Enzalutamide-containing pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition containing enzalutamide having excellent dissolution and dissolution retention properties, and a method for producing the pharmaceutical composition. [Solution] A pharmaceutical composition containing enzalutamide solid dispersion particles and a cellulose-based polymer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing enzalutamide as an active ingredient and a method for producing the same.

Background Art

[0002] Enzalutamide (chemical name: 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide) has an androgen receptor antagonist effect and is commercially available as an oral drug under the name of "Xtandi (registered trademark) tablets 40 mg / 80 mg" (hereinafter also referred to as "pre-approved preparation"). Usually, it is necessary to orally administer two tablets (a total of 160 mg as a drug) once a day of a tablet of about 670 mg. The pre-approved preparation is a film-coated tablet in which a core tablet composed of enzalutamide, hypromellose acetate succinate, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, and magnesium stearate is coated with a coating agent composed of hypromellose, talc, macrogol, titanium oxide, and yellow iron sesquioxide (Non-Patent Document 1).

[0003]

Chemical Formula

[0004] Enzalutamide has a solubility of 2.0×10 in pH 1-7 ,

[0004] , , , , ,

[0003] , -3 , , , Enzalutamide is a poorly soluble drug at mg / mL, and solid dispersions of enzalutamide amorphous with polymers have been proposed to improve its solubility and bioavailability. For example, Patent Document 1 discloses a tablet containing a solid amorphous dispersion of enzalutamide and a polymer selected from the group consisting of ionizable cellulose polymers, non-ionizable cellulose polymers, and non-cellulose polymers, while Patent Documents 2 and 3 disclose tablets containing a solid dispersion of enzalutamide and Eudragit®. Furthermore, Patent Document 4 discloses a tablet containing a solid dispersion of enzalutamide and polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer ("Soluplus," manufactured by BASF). However, the dissolution rate of such tablets shows a temporary increase in enzalutamide concentration, but then decreases to below 40%.

[0005] Thus, because enzalutamide is poorly soluble, its dissolution can be temporarily improved by using a solid dispersion of amorphous enzalutamide. However, as the drug concentration in the test solution increases, it becomes difficult to maintain a supersaturated state, and enzalutamide precipitates over time, leading to a decrease in the dissolution rate. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2014 / 043208 [Patent Document 2] International Publication No. 2019 / 155416 [Patent Document 3] International Publication No. 2021 / 240206 [Patent Document 4] Japanese Patent Publication No. 2024-40951 [Non-patent literature]

[0007] [Non-Patent Document 1] Xtandi® Tablets 40mg / Xtandi® Tablets 80mg Interview Form, Revised October 2023 (8th Edition) [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention aims to provide an enzalutamide-containing pharmaceutical composition having excellent dissolution and dissolution retention properties, and a method for producing the pharmaceutical composition. [Means for solving the problem]

[0009] As a result of investigations aimed at solving the above-mentioned problems, the present inventors found that by coexisting a cellulose-based polymer with an enzalutamide solid dispersion, the precipitation of enzalutamide is suppressed and the elution maintenance can be ensured.

[0010] In other words, the present invention relates to the following 1) to 10). 1) A pharmaceutical composition containing enzalutamide solid dispersion particles and a cellulose-based polymer. 2) The composition according to 1), wherein the cellulose polymer is one or more selected from hypromellose acetate succinate, hypromellose, and hydroxypropylcellulose. 3) The composition according to 1) or 2), wherein the proportion of cellulose polymer in the composition (enzalutamide:cellulose polymer) is 1:0.1 to 1:7 by mass ratio. 4) The composition according to 1) or 2), wherein the enzalutamide solid dispersion particles contain one or more polymers selected from methacrylate copolymer and hydroxypropyl cellulose in the particles. 5) The composition according to 4), wherein the blending ratio of the polymer (enzalutamide:polymer) in the enzalutamide solid dispersion particles is 1:0.5 to 1:3 by mass ratio. 6) The composition according to 1) or 2), comprising a disintegrant, a lubricant, and a fluidizing agent. 7) The composition according to 1) or 2), in the form of a tablet. 8) A method for manufacturing the tablet according to 7), which includes a step of preparing a granulated product containing enzalutamide solid dispersion particles and a cellulose-based polymer. 9) A method for manufacturing the tablet according to 7), which includes a step of preparing a granulated product containing enzalutamide solid dispersion particles and a cellulose-based polymer, and a step of mixing and tableting the granulated product, a disintegrant, and a lubricant. 10) A method for manufacturing the tablet according to 7), which includes a step of granulating after mixing enzalutamide solid dispersion particles, a cellulose-based polymer, a disintegrant, and a lubricant.

