JP6427634B1 - An oral solid preparation containing silodosin excellent in light stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral solid preparation excellent in photostability in which degradation of silodosin by light is suppressed.
SOLUTION: The present invention relates to an oral solid preparation such as an orally disintegrating tablet or the like which separately contains a drug granule containing shirodocin and a light stabilizer. The light stabilizer includes titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, food yellow No. 4, food yellow No. 5, food yellow No. 4 aluminum lake, food red No. 2, food edible It is preferred to be selected from the group consisting of Red No. 3 and Edible Red No. 102.
[Selected figure] None

Description

  The present invention relates to an oral solid preparation containing silodosin having excellent photostability, and more particularly, to an oral solid preparation which is inhibited from degradation by light of silodosin which is relatively unstable to light. Specifically, the present invention relates to an oral solid preparation which separately contains a drug granule containing shirodocin and a light stabilizer.

Silodosin is an agent for treating urination disorder that has a selective urethral smooth muscle contraction inhibitory action and does not cause a strong blood pressure lowering action (see, for example, Patent Document 1), and urination disorder associated with prostatic hyperplasia It is widely used as a therapeutic agent. Capsules and tablets (film-coated tablets) (see, for example, Patent Documents 2 and 3) are known as pharmaceutical preparations containing shirodocin, which are marketed as Uleaf (registered trademark) tablets and used in medical practice There is. These dosage forms need to be taken with water, and contain titanium oxide in the body of the capsule and the film-coated portion of the tablet for the stabilization of silodosin against light. In recent years, development of a preparation that can be easily taken without water is required as a preparation that is easy to take even for patients who have difficulty swallowing such as elderly people. Several orally disintegrating tablets of silodosin have been reported as one of the preparations intended to improve adherence (see, for example, Patent Documents 4 and 5).
JP-A-2017-048174 (Patent Document 4) discloses an orally disintegrating tablet comprising silodosin-containing coated particles coated with a water-soluble polymer or an enteric polymer containing a pH adjuster. WO 2014/157137 (patent document 5) contains masking particles obtained by granulating or coating drug particles containing fine powder of silodosin with a coating agent containing non-enteric polymer, and the masking particles An orally disintegrating tablet is disclosed.
However, Patent Documents 4 and 5 do not describe specific means for suppressing the degradation of shirodocin to light.

As a method of suppressing the decomposition of shirodocin to light, a method of adding a light-shielding agent to a tablet, a method of physically shielding shirodocin and light in a form such as a dry tablet, and the like are known. , Patent documents 6-8).
JP-A-2013-532651 (patent document 6) discloses a drug for oral administration containing a mixture of shirodocin and a basic polymer as an oral drug having improved storage stability under the action of light and temperature. There is.
JP-A-2016-210760 (Patent Document 7) discloses a tablet containing silodosin containing a light shielding agent and silodosin and colored in a color selected from pale yellow, yellow, pale red, and red. It is done.
Japanese Patent Application Laid-Open No. 2017-014151 (Patent Document 8) discloses a cored tablet in which the periphery of an inner core tablet containing shirodocin is covered with an outer layer obtained by compression molding of granular material. It is generally considered that special punches, dies and tableting machines are required to produce such dry-coated tablets.
However, in any of the documents, the constitution relating to the oral solid preparation which separately contains the drug granule containing shirodocin of the present invention and the light stabilizer, is not described, and it can be easily manufactured. Formulation development is desired.

Japanese Patent Application Laid-Open No. 6-220015 International Publication WO2004 / 054574 Brochure JP 2008-44960A JP, 2017-048174, A International Publication WO 2014/157137 Brochure Japanese Patent Application Publication No. 2013-532651 JP, 2016-210760, A JP 2017-014151 A

  An object of the present invention is to provide an oral solid preparation excellent in photostability in which degradation of silodosin by light is suppressed.

In producing the oral solid preparation of the present invention, silodosin had various points to be overcome due to its characteristics. Silodosin is relatively unstable to light, and in addition to the increase in analogues derived from silodosin and discoloration of tablets caused by light, it is easily decomposed by excipients and the like widely used as pharmaceutical additives. It has chemical properties.
As a result of intensive studies to solve the above problems while the present inventors overcome these points, the present inventors have surprisingly found that they separately contain a drug granule containing shirodocin and a light stabilizer. In the present invention, it has been found that an oral solid preparation exhibiting extremely desirable performance can be obtained, such as suppressing degradation of shirodocin by light and achieving light stability equivalent to that of Yulief (registered trademark) tablets, thus completing the present invention. did.

