Orally administered formulation masking bitterness of silodosin

Abstract

To provide a novel orally administered formulation that makes it possible to take silodosin, an extremely bitter-tasting drug, without a feeling of a foreign matter and without water and has an elution property that can reproduce blood concentration effective for treatment of dysuria associated with benign prostatic hyperplasia.SOLUTION: There are provided masking particles obtained by granulating or coating drug particles containing fine powder of silodosin with a coating agent containing a non-enteric polymer. A content of the non-enteric polymer is 80 pts.mass to 400 pts.mass with respect to 100 pts.mass of silodosin. There is also provided a novel orally administered formulation comprising the masking particles.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel oral dosage form that enables silodosin, which is an extremely bitter drug, to be taken without water and without a foreign body sensation, and has an elution property capable of reproducing a blood concentration effective for the treatment of urinary disorders associated with benign prostatic hyperplasia and the like.

Background Art

[0002] Silodosin is a therapeutic agent for urinary disorders that has a selective inhibitory effect on urethral smooth muscle contraction and does not cause a strong blood pressure lowering effect (see, for example, Patent Document 1), and is widely used as a therapeutic agent for urinary disorders associated with benign prostatic hyperplasia. As pharmaceutical preparations containing silodosin, capsule preparations and tablet preparations (see, for example, Patent Documents 2 and 3) are used, but these preparations need to be taken with water. In recent years, there has been a demand for the development of preparations that can be easily taken without water as preparations that are easy to take even for patients with swallowing difficulties such as the elderly. When a drug has a bitter taste, methods for suppressing the bitter taste include chemical masking methods such as chemical modification and inclusion of the drug itself (see, for example, Patent Document 4), functional masking methods by adding sweeteners, fragrances, etc. (see, for example, Patent Documents 5 and Non-Patent Document 1), and physical masking methods in which the drug is coated with a coating agent such as a gastric-soluble polymer or an enteric-soluble polymer (see, for example, Patent Documents 6 to 9) (see, for example, Non-Patent Document 2). However, in the case of drugs with a strong bitter taste, the functional masking method may not be able to sufficiently suppress the bitter taste, and in the physical masking method, the coating amount of the coating agent has to be increased, which causes a problem that the elution property of the drug in the digestive tract decreases. Thus, it has been difficult to achieve both suppression of bitterness and elution properties in various liquidities.

[0003] Japanese Patent Application Laid-Open No. 2008-231029 (Patent Document 6) discloses bitter taste masking granules of levamisole, which are obtained by spraying levamisole and methylcellulose on partially α - modified starch to form granules and then coating them with polyvinyl acetal diethylaminoacetate, a gastric - soluble polymer. Japanese Patent Application Laid-Open No. 2005-513008 (Patent Document 7) discloses coated granules of fexofenadine, which are obtained by granulating a mixture of fexofenadine and precipitated silica using Eudragit® E100 and then further coating them with a polymer dispersion of Eudragit® E100 containing precipitated silica. WO2008 / 018371 (Patent Document 8) discloses granules obtained by spraying a mixture of mitiglinide and crystalline cellulose with aminoalkyl methacrylate copolymer E. Japanese Patent Application Laid-Open No. 2007-63263 (Patent Document 9) discloses amlodipine - containing particles obtained by spraying a coating liquid containing aminoalkyl methacrylate copolymer E on a mixture of amlodipine besylate and light anhydrous silicic acid. However, none of the documents describe a formulation that can be taken without water, which achieves both bitter taste suppression of silodosin and elution properties in various liquidities. Thus, the development of a new formulation has been desired.

[0004]

Non - Patent Document 1

Non - Patent Document 2

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

[0005] An object of the present invention is to provide a novel oral dosage form that enables silodosin, which is an extremely bitter drug, to be taken without water and without a foreign body sensation, and has an elution property capable of reproducing a blood concentration effective for the treatment of dysuria associated with benign prostatic hyperplasia. [Means for Solving the Problems]

[0006] In preparing the oral dosage form of the present invention, there were various points to be overcome due to the characteristics of silodosin. First, silodosin has a chemical property that it is easily decomposed by excipients and the like that are widely used as pharmaceutical additives. In addition, since it is a needle-shaped crystalline substance with extremely strong bitterness, a large amount of coating agents are required to suppress the bitterness, resulting in problems such as a decrease in elution property and a foreign body sensation remaining when taken without water. Furthermore, as a therapeutic agent for dysuria associated with benign prostatic hyperplasia, it must be a formulation that can appropriately reproduce the blood concentration at which the already used silodosin formulation exhibits efficacy. The inventors made intensive studies to solve the above problems while overcoming these points. For example, in the sensory masking method using cocoa powder, calcium lactate, etc., and the chemical masking method using carrageenan, etc., the intense bitterness of silodosin could not be masked. Also, enteric base agents (enteric polymers) generally used in physical masking methods were found to cause a formulation change with silodosin and thus could not be used. As a result of further various studies, surprisingly, by using the masking particles of the present invention, an oral administration preparation can be obtained that exhibits extremely desirable performance such as being able to be taken without water without feeling strong bitterness and achieving an effective blood concentration in humans due to the desired dissolution characteristics, and the present invention was completed.

[0007] That is, the present invention relates to [1] Masking particles obtained by granulating or coating drug particles containing fine powder of silodosin with a coating agent containing a non-enteric polymer, wherein the non-enteric polymer content is 80 parts by mass to 400 parts by mass with respect to 100 parts by mass of silodosin; [2] The masking particles according to [1] above, wherein the dissolution rate of the oral administration preparation containing the masking particles after 15 minutes at pH 6.8 is 85% or more; [3] The masking particles according to [1] or [2] above, wherein the time to start feeling bitterness in the human bitterness sensory test of the oral administration preparation containing the masking particles is 30 seconds or more; [4] The masking particles according to any one of [1] to [3] above, wherein the drug particles containing fine powder of silodosin are a mixture of silodosin and an additive; [5] The masking particles according to [4] above, wherein the drug particles containing fine powder of silodosin are a granulated product of silodosin and an additive; [6] The masking particles according to [4] or [5] above, wherein the additive is at least one additive selected from sugars or sugar alcohols and starches; [7] The masking particles according to any one of [1] to [6] above, wherein the non-enteric polymer is a gastric-soluble polymer; [8] The masking particles according to any one of [1] to [6] above, wherein the non-enteric polymer is ethyl cellulose, polyvinyl acetal diethylaminoacetate or aminoalkyl methacrylate copolymer E;

