RU2779057C2 - Preparation containing vonoprazan - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention is aimed at the provision of a preparation, which, as it is expected, will improve a bitter taste of salt of organic vonoprazan acid and provide a possibility of fast dissolution of salt of organic vonoprazan acid after the administration. The present invention provides for a preparation containing fine granules or granules containing (1) a core granule containing salt of organic vonoprazan acid, (2) an intermediate layer containing the same organic acid as organic acid forming vonoprazan salt in (1), or its salt, and (3) a coating layer containing water-insoluble polymer.

EFFECT: obtaining a preparation for improvement of a taste and provision of a possibility of fast dissolution of salt of organic vonoprazan acid.

11 cl, 26 ex, 4 tbl, 16 dwg

Description

[Technical field]

[0001]

The present invention relates to a preparation with possibly improved bitter taste of the organic acid salt of vonoprazan.

[0002]

(Prerequisites for the creation of the invention)

Along with population aging and habitat changes, there is a need to develop an orally disintegrating tablet that can be easily taken anytime, anywhere without water, and that can maintain ease of handling as a feature of the tablet.

When the pharmaceutically active ingredient or other additive is a substance having an unpleasant taste such as bitter taste and the like, it is preferable from the point of view of compliance to mask such an unpleasant taste by coating. On the other hand, it is desirable that the pharmaceutically active ingredient is rapidly dissolved in order to exhibit pharmacological effects after administration. However, when the pharmaceutically active ingredient has a strong bitter taste, the thick coating to mask it prevents rapid dissolution, and these two properties are difficult to achieve at the same time.

It is known that 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (vonoprazan fumarate) has an excellent proton pump inhibitory effect (patent document 1) and may be useful as a drug. Vonoprazan organic acid salts such as vonoprazan fumarate and the like are known to have a bitter taste.

[List of documents]

[Patent Documents]

[0003]

[patent document 1] WO 2007/026916

[patent document 2] WO 2010/013823

[SUMMARY]

[Problems to be solved by the present invention]

[0004]

The present invention is directed to providing a preparation that is expected to improve the bitter taste of the organic acid salt of vonoprazan and allow the organic acid salt of vonoprazan to dissolve rapidly after administration.

[Tools for solving problems]

[0005]

The inventors of the present invention have carried out intensive studies in an attempt to solve the above problems, and it has been found that a preparation comprising fine granules or granules comprising (1) a core granule containing an organic acid salt of vonoprazan, (2) an intermediate layer containing the same organic acid that both the organic acid forming the salt of vonoprazan in (1) or its salt and (3) the coating layer containing the water-insoluble polymer can provide a certain time during which the organic acid salt of vonoprazan does not dissolve after administration (i.e. . delay time). The delay time prevents the pharmaceutical active ingredient from dissolving until it has passed through the throat, thus the bitter taste is expected to improve.

The present inventors have also found that the above structure can achieve rapid dissolution as well as an improvement in bitter taste after a delay time.

The inventors of the present invention continued their studies based on the above discovery and completed the present invention.

[0006]

In other words, the present invention provides the following.

[1] A preparation comprising fine granules or granules comprising (1) a core granule containing an organic acid salt of vonoprazan,

(2) an intermediate layer containing the same organic acid as the organic acid forming the salt of vonoprazan in (1) or a salt thereof, and

(3) a coating layer containing a water-insoluble polymer.

[2] The preparation according to the above [1], wherein the organic acid salt of vonoprazan is vonoprazan fumarate, the organic acid or its salt in the above (2) is fumaric acid or a fumaric acid salt.

[3] The preparation according to [1] or [2] above, wherein the water-insoluble polymer is a pH-independent water-insoluble polymer.

[4] The preparation according to the above [3], wherein the pH-independent water-insoluble polymer is an ammonioalkyl methacrylate copolymer.

[5] The preparation according to any of the above [1] to [4], wherein the organic acid or salt thereof in the above (2) is not less than about 0.5 parts by mass per 100 parts by mass of vonoprazan in the above (1) .

[6] The preparation according to any of the above [1] to [5], wherein the water-insoluble polymer (solid content) in the coating layer in the above (3) is about 0.5 to 15 mass parts per 100 mass parts of the particles including the core granule in the above item (1) and the intermediate layer of the above item (2).

[7] The preparation according to any one of [1] to [6] above, wherein said fine granules or granules have an average particle size of about 75 µm to about 750 µm.

[8] The preparation according to [1], wherein the intermediate layer (2) contains the same organic acid as the organic acid forming the salt of vonoprazan in (1), or its salt and the dissolution control agent in one layer or separate layers .

[9] The preparation according to the above [8], wherein the dissolution controlling agent has a solubility in water (100 g) at 20° C. of 0.01-500.

[10] The preparation according to the above [8], wherein the dissolution controlling agent has a pH of 2-4 when dissolved in water.

[11] The preparation according to the above [8], wherein the dissolution controlling agent is an organic acid salt or an organic acid.

[12] The preparation according to the above [8], wherein the dissolution controlling agent is a divalent carboxylic acid or a salt thereof.

[13] The preparation according to the above [8], wherein the dissolution controlling agent is succinic acid or succinic acid salt.

[14] The preparation according to any of the above [1] to [13], wherein the above fine granules or granules are further coated with a coagulation-inhibiting substance.

[15] The preparation according to the above [14], wherein the above coagulation inhibiting substance is an inorganic substance, a sugar alcohol or a saccharide.

[16] The preparation according to any of the above [1] to [15], further comprising a polymeric binder.

[17] The preparation according to any of the above [1] to [16] is in the form of an orally disintegrating tablet.

[Invention effect]

[0007]

The preparation of the present invention is a preparation that is expected to achieve both an improvement in the bitter taste of the organic acid salt of vonoprazan and a rapid dissolution.

[Brief Description of Drawings]

[0008]

Fig. 1 is a graph showing the results of a dissolution test of a tablet containing particles coated with a water-insoluble polymer obtained in Example 1 and a tablet containing particles coated with an organic acid obtained in Comparative Example 1. In the drawing legend, JP2 shows the second solution Japanese Pharmacopoeia dissolution test. The same is true for the following drawings.

Fig. 2 is a graph showing the results of a dissolution test for tablets containing particles coated with a water-insoluble polymer prepared in Examples 2-5.

Fig. 3 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 6.

Fig. 4 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 7.

Fig. 5 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 8.

Fig. 6 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 9.

Fig. 7 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 10.

Fig. 8 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 11.

Fig. 9 is a graph showing the results of a dissolution test for tablets containing particles coated with a water-insoluble polymer prepared in Examples 12-13.

Fig. 10 is a graph showing the results of a dissolution test for a tablet containing particles coated with a water-insoluble polymer prepared in Example 14.

Fig. 11 is a graph showing the results of Experimental Example 3.

Fig. 12 is a graph showing the results of the dissolution test of Experimental Example 4, which was carried out using the particles coated with the water-insoluble polymer obtained in Example 1.

Fig. 13 is a graph showing the results of a dissolution test of Experimental Example 4, which was carried out using the coagulation-inhibiting substance-coated particles obtained in Reference Example 3.

Fig. 14 is a graph showing the results of a dissolution test of Experimental Example 5, which was carried out using particles coated with water-insoluble polymer 3 obtained in Reference Example 2.

Fig. 15 is a graph showing the results of the dissolution test of Experimental Example 6, which was carried out using the particles coated with the water-insoluble polymer obtained in Reference Example 1.

Fig. 16 is a graph showing the results of a dissolution test of Experimental Example 6, which was carried out using Compound A-coated particles obtained in Reference Example 1.

[0009]

(Detailed description of the invention)

The preparation of the present invention is characterized in that it includes small granules or granules comprising (1) a core granule containing the organic acid salt of vonoprazane (sometimes described as core granule (1) in the present description), (2) an intermediate layer containing the same organic an acid that is both an organic acid forming a salt of vonoprazan in (1), or a salt thereof (sometimes described as an intermediate layer (2) in the present description), and (3) a coating layer containing a water-insoluble polymer (sometimes described as a coating layer (3) in the present description).

[0010]

In the present invention, fine granules or granules having a core granule (1), an intermediate layer (2) and a coating layer (3) have an average particle size of generally from about 50 µm to about 1 mm, preferably from about 75 µm to about 750 µm, more preferably from about 80 µm to about 500 µm, even more preferably from about 100 µm to about 400 µm.

When fine granules or granules are further coated with the following coagulation inhibiting substance (eg, D-mannitol, light anhydrous silicic acid), the above average particle size corresponds to the particle size after coating with the coagulation inhibiting substance.

[0011]

In the present description, "average particle size" indicates, unless otherwise indicated, the volume standard median size (median size: 50% particle size of the cumulative distribution). Examples of how it can be measured include determining the particle size distribution by laser diffraction. Specific examples include determination of particle size distribution by laser diffraction using a HEROS RODOS device (manufactured by Sympatec (Germany)). The average particle size of the "fine granules or granules" in the present invention can be measured after the preparation of the "fine granules or granules" and before the final formulation step of the preparation process, or can be measured by extracting the "fine granules or granules" from the formulated finished drug or the like . When measuring average particle size with this measurement method, the error is considered to be about ±10%, including measurement errors depending on the equipment and measurement method. The term "about" used with the numerical value of the average particle size is used to cover the error "±10%". That is, in the present description, for example, the range of numerical values of the average particle size of "from about 75 μm to about 750 μm" means 67.5 μm - 825 μm.

When the average particle size of the granules or fine granules contained in the formulation of the present invention is measured, a portion of the granules or fine granules may be associated with the formation of aggregates during preparation of the formulation. In this case, it is desirable to separate the above aggregate and individual granules or fine granules by a method such as sieving and the like, for example, and then measure the size. In particular, when the final preparation is a tablet such as an orally disintegrating tablet and the like, after tableting the tablet is ground into powder and the average particle size of granules or fine granules contained in the tablet is measured, it is desirable to confirm, if necessary, the existence state and particle size of the aggregate by visual analysis, sieving the aggregate, individual granules and small granules with a sieve of such a size that is able to separate them from the aggregate, and then measure the size.

In the present description, the term "coating" is used to mean not only covering the entire surface of the coated object, (eg core), but also partial coverage or adsorption or absorption.

In the present description, "granules" means particles granulated into a granular state.

As used herein, “fine granules” refers to those that completely pass through the #18 sieve and which pass through the #30 sieve with no more than 10% of the total granules remaining on the #30 sieve.

In the present invention, “granule or fine granule” means one granule or fine granule obtained by coating one “core granule”. When one aggregate having a plurality of “core granules” is formed by combining a portion of granules or fine granules as above, such one aggregate is not considered one “granule or fine granule”, and “granule or fine granule” means an independent single particle, obtained by coating individual core granules.

[0012]

The preparation of the present invention is characterized in that it contains an organic acid salt of vonoprazan (sometimes referred to as component (I) in the present description) as a pharmaceutically active ingredient in a core granule (1).

In the present invention, as the organic acid forming a salt of vonoprazan in the organic acid salt of vonoprazan (component (I)), for example, fumaric acid, succinic acid, benzoic acid, citric acid, mesylic acid, tartaric acid, besylic acid and the like, and fumaric acid is preferred.

In the present invention, as the organic acid salt of vonoprazan, vonoprazan fumarate is preferable.

[0013]

In the present invention, the core pellet (1) may be the following inactive carrier core coated with a layer containing the organic acid salt of vonoprazan.

[0014]

The preparation of the present invention is characterized in that the intermediate layer (2) contains an organic acid or a salt thereof, and the organic acid of the "organic acid or salt thereof" is the same as the organic acid that forms a salt with vonoprazan in component (I). In the present specification, the "organic acid or salt thereof" contained in the intermediate layer (2) is sometimes referred to as component (II).

The organic acid of component (II) is the same as the organic acid described in the above component (I).

Examples of the organic acid salt of component (II) include an alkali metal salt such as a sodium salt, a potassium salt and the like, an alkaline earth metal salt such as a calcium salt, a magnesium salt and the like, and an ammonium salt.

[0015]

In the present invention, the organic acid salt of vonoprazan (component (I)) contained in the core granule (1) is preferably vonoprazan fumarate, and the organic acid or salt thereof (component (II)) contained in the intermediate layer (2) is preferably is fumaric acid or a salt of fumaric acid (preferably fumaric acid or monosodium fumarate).

[0016]

The content of organic acid salt of vonoprazan (component (I)) in the preparation of the present invention is usually from about 1 wt.% to about 80 wt.%, preferably from about 5 wt.% to about 50 wt.%, more preferably from about 15 wt.% up to about 35 wt.%, in relation to the "core of the granule (1)".

[0017]

The content of organic acid or its salt (component (II)) in the intermediate layer (2) in the preparation of the present invention is preferably not less than about 0.5 mass parts, more preferably not less than about 10 mass parts, even more preferably not less than than about 150 mass parts per 100 mass parts of vonoprazan (in free form) in the core granule (1).

The content of organic acid or its salt (component (II)) in the intermediate layer (2) in the preparation of the present invention is usually from about 0.5 mass parts to about 5000 mass parts, preferably from about 1 mass part to about 5000 mass parts, more preferably from about 10 mass parts to about 1000 mass parts, even more preferably from about 50 mass parts to about 500 mass parts, per 100 mass parts of vonoprazan (in free form) in the core granule (1).

The weight of the above “vonoprazan (free form)” is based on the free form of vonoprazan in the organic acid salt of vonoprazan contained in the core granule (1).

[0018]

The preparation according to the present invention is characterized in that it has a coating layer (3) on the outside of the intermediate layer (2).

In the present invention, examples of the “water-insoluble polymer” contained in the coating layer (3) include a pH-independent water-insoluble polymer (e.g., ammonioalkyl methacrylate copolymer (otherwise referred to as ammonioalkyl methacrylate copolymer RS (e.g., Eudragit RS30D (trade name), Eudragit RSPO (trade name)), otherwise known as RL ammonioalkyl methacrylate copolymer (e.g. Eudragit RL30D (trade name), Eudragit RLPO (trade name)), ethyl cellulose, ethyl cellulose aqueous dispersion, ethyl acrylate-methyl methacrylate copolymer dispersion solution (e.g. Eudragit NE30D ( trade name)), vinyl acetate resin (Kollicoat SR (trade name)), gastrosoluble polymer (e.g. aminoalkyl methacrylate copolymer E, polyvinyl acetal-diethylaminoacetate, Kollicoat Smartseal 30D (trade name)), enteric polymer (e.g. methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer acid S, cellulose acetate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate), preferably a pH-independent water-insoluble polymer (e.g. ammonioalkyl methacrylate copolymer (otherwise called ammonioalkyl methacrylate copolymer RS, otherwise called ammonioalkyl methacrylate copolymer RL)), more preferably ammonioalkyl methacrylate copolymer (otherwise referred to as ammonioalkyl methacrylate copolymer RS, otherwise referred to as ammonioalkyl methacrylate copolymer RL).

One or more kinds of water-insoluble polymers can be used in combination.

[0019]

The content of water-insoluble polymer (solid content) in the coating layer (3) in the preparation of the present invention is preferably from about 0.5 mass parts to about 15 mass parts, more preferably from about 1 mass part to about 10 mass parts, still more preferably from about 1 mass part to about 7 mass parts per 100 mass parts of particles consisting of a core granule (1) and an intermediate layer (2).

In the present invention, the term "particles consisting of a core granule (1) and an intermediate layer (2)" refers to the particles before applying the coating layer (3).

[0020]

The preparation of the present invention preferably has an intermediate layer containing a dissolution control agent between the bead core (1) and the coating layer (3).

The interlayer containing the dissolution control agent may be the above interlayer (2) containing the dissolution control agent or the "intermediate layer containing the dissolution control agent" other than the above interlayer (2).

As an embodiment of the formulation of the present invention, a formulation comprising fine granules or granules comprising

(1) a core granule containing an organic acid salt of vonoprazan (component (I)),

(2) an intermediate layer containing the same organic acid as the organic acid forming the salt of vonoprazan in (1) or its salt (component (II)) and a dissolution control agent in the same layer or in separate layers, and

(3) a coating layer containing a water-insoluble polymer.

[0021]

In the preparation of the present invention, in order to exhibit the effect of providing a certain time (i.e., delay time) during which the organic acid salt of vonoprazan does not dissolve after administration, the intermediate layer containing the component (II) is preferably present near the core granule containing the component (I).

Therefore, in the preparation of the present invention, the intermediate layer (2) is an intermediate layer containing the component (II) and the dissolution control agent in one layer; or the intermediate layer (2) is an intermediate layer consisting of a plurality of layers separately containing component (II) and a dissolution control agent, while the intermediate layer containing component (II) is preferably present on the side of the core granule (1) (on core granule (1)).

[0022]

In the present invention, a dissolution control agent refers to a substance capable of providing a delay time to dissolution of vonoprazan (free form). For example, it is a substance that, when dissolved, temporarily renders vonoprazan (free form) insoluble or reduces the solubility.

In the present invention, the dissolution control agent preferably has a solubility of 0.01-500 (preferably 0.1-100, more preferably 0.5-40) in 100 g of water at 20°C.

In the present invention, the dissolution control agent is preferably a substance having a pH of 2-4 when dissolved in water.

[0023]

In the present invention, examples of the dissolution control agent include an organic acid (including a hydrate) (eg, a divalent carboxylic acid (eg, succinic acid, malic acid, adipic acid, malonic acid, and the like), salicylic acid, and the like); organic acid salt (including hydrate) (for example, divalent carboxylic acid salt (for example, succinic acid salt (for example, disodium succinate, disodium succinate hexahydrate and the like) and the like), ammonium carbonate, potassium hydrogen carbonate, sodium carbonate decahydrate, hydrogen carbonate sodium, sodium acetate trihydrate and the like); sugar alcohol (eg mannitol, erythritol, maltitol and the like); saccharides (eg lactose, maltose, trehalose and the like); a disintegrant (eg low substituted hydroxypropyl cellulose, carmellose and the like); a water soluble polymer (eg hydroxypropyl methylcellulose and the like); inorganic salt (including hydrate) (for example, ammonium chloride, ammonium nitrate, potassium chloride, disodium hydrogen phosphate 12-water, sodium thiosulfate pentahydrate, ammonium oxalate monohydrate, sodium pyrrophosphate and the like); an amide compound (eg urea and the like); amino acid (eg glycine and the like); an amino acid salt (eg, cysteine hydrochloride and the like); phenols (eg hydroquinone and the like); a water-insoluble polymer (for example, a vinyl polymer (for example, poly(N-acrylamide) and the like), and the like), and a salt of succinic acid or succinic acid is preferred.

One or more kinds of dissolution control agents may be used in combination.

