Enzalutamide tablet

Abstract

To provide a pharmaceutical tablet containing enzalutamide as an active ingredient which has physical properties that a dissolved state of eluted enzalutamide is maintained for a long period.SOLUTION: A pharmaceutical tablet containing enzalutamide as an active ingredient includes a solid dispersion composition containing enzalutamide and water-soluble polymer carrier, disintegrator, and hydroxypropyl methyl cellulose acetate succinate. By prescribing hydroxypropyl methyl cellulose acetate succinate in combination with solid dispersion containing the active ingredient, the concentration of solution of poorly water soluble enzalutamide can be maintained for a long time.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical tablet containing enzalutamide as an active ingredient and a method for producing the same. [Background technology]

[0002] Enzalutamide is an antiandrogen that inhibits the signal transduction of androgen receptor (AR) at multiple stages and is used as a therapeutic agent for castration-resistant prostate cancer. Enzalutamide was initially provided as a capsule formulation. However, since capsule formulations can be difficult to take, tablets that reduce the burden have been developed (Non-Patent Document 1). Enzalutamide is poorly water-soluble, and tablets using a solid dispersion prepared by dispersing enzalutamide in a water-soluble polymer carrier have been reported. Patent Document 1 describes a solid dispersion prepared by spray-drying a solution containing enzalutamide and a non-cellulosic polymer such as an ionizable or non-ionizable cellulose polymer or a carboxylic acid-functionalized poly(meth)acrylate. Patent Document 2 describes a solid dispersion of enzalutamide and polyvinyl alcohol. Patent Document 3 describes a formulation using an adsorbent of enzalutamide prepared on an inorganic carrier such as porous silicon dioxide. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmaceutical Interview Form XTANDI(R) Tablets 40mg, XTANDI(R) Tablets 80mg

[0004] [Patent Document 1] Special table 2015-527411 publication [Patent Document 2] International Publication No. 2018 / 199282 [Patent Document 3] Special Publication No. 2017-507928 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a pharmaceutical tablet having excellent stability of the dissolved state of enzalutamide. [Means for solving the problem]

[0006] [1] A solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier. Disintegrants, as well as hydroxypropyl methylcellulose acetate succinate, A medicinal tablet containing the active ingredient enzalutamide. [2] The pharmaceutical tablet according to [1], containing 5 to 40 parts by mass of hydroxypropyl methylcellulose acetate succinate. [3] The pharmaceutical tablet according to [1] or [2], wherein the water-soluble polymer carrier is one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose, and hydroxypropyl methylcellulose. [4] The pharmaceutical tablet according to any one of [1] to [4], wherein the water-soluble polymer carrier is one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, and hydroxypropylmethylcellulose acetate succinate (HPMCAS). [5] The pharmaceutical tablet according to any one of [1] to [4], wherein the water-soluble polymer carrier is contained in an amount of 0.5 to 5 parts by mass per part by mass of enzalutamide.

[0007] [6] A method for producing a pharmaceutical tablet containing enzalutamide as an active ingredient, comprising: (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant and hydroxypropyl methylcellulose acetate succinate to prepare a granule; (3) mixing the granules with a lubricant and compressing the mixture; A method for producing a pharmaceutical tablet comprising the steps of: [7] A method for producing a pharmaceutical tablet containing enzalutamide as an active ingredient, comprising: (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant to prepare a granule; (3) mixing the granules with hydroxypropyl methylcellulose acetate succinate and a lubricant, and compressing the mixture; A method for producing a pharmaceutical tablet comprising the steps of: Effect of the Invention

[0008] The present invention can provide a pharmaceutical preparation in which the dissolved enzalutamide is stably maintained in a solution state. In addition, as another preferred effect, it can provide a pharmaceutical tablet having excellent dissolution properties of enzalutamide. In addition, as another preferred effect, it can provide a miniaturized tablet that is easy to take. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The pharmaceutical tablet of the present invention uses enzalutamide as an active ingredient. Enzalutamide has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. This compound is reported in Japanese Patent No. 4644737 and can be synthesized by the method described therein. It is desirable to use enzalutamide as a compound of a quality level that allows it to be used as an active ingredient in pharmaceuticals. The active ingredient enzalutamide is preferably used in an amount of 10% by mass to 30% by mass, more preferably 10% by mass to 20% by mass, based on the total weight of the pharmaceutical tablet.

