Patent Description:
More particularly, the present invention relates to a pharmaceutical composition for oral administration comprising enzalutamide and polyvinyl alcohol.

In recent drug discovery research, poorly water-soluble drugs often become candidates for development. Alternatively, there is also a need to improve medical opportunities through early provision of therapeutic drugs in clinical settings, and general-purpose solubilization technology remains an important issue.

Enzalutamide is an androgen receptor signaling inhibitor. The chemical name is <NUM>-{<NUM>-[<NUM>-cyano-<NUM>-(trifluoromethyl)phenyl]-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>-sulfanylideneimidazolidin-<NUM>-yl}-<NUM>-fluoro-N-methylbenzamide, and is represented by the following chemical structural formula:
<CHM>.

Enzalutamide is known as an active ingredient in therapeutic agents for metastatic castration-resistant prostate cancer or the like (Patent literature <NUM>). Enzalutamide is on the market as soft capsules ("XTANDI (registered trademark)") comprising <NUM> of enzalutamide per capsule and pharmaceutical additives. According to the Package Insert of the product (Non-patent literature <NUM>), <NUM> is orally administered to an adult once daily, and this indicates that capsules with a major axis of approximately <NUM> and a minor axis of approximately <NUM> are taken in one dose of four capsules. In particular, a reasonably sized single tablet containing a predetermined amount of enzalutamide and having appropriate and good solubility and/or dissolution stability, and oral absorbability, would be useful as a suitable replacement for the soft capsules.

As methods of solubilizing enzalutamide, a method of amorphizing enzalutamide, and methods of preparing a solid dispersion of enzalutamide with a carrier, are known (Patent literatures <NUM> to <NUM>).

[Non-patent literature <NUM>] "XTANDI (registered trademark) Capsule <NUM>" Package Insert.

Even in the current situation, formulation design to improve the solubility of enzalutamide and improve the oral absorbability in a pH-independent manner is an important technical problem for the efficacy expression of the drug, and there is room for further improvement.

An object of the present invention is to provide a pharmaceutical composition for oral administration in which, in a pH-independent manner, the solubility and/or the dissolution properties of enzalutamide are improved, and supersaturation is maintained. Another object of the present invention is to provide a pharmaceutical composition for oral administration in which the oral absorbability is improved.

By preparing a solid dispersion using enzalutamide and polyvinyl alcohol having a saponification degree of <NUM> mol% or more and less than <NUM> mol% (hereinafter sometimes abbreviated as PVA), pH-independent solubilization and/or dissolution of enzalutamide was achieved, and its supersaturation could be maintained, and further, its bioavailability was improved by oral administration to a living body.

According to the present invention, a pharmaceutical composition for oral administration in which, in a pH-independent manner, the solubility and/or the dissolution properties of enzalutamide are improved, and supersaturation is maintained can be provided. Further, a pharmaceutical composition for oral administration in which the bioavailability and the absorption rate of enzalutamide are increased can be provided.

The term "to improve solubility" as used herein means that the solubility, the dissolved concentration, or the dissolved rate of enzalutamide in a solvent is increased. More particularly, as an embodiment, with respect to the fact that the solubility of enzalutamide in water (<NUM>±<NUM>) is <NUM>µg/mL, when it is evaluated by, for example, a dissolution test of Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, or Experimental Example <NUM> described below, it is defined that the effect to improve the dissolved concentration is <NUM> times or more, <NUM> times or more in an embodiment, and <NUM> times or more in an embodiment.

The term "to improve dissolution properties" as used herein means that the dissolution rate of enzalutamide from a pharmaceutical composition is improved. More particularly, as an embodiment, when it is evaluated by a dissolution test of Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, Experimental Example <NUM>, or Experimental Example <NUM> described below, it is defined that the dissolution rate after <NUM> minutes from the beginning of the test is <NUM>% or more, and <NUM>% or more in an embodiment.

The term "to maintain supersaturation" as used herein means that enzalutamide is dissolved in a solution more than the solubility of enzalutamide. More particularly, as an embodiment, when a pharmaceutical composition comprising enzalutamide is evaluated by a precipitation test of Experimental Example <NUM> or Experimental Example <NUM> described below, it is defined that the time during which the change in the dissolved rate of enzalutamide in the pharmaceutical composition is within <NUM>%, with respect to the dissolved rate at the beginning of the test, is <NUM> minutes or longer, <NUM> minutes or longer in an embodiment, and <NUM> minutes or longer in an embodiment.

The term "to improve oral absorbability" as used herein means, as an embodiment, to have oral absorbability, absorption rate, or PK parameters equal to, or superior to those of an XTANDI (registered trademark) Capsule, which is a preceding product, in a test subject, such as a dog, a human, or the like. In particular, it means to have properties equal to or superior to those of the XTANDI (registered trademark) Capsule in a single dose.

More particularly, it is defined that, for example, the Cmax or the AUC in a dog is <NUM> times or more, preferably <NUM> times or more, and more preferably <NUM> time or more, in comparison with the XTANDI (registered trademark) Capsule.

In order to be in a state of improving oral absorbability, it means that a drug in a solution is in a state that the drug is easily absorbed, such as an amorphous state or their transition states, for example, evaluated by X-ray diffraction, Raman scattering, infrared absorption, terahertz, or the like.

The term "solid dispersion" as used herein means a dispersion comprising enzalutamide and polyvinyl alcohol, wherein most enzalutamide exists in a shapeless form. The term "shapeless" as used herein means amorphous or their transition states. Shapeless enzalutamide exists as a solid solution that is homogeneously dispersed throughout polyvinyl alcohol. The term "most" as used herein means that the crystal of enzalutamide accounts for <NUM>% or less, preferably <NUM>% or less, when the dispersion is prepared. As another embodiment, it means that the amount of the enzalutamide crystal is <NUM>% or less, preferably <NUM>% or less, and more preferably <NUM>% or less, when measured by powder X-ray diffraction, differential scanning calorimetry (DSC), or any other standard quantitative means.