Advantages of the Invention

[0011] The pharmaceutical composition of the present invention has excellent elution property and elution maintenance property of enzalutamide.

Brief Description of the Drawings

[0012] [Figure 1] XRD charts of the enzalutamide solid dispersions and enzalutamide of Examples 1 and 3 [Figure 2] Dissolution tests of Example 1 and Comparative Example 1

Modes for Carrying Out the Invention

[0013] In the pharmaceutical composition of the present invention, since the absorption site of enzalutamide is the small intestine, the dissolution rate in a test solution of pH 6.8 is 50% or more, preferably 60% or more in 15 minutes. In the present invention, the dissolution rate is measured according to the dissolution test method of the 18th revised Japanese Pharmacopoeia, and the first solution and the second solution of the Japanese Pharmacopoeia are used as the test solutions of pH 1.2 and pH 6.8. Usually, when the maximum dissolution rate of enzalutamide reaches 40% or more, especially 50% or more, it becomes a supersaturated state, precipitation occurs over time, and the dissolution rate decreases. In the pharmaceutical composition of the present invention, even when the dissolution rate of enzalutamide reaches 40% or more, further 50% or more, and further 70% or more, the decrease in the dissolution rate over time is suppressed.

[0014] In the present invention, the sustained dissolution of enzalutamide refers to suppressing the decrease in the dissolution rate over time, that is, suppressing the decrease in the dissolution rate of the supersaturated solution of enzalutamide. For example, in a test solution with a pH of 6.8, the enzalutamide solid dispersion rapidly dissolves within 5 to 15 minutes, and then the dissolution over time decreases. Therefore, it is determined by the decrease rate of the dissolution rate at 60 minutes relative to the dissolution rate at 15 minutes (see the following formula). In the pharmaceutical composition of the present invention, the decrease rate of enzalutamide dissolution is, for example, 20% or less, preferably 15% or less, more preferably 10% or less, and even more preferably 5% or less.

[0015] [Formula 1] Dissolution decrease rate [%] = (Dissolution rate at 15 minutes - Dissolution rate at 60 minutes) / Dissolution rate at 15 minutes × 100

[0016] In the pharmaceutical composition of the present invention, by coexisting a cellulose-based polymer, precipitation of enzalutamide can be suppressed. The cellulose-based polymer is considered to suppress the precipitation of enzalutamide by suppressing the growth of the formed precipitation nuclei of enzalutamide and / or the aggregation of the precipitation nuclei of enzalutamide in the enzalutamide supersaturated solution. Therefore, it is a substance with a charge, hydrogen bond, and is easily electrically bonded on the surface of the precipitated particles of enzalutamide and has a molecular weight above a certain level.

[0017] According to the pharmaceutical composition of the present invention, the amorphous nature of enzalutamide is maintained, and the dissolution property of the enzalutamide preparation can be maintained, so that the preparation stability can be ensured.

[0018] The enzalutamide solid dispersion particles of the present invention contain one or more polymers selected from enzalutamide, ionic non-cellulose polymers, non-ionic non-cellulose polymers, non-ionic cellulose polymers, and ionic cellulose polymers, and enzalutamide is amorphous. Thereby, the dissolution property of enzalutamide is improved. The solid dispersion phase of enzalutamide and the above polymer is characterized by a state in which enzalutamide and the polymer are homogeneously dispersed, particularly molecularly, with cluster sizes smaller than or equal to the size of enzalutamide molecules or crystals that cannot be measured. This can be confirmed by XRD or thermal analysis. In XRD, it is essentially a halo pattern, and the characteristic peaks of enzalutamide around 13°, 16°, 19°, and 21° are not visible in the chart. In thermal analysis, it is characterized by the presence of a glass transition temperature on a suggestive scanning calorimeter.

[0019] The enzalutamide used in the present invention is not particularly limited, but for example, those produced by known methods such as those described in JP 2013-520519, JP 2008-540523, or International Publication No. 2016 / 194813 can be used. The form of the enzalutamide used in the present invention is not particularly limited as long as it does not hinder amorphous formation. The particle size is also not particularly limited as long as it is within a range that does not cause problems in the production of amorphous enzalutamide. For example, for particle size d50, enzalutamide with a particle size of 0.1 μm to 100 μm can be used, and for particle size d90, enzalutamide with a particle size of 0.2 μm to 200 μm can be used. The particle size is based on the volume-based particle size distribution measured using a laser diffraction / scattering particle size distribution analyzer. An example of a laser diffraction / scattering particle size distribution analyzer is the DMS2 Ver11.1.0-257F2 from Microtrac-Bell Corporation.

