Solid dispersion, preparation containing solid dispersion, and method for producing solid dispersion

Abstract

One embodiment of the present invention provides a solid dispersion which suppresses the production of related substances. Alternatively, one embodiment of the present invention provides a preparation containing a solid dispersion which suppresses the production of related substances. Alternatively, one embodiment of the present invention provides a method for producing a solid dispersion which suppresses the production of related substances. According to one embodiment of the present invention, provided is a solid dispersion comprising: a drug in an amorphous form; an amorphousness-maintaining polymer; and a pharmaceutically acceptable acidic pH adjuster. The pharmaceutically acceptable acidic pH adjuster may be an organic acid.

Description

Solid dispersion, preparation containing solid dispersion, and method for producing solid dispersion

[0001] One embodiment of the present invention relates to a solid dispersion in which the production of related substances is suppressed, or to a formulation containing the solid dispersion in which the production of related substances is suppressed, or to a method for producing the solid dispersion in which the production of related substances is suppressed.

[0002] One known method for improving the dissolution property of poorly water-soluble drugs is to use a solid dispersion. In a solid dispersion, an amorphous drug is dispersed in an inert carrier as a base, and crystallization of the drug is suppressed by interaction with the inert carrier, thereby maintaining a supersaturated state of the drug. One known method for producing a solid dispersion is the hot-melt extrusion (HME) method, which allows for continuous production of a solid dispersion without using a solvent.

[0003] For example, Patent Document 1 describes a pharmaceutical composition comprising a solid dispersion containing enzalutamide (4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide) in a solid form and a polymer, wherein the 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] One object of one embodiment of the present invention is to provide a solid dispersion in which the production of related substances is suppressed. Alternatively, one object of one embodiment of the present invention is to provide a formulation containing a solid dispersion in which the production of related substances is suppressed. Alternatively, one object of one embodiment of the present invention is to provide a method for producing a solid dispersion in which the production of related substances is suppressed.

[0009] A solid dispersion according to one embodiment of the present invention comprises a drug in amorphous form, an amorphous-maintaining polymer, and a pharmaceutically acceptable acidic pH adjusting agent.

[0010] The pharmaceutically acceptable acidic pH adjusting agent may be an organic acid.

[0011] The organic acid may be one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

[0012] In a graph in which the total amount of related substances derived from the drug is plotted against the pH of a liquid obtained by dissolving and / or dispersing 200 mg of the solid dispersion in 5 ml of water, the solid dispersion may contain a pharmaceutically acceptable acidic pH adjuster in a range of ±2.00 of the pH value at which the total amount of related substances is minimized.

[0013] The drug may be enzalutamide and the amorphous maintaining polymer may be hydroxypropyl cellulose.

[0014] A formulation according to one embodiment of the present invention comprises any of the solid dispersions described above and one or more pharmaceutically acceptable additives.

[0015] A method for producing a solid dispersion according to one embodiment of the present invention comprises mixing a drug, an amorphous-maintaining polymer, and a pharmaceutically acceptable acidic pH adjuster, hot-melt-extruding the mixture, and pulverizing the extrudate.

[0016] The pharmaceutically acceptable acidic pH adjusting agent may be an organic acid.

[0017] The organic acid may be one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

[0018] In a graph plotting the total amount of related substances derived from the drug against the pH of a liquid obtained by dissolving and / or dispersing 200 mg of the solid dispersion in 5 ml of water, a pharmaceutically acceptable acidic pH adjuster may be added to the mixture in a range of ±2.00 of the pH value at which the total amount of related substances is minimized.

[0019] The drug may be enzalutamide and the amorphous maintaining polymer may be hydroxypropyl cellulose.

[0020] According to one embodiment of the present invention, there is provided a solid dispersion in which the production of related substances is suppressed. Alternatively, according to one embodiment of the present invention, there is provided a formulation comprising the solid dispersion in which the production of related substances is suppressed. Alternatively, according to one embodiment of the present invention, there is provided a method for producing the solid dispersion in which the production of related substances is suppressed.

[0021] 1 is a graph plotting the total amount of related substances derived from enzalutamide against pH. 2 is a diagram showing the results of evaluation of the crystalline form of enzalutamide by XRD.

