Orally disintegrating tablet comprising diamine derivative

Abstract

The present application relates to an orally disintegrating tablet comprising a diamine derivative. Specifically, provided is an orally disintegrating tablet comprising edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof. The orally disintegrating tablet comprises (A) edoxaban, a pharmacologically acceptable salt thereof or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0 wt% of a water-soluble polymer relative to the total weight of the tablet, and (D) a disintegrating agent.

Description

[0001] This application is a divisional application of the invention patent application filed on November 30, 2017, with application number 201780074493.5 and entitled "Orally Disintegrating Tablet Containing a Diamine Derivative". Technical Field

[0002] This invention relates to orally disintegrating tablets comprising edoxaban, a pharmacologically acceptable salt thereof, or a solvation thereof, said tablets rapidly disintegrating when placed in the mouth or in water and having sufficient hardness in normal production, transport, and use; and to a method for preparing said orally disintegrating tablets. Background Technology

[0003] Known oral solid dosage forms in the pharmaceutical and food industries include tablets, capsules, granules, and powders, but there is a desire to develop orally disintegrating tablets that rapidly disintegrate when placed in the mouth or in water as a dosage form that is easier for the elderly, infants, and patients with swallowing difficulties to take.

[0004] In addition to its rapid disintegration in the oral cavity, orally disintegrating tablets, as required of conventional tablets, should also possess sufficient hardness to withstand physical impacts during production, transportation, and use. Furthermore, also from the perspective of medication adherence, orally disintegrating tablets preferably have a pleasant taste, with unpleasant flavors and irritations suppressed when placed in the mouth.

[0005] To date, there have been various reports regarding orally disintegrating tablets. For example, Patent Document 1 describes an orally disintegrating tablet containing a drug with a bulk density of 0.23 g / cm³. 3 The following are microcrystalline cellulose, sugar alcohols, and pregelatinized starch. However, this literature does not describe orally disintegrating tablets containing edoxaban and organic acids.

[0006] Furthermore, Patent Document 2 describes an invention of a tablet containing levofloxacin and hydroxypropyl cellulose that exhibits excellent disintegration and suspension upon contact with water, but does not describe an orally disintegrating tablet containing edoxaban, organic acids, and hydroxypropyl cellulose.

[0007] Meanwhile, Patent Document 3 describes an invention of a pharmaceutical composition with improved dissolution properties, wherein the composition comprises (a) edoxaban, a pharmacologically acceptable salt thereof or a solvation thereof, and (b) one or more selected from sugar alcohols and water-swellable additives; and a coated tablet comprising (a) and (b) above, and further comprising (c) a water-swellable additive, the tablet coating having a coating comprising at least one or more selected from hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose and polyvinyl alcohol. However, the purpose of this document is to obtain a pharmaceutical composition comprising edoxaban with improved dissolution properties, and this document does not describe an orally disintegrating tablet comprising edoxaban and an organic acid and having high water disintegration and dissolution properties.

[0008] In addition, Patent Document 4 describes a formulation with improved dissolution properties comprising (a) edoxaban, its pharmacologically acceptable salt or a solvation thereof and (b) an organic acid, but does not describe an orally disintegrating tablet with high water disintegration and sufficient hardness to withstand physical shocks during production, transport and use.

[0009] Reference List Patent documents Patent Document 1: U.S. Patent Application Publication No. 2015 / 110880 Patent Document 2: Japanese Patent No. 5295506 Patent Document 3: US Patent No. 9149532 Patent document 4: US Patent No. 9402907. Summary of the Invention

[0010] Technical issues One object of the present invention is to provide an orally disintegrating tablet comprising edoxaban, a pharmacologically acceptable salt thereof, or a solvation thereof, which disintegrates rapidly when placed in the mouth or in water and has sufficient hardness and excellent storage stability during normal production, transport and use.

[0011] Solution to the problem To solve this problem, the inventors conducted diligent research and found that orally disintegrating tablets containing (A) edoxaban, its pharmacologically acceptable salt or solvates thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of a water-soluble polymer relative to the total weight of the tablet, and (D) a disintegrant can solve the problem, thus completing the present invention.

[0012] Therefore, the present invention provides an orally disintegrating tablet comprising (A) edoxaban, a pharmacologically acceptable salt thereof or a solvation thereof, (B) an organic acid, (C) a water-soluble polymer of 0.1 to 2.0% by weight relative to the total weight of the tablet, and (D) a disintegrant; and a method for preparing said orally disintegrating tablet.

[0013] Therefore, the present invention relates to the following (1) to (24).

[0014] (1) Orally disintegrating tablets comprising (A) edoxaban, its pharmacologically acceptable salt or solvation thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of a water-soluble polymer relative to the total weight of the tablet, and (D) a disintegrant.

[0015] (2) The orally disintegrating tablet according to (1), wherein (B) organic acid is one or more components selected from fumaric acid, alginic acid and aspartic acid.

[0016] (3) According to the orally disintegrating tablets described in (1), wherein (B) organic acid is fumaric acid.

[0017] (4) The orally disintegrating tablet according to any one of (1)-(3), wherein the content of (B) organic acid is 0.1-15% by weight relative to the total weight of the tablet.

[0018] (5) The orally disintegrating tablet according to any one of (1)-(4), wherein (C) the water-soluble polymer is one or more components selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.

[0019] (6) The orally disintegrating tablet according to any one of (1)-(4), wherein (C) the water-soluble polymer is hydroxypropyl cellulose.

[0020] (7) The orally disintegrating tablet according to any one of (1)-(6), wherein (D) the disintegrant is one or more components selected from carboxymethyl cellulose, crosspovidone, calcium carboxymethyl cellulose, croscarmellose sodium, corn starch, sodium glycolate starch and pregelatinized starch.

[0021] (8) The orally disintegrating tablet according to any one of (1)-(6), wherein (D) the disintegrant is carboxymethyl cellulose, crosspovidone and pregelatinized starch.

[0022] (9) The orally disintegrating tablet according to (7) or (8) further comprises a sugar alcohol and a bulk density of 0.26 g / cm³. 3 The following are microcrystalline celluloses.

[0023] (10) The orally disintegrating tablet according to (9), wherein the sugar alcohol is D-mannitol.

[0024] (11) The orally disintegrating tablet according to any one of (8)-(10), wherein the average degree of gelatinization of the pregelatinized starch is 90% or less.

[0025] (12) Orally disintegrating tablets comprising (A) edoxaban, its pharmacologically acceptable salt or solvation thereof, (B) an organic acid, (C) 0.1-2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablets, (E) carboxymethyl cellulose, (F) D-mannitol, and (G) a bulk density of 0.26 g / cm³. 3 The following are microcrystalline cellulose and (H) pregelatinized starch.

