Tablets, their manufacturing method, and pharmaceutical products

Abstract

To provide a tablet that has improved storage stability, disintegrates in a proper time when taken, and has improved leaching of an agent when taken.SOLUTION: A tablet has at least one granule containing loxoprofen or a salt thereof, and the exterior coating the granule. The exterior of the granule contains anhydrous calcium hydrogen phosphate, low-degree-substitution hydroxypropyl cellulose, and a disintegrator.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a tablet, a manufacturing method thereof, and a pharmaceutical product. More specifically, the present invention relates to a tablet containing loxoprofen or a salt thereof, which has excellent stability during storage, an appropriate disintegration time when taken, and excellent drug dissolution properties, a manufacturing method thereof, and a pharmaceutical product. [Background technology]

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter referred to as NSAIDs), exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, but is known to have strong antipyretic, analgesic, and anti-inflammatory effects. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract unchanged after oral administration, with little irritation to the gastric mucosa, and becomes active in the body. Therefore, it is known to have the characteristic of causing less gastric mucosal damage than other NSAIDs (see, for example, Non-Patent Document 1).

[0003] As techniques for further suppressing gastric mucosal damage by orally administering loxoprofen or a salt thereof in combination with other active ingredients, there have been disclosed techniques for incorporating specific sugars (lactose, sucrose, maltitol, fructose, xylitol, or lactitol) into loxoprofen (see Patent Document 1), for incorporating an antacid (magnesium oxide) (see Patent Document 2), and for incorporating the antiplasmin drug tranexamic acid (see Patent Document 3).

[0004] It has also been disclosed that loxoprofen sodium or its hydrate is highly hygroscopic, making it difficult to formulate it stably and to make it into a formulation with excellent storage stability after formulation (Patent Document 4).

[0005] Furthermore, an orally disintegrating tablet containing cetirizine (see Patent Document 5) is known as a rapidly disintegrating tablet. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 4585220 [Patent Document 2] Patent No. 6106727 [Patent Document 3] Patent No. 5835865 [Patent Document 4] Patent No. 6292744 [Patent Document 5] Special Re-publication 2009-054432 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmacology and Therapy Vol.16 No.2 1988 p.611-619 Summary of the Invention [Problem to be solved by the invention]

[0008] However, there are no known tablets containing loxoprofen or a salt thereof that have excellent storage stability during storage, an appropriate disintegration time when taken, and excellent drug dissolution properties.

[0009] The object of the present invention is to solve the above-mentioned problems, and to clarify the influence on the disintegration and solubility of tablets containing loxoprofen or a salt thereof in order to achieve "improved storage stability of the tablet," "tablet disintegration and dissolution in an appropriate time when taken," and "improved drug dissolution when taken." The object of the present invention is to provide a tablet that contains loxoprofen or a salt thereof, but is stable during storage, disintegrates and dissolves in an appropriate time when taken, and has suitable drug dissolution properties. [Means for solving the problem]

[0010] As a result of extensive research to solve the above-mentioned problems, the inventors of the present invention have discovered a tablet containing loxoprofen or a salt thereof that is stable during storage, disintegrates and dissolves within an appropriate time when taken, and has suitable drug dissolution properties, by providing a specific composition and structure to the tablet, thereby completing the present invention.

[0011] That is, the aspects of the present invention are as follows. (1) A tablet comprising at least one granule containing loxoprofen or a salt thereof and an outer granule configured to cover the granule, The extragranular portion contains anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a disintegrant. tablet. (2) The tablet according to (1), wherein at least one of the granules and the extragranules further contains an antacid. (3) The tablet according to (1) or (2), wherein the disintegrant comprises at least one of croscarmellose sodium and crospovidone. (4) The tablet according to any one of (1) to (3), wherein the granules further contain a third excipient other than anhydrous calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose. (5) The tablet according to (4), wherein the extragranular portion further comprises anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a fourth excipient different from the third excipient. (6) The tablet according to any one of (1) to (5), wherein the extragranular portion further comprises a lubricant. (7) A tablet according to any one of (1) to (6), which can begin to disintegrate within 3 minutes when measured according to the disintegration test method of the 17th edition of the Japanese Pharmacopoeia. (8) A tablet according to any one of (1) to (7), wherein the moisture content of the granules is less than 5% by weight. (9) A tablet according to any one of (1) to (8), wherein the moisture content of the tablet is less than 5% by weight. (10) producing at least one granule containing loxoprofen or a salt thereof; and a step of mixing the granules, anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a disintegrant, and compressing the mixture to produce tablets; The method for producing a tablet according to any one of (1) to (9), comprising: (11) A pharmaceutical product comprising the tablet according to any one of (1) to (9) and a packaging material for packaging the tablet. (12) The pharmaceutical product according to (11), wherein the packaging material is made of a moisture-proof material. [Effects of the Invention]

[0012] The tablet of the present invention contains rofecoxib or a salt thereof, has improved storage stability, an appropriate disintegration time when taken, and is useful as a tablet of excellent quality with improved drug dissolution when taken. DETAILED DESCRIPTION OF THE INVENTION

