TW202135802A - Orally disintegrating tablet of pyrrolecarboxamide - Google Patents

Abstract

The present invention provides an orally disintegrating tablet that includes esaxerenone or a pharmaceutically acceptable salt thereof, the tablet disintegrating rapidly when placed in the mouth or in water, having a hardness that is enough to withstand normal production, transportation, and use, having good solubility and divisibility, and having little segregation of drug content. The orally disintegrating tablet includes esaxerenone or a pharmaceutically acceptable salt thereof, a lactose hydrate, and a light anhydrous silicic acid.

Description

Orally disintegrating tablets containing pyrrole carboxamide

The present invention relates to an orally disintegrating tablet with good dissolution, good partitionability, and less segregation of drug content, and a method for producing the same. The orally disintegrating tablet contains esaxerenone or a pharmacologically acceptable salt thereof. It disintegrates quickly when contained in the mouth or when placed in water, and has sufficient hardness during normal manufacturing, transportation or use.

Isalidone has the following structural formula:

Indicates the compound (Compound 1).

Compound (I) is disclosed in U.S. Patent No. 8,524,918, and is known as the following agent: It has excellent activity as a mineralocorticoid receptor (MR) (aldosterone receptor) antagonist, and is based on various clinical trials. As a result, it has an excellent therapeutic effect for hypertension. In addition, for heart disease [narrow heart disease, 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 disorders (arteriosclerosis, restenosis after PTCA, peripheral circulatory disorders) and other diseases. It is expected to have excellent therapeutic and/or preventive effects, as well as alleviating effects on diabetic nephropathy. (International Publication WO2017/164208).

As the dosage forms of oral solid preparations in the fields of medicines and foods, tablets, capsules, granules, powders, etc. are known, but as dosage forms that are easier to take for the elderly, children, or patients with dysphagia , And expect to develop an orally disintegrating tablet that disintegrates quickly when contained in the mouth or when placed in water.

Orally disintegrating tablets are considered to not only disintegrate quickly in the oral cavity, but also must have sufficient hardness to withstand physical shocks during manufacture, delivery or use like ordinary tablets, and further have both Dissolution with less deviation. In addition, from the aspect of medication compliance, it is also desirable that when it is contained in the mouth, unpleasant taste or irritation is suppressed, and it has a good mouthfeel.

There have been various reports about oral disintegrating tablets. For example, Patent Document 2 describes ^{an orally disintegrating tablet containing a drug, crystalline cellulose having an overall density of 0.23 g/cm 3} or less, sugar alcohol, and gelatinized starch. However, in this document, there is no description of orally disintegrating tablets containing esalione, light anhydrous silicic acid, and lactose hydrate with an average particle size in the range of 5-50 μm.

Patent Document 3 describes an orally disintegrating tablet containing prasugrel, carboxymethyl cellulose, and hydroxypropyl cellulose, and a method for producing the same. Although this document describes an orally disintegrating tablet containing arginine, which contains carboxymethyl cellulose and hydroxypropyl cellulose, has sufficient hardness and exhibits less deviation in dissolution properties, there is nothing about containing moxa A description of orally disintegrating tablets with salidone, light anhydrous silicic acid, and lactose hydrate with an average particle size in the range of 5-50μm, good partitionability, and less segregation of drug content. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] Pamphlet No. WO2008/126831 (US Patent No. 8524918) [Patent Document 2] Pamphlet No. WO2013/161823 [Patent Document 3] Japanese Patent Application Publication No. 2019-034935

[Summary of Invention] [The problem to be solved by the invention]

The subject of the present invention is to provide an orally disintegrating tablet with good dissolution, good partitionability, and less segregation of drug content, and a method for producing the same, the orally disintegrating tablet containing esalione or a pharmacologically acceptable salt thereof, It disintegrates quickly when it is in the mouth or when it is put in water, and has sufficient hardness during normal manufacturing, transportation or use. [Means to solve the problem]

In order to solve the above-mentioned problems, the inventors of the present invention have conducted intensive research and found that it contains esalione or its pharmacologically acceptable salt, light anhydrous silicic acid, and lactose hydrate (preferably with an average particle size of 5-50 μm). The orally disintegrating tablets within the range) can solve the above-mentioned problems, and thus the present invention has been completed.

That is, the present invention provides orally disintegrating tablets containing esalione or its pharmacologically acceptable salt, light anhydrous silicic acid and lactose hydrate (preferably with an average particle diameter in the range of 5-50 μm) and其制造方法。 Its manufacturing method.

The present invention relates to the following (1) to (29). (1) An orally disintegrating powder tablet containing esalione or its pharmacologically acceptable salt, lactose hydrate and light anhydrous silicic acid. (2) An orally disintegrating powder tablet containing esalione or its pharmacologically acceptable salt, lactose hydrate with an average particle diameter in the range of 5-50 μm, low-substituted hydroxypropyl cellulose, and hydroxypropyl Base cellulose, light anhydrous silicic acid, sugar alcohol, crystalline cellulose and gelatinized starch. (3) The orally disintegrating tablet as described in any one of (1) or (2), wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. (4) The orally disintegrating tablet as described in any one of (1) or (2), wherein the content of light anhydrous silicic acid is equivalent to 0.3 to 2.0% by weight of the total weight of the tablet. (5) The orally disintegrating tablet as described in any one of (1) or (2), wherein the content of light anhydrous silicic acid is equivalent to 0.3 to 1% by weight of the total weight of the tablet.

(6) The orally disintegrating tablet as described in any one of (1) to (5), which further contains crospovidone. (7) The orally disintegrating tablet as described in (6), wherein the content of crospovidone is equivalent to 1 to 10% by weight of the total weight of the tablet. (8) The orally disintegrating tablet as described in any one of (2) to (7), wherein the average degree of gelatinization of the gelatinized starch is 90% or less. (9) The orally disintegrating tablet as described in any one of (2) to (8), wherein the overall density of the crystalline cellulose is 0.26 g/cm ³ or less.

(10) An orally disintegrating powder tablet comprising: medicated granules comprising esalione or a pharmacologically acceptable salt thereof, lactose hydrate with an average particle diameter in the range of 5-50 μm, and a low degree of substitution hydroxyl group Propyl cellulose and hydroxypropyl cellulose; drug-free granules, which contain D-mannitol, ^{crystalline cellulose with a total density of 0.26 g/cm 3} or less, and alpha starch; and light anhydrous silicic acid, as Relative to the extra-granular component of the aforementioned two kinds of particles. (11) The orally disintegrating tablet as described in (10), which further contains crospovidone as an extragranular component. (12) The orally disintegrating tablet as described in (11), wherein the content of crospovidone is equivalent to 2 to 6% by weight of the total weight of the tablet. (13) The orally disintegrating tablet as described in (12), characterized in that the swelling of the tablet is suppressed. (14) The orally disintegrating tablet according to any one of (10) to (13), which further contains a coloring agent and magnesium stearate as extragranular components. (15) The orally disintegrating tablet as described in (14), wherein the coloring agent is yellow iron trioxide or iron trioxide.

(16) The orally disintegrating tablet as described in any one of (10) to (15), wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. (17) The orally disintegrating tablet as described in any one of (10) to (16), wherein the content of hydroxypropyl cellulose is equivalent to 0.1 to 15% by weight of the total weight of the tablet. (18) The orally disintegrating tablet according to any one of (10) to (17), wherein the content of the gelatinized starch is equivalent to 0.1 to 10% by weight of the total weight of the tablet.

(19) The orally disintegrating tablet as described in any one of (1) to (18), which disintegrates within 1 second or more and 45 seconds or less in a disintegration test performed by a device. (20) The orally disintegrating tablet as described in any one of (1) to (19), which improves the partition with secant. (21) The orally disintegrating tablet as described in (20), which improves the tablet strength and abrasion resistance of the divided half tablets with secant lines.

