Solid preparation and method for producing same

Abstract

The present invention addresses the problem of providing: a stable solid preparation in which an antacid and at least one substance selected from the group consisting of loxoprofen and salts thereof are blended, and in which a decrease in the loxoprofen content in the preparation is suppressed; and a method for producing the solid preparation. According to the present invention, provided is a solid preparation containing at least one substance selected from loxoprofen and salts thereof, a compound containing magnesium and / or aluminum, and a hydroxy propyl cellulose.

Description

Technical Field

[0001] The present invention relates to a solid preparation and a method for producing the same. More specifically, the present invention relates to a stable solid preparation containing loxoprofen and / or its salt and a method for producing the same. Background Art

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic and anti-inflammatory drug (hereinafter referred to as NSAIDs), is known to have strong antipyretic / analgesic / anti-inflammatory effects, although it shows the same prostaglandin biosynthesis inhibitory effect as other NSAIDs. It is also known that loxoprofen is a prodrug that is absorbed from the digestive tract in the form of an unchanged form with a weak gastric mucosal irritation effect after oral administration and becomes an active form in the body, and therefore has a feature of less gastric mucosal obstruction than other NSAIDs (for example, refer to Non-Patent Document 1).

[0003] As a technology for further suppressing gastric mucosal disorders by orally administering loxoprofen and / or its salt in combination with other active ingredients, there are disclosed a technology for making loxoprofen contain specific sugars (lactose, sucrose, maltitol, fructose, xylitol or lactitol) (see Patent Document 1), a technology for containing an antacid (magnesium oxide) (see Patent Document 2), a technology for containing tranexamic acid which is a plasmin inhibitor (see Patent Document 3), and the like.

[0004] In addition, it is disclosed that loxoprofen sodium or its hydrate has high hygroscopicity and is difficult to prepare into a stable formulation, and that a formulation having excellent storage stability after preparation is prepared (Patent Document 4).

[0005] On the other hand, as an oral solid composition for masking the bitter taste of a bitter drug, an oral solid preparation has been reported, which is obtained by using low-substituted hydroxypropyl cellulose as a hydrophilic polymer, adding water to the hydrophilic polymer in a range of water:hydrophilic polymer = 1 to 10:1 to prepare a hydrophilic polymer, mixing it with (A) a bitter drug, granulating it, and then drying it until the moisture content is 7.5% by mass or less (Patent Document 5).

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent document 1: Japanese Patent No. 4585220;

[0009] Patent document 2: Japanese Patent No. 6106727;

[0010] Patent document 3: Japanese Patent No. 5835865;

[0011] Patent document 4: Japanese Patent No. 6292744;

[0012] Patent document 5: Japanese Patent No. 5527921;

[0013] Non-patent literature

[0014] Non-patent literature 1: Pharmacology and Therapy (Pharmacology and Therapy), Vol. 16, No. 2, 1988, pp. 611-619. Summary of the invention

[0015] Problems to be solved by the invention

[0016] The present inventors have focused on the fact that, when manufacturing a solid preparation mixed with loxoprofen and / or its salt and an antacid such as magnesium oxide, the content of loxoprofen decreases over time during storage. The present invention aims to provide a stable solid preparation in which the decrease in the content of loxoprofen in the preparation is suppressed, and a method for manufacturing the same.

[0017] Means for solving problems

[0018] In order to solve the above problems, the present inventors conducted intensive research and found that by adding hydroxypropyl cellulose, the reduction in the loxoprofen content can be suppressed even in solid preparations mixed with loxoprofen and / or its salts and antacids such as magnesium oxide, and an excellent preparation can be obtained, thereby completing the present invention.

[0019] That is, the aspects of the present invention are as follows.

[0020] (1) A solid preparation comprising: at least one selected from loxoprofen and a salt thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose.

[0021] (2) The solid preparation according to (1), wherein the hydroxypropyl cellulose comprises at least one of hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose.

[0022] (3) The solid preparation according to (2), wherein the particle size ratio D90 / D50 of the low-substituted hydroxypropyl cellulose is 1.5 to 3.0.

[0023] (4) The solid preparation according to (2) or (3), wherein the low-substituted hydroxypropyl cellulose has an average particle size of 30 to 60 μm.

[0024] (5) The solid preparation according to (2) or (3), wherein the ratio of the hydroxypropoxy group in the low-substituted hydroxypropyl cellulose is 7 to 16%.

[0025] (6) The solid preparation according to any one of (1) to (5), wherein the compound containing at least one of magnesium and aluminum is one or more selected from the group consisting of magnesium oxide, magnesium aluminum metasilicate, and synthetic hydrotalcite.

[0026] (7) The solid preparation according to any one of (1) to (6), further comprising one or more selected from crude drugs and extracts thereof, caffeine, and sedatives.

[0027] (8) The solid preparation according to any one of (1) to (7), further comprising a compound having an amino group.

[0028] (9) A method for producing a solid preparation comprising at least one selected from loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and a hydroxypropyl cellulose, comprising the following first step: before adding at least one selected from loxoprofen and its salts and a compound containing at least one of magnesium and aluminum for granulation, water is added to the hydroxypropyl cellulose for granulation.

[0029] (10) The method for producing a solid preparation according to (9), wherein in the first step, the mass of the water is 0.4 times or more the mass of the hydroxypropyl cellulose.

[0030] Effects of the Invention

[0031] According to the present invention, there is provided an excellent solid preparation in which a decrease in the content of loxoprofen is suppressed even in a solid preparation in which loxoprofen and / or a salt thereof is mixed with an antacid such as magnesium oxide. DETAILED DESCRIPTION

[0032] The solid preparation of the present invention contains at least one selected from loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose.

[0033] The solid preparation of the present invention is a tablet, powder, granule, capsule or pill recorded in the 18th edition of the Japanese Pharmacopoeia (Japanese Pharmacopoeia), preferably a granule or a tablet. Most preferably, it is a tablet. In addition, among granules, when the particle size test method of the preparation is performed according to the 18th edition of the Japanese Pharmacopoeia, the granules whose total amount passes through the No. 18 (850 μm) sieve and the particles remaining on the No. 30 (500 μm) sieve are less than 10% of the total amount are sometimes referred to as fine granules.

