Pharmaceutical composition comprising enzalutamide solid dispersion, and formulation comprising said pharmaceutical composition

Abstract

One embodiment of the present invention provides a pharmaceutical composition in which enzalutamide is amorphized as a result of solid dispersion, and consequently a supersaturated state is maintained. Alternatively, one embodiment of the present invention provides a formulation comprising a pharmaceutical composition in which enzalutamide is amorphized as a result of solid dispersion, and consequently a supersaturated state is maintained. According to one embodiment of the present invention, the pharmaceutical composition includes an enzalutamide solid dispersion comprising enzalutamide in an amorphous form and a base. The pharmaceutical composition includes a pharmaceutically acceptable cationic polymer. The pharmaceutically acceptable cationic polymer may be a pharmaceutically acceptable cationic acrylic polymer or a pharmaceutically acceptable cationic vinyl polymer.

Description

Pharmaceutical composition containing enzalutamide solid dispersion and formulation containing said pharmaceutical composition

[0001] One embodiment of the present invention relates to a pharmaceutical composition in which enzalutamide is solid dispersed to form an amorphous state and maintain a supersaturated state, or to a formulation comprising a pharmaceutical composition in which enzalutamide is solid dispersed to form an amorphous state and maintain a supersaturated state.

[0002] Enzalutamide (4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide) is known as a poorly water-soluble drug. One method for improving the dissolution of enzalutamide is to use a solid dispersion (see, for example, Patent Document 1). In a solid dispersion, an amorphous drug is dispersed in an inert carrier, which serves as a base. Crystallization of the drug is inhibited by interaction with the inert carrier, thereby improving the dissolution of the drug.

[0003] Patent Document 1 describes a pharmaceutical composition comprising a solid dispersion containing enzalutamide in a solid form and a polymer, wherein the enzalutamide is in an amorphous state and the polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate.

[0004] Furthermore, Patent Document 2 describes a pharmaceutical composition for oral administration that contains enzalutamide and polyvinyl alcohol, wherein the degree of saponification of the polyvinyl alcohol is 30 mol% or more and less than 85 mol%, and that contains a solid dispersion containing enzalutamide and polyvinyl alcohol.

[0005] In order for the active ingredient to be rapidly absorbed into the body after ingestion, it is desirable for the active ingredient to dissolve from the formulation in the upper part of the gastrointestinal tract and then maintain a sufficient amount of dissolved active ingredient until it reaches the small intestine, the main absorption site. If crystallization occurs in the gastrointestinal tract, the supersaturated state of enzalutamide cannot be maintained, so crystallization in the gastrointestinal tract must be suppressed for a long period of time.

[0006] Patent No. 6404217 Patent No. 7172997

[0007] One object of one embodiment of the present invention is to provide a pharmaceutical composition in which enzalutamide is made amorphous by solid dispersion, thereby maintaining a supersaturated state. Alternatively, one object of one embodiment of the present invention is to provide a formulation comprising a pharmaceutical composition in which enzalutamide is made amorphous by solid dispersion, thereby maintaining a supersaturated state.

[0008] A pharmaceutical composition according to one embodiment of the present invention comprises an enzalutamide solid dispersion comprising an amorphous form of enzalutamide and a carrier, the pharmaceutical composition comprising a pharmaceutically acceptable cationic polymer.

[0009] The pharmaceutically acceptable cationic polymer may be a pharmaceutically acceptable cationic acrylic polymer or a pharmaceutically acceptable cationic vinyl polymer.

[0010] The pharmaceutically acceptable cationic acrylic polymer may be an aminoalkyl methacrylate copolymer or an ammonioalkyl methacrylate copolymer.

[0011] The base may comprise a pharmaceutically acceptable cationic polymer.

[0012] A pharmaceutically acceptable cationic polymer may be disposed externally of the enzalutamide solid dispersion.

[0013] The base may contain a pharmaceutically acceptable cationic polymer, and the pharmaceutically acceptable cationic polymer may also be disposed outside the enzalutamide solid dispersion.

[0014] It may further contain a pharmaceutically acceptable acidic pH adjuster, and the pharmaceutically acceptable acidic pH adjuster may be contained inside the enzalutamide solid dispersion and / or outside the enzalutamide solid dispersion.

[0015] The pharmaceutically acceptable acidic pH adjusting agent may be an organic acid.

[0016] The organic acid may be one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, and fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

[0017] The base may further include hydroxypropyl cellulose.

[0018] The pharmaceutical composition may further comprise a fluidizing agent disposed externally to the enzalutamide solid dispersion.

[0019] A formulation according to one embodiment of the present invention comprises any of the enzalutamide pharmaceutical compositions described above and one or more pharmaceutically acceptable additives.

[0020] According to one embodiment of the present invention, there is provided a pharmaceutical composition in which enzalutamide is solid dispersed to form an amorphous state and maintain a supersaturated state, or according to one embodiment of the present invention, there is provided a formulation comprising a pharmaceutical composition in which enzalutamide is solid dispersed to form an amorphous state and maintain a supersaturated state.

[0021] 1 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 2 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 3 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 4 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 5 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 6 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 7 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 8 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. FIG. 9 is a diagram showing the evaluation results of the amorphous state of enzalutamide by powder X-ray diffraction measurement. FIG. 10 is a diagram showing the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. Fig. 1 shows the evaluation results of the dissolution of enzalutamide from an enzalutamide solid dispersion. Fig. 2 shows the evaluation results of the dissolution of enzalutamide from an enzalutamide-containing formulation. Fig. 3 shows the evaluation results of the dissolution of enzalutamide from an enzalutamide-containing formulation.

[0022] Hereinafter, a pharmaceutical composition containing an enzalutamide solid dispersion according to the present invention and a formulation containing the pharmaceutical composition will be described with reference to the drawings. The pharmaceutical composition containing an enzalutamide solid dispersion according to the present invention and a formulation containing the pharmaceutical composition are not to be construed as being limited to the description of the following embodiments and examples. In the drawings referred to in the present embodiments and examples described below, identical parts or parts having similar functions are designated by the same reference numerals, and repeated description thereof will be omitted.

