Solid pharmaceutical preparation and pharmaceutical product

Abstract

A solid pharmaceutical preparation according to the present invention comprises: (A) at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; (B) at least one substance selected from the group consisting of tranexamic acid and salts thereof; and (C) at least substance selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeine, said solid pharmaceutical preparation being in the form of a tablet or pill, wherein at the 15-minute point in an elution test, the elution rate of the component (A) is not less than 60%.

Description

Solid Dosage Forms and Pharmaceuticals

[0001] The present invention relates to a solid formulation and a pharmaceutical product.

[0002] Currently, preparations containing multiple medicinal ingredients are widely used for general cold medicines, antipyretics, analgesics, etc. For example, general cold medicines are known to contain many ingredients, such as antipyretics, analgesics, antitussives, expectorants, and rhinitis medications. These drugs are widely sold as over-the-counter medicines, and therefore must be highly stable as formulations from the standpoints of efficacy and safety.

[0003] Loxoprofen sodium or its hydrate is widely used clinically as a nonsteroidal antipyretic analgesic, while tranexamic acid is used as an active ingredient in cold medicines and other medicines as an anti-inflammatory agent.

[0004] The combined use of loxoprofen sodium or a hydrate thereof with tranexamic acid and a pharmaceutical composition combining them have already been reported (see Patent Document 1). This document describes that by further containing magnesium oxide, a solid preparation having mutually contradictory properties, namely high hardness and good disintegrability, can be obtained.

[0005] JP 2014-162743 A

[0006] However, as a result of investigations by the present inventors, it was found that there is room for improvement in terms of the dissolution of loxoprofen in tablets produced under the compression conditions of Patent Document 1.

[0007] As a result of further investigation, the present inventors have found that in a solid preparation comprising component (A) at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof, component (B) at least one selected from the group consisting of tranexamic acid and its salts, and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol and caffeines, by appropriately lowering the pressure in the preparation extrusion process, the dissolution of loxoprofen in the shaped solid preparation can be improved, leading to the completion of the present invention.

[0008] According to one aspect of the present invention, the following solid formulations and pharmaceuticals are provided. 1. A solid formulation containing the following components (A), (B), and (C): (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; (B) at least one selected from the group consisting of tranexamic acid and salts thereof; and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeines. The solid formulation is in the form of a tablet or pill, and the dissolution rate of component (A) at 15 minutes in a dissolution test is 60% or more. 2. The solid formulation according to 1., wherein the standard deviation of the dissolution rate of component (A) at 15 minutes in the dissolution test is 11.0% or less. 3. The solid formulation according to 1. or 2., wherein the dissolution rate of component (A) at 30 minutes in a dissolution test is 90% or more. 4. 1. to 3. 5. The solid preparation according to any one of 1. to 4., wherein the content of the component (A) contained in the solid preparation is C Ａ , the content of the component (B) is C Ｂ , the content of the component (C) is C Ｃ When this is done, C Ｃ / (C Ａ +C Ｂ +C Ｃ 6. A solid formulation, wherein the value of (a) is 0.02 or more and 0.95 or less. 6. A pharmaceutical product, comprising the solid formulation according to any one of 1. to 5.

[0009] According to the present invention, there are provided a solid preparation having excellent loxoprofen dissolution properties and a pharmaceutical product using the same.

[0010] The solid preparation of this embodiment will be described.

[0011] (Solid Preparation) The solid preparation of this embodiment contains the following components (A), (B), and (C): (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; (B) at least one selected from the group consisting of tranexamic acid and salts thereof; and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeines. The solid preparation is in the form of a tablet or pill, and the dissolution rate of component (A) at 15 minutes in a dissolution test is 60% or more.

[0012] According to the findings of the present inventors, it has been found that when the external pressure applied during the extrusion of a solid preparation is set high, the release of loxoprofen from the solid preparation is delayed. Although the detailed mechanism is unclear, it is presumed that when the external pressure applied during the extrusion of a solid preparation is excessively high, the components contained in the preparation aggregate, making it difficult for them to be released to the outside.