[0024]

The content of the dissolution control agent in the preparation of the present invention is usually from about 10 mass parts to about 1000 mass parts, preferably from about 50 mass parts to about 600 mass parts, more preferably from about 200 mass parts to about 500 mass parts per 100 mass parts of water-insoluble polymer (solids content) in the coating layer (3).

In the present invention, when succinic acid is contained as a dissolution controlling agent, ammonioalkyl methacrylate copolymer (otherwise referred to as RS ammonioalkyl methacrylate copolymer) is preferably used as the above water-insoluble polymer, since the organic acid salt of vonoprazane can be expected to dissolve rapidly after the delay time has elapsed.

In the present invention, when succinic acid or a salt thereof is used as component (II) in the intermediate layer (2) and the amount of succinic acid or a salt thereof is in the above range, the above effect is expected to be obtained.

In the present invention, when succinic acid is contained as a dissolution control agent, it is expected that it will contribute to the stabilization of vonoprazan and a drug having excellent long-term stability will be obtained.

[0025]

In the preparation of the present invention, "fine granules or granules comprising a core granule (1), an intermediate layer (2) and a coating layer (3)" are preferably further coated with a coagulation-inhibiting substance.

Examples of the coagulation inhibiting substance include an inorganic substance, a sugar alcohol, and saccharides.

Examples of the inorganic substance include light anhydrous silicic acid (for example, Sylysia 320 (trade name), AEROSIL 200 (trade name)), hydrated silica, talc, titanium oxide, bentonite, kaolin, and magnesium aluminometasilicate, and light anhydrous silicic acid is preferred.

Examples of the sugar alcohol include D-mannitol, sorbitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, lactitol, and isomalt.

Examples of saccharides include monosaccharides (eg glucose, fructose) and disaccharides (eg lactose, sucrose, maltose, white sugar, trehalose).

[0026]

The amount of the coagulation inhibitor to be used to coat the fine granules or granules when a saccharide or sugar alcohol is used as the coagulation inhibitor is generally from about 1 mass part to about 30 mass parts, preferably from about 3 mass parts to about 20 mass parts, more preferably from about 4 mass parts to about 15 mass parts per 100 mass parts of “fine granules or granules, including core granule (1), intermediate layer (2) and coating layer (3)” (fine granules or granules prior to application of a coagulation inhibitor).

The amount of the coagulation inhibitor to be used to coat the fine granules or granules when an inorganic substance is used as the coagulation inhibitor is generally about 0.01 mass parts to about 10 mass parts, preferably about 0.05 mass parts up to about 5 mass parts, more preferably from about 0.1 mass parts to about 1 mass parts, per 100 mass parts of “fine granules or granules, including core granule (1), intermediate layer (2) and coating layer (3)” (small granules or granules before application of a coagulation inhibitor).

In the present invention, the film coating of a coagulation-inhibiting substance is expected to provide the effects of improved workability (reduced sticking due to static electricity) and suppression of drug dissolution delay after storage.

[0027]

The formulation of the present invention preferably further comprises a polymeric binder.

The polymeric binder may be any as long as it has the property of causing each additive to bind sufficiently strongly to the granules or fine granules in terms of attrition resistance. Examples thereof include water-soluble polymer (hydroxypropyl methylcellulose (HPMC) (e.g., hydroxypropyl methylcellulose 2910), hydroxypropyl cellulose, carmellose sodium, methylcellulose (e.g., Metolose SM-4 (trade name)), poly(vinyl alcohol), sodium alginate, poly(vinyl alcohol) copolymer )-acrylic acid-methyl methacrylate, polyethylene oxide, povidone, copolyvidone, polyethylene glycol), gastrosoluble polymer (Eudragit E (trade name), Eudragit EPO (trade name)), pH-independent water-insoluble polymer (Eudragit NE (trade name) , Eudragit RL (trade name) (e.g. Eudragit RLPO (trade name), Eudragit RL30D (trade name)), Eudragit RS (trade name), ethyl cellulose), preferably hydroxypropyl methylcellulose (HPMC), Eudragit E (trade name), Eudragit EPO (trade name), Eudragit NE (trade name), Eudragit RL (trade name) and methylcellulose (eg Metolose SM-4 (trade name)).

The content of the polymeric binder in the preparation of the present invention is usually 0.1 mass parts - 100 mass parts, preferably 0.5 mass parts - 90 mass parts, more preferably 1 mass part - 80 mass parts per 100 mass parts of the organic acid contained in the preparation .

In the present invention, a polymeric binder is used as, but not limited to, for example, a binder layer containing an organic acid.

[0028]

The preparation of the present invention may further contain a cyclodextrin.

As the cyclodextrin, α-cyclodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin can be mentioned, and β-cyclodextrin is preferred.

In the present invention, the cyclodextrin (particularly β-cyclodextrin) contained can be expected to mask the sour taste of the organic acid component (eg, fumaric acid, succinic acid).

In the present invention, the cyclodextrin may be contained in any part of the preparation of the present invention. It is preferably contained in the outer layer granules below or in the outer part of the granules, and is more preferably contained in the outer layer granules.

The content of cyclodextrin in the preparation of the present invention is usually 1 mass part - 1000 mass parts, preferably 10 mass parts - 500 mass parts, more preferably 25 mass parts - 100 mass parts per 100 mass parts of the organic acid contained in the preparation.

[0029]

The preparation of the present invention may be formulated as an orally disintegrating tablet containing the above fine granules or granules, or the like. This is explained in detail below.

[0030]

Examples of the preparation of the present invention include solid preparations such as tablets, granules, fine granules, capsules, foam preparations and the like, liquids such as suspension and the like, and the like. From the viewpoint of ease of handling and the like, a tablet is preferred, and an orally disintegrating tablet is especially preferred.

As used herein, an "orally disintegrating tablet" is a tablet having an appropriate disintegrating property that can be taken by rapid dissolution or disintegration in the oral cavity.

[0031]

The preparation of the present invention can be obtained using the above components and in accordance with the method known in the field of pharmaceutical preparations.

For example, when the preparation of the present invention is an orally disintegrating tablet, it can be prepared as follows.

In the following manufacturing method, the application of a layer of component (c) is optional.

[0032]

The core, which is an inactive carrier, is successively sprayed with coating liquids, which are the following (a), (b), (c), obtained in advance, dried and sieved, if necessary, to obtain component (I)-containing particles. Alternatively, the inactive carrier core is successively sprayed with coating liquids of the following (a), (d), obtained in advance, dried and sieved, if necessary, to obtain component (I)-containing particles.

(a) The binder is suspended or dissolved in water or a solvent (e.g. ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropyl alcohol), component (I) (e.g. vonoprazan fumarate) is added and suspended or dissolved in the mixture to form a coating liquid, containing component (I).

(b) The binder is suspended or dissolved in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropyl alcohol), component (II) (e.g., fumaric acid, monosodium fumarate) is added, and suspended or dissolved in a mixture to obtain a coating liquid containing component (II).

(c) The binder is suspended or dissolved in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropyl alcohol), a dissolution control agent (e.g., succinic acid) is added, and suspended or dissolved in the mixture to form a coating liquid containing a dissolution control agent.

(d) The binder is suspended or dissolved in water or a solvent (e.g. ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropyl alcohol), a dissolution control agent (e.g. succinic acid) is added and suspended or dissolved in the mixture, then the component is added (II) (eg, fumaric acid, monosodium fumarate) and suspended or dissolved in the mixture to form a coating liquid containing component (II)/dissolution control agent.

Examples of the binder include the above polymeric binders.

Coating layers can be applied in any order and can be applied multiple times. For example, (a), (b), (c) can be applied to the core in this order, (a), (b), (c), (b) can be applied to the core in this order, (a), (b ), (b), (c) may be applied to the core in that order, or (a), (d) may be applied to the core in that order.

[0033]

Particles containing component (I) may additionally have a coating layer that does not contain component (I), component (II) or a dissolution control agent, but contains a binder (eg, HPMC). Such a layer may be formed between the active pharmaceutical ingredient layer (layer (a)) and the organic acid layer (layer (b), layer (c) or layer (d)).

Each layer may further contain the following additive (eg, flavor (eg, monosodium glutamate), surfactant (eg, polysorbate 80), coagulation inhibitor (eg, talc)) used for conventional preparations. These components can be used by adding to the above coating liquids.

[0034]

A coating liquid containing a water-insoluble polymer (for example, an ammonioalkyl methacrylate copolymer (for example, Eudragit RS30D (trade name), Eudragit RSPO (trade name), Eudragit RLPO (trade name))) is sprayed onto the resulting particles containing component (I), and they are dried and sieved, if necessary, to obtain fine granules or granules.

The coating layer containing the water-insoluble polymer may further contain the following additives used for conventional preparations (for example, a plasticizer (for example, triacetin), a coagulation inhibitor (for example, talc), a dye (for example, iron oxide red, iron oxide yellow, titanium oxide), plasticizer (eg polysorbate 80), pH adjuster (eg citric anhydride), coloring agent (eg titanium oxide)). These components can be used by adding a coating to the above liquids.

The resulting fine granules or granules may be further coated with a coagulation-inhibiting substance. In this case, a coagulation-inhibiting substance (for example, D-mannitol, light anhydrous silicic acid) is suspended or dissolved in a solvent such as water and the like to form a coating liquid containing the coagulation-inhibiting substance, and the coating liquid is sprayed onto fine granules or granules are dried and, if necessary, sieved to obtain particles coated with a coagulation-inhibiting substance. A coagulation-inhibiting substance (eg, D-mannitol, light anhydrous silicic acid) is mixed with fine granules or granules, whereby particles coated with the coagulation-inhibiting substance can also be obtained.

[0035]

The resulting fine granules or granules (or particles coated with a coagulation-inhibiting substance) are formed (tabletted) together with optionally added outer layer granules and/or a component on the outside of the granules to form an orally disintegrating tablet of the present invention.

The outer layer granules can be prepared, for example, using a granulating excipient (eg D-mannitol, crystalline cellulose), a flavoring agent (eg citric anhydride), a disintegrant (eg low substituted hydroxypropyl cellulose, crospovidone) and optionally β- cyclodextrin.

Examples of the component outside of the granules include sweetener (eg aspartame, acesulfame potassium, thaumatin), flavoring agent (eg l-menthol, monosodium fumarate), lubricant (eg sodium stearyl fumarate, magnesium stearate), excipient (eg crystalline cellulose), disintegrant (eg, crospovidone, partially pregelatinized starch), flavor (eg, lime flavor, orange flavor, strawberry flavor, strawberry D, peppermint cortone), fluidizer (eg, Neusilin FL2 (trade name), Neusilin UFL2 (trade name), AEROSIL 200 (trade name), Sylysia 320 (trade name)) and β-cyclodextrin.

A commercially available premixed direct tableting preparation can also be used as the outer layer granules. For example, you can specify SmartEX (trade name), Parteck ODT (trade name), Granutol F (trade name), Rudy flash (trade name), GRANFILLER-D (trade name) SWELLWiCK (trade name). It is also possible to use a processing raw material suitable for direct tableting, such as a sprayable dry product or a granular product of mannitol, lactose and the like, and the like.

The content of the granules of the outer layer in the total amount is usually 10 wt.% - 95 wt.%, preferably 30 wt.% - 90 wt.%, more preferably 35 wt.% - 80 wt.%, relative to the weight of the entire drug.

The content of the component outside the granules in the total amount is usually 0.5 wt.% - 40 wt.%, preferably 0.75 wt.% - 35 wt.%, more preferably 1 wt.% - 30 wt.%, in relation to the mass the entire drug.

[0036]

Examples of the inactive carrier core include (1) crystalline cellulose and lactose spherical granular product, (2) mannitol spherical granular product, (3) 75-300 µm spherical crystalline cellulose (CELPHERE manufactured by Asahi Kasei Chemicals Co., Ltd.), (4 ) 50-250 µm granular product of mixing lactose (9 parts) and α starch (1 part), (5) a microparticle of 250 µm or less obtained by classifying microcrystalline cellulose spherical granules described in JP-A-61-213201, ( 6) a processed product of waxes and the like spherically formed by spray cooling or melt granulation, (7) a processed product such as gelatin beads containing an oil component, and the like, (8) calcium silicate, (9 ) starch, (10) partially pregelatinized starch, (11) porous particles of chitin, cellulose, chitosan and the like, (12) bulk product of mannitol, granulated sugar, crystalline lactose, crystalline c cellulose or sodium chloride and the like and obtaining their processed products. In addition, these cores can be obtained by a spraying method or a granulation method known per se and sieved to obtain particles with the desired particle size.

Examples of a "spherical granular product of crystalline cellulose and lactose" include (i) 100-200 µm spherical granulated product of crystalline cellulose (3 parts) and lactose (7 parts) (for example, NONPAREIL 105 (70-140) (particle size 100-200 µm ), manufactured by Freund Corporation), (ii) 150-250 µm spherical granular product of crystalline cellulose (3 parts) and lactose (7 parts) (for example, NONPAREIL NP-7:3, manufactured by Freund Corporation), (iii) 100-200 µm spherical granular product of crystalline cellulose (4.5 parts) and lactose (5.5 parts) (for example, NONPAREIL 105T (70-140) (particle size 100-200 µm), manufactured by Freund Corporation) and the like, (iv) 150 -250 µm spherical granular product of crystalline cellulose (5 parts) and lactose (5 parts) [for example, NONPAREIL NP-5:5, manufactured by Freund Corporation].

[0037]

"Mixing" is carried out by a commonly used mixing method such as mixing, kneading, granulating. “Mixing” is carried out using an apparatus such as vertical granulator (VG10 (manufactured by POWREX CORPORATION)), universal kneading machine (manufactured by HATA TEKKOSHO CO.,LTD.), fluid bed granulator (LAB-1, FD-3S, FD- WSG-60, FD-WSG-60TW, FD-GPCG-120SPC, FD-MP-01 (SPC/SFP/FD), MP-10 type toku-2 (manufactured by POWREX CORPORATION)), V-TYPE MIXER, tumbler mixer , mixing plant of container type.

“Shaping” is carried out using a single-die tablet machine (manufactured by Kikusui Seisakusho Ltd.), a rotary tablet machine (manufactured by Kikusui Seisakusho Ltd.) and the like, by punching at a pressure of about 1 to about 30 kN/cm ² , preferably from about 2 to about 20 kN/cm ² .

“Drying” can be performed by any method used for conventional drug drying, such as vacuum drying, fluid bed drying, and the like.

"Spraying", "coating", "granulating", "sieving" is carried out by methods known per se.

The method of tableting an orally disintegrating tablet can be carried out at room temperature or at a temperature above room temperature. “Room temperature” generally refers to a temperature between about 10°C and about 30°C. The temperature may vary depending on the quality of the desired tablet.

The orally disintegrating tablet may be an uncoated tablet, a film-coated preparation, or a sugar-coated tablet, and preferably an uncoated tablet. In the present specification, “uncoated tablet” means a tablet that has not been subjected to such treatment as coating such as film coating, sugar coating, and the like, on the surface of an orally disintegrating tablet obtained in the tabletting step.

[0038]

The preparation of the present invention may further contain, as ingredients other than those mentioned above, additives used in the preparation of conventional preparations. The added amount is that which is used to obtain conventional drugs.

Water-soluble sugar alcohol, crystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC) and a binder are used as an additive, an acidifying agent, a foaming agent, a sweetener, a flavor, a lubricant, a dye, an excipient, a leavening agent, a flavoring agent, a plasticizer, a surfactant are additionally added. the active substance, coagulation inhibitor, fluidizer, pH adjuster and the like are mixed and compression molded to form an orally disintegrating tablet.

Water-soluble sugar alcohol means a sugar alcohol that requires less than 30 ml of water when sugar alcohol (1 g) is added to water and dissolved in about 30 minutes by vigorous shaking for 30 seconds at 20°C every 5 minutes.

Examples of the water-soluble sugar alcohol include mannitol, sorbitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, lactitol, preferred are mannitol, sorbitol, maltitol, xylitol, erythritol, more preferred are mannitol, sorbitol, maltitol, erythritol, even more preferred are mannitol, erythritol. Two or more of these species can be used in a mixture in an appropriate ratio. Erythritol is usually obtained from glucose as a starting material and by fermentation using yeast and the like. Use erythritol with a particle size of 50 mesh or less. Erythritol is obtained as a commercially available product [Nikken Chem. Co.,Ltd. etc.]. The water soluble sugar alcohol is typically used in an amount of 3 to about 60 parts by weight, preferably from about 5 to about 50 parts by weight per 100 parts by weight of the total preparation.

The crystalline cellulose can be of any kind, provided that it is obtained by partial depolymerization of α-cellulose and its purification. It also includes cellulose called microcrystalline cellulose. As crystalline cellulose, mention can be made in particular of, for example, CEOLUS KG-1000, CEOLUS KG-802, CEOLUS PH-101, CEOLUS PH-102, CEOLUS PH-301, CEOLUS PH-302, CEOLUS UF-702, CEOLUS UF -711. Preferably, you can specify CEOLUS KG-802 or CEOLUS UF-711. These crystalline celluloses may be used alone, or two or more of them may be used in combination. These crystalline celluloses can be obtained as commercially available products [manufactured by Asahi Kasei Chemicals Co., Ltd.]. Crystalline cellulose may be added in an amount of 1 to about 50 parts by weight, preferably about 3 to about 40 parts by weight, most preferably about 5 to about 20 parts by weight per 100 parts by weight of the total preparation.

Examples of low substituted hydroxypropyl cellulose include LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, LH-33. These LHPCs can be obtained as commercially available products [manufactured by Shin-Etsu Chemical Co., Ltd.]. The low substituted hydroxypropyl cellulose may be added in an amount of 1 to about 50 parts by weight, preferably about 3 to about 40 parts by weight, most preferably about 3 to about 20 parts by weight per 100 parts by weight of the total preparation.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, pectin, xanthan gum, carrageenan, guar gum, gellan gum, poly(vinyl alcohol), poly(vinyl alcohol)-polyethylene glycol graft- copolymer, copolyvidone, methyl cellulose, low substituted hydroxypropyl cellulose, poly(vinyl alcohol)-acrylic acid-methyl methacrylate copolymer. Two or more types of these binders can be used in a mixture in an appropriate ratio.

Examples of the acidifying agent include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, acetic acid, adipic acid, glucono delta lactone, phytic acid, and salts thereof.

Examples of a blowing agent include sodium bicarbonate.

Examples of the sweetener include xylose, starch syrup, hydrogenated maltose starch syrup, maltose, glucose, fructose, simple syrup, dextrin, cyclodextrin, maltose, lactose, trehalose, malt oligosaccharide, isomalt oligosaccharide, gentiooligosaccharide, sodium saccharin, glycyrrhizin, aspartame, sucralose potassium, stevia, thaumatin, advantam, neotame.