[0034] In addition, as an embodiment of the granules or tablets of the present invention, the preparation may be coated with a water-soluble polymer, etc. That is, examples include film-coated granules, film-coated tablets, etc. In addition, the solid preparation of the present invention may be coated with sugar.

[0035] Furthermore, when the solid preparation of the present invention is a tablet, in addition to the monolayer tablet mainly shown in this specification, it can also be a multilayer tablet formed by compressing and molding powders or granules of different compositions in 2 or 3 layers or more. It should be noted that in the present invention, when the tablet is made into a multilayer tablet, loxoprofen and / or its salt, the compound containing at least one of magnesium and aluminum, and the hydroxypropylcellulose enter the same layer.

[0036] The solid preparation of the present invention comprises loxoprofen and / or its salt.

[0037] In the present invention, "loxoprofen and / or its salt", in other words "at least one selected from loxoprofen and its salt", is loxoprofen and / or its salt (including hydrated salt) (the salt is preferably a pharmacologically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

[0038] Loxoprofen and / or its salt used in the present invention is included in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0039] There is no limitation on the content of loxoprofen and / or its salt contained in the solid preparation of the present invention. The amount of the components contained in the solid preparation per dosage unit (single dosage) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg in terms of anhydrous equivalent, and the number of administrations is 1 to 3 times a day.

[0040] When the solid preparation of the present invention is a tablet, the content of loxoprofen and / or its salt contained in the granulated particles in the tablet is not particularly limited. The amount of the ingredients contained in the tablet per dosage unit (single dosage) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, further preferably 30 to 90 mg, and may also be 45 to 90 mg in terms of anhydrous conversion. In this case, the number of administrations is also 1 to 3 times a day.

[0041] The amount of loxoprofen and / or its salt contained in the tablet is not particularly limited, but is 1 to 80% by mass, preferably 2 to 50% by mass, more preferably 5 to 30% by mass, and may be 5 to 20% by mass based on the total mass of the solid preparation.

[0042] The solid preparation of the present invention contains a compound containing at least one of magnesium and aluminum.

[0043] Examples of the compound containing at least one of magnesium and aluminum include magnesium oxide, magnesium silicate, magnesium aluminosilicate (magnesium aluminum silicate), magnesium aluminum silicate, magnesium hydroxide, a coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminum metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium hydrogen carbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, etc. Among the above, the compound containing at least one of magnesium and aluminum is preferably one or more selected from magnesium oxide, magnesium aluminum metasilicate, and synthetic hydrotalcite.

[0044] When magnesium aluminum metasilicate is used in the present invention, magnesium aluminum metasilicate listed in the 18th edition of the Japanese Pharmacopoeia can be used, and magnesium aluminum metasilicate listed in the Dictionary of Pharmaceutical Additives can also be used, and both are easily available.

[0045] Commercially available magnesium aluminum metasilicate is not particularly limited, and an example thereof is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.

[0046] The content ratio of magnesium aluminum metasilicate in the solid preparation of the present invention can be selected in consideration of the disintegration of the solid preparation / dissolution of the drug and the function as an antacid, and is not particularly limited. Based on the overall mass of the solid preparation, it can be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass.

[0047] When magnesium oxide is used in the present invention, magnesium oxide listed in the 18th edition of the Japanese Pharmacopoeia can be used, and magnesium oxide listed in the Dictionary of Pharmaceutical Additives can also be used, and both are easily available.

[0048] The commercially available magnesium oxide is not particularly limited, and for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd., magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd., and the like can be used.

[0049] The content ratio of magnesium oxide in the solid preparation of the present invention can be selected in consideration of the disintegration property of the solid preparation / dissolution property of the drug and the function as an antacid, and is not particularly limited. It can be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass based on the total mass of the solid preparation.

[0050] When synthetic hydrotalcite is used in the present invention, synthetic hydrotalcite listed in the Japanese Pharmacopoeia Standards for Non-Japanese Drugs 2002 or synthetic hydrotalcite listed in the Dictionary of Pharmaceutical Additives can be used, and both are easily available.

[0051] The commercially available synthetic hydrotalcite is not particularly limited, and examples thereof include Alcamac (B grade) manufactured by Kyowa Chemical Industry Co., Ltd., Alcamac (L grade) manufactured by Kyowa Chemical Industry Co., Ltd., Alcamac (SH grade) manufactured by Kyowa Chemical Industry Co., Ltd., and Alcamac (SN grade) manufactured by Kyowa Chemical Industry Co., Ltd.

[0052] The content ratio of the synthetic hydrotalcite in the solid preparation of the present invention can be selected in consideration of the disintegration property of the solid preparation / dissolution property of the drug and the function as an antacid, and is not particularly limited. It can be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass based on the total mass of the solid preparation.

[0053] The solid preparation of the present invention contains hydroxypropylcellulose.

[0054] As the hydroxypropyl cellulose, at least one of hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose is preferably used.

[0055] When hydroxypropyl cellulose is measured using a particle size distribution meter utilizing laser diffraction / scattering (e.g., Microtrac MT 3000II series manufactured by MicrotracBEL Co., Ltd.), the ratio of the 50% cumulative diameter to the 90% cumulative diameter of the obtained particle size distribution, i.e., D90 / D50, is preferably 1.5 to 3.0.

[0056] When the hydroxypropyl cellulose is measured for particles using a particle size distribution meter utilizing laser diffraction / scattering (for example, Microtrac MT 3000II series manufactured by Microtrac BEL Co., Ltd.), the average particle size (50% cumulative diameter) is preferably 30 to 60 μm.

[0057] When hydroxypropyl cellulose is measured according to the quantitative method described in the section of low-substituted hydroxypropyl cellulose in the 18th edition of the Japanese Pharmacopoeia, the ratio of the hydroxypropoxy group is preferably 7 to 16%.