[0008] [9] The masking particles according to any one of [1] to [8] above, wherein the non-enteric polymer content is 100 parts by mass to 200 parts by mass with respect to 100 parts by mass of silodosin;

[10] The masking particles according to any one of [1] to [9] above, wherein the silodosin content in the masking particles is 5 to 25% by mass;

[11] The masking particles according to any one of [1] to

[10] above, wherein the non-enteric polymer content in the masking particles is 15 to 30% by mass;

[12] The masking particles according to any one of [1] to

[10] above, wherein the non-enteric polymer content is 20 parts by mass to 40 parts by mass with respect to 100 parts by mass of drug particles;

[13] An oral dosage form containing the masking particles according to any one of [1] to

[12] above;

[14] An oral dosage form containing the masking particles according to

[13] above, wherein the dosage form is a tablet; and

[15] A method for producing masking particles, comprising: (a) a step of mixing or granulating fine powder of silodosin and an additive to prepare drug particles; and (b) a step of granulating or coating the drug particles obtained in step (a) with a coating agent containing a non-enteric polymer to prepare masking particles, wherein the non-enteric polymer content is 80 parts by mass to 400 parts by mass with respect to 100 parts by mass of silodosin; etc.

[0009] In the present invention, the "non-enteric polymer" refers to a water-insoluble polymer other than an enteric polymer, and examples thereof include a gastric-soluble polymer or a water-insoluble polymer. Examples of the gastric-soluble polymer include a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer such as aminoalkyl methacrylate copolymer E (for example, Eudragit (registered trademark) EPO, Eudragit (registered trademark) E100), a methyl methacrylate-diethylaminoethyl methacrylate copolymer (for example, Kollicoat (registered trademark) Smart Seal 30D), and gastric-soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate (for example, AEA (registered trademark)). Examples of the water-insoluble polymer include ethyl acrylate-methyl methacrylate copolymers such as ethyl acrylate-methyl methacrylate copolymer dispersions (e.g., Eudragit® NE30D), aminoalkyl methacrylate copolymers RS (e.g., Eudragit® RS100, Eudragit® RSPO, Eudragit® RL, Eudragit® RLPO), and aminoalkyl methacrylate copolymer RS aqueous dispersions (e.g., Eudragit® RS30D, Eudragit® RL30D), etc., water-insoluble acrylic acid copolymers such as ethyl acrylate-methyl methacrylate-trimethylammonium chloride ethyl methacrylate copolymer, ethyl cellulose (e.g., Ethocel®), water-insoluble cellulose ethers such as ethyl cellulose aqueous dispersions (e.g., Aquacoat®), vinyl acetate resins (e.g., Kollicoat® SR, Kollicoat® SR30D), etc. The non-enteric polymer is preferably ethyl cellulose or a gastric-soluble polymer, more preferably ethyl cellulose, methyl methacrylate-diethylaminoethyl methacrylate copolymer, aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, still more preferably ethyl cellulose, aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, still more preferably ethyl cellulose or aminoalkyl methacrylate copolymer E, still more preferably aminoalkyl methacrylate copolymer E. These non-enteric polymers may be used in combination of two or more as needed.

[0010] The coating agent containing the non-enteric polymer used in the present invention may contain, in addition to the above non-enteric polymer, additives, water-soluble polymers, etc. as required. When using a water-soluble polymer, the ratio of the mass of the water-soluble polymer to the total mass of the non-enteric polymer and the water-soluble polymer is preferably 20% or less. Examples of the additives include plasticizers, lubricants, surfactants, etc. Examples of the plasticizer include stearic acid, triacetin, triethyl citrate, macrogol, glycerin, glycerin fatty acid ester, castor oil, diethyl sebacate, dibutyl sebacate, etc. Examples of the lubricant include talc, stearic acid, magnesium stearate, calcium stearate, etc. Examples of the surfactant include sodium lauryl sulfate, polysorbate, etc. Examples of the water-soluble polymer include hypromellose, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, povidone, sodium carboxymethylcellulose, sodium alginate, etc. These additives and water-soluble polymers can also be used in combination of two or more. In the present invention, the content of the non-enteric polymer can be, for example, 80 to 400 parts by mass, 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. with respect to 100 parts by mass of silodosin, and more preferably 100 to 200 parts by mass. The content of the non-enteric polymer in the masking particles of the present invention is preferably 15 to 30% by mass, and more preferably 15 to 25% by mass. In the present invention, the content of the non-enteric polymer is generally 20 to 50 parts by mass, preferably 20 to 40 parts by mass, and more preferably 30 to 40 parts by mass with respect to 100 parts by mass of the drug particles. In the present invention, the "average particle diameter" means the 50% particle diameter (mass-based median diameter). This 50% particle diameter can be measured by a sieving particle size distribution measuring machine (for example, Robot Shifter RPS-205 type, manufactured by Seishin Enterprise Co., Ltd.). The average particle diameter of the masking particles of the present invention is, for example, generally 300 μm or less, preferably about 100 to 250 μm.

[0011] For the silodosin used in the present invention, commercially available silodosin can be used, or it can also be produced by the methods described in the literature (for example, see Patent Document 1) or methods analogous thereto. The "fine powder of silodosin" used in the present invention may be particles that are not in the form of agglomerated lumps, and may be crushed, pulverized, etc. as necessary. The average particle diameter of the fine powder of silodosin is preferably about 50 μm or less, more preferably about 1 to 30 μm. For the "drug particles containing the fine powder of silodosin" used in the present invention, it is desirable to use appropriate additives in addition to silodosin. Examples include mixtures of silodosin and appropriate additives, granules of silodosin and appropriate additives, and materials obtained by coating appropriate additives with silodosin.