The flavoring agent can be any of a synthetic substance and a substance of natural origin. For example, you can specify lemon, lime, orange, menthol, strawberry, mint, banana, ginger, Japanese apricot, grapefruit, yogurt, vanilla, Chinese lemon, blueberry, green tea, cole, grape, sugar.

Examples of the flavor include monosodium glutamate, citric anhydride, l-menthol, monosodium fumarate.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, polyethylene glycol, talc, sodium stearyl fumarate, glycerin, stearic acid monoglyceride, castor oil, hydrogenated castor oil.

Examples of the coloring include food colorings such as food coloring yellow No. 5, food coloring red No. 2, food coloring blue No. 2; food lacquer dyes, red iron oxide pigment, iron oxide red, iron oxide yellow, iron oxide black, black dye and the like.

Examples of the excipient include lactose, sucrose, isomaltose, D-mannitol, sorbitol, anhydrous calcium phosphate, starch, corn starch, partially pregelatinized starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide.

Examples of the disintegrant include crospovidone [manufactured by ISP Inc. (USA), BASF (Germany)], croscarmellose sodium (FMC-Asahi Kasei Corporation), calcium carmellose (GOTOKU CHEMICAL CO., LTD.), low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch (Matsutani Chemical Industry Co., Ltd.) , corn starch, pregelatinized starch, crystalline cellulose. Of these, crospovidone is preferably used. Two or more types of these leavening agents can be used in a mixture in an appropriate ratio. For example, crospovidone can be used alone, or crospovidone can be used in combination with another disintegrant. Crospovidone can be anything as long as it is a crosslinked polymeric substance called 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpolypyrrolidone (PVPP), a 1-vinyl-2-pyrrolidinone homopolymer. Typically, crospovidone with a molecular weight of at least 1,000,000 is used. Specific examples of commercially available crospovidone products include cross-linked (cross-linked) povidone, Kollidon CL, Kollidon CL-F, Kollidon CL-SF [manufactured by BASF (Germany)], Polyplasdone XL, Polyplasdone XL- 10, INF-10 [Manufacturer ISP Inc. (USA)], polyvinylpyrrolidone, PVPP, 1-vinyl-2-pyrrolidinone homopolymer. Such disintegrant is used, for example, in an amount of from about 0.1 to about 30 parts by weight, preferably from about 1 to about 25 parts by weight, even more preferably from about 1.5 to about 20 parts by weight per 100 parts by weight of the total preparation.

Examples of the plasticizer include polyethylene glycol, propylene glycol, ethanol, triethyl citrate, triacetin, polysorbate 80.

Examples of the surfactant include sodium lauryl sulfate, cetyltrimethylammonium bromide, sodium docusate, polyoxyethylene hydrogenated castor oil, polysorbate 80, polysorbate 20.

Examples of the coagulation inhibitor include talc, titanium oxide, light anhydrous silicic acid, kaolin, bentonite, hydrated silica, stearic acid monoglyceride, mannitol, trehalose, erythritol, lactose, maltose.

Examples of the fluidizer include magnesium aluminometasilicate, light anhydrous silicic acid, hydrated silica, talc.

Examples of the pH adjuster include citric anhydride, hydrochloric acid, sodium hydroxide.

[0039]

As an embodiment, the small granules or granules included in the formulation of the present invention may have an inert carrier core, a layer containing component (I) on the outside of the inactive carrier core, a layer containing component (II) on the outer the side of the layer containing the component (I) and the layer containing the water-insoluble polymer on the outside of the layer containing the component (II).

[0040]

As an embodiment, the small granules or granules included in the formulation of the present invention may have an inert carrier core, a layer containing component (I) on the outside of the inactive carrier core, a layer containing component (II) on the outer side of the layer containing the component (I), a layer containing the dissolution control agent on the outside of the layer containing the component (II), and a coating layer containing the water-insoluble polymer on the outside of the layer containing the dissolution control agent.

[0041]

As an embodiment, the small granules or granules included in the preparation of the present invention may have a core of an inert carrier, a layer containing component (I) on the outside of the core of an inactive carrier, a layer containing component (II), and a substance , controlling dissolution, on the outside of the layer containing the component (I) and the layer containing the water-insoluble polymer, on the outside of the layer containing the component (II) and the substance that controls the dissolution.

[0042]

As an option, the small granules or granules included in the formulation of the present invention may have an inert carrier core, a layer containing component (I) on the outside of the inactive carrier core, a polymeric binder containing layer on the outside of the layer containing component (I), a layer containing component (II) on the outer side of the layer containing a polymeric binder, and a coating layer containing a water-insoluble polymer on the outer side of the layer containing component (II).

[0043]

As an option, the small granules or granules included in the formulation of the present invention may have an inert carrier core, a layer containing component (I) on the outside of the inactive carrier core, a polymeric binder containing layer on the outside of the layer containing component (I), a layer containing component (II) on the outside of the layer containing a polymeric binder, a layer containing a dissolution control agent on the outside of a layer containing component (II), and a coating layer containing insoluble in water polymer, on the outside of the layer containing the dissolution control agent.

[0044]

As an option, the small granules or granules included in the formulation of the present invention may have an inert carrier core, a layer containing component (I) on the outside of the inactive carrier core, a polymeric binder containing layer on the outside of the layer containing component (I), a layer containing component (II) and a dissolution control substance on the outside of a layer containing a polymer binder, and a layer containing a water-insoluble polymer on the outside of a layer containing component (II) and a substance , which controls the dissolution.

[0045]

The orally disintegrating tablet of the present invention exhibits a rapid disintegration or dissolution property in the oral cavity.

The orally disintegrating tablet of the present invention can be easily taken while maintaining ease of handling. In addition, it can be taken anytime anywhere without water, and the oral disintegration time (time to complete disintegration of an orally disintegrating saliva tablet in the oral cavity of healthy men and women) is no more than 1 minute, usually no more than than about 50 seconds, preferably no more than about 40 seconds, even more preferably no more than about 30 seconds.

[0046]

It is expected that the preparation of the present invention will provide a certain delay time before dissolution of the pharmaceutically active ingredient (organic acid salt of vonoprazan).

In particular, the preparation of the present invention preferably has the following dissolution properties (1) or (2).

(1) In a dissolution test according to the Japanese Pharmacopoeia paddle method (rotation speed 50 rpm, 37°C) or the Japanese Pharmacopoeia spinning basket method (rotation speed 100 rpm, 37°C) with using the second Japanese Pharmacopeia dissolution test liquid (900 ml), the time from the start of the test to the dissolution of 5% of the pharmaceutically active ingredient is not less than 2 minutes and not more than 15 minutes.

(2) In the dissolution test using the second Japanese Pharmacopoeia dissolution test liquid (10 ml), the dissolution rate of the pharmaceutical active ingredient 1 minute after the start of the test is not more than 5%.

The preparation of the present invention more preferably has the above dissolution property (2).

Whereas the formulation of the present invention (particularly the orally disintegrating tablet) is intended to provide a certain amount of time (delay time) during which the organic acid salt of vonoprazan does not dissolve after administration, in order to prevent the pharmaceutical active ingredient from dissolving until the drug has passed through the throat , it is desirable that the ingredient dissolves rapidly after a delay time, and it is not necessary to form an enteric layer that inhibits dissolution until the drug has reached the small intestine.

[0047]

The preparation of the present invention can be safely administered orally to mammals (eg, mouse, rat, rabbit, cat, dog, bovine, horse, monkey, human, etc.). Although the dose of the preparation of the present invention varies, for example, depending on the subject of administration, the kind of disease, and the like, it can be appropriately selected from the range in which the dose of the pharmaceutically active ingredient is effective.

The preparation of the present invention contains an organic acid salt of vonoprazan (particularly vonoprazan fumarate) as a pharmaceutically active ingredient. It has a lower toxicity, is a safe drug, and is useful in gastric ulcer, duodenal ulcer, reflux esophagitis, non-erosive reflux disease, suppression of recurrence of gastric or duodenal ulcer when a low dose of acetylsalicylic acid is administered, to suppress recurrence of gastric or duodenal ulcer intestines with the introduction of non-steroidal anti-inflammatory drugs; as an aid to eradicate Helicobacter pylori in the following conditions: gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, stomach after endoscopic resection of early gastric cancer or Helicobacter pylori-associated gastritis and the like. Its dose based on vonoprazan is from about 10 to about 40 mg/day per adult patient (body weight 60 kg). The drug can be administered once a day or 2-3 portions a day.

The preparation of the present invention can be used in combination with a low dose of acetylsalicylic acid and/or non-steroidal anti-inflammatory drugs (NSAIDs). Examples of non-steroidal anti-inflammatory agents include acetylsalicylic acid, indomethacin, ibuprofen, mefenamic acid, diclofenac, etodolac, piroxicam, celecoxib, loxoprofen sodium, naproxen and the like.

It can also be used in combination with an anti-Helicobacter pylori active, an imidazole compound, a bismuth salt, a quinolone compound, and the like as an Helicobacter pylori eradication aid or as a Helicobacter pylori eradication agent.

Examples of “active substance against Helicobacter pylori” include penicillin antibiotics (e.g. amoxicillin, benzylpenicillin, piperacillin, mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, lenampicillin, etc.), cephem antibiotics (e.g. cefixime, cefaclor, etc.). .d.), macrolide antibiotics (e.g. erythromycin, clarithromycin, roxithromycin, rokitamycin, flurithromycin, telithromycin, etc.), tetracycline antibiotics (e.g. tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (e.g., gentamicin, amikacin, etc.), imipenem and the like. Of these, penicillin antibiotic, macrolide antibiotic and the like are preferable.

Examples of the “imidazole compound” include metronidazole, miconazole, and the like.

Examples of the "bismuth salt" include bismuth acetate, bismuth citrate, bismuth subsalicylate, and the like.

Examples of the “quinolone compound” include ofloxacin, ciploxacin, and the like.

Among others, penicillin antibiotics (eg, amoxicillin, etc.), erythromycin antibiotics (eg, clarithromycin, etc.), and/or imidazole compounds (eg, metronidazole, etc.) are preferably used to eliminate Helicobacter pylori.

[Examples]

[0048]

Although the present invention is more specifically explained below with reference to Examples and Experimental Examples, the present invention is not limited thereto.

In Examples, Comparative Examples, Reference Examples and Experimental Examples, Compound A is vonoprazan fumarate.

In the following Examples, etc. “coated liquid containing an organic acid” refers to a coating liquid containing an organic acid or an organic acid salt, and “particles coated with an organic acid” refers to particles coated with a liquid containing an organic acid or an organic acid salt.

[0049]

Example 1

[Preparation of a Coating Liquid Containing Compound A]

To purified water (399.8 g) was added hydroxypropyl methylcellulose 2910 (otherwise referred to as hypromellose (2910), TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd., hereinafter the same) (24.3 g), compound A ( 180.3 g) and the mixture was well stirred to obtain a coating liquid containing Compound A.

[Preparation of Compound A Coated Particles]

Spherical granules of lactose/crystalline cellulose (NONPAREIL 105T, manufactured by Freund Corporation, hereinafter the same) (300.5 g) were placed in a fine particle coating granulator/Wurster and fluidized (FD-MP-01(SPC/SFP/FD) , manufacturer POWREX, hereinafter the same), a coating liquid containing compound A (570.0 g) was sprayed at an air supply pressure of 0.5 MPa, an air flow rate during spraying of 60 Nl / min, an air inlet temperature of 65-75 °C, an inlet air flow rate of 0.4-0.5 m ³ /min, a spray liquid feed rate of 5 g/min, and the particles were dried to obtain particles after drying (445.5 g). The total number of particles after drying was sieved to obtain particles coated with compound A (300 μm - 105 μm) (413.6 g).

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (24.3 g) and jet-milled fumaric acid, (manufacturer POLYNT, hereinafter the same) (120.5 g) were added to purified water (480.5 g) and the mixture was well mixed to obtain a coating liquid, containing organic acids.

[Production of particles coated with organic acid]

Particles coated with Compound A (300 µm-105 µm) (400.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid (561.5 g) was sprayed at a supply pressure on the air sprayer 0.4-0.5 MPa, air flow rate during spraying 50-70 nl / min, air inlet temperature 73 ° C, incoming air flow rate 0.5 m ³ /min, flow rate of the sprayed liquid 3- 9 g/min and the particles were dried to obtain particles after drying (499.3 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (374.6 g).

[Production of a coating liquid containing a water-insoluble polymer]

In purified water (350.3 g), triacetin (manufactured by Merck, hereinafter ditto) (6.05 g), talc (manufacturer matsumura sangyo Co., Ltd., hereinafter ditto) (30.3 g) and iron oxide red (LCW, hereinafter the same) (0.1321 g) and the mixture was added to stirred aminoalkyl methacrylate copolymer RS (otherwise called ammonioalkyl methacrylate copolymer, Eudragit RS30D, manufactured by Evonik) (199.8 g) to obtain a coating liquid containing insoluble in water polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with organic acid (355 µm - 105 µm) (299.8 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer (330.0 g) was sprayed at air supply pressure 0.4 MPa, air flow rate during spraying 60 nl/min, air inlet temperature 43°C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 2-3 g/min to obtain particles after spraying (316.7 g). Talc (1.2 g) was added to 228.0 g of particles after spraying, and they were well stirred in a plastic bag, and dried and cured in a constant temperature forced convection oven (DNF400, manufactured by Yamato Scientific co., ltd., hereinafter the same ) at 60°C for 12 hours. The particles, after drying and curing, were sieved through a 300 µm sieve to obtain sieved particles, particles coated with a water-insoluble polymer (220.9 g).

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Further, unless specifically described, the content of compound A in the particles obtained in advance in the preliminary stage before obtaining the tableting mixture was measured by HPLC, the amount of particles obtained in the preliminary stage required for 20 mg of compound A as a free base, which should contained in the tablet, calculated and used at the stage of mixing.

Particles coated with a water-insoluble polymer (650.9 mg), ODT direct compression excipient (SmartEX QD-100, manufactured by Shin-Etsu Chemical Co., Ltd., hereinafter the same) (416.1 mg), aspartame (manufactured by Ajinomoto Co., Inc., hereinafter id.) (11 mg), l-menthol (manufactured by THE SUZUKI MENTHOL CO., LTD., hereinafter id.) (2.75 mg), acesulfame potassium (Sunett manufacturer MC Food Specialties Inc. , hereinafter ditto) (2.75 mg), sodium stearyl fumarate (PRUV, manufactured by JRS Pharma, hereinafter ditto) (16.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (275 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. The mixed product containing particles coated with a water-insoluble polymer (250 mg) was weighed, tabletted using a flat punch with a diameter of 8.5 mm and a single-die tablet machine (HANDTAB-200, manufactured by ICHIHASHI SEIKI, hereinafter the same) at 3 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg Compound A as free base per tablet).

[0050]

Example 2

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (24.21 g) was dissolved in purified water (399.8 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (180.0 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (33.59 g) was dissolved in purified water (673.9 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (100.8 g) was suspended in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (300.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (555.0 g) was sprayed at a spray air pressure of 0.5 MPa , air flow rate during spraying 60 nl/min, inlet air temperature 74°C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 6-7 g/min. Then, a coating liquid containing an organic acid (620.0 g) was sprayed at a pressure of 0.50 MPa air supplied to the atomizer, a spray air flow rate of 60 Nl/min, an inlet air temperature of 74-85°C, an inlet air flow rate of 0.5 m ³ /min, spray liquid feed rates 5-6 g/min, and the particles were dried to obtain particles after drying (542.5 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (300 μm - 105 μm) (505.3 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (5.98 g), talc (30.2 g) and iron oxide red (0.2000 g) were suspended and dissolved in purified water (363.8 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (200.0 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with organic acid (300 μm - 105 μm) (300.3 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (375.0 g) was sprayed at air supply pressure 0.5 MPa, air flow rate during spraying 60 nl/min, air inlet temperature 40°C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 2-4 g/min , to obtain particles after spraying (331.7 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer (325.0 g).

[Obtaining Granules of the Outer Layer]

D-mannitol (14.99 g) was dissolved in purified water (315.0 g) to form a binder. D-mannitol (394.8 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (60.28 g), low substituted hydroxypropyl cellulose (L-HPC LH-33, manufactured by Shin-Etsu Chemical Co. , Ltd., hereinafter the same) (59.95 g) and crospovidone (Polyplasdone XL-10, manufacturer ISP) (30.22 g) were fed and fluidized in a fluid bed granulator and the binder (198.0 g) was sprayed under pressure air supplied to the atomizer 0.1 MPa, air flow rate during spraying 60 nl / min, air inlet temperature 85 ° C, inlet air flow rate 0.2 m ³ /min, spray liquid supply rate 6 g / min, and granules dried up. The dried granules were sieved through an 850 µm sieve to obtain sieved particles, outer layer granules (519.8 g).

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1153.8 mg), outer layer granules (2446.1 mg), aspartame (21.0 mg), l-menthol (13.1 mg), acesulfame potassium (5.3 mg) , sodium stearyl fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a blended product containing particles coated with a water-insoluble polymer. A blended product containing water insoluble polymer coated particles (400 mg) was weighed and tabletted using a 10.0 mm diameter flat punch, single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0051]

Example 3

[Production of particles coated with water-insoluble polymer]

In the step of obtaining particles coated with the water-insoluble polymer of Example 2, samples were taken at the time of spraying the coating liquid containing the water-insoluble polymer (225.0 g) to obtain particles after spraying (3.4 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1076.9 mg), outer layer granules (2523.0 mg) obtained in Example 2, aspartame (21.0 mg), l-menthol (13.1 mg), acesulfame potassium ( 5.3 mg), sodium stearyl fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottles to obtain a mixed product containing particles coated with a water-insoluble polymer. The blended product containing water insoluble polymer coated particles (400 mg) was weighed, tabletted using a 10.0 mm diameter flat punch and a single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0052]

Example 4

[Production of particles coated with water-insoluble polymer]

In the step of obtaining particles coated with the water-insoluble polymer of Example 2, samples were taken at the time of spraying the coating liquid containing the water-insoluble polymer (300.0 g) to obtain particles after spraying (3.0 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1123.0 mg), outer layer granules (2476.9 mg) obtained in Example 2, aspartame (21.0 mg), l-menthol (13.1 mg), acesulfame potassium (5 .3 mg), sodium stearyl fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. The blended product containing water insoluble polymer coated particles (400 mg) was weighed, tabletted using a 10.0 mm diameter flat punch and a single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0053]

Example 5

[Production of particles coated with water-insoluble polymer]

In the step of obtaining particles coated with the water-insoluble polymer of Example 2, sampling was carried out at the time of spraying the coating liquid containing the water-insoluble polymer (330.0 g) to obtain particles after spraying (3.5 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1141.3 mg), outer layer granules (2458.6 mg) obtained in Example 2, aspartame (21.0 mg), l-menthol (13.1 mg), acesulfame potassium ( 5.3 mg), sodium stearyl fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottles to obtain a mixed product containing particles coated with a water-insoluble polymer. The blended product containing water insoluble polymer coated particles (400 mg) was weighed, tabletted using a 10.0 mm diameter flat punch and a single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0054]

Example 6

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (28.76 g) was dissolved in purified water (479.75 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (215.6 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing compound A.

