JP7665531B2 - Orally disintegrating tablets containing pyrrole carboxamide - Google Patents

Description

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

Esakiserenone has the following structural formula:

(Compound (I)).

Compound (I) is disclosed in U.S. Patent No. 8,524,918 and is known as a drug having excellent activity as a mineralocorticoid receptor (MR) (aldosterone receptor) antagonist and having excellent therapeutic effects 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 disease [angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure or cardiac hypertrophy], kidney disease (diabetic nephropathy, glomerulonephritis or nephrosclerosis), cerebrovascular disease (cerebral infarction or cerebral hemorrhage) or vascular disorder (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorder), and is also expected to be effective in remission of diabetic nephropathy (International Publication WO2017/164208).

In the fields of pharmaceuticals and food, tablets, capsules, granules, powders, etc. are known as oral solid dosage forms. However, there is hope for the development of orally disintegrating tablets that disintegrate quickly when placed in the mouth or when immersed in water, as a dosage form that is easier to take for the elderly, children, and patients with difficulty swallowing.

Orally disintegrating tablets, in addition to the property of disintegrating quickly in the mouth, are required to have sufficient hardness to withstand physical shocks during manufacture, transportation and use, just like regular tablets, and also to have dissolution properties with little variation. In addition, from the perspective of medication compliance, it is desirable for the tablets to have a good mouthfeel with reduced unpleasant taste and irritation when placed in the mouth.

Various reports have been made on orally disintegrating tablets. For example, Patent Document 2 describes an orally disintegrating tablet containing a drug, crystalline cellulose having a bulk density of 0.23 g/cm3 or ^less , a 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 size in the range of 5 to 50 μm.

Patent Document 3 describes an orally disintegrating tablet containing prasugrel, carmellose, and hydroxypropyl cellulose, and a method for producing the same. This document describes an orally disintegrating tablet containing prasugrel that has sufficient hardness and shows little variation in dissolution properties due to the inclusion of carmellose and hydroxypropyl cellulose, but does not describe an orally disintegrating tablet that contains esaxerenone, light anhydrous silicic acid, and lactose hydrate with an average particle size in the range of 5 to 50 μm, has good divisibility, and has little segregation of the drug content.

WO2008/126831 Pamphlet (U.S. Patent No. 8,524,918) WO2013/161823 Brochure Patent Publication No. 2019-034935

The objective of the present invention is to provide an orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, which disintegrates rapidly when placed in the mouth or in water, has sufficient hardness for normal production, transportation or use, and has good dissolution properties, good divisibility and little segregation of the drug content, and a method for producing the same.

As a result of intensive research conducted by the inventors to solve the above-mentioned problems, they discovered that an orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, light anhydrous silicic acid and lactose hydrate (preferably having an average particle size within the range of 5 to 50 μm) solves the above-mentioned problems, and thus completed the present invention.

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

The present invention relates to the following (1) to (29).
(1) An orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate and light anhydrous silicic acid.
(2) An orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate having an average particle size 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 either (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 either (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.
(5) The orally disintegrating tablet according to either (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.

(6) The orally disintegrating tablet according to any one of (1) to (5), further comprising crospovidone.
(7) 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.
(8) The orally disintegrating tablet according to any one of (2) to (7), wherein the average degree of pregelatinization of the pregelatinized starch is 90% or less.
(9) The orally disintegrating tablet according to any one of (2) to (8), wherein the bulk density of the crystalline cellulose is 0.26 g/ ^cm3 or less.

(10) Drug-containing granules comprising esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate having an average particle size within the range of 5 to 50 μm, low-substituted hydroxypropylcellulose, and hydroxypropylcellulose; drug-free granules comprising D-mannitol, crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less , and pregelatinized starch; and an orally disintegrating tablet comprising light anhydrous silicic acid as an extragranular component for the above two types of granules.
(11) The orally disintegrating tablet according to (10), further comprising crospovidone as an extragranular 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 swelling of the tablet is inhibited.
(14) The orally disintegrating tablet according to any one of (10) to (13), further comprising a colorant and magnesium stearate as extragranular components.
(15) The orally disintegrating tablet according to (14), wherein the colorant is yellow ferric oxide or ferric oxide.

(16) The 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) The orally disintegrating tablet according to any one of (10) to (16), wherein the content of hydroxypropyl cellulose is 0.1 to 15% by weight based on the total weight of the tablet.
(18) The orally disintegrating tablet according to any one of (10) to (17), wherein the content of the pregelatinized starch is 0.1 to 10% by weight based on the total weight of the tablet.

(19) The orally disintegrating tablet according to any one of (1) to (18), which disintegrates in 1 second or more and 45 seconds or less in a disintegration test using a disintegration device.
(20) The orally disintegrating tablet according to any one of (1) to (19), having improved divisibility having a score line.
(21) The orally disintegrating tablet according to (20), in which the tablet strength and friability of the half tablets after division along the score line are improved.

(22) The 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) The 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) The orally disintegrating tablet according to either (22) or (23), in which segregation of the drug content is improved.

(25) A method for producing an orally disintegrating tablet, comprising the steps of: preparing drug-containing granules by mixing esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate having an average particle size within the range of 5 to 50 μm, low-substituted hydroxypropylcellulose, and hydroxypropylcellulose; preparing drug-free granules by mixing D-mannitol and crystalline cellulose having a bulk density of 0.26 g/ ^cm3 or less, and spraying pregelatinized starch dispersed in water; and adding light anhydrous silicic acid and crospovidone as extragranular components to the two types of granules, and compressing the mixture.
(26) A method for producing an orally disintegrating tablet according to (25), further comprising the steps of adding a colorant as an extragranular component, adding magnesium stearate, and compressing the mixture.
(27) The method for producing an orally disintegrating tablet according to (26), wherein the colorant is yellow ferric oxide or ferric oxide.
(28) The method for producing an orally disintegrating tablet according to any one of (25) to (27), wherein the process for producing drug-containing granules comprises a high-speed stirring granulation process.
(29) The method for producing an orally disintegrating tablet according to any one of (25) to (28), characterized in that a decrease in dissolution of esaxerenone or a pharmacologically acceptable salt thereof is prevented.

