Orally disintegrating tablet including pyrrole carboxamide

Abstract

To provide an orally disintegrating tablet including esaxerenone that disintegrates rapidly when placed in the mouth or in water, has a hardness sufficient to withstand normal production, transportation, or use, has good solubility and good divisibility, and has little segregation of drug content, and a method for producing the same.SOLUTION: The present invention provides an orally disintegrating tablet including esaxerenone or a pharmaceutically acceptable salt thereof, a lactose hydrate, a low-substituted hydroxypropyl cellulose, a hydroxypropyl cellulose, a light anhydrous silicic acid, a sugar alcohol, a crystalline cellulose, and an alpha starch. A method for producing the orally disintegrating tablet is also provided.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, which rapidly disintegrates when placed in the mouth or in water, has sufficient hardness during normal production, transportation or use, has good elution properties, good divisibility and little segregation of drug content, and a method for producing the same.

Background Art

[0002] Esaxerenone has the following structural formula:

[0003]

Chemical Formula

[0004] (Compound (I)) shown below.

[0005] Compound (I) is disclosed in US Patent No. 8,524,918, has excellent activity as a mineralocorticoid receptor (MR) (aldosterone receptor) antagonist, and is known as a drug having an excellent therapeutic effect for hypertension based on the results of various clinical trials. In addition, it is expected to have excellent therapeutic and / or preventive effects on diseases such as heart diseases [angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure or cardiac hypertrophy], kidney diseases (diabetic nephropathy, glomerulonephritis or nephrosclerosis), cerebrovascular diseases (cerebral infarction or cerebral hemorrhage) or vascular disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorder), and is also expected to be effective in the remission of diabetic nephropathy (International Publication WO2017 / 164208).

[0006] As dosage forms of oral solid preparations in the fields of pharmaceuticals and foods, tablets, capsules, granules, powders, etc. are known, but as a dosage form that is easier to take for the elderly, children and patients with difficulty in swallowing, the development of orally disintegrating tablets that rapidly disintegrate when placed in the mouth or in water is expected.

[0007] In addition to the characteristic of rapid disintegration in the oral cavity, orally disintegrating tablets are required to have sufficient hardness to withstand physical impact during manufacturing, transportation, or use, similar to ordinary tablets, and further to have elution properties with little variation. Also, when placed in the mouth, it is desirable in terms of medication compliance that unpleasant taste and irritation are suppressed and that it has a good mouthfeel.

[0008] Regarding orally disintegrating tablets, various reports have been made so far. For example, Patent Document 2 describes an orally disintegrating tablet containing a drug, crystalline cellulose having a bulk density of 0.23 g / cm 3 the following crystalline cellulose, sugar alcohol, and pregelatinized starch. However, this document does not describe an orally disintegrating tablet containing esaxerenone, light anhydrous silicic acid, and lactose hydrate having an average particle diameter in the range of 5 to 50 μm.

[0009] Patent Document 3 describes an orally disintegrating tablet containing prasugrel, carmellose, and hydroxypropyl cellulose and a method for producing the same. In this document, an orally disintegrating tablet containing prasugrel having sufficient hardness and showing elution properties with little variation by containing carmellose and hydroxypropyl cellulose is described, but there is no description of an orally disintegrating tablet having good divisibility and little segregation of drug content and containing esaxerenone, light anhydrous silicic acid, and lactose hydrate having an average particle diameter in the range of 5 to 50 μm.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide an orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, which rapidly disintegrates when placed in the mouth or in water, has sufficient hardness during normal production, transportation or use, has good elution properties, good divisibility and little segregation of drug content, and a method for producing the same.

Means for Solving the Problems

[0012] As a result of intensive studies to solve the above problems, the present inventors have found that an orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, light anhydrous silicic acid and lactose hydrate (preferably having an average particle diameter in the range of 5 to 50 μm) solves the above problems, and completed the present invention.

[0013] That is, the present invention provides an orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, light anhydrous silicic acid and lactose hydrate (preferably having an average particle diameter in the range of 5 to 50 μm) and a method for producing the same.

[0014] The present invention relates to the following (1) to (29). (1) An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate and light anhydrous silicic acid. (2) An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate having an average particle diameter in the range of 5 to 50 μm, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, sugar alcohol, crystalline cellulose and pregelatinized starch. (3) The orally disintegrating tablet according to any one of (1) or (2), wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet. (4) The orally disintegrating tablet according to any one of (1) or (2), wherein the content of light anhydrous silicic acid is 0.3 to 2.0% by weight based on the total weight of the tablet. The orally disintegrating tablet according to any one of (1) or (2), wherein the content of light anhydrous silicic acid is 0.3 to 1% by weight based on the total weight of the tablet.

[0015] The orally disintegrating tablet according to any one of (1) to (5), further containing crospovidone. The orally disintegrating tablet according to (6), wherein the content of crospovidone is 1 to 10% by weight based on the total weight of the tablet. The orally disintegrating tablet according to any one of (2) to (7), wherein the average degree of α - conversion of the α - starch is 90% or less. (9) The bulk density of crystalline cellulose is 0.26 g / cm 3 The orally disintegrating tablet according to any one of (2) to (8), which is as follows.

[0016] (10) A drug - containing granule containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate having an average particle diameter in the range of 5 - 50 μm, low - substituted hydroxypropyl cellulose, and hydroxypropyl cellulose; a drug - free granule containing D - mannitol, crystalline cellulose having a bulk density of 0.26 g / cm 3 The following and an orally disintegrating tablet containing light anhydrous silicic acid as an extra - granule component for the two types of granules; and. (11) The orally disintegrating tablet according to (10), further containing crospovidone as an extra - granule component. (12) The orally disintegrating tablet according to (11), wherein the content of crospovidone is 2 to 6% by weight based on the total weight of the tablet. (13) The orally disintegrating tablet according to (12), characterized in that the swelling of the tablet is suppressed. (14) The orally disintegrating tablet according to any one of (10) to (13), further containing a colorant and magnesium stearate as an extra - granule component. (15) The orally disintegrating tablet according to (14), wherein the colorant is yellow ferric oxide or ferric oxide.

[0017] (16) An orally disintegrating tablet according to any one of (10) to (15), wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet. (17) An orally disintegrating tablet according to any one of (10) to (16), wherein the content of hydroxypropylcellulose is 0.1 to 15% by weight based on the total weight of the tablet. (18) An orally disintegrating tablet according to any one of (10) to (17), wherein the content of pregelatinized starch is 0.1 to 10% by weight based on the total weight of the tablet.

[0018] (19) An orally disintegrating tablet according to any one of (1) to (18), which disintegrates within 1 second or more and 45 seconds or less in the disintegration test by a device. (20) An orally disintegrating tablet according to any one of the preceding items (1) to (19), which has improved divisibility with a score line. (21) An orally disintegrating tablet according to (20), wherein the tablet strength and abrasion degree of the half tablet after division having a score line are improved.

[0019] (22) An orally disintegrating tablet according to any one of (10) to (21), wherein 50% or more of the drug-containing granules have a particle size of 80 μm or less. (23) An orally disintegrating tablet according to any one of (10) to (22), wherein 90% or more of the drug-containing granules have a particle size of 380 μm or less. (24) An orally disintegrating tablet according to either (22) or (23), wherein the segregation of the drug content is improved.

