Enzalutamide solid dispersion and method for producing same, and enzalutamide-containing preparation and method for producing same

Abstract

One embodiment of the present invention provides an enzalutamide solid dispersion that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one embodiment of the present invention provides an enzalutamide-containing preparation that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one embodiment of the present invention provides a method for producing an enzalutamide solid dispersion that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one embodiment of the present invention provides a method for producing an enzalutamide-containing preparation that maintains the amorphous state of enzalutamide and has improved dissolution properties. According to one embodiment of the present invention, an enzalutamide solid dispersion which includes enzalutamide in an amorphous state and hydroxypropyl cellulose that serves as an amorphousness-maintaining polymer is provided.

Description

Enzalutamide solid dispersion and method for producing the same, and enzalutamide-containing preparation and method for producing the same

[0001] One embodiment of the present invention relates to an enzalutamide solid dispersion. Alternatively, one embodiment of the present invention relates to an enzalutamide-containing formulation. Alternatively, one embodiment of the present invention relates to a method for producing an enzalutamide solid dispersion. Alternatively, one embodiment of the present invention relates to a method for producing an enzalutamide-containing formulation.

[0002] Enzalutamide (4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide) is an androgen receptor signaling inhibitor used to treat castration-resistant prostate cancer. Because enzalutamide is a poorly soluble drug, traditional enzalutamide-containing formulations were provided as soft capsules filled with a liquid containing enzalutamide and pharmaceutical excipients. Currently, a formulation is available in which enzalutamide is amorphousized using a solid dispersion containing enzalutamide and a polymer, improving dissolution properties.

[0003] As an example of a formulation containing a solid dispersion containing enzalutamide and a polymer, Patent Document 1 describes a pharmaceutical composition containing a solid dispersion containing enzalutamide and a polymer in a solid form, in which enzalutamide is in an amorphous state and the polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate.

[0004] Patent Document 2 also describes a composition comprising (a) enzalutamide or ARN-509, (b) a carrier, and (c) a surfactant, wherein the enzalutamide or ARN-509 is mainly amorphous, and the components (a) and (b) are combined in the form of a solid adsorbent in which the enzalutamide or ARN-509 is adsorbed onto the surface of the carrier, and the carrier for the solid adsorbent of component (b) is selected from the group consisting of magnesium aluminometasilicate, colloidal silicon dioxide, and porous silica. or components (a) and (b) are combined in the form of a solid dispersion or solid solution of enzalutamide or ARN-509 and a polymer, the polymer of component (b) being hydroxypropyl methylcellulose (HPMC) or hypromellose acetate succinate (HPMC-AS), and component (c) being selected from the group consisting of sodium lauryl sulfate, PEG 6000, Tween 80, and mixtures thereof.

[0005] Patent Document 3 describes an oral pharmaceutical composition containing enzalutamide and polyvinyl alcohol, the polyvinyl alcohol having a degree of saponification of 30 mol% or more and less than 85 mol%. Patent Document 3 also describes that by preparing a solid dispersion using enzalutamide and polyvinyl alcohol, the solid dispersion dissolves and / or dissolves in a pH-independent manner, maintains supersaturation, and improves its bioavailability upon oral administration to a living body.

[0006] Patent Document 4 also describes nanoparticles containing enzalutamide, and states that the nanoparticles contain (i) at least one surfactant and at least one polymer; (ii) at least two different surfactants; and / or (iii) at least two different polymers.

[0007] Patent No. 6404217 Publication Patent No. 6666254 Publication Patent No. 7172997 Publication Special Publication No. 2022-533463 Publication

[0008] In solid dispersions that maintain the amorphous state of enzalutamide, a poorly soluble drug, there is room for improvement in its dissolution. Therefore, one object of one embodiment of the present invention is to provide an enzalutamide solid dispersion that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one object of one embodiment of the present invention is to provide an enzalutamide-containing formulation that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one object of one embodiment of the present invention is to provide a method for producing an enzalutamide solid dispersion that maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, one object of one embodiment of the present invention is to provide a method for producing an enzalutamide-containing formulation that maintains the amorphous state of enzalutamide and has improved dissolution properties.

[0009] An enzalutamide solid dispersion according to one embodiment of the present invention comprises enzalutamide in an amorphous form and hydroxypropyl cellulose as an amorphous-maintaining polymer.

[0010] An enzalutamide-containing formulation according to one embodiment of the present invention comprises enzalutamide in an amorphous form and hydroxypropyl cellulose as an amorphous-maintaining polymer.