The term "saponification degree" as used herein means a saponification value determined by a measurement method described in The Japanese Pharmacopoeia, Seventeenth Edition, or a measurement method correlated with the measurement method, and can be calculated by the following equation (<NUM>). In connection with this, it is desirable that the measurement method has a correlation coefficient of <NUM> or more, and <NUM> or more in an embodiment, with the measurement method described in<NPL>on. <CHM>
<MAT> [m: number of hydroxyl groups, n: number of acetyl groups].

The term "polymerization degree" as used herein means an "average polymerization degree", and is defined as a value calculated on the basis of a viscosity value when evaluated according to the Japanese Pharmaceutical Excipients or a molecular weight measured by gel filtration or the like, or a value measured according to a measurement method correlated with the measurement method. Alternatively, it is defined as a value measured by (<NUM>) Measurement Method of Average Polymerization Degree in JIS K6726 "Testing methods for polyvinyl alcohol", or a value measured according to a measurement method correlated with the measurement method. In connection with this, it is desirable that the measurement method correlated with the measurement method of a viscosity value when evaluated according to the Japanese Pharmaceutical Excipients or gel filtration or the like is a measurement method having a correlation coefficient of <NUM> or more, and <NUM> or more in an embodiment, with the measurement method of a viscosity value when evaluated according to the Japanese Pharmaceutical Excipients or gel filtration or the like. Further, it is desirable that the measurement method correlated with (<NUM>) Measurement Method of Average Polymerization Degree in JIS K6726 "Testing methods for polyvinyl alcohol" is a measurement method having a correlation coefficient of <NUM> or more, and <NUM> or more in an embodiment, with (<NUM>) Measurement Method of Average Polymerization Degree in JIS K6726 "Testing methods for polyvinyl alcohol".

The term "stable" as used herein means to have stability against, for example, heat, light, temperature, and/or humidity. For example, after a pharmaceutical composition is allowed to stand under predetermined conditions, it is defined as an embodiment in which the percentage of a maximum related substance of enzalutamide contained in the pharmaceutical composition is a specific amount or less, or it is defined as an embodiment in which, even if a solid dispersion is prepared by heating and melting, the percentage of a maximum related substance of enzalutamide contained in the pharmaceutical composition is a specific amount or less.

For example, as an embodiment, it means that the percentage of a maximum related substance of enzalutamide after storage at <NUM> for <NUM> days (tightly sealed) is <NUM>% or less, and <NUM>% or less in an embodiment.

As an embodiment, it means that the percentage of a maximum related substance of enzalutamide, after storage at <NUM> and <NUM>% relative humidity (hereinafter sometimes referred to as <NUM>, <NUM>%RH) for <NUM> month, at <NUM>, <NUM>%RH for <NUM> months, at <NUM>, <NUM>%RH for <NUM> months, at <NUM> and <NUM>% relative humidity (hereinafter sometimes referred to as <NUM>, <NUM>%RH) for <NUM> month, at <NUM>, <NUM>%RH for <NUM> months, or at <NUM>, <NUM>%RH for <NUM> months, is <NUM>% or less, and <NUM>% or less in an embodiment.

The term "maximum related substance" as used herein means the most abundant related substance among related substances of enzalutamide. More particularly, for example, when the amount of each related substance contained in a pharmaceutical composition is measured by a high-performance liquid chromatographic method (hereinafter referred to as an HPLC method), it is defined that a related substance having the largest peak area among the obtained related substances is the maximum related substance.

The term "the amount of the maximum related substance" as used herein is defined as a percentage of the maximum related substance with respect to the total peak area of enzalutamide and its related substances, when the peak area of the maximum related substance contained in a pharmaceutical composition is measured by an HPLC method.

Enzalutamide is a poorly water-soluble drug having a solubility of <NUM>µg/mL in water (<NUM>±<NUM>). It is possible to obtain good solubility and/or good dissolution properties by applying the technology of the present invention. Further, it is possible to obtain good oral absorbability by applying the technology of the present invention.

The dose of enzalutamide can be appropriately determined depending on the individual case by taking into consideration, for example, symptoms of the disease, age of the patient, race, sex, or the like.

The daily dose is, for example, about <NUM>/kg to <NUM>/kg, <NUM>/kg to <NUM>/kg in an embodiment, and <NUM>/kg to <NUM>/kg in an embodiment, which is administered once or divided into two to four doses per day. Each lower limit and each upper limit can be arbitrarily combined as desired.

The content of enzalutamide is, for example, <NUM> to <NUM>, <NUM> to <NUM> in an embodiment, <NUM> to <NUM> in an embodiment, <NUM> to <NUM> in an embodiment, and <NUM> to <NUM> in an embodiment, per pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired.

The content ratio of enzalutamide is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the total weight of the pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired.

Polyvinyl alcohol used in the present invention is not particularly limited, so long as it is pharmaceutically acceptable. The saponification degree of polyvinyl alcohol used in the present invention is <NUM> mol% or more and less than <NUM> mol%, more preferably <NUM> mol% or more and <NUM> mol% or less, and still more preferably <NUM> mol% or more and <NUM> mol% or less. Each lower limit and each upper limit above (and each lower limit and each upper limit described in the Examples below) can be arbitrarily combined as desired.

The polymerization degree of polyvinyl alcohol used in the present invention is not particularly limited, so long as it is pharmaceutically acceptable.

