Method for producing solid preparation, and tablets

Abstract

A method for producing a solid preparation according to the present invention is for producing a solid preparation which contains (A) at least one substance that is selected from the group consisting of loxoprofen, salts thereof, and hydrates of loxoprofen and the salts, and (B) at least one substance that is selected from the group consisting of tranexamic acid and salts thereof. The method includes a wet granulation step for obtaining granules by supplying water to a starting material powder that contains the components (A) and (B). In the wet granulation step, X is adjusted so as to satisfy 0.20 ≤ Ig ≤ 0.99, wherein X is the addition rate of water to be supplied, PL is the plastic limit water addition rate of the starting material powder, and Ig is the granulation index that is represented by X / PL.

Description

Manufacturing method of solid preparation and tablet

[0001] The present invention relates to a method for producing a solid preparation and a tablet.

[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] A solid preparation containing loxoprofen or a salt thereof, tranexamic acid or a salt thereof, and magnesium oxide has already been reported (see Patent Document 1). This document describes that by incorporating magnesium oxide, a solid preparation having the contradictory properties of 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 has been found that the method for producing a preparation described in Patent Document 1 above leaves room for improvement in terms of the shape retention and dissolution variation of the resulting preparation.

[0007] As a result of further investigation, the present inventors have found that in the wet granulation process of raw material powders containing (A) loxoprofen or a salt thereof and (B) tranexamic acid or a salt thereof, by appropriately controlling the amount of water added to the raw material powders based on a predetermined granulation index, it is possible to obtain a solid preparation that has relatively high hardness and reduces dissolution variation, and therefore has excellent shape retention and ensures stable dissolution, thereby completing the present invention.

[0008] According to one aspect of the present invention, there are provided the following method for producing a solid formulation and a tablet: 1. A method for producing a solid formulation containing the following components (A) and (B): (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and (B) at least one selected from the group consisting of tranexamic acid and a salt thereof, the method comprising a wet granulation step of supplying water to a raw material powder containing the components (A) and (B) to obtain a granule, wherein, in the wet granulation step, X is adjusted so that 0.20≦Ig≦0.99 is satisfied, where X is the addition rate of the water supplied, PL is the plastic limit water addition rate of the raw material powder measured according to the following procedure, and Ig is a granulation index expressed as X / PL. (Procedure for measuring the plastic limit water addition rate (PL)) Using a mixer torque rheometer equipped with a four-blade main blade and two-blade auxiliary blade rotating in opposite directions inside a stirring vessel, 25 g of the raw material powder is placed in the stirring vessel, water is added dropwise at a predetermined addition rate, and the main blade is stirred and mixed at 50 rpm for 45 seconds. The mixture is then stirred for 20 seconds, during which the torque of the stirring blade is measured using a strain gauge. The water addition and torque measurement are repeated under different addition rates, and the relationship between the water addition rate added to the raw material powder and the average torque value (N m) of the stirring blade over 20 seconds is plotted. The water addition rate at which this torque value is maximized is defined as the plastic limit water addition rate (PL). The water addition rate is defined as "mass of water (g) / mass of raw material powder (g)." 2.1. 2. A method for producing a solid preparation according to claim 1, wherein the mass of said component (A) / the mass of said component (B) in the raw material powder is 0.01 or more and 4.0 or less, calculated on an anhydrous basis. 3. A method for producing a solid preparation according to claim 1 or 2, wherein, when D50 is the particle diameter at which the cumulative volume from the small particle side becomes 50% in a volume-based cumulative distribution measured by a laser diffraction scattering method, D50 of at least one of said component (A) and said component (B) contained in the raw material powder is 10 μm or more and 200 μm or less.4. A method for producing a solid formulation according to any one of 1. to 3., wherein the wet granulation step involves carrying out one granulation treatment selected from the group consisting of fluidized bed granulation, extrusion granulation, and high-pressure granulation. 5. A method for producing a solid formulation according to any one of 1. to 4., comprising a drying step of drying the obtained granulated product. 6. A method for producing a solid formulation according to any one of 1. to 5., comprising a step of subjecting the obtained granulated product to one or more treatments selected from the group consisting of crushing, sieving, and classification. 7. A method for producing a solid formulation according to any one of 1. to 6., comprising a step of molding the obtained granulated product into the form of granules, powder, capsules, pills, or tablets. 8. A tablet comprising the following components (A) and (B): (A) at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof; and (B) at least one selected from the group consisting of tranexamic acid and its salts. (1) The tablet has a hardness of 30N or more, and (2) in a dissolution test, the dissolution rate is 50% or more and the standard deviation of the dissolution rate is 3.0 or less at 15 minutes.