That is, the present invention
[1] An oral solid preparation which separately contains a drug granule containing shirodocin and a light stabilizer;
[2] The oral solid preparation according to the above [1], which contains a light stabilizer as a granule containing a light stabilizer or a posterior powder component separately from the drug granules containing shirodocin;
[3] The oral solid preparation according to the above [1] or [2], wherein the drug granules containing shirodocin are masking particles;
[4] An oral solid preparation according to any one of the above [1] to [3], which is an orally disintegrating tablet;
[5] Light stabilizers are titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, food yellow No. 4, food yellow No. 5, food yellow No. 4 aluminum lake, food red No. 2, The oral solid preparation according to any one of the above [1] to [4], which is one or more selected from the group consisting of food red No. 3 and food red No. 102;
[6] Any of the above-mentioned [1] to [4], wherein the light stabilizer is one or more selected from the group consisting of titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide and ferric oxide Oral solid preparation described in
[7] The light stabilizer according to any one of the above [1] to [4], which is one or more selected from the group consisting of yellow iron oxide, yellow ferric oxide, brown iron oxide and ferric oxide Oral solid dosage form;
[8] At least one light stabilizers selected from the group consisting of food yellow No. 4, food yellow No. 5, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3 and food red No. 102 An oral solid preparation according to the above [1] to [4];
[9] The oral solid preparation according to the above [1] to [4], wherein the light stabilizer is one or more selected from the group consisting of yellow ferric oxide and ferric oxide;
[10] The oral solid preparation according to the above [9], which is a pale yellow, pale red or pale horizontal colored tablet.
[11] The oral solid preparation according to any one of the above [1] to [10], wherein the content of the light stabilizer is 0.05 to 1.0% by weight based on the total weight of the tablet;
[12] The oral solid preparation according to any one of the above [1] to [11], wherein the content of the light stabilizer is 0.1 to 0.2% by weight based on the total weight of the tablet;
[13] The oral solid preparation according to any one of the above [1] to [12], wherein the content of total related substances of silodosin after receiving a total illuminance of 1.2 million lx · hr at a light intensity of 4000 lx is 5% or less;
[14] The process according to any one of the above [1] to [13], which comprises the step of mixing and tableting a mixture of tablet containing a drug granule containing silodosin, a light stabilizer and a lubricant. A method of producing an oral solid preparation;
And so on.

Silodocin used in the present invention may be commercially available, or may be produced by a method described in the literature (see, for example, Patent Document 1) or a method analogous thereto.
The silodosin used in the present invention may be any particle that does not have agglomerated clumps, and may be crushed or crushed if necessary. The average particle diameter of shirodocin is preferably about 50 μm or less, and more preferably about 1 to 30 μm.

In the present invention, "a drug granule containing silodosin" is a drug particle which is a granulated product containing silodosin and a suitable additive, or a coating containing silodosin and a suitable additive and containing a non-enteric polymer. Agents are masking particles that mask the bitter taste of shirodocin, for example, drug particles obtained by granulating silodosin and an appropriate additive, drug particles obtained by coating an appropriate additive with Masking particles obtained by granulating or coating a mixture with an additive with a coating agent containing a non-enteric polymer, drug particles obtained by granulating shirodocin and an appropriate additive, are highly enteric-free The masking particle etc. which are obtained by coating with the coating agent containing a molecule | numerator are mentioned.
The silodosin-containing drug granules are preferably a masking particle obtained by granulating or coating a mixture of silodosin and an appropriate additive with a coating agent containing a non-enteric polymer, or a suitable mixture with silodosin. It is a masking particle obtained by coating drug particles obtained by granulating an additive with a coating agent containing a non-enteric polymer, and more preferably obtained by granulating silodosin and a suitable additive. Drug particles are coated with a coating agent containing a non-enteric polymer.

In the present invention, the “light stabilizer” may be any additive capable of preventing or reducing degradation or photodegradation of shirodocin when exposed to light (such as sunlight or indoor light), for example, food Foods such as Yellow No. 4, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Blue No. 1, Food Blue No. 2, Food Blue No. 2 Aluminum Lake, etc. Examples thereof include dyes, titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide and the like which are conventionally used as a light shielding agent or a colorant, as long as the invention is not hindered. The light stabilizers may be used alone or in combination of two or more.
The light stabilizer is preferably titanium oxide, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide and the like, more preferably yellow ferric oxide and ferric oxide, and yellow ferric oxide. It is particularly preferred to use in combination with ferric oxide.
In the present invention, the light stabilizer content is preferably in the range of 0.01 to 5.0% by weight based on the total weight of the tablet, and more preferably 0.05 to 1.0. It is preferable that the content is in the range of 0.1% to 0.2% by weight.
In the present invention, the oral solid preparation containing shirodocin is not necessarily required to be colored depending on the kind of light stabilizer and the content in the preparation, but light yellow, yellow, light yellow red, light red, and red It is preferable that it is colored in a selected color, more preferably pale yellow, pale yellow red, pale red, and more preferably pale red, pale yellow red.