[0011] A method for producing an enzalutamide solid dispersion according to one embodiment of the present invention includes heating enzalutamide and hydroxypropyl cellulose as an amorphous maintaining polymer to melt the enzalutamide and soften the hydroxypropyl cellulose, mixing and homogenizing the molten material containing enzalutamide and hydroxypropyl cellulose, and cooling the molten material while extruding it to obtain a hot-melt extrudate containing enzalutamide and hydroxypropyl cellulose.

[0012] When enzalutamide and hydroxypropyl cellulose as an amorphous maintaining polymer are heated, the maximum temperature may be controlled to a range of 190°C to 230°C.

[0013] The method may further comprise grinding the hot melt extrudate.

[0014] When the hot-melt extrudate is pulverized, light anhydrous silicic acid may be added and the hot-melt extrudate may be pulverized.

[0015] A method for producing an enzalutamide-containing formulation according to one embodiment of the present invention comprises mixing an enzalutamide solid dispersion obtained by a method for producing an enzalutamide solid dispersion with one or more pharmaceutically acceptable additives, and compressing the resulting mixture into tablets.

[0016] According to one embodiment of the present invention, an enzalutamide solid dispersion is provided which maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, according to one embodiment of the present invention, an enzalutamide-containing formulation is provided which maintains the amorphous state of enzalutamide and has improved dissolution properties. Alternatively, according to one embodiment of the present invention, a method for producing an enzalutamide solid dispersion which maintains the amorphous state of enzalutamide and has improved dissolution properties is provided. Alternatively, according to one embodiment of the present invention, an enzalutamide-containing formulation is provided which maintains the amorphous state of enzalutamide and has improved dissolution properties.

[0017] FIG. 1 is a diagram showing the dissolution profile of amorphous enzalutamide of Comparative Example 1. FIG. 2 is a diagram showing the dissolution profile of enzalutamide solid dispersions of Example 1 and Comparative Examples 2 to 8 of the present invention. FIG. 3 is a diagram showing infrared absorption spectra of enzalutamide solid dispersions of Example 1 and Comparative Examples 2, 3, and 8 of the present invention, amorphous enzalutamide of Comparative Example 1, and crystalline enzalutamide of Reference Example 1. FIG. 4 is a diagram showing diffraction patterns of enzalutamide solid dispersions of Example 1 and Comparative Examples 2, 3, and 8 of the present invention, crystalline enzalutamide of Reference Example 1, and POVACOAT alone of Reference Example 2. FIG. 5 is a diagram showing the dissolution profile of amorphous enzalutamide of Comparative Example 1 and enzalutamide solid dispersions of Examples 1 to 4 and Reference Example 3 of the present invention. FIG. 6 is a diagram showing the dissolution profile of enzalutamide solid dispersions of Examples 6 to 8 and 9 of the present invention. FIG. 7 is a diagram showing the dissolution profile of enzalutamide solid dispersions of Examples 1, 3, 5, and Reference Example 4 of the present invention. FIG. 8 is a diagram showing the dissolution profile of enzalutamide solid dispersions of Examples 9 to 11 of the present invention. Fig. 1 shows the diffraction patterns of the enzalutamide solid dispersions of Examples 3, 7, and 10 of the present invention, and Reference Example 4. Fig. 2 shows the dissolution properties of the enzalutamide solid dispersions of Examples 3, 7, 10, and 12 to 14 of the present invention. Fig. 3 shows the dissolution properties of the enzalutamide solid dispersions of Example 3 and Reference Examples 4 to 6 of the present invention.

[0018] The enzalutamide-containing formulation of the present invention will be described below with reference to the drawings. The enzalutamide-containing formulation of the present invention should not be construed as being limited to the description of the following embodiments and examples. In the drawings referred to in the present embodiments and examples described below, identical parts or parts having similar functions are designated by the same reference numerals, and repeated explanations thereof will be omitted.

[0019] [Solid Dispersion] The enzalutamide solid dispersion of this embodiment contains amorphous enzalutamide and hydroxypropyl cellulose (hereinafter also referred to as HPC) as an amorphous-state maintaining polymer. As used herein, "amorphous-state maintaining polymer" collectively refers to polymers capable of maintaining enzalutamide in an amorphous state in the enzalutamide solid dispersion. In one embodiment, the enzalutamide solid dispersion may contain, in addition to HPC, one or more amorphous-state maintaining polymers selected from the group consisting of copolyvidone, methylcellulose, and methacrylic acid copolymer. In the enzalutamide solid dispersion, enzalutamide is dispersed in a matrix formed by the amorphous-state maintaining polymer, HPC, and maintained in an amorphous state.