[0026] (13) The orally disintegrating tablet according to (12) comprises: a drug-containing mixed powder or drug-containing granules, said powder or granules comprising (A) edoxaban, a pharmacologically acceptable salt thereof or a solvation thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and a drug-free mixed powder comprising (F) D-mannitol, and (G) a bulk density of 0.26 g / cm³. 3 The following are microcrystalline cellulose and (H) pregelatinized starch.

[0027] (14) The orally disintegrating tablet according to (12) comprises: a drug-containing mixed powder or drug-containing granules, said powder or granules comprising (A) edoxaban, a pharmacologically acceptable salt thereof or a solvation thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and drug-free granules comprising (F) D-mannitol, and (G) a bulk density of 0.26 g / cm³. 3 The following are microcrystalline cellulose and (H) pregelatinized starch.

[0028] (15) The orally disintegrating tablet according to (12), comprising medicated particles containing (A) edoxaban, a pharmacologically acceptable salt thereof or a solvation thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and medicated particles containing (F) D-mannitol, and (G) a bulk density of 0.26 g / cm³. 3 The following are microcrystalline cellulose and (H) pregelatinized starch.

[0029] (16) The orally disintegrating tablet according to any one of (12)-(15), wherein (B) the organic acid is one or more components selected from fumaric acid, alginic acid and aspartic acid.

[0030] (17) An orally disintegrating tablet according to any one of (12)-(15), wherein (B) the organic acid is fumaric acid.

[0031] (18) The orally disintegrating tablet according to any one of (12)-(17) further comprises one or more components selected from crospovidone, calcium carboxymethyl cellulose, sodium crospovidone carboxymethyl cellulose, corn starch, sodium glycolate starch and pregelatinized starch.

[0032] (19) The orally disintegrating tablet according to any one of (12)-(17) further comprises cropovidone.

[0033] (20) An orally disintegrating tablet according to any one of (12)-(19), wherein the organic acid is 0.1-15% by weight relative to the total weight of the tablet.

[0034] (21) An orally disintegrating tablet according to any one of (12)-(20), wherein the microcrystalline cellulose is 1-50% by weight relative to the total weight of the tablet.

[0035] (22) The orally disintegrating tablet according to any one of (12)-(21), wherein the average degree of gelatinization of the pregelatinized starch is 90% or less.

[0036] (23) An orally disintegrating tablet according to any one of (12)-(22), wherein the tablet disintegrates within 60 seconds in a disintegration test.

[0037] (24) A method for preparing orally disintegrating tablets, comprising: mixing (A) edoxaban, a pharmacologically acceptable salt thereof or a solvate thereof, (B) fumaric acid and (E) carboxymethyl cellulose and spraying (C) hydroxypropyl cellulose dissolved in water at 0.1-2.0% by weight relative to the total weight of the tablets onto the mixture to produce drug-containing particles; and mixing (F) D-mannitol and (G) a bulk density of 0.26 g / cm³. 3 The steps are as follows: mixing microcrystalline cellulose and spraying (H) pregelatinized starch dissolved or dispersed in water onto the mixture to produce drug-free granules; and compression molding the resulting two types of granules.

[0038] (25) A method for preparing orally disintegrating tablets, comprising: mixing (A) edoxaban, a pharmacologically acceptable salt thereof or a solvate thereof, (B) fumaric acid, (C) hydroxypropyl cellulose in an amount of 0.1-2.0% by weight relative to the total weight of the tablets, and (E) carboxymethyl cellulose, and spraying water onto the mixture to produce drug-containing particles; and mixing (F) D-mannitol and (G) a bulk density of 0.26 g / cm³. 3The steps are as follows: mixing microcrystalline cellulose and spraying (H) pregelatinized starch dissolved or dispersed in water onto the mixture to produce drug-free granules; and compression molding the resulting two types of granules.

[0039] Advantages of the invention The present invention successfully provides an orally disintegrating tablet comprising edoxaban, its pharmacologically acceptable salt or solvation thereof, which has rapid disintegration and solubility when placed in the mouth or water, has a good taste, has sufficient hardness during normal production, transportation and use, and excellent storage stability.

[0040] Furthermore, the present invention successfully provides a method for preparing orally disintegrating tablets with the above-mentioned excellent properties by conventional compression molding, without the need for complex steps or special equipment.

[0041] Implementation Plan Description In this invention, the orally disintegrating tablet is a compression-molded product that exhibits rapid disintegration and solubility when placed in the mouth or in water. Specifically, the term refers to a tablet that disintegrates typically within about 5 to 180 seconds, preferably about 5 to 60 seconds, and more preferably within about 5 to 40 seconds, in an oral disintegration test primarily utilizing saliva, or in an instrumental disintegration test.

[0042] The orally disintegrating tablets according to the present invention have sufficient hardness during normal production, transportation, and use. For example, the tablets are orally disintegrating tablets with a hardness of 2 kg or more in hardness tests, more preferably 3 kg or more, and even more preferably 5 kg or more.

[0043] The orally disintegrating tablets according to the invention have dissolution properties suitable for pharmaceutical formulations. For example, the tablets are orally disintegrating tablets that typically exhibit an average dissolution percentage of more than 80% at a 30-minute time point in a dissolution test, preferably more than 85%.

[0044] The edosaban used in this invention is represented by N according to the following formula (1). 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)glycan (hereinafter, also referred to as compound 1).

[0045] [Chemical Formula 1] Compound 1 may be a solvate (including a hydrate) and may be a pharmacologically acceptable salt or solvate (including a hydrate). Its pharmacologically acceptable salt or solvate is preferably N represented by the following formula (1a). 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethylenediamide p-toluenesulfonic acid monohydrate (edoxaban p-toluenesulfonate hydrate).

[0046] [Chemical Formula 2] .

[0047] The edoxaban used in this invention exhibits thrombus formation inhibitory activity by selectively, reversibly and directly inhibiting activated coagulation factor X (FXa), which plays a role in thrombus formation by generating thrombin from prothrombin and promoting fibrin formation in the blood coagulation cascade.

[0048] The edoxaban used in this invention has been used in clinical trials in Japan and other countries to inhibit the development of venous thromboembolism in patients who have undergone lower extremity orthopedic surgery (including total knee replacement, total hip replacement, and hip fracture surgery), as well as to inhibit the development of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and to treat and inhibit the recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism).

[0049] The orally disintegrating tablets of the present invention contain edoxaban, administered orally once daily, for the purpose of inhibiting the development of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the treatment and inhibition of recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism). For adults, the dose is typically 30 mg (when weighing less than 60 kg) or 60 mg (when weighing more than 60 kg) (in the case of edoxaban). Depending on renal function and any one or more concomitant medications, the dose may be reduced to 30 mg (once daily). Furthermore, in the inhibition of the development of venous thromboembolism in patients who have undergone lower extremity orthopedic surgery, for adults, the tablets may typically be administered orally once daily at a dose of 30 mg (in the case of edoxaban).