In the present invention, “the drug granules containing shirodocin and the light stabilizer are separately contained” may be in contact with drug granules containing shirodocin in an oral solid preparation, but Means being separated and containing a light stabilizer, for example, containing a light stabilizer as a granule containing the light stabilizer or as a posterior powder component separately from the drug granules containing silodosin, etc. It can be mentioned. Preferably, a light stabilizer is contained as a posterior component separately from the drug granules containing shirodocin.
In the present invention, “post-end ingredient” means an additive (pharmaceutical additive) added to the outside of granulated granules.

  In the present invention, the "non-enteric polymer" refers to a polymer insoluble in water other than the enteric polymer, and includes, for example, a stomach-soluble polymer or a water-insoluble polymer. As the gastric soluble polymer, for example, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer such as aminoalkyl methacrylate copolymer E (for example, Eudragit (registered trademark) EPO, Eudragit (registered trademark) E100), etc. Examples thereof include gastric-soluble polyvinyl derivatives such as methyl methacrylate-diethylaminoethyl methacrylate copolymer (for example, Kollicoat (registered trademark) Smart Seal 30D), polyvinyl acetal diethylamino acetate (for example, AEA (registered trademark)), and the like. Examples of the water-insoluble polymer include ethyl acrylate-methyl methacrylate copolymer such as ethyl acrylate-methyl methacrylate copolymer dispersion (for example, Eudragit (registered trademark) NE30D), aminoalkyl methacrylate copolymer RS (for example, Eudragit (R) RS 100, Eudragit (R) RSPO, Eudragit (R) RL, Eudragit (R) RLPO, and aminoalkyl methacrylate copolymer RS water dispersions (e.g. Eudragit (R) RS 30 D, Eudragit ( Water-insoluble acrylic acid copolymers such as ethyl acrylate-methyl methacrylate-methacrylated trimethyl ammonium ethyl copolymer such as RL 30 D)), ethyl cellulose (eg Etcel (registered trademark)), ethyl cellulose Examples include water-insoluble dispersions (for example, water-insoluble cellulose ethers such as Aquacoat (registered trademark), vinyl acetate resins (for example, Kollicoat (registered trademark) SR, Kolicoat (registered trademark) SR30D), and the like. The non-enteric polymer is preferably ethyl cellulose or a stomach-soluble polymer, more preferably ethyl cellulose, aminoalkyl methacrylate copolymer E or polyvinylacetal diethylaminoacetate, more preferably ethyl cellulose or aminoalkyl methacrylate copolymer E, more preferably Preferred is aminoalkyl methacrylate copolymer E. These non-enteric polymers may be used in combination of two or more as needed.

In the present invention, the coating agent containing the non-enteric polymer may contain, in addition to the above-mentioned non-enteric polymer, an additive, a water-soluble polymer and the like as required. When a water-soluble polymer is used, 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. As an additive, a plasticizer, a lubricant, surfactant, etc. are mentioned, for example. Examples of the plasticizer include stearic acid, triacetin, triethyl citrate, macrogol, glycerin, glycerin fatty acid ester, castor oil, diethyl sebacate, dibutyl sebacate and the like. As the lubricant, for example, talc, stearic acid, magnesium stearate, calcium stearate and the like can be mentioned. As surfactant, sodium lauryl sulfate, polysorbate, etc. are mentioned, for example. Examples of the water-soluble polymer include hypromellose, methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, carmellose sodium, sodium alginate and the like. These additives and water-soluble polymers can be used alone or in combination of two or more.
In the present invention, the content of the non-enteric polymer is, 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 100 parts by mass of silodosin, for example. 300 parts by mass, 100 to 200 parts by mass and the like can be mentioned, and more preferably 100 to 200 parts by mass.
In the present invention, the content of the non-enteric polymer in the masking particles is preferably 15 to 30% by mass, more preferably 15 to 25% by mass.
In the present invention, the content of the non-enteric polymer is, for example, about 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. It is a department.
In the present invention, “average particle size” means 50% particle size (mass-based median size). The 50% particle size can be measured by a sieving particle size distribution measuring apparatus (for example, Robot Shifter RPS-205, manufactured by Seishin Enterprise Co., Ltd.).
In the present invention, the average particle size of the masking particles is, for example, about 300 μm or less, preferably about 100 to 250 μm.