[0058] As hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose, those listed in the 18th edition of the Japanese Pharmacopoeia or those listed in the Dictionary of Pharmaceutical Additives can be used, and they are easily available.

[0059] The commercially available hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose are not particularly limited, and for example, NISSO HPC (HPC-SL grade) manufactured by Nippon Soda Co., Ltd., NISSO HPC (HPC-SSL grade) manufactured by Nippon Soda Co., Ltd., NISSO HPC (HPC-L grade) manufactured by Nippon Soda Co., Ltd., NISSO HPC (HPC-H grade) manufactured by Nippon Soda Co., Ltd., KLUCEL manufactured by Ashland Co., Ltd. TM (ELF Pharm grade), KLUCELTM manufactured by Ashland (EF Pharm grade), KLUCELTM manufactured by Ashland (LF Pharm grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-21 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-22 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-11 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-B1 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-31 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (LH-32 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (NBD-22 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (NBD-21 grade), L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. TM (NBD-20 level), etc.

[0060] The content ratio of the hydroxypropylcellulose in the solid preparation of the present invention can be selected in consideration of the disintegration property of the solid preparation / the dissolution property of the drug and the function as an antacid, and is not particularly limited. It can be 1 to 80% by mass, 3 to 70% by mass, and preferably 5 to 50% by mass based on the total mass of the solid preparation.

[0061] The solid preparation of the present invention may preferably further contain one or more selected from crude drugs and extracts thereof, caffeine and sedatives.

[0062] Examples of caffeine include caffeine hydrate, anhydrous caffeine, caffeine sodium benzoate, and caffeine citrate.

[0063] The content ratio of caffeine in the solid preparation of the present invention is not particularly limited, and may be, for example, 1 to 80% by mass, 3 to 80% by mass, or 5 to 70% by mass based on the total mass of the solid preparation.

[0064] Examples of the sedative include allyl isopropyl acetyl urea and bromovaleryl urea.

[0065] The content ratio of the sedative in the solid preparation of the present invention is not particularly limited, and may be, for example, 1 to 80% by mass, 2 to 80% by mass, or 2 to 70% by mass based on the total mass of the solid preparation.

[0066] When using crude drugs, there is no particular limitation on their types, and for example, they can be mixed with herbs selected from ephedra, basil, cherry peel, polygala, licorice, platycodon, plantain, plantain, lycoris, polygala, fritillaria, fennel, phellodendron, coptis, zedoaria, matricaria, cassia bark, gentian, bezoar, animal gall (including bear gall), adenophora, ginger, atractylodes, clove, tangerine peel, atractylodes, earthworm, bamboo ginseng, ginseng, wild sycamore, immortal medicine, epimedium, corydalis, scutellaria, polygonatum, valerian, trichosanthes, apricot One or more ingredients of crude drugs such as ginseng, wolfberry, wolfberry leaf, schizonepeta, cassia seed, geranium, cyperus, schisandra, asarum, sansho, aster, lycium bark, peony root, musk, magnolia, chuanxiong, peucedanum, angelica, mulberry bark, perilla, garlic, angelica, ipecac, ophiopogon, pinellia, saffron, agkistrodon, angelica dahurica, poria, peony bark, oyster, pilose antler, stephania tetrandra, and their extracts (extracts, tinctures, dry extracts, etc.).

[0067] The solid preparation of the present invention preferably contains at least one of a licorice extract, a peony extract, and a valerian extract, and more preferably contains at least one of a licorice extract and a valerian extract.

[0068] The content ratio of the crude drug and its extract in the solid preparation of the present invention is not particularly limited. For example, when each crude drug is an extract, it can be 1 to 80% by mass, 1 to 70% by mass, 1 to 60% by mass, or 1 to 50% by mass based on the mass of the entire solid preparation.

[0069] The crude drugs such as licorice, peony, and valerian used in the present invention have been used for medicinal purposes in the form of single flavors or Chinese medicine prescriptions since ancient times, and the crude drug powders or extract components obtained by the respective conventional methods can be directly used. The form of the crude drug powder or the extract component can also use a common commercial product or its processed product. As a crude drug powder, for example, the dried and chopped processed product can be further crushed into a very fine powder (micro powder) and used as a dry powder. In addition, there is no particular limitation on the form of the extract component from the crude drug, for example, it can also be used as any form of a dry extract, an extract powder, a soft extract, a liquid extract (fluid extract), a tincture containing ethanol or ethanol and water, etc. Preferred crude drugs include extract components with a high degree of freedom in formulation, such as soft extracts, dry extract powders, etc.

[0070] The extract component can be obtained by extracting the active ingredient with antibacterial effect from the above-mentioned herbal medicine by conventional methods, for example, using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent or a mixed solvent thereof is often used. Examples of the above-mentioned hydrophilic solvent include: alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, etc.; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc. These hydrophilic solvents can be used alone or as a mixed solvent of two or more.

[0071] Licorice can be used as an anti-inflammatory drug, cold medicine, antipyretic analgesic, cough expectorant, gastrointestinal medicine, anthelmintic, internal medicine for rhinitis, throat coolant, stomachic coolant, vitamin-containing health medicine, sweetener, flavoring agent, colorant, fragrance, flavor or excipient as in the past.

[0072] When "licorice" is used in the present invention, licorice, licorice powder, licorice extract, and licorice crude extract described in the 18th edition of the Japanese Pharmacopoeia can be preferably used.

[0073] In addition, the above and other various licorice are commercially available and can be easily obtained.

[0074] As commercially available licorice, there are extracts obtained by using water or 30% ethanol aqueous solution as extraction solvents, for example, licorice extracts, licorice dry extracts, licorice soft extracts, licorice liquid extracts, etc., and products with various original drug conversion ratios are sold. In addition to these licorice extracts, licorice extracts, licorice extract liquids, etc. can also be used appropriately without particular limitation.