Another aspect of the present invention relates to the following (1A) to (30A).
(1A) An orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate and light anhydrous silicic acid.
(2A) An orally disintegrating tablet containing esaxerenone or a pharmacologically 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 either (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 size of the lactose hydrate is within the range of 5 to 50 μm.
(5A) An orally disintegrating tablet according to any one of (2A) to (4A), wherein the bulk density of the crystalline cellulose is 0.26 g/cm3 or ^less .

(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 the pregelatinized starch is 90% or less.
(8A) The orally disintegrating tablet according to any one of (1A) to (7A), further comprising crospovidone.
(9A) An orally disintegrating tablet according to any one of (1A) to (8A), further comprising a colorant and magnesium stearate.
(10A) The orally disintegrating tablet according to (9A), wherein the colorant is yellow ferric oxide or ferric oxide.

(11A) Drug-containing granules comprising esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropylcellulose, and hydroxypropylcellulose; drug-free granules comprising D-mannitol, crystalline cellulose, and pregelatinized starch; and an orally disintegrating tablet comprising light anhydrous silicic acid as an extragranular component for the above 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 size of the lactose hydrate is within the range of 5 to 50 μm.
(14A) An orally disintegrating tablet according to any one of (11A) to (13A), wherein the bulk density of the crystalline cellulose is 0.26 g/cm3 or ^less .
(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.

(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 comprising crospovidone as an extragranular component.
(18A) An orally disintegrating tablet according to any one of (11A) to (17A), further comprising a colorant and magnesium stearate as extragranular components.
(19A) The orally disintegrating tablet according to (18A), wherein the colorant is yellow ferric oxide or ferric oxide.
(20A) The orally disintegrating tablet according to any one of (1A) to (19A), which disintegrates in 1 second or more and 45 seconds or less in a disintegration test using a disintegration apparatus.

(21A) The orally disintegrating tablet according to any one of (1A) to (20A), having good divisibility having a score line.
(22A) The orally disintegrating tablet according to (21A), wherein the tablet strength and friability of the half tablets after division having a score line are good.
(23A) The 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) The 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) The orally disintegrating tablet according to any one of (23A) and (24A), which has little segregation of the drug content.

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

The present invention makes it possible to provide an orally disintegrating tablet which contains esaxerenone or a pharmacologically acceptable salt thereof, which disintegrates rapidly when placed in the mouth or in water, has sufficient hardness for normal production, transportation or use, and has good dissolution properties, good divisibility and little segregation of the drug content.
Furthermore, the present invention can provide a method for producing an orally disintegrating tablet having the above-mentioned excellent properties by ordinary compression molding, without requiring complicated steps or special equipment.

This shows the results of monitoring the content fluctuation over time during the tableting process.

In the present invention, an orally disintegrating tablet is a compressed product that disintegrates quickly when held in the mouth or placed in water. Specifically, it means a tablet that disintegrates in a disintegration test in the mouth mainly by saliva or in a disintegration test using a device, usually in 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 disintegration test using a device are measured with reference to the "Disintegration Test Method" of the 17th Revised Japanese Pharmacopoeia. Specifically, one tablet is placed in each of six glass tubes of a tester, and the tester is operated at 37±2°C without an auxiliary plate and using water as the test liquid, and the disintegration state of the tablet is observed. When no residue is found in the glass tube, or if any residue is found, it is a soft substance that clearly does not retain its original shape, or fragments of insoluble drug coatings, etc., the tablet is considered to have disintegrated, and the time until disintegration in each glass tube is evaluated.

The orally disintegrating tablet of the present invention has good and low-variation dissolution properties suitable for pharmaceuticals. For example, in an evaluation in accordance with the "Dissolution Test Method (Paddle Method, 50 rpm)" of the 17th Revised Edition of the Japanese Pharmacopoeia, using 900 ml of 0.1% polysorbate 80 (TW-O120V, Kao) aqueous solution as the test liquid, the orally disintegrating tablet has a dissolution rate of 75% or more at 30 minutes and reduced variability (standard deviation) in the dissolution rate between vessels.

The orally disintegrating tablet of the present invention has sufficient hardness during normal manufacturing, transportation or use. For example, in a hardness test, the orally disintegrating tablet usually has a hardness of 1.5 kg or more, preferably 2.0 kg or more, and more preferably 3.0 kg or more. Here, the hardness test is measured 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).

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

The orally disintegrating tablet of the present invention has tablet characteristics that allow for good divisibility. For example, when a tablet with a score line on one side is divided, the mass variation (SD) of the divided half tablets is 2.0 mg or less.

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

(5P)-1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide represented by the formula:
((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
The compound is ((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), and the like.

Esaxerenone may be a solvate (including hydrate), or a pharmacologically acceptable salt or a solvate thereof (including hydrate). Examples of the pharmacologically acceptable salt 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, lysine, arginine, ornithine, glutamate, or aspartate.

Esakiserenone is an atropisomer compound (compound (I)), but the esakiserenone used in the present invention may be not only a pure atropisomer, but also any mixture of atropisomers.

The orally disintegrating tablet of the present invention contains esaxerenone, which is orally administered to hypertensive patients in Japan at a dose of 2.5 mg of esaxerenone once a day to adults. However, in some cases, the dosage may be carefully started at 1.25 mg, and if the effect is insufficient, the dosage may be increased to 5 mg.