[0020] (25) A step of producing drug-containing granules by mixing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate having an average particle diameter in the range of 5 to 50 μm, low-substituted hydroxypropylcellulose, and hydroxypropylcellulose; D-mannitol and a bulk density of 0.26 g / cm 3 A step of mixing the following crystalline cellulose and spraying pregelatinized starch dispersed in water to produce drug-free granules; and a step of adding light anhydrous silicic acid and crospovidone as extra-granular components to the two types of granules and compression molding, which is a method for producing an orally disintegrating tablet. The method for producing an orally disintegrating tablet according to (25), which further comprises a step of adding a colorant as an external component of the granules, adding magnesium stearate, and performing compression molding. The method for producing an orally disintegrating tablet according to (26), wherein the colorant is yellow ferric oxide or ferric oxide. The method for producing an orally disintegrating tablet according to any one of (25) to (27), wherein the step of producing the drug-containing granules includes a high-speed stirring granulation step. The method for producing an orally disintegrating tablet according to any one of (25) to (28), characterized in that the elution decrease of esaxerenone or a pharmaceutically acceptable salt thereof is prevented.

[0021] Another aspect of the present invention relates to the following (1A) to (30A). (1A) An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, and light anhydrous silicic acid. (2A) An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, sugar alcohol, crystalline cellulose, and pregelatinized starch. (3A) The orally disintegrating tablet according to any one of (1A) or (2A), wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet. (4A) The orally disintegrating tablet according to any one of (1A) to (3A), wherein the average particle diameter of lactose hydrate is in the range of 5 to 50 μm. (5A) The bulk density of crystalline cellulose is 0.26 g / cm 3 The orally disintegrating tablet according to any one of (2A) to (4A), which is as follows.

[0022] (6A) The orally disintegrating tablet according to any one of (2A) to (5A), wherein the content of hydroxypropyl cellulose is 0.1 to 15% by weight based on the total weight of the tablet. (7A) The orally disintegrating tablet according to any one of (2A) to (6A), wherein the average degree of pregelatinization of pregelatinized starch is 90% or less. The orally disintegrating tablet according to any one of (1A) to (7A), further containing crospovidone. (9A) The orally disintegrating tablet according to any one of (1A) to (8A), further containing a coloring agent and magnesium stearate. (10A) The orally disintegrating tablet according to (9A), wherein the coloring agent is yellow iron sesquioxide or iron sesquioxide.

[0023] (11A) A drug-containing granule containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose; a drug-free granule containing D-mannitol, crystalline cellulose, and pregelatinized starch; and an orally disintegrating tablet containing light anhydrous silicic acid as an extra-granular component for the two types of granules. (12A) The orally disintegrating tablet according to (11A), wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet. (13A) The orally disintegrating tablet according to (11A) or (12A), wherein the average particle diameter of lactose hydrate is in the range of 5 to 50 μm. (14A) The bulk density of crystalline cellulose is 3 as follows, the orally disintegrating tablet according to any one of (11A) to (13A). (15A) The orally disintegrating tablet according to any one of (11A) to (14A), wherein the content of hydroxypropyl cellulose is 0.1 to 15% by weight based on the total weight of the tablet.

[0024] (16A) The orally disintegrating tablet according to any one of (11A) to (15A), wherein the content of pregelatinized starch is 0.1 to 10% by weight based on the total weight of the tablet. (17A) The orally disintegrating tablet according to any one of (11A) to (16A), further containing crospovidone as an extra-granular component. (18A) The orally disintegrating tablet according to any one of (11A) to (17A), further containing a coloring agent and magnesium stearate as an extra-granular component. (19A) The orally disintegrating tablet according to (18A), wherein the coloring agent is yellow iron sesquioxide or iron sesquioxide. (20A) An orally disintegrating tablet according to any one of (1A) to (19A), which disintegrates within 1 second or more and 45 seconds or less in a disintegration test by a device.

[0025] (21A) An orally disintegrating tablet according to any one of (1A) to (20A), which has good divisibility and has a score line. (22A) An orally disintegrating tablet according to (21A), wherein the tablet strength and abrasion degree of the half tablet after division having a score line are good. (23A) An orally disintegrating tablet according to any one of (11A) to (22A), wherein 50% or more of the drug-containing granules have a particle size of 80 μm or less. (24A) An orally disintegrating tablet according to any one of (11A) to (23A), wherein 90% or more of the drug-containing granules have a particle size of 380 μm or less. (25A) An orally disintegrating tablet according to either (23A) or (24A), which has less segregation of the drug content.

[0026] (26A) A process for producing drug-containing granules by mixing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose; a process for producing drug-free granules by mixing D-mannitol and crystalline cellulose and spraying pregelatinized starch dispersed in water; and a process for compression molding by adding light anhydrous silicic acid and crospovidone as extragranular components to the two types of granules. A method for producing an orally disintegrating tablet comprising the steps. (27A) A method for producing an orally disintegrating tablet according to (26A), which further comprises a step of adding a colorant as an extragranular component and adding magnesium stearate for compression molding. (28A) A method for producing an orally disintegrating tablet according to (27A), wherein the colorant is yellow ferric oxide or ferric oxide. (29A) A method for producing an orally disintegrating tablet according to any one of (26A) to (28A), wherein the step of producing drug-containing granules includes a high-speed stirring granulation step. (30A) A method for producing an orally disintegrating tablet according to any one of (26A) to (29A), which is characterized in that the elution reduction of esaxerenone or a pharmaceutically acceptable salt thereof is prevented.

Advantages of the Invention

[0027] According to the present invention, there is provided an orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, which rapidly disintegrates when placed in the mouth or in water, has sufficient hardness during normal production, transportation or use, has good elution properties, good divisibility and little segregation of drug content. Furthermore, according to the present invention, there is provided a manufacturing method for producing an orally disintegrating tablet having the above excellent characteristics by ordinary compression molding without requiring complicated processes or special equipment.

Brief Description of the Drawings

[0028]

Figure 1

Embodiments for Carrying Out the Invention

[0029] In the present invention, an orally disintegrating tablet is a compression molded product having rapid disintegrability when placed in the mouth or in water. Specifically, in a disintegration test mainly by saliva in the mouth or a disintegration test by an apparatus, etc., it generally means a tablet that disintegrates within 1 second or more and 180 seconds or less, preferably 1 second or more and 45 seconds or less, more preferably 1 second or more and 40 seconds or less. Here, the disintegration test and the disintegration test by an apparatus are measured with reference to the "Disintegration Test Method" in the 17th Revised Japanese Pharmacopoeia. Specifically, one tablet is placed in each of six glass tubes of a tester, without an auxiliary plate, using water as the test solution, operating the tester at 37 ± 2°C, and observing the disintegration state of the tablet. When no residue is observed in the glass tube, or even if observed, it is a soft substance that does not clearly retain its original shape, or a fragment of an insoluble coating, etc., the tablet is considered to have disintegrated, and the time until disintegration in each glass tube is evaluated.

