Empagliflozin-containing pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing empagliflozin while preserving its amorphous state.SOLUTION: The present invention provides an empagliflozin-containing pharmaceutical composition that comprises amorphous empagliflozin and an amorphous state-maintaining additive.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition containing amorphous empagliflozin. [Background technology]

[0002] Empagliflozin used in the present invention has the chemical name (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol, is known to be a selective SGLT2 inhibitor (therapeutic agent for type 2 diabetes and chronic heart failure), and is sold as Jardiance (registered trademark) tablets 10 mg / 25 mg (Non-Patent Document 1).

[0003] The dosage for type 2 diabetes patients is usually 10 mg of empagliflozin orally administered once a day before or after breakfast for adults. If the effect is insufficient, the dosage can be increased to 25 mg once a day while closely monitoring the progress.

[0004] The dosage for patients with chronic heart failure is usually 10 mg of empagliflozin administered orally once a day before or after breakfast for adults.

[0005] Patent Document 1 describes an invention relating to a solid dispersion containing empagliflozin and at least one pharma- ceutically acceptable excipient that can maintain an amorphous state. The solid dispersion is obtained by dissolving empagliflozin and the excipient in an organic solvent and then removing the solvent.

[0006] Patent Document 2 describes an invention related to a solid dispersion containing empagliflozin and at least one polymer that can maintain an amorphous state. The solid dispersion is obtained by dissolving empagliflozin and a polymer in an organic solvent, and then spraying the organic solvent onto a mixture of crystalline cellulose, corn starch, and croscarmellose sodium.

[0007] Patent Document 3 describes an invention relating to a pharmaceutical composition that contains amorphous empagliflozin, which can maintain an amorphous state, and at least one excipient selected from the group consisting of polycarbophil or a salt thereof, magnesium aluminometasilicate, and nonporous colloidal silica. The pharmaceutical composition is obtained by mixing amorphous empagliflozin and the excipient in a 1:1 ratio to form a physical mixture.

[0008] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2016 / 169534 [Patent Document 2] International Publication No. 2021 / 123165 [Patent Document 3] International Publication No. 2021 / 210929 [Non-patent literature]

[0010] [Non-Patent Document 1] Package insert "Jardiance (registered trademark) tablets 10 mg / 25 mg", revised April 2022 (3rd edition) Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a pharmaceutical composition containing empagliflozin in an amorphous state. [Means for solving the problem]

[0012] The present inventors have investigated the composition of a pharmaceutical composition containing amorphous empagliflozin and found that the amorphous state can be maintained by using an additive having a specific function, thereby completing the present invention.

[0013] That is, the present invention provides (1) An empagliflozin-containing pharmaceutical composition comprising amorphous empagliflozin and an amorphous maintaining excipient; (2) The pharmaceutical composition according to (1) above, wherein the amorphous state-maintaining additive is one or more additives selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyoxyethylene (160) polyoxypropylene (30) glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and vinyl acetate-vinylpyrrolidone copolymer. (3) The pharmaceutical composition according to (1) above, wherein the amorphous state-maintaining additive is one or more additives selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, and vinyl acetate-vinylpyrrolidone copolymer. (4) The pharmaceutical composition according to (1) above, wherein the amorphous state maintaining additive is one or more additives selected from the group consisting of polyvinyl alcohol, light anhydrous silicic acid, and magnesium stearate. (5) The pharmaceutical composition according to (1) above, wherein the amorphous state-maintaining additive is one or more additives selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, and vinyl acetate-vinylpyrrolidone copolymer. (6) The pharmaceutical composition according to any one of (1) to (5), wherein the amount of the amorphous-maintaining additive is 0.05 to 15, relative to the amount of amorphous empagliflozin per pharmaceutical composition being 1. (7) The pharmaceutical composition according to any one of (1) to (5), which is a tablet. (8) The pharmaceutical composition according to (7), wherein the tablet is a film-coated tablet. (9) A method for producing the pharmaceutical composition according to (1), comprising dissolving empagliflozin in a mixed solution of ethanol and water. (10) The method for producing a pharmaceutical composition according to (9), wherein the mixed solution of ethanol and water contains 34.4% by weight to 54.2% by weight of ethanol. (11) A method for producing the pharmaceutical composition according to any one of (9) to (10) above, comprising a step of direct compression. (12) A method for producing the pharmaceutical composition according to any one of (9) to (10) above, comprising a step of dissolving empagliflozin in methanol. (13) A method for producing the pharmaceutical composition according to any one of (9) to (10) above, comprising dissolving empagliflozin in a mixed solution of methanol and acetone. This is regarding. Effect of the Invention

