Apalutamide-containing pharmaceutical composition

Abstract

The present invention provides an apalutamide-containing pharmaceutical composition that maintains the stability of apalutamide in the formulation and exhibits excellent apalutamide dissolution from the formulation. [Solution] A pharmaceutical composition containing an apalutamide solid dispersion containing an enteric-coated polymer, and a polymer and / or a surfactant.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing apalutamide.

Background Art

[0002] Apalutamide is an oral androgen receptor signaling inhibitor, a small molecule compound that blocks the androgen signaling pathway in prostate cancer cells, selectively inhibits androgen from binding to the androgen receptor (AR), and inhibits the growth of cancer cells.

[0003] In Japan, it was approved for manufacturing on March 26, 2019, as a drug for castration-resistant prostate cancer without distant metastasis. Apalutamide is classified into Biopharmaceutics Classification System (BCS) class 2 (low water solubility and high membrane permeability), and it is described in the package insert that it dissolves well in acetonitrile, is slightly less soluble in ethanol, and hardly dissolves in water, corresponding to a poorly soluble drug. Generally, in order for a drug to exert its effect, it needs to dissolve in the stomach or intestine and be absorbed in the living body, so it was necessary to improve the elution property of apalutamide.

[0004] Regarding the above problem, for example, Patent Document 1 discloses a solid dispersion obtained by adding hypromellose acetate succinate (HPMCAS) to apalutamide. Also, Patent Document 2 discloses a solid pharmaceutical composition of a solid dispersion obtained by adding a poly(meth)acrylate copolymer to apalutamide. Also, Patent Document 3 discloses a solid pharmaceutical composition of a solid dispersion obtained by adding HPMCAS and a poly(meth)acrylate copolymer to apalutamide. Also, Patent Document 4 discloses a pharmaceutical composition of a solid dispersion obtained by adding carboxymethylethyl cellulose (CMEC) and / or hypromellose phthalate (HPMCP) to apalutamide. Furthermore, Patent Document 5 discloses a solid dispersion containing apalutamide, a polymer, glycosylated hesperidin, or methyl hesperidin, and a surfactant, or a pharmaceutical composition containing such a solid dispersion.

[0005] However, further investigation was needed regarding the stability and dissolution properties of amorphous apalutamide in the aforementioned pharmaceutical composition. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2016 / 090098 [Patent Document 2] International Publication No. 2016 / 090101 [Patent Document 3] International Publication No. 2016 / 090105 [Patent Document 4] Japanese Patent Publication No. 2024-94310 [Patent Document 5] Japanese Patent Publication No. 2023-165408 [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention relates to providing an apalutamide-containing pharmaceutical composition that maintains the stability of apalutamide in the formulation and exhibits excellent apalutamide dissolution properties from the formulation. [Means for solving the problem]

[0008] As a result of diligent research to solve the above problems, the present inventors have found that a pharmaceutical composition containing a polymer and / or a surfactant in a solid dispersion of apalutamide containing an enteric polymer can maintain the amorphous state of apalutamide and exhibits excellent stability and dissolution properties of apalutamide, thus completing the present invention.

[0009] In other words, the present invention relates to the following 1) to 6). 1) A pharmaceutical composition containing an apalutamide solid dispersion containing an enteric-coated polymer, and a polymer and / or a surfactant. 2) The pharmaceutical composition according to 1), wherein the enteric-coated polymer is one or more selected from methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose. 3) The pharmaceutical composition according to 1), wherein the polymer is one or more selected from the group consisting of cellulose polymers, synthetic polymer monopolymers, synthetic polymer polymers, and natural polymers. 4) The surfactant is selected from the group consisting of sodium lauryl sulfate, sodium lauryl sulfonate polysorbate, sodium laurylbenzenesulfonate, sucrose fatty acid ester, polysorbate, polysorbate 80, polyoxyethylene glycol ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer. A pharmaceutical composition as described in 1), comprising one or more types. 5) A pharmaceutical composition as described in 1), which is a solid dosage form. 6) The pharmaceutical composition according to 5), wherein the solid dosage form is a tablet. [Effects of the Invention]

[0010] According to the present invention, it is possible to provide an apalutamide-containing pharmaceutical composition that exhibits excellent stability and dissolution properties of apalutamide. [Modes for carrying out the invention]

[0011] The apalutamide solid dispersion of the present invention refers to a solid in which at least a portion of apalutamide is dispersed at the molecular level within an enteric-coated polymer. The apalutamide contained in the solid dispersion is substantially free of crystalline apalutamide, meaning it contains substantially only amorphous apalutamide. "Substantially free of crystalline apalutamide" means that when the solid dispersion is subjected to powder X-ray diffraction (XRD) and the resulting diffraction spectrum is predominantly detected as a halo pattern corresponding to amorphous apalutamide, and no peaks for crystalline apalutamide are detected. The apalutamide solid dispersion of the present invention mainly takes the form of a powder or particulate matter.