[0050] In this invention, "acid" refers to a compound that is acidic and can be added to a pharmaceutical preparation, including organic acids and inorganic acids.

[0051] In this invention, "organic acid" refers to an acidic organic compound that can be used as an excipient in pharmaceutical preparations. Examples of organic acids include carboxylic acids, sulfonic acids, enols, or their salts.

[0052] In this invention, "acidic" means that the pH (hydrogen ion index) of the aqueous solution is less than 7, and "neutral" means that the pH is 7.

[0053] There are no particular limitations on the inorganic acids used in the orally disintegrating tablets according to the invention, as long as they are inorganic acids that can be added to pharmaceutical preparations, but examples include hydrochloric acid or phosphoric acid.

[0054] There are no particular limitations on the inorganic acid salts used in the orally disintegrating tablets according to the invention, as long as they are inorganic acid salts that can be added to pharmaceutical formulations, but examples include sodium bisulfite, potassium dihydrogen phosphate or sodium dihydrogen phosphate.

[0055] The carboxylic acid used in the orally disintegrating tablets according to the present invention is not particularly limited, as long as it is a carboxylic acid that can be added to a pharmaceutical formulation, but examples include adipic acid, aspartic acid, alginic acid, benzoic acid, carboxyvinyl polymer, carboxymethyl cellulose, citric acid, glutamic acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, anhydrous citric acid, methacrylic acid copolymer, or malic acid; preferred examples include adipic acid, aspartic acid, alginic acid, carboxyvinyl polymer, carboxymethyl cellulose, citric acid, tartaric acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, methacrylic acid copolymer, or malic acid; and more preferred examples include aspartic acid, alginic acid, carboxymethyl cellulose, or fumaric acid.

[0056] There are no particular limitations on the carboxylates used in the orally disintegrating tablets according to the present invention, as long as they are carboxylates that can be added to pharmaceutical formulations, but examples include sodium L-aspartate, sodium benzoate, sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium dihydrogen citrate, disodium citrate, calcium gluconate, monosodium L-glutamate, croscarmellose sodium, monosodium succinate, calcium acetate, vinyl acetate resin, sodium tartrate, potassium hydrogen tartrate, potassium sorbate, calcium lactate, monosodium fumarate, sodium stearate, anhydrous sodium citrate, or sodium malate; preferred examples include sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, or sodium stearate; and more preferred examples include potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, or sodium stearate.

[0057] There are no particular limitations on the enols used in the orally disintegrating tablets according to the invention, as long as they can be added to the pharmaceutical formulation, but examples include ascorbic acid or isoascorbic acid, and preferred examples include ascorbic acid.

[0058] There are no particular limitations on the enol salts used in the orally disintegrating tablets according to the invention, as long as they can be added to the pharmaceutical formulation, but examples include sodium ascorbate or sodium isoascorbate, and preferred examples include sodium ascorbate.

[0059] Examples of carboxylic acids or their salts used in orally disintegrating tablets according to the invention and which are solid at room temperature include adipic acid, aspartic acid, alginic acid, benzoic acid, carboxyvinyl polymers, carboxymethyl cellulose, citric acid, glutamic acid, succinic acid, tartaric acid, sorbic acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, anhydrous citric acid, methacrylic acid copolymer, malic acid, sodium L-aspartate, sodium benzoate, sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium dihydrogen citrate, disodium citrate, calcium gluconate, monosodium L-glutamate, cross-linked sodium carboxymethyl cellulose, monosodium succinate, calcium acetate, vinyl acetate resin, and tartaric acid. Sodium, potassium bitartrate, potassium sorbate, calcium lactate, sodium fumarate, sodium stearate, anhydrous sodium citrate, or sodium malate; preferred examples include adipic acid, aspartic acid, alginic acid, carboxyvinyl polymers, carboxymethyl cellulose, citric acid, tartaric acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, methacrylic acid copolymer, malic acid, sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, or sodium stearate; and more preferred examples include carboxymethyl cellulose, fumaric acid, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, or sodium stearate. Preferred examples include aspartic acid, alginic acid, carboxymethyl cellulose, or fumaric acid.

[0060] The amount of acid (preferably an organic acid) contained in the orally disintegrating tablets according to the invention is not particularly limited, but shall be determined at the discretion of those skilled in the art by referring to the standards of disintegration and hardness testing described herein, so that the tablets exhibit the desired disintegration and hardness. This amount is preferably 0.1 to 30% by weight per 100% by weight of the orally disintegrating tablets, more preferably 0.1 to 15% by weight.

[0061] Examples of water-soluble polymers in this invention include combinations of one, two, or more of the following: cellulose derivatives such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, and sodium carboxymethyl cellulose; synthetic polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymers, carboxyvinyl polymers, polyvinyl alcohol, and polyethylene glycol; gum arabic, agar, gelatin, sodium alginate, etc. The water-soluble polymer used in this invention is preferably a cellulose derivative, more preferably hydroxypropyl cellulose.

[0062] The aforementioned hydroxypropyl cellulose is not limited, as long as it retains the desired properties (disintegration time, hardness, dissolution properties) for oral disintegrating tablets, and examples of commercially available products include L grade (viscosity = 6 to 10 mPa*s) or H grade (viscosity = 1000 to 4000 mPa*s) sold by Nippon Soda Co., Ltd.

[0063] Considering formability, water disintegration, and suspendability, the content of water-soluble polymer in the tablets according to the invention is typically 0.1 to 3.0 wt% per 100% orally disintegrating tablets, preferably 0.1 to 2.0 wt%, particularly preferably 0.1 to 0.7 wt%. When the content of water-soluble polymer is too high, suspension takes too long and the tablet becomes less suitable as an orally disintegrating tablet.

[0064] In addition to the above-mentioned ingredients, the orally disintegrating tablets according to the present invention may also contain excipients.

[0065] Examples of excipients include organic excipients selected from sugars, sugar alcohols, starches and cellulose; and inorganic excipients, with sugar alcohols and / or cellulose being preferred.

[0066] Examples of sugars include one or more combinations of lactose, sucrose, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered sucrose, fructose, isomerized lactose, and honey.