(22) The orally disintegrating tablet according to any one of (10) to (21), wherein more than 50% of the drug-containing particles have a particle size of 80 μm or less. (23) The orally disintegrating tablet according to any one of (10) to (22), wherein more than 90% of the drug-containing particles have a particle size of 380 μm or less. (24) The orally disintegrating tablet as described in any one of (22) or (23), which improves the segregation of drug content.

(25) A method for producing orally disintegrating powder tablets, which comprises: preparing esalione or a pharmacologically acceptable salt thereof, lactose hydrate with an average particle diameter in the range of 5 to 50 μm, and a low degree of substitution hydroxyl group The step of mixing propyl cellulose and hydroxypropyl cellulose to produce drug-containing particles; by mixing D-mannitol and ^{crystalline cellulose with a total density of 0.26 g/cm 3} or less, and dispersing α in water A step of spraying starch to produce drug-free granules; and a step of adding light anhydrous silicic acid and crospovidone as extragranular components relative to the aforementioned two kinds of granules, and then performing compression molding. (26) The method for producing an orally disintegrating tablet as described in (25), which comprises the step of further adding a coloring agent as an extragranular component and adding magnesium stearate to perform compression molding. (27) The method for producing orally disintegrating tablets as described in (26), wherein the colorant is yellow iron trioxide or iron trioxide. (28) The method for manufacturing an orally disintegrating tablet as described in any one of (25) to (27), wherein the step of manufacturing the drug-containing granules includes a high-speed stirring granulation step. (29) The method for producing orally disintegrating powder tablets as described in any one of (25) to (28), which prevents a decrease in the elution of esalione or its pharmacologically acceptable salt.

In terms of other aspects of the present invention, it relates to the following (1A) to (30A). (1A) An orally disintegrating powder tablet, which contains esalione or its pharmacologically acceptable salt, lactose hydrate and light anhydrous silicic acid. (2A) An orally disintegrating powder tablet containing esalione or its pharmacologically acceptable salt, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, sugar Alcohol, crystalline cellulose and gelatinized starch. (3A) The orally disintegrating tablet as described in any one of (1A) or (2A), wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. (4A) The orally disintegrating tablet as described in any one of (1A) to (3A), wherein the average particle size of lactose hydrate is in the range of 5-50 μm. (5A) The orally disintegrating tablet as described in any one of (2A) to (4A), wherein the overall density of crystalline cellulose is 0.26 g/cm ³ or less.

(6A) The orally disintegrating tablet as described in any one of (2A) to (5A), wherein the content of hydroxypropyl cellulose is equivalent to 0.1 to 15% by weight of the total weight of the tablet. (7A) The orally disintegrating tablet according to any one of (2A) to (6A), wherein the average degree of gelatinization of the gelatinized starch is 90% or less. (8A) The orally disintegrating tablet as described in any one of (1A) to (7A), which further contains crospovidone. (9A) The orally disintegrating tablet as described in any one of (1A) to (8A), which further contains a coloring agent and magnesium stearate. (10A) The orally disintegrating tablet as described in (9A), wherein the coloring agent is yellow iron trioxide or iron trioxide.

(11A) An orally disintegrating powder tablet comprising: medicated granules comprising esalione or its pharmacologically acceptable salt, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose; Drug-free granules, which contain D-mannitol, crystalline cellulose, and gelatinized starch; and light anhydrous silicic acid, which is an extragranular component relative to the aforementioned two types of granules. (12A) The orally disintegrating tablet as described in (11A), wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. (13A) The orally disintegrating tablet as described in (11A) or (12A), wherein the average particle size of lactose hydrate is in the range of 5-50 μm. (14A) The orally disintegrating tablet as described in any one of (11A) to (13A), wherein the overall density of crystalline cellulose is 0.26 g/cm ³ or less. (15A) The orally disintegrating tablet as described in any one of (11A) to (14A), wherein the content of hydroxypropyl cellulose is equivalent to 0.1 to 15% by weight of the total weight of the tablet.

(16A) The orally disintegrating tablet as described in any one of (11A) to (15A), wherein the content of the gelatinized starch is equivalent to 0.1 to 10% by weight of the total weight of the tablet. (17A) The orally disintegrating tablet as described in any one of (11A) to (16A), which further contains crospovidone as an extragranular component. (18A) The orally disintegrating tablet as described in any one of (11A) to (17A), which further contains a coloring agent and magnesium stearate as extragranular components. (19A) The orally disintegrating tablet as described in (18A), wherein the coloring agent is yellow iron trioxide or iron trioxide. (20A) The orally disintegrating tablet as described in any one of (1A) to (19A), which disintegrates within 1 second or more and 45 seconds or less in a disintegration test performed by a device.

(21A) The orally disintegrating tablet as described in any one of (1A) to (20A), which has good partitionability with secant lines. (22A) The orally disintegrating tablet as described in (21A), which is divided into half tablets with secant lines, has good strength and abrasion resistance. (23A) The orally disintegrating tablet as described in any one of (11A) to (22A), wherein more than 50% of the drug-containing particles have a particle size of 80 μm or less. (24A) The orally disintegrating tablet as described in any one of (11A) to (23A), wherein more than 90% of the drug-containing particles have a particle size of 380 μm or less. (25A) The orally disintegrating powder as described in any one of (23A) or (24A) has less segregation of drug content.

(26A) A method for manufacturing orally disintegrating powder tablets, which comprises: mixing esalione or its pharmacologically acceptable salt, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose , And the step of manufacturing drug-containing particles; the step of manufacturing drug-free particles by mixing D-mannitol and crystalline cellulose, and spraying the gelatinized starch dispersed in water; and adding light anhydrous silicic acid and Cross-linked povidone is used as an extra-granular component relative to the aforementioned two kinds of particles, and undergoes a compression molding step. (27A) The method for producing an orally disintegrating tablet as described in (26A), including the step of further adding a coloring agent as an extragranular component, and adding magnesium stearate to perform compression molding. (28A) The method for producing orally disintegrating tablets as described in (27A), wherein the coloring agent is yellow iron trioxide or iron trioxide. (29A) The method for producing an orally disintegrating tablet as described in any one of (26A) to (28A), wherein the step of producing drug-containing granules includes a high-speed stirring granulation step. (30A) The method for producing an orally disintegrating tablet as described in any one of (26A) to (29A), which prevents a decrease in the dissolution of esalione or a pharmacologically acceptable salt thereof.

[Effects of Invention]

According to the present invention, it is possible to provide an orally disintegrating tablet with good dissolution, good partitionability and less segregation of drug content, which contains esaxerenone or a pharmacologically acceptable salt thereof, when contained in the mouth or It disintegrates quickly when placed in water, and has sufficient hardness during normal manufacturing, transportation or use. Furthermore, according to the present invention, a manufacturing method can be provided, which does not require complicated steps or special equipment, and is conventionally compressed and formed to manufacture orally disintegrating tablets with excellent characteristics as described above.

[Form to implement the invention]

In the present invention, the orally disintegrating tablet refers to a compression-molded product that has rapid disintegration when contained in the mouth or when placed in water. Specifically, it means that in the oral cavity disintegration test performed mainly by saliva or the disintegration test performed by a device, it is usually 1 second or more, 180 seconds or less, preferably 1 second or more, 45 seconds or less, more preferably tablets that disintegrate in 1 second or more and 40 seconds or less. Here, the disintegration test performed by the disintegration test and the device means the test with reference to the "Disintegration Test Method" of the 17th revision of the Japanese Pharmacopoeia. Specifically, one lozenge was put into each of the six glass tubes of the tester without an auxiliary plate, and water was used as the test solution. The tester was started at 37±2°C to observe the disintegration of the lozenges. The following cases were regarded as the tablet disintegration, and the time from the disintegration in each glass tube was evaluated: no residue was visible in the glass tube; or even if it was seen, it was obviously soft and did not maintain the original shape At the time of the substance, or at the time of the insoluble agent skin and other fragments.

