RU2830564C2 - Pharmaceutical composition for oral administration containing enzalutamide - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutics, namely to a pharmaceutical composition for oral administration of enzalutamide and a method for preparing it. Pharmaceutical composition for oral administration of enzalutamide includes enzalutamide and polyvinyl alcohol, where polyvinyl alcohol has a degree of saponification from 63 mol.% to 85 mol.%, and a degree of polymerisation from 100 to 500, where the content of polyvinyl alcohol ranges from 50 wt.% to 500 wt.% with respect to the weight of enzalutamide, and further includes potassium chloride, sodium chloride or potassium dihydrophosphate as a co-disintegrant. Method of producing said pharmaceutical composition involves a step for preparing a solid dispersion containing enzalutamide and polyvinyl alcohol.

EFFECT: obtained pharmaceutical composition has improved solubility, increased bioavailability and rate of absorption of enzalutamide.

11 cl, 2 dwg, 28 tbl, 16 ex

Description

Field of technology to which the invention relates

The present invention relates to a pharmaceutical composition for oral administration, with improved absorption of enzalutamide upon oral administration.

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

State of the art

In recent drug discovery research, poorly water-soluble drugs are often candidates for development. Alternatively, there is also a need to improve medical options by providing therapeutics early in clinical settings, and the overall solubilization technology remains an important issue.

Enzalutamide is an inhibitor of the androgen receptor signaling pathway. It has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide and is represented by the following chemical structural formula:

Enzalutamide is known as an active ingredient for use in therapeutic agents for the treatment of metastatic castration-resistant prostate cancer or the like (Patent Literature 1). Enzalutamide is marketed as soft capsules (XTANDI (registered trademark)) containing 40 mg of enzalutamide per capsule and pharmaceutical additives. According to the instruction manual of the product (Non-Patent Literature 1), adults are orally administered 160 mg once a day, and it is indicated that capsules with a longitudinal size of approximately 21 mm and a transverse size of approximately 10 mm are taken, and four capsules are taken in one dose. In particular, one tablet of an appropriate size containing a predetermined amount of enzalutamide and having reasonable and good solubility and/or stability in dissolution and absorption upon oral administration would be useful as a suitable substitute for these soft capsules.

As methods for solubilizing enzalutamide, a method for amorphizing enzalutamide and a method for preparing a solid dispersion of enzalutamide with a carrier are known (Patent Literature 2-4).

List of references

Patent literature

Patent Literature 1 - WO 2006/124118

Patent Literature 2 - WO 2014/043208

Patent Literature 3 - WO 2014/041487

Patent Literature 4 - WO 2014/167428

Non-patent literature

Non-patent literature 1 - Instructions for use of "XTANDI" (registered trademark), Capsule 40 mg

The essence of the invention

Technical task

Even at present, developing formulations to improve the solubility of enzalutamide and enhance its oral absorption regardless of pH is an important technical challenge to ensure drug efficacy, and there is room for further improvement in this area.

The problem solved in the present invention is to create a pharmaceutical composition for oral use, in which, regardless of pH, the solubility and/or dissolution properties of enzalutamide are improved, and the state of supersaturation is maintained. Another objective of the present invention is to create a pharmaceutical composition for oral use, characterized by improved absorption upon oral administration.

Solution to the problem

By preparing a solid dispersion using enzalutamide and polyvinyl alcohol (hereinafter sometimes referred to as PVA), pH-independent solubilization and/or dissolution of enzalutamide can be achieved, and its supersaturation state can be maintained, and, in addition, its bioavailability upon oral administration to a living organism is improved.

The present invention relates to:

[1] a pharmaceutical composition for oral use comprising enzalutamide and polyvinyl alcohol;

[2] a pharmaceutical composition for oral use according to [1], wherein the polyvinyl alcohol has a degree of saponification of 30 mol.% or more and 99 mol.% or less;

[3] a pharmaceutical composition for oral use according to [1] or [2], wherein the polyvinyl alcohol has a degree of polymerization of 50 or more and 600 or less;

[4] a pharmaceutical composition for oral use according to any one of [1] to [3], comprising a solid dispersion comprising enzalutamide and polyvinyl alcohol;

[5] a pharmaceutical composition for oral use according to any one of [1] to [4], further comprising a substance having a functional group capable of functioning as a hydrogen bond acceptor;

[6] a pharmaceutical composition for oral use according to [5], wherein the substance having a functional group capable of functioning as a hydrogen bond acceptor is polyvinylpyrrolidone and/or copolyvidone;

[7] a pharmaceutical composition for oral use according to any one of [1]-[6], further comprising a co-disintegrant;

[8] a pharmaceutical composition for oral use according to [7], wherein the co-disintegrant is a compound or two or more compounds selected from the group consisting of potassium chloride, sodium chloride, magnesium chloride and potassium dihydrogen phosphate;

[9] a pharmaceutical composition for oral use according to [7] or [8], in which the co-disintegrant is potassium chloride;

[10] a pharmaceutical composition for oral use according to any one of [1]-[9], further comprising a disintegrant;

[11] a pharmaceutical composition for oral use according to [10], wherein the disintegrant is a compound, or two or more compounds, selected from the group consisting of crospovidone and low-substituted hydroxypropyl cellulose;

[12] a pharmaceutical composition for oral use according to [10] or [11], wherein the disintegrant is crospovidone;

[13] a pharmaceutical composition for oral use according to any one of [1] to [12], wherein the pharmaceutical composition is a tablet;

[14] a pharmaceutical composition according to any one of [1]-[13], wherein the enzalutamide is amorphous;

[15] a method for producing a pharmaceutical composition for oral administration comprising enzalutamide and polyvinyl alcohol,

[16] a method for producing a pharmaceutical composition for oral use according to [15], comprising the step of preparing a solid dispersion containing enzalutamide and polyvinyl alcohol;

[17] a method for producing a pharmaceutical composition for oral use according to [16], in which the solid dispersion is obtained by a hot melt extrusion method;

[18] a method for producing a pharmaceutical composition for oral use according to [16], in which the solid dispersion is obtained by a method using a solvent; and

[19] the use of a substance having a functional group capable of functioning as a hydrogen bond acceptor in the production of a pharmaceutical composition for oral use containing enzalutamide and polyvinyl alcohol.

The beneficial effects provided by the invention

According to the present invention, a pharmaceutical composition for oral use can be provided, in which, regardless of pH, the solubility and/or dissolution properties of enzalutamide are improved, and its supersaturation is maintained. In addition, a pharmaceutical composition for oral use can be provided, in which the bioavailability and absorption rate of enzalutamide are increased.

Brief description of the drawings

Fig. 1 is a graph showing the results of the sedimentation test in Experimental Example 1.

Fig. 2 is a graph showing the results of the sedimentation test in Experimental Example 2.

Description of embodiments of the invention

The term "to improve solubility" as used in the present invention means that the solubility, dissolved concentration or dissolution rate of enzalutamide in a solvent is increased. More specifically, in one embodiment, with respect to the fact that the solubility of enzalutamide in water (20±5°C) is 2 μg/mL when evaluated in, for example, the dissolution test according to Experimental Example 3, Experimental Example 4, Experimental Example 5, Experimental Example 8, Experimental Example 11, Experimental Example 13, Experimental Example 15 or Experimental Example 16 described below, this term is defined as an effect of improving the dissolved concentration by 5 times or more, by 10 times or more in one embodiment, and by 20 times or more in another embodiment.

The term "to improve dissolution properties" as used in the present invention means that the dissolution rate of enzalutamide from the pharmaceutical composition is improved. More specifically, in one embodiment, when measured in the dissolution test according to Experimental Example 3, Experimental Example 4, Experimental Example 5, Experimental Example 8, Experimental Example 11, Experimental Example 13, Experimental Example 15 or Experimental Example 16 described below, this term is defined as the dissolution rate after 10 minutes from the start of the test is 60% or more, and in one embodiment, 80% or more.

