TW201618770A - Oral preparation in which bitter taste of bitter-tasting drug is masked - Google Patents

Abstract

Provided is a novel oral preparation (specifically, an intraoral quickly-disintegrating preparation) that allows a bitter-tasting drug such as silodosin, which has a very strong bitter taste, to be taken without an uncomfortable feeling and even without water, and that has solubility sufficient for reproducing a blood concentration effective for treating dysuria accompanying benign prostatic hyperplasia. The present invention pertains to masking particles and a novel oral preparation containing said masking particles. The masking particles are obtained by granulating or coating drug particles containing a bitter-tasting drug (e.g. silodosin) with a coating agent containing a methyl methacrylate-diethylaminoethyl methacrylate copolymer, wherein the content of said copolymer is 80-400 parts by mass relative to 100 parts by mass of the bitter-tasting drug (e.g. silodosin).

Description

Oral administration of bitterness by masking bitterness

The present invention relates to a silotic drug, for example, Silodosin which is a very strong bitterness agent, which can be used without any foreign body sensation, even if it is not used with water, and has urinary dysfunction associated with prostatic hypertrophy. In the treatment, a novel oral administration preparation (especially an oral disintegration preparation) capable of reproducing the dissolution of an effective blood concentration can be reproduced.

A bitter-tasting agent (for example, silodosin) is a therapeutic drug for urinary dysfunction which has a selective urethral smooth muscle contraction-inhibiting action and does not induce a strong blood pressure lowering action (for example, refer to Patent Document 1), and is widely used as a result of prostatic hypertrophy. A therapeutic agent for urinary disorders. Capsules and lozenges are used for the pharmaceutical preparation containing sirolimus (for example, refer to Patent Documents 2 and 3), but these preparations must be taken together with water. In recent years, preparations that can be easily taken, such as elderly people who have difficulty swallowing, are expected to develop a preparation (especially an oral disintegration preparation) which can be easily taken even without water.

When the drug has a bitter taste, it is known that a method for suppressing the bitterness is, for example, a chemical masking method for chemically modifying or occluding the drug itself (for example, refer to Patent Document 4), a functional property obtained by adding a sweetener, a flavor, or the like. A masking method (for example, refer to Patent Document 5 and Non-Patent Document 1), and a physical masking method of coating a drug with a coating agent such as a gastric-soluble polymer or an enteric polymer (for example, refer to Patent Documents 6 to 9) (for example, refer to Non-patent document 2).

However, in the case of a strong bitter agent, the use of a functional masking method may not sufficiently suppress the bitterness. If a physical masking method is used, it is necessary to increase the amount of the coating agent, thereby causing drug dissolution in the digestive system. Problems such as reduced sexuality, it is difficult to balance the inhibition of bitterness and the dissolution of various liquids.

In addition, in order to form an extremely rapid bitterness agent into an orally disintegrating preparation, in addition to the above, it is necessary to make the time until the start of the bitterness is longer than the time of disintegration in the oral cavity, and it is difficult to balance the bitterness suppression time and dissolution property. .

Japanese Patent Laid-Open No. 2008-231029 (Patent Document 6) discloses that a part of a gelatinized starch is sprayed with rebamipide and methylcellulose to form a granulated product, and a polyglycolic polymer is used. A bitter taste masking granule of rebamipide coated with ethylene acetal diethylaminoacetate.

Japanese Patent Laid-Open Publication No. 2005-513008 (Patent Document 7) discloses that a mixture of fexofenadine and precipitated cerium oxide is granulated by using EUDRAGIT (registered trademark) E100, and further contains precipitated dioxide. The polymer dispersion of EUDRAGIT (registered trademark) E100 of ruthenium was coated to obtain particles coated with fexofenadine.

WO 2008/018371 (Patent Document 8) discloses that a mixture of mitiglinide and crystalline cellulose is sprayed with an aminoalkylalkyl methacrylate copolymer E to obtain a granulated product.

Japanese Patent Laid-Open No. 2007-63263 (Patent Document 9) discloses that a mixture of amlodipine besulfonate (Amlodipine Besilate) and light anhydrous citric acid is used to carry an aminoalkylalkyl methacrylate copolymer. A spray of the coating liquid of E is obtained to obtain particles containing amlopropine.

However, none of the literatures have taken into account the inhibition of bitterness of silodosin, and Various liquid dissolution properties, even in the case of preparations that can be taken without water, are expected to develop new preparations.

[Previous Technical Literature] [Patent Literature]

Patent Document 1: Japanese Patent Laid-Open No. Hei 6-220015

Patent Document 2: International Publication No. 2004/054574

Patent Document 3: Japanese Patent Laid-Open Publication No. 2008-44960

Patent Document 4: Japanese Patent Laid-Open Publication No. 2008-44870

Patent Document 5: Japanese Patent Laid-Open Publication No. 2008-94837

Patent Document 6: Japanese Patent Laid-Open Publication No. 2008-231029

Patent Document 7: Japanese Patent Laid-Open Publication No. 2005-513008

Patent Document 8: International Publication No. 2008/018371

Patent Document 9: Japanese Patent Laid-Open Publication No. 2007-63263

[Non-patent literature]

Non-Patent Document 1: PHARM TECH JAPAN Vol. 23, p1413-1417, 2007

Non-Patent Document 2: PHARM TECH JAPAN Vol.28, No.2, 2012 Temporary Supplement No. "Full Solution Oral Disintegration Handbook" PLCM (Tillage) Research Association

An object of the present invention is to provide a sirolimus having a bitter taste agent such as a very strong bitterness agent, which can be used without a foreign body sensation, and can be taken even without water. There is a novel oral administration preparation (especially an oral disintegration preparation) which can reproduce the dissolution of an effective blood concentration in the treatment of urinary dysfunction associated with benign prostatic hyperplasia.