  As an additive used for the drug granules containing shirodocin, various additives which do not cause a formulation change with silodosin can be used. For example, disintegrant, excipient, binder, lubricant, sweetening agent, An acidulant, a foaming agent, a fragrance, etc. can be used suitably. As the disintegrant, for example, low substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, rice starch, corn starch, potato starch, carboxymethyl starch sodium, carmellose, partially pregelatinized starch, pregelatinized Starch, crospovidone, crystalline cellulose and the like can be mentioned. As an excipient, for example, rice starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, trehalose, crystalline cellulose, magnesium aluminum metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate Lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like. Examples of the binder include starches, crystalline cellulose, hydroxypropyl cellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like. As the lubricant, for example, magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, glycerin monostearate and the like can be mentioned. Examples of sweetening agents include aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame potassium, sucralose and the like. Examples of the acidulant include citric acid, tartaric acid, malic acid, ascorbic acid and the like. As a foaming agent, sodium hydrogencarbonate, sodium carbonate, calcium carbonate etc. are mentioned, for example. Examples of the flavoring agent include L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, L-glutamate sodium, sodium hydrogen carbonate and the like. Examples of the flavor include strawberry, yoghurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, green tea and the like.

In the present invention, the following additives can be mentioned as preferable additives used for shirodocin-containing drug granules.
As the excipient or disintegrant, for example, sugar or sugar alcohol and starches are preferable. Examples of the sugar or sugar alcohol include D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like, with D-mannitol being more preferable. Examples of 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 needed.
In the present invention, the content of silodosin in the masking particles is preferably 30% by mass or less, more preferably 5 to 25% by mass, and still more preferably 5 to 16% by mass.
In the present invention, the content of silodosin in the drug particles is preferably 50% by mass or less, and for example, 10 to 40% by mass, 10 to 30% by mass, 20 to 27% by mass or the like.

(Method for producing drug granules containing silodosin)
In the present invention, a drug granule containing shirodocin can be produced by a method generally used in the production of drug particles and masking particles.
For example, a drug particle containing silodosin can also be produced by granulating a mixture of silodosin and an additive with a solution of a water soluble binder. Moreover, it can also be manufactured by coat | covering the nucleus particle | grains, such as commercially available or granulated crystalline cellulose, D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, sucrose, with the dispersion containing silodosin.
For example, masking particles containing silodosin can be produced by methods generally used in producing masking particles, such as nuclear granule coating method, granulation matrix method, granulation coating method and the like. For example, it can also be produced by granulating or coating a mixture of shirodocin and an additive with a coating agent containing a non-enteric polymer. Alternatively, masking particles can also be produced by granulating or coating the above-mentioned drug substance containing shirodocin with a coating agent containing non-enteric polymer. In this series of production, as a method for granulation or coating, a high speed mixing and stirring granulation method, a tumbling fluidized bed granulation method, a fluidized bed granulation method and the like can be mentioned, and a fluidized bed granulation method is preferable.
Specifically, for example, in the nuclear granule coating method, commercially available or granulated crystalline cellulose such as D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, sucrose and the like, dispersion containing silodosin and non-silodosin Masking particles can also be produced by sequentially coating with a solution or dispersion of a coating agent containing an enteric polymer, or by coating a mixture thereof.

Also, for example, in the granulation matrix method, a coating containing a non-enteric polymer, and a mixture of silodosin and additives (eg, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) The masking particles can also be produced by granulation or coating while spraying a solution or dispersion of the agent.
Also, for example, in the granulation coating method, a mixture of shirodocin and an additive (for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) is sprayed with a solution of a water-soluble binder. After granulating and granulating, masking particles can also be produced by coating the obtained granulated product while spraying a solution or dispersion of a non-enteric polymer-containing coating agent. As a water soluble binder, hydroxypropyl cellulose and hypromellose are preferable.
Among the above methods, a granulation matrix method or a granulation coating method is preferable, and a granulation coating method is more preferable.

  The solvent used to dissolve or disperse 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, mixed solvents of these, and the like. , Ethanol and water are preferred, and water is more preferred. Aminoalkyl methacrylate copolymer E is insoluble in water, but used as an aqueous solution dissolved in acidic (pH 5 or less) water, or selected from sodium lauryl sulfate and stearic acid, diethyl sebacate and dibutyl sebacate for amino alkyl methacrylate copolymer E It is also possible to use an aqueous dispersion in which at least one plasticizer is mixed in any proportion.