[0020] The enzalutamide solid dispersion particles of the present invention may be formed by creating a continuous layer of enzalutamide solid dispersion around an excipient such as a nucleating agent. Alternatively, the enzalutamide solid dispersion may be adsorbed or supported in the pores of a porous material.

[0021] The polymer used to prepare the enzalutamide solid dispersion is one or more selected from ionic noncellulose polymers, nonionic noncellulose polymers, nonionic cellulose polymers, and ionic cellulose polymers, and two or more may be used in combination.

[0022] Examples of ionic noncellulose polymers include methacrylic acid copolymers, and nonionic noncellulose polymers include vinyl acetate-vinylpyrrolidone copolymers, copovidone, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymers, polyethylene glycol, polyethylene oxide, polypropylene glycol, and the like, with methacrylic acid copolymers being preferred.

[0023] The methacrylic acid copolymer is one or more selected from methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. For example, Eudragit® L100 (manufactured by Evonik), Eudragit® L100-55 (manufactured by Evonik), Eudragit® S100 (manufactured by Evonik), Eudragit® L30D-55 (manufactured by Evonik), etc. are available. Preferably, methacrylic acid copolymer L has a high methacrylic acid ratio.

[0024] Examples of nonionic cellulose polymers include hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate, and hydroxyethyl cellulose acetate, with hydroxypropyl cellulose and hydroxyethyl cellulose being preferred.

[0025] The blending ratio of the above polymer (enzalutamide:polymer) in the enzalutamide solid dispersion particles is, for example, 1:0.1 to 1:7 by mass ratio, preferably 1:0.2 to 1:5, more preferably 1:0.3 to 1:3, and even more preferably 1:0.4 to 1:2. The enzalutamide solid dispersion particles of the present invention may be compounded with the pharmaceutical additives described below to adjust the tablet properties, to the extent that they do not affect the dissolution rate.

[0026] The size of the enzalutamide solid dispersion particles of the present invention is such that it is easy to manufacture granules as described later, and the average particle diameter is 1 to 100 μm, preferably 1 to 80 μm, and more preferably 2 to 60 μm. The average particle diameter is the median diameter (D50) based on volume and can be measured using a dry laser diffraction / scattering particle size distribution analyzer. In terms of shape, a spherical shape is preferred because it is easy to manufacture granules as described later, and the spherical shape can be observed from SEM images, etc.

[0027] Enzalutamide solid dispersion particles can be manufactured by preparing a solution by dissolving or suspending enzalutamide and the above polymer in a solvent, and then spraying the solution into a stream of air (aerosol spraying method) to remove the solvent in a short time.

[0028] Examples of spraying methods include the fluidized bed method, spray drying method, rolling bed method, stirring method, and supercritical method. However, the spray drying method or fluidized bed method is preferred because it allows for the formation of particles in a short time in an airflow and the resulting particles exhibit high elutionability and stability. The time required for solvent removal to obtain the enzalutamide solid dispersion particles of the present invention is within 2 minutes, preferably within 1 minute, and more preferably within 30 seconds. The drying time here is the time required to obtain the solid and is not affected by the complete residual solvent. Specifically, if the residual solvent is 5% or less by weight, preferably 1% or less, highly amorphous enzalutamide solid dispersion particles can be obtained. If, after obtaining the enzalutamide solid dispersion particles, an amount of solvent remains that is problematic for use as a pharmaceutical product, it can be reduced to the amount of residual solvent specified in the ICH guidelines by known methods such as vacuum drying.

[0029] The solvent used in the spraying method described above can be any solvent in which enzalutamide and the polymer can be dissolved and which is suitable for pharmaceutical manufacturing. Examples include alcohols such as ethanol, methanol, and 2-propanol; ketones such as acetone, 2-butanone, and methyl isobutyl ketone; ethers such as tetrahydrofuran (THF), tetrahydropyran (THP), 1,4-dioxane, diethyl ether, diisopropyl ether, and t-butyl methyl ether; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO); aromatic hydrocarbons such as toluene; methyl acetate, ethyl acetate, butylacetic acid, formic acid, or water. However, two or more types may be used in combination, for example, a mixed solvent of THF and water, THF and ethanol, acetone and water, ethanol and water, acetone and ethanol, or dichloromethane and ethanol. The solvent is selected based on the solubility of the amorphous agent used. When the polymer is a methacrylic acid copolymer, a mixed solvent of acetone and ethanol is preferred. The mixing ratio is preferably, for example, acetone:ethanol = 5:1 to 1:2 by mass ratio, and more preferably 3:1 to 1:1. Here, ethanol may be, for example, anhydrous ethanol or pharmacopoeial ethanol, which are commonly used in the manufacture of pharmaceuticals, but anhydrous ethanol is preferred.