[0023] In this specification, "maintaining a supersaturated state" means that, when evaluated using the methods described in the reference examples, comparative examples, or examples below, the dissolution rate of enzalutamide in a pharmaceutical composition or formulation does not decrease over a long period of time (e.g., 2 hours or more, preferably 3 hours or more) from the dissolution rate that peaked after the start of the dissolution test of enzalutamide, or suppresses the decrease in the dissolution rate.

[0024] [Pharmaceutical composition containing enzalutamide solid dispersion] The pharmaceutical composition of this embodiment comprises a solid dispersion in which a base supports amorphous enzalutamide, and a pharmaceutically acceptable cationic polymer. In the enzalutamide solid dispersion, the amorphous enzalutamide may have a structure in which it is dispersed in the base. In this specification, the term "base" collectively refers to a polymer capable of maintaining the drug in an amorphous form in the solid dispersion.

[0025] In one embodiment, the enzalutamide solid dispersion may be a pharmaceutical composition containing a pharmaceutically acceptable cationic polymer. That is, by using a pharmaceutically acceptable cationic polymer as a base or carrier constituting the enzalutamide solid dispersion, the pharmaceutically acceptable cationic polymer may support enzalutamide and maintain enzalutamide in an amorphous state, thereby maintaining a supersaturated state of enzalutamide in the stomach and small intestine upon administration.

[0026] Alternatively, in one embodiment, the pharmaceutical composition may be one in which the enzalutamide solid dispersion does not contain a pharmaceutically acceptable cationic polymer, but the pharmaceutically acceptable cationic polymer is disposed outside the enzalutamide solid dispersion. That is, a pharmaceutically acceptable cationic polymer may be added to the pharmaceutical composition separately from the enzalutamide solid dispersion to maintain enzalutamide in an amorphous state and to use the pharmaceutically acceptable cationic polymer as an additive that maintains a supersaturated state of enzalutamide in the stomach and small intestine upon administration.

[0027] Alternatively, in one embodiment, the pharmaceutical composition may be one in which the enzalutamide solid dispersion contains a pharmaceutically acceptable cationic polymer, and the pharmaceutically acceptable cationic polymer is also disposed outside the enzalutamide solid dispersion.

[0028] In one embodiment, the pharmaceutical composition preferably contains 90 mg or more of cationic polymer per 80 mg of enzalutamide, and preferably 400 mg or less in terms of the weight per tablet of the formulation, and more preferably 200 mg to 360 mg of cationic polymer per 80 mg of enzalutamide.

[0029] As used herein, the term "cationic polymer" collectively refers to a polymer in which the side chain of the polymer is positively charged, or a polymer in which the side chain of the polymer is positively charged in a solution such as a digestive fluid or a test solution. In the pharmaceutical composition of this embodiment, the pharmaceutically acceptable cationic polymer is an additive that supports enzalutamide, maintains enzalutamide in an amorphous state, and maintains a supersaturated state of enzalutamide in the stomach and small intestine when ingested. In this embodiment, by including a pharmaceutically acceptable cationic polymer in the enzalutamide solid dispersion or by disposing a pharmaceutically acceptable cationic polymer outside the enzalutamide solid dispersion, enzalutamide can be maintained in an amorphous state in the pharmaceutical composition, and a supersaturated state of enzalutamide can be maintained in the stomach and small intestine when ingested.

[0030] In this embodiment, the pharmaceutically acceptable cationic polymer is a pharmaceutically acceptable cationic acrylic polymer or a pharmaceutically acceptable cationic vinyl polymer. In one embodiment, the pharmaceutically acceptable cationic acrylic polymer is, for example, an aminoalkyl methacrylate copolymer or an ammonioalkyl methacrylate copolymer. More specifically, the aminoalkyl methacrylate copolymer may be Evonik's EUDRAGIT® E 100 or EUDRAGIT® E PO. Furthermore, examples of ammonioalkyl methacrylate copolymers that can be used include Evonik's EUDRAGIT® RL 100, EUDRAGIT® RL PO, EUDRAGIT® RL 30 D, EUDRAGIT® RS 100, EUDRAGIT® RS PO, and EUDRAGIT® RS 30 D. In one embodiment, examples of pharmaceutically acceptable cationic vinyl polymers include polyvinyl acetal diethylaminoacetate. More specifically, Mitsubishi Chemical Corporation's AEA can be used.

[0031] The pharmaceutical composition of this embodiment uses a cationic polymer as a base or carrier, or as an additive in a pharmaceutical composition containing an enzalutamide solid dispersion, thereby maintaining enzalutamide in an amorphous state and maintaining a supersaturated state of enzalutamide in the stomach and small intestine upon administration. Therefore, the pharmaceutical composition containing the enzalutamide solid dispersion of this embodiment is expected to dramatically improve the bioavailability of enzalutamide compared to conventional compositions.

[0032] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable acidic pH adjuster. In this embodiment, the pharmaceutically acceptable acidic pH adjuster is contained inside the enzalutamide solid dispersion and / or outside the enzalutamide solid dispersion. As used herein, the inclusion of a pharmaceutically acceptable acidic pH adjuster "inside the enzalutamide solid dispersion" refers to a state in which the enzalutamide solid dispersion contains a pharmaceutically acceptable acidic pH adjuster, or a state in which the pharmaceutically acceptable acidic pH adjuster is dispersed and disposed in the enzalutamide solid dispersion, or a state in which the pharmaceutically acceptable acidic pH adjuster is added during the production of the enzalutamide solid dispersion, mixed with enzalutamide and a base, and solidified. As used herein, the phrase "a pharmaceutically acceptable acidic pH adjuster being contained "outside the enzalutamide solid dispersion" refers to a state in which the pharmaceutically acceptable acidic pH adjuster is not contained in the solid dispersion, but is contained in the pharmaceutical composition together with the solid dispersion, or a state in which the pharmaceutical composition is obtained by adding an acidic pH adjuster after producing the enzalutamide solid dispersion.