[0020] Furthermore, in one embodiment, the enzalutamide solid dispersion contains amorphous enzalutamide and HPC, thereby improving the dissolution property of enzalutamide. As described above, enzalutamide is a poorly soluble drug, but the enzalutamide solid dispersion of this embodiment uses HPC as the amorphous maintaining polymer, thereby improving the dissolution property of enzalutamide. Furthermore, as shown in the examples described below, the solid dispersion of this embodiment using HPC as the amorphous maintaining polymer can provide superior dissolution property of enzalutamide compared to solid dispersions using other amorphous maintaining polymers.

[0021] It has not been known that a solid dispersion using HPC as an amorphous-state maintaining polymer maintains enzalutamide in an amorphous form while improving the dissolution of enzalutamide compared to solid dispersions using other amorphous-state maintaining polymers. For example, Patent Document 1 shows that using an ionizable polymer with a cellulose backbone as an amorphous-state maintaining polymer maintains enzalutamide in an amorphous form and improves dissolution, but does not demonstrate that HPC exhibits superior effects compared to other amorphous-state maintaining polymers. Similarly, Patent Document 2 only shows the effects of using an ionizable polymer with a cellulose backbone as an amorphous-state maintaining polymer, but does not demonstrate that HPC exhibits superior effects compared to other amorphous-state maintaining polymers.

[0022] Patent Document 3 only describes a solid dispersion using polyvinyl alcohol, and does not demonstrate at all that HPC exhibits superior effects to other amorphous-maintaining polymers. Furthermore, Patent Document 4 also only describes nanoparticles using a vinyl compound or a compound having a methylcellulose main skeleton as the amorphous-maintaining polymer, and does not demonstrate at all that HPC exhibits superior effects to other amorphous-maintaining polymers.

[0023] Therefore, the inventors' finding that in a solid dispersion using HPC as an amorphous state maintaining polymer, enzalutamide is maintained in an amorphous form and can provide superior dissolution properties of enzalutamide compared to solid dispersions using other amorphous state maintaining polymers is completely unpredictable from the prior art.

[0024] The enzalutamide solid dispersion according to this embodiment may contain HPC selected from, for example, grades SSL, SL, L, M, and H, and Klucel HF, MF, and EF. One grade of HPC may be selected from these grades, or two or more grades of HPC may be combined. In one embodiment, the grade of HPC contained in the enzalutamide solid dispersion is preferably L or M, with L being most preferred. The molecular weights and viscosities of 2% aqueous solutions at 20°C of HPC of each grade SSL, SL, L, M, and H are shown in Table 1. Furthermore, the physical properties of each grade of Klucel HF, MF, and EF are shown in Table 2. [Table 1] [Table 2]

[0025] In one embodiment of the enzalutamide solid dispersion, the content of HPC can be adjusted so that the mass ratio of enzalutamide:HPC is in the range of 1:3 to 1:6.

[0026] [Preparation] The enzalutamide-containing formulation according to this embodiment includes the solid dispersion according to the above-described embodiment, which contains amorphous enzalutamide and HPC. The amount of enzalutamide contained in the enzalutamide-containing formulation can be adjusted as desired within a range that achieves a therapeutic effect, for example, 40 mg or 80 mg per tablet of the enzalutamide-containing formulation.

[0027] In addition to the solid dispersion, the enzalutamide-containing formulation of this embodiment may further contain one or more pharmaceutically acceptable additives, including, but not limited to, excipients, binders, disintegrants, acidulants, effervescent agents, sweeteners, flavoring agents, lubricants, colorants, stabilizers, antioxidants, and fluidizing agents.

[0028] Examples of excipients include, but are not limited to, mannitol, lactose, starch, corn starch, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, refined sucrose, and glucose.

[0029] Examples of binders include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, and gum arabic.

[0030] Examples of disintegrants include, but are not limited to, corn starch, starch, crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium starch glycolate, powdered agar, crospovidone, synthetic aluminum silicate, sucrose fatty acid ester, lactose hydrate, D-mannitol, and anhydrous citric acid.

[0031] Examples of acidulants include, but are not limited to, citric acid, tartaric acid, and malic acid.

[0032] Examples of foaming agents include sodium bicarbonate, but are not limited to this.

[0033] Examples of sweeteners include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0034] Examples of flavoring agents include lemon, lemon lime, orange, and menthol, but are not limited to these.

[0035] Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

[0036] Examples of coloring agents include, but are not limited to, yellow iron oxide, red iron oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, and Food Blue No. 3.

[0037] Examples of stabilizers include, but are not limited to, citric acid, succinic acid, fumaric acid, tartaric acid, and ascorbic acid, or salts thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine, and arginine, or salts thereof; magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, and boric acid, or salts thereof.