[0030] In the aforementioned spray manufacturing method, enzalutamide and polymer are dissolved in an organic solvent. The concentration at this time should be such that the enzalutamide and polymer are dissolved and can be sprayed, and the solid content should be 0.1 to 10% by weight, preferably 0.5 to 6% by weight. The solution is then sprayed into an airflow to simultaneously remove the solvent and granulate.

[0031] In the aforementioned spraying method, when spray drying is used, a spraying device is used, and as the spraying device, a disc-type or nozzle-type (for example, a pressurized nozzle, a two-fluid nozzle, or a four-fluid nozzle) spray dryer is used. The temperature during spray drying is preferably an inlet temperature of about 40 to 100°C and an outlet temperature of about 20 to 80°C.

[0032] In the production of the enzalutamide solid dispersion particles of the present invention, when spraying the aforementioned enzalutamide solution onto a carrier by a fluidized bed method, spray drying method, rolling bed method, stirring method, etc., a nozzle type is used, similar to the spray method described above. Preferably, the inlet temperature is about 40 to 100°C and the outlet temperature is about 20 to 80°C. The air supply conditions and carrier dynamic conditions are set arbitrarily according to the equipment used and the characteristics of the solvent and carrier used. As the carrier, additives usable in pharmaceuticals, as described later and commonly used in these production methods, can be used.

[0033] In the production of enzalutamide solid dispersion particles of the present invention, when fluid bed granulation is used, a solution of the aforementioned enzalutamide, the above polymer, and optionally a binder is sprayed onto a granulation core to serve as a support, and granulation is carried out. The binder described above can be used here. Examples of carriers include sugars (glucose, fructose, lactose (including lactose monohydrate), sucrose, trehalose, maltose, oligosaccharides, etc.), crystalline celluloses (crystalline cellulose, etc.), starches (corn starch, potato starch, rice starch, wheat starch, etc.), sugar alcohols (mannitol, erythritol, xylitol, sorbitol, maltitol, etc.), sodium phosphates, calcium phosphates (calcium hydrogen phosphate, etc.), gelatin, sucrose / starch spherical granules, lactose / crystalline cellulose spherical granules, and spherical silicon dioxide. The conditions for fluid bed granulation can be those commonly used in pharmaceutical manufacturing, and after granulation, drying can be performed to remove residual solvent using the same method as the spray drying described above.

[0034] The enzalutamide solid dispersion particles obtained by fluid bed granulation form a particle structure in which a drug layer is formed around the nucleating agent by spraying a solution containing enzalutamide and methacrylic acid copolymer onto the nucleating agent.

[0035] In the pharmaceutical composition of the present invention, examples of cellulose-based polymers to be coexisted with the enzalutamide solid dispersion particles include ionic cellulose polymers and nonionic cellulose polymers, but ionic cellulose polymers are preferred.

[0036] Examples of ionic cellulose polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, ethyl carboxymethylcellulose, carboxymethyl cellulose, carboxymethyl ethylcellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose succinate phthalate, and cellulose propionate phthalate. These include hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine carboxylate, cellulose salicylate acetate, hydroxypropyl salicylate acetate, ethyl benzoate acetate, hydroxypropyl ethyl benzoate acetate, ethyl phthalate acetate, ethyl nicotinate acetate, ethyl picolinate acetate, and hypromellose acetate succinate.

[0037] Examples of nonionic cellulose polymers include hypromellose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose acetate, and hydroxyethylcellulose acetate, with hypromellose and hydroxypropylcellulose being preferred.

[0038] The blending ratio of the cellulose polymer in the pharmaceutical composition of the present invention (enzalutamide:cellulose polymer) is 1:0.5 to 1:5 by mass ratio, preferably 1:0.8 to 1:3, and more preferably 1:1 to 1:2. In the pharmaceutical composition of the present invention, the cellulose polymer may coexist with the enzalutamide solid dispersion particles, but it is preferable for it to exist together with the enzalutamide solid dispersion particles as granules, in terms of reducing the time-dependent dissolution of enzalutamide.

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

[0040] When the pharmaceutical composition of the present invention is made into tablets, examples include (1) tablets produced by preparing granules containing an enzalutamide solid dispersion, a cellulose polymer, and a pharmaceutical additive, mixing in the pharmaceutical additive, and then compression molding, and (2) tablets produced by adding and mixing an enzalutamide solid dispersion, a cellulose polymer, and a pharmaceutical additive, and then compression molding.