[0033] As used herein, the term "pharmaceutically acceptable acidic pH adjuster" refers collectively to pharmaceutically acceptable acidic additives that can adjust the pH of a pharmaceutical composition and thereby dissolve the cationic polymer contained in the pharmaceutical composition. The term "pharmaceutically acceptable acidic pH adjuster" includes pharmaceutically acceptable inorganic acids and organic acids.

[0034] As used herein, the term "inorganic acid" refers collectively to inorganic compounds that exhibit pharmaceutically acceptable acidity. Examples of inorganic acids contained in the pharmaceutical composition according to this embodiment include, but are not limited to, one or more selected from the group consisting of phosphoric acid, hydrochloric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, and anhydrous sodium dihydrogen phosphate, or hydrates thereof.

[0035] As used herein, the term "organic acid" refers collectively to organic compounds that exhibit pharmaceutically acceptable acidity. Examples of organic acids contained in the pharmaceutical composition according to this embodiment include, but are not limited to, one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, maleic acid, aspartic acid, sorbic acid, adipic acid, and malonic acid, or the group consisting of salts, hydrates, and stereoisomers of these organic acids.

[0036] In one embodiment, the pharmaceutical composition may further comprise a fluidizing agent outside the enzalutamide solid dispersion, including, but not limited to, light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, colloidal silicon dioxide, fumed silica, CAB-O-SIL® M-5P, AEROSIL®, talc, starch, and magnesium aluminum silicate.

[0037] [Enzalutamide Solid Dispersion] The enzalutamide solid dispersion of this embodiment contains amorphous enzalutamide and a base. In one embodiment, the base may contain a pharmaceutically acceptable cationic polymer. Alternatively, in one embodiment, when the enzalutamide solid dispersion does not contain a pharmaceutically acceptable cationic polymer, the above-mentioned pharmaceutical composition may contain a pharmaceutically acceptable cationic polymer.

[0038] Examples of bases that can be used in the enzalutamide solid dispersion according to this embodiment include polyvinyl alcohol; polyvinyl alcohol-polyvinyl acetate copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate, polyethylene-polyvinyl alcohol copolymers, carboxylic acid-functionalized polymethacrylates and carboxylic acid-functionalized polyacrylates (e.g., EUDRAGIT®), aminoalkyl methacrylate copolymers, proteins, carboxylic acid-functionalized starches (e.g., starch glycolate), copolymers of methacrylates and acrylates (e.g., EUDRAGIT®), polyethylene glycol, graft copolymers of polyvinyl caprolactam and polyvinyl acetate, SOLUPLUS®, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose acetate ... Propyl cellulose, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate,Cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropyl salicylate cellulose acetate, cellulose acetate ethyl benzoate, hydroxypropyl ethyl benzoate cellulose acetate, cellulose acetate ethyl phthalate, cellulose acetate ethyl nicotinate, and cellulose acetate ethyl picolinate, hydroxypropyl methylcellulose phthalate (HPMC) Examples of suitable solid dispersions include, but are not limited to, polyethylene oxide (PEO), poly(vinylpyrrolidone-co-vinyl acetate), polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, and spirulan. In one embodiment, when the solid dispersion contains enzalutamide, hydroxypropyl cellulose (HPC) may be used. In one embodiment, the base may contain one or more of the above polymers. In the solid dispersion of this embodiment, the drug is dispersed in a matrix formed by the base and maintained in an amorphous form.

[0039] In the enzalutamide solid dispersion of this embodiment, the pharmaceutically acceptable cationic polymer is a base or carrier that supports enzalutamide, maintains enzalutamide in an amorphous state, and maintains a supersaturated state of enzalutamide in the stomach and small intestine when ingested. The enzalutamide solid dispersion has a structure in which amorphous enzalutamide is dispersed in a pharmaceutically acceptable cationic polymer, and / or a structure in which amorphous enzalutamide is supported by a pharmaceutically acceptable cationic polymer.

[0040] In one embodiment, the enzalutamide solid dispersion may contain hydroxypropyl cellulose (HPC) as a base or carrier for maintaining enzalutamide in an amorphous state. The enzalutamide solid dispersion may have a structure in which amorphous enzalutamide is dispersed in a mixture of the above-mentioned pharmaceutically acceptable cationic polymer and hydroxypropyl cellulose (or hydroxypropyl cellulose alone), and / or a structure in which amorphous enzalutamide is supported on a mixture of the above-mentioned pharmaceutically acceptable cationic polymer and hydroxypropyl cellulose (or hydroxypropyl cellulose alone).

[0041] In one embodiment, the enzalutamide solid dispersion may further contain the above-mentioned pharmaceutically acceptable acidic pH adjuster. In the enzalutamide solid dispersion, the pharmaceutically acceptable acidic pH adjuster can adjust the pH of the enzalutamide solid dispersion, thereby suppressing the production of enzalutamide-derived analogs. The pharmaceutically acceptable acidic pH adjuster includes pharmaceutically acceptable inorganic acids and organic acids.

[0042] When the enzalutamide solid dispersion according to this embodiment is produced using a production method involving a heating step (e.g., hot-melt extrusion), an inorganic compound that is non-volatile under heating conditions (e.g., 80°C to 280°C, preferably 100°C to 250°C) can be used as the inorganic acid. Examples of the inorganic acid contained in the enzalutamide solid dispersion according to this embodiment include, but are not limited to, one or more selected from the group consisting of phosphoric acid, hydrochloric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, and anhydrous sodium dihydrogen phosphate, or the group consisting of hydrates thereof.