[0038] Examples of antioxidants include, but are not limited to, ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

[0039] Examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, colloidal 20 silicon dioxide, fumed silica, CAB-O-SIL (registered trademark) M-5P, AEROSIL (registered trademark), talc, starch, and magnesium aluminum silicate.

[0040] In the enzalutamide-containing formulation according to this embodiment, which uses HPC as the amorphous-maintaining polymer, a salt may be added to the enzalutamide-containing formulation to cause salting out in order to improve the disintegration property of the tablet. Examples of salts that can be added to the enzalutamide-containing formulation include one or more selected from the group consisting of sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, potassium bicarbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, potassium chloride, sodium sulfate, sodium sulfite, sodium citrate, disodium citrate, sodium glutamate, disodium succinate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, fructose, and hydrates thereof.

[0041] In one embodiment, the enzalutamide solid dispersion according to this embodiment may be coated with a coating composition to improve the disintegration properties of the tablet. Examples of the coating composition include water-soluble polymers, insoluble polymers, sugars, and minerals such as talc.

[0042] In one embodiment, a plasticizer may be added to an enzalutamide-containing formulation using HPC as the amorphous-maintaining polymer to improve manufacturability. Examples of the plasticizer include one or more selected from the group consisting of polyethylene glycol (macrogol) 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, triethyl citrate, glycerin, glyceric acid esters, triacetin, propylene glycol, medium-chain triglycerides, polysorbate 80, glycerin monostearate, and copolyvidone.

[0043] In one embodiment, the enzalutamide solid dispersion may further contain an additive such as an antioxidant to improve the compatibility of enzalutamide with HPC, thereby improving the stability of enzalutamide. The antioxidant may be one or more selected from the antioxidants described above.

[0044] [Method for Producing Enzalutamide Solid Dispersion] Since enzalutamide is a poorly soluble drug, methods for producing a solid dispersion include solvent evaporation (e.g., spray drying, fluidized bed granulation, and tumbling granulation), melting (e.g., hot melt extrusion), and co-grinding (e.g., ball milling), with hot melt extrusion being particularly preferred. In one embodiment, enzalutamide is melted by heating, and HPC is softened. The melt is mixed and homogenized, and the mixture is extruded while cooling to produce the enzalutamide solid dispersion of this embodiment. When enzalutamide is melted by heating or dissolved in a solvent, the enzalutamide used as a raw material may be in either an amorphous or crystalline form. In one embodiment, the temperature conditions for the step of melting enzalutamide by heating and softening HPC and the step of mixing and homogenizing the melt are not particularly limited, as long as they are production conditions that allow enzalutamide to be amorphous. Since the melting point of enzalutamide is approximately 200°C, it is preferable to control the maximum temperature to around 200°C in order to amorphize enzalutamide, which has a crystalline structure. Considering the possibility of a melting point depression due to the amorphous-maintaining polymer, in one embodiment, it is preferable to control the maximum temperature to a range of 190°C to 230°C. In one embodiment, it is preferable to produce an enzalutamide solid dispersion by mixing enzalutamide and HPC in a ratio of enzalutamide:HPC of 1:3 to 1:6. The obtained enzalutamide solid dispersion can be pulverized and, if necessary, sized to obtain an enzalutamide solid dispersion for use in an enzalutamide-containing formulation.

[0045] [Method for producing an enzalutamide-containing formulation] The enzalutamide solid dispersion according to the present embodiment can be produced by mixing the enzalutamide solid dispersion according to the present embodiment described above with one or more pharmaceutically acceptable additives and tableting. In one embodiment, the enzalutamide solid dispersion according to the present embodiment is mixed with a pharmaceutically acceptable additive so that each tablet contains 40 mg or 80 mg of enzalutamide. However, the amount of enzalutamide contained in the enzalutamide-containing formulation can be adjusted as desired within a range that achieves a therapeutic effect. In another embodiment, a film-coated tablet can be obtained by coating the obtained uncoated enzalutamide-containing formulation with a film. The composition constituting the film can be a combination of known additives.

[0046] [Evaluation of Amorphous State] The amorphous state of enzalutamide in enzalutamide solid dispersions and enzalutamide-containing formulations can be evaluated by infrared absorption spectroscopy or powder X-ray diffraction. As used herein, "amorphous" means that no peaks derived from crystalline components are detected in the infrared absorption spectrum obtained by infrared absorption spectroscopy or the diffraction pattern obtained by powder X-ray diffraction. In particular, in powder X-ray diffraction, "no peaks detected" means that a broad halo pattern is observed relative to the baseline, and no significant peaks derived from crystalline components are observed.