[0041] In the granules containing enzalutamide and a cellulosic polymer used to prepare the tablets described in (1) above, it is preferable to add one or more of the disintegrants, excipients, fluidizers, and lubricants selected from the pharmaceutical additives described below to adjust the tablet properties to the extent that they do not affect the dissolution. The proportion of the disintegrant in such granules (enzalutamide: disintegrant) is 1:0.1 to 1:3 by mass, preferably 1:0.5 to 1:1. Furthermore, the mixing ratio of the fluidizing agent in the granules (enzalutamide: fluidizing agent) is 1:0.1 to 1:0.5 by mass ratio, preferably 1:0.15 to 1:0.3. Furthermore, the mixing ratio of the lubricant in the granules (enzalutamide: lubricant) is 1:0.01 to 1:0.2 by mass, preferably 1:0.05 to 1:0.1.

[0042] The size of the granules containing enzalutamide and cellulosic polymer can be such that they facilitate the manufacture of tablets as described later, and the average particle size is 60 to 1500 μm, preferably 100 to 1000 μm, and more preferably 100 to 600 μm. The average particle size is the median diameter (D50) based on volume, and can be measured using a dry laser diffraction / scattering particle size distribution analyzer or the sieving method of the Japanese Pharmacopoeia.

[0043] The tablets described in (2) above may contain, in addition to enzalutamide solid dispersion particles and cellulose-based polymer, pharmaceutical additives described later to adjust the tablet properties, to the extent that they do not affect dissolution. In such tablets, the blending ratio of the cellulose-based polymer (enzalutamide:cellulose-based polymer) is 1:0.5 to 1:3 by mass ratio, preferably 1:0.8 to 1:3, and more preferably 1:1 to 1:2.

[0044] Pharmaceutical additives used in the pharmaceutical composition of the present invention include one or more selected from disintegrants, excipients, fluidizers, lubricants, colorants, light-shielding agents, antioxidants, binders, and sweeteners. Examples of disintegrants include lactose, sucrose, starch, crospovidone, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Preferably, croscarmellose sodium and low-substituted hydroxypropylcellulose are used.

[0045] Examples of excipients include sugars such as lactose, sucrose, D-mannitol, and D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, acacia gum, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Preferably, crystalline cellulose, lactose, and D-mannitol are used.

[0046] Examples of fluidizing agents include talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate. Light anhydrous silicic acid, hydrated silicon dioxide, and talc are preferred.

[0047] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate, with magnesium stearate being preferred.

[0048] Examples of binders include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, pullulan, gelatin, acacia gum, crystalline cellulose, sucrose, pregelatinized starch, sucrose, D-mannitol, trehalose, and dextrin. Polyvinylpyrrolidone and hydroxypropylcellulose are preferred.

[0049] The antioxidant is not particularly limited as long as it can avoid the effects of elution behavior. Examples include dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, and sodium edetate. Other embodiments include dibutylhydroxytoluene, propyl gallate, and sodium ascorbate, and a further embodiment is dibutylhydroxytoluene. These antioxidants are expected to suppress the oxidation of enzalutamide by oxidizing components such as oxygen.

[0050] Examples of colorants include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 aluminum lake, Food Blue No. 2 aluminum lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel, and talc. These colorants are expected to suppress the decomposition of enzalutamide by light.

[0051] Examples of light-shielding agents include titanium dioxide, calcium carbonate, zinc oxide, talc, iron oxides such as yellow iron(III) oxide, iron(III) oxide, and black iron oxide, as well as food colorings such as Yellow No. 5 and Red No. 102, with titanium dioxide and calcium carbonate being preferred. These light-shielding agents are expected to suppress the decomposition of enzalutamide by light.

[0052] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0053] The enzalutamide tablets may be made into film-coated tablets to prevent contact with other drugs and scattering. The film coating can typically be made using film coating agents and their additives commonly used in pharmaceutical formulations. For example, film coating agents, plasticizers, lubricants, colorants, and light-blocking agents can be incorporated. Here, the film coating agent is not particularly limited, but examples include cellulose-based film coating agents such as hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, lumellose, carmellose sodium, and carmellose calcium, as well as acacia powder, gelatin pullulan, dextrin, carboxymethyl starch sodium, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol. Cellulose-based film coating agents are preferred, and hypromellose is more preferred.

[0054] The plasticizer is not particularly limited, but examples include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, propylene glycol hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, etc., with triacetin being preferred.

[0055] The lubricant for film coating is not particularly limited, but examples include talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate, with talc being preferred.

[0056] Examples of dyes for film coating include those listed above as colorants, with titanium dioxide being preferred.

[0057] Examples of solvents for dissolving / suspending film coating agents include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixtures thereof. Ethanol and water are preferred, and water is more preferred.

[0058] In the film-coated tablets, there are no clear limitations on the amount of film coating, but for example, it is preferable that a 600 mg / tablet uncoated tablet is coated with a film coating in the range of 5 to 50 mg / tablet, and more preferably in the range of 10 to 30 mg / tablet.