[0012] As additives used for drug particles, various additives that do not cause formulation changes when combined with silodosin can be used. For example, disintegrants, excipients, binders, lubricants, sweeteners, acidulants, foaming agents, flavors, colorants, etc. can be appropriately used. Examples of disintegrants include low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, corn starch, corn starch, potato starch, sodium carboxymethyl starch, carmellose, partially pregelatinized starch, pregelatinized starch, crospovidone, crystalline cellulose, etc. Examples of excipients include corn starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, trehalose, crystalline cellulose, magnesium aluminometasilicate, calcium phosphate anhydrous, precipitated calcium carbonate, calcium silicate, calcium lactate, lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, etc. Examples of binders include starches, crystalline cellulose, hydroxypropyl cellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol, etc. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, glycerin monostearate, etc. Examples of sweeteners include aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame potassium, sucralose, etc. Examples of acidulants include citric acid, tartaric acid, malic acid, ascorbic acid, etc. Examples of foaming agents include sodium hydrogen carbonate, sodium carbonate, calcium carbonate, etc. Examples of flavor correctives include L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, sodium hydrogen carbonate, etc.Examples of the fragrance include strawberry, yogurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, matcha, and the like. Examples of the colorant include food dyes such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, yellow ferric oxide, ferric oxide, caramel pigment, titanium oxide, and the like.

[0013] In the present invention, as additives used for drug particles, as excipients or disintegrants, for example, sugars or sugar alcohols and starches are preferable, and starches are more preferable. Examples of the sugar or sugar alcohol include D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, and the like, and D-mannitol is more preferable. Examples of the starches include corn starch, rice starch, potato starch, partially pregelatinized starch, pregelatinized starch, and the like, and partially pregelatinized starch and pregelatinized starch are more preferable. As the lubricant, for example, magnesium stearate, calcium stearate, talc, and the like are preferable, and talc is more preferable. As the binder, for example, starches, hydroxypropyl cellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol, and the like are preferable, and hydroxypropyl cellulose and hypromellose are more preferable. These additives may be used in combination of two or more as necessary. The content of silodosin in the masking particles of the present invention is preferably 30% by mass or less, more preferably 5 to 25% by mass, and still more preferably 5 to 16% by mass. The content of silodosin 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, and the like.

[0014] (Method for producing masking particles) The masking particles of the present invention can be produced by methods generally used in producing masking particles, such as the core particle coating method, the granulation matrix method, the granulation coating method, etc. For example, it can also be produced by granulating or coating drug particles obtained by mixing or granulating cilostazol and an additive with a coating agent containing a non-enteric polymer. In these series of productions, examples of the granulating or coating method include the high-speed mixing and stirring granulation method, the rolling fluidized bed granulation method, the fluidized bed granulation method, etc., and the fluidized bed granulation method is preferred. Specifically, for example, in the core particle coating method, core particles such as commercially available or granulated crystalline cellulose, D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, sucrose, etc. are sequentially coated with a dispersion containing cilostazol and a solution or dispersion of a coating agent containing a non-enteric polymer, or coated with a mixture thereof to produce masking particles.

[0015] Also, for example, in the granulation matrix method, a mixture of cilostazol and an additive (for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) is granulated or coated while spraying a solution or dispersion of a coating agent containing a non-enteric polymer to produce masking particles. Also, for example, in the granulation coating method, a mixture of cilostazol and an additive (for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) is granulated while spraying a solution of a water-soluble binder, and then the obtained granulated product is coated while spraying a solution or dispersion of a coating agent containing a non-enteric polymer to produce masking particles. Hydroxypropyl cellulose and hypromellose are preferred as the water-soluble binder. In the above method, the granulation matrix method or the granulation coating method is preferred, and the granulation coating method is more preferred.

[0016] The solvent used for dissolving or dispersing the non-enteric polymer is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, methyl ethyl ketone, and water, or a mixed solvent thereof. Ethanol and water are preferred, and water is more preferred. Although aminoalkyl methacrylate copolymer E is insoluble in water, it can be used as an aqueous solution dissolved in acidic (pH 5 or lower) water, or as an aqueous dispersion in which at least one plasticizer selected from sodium lauryl sulfate, stearic acid, diethyl sebacate, and dibutyl sebacate is mixed with aminoalkyl methacrylate copolymer E at an arbitrary ratio.

[0017] In order to prevent aggregation during production, the masking particles of the present invention may be further overcoated with a suitable additive and then used. The masking particles of the present invention include those that have been overcoated. However, in this specification, the mass of the masking particles does not include the mass of the additive used for overcoating. Examples of the additive used for overcoating include sugars such as lactose, glucose, sucrose, and fructose, and sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol. Preferably, it is D-mannitol. The method of overcoating is not particularly limited. For example, it can also be produced by coating while spraying an aqueous solution of an additive (for example, sugar or sugar alcohol) on the masking particles of the present invention. The content of the additive used for overcoating is usually 1 to 20 parts by mass, preferably 2 to 15 parts by mass, and more preferably 5 to 10 parts by mass with respect to 100 parts by mass of the masking particles.

[0018] (Oral dosage form) Oral dosage forms of various dosage forms can be produced using the masking particles of the present invention. Examples of the dosage form of the oral dosage form of the present invention include granules, powders, tablets, and the like.

[0019] The oral administration preparation of the present invention can be produced by a method conventional in the pharmaceutical field using the masking particles of the present invention and pharmaceutical additives generally used in orally disintegrating preparations.

[0020] For example, in the case of tablets, the oral administration preparation can also be produced by tableting the masking particles of the present invention together with pharmaceutical additives generally used in orally disintegrating preparations by a known method such as the direct powder compression method (direct compression method), granulation method or a method analogous thereto. Specifically, for example, in the direct compression method, a mixture containing the masking particles of the present invention and pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc. is mixed using a mixer without granulation and then tabletted to produce an oral administration preparation. Also, for example, in the granulation method, a mixture of excipients, disintegrants, etc. is granulated using water, a mixture of water and ethanol, or a solution or suspension of a binder or disintegrant, etc., and then mixed with the masking particles of the present invention, lubricants, etc. using a mixer and then tabletted, or a mixture of the masking particles of the present invention and excipients, disintegrants, etc. is granulated using water, a mixture of water and ethanol, or a solution or suspension of a binder or disintegrant, etc., and then further lubricant is added and mixed using a mixer and then tabletted to produce an oral administration preparation.