As used herein, the term "to maintain supersaturation" means that enzalutamide is dissolved in a solution in an amount exceeding the solubility of enzalutamide. More specifically, in one embodiment, when a pharmaceutical composition comprising enzalutamide is evaluated by the precipitation test according to Experimental Example 1 or Experimental Example 2 described below, this term is defined as the time during which the change in the dissolution level of enzalutamide in the pharmaceutical composition is within 10% relative to the dissolution level at the beginning of the test is 30 minutes or more, in one embodiment 60 minutes or more, and in another embodiment 90 minutes or more.

As used in this application, the term "for improving oral absorption" means, in one embodiment, that the oral absorption parameters, absorption rate or PK are equal to or superior to those of the XTANDI capsule (registered trademark), which is a product of the prior art, in a test subject such as a dog, a human or the like. In particular, this means having properties equal to or superior to those of the XTANDI capsule (registered trademark) in a single dose.

More specifically, the present invention defines that, for example, the Cmax or AUC values in a dog are 0.8 or more, preferably 0.9 or more, and more preferably 1 or more of the corresponding value obtained for the XTANDI capsule (registered trademark).

The state of improving absorption upon oral administration means that the drug in solution is in a state in which the drug is easily absorbed, such as an amorphous state or transition states, for example, as assessed using X-ray diffraction, Raman scattering, infrared absorption, terahertz spectroscopy, or the like.

As used in the present invention, the term "solid dispersion" means a dispersion comprising enzalutamide and polyvinyl alcohol, wherein the majority of the enzalutamide exists in amorphous form. As used herein, the term "amorphous" means amorphous or transition states. The amorphous enzalutamide exists as a solid solution that is homogeneously distributed in the polyvinyl alcohol. As used in the present application, the term "majority" ("majority") means that when preparing the dispersion, the enzalutamide crystal accounts for 40% or less, preferably 20% or less. In another embodiment, this means that the amount of enzalutamide crystals is 40% or less, preferably 20% or less, and more preferably 10% or less, when measured by X-ray powder diffraction, differential scanning calorimetry (DSC) or any other standard quantitative analysis means.

The term "degree of saponification" used in the present invention means the amount of saponification determined by the measurement method described in the Japanese Pharmacopoeia, Seventeenth Edition, or a measurement method providing results correlated therewith, and can be calculated by the following equation (1). In this regard, it is necessary that the measurement method have a correlation coefficient of 0.5 or more, and 0.6 or more in one embodiment with the measurement method described in the Japanese Pharmacopoeia, Seventeenth Edition.

Degree of saponification = m/(m + n) × 100 (1)

(m: number of hydroxyl groups; n: number of acetyl groups)

The term "degree of polymerization" used in the present invention means "average degree of polymerization" and is defined as a value calculated based on the viscosity value as evaluated in accordance with the "Excipients" section of the Japanese Pharmacopoeia, or as a molecular weight value measured by gel filtration or the like, or a value measured in accordance with a measurement method that provides results correlated therewith. Alternatively, this term is defined as a value measured by (4) the Average Degree of Polymerization Measurement Method in JIS K6726 "Polyvinyl Alcohol Test Methods", or a value measured in accordance with a measurement method that provides results correlated therewith. In this regard, it is necessary that the measurement method correlated with the measurement method of the viscosity value in the evaluation according to the Excipients Section of the Japanese Pharmacopoeia or the gel filtration or similar methods be a measurement method having a correlation coefficient of 0.5 or more, and in one embodiment, 0.6 or more, with respect to the measurement method of the viscosity value in the evaluation according to the Excipients Section of the Japanese Pharmacopoeia or the gel filtration or similar method. In addition, it is necessary that the measurement method correlated with (4) Measurement Method of Average Degree of Polymerization in JIS K6726 Test Methods for Polyvinyl Alcohol be a measurement method having a correlation coefficient of 0.5 or more, and in one embodiment, 0.6 or more, with (4) Measurement Method of Average Degree of Polymerization in JIS K6726 Test Methods for Polyvinyl Alcohol.

As used in the present invention, the term "stable" means resistance to, for example, heat, light, temperature and/or humidity. For example, after the pharmaceutical composition is allowed to stand under given conditions, this term is defined as an embodiment wherein the percentage of the maximum enzalutamide-related substance in the pharmaceutical composition does not exceed a given value, or this term is defined as an embodiment wherein, even if a solid dispersion is obtained by heating and melting, the percentage of the maximum enzalutamide-related substance contained in the pharmaceutical composition does not exceed a given value.

For example, in one embodiment, the term means that the percentage of maximum enzalutamide-related substance after storage at 70°C for 9 days (in sealed form) is no more than 0.5%, and in one embodiment no more than 0.3%.

In one embodiment, this term means that the percentage of maximum enzalutamide-related substance after storage at 25°C and 60% relative humidity (hereinafter sometimes referred to as 25°C, 60% RH) for 1 month, at 25°C 60% RH for 3 months, at 25°C, 60% RH for 6 months, at 40°C and 75% relative humidity (hereinafter sometimes referred to as 40°C, 75% RH) for 1 month, at 40°C, 75% RH for 3 months, or at 40°C, 75% RH for 6 months, is no more than 0.5%, and in one embodiment no more than 0.3%.

The term "maximum related substance" as used in the present invention means the most represented related substance among enzalutamide related substances. More specifically, for example, when the amount of each related substance contained in a pharmaceutical composition is measured by a high-performance liquid chromatography method (hereinafter referred to as the HPLC method), the maximum related substance is defined as the related substance characterized by the largest peak area among the related substances obtained.

The term "amount of maximal related substance" as used in this invention is defined as the percentage of maximal related substance relative to the total peak area of enzalutamide and its related substances, as measured by HPLC as the peak area of maximal related substance contained in the pharmaceutical composition.

Enzalutamide is a poorly water-soluble drug having a solubility in water of 2 μg/mL (20±5°C). Good solubility and/or good dissolution properties can be achieved using the technology of the present invention. In addition, good absorption by oral administration can be achieved using the technology of the present invention.

The dose of enzalutamide can be appropriately determined depending on the specific case, taking into account, for example, the symptoms of the disease, the patient's age, race, gender, or the like.

The daily dose is, for example, about 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 100 mg/kg in one embodiment, 1 mg/kg to 10 mg/kg in another embodiment, administered once or divided into two to four doses per day. Each of the said lower limits and each of the said upper limits can be arbitrarily combined if desired.

The content of enzalutamide is, for example, 0.05 mg to 10,000 mg, 0.5 mg to 10,000 mg in one embodiment, 5 mg to 1,000 mg in another embodiment, 10 mg to 200 mg in another embodiment, and 40 mg to 160 mg in another embodiment per pharmaceutical composition for oral use. Each of said lower limits and each of said upper limits can be arbitrarily combined if desired.

The relative content of enzalutamide is, for example, from 1 wt.% to 75 wt.%, from 2 wt.% to 50 wt.% in one embodiment, from 2 wt.% to 30 wt.% in another embodiment, and from 6.7 wt.% to 50 wt.% in another embodiment, relative to the total weight of the pharmaceutical composition for oral administration. Each of said lower limits and each of said upper limits can be arbitrarily combined if desired.

The polyvinyl alcohol used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. The saponification degree of the polyvinyl alcohol used in the present invention is, for example, 30 mol% to 99 mol%, preferably 55 mol% to 85 mol%, more preferably 63 mol% to 82 mol%, and still more preferably 66 mol% to 80 mol%. Each of the above lower and upper limits (and each of the lower and upper limits described in Examples below) can be arbitrarily combined as desired.

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

More specifically, the degree of polymerization is, for example, less than 2200, 2 or more and less than 2200 in one embodiment, 10 or more and less than 2200 in another embodiment, 100 or more and less than 2200 in another embodiment, 2 or more and 600 or less in another embodiment, 10 or more and 600 or less in another embodiment, 50 or more and 600 or less in another embodiment, and 100 or more and 500 or less in another embodiment. Each of the above lower and upper limits (and each of the lower and upper limits described in Examples below) can be arbitrarily combined as desired.