[0010] The present invention is characterized by including a solid dispersion composition containing enzalutamide and a water-soluble polymer carrier. The solid dispersion composition is a composition in which enzalutamide is dispersed in an amorphous state in a water-soluble polymer carrier. Although not particularly limited, for example, it can be prepared by preparing a solution containing enzalutamide, a water-soluble polymer carrier, and any additives, and removing the solvent from the solution (solution method). Alternatively, it can be prepared by heating and melting enzalutamide, a water-soluble polymer carrier, and any additives, and then cooling the solution (hot melt method). In the solution method, a solution containing enzalutamide, a water-soluble polymer carrier, and any additives can be prepared using a solvent that dissolves both of these, and examples of such solvents include ketone solvents such as acetone, methyl ethyl ketone, and methyl-t-butyl ketone; ester solvents such as ethyl acetate and isopropyl acetate; ether solvents such as diethyl ether and diisopropyl ether; alcohol solvents such as methanol, ethanol, and isopropanol; halogen-based solvents such as chloroform and dichloromethane; and water, and these can be used alone or as a mixed solvent. A solution containing enzalutamide and a water-soluble polymer carrier can be subjected to reduced pressure distillation or spray drying to remove the solvent, and then appropriately dried to prepare a solid dispersion composition.

[0011] The water-soluble polymer carrier contained in the solid dispersion composition may be any polymer additive having water solubility that is used as a pharmaceutical additive, and examples thereof include poly(meth)acrylic acid copolymers such as poly(meth)acrylic acid copolymer, poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, etc.; polyvinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, etc.; cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), etc. The water-soluble polymer carrier is preferably one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose, and hydroxypropyl methylcellulose, and more preferably one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, and hydroxypropyl cellulose. More preferably, the copolymer is at least one selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, and hydroxypropylmethylcellulose acetate succinate (HPMCAS), and more preferably, the copolymer is at least one selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, and polyvinylpyrrolidone-polyvinyl acetate copolymer. Particularly preferred is a poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, such as a poly[(meth)acrylic acid-(meth)acrylic acid methyl ester] copolymer or a poly[(meth)acrylic acid-(meth)acrylic acid ethyl ester] copolymer. A preferred embodiment of the present invention is a combination in which a poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer is used as a carrier for the solid dispersion, and hydroxypropylmethylcellulose acetate succinate (HPMCAS), which will be described later, is formulated in the formulation separately from the solid dispersion. The poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymers include Eudragit® L100-55 (poly(methacrylic acid-ethyl ester acrylate) copolymer), Eudragit® L30-D55 (poly(methacrylic acid-ethyl ester acrylate) copolymer), Eudragit® L100 (poly(methacrylic acid-methyl ester methacrylate) copolymer), Eudragit® L12.5 ... They are available as Eudragit® S100 (poly(methacrylic acid-methyl methacrylate) copolymer), Eudragit® S12.5 (poly(methacrylic acid-methyl methacrylate) copolymer), Eudragit® FS100 (poly(methyl acrylate-methyl methacrylate-methacrylic acid) copolymer), Eudragit® FS30D (poly(methyl acrylate-methyl methacrylate-methacrylic acid) copolymer), etc. Poly(methacrylic acid-ethyl acrylate) copolymers are particularly preferred. The water-soluble polymer carrier contained in the solid dispersion composition is used in an amount of 0.5 parts by mass or more and 5 parts by mass or less per 1 part by mass of enzalutamide. It is preferably used in an amount of 1 part by mass or more and 5 parts by mass or less, more preferably 1 part by mass or more and 3 parts by mass or less. It is also preferably contained in an amount of 10% by mass or more and 50% by mass or less with respect to the total amount of the pharmaceutical tablet. It is preferably contained in an amount of 20% by mass or more and 50% by mass or less.

[0012] The solid dispersion may further contain any additives such as a binder, a solubilizer, and an excipient. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these are preferably used alone or in combination of two or more. Preferred are hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, and methylcellulose. Examples of the solubilizing agent include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, polyoxyethylene-polyoxypropylene block copolymer, and the like. Examples of excipients include celluloses such as crystalline cellulose, sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, inositol, and the like, starches such as corn starch, and inorganic salts such as magnesium aluminometasilicate and anhydrous calcium phosphate, and the like. In addition, the formulation may contain conventional pharmaceutical additives within the range that does not reduce the solubility and dissolution property of enzalutamide. When the solid dispersion contains other optional additives such as a binder or a solubilizer, each additive is preferably used in an amount of 0.1% by mass to 10% by mass based on the total weight of the pharmaceutical tablet.