In the preparation of the oral administration preparation of the present invention, in particular, silodosin has a very strong bitter taste, and since it is a needle-like crystalline substance, it is necessary to have a large amount of coating agent for suppressing bitterness. This phenomenon may cause problems such as a decrease in the dissolution property and a residual foreign matter sensation when not taken with water. Further, the silodosin system has a chemical property which is easily decomposed by an excipient which is common to pharmaceutical additives, and there are many problems to be overcome in terms of the characteristics of silodosin. Further, a therapeutic agent for urinary dysfunction associated with benign prostatic hypertrophy is required to be a preparation which can appropriately reproduce the blood concentration which is effective in the use of the sirolimus preparation.

The inventors of the present invention have conducted intensive studies in order to overcome these problems and solve the above problems. For example, a functional masking method using cocoa powder, calcium lactate, or the like, and a chemical masking method using carrageenan or the like cannot block the strong bitterness of silodosin. Further, it was found that an enteric base (enteric polymer) used in a general physical masking method is blended with sirolimus, and it is unusable. Further, various reviews have been carried out, and as a result, it has been surprisingly found that by using the masking particles of the present invention, it is possible to obtain a strong bitterness without feeling strong, even if it is not used with water, and to achieve effective blood in the human body by using the desired dissolution characteristics. The present invention can be accomplished by oral administration of a concentration and the like which can exert an extremely desirable performance. Further, the orally disintegrating preparation using the masking particles of the present invention does not feel strong bitterness, and rapidly disintegrates in the oral cavity even if it is not mixed with water, and has desired dissolution characteristics, and the present invention has been completed.

That is, the present invention relates to the following: [1] A masking particle which contains a drug particle containing a bitterness agent, and contains a coating agent obtained by granulating or coating a coating agent of methyl methacrylate-diethylaminoethyl methacrylate copolymer; wherein the content of the copolymer is 80 masses relative to 100 parts by mass of the bitterness agent [2] The shielding particles according to the above [1], wherein the shielding particles according to the above [1], the shielding particles according to the above [2], wherein The release ratio of the orally administered preparation containing the masking particles at a pH of 6.8 for 15 minutes is 85% or more; [4] The masking particles according to any one of the above [1] to [3], In the case of the oral administration preparation containing the masking particles, the time until the bitterness of the bitterness is started in the human bitterness-featured test is 30 seconds or longer. [5] The masking particles according to the above [1], wherein The medicinal particle of the bitterness agent is a mixture of sirolimus and an additive; [6] The shielding particle according to the above [5], wherein the drug particle containing the bitter drug is a granulated substance of sirolioxine and an additive; [7] The masking particle according to [5] or [6] above, wherein the additive is from sugar or The shielding particles according to any one of the above [1] to [7], wherein the content of the copolymer is 100 parts by mass relative to the bitterness agent. The masking particle according to any one of the above-mentioned [1] to [8] wherein the content of the bitter taste agent in the masking particle is 5 to 25% by mass; The masking particle according to any one of the above-mentioned [1], wherein the methyl methacrylate-diethylaminoethyl methacrylate copolymer content in the masking particle is 10 to 30. [11] The masking particle according to any one of the above [1] to [10] wherein The content of the ethyl methacrylate-diethylaminoethyl methacrylate copolymer is 20 parts by mass to 40 parts by mass based on 100 parts by mass of the drug particles; [12] an orally administered preparation containing the above [1]~ [11] The orally administered preparation according to the above [12], wherein the component other than the masking particles further contains an excipient, a disintegrating agent, and [14] The orally administered preparation according to the above [13], wherein the excipient and the disintegrating agent are contained in at least the granular form; [15] as described in [13] above. The orally administered preparation, wherein the excipient is from lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, rice starch, corn starch And the orally administered preparation according to the above [13], wherein the disintegrating agent is partially gelatinized from the starch, Crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, carboxymethyl The oral administration preparation according to the above [13], wherein the lubricant is hard from the hard acid, the carboxymethylcellulose calcium, and the sodium carboxymethylcellulose. One or more selected from the group consisting of sodium sulfonate fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, talc and light anhydrous citric acid; [18] as described above [12]~ The oral administration preparation according to any one of the above [18], wherein the orally administered preparation is an orally administered preparation according to the above [18], wherein Oral disintegrating preparation tablet; [20] The orally administered preparation according to the above [19], wherein, when disintegrating in the oral cavity [21] The oral administration preparation according to the above [20], wherein the time until the start of the bitterness is longer than the intraoral disintegration time; [22] as described above [12] The oral administration preparation according to any one of the above aspects, wherein the dissolution rate after 15 minutes at pH 6.8 is 85% or more; [23] a method for producing masking particles, comprising: (a) a step of preparing a drug particle by mixing or granulating a bitter agent with an additive; and (b) a drug particle obtained by the step (a) using a methyl methacrylate-diethylamino methacrylate group The content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer is prepared by granulating or coating the coating agent of the ethyl ester copolymer, and is 80 to 400 masses per 100 parts by mass of the bitterness agent. [24] The method for producing a masking particle according to the above [23], wherein the bitter taste agent is silodosin.

In the present invention, "methyl methacrylate-diethylaminoethyl methacrylate copolymer" may be, for example, KOLLICOAT (registered trademark) SMARTSEAL 30D.

The methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may be used in combination with a non-enteric polymer, if necessary.

The "non-enteric polymer" refers to a polymer other than an enteric polymer which is insoluble in water, such as a stomach-soluble polymer or a water-insoluble polymer.

The gastric-soluble polymer may, for example, be a methyl methacrylate-methacrylic acid butyl-methyl group such as an aminoalkyl methacrylate copolymer E [for example, EUDRAGIT (registered trademark) EPO, EUDRAGIT (registered trademark) E100] Dimethylaminoethyl acrylate copolymer, polyvinyl acetal diethylaminoacetate [eg AEA (registered trademark)] and other stomach solutions Polyethylene derivatives and the like.