Each degree of saponification and each degree of polymerization can be arbitrarily combined as desired, and in one embodiment, the degree of saponification and the degree of polymerization of the polyvinyl alcohol are, respectively, 63 mol % or more and 82 mol % or less, and 50 or more and 600 or less.

In this regard, polyvinyl alcohol improves the solubility and/or dissolution properties of enzalutamide and maintains the supersaturation of enzalutamide. In addition, polyvinyl alcohol has the function of improving the absorption of enzalutamide upon oral administration.

Examples of polyvinyl alcohols used in the present invention include:

GOHSENOL (registered trademark) EG-03P (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 3.0 to 3.8 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 86.5 to 89.0 mol.%);

GOHSENOL (registered trademark) KL-05 (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 4.0 to 5.0 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 78.5 to 82.0 mol %),

GOHSENOL (registered trademark) KL-03 (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 2.8 to 3.4 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 78.5 to 82.0 mol.%);

GOHSENOL (registered trademark) KP-08R (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 6.0 to 8.0 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 71.0 to 73.5 mol.%);

GOHSENOL (registered trademark) NK-05R (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 4.5 to 5.5 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 71.0 to 75.0 mol.%);

GOHSENX (registered trademark) LL-810 (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 7.0 to 10.0 mPa⋅s (10% solution in methanol/water (mass ratio 1/1)), saponification degree: 45.0 to 51.0 mol.%);

GOHSENX (registered trademark) LL-920 (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 9.0 to 13.0 mPa⋅s (10% solution in methanol/water (mass ratio 1/1)), saponification degree: 30.0 to 38.0 mol.%);

GOHSENX (registered trademark) LL-940 (Nippon Synthetic Chemical Industry Co., Ltd., viscosity: 20.0 to 28.0 mPa⋅s (10% solution in methanol/water (mass ratio 1/1)), saponification degree: 34.0 to 41.0 mol.%);

POVAL (registered trademark) JR-05 (JAPAN VAM & POVAL CO., LTD., viscosity: 4.5 to 6.5 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 70.0 to 74.0 mol.%);

POVAL (registered trademark) JL-05E (JAPAN VAM & POVAL CO., LTD., viscosity: 4.0 to 6.0 mPa⋅s (4% aqueous solution, 20°C), saponification degree: 80.0 to 84.0 mol.%);

POVAL (registered trademark) JMR-10M (JAPAN VAM & POVAL CO., LTD., degree of polymerization: 200 to 280, degree of saponification: 63.0 to 67.0 mol.%);

POVAL (registered trademark) JMR-10L (JAPAN VAM & POVAL CO., LTD., degree of polymerization: 200 to 280, degree of saponification: 30.0 to 40.0 mol.%);

polyvinyl alcohol (Polysciences, Inc., degree of polymerization: approximately 100, degree of saponification: 80% mol.%) and the like.

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

The relative content of polyvinyl alcohol is not particularly limited as long as it can improve the solubility, dissolution properties and/or absorption of enzalutamide upon oral administration. The relative content of polyvinyl alcohol is, for example, 2% by weight to 90% by weight, 5% by weight to 75% by weight in one embodiment, and 10% by weight to 20% by weight in another embodiment, relative to the total weight of the pharmaceutical composition for oral use. Each of the lower limits and each of the upper limits can be arbitrarily combined if desired. For example, the content is 20% by weight to 1000% by weight, 50% by weight to 500% by weight in one embodiment, and 150% by weight to 350% by weight in another embodiment, relative to the weight of enzalutamide. Each of the lower limits and each of the upper limits can be combined in any way desired.

The pharmaceutical composition for oral use 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 one embodiment.

The pharmaceutical composition for oral use according to the present invention may contain a solid dispersion comprising enzalutamide and polyvinyl alcohol.

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

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

The co-disintegrant is not particularly limited as long as it imparts the property of rapid dissolution to enzalutamide in the preparation.

More specifically, 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 examples include potassium chloride in one embodiment.

Co-disintegrants may be added individually or as a combination of two or more disintegrants.

The relative content of the co-disintegrant is not particularly limited as long as it allows the rapid dissolution property of enzalutamide to be achieved. The relative content of the co-disintegrant is 1% by weight to 50% by weight, 2% by weight to 40% by weight in one embodiment, and 5% by weight to 30% by weight in another embodiment, relative to the total weight of the pharmaceutical composition for oral administration. Each of the lower limits and each of the upper limits can be arbitrarily combined if desired.

The disintegrant is not specifically limited, provided that it imparts the property of rapid dissolution to enzalutamide in the preparation.

More specifically, examples of disintegrants include crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, sodium carboxymethyl cellulose, sodium starch glycolate and the like; examples include crospovidone, low-substituted hydroxypropyl cellulose and the like in one embodiment; and examples include crospovidone in one embodiment.

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

Disintegrants may be added individually or as a combination of two or more of them.

The relative content of the disintegrant is not particularly limited as long as it allows rapid dissolution properties of enzalutamide to be achieved. The relative content of the disintegrant is 0.5 wt % to 30 wt %, 1 wt % to 20 wt % in one embodiment, and 2 wt % to 10 wt % in another embodiment, relative to the total weight of the pharmaceutical composition for oral administration. Each of the lower limits and each of the upper limits can be arbitrarily combined if desired.

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

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

Examples of effervescent agents include sodium bicarbonate and the like.

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

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

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

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

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

Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

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

These pharmaceutical additives may be suitably added individually or in combination of two or more of them in appropriate amounts. As for the relative contents of the pharmaceutical additives, each pharmaceutical additive may be contained in such an amount that the desired effects of the present invention can be achieved.

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

The substance having a functional group capable of functioning as a hydrogen bond acceptor is not particularly limited as long as it is a polymer that inhibits hydrogen bonds between polyvinyl alcohol molecules, has a function of enhancing the amorphous properties of polyvinyl alcohol, or improves the stability and solubility of enzalutamide. Examples include substances with negatively charged atoms such as fluorine, oxygen, nitrogen, or the like; in one embodiment, polyvinylpyrrolidone and copolyvidone, and in another embodiment, copolyvidone.

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

Examples of polyvinylpyrrolidone include Kollidon 30 (product name, BASF) and the like.

A substance having a functional group capable of functioning as a hydrogen bond acceptor can be added to the pharmaceutical composition for oral use of the present invention in any manner as long as the desired effects of the present invention can be achieved.

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

A 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 substances.

The relative content of the substance having a functional group capable of functioning as a hydrogen bond acceptor is not particularly limited as long as it can achieve rapid dissolution properties of enzalutamide and a stable pharmaceutical composition can be obtained. The relative content of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, 1 wt % to 40 wt %, 2 wt % to 30 wt % in one embodiment, 5 wt % to 25 wt % in another embodiment, 10 wt % to 20 wt % in another embodiment, and 6.7 wt % to 40 wt % in another embodiment, based on the total weight of the pharmaceutical composition for oral administration. Each of the lower limits and each of the upper limits can be arbitrarily combined as desired. Relative to the weight of enzalutamide, the relative content of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, from 1 wt. % to 1000 wt. %, from 50 wt. % to 500 wt. % in one embodiment, and from 100 wt. % to 300 wt. % in another embodiment. Each of the lower limits and each of the upper limits can be arbitrarily combined if desired. Relative to the weight of polyvinyl alcohol, the relative content of the substance having a functional group capable of functioning as a hydrogen bond acceptor is, for example, from 10 wt. % to 1000 wt. %, from 20 wt. % to 200 wt. % in one embodiment, from 30 wt. % to 150 wt. % in another embodiment. Each of the lower limits and each of the upper limits can be arbitrarily combined if desired.

The pharmaceutical composition for oral use of the present invention can be manufactured according to known methods, including, for example, amorphization of enzalutamide, mixing, granulation, molding (tabletting), film coating and the like.

