Pharmaceutical composition containing solid dispersion of androgen receptor antagonist

Abstract

To provide a pharmaceutical composition containing a solid dispersion of an androgen receptor antagonist, which comprises various polymers and the like, and surfactants, with improved solubility for enhanced patient bioavailability and compliance, to provide a method for producing the same, and to provide a method for dissolving an androgen receptor antagonist.SOLUTION: The present invention relates to enzalutamide or epalutamide, and polymers and the like, or a solid dispersion comprising them and surfactants, or a pharmaceutical composition comprising the solid dispersion.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a solid dispersion of androgen receptor antagonists enzalutamide and apalutamide, or a pharmaceutical composition comprising the solid dispersion, a method for preparing the same, and a method for dissolving the androgen receptor antagonists, the pharmaceutical composition being useful in the treatment of prostate cancer. [Background technology]

[0002] Enzalutamide and apalutamide are androgen receptor antagonists. The chemical name of enzalutamide is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The structural formula is:

[0003] [ka] (Patent Document 1: International Publication No. 2006 / 124118).

[0004] The chemical name of apalutamide is: 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide. The structural formula is:

[0005] [ka] (Patent Document 2: International Publication WO 2007 / 126765).

[0006] Enzalutamide and apalutamide are poorly soluble, in particular, they are only sparingly soluble in absolute ethanol and practically insoluble in water at pH 1-11. They are soluble in acetone and N-methyl-2-pyrrolidone (NMP). Furthermore, they are non-hygroscopic crystalline solids that remain unionized in the physiological pH range. They belong to class 2 drugs using the biopharmaceutical classification system. However, poor drug solubility leads to impaired dissolution and critically impacts drug bioavailability.

[0007] As a means of overcoming these drawbacks, Patent Document 3 (WO 2014 / 043208) describes a pharmaceutical composition of an amorphous solid dispersion in which enzalutamide is combined with a cellulose-based polymer.

[0008] Furthermore, Patent Document 4 (WO 2015 / 118015) describes a solid pharmaceutical composition of a solid dispersion in which a polymer and a surfactant are added to enzalutamide and apalutamide.

[0009] However, these compositions are limited in the polymer and surfactant, and the amount of each is also limited in both upper and lower limits, which restricts formulation. In addition, there is also a problem that sufficient data is not necessarily available on the safety of these polymers and surfactants. Patent document 5 (International Publication No. 2020 / 234448) discloses fine particle crystals of enzalutamide containing a polymer and a surfactant. However, it is known that enzalutamide crystals have lower solubility than solid dispersions and are therefore disadvantageous in terms of bioavailability.

[0010] Therefore, there is a need for other options for pharmaceutical compositions, including solid dispersions containing various polymers and surfactants with improved solubility to improve bioavailability and patient compliance. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2006 / 124118 [Patent Document 2] International Publication No. 2007 / 126765 [Patent Document 3] International Publication No. 2014 / 043208 [Patent Document 4] International Publication No. 2015 / 118015 [Patent Document 5] International Publication No. 2020 / 234448 Summary of the Invention [Problem to be solved by the invention]

[0012] An objective of the present invention is to provide a pharmaceutical composition comprising a solid dispersion of an androgen receptor antagonist containing various polymers and surfactants and having improved solubility in order to improve bioavailability and compliance in patients, a method for producing the same, and a method for dissolving the androgen receptor antagonist. [Means for solving the problem]

[0013] The inventors prepared solid dispersions of enzalutamide and apalutamide using enzalutamide and apalutamide with various polymers, etc. and surfactants, and examined their solubility in aqueous solutions.They found that certain polymers, etc., or novel combinations of certain polymers, etc. and surfactants have solubility equivalent to or greater than that of conventional solid dispersions, thereby completing the present invention. That is, the present invention relates to the following.

[0014] [1] A solid dispersion containing enzalutamide or apalutamide, a polymer, glycosyl hesperidin, or methylhesperidin, and a surfactant, or a pharmaceutical composition comprising such a solid dispersion.

[0015] [2] (i) enzalutamide or apalutamide, and (ii) at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, glycosyl hesperidin, or methyl hesperidin; or a pharmaceutical composition comprising the solid dispersion.

[0016] [3] A solid dispersion described in [1] or a pharmaceutical composition containing the solid dispersion, wherein enzalutamide or apalutamide has a maximum solubility of 60 μg / mL or more when dissolved in an aqueous solution.

[0017] [4] A solid dispersion described in [2] or a pharmaceutical composition containing the solid dispersion, in which enzalutamide or apalutamide is adjusted so that the maximum solubility of enzalutamide or apalutamide when dissolved in an aqueous solution is 60 μg / mL or more. [5] moreover, (iii) Surfactant The solid dispersion according to [2] or a pharmaceutical composition comprising the solid dispersion. [6] The solid dispersion according to [5], or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

[0018] [7] The solid dispersion according to [6], or a pharmaceutical composition comprising the solid dispersion, wherein the polymer, transglycosylated hesperidin, or methylhesperidin (ii) is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, methylhesperidin, or copolyvidone, and the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

[0019] [8] A solid dispersion containing enzalutamide or apalutamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium lauryl sulfate, or a pharmaceutical composition comprising the solid dispersion.

[0020] [9] A solid dispersion according to any one of [1], [3], and [5] to [8], or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant is 10 parts by weight or more per 100 parts by weight of enzalutamide or apalutamide.

[0021]

[10] A solid dispersion according to any one of [1] to [8], or a pharmaceutical composition comprising the solid dispersion, wherein the weight ratio of enzalutamide or apalutamide to a polymer, glycosyl hesperidin, or methylhesperidin is 1:1 or more.

[11] The pharmaceutical composition according to any one of [1] to [8], which is a granule, a tablet, a pellet, or a capsule.

[12] a) Enzalutamide or apalutamide is dissolved in a solvent; b) dissolving the polymer, transglycosylated hesperidin, or methylhesperidin described in [1] or [2] in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) optionally carrying out an additional step selected from granulating, compressing, tableting, pelletizing and encapsulating, coating; A method for producing a solid dispersion containing enzalutamide or apalutamide, or a pharmaceutical composition containing the solid dispersion, comprising:

[13] The method according to

[12] , wherein a surfactant is added in any one of steps a) to c).