[0021] Also, in the case of granules, it can also be produced by performing fluidized bed granulation or agitation granulation according to the granulation method of tablets. Powders, etc. can also be produced by mixing pharmaceutical additives according to the direct compression method of tablets.

[0022] As pharmaceutical additives generally used in orally disintegrating preparations, additives used for the drug particles can be used. As disintegrants, partially pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carmellose, sodium carmellose, corn starch, etc. are preferable. As excipients, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, etc., corn starch, crystalline cellulose, etc. are preferable. As lubricants, sodium stearyl fumarate, calcium stearate, talc, light anhydrous silicic acid, etc. are preferable. These pharmaceutical additives may be used in combination of two or more as necessary.

[0023] (Manufacturing Example of Oral Administration Preparation) Hereinafter, the manufacturing method of the oral administration preparation of the present invention will be exemplified, but it is not limited thereto.

[0024] [Manufacturing Example 1] For example, the masking particles of the present invention and at least one pharmaceutical additive selected 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 pregelatinized starch, crystalline cellulose, and crospovidone are mixed using a mixer to produce a powder. In the mixing step, if necessary, an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added singly or in combination of two or more.

[0025] [Manufacturing Example 2] For example, the masking particles of the present invention can be mixed with at least one pharmaceutical additive selected from sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol, starches such as corn starch, rice starch, potato starch, pregelatinized starch, and gelatinized starch, crystalline cellulose, crospovidone, sodium stearyl fumarate, calcium stearate, talc, and light anhydrous silicic acid using a mixer, and then the mixture can be tableted to produce tablets. In the mixing step, if necessary, further excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, fragrances, coloring agents, etc. may be added singly or in combination of two or more.

[0026] [Production Example 3] For example, at least one pharmaceutical additive selected from sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol, starches such as corn starch, rice starch, potato starch, pregelatinized starch, and gelatinized starch, and crystalline cellulose can be mixed, and granule (1) can be produced by granulating while spraying a solution or dispersion of pregelatinized starch or crospovidone. The mixing and granulating steps can use a high-speed mixing and stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, etc., and preferably a fluidized bed granulation method. Then, the masking particles of the present invention, the granule (1), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc, and light anhydrous silicic acid can be mixed using a mixer and then tableted to produce tablets. In the mixing step, if necessary, further excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, fragrances, coloring agents, etc. may be added singly or in combination of two or more.

[0027] [Production Example 4] For example, at least one pharmaceutical additive selected from sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol, starches such as corn starch, rice starch, potato starch, partially pregelatinized starch, and pregelatinized starch, and crystalline cellulose is mixed, and granulation is carried out while spraying water or a mixture of water and ethanol, whereby granules (2) can also be produced. For the mixing and granulation steps, a high-speed mixing and stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, etc. can be used, and preferably a fluidized bed granulation method. Next, the masking particles of the present invention, the granules (2), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc, and light anhydrous silicic acid are mixed using a mixer and then tabletted to produce tablets. In the mixing step, if necessary, further excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, fragrances, colorants, etc. may be added singly or in combination of two or more.

[0028] [Production Example 5] For example, the masking particles of the present invention and the granules (1) or the granules (2) can be mixed using a mixer to produce a granule agent. In the mixing step, if necessary, further excipients, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, fragrances, colorants, etc. may be added singly or in combination of two or more.

[0029] [Production Example 6] For example, a mixture of D-mannitol and crystalline cellulose is mixed using a fluidized bed granulation dryer, granulation is carried out while spraying an aqueous dispersion of crospovidone thereon, and then sizing is carried out using a sizing machine to produce granules (3). Next, the masking particles of the present invention, the granules (3), and sodium stearyl fumarate are mixed using a mixer and then tabletted to produce tablets. In the mixing step, if necessary, further excipients, lubricants, foaming agents, sweeteners, flavoring agents, fluidizing agents, fragrances, colorants, etc. may be added singly or in combination of two or more.

[0030] [Production Example 7] For example, a mixture of D-mannitol, crystalline cellulose, and crospovidone can be mixed using a fluidized bed granulator / dryer, granulated while spraying water thereon, and then sized using a sizing machine to produce granules (4). Subsequently, the masking particles of the present invention, the granules (4), and sodium stearyl fumarate can be mixed using a mixer and then tableted to produce tablets. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more.

[0031] [Production Example 8] In the above Production Example 6 or 7, tablets can also be produced in the same manner as in Production Example 6 or 7 using corn starch instead of crystalline cellulose and pregelatinized starch instead of crospovidone.

[0032] In the step of producing the masking particles or oral dosage forms of the present invention, "granulation", "coating", "mixing", and "tableting" may be carried out using conventional methods in the pharmaceutical technology field. For "granulation" and "coating", for example, a fluidized bed granulator, a rolling fluidized bed granulation method, a high-speed mixing and stirring granulator, etc. can also be used. For "mixing", for example, a V-type mixer, a Borre container, etc. can also be used. "Tableting" can be carried out using, for example, a single-shot tableting machine, a rotary tableting machine, etc. The tableting pressure is, for example, 1 to 20 kN, preferably 2 to 15 kN.

[0033] The masking particles of the present invention and oral dosage forms containing the same exhibit a good bitter taste masking effect. The bitter taste masking effect can be quantitatively evaluated by a bitter taste sensory test described later. Those having an average bitter taste score of 2 or less are preferred, and those having an average bitter taste score of 1 or less are more preferred. Also, the time until the start of feeling bitterness is preferably 30 seconds or more, and more preferably longer, such as 40 seconds or more, or 50 seconds or more.

[0034] The oral dosage form of the present invention exhibits rapid elution without depending on the pH in the digestive tract. That is, the oral dosage form of the present invention shows an elution rate of 80% or more after 15 minutes in the first fluid (pH about 1.2) and the second fluid (pH about 6.8) of the Japanese Pharmacopoeia dissolution test. Preferably, in the first fluid (pH about 1.2) of the Japanese Pharmacopoeia dissolution test, the elution rate after 15 minutes is 85% or more, and more preferably, even in the second fluid (pH about 6.8) of the Japanese Pharmacopoeia dissolution test, the elution rate after 15 minutes is 85% or more. The elution property can be quantitatively evaluated by the dissolution test described below.