[0013] <Tablets> The tablet of the present invention comprises at least one granulated granule containing loxoprofen or a salt thereof, and an extragranular portion configured to cover the granulated granule, and the extragranular portion contains anhydrous calcium hydrogen phosphate as a first excipient, low-substituted hydroxypropyl cellulose as a second excipient, and a disintegrant. In the present invention, "disintegration and dissolution of a tablet within an appropriate time" is not particularly limited, but refers to a tablet disintegrating and dissolving so as to release loxoprofen or a salt thereof within an appropriate time after ingestion. For example, in a tablet disintegration test according to the "Disintegration Test Method" of the Japanese Pharmacopoeia, 17th Edition, the disintegration time of the tablet may be 3.4 minutes or less. In the present invention, a tablet with a disintegration time of 3.4 minutes or less is defined as a rapidly disintegrating tablet. In the above tablet disintegration test, the disintegration time of the tablet in the present invention is preferably 3 minutes or less, more preferably 2.9 minutes or less, and even more preferably 2.7 minutes or less.

[0014] The outline of the equipment used for the "Disintegration Test" in the 17th Edition of the Japanese Pharmacopoeia is described below. 1. Equipment The apparatus consists of a 1000 mL low-profile beaker with a height of 138-160 mm and an inner diameter of the immersion section of 97-115 mm, a thermostatic bath with a temperature controllable to 37±2°C, a tester that moves up and down 29-32 times per minute with an amplitude of 53-57 mm, and a motor. The amount of test liquid in the beaker is such that when the tester is at its highest point, the mesh surface of the tester is at least 15 mm below the liquid surface. When the tester is at its lowest point, the mesh surface must be at least 25 mm above the bottom of the beaker, and the tester must not be completely submerged. The motor's upward and downward movements should be equal in duration, and the upward and downward direction changes should be smooth, not abrupt. The tester should operate along a vertical axis, with no horizontal movement or displacement. (i) Test Apparatus: The test apparatus contains six open-ended transparent tubes measuring 77.5±2.5 mm in length, 20.7–23 mm in inner diameter, and 1.0–2.8 mm in thickness. Two plastic plates, each measuring 88–92 mm in diameter and 5–8.5 mm in thickness, hold the tubes vertically. Each plate has six holes, each 22–26 mm in diameter, equidistant and evenly spaced from the center. A flat stainless steel mesh with a mesh opening of 1.8–2.2 mm and a wire diameter of 0.57–0.66 mm is attached to the underside of the lower plastic plate. The test apparatus is assembled and secured using three supports that penetrate the two plastic plates. The test apparatus conforms to the structure shown in Figure 6.09-1 of the 17th Edition of the Japanese Pharmacopoeia. As long as the glass tube and mesh comply with the specifications, minor modifications to other parts are permitted. For example, to secure the glass tube to the tester, acid-resistant metal plates 88-92 mm in diameter and 0.5-1 mm thick with six holes of 22-26 mm diameter may be attached to the top surface of the upper plastic plate and the underside of the lower plastic plate. The tester is hung from an electric motor in an appropriate manner so that it can move up and down along its central axis.

[0015] 2.Operation method One tablet sample is placed in each of the six glass tubes of the tester, and the tester is operated at 37±2°C using water as the test liquid. The tester is removed from the test liquid as needed, and the state of disintegration of the sample is observed. When no sample residue is found in the glass tube, the sample is deemed to have disintegrated, and the disintegration time of the six samples is measured.

[0016] [Tablet hardness] The hardness of the tablet of the present invention is not particularly limited, but is preferably 10 kgf or more, more preferably 17 to 20 kgf.

[0017] [Granulated granules] The granules of the present invention contain loxoprofen or a salt thereof. In the present invention, "loxoprofen or a salt thereof" refers to loxoprofen or a salt thereof (including a hydrate salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. Loxoprofen or a salt thereof used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0018] The content of loxoprofen or a salt thereof in the tablet of the present invention is not limited, but the amount of the ingredient contained in one tablet per dosage unit (single dose) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 60 to 90 mg, in anhydrous equivalent, and the number of doses is 1 to 3 times a day.

[0019] In the tablet of the present invention, the content of rofecoxib or a salt thereof contained in the granulated granules is not particularly limited, but the amount of the ingredient contained in one tablet per dosage unit (single dose) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 60 to 90 mg, in anhydrous equivalent.

[0020] The amount of rofecoxib or a salt thereof contained in the granulated granules is not particularly limited, but is 1 to 80 parts by weight, preferably 20 to 75 parts by weight, more preferably 35.1 to 70 parts by weight, and may be 40 to 60 parts by weight per 100 parts by weight of the granulated granules.

[0021] [Outside of the granule (outside of the granule)] The extragranular portion (extragranular portion of granulated granules) in the present invention is a portion that constitutes the exterior of the granulated granules in a tablet. For example, the extragranular portion (extragranular portion of a granulated granule) may be a portion configured to cover one granulated granule in a tablet, or may be a portion configured to cover multiple granulated granules.