[0059] When manufacturing the tablets described in (1) above, a method of granulation and drying using a solvent, known as wet granulation, or a method of compaction followed by crushing and disintegration, known as dry granulation, can be employed. However, since the use of a solvent tends to affect the enzalutamide solid dispersion particles, dry granulation is preferred.

[0060] In the dry granulation method, enzalutamide solid dispersion particles, cellulose-based polymer, fluidizer, lubricant, and disintegrant are added, compacted, and then crushed and sizing are performed to obtain enzalutamide granules. Dry granulation is a method of granulation in which the compounding components are compacted, then crushed and broken down, without adding any external solutions such as water. Compaction methods include the roll compression method using a roller compactor and the slug compression method using a conventional tablet press. From the standpoint of manufacturing efficiency, the roll compression method is preferred. The conditions for the roller compactor, such as roll pressure, roll rotation speed, and powder supply screw rotation speed, vary depending on the size and type of equipment. For example, for Freund Industrial Co.'s TFmini or TF-208, a roll pressure of 2 to 20 MPa, a roll rotation speed of 2 to 30 rpm, and a powder supply screw rotation speed of 5 to 80 rpm are preferred. The flakes obtained by the roller compactor may be crushed and sized to a predetermined particle size using a crusher or pulverizer such as an oscillator, co-mill, quick mill, or power mill.

[0061] Furthermore, the enzalutamide solid dispersion particles can be granulated by a wet granulation method under conditions that do not impart an amorphous state to the enzalutamide or impart the elution properties of enzalutamide. Any wet granulation method that uses a solvent to granulate the granulation raw material is acceptable, such as extrusion granulation, rolling granulation, fluidized bed granulation, mixing and stirring granulation, spray drying granulation, and vibration granulation. These wet granulation methods may be used in combination. Among these wet granulation methods, mixing and stirring granulation and fluidized bed granulation are preferred from the viewpoint of productivity, and fluidized bed granulation is more preferred. Mixing and stirring granulation and fluidized bed granulation may also be used in combination.

[0062] The fluidized bed granulation method is not particularly limited as long as it involves spraying a granulation solution onto a raw material powder that has been fluidized by an airflow to obtain granules; conventional methods can be used. The raw material powder can be prepared using a mixing and stirring granulation method, which involves adding or spraying a granulation solution onto the raw material powder to obtain granules; any method commonly used in the pharmaceutical field can be used.

[0063] Enzalutamide can be produced by the following methods of adding raw materials during granulation: placing enzalutamide solid dispersion particles into the apparatus and spraying a suspension solution of a cellulose-based polymer and a binder to obtain enzalutamide granules; placing enzalutamide solid dispersion particles and a cellulose-based polymer into the apparatus and spraying a binder solution to obtain enzalutamide granules; or placing enzalutamide solid dispersion particles and a portion of a cellulose-based polymer into the apparatus and spraying a suspension solution of a portion of a cellulose-based polymer and a binder to obtain enzalutamide granules.

[0064] In fluidized bed granulation or mixing and stirring granulation, the granulation liquid only needs to contain a binder and a granulation solvent, and is usually an aqueous dispersion or aqueous solution consisting of a binder and a granulation solvent.

[0065] While there are no particular restrictions on the granulation solvent, water and aqueous solvents can be used for safety reasons. Examples of aqueous solvents include lower alcohols (e.g., ethanol, isopropanol, etc.) and aliphatic ketones (e.g., acetone, etc.). These solvents can be used individually or in combination of two or more.

[0066] The tablets described in (2) above can be manufactured by direct compression, after appropriately selecting and mixing enzalutamide solid dispersion particles, a cellulose polymer, a lubricant, a disintegrant, and other pharmaceutical additives, and then compressing them. Mixing can be carried out by commonly used mixing methods, such as mixing, kneading, and granulation. Mixing can be performed using, for example, a high-speed agitator, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double-cone mixer, a ribbon mixer, a swirling screw mixer, or manual mixing in bags. Compression molding can be performed using rotary tablet presses or the like commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ12mm tablet, it is 1 to 20kN, preferably 5 to 15kN.

[0067] Furthermore, when using an external lubrication method during compression molding, the dry granules, disintegrant, and excipient can be mixed, and then a lubricant can be applied during compression molding to obtain the uncoated tablets.

[0068] As described above, the manufactured uncoated tablets can be film-coated in accordance with common methods in the pharmaceutical field. Film coating can be performed using equipment normally used for aqueous or non-aqueous coating of tablets, such as a pan-coating system.