[0009] According to the present invention, there is provided a production method for providing a solid preparation and a tablet that are excellent in shape retention and can ensure stable dissolution.

[0010] The method for producing the solid preparation of this embodiment will be described below.

[0011] (Method for Producing a Solid Preparation) The method for producing a solid preparation of this embodiment is a method for producing a solid preparation containing the following components (A) and (B): (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) at least one selected from the group consisting of tranexamic acid and a salt thereof This method for producing a solid preparation includes a wet granulation step of supplying water to a raw material powder containing the components (A) and (B) to obtain a granule, wherein X is the addition rate of water supplied in the wet granulation step, PL is the plastic limit water addition rate of the raw material powder measured according to the procedure below, and Ig is the granulation index expressed by X / PL, and X is adjusted so as to satisfy 0.20≦Ig≦0.99.

[0012] The procedure for measuring the plastic limit water addition rate (PL) of raw powder is as follows. Using a mixer torque rheometer equipped with a four-blade main blade and two-blade auxiliary blade rotating in opposite directions inside a stirring vessel, 25 g of raw powder is placed in the stirring vessel, water is dripped into the stirring vessel at a predetermined addition rate, and the main blade is stirred and mixed at 50 rpm for 45 seconds. The mixture is then stirred for 20 seconds, during which the torque of the stirring blade is measured using a strain gauge. Water dripping and torque measurements are repeated under different addition rates, and the relationship between the water addition rate dripped to the raw powder and the average torque value (N m) of the stirring blade over 20 seconds is plotted. The water addition rate at which this torque value is maximized is defined as the plastic limit water addition rate (PL). The water addition rate is defined as "mass of water (g) / mass of raw powder (g)."

[0013] According to the findings of the present inventors, it has been found that in the wet granulation process of a raw material powder containing component (A) and component (B), by appropriately controlling the amount of water added based on a predetermined granulation index, it is possible to improve the shape retention of a solid preparation and ensure stable dissolution properties.

[0014] The lower limit of the granulation index Ig in the wet granulation step is 0.20 or more, preferably 0.30 or more, more preferably 0.40 or more, and even more preferably 0.55 or more. This can improve the shape retention, such as hardness, of the solid preparation. This can prevent damage to the appearance of the preparation due to cracking or chipping during production or transportation. In addition, the length of the disintegration time can be adjusted as necessary. On the other hand, the upper limit of the granulation index Ig in the wet granulation step is 0.99 or less, preferably 0.90 or less, more preferably 0.80 or less, and even more preferably 0.75 or less. This can reduce the variation in dissolution of the solid preparation.

[0015] In the wet granulation step, the mass of component (A) / mass of component (B) in the raw material powder, calculated on an anhydrous basis, is, for example, 0.01 to 4.0, preferably 0.05 to 3.0, and more preferably 0.1 to 2.0. By adjusting the ratio within such a range, the plastic limit water addition rate (PL) of the raw material powder can be stably controlled.

[0016] In the volume-based cumulative distribution of the raw material powder measured by laser diffraction scattering, the particle diameter at the point where the cumulative volume from the small particle side is 50% is defined as D50. In the wet granulation process, the D50 of at least one of the components (A) and (B) contained in the raw material powder is, for example, 10 μm or more and 200 μm or less, preferably 15 μm or more and 180 μm or less, and more preferably 20 μm or more and 150 μm or less. It is preferable that the D50 of both the component (A) and the component (B) is within the range between the upper limit and the lower limit. By setting the numerical range in this way, the plastic limit water addition rate (PL) of the raw material powder can be stably controlled.