[0014] According to the present invention, a pharmaceutical composition containing amorphous empagliflozin can be provided. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 1 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Diagram 2] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 2 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Diagram 3]FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 3 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 4] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 4 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Diagram 5] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 5 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 6] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 6 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 7] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 7 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 8] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 8 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 9] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 9 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 10] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 10 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 11] FIG. 11 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 11 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 12] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 12 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 13] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 13 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 14] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 14 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 15] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 15 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 16] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 16 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 17] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 17 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 18] FIG. 14 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Example 18 at the start of storage, and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 19] FIG. 1 shows powder X-ray diffraction patterns of the additive alone and the physical mixture of Comparative Example 1 at the start of storage and after storage for 1 day and 2 days at 25° C., relative humidity of 75%, and 40° C. [Figure 20] 1 shows the results of measuring the solubility of empagliflozin in ethanol / water and methanol / water solvents. [Figure 21] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, solid dispersion SD1 prepared in Example 19, and physical mixture 1 prepared in Example 20. [Figure 22] FIG. 2 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, solid dispersion SD2 prepared in Example 21, and physical mixture 2 prepared in Example 22. [Figure 23] FIG. 2 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, solid dispersion SD3 prepared in Example 23, and physical mixture 3 prepared in Example 24. [Figure 24]FIG. 2 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, solid dispersion SD4 prepared in Example 25, and physical mixture 4 prepared in Example 26. [Diagram 25] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD1 stored at 60° C. for 7 days. [Figure 26] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD2 stored at 60° C. for 7 days. [Figure 27] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD3 stored at 60° C. for 7 days. [Figure 28] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD4 stored at 60° C. for 7 days. [Figure 29] 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, amorphous empagliflozin drug substance stored at 25° C. and 50% relative humidity, and at 25° C. and 75% relative humidity for 7 days, and SD1. [Diagram 30] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD2 stored at 25° C. and 50% relative humidity for 7 days. [Diagram 31] 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, amorphous empagliflozin drug substance stored at 25° C. and 50% relative humidity, and at 25° C. and 75% relative humidity for 7 days, and SD3. [Diagram 32] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, and amorphous empagliflozin drug substance and SD4 stored at 25° C. and 50% relative humidity for 7 days. [Diagram 33]FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD5, and amorphous empagliflozin drug substance and SD5 stored at 60° C. for one month. [Diagram 34] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD5, and amorphous empagliflozin drug substance and SD5 stored at 25° C. and 75% relative humidity for one month. [Diagram 35] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD6, and amorphous empagliflozin drug substance and SD6 stored at 60° C. for one month. [Diagram 36] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD10, and amorphous empagliflozin drug substance and SD10 stored at 60° C. for one month. [Figure 37] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD7, and amorphous empagliflozin drug substance and SD7 stored at 60° C. for one month. [Figure 38] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD8, and amorphous empagliflozin drug substance and SD8 stored at 60° C. for one month. [Figure 39] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD6, and amorphous empagliflozin drug substance and SD6 stored at 25° C. and 75% relative humidity for one month. [Diagram 40] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD8, and amorphous empagliflozin drug substance and SD8 stored at 25° C. and 75% relative humidity for one month. [Diagram 41] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD9, and amorphous empagliflozin drug substance and SD9 stored at 25° C. and 75% relative humidity for one month. [Diagram 42]FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD11, and amorphous empagliflozin drug substance and SD11 stored at 60° C. for one month. [Diagram 43] FIG. 1 shows powder X-ray diffraction patterns of crystallized empagliflozin drug substance, amorphous empagliflozin drug substance, SD11, and amorphous empagliflozin drug substance and SD11 stored at 25° C. and 75% relative humidity for one month. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The term "physical mixture" as used herein means a pharmaceutical composition comprising amorphous empagliflozin and one or more additives, which are coexisting in a mixed state without using a solvent during production.

[0017] As used herein, the term "solid dispersion" means a dispersion in which at least a portion of an amorphous drug (empagliflozin) is uniformly dispersed or dissolved at the molecular level in a carrier such as a polymer.

[0018] In the present specification, the term "amorphous empagliflozin" means a state in which substantially no diffraction peaks derived from empagliflozin crystals are observed by powder X-ray diffraction measurement etc. For example, it means a state in which, among the six diffraction peaks derived from empagliflozin crystals (2θ=14.69°±0.05°, 18.84°±0.05°, 19.16°±0.05°, 19.50°±0.05°, 20.36°±0.05°, 25.21°±0.05°) described in Japanese Patent No. 4226070, one to five peaks are observed, or none of the six diffraction peaks are observed by powder X-ray diffraction measurement.

[0019] In the present specification, "maintaining an amorphous state" means that the drug substance is amorphous under severe temperature and humidity conditions. For example, the evaluation method includes a method in which a pharmaceutical composition is stored under severe temperature and humidity conditions, and then a test is performed by powder X-ray diffraction measurement to confirm a diffraction peak derived from empagliflozin crystals. For example, the empagliflozin-containing pharmaceutical composition is confirmed after storage at 25°C and 75% RH for 2 days, or the empagliflozin-containing pharmaceutical composition is confirmed after storage at 40°C for 2 days.