[0012] In the present invention, apalutamide can be produced by known methods, for example, the method described in International Publication No. 2007 / 126765.

[0013] Enteric-coated polymers are used in the preparation of solid dispersions, specifically, enteric-coated methacrylic acid copolymers such as methacrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD, and methyl acrylate / methyl methacrylate / methacrylic acid copolymer; and enteric-coated cellulose polymers such as methylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose acetate maleate, hydroxypropyl methylcellulose trimellitate, carboxymethyl ethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, and cellulose acetate succinate. Examples include enteric-coated vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate, preferably enteric-coated methacrylic acid copolymers (preferably methacrylic acid copolymer L, methacrylic acid copolymer LD), enteric-coated cellulose polymers, more preferably enteric-coated cellulose polymers, and even more preferably hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose acetate maleate, cellulose acetate phthalate, and carboxymethyl ethyl cellulose, among which hydroxypropyl methyl cellulose phthalate is preferred. These enteric-coated polymers can be used individually or in combination of two or more. When using a mixture of two or more enteric-coated polymers, preferred examples include carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxymethyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, and it is preferable to blend them in a weight ratio of 1:10 to 10:1, preferably in the range of 1:5 to 5:1.

[0014] The content of the enteric polymer in the apalutamide solid dispersion can be used in a weight ratio of 1:0.2 to 1:20 with respect to apalutamide, preferably 1:0.3 to 1:15, more preferably 1:0.5 to 1:10, still more preferably 1:0.5 to 1:5, and still more preferably 1:1 to 1:5.

[0015] Such an apalutamide solid dispersion can be produced, for example, by preparing a spray solution of apalutamide and one or more enteric polymers, spraying the obtained spray solution into an air stream (spray method), and removing the solvent from the droplets formed by spraying, or by spraying the spray solution onto a flowing carrier and removing the solvent (granulation).

[0016] <{ As the solvent used in the above spray solution, any solvent that can dissolve apalutamide can be used. For example, alcohols such as methanol, ethanol, and 2-propanol; ketones such as acetone, 2-butanone, and methyl isobutyl ketone; ethers such as tetrahydrofuran (THF), tetrahydropyran (THP), 1,4-dioxane, diethyl ether, diisopropyl ether, and t-butyl methyl ether; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane and chloroform; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO); aromatic hydrocarbons such as toluene; esters such as methyl acetate, ethyl acetate, and butyl acetate; organic acids such as acetic acid and formic acid; and mixed solvents thereof. The solvent is selected according to the solubility of the enteric polymer used. In addition, these solvents can be used as a mixture with water within the range where apalutamide is soluble. For example, THF and water, acetone and water, ethanol and water, etc. are included. Examples of the mixed solvent include a mixed solvent of dichloromethane and methanol or ethanol.

[0017] The spray solution only needs to have no undissolved residue and be at a concentration that can be sprayed. For example, the solid content is 0.1 to 80% by mass, preferably 1 to 70% by mass.

[0018] Examples of the spray method include, for example, the fluidized bed method, the spray drying method, the rolling fluidized bed method, etc. Among them, the spray drying method or the fluidized bed method is preferred because particles can be formed in a short time in an air stream and the elution property of the obtained particles is high.

[0019] The spray drying method is carried out using a disk type or nozzle type (for example, a pressure nozzle, a two-fluid nozzle, a four-fluid nozzle) spray dryer. As the temperature during spray drying, the inlet temperature is preferably about 30 to 150°C, and the outlet temperature is preferably about 10 to 80°C.

[0020] Moreover, the apalutamide solid dispersion may be supported by a carrier.