A method for producing a pharmaceutical composition for oral administration according to the present invention will be explained below.

Amorphization stage

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

(I) Solvent method

Examples of the method using a solvent 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 as long as enzalutamide and polyvinyl alcohol can be dissolved and/or suspended in the solvent. More specifically, examples of the solvent include methanol, dichloromethane, water, ethanol, acetone, propylene glycol, dimethyl sulfoxide and the like; and in one embodiment, these examples include methanol and water. These solvents can be suitably used singly or in combination of two or more in appropriate amounts.

Examples of the method for removing the solvent include spray drying, evaporation, freeze drying, and the like; and in one embodiment, these examples include spray drying.

Examples of steps in preparing a spray solution containing enzalutamide for use in spray drying include the steps of:

(1) dissolving and/or suspending polyvinyl alcohol in water;

(2) adding methanol to (1) to prepare a mixed solution; and

(3) adding enzalutamide to the mixed solution (2) to prepare a solution for nebulization.

The spray drying apparatus is not particularly limited as long as enzalutamide can be converted into an amorphous form or a solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. Examples of such apparatuses include a spray dryer. The conditions of the spray drying are not particularly limited as long as a solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. The outlet temperature of the spray dryer is, for example, 20°C to 80°C.

The drying method is not particularly limited as long as it is a conventional method in which pharmaceutical drying can be carried out. Examples of suitable apparatuses include a forced-air dryer, a reduced-pressure dryer, a vacuum dryer, a fluidized-bed dryer, and the like.

(II) Hot melt extrusion method

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 according to the melting point of enzalutamide or the glass transition temperature of polyvinyl alcohol. The temperature is, for example, 100°C to 220°C. The temperature during heating and melting can be appropriately set considering the solubility, dissolution properties, supersaturation ability and/or stability of enzalutamide.

The apparatus is not particularly limited as long as enzalutamide can be converted into an amorphous form or a solid dispersion of enzalutamide and polyvinyl alcohol can be obtained. Examples of such apparatus include a twin-screw extruder.

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

The grinding method is not particularly limited as long as it is a conventional method in which pharmaceutical grinding can be performed. Examples of the apparatus include an impact mill (Hosokawa Micron Corporation; fine grinding mill), a dry and wet grinding mill (Powrex Corporation: Comil), a knife mill (Dalton Corporation; Power Mill), and the like.

Mixing stage

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

Granulation stage

The granulation method is not particularly limited as long as it is a conventional method in which granulation can be carried out pharmaceutically. Examples of the apparatus include a fluidized bed granulator, a melt-stirring granulator, a high-shear granulator, a milling (pulverizing) granulator, an extrusion granulator, a fluidized bed drum granulator, a spray granulator, a dry granulator, a twin-screw extruder, and the like; and a dry granulator in one embodiment.

Molding (tabletting) stage

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

In the molding step, for example, a method may be used in which a granular product containing a 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 granular product with various pharmaceutical additives such as a lubricant is subjected to compression molding to obtain tablets; a direct tableting method may be used in which a solid dispersion of enzalutamide is mixed with suitable pharmaceutical additives and the mixture is compressed to obtain tablets; or the like.

Film application stage

The method for applying the film coating is not particularly limited, provided that it is a conventional method in which film coating can be carried out pharmaceutically.

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

The film coating base materials and coloring agents may be appropriately added individually or in combination of two or more materials in suitable amounts.

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

The present invention includes, in the case of a pharmaceutical composition for oral use comprising enzalutamide and polyvinyl alcohol, the use of a substance having a functional group capable of functioning as a hydrogen bond acceptor in the manufacture of a stable pharmaceutical composition for oral use.

With respect to the terms “enzalutamide”, “polyvinyl alcohol” and “a substance having a functional group capable of functioning as a hydrogen bond acceptor”, which are used in the context of using the present invention, the explanations for the corresponding terms given for the pharmaceutical composition for oral use of the present invention can be directly applied.

Examples

Enzalutamide, which was used in the examples below, was prepared according to the method described in WO 2011/106570.

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

Experimental Example 1. Sedimentation Test

The following precipitation test was performed to confirm the effect of polyvinyl alcohols with different degrees of saponification on improving the solubility of enzalutamide and maintaining supersaturation. The polyvinyl alcohols used were POVAL (JMR-10M, JAPAN VAM & POVAL CO., LTD., hereinafter sometimes referred to as "A1"), GOHSENOL (NK-05R, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes referred to as "A2"), GOHSENOL (KL-05, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes referred to as "A3"), POVAL (PE-05JPS, JAPAN VAM & POVAL CO., LTD., hereinafter sometimes referred to as "B1"), POVAL (JT-05, JAPAN VAM & POVAL CO., LTD., hereinafter sometimes referred to as "B2", and GOHSENOL (NL-05, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes referred to as "B3"). Degrees of saponification and degrees of polymerization The polyvinyl alcohols used in this test are shown in Table 1. After 200 mg of each polyvinyl alcohol was previously dissolved in 500 ml of water, 1 ml of an acetone solution of enzalutamide (containing 40 mg equivalent of enzalutamide) was added to the solution, with the concentration adjusted to 40 mg/ml, and a precipitation test was performed according to the dissolution test by the paddle method of the Japanese Pharmacopoeia, with the stirrer speed set at 50 rpm and the temperature constant at 37°C. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 1.579 in a 5-mm cell as 100%.

Table 1

A1 A2 A3 B1 B2 B3 Degree of saponification (mol.%) 66 73 80 88 94 99 Degree of polymerization 260 500 500 500 500 500

The test results are shown in Fig. 1. Each test was repeated three times, and the average values are shown. In the saponification range (66 mol % to 99 mol %) of the polyvinyl alcohols used in Experimental Example 1, when the saponification degree was lower, the solubility was improved and the supersaturation was maintained. In particular, in the saponification range of 66 mol % to 80 mol %, it was found that in addition to the high dissolution level, the supersaturation could also be maintained to a high degree.

Experimental Example 2. Sedimentation Test

The following precipitation test was performed to confirm the effect of polyvinyl alcohols with different degrees of polymerization on improving the solubility of enzalutamide and maintaining supersaturation. The polyvinyl alcohols used were polyvinyl alcohol having a degree of saponification of 80 and a degree of polymerization of approximately 100 (manufactured by Polysciences, Inc., hereinafter sometimes abbreviated as “A4”), polyvinyl alcohol having a degree of saponification of 80 and a degree of polymerization of approximately 300 (GOHSENOL, KL-03, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes abbreviated as “A5”), and polyvinyl alcohol having a degree of saponification of 80 and a degree of polymerization of approximately 2200 (GOHSENOL, KH-17, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes abbreviated as “B4”). The degrees of saponification and degrees of polymerization of the polyvinyl alcohols used in the test are shown in Table 2. After 200 mg of each polyvinyl alcohol was previously dissolved in 500 ml of water, 1 ml of an acetone solution of enzalutamide (containing 40 mg equivalent of enzalutamide) was added to the solution, with the concentration adjusted to 40 mg/ml, and a precipitation test was performed according to the dissolution test by the paddle method of the Japanese Pharmacopoeia, with the stirrer rotating at 50 rpm and the temperature constant at 37°C. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 1.579 in a 5-mm cell as 100%.

Table 2

A4 A5 B4 Degree of saponification (mol.%) 80 80 80 Degree of polymerization 100 300 2200

The test results are shown in Fig. 2. Each test was repeated three times, and the average values are shown. Fig. 2 shows the result for A3 in Experimental Example 1. In the range of polymerization values (100 to 2200) of the polyvinyl alcohols used in Experimental Example 2, when the polymerization degree was lower, the dissolution rate was improved. In particular, in the range of polymerization values from 100 to 500, it was found that in addition to the high dissolution rate, supersaturation could also be maintained to a high degree.