[0020] The solid pharmaceutical composition containing amorphous empagliflozin of the present invention will be described below.

[0021] Empagliflozin used in the present invention can be produced, for example, according to the method described in Japanese Patent No. 4181605. Empagliflozin can be used in either a crystalline or amorphous form.

[0022] The form of empagliflozin used in the present invention may be either a crystalline state or an amorphous state as a raw material (also referred to as an active pharmaceutical ingredient) before being contained in a pharmaceutical composition, but when it is contained in the pharmaceutical composition, it is in an amorphous state.

[0023] The method of containing the amorphous state maintaining additive used in the present invention is not particularly limited as long as it is contained together with empagliflozin. That is, the pharmaceutical composition of the present invention may be any of a physical mixture, a granule, or a solid dispersion containing amorphous empagliflozin and an amorphous state maintaining additive.

[0024] The blending ratio of empagliflozin used in the present invention is 1 to 40 wt % in one embodiment, 2 to 30 wt % in one embodiment, and 3 to 20 wt % in one embodiment, as empagliflozin per pharmaceutical composition.

[0025] The amorphous state maintaining additive used in the present invention is not particularly limited as long as it has the function of maintaining the amorphous state of amorphous empagliflozin. Specifically, for example, it includes additives other than those that show one to five diffraction peaks derived from empagliflozin crystals one day after the start of a storage stability test at 25°C and a relative humidity of 75% in amorphous empagliflozin and a pharmaceutical composition containing the additive, and show all six diffraction peaks derived from empagliflozin crystals two days after the start of the storage stability test. Specifically, hydroxypropyl cellulose (e.g., product names HPC-H, HPC-M, HPC-L, HPC-SL, HPC-SSL; Nippon Soda Co., Ltd., product names Klucel(H), Klucel(M), Klucel(G), Klucel(J), Klucel(L), Klucel(E); Ashland Japan Co., Ltd.), hydroxypropyl methylcellulose (e.g., product names TC-5(registered trademark)E, TC-5(registered trademark)M, TC-5(registered trademark)R, TC-5(registered trademark)S; Shin-Etsu Chemical Co., Ltd., product names METHOCEL(registered trademark) Premium E, METHOCEL(registered trademark) Premium F, METHOCEL(registered trademark) Premium K; Colorcon Japan LLC, product names Benecel® K4M, Benecel® K15M, Benecel® K100M; Ashland Japan Co., Ltd.), hypromellose acetate succinate (e.g., product names Shin-Etsu AQOAT® AS-LF, Shin-Etsu AQOAT® AS-MF, Shin-Etsu AQOAT® AS-HF; Shin-Etsu Chemical Co., Ltd.), methacrylic acid copolymer LD (e.g., product name EUDRAGIT® L100-55; EVONIK, product name Kollicoat MAE30DP; BASF Japan Ltd., product name Polyquid PA-30; Sanyo Chemical Industries, Ltd.), aminoalkyl methacrylate copolymer E (e.g., product names EUDRAGIT® EPO, EUDRAGIT® E100; EVONIK), polyvinylpyrrolidone (e.g., product name Eiftact K-30PH; Daiichi Kogyo Seiyaku Co., Ltd., Kollidon® 30;BASF Japan Ltd., product name Plasdone K30), low-substituted hydroxypropyl cellulose (e.g., product names LH-11, LH-21, LH-22, LH-B1, LH-31, LH-32, NBD-020, NBD-021, NBD-022; Shin-Etsu Chemical Co., Ltd.), polyvinyl alcohol (e.g., product names GOHSENOL® EG-03P, EG-05P, EG-18P, EG-22P, EG-30P, EG-40P, EG-48P; Mitsubishi Chemical Corporation, Poval PE-05JPS; Nippon Vacuum & Poval Co., Ltd., PVA 4-88, PVA 5-88, PVA 8-88, PVA 18-88, PVA 26-88, PVA 40-88; Merck Ltd.), light anhydrous silicic acid (e.g., product name Adsolider (registered trademark) 101; Freund Corporation, Cysilia 320, Cysilia 350; Fuji Silysia Chemical Co., Ltd.), magnesium stearate (e.g., product name Magnesium stearate (vegetable); Taihei Chemical Industry Co., Ltd., product name Partec (registered trademark) LUB MST; Merck Ltd.), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (e.g., product names POVACOAT (registered trademark) Type F, POVACOAT (registered trademark) Type FM, POVACOAT (registered trademark) Type MP; Daido Chemical Industry Co., Ltd.), polyvinyl alcohol-polyethylene glycol-graft copolymer (e.g., product name Kollicoat (registered trademark) IR; BASF Japan Ltd.), polyoxyethylene (160) polyoxypropylene (30) glycol (e.g., product names Kolliphor (registered trademark) P 188 Geismar, Kolliphor (registered trademark) P 188 micro Examples of the amorphous-maintaining additive include Geismar (BASF Japan Ltd.), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., product name Soluplus (registered trademark); BASF Japan Ltd.), and vinyl acetate-vinyl pyrrolidone copolymer (e.g., product name Kollidon (registered trademark) VA64; BASF Japan Ltd.). One or more types of amorphous-maintaining additives may be blended in combination.