More particularly, the polymerization degree is, for example, less than <NUM>, <NUM> or more and less than <NUM> in an embodiment, <NUM> or more and less than <NUM> in an embodiment, <NUM> or more and less than <NUM> in an embodiment, <NUM> or more and <NUM> or less in an embodiment, <NUM> or more and <NUM> or less in an embodiment, <NUM> or more and <NUM> or less in an embodiment, and <NUM> or more and <NUM> or less in an embodiment. Each lower limit and each upper limit above (and each lower limit and each upper limit described in the Examples below) can be arbitrarily combined as desired.

Each saponification degree and each polymerization degree can be arbitrarily combined as desired, and as an embodiment, the saponification degree and the polymerization degree of polyvinyl alcohol are respectively <NUM> mol% or more and <NUM> mol% or less, and <NUM> or more and <NUM> or less.

In connection with this, polyvinyl alcohol improves the solubility and/or dissolution properties of enzalutamide, and maintains the supersaturation of enzalutamide. Further, polyvinyl alcohol has a function to improve oral absorbability of enzalutamide.

Examples of polyvinyl alcohol used in the present invention include:.

These polyvinyl alcohols may be added alone, or as a combination of two or more polyvinyl alcohols having different saponification degrees and/or polymerization degrees.

The content ratio of the polyvinyl alcohol is not particularly limited, so long as they can improve the solubility, dissolution properties and/or oral absorbability of enzalutamide. The content ratio of polyvinyl alcohol is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the total weight of the pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired. It is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the weight of enzalutamide. Each lower limit and each upper limit can be arbitrarily combined as desired.

The pharmaceutical composition for oral administration of the present invention may be, for example, a solid preparation, such as tablets, capsules, granules, powder, fine granules, or the like, and tablets in an embodiment.

The pharmaceutical composition for oral administration of the present invention may comprise a solid dispersion comprising enzalutamide and the polyvinyl alcohol.

In an embodiment, enzalutamide exists as an amorphous in the pharmaceutical composition for oral administration of the present invention.

In the pharmaceutical composition for oral administration of the present invention, it may be formulated by appropriately using various pharmaceutical additives, if desired, to the extent that the desired effects of the present invention can be achieved. Such pharmaceutical additives are not particularly limited, so long as they are pharmaceutically acceptable and pharmacologically acceptable. Examples of the pharmaceutical additives include co-disintegrants, disintegrants, fillers, corrigents, effervescent agents, sweeteners, flavors, lubricants, buffers, antioxidants, surfactants, glidants, and the like.

The co-disintegrant is not particularly limited, so long as it imparts a function to achieve rapid dissolution properties of enzalutamide to the preparation.

More particularly, examples of the co-disintegrants include potassium chloride, sodium chloride, magnesium chloride, potassium dihydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen phosphate, potassium sulfate, sodium sulfate, sodium carbonate, calcium chloride, and the like; and the examples include potassium chloride in an embodiment.

The co-disintegrants may be added alone, or as a combination of two or more.

The content ratio of the co-disintegrant is not particularly limited, so long as it can achieve rapid dissolution properties of enzalutamide. The content ratio of the co-disintegrant is <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the total weight of the pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired.

The disintegrant is not particularly limited, so long as it imparts a function to achieve rapid dissolution properties of enzalutamide to the preparation.

More particularly, examples of the disintegrants include crospovidone, low substituted hydroxypropylcellulose, crystalline cellulose, sodium carboxymethylcellulose, sodium starch glycolate, and the like; the examples include crospovidone, low substituted hydroxypropylcellulose, and the like in an embodiment; and the examples include crospovidone in an embodiment.

Examples of crospovidone include Kollidon CL (product name, BASF) and the like.

The disintegrants may be added alone, or as a combination of two or more.

The content ratio of the disintegrant is not particularly limited, so long as it can achieve rapid dissolution properties of enzalutamide. The content ratio of the disintegrant is <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the total weight of the pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired.

Examples of the fillers include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.

Examples of the corrigents include citric acid, tartaric acid, malic acid, and the like.

Examples of the effervescent agents include sodium bicarbonate, and the like.

Examples of the sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.

Examples of the flavors include lemon, lemon-lime, orange, menthol, and the like.

Examples of the lubricants include magnesium stearate, calcium stearate, stearic acid, hydrogenated oil, and the like.

Examples of the buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, and salts thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, and salts thereof; magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, and salts thereof; and the like.

Examples of the antioxidants include ascorbic acid, dibutyl hydroxytoluene, propyl gallate, and the like.

Examples of the surfactants include polysorbate <NUM>, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

Examples of the glidants include light anhydrous silicic acid, and the like.

These pharmaceutical additives may be appropriately added alone, or as a combination of two or more, in appropriate amounts. With respect to the content ratios of the pharmaceutical additives, each pharmaceutical additive may be contained in an amount such that the desired effects of the present invention may be achieved.

A "substance having a functional group capable of functioning as a hydrogen bond acceptor" may be further added.

The substance having a functional group capable of functioning as a hydrogen bond acceptor is not particularly limited, so long as it is a polymer which inhibits hydrogen bonds between polyvinyl alcohol molecules, which has a function to increase amorphous properties of polyvinyl alcohol, or which improves the stability and dissolution properties of enzalutamide. Examples thereof include substances with negative atoms, such as fluorine, oxygen, nitrogen, or the like; polyvinylpyrrolidone and copolyvidone in an embodiment; and copolyvidone in an embodiment.

Examples of copolyvidone include Kollidon VA64 (product name, BASF), Kollidon VA64 Fine (product name, BASF), and the like.

Examples of polyvinylpyrrolidone include Kollidon <NUM> (product name, BASF), and the like.