[0075] When commercially available licorice is used in a solid preparation, for example, licorice can be used in consideration of the original drug conversion ratio so that the licorice content in the solid preparation is appropriate.

[0076] The content of licorice (licorice or licorice extract) in the solid preparation of the present invention is not particularly limited. The amount of the component contained in the solid preparation per daily dosage is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, further preferably 500 mg to 3000 mg, and can be 500 mg to 1500 mg. The number of administrations is 1 to 3 times a day.

[0077] When, for example, a dry licorice extract is used in the solid preparation of the present invention, the content ratio of the dry licorice extract is not particularly limited, and 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 solid preparation.

[0078] When "valerian" is used in the present invention, as "valerian", valerian described in the 18th edition of the Japanese Pharmacopoeia and valerian powder can be preferably used.

[0079] In addition, the above and other valerian are also commercially available and can be easily obtained.

[0080] As commercially available valerian, for example, valerian powder or valerian extract (for example, soft extract or dry extract) can be used without particular limitation.

[0081] When commercially available valerian is used in a solid preparation, valerian may be used in consideration of the original drug conversion ratio so that the valerian content in the solid preparation is appropriate.

[0082] When valerian (valerian or an extract of valerian) is used in the present invention, the content is not particularly limited. For example, the amount of the component contained in the solid preparation per daily dosage can be 25 to 6000 mg, preferably 50 to 5000 mg, more preferably 100 to 4000 mg, further preferably 200 mg to 3200 mg, and can be 400 to 1600 mg, based on the amount of the original drug, and the number of administrations is 1 to 3 times a day.

[0083] When a valerian extract is used in the solid preparation of the present invention, for example, the content ratio of the valerian extract is not particularly limited, and 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 solid preparation.

[0084] When "peony" is used in the present invention, as the "peony", the peony described in the 18th edition of the Japanese Pharmacopoeia and peony powder can be preferably used.

[0085] In addition, the above and other peonies are also commercially available and can be easily obtained.

[0086] As commercially available peony, for example, peony powder or peony extract (for example, including dry extract or soft extract) can be used without particular limitation.

[0087] When commercially available peony is used in a solid preparation, the peony may be used in consideration of the original drug conversion ratio so that the peony content in the solid preparation is appropriate.

[0088] When using peony (peony or its extract) in the present invention, the content is not particularly limited. In terms of native drug conversion, it is preferably administered in an amount of 100 to 5000 mg per day, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg. The frequency of administration is 1 to 3 times a day.

[0089] When, for example, a peony dry extract is used in the solid preparation of the present invention, the content ratio of the peony dry extract is not particularly limited, and may be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass based on the total mass of the solid preparation.

[0090] The solid preparation of the present invention may preferably further contain a compound having an amino group.

[0091] The compound having an amino group is not particularly limited as long as it is a compound having an amino group, and for example, one or more components selected from amino acids such as isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, tyrosine, cysteine, aspartic acid, asparagine, serine, glutamic acid, glutamine, proline, glycine, alanine, and arginine, carboxymethylcysteine, tranexamic acid or a salt thereof, etc. may be blended.

[0092] The amount of the compound having an amino group contained in the solid preparation is not particularly limited, and may be 1 to 90% by mass, 2 to 80% by mass, or 5 to 60% by mass based on the total mass of the solid preparation.

[0093] The amount of the compound having an amino group in the composition may be, for example, 100 to 1000 mg or 200 to 700 mg per dose of a solid preparation per day, and the number of doses may be 1 to 3 times per day.

[0094] In addition, the solid preparation of the present invention may contain "hesperidins".

[0095] When hesperidins are used in the present invention, hesperidin and hesperidin derivatives such as glucosyl hesperidin can be mentioned. Hesperidin is also called vitamin P and is included in the Japanese Pharmacopoeia Standards for Non-Japanese Drugs 2002 and the like.

[0096] The content ratio of hesperidin in the solid preparation of the present invention is not particularly limited, and may be 0 to 30% by mass, or 0.1 to 15% by mass, based on the mass of the entire solid preparation.

[0097] The amount of the compound containing hesperidin in the composition may be, for example, 10 to 500 mg or 20 to 300 mg per dose in a solid preparation per day, and the number of doses may be 1 to 3 times per day.

[0098] The solid preparation of the present invention can be prepared into a preparation according to a conventional method.

[0099] In the present invention, for example, granulated particles containing loxoprofen and / or its salt, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose can be prepared, and post-added powder (post-powder) components are added to the obtained granulated particles to form the outside of the granulated particles, and tableting is performed to prepare tablets.

[0100] That is, the tablet can be manufactured, for example, by the following steps: a step of manufacturing granulated particles (at least one type of granulated particles) containing loxoprofen and / or its salt, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose; and a step of manufacturing tablets by mixing the granulated particles and desired additives (post-addition powder components) and tableting. In addition, the components arranged outside the particles can also be arbitrarily formed into particles.

[0101] The post-added powder component (outside of granulated particles) in the present invention is a part of the tablet that constitutes the outside of the granulated particles, and may be, for example, a part of the tablet that is formed by coating one granulated particle, or a part that is formed by coating a plurality of granulated particles. In addition, it may be a part of the tablet that coats at least one granulated particle and is also a part that constitutes the outer surface of the tablet. The tablet may be: a tablet having granulated particles, wherein loxoprofen and / or its salt, a compound containing at least one of magnesium and aluminum, and at least one of hydroxypropylcellulose are contained in the granulated particles.

[0102] The method for producing a solid preparation containing loxoprofen and / or a salt thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose according to the present invention may include a step of granulating water and hydroxypropylcellulose (first step).

[0103] In the first step, the mass of water added can be 0.4 times or more relative to the mass of hydroxypropyl cellulose, and can be 0.5 times or more, 0.6 times or more, 0.7 times or more, 0.8 times or more, or 1.0 times or more. The upper limit of the mass of hydroxypropyl cellulose relative to the mass of water is not particularly limited, and is usually 3 times or less.

