WO2019131891A1

WO2019131891A1 - Bitterness-masked drug-containing particles and formulation containing said drug-containing particles

Info

Publication number: WO2019131891A1
Application number: PCT/JP2018/048185
Authority: WO
Inventors: 吉田　勝; 光昭木挽; 拓海淺田
Original assignee: 大日本住友製薬株式会社
Priority date: 2017-12-28
Filing date: 2018-12-27
Publication date: 2019-07-04

Abstract

Provided are: bitterness-masked drug-containing particles; and a bitterness-masked formulation which uses said drug-containing particles to maintain drug absorption. This invention pertains to: drug-containing particles which have the outer layer thereof coated with sodium stearyl fumarate, and containing (S)-4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl)methyl]-2-morpholinyl}methyl]-2-methoxybenzamide or a pharmacologically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a formulation containing said drug-containing particles.

Description

Drug-containing particles in which bitter taste is masked and preparation containing the drug-containing particles

The present invention relates to drug-containing particles for use in formulations. Specifically, the present invention relates to a drug-containing particle that suppresses unpleasant taste, and a preparation that uses the drug-containing particle to suppress unpleasant taste and achieve bioabsorbability.

An orally disintegrating tablet (OD tablet) is a tablet that can be taken without water while leaving the tablet easy to handle. OD tablets are rapidly disintegrated by saliva and a small amount of water, so they are easy to use even in children, elderly people, and patients with reduced swallowing ability (food and medicine swallowing ability). The importance of society is increasing as the society progresses. When the OD tablet is taken, the drug dissolves in the oral cavity, and a living organ called a taste chamber present in the tongue reacts to the dissolved drug, and the taste of the drug is felt. When the drug has an unpleasant taste such as bitter taste or astringent taste, there is a problem in drug treatment that the user can not tolerate the bitter taste and vomits or compliance is lowered. When making a drug with an unpleasant taste into an OD tablet, a physical masking method that uses a sweetening component or physical masking that reduces the dissolution rate of the drug in the oral cavity by coating and reduces the amount dissolved in the oral cavity Bitter masking techniques such as methods are required. However, when bitter masking technology using physical masking by coating is used, the drug does not dissolve in the oral cavity while it is not dissolved or absorbed in the digestive tract such as the stomach or intestine, and a therapeutic effect is obtained. The problem of not being often arises. If the degree of coating is reduced again and the dissolution rate is improved to obtain a therapeutic effect, the drug dissolves in the oral cavity to give a bitter taste. Thus, a bitter taste masking technology that achieves both suppression of unpleasant taste and bioabsorbability is very difficult.

Patent Document 1 describes a particle coated with a lubricant and a drug by spraying a core particle with a coating solution prepared by dissolving a drug having strong cohesiveness, a lubricant and a polymer in granules. However, Patent Document 1 discloses that a lubricant is used to enhance dispersibility, and it is not disclosed that bitterness can be masked by the lubricant.

Patent Document 2 describes particles coated with drug-containing granules by spraying a liquid containing a polymer, a disintegrant and a lubricant. However, in Patent Document 2, the lubricant is merely used as a dispersing agent for improving the manufacturability, and it is not disclosed that the bitter taste can be masked by the lubricant.

Thus, it is not known to perform bitter taste masking (bitter taste mask) by the presence of a lubricant in the coating film of the drug-containing particles, and tablets using the particles exhibit an unpleasant taste. It was not known that the bitter taste of drugs could be masked.

JP, 2015-151337, A Patent No. 5405752

(S) -4-Amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide (the present compound) or a pharmaceutical thereof Since the pharmaceutically acceptable salt, or the hydrate or solvate thereof (the drug of the present invention) has a very high dissolution rate and a very strong unpleasant taste, it can be contained as a drug in producing OD tablets. It is necessary to mask off the unpleasant taste efficiently at the stage of granules. Furthermore, in order to ensure bioabsorbability, it is necessary to produce a preparation that exhibits good dissolution behavior.

As a result of intensive investigations, the present inventors have been able to mask the bitter taste of the drug of the present invention exhibiting extremely strong unpleasant taste by using sodium stearyl fumarate as a coating agent, which is usually used as a lubricant. I found it. Furthermore, it has been found that tablets using the present drug-containing particles using sodium stearyl fumarate surprisingly show dissolution and drug absorption comparable to tablets without coating. The present inventors have found an OD tablet subjected to bitter taste masking while maintaining drug absorbability, and have completed the present invention.

That is, the present invention is as described in the following items.

[Item 1] A composition for masking the bitter taste of a component having bitterness, which comprises sodium stearyl fumarate as a coating.
[Item 2] The component is (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxy The composition according to Item 1, which is benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[Item 3] The composition according to

item

1 or 2, wherein the component is contained in drug-containing particles.
[Item 4] Sodium stearyl fumarate and (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl having bitter taste ] A composition for masking the bitter taste, which comprises -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[Item 5] The composition according to item 4, wherein the sodium stearyl fumarate is included as a coating.
[Item 6] The (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide or the above Item 6. The composition according to Item 4 or 5, wherein a pharmaceutically acceptable salt, or a hydrate or solvate thereof is contained in the drug-containing particle.
[Item 7] The composition according to item 3 or 6, wherein the outer layer of the drug-containing particle is coated with the sodium stearyl fumarate.
[Item 8] The composition according to any one of Items 3, 6, or 7, wherein the drug-containing particles further contain a polymer.
[Item 9] The drug according to item 8, wherein the polymer is one or more selected from the group consisting of a water-insoluble polymer, an enteric polymer, a gastric polymer and a biodegradable polymer. Containing particles.
[Item 10] The water-insoluble polymer according to Item 9, selected from the group consisting of ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof. Composition.
[Item 11] The enteric polymer is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and a mixture of one or more thereof Item 11. The drug-containing particle according to item 9 or 10, selected from the group consisting of
[Item 12] The composition according to any one of Items 3 to 6, wherein the drug-containing particles further contain an additive for drug-containing particles.
[Item 13] The drug-containing particle additive is an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, and a plastic Item 13. The composition according to item 12, selected from the group consisting of an agent, an anticoagulant and a coating agent.
[Item 14] The additive for drug-containing particles is selected from the group consisting of an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent. Item 13. The composition according to item 13.
[Item 15] The sweetening agent and the flavoring agent are at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, respectively. The composition as described in.
[Item 16] The excipient is lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol, xylitol, kaolin The composition according to any one of items 13 to 15, which is at least one selected from the group consisting of calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
[Item 17] The composition according to any one of Items 3 or 6 to 16, wherein the content of the sodium stearyl fumarate is 1 to 70% by weight per 100% by weight of the drug-containing particles.
[Item 18] The composition according to any one of Items 17, wherein the content of the sodium stearyl fumarate is 10 to 50% by weight per 100% by weight of the drug-containing particles.
[Item 19] The composition according to any one of items 18, wherein the content of the sodium stearyl fumarate is 20 to 40 wt% per 100 wt% of the drug-containing particles.
[Item 20] The composition according to any one of items 3 or 6 to 19, wherein the content of the drug is 0.1 to 96% by weight per 100% by weight of the drug-containing particles.
[Item 21] The composition according to item 20, wherein the content of the drug is 5 to 50% by weight per 100% by weight of the drug-containing particles.
[Item 22] The composition according to item 21, wherein the content of the drug is 15 to 30% by weight per 100% by weight of the drug-containing particles.
[Item 23] The composition according to items 8 to 22, wherein the content of the polymer is 1 to 70% by weight per 100% by weight of the drug-containing particles.
[Item 24] The composition according to item 23, wherein the content of the polymer is 10 to 30% by weight per 100% by weight of the drug-containing particles.
[Item 25] The composition according to any one of Items 3 to 6, wherein the drug-containing particles are particles consisting of a shell and a hollow portion.
[Item 26] The composition according to item 25, wherein the shell comprises the drug and the polymer.
[Item 27] The composition according to item 26, wherein the shell further comprises the drug-containing particle additive.
[Item 28] The composition according to any one of Items 25 to 27, wherein the hollow volume ratio to the whole particle is 1% to 50%.
[Item 29] The composition according to item 28, wherein the hollow volume ratio to the whole particle is 5% to 30%.
[Item 30] The composition according to any one of items 25 to 29, wherein the thickness of the shell is 15 μm or more.
[Item 31] The composition according to items 8 to 30, wherein the average particle size of the polymer used as a raw material is five or more times the average particle size of the drug used as a raw material.
[Item 32] The composition according to item 31, wherein the average particle size of the polymer used as a raw material is at least 10 times the average particle size of the drug used as a raw material.
[Item 33] The composition according to item 32, wherein the average particle size of the polymer used as a raw material is at least 15 times the average particle size of the drug used as a raw material.
[Item 34] In items 12 to 33, the average particle size of the polymer used as a raw material is at least 5 times the average particle size of the mixed powder of the drug and the additive for drug-containing particles used as a raw material. Composition as described.
[Item 35] The composition according to any one of Items 25 to 34, wherein the diameter of the hollow portion is 10 μm or more.
[Item 36] The composition according to any one of items 3 or 6 to 35, wherein the aspect ratio of the drug-containing particle is 1.0 to 1.5.
[Item 37] The composition according to any one of Items 3 to 6, wherein the particle shell strength of the drug-containing particles is 2.0 MP or more.
[Item 38] The composition according to any one of items 3 or 6 to 37, wherein the particle size distribution width (D90 / D10) of the drug-containing particles is 6 or less.
[Item 39] The composition according to any one of items 3 or 6 to 38, wherein the average particle size of the drug-containing particles is 50 to 1000 μm.
[Item 40] The composition according to any one of items 3 or 6 to 39, wherein the composition comprises the drug-containing particles.
[Item 41] (S) -4-Amino-4-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl whose outer layer is coated with sodium stearyl fumarate } Drug-containing particles comprising: methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[Item 42] The drug-containing particle according to Item 41, further comprising a polymer.
[Item 43] The drug according to item 42, wherein the polymer is one or more selected from the group consisting of water insoluble polymers, enteric polymers, gastric polymers and biodegradable polymers. Containing particles.
[Item 44] The water-insoluble polymer according to item 43, wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof. Drug-containing particles.
[Item 45] The enteric polymer comprises hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and mixtures of one or more thereof The drug-containing particle according to item 43 or 44, selected from the group consisting of
[Item 46] The drug-containing particle according to any one of Items 41 to 45, further comprising an additive for a drug-containing particle.
[Item 47] The drug-containing particle additive is an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, and a plastic The drug-containing particle according to item 46, selected from the group consisting of an agent, an anticoagulant agent and a coating agent.
[Item 48] The drug-containing particle additive is selected from the group consisting of an excipient, a binder, a sweetener, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent The drug-containing particle according to Item 47.
[Item 49] The sweetening agent and the flavoring agent are at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, respectively. Drug-containing particles as described in.
[Item 50] The excipient is lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, erythritol, sorbitol, maltitol, mannitol, xylitol, kaolin The drug-containing particle according to any one of paragraphs 47 to 49, which is at least one selected from the group consisting of calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
[Item 51] The drug-containing particle according to any one of items 41 to 50, wherein the content of the sodium stearyl fumarate is 1 to 70% by weight per 100% by weight of the drug-containing particle.
[Item 52] The drug-containing particle according to any one of Items 51, wherein the content of the sodium stearyl fumarate is 10 to 50% by weight per 100% by weight of the drug-containing particle.
[Item 53] The drug-containing particle according to any one of Items 52, wherein the content of the sodium stearyl fumarate is 20 to 40% by weight per 100% by weight of the drug-containing particle.
[Item 54] The drug-containing particle according to any one of items 41 to 53, wherein the content of the drug is 0.1 to 96% by weight per 100% by weight of the drug-containing particle.
[Item 55] The drug-containing particle according to item 54, wherein the content of the drug is 5 to 50% by weight per 100% by weight of the drug-containing particle.
[Item 56] The drug-containing particle according to item 55, wherein the content of the drug is 15 to 30% by weight per 100% by weight of the drug-containing particle.
[Item 57] The drug-containing particles according to items 42 to 56, wherein the content of the polymer is 1 to 70% by weight per 100% by weight of the drug-containing particles.
[Item 58] The drug-containing particle according to Item 57, wherein the content of the polymer is 10 to 30% by weight per 100% by weight of the drug-containing particle.
[Item 59] The drug-containing particle according to any one of items 41 to 58, wherein the drug-containing particle is a particle consisting of a shell and a hollow portion.
[Item 60] The drug-containing particle according to item 59, wherein the shell comprises the drug and the polymer.
[Item 61] The drug-containing particle according to item 60, wherein the shell further contains the drug-containing particle additive.
[Item 62] The drug-containing particle according to any one of Items 59 to 61, wherein the hollow volume ratio to the whole particle is 1% to 50%.
[Item 63] The drug-containing particle according to Item 62, wherein the hollow volume ratio to the whole particle is 5% to 30%.
[Item 64] The drug-containing particle according to any one of Items 59 to 63, wherein the thickness of the shell is 15 μm or more.
[Item 65] The drug-containing particles according to items 42 to 64, wherein the average particle size of the polymer used as a raw material is five or more times the average particle size of the drug used as a raw material.
[Item 66] The drug-containing particles according to Item 65, wherein the average particle size of the polymer used as a raw material is at least 10 times the average particle size of the drug used as a raw material.
[Item 67] The drug-containing particles according to Item 66, wherein the average particle size of the polymer used as a raw material is at least 15 times the average particle size of the drug used as a raw material.
[Item 68] In items 46 to 67, the average particle size of the polymer used as a raw material is at least 5 times the average particle size of the mixed powder of the drug and the additive for drug-containing particles used as a raw material. Drug-containing particles as described.
[Item 69] The drug-containing particle according to any one of Items 59 to 68, wherein the diameter of the hollow portion is 10 μm or more.
[Item 70] The drug-containing particle according to any one of items 41 to 69, wherein the aspect ratio of the drug-containing particle is 1.0 to 1.5.
[Item 71] The drug-containing particle according to any one of Items 41 to 70, wherein the particle shell strength of the drug-containing particle is 2.0 MPa or more.
[Item 72] The drug-containing particle according to any one of Items 41 to 71, wherein the particle size distribution width (D90 / D10) is 6 or less.
[Item 73] The drug-containing particle according to any one of Items 41 to 72, wherein the average particle size is 50 to 1000 μm.
[Item 74] A pharmaceutical composition comprising the drug-containing particle according to any one of items 41 to 73.
[Item 75] The pharmaceutical composition of Item 74, which is in the form of granules, a tablet or a capsule.
[Item 76] The pharmaceutical composition according to item 75, which is in the form of a tablet.
[Item 77] The pharmaceutical composition according to Item 76, which is in the form of an orally disintegrating tablet.
[Item 78] The pharmaceutical composition according to any one of Items 74 to 77, further comprising a formulation additive.
[Item 79] The formulation additive is an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, a plasticizer 79. A pharmaceutical composition according to item 78, selected from the group consisting of an anticoagulant and a coating agent.
[Item 80] The formulation additive is selected from the group consisting of an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent 80. The pharmaceutical composition according to Item 79.
[Item 81] The item 79 is at least one selected from the group consisting of high-intensity sweeteners such as aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, etc. [Item 81] Or the pharmaceutical composition according to 80.
[Item 82] The excipient is lactose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, powdered sugar, saccharides such as reduced lactose, erythritol, sorbitol, maltitol, mannitol, The pharmaceutical composition according to item 79 or 80, which is at least one selected from the group consisting of sugar alcohols such as xylitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
[Item 83] The pharmaceutical composition according to any one of Items 74 to 82, wherein the digestive system disease or digestive system symptom is a target disease.
[Item 84] A pharmaceutical composition for treating and / or preventing digestive system diseases or digestive system conditions, which comprises the drug-containing particle according to any one of items 41 to 73. .
[Item 85] The pharmaceutical composition according to item 83 or 84, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.
[Item 86] A therapeutic agent and / or a preventive agent for digestive system diseases or digestive system conditions, comprising the drug-containing particle according to any one of items 41 to 73.
[Item 87] The therapeutic agent and / or the prophylactic agent according to item 86, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.
[Item 88] A method for treating and / or preventing digestive system disease or digestive system condition, which is a therapeutically and / or prophylactically effective amount to a patient in need of treatment and / or prevention, item 41 to 73 Administering a drug-containing particle according to any one of the preceding claims.
[Item 89] The method according to Item 88, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.
[Item 90] Use of the drug-containing particle according to any one of Items 41 to 73 for producing a therapeutic agent and / or a preventive agent for digestive system disease or digestive system condition.
[Item 91] The use according to Item 90, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.
[Item 92] The drug-containing particle according to any one of Items 41 to 73, for use in the treatment and / or prevention of digestive diseases or digestive conditions.
[Item 93] The drug-containing particle according to item 92, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.