[0043] As described above, when the enzalutamide solid dispersion according to this embodiment is produced using a production method involving a heating step (e.g., hot-melt extrusion), a non-volatile organic compound can be used as the organic acid under heating conditions (e.g., 80°C to 280°C, preferably 100°C to 250°C). Examples of the organic acid contained in the enzalutamide solid dispersion according to this embodiment include, but are not limited to, one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, maleic acid, aspartic acid, sorbic acid, adipic acid, and malonic acid, or the group consisting of salts, hydrates, and stereoisomers of these organic acids.

[0044] The enzalutamide solid dispersion of this embodiment uses a cationic polymer as a base or carrier, or as an additive in a pharmaceutical composition containing the enzalutamide solid dispersion, thereby maintaining enzalutamide in an amorphous state and maintaining a supersaturated state of enzalutamide in the stomach and small intestine upon administration. Therefore, a formulation using the enzalutamide solid dispersion of this embodiment is expected to dramatically improve the bioavailability of enzalutamide compared to conventional formulations.

[0045] In one embodiment, the enzalutamide solid dispersion according to this embodiment may be coated with a coating composition to improve the disintegration properties of the tablet. Examples of the coating composition include water-soluble polymers, insoluble polymers, sugars, and minerals such as talc.

[0046] [Preparation containing enzalutamide solid dispersion] The preparation according to this embodiment comprises a pharmaceutical composition containing the enzalutamide solid dispersion according to the embodiment described above. The preparation according to this embodiment may be a capsule containing the pharmaceutical composition containing enzalutamide described above, or may be a tablet. In one embodiment, the tablet may be a film-coated tablet or a plain tablet (or regular tablet) without a film. The amount of enzalutamide contained in this preparation can be adjusted as desired within a range in which a therapeutic effect can be obtained, and is not particularly limited. In one embodiment, each tablet may contain 40 mg or 80 mg of enzalutamide.

[0047] In addition to the pharmaceutical composition containing the enzalutamide solid dispersion, the formulation according to this embodiment may further contain one or more pharmaceutically acceptable additives, including, but not limited to, excipients, binders, disintegrants, acidulants, effervescent agents, sweeteners, flavoring agents, lubricants, colorants, stabilizers, antioxidants, and fluidizing agents.

[0048] Examples of excipients include, but are not limited to, mannitol, lactose, starch, corn starch, crystalline cellulose, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, refined sucrose, and glucose.

[0049] Examples of binders include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, hypromellose acetate succinate, and gum arabic.

[0050] Examples of disintegrants include, but are not limited to, corn starch, starch, crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium starch glycolate, powdered agar, crospovidone, synthetic aluminum silicate, sucrose fatty acid esters, lactose, mannitol, and anhydrous citric acid.

[0051] Examples of acidulants include, but are not limited to, citric acid, tartaric acid, and malic acid.

[0052] Examples of foaming agents include sodium bicarbonate, but are not limited to this.

[0053] Examples of sweeteners include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0054] Examples of flavoring agents include lemon, lemon lime, orange, and menthol, but are not limited to these.

[0055] Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

[0056] Examples of coloring agents include, but are not limited to, yellow iron oxide, red iron oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 1, and Food Blue No. 2.

[0057] Examples of stabilizers include, but are not limited to, citric acid, succinic acid, fumaric acid, tartaric acid, and ascorbic acid, or salts thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine, and arginine, or salts thereof; magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, and boric acid, or salts thereof.

[0058] Examples of antioxidants include, but are not limited to, ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

[0059] Examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, colloidal silicon dioxide, fumed silica, CAB-O-SIL (registered trademark) M-5P, AEROSIL (registered trademark), talc, starch, and magnesium aluminum silicate.

[0060] In the formulation of this embodiment, a salt may be added to cause salting out in order to improve the disintegration property of the tablet. Examples of salts that can be added to the formulation include one or more selected from the group consisting of sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, potassium bicarbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, potassium chloride, sodium sulfate, sodium sulfite, sodium citrate, disodium citrate, sodium glutamate, disodium succinate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, fructose, and hydrates thereof.

[0061] In one embodiment, a plasticizer may be added to improve the manufacturability of the formulation. Examples of the plasticizer include one or more selected from the group consisting of polyethylene glycol (macrogol) 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, triethyl citrate, glycerin, glyceric acid esters, triacetin, propylene glycol, medium-chain fatty acid triglycerides, polysorbate 80, glycerin monostearate, and copolyvidone.

[0062] [Method for Producing Enzalutamide Solid Dispersion] The enzalutamide solid dispersion according to the present embodiment is not particularly limited and can be produced, for example, by hot melt extrusion (HME). In one embodiment, enzalutamide, a pharmaceutically acceptable cationic polymer, and a pharmaceutically acceptable acidic pH adjuster are mixed, and the mixture is heated to melt the drug and soften the pharmaceutically acceptable cationic polymer. The enzalutamide solid dispersion according to the present embodiment can be produced by mixing the molten mixture to homogenize it, and then extruding and cooling it. In one embodiment, hydroxypropyl cellulose and / or a fluidizing agent may be further added when these additives are mixed. Note that, since enzalutamide is melted by heating, the enzalutamide used as a raw material may be in either an amorphous or crystalline form. Regardless of the form of enzalutamide used, a solid dispersion containing amorphous enzalutamide can be obtained by production using the HME method. In one embodiment, the temperature conditions for the step of melting enzalutamide by heating, softening the pharmaceutically acceptable cationic polymer, and the step of mixing the molten mixture to homogenize are not particularly limited as long as the manufacturing conditions are such that enzalutamide can be made amorphous. The resulting enzalutamide solid dispersion can be pulverized and, if necessary, sized and / or coated to obtain the enzalutamide solid dispersion used in the formulation of this embodiment.