The water-insoluble polymer may be, for example, an ethyl acrylate-methyl methacrylate copolymer such as an ethyl acrylate-methyl methacrylate copolymer dispersion (for example, EUDRAGIT (registered trademark) NE30D); Base ester copolymer RS (for example: EUDRAGIT (registered trademark) RS100, EUDRAGIT (registered trademark) RSPO, EUDRAGIT (registered trademark) RL, EUDRAGIT (registered trademark) RLPO; and aminoalkyl methacrylate copolymer RS water Water-insoluble acrylic copolymer such as ethyl acrylate-methyl methacrylate-trimethylammonium methacrylate methacrylate copolymer such as a dispersion (for example, EUDRAGIT (registered trademark) RS30D, EUDRAGIT (registered trademark) RL30D) ; a water-insoluble cellulose ether such as ethyl cellulose (for example, ETHOCEL (registered trademark)), an aqueous dispersion of ethyl cellulose (for example, AQUACOAT (registered trademark)); a vinyl acetate resin (for example, KOLLICOAT (registered trademark) SR, KOLLICOAT (registered trademark) SR30D), etc.

The coating agent containing the methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may contain an additive or a water-soluble polymer as needed in addition to the above-mentioned non-enteric polymer. Wait. When a water-soluble polymer is used, the ratio of the water-soluble polymer mass to the total mass of the non-enteric polymer and the water-soluble polymer is preferably 20% or less. The additive may be, for example, a plasticizer, a lubricant, a surfactant, an antioxidant, or the like. The plasticizer can be, for example, stearic acid, triacetin, triethyl citrate, macrogol, glycerin, glycerin fatty acid ester, castor oil, diethyl sebacate, sebacic acid. Dibutyl ester and the like. The lubricant may be, for example, talc, stearic acid, magnesium stearate, calcium stearate or the like. The surfactant may be, for example, sodium lauryl sulfate, polysorbate or the like. The water-soluble polymer may be, for example, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, povidone, sodium carboxymethylcellulose, Sodium alginate and the like. The antioxidant may be, for example, dibutylhydroxytoluene, butylhydroxyanisole, vitamin E (tocopherol) or the like. These additives and the water-soluble polymer may be used in combination of two or more kinds.

In the present invention, the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, 80 to 400 parts by mass, based on 100 parts by mass of the bitterness agent (for example, sirolimus). 80 to 300 parts by mass, 80 to 200 parts by mass, 100 to 400 parts by mass, 100 to 300 parts by mass, 100 to 200 parts by mass, etc., more preferably 100 to 200 parts by mass.

The content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles of the present invention is preferably 10 to 30% by mass, more preferably 15 to 25% by mass.

In the present invention, the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, about 20 to 50 parts by mass, preferably 20 to 40 parts by mass, based on 100 parts by mass of the drug particles. Good quality 30 to 40 parts by mass.

Further, when a methyl methacrylate-diethylaminoethyl methacrylate copolymer and a non-enteric polymer are used in combination, the total amount of these is the same as described above.

In the present invention, the "average particle diameter" means a 50% particle diameter (mass-based median diameter). The 50% particle size can be measured by a sieve size distribution measuring apparatus (for example, an automatic control sound wave sieve analyzer GA-6 or a Gilson company).

The average particle diameter of the masking particles of the present invention is, for example, about 300 μm or less, preferably about 100 to 250 μm.

In the present invention, the "bittering agent" is an active ingredient and can be used for the treatment or prevention of diseases as long as it has an unpleasant taste such as bitterness, for example, sirolimus, mitiglinide, acetaminophen, amine tea. Alkali, Ecabapide, ethionamide, epirizole, caffeine, chloramphenicol, diphenhydramine, cimetidine, s And Sulpyrine, theophylline, Nizatidine, and Pyridine Pyrazinamide, famotidine, phenylbutazone, phenobarbital, metoclopramide, and such pharmaceutically acceptable salts Preferably, it is silodosin.

In addition, the bitterness agent is not limited to this.

For example, a commercially available product may be used as the sirolimus, or it may be produced by a method described in the literature (for example, refer to Patent Document 1) or a method using the same.

The "sirrodin" used in the present invention may be any particle which is not agglomerated into a block, and may be crushed or pulverized as needed. The average particle diameter of sirolimus is preferably about 50 μm or less, more preferably about 1 to 30 μm.

The "pharmaceutical particles containing a bittering agent" used in the present invention is a bitterness agent, for example, in the case of silodosin, in addition to silodosin, it is preferred to use an appropriate additive such as: Sirodosin and an appropriate additive. The mixture, the granules of sirolimus with appropriate additives, and the appropriate additives are coated with lixiserol or the like.

The additive used for the drug particles may be a variety of additives which do not cause a blending change with a bitterness agent such as sirolimus, and may be suitably used, for example, a disintegrant, an excipient, a binder, a lubricant, and a sweet taste. Agents, sour agents, foaming agents, perfumes, colorants, and the like. The disintegrating agent can be, for example, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethylcellulose, rice starch, corn starch, potato starch, carboxymethyl Sodium starch, carboxymethyl cellulose, partially gelatinized starch, alpha-starch starch, crospovidone, crystalline cellulose, and the like. Excipients can be, for example, rice starch, Corn starch, potato starch, partially gelatinized starch, alpha-starch starch, trehalose, crystalline cellulose, magnesium aluminum metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium citrate, calcium lactate, lactose, fructose, D-mannose Sugar alcohol, erythritol, xylitol, maltose, D-sorbitol, maltitol, and the like. The binder can be, for example, starch, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, dextrin, gelatin, polytriglucose, polyvinyl alcohol, sodium alginate, polyethyl b. Glycol and the like. The lubricant may be, for example, magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous citric acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, single hard. Glyceryl ester and the like. The sweetener system can be, for example, aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, potassium acesulfame, sucralose and the like. The sour agent may be, for example, citric acid, tartaric acid, malic acid, ascorbic acid or the like. The blowing agent may be, for example, sodium hydrogencarbonate, sodium carbonate, calcium carbonate or the like. The flavoring agent may, for example, be L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, sodium hydrogencarbonate or the like. The fragrance may be, for example, strawberry, yogurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, matcha, and the like. The coloring agent may be, for example, edible food color such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; yellow ferric oxide, ferric oxide, caramel color, titanium oxide, or the like.