It has been found that by using sodium stearyl fumarate, which is usually used as a lubricant, as a coating agent, it is possible to mask the bitter taste of the drug of the present invention exhibiting a very strong unpleasant taste. As compared with the case where sodium stearyl fumarate is simply contained, the bitter taste suppressing effect was extremely remarkably improved by the coating. Furthermore, it has been found that tablets using the present drug-containing particles using sodium stearyl fumarate surprisingly show dissolution and drug absorbability comparable to those of uncoated tablets. The present inventors have found an OD tablet subjected to bitter taste masking while maintaining drug absorbability, and have completed the present invention.

FIG. 1 is a view showing the results of dissolution tests of Example 1-2 and Comparative Example 1-2. FIG. 2 is a diagram showing the results of sensory evaluation tests of Example 1-2 and Comparative Example 1-2. FIG. 3 is a view showing the results of the dissolution tests of Comparative Example 1-2 and Comparative Examples 1-9 to 1-14. FIG. 4 is a view showing the results of sensory evaluation tests of Comparative Example 1-2 and Comparative Examples 1-9 to 1-14.

Hereinafter, the present invention will be described in more detail. Throughout the specification, it is to be understood that the singular form also includes the concepts of the plural, unless specifically stated otherwise. Thus, it is to be understood that the singular article (eg, “a”, “an”, “the” and the like in the case of English) also includes the plural concept thereof unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meanings commonly used in the art unless otherwise stated. Thus, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
The terms in the present specification are described below together with preferred embodiments.

In the present invention, the "average particle size" means the 50% cumulative particle size D50 in the volume-based measurement of powder particles. The average particle size is measured on a volume basis with a laser diffraction type particle size distribution measuring apparatus (for example, Particle Viewer manufactured by Powrex Corp. or SALD-3000 J manufactured by Shimadzu Corp. or HELOS & RODOS manufactured by Sympatec).

(1) Drug-containing particles The drug-containing particles of the present invention comprise (i) a drug and (ii) a sodium stearyl fumarate coating, optionally for (iii) a polymer, and / or (iv) for drug-containing particles It may contain an additive. Preferred examples of the drug-containing particles of the present invention include (v) drug-containing hollow particles described later. Also, the particles mean both a single particle and an assembly of a plurality of particles.
Unless otherwise specified herein, "drug-containing particles" mean particles coated with sodium stearyl fumarate.
The "per 100% by weight of the drug-containing particles" means a weight percentage when the "weight of the drug-containing particles" is 100%. Here, "the weight of the drug-containing particles" means the weight of the entire drug-containing particles to which the amount of sodium stearyl fumarate is added.

(I) Drug In the present invention, the “drug” means (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl ] 2-methoxybenzamide (the present compound) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. This means that the drug may be present in the form of a hydrate or a solvate.
(S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide or pharmaceutically acceptable thereof The salt, or a hydrate or solvate thereof, is a serotonin 4 receptor agonist and is a therapeutic agent and / or prevention of digestive system diseases, digestive system conditions, neuropsychiatric diseases, or urological diseases It is effective as an agent.
The pharmaceutically acceptable salt is preferably a hydrochloride or bromate, and more preferably a bromate.
The content of the drug of the present invention is usually 0.1 to 96% by weight, preferably 1 to 70% by weight, more preferably 5 to 50% by weight, based on 100% by weight of the drug-containing particles. More preferably, it is 10 to 40% by weight, and most preferably 15 to 30% by weight.
The average particle size of the drug is usually 20 μm or less, preferably 15 μm or less, more preferably 10 μm or less. The average particle size of the drug is usually 0.1 μm or more. The average particle size of the drug may be within the above range as the raw material, and may be changed in the production process of the drug-containing particles and the like.

(Ii) Sodium Stearyl Fumarate Sodium stearyl fumarate (PRUV) is generally used as a lubricant for pharmaceutical tablets, but has a feature of being used as a coating for particles in the present invention.
The content of sodium stearyl fumarate is usually 1 to 70% by weight, preferably 5 to 60% by weight, and more preferably 10 to 50% by weight, based on 100% by weight of the drug-containing particles. Preferably, it is 15 to 45% by weight, most preferably 20 to 40% by weight.
The average particle size of sodium stearyl fumarate is usually 30 μm or less, preferably 20 μm or less, more preferably 15 μm or less. The average particle size of sodium stearyl fumarate is usually 0.1 μm or more. The average particle diameter of sodium stearyl fumarate may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.

(Iii) Polymer "Polymer" refers to a molecule having a large relative molecular mass and having a structure formed by many repetitions of a molecule having a small relative molecular mass, and particularly refers to a functional polymer. The above-mentioned "molecule having a large relative molecular mass" usually refers to one having an average molecular weight (weight average molecular weight) of 1,000 or more, preferably 5,000 or more, and more preferably 10,000 or more. The upper limit of the molecular weight is not particularly limited, but preferably 10,000,000 or less, more preferably 5000000 or less, more preferably 2000000 or less, and most preferably 1000000 or less. Here, the polymers may be used alone or in combination of two or more.

Examples of the polymer include water-soluble polymers, water-insoluble polymers, enteric polymers, gastric polymers, or biodegradable polymers.
The polymer is preferably a water-insoluble polymer, an enteric polymer, a gastric polymer, or a biodegradable polymer.
The polymer is more preferably a water-insoluble polymer, an enteric polymer, or a gastric polymer.
As the polymer, more preferably, a water-insoluble polymer or an enteric polymer is mentioned.
The polymer is most preferably a water-insoluble polymer.

As the water-soluble polymer, for example, methylcellulose (eg, trade name: SM-4, SM-15, SM-25, SM-100, SM-400, SM-1500, SM-4000, 60SH-50, 60SH- 4000, 60SH-10000, 65SH-50, 65SH-400, 65SH-4000, 90SH-100SR, 90SH-4000SR, 90SH-15000SR, 90SH-100000SR), hydroxypropyl cellulose (eg, trade names: HPC-SSL, HPC- SL, HPC-L, HPC-M, HPC-H), hydroxypropyl methylcellulose (eg, trade name: TC5-E, TC5-M, TC5-R, TC5-S, SB-4), hydroxyethylcellulose (eg, Product Name: SP200, SP400, SP500, SP Cellulose derivatives such as 00, SP 850, SP 900, EP 850, SE 850, SE 400, SE 500, SE 600, SE 600, SE 850, SE 900, EE 820), hydroxymethyl cellulose, carboxymethyl cellulose (eg, trade name: NS-300) and their salts, polyvinylpyrrolidone (eg, goods) Name: Plasdone K12, Plasdone K17, Plasdone K25, Plasdone K29-32, Plasdone K90, Plasdone K90D), polyvinyl alcohol (eg, trade name: Gohsenol EG-05, Gohsenol EG-40, Gohsenol EG-05P, Gohsenol EG-05PW , Goshenol EG-30P, Goshenol EG-30PW, Goshenol EG-40P, Goshenol EG-40PW, copolyvidone (eg, trade name: Coridone) A64, Prasdon S-630), polyethylene glycol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (eg, trade name: POVACOAT), vinyl acetate / vinyl pyrrolidone copolymer (eg, trade name: Kollidon VA 64), Water-soluble vinyl derivatives such as polyvinyl alcohol, polyethylene glycol, graft copolymer (eg, trade name: Kollicoat IR), pregelatinized starch (eg, trade name: amicol C), dextrin, dextran, pullulan, alginic acid, gelatin, pectin, etc. These may be used alone or in combination of two or more.
Preferred examples of the water-soluble polymer include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and pregelatinized starch.
More preferably, hydroxypropyl cellulose is mentioned as a water-soluble polymer.