The orally disintegrating powder tablet of the present invention has good dissolution properties suitable for pharmaceuticals with little variation. For example, the following orally disintegrating tablets: According to the "Dissolution Test Method (paddle method, 50 rpm)" of the Japanese Pharmacopoeia of the Seventeenth Revision, using 900 ml of 0.1% Polysorbate 80 (TW-O120V) In the evaluation of an aqueous solution made by Kao as a test solution, at 30 minutes, the dissolution rate was 75% or more and the deviation per tank (standard deviation) of the dissolution rate was reduced.

The orally disintegrating powder tablet of the present invention has sufficient hardness during normal manufacturing, transportation or use. For example, in a hardness test, the hardness is usually 1.5 kg or more, preferably 2.0 kg or more, and more preferably orally disintegrating tablets having a hardness of 3.0 kg or more. Here, the hardness test refers to a person who uses 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 powder tablet of the present invention has the preparation characteristics of less segregation of drugs suitable for pharmaceuticals. For example, it is the following orally disintegrating tablets: the content variation in the tableting time series is suppressed, the content deviation per tablet within the batch is small, and the content uniformity is good.

The orally disintegrating powder tablet of the present invention has the characteristics of a tablet with good partitionability. For example, it is the following orally disintegrating tablet: when a tablet with a secant on one side is divided, the mass deviation (SD) of the divided half tablet is 2.0 mg or less.

The esaxerenone used in the present invention refers to the following structural formula:

Represented (5P)-1-(2-hydroxyethyl)-N-[4-(methylsulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl] -1H-pyrrole-3-carboxamide((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) can be manufactured according to the methods described in, for example, International Publication WO2006/012642 (US Publication US2008-0234270), International Publication WO2008/126831 (US Publication US2010-0093826).

Estalidone may be a solvate (including a hydrate), or a pharmacologically acceptable salt or their solvate (including a hydrate). As far as the pharmacologically acceptable salts are concerned, examples include: hydrohalide lactate such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide; such as nitrate, perchlorate, sulfate Or inorganic acid salt of phosphate; such as lower alkyl sulfonate of methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; such as arylsulfonic acid of benzenesulfonate or p-toluenesulfonate Salt; such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate organic acid salt; or such as glycinate, ion Amine salt, arginine salt, ornithine salt, glutamate or aspartate amino acid salt, etc.

Estalidone is a compound (compound (I)) with an atropisomer. However, the esalione used in the present invention is not only a pure form of the isomer, but also a configuration Any mixture of isomers.

The esalenone contained in the orally disintegrating powder tablet of the present invention is generally administered to adults with hypertension in an amount of 2.5 mg orally once a day as esalenone for adults in Japan. In addition, there are cases where the dose is cautiously started from 1.25mg, and the effect is not sufficient, and it can be increased to 5mg.

The blending amount of esalione or its pharmacologically acceptable salt contained in the orally disintegrating tablet of the present invention is not particularly limited, but for example, the blending amount is preferably equivalent to 0.5 of the total weight of the orally disintegrating tablet. ~10% by weight (preferably 1 to 3% by weight). In addition, the blending amount of additives in the total weight of the orally disintegrating tablet is not particularly limited, but for example, it is preferable to blend 10.0-93.5 wt% (preferably 44 to 90%) of the total weight of the orally disintegrating tablet. Weight %) also includes the excipient of lactose hydrate, 0.5 to 5 weight% (preferably 0.5 to 2 weight %) of lubricant, 0 to 15 weight% (preferably 1 to 5 weight %) of combination Disintegrant, 2.5-40% by weight (preferably 5-30% by weight) disintegrating powder.

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 diameter is preferably in the range of 5-50 μm. However, for example, DFE Pharma's Lactochem (registered trademark) Powder, Lactochem (registered trademark) Fine Powder, Lactochem (registered trademark) Extra Fine Powder, Pharmatose (registered trademark) 450M, and Lactohale (registered trademark) 201 are preferable. The "average particle size" in the present invention means a particle size that is 50% of the cumulative value in the particle size distribution obtained by a sieving device (for example, made by ATM company, type "ATM sonic sifter", etc.).

The lightweight 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, it can be Sylysia 320 and Sylysia 350 of Fuji SILYSIA Chemical Company, Adsolider-101 of FREUND Industrial Company, And AEROSIL 200 Pharm and AEROSIL 300 Pharm of Japan AEROSIL Company are better. The amount is determined by those skilled in the art with reference to the standards of disintegration test, dissolution test, hardness test, split test, and content test described in this manual, so that the desired disintegration, dissolution, hardness, and split are displayed. Sex and uniformity. Preferably, the orally disintegrating tablet is 0.05 to 5% by weight per 100% by weight, more preferably 0.3 to 2% by weight, further preferably 0.3 to 1% by weight, particularly preferably 0.4 to 0.6% by weight.

The orally disintegrating powder of the present invention may contain sugar alcohol and ^{crystalline cellulose with a total density of 0.26 g/cm 3} or less in addition to the above-mentioned components, and may further contain gelatinized starch if necessary.

As for sugar alcohols, D-mannitol, erythritol, xylitol, maltitol, sorbitol, etc. are mentioned, D-mannitol, erythritol, xylitol are preferred, and more preferred It is D-mannitol. As far as D-mannitol is concerned, it can usually be used in accordance with the pharmacies of Japan, Europe and the United States. The crystal form, particle size and specific surface area of the blended D-mannitol are not particularly limited. The crystal form can be any of α-type, β-type, δ-type, and amorphous. The particle size is 10 μm or more and 250 μm or less. preferably, more preferably 20μm or more, 150 m or less, and specific surface area is 0.1m ² / g or more, 4m ² / g or less is preferred, more preferably 0.1m ² / g or more, 2m ² / g or less, crystalline, The particle size and specific surface area can be measured separately by, for example, X-ray diffraction method, laser diffraction particle size measurement method, and BET specific surface area measurement method (multipoint method). As for the commercial ones, for example, D-mannitol of MERK company, Rocket company, Towa Kasei company, Kao company, etc. can be mentioned.

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

The sugar alcohol can be mixed with other ingredients as it is to form a tablet powder and then compressed and molded, or it can be granulated using a suitable binder and then compressed and molded.

In the present invention, as for crystalline cellulose, a ^{grade with a bulk density of 0.10 to 0.46 g/cm 3} is generally used, and crystalline cellulose having a bulk density of 0.26 g/cm ³ or less is preferably used. As far as the marketers are concerned, for example, Ceolus KG-1000 (registered trademark; overall density 0.10 to 0.15 g/cm ³ ), Ceolus KG-802 (registered trademark; overall density 0.13 to 0.23 g/cm ³ ), Ceolus UF -711 (registered trademark; overall density 0.20 to 0.26 g/cm ³ ) (above, manufactured by Asahi Kasei Chemicals Co., Ltd.), preferably ^{crystalline cellulose with an overall density of 0.10 to 0.26 g/cm 3} , more preferably an overall density of 0.13 to 0.23g/cm ³ of crystalline cellulose. In addition, it is also possible to use a combination of two or more types of crystalline celluloses having different overall densities to adjust the overall density to a desired overall density.

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

The blending ratio (weight ratio) of the above-mentioned crystalline cellulose and sugar alcohol, when D-mannitol is used as the sugar alcohol, is 1 relative to the crystalline cellulose, and the sugar alcohol is 1 to 10 times, preferably 1 To 8.5 times, more preferably 1 to 5 times, still more preferably 1 to 2 times.

The above-mentioned crystalline cellulose can be mixed as a powder with other ingredients to form a tablet powder and subjected to compression molding, or it can be granulated using a suitable binder and then subjected to compression molding.

The gelatinized starch used in the present invention refers to the starch that has been gelatinized by heat treatment, and also includes part of the gelatinized starch. In addition, for the above-mentioned gelatinized starch, those described in the Japanese Pharmaceutical Additives Specification can be used. The average degree of gelatinization is preferably 90% or less, more preferably 70 to 80%. In the case of a commercially available product, for example, a gelatinized starch swelstar PD-1 (manufactured by Asahi Kasei Chemical Co., Ltd.) can be used.