The amount of esaxerenone or a pharmacologically acceptable salt thereof contained in the orally disintegrating tablet of the present invention is not particularly limited, but it is preferable to incorporate, for example, 0.5 to 10% by weight (preferably 1 to 3% by weight) based on the total weight of the orally disintegrating tablet.
In addition, there is no particular restriction on the amount of additives blended in the total weight of the orally disintegrating tablet, but for example, it is preferable to blend 10.0 to 93.5% by weight (preferably 44 to 90% by weight) of excipients including lactose hydrate, 0.5 to 5% by weight (preferably 0.5 to 2% by weight) of lubricant, 0 to 15% by weight (preferably 1 to 5% by weight) of binder, and 2.5 to 40% by weight (preferably 5 to 30% by weight) of disintegrant, based on the total weight of the orally disintegrating tablet.

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 within the range of 5 to 50 μm. For example, Lactochem® Powder, Lactochem® Fine Powder, Lactochem® Extra Fine Powder, Pharmatose® 450M, and Lactohale® 201 from DFE Pharma are suitable.
In the present invention, the "average particle size" refers to the particle size at an integrated value of 50% in the particle size distribution determined by a sieving device (for example, ATM sonic sifter, manufactured by ATM Corp).

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, but for example, Fuji Silysia Chemical's Sylysia 320 and Sylysia 350, Freund Corporation's Adsolider-101, and Nippon Aerosil's AEROSIL 200 Pharm and AEROSIL 300 Pharm are suitable. The amount is appropriately determined by a person skilled in the art with reference to the standards of disintegration test, dissolution test, hardness test, division test, and content test described in this specification so as to show the desired disintegration, dissolution, hardness, divisibility, and uniformity. It is preferably 0.05 to 5% by weight, more preferably 0.3 to 2% by weight, even 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.

The oral disintegrant of the present invention may contain, in addition to the above-mentioned components, a sugar alcohol and crystalline cellulose having a bulk density of 0.26 g/ ^cm3 or less, and may further contain pregelatinized starch, if desired.

Examples of sugar alcohols include D-mannitol, erythritol, xylitol, maltitol, sorbitol, etc., and preferably D-mannitol, erythritol, xylitol, and more preferably D-mannitol. As D-mannitol, one conforming to the pharmacopoeias of Japan, Europe, and the United States can be used. The crystal form, particle size, and specific surface area of the D-mannitol to be blended are not particularly limited, but the crystal form may 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, and the crystal form, particle size, and specific surface area can be measured by, for example, X-ray diffraction method, laser diffraction type particle size measurement method, and BET type specific surface area measurement method (multipoint method), respectively. Examples of commercially available D-mannitol include those from Merck, Roquette, Towa Kasei, Kao, and the like.

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

The sugar alcohol may be mixed in powder form with other ingredients to form tablet powder and then compressed, or may be granulated using a suitable binder and then subjected to compression molding.

In the present invention, the crystalline cellulose is usually one having a bulk density of 0.10 to 0.46 g/cm ³ , preferably one having a bulk density of 0.26 g/cm ³ or less. Commercially available crystalline cellulose includes, 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 ), and CEOLUS UF-711 (registered trademark, bulk density 0.20 to 0.26 g/cm ³ ) (all manufactured by Asahi Kasei Chemicals). Preferably, the crystalline cellulose has a bulk density of 0.10 to 0.26 g/cm ³ , more preferably, the crystalline cellulose has a bulk density of 0.13 to 0.23 g/cm ³ . In addition, a combination of two or more kinds of crystalline celluloses having different bulk densities and adjusted to a desired bulk density can also be used.

The amount of the 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 manufacturability may decrease. A more preferred amount is 5 to 30% by weight, and an even more preferred amount is 5 to 20% by weight.

When D-mannitol is used as the sugar alcohol, the mixing ratio (weight ratio) of the above-mentioned crystalline cellulose to 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, sugar alcohol to 1 part of crystalline cellulose.

The above-mentioned crystalline cellulose may be mixed in the powder form with other ingredients to form tablet powder and then compression molded, or it may be granulated using a suitable binder and then compression molded.

The pregelatinized starch used in the present invention is starch that has been pregelatinized by heat treatment, and includes partially pregelatinized starch. The pregelatinized starch may be one specified in the Japanese Pharmaceutical Excipients Standards. The average degree of pregelatinization is preferably 90% or less, and more preferably 70 to 80%. As a commercially available product, for example, pregelatinized starch Swelstar PD-1 (manufactured by Asahi Kasei Chemicals) may be used.

The amount of the above-mentioned pregelatinized 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.

The above pregelatinized starch may be mixed with other ingredients as a powder to be compressed into tablets, or it may be granulated with other ingredients and then subjected to compression molding.

In the orally disintegrating tablet of the present invention, pregelatinized starch plays a role as a disintegrant, but on the other hand, when it is dispersed in a liquid, for example, water, it exhibits viscosity during production, so that when it is sprayed on a ^powdered raw material, granulation proceeds and it can be made into granules. Utilizing this property, a dispersion of pregelatinized starch dispersed in water is sprayed on a powdered mixture containing crystalline cellulose and sugar alcohol with a bulk density of 0.26 g/cm3 or less, and fluidized bed granulation is performed to produce granules, which are then mixed with other ingredients as necessary and compressed to obtain tablets with good moldability and desired oral disintegration properties. Such advantages in production are unique to pregelatinized starch, and are hardly obtained when using conventional disintegrants such as low-substituted hydroxypropylcellulose and crospovidone.

The amount of hydroxypropyl cellulose (e.g., HPC-L, Nippon Soda Co., Ltd.) contained in the orally disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by a person skilled in the art with reference to the standards of disintegration test, dissolution test, hardness test, division test, and content test described in this specification so as to show the desired disintegration, dissolution, hardness, divisibility, and uniformity. The amount of hydroxypropyl cellulose is preferably 0.1 to 15% by weight, more preferably 0.5 to 5% by weight, and even more preferably 1.5 to 2.5% by weight per 100% by weight of the orally disintegrating tablet.