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (43.24 g) was dissolved in purified water (864.70 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (216.3 g) was then suspended in a solution of hydroxypropyl methylcellulose to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (350.8 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (642.0 g) was sprayed at a spray air pressure of 0.5 MPa , air flow rate during spraying 60 nl/min, inlet air temperature 65-72°C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 5-8 g/min. Then, an organic acid-containing coating liquid (925.0 g) was sprayed at an air supply pressure of 0.5 MPa to the atomizer, a spray air flow rate of 60 Nl/min, an inlet air temperature of 81-82°C, an inlet air flow rate of 0.5 m ³ /min, spray liquid feed rates 6-7 g/min, and the particles were dried to obtain particles after drying (722.4 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (300 μm - 105 μm) (664.4 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (30.4 g), succinic acid (119.98 g) was dissolved in purified water (1851.3 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (300 μm - 105 μm) (340.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a dissolution control agent (1295 g) was sprayed under the pressure of the applied to the air atomizer 0.5 MPa, air flow rate during spraying 60 Nl/min, air inlet temperature 85°C, inlet air flow rate 0.5 m ³ /min, flow rate of the spray liquid 4-5 g/min, and the particles were dried to obtain particles after drying (415.2 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 μm - 105 μm) (412.3 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (5.98 g), talc (30.15 g) and iron oxide red (0.2131 g) were suspended and dissolved in purified water (363.9 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (200.2 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 μm - 105 μm) (400.5 g) were placed in a fine particle coating granulator/Wurster and fluidized and sampled at the point in time when the coating liquid containing the water-insoluble polymer (250.0 g), sprayed at an air pressure of 0.5 MPa supplied to the atomizer, an air flow rate during spraying of 60 Nl / min, an air inlet temperature of 43 ° C, an inlet air flow rate of 0.5 m ³ /min, speeds spray liquid supply 5 g/min, obtaining particles after spraying (39.9 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1478.9 mg), outer layer granules (2121.1 mg) obtained in Example 2, aspartame (21.0 mg), l-menthol (13.1 mg), acesulfame potassium ( 5.3 mg), sodium stearyl fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottles to obtain a mixed product containing particles coated with a water-insoluble polymer. The blended product containing water insoluble polymer coated particles (400 mg) was weighed, tabletted using a 10.0 mm diameter flat punch and a single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0055]

Example 7

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (28.8 g) was dissolved in purified water (480.0 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (216.1 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a Coating Liquid Containing an Organic Acid]

In purified water (864.0 g) was dissolved hydroxypropyl methylcellulose 2910 (43.2 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (216.1 g) was suspended in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (349.8 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (642.0 g) was sprayed at a spray air pressure of 0.5 MPa , air flow rate during spraying 60 nl/min, inlet air temperature 73°C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 6-8 g/min. Then, an organic acid-containing coating liquid (925.0 g) was sprayed at a spray air supply pressure of 0.5 MPa, a spray air flow rate of 60 Nl/min, an inlet air temperature of 80°C, an inlet air flow rate of 0, 5 m ³ /min, spray liquid feed rates 5-8 g/min, and the particles were dried to obtain particles after drying (714.8 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (686.4 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (22.5 g), succinic acid (89.96 g) was dissolved in purified water (1387.5 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (355 µm - 105 µm) (329.8 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a dissolution control agent (1257.0 g) was sprayed under pressure air supplied to the atomizer 0.5 MPa, air flow rate during spraying 60 nl / min, air inlet temperature 85 ° C, incoming air flow rate 0.5 m ³ / min, spray liquid supply rate 4-5 g / min, and the particles were dried to obtain particles after drying (401.2 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (sieved granule 355 μm).

[Production of a coating liquid containing a water-insoluble polymer]

Polysorbate 80 (manufactured by Merck) (0.4071 g) was dissolved in purified water (499.7 g), and then talc (25.09 g), iron oxide red (0.2000 g) was added and the mixture was uniformly dispersed to obtain a suspension. The suspension was added in small portions to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (142.1 g). Citric anhydride (0.0779 g) was dissolved in separately prepared purified water (500.6 g), and the solution was added in small portions to a dispersion of ethyl acrylate-methyl methacrylate copolymer (Eudragit NE30D, manufactured by Evonik) (25.1 g) and the mixture was well stirred. To a first liquid containing an aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik), a solution containing a dispersion of an ethyl acrylate-methyl methacrylate copolymer was added in small portions, and the mixture was well mixed to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 μm sieved granule) (350.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (751.0 g) was sprayed at air supply pressure 0.5 MPa, air flow rate during spraying 60 nl/min, air inlet temperature 40-46°C, incoming air flow rate 0.5-0.6 m ³ /min, spray liquid supply rate 2-3 g/min to obtain particles after spraying (321.7 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1598.2 mg), outer layer granules (2013.8 mg) obtained in Example 2, aspartame (21.0 mg), l-menthol (5.3 mg), acesulfame potassium ( 5.3 mg), sodium stearyl fumarate (31.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles, coated with a water-insoluble polymer. The blended product containing water insoluble polymer coated particles (400 mg) was weighed, tabletted using a 10.0 mm diameter flat punch and a single punch tablet machine at 6 kN to give an orally disintegrating tablet containing water insoluble polymer coated particles ( corresponds to 20 mg of Compound A as free base per tablet).

[0056]

Example 8

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (23.98 g) was dissolved in purified water (399.7 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (179.7 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a coating liquid containing an organic acid (1)]

Hydroxypropyl methylcellulose 2910 (12.53 g) was dissolved in purified water (324.8 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (50.15 g) was suspended in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid (1)]

Lactose/crystalline cellulose spherical granules (450.4 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (522.0 g) was sprayed at a spray air pressure of 0.5 MPa , spray air flow rate 60 Nl/min, inlet air temperature 75°C, inlet air flow rate 0.5 m ³ /min, spray liquid feed rate 6 g/min. Then, a coating liquid containing an organic acid (1) (222.0 g) was sprayed at a spray air pressure of 0.5 MPa, a spray air flow rate of 60 Nl/min, an inlet air temperature of 85°C, an inlet flow rate of air 0.5-0.6 m ³ /min, spray liquid feed rate 6-7 g/min, and the particles were dried to obtain particles after drying (631.0 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (1) (355 μm - 105 μm) (623.6 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (33.25 g), succinic acid (84.11 g) was dissolved in purified water (1540.2 g) to obtain a coating liquid containing a dissolution control agent.

[Production of a coating liquid containing an organic acid (2)]

Hydroxypropyl methylcellulose 2910 (16.20 g) was dissolved in purified water (416.3 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (64.15 g) was then suspended in a solution of hydroxypropyl methylcellulose to obtain an organic acid-containing coating liquid (2).

[Production of particles coated with organic acid (2)]

Particles coated with organic acid (1) (355 µm - 105 µm) (320.1 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a dissolution control agent (1375.0 g) sprayed at a pressure of air supplied to the atomizer of 0.5 MPa, an air flow rate during spraying of 60 nl / min, an air inlet temperature of 85 ° C, an incoming air flow rate of 0.5-0.6 m ³ /min, a spray liquid supply rate 4-5 g/min. Then, a coating liquid containing organic acid (2) (420.0 g) was sprayed at a spray air pressure of 0.5 MPa, a spray air flow rate of 60 Nl/min, an inlet air temperature of 80°C, an inlet flow rate of air 0.6 m ³ /min, spray liquid feed rate 5-6 g/min, and the particles were dried to obtain particles after drying (446.0 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (2) (355 μm - 125 μm) (402.5 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (9.0 g), talc (45.10 g) was suspended and dissolved in purified water (545.1 g) and iron oxide red (0.9215 g) was added. The mixture was added to stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (300.1 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with organic acid (2) (355 μm - 125 μm) (399.8 g) were placed in a fine particle coating granulator/Wurster and fluidized and sampled at the point in time when the coating liquid containing insoluble in polymer (307.0 g) was sprayed with water at a pressure of 0.3–0.5 MPa air supplied to the spray gun, an air flow rate during spraying of 60 nl/min, an inlet air temperature of 35–43°C, an incoming air flow rate of 0 ,5-0.6 m ³ /min, spray liquid feed rate 2-3 g/min to obtain particles after spraying (20.4 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (3510.3 mg), outer layer granules (5550.7 mg) obtained in Example 2, aspartame (82.0 mg), l-menthol (10.3 mg), acesulfame potassium ( 10.3 mg), sodium stearyl fumarate (61.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (1025.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles, coated with a water-insoluble polymer. The blended product containing particles coated with water-insoluble polymer (500 mg) was weighed, tabletted using a flat punch with a diameter of 11.0 mm and a single-die tablet machine at 6 kN to obtain an orally disintegrating tablet containing particles coated with water-insoluble polymer ( corresponds to 20 mg of Compound A as free base per tablet).

[0057]

Example 9

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (18.04 g) was dissolved in purified water (700.0 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (180.0 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a coating liquid containing an organic acid (1)]

Hydroxypropyl methylcellulose 2910 (12.49 g) was dissolved in purified water (399.7 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (50.12 g) was suspended in a solution of hydroxypropyl methylcellulose to obtain a coating liquid containing an organic acid (1).

[Production of particles coated with organic acid (1)]

Partially pregelatinized starch (PCS PC-10, manufactured by Asahi Kasei Corporation, hereinafter the same) (310.1 g), classified (D50=116.4 µm) using a 75 µm sieve with an opening of 180, was placed in a granulator for application fine particle coatings/Wurster and fluidized and a coating liquid containing Compound A (830.0 g) was sprayed at an air supply pressure of 0.3 MPa, an air flow rate during spraying of 60 Nl/min, an air inlet temperature of 83° C, incoming air flow rate 0.5-0.6 m ³ /min, spray liquid supply rate 3-7 g/min. Then, a coating liquid containing organic acid (1) (290.0 g) was sprayed at a pressure of air supplied to the sprayer of 0.3 MPa, an air flow rate during spraying of 60 Nl/min, an air inlet temperature of 73-83°C, a speed of an incoming air flow of 0.6 m ³ /min, a spray liquid feed rate of 5-6 g/min, and the particles were dried to obtain particles after drying (476.5 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (1) (180 μm - 75 μm) (356.8 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (33.25 g), succinic acid (84.01 g) was dissolved in purified water (1540.0 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (1) (180 μm - 75 μm) (300.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a dissolution control agent (1620.0 g) sprayed at a pressure of 0.4 MPa air supplied to the atomizer, an air flow rate during spraying of 60 nl/min, an air inlet temperature of 84-85°C, an inlet air flow rate of 0.5-0.6 m ³ /min, a feed rate spray liquid 4 g/min and the particles were dried to obtain particles after drying (396.8 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (212 µm - 75 µm) (357.8 g).

[Production of a coating liquid containing an organic acid (2)]

Hydroxypropyl methylcellulose 2910 (17.02 g) was dissolved in purified water (640.0 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (80.1 g) was then suspended in a hydroxypropyl methylcellulose solution to obtain an organic acid-containing coating liquid (2).

[Production of particles coated with organic acid (2)]

Particles coated with a dissolution control agent (212 μm - 75 μm) (349.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, coating liquid containing organic acid (2) (540.0 g), sprayed at an air supply pressure of 0.4 MPa, an air flow rate during spraying of 60 Nl/min, an air inlet temperature of 85°C, an incoming air flow rate of 0.5 m ³ /min, a spray liquid feed rate of 4 g/min , and the particles were dried to obtain particles after drying (396.1 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (2) (250 μm - 75 μm) (390.0 g).

[Production of a coating liquid containing a water-insoluble polymer (1)]

Triacetin (4.5 g), talc (22.5 g) and iron oxide red (0.4452 g) were suspended and dissolved in purified water (272.5 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (150.0 g) to obtain a coating liquid containing a water-insoluble polymer (1).

[Production of particles coated with water-insoluble polymer (1)]

Particles coated with organic acid (2) (250 μm - 105 μm) (350.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (1) (315, 0 g), sprayed at a pressure of air supplied to the atomizer of 0.3 MPa, an air flow rate during spraying of 60 nl / min, an air temperature at the inlet of 38 ° C, an inlet air flow rate of 0.5-0.6 m ³ /min, spray liquid feed rate of 2-3 g/min, resulting in particles after spraying (340.5 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles after drying and curing were sieved through a 250 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer (1).

[Production of a coating liquid containing a water-insoluble polymer (2)]

Triacetin (2.31 g), talc (11.26 g) and iron oxide red (0.2253 g) were suspended and dissolved in purified water (361.2 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (75.1 g) to obtain a coating liquid containing a water-insoluble polymer (2).

[Production of particles coated with water-insoluble polymer (2)]

The particles coated with the water insoluble polymer (1) (314.8 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing the water insoluble polymer (2) (200.0 g) was sprayed at pressure of air supplied to the atomizer 0.3 MPa, air flow rate during spraying 60 nl/min, air inlet temperature 35-38°C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 2-3 g /min, with particles after spraying (251.5 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles after drying and curing were sieved through a 350 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer (2).

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Particles coated with water-insoluble polymer (2) (1584.9 mg), outer layer granules (1901.1 mg) obtained in Example 2, aspartame (42.0 mg), sodium stearyl fumarate (42.0 mg), monosodium fumarate (Wako primary, manufactured by Wako Pure Chemical Industries, Ltd.) (105.0 mg) and partially pregelatinized starch (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with water insoluble polymer (2). The mixed product containing particles coated with water-insoluble polymer (2) (400 mg) was weighed and tabletted using a flat punch with a diameter of 10.0 mm and a single-die tablet machine at 6 kN to obtain an orally disintegrating tablet containing particles coated with water-insoluble water with polymer (2) (corresponding to 20 mg compound A as free base per tablet).

[0058]

Example 10

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (16.80 g) was dissolved in purified water (449.98 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (126.1 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (62.64 g) was dissolved in purified water (2609.9 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (313.2 g) was then suspended in a solution of hydroxypropyl methylcellulose to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (300.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (490.0 g) was atomized at an air supply pressure of 0.3 MPa to the atomizer , air flow rate during spraying 60 nl/min, inlet air temperature 73°C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 5-6 g/min. Then, a coating liquid containing an organic acid (2750.0 g) was sprayed at a pressure of air supplied to the sprayer of 0.3 MPa, an air flow rate during spraying of 60-70 Nl/min, an air inlet temperature of 78-80°C, an air inlet velocity of an air flow of 0.6 m ³ /min, a spray liquid feed rate of 6-7 g/min, and the particles were dried to obtain particles after drying (659.4 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (604.5 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

In purified water (1300.15 g), methyl cellulose (28.12 g), succinic acid (84.31 g) was dissolved to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (355 µm - 105 µm) (300.4 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a dissolution control agent (1190.0 g) was sprayed under pressure air supplied to the atomizer 0.3 MPa, air flow rate during spraying 60 nl / min, air inlet temperature 83 ° C, inlet air flow rate 0.6 m ³ /min, spray liquid supply rate 3-5 g / min and the particles were dried to obtain particles after drying (384.3 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 µm - 125 µm) (372.9 g).

[Production of a coating liquid containing a water-insoluble polymer]

In purified water (272.5 g) were suspended and dissolved triacetin (4.50 g), talc (22.48 g) and iron oxide yellow (LCW, hereinafter the same) (0.4532 g), and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (150.1 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 µm - 125 µm) (360.1 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (200.0 g) was sprayed at a pressure of air supplied to the atomizer 0.2 MPa, air flow rate during spraying 60 Nl / min, air inlet temperature 36 ° C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 2-3 g / min to obtain particles after spraying (372.2 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[Obtaining Granules of the Outer Layer]

D-mannitol (31.59 g) and citric anhydride (21.35 g) were dissolved in purified water (314.8 g) to form a binder. D-mannitol (383.4 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (59.64 g), low-substituted hydroxypropyl cellulose (59.96 g), and crospovidone (Polyplasdone XL-10, manufactured by ISP) (30.23 g) was fed and fluidized in a fluidized bed granulator and the binder (210.0 g) was sprayed at a spray air pressure of 0.1 MPa, spray air flow rate of 60 Nl/min, air inlet temperature 85°C, inlet air flow rate 0.2-0.3 m ³ /min, spray liquid feed rate 11 g/min, and the granules were dried. The dried granules were sieved through an 850 µm sieve to obtain sifted granules, outer layer granules (526.6 g).

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (2573.5 mg), outer layer granules (2566.2 mg), aspartame (63.0 mg), orange flavor (San fix orange, manufactured by San-Ei Gen F.F.I., Inc., further ditto) (5.3 mg), sodium stearyl fumarate (42.0 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. A mixed product containing particles coated with a water-insoluble polymer (550.0 mg) was weighed and tabletted using a flat punch with a diameter of 11.5 mm and a single-die tablet machine at 6 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg of Compound A as free base per tablet).

[0059]

Example 11

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (16.83 g) was dissolved in purified water (450.21 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (126.3 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing compound A.

[Production of a Coating Liquid Containing an Organic Acid]

In purified water (3330.1 g) was dissolved hydroxypropyl methylcellulose 2910 (79.92 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (399.6 g) was then suspended in a solution of hydroxypropyl methylcellulose to obtain a coating liquid containing an organic acid.

[Production of a Coating Liquid Containing a Dissolution Control Substance]

In purified water (1300.0 g), methyl cellulose (28.1 g), succinic acid (84.0 g) was dissolved to obtain a coating liquid containing a dissolution control agent.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (300.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (490.0 g) was atomized at an air supply pressure of 0.3 MPa to the atomizer , air flow rate during spraying 80 nl/min, inlet air temperature 83°C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 5-6 g/min. Then, an organic acid-containing coating liquid (2920.0 g) was sprayed at a spray air supply pressure of 0.3 MPa, a spray air flow rate of 70 Nl/min, an inlet air temperature of 80°C, an inlet air flow rate of 0, 6 m ³ /min, spray liquid feed rates 5-6 g/min, and the particles were dried to obtain particles after drying (730.9 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (726.5 g).