[0063] In one embodiment, when a cationic polymer is used as an additive in the pharmaceutical composition in addition to the solid dispersion, enzalutamide, hydroxypropyl cellulose, and a pharmaceutically acceptable acidic pH adjuster are mixed, and the mixture is heated to melt the drug and soften the hydroxypropyl cellulose. The enzalutamide solid dispersion according to this embodiment may be produced by mixing the molten mixture to homogenize it, and then cooling while extruding. A fluidizer may also be added when mixing these additives.

[0064] [Method for Producing a Formulation] A capsule formulation can be produced by mixing the enzalutamide solid dispersion according to the present embodiment described above with one or more pharmaceutically acceptable additives and encapsulating the mixture. Alternatively, a formulation according to the present embodiment can be produced by mixing the enzalutamide solid dispersion according to the present embodiment with one or more pharmaceutically acceptable additives and compressing the mixture into tablets. As described above, the amount of enzalutamide contained in one tablet of the formulation can be adjusted as desired within a range that achieves a therapeutic effect. In one embodiment, a film-coated tablet can be obtained by coating the obtained uncoated formulation with a film. A combination of known additives can be used as the composition constituting the film.

[0065] [Evaluation of Dissolution] In the present specification, the dissolution of enzalutamide in enzalutamide solid dispersions and formulations can be evaluated in accordance with the dissolution test method (paddle method) of the 18th Edition of the Japanese Pharmacopoeia.

[0066] [Evaluation of Amorphous State] The amorphous state of enzalutamide in a pharmaceutical composition containing an enzalutamide solid dispersion and in a formulation containing the pharmaceutical composition can be evaluated by infrared absorption spectroscopy or powder X-ray diffraction. As used herein, "amorphous" means that no peaks derived from crystalline components are detected in the infrared absorption spectrum obtained by infrared absorption spectroscopy or the diffraction pattern obtained by powder X-ray diffraction. In particular, in powder X-ray diffraction, "no peaks detected" means that a broad halo pattern is observed relative to the baseline, and no significant peaks derived from crystalline components are observed.

[0067] Reference Example 1 64.0 g of enzalutamide, 288.0 g of HPC (L, Nippon Soda Co., Ltd.), and 2.0 g of tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 3.2 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion.

[0068] 27.8 g of hypromellose acetate succinate (HPMC: Shin-Etsu AQOAT (registered trademark) AS-L, Shin-Etsu Chemical Co., Ltd.) and 7.0 g of talc (Fuji Talc Industry Co., Ltd.) were dissolved and dispersed in 194.9 g of ethanol and 66.1 g of purified water, and 259.0 g of the enzalutamide solid dispersion was added to a tumbling fluidized bed granulator (MP-01, Powrex Corporation) and fine particle coating was performed at a rotor rotation speed of 300 rpm, an intake air flow rate of 0.35 L / min to 0.40 L / min, an intake air temperature of 60.0°C to 65.0°C, and a spray liquid rate of 3 g / min to obtain coated granules.

[0069] [Polymer Screening] Screening for polymers that enable the maintenance of a supersaturated state in enzalutamide solid dispersions was carried out using the polymers shown in Table 1. Screening was carried out by evaluating the dissolution of enzalutamide in accordance with the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia.

[0070]

[0071] 20 mL of the second dissolution test fluid was taken from a vessel (900 mL), and 120 mg of hypromellose acetate succinate (HPMC: Shin-Etsu AQOAT (registered trademark) AS, Shin-Etsu Chemical Co., Ltd.) LMP, MMP, or HMP (also referred to herein as simply L, M, or H, respectively, by their initials) was dissolved therein. The solution was returned to the vessel, and the dissolution properties of the coated granules were then evaluated.

[0072] 10 mL of the second dissolution test solution in the vessel (900 mL) was discarded, and 120 mg of aminoalkyl methacrylate copolymer (Eudragit (registered trademark) E PO, Evonik) was dissolved in 10 mL of the first dissolution test solution. After the solution was added to the vessel, the dissolution properties of the coated granules were evaluated.

[0073] For polymers other than those listed above, 10 mL of the second dissolution test solution was taken from a vessel (900 mL) and 120 mg of each polymer was dissolved therein. After the solution was returned to the vessel, the dissolution properties of the coated granules were evaluated. Eudragit (registered trademark) L 100 and L 100-55 from Evonik were used as methacrylic acid copolymers. Kollidon (registered trademark) VA64 from BASF and K-90 from Dai-ichi Kogyo Seiyaku Co., Ltd. were used as polyvinylpyrrolidone. L, M, and H from Nippon Soda Co., Ltd. were used as HPC. TC-5 (registered trademark) M and R from Shin-Etsu Chemical Co., Ltd. were used as hypromellose (hydroxypropyl methylcellulose). METOLOSE (registered trademark) SM-4 from Shin-Etsu Chemical Co., Ltd. was used as methylcellulose. Kollicoat (registered trademark) IR from BASF was used as the polyvinyl alcohol-polyethylene glycol graft copolymer. PEG 6000 was used as the macrogol. POVACOAT (registered trademark) MP from Daido Chemical Industry Co., Ltd. was used as the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. As a control, the dissolution properties of the coated granules of Reference Example 1 alone, without adding any polymer to the second solution for the dissolution test, were also evaluated.

[0074] The evaluation results of the dissolution properties of enzalutamide from the enzalutamide solid dispersions are shown in Figures 1 to 3. Based on the dissolution curve of Reference Example 1 alone, it was revealed that hypromellose acetate succinate (Shin-Etsu AQOAT (registered trademark) AS-L), HPC L, M, and H, hypromellose (TC-5 (registered trademark) M and R), and methylcellulose (METOLOSE (registered trademark) SM-4) do not affect the maintenance of the supersaturated state of enzalutamide. On the other hand, polyvinylpyrrolidone (Kollidon® VA64, K-90), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT®), macrogol (PEG 6000), and methacrylic acid copolymer (Eudragit® L 100 and L 100-55) weakened the maintenance of the supersaturated state of enzalutamide. In contrast, M and H of hypromellose acetate succinate (HPMC: Shin-Etsu AQOAT® AS, Shin-Etsu Chemical Co., Ltd.) and aminoalkyl methacrylate copolymer (Eudragit® E PO) were found to improve the supersaturated state of enzalutamide.