Examples of the water-insoluble polymer include water-insoluble cellulose ethers such as ethyl cellulose (eg, trade name: ETCELL (ETCEL 10P)), cellulose acetate, etc. Ammonio alkyl methacrylate copolymer RS (eg, trade name: Eudragit RL100, Eudragit RLPO, Water-insoluble acrylic acid copolymers such as Eudragit RL 30 D, Eudragit RS 100, Eudragit RSPO, Eudragit RS 30 D), ethyl acrylate / methyl methacrylate copolymer dispersion (eg, trade name: Eudragit NE 30 D), or vinyl acetate resin One or two or more may be mixed and used. In the present invention, by using a water-insoluble polymer as the polymer, it is possible to impart the function of a bitter taste mask of a drug having sustained release or bitter taste.
Preferred examples of the water-insoluble polymer include ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more of them.
More preferable examples of the water-insoluble polymer include ethyl cellulose, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof.
More preferable examples of the water-insoluble polymer include ethyl cellulose, ammonio alkyl methacrylate copolymer RS, and a mixture of one or more thereof.
The water insoluble polymer is most preferably an ammonio alkyl methacrylate copolymer RS.

Examples of enteric polymers include hydroxypropyl methylcellulose acetate succinate (eg, trade names: AQOAT LF, AQOAT MF, AQOAT HF, AQOAT LG, AQOAT MG, AQOAT HG), hydroxypropyl methylcellulose phthalate (eg, trade name: HPMCP50, HPMCP55, HPMCP55S), methacrylic acid copolymer L (eg, trade name: Eudragit L100), methacrylic acid copolymer LD (eg, trade name: Eudragit L30D-55), dry methacrylic acid copolymer LD (eg, trade name: Eudragit L100) -55), methacrylic acid copolymer S (eg, trade name: Eudragit S 100), or methacrylic acid copolymer such as methacrylic acid-n-butyl acrylate copolymer, etc. The recited, may be mixed and used one or two or more.
Preferred enteric polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, or a mixture of one or more thereof.
More preferably, the enteric polymer is hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, or a mixture of one or more thereof.
The enteric polymer is further preferably a methacrylic acid copolymer L, a dry methacrylic acid copolymer LD, a methacrylic acid copolymer S, or a mixture of one or more thereof.
The enteric polymer is most preferably a dry methacrylic acid copolymer LD.

Examples of the gastric soluble polymer include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylamino acetate, and gastric soluble acrylic acid copolymers such as aminoalkyl methacrylate copolymer E (eg, trade name: Eudragit E 100, Eudragit EPO). And one or more kinds may be mixed and used.
Preferred examples of the stomach-soluble polymer include aminoalkyl methacrylate copolymer E.

A biodegradable polymer is a polymer that can be degraded in vivo. For example, polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof, collagen, chitin, or chitosan (eg, trade name: Flonac C-100M), etc. may be mentioned, and one or more of them may be mixed You may use.
Preferred biodegradable polymers include gelatin and chitosan.

The polymer can be selected according to the purpose. For example, in order to achieve rapid elution of drug from drug-containing particles in the digestive tract, it is preferable to use a water-soluble polymer as the polymer, and to achieve sustained release of the drug, as the polymer. It is preferable to use a water-insoluble polymer, and in order to achieve a bitter taste mask, it is preferable to use a water-insoluble polymer, an enteric polymer, a stomach-soluble polymer, etc. It is preferable to use an enteric polymer to accelerate elution in the small intestine, and it is preferable to use chitosan or the like to achieve colonic targeting. Moreover, you may mix and use 2 or more types of polymers which have a different function like a water-soluble polymer, a water-insoluble polymer etc. according to the objective.

It is preferable to use such a polymer in a powder state, and one having an appropriate average particle size and particle size distribution can be selected according to the average particle size and particle size distribution of the desired drug-containing particles. Further, among those exemplified above, those in the state of dispersion are also included, but they can be used in the present invention, for example, by using them as powder after being powdered by spray drying or the like. For example, to obtain drug-containing particles with a narrow particle size distribution, it is preferable to use a polymer powder with a narrow particle size distribution. Furthermore, in order to obtain drug-containing particles having a large average particle size, it is preferable to use a polymer powder having a large average particle size, and in order to obtain drug-containing particles having a small average particle size, a polymer having a small average particle size It is preferred to use a powder. This means that by adjusting the size and particle size distribution of the polymer powder, drug-containing particles having a particle size distribution according to the purpose can be produced.

The content of the polymer varies depending on the amount of drug, additive for drug-containing particles, particle diameter, strength of bonding force of polymer, etc., but usually 1 to 70% by weight per 100% by weight of drug-containing particles It is preferably 1 to 60% by weight, more preferably 1 to 40% by weight, still more preferably 10 to 40% by weight, and most preferably 10 to 30% by weight.
Another preferable embodiment of the content of the polymer is 5 to 50% by weight, more preferably 5 to 40% by weight, still more preferably 5 to 30% by weight, and most preferably 5 to 25% by weight. % Is listed.

The drug-containing particles of the present invention preferably include those containing 1 to 70% by weight of the drug and 1 to 30% by weight of the polymer per 100% by weight of the drug-containing particle.
More preferably, the drug-containing particles contain 5 to 50% by weight of the drug and 1 to 40% by weight of the polymer per 100% by weight of the drug-containing particle.
More preferably, the drug-containing particles contain 10 to 40% by weight of the drug and 10 to 40% by weight of the polymer per 100% by weight of the drug-containing particle.
The drug-containing particles are most preferably those containing 115 to 30% by weight of the drug and 10 to 30% by weight of the polymer per 100% by weight of the drug-containing particle.

The preferable average particle diameter of the polymer used as the raw material in the present invention is 0.5 μm or more, preferably 5 μm or more, and as a preferable embodiment, 20 μm or more, 25 μm or more, 40 μm or more, 50 μm or more 5 times or more, preferably 10 times or more, more preferably 15 times or more, more preferably 20 times or more, particularly preferably 25 times the average particle diameter of the drug and / or the additive for drug-containing particles described below The above are preferred.
Here, in the present specification, how many times the average particle size of the polymer used as the raw material is with respect to the average particle size of the drug used as the raw material and / or the drug-containing particle additive described below It is indicated by the particle size distribution ratio (D50 / D50) of the average particle size of the polymer used as the raw material, the drug used as the raw material and / or the additive for drug-containing particles described below.
For example, in Example 1-1 described later, the D50 of the polymer (ammonio alkyl methacrylate copolymer RS (100-200 mesh)) used as the raw material is 107.78, and the D50 of the drug used as the raw material (the present compound) is 4.66. The particle size distribution ratio (D50 / D50) is 23.1 (107.78 / 4.66 = 23.1), but the average particle size of the polymer used as the raw material is the average value of the drug used as the raw material It can be said that it is 23.1 times the particle diameter.
From the viewpoint of particle shell strength, the larger the particle size distribution ratio (D50 / D50) of the mixture end of the polymer used as the raw material and the drug used as the raw material and the additive for drug-containing particles, the better. Also, it is usually 1000 times or less, preferably 500 times or less, more preferably 100 times or less. The average particle size of the polymer is usually 5 mm or less. Preferably, it is 1 mm or less, more preferably 300 μm or less, still more preferably 250 μm, and particularly preferably 200 μm or less. As the polymer powder, for example, a particle size fraction can be selectively used by sieving.
For example, a sieve having a sieve number described in USP (US Pharmacopoeia), EP (European Pharmacopoeia), JP (Japan Pharmacopoeia) is appropriately selected and fractionated to be used as a polymer having a desired particle size distribution. It becomes possible. From the viewpoint of particle shell strength, the smaller the particle size distribution width (D90 / D10) of the polymer used as the raw material, the better.
In the present invention, the average particle size of the polymer may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.

In the drug-containing particles of the present invention, the polymer is not used as a solution or suspension in the form of a granulation liquid, but is mixed with the drug in the form of a powder and then granulated while adding a solvent, eg, spraying It is preferable to do. However, as long as the effects of the present invention are exhibited, a part of the polymer or the drug may be dissolved or suspended in a solvent and used.

(Iv) Additives for drug-containing particles (other additives used for drug-containing particles)
The additive for drug-containing particles is not particularly limited as long as it is a commonly used additive, for example, an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavor, a fluidizing agent, Antistatic agents, coloring agents, disintegrants, lubricants, plasticizers, anticoagulants, coating agents and the like can be mentioned.
The additive for drug-containing particles preferably includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, or a coating agent.
More preferably, the additive for drug-containing particles includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent.
Further preferably, the additive for drug-containing particles includes an excipient, a binder, a sweetener, a flavoring agent, a fluidizer, an antistatic agent, a colorant and a coating agent.
Most preferably, the additive for drug-containing particles includes an excipient, a binder, and a sweetener.

As the excipient, for example, saccharides, sugar alcohols, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose can be mentioned.
As an excipient used for drug-containing particles, lactose, sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol are preferably used. And xylitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose.
More preferably, the excipient used for the drug-containing particles includes lactose, sucrose, mannitol, xylitol, erythritol, calcium hydrogen phosphate, calcium carbonate and crystalline cellulose.
More preferably, excipients used for drug-containing particles include lactose, mannitol, erythritol, and crystalline cellulose.
Most preferably, the excipient used for the drug-containing particles includes mannitol.

Examples of sugars include lactose, sucrose, sucrose, fructose, fructooligosaccharides, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, or reduced lactose.

Sugar alcohols include, for example, erythritol, sorbitol, maltitol, xylitol, or mannitol.
Preferably, the sugar alcohols used for the drug-containing particles include mannitol.

As a binder, for example, cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose and salts thereof, polyvinyl pyrrolidone, polyvinyl alcohol, copolyvidone, vinyl acetate / vinyl pyrrolidone copolymer, polyvinyl Water-soluble vinyl derivatives such as alcohol, polyethylene glycol and graft copolymer, pregelatinized starch, dextrin, dextran, pullulan, alginic acid, gelatin, pectin, ethyl cellulose, water-insoluble cellulose ether such as cellulose, acetate Ammonio alkyl methacrylate copolymer RS, acrylic acid Water, such as ethyl methyl methacrylate copolymer dispersion Soluble acrylic copolymer, vinyl acetate resin, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, methacrylic acid-acrylic acid n- Methacrylic acid copolymer such as butyl copolymer, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, gastric acid soluble polyvinyl derivative such as polyvinyl acetal diethyl aminoacetate, or aminoalkyl Stomach-soluble acrylic acid such as methacrylate copolymer E Polymers, polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof, collagen, chitin, or chitosan (eg, trade name: Fronach C-100M) may be mentioned, and one or more of them may be mixed and used May be
As a binder used for drug-containing particles, preferably, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, pregelatinized starch, ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, hydroxypropyl methyl cellulose Phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, gelatin, chitosan may be mentioned, and one or more kinds may be mixed and used.
More preferably, as a binder used for drug-containing particles, hydroxypropyl cellulose, ethyl cellulose, ammonio alkyl methacrylate copolymer RS, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, chitosan And may be used alone or in combination of two or more.
Most preferably, as a binder used for drug-containing particles, hydroxypropyl cellulose, ammonio alkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer E may be mentioned, and one or more kinds may be mixed and used.

