Formulations comprising voneranib

Abstract

The present invention aims to provide a preparation which is expected to improve the bitter taste of the organic acid salt of voneranib and allow the organic acid salt of voneranib to be rapidly dissolved after administration. The present invention provides a preparation containing a microparticle or granule comprising: (1) a core particle containing an organic acid salt of voneranib, (2) an intermediate layer containing the same organic acid as the organic acid forming the salt of voneranib in (1), or a salt thereof, and (3) a coating layer containing a water-insoluble polymer.

Description

Technical Field

[0001] This invention relates to a formulation that improves the bitterness of vonoprazan's organic acid salts. Background Technology

[0002] With an aging population and changes in the living environment, there is a need to develop orally disintegrating tablets that can be taken anytime, anywhere without water and retain the operational convenience characteristic of tablets.

[0003] When the active pharmaceutical ingredient or other additives have an unpleasant taste, such as bitterness, it is preferable to mask this unpleasant taste through coating from the perspective of medication adherence. On the other hand, it is desirable for the active pharmaceutical ingredient to dissolve rapidly after administration to express its pharmacological effect. However, when the active pharmaceutical ingredient has a strong bitter taste, a thick coating that masks this bitterness hinders rapid dissolution, making it difficult to achieve both effects simultaneously.

[0004] 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine monofumarate (vonoprazan fumarate) is known to have good proton pump inhibitory activity (Patent Document 1) and can be used as a drug. Organic acid salts of vonoprazan, such as vonoprazan fumarate, are known to have a bitter taste.

[0005] [List of References]

[0006] [Patent Literature]

[0007] Patent Document 1: WO 2007 / 026916

[0008] Patent Document 2: WO 2010 / 013823 Summary of the Invention

[0009] The technical problem to be solved by the present invention

[0010] The present invention aims to provide a formulation that is expected to improve the bitterness of vonorazan's organic acid salts and allow vonorazan's organic acid salts to dissolve rapidly after application.

[0011] Methods for solving technical problems

[0012] The inventors have conducted in-depth research in an attempt to address the aforementioned problems and have discovered that formulations containing microparticles or particles can ensure that, for a given time (i.e., a lag time), the organic acid salt of vonorazan does not dissolve during that given time period after administration. The microparticles or particles comprise (1) a core particle containing the organic acid salt of vonorazan, (2) an intermediate layer containing the same organic acid as the organic acid forming the vonorazan salt in (1), or a salt thereof, and (3) a coating layer containing a water-insoluble polymer. The lag time does not impede the dissolution of the active pharmaceutical ingredient until it passes through the throat, thereby potentially improving bitterness.

[0013] The inventors have further discovered that the above composition can achieve rapid dissolution and improve bitterness after the lag time has expired.

[0014] Based on the above findings, the inventors conducted further research and completed this invention.

[0015] In other words, the present invention provides the following content.

[0016] [1] A formulation containing microparticles or particles, said microparticles or particles comprising

[0017] (1) Core particles containing vonorazan organic acid salts

[0018] (2) An intermediate layer comprising an organic acid, or a salt thereof, that is the same as the organic acid forming the salt of vonorazan described in (1), and

[0019] (3) A coating layer containing a water-insoluble polymer.

[0020] [2] The formulation described in [1] above, wherein the organic acid salt of vonorazan is vonorazan fumarate, and the organic acid or its salt in (2) above is fumaric acid or a salt of fumaric acid.

[0021] [3] The formulation described in [1] or [2] above, wherein the water-insoluble polymer is a non-pH-dependent water-insoluble polymer.

[0022] [4] The formulation described in [3] above, wherein the non-pH-dependent water-insoluble polymer is an ammonium methacrylate alkyl ester copolymer.

[0023] [5] The formulation of any one of [1]-[4] above, wherein the amount of organic acid or salt thereof in the above (2) is not less than about 0.5 parts by weight relative to 100 parts by weight of vonorazan in the above (1).

[0024] [6] The formulation described in any one of [1]-[5] above, wherein the amount (solid content) of the water-insoluble polymer in the coating layer of the above (3) is about 0.5 parts by weight to about 15 parts by weight relative to each 100 parts by weight of particles comprising the core particles of the above (1) and the intermediate layer of the above (2).

[0025] [7] The formulation described in any one of [1]-[6] above, wherein the above-mentioned microparticles or particles have an average particle size of about 75 μm to about 750 μm.

[0026] [8] The formulation described in [1] above, wherein the intermediate layer of (2) contains, in a single layer or in separate layers, an organic acid or a salt thereof that forms the salt of vonorazan described in (1), and a dissolution control substance.

[0027] [9] The preparation described in [8] above, wherein the solubility of the dissolution control substance in water (100g) at 20°C is 0.01-500.

[0028]

[10] The preparation described in [8] above, wherein the dissolution control substance has a pH of 2-4 when dissolved in water.

[0029]

[11] The preparation described in [8] above, wherein the dissolution control substance is a salt of an organic acid or an organic acid.

[0030]

[12] The preparation described in [8] above, wherein the dissolution control substance is a divalent carboxylic acid or its salt.

[0031]

[13] The preparation described above [8], wherein the dissolution control substance is succinic acid or a salt of succinic acid.

[0032]

[14] The formulation of any one of [1]-

[13] above, wherein the above-mentioned microparticles or particles are further coated with a coagulation inhibitor.

[0033]

[15] The preparation described in

[14] above, wherein the above-mentioned coagulation inhibitor is an inorganic substance, sugar alcohol or sugar.

[0034]

[16] The formulation described in any one of [1]-

[15] above further comprises a polymer binder.

[0035]

[17] The formulation described in any one of [1]-

[16] above is used as an orally disintegrating tablet.

[0036] Effects of the present invention

[0037] The formulations of the present invention are intended to achieve both the improvement of the bitterness of vonorazine organic acid salts and the rapid dissolution of vonorazine organic acid salts. Attached Figure Description

[0038] Figure 1 The graph shows the dissolution test results for the tablets containing water-insoluble polymer-coated particles obtained in Example 1 and the tablets containing organic acid-coated particles obtained in Comparative Example 1. In the legend, JP2 shows the second scheme of the Japanese Pharmacopoeia dissolution test. The same applies to the graph below.

[0039] Figure 2 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Examples 2-5.

[0040] Figure 3 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 6.

[0041] Figure 4 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 7.

[0042] Figure 5 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 8.

[0043] Figure 6 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 9.

[0044] Figure 7 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 10.

[0045] Figure 8 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 11.

[0046] Figure 9 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Examples 12-13.

[0047] Figure 10 The graph shows the dissolution test results of the tablets containing water-insoluble polymer-coated particles obtained in Example 14.

[0048] Figure 11 It is a graph showing the results of Experiment Example 3.

[0049] Figure 12The graph shows the dissolution test results of Experiment Example 4 using particles coated with the water-insoluble polymer obtained in Example 1.

[0050] Figure 13 The graph shows the dissolution test results of Experiment Example 4 using particles coated with the aggregation inhibitor obtained in Reference Example 3.

[0051] Figure 14 The graph shows the leaching test results of Experiment Example 5 using particles 3 coated with the water-insoluble polymer obtained in Reference Example 2.

[0052] Figure 15 The graph shows the leaching test results of Experiment Example 6 using particles coated with the water-insoluble polymer obtained in Reference Example 1.

[0053] Figure 16 The graph shows the dissolution test results of Experiment Example 6 using particles coated with compound A obtained in Reference Example 1. Detailed Implementation

[0054] The formulations of the present invention are characterized by containing microparticles or particles comprising (1) a core particle containing an organic acid salt of vonorazan (sometimes described in this application as core particle (1)), (2) an intermediate layer containing the same organic acid as the organic acid forming the vonorazan salt in (1), or a salt thereof (sometimes described in this application as intermediate layer (2)), and (3) a coating layer containing a water-insoluble polymer (sometimes described in this application as coating layer (3)).

[0055] In this invention, the microparticles or particles containing a core particle (1), an intermediate layer (2), and a coating layer (3) generally have an average particle size of about 50 μm to about 1 mm, preferably about 75 μm to about 750 μm, more preferably about 80 μm to about 500 μm, and even more preferably about 100 μm to about 400 μm.

[0056] When the microparticles or particles are further coated with agglomeration inhibitors (e.g., D-mannitol, light anhydrous silica), the above-mentioned average particle size is the average particle size that the particles have after being coated with the agglomeration inhibitor.

[0057] In this application specification, unless otherwise specified, "average particle size" refers to the median size of the volume standard (median size: 50% of the particle size from the cumulative distribution). Examples of measurement methods include laser diffraction particle size distribution measurement methods. Specific examples include methods using the HEROS RODOS laser diffraction particle size distribution measurement equipment (manufactured by Sympatec (Germany)). The average particle size of the "microparticles or particles" of the present invention can be measured after the production of the "microparticles or particles" and before the formulation of the final formulation in the formulation manufacturing process, or can be measured from "microparticles or particles" removed from the formulated final formulation, or similar methods. When measuring the average particle size by this measurement method, the error is considered to be about ±10%, including measurement errors caused by the equipment and measurement method. The word "about" used in conjunction with the numerical value of the average particle size is used to include an error of "±10%". That is, in this application specification, for example, the numerical range of average particle size "about 75 μm to about 750 μm" represents 67.5 μm to 825 μm.

[0058] When measuring the average particle size of particles or microparticles contained in the formulation of the present invention, some of the particles or microparticles may agglomerate during the formulation manufacturing process. In this case, it is desirable to separate the agglomerates from the individual particles or microparticles by methods such as sieving, and then measure their size. In particular, when the final formulation is a tablet, such as an orally disintegrating tablet, the tablets are pulverized after compression, the average particle size of the particles or microparticles contained in the tablets is measured, and it is desirable to confirm the presence and particle size of the agglomerates by image analysis when necessary. The agglomerates, individual particles, or microparticles are sieved using a sieve with a size capable of separating individual particles or microparticles from the agglomerates, and then their size is measured.

[0059] In this application specification, "coating" is used not only to refer to covering the entire surface of the object to be coated (e.g., the core), but also to refer to partial covering, adsorption, or absorption.

[0060] In this application specification, "granules" refers to those granulated into a granular state.

[0061] In this application specification, "microparticles" refers to those microparticles that completely pass through sieve No. 18 and can pass through sieve No. 30, but no more than 10% of the total amount remains on sieve No. 30.

[0062] In this invention, "particle or microparticle" refers to a particle or microparticle made by coating a "core particle". When an aggregate having multiple "core particles" is formed due to the bonding of a portion of the aforementioned particles or microparticles, the aggregate is not considered a "particle or microparticle", which refers to an independent single particle made by coating a separate core particle.

[0063] The formulations of the present invention are characterized by containing an organic acid salt of vonorazan (sometimes referred to as component (I) in this application specification) as a pharmaceutically active ingredient in the core particles (1).

[0064] In this invention, the organic acid that forms the salt of vonorazine in the organic acid salt (component (I)) of vonorazine may include, for example, fumaric acid, succinic acid, benzoic acid, citric acid, methanesulfonic acid, tartaric acid, besylic acid, etc., and fumaric acid is preferred.

[0065] In this invention, vonorazine fumarate is preferred as the organic acid salt of vonorazine.

[0066] In this invention, the core particle (1) may be the following core of an inert carrier coated with an organic acid salt containing vonorazan.

[0067] The formulation 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 in component (I) that forms a salt with vonorazan. In this application specification, the “organic acid or salt thereof” contained in the intermediate layer (2) is sometimes referred to as component (II).

[0068] The organic acid in component (II) is the same as the organic acid described in component (I) above.

[0069] Examples of salts of organic acids in component (II) include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts.

[0070] In this invention, the organic acid salt of vonorazan contained in the core particle (1) (component (I)) is preferably vonorazan fumarate, and the organic acid or its salt contained in the intermediate layer (2) (component (II)) is preferably fumarate or a salt of fumarate (preferably fumarate or a monosodium fumarate).

[0071] The content of the organic acid salt of vonorazan (component (I)) in the formulation of the present invention is typically from about 1 wt% to about 80 wt%, preferably from about 5 wt% to about 50 wt%, and more preferably from about 15 wt% to about 35 wt%, relative to the "core particle (1)".

[0072] The content of organic acid or its salt (component (II)) in the intermediate layer (2) in the formulation of the present invention is preferably not less than about 0.5 parts by weight, more preferably not less than about 10 parts by weight, and even more preferably not less than about 150 parts by weight, relative to 100 parts by weight of vonorazan (in free form) in the core particles (1).

[0073] The content of organic acid or its salt (component (II)) in the intermediate layer (2) in the formulation of the present invention is generally about 0.5 parts by weight to about 5,000 parts by weight, preferably about 1 part by weight to about 5,000 parts by weight, more preferably about 10 parts by weight to about 1,000 parts by weight, and even more preferably about 50 parts by weight to about 500 parts by weight, relative to 100 parts by weight of vonorazan (in free form) in the core particles (1) per 100 parts by weight.

[0074] The weight of the aforementioned “Vonorazan (free form)” is based on the free form of vonorazan, which is an organic acid salt of vonorazan contained in the core particle (1).

[0075] The formulation of the present invention is characterized by having a coating layer (3) on the outer side of the intermediate layer (2).

[0076] In this invention, the "water-insoluble polymer" contained in the coating layer (3) includes non-pH-dependent water-insoluble polymers (e.g., ammonium alkyl methacrylate copolymers (also known as ammonium alkyl methacrylate copolymers RS (e.g., Eudragit RS30D (trade name), Eudragit RSPO (trade name)), also known as ammonium alkyl methacrylate copolymers RL (e.g., Eudragit RL30D (trade name), Eudragit RLPO (trade name))), ethyl cellulose, ethyl cellulose aqueous dispersion solutions, ethyl acrylate-methyl methacrylate copolymer dispersion solutions (e.g., Eudragit NE30D (trade name))), vinyl acetate resin (Kollicoat SR (trade name)), gastric-soluble polymers (e.g., ammonium alkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, Kollicoat Smartseal)). 30D (trade name)), enteric polymers (e.g., methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate), preferably pH-independent water-insoluble polymers (e.g., ammonium alkyl methacrylate copolymers (also known as ammonium alkyl methacrylate copolymers RS, also known as ammonium alkyl methacrylate copolymers RL)), more preferably ammonium alkyl methacrylate copolymers (also known as ammonium alkyl methacrylate copolymers RS, also known as ammonium alkyl methacrylate copolymers RL).

[0077] One or more types of water-insoluble polymers can be used in combination.

[0078] Relative to 100 parts by weight of particles consisting of a core particle (1) and an intermediate layer (2), the content (solid content) of the water-insoluble polymer in the coating layer (3) of the formulation of the present invention is preferably about 0.5 parts by weight to about 15 parts by weight, more preferably about 1 part by weight to about 10 parts by weight, and even more preferably about 1 part by weight to about 7 parts by weight.

[0079] In this invention, "particles consisting of a core particle (1) and an intermediate layer (2)" refers to particles before they are coated with a coating layer (3).

[0080] The formulation of the present invention preferably has an intermediate layer containing a dissolution control substance between the core particles (1) and the coating layer (3).

[0081] The intermediate layer containing the dissolution control substance may be the aforementioned intermediate layer (2) containing the dissolution control substance or an intermediate layer containing the dissolution control substance that is different from the aforementioned intermediate layer (2).

[0082] As one embodiment of the formulation of the present invention, a formulation containing microparticles or particles may be mentioned, wherein the microparticles or particles comprise

[0083] (1) Core particles containing vonorazan organic acid salts (component (I)),

[0084] (2) An intermediate layer, which, in a single layer or in separate layers, contains an organic acid or a salt thereof (component (II)) that is the same as the organic acid forming the salt of vonorazan described in (1), and a dissolution control substance, and

[0085] (3) A coating layer containing a water-insoluble polymer.

[0086] In the formulation of the present invention, in order to ensure that the organic acid salt of vonorazan therein does not dissolve at a certain time after application (i.e., lag time), the intermediate layer containing component (II) is preferably present adjacent to the core particles containing component (I).

[0087] Therefore, in the formulation of the present invention, the intermediate layer (2) is an intermediate layer containing component (II) and dissolution control substance in a single layer; or the intermediate layer (2) is an intermediate layer composed of multiple layers respectively containing component (II) and dissolution control substance, wherein the intermediate layer containing component (II) is preferably present on one side of the core particle (1) (on the core particle (1)).

[0088] In this invention, a dissolution control substance refers to a substance that can create a lag time before vonorazine (in its free form) dissolves. For example, a dissolution control substance is a substance that temporarily prevents vonorazine (in its free form) from dissolving or reduces the solubility of vonorazine (in its free form) during dissolution.

[0089] In this invention, the dissolution control substance preferably has a solubility of 0.01-500 in 100g of water at 20°C (preferably 0.1-100, more preferably about 0.5-40).

[0090] In this invention, the leaching control substance is preferably a substance with a pH of 2-4 when dissolved in water.

[0091] In this invention, examples of dissolution control substances include organic acids (including hydrates) (e.g., divalent carboxylic acids (e.g., succinic acid, malic acid, adipic acid, malonic acid, etc.), salicylic acid, etc.); salts of organic acids (including hydrates) (e.g., salts of divalent carboxylic acids (e.g., salts of succinic acid (e.g., disodium succinate, disodium succinate hexahydrate, etc.) etc.), ammonium carbonate, potassium bicarbonate, sodium carbonate decahydrate, sodium bicarbonate, sodium acetate trihydrate, etc.); sugar alcohols (e.g., mannitol, erythritol, maltitol, etc.); sugars (e.g., sucrose, lactose, maltose, trehalose, etc.); disintegrants (e.g., low-substituted hydroxyl groups). Propyl cellulose, carboxymethyl cellulose, etc.; water-soluble polymers (e.g., hydroxypropyl methyl cellulose, etc.); inorganic salts (including hydrates) (e.g., ammonium chloride, ammonium nitrate, potassium chloride, disodium hydrogen phosphate dodecahydrate, sodium thiosulfate pentahydrate, ammonium oxalate monohydrate, sodium pyrophosphate, etc.); amide compounds (e.g., urea, etc.); amino acids (e.g., glycine, etc.); salts of amino acids (e.g., cysteine ​​hydrochloride, etc.); phenols (e.g., hydroquinone, etc.); water-insoluble polymers (e.g., vinyl polymers (e.g., poly(N-acrylamide), etc.) etc.); and salts of succinic acid or succinic acid are preferred.