[0104] After granulating water and hydroxypropyl cellulose, loxoprofen and / or its salt and a compound containing at least one of magnesium and aluminum are granulated, thereby incorporating loxoprofen and / or its salt and a compound containing at least one of magnesium and aluminum into hydroxypropyl cellulose (especially low-substituted hydroxypropyl cellulose), thereby easily achieving stabilization.

[0105] As an example, after adding water to low-substituted hydroxypropyl cellulose for granulation, loxoprofen and / or its salt and a compound containing at least one of magnesium and aluminum are added for granulation, and then water is added as needed for granulation. After the above granulation, other additives (for example, herbal extracts, cross-linked carboxymethyl cellulose sodium, hydroxypropyl cellulose, etc.) can be added, and water can be added as needed for granulation to produce granulated particles. After mixing and adding powder to the granulated particles, tablets can be produced by tableting with a tablet press.

[0106] As another example, after adding a crude drug extract dispersed in water to low-substituted hydroxypropyl cellulose for granulation, light anhydrous silicic acid is added, and water is added for granulation. After the above granulation, loxoprofen and / or its salt, a compound containing at least one of magnesium and aluminum, and other additives as needed (for example, crude drug extract, erythritol, partially alpha-starch, hydroxypropyl cellulose, etc.) are added for granulation, and water is added as needed for granulation to produce granulated particles. After mixing and adding powder to the granulated particles, tablets can be produced by tabletting with a tablet press.

[0107] When preparing the formulation, known methods and additives may be appropriately used. Additives may be appropriately added within a range that does not impair the effects of the present invention.

[0108] Examples of additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, flow agents, glossing agents, foaming agents, anti-humidifying agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar-coating agents, plasticizers, dispersants, and defoaming agents. For the above purposes, conventionally known formulation additives that can be used for solid preparations can be used.

[0109] Examples of the excipient include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, crystalline cellulose, crystalline cellulose / sodium carboxymethyl cellulose, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic Aluminum silicate / hydroxypropyl starch / crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, purified white sugar, purified white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially alpha-starch, powdered sugar, powdered sugar, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, calcium sulfate, erythritol, glucose, fructose, etc.

[0110] As a binder, for example, one or more components selected from the following can be mixed: gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0111] Examples of the disintegrant include sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, cross-linked polyvinylpyrrolidone, hydroxypropyl starch, and partially pregelatinized starch.

[0112] Examples of the disintegration aid include sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0113] Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, fatty acid glycerides, polyethylene glycol, hydrogenated oil, and sodium stearyl fumarate.

[0114] As a fluidizing agent, for example, one or more components selected from the following can be blended: hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, calcium hydrogen phosphate granules, etc.

[0115] As the glossing agent, for example, one or more components selected from the group consisting of carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc. can be blended.

[0116] As the foaming agent, for example, one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, citric anhydride, etc. can be blended.

[0117] As an anti-humidification agent, for example, one or more components selected from the following can be blended: ethyl cellulose, olive oil, dry aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylamino acetate, etc.

[0118] As the surfactant, for example, one or more components selected from the group consisting of sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene 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, polyethylene glycol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0119] As the stabilizer, for example, one or more components selected from the group consisting of 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, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyethyl Olefin polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerol fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, 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 hydrolyzate, sorbitan fatty acid ester, taurine, talc, Calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl 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 glycerides (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, citric anhydride, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glyceryl 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.

[0120] Examples of the emulsifier include fatty acid glyceryl esters, fatty acid propylene glycol esters, polyoxyethylene glyceryl fatty acid esters, polyglyceryl 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 lecithin.

[0121] Examples of the antioxidant include ascorbic acid, L-ascorbyl stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, and the like.

[0122] Examples of the filler include RSS No. 1 raw rubber, acrylic starch 1000, hydrated silica, titanium oxide, silicon dioxide, and calcium monohydrogen phosphate.

[0123] Examples of the preservative include benzoic acid, sodium benzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, methyl p-hydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0124] As sweeteners, for example, one or more ingredients selected from the following can be blended: aspartame, acesulfame potassium, licorice, licorice powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, stevia extract purification, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0125] As the flavoring agent, for example, one or more ingredients selected from the group consisting of sodium chloride, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, stevia extract purified product, Japanese thyme, D-sorbitol, tannic acid, trehalose hydrate, oligofructose, powdered sugar, mint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc. can be blended.

[0126] Examples of the cooling agent include anise oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0127] As flavors, for example, one or more components selected from the following can be blended: orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach flavor, fruit flavor, mint, melon powder flavor, l-menthol, peppermint oil, etc.

[0128] Examples of the aromatic agent include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine, pineapple powder flavor 51357, pineapple powder flavor 59492, mint water, mint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0129] As a colorant, for example, one or more components selected from the following can be blended: yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold foil, black iron oxide, titanium oxide, ferric oxide, disazo yellow, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, ferric oxide / glycerol suspension, sodium copper chlorophyll, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil, etc.

[0130] As the base, one or more components selected from the group consisting of: gum arabic powder, alpha starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, fatty acid glyceride, light anhydrous silicic acid, crystalline cellulose, hydrogenated 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, Oil, potato starch, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, shark liver monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0131] Examples of the coating agent 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 foil, silver foil, triethyl citrate, glycerin, fatty acid glycerides, hydrogenated 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 foil, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium oxide / polyethylene glycol 400 mixture, hydroxypropyl methylcellulose, fumaric acid / stearic acid / polyvinyl acetal diethylamino acetate / hydroxypropyl methylcellulose 2 910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylamino acetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridinemethyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0132] As the sugar coating agent, for example, one or more ingredients selected from the group consisting of gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. can be blended.

[0133] As the plasticizer, for example, one or more components selected from the following can be blended: triethyl citrate, glycerol, fatty acid glyceride, D-sorbitol, medium-chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc.