As the sweetening agent, for example, saccharides, sugar alcohols, licorice extract which is a natural sweetener, stevia extract, lacanca extract, thaumatin, or a synthetic sweetener, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, Sucralose or acesulfame K is mentioned. As a sweetening agent used for drug-containing particles, preferably erythritol, sorbitol, maltitol, mannitol, xylitol, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia extract, thaumatin, sucralose, or acesulfame K.
More preferably, as a sweetener used for the drug-containing particles, aspartame, thaumatin, sucralose, lactose, stevia extract, thaumatin, acesulfame K can be mentioned.
More preferably, as a sweetening agent used for drug-containing particles, aspartame, thaumatin and sucralose can be mentioned.
Most preferably, the sweetening agent used for the drug-containing particles includes aspartame.

Flavoring agents and flavoring agents include sweetening components such as sucrose, saccharin and various fruit syrups, organic acids such as fumaric acid, citric acid and tartaric acid, and fruit essences.

Examples of the flavor include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, or low-substituted hydroxypropyl cellulose.
As a fragrance | flavor used for drug containing particle | grains, corn starch and low substituted hydroxypropyl cellulose are mentioned preferably.
More preferably, corn starch is mentioned as a fragrance used for drug-containing particles.

As a fluidizing agent, for example, talc, light anhydrous silicic acid, magnesium aluminometasilicate, hydrous silicic acid silicic acid can be mentioned.
Preferably, the fluidizing agent used for the drug-containing particles includes talc.

Examples of the antistatic agent include magnesium aluminometasilicate.

Examples of colorants include tar dyes, lake dyes, yellow ferric oxide, ferric oxide, and titanium oxide.
Preferably, the coloring agent used for drug-containing particles includes yellow ferric oxide.

As the disintegrant, for example, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium can be mentioned, and one or more of them can be mixed You may use it.

As the lubricant, for example, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax or sucrose fatty acid ester may be mentioned, and one or more kinds may be mixed and used.

As the plasticizer, for example, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester can be mentioned.

As the anticoagulant, for example, silicon dioxide, light anhydrous silicic acid, talc, magnesium stearate, sodium stearyl fumarate may be mentioned.

As the coating agent, for example, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax or sucrose fatty acid ester may be mentioned, and one or more kinds may be mixed and used.
Preferred examples of the coating agent used for the drug-containing particles include sodium stearyl fumarate, talc, and magnesium stearate, and one or more kinds of them may be mixed and used.
More preferably, the coating agent used for the drug-containing particles includes sodium stearyl fumarate and talc.
More preferably, sodium stearyl fumarate is mentioned as a coating agent used for drug-containing particles.

The content of the additive for drug-containing particles can be optionally set, but generally 95.9 wt% or less, preferably 90 wt% or less, more preferably 80 wt% or less, per 100 wt% of drug-containing particles, more preferably Is 70 wt% or less, most preferably 60 wt% or less. Specifically, 0.1 to 95.9% by weight, preferably 1 to 90% by weight, more preferably 5 to 80% by weight, still more preferably 10 to 70% by weight, per 100% by weight of the drug-containing particles, most preferably Is 20 to 60% by weight.

The drug-containing particle additive is preferably a powder. When the additive is a powder, the average particle size of the additive of the powder used as the raw material is 20 μm or less, preferably 15 μm or less, more preferably 10 μm or less, and may be similar to the average particle size of the drug powder used as the raw material Less than that is preferable. The average particle size of the other additives is usually 0.005 μm or more.
The average particle diameter of the drug-containing particle additive may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.

(V) Drug-containing hollow particles Drug-containing hollow particles are "particles comprising a shell (or a wall) and a hollow portion and containing a drug and a polymer in the shell" or "containing a drug and a polymer" It means "particles having a structure in which a hollow portion is surrounded by a wall made of a composition.
The feature of the drug-containing hollow particle is that the inside of the particle has a hollow structure. This "hollow" is surrounded by the wall (shell (shell)) of the drug-containing composition and completely independent, unlike the state in which there are a large number of voids whose positions do not exist as in the case of ordinary tablets. Point indicates a void existing in the particle center, and its presence can be confirmed by, for example, an electron microscope or an optical microscope.
The hollow volume ratio to the total volume of the drug-containing hollow particles is preferably 1% to 50%, more preferably 1% to 30%, still more preferably 1.5% to 30%, most preferably 2% to There is about 30%. Another preferred embodiment of the hollow volume ratio is about 4% to 50%, more preferably 4% to 40%, still more preferably 10% to 40%, and most preferably about 10 to 30%. The hollow volume ratio is determined by dividing the hollow volume by the volume of the particles. Since the particles of the present invention generally have high sphericity, the volume is determined assuming that both hollow and particles are spherical. The hollow and particle volumes are determined by X-ray CT (computed tomography apparatus) to determine the major and minor diameters of the hollow and particles at the center of the particle, assuming that the average is the hollow diameter and particle diameter, respectively. Calculated by asking for
Specifically, the “hollow volume ratio” in the present invention is calculated by the following equation.
Hollow volume ratio [%] = (4/3 × π × (diameter of hollow portion / 2) ³ ) / (4/3 × π × (particle diameter of drug-containing particles / 2) ³ ) × 100
The particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

The drug-containing hollow particles have a wall (shell) outside the hollow. The shell thickness can be set arbitrarily, but if the shell thickness is small, the strength of the particles is weakened. The shell thickness of the present invention is preferably 10 μm or more, more preferably 15 μm or more, still more preferably 20 μm or more, and most preferably 30 μm or more. The shell thickness can be measured, for example, by X-ray CT (computed tomography apparatus).
Further, the shell thickness ratio of the present invention is arbitrary, and can be obtained by the following equation. The shell thickness ratio is preferably 20 to 80%, more preferably 30 to 70%.
Shell thickness ratio [%] = (shell thickness / (particle diameter of drug-containing particles / 2)) × 100

The characteristics of the drug-containing hollow particles are that the size of the particles can be freely adjusted. Therefore, the average particle diameter is about 1 to about 7000 μm, preferably about 5 to about 1000 μm, more preferably about 10 to about 500 μm, still more preferably about 10 to about 400 μm, still more preferably about 20 to about 300 μm, and most preferably about 50 to about 300 μm The particles of the can be adjusted.
From the viewpoint of the strength of the particles, the size of the particles is preferably about 50 to about 7000 μm, more preferably about 50 to about 1000 μm, and still more preferably about 50 to about 500 μm. From another point of view, the particle size is preferably about 70 to about 7000 μm, more preferably about 70 to about 1000 μm, still more preferably about 70 to about 500 μm, particularly preferably about 70 to about 300 μm, and most preferably about 100 to about 300 μm Can be adjusted.
In the present invention, the size of the drug-containing particles can be adjusted by adjusting the average particle size of the polymer.

In the drug-containing hollow particles, the diameter of the hollow portion is usually 10 μm or more. In addition, the diameter of the hollow portion can be freely adjusted, and usually adjusted to about 10 to 5000 μm, preferably about 20 to 700 μm, more preferably about 30 to 300 μm, and still more preferably about 50 to 200 μm. it can. It is possible to freely change the proportion of hollow in combination with the size of the particles described above.

The drug-containing particles of the present invention also have an aspect that the "surface is smooth" as one aspect. Here, the surface being smooth means that there are no corners and the surface is not uneven. Since the flowability of the particles to be filled is required at the time of tablet-containing, drug-containing particle filling at the time of capsule preparation, etc., it is preferable that the drug-containing particles have a smooth surface. It is preferable that the drug-containing particles have a smooth surface, because the efficiency is improved also in coating for further imparting functionality to the drug-containing particles. Such surface smoothness can be observed visually, for example. When observing visually, you may expand and observe with a microscope etc. The evaluation is represented as "very smooth" (+++), "smooth" (++), "smoothly" (+), or "not smooth" (-). "Very smooth" means that no apparent corners are observed on the particle surface, and the surface is not uneven. "Smooth" means that although there are no obvious corners on the particle surface, gentle asperities are observed on the surface. "Slightly smooth" indicates that the surface of the particle has a clear angle or a clear unevenness. "Unsmooth" means that clear corners are observed on the particle surface, and clear unevenness is observed. The drug-containing particles of the present invention may be "not smooth" but are preferably "very smooth", "smooth" or "smoothly", more preferably "very smooth" or "smooth", "Very smooth" is more preferred. Also, it can be measured using a shape measuring laser microscope VK-X200 (KEYENCE). Specifically, "surface is smooth" means that the surface roughness (Ra value) measured by the above-mentioned instrument is 3.5 or less, preferably 2.5 or less, more preferably 1.5 or less. means.
The smoothness of the surface is influenced by the ratio of the average particle size of the polymer to the drug and / or other additives.

In addition, the drug-containing particles of the present invention have a spherical shape as one aspect. Here, “spherical” means that the aspect ratio is 1.0 to 1.5. Preferably, it is 1.0 to 1.4, more preferably 1.0 to 1.3. By having this shape, the flowability at the time of tablet-containing, drug-containing particle filling at the time of capsule preparation, etc. is good at the time of tableting, and also the efficiency improves when processing such as coating.

The drug-containing particles of the present invention preferably contain 1 to 70% by weight of the drug, 1 to 30% by weight of the polymer, and 1 to 90% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle. The thing is mentioned.
More preferably, the drug-containing particles of the present invention contain 5 to 50% by weight of the drug, 1 to 40% by weight of the polymer, and 5 to 80% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle. The thing to do is mentioned.
More preferably, the drug-containing particles of the present invention contain 10 to 40% by weight of the drug, 10 to 40% by weight of the polymer, and 10 to 70% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle. The thing to do is mentioned.
The drug-containing particles of the present invention most preferably contain 15 to 30% by weight of drug, 10 to 30% by weight of polymer, and 20 to 60% by weight of additive for drug-containing particle per 100% by weight of drug-containing particle The thing to do is mentioned.

The average particle size of the polymer used as the raw material is usually 5 times or more, preferably 10 times or more, more preferably 15 times the average particle size of the drug and / or the drug-containing particle additive used as the raw material Or more, more preferably 20 times or more, and most preferably 25 times or more. Also, those having a magnification of 1,000 times or less, preferably 500 times or less, more preferably 100 times or less can be mentioned.
Furthermore, it is preferable that the particle size distribution of the polymer used as the raw material and the particle size distribution of the drug and / or the additive for drug-containing particles used as the raw material do not overlap. Specifically, it is preferable that, for example, the cumulative 10% particle diameter D10 in the volume-based measurement of the polymer is larger than the cumulative 90% particle diameter D90 of the drug and / or the additive for drug-containing particles. In other words, the 10% particle diameter D10 of the polymer is preferably one or more times larger than the 90% particle diameter D90 of the drug and / or the drug-containing particle additive, and more preferably twice or more. Preferably, it is more preferably 4 times or more. Also, it is usually 5,000,000 times or less.

The drug-containing particles of the present invention preferably contain 1 to 70% by weight of the drug and 1 to 30% by weight of the polymer per 100% by weight of the drug-containing particle (more preferably 5 to 50% by weight of the drug) 1 to 40% by weight of a polymer; more preferably 10 to 40% by weight of a drug and 10 to 40% by weight of a polymer: most preferably 15 to 30% by weight of a drug The polymer preferably contains 10 to 30% by weight) and the “preferred average particle size of the polymer used as the raw material” is usually 10 or more times the average particle size of the drug used as the raw material (preferably Those having 15 times or more, more preferably 25 times or more) can be mentioned.