In the present invention, the additive used for the drug particles is preferably an excipient or a disintegrating agent such as a sugar or a sugar alcohol or a starch, and more preferably a starch. The sugar or sugar alcohol may be, for example, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol or the like, more preferably D-mannitol. The starch system may be, for example, corn starch, rice starch, potato starch, partially gelatinized starch, alpha-starch starch or the like, and is preferably a partially gelatinized starch or a gelatinized starch. The lubricant is preferably, for example, magnesium stearate, calcium stearate, talc or the like, more preferably talc. Preferably, the binder is, for example, starch, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, povidone, dextrin, gelatin, polytriglucose, polyvinyl alcohol, sodium alginate, polyethylene glycol, etc., more preferably hydroxypropyl cellulose, hydroxypropyl methyl fiber Prime. These additives may be used in combination of two or more kinds as needed.

The content of the bitterness agent (for example, sirolimus) in the masking particles of the present invention is preferably 30% by mass or less, more preferably 5 to 25% by mass, and particularly preferably 5 to 16% by mass.

The content of the bitterness agent (for example, sirolimus) in the drug particles used in the present invention is preferably 50% by mass or less, for example, 10 to 40% by mass, 10 to 30% by mass, 20 to 27% by mass or the like.

(Method of manufacturing masking particles)

Hereinafter, the method for producing the masking particles is described by taking silodosin as an example, but the bitterness agent is not limited thereto.

The masking particles of the present invention can be produced by a method generally employed in the production of masking particles, for example, a core particle coating method, a granulation matrix method, or a granulation coating method. For example, a drug particle obtained by mixing or granulating sirolimus with an additive may be produced by granulation or coating with a coating agent containing a non-enteric polymer. In the series of production, the method of granulating or coating may be, for example, a high-speed mixing and stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like, and a fluidized bed granulation method is preferred.

Specifically, for example, in the case of a core particle coating method, commercially available or granulated crystalline cellulose, D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, white sugar or the like is used as a core particle containing siroliol. The solution or dispersion of the symplectic dispersion and the coating agent containing the non-enteric polymer is sequentially coated or coated with the mixed solution, Masking particles can be produced.

Further, for example, in the granulation matrix method, a mixture of sirolioxine and an additive (for example, D-mannitol, partially gelatinized starch, gelatinized starch, light anhydrous citric acid, etc.) is sprayed and contained. The masking particles can also be produced by granulating or coating the solution or dispersion of the coating agent of the non-enteric polymer.

Further, for example, in the granulation coating method, a mixture of sirolioxine and an additive (for example, D-mannitol, partially gelatinized starch, gelatinized starch, light anhydrous citric acid, etc.) is sprayed in water. After the granulation is carried out in a solution state of the soluble binder, the granulated product is coated by spraying a solution or dispersion containing a coating agent containing a non-enteric polymer, whereby the shielding particles can be produced. The water-soluble binder is preferably hydroxypropylcellulose or hydroxypropylmethylcellulose.

Among the above methods, a granulation matrix method or a granulation coating method, and a more preferred granulation coating method is preferred.

The solvent to be used for dissolving or dispersing the non-enteric polymer is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropanol; acetone, toluene, methyl ethyl ketone, and water, or a mixed solvent thereof. Etc., preferably ethanol and water, more preferably water. Although the aminoalkyl methacrylate copolymer E is insoluble in water, it can also be used as an aqueous solution dissolved in an acidic (pH 5 or lower) water, or can be used as an aminoalkyl methacrylate copolymer E. An aqueous dispersion of at least one plasticizer selected from the group consisting of sodium lauryl sulfate and from stearic acid, diethyl sebacate and dibutyl sebacate in an arbitrary ratio.

The masking particles of the present invention are used to prevent agglomeration during production, and may be further used after being overcoated with a suitable additive. The masking particles of the present invention also encompass the coated person. However, in the present specification, the quality of the masking particles does not include the quality of the additive used in the coating. The additive used in the coating For example, sugars such as lactose, glucose, sucrose, and fructose; sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol, preferably D-mannitol. .

The method of coating is not particularly limited, and for example, it can be produced by coating with an aqueous solution of an additive (for example, a sugar or a sugar alcohol) of the masking particles of the present invention. The content of the additive used in the coating is usually 1 to 20 parts by mass, preferably 2 to 15 parts by mass, more preferably 5 to 10 parts by mass, per 100 parts by mass of the masking particles.

(oral preparation and preparation)

By using the masking particles of the present invention, oral administration preparations of various dosage forms can be produced. The dosage form of the orally administered preparation of the present invention may be, for example, granules, powders, lozenges and the like.

The orally administered preparation of the present invention is, for example, preferably an orally disintegrating preparation such as an orally disintegrating granule, an orally disintegrating granule, an oral disintegrating tablet, or the like, and more preferably an orally disintegrating tablet.

The oral administration preparation of the present invention can be produced by a method conventionally used in the field of preparation, using the masking particles of the present invention and a pharmaceutical additive generally used in an orally disintegrating preparation.