The substance having a functional group capable of functioning as a hydrogen bond acceptor may be added to the pharmaceutical composition for oral administration of the present invention in any arbitrary way, to the extent that the desired effects of the present invention can be achieved.

Examples of such an embodiment include an embodiment in which the substance having a functional group capable of functioning as a hydrogen bond acceptor is added to a solid dispersion comprising enzalutamide and polyvinyl alcohol.

The substance having a functional group capable of functioning as a hydrogen bond acceptor may be added alone, or as a combination of two or more.

The content ratio of the substance having a functional group capable of functioning as a hydrogen bond acceptor is not particularly limited, so long as rapid dissolution properties of enzalutamide can be achieved, and a stable pharmaceutical composition ca be obtained. The content ratio of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, <NUM>% by weight to <NUM>% by weight in an embodiment, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment, with respect to the total weight of the pharmaceutical composition for oral administration. Each lower limit and each upper limit can be arbitrarily combined as desired. With respect to the weight of enzalutamide, the content ratio of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment. Each lower limit and each upper limit can be arbitrarily combined as desired. With respect to the weight of polyvinyl alcohol, the content ratio of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, <NUM>% by weight to <NUM>% by weight, <NUM>% by weight to <NUM>% by weight in an embodiment, and <NUM>% by weight to <NUM>% by weight in an embodiment. Each lower limit and each upper limit can be arbitrarily combined as desired.

The pharmaceutical composition for oral administration of the present invention can be produced in accordance with known methods including, for example, amorphization of enzalutamide, mixing, granulation, forming (tableting), film coating, and the like.

The process of manufacturing the pharmaceutical composition for oral administration of the present invention will be explained below.

Examples of a method of amorphizing enzalutamide include a method of preparing a solid dispersion. The method of preparing a solid dispersion of enzalutamide and polyvinyl alcohol is not particularly limited, so long as it is a conventional method of preparing a solid dispersion. Examples of the method include a solvent method, a hot melt extrusion method, and the like.

Examples of the solvent method include a method in which after enzalutamide and polyvinyl alcohol are dissolved and/or suspended in a solvent, the solvent is removed; and the like.

The solvent used is not particularly limited, so long as enzalutamide and polyvinyl alcohol can be dissolved and/or suspended in the solvent. More particularly, examples of the solvent include methanol, dichloromethane, water, ethanol, acetone, propylene glycol, dimethyl sulfoxide, and the like; and the examples include methanol and water in an embodiment. These solvents can be appropriately used alone, or as a combination of two or more, in appropriate amounts.

Examples of a method of removing the solvent include spray drying, evaporation, freeze drying, and the like; and the examples include spray drying in an embodiment.

Examples of steps for preparing a spray solution comprising enzalutamide, which is used in the spray drying, include the steps of:.

An apparatus for spray drying is not particularly limited, so long as enzalutamide can be formed into an amorphous form, or a solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. Examples of the apparatus include a spray dryer. The conditions for spray drying are not particularly limited, so long as the solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. The outlet temperature of the spray dryer is, for example, <NUM> to <NUM>.

A method for drying is not particularly limited, so long as it is a conventional method in which it can be pharmaceutically dried. Examples of an apparatus include a forced-air dryer, a dryer under reduced pressure, a vacuum dryer, a fluidized bed dryer, and the like.

In the hot melt extrusion method, enzalutamide and polyvinyl alcohol are heated and melted, and then, cooled.

The temperature during heating and melting can be appropriately set in accordance with the melting point of enzalutamide, or the glass transition temperature of polyvinyl alcohol. The temperature is, for example, <NUM> to <NUM>. The temperature during heating and melting can be appropriately set in consideration of the solubility, dissolution properties, supersaturation maintaining ability, and/or stability of enzalutamide.

An apparatus is not particularly limited, so long as enzalutamide can be formed into an amorphous form, or the solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. Examples thereof include a twin-screw extruder.

As a carrier for solid dispersion, the "substance having a functional group capable of functioning as a hydrogen bond acceptor" may be further added.

A method for pulverization is not particularly limited, so long as it is a conventional method in which it can be pharmaceutically pulverized. Examples of an apparatus include an impact mill (Hosokawa Micron Corporation; Fine Impact Mill), a dry & wet mill (Powrex Corporation: Comil), a cutting mill granulator (Dalton Corporation; Power Mill), and the like.

A mixing method is not particularly limited, so long as it is a conventional method in which each component can be pharmaceutically and uniformly mixed. Examples of an apparatus include a V-type mixer, a ribbon-type mixer, a container mixer, a high speed mixer, and the like.

A granulation method is not particularly limited, so long as it is a conventional method in which granulation can be pharmaceutically carried out. Examples of an apparatus include a fluidized bed granulator, a melting agitation granulator, a high shear granulator, a milling (pulverization) and granulating machine, an extrusion granulator, a tumbling fluidized bed granulator, a spray granulator, a dry granulator, a twin-screw extruder, and the like; and a dry granulator in an embodiment.

A forming method is not particularly limited, so long as it is a conventional method in which forming can be pharmaceutically carried out. Examples of an apparatus include a rotary tableting machine, a single punch tableting machine, an oil press, and the like.

In the forming step, for example, a method in which a granulated product containing the solid dispersion of enzalutamide, or a mixed product (a mixed product before compression-molding, in particular, a mixed product before tableting) prepared by mixing the granulated product with various pharmaceutical additives, such as a lubricant, is compression-molded to form tablets; a direct tableting method in which the solid dispersion of enzalutamide is mixed with appropriate pharmaceutical additives, and the mixture is compression-molded to obtain tablets; or the like, may be used.