The drug-containing particles of the present invention contain 1 to 70% by weight of the drug, 1 to 30% by weight of the polymer, and 1 to 90% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle (More preferably, 5 to 50% by weight of the drug, 1 to 40% by weight of the polymer, 5 to 80% by weight of the additive for drug-containing particles; further preferably, 10 to 40% by weight of the drug 10 to 40% by weight of a polymer and 10 to 70% by weight of an additive for drug-containing particles; most preferably, 15 to 30% by weight of a drug, 10 to 30% by weight of a polymer The additive for particles is contained at 20 to 60% by weight), and the preferable average particle size of the polymer used as the raw material is 10 with respect to the average particle size of the mixed powder of the drug and other additives used as the raw material Times or more (preferably 15 times or more, Ri preferably include those that are more than 25 times).

(2) Preparation containing drug-containing particles The preparation of the present invention contains the drug-containing particles of (1), and may optionally contain (vi) a formulation additive.
Examples of the dosage form of the preparation containing drug-containing particles in the present invention include granules, tablets, capsules, suspensions (aqueous suspensions, oily suspensions), and emulsions. Preferred examples of the dosage form include granules, tablets, or capsules. More preferably, a tablet is mentioned as a dosage form. The tablet preferably includes an orally disintegrating tablet.
The "per 100% by weight of the preparation" means a weight percentage when the "weight of the whole preparation containing the drug-containing particles" is 100%.

(Vi) Additives for formulation (other additives used for formulation)
The “formulation additive” is not particularly limited as long as it is a commonly used additive, and examples of the additive are as described in the “drug-containing particle additive” in (iv) above. Excipients, binders, sweeteners, flavoring agents, flavoring agents, flavors, fluidizers, antistatic agents, coloring agents, disintegrants, lubricants, plasticizers, anticoagulants, coating agents, etc. .
Preferred additives used for formulation include excipients, binders, sweeteners, flavoring agents, flavoring agents, flavoring agents, fluidizers, antistatic agents, coloring agents, disintegrants and lubricants. .
More preferably, the additive used in the formulation includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavor, a fluidizing agent, a disintegrant and a lubricant.
As an additive used for formulation, an excipient, a disintegrant, and a lubricant are mentioned more preferably.

Excipients, binders, sweeteners, flavoring agents, flavoring agents, flavors, fluidizers, antistatic agents, coloring agents, disintegrants, lubricants, plasticizers, anticoagulants, coatings used in formulation Examples of the agent are as described in the “drug-containing particle additive” of (iv) above.

Excipients used for formulation include, for example, saccharides, sugar alcohols, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose.
As an excipient used for formulation, lactose, sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol, are preferably used. And xylitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose.
More preferably, the excipient used for formulation includes lactose, sucrose, erythritol, mannitol, calcium carbonate, or crystalline cellulose.
More preferably, the excipient used for formulation includes lactose, mannitol, calcium carbonate, or crystalline cellulose.
Most preferably, the excipient used for formulation includes mannitol or crystalline cellulose.

As saccharides used for formulation, lactose, sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, or reduced lactose is preferably mentioned.

Preferred sugar alcohols used for formulation include erythritol, sorbitol, maltitol, xylitol or mannitol.
More preferably, the sugar alcohols used for formulation include mannitol.

Preferred binders used for formulation are cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose and salts thereof, polyvinyl pyrrolidone, polyvinyl alcohol, copolyvidone, vinyl acetate / vinyl acetate Water-soluble vinyl derivatives such as pyrrolidone copolymers, polyvinyl alcohol / polyethylene glycol graft copolymers, etc., pregelatinized starch, dextrin, dextran, pullulan, alginic acid, gelatin, pectin, ethyl cellulose, water insoluble cellulose ethers such as cellulose acetate, ammonio alkyl Methacrylate copolymer RS, ethyl acrylate, methyl methacrylate Water-insoluble acrylic acid-based copolymers such as Rimmer dispersion, vinyl acetate resin, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, methacrylic Acid-acrylic acid methacrylic acid copolymer such as n-butyl copolymer, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, polyvinyl acetal diethylaminoacetate etc Polyvinyl derivatives, or aminoalkyl methacrylate copolymer E, etc. Stomach-soluble acrylic acid-based copolymer, polylactic acid, polyglycolic acid, polycaprolactone and their copolymers, collagen, chitin, or chitosan (eg, trade name: Flonac C-100M), and one or two kinds thereof. You may mix and use the above.

As a sweetening agent used for formulation, preferably erythritol, sorbitol, maltitol, mannitol, xylitol, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia extract, thaumatin, sucralose or acesulfame K can be mentioned.
More preferably, as a sweetening agent used for formulation, aspartame, mannitol, thaumatin, sucralose, or acesulfame K can be mentioned.
More preferably, as a sweetening agent used for formulation, aspartame, mannitol, thaumatin can be mentioned.
Most preferably, the sweetening agent used for formulation includes aspartame.

Preferred flavoring agents and flavoring agents used for formulation include sucrose, saccharin, sweetening ingredients such as various fruit syrups, organic acids such as fumaric acid, citric acid and tartaric acid, and fruit essences.
More preferably, fumaric acid, citric acid and fruit essence are used as flavoring agents and flavoring agents used for formulation.
As the flavoring agent and flavoring agent used for formulation, fumaric acid and fruit essence are more preferable.
Most preferably, as a flavoring agent and a flavoring agent used for formulation, a fruit essence is mentioned.

As a fragrance used for formulation, preferably croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low substituted hydroxypropyl cellulose are mentioned.
More preferably, as a fragrance used for formulation, corn starch and low substituted hydroxypropyl cellulose are mentioned.
More preferably, corn starch is mentioned as a fragrance used for formulation.

As a fluidizing agent used for formulation, preferably, talc, light anhydrous silicic acid, magnesium aluminometasilicate, hydrous silicic acid silicic acid can be mentioned.
More preferably, talc, light anhydrous silicic acid and magnesium aluminometasilicate are mentioned as a fluidizing agent used for formulation.

As an antistatic agent used for formulation, preferably magnesium aluminometasilicate is mentioned.

As a coloring agent used for formulation, a tar pigment, lake pigment, yellow ferric oxide, ferric oxide, titanium oxide are preferably mentioned.
More preferably, the coloring agent used for formulation includes lake pigment and yellow ferric oxide.
More preferably, yellow ferric oxide is mentioned as a coloring agent used for formulation.

As disintegrants used for formulation, preferably, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are mentioned.

Plasticizers used for formulation include, for example, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester.

As the anticoagulant used for formulation, for example, silicon dioxide, light anhydrous silicic acid, talc, magnesium stearate, sodium stearyl fumarate may be mentioned.

As a coating agent used for formulation, preferably hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonio alkyl methacrylate copolymer RS, ethyl acrylate · ethyl acrylate · A combination of a base such as methyl methacrylate copolymer and a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester and the like can be mentioned. In addition, additives such as titanium oxide, talc and coloring agents can also be added. Furthermore, after film coating, carnauba wax, talc and the like can be added as a brightening agent. As an apparatus, the apparatus classified into a coating pan is mentioned, for example. Preferably, an apparatus classified as a vented coating system can be mentioned.

The content of additives used for formulation can be optionally set, but generally 95.9 wt% or less, preferably 90 wt% or less, more preferably 80 wt% or less, per 100 wt% of the formulation, more preferably Is 70 wt% or less, most preferably 60 wt% or less. Specifically, 0.1 to 95.9 wt%, preferably 1 to 90 wt%, more preferably 5 to 80 wt%, further preferably 10 to 70 wt%, most preferably 20 to 100 wt% of the preparation. Up to 60% by weight can be mentioned.

Production method
Production method 1: Method for producing "drug-containing hollow particles coated with an outer layer with sodium stearyl fumarate" The drug-containing hollow particles (the above (v)) of the present invention are a drug (the above (i)) and a polymer (the above It can be manufactured by adding a solvent capable of dissolving the polymer to a powdered mixture containing (iii)) and other additives (the above (iv)), for example, granulating while spraying. . Thereafter, sodium stearyl fumarate ((ii) above) is added to and mixed with the drug-containing hollow particles, and then a solvent capable of dissolving the polymer is added, for example, mixed while spraying, and dried. Drug-containing hollow particles coated with an outer layer with sodium stearyl fumarate can be produced.
The granulation method can be appropriately selected as long as it has a function of rolling core particles into a coating. For example, it can be manufactured using a stirring granulation method, a mixing stirring granulation method, a high speed stirring granulation method, a high speed mixing stirring granulation method, a rolling stirring fluidized bed granulation method, a rolling granulation method. Among these, it is preferable to use a stirring granulation method, a mixing stirring granulation method, a high speed stirring granulation method, and a high speed mixing stirring granulation method. As a granulator used for stirring granulation, mixing stirring granulation, etc., for example, intensive mixer (manufactured by Nippon Eirich), universal mixer (manufactured by Shinagawa Kogyosho), super mixer (manufactured by Kawata Co., Ltd.), FM mixer (manufactured by Japan) Coke Industry Co., Ltd. made SPG series (made by Fuji Paudal Co., Ltd.), vertical granulator (eg FM-VG-05 type, FM-VG-100 type, made by Powrex Co., Ltd.), high speed stirring mixing granulator pharma Matrix (made by Nara Machinery Co., Ltd.), high-speed mixer (made by Fukae Pautech Co., Ltd.), granumist (made by Freund Industrial Co., Ltd.), Neugra Machine (made by Seishin Co., Ltd.), Triple Master (made by Shinagawa Kogyosho Co., Ltd.) And the like. In the present invention, the simple fluidized bed granulation method is not preferable because the drying efficiency is too high and granulation does not proceed.
As the drying method, a method known per se can be appropriately selected. For example, drying by a tray dryer or a fluidized bed may, for example, be mentioned. From the viewpoint of manufacturability, drying by a fluidized bed is preferable.
As a mixing method, any one having a mixing function can be appropriately selected. For example, a convective mixer such as a tumble mixer, a V-type mixer, a diffusion mixer such as a W-type mixer, a ribbon mixer, a Nauta mixer, or a planetary mixer can be used.

Production method 2: Method for producing orally disintegrating tablet using drug-containing hollow particles The orally disintegrating tablet using the drug-containing hollow particles of the present invention is formulated as drug-containing hollow particles (above (v)) and (vi) The additives can be mixed and manufactured into tablets.
As a mixing method, any one having a mixing function can be appropriately selected. For example, a convective mixer such as a tumble mixer, a V-type mixer, a diffusion mixer such as a W-type mixer, a ribbon mixer, a Nauta mixer, or a planetary mixer can be used.
A tableting method can be appropriately selected as long as it has a function of compression molding a powder. For example, a tableting device classified as a tablet press can be mentioned. A lubricant can also be added to the tablet of the present invention by an external lubricant method.

The "solvent" in the present invention means all solvents acceptable in the fields of pharmaceuticals, quasi-drugs, cosmetics, food and the like, and any solvent can be used as long as it can dissolve the polymer used. From the viewpoint of using the drug-containing particles of the present invention as a medicament, pharmaceutically acceptable solvents are preferred. Such a solvent is appropriately selected according to the type of drug, polymer, additive and the like, and several solvents may be mixed and used.

As the “solvent” in the present invention, for example, water, alcohol solvents (eg, methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, etc. may be substituted) The lower alkanol), ketone solvents (for example, lower alkyl ketones such as acetone and methyl ethyl ketone), ester solvents (for example, lower alkyl esters of acetic acid such as ethyl acetate and the like), and mixed solvents thereof can be mentioned.
Specifically, in the present invention, when a water-soluble polymer is used as the polymer, a solvent capable of dissolving the polymer (for example, water, a water-containing alcohol solvent, etc.) can be used as a solvent, Water or hydrous ethanol can be used particularly preferably. When a water-insoluble polymer is used as the polymer, a solvent capable of dissolving the polymer (for example, an alcohol-based solvent, a ketone-based solvent, an ester-based solvent, etc.) can be used as a solvent. Also, polymers such as polymers, enteric polymers, and chitosan can all be used as solvents which can dissolve the polymers (for example, alcohol solvents, more specifically, ethanol).
The amount of solvent used in the present invention varies depending on the type and amount of drug, polymer, etc., but usually 5 to 60% by weight, preferably 10 to 53% by weight, per 100% by weight of the total amount of each component constituting particles. More preferably, it is 10 to 40% by weight, still more preferably 15 to 40% by weight. The addition to the powdered mixture containing drug and polymer is preferably carried out by spraying.