For example, in the case of a tablet, the masking particles of the present invention together with a pharmaceutical additive generally used in an orally disintegrating preparation are subjected to a known method such as direct powder compression (direct compression method) or granulation method, or a quasi-use method. The method of tableting can be used to manufacture an orally administered preparation.

Specifically, for example, in the case of the direct tableting method, a mixture containing the masking particles of the present invention and a pharmaceutical additive such as an excipient, a disintegrating agent, a binder, or a lubricant is used in the case where granulation is not performed. After the machine is mixed, the ingot is applied again. Oral administration of the preparation can be made.

Further, for example, in the granulation method, a mixture of an excipient, a disintegrator, or the like is used, and a mixture of water, water, and ethanol, or a solution (or a suspension) of a binder or a disintegrating agent is used. After the granules are formed into granules, the masking particles, lubricants, and the like of the present invention are mixed by using a mixer, and then tableting is carried out; and the mixture of the masking particles of the present invention, an excipient, a disintegrator, and the like may be used. After the granulation is carried out by mixing a mixture of water and ethanol or a solution (or a suspension) of a binder or a disintegrating agent, a lubricant is further added, and after being mixed by using a mixer, the tableting may be performed. Manufacture of oral administration preparations.

Further, the granules may be produced by performing flow layer granulation according to a granulation method of a tablet or performing agitation granulation. A powder or the like can also be produced by mixing a pharmaceutical additive according to a direct tableting method of a tablet.

The pharmaceutical additive generally used in the orally disintegrating preparation can use the additive used in the above-mentioned drug particles, and the disintegrant is preferably partially gelatinized starch, crospovidone, and low-substituted hydroxypropylcellulose. , carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, corn starch, etc., more preferably crospovidone. The excipient is preferably a sugar alcohol such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol or maltitol; corn starch, crystalline cellulose or the like. The lubricant is preferably stearic acid sodium fumarate, calcium stearate, talc, light anhydrous citric acid, etc., more preferably stearin sodium fumarate. These pharmaceutical additives may be used in combination of two or more kinds as needed.

(Manufacturing example of oral administration of preparation)

Hereinafter, the method for producing the orally administered preparation of the present invention will be exemplified, but it is not limited thereto.

[Manufacturing Example 1]

For example, the masking particles of the present invention are derived from sugars such as lactose and fructose; sugar alcohols such as D-mannitol, erythritol, and xylitol; starches such as rice starch, corn starch, potato starch, and partially gelatinized starch. A pharmaceutical preparation in which at least one of crystalline cellulose and crospovidone is selected and mixed using a mixer can be used to obtain a powder. In the above mixing step, if necessary, a combination of, for example, an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetener, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be further added. One or two or more.

[Manufacturing Example 2]

For example, the masking particles of the present invention are derived from sugars such as lactose and fructose; sugar alcohols such as D-mannitol, erythritol, and xylitol; starches such as rice starch, corn starch, potato starch, and partially gelatinized starch. ; at least one pharmaceutical additive selected from the group consisting of crystalline cellulose, crospovidone, sodium stearyl fumarate, calcium stearate, talc, and light anhydrous citric acid, and mixed using a mixer Thereafter, the mixture is subjected to tableting to obtain a tablet. In the above mixing step, if necessary, a combination of, for example, an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetener, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be further added. One or two or more.

[Manufacturing Example 3]

For example, sugars such as lactose and fructose; sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol; corn starch, rice starch, potato starch, and partial gelatinization Mixing at least one of the starches such as starch and alpha-starch and the crystalline cellulose, and then spraying a part of the gelatinized starch In the case of a solution or dispersion of crospovidone, granulation is carried out, whereby granules (1) can be obtained. The mixing and granulation step may be carried out by a high-speed mixing and stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like, and is preferably a fluidized bed granulation method. Next, the masking particles of the present invention, the above-mentioned particles (1), and a lubricant selected from at least one of stearin, sodium stearate, talc, and light anhydrous citric acid are used. After the mixing machine is mixed, the tablet can be obtained by performing ingot casting. In the above mixing step, if necessary, a combination of, for example, an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetener, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be further added. One or two or more.

[Manufacturing Example 4]

For example, sugars such as lactose and fructose; sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol; corn starch, rice starch, potato starch, and partial gelatinization A medicinal product containing at least one selected from starch and crystalline cellulose such as starch or gelatinized starch is mixed, and granulated by spraying water or a mixture of water and ethanol to obtain granules (2) ). The mixing and granulation step may be carried out by a high-speed mixing and stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like, and is preferably a fluidized bed granulation method. Next, the masking particles of the present invention, the particles (2), and a lubricant selected from at least one of stearin, sodium stearate, talc, and light anhydrous citric acid are used. After mixing by the mixer, the tablet can be obtained by performing ingot casting. In the above mixing step, if necessary, a combination of, for example, an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetener, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be further added. One or two or more.

[Manufacturing Example 5]

For example, the masking particles of the present invention and the pellets (1) or the pellets (2) are mixed by a mixer to obtain a granule. In the above-mentioned mixing step, one or two or more kinds of excipients, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, perfumes, coloring agents, and the like may be further added in combination.

[Manufacturing Example 6]

For example, a mixture of D-mannitol and crystalline cellulose is mixed by using a fluidized layer granulating dryer, and then granulated by spraying an aqueous dispersion of crospovidone, and then using a granulator. Granules (3) can be obtained by whole graining. Next, the masking particles of the present invention, the pellets (3), and sodium stearyl fumarate are mixed and mixed using a mixer, and then a tablet can be obtained by performing ingoting. In the above-mentioned mixing step, one or two or more kinds of excipients, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, perfumes, coloring agents, and the like may be further added in combination.