[0026] The amount of the amorphous state-maintaining additive used in the present invention is 0.05 to 15 in one embodiment, 0.1 to 10 in one embodiment, 0.2 to 8 in one embodiment, 0.3 to 5 in one embodiment, and 0.5 to 3 in one embodiment, relative to the amount of amorphous empagliflozin per pharmaceutical composition being 1. The production method used in the present invention includes the steps of: adding an excipient to a granulation mixer; dissolving empagliflozin and an amorphous maintaining additive in a solvent to prepare a solution; adding the solution to the granulation mixer and granulating; and drying after granulation. In one embodiment, the steps include the steps of adding an excipient to a granulation mixer; dissolving empagliflozin and an amorphous maintaining additive in an ethanol / water mixture to prepare a solution; and drying after granulation. The production method used in the present invention includes a step of dissolving empagliflozin and an amorphous maintaining additive in a solvent to prepare a solution, and a step of distilling off the solvent from the solution. In one embodiment, the production method includes a step of dissolving empagliflozin and an amorphous maintaining additive in methanol to prepare a solution, and a step of distilling off the solvent from the solution. In one embodiment, the production method includes a step of dissolving empagliflozin and an amorphous maintaining additive in methanol / acetone to prepare a solution, and a step of distilling off the solvent from the solution.

[0027] The pharmaceutical composition of the present invention may contain pharmaceutical additives as necessary, such as excipients, binders, disintegrants, lubricants, surfactants, flow agents, coating agents, acidulants, foaming agents, sweeteners, flavors, colorants, buffers, antioxidants, etc.

[0028] Examples of excipients include D-mannitol, corn starch, crystalline cellulose, trehalose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, pregelatinized starch, sodium carmellose, synthetic aluminum silicate, magnesium aluminometasilicate, gum arabic, dextrin, and pullulan.

[0029] Examples of disintegrants include corn starch, potato starch, sodium starch glycolate, carmellose, carmellose calcium, hydroxypropyl starch, croscarmellose, croscarmellose sodium, crospovidone, pregelatinized starch, and the like.

[0030] Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

[0031] Examples of binders include gum arabic and hydroxyethyl cellulose.

[0032] Examples of lubricants include stearic acid, sodium stearate, calcium stearate, talc, sodium stearyl fumarate, hardened oil, and sucrose fatty acid ester.

[0033] The fluidizing agent may, for example, be talc.

[0034] Examples of coating agents include methylcellulose, polyethylene glycol, glycerin monostearate, titanium oxide, and talc.

[0035] Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

[0036] The foaming agent may be, for example, bilayer foam.

[0037] Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0038] Examples of the flavoring include lemon, lemon-lime, orange, and menthol.

[0039] Examples of coloring agents include ferric oxide, yellow ferric oxide, black ferric oxide, titanium oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 3, and the like.

[0040] Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, or salts thereof, and the like.

[0041] Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

[0042] In the empagliflozin-containing pharmaceutical composition of the present invention, various further pharmaceutical additives are appropriately used within a range in which the desired effects of the present invention are achieved.

[0043] The various additional pharmaceutical additives incorporated in the empagliflozin-containing pharmaceutical composition of the present invention can be combined as appropriate.

[0044] The blending amount is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

[0045] The amorphous empagliflozin-containing pharmaceutical composition or an oral solid preparation obtained from the pharmaceutical composition specifically includes powders, granules, and tablets. The tablets also include orally disintegrating tablets, which may be plain tablets or film-coated tablets.