[0013] Based on these findings, the present inventors have conducted extensive research and found that the dissolution of loxoprofen in solid dosage forms can be improved by appropriately reducing the pressure applied in the extrusion process that imparts a shape to the dosage form, such as the compression pressure applied in the tablet compression process. It has been found that the level of pressure applied in the extrusion process can be stably evaluated by using the initial dissolution rate of component (A), i.e., the dissolution rate of component (A) at 15 minutes in a dissolution test, as an index. Therefore, by setting the initial dissolution rate of component (A) to the above-mentioned upper limit or higher, a solid dosage form can be formed under appropriately low pressure conditions, thereby improving the dissolution rate of loxoprofen.

[0014] In this embodiment, it is possible to control the dissolution rate of component (A) at 15 minutes in the above dissolution test by, for example, appropriately selecting the type and amount of each component contained in the solid formulation, the preparation method of the solid formulation, etc. Among these, for example, appropriately lowering the external pressure applied during the shaping of the solid formulation is an example of a factor for setting the dissolution rate of component (A) at 15 minutes in the above dissolution test within a desired range.

[0015] Here, the dissolution rates of component (A) at 15 minutes and 30 minutes in the dissolution test are referred to as the "15-minute dissolution rate" and "30-minute dissolution rate," respectively. The lower limit of the 15-minute dissolution rate is 60% or more, preferably 62% or more, and more preferably 65% ​​or more. On the other hand, the upper limit of the 15-minute dissolution rate is not particularly limited, but may be 95% or less.

[0016] The upper limit of the standard deviation of the dissolution rate at 15 minutes is, for example, 11.0% or less, preferably 7.0% or less, and more preferably 6.0% or less. This allows the active ingredient in the formulation to stably exert its medicinal effect. On the other hand, the lower limit of the standard deviation of the dissolution rate at 15 minutes is not particularly limited, but may be 0% or more. In measuring the standard deviation of the dissolution rate as described above, any two or more solid preparations contained in the same package can be used as samples. The number of samples to be measured is not particularly limited, but may be, for example, three or more.

[0017] The lower limit of the dissolution rate after 30 minutes is 90% or more, preferably 95% or more, and more preferably 96% or more, thereby further improving the dissolution of loxoprofen. On the other hand, the upper limit of the dissolution rate after 30 minutes is not particularly limited, but may be 100% or less.

[0018] The lower limit of the hardness of the solid preparation is, for example, 40 N or more, preferably 45 N or more, and more preferably 50 N or more. This can prevent damage to the appearance of the preparation due to cracks or chips that occur during production or transportation. On the other hand, the upper limit of the hardness of the solid preparation is not particularly limited, but may be 200 N or less.

[0019] Specific examples of the form of the solid preparation include tablets and pills described in the 18th edition of the Japanese Pharmacopoeia. The "solid preparation" of the present invention is preferably a tablet.

[0020] The above-mentioned tablets may be coated with a water-soluble polymer or sugar. That is, film-coated tablets, sugar-coated tablets, etc. are preferred. Furthermore, the above-mentioned tablets may be multilayer tablets formed by compressing two or more layers of powders or granules with different compositions.

[0021] Furthermore, since the solid preparation of this embodiment has an excellent antipyretic effect, it is suitable for use, for example, as a cold medicine such as a general cold medicine or an antipyretic analgesic. For example, by adding various ingredients, it can be administered to patients suffering from various cold symptoms, particularly fever, chills, headache, sore throat, runny nose, nasal congestion, cough, phlegm, joint pain, muscle pain, sneezing, etc., to alleviate these symptoms. From the viewpoint of ease of ingestion, the solid preparation can be used, for example, as an oral solid preparation.

[0022] (Method for Producing a Solid Preparation) An example of a method for producing a solid preparation of the present embodiment includes a wet granulation step of adding water to raw ingredients including component (A), component (B), and component (C), mixing them, and granulating them, and a drying step of drying the granules obtained after the wet granulation step.

[0023] In the wet granulation step, it is preferable to carry out one granulation process selected from the group consisting of fluidized bed granulation, extrusion granulation, and agitation granulation, but the granulation process is not limited to this, and any known method may be used.

[0024] The drying step is not particularly limited, but may be performed, for example, at a heating temperature of 30 to 100°C, preferably 60 to 90°C. The heating time may be, for example, 0.01 to 24 hours, preferably 0.1 to 6 hours. The environmental conditions during the drying step may be, for example, atmospheric pressure.