[0022] For example, the extragranular portion may be a portion that covers at least one granulated granule in a tablet and also constitutes the outer surface of the tablet. The extragranular space contains anhydrous calcium hydrogen phosphate as a first excipient, low-substituted hydroxypropyl cellulose as a second excipient, and a disintegrant. The first and second excipients and the disintegrant are different compounds. Here, "the first excipient, the second excipient, and the disintegrant are different compounds" means that three different compounds, namely, the first excipient (anhydrous calcium hydrogen phosphate), the second excipient (low-substituted hydroxypropyl cellulose), and the disintegrant, are used to form the extragranular portion. By including three different compounds, namely, the first excipient (anhydrous calcium hydrogen phosphate), the second excipient (low-substituted hydroxypropyl cellulose), and a disintegrant, it is possible to improve the tablet's properties such as "storage stability of the tablet," "disintegration and dissolution of the tablet at an appropriate time when taken," and "dissolution of the drug when taken."

[0023] The first excipient contained within the extragranules is anhydrous calcium hydrogen phosphate. Furthermore, the first excipient contained outside the granules is preferably anhydrous calcium hydrogen phosphate having an apparent specific volume of 1.2 to 5 mL / g, more preferably anhydrous calcium hydrogen phosphate having an apparent specific volume of 1.5 to 4 mL / g. If the first excipient contained outside the granules is anhydrous calcium hydrogen phosphate, it is possible to prevent the tablet from cracking during storage, and contribute to disintegration by its water-conducting effect when the tablet is taken, while reducing the risk of the tablet cracking due to moisture absorption and expansion after tablet formation (during tablet storage, before tablet taking), thereby obtaining a tablet with excellent storage stability. The content of the first excipient, anhydrous calcium hydrogen phosphate, contained in the extragranular portion is not particularly limited, but is 0.1 to 30 parts by weight, preferably 1 to 25 parts by weight, more preferably 2 to 20 parts by weight, may be 3 to 15 parts by weight, or may be 5 to 10 parts by weight, per 100 parts by weight of the extragranular portion. Furthermore, the anhydrous calcium hydrogen phosphate used as the first excipient may be, for example, one listed in the Pharmaceutical Additives Encyclopedia, and for example, anhydrous calcium hydrogen phosphate (heavy) manufactured by Kyowa Chemical Industry Co., Ltd. may be used.

[0024] The second excipient contained outside the granules is low-substituted hydroxypropyl cellulose. "Low-substituted hydroxypropyl cellulose" is hydroxypropyl cellulose in which a small number of hydroxypropoxy groups have been introduced into the glucose ring (hydroxypropyl cellulose in which the hydroxypropoxy groups are 5.0 to 16.0% and the number of molar substitutions per glucose residue is 0.11 to 0.39). In addition, commercially available low-substituted hydroxypropyl cellulose may be that listed in the 17th edition of the Japanese Pharmacopoeia or that listed in the Pharmaceutical Additives Dictionary, such as L-HPC (manufactured by Shin-Etsu Chemical Co., Ltd.). If the second excipient contained outside the granules is low-substituted hydroxypropyl cellulose, there is a low risk of the tablet cracking due to moisture absorption and expansion after tablet formation (during tablet storage, before tablet administration), and tablets with excellent storage stability can be obtained. The content of low-substituted hydroxypropyl cellulose, which is the second excipient contained in the outside of the granules, is not particularly limited, but is 0.1 to 50 parts by weight, preferably 1 to 40 parts by weight, more preferably 5 to 35 parts by weight, and even more preferably 10 to 35 parts by weight, and may be 12 to 20 parts by weight per 100 parts by weight of the outside of the granules.

[0025] The disintegrant contained outside the granule is preferably, for example, croscarmellose sodium or crospovidone. Furthermore, the disintegrant contained outside the granules is more preferably croscarmellose sodium. If the disintegrant contained outside the granules is crospovidone, the disintegration time of the tablet when taken is appropriate, and cracking of the tablet due to moisture absorption and expansion after tablet formation (during tablet storage and before taking the tablet) is prevented. The croscarmellose sodium or crospovidone used in the present invention may be, for example, any of those listed in the Dictionary of Pharmaceutical Additives.

[0026] If the disintegrant contained outside the granules is croscarmellose sodium, the disintegration time of the tablet when taken is appropriate, and cracking of the tablet due to moisture absorption and expansion after tablet formation (during tablet storage, before taking the tablet) is prevented, and good stability (good dissolution stability, for example, good dissolution stability of the drug after tablet storage) can be achieved without delay in dissolution of loxoprofen or a salt thereof. The content of the disintegrant contained in the outside of the granules is not particularly limited, but is 0.1 to 65 parts by weight, preferably 1 to 60 parts by weight, more preferably 10 to 60 parts by weight, even more preferably 15 to 60 parts by weight, and may be 15 to 50 parts by weight, 15 to 40 parts by weight, or 15 to 30 parts by weight, per 100 parts by weight of the outside of the granules.