[0134] As the dispersant, one or more components selected from the group consisting of aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerol fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose, polyol Vitone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0135] As defoaming agents, one or more components selected from the following can be mixed: ethanol, fatty acid glycerides, dimethylpolysiloxane (for oral administration), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid esters, silicon defoaming agents, silicone oils, sorbitan fatty acid esters, polysorbate 80, etc.

[0136] These additives are not limited to those listed above, and they may be used alone or in combination of two or more.

[0137] Solid preparation of the present invention can be used for the purpose of suppressing fever, pain, inflammation. Because loxoprofen and / or its salt as effective ingredient have antipyretic, analgesic and anti-inflammatory effects, it can be used as antipyretic and analgesic particularly suitably for the analgesia of headache, menstrual pain (physiological pain), toothache, pain after tooth extraction, sore throat, back pain, arthralgia, muscle pain, shoulder pain, earache, contusion pain, fracture pain, sprain pain, trauma pain, etc., antipyretic during aversion to cold / fever, in addition, can be used for the purpose of relieving the various symptoms (runny nose, nasal congestion, cough, sputum, sore throat, fever, aversion to cold, headache, sneezing, arthralgia, muscle pain) of cold as cold treatment medicine.

[0138] The solid preparation of the present invention can be prepared into, for example, preparations for oral administration (including tablets, orally disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets, dissolving tablets, etc.), preparations suitable for oral administration (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gelatinous agents, etc.), and other dosage forms described in the 18th edition of the Japanese Pharmacopoeia General Guidelines for Preparations.

[0139] These compositions may be further appropriately blended with other active ingredients as needed, such as antipyretic analgesics, antitussive / expectorant drugs, antihistamines, anti-inflammatory drugs, anticholinergic drugs, other vitamins, and xanthine derivatives, without prejudice to the present invention. If there are any contraindications to their combination, they may be prepared by appropriately performing particle separation or the like.

[0140] As antipyretic analgesics, one or more ingredients selected from the following can be mixed: aspirin, aspirin aluminum, acetaminophen, salicylamide, disalicylate, salicylamide, lactylphenethylamine, ibuprofen, isopropyl antipyrine, pranoprofen, diclofenac sodium, mefenamic acid, indomethacin farnesate, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate and thiamide hydrochloride, etc.

[0141] Examples of the antitussive / expectorant include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium dibunate, dimethorphan phosphate, tipedine citrate, tipedine hyaluronate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein, allocamide hydrochloride, cloperastine hydrochloride, cloperastine fendicarboxate, pentoxyverine citrate, noscarbine, noscarbine hydrochloride, trimequinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine hydrochloride, racemic methylephedrine hydrochloride, racemic methylephedrine saccharinate, guaiacol glyceryl ether, potassium guaiacol sulfonate, potassium cresol sulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-cysteine ​​ethyl ester hydrochloride.

[0142] Examples of the antihistamine include azelastine hydrochloride, alimamazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatamide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyl disulfonate, carbinoxamine maleate, chlorpheniramine maleate, racemic chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripeliramine hydrochloride, pyrimidine diamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, medichloride, loratadine, isopentyl hydrochloride, difetenol hydrochloride, mefenamic acid hydrochloride, mefenamic acid naphthalene disulfonate, methylene disalicylates promethazine, difetenol phosphate, etc.

[0143] Examples of the anti-inflammatory drug include glycyrrhizic acid and its derivatives and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), and tranexamic acid.

[0144] Examples of the anticholinergic drug include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropyl iodide, diphenylpiperidinylmethyldioxolane iodide, scopolamine extract, scopolamine root, scopolamine root total alkaloid citrate, and the like.

[0145] Vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, niacin, niacinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, a mixture of potassium / magnesium aspartate and the like, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrots, coix seeds, and iodic acid.

[0146] Examples of the xanthine derivatives other than caffeine (other xanthine derivatives) include theophylline and theobromine.

[0147] These additives are not limited to those listed above, and they may be used alone or in combination of two or more.

[0148] The solid preparation of the present invention can be temporarily packaged and airtightly stored by SP packaging, PTP packaging, bag packaging, stick packaging, bottle packaging, etc. They can also be pillow-packaged or stored in boxes, etc.

[0149] In other words, a medicine according to one embodiment of the present invention may include a solid preparation and a packaging material for packaging the solid preparation.

[0150] There is no particular limitation on the materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging. For example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, or multilayer films formed by combining these resin films, or materials formed by attaching aluminum foil to these resin films, can be used. In addition, the drug involved in one embodiment of the present invention can use an environment-compatible container that takes the environment into consideration (less environmental load) as a packaging material, and materials that use raw materials (for example, recycled plastics, biomass plastics, biodegradable plastics) that take the environment into consideration (less environmental load) can be used in at least a portion of the packaging material.

[0151] In addition, the medicine according to one embodiment of the present invention may use cellophane or a vapor-deposited film as at least a part of the packaging material.

[0152] The packaging material of the solid preparation of the present invention is preferably a package made of a material that is not easily affected by moisture (a package formed of at least one of a moisture-proof material and a gas-barrier material), for example.

[0153] For example, as a packaging material (moisture-proof material) with little influence of moisture, PTP (polypropylene) + polyethylene aluminum pillow packaging (combination packaging of PTP and polyethylene aluminum pillow) can be used. In addition, considering the suppression of the increase of moisture value in solid preparations, the storage stability of solid preparations, the stability of solid preparations after opening, etc., as a packaging material (moisture-proof material) that is not easily affected by moisture, PTP packaging with aluminum used on both sides (Al-Al packaging) can be used.

[0154] If hygroscopicity is a concern, a desiccant or the like may be stored in the bottle package or pillow package.

[0155] As the gas barrier material, a known material can be used without particular limitation, and for example, a laminate film having a functional barrier layer may be used, and the material may also function as the above-mentioned moisture-proof material or be used together with the above-mentioned moisture-proof material.

[0156] Example

[0157] In order to explain the present invention in more detail, comparative examples and examples are described below, but the present invention is not limited to these.