[0069] Film-coated tablets can be manufactured using methods commonly employed in the pharmaceutical field. A suspension of film coating agents, plasticizers, lubricants, light-shielding agents, colorants, etc., dissolved and dispersed in a solvent such as water or ethanol is sprayed into a coating pan containing uncoated tablets at a constant supply air temperature of approximately 70°C and exhaust temperature of approximately 40-50°C. The film coating is uniformly applied to the surface of the uncoated tablets, and then dried as necessary to form a film coating layer. [Examples]

[0070] (Example 1) A spray solution was prepared by dissolving 4.8 g of enzalutamide and 9.6 g of methacrylic acid copolymer (Evonik, EUDRAGITR L100-55) in a mixture of 310 g of acetone and 155 g of ethanol. The spray solution was dried in a spray dryer (Büch: mini spray dryer B-191) under the conditions of input heat of 95°C, exhaust heat of 51-52°C, and flow rate of 10-15 g / min to obtain a white powder. Next, it was dried under reduced pressure at 60°C for 18 hours to obtain a powder of enzalutamide solid dispersion. XRD measurement results (Figure 1) showed a halo pattern, indicating that enzalutamide is amorphous and a solid dispersion was formed. 240 parts by mass of enzalutamide solid dispersion powder, 160 parts by mass of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT AS-MF), 18 parts by mass of light anhydrous silicic acid, 28 parts by mass of crystalline cellulose, 28 parts by mass of lactose monohydrate, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed. Then, using a dry granulator, the mixture was compacted with a roller compactor and crushed with an oscillator to obtain granulated granules. 540 parts by mass of granulated granules and 60 parts by mass of croscarmellose sodium were mixed and compressed using a rotary tablet press with a 12 mm diameter, flat-cornered punch to obtain 600 mg tablets.

[0071] (Example 2) 240 parts by mass of the enzalutamide solid dispersion powder from Example 1, 80 parts by mass of hypromellose acetate succinate, 18 parts by mass of light anhydrous silicic acid, 68 parts by mass of crystalline cellulose, 68 parts by mass of lactose monohydrate, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed. Then, using a dry granulator, the mixture was compacted with a roller compactor and crushed with an oscillator to obtain granulated granules. 540 parts by mass of granulated granules and 60 parts by mass of croscarmellose sodium were mixed and compressed using a rotary tablet press with a 12 mm diameter, flat-cornered punch to obtain 600 mg tablets.

[0072] (Example 3) A spray solution was prepared by dissolving 8 g of enzalutamide and 4 g of methacrylic acid copolymer in a mixture of 259 g of acetone and 129 g of ethanol. The spray solution was dried in a spray dryer under the conditions of input 95°C, exhaust heat 51-52°C, and flow rate 10-15 g / min to obtain a white powder. Next, it was dried under reduced pressure at 60°C for 18 hours to obtain a powder of enzalutamide solid dispersion. XRD measurement results (Figure 1) showed a halo pattern, indicating that enzalutamide is amorphous and a solid dispersion was formed. 120 parts by mass of enzalutamide solid dispersion powder, 160 parts by mass of hypromellose acetate succinate, 18 parts by mass of light anhydrous silicic acid, 88 parts by mass of crystalline cellulose, 88 parts by mass of lactose, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed, and then compacted using a roller compactor and crushed with an oscillator to obtain granulated granules. 540 parts by mass of granulated granules and 60 parts by mass of croscarmellose sodium were mixed and compressed using a rotary tablet press with a 12 mm diameter, flat-cornered punch to obtain 600 mg tablets.

[0073] (Example 4) 240 parts by mass of the enzalutamide solid dispersion powder from Example 1, 160 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd., METOLOSE), 18 parts by mass of light anhydrous silicic acid, 58 parts by mass of crystalline cellulose, 58 parts by mass of lactose, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed. Then, using a dry granulator, the mixture was compacted with a roller compactor and crushed with an oscillator to obtain granulated granules.

[0074] (Example 5) A spray solution was prepared by dissolving 8 g of enzalutamide, 8 g of methacrylic acid copolymer (EUDRAGIT L100, Evonik), and 8 g of hydroxypropyl cellulose in a mixture of 384 g of acetone and 192 g of ethanol. The spray solution was dried in a spray dryer under the conditions of an input of 95°C, an exhaust of 51-52°C, and a flow rate of 10-15 g / min to obtain a white powder. Subsequently, it was dried under reduced pressure at 60°C for 18 hours to obtain a powder of enzalutamide solid dispersion. 240 parts by mass of enzalutamide solid dispersion powder, 160 parts by mass of hypromellose acetate succinate, 18 parts by mass of light anhydrous silicic acid, 28 parts by mass of crystalline cellulose, 28 parts by mass of lactose, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed, and then compacted using a dry granulator with a roller compactor and crushed with an oscillator to obtain granulated granules. 540 parts by mass of granulated granules and 60 parts by mass of croscarmellose sodium were mixed and compressed using a rotary tablet press with a 12 mm diameter, flat-cornered punch to obtain 600 mg tablets.