[0046] The method for producing a pharmaceutical composition containing amorphous empagliflozin may be any method as long as it can contain amorphous empagliflozin in a solid pharmaceutical composition. More specifically, for example, when producing tablets, the amorphous maintaining additive is added to the amorphized empagliflozin and physically mixed, and then an excipient, a binder, a disintegrant, and a lubricant are mixed to obtain a powder for tableting. In another embodiment, empagliflozin and the amorphous maintaining additive are dissolved in a suitable solvent to produce a solid dispersion containing amorphous empagliflozin, and the solid dispersion is mixed with an excipient, a binder, and a disintegrant, and then a lubricant is mixed to obtain a powder for tableting. In another embodiment, empagliflozin is dissolved in a suitable solvent, sprayed on the amorphous maintaining additive, and dried to produce a solid dispersion, and the solid dispersion is mixed with an excipient, a binder, and a disintegrant, and then a lubricant is mixed to obtain a powder for tableting. The solvent for dissolving empagliflozin may be any solvent that does not affect the amorphization of empagliflozin, and in one embodiment, it is any one of water, methanol, ethanol, acetone, and tetrahydrofuran, or a mixed solution of two or more of them. Ethanol may have a purity that does not affect the amorphization of empagliflozin, and in one embodiment, it may have a purity of 99% or more, and in one embodiment, it is 99.5% or more. Methanol may have a purity that does not affect the amorphization of empagliflozin, and in one embodiment, it may have a purity of 99% or more, and in one embodiment, it is 99.5% or more. Acetone may have a purity that does not affect the amorphization of empagliflozin, and in one embodiment, it may have a purity of 99% or more, and in one embodiment, it is 99.5% or more. The mixed solution may be a mixed solution of methanol and water in one embodiment, a mixed solution of ethanol and water in one embodiment, or a mixed solution of methanol and acetone in one embodiment. The mixed solution of ethanol and water can contain 34.4% by weight to 54.2% by weight in one embodiment, 44.1% by weight to 54.2% by weight in one embodiment, and 50% by weight to 54.2% by weight in another embodiment.The mixed solution of methanol and acetone can contain 34.4% by weight to 54.2% by weight, in one embodiment, 44.1% by weight to 54.2% by weight, and in another embodiment, 50% by weight to 54.2% by weight of methanol. The obtained powder for tableting is tableted with a tableting machine to obtain uncoated tablets. During tableting, a lubricant may be sprayed onto the tablets using an external lubricating device. If necessary, a film-coating liquid is sprayed onto the uncoated tablets to perform film coating. The pharmaceutical composition of the present invention may be packaged using various pharmaceutical packaging materials. EXAMPLES

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples in any way. EXAMPLES

[0048] Hydroxypropyl cellulose 1 (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.; HPC-L) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0049] Hydroxypropylcellulose 2 (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.; HPC-SSL) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0050] Hydroxypropyl methylcellulose 1 (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; TC-5 (registered trademark) E) were mixed in a plastic bag, sieved through a sieve having an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0051] Hydroxypropyl methylcellulose 2 (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; TC-5 (registered trademark) M) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0052] Hypromellose acetate succinate (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd.; Shin-Etsu AQOAT (registered trademark) AS-LF) were mixed in a plastic bag and sieved through a sieve having an opening of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0053] Methacrylic acid copolymer LD (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of methacrylic acid copolymer LD (manufactured by EVONIK; EUDRAGIT (registered trademark) L100-55) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0054] Aminoalkyl methacrylate copolymer E (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of aminoalkyl methacrylate copolymer E (manufactured by EVONIK; EUDRAGIT (registered trademark) EPO) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0055] Polyvinylpyrrolidone (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of polyvinylpyrrolidone (Kollidon (registered trademark) 30, manufactured by BASF Japan) were mixed in a plastic bag, sieved through a sieve having an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0056] Low-substituted hydroxypropyl cellulose (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.; LH-11) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0057] Polyvinyl alcohol (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl alcohol (manufactured by Mitsubishi Chemical; GOHSENOL (registered trademark) EG-05P) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0058] Light anhydrous silicic acid (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of light anhydrous silicic acid (manufactured by Freund Corporation; Adsolider (registered trademark) 101) were mixed in a plastic bag, sieved through a sieve with an opening of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0059] Magnesium stearate (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of magnesium stearate (manufactured by Taihei Chemical Industry; magnesium stearate (vegetable)) were mixed in a plastic bag, sieved through a sieve with openings of 500 μm, and then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0060] Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer 1 (pharmaceutical substance:additive=9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark) Type F, manufactured by Daido Chemical Industry Co., Ltd.) were mixed in a plastic bag and sieved through a sieve with openings of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0061] Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer 2 (pharmaceutical substance:additive=9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark) Type FM, manufactured by Daido Chemical Industry Co., Ltd.) were mixed in a plastic bag and sieved through a sieve with openings of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0062] Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer 3 (pharmaceutical substance:additive=9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark) Type MP, manufactured by Daido Chemical Industry Co., Ltd.) were mixed in a plastic bag and sieved through a sieve with openings of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0063] Polyvinyl alcohol-polyethylene glycol graft copolymer (pharmaceutical substance:additive=9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl alcohol-polyethylene glycol graft copolymer (manufactured by BASF Japan; Kollicoat (registered trademark) IR) were mixed in a plastic bag and sieved through a sieve with an opening of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0064] Polyoxyethylene (160) Polyoxypropylene (30) Glycol (pharmaceutical substance:additive = 9:1) 18 g of amorphous empagliflozin and 2 g of polyoxyethylene (160) polyoxypropylene (30) glycol (manufactured by BASF Japan; Kolliphor (registered trademark) P 188 Geismar) were mixed in a plastic bag and sieved through a sieve having an opening of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture. EXAMPLES

[0065] Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (pharmaceutical substance:additive=9:1) 18 g of amorphous empagliflozin and 2 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus (registered trademark) manufactured by BASF Japan) were mixed in a plastic bag and sieved through a sieve having an opening of 500 μm. The mixture was then mixed again in the plastic bag to obtain a physical mixture.