Example 1

In 40 ml of water, 3 g of “A2” was stirred until dissolved. To the mixed solution prepared by further adding 160 ml of methanol to the “A2” solution, 1 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM dryer, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 1.

Example 2

In 280 ml of water, 10 g of “A6” (polyvinyl alcohol obtained by purifying “A5” from Nippon Synthetic Chemical Industry Co., Ltd. to reduce the amount of residual solvent, hereinafter sometimes abbreviated as “A6”) was stirred until dissolved. To a mixed solution prepared by further adding 1120 ml of methanol to the “A6” solution, 10 g of enzalutamide were added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM dryer, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 2. The saponification degree and polymerization degree of “A6” used in the following Examples are shown in Table 3.

Example 3

In 2356.8 g of water, 120 g of “A6” was stirred until dissolved. To the mixed solution prepared by further adding 7463.2 g of methanol to the “A6” solution, 60 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (QSD-0.8-CC, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 3. It was confirmed by X-ray diffraction that the pharmaceutical composition (solid dispersion) of Example 3 was in an amorphous state.

Example 4

In 2342.4 g of water, 180 g of “A6” was stirred until dissolved. To the mixed solution prepared by further adding 7417.7 g of methanol to the “A6” solution, 60 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (QSD-0.8-CC, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 4. It was confirmed by X-ray diffraction that the pharmaceutical composition (solid dispersion) of Example 4 was in an amorphous state.

Example 5

In 3513.6 g of water, 270 g of GOHSENOL (EG-05P, Nippon Synthetic Chemical Industry Co., Ltd., hereinafter sometimes abbreviated as “B5”) was stirred under heating until dissolved. To a mixed solution prepared by further adding 11126.4 g of methanol to the “B5” solution, 90 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (QSD-0.8-CC, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 5. The saponification degree and polymerization degree of “B5” used in the tests are shown in Table 3.

Table 3

A6 B5 Degree of saponification (mol.%) 81 88 Degree of polymerization 300 600

Example 6

In 96 ml of water, 3 g of “B2” was stirred under heating until dissolved. To the mixed solution prepared by further adding 224 ml of methanol to the “B2” solution, 1 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM , GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 6.

Example 7

In 175 ml of water, 3 g of “B3” was stirred under heating until dissolved. To the mixed solution prepared by further adding 325 ml of methanol to the “B3” solution, 1 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM , GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 7.

Experimental Example 3. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (solid dispersions) obtained in Examples 1 to 7 (containing 80 mg equivalent of enzalutamide). The composition of each pharmaceutical composition is shown in Table 4. A powder mixed with the same amount of mannitol (PEARLITOL 200SD) was used for the test for each pharmaceutical composition (solid dispersion). The dissolution test was performed using water (test liquid volume: 500 mL, liquid temperature: 37°C) as the dissolution test liquid in accordance with the Dissolution Test, Paddle Method of the Japanese Pharmacopoeia, at a stirrer speed of 50 rpm (250 rpm for a period of 0 to 3 minutes from the start of the test, and 200 rpm for 3 to 5 minutes). The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 0.6316 in a 1 mm cell as 100%.

Table 4

Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Enzalutamide 80 80 80 80 80 80 80 A2 240 - - - - - - A6 - 80 160 240 - - - B5 - - - - 240 - - B2 - - - - - 240 - B3 - - - - - - 240

(Units: mg)

The dissolution rates at 10 minutes after the start of the dissolution test (D _10min ) are shown in Table 5. High dissolution rates of 60% or more were obtained in the pharmaceutical compositions (solid dispersions) of Examples 1 to 4 using polyvinyl alcohol having a saponification degree of 81 mol % or less. Among the pharmaceutical compositions (solid dispersions) of Examples 2 to 4 using “A6”, extremely high dissolution rates of 80% or more were obtained in the pharmaceutical compositions (solid dispersions) containing two or more times of “A6” compared to enzalutamide. In the pharmaceutical compositions (solid dispersions) of Examples 5 to 7 using polyvinyl alcohol having a saponification degree of 88 mol % or less, the dissolution rates of 80% or more were obtained in the pharmaceutical compositions (solid dispersions) of Examples 2 to 4 using “A6”. % or more, while the solubility of enzalutamide in water (20±5°C) is 2 μg/mL, even the pharmaceutical composition of Example 7 showed a dissolved concentration of 15.2 μg/mL (= 80 mg × 9.5%/500 mL), and an effect of improving the dissolved concentration by 7 times or more was observed. Similarly, the pharmaceutical compositions of Examples 5 and 6, respectively, showed dissolved concentrations of 22.56 μg/mL (an increase of 11.28 times) and 41.6 μg/mL (an increase of 20.8 times), and an effect of improving the dissolved concentration by 10 times or more was observed.

Table 5

  Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 D _10min (%) 93.9 70.3 97.7 94.2 14.1 26.0 9.5

Example 8

In 120 ml of water, 10 g of “A6” was stirred until dissolved. To the mixed solution prepared by adding 480 ml of methanol to the “A6” solution, 2 g of enzalutamide was added and stirred until dissolved to prepare a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM dryer, GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 8.

Experimental Example 4. Dissolution Test

A dissolution test was conducted on the pharmaceutical composition (solid dispersion) obtained in Example 8 (containing 80 mg equivalent of enzalutamide). The composition of Example 8 is shown in Table 6. A powder mixed with the same amount of mannitol (PEARLITOL 200SD) for each pharmaceutical composition (solid dispersion) was used for the test. The dissolution test was performed using 500 mL of water, 500 mL of the 1st disintegration test liquid of the Japanese Pharmacopoeia (JP1), and a solution prepared by dissolving 895 mg of SIF powder (simulated intestinal fluid powder, Biorelevant.com) in 500 mL of the 2nd disintegration test liquid of the Japanese Pharmacopoeia (JP2 + SIF) as three types of dissolution test liquids, according to the dissolution test method with a paddle stirrer of the Japanese Pharmacopoeia at a stirrer speed of 50 rpm (250 rpm for a period of 0 to 3 minutes from the start of the test and 200 rpm for 3 to 5 minutes) at a liquid temperature of 37°C. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 0.6316 in a 1 mm cell as 100%.

Table 6

Example 8 Enzalutamide 80 A6 400

(Units: mg)

The dissolution rate after 10 minutes from the start of the dissolution test ( _D10min ) is shown in Table 7. Extremely high dissolution rates of 80% or higher were observed in any test liquid of water, JP1, and JP2 + SIF. Since the pharmaceutical composition (solid dispersion) of the present invention, which can be prepared using polyvinyl alcohol, is not affected by pH, it is expected that it can be dissolved even in a low pH environment such as the environment in the stomach, and that rapid absorption of the drug can be achieved.

Table 7

  Water JP1 JP2+SIF D _10min (%) 98.8 91.8 94.4

Comparative example 1

After mixing 20 g of a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type F, Daido Chemical Corporation) with 4 g of enzalutamide, 22.5 g of the mixture was melted and mixed using an extruder (DSM Xplore Pharma Micro) and pulverized to obtain the pharmaceutical composition (solid dispersion) of Comparative Example 1.

Experimental Example 5. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (solid dispersions) obtained in Example 4 and Comparative Example 1 (containing 160 mg of enzalutamide equivalent). The composition of each pharmaceutical composition is shown in Table 8. A powder mixed with the same amount of mannitol (PEARLITOL 200SD) was used for the test for each pharmaceutical composition (solid dispersion). The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid in accordance with the Dissolution Test, Paddle Method of the Japanese Pharmacopoeia, at a stirrer rotation speed of 50 rpm. After the powder mixed with mannitol was pre-filled into a syringe, 20 ml of the dissolution test liquid was withdrawn with the syringe. The powder was dispersed by shaking, and the syringe was placed in the dissolution tester to start the test. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 1.2632 in a 1-mm cell as 100%.