[0030] The orally disintegrating tablets of the present invention have good elution properties suitable for pharmaceuticals and little variation. For example, in the evaluation using 900 ml of an aqueous solution of 0.1% polysorbate 80 (TW-O120V, manufactured by Kao Corporation) as the test solution in accordance with the "Dissolution Test Method (Paddle Method, 50 rpm)" of the 17th Revised Japanese Pharmacopoeia, the orally disintegrating tablets have an elution rate of 75% or more at the 30-minute time point and a reduced variation (standard deviation) of the elution rate for each vessel.

[0031] The orally disintegrating tablets of the present invention have sufficient hardness during normal manufacturing, transportation, or use. For example, in the hardness test, the orally disintegrating tablets have a hardness of usually 1.5 kg or more, preferably 2.0 kg or more, and more preferably 3.0 kg or more. Here, the hardness test is performed using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH) or a tablet hardness tester (PTB-302, PHARMA TEST APPRATEBAU GmbH).

[0032] The orally disintegrating tablets of the present invention have formulation properties with little drug segregation suitable for pharmaceuticals. For example, the orally disintegrating tablets have suppressed content variation during the tableting time series, small content variation for each tablet within a lot, and good content uniformity.

[0033] The orally disintegrating tablets of the present invention have tablet properties with good divisibility. For example, when dividing a tablet with a single-sided score line, the orally disintegrating tablets have a mass variation (SD) of 2.0 mg or less for the half tablets after division.

[0034] The esaxerenone used in the present invention has the following structural formula:

[0035]

Chemical formula

[0036] (5P)-1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide represented by ((5P)-1-(2-Hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide) or (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide ((S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide), and can be produced, for example, according to the methods described in International Publication WO2006 / 012642 (U.S. Publication US2008-0234270), International Publication WO2008 / 126831 (U.S. Publication US2010-0093826), etc.

[0037] Esaxerenone may be a solvate (including hydrate), or a pharmaceutically acceptable salt or a solvate thereof (including hydrate). Examples of the pharmaceutically acceptable salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate or phosphate; lower alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; arylsulfonates such as benzenesulfonate or p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate or aspartate, etc.

[0038] Esaxerenone is an atropisomer compound (compound (I)), but in the present invention, esaxerenone used can be not only a pure form of atropisomer but also any mixture of atropisomers.

[0039] Esaxerenone contained in the orally disintegrating tablets of the present invention is usually orally administered once a day at a dose of 2.5 mg as esaxerenone to adult patients with hypertension in Japan. In some cases, it may be administered carefully at 1.25 mg, and if the effect is insufficient, the dose can be increased up to 5 mg.

[0040] There is no particular limitation on the blending amount of esaxerenone or a pharmaceutically acceptable salt thereof contained in the orally disintegrating tablets of the present invention. For example, it is preferably blended at 0.5 to 10% by weight (preferably 1 to 3% by weight) based on the total weight of the orally disintegrating tablets. In addition, there is no particular limitation on the blending amount of the additive in the total amount of the orally disintegrating tablets. For example, based on the total weight of the orally disintegrating tablets, the excipient including lactose hydrate is 10.0 to 93.5% by weight (preferably 44 to 90% by weight), the lubricant is 0.5 to 5% by weight (preferably 0.5 to 2% by weight), the binder is 0 to 15% by weight (preferably 1 to 5% by weight), and the disintegrant is 2.5 to 40% by weight (preferably 5 to 30% by weight).

[0041] The lactose hydrate used in the present invention is not limited as long as it can be used as a pharmaceutical additive, and its average particle size is preferably in the range of 5 to 50 μm. For example, Lactochem (registered trademark) Powder, Lactochem (registered trademark) Fine Powder, Lactochem (registered trademark) Extra Fine Powder, Pharmatose (registered trademark) 450M, Lactohale (registered trademark) 201 of DFE Pharma are preferred. The "average particle size" in the present invention means the particle size at the integrated value of 50% in the particle size distribution determined by a sieving device (for example, manufactured by ATM corp, model "ATM sonic sifter", etc.).

[0042] The light anhydrous silicic acid used in the present invention is not particularly limited as long as it can be used as a pharmaceutical additive. For example, Sylysia 320, Sylysia 350 of Fuji Silysia Chemical, Adsorider-101 of Freund Industry, and AEROSIL 200 Pharm, AEROSIL 300 Pharm of Nippon Aerosil are preferred. The amount is appropriately determined by those skilled in the art with reference to the criteria of the disintegration test, dissolution test, hardness test, splitting test, and content test described in this specification so as to exhibit the desired disintegration property, elution property, hardness, splitting property, and uniformity. Preferably, it is 0.05 to 5% by weight, more preferably 0.3 to 2% by weight, still more preferably 0.3 to 1% by weight, and particularly preferably 0.4 to 0.6% by weight per 100% by weight of the orally disintegrating tablet.

[0043] In addition to the above components, the orally disintegrating agent in the present invention can contain sugar alcohol and crystalline cellulose having a bulk density of 0.26 g / cm 3 as follows, and further, if desired, pregelatinized starch.

[0044] Examples of the sugar alcohol include D-mannitol, erythritol, xylitol, maltitol, sorbitol, etc. Preferably, they are D-mannitol, erythritol, xylitol, and more preferably D-mannitol. As D-mannitol, those conforming to the pharmacopoeias of Japan, Europe, and the United States can usually be used. The crystal form, particle size, and specific surface area of the D-mannitol to be blended are not particularly limited. 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 m 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. The crystal form, particle size, and specific surface area can be measured by, for example, X-ray diffraction method, laser diffraction particle size measurement method, and BET specific surface area measurement method (multi-point method). Commercially available products include, for example, D-mannitol of Merck, Rocket, Towa Kasei, Kao, etc.

[0045] The blending amount of the above sugar alcohol can be appropriately selected. When using D-mannitol, it is usually 1 to 90% by weight, preferably 5 to 70% by weight, preferably 5 to 40% by weight, and more preferably 10 to 20% by weight per 100% by weight of the orally disintegrating tablet.

[0046] The above sugar alcohol may be mixed with other components as powder to obtain a tablet-forming powder and then compression-molded, or may be granulated using a suitable binder and then subjected to compression molding.

[0047] In the present invention, as the crystalline cellulose, those having a bulk density of usually 0.10 to 0.46 g / cm 3 are generally used, and preferably those having a bulk density of 0.26 g / cm 3 or less are the following crystalline celluloses. As commercially available products, for example, Ceolus KG-1000 (registered trademark, bulk density 0.10 to 0.15 g / cm 3 ), Ceolus KG-802 (registered trademark, bulk density 0.13 to 0.23 g / cm 3 ), Ceolus UF-711 (registered trademark, bulk density 0.20 to 0.26 g / cm 3 )(all manufactured by Asahi Kasei Chemicals Corporation) may be mentioned. Preferably, it is crystalline cellulose having a bulk density of 0.10 to 0.26 g / cm 3 , and more preferably crystalline cellulose having a bulk density of 0.13 to 0.23 g / cm 3 . Also, a combination of two or more types of crystalline cellulose having different bulk densities adjusted to have a desired bulk density can be used.

[0048] The blending amount of the above crystalline cellulose is preferably 1 to 50% by weight per 100% by weight of the orally disintegrating tablet. If it exceeds 50% by weight, the fluidity may deteriorate and the manufacturability may decrease. A more preferable blending amount is 5 to 30% by weight, and an even more preferable blending amount is 5 to 20% by weight.