(Overcoat of drug granules containing silodosin)
In the present invention, the drug granules containing shirodocin may be overcoated with further suitable additives, if necessary. Examples of the additive used for the overcoat include sugars such as lactose, glucose, sucrose and fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and sugar alcohols such as maltitol, and preferably D-mannitol. The overcoat may contain a light stabilizer.
The method of overcoating is not particularly limited, but, for example, in the present invention, an aqueous solution of an additive (for example, sugar or sugar alcohol) in a drug particle or masking particle containing silodosin (if necessary, a light stabilizer) Can be produced by coating while spraying. The content of the additive used in the overcoat is usually 1 to 20 parts by mass, preferably 2 to 15 parts by mass, and more preferably 5 to 15 parts by mass with respect to 100 parts by mass of the drug granules (masking particles) containing silodosin. It is 10 parts by mass.

(Oral solid preparation)
The oral solid preparation of the present invention can be produced by a method conventionally used in the pharmaceutical field, using drug granules containing shirodocin, a light stabilizer, and pharmaceutical additives generally used for an oral fast disintegrating preparation. it can. The dosage form of the oral solid preparation of the present invention includes, for example, tablets, orally disintegrating tablets and the like, preferably, orally disintegrating tablets.
Further, in the present invention, the tablet and the orally disintegrating tablet are preferably uncoated tablets, but can be covered with a film coating layer as required. As an additive which can be used for a film coating layer, Preferably hypromellose, a polyvinyl alcohol * acrylic acid * methyl methacrylate copolymer, polyvinyl alcohol, polyethyleneglycol etc. can be mentioned, More preferably, it is a hypromellose. The film coating layer may optionally contain a light stabilizer.

For example, in the case of tablets and orally disintegrating tablets, a direct powder compression method (a direct compression method) is used along with light stabilizers and pharmaceutical additives generally used for oral fast disintegrating formulations, which contain silodosin. An oral solid preparation can also be produced by tableting according to a known method such as granulation method, or a method according thereto.
Specifically, for example, in the direct hitting method, a mixture containing a drug granule containing silodosin and a light stabilizer, and a pharmaceutical additive such as an excipient, a disintegrant, a binder, a lubricant and the like is granulated. Alternatively, after mixing using a mixer, it is possible to produce an oral solid preparation by tableting.
Also, for example, in the granulation method, after a mixture of an excipient, a disintegrant and the like is granulated with water, a mixture of water and ethanol or a solution or suspension of a binder or disintegrant, etc. After mixing with drug granules to be contained, a light stabilizer as a final component, a lubricant and the like using a mixer, it is also possible to produce an oral preparation by tableting. In addition, after a mixture of an excipient, a disintegrant, a light stabilizer, etc. is granulated with water, a mixture of water and ethanol or a solution or suspension of a binder or disintegrant, etc., it contains sirodocin. After mixing with drug granules, lubricants and the like using a mixer, it is also possible to produce an oral solid preparation by tableting. Furthermore, a mixture of an excipient, a disintegrant, etc. was granulated with an aqueous solution or suspension of a light stabilizer, etc., and then mixed with silodosin-containing drug granules, lubricants, etc. using a mixer. Thereafter, it can be tableted to produce an oral solid preparation.

  As a pharmaceutical additive generally used for an oral fast disintegrating preparation, an additive used for the above drug granules can be used, but as a disintegrant, partially pregelatinized starch, crospovidone, low substitution degree of hydroxy Propyl cellulose, carmellose calcium, carmellose sodium, corn starch and the like are preferable. As the excipient, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, sugar alcohols such as maltitol, corn starch, crystalline cellulose and the like are preferable. As the lubricant, sodium stearyl fumarate, calcium stearate, talc, light anhydrous silicic acid and the like are preferable. These pharmaceutical additives may be used in combination of two or more as needed.

(Production example of oral solid preparation)
Hereinafter, although the manufacturing method of the oral solid preparation of this invention is illustrated, it is not restricted to this.