[Manufacturing Example 7]

For example, a mixture of D-mannitol, crystalline cellulose, and crospovidone is mixed using a fluidized layer granulating dryer, and then granulated under sprayed water, and then granulated by a granulator. Granules (4) can be obtained. Next, the masking particles of the present invention, the above-mentioned granules (4), and sodium stearyl fumarate are mixed and mixed by a mixer, and then a tablet can be obtained by performing ingoting. In the above-mentioned mixing step, one or two or more kinds of excipients, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, perfumes, coloring agents, and the like may be further added in combination.

[Manufacturing Example 8]

In the above Production Example 6 or 7, the substituted crystalline cellulose was replaced with corn starch, and the substituted crospovidone was used instead of the partially gelatinized starch, and the same procedure as in Production Example 6 or 7 was carried out. Lozenges.

In the step of producing the masking particles of the present invention or the oral administration preparation, "granulation", "coating", "mixing", and "ingoting" may be carried out by a conventional method in the field of preparation technology. For the "granulation" and "coating", for example, a fluidized bed granulator, a rolling fluidized bed granulation method, a high-speed mixing and stirring granulator, or the like can be used. For "mixing", for example, a V-type mixer, a Bohle container mixer, or the like can be used. For example, a click type ingot machine, a rotary type ingot machine, and the like can be used. The tableting pressure system is, for example, 1 to 20 kN, preferably 2 to 15 kN.

The masking particles of the present invention and the orally administered preparation containing the same exhibit a good bitterness shielding effect. The bitterness masking effect can be quantitatively evaluated by the bitterness-featured test described later. Those with an average score of 2 or less of the bitterness score are "better", and those with a score of 1 or less are "better". Further, the time until the start of the bitterness is preferably 30 seconds or longer, more preferably 40 seconds or longer, or 60 seconds or longer, and the longer the time, the better.

The oral administration preparation of the present invention exhibits rapid dissolution properties regardless of the pH in the digestive system. That is, the oral administration preparation of the present invention is the first liquid of the Japanese Pharmacopoeia dissolution test (pH about 1.2) and the second liquid (pH of about 6.8), and the dissolution rate after 15 minutes is 80% or more, preferably Japan. The dissolution rate of the first solution of the pharmacopoeia dissolution test (pH about 1.2) after 15 minutes reached 85% or more, and the second solution of the Japanese Pharmacopoeia dissolution test (pH about 6.8) was also 85% after 15 minutes. the above. The elution system can be quantitatively evaluated by a dissolution test described later.

The oral administration preparation of the present invention is served in the absence of water It is used in the oral cavity to disintegrate in a short time. For example, in the oral disintegration test described later, the average intraoral disintegration time can be adjusted to be shorter than the time until the bitterness is started, and it is usually adjusted to within 60 seconds, preferably within 40 seconds, and more preferably within 30 seconds. .

In the case where the orally administered preparation of the present invention is a tablet, it is preferable to have a moderate hardness from the viewpoints of convenience in production and transportation. For example, in the hardness test described later, it is usually adjusted to 20 N or more, preferably 30 N or more, and more preferably 40 N or more.

The intraoral disintegration time and hardness can be adjusted by appropriately selecting, for example, the type and amount of the pharmaceutical additive, the production method (for example, a granulation method), the production conditions (for example, a tableting pressure, etc.).

In the case of the oral administration preparation of the present invention, in the case of the bitter taste drug silodosin, the sirolimus content per unit preparation is usually 2 to 8 mg, preferably 2 mg, 4 mg or 8 mg.

When the orally administered preparation of the present invention is, for example, a tablet, the mass per one tablet may be, for example, 50 to 500 mg, 50 to 300 mg, 100 to 250 mg, 100 to 200 mg, etc., and the content of sirolimus at this time. The system can be, for example, 0.4 to 16%. In the case of granules, powders, and the like, the mass per administration may be, for example, 200 to 3000 mg, 500 to 2000 mg, 500 to 1000 mg, etc., and the sirolimus content at this time may be, for example, 0.06 to 4%.

When the orally administered preparation of the present invention is used for actual treatment, the administration amount of the active ingredient is appropriately determined according to the sex, age, body weight, degree of disease, etc. of the patient, but when the bitter taste agent is silodosin About 1~16mg can be administered to adults every 1 day. Preferably, the adult is administered 2 to 8 mg once or twice a day for 1 day or 2 times.

The masking particles of the present invention are pharmaceutically stable, can suppress the extremely strong bitterness of a drug (for example, silodosin), and have the same rapid dissolution property as a commercially available tablet (for example, a YURIEF (registered trademark) ingot, and thus can be used. In order to take the preparation, it can be administered without any foreign body sensation even if it is not mixed with water. Further, since the orally administered preparation of the present invention can suppress the bitter taste peculiar to sirolimus, and has the same rapid dissolution property as the commercially available sirolimus tablet (YURIEF (registered trademark) ingot), it can be effectively used. A sirolimus-containing preparation that can be taken without any foreign body sensation even if it is not mixed with water. In addition to the above, the masking particles of the present invention have a long time to start to feel bitterness, and therefore, by using a technique of disintegrating an ingot in the oral cavity, an excellent oral disintegration preparation can be provided.

The following test examples and examples are described in more detail with respect to the present invention, but the present invention is not limited thereto.

[Examples] [Test Example 1]

Bitter taste test

From 1 to 3 healthy males, one tablet of the tablets prepared in Examples 1 to 3 was contained in the oral cavity, and scores were given for the bitterness when bitterness was felt according to the scoring standard shown in Table 1, and the average value was obtained. Further, the relevant tablet was in the form of a lozenge in the oral cavity, and the tablet was disintegrated by gently flipping the tongue, and the time until the start of the bitterness was also evaluated.

[Test Example 2]

Oral disintegration test

One tablet of the tablets prepared in Examples 1 to 3 was placed in the oral cavity from 1 to 3 healthy men, and the tablet was disintegrated by gently turning the tongue, and the time for disintegration of the tablet in the oral cavity was measured, and an average value was obtained. .