Table 8

Example 4 Comp. Example 1 Enzalutamide 160 160 A6 480 - POVACOAT - 800

(Units: mg)

The dissolution levels after 10 minutes of the dissolution test (D _10min ) are shown in Table 9. Even compared with POVACOAT, “A6” showed a high solubility improvement effect. In other words, a high solubility improvement effect was achieved for selecting polyvinyl alcohol having a low saponification degree.

Table 9

  Example 4 Comp. Example 1 D _10min (%) 103.3 11.2

Experimental Example 6. Oral Absorption Test in Dogs

The suspensions of the pharmaceutical compositions (solid dispersions) prepared in Examples 2, 3 and 5 and XTANDI (registered trademark) capsules (each containing 160 mg enzalutamide equivalent) were orally administered to five male beagle dogs separately under fasting conditions. The composition of each pharmaceutical composition (solid dispersion) is shown in Table 10. After administration, blood was collected periodically and the concentration of unchanged enzalutamide in plasma obtained by centrifugation was measured. The dogs were fasted for more than 16 hours before the scheduled administration time. The dogs were treated with pentagastrin (intramuscular injection in the buttocks; 30 minutes before administration and 30 and 90 minutes after administration) to control the acidity of the intragastric pH, and the test was performed.

Table 10

  Example 2 Example 3 Example 5 Enzalutamide 160 160 160 A6 160 320 - B5 - - 480

(Units: mg)

The maximum plasma concentration in unchanged form (Cmax), the area under the plasma concentration-time curve for unchanged form from 0 to 24 hours (AUC) and the time to reach the maximum plasma concentration for unchanged form (Tmax) of the suspensions of the pharmaceutical compositions (solid dispersions) of Examples 2, 3 and 5 and XTANDI capsules (registered trademark) and their correlation with the values for XTANDI capsules (GMR) are shown in Table 11. In Example 5 containing “B5” having a saponification degree of 88 mol % in an amount 3 times higher than the amount of enzalutamide, both Cmax and AUC showed the same absorption as XTANDI capsules (registered trademark). In Examples 2 and 3 containing “A6” having a saponification degree of 81 mol %, the absorption of XTANDI capsules (registered trademark) was similar to that of enzalutamide. %, in an amount of 1-fold and 2-fold that of enzalutamide, respectively, both Cmax and AUC showed absorption higher than that of XTANDI capsules (registered trademark), and high absorption was achieved. In addition, in Examples 2 and 3, the Tmax value was lower than that of XTANDI capsules (registered trademark), and rapid absorption was observed.

Table 11

  Capsules
XTANDI Example 2 Example 3 Example 5 Cmax mcg/ml 20.9±3.8 21.4±4.7 22.4±2.7 19.2±3.3 GMR - 1.02 1.08 0.92 AUC mcg/ml h 367.7±79.7 377.8±112.1 389.2±71.3 348.8±72.9 GMR - 1.01 1.06 0.95 Tmax h 7.80±1.79 3.90±4.04 4.80±3.03 9.00±2.24

Comparative example 2

After 15 g of polyvinylpyrrolidone (Kollidon 30, BASF) was mixed with 5 g of enzalutamide, 18 g of the mixture was melted and mixed using an extruder (DSM Xplore Pharma Micro) and ground into powder to obtain the pharmaceutical composition (solid dispersion) of Comparative Example 2.

Experimental Example 7. Oral Absorption in Dogs

The suspensions of the pharmaceutical compositions (solid dispersions) prepared in Example 4 and Comparative Example 2 and XTANDI (registered trademark) capsules (each containing 160 mg of enzalutamide equivalent) were orally administered to four male beagle dogs separately on an empty stomach. The composition of each pharmaceutical composition is shown in Table 12. The test was conducted under the same conditions as in Experimental Example 6.

Table 12

  Example 4 Comparative example 2 Enzalutamide 160 160 A6 480 - Polyvinylpyrrolidone - 480

(Units: mg)

The maximum plasma concentration in unchanged form (Cmax), the area under the plasma concentration-time curve for unchanged form from 0 to 24 hours (AUC) and the time to reach the maximum plasma concentration for unchanged form (Tmax) of the suspension of the pharmaceutical compositions (solid dispersions) of Example 4 and Comparative Example 2 and XTANDI capsules (registered trademark), as well as their correlation with the values for XTANDI capsules (GMR) are shown in Table 13. While the Cmax and AUC values were lower than those of XTANDI capsules (registered trademark), in Comparative Example 2 containing polyvinylpyrrolidone (commonly used as a base material for solid dispersion) in an amount 3 times the amount of enzalutamide, both Cmax and AUC were higher than those of XTANDI capsules (registered trademark), in Example 4 containing "A6" in an amount 3 times that of enzalutamide, and high absorption was achieved. In addition, in Example 4, as in Examples 2 and 3, the Tmax value was lower than that of XTANDI capsules (registered trademark), and rapid absorption was observed.

Table 13

XTANDI capsules Example 4 Comp. Example 2 Cmax mcg/ml 16.0±6.6 16.5±4.8 11.4±4.3 GMR - 1.07 0.73 AUC mcg/ml h 266.9±101.6 281.1±100.1 193.9±77.1 GMR - 1.06 0.73 Tmax h 8.00±2.83 4.88±4.84 5.75±3.86

Example 9

After mixing 300 g of enzalutamide, 900 g of "A6" and 300 g of polyvinylpyrrolidone (Kollidon 30, BASF), the mixture was melted and mixed with an extruder (KEX-25, Kurimoto, Ltd.) and pulverized to obtain the pharmaceutical composition (solid dispersion) of Example 9. It was confirmed by X-ray diffraction that the solid dispersion of Example 9 was in an amorphous state.

Example 10

After mixing 200 g of enzalutamide, 400 g of “A6” and 400 g of copolyvidone (Kollidon VA64, BASF), the mixture was melted and mixed using an extruder (KEX-25, Kurimoto, Ltd.) and ground into powder to obtain the pharmaceutical composition (solid dispersion) of Example 10.

Experimental Example 8. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (solid dispersions) obtained in Examples 9 and 10 (containing 160 mg of enzalutamide equivalent). The composition of each pharmaceutical composition (solid dispersion) was as shown in Table 14. The powder mixed with the same amount of mannitol (PEARLITOL 200SD) was used for the test for each pharmaceutical composition (solid dispersion). The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid in accordance with the dissolution test by paddle method of the Japanese Pharmacopoeia at a stirrer rotation speed of 50 rpm. After the powder mixed with mannitol was preliminarily filled into a syringe, 20 ml of the dissolution test liquid was withdrawn with the syringe. The powder was dispersed by shaking and the syringe was placed in the dissolution tester to begin the test. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 1.2632 in a 1 mm cell as 100%.

Table 14

Example 9 Example 10 Enzalutamide 160 160 A6 480 320 Polyvinylpyrrolidone 160 - Copolyvidone - 320

(Units: mg)

The dissolution levels after 10 minutes of the dissolution test (D _10min ) are shown in Table 15. In both Examples 9 and 10, extremely high dissolution levels of 80% or higher were obtained.

Table 15

Example 9 Example 10 D _10min (%) 108.1 110.8

Experimental Example 9 Oral Absorption in Dogs

The suspensions of the pharmaceutical compositions (solid dispersions) prepared in Examples 9 and 10 and XTANDI (registered trademark) capsules (each containing 160 mg of enzalutamide equivalent) were orally administered to five male beagle dogs separately on an empty stomach. The composition of each pharmaceutical composition is shown in Table 14. The test was conducted under the same conditions as in Experimental Example 6.

The maximum plasma concentration in unchanged form (Cmax), the area under the plasma concentration-time curve for unchanged form from 0 to 24 hours (AUC) and the time to reach the maximum plasma concentration for unchanged form (Tmax) of the suspension of the pharmaceutical compositions of Examples 9 and 10 and XTANDI capsules (registered trademark) and their relationship with the corresponding values of XTANDI capsules (GMR) are shown in Table 16. Cmax in Example 9 and Cmax and AUC in Example 10 were higher than those of XTANDI capsules (registered trademark), and high absorption was obtained. In addition, in Examples 9 and 10, Tmax was lower than those of XTANDI capsules (registered trademark), and rapid absorption was observed.