[0013] The pharmaceutical tablet of the present invention contains the solid dispersion composition containing enzalutamide, a disintegrant, and hydroxypropylmethylcellulose acetate succinate. Preferably, it further contains an excipient. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a cellulose derivative that is soluble at pH 5.5 or higher, and is obtained by introducing acetyl and succinoyl groups into hydroxypropyl methylcellulose. HPMCAS-L type has an acetyl group introduction rate of 5-9% and a succinoyl group introduction rate of 14-18%, HPMCAS-M type has an acetyl group introduction rate of 7-11% and a succinoyl group introduction rate of 10-14%, and HPMCAS-H type has an acetyl group introduction rate of 10-14% and a succinoyl group introduction rate of 4-8%. HPMCAS-H type has an acetyl group introduction rate of 10-14% and a succinoyl group introduction rate of 4-8%. Hydroxypropyl methylcellulose acetate succinate is used in an amount of 0.5 to 5 parts by mass per part by mass of enzalutamide. Preferably, it is used in an amount of 1 to 5 parts by mass, more preferably 1 to 3 parts by mass. In addition, it is preferably contained in an amount of 5 to 40% by mass relative to the total amount of the pharmaceutical tablet. Preferably, it is contained in an amount of 5 to 40% by mass, more preferably 10 to 40% by mass, or 20 to 40% by mass.

[0014] Examples of disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose, carmellose calcium, low-substituted carboxymethyl starch sodium, etc., and these are preferably used alone or in combination of two or more. Preferred are croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. More preferred is croscarmellose sodium. When a disintegrant is used, it is preferably used in an amount of 2% by mass to 20% by mass, more preferably 3% by mass to 15% by mass, based on the total weight of the pharmaceutical tablet.

[0015] Examples of the excipient include celluloses such as crystalline cellulose, sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, inositol, starches such as corn starch, and inorganic salts such as magnesium aluminometasilicate and anhydrous calcium phosphate, and these are preferably used alone or in combination of two or more. Preferred are crystalline cellulose, lactose, and mannitol, and the excipient contains one or more of these. The excipient is preferably contained in an amount of 0% by mass or more and 50% by mass or less based on the total amount of the pharmaceutical tablet. Preferably, it is 0% by mass or more and 40% by mass or less. When aiming to make the tablet smaller, the amount of the disintegrant may be reduced, and in that case, it is preferably contained in an amount of 0% by mass or more and 20% by mass or less based on the total amount of the pharmaceutical tablet.

[0016] The pharmaceutical tablet of the present invention may contain other additives such as binders, lubricants, colorants, solubilizers, fluidizing agents, stabilizers, preservatives, and flavoring agents in addition to the above-mentioned ingredients. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these are preferably used alone or in combination of two or more. Preferred are hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, and methylcellulose. When a binder is used, it is preferably used in an amount of 0.5% by mass to 10% by mass, more preferably 1% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0017] Examples of lubricants include magnesium stearate, stearic acid, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax, and the like. These are preferably used alone or in combination of two or more kinds. When a lubricant is used, it is preferably used in an amount of 0.1% by mass to 10% by mass, more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0018] Examples of colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Preferred are titanium oxide and ferric oxide. When a colorant is used, it is preferably used in an amount of 0.001% by mass to 10% by mass, more preferably 0.002% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0019] Examples of the solubilizing agent include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, polyoxyethylene-polyoxypropylene block copolymer, and the like. The fluidizing agent includes light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like. The stabilizers include dibutylhydroxytoluene, tocopherol, ascorbic acid, sulfites, and the like. Examples of preservatives include paraoxybenzoic acid esters. Examples of flavoring agents include sucrose, D-sorbitol, and xylitol. These additives can be used without any particular limitation as long as they have a purity acceptable for use in pharmaceutical preparations. These additives may be used alone or in combination. They are optionally used when preparing the pharmaceutical composition or pharmaceutical preparation.

[0020] The pharmaceutical tablet of the present invention can be produced by the following method. (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant, hydroxypropyl methylcellulose acetate succinate, and optionally an excipient to prepare a granule; (3) A step of mixing the granulated material with a lubricant and compressing the mixture. Alternatively, the following method may be used in which hydroxypropyl methylcellulose acetate succinate is added last. (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant and, optionally, an excipient to prepare a granule; (3) A step of mixing the granules with hydroxypropyl methylcellulose acetate succinate and a lubricant, and compressing the mixture.

[0021] In the first step, the solid dispersion composition containing enzalutamide and a water-soluble polymer carrier is a composition in which enzalutamide is dispersed in an amorphous state in the water-soluble polymer carrier. The water-soluble polymer carrier has the same meaning as above. This solid dispersion may optionally contain any additive such as a binder, a solubilizer, or an excipient. The method for producing the formulation can be either by preparing a solution containing enzalutamide, a water-soluble polymer carrier, and any additives, and then removing the solvent (solution method), or by heating and melting enzalutamide, a water-soluble polymer carrier, and any additives, and then cooling (hot melt method).