[0092] One or more types of dissolution control substances can be used in combination.

[0093] The content (solid content) of the dissolution control substance in the formulation of the present invention is generally about 10 parts by weight to about 1,000 parts by weight, preferably about 50 parts by weight to about 600 parts by weight, and more preferably about 200 parts by weight to about 500 parts by weight, relative to 100 parts by weight of water-insoluble polymer in the coating layer (3) per 100 parts by weight.

[0094] When succinic acid is included in the present invention as a dissolution control substance, ammonium alkyl methacrylate copolymer (also known as ammonium alkyl methacrylate copolymer RS) is preferably used as the above-mentioned water-insoluble polymer, because rapid dissolution of the organic acid salt of vonorazan can be expected after the hysteresis time has expired.

[0095] In this invention, the above-mentioned effects are expected to occur when succinic acid or its salt is used as component (II) in the intermediate layer (2) and the amount of succinic acid or its salt is within the above-mentioned range.

[0096] When succinic acid is included in this invention as a dissolution control substance, it is expected to contribute to the stability of vonoprazan and is expected to provide a formulation with better long-term stability.

[0097] In the formulation of the present invention, the "microparticles or particles comprising a core particle (1), an intermediate layer (2), and a coating layer (3)" are preferably further coated with an aggregation inhibitor.

[0098] Examples of substances that inhibit aggregation include inorganic substances, sugar alcohols, and sugars.

[0099] Examples of inorganic substances include light anhydrous silica (e.g., Sylysia 320 (trade name), AEROSIL 200 (trade name)), hydrated silica, talc, titanium dioxide, bentonite, kaolin, and magnesium aluminum metasilicate, with light anhydrous silica being preferred.

[0100] Examples of sugar alcohols include D-mannitol, sorbitol, maltitol, reduced starch sugars, xylitol, reduced paratinose, erythritol, lactitol, and isomaltitol.

[0101] Examples of sugars include monosaccharides (e.g., glucose, fructose) and disaccharides (e.g., lactose, sucrose, maltose, granulated sugar, trehalose).

[0102] The amount of aggregation inhibitor to be applied to the coated microparticles or particles, when sugars or sugar alcohols are used as aggregation inhibitors, is typically about 1 to about 30 parts by weight, preferably about 3 to about 20 parts by weight, and more preferably about 4 to about 15 parts by weight, relative to 100 parts by weight of “microparticles or particles comprising a core particle (1), an intermediate layer (2), and a coating layer (3)” (microparticles or particles before the application of the aggregation inhibitor).

[0103] The amount of agglomeration inhibitor to be used for coating microparticles or particles is typically about 0.01 to about 10 parts by weight, preferably about 0.05 to about 5 parts by weight, more preferably about 0.1 to about 1 part by weight, when the inorganic substance is used as the agglomeration inhibitor.

[0104] In this invention, the coating film of the aggregation inhibitor is expected to provide both improved handling properties (reducing adhesion due to static electricity) and delayed inhibition of dissolution of the formulation after storage.

[0105] The formulation of the present invention preferably further comprises a polymer binder.

[0106] The polymer adhesive can be any polymer adhesive, as long as it has the property of bonding the additives to the particles or microparticles sufficiently firmly from the perspective of abrasion resistance. Examples include water-soluble polymers (hydroxypropyl methylcellulose (HPMC) (e.g., hydroxypropyl methylcellulose 2910), hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose (e.g., Metolose SM-4), poly(vinyl alcohol), sodium alginate, poly(vinyl alcohol)-acrylate-methyl methacrylate copolymer, polyethylene oxide, povidone, copovidone, polyethylene glycol), gastric-soluble polymers (Eudragit E, Eudragit EPO), non-pH-dependent water-insoluble polymers (Eudragit NE, Eudragit RL (e.g., Eudragit RLPO, Eudragit RL30D), Eudragit RS, ethyl cellulose), preferably hydroxypropyl methylcellulose (HPMC), Eudragit E, Eudragit EPO, Eudragit... NE (trade name), Eudragit RL (trade name), and methylcellulose (e.g., Metolose SM-4 (trade name)).

[0107] The content of the polymer binder in the formulation of the present invention is typically from 0.1 to 100 parts by weight, preferably from 0.5 to 90 parts by weight, and more preferably from 1 to 80 parts by weight, relative to 100 parts by weight of organic acid contained in the formulation.

[0108] In this invention, polymeric adhesives are used, but are not limited to, adhesives for layers containing organic acids.

[0109] The formulations of the present invention may further contain cyclodextrin.

[0110] As for cyclodextrins, α-cyclodextrin, β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin can be mentioned, with β-cyclodextrin being preferred.

[0111] In this invention, by including cyclodextrin (especially β-cyclodextrin), it is expected that the sour taste of organic acid components (e.g., fumaric acid, succinic acid) can be masked.

[0112] In this invention, cyclodextrin may be included in any part of the formulation of this invention. Cyclodextrin is preferably included in the outer particles or the components outside the particles, more preferably included in the outer particles.

[0113] The content of cyclodextrin in the formulation of the present invention is generally from 1 part by weight to 1000 parts by weight, preferably from 10 parts by weight to 500 parts by weight, and more preferably from 25 parts by weight to 100 parts by weight, relative to 100 parts by weight of organic acid contained in the formulation.

[0114] The formulations of the present invention can be formulated as orally disintegrating tablets containing the aforementioned microparticles or granules. This will be explained in detail below.

[0115] Examples of formulations of the present invention include: solid dosage forms such as tablets, granules, microparticles, capsules, foaming agents, etc., and liquids such as suspensions, etc. Tablets are preferred in consideration of ease of handling, etc., and orally disintegrating tablets are particularly preferred.

[0116] In this application specification, "orally disintegrating tablet" is a tablet characterized by suitable disintegration properties, which can be ingested by rapidly dissolving or disintegrating in the oral cavity.

[0117] The formulations of the present invention can be prepared using the above-mentioned fats and according to methods known in the field of pharmaceutical formulations.

[0118] For example, when the formulation of the present invention is an orally disintegrating tablet, it can be prepared as follows.

[0119] In the following preparation methods, the coating of component (c) is optional.

[0120] The core of the inert support is sequentially sprayed, dried, and sieved with the pre-prepared coating solutions (a), (b), and (c) below to obtain particles containing component (I). Alternatively, the core of the inert support is sequentially sprayed, dried, and sieved with the pre-prepared coating solutions (a) and (d) below below to obtain particles containing component (I).

[0121] (a) The adhesive is suspended or dissolved in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropanol), component (I) (e.g., vonoprazan fumarate) is added and suspended or dissolved therein to obtain a coating solution of component (I).

[0122] (b) The adhesive is suspended or dissolved in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropanol), component (II) (e.g., fumaric acid, monosodium fumarate) is added and suspended or dissolved therein to obtain a coating solution of component (II).

[0123] (c) Suspend or dissolve the adhesive in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropanol), add a dissolution control substance (e.g., succinic acid), and suspend or dissolve it therein to obtain a dissolution control substance coating solution.

[0124] (d) The adhesive is suspended or dissolved in water or a solvent (e.g., ethanol, methanol, acetone, ethyl acetate, propylene glycol, isopropanol), a dissolution control substance (e.g., succinic acid) is added and suspended or dissolved therein, and then component (II) (e.g., fumaric acid, monosodium fumarate) is added and suspended or dissolved therein to obtain a component (II) / dissolution control substance coating solution.

[0125] Examples of adhesives include the polymer adhesives described above.

[0126] The coating layer can be applied in any order and can be applied multiple times. For example, it can be applied to the core in the order of (a), (b), (c), (a), (b), (c), (b), (a), (b), (b), (c), or (a), (d).

[0127] The particles containing component (I) may further have a coating layer that does not contain component (I), component (II), or dissolution control substances but contains a binder (e.g., HPMC). Such a layer may be formed between a pharmaceutical active ingredient layer (layer (a)) and an organic acid layer (layer (b), layer (c), or layer (d)).

[0128] Each layer may further contain additives used in general formulations (e.g., flavoring agents (e.g., monosodium glutamate), surfactants (e.g., polysorbate 80), aggregation inhibitors (e.g., talc)). These components can be used by adding them to the coating solution described above.

[0129] A coating solution containing a water-insoluble polymer (e.g., ammonium alkyl methacrylate copolymers (e.g., 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, if necessary, sieved to obtain microparticles or granules.

[0130] The coating solution containing the water-insoluble polymer may further contain additives used in general formulations (e.g., plasticizers (e.g., triacetin), coagulation inhibitors (e.g., talc), colorants (e.g., red iron oxide, yellow iron oxide, titanium dioxide), plasticizers (e.g., polysorbate 80), pH adjusters (e.g., citric anhydride), and opacifiers (e.g., titanium dioxide)). These components can be used by adding them to the coating solution described above.

[0131] The resulting microparticles or particles can be further coated with a coagulation inhibitor. In this case, the coagulation inhibitor (e.g., D-mannitol, light anhydrous silica) is suspended or dissolved in a solvent such as water to obtain a coagulation inhibitor coating solution. The coating solution is sprayed onto the microparticles or particles, dried, and, if necessary, sieved to obtain particles coated with the coagulation inhibitor. Alternatively, particles coated with the coagulation inhibitor can be obtained by mixing the coagulation inhibitor (e.g., D-mannitol, light anhydrous silica) with the microparticles or particles.

[0132] The resulting microparticles or particles (or particles coated with agglomeration inhibitors) are formed (compressed) together with optionally added outer particles and / or components outside the particles to obtain the orally disintegrating tablets of the present invention.

[0133] The outer granules can be obtained by granulation, for example, by adding excipients (e.g., D-mannitol, crystalline cellulose), flavoring agents (e.g., citric anhydride), disintegrants (e.g., low-substituted hydroxypropyl cellulose, crospovidone), and β-cyclodextrin, if necessary.

[0134] Examples of components outside the particles include sweeteners (e.g., aspartame, acesulfame potassium, sematriol), flavoring agents (e.g., l-menthol, sodium fumarate), lubricants (e.g., sodium stearate fumarate, magnesium stearate), excipients (e.g., crystalline cellulose), disintegrants (e.g., crospovidone, partially pregelatinized starch), flavorings (e.g., lime flavoring, mandarin flavoring, strawberry flavoring, strawberry D, menthol cortisone), fluidizing agents (e.g., Neusilin FL2 (trade name), Neusilin UFL2 (trade name), AEROSIL 200 (trade name), Sylysia 320 (trade name)), and β-cyclodextrin.

[0135] Commercially available premixed formulations can also be used for direct tableting as the outer granules. Examples include SmartEX, Parteck ODT, Granulol F, Rudy Flash, GranFiller-D, and SwellWick. Spray-dried or granulated products of processing starting materials suitable for direct tableting, such as mannitol or lactose, can also be used.

[0136] The content of outer layer particles, relative to the total weight of the entire formulation, is typically 10 wt% to 95 wt%, preferably 30 wt% to 90 wt%, and more preferably about 35 wt% to 80 wt%.

[0137] The content of the non-particle components, relative to the total weight of the entire formulation, is typically 0.5 wt% to 40 wt%, preferably 0.75 wt% to 35 wt%, and more preferably about 1 wt% to 30 wt%.

[0138] Examples of inert carrier cores include (1) spherical granulation products of crystalline cellulose and lactose, (2) spherical granulation products of mannitol, and (3) 75-300 μm spherical crystalline cellulose (CELPHERE, produced by Asahi Kasei Chemicals). (4) Granulated products of 50-250 μm stirring of lactose (9 parts) and α-starch (1 part), (5) Microparticles of 250 μm or smaller obtained by classifying microcrystalline cellulose spherical particles as described in JP-A-61-213201, (6) Processed products of waxes, etc., formed into spheres by spray cooling or melt granulation, (7) Processed products, such as gelatin beads of oil components, etc., (8) Calcium silicate, (9) Starch, (10) Partially pregelatinized starch, (11) Porous particles of chitin, cellulose, chitosan, etc., (12) Batch products of mannitol, sugar, crystalline lactose, crystalline cellulose or sodium chloride, etc., and their preparation and processing products. In addition, these cores can be prepared by pulverizing methods or granulation methods known per se, and sieved to prepare particles with the desired particle size.

[0139] Examples of “spherical granulated products of crystalline cellulose and lactose” include (i) 100-200 μm spherical granulated products of crystalline cellulose (3 parts) and lactose (7 parts) (e.g., NONPAREIL 105(70-140) (100-200 μm particle size), manufactured by Freund Corporation), (ii) 150-250 μm spherical granulated products of crystalline cellulose (3 parts) and lactose (7 parts) (e.g., NONPAREIL NP-7:3, manufactured by Freund Corporation), and (iii) 100-200 μm spherical granulated products of crystalline cellulose (4.5 parts) and lactose (5.5 parts) (e.g., NONPAREIL 105T(70-140) (100-200 μm particle size), manufactured by Freund Corporation). (iv) 150-250 μm spherical granules of crystalline cellulose (5 parts) and lactose (5 parts) [e.g., NONPAREIL NP-5:5, manufactured by Freund Corporation].

[0140] "Mixing" is carried out through commonly used mixing methods such as mixing, kneading, and granulation. "Mixing" is carried out using equipment such as vertical granulators (VG10 (manufactured by POWREX CORPORATION)), general-purpose kneaders (manufactured by HATA TEKKOSHO CO.,LTD.), fluidized bed granulators (LAB-1, FD-3S, FD-WSG-60, FD-WSG-60TW, FD-GPCG-120SPC, FD-MP-01 (SPC / SFP / FD), MP-10toku-2 type machines (manufactured by POWREX CORPORATION)), V-type mixers, drum mixers, and containerized blending machines.

[0141] "Forming" is achieved through a single-punch tablet press (manufactured by Kikusui Seisakusho Ltd.) and a rotary tablet press (manufactured by Kikusui Seisakusho Ltd.), using a pressure of approximately 1 to approximately 30 kN / cm. 2 Preferably about 2 to about 20 kN / cm 2 It is performed by pressure stamping.

[0142] "Drying" can be carried out by any method commonly used for drying of formulations, such as vacuum drying, fluidized bed drying, etc.

[0143] "Spraying", "coating", "granulation" and "screening" are carried out by methods known to them.

[0144] Orally disintegrating tablets can be compressed at room temperature or above. "Room temperature" typically refers to approximately 10°C to approximately 30°C. The temperature can be varied depending on the desired tablet quality.

[0145] Orally disintegrating tablets can be uncoated tablets, film-coated tablets, or sugar-coated tablets, preferably uncoated tablets. In this application specification, "uncoated tablets" means tablets that have not undergone coating treatment, such as film coating, sugar coating, etc., on the surface of orally disintegrating tablets obtained by compression.

[0146] The formulations of the present invention may further include additives for preparing general formulations as components other than those described above. The amount of additive to be added is the amount used for preparing a general formulation.

[0147] Water-soluble sugar alcohols, crystalline cellulose, and low-substituted hydroxypropyl cellulose (L-HPC) are used as additives, and binders, acidifiers, foaming agents, sweeteners, flavorings, lubricants, colorants, excipients, disintegrants, flavoring agents, plasticizers, surfactants, coagulation inhibitors, fluidizing agents, pH adjusters, etc. are further added. These are mixed and compressed to obtain orally disintegrating tablets.

[0148] Water-soluble sugar alcohols refer to the following sugar alcohols that require less than 30 ml of water when 1 g of sugar alcohol is added to water, and that can be dissolved in about 30 minutes by vigorous shaking for 30 seconds every 5 minutes at 20°C.

[0149] Examples of water-soluble sugar alcohols include mannitol, sorbitol, maltitol, reduced starch sugars, xylitol, reduced paraffinose, erythritol, and lactitol. Mannitol, sorbitol, maltitol, xylitol, and erythritol are preferred, more preferably mannitol, sorbitol, maltitol, and erythritol, and even more preferably mannitol and erythritol. Two or more types of water-soluble sugar alcohols can be used in a suitable mixture. Erythritol is typically prepared from glucose as a starting material by fermentation with yeast or the like. Erythritol with a particle size of 50 mesh or less is used. Erythritol is obtained as a commercially available product [Nikken Chem. Co., Ltd., etc.]. The amount of water-soluble sugar alcohol used is typically about 3 to about 60 parts by weight, preferably about 5 to about 50 parts by weight, relative to 100 parts by weight of the whole formulation.

[0150] Crystalline cellulose can be any crystalline cellulose, as long as it is obtained by partially depolymerizing and purifying α-cellulose. This also includes cellulose called microcrystalline cellulose. Examples of crystalline cellulose include, for instance, CEOLUS KG-1000, CEOLUS KG-802, CEOLUS PH-101, CEOLUS PH-102, CEOLUS PH-301, CEOLUS PH-302, CEOLUS UF-702, and CEOLUS UF-711. Preferably, CEOLUS KG-802 or CEOLUS UF-711 may be mentioned. These crystalline celluloses can be used alone, or two or more types of crystalline cellulose can be used in combination. These crystalline celluloses are available as commercially available products [manufactured by Asahi Kasei Chemicals Co., Ltd.]. Crystalline cellulose can be added in the following amounts relative to 100 parts by weight of the whole formulation: about 1 to about 50 parts by weight, preferably about 3 to about 40 parts by weight, and most preferably about 5 to about 20 parts by weight.

[0151] Examples of low-substituted hydroxypropyl cellulose include LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, and LH-33. These LHPCs are available as commercially available products [manufactured by Shin-Etsu Chemical Co., Ltd.]. The low-substituted hydroxypropyl cellulose can be added in the following amounts per 100 parts by weight of the whole formulation: about 1 to about 50 parts by weight, preferably about 3 to about 40 parts by weight, and most preferably about 3 to about 20 parts by weight.

[0152] Examples of adhesives include hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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, copovidone, methylcellulose, low-substituted hydroxypropyl cellulose, and poly(vinyl alcohol)-acrylic acid-methyl methacrylate copolymer. Two or more of these adhesives can be used in mixtures in suitable proportions.

[0153] Examples of acidifying agents include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, acetic acid, adipic acid, glucono-δ-lactone, phytic acid, and their salts.