[0017] 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.

[0018] In another embodiment, the method for producing a solid formulation may include a drying step in which the obtained granules are dried. This can prevent a decrease in the content ratio of component (A) in the solid formulation even after storage. Furthermore, since a decrease in the content ratio of component (A) during storage of the solid formulation can be prevented, storage stability can be improved. The drying step is not particularly limited, but may be, for example, 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. In this specification, unless otherwise specified, the symbol "to" indicates that the upper and lower limits are included.

[0019] In another embodiment, the method for producing a solid preparation may, if necessary, include a particle size adjustment step in which the obtained granules are subjected to one or more treatments selected from the group consisting of crushing, sieving, and classification, thereby enabling more stable control of the quality of the final product.

[0020] In another embodiment, the method for producing a solid preparation may include a molding step of molding the obtained granulated product into the form of granules, powder, capsules, pills, or tablets.

[0021] Specific examples of the form of the solid preparation include granules, powders, capsules, tablets, pills, etc., as described in the 18th Edition of the Japanese Pharmacopoeia. The "solid preparation" of the present invention is preferably granules, powders, capsules, or tablets, and more preferably tablets.

[0022] One aspect of the tablet of this embodiment contains the above-mentioned components (A) and (B), and is a tablet that (1) has a hardness of 30 N or more, and (2) has a dissolution rate of 50% or more and a standard deviation of the dissolution rate of 3.0 or less at 15 minutes in a dissolution test. (1) The lower limit of the hardness is 30 N or more, preferably 40 N or more, and more preferably 50 N or more. This prevents damage to the appearance of the formulation due to cracking or chipping during production or transportation. On the other hand, (1) the upper limit of the hardness is not particularly limited, but may be 200 N or less. (2) The lower limit of the dissolution rate at 15 minutes is 50% or more, preferably 55% or more, more preferably 60% or more, and even more preferably 75% or more. In this case, the upper limit of the standard deviation of the dissolution rate at 15 minutes is, for example, 3.0 or less, preferably 2.5 or less, and more preferably 2.0 or less. This allows the active ingredient in the tablet to stably exert its medicinal effect. On the other hand, (2) the upper limit of the dissolution rate at 15 minutes is not particularly limited, but may be 95% or less. (2) 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, any number of tablets contained in the same package can be used as samples. The number of tablets measured is not particularly limited, but may be, for example, 3 or more.

[0023] The above-mentioned granules or tablets may be coated with a water-soluble polymer or sugar. That is, preferred embodiments of the granules and tablets include film-coated granules, film-coated tablets, and sugar-coated tablets. Preferred embodiments of the above-mentioned tablets include multilayer tablets formed by compressing two or more layers of powders or granules with different compositions.

[0024] The solid preparation preferably has a mixed phase in which component (A) and component (B) are in contact with each other. The dispersion state of component (A) and component (B) in the mixed phase is not particularly limited, but they may each be uniformly dispersed. The solid preparation may partially have a separate phase in which component (A) and component (B) are not substantially in contact with each other, but may also have no such separate phase.

[0025] <Component (A)> Component (A) contains at least one compound selected from the group consisting of loxoprofen, its salts, and hydrates thereof. Component (A) is a known compound and can be produced by known methods, or a commercially available product can be used. Loxoprofen salts are listed in the 18th Edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0026] Specific examples of loxoprofen, its salts, and hydrates thereof include loxoprofen, loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. These may be used alone or in combination of two or more. Component (A) preferably contains loxoprofen sodium, and more preferably contains a hydrate salt such as loxoprofen sodium dihydrate.

[0027] 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.

[0028] <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.