[0067] Examples of sugar alcohols include D-mannitol, erythritol, xylitol, maltitol, sorbitol, etc., with preferred examples being D-mannitol, erythritol, and xylitol, and further preferred examples being D-mannitol. D-mannitol can generally be any type of D-mannitol suitable for meeting the requirements of the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopoeia. There are no particular limitations on the crystal form, particle size, and specific surface area of ​​the D-mannitol to be incorporated, but the crystal form can be any of α-type, β-type, δ-type, and amorphous; the particle size is preferably 10 μm or more and 250 μm or less, more preferably 20 μm or more and 150 μm or less; the specific surface area is preferably 0.1 m². 2 / g or more and 4 m 2 / g or less, more preferably 0.1 m 2 / g or more and 2 m 2 / g or less. Crystal form, particle size, and specific surface area can be measured, for example, by X-ray diffraction, laser diffraction particle size distribution measurement, and BET specific surface area measurement (multi-point). Examples of commercially available D-mannitol include D-mannitol from Merck & Co., Roquette, Towa Kasei Co., Ltd., Kao Corporation, etc.

[0068] The amount of the sugar alcohol incorporated can be appropriately selected. When using D-mannitol, the amount is typically 20 to 95% by weight, preferably 30 to 85% by weight, relative to 100% orally disintegrating tablets.

[0069] The aforementioned sugar alcohols can be mixed with other ingredients in powder form and compressed into tablets, or they can be granulated using a suitable binder and then compressed into tablets.

[0070] Besides microcrystalline cellulose, examples of cellulose include one or more combinations of powdered cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium. Microcrystalline cellulose is typically a microcrystalline cellulose grade with a bulk density of 0.10–0.46 g / cm³. 3 The preferred concentration is 0.10-0.42 g / cm³. 3 Further optimization was performed using 0.10-0.26 g / cm³. 3 Examples of commercially available microcrystalline cellulose include CEOLUS KG-1000 (bulk density of 0.10 to 0.15 g / cm³). 3 CEOLUS KG-802 (bulk density of 0.13 to 0.23 g / cm³) 3 ) and CEOLUS UF-711 (bulk density of 0.20 to 0.26 g / cm³) 3 (The above are products manufactured by Asahi Kasei Chemicals Corporation). Furthermore, combinations of two or more microcrystalline celluloses with different bulk densities, adjusted to have the desired bulk density, can be used.

[0071] The preferred amount of microcrystalline cellulose incorporated is 1 to 50% by weight per 100% orally disintegrating tablets. If this amount exceeds 50% by weight, the flowability deteriorates and manufacturability may decrease. A more preferred amount is 5 to 30% by weight.

[0072] When the sugar alcohol is D-mannitol, the ratio of the above-mentioned microcrystalline cellulose to sugar alcohol is 1 to 10 parts by weight, preferably 1.5 to 8.5 parts by weight, and more preferably 2 to 3 parts by weight of sugar alcohol to 1 part of microcrystalline cellulose.

[0073] The aforementioned microcrystalline cellulose can be mixed with other ingredients in powder form and compressed to prepare tablets, or it can be granulated using a suitable binder and then compressed.

[0074] Examples of starch include one or more combinations of corn starch, potato starch, rice starch and pregelatinized starch.

[0075] Examples of inorganic excipients include one or more combinations of synthetic hydrotalcite, precipitated calcium carbonate, hydrated silica, light anhydrous silica, magnesium aluminum silicate, and magnesium hydroxide.

[0076] In addition to the above-mentioned ingredients, the orally disintegrating tablets of the present invention may also contain a disintegrant.

[0077] Examples of disintegrants include combinations of one, two, or more of the following: crospovidone (e.g., products compatible with the Japanese Pharmacopoeia), calcium carboxymethyl cellulose (e.g., products compatible with the Japanese Pharmacopoeia), carboxymethyl cellulose (e.g., products compatible with the Japanese Pharmacopoeia), crospovidone sodium carboxymethyl cellulose (e.g., products compatible with the Japanese Pharmacopoeia), low-substituted hydroxypropyl cellulose (e.g., products compatible with the Japanese Pharmacopoeia), corn starch (e.g., products compatible with the Japanese Pharmacopoeia), sodium glycolate starch (e.g., products compatible with the Japanese Pharmacopoeia), and pregelatinized starch; particularly preferred examples are combinations of one, two, or more of crospovidone, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and pregelatinized starch; further preferred examples are combinations of carboxymethyl cellulose, crospovidone, and pregelatinized starch.

[0078] The aforementioned pregelatinized starch is a starch pregelatinized through heat treatment, and includes partially pregelatinized starch. Furthermore, the aforementioned pregelatinized starch can be the pregelatinized starch described in Japanese pharmaceutical excipients. The average degree of gelatinization is preferably 90% or less, more preferably 70%-80%. An example of commercially available pregelatinized starch is pregelatinized starch swelstar PD-1 (manufactured by Asahi Kasei Chemicals Corporation).

[0079] The amount of the pregelatinized starch incorporated is typically 1 to 15% by weight, preferably 1 to 10% by weight, relative to 100% orally disintegrating tablets.

[0080] Pregelatinized starch can be mixed with other ingredients in powder form and compressed to prepare tablets, or it can be granulated with other ingredients and then compressed.

[0081] Although pregelatinized starch is used as a disintegrant in the orally disintegrating tablets according to the invention, in production it can also be sprayed onto powdered raw materials to promote granulation and granulation, as it becomes viscous when dissolved or dispersed in a liquid such as water. Using this property, a solution or liquid dispersion in which pregelatinized starch is dissolved or dispersed in water is sprayed onto a substrate containing a bulk density of 0.26 g / cm³. 3The following mixture of microcrystalline cellulose and sugar alcohol powders is granulated in a fluidized bed to produce granules, which are then mixed with other ingredients as needed and compressed and molded to obtain tablets with good formability and desired intraoral disintegration. This advantage in production is one of the unique characteristics of pregelatinized starch, which is difficult to obtain when using conventional disintegrants such as low-substituted hydroxypropyl cellulose and cropovidone.

[0082] The amount of the disintegrant incorporated is typically 0.5 to 20% by weight, preferably 2 to 20% by weight, relative to 100% orally disintegrating tablets.

[0083] Unless it hinders the effects of the invention, the orally disintegrating tablets according to the invention may contain various additives commonly used in the preparation of tablets.

[0084] Examples of additives include adhesives, lubricants, coatings, plasticizers, colorants, flavorings, sweeteners, flavoring agents, fluidizing agents, foaming agents, and surfactants.

[0085] Examples of adhesives include one or more combinations of gum arabic, sodium alginate, carboxyvinyl polymers, gelatin, dextrin, pectin, sodium polyacrylate, amylopectin, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and polyethylene glycol.

[0086] Examples of lubricants include one or more combinations of magnesium stearate (e.g., products compatible with the Japanese Pharmacopoeia), calcium stearate (e.g., products compatible with the Japanese Pharmacopoeia), sodium stearate fumarate (e.g., products compatible with Japanese pharmaceutical excipients), and talc (e.g., products compatible with the Japanese Pharmacopoeia), with magnesium stearate being a particularly preferred example.

[0087] The lubricant is preferably added at a rate of 0.1 to 5.0% by weight per 100% orally disintegrating tablets.