A film coating method is not particularly limited, so long as it is a conventional method in which film coating can be pharmaceutically carried out.

Examples of an apparatus include a pan coating machine, a fluidized bed coating machine, and the like.

Base materials for film coating and coloring agents may be appropriately added alone, or as a combination of two or more, in appropriate amounts.

If desired, after the film coating, the coated product may be dried. The drying method is not particularly limited, so long as it is a conventional method in which drying can be pharmaceutically carried out. Examples of an apparatus include a pan coating machine, a fluidized bed coating machine, and the like. The conditions for drying are not particularly limited, so long as the conditions are appropriately determined depending on the stability of the preparation.

Enzalutamide, which was used in the Examples below, had been prepared in accordance with a method described in <CIT>.

The present invention will now be further illustrated by, but is by no means limited to, the following Examples, Comparative Examples, and Experimental Examples.

<<Experimental Example <NUM>>> Precipitation test.

The following precipitation test was carried out in order to confirm the effects of polyvinyl alcohols with different saponification degrees to improve the solubility of enzalutamide and to maintain supersaturation. As the polyvinyl alcohols, POVAL (JMR-<NUM>, JAPAN VAM & POVAL CO. , hereinafter sometimes abbreviated as "A1"), GOHSENOL (NK-05R, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "A2"), GOHSENOL (KL-<NUM>, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "A3"), POVAL (PE-05JPS, JAPAN VAM & POVAL CO. , hereinafter sometimes abbreviated as "B1"), POVAL (JT-<NUM>, JAPAN VAM & POVAL CO. , hereinafter sometimes abbreviated as "B2"), and GOHSENOL (NL-<NUM>, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "B3") were used. The saponification degrees and the polymerization degrees of the polyvinyl alcohols used in the test are shown in Table <NUM>. After <NUM> of each polyvinyl alcohol was previously dissolved in <NUM> of water, <NUM> of an acetone solution of enzalutamide (containing <NUM> equivalent of enzalutamide) adjusted to a concentration of <NUM>/mL was added thereto, and a precipitation test was carried out in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm under a constant temperature of <NUM>. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolved rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The test results are shown in <FIG>. Each test was repeated three times, and the average values are shown. In the saponification value range (<NUM> mol% to <NUM> mol%) of the polyvinyl alcohols used in Experimental Example <NUM>, as the saponification degree was lower, the solubility was improved and the supersaturation was maintained. In particular, in a saponification value range of <NUM> mol% to <NUM> mol%, it was clarified that supersaturation could be highly maintained in addition to a high dissolved rate.

The following precipitation test was carried out in order to confirm the effects of polyvinyl alcohols with different polymerization degrees to improve the solubility of enzalutamide and to maintain supersaturation. As the polyvinyl alcohols, polyvinyl alcohol having a saponification degree of <NUM> and a polymerization degree of approximately <NUM> (manufactured by Polysciences, Inc. , hereinafter sometimes abbreviated as "A4"), polyvinyl alcohol having a saponification degree of <NUM> and a polymerization degree of approximately <NUM> (GOHSENOL, KL-<NUM>, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "A5"), and polyvinyl alcohol having a saponification degree of <NUM> and a polymerization degree of approximately <NUM> (GOHSENOL, KH-<NUM>, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "B4") were used. The saponification degrees and the polymerization degrees of the polyvinyl alcohols used in the test are shown in Table <NUM>. After <NUM> of each polyvinyl alcohol was previously dissolved in <NUM> of water, <NUM> of an acetone solution of enzalutamide (containing <NUM> equivalent of enzalutamide) adjusted to a concentration of <NUM>/mL was added thereto, and a precipitation test was carried out in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm under a constant temperature of <NUM>. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolved rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The test results are shown in <FIG>. Each test was repeated three times, and the average values are shown. <FIG> includes the result of A3 in Experimental Example <NUM>. In the polymerization value range (<NUM> to <NUM>) of the polyvinyl alcohols used in Experimental Example <NUM>, as the polymerization degree was lower, the dissolved rate was improved. In particular, in a polymerization value range of <NUM> to <NUM>, it was clarified that supersaturation could be highly maintained in addition to a high dissolved rate.

In <NUM> of water, <NUM> of "A2" was stirred until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "A2" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>.

In <NUM> of water, <NUM> of "A6" (polyvinyl alcohol prepared by purifying "A5" by The Nippon Synthetic Chemical Industry Co. to reduce the amount of residual solvent, hereinafter sometimes abbreviated as "A6") was stirred until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "A6" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>. The saponification degree and the polymerization degree of "A6" used in the following Examples are shown in Table <NUM>.

In <NUM> of water, <NUM> of "A6" was stirred until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "A6" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (QSD-<NUM>-CC, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>. It was confirmed by X-ray diffraction that the pharmaceutical composition (a solid dispersion) of Example <NUM> was in an amorphous state.

In <NUM> of water, <NUM> of GOHSENOL (EG-05P, The Nippon Synthetic Chemical Industry Co. , hereinafter sometimes abbreviated as "B5") was stirred while heating until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "B5" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (QSD-<NUM>-CC, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>. The saponification degree and the polymerization degree of "B5" used in tests are shown in Table <NUM>.

In <NUM> of water, <NUM> of "B2" was stirred while heating until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "B2" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>.

In <NUM> of water, <NUM> of "B3" was stirred while heating until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "B3" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>.