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (355 μm - 105 μm) (360.1 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing organic acid (357.0 g) was sprayed under the pressure of the supplied on the air atomizer 0.3 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 80 ° C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 4-5 g / min. Then, a coating liquid containing a dissolution control agent (750.0 g) was sprayed at a spray air supply pressure of 0.3 MPa, a spray air flow rate of 70 Nl/min, an inlet air temperature of 80°C, an inlet air flow rate of 0 .6 m ³ /min, spray liquid feed rates of 2-4 g/min, and the particles were dried to obtain particles after drying (443.0 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 µm - 125 µm) (433.0 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (4.50 g), talc (22.51 g) and iron oxide yellow (0.4503 g) were suspended and dissolved in purified water (272.5 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (150.3 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 µm - 125 µm) (420.3 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (238.0 g) was sprayed at a pressure of air supplied to the sprayer 0.2 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 36 ° C, incoming air flow rate 0.6-0.7 m ³ /min, spray liquid supply rate 2 g/min to obtain particles after spraying (426.9 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (2900.6 mg), outer layer beads (2449.2 mg) obtained in Example 10, aspartame (63.0 mg), orange flavor (5.3 mg), sodium stearyl fumarate (42 .0 mg) and crystalline cellulose (CEOLUS KG-1000, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. A blended product containing particles coated with a water-insoluble polymer (570.0 mg) was weighed and tabletted using a flat punch with a diameter of 11.5 mm and a single-die tablet machine at 6 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg of Compound A as free base per tablet).

[0060]

Example 12 (with protective layer)

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (20.41 g) was dissolved in purified water (550.03 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (153.0 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a coating liquid containing a water-soluble polymer]

Hydroxypropyl methylcellulose 2910 (30.03 g) was dissolved in purified water (955.01 g) to obtain a solution of hydroxypropyl methylcellulose. Then, talc (14.99 g) was suspended to form a coating liquid containing a water-soluble polymer.

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (30.04 g) was dissolved in purified water (1350.2 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (162.0 g) was slurried to form a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Lactose/crystalline cellulose spherical granules (399.2 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (655.0 g) was sprayed at a spray air pressure of 0.3 MPa , air flow rate during spraying 60 nl/min, air inlet temperature 76°C, incoming air flow rate 0.6-0.7 m ³ /min, spray liquid supply rate 1-7 g/min. A coating liquid containing a water-soluble polymer (400.0 g) was sprayed at an air supply pressure of 0.3 MPa to the atomizer, a spray air flow rate of 60 Nl/min, an air inlet temperature of 84°C, an inlet air flow rate of 0.7 m ³ /min, spray liquid feed rate 4-6 g/min. A coating liquid containing an organic acid (1233.0 g) was sprayed at an air supply pressure of 0.3 MPa to the atomizer, a spray air flow rate of 60 Nl/min, an inlet air temperature of 76°C, an inlet air flow rate of 0.6 -0.7 m ³ /min, spray liquid feed rate 6 g/min. Then the particles were dried to obtain particles after drying (667.5 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 125 μm) (662.5 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (28.04 g), succinic acid (84.02 g) was dissolved in purified water (1330.0 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (355 μm - 125 μm) (330.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a dissolution control agent (1008.0 g) was sprayed under pressure air supplied to the atomizer 0.30 MPa, air flow rate during spraying 65 nl / min, air inlet temperature 83 ° C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 4-5 g / min, and the particles were dried to obtain particles after drying (377.5 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 µm - 125 µm) (376.5 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (4.51 g) and talc (22.52 g) were suspended and dissolved in purified water (273.0 g) and the mixture was added to stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (150.0 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 µm - 125 µm) (370.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (277.0 g) was sprayed at a pressure of air supplied to the sprayer 0.2 MPa, air flow rate during spraying 65 nl / min, air inlet temperature 36 ° C, incoming air flow rate 0.6-0.7 m ³ /min, flow rate of the sprayed liquid 2 -3 g/min to obtain particles after spraying (397.1 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 2 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[Obtaining Granules of the Outer Layer]

D-mannitol (27.19 g) and citric anhydride (17.24 g) were dissolved in purified water (320.0 g) to form a binder. D-mannitol (225.2 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (36.08 g), low-substituted hydroxypropyl cellulose (35.18 g), and crospovidone (Polyplasdone XL-10, manufactured by ISP) (17.58 g), β-cyclodextrin (68.80 g) was fed and fluidized in a fluid bed granulator, and the binder (145.6 g) was sprayed at an air supply pressure of 0.1 MPa to the atomizer, an air flow rate at spraying 60 Nl/min, inlet air temperature 85°C, inlet air flow rate 0.2-0.3 m ³ /min, spray liquid feed rate 6 g/min, and the granules were dried. The dried granules were sieved through an 850 µm sieve to obtain sieved granules, outer layer granules (363.1 g).

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (2042.8 mg), outer layer granules (3049.7 mg), aspartame (63.0 mg), sodium stearyl fumarate (94.5 mg) and crystalline cellulose (CEOLUS KG-802, manufacturer Asahi Kasei Corporation) (525.0 mg) was mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. A blended product containing particles coated with a water-insoluble polymer (550.0 mg) was weighed and tabletted using a flat punch with a diameter of 11.5 mm and a single-die tablet machine at 9 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg of Compound A as free base per tablet).

[0061]

Example 13 (with protective layer)

[Production of a Coating Liquid Containing an Organic Acid]

Hydroxypropyl methylcellulose 2910 (17.51 g) was dissolved in purified water (787.53 g) to obtain a solution of hydroxypropyl methylcellulose. Then, jet-milled fumaric acid (94.5 g) was slurried to form an organic acid-containing coating liquid.

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Hydroxypropyl methylcellulose 2910 (28.03 g), succinic acid (83.98 g) was dissolved in purified water (1330.0 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Organic acid coated particles (355 µm - 125 µm) (330.0 g) obtained in Example 12 were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing organic acid (559.4 g) , sprayed at a pressure of air supplied to the atomizer of 0.3 MPa, an air flow rate during spraying of 65 nl / min, an air inlet temperature of 76 ° C, an incoming air flow rate of 0.6-0.7 m ³ /min, a spray liquids 3-9 g/min. A coating liquid containing a dissolution control agent (1008.0 g) was sprayed with an air supply pressure of 0.3 MPa to the sprayer, a spray air flow rate of 65 Nl/min, an air inlet temperature of 76°C, an inlet air flow rate of 0, 6-0.7 m ³ /min, spray liquid feed rate 4-6 g/min. Then the particles were dried to obtain particles after drying (459.9 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 µm - 125 µm) (451.3 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (4.50 g) and talc (22.50 g) were suspended and dissolved in purified water (273.0 g) and the mixture was added to stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (150.0 g) with obtaining a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 μm - 125 μm) (445.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (284.5 g) was sprayed at a pressure of air supplied to the atomizer 0.2 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 34-36 ° C, incoming air flow rate 0.7 m ³ /min, spray liquid supply rate 2-3 g/min to obtain particles after spraying (430.9 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

D-mannitol (50.15 g) was dissolved in purified water (450.05 g) to obtain a coating liquid containing a coagulation inhibitory substance.

[Production of particles coated with a coagulation-inhibiting substance]

The particles coated with the water-insoluble polymer (415.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing a coagulation-inhibiting substance (222.2 g) was atomized at an atomizer air pressure of 0 .3 MPa, spray air flow rate 65 Nl/min, inlet air temperature 68°C, inlet air flow rate 0.7 m ³ /min, spray liquid feed rate 4 g/min, and the particles were dried to obtain particles after drying (428.0 g). The total number of particles after spraying was sieved to obtain 355 μm - 125 μm granules in the form of particles coated with a coagulation inhibitory substance (427.5 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (2545.5 mg), outer layer granules (2751.8 mg) obtained in Example 12, aspartame (63.0 mg), menthol flavor (menthol cortone HL33855, manufactured by Ogawa & Co., Ltd .) (5.3 mg), sodium stearyl fumarate (94.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product, containing particles coated with a coagulation-inhibiting substance. A mixed product containing particles coated with a coagulation-inhibiting substance (570.0 mg) was weighed and tabletted using a flat punch with a diameter of 11.5 mm and a single-die tablet machine at 9 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg of Compound A as free base per tablet).

[0062]

Example 14

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (20.41 g) was dissolved in purified water (550.0 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (153.1 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Production of a coating liquid containing a water-soluble polymer]

Hydroxypropyl methylcellulose 2910 (29.70 g) was dissolved in purified water (955.0 g) to obtain a solution of hydroxypropyl methylcellulose. Then, talc (15.00 g) was suspended to form a coating liquid containing a water-soluble polymer.

[Production of Particles Coated with Water-Soluble Resin]

Lactose/crystalline cellulose spherical granules (399.2 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (655.0 g) was atomized at an air supply pressure of 0.3 MPa to the atomizer , air flow rate during spraying 70 nl/min, inlet air temperature 76°C, incoming air flow rate 0.6-0.7 m ³ /min, spray liquid supply rate 5-7 g/min. A coating liquid containing a water-soluble polymer (520.0 g) was sprayed at an air supply pressure of 0.3 MPa to the atomizer, a spray air flow rate of 70 Nl/min, an air inlet temperature of 76°C, an inlet air flow rate of 0.7 m ³ /min, the flow rate of the spray liquid 4-5 g/min, the particles were dried to obtain particles after drying (505.3 g). The total number of particles after drying was sieved to obtain particles coated with a water-soluble polymer (355 μm - 125 μm) (504.5 g).

[Production of a Coating Liquid Containing an Organic Acid]

Aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik, hereinafter ditto) (19.01 g) was added to purified water (1530.0 g), and pre-jet milled fumaric acid (240.0 g) was added, and the mixture was stirred to obtain coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Particles coated with water-soluble polymer (355 µm - 125 µm) (500.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing an organic acid (1665.5 g) was sprayed at a supply pressure to the air atomizer 0.3 MPa, air flow rate during spraying 65 Nl/min, air inlet temperature 76°C, inlet air flow rate 0.7 m ³ /min, spray liquid supply rate 6 g/min and the particles were dried with obtaining particles after drying (675.8 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 125 μm) (674.9 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

Aminoalkyl methacrylate copolymer E (5.03 g), succinic acid (76.01 g) was added to purified water (1200.0 g), and the mixture was stirred to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with organic acid (355 µm - 125 µm) (330.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a dissolution control agent (839.0 g) was sprayed under pressure air supplied to the atomizer 0.30 MPa, air flow rate during spraying 65 nl / min, air inlet temperature 70-76 ° C, incoming air flow rate 0.6-0.7 m ³ /min, spray liquid supply rate 3 -5 g/min, and the particles were dried to obtain particles after drying (371.5 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (355 µm - 125 µm) (370.5 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (4.53 g) and talc (22.51 g) were suspended and dissolved in purified water (273.0 g) and the mixture was added to stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufactured by Evonik) (150.04 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (355 μm - 125 μm) (365.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and sampled at the point in time when the coating liquid containing the water-insoluble polymer (200.0 g), sprayed at a pressure of 0.2 MPa air supplied to the atomizer, an air flow rate during spraying of 65 Nl/min, an air inlet temperature of 35°C, an inlet air flow rate of 0.7 m ³ /min, speeds spray liquid supply 1-2 g/min to obtain particles after spraying (7.23 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[Production of an orally disintegrating tablet containing particles coated with a water-insoluble polymer]

Water-insoluble polymer coated particles (1924.8 mg), outer layer granules (3377.7 mg) obtained in Example 12, aspartame (63.0 mg), sodium stearyl fumarate (94.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) was mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a water-insoluble polymer. A mixed product containing particles coated with a water-insoluble polymer (570.0 mg) was weighed and tabletted using a flat punch with a diameter of 11.5 mm and a single-die tablet machine at 7 kN to obtain an orally disintegrating tablet containing particles coated with a water-insoluble polymer (corresponding to 20 mg of Compound A as free base per tablet).

[0063]

Comparative Example 1

[Production of an orally disintegrating tablet containing particles coated with an organic acid]

Organic acid coated particles (567.0 mg) prepared in Example 1, direct compression excipient ODT (SmartEX, manufactured by Freund Corporation) (500.0 mg), aspartame (11.0 mg), l-menthol (2. 8 mg), acesulfame potassium (2.8 mg), sodium stearyl fumarate (16.5 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (275.0 mg) were mixed by shaking 100 times in a glass bottle with obtaining a mixed product containing particles coated with an organic acid. The mixed product containing organic acid coated particles (250 mg) was weighed and tabletted using a flat punch with a diameter of 8.5 mm and a single punch tablet machine at 3 kN to obtain an orally disintegrating tablet containing organic acid coated particles (corresponding to 20 mg of the compound And in the form of a free base per tablet).

[0064]

Reference Example 1

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (15.62 g) was dissolved in purified water (417.9 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (117.0 g) was then evenly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (299.8 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing Compound A (490.0 g) was sprayed at a spray air pressure of 0.4 MPa , spray air flow rate 60 Nl/min, inlet air temperature 75°C, inlet air flow rate 0.7 m ³ /min, spray liquid feed rate 6 g/min and the particles were dried to obtain particles after drying (360, 4 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 125 μm) (358.3 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (5.96 g), talc (30.01 g) and iron oxide red (0.6010 g) were suspended and dissolved in purified water (363.4 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (200.0 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Compound A (355 µm-125 µm) coated particles (330.0 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (461.0 g) was sprayed at pressure of air supplied to the atomizer 0.4 MPa, air flow rate during spraying 60 nl/min, air inlet temperature 38°C, inlet air flow rate 0.7 m ³ /min, spray liquid supply rate 3 g/min to obtain particles after spraying (347.3 g). Then, the sprayed particles were dried and cured in a constant temperature forced convection oven at 60° C. for 14 hours. The particles, after drying and curing, were screened through a 355 μm sieve to obtain screened particles, particles coated with a water-insoluble polymer.

[0065]

Reference Example 2

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (12.01 g) was dissolved in purified water (320.1 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (90.15 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing Compound A.

[Preparation of Compound A Coated Particles]

Crystalline cellulose (particles) (CELPHERE CP203, manufactured by Asahi Kasei Corporation) (450.4 g) was placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing Compound A (380.0 g) was sprayed under pressure air supplied to the atomizer 0.3 MPa, air flow rate during spraying 60-70 nl / min, air inlet temperature 74-78 ° C, incoming air flow rate 0.6 m ³ /min, spray liquid supply rate 4-5 g/min and the particles were dried to obtain particles after drying (500.1 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 125 μm) (493.1 g).

[Production of a coating liquid containing a water-soluble polymer (1)]

HPMC (120.1 g) was dissolved in purified water (4000.0 g) and talc (60.05 g) was suspended to obtain a coating liquid containing a water-soluble polymer (1).

[Production of particles coated with water-soluble polymer (1)]

Particles coated with Compound A (355 µm - 125 µm) (480.1 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-soluble polymer (1) (4020.0 g) was sprayed at a pressure of air supplied to the atomizer 0.3 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 84 ° C, inlet air flow rate 0.7 m ³ /min, spray liquid supply rate 4-8 g / min and the particles were dried to obtain particles after drying (611.5 g). The total number of particles after drying was sieved to obtain particles coated with water-soluble polymer (1) (425 μm - 125 μm) (566.6 g).

[Production of a coating liquid containing a water-soluble polymer (2)]

HPMC (120.3 g) was dissolved in purified water (4000.0 g), and talc (60.13 g) was suspended to obtain a coating liquid containing a water-soluble polymer (2).

[Production of particles coated with water-soluble polymer (2)]

Particles coated with water-soluble polymer (1) (425 µm - 125 µm) (566.6 g) were placed in a fine particle coating granulator/Wurster and fluidized coating liquid containing water-soluble polymer (2) (4000.0 g) , sprayed at a pressure of air supplied to the atomizer of 0.3 MPa, an air flow rate during spraying of 60-75 nl / min, an air temperature at the inlet of 81 ° C, an inlet air flow rate of 0.7 m ³ /min, a spray liquid supply rate of 4 -7 g/min and the particles were dried to obtain particles after drying (722.8 g). The total number of particles after drying was sieved to obtain particles coated with water-soluble polymer (2) (500 μm - 150 μm) (714.2 g).

[Production of a coating liquid containing a water-soluble polymer (3)]

HPMC (120.3 g) was dissolved in purified water (4000.0 g) and talc (60.06 g) was suspended to obtain a coating liquid containing a water-soluble polymer (3).

[Production of particles coated with water-soluble polymer (3)]

The particles coated with water soluble polymer (2) (500 µm - 150 µm) (680.0 g) were placed in a fine particle coating granulator/Wurster and fluidized coating liquid containing water soluble polymer (3) (4000.0 g ), sprayed at a pressure of air supplied to the atomizer of 0.3 MPa, an air flow rate during spraying of 70-80 nl / min, an air inlet temperature of 81-84 ° C, an inlet air flow rate of 0.7 m ³ /min, a feed rate spray liquid 5-7 g/min and the particles were dried to obtain particles after drying (821.0 g). The total number of particles after drying was sieved to obtain particles coated with water-soluble polymer (3) (500 μm - 150 μm) (757.6 g).

[0066]

Reference Example 3

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (24.01 g) was dissolved in purified water (399.92 g) to obtain a solution of hydroxypropyl methylcellulose. Compound A (180.3 g) was then uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating liquid containing compound A.

[Production of a coating liquid containing a water-soluble polymer]

Hydroxypropyl methylcellulose 2910 (21.88 g) was dissolved in purified water (400.30 g) to obtain a solution of hydroxypropyl methylcellulose. Talc (11.21 g) was added and evenly dispersed to give a coating liquid containing a water soluble polymer.

[Production of Particles Coated with Water-Soluble Resin]

Lactose/crystalline cellulose spherical granules (300.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing Compound A (600.0 g) was sprayed at a spray air pressure of 0.5 MPa , air flow rate during spraying 60 nl/min, inlet air temperature 70°C, incoming air flow rate 0.5-0.6 m ³ /min, spray liquid supply rate 5-7 g/min. Then HPMC coating liquid (400.0 g) was sprayed at a pressure of air supplied to the sprayer of 0.5 MPa, an air flow rate during spraying of 60 Nl/min, an air inlet temperature of 85°C, an inlet air flow rate of 0.5-0 .6 m ³ /min, spray liquid feed rates of 3-4 g/min, and the particles were dried to obtain particles after drying (465.3 g). The total number of particles after drying was sieved to obtain particles coated with a water-soluble polymer (250 μm - 105 μm) (409.3 g).

[Production of a Coating Liquid Containing a Dissolution Control Substance]

In purified water (1750.4 g) were dissolved hydroxypropyl methylcellulose 2910 (30.3 g) and polysorbate 80 (manufactured by NOF CORPORATION) (0.1498 g), succinic acid (special grade Wako, manufactured by Wako Pure Chemical Industries, Ltd., hereinafter ditto) (119.58 g) to obtain a coating liquid containing a dissolution control agent.