[0088] Examples of coatings that cover the surface of powdered drugs (crystal surfaces) or granular drug particles include one or a combination of two or more of the following: ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylate copolymer L, dried methacrylate copolymer LD, methacrylate copolymer LD, methacrylate copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylaminoacetate, and polyvinyl acetate resin.

[0089] Examples of plasticizers to be combined with coating include one or more combinations of diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

[0090] Examples of colorants include one or more combinations of food dyes, such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; food lake dyes; yellow iron oxide; ferric oxide; titanium dioxide; beta-carotene; and riboflavin.

[0091] Examples of flavorings include one or more combinations of orange, lemon, strawberry, mint, menthol, menthol micron, and various flavorings.

[0092] Examples of sweeteners include one or more combinations of sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizate, sucralose, stevia, and kiwifruit protein.

[0093] Examples of flavoring agents include one or a combination of two or more of sodium chloride, magnesium chloride, disodium inosinate, monosodium L-glutamate, and honey.

[0094] Examples of fluidizing agents include one or a combination of two or more selected from hydrated silica, light anhydrous silica, and talc.

[0095] Examples of foaming agents include tartaric acid and / or anhydrous citric acid.

[0096] Examples of surfactants include one or a combination of two or more selected from polyoxyethylene 40 stearate, sorbitol fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate and sodium lauryl sulfate.

[0097] The method for preparing orally disintegrating tablets according to the present invention can be a well-known method for preparing solid dosage forms, and the tablets can be obtained, for example, by granulating the active ingredient together with additives, then adding lubricants, etc., mixing them, and compressing them into tablets. Furthermore, one or more operations, such as drying and screening, can be performed as needed after granulation. Hereinafter, embodiments (embodiments A and B) of the orally disintegrating tablets according to the present invention and their preparation methods will be described.

[0098] Implementation scheme A: Orally disintegrating tablets obtained by compressing drug-free particles (hereinafter also referred to as rapidly disintegrating particles) containing crystalline cellulose, sugar alcohol and pregelatinized starch with a bulk density of less than 0.26 g / cm3 and drug or drug-containing particles.

[0099] In this embodiment, no drug particles act as the formulation skeleton, which imparts the required disintegration and formability to the orally disintegrating tablets. This is achieved solely by incorporating particles with a bulk density of 0.26 g / cm³. 3 The following three components—microcrystalline cellulose, sugar alcohol, and pregelatinized starch—exhibit excellent disintegration and formability without drug particles, but other components can be incorporated as needed. Furthermore, the orally disintegrating tablets of this embodiment contain 0.1-2.0% by weight of a water-soluble polymer relative to the total weight of the tablet and organic acid, thus exhibiting even superior disintegration and dissolution properties.

[0100] The method for preparing the orally disintegrating tablet of embodiment A includes the steps of preparing drug-free particles (A-1) and preparing drug-containing particles (A-2), and the step of mixing the drug-free particles, the drug or drug-containing particles and other components and compressing the resulting mixture (A-3).

[0101] A-1: Steps for preparing drug-free particles Drug-free particles can be prepared by the following method 1) or 2).

[0102] 1) Containing a material with a bulk density of 0.26 g / cm³ 3 The following is a wet granulation method for a mixture of microcrystalline cellulose, sugar alcohol (e.g., D-mannitol), and pregelatinized starch with water.

[0103] 2) Containing a material with a bulk density of 0.26 g / cm³ 3 The following is a method for granulating a mixture of microcrystalline cellulose and sugar alcohol (e.g., D-mannitol) with a liquid such as water in which pregelatinized starch is dissolved or dispersed.

[0104] Here, granulation can be carried out through conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, oscillating granulation, etc.

[0105] Pregelatinized starch exhibits a viscosity suitable for granulation when dissolved or dispersed in a liquid (e.g., water). Granulation methods include: methods involving mixing pregelatinized starch in powder form with other ingredients and granulating the resulting mixture with water, and methods involving granulating with a liquid in which the pregelatinized starch is dissolved or dispersed in water. Either method imparts the desired properties to the tablets, with the latter being preferred.

[0106] Furthermore, when granulating with a liquid containing dissolved or dispersed pregelatinized starch, either high-speed stirring granulation or fluidized bed granulation can be used, with fluidized bed granulation yielding excellent orally disintegrating tablets. When other components, such as conventional disintegrants, are mixed with drug-free particles, they can be incorporated into the mixture before granulation.

[0107] When the sugar alcohol is D-mannitol, the bulk density is 0.26 g / cm³. 3 The following microcrystalline cellulose to sugar alcohol ratio is 1.5 to 8.5 parts by weight or preferably 2 to 3 parts by weight of sugar alcohol to 1 part of microcrystalline cellulose.

[0108] A-2: Steps for preparing drug-containing particles The drug can be mixed with drug-free particles in powder form or, if necessary, after granulation. Drug-containing particles can be prepared by conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or vibratory granulation.

[0109] Drug particles can be produced by, for example, mixing powdered or granular drugs, organic acids, or materials with a bulk density of 0.26 g / cm³. 3 The following mixture of microcrystalline cellulose and sugar alcohol powders is granulated together with a liquid in which hydroxypropyl cellulose is dissolved or dispersed in water. Additionally, drug-containing particles can be prepared by granulating powdered or granular drugs, organic acids, and a bulk density of 0.26 g / cm³. 3 The following mixture of microcrystalline cellulose, sugar alcohol, and hydroxypropyl cellulose powders was granulated with water to prepare the product.

[0110] Drugs or drug-containing particles can be coated to mask unpleasant tastes such as bitterness and irritation, and / or odors and / or control dissolution properties. For coating, the aforementioned coating agents and plasticizers can be used appropriately. Coating methods include, for example, using a fluidized bed granulator-coating machine, a stirred fluidized bed granulator-coating machine, a centrifugal fluid granulator-coating machine, or a Wurster fluidized bed granulator-coating machine.

[0111] When two or more drugs are used, depending on the compatibility between the drugs, the drugs can be incorporated into the same particles or into separate particles and processed by compression molding.

[0112] A-3: The step of mixing a mixture of drug-free particles, a drug, or a mixture containing drug particles and other components, and then compressing and molding the resulting mixture. As needed, drug-free particles and drug-containing particles, along with ingredients such as disintegrants and lubricants, are mixed and processed into orally disintegrating tablets using compression molding. Mixing is performed using, for example, a drum mixer or a convection mixer. Drugs can be mixed with other ingredients and used as drug-containing powder mixtures.

[0113] The compression molding of the orally disintegrating tablets according to the present invention can be performed using a conventional tableting machine. The molding pressure of the tableting machine can be at the same level as that used for conventional tablets, preferably about 2 to 20 kN, more preferably about 4 to 14 kN, depending on the shape and size of the tablet.