[0035] The oral dosage form of the present invention preferably disintegrates in the oral cavity in a short time for taking without water. For example, in the in - mouth disintegration test described below, the average in - mouth disintegration time is usually adjusted to be within 60 seconds, preferably 40 seconds, and more preferably within 30 seconds. The oral dosage form of the present invention preferably has an appropriate hardness for convenience in manufacturing and transportation, etc. For example, in the hardness test described below, it is usually adjusted to be 20 N or more, preferably 30 N or more, and more preferably 40 N or more. The in - mouth disintegration time and hardness can also be adjusted by appropriately selecting the type and amount of pharmaceutical additives, manufacturing methods (e.g., granulation method, etc.), manufacturing conditions (e.g., tableting pressure, etc.).

[0036] In the oral dosage form of the present invention, the silodosin content per unit dosage form is usually 2 - 8 mg, preferably 2 mg, 4 mg or 8 mg. The oral dosage form of the present invention, for example, in the case of tablets, the mass per tablet can be 50 - 500 mg, 50 - 300 mg, 100 - 250 mg, 100 - 200 mg, etc., and the silodosin content at that time can be 0.4 - 16%. In the case of granules, powders, etc., the mass per single dose can be 200 - 3000 mg, 500 - 2000 mg, 500 - 1000 mg, etc., and the silodosin content at that time can be 0.06 - 4%.

[0037] When the oral dosage form of the present invention is used for actual treatment, the dosage of the active ingredient is appropriately determined according to the sex, age, weight, degree of disease, etc. of the patient. Generally, it can be administered in the range of 1 to 16 mg per day for adults. Preferably, 2 to 8 mg per day for adults is orally administered once or twice a day.

Effects of the Invention

[0038] The masking particles of the present invention are pharmaceutically stable, suppress the extremely strong bitter taste of silodosin, and have the same rapid elution property as commercially available silodosin tablets (Yurif (registered trademark) tablets). Therefore, they can be used in oral dosage forms that can be taken without a foreign body sensation even without water. In addition, the oral dosage form of the present invention suppresses the bitter taste peculiar to silodosin and has the same rapid elution property and biological equivalence as commercially available silodosin tablets (Yurif (registered trademark) tablets). Therefore, it is useful as a silodosin-containing preparation that can be taken without a foreign body sensation even without water.

Modes for Carrying Out the Invention

[0039] The content of the present invention will be described in more detail by the following test examples, examples and comparative examples, but the content of the present invention is not limited thereto.

Examples

[0040] 〔Test Example 1〕 Bitter Taste Sensory Test In 1 to 3 healthy adult males, about 200 mg of the masking particles prepared in Examples 1 to 3 or 1 tablet of the tablets prepared in Examples 4 to 9 were each placed in the mouth, and the bitter taste when the bitter taste was felt was scored according to Table 1, and the average was obtained. In addition, for the tablets, the tablets were placed in the mouth, and the tablets were disintegrated while gently rolling them with the tongue, and the time until the bitter taste began to be felt was also evaluated.

[0041]

Table 1

[0042] 〔Test Example 2〕 Oral Disintegration Test In 1 to 3 healthy male subjects, one tablet of the test preparation and the tablets prepared in Examples 4 to 11 were each placed in the oral cavity, and the tablets were disintegrated while gently rolling them with the tongue, and the time taken for the tablets to disintegrate in the oral cavity was measured, and the average was determined.

[0043] 〔Test Example 3〕 Hardness Test The hardness of the test preparation and the tablets prepared in Examples 5 to 11 was measured using a hardness tester (PC-30, manufactured by Okada Seiko Co., Ltd.).

[0044] 〔Test Example 4〕 Dissolution Test Method 1 For the granules prepared in Examples 1 to 3 and Comparative Example 1, a dissolution test was carried out according to the paddle method of the dissolution test method described in the 16th revised Japanese Pharmacopoeia, with a paddle rotation speed of 50 rpm and using the second solution for dissolution test in the Japanese Pharmacopoeia as the test solution, and the dissolution rate at 15 minutes was determined using an ultraviolet absorption photometer. The dissolution rate was determined by performing the test twice for each preparation and calculating the average value. Detector: Ultraviolet absorption photometer (measurement wavelengths: 270 nm, 350 nm)

[0045] 〔Test Example 5〕 Dissolution Test Method 2 For the test preparation and the tablets prepared in Examples 4 to 11, a dissolution test was carried out according to the paddle method of the dissolution test method described in the 16th revised Japanese Pharmacopoeia, with a paddle rotation speed of 50 rpm and using the second solution for dissolution test in the Japanese Pharmacopoeia as the test solution. The silodosin in the sampling solution was quantified by high performance liquid chromatography to determine the dissolution rate. The dissolution rate was determined by randomly extracting 2 to 3 samples for each preparation and performing the test, and calculating the average value. Detector: Ultraviolet absorption photometer (measurement wavelength: 270 nm)

[0046] 〔Test Example 6〕 Dissolution Test Method 3 For the test preparation, using the Japanese Pharmacopoeia dissolution test solution 1 as the test solution, a dissolution test was carried out in the same manner as in Test Example 5 to determine the dissolution rate. As a result, the dissolution rate of the test preparation after 15 minutes was 102.1%.

[0047] 〔Test Example 7〕 Particle size distribution measurement Using a robot sifter (RPS-205 type, manufactured by Seishin Enterprise Co., Ltd.), the particle size distribution was measured by sieving to determine the 50% particle diameter (mass median diameter).

[0048] 〔Test Example 8〕 Formulation change test Silodosin and various polymer substrates were mixed at a mass ratio of 1:1 and stored at a temperature of 40 °C and a relative humidity of 75% for 4 weeks, and then the formulation change was confirmed. The decomposition products were quantified by liquid chromatography, and for discoloration, the degree of discoloration was confirmed by visual observation. Quantification method A sample corresponding to 20 mg of silodosin was weighed to prepare a sample solution, and the test was carried out by liquid chromatography. The peak areas were measured by the automatic integration method, and the content (%) of the decomposition product (KMD-3241) was determined by the area percentage method. Detector: Ultraviolet absorptiometer (measurement wavelength: 225 nm)

[0049]

Table 2

[0050] As shown in Table 2, hydroxypropyl methylcellulose acetate succinate AS-MF had a significant increase in decomposition products and was unsuitable. Also, methacrylic acid copolymer L and dry methacrylic acid copolymer LD had significant changes in color tone and an increase in decomposition products and were unsuitable.