[14] The method according to

[12] , wherein the solvent is acetone and the drying is spray drying.

[15] The method according to

[13] , wherein the surfactant is sodium lauryl sulfate or polysorbate 80.

[0022]

[16] The method according to

[13] , wherein the polymer, transglycosylated hesperidin, or methyl hesperidin is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, methyl hesperidin, or copolyvidone, and the surfactant is sodium lauryl sulfate or polysorbate 80.

[17] a) Enzalutamide or apalutamide is dissolved in a solvent; b) dissolving the polymer, transglycosylated hesperidin, or methylhesperidin described in [1] or [2] in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) dissolving the solid dispersion of c) or a pharmaceutical composition comprising the solid dispersion in an aqueous solution; Including, wherein the maximum solubility of enzalutamide or apalutamide in water is 60 μg / mL or more; Method for dissolving enzalutamide or apalutamide.

[18] The dissolution method according to

[17] , wherein a surfactant is added in any one of steps a) to c).

[19] The dissolution method according to

[18] , wherein the surfactant is sodium lauryl sulfate or polysorbate 80.

[0023]

[20] The method for dissolving according to

[18] , wherein the polymer, transglycosylated hesperidin, or methyl hesperidin is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, methyl hesperidin, or copolyvidone, and the surfactant is sodium lauryl sulfate or polysorbate 80. [twenty one]

[17] The method for dissolving according to claim 1, wherein the solvent is acetone.

[0024] [twenty two] A composition for treating a patient having a hyperproliferative disorder, comprising the solid dispersion according to any one of [1] to [8] or a pharmaceutical composition comprising the solid dispersion. [twenty three] The composition described in

[22] , wherein the hyperproliferative disorder is selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer.

[0025] [twenty four] The composition described in

[23] , wherein the hyperproliferative disorder is prostate cancer, and the prostate cancer is selected from the group consisting of hormone-refractory prostate cancer and hormone-sensitive prostate cancer. The present invention also relates to the following:

[0026] [1] A solid dispersion containing enzalutamide or apalutamide, a polymer, glycosyl hesperidin, or methylhesperidin, and a surfactant, or a pharmaceutical composition comprising such a solid dispersion.

[0027] [2] (i) enzalutamide or apalutamide, and (ii) at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, glycosyl hesperidin, or methyl hesperidin; or a pharmaceutical composition comprising the solid dispersion.

[0028] [3] A solid dispersion described in [1] or [2], or a pharmaceutical composition containing the solid dispersion, in which enzalutamide or apalutamide has a maximum solubility of 60 μg / mL or more when dissolved in an aqueous solution. [4] moreover, (iii) Surfactant The solid dispersion according to [2] or [3], or a pharmaceutical composition comprising the solid dispersion. [5] The solid dispersion according to [4], or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

[0029] [6] The solid dispersion according to [4] or [5], or a pharmaceutical composition comprising the solid dispersion, wherein the polymer, transglycosylated hesperidin, or methylhesperidin (ii) is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, methylhesperidin, or copolyvidone, and the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

[0030] [7] A solid dispersion containing enzalutamide or apalutamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium lauryl sulfate, or a pharmaceutical composition comprising the solid dispersion.

[0031] [8] A solid dispersion according to any one of [1] and [3] to [7], or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant is 10 parts by weight or more per 100 parts by weight of enzalutamide or apalutamide.

[0032] [9] A solid dispersion described in any one of [1] to [8], or a pharmaceutical composition comprising the solid dispersion, wherein the weight ratio of enzalutamide or apalutamide to polymer, glycosyl hesperidin, or methylhesperidin is 1:1 or more.

[10] The pharmaceutical composition according to any one of [1] to [9], which is a granule, a tablet, a pellet, or a capsule.

[11] a) Enzalutamide or apalutamide is dissolved in a solvent; b) dissolving the polymer, transglycosylated hesperidin, or methylhesperidin described in [1] or [2] in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) optionally carrying out an additional step selected from granulating, compressing, tableting, pelletizing and encapsulating, coating; A method for producing a solid dispersion containing enzalutamide or apalutamide, or a pharmaceutical composition containing the solid dispersion, comprising:

[12] The method according to

[11] , wherein a surfactant is added in any one of steps a) to c).

[13] The method according to

[11] or

[12] , wherein the solvent is acetone and the drying is spray drying.

[14] The method according to

[12] or

[13] , wherein the surfactant is sodium lauryl sulfate or polysorbate 80.

[0033]

[15] The method according to any one of

[12] to

[14] , wherein the polymer, the transglycosylated hesperidin, or the methyl hesperidin is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the transglycosylated hesperidin, the methyl hesperidin, or the copolyvidone, and the surfactant is sodium lauryl sulfate or polysorbate 80.

[16] a) Enzalutamide or apalutamide is dissolved in a solvent; b) dissolving the polymer, transglycosylated hesperidin, or methylhesperidin described in [1] or [2] in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) dissolving the solid dispersion of c) or a pharmaceutical composition comprising the solid dispersion in an aqueous solution; Including, wherein the maximum solubility of enzalutamide or apalutamide in water is 60 μg / mL or more; Method for dissolving enzalutamide or apalutamide.

[17] The dissolution method according to

[16] , wherein a surfactant is added in any one of steps a) to c).

[18] The dissolution method according to

[17] , wherein the surfactant is sodium lauryl sulfate or polysorbate 80.

[0034]

[19] The method for dissolving according to

[17] or

[18] , wherein the polymer, glycosyltransferred methylhesperidin, or methylhesperidin is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, methylhesperidin, or copolyvidone, and the surfactant is sodium lauryl sulfate or polysorbate 80.

[20] The dissolving method according to any one of

[16] to

[19] , wherein the solvent is acetone.

[0035] [twenty one] A composition for treating a patient having a hyperproliferative disorder, comprising the solid dispersion according to any one of [1] to

[10] or a pharmaceutical composition comprising the solid dispersion. [twenty two] The composition described in

[21] , wherein the hyperproliferative disorder is selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer.