[0114] The incorporation ratio of the total weight of drug-free particles / tablet components can be 30% to 90%. When the drug is in powder form, the incorporation ratio is 30% to 70%, preferably 30% to 60%. When the drug is used after granulation, the incorporation ratio is 30% to 70%, preferably 30% to 60%. Furthermore, when the drug is used after granulation, the incorporation weight ratio of drug-free particles to drug-containing particles is preferably 0.5-2.0 (drug-free particles): 1 (drug-containing particles).

[0115] Implementation Scheme B: Compression molding containing a bulk density of 0.26 g / cm³ 3 The following are drug-free mixtures of microcrystalline cellulose, sugar alcohols, and pregelatinized starch, as well as orally disintegrating tablets obtained from drugs or drug-containing particles.

[0116] In this embodiment, the drug-free mixed powder provides the required disintegration and formability in orally disintegrating tablets. This is achieved solely by mixing powders with a bulk density of 0.26 g / cm³. 3 The following three components—microcrystalline cellulose, sugar alcohol, and pregelatinized starch—exhibit excellent disintegration and formability without drug particles, but other components can be mixed in as needed. Furthermore, the orally disintegrating tablets in this embodiment contain 0.1-2.0% by weight of water-soluble polymers and organic acids, thus exhibiting even better disintegration and dissolution properties.

[0117] The method for preparing the orally disintegrating tablets of embodiment B includes the steps of preparing drug-containing particles as needed, and the steps of mixing the drug or drug-containing particles with other ingredients and compressing the resulting mixture. The step of preparing the drug-containing particles is the same as that described in A-2 above.

[0118] In the step of mixing the drug or a mixture containing drug particles and other ingredients and then compressing and molding the mixture, the mixing or compression molding steps are the same as those described in A-3 above.

[0119] The oral disintegrating tablets obtained in this way according to the present invention have excellent disintegration and solubility when placed in the mouth or in water, and have excellent physical and chemical stability.

[0120] The disintegration or solubility of the orally disintegrating tablets according to the invention results in a disintegration and dissolution time in the oral cavity (the time it takes for the tablet to completely disintegrate or dissolve in the oral cavity of a healthy adult male using only saliva without water) typically being about 5 to 180 seconds, preferably about 5 to 60 seconds, and more preferably about 5 to 40 seconds.

[0121] The orally disintegrating tablets according to the invention are gradually disintegrated or dissolved by saliva when placed in the mouth, but the tablets are also disintegrated or dissolved by intraoral pressure (i.e., pressure from the palate and tongue or friction with the tongue, i.e., the action of "licking") within a short period of time. For people with dry mouth or reduced saliva, the tablets can be disintegrated and / or dissolved in the mouth with water or hot water, or can be taken with water as is in the same manner as regular tablets.

[0122] Meanwhile, the oral disintegrating tablets according to the present invention exhibit sufficient hardness after stability tests under certain temperature and humidity conditions (e.g., for one week in an open system at a temperature of 25°C and a humidity of 75%).

[0123] Therefore, the tablets have sufficient hardness to prevent disintegration during preparation and formulation distribution, practical storage hardness under certain temperature and humidity conditions, and excellent storage stability.

[0124] The orally disintegrating tablets according to the present invention can be used as a formulation that is easy for the elderly, infants and patients with dysphagia to take, or as a safe formulation for general adults to treat diseases. Example

[0125] The following examples are for illustrative purposes only and are not intended to limit the invention to these examples.

[0126] [Comparative Example 1-1] 384.9 g of edoxaban p-toluenesulfonate hydrate, 355.1 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 95.24 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 95.24 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300). The mixture was sprayed with a binder solution (in which 12.38 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 1364 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18,480 g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8,360 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS KG-100) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1,100 g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12,650 g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400mg).

[0127] [Example 1-1] 392.6 g of edoxaban p-toluenesulfonate hydrate, 384.6 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 5.714 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 7.619 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 839.0 g of purified water) and then dried to obtain granules (containing drug particles). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), 13.71 g of sucralose (manufactured by San-Ei Gen FFI, Inc.), and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400mg).

[0128] [Examples 1-2] 392.6 g of edoxaban p-toluenesulfonate hydrate, 371.2 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 19.05 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 7.619 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 839.0 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), 13.71 g of sucralose (manufactured by San-Ei Gen FFI, Inc.), and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). 400 mg).

[0129] [Examples 1-3] 384.9 g of edoxaban p-toluenesulfonate hydrate, 171.3 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 228.6 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 5.714 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 629.2 g of purified water) and then dried to obtain granules (containing drug particles). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400 mg).

[0130] [Comparative Example 2-1] 384.9 g of edoxaban p-toluenesulfonate hydrate, 355.1 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 95.24 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 95.24 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300). The mixture was sprayed with a binder solution (in which 12.38 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 1364 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS KG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400mg).

[0131] [Comparative Example 2-2] 384.9 g of edoxaban p-toluenesulfonate hydrate, 352.3 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 5.714 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 47.62 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 632.9 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 12.60 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., 18HUK) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400 mg).

[0132] [Comparative Examples 2-3] 384.9 g of edoxaban p-toluenesulfonate hydrate, 352.3 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 5.714 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 47.62 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 3920 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 12.60 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., 18HUK) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400 mg).

[0133] [Example 2-1] 384.9 g of edoxaban p-toluenesulfonate hydrate, 392.3 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 5.714 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 7.619 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 101.3 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 12.60 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., 18HUK) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). , 400 mg).

[0134] [Example 2-2] 392.6 g of edoxaban p-toluenesulfonate hydrate, 384.6 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 5.714 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 7.619 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 839.0 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), 13.71 g of sucralose (manufactured by San-Ei Gen FFI, Inc.), and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). 400 mg).

[0135] [Comparative Example 3-1] 16.16 g of edoxaban p-toluenesulfonate hydrate, 15.92 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), and 4.0 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711) were mixed using a mortar and pestle to obtain a mixture (a drug-containing powder). 36.08 g of the obtained drug-containing powder was mixed with 0.72 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712), and further mixed with 0.1 g of fumaric acid (manufactured by Nippon Shokubai) and 0.1 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L). The mixture was then compressed using a bench-top tablet molding machine (Ichihashi Seiki, HANDTAB) at a compression force of 10 kN to obtain orally disintegrating tablets (8.0 mm). , 194 mg).

[0136] [Comparative Example 3-2] 16.16 g of edoxaban p-toluenesulfonate hydrate, 15.92 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), and 4.0 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711) were mixed using a mortar and pestle to obtain a mixture (a drug-containing powder). 36.08 g of the obtained drug-containing powder was mixed with 0.72 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712), and further mixed with 0.1 g of cropovidone (manufactured by BASF AG, Kollidon CL-F) and 0.1 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300). The mixture was then compressed into tablets using a benchtop tablet molding machine (Ichihashi Seiki, HANDTAB) at a compression force of 10 kN to obtain orally disintegrating tablets (8.0 mm). , 194 mg).