[Test Example 3]

Hardness test

The hardness of the tablets prepared in Examples 1 to 3 was measured using a fully automatic tablet measuring device (WHT, manufactured by PHARMA TEST Co., Ltd.).

[Test Example 4]

Dissolution test method

For the tablets prepared in Examples 1 to 3, according to the dissolution test method blade method described in the Japanese Pharmacopoeia of the sixteenth revised edition, the second liquid of the Japanese Pharmacopoeia dissolution test was used for the test liquid according to the number of rotations of the blade 50 rpm, and the dissolution was performed. In the test, the sirolimus in the sampling solution was quantified by high-speed liquid chromatography, and the dissolution rate was determined. In addition, the dissolution rate is for each system. The agents were randomly sampled for 2 to 3 trials and averaged.

Detector: UV spectrophotometer (measuring wavelength: 270 nm)

[Test Example 5]

Particle size distribution determination

Using a sieve size distribution measuring apparatus (automatically controlled sound wave sieve analyzer GA-6, manufactured by Gilson Co., Ltd.), the particle size distribution was measured by sieving, and a 50% particle diameter (mass-based median diameter) was determined.

[Example 1]

4,400 g of sirolimus, a part of the gelatinized starch (manufactured by K.K.), and 1,100 g of talc (manufactured by Matsumura Co., Ltd.) were mixed using a fluidized bed granulation dryer (NFLO-30SJC, manufactured by FREUND Industries Co., Ltd.). This was granulated by spraying a solution formed by adding 308 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.) to purified water by a spray nozzle. The obtained granules were sieved using a granulator (Millmeist, FREUND Industries, Inc.) When the whole grain is applied at 1.0 mm, drug particles are obtained.

On the other hand, 985.0 g of a methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF Corporation) (solid content: 295.5 g), sodium lauryl sulfate (manufactured by Kao Corporation), 53.18 g, lemon 44.63 g of acid triethyl ester (manufactured by Morimura Co., Ltd.) and 236.4 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating liquid (c-1).

1000 g of the obtained drug particles were placed in a fluidized bed granulation dryer (FLO-5M, manufactured by FREUND Industries, Ltd.), and the coating liquid (c-1) was sprayed, and the film was coated with respect to 100 parts by mass of silodosin. 98.5 parts by mass of a methyl acrylate-diethylaminoethyl methacrylate copolymer was obtained to obtain a masking particle (a-1).

The granulated product (b-1) was obtained according to a usual method using 19,326 g of D-mannitol (manufactured by FREUND CORPORATION), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), and 1,700 g of crospovidone (manufactured by ISP).

113.6 g of masking particles (a-1), 614.4 g of granulated material (b-1), 56 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), and sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.) 16 g was mixed using a V-type mixer (S-3-S, manufactured by Tsutsui Chemical Instruments Co., Ltd.) to obtain a mixture for tableting. The mixed powder for ingots was subjected to ingot casting under the conditions of 8 mm and a tableting pressure of about 6 kN using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 4 mg of sirolimus per one spindle. Quality 200mg lozenge.

[Embodiment 2]

In the case of sirocalin, 20,000 g of partially gelatinized starch (manufactured by K.K.), and talc (manufactured by Matsumura Sangyo Co., Ltd.), 5000 g were mixed using a fluidized bed granulating dryer (FL-120U, manufactured by Frenud Industries Co., Ltd.). This was granulated by spraying a solution formed by adding 1400 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.) to purified water by a spray nozzle. The obtained granules were sieved using a granulator (Millmeist, FREUND Industries, Inc.) When the whole grain is applied at 1.0 mm, drug particles are obtained.

On the other hand, 806.6 g of methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF Corporation) (solid content: 242.0 g), sodium lauryl sulfate (manufactured by Kao Corporation), 87.12 g, lemon 36.54 g of the acid triethyl ester (manufactured by Morimura Co., Ltd.) and 193.6 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating liquid (c-2).

1000 g of the obtained drug particles were placed in a fluidized bed granulation dryer (FLO-5M, manufactured by FREUND Industries, Ltd.), and the coating liquid (c-2) was sprayed, and the film was coated with respect to 100 parts by mass of sirolimus. Methyl methacrylate-diethylamine methacrylate 106 parts by mass of the ethyl ester copolymer, the masking particles (a-2) were obtained.

The granulated product (b-2) was obtained according to a usual method using 19,326 g of D-mannitol (manufactured by FREUND CORPORATION), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), and 1,700 g of crospovidone (manufactured by ISP).

119 g of masking particles (a-2), 609 g of granulated material (b-2), 56 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), and 16 g of sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.). The mixture was mixed using a V-type mixer (S-3-S, manufactured by Tsutsui Chemical Instruments Co., Ltd.) to obtain a mixture for tableting. The mixed powder for ingots was subjected to ingot casting under the conditions of 8 mm and a tableting pressure of about 6 kN using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 4 mg of sirolimus per one spindle. Quality 200mg lozenge.

[Example 3]

In the case of sirocalin, 20,000 g of partially gelatinized starch (manufactured by K.K.), and talc (manufactured by Matsumura Sangyo Co., Ltd.), 5000 g were mixed using a fluidized bed granulating dryer (FL-120U, manufactured by Frenud Industries Co., Ltd.). This was granulated by spraying a solution formed by adding 1400 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.) to purified water by a spray nozzle. The obtained granules were sieved using a granulator (Millmeist, FREUND Industries, Inc.) When the whole grain is applied at 1.0 mm, drug particles are obtained.