[0049] When using D-mannitol as the sugar alcohol, the blending ratio (weight ratio) of the crystalline cellulose and the sugar alcohol is 1 to 10 times, preferably 1 to 8.5 times, more preferably 1 to 5 times, and even more preferably 1 to 2 times that of the sugar alcohol with respect to 1 of the crystalline cellulose.

[0050] The above-mentioned crystalline cellulose may be mixed with other components as a powder to form a tableting powder and then compression-molded, or may be granulated using a suitable binder and then subjected to compression molding.

[0051] The α-starch used in the present invention is starch that has been heat-treated to be α-converted and includes partially α-converted starch. Further, as the above-mentioned α-starch, those described in the Japanese Pharmaceutical Additives Standard can be used. The average degree of α-conversion is preferably 90% or less, more preferably 70 to 80%. As commercially available products, for example, α-starch swelstar PD-1 (manufactured by Asahi Kasei Chemicals) can be used.

[0052] The blending amount of the above-mentioned α-starch is usually 0.1 to 15% by weight, preferably 0.1 to 10% by weight, and more preferably 1 to 3% by weight per 100% by weight of the orally disintegrating tablet.

[0053] The above-mentioned α-starch may be mixed with other components as a powder to form a tableting powder and then compression-molded, or may be granulated together with other components and then subjected to compression molding.

[0054] In the orally disintegrating tablet of the present invention, the α-starch serves as a disintegrant. On the other hand, during production, it shows viscosity when dispersed in a liquid, for example, water. Therefore, when sprayed on the raw material in a powder state, granulation can proceed and it can be made into granules. Utilizing this property, the bulk density is 0.26 g / cm 3By spraying a dispersion of pregelatinized starch in water onto a powdery mixture containing the following crystalline cellulose and sugar alcohol and performing fluidized bed granulation to produce granules, and mixing these with other components as necessary and compression molding, tablets with good moldability and desired intraoral disintegrability can be obtained. Such manufacturing advantages are properties specific to pregelatinized starch that are hardly obtained when using conventional disintegrants such as low-substituted hydroxypropyl cellulose and crospovidone.

[0055] The blending amount of hydroxypropyl cellulose (for example, HPC-L, product of Nippon Soda) contained in the intraoral disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by those skilled in the art with reference to the criteria of the disintegration test, dissolution test, hardness test, splitting test, and content test described herein so as to exhibit desired disintegrability, elution property, hardness, splitting property, and uniformity. The blending amount of the above hydroxypropyl cellulose is preferably 0.1 to 15% by weight, more preferably 0.5 to 5% by weight, and still more preferably 1.5 to 2.5% by weight per 100% by weight of the intraoral disintegrating tablet.

[0056] The blending amount of low-substituted hydroxypropyl cellulose (for example, LH-21, product of Shin-Etsu Chemical Co., Ltd.) contained in the intraoral disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by those skilled in the art with reference to the criteria of the disintegration test, dissolution test, hardness test, splitting test, and content test described herein so as to exhibit desired disintegrability, elution property, hardness, splitting property, and uniformity. The blending amount of the above low-substituted hydroxypropyl cellulose is preferably 1 to 50% by weight, more preferably 5 to 30% by weight, and still more preferably 5 to 20% by weight per 100% by weight of the intraoral disintegrating tablet.

[0057] The blending amount of crospovidone (for example, Kollidon CL-F, manufactured by BASF) contained in the orally disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by those skilled in the art with reference to the criteria of the disintegration test, dissolution test, hardness test, splitting test, and content test described in this specification so as to exhibit desired disintegration property, dissolution property, hardness, splitting property, and uniformity. The blending amount of the above crospovidone is preferably 0.5 to 30% by weight, more preferably 0.5 to 20% by weight, still more preferably 1 to 10% by weight, and particularly preferably 2 to 6% by weight per 100% by weight of the orally disintegrating tablet.

[0058] The orally disintegrating tablet of the present invention can contain various one or more additives generally used in the production of tablets as long as it does not interfere with the effects of the invention.

[0059] Examples of the above additives include excipients, binders, disintegrants, emulsifiers, stabilizers, lubricants, coating agents, plasticizers, coloring agents, flavoring agents, sweetening agents, taste and odor correctors, flavor correctors, fluidizing agents, foaming agents, and surfactants.

[0060] Examples of the "excipients" used in addition to lactose hydrate, crystalline cellulose, and D-mannitol include sugar derivatives such as lactose, sucrose, glucose, or sorbitol; starch derivatives such as corn starch, potato starch, α-starch, or dextrin; cellulose derivatives; gum arabic; dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as calcium sulfate.

[0061] Examples of the "binders" used in addition to light anhydrous silicic acid and hydroxypropyl cellulose include hypromellose, polyvinylpyrrolidone, polyethylene glycol, or compounds similar to the above excipients.

[0062] Examples of the "emulsifier" used include colloidal clays such as bentonite or beidellite; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

[0063] Examples of the "stabilizer" used include paraoxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid, etc.

[0064] Examples of the "flavoring and odor-correcting agent" used include sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or fragrances such as menthol, lemon or orange.

[0065] A disintegrant generally refers to an additive that is added for the purpose of disintegrating and dispersing to the original drug particles and facilitating absorption by its water conductivity and swelling property when taken. In addition to low-substituted hydroxypropyl cellulose, pregelatinized starch, and crospovidone, examples of "disintegrants" used include cellulose derivatives such as carboxymethyl cellulose (carboxymethylcellulose), carboxymethyl cellulose calcium, croscarmellose sodium (e.g., Japanese Pharmacopoeia conforming products), or sodium carboxymethylcellulose with internal cross-linking; cross-linked polyvinylpyrrolidone; or chemically modified starches and celluloses such as corn starch (e.g., Japanese Pharmacopoeia conforming products), sodium starch glycolate (e.g., Japanese Pharmacopoeia conforming products), or carboxymethyl starch or sodium carboxymethyl starch, etc.

[0066] Examples of "lubricants" used include, for example, stearic acid; metal stearates such as calcium stearate (e.g., Japanese Pharmacopoeia conforming products) or magnesium stearate (e.g., Japanese Pharmacopoeia conforming products); talc (e.g., Japanese Pharmacopoeia conforming products); colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycols; fumaric acid; sodium stearyl fumarate (e.g., conforming to pharmaceutical additive standards); sucrose fatty acid esters; sodium benzoate; D,L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicas such as anhydrous silicic acid or hydrated silicic acid; or the above-mentioned starch derivatives, etc. Preferably, they are metal stearates, and particularly preferably, magnesium stearate.

[0067] The blending amount of the lubricant is preferably 0.1 to 5% by weight per 100% by weight of the orally disintegrating tablets.

[0068] Examples of coating agents for coating the surface of powdered drugs (crystal surfaces) or the surface of granules of granulated drugs include one or more combinations selected from ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylaminoacetate, and polyvinyl acetate resin.

[0069] Examples of plasticizers combined with the coating agent include one or more combinations selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

[0070] Examples of coloring agents include one or more combinations selected from food dyes such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2; food lake pigments, yellow ferric oxide, ferric oxide, black iron oxide, titanium oxide, β-carotene, and riboflavin.