[0036] [twenty three] The composition described in

[22] , wherein the hyperproliferative disorder is prostate cancer, and the prostate cancer is selected from the group consisting of hormone-refractory prostate cancer and hormone-sensitive prostate cancer. Effect of the Invention

[0037] The pharmaceutical composition comprising the solid dispersion of the present invention has a composition different from that of conventional pharmaceutical compositions comprising solid dispersions, has excellent solubility in water, and can provide a new option that is expected to improve bioavailability and compliance in patients. [Brief description of the drawings]

[0038] [Figure 1] FIG. 1 shows the solubilities of Examples 1 to 3 (samples (1) to (3)), Reference Example 1 (sample (6)), Comparative Example 1 (sample (8)), and Comparative Example 2 in the dissolution test (Test Example 1). [Diagram 2] FIG. 2 shows the solubilities of Comparative Example 1 (sample (8)) and Examples 1 and 2 (samples (1) and (2)) in the dissolution test (Test Example 2). [Diagram 3] FIG. 3 shows the solubilities of Comparative Example 1 (sample (8)) and Examples 1 and 2 (samples (1) and (2)) in the dissolution test (Test Example 3). [Figure 4] FIG. 4 shows the solubilities of Examples 4 to 5 (samples (4) and (5)), Reference Example 2 (sample (7)), and Comparative Example 3 in the dissolution test (Test Example 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications and other publications and information referenced herein are incorporated herein by reference in their entirety.

[0040] In one aspect of the present invention, the present invention provides a method for producing a composition comprising: (i) enzalutamide or apalutamide, and (ii) at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer (e.g., methacrylic acid copolymer LD, methacrylic acid copolymer S), ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, glycosyl hesperidin, or methyl hesperdin; A solid dispersion or a pharmaceutical composition comprising the solid dispersion comprising A solid dispersion or a pharmaceutical composition comprising a solid dispersion, wherein the enzalutamide or apalutamide has a maximum solubility of 60 μg / mL or more when dissolved in an aqueous solution; to provide.

[0041] Enzalutamide or apalutamide in the present invention includes enzalutamide or apalutamide, as well as closely related compounds that are expected to have the same properties, including activity as an androgen receptor antagonist. Active compounds may also be referred to herein as "API" or "API compounds." Preferably, in all aspects, embodiments and descriptions disclosed herein, enzalutamide has the formula: [ka] It is expressed as or apalutamide, which has the formula: [ka] It is expressed as:

[0042] In some embodiments of the present invention, the polymer, sugar-transferred hesperidin, or methyl hesperidin is selected from, but is not limited to, hydrophilic polymers, preferably water-soluble polymers. A preferred polymer is one that allows enzalutamide or apalutamide to exist mainly, preferably essentially, most preferably completely in solid dispersion, and advantageously maintains this form for a long time. Examples include at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer (e.g., methacrylic acid copolymer LD, methacrylic acid copolymer S), ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, sugar-transferred hesperidin, or methyl hesperidin. Preferred are polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus), methyl hesperidin, or copolyvidone, and more preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus).

[0043] In another aspect of the invention, the composition may be formed using at least one polymer selected from the group consisting of hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene glycol (PEG), polyethylene oxide (PEO), hypromellose acetate succinate (HPMC-AS), polyacrylate, gum arabic, xanthan gum, tragacanth, acacia, carrageenan, guar gum, locust bean gum, pectin, alginate, and mixtures thereof. In some forms of the invention, enzalutamide or apalutamide is included in the pharmaceutical composition of the invention in the form of a solid dispersion.

[0044] In the present invention, "dispersion" refers to a dispersion system in which one substance, the dispersed phase, is dispersed as a distinct unit in a second substance (the continuous phase or medium). The size of the dispersed phase can vary widely (e.g., from colloidal particles of nanometer volume to a few microns in size). In general, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase) or an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, the solid dispersion includes a polymer that constitutes the dispersed phase and a drug that constitutes the continuous phase. In some embodiments, the dispersion includes an amorphous compound or a substantially amorphous compound.

[0045] In the present invention, the term "amorphous" is used in a general sense and refers to a state in which atoms in a solid are strongly bonded to each other and arranged irregularly. It may also contain some crystals.

[0046] As used herein, the term "amorphous" refers to a solid material that has no long-range order in the location of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random fashion, so that there is no definite ordering, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and they do not have a definite melting point. For example, an amorphous material is a solid material that does not have a sharp characteristic crystalline peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline as measured by XRPD). Instead, it may have one or several Broad peaks (eg, halos) appear in the XRPD pattern.

[0047] In the present invention, the "solid dispersion enzalutamide or apalutamide" dissolves more rapidly and to a greater extent than crystalline enzalutamide in an aqueous use environment, such as an aqueous dissolution medium of an in vitro dissolution test (e.g., phosphate buffered saline or model fasted duodenal fluid or simulated gastric fluid) or an in vivo gastric or small intestinal environment. This enhanced dissolution results in a higher oral bioavailability of enzalutamide compared to the crystalline drug. In some embodiments, the solid dispersion of enzalutamide or apalutamide may contain crystals. Amorphous enzalutamide can be prepared by any known means, including spray drying, hot melt extrusion, precipitation from solution by addition of a non-solvent, and the like.

[0048] In some embodiments of the present invention, the solvent for drying the enzalutamide or apalutamide / polymer solution is acetone, ethanol, methanol, mixtures thereof, and mixtures with water. In one form of the invention, the solvent for drying the enzalutamide or apalutamide / polymer solution is acetone. In one aspect of the invention, the solvent is acetone and the drying is spray drying. The spray drying may be carried out according to a known method, for example, the following method.

[0049] In one example, one or more polymers and enzalutamide or apalutamide are mixed with one or more solvents (e.g., acetone) to form a solution having a total solids content of about 4% (w / w) to about 15% (w / w). The percentage of total solids content (w / w) is determined by dividing the total mass of the compound and one or more polymers by the total mass of enzalutamide or apalutamide, one or more polymers, and one or more solvents. The solution can then be spray-dried to form a solid dispersion, which can optionally include an additional drying step.

[0050] In the present invention, the term "pharmaceutical composition" is not particularly limited and is used to refer to any composition that exerts some pharmacological action when administered to a patient, and is a concept that includes "medicinal compositions", and is not limited to pharmaceutical products as long as they exert a pharmacological action.

[0051] In some forms of the present invention, the "pharmaceutical composition" of the present invention is a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 60 μg / mL or more.

[0052] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 60 μg / mL or more provides a new option for formulation that provides good bioavailability and compliance to patients administered the composition.