[0025] Furthermore, if necessary, other medicinal ingredients may be blended with the raw ingredients during the wet granulation process according to conventional methods, provided that the blending does not affect the present invention, and further additives may be added if necessary. For example, when the solid formulation is a tablet, components (A), (B), (C), and other appropriate components are mixed and wet granulated, and then the granules are dried. The resulting granules are then added with the final component to form the outer granules, followed by tableting. That is, tablets can be produced by, for example, the steps of producing granulated granules (at least one granulated granule) containing components (A), (B), (C), and other appropriate components; and then mixing the granulated granules with desired additives (final component) and tableting to produce tablets. The components to be placed in the outer granules may optionally be in the form of granules. The upper limit of the tableting pressure can be set, for example, to 9 kN or less, preferably 8 kN or less, and more preferably 7 kN or less. On the other hand, the lower limit of the hitting pressure during tableting is not particularly limited, but may be 3 kN or more.

[0026] The final component (external part of granulated granules) is a part that constitutes the exterior of the granulated granules in a tablet, and may be, for example, a part that is configured to cover one granulated granule in a tablet, or may be a part that is configured to cover multiple granulated granules. Also, it may be a part that covers at least one granulated granule in a tablet and also constitutes the outer surface of the tablet.

[0027] In one embodiment of the present invention, the solid preparation may be used as a material (intermediate material) composed of components (A), (B), and (C), or may be produced by producing a solid preparation (material / intermediate material) composed of components (A), (B), and (C) and further containing components other than components (A), (B), and (C). That is, the solid preparation of the present invention may contain a solid preparation composed of components (A), (B), and (C) as an intermediate material and be used in the form of a pill or tablet. In other words, the pharmaceutical product of one embodiment of the present invention may be in the form of a pill or tablet containing the solid preparation of the present invention.

[0028] As a method for storing a solid preparation, it is preferable to store the prepared solid preparation in a sealed state in a storage container such as a glass bottle, a PTP, etc. As severe storage conditions, an external environmental temperature of 30°C or higher and / or an external environmental humidity of 60% RH or higher may be adopted.

[0029] Each component contained in the solid preparation will be described in detail below.

[0030] <Component (A)> Component (A) contains at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. The at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof contains one or more selected from the group consisting of loxoprofen, loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 18th Edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0031] The amount of component (A) contained in the solid preparation is not limited, but is 1 to 80 parts by mass, preferably 2 to 50 parts by mass, more preferably 5 to 30 parts by mass, and may be 7 to 20 parts by mass per 100 parts by mass of the solid preparation.

[0032] <Component (B)> Component (B) contains at least one selected from the group consisting of tranexamic acid and its salts. Component (B) 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.

[0033] The content of component (B) is not limited, but is preferably 10% by mass or more, more preferably 12.5% ​​by mass or more, based on 100% by mass of the solid preparation, from the viewpoint of improving the antipyretic effect. Also, the content of component (B) is not limited, but is preferably 50% by mass or less, more preferably 40% by mass or less, based on 100% by mass of the solid preparation, from the viewpoint of improving the physical properties of the preparation.

[0034] Measurement is performed at 80°C, and the loss on drying (% by mass) of the solid preparation at the point when the mass loss per 50 seconds becomes less than 1 mg is taken as the water content. The water content of the solid preparation is, for example, 2.5% by mass or less, preferably 1.5% by mass or less, and more preferably 1.0% by mass or less. This allows the reduction in the content ratio of component (A) in the solid preparation to be suppressed even after storage under harsh storage conditions.

[0035] <Component (C)> Component (C) contains at least one member selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeines.

[0036] The content of component (A) contained in the solid preparation is C Ａ , the content of component (B) is C Ｂ , the content of component (C) is C Ｃ In this case, C Ｃ / (C Ａ +C Ｂ +C Ｃ ) may be, for example, 0.02 or more and 0.95 or less, 0.2 or more and 0.9 or less, 0.25 or more and 0.8 or less, preferably 0.26 or more and 0.7 or less, more preferably 0.27 or more and 0.65 or less. By making it equal to or more than the above lower limit, dissolution property can be improved. By making it equal to or less than the above upper limit, storage stability can be improved.

[0037] The magnesium oxide used may be one listed in the 18th edition of the Japanese Pharmacopoeia, and is readily available. Commercially available magnesium oxide is not limited to, but may include, for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd. and magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd.

