such as antipyretic effect, in addition to the hardness and disintegrability. Furthermore, the mass ratio of the content of any one of components (B) to (D) to the content of component (A) can be, for example, within the range described in the first embodiment.

[0111] The mass ratio (((B)+(C)+(D)) / ((A)+(E))) of the total content of components (B) to (D) to the total content of component (A) (as an anhydride) and component (E) in the granules is preferably 0.1 or more, more preferably 0.13 or more, and even more preferably 0.17 or more, from the viewpoint of improving the hardness and disintegrability of the solid preparation. Furthermore, from the viewpoint of reducing the size of the solid preparation, the mass ratio (((B)+(C)+(D)) / ((A)+(E))) is preferably 0.5 or less, more preferably 0.4 or less, and even more preferably 0.3 or less.

[0112] <Third Embodiment> (Solid Preparation) A solid preparation according to a third embodiment comprises granules containing the following components (A) to (C) and component (E), and also contains component (D) outside the granules: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) anhydrous calcium hydrogen phosphate (C) silicon dioxide (D) a disintegrant (E) at least one selected from the group consisting of tranexamic acid and a salt thereof. Specifically, the solid preparation is a pharmaceutical composition.

[0113] This embodiment can have the same configuration as the second embodiment, except that the disintegrant (D) is not contained inside the granules but is contained outside the granules.

[0114] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various other configurations can also be adopted.

[0115] The present embodiment will be specifically described below with reference to examples, but the present embodiment is not limited to these examples. Note that % in the following tables means % by mass.

[0116] Test Example 1: Production and evaluation of solid preparations Solid preparations were produced according to the procedure described below, and the hardness and disintegration time were measured according to the following procedures. In some cases, the moisture content of the granules was measured by the following method.

[0117] (Hardness Test) Tablet hardness was measured using a tablet hardness tester (Tablet Tester 8M, manufactured by DR. SCHLEUNIGER). Tablets with a hardness of 40 N or more were considered to pass.

[0118] (Disintegration test) Measurement was carried out using a disintegration tester (NT-2HSF, manufactured by Toyama Sangyo Co., Ltd.) according to the disintegration test method described in the 17th edition of the Japanese Pharmacopoeia. Tablets with a disintegration time of 9 minutes or less were rated as passing.

[0119] (Measurement of moisture content) The moisture content was determined by measuring the loss on drying (LOD, %) of the obtained tablet. Specifically, using a halogen moisture meter (Mettler Toledo, HX204), the tablet was heated at 80°C until the mass fluctuation reached 1 mg / 50 seconds, and the loss on drying was measured as the moisture value.

[0120] (Example 1) The granule raw materials listed in Table 1 were charged into a high-speed agitating granulator (FM-VG-25, manufactured by Powrex Corporation), and purified water was added to granulate, yielding Granule 1. Granule 1 and the subsequent powder raw materials listed in Table 1 were mixed, and tableted using the tableting punch diameter φ (mm), curvature radius R (mm), and punching pressure conditions listed in Table 1, yielding round tablets with a diameter of 7 mm. (Comparative Example 1) Granule 2 was obtained in the same manner as in Example 1, except that the blend of the granule raw materials in Example 1 was as listed in Table 1. Granule 2 and the subsequent powder raw materials listed in Table 1 were mixed, and tablets were obtained in the same manner as in Example 1.

[0121]

[0122] Examples 2 to 16 Tablets of each example were obtained in the same manner as in Example 1, except that the blending of granule 1 and the final component was as shown in Tables 2 to 4.

[0123]

[0124]

[0125]

[0126] Details of the ingredients listed in Tables 1 to 6 are as follows: Loxoprofen sodium hydrate: manufactured by KOLON LIFE SCIENCE, INC. Lactose: manufactured by DFE Pharma Co., Ltd. Low-substituted hydroxypropyl cellulose: L-HPC LH-21, manufactured by Shin-Etsu Chemical Co., Ltd. Croscarmellose sodium: Ac-di-sol SD-711, manufactured by DUPONT DE NEMOURS, INC. Anhydrous calcium hydrogen phosphate: manufactured by Taihei Chemical Industry Co., Ltd. Hydrous silicon dioxide: Sylosphere C-1510, manufactured by Fuji Silysia Chemical Ltd., specific surface area 520 m 2 / g Magnesium stearate: manufactured by Taihei Chemical Industry Co., Ltd. Potassium dihydrogen phosphate: manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., crushed product Sodium dihydrogen phosphate: manufactured by Taihei Chemical Industry Co., Ltd., crushed product Calcium hydrogen phosphate hydrate: manufactured by Taihei Chemical Industry Co., Ltd. Sodium hydrogen phosphate hydrate: manufactured by Taihei Chemical Industry Co., Ltd. Direct compression mannitol: Granutol R, manufactured by Freund Corporation Direct compression lactose: Dilactose, manufactured by Freund Corporation Direct compression erythritol: manufactured by Microfoods Japan Co., Ltd. Sorbitol: Sorbitol SP, manufactured by Bussan Food Science Co., Ltd. Maltitol powder 1: Amalty MR-20, manufactured by Mitsubishi Corporation Life Sciences (particle size: D50 approximately 500 μm) Maltitol powder 2: Amalty MR-50, manufactured by Mitsubishi Corporation Life Sciences (particle size: D50 approximately 145 μm)