[0053] To prepare a maximum solubility of 60 μg / mL or more, the blending ratio with enzalutamide or apalutamide, the preparation conditions of the solid dispersion, etc. are appropriately adjusted depending on the specific polymer and / or surfactant.

[0054] Furthermore, by specifying the polymer and / or surfactant, it is possible to adjust the maximum solubility by appropriately adjusting the blending ratio with enzalutamide or apalutamide, the preparation conditions of the solid dispersion, etc., thereby obtaining the maximum solubility below.

[0055] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 70 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0056] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 80 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0057] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 90 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0058] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 100 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0059] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 110 μg / mL or greater provides a formulation option that provides good bioavailability and compliance to administered patients.

[0060] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 120 μg / mL or greater provides a formulation option that provides good bioavailability and compliance to administered patients.

[0061] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 130 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0062] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 140 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0063] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 150 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0064] In one aspect of the present invention, a pharmaceutical composition prepared such that the maximum solubility of enzalutamide or apalutamide in an aqueous solution is 160 μg / mL or more provides a formulation option that provides good bioavailability and compliance to administered patients.

[0065] In the present invention, the term "aqueous solution" is not particularly limited as long as it contains water. It may be water itself, but it may also be, for example, an artificial gastric juice or intestinal juice. The term also includes biologically relevant media such as aqueous dissolution media for in vitro dissolution tests (e.g., phosphate buffered saline, the second fluid of the Japanese Pharmacopoeia dissolution test, or model fasting duodenal fluid or simulated gastric fluid) or biological fluids such as in vivo gastric fluid or small intestinal fluid. In another embodiment of the present invention, the pharmaceutical composition of the present invention may further comprise a surfactant.

[0066] The surfactant used in the present invention is not particularly limited, but as generally understood by those skilled in the art, it is a substance that can reduce the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. Preferably, the term "surfactant" used in this specification means a substance that can act as a wetting agent, an emulsifier, a detergent, and a dispersant, more preferably a substance that can act as a wetting agent. The general function of a substance that is a surfactant can typically be known in advance by those skilled in the art. More specifically, the above-mentioned ability of the surfactant to be used can be examined by a simple measurement of whether the dissolution of enzalutamide or apalutamide in a given composition or formulation can be enhanced under the same specified conditions such as dissolution medium, temperature, and stirring conditions compared to the same composition or formulation except that it does not contain the surfactant, for example, using the dissolution test preferred in the present invention in fasting simulated intestinal fluid (FaSSIF) pH 6.5 medium at 100 rpm using USP apparatus 2 (paddle method) for 45 minutes.

[0067] The surfactant used in the present invention is not particularly limited, but may be selected from the group consisting of anionic surfactants, preferably sodium lauryl sulfate; polyethylene glycol (PEG), preferably PEG having a molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylate, such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleate and caprylate (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylates (glycerol polyethylene glycol ricinoleate), such as Cremophor EL and Cremophor RH 40. More preferably, the surfactant is selected from the group consisting of sodium lauryl sulfate; PEG 3350, PEG 4000, PEG 6000 or PEG 8000, preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycols and fatty acids, most preferably sodium lauryl sulfate and Tween 80, especially sodium lauryl sulfate.

[0068] In some embodiments, the pharmaceutical composition of the present invention comprises a polymer, a glycosyl hesperidin, or a methyl hesperidin, which is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a methyl hesperidin, or a copolyvidone, and the surfactant is sodium lauryl sulfate or polysorbate 80.

[0069] In another aspect of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a solid dispersion containing enzalutamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium lauryl sulfate.

[0070] In some embodiments of the present invention, the compounding ratio of the surfactant to enzalutamide or apalutamide is not particularly limited, but may be, for example, 300 parts by weight or less, 200 parts by weight or less, 150 parts by weight or less, 100 parts by weight or less, 50 parts by weight or less, 40 parts by weight or less, 30 parts by weight or less, or 20 parts by weight or less relative to 100 parts by weight of enzalutamide or apalutamide. It is preferably 150 parts by weight or less. In addition, since the physical properties of the surfactant vary depending on the type of surfactant, the compounding ratio is not limited to these values.

[0071] In another aspect of the present invention, the compounding ratio of the surfactant to enzalutamide or apalutamide may be, for example, 10 parts by weight or more, 20 parts by weight or more, 30 parts by weight or more, 40 parts by weight or more, 50 parts by weight or more, 60 parts by weight or more, 70 parts by weight or more, 80 parts by weight or more, 90 parts by weight or more, 100 parts by weight or more, 110 parts by weight or more, 120 parts by weight or more, 130 parts by weight or more, 140 parts by weight or more, and 150 parts by weight or more relative to 100 parts by weight of enzalutamide or apalutamide. Preferably, it is 50 parts by weight or more.

[0072] In another aspect of the present invention, the blending ratio of the surfactant to enzalutamide or apalutamide is, for example, 10 to 300 parts by weight, 20 to 200 parts by weight, preferably 50 to 150 parts by weight, per 100 parts by weight of enzalutamide or apalutamide.

[0073] In another aspect of the present invention, the ratio of the surfactant to enzalutamide or apalutamide is, for example, 1:0.1 or more, 1:0.2 or more, 1:0.5 or more, 1:0.1 to 1:3, preferably 1:0.2 to 1:2, and more preferably 1:0.5 to 1:1.5 by weight.

[0074] In general, the lower the surfactant ratio, the lower the dosage of the formulation and the better the patient compliance in terms of the burden, and the higher the surfactant ratio, the better the solubility. In the present invention, the above ratio was found by the inventors after extensive research and by adjusting it according to the characteristics of the surfactant.

[0075] In some aspects of the present invention, the blending ratio of enzalutamide or apalutamide to polymer, transglycosylated hesperidin, or methylhesperidin is, for example, by weight, 1:20 or less, 1:10 or less, 1:7 or less, and preferably 1:5 to 1:1.

[0076] In some aspects of the present invention, the blending ratio of enzalutamide or apalutamide to polymer, glycosyl hesperidin, or methylhesperidin is, for example, 2000 parts by weight or less, 1000 parts by weight or less, 700 parts by weight or less, preferably 500 to 100 parts by weight per 100 parts by weight of enzalutamide or apalutamide.