[0029] Specific examples of salts of tranexamic acid among component (B) include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; alkanesulfonates having from 1 to 4 carbon atoms such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; acetate, malate, fumarate, succinate, citrate, ascorbate, and tartrate; Examples include organic acid salts such as oxalates and maleates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic amine salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; and salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt. These may be used alone or in combination of two or more.

[0030] 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 physical properties of the preparation. The content of component (B) is not limited, but is preferably 40% by mass or less, more preferably 36% by mass or less, based on 100% by mass of the solid preparation, from the viewpoint of improving the antipyretic effect.

[0031] 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.

[0032] <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.

[0033] Antacids include, for example, alkaline earth metal and / or earth metal basic inorganic compounds such as magnesium oxide, 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, and a co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate. Examples of alkali metal basic inorganic compounds 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 alkali 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; and other compounds include borax and glycine, and one or more components selected from these may be blended. Among these, one or more components selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are preferred.

[0034] When magnesium oxide is used as an antacid, those listed in the 18th Edition of the Japanese Pharmacopoeia may be used and are readily available. Commercially available magnesium oxide is not limited, but examples thereof include magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd. and magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd. The content of magnesium oxide 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 25% by mass, based on the mass of the entire solid formulation.

[0035] 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.

[0036] <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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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, the tablet may be produced by wet granulating component (A) and component (B) and other appropriate components, drying the granules, adding the final component to the resulting granulated granules so as to form the outer granules, and compressing the mixture. That is, tablets can be produced, for example, by the steps of: producing granulated granules (at least one granulated granule) containing component (A) and component (B) and other appropriate components; and mixing the granulated granules with desired additives (final component), followed by tableting. Furthermore, the component to be placed in the outer granules may optionally be in the form of a granule.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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 stearate Examples of suitable starch and crystalline cellulose include 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, erythritol, glucose, and fructose. These may be used alone or in combination of two or more.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 cis-hydrochloride. Ingredients: tein, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, 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 soy 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 (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.

[0063] 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.

[0064] 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.

[0065] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

[0066] Examples of preservatives include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0067] As the sweetener, for example, one or more components selected from 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, erythritol, etc. may be blended.

[0068] 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.

[0069] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] These additives are not limited to those listed above, and one of these may be used alone or in combination of two or more.

[0080] Furthermore, the solid preparation may further contain, as necessary, medicinal ingredients other than the components (A) and (B), 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 incorporation of these ingredients, the solid preparation may be formulated by appropriately dividing the ingredients into granules or the like.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] Examples of anti-inflammatory agents include glycyrrhizinic acid and its derivatives, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0085] 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.

[0086] 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.

[0087] Examples of xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate. Examples of sedatives include allylisopropylacetylurea and bromvalerylurea.

[0088] These additives are not limited to those listed above, and one of these may be used alone or in combination of two or more.

[0089] 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).

[0090] (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.).

[0091] Examples of the dosage form of the solid preparation include capsules, pills, granules, fine granules, powders, 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, sugar-coated tablets, granules, fine granules, or capsules, and more preferably granules, plain tablets, film-coated tablets, or sugar-coated tablets.

[0092] (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.

[0093] (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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] <Measurement of Plastic Limit Water Addition Ratio (PL) for Raw Powder Comprising Component (A) and Component (B)> Using a mixer torque rheometer (MTR-3, manufactured by Higuchi Shokai Co., Ltd.) equipped with a four-blade main blade and a two-blade auxiliary blade rotating in opposite directions inside a stirring vessel, 25 g of raw powder (component (A): 6.25 g of loxoprofen sodium hydrate (manufactured by KOLON Corporation, D50 = 64 μm) and component (B): 18.75 g of tranexamic acid (manufactured by AMI, D50 = 34 μm)) was placed in the stirring vessel, and a predetermined addition rate of water (purified water) was added dropwise. The mixture was stirred and mixed with the main blade at 50 rpm for 45 seconds. Stirring was then continued for 20 seconds, during which the torque of the stirring blade was measured with a strain gauge. Water addition and torque measurements were repeated under conditions where the water addition rate was changed (between 0.00 and 0.16 in increments of 0.02). The relationship between the water addition rate added to the raw powder and the average torque value (N m) of the stirring blade for 20 seconds was plotted. The water addition rate at which this torque value reached its maximum was taken as the plastic limit water addition rate (PL). The water addition rate (g / g) was defined as "mass of water (g) / mass of raw powder (g)." The specific gravity of purified water was 1.0. The PL (plastic limit water addition rate) of the raw powder was 0.08 (g / g). The D50 was the particle diameter (median diameter) at which the cumulative volume from the small particle side reached 50% in the volume-based cumulative distribution of powder particle diameters measured by laser diffraction scattering.