The amount of low-substituted hydroxypropyl cellulose (e.g., LH-21, Shin-Etsu Chemical Co., Ltd.) contained in the orally disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by a person skilled in the art with reference to the standards of disintegration test, dissolution test, hardness test, division test, and content test described in this specification so as to show the desired disintegration, dissolution, hardness, divisibility, and uniformity. The amount of the low-substituted hydroxypropyl cellulose is preferably 1 to 50% by weight, more preferably 5 to 30% by weight, and even more preferably 5 to 20% by weight per 100% by weight of the orally disintegrating tablet.

The amount of crospovidone (e.g., Kollidon CL-F, BASF product) contained in the orally disintegrating tablet of the present invention is not particularly limited, but is appropriately determined by a person skilled in the art with reference to the standards of disintegration test, dissolution test, hardness test, division test, and content test described in this specification so as to show the desired disintegration, dissolution, hardness, divisibility, and uniformity. The amount of crospovidone is preferably 0.5 to 30% by weight, more preferably 0.5 to 20% by weight, even more preferably 1 to 10% by weight, and particularly preferably 2 to 6% by weight, per 100% by weight of the orally disintegrating tablet.

The orally disintegrating tablet of the present invention may contain one or more of various additives commonly used in the manufacture of tablets, as long as the effects of the invention are not impaired.

Examples of the additives include excipients, binders, disintegrants, emulsifiers, stabilizers, lubricants, coating agents, plasticizers, colorants, flavorings, sweeteners, flavoring agents, flavorings, flow agents, foaming agents, and surfactants.

In addition to lactose hydrate, crystalline cellulose and D-mannitol, other "excipients" that may be used include, for example, 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 sulfates such as calcium sulfate, and other inorganic excipients.

In addition to light anhydrous silicic acid and hydroxypropyl cellulose, other "binders" that may be used include, for example, hypromellose, polyvinylpyrrolidone, polyethylene glycol, or compounds similar to the excipients described above.

The "emulsifiers" used may include, for example, colloidal clays such as bentonite or veegum; 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 ethers, polyoxyethylene sorbitan fatty acid esters, or sucrose fatty acid esters.

Examples of "stabilizers" that may be used include paraoxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid.

The "flavoring agents" used may include, for example, sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or flavorings such as menthol, lemon or orange.

Disintegrants are generally additives that are added to disintegrate and disperse the original drug particles when taken due to their water conductivity and swelling properties, making them easier to absorb. In addition to low-substituted hydroxypropylcellulose, pregelatinized starch, and crospovidone, other "disintegrants" that can be used include cellulose derivatives such as carboxymethylcellulose (carmellose), carboxymethylcellulose calcium, croscarmellose sodium (e.g., products that comply with the Japanese Pharmacopoeia), or internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or chemically modified starches and celluloses such as corn starch (e.g., products that comply with the Japanese Pharmacopoeia), sodium starch glycolate (e.g., products that comply with the Japanese Pharmacopoeia), or carboxymethyl starch or sodium carboxymethyl starch.

Examples of the "lubricant" used include stearic acid; metal stearates such as calcium stearate (e.g., products conforming with the Japanese Pharmacopoeia) or magnesium stearate (e.g., products conforming with the Japanese Pharmacopoeia); talc (e.g., products conforming with the Japanese Pharmacopoeia); colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium stearyl fumarate (e.g., products conforming with pharmaceutical additive standards); sucrose fatty acid esters; sodium benzoate; D,L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicic acid hydrate; or starch derivatives as mentioned above. Metal stearates are preferred, and magnesium stearate is particularly preferred.

The amount of lubricant is preferably 0.1 to 5% by weight per 100% by weight of the orally disintegrating tablet.

Examples of coating agents that cover the surface (crystal surface) of a powdered drug or the granule surface of a granulated drug include one or a combination of two or more 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-diethylamino acetate, and polyvinyl acetate resin.

Plasticizers to be combined with the coating agent may include one or a combination of two or more selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

Examples of coloring agents include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2; and one or a combination of two or more selected from food lake color, yellow ferric oxide, ferric oxide, black ferric oxide, titanium oxide, beta-carotene, and riboflavin.

Flavoring agents may include, for example, one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, menthol micron, and various fragrances.

Examples of sweeteners include one or a combination of two or more selected from sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thaumatin.

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

Examples of flow agents include one or a combination of two or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and talc.

Foaming agents may include, for example, tartaric acid and/or anhydrous citric acid.

Examples of surfactants 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.

The orally disintegrating tablet of the present invention can be produced by a known production method for solid preparations. For example, a tablet can be obtained by adding and mixing the main ingredient and additives, and tableting. After granulation with the main ingredient and additives, a lubricant can be added and mixed, and tableting can be obtained. After granulation, operations such as drying and granulation may be performed as necessary. Below, one embodiment (embodiments A and B) of the orally disintegrating tablet of the present invention will be described together with its production method.

Aspect A: An orally disintegrating tablet obtained by compression molding drug-free granules containing crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less , sugar alcohol, and pregelatinized starch, and a drug or drug-containing granules.
In this embodiment, the drug-free granules function as a framework for a preparation that can provide the desired disintegration and moldability of an orally disintegrating tablet. The drug-free granules exhibit excellent disintegration and moldability even when only the ^three components of crystalline cellulose with a bulk density of 0.26 g/cm3 or less, sugar alcohol, and pregelatinized starch are blended, but other additives may be blended as necessary. In addition, the orally disintegrating tablet in this embodiment can be made into a preparation with good divisibility and little content segregation by adding 0.05 to 5% by weight of light anhydrous silicic acid.
The method for producing the orally disintegrating tablet of aspect A includes a step (A-1) of producing drug-free granules, a step (A-2) of producing drug-containing granules, and a step (A-3) of mixing the drug-free granules, a drug or drug-containing granules, and other additives, followed by compression molding.