[0047] [Evaluation of Dissolution] In the present specification, the dissolution of enzalutamide in the enzalutamide solid dispersion and the enzalutamide-containing formulation can be evaluated in accordance with the dissolution test method (paddle method) of the Japanese Pharmacopoeia, 18th Edition, using the second dissolution test fluid (1 volume of phosphate buffer solution at pH 6.8 plus 1 volume of water).

[0048] Comparative Example 1 In Comparative Example 1, 80 mg of amorphous enzalutamide was prepared.

[0049] Example 1 1.5 g of enzalutamide and 6.0 g of HPC (L, Nippon Soda Co., Ltd.) were placed in a capillary rheometer (RHEOGRAPH 20, GOTTFERT) and passed through the capillary five times at 210°C. 0.07 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added to 7.0 g of the resulting hot-melt extrudate, and the mixture was milled using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm. The resulting particles were placed in the capillary rheometer and passed through the capillary three times at 210°C. 0.06 g of light anhydrous silicic acid was added to 6.0 g of the obtained hot-melt extrudate, and the mixture was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain the enzalutamide solid dispersion of Example 1.

[0050] Comparative Example 2 An enzalutamide solid dispersion of Comparative Example 2 was obtained by the same method as in Example 1, except that HPC was changed to hypromellose acetate succinate (HPMC: Shin-Etsu AQOAT (registered trademark) AS-MMP, Shin-Etsu Chemical Co., Ltd.).

[0051] Comparative Example 3 An enzalutamide solid dispersion of Comparative Example 3 was obtained by the same method as in Example 1, except that HPC was changed to polyvinylpyrrolidone (PVP: Kollidon (registered trademark) VA 64, BASF).

[0052] Comparative Example 4 An enzalutamide solid dispersion of Comparative Example 4 was obtained by the same method as in Example 1, except that the HPC was changed to dry methacrylic acid copolymer LD (Eudragit (registered trademark) L100-55, Evonik Japan Co., Ltd.) and the number of treatments was changed to one.

[0053] [Comparative Example 5] An enzalutamide solid dispersion of Comparative Example 5 was obtained by the same method as in Example 1, except that HPC was changed to a polyvinyl alcohol-polyethylene glycol graft copolymer (Kolicoat (registered trademark) IR, BASF).

[0054] [Comparative Example 6] An enzalutamide solid dispersion of Comparative Example 6 was obtained in the same manner as in Example 1, except that HPC was changed to hypromellose (TC-5 (registered trademark) M, Shin-Etsu Chemical Co., Ltd.).

[0055] [Comparative Example 7] An enzalutamide solid dispersion of Comparative Example 7 was obtained in the same manner as in Example 1, except that HPC was changed to methylcellulose (METOLOSE (registered trademark) SM-4, Shin-Etsu Chemical Co., Ltd.).

[0056] [Comparative Example 8] The enzalutamide solid dispersion of Comparative Example 8 was obtained by the same method as in Example 1, except that HPC was changed to polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark), Daido Chemical Industry Co., Ltd.).

[0057] [Evaluation of Dissolution] Using the second dissolution test fluid, the dissolution properties of the amorphous enzalutamide of Comparative Example 1 and the enzalutamide solid dispersions of Example 1 and Comparative Examples 2 to 8 were evaluated in accordance with the dissolution test method (paddle method) of the Eighteenth Edition of the Japanese Pharmacopoeia. For the dissolution evaluation, each solid dispersion was used in an amount containing 80 mg of enzalutamide. FIG. 1 shows the dissolution properties of the amorphous enzalutamide of Comparative Example 1. FIG. 2 shows the dissolution properties of the enzalutamide solid dispersions of Example 1 and Comparative Examples 2 to 8. Almost no enzalutamide was dissolved from the amorphous enzalutamide of Comparative Example 1. This is thought to be due to the hydrophobicity of enzalutamide and the rapid crystallization of enzalutamide upon contact with water. On the other hand, the enzalutamide solid dispersions of Example 1 and Comparative Examples 2 to 8 showed improved dissolution properties of enzalutamide compared to the amorphous enzalutamide of Comparative Example 1. Among them, the enzalutamide solid dispersion of Example 1 was confirmed to have superior dissolution properties of enzalutamide compared to the enzalutamide solid dispersions of Comparative Examples 2 to 8. Even compared to the enzalutamide solid dispersion of Comparative Example 2, which uses hypromellose acetate succinate as described in Patent Document 1, the enzalutamide solid dispersion of Example 1 was confirmed to have rapid dissolution of enzalutamide.