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

The above-mentioned gelatinized starch may be mixed with other components as a powder to form a tablet powder and compressed and molded, or it may be granulated together with other components and then subjected to compression molding.

In the orally disintegrating tablet of the present invention, the gelatinized starch acts as a disintegrating agent. However, on the other hand, since it exhibits viscosity when dispersed in a liquid (for example, water) during manufacture, it becomes a powder state if sprayed The raw material is granulated and can be made into granules. Taking advantage of this property, a powdered mixture containing crystalline cellulose and sugar alcohol with an overall density of 0.26 g/cm ³ or less is sprayed into a dispersion of gelatinized starch in water, and the fluidized bed granulation method is carried out. The granules are produced and mixed with other ingredients as necessary to perform compression molding, thereby obtaining tablets with good moldability and desired oral disintegration properties. The advantage of this kind of manufacturing is the peculiar property of alpha starch which is almost impossible to obtain when using low-substituted hydroxypropyl cellulose, cross-linked povidone, etc. which are commonly used disintegrants.

The blending amount of hydroxypropyl cellulose (for example, HPC-L, a product of Soda Japan) contained in the orally disintegrating tablet of the present invention is not particularly limited, but please refer to the disintegration test, dissolution test, and dissolution test described in this specification. The standards of the hardness test, the split test, and the content test are appropriately determined by those skilled in the art, so that the desired disintegration, dissolution, hardness, split, and uniformity can be displayed. The blending amount of the above-mentioned hydroxypropyl cellulose is preferably 0.1 to 15% by weight per 100% by weight of the orally disintegrating tablet, more preferably 0.5 to 5% by weight, and still more preferably 1.5 to 2.5% by weight.

The blending amount of the low-substituted hydroxypropyl cellulose (such as LH-21, Shin-Etsu Chemical Co., Ltd.) contained in the orally disintegrating tablet of the present invention is not particularly limited, but refer to the disintegration properties described in this specification. The standards of the test, dissolution test, hardness test, division test, and content test are appropriately determined by those skilled in the art, so that the desired disintegration, dissolution, hardness, division, and uniformity are displayed. The blending amount of the above-mentioned low-substituted hydroxypropyl cellulose is preferably 1 to 50% by weight per 100% by weight of the orally disintegrating tablet, more preferably 5 to 30% by weight, and still more preferably 5 to 20% by weight %.

The blending amount of crospovidone (for example, Kollidon CL-F, BASF product) contained in the orally disintegrating tablet of the present invention is not particularly limited, but please refer to the disintegration test, dissolution test, and dissolution test described in this specification. The standards of the hardness test, the split test, and the content test are appropriately determined by those skilled in the art, so that the desired disintegration, dissolution, hardness, split, and uniformity can be displayed. The blending amount of the above-mentioned cross-linked povidone is preferably 0.5 to 30% by weight per 100% by weight of the orally disintegrating tablet, more preferably 0.5 to 20% by weight, and still more preferably 1 to 10% by weight. Preferably it is 2 to 6% by weight.

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

The above-mentioned additives include, for example, excipients, binders, disintegrating agents, emulsifiers, stabilizers, lubricants, coating agents, plasticizers, colorants, flavoring agents, sweeteners, and flavoring agents. , Flavoring agents, fluidizers, foaming agents and surfactants, etc.

As for the "excipients" used in addition to lactose hydrate, crystalline cellulose and D-mannitol, for example, sugar derivatives such as lactose, white sugar, glucose, or sorbitol; such as corn starch, Potato starch, α-starch or starch derivatives of dextrin; cellulose derivatives; gum arabic; dextran; or organic excipients such as pullulan; or light anhydrous silicic acid, synthetic silicon Silicate derivatives of aluminum, calcium silicate or magnesium metasilicate aluminate; such as phosphate of calcium hydrogen phosphate; carbonate of calcium carbonate; or inorganic excipients such as sulfate of calcium sulfate.

As for the "binders" used in addition to light anhydrous silicic acid and hydroxypropyl cellulose, for example, hypromellose, polyvinylpyrrolidone, polyethylene glycol, Or the same compound as the aforementioned excipient, etc.

As for the "emulsifier" used, for example: colloidal clay such as bentonite or propolis; metal hydroxide such as magnesium hydroxide or aluminum hydroxide; such as sodium lauryl sulfate or calcium stearate Anionic surfactants; cationic surfactants such as benzalkonium chloride (benzalkonium chloride); or non-fatty acid esters such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester Ionic surfactant.

As for the "stabilizer" used, for example, parabens such as methyl paraben or propyl paraben; such as chlorobutanol, benzyl alcohol or benzene Alcohols such as ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid, etc.

As for the "flavoring agent" used, for example, sweeteners such as sodium saccharin or aspartame; sour flavoring agents such as citric acid, malic acid or tartaric acid; or menthol, lemon Or orange spices and so on.

Disintegrating powder refers to additives that are generally added for the purpose of disintegrating and dispersing into the original drug particles due to water conductivity or swelling properties, and for easy absorption, except for low-substituted hydroxypropyl Examples of "disintegrants" used in addition to base cellulose, gelatinized starch and crospovidone include, for example, carboxymethyl cellulose (carmellose), carboxymethyl cellulose Calcium, croscarmellose sodium (for example, qualified product of Japanese Pharmacopoeia), or cellulose derivative of internal croscarmellose sodium; cross-linked polyvinylpyrrolidone; or such as corn Starch (e.g., qualified product of the Japanese Pharmacopoeia), sodium starch glycolate (e.g. qualified product of the Japanese Pharmacopoeia), or chemically modified starch, cellulose, etc. of carboxymethyl starch or sodium carboxymethyl starch.

As for the "lubricant" used, for example, stearic acid; such as calcium stearate (e.g., qualified product of Japanese Pharmacopoeia) or magnesium stearate (e.g. qualified product of Japanese Pharmacopoeia) Metal stearate; talc powder (for example, qualified product of Japanese Pharmacopoeia); colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; Maleic acid; sodium stearyl fumarate (for example, qualified product of pharmaceutical additives); sucrose fatty acid ester; sodium benzoate; D,L-leucine; such as sodium lauryl sulfate or laurel of magnesium lauryl sulfate Sulfate; silicic acid such as anhydrous silicic acid or silicic acid hydrate; or the above-mentioned starch derivatives, etc., preferably metal stearate, particularly preferably magnesium stearate.

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

As for the coating agent that is coated on the surface of the powdered drug (the surface of the crystal) or the particle surface of the granulated drug, for example, it is selected from the group consisting of 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 in one or a combination of two or more.

As for the plasticizer combined with the coating agent, examples include diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triethylglycerol ( Triacetin) one or a combination of two or more.

As for the coloring agent, for example, food coloring selected from the group consisting of food yellow No. 5, food red No. 2, and food blue No. 2; food lake pigments, yellow ferric oxide, ferric oxide, One or a combination of two or more of black iron oxide, titanium oxide, β-carotene, and riboflavin.

The flavoring agent includes, for example, one or a combination of two or more selected from citrus, lemon, strawberry, mint, menthol, menthol powder (Menthol micron), and various flavors.

As for the sweetener, for example, selected from the group consisting of sodium saccharin, saccharin, aspartame, acesulfame K, dipotassium glycyrrhizinate, sucralose, stevia, and soma One kind or a combination of two or more kinds of sweet (thaumatin), etc.

The flavoring agent includes, for example, one kind or a combination of two or more kinds selected from sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

As for the fluidizing agent, for example, one kind or a combination of two or more kinds selected from hydrous silica, light anhydrous silicic acid, and talc can be mentioned.

As for the foaming agent, for example, tartaric acid and/or citric anhydride can be mentioned.

As for the surfactant, for example, one selected from the group consisting of Polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hardened castor oil, Polysorbate, glycerol monostearate, and sodium lauryl sulfate, or A combination of 2 or more.