[0022] When the solution method is used in the first step, the solution containing enzalutamide, a water-soluble polymer carrier, and any additives may be prepared using a solvent that dissolves both of them, and examples of such solvents include ketone solvents such as acetone, methyl ethyl ketone, and methyl-t-butyl ketone, ester solvents such as ethyl acetate and isopropyl acetate, ether solvents such as diethyl ether and diisopropyl ether, alcohol solvents such as methanol, ethanol, and isopropanol, halogen-based solvents such as chloroform and dichloromethane, and water, which can be used alone or as a mixed solvent. The solution may be prepared by heating to a temperature below the boiling point of the solvent as appropriate. Enzalutamide and the water-soluble polymer carrier are used in an amount of 0.5 parts by mass or more and 5 parts by mass or less, preferably 1 part by mass or more and 5 parts by mass or less, and more preferably 1 part by mass or more and 3 parts by mass or less, per part by mass of enzalutamide. The solvent is removed from the resulting solution by vacuum distillation or spray drying, and the resulting solution is then dried as appropriate to prepare a solid dispersion composition.

[0023] When the hot melt method is used in the first step, a mixture of enzalutamide, a water-soluble polymer carrier, and any additives is heated to prepare a melt of enzalutamide and a water-soluble polymer carrier. The melt is cooled to prepare a solid dispersion composition. During cooling, the solid dispersion may be formed by a kneading extrusion method. The cooled solid dispersion composition may be further pulverized to prepare a suitable particle size.

[0024] In the second step, the solid dispersion composition prepared in the first step is mixed with a disintegrant, hydroxypropylmethylcellulose acetate succinate, and an optional excipient. Any other additives such as binders, lubricants, colorants, solubilizers, flow agents, stabilizers, preservatives, and flavoring agents may be added to the solid dispersion composition. The types and suitable amounts of each additive are as described above. The mixture is then granulated to prepare a granulated product. The granulated product is a granular product having a certain particle size formed by the mixture containing the active ingredient and various additives adhering to each other, and is prepared in order to improve the compression molding ability in a later process. The granulation operation for preparing the granulated product may be either dry granulation or wet granulation. Dry granulation is a granulation method in which water is not added during granulation, while wet granulation is an operation in which an appropriate amount of an aqueous medium such as water, an organic solvent such as ethanol or methanol, or a mixed solvent thereof is added to the mixture, and the mixture is adhered to itself by applying mechanical pressure such as a mixing operation, thereby granulating the mixture into a granular product. Examples of the granulation operation include compression granulation, melt granulation, roller compactor method, rolling granulation, fluidized bed granulation, stirring granulation, and extrusion granulation. The granulation operation according to the present invention can be appropriately selected from these operation methods to prepare the granulated product.

[0025] In the third step, a lubricant is added to the granules prepared in the second step. At this point, excipients, disintegrants, binders, colorants, solubilizers, flow agents, stabilizers, preservatives, and flavoring agents may also be added. Examples of the molding method of the pharmaceutical tablet include rotary tableting and single shot tableting. Pharmaceutical tablets are prepared by molding using these methods. The dosage form may be any of bare tablets, film-coated tablets, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.

[0026] Alternatively, the hydroxypropyl methylcellulose acetate succinate is added in the third step rather than in the second step. In this case, in the second step, the solid dispersion composition prepared in the first step is mixed with a disintegrant, an optional excipient, and further optional other additives such as a binder, a lubricant, a colorant, a solubilizer, a flow agent, a stabilizer, a preservative, and a flavoring agent, and then a granule is prepared. The amount of additives to be added and the method for preparing the granule are the same as those described above. In the third step, the granules are mixed with hydroxypropylmethylcellulose acetate succinate, a lubricant, and any excipients, disintegrants, binders, colorants, solubilizers, flow agents, stabilizers, preservatives, and flavoring agents, and then molded to prepare pharmaceutical tablets. The amounts of additives and the molding method are the same as those described above.

[0027] The pharmaceutical tablet may be further coated with a coating agent and an optional plasticizer, light-shielding agent, colorant, etc. to form a film-coated tablet.

[0028] Examples of coating agents include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose phthalate, ethyl cellulose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like. It is preferable to use these alone or in combination of two or more kinds. The coating agent is preferably used in an amount of 0.1% by mass to 20% by mass, more preferably 0.2% by mass to 10% by mass, based on the total weight of the pharmaceutical tablet.