[0058] [Evaluation of amorphous substance] The infrared absorption spectrum was measured for the amorphous enzalutamide of Comparative Example 1 and the enzalutamide solid dispersions of Example 1, Comparative Examples 2, 3, and 8. In addition, the infrared absorption spectrum of crystalline enzalutamide was measured in Reference Example 1. Figure 3 shows the infrared absorption spectrum. The enzalutamide crystal of Reference Example 1 exhibited a peak at 1528 cm －１ A peak was detected at π-π stacking, but this peak was not observed in the amorphous enzalutamide of Comparative Example 1. Furthermore, no peak derived from enzalutamide crystals was observed in the enzalutamide solid dispersions of Example 1, Comparative Examples 2, 3, and 8. Enzalutamide is known to form π-π stacking between molecules. Since the infrared absorption spectra measured for the enzalutamide solid dispersions of Example 1, Comparative Examples 2, 3, and 8 were different from one another, it is presumed that the π-π stacking distance varies depending on the type of amorphous-maintaining polymer used in the solid dispersion.

[0059] In addition, powder X-ray diffraction measurements were performed on the enzalutamide solid dispersions of Example 1 and Comparative Examples 2, 3, and 8. Powder X-ray diffraction measurements were performed on enzalutamide crystals in Reference Example 1. Powder X-ray diffraction measurements were performed on polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in Reference Example 2. FIG. 4 shows the diffraction patterns. The enzalutamide solid dispersions of Example 1 and Comparative Examples 2, 3, and 8 did not exhibit any significant peaks, as observed in the enzalutamide crystals of Reference Example 1. This indicates that enzalutamide is maintained in an amorphous state in the enzalutamide solid dispersions of Example 1 and Comparative Examples 2, 3, and 8. Furthermore, a comparison with the diffraction pattern of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer of Reference Example 2 reveals that the peaks observed in the diffraction pattern of the enzalutamide solid dispersion of Comparative Example 8 are derived from the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0060] Example 2 3.0 g of enzalutamide and 15.0 g of HPC (L, Nippon Soda Co., Ltd.) were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific Inc.) and subjected to a single extrusion process at 210°C and a screw rotation speed of 80 rpm. 0.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added to 10.0 g of the resulting hot-melt extrudate, and the mixture was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain the enzalutamide solid dispersion of Example 2. The enzalutamide solid dispersion of Example 2 contained enzalutamide:HPC in a ratio of 1:5.

[0061] [Example 3] An enzalutamide solid dispersion of Example 3 was obtained by the same method as in Example 2, except that the amount of enzalutamide was changed to 4.0 g and the amount of HPC was changed to 16.0 g. The enzalutamide solid dispersion of Example 3 contained enzalutamide:HPC in a ratio of 1:4.

[0062] [Example 4] An enzalutamide solid dispersion of Example 4 was obtained by the same method as in Example 2, except that the amount of enzalutamide was changed to 4.0 g and the amount of HPC was changed to 12.0 g. The enzalutamide solid dispersion of Example 4 contained enzalutamide:HPC in a ratio of 1:3.

[0063] [Reference Example 3] An enzalutamide solid dispersion of Reference Example 3 was obtained by the same method as in Example 2, except that the amount of enzalutamide was changed to 5.0 g and the amount of HPC was changed to 10.0 g. The enzalutamide solid dispersion of Reference Example 3 contained enzalutamide:HPC in a ratio of 1:2.

[0064] [Evaluation of Dissolution] The dissolution properties of enzalutamide were evaluated for the enzalutamide solid dispersions of Examples 2 to 4 and Reference Example 3 by the method described above. For the dissolution evaluation, each solid dispersion was used in an amount containing 80 mg of enzalutamide. Figure 5 shows the dissolution properties of the enzalutamide solid dispersions of Examples 2 to 4 and Reference Example 3. Figure 5 also shows the dissolution properties of amorphous enzalutamide of Comparative Example 1 and the enzalutamide solid dispersion of Example 1. The results in Figure 5 clearly demonstrate that the higher the blending ratio of HPC, the more improved the dissolution properties of enzalutamide. On the other hand, it is presumed that the enzalutamide solid dispersion of Reference Example 3, which contained enzalutamide:HPC in a ratio of 1:2, exhibited lower dissolution properties than the enzalutamide solid dispersions of the Examples due to the hydrophobicity of enzalutamide.

[0065] [Example 5] In the above Examples 1 to 4, Comparative Examples 2 to 8, and Reference Example 3, the steps of melting enzalutamide by heating, softening HPC, and mixing the molten material to homogenize were carried out at 210°C. The effect of the processing temperature on the amorphization of enzalutamide and the dissolution properties of enzalutamide was investigated. The enzalutamide solid dispersion of Example 5 was obtained by the same manufacturing method as in Example 3, except that the extruder temperature was changed to 230°C.