[0027] [Optional ingredients in granules and / or outside the granules] The granules of the present invention may contain an excipient (third excipient). The excipient (third excipient) contained in the granules can be one or more components selected from, for example, crystalline cellulose, powdered cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, etc. Among these, the excipient (third excipient) contained in the granules is preferably anhydrous calcium hydrogen phosphate, more preferably anhydrous calcium hydrogen phosphate having an apparent specific volume of less than 1.2 mL / g, and even more preferably anhydrous calcium hydrogen phosphate having an apparent specific volume of 1.15 mL / g or less. If the excipient (third excipient) contained in the granules is anhydrous calcium hydrogen phosphate, the granules can be easily disintegrated by the addition of water when the tablet is taken. The content of the third excipient contained in the granules is not particularly limited, but is 0.1 to 30 parts by weight, preferably 1 to 20 parts by weight, and more preferably 5 to 15 parts by weight per 100 parts by weight of the granules. Furthermore, as the third excipient, anhydrous calcium hydrogen phosphate, for example, one listed in the Pharmaceutical Additives Encyclopedia can be used.

[0028] At least one of the granules and the extragranules may contain an antacid. In other words, either the granules or the extragranules may contain an antacid, or both the granules and the extragranules may contain an antacid. If an antacid is contained in at least one of the granules and the outer part of the granules in the tablet, damage to the gastric mucosa can be suitably suppressed. Examples of antacids contained in at least one of the granules and the exterior of the granules include ingredients that raise the pH of gastric acid, such as glycine (also known as aminoacetic acid), magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, co-precipitation products 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, co-precipitation products of aluminum hydroxide and sodium bicarbonate, dried mixed gel of aluminum hydroxide and magnesium carbonate, co-precipitation products of aluminum hydroxide, magnesium carbonate and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and salts 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.

[0029] Among these, the antacid contained in at least one of the granules and the outer part of the granules in the tablet is preferably magnesium aluminometasilicate. If the granules in the tablet contain magnesium aluminometasilicate, the effect of suppressing gastric mucosal damage is obtained, and in addition, the hardness of the granules is improved. If magnesium aluminometasilicate is contained outside the granules of the tablet, the disintegration time can be shortened in addition to the effect of suppressing gastric mucosal damage. From the viewpoint of improving the hardness of the granules and shortening the disintegration time of the tablet, it is more preferable that the tablet of the present invention contains magnesium aluminometasilicate both in the granules and outside the granules. The magnesium aluminometasilicate used in the present invention may be, for example, one listed in the Dictionary of Pharmaceutical Additives.

[0030] The content of the antacid contained in the granules is not particularly limited, but is 0.1 to 80 parts by weight, preferably 15 to 70 parts by weight, and more preferably 30 to 60 parts by weight per 100 parts by weight of the granules. The content of the antacid contained in the extragranular portion is not particularly limited, but is 0.1 to 70 parts by weight, preferably 1 to 65 parts by weight, more preferably 10 to 60 parts by weight, even more preferably 20 to 60 parts by weight, particularly preferably 30 to 50 parts by weight, and may be 35 to 50 parts by weight or 40 to 50 parts by weight per 100 parts by weight of the extragranular portion.

[0031] At least one of the granules and the extragranules may contain a gastrointestinal ingredient. Examples of gastrointestinal drug ingredients include gefarnate, cetraxate hydrochloride, rebamipide, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like.

[0032] The moisture content of the granules is not particularly limited, but is preferably less than 5% by weight, more preferably 4% by weight or less, even more preferably 3% by weight or less, and particularly preferably 2% by weight or less. Furthermore, if the moisture content of the granules is 2% by weight or less, it is possible to suppress a decrease in the loxoprofen content and to obtain tablets with excellent long-term stability. The moisture content of the tablet (uncoated tablet) is not particularly limited, but is preferably less than 5% by weight, more preferably 4% by weight or less, even more preferably 3% by weight or less, and particularly preferably 2% by weight or less. If the moisture content of the tablet (uncoated tablet) is 3% by weight or less, the decrease in the loxoprofen content can be suppressed and tablets with excellent long-term stability can be obtained.

[0033] The extragranular portion may contain an "optional excipient (fourth excipient)." The optional excipient (fourth excipient) may be one or more components selected from, for example, crystalline cellulose, powdered cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, etc. Preferably, the optional excipient included outside the granule (fourth excipient) is lactose. If the optional excipient (fourth excipient) contained outside the granules is lactose, the three effects of "improving the storage stability of the tablet," "disintegrating and dissolving the tablet at an appropriate time when taken," and "improving the dissolution and stability of the drug when taken" can be more effectively achieved. The content of the fourth excipient contained in the extragranular portion is not particularly limited, but is 0.1 to 70 parts by weight, preferably 1 to 50 parts by weight, more preferably 2 to 40 parts by weight, even more preferably 3 to 30 parts by weight, and particularly preferably 5 to 20 parts by weight, per 100 parts by weight of the extragranular portion. The lactose used as the fourth excipient in the present invention may be, for example, any of those listed in the Pharmaceutical Additives Encyclopedia.

[0034] The extragranular space may contain a lubricant. The lubricant may be one or more components selected from, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hardened oil, and the like. The lubricant contained outside the granules is preferably magnesium stearate. The content of the lubricant contained in the outside of the granules is not particularly limited, but may be 0.1 to 10 parts by weight per 100 parts by weight of the outside of the granules.

[0035] The tablet of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. The active ingredient, loxoprofen or a salt thereof, has antipyretic, analgesic, and anti-inflammatory effects, and therefore can be suitably used as an analgesic and antipyretic, particularly 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, and trauma pain, as well as for the fever reduction during chills and fever, and can also be suitably used as a cold treatment 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).