A dissolution test of the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM> to <NUM> (containing <NUM> equivalent of enzalutamide) was carried out. The formulation of each pharmaceutical composition is shown in Table <NUM>. Powder mixed with the same amount of mannitol (PEARLITOL 200SD) as that of each pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm (<NUM> rpm for <NUM> to <NUM> minutes from the beginning of the test, and <NUM> rpm for <NUM> to <NUM> minutes). The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. High dissolution rates of <NUM>% or higher were obtained in the pharmaceutical compositions (solid dispersions) of Examples <NUM> to <NUM>, using polyvinyl alcohol having a saponification degree of <NUM> mol% or less. Among the pharmaceutical compositions (solid dispersions) of Examples <NUM> to <NUM> using "A6", extremely high dissolution rates of <NUM>% or higher were obtained in the pharmaceutical compositions (solid dispersions) containing "A6" two or more times to enzalutamide. In the pharmaceutical compositions (solid dispersions) of Examples <NUM> to <NUM>, using polyvinyl alcohol having a saponification degree of <NUM> mol% or more, whereas the solubility of enzalutamide in water (<NUM>±<NUM>) was <NUM>µg/mL, even the pharmaceutical composition of Example <NUM> showed a dissolved concentration of <NUM>µg/mL (= <NUM> × <NUM>%/<NUM>), and an improvement effect of <NUM> times or more in the dissolved concentration was observed. Similarly, the pharmaceutical compositions of Examples <NUM> and <NUM> respectively showed dissolved concentrations of <NUM>µg/mL (<NUM> times) and <NUM>µg/mL (<NUM> times), and improvement effects of <NUM> times or more in the dissolved concentration were observed.

In <NUM> of water, <NUM> of "A6" was stirred until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "A6" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>.

A dissolution test of the pharmaceutical composition (solid dispersion) prepared in Example <NUM> (containing <NUM> equivalent of enzalutamide) was carried out. The formulation of Example <NUM> is shown in Table <NUM>. Powder mixed with the same amount of mannitol (PEARLITOL 200SD) as that of the pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was carried out, using <NUM> of water, <NUM> of 1st fluid for disintegration test of the Japanese Pharmacopoeia (JP1st), and a solution prepared by dissolving <NUM> of SIF Powder (Simulated Intestinal Fluid Powder, Biorelevant. com) in <NUM> of 2nd fluid for disintegration test of the Japanese Pharmacopoeia (JP2nd+SIF) as three types of dissolution test fluids, in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm (<NUM> rpm for <NUM> to <NUM> minutes from the beginning of the test, and <NUM> rpm for <NUM> to <NUM> minutes) under a fluid temperature of <NUM>. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rate after <NUM> minutes from the beginning of the dissolution test (D<NUM>) is shown in Table <NUM>. Extremely high dissolution rates of <NUM>% or higher were observed in any test fluid of water, JP1st, and JP2nd+SIF. Since the pharmaceutical composition (solid dispersion) of the present invention, which can be prepared using polyvinyl alcohol, is not pH-dependent, it is expected that it can be dissolved even in a low pH environment, such as in the stomach, and that a rapid drug absorbability can be obtained.

After <NUM> of a copolymer of polyvinyl alcohol, acrylic acid, and methyl methacrylate (POVACOAT Type F, Daido Chemical Corporation) was mixed with <NUM> of enzalutamide, <NUM> of the mixture was melted and kneaded using an extruder (DSM Xplore Pharma Micro Extruder), and pulverized to obtain a pharmaceutical composition (solid dispersion) of Comparative Example <NUM>.

A dissolution test of the pharmaceutical compositions (solid dispersions) prepared in Example <NUM> and Comparative Example <NUM> (containing <NUM> equivalent of enzalutamide) was carried out. The formulation of each pharmaceutical composition is shown in Table <NUM>. Powder mixed with the same amount of mannitol (PEARLITOL 200SD) as that of each pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm. After the powder mixed with mannitol was previously filled in a syringe, <NUM> of the dissolution test fluid was suctioned into the syringe. The powder was dispersed by shaking, and the syringe was put into a dissolution tester to start the test. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. Even when compared to POVACOAT, "A6" showed a high effect to improve solubility. In other words, a high effect to improve solubility was obtained to select polyvinyl alcohol having a low saponification degree.

Suspensions of the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM>, <NUM>, and <NUM>, and XTANDI (registered trademark) Capsules (each containing <NUM> equivalent of enzalutamide) were orally administered to five male beagle dogs separately under fasting conditions. The formulation of each pharmaceutical composition (solid dispersion) is shown in Table <NUM>. After the administration, blood was periodically collected, and the concentration of unchanged enzalutamide in plasma obtained by centrifugation was measured. The dogs were in a fasting state for more than <NUM> hours prior to the scheduled administration time. The dogs were subjected to pentagastrin treatment (intramuscular administration in the buttocks; <NUM> minutes before administration, and <NUM> and <NUM> minutes after administration) to control the intragastric pH to acidity, and the test was carried out.

The maximum plasma concentration of an unchanged form (Cmax), the area under the plasma concentration time curve of an unchanged form from <NUM> to <NUM> hours (AUC), and the time to reach the maximum plasma concentration of an unchanged form (Tmax) of the suspensions of the pharmaceutical compositions (solid dispersions) of Examples <NUM>, <NUM>, and <NUM>, and the XTANDI (registered trademark) Capsules, and the ratios thereof to the values of the XTANDI Capsules (GMR) are shown in Table <NUM>. In Example <NUM> containing "B5" having a saponification degree of <NUM> mol% in <NUM> times the amount of enzalutamide, both Cmax and AUC showed the same absorbabilities as those of the XTANDI (registered trademark) Capsules. In Examples <NUM> and <NUM> containing "A6" having a saponification degree of <NUM> mol% in <NUM> time and <NUM> times the amount of enzalutamide, respectively, both Cmax and AUC showed absorbabilities higher than those of the XTANDI (registered trademark) Capsules, and a high absorption was obtained. Further, in Examples <NUM> and <NUM>, Tmax was shorter than that of the XTANDI (registered trademark) Capsules, and a rapid absorbability was observed.