[0071] Examples of flavoring agents include one or more combinations selected from orange, lemon, strawberry, mint, menthol micron, and various flavors.

[0072] Examples of sweeteners include one or more combinations selected from sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thaumatin.

[0073] Examples of flavor correctives include one or more combinations selected from sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

[0074] Examples of the fluidizing agent include one or a combination of two or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and talc.

[0075] Examples of the foaming agent include tartaric acid and / or citric anhydride.

[0076] Examples of the surfactant include one or a combination of two or more selected from polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glycerin monostearate, and sodium lauryl sulfate.

[0077] The method for producing the orally disintegrating tablets of the present invention can employ well-known production methods for solid preparations. For example, tablets can be obtained by adding and mixing the active ingredient, additives, etc., and then tableting. Tablets can also be obtained by granulating together with the active ingredient, additives, etc., adding a lubricant, etc., and then mixing and tableting. Further, after granulation, operations such as drying and sizing may be performed as necessary. Hereinafter, one embodiment (Embodiments A and B) of the orally disintegrating tablets of the present invention will be described together with its production method.

[0078] Embodiment A: The bulk density is 0.26 g / cm 3 An orally disintegrating tablet obtained by compression molding a drug-free granule containing the following crystalline cellulose, sugar alcohol, and pregelatinized starch, and a drug or a drug-containing granule. In this embodiment, the drug-free granule functions as a skeleton of a formulation that can impart desirable disintegrability and moldability as an orally disintegrating tablet. The drug-free granule has a bulk density of 0.26 g / cm 3 Excellent disintegrability and moldability can also be exhibited by blending only the three components of the following crystalline cellulose, sugar alcohol, and pregelatinized starch, but other additives may be blended as necessary. Further, the orally disintegrating tablet in this embodiment can be made into a formulation having good divisibility and less content segregation by adding 0.05 to 5% by weight of light anhydrous silicic acid. The method for manufacturing an orally disintegrating tablet of Form A includes a step (A-1) of manufacturing drug-free granules, a step (A-2) of manufacturing drug-containing granules, and a step (A-3) of mixing the drug-free granules, the drug or the drug-containing granules, and other additives and compression molding them.

[0079] A-1: Step of manufacturing drug-free granules Drug-free granules can be manufactured using the following method 1) or 2). 1) Using a method of wet granulating a mixture containing the following crystalline cellulose, sugar alcohol (e.g., D-mannitol), and pregelatinized starch with water, with a bulk density of 0.26 g / cm 3 2) Using a method of granulating a mixture containing the following crystalline cellulose and sugar alcohol (e.g., D-mannitol) with a liquid in which pregelatinized starch is dispersed in water or the like, with a bulk density of 0.26 g / cm 2) Using a method of granulating a mixture containing the following crystalline cellulose and sugar alcohol (e.g., D-mannitol) with a liquid in which pregelatinized starch is dispersed in water or the like, with a bulk density of 0.26 g / cm 3 2) Using a method of granulating a mixture containing the following crystalline cellulose and sugar alcohol (e.g., D-mannitol) with a liquid in which pregelatinized starch is dispersed in water or the like, with a bulk density of 0.26 g / cm Here, for granulation, a conventional extrusion granulation method, a mixing and stirring granulation method, a high-speed stirring granulation method, a fluidized bed granulation method, a rolling granulation method, or the like can be used. When pregelatinized starch is dispersed in a liquid, such as water, it exhibits viscosity suitable for granulation. For the granulation method, there are a method of mixing pregelatinized starch in a powdery state with other components and compression molding the granulated particles, and a method of compression molding the granulated particles granulated with a liquid in which pregelatinized starch is dispersed in water. Both methods can provide tablets with desired properties, but preferably the latter method is mentioned. Also, when granulating using a liquid in which pregelatinized starch is dispersed, either a high-speed stirring granulation method or a fluidized bed granulation method can be applied. However, when manufacturing granules by the fluidized bed granulation method, more excellent orally disintegrating tablets can be obtained. When blending other additives, such as a conventional disintegrant, into the drug-free granules, they can be blended into the mixture before granulation. In the drug-free granules, with a bulk density of 0.26 g / cm 3When using D-mannitol as the sugar alcohol, the mixing ratio of the following crystalline cellulose and sugar alcohol is 1 to 8.5 parts by weight, preferably 1 to 5 parts by weight, more preferably 1 to 2 parts by weight of the sugar alcohol with respect to 1 part by weight of the crystalline cellulose.

[0080] A-2: Step of manufacturing drug-containing granules The drug can be mixed with the drug-free granules as it is in powder form or, if desired, in granular form. The drug-containing granules can be produced, for example, by a conventional extrusion granulation method, a mixing and stirring granulation method, a high-speed stirring granulation method, a fluidized bed granulation method, or a rolling granulation method. It is also possible to dry the granulation powder with a dryer and then screen it using a comminuting mill or a pin mill to obtain the drug-containing granules. The particle size of the drug-containing granules can be adjusted according to the screening conditions. 50% or more of the drug-containing granules are 95 μm or less, preferably 80 μm or less, more preferably 70 μm or less, and particularly preferably 60 μm or less. 90% or more of the drug-containing granules are 420 μm or less, preferably 380 μm or less, more preferably 250 μm or less, and particularly preferably 150 μm or less. The particle diameter (median diameter) corresponding to 50% or 90% of the cumulative sieve undersize distribution can be measured by a dry sieving method. Also, a mixture of a powdery or granular drug and a sugar alcohol can be granulated with a solution in which hydroxypropylcellulose is dissolved or dispersed in water to obtain drug-containing granules. The drug or drug-containing granules can also be coated for masking unpleasant tastes such as bitterness and irritation, and for controlling elution properties. For the coating, the aforementioned coating agents and plasticizers can be appropriately used. The coating method is carried out, for example, by using a fluidized bed granulation and coating machine, a rolling fluidized bed granulation and coating machine, a centrifugal fluidized type granulation and coating machine, or a Wurster type fluidized bed granulation and coating machine. When using two or more drugs, depending on the compatibility of the drugs, they can be contained in the same granule or separately in different granules and then subjected to compression molding.

[0081] Step A-3: Mixing a drug-free granule with a drug or a drug-containing granule and other additives, followed by compression molding A drug-free granule is mixed with a drug or a drug-containing granule, light anhydrous silicic acid, crospovidone, and optionally other disintegrants, binders, excipients, colorants, lubricants, and other additives, and then compression molded into an orally disintegrating tablet. The mixing can be carried out, for example, using a tumble mixer or a convection mixer. The drug can also be mixed with other additives and used as a drug-containing mixed powder. The drug-free granule and additives other than the drug or the drug-containing granule can be mixed and used as an extra-granular mixed powder. The compression molding of the orally disintegrating tablet of the present invention can be carried out using an ordinary tableting machine. The molding pressure by the tableting machine may be similar to that of ordinary tablets, and although it depends on the shape and size of the tablet, preferably it is about 2 to 20 kN, more preferably about 4 to 14 kN.