Production Example 1
For example, drug granules containing shirodocin, light stabilizers and sugars, sugars such as fructose, D-mannitol, sugar alcohols such as erythritol, xylitol, rice starch, corn starch, corn starch, potato starch, starches such as partially pregelatinized starch Mixing at least one pharmaceutical additive selected from microcrystalline cellulose, crospovidone, sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid using a mixer, and then tableting the mixture Can also produce tablets. In the mixing step, if necessary, one or more of an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a flavor and the like are further added in combination. You may

Production Example 2
For example, 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 Granules (1) can also be produced by mixing at least one pharmaceutical additive selected from cellulose and crystalline cellulose and granulating while spraying a solution or dispersion of partially pregelatinized starch or crospovidone. . The mixing and granulation processes can be performed by a high speed mixing and stirring granulation method, a tumbling fluidized bed granulation method, a fluidized bed granulation method or the like, and preferably a fluidized bed granulation method. Next, a mixer containing at least one lubricant selected from silodosin-containing drug granules, light stabilizers, the granules (1), and further sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid is used. Tablets can also be produced by tableting, after use and mixing. In the mixing step, if necessary, one or more of an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a flavor and the like are further added in combination. You may

Production Example 3
For example, 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 Granules (2) can also be produced by mixing at least one pharmaceutical additive selected from class and crystalline cellulose and granulating while spraying water or a mixture of water and ethanol. The mixing and granulation processes can be performed by a high speed mixing and stirring granulation method, a tumbling fluidized bed granulation method, a fluidized bed granulation method or the like, and preferably a fluidized bed granulation method. Next, a mixer containing at least one lubricant selected from silodosin-containing drug granules, light stabilizers, the granules (2), and further sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid is used. Tablets can also be produced by tableting after use and mixing. In the mixing step, if necessary, one or more of an excipient, a disintegrant, a binder, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a flavor and the like are further added in combination. You may

Production Example 4
For example, a mixture of D-mannitol and crystalline cellulose is mixed using a fluid bed granulator / dryer, and the mixture is granulated while spraying an aqueous dispersion of crospovidone to this, and then it is sieved using a granulator. It is also possible to granulate and produce granules (3). Subsequently, a tablet can also be produced by tableting the drug granules containing shirodocin, the photostabilizer, the granules (3) and sodium stearyl fumarate using a mixer and then tableting. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a flavor and the like may be further added in combination of one or more.

Production Example 5
For example, a mixture of D-mannitol, crystalline cellulose and crospovidone is mixed using a fluid bed granulator / dryer and granulated while this is sprayed with water, and then sized using a granulator. , Granules (4) can also be produced. Subsequently, a tablet can also be produced by tableting after mixing the sirodosin-containing drug granules, the light stabilizer, the granules (4) and the sodium stearyl fumarate using a mixer. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a flavoring agent, a fluidizing agent, a flavor and the like may be further added in combination of one or more.

Production Example 6
In Production Example 4 or 5 above, tablets can also be produced by producing in the same manner as in Production Example 4 or 5 using corn starch in place of microcrystalline cellulose and partially pregelatinized starch in place of crospovidone.

  In the present invention, "granulation", "coating", "mixing" and "tabletting" may be carried out using conventional methods in the field of formulation technology. For "granulation" and "coating", for example, a fluidized bed granulator, a tumbling 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 bole container or the like can also be used. As the “tablet”, for example, a single-shot tableting machine, a rotary tableting machine or the like can be used. The tableting pressure is, for example, 1 to 20 kN, preferably 2 to 15 kN.

  In the present invention, the masking particles and the oral solid preparation containing the same exhibit a good bitter taste masking effect.

  The oral solid preparation of the present invention exhibits rapid dissolution independently of pH in the digestive tract.

The oral solid preparation of the present invention is preferably one that disintegrates in a short time in the oral cavity to be taken without water. For example, in the oral cavity disintegration test, the average oral cavity disintegration time may be adjusted so as to be usually within 60 seconds, preferably 40 seconds, more preferably 30 seconds.
The oral solid preparation of the present invention preferably has an appropriate hardness from the viewpoint of convenience of production and transportation and the like. For example, in the hardness test, it may be adjusted to be usually 20 N or more, preferably 30 N or more, and more preferably 40 N or more.
The oral disintegration time and hardness can be adjusted appropriately by selecting the type and amount of the pharmaceutical additive, the production method (for example, granulation method etc.), production conditions (for example tableting pressure etc.), etc. .

In the oral solid preparation of the present invention, the silodosin content per tablet is usually 2 to 8 mg, preferably 2 mg, 4 mg or 8 mg.
In the case of tablets and orally disintegrating tablets, the oral solid preparation of the present invention can be, for example, 50 to 500 mg, 50 to 300 mg, 100 to 250 mg, 100 to 200 mg, and the like per tablet mass. As a silodosin content in that case, 0.4 to 16% can be mentioned.

  When the oral solid preparation of the present invention is used for actual treatment, the dose of the active ingredient is appropriately determined according to the sex, age, body weight of the patient, degree of disease, etc. It can be dosed in the range of Preferably, 2 to 8 mg is orally administered once or twice a day per adult daily.