[Production of Particles Coated with a Dissolution Controlling Substance]

Particles coated with water-soluble polymer (250 µm - 105 µm) (399.8 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a dissolution control agent (1870.0 g) was sprayed under pressure air supplied to the atomizer 0.5 MPa, air flow rate during spraying 60 nl / min, air inlet temperature 85 ° C, incoming air flow rate 0.5 m ³ /min, spray liquid supply rate 4-5 g / min and the particles were dried to obtain particles after drying (505.0 g). The total number of particles after drying was sieved to obtain particles coated with a dissolution control agent (250 μm - 105 μm) (497.5 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (9.01 g), talc (45.3 g) and iron oxide red (0.2935 g) were suspended and dissolved in purified water (546.0 g) and the mixture was added to a stirred aminoalkyl methacrylate copolymer RS (Eudragit RS30D, manufacturer Evonik) (300.3 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of particles coated with water-insoluble polymer]

Particles coated with a dissolution control agent (250 μm - 105 μm) (440.3 g) were placed in a fine particle coating granulator/Wurster and fluidized and a coating liquid containing a water-insoluble polymer (550.0 g) was sprayed at a pressure of air supplied to the atomizer 0.5 MPa, air flow rate during spraying 60 Nl / min, air inlet temperature 44 ° C, incoming air flow rate 0.4-0.5 m ³ /min, flow rate of the sprayed liquid 3 g/min to obtain particles after spraying (492.9 g). The total number of particles after spraying was sieved to obtain particles after spraying (355 μm - 105 μm). Then the particles after spraying (355 μm - 105 μm) were dried and cured in a constant temperature oven with forced convection at 60°C for 14 hours. The particles, after drying and curing, were sieved through a 300 μm sieve to obtain sieved particles, particles coated with a water-insoluble polymer.

[Obtaining Granules of the Outer Layer]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (31.56 g), citric anhydride (manufactured by ADM Far East) (41.97 g) was dissolved in purified water (316.9 g) to form a binder. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (371.4 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (59.83 g), low substituted hydroxypropyl cellulose (59.94 g) and crospovidone (Polyplasdone XL-10, manufactured by ISP) (29.66 g) was fed and fluidized in a fluid bed granulator (LAB-1, manufactured by POWREX, hereinafter the same) and a binder (210.0 g) was sprayed under the pressure applied to the sprayer air 0.1 MPa, spray air flow rate 60 Nl/min, inlet air temperature 85°C, inlet air flow rate 0.3 m ³ /min, spray liquid feed rate 10 g/min, and the granules were dried. The dried granules were sieved through an 850 µm sieve to obtain sifted granules, outer layer granules (533.0 g).

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (37.50 g) was dissolved in purified water (262.6 g) to obtain a coating liquid containing a coagulation inhibitory substance.

[Production of particles coated with a coagulation-inhibiting substance]

The particles coated with the water-insoluble polymer (250.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, and a coating liquid containing a coagulation-inhibiting substance (200.0 g) was atomized at an atomizer air pressure of 0. 5 MPa, spray air flow rate 60 Nl/min, inlet air temperature 53-60°C, inlet air flow rate 0.5 m ³ /min, spray liquid feed rate 2-4 g/min, and the particles were dried to obtain particles after drying (263.9 g). The total number of particles after spraying was sieved to obtain particles coated with a coagulation inhibitory substance with a size of 355 μm - 105 μm.

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Coagulation inhibitor coated particles (21543.6 mg), outer layer granules (33483.8 mg), aspartame (321 mg), l-menthol (200.6 mg), acesulfame potassium (80.3 mg), sodium stearyl fumarate (481.5 mg), strawberry flavor (STRAWBERRY DURAROME, manufactured by Nihon Firmenich K. K., hereinafter id.) (64.2 mg) and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (8025.0 mg) were mixed by shaking 100 times in a glass bottle to obtain a mixed product containing particles coated with a coagulation-inhibiting substance. The mixed product containing particles coated with a coagulation inhibitory substance (400 mg) was weighed and tabletted using a flat punch with a diameter of 10.0 mm and a single punch tablet machine at 6 kN to obtain an orally disintegrating tablet containing particles coated with a coagulation inhibitory substance (corresponding to 20 mg Compound A as free base per tablet).

[0067]

Compositions (calculated) of the preparations of Examples 1-14, Comparative Example 1 and Reference Examples 1-3 are shown in Tables 1-1 to 1-4.

Eudragit RS30D (trade name) is sold as a 30% aqueous dispersion. In the tables Eudragit RS30D shows solids content.

[0068]

Table 1-1 Example 1 Example 2 Example 3 Example 4 Example 5 particles containing compound A NONPAREIL 105T 47.2 48.9 48.9 48.9 48.9 compound A 26.7 26.7 26.7 26.7 26.7 HPMC TC-5E 3.56 3.56 3.56 3.56 3.56 coating layer containing organic acid fumaric acid 20.9 12.6 12.6 12.6 12.6 HPMC TC-5E 4.18 4.21 4.21 4.21 4.21 coating layer containing a water-insoluble polymer Eudragit RS30D 11.5 12 7.2 9.6 10.6 triacetin 1.15 1.2 0.72 0.96 1.06 talc 5.77 6 3.6 4.8 5.28 iron oxide red 0.0192 0.04 0.024 0.032 0.0352 outer layer granule component D-mannitol - 167 173 170 169 L-HPC LH-33 - 24.3 25.1 24.7 24.5 crospovidone XL-10 - 12.1 12.5 12.3 12.3 crystalline cellulose KG-802 - 24.3 25.1 24.7 24.5 Smart EX QD-100 73 - - - - mixed product component aspartame 2 2 2 2 2 l-menthol 0.5 1.25 1.25 1.25 1.25 acesulfame potassium 0.5 0.5 0.5 0.5 0.5 sodium stearyl fumarate 3 3 3 3 3 crystalline cellulose KG-802 fifty fifty fifty fifty fifty strawberry D - 0.4 0.4 0.4 0.4 total (mg/tablet) 250 400 400 400 400

[0069]

Table 1-2 Example 6 Example 7 Example 8 Example 9 particles containing compound A NONPAREIL 105T 48.9 48.9 77.6 - partially pregelatinized starch - - - 49.8 compound A 26.7 26.7 26.7 26.7 HPMC TC-5E 3.56 3.56 3.56 2.67 coating layer containing organic acid (1) fumaric acid 24.8 24.8 4.9 5.0 HPMC TC-5E 4.97 4.97 1.22 1.26 coating layer containing a dissolution control agent succinic acid 24.9 24.9 24.8 23.4 HPMC TC-5E 6.23 6.23 9.83 9.26 coating layer containing organic acid (2) fumaric acid - - 19.3 19.8 HPMC TC-5E - - 4.83 4.22 coating layer containing a water-insoluble polymer Eudragit RS30D 8.75 10.7 13.5 eighteen triacetin 0.88 - 1.35 1.8 talc 4.38 6.30 6.75 9 iron oxide red 0.0292 0.0504 0.135 0.18 Eudragit NE30D - 1.89 - - polysorbate 80 - 0.101 - - citric anhydride - 0.0189 - - outer layer granule component D-mannitol 138 136 182 118 L-HPC LH-33 20.1 19.7 26.4 17.1 crospovidone XL-10 10.1 9.9 13.2 8.57 crystalline cellulose KG-802 20.1 19.7 26.4 17.1 mixed product component aspartame 2 2 four four l-menthol 1.25 0.5 0.5 - acesulfame potassium 0.5 0.5 0.5 - sodium fumarate 3 3 3 four crystalline cellulose KG-802 fifty fifty fifty - partially pregelatinized starch - - - fifty monosodium fumarate - - - ten strawberry D 0.400 - - - total (mg/tablet) 400 400 500 400

[0070]

Table 1-3 Example 10 Example 11 Example 12 Example 13 Example 14 particles containing compound A NONPAREIL 105T 77 77 77 77 77 compound A 26.7 26.7 26.7 26.7 26.7 HPMC TC-5E 3.56 3.56 3.56 3.56 3.56 intermediate layer HPMC - - 2.31 2.31 3 talc - - 1.16 1.16 1.5 coating layer containing organic acid fumaric acid 74 99.5 25 fifty fifty HPMC TC-5E 14.8 19.91 4.63 9.26 - Eudragit EPO - - - - 3.96 coating layer containing a dissolution control agent succinic acid 46.3 25 25 25 25 HPMC TC-5E - - 8.33 8.33 - methylcellulose SM-4 15.4 8.33 - - - Eudragit EPO - - - - 1.64 coating layer containing a water-insoluble polymer Eudragit RS30D 14.7 14.7 13 13 13 triacetin 1.47 1.47 1.3 1.3 1.3 talc 7.36 7.37 6.5 6.5 6.5 iron oxide yellow 0.147 0.147 - - - coating layer containing a coagulation-inhibiting substance D-mannitol - - - 12 - outer layer granule component D-mannitol 148 156 171 158 158 citric anhydride 4.44 4.66 4.94 4.56 4.55 L-HPC LH-33 22.2 23.3 25.6 23.6 23.6 crospovidone XL-10 11.1 11.6 12.8 11.8 11.8 crystalline cellulose KG-802 22.2 23.3 25.9 23.9 23.8 β-cyclodextrin - - fifty 46.2 46.1 mixed product component aspartame 6 6 6 6 6 l-menthol flavor - - - 0.5 - sodium fumarate four four 9 9 9 crystalline cellulose KG-802 fifty - fifty fifty fifty crystalline cellulose KG-1000 - fifty - - - orange flavor 0.5 0.5 - - - total (mg/unit) 550 570 550 570 570

[0071]

Table 1-4 Comparative Example 1 Reference Example 1 Reference Example 2 Reference Example 3 particles containing compound A NONPAREIL 105T 47.2 77.0 - 44.8 CELPHERE CP203 - - 148 - compound A 26.7 26.7 26.7 26.7 HPMC TC-5E 3.56 3.56 3.56 3.56 coating layer containing a water-soluble polymer HPMC - - 146 3 talc - - 72.9 1.5 coating layer containing organic acid fumaric acid 20.9 - - - HPMC TC-5E 4.18 - - - coating layer containing a dissolution control agent succinic acid - - - 23.5 HPMC TC-5E - - - 5.88 polysorbate 80 - - - 0.0294 coating layer containing a water-insoluble polymer Eudragit RS30D - 15.0 - 13.6 triacetin - 1.50 - 1.36 talc - 7.49 - 6.82 iron oxide red - 0.150 - 0.0454 coating layer containing a coagulation-inhibiting substance D-mannitol - - - 13.1 outer layer granule component D-mannitol - - - 137 citric anhydride - - - 8.48 L-HPC LH-33 - - - 21.2 crospovidone XL-10 - - - 10.6 crystalline cellulose KG-802 - - - 21.2 SmartEX 91.5 - - - mixed product component aspartame 2.00 - - 2 l-menthol 0.500 - - 1.25 acesulfame potassium 0.500 - - 0.5 sodium fumarate 3.00 - - 3 crystalline cellulose KG-802 50.0 - - fifty strawberry D - - - 0.4 total (mg/unit) 250 131.4 397.3 400

[0072]

Example 15

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (77.08 g) was dissolved in purified water (1763.0 g) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (627.9 g) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (1463.0 g) were placed in a fine particle coating granulator/Wurster and fluidized (FD-MP-10, manufactured by POWREX, hereinafter id.) a coating liquid containing Compound A (2294.0 d), sprayed at a pressure of 0.21 MPa of air supplied to the atomizer, an air flow rate during spraying of 70 nl / min, an air inlet temperature of 67-70 ° C, an inlet air flow rate of 1.3 m ³ /min, a spray liquid 15 g/min and the particles were dried to obtain particles after drying (1939.6 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 105 μm) (1936.0 g).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (21.00 g) and succinic acid (350.0 g) were dissolved in purified water (3675.0 g) and anhydrous ethanol (1575.0 g). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (700.0 g) was uniformly dispersed to obtain an organic acid-containing coating liquid.

[Production of particles coated with organic acid]

Particles coated with Compound A (355 µm - 105 µm) (1391.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid (6104.0 g) was sprayed under the pressure of the supplied on the air atomizer 0.21 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 68-73 ° C, incoming air flow rate 1.3-1.4 m ³ /min, spray liquid supply rate 18- 19 g/min and the particles were dried to give particles after drying (2035.0 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (6.6 g), titanium oxide (6.6 g) and talc (33.0 g) were suspended in purified water (99.0 g) and anhydrous ethanol (891.0 g), followed by ammonioalkyl methacrylate copolymer (Eudragit RSPO , manufactured by Evonik) (52.8 g) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (13.20 g) were dissolved to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (Sylysia 320, manufactured by FUJI SILYSIA CHEMICAL LTD.) (9.0 g) was dispersed in purified water (171.0 g) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 µm - 105 µm) (1110.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer (661.3 g) was sprayed at pressure of air supplied to the atomizer 0.21 MPa, air flow rate during spraying 70 nl/min, air inlet temperature 27-28°C, incoming air flow rate 1.2-1.3 m ³ /min, spray liquid supply rate 4 g/min to obtain particles coated with a water-insoluble polymer. Then, a coating liquid containing a coagulation-inhibiting substance (79.2 g) was sprayed at a spray air supply pressure of 0.21 MPa, a spray air flow rate of 70 Nl/min, an inlet air temperature of 28-73°C, an inlet flow rate of air 1.3 m ³ /min, spray liquid feed rate 5 g/min, and the particles were dried to obtain particles after drying (1131.0 g). The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 μm - 105 μm) (1130.0 g).

[Obtaining Granules of the Outer Layer]

In purified water (600.0 g), D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (30.0 g), citric anhydride (30.0 g) and crospovidone (Kollidon CL-SF, manufactured by BASF) were dissolved and suspended ( 30.0 g) to obtain a spray liquid. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (84.0 g), D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (240.0 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) ( 48.0 g), low substituted hydroxypropyl cellulose (48.0 g) and crospovidone (Kollidon CL-F, manufactured by BASF) (24.0 g) were placed in a fluid bed granulator dryer and fluidized (LAB-1, manufactured by POWREX), spray liquid (230.0 g) was sprayed at a spray air supply pressure of 0.14 MPa, spray air flow rate of 60 Nl/min, inlet air temperature of 82-83°C, inlet air flow rate of 0, 2 m ³ /min, spray rate of 6 g/min and the granules were dried to give the outer layer granules (443.4 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (107.4 g), outer layer granules (142.2 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (14.4 g), crospovidone (Kollidon CL-F, manufactured by BASF) (14.4 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd., hereinafter the same) (0.78 g), acesulfame potassium (2.4 g), aspartame (2, 4 g), peppermint cortone (0.48 g) and sodium stearyl fumarate (2.88 g) were mixed in a 10 L plastic bag by manual mixing to obtain a blended product. The blended product was tabletted using a rotary type tablet machine with an average force of 7.5 kN to give an orally disintegrating tablet (weight 478.9 mg and diameter 10.5 mm) containing 20 mg Compound A in free form.

[0073]

Example 16

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (78.72 g) was dissolved in purified water (1800.0 g) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (641.3 g) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (1463.0 g) were placed in a fine particle coating granulator/Wurster and fluidized (FD-MP-10, manufactured by POWREX, hereinafter id.) a coating liquid containing Compound A (2394.0 d), sprayed at a pressure of 0.21 MPa of air supplied to the atomizer, an air flow rate during spraying of 70 nl / min, an air inlet temperature of 66-68 ° C, an inlet air flow rate of 1.3 m ³ /min, a spray liquid 15 g/min and the particles were dried to obtain particles after drying (1986.5 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 105 μm) (1985.5 g).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (24.60 g) and succinic acid (410.0 g) were dissolved in purified water (4305.0 g) and anhydrous ethanol (1845.0 g). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (820.0 g) was uniformly dispersed to obtain an organic acid-containing coating liquid.

[Production of particles coated with organic acid]

Particles coated with compound A (355 µm - 105 µm) (1605.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid (7043.0 g) was sprayed under the pressure of the supplied on the air atomizer 0.21 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 66-69 ° C, incoming air flow rate 1.3-1.4 m ³ /min, spray liquid supply rate 16- 18 g/min and the particles were dried to give particles after drying (2309.6 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (2803.6 g).

[Production of a coating liquid containing a water-insoluble polymer]

In purified water (129.6 g) and anhydrous ethanol (1166 g), triacetin (8.64 g), titanium oxide (8.96 g) and talc (43.2 g) were suspended, then ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (60.48 g) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (25.92 g) to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (Sylysia 320, manufactured by FUJI SILYSIA CHEMICAL LTD.) (6.0 g) was dispersed in purified water (114.0 g) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 µm - 105 µm) (1682.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer (902.0 g) was sprayed at air supply pressure 0.21 MPa, air flow rate during spraying 70 nl/min, air inlet temperature 28-29°C, incoming air flow rate 1.3 m ³ /min, spray liquid supply rate 4 g/min to obtain particles coated with a water-insoluble polymer. Then, a coating liquid containing a coagulation-inhibiting substance (120.0 g) was sprayed at a spray air supply pressure of 0.21 MPa, a spray air flow rate of 70 Nl/min, an inlet air temperature of 28-73°C, an inlet flow rate of air 1.3 m ³ /min, the flow rate of the spray liquid 5 g/min, and the particles were dried to obtain particles after drying (1745.0 g). The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 µm - 105 µm) (1743.0 g).

[Obtaining sieved outer layer granules]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (200.0 g), citric anhydride (200.0 g) and crospovidone (Kollidon CL-SF, manufactured by BASF) were dissolved and suspended in purified water (4000.0 g) ( 200.0 g) to obtain a spray liquid. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (529.1 g), D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (2035.0 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) ( 370.0 g), low substituted hydroxypropyl cellulose (370.0 g) and crospovidone (Kollidon CL-F, manufactured by BASF) (185.0 g) were placed in a fluid bed granulator dryer and fluidized (FD-5S, manufactured by POWREX), spray liquid (2128.0 g) was sprayed at a pressure of air supplied to the sprayer of 0.24 MPa, an air flow rate during spraying of 2600 nl / h, an air inlet temperature of 70-72 ° C, an inlet air flow rate of 1, 3 m ³ /min, spray rate of 45 g/min and the granules were dried to give an outer layer granule (3741.3 g). The outer layer granules (3665.0 g) were placed in a mechanical mill and sieved with a sieve size of 1.5 mm to obtain sieved outer layer granules (3644.6 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (1629.0 g, outer layer sieved granules (1424.0 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (176.0 g), crospovidone (Kollidon CL-F, manufactured by BASF) (176.0 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (9.6 g), acesulfame potassium (32.0 g), aspartame (32.0 g), peppermint cortone (6.4 g) and sodium stearyl fumarate (35.2 g) were placed in a tumbler-type mixer, mixed at 30 rpm for 5 minutes to obtain a blended product (3509.5 g). using a rotary type tablet machine at an average force of 7.8 kN to obtain an orally disintegrating tablet (weight 440 mg and diameter 10 mm) containing 20 mg of Compound A in free form.