[0066] Comparative Example 1: Amorphous empagliflozin drug substance In Comparative Example 1, only amorphous empagliflozin was used.

[0067] <Test Example 1> (Storage stability at 25°C and 75% relative humidity) The obtained physical mixture and amorphous empagliflozin drug substance were stored at 25°C and 75% relative humidity for 2 days, and were confirmed to be in an amorphous state by powder X-ray diffraction measurement. For the measurement, a powder X-ray diffraction device Smart Lab 3kW was used, and the measurement was performed under the following conditions: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation criteria and evaluation results for the crystalline state are shown below.

[0068] [Table 1]

[0069] [Table 2]

[0070] From the results of the empagliflozin-containing pharmaceutical compositions of Examples 1 to 5 and Examples 7 to 18, the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical compositions after storage for 2 days, even when the empagliflozin and the empagliflozin were simply coexisted as a physical mixture.

[0071] <Test Example 2> (Storage stability at 40℃) The obtained physical mixture and amorphous empagliflozin drug substance were sealed and stored at 40°C for 2 days, and the amorphous state was confirmed by powder X-ray diffraction measurement. For the measurement, a powder X-ray diffraction device Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown below. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0072] [Table 3]

[0073] The results of the empagliflozin-containing pharmaceutical compositions of Examples 2 to 6 and Examples 8 to 12 demonstrated that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical compositions after storage for 2 days by containing the amorphous state maintaining additive, even when the empagliflozin was simply coexisted as a physical mixture.

[0074] <Test Example 3> (Confirmation of solubility of empagliflozin in various solvents) Various solvents were added to a glass container, and amorphous empagliflozin was added until it became a saturated solution, and the solution was shaken for 1 hour. The shaken solution was filtered through a membrane filter with a pore size of 0.45 μm or less, and the solubility of the filtrate was calculated by liquid chromatography. The ultraviolet absorbance of empagliflozin was measured at 230 nm. The results are shown in Table 4.

[0075] [Table 4]

[0076] Regarding the solubility of empagliflozin in various solvents, it showed high solubility in methanol and tetrahydrofuran, but the solubility of empagliflozin in water, ethanol (99.5), and acetone was low.

[0077] <Test Example 4> (Confirmation of the solubility of empagliflozin in ethanol / water and methanol / water systems) The solvents used were an ethanol / water mixture and a methanol / water mixture. The liquid compositions were arbitrarily changed, and the solubility of empagliflozin was calculated in the same manner as in Test Example 3. The results are shown in Tables 5 and 6.

[0078] [Table 5]

[0079] In an ethanol / water system, a specific improvement in solubility was confirmed in a mixture of a certain composition (e.g., water:ethanol=60:40 to 40:60) compared to the solubility in water alone or ethanol alone, which is greater than that in a single solvent.

[0080] [Table 6]

[0081] In the methanol / water system, no specific improvement in solubility at a specific composition was observed, as was observed in the ethanol / water system. A monotonically increasing tendency for solubility to increase as the ratio of methanol, a good solvent, increases was confirmed. EXAMPLES

[0082] Preparation of solid dispersion (hydroxypropyl methylcellulose, (pharmaceutical substance:additive = 1:1)) 20 g of crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (manufactured by Powrex; MP-01), and granulated with a solution prepared by dissolving 15 g of amorphous empagliflozin and 15 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; TC-5 (registered trademark) E) in 470 g of a 50 wt % ethanol / water mixture, and then dried to obtain a solid dispersion (SD1). EXAMPLES

[0083] Manufacturing of physical mixture (hydroxypropyl methylcellulose, (pharmaceutical substance:additive = 1:1)) A physical mixture 1 was obtained by mixing 150 mg of amorphous empagliflozin, 150 mg of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; TC-5 (registered trademark) E), and 200 mg of crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) in a mortar. EXAMPLES

[0084] Preparation of solid dispersion (hydroxypropyl cellulose, (pharmaceutical substance:additive = 1:1)) 20 g of crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (manufactured by Powrex; MP-01), and granulated with a solution prepared by dissolving 15 g of amorphous empagliflozin and 15 g of hydroxypropyl cellulose (manufactured by Nippon Soda; HPC-SSL) in 470 g of a 50 wt% ethanol / water mixture, and then dried to obtain a solid dispersion (SD2). EXAMPLES

[0085] Manufacturing of physical mixtures (hydroxypropyl cellulose, (pharmaceutical substance:additive = 1:1)) Amorphous empagliflozin (150 mg), hydroxypropyl cellulose (manufactured by Nippon Soda; HPC-SSL) (150 mg), and crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) (200 mg) were mixed in a mortar to obtain a physical mixture 2. EXAMPLES