[0021] The solid dispersion supported by the carrier can be produced by spraying the above-mentioned spray liquid onto the carrier by the fluidized bed method, the rolling fluidized bed method, etc. in the production of the solid dispersion.

[0022] As the carrier, additives that can be used in pharmaceuticals can be used. For example, saccharides (glucose, fructose, lactose (including lactose hydrate), sucrose, trehalose, maltose, oligosaccharides, etc.), crystalline celluloses (crystalline cellulose, etc.), starches (corn starch, potato starch, rice starch, wheat starch, etc.), sugar alcohols (mannitol, erythritol, xylitol, sorbitol, maltitol, etc.), sodium phosphates, calcium phosphates (calcium hydrogen phosphate, etc.), gelatin, sucrose-starch spherical granules, lactose-crystalline cellulose spherical granules, spherical silicon dioxide, etc. can be mentioned.

[0023] In the case of the fluidized bed method or the rolling fluidized bed method, an enteric polymer is added to the solution of apalutamide, and the obtained solution is sprayed onto the carrier to obtain a solid dispersion supported by the carrier. The enteric polymer also functions as a binder.

[0024] The solid dispersion obtained by the fluidized bed method or the rolling fluidized bed method has a particle structure in which a drug layer containing amorphous apalutamide and an enteric polymer is formed around the carrier.

[0025] The above-described fluidized bed method and rolling-bed fluidized bed method can be carried out under conditions commonly used in pharmaceutical manufacturing. Furthermore, drying can be performed as appropriate after granulation to remove residual solvents.

[0026] The average particle size of the obtained apalutamide solid dispersion is 1 to 100 μm, preferably 1 to 80 μm, and more preferably 2 to 60 μm. The average particle size is the median diameter (D50) based on volume and can be measured using a dry laser diffraction / scattering particle size distribution analyzer.

[0027] Furthermore, the above apalutamide solid dispersion may contain the following pharmaceutical additives (excipients, lubricants, plasticizers, binders, disintegrants, fluidizers, surfactants, colorants, antistatic agents, etc.) to the extent that they do not affect the amorphous state of apalutamide.

[0028] The pharmaceutical composition of the present invention contains, in addition to the above-mentioned apalutamide solid dispersion, a polymer and / or a surfactant. The stability of apalutamide in a pharmaceutical composition is improved by the coexistence of polymers and / or surfactants. Here, improved stability of apalutamide means that (1) the amorphous state of amorphous apalutamide is maintained, and (2) the decomposition and reaction of apalutamide are suppressed. Maintaining the amorphous state of amorphous apalutamide means that the formation of apalutamide crystals is suppressed in an environment of 40°C.

[0029] Examples of polymers used in the present invention include cellulose polymers, synthetic polymer monopolymers, synthetic polymer polymers, and natural polymers. Cellulose polymers include nonionic cellulose polymers and ionic cellulose polymers. Examples of nonionic cellulose polymers include hypromellose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose acetate, and hydroxyethylcellulose acetate.

[0030] Examples of ionic cellulose polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, ethyl carboxymethylcellulose, carboxymethyl ethylcellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose succinate phthalate, and cellulose Examples include cellulose-propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine carboxylate, cellulose salicylate acetate, hydroxypropyl salicylate acetate, ethyl benzoate acetate, hydroxypropyl ethyl benzoate acetate, ethyl phthalate acetate, ethyl nicotinate acetate, and ethyl picolinate acetate.

[0031] Examples of synthetic polymer monopolymers include polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl acetal diethylaminoacetate, and carboxyvinyl polymer.

[0032] Examples of synthetic polymer copolymers include methacrylic acid copolymer, aminoalkyl methacrylate copolymer, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol polypropylene glycol copolymer, polyethylene polyvinyl alcohol copolymer, and polyvinylpyrrolidone copolymer.

[0033] Examples of natural polymers include gum arabic, agar, guar gum, grain gum, dextran, casein, pectin, carrageenan, wax, and shellac.

[0034] Examples of such polymers include cellulose-based polymers, more preferably ionic cellulose-based polymers, even more preferably hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylacetate maleate, and more preferably hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, etc.

[0035] The amount of the polymer in the pharmaceutical composition of the present invention can be used in a weight ratio of 1:0.1 to 1:10 relative to apalutamide, preferably 1:0.2 to 1:6, more preferably 1:0.2 to 1:4, and even more preferably 1:1 to 1:4. Furthermore, two or more types of polymers can be combined and used in appropriate combinations within the above range.