[0077] In some embodiments of the present invention, other excipients can be included in the pharmaceutical composition of the present invention. These excipients can be utilized with the enzalutamide or apalutamide and polymer composition to formulate the pharmaceutical composition into tablets, capsules, suspensions, powders for suspension, creams, transdermal patches, depots, and the like. The enzalutamide or apalutamide and polymer composition can be added to the enzalutamide or apalutamide or other formulation ingredients in essentially any manner that does not substantially alter the enzalutamide or apalutamide. The excipients can be physically mixed with and / or included in the dispersion.

[0078] The solid dispersion comprising enzalutamide or apalutamide and a polymer is further mixed with one or more pharma- ceutically acceptable excipients to prepare a pharmaceutical composition.

[0079] The additives are not particularly limited as long as they are pharma- ceutically acceptable. Examples of additives include fillers, binders, disintegrators, acidulants, foaming agents, artificial sweeteners, flavoring agents, lubricants, coloring agents, stabilizers, buffers, antioxidants, glidants, etc.

[0080] The fillers may be selected, for example, from mannitol, lactose, starch, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, refined sucrose, glucose, and the like.

[0081] The binder may be selected, for example, from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, gum arabic, and the like.

[0082] The disintegrant may be selected from, for example, starch, microcrystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium carboxymethyl starch, agar powder, crospovidone, synthetic aluminum silicate, sucrose fatty acid ester, lactose hydrate, D-mannitol, anhydrous citric acid, and the like. The acidulant may be selected, for example, from citric acid, tartaric acid, malic acid, and the like. The effervescent agent may be selected from, for example, sodium bicarbonate and the like. Artificial sweeteners may be selected, for example, from sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like. Flavoring agents may be selected from, for example, lemon, lemon-lime, orange, menthol, and the like.

[0083] The lubricants may be selected, for example, from magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and the like. Colorants may be selected, for example, from 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. 3, and the like.

[0084] The buffering agent may be selected from, for example, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, or a salt thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, or a salt thereof; magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, or a salt thereof, and the like. The antioxidant may be selected, for example, from ascorbic acid, dibutylhydroxytoluene, propyl gallate, and the like.

[0085] The glidants may be selected from, for example, light anhydrous silicic acid, titanium dioxide, stearic acid, colloidal silica, colloidal 20 silicon dioxide, fumed silica, CAB-O-SIL® M-5P, AEROSIL®, talc, starch, and magnesium aluminum silicate. These additives may be added singly in suitable amounts or in combination of two or more of them in suitable amounts.

[0086] The pharmaceutical composition of the present invention is preferably in a compressed or non-compressed dosage form.Preferably, the pharmaceutical composition of the present invention is in the form of granules, capsules such as capsules filled with granules, sachets, pellets, sugar-coated tablets, lozenges, pastilles, or tablets such as uncoated tablets, coated tablets, effervescent tablets, soluble tablets, dispersible tablets, or extrudates.More preferred dosage forms are compressed dosage forms such as capsules or tablets filled with enzalutamide or apalutamide-containing granules.Tablets can be prepared by compressing uniform volume particles, particle agglomerates, or granules preferably produced by a granulation process.

[0087] In one aspect of the invention, the pharmaceutical composition of the invention is prepared by the following process. a) Enzalutamide or apalutamide is dissolved in a solvent; b) Dissolving a polymer, glycosylated hesperidin, or methylhesperidin in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b) such that the maximum solubility of enzalutamide or apalutamide when dissolved in an aqueous solution is 60 μg / mL or more; d) optionally carrying out an additional step selected from granulating, compressing, tableting, pelletizing and encapsulating, coating; A manufacturing method comprising: In some embodiments of the present invention, the pharmaceutical composition of the present invention is a preparation method further comprising adding a surfactant in any one of steps a) to c).

[0088] In some forms of the invention, the solvent for dissolving enzalutamide or apalutamide can be, but is not limited to, any organic compound in which enzalutamide or apalutamide and the polymer are mutually soluble. In some embodiments, the solvent is also volatile with a boiling point of 150° C. or less. In addition, the solvent should be relatively low toxic and removed from the dispersion to a level acceptable by the International Committee on Harmonization (ICH) guidelines. Removal of the solvent to this level may require processing steps, such as tray drying followed by a spray drying or spray coating process. Solvents include alcohols, such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones, such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters, such as ethyl acetate and propyl acetate; and various other solvents, such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Less volatile solvents, such as dimethylacetamide or dimethylsulfoxide, can also be used. As long as the polymer and enzalutamide are sufficiently soluble to make the spray-drying process feasible, mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, as well as mixtures with water. Generally, non-aqueous solvents are used due to the hydrophobic nature of enzalutamide or apalutamide. Non-aqueous solvents contain less than about 10% water by weight, and in some embodiments, less than 1% water by weight.

[0089] In some embodiments of the present invention, the solvent for drying the enzalutamide or apalutamide / polymer solution is acetone, ethanol, methanol, mixtures thereof, and mixtures with water. In one form of the invention, the solvent for drying the enzalutamide or apalutamide / polymer, transglycosylated hesperidin, or methylhesperidin solution is acetone. In one aspect of the invention, the solvent is acetone and the drying is spray drying. The spray drying may be carried out according to a known method, for example, the following method.

[0090] In one example, one or more polymers and enzalutamide or apalutamide are mixed with one or more solvents (e.g., acetone) to form a solution with a total solid content of about 50% (w / w).The percentage of total solid content (w / w) is determined by dividing the total mass of compound and one or more polymers by the total mass of enzalutamide or apalutamide, one or more polymers, and one or more solvents.The solution can then be spray-dried to form a solid dispersion, which can also be optionally subjected to an additional drying step.

[0091] The polymer, sugar-transferred hesperidin, or methyl hesperidin used in the preparation method of the present invention is not particularly limited, but is selected from hydrophilic polymers, preferably water-soluble polymers. A preferred polymer is one that allows enzalutamide or apalutamide to exist mainly, preferably essentially, most preferably completely in solid dispersion, and advantageously maintains this form for a long time. For example, it may be at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer (e.g., methacrylic acid copolymer LD), methacrylic acid copolymer S, ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus), or methyl hesperidin. It is preferably polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus), methyl hesperidin, or copolyvidone, and more preferably polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus).