[0137] [Example 3-1] 392.6 g of edoxaban p-toluenesulfonate hydrate, 371.2 g of D-mannitol (manufactured by Roquette, Pearlitol 50C), 95.24 g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUS UF-711), 19.05 g of fumaric acid (manufactured by Merck), 57.14 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), and 57.14 g of carboxymethyl cellulose (manufactured by Gotoku Chemical Company Ltd., NS-300) were added to a fluidized bed granulation dryer (manufactured by Freund-Vector Corporation, model FLO-2). The mixture was sprayed with a binder solution (in which 7.619 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-H) was dissolved in 839.0 g of purified water) and then dried to obtain granules (containing drug granules). In addition, 18480g of D-mannitol (manufactured by Roquette, Pearlitol 50C) and 8360g of microcrystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation, CEOLUSKG-1000) were added to a fluidized bed granulation dryer (manufactured by Powrex Corporation, GPCG-15), and the mixture was sprayed with a liquid (in which 1100g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Corporation, swelstar PD-1) was dispersed in 12650g of purified water) and then dried to obtain granules (rapidly disintegrating granules). In addition, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of cropovidone (manufactured by BASF AG, Kollidon CL-F), 13.71 g of sucralose (manufactured by San-Ei Gen FFI, Inc.), and 22.86 g of magnesium stearate (manufactured by Mallinckrodt Pharmaceuticals, HyQual 5712) were mixed, and then the mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Ltd., VIRGO) at a compression force of 5 kN to obtain orally disintegrating tablets (11 mm). 400 mg).

[0138] [Evaluation Method] The tablets obtained in the examples and comparative examples were evaluated using the following methods.

[0139] Tablet thickness and hardness were measured using a fully automated tablet tester (WHT-2, PHARMA TEST APPARATEBAU GmbH) (the average value of 20 tablets is described).

[0140] Disintegration tests were conducted according to the "Disintegration Test" section of the 16th edition of the Japanese Pharmacopoeia (which describes the maximum values ​​for 6 tablets).

[0141] Dissolution tests were conducted according to the second method (paddle method, 50 rpm) described in the Japanese Pharmacopoeia. The dissolution percentage is expressed as the average dissolution percentage of 6 tablets. The dissolution test solution (pH 6.0) used was obtained by adding an appropriate amount of citric acid solution (0.025 mol / L) to disodium hydrogen phosphate solution (0.05 mol / L) and adjusting the solution to pH 6.0.

[0142] The results are shown in Tables 1 to 5.

[0143] [Results Summary] Table 1: Compared with formulations without fumaric acid (e.g., Comparative Example 1-1), tablets containing fumaric acid (e.g., Examples 1-1 to 1-3) rapidly disintegrate within 60 seconds and exhibit excellent function as orally disintegrating tablets. Furthermore, the increased amount of fumaric acid incorporated ensures even faster disintegration and dissolution.

[0144] Table 2: Compared to formulations without fumaric acid (e.g., Comparative Example 2-1) or formulations with a large amount of hydroxypropyl cellulose (e.g., Comparative Examples 2-2 and 2-3), formulations containing fumaric acid and a small amount of hydroxypropyl cellulose (e.g., Examples 2-1 and 2-2) exhibit a short disintegration time of less than 60 seconds and excellent function as orally disintegrating tablets. Furthermore, the disintegration time is very short in this case, regardless of the physical properties of hydroxypropyl cellulose.

[0145] Table 3: Compared with formulations containing fumaric acid and hydroxypropyl cellulose but not containing a disintegrant (e.g., Comparative Example 3-1) or formulations containing a disintegrant but not containing either fumaric acid or hydroxypropyl cellulose (e.g., Comparative Example 3-2), tablets containing a disintegrant, fumaric acid and a small amount of hydroxypropyl cellulose (e.g., Example 3-1) exhibit a short disintegration time of less than 60 seconds and excellent function as orally disintegrating tablets.

[0146] Tables 4 and 5: The orally disintegrating tablets of Example 4 were prepared according to the preparation methods described in Examples 1 to 3 and the formulations listed in Table 4. Tablets in which fumaric acid and a small amount of hydroxypropyl cellulose and a disintegrant were blended with edoxaban (e.g., Examples 4-1 to 4-9) exhibited short disintegration times of less than 60 seconds, excellent function as orally disintegrating tablets, and rapid dissolution.

[0147] Tables 6 and 7: Illustrative Examples of Formulations According to the Invention [Table 1] Comparative / Example Comparative Example 1-1 Example 1-1 Example 1-2 Example 1-3 Incorporation amount of fumaric acid (%) 0 0.3 1 12 Incorporation amount of hydroxypropyl cellulose (%) 0.65 0.4 0.4 0.3 Viscosity of hydroxypropyl cellulose (mPa*s) (20°C, 2% aqueous solution) 2790 2790 2790 2790 Molecular weight of hydroxypropyl cellulose -910,000- -910,000- -910,000- -910,000- Tablet thickness (average value, mm) 5.7 5.6 5.6 5.5 Tablet hardness (average value, kg) 3.4 3.4 3.4 3.3 Disintegration time (individual maximum, sec) 84 36 28 26 Dissolution percentage at 15 minutes (pH 6.0, %) 71 82 90 95 Dissolution percentage at 30 minutes (pH 6.0, %) 82 90 96 98 Dissolution percentage at 45 minutes (pH 6.0, %) 87 94 98 99 * Values ​​from the manufacturer's catalog.