[0075] The polymers that were confirmed to have the effect of increasing the supersaturation state of enzalutamide were further examined using solid dispersions without a coating.

[0076] Reference Example 2 6.4 g of enzalutamide, 28.8 g of HPC (L, Nippon Soda Co., Ltd.), and 0.2 g of tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 0.32 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion.

[0077] The dissolution properties of enzalutamide solid dispersions were evaluated under the conditions described above for hypromellose acetate succinate (HPMC: Shin-Etsu AQOAT® AS, Shin-Etsu Chemical Co., Ltd.) M and H, and aminoalkyl methacrylate copolymer (Eudragit® E PO). For ammonioalkyl methacrylate copolymer (Eudragit® RS 30 D, Evonik), 400 μL of the second solution for dissolution test in a 900 mL vessel was discarded, and 400 μL (120 mg as solids) of Eudragit® RS 30 D was added and mixed. The dissolution properties of the enzalutamide solid dispersions were then evaluated. As a control, the dissolution properties of the enzalutamide solid dispersion of Reference Example 2 alone, without adding any polymer to the second solution for dissolution test, were also evaluated.

[0078] The evaluation results of the dissolution of enzalutamide from the enzalutamide solid dispersion are shown in Figure 4. The results in Figure 4 demonstrate that the cationic polymers Eudragit (registered trademark) EPO and Eudragit (registered trademark) RS 30 D improve the supersaturation maintenance effect of enzalutamide. In particular, for Eudragit (registered trademark) EPO, a high dissolution rate of more than 80% was confirmed even after 360 minutes, demonstrating a dramatic improvement in the supersaturation maintenance effect of enzalutamide.

[0079] The amount of HPC contained in the enzalutamide solid dispersion was investigated.

[0080] [Reference Example 3] The enzalutamide solid dispersion of Reference Example 2 was prepared so that 360 mg of HPC was used per 80 mg of enzalutamide. In Reference Example 3, an enzalutamide solid dispersion was prepared so that 320 mg of HPC was used per 80 mg of enzalutamide. Specifically, 64.0 g of enzalutamide, 256.0 g of HPC (L, Nippon Soda Co., Ltd.), and 2.0 g of tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific Inc.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 3.2 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion.

[0081] The dissolution properties of enzalutamide were evaluated using the enzalutamide solid dispersions of Reference Examples 2 and 3 using the evaluation method for Eudragit (registered trademark) EPO described above. As a control, the dissolution properties of the enzalutamide solid dispersions alone of Reference Examples 2 and 3 described above were also evaluated. The evaluation results are shown in Figure 5. The results in Figure 5 demonstrate that the supersaturated state of enzalutamide is maintained even when the content of the carrier HPC is reduced.

[0082] Using the enzalutamide solid dispersion of Reference Example 2, the effect of the amount of Eudragit (registered trademark) EPO on maintaining the supersaturated state of enzalutamide was examined. 10 mL of the second dissolution test solution in the vessel (900 mL) was discarded, and 30 mg, 60 mg, 90 mg, 120 mg, or 150 mg of Eudragit (registered trademark) EPO was dissolved in 10 mL of the first dissolution test solution. After adding the dissolution solution to the vessel, the dissolution properties of the enzalutamide solid dispersion were evaluated. As a control, the dissolution properties of the enzalutamide solid dispersion of Reference Example 2 alone were also evaluated.

[0083] The evaluation results are shown in Figure 6. The results in Figure 6 reveal that the effect of maintaining the supersaturated state of enzalutamide improves in proportion to the amount of Eudragit (registered trademark) EPO added.

[0084] The influence of the dissolution environment (pH of the dissolution test solution) on maintaining the supersaturated state of enzalutamide was investigated using the enzalutamide solid dispersion of Reference Example 2. In the first dissolution test solution at pH 1.2, the dissolution properties of the enzalutamide solid dispersion of Reference Example 2 alone and the mixed powder of the enzalutamide solid dispersion of Reference Example 2 and Eudragit (registered trademark) E PO (30 mg, 60 mg, 90 mg, or 120 mg) were evaluated by the method described above.

[0085] The evaluation results are shown in Figure 7. Here, in the "Guidelines for Bioequivalence Testing of Generic Drugs" (revised March 19, 2020), "IV. Dissolution Test" of "B. Oral Sustained-Release Preparations" section, "2. Test Time" states that, taking into account the drug residence time in the stomach, "the test time is usually 24 hours, but can be completed in 2 hours at pH 1.2." The results in Figure 7 demonstrate that even in an acidic environment, the effect of Eudragit® E PO in maintaining the supersaturated state of enzalutamide can be sufficiently achieved for a period of 2 hours or more.

[0086] The evaluation results for Eudragit (registered trademark) EPO in powder form were compared with those for Eudragit (registered trademark) EPO in the above-mentioned liquid form. 10 mL of the first liquid for dissolution testing in a 900 mL vessel was collected, and 120 mg of Eudragit (registered trademark) EPO was dissolved in the liquid. After the solution was returned to the vessel, the dissolution properties of the enzalutamide solid dispersion of Reference Example 2 were evaluated.

[0087] The comparison results are shown in Figure 8. From the results in Figure 8, it was inferred that the effect of maintaining the supersaturated state of enzalutamide was greater when Eudragit (registered trademark) EPO was added as a liquid, and therefore the effect of maintaining the supersaturated state of enzalutamide was greater when Eudragit (registered trademark) EPO was quickly dissolved.

[0088] Example 1 1.6 g of enzalutamide, 4.8 g of HPC (L, Nippon Soda Co., Ltd.), 2.4 g of Eudragit® E PO, and 0.8 g of tartaric acid were charged into an extruder (HAAKE® MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 0.08 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and a rotation speed of 12,000 rpm to obtain an enzalutamide solid dispersion.