[0036] The tablet of the present invention can be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc., such as tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and oral tablets (including lozenges, sublingual tablets, buccal tablets, adhesive tablets, etc.). These compositions may further contain other active ingredients, such as antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives, as needed, within the scope of the present invention. If there are any contraindications for these ingredients, they may be formulated by dividing them into granules or the like. Regarding granulation, if there is any incompatibility, for example, the granulation may be divided so that different active ingredients are contained in the granules and outside the granules in order to avoid the incompatibility.

[0037] 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, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.

[0038] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyldisulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, etc.

[0039] Anti-inflammatory agents include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

[0040] 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.

[0041] Vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, a mixture of equal parts 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.

[0042] Xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate. Sedatives include allylisopropylacetylurea and bromvalerylurea.

[0043] The tablets of the present invention can be formulated according to conventional methods. In the present invention, tablets may be produced by preparing granules containing loxoprofen or a salt thereof, adding anhydrous calcium hydrogen phosphate as a first excipient, low-substituted hydroxypropyl cellulose as a second excipient, a disintegrant, and a lubricant as powders to the obtained granules so as to form an outer granule portion, and compressing the mixture. That is, the tablets of the present invention can be produced by the steps of: preparing at least one granule containing loxoprofen or a salt thereof; and mixing the granules with anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, a disintegrant, and optionally other additives, followed by compressing the mixture to produce tablets. Furthermore, as described in the above section on "Tablets," the tablets may be produced by optionally adding additives (optional ingredients such as antacids, gastrointestinal ingredients, third excipients, fourth excipients, etc.) to the outside of the granules. The components placed outside the granules may optionally be in the form of granules.

[0044] The formulation can be prepared using known methods and additives as appropriate, provided that the additives do not impair the effects of the present invention. Examples of additives include any coating agent, binder, fluidizing agent, plasticizer, sugar coating agent, glossing agent, solvent, pH adjuster, colorant, flavoring agent, sweetener, flavoring agent, flavoring agent, and the like.

[0045] The optional coating agent may be one or more components selected from, for example, aminoalkyl methacrylate copolymer, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, talc, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pullulan, povidone, polyvinyl alcohol, macrogol, etc.

[0046] The binder may be one or more components selected from the group consisting of gum arabic, powdered gum arabic, agar, powdered agar, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol, methacrylic acid copolymer L, methacrylic acid copolymer, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, etc.

[0047] The fluidizing agent may be one or more components selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, calcium triphosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0048] As the plasticizer, one or more components selected from triethyl citrate, glycerin, glycerin fatty acid ester, medium-chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, liquid paraffin, etc. can be blended.

[0049] The sugar-coating agent may be 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, polyoxyethylene, polyvinyl alcohol, macrogol, etc.

[0050] As the glossing agent, one or more components selected from carnauba wax, purified shellac, macrogol, beeswax, etc. can be blended.

[0051] As the solvent, one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol, and the like can be blended.

[0052] The pH adjuster may be one or more components selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine, etc.

[0053] The coloring agent may be one or more components selected from yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium oxide, yellow iron sesquioxide, iron sesquioxide, iron sesquioxide-glycerin suspension, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, copper chlorophyllin sodium, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc.

[0054] Flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron bark extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and ginger. It can contain one or more ingredients selected from the group consisting of sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, Ryuno, Ryuno powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil.

[0055] The sweetener may be one or more ingredients selected from aspartame, acesulfame potassium, amacha, amacha 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 white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0056] The flavoring may be one or more ingredients 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, l-menthol, peppermint oil, etc.

[0057] Flavoring agents and fragrances include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, and Vitabase. It can contain one or more ingredients selected from the following: Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0058] These additives are not limited to those listed above, and one of these may be used alone or two or more of them may be used in combination.

[0059] The tablets of the present invention may be temporarily packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and then stored airtight. They may also be pillow-packaged, and 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 a tablet according to the above embodiment and a packaging material for packaging the tablet. The materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples thereof include resin films such as polyethylene, polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached thereto.

[0060] The packaging material for the tablets of the present invention is preferably, for example, packaging made of a material that is not easily affected by moisture (packaging made of a moisture-proof material). For example, PTP (polypropylene) + polyethylene aluminum pillow packaging (combined packaging of PTP and polyethylene aluminum pillow) may be used as packaging made of a material that is less susceptible to moisture (moisture-proof material). Also, taking into consideration the prevention of an increase in the moisture content of tablets, the storage stability of tablets, and the stability of tablets after opening, PTP packaging (Al-Al packaging) using aluminum on both sides may be used as 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 in the bottle packaging or pillow packaging at the same time.

[0061] The present invention will be explained in more detail below by way of examples, but is not limited to these examples. [Example]

[0062] <Production of tablets of Example 1> Loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.), lactose hydrate (Dilactose F, Freund Corporation), anhydrous calcium hydrogen phosphate (heavy calcium hydrogen phosphate, Kyowa Chemical Industry Co., Ltd.), and ferric oxide (Titanium Industry Co., Ltd.) were mixed to form granules. To the granules were added anhydrous calcium hydrogen phosphate (Fuji Chemical Industry Co., Ltd., Fujicalin SG), croscarmellose sodium (FMC International, AcDiSol Croscarmellose Sodium), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC LH-11), and magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)). Thereafter, the mixture of the granulated granules and the powder was compressed to form an outer granule portion, thereby obtaining tablets. The composition of Example 1 is shown in Table 1.