  The oral solid preparation of the present invention is very simple and can suppress the generation of a degradation product derived from shirodocin (in particular KMD-3241) by light by the incorporation of a slight amount of a light stabilizer. It is useful as an oral solid preparation excellent in light stability in which degradation by light is suppressed.

  The contents of the present invention will be explained in more detail by the following test examples, examples and comparative examples, but the contents of the present invention are not limited thereto.

Example 1
720 g of silodosin, 2649.6 g of partially pregelatinized starch (manufactured by Nippon Colorcon) and 180 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) are mixed using a fluid bed granulator / dryer (FLO-5MEX, manufactured by Freund Sangyo Co., Ltd.), Granulation was performed while spraying a solution prepared by adding 50.4 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water using a spray nozzle. The obtained granulated material was sized with a screen size of 10.991 mm using a sizing machine (Cormill, manufactured by Powrex Corp.) to obtain drug particles.
Meanwhile, 1574.4 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan), 157.4 g of sodium lauryl sulfate (manufactured by Kao), 236.2 g of stearic acid (manufactured by Mallinklot) and 551.0 g of talc (manufactured by Matsumura Sangyo) The mixture was added to water to obtain a coating solution (c-1).
Further, 433.2 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.) was added to purified water to obtain a coating solution (c-2).
The obtained drug particles 3200 g were placed in a fluid bed granulator dryer (FLO-5MEX, manufactured by Freund Corporation), and the coating solution (c-1) was sprayed to obtain aminoalkyl methacrylate per 100 parts by mass of silodosin. 200 parts by weight of copolymer E were coated. The obtained coated granules were sized with a screen size of φ0.991 mm using a sizing machine (Cormill, manufactured by Powrex Corp.) to obtain masking particles.
Next, the coating liquid (c-2) was sprayed on the obtained masking particles to coat 10 parts by mass with respect to 100 parts by mass of the masking particles. The obtained coated granules were sized with a screen size of φ0.991 mm using a sizing machine (Cormill, manufactured by Powrex Corp.) to obtain overcoated masking particles (a-1).
D-Mannitol (manufactured by Mitsubishi Foodtech) 80-7.5 D-Mannitol (manufactured by Mitsubishi Foodtech) manufactured by the screen size φ 1.0 mm using a particle sizer (P-02S, manufactured by Dalton) A granulated product (b-1) was obtained according to a conventional method using 42.5 g of low substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.).
90.25 g of overcoated masking particles (a-1), 364.5 g of granules (b-1), 35 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), 10 g of sodium stearyl fumarate (manufactured by PHARMATRANS SANAQ AG), 0.5 g of yellow ferric oxide (manufactured by Tokai Kasei Co., Ltd.) was mixed to obtain a mixture for tableting. This tableting mixture is tableted using a rotary tableting machine (CLEANPRESS Correct 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) under conditions of 8 mm die and tableting pressure of about 5 kN, and a mass containing 4 mg of silodosin per tablet 200.1 mg tablets were obtained.

Example 2
4400 g of silodosin, 16192 g of partially pregelatinized starch (manufactured by Nippon Colorcon), and 1100 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) are mixed using a fluid bed granulator / dryer (NFLO-30SJC, manufactured by Freund Sangyo Co., Ltd.), Granulation was performed while spraying a solution prepared by adding 308 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water using a spray nozzle. The obtained granulated material was sized with a screen size of 10.991 mm using a sizing machine (Cormill, manufactured by Powrex Corp.) to obtain drug particles.
Meanwhile, 5687.5 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan), 568.8 g of sodium lauryl sulfate (manufactured by Kao), 853.1 g of stearic acid (manufactured by Mallinklot) and 1990.6 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were purified The mixture was added to water to obtain a coating solution (c-3).
Further, 2535 g of D-mannitol (manufactured by Mitsubishi Foodtech Co., Ltd.) was added to purified water to obtain a coating solution (c-4).
16250 g of the obtained drug particles are placed in a fluidized bed granulator / dryer (NFLO-30SJC, manufactured by Freund Corporation), and the coating solution (c-3) is sprayed to obtain aminoalkyl methacrylate per 100 parts by mass of silodosin. 175 parts by weight of copolymer E was coated to obtain masking particles.
Next, the coating liquid (c-4) was sprayed on 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-2).
Granulated product was produced twice according to a conventional method using 19325.6 g of D-mannitol (manufactured by Freund Corporation), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals) and 1700 g of crospovidone (manufactured by ISP) I got (b-2).
10296 g of overcoated masking particles (a-2), 44304 g of granules (b-2), 4200 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), 30 g of ferric oxide (manufactured by Toka Kasei Co., Ltd.), yellow three 60 g of iron dioxide (manufactured by Toka Kasei Co., Ltd.), 1200 g of stearyl sodium fumarate (manufactured by PHARMATRANS SANAQ AG), 30 g of a sweetening agent (manufactured by San-Ei Gen F.F. I.) and 60 (manufactured by Takasago Kogyo Co., Ltd.) The g was mixed to obtain a mixture for tableting. This tableting mixture is tableted using a rotary tableting machine (HT-X20SS-UW, manufactured by Hatako Shoji Co., Ltd.) under a condition of 8 mm die and a tableting pressure of about 7 kN, and silodosin 4 mg per tablet Tablets having a weight of 200.6 mg were obtained.