[0099] <Production of Solid Preparations> (Examples 1 to 5) 10.0 g of loxoprofen sodium hydrate (manufactured by KOLON Pharmaceuticals) and 30.0 g of tranexamic acid (manufactured by AMI Pharmaceuticals) were mixed, and 0.6 g, 2.0 g, 2.72 g, 3.04 g, or 3.17 g of purified water was added according to the water addition ratio conditions such that Ig was 0.20, 0.63, 0.85, 0.95, or 0.99, respectively. The mixture was kneaded in a mortar and dried at 80°C for 1 hour to obtain granules of Examples 1 to 5.

[0100] Comparative Example 1 10.0 g of loxoprofen sodium hydrate (KOLON Pharmaceuticals) and 30.0 g of tranexamic acid (AMI Pharmaceuticals) were mixed, and 0.3 g of purified water was added in accordance with the water addition rate conditions such that Ig was 0.09. The mixture was kneaded in a mortar and dried at 80°C for 1 hour to obtain granules of Comparative Example 1.

[0101] Comparative Example 2 10.0 g of loxoprofen sodium hydrate (KOLON Pharmaceuticals) and 30.0 g of tranexamic acid (AMI Pharmaceuticals) were mixed, and 3.2 g of purified water was added in accordance with the water addition rate conditions such that Ig was 1.00. The mixture was kneaded in a mortar and dried at 80°C for 1 hour to obtain granules of Comparative Example 2.

[0102]

[0103] The obtained granule samples (solid preparations) were subjected to the following evaluations.

[0104] (Preparation of tablet samples) For Examples 2 to 5 and Comparative Example 2, 0.8 g of crystalline cellulose (manufactured by Asahi Kasei Corporation), 0.1 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), and 0.1 g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) were added to 9.0 g of the granules obtained above as post-powder, and the mixture was mixed 100 times in a 10K standard bottle to obtain 10.0 g of a mixture of granules and post-powder. The obtained mixture was subjected to single-shot tableting in a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) using a 9.5 mm diameter die and a punch with a curvature radius of 11.4 mm R-face at a tableting pressure of 10 kN to obtain tablet samples. For Example 1 and Comparative Example 1, 0.6 g of crystalline cellulose (Asahi Kasei Corporation), 0.3 g of croscarmellose sodium (Dupont Co., Ltd.), and 0.1 g of magnesium stearate (Taihei Chemical Co., Ltd.) were added to 9.0 g of the granules obtained above as post-powder, and the mixture was mixed 100 times in a 10K standard bottle to obtain 10.0 g of a mixture of granules and post-powder. The mixture obtained was subjected to single-shot tableting in a hydraulic pump tableting machine (Riken Seiki Co., Ltd.) using a 9.5 mm diameter die and a punch with a curvature radius of 11.4 mm R-face at a tableting pressure of 10 kN to obtain tablet samples.

[0105] <Hardness> The hardness (N) of the tablet samples was measured using a hardness tester (Tablet Tester 8M, manufactured by Dr. Schleuniger Pharmatron). The hardness was taken as the average value of two samples. The results are shown in Table 1.

[0106] <Disintegration Time> The disintegration time (minutes) of tablet samples 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 hardness was taken as the average value of two samples. The results are shown in Table 1.