[0082] The blending ratio of the drug-free granule to the total weight of the tablet components is usually 5 to 90% (wt%), preferably 10 to 70%, more preferably 15 to 50%, and even more preferably 20 to 30%, whether the drug is in powder form or granulated. When the drug is used in granulated form, the blending weight ratio of the drug-free granule to the drug-containing granule is preferably 0.1 to 2.0, more preferably 0.2 to 1.0, and even more preferably 0.3 to 0.5 with respect to 1 of the drug-containing granule.

[0083] Aspect B: Bulk density of 0.26 g / cm 3 An orally disintegrating tablet obtained by compression molding a drug-free mixed powder containing the following crystalline cellulose, sugar alcohol, and pregelatinized starch, and a drug or a drug-containing granule.

[0084] In this aspect, the drug-free mixed powder imparts desirable disintegrability and moldability to the orally disintegrating tablet. The drug-free mixed powder has a bulk density of 0.26 g / cm 3Excellent disintegrability and moldability can be exhibited by blending only the following three components: crystalline cellulose, sugar alcohol, and pre-gelatinized starch. However, other additives may be blended as necessary. Further, the orally disintegrating tablets in this embodiment can be formulated to have good divisibility and less content segregation by adding 0.05 to 5% by weight of light anhydrous silicic acid.

[0085] The method for producing the orally disintegrating tablets of Embodiment B includes a step of producing drug-containing granules, if desired, and a step of mixing and compression molding a drug or drug-containing granules and other additives. The step of producing drug-containing granules is the same as A-2 described above.

[0086] In the step of mixing and compression molding a drug-free mixed powder, a drug or drug-containing granules, and other additives, the mixing or compression molding step is the same as A-3 described above.

[0087] Examples of the film coating base material that can be used in the present invention include a sugar coating base material, a water-soluble film coating base material, and the like. As the sugar coating base material, sucrose is used, and further, one or more selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan, and the like can be used in combination. Examples of the water-soluble film coating base material include cellulose derivatives such as hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, or sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, or polyvinylpyrrolidone; or polysaccharides such as pullulan.

[0088] The above coating base materials may be used by mixing two or more of them at an appropriate ratio. Further, if necessary, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents, and / or preservatives can be included.

[0089] The types of plasticizers that can be included in the coating base are not particularly limited and can be appropriately selected by those skilled in the art. Examples of such plasticizers include propylene glycol, polyethylene glycol, polypropylene glycol, glycerin, and sorbitol, glycerin triacetate, diethyl phthalate, and triethyl citrate, lauric acid, sucrose, dextrose, sorbitol, triacetin, acetyltriethyl citrate, triethyl citrate, tributyl citrate, or acetyltributyl citrate, and the like.

[0090] Examples of the masking agent that can be included in the coating base include titanium oxide and the like.

[0091] Examples of the colorant that can be included in the coating base include iron sesquioxide, yellow iron sesquioxide, black iron oxide, titanium oxide, Brilliant Blue FCF, Indigo carmine, Erythrosine, Tartrazine, Sunset Yellow FCF, and the like. Preferably, they are iron sesquioxide, yellow iron sesquioxide, and black iron oxide, and more preferably, they are iron sesquioxide and yellow iron sesquioxide.

[0092] The content of the colorant that can be included in the coating base is preferably 0.003 to 0.1% by weight (more preferably 0.01% or more to 0.1% by weight) based on the total weight of the core tablets.

[0093] Examples of the preservative that can be included in the coating base include parabens and the like.

[0094] The orally disintegrating tablets of the present invention thus obtained have little segregation of the drug content, excellent divisibility in scored tablets, excellent disintegrability when placed in the mouth or in water, and good dissolution properties.

[0095] The disintegration property of the orally disintegrating tablet of the present invention is such that the disintegration time in the oral cavity (the time until the tablet completely disintegrates with only saliva without containing water in the oral cavity of a healthy adult male) is usually 1 second or more and 180 seconds or less, preferably 1 second or more and 60 seconds or less, more preferably 1 second or more and 45 seconds or less, and even more preferably 1 second or more and 40 seconds or less. The orally disintegrating tablet of the present invention gradually disintegrates by saliva when placed in the mouth, but disintegrates in a shorter time by the pressure in the oral cavity, that is, the pressure by the upper jaw and the tongue, or the friction by the tongue, that is, the "licking" action, etc. In a person with a dry oral cavity or a person with little saliva, it may disintegrate in the oral cavity using water or hot water, or it can be taken as it is with water in the same manner as a normal tablet without any problem.

[0096] The good and less variable elution property of the orally disintegrating tablet of the present invention, in the evaluation using 900 ml of an aqueous solution of 0.1% polysorbate 80 (TW-O120V, manufactured by Kao Corporation) as the test solution in accordance with the "Dissolution Test Method (Paddle Method, 50 rpm)" of the 17th revised Japanese Pharmacopoeia, usually has an elution rate of 75% or more at the 30-minute time point, preferably 80% or more at the 30-minute time point, more preferably 85% or more at the 30-minute time point, and the variation (standard deviation) of the elution rate for each vessel can be evaluated.

[0097] Since the orally disintegrating tablet of the present invention has little drug segregation in the formulation, the content variation per tablet within a lot is small, and in the measurement (RSD) of the variation among 10 tablets in one lot, it is preferably 2.0 or less, more preferably 1.5 or less, and even more preferably 1.2 or less. Also, the content variation range in the tableting time series is preferably 5.0 or less, more preferably 4.0 or less, even more preferably 3.0 or less, and particularly preferably 2.0 or less.

[0098] The orally disintegrating tablets of the present invention are provided as tablets with good divisibility, and score lines can be provided on one side of the front or back surface of the tablet, or on both sides of the front and back surfaces. The "score line" is provided on the surface of the tablet, preferably on one side of the front or back surface of a circular or elliptical surface, or on both sides of the front and back surfaces as needed to facilitate the splitting of the tablet into two parts. Generally, it is a depression with a deepest part extending linearly. A triangular shape is adopted as the cross-sectional shape of the depression, but in some cases, it may be combined with shapes such as a triangle and a square, rectangle, or semi-circular shape. Note that the cross-sectional shape of the depression is the shape observed as the depression in the part to be split in the cross-section cut perpendicular to the score line. Triangles can include synonymous terms such as wedge shape and V shape. The cross-sectional shape may be constant according to the surface shape of the tablet, or may change as appropriate, but is not particularly limited.

[0099] In this specification, "splitting" means preparing two partial tablets (half tablets) by applying stress to cut one tablet. It is desirable that the drug content or tablet mass of each half tablet is ideally 50% of the tablet before splitting. Generally, when the hardness of the tablet itself is low, the stress required for splitting is small, but the mass variation of the half tablets may increase due to the disintegration of the tablet during splitting. In addition, tablets with low hardness are prone to tablet breakage such as cracking and chipping during manufacturing, transportation, and storage, and there is also a concern that the shape stability of the half tablets after splitting may decrease.

[0100] The orally disintegrating tablets of the present invention have good divisibility while maintaining the characteristics (disintegratability) of orally disintegrating tablets. In the present invention, "good divisibility" means that when splitting a tablet with a score line on one side, the mass variation (SD) of the half tablets after splitting is small. Preferably, the mass variation (SD) of the half tablets after splitting is 7.5 mg or less, more preferably 5.0 mg or less, still more preferably 3.0 mg or less, and particularly preferably 2.0 mg or less.