[0063] <Evaluation of characteristics of the tablet of Example 1> (1) The disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. The conditions are as follows: (1) The disintegration time of the tablets was measured in accordance with the "Disintegration Test Method" of the 17th Edition of the Japanese Pharmacopoeia. (2) The tablets were placed in a petri dish and left in the open at 25°C and 60% RH for 3 days to check whether cracks occurred.

[0064] The results of the evaluation of the properties of the tablets of Example 1 are shown in Table 1. In Table 1 and the following tables, the correspondence for the "Tablet cracking" item is as follows: ◯: No cracking of the tablet occurred in the test (2) above. ×: In the test (2) above, the tablet absorbed moisture, expanded, and cracked. In addition, in Table 1 and the following tables, "-" means that no ingredient was added to the tablet, and "N / A" means that no evaluation was performed.

[0065] The tablet hardness, moisture content of the granules, and moisture content of the uncoated tablets (tablets) were also measured. The hardness of the tablets was measured using a hardness tester, model KHT-20 (manufacturer: Fujiwara Seisakusho Co., Ltd.). The moisture content of the granulated granules and the uncoated tablets was measured using a halogen moisture meter, model HB43 (manufacturer: Mettler-Toledo K.K.), and the loss on drying after heating at 80°C for 15 minutes was used to measure the moisture content. In the following Examples and Comparative Examples, the tablet hardness, the moisture content of the granulated granules, and the moisture content of the uncoated tablets (tablets) were measured in the same manner as in Example 1.

[0066] <Production of tablets of Comparative Example 1> Tablets of Comparative Example 1 were prepared in the same manner as in Example 1, except that low-substituted hydroxypropyl cellulose was not added to the final powder. The composition of Comparative Example 1 is shown in Table 1.

[0067] <Characteristics evaluation of Comparative Example 1> Using the same method as in Example 1, (1) the disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. The results of the characteristic evaluation of Comparative Example 1 are shown in Table 1.

[0068] [Table 1]

[0069] The results of Example 1 and Comparative Example 1 confirmed that by incorporating low-substituted hydroxypropyl cellulose (L-HPC) into tablets, cracking of the tablets due to moisture absorption and expansion tends to be suppressed.

[0070] <Production of tablets of Example 2> Loxoprofen sodium hydrate, Neusilin (magnesium aluminometasilicate) as an antacid, lactose hydrate as an excipient, anhydrous calcium hydrogen phosphate as an excipient, and ferric oxide as a colorant were mixed to form granules. To the granules, anhydrous calcium hydrogen phosphate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose were added as powders. Thereafter, the mixture of the granulated granules and the powder was compressed to form an outer granule portion, thereby obtaining tablets. The composition of Example 2 is shown in Table 2.

[0071] <Evaluation of tablet properties of Example 2> Using the same method as in Example 1, (1) the disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. The results of the evaluation of the properties of the tablets of Example 2 are shown in Table 2.

[0072] <Production of tablets of Comparative Example 2> Tablets of Comparative Example 2 were prepared in the same manner as in Example 2, except that carmellose, a "disintegrant," was added to the final powder instead of anhydrous calcium hydrogen phosphate, a "filler." The composition of Comparative Example 2 is shown in Table 2.

[0073] <Characteristics Evaluation of Comparative Example 2> Using the same method as in Example 2, (1) the disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. The results of the characteristic evaluation of Comparative Example 2 are shown in Table 2.

[0074] [Table 2]

[0075] As shown in Example 2, when anhydrous calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose were added as excipients and croscarmellose sodium as a disintegrant to the outside of the granules, the disintegration time of the tablets was within 3.3 minutes, and no cracking of the tablets due to swelling due to moisture absorption occurred in the characteristic evaluation test described in (2) above. As shown in Comparative Example 2, when carmellose, a water-conducting disintegrant, was added to tablets instead of anhydrous calcium hydrogen phosphate, which is an excipient and a water-conducting disintegrant, the disintegration time of the tablets was shortened, but the risk of tablet cracking in the characteristic evaluation test in (2) above increased.

[0076] <Production of tablets of Example 3> Loxoprofen sodium hydrate, Neusilin (magnesium aluminometasilicate) as an antacid, lactose hydrate as an excipient, anhydrous calcium hydrogen phosphate as an excipient, and ferric oxide as a colorant were mixed to form granules. To the granules, anhydrous calcium hydrogen phosphate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose were added as powders. Thereafter, the mixture of the granulated granules and the powder was compressed to form an outer granule portion, thereby obtaining tablets. The composition of Example 3 is shown in Table 3.

[0077] <Evaluation of tablet characteristics of Example 3> Using the same method as in Example 1, (1) the disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. The results of the evaluation of the properties of the tablets of Example 3 are shown in Table 3.