The manufacturing method of the orally disintegrating tablet of the present invention can adopt well-known manufacturing methods for solid preparations. For example, a tablet can be obtained by adding a main drug, additives, etc., mixing the tablet, and then making a tablet. It is also possible to obtain a tablet by granulating the main drug, additives, etc. together, adding a lubricant, etc., and then mixing and tableting. Furthermore, after granulation, operations such as drying and granulation may be performed as needed. Hereinafter, one aspect (aspects A and B) of the orally disintegrating tablet of the present invention will be described together with its manufacturing method.

Aspect A: Orally disintegrating tablets obtained by compression molding of drug-free granules containing crystalline cellulose, sugar alcohol, and gelatinized starch with a total density of 0.26 g/cm ^{3 or less, together with drugs or drug-containing granules.} In this aspect, the drug-free granules function as a skeleton of a preparation capable of imparting disintegration and moldability desired as an orally disintegrating tablet. It does not contain drug particles, and only blends ^{the three components of crystalline cellulose, sugar alcohol, and gelatinized starch with a total density of 0.26 g/cm 3} or less. It can also exhibit excellent disintegration and formability, but it can also be used as needed. Blend other additives. In addition, the orally disintegrating tablets in this aspect can be prepared by adding 0.05 to 5% by weight of light anhydrous silicic acid to produce a preparation with good partitionability and less segregation. The manufacturing method of the orally disintegrating tablet of aspect A includes the step of manufacturing drug-free granules (A-1) and the step of manufacturing drug-containing particles (A-2). The granules and other additives are mixed and subjected to a compression molding step (A-3).

A-1: The steps of manufacturing drug-free granules can use the following methods 1) or 2) to manufacture drug-free granules. 1) A method of wet granulation of a mixture containing crystalline cellulose with an overall density of 0.26 g/cm ³ or less, sugar alcohol (such as D-mannitol), and alpha starch with water. 2) A method of granulating a mixture containing crystalline cellulose with an overall density of 0.26 g/cm ³ or less and a sugar alcohol (for example, D-mannitol) due to the gelatinized starch liquid dispersed in water or the like. In granulation, the conventional extrusion granulation method, mixing and stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method, or rotating granulation method can be used. If the gelatinized starch is dispersed in a liquid, such as water, it exhibits viscosity suitable for granulation. In the method of granulation, there are a method of mixing the alpha starch in a powder state with other ingredients, and compressing the granulated particles, and the granulation of the granules from the liquid in which the alpha starch is dispersed in water The method of compression molding. Either method provides tablets with desired properties, but preferably the latter method can be cited. In addition, in the case of granulation using a liquid dispersed with alpha starch, either of the high-speed stirring granulation method and the fluidized bed granulation method can be applied. However, in the case of granules produced by the fluidized bed granulation method, Obtain better orally disintegrating loose tablets. When the drug-free granules are blended with conventional disintegrating powders and other additives, they only need to be blended in the mixture before granulation. The blending ratio of crystalline cellulose and sugar alcohol with a total density of 0.26 g/cm ³ or less in the drug-free granules. When D-mannitol is used as the sugar alcohol, the sugar is relative to 1 part by weight of the crystalline cellulose. The alcohol is 1 to 8.5 parts by weight, preferably 1 to 5 parts by weight, more preferably 1 to 2 parts by weight.

A-2: Steps for manufacturing medicated granules The drug can be powdered as it is, or after being granulated as desired, it can be mixed with drug-free granules. The drug-containing granules can be produced by, for example, the conventional extrusion granulation method, mixing and stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method, or rotational granulation method. The granulated powder can also be dried by a dryer, and then sieved using a Comil sizing machine or a Pin Mill pulverizer to obtain drug-containing granules. The particle size of the drug-containing particles can be adjusted by sieving conditions. More than 50% of the drug-containing particles are 95 μm or less, preferably 80 μm or less, more preferably 70 μm or less, particularly preferably 60 μm or less, and 90 μm or less of the drug-containing particles % Or more is 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 diameter) equivalent to 50% or 90% of the cumulative distribution of the undersize material can be determined by dry sieving method. In addition, a mixed powder of powdered or granular drugs and sugar alcohols can be granulated by a liquid in which hydroxypropyl cellulose is dissolved or dispersed in water to form drug-containing granules. Drugs or drug-containing particles can also be coated for the purpose of masking unpleasant tastes or odors such as bitterness or irritation, or for controlling dissolution. For coating, the aforementioned coating agent and plasticizer can be suitably used. The coating method can be carried out, for example, by using a fluidized bed granulation/coating machine, a rotating fluidized bed granulation/coating machine, a centrifugal flow type granulating/coating machine, or a Wurster type fluidized bed granulating/coating machine. . In the case of using two or more drugs, the same particles can be contained in the same particles according to the compatibility of the drugs with each other, or individual particles can be contained separately for compression molding.

A-3: The steps of mixing drug-free particles, drugs or drug-containing particles, and other additives and compressing them Mix drug-free particles, drugs or drug-containing particles, light anhydrous silicic acid, cross-linked povidone and other disintegrating agents, binders, excipients, coloring agents, lubricants, and other additives as needed, and compress them to form , Made into oral disintegrating tablets. The mixing system is performed, for example, by using a tumble mixer or a convection mixer. The medicine can also be mixed with other additives and used as a mixed powder containing medicine. It is also possible to mix drug-free particles and additives other than drugs or drug-containing particles to be used as an extra-granular mixed powder. The compression molding of the orally disintegrating tablet of the present invention can be carried out using a usual tableting machine. The forming pressure of the tablet machine can be about the same as that of ordinary tablets, and also varies with the shape and size of the tablets, but is preferably about 2-20 kN, more preferably about 4-14 kN.

The blending ratio of drug-free granules to the total weight of the ingredients of the tablet is usually 5 to 90% (wt%) when the drug is in powder form, or when the drug is granulated for use. 10 to 70%, more preferably 15 to 50%, still more preferably 20 to 30%. In addition, in the case of granulating drugs for use, the blending weight ratio of drug-free particles to drug-containing particles is 1 relative to drug-containing particles, and drug-free particles are preferably 0.1 to 2.0, and more preferably It is 0.2 to 1.0, more preferably 0.3 to 0.5.

Aspect B: An orally disintegrating tablet obtained by compression molding of a drug-free mixed powder containing crystalline cellulose, sugar alcohol, and gelatinized starch with a total density of 0.26 g/cm ^{3 or less, and a drug or drug-containing granules} .

In this aspect, the drug-free mixed powder imparts the disintegration and moldability desired as an orally disintegrating tablet. The drug-free mixed powder exhibits excellent disintegration and moldability even if it only blends the three components of crystalline cellulose, sugar alcohol, and gelatinized starch with a ^{total density of 0.26 g/cm 3 or less, but it can also be used as needed.} And blend other additives. In addition, the orally disintegrating tablets in this aspect can be prepared by adding 0.05 to 5% by weight of light anhydrous silicic acid to produce a preparation with good partitionability and less segregation.

The manufacturing method of the orally disintegrating tablet of aspect B includes the steps of manufacturing drug-containing particles, mixing the drugs or the drug-containing particles and other additives and performing compression molding according to expectations. The steps of manufacturing drug-containing granules are the same as the above A-2.

In the step of mixing the drug-free mixed powder, drugs or drug-containing particles, and other additives and performing compression molding, the steps of mixing or compression molding are the same as the above-mentioned A-3.

Examples of the film coating bases that can be used in the present invention include sugar coating bases, water-soluble film coating bases, and the like. As far as the sugar coating base is concerned, sugar can be used. Furthermore, it can also be selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, acacia, polyvinylpyrrolidone and triglucose, etc. One type or two or more types are used in combination. As for the water-soluble film coating base, for example, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, methyl hydroxy ethyl cellulose or sodium carboxymethyl cellulose Cellulose derivatives; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymer or polyvinyl pyrrolidone; or polysaccharides such as triglucose.

The above-mentioned coating bases can also be used by mixing two or more of them at an appropriate ratio. In addition, it may further contain suitable pharmacologically acceptable plasticizers, excipients, lubricants, concealing agents, coloring agents, and/or preservatives as necessary.