[0127] As can be seen from Tables 1 to 3, in each Example, tablets containing a high concentration of component (A) and having excellent hardness and disintegrability were obtained. Furthermore, as can be seen from Table 4, in Examples 14 to 16, even when the particle size of the maltitol powder was different from that used in the Examples listed in Table 3, tablets containing a high concentration of component (A) and having excellent hardness and disintegrability were obtained.

[0128] (Example 17) The granule raw materials shown in Table 5 were granulated with an appropriate amount of purified water using a pestle and mortar to obtain granules. The granules and the powder raw materials shown in Table 5 were mixed and compressed using a tableting punch with a diameter φ (mm), a curvature radius R (mm), and a compression force as shown in Table 5 to obtain round tablets with a diameter of 9 mm.

[0129]

[0130] Among the components listed in Table 5, details of the components other than those mentioned above are as follows: Tranexamic acid: manufactured by Kyowa Pharma Chemical Co., Ltd. Hydroxypropyl cellulose: HPC-SL, manufactured by Nippon Soda Co., Ltd. Details of the other components listed in Table 5 are the same as the components used in Tables 1 to 4.

[0131] As can be seen from Table 5, in Example 17, tablets containing a high concentration of component (A) and component (E) combined and having excellent hardness and disintegrability were obtained.

[0132] (Comparative Example 2) Granules 4 were obtained in the same manner as in Example 1, except that the blending of the granule raw materials was changed to the contents shown in Table 6. Granules 4 and the powder raw materials shown in Table 6 were mixed, and tablets were obtained in the same manner as in Example 1.

[0133]

[0134] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

[0135] In the present invention, the solid preparation is excellent in storage stability and therefore extremely useful in terms of quality. The solid preparation is suitably used as an antipyretic analgesic, specifically for relieving pain such as headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, and pain from trauma, and for reducing fever during chills and fever, and is also suitably used as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0136] This application claims priority based on Japanese Patent Application No. 2023-196225, filed November 17, 2023, the disclosure of which is incorporated herein in its entirety by reference.

Claims

1. A solid preparation comprising granules containing the following components (A) to (C), and the following component (D) being contained either inside or outside the granules: (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) anhydrous calcium hydrogen phosphate (C) silicon dioxide (D) a disintegrant 2. The solid dosage form of claim 1, further comprising an extragranular component.

3. The solid formulation according to claim 2, wherein the extragranular component comprises one or more members selected from the group consisting of phosphate compounds, sugar alcohols and sugars.

4. The solid formulation according to claim 3, wherein the sugar alcohol comprises one or more compounds selected from the group consisting of erythritol, sorbitol, mannitol, maltitol and xylitol.

5. The solid formulation according to claim 3 or 4, wherein the phosphate compound comprises one or more compounds selected from the group consisting of potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate and sodium hydrogen phosphate.

6. A solid formulation according to any one of claims 1 to 5, which is a tablet having a diameter of 7 mm or less.

7. The solid formulation according to claim 6, wherein the content of said component (A) in said solid formulation is 45% by mass or more based on the total mass of said solid formulation.

8. Volume: 350mm 3 8. The solid formulation according to claim 1 , which is a tablet:

9. The solid formulation according to claim 8, wherein the content of said component (A) in said solid formulation is 45% by mass or more based on the total mass of said solid formulation.

10. A solid preparation according to any one of claims 1 to 9, which is a tablet and has a hardness of 40 N or more.

11. The solid preparation according to any one of claims 1 to 10, which is in the form of a tablet and contains 30 mg or more of said component (A) per tablet.

12. A solid formulation according to any one of claims 1 to 11, which is a tablet and the proportion of said component (A) in the total mass of one tablet is 45 mass% or more.

13. A solid formulation according to any one of claims 1 to 12, wherein the component (D) comprises one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, partially pregelatinized starch, crospovidone, and sodium starch glycolate.

14. A solid formulation according to any one of claims 1 to 13, wherein the granules further contain component (E): at least one selected from the group consisting of tranexamic acid and salts thereof.

15. A package comprising a solid preparation according to any one of claims 1 to 14 housed in a packaging container.

Images