[0051] 〔Test Example 9〕 Bioequivalence Test (1) Test Method Using healthy adult males, the plasma concentration of silodosin was measured when a test preparation containing 4 mg of silodosin was orally disintegrated without water in a single oral administration on an empty stomach, and when a commercially available tablet (standard preparation) containing 4 mg of silodosin was orally administered once with water. The bioequivalence between the two preparations was examined. (2) Test Drug As the standard preparation, commercially available Yurif (registered trademark) 4 mg tablets were used. The test preparation was prepared into tablets with the composition described in Table 3 according to the method of Example 10.

[0052]

Table 3

[0053]

Table 4

[0054] Example 1 100 g of silodosin, 300 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 75 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). Then, a coating solution prepared by adding 100 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan Co., Ltd.), 10 g of sodium lauryl sulfate (manufactured by Kao Corporation), 15 g of stearic acid (manufactured by Mallinckrodt), and 35 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) to purified water was sprayed through a spray nozzle to perform granulation. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ0.55 mm to obtain masking particles (a-1). Using 948 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 41 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 11 g of partially α - gelatinized starch (manufactured by Nippon Calcon Co., Ltd.), granulated product (b-1) was obtained according to a conventional method. 528 mg of masking particles (a-1), 3101.8 mg of granulated product (b-1), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 60 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), and 20 mg of light anhydrous silicic acid (manufactured by Freund Industry Co., Ltd.) were mixed to obtain a granule containing 4 mg of silodosin in a mass of 199.5 mg per unit dosage.

[0055] Example 2 33.3 g of silodosin, 366.7 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 75 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). Then, a coating solution prepared by adding 100 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan Co., Ltd.), 10 g of sodium lauryl sulfate (manufactured by Kao Corporation), 15 g of stearic acid (manufactured by Mallinckrodt), and 35 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) to purified water was sprayed through a spray nozzle to perform granulation. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ0.55 mm to obtain masking particles (a-2). 792 mg of masking particles (a-2), 1477 mg of granulated product (b-1), 175 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 37.5 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.) and 12.5 mg of light anhydrous silicic acid (manufactured by Freund Industry Co., Ltd.) were mixed to obtain a granule containing 4 mg of silodosin in a mass of 249.4 mg per unit preparation.

[0056] Example 3 100 g of silodosin, 300 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 75 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) and 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). To this, a coating solution prepared by adding 333.3 g of an ethyl cellulose aqueous dispersion (manufactured by Asahi Kasei Chemicals Corporation) with a solid content concentration of 30% and 20 g of triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) to purified water was sprayed with a spray nozzle to perform granulation. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ0.55 mm to obtain masking particles (a-3). 496 mg of masking particles (a-3), 3134.0 mg of granulated product (b-1), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 60 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.) and 20 mg of light anhydrous silicic acid (manufactured by Freund Industry Co., Ltd.) were mixed to obtain a granule containing 4 mg of silodosin in a mass of 199.5 mg per unit preparation.

[0057] Example 4 120 g of silodosin, 348 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 90 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) and 30 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). Granulation was performed while spraying a solution prepared by adding 12 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ1.0 mm to obtain drug particles. On one hand, 180 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan), 18 g of sodium lauryl sulfate (manufactured by Kao Corporation), 27 g of stearic acid (manufactured by Mallinckrodt), and 63 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating solution. 500 g of the obtained drug particles were put into a fluidized bed granulator dryer (MP-01, manufactured by Powrex), and the coating solution was sprayed to coat 150 parts by mass of aminoalkyl methacrylate copolymer E with respect to 100 parts by mass of silodosin. The obtained coated granules were sized using a sizing machine (P-02S, manufactured by Dalton) with a screen size of φ0.55 mm to obtain masking particles (a-4). 948 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.) and 52 g of crospovidone (manufactured by ISP) were used to obtain a granulated product (b-2) according to a conventional method. 592 mg of masking particles (a-4), 3038 mg of granulated product (b-2), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 80 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.) were mixed to obtain a mixture for tableting. This mixture for tableting was tableted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle and mortar of 8 mm and a tableting pressure of about 5 kN to obtain tablets with a mass of 199.5 mg containing 4 mg of silodosin per tablet.

[0058] Example 5 100 g of silodosin, 300 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 75 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). To this, 75 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan Co., Ltd.), 7.5 g of sodium lauryl sulfate (manufactured by Kao Corporation), 11.25 g of stearic acid (manufactured by Mallinckrodt), 26.25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.), and 250 g of an ethyl cellulose aqueous dispersion with a solid content concentration of 30% (manufactured by Asahi Kasei Chemicals Corporation) added to purified water were sprayed with a spray nozzle to perform granulation. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) at a screen size of φ0.55 mm to obtain masking particles (a-5). 556 mg of masking particles (a-5), 3074 mg of granulated product (b-2), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 60 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), and 20 mg of light anhydrous silicic acid (manufactured by Freund Industry Co., Ltd.) were mixed to obtain a mixture for tableting. This mixture for tableting was tableted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle and mortar of 11×6 mm and a tableting pressure of approximately 7 kN to obtain tablets with a mass of 199.5 mg containing 4 mg of silodosin per tablet.

[0059] Example 6 120 g of silodosin, 348 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 90 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 30 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). Granulation was performed while spraying a solution prepared by adding 12 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) at a screen size of φ1.0 mm to obtain drug particles. On the one hand, 180 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan), 18 g of sodium lauryl sulfate (manufactured by Kao Corporation), 27 g of stearic acid (manufactured by Mallinckrodt), and 63 g of talc (manufactured by Matsumura Sangyo) were added to purified water to obtain a coating solution (c-1). Also, 50 g of D-mannitol (manufactured by Mitsubishi Foodtech) was added to purified water to obtain a coating solution (c-2). 500 g of the obtained drug particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex), and the coating solution (c-1) was sprayed to coat 150 parts by mass of aminoalkyl methacrylate copolymer E with respect to 100 parts by mass of silodosin. The obtained coated granules were sized using a sizing machine (P-02S, manufactured by Dalton) with a screen size of φ0.55 mm to obtain masking particles. Next, 500 g of the obtained masking particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex), and the coating solution (c-2) was sprayed to coat 10 parts by mass with respect to 100 parts by mass of the masking particles. The obtained coated granules were sized using a sizing machine (P-02S, manufactured by Dalton) with a screen size of φ0.55 mm to obtain overcoated masking particles (a-6). 976.8 mg of the overcoated masking particles (a-6), 4468.2 mg of the granulated product (b-1), 420 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 120 mg of sodium stearyl fumarate (manufactured by Pharmatrans Sanaq AG) were mixed to obtain a mixture for tableting. This mixture for tableting was tabletted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko) under the conditions of a pestle and mortar of 8 mm and a tableting pressure of about 5 kN to obtain tablets with a mass of 199.5 mg containing 4 mg of silodosin per tablet.