A-1: Step for Producing Drug-Free Granules Drug-free granules can be produced using the following method 1) or 2).
1) A method of wet granulating a mixture containing crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less , a sugar alcohol (e.g., D-mannitol) and pregelatinized starch with water.
2) A method of granulating a mixture containing crystalline cellulose having a bulk density of 0.26 g/cm3 or ^less and a sugar alcohol (e.g., D-mannitol) with a liquid in which pregelatinized starch is dispersed in water or the like.
Here, for the 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 a viscosity suitable for granulation. There are two methods for granulation: one is to mix pregelatinized starch in powder form with other ingredients and compress the granules, and the other is to granulate the granules with a liquid in which pregelatinized starch is dispersed in water and compress the granules. Either method gives tablets with the desired properties, but the latter method is preferred.
In addition, when granulation is performed using a liquid in which pregelatinized starch is dispersed, either the high-speed stirring granulation method or the fluidized bed granulation method can be applied, but when granules are produced by the fluidized bed granulation method, better orally disintegrating tablets can be obtained. When other additives such as conventional disintegrants are to be blended into the drug-free granules, they may be blended into the mixture before granulation.
The blending ratio of crystalline cellulose having a bulk density of 0.26 g/ ^cm3 or less to sugar alcohol in the drug-free granules is, when D-mannitol is used as the sugar alcohol, 1 to 8.5 parts by weight, preferably 1 to 5 parts by weight, and more preferably 1 to 2 parts by weight of sugar alcohol per 1 part of crystalline cellulose.

A-2: Step for Producing Drug-Containing Granules The drug can be mixed with drug-free granules as powder or, if desired, after granulation. Drug-containing granules can be produced, for example, by conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or rolling granulation. The granulated powder can also be dried in a dryer and then sieved using a Comil or pin mill to obtain drug-containing granules.
The particle size of the drug-containing granules can be adjusted by the sieving conditions, with 50% or more of the drug-containing granules being 95 μm or less, preferably 80 μm or less, more preferably 70 μm or less, and particularly preferably 60 μm or less, and 90% or more of the drug-containing granules being 420 μm or less, preferably 380 μm or less, more preferably 250 μm or less, and particularly preferably 150 μm or less. The particle size (median size) corresponding to 50% or 90% of the cumulative undersieve distribution can be measured by a dry sieving method.
Alternatively, a powdered or granular mixture of a drug and sugar alcohol can be granulated with a solution in which hydroxypropyl cellulose is dissolved or dispersed in water to give drug-containing granules.
The drug or drug-containing granules may be coated to mask unpleasant tastes such as bitterness or irritation, odors, or to control dissolution. The above-mentioned coating agents and plasticizers may be used as appropriate for coating. Coating methods include, for example, fluidized bed granulation/coating machines, rolling fluidized bed granulation/coating machines, centrifugal fluidized bed granulation/coating machines, and Wurster type fluidized bed granulation/coating machines.
When two or more drugs are used, they can be contained in the same granule or in separate granules depending on the compatibility of the drugs, and then compression molded.

A-3: A step of mixing drug-free granules, a drug or drug-containing granules, and other additives and compressing the mixture The drug-free granules, a drug or drug-containing granules, light anhydrous silicic acid, crospovidone, and optionally other disintegrants, binders, excipients, colorants, lubricants, and other additives are mixed and compressed to form an orally disintegrating tablet. The mixing is 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 granules and additives other than the drug or drug-containing granules can also be mixed and used as an extragranular mixed powder.
The compression molding of the orally disintegrating tablet of the present invention can be carried out using a conventional tablet press. The molding pressure applied by the tablet press may be similar to that applied to conventional tablets, and although it depends on the shape and size of the tablet, it is preferably about 2 to 20 kN, more preferably about 4 to 14 kN.

The blending ratio of drug-free granules to the total weight of the tablet ingredients is usually 5 to 90% (weight %), 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 for use. When the drug is granulated for use, the blending weight ratio of drug-free granules to drug-containing granules is preferably 1 part drug-containing granule to 0.1 to 2.0 parts drug-free granule, more preferably 0.2 to 1.0, and even more preferably 0.3 to 0.5.

Aspect B: An orally disintegrating tablet obtained by compression molding a drug-free mixed powder containing crystalline cellulose, sugar alcohol, and pregelatinized starch having a bulk density of 0.26 g/cm3 or ^less , and a drug or drug-containing granules.

In this embodiment, the drug-free mixed powder provides desirable disintegration and moldability for an orally disintegrating tablet. The drug-free mixed powder exhibits excellent disintegration and moldability even when it is formulated with only ^three components, namely, crystalline cellulose, sugar alcohol, and pregelatinized starch, each having a bulk density of 0.26 g/cm3 or less, but other additives may be formulated as necessary. In addition, the orally disintegrating tablet in this embodiment can be made into a preparation with good divisibility and little content segregation by adding 0.05 to 5% by weight of light anhydrous silicic acid.

The method for producing the orally disintegrating tablet of embodiment B includes, if desired, a step of producing drug-containing granules, and a step of mixing and compressing the drug or the drug-containing granules and other additives. The step of producing the drug-containing granules is the same as that of A-2 described above.

In the process of mixing and compressing the drug-free mixed powder, the drug or drug-containing granules, and other additives, the mixing or compression molding process is the same as A-3 described above.

Examples of film coating bases that can be used in the present invention include sugar coating bases and water-soluble film coating bases.
As the sugar-coating base, white sugar is used, and one or more of the following may be used in combination: talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan, etc.
Examples of water-soluble film coating bases include cellulose derivatives such as hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, or sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer, or polyvinylpyrrolidone; or polysaccharides such as pullulan.