[0158] Test Example 1: Storage stability test of tablets containing loxoprofen sodium hydrate and antacid 1. Preparation of tablets

[0159] The preparations (tablets) of Comparative Example 1 and Examples 1 to 5 used in the test were prepared by the following method. In addition, the formulations (6 tablets per) of Comparative Example 1 and Examples 1 to 5 are shown in Tables 1 and 2. % appearing in Table 1 and the following tables refers to mass % unless otherwise specified.

[0160] (Comparative Example 1)

[0161] Loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), dry licorice extract (manufactured by Alps Pharmaceutical Ind. Co., Ltd.), partially alpha-starch (manufactured by Asahi Kasei Corporation, PCS PC-10), croscarmellose sodium (manufactured by FMC International, AcDiSol Croscarmellose Sodium) and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL) weighed according to the ratio in Table 1 were mixed using a high-speed stirring granulator (model: FM-VG05, manufacturer: Powrex Co., Ltd.), and then granulated by adding purified water to prepare granulated particles.

[0162] The granulated granules were mixed with sodium stearyl fumarate (manufactured by Kimura Sangyo, PRUV) as a post-addition powder in a plastic bag according to Table 1, and then tableted using a tablet press (model: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets.

[0163] (Example 1)

[0164] Low-substituted hydroxypropyl cellulose (L-HPC NBD-022 manufactured by Shin-Etsu Chemical Co., Ltd.) weighed in the ratio shown in Table 1 was placed in a high-speed stirring granulator (model: FM-VG05, manufacturer: Powrex Co., Ltd.), and purified water was added to perform granulation 1. Then, loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.) and magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.) were added, and purified water was added as needed to perform granulation 2. After granulation 2, a dry licorice extract (manufactured by Alps Pharmaceutical Ind. Co., Ltd.), croscarmellose sodium (manufactured by FMC International, AcDiSol Croscarmellose Sodium), and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL) were added, and purified water was added as needed to perform granulation to prepare granulated particles.

[0165] The granulated particles were mixed with sodium stearyl fumarate (manufactured by Kimura Sangyo, PRUV) weighed in the ratio shown in Table 1 as a post-addition powder in a plastic bag, and then tableted using a tablet press (model: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets.

[0166] In Examples 2 to 5, tablets were obtained in the same manner as in Example 1 except that the compositions were changed to those shown in Tables 1 and 2. In Examples 4 and 5, D-mannitol (Granutol R, manufactured by Freund Sangyo Co., Ltd.) was added to the post-added powder to produce tablets.

[0167] 2. Test methods

[0168] The tablets of Comparative Example 1 and Examples 1 to 5 were filled into glass bottles (3k standard bottles), sealed with metal caps (Medicinal No. 3), and left at 60° C. for 1 month. After storage, the loxoprofen sodium content was measured by HPLC, and the residual rate before storage was calculated.

[0169] 3. Test results

[0170] The residual rate of loxoprofen sodium obtained the results shown in Table 1 and Table 2. It should be noted that "-" in Table 1 to Table 4 means that the tablet does not contain the substance.

[0171] In addition, as an index of the loxoprofen sodium residual rate in this test, evaluation was performed according to the following criteria.

[0172] A (excellent): the residual rate of loxoprofen sodium is more than 95%;

[0173] B (acceptable): The residual rate of loxoprofen sodium is less than 95%.

[0174] [Table 1]

[0175]

[0176] [Table 2]

[0177]

[0178] As shown in Comparative Example 1, it is known that when loxoprofen sodium hydrate and magnesium oxide are mixed, the residual rate of loxoprofen sodium decreases, but by adding loxoprofen sodium hydrate and magnesium oxide to the low-substituted hydroxypropyl cellulose granules added with purified water and granulating them as shown in Example 1, and then adding other ingredients for granulation, the reduction in the content of loxoprofen sodium can be suppressed.

[0179] As shown in Example 2, the same results were obtained when the dry extract of licorice was removed.

[0180] In addition, as shown in Examples 3 and 5, even when magnesium oxide is replaced with an antacid such as magnesium aluminum metasilicate or synthetic hydrotalcite, the same results can be obtained.

[0181] Furthermore, as shown in Example 4, it was found that even when the grade of low-substituted hydroxypropyl cellulose was changed, the reduction in the content of loxoprofen sodium could be suppressed.

[0182] <Examples 6 to 9>

[0183] The formulations of Examples 6 to 9 (6 tablets each) are shown in Table 3.

[0184] (Example 6)

[0185] Low-substituted hydroxypropyl cellulose (L-HPC NBD-022 manufactured by Shin-Etsu Chemical Co., Ltd.) weighed according to the ratio in Table 3 was placed in a high-speed stirring granulator (model: FM-VG-25, manufacturer: Powrex Co., Ltd.), and valerian extract dispersed in purified water was added to perform granulation 1, and then light anhydrous silicic acid (Aerosil 200 manufactured by Nippon Aerosil Co., Ltd.) was added, and purified water was added to perform granulation 2. After granulation 2, loxoprofen sodium dihydrate (manufactured by KOLON LIFESCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), dry licorice extract (manufactured by Alps Pharmaceutical Ind. Co., Ltd.), erythritol (manufactured by Bussan Food Science Co., Ltd.), partially alpha-starch (manufactured by Asahi Kasei Corporation, PCS PC-10) and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL fine powder) were added and granulated to prepare granulated particles.

[0186] The granulated particles were mixed with light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and sodium stearyl fumarate (PRUV, manufactured by Kimura Sangyo) as post-addition powders in the proportions shown in Table 3 using a mixer (model: TM-30S, manufacturer: Showa Chemical Machinery Works, Ltd.), and then tableted using a tablet press (model: Correct 19HUK, manufacturer: Kikusui Seisakusho, Ltd.) to obtain tablets.