[0022] Hereinafter, the solid dispersion, a formulation containing the solid dispersion, and a method for producing the solid dispersion according to the present invention will be described with reference to the drawings. Note that the formulation containing the solid dispersion and the method for producing the solid dispersion according to the present invention should not be construed as being limited to the description of the following embodiments and examples. Note that in the drawings referred to in the present embodiments and examples described below, the same parts or parts having similar functions are denoted by the same reference numerals, and repeated description thereof will be omitted.

[0023] [Solid Dispersion] The solid dispersion of this embodiment contains an amorphous drug, an amorphous-maintaining polymer, and an organic acid. The drug in the solid dispersion of this embodiment is not particularly limited, and any drug that is required to maintain an amorphous form in the solid dispersion in order to obtain dissolution properties can be used. The solid dispersion of this embodiment is suitable for drugs that are stable at pH levels lower than neutral (pH 7.0) or drugs that produce related substances at pH levels higher than neutral (pH 7.0). The solid dispersion of this embodiment is suitable for, but not limited to, enzalutamide, as an example.

[0024] In one embodiment, the solid dispersion may comprise, in place of enzalutamide, a drug selected from the group consisting of griseofulvin, ritonavir, lopinavir, metformin, itraconazole, verapamil, azithromycin, ibuprofen, fenofibrate, posaconazole, ombitasvir, paritaprevir, venetoclax, glecaprevir, pibrentasvir, oxycodone, tapentadol, and oxymorphone.

[0025] As used herein, the term "amorphous state-maintaining polymer" collectively refers to polymers capable of maintaining a drug in an amorphous form in a solid dispersion. Examples of amorphous state-maintaining polymers include polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate, polyethylene-polyvinyl alcohol copolymers, carboxylic acid-functionalized polymethacrylates and carboxylic acid-functionalized polyacrylates (e.g., EUDRAGIT® S), amine-functionalized polyacrylates and polymethacrylates (e.g., EUDRAGIT® E), proteins, carboxylic acid-functionalized starch (e.g., starch glycolate), polyethylene glycol, graft copolymers of polyvinyl caprolactam and polyvinyl acetate, SOLUPLUS®, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, succinic acid Hydroxypropyl cellulose acetate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate,Hydroxypropyl cellulose acetate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropyl salicylate cellulose acetate, cellulose acetate ethyl benzoate, hydroxypropyl ethyl benzoate cellulose acetate, cellulose acetate ethyl phthalate, cellulose acetate ethyl nicotinate, cellulose acetate ethyl picolinate, phthalic acid Examples of suitable solid dispersions include, but are not limited to, hydroxypropyl methylcellulose (HPMCP), polyethylene oxide (PEO), poly(vinylpyrrolidone-co-vinyl acetate), polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid), lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, and spirulan. In one embodiment, when the solid dispersion contains enzalutamide, hydroxypropyl cellulose (HPC) may be used. In the solid dispersion of this embodiment, the drug is dispersed in a matrix formed by the amorphous maintaining polymer, and is maintained in an amorphous form.

[0026] As used herein, the term "pharmaceutically acceptable acidic pH adjuster" refers collectively to pharmaceutically acceptable acidic additives that can adjust the pH of a solid dispersion to suppress the production of drug-derived analogues. The term "pharmaceutically acceptable acidic pH adjuster" includes pharmaceutically acceptable inorganic acids and organic acids.

[0027] As used herein, the term "inorganic acid" refers collectively to inorganic compounds that exhibit pharmaceutically acceptable acidity. As described below, the solid dispersion according to this embodiment is produced using a hot-melt extrusion method, and therefore, an inorganic compound that is non-volatile under heating conditions (e.g., 80°C to 280°C, preferably 100°C to 250°C) can be used as the inorganic acid. Examples of the inorganic acid contained in the solid dispersion according to this embodiment include, but are not limited to, one or more selected from the group consisting of phosphoric acid, hydrochloric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, and anhydrous sodium dihydrogen phosphate, or the group consisting of hydrates thereof.

[0028] As used herein, the term "organic acid" refers collectively to organic compounds that exhibit pharmaceutically acceptable acidity. As described above, the solid dispersion according to this embodiment is produced using a hot-melt extrusion method, and therefore, an organic compound that is non-volatile under heating conditions (e.g., 80°C to 280°C, preferably 100°C to 250°C) can be used as the organic acid. Examples of the organic acid contained in the solid dispersion according to this embodiment include, but are not limited to, one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, maleic acid, aspartic acid, sorbic acid, adipic acid, and malonic acid, or the group consisting of salts, hydrates, and stereoisomers of these organic acids.