Example 3
90.25 g of overcoated masking particles (a-1), 364 g of granules (b-1), 35 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.), 10 g of stearyl sodium fumarate (manufactured by PHARMATRANS SANAQ AG), A mixture for tableting was obtained by mixing 0.5 g of ferric oxide (manufactured by Tokai Kasei Co., Ltd.) and 0.5 g of yellow ferric oxide (manufactured by Tokai Kasei Co., Ltd.). This tableting mixture is tableted using a rotary tableting machine (CLEANPRESS Correct 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) under conditions of 8 mm die and tableting pressure of about 5 kN, and a mass containing 4 mg of silodosin per tablet 200.1 mg tablets were obtained.

Comparative Example 1
90.25 g of overcoated masking particles (a-1), 365 g of granules (b-1), 35 g of corn starch (manufactured by Nippon Food Chemical Co., Ltd.) and 10 g of sodium stearyl fumarate (manufactured by PHARMATRANS SANAQ AG) It mixed and obtained the mixture for tableting. This tableting mixture is tableted using a rotary tableting machine (CLEANPRESS Correct 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) under conditions of 8 mm die and tableting pressure of about 5 kN, and a mass containing 4 mg of silodosin per tablet 200.1 mg tablets were obtained.

[Test Example 1]
Similar Substance Measurement Test The tablets obtained in Examples 1 to 3 and Comparative Example 1 were subjected to a light stability test.
Each tablet was stored at a temperature of 25 ° C. and 4000 lx (D65 lamp) until it reached about 1.2 million lx · hr, and then the content of related substances was measured. The content of related substances was quantified by liquid chromatography.
Quantitative method A sample equivalent to 20 mg of silodosin is weighed to prepare a sample solution, a test is conducted by liquid chromatography, and the peak area of each is measured by an automatic integration method, and the decomposition product (KMD-3241) and The content (%) of total related substances was determined.

Detector: Ultraviolet absorptiometer (measurement wavelength: 225 nm)

The results of measurement of the contents of degradation products and total similar substances after light irradiation of the tablets produced in Examples 1 to 3 and Comparative Example 1 are shown in Table 1.

  It can be seen from Table 1 that the tablet containing no light stabilizer of Comparative Example 1 has a content of decomposition of more than 1%. On the other hand, it was found that the tablets of Examples 1 to 3 containing the light stabilizer suppress the formation of the degradation product. Therefore, it becomes possible to suppress the degradation of silodosin by light by separately containing the drug granules containing shirodocin and the light stabilizer.

  According to the present invention, it is possible to provide an oral solid preparation excellent in photostability, in which the degradation of silodosin by light is suppressed.

Claims (6)

An orally disintegrating tablet, which separately contains masking particles containing shirodocin and a light stabilizer ,
Light stabilizers yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, food yellow No. 4, food yellow No. 5, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3 and food An orally disintegrating tablet which is one or more selected from the group consisting of Red No. 102. The orally disintegrating tablet according to claim 1 , wherein the light stabilizer is one or more selected from the group consisting of yellow ferric oxide and ferric oxide. The orally disintegrating tablet according to claim 1 or 2 , which is a pale yellow, pale red or pale yellowish red colored tablet . The orally disintegrating tablet according to any one of claims 1 to 3 , wherein the content of the light stabilizer is 0.05 to 1.0% by weight based on the total weight of the tablet . The orally disintegrating tablet according to any one of claims 1 to 3 , wherein the content of the light stabilizer is 0.1 to 0.2% by weight based on the total weight of the tablet . The method for producing the orally disintegrating tablet according to any one of claims 1 to 5 , comprising the step of tableting a tableting mixture containing masking particles containing shirodocin, a light stabilizer and a lubricant.