[0154] Examples of foaming agents include sodium bicarbonate.

[0155] Examples of sweeteners include xylose, starch syrup, hydrogenated maltose starch syrup, maltose, glucose, fructose, monosyrup, dextrin, cyclodextrin, maltose, lactose, trehalose, maltodextrin, isomaltooligosaccharide, gentiosaccharide, sodium saccharin, glycyrrhizin, aspartame, sucralose, acesulfame potassium, steviol glycosides, sematrandezidine, advantame, and neotame.

[0156] Flavorings can be any substance, whether synthetic or naturally occurring. For example, lemon, lime, orange, menthol, strawberry, mint, banana, ginger, plum, grapefruit, yogurt, vanilla, Chinese lemon, blueberry, green tea, rapeseed, grape, and sugar can be mentioned.

[0157] Examples of flavoring agents include monosodium glutamate, citric anhydride, L-menthol, and monosodium fumarate.

[0158] Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, polyethylene glycol, talc, sodium stearate fumarate, glycerin, glyceryl monostearate, castor oil, and hydrogenated castor oil.

[0159] Examples of colorants include food colorings such as food coloring yellow 5#, food coloring red 2#, food coloring blue 2#; food lake dyes, iron oxide red, red iron oxide, yellow iron oxide, iron oxide black, carbon black, etc.

[0160] Examples of excipients include lactose, sucrose, isomaltose, D-mannitol, sorbitol, anhydrous calcium phosphate, starch, corn starch, partially pregelatinized starch, crystalline cellulose, light anhydrous silica, and titanium dioxide.

[0161] Examples of disintegrants include crospovidone [manufactured by ISP Inc. (USA), BASF (Germany)], crospovidone sodium carboxymethyl cellulose (FMC-Asahi Kasei Corporation), calcium carboxymethyl cellulose (GOTOKU CHEMICAL CO., LTD.), low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch (Matsutani Chemical Industry Co., Ltd.), corn starch, pregelatinized starch, and crystalline cellulose. Among these, crospovidone is preferred. Two or more of these disintegrants can be used in mixtures in suitable proportions. For example, crospovidone can be used alone or in combination with other disintegrants. Crospovidone can be any crospovidone, as long as it is a cross-linked polymeric substance called 1-vinyl-2-pyrrolidone homopolymer (including polyvinyl polypyrrolidone (PVPP), 1-vinyl-2-pyrrolidone homopolymer). Crospovidones with a molecular weight of not less than 1,000,000 are typically used. Specific examples of commercially available crosslinked polyvinylpyrrolidone include crosslinked (crosslinked) polyvinylpyrrolidone, Kollidon CL, Kollidon CL-F, Kollidon CL-SF [manufactured by BASF (Germany)], Polyplasdone XL, Polyplasdone XL-10, INF-10 [manufactured by ISP Inc. (USA)], polyvinylpyrrolidone, PVPP, and 1-vinyl-2-pyrrolidone homopolymers. The amount of such disintegrant relative to 100 parts by weight of the entire formulation is, for example, from about 0.1 to about 30 parts by weight, preferably from about 1 to about 25 parts by weight, and more preferably from about 1.5 to about 20 parts by weight.

[0162] Examples of plasticizers include polyethylene glycol, propylene glycol, ethanol, triethyl citrate, glyceryl triacetate, and polysorbate 80.

[0163] Examples of surfactants include sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, sodium docusate, polyoxyethylene hydrogenated castor oil, polysorbate 80, and polysorbate 20.

[0164] Examples of coagulation inhibitors include talc, titanium dioxide, light anhydrous silica, kaolin, bentonite, hydrated silica, glyceryl monostearate, mannitol, trehalose, erythritol, lactose, and maltose.

[0165] Examples of fluidizing agents include magnesium aluminum metasilicate, light anhydrous silica, hydrated silica, and talc.

[0166] Examples of pH adjusters include citric anhydride, hydrochloric acid, and sodium hydroxide.

[0167] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing component (II) on the outside of the layer containing component (I), and a layer containing a water-insoluble polymer on the outside of the layer containing component (II).

[0168] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing component (II) on the outside of the layer containing component (I), a layer containing a dissolution control substance on the outside of the layer containing component (II), and a coating layer containing a water-insoluble polymer on the outside of the layer containing the dissolution control substance.

[0169] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing component (II) and a dissolution control substance on the outside of the layer containing component (I), and a layer containing a water-insoluble polymer on the outside of the layer containing component (II) and the dissolution control substance.

[0170] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing a polymer binder on the outside of the layer containing component (I), a layer containing component (II) on the outside of the layer containing the polymer binder, and a coating layer containing a water-insoluble polymer on the outside of the layer containing component (II).

[0171] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing a polymer binder on the outside of the layer containing component (I), a layer containing component (II) on the outside of the layer containing the polymer binder, a layer containing a dissolution control substance on the outside of the layer containing component (II), and a coating layer containing a water-insoluble polymer on the outside of the layer containing the dissolution control substance.

[0172] As one embodiment of the microparticles or particles included in the formulation of the present invention, they may have: a core of an inert carrier, a layer containing component (I) on the outside of the core of the inert carrier, a layer containing a polymer binder on the outside of the layer containing component (I), a layer containing component (II) and a dissolution control substance on the outside of the layer containing the polymer binder, and a layer containing a water-insoluble polymer on the outside of the layer containing component (II) and the dissolution control substance.

[0173] The orally disintegrating tablets of the present invention exhibit rapid disintegration or solubility in the oral cavity.

[0174] The orally disintegrating tablets of the present invention are easy to take while maintaining ease of use. Moreover, they can be taken anytime and anywhere without water, and the orally disintegrating time (the time before the orally disintegrating tablet is completely disintegrated by saliva in the mouth of a healthy male or female adult) is within 1 minute, typically no more than about 50 seconds, preferably no more than about 40 seconds, and more preferably no more than about 30 seconds.

[0175] The formulation of the present invention is expected to ensure a certain lag time before the dissolution of the active pharmaceutical ingredient (the organic acid salt of vonorazan).

[0176] Specifically, the formulation of the present invention preferably has the following dissolution properties (1) or (2).

[0177] (1) In the dissolution test using the Japanese Pharmacopoeia Dissolution Test 2 liquid (900 mL) according to the Japanese Pharmacopoeia paddle method (rotation speed 50 rpm, 37°C) or the Japanese Pharmacopoeia basket method (rotation speed 100 rpm, 37°C), the time taken from the start of the test until 5% of the active pharmaceutical ingredient is dissolved shall be not less than 2 minutes and not more than 15 minutes.

[0178] (2) In the dissolution test using the Japanese Pharmacopoeia Dissolution Test 2 liquid (10 mL), the dissolution rate of the active pharmaceutical ingredient shall not exceed 5% within 1 minute from the start of the test.

[0179] The formulation of the present invention preferably has the dissolution properties described in (2) above.

[0180] Although the formulations of the present invention (particularly orally disintegrating tablets) are designed to ensure that the organic acid salt of vonoprazan does not dissolve at a certain time after administration (lag time) to prevent the active pharmaceutical ingredient from dissolving until it has passed through the throat, it is desirable that the ingredient dissolves rapidly after the lag time without the need to form an enteric coating that inhibits dissolution until the formulation reaches the small intestine.

[0181] The formulations of the present invention can be safely administered orally to mammals (e.g., mice, rats, rabbits, cats, dogs, cattle, horses, monkeys, humans, etc.). Although the dosage of the formulations of the present invention varies, for example, depending on the recipient, the type of disease, etc., it can be suitably selected from the effective range of dosage of the active pharmaceutical ingredient.

[0182] The formulation of this invention comprises an organic acid salt of vonorazan (particularly vonorazan fumarate) as the active pharmaceutical ingredient. It has low toxicity, is a safe formulation, and is used for: gastric ulcers, duodenal ulcers, reflux esophagitis, non-erosive reflux disease; inhibiting the recurrence of gastric or duodenal ulcers when taking low doses of acetylsalicylic acid; inhibiting the recurrence of gastric or duodenal ulcers when taking nonsteroidal anti-inflammatory drugs; and adjuvant eradication of Helicobacter pylori in the following cases: gastric ulcers, duodenal ulcers, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, gastric cancer after endoscopic resection, or Helicobacter pylori gastritis, etc. For an adult (60 kg body weight), the dose of vonorazan is approximately 10 to approximately 40 mg / day. The formulation can be administered once daily or in 2-3 doses daily.

[0183] The formulations of this invention can be used in combination with low doses of acetylsalicylic acid and / or nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include acetylsalicylic acid, indomethacin, ibuprofen, mefenamic acid, diclofenac, etodorac, piroxicam, celecoxib, loxoprofen sodium, naproxen, etc.

[0184] To help eradicate Helicobacter pylori activity, the formulations of the present invention can also be used in combination with anti-Helicobacter pylori active substances, imidazole compounds, bismuth salts, quinolone compounds, etc.

[0185] Examples of "anti-Helicobacter pylori active substances" include: penicillin antibiotics (such as amoxicillin, penicillin, piperacillin, mecillin, ampicillin, temoxicillin, bamectin, apucillin, sultamicillin, lenamicillin, etc.), cephalosporin antibiotics (such as cefixime, cefaclor, etc.), macrolide antibiotics (such as erythromycin, clarithromycin, roxithromycin, rotamycin, fluerythromycin, telithromycin, etc.), tetracycline antibiotics (such as tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (such as gentamicin, amikacin, etc.), imipenem, etc. Among these active substances, penicillin antibiotics and macrolide antibiotics are preferred.

[0186] Examples of "imidazole compounds" include metronidazole, miconazole, etc.

[0187] Examples of "bismuth salts" include bismuth acetate, bismuth citrate, and basic bismuth salicylate.

[0188] Examples of "quinolone compounds" include ofloxacin and ciprofloxacin.

[0189] To eradicate Helicobacter pylori, penicillin antibiotics (e.g., amoxicillin), erythromycin antibiotics (e.g., clarithromycin), and / or imidazole compounds (e.g., metronidazole) are particularly preferred.

[0190] Example

[0191] Although the invention is explained in more detail below with reference to embodiments and experimental examples, the invention is not limited to these embodiments and experimental examples.

[0192] In the various examples, comparative examples, reference examples, and experimental examples, compound A is vonoprazan fumarate.

[0193] In the following examples or equivalents, "organic acid coating solution" refers to a coating solution containing an organic acid or a salt of an organic acid, and "organic acid coated particles" refers to particles coated with a coating solution containing an organic acid or a salt of an organic acid.

[0194] Example 1

[0195] Preparation of coating solution for compound A

[0196] Add 24.3g of hydroxypropyl methylcellulose 2910 (also known as hydroxypropyl methylcellulose (2910), TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd., the same below) to purified water (399.8g), add compound A (180.3g), and stir the mixture thoroughly to obtain the coating solution of compound A.

[0197] Preparation of particles coated with compound A

[0198] Lactose / crystalline cellulose spherical granules (NONPAREIL 105T, manufactured by Freund Corporation, hereinafter the same) (300.5 g) were placed in a microparticle coating granulator / Wurster (FD-MP-01(SPC / SFP / FD), manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A (570.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air flow rate of 60 NL / min, inlet air temperature of 65-75 °C, and inlet air flow rate of 0.4-0.5 m / min. 3 The spray feed rate was 5 g / min; the particles were dried to obtain dried particles (445.5 g). The total amount of dried particles was sieved to obtain compound A-coated particles (300 μm-105 μm) (413.6 g).

[0199] Preparation of organic acid coating solution

[0200] Hydroxypropyl methylcellulose 2910 (24.3g) and pre-sprayed fumaric acid (manufactured by POLYNT, the same below) (120.5g) were added to purified water (480.5g), and the mixture was stirred thoroughly to obtain an organic acid coating solution.

[0201] Preparation of organic acid coated particles

[0202] 400.0 g of particles coated with compound A (300 μm-105 μm) were placed in a microparticle coating granulator / Wurster and fluidized therein; 561.5 g of the organic acid coating solution was sprayed under the following conditions: spray air pressure 0.4-0.5 MPa, spray air velocity 50-70 NL / min, inlet air temperature 73℃, and inlet air velocity 0.5 m / min. 3 The spray feed rate was 3-9 g / min; the particles were dried to obtain dried particles (499.3 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (374.6 g).

[0203] Preparation of water-insoluble polymer coating solution

[0204] Triglycerides (manufactured by Merck, hereinafter the same) (6.05 g), talc (manufactured by matsumura sangyo Co., Ltd., hereinafter the same) (30.3 g), and red iron oxide (LCW, hereinafter the same) (0.1321 g) were suspended and dissolved in purified water (350.3 g). The mixture was added to stirred ammonium alkyl methacrylate copolymer RS ​​(also known as ammonium alkyl methacrylate copolymer, Eudragit RS30D, manufactured by Evonik) (199.8 g) to obtain a water-insoluble polymer coating solution.

[0205] Preparation of water-insoluble polymer-coated particles

[0206] Organic acid-coated particles (355μm-105μm) (299.8g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (330.0g) was sprayed under the following conditions to obtain sprayed particles (316.7g): spray air pressure 0.4MPa, spray air flow rate 60NL / min, inlet air temperature 43℃, and inlet air flow rate 0.5m. 3The feed rate of the spray liquid was 2-3 g / min. Talc (1.2 g) was added to 228.0 g of sprayed particles, and they were thoroughly mixed in a plastic bag and dried and cured at 60°C for 12 hours in a forced convection oven (DNF400, manufactured by Yamato Scientific Co., Ltd., hereinafter the same). The dried and cured particles were sieved through a 300 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles (220.9 g).

[0207] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0208] In the following text, unless otherwise specified, the content of compound A in the particles obtained in advance in the preparative step prior to the preparation of the formulation for tableting is measured by HPLC, the amount of particles prepared in the preparative step (which requires 20 mg of compound A as the free base to be contained in each tablet) is calculated and used in the blending step.

[0209] The water-insoluble polymer-coated particles (650.9 mg), the excipient for direct compression of ODT (SmartEXQD-100, manufactured by Shin-Etsu Chemical Co., Ltd., hereinafter the same) (416.1 mg), aspartame (manufactured by Ajinomoto Co., Inc., hereinafter the same) (11 mg), l-menthol (manufactured by THE SUZUKI MENTHOL CO., LTD., hereinafter the same) (2.75 mg), acesulfame potassium (Sunett, manufactured by MC Food Specialties Inc., hereinafter the same) (2.75 mg), sodium stearate fumarate (PRUV, manufactured by JRS Pharma, hereinafter the same) (16.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (275 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend product (250 mg) containing particles coated with a water-insoluble polymer was weighed and compressed at 3 kN using an 8.5 mm flat punch and a single-punch tablet press (HANDTAB-200, manufactured by ICHHIHASHI SEIKI, hereinafter the same) to obtain orally disintegrating tablets containing particles coated with a water-insoluble polymer (corresponding to 20 mg of compound A free base per tablet).

[0210] Example 2

[0211] Preparation of coating solution for compound A

[0212] Hydroxypropyl methylcellulose 2910 (24.21 g) was dissolved in purified water (399.8 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (180.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0213] Preparation of organic acid coating solution

[0214] Hydroxypropyl methylcellulose 2910 (33.59 g) was dissolved in purified water (673.9 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (100.8 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0215] Preparation of organic acid coated particles

[0216] Lactose / crystalline cellulose spherical granules (300.0 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (555.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air velocity of 60 NL / min, inlet air temperature of 74 °C, and inlet air velocity of 0.5 m / min. 3 The feed rate of the spray liquid was 6-7 g / min. Next, the organic acid coating solution (620.0 g) was sprayed under the following conditions: spray air pressure 0.50 MPa, spray air velocity 60 NL / min, inlet air temperature 74-85℃, and inlet air velocity 0.5 m / min. 3 The spray feed rate was 5-6 g / min; the particles were dried to obtain dried particles (542.5 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (300 μm-105 μm) (505.3 g).

[0217] Preparation of water-insoluble polymer coating solution

[0218] Triglycerides (5.98 g), talc (30.2 g), and red iron oxide (0.2000 g) were suspended and dissolved in purified water (363.8 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (200.0 g) to obtain a water-insoluble polymer coating solution.

[0219] Preparation of water-insoluble polymer-coated particles

[0220] Organic acid-coated particles (300 μm-105 μm) (300.3 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (375.0 g) was sprayed under the following conditions to obtain sprayed particles (331.7 g): spray air pressure 0.5 MPa, spray air flow rate 60 NL / min, inlet air temperature 40 °C, and inlet air flow rate 0.5 m / min. 3 The spray feed rate was 2-4 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved through a 350 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles (325.0 g).

[0221] Preparation of outer layer particles

[0222] D-Mannitol (14.99 g) was dissolved in purified water (315.0 g) to obtain the 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, manufactured by ISP) (30.22 g) were fed into a fluidized bed dryer and vulcanized therein; the binder (198.0 g) was sprayed under the following conditions: spray air pressure 0.1 MPa, spray air velocity 60 NL / min, inlet air temperature 85 °C, and inlet air velocity 0.2 m / min. 3 The spray feed rate was 6 g / min; the particles were dried. The dried particles were sieved through an 850 μm sieve to obtain the sieved particles, i.e., the outer layer particles (519.8 g).

[0223] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0224] The water-insoluble polymer-coated particles (1153.8 mg), outer particles (2446.1 mg), aspartame (21.0 mg), L-menthol (13.1 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended in a glass bottle by shaking 100 times to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed using a φ10.0 mm flat punch, single-punch tablet press at 6 kN to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0225] Example 3

[0226] Preparation of water-insoluble polymer-coated particles

[0227] In the preparation step of the water-insoluble polymer-coated particles in Example 2, a sample was taken during the spraying of the water-insoluble polymer coating solution (225.0 g) to obtain sprayed particles (3.4 g). Next, the sprayed particles were dried and cured in a forced convection oven at 60°C for 14 hours. The dried and cured particles were then sieved using a 350 μm sieve to obtain the sieved particles, which are the water-insoluble polymer-coated particles.