[0075] (Comparative Example 1) 240 parts by mass of the enzalutamide solid dispersion powder obtained in Example 1, 18 parts by mass of light anhydrous silicic acid, 108 parts by mass of crystalline cellulose, 108 parts by mass of lactose, 60 parts by mass of croscarmellose sodium, and 6 parts by mass of magnesium stearate were mixed. Then, using a dry granulator, the mixture was compacted with a roller compactor and crushed with an oscillator to obtain granulated granules. 540 parts by mass of the granulated granules and 60 parts by mass of croscarmellose sodium were mixed and compressed using a rotary tablet press with a tablet diameter of 12 mm and a flat-corner punch to obtain 600 mg tablets.

[0076] (dissolution) Dissolution tests were performed using the Japanese Pharmacopoeia Solution No. 2 (pH 6.8) under the paddle method at a rotation speed of 50 rpm, in accordance with the dissolution test method of the Japanese Pharmacopoeia. Enzalutamide was measured using HPLC. Table 1 shows the decrease in dissolution rate at 60 minutes compared to 15 minutes. Figure 2 shows the dissolution behavior.

[0077] [Table 1]

[0078] The enzalutamide compositions in Examples 1-5, to which the concentration-maintaining agents were added externally, showed sufficient enzalutamide elution within 15 minutes, and thereafter, the elution rate of enzalutamide did not decrease over time, maintaining good elution properties. In contrast, the composition without Comparative Example 1, which does not contain a cellulose polymer, showed a sufficient elution rate until 15 minutes, but the elution rate decreased significantly after 60 minutes. Furthermore, as shown in Figure 2 regarding dissolution, the enzalutamide tablets of Example 1 achieved a dissolution rate of over 70% at 10 minutes and maintained this rate until 60 minutes. In contrast, the composition of Comparative Example 1 had a maximum dissolution rate of 45% at 5-15 minutes, which decreased over time, reaching approximately 10% after 60 minutes.

[0079] (Example of formulation 1) Enzalutamide tablets are manufactured using the same procedure as in Example 1, according to the ingredients and amounts shown in Table 2.

[0080] [Table 2]

[0081] (Formulation Example 2) Enzalutamide tablets are manufactured using the same procedure as in Example 1, according to the ingredients and proportions shown in Table 3.

[0082] [Table 3] (Formulation Example 3) Enzalutamide tablets are manufactured using the same procedure as in Example 1, according to the ingredients and amounts shown in Table 4.

[0083] [Table 4] The enzalutamide tablets of the present invention satisfy the following conditions as a pharmaceutical formulation. (1) There are no tableting defects such as capping or sticking during tableting, and the content of the active ingredient is uniform. (2) It must have sufficient strength to prevent chipping or cracking during manufacturing or transportation. (3) There is no significant increase in impurities derived from the active pharmaceutical ingredient during manufacturing or over time. (4) The tablets weigh 650 mg or less, making them relatively easy to swallow.

Claims

1. A pharmaceutical composition containing enzalutamide solid dispersion particles and a cellulose-based polymer.

2. The composition according to claim 1, wherein the cellulose polymer is one or more selected from hypromellose acetate succinate, hypromellose, and hydroxypropylcellulose.

3. The composition according to claim 1 or 2, wherein the proportion of cellulose-based polymer in the composition (enzalutamide:cellulose-based polymer) is 1:0.1 to 1:7 by mass ratio.

4. The composition according to claim 1 or 2, wherein the enzalutamide solid dispersion particles contain one or more polymers selected from methacrylic acid copolymer and hydroxypropyl cellulose within the particles.

5. The composition according to claim 4, wherein the blending ratio of the polymer (enzalutamide:polymer) in the enzalutamide solid dispersion particles is 1:0.5 to 1:3 by mass ratio.

6. The composition according to claim 1 or 2, comprising a disintegrant, a lubricant, and a fluidizing agent.

7. The composition according to claim 1 or 2, in the form of a tablet.

8. A method for producing a tablet according to claim 7, comprising the step of preparing granules containing enzalutamide solid dispersion particles and a cellulosic polymer.

9. A method for producing tablets according to claim 7, comprising the steps of: preparing granules containing enzalutamide solid dispersion particles and a cellulosic polymer; and mixing and compressing the granules, a disintegrant, and a lubricant into tablets.

10. A method for producing tablets according to claim 7, comprising the step of mixing enzalutamide solid dispersion particles, a cellulose polymer, a disintegrant, and a lubricant, and then granulating them.

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