[0029] Examples of the plasticizer include triacetin, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, polysorbate, D-sorbitol, and liquid paraffin. These are preferably used alone or in combination of two or more kinds. When a plasticizer is used, it is preferably used in an amount of 0.01% by mass to 5% by mass, more preferably 0.02% by mass to 3% by mass, based on the total weight of the pharmaceutical tablet.

[0030] Examples of light-shielding agents and colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Titanium oxide and ferric oxide are preferred. When a light-shielding agent or a coloring agent is used, it is preferable to use it in an amount of 0.001% by mass or more and 10% by mass or less, and more preferably 0.002% by mass or more and 5% by mass or less, based on the total amount of the pharmaceutical tablet.

[0031] The manufacturing process for film-coated tablets involves dissolving or suspending the coating agent and any plasticizers, light-blocking agents, colorants, etc. in an aqueous solvent to prepare an aqueous solution of the coating agent, which is then applied to the tablet surface by spraying or the like, and hot air is then blown in to remove the solvent from the tablet surface, followed by drying. The aqueous solvent is a solvent containing water, and may be water alone or a mixed solvent of water and a water-miscible organic solvent, such as ethanol or acetone.

[0032] The present invention can provide a pharmaceutical tablet having excellent dissolution and solubility of enzalutamide. Since enzalutamide is poorly water-soluble, it dissolves slowly in an aqueous medium alone, and has physical properties that make it difficult to ensure a sufficient dissolution amount. Furthermore, even if the dissolution in an aqueous medium can be temporarily increased as a solid dispersion composition, if the dissolution state cannot be maintained sufficiently, such as by causing rapid precipitation thereafter, it will affect bioavailability and become a problem. The pharmaceutical tablet of the present invention has excellent dissolution properties, and can quickly dissolve enzalutamide in a dissolution test at pH 6.8 and maintain the dissolution amount over a long period of time. That is, in a dissolution test at pH 6.8, it shows a dissolution rate of 45% or more in 60 minutes, and the dissolution concentration is continuously maintained, and there is no decrease in the dissolution amount. In other words, it is characterized as a pharmaceutical tablet having excellent stability of the dissolved state of enzalutamide. In a preferred embodiment, it shows a dissolution rate of 50% or more in 15 minutes, and in a more preferred embodiment, it shows a dissolution rate of 60% or more. In a preferred embodiment, it can maintain a dissolution rate of 60% or more even after 60 minutes. EXAMPLES

[0033] The present invention will be further described below with reference to examples, although the present invention is not limited to these examples.

[0034] [Example 1] Enzalutamide and poly(methacrylic acid-acrylic acid ethyl ester) copolymer (Eudragit (registered trademark) L100-55) were dissolved in an acetone / ethanol mixture (volume ratio 2:1) at a mass ratio of 1:3. The solvent was removed using a spray dryer, and the mixture was further dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed at a ratio of 320 mg, crystalline cellulose at 92 mg, light anhydrous silicic acid at 6.5 mg, croscarmellose sodium at 32.5 mg, and hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) at 160 mg per tablet. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 1 were prepared by mixing and tableting at a ratio of 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of the granulated product.

[0035] [Example 2] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 172 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 80 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare tablets according to Example 2.

[0036] [Example 3] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 212 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 40 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare the tablets of Example 3.

[0037] [Example 4] Enzalutamide and poly(methacrylic acid-acrylic acid ethyl ester) copolymer (Eudragit (registered trademark) L100-55) were dissolved in an acetone / ethanol mixture (volume ratio 2:1) at a mass ratio of 1:2. The solvent was removed using a spray dryer, and the mixture was further dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed in a ratio of 240 mg, crystalline cellulose in 172 mg, light anhydrous silicic acid in 6.5 mg, croscarmellose sodium in 32.5 mg, and hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) in 160 mg per tablet. The same procedure as in Example 1 was then carried out to prepare the tablet according to Example 4.

[0038] [Example 5] The contents per tablet were 240 mg of the solid dispersion composition similar to that in Example 4, 252 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 80 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type), mixed in a ratio of 1.0 mg to 1.0 mg. The same operations as in Example 1 were then carried out to prepare the tablets of Example 5.

[0039] [Example 6] The contents per tablet were 240 mg of the solid dispersion composition similar to that in Example 4, 292 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 40 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type), mixed in a ratio of 1.0 mg to 1.0 mg. The same operations as in Example 1 were then carried out to prepare the tablets of Example 6.

[0040] [Example 7] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-M type), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare the tablets of Example 7.