The type of plasticizer that can be included in the coating base is not particularly limited, and those skilled in the art can appropriately select it. Such plasticizers include, for example, propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and sorbitol, triacetin, diethyl phthalate and triethyl citrate, lauric acid, sucrose, Glucose, sorbitol, triacetyl glycerol, triethyl acetyl citrate, triethyl citrate, tributyl citrate or tributyl acetyl citrate, etc.

As for the masking agent which can be contained in the said coating base agent, titanium oxide etc. are mentioned, for example.

As for the coloring agent that can be included in the above-mentioned coating base, for example, ferric oxide, yellow ferric oxide, black iron oxide, titanium oxide, Brilliant Blue FCF, and Blue No. 2 ( Indigo carmine), Red No. 3 (Erythrosine), Yellow No. 4 (Tartrazine), Yellow No. 5 (Sunset Yellow FCF), etc. Preferred are iron trioxide, yellow iron trioxide, and black iron oxide, and more preferred are iron trioxide and yellow iron trioxide.

The content of the coloring agent that can be contained in the coating base is preferably 0.003 to 0.1% by weight (more preferably 0.01% or more to 0.1% by weight) of the total weight of the plain tablet.

As for the preservatives that can be included in the coating base, for example, parabens and the like can be cited.

The thus-obtained orally disintegrating tablet of the present invention has less segregation of drug content, is excellent in splitting when it is a secant tablet, has excellent disintegration in the oral cavity or when placed in water, and has good dissolution.

The disintegration of the orally disintegrating tablet of the present invention, the disintegration time in the oral cavity (in the oral cavity of a healthy adult man, there is no water in the mouth and the time until the tablet is completely disintegrated by saliva) is usually 1 Seconds 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 still more preferably 1 second or more and 40 seconds or less. Although the oral disintegrating tablet of the present invention gradually disintegrates by saliva when contained in the mouth, it will be caused by pressure in the oral cavity, that is, by the pressure of the palate and tongue, or by the friction of the tongue, that is, " The action of licking, etc., collapsed in a shorter time. For people with dry mouth or low saliva, water or hot soup can be used to disintegrate in the mouth, or it can be taken as-is with water in the same way as usual lozenges.

The orally disintegrating tablet of the present invention has good dissolution with little deviation, based on the "Dissolution Test Method (Paddle Method, 50 rpm)" of the Japanese Pharmacopoeia of the 17th Revision, using 900 ml of 0.1% Polysorbate 80 (TW-O120V, Kao) In the evaluation of the aqueous solution as a test solution, it usually has a dissolution rate of 75% or more at 30 minutes, preferably a dissolution rate of 80% or more at 30 minutes, and more preferably 30 minutes At the time point, the dissolution rate was over 85%, and the deviation (standard deviation) per vessel of the dissolution rate was used for evaluation.

The orally disintegrating tablet of the present invention has less drug segregation in the preparation, and the content deviation of each tablet in the batch is small. In the determination of the deviation (RSD) between 10 tablets in a batch, it is preferably 2.0 or less, more preferably 1.5 or less, still more preferably 1.2 or less. In addition, the range of content variation in the time series of ingots is preferably 5.0 or less, more preferably 4.0 or less, still more preferably 3.0 or less, and particularly preferably 2.0 or less.

The orally disintegrating tablet of the present invention can be provided as a tablet with good partitionability, and cuts can be provided on one side of the surface or the back of the tablet, or on both sides of the surface and the back. "Secant line" means that it is installed on the surface of the tablet as needed in order to make it easy to divide the tablet into two. It is preferably installed on one side of the surface or back of the round or oval shape, or on the surface and back of the tablet. On both sides, generally speaking, the deepest part of the depression extending in a straight line. Regarding the cross-sectional shape of the recess, although a triangle is used, a triangle and a square, a rectangle, or a semicircle can also be combined depending on the situation. Furthermore, the cross-sectional shape of the depression is the shape observed as the depression of the portion to be divided in the cross section cut at right angles to the secant line. For the analogy, the triangle includes a wedge shape, a V shape, and the like. The cross-sectional shape may vary depending on the surface shape of the tablet, or may be appropriately changed, but is not particularly limited.

In this specification, "division" means to separate 1 tablet by applying stress to prepare 2 partial tablets (half tablets). The drug content or tablet quality of each half tablet is ideally divided into 50% of the first lozenge. Generally speaking, when the hardness of the tablet itself is low, the stress required for division becomes smaller. However, due to the disintegration of the tablet during division, the quality deviation of the half tablet may increase. In addition, tablets with low hardness are prone to breakage such as chipping or chipping during manufacture, transportation, and storage, and there is a concern that the shape stability may be reduced in half tablets after division.

The orally disintegrating tablet of the present invention maintains the characteristics of the orally disintegrating tablet (disintegratability) on the one hand, and has the preparation characteristics of good partitionability. In the present invention, "good partitionability" means that when a tablet with a secant on one side is divided, the mass deviation (SD) of the half of the tablet after the division is small. It is preferable that the mass deviation (SD) of the divided half tablet 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.

On the other hand, the oral fast disintegrating tablet of the present invention is capable of not disintegrating even after a stability test under a specific temperature and humidity (for example, temperature 25°C, humidity 75%, PTP primary packaging, 6 months) Hardness, that is, has the hardness that does not disintegrate during the manufacturing step and the circulation process of the preparation, and the hardness is the hardness that is also practical for storage under a specific temperature and humidity.

The orally disintegrating tablet of the present invention can be used as a preparation that is easy to take for the elderly, children or patients with dysphagia, and can be used as a safe preparation for general adults for the treatment of diseases. [Example]

Then, the present invention will be described in more detail with examples and so on. However, the following examples are used to illustrate the present invention and should not be construed as limiting the present invention to these examples.

(Example 1) The particle size of drug-containing particles and the uniformity of the content of the formulation (1-1) How to make tablets According to the blending ratio shown in Table 2, estalidone (drug), lactose hydrate (Pharmatose 450M, DFE pharma), low-substituted hydroxypropyl cellulose (LH-21, Shin-Etsu Chemical) and hydroxypropyl were measured according to the blending ratio shown in Table 2. Cellulose (HPC-L, Japan Soda) is put into a high-speed stirring granulator (VG-25 or VG-100, Powrex) together with purified water, and then mixed for 3 minutes to 4 minutes to obtain granulated powder. Dry the granulated powder with a fluidized bed granulation dryer (NFLO-5, Freund Sangyo, or GPCG-30, Powrex) until the product temperature reaches 60°C, and then use Comil (QC-194S, QUADRO) or Pin Mill (100UPZ, Hosokawa Micron), according to the number of rotations shown in Table 2, to obtain the drug-containing particles. In addition, D-mannitol (Pearlitol 50C, Rocket) and crystalline cellulose (Ceolus KG-802, Asahi Kasei Chemicals) were measured according to the blending ratio shown in Table 2, and put into a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex), sprayed into purified water to disperse a liquid of α-starch (swelstar PD-1, Asahi Kasei Chemicals), and then dried to obtain drug-free granules. Furthermore, crospovidone (Kollidon CL-F, BASF), yellow iron sesquioxide (yellow iron sesquioxide, Kusi Kasei) and light anhydrous silicic acid were measured according to the blending ratio shown in Table 2. Sylysia 350, Fuji SILYSIA Chemical), put it into a high-speed mixing granulator (VG-25 or VG-100, Powrex), and mix for 15 minutes to obtain an extra-granular mixed powder. Put the drug-containing granules, drug-free granules, extra-granular mixed powder and magnesium stearate (HyQual 5712, Mallinckrodt) into a V-type mixer (Desk Works), mix for 10 minutes, and use a rotary tablet The machine (VIRGO or VELA2, Kikusui Manufacturing Co., Ltd.) was used for molding. Comparative Example 1 and Examples 1-1 to 1-3 and 1-5 made the tablet mass 85mg, and Example 1-4 made the tablet mass 87mg. And a plain ingot of about φ-6.5 mm is obtained.