[0228] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0229] The water-insoluble polymer-coated particles (1076.9 mg), the outer particles obtained in Example 2 (2523.0 mg), aspartame (21.0 mg), L-menthol (13.1 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed into tablets at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0230] Example 4

[0231] Preparation of water-insoluble polymer-coated particles

[0232] In the preparation steps of Example 2 of the water-insoluble polymer-coated particles, samples were taken during the spraying of the water-insoluble polymer coating solution (300.0 g) to obtain sprayed particles (3.0 g). Next, the sprayed particles were dried and cured in a forced convection constant temperature oven at 60°C for 14 hours. The dried and cured particles were then sieved using a 350 μm sieve to obtain the sieved particles, which are the water-insoluble polymer-coated particles.

[0233] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0234] The water-insoluble polymer-coated particles (1123.0 mg), the outer particles obtained in Example 2 (2476.9 mg), aspartame (21.0 mg), L-menthol (13.1 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended in a glass bottle by shaking 100 times to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed into tablets at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0235] Example 5

[0236] Preparation of water-insoluble polymer-coated particles

[0237] In the preparation step of the water-insoluble polymer-coated particles in Example 2, a sample was taken during the spraying of the water-insoluble polymer coating solution (330.0 g) to obtain sprayed particles (3.5 g). Next, the sprayed particles were dried and cured in a forced convection constant temperature oven at 60°C for 14 hours. The dried and cured particles were then sieved using a 350 μm sieve to obtain the sieved particles, which are the water-insoluble polymer-coated particles.

[0238] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0239] The water-insoluble polymer-coated particles (1141.3 mg), the outer particles obtained in Example 2 (2458.6 mg), aspartame (21.0 mg), L-menthol (13.1 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed into tablets at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0240] Example 6

[0241] Preparation of coating solution for compound A

[0242] Hydroxypropyl methylcellulose 2910 (28.76 g) was dissolved in purified water (479.75 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (215.6 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0243] Preparation of organic acid coating solution

[0244] Hydroxypropyl methylcellulose 2910 (43.24 g) was dissolved in purified water (864.70 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (216.3 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0245] Preparation of organic acid coated particles

[0246] Lactose / crystalline cellulose spherical granules (350.8 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (642.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air velocity of 60 NL / min, inlet air temperature of 65-72℃, and inlet air velocity of 0.5 m / min. 3 The feed rate of the spray liquid was 5-8 g / min. Next, the organic acid coating solution (925.0 g) was sprayed under the following conditions: spray air pressure 0.5 MPa, spray air velocity 60 NL / min, inlet air temperature 81-82℃, and inlet air velocity 0.5 m / min. 3The spray feed rate was 6-7 g / min; the particles were dried to obtain dried particles (722.4 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (300 μm-105 μm) (664.4 g).

[0247] Preparation of dissolution control substance coating solution

[0248] Hydroxypropyl methylcellulose 2910 (30.4g) and succinic acid (119.98g) were dissolved in purified water (1851.3g) to obtain a dissolution control substance coating solution.

[0249] Preparation of particles coated with dissolution control substances

[0250] Organic acid-coated particles (300μm-105μm) (340.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1295g) was sprayed under the following conditions: spray air pressure 0.5MPa, spray air velocity 60NL / min, inlet air temperature 85℃, and inlet air velocity 0.5m. 3 The feed rate of the spray liquid is 4-5 g / min; the particles are dried to obtain dried particles (415.2 g). The total amount of dried particles is sieved to obtain particles coated with dissolution control substance (355 μm-105 μm) (412.3 g).

[0251] Preparation of water-insoluble polymer coating solution

[0252] Triglycerides (5.98 g), talc (30.15 g), and red iron oxide (0.2131 g) were suspended and dissolved in purified water (363.9 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (200.2 g) to obtain a water-insoluble polymer coating solution.

[0253] Preparation of water-insoluble polymer-coated particles

[0254] Particles (355μm-105μm) (400.5g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein. Samples were taken at time points when the water-insoluble polymer coating solution (250.0g) was sprayed under the following conditions to obtain the sprayed particles (39.9g): spray air pressure 0.5MPa, spray air velocity 60NL / min, inlet air temperature 43℃, and inlet air velocity 0.5m. 3The feed rate of the spray liquid was 5 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved through a 350 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0255] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0256] The water-insoluble polymer-coated particles (1478.9 mg), the outer particles obtained in Example 2 (2121.1 mg), aspartame (21.0 mg), L-menthol (13.1 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), strawberry flavor (4.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed into tablets at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0257] Example 7

[0258] Preparation of coating solution for compound A

[0259] Hydroxypropyl methylcellulose 2910 (28.8 g) was dissolved in purified water (480.0 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (216.1 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0260] Preparation of organic acid coating solution

[0261] Hydroxypropyl methylcellulose 2910 (43.2 g) was dissolved in purified water (864.0 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (216.1 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0262] Preparation of organic acid coated particles

[0263] Lactose / crystalline cellulose spherical granules (349.8 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (642.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air velocity of 60 NL / min, inlet air temperature of 73 °C, and inlet air velocity of 0.5 m / min. 3 The feed rate of the spray liquid was 6-8 g / min. Next, the organic acid coating solution (925.0 g) was sprayed under the following conditions: spray air pressure 0.5 MPa, spray air velocity 60 NL / min, inlet air temperature 80℃, and inlet air velocity 0.5 m / min. 3 The spray feed rate was 5-8 g / min; the particles were dried to obtain dried particles (714.8 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (686.4 g).

[0264] Preparation of dissolution control substance coating solution

[0265] Hydroxypropyl methylcellulose 2910 (22.5g) and succinic acid (89.96g) were dissolved in purified water (1387.5g) to obtain a dissolution control substance coating solution.

[0266] Preparation of particles coated with dissolution control substances

[0267] Organic acid-coated particles (355μm-105μm) (329.8g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1257.0g) was sprayed under the following conditions: spray air pressure 0.5MPa, spray air velocity 60NL / min, inlet air temperature 85℃, and inlet air velocity 0.5m. 3 The spray feed rate was 4-5 g / min; the particles were dried to obtain 401.2 g of dried particles. The total amount of dried particles was sieved to obtain particles coated with dissolution control material (particles sieved at 355 μm).

[0268] Preparation of water-insoluble polymer coating solution

[0269] Polysorbate 80 (manufactured by Merck) (0.4071 g) was dissolved in purified water (499.7 g), and then talc (25.09 g) and red iron oxide (0.2000 g) were added. The mixture was then uniformly dispersed to obtain a suspension. The suspension was added in small portions to a stirred mixture of ammonium alkyl 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 an ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit NE30D, manufactured by Evonik) (25.1 g). The mixture was thoroughly stirred. A solution containing an ethyl acrylate-methyl methacrylate copolymer dispersion is added in small portions to a previous liquid containing an ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik), and the mixture is stirred thoroughly to obtain a water-insoluble polymer coating solution.

[0270] Preparation of water-insoluble polymer-coated particles

[0271] Particles coated with a dissolution control agent (355 μm sieved particles) (350.0 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (751.0 g) was sprayed under the following conditions to obtain sprayed particles (321.7 g): spray air pressure 0.5 MPa, spray air flow rate 60 NL / min, inlet air temperature 40-46℃, and inlet air flow rate 0.5-0.6 m / min. 3 The feed rate of the spray liquid was 2-3 g / min. Next, the sprayed particles were dried and cured in a forced convection oven at 60°C for 14 hours. The dried and cured particles were then sieved through a 350 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0272] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0273] The water-insoluble polymer-coated particles (1598.2 mg), the outer particles obtained in Example 2 (2013.8 mg), aspartame (21.0 mg), L-menthol (5.3 mg), acesulfame potassium (5.3 mg), sodium stearate fumarate (31.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed into tablets at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0274] Example 8

[0275] Preparation of coating solution for compound A

[0276] Hydroxypropyl methylcellulose 2910 (23.98 g) was dissolved in purified water (399.7 g) to obtain a hydroxypropyl methylcellulose solution. Then, compound A (179.7 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0277] Preparation of organic acid coating solution (1)

[0278] Hydroxypropyl methylcellulose 2910 (12.53 g) was dissolved in purified water (324.8 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (50.15 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0279] Preparation of organic acid-coated particles (1)

[0280] Lactose / crystalline cellulose spherical granules (450.4 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (522.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air velocity of 60 NL / min, inlet air temperature of 75 °C, and inlet air velocity of 0.5 m / min. 3 The feed rate of the spray liquid was 6 g / min. Next, the organic acid coating solution (1) (222.0 g) was sprayed under the following conditions: spray air pressure was 0.5 MPa, spray air velocity was 60 NL / min, inlet air temperature was 85℃, and inlet air velocity was 0.5-0.6 m / min. 3The feed rate of the spray liquid was 6-7 g / min; the particles were dried to obtain dried particles (631.0 g). The total amount of dried particles was sieved to obtain organic acid coated particles (1) (355 μm-105 μm) (623.6 g).

[0281] Preparation of dissolution control substance coating solution

[0282] Hydroxypropyl methylcellulose 2910 (33.25g) and succinic acid (84.11g) were dissolved in purified water (1540.2g) to obtain a dissolution control coating solution.

[0283] Preparation of organic acid coating solution (2)

[0284] Hydroxypropyl methylcellulose 2910 (16.20 g) was dissolved in purified water (416.3 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (64.15 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution (2).

[0285] Preparation of organic acid-coated particles (2)

[0286] Organic acid-coated particles (1) (355μm-105μm) (320.1g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1375.0g) was sprayed under the following conditions: spray air pressure 0.5MPa, spray air flow rate 60NL / min, inlet air temperature 85℃, and inlet air flow rate 0.5-0.6m. 3 The feed rate of the spray liquid was 4-5 g / min. Next, the organic acid coating solution (2) (420.0 g) was sprayed under the following conditions to obtain dried particles (446.0 g): spray air pressure was 0.5 MPa, spray air velocity was 60 NL / min, inlet air temperature was 80 °C, and inlet air velocity was 0.6 m / min. 3 / min, the spray liquid feed rate is 5-6g / min; the particles are dried. The total amount of dried particles is sieved to obtain organic acid coated particles (2) (355μm-125μm) (402.5g).

[0287] Preparation of water-insoluble polymer coating solution

[0288] Triglycerides (9.0 g), talc (45.10 g), and red iron oxide (0.9215 g) were suspended and dissolved in purified water (545.1 g). The mixture was added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (300.1 g) to obtain a water-insoluble polymer coating solution.

[0289] Preparation of water-insoluble polymer-coated particles

[0290] Organic acid-coated particles (2) (355μm-125μm) (399.8g) were placed in a microparticle coating granulator / Wurster and fluidized therein. Samples were taken at time points when the water-insoluble polymer coating solution (307.0g) was sprayed under the following conditions to obtain sprayed particles (20.4g): spray air pressure 0.3-0.5MPa, spray air velocity 60NL / min, inlet air temperature 35-43℃, and inlet air velocity 0.5-0.6m. 3 The feed rate of the spray liquid was 2-3 g / min. Next, the sprayed particles were dried and cured in a forced convection oven at 60°C for 14 hours. The dried and cured particles were then sieved through a 350 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0291] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0292] The water-insoluble polymer-coated particles (3510.3 mg), the outer particles obtained in Example 2 (5550.7 mg), aspartame (82.0 mg), L-menthol (10.3 mg), acesulfame potassium (10.3 mg), sodium stearate fumarate (61.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (1025.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (500 mg) was weighed and compressed into tablets at 6 kN using a φ11.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0293] Example 9

[0294] Preparation of coating solution for compound A

[0295] Hydroxypropyl methylcellulose 2910 (18.04 g) was dissolved in purified water (700.0 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (180.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0296] Preparation of organic acid coating solution (1)

[0297] Hydroxypropyl methylcellulose 2910 (12.49 g) was dissolved in purified water (399.7 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (50.12 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution (1).

[0298] Preparation of organic acid-coated particles (1)

[0299] Classified using a 75μm sieve with an aperture of 180 mm (D) 50 Partially pregelatinized starch (PCS PC-10, manufactured by Asahi Kasei Corporation, hereinafter the same) (310.1 g) was placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (830.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air flow rate of 60 NL / min, inlet air temperature of 83 °C, and inlet air flow rate of 0.5-0.6 m / min. 3 The feed rate of the spray liquid was 3-7 g / min. Next, the organic acid coating solution (1) (290.0 g) was sprayed under the following conditions: spray air pressure was 0.3 MPa, spray air velocity was 60 NL / min, inlet air temperature was 73-83℃, and inlet air velocity was 0.6 m / min. 3 The spray feed rate was 5-6 g / min; the particles were dried to obtain dried particles (476.5 g). The total amount of dried particles was sieved to obtain organic acid coated particles (1) (180 μm-75 μm) (356.8 g).

[0300] Preparation of dissolution control substance coating solution

[0301] Hydroxypropyl methylcellulose 2910 (33.25 g) and succinic acid (84.01 g) were dissolved in purified water (1540.0 g) to obtain a dissolution control coating solution.

[0302] Preparation of particles coated with dissolution control substances

[0303] Organic acid-coated particles (1) (180μm-75μm) (300.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1620.0g) was sprayed under the following conditions: spray air pressure 0.4MPa, spray air flow rate 60NL / min, inlet air temperature 84-85℃, and inlet air flow rate 0.5-0.6m. 3 The feed rate of the spray liquid was 4 g / min; the particles were dried to obtain dried particles (396.8 g). The total amount of dried particles was sieved to obtain particles coated with dissolution control substance (212 μm-75 μm) (357.8 g).

[0304] Preparation of organic acid coating solution (2)

[0305] Hydroxypropyl methylcellulose 2910 (17.02 g) was dissolved in purified water (640.0 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (80.1 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution (2).

[0306] Preparation of organic acid-coated particles (2)

[0307] Particles (212μm-75μm) (349.0g) coated with dissolution control substances were placed in a microparticle coating granulator / Wurster and fluidized therein; organic acid coating solution (2) (540.0g) was sprayed under the following conditions: spray air pressure of 0.4MPa, spray air flow rate of 60NL / min, inlet air temperature of 85℃, and inlet air flow rate of 0.5m. 3 The spray feed rate was 4 g / min; the particles were dried to obtain dried particles (396.1 g). The total amount of dried particles was sieved to obtain organic acid coated particles (2) (250 μm-75 μm) (390.0 g).

[0308] Preparation of water-insoluble polymer coating solution (1)

[0309] Triglycerides (4.5 g), talc (22.5 g), and red iron oxide (0.4452 g) were suspended and dissolved in purified water (272.5 g). The mixture was added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.0 g) to obtain a water-insoluble polymer coating solution (1).

[0310] Preparation of water-insoluble polymer-coated particles (1)

[0311] Organic acid-coated particles (2) (250μm-105μm) (350.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; water-insoluble polymer coating solution (1) (315.0g) was sprayed under the following conditions to obtain sprayed particles (340.5g): spray air pressure 0.3MPa, spray air flow rate 60NL / min, inlet air temperature 38℃, and inlet air flow rate 0.5-0.6m. 3 The feed rate of the spray liquid was 2-3 g / min. Then, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection constant temperature oven. The dried and cured particles were sieved through a 250 μm sieve to obtain the sieved particles, namely the water-insoluble polymer-coated particles (1).

[0312] Preparation of water-insoluble polymer coating solution (2)

[0313] Triglycerides (2.31 g), talc (11.26 g), and red iron oxide (0.2253 g) were suspended and dissolved in purified water (361.2 g). The mixture was added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (75.1 g) to obtain a water-insoluble polymer coating solution (2).

[0314] Preparation of water-insoluble polymer-coated particles (2)

[0315] Particles (1) (314.8 g) coated with a water-insoluble polymer were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-insoluble polymer coating solution (2) (200.0 g) was sprayed under the following conditions to obtain sprayed particles (251.5 g): spray air pressure 0.3 MPa, spray air flow rate 60 NL / min, inlet air temperature 35-38℃, and inlet air flow rate 0.6 m. 3 / min, the feed rate of the spray liquid is 2-3g / min. Then, the sprayed particles are dried and cured in a forced convection constant temperature oven at 60℃ for 14 hours. The dried and cured particles are sieved through a 350μm sieve to obtain the sieved particles, namely the water-insoluble polymer-coated particles (2).

[0316] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0317] The water-insoluble polymer-coated particles (2) (1584.9 mg), the outer particles obtained in Example 2 (1901.1 mg), aspartame (42.0 mg), sodium stearate 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 blended by shaking 100 times in a glass bottle to obtain a blend product (2) containing water-insoluble polymer-coated particles. The blend product (2) containing water-insoluble polymer-coated particles (400 mg) was weighed and compressed at 6 kN using a φ10.0 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets (2) containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0318] Example 10

[0319] Preparation of coating solution for compound A

[0320] Hydroxypropyl methylcellulose 2910 (16.80 g) was dissolved in purified water (449.98 g) to obtain a hydroxypropyl methylcellulose solution. Then, compound A (126.1 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0321] Preparation of organic acid coating solution

[0322] Hydroxypropyl methylcellulose 2910 (62.64 g) was dissolved in purified water (2609.9 g) to obtain a hydroxypropyl methylcellulose solution. Next, pre-milled fumaric acid (313.2 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0323] Preparation of organic acid coated particles

[0324] Lactose / crystalline cellulose spherical granules (300.0 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (490.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air velocity of 60 NL / min, inlet air temperature of 73 °C, and inlet air velocity of 0.6 m / min. 3 The feed rate of the spray liquid was 5-6 g / min. Next, the organic acid coating solution (2750.0 g) was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 60-70 NL / min, inlet air temperature 78-80℃, and inlet air velocity 0.6 m / min. 3The spray feed rate was 6-7 g / min; the particles were dried to obtain dried particles (659.4 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (604.5 g).

[0325] Preparation of dissolution control substance coating solution

[0326] Methyl cellulose (28.12 g) and succinic acid (84.31 g) were dissolved in purified water (1300.15 g) to obtain a dissolution control substance coating solution.

[0327] Preparation of particles coated with dissolution control substances

[0328] Organic acid-coated particles (355μm-105μm) (300.4g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1190.0g) was sprayed under the following conditions: spray air pressure 0.3MPa, spray air flow rate 60NL / min, inlet air temperature 83℃, and inlet air flow rate 0.6m. 3 The feed rate of the spray liquid was 3-5 g / min; the particles were dried to obtain dried particles (384.3 g). The total amount of dried particles was sieved to obtain particles coated with dissolution control substance (355 μm-125 μm) (372.9 g).