Spraying of the solvent in the present invention may be carried out using a spray gun usually used in granulation. Specifically, a needle spray gun (manufactured by Tomita Engineering Co., Ltd.) and the like can be mentioned. In order to increase the yield of granules, the spray on the portion other than the powder in the granulation container, that is, the inner wall of the granulation container is as small as possible, and the solvent is sprayed over the widest possible range of the powder in the granulation container. It is preferable to do.

When the drug-containing particle additive is used, the average particle size of the mixed powder of the drug used as a raw material and the drug-containing particle additive is important in producing the drug-containing particles. In this case, the average particle size of the polymer used as the raw material is 5 times or more, preferably 10 times or more, more preferably 15 times the average particle size of the mixed powder of the drug used as the raw material and the additive for drug-containing particles. The above, particularly preferably 25 times or more is preferable. Also, it is usually 1000 times or less, preferably 500 times or less, more preferably 100 times or less.
Furthermore, it is preferable that the particle size distribution of the polymer used as the raw material and the particle size distribution of the mixed powder of the drug used as the raw material and the additive for the drug-containing particles do not overlap. Specifically, for example, one having a cumulative 10% particle diameter D10 in volume-based measurement of a polymer used as a raw material larger than 90% particle diameter D90 of a mixed powder of a drug used as a raw material and a drug-containing particle additive preferable. In other words, the cumulative 10% particle diameter D10 of the polymer used as the raw material is preferably 1 or more times the 90% particle diameter D90 of the mixed powder of the drug used as the raw material and the additive for drug-containing particles It is more preferably twice or more, and more preferably 4 times or more. Also, it is usually 500 times or less, preferably 250 times or less, more preferably 50 times or less.

The "aspect ratio" in the present invention is the ratio of the minor axis to the major axis of the particle, and serves as a standard indicating the sphericity. The aspect ratio can be calculated, for example, by the following equation.
Aspect ratio = long diameter of particle / short diameter of particle The long diameter and short diameter of the particle are nondestructively measured by a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
Moreover, it can measure using Millitrack JPA (Nikkiso Co., Ltd.).

The “particle size distribution width” in the present invention is determined by the ratio (D90 / D10) of the 90% cumulative particle diameter D90 to the cumulative 10% particle diameter D10 in the volume-based measurement of powder particles. In the drug-containing particles of the present invention, the particle size distribution can be simply adjusted by adjusting the particle size of the polymer, and, for example, particles having a narrow particle size distribution width can be produced. The particle size distribution width is measured on a volume basis with a laser diffraction type particle size distribution measuring apparatus (Powrex Inc., Particle Viewer).

In the present invention, “the particle size distribution width is narrow” means that the specific particle size distribution width (D90 / D10) is 6.0 or less, preferably 5.0 or less, more preferably 4.0 or less, still more preferably 3. It means that it is 0 or less.

The strength of hollow particles can be evaluated by the particle shell strength. The “particle shell strength” in the present invention is calculated by the following equation.
Particle shell strength [MPa] = 2.8 P / (π × d ² −π × d ′ ² ) × 1000
P: Destructive test force of particle [mN], d: diameter of drug-containing particle [μm], d ': diameter of hollow portion [μm]
The breaking test force of the particles and the diameter of the drug-containing particles are measured by Shimadzu micro compression tester MCT-W500 (manufactured by Shimadzu Corporation).

The “hollow portion diameter” in the present invention can be calculated by the following equation.
Hollow part diameter [μm] = (long diameter of hollow part + short diameter of hollow part) / 2
The major axis and minor axis of the hollow portion of such particles are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

In the present invention, the drug-containing particles are coated with a functional polymer or the like using a fluid bed granulator or various fine particle coating devices that require mechanical strength of the particles to impart additional functions. It is desirable to have sufficient particle strength such that it can be coated efficiently without cracking and cracking and can remain hollow without tableting.
The drug-containing hollow particles of the present invention have sufficient particle strength. Since the drug-containing hollow particle has a hollow portion, the hollow shell can not be correctly evaluated by calculating the hollow portion as a solid by the ordinary method of measuring the particle strength, and therefore the particle shell strength excluding the hollow portion can be measured. It is. Specifically, “sufficient particle strength” in the present invention means that the particle shell strength of the drug-containing particles is 2.0 MPa or more, preferably 3.0 MPa or more, more preferably 4.0 MPa or more, and still more preferably 5. It means that it is 0 MPa or more.

The “particle diameter of drug-containing particles” in the present invention can be calculated by the following equation.
Particle diameter of drug-containing particles [μm] = (long diameter of particles + short diameter of particles) / 2
The major axis and minor axis of the particles are nondestructively measured by a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

The “shell thickness” in the present invention is calculated by the following equation.
Shell thickness [μm] = (particle diameter of drug-containing particle-diameter of hollow portion) / 2
The particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

The “shell thickness ratio” in the present invention is calculated by the following equation.
Shell thickness ratio [%] = (shell thickness / (particle diameter of drug-containing particles / 2)) × 100
The particle diameter of the drug-containing particles is nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

The “hollow volume ratio” in the present invention is calculated by the following equation.
Hollow volume ratio [%] = (4/3 × π × (diameter of hollow portion / 2) ³ ) / (4/3 × π × (particle diameter of drug-containing particles / 2) ³ ) × 100
The particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.

The “particle size distribution ratio of polymer to drug (D50 / D50)” in the present invention can be calculated by the following equation.
Particle size distribution ratio of polymer to drug (D50 / D50) = polymer D50 / drug D50
The “particle size distribution ratio of the polymer, the mixture end of the drug and the other additive (D50 / D50)” in the present invention can be calculated by the following formula.
Particle size distribution ratio of polymer, mixed powder of drug and other additive (D50 / D50) = polymeric D50 / mixed powder of drug and other additive D50
The particle size distribution of the mixed powder of such a polymer, drug, drug and other additives may be obtained by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD) -Measured on a volume basis with -3000 J, SYMPATEC HELOS & RODOS).

The “particle size distribution ratio of polymer to drug (D10 / D90)” in the present invention can be calculated by the following equation.
Particle size distribution ratio of polymer to drug (D10 / D90) = polymer D10 / drug D90
The “particle size distribution ratio of the polymer, the mixture end of the drug and the other additive (D10 / D90)” in the present invention can be calculated by the following equation.
Particle size distribution ratio of polymer, mixed powder of drug and other additive (D10 / D90) = polymer D10 / mixed powder of drug and other additive D90
The particle size distribution of the mixed powder of such a polymer, drug, drug and other additives may be obtained by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD) -Measured on a volume basis with -3000 J, SYMPATEC HELOS & RODOS).

The present invention also includes a step of granulation while spraying a solvent capable of dissolving a polymer into a powdery mixture containing a drug and a polymer, and a method for producing hollow particles, and the method It also relates to the hollow particles produced.
Examples of the solvent capable of dissolving the drug, the polymer and the polymer include the same as those described above for the method for producing the drug-containing particle of the present invention. In the method, other additives may be contained as needed, and examples of the other additives are the same as those described above for the method of producing the drug-containing particle of the present invention.
As the granulation method, the drying method, the spraying method of the solvent and the like, those similar to those described above for the method for producing the drug-containing particle of the present invention are exemplified.

(3) Pharmaceutical composition and use thereof The present invention relates to a pharmaceutical composition, a therapeutic agent for treating and / or preventing digestive diseases or digestive conditions, which comprises drug-containing particles containing the drug of the present invention. And / or preventative agents. Preferably, said digestive system disorder is constipation type irritable bowel syndrome (IBS), or chronic constipation. The drug-containing particles containing the drug of the present invention preferably include the drug-containing particles of the above (1), and more preferably include the above (v) drug-containing hollow particles. The pharmaceutical composition, the therapeutic agent and / or the prophylactic agent preferably include a preparation containing the above (2) drug-containing particles.

In the present invention, “prevention” refers to the act of administering the drug of the present invention, which is an active ingredient, to healthy individuals who do not develop disease or have a poor health at the time of administration. It is intended to be administered to such healthy people, for example, for the purpose of preventing the onset of the disease, and in particular, the risk of suffering from a person who has had a symptom of the disease or suffering from the disease is increased. It is expected to be appropriate for those who are considered to be "Treatment" is the act of administering the drug of the present invention, which is the active ingredient, to a person (patient) who has been diagnosed as having a disease by a doctor, and the "therapeutic agent" is such a patient. For the purpose of, for example, alleviating the disease or condition, not aggravating the disease or condition, or returning to the state before the onset of the disease. In addition, even if the purpose of administration is to prevent deterioration of a disease or condition, it is a therapeutic action if it is a patient to be administered.

In the present invention, “digestive system diseases or digestive system conditions” specifically include the following diseases or conditions (i) to (iii):
(I) For example, irritable bowel syndrome, flaccid constipation, chronic constipation, chronic constipation, drug-induced constipation with drugs such as morphine and antipsychotics, constipation with Parkinson's disease, constipation with multiple sclerosis, diabetes Gastrointestinal diseases such as constipation with constipation or constipation or dysphagia due to contrast media (as pretreatment at endoscopy or barium enteral x-ray examination);
(Ii) functional dyspepsia, acute and chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-diffuse gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal diseases such as gastroparesis, post-gastrectomy syndrome, or pseudo intestinal obstruction;
And (iii) digestive system diseases described in the above (i) and (ii), scleroderma, diabetes, anorexia, nausea, vomiting, abdominal bloating, upper abdominal discomfort, abdominal pain in esophagus / biliary diseases Gastrointestinal symptoms such as heartburn or vagueness.

The administration mode of the drug of the present invention may be oral administration or parenteral administration. Although the dose varies depending on the administration method, patient's condition, age, etc., it is usually 0.01-30 mg / kg / day, preferably 0.05-10 mg / kg / day, more preferably 0.1-3 mg / kg. / Day range. In another preferred embodiment of the dosage, it is usually 0.01 mg to 1000 mg / day, preferably 0.1 mg to 500 mg / day, more preferably 0.5 mg to 300 mg / day, still more preferably 1 mg to 200 mg / day, most preferably Is in the range of 5 mg to 100 mg / day. The number of daily doses may be, for example, once, or several times a day, for example 1, 2 or 3 doses each time.

As a dosage form of the preparation for oral administration, for example, granules, tablets, capsules, suspensions (aqueous suspensions, oily suspensions), emulsions, etc. can be mentioned, and for parenteral administration Examples of the preparation include injections, drips, suppositories (rectal administrations), nasals, sublinguals, transdermal absorbents [lotion, milky lotion, ointment, cream, jelly, gel] Patch (tape agent, transdermal patch preparation, poultice, etc.), external use powder, etc.] and the like.
Preferably, the drug of the present invention is orally administered as a drug-containing particle or formulation of the present invention. More preferably, the dosage form of the preparation for oral administration includes a tablet as described in the above-mentioned (2) preparation containing drug-containing particles. Further, as tablets, preferred are orally disintegrating tablets.