[0074]

Example 17

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (105.0 g) was dissolved in purified water (2400.0 g) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (855.0 g) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (1848.0 g) were placed in a fine particle coating granulator/Wurster and fluidized (FD-MP-10, manufactured by POWREX, hereinafter the same) a coating liquid containing Compound A (3024.0 d), sprayed at a pressure of 0.21 MPa of air supplied to the atomizer, an air flow rate during spraying of 70 nl / min, an air inlet temperature of 65-67 ° C, an inlet air flow rate of 1.3 m ³ /min, a spray liquid 11-14 g/min, and the particles were dried to obtain particles after drying (2539.8 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 105 μm) (2512.1 g).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (18.00 g) and succinic acid (300.0 g) were dissolved in purified water (2100.0 g) and anhydrous ethanol (900.0 g). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (300.0 g) was uniformly dispersed to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Particles coated with Compound A (355 µm - 105 µm) (1124.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid (3292.0 g) was sprayed under the pressure of the supplied to the air atomizer 0.21 MPa, air flow rate during spraying 70 nl / min, air inlet temperature 66-68 ° C, incoming air flow rate 1.3 m ³ /min, spray liquid supply rate 16-17 g / min and the particles were dried to obtain particles after drying (1591.0 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (1574.0 g).

[Production of a coating liquid containing a water-insoluble polymer]

In purified water (86.4 g) and anhydrous ethanol (777.6 g), triacetin (5.76 g), titanium oxide (6.72 g), iron oxide yellow (0.72 g) and talc (28. 8 g), then ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (34.56 g) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (23.04 g) were dissolved to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (Sylysia 320, manufactured by FUJI SILYSIA CHEMICAL LTD.) (4.5 g) was dispersed in purified water (85.5 g) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 µm - 105 µm) (1112.0 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer (602.3 g) was sprayed at air supply pressure 0.20 MPa, air flow rate during spraying 70 nl/min, air inlet temperature 27-29°C, incoming air flow rate 1.3 m ³ /min, spray liquid supply rate 4 g/min to obtain particles coated with a water-insoluble polymer. Then, a coating liquid containing a coagulation-inhibiting substance (90.0 g) was sprayed at a spray air supply pressure of 0.20 MPa, a spray air flow rate of 70 Nl/min, an inlet air temperature of 28-73°C, an inlet flow rate of air 1.3 m ³ /min, spray liquid feed rate 5-6 g/min, and the particles were dried to obtain particles after drying (1149.0 g). The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 μm - 105 μm) (1143.0 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (94.8 g), sieved outer layer granules (106.3 g) obtained in Example 16, crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (11.4 g), crospovidone (Kollidon CL-F, manufactured by BASF) (6.84 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (1.14 g), acesulfame potassium (2.4 g), aspartame ( 2.4 g), peppermint cortone (0.48 g) and sodium stearyl fumarate (2.28 g) were placed in a 10 L plastic bag and mixed 200 times by manual agitation to obtain a blended product. The blended product was tabletted using a rotary type tablet machine with an average force of 7 kN to obtain an orally disintegrating tablet (weight 380 mg and diameter 9.5 mm) containing 20 mg Compound A in free form.

[0075]

Example 18

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (19.07 g) was dissolved in purified water (467.2 g) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (171.0 g) was then evenly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (385.0 g) were placed in a fine particle coating granulator/Wurster and fluidized (FD-MP-01, manufactured by POWREX, hereinafter the same) a coating liquid containing Compound A (590.6 d), sprayed at a pressure of 0.3 MPa air supplied to the atomizer, an air flow rate during spraying of 70 nl/min, an air inlet temperature of 77°C, an inlet air flow rate of 0.5-0.6 m ³ /min, speeds spray liquid feed rate of 4-5 g/min and the particles were dried to obtain particles after drying (509.3 g). The total number of particles after drying was sieved to obtain particles coated with compound A (355 μm - 105 μm) (490.7 g).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (6.0 g) and succinic acid (100.0 g) were dissolved in purified water (840.0 g) and anhydrous ethanol (1260.0 g). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (300.0 g) was uniformly dispersed to obtain a coating liquid containing an organic acid.

[Production of particles coated with organic acid]

Particles coated with Compound A (355 µm - 105 µm) (384.1 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid (2165.0 g) was sprayed under the pressure of the applied to the air atomizer 0.3 MPa, air flow rate during spraying 60 nl / min, air inlet temperature 77 ° C, incoming air flow rate 0.5-0.6 m ³ /min, spray liquid supply rate 5-7 g /min and the particles were dried to obtain particles after drying (608.0 g). The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 105 μm) (604.0 g).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (3.6 g), titanium oxide (1.2 g) and talc (18.0 g) were suspended in purified water (294.0 g), followed by RS aminoalkyl methacrylate copolymer (Eudragit RS30D, manufactured by Evonik) (120.0 d) suspended to form a coating liquid containing a water-insoluble polymer.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 µm - 105 µm) (300.6 g) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer (116.5 g) was sprayed at pressure of air supplied to the atomizer 0.3 MPa, air flow rate during spraying 50 nl/min, air inlet temperature 39°C, inlet air flow rate 0.5 m ³ /min, spray liquid supply rate 2 g/min to obtain particles coated with a water-insoluble polymer (299.2 g). Light anhydrous silicic acid (Sylysia 320, manufactured by FUJI SILYSIA CHEMICAL LTD.) (0.89 g) was added to the total number of particles, mixed in a 10 L plastic bag by manual stirring, and cured on a drying rack at 60°C for 13 hours . The total number of particles was sieved to obtain particles coated with a coagulation inhibitory substance (355 µm - 105 µm) (298.9 g).

[Obtaining Granules of the Outer Layer]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (80.0 g) and citric anhydride (48.0 g) were dissolved in purified water (800.0 g) to obtain a spray liquid. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (357.2 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (50.0 g), low-substituted hydroxypropyl cellulose (50.0 g), and crospovidone (Polyplasdone XL-10, manufactured by ISP) (25.0 g) was placed in a fluidized bed granulator dryer and fluidized (LAB-1, manufactured by POWREX), the nebulization liquid (232.0 g) was nebulized under the pressure applied to the nebulizer air flow rate 0.13 MPa, spraying air flow rate 60 Nl/min, inlet air temperature 85°C, incoming air flow rate 0.2-0.3 m ³ /min, spray liquid flow rate 6 g/min and granules dried to give an outer layer granule (472.2 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (138.8 g), outer layer granules (180.0 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (37.1 g), acesulfame potassium (3.5 g ), aspartame (3.5 g), peppermint cortone (0.7 g) and sodium stearyl fumarate (3.5 g) were mixed 200 times in a 10 L plastic bag by manual mixing to obtain a blended product. The blended product was tabletted using a rotary type tablet machine with an average force of 7 kN to give an orally disintegrating tablet (weight 524.4 mg and diameter 10.5 mm) containing 20 mg Compound A in free form.

[0076]

Example 19

[Obtaining Granules of the Outer Layer]

In purified water (600.0 g), D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (30.0 g), citric anhydride (30.0 g) and crospovidone (Kollidon CL-SF, manufactured by BASF) were dissolved and suspended ( 30.0 g) to obtain a spray liquid. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (66.24 g), D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (264.0 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) ( 48.0 g), low substituted hydroxypropyl cellulose (48.0 g) and crospovidone (Kollidon CL-F, manufactured by BASF) (24.0 g) were placed in a fluid bed granulator dryer and fluidized (LAB-1, manufactured by POWREX), spray liquid (276.0 g) was sprayed at a spray air supply pressure of 0.14 MPa, spray air flow rate of 60 Nl/min, inlet air temperature of 83-85°C, inlet air flow rate of 0, 2 m ³ /min, spraying rate 6 g/min and the granules were dried to give the outer layer granules (444.7 g).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (107.4 g) obtained in Example 15, outer layer granules (121.6 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (13.2 g), crospovidone ( Polyplasdone XL-10, manufactured by ISP) (13.2 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.72 g), acesulfame potassium (2.4 g), aspartame (2 .4 g), peppermint cortone (0.48 g) and sodium stearyl fumarate (2.64 g) were mixed in a 10 L plastic bag by manual mixing to obtain a blended product. The blended product was tabletted using a rotary type tablet machine at an average force of 6.7 kN to give an orally disintegrating tablet (weight 440 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0077]

Example 20

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

The mixed product obtained in Example 19 was tabletted using a rotary type tablet machine with an average force of 4.0 kN to obtain an orally disintegrating tablet (weight 220 mg and diameter 8.0 mm) containing 10 mg of Compound A in free form.

[0078]

Compositions (calculated) of the preparations of Examples 15-20 are shown in Table 1-5.

Eudragit RS30D (trade name) is sold as a 30% aqueous dispersion. In the Table Eudragit RS30D shows the solids content.

[0079]

Table 1-5 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 particles containing compound A NONPAREIL 105T 77 77 77 77 77 38.5 compound A 26.72 26.72 26.72 26.72 26.72 13.36 HPMC TC-5E 3.28 3.28 3.28 2.98 3.28 1.64 coating layer containing organic acid monosodium fumarate 40 40 twenty 60 40 twenty succinic acid twenty twenty twenty twenty twenty ten Eudragit RLPO 1.2 1.2 1.2 1.2 1.2 0.6 coating layer containing a water-insoluble polymer Eudragit RS30D - - - 6 - - Eudragit RSPO 4.8 3.78 2.88 - 4.8 2.4 Eudragit RLPO 1.2 1.62 1.92 - 1.2 0.6 triacetin 0.6 0.54 0.48 0.6 0.6 0.3 talc 3 2.7 2.4 3 3 1.5 titanium oxide 0.6 0.56 0.56 0.2 0.6 0.3 iron oxide yellow - - 0.06 - - - coating layer containing a coagulation-inhibiting substance Sylysia 320 0.6 0.6 0.6 0.6 0.6 0.3 outer layer granule component D-mannitol 167 143.6 143.6 188.6 142.6 71.3 citric anhydride 5 5 5 6 5 2.5 crystalline cellulose KG-802 24 twenty twenty 25 twenty ten crospovidone 17 fifteen fifteen 12.5 twenty ten L-HPC LH-33 24 ten ten 25 fifteen 7.5 mixed product component crystalline cellulose KG-802 24 22 19 53 22 eleven crospovidone 24 22 11.4 - 22 eleven Neusilin FL2 1.3 1.2 1.9 - 1.2 0.6 acesulfame potassium four four four 5 four 2 aspartame four four four 5 four 2 peppermint cortone 0.8 0.8 0.8 one 0.8 0.4 sodium stearyl fumarate 4.4 4.4 3.8 5 4.4 2.2 total (mg/tablet) 478.9 440 380 524.4 440 220

[0080]

Example 21

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (1.153 kg) was dissolved in purified water (27.056 kg) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (9.639 kg) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (25.025 kg) were placed in a fine particle coating granulator/Wurster and fluidized (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same), the coating liquid containing Compound A was sprayed at an air flow rate when spraying 400-500 nl/min, inlet air temperature 71°C, inlet air flow rate 13-14 m ³ /min, spray liquid feed rate 100-135 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with compound A (300 μm - 132 μm).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.484 kg) and succinic acid (8.060 kg) were dissolved in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (16.120 kg) was uniformly dispersed to obtain an organic acid-containing coating liquid.

[Production of particles coated with organic acid]

Particles coated with compound A (300 µm - 132 µm) (33.170 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid was sprayed at an air flow rate of spraying 550-700 nl/ min, inlet air temperature 71-73° C., inlet air flow rate 14-17 m ³ /min, spray liquid feed rate 160-240 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 132 μm).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (0.222 kg), titanium oxide (0.230 kg) and talc (1.110 kg) were suspended in purified water (3.329 kg) and anhydrous ethanol (29.962 kg), followed by ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.776 kg) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.444 kg) was dissolved to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (0.164 kg) was dispersed in purified water (3.124 kg) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 µm - 132 µm) (46.087 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer was sprayed at an air flow rate of spraying 400-500 Nl/min, inlet air temperature 31-32°C, incoming air flow rate 17 m ³ /min, spray liquid feed rate 80-100 g/min to obtain particles coated with a water-insoluble polymer. Then, the coating liquid containing the coagulation-inhibiting substance was sprayed at a spraying air flow rate of 500 Nl/min, an inlet air temperature of 32-68°C, an inlet air flow rate of 17 m ³ /min, a spray liquid feed rate of 112 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 μm - 132 μm).

[Obtaining Granules of the Outer Layer]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (2.160 kg), citric anhydride (0.810 kg) and crospovidone (Kollidon CL-SF, manufactured by BASF) (1.350 kg) were dissolved and suspended in purified water (27,000 kg) to obtain a liquid for spraying. D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (37.395 kg), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (5.400 kg), low substituted hydroxypropyl cellulose (L-HPC LH-33, manufactured by Shin- Etsu Chemical Co., Ltd.) (5.400 kg) and crospovidone (Kollidon CL-F, manufactured by BASF) (2.700 kg) were placed in a fluid bed granulator dryer and fluidized (FD-WSG-60TW, manufactured by POWREX), liquid for spraying was sprayed at a spraying air flow rate of 750-850 nl/min, inlet air temperature of 73-77°C, inlet air flow rate of 17-19 m ³ /min, spray liquid feed rate of 350-400 g/min, and the granules were dried to obtain an outer layer granule.

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (146.1 g), outer layer granules (163.6 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (17.60 g), crospovidone (Kollidon CL-F, manufactured by BASF) (14.08 g), magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (1.760 g), acesulfame potassium (2.4 g), aspartame (2.4 g), strawberry flavor (0.56 g) and sodium stearyl fumarate (3.52 g) were placed in a 10 L plastic bag and mixed 200 times by manual mixing to obtain a blended product. The mixed product was tabletted using a rotary type tablet machine with an average force of 10 kN to obtain an orally disintegrating tablet (weight 440 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0081]

Example 22

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (146.1 g) obtained in Example 21, outer layer granules (163.6 g) obtained in Example 21, crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (17.60 d), crospovidone (Kollidon CL-F, manufactured by BASF) (14.08 g), magnesium aluminometasilicate (Neusilin UFL2, manufactured by Fuji Chemical Industries Co., Ltd.) (1.760 g), acesulfame potassium (2.4 g), aspartame (2.4 g), strawberry flavor (0.56 g) and sodium stearyl fumarate (3.52 g) were placed in a 10 L plastic bag and mixed 200 times by manual agitation to obtain a blended product. The mixed product was tabletted using a rotary type tablet machine with an average force of 10 kN to obtain an orally disintegrating tablet (weight 440 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0082]

Example 23

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (1.130 kg) was dissolved in purified water (25.840 kg) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (9.639 kg) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (25.025 kg) were placed in a fine particle coating granulator/Wurster and fluidized (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same), the coating liquid containing Compound A was sprayed at an air flow rate when spraying 400-500 nl/min, inlet air temperature 71°C, inlet air flow rate 13-14 m ³ /min, spray liquid feed rate 100-135 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with compound A (300 μm - 132 μm).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.484 kg) and succinic acid (8.060 kg) were dissolved in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (16.120 kg) was uniformly dispersed to obtain an organic acid-containing coating liquid.

[Production of particles coated with organic acid]

Particles coated with compound A (300 μm - 132 μm) (33.170 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid was sprayed at a spray air flow rate of 550-700 nl/ min, inlet air temperature 71-73° C., inlet air flow rate 14-17 m ³ /min, spray liquid feed rate 160-240 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 132 μm).

[Production of a coating liquid containing a water-insoluble polymer]

In purified water (2.312 kg) and anhydrous ethanol (20.806 kg), triacetin (0.154 kg), titanium oxide (0.160 kg) and talc (0.771 kg) were suspended, then ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.541 kg) was dissolved with obtaining a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (0.086 kg) was dispersed in purified water (1.627 kg) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 μm - 132 μm) (24.002 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer was sprayed at a spray air flow rate of 300 nl/ min, inlet air temperature 32° C., inlet air flow rate 14 m ³ /min, spray liquid feed rate 75 g/min to obtain particles coated with a water-insoluble polymer. Then, the coating liquid containing the coagulation-inhibiting substance was sprayed at a spraying air flow rate of 400 NL/min, an inlet air temperature of 32-71°C, an inlet air flow rate of 14 m ³ /min, a spray liquid flow rate of 85 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 µm - 132 µm).

[Obtaining Granules of the Outer Layer]

D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (1.375 kg), citric anhydride (1.375 kg) and crospovidone (Kollidon CL-SF, manufactured by BASF) (1.375 kg) were dissolved and suspended in purified water (27.500 kg) to obtain a liquid for spraying. D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (7.865 kg), D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (30.250 kg), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (5.500 kg), low substituted hydroxypropyl cellulose (L-HPC LH-33, manufactured by Shin-Etsu Chemical Co., Ltd.) (5.500 kg) and crospovidone (Kollidon CL-F, manufactured by BASF) (2.750 kg) were placed in a fluidized granulator dryer. layered and fluidized (FD-WSG-60TW, manufactured by POWREX), the spray liquid was sprayed at a spray air flow rate of 750-850 Nl/min, inlet air temperature of 70°C, inlet air flow rate of 18-20 m ³ /min , spray liquid feed rates of 350-400 g/min, and the granules were dried to obtain an outer layer granule.

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (28.50 g), outer layer granules (28.50 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (3.08 g), crospovidone CL-F (Kollidon CL -F, manufactured by BASF) (3.08 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.308 g), acesulfame potassium (0.56 g), aspartame (0.56 g) , peppermint flavor (0.112 g) and sodium stearyl fumarate (0.616 g) were placed in a glass bottle and mixed 100 times by manual agitation to obtain a blended product. The blended product was tabletted using a single punch tablet machine to give an orally disintegrating tablet (weight 450 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0083]

Example 24

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (0.154 kg), titanium oxide (0.160 kg) and talc (0.771 kg) were suspended in purified water (2.312 kg) and anhydrous ethanol (20.806 kg), followed by ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.233 kg) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.308 kg) was dissolved to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (0.086 kg) was dispersed in purified water (1.627 kg) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Organic acid coated particles (355 µm - 132 µm) (24.002 kg) obtained in Example 23 were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer was sprayed at an air flow rate when spraying 400 nl/min, inlet air temperature 30°C, inlet air flow rate 14 m ³ /min, spray liquid feed rate 75 g/min to obtain particles coated with a water-insoluble polymer. Then, the coating liquid containing the coagulation-inhibiting substance was sprayed at a spraying air flow rate of 500 NL/min, an inlet air temperature of 30-71°C, an inlet air flow rate of 14 m ³ /min, a spray liquid feed rate of 85 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 μm - 132 μm).