[0086] Manufacture of solid dispersion (Polyvinylpyrrolidone, (Drug substance:Additive = 1:1)) 20 g of crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (manufactured by Powrex; MP-01), and granulated with a solution prepared by dissolving 15 g of amorphous empagliflozin and 15 g of polyvinylpyrrolidone (manufactured by BASF Japan; Kollidon (registered trademark) 30) in 470 g of a 50 wt % ethanol / water mixture, and then dried to obtain a solid dispersion (SD3). EXAMPLES

[0087] Manufacturing of physical mixtures (Polyvinylpyrrolidone, (pharmaceutical substance:additive = 1:1)) Amorphous empagliflozin (150 mg), polyvinylpyrrolidone (manufactured by BASF Japan; Kollidon (registered trademark) 30) (150 mg), and crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) (200 mg) were mixed in a mortar to obtain physical mixture 3. EXAMPLES

[0088] Preparation of solid dispersion (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, (pharmaceutical substance:additive = 1:1)) 20 g of crystalline cellulose (Asahi Kasei Corporation; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (Powrex Corporation; MP-01) and granulated with a solution of 15 g of amorphous empagliflozin and 15 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Kasei Corporation; POVACOAT (registered trademark) Type FM) dissolved in 470 g of a 50 wt% ethanol / water mixture, and then dried to obtain a solid dispersion (SD4). EXAMPLES

[0089] Manufacturing of physical mixtures (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, (pharmaceutical substance:additive = 1:1)) Physical mixture 4 was obtained by mixing 150 mg of amorphous empagliflozin, 150 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (manufactured by Daido Chemical Industry Co., Ltd.; POVACOAT (registered trademark) Type FM), and 200 mg of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.; CEOLUS (registered trademark) PH-102) in a mortar.

[0090] The formulations of the solid dispersions SD1 to SD4 are shown in Table 7.

[0091] [Table 7]

[0092] <Test Example 5> (Confirmation of crystal form of prepared solid dispersion) For the solid dispersions SD1 to SD4 prepared in Examples 19, 21, 23, and 25 and the physical mixtures 1 to 4 prepared in Examples 20, 22, 24, and 26, it was confirmed that empagliflozin was in an amorphous state by powder X-ray diffraction measurement. For the measurement, a powder X-ray diffractometer Smart Lab 3kW was used, and the measurement was performed under the following conditions: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40 kV, 30 mA, measurement range: 2θ=3 to 40 deg, scan speed: 8 deg / min, step width: 0.02 deg. The evaluation results of the crystalline state are shown in Table 8. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0093] [Table 8] HPMC: Hydroxypropyl methylcellulose HPC: Hydroxypropyl cellulose PVP: Polyvinylpyrrolidone PVA Copolymer: Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer

[0094] The crystalline state of the solid dispersions SD1 to SD4 and the physical mixtures 1 to 4 prepared in Examples 19 to 26 was all amorphous.

[0095] <Test Example 6> (Storage stability at 60℃) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD1 to SD4 stored at 60°C for 7 days. The measurement was performed using a powder X-ray diffraction device Smart Lab 3kW under the following conditions: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3 to 40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 9. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0096] [Table 9]

[0097] The results for the empagliflozin-containing solid dispersions SD1 to SD4 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage for 7 days by including the amorphous state maintaining additive.

[0098] <Test Example 7> (Storage stability at 25°C and 50% relative humidity) The amorphous state of SD1 to SD4, which had been stored for 7 days at 25°C and 50% relative humidity, was confirmed by powder X-ray diffraction measurement. For the measurement, a powder X-ray diffraction device Smart Lab 3kW was used, and the conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 10. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0099] [Table 10]

[0100] The results for the empagliflozin-containing solid dispersions SD1 to SD4 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage for 7 days by including the amorphous state maintaining additive.

[0101] <Test Example 8> (Storage stability at 25°C and 75% relative humidity) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD1 and 3 stored at 25°C and 75% relative humidity for 7 days. For the measurement, a powder X-ray diffractometer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 11. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0102] [Table 11]

[0103] The results for the empagliflozin-containing solid dispersions SD1 and 3 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage for 7 days by including the amorphous state maintaining additive. EXAMPLES

[0104] Preparation of solid dispersion (hydroxypropyl methylcellulose, (pharmaceutical substance:additive = 1:0.5)) 20 g of crystalline cellulose (manufactured by Asahi Kasei; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (manufactured by Powrex; MP-01), and granulated with a solution prepared by dissolving 15 g of amorphous empagliflozin and 7.5 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; TC-5 (registered trademark) E) in 470 g of a 50 wt % ethanol / water mixture, and then dried to obtain a solid dispersion (SD5).

[0105] [Table 12]

[0106] <Test Example 9> (Storage stability at 60℃) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD5 stored at 60°C for one month. The measurement was performed using a powder X-ray analyzer Smart Lab 3kW under the following conditions: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 13. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0107] [Table 13]

[0108] The results for the empagliflozin-containing solid dispersion SD5 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage at 60°C for 1 month by including the amorphous state-maintaining additive.