The above coating bases may be used by mixing two or more of them in an appropriate ratio. In addition, if necessary, they may further contain appropriate pharmacologically acceptable additives such as plasticizers, excipients, lubricants, masking agents, colorants and/or preservatives.

The type of plasticizer that can be contained in the coating base is not particularly limited, and can be appropriately selected by a person 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, acetyl triethyl titrate, triethyl titrate, tributyl titrate, and acetyl tributyl titrate.

Examples of masking agents that can be included in the above coating base include titanium oxide.

Examples of colorants that can be contained in the coating base include ferric oxide, yellow ferric oxide, black ferric oxide, titanium oxide, Blue No. 1 (Brilliant Blue FCF), Blue No. 2 (Indigo carmine), Red No. 3 (Erythrosine), Yellow No. 4 (Tartrazine), Yellow No. 5 (Sunset Yellow FCF), and the like.
Preferred are iron sesquioxide, yellow iron sesquioxide, and black iron oxide, and more preferred are iron sesquioxide and yellow iron sesquioxide.

The content of colorant that can be contained in the above coating base is preferably 0.003 to 0.1% by weight (more preferably 0.01% or more to 0.1% by weight) relative to the total weight of the uncoated tablet.

Examples of preservatives that can be included in the coating base include parabens.

The orally disintegrating tablet of the present invention thus obtained has little segregation of drug content, excellent dividing properties when broken into scored tablets, and excellent disintegration properties when placed in the oral cavity or in water, as well as good dissolution properties.

The orally disintegrating tablet of the present invention has a disintegration property in terms of a disintegration time in the oral cavity (the time until the tablet completely disintegrates in the oral cavity of a healthy adult male with only saliva without containing any moisture in the mouth) of 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 disintegrates gradually due to saliva when placed in the mouth, but disintegrates in a shorter time when pressed in the mouth, i.e., by pressure from the upper jaw and tongue, or by friction with the tongue, i.e., by "licking", etc. For people with dry mouths or people with little saliva, the tablet may be disintegrated in the mouth using water or hot water, or may be taken as is with water in the same manner as ordinary tablets.

The good and less variable dissolution properties of the orally disintegrating tablet of the present invention are evaluated in accordance with the "Dissolution Test Method (Paddle Method, 50 rpm)" of the 17th Edition of the Japanese Pharmacopoeia using 900 ml of 0.1% aqueous solution of polysorbate 80 (TW-O120V, Kao) as the test liquid, and are usually a dissolution rate of 75% or more at 30 minutes, preferably a dissolution rate of 80% or more at 30 minutes, and more preferably a dissolution rate of 85% or more at 30 minutes, and can be evaluated by the variation (standard deviation) of the dissolution rate for each vessel.

The orally disintegrating tablet of the present invention has little drug segregation in the formulation, and therefore has small variation in content per tablet within a lot, and the RSD (residual standard deviation) between 10 tablets in one lot is preferably 2.0 or less, more preferably 1.5 or less, and even more preferably 1.2 or less. The content fluctuation range during the tableting time series is preferably 5.0 or less, more preferably 4.0 or less, even more preferably 3.0 or less, and especially preferably 2.0 or less.

The orally disintegrating tablet of the present invention is provided as a tablet with good divisibility, and a score line can be provided on one side of the front or back surface of the tablet, or on both the front and back surfaces. The "score line" is a depression that is provided on the surface of the tablet, preferably on one side of the front or back surface of a circular or elliptical shape, or on both the front and back surfaces, as necessary to facilitate the division of the tablet into two, and generally extends linearly at its deepest part. A triangular cross-sectional shape is used for the depression, but in some cases, a triangle may be combined with a square, rectangular, or semicircular shape. The cross-sectional shape of the depression is the shape observed as a depression in the part to be divided in a cross section cut at right angles to the score line, and synonyms for the triangle include a wedge shape and a V-shape. The cross-sectional shape may be constant or may change appropriately depending on the surface shape of the tablet, but is not particularly limited.

In this specification, "splitting" means preparing two partial tablets (half tablets) by applying stress to split one tablet, and the drug content or tablet mass of each half tablet is ideally 50% of the tablet before splitting. In general, if the tablet hardness itself is low, the stress required for splitting is small, but the tablet may crumble during splitting, which may increase the mass variation of the half tablets. In addition, tablets with low hardness may easily break or chip during production, transportation, and storage, and there is a concern that the shape stability of the half tablets after splitting may be reduced.

The orally disintegrating tablet of the present invention has formulation properties that allow good divisibility while maintaining the characteristics (disintegrability) of an orally disintegrating tablet. In the present invention, "good divisibility" means that when a tablet with a score line on one side is divided, the mass variation (SD) of the half tablets after division is small. Preferably, the mass variation (SD) of the half tablets after division is 7.5 mg or less, more preferably 5.0 mg or less, even more preferably 3.0 mg or less, and particularly preferably 2.0 mg or less.

On the other hand, the intraorally rapidly disintegrating tablet of the present invention has a hardness that does not crumble even after a stability test under a specific temperature and humidity (e.g., temperature 25°C, humidity 75%, PTP primary packaging, 6 months), i.e., a hardness that does not crumble during the manufacturing and distribution processes of the formulation, and the hardness is practical even when stored under the specific temperature and humidity.

The orally disintegrating tablet of the present invention can be used to treat illnesses as a formulation that is easy to take for the elderly, children, and patients with swallowing difficulties, and as a safe formulation for general adults.

Next, the present invention will be explained in more detail using examples, etc., but the following examples are intended to explain the present invention and should not be interpreted as limiting the present invention to these examples.