[0029] The solid dispersion according to this embodiment contains a pharmaceutically acceptable acidic pH adjuster in a range of ±2.00, preferably ±1.00, of the pH at which the total amount of related substances derived from the drug is minimized in a graph plotting the total amount of related substances derived from the drug against the pH of a liquid obtained by dissolving and / or dispersing 200 mg of the solid dispersion in 5 ml of water. The minimum value in the graph of the total amount of related substances can also be regarded as the minimum value. Therefore, the solid dispersion according to this embodiment may contain a pharmaceutically acceptable acidic pH adjuster in a range of ±1.0, of the pH at which the total amount of related substances is minimized. Furthermore, the solid dispersion according to this embodiment more preferably contains a pharmaceutically acceptable acidic pH adjuster in a range of ±0.50, of the pH at which the total amount of related substances is minimized (or minimal). In this embodiment, it is more preferable that the content of the pharmaceutically acceptable acidic pH adjuster is a value within a range in which the amount of each related substance derived from the drug is less than the threshold value required for structure determination or the threshold value required for safety confirmation, as described in Appendix 1: Threshold Values ​​for Degradation Products in New Formulations of the "Guidelines for Impurities in Pharmaceutical Preparations Containing New Active Ingredients" by the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In one embodiment, it is more preferable that the solid dispersion contains a pharmaceutically acceptable acidic pH adjuster in a range of ±0.10 of the pH value at which the total amount of related substances is minimal (or extremely minimal).

[0030] The solid dispersion according to this embodiment can improve dissolution by maintaining the drug in an amorphous form. Furthermore, in the solid dispersion according to this embodiment, drugs that are stable at pH levels lower than neutral (pH 7.0) or drugs that produce related substances at pH levels higher than neutral (pH 7.0) can be supported on an amorphous-maintaining polymer together with a pharmaceutically acceptable acidic pH adjuster, thereby suppressing the production of related substances. Addition of an antioxidant may be considered to improve the stability of the drug in the solid dispersion. However, the fact that the inclusion of a pharmaceutically acceptable acidic pH adjuster in a solid dispersion improves drug stability is a finding that has not been reported before and is reported for the first time in the present application. The solid dispersion according to this embodiment is suitable for use when the addition of an antioxidant is not sufficient to achieve drug stability.

[0031] In one embodiment, the solid dispersion according to this embodiment may be coated to improve the disintegration property of the tablet. Examples of the coating composition include water-soluble polymers, insoluble polymers, sugars, and minerals such as talc.

[0032] [Formulation] The formulation according to this embodiment includes the solid dispersion according to the above-described embodiment, which contains an amorphous drug, an amorphous-maintaining polymer, and a pharmaceutically acceptable acidic pH adjuster. The amount of the drug contained in this formulation can be adjusted as desired within a range that provides a therapeutic effect, and is not particularly limited.

[0033] In addition to the solid dispersion, the formulation according to this embodiment may further comprise 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.

[0034] Examples of excipients include, but are not limited to, mannitol, lactose, starch, corn starch, crystalline cellulose, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, refined sucrose, and glucose.

[0035] Examples of binders include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, hypromellose acetate succinate, and gum arabic.

[0036] 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.

[0037] Examples of acidulants include, but are not limited to, citric acid, tartaric acid, and malic acid.

[0038] Examples of foaming agents include, but are not limited to, sodium bicarbonate.

[0039] Examples of sweeteners include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0040] Examples of flavoring agents include lemon, lemon lime, orange, menthol, etc., but are not limited to these.

[0041] 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.

[0042] 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, Food Blue No. 1, and Food Blue No. 2.

[0043] 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.

[0044] Examples of antioxidants include, but are not limited to, ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

[0045] 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.

[0046] In the formulation of this embodiment, a salt may be added to cause salting out in order to improve the disintegration property of the tablet. Examples of salts that can be added to the 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.

[0047] In one embodiment, a plasticizer may be added to improve the manufacturability of the formulation. 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 fatty acid triglycerides, polysorbate 80, glycerin monostearate, and copolyvidone.