[0187] The tablets (plain tablets) prepared according to Table 3 are loaded into a film coating machine (model: HCT-MINI, manufacturer: Freund Industry Co., Ltd.), and then polyvinyl alcohol (manufactured by Mitsubishi Chemical Corporation, Gohsenol EG-05P), hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5R), titanium oxide (manufactured by Freund Industry Co., Ltd., titanium oxide FG), sucrose fatty acid ester (Surfhope SE PHARMA J-2203F), polyethylene glycol (manufactured by NOF Corporation, polyethylene glycol 6000P), ferric oxide (manufactured by Keisi Chemical Co., Ltd.) and yellow ferric oxide (manufactured by Keisi Chemical Co., Ltd.) are mixed with purified water to prepare a film coating solution. Next, a target amount of the obtained coating solution was applied to tablets (plain tablets) using a film coater, and then carnauba wax (Carnauba wax 105 manufactured by Freund Sangyo Co., Ltd.) was added for polishing to prepare film-coated tablets.

[0188] In Examples 7 to 9, film-coated tablets were prepared by the same procedure as in Example 6 except that the compositions were changed to the compositions shown in Table 3.

[0189] [Table 3]

[0190]

[0191] <Example 10>

[0192] The formulation of Example 10 (6 tablets per serving) is shown in Table 4.

[0193] Low-substituted hydroxypropyl cellulose (L-HPC NBD-022 manufactured by Shin-Etsu Chemical Co., Ltd.) weighed according to the ratio in Table 4 was placed in a high-speed stirring granulator (model: FM-VG-400P, manufacturer: Powrex Co., Ltd.), and the valerian extract dispersed in purified water was added and kneaded for 1. Then, light anhydrous silicic acid (Aerosil 200 manufactured by Nippon Aerosil Co., Ltd.) was added, and purified water was added and kneaded for 2. After kneading 2, loxoprofen sodium dihydrate (manufactured by KOLONLIFE SCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), licorice dry extract (manufactured by Alps Pharmaceutical Ind. Co., Ltd.), erythritol (manufactured by Bussan Food Science Co., Ltd.), partially alpha-starch (manufactured by Asahi Kasei Corporation, PCS PC-10) and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL fine powder) were added and granulated to prepare granulated particles.

[0194] For the granulated particles, light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and sodium stearyl fumarate (PRUV, manufactured by Kimura Sangyo) weighed in the ratio shown in Table 10 were mixed using a mixer (model: TM-1000S, manufacturer: Showa Chemical Machinery Works, Ltd.) as post-addition powders, and then tableted using a tablet press (model: AQUARIUS, manufacturer: Kikusui Seisakusho, Ltd.) to obtain tablets.

[0195] In Example 10, except that the composition was changed to the composition shown in Table 4, a film-coated tablet was produced in the same manner as in Example 6.

[0196] The tablets of Example 10 were filled with PTP (polypropylene), and then packaged with polyethylene aluminum pillows (combination packaging of PTP and polyethylene aluminum pillows), and placed at 60° C. for 1 month. After storage, the loxoprofen sodium content was measured by HPLC, and the residual rate before storage was calculated.

[0197] As a result, as shown in Example 10 (Table 4), good results were observed even when the tablets were filled with PTP (polypropylene) and stored in polyethylene aluminum pillow packaging.

[0198] [Table 4]

[0199]

[0200] <Preparation Examples 1 to 60>

[0201] The formulations of Preparation Examples 1 to 60 (6 tablets each) are shown in Tables 5 to 12.

[0202] In Preparation Examples 1 to 60, tablets can be prepared by the same method as in Example 1 except that the compositions were changed to the compositions shown in Tables 5 to 12.

[0203] [Table 5]

[0204]

[0205] [Table 6]

[0206]

[0207] [Table 7]

[0208]

[0209] [Table 8]

[0210]

[0211] [Table 9]

[0212]

[0213] [Table 10]

[0214]

[0215] [Table 11]

[0216]

[0217] [Table 12]

[0218]

[0219] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto, and additions, omissions, substitutions, and other changes to the configuration may be made without departing from the spirit of the present invention.

[0220] Industrial Applicability

[0221] The solid preparation of the present invention is particularly suitable as an antipyretic and analgesic for headache, menstrual pain (menstrual pain), toothache, pain after tooth extraction, sore throat, back pain, joint pain, muscle pain, shoulder pain, earache, contusion pain, fracture pain, sprain pain, trauma pain, etc., and for relieving fever during aversion to cold / fever. In addition, as a cold remedy, it is suitable for relieving various symptoms of colds (runny nose, nasal congestion, cough, sputum, sore throat, fever, aversion to cold, headache, sneezing, joint pain, muscle pain).

Claims

1. A solid preparation comprising: at least one selected from loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and hydroxypropyl cellulose.

2. The solid preparation according to claim 1, wherein The hydroxypropyl celluloses include at least one of hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose.

3. The solid preparation according to claim 2, wherein The particle size ratio D90 / D50 of the low-substituted hydroxypropyl cellulose is 1.5 to 3.

0.

4. The solid preparation according to claim 2 or 3, wherein The average particle size of the low-substituted hydroxypropyl cellulose is 30 to 60 μm.

5. The solid preparation according to claim 2 or 3, wherein The ratio of the hydroxypropoxy group in the low-substituted hydroxypropyl cellulose is 7 to 16%.

6. The solid preparation according to claim 2 or 3, wherein The compound containing at least one of magnesium and aluminum is one or more selected from magnesium oxide, magnesium aluminum metasilicate and synthetic hydrotalcite.

7. The solid preparation according to claim 2 or 3, further comprising one or more selected from crude drugs and extracts thereof, caffeine and sedatives.

8. The solid preparation according to claim 2 or 3, further comprising a compound having an amino group.

9. A method for producing a solid preparation, comprising: a method for producing a solid preparation containing at least one selected from loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose, comprising the following first step: Before adding at least one selected from loxoprofen and its salts and a compound containing at least one of magnesium and aluminum to granulate, water is added to the hydroxypropylcellulose to granulate.

10. The method for producing a solid preparation according to claim 9, wherein: In the first step, the mass of the water is 0.4 times or more relative to the mass of the hydroxypropyl cellulose.

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