Example 1: Drug-containing granule particle size and content uniformity of formulation (1-1) Manufacturing method of tablets Esaxerenone (drug), lactose hydrate (Pharmatose 450M, DFE pharma), low-substituted hydroxypropylcellulose (LH-21, Shin-Etsu Chemical) and hydroxypropylcellulose (HPC-L, Nippon Soda) were weighed out in the mixing ratio shown in Table 2, and charged together with purified water into a high-speed mixing granulator (VG-25 or VG-100, Powrex), and kneaded for 3 to 4 minutes to obtain a granulated powder. This granulated 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 using a Comil (QC-194S, QUADRO) or a pin mill (100UPZ, Hosokawa Micron) at the rotation speed shown in Table 2 to obtain a drug-containing granule.
Furthermore, D-mannitol (Pearlitol 50C, Rocket) and microcrystalline cellulose (CEOLUS KG-802, Asahi Kasei Chemicals) were weighed out in the mixing ratio shown in Table 2 and placed in a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex). A dispersion of pregelatinized starch (swelstar PD-1, Asahi Kasei Chemicals) in purified water was sprayed onto the mixture, followed by drying to obtain drug-free granules.
Furthermore, crospovidone (Kollidon CL-F, BASF), yellow ferric oxide (yellow ferric oxide, Kishi Chemical) and light anhydrous silicic acid (Silysia 350, Fuji Silysia Chemical) were weighed out in the mixing ratio shown in Table 2, charged into a high-speed mixing granulator (VG-25 or VG-100, Powrex) and mixed for 15 minutes to obtain an extragranular mixed powder.
The drug-containing granules, drug-free granules, extragranular mixed powder and magnesium stearate (HyQual 5712, Mallinckrodt) were placed in a V-type mixer (Tokuju Machine Works) and mixed for 10 minutes, after which they were molded using a rotary tablet press (VIRGO or VELA2, Kikusui Seisakusho) to give tablet masses of 85 mg for Comparative Example 1 and Examples 1-1 to 1-3 and 1-5, and 87 mg for Example 1-4, to give plain tablets of approximately φ-6.5 mm.

(1-2) Evaluation method and results The ingredients and evaluation results of the manufactured uncoated tablets are shown in Table 2 and Figure 1. The particle size of the drug-containing granules (x50; particle size [median size] corresponding to 50% of cumulative undersieve distribution and x90; particle size [median size] corresponding to 90% of cumulative undersieve distribution) was measured by dry sieving method (Robot Sifter, Seishin Enterprise). The content of the uncoated tablets was measured using HPLC (LC-20AD, Shimadzu) under the conditions shown in Table 1. The time series content fluctuation width of the tableting process was calculated by measuring the content at each time point at 5-10 minute intervals during continuous tableting for about 1 hour, and the difference between the value at the highest content and the value at 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). The disintegration test was performed in accordance with the disintegration test method of the 17th revised Japanese Pharmacopoeia without an auxiliary platen. The dissolution properties of the tablets of Examples 1-1 to 1-5 were all good.

※ロットの縮分品(縮分方法によってサンプリングされた集合品)から10錠をサンプリングし、10錠間のバラツキを測定

*10 tablets were sampled from a batch of reduced products (a collection of products sampled using a reduction method) and the variation among the 10 tablets was measured.

In the case of Comparative Example 1, in which the particle size of the drug-containing granules was large, the content fluctuation range in the time series of the tabletting process was 6.0%. In contrast, in the cases of Examples 1-1, 1-2, 1-3, 1-4, and 1-5, in which the particle size was smaller, the content fluctuation range decreased to 3.7%, 1.0%, 2.0%, 2.1%, and 1.8%, respectively.
In addition, the lot content variation (RSD) was 2.7 in Comparative Example 1, but decreased to 1.1, 1.2, 0.8, 0.7, and 0.7 in Examples 1-1, 1-2, 1-3, 1-4, and 1-5.
Therefore, it was shown that a formulation with a small drug granule particle size suppresses content fluctuations during the tableting time series and reduces content variation between lots, resulting in a formulation with a uniform content, compared to a formulation with a large drug granule particle size.

(Example 2) Tablet Ingredients and Tablet Dividability (2-1) Manufacturing Method of Tablets Esaxerenone (drug), lactose hydrate (Pharmatose 450M, DFE pharma), low-substituted hydroxypropylcellulose (LH-21, Shin-Etsu Chemical) and hydroxypropylcellulose (HPC-L, Nippon Soda) were weighed out in the mixing ratio shown in Table 3, and then charged into a high-speed mixing granulator (VG-10 or VG-400, Powrex) together with purified water, and kneaded for 3 to 4 minutes to obtain a granulated powder. This granulated 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 Manufacturing Co., Ltd.) to obtain a drug-containing granule.
Furthermore, D-mannitol (Pearlitol 50C, Rocket) and microcrystalline cellulose (CEOLUS KG-802, Asahi Kasei Chemicals) were weighed out in the mixing ratio shown in Table 3 and placed in a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex). A dispersion of pregelatinized starch (swelstar PD-1, Asahi Kasei Chemicals) in purified water was sprayed onto the mixture, followed by drying to obtain drug-free granules.
Furthermore, in Comparative Example 2-1, crospovidone (Kollidon CL-F, BASF) and yellow ferric oxide (yellow ferric oxide, Kishi Chemicals) were used, in Comparative Example 2-2, crospovidone (Kollidon CL-F, BASF), yellow ferric oxide (yellow ferric oxide, Kishi Chemicals) 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, Kishi Chemicals) and light anhydrous silicic acid (Silysia 350, Fuji Silysia Chemicals) were used, and in Example 2-2, crospovidone (Kollidon The mixture was weighed out in the proportions shown in Table 3, and then charged into a high-speed mixing granulator (VG-10 or VG-400, Powrex) and mixed for 15 minutes to obtain an extragranular mixed powder.
The drug-containing granules, drug-free granules, extragranular mixed powder, and magnesium stearate (HyQual 5712, Mallinckrodt) were charged into a V-type mixer (Tokuju Manufacturing) or a tumble mixer (Totec), and mixed for 5 minutes in Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, and for 30 minutes in Examples 2-2 and 2-3. This was molded into tablets with a mass of 200 mg using a benchtop tablet molding machine (Ichihashi Seiki, HANDTAB) in Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, and into tablets with a mass of 174 mg using a rotary tablet press (VELA2, Kikusui Manufacturing) to obtain plain tablets with a score line on one side, each having a size of about φ-8.0 mm.