Table 16

XTANDI capsules Example 9 Example 10 Cmax mcg/ml 20.9±3.8 26.6±2.9 23.6±6.2 GMR - 1.29 1.11 AUC mcg/ml h 367.7±79.7 360.6±17.2 400.8±129.5 GMR - 1.00 1.07 Tmax h 7.80±1.79 2.80±4.07 3.90±3.78

Experimental Example 10. Measurement of the amount of the maximum related substance

For the pharmaceutical compositions (solid dispersions) obtained in Examples 9 and 10 (each containing 80 mg enzalutamide equivalent), the amount of the maximum enzalutamide-related substance was measured by HPLC.

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

- The HPLC column used was Zorbax SB-CN, particle size: 5 μm, 4.6 mm (internal diameter) × 150 mm (manufactured by Agilent), at a temperature of 30°C.

- A 0.05% aqueous solution of trifluoroacetic acid was used as mobile phase A.

- A 0.05% solution of trifluoroacetic acid in acetonitrile was used as mobile phase B.

- A mixture of acetonitrile/water (9:1) was used as a dilution solution for samples, so that the concentration of enzalutamide was 240 μg/mL.

- The amounts of related substances were measured using a spectrophotometer with ultraviolet absorption (wavelength: 260 nm), according to the gradient program shown in Table 17 below and by adjusting the flow rate to 1 ml/min. The peak area percentage of the highest related substance was calculated as a percentage of the total peak area of enzalutamide and related substances.

Table 17

Time after administration Mobile phase A (%) Mobile phase B (%) 0 → 30 90 →10 10 →90 30 → 31 10 → 90 90 →10 31 → 40 90 10

The results of Experimental Example 10 are shown in Table 18.

Table 18

  Example 9 Example 10 Maximum related substance amount 0.20% 0.24%

Example 11

In a mortar, 1200 mg of the pharmaceutical composition (solid dispersion) of Example 9, 1446 mg of mannitol (PEARLITOL 200SD), 720 mg of potassium chloride, 180 mg of crospovidone (Kollidon CL), 36 mg of light anhydrous silicic acid (Silysia 320TP) and 18 mg of magnesium stearate were added and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 11.

Example 12

In a mortar, 1200 mg of the pharmaceutical composition of Example 9, 1446 mg of mannitol (PEARLITOL 200SD), 720 mg of sodium chloride, 180 mg of crospovidone (Kollidon CL), 36 mg of light anhydrous silicic acid (Silysia 320TP), and 18 mg of magnesium stearate were added and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 12.

Example 13

In a mortar were added 1200 mg of the pharmaceutical composition of Example 9, 1446 mg of mannitol (PEARLITOL 200SD), 720 mg of magnesium chloride hexahydrate, 180 mg of crospovidone (Kollidon CL), 36 mg of light anhydrous silicic acid (Silysia 320TP) and 18 mg of magnesium stearate, and mixed using a pestle. The resulting mixed powder was tableted using a single punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 13.

Table 19

  Example 11 Example 12 Example 13 Example 9 200 200 200 Mannitol 241 241 241 Potassium chloride 120 - - Sodium chloride - 120 - Magnesium chloride hexahydrate - - 120 Crospovidone 30 30 30 Light anhydrous silicic acid 6 6 6 Magnesium stearate 3 3 3 Total 600 600 600

(Units: mg)

Experimental Example 11. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (tablets containing 40 mg equivalent of enzalutamide) obtained in Examples 11 to 13. The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid in accordance with the dissolution test by the paddle method of the Japanese Pharmacopoeia, with the stirrer rotating at a speed of 50 rpm. The absorbance of enzalutamide in the ultraviolet region was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 0.3158 in a 1-mm cell as 100%.

The dissolution levels after 10 minutes from the start of the dissolution test (D _10min ) are shown in Table 20. A high dissolution level of 60% or higher was observed in Example 13 using magnesium chloride hexahydrate. In addition, extremely high dissolution levels of 80% or higher were obtained in Example 11 using potassium chloride and in Example 12 using sodium chloride.

Table 20

Example 11 Example 12 Example 13 D _10min (%) 100.1 92.5 72.7

Experimental Example 12. Oral absorption test in dogs.

The pharmaceutical composition (tablets containing 160 mg equivalent of enzalutamide (four tablets)) prepared in Example 11 and XTANDI (registered trademark) capsules were orally administered to four male beagle dogs separately on an empty stomach. The test was conducted under the same conditions as in Experimental Example 6.

The maximum plasma concentration of unchanged drug (Cmax), the area under the plasma concentration-time curve for unchanged drug from 0 to 24 hours (AUC), and the time to reach the maximum plasma concentration for unchanged drug (Tmax) of the pharmaceutical composition of Example 11 and XTANDI capsules (registered trademark), and their relationship with the XTANDI capsules (GMR) values are shown in Table 21. In Example 11, the Cmax and AUC values were higher than those of XTANDI capsules (registered trademark), and high absorption was obtained. In addition, in Example 11, the Tmax value was lower than that of XTANDI capsules (registered trademark), and rapid absorption was observed.

Table 21

XTANDI capsules Example 9 Cmax mcg/ml 16.0±6.6 15.9±3.1 GMR - 1.05 AUC mcg/ml h 266.9±101.6 274.0±70.1 GMR - 1.06 Tmax h 8.00±2.83 5.75±4.92

Example 14

In a mortar were added 4000 mg of the pharmaceutical composition (solid dispersion) of Example 10, 4820 mg of mannitol (PEARLITOL 200SD), 2400 mg of potassium chloride, 600 mg of crospovidone (Kollidon CL), 120 mg of light anhydrous silicic acid (Silysia 320TP) and 60 mg of magnesium stearate, and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 14.

Example 15

In a mortar were added 2000 mg of the pharmaceutical composition (solid dispersion) of Example 10, 2410 mg of mannitol (PEARLITOL 200SD), 1200 mg of sodium chloride, 300 mg of crospovidone (Kollidon CL), 60 mg of light anhydrous silicic acid (Silysia 320TP) and 30 mg of magnesium stearate, and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 15.

Example 16

In a mortar were added 2000 mg of the pharmaceutical composition (solid dispersion) of Example 10, 2410 mg of mannitol (PEARLITOL 200SD), 1200 mg of potassium dihydrogen phosphate, 300 mg of crospovidone (Kollidon CL), 60 mg of light anhydrous silicic acid (Silysia 320TP) and 30 mg of magnesium stearate, and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 16.

Table 22

  Example 14 Example 15 Example 16 Example 10 200 200 200 Mannitol 241 241 241 Potassium chloride 120 - - Sodium chloride - 120 - Potassium dihydrogen phosphate - - 120 Crospovidone 30 30 30 Light anhydrous silicic acid 6 6 6 Magnesium stearate 3 3 3 Total 600 600 600

(Units: mg)

Experimental Example 13. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (tablets containing 40 mg equivalent of enzalutamide) obtained in Examples 14 to 16. The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid in accordance with the dissolution test by the paddle method of the Japanese Pharmacopoeia, with the stirrer rotating at a speed of 50 rpm. The absorbance of enzalutamide in the ultraviolet region was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 0.3158 in a 1-mm cell as 100%.

The dissolution levels after 10 minutes of the dissolution test (D _10min ) are shown in Table 23. In each of the examples, extremely high dissolution levels of 80% or higher were obtained.

Table 23

Example 14 Example 15 Example 16 D _10min (%) 103.5 86.3 85.5

Experimental Example 14. Oral Absorption Test in Dogs

The pharmaceutical composition (tablets containing 160 mg equivalent of enzalutamide (four tablets)) prepared in Example 14 and XTANDI (registered trademark) capsules were orally administered to three male beagle dogs separately on an empty stomach. The test was conducted under the same conditions as in Experimental Example 6.