[0329] Preparation of water-insoluble polymer coating solution

[0330] Triglycerides (4.50 g), talc (22.48 g), and yellow iron oxide (LCW, hereinafter the same) (0.4532 g) were suspended and dissolved in purified water (272.5 g). The mixture was added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.1 g) to obtain a water-insoluble polymer coating solution.

[0331] Preparation of water-insoluble polymer-coated particles

[0332] Particles (355μm-125μm) (360.1g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (200.0g) was sprayed under the following conditions to obtain sprayed particles (372.2g): spray air pressure 0.2MPa, spray air flow rate 60NL / min, inlet air temperature 36℃, and inlet air flow rate 0.6m. 3The feed rate of the spray liquid was 2-3 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved using a 355 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0333] Preparation of outer layer particles

[0334] D-mannitol (31.59 g) and citric anhydride (21.35 g) were dissolved in purified water (314.8 g) to obtain the 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) were fed into a fluidized bed dryer and fluidized therein; the binder (210.0 g) was sprayed under the following conditions: spray air pressure of 0.1 MPa, spray air velocity of 60 NL / min, inlet air temperature of 85 °C, and inlet air velocity of 0.2-0.3 m / min. 3 The spray feed rate was 11 g / min; the particles were dried. The dried particles were sieved through an 850 μm sieve to obtain the sieved particles, i.e., the outer layer particles (526.6 g).

[0335] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0336] The water-insoluble polymer-coated particles (2573.5 mg), outer particles (2566.2 mg), aspartame (63.0 mg), orange flavoring (San fix orange, manufactured by San-Ei Gen FFI, Inc., hereinafter the same) (5.3 mg), sodium stearate fumarate (42.0 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (550.0 mg) was weighed and compressed using a φ11.5 mm flat punch and a single-punch tablet press at 6 kN to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0337] Example 11

[0338] Preparation of coating solution for compound A

[0339] Hydroxypropyl methylcellulose 2910 (16.83 g) was dissolved in purified water (450.21 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (126.3 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0340] Preparation of organic acid coating solution

[0341] Hydroxypropyl methylcellulose 2910 (79.92 g) was dissolved in purified water (3330.1 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (399.6 g) was suspended in the hydroxypropyl methylcellulose solution to obtain an organic acid coating solution.

[0342] Preparation of dissolution control substance coating solution

[0343] Methylcellulose (28.1g) and succinic acid (84.0g) were dissolved in purified water (1300.0g) to obtain a dissolution control substance coating solution.

[0344] Preparation of organic acid coated particles

[0345] Lactose / crystalline cellulose spherical granules (300.0 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (490.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air velocity of 80 NL / min, inlet air temperature of 83 °C, and inlet air velocity of 0.6 m / min. 3 The feed rate of the spray liquid was 5-6 g / min. Next, the organic acid coating solution (2920.0 g) was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 70 NL / min, inlet air temperature 80℃, and inlet air velocity 0.6 m / min. 3 The spray feed rate was 5-6 g / min; the particles were dried to obtain dried particles (730.9 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (726.5 g).

[0346] Preparation of particles coated with dissolution control substances

[0347] Organic acid-coated particles (355μm-105μm) (360.1g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (357.0g) was sprayed under the following conditions: spray air pressure 0.3MPa, spray air velocity 70NL / min, inlet air temperature 80℃, and inlet air velocity 0.6m. 3The feed rate of the spray liquid was 4-5 g / min. Next, the dissolution control substance coating solution (750.0 g) was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 70 NL / min, inlet air temperature 80℃, and inlet air velocity 0.6 m / min. 3 The feed rate of the spray liquid is 2-4 g / min; the particles are dried to obtain dried particles (443.0 g). The total amount of dried particles is sieved to obtain particles coated with dissolution control substance (355 μm-125 μm) (433.0 g).

[0348] Preparation of water-insoluble polymer coating solution

[0349] Triglycerides (4.50 g), talc (22.51 g), and yellow iron oxide (0.4503 g) were suspended and dissolved in purified water (272.5 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.3 g) to obtain a water-insoluble polymer coating solution.

[0350] Preparation of water-insoluble polymer-coated particles

[0351] Particles (355μm-125μm) (420.3g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (238.0g) was sprayed under the following conditions to obtain sprayed particles (426.9g): spray air pressure 0.2MPa, spray air flow rate 70NL / min, inlet air temperature 36℃, and inlet air flow rate 0.6-0.7m. 3 The feed rate of the spray liquid was 2 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved through a 355 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0352] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0353] The water-insoluble polymer-coated particles (2900.6 mg), the outer particles obtained in Example 10 (2449.2 mg), aspartame (63.0 mg), orange flavor (5.3 mg), sodium stearate fumarate (42.0 mg), and crystalline cellulose (CEOLUS KG-1000, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (570.0 mg) was weighed and compressed using a φ11.5 mm flat punch and a single-punch tablet press at 6 kN to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0354] Example 12 (with sealed coating)

[0355] Preparation of coating solution for compound A

[0356] Hydroxypropyl methylcellulose 2910 (20.41 g) was dissolved in purified water (550.03 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (153.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0357] Preparation of water-soluble polymer coating solution

[0358] Hydroxypropyl methylcellulose 2910 (30.03 g) was dissolved in purified water (955.01 g) to obtain a hydroxypropyl methylcellulose solution. Then, talc (14.99 g) was suspended to obtain a water-soluble polymer coating solution.

[0359] Preparation of organic acid coating solution

[0360] Hydroxypropyl methylcellulose 2910 (30.04 g) was dissolved in purified water (1350.2 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (162.0 g) was suspended to obtain an organic acid coating solution.

[0361] Preparation of organic acid coated particles

[0362] Lactose / crystalline cellulose spherical granules (399.2 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (655.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air velocity of 60 NL / min, inlet air temperature of 76 °C, and inlet air velocity of 0.6-0.7 m / min. 3The feed rate of the spray liquid is 1-7 g / min. The water-soluble polymer coating liquid (400.0 g) is sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 60 NL / min, inlet air temperature 84℃, and inlet air velocity 0.7 m / min. 3 The feed rate of the spray liquid was 4-6 g / min. The organic acid coating solution (1233.0 g) was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 60 NL / min, inlet air temperature 76℃, and inlet air velocity 0.6-0.7 m / min. 3 The feed rate of the spray liquid was 6 g / min. Next, the particles were dried to obtain 667.5 g of dried particles. The total amount of dried particles was then sieved to obtain organic acid-coated particles (355 μm-125 μm) (662.5 g).

[0363] Preparation of dissolution control substance coating solution

[0364] Hydroxypropyl methylcellulose 2910 (28.04 g) and succinic acid (84.02 g) were dissolved in purified water (1330.0 g) to obtain a dissolution control coating solution.

[0365] Preparation of particles coated with dissolution control substances

[0366] Organic acid-coated particles (355μm-125μm) (330.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1008.0g) was sprayed under the following conditions: spray air pressure 0.30MPa, spray air velocity 65NL / min, inlet air temperature 83℃, and inlet air velocity 0.6m. 3 The spray feed rate is 4-5 g / min; the particles are dried to obtain dried particles (377.5 g). The total amount of dried particles is sieved to obtain particles coated with dissolution control substance (355 μm-125 μm) (376.5 g).

[0367] Preparation of water-insoluble polymer coating solution

[0368] 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 ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.0 g) to obtain a water-insoluble polymer coating solution.

[0369] Preparation of water-insoluble polymer-coated particles

[0370] Particles (355μm-125μm) (370.0g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (277.0g) was sprayed under the following conditions to obtain sprayed particles (397.1g): spray air pressure 0.2MPa, spray air velocity 65NL / min, inlet air temperature 36℃, and inlet air velocity 0.6-0.7m. 3 The feed rate of the spray liquid was 2-3 g / min. Next, the sprayed particles were dried and cured in a forced convection oven at 60°C for 2 hours. The dried and cured particles were then sieved using a 355 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0371] Preparation of outer layer particles

[0372] D-Mannitol (27.19 g) and citric anhydride (17.24 g) were dissolved in purified water (320.0 g) to obtain the 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), crospovidone (Polyplasdone XL-10, manufactured by ISP) (17.58 g), and β-cyclodextrin (68.80 g) were fed into a fluidized bed dryer and fluidized therein; the binder (145.6 g) was sprayed under the following conditions: spray air pressure of 0.1 MPa, spray air velocity of 60 NL / min, inlet air temperature of 85 °C, and inlet air velocity of 0.2-0.3 m / min. 3 The spray feed rate was 6 g / min; the particles were dried. The dried particles were then sieved through an 850 μm sieve to obtain the sieved particles, i.e., the outer layer particles (363.1 g).

[0373] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0374] The water-insoluble polymer-coated particles (2042.8 mg), outer particles (3049.7 mg), aspartame (63.0 mg), sodium stearate fumarate (94.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (550.0 mg) was weighed and compressed using a φ11.5 mm flat punch and a single-punch tablet press at 9 kN to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0375] Example 13 (with sealed coating)

[0376] Preparation of organic acid coating solution

[0377] Hydroxypropyl methylcellulose 2910 (17.51 ​​g) was dissolved in purified water (787.53 g) to obtain a hydroxypropyl methylcellulose solution. Then, pre-milled fumaric acid (94.5 g) was suspended to obtain an organic acid coating solution.

[0378] Preparation of dissolution control substance coating solution

[0379] Hydroxypropyl methylcellulose 2910 (28.03g) and succinic acid (83.98g) were dissolved in purified water (1330.0g) to obtain a dissolution control substance coating solution.

[0380] Preparation of particles coated with dissolution control substances

[0381] The organic acid-coated particles (355 μm-125 μm) (330.0 g) obtained in Example 12 were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (559.4 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air flow rate of 65 NL / min, inlet air temperature of 76 °C, and inlet air flow rate of 0.6-0.7 m / min. 3 The feed rate of the spray liquid is 3-9 g / min. The dissolution control substance coating solution (1008.0 g) is sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 65 NL / min, inlet air temperature 76℃, and inlet air velocity 0.6-0.7 m / min. 3The feed rate of the spray liquid was 4-6 g / min. Next, the particles were dried to obtain dried particles (459.9 g). The total amount of dried particles was sieved to obtain particles coated with dissolution control material (355 μm-125 μm) (451.3 g).

[0382] Preparation of water-insoluble polymer coating solution

[0383] Triacetin (4.50 g) and talc (22.50 g) were suspended and dissolved in purified water (273.0 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.0 g) to obtain a water-insoluble polymer coating solution.

[0384] Preparation of water-insoluble polymer-coated particles

[0385] Particles (355μm-125μm) (445.0g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (284.5g) was sprayed under the following conditions to obtain sprayed particles (430.9g): spray air pressure 0.2MPa, spray air flow rate 70NL / min, inlet air temperature 34-36℃, and inlet air flow rate 0.7m. 3 The feed rate of the spray liquid was 2-3 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved using a 355 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0386] Preparation of Coating Solution for Aggregation Inhibitor

[0387] D-mannitol (50.15g) was dissolved in purified water (450.05g) to obtain a coating solution containing a coagulation inhibitor.

[0388] Preparation of particles coated with agglomeration inhibitor

[0389] 415.0 g of water-insoluble polymer-coated particles were placed in a microparticle coating granulator / Wurster and fluidized therein; 222.2 g of agglomeration inhibitor coating solution was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 65 NL / min, inlet air temperature 68 °C, and inlet air velocity 0.7 m / min. 3The spray feed rate was 4 g / min; the particles were dried to obtain dried particles (428.0 g). The total amount of sprayed particles was sieved to obtain 355 μm-125 μm particles (427.5 g) coated as agglomeration inhibitors.

[0390] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0391] The particles coated with the aggregation inhibitor (2545.5 mg), the outer particles obtained in Example 12 (2751.8 mg), aspartame (63.0 mg), menthol flavoring (menthol cortisone HL33855, manufactured by Ogawa & Co., Ltd.) (5.3 mg), sodium stearate fumarate (94.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing particles coated with the aggregation inhibitor. The blend containing particles coated with the aggregation inhibitor (570.0 mg) was weighed and compressed at 9 kN using a φ11.5 mm flat punch and a single-punch tablet press to obtain orally disintegrating tablets (corresponding to 20 mg of compound A free base per tablet) containing particles coated with a water-insoluble polymer.

[0392] Example 14

[0393] Preparation of coating solution for compound A

[0394] Hydroxypropyl methylcellulose 2910 (20.41 g) was dissolved in purified water (550.0 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (153.1 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0395] Preparation of water-soluble polymer coating solution

[0396] Hydroxypropyl methylcellulose 2910 (29.70 g) was dissolved in purified water (955.0 g) to obtain a hydroxypropyl methylcellulose solution. Then, talc (15.00 g) was suspended in the solution to obtain a water-soluble polymer coating solution.

[0397] Preparation of water-soluble polymer-coated particles

[0398] Lactose / crystalline cellulose spherical granules (399.2 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (655.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air velocity of 70 NL / min, inlet air temperature of 76 °C, and inlet air velocity of 0.6-0.7 m / min. 3 The feed rate of the spray liquid was 5-7 g / min. The water-soluble polymer coating liquid (520.0 g) was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 70 NL / min, inlet air temperature 76℃, and inlet air velocity 0.7 m / min. 3 The spray feed rate was 4-5 g / min; the particles were dried to obtain 505.3 g of dried particles. The total amount of dried particles was sieved to obtain water-soluble polymer-coated particles (355 μm-125 μm) (504.5 g).

[0399] Preparation of organic acid coating solution

[0400] Add 19.01 g of ammonium alkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik, the same below) to purified water (1530.0 g), add pre-milled fumaric acid (240.0 g), stir the mixture to obtain an organic acid coating solution.

[0401] Preparation of organic acid coated particles

[0402] 500.0 g of water-soluble polymer-coated particles (355 μm-125 μm) were placed in a microparticle coating granulator / Wurster and fluidized therein; 1665.5 g of organic acid coating solution was sprayed under the following conditions: spray air pressure 0.3 MPa, spray air velocity 65 NL / min, inlet air temperature 76 °C, and inlet air velocity 0.7 m / min. 3 The spray feed rate was 6 g / min; the particles were dried to obtain dried particles (675.8 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-125 μm) (674.9 g).

[0403] Preparation of dissolution control substance coating solution

[0404] Add 5.03g of ammonium methacrylate copolymer E and 76.01g of succinic acid to purified water (1200.0g), stir the mixture, and obtain a dissolution control substance coating solution.

[0405] Preparation of particles coated with dissolution control substances

[0406] Organic acid-coated particles (355μm-125μm) (330.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (839.0g) was sprayed under the following conditions: spray air pressure 0.30MPa, spray air velocity 65NL / min, inlet air temperature 70-76℃, and inlet air velocity 0.6-0.7m. 3 The spray liquid feed rate is 3-5 g / min; the particles are dried to obtain dried particles (371.5 g). The total amount of dried particles is sieved to obtain particles coated with dissolution control substance (355 μm-125 μm) (370.5 g).

[0407] Preparation of water-insoluble polymer coating solution

[0408] Triacetin (4.53 g) and talc (22.51 g) were suspended and dissolved in purified water (273.0 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (150.04 g) to obtain a water-insoluble polymer coating solution.

[0409] Preparation of water-insoluble polymer-coated particles

[0410] Particles (355μm-125μm) (365.0g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein. Samples were taken at time points when the water-insoluble polymer coating solution (200.0g) was sprayed under the following conditions, resulting in particles (7.23g) after spraying: spray air pressure 0.2MPa, spray air flow rate 65NL / min, inlet air temperature 35℃, and inlet air flow rate 0.7m. 3 The feed rate of the spray liquid was 1-2 g / min. Next, the sprayed particles were dried and cured at 60°C for 14 hours in a forced convection oven. The dried and cured particles were then sieved using a 355 μm sieve to obtain the sieved particles, i.e., the water-insoluble polymer-coated particles.

[0411] Preparation of orally disintegrating tablets containing particles coated with water-insoluble polymers

[0412] The water-insoluble polymer-coated particles (1924.8 mg), the outer particles obtained in Example 12 (3377.7 mg), aspartame (63.0 mg), sodium stearate fumarate (94.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (525.0 mg) were blended by shaking 100 times in a glass bottle to obtain a blend containing water-insoluble polymer-coated particles. The blend containing water-insoluble polymer-coated particles (570.0 mg) was weighed and compressed using a φ11.5 mm flat punch and a single-punch tablet press at 7 kN to obtain orally disintegrating tablets containing water-insoluble polymer-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0413] Comparative Example 1

[0414] Preparation of orally disintegrating tablets containing particles coated with organic acids

[0415] The organic acid-coated particles (567.0 mg) obtained in Example 1, the excipient for direct compression of ODT (SmartEX, manufactured by Freund Corporation) (500.0 mg), aspartame (11.0 mg), L-menthol (2.8 mg), acesulfame potassium (2.8 mg), sodium stearate fumarate (16.5 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by AsahiKasei Corporation) (275.0 mg) were blended in a glass bottle by shaking 100 times to obtain a blend containing organic acid-coated particles. The blend containing organic acid-coated particles (250 mg) was weighed and compressed using an 8.5 mm flat punch and a single-punch tablet press at 3 kN to obtain orally disintegrating tablets containing organic acid-coated particles (corresponding to 20 mg of compound A free base per tablet).

[0416] Reference Example 1

[0417] Preparation of coating solution for compound A

[0418] Hydroxypropyl methylcellulose 2910 (15.62 g) was dissolved in purified water (417.9 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (117.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0419] Preparation of particles coated with compound A

[0420] Lactose / crystalline cellulose spherical granules (299.8 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (490.0 g) was sprayed under the following conditions: spray air pressure of 0.4 MPa, spray air flow rate of 60 NL / min, inlet air temperature of 75 °C, and inlet air flow rate of 0.7 m / min. 3 The spray feed rate was 6 g / min; the particles were dried to obtain dried particles (360.4 g). The total amount of dried particles was sieved to obtain compound A-coated particles (355 μm-125 μm) (358.3 g).

[0421] Preparation of water-insoluble polymer coating solution

[0422] Triglycerides (5.96 g), talc (30.01 g), and red iron oxide (0.6010 g) were suspended and dissolved in purified water (363.4 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (200.0 g) to obtain a water-insoluble polymer coating solution.