(2-2) Evaluation method and results The ingredients of the produced uncoated tablets and the evaluation results are shown in Table 3. Dividability was evaluated using the mass variation (SD, mg) of 10 half tablets obtained by dividing 5 tablets as an index. The uncoated tablets were divided by placing a spatula on the side opposite the score line and pushing open the score line. The tablet hardness was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). The disintegration test was performed in accordance with the disintegration test method of the 17th revised Japanese Pharmacopoeia without an auxiliary disk.
In Comparative Example 2-1, nothing was added to the extragranular mixed powder other than crospovidone and yellow ferric oxide. The mass variation (SD) of the half tablet when the uncoated tablet was divided was 5.5 mg. In Comparative Example 2-2, in addition to crospovidone and yellow ferric oxide, hydroxypropyl cellulose (HPC-SSL) was added as a binder to the extragranular mixed powder. The mass variation (SD) of the half tablet when the uncoated tablet was divided was 4.0 mg. In Examples 2-1, 2-2, and 2-3, light anhydrous silicic acid was added to the extragranular mixed powder in addition to crospovidone and yellow ferric oxide or ferric oxide. The mass variation (SD) of the half tablet when the uncoated tablet was divided was 1.0 mg, 1.7 mg, and 1.5 mg. The disintegration times of the tablets in Examples 2-1, 2-2, and 2-3 were 25 seconds, 33 seconds, and 35 seconds, which were as fast as those of Comparative Example 2-1.
Therefore, it was demonstrated that when light anhydrous silicic acid was added to the extragranular mixed powder, the mass variation of the half tablets after splitting the plain tablet was significantly reduced without impairing the disintegration property as an orally disintegrating tablet, and good divisibility was imparted.

The present invention provides an orally disintegrating tablet containing esaxerenone or a pharmacologically acceptable salt thereof, which disintegrates quickly when placed in the oral cavity or in water, has sufficient hardness during normal production, transportation or use, has good dissolution properties, good divisibility and little segregation of the drug content, and a method for producing the same.
Furthermore, according to the present invention, an orally disintegrating tablet having the above-mentioned excellent properties can be produced by ordinary compression molding without requiring complicated steps or special equipment.

Claims (20)

The orally disintegrating tablet comprises drug-containing granules comprising esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropylcellulose and hydroxypropylcellulose; drug-free granules comprising D-mannitol, crystalline cellulose and pregelatinized starch; and light anhydrous silicic acid as an extragranular component for the above two types of granules , wherein 50% or more of the drug-containing granules have a particle size of 80 μm or less . 2. The orally disintegrating tablet according to claim 1 , wherein the content of the light anhydrous silicic acid is from 0.05 to 5% by weight based on the total weight of the tablet. 3. The orally disintegrating tablet according to claim 1 or 2 , wherein the average particle size of the lactose hydrate is within the range of 5 to 50 μm. 4. The orally disintegrating tablet according to claim 1 , wherein the bulk density of the crystalline cellulose is 0.26 g/ ^cm3 or less. 5. The orally disintegrating tablet according to claim 1 , wherein the content of hydroxypropyl cellulose is from 0.1 to 15% by weight based on the total weight of the tablet. 6. The orally disintegrating tablet according to claim 1 , wherein the content of pregelatinized starch is from 0.1 to 10% by weight, based on the total weight of the tablet. 7. The orally disintegrating tablet according to claim 1, wherein the average degree of pregelatinization of the pregelatinized starch is 90% or less. 8. The orally disintegrating tablet according to claim 1 , further comprising crospovidone as an extragranular component. 9. The orally disintegrating tablet according to claim 1 , further comprising a colouring agent and magnesium stearate as extragranular components. 10. The orally disintegrating tablet according to claim 9 , wherein the colorant is yellow ferric oxide or ferric oxide. The orally disintegrating tablet according to any one of claims 1 to 10 , which disintegrates in 1 second or more and 45 seconds or less in a disintegration test using a disintegration device. The orally disintegrating tablet according to any one of claims 1 to 11 , which has good divisibility having a score line. The orally disintegrating tablet according to claim 12 , wherein the half tablets after dividing along the score line have good tablet strength and friability. 14. The orally disintegrating tablet according to claim 1 , wherein 90% or more of the drug-containing granules have a particle size of 380 μm or less. The orally disintegrating tablet according to claim 1 , which has little segregation of the drug content. 16. A method for producing the orally disintegrating tablet according to any one of claims 1 to 15, comprising the steps of: preparing drug-containing granules by mixing esaxerenone or a pharmacologically acceptable salt thereof, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose; preparing drug-free granules by mixing D-mannitol and crystalline cellulose and spraying pregelatinized starch dispersed in water ; and adding light anhydrous silicic acid and crospovidone as extragranular components to the two types of granules and compressing the mixture. The method for producing an orally disintegrating tablet according to claim 16 , further comprising the step of adding a colorant as an extragranular component, adding magnesium stearate, and compressing the mixture. The method for producing an orally disintegrating tablet according to claim 17 , wherein the colorant is yellow ferric oxide or ferric oxide. The method for producing an orally disintegrating tablet according to any one of claims 16 to 18 , wherein the step of producing the drug-containing granules comprises a high-speed stirring granulation step. The method for producing an orally disintegrating tablet according to any one of claims 16 to 19 , wherein a decrease in dissolution of esaxerenone or a pharmacologically acceptable salt thereof is prevented.