[0101] On the one hand, the orally disintegrating tablets of the present invention have a hardness that does not disintegrate even after a stability test under specific temperature and humidity conditions (for example, temperature 25°C, humidity 75%, PTP primary packaging, 6 months), that is, a hardness that does not disintegrate during the manufacturing process and distribution process of the preparation, and the hardness is a practical hardness even during storage under specific temperature and humidity conditions.

[0102] The orally disintegrating tablets of the present invention can be used for the treatment of diseases as a preparation that is easy to take for the elderly, children, and patients with difficulty in swallowing, and also as a safe preparation for general adults.

Examples

[0103] Next, the present invention will be described in more detail by way of examples and the like. However, the following examples are for explaining the present invention, and the present invention should not be construed as being limited to these examples.

[0104] (Example 1) Drug-containing granule particle size and preparation content uniformity (1-1) Tablet manufacturing method Esaxerenone (drug), lactose hydrate (Pharmatose 450M, DFE pharma), low-substituted hydroxypropyl cellulose (LH-21, Shin-Etsu Chemical), and hydroxypropyl cellulose (HPC-L, Nippon Soda) were weighed according to the compounding ratios shown in Table 2, and after being put into a high-speed stirring granulator (VG-25 or VG-100, Powrex) together with purified water, they were kneaded for 3 to 4 minutes to obtain granulation powder. This granulation powder was dried in a fluidized bed granulation dryer (NFLO-5, Freund Industries, or GPCG-30, Powrex) until the product temperature reached 60°C, and then sized at the rotation speeds shown in Table 2 using a Comil (QC-194S, QUADRO) or a pin mill (100UPZ, Hosokawa Micron) to obtain drug-containing granules. Also, D-mannitol (Pearlitol 50C, Rocket), crystalline cellulose (Ceolus KG-802, Asahi Kasei Chemicals) were weighed at the blending ratios shown in Table 2, put into a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex), and after spraying a liquid in which pregelatinized starch (Swelstar PD-1, Asahi Kasei Chemicals) was dispersed in purified water, it was dried to obtain drug-free granules. Furthermore, crospovidone (Kollidon CL-F, BASF), yellow ferric oxide (Yellow Ferric Oxide, Kisuika Kasei), and light anhydrous silicic acid (Silicia 350, Fuji Silysia Chemical) were weighed at the blending ratios shown in Table 2, put into a high-speed stirring granulator (VG-25 or VG-100, Powrex), and mixed for 15 minutes to obtain an outer granule mixed powder. This drug-containing granule, drug-free granule, outer granule mixed powder, and magnesium stearate (HyQual 5712, Mallinckrodt) were put into a V-type mixer (Tokuju Works) and mixed for 10 minutes, and then using a rotary tableting machine (VIRGO or VELA2, Kikusui Seisakusho), for Comparative Example 1 and Examples 1-1 to 1-3 and 1-5, the tablet mass was set to 85 mg, and for Example 1-4, the tablet mass was set to 87 mg and molded to obtain plain tablets of about φ-6.5 mm.

[0105] (1-2) Evaluation Methods and Results The components and evaluation results of the manufactured plain tablets are shown in Table 2 and Figure 1. The particle sizes of the drug-containing granules (x50; particle diameter [median diameter] corresponding to 50% of the cumulative undersize distribution and x90; particle diameter [median diameter] corresponding to 90% of the cumulative undersize distribution) were measured by a dry sieving method (Robot Sifter, Seishin Enterprise). The content of the plain tablets was measured under the conditions shown in Table 1 using HPLC (LC-20AD, Shimadzu). Also, for the content variation range in the tableting process over time, the content at each time point at 5- to 10-minute intervals during continuous tableting for about 1 hour was measured, and the difference between the value at the time point with the highest content and the value at the time point with the lowest content was calculated. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). Also, the disintegration test was evaluated according to the disintegration test method of the 17th revised Japanese Pharmacopoeia without an auxiliary disk. The dissolution properties of the tablets of Examples 1-1 to 1-5 were all good.

[0106]

Table 1

[0107]

Table 2

[0108] In the case of Comparative Example 1 where the particle size of the drug-containing granules was large, the content variation range in the tableting process in time series was 6.0%. In contrast, in the cases of Example 1-1, Example 1-2, Example 1-3, Example 1-4, and Example 1-5 with smaller particle sizes, the content variation ranges decreased to 3.7%, 1.0%, 2.0%, 2.1%, and 1.8%. Also, regarding the content variation (RSD) of the lot, compared with 2.7 of Comparative Example 1, in Example 1-1, Example 1-2, Example 1-3, Example 1-4, and Example 1-5, it decreased to 1.1, 1.2, 0.8, 0.7, and 0.7. Therefore, it was shown that the formulation with small drug particle size suppresses the content variation during the tableting time series compared to the formulation with large drug particle size, and the content variation of the lot also becomes smaller, resulting in a formulation with uniform content.

[0109] (Example 2) Tablet Formulation Components and Tablet Divisibility (2-1) Method for Manufacturing Tablets Esaxerenone (drug), lactose monohydrate (Pharmatose 450M, DFE Pharma), low-substituted hydroxypropyl cellulose (LH-21, Shin-Etsu Chemical), and hydroxypropyl cellulose (HPC-L, Nippon Soda) were weighed at the compounding ratios shown in Table 3, and after being charged together with purified water into a high-speed stirring granulator (VG-10 or VG-400, Powrex), they were kneaded for 3 to 4 minutes to obtain granulation powder. This granulation powder was dried in a fluidized bed granulation dryer (NFLO-2, Freund Industries, or WSG-120, Powrex) until the product temperature reached 60°C, and then sized using a Comil (QC-197 or QC-194S, QUADRO) or a pin mill (SCM-3, Nara Machinery Co., Ltd.) to obtain drug-containing granules. Also, D-mannitol (Pearlitol 50C, Roquette) and crystalline cellulose (Ceolus KG-802, Asahi Kasei Chemicals) were weighed at the compounding ratios shown in Table 3, charged into a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex), and after spraying a liquid in which pregelatinized starch (Swelstar PD-1, Asahi Kasei Chemicals) was dispersed in purified water, they were dried to obtain drug-free granules. Furthermore, in Comparative Example 2-1, crospovidone (Kollidon CL-F, BASF) and yellow ferric oxide (yellow ferric oxide, Kisuika Chemical) were used. In Comparative Example 2-2, crospovidone (Kollidon CL-F, BASF), yellow ferric oxide (yellow ferric oxide, Kisuika Chemical), and hydroxypropyl cellulose (HPC-SSL, Nippon Soda) were used. In Examples 2-1 and 2-3, crospovidone (Kollidon CL-F, BASF), yellow ferric oxide (yellow ferric oxide, Kisuika Chemical), and light anhydrous silicic acid (Silicia 350, Fuji Silysia Chemical) were used. In Example 2-2, crospovidone (Kollidon CL-F, BASF), ferric oxide (ferric oxide, Kisuika Chemical), and light anhydrous silicic acid (Silicia 350, Fuji Silysia Chemical) were weighed at the compounding ratios shown in Table 3, charged into a high-speed stirring granulator (VG-10 or VG-400, Powrex), and then mixed for 15 minutes to obtain an externally mixed powder of granules. This drug-containing granule, drug-free granule, extra-granular mixed powder, and magnesium stearate (HyQual 5712, Mallinckrodt) were charged into a V-type mixer (Tokuju Works) or a tumble mixer (Totech), and mixed for 5 minutes in Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, and for 30 minutes in Example 2-2 and Example 2-3. Using a tabletting machine (manufactured by Ichibashi Seiki, HANDTAB), tablets with a mass of 200 mg were formed in Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, and using a rotary tablet press (VELA2, Kikusui Seisakusho), tablets with a mass of 174 mg were formed in Example 2-2 and Example 2-3 to obtain approximately φ-8.0 mm tablets with a score line on one side.