[0041] [Example 8] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-L type), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare the tablets of Example 8.

[0042] [Example 9] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 75.2 mg of crystalline cellulose, 5.4 mg of light anhydrous silicic acid, 27 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 9 were prepared by mixing and tableting in a ratio of 27 mg of croscarmellose sodium and 5.4 mg of magnesium stearate per 507.6 mg of the granulated product.

[0043] [Example 10] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 76 mg of crystalline cellulose, 4.5 mg of light anhydrous silicic acid, 22.5 mg of croscarmellose sodium, and 80 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 10 were prepared by mixing and tableting 22.5 mg of croscarmellose sodium and 4.5 mg of magnesium stearate per 423 mg of granulated product.

[0044] [Example 11] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 72 mg of crystalline cellulose, 4 mg of light anhydrous silicic acid, 20 mg of croscarmellose sodium, and 40 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 11 were prepared by mixing 20 mg of croscarmellose sodium and 4 mg of magnesium stearate per 376 mg of granulated product and tableting.

[0045] [Example 12] The contents per tablet were 320 mg of the solid dispersion composition as in Example 1, 84 mg of crystalline cellulose, 5.5 mg of light anhydrous silicic acid, 27.5 mg of croscarmellose sodium, and 80 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 12 were prepared by mixing 27.5 mg of croscarmellose sodium and 5.5 mg of magnesium stearate per 517 mg of granulated product and tableting.

[0046] [Example 13] The contents per tablet were 320 mg of the solid dispersion composition as in Example 1, 80 mg of crystalline cellulose, 5 mg of light anhydrous silicic acid, 25 mg of croscarmellose sodium, and 40 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 13 were prepared by mixing 25 mg of croscarmellose sodium and 5 mg of magnesium stearate per 470 mg of the granulated product and tableting.

[0047] [Example 14] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 4.5 mg of light anhydrous silicic acid, 22.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 14 were prepared by mixing 22.5 mg of croscarmellose sodium and 4.5 mg of magnesium stearate per 427 mg of granulated product and tableting.

[0048] [Example 15] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 4 mg of light anhydrous silicic acid, 20.5 mg of croscarmellose sodium, and 120 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 15 were prepared by mixing 20.5 mg of croscarmellose sodium and 4 mg of magnesium stearate per 384.5 mg of the granulated product and tableting.

[0049] [Example 16] The same granules as in Example 14 were mixed in a ratio of 427 mg to 4.5 mg of magnesium stearate and compressed into tablets to prepare tablets according to Example 16.

[0050] [Example 17] The contents per tablet were 240 mg of the solid dispersion composition as in Example 4, 23.4 mg of crystalline cellulose, 4.8 mg of light anhydrous silicic acid, 24 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type). The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 17 were prepared by mixing and tableting 24 mg of croscarmellose sodium and 4.8 mg of magnesium stearate per 452.2 mg of the granulated product.

[0051] [Example 18] The contents per tablet were 320 mg of the solid dispersion composition, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium, which were the same as those in Example 1. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 18 were prepared by mixing 160 mg of hydroxypropyl methylcellulose acetate succinate (HPMCAS-H type), 32.5 mg of croscarmellose sodium, and 6.5 mg of magnesium stearate per 451 mg of the granulated product and tableting.

[0052] [Example 19] Enzalutamide and hydroxypropyl cellulose were dissolved in an acetone / ethanol mixed solution (volume ratio 1:5) at a mass ratio of 1:1.5. The solvent was removed using a spray dryer, and the solution was further dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed at a ratio of 200 mg, 212 mg, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) per tablet. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 19 were prepared by mixing and tableting at a ratio of 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of granulated product.

[0053] [Example 20] Enzalutamide and polyvinylpyrrolidone-polyvinyl acetate copolymer were dissolved in acetone at a mass ratio of 1:1.27. The solvent was removed using a spray dryer, and the solution was further dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed in a ratio of 181.6 mg, 230.4 mg, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) per tablet. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 20 were prepared by mixing and tableting in a ratio of 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of granulated product.

[0054] [Example 21] Enzalutamide and poly(methacrylic acid-methacrylic acid methyl ester) copolymer (Eudragit (registered trademark) L100) were dissolved in an acetone / ethanol mixture (volume ratio 2:1) at a mass ratio of 1:3. The solvent was removed using a spray dryer, and the resulting solution was dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed at a ratio of 320 mg, crystalline cellulose at 92 mg, light anhydrous silicic acid at 6.5 mg, croscarmellose sodium at 32.5 mg, and hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) at 160 mg per tablet. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 21 were prepared by mixing and tableting at a ratio of 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of granulated product.