[0092] In another aspect of the invention, the composition may be prepared using at least one polymer selected from the group consisting of hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene glycol (PEG), polyethylene oxide (PEO), hypromellose acetate succinate (HPMC-AS), polyacrylate, gum arabic, xanthan gum, tragacanth, acacia, carrageenan, guar gum, locust bean gum, pectin, alginate, and mixtures thereof.

[0093] The surfactant used in the production method according to the present invention is not particularly limited, and may be selected from the group consisting of anionic surfactants, preferably sodium lauryl sulfate; polyethylene glycol (PEG), preferably PEG having a molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylate, such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleate and caprylate (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylates (glycerol polyethylene glycol ricinoleate), such as Cremophor EL and Cremophor RH 40. More preferably, the surfactant is selected from the group consisting of sodium lauryl sulfate; PEG 3350, PEG 4000, PEG 6000 or PEG 8000, preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycols and fatty acids, most preferably sodium lauryl sulfate and Tween 80, especially sodium lauryl sulfate.

[0094] In one embodiment of the invention, the process of the invention comprises d) optionally carrying out an additional step selected from granulation, compression, tableting, pelleting and encapsulation, coating. In the manufacturing method according to the present invention, granulation, compression, tableting, pelleting, encapsulation and coating can be carried out by known methods.

[0095] In one aspect of the present invention, the present invention relates to a method for dissolving enzalutamide or apalutamide as follows: a) Enzalutamide or apalutamide is dissolved in a solvent; b) Dissolving a polymer, glycosylated hesperidin, or methylhesperidin in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b) such that the maximum solubility of enzalutamide or apalutamide when dissolved in an aqueous solution is 60 μg / mL or more; d) dissolving the solid dispersion of c) in an aqueous solution; Including, Method for dissolving enzalutamide or apalutamide. In some embodiments of the present invention, the dissolution method of the present invention is a dissolution method in which a surfactant is further added in any one of steps a) to c).

[0096] In some forms of the invention, the solvent for dissolving enzalutamide or apalutamide can be, but is not limited to, any organic compound in which enzalutamide or apalutamide and the polymer are mutually soluble. In some embodiments, the solvent is also volatile with a boiling point of 150° C. or less. In addition, the solvent should be relatively low toxic and removed from the dispersion to a level acceptable by the International Committee on Harmonization (ICH) guidelines. Removal of the solvent to this level may require processing steps, such as tray drying followed by a spray drying or spray coating process. Solvents include alcohols, such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones, such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters, such as ethyl acetate and propyl acetate; and various other solvents, such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Less volatile solvents, such as dimethylacetamide or dimethylsulfoxide, can also be used. As long as the polymer and enzalutamide or apalutamide are sufficiently soluble to make the spray-drying process feasible, a mixture of solvents, such as 50% methanol and 50% acetone, can also be used, as well as a mixture with water. Generally, due to the hydrophobic nature of enzalutamide, a non-aqueous solvent is used. A non-aqueous solvent contains less than about 10% water by weight, and in some embodiments, less than 1% water by weight.

[0097] In some embodiments of the present invention, the solvent for drying the enzalutamide or apalutamide / polymer, transglycosylated hesperidin, or methylhesperidin solution is acetone, ethanol, methanol, mixtures thereof, and mixtures with water.

[0098] In one form of the invention, the solvent for drying the enzalutamide or apalutamide / polymer, transglycosylated hesperidin, or methylhesperidin solution is acetone.

[0099] The polymer used in the dissolution method of the present invention is not particularly limited, but is selected from hydrophilic polymers, preferably water-soluble polymers. A preferred polymer is one that allows enzalutamide or apalutamide to exist mainly, preferably essentially, most preferably completely in solid dispersion, and advantageously maintains this form for a long time. For example, it may be at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer (e.g., methacrylic acid copolymer LD, methacrylic acid copolymer S), ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus), or sugar-transferred hesperidin or methyl hesperidin as a non-polymer. It is preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus), methyl hesperidin, or copolyvidone, and more preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus).

[0100] In another aspect of the invention, the composition may be dissolved using at least one polymer selected from the group consisting of hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene glycol (PEG), polyethylene oxide (PEO), hypromellose acetate succinate (HPMC-AS), polyacrylate, gum arabic, xanthan gum, tragacanth, acacia, carrageenan, guar gum, locust bean gum, pectin, alginate, and mixtures thereof.

[0101] The surfactant used in the dissolution method according to the present invention is not particularly limited, and may be selected from the group consisting of anionic surfactants, preferably sodium lauryl sulfate; polyethylene glycol (PEG), preferably PEG having a molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylate, such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleate and caprylate (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylates (glycerol polyethylene glycol ricinoleate), such as Cremophor EL and Cremophor RH 40. More preferably, the surfactant is selected from the group consisting of sodium lauryl sulfate; PEG 3350, PEG 4000, PEG 6000 or PEG 8000, preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycols and fatty acids, most preferably sodium lauryl sulfate and Tween 80, especially sodium lauryl sulfate. In some forms of the invention, the invention relates to compositions for treating a patient having a hyperproliferative disorder, comprising a pharmaceutical composition of the invention.

[0102] The hyperproliferative disorder in the present invention may be selected from the group consisting of, but is not limited to, benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer, and is preferably prostate cancer, which may be selected from the group consisting of hormone refractory prostate cancer and hormone sensitive prostate cancer. EXAMPLES

[0103] Example 1: Preparation of Enzalutamide Solid Dispersion by Spray Drying Method (Sample (1)) 5 g of enzalutamide and 25 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ("Soluplus" manufactured by BASF) were dissolved in 375 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 16.67% by mass of enzalutamide.

[0104] Example 2: Preparation of Enzalutamide Solid Dispersion by Spray Drying Method (Sample (2)) 5 g of enzalutamide and 25 g of methylhesperidin (manufactured by Alps Pharmaceutical Co., Ltd.) were dissolved in 375 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 16.67% by mass of enzalutamide.

[0105] Example 3: Preparation of Enzalutamide Solid Dispersion by Spray Drying Method (Sample (3)) 5 g of enzalutamide, 25 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ("Soluplus" manufactured by BASF), and 5 g of sodium lauryl sulfate ("SLS-P" manufactured by Nippon Surfactant Industry Co., Ltd.) were dissolved in 375 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 14.29% by mass of enzalutamide.