[0048] [Method for Producing Solid Dispersion] The solid dispersion according to this embodiment can be produced by hot melt extrusion (HME). Hot melt extrusion involves a step of melting the carrier, which may result in the production of drug-related substances. Therefore, the method for producing the solid dispersion according to this embodiment can be suitably used. In one embodiment, a drug, an amorphous maintaining polymer, and a pharmaceutically acceptable acidic pH adjuster are mixed, and the mixture is heated to melt the drug and soften the amorphous maintaining polymer. The solid dispersion according to this embodiment can be produced by mixing the molten mixture, homogenizing it, and cooling it while extruding. Since the drug is melted by heating, the drug 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 the drug by heating and softening the amorphous maintaining polymer and the step of mixing and homogenizing the molten mixture are not particularly limited, as long as they are manufacturing conditions that can amorphize the drug. The obtained solid dispersion can be pulverized and, if necessary, sized and / or coated to obtain the solid dispersion used in the formulation according to this embodiment. The pharmaceutically acceptable acidic pH adjuster used in the method for producing a solid dispersion according to this embodiment can also be applied to other production methods involving a heating step.

[0049] [Method for producing a formulation] The formulation according to this embodiment can be produced by mixing the solid dispersion according to this embodiment described above with one or more pharmaceutically acceptable additives and compressing the mixture into tablets. In one embodiment, the amount of drug contained in one tablet of the formulation can be adjusted as desired within a range in which a therapeutic effect can be obtained. In another embodiment, a film-coated tablet can be obtained by coating the obtained plain tablet of the formulation with a film. As the composition constituting the film, a combination of known additives can be used.

[0050] [Evaluation of Stability] In the present specification, the stability of a drug in a formulation can be evaluated by measuring the amount of related substances using high performance liquid chromatography (HPLC).

[0051] [pH Measurement] In this specification, the pH of the solid dispersion is measured by adding 200 mg of the solid dispersion according to this embodiment to 5 ml of water, dissolving and / or dispersing the solid dispersion in a vortex mixer, and then measuring the pH of the resulting liquid.

[0052] [Evaluation of amorphous form] In the present specification, a substance is considered to be amorphous if no peaks derived from enzalutamide crystals are detected by X-ray diffraction (XRD).

[0053] Comparative Example 1 1.4 g of enzalutamide and 5.6 g of hydroxypropyl methylcellulose (abbreviated as HPMC, TC-5M, Shin-Etsu Chemical Co., Ltd.) were placed in a capillary rheometer (RHEOGRAPH 20, GOTTFERT), and the mixture was passed through the capillary five times at 210° C. to obtain a hot-melt extrudate. The obtained hot-melt extrudate was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion of Comparative Example 1.

[0054] Comparative Example 2 An enzalutamide solid dispersion of Comparative Example 2 was obtained by the same production method as in Comparative Example 1, except that the amorphous-maintaining polymer was changed from HPMC to HPC (L, Nippon Soda Co., Ltd.).

[0055] Comparative Example 3 An enzalutamide solid dispersion of Comparative Example 3 was obtained by the same production method as in Comparative Example 1, except that the amorphous-maintaining polymer was changed from HPMC to methyl cellulose (SM-4, Shin-Etsu Chemical Co., Ltd.).

[0056] [Comparative Example 4] An enzalutamide solid dispersion of Comparative Example 4 was obtained by the same production method as in Comparative Example 1, except that the amorphous-maintaining polymer was changed from HPMC to polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type F, Daido Chemical Industry Co., Ltd.).

[0057] [Stability Evaluation] The amounts (%) of enzalutamide and related substances were measured for the solid dispersions of Comparative Examples 1 to 4. A solid dispersion containing 80 mg of enzalutamide was weighed out, and approximately 70 ml of a 4:1 acetonitrile / water mixture was added and stirred. A 4:1 acetonitrile / water mixture was then added to make exactly 100 ml. 12.5 ml of this solution was accurately measured, and a 4:1 acetonitrile / water mixture was added to make exactly 20 ml. This solution was filtered through a membrane filter with a pore size of 0.45 μm or less. At least 5 ml of the first filtrate was removed, and the next filtrate was used as the sample solution. The amount of related substances was measured by HPLC using an accurate 20 μl sample of the sample solution. Using the area percentage method, the sum of the peak areas of each component of enzalutamide and enzalutamide-derived related substances obtained on the chromatogram was set to 100, and the amount (%) of enzalutamide-derived related substances was calculated from the peak area ratio. The calculated amounts of related substances are shown in Table 1.