(1-2) Evaluation methods and results The components and evaluation results of the produced plain ingots are shown in Table 2 and FIG. 1. The particle size of the drug-containing particles (x50; the particle size [median diameter] equivalent to 50% of the cumulative distribution of the sieve [median diameter] and x90; the particle size [median diameter] equivalent to 90% of the cumulative distribution of the sieve product), Measured by dry sieving method (Robot Shifter, SEISHIN company). The content of Su Ding was measured by HPLC (LC-20AD, Shimadzu) according to the conditions shown in Table 1. In addition, the content variation range of the time series of the tableting step is to measure the content at each time point at 5-10 minute intervals during about 1 hour of continuous tableting, and calculate the difference between the value at the highest time point and the value at the lowest time point. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). In addition, the disintegration test is based on the 17th revision of the Japanese Pharmacopoeia's disintegration test method, and the evaluation is carried out without a supplementary disk. Regarding the dissolution properties of the tablets of Examples 1-1 to 1-5, any of them was good.

[Table 1] Measuring wavelength 234 nm Pipe string YMC-Pack Pro C18 RS (4.6 mmID×100 mm, 3 μm, manufactured by YMC) Column temperature Constant temperature near 40℃ Mobile phase A Methanol/0.01 mol/L phosphate buffer (pH 3.4)/acetonitrile mixture (27:20:3) Analysis time 13 minutes Injection volume 10 mL Sample cooler temperature Constant temperature around 25℃

[Table 2] Comparative Examples/Examples Comparative example 1 Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Ingredients (mg) Isalidone (drug) 1.25 1.25 1.25 1.25 1.25 1.25 Lactose hydrate 48.77 45.49 45.49 45.49 48.25 48.77 Low degree of substitution hydroxypropyl cellulose 9.15 8.55 8.55 8.55 8.75 9.15 Hydroxypropyl cellulose 1.83 1.71 1.71 1.71 1.75 1.83 D-mannitol 9.52 11.68 11.68 11.68 11.95 9.52 Crystalline cellulose 7.05 8.65 8.65 8.65 8.85 7.05 Alpha starch 1.06 1.30 1.30 1.30 1.33 1.06 Crospovidone 5.10 5.10 5.10 5.10 3.55 5.10 Yellow iron trioxide 0.085 0.085 0.085 0.085 0.087 0.085 Light anhydrous silicic acid 0.425 0.425 0.425 0.425 0.435 0.425 Magnesium stearate 0.85 0.85 0.85 0.85 0.87 0.85 Mass of vegetarian tablets (mg) 85.09 85.09 85.09 85.09 87.07 85.09 Screening conditions for medicated particles Comil φ1.143 2200 rpm Pin Mill 5000 rpm Pin Mill 6000 rpm Pin Mill 7000 rpm Pin Mill 7000 rpm Pin Mill 11000 rpm Particle size of drug-containing particles (X50, μm) 99.0 75.1 74.8 65.2 71.2 53.2 Particle size of drug-containing particles (X90, μm) 435.1 372.9 307.5 235.9 329.5 131.5 The content change range of the time series of the ingoting step (%) 6.0 3.7 1.0 2.0 2.1 1.8 Batch content deviation (RSD) (1 spindle, n=10※) 2.7 1.1 1.2 0.8 0.7 0.7 Hardness of plain ingot (average, kg) 3.3 3.2 3.4 3.8 4.2 3.9 Disintegration time (average, sec) 20 18 19 20 25 27 ※Sampling 10 ingots from the reduced product of the batch (collective product sampled by the reduced method), and measure the deviation between the 10 ingots

In the case of Comparative Example 1 where the particle size of the drug-containing particles is relatively large, the content variation range in the time series of the tableting step is 6.0%. In contrast to this, the content variation range in the case of Example 1-1, Example 1-2, Example 1-3, Example 1-4, and Example 1-5 with smaller particle sizes was reduced to 3.7% and 1.0 %, 2.0%, 2.1% and 1.8%. In addition, with regard to the content deviation (RSD) of the batch, compared to 2.7 of Comparative Example 1, in Example 1-1, Example 1-2, Example 1-3, Example 1-4, and Example 1- 5, also reduced to 1.1, 1.2, 0.8, 0.7 and 0.7. Therefore, it is shown that, compared with the preparation where the drug particle size is larger, where the drug particle size is smaller, the content variation in the tablet time series is suppressed, and the content deviation of the batch is also reduced, resulting in a uniform content preparation.

(Example 2) Tablet blending ingredients and tablet partitioning (2-1) How to make tablets According to the blending ratio shown in Table 3, quantify esalione (drug), lactose hydrate (Pharmatose 450M, DFE pharma), low-substituted hydroxypropyl cellulose (LH-21, Shin-Etsu Chemical) and hydroxypropyl Cellulose (HPC-L, Japan Soda) is put into a high-speed stirring granulator (VG-10 or VG-400, Powrex) together with purified water, and then mixed for 3 to 4 minutes to obtain granulated powder. Dry the granulated powder in a fluidized bed granulation dryer (NFLO-2, Freund Industry, or WSG-120, Powrex) until the product temperature becomes 60℃, and then use Comil (QC-197 or QC-194S, QUADRO) Or Pin Mill (SCM-3, Nara Machinery Manufacturing Co., Ltd.) granules to obtain medicine-containing granules. In addition, D-mannitol (Pearlitol 50C, Rocket) and crystalline cellulose (Ceolus KG-802, Asahi Kasei Chemicals) were measured according to the blending ratio shown in Table 3, and put into a fluidized bed granulation dryer (GPCG-15 or WSG-120, Powrex), disperse α-starch (swelstar PD-1, Asahi Kasei Chemicals) into a liquid spray of purified water, and then dry it to obtain drug-free granules. Furthermore, according to the blending ratio shown in Table 3, in Comparative Example 2-1, cross-linked povidone (Kollidon CL-F, BASF) and yellow iron trioxide (yellow iron trioxide, Guisi) were measured. Chemicals), in Comparative Example 2-2, weigh cross-linked povidone (Kollidon CL-F, BASF), yellow iron trioxide (yellow iron trioxide, Kusi Chemical) and hydroxypropyl cellulose (HPC-HPC- SSL, Japan Soda), in Example 2-1 and Example 2-3 crospovidone (Kollidon CL-F, BASF), yellow iron sesquioxide (yellow iron sesquioxide, Kusi Kasei) And light anhydrous silicic acid (Sylysia 350, Fuji SILYSIA Chemicals), in Example 2-2, measure cross-linked povidone (Kollidon CL-F, BASF), ferric oxide (ferric oxide, decyl ) And lightweight anhydrous silicic acid (Sylysia 350, Fuji SILYSIA Chemicals), put them into a high-speed mixing granulator (VG-10 or VG-400, Powrex), and mix for 15 minutes to obtain an extra-granular mixed powder. Put the drug-containing granules, non-medicine granules, extra-granular mixed powder and magnesium stearate (HyQual 5712, Mallinckrodt) into a V-type mixer (Desk Works) or a tumble mixer (Totec), In Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, they were mixed for 5 minutes, and in Examples 2-2 and 2-3, they were mixed for 30 minutes. In Comparative Example 2-1, Comparative Example 2-2, and Example 2-1, a desktop tablet molding machine (Ichihashi Seiki, HANDTAB) was used to make the tablet mass 200 mg. In Example 2-2 And the 2-3 series uses a rotary tablet machine (VELA2, Kikusui Manufacturing Co., Ltd.) to make the tablet mass 174 mg, and shape the tablet to obtain a plain ingot of about φ-8.0 mm with a secant on one side.