The present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a drug-containing particle, preparation, or pharmaceutical composition of the present invention for the treatment of the diseases described herein. , Combination therapy administered sequentially or simultaneously, in combination with one or more of the following other agents.
Specifically, in the case of digestive system diseases accompanied by constipation, for example, salts such as magnesium sulfate, magnesium oxide, magnesium citrate and the like, for example, infiltrating agents such as dioctyl sodium, sulfosuccinate, casanthranol Laxatives, for example, swelling laxatives such as carmellose, for example, large intestine stimulating laxatives such as bisacodyl, picosulfa, senna, sennoside, for example, small intestine irritating laxatives such as castor oil, for example, intestinal detergents such as Be
Functional dyspepsia, acute and chronic gastritis, reflux esophagitis, non-diffuse gastroesophageal reflux disease, diabetic gastroparesis, gastric ulcer, duodenal ulcer, NSAID ulcer, gastric neurosis, postoperative ileus, senile ileus In the digestive system diseases such as post-gastrectomy syndrome or pseudo intestinal obstruction, for example, proton pump inhibitors such as omeprazole, rabeprazole, lansoprozole, and histamine H ₂ receptor inhibitors such as cimetidine, ranitidine, famotidine And antacid agents, for example, gastrointestinal tract function modifiers such as mosapride and domperidone, gastric mucous membrane protective agents, and intestinal stabilizers.

(4) Composition for Masking Bitter Taste and Application Thereof The present invention is provided based on the finding that the bitter taste of a component having bitterness was significantly masked when sodium stearyl fumarate was used for coating. It provides a new application of masking the bitter taste of sodium stearyl fumarate. As a specific example, (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide or The bitter taste of the pharmaceutically acceptable salt, or the hydrate or solvate thereof, is masked by coating sodium stearyl fumarate. More preferably, sodium stearyl fumarate is included as a coating of drug-containing particles.

The invention also relates to sodium stearyl fumarate and (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl]- The present invention relates to a composition for masking bitter taste, which comprises 2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Preferably, sodium stearyl fumarate is included as a coating. More preferably, the composition according to the invention comprises drug-containing particles, which are (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) Methyl] -2-morpholinyl} methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

In one embodiment, the composition for masking bitter taste of the present invention is characterized in that the outer layer of the drug-containing particle of the present invention is coated with the above sodium stearyl fumarate. By the presence of sodium stearyl fumarate, which is usually used as a lubricant, as a coating of the drug-containing particles, bitter taste masking (bitter taste mask) of the drug of the present invention exhibiting extremely strong unpleasant taste can be performed. This effect was found to be extremely remarkable as compared with the case of simply containing sodium stearyl fumarate. The drug-containing particles of the present invention preferably include the above (1) drug-containing particles, and more preferably include the above (v) drug-containing hollow particles.

As a method for producing a composition for masking such bitter taste, any coating method known in the art can be mentioned, and one example is a drug (the above (i)) as a raw material and a polymer (the above) A solvent capable of dissolving the polymer is added to a powdery mixture containing the above (iii) and the other additives (the above (iv)), for example, by granulating while spraying, (v) a drug After the hollow particles are prepared and then sodium stearyl fumarate ((ii) above) is added to the drug-containing hollow particles and mixed, a solvent capable of dissolving the polymer is added, for example, mixed while spraying. By drying, it can be mentioned a method of manufacturing.

By performing a sensory evaluation test of the composition for masking bitterness, the degree of bitterness of the composition can be evaluated to confirm the bitterness masking effect. As the test method, any test method known in the art can be mentioned, and as an example, the following test methods can be mentioned. Several subjects contain each sample in the oral cavity, hold it until it breaks down in the oral cavity, and then discharge it, and evaluate the bitter taste in the oral cavity, at the time of discharge (immediately after the collapse) and one minute after discharge. Bitterness is acceptable, setting two criteria that it is not acceptable, "0" to "2" are evaluated in 5 steps of 0.5, and if the average score is 0.5 or less, there is a problem with taking about bitterness If the average score is 1.0 or more, it is judged that it is difficult to take because of bitter taste. It is recognized that the composition has a bitter taste masking effect if the bitter taste is not a problem for taking.

Hereinafter, the present invention will be more specifically described by way of Examples, Test Examples and Comparative Examples, but the present invention is not limited thereto. Further, the present invention may be changed without departing from the scope of the present invention. The compound names shown in the following Examples, Test Examples and Comparative Examples do not necessarily follow the IUPAC nomenclature.

In the examples, test examples and comparative examples,% in the solvent indicates (W / W%) and% in the particles indicates% by weight unless otherwise noted.
The additives used in the examples, test examples and comparative examples were as follows unless otherwise noted.
Ammonio alkyl methacrylate copolymer RS (Eudragit RSPO): Evonik Degussa Japan D-mannitol (Peritol 25C): Rocket Japan KK crystalline cellulose (Theorus KG-1000): Asahi Kasei Chemicals Corp. crystalline cellulose (Theorus UF-702): Asahi Kasei Chemicals Corporation corn starch (corn starch XX16): Japan Food Chemical Industries Co., Ltd. Aspartame (aspartame): Ajinomoto magnesium stearate (magnesium stearate): Taiping Chemical Industries, Ltd. magnesium aluminometasilicate (Neusilin UFL2): Fuji Chemical Co., Ltd. Company D-Mannitol 80% and corn starch 20% premixed product (PEARLITOL FLASH): Rocket Japan Fumaric acid Co., Ltd. Stearyl sodium (PRUV): JRS PHARMA
Fragrance (Lemonmicron ZD-4061): Takasago Fragrance Industry Co., Ltd. Hardened oil (Labry wax-103): Freund Industrial Co., Ltd. Light anhydrous silica (Adsolider 101): Freund Industrial Co., Ltd. Talc (Talc MS-P): Japan Talc Sucrose fatty acid ester (DK ester): Daiichi Kogyo Seiyaku Co., Ltd. sodium lauryl sulfate (sodium lauryl sulfate): Merck anhydrous ethanol: Wako Pure Chemical Industries, Ltd. yellow ferric oxide: San-Ei Gen FFI

The test methods in the examples, test examples and comparative examples are as follows.
(Particle size distribution)
The particle size distribution of the drug, polymer, other additives, mixed powder of drug and other additives, and the drug-containing particles obtained is obtained by using a laser diffraction type particle size distribution measuring device (Powlec, Particle Viewer) or a laser diffraction type. It was measured on a volume basis with a particle size distribution measuring apparatus (SALD-3000J, manufactured by Shimadzu Corporation).
(Appearance and cross section of drug-containing particles)
The appearance and cross section of the particles were observed with a scanning electron microscope (S-3400N, manufactured by Hitachi, Ltd.).
(Internal state of drug-containing particles)
The internal state of the drug-containing particles was nondestructively observed with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN).
(Calculation of aspect ratio)
Unless otherwise noted, the aspect ratio of the obtained drug-containing particles is nondestructively measured by using a desktop micro CT scanner (SKYSCAN 1172, SKYSCAN 1172) and the following formula Calculated. The average value measured ten times was used.
Aspect ratio = major axis of particle / minor axis of particle (measurement of particle strength of comparative example)
The breaking test force and particle diameter of the particles of the comparative example having no hollow structure were measured by Shimadzu micro compression tester MCT-W500 (manufactured by Shimadzu Corporation), and the particle strength was calculated by the following equation (n = 5).
Particle strength [MPa] = 2.8 P / (π × d ² ) × 1000
P: Destructive test force of particles [mN], d: Diameter of drug-containing particles [μm]
(Measurement of particle shell strength)
The particle shell strength was calculated by the following equation (n = 5).
Particle shell strength [MPa] = 2.8 P / (π × d ² −π × d ′ ² ) × 1000
P: Destructive test force of particle [mN], d: diameter of drug-containing particle [μm], d ': diameter of hollow portion [μm]
The diameter of the hollow portion is a value calculated from the shell thickness ratio (measured and calculated using a desktop micro CT scanner described below). That is, it is calculated by the following equation.
Hollow diameter [μm] = diameter of drug-containing particle × (1−shell thickness ratio / 100)
The breaking test force of the particles and the diameter of the drug-containing particles were measured by Shimadzu micro compression tester MCT-W500 (manufactured by Shimadzu Corporation).
(Particle diameter of drug-containing particles)
The particle diameter of the drug-containing particles was determined by the following equation.
Particle diameter of drug-containing particles [μm] = (long diameter of particles + short diameter of particles) / 2
The major axis and minor axis of the particles were nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
(Diameter of hollow)
The diameter of the hollow portion was calculated by the following equation.
Hollow part diameter [μm] = (long diameter of hollow part + short diameter of hollow part) / 2
The major axis and minor axis of the hollow portion of the particles were measured nondestructively with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
(Shell thickness)
The shell thickness was calculated by the following equation.
Shell thickness [μm] = (particle diameter of drug-containing particle-diameter of hollow portion) / 2
The particle diameter of the drug-containing particles and the diameter of the hollow portion were nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
(Shell thickness ratio)
The “shell thickness ratio” in the present invention was calculated by the following equation.
Shell thickness ratio [%] = (shell thickness / (particle diameter of drug-containing particles / 2)) × 100
The particle diameter of the drug-containing particles was nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
(Hollow volume ratio)
The hollow volume ratio was calculated by the following equation.
Hollow volume ratio [%] = (4/3 × π × (diameter of hollow portion / 2) ³ ) / (4/3 × π × (particle diameter of drug-containing particles / 2) ³ ) × 100
The particle diameter of the drug-containing particles and the diameter of the hollow portion were nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
Particle size distribution ratio of polymer to drug (D50 / D50); Particle size distribution ratio of polymer, drug and other additives (D50 / D50)
The particle size distribution ratio (D50 / D50) of the polymer and the drug was determined by the following equation.
Particle size distribution ratio of polymer to drug (D50 / D50) = polymer D50 / drug D50
The particle size distribution ratio (D50 / D50) of the mixture end of the polymer, the drug and the other additives was calculated by the following equation.
Particle size distribution ratio of polymer, mixed powder of drug and other additive (D50 / D50) = polymeric D50 / mixed powder of drug and other additive D50
The particle size distribution of the mixed powder of such a polymer, drug, drug and other additives is determined by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD Measured by volume basis at -3000 J). Particle size distribution ratio of polymer to drug (D10 / D90); Particle size distribution ratio of polymer, drug and other additives (D10 / D90))
The particle size distribution ratio of the polymer to the drug (D10 / D90) was determined by the following equation.
Particle size distribution ratio of polymer to drug (D10 / D90) = polymer D10 / drug D90
The particle size distribution ratio (D10 / D90) of the mixture end of the polymer, the drug and the other additives was calculated by the following equation.
Particle size distribution ratio of polymer, mixed powder of drug and other additive (D10 / D90) = polymer D10 / mixed powder of drug and other additive D90
The particle size distribution of the mixed powder of such a polymer, drug, drug and other additives is determined by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD Measured by volume basis at -3000 J).
(Smoothness of surface)
It observed visually. In the evaluation, “very smooth” is represented by (+++), “smooth” is represented by (++), “smoothly smooth” is represented by (+), and “not smooth” is represented by (−). "Very smooth" means that no apparent corners are observed on the particle surface, and the surface is not uneven. "Smooth" means that although there are no obvious corners on the particle surface, gentle asperities are observed on the surface. "Slightly smooth" indicates that the surface of the particle has a clear angle or a clear unevenness. "Unsmooth" means that clear corners are observed on the particle surface, and clear unevenness is observed.
(Particle size distribution width)
The particle size distribution width was calculated by the following equation.
Particle size distribution width = D90 of drug-containing particles / D10 of drug-containing particles
The particle size distribution of the drug-containing particles was measured on a volume basis with a laser diffraction type particle size distribution measuring apparatus (Powrex Inc., Particle Viewer).
(Elution rate)
The dissolution rate of the drug-containing hollow particles and the tablet was measured by the following method.
Japan Pharmacopoeia 18 stations Paddle method was followed. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia. The sampling of the elution test solution was performed by selecting from

elution times

1, 3, 5, 10, 15, 30, and 60 minutes. 5 mL was sampled with a 5 mL plastic syringe with a SUS cannula. The eluate was filtered through a membrane filter (Millex-HV, Ф 13 mm) with a pore diameter of 0.45 μm, 2 mL of the first filtrate was removed, and the next filtrate was subjected to HPLC measurement as a sample solution. The filter was replaced every sampling.
The dissolution rate was calculated based on the following equation.