[0055] [Example 22] Enzalutamide and polyvinylpyrrolidone were dissolved in an acetone / ethanol mixed solution (volume ratio 1:5) at a mass ratio of 1:2.5. The solvent was removed using a spray dryer, and the solution was further dried under reduced pressure to obtain a solid dispersion composition. The solid dispersion composition was mixed at a ratio of 280 mg, crystalline cellulose at 132 mg, light anhydrous silicic acid at 6.5 mg, croscarmellose sodium at 32.5 mg, and hydroxypropylmethylcellulose acetate succinate (HPMCAS-H type) at 160 mg per tablet. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Example 22 were prepared by mixing and tableting at a ratio of 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of granulated product.

[0056] [Comparative Example 1] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose phthalate (HPMCP), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare tablets according to Comparative Example 1.

[0057] [Comparative Example 2] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of hydroxypropylmethylcellulose (HPMC), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare tablets according to Comparative Example 2.

[0058] [Comparative Example 3] The contents per tablet were 320 mg of the solid dispersion composition similar to that in Example 1, 92 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, 32.5 mg of croscarmellose sodium, and 160 mg of poly(vinylpyrrolidone-vinyl acetate) copolymer (PVP-VA64), mixed in a ratio of 1. The same operations as in Example 1 were then carried out to prepare tablets according to Comparative Example 3.

[0059] [Comparative Example 4] The contents per tablet were 320 mg of the solid dispersion, 252 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium, which were the same as in Example 1. The same operations as in Example 1 were then carried out to prepare tablets according to Comparative Example 4.

[0060] [Comparative Example 5] The contents per tablet were 200 mg of the solid dispersion composition, 372 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium, which were the same as those in Example 19. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Comparative Example 5 were prepared by mixing 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of the granulated product and tableting.

[0061] [Comparative Example 6] The contents per tablet were the same as in Example 20: 181.6 mg of the solid dispersion composition, 390.4 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granule. The tablets according to Comparative Example 6 were prepared by mixing and tableting 611 mg of the granule, 32.5 mg of croscarmellose sodium, and 6.5 mg of magnesium stearate.

[0062] [Comparative Example 7] The contents per tablet were 320 mg of the solid dispersion composition, 252 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium, which were the same as those in Example 21. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Comparative Example 7 were prepared by mixing 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of the granulated product and tableting.

[0063] [Comparative Example 8] The contents per tablet were 280 mg of the solid dispersion composition, 292 mg of crystalline cellulose, 6.5 mg of light anhydrous silicic acid, and 32.5 mg of croscarmellose sodium, which were the same as those in Example 22. The mixture was compressed and molded, and the molded product was crushed and sieved through a 30M sieve to obtain a granulated product. The tablets according to Comparative Example 8 were prepared by mixing 32.5 mg of croscarmellose sodium and 6.5 mg of magnesium stearate per 611 mg of the granulated product and tableting.

[0064] The formulations of Examples 1 to 8 are summarized in Table 1, the formulations of Examples 9 to 17 in Table 2, the formulations of Examples 18 to 22 in Table 3, the formulations of Comparative Examples 1 to 4 in Table 4, and the formulations of Comparative Examples 5 to 8 in Table 5.

[0065] [Table 1]

[0066] [Table 2]

[0067] [Table 3]

[0068] [Table 4]

[0069] [Table 5]

[0070] [Test Example 1] The tablets of Examples 1 to 8 and Comparative Examples 1 to 4, and XTANDI (registered trademark) tablets (80 mg) were subjected to a dissolution test according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a test solution of pH 6.8 prepared by the method described in the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6600A, manufactured by Toyama Sangyo Co., Ltd.), the test liquid volume was 900 mL, the test liquid temperature was 37±0.5°C, and the paddle rotation speed was 50 rpm. The enzalutamide concentration in the sample solution sampled at each time point was measured, and the dissolution rate was evaluated. The test results are summarized in Table 6.

[0071] [Table 6]

[0072] The pharmaceutical tablets of Examples 1 to 6 showed a dissolution rate of 60% or more in 15 minutes, and maintained a dissolution rate of 60% or more even at 60 minutes, similar to the existing formulation XTANDI Tablets 80 mg. On the other hand, the tablets of Comparative Examples 1 and 4 showed a high dissolution rate at the beginning, but the dissolution rate was not maintained sufficiently. In addition, the tablets of Comparative Examples 2 and 3 showed a low dissolution rate. That is, by applying the present invention, it is possible to provide pharmaceutical tablets that stably maintain a high dissolution rate, similar to the existing formulation.