[0423] Preparation of water-insoluble polymer-coated particles

[0424] 330.0 g of particles coated with compound A (355 μm-125 μm) were placed in a microparticle coating granulator / Wurster and fluidized therein; 461.0 g of the water-insoluble polymer coating solution was sprayed under the following conditions: spray air pressure 0.4 MPa, spray air flow rate 60 NL / min, inlet air temperature 38 °C, and inlet air flow rate 0.7 m / min. 3 The spray feed rate was 3 g / min; after spraying, 347.3 g of particles were obtained. The sprayed particles were then dried and cured in a forced convection oven at 60°C for 14 hours. The dried and cured particles were then sieved using a 355 μm sieve to obtain sieved particles, i.e., water-insoluble polymer-coated particles.

[0425] See Example 2

[0426] Preparation of coating solution for compound A

[0427] Hydroxypropyl methylcellulose 2910 (12.01 g) was dissolved in purified water (320.1 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (90.15 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0428] Preparation of particles coated with compound A

[0429] Crystalline cellulose (particles) (CELPHERE CP203, manufactured by Asahi Kasei Corporation) (450.4 g) was placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (380.0 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air velocity of 60-70 NL / min, inlet air temperature of 74-78 °C, and inlet air velocity of 0.6 m / min. 3 The spray feed rate was 4-5 g / min; the particles were dried to obtain 500.1 g of dried particles. The total amount of dried particles was sieved to obtain 493.1 g of particles coated with compound A (355 μm-125 μm).

[0430] Preparation of water-soluble polymer coating solution (1)

[0431] HPMC (120.1 g) was dissolved in purified water (4000.0 g) to suspend talc (60.05 g) and obtain a water-soluble polymer coating solution (1).

[0432] Preparation of water-soluble polymer-coated particles (1)

[0433] Particles coated with compound A (355μm-125μm) (480.1g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-soluble polymer coating solution (1) (4020.0g) was sprayed under the following conditions: spray air pressure 0.3MPa, spray air flow rate 70NL / min, inlet air temperature 84℃, and inlet air flow rate 0.7m. 3 The feed rate of the spray liquid is 4-8 g / min; the particles are dried to obtain dried particles (611.5 g). The total amount of dried particles is sieved to obtain water-soluble polymer-coated particles (1) (425 μm-125 μm) (566.6 g).

[0434] Preparation of water-soluble polymer coating solution (2)

[0435] HPMC (120.3g) was dissolved in purified water (4000.0g) to suspend talc (60.13g) and obtain a water-soluble polymer coating solution (2).

[0436] Preparation of water-soluble polymer-coated particles (2)

[0437] Particles (1) (425μm-125μm) (566.6g) coated with water-soluble polymer were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-soluble polymer coating solution (2) (4000.0g) was sprayed under the following conditions: spray air pressure of 0.3MPa, spray air velocity of 60-75NL / min, inlet air temperature of 81℃, and inlet air velocity of 0.7m. 3 The feed rate of the spray liquid was 4-7 g / min; the particles were dried to obtain dried particles (722.8 g). The total amount of dried particles was sieved to obtain water-soluble polymer-coated particles (2) (500 μm-150 μm) (714.2 g).

[0438] Preparation of water-soluble polymer coating solution (3)

[0439] HPMC (120.3g) was dissolved in purified water (4000.0g) to suspend talc (60.06g) and obtain a water-soluble polymer coating solution (3).

[0440] Preparation of water-soluble polymer-coated particles (3)

[0441] Particles (2) (500μm-150μm) (680.0g) coated with water-soluble polymer were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-soluble polymer coating solution (3) (4000.0g) was sprayed under the following conditions: spray air pressure of 0.3MPa, spray air velocity of 70-80NL / min, inlet air temperature of 81-84℃, and inlet air velocity of 0.7m. 3 The feed rate of the spray liquid is 5-7 g / min; the particles are dried to obtain dried particles (821.0 g). The total amount of dried particles is sieved to obtain water-soluble polymer-coated particles (3) (500 μm-150 μm) (757.6 g).

[0442] See Example 3

[0443] Preparation of coating solution for compound A

[0444] Hydroxypropyl methylcellulose 2910 (24.01 g) was dissolved in purified water (399.92 g) to obtain a hydroxypropyl methylcellulose solution. Next, compound A (180.3 g) was uniformly dispersed in the hydroxypropyl methylcellulose solution to obtain a coating solution of compound A.

[0445] Preparation of water-soluble polymer coating solution

[0446] Hydroxypropyl methylcellulose 2910 (21.88 g) was dissolved in purified water (400.30 g) to obtain a hydroxypropyl methylcellulose solution. Talc (11.21 g) was added and dispersed uniformly to obtain a water-soluble polymer coating solution.

[0447] Preparation of water-soluble polymer-coated particles

[0448] Lactose / crystalline cellulose spherical granules (300.0 g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the coating solution of compound A (600.0 g) was sprayed under the following conditions: spray air pressure of 0.5 MPa, spray air velocity of 60 NL / min, inlet air temperature of 70 °C, and inlet air velocity of 0.5-0.6 m / min. 3 The feed rate of the spray liquid was 5-7 g / min. Next, the HPMC coating solution (400.0 g) was sprayed under the following conditions: spray air pressure 0.5 MPa, spray air velocity 60 NL / min, inlet air temperature 85℃, and inlet air velocity 0.5-0.6 m / min. 3 The spray feed rate was 3-4 g / min; the particles were dried to obtain dried particles (465.3 g). The total amount of dried particles was sieved to obtain water-soluble polymer-coated particles (250 μm-105 μm) (409.3 g).

[0449] Preparation of dissolution control substance coating solution

[0450] Hydroxypropyl methylcellulose 2910 (30.3 g), polysorbate 80 (manufactured by NOF CORPORATION) (0.1498 g), and succinic acid (Wako premium grade, manufactured by Wako Pure Chemical Industries, Ltd., hereinafter the same) (119.58 g) were dissolved in purified water (1750.4 g) to obtain a dissolution control substance coating solution.

[0451] Preparation of particles coated with dissolution control substances

[0452] 399.8 g of water-soluble polymer-coated particles (250 μm-105 μm) were placed in a microparticle coating granulator / Wurster and fluidized therein; the dissolution control substance coating solution (1870.0 g) was sprayed under the following conditions: spray air pressure 0.5 MPa, spray air velocity 60 NL / min, inlet air temperature 85 °C, and inlet air velocity 0.5 m / min. 3The feed rate of the spray liquid is 4-5 g / min; the particles are dried to obtain dried particles (505.0 g). The total amount of dried particles is sieved to obtain particles coated with dissolution control substance (250 μm-105 μm) (497.5 g).

[0453] Preparation of water-insoluble polymer coating solution

[0454] Triglycerides (9.01 g), talc (45.3 g), and red iron oxide (0.2935 g) were suspended and dissolved in purified water (546.0 g). The mixture was then added to stirred ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (300.3 g) to obtain a water-insoluble polymer coating solution.

[0455] Preparation of water-insoluble polymer-coated particles

[0456] Particles (250μm-105μm) (440.3g) coated with a dissolution control substance were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (550.0g) was sprayed under the following conditions to obtain sprayed particles (492.9g): spray air pressure 0.5MPa, spray air flow rate 60NL / min, inlet air temperature 44℃, and inlet air flow rate 0.4-0.5m. 3 The feed rate of the spray liquid was 3 g / min. The total amount of sprayed particles was sieved to obtain sprayed particles (355 μm-105 μm). Next, the sprayed particles (355 μm-105 μm) were dried and cured in a forced convection constant temperature oven at 60 °C for 14 hours. The dried and cured particles were then sieved through a 300 μm sieve to obtain sieved particles, i.e., water-insoluble polymer-coated particles.

[0457] Preparation of outer layer particles

[0458] Dissolve D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (31.56g) and citric anhydride (manufactured by ADM Far East) (41.97g) in purified water (316.9g) to obtain an adhesive. 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) were fed into a fluidized bed dryer / granulator (LAB-1, manufactured by POWREX, hereinafter the same) and fluidized therein; the binder (210.0 g) was sprayed under the following conditions: spray air pressure of 0.1 MPa, spray air velocity of 60 NL / min, inlet air temperature of 85 °C, and inlet air velocity of 0.3 m. 3 The spray feed rate was 10 g / min; the particles were dried. The dried particles were then sieved through an 850 μm sieve to obtain the sieved particles, i.e., the outer layer particles (533.0 g).

[0459] Preparation of Coating Solution for Aggregation Inhibitor

[0460] Dissolve D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (37.50g) in purified water (262.6g) to obtain a coating solution containing a coagulation inhibitor.

[0461] Preparation of particles coated with agglomeration inhibitor

[0462] 250.0 g of water-insoluble polymer-coated particles were placed in a microparticle coating granulator / Wurster and fluidized therein; 200.0 g of agglomeration inhibitor coating solution was sprayed under the following conditions: spray air pressure 0.5 MPa, spray air velocity 60 NL / min, inlet air temperature 53-60℃, and inlet air velocity 0.5 m / min. 3 The spray liquid feed rate was 2-4 g / min; the particles were dried to obtain dried particles (263.9 g). The total amount of sprayed particles was sieved to obtain particles coated with agglomeration inhibitors in the range of 355 μm-105 μm.

[0463] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0464] The particles coated with agglomeration inhibitor (21543.6 mg), outer particles (33483.8 mg), aspartame (321 mg), L-menthol (200.6 mg), acesulfame potassium (80.3 mg), sodium stearate fumarate (481.5 mg), strawberry flavoring (STRAWBERRY DURAROME, manufactured by Nihon Firmenich KK, hereinafter the same) (64.2 mg), and crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (8025.0 mg) were blended in a glass bottle by shaking 100 times to obtain a blend containing particles coated with agglomeration inhibitor. The blend containing particles coated with agglomeration inhibitor (400 mg) was weighed and compressed using a φ10.0 mm flat punch and a single-punch tablet press at 6 kN to obtain orally disintegrating tablets containing particles coated with agglomeration inhibitor (corresponding to 20 mg of compound A free base per tablet).

[0465] The formulations (calculated values) of the preparations of Examples 1-14, Comparative Example 1, and Reference Examples 1-3 are shown in Tables 1-1 to 1-4.

[0466] Eudragit RS30D (trade name) is sold as a 30% aqueous dispersion. The solids content is shown in the individual tables for Eudragit RS30D.

[0467] Table 1-1

[0468]

[0469]

[0470] Table 1-2

[0471]

[0472] Table 1-3

[0473]

[0474] Table 1-4

[0475]

[0476]

[0477] Example 15

[0478] Preparation of coating solution for compound A

[0479] Hydroxypropyl methylcellulose 2910 (77.08 g) was dissolved in purified water (1763.0 g) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (627.9 g) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0480] Preparation of particles coated with compound A

[0481] Lactose / crystalline cellulose spherical granules (1463.0 g) were placed in a microparticle coating granulator / Wurster (FD-MP-10, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A (2294.0 g) was sprayed under the following conditions: spray air pressure of 0.21 MPa, spray air flow rate of 70 NL / min, inlet air temperature of 67-70 °C, and inlet air flow rate of 1.3 m. 3 The spray feed rate was 15 g / min; the particles were dried to obtain dried particles (1939.6 g). The total amount of dried particles was sieved to obtain compound A-coated particles (355 μm-105 μm) (1936.0 g).

[0482] Preparation of organic acid coating solution

[0483] An organic acid coating solution was prepared by dissolving 21.00 g of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 350.0 g of succinic acid in purified water (3675.0 g) and anhydrous ethanol (1575.0 g). Then, pre-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (700.0 g) was uniformly dispersed.

[0484] Preparation of organic acid coated particles

[0485] Particles coated with compound A (355μm-105μm) (1391.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (6104.0g) was sprayed under the following conditions: spray air pressure 0.21MPa, spray air velocity 70NL / min, inlet air temperature 68-73℃, and inlet air velocity 1.3-1.4m. 3 The spray feed rate was 18-19 g / min; the particles were dried to obtain 2035.0 g of dried particles. The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm).

[0486] Preparation of water-insoluble polymer coating solution

[0487] Triacetin (6.6 g), titanium dioxide (6.6 g), and talc (33.0 g) were suspended in purified water (99.0 g) and anhydrous ethanol (891.0 g), and then dissolved in water to obtain a water-insoluble polymer coating solution. Eudragit RSPO (manufactured by Evonik) (52.8 g) and Eudragit RLPO (manufactured by Evonik) (13.20 g) were further dissolved to obtain a water-insoluble polymer coating solution.

[0488] Preparation of Coating Solution for Aggregation Inhibitor

[0489] Light anhydrous silica (Sylysia 320, manufactured by FUJI SILYSIACHEMICAL LTD.) (9.0 g) was dispersed in purified water (171.0 g) to obtain a coating solution containing a coagulation inhibitor.

[0490] Preparation of particles coated with agglomeration inhibitor

[0491] Organic acid-coated particles (355μm-105μm) (1110.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (661.3g) was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air pressure 0.21MPa, spray air flow rate 70NL / min, inlet air temperature 27-28℃, and inlet air flow rate 1.2-1.3m. 3 The feed rate of the spray liquid was 4 g / min. Next, the agglomeration inhibitor coating liquid (79.2 g) was sprayed under the following conditions: spray air pressure 0.21 MPa, spray air velocity 70 NL / min, inlet air temperature 28-73℃, and inlet air velocity 1.3 m / min. 3 The feed rate of the spray liquid was 5 g / min; the particles were dried to obtain dried particles (1131.0 g). The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-105 μm) (1130.0 g).

[0492] Preparation of outer layer particles

[0493] D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (30.0g), citric anhydride (30.0g), and crospovidone (Kollidon CL-SF, manufactured by BASF) (30.0g) were dissolved and suspended in purified water (600.0g) to obtain a spray solution. 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 fluidized bed dryer / granulator (LAB-1, manufactured by POWREX) and fluidized therein. The spray liquid (230.0 g) was sprayed under the following conditions: spray air pressure of 0.14 MPa, spray air flow rate of 60 NL / min, inlet air temperature of 82-83 °C, and inlet air flow rate of 0.2 m / min. 3 The spray liquid feed rate was 6 g / min; the particles were dried to obtain outer layer particles (443.4 g).

[0494] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0495] The following components were mixed manually in a 10L plastic bag to obtain a blend: 107.4 g of particles coated with agglomeration inhibitor, 142.2 g of outer particles, 14.4 g of crystalline cellulose (CEOLUSKG-802, manufactured by Asahi Kasei Corporation), 14.4 g of crospovidone (Kollidon CL-F, manufactured by BASF), 0.78 g of magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd., hereinafter the same), 2.4 g of acesulfame potassium, 2.4 g of aspartame, 0.48 g of menthol cortisone, and 2.88 g of sodium stearate fumarate. The blend was then compressed using a rotary tablet press at an average pressure of 7.5 kN to obtain orally disintegrating tablets (478.9 mg in weight and 10.5 mm in diameter) containing 20 mg of compound A in its free form.

[0496] Example 16

[0497] Preparation of coating solution for compound A

[0498] Hydroxypropyl methylcellulose 2910 (78.72 g) was dissolved in purified water (1800.0 g) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (641.3 g) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0499] Preparation of particles coated with compound A

[0500] Lactose / crystalline cellulose spherical granules (1463.0 g) were placed in a microparticle coating granulator / Wurster (FD-MP-10, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A (2394.0 g) was sprayed under the following conditions: spray air pressure of 0.21 MPa, spray air flow rate of 70 NL / min, inlet air temperature of 66-68 °C, and inlet air flow rate of 1.3 m. 3 The spray feed rate was 15 g / min; the particles were dried to obtain dried particles (1986.5 g). The total amount of dried particles was sieved to obtain compound A-coated particles (355 μm-105 μm) (1985.5 g).

[0501] Preparation of organic acid coating solution

[0502] An organic acid coating solution was prepared by dissolving 24.60 g of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 410.0 g of succinic acid in purified water (4305.0 g) and anhydrous ethanol (1845.0 g). Then, pre-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (820.0 g) was uniformly dispersed.

[0503] Preparation of organic acid coated particles

[0504] Particles coated with compound A (355μm-105μm) (1605.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (7043.0g) was sprayed under the following conditions: spray air pressure 0.21MPa, spray air velocity 70NL / min, inlet air temperature 66-69℃, and inlet air velocity 1.3-1.4m. 3 The feed rate of the spray liquid was 16-18 g / min; the particles were dried to obtain dried particles (2309.6 g). The total amount of dried particles was sieved to obtain organic acid coated particles (355 μm-105 μm) (2803.6 g).

[0505] Preparation of water-insoluble polymer coating solution

[0506] Triacetin (8.64 g), titanium dioxide (8.96 g), and talc (43.2 g) were suspended in purified water (129.6 g) and anhydrous ethanol (1166 g), and then dissolved in water to obtain a water-insoluble polymer coating solution.

[0507] Preparation of Coating Solution for Aggregation Inhibitor

[0508] Light anhydrous silica (Sylysia 320, manufactured by FUJI SILYSIACHEMICAL LTD.) (6.0 g) was dispersed in purified water (114.0 g) to obtain a coagulation inhibitor coating solution.

[0509] Preparation of particles coated with agglomeration inhibitor

[0510] Organic acid-coated particles (355μm-105μm) (1682.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (902.0g) was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air pressure 0.21MPa, spray air flow rate 70NL / min, inlet air temperature 28-29℃, and inlet air flow rate 1.3m. 3 The feed rate of the spray liquid was 4 g / min. Next, the agglomeration inhibitor coating liquid (120.0 g) was sprayed under the following conditions: spray air pressure 0.21 MPa, spray air velocity 70 NL / min, inlet air temperature 28-73℃, and inlet air velocity 1.3 m / min. 3 The feed rate of the spray liquid was 5 g / min; the particles were dried to obtain dried particles (1745.0 g). The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-105 μm) (1743.0 g).