Comparative Example 1-1
<Drug-containing core particles>
The raw materials listed in Table 1 were charged into a stirring granulator (FM-VG-05, manufactured by Powrex Corp.) and pre-mixed for 2 minutes (stirring blade speed 400 min ^-1 , broken blade speed 3000 min ^-1 , all the same in mixing operation) Done under stirring conditions). Granulation was performed by mixing while spraying with absolute ethanol to obtain drug-containing core particles in a wet powder state. The wet powder particles were charged into a fluid bed granulator (MP-01, manufactured by Powrex Corp.) and dried to obtain drug-containing core particles. Further, magnesium aluminometasilicate was added to the fluid bed granulator and mixed to obtain Comparative Example 1-1.

Example 1-1
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the sodium stearyl fumarate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, 1⁄4 volume of sodium stearyl fumarate was added, and coating was performed by spraying and mixing with absolute ethanol. Further, a mixture of 1⁄4 volume of sodium stearyl fumarate and yellow ferric oxide was added, and coating was carried out by mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed to obtain Example 1-1. The preparation amounts of the respective raw materials of Example 1-1 are as described in Table 2.

Example 1-2, comparative example 1-2
The ingredients were weighed according to Table 3 and mixed in a V-type mixer. The mixed tableted powder was tableted with a rotary tableting machine (杵: 8 mmφ, 12 R) to obtain Example 1-2 and Comparative Example 1-2.

Test Example 1
The dissolution test of Example 1-2 and Comparative Example 1-2 was performed (FIG. 1). The dissolution test was conducted according to the Japanese Pharmacopoeia 18 station paddle method. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia. The sampling of the elution test solution was performed at

elution times

1, 3, 5, 10, 15, 30, and 60 minutes. Elution Test The dissolution rate at 15 minutes was equal.

Test example 2
The sensory evaluation of Example 1-2 and Comparative Example 1-2 was performed (FIG. 2). In this experiment, in consideration of safety, it was confirmed that the preparation was not bioabsorbable in the oral cavity, and strict adherence to discharge was observed after the test. The subjects were 5 persons, and each sample was contained in the oral cavity and was discharged after being held until it collapsed in the oral cavity. During intraoral retention, at the time of discharge (immediately after collapse), the bitter taste at 1 minute after discharge was evaluated. The bitter taste was acceptable, and two criteria were set: unacceptable. When the average score was 0.5 or less, there was no problem in taking the bitter taste, and when the average score was 1.0 or more, it was judged that it was difficult to take because of the bitter taste.
Score “0”: not bitter at all Score “0.5”: slightly bitter feeling Score “1.0”: bitter Score “1.5”: strong bitterness can be tolerated Score “2.0”: bitterness I can not stand strongly

As a result of the bitter taste evaluation test, Example 1-2 had an acceptable taste, but Comparative Example 1-2 had a strong bitter taste and an unacceptable taste.

From Test Examples 1 and 2, Example 1-2 had the same dissolution property as Comparative Example 1-2, and an excellent bitterness masking effect was observed. Example 1-2 was revealed to be a desirable preparation having the feature of "high bitter taste masking property" while securing the dissolution property.

Comparative Example 1-3
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the magnesium stearate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of the amount of magnesium stearate was added, and coating was carried out by mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-3. The preparation amounts of the respective raw materials of Comparative Example 1-3 are as described in Table 4.

Comparative Example 1-4
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the hydrogenated oil (castor oil) was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of the hydrogenated oil (castor oil) was added, and coating was performed by spraying and mixing with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-4. The preparation amounts of the respective raw materials of Comparative Example 1-4 are as described in Table 4.

Comparative Example 1-5
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the light anhydrous silicic acid was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of light anhydrous silicic acid was added and coating was carried out by mixing while spraying absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-5. The preparation amounts of the respective raw materials of Comparative Example 1-5 are as described in Table 4.

Comparative Example 1-6
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, a half amount of talc was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, the coating was carried out by adding a half amount of talc and mixing while spraying with absolute ethanol after drying mixing was performed again for 1 minute. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-6. The preparation amounts of the respective raw materials of Comparative Example 1-6 are as described in Table 5.

Comparative Example 1-7
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the sucrose fatty acid ester was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, a half amount of sucrose fatty acid ester was added, and coating was performed by spraying and mixing with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-7. The preparation amounts of the respective raw materials of Comparative Example 1-7 are as described in Table 5.

Comparative Example 1-8
After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half the amount of sodium lauryl sulfate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, coating was carried out by adding half of the amount of sodium lauryl sulfate and mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-8. The preparation amounts of the respective raw materials of Comparative Example 1-8 are as described in Table 5.

Comparative Example 1-9 to Comparative Example 1-14
Each component was weighed according to Tables 6 and 7 and mixed in a V-type mixer. The mixed tableted powder was tableted using a rotary tableting machine (杵: 8 mmφ, 12 R) to obtain Comparative Examples 1-9 to 1-14.

Test Example 3
The dissolution tests of Comparative Examples 1-9, 1-10, 1-11, 1-12, 1-13, and Comparative Example 1-14 were conducted (FIG. 3). The dissolution test was conducted according to the Japanese Pharmacopoeia 18 station paddle method. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia. The sampling of the elution test solution was performed at

elution times

5, 10, 15, 30, and 60 minutes. While the dissolution properties are worse in Comparative Examples 1-9, 1-12, 1-13, and 1-14 compared to Comparative Example 1-2, the dissolution properties in Comparative Examples 1-10, and 1-11 Was maintained.

Test Example 4
The sensory evaluation of Comparative Examples 1-9, 1-10, 1-11, 1-12, 1-13, and Comparative Example 1-14 was performed in the same manner as in Test Example 2 (FIG. 4). The bitter taste was suppressed in Comparative Example 1-13, and the taste was acceptable. Comparative examples 1-9 and 1-12 have slightly suppressed bitter taste but are not acceptable taste, while comparative examples 1-10, 1-11 and 1-14 have strong bitter taste and unacceptable taste Met.

From Test Examples 3 and 4, all comparative examples did not have the feature of “high bitterness masking property” while maintaining the elution equivalent to that of Comparative Example 1-2.

According to Test Examples 1, 2, 3 and 4, only the preparation using the drug-containing particles coated with sodium stearyl fumarate is characterized by “high bitter taste masking property” while maintaining the dissolution equivalent to the preparation without the coating. It became clear that it is a desirable formulation having

As mentioned above, although the present invention is illustrated using a preferred embodiment of the present invention, it is understood that the present invention should be interpreted the scope only by a claim. Patents, patent applications and other documents cited in the present specification should be incorporated by reference for the same as the content itself is specifically described in the present specification. It is understood.

According to the present invention, (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] has a very high dissolution rate and a very strong unpleasant taste. With respect to -2-morpholinyl} methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, it is possible to provide a drug-containing particle in which bitter taste is masked. By using the drug-containing particles, it is possible to provide a preparation subjected to bitter taste masking while maintaining the absorbability of the drug. By using the preparation, it is possible to achieve both a good therapeutic effect and medication adherence.

Claims

(S) -4-Amino-4-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl]-, outer layer coated with sodium stearyl fumarate Drug-containing particles comprising 2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
The drug-containing particle according to claim 1, further comprising a polymer.
The drug-containing particle according to claim 2, wherein the polymer is one or more selected from the group consisting of a water-insoluble polymer, an enteric polymer, a gastric polymer and a biodegradable polymer.
The drug-containing particles according to claim 3, wherein the water-insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof. .
The enteric polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and mixtures of one or more thereof The drug-containing particle according to claim 3 or 4, which is
The drug-containing particle according to any one of claims 1 to 5, further comprising a drug-containing particle additive.
The drug-containing particle additive is an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavoring agent, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, a plasticizer, an aggregation preventing agent. 7. The drug-containing particle according to claim 6, which is selected from the group consisting of an agent and a coating agent.
The drug-containing according to claim 7, wherein the sweetening agent and the flavoring agent are at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, respectively. particle.
The excipient is lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, powdered lactose, erythritol, erythritol, sorbitol, maltitol, mannitol, xylitol, kaolin, hydrogen phosphate The drug-containing particle according to claim 7 or 8, which is at least one selected from the group consisting of calcium, calcium sulfate, calcium carbonate, and crystalline cellulose.
The drug-containing particle according to any one of claims 1 to 9, wherein the content of the sodium stearyl fumarate is 1 to 70% by weight per 100% by weight of the drug-containing particle.
The drug-containing particle according to any one of claims 1 to 10, wherein the content of the drug is 0.1 to 96% by weight per 100% by weight of the drug-containing particle.
The drug-containing particles according to any one of claims 2 to 11, wherein a content of the polymer is 1 to 70 wt% per 100 wt% of the drug-containing particles.
The drug-containing particle according to any one of claims 1 to 12, wherein the drug-containing particle is a particle comprising a shell and a hollow portion.
14. The drug-containing particle of claim 13, wherein the shell comprises the drug and the macromolecule.
15. The drug-containing particle of claim 14, wherein the shell further comprises the drug-containing particle additive.
The drug-containing particle according to any one of claims 13 to 15, wherein the hollow volume ratio to the whole particle is 1% to 50%.
The drug-containing particle according to any one of claims 13 to 16, wherein the thickness of the shell is 15 μm or more.
The drug-containing particles according to any one of claims 2 to 17, wherein an average particle size of the polymer used as a raw material is five or more times an average particle size of the drug used as a raw material.
The drug according to any one of claims 15 to 18, wherein an average particle size of the polymer used as a raw material is five or more times an average particle size of a mixed powder of the drug used as a raw material and the additive for drug containing particles. Containing particles.
The drug-containing particle according to any one of claims 13 to 19, wherein a diameter of the hollow portion is 10 μm or more.
The drug-containing particle according to any one of claims 1 to 20, wherein the aspect ratio of the drug-containing particle is 1.0 to 1.5.
The drug-containing particle according to any one of claims 1 to 21, wherein a particle shell strength of the drug-containing particle is 2.0 MPa or more.
The drug-containing particle according to any one of claims 1 to 22, wherein the particle size distribution width (D90 / D10) is 6 or less.
The drug-containing particles according to any one of claims 1 to 23, which have an average particle size of 50 to 1000 μm.
A pharmaceutical composition comprising the drug-containing particle according to any one of claims 1 to 24.
The pharmaceutical composition according to claim 25, which is in the form of granules, tablets or capsules.
The pharmaceutical composition according to claim 26, which is in the form of a tablet.
The pharmaceutical composition according to claim 27, which is in the form of an orally disintegrating tablet.
The pharmaceutical composition according to any one of claims 25 to 28, further comprising a formulation additive.
The formulation additive is an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavoring agent, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, a plasticizer, an anticoagulant agent. The pharmaceutical composition according to claim 29, which is selected from the group consisting of and a coating agent.
31. The sweetening agent according to claim 30, wherein the sweetening agent is at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and high-intensity sweeteners such as acesulfame K. Pharmaceutical composition.
The excipient is lactose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, powdered sugar, saccharides such as powdered lactose, erythritol, sorbitol, maltitol, mannitol, xylitol, etc. The pharmaceutical composition according to claim 30 or 31, which is at least one selected from the group consisting of alcohols, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
A pharmaceutical composition for treating and / or preventing digestive diseases or digestive conditions, comprising the drug-containing particles according to any one of claims 1 to 24.
34. The pharmaceutical composition according to claim 33, wherein the digestive system disease is constipation type irritable bowel syndrome (IBS), or chronic constipation.
A composition for masking the bitter taste of a component having bitterness, comprising sodium stearyl fumarate as a coating.
Sodium stearyl fumarate and bitter (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2- A composition for masking the bitter taste, which comprises methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.