[0060] Example 7 120 g of silodosin, 438 g of partially pregelatinized starch (manufactured by Nippon Karakon Co., Ltd.), and 30 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation). A solution prepared by adding 12 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water was sprayed through a spray nozzle while granulating. The obtained granules were sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ1.0 mm to obtain drug particles. On the other hand, 240 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan Co., Ltd.), 24 g of sodium lauryl sulfate (manufactured by Kao Corporation), 36 g of stearic acid (manufactured by Mallinckrodt), and 84 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating solution (c-3). 500 g of the obtained drug particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and the coating solution (c-3) was sprayed to coat 200 parts by mass of aminoalkyl methacrylate copolymer E per 100 parts by mass of silodosin. The obtained coated granules were sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ0.55 mm to obtain masking particles (a-7). 984 mg of masking particles (a-7), 4461 mg of granules (b-1), 420 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 120 mg of sodium stearyl fumarate (manufactured by Pharmatrans Sanaq AG) were mixed to obtain a tableting mixture. This tableting mixture was tableted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle of 8 mm and a tableting pressure of approximately 5 kN to obtain tablets with a mass of 199.5 mg containing 4 mg of silodosin per tablet.

[0061] Example 8 120 g of silodosin, 441.6 g of pregelatinized starch (manufactured by Nippon Starch Chemical Co., Ltd.), and 30 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation). A solution prepared by adding 8.4 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water was sprayed through a spray nozzle while granulating. The obtained granules were sized using a sizing machine (P-02S, manufactured by Dalton Corporation) with a screen size of φ1.0 mm to obtain drug particles. 500 g of the obtained drug particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and coating solution (c-3) was sprayed to coat 200 parts by mass of aminoalkyl methacrylate copolymer E with respect to 100 parts by mass of silodosin, obtaining masking particles. Next, 500 g of the obtained masking particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and coating solution (c-2) was sprayed to coat 10 parts by mass with respect to 100 parts by mass of the masking particles. The obtained granules were sieved using a No. 30 sieve to obtain overcoated masking particles (a-8). 721.6 mg of overcoated masking particles (a-8), 2918.4 mg of granulated product (b-1), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 80 mg of sodium stearyl fumarate (manufactured by Pharmatrans Sanaq AG) were mixed to obtain a tableting mixture. This tableting mixture was tabletted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle of 8 mm and a tableting pressure of about 7 kN to obtain tablets with a mass of 200.0 mg containing 4 mg of silodosin per tablet.

[0062] Example 9 4400 g of cilodosin, 16192 g of partially pre-gelatinized starch (manufactured by Nippon Karakon Co., Ltd.), and 1100 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulator dryer (NFLO-30SJC, manufactured by Freund Industry Co., Ltd.). A solution prepared by adding 308 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water was sprayed through a spray nozzle while granulation was carried out. The obtained granulated product was sized using a sizing machine (Mill Mist, manufactured by Freund Industry Co., Ltd.) with a screen size of φ1.0 mm to obtain drug particles. On the other hand, 6825 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan Co., Ltd.), 682.5 g of sodium lauryl sulfate (manufactured by Kao Corporation), 1023.8 g of stearic acid (manufactured by Mallinckrodt), and 2388.8 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating solution (c-4). Also, 3000 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.) was added to purified water to obtain a coating solution (c-5). 16250 g of the obtained drug particles were placed in a fluidized bed granulator dryer (NFLO-30SJC, manufactured by Freund Industry Co., Ltd.), and the coating solution (c-4) was sprayed. With respect to 100 parts by mass of cilodosin, 175 parts by mass of aminoalkyl methacrylate copolymer E was coated to obtain masking particles. Next, the coating solution (c-5) was sprayed onto the obtained masking particles, and 10 parts by mass was coated with respect to 100 parts by mass of the masking particles. The obtained granules were sieved using a No. 30 sieve to obtain over-coated masking particles (a-9). Using 19399 g of D-mannitol (manufactured by Freund Industry Co., Ltd.), 4095 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), and 1706 g of crospovidone (manufactured by ISP), a granulated product (b-3) was obtained according to a conventional method. 343 mg of overcoated masking particles (a-9), 1477 mg of granulated product (b-3), 140 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 40 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.) were mixed to obtain a tableting mixture. This tableting mixture was tabletted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle diameter of 8 mm and a tableting pressure of about 6 kN to obtain tablets with a mass of 200.0 mg containing 4 mg of silodosin per tablet.

[0063] Example 10 4400 g of silodosin, 16192 g of partially pregelatinized starch (manufactured by Nippon Karakon Co., Ltd.), and 1100 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (NFLO-30SJC, manufactured by Freund Industry Co., Ltd.), and granulation was carried out while spraying a solution prepared by adding 308 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water through a spray nozzle. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ1.0 mm to obtain drug particles. 16250 g of the obtained drug particles were placed in a fluidized bed granulation dryer (NFLO-30SJC, manufactured by Freund Industry Co., Ltd.), and coating solution (c-4) was sprayed to coat 175 parts by mass of aminoalkyl methacrylate copolymer E with respect to 100 parts by mass of silodosin to obtain masking particles. Next, coating solution (c-5) was sprayed onto the obtained masking particles to coat 10 parts by mass with respect to 100 parts by mass of the masking particles. The obtained granules were sieved using a No. 30 sieve to obtain overcoated masking particles (a-10). 19399 g of D-mannitol (manufactured by Freund Industry Co., Ltd.), 4095 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), and 1706 g of crospovidone (manufactured by ISP) were used to obtain a granulated product (b-4) according to a conventional method. 171.5 g of overcoated masking particles (a-10), 738.5 g of granulated product (b-4), 70 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 20 g of sodium stearyl fumarate (manufactured by PHARMATRANS SANAQ AG) were mixed to obtain a mixture for tableting. This mixture for tableting was tableted using a rotary tablet press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a pestle and mortar of 8 mm and a tableting pressure of about 7 kN to obtain tablets with a mass of 200.0 mg containing 4 mg of silodosin per tablet.