[0038] The content of magnesium oxide in the solid preparation may be 0 to 80% by mass, or 0.1 to 70% by mass, and preferably 1 to 30% by mass, based on the mass of the entire solid preparation.

[0039] Glycine is listed in the 18th edition of the Japanese Pharmacopoeia, and commercially available products are readily available. Commercially available glycine may be used after being appropriately pulverized. Examples include glycine (Yuko Gosei Yakuhin Kogyo Co., Ltd.), glycine "for manufacturing only" (Fujifilm Wako Pure Chemical Industries, Ltd.), glycine (Ajinomoto Healthy Supply Co., Ltd.), glycine (crystals) (Merck Co., Ltd.), and glycine (granules) (Merck Co., Ltd.). The amount of glycine contained in the solid formulation is not limited, but is 0.01 to 90 parts by mass, preferably 0.05 to 80 parts by mass, and more preferably 0.1 to 70 parts by mass per 100 parts by mass of the solid formulation.

[0040] Erythritol is readily available on the market. For example, erythritol (Butsusan Food Science Co., Ltd.) can be mentioned. The amount of erythritol contained in the solid preparation is not limited, but may be 0.1 to 95 parts by mass, 0.5 to 90 parts by mass, or 1 to 80 parts by mass, more preferably 10 to 75 parts by mass, and particularly preferably 20 to 70 parts by mass, per 100 parts by mass of the solid preparation.

[0041] The caffeine compound is one or more selected from the group consisting of anhydrous caffeine, caffeine hydrate, and sodium caffeine benzoate, which are listed in the 18th edition of the Japanese Pharmacopoeia.

[0042] The amount of caffeines contained in the solid preparation is not limited, but is 1 to 80 parts by mass, preferably 2 to 50 parts by mass, and more preferably 5 to 30 parts by mass per 100 parts by mass of the solid preparation.

[0043] In this embodiment, the solid preparation may further contain components other than components (A), (B), and (C). The solid preparation of the present invention may be used as a material (intermediate material) composed of components (A), (B), and (C), or may further contain components other than components (A), (B), and (C). Examples of such components are listed below.

[0044] <Antacid> In the present embodiment, the solid preparation may preferably further contain an antacid from the viewpoint of suppressing damage to the gastric mucosal membrane.

[0045] Examples of antacids include alkaline earth metal and / or earth metal basic inorganic compounds such as magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, a co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, a co-precipitation product of aluminum hydroxide and sodium hydrogencarbonate, a mixed dried gel of aluminum hydroxide and magnesium carbonate, a co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, Examples of suitable inorganic salts include inorganic salts of metals selected from magnesium, aluminum, and calcium, such as bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Examples of alkaline metal basic inorganic compounds include inorganic salts of metals selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, and potassium carbonate. Other examples include borax, and one or more of these may be blended. Among these, one or more selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, and precipitated calcium carbonate are preferred.

[0046] When magnesium aluminometasilicate is used, those listed in the 18th Edition of the Japanese Pharmacopoeia may be used and are readily available. Commercially available magnesium aluminometasilicate is not limited, but an example is Neusilin manufactured by Fuji Chemical Industry Co., Ltd. The content of magnesium aluminometasilicate in the solid formulation may be selected taking into consideration the disintegration property of the solid formulation, the drug dissolution property, and the function as an antacid, and is not limited, but may be 0 to 80% by mass, or more than 0 to 80% by mass, or 0.1 to 70% by mass, and preferably 1 to 50% by mass, based on the mass of the entire solid formulation.