[0066] Reference Example 4 An enzalutamide solid dispersion of Reference Example 4 was obtained by the same method as in Example 3, except that the number of times of treatment with the extruder was changed to two.

[0067] [Example 6] In the above-mentioned examples, HPC-L was used as the amorphous-maintaining polymer, but the grade of HPC was changed to produce an enzalutamide solid dispersion. The enzalutamide solid dispersion of Example 6 was obtained by the same method as in Example 1, except that the grade of HPC was changed to HPC (SSL, Nippon Soda Co., Ltd.).

[0068] Example 7 An enzalutamide solid dispersion of Example 7 was obtained by the same method as in Example 3, except that the grade of HPC was changed to HPC (SSL, Nippon Soda Co., Ltd.).

[0069] Example 8 An enzalutamide solid dispersion of Example 8 was obtained in the same manner as in Example 7, except that the extruder temperature was changed to 230°C.

[0070] Example 9 An enzalutamide solid dispersion of Example 9 was obtained by the same method as in Example 1, except that the grade of HPC was changed to HPC (M, Nippon Soda Co., Ltd.).

[0071] Example 10 An enzalutamide solid dispersion of Example 10 was obtained by the same method as in Example 3, except that the grade of HPC was changed to HPC (M, Nippon Soda Co., Ltd.).

[0072] Example 11 An enzalutamide solid dispersion of Example 11 was obtained in the same manner as in Example 10, except that the extruder temperature was changed to 230°C.

[0073] [Evaluation of Dissolution] The dissolution properties of enzalutamide for the enzalutamide solid dispersions of Examples 5 to 11 were evaluated by the method described above. For the dissolution evaluation, an amount of each solid dispersion containing 80 mg of enzalutamide was used. Figure 6A shows the dissolution properties of the enzalutamide solid dispersions of Examples 6 to 8, in which HPC-SSL was used as the amorphous maintaining polymer. Figure 6B shows the dissolution properties of the enzalutamide solid dispersions of Examples 1, 3, and 5, and Reference Example 4, in which HPC-L was used as the amorphous maintaining polymer. Figure 6C shows the dissolution properties of the enzalutamide solid dispersions of Examples 9 to 11, in which HPC-M was used as the amorphous maintaining polymer. The results of Figures 6A to 6C reveal that the dissolution properties of enzalutamide are significantly affected by the grade of HPC and the manufacturing temperature.

[0074] [Evaluation of amorphousness] Powder X-ray diffraction measurements were performed on the enzalutamide solid dispersions of Examples 3, 7, and 10. Powder X-ray diffraction measurements were also performed on the enzalutamide solid dispersion of Reference Example 4, which had been passed through an extruder twice. Figure 7 shows the diffraction patterns. It was revealed that enzalutamide was maintained in an amorphous state in the enzalutamide solid dispersions of Examples 3, 7, 10, and Reference Example 4.

[0075] Example 12 In the above-described example, the extruder was used with a throughput of 20 g. However, the effect of scaling up the throughput by 5 times was examined on the dissolution properties of the enzalutamide solid dispersion. 20.0 g of enzalutamide and 80.0 g of HPC (SSL, Nippon Soda Co., Ltd.) were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific Inc.) and subjected to a single extrusion process at 210°C and a screw rotation speed of 80 rpm. 0.5 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added to 50.0 g of the resulting hot-melt extrudate, and the mixture was milled using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain the enzalutamide solid dispersion of Example 12.

[0076] Example 13 An enzalutamide solid dispersion of Example 13 was obtained by the same method as in Example 12, except that the grade of HPC was changed to HPC (L, Nippon Soda Co., Ltd.).

[0077] Example 14 An enzalutamide solid dispersion of Example 14 was obtained by the same method as in Example 12, except that the grade of HPC was changed to HPC (M, Nippon Soda Co., Ltd.).

[0078] [Evaluation of Dissolution] The enzalutamide dissolution properties of the enzalutamide solid dispersions of Examples 3, 7, 10, and 12 to 14 were evaluated by the method described above. For the dissolution evaluation, each solid dispersion was used in an amount containing 80 mg of enzalutamide. Figure 8 shows the dissolution properties of the enzalutamide solid dispersions of each Example. The results of Figure 8 revealed that, regardless of the grade of HPC used, the dissolution properties of enzalutamide improved with increasing extruder throughput. This is presumably because the increased throughput allowed the powder to be fully packed into the manufacturing equipment, resulting in high shear stress on the powder, resulting in the formation of a uniform solid dispersion. Furthermore, when comparing the dissolution properties of enzalutamide with different grades of HPC for enzalutamide solid dispersions produced at a scaled-up scale, it was found that the maximum attainable dissolution rate of enzalutamide was low (approximately 70%) with the low-viscosity SSL, while the high-viscosity M HPC resulted in a slow dissolution of enzalutamide. These results suggest that SSL has a high potential for favorable disintegration properties when tableted due to its low viscosity. On the other hand, M exhibits a slow dissolution rate of enzalutamide, which is expected to result in high oral absorption.