[0511] Preparation of outer layer sieved particles

[0512] D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (200.0g), citric anhydride (200.0g), and crospovidone (Kollidon CL-SF, manufactured by BASF) (200.0g) were dissolved and suspended in purified water (4000.0g) to obtain a spray solution. 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 fluidized bed dryer / granulator (FD-5S, manufactured by POWREX) and fluidized therein; the spray liquid (2128.0 g) was sprayed under the following conditions: spray air pressure 0.24 MPa, spray air velocity 2600 NL / hr, inlet air temperature 70-72°C, and inlet air velocity 1.3 m / s. 3 The spray feed rate was 45 g / min; the particles were dried to obtain outer layer particles (3741.3 g). The outer layer particles (3665.0 g) were put into a grinding mill and sieved using a 1.5 mm sieve to obtain outer layer sieved particles (3644.6 g).

[0513] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0514] The particles coated with agglomeration inhibitors (1629.0g), the outer sieved particles (1424.0g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (176.0g), crospovidone (Kollidon CL-F, manufactured by BASF) (176.0g), and magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries) were also included. The following ingredients (9.6 g), acesulfame potassium (32.0 g), aspartame (32.0 g), menthol cortisone (6.4 g), and sodium stearate fumarate (35.2 g) were placed in a rotary drum mixer and mixed at 30 rpm for 5 min to obtain a blend (3509.5 g). The blend was then compressed using a rotary tablet press at an average pressure of 7.8 kN to obtain orally disintegrating tablets (440 mg in weight and 10 mm in diameter) containing 20 mg of compound A in its free form.

[0515] Example 17

[0516] Preparation of coating solution for compound A

[0517] Hydroxypropyl methylcellulose 2910 (105.0 g) was dissolved in purified water (2400.0 g) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (855.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0518] Preparation of particles coated with compound A

[0519] Lactose / crystalline cellulose spherical granules (1848.0 g) were placed in a microparticle coating granulator / Wurster (FD-MP-10, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A (3024.0 g) was sprayed under the following conditions: spray air pressure of 0.21 MPa, spray air flow rate of 70 NL / min, inlet air temperature of 65-67 °C, and inlet air flow rate of 1.3 m. 3 The feed rate of the spray liquid was 11-14 g / min; the particles were dried to obtain dried particles (2539.8 g). The total amount of dried particles was sieved to obtain particles coated with compound A (355 μm-105 μm) (2512.1 g).

[0520] Preparation of organic acid coating solution

[0521] An organic acid coating solution was prepared by dissolving 18.00 g of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 300.0 g of succinic acid in purified water (2100.0 g) and anhydrous ethanol (900.0 g). Then, pre-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (300.0 g) was uniformly dispersed.

[0522] Preparation of organic acid coated particles

[0523] 1124.0 g of particles coated with compound A (355 μm-105 μm) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (3292.0 g) was sprayed under the following conditions: spray air pressure 0.21 MPa, spray air velocity 70 NL / min, inlet air temperature 66-68 °C, and inlet air velocity 1.3 m / min. 3The spray feed rate was 16-17 g / min; the particles were dried to obtain dried particles (1591.0 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (1574.0 g).

[0524] Preparation of water-insoluble polymer coating solution

[0525] Triacetin (5.76 g), titanium dioxide (6.72 g), yellow iron oxide (0.72 g), and talc (28.8 g) were suspended in purified water (86.4 g) and anhydrous ethanol (777.6 g). Then, ammonium alkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (34.56 g) and ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (23.04 g) were further dissolved to obtain a water-insoluble polymer coating solution.

[0526] Preparation of Coating Solution for Aggregation Inhibitor

[0527] Light anhydrous silica (Sylysia 320, manufactured by FUJI SILYSIA CHEMICALL TD.) (4.5g) was dispersed in purified water (85.5g) to obtain a coating solution containing a coagulation inhibitor.

[0528] Preparation of particles coated with agglomeration inhibitor

[0529] Organic acid-coated particles (355μm-105μm) (1112.0g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (602.3g) was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air pressure 0.20MPa, spray air flow rate 70NL / min, inlet air temperature 27-29℃, and inlet air flow rate 1.3m. 3 The feed rate of the spray liquid was 4 g / min. Next, the agglomeration inhibitor coating liquid (90.0 g) was sprayed under the following conditions: spray air pressure 0.20 MPa, spray air velocity 70 NL / min, inlet air temperature 28-73℃, and inlet air velocity 1.3 m / min. 3 The feed rate of the spray liquid was 5-6 g / min; the particles were dried to obtain dried particles (1149.0 g). The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-105 μm) (1143.0 g).

[0530] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0531] The particles coated with agglomeration inhibitor (94.8 g), the outer sieved particles obtained in Example 16 (106.3 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (11.4 g), crospovidone (Kollidon CL-F, manufactured by BASF) (6.84 g), magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (1.14 g), potassium acesulfame potassium (2.4 g), aspartame (2.4 g), menthol cortisone (0.48 g), and sodium stearate fumarate (2.28 g) were placed in a 10 L plastic bag and mixed 200 times by hand to obtain a blend. The blend was then compressed using a rotary tablet press at an average of 7 kN to obtain orally disintegrating tablets (380 mg in weight, 9.5 mm in diameter) containing 20 mg of compound A in its free form.

[0532] Example 18

[0533] Preparation of coating solution for compound A

[0534] Hydroxypropyl methylcellulose 2910 (19.07 g) was dissolved in purified water (467.2 g) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (171.0 g) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0535] Preparation of particles coated with compound A

[0536] Lactose / crystalline cellulose spherical granules (385.0 g) were placed in a microparticle coating granulator / Wurster (FD-MP-01, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A (590.6 g) was sprayed under the following conditions: spray air pressure of 0.3 MPa, spray air flow rate of 70 NL / min, inlet air temperature of 77 °C, and inlet air flow rate of 0.5-0.6 m. 3 The spray feed rate was 4-5 g / min; the particles were dried to obtain dried particles (509.3 g). The total amount of dried particles was sieved to obtain compound A-coated particles (355 μm-105 μm) (490.7 g).

[0537] Preparation of organic acid coating solution

[0538] An ammonium alkyl 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). Next, pre-milled monosodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) (300.0 g) was uniformly dispersed to obtain an organic acid coating solution.

[0539] Preparation of organic acid coated particles

[0540] Particles coated with compound A (355μm-105μm) (384.1g) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution (2165.0g) was sprayed under the following conditions: spray air pressure 0.3MPa, spray air velocity 60NL / min, inlet air temperature 77℃, and inlet air velocity 0.5-0.6m. 3 The spray feed rate was 5-7 g / min; the particles were dried to obtain dried particles (608.0 g). The total amount of dried particles was sieved to obtain organic acid-coated particles (355 μm-105 μm) (604.0 g).

[0541] Preparation of water-insoluble polymer coating solution

[0542] Triglycerides (3.6 g), titanium dioxide (1.2 g), and talc (18.0 g) were suspended in purified water (294.0 g), and then ammonium alkyl methacrylate copolymer RS ​​(Eudragit RS30D, manufactured by Evonik) (120.0 g) was further suspended to obtain a water-insoluble polymer coating solution.

[0543] Preparation of particles coated with agglomeration inhibitor

[0544] Organic acid-coated particles (355μm-105μm) (300.6g) were placed in a microparticle coating granulator / Wurster and fluidized therein; a water-insoluble polymer coating solution (116.5g) was sprayed under the following conditions to obtain water-insoluble polymer-coated particles (299.2g): spray air pressure 0.3MPa, spray air flow rate 50NL / min, inlet air temperature 39℃, and inlet air flow rate 0.5m. 3The feed rate of the spray liquid was 2 g / min. Light anhydrous silica (Sylysia 320, manufactured by FUJI SILYSIA CHEMICAL LTD.) (0.89 g) was added to the total amount of particles, mixed manually in a 10L plastic bag, and cured by tray drying at 60°C for 13 hours. The total amount of particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-105 μm) (298.9 g).

[0545] Preparation of outer layer particles

[0546] Dissolve D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (80.0g) and citric anhydride (48.0g) in purified water (800.0g) to obtain a spray solution. 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) were placed in a fluidized bed dryer / granulator (LAB-1, manufactured by POWREX) and fluidized therein. The spray liquid (232.0 g) was sprayed under the following conditions: spray air pressure of 0.13 MPa, spray air velocity of 60 NL / min, inlet air temperature of 85 °C, and inlet air velocity of 0.2-0.3 m / min. 3 The spray liquid feed rate was 6 g / min; the particles were dried to obtain outer layer particles (472.2 g).

[0547] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0548] The particles coated with agglomeration inhibitor (138.8 g), outer particles (180.0 g), crystalline cellulose (CEOLUSKG-802, manufactured by Asahi Kasei Corporation) (37.1 g), acesulfame potassium (3.5 g), aspartame (3.5 g), menthol cortisone (0.7 g), and sodium stearate fumarate (3.5 g) were manually mixed 200 times in a 10 L plastic bag to obtain a blend. The blend was then compressed using a rotary tablet press at an average of 7 kN to obtain orally disintegrating tablets (524.4 mg in weight, 10.5 mm in diameter) containing 20 mg of compound A in its free form.

[0549] Example 19

[0550] Preparation of outer layer particles

[0551] D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (30.0g), citric anhydride (30.0g), and crospovidone (Kollidon CL-SF, manufactured by BASF) (30.0g) were dissolved and suspended in purified water (600.0g) to obtain a spray solution. 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 fluidized bed dryer / granulator (LAB-1, manufactured by POWREX) and fluidized therein. The spray liquid (276.0 g) was sprayed under the following conditions: spray air pressure of 0.14 MPa, spray air flow rate of 60 NL / min, inlet air temperature of 83-85 °C, and inlet air flow rate of 0.2 m / min. 3 The spray liquid feed rate was 6 g / min; the particles were dried to obtain outer layer particles (444.7 g).

[0552] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0553] The particles coated with the aggregation inhibitor obtained in Example 15 (107.4 g), outer particles (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 aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.72 g), potassium acesulfame potassium (2.4 g), aspartame (2.4 g), menthol cortisone (0.48 g), and sodium stearate fumarate (2.64 g) were manually mixed in a 10 L plastic bag to obtain a blend. The blend was compressed using a rotary tablet press at an average pressure of 6.7 kN to obtain orally disintegrating tablets (440 mg in weight, 10.0 mm in diameter) containing 20 mg of compound A in its free form.

[0554] Example 20

[0555] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0556] The blend product obtained in Example 19 was compressed using a rotary tablet press at an average of 4.0 kN to obtain orally disintegrating tablets (220 mg in weight and 8.0 mm in diameter) containing 10 mg of compound A in its free form.

[0557] The formulations (calculated values) for Examples 15-20 are shown in Tables 1-5.

[0558] Eudragit RS30D (trade name) is sold as a 30% aqueous dispersion. The solids content is shown in the individual tables for Eudragit RS30D.

[0559] Table 1-5

[0560]

[0561]

[0562] Example 21

[0563] Preparation of coating solution for compound A

[0564] Hydroxypropyl methylcellulose 2910 (1.153 kg) was dissolved in purified water (27.056 kg) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (9.639 kg) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0565] Preparation of particles coated with compound A

[0566] Lactose / crystalline cellulose spherical granules (25.025 kg) were placed in a microparticle coating granulator / Wurster (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A was sprayed under the following conditions: spray air velocity of 400-500 NL / min, inlet air temperature of 71°C, and inlet air velocity of 13-14 m / min. 3 The spray feed rate was 100-135 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with compound A (300 μm-132 μm).

[0567] Preparation of organic acid coating solution

[0568] An organic acid coating solution was prepared by dissolving 0.484 kg of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 8.060 kg of succinic acid in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, 16.120 kg of pre-sprayed sodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) was uniformly dispersed.

[0569] Preparation of organic acid coated particles

[0570] Particles coated with compound A (300μm-132μm) (33.170kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution was sprayed under the following conditions: spray air velocity of 550-700NL / min, inlet air temperature of 71-73℃, and inlet air velocity of 14-17m. 3 The spray feed rate is 160-240 g / min; the particles are dried to obtain dried particles. The total amount of dried particles is sieved to obtain organic acid-coated particles (355 μm-132 μm).

[0571] Preparation of water-insoluble polymer coating solution

[0572] Triacetin (0.222 kg), titanium dioxide (0.230 kg), and talc (1.110 kg) were suspended in purified water (3.329 kg) and anhydrous ethanol (29.962 kg). Then, ammonium alkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.776 kg) and ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.444 kg) were dissolved to obtain a water-insoluble polymer coating solution.

[0573] Preparation of Coating Solution for Aggregation Inhibitor

[0574] Light anhydrous silica (0.164 kg) was dispersed in pure water (3.124 kg) to obtain a coating solution containing a coagulation inhibitor.

[0575] Preparation of particles coated with agglomeration inhibitor

[0576] Organic acid-coated particles (355μm-132μm) (46.087kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-insoluble polymer coating solution was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air velocity of 400-500 NL / min, inlet air temperature of 31-32℃, and inlet air velocity of 17m. 3 The feed rate of the spray liquid is 80-100 g / min. Next, the agglomeration inhibitor coating liquid is sprayed under the following conditions: spray air velocity of 500 NL / min, inlet air temperature of 32-68℃, and inlet air velocity of 17 m / min. 3 The feed rate of the spray liquid was 112 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-132 μm).

[0577] Preparation of outer layer particles

[0578] 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 spray solution. 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 fluidized bed dryer / granulator (FD-WSG-60TW, manufactured by POWREX) and fluidized therein; the spray liquid was sprayed under the following conditions: spray air velocity of 750-850 NL / min, inlet air temperature of 73-77℃, and inlet air velocity of 17-19 m / min. 3 The spray liquid feed rate is 350-400 g / min; the particles are dried to obtain the outer layer particles.

[0579] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0580] The following ingredients were mixed 200 times by hand: 146.1 g of particles coated with agglomeration inhibitor, 163.6 g of outer particles, 17.60 g of crystalline cellulose (CEOLUSKG-802, manufactured by Asahi Kasei Corporation), 14.08 g of crospovidone (Kollidon CL-F, manufactured by BASF), 1.760 g of magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.), 2.4 g of acesulfame potassium, 2.4 g of aspartame, 0.56 g of strawberry flavoring, and 3.52 g of sodium stearate fumarate. The mixture was then placed in a 10 L plastic bag to obtain a blend. The blend was then compressed using a rotary tablet press at an average of 10 kN to obtain orally disintegrating tablets (440 mg in weight, 10.0 mm in diameter) containing 20 mg of compound A in its free form.

[0581] Example 22

[0582] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0583] The particles coated with the aggregation inhibitor obtained in Example 21 (146.1 g), the outer particles obtained in Example 21 (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 UFL2, manufactured by Fuji Chemical Industries Co., Ltd.) (1.760 g), potassium acesulfame potassium (2.4 g), aspartame (2.4 g), strawberry flavoring (0.56 g), and sodium stearate fumarate (3.52 g) were placed in a 10 L plastic bag and mixed 200 times by hand to obtain a blend product. The blend was compressed using a rotary tablet press at an average of 10 kN to obtain orally disintegrating tablets (440 mg in weight and 10.0 mm in diameter) containing 20 mg of the free form of compound A.

[0584] Example 23

[0585] Preparation of coating solution for compound A

[0586] Hydroxypropyl methylcellulose 2910 (1.130 kg) was dissolved in purified water (25.840 kg) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (9.639 kg) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0587] Preparation of particles coated with compound A

[0588] Lactose / crystalline cellulose spherical granules (25.025 kg) were placed in a microparticle coating granulator / Wurster (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A was sprayed under the following conditions: spray air velocity of 400-500 NL / min, inlet air temperature of 71°C, and inlet air velocity of 13-14 m / min. 3 The spray feed rate was 100-135 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with compound A (300 μm-132 μm).

[0589] Preparation of organic acid coating solution

[0590] An organic acid coating solution was prepared by dissolving 0.484 kg of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 8.060 kg of succinic acid in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, 16.120 kg of pre-sprayed sodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) was uniformly dispersed.

[0591] Preparation of organic acid coated particles

[0592] Particles coated with compound A (300μm-132μm) (33.170kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution was sprayed under the following conditions: spray air velocity of 550-700NL / min, inlet air temperature of 71-73℃, and inlet air velocity of 14-17m. 3 The spray feed rate is 160-240 g / min; the particles are dried to obtain dried particles. The total amount of dried particles is sieved to obtain organic acid-coated particles (355 μm-132 μm).

[0593] Preparation of water-insoluble polymer coating solution

[0594] Triacetin (0.154 kg), titanium dioxide (0.160 kg), and talc (0.771 kg) were suspended in purified water (2.312 kg) and anhydrous ethanol (20.806 kg), and then dissolved in ammonium alkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.541 kg) to obtain a water-insoluble polymer coating solution.

[0595] Preparation of Coating Solution for Aggregation Inhibitor

[0596] Light anhydrous silica (0.086 kg) was dispersed in pure water (1.627 kg) to obtain a coating solution containing a coagulation inhibitor.

[0597] Preparation of particles coated with agglomeration inhibitor

[0598] Organic acid-coated particles (355μm-132μm) (24.002kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-insoluble polymer coating solution was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air velocity of 300NL / min, inlet air temperature of 32℃, and inlet air velocity of 14m. 3 The feed rate of the spray liquid was 75 g / min. Next, the agglomeration inhibitor coating liquid was sprayed under the following conditions: spray air velocity of 400 NL / min, inlet air temperature of 32-71℃, and inlet air velocity of 14 m / min. 3 The spray feed rate was 85 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-132 μm).

[0599] Preparation of outer layer particles

[0600] 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 spray solution. D-Mannitol (PEARLITOL 50C, manufactured by ROQUETTE, Japan) (7.865 kg), D-Mannitol (PEARLITOL 100SD, manufactured by ROQUETTE, Japan) (30.250 kg), crystalline cellulose (CEOLUSKG-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 bed dryer / granulator (FD-WSG-60TW, manufactured by POWREX) and fluidized therein; the spray liquid was sprayed under the following conditions: spray air velocity of 750-850 NL / min, inlet air temperature of 70°C, and inlet air velocity of 18-20 m / min. 3 The spray liquid feed rate is 350-400 g / min; the particles are dried to obtain the outer layer particles.