[0047] <Herbal medicines (herbal medicine components)> The solid formulation of the present invention may contain herbal medicines. The herbal medicines used in the present invention are not particularly limited, but include, for example, ephedra, nandina, scutellaria, onji, licorice, platycodon, chinese laurel, chinese laurel, scutellaria, saxifrage, saxifrage (garlic root), senega, fritillary, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yutan), shang rhizome, ginger, atractylodes, clove, tangerine peel, atractylodes rhizome, scutellaria, ginseng, carrot, Mallotus japonicus, echinacea, corydalis, Scutellaria root, scutellaria, and valerian. It is possible to compound one or more ingredients selected from herbal medicines such as ginseng, kalonin, apricot kernel, lycium berry, lycium bark, kaempferia chinensis, cassia berry, geranium herb, magnolia berry, Chinese laurel, Chinese pepper, schisandra chinensis, zanthoxylum chinense, rhubarb, peony root, musk, rhododendron bark, Cnidium officinalis, Zenko, Swertia japonica, Magnolia officinalis, Perilla frutescens, tang, angelica acutiloba, ipecac, rhododendron bark, Pinellia chinensis, Angelica acutiloba, ipecac, Pinellia chinensis, Angelica acutiloba, rhododendron bark, rhubarb, Poria cocos, Peony root, Boehme rhizome, Rokujo, and Bowie, and extracts thereof (extracts, tinctures, dried extracts, etc.). The solid preparation of the present invention preferably contains at least one of licorice extract, peony root extract, and valerian extract. The content ratio of the herbal medicines in the solid preparation of the present invention is not particularly limited, but for example, when each herbal medicine is an extract, it is 1 to 80 mass %, alternatively 1 to 50 mass %, alternatively 1 to 40 mass %, or alternatively 1 to 30 mass %, based on the mass of the entire solid preparation.

[0048] The herbal medicines used in the present invention, such as licorice, peony, and valerian, have been used medicinally since ancient times as single ingredients or as traditional Chinese medicines. Herbal powders or extracts obtained according to conventional methods can be used as they are. The herbal powders or extracts can be in the form of ordinary commercially available products or processed products thereof. For example, dried, chopped, processed products can be further pulverized into a fine powder (fine powder) for use as a dry powder. The form of the extract from the herbal medicine is not particularly limited, and any form, such as a dried extract, extract powder, soft extract, liquid extract, or tincture containing ethanol or ethanol and water, can be used. Preferred herbal medicines include extracts that offer a high degree of formulation flexibility, such as soft extracts and dried extract powders.

[0049] The extract can be obtained by conventional methods, for example, by extracting the active ingredients having antibacterial activity from the herbal medicine using an extraction solvent. The extraction solvent is often water, a hydrophilic solvent, or a mixture thereof. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or as a mixture of two or more of them. Licorice may be used as a conventional anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive expectorant, gastrointestinal medicine, anthelmintic, internal medicine for rhinitis, throat freshener, stomachic freshener, vitamin-containing health supplement, sweetener, flavoring agent, colorant, flavoring agent, perfume, or excipient.

[0050] When "licorice" is used in the present invention, it is preferable to use those listed in the 18th edition of the Japanese Pharmacopoeia. Licorice other than those mentioned above is also commercially available and therefore easily available. Commercially available licorice includes extracts using water or 30% ethanol aqueous solution as an extraction solvent, and various extracts with different crude drug equivalent ratios are sold, such as licorice extract, dried licorice extract, soft licorice extract, and liquid licorice extract, depending on the type of extract. In addition to these licorice extracts, licorice extracts, licorice extract solutions, etc. may also be used as appropriate and are not particularly limited. When commercially available licorice is used in an oral pharmaceutical composition, it is sufficient to use licorice so that the licorice content in the tablet is appropriate, taking into account, for example, the crude drug equivalent ratio.

[0051] The amount of licorice (licorice or licorice extract) contained in the solid preparation of the present invention is not particularly limited, but the amount of the ingredient contained in a tablet per daily dose, calculated as the amount of the crude drug, is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, and may be 500 mg to 1500 mg, and the number of administrations is 1 to 3 times a day.

[0052] In the solid preparation of the present invention, for example, when a licorice dry extract is used, the content of the licorice dry extract is not particularly limited, but may be 0.1 to 80% by mass, or 1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass, based on the mass of the entire tablet.

[0053] When "valerian" is used in the present invention, the "valerian" can preferably be one listed in the 18th edition of the Japanese Pharmacopoeia. Valerian other than those mentioned above is also commercially available and can be easily obtained. As commercially available valerian, for example, valerian powder or valerian extract (e.g., soft extract, dry extract, etc.) can be used, and is not particularly limited. When commercially available valerian is used in an oral pharmaceutical composition, it is sufficient to use valerian so that the valerian content in the tablet is appropriate, taking into account the crude drug conversion ratio.