(2-2) Evaluation methods and results Table 3 shows the components and evaluation results of the produced plain ingots. The partitionability was evaluated by using the mass deviation (SD, mg) of 10 half-diamonds obtained by dividing 5 ingots as an index. The division of the ingot is to place a spatula on the opposite side of the secant line, and divide it by pressing the secant line. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). In addition, the disintegration test is based on the 17th revision of the Japanese Pharmacopoeia's disintegration test method, and the evaluation is carried out without a supplementary disk. In Comparative Example 2-1, nothing was added to the extra-granular mixed powder except for crospovidone and yellow ferric oxide. The mass deviation (SD) of the half-tablet when the tablet is divided is 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 mixed powder outside the granules. The mass deviation (SD) of the half-tablet at the time of division of the original tablet is 4.0 mg. Example 2-1, Example 2-2, and Example 2-3 are based on the addition of light anhydrous silicon in addition to crospovidone and yellow ferric oxide or ferric oxide in the mixed powder outside the granules. acid. The mass deviations (SD) of the half-tablets when the tablets are divided are 1.0mg, 1.7mg and 1.5mg. In addition, the disintegration times of the tablets of Example 2-1, Example 2-2, and Example 2-3 were 25 seconds, 33 seconds, and 35 seconds, which were as fast as Comparative Example 2-1. Therefore, it is shown that the addition of light anhydrous silicic acid to the extra-granular mixed powder does not impair the disintegration properties of the orally disintegrating tablets, and the quality deviation of the half tablets after the division of the plain ingots is significantly reduced, which is given good quality. Severability.

[table 3] Comparative Examples/Examples Comparative example 2-1 Comparative example 2-2 Example 2-1 Example 2-2 Example 2-3 Ingredients (mg) Isalidone (drug) 5.0 5.0 5.0 5.0 2.5 Lactose hydrate 77.0 77.0 77.0 90.7 93.2 Low degree of substitution hydroxypropyl cellulose 15.0 15.0 15.0 17.5 17.5 Hydroxypropyl cellulose (HPC-L) 3.0 3.0 3.0 3.5 3.5 D-mannitol 46.45 43.21 45.91 23.90 23.90 Crystalline cellulose (KG-802) 34.40 32.00 34.00 17.70 17.70 Alpha starch 5.16 4.80 5.10 2.66 2.66 Crospovidone 11.94 11.94 11.94 7.10 7.10 Yellow iron trioxide 0.06 0.06 0.06 - 0.17 Ferric oxide - - - 0.0174 - Hydroxypropyl cellulose (HPC-SSL) - 6.0 - - - Crystalline cellulose (UF-702) - - - - - Light anhydrous silicic acid - - 1.0 0.87 0.87 Magnesium stearate 2.0 2.0 2.0 1.7 1.7 Mass of vegetarian tablets (mg) 200.0 200.0 200.0 174.0 174.1 Severability (quality deviation (SD) of half-tablet, mg) 5.5 4.0 1.0 1.7 1.5 Hardness of plain ingot (average, kg) 4.9 6.5 5.7 4.3 4.9 Disintegration time (average, sec) 26 39 25 36 33 [Possibility of Industrial Use]

According to the present invention, it is possible to provide an orally disintegrating tablet with good dissolution, good partitionability and less segregation of the drug content, and a method for producing the tablet, the orally disintegrating tablet containing esalione or a pharmacologically acceptable salt thereof, It has rapid disintegration in the oral cavity or in water, and maintains sufficient hardness during the usual manufacturing, transportation or use process. Furthermore, the present invention can be used to produce the above-mentioned orally disintegrating tablets with excellent characteristics without complicated steps or special equipment.

without.

Figure 1 shows the results of time-series content change monitoring in the ingoting step.

without.

Claims (30)

An orally disintegrating powder tablet which contains esalione or its pharmacologically acceptable salt, lactose hydrate and light anhydrous silicic acid. An orally disintegrating tablet containing esalione or its pharmacologically acceptable salt, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, sugar alcohol, crystals Cellulose and gelatinized starch. Such as the orally disintegrating tablet of claim 1 or 2, wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. An orally disintegrating tablet according to any one of claims 1 to 3, wherein the average particle size of the lactose hydrate is in the range of 5-50 μm. The orally disintegrating tablet of any one of claims 2 to 4, wherein the overall density of the crystalline cellulose is 0.26 g/cm ³ or less. The orally disintegrating tablet of any one of claims 2 to 5, wherein the content of hydroxypropyl cellulose is equivalent to 0.1 to 15% by weight of the total weight of the tablet. The orally disintegrating tablet of any one of Claims 2 to 6, wherein the average degree of gelatinization of the gelatinized starch is 90% or less. Such as the orally disintegrating tablet of any one of claims 1 to 7, which further contains crospovidone. The orally disintegrating tablet according to any one of claims 1 to 8, which further contains a coloring agent and magnesium stearate. Such as the orally disintegrating tablet of claim 9, wherein the coloring agent is yellow iron trioxide or iron trioxide. An orally disintegrating powder tablet, which contains: Drug-containing granules, which comprise esalione or its pharmacologically tolerable salt, lactose hydrate, low degree of substitution hydroxypropyl cellulose and hydroxypropyl cellulose; Drug-free granules, which contain D-mannitol, crystalline cellulose and gelatinized starch; and Lightweight anhydrous silicic acid, which is used as an extra-granular component relative to the above two types of particles. The orally disintegrating tablet as described in claim 11, wherein the content of light anhydrous silicic acid is equivalent to 0.05 to 5% by weight of the total weight of the tablet. The orally disintegrating tablet of claim 11 or 12, wherein the average particle size of the lactose hydrate is in the range of 5-50 μm. The orally disintegrating tablet of any one of claims 11 to 13, wherein the overall density of the crystalline cellulose is 0.26 g/cm ³ or less. The orally disintegrating tablet of any one of claims 11 to 14, wherein the content of hydroxypropyl cellulose is equivalent to 0.1 to 15% by weight of the total weight of the tablet. The orally disintegrating tablet of any one of claims 11 to 15, wherein the content of the alpha starch is equivalent to 0.1 to 10% by weight of the total weight of the tablet. The orally disintegrating tablet according to any one of claims 11 to 16, which further contains crospovidone as an extragranular component. The orally disintegrating tablet according to any one of claims 11 to 17, which further contains a coloring agent and magnesium stearate as extragranular ingredients. Such as the orally disintegrating tablet of claim 18, wherein the coloring agent is yellow iron trioxide or iron trioxide. Such as the orally disintegrating tablet of any one of claims 1 to 19, which disintegrates within 1 second or more and 45 seconds or less in a disintegration test performed by a device. Such as the orally disintegrating tablet of any one of claims 1 to 20, which has good partitionability with secant lines. For example, the orally disintegrating tablet of claim 21, which is divided into half tablets with secant lines, has good strength and abrasion resistance. An orally disintegrating tablet according to any one of claims 11 to 22, wherein more than 50% of the drug-containing particles have a particle size of 80 μm or less. The orally disintegrating tablet of any one of claims 11 to 23, wherein more than 90% of the drug-containing particles have a particle size of 380 μm or less. For example, the orally disintegrating powder tablet of any one of claim 23 or 24 has less segregation of the drug content. A method for producing orally disintegrating powder tablets, which comprises: mixing esalione or its pharmacologically acceptable salt, lactose hydrate, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose to produce The step of drug-containing granules; the step of manufacturing drug-free granules by mixing D-mannitol and crystalline cellulose, and spraying gelatinized starch dispersed in water; and adding light anhydrous silicic acid and cross-linked polymer Vividone is used as an extra-granular component relative to the aforementioned two kinds of granules, and undergoes a compression molding step. According to claim 26, the method for manufacturing an orally disintegrating tablet comprises: further adding a coloring agent as an extragranular component, and adding magnesium stearate, and performing compression molding. According to claim 27, the method for manufacturing orally disintegrating loose tablets, wherein the colorant is yellow iron trioxide or iron trioxide. The method for manufacturing an orally disintegrating powder tablet according to any one of claims 26 to 28, wherein the step of manufacturing the drug-containing granules includes a high-speed stirring granulation step. Such as the method for producing orally disintegrating powdered tablets according to any one of claims 26 to 29, which prevents the elution of esalione or its pharmacologically acceptable salt from being reduced.

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