[0064] Example 11 120 g of silodosin, 441.6 g of partially pregelatinized starch (manufactured by National Starch&Chemical), and 30 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and granulation was performed while spraying a solution prepared by adding 8.4 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water through a spray nozzle. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ1.0 mm to obtain drug particles. 500 g of the obtained drug particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and coating solution (c-3) was sprayed to coat 200 parts by mass of aminoalkyl methacrylate copolymer E with respect to 100 parts by mass of silodosin to obtain masking particles. Next, 500 g of the obtained masking particles were placed in a fluidized bed granulator dryer (MP-01, manufactured by Powrex Corporation), and coating solution (c-2) was sprayed to coat 10 parts by mass with respect to 100 parts by mass of the masking particles. The obtained granules were sieved using a No. 30 sieve to obtain overcoated masking particles (a-11). 721.6 mg of overcoated masking particles (a-11), 2918.4 mg of granulated product (b-1), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 80 mg of sodium stearyl fumarate (manufactured by Pharmatrans Sanaq AG) were mixed to obtain a mixture for tableting. This mixture for tableting was tableted using a single-punch tableting machine (N-30E, manufactured by Okada Seiko Co., Ltd.) under the conditions of a pestle diameter of 8 mm and a tableting pressure of about 7 kN to obtain tablets with a mass of 200.0 mg containing 4 mg of silodosin per tablet.

[0065] Comparative Example 1 100 g of silodosin, 300 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.), 75 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were mixed using a fluidized bed granulation dryer (MP-01, manufactured by Powrex Co., Ltd.). To this, 166.7 g of a vinyl acetate resin aqueous dispersion with a solid content concentration of 30% (manufactured by BASF), 2.5 g of triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.), 37.5 g of polyvinylpyrrolidone (manufactured by ISP), and purified water were mixed. Further, 25 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) was added and mixed, and the resulting coating solution was sprayed with a spray nozzle to perform granulation. The obtained granulated product was sized using a sizing machine (P-02S, manufactured by Dalton Co., Ltd.) with a screen size of φ0.55 mm to obtain masking particles (a-12). 492 mg of masking particles (a-12), 3138.0 mg of granulated product (b-1), 280 mg of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 60 mg of calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), and 20 mg of light anhydrous silicic acid (manufactured by Freund Industry Co., Ltd.) were mixed to obtain granules with a mass of 199.5 mg containing 4 mg of silodosin per tablet.

[0066] Table 5 shows the results of the average particle diameter of the masking particles measured in Test Examples 1 to 7, and the bitterness, time until the onset of bitterness, in-mouth disintegration time, hardness, and dissolution rate of the granules and tablets containing the masking particles.

[0067]

Table 5

[0068] Table 6 shows the masses of silodosin, drug particles, non-enteric polymer, and masking particles contained in the unit dosage form and the total mass per unit dosage form.

[0069] [Table 6]

Industrial Applicability

[0070] According to the present invention, a novel oral dosage form can be provided, which has elution properties that enable silodosin, an extremely bitter drug, to be taken without a foreign body sensation and even without water, and can reproduce a blood concentration effective for the treatment of dysuria associated with benign prostatic hyperplasia.

Claims

1. Masking particles obtained by granulating or coating drug particles containing microsized powder of cilodosin with a coating agent containing a non-enteric polymer, wherein the non-enteric polymer content is 80 parts by mass to 400 parts by mass with respect to 100 parts by mass of cilodosin.

2. The masking particles according to claim 1, wherein the dissolution rate after 15 minutes at pH 6.8 of the oral dosage form containing the masking particles is 85% or more.

3. The masking particles according to claim 1 or 2, wherein the time to start feeling bitterness in the human bitterness sensory test of the oral dosage form containing the masking particles is 30 seconds or more.

4. The masking particles according to any one of claims 1 to 3, wherein the drug particles containing microsized powder of cilodosin are a mixture of cilodosin and an additive.

5. The masking particles according to claim 4, wherein the drug particles containing microsized powder of cilodosin are a granulated product of cilodosin and an additive.

6. The masking particles according to claim 4 or 5, wherein the additive is at least one additive selected from sugars or sugar alcohols and starches.

7. The masking particles according to any one of claims 1 to 6, wherein the non-enteric polymer is a gastric-soluble polymer.

8. The masking particles according to any one of claims 1 to 6, wherein the non-enteric polymer is ethylcellulose, polyvinyl acetal diethylaminoacetate or aminoalkyl methacrylate copolymer E.

9. The masking particles according to any one of claims 1 to 8, wherein the non-enteric polymer content is 100 parts by mass to 200 parts by mass with respect to 100 parts by mass of cilodosin.

10. The masking particles according to any one of claims 1 to 9, wherein the cilodosin content in the masking particles is 5 to 25% by mass.

11. The masking particles according to any one of claims 1 to 10, wherein the non-enteric polymer content in the masking particles is 15 to 30% by mass.

12. The masking particles according to any one of claims 1 to 10, wherein the non-enteric polymer content is 20 parts by mass to 40 parts by mass with respect to 100 parts by mass of the drug particles.

13. An oral dosage form containing the masking particles according to any one of claims 1 to 12.

14. An oral dosage form containing the masking particles according to claim 13, wherein the dosage form is a tablet.

15. (a) A step of preparing drug particles by mixing or granulating fine powder of silodosin and an additive, and (b) A step of preparing masking particles, which comprises granulating or coating the drug particles obtained in step (a) with a coating agent containing a non-enteric polymer, wherein the content of the non-enteric polymer is 80 to 400 parts by mass with respect to 100 parts by mass of silodosin.

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