[0036] Examples of surfactants used in the present invention include sodium lauryl sulfate, sodium lauryl sulfonate polysorbate, sodium laurylbenzenesulfonate, sucrose fatty acid ester, polysorbate, polysorbate 80, polyoxyethylene glycol ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer. Preferably, sodium lauryl sulfate, polysorbate, polysorbate 80, and poloxamer are used, and particularly preferably, sodium lauryl sulfate, polysorbate, and polysorbate 80.

[0037] The amount of the surfactant in the pharmaceutical composition of the present invention is 1: by weight relative to apalutamide. The ratio is 0.01 to 1:6, preferably 1:0.02 to 1:5, more preferably 1:0.02 to 1:4, and even more preferably 1:0.02 to 1:3.

[0038] The pharmaceutical composition of the present invention can be produced by mixing the apalutamide solid dispersion with a polymer and / or surfactant, and optionally with pharmaceutical additives described below. Alternatively, it can be produced by dissolving or dispersing the polymer and / or surfactant in water, methanol, ethanol, propanol, butanol, acetone, or a mixture thereof to prepare a spray solution, which is then sprayed onto the apalutamide solid dispersion and dried. Production can be carried out by generally known methods, for example, by the fluidized bed method, rolling bed method, etc.

[0039] The pharmaceutical composition of the present invention can be prepared as various solid dosage forms such as powders, granules, tablets, orally disintegrating tablets, and capsules, but tablets, orally disintegrating tablets, and capsules are preferred, and tablets are more preferred. When preparing each formulation, the following pharmaceutical additives may be added as appropriate.

[0040] Examples of pharmaceutical additives include excipients, lubricants, plasticizers, binders, disintegrants, fluidizers, surfactants, light-blocking agents, pH adjusters, colorants, and antistatic agents. Specifically, these are as follows:

[0041] Excipients include, for example, sugars such as lactose, sucrose, trehalose, and glucose; sugar alcohols such as D-mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, and xylitol; crystalline cellulose; anhydrous calcium hydrogen phosphate; magnesium aluminometasilicate; and preferably lactose, sugar alcohol, or crystalline cellulose.

[0042] Lubricant: For example, talc, glyceryl monostearate, macrogol, magnesium stearate, calcium stearate, or sodium stearyl fumarate, preferably talc, glyceryl monostearate, magnesium stearate, calcium stearate, or sodium stearyl fumarate, most preferably magnesium stearate.

[0043] Plasticizers include, for example, polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, propylene glycol, glycerin, castor oil, polyoxyethylene hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, sorbitan monolaurate, monostearin, poloxamer, and polysorbate, with triethyl citrate being preferred.

[0044] Binders: Examples include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, macrogol, Pluronic® F68, gum arabic, gelatin, starch, etc. Preferably, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose are used, and more preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose are used.

[0045] Disintegrants include, for example, starches such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, and hydroxypropyl starch.

[0046] Fluidizing agents include, for example, talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate.

[0047] Surfactants include, for example, sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer. Surfactants can be added to improve the elution rate of apalutamide, particularly to improve the elution rate up to about 10 minutes. The addition ratio (mass ratio) of the surfactant to apalutamide is 1:0.01 to 1:2, preferably 1:0.02 to 1:1.5.

[0048] Light-blocking agent: Examples include titanium dioxide, zinc oxide, talc, iron oxides such as yellow iron(III) oxide, iron(III) oxide, and black iron oxide, food yellow No. 5, food red No. 102, and titanium dioxide is preferred.

[0049] Coating agents include, for example, hypromellose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and methacrylic acid copolymer.

[0050] Colorants: For example, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel Examples include talc, etc.

[0051] Antistatic agents include, for example, silicon dioxide (including hydrated silicon dioxide), anhydrous silicon, talc, titanium dioxide, stearic acid, magnesium stearate, calcium stearate, and glycerol monostearate.

[0052] When formulating the pharmaceutical composition of the present invention as tablets, the necessary pharmaceutical additives should be added to the components of the present invention as described above, mixed, and then compressed and molded using a tablet press.