[0106] Example 4: Preparation of apalutamide solid dispersion by spray drying method (sample (4)) 5 g of apalutamide and 15 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ("Soluplus" manufactured by BASF) were dissolved in 230 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 25% by mass of apalutamide.

[0107] Example 5: Preparation of apalutamide solid dispersion by spray drying method (sample (5)) 5 g of apalutamide, 15 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ("Soluplus" manufactured by BASF), and 5 g of sodium lauryl sulfate ("SLS-P" manufactured by Nippon Surfactant Industry Co., Ltd.) were dissolved in 287.5 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 20% ​​by mass of apalutamide.

[0108] Reference Example 1: Preparation of Enzalutamide Solid Dispersion by Spray Drying Method (Sample (6)) 5 g of enzalutamide and 25 g of hypromellose acetate succinate ("Shin-Etsu AQOAT-MG" Shin-Etsu Chemical Co., Ltd.) were dissolved in 375 g of acetone and spray-dried using a mini spray dryer B-290 (BUCHI) to obtain a solid dispersion powder containing 16.67% by mass of enzalutamide.

[0109] Reference Example 2: Preparation of apalutamide solid dispersion by spray drying method (sample (7)) 5 g of apalutamide and 15 g of hypromellose acetate succinate ("Shin-Etsu AQOAT-LG" manufactured by Shin-Etsu Chemical Co., Ltd.) were dissolved in 230 g of acetone and spray-dried using a mini spray dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 25% by mass of apalutamide.

[0110] Comparative Example 1: Preparation of Enzalutamide Solid Dispersion by Spray Drying Method (Sample (8)) 5 g of enzalutamide and 25 g of ammonioalkyl methacrylate copolymer ("Eudragit RL100" manufactured by Evonic) were dissolved in 375 g of acetone and spray-dried using a Mini Spray Dryer B-290 (manufactured by BUCHI) to obtain a solid dispersion powder containing 16.67% by mass of enzalutamide. Comparative Example 2: Crystalline Enzalutamide Drug Substance Comparative Example 3: Crystalline Apalutamide Drug Substance

[0111] Test Example 1: Dissolution test The test solution used was the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8). In 200 mL of test solution heated to 37±0.5°C, a solid dispersion powder equivalent to 40 mg of enzalutamide or enzalutamide drug substance was added, and the paddle was rotated at 200 rpm. 7 mL was collected after 5, 15, 30, 60, and 360 minutes, and filtered through a membrane filter with a pore size of 0.45 μm. The first filtrate (5 mL or more) was removed, and the next filtrate (1 mL) was accurately measured, and 3 mL of test solution and 4 mL of water / acetonitrile mixture (1:1) were added to prepare the sample solution.

[0112] Separately, about 25 mg of enzalutamide was precisely weighed out, and a water / acetonitrile mixture (1:1) was added to accurately adjust the total volume to 50 mL. 4 mL of this liquid was weighed out, and a water / acetonitrile mixture (1:1) was added to adjust the total volume to 20 mL. 5 mL of this liquid was added to 5 mL of the test liquid to make the standard solution. 10 μL each of the sample solution and standard solution was analyzed by liquid chromatography under the following conditions to quantify enzalutamide. Analytical equipment: "High-performance liquid chromatograph" manufactured by Shimadzu Corporation and Waters Detector: "Ultraviolet spectrophotometer" manufactured by Shimadzu Corporation and Waters Column: L-column2 C8, 4.6mm x 50mm, 5μm Detection wavelength: 235 nm Flow rate: 1.2mL / min Sample cooler temperature: 25℃ Column temperature: about 50℃ Mobile phase: Dilute phosphoric acid (1→1000) / acetonitrile mixture (13:7)

[0113] Test Example 2: Dissolution test The test solution used was the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8) containing 1% polysorbate 80. A solid dispersion powder equivalent to 40 mg of enzalutamide was placed in 200 mL of test solution heated to 37±0.5°C, and the paddle was rotated at 200 rpm. 7 mL was collected after 5, 15, 30, 60, and 360 minutes and filtered through a membrane filter with a pore size of 0.45 μm. The first filtrate (5 mL or more) was removed, and the next filtrate (1 mL) was accurately measured, and 3 mL of test solution and 4 mL of water / acetonitrile mixture (1:1) were added to prepare the sample solution.

[0114] Separately, about 25 mg of enzalutamide was precisely weighed out, and a water / acetonitrile mixture (1:1) was added to accurately adjust the total volume to 50 mL. 4 mL of this liquid was weighed out, and a water / acetonitrile mixture (1:1) was added to adjust the total volume to 20 mL. 5 mL of this liquid was added to 5 mL of the test liquid to make the standard solution. 10 μL each of the sample solution and standard solution was analyzed by liquid chromatography under the following conditions to quantify enzalutamide. Analytical equipment: "High-performance liquid chromatograph" manufactured by Shimadzu Corporation and Waters Detector: "Ultraviolet spectrophotometer" manufactured by Shimadzu Corporation and Waters Column: L-column2 C8, 4.6mm x 50mm, 5μm Detection wavelength: 235 nm Flow rate: 1.2mL / min Sample cooler temperature: 25℃ Column temperature: about 50℃ Mobile phase: Dilute phosphoric acid (1→1000) / acetonitrile mixture (13:7)

[0115] Test Example 3: Dissolution test The test solution used was 200 mL of the Japanese Pharmacopoeia Dissolution Test 2nd Fluid (pH 6.8) in which 75 mg of sodium lauryl sulfate ("SLS-P" manufactured by Nippon Surfactant Industries Co., Ltd.) was dissolved. A solid dispersion powder equivalent to 40 mg of enzalutamide was placed in 200 mL of test solution heated to 37±0.5°C, and the paddle was rotated at 200 rpm. 7 mL was collected after 5, 15, 30, 60, and 360 minutes, and filtered through a membrane filter with a pore size of 0.45 μm. The first filtrate (5 mL or more) was removed, and the next filtrate (1 mL) was accurately measured, and 3 mL of test solution and 4 mL of water / acetonitrile mixture (1:1) were added to prepare the sample solution.