[0058]

[0059] The results in Table 1 reveal that all solid dispersions produce analogues derived from enzalutamide.

[0060] Comparative Example 5 1.4 g of enzalutamide and 5.6 g of HPC (L, Nippon Soda Co., Ltd.) were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and the mixture was circulated in the extruder for 10 minutes at 210°C and a screw rotation speed of 80 rpm to obtain a hot-melt extrudate. The obtained hot-melt extrudate was pulverized using a rotor speed mill (P-14, Fritsch Japan) at a diameter of 0.5 mm and 12,000 rpm to obtain an enzalutamide solid dispersion of Comparative Example 5.

[0061] [Comparative Example 6] An enzalutamide solid dispersion of Comparative Example 6 was obtained by the same production method as in Comparative Example 5, except that 0.0875 g of propyl gallate used as an antioxidant was added in addition to enzalutamide and HPC.

[0062] [Comparative Example 7] The enzalutamide solid dispersion of Comparative Example 7 was obtained by the same manufacturing method as in Comparative Example 5, except that 0.07 g of dibutylhydroxytoluene (BHT) (Tokyo Chemical Industry Co., Ltd.), used as an antioxidant, was added in addition to enzalutamide and HPC.

[0063] [Example 1] The enzalutamide solid dispersion of Example 1 was obtained by the same manufacturing method as in Comparative Example 5, except that 0.175 g of tartaric acid, an organic acid, was added in addition to enzalutamide and HPC. The amount of tartaric acid added was 10 mg per 80 mg of enzalutamide.

[0064] [Example 2] The enzalutamide solid dispersion of Example 2 was obtained by the same production method as in Comparative Example 5, except that 0.0875 g of tartaric acid, an organic acid, was added in addition to enzalutamide and HPC. The amount of tartaric acid added was 5 mg per 80 mg of enzalutamide.

[0065] [Example 3] The enzalutamide solid dispersion of Example 3 was obtained by the same production method as in Comparative Example 5, except that 0.04375 g of tartaric acid, an organic acid, was added in addition to enzalutamide and HPC. The amount of tartaric acid added was 2.5 mg per 80 mg of enzalutamide.

[0066] [Example 4] The enzalutamide solid dispersion of Example 4 was obtained by the same production method as in Comparative Example 5, except that 0.04375 g of an organic acid, citric acid, was added in addition to enzalutamide and HPC. The amount of citric acid added was 2.5 mg per 80 mg of enzalutamide.

[0067] [Example 5] The enzalutamide solid dispersion of Example 5 was obtained by the same production method as in Comparative Example 5, except that 0.04375 g of succinic acid, an organic acid, was added in addition to enzalutamide and HPC. The amount of succinic acid added was 2.5 mg per 80 mg of enzalutamide.

[0068] [Example 6] An enzalutamide solid dispersion of Reference Example 5 was obtained by the same production method as in Comparative Example 5, except that 0.04375 g of an organic acid, fumaric acid, was added in addition to enzalutamide and HPC. The amount of fumaric acid added was 2.5 mg per 80 mg of enzalutamide.

[0069] [Evaluation of Stability] The amounts (%) of enzalutamide and related substances were measured using the above-mentioned evaluation method for the solid dispersions of Comparative Examples 5 to 7 and Examples 1 to 6. The calculated amounts of the main related substances and total related substances are shown in Table 2.

[0070]

[0071] The results in Table 2 show that the solid dispersions of Comparative Examples 6 and 7, to which an antioxidant was added, produced enzalutamide-derived analogs to the same extent as the solid dispersion of Comparative Example 5, which contained only the drug and an amorphous-maintaining polymer. On the other hand, the solid dispersions of Examples 1 to 6, to which an organic acid was added, significantly suppressed the production of enzalutamide-derived analogs. The solid dispersion of Example 3, to which tartaric acid was added in an amount of 2.5 mg per 80 mg of enzalutamide, produced the smallest amount of enzalutamide-derived analogs.