[0078] <Production of tablets of Example 4> The tablets of Example 4 were prepared in the same manner as in Example 3, except that the granules were prepared so as not to contain ferric oxide as a colorant. The composition of Example 4 is shown in Table 3.

[0079] <Characteristics Evaluation of Example 4> Using the same method as in Example 3, (1) the disintegration time of the tablets was measured, and (2) the presence or absence of cracks due to moisture absorption and expansion of the tablets was confirmed. In Example 4, (3) "Test to confirm drug dissolution and tablet stability (dissolution stability)" was conducted. The following experiment was conducted as a "test to confirm the drug dissolution and tablet stability (dissolution stability)."

[0080] For the dissolution test, the following standard test method for "Loxoprofen Sodium Tablets" in the 17th Edition of the Japanese Pharmacopoeia was adopted. When the test was conducted using 900 mL of water as the test liquid at 50 revolutions per minute (50 rpm) using the paddle method, if the dissolution rate after 30 minutes was 85% or more, the tablet was judged to have good dissolution properties. Furthermore, a tablet was judged to be stable if the difference in dissolution rate at 30 minutes after storage at 60°C for 1 month compared to the dissolution rate at 30 minutes after storage in a dissolution test for a tablet immediately after production was within 2%.

[0081] In this and the following examples, the following indicators were used: The "Dissolution Stability" section in the table corresponds to the results of the "test to confirm drug dissolution and tablet stability (dissolution stability)," and the symbols in the table have the following meanings. ○: The drug dissolution was excellent immediately after production and in tests on aged tablets, and the tablet stability was also excellent (in other words, in the above dissolution test, when the paddle method was used at 50 rpm and the test liquid was water, 85% or more of the drug was dissolved within 30 minutes, and when the tablet was stored at 60°C for 1 month, the difference between the dissolution rate at 30 minutes in the dissolution test and the dissolution rate at 30 minutes in the dissolution test on a tablet immediately after production was within 2%). △: Excellent drug dissolution was observed immediately after production, but there was a slight delay in dissolution in tests on aged tablets, and the results of tests to confirm tablet stability (dissolution stability) were slightly inferior compared to the above "○" cases (in other words, in the above dissolution test, 85% or more of the drug was dissolved within 30 minutes using the paddle method at 50 rpm and water as the test liquid, but even after storing the tablets at 60°C for 1 month, the difference in dissolution rate at 30 minutes in the dissolution test compared to the dissolution rate at 30 minutes in the dissolution test of tablets immediately after production was more than 2%). ×: The results of the tests to confirm the drug dissolution and tablet stability (dissolution stability) were not good. The results of the characteristic evaluation of Example 4 are shown in Table 3.

[0082] <Production of tablets of Example 5> Tablets of Example 5 were prepared in the same manner as in Example 4, except that the outer part of the granules was prepared so as to contain crospovidone (Kollidon CL, manufactured by BASF) as a disintegrant instead of croscarmellose sodium. The composition of Example 5 is shown in Table 3.

[0083] <Characteristics Evaluation of Example 5> Using the same methods as in Example 4, (1) measurement of tablet disintegration time, (2) confirmation of whether or not the tablet had cracked due to moisture absorption and expansion, and (3) "test to confirm drug dissolution and tablet stability (dissolution stability)" were conducted.

[0084] <Production of tablets of Example 6> The tablets of Example 6 were prepared in the same manner as in Example 4, except that the outer granules were prepared to contain crospovidone (Kollidon CL-F, manufactured by BASF) as a disintegrant instead of croscarmellose sodium. The composition of Example 6 is shown in Table 3.

[0085] <Characteristics Evaluation of Example 6> Using the same methods as in Example 4, (1) measurement of tablet disintegration time, (2) confirmation of whether or not the tablet had cracked due to moisture absorption and expansion, and (3) "test to confirm drug dissolution and tablet stability (dissolution stability)" were conducted.

[0086] <Production of tablets of Example 7> The tablets of Example 7 were prepared in the same manner as in Example 6, except that the tablets were prepared so that part of the magnesium aluminometasilicate and lactose were included outside the granules instead of being included in the granulated granules. The composition of Example 7 is shown in Table 3.

[0087] <Characteristics Evaluation of Example 7> Using the same method as in Example 6, (1) measurement of tablet disintegration time, (2) confirmation of whether or not the tablet had cracked due to moisture absorption and expansion, and (3) "test to confirm drug dissolution and tablet stability (dissolution stability)" were conducted.

[0088] <Production of tablets of Example 8> The tablets of Example 8 were prepared in the same manner as in Example 7, except that croscarmellose sodium (Ac-Di-Sol, manufactured by FMC International) was used instead of crospovidone (Kollidon CL-F, manufactured by BASF) outside the granules. The composition of Example 8 is shown in Table 3.

[0089] <Characteristics Evaluation of Example 8> Using the same method as in Example 7, (1) measurement of tablet disintegration time, (2) confirmation of whether or not the tablet had cracked due to moisture absorption and expansion, and (3) "test to confirm drug dissolution and tablet stability (dissolution stability)" were conducted.

[0090] [Table 3]

[0091] From the results of Examples 3 and 4, no significant changes in properties were observed even when ferric oxide was not used as a colorant. Furthermore, the tablets of Example 4 were excellent in drug dissolution and tablet stability (dissolution stability).