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (28.50 g), outer layer granules (28.50 g) obtained in Example 23, crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (3.08 g), crospovidone ( Kollidone CL-F, manufactured by BASF) (3.08 g), magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.308 g), acesulfame potassium (0.56 g), aspartame (0.56 d), peppermint flavor (0.112 g) and sodium stearyl fumarate (0.616 g) were placed in a glass bottle and mixed 100 times by manual agitation to obtain a blended product. The blended product was tabletted using a single punch tablet machine to give an orally disintegrating tablet (weight 450 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0084]

Example 25

[Preparation of a Coating Liquid Containing Compound A]

Hydroxypropyl methylcellulose 2910 (1.100 kg) was dissolved in purified water (25.840 kg) to obtain a solution of hydroxypropyl methylcellulose 2910. Compound A (9.205 kg) was then uniformly dispersed in a solution of hydroxypropyl methylcellulose 2910 to obtain a coating liquid containing compound A.

[Preparation of Compound A Coated Particles]

Lactose/crystalline cellulose spherical granules (25.025 kg) were placed in a fine particle coating granulator/Wurster and fluidized (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same), the coating liquid containing Compound A was sprayed at an air flow rate when spraying 400-500 nl/min, inlet air temperature 71°C, inlet air flow rate 13-14 m ³ /min, spray liquid feed rate 100-135 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with compound A (300 μm - 132 μm).

[Production of a Coating Liquid Containing an Organic Acid]

Ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.484 kg) and succinic acid (8.060 kg) were dissolved in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, jet-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (16.120 kg) was uniformly dispersed to obtain an organic acid-containing coating liquid.

[Production of particles coated with organic acid]

Particles coated with compound A (300 µm - 132 µm) (33.170 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing an organic acid was sprayed at an air flow rate of spraying 550-700 nl/ min, inlet air temperature 71-73° C., inlet air flow rate 14-17 m ³ /min, spray liquid feed rate 160-240 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with organic acid (355 μm - 132 μm).

[Production of a coating liquid containing a water-insoluble polymer]

Triacetin (0.259 kg), titanium oxide (0.269 kg) and talc (1.295 kg) were suspended in purified water (3.884 kg) and anhydrous ethanol (34.956 kg), followed by ammonioalkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (2.071 kg) and ammonioalkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.518 kg) was dissolved to obtain a coating liquid containing a water-insoluble polymer.

[Production of a Coating Liquid Containing a Coagulation Inhibiting Substance]

Light anhydrous silicic acid (0.164 kg) was dispersed in purified water (3.124 kg) to obtain a coating liquid containing a coagulation-inhibiting substance.

[Production of particles coated with a coagulation-inhibiting substance]

Particles coated with organic acid (355 μm - 132 μm) (46.087 kg) were placed in a fine particle coating granulator/Wurster and fluidized, a coating liquid containing a water-insoluble polymer was sprayed at an air flow rate of spraying 400-500 Nl/min, inlet air temperature 31°C, incoming air flow rate 17 m ³ /min, spray liquid feed rate 80-100 g/min to obtain particles coated with a water-insoluble polymer. Then, the coating liquid containing the coagulation-inhibiting substance was sprayed at a spraying air flow rate of 500 NL/min, an inlet air temperature of 31-68°C, an inlet air flow rate of 17 m ³ /min, a spray liquid feed rate of 130 g/min, and the particles were dried to obtain particles after drying. The total number of particles after drying was sieved to obtain particles coated with a coagulation inhibitory substance (355 µm - 132 µm).

[Obtaining Granules of the Outer Layer]

In purified water (27,000 kg) were dissolved and suspended D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE Japan) (1.350 kg), citric anhydride (1.350 kg) and crospovidone CL-SF (Kollidon CL-SF, manufactured by BASF) (1.350 kg) to obtain liquid for spraying. D-mannitol (PEARLITOL 100SD, manufactured by ROQUETTE Japan) (35.910 kg), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (5.400 kg), low substituted hydroxypropyl cellulose (L-HPC LH-33, manufactured by Shin- Etsu Chemical Co., Ltd.) (5.400 kg) and crospovidone (Kollidon CL-F, manufactured by BASF) (2.700 kg) were placed in a fluid bed granulator dryer and fluidized (FD-WSG-60TW, manufactured by POWREX), liquid for spraying was sprayed at a spraying air flow rate of 750-850 nl/min, inlet air temperature of 73-78°C, inlet air flow rate of 17-19 m ³ /min, spray liquid feed rate of 350-400 g/min, and the granules were dried to obtain an outer layer granule.

[Production of an orally disintegrating tablet containing particles coated with a coagulation-inhibiting substance]

Particles coated with a coagulation-inhibiting substance (13.70 g), outer layer granules (14.85 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (1.65 g), crospovidone (Kollidon CL-F, manufactured by BASF) (1.65 g), magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.165 g), acesulfame potassium (0.3 g), aspartame (0.3 g), strawberry flavor (0.06 g) and sodium stearyl fumarate (0.33 g) were placed in a glass bottle and mixed 100 times by manual stirring to obtain a blended product. The blended product was tabletted using a single punch tablet machine to give an orally disintegrating tablet (weight 440 mg and diameter 10.0 mm) containing 20 mg Compound A in free form.

[0085]

Example 26

The blended product obtained in Example 25 was tabletted using a single punch tablet machine to give an orally disintegrating tablet (weight 220 mg and diameter 8.0 mm) containing 10 mg Compound A in free form.

[0086]

Compositions (calculated) of the preparations of Examples 21-26 are shown in Table 1-6.

[0087]

Table 1-6 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 particles containing compound A NONPAREIL 105T 77 77 77 77 77 38.5 compound A 26.72 26.72 26.72 26.72 26.72 13.36 HPMC TC-5E 3.28 3.28 3.28 3.28 3.28 1.64 coating layer containing organic acid
(intermediate layer) monosodium fumarate 40 40 40 40 40 twenty succinic acid twenty twenty twenty twenty twenty ten Eudragit RLPO 1.2 1.2 1.2 1.2 1.2 0.6 coating layer containing a water-insoluble polymer Eudragit RSPO 6.48 6.48 10.8 8.64 6.48 3.24 Eudragit RLPO 1.62 1.62 - 2.16 1.62 0.81 triacetin 0.81 0.81 1.08 1.08 0.81 0.405 talc 4.05 4.05 5.4 5.4 4.05 2.025 titanium oxide 0.84 0.84 1.12 1.12 0.84 0.42 coating layer containing a coagulation-inhibiting substance light anhydrous silicic acid 0.6 0.6 0.6 0.6 0.6 0.3 outer layer granule component D-mannitol 146.5 146.5 143.6 143.6 138 69 citric anhydride 3 3 5 5 5 2.5 crystalline cellulose KG-802 twenty twenty twenty twenty twenty ten crospovidone fifteen fifteen fifteen fifteen fifteen 7.5 L-HPC LH-33 twenty twenty twenty twenty twenty ten mixed product component crystalline cellulose KG-802 22 22 22 22 22 eleven crospovidone 17.6 17.6 22 22 22 eleven Neusilin 2.2 2.2 2.2 2.2 2.2 1.1 acesulfame potassium 3 3 four four four 2 aspartame 3 3 four four four 2 flavoring 0.7 0.7 0.8 0.8 0.8 0.4 sodium stearyl fumarate 4.4 4.4 4.4 4.4 4.4 2.2 total (mg/tablet) 440 440 450.2 450.2 440 220

[0088]

Experimental Example 1 (drug dissolution test)

The dissolution test was carried out in accordance with Japanese Pharmacopoeia General Test Method 6.10, Dissolution Test Method, using a paddle stirrer (50 rpm) or in accordance with Japanese Pharmacopoeia General Test Method 6.10, Dissolution Test Method, using a "rotary basket "(100 rpm). In other words, the dissolution test solution (900 ml) heated to 37° C. was added to disperse the preparation. Sampling was carried out at every predetermined time while rotating the paddle or basket at a predetermined rotation speed, and the amount of dissolved target compound in the filtrate obtained using the membrane filter was determined by HPLC.

The results are shown in FIG. 1 - Fig. ten.

All preparations showed a delay time of at least 2 minutes and showed that they can significantly reduce the bitter taste of Compound A.

[0089]

Experimental Example 2 (dissolved amount of compound A in saturated organic acid)

Citric acid, succinic acid, fumaric acid or malic acid was dissolved and saturated in the second Japanese Pharmacopoeia (JP2) dissolution test liquid and filtered. Then compound A (0.4 g) was added to the filtrate (10 ml) saturated with organic acid, and the mixture was shaken at room temperature for 1 hour. The shaking solution was filtered, diluted 50-fold with the second Japanese Pharmacopoeia dissolution test liquid, and the diluted solution was diluted 20-fold with the second Japanese Pharmacopoeia dissolution test liquid. The solution obtained by diluting twice was subjected to HPLC measurement, and the amount of dissolved compound A was measured.

The results are shown in Table 2. Compound A in the form of fumarate showed a low concentration only when a high concentration of fumaric acid was present. It was also shown that succinic acid has practically no effect on the amount of compound A dissolved.

[0090]

table 2 Saturated organic acid No succinic acid fumaric acid lemon acid Apple acid concentration (µg⋅ml) 5.22 5.76 0.67 26.30 26.64

[0091]

Experimental Example 3 (Influence of the concentration of an organic acid, such as an organic acid that forms a salt with a pharmaceutically active ingredient, or a salt thereof, on the dissolving amount of a pharmaceutically active ingredient that forms a salt with an organic acid (confirmation of the common ion effect))

Received solutions containing various concentrations of fumaric acid or monosodium fumarate, dissolved in the second liquid for testing the dissolution of the Japanese Pharmacopoeia. Then, 50 mg of Compound A was measured and loaded into a 10 ml plastic tube, and each of the above solutions (5 ml) was added and the mixture was vigorously shaken at room temperature for 1 hour. The suspension, after shaking, was filtered, diluted 100-fold and measured by HPLC. The amount of dissolved Compound A was measured. The results are shown in FIG. 11. It was shown that the amount of dissolved compound A in the form of fumarate depends on the concentration of fumaric acid or monosodium fumarate in the solvent.

[0092]

Experimental Example 4 (Measurement of the dissolution profile of compound A, fumaric acid, succinic acid)

The particle coated with the water-insoluble polymer of Example 1 or the particle coated with the coagulation-inhibiting substance of Reference Example 3, each containing 60 mg of Compound A, was subjected to a dissolution test using a rotating basket at 100 rpm, and in the same manner, as in Experimental Example 1. The amount of dissolved fumaric acid or succinic acid as well as compound A was also measured. As for fumaric acid and succinic acid, the residual content of each organic acid in the particles was inversely proportional to the dissolution rate, and the value of the maximum dissolved amount was normalized, based on a residual content of 0%.

The results are shown in FIG. 12 - Fig. 13. It was observed that the dissolution of compound A started after the dissolution of fumaric acid or succinic acid from the granules.

[0093]

Experimental Example 5 (confirmation of dissolution control mechanism - 1)

Particle 3 coated with a water-soluble polymer obtained in Reference Example 2 and containing 60 mg of Compound A was subjected to a dissolution test using a paddle at 100 rpm and in the same manner as in Experimental Example 1. The dissolution medium was the second liquid from Japanese Pharmacopeia dissolution test, Japanese Pharmacopoeia second dissolution test liquid with 10% (w/w) sodium carbonate, Japanese Pharmacopeia second dissolution test liquid with 13% (w/w) succinic acid, or Japanese Pharmacopoeia second dissolution test liquid pharmacopoeias with the addition of 0.6% (w/w) fumaric acid.

The results are shown in FIG. 14. Sodium carbonate, which has a salting-out effect on water-soluble polymers, inhibited the dissolution of compound A, while fumaric acid and succinic acid did not show a dissolution inhibitory effect. Based on the results, it was shown that fumaric acid and succinic acid had no salting out effect on the water-soluble polymer.

[0094]

Experimental Example 6 (confirmation of dissolution control mechanism - 2)

The water-insoluble polymer coated particle obtained in Reference Example 1 and containing 60 mg of Compound A was subjected to a dissolution test using a paddle at 100 rpm and in the same manner as in Experimental Example 1. The dissolution medium was the second liquid from the Japanese Pharmacopoeia dissolution test, the second liquid of the Japanese Pharmacopeia dissolution test with the addition of 13% (w/w) succinic acid, the second liquid of the Japanese Pharmacopoeia dissolution test with the addition of 0.6% (w/w) monosodium fumarate, or the second test liquid on the solubility of the Japanese Pharmacopoeia with the addition of 0.6% (w/w) fumaric acid.

The compound A-coated particle obtained in Reference Example 1 and containing 60 mg of compound A was subjected to a dissolution test using a paddle at 100 rpm and in the same manner as in Experimental Example 1. The dissolution medium was the second liquid from the test on solubility of the Japanese Pharmacopoeia, the second liquid of the dissolution test of the Japanese Pharmacopoeia with the addition of 0.6% (w/w) monosodium fumarate, or the second liquid of the dissolution test of the Japanese Pharmacopoeia with the addition of 0.6% (w/w) of fumaric acid.

The results are shown in FIG. 15 - Fig. 16. The dissolution of the particles coated with the water-insoluble polymer was suppressed by the presence of fumaric acid or monosodium fumarate in the dissolution medium, while the dissolution of the particles coated with Compound A without being coated with the water-insoluble polymer was not inhibited by the two compounds. The results showed that the dissolution-suppressing effect on compound A by the effect of total fumaric acid ion or monosodium fumarate requires coating the particles containing compound A with a water-insoluble polymer. It has also been shown that fumaric acid or monosodium fumarate needs to be dissolved at a high concentration close to the particles coated with the water-insoluble polymer containing compound A, so that the effect of their common ion can induce the dissolution-suppressing effect of compound A. Based on the results, it was also assumed that fumaric acid or monosodium fumarate dissolved from the preparation can be present at a high concentration in the oral cavity having a low water content, and the dissolution of Compound A is effectively suppressed (bitter masking), and that the dissolution inhibitory effect on Compound A by the effect of a common ion fumaric acid or monosodium fumarate no longer occurs in the gastrointestinal tract having a relatively high water content, and Compound A can dissolve rapidly.

[0095]

Experimental Example 7 (sensory score - 1)

The orally disintegrating tablets prepared in Examples 15-20 were subjected to sensory evaluation. The drugs were placed in the mouth, crushed and spit out. The bitter taste was evaluated in 5 stages (Table 3). Surprisingly, the bitter taste was remarkably suppressed in all preparations.

Compound A-coated particles, organic acid-coated particles, and coagulation-inhibiting substance-coated particles obtained in Example 18 were subjected to sensory evaluation. The drugs were placed in the mouth and spit out. The bitter taste was evaluated in 5 stages (Table 3). As a result, the bitter taste was noticeably suppressed only in the particles coated with the coagulation-inhibiting substance.

[0096]

Table 3 Example 15 - Example 16 - Example 17 ± Example 18 - compound A coated particles of Example 18 +++ organic acid coated particles Example 18 ++ particles coated with a coagulation-inhibiting substance, Example 18 - Example 19 - Example 20 - +++: a very strong bitter taste was felt
++: a strong bitter taste was felt
+: a rather strong bitter taste was felt
+ : slightly bitter taste
- almost no bitter taste

[0097]

Experimental Example 8 (sensory evaluation - 2)

The orally disintegrating tablets prepared in Examples 21-26 were subjected to sensory evaluation. The drugs were placed in the mouth, crushed and spit out. The bitter taste was evaluated in 5 stages (Table 4). Surprisingly, the bitter taste was remarkably suppressed in all preparations.

[0098]

Table 4 Example 21 - Example 22 - Example 23 - Example 24 - Example 25 - Example 26 - +++: a very strong bitter taste was felt
++: a strong bitter taste was felt
+: a rather strong bitter taste was felt
+ : slightly bitter taste
- almost no bitter taste

[0099]

The present application is based on Japanese Patent Application No. 2017-135046, the contents of which are hereby incorporated by reference in their entirety.

Claims (16)

1. A bitter taste masking preparation comprising granules comprising (1) a core granule containing an organic acid salt of vonoprazan, (2) an intermediate layer containing the same organic acid as the organic acid forming the salt of vonoprazan in (1) or a salt thereof, and (3) a coating layer containing a water-insoluble polymer, where the organic acid salt of vonoprazan is vonoprazan fumarate, the organic acid or salt thereof in said (2) is fumaric acid or a salt of fumaric acid, and the water-insoluble polymer is an ammonioalkyl methacrylate copolymer. 2. The preparation according to claim 1, wherein the organic acid or salt thereof in said item (2) is not less than 0.5 parts by mass per 100 parts by mass of vonoprazan in said item (1). 3. The preparation according to claim 1 or 2, wherein the water-insoluble polymer (solid content) in the coating layer in the specified item (3) is 0.5-15 mass parts per 100 mass parts of particles including the core granule in the specified item ( 1) and an intermediate layer in the specified point (2). 4. The drug according to any one of paragraphs. 1-3, where the granules have an average particle size of 75 µm to 750 µm. 5. The preparation according to claim 1, wherein the intermediate layer (2) contains the same organic acid as the organic acid forming the salt of vonoprazan in (1), or its salt, and the dissolution control agent, in one layer or separate layers, where the dissolution control agent is a divalent carboxylic acid or a salt thereof. 6. The formulation according to claim 5, wherein the dissolution control agent has a solubility in water (100 g) at 20°C of 0.01-500. 7. The formulation of claim 5, wherein the dissolution control agent has a pH of 2-4 when dissolved in water. 8. The formulation of claim 5 wherein the dissolution control agent is succinic acid or a salt of succinic acid. 9. The drug according to any one of paragraphs. 1-8, wherein the granules are further coated with a coagulation-inhibiting substance, wherein the coagulation-inhibiting substance is an inorganic substance, a sugar alcohol, or a saccharide. 10. The drug according to any one of paragraphs. 1-9, further comprising a polymeric binder, where the polymeric binder is a water-soluble polymer, a gastric-soluble polymer, or a pH-independent water-insoluble polymer. 11. The drug according to any one of paragraphs. 1-10 as an orally disintegrating tablet.

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