[0089] Example 2 4.0 g of enzalutamide, 6.0 g of HPC (L, Nippon Soda Co., Ltd.), 12.0 g of Eudragit® E PO, and 4.0 g of tartaric acid were charged into an extruder (HAAKE® MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 0.2 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion.

[0090] Example 3 1.6 g of enzalutamide, 7.2 g of Eudragit (registered trademark) E PO, and 2.4 g of tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and a hot-melt extrudate was obtained at 210°C and a screw rotation speed of 80 rpm. The hot-melt extrudate and 0.08 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion.

[0091] The enzalutamide solid dispersions of Reference Example 2 and Examples 1 to 3 were evaluated by powder X-ray diffraction measurement to determine whether enzalutamide was in an amorphous state. Figure 9 shows the results of evaluation of the amorphous state of enzalutamide by powder X-ray diffraction measurement. As a control, the measurement results of enzalutamide crystals are also shown. From the measurement results in Figure 9, no diffraction peaks specific to enzalutamide crystals were observed in the enzalutamide solid dispersions of Reference Example 2 and Examples 1 to 3. That is, it was confirmed that enzalutamide was in an amorphous state in the enzalutamide solid dispersions of Reference Example 2 and Examples 1 to 3.

[0092] The dissolution properties of the enzalutamide solid dispersions of Reference Example 2 and Examples 1 to 3 were evaluated using the first or second dissolution test fluid. The results of the evaluation using the first dissolution test fluid (pH 1.2) are shown in Figure 10 . The results of the evaluation using the second dissolution test fluid (pH 6.8) are shown in Figure 11 . It was revealed that, regardless of the pH environment, the enzalutamide solid dispersion containing the cationic polymer Eudragit (registered trademark) EPO as a base or carrier had an improved effect of maintaining the supersaturated state of enzalutamide, and this effect persisted for more than 2 hours.

[0093] Comparative Example 1: Whether the effect of maintaining the supersaturated state of enzalutamide could be achieved even when other cationic additives were used was investigated. 10 mL of the second dissolution test solution was taken from a vessel (900 mL), and 120 mg of arginine was dissolved therein. After the solution was returned to the vessel, the dissolution properties of the enzalutamide solid dispersion of Comparative Example 2 were evaluated.

[0094] [Comparative Example 2] 10 mL of the second solution for dissolution test in a vessel (900 mL) was taken, and 120 mg of histidine was dissolved in it. After the solution was returned to the vessel, the dissolution property of the enzalutamide solid dispersion of Comparative Example 2 was evaluated.

[0095] The evaluation results are shown in Figure 12. The results in Figure 12 reveal that even if an amino acid is used as a cationic additive, it is unable to maintain the supersaturated state of enzalutamide. It has become clear that in order to maintain the supersaturated state of enzalutamide, it is necessary to use a cationic polymer as a base or carrier for the enzalutamide solid dispersion.

[0096] [Method of grinding additives used in Examples 4, 5 and Comparative Example 3] Eudragit (registered trademark) E100 was ground using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 1.0 mm and 6,000 rpm. Tartaric acid, potassium chloride, and sodium chloride were ground using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm. Aspartic acid was ground using a sample mill (KIIWG-1F, Dalton Co., Ltd.) at a diameter of 1.0 mm and 12,000 rpm. Ground products of these additives were used in Examples 4, 5, and Comparative Example 3.

[0097] [Method for producing the additive granulation part used in Examples 4 and 5] 81 parts of D-mannitol (Mannit P, Mitsubishi Corporation Life Sciences Co., Ltd.), 5 parts of low-substituted hydroxypropyl cellulose (NBD-022, Shin-Etsu Chemical Co., Ltd.), 2 parts of crospovidone (Kollidon (registered trademark) CL-F, BASF), 2 parts of crospovidone (Kollidon (registered trademark) CL-M, BASF), and 10 parts of microcrystalline cellulose (Ceolus (registered trademark) PH101, Asahi Kasei Corporation) were mixed in the proportions used in a fluidized bed granulation apparatus, and fluidized bed granulation was carried out while spraying purified water onto the resulting mixture. The resulting granules were sized using a No. 22 sieve to obtain an additive granulation part.

[0098] Example 4 A formulation containing the enzalutamide solid dispersion according to the present invention was further investigated in Example 4. 160 g of enzalutamide, 160 g of HPC (L, Nippon Soda Co., Ltd.), 480 g of aminoalkyl methacrylate copolymer (EUDRAGIT (registered trademark) E100), and 5.0 g of tartaric acid were charged into an extruder (PHARMA11 twin-screw compounder, Thermo Fisher Scientific K.K.) at a powder supply rate of 0.5 kg / hr, and extruded at a maximum barrel temperature of 210°C and a screw rotation speed of 400 rpm to obtain a hot-melt extrudate. To the obtained hot-melt extrudate, 4.0 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added, and the mixture was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 1.0 mm and 12,000 rpm to obtain the solid dispersion of Example 4.

[0099] 6.07 g of the obtained solid dispersion, 2.57 g of the additive granulation part described above, 2.4 g of tartaric acid, 0.72 g of crospovidone (Kollidon (registered trademark) CL-F, BASF), 1.5 g of potassium chloride, and 0.24 g of sodium stearyl fumarate (PRUV, Rettenmaier Japan) were mixed in a vinyl bag and compressed into tablets using a manual tablet press (TK-HP20KN, Tokushu Keisoku Co., Ltd.) to obtain enzalutamide-containing tablets of Example 4 each weighing 900 mg.