[0601] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0602] The following ingredients were mixed 100 times by hand in a glass bottle: 28.50 g of particles coated with agglomeration inhibitor, 28.50 g of outer particles, 3.08 g of crystalline cellulose (CEOLUSKG-802, manufactured by Asahi Kasei Corporation), 3.08 g of crospovidone CL-F (Kollidon CL-F, manufactured by BASF), 0.308 g of magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.), 0.56 g of acesulfame potassium, 0.56 g of aspartame, 0.112 g of peppermint flavoring, and 0.616 g of sodium stearate fumarate. The resulting blend was then compressed using a single-punch tablet press to obtain orally disintegrating tablets (450 mg in weight, 10.0 mm in diameter) containing 20 mg of the free form of compound A.

[0603] Example 24

[0604] Preparation of water-insoluble polymer coating solution

[0605] Triacetin (0.154 kg), titanium dioxide (0.160 kg), and talc (0.771 kg) were suspended in purified water (2.312 kg) and anhydrous ethanol (20.806 kg). Then, ammonium alkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (1.233 kg) and ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.308 kg) were dissolved to obtain a water-insoluble polymer coating solution.

[0606] Preparation of Coating Solution for Aggregation Inhibitor

[0607] Light anhydrous silica (0.086 kg) was dispersed in pure water (1.627 kg) to obtain a coating solution containing a coagulation inhibitor.

[0608] Preparation of particles coated with agglomeration inhibitor

[0609] The organic acid-coated particles (355 μm-132 μm) (24.002 kg) obtained in Example 23 were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-insoluble polymer coating solution was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air flow rate of 400 NL / min, inlet air temperature of 30°C, and inlet air flow rate of 14 m. 3 The feed rate of the spray liquid was 75 g / min. Next, the agglomeration inhibitor coating liquid was sprayed under certain conditions: the spray air velocity was 500 NL / min, the inlet air temperature was 30-71℃, and the inlet air velocity was 14 m / min. 3 The spray feed rate was 85 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-132 μm).

[0610] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0611] The particles coated with the aggregation inhibitor (28.50 g), the outer particles obtained in Example 23 (28.50 g), crystalline cellulose (CEOLUS KG-802, manufactured by Asahi Kasei Corporation) (3.08 g), crospovidone (Kollidon CL-F, manufactured by BASF) (3.08 g), magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.) (0.308 g), potassium acesulfame potassium (0.56 g), aspartame (0.56 g), peppermint flavor (0.112 g), and sodium stearate fumarate (0.616 g) were placed in a glass bottle and mixed 100 times by hand to obtain a blend. The blend was then compressed using a single-punch tablet press to obtain orally disintegrating tablets (450 mg in weight, 10.0 mm in diameter) containing 20 mg of compound A in its free form.

[0612] Example 25

[0613] Preparation of coating solution for compound A

[0614] Hydroxypropyl methylcellulose 2910 (1.100 kg) was dissolved in purified water (25.840 kg) to obtain a hydroxypropyl methylcellulose 2910 solution. Next, compound A (9.205 kg) was uniformly dispersed in the hydroxypropyl methylcellulose 2910 solution to obtain a coating solution of compound A.

[0615] Preparation of particles coated with compound A

[0616] Lactose / crystalline cellulose spherical granules (25.025 kg) were placed in a microparticle coating granulator / Wurster (FD-GPCG-120SPC, manufactured by POWREX, hereinafter the same) and fluidized therein; the coating solution of compound A was sprayed under the following conditions: spray air velocity of 400-500 NL / min, inlet air temperature of 71°C, and inlet air velocity of 13-14 m / min. 3 The spray feed rate was 100-135 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with compound A (300 μm-132 μm).

[0617] Preparation of organic acid coating solution

[0618] An organic acid coating solution was prepared by dissolving 0.484 kg of ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) and 8.060 kg of succinic acid in purified water (84.630 kg) and anhydrous ethanol (46.270 kg). Then, 16.120 kg of pre-sprayed sodium fumarate (MONOFUMAR, manufactured by NIPPON SHOKUBAI CO., LTD.) was uniformly dispersed.

[0619] Preparation of organic acid coated particles

[0620] Particles coated with compound A (300μm-132μm) (33.170kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the organic acid coating solution was sprayed under the following conditions: spray air velocity of 550-700NL / min, inlet air temperature of 71-73℃, and inlet air velocity of 14-17m. 3 The spray feed rate is 160-240 g / min; the particles are dried to obtain dried particles. The total amount of dried particles is sieved to obtain organic acid-coated particles (355 μm-132 μm).

[0621] Preparation of water-insoluble polymer coating solution

[0622] Triacetin (0.259 kg), titanium dioxide (0.269 kg), and talc (1.295 kg) were suspended in purified water (3.884 kg) and anhydrous ethanol (34.956 kg). Then, ammonium alkyl methacrylate copolymer (Eudragit RSPO, manufactured by Evonik) (2.071 kg) and ammonium alkyl methacrylate copolymer (Eudragit RLPO, manufactured by Evonik) (0.518 kg) were dissolved to obtain a water-insoluble polymer coating solution.

[0623] Preparation of Coating Solution for Aggregation Inhibitor

[0624] Light anhydrous silica (0.164 kg) was dispersed in pure water (3.124 kg) to obtain a coating solution containing a coagulation inhibitor.

[0625] Preparation of particles coated with agglomeration inhibitor

[0626] Organic acid-coated particles (355μm-132μm) (46.087kg) were placed in a microparticle coating granulator / Wurster and fluidized therein; the water-insoluble polymer coating solution was sprayed under the following conditions to obtain water-insoluble polymer-coated particles: spray air velocity of 400-500 NL / min, inlet air temperature of 31℃, and inlet air velocity of 17m. 3 The feed rate of the spray liquid is 80-100 g / min. Next, the agglomeration inhibitor coating liquid is sprayed under the following conditions: spray air velocity of 500 NL / min, inlet air temperature of 31-68℃, and inlet air velocity of 17 m / min. 3 The spray feed rate was 130 g / min; the particles were dried to obtain dried particles. The total amount of dried particles was sieved to obtain particles coated with agglomeration inhibitor (355 μm-132 μm).

[0627] Preparation of outer layer particles

[0628] 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) were dissolved and suspended in purified water (27.000 kg) to obtain a spray solution. 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 fluidized bed dryer / granulator (FD-WSG-60TW, manufactured by POWREX) and fluidized therein; the spray liquid was sprayed under the following conditions: spray air velocity of 750-850 NL / min, inlet air temperature of 73-78℃, and inlet air velocity of 17-19 m / min. 3 The spray liquid feed rate is 350-400 g / min; the particles are dried to obtain the outer layer particles.

[0629] Preparation of orally disintegrating tablets containing particles coated with aggregation inhibitors.

[0630] The following ingredients were mixed 100 times by hand in a glass bottle: 13.70 g of particles coated with agglomeration inhibitor, 14.85 g of outer particles, 1.65 g of crystalline cellulose (CEOLUSKG-802, manufactured by Asahi Kasei Corporation), 1.65 g of crospovidone (Kollidon CL-F, manufactured by BASF), 0.165 g of magnesium aluminum metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries Co., Ltd.), 0.3 g of acesulfame potassium, 0.3 g of aspartame, 0.06 g of strawberry flavoring, and 0.33 g of sodium stearate fumarate. The resulting blend was then compressed using a single-punch tablet press to obtain orally disintegrating tablets (440 mg in weight, 10.0 mm in diameter) containing 20 mg of compound A in its free form.

[0631] Example 26

[0632] The blend product obtained in Example 25 was tableted using a single-punch tablet press to obtain orally disintegrating tablets (weighing 220 mg and having a diameter of 8.0 mm) containing 10 mg of compound A in its free form.

[0633] The formulations (calculated values) for Examples 21-26 are shown in Tables 1-6.

[0634] Table 1-6

[0635]

[0636] Experimental Example 1 (Dissolution Test of the Formulation)

[0637] Dissolution tests were performed using either the paddle method (50 rpm) or the basket method (100 rpm) according to General Test Method 6.10 of the Japanese Pharmacopoeia. Specifically, 900 mL of dissolution test solution heated to 37°C was added to disperse the formulation. Samples were taken at predetermined times while rotating the paddle or basket at a predetermined speed, and the amount of the target compound dissolved in the filtrate using a properly applied membrane filter was quantified by HPLC.

[0638] The results are shown in Figures 1-10 .

[0639] All formulations showed a lag time of at least 2 minutes and demonstrated a significant reduction in bitterness derived from compound A.

[0640] Experimental Example 2 (Dissolution of Compound A in Saturated Organic Acid)

[0641] Citric acid, succinic acid, fumaric acid, or malic acid were dissolved in Japanese Pharmacopoeia Dissolution Test 2 solution (JP2) and saturated, then filtered. Next, compound A (0.4 g) was added to the filtrate saturated with the organic acid (10 mL), and the mixture was shaken at room temperature for 1 hour. The shaken solution was filtered, diluted 50-fold with Japanese Pharmacopoeia Dissolution Test 2 solution, and then diluted 20-fold with Japanese Pharmacopoeia Dissolution Test 2 solution. The solutions obtained from the two dilutions were subjected to HPLC analysis to determine the amount of compound A dissolved.

[0642] The results are shown in Table 2. Compound A in its fumarate form only showed low concentrations in the presence of high concentrations of fumaric acid. This also indicates that succinic acid has almost no effect on the dissolution of compound A.

[0643] Table 2

[0644] Concentration (μg·mL) 5.22 5.76 0.67 26.30 26.64

[0645] Experimental Example 3 (The effect of the concentration of the same organic acid or its salt as the organic acid that forms a salt with the same active pharmaceutical ingredient on the dissolution amount of the active pharmaceutical ingredient that forms a salt with the organic acid (confirmation of the common ion effect))

[0646] Solutions containing various concentrations of fumaric acid or monosodium fumarate dissolved in the solution of the Japanese Pharmacopoeia Dissolution Test 2 were prepared. Then, 50 mg of compound A was measured, placed in a 10 mL plastic tube, and each of the above solutions (5 mL) was added. The mixture was vigorously shaken at room temperature for 1 hour. The shaken suspension was filtered, diluted 100-fold, and subjected to HPLC analysis. The dissolution rate of compound A was measured. The results are shown in... Figure 11 This indicates that the dissolution rate of compound A in the fumarate form is affected by the concentration of fumaric acid or the monosodium fumarate in the solvent.

[0647] Experiment Example 4 (Measurement of dissolution curves of compound A, fumaric acid, and succinic acid)

[0648] Dissolution tests were performed on particles coated with the water-insoluble polymer of Example 1 or particles coated with the aggregation inhibitor of Reference Example 3 (each containing 60 mg of compound A) using a rotating basket at 100 rpm, in the same manner as in Experimental Example 1. The dissolution amounts of fumaric acid or succinic acid and compound A were also measured. For fumaric acid and succinic acid, the residual rate of each organic acid in the particles was calculated backwards from the dissolution rate, and the maximum dissolution amount was standardized assuming a residual rate of 0%.

[0649] The results are shown in Figures 12-13 It can be observed that the dissolution of compound A begins after fumaric acid or succinic acid dissolves from the particles.

[0650] Experimental Example 5 (Confirmation of Dissolution Control Mechanism - 1)

[0651] Dissolution tests were conducted using a paddle at 100 rpm on particles 3 coated with a water-soluble polymer containing 60 mg of compound A, obtained in Reference Example 2, in the same manner as in Experimental Example 1. The dissolution media were Japanese Pharmacopoeia Dissolution Test Liquid 2, Japanese Pharmacopoeia Dissolution Test Liquid 2 with 10% (w / w) sodium carbonate, Japanese Pharmacopoeia Dissolution Test Liquid 2 with 13% (w / w) succinic acid, or Japanese Pharmacopoeia Dissolution Test Liquid 2 with 0.6% (w / w) fumaric acid.

[0652] The results are shown in Figure 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 any dissolution inhibition. These results indicate that fumaric acid and succinic acid do not exhibit a salting-out effect on water-soluble polymers.

[0653] Experimental Example 6 (Confirmation of Dissolution Control Mechanism - 2)

[0654] Dissolution tests were conducted using a paddle at 100 rpm on particles coated with a water-insoluble polymer, obtained in Reference Example 1 and containing 60 mg of compound A, in the same manner as in Experimental Example 1. The dissolution media were Japanese Pharmacopoeia Dissolution Test Liquid 2, Japanese Pharmacopoeia Dissolution Test Liquid 2 with 13% (w / w) succinic acid, Japanese Pharmacopoeia Dissolution Test Liquid 2 with 0.6% (w / w) monosodium fumarate, or Japanese Pharmacopoeia Dissolution Test Liquid 2 with 0.6% (w / w) fumaric acid.

[0655] Dissolution tests were performed on particles coated with compound A, obtained in Reference Example 1 and containing 60 mg of compound A, using a paddle at 100 rpm and in the same manner as in Experimental Example 1. The dissolution media were Japanese Pharmacopoeia Dissolution Test Liquid 2, Japanese Pharmacopoeia Dissolution Test Liquid 2 with 0.6% (w / w) of monosodium fumarate, or Japanese Pharmacopoeia Dissolution Test Liquid 2 with 0.6% (w / w) of fumaric acid.

[0656] The results are shown in Figures 15-16The dissolution of particles coated with water-insoluble polymers was inhibited by fumaric acid or monosodium fumarate present in the dissolution medium, while the dissolution of particles coated with compound A, when not coated with water-insoluble polymers, was not inhibited by either compound. The results indicate that the dissolution inhibition of compound A by the common ion effect of fumaric acid or monosodium fumarate requires coating the particles containing compound A with a water-insoluble polymer. It also indicates that fumaric acid or monosodium fumarate needs to dissolve at a high concentration close to that of the water-insoluble polymer-coated particles containing compound A, so that its common ion effect can induce the dissolution inhibition of compound A. From these results, it is further hypothesized that fumaric acid or monosodium fumarate dissolved from the formulation can be present at a high concentration in the oral cavity with low water content, effectively inhibiting the dissolution of compound A (masking bitterness); and that the dissolution inhibition of compound A by the common ion effect of fumaric acid or monosodium fumarate no longer occurs in the gastrointestinal tract with higher water content, allowing compound A to dissolve rapidly.

[0657] Experiment Example 7 (Sensory Evaluation-1)

[0658] Sensory evaluations were performed on the orally disintegrating tablets obtained in Examples 15-20. The formulations were placed in the mouth to disintegrate and then spat out. Bitterness was evaluated on a 5-point scale (Table 3). Surprisingly, bitterness was significantly suppressed in all formulations.

[0659] Sensory evaluations were performed on the particles coated with compound A, organic acid, and aggregation inhibitor obtained in Example 18. The formulations were placed in the mouth and spat out. Bitterness was evaluated on a 5-point scale (Table 3). As a result, bitterness was significantly suppressed only in particles coated with aggregation inhibitors.

[0660] Table 3

[0661] Example 16 - Example 17 ± Example 18 - Particles coated with compound A in Example 18 +++ Organic acid-coated particles of Example 18 ++ Particles coated with a coagulation inhibitor in Example 18 - Example 19 - Example 20 -

[0662] +++: I tasted a very strong bitterness.

[0663] ++: I tasted a strong bitterness.

[0664] +: I detected a certain intensity of bitterness.

[0665] ±: I tasted a slight bitterness.

[0666] -: Almost no bitterness can be detected

[0667] Experiment Example 8 (Sensory Evaluation-2)

[0668] Sensory evaluation was performed on the orally disintegrating tablets obtained in Examples 21-26. The formulations were placed in the mouth, allowed to disintegrate, and then spat out. Bitterness was evaluated on a 5-point scale (Table 4). Surprisingly, bitterness was significantly suppressed in all formulations.

[0669] Table 4

[0670] Example 22 - Example 23 - Example 24 - Example 25 - Example 26 -

[0671] +++: I tasted a very strong bitterness.

[0672] ++: I tasted a strong bitterness.

[0673] +: I detected a certain intensity of bitterness.

[0674] ±: I tasted a slight bitterness.

[0675] -: Almost no bitterness can be detected

[0676] This application is based on Japanese patent application 2017-135046, the entire contents of which are incorporated herein by reference.

Claims

1. A formulation containing microparticles or particles, said microparticles or particles comprising: (1) Core particles containing vonorazan organic acid salts (2) An intermediate layer comprising an organic acid, or a salt thereof, that is the same as the organic acid forming the salt of vonorazan described in (1), and (3) A coating layer containing a water-insoluble polymer, The organic acid salt of vonorazan is vonorazan fumarate, and the organic acid or its salt in (2) is fumarate or a salt of fumarate. The formulation does not contain an enteric coating that inhibits dissolution until it reaches the small intestine, and The water-insoluble polymer is an ammonium methyl methacrylate copolymer.

2. The formulation according to claim 1, wherein the amount of organic acid or its salt in (2) is not less than 0.5 parts by weight relative to 100 parts by weight of vonorazan in (1).

3. The formulation according to claim 1, wherein the amount of the water-insoluble polymer in the coating layer of (3) is from 0.5 parts by weight to 15 parts by weight relative to each 100 parts by weight of particles comprising the core particles of (1) and the intermediate layer of (2).

4. The formulation according to claim 1, wherein the average particle size of the microparticles or granules is 75. m to 750 m.

5. The formulation according to claim 1, wherein the intermediate layer of (2) contains, in a single layer or in separate layers, an organic acid or a salt thereof that is the same as the organic acid forming the salt of vonorazan in (1), and a dissolution control substance.

6. The formulation according to claim 5, wherein the solubility of the dissolution control substance in 100 g of water at 20°C is 0.01-500.

7. The formulation according to claim 5, wherein the dissolution control substance has a pH of 2-4 when dissolved in water.

8. The formulation according to claim 5, wherein the dissolution control substance is a salt of an organic acid or an organic acid.

9. The formulation according to claim 5, wherein the dissolution control substance is a divalent carboxylic acid or a salt thereof.

10. The formulation according to claim 5, wherein the dissolution control substance is succinic acid or a salt of succinic acid.

11. The formulation according to any one of claims 1 to 10, wherein the microparticles or particles are further coated with an aggregation inhibitor.

12. The formulation according to claim 11, wherein the aggregation inhibitor is an inorganic substance, a sugar alcohol, or a sugar.

13. The formulation according to any one of claims 1 to 10, further comprising a polymer binder.

14. The formulation according to any one of claims 1 to 10, which is used as an orally disintegrating tablet.

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