The maximum plasma concentration of unchanged form (Cmax), the area under the plasma concentration-time curve for unchanged form from 0 to 24 hours (AUC), and the time to reach the maximum plasma concentration for unchanged form (Tmax) of the pharmaceutical composition (tablets) of Example 14 and XTANDI capsule (registered trademark), and their relationship with the values of XTANDI capsules (GMR) are shown in Table 24. In Example 14, both Cmax and AUC showed high values compared with XTANDI capsules (registered trademark), and high absorption was obtained. In addition, in the pharmaceutical composition (tablets) of Example 14, Tmax was lower than that of XTANDI capsules (registered trademark), and rapid absorption was observed.

Table 24

XTANDI capsules Example 14 Cmax mcg/ml 18.6±2.6 21.5±4.6 GMR - 1.15 AUC mcg/ml h 326.2±48.9 375.8±73.0 GMR - 1.15 Tmax h 7.00±1.73 5.50±4.33

Example 17

In a mortar, 1200 mg of the pharmaceutical composition of Example 9, 1266 mg of mannitol (PEARLITOL 200SD), 720 mg of potassium chloride, 360 mg of crospovidone (Kollidon CL), 36 mg of light anhydrous silicic acid (Silysia 320TP), and 18 mg of magnesium stearate were added and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 17.

Example 18

In a mortar, 1200 mg of the pharmaceutical composition of Example 9, 1266 mg of mannitol (PEARLITOL 200SD), 720 mg of potassium chloride, 360 mg of low-substituted hydroxypropyl cellulose (L-HPC, LH-21), 36 mg of light anhydrous silicic acid (Silysia 320TP) and 18 mg of magnesium stearate were added and mixed using a pestle. The resulting mixed powder was tableted using a single-punch tableting machine to obtain the pharmaceutical composition (tablets, 600 mg per tablet) of Example 18.

Table 25

Example 17 Example 18 Example 9 200 200 Mannitol 211 211 Potassium chloride 120 120 Crospovidone 60 - Low substituted hydroxypropyl cellulose - 60 Light anhydrous silicic acid 6 6 Magnesium stearate 3 3 Total 600 600

(Units: mg)

Experimental Example 15. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (tablets containing 40 mg equivalent of enzalutamide) obtained in Examples 17 and 18. The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid, in accordance with the dissolution test method using a paddle stirrer of the Japanese Pharmacopoeia, with the stirrer rotating at a speed of 50 rpm. The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rates were calculated by taking the absorbance of 0.3158 in a 1-mm cell as 100%.

The dissolution levels after 10 minutes from the start of the dissolution test (D _10min ) are shown in Table 26. Extremely high dissolution levels of 80% or higher were observed in the pharmaceutical compositions (tablets) of Example 17 using crospovidone and Example 18 using low-substituted hydroxypropyl cellulose.

Table 26

Example 17 Example 18 D _10min (%) 91.4 90.6

Example 19

In 40 ml of water, 3 g of “A1” was stirred until dissolved. To the mixed solution prepared by further adding 160 ml of methanol to the “A1” solution, 1 g of enzalutamide was added and stirred until dissolved to obtain a spray solution. The spray solution was spray dried using a spray dryer (Niro SD-Micro ^TM , GEA) to obtain the pharmaceutical composition (solid dispersion) of Example 19.

Experimental Example 16. Dissolution Test

A dissolution test was performed on the pharmaceutical compositions (solid dispersions) obtained in Examples 5 to 7 and 19 (containing 80 mg equivalent of enzalutamide). The composition of each pharmaceutical composition is shown in Table 27. A powder mixed with the same amount of mannitol (PEARLITOL 200SD) was used for the test for each pharmaceutical composition (solid dispersion). The dissolution test was performed using water (test liquid volume: 500 ml, liquid temperature: 37°C) as the dissolution test liquid in accordance with the dissolution test method using a paddle stirrer of the Japanese Pharmacopoeia at a stirrer rotation speed of 50 rpm (250 rpm for a period of 0 to 3 minutes from the start of the test, and 200 rpm for 3 to 5 minutes). The ultraviolet absorbance of enzalutamide was measured at 260 nm. The dissolution rate was calculated by taking the absorbance of 0.6316 in a 1 mm cell as 100%.

Table 27

Example 5 Example 6 Example 7 Example 19 Enzalutamide 80 80 80 80 B5 240 - - - B2 - 240 - - B3 - - 240 - A1 - - - 240

(Units: mg)

The dissolution rates at 10 minutes after the start of the dissolution test ( _D10min ) are shown in Table 28. A high dissolution rate of 100% or more was obtained in the pharmaceutical composition (solid dispersion) of Example 19 using polyvinyl alcohol having a saponification degree of 66 mol%. In the pharmaceutical composition (solid dispersion) of Examples 5 to 7 using polyvinyl alcohol having a saponification degree of 88 mol% or more, even the pharmaceutical composition of Example 7 showed a dissolved concentration of 15.2 μg/mL (= 80 mg × 9.5%/500 mL), and an effect of improving the dissolved concentration by 7 times or more with respect to the solubility of enzalutamide in water was observed.

Table 28

Example 5 Example 5 Example 7 Example 19 D _10min (%) 14.1 26.0 9.5 112.6

Industrial applicability

According to the present invention, a pharmaceutical composition for oral use can be provided in which the solubility and/or dissolution properties of enzalutamide are improved, supersaturation is maintained, and the absorption of enzalutamide upon oral administration is improved.

Although the present invention has been described with reference to specific embodiments, various changes and modifications obvious to those skilled in the art are possible without departing from the scope of the appended claims.

Claims (11)

1. A pharmaceutical composition for oral administration of enzalutamide, comprising enzalutamide and polyvinyl alcohol, wherein the polyvinyl alcohol has a degree of saponification from 63 mol.% to 85 mol.%, and a degree of polymerization from 100 to 500, wherein the content of polyvinyl alcohol is from 50 wt.% to 500 wt.% relative to the weight of enzalutamide, and additionally comprising potassium chloride, sodium chloride, or potassium dihydrogen phosphate as a co-disintegrant. 2. A pharmaceutical composition for oral administration according to claim 1, comprising a solid dispersion containing said enzalutamide and said polyvinyl alcohol. 3. A pharmaceutical composition for oral administration according to any one of claims 1, 2, further comprising a substance having a functional group capable of functioning as a hydrogen bond acceptor, wherein the substance having a functional group capable of functioning as a hydrogen bond acceptor is polyvinylpyrrolidone and/or copolyvidone. 4. A pharmaceutical composition for oral administration according to any one of claims 1-3, additionally comprising a disintegrant. 5. A pharmaceutical composition for oral administration according to claim 4, wherein the disintegrant is a compound or two or more compounds selected from the group consisting of crospovidone and low-substituted hydroxypropyl cellulose. 6. A pharmaceutical composition for oral administration according to claim 4 or 5, wherein the disintegrant is crospovidone. 7. A pharmaceutical composition for oral administration according to any one of claims 1-6, which is a tablet. 8. A pharmaceutical composition according to any one of claims 1-7, wherein enzalutamide is amorphous. 9. A method for producing a pharmaceutical composition for oral administration comprising enzalutamide and polyvinyl alcohol, wherein the polyvinyl alcohol has a degree of saponification from 63 mol.% to 85 mol.% and a degree of polymerization from 100 to 500, wherein the content of polyvinyl alcohol is from 50 wt.% to 500 wt.% relative to the weight of enzalutamide, and additionally comprising potassium chloride, sodium chloride, potassium dihydrogen phosphate as a co-disintegrant, wherein said method includes the step of preparing a solid dispersion containing enzalutamide and polyvinyl alcohol. 10. A method for producing a pharmaceutical composition for oral administration according to claim 9, wherein the solid dispersion is obtained by hot melt extrusion. 11. A method for producing a pharmaceutical composition for oral administration according to claim 10, wherein the solid dispersion is obtained by a method using a solvent.