[0092] Furthermore, a comparison between Example 6 and Example 7 showed that the disintegration time tended to be shortened by adding a portion of the Neusilin added to the granules and lactose to the outside of the granules (final part). Comparison of Example 4 with Examples 5 and 6 showed that when the disintegrant added outside the granules was crospovidone, the disintegration time tended to be shorter than when the disintegrant added outside the granules was croscarmellose sodium. On the other hand, a comparison of Example 4 with Examples 5 and 6 showed that the dissolution of the drug and the stability of the tablets (dissolution stability) tended to be better when croscarmellose sodium was used as the disintegrant added to the outside of the granules than when crospovidone was used as the disintegrant added to the outside of the granules. The results of this experiment confirmed that by adding a portion of Neusilin, lactose as an excipient, and croscarmellose sodium as a disintegrant to the outside of the granules (final part), (1) the tablet disintegration time is within 3 minutes, (2) cracking of the tablet is prevented, and (3) the drug dissolution is excellent and the tablet stability (dissolution stability) tends to be excellent.

[0093] For Examples 9 and 10, in order to verify the storage stability of the tablets under even harsher conditions, tablets having the same composition as Example 8 except for the moisture content were prepared and the following investigation was carried out. <Production of tablets of Examples 9 and 10> Using the same method as in Example 8, tablets of Examples 9 and 10 were prepared to have the compositions shown in Table 4. The tablets of Examples 9 and 10 have the same composition as Example 8 except for the moisture content, and from the viewpoint of the evaluations (1) to (3) shown in Examples 1 to 8 above, they are tablets with improved storage stability, appropriate disintegration times when taken, and improved drug dissolution when taken.

[0094] <Characterization of Examples 9 and 10> The tablets were packaged in press-through packages (Al-Al packaging) and left for 6 months at 40°C and 75% RH. After storage for 6 months at 40°C and 75% RH, the loxoprofen sodium content in the tablets was measured by HPLC, and the residual rate from before storage (the ratio of the loxoprofen sodium content in the tablets after 6 months of storage at 40°C and 75% RH to the loxoprofen sodium content in the tablets before storage (100%)) was calculated.

[0095] [Table 4]

[0096] Furthermore, a comparison between Example 9 and Example 10 revealed that tablets with a lower moisture content tended to have better storage stability (remaining rate of rofecoxib sodium) even under harsher conditions (storage for 6 months at 40°C and 75% RH). The results of this experiment confirmed that by lowering the moisture content of the formulation, the storage stability (remaining rate of loxoprofen sodium) of the tablets tends to be better even under harsh conditions.

[0097] (Formulation Examples 1 to 4) Using the same method as in Example 1, tablets of Preparation Examples 1 to 4 were prepared to have the compositions shown in Table 5.

[0098] [Table 5]

[0099] 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. [Industrial Applicability]

[0100] The tablet of the present invention contains rofecoxib or a salt thereof, yet has excellent tablet stability (dissolution stability) during storage, an appropriate disintegration time when taken, and excellent drug dissolution, making it extremely useful in terms of quality. The tablet of the present invention is suitably used as an antipyretic and analgesic, particularly 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 shoulders, 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 treatment to relieve various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims

1. A tablet comprising at least one granulated granule containing loxoprofen or a salt thereof, and an outer granule configured to cover the granulated granule, the extragranular portion contains anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a disintegrant; the anhydrous calcium hydrogen phosphate, the low-substituted hydroxypropyl cellulose, and the disintegrant are added as powders to the granules, the content of the low-substituted hydroxypropyl cellulose outside the granule is 10 to 50 parts by weight, The content of the disintegrant outside the granule is 10 to 60 parts by weight. tablet.

2. 10. The tablet of claim 1, wherein at least one of the granules and the extragranules further comprises an antacid.

3. 3. The tablet of claim 1, wherein the disintegrant comprises at least one of croscarmellose sodium and crospovidone.

4. 4. The tablet according to claim 1, wherein the granules further comprise a third excipient other than anhydrous calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose.

5. 5. The tablet of claim 4, wherein the extragranular portion further comprises anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a fourth excipient different from the third excipient.

6. 6. The tablet of claim 1, wherein the extragranular portion further comprises a lubricant.

7. 7. The tablet according to claim 1, which can begin to disintegrate within 3 minutes when measured according to the disintegration test method of the Japanese Pharmacopoeia, 17th Edition.

8. The tablet according to any one of claims 1 to 7, wherein the moisture content of the granules is less than 5% by weight.

9. 9. A tablet according to any one of claims 1 to 8, wherein the moisture content of the tablet is less than 5% by weight.

10. Producing at least one granule containing loxoprofen or a salt thereof; and a step of mixing the granules, anhydrous calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose, and a disintegrant, and compressing the mixture to produce tablets; A method for producing the tablet according to any one of claims 1 to 9, comprising:

11. A pharmaceutical product comprising the tablet according to any one of claims 1 to 9 and a packaging material for packaging the tablet.

12. The pharmaceutical product of claim 11 , wherein the packaging material is formed from a moisture-proof material.

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