[0053] Mixing can be carried out by commonly used mixing methods, such as mixing, kneading, and granulation. Mixing can be performed using, for example, a high-speed agitator, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double-cone mixer, a ribbon mixer, a swirling screw mixer, or manual mixing in bags.

[0054] Compression molding can be performed using rotary tablet presses or the like commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ10mm tablet, it is 2 to 15kN, preferably 5 to 15kN. At this time, the set hardness is 30 to 200N, preferably 40 to 180N, and more preferably 50 to 150N.

[0055] The dissolution properties of such tablets can be measured by the following method. (Measurement of elution properties) Dissolution was measured using the Japanese Pharmacopoeia dissolution test method, except that a second dissolution test solution (pH 6.8) was prepared by adding 1 volume of water to 1 volume of phosphate buffer at pH 6.8, and the paddle method was used under conditions of 50 rpm.

[0056] Although preferred embodiments of the present invention have been described above, the present invention is not limited to these examples. The combinations shown in the above examples are merely examples, and various modifications can be made based on design, specifications, etc., without departing from the spirit of the present invention. [Examples]

[0057] (Example 1) A spray solution was prepared by dissolving 5 g of crystalline apalutamide and 15 g of hydroxypropyl methylcellulose phthalate (HPMCP) in a mixed solvent of 210 g of dichloromethane and 70 g of ethanol. A white powder was obtained from the resulting spray liquid using a spray drying apparatus. The operating conditions of the apparatus were: airflow rate 0.5 m³ / min, spray liquid input temperature 70°C, exhaust temperature 40°C, and flow rate 8 mL / min. The obtained powder was dried under reduced pressure at 40°C overnight to obtain 16 g of solid dispersion powder. The obtained solid dispersion powder and 4 g of hydroxypropyl methylcellulose acetate succinate (HPMCAS) were mixed in a plastic bag to obtain 20 g of the pharmaceutical composition of the present invention. XRD measurements of the obtained powder confirmed that there were no peaks indicating apalutamide crystals, thus maintaining the amorphous state of apalutamide.

[0058] (Examples 2) to (Examples 11) The pharmaceutical composition of the present invention was prepared in the same manner as in Example 1, according to the formulation shown in Table 1.

[0059] [Table 1]

[0060] (Example 12) A pharmaceutical composition was prepared by mixing 50 parts by mass of the solid dispersion-containing pharmaceutical product prepared in Example 1, 1 part by mass of light anhydrous silicic acid, 28 parts by mass of lactose, 10 parts by mass of crystalline cellulose, 10 parts by mass of croscarmellose sodium, and 1 part by mass of magnesium stearate. The composition was compressed using a φ12 × R14 punch at a set hardness of 100N to obtain 600 mg tablets containing 60 mg of apalutamide.

[0061] (Examples 13) to (Examples 22) Using the pharmaceutical compositions prepared in (Examples 2) to (Example 11), 600 mg tablets containing 60 mg of apalutamide were obtained in the same manner as in Example 12.

[0062] (Examples 23) to (Examples 32) The pharmaceutical composition of the present invention was prepared in the same manner as in Example 1, according to the formulation shown in Table 2.

[0063] [Table 2]

[0064] (Examples 33) to (Examples 42) Using the pharmaceutical compositions prepared in (Examples 23) to (Examples 32), 600 mg tablets containing 60 mg of apalutamide were obtained in the same manner as in Example 12.

Claims

1. A pharmaceutical composition containing an apalutamide solid dispersion containing an enteric-coated polymer, and a polymer and / or a surfactant.

2. The pharmaceutical composition according to claim 1, wherein the enteric-coated polymer is one or more selected from methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and carboxymethyl ethylcellulose.

3. The pharmaceutical composition according to claim 1, wherein the polymer is one or more selected from the group consisting of cellulosic polymers, synthetic polymer monopolymers, synthetic polymer polymers, and natural polymers.

4. The pharmaceutical composition according to claim 1, wherein the surfactant is one or more selected from the group consisting of sodium lauryl sulfate, sodium lauryl sulfonate polysorbate, sodium laurylbenzene sulfonate, sucrose fatty acid ester, polysorbate, polysorbate 80, polyoxyethylene glycol ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer.

5. The pharmaceutical composition according to claim 1, which is a solid dosage form.

6. The pharmaceutical composition according to claim 5, wherein the solid dosage form is a tablet.

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