[0100] [Example 5] Film-coated tablets were produced in Example 5. Specifically, 160 g of enzalutamide, 80 g of HPC (L, Nippon Soda Co., Ltd.), 560 g of aminoalkyl methacrylate copolymer (EUDRAGIT (registered trademark) E100), and 5.0 g of tartaric acid were charged into an extruder (PHARMA11 twin-screw compounder, Thermo Fisher Scientific K.K.) at a powder feed rate of 0.5 kg / hr, and extruded at a maximum barrel temperature of 220°C and a screw rotation speed of 400 rpm to obtain hot-melt extrudates. To the obtained hot-melt extrudate, 4.0 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added, and the mixture was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 1.0 mm and 12,000 rpm to obtain the solid dispersion of Example 5.

[0101] 80.9 g of the obtained solid dispersion, 11.3 g of the additive granulation portion, 5.0 g of fumaric acid, 30.0 g of aspartic acid, 9.6 g of crospovidone (Kollidon (registered trademark) CL-F, BASF), 20.0 g of potassium chloride, 20.0 g of sodium chloride, and 3.2 g of sodium stearyl fumarate (PRUV, Rettenmaier Japan) were mixed in a plastic bag and compressed into tablets using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain enzalutamide-containing tablets (plain tablets) of Example 5, each weighing 900 mg.

[0102] A film coating solution was prepared by stirring and dissolving and dispersing 8.4 g of polyvinyl alcohol (partially saponified) (EG-05 PW, Mitsubishi Chemical Corporation), 4.2 g of Macrogol 6000 (NOF Corporation), 5.6 g of titanium oxide (NA61, Toho Titanium Co., Ltd.), 2.8 g of D-mannitol (Mannit P) and 0.5 g of yellow ferric oxide (Kishi Kasei Co., Ltd.) in 105 g of purified water using a mixer. The above-mentioned plain tablets were coated with the film coating solution until the mass per tablet increased by approximately 30 mg, thereby producing the film-coated tablets of Example 5.

[0103] [Comparative Example 3] In Comparative Example 3, tablets containing only HPC as the polymer were produced. Specifically, 64.0 g of enzalutamide, 288.0 g of HPC (L, Nippon Soda Co., Ltd.), and 2.0 g of tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific Inc.), and a hot-melt extrudate was obtained at 210 ° C. and a screw rotation speed of 80 rpm. The hot-melt extrudate and 3.2 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) were pulverized using a rotor speed mill (P-14, Fritsch Japan) under conditions of a diameter of 0.5 mm and 12,000 rpm, to obtain the enzalutamide solid dispersion of Comparative Example 3.

[0104] 39.29 g of the obtained solid dispersion, 12.1 g of crystalline cellulose (PH-102), 2.64 g of croscarmellose sodium (Acdisol), 1.76 g of hydroxypropyl cellulose (HPC-SSL SFP), 7.04 g of potassium chloride, and 0.53 g of magnesium stearate (plant-derived, Taihei Chemical Industry Co., Ltd.) were mixed in a vinyl bag and compressed into tablets using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain enzalutamide-containing tablets of Comparative Example 3, each weighing 720 mg.

[0105] A film coating solution was prepared by stirring and dissolving 21.0 g of hypromellose (TC-5M), 2.0 g of Macrogol 6000 (NOF Corporation), 2.0 g of titanium oxide (NA61, Toho Titanium Co., Ltd.), 2.0 g of talc (Fuji Talc Industrial Co., Ltd., ML115), and 0.14 g of yellow ferric oxide (Kishi Kasei Co., Ltd.) in 250.0 g of purified water using a mixer. The above-mentioned plain tablets were coated with the film coating solution until the mass per tablet increased by approximately 27 mg, producing the film-coated tablets of Comparative Example 3.

[0106] The dissolution properties of the enzalutamide-containing formulations (tablets or film-coated tablets) of Examples 4 to 5 and Comparative Example 3 were evaluated using the first or second dissolution test fluid. The results of the evaluation using the first dissolution test fluid (pH 1.2) are shown in Figure 13 . The results of the evaluation using the second dissolution test fluid (pH 6.8) are shown in Figure 14 . It was revealed that, regardless of the pH environment, the formulations containing enzalutamide solid dispersions containing the cationic polymer Eudragit (registered trademark) E 100 as a base or carrier exhibited an improved effect of maintaining the supersaturated state of enzalutamide, and this effect persisted for 2 hours or more. On the other hand, the tablets of Comparative Example 3, which contained only HPC as the polymer, did not exhibit the effect of maintaining the supersaturated state of enzalutamide in the second dissolution test fluid.

Claims

1. A pharmaceutical composition comprising an enzalutamide solid dispersion comprising an amorphous form of enzalutamide and a base, wherein the pharmaceutical composition comprises a pharmaceutically acceptable cationic polymer.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable cationic polymer is a pharmaceutically acceptable cationic acrylic polymer or a pharmaceutically acceptable cationic vinyl polymer.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable cationic acrylic polymer is an aminoalkyl methacrylate copolymer or an ammonioalkyl methacrylate copolymer.

4. The pharmaceutical composition of claim 3, wherein the base comprises the pharmaceutically acceptable cationic polymer.

5. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable cationic polymer is disposed externally of the enzalutamide solid dispersion.

6. The pharmaceutical composition according to claim 3, wherein the base comprises the pharmaceutically acceptable cationic polymer, and the pharmaceutically acceptable cationic polymer is also disposed outside the enzalutamide solid dispersion.

7. The pharmaceutical composition described in claim 1, further comprising a pharmaceutically acceptable acidic pH adjuster, wherein the pharmaceutically acceptable acidic pH adjuster is contained inside the enzalutamide solid dispersion and / or outside the enzalutamide solid dispersion.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable acidic pH adjusting agent is an organic acid.

9. The pharmaceutical composition of claim 8, wherein the organic acid is one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, and fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

10. The pharmaceutical composition of claim 1, wherein the base comprises hydroxypropyl cellulose.

11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises a fluidizing agent disposed externally to the enzalutamide solid dispersion.

12. A formulation comprising the pharmaceutical composition of any one of claims 1 to 11 and one or more pharmaceutically acceptable excipients.

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