After <NUM> of polyvinylpyrrolidone (Kollidon <NUM>, BASF) was mixed with <NUM> of enzalutamide, <NUM> of the mixture was melted and kneaded using an extruder (DSM Xplore Pharma Micro Extruder), and pulverized to obtain a pharmaceutical composition (solid dispersion) of Comparative Example <NUM>.

Suspensions of the pharmaceutical compositions (solid dispersions) prepared in Example <NUM> and Comparative Example <NUM>, and XTANDI (registered trademark) Capsules (each containing <NUM> equivalent of enzalutamide) were orally administered to four male beagle dogs separately under fasting conditions. The formulation of each pharmaceutical composition is shown in Table <NUM>. The test was carried out under the same test conditions as those in Experimental Example <NUM>.

The maximum plasma concentration of an unchanged form (Cmax), the area under the plasma concentration time curve of an unchanged form from <NUM> to <NUM> hours (AUC), and the time to reach the maximum plasma concentration of an unchanged form (Tmax) of the suspensions of the pharmaceutical compositions (solid dispersions) of Example <NUM> and Comparative Example <NUM>, and the XTANDI (registered trademark) Capsules, and the ratios thereof to the values of the XTANDI Capsules (GMR) are shown in Table <NUM>. Whereas both Cmax and AUC were lower than those of the XTANDI (registered trademark) Capsules in Comparative Example <NUM> containing polyvinylpyrrolidone (generally used as a base material for solid dispersion) in <NUM> times the amount of enzalutamide, both Cmax and AUC were higher than those of the XTANDI (registered trademark) Capsules in Example <NUM> containing "A6" in <NUM> times the amount of enzalutamide, and a high absorbability was obtained. Further, in Example <NUM>, as similar to Examples <NUM> and <NUM>, Tmax was shorter than that of the XTANDI (registered trademark) Capsules, and a rapid absorbability was observed.

After <NUM> of enzalutamide, <NUM> of "A6", and <NUM> of polyvinylpyrrolidone (Kollidon <NUM>, BASF) were mixed, the mixture was melted and kneaded using an extruder (KEX-<NUM>, Kurimoto, Ltd. ), and pulverized to obtain a pharmaceutical composition (solid dispersion) of Example <NUM>. It was confirmed by X-ray diffraction that the solid dispersion of Example <NUM> was in an amorphous state.

After <NUM> of enzalutamide, <NUM> of "A6", and <NUM> of copolyvidone (Kollidon VA64, BASF) were mixed, the mixture was melted and kneaded using an extruder (KEX-<NUM>, Kurimoto, Ltd. ), and pulverized to obtain a pharmaceutical composition (solid dispersion) of Example <NUM>.

A dissolution test of the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM> and <NUM> (containing <NUM> equivalent of enzalutamide) was carried out. The formulation of each pharmaceutical composition (solid dispersion) is shown in Table <NUM>. Powder mixed with the same amount of mannitol (PEARLITOL 200SD) as that of each pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm. After the powder mixed with mannitol was previously filled in a syringe, <NUM> of the dissolution test fluid was suctioned into the syringe. The powder was dispersed by shaking, and the syringe was put into a dissolution tester to start the test. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. Extremely high dissolution rates of <NUM>% or higher were obtained in both Examples <NUM> and <NUM>.

Suspensions of the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM> and <NUM>, and XTANDI (registered trademark) Capsules (each containing <NUM> equivalent of enzalutamide) were orally administered to five male beagle dogs separately under fasting conditions. The formulation of each pharmaceutical composition is shown in Table <NUM>. The test was carried out under the same test conditions as those in Experimental Example <NUM>.

The maximum plasma concentration of an unchanged form (Cmax), the area under the plasma concentration time curve of an unchanged form from <NUM> to <NUM> hours (AUC), and the time to reach the maximum plasma concentration of an unchanged form (Tmax) of the suspensions of the pharmaceutical compositions of Examples <NUM> and <NUM>, and the XTANDI (registered trademark) Capsules, and the ratios thereof to the values of the XTANDI Capsules (GMR) are shown in Table <NUM>. Cmax in Example <NUM>, and both Cmax and AUC in Example <NUM> were higher than those of the XTANDI (registered trademark) Capsules, and a high absorbability was obtained. Further, in Examples <NUM> and <NUM>, Tmax was shorter than that of the XTANDI (registered trademark) Capsules, and a rapid absorbability was observed.

With respect to the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM> and <NUM> (each containing <NUM> equivalent of enzalutamide), the amount of the maximum related substance of enzalutamide was measured by an HPLC method.

The measurement of the amount of the maximum related substance was carried out under the following conditions:.

The results of Experimental Example <NUM> are shown in Table <NUM>.

In a mortar, <NUM> of the pharmaceutical composition (solid dispersion) of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of potassium chloride, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

In a mortar, <NUM> of the pharmaceutical composition of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of sodium chloride, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

In a mortar, <NUM> of the pharmaceutical composition of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of magnesium chloride hexahydrate, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

A dissolution test of the pharmaceutical compositions (tablets containing <NUM> equivalent of enzalutamide) prepared in Examples <NUM> to <NUM> was carried out. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. A high dissolution rate of <NUM>% or higher was observed in Example <NUM>, using magnesium chloride hexahydrate. Further, extremely high dissolution rates of <NUM>% or higher were obtained in Example <NUM> using potassium chloride and Example <NUM> using sodium chloride.