[0054] When "valerian (valerian or valerian extract)" is used in the present invention, the content is not particularly limited, but for example, the amount of the ingredient contained in a tablet per daily dose, converted into the amount of the original herbal drug, may be 1 to 6,000 mg, preferably 10 to 2,000 mg, more preferably 20 to 1,440 mg, even more preferably 60 mg to 1,000 mg, or may be 60 to 450 mg, and the number of administrations is 1 to 3 times a day.

[0055] In the solid preparation of the present invention, for example, when valerian extract is used, the content of the valerian extract is not particularly limited, but may be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass, based on the mass of the entire tablet.

[0056] When "peony" is used in the present invention, it is preferable to use one listed in the 18th edition of the Japanese Pharmacopoeia. Peony other than those mentioned above is also commercially available and therefore easily available. Examples of commercially available peony include peony powder and peony extract (including, for example, dried extract and soft extract), and are not particularly limited. When using commercially available peony in an oral pharmaceutical composition, it is sufficient to use peony so that the peony content in the tablet is appropriate, taking into account the crude drug equivalent ratio.

[0057] When "peony (peony or extract thereof)" is used in the present invention, the content is not particularly limited, but is preferably administered in an amount of 100 to 5000 mg, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg per day in terms of the crude drug content of peony, and the number of administrations is 1 to 3 times per day.

[0058] In the solid preparation of the present invention, for example, when a peony dry extract is used, the content of the peony dry extract is not particularly limited, but may be 1 to 50 mass %, preferably 2 to 40 mass %, and more preferably 3 to 20 mass %, based on the mass of the entire tablet.

[0059] The formulation can be prepared using known methods and additives as appropriate. Additives may be added as appropriate within a range that does not impair the effects of the present invention. Examples of additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, flavorings, fragrances, colorants, bases, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. Conventional formulation additives that can be used in known solid formulations can also be used for the above-mentioned purposes. These additives may be used alone or in combination of two or more.

[0060] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, 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 Examples of suitable sugars include pill starch, crystalline 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, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, 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, glucose, fructose, etc. These may be used alone or in combination of two or more.

[0061] The binder may be one or more components 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 (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0062] Examples of disintegrants include carboxymethylethyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, etc. These may be used alone or in combination of two or more.

[0063] Examples of disintegration aids include 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, macrogol 4000, and the like.

[0064] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oil, and sodium stearyl fumarate.

[0065] The fluidizing agent may be one or more components selected from, for example, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, calcium hydrogen phosphate granules, etc.

[0066] The glossing agent may be one or more components selected from, for example, carnauba wax, white beeswax, purified shellac, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, beeswax, etc.

[0067] The foaming agent may be one or more components selected from the group consisting of dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, and the like.

[0068] The moisture-proofing agent may be one or more components 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 sucrose, 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.

[0069] The surfactant may be one or more components selected from, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan 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, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0070] 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, and calcium chloride. Stain, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, 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 gel Ingredients: lecithin, purified soybean 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) poly Polyoxypropylene (67) 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,One or more ingredients selected from anhydrous sodium monohydrogen phosphate, 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, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc. may be blended.

[0071] Examples of emulsifiers include 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.

[0072] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium pyrosulfite.

[0073] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

[0074] Examples of preservatives include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0075] The sweetener may be one or more components selected from, for example, 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 the like.

[0076] The flavoring agent may be one or more ingredients selected from 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, sodium saccharin 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, rose oil, and the like.

[0077] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0078] As the flavoring, for example, one or more components selected from 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, peppermint oil, etc. can be blended.

[0079] Examples of fragrances include 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.

[0080] Examples of colorants that can be blended include one or more components selected from 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.

[0081] Examples of bases include powdered gum arabic, pregelatinized starch, partially pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium 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, hydrous The composition may contain one or more ingredients selected from the group consisting of hydroxypropyl cellulose, hypromellose, 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.

[0082] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous 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, hydroxypropyl methylcellulose 2910-titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydrogenated cellulose. Examples of suitable surfactants include hydroxypropyl methylcellulose 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 S, magnesium aluminometasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0083] Examples of sugar-coating agents that can be blended include one or more components selected from 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, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0084] Examples of the plasticizer that can be blended include one or more components selected from 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.

[0085] Examples of dispersing agents include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, 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, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene The composition may contain one or more ingredients selected from the group consisting of polyethylene 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, sodium lauryl sulfate, and the like.