On the other hand, 982.6 g of a methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF Corporation) (solid content: 294.8 g), sodium lauryl sulfate (manufactured by Kao Corporation), 53.07 g, lemon Acidic triethyl ester (manufactured by Morimura Co., Ltd.), 44.52g, 2,6-di-tert-butyl-4-methylphenol (manufactured by Wako Pure Chemical Industries, Ltd.), 7.37g, and talc (made by Matsumura Industry Co., Ltd.), 235.9g, added to The water was purified to obtain a coating liquid (c-3).

1000 g of the obtained drug particles were charged into a flow layer granulation dryer (FLO-5M, manufactured by FREUND Industries Co., Ltd.), the coating liquid (c-3) was sprayed, and 100 parts by mass of sirolimus was coated with methyl methacrylate-diethylaminoethyl methacrylate. 153 parts by mass of the copolymer was obtained, and the masking particles (a-3) were obtained.

The granulated product (b-3) was obtained according to a usual method using 19,326 g of D-mannitol (manufactured by FREUND CORPORATION), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), and 1,700 g of crospovidone (manufactured by ISP).

132.6 g of masking particles (a-3), 595.4 g of granulated product (b-3), 56 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), and sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.) 16 g was mixed using a V-type mixer (S-3-S, manufactured by Tsutsui Chemical Instruments Co., Ltd.) to obtain a mixture for tableting.

The mixed powder for ingots was subjected to ingot casting under the conditions of 8 mm and a tableting pressure of about 6 kN using a rotary tableting machine (VELA-2, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain 4 mg of sirolimus per one spindle. Quality 200mg lozenge.

The results of the average particle diameter of the masking particles measured in Test Examples 1 to 5, the bitterness of the lozenge containing the masking particles, the time until the bitterness began to be felt, the time of disintegration in the oral cavity, the hardness, and the dissolution rate were as shown in Table 2. Show.

Each mass and each of the sirolimus, the drug particles, the methyl methacrylate-diethylaminoethyl methacrylate copolymer and the masking particles contained in the unit preparation The total mass of the unit preparation is shown in Table 3.

As described above, the preparations of Examples 1 to 3 all belonged to the case where the strong bitterness was suppressed and the time until the bitterness began to be felt was longer than the intraoral disintegration time. Further, the Japanese Pharmacopoeia (16th revised edition) dissolves the second liquid of the test solution, and the dissolution rate after 15 minutes is 85% or more.

It is confirmed from the above that the orally administered preparation containing the masking particles of the present invention can be effectively used so that it does not feel strong bitterness, can be rapidly disintegrated, can be taken even without water, and has an effective blood reproducible during treatment. Medium concentration dissolution of oral cavity disintegration preparation.

(industrial availability)

According to the present invention, it is possible to provide a sirolimus which can be used as a potent medicinal agent without any foreign matter, such as a very strong bitter medicinal agent, and has a treatment for urinary dysfunction accompanied by prostatic hypertrophy. A novel oral administration preparation (especially an orally disintegrating preparation) which can reproduce the dissolution of an effective blood concentration.

Claims (21)

A masking particle is a masking particle obtained by granulating or coating a drug particle containing a bitterness agent by using a coating agent containing a methyl methacrylate-diethylaminoethyl methacrylate copolymer; The content of the copolymer is 80 parts by mass to 400 parts by mass based on 100 parts by mass of the bitterness-treating agent. The masking particle of claim 1, wherein the bitter taste agent is Silodosin. The masking particle of claim 2, wherein the oral administration preparation containing the masking particle has a dissolution rate of 85% or more after 15 minutes at pH 6.8. The masking particle according to any one of claims 1 to 3, wherein the orally administered preparation containing the masking particle has a time of feeling bitterness in a human bitterness functional test for 30 seconds or more. The masking particle of claim 1, wherein the drug particle containing the bitterness agent is a mixture of silodosin and an additive. The masking particle of claim 5, wherein the drug particle containing the bitterness agent is granulated substance of silodosin and an additive. The masking particle of claim 5 or 6, wherein the additive is at least one selected from the group consisting of a sugar or a sugar alcohol and a starch. The masking particle of claim 1, wherein the copolymer content is 100 parts by mass to 200 parts by mass relative to 100 parts by mass of the bitterness-treating agent. The masking particle of claim 1, wherein the content of the bitter taste agent in the masking particle is 5 to 25% by mass. The masking particle of claim 1, wherein the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles is 10 to 30% by mass. The masking particle of claim 1, wherein the methyl methacrylate-diethylaminoethyl methacrylate copolymer content is 20 parts by mass to 40 parts by mass based on 100 parts by mass of the drug particles. An orally administered preparation comprising the masking particles of claim 1. The preparation according to claim 12, wherein the component other than the masking particles further contains an excipient, a disintegrating agent, and a lubricant. The preparation according to claim 13, wherein the excipient and the disintegrant are contained in at least the granules. The orally administered preparation according to any one of claims 12 to 14, wherein the preparation is orally administered as an orally disintegrating preparation. The preparation according to claim 15, wherein the orally disintegrating preparation is a tablet. The preparation of claim 16 is administered orally, wherein the intraoral disintegration time is within 40 seconds. The preparation according to claim 17 is administered orally, wherein the time until the start of the bitterness is longer than the time of disintegration in the oral cavity. The preparation for oral administration according to any one of claims 12 to 14, wherein the dissolution rate after 15 minutes at pH 6.8 is 85% or more. A method for producing a masking particle, comprising: (a) a step of preparing a drug particle by mixing or granulating a bitterness agent with an additive; and (b) a drug particle obtained by the step (a), using a methyl group The methacrylate-diethylaminoethyl methacrylate copolymer coating agent is granulated or coated to prepare a methyl methacrylate-diethylaminoethyl methacrylate copolymer content relative to a bitter odor agent 100 parts by mass of the step of masking particles of 80 parts by mass to 400 parts by mass. A method of producing a masking particle according to claim 20, wherein the bitter taste agent is silodosin.