[0072] [pH Measurement] The pH was measured for the solid dispersions of Examples 1 to 3 and 5 to 6 and the solid dispersions of Comparative Examples 1 to 5. 200 mg of each solid dispersion was added to 5 ml of water, and the pH of the resulting solution was measured using a vortex mixer. The pH measurement results are shown in Table 3. Figure 1 shows a graph in which the total amount of enzalutamide-derived related substances is plotted against pH for the solid dispersions of Examples 1 to 3 and 5 to 6 and the solid dispersion of Comparative Example 5.

[0073]

[0074] 1 , the solid dispersion of Example 3, in which the production of related substances was most suppressed, had a pH of 3.40, and it was revealed that the production of related substances was suppressed in the solid dispersions of Examples 1-2 and 5-6, in which the pH was in the range of 3.40±1.00. On the other hand, it is presumed that the solid dispersions of Comparative Examples 1-4 produced related substances because the pH was in the range of 4.60 or higher. In Comparative Example 4, it is presumed that the pH was higher than the actual value because POVACOAT was not completely dissolved in the amount of solvent used in the example.

[0075] Example 7 Enzalutamide, HPC (L, Nippon Soda Co., Ltd.), and tartaric acid were charged into an extruder (HAAKE (registered trademark) MiniCTW microconical twin-screw compounder, Thermo Fisher Scientific K.K.), and extruded at 210°C and a screw rotation speed of 50 rpm to obtain a hot-melt extrudate. Light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) was added to 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 7. The composition of the enzalutamide solid dispersion of Example 7 is shown in Table 4.

[0076]

[0077] [Evaluation of amorphous form] The crystalline form of enzalutamide was evaluated by XRD for the enzalutamide crystals and the enzalutamide solid dispersion of Example 7. The measurement results are shown in Figure 2. (XRD conditions) X-ray diffractometer: D8 ADVANCE (Bruker) Measurement conditions: Tube: Cu, Tube voltage: 40 kV, Tube current: 40 mA, Divergence slit: 0.3°, Antiscattering slit: 0.5°, Scanning range: 2° to 40°

[0078] From the results shown in Figure 2, it was determined that the enzalutamide solid dispersion of Example 7 maintained its amorphous state, since no peaks derived from enzalutamide crystals were observed.

Claims

1. A solid dispersion comprising an amorphous form of a drug, an amorphous-maintaining polymer, and a pharmaceutically acceptable acidic pH adjuster.

2. The solid dispersion according to claim 1, wherein the pharmaceutically acceptable acidic pH adjuster is an organic acid.

3. The solid dispersion according to claim 2, wherein the organic acid is one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

4. The solid dispersion according to claim 1, wherein in a graph plotting the total amount of related substances derived from the drug against the pH of a liquid obtained by dissolving and / or dispersing 200 mg of the solid dispersion in 5 ml of water, the pharmaceutically acceptable acidic pH adjuster is included in a range of pH values ±2.00 at which the total amount of related substances is minimized.

5. The solid dispersion according to claim 1, wherein the drug is enzalutamide and the amorphous-maintaining polymer is hydroxypropyl cellulose.

6. A formulation comprising the solid dispersion according to any one of claims 1 to 5 and one or more pharmaceutically acceptable additives.

7. A method for producing a solid dispersion, comprising mixing a drug, an amorphous-maintaining polymer, and a pharmaceutically acceptable acidic pH adjuster, heat-melting and extruding the mixture, and pulverizing the extrudate.

8. The method for producing a solid dispersion according to claim 7, wherein the pharmaceutically acceptable acidic pH adjuster is an organic acid.

9. The method for producing a solid dispersion according to claim 8, wherein the organic acid is one or more selected from the group consisting of tartaric acid, citric acid, succinic acid, fumaric acid, lactic acid, ascorbic acid, malic acid, and malonic acid.

10. The method for producing a solid dispersion according to claim 7, wherein the pharmaceutically acceptable acidic pH adjuster is added to the mixture in a range of pH values ±2.00 at which the total amount of related substances derived from the drug is minimized in a graph plotting the total amount of related substances derived from the drug against the pH of a liquid obtained by dissolving and / or dispersing 200 mg of the solid dispersion in 5 ml of water.

11. The method for producing a solid dispersion according to any one of claims 7 to 10, wherein the drug is enzalutamide and the amorphous-maintaining polymer is hydroxypropyl cellulose.

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