[0116] Separately, about 25 mg of enzalutamide was precisely weighed out, and a water / acetonitrile mixture (1:1) was added to accurately adjust the total volume to 50 mL. 4 mL of this liquid was weighed out, and a water / acetonitrile mixture (1:1) was added to adjust the total volume to 20 mL. 5 mL of this liquid was added to 5 mL of the test liquid to make the standard solution. 10 μL each of the sample solution and standard solution was analyzed by liquid chromatography under the following conditions to quantify enzalutamide. Analytical equipment: "High-performance liquid chromatograph" manufactured by Shimadzu Corporation and Waters Detector: "Ultraviolet spectrophotometer" manufactured by Shimadzu Corporation and Waters Column: L-column2 C8, 4.6mm x 50mm, 5μm Detection wavelength: 235 nm Flow rate: 1.2mL / min Sample cooler temperature: 25℃ Column temperature: about 50℃ Mobile phase: Dilute phosphoric acid (1→1000) / acetonitrile mixture (13:7) (X-ray diffraction measurement of Enzalutamide in solid dispersion) The crystal forms of the prepared solid dispersion powders of Examples 1 to 3, Reference Example 1, and Comparative Example 1 were analyzed by X-ray diffraction (XRD).

[0117] Test Example 4: Dissolution test The test solution used was the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8). A solid dispersion powder or apalutamide bulk drug equivalent to 60 mg of apalutamide was placed in 200 mL of test solution heated to 37±0.5°C, and the paddle was rotated at 200 rpm. 7 mL was collected after 5, 15, 30, 60, and 360 minutes, and filtered through a membrane filter with a pore size of 0.45 μm. The first filtrate (5 mL or more) was removed, and the next filtrate (1 mL) was accurately measured, and 9 mL of test solution and 10 mL of a water / acetonitrile mixture (1:1) were added to prepare a sample solution.

[0118] Separately, about 25 mg of apalutamide was precisely weighed out and a water / acetonitrile mixture (1:1) was added to accurately adjust the total volume to 50 mL. 5 mL of this liquid was weighed out and a water / acetonitrile mixture (1:1) was added to accurately adjust the total volume to 50 mL. 1 mL of this liquid was mixed with 1 mL of the test liquid to prepare a standard solution. 10 μL each of the sample solution and the standard solution was analyzed by liquid chromatography under the following conditions to quantify apalutamide. Analytical equipment: "High-performance liquid chromatograph" manufactured by Shimadzu Corporation and Waters Detector: "Ultraviolet spectrophotometer" manufactured by Shimadzu Corporation and Waters Column: InertSustain C18, 4.6×100mm, 5μm Detection wavelength: 270nm Flow rate: 1.0mL / min Sample cooler temperature: 15℃ Column temperature: about 30℃ Mobile phase: 20 mM ammonium acetate / acetonitrile mixture (1:1) adjusted to pH 4.5 with acetic acid

Claims

1. A solid dispersion containing enzalutamide or apalutamide, a polymer, glycosyl hesperidin, or methylhesperidin, and a surfactant, or a pharmaceutical composition containing the solid dispersion.

2. (i) enzalutamide or apalutamide, and (ii) at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, or methyl hesperidin; or a pharmaceutical composition comprising the solid dispersion.

3. A solid dispersion according to claim 1, or a pharmaceutical composition comprising said solid dispersion, wherein the maximum solubility of enzalutamide or apalutamide when dissolved in an aqueous solution is adjusted to be 60 μg / mL or more.

4. A solid dispersion according to claim 2, or a pharmaceutical composition comprising said solid dispersion, wherein the maximum solubility of enzalutamide or apalutamide when dissolved in an aqueous solution is adjusted to be 60 μg / mL or more.

5. moreover, (iii) surfactant 3. The solid dispersion of claim 2, or a pharmaceutical composition comprising the solid dispersion.

6. 6. The solid dispersion according to claim 5, or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

7. 7. The solid dispersion according to claim 6, or a pharmaceutical composition comprising the solid dispersion, wherein the polymer, transglycosylated hesperidin, or methylhesperidin (ii) is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, methylhesperidin, or copolyvidone, and the surfactant (iii) is sodium lauryl sulfate or polysorbate 80.

8. A solid dispersion containing enzalutamide or apalutamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium lauryl sulfate, or a pharmaceutical composition comprising the solid dispersion.

9. A solid dispersion according to any one of claims 1, 3, and 5 to 8, or a pharmaceutical composition comprising the solid dispersion, wherein the surfactant is present in an amount of 10 parts by weight or more per 100 parts by weight of enzalutamide or apalutamide.

10. 9. The solid dispersion according to claim 1, wherein the weight ratio of enzalutamide or apalutamide to the polymer, transglycosylated hesperidin, or methylhesperidin is 1:1 or more, or a pharmaceutical composition comprising the solid dispersion.

11. The pharmaceutical composition according to any one of claims 1 to 8, which is in the form of a granule, a tablet, a pellet, or a capsule.

12. a) dissolving enzalutamide or apalutamide in a solvent; b) dissolving the polymer according to claim 1 or 2, transglycosylated hesperidin, or methylhesperidin in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) optionally carrying out an additional step selected from granulating, compressing, tableting, pelletizing and encapsulating, coating; A method for producing a solid dispersion containing enzalutamide or apalutamide, or a pharmaceutical composition containing the solid dispersion, comprising:

13. a) dissolving enzalutamide or apalutamide in a solvent; b) dissolving the polymer according to claim 1 or 2, transglycosylated hesperidin, or methylhesperidin in the solution of a); c) preparing a solid dispersion of enzalutamide or apalutamide from the solution of b); d) dissolving the solid dispersion or a pharmaceutical composition comprising the solid dispersion of c) in an aqueous solution; This includes: wherein the maximum solubility of enzalutamide or apalutamide in water is 60 μg / mL or more; Method for dissolving enzalutamide or apalutamide.

14. A pharmaceutical composition comprising enzalutamide or apalutamide, a polymer, transglycosylated hesperidin, or methylhesperidin, and a surfactant.

15. (i) enzalutamide or apalutamide, and (ii) at least one polymer selected from the group consisting of hydroxypropyl cellulose, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, povidone, copolyvidone, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, transglycosylated hesperidin, or methyl hesperidin; 10. A pharmaceutical composition comprising:

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