[0079] Reference Example 4 In the above-mentioned examples, an enzalutamide solid dispersion was produced by hot melt extrusion. In Reference Example 4, a solid dispersion was produced using a film casting method, which is a solvent distillation method. 160.0 mg of enzalutamide and 640.0 mg of HPC (L, Nippon Soda Co., Ltd.) were dissolved in 6.4 ml of acetone, and the resulting solution was heated at 70°C for 3 hours in a mini-jet oven (manufactured by Fujimac Co., Ltd.) and dried. The dried mixture was pulverized in an agate pestle and mortar to obtain the enzalutamide solid dispersion of Reference Example 4.

[0080] Reference Example 5: A solid dispersion was produced using a fluidized bed granulation method in Reference Example 5. 20.0 g of enzalutamide and 80.0 g of HPC (L, Nippon Soda Co., Ltd.) were dissolved in a mixture of 560.0 g of acetone and 240.0 g of purified water to prepare a granulation liquid. 50.0 g of microcrystalline cellulose (PH-101, Asahi Kasei Corporation) was charged into a fluidized bed granulator (MP-01, Powrex Corporation), and fluidized bed granulation was performed while spraying the granulation liquid. The granules were then dried for 2 minutes at an inlet air temperature of 85°C. This yielded the enzalutamide solid dispersion of Reference Example 5.

[0081] [Reference Example 6] In Reference Example 6, a solid dispersion was produced using a spray drying method. 8.0 g of enzalutamide and 32.0 g of HPC (L, Nippon Soda Co., Ltd.) were dissolved in 320.0 g of acetone. The solution containing enzalutamide was spray-dried using a spray dryer (Mini Spray Dryer B-290, BUCHI) with an inlet air temperature of 100°C, to obtain the enzalutamide solid dispersion of Reference Example 6.

[0082] [Evaluation of Dissolution] The dissolution properties of the enzalutamide solid dispersions of Example 13 and Reference Examples 4 to 6 were evaluated by the method described above using the second dissolution test fluid. For the evaluation of dissolution properties, each solid dispersion was used in an amount containing 80 mg of enzalutamide. Figure 9 shows the dissolution properties of the enzalutamide solid dispersions of Example 3 and Reference Examples 4 to 6. The results of Figure 9 reveal that the enzalutamide solid dispersion of Example 3 produced by hot-melt extrusion had a higher maximum dissolution rate at an early stage of dissolution than the enzalutamide solid dispersions of Reference Examples 4 to 6 produced by other production methods.

Claims

1. An enzalutamide solid dispersion comprising an amorphous form of enzalutamide and hydroxypropyl cellulose as an amorphous maintaining polymer.

2. The enzalutamide solid dispersion of claim 1, further comprising one or more amorphous maintaining polymers selected from the group consisting of copolyvidone, methylcellulose and methacrylic acid copolymers.

3. The enzalutamide solid dispersion of claim 1, wherein the mass ratio of enzalutamide:HPC is in the range of 1:3 to 1:

6.

4. An enzalutamide-containing formulation comprising the enzalutamide solid dispersion described in any one of claims 1 to 3.

5. A method for producing an enzalutamide solid dispersion, comprising heating enzalutamide and hydroxypropyl cellulose as an amorphous maintaining polymer, melting the enzalutamide, softening the hydroxypropyl cellulose, mixing and homogenizing a molten material containing the enzalutamide and the hydroxypropyl cellulose, and cooling the molten material while extruding to obtain a hot melt extrudate containing the enzalutamide and the hydroxypropyl cellulose.

6. A method for producing an enzalutamide solid dispersion as described in claim 5, wherein when heating the enzalutamide and hydroxypropyl cellulose as the amorphous maintaining polymer, the maximum temperature is controlled to a range of 190°C to 230°C.

7. A method for producing the enzalutamide solid dispersion of claim 5, further comprising grinding the hot melt extrudate.

8. A method for producing an enzalutamide solid dispersion as described in claim 7, wherein when the hot-melt extrudate is pulverized, light anhydrous silicic acid is added and the hot-melt extrudate is pulverized.

9. A method for producing an enzalutamide-containing formulation, comprising mixing an enzalutamide solid dispersion obtained by the method for producing an enzalutamide solid dispersion according to any one of claims 5 to 8 with one or more pharma- ceutically acceptable additives, and compressing the resulting mixture into tablets.

Images