[0110] (2-2) Evaluation Method and Results The components and evaluation results of the manufactured tablets are shown in Table 3. The divisibility was evaluated using the mass variation (SD, mg) of 10 half tablets obtained by dividing 5 tablets as an index. The tablets were divided by applying a spatula to the side opposite the score line and pushing open the score line. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). The disintegration test was evaluated according to the disintegration test method of the 17th revised Japanese Pharmacopoeia without an auxiliary disk. In Comparative Example 2-1, nothing was added to the extra-granular mixed powder except crospovidone and yellow ferric oxide. The mass variation (SD) of the half tablets during the division of this tablet was 5.5 mg. In Comparative Example 2-2, hydroxypropyl cellulose (HPC-SSL) was added as a binder in addition to crospovidone and yellow ferric oxide in the extra-granular mixed powder. The mass variation (SD) of the half tablets during the division of this tablet was 4.0 mg. In Example 2-1, Example 2-2, and Example 2-3, light anhydrous silicic acid was added to the extra-granular mixed powder in addition to crospovidone and yellow ferric oxide or ferric oxide. The mass variations (SD) of the half tablets during the division of these tablets were 1.0 mg, 1.7 mg, and 1.5 mg, respectively. Also, the disintegration times of the tablets in Example 2-1, Example 2-2, and Example 2-3 were 25 seconds, 33 seconds, and 35 seconds, respectively, which were at the same speed as Comparative Example 2-1. Therefore, when adding light anhydrous silicic acid to the externally granulated mixture powder, it was shown that the mass variation of half tablets after splitting the plain tablets becomes extremely small without impairing the disintegration property as an orally disintegrating tablet, and good divisibility is imparted.

[0111]

Table 3

Industrial Applicability

[0112] According to the present invention, an orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, having rapid disintegration property when placed in the oral cavity or in water, having sufficient hardness during normal manufacturing, transportation or use, good elution property, good divisibility and little segregation of drug content, and a method for manufacturing the same can be provided. Furthermore, according to the present invention, an orally disintegrating tablet having excellent characteristics as described above can be manufactured by ordinary compression molding without requiring complicated processes or special equipment.

Claims

1. An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, and light anhydrous silicic acid.

2. An orally disintegrating tablet containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, sugar alcohol, crystalline cellulose, and pregelatinized starch.

3. The orally disintegrating tablet according to any one of Claims 1 or 2, wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet.

4. The orally disintegrating tablet according to any one of Claims 1 to 3, wherein the average particle diameter of lactose hydrate is in the range of 5 to 50 μm.

5. The bulk density of crystalline cellulose is 0.26 g / cm ３ The orally disintegrating tablet according to any one of claims 2 to 4, wherein the bulk density is 0.26 g / cm or less.

6. The orally disintegrating tablet according to any one of Claims 2 to 5, wherein the content of hydroxypropyl cellulose is 0.1 to 15% by weight based on the total weight of the tablet.

7. The orally disintegrating tablet according to any one of Claims 2 to 6, wherein the average degree of pregelatinization of pregelatinized starch is 90% or less.

8. The orally disintegrating tablet according to any one of Claims 1 to 7, further containing crospovidone.

9. The orally disintegrating tablet according to any one of Claims 1 to 8, further containing a colorant and magnesium stearate.

10. The orally disintegrating tablet according to Claim 9, wherein the colorant is yellow iron oxide (III) or iron oxide (III).

11. A drug-containing granule containing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose; a drug-free granule containing D-mannitol, crystalline cellulose, and pregelatinized starch; and an orally disintegrating tablet containing light anhydrous silicic acid as an extra-granular component for the two types of granules.

12. The orally disintegrating tablet according to Claim 11, wherein the content of light anhydrous silicic acid is 0.05 to 5% by weight based on the total weight of the tablet.

13. The orally disintegrating tablet according to Claim 11 or 12, wherein the average particle diameter of lactose hydrate is in the range of 5 to 50 μm.

14. The bulk density of crystalline cellulose is 0.26 g / cm ３ The orally disintegrating tablet according to any one of claims 11 to 13, wherein the bulk density is 0.26 g / cm or less.

15. The orally disintegrating tablet according to any one of Claims 11 to 14, wherein the content of hydroxypropyl cellulose is 0.1 to 15% by weight based on the total weight of the tablet.

16. The orally disintegrating tablet according to any one of claims 11 to 15, wherein the content of pregelatinized starch is 0.1 to 10% by weight based on the total weight of the tablet.

17. The orally disintegrating tablet according to any one of claims 11 to 16, further containing crospovidone as an extragranular component.

18. The orally disintegrating tablet according to any one of claims 11 to 17, further containing a colorant and magnesium stearate as extragranular components.

19. The orally disintegrating tablet according to claim 18, wherein the colorant is yellow ferric oxide or ferric oxide.

20. The orally disintegrating tablet according to any one of claims 1 to 19, which disintegrates in 1 second or more and 45 seconds or less in a disintegration test by a device.

21. The orally disintegrating tablet according to any one of claims 1 to 20, which has good divisibility with a score line.

22. The orally disintegrating tablet according to claim 21, wherein the tablet strength and abrasion degree of the half tablet after division having a score line are good.

23. The orally disintegrating tablet according to any one of claims 11 to 22, wherein 50% or more of the drug-containing granules have a particle size of 80 μm or less.

24. The orally disintegrating tablet according to any one of claims 11 to 23, wherein 90% or more of the drug-containing granules have a particle size of 380 μm or less.

25. The orally disintegrating tablet according to any one of claims 23 or 24, having less segregation of the drug content.

26. A process for producing drug-containing granules by mixing esaxerenone or a pharmaceutically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose; a process for producing drug-free granules by mixing D-mannitol and crystalline cellulose and spraying pregelatinized starch dispersed in water; and a process for producing an orally disintegrating tablet, which comprises adding light anhydrous silicic acid and crospovidone as extragranular components to the two types of granules and compression molding.

27. The method for producing an orally disintegrating tablet according to claim 26, further comprising a step of adding a colorant as an extragranular component and adding magnesium stearate and compression molding.

28. The method for producing an orally disintegrating tablet according to claim 27, wherein the colorant is yellow ferric oxide or ferric oxide.

29. The method for producing an orally disintegrating tablet according to any one of claims 26 to 28, wherein the step of producing drug-containing granules includes a high-speed stirring granulation step.

30. A method for producing an orally disintegrating tablet according to any one of claims 26 to 29, characterized in that elution reduction of esaxerenone or a pharmacologically acceptable salt thereof is prevented.

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