[0107] <Dissolution Test> The dissolution rates of tablet samples were measured according to the "Dissolution Test Method" of the Japanese Pharmacopoeia, 18th Edition, in accordance with Japanese Pharmacopoeia Dissolution Test Report 2 (Paddle Method) using 900 mL of purified water as the test medium at 50 revolutions per minute (50 rpm), and the dissolution rates (%) at 15 minutes and 30 minutes were measured. The standard deviation of each dissolution rate was calculated using the measured values ​​for three samples. The results are shown in Table 1. The average dissolution rates of Examples 1 to 5 were all 69% or more at 15 minutes and 97% or more at 30 minutes.

[0108] The solid preparations of Examples 1 to 5 showed higher hardness when prepared into tablets than Comparative Example 1, and showed results that the variation in dissolution of the tablets could be suppressed compared to Comparative Example 2. It was found that the solid preparations of these Examples provided tablets that were excellent in shape retention and ensured stable dissolution.

[0109] 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.

[0110] 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).

[0111] This application claims priority based on Japanese Patent Application No. 2023-192199, filed November 10, 2023, the disclosure of which is incorporated herein by reference in its entirety.

Claims

1. A method for producing a solid preparation containing the following components (A) and (B): (A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof (B) at least one selected from the group consisting of tranexamic acid and a salt thereof, the method comprising a wet granulation step of supplying water to a raw material powder containing the components (A) and (B) to obtain a granulated product, wherein, in the wet granulation step, X is adjusted so as to satisfy 0.20≦Ig≦0.99, where X is the addition rate of the water supplied, PL is the plastic limit water addition rate of the raw material powder measured according to the following procedure, and Ig is the granulation index represented by X / PL. (Procedure for measuring the plastic limit water addition rate PL) Using a mixer torque rheometer equipped with a four-blade main blade and a two-blade auxiliary blade rotating in opposite directions in a stirring vessel, 25 g of the raw material powder is placed in the stirring vessel, water is added dropwise at a predetermined addition rate, and the main blade is stirred and mixed at 50 rpm for 45 seconds. The mixture is then stirred for 20 seconds, during which the torque of the stirring blade is measured using a strain gauge. Water is repeatedly added and the torque is measured under conditions of different addition rates, and the relationship between the water addition rate added to the raw powder and the average torque value (N·m) of the stirring blade over 20 seconds at that time is plotted to obtain the relationship. The water addition rate at which the torque value is maximized is defined as the plastic limit water addition rate (PL). The water addition rate is defined as "mass of water (g) / mass of raw powder (g)".

2. A method for producing a solid preparation according to claim 1, wherein the mass ratio of said component (A) to said component (B) in said raw material powder, calculated on an anhydrous basis, is 0.01 or more and 4.0 or less.

3. A method for producing a solid preparation according to claim 1 or 2, wherein, when D50 is the particle diameter at which the cumulative volume from the small particle side is 50% in a volume-based cumulative distribution measured by a laser diffraction scattering method, D50 of at least one of the components (A) and (B) contained in the raw material powder is 10 μm or more and 200 μm or less.

4. A method for producing a solid preparation according to any one of claims 1 to 3, wherein in the wet granulation step, a granulation treatment selected from the group consisting of fluidized bed granulation, extrusion granulation, and high-pressure granulation is carried out.

5. A method for producing a solid preparation according to any one of claims 1 to 4, comprising a drying step of drying the obtained granules.

6. A method for producing a solid preparation according to any one of claims 1 to 5, comprising the step of subjecting the obtained granules to one or more treatments selected from the group consisting of crushing, sieving and classification.

7. A method for producing a solid preparation according to any one of claims 1 to 6, comprising the step of forming the obtained granulated product into the form of granules, powder, capsules, pills, or tablets.

8. A tablet comprising the following components (A) and (B): (A) at least one selected from the group consisting of loxoprofen, its salts, and their hydrates; and (B) at least one selected from the group consisting of tranexamic acid and its salts. (1) A hardness of 30N or more. (2) A dissolution rate of 50% or more and a standard deviation of the dissolution rate of 3.0 or less at 15 minutes in a dissolution test.

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