[0086] The antifoaming agent may be one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc.

[0087] These additives are not limited to those listed above, and one of these may be used alone or in combination of two or more.

[0088] Furthermore, the solid preparation may further contain, as necessary, medicinal ingredients other than the components (A), (B), and (C), such as antipyretic analgesics, antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives, within the range that does not impair the effects of the present invention. If there are any contraindications for the inclusion of these ingredients, the solid preparation may be formulated after appropriate granulation or the like.

[0089] Examples of the antipyretic analgesic include aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, prazolam, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate, and tiaramide hydrochloride, and may contain one or more ingredients selected from these.

[0090] 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, and nosca pine, 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, L-ethylcysteine ​​hydrochloride, and the like.

[0091] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, difenyl pyraline hydrochloride, diphenyl pyraline teoclate ... Examples of such antihistamines include phenhydramine hydrochloride, 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.

[0092] Examples of anti-inflammatory agents include glycyrrhizinic acid and its derivatives, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0093] Examples of anticholinergic agents include 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.

[0094] Examples of vitamins include 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.

[0095] Sedatives include, for example, allylisopropylacetylurea and bromvalerylurea.

[0096] These additives are not limited to those listed above, and one of these may be used alone or in combination of two or more.

[0097] The solid preparation can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient, loxoprofen, its salts, and hydrates thereof, 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 remedy 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).

[0098] (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.).

[0099] Furthermore, examples of the dosage form of the solid preparation include pills and tablets. These solid preparations may be coated with sugar coating, film coating, or the like by known methods, if necessary. The dosage form of the solid preparation is preferably plain tablets, film-coated tablets, or sugar-coated tablets, more preferably plain tablets, film-coated tablets, or sugar-coated tablets.

[0100] (Package) The package is a package in which the solid preparation of the present embodiment is housed in a packaging container. By forming the package, for example, convenience in using the solid preparation can be improved.

[0101] (Packaging Form) The solid formulation may be packaged in a strip package (SP package), a press-through package (PTP package), stick packaging, bottle packaging, pouch packaging, or the like, and then stored in an airtight container. That is, the solid formulation may be housed in an airtight package. These may then be pillow-packaged, or may be stored in a box or the like. In other words, a pharmaceutical product according to one embodiment of the present invention may include the solid formulation according to the above embodiment and a packaging material for packaging the solid formulation. Materials used for the SP package, PTP package, stick packaging, and pillow packaging are not limited, and include, for example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, multi-layer films combining these resin films, and resin films to which aluminum foil is attached.

[0102] The packaging material for solid preparations is preferably packaging made of a material that is less susceptible to moisture (packaging made of at least one of a moisture-proof material and a gas barrier material). For example, a packaging made of a material that is less susceptible to moisture (moisture-proof material) may be press-through packaging (polypropylene) + polyethylene aluminum pillow packaging (a combination of press-through packaging and polyethylene aluminum pillow packaging). Furthermore, in consideration of suppressing an increase in the moisture content of tablets, tablet storage stability, and tablet stability after opening, a press-through packaging (Al-Al packaging) using aluminum on both sides may be used as a packaging made of a material that is less susceptible to moisture (moisture-proof material). If moisture absorption is a concern, a desiccant or the like may be stored simultaneously in the bottle packaging or pillow packaging. Known gas barrier materials may be used, but are not limited to, for example, 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.

[0103] 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.

[0104] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various other configurations may be adopted. Furthermore, the present invention is not limited to the above-described embodiments, and modifications and improvements within the scope of achieving the object of the present invention are included in the present invention.

[0105] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the descriptions of these examples.

[0106] <Production of Solid Preparation> (Example 1) Loxoprofen sodium hydrate (KOLON), tranexamic acid (Kyowa Pharma Chemical Co., Ltd.), magnesium oxide (Kyowa Chemical Industry Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), and carmellose calcium (Gotok Pharmaceutical Co., Ltd.) were weighed, and an appropriate amount of purified water was added. The mixture was kneaded in a mortar and dried at 80°C for 1 hour to obtain granules. The obtained granules were sieved through an 18-mesh sieve, and magnesium stearate (Taihei Chemical Co., Ltd.) was weighed and added as a final powder. The mixture was mixed 100 times in a 10K standard bottle to obtain a mixture of granules and final powder. The resulting mixture was tableted in a hydraulic pump tableting machine (Riken Seiki Co., Ltd.) using a 9.0 mm diameter mortar and a punch with a curvature radius of 10.8 mm and a rounded surface at a tableting pressure of 5 kN to obtain tablets (solid preparations) with a mass of 341.9 mg per tablet. The ingredients and contents (mg) per tablet of the obtained tablets are shown in Table 1.