[0073] [Test Example 2] The tablets of Examples 9 to 17 and 80 mg of XTANDI (registered trademark) tablets were subjected to a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a test solution of pH 6.8 prepared by the method described in the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6600A, manufactured by Toyama Sangyo Co., Ltd.), the test liquid volume was 900 mL, the test liquid temperature was 37±0.5°C, and the paddle rotation speed was 50 rpm. The enzalutamide concentration in the sample solution sampled at each time point was measured, and the dissolution rate was evaluated. The test results are summarized in Table 7.

[0074] [Table 7]

[0075] The pharmaceutical tablets of Examples 9 to 17 showed a dissolution rate of 60% or more in 15 minutes, and maintained a dissolution rate of 60% or more even in 60 minutes, similar to the existing formulation XTANDI Tablets 80 mg. The pharmaceutical tablets of Examples 9 to 17 are smaller than the existing formulations, and are formulations that are easy to take and have improved convenience. The formulation of the present application can provide pharmaceutical tablets that are excellent in dissolution characteristics and easy to take.

[0076] [Test Example 3] Example 18 and XTANDI (registered trademark) tablets 80 mg were subjected to a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a test solution of pH 6.8 prepared by the method described in the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6600A, manufactured by Toyama Sangyo Co., Ltd.), the test liquid volume was 900 mL, the test liquid temperature was 37±0.5°C, and the paddle rotation speed was 50 rpm. The enzalutamide concentration in the sample solution sampled at each time point was measured, and the dissolution rate was evaluated. The test results are summarized in Table 8.

[0077] [Table 8]

[0078] The pharmaceutical tablet of Example 18 showed a dissolution rate of 60% or more in 15 minutes, similar to the existing formulation XTANDI Tablet 80 mg, and maintained a dissolution rate of 60% or more even at 60 minutes. In other words, by applying the present invention, a pharmaceutical tablet that stably maintains a high dissolution rate, similar to the existing formulation, can be provided.

[0079] [Test Example 4] The tablets of Examples 19 to 22 and Comparative Examples 5 to 8 were subjected to a dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a test solution of pH 6.8 prepared by the method described in the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6600A, manufactured by Toyama Sangyo Co., Ltd.), the test liquid volume was 900 mL, the test liquid temperature was 37±0.5°C, and the paddle rotation speed was 50 rpm. The enzalutamide concentration in the sample solution sampled at each time point was measured, and the dissolution rate was evaluated. The test results are summarized in Table 9.

[0080] [Table 9]

[0081] The pharmaceutical tablets of Examples 19 to 22 maintained a dissolution rate of 50% or more even at 360 minutes. On the other hand, the tablets of Comparative Examples 5 to 8 showed a large drop in dissolution rate at 360 minutes. In other words, by applying the present invention, it is possible to provide pharmaceutical tablets that stably maintain a high dissolution rate, similar to existing formulations.

Claims

1. A solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; Disintegrants, as well as hydroxypropyl methylcellulose acetate succinate, A medicinal tablet containing the active ingredient enzalutamide.

2. 2. The pharmaceutical tablet according to claim 1, containing 5 to 40 parts by weight of hydroxypropyl methylcellulose acetate succinate.

3. The pharmaceutical tablet according to claim 1, wherein the water-soluble polymer carrier is one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose, and hydroxypropylmethylcellulose.

4. The pharmaceutical tablet according to claim 1, wherein the water-soluble polymer carrier is one or more selected from the group consisting of poly[(meth)acrylic acid-(meth)acrylic acid alkyl ester] copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, and hydroxypropylmethylcellulose acetate succinate (HPMCAS).

5. The pharmaceutical tablet according to claim 1, comprising 1 to 5 parts by mass of a water-soluble polymer carrier per 1 part by mass of enzalutamide.

6. A method for producing a pharmaceutical tablet containing enzalutamide as an active ingredient, comprising: (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant and hydroxypropyl methylcellulose acetate succinate to prepare a granule; (3) mixing the granules with a lubricant and compressing the mixture; A method for producing a pharmaceutical tablet comprising the steps of:

7. A method for producing a pharmaceutical tablet containing enzalutamide as an active ingredient, comprising: (1) preparing a solid dispersion composition comprising enzalutamide and a water-soluble polymer carrier; (2) mixing the solid dispersion composition with a disintegrant to prepare a granule; (3) mixing the granules with hydroxypropyl methylcellulose acetate succinate and a lubricant, and compressing the mixture; A method for producing a pharmaceutical tablet comprising the steps of:

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