[0148] [Table 2] Comparative / Example Comparative Example 2-1 Comparative Example 2-2 Comparative Example 2-3 Example 2-1 Example 2-2 Incorporation amount of fumaric acid (%) 0 0.3 0.3 0.3 0.3 Viscosity of hydroxypropyl cellulose (mPa*s) (20°C, 2% aqueous solution) 2790 8.3 2790 8.3 2790 Molecular weight of hydroxypropyl cellulose -910,000- -140,000- -910,000- -140,000- -910,000- Incorporation amount of HPC (%) 0.65 2.5 2.5 0.4 0.4 Uncoated tablet thickness (average value, mm) 5.7 5.6 5.6 5.7 5.6 Uncoated tablet hardness (average value, kg) 3.4 5.2 5.1 3.5 3.4 Disintegration time (individual maximum, sec) 84 64 75 34 36 Dissolution percentage at 15 minutes (pH 6.0, %) 71 90 82 84 82 Dissolution percentage at 30 minutes (pH 6.0, %) 82 94 92 90 90 Dissolution percentage at 45 minutes (pH 6.0, %) Comparative / Example Comparative Example 1-1 Example 1-1 Example 1-2 Example 1-3 Incorporation amount of fumaric acid (%) Incorporation amount of hydroxypropyl cellulose (%) Viscosity of hydroxypropyl cellulose (mPa*s) (20°C, 2% aqueous solution) Molecular weight of hydroxypropyl cellulose Tablet thickness (average value, mm) Tablet hardness (average value, kg) Disintegration time (individual maximum, sec) Dissolution percentage at 15 minutes (pH 6.0, %) Dissolution percentage at 30 minutes (pH 6.0, %) Dissolution percentage at 45 minutes (pH 6.0, %) Comparative / Example Comparative Example 2-1 Comparative Example 2-2 Comparative Example 2-3 Example 2-1 Example 2-2 Incorporation amount of fumaric acid (%) Viscosity of hydroxypropyl cellulose (mPa*s) (20°C, 2% aqueous solution) Molecular weight of hydroxypropyl cellulose Incorporation amount of HPC (%) Uncoated tablet thickness (average value, mm) Uncoated tablet hardness (average value, kg) Disintegration time (individual maximum, sec) Dissolution percentage at 15 minutes (pH 6.0, %) Dissolution percentage at 30 minutes (pH 6.0, %) Dissolution percentage at 45 minutes (pH 6.0, %) Comparative / Example Comparative Example 1-1 Example 1-1 Example 1-2 Example 1-3 Incorporation amount of fumaric acid (%) Incorporation amount 87 96 95 92 94 * Values ​​from the manufacturer's catalog.

[0149] [Table 3]

[0150] [Table 4]

[0151] [Table 5]

[0152] [Table 6]

[0153] [Table 7]

Claims

1. An orally disintegrating tablet comprising (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of a water-soluble polymer relative to the total weight of the tablet, and (D) a disintegrant.

2. The orally disintegrating tablet according to claim 1, wherein (B) The organic acid is one or more components selected from the group consisting of fumaric acid, alginic acid, and aspartic acid.

3. The orally disintegrating tablet according to claim 1, wherein (B) The organic acid is fumaric acid.

4. The orally disintegrating tablet according to any one of claims 1 to 3, wherein The content of the organic acid is 0.1 to 15% by weight relative to the total weight of the tablet.

5. The orally disintegrating tablet according to any one of claims 1 to 4, wherein (C) The water-soluble polymer is one or more components selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol.

6. The orally disintegrating tablet according to any one of claims 1 to 4, wherein (C) The water-soluble polymer is hydroxypropyl cellulose.

7. The orally disintegrating tablet according to any one of claims 1 to 6, wherein (D) The disintegrant is one or more components selected from the group consisting of carboxymethyl cellulose, crospovidone, calcium carboxymethyl cellulose, sodium croscarmellose, corn starch, sodium starch glycolate, and pregelatinized starch.

8. The orally disintegrating tablet according to any one of claims 1 to 6, wherein (D) The disintegrant is carboxymethyl cellulose, crospovidone, and pregelatinized starch.

9. The orally disintegrating tablet according to claim 7 or 8, further comprising a sugar alcohol and a bulk density of 0.26 g / cm3 3 The following microcrystalline cellulose.

10. The orally disintegrating tablet according to claim 9, wherein The sugar alcohol is D-mannitol.

11. An orally disintegrating tablet comprising (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, (E) carboxymethyl cellulose, (F) D-mannitol, (G) a bulk density of 0.26 g / cm 3 the following microcrystalline cellulose, and (H) pregelatinized starch.

12. The orally disintegrating tablet according to claim 11, comprising: a drug-containing mixed powder or drug-containing granules, the powder or granules comprising (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and a non-drug-containing mixed powder, the powder comprising (F) D-mannitol, (G) microcrystalline cellulose having a bulk density of 0.26 g / cm 3 and (H) pregelatinized starch.

12. The orally disintegrating tablet according to claim 11, comprising: a drug-containing mixed powder or drug-containing granules, the powder or granules comprising (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and a non-drug-containing mixed powder, the powder comprising (F) D-mannitol, (G) microcrystalline cellulose having a bulk density of 0.26 g / cm 3 and (H) pregelatinized starch.

13. The orally disintegrating tablet according to claim 11, comprising: a drug-containing mixed powder or a drug-containing granule, the powder or granule comprising (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose relative to the total weight of the tablet, and (E) carboxymethyl cellulose; and a drug-free granule, the granule comprising (F) D-mannitol, (G) a bulk density of 0.26 g / cm 3 the following microcrystalline cellulose, and (H) pregelatinized starch.

14. The orally disintegrating tablet according to any one of claims 11 to 13, wherein, (B) The organic acid is one or more components selected from the group consisting of fumaric acid, alginic acid, and aspartic acid.

15. The orally disintegrating tablet according to any one of claims 11-13, wherein, (B) The organic acid is fumaric acid.

16. The orally disintegrating tablet according to any one of claims 11 to 15, further comprising one or more components selected from the group consisting of crospovidone, calcium carboxymethyl cellulose, sodium croscarmellose, corn starch, sodium starch glycolate, and pregelatinized starch.

17. The orally disintegrating tablet according to any one of claims 11 to 15, further comprising crospovidone.

18. The orally disintegrating tablet according to any one of claims 11-17, wherein, The organic acid is 0.1 to 15% by weight relative to the total weight of the tablet.

19. The orally disintegrating tablet according to any one of claims 11 to 18, wherein the tablet disintegrates within 60 seconds in a disintegration test.

20. A process for the preparation of an orally disintegrating tablet comprising: mixing (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) fumaric acid, and (E) carboxymethylcellulose, and spraying (C) hydroxypropylcellulose dissolved or dispersed in water at 0.1 to 2.0% by weight relative to the total weight of the tablet onto the mixture to produce drug-containing granules; a step of mixing (F) D-mannitol and (G) calcium hydrogen phosphate having a bulk density of 0.26 g / cm 3 the following microcrystalline cellulose and spraying (H) pregelatinized starch dissolved or dispersed in water onto the mixture to produce drug-free granules; and a step of compression-molding the resulting two types of granules.

21. A process for the preparation of an orally disintegrating tablet comprising: mixing (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) fumaric acid, (C) hydroxypropyl cellulose at 0.1 to 2.0% by weight relative to the total weight of the tablet, and (E) carboxymethyl cellulose, and spraying water onto the mixture to produce drug-containing granules; and a step of mixing (F) D-mannitol and (G) calcium hydrogen phosphate having a bulk density of 0.26 g / cm 3 mixing the following and spraying (H) pregelatinized starch dissolved or dispersed in water onto the mixture to produce drug-free granules: microcrystalline cellulose, and a step of compression-molding the resulting two types of granules.

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