[0107] Examples 2 to 4 Tablets were obtained in the same manner as in Example 1, except that magnesium oxide (Kyowa Chemical Industry Co., Ltd.) was replaced with glycine (Fujifilm Wako Pure Chemical Industries Co., Ltd.), erythritol (Butsusan Food Science Co., Ltd.), or a combination of crystalline cellulose (Asahi Kasei Corporation) and anhydrous caffeine (Shizuoka Caffeine Industry Co., Ltd.).

[0108] (Comparative Example 1) Except for using crystalline cellulose (manufactured by Asahi Kasei Corporation) instead of magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.) and changing the tableting pressure to 10 kN, tablets were obtained in the same manner as in Example 1. (Comparative Example 2) Except for changing the tableting pressure to 10 kN, tablets were obtained in the same manner as in Example 1.

[0109]

[0110] The obtained tablets were subjected to the following evaluations.

[0111] <Hardness> The hardness (N) of the tablets was measured using a hardness tester (Tablet Tester 8M, manufactured by Dr. Schleuniger Pharmatron). The hardness was the average value of two samples (n=2). The results are shown in Table 1. The hardness of Example 1 was smaller than that of any of Examples 2 to 4, and also smaller than that of Comparative Examples 1 and 2.

[0112] <Disintegration time> The disintegration time (min) of the tablets of Comparative Examples 1 and 2 was measured using a disintegration tester (NT-2HSF, manufactured by Toyama Sangyo Co., Ltd.) in accordance with the "Disintegration Test Method" of the 18th Edition of the Japanese Pharmacopoeia. The disintegration time was the average value of two samples. The results are shown in Table 1.

[0113] <Dissolution Test> The dissolution rate of loxoprofen sodium hydrate in the tablets was measured in accordance with the "Dissolution Test Method" of the Japanese Pharmacopoeia, 18th Edition, by the Japanese Pharmacopoeia Dissolution Test Report 2 (paddle method) using 900 mL of purified water as the test solution at 50 revolutions per minute (50 rpm), and the dissolution rates (%) at 15 minutes and 30 minutes were measured. The average and standard deviation of each dissolution rate were calculated using the measured values ​​for three samples. The results are shown in Table 1. The time (min) at which the dissolution rate reached 90% was also determined as a theoretical value calculated from an approximate formula.

[0114] The solid preparations of Examples 1 to 4 showed superior results in terms of dissolution of loxoprofen (ingredient (A)) compared to Comparative Examples 1 and 2.

[0115] 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.

[0116] 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).

[0117] This application claims priority based on Japanese Patent Application No. 2024-045259, filed March 21, 2024, the disclosure of which is incorporated herein by reference in its entirety.

Claims

1. A solid preparation containing the following ingredients (A), (B), and (C): (A) at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof; (B) at least one selected from the group consisting of tranexamic acid and its salts; and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeines. The solid preparation is in the form of a tablet or pill, and the dissolution rate of ingredient (A) at 15 minutes in a dissolution test is 60% or more.

2. A solid preparation according to claim 1, wherein the standard deviation of the dissolution rate of said component (A) at 15 minutes in said dissolution test is 11.0% or less.

3. A solid preparation according to claim 1 or 2, wherein the dissolution rate of component (A) is 90% or more at 30 minutes in a dissolution test.

4. A solid preparation according to any one of claims 1 to 3, having a hardness of 40N or more.

5. A solid preparation according to any one of claims 1 to 4, wherein the content of the component (A) contained in the solid preparation is C Ａ , the content of the component (B) is C Ｂ , the content of the component (C) is C Ｃ When this is done, C Ｃ / (C Ａ +C Ｂ +C Ｃ ) is 0.02 or more and 0.95 or less.

6. A pharmaceutical product comprising the solid formulation according to any one of claims 1 to 5.

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