The pharmaceutical composition (tablets containing <NUM> equivalent of enzalutamide (four tablets)) prepared in Example <NUM>, and XTANDI (registered trademark) Capsules were orally administered to four male beagle dogs separately under fasting conditions. The test was carried out under the same test conditions as those in Experimental Example <NUM>.

The maximum plasma concentration of an unchanged form (Cmax), the area under the plasma concentration time curve of an unchanged form from <NUM> to <NUM> hours (AUC), and the time to reach the maximum plasma concentration of an unchanged form (Tmax) of the pharmaceutical composition of Example <NUM>, and the XTANDI (registered trademark) Capsules, and the ratios thereof to the values of the XTANDI Capsules (GMR) are shown in Table <NUM>. In Example <NUM>, both Cmax and AUC were higher than those of the XTANDI (registered trademark) Capsules, and a high absorbability was obtained. Further, in Example <NUM>, Tmax was shorter than that of the XTANDI (registered trademark) Capsules, and a rapid absorbability was observed.

In a mortar, <NUM> of the pharmaceutical composition (solid dispersion) of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of sodium chloride, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

In a mortar, <NUM> of the pharmaceutical composition (solid dispersion) of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of potassium dihydrogen phosphate, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. Extremely high dissolution rates of <NUM>% or higher were obtained in any of the Examples.

The pharmaceutical composition (tablets containing <NUM> equivalent of enzalutamide (four tablets)) prepared in Example <NUM>, and XTANDI (registered trademark) Capsules were orally administered to three male beagle dogs separately under fasting conditions. The test was carried out under the same test conditions as those in Experimental Example <NUM>.

The maximum plasma concentration of an unchanged form (Cmax), the area under the plasma concentration time curve of an unchanged form from <NUM> to <NUM> hours (AUC), and the time to reach the maximum plasma concentration of an unchanged form (Tmax) of the pharmaceutical composition (tablets) of Example <NUM>, and the XTANDI (registered trademark) Capsules, and the ratios thereof to the values of the XTANDI Capsules (GMR) are shown in Table <NUM>. In Example <NUM>, both Cmax and AUC showed high values in comparison with those of the XTANDI (registered trademark) Capsules, and a high absorbability was obtained. Further, in the pharmaceutical composition (tablets) of Example <NUM>, Tmax was shorter than that of the XTANDI (registered trademark) Capsules, and a rapid absorbability was observed.

In a mortar, <NUM> of the pharmaceutical composition of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of potassium chloride, <NUM> of crospovidone (Kollidon CL), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

In a mortar, <NUM> of the pharmaceutical composition of Example <NUM>, <NUM> of mannitol (PEARLITOL 200SD), <NUM> of potassium chloride, <NUM> of low substituted hydroxypropylcellulose (L-HPC, LH-<NUM>), <NUM> of light anhydrous silicic acid (Silysia 320TP), and <NUM> of magnesium stearate were prepared, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain a pharmaceutical composition (tablets, <NUM> per tablet) of Example <NUM>.

A dissolution test of the pharmaceutical compositions (tablets containing <NUM> equivalent of enzalutamide) prepared in Examples <NUM> and <NUM> was carried out. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm. The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. Extremely high dissolution rates of <NUM>% or higher were observed in the pharmaceutical compositions (tablets) of Example <NUM> using crospovidone and Example <NUM> using low substituted hydroxypropylcellulose.

In <NUM> of water, <NUM> of "A1" was stirred until dissolved. To a mixed solution prepared by further adding <NUM> of methanol to the "A1" solution, <NUM> of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray-dried with a spray dryer (Niro SD-Micro™ Spray Dryer, GEA) to obtain a pharmaceutical composition (a solid dispersion) of Example <NUM>.

A dissolution test of the pharmaceutical compositions (solid dispersions) prepared in Examples <NUM> to <NUM> and <NUM> (containing <NUM> equivalent of enzalutamide) was carried out. The formulation of each pharmaceutical composition is shown in Table <NUM>. Powder mixed with the same amount of mannitol (PEARLITOL 200SD) as that of each pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was carried out using water (test fluid volume: <NUM>, fluid temperature: <NUM>) as a dissolution test fluid in accordance with a Dissolution Test, a paddle method of the Japanese Pharmacopoeia at a paddle rotation speed of <NUM> rpm (<NUM> rpm for <NUM> to <NUM> minutes from the beginning of the test, and <NUM> rpm for <NUM> to <NUM> minutes). The ultraviolet absorbance of enzalutamide was measured at <NUM>. The dissolution rate was calculated when an absorbance of <NUM> in a <NUM>-mm cell was regarded as <NUM>%.

The dissolution rates after <NUM> minutes from the beginning of the dissolution test (D<NUM>) are shown in Table <NUM>. A high dissolution rate of <NUM>% or higher were obtained in the pharmaceutical composition (solid dispersion) of Example <NUM> using polyvinyl alcohol having a saponification degree of <NUM> mol%. In the pharmaceutical composition (solid dispersion) of Examples <NUM> to <NUM> using polyvinyl alcohol having a saponification degree of <NUM> mol% or more, even the pharmaceutical composition of Example <NUM> showed a dissolved concentration of <NUM>µg/mL (= <NUM> × <NUM>%/<NUM>), and an improvement effect of <NUM> times or more in the dissolved concentration was observed, with respect to the solubility of enzalutamide in water.

Claim 1:
A pharmaceutical composition for oral administration, comprising enzalutamide and polyvinyl alcohol, wherein polyvinyl alcohol has a saponification degree of <NUM> mol% or more and less than <NUM> mol%, and wherein the saponification degree is defined as m/(m +n) × <NUM> wherein m is the number of hydroxyl groups and n is the number of acetyl groups in the polyvinylalcohol.