[0109] <Test Example 10> (Storage stability at 25°C and 75% relative humidity) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD5 stored for one month at 25°C and 75% relative humidity. For the measurement, a powder X-ray analyzer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 14. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0110] [Table 14]

[0111] The results for the empagliflozin-containing solid dispersion SD5 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage at 25°C and 75% relative humidity for one month by including the amorphous state maintaining additive. EXAMPLES

[0112] Manufacture of solid dispersion (methacrylic acid copolymer LD (pharmaceutical substance:additive = 1:0.2)) A solution of 2 g of amorphous empagliflozin and 0.4 g of methacrylic acid copolymer LD (manufactured by EVONIK; EUDRAGIT (registered trademark) L100-55) in 100 g of methanol was placed in a recovery flask, and the solvent was removed using an evaporator (manufactured by Tokyo Rikakikaisha; N-1000) to obtain a solid dispersion (SD6). EXAMPLES

[0113] Preparation of solid dispersion (aminoalkyl methacrylate copolymer E (pharmaceutical substance:additive = 1:0.2)) A solution of 2 g of amorphous empagliflozin and 0.4 g of aminoalkyl methacrylate copolymer E (manufactured by EVONIK; EUDRAGIT (registered trademark) EPO) in 100 g of methanol was placed in a recovery flask, and the solvent was removed using an evaporator (manufactured by Tokyo Rikakikaisha; N-1000) to obtain a solid dispersion (SD7). EXAMPLES

[0114] Preparation of solid dispersion (hypromellose acetate succinate ((pharmaceutical substance:additive = 1:0.2)) A solution of 2 g of amorphous empagliflozin and 0.4 g of hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd.; Shin-Etsu AQOAT (registered trademark) AS-LF) dissolved in 100 g of a 50 wt % methanol / acetone mixture was placed in a recovery flask, and the solvent was distilled off using an evaporator (manufactured by Tokyo Rikakikai Co., Ltd.; N-1000) to obtain a solid dispersion (SD8). EXAMPLES

[0115] Preparation of solid dispersion (aminoalkyl methacrylate copolymer E (pharmaceutical substance:additive = 1:1)) A solution of 1 g of amorphous empagliflozin and 1 g of aminoalkyl methacrylate copolymer E (manufactured by EVONIK; EUDRAGIT (registered trademark) EPO) dissolved in 100 g of methanol was placed in a recovery flask, and the solvent was removed using an evaporator (manufactured by Tokyo Rikakikaisha; N-1000) to obtain a solid dispersion (SD9). EXAMPLES

[0116] Preparation of solid dispersion (hypromellose acetate succinate ((pharmaceutical substance:additive = 1:1)) A solution of 1 g of amorphous empagliflozin and 1 g of hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd.; Shin-Etsu AQOAT (registered trademark) AS-LF) dissolved in 100 g of a 50 wt % methanol / acetone mixture was placed in a recovery flask, and the solvent was distilled off using an evaporator (manufactured by Tokyo Rikakikai Co., Ltd.; N-1000) to obtain a solid dispersion (SD10).

[0117] [Table 15]

[0118] <Test Example 11> (Storage stability at 60℃) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD6 to SD8 stored at 60°C for one month. For the measurement, a powder X-ray analyzer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3 to 40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 16. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0119] [Table 16]

[0120] The results for the empagliflozin-containing solid dispersions SD6 to SD8 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical compositions after storage at 60°C for 1 month by including the amorphous state maintaining additive.

[0121] <Test Example 12> (Storage stability at 25°C and 75% relative humidity) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD6 and SD10 stored for one month at 25°C and 75% relative humidity. For the measurement, a powder X-ray analyzer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 16. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0122] [Table 17]

[0123] The results for the empagliflozin-containing solid dispersions SD6 and SD10 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical compositions after storage at 25°C and a relative humidity of 75% for one month by the inclusion of an amorphous state-maintaining additive.

[0124] <Test Example 13> (Storage stability at 25°C and 75% relative humidity) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD8 and SD9 stored for 1 week at 25°C and 75% relative humidity. For the measurement, a powder X-ray analyzer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 18. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0125] [Table 18]

[0126] The results for the empagliflozin-containing solid dispersions SD8 and SD9 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage at 25°C and a relative humidity of 75% for one month by including the amorphous state-maintaining additive. EXAMPLES

[0127] Preparation of solid dispersion (vinyl acetate-vinylpyrrolidone copolymer, (pharmaceutical substance:additive = 1:1)) 20 g of crystalline cellulose (Asahi Kasei Corporation; CEOLUS (registered trademark) PH-102) was placed in a fluidized bed granulator (Powrex Corporation; MP-01), and granulated with a solution prepared by dissolving 15 g of amorphous empagliflozin and 15 g of vinyl acetate-vinylpyrrolidone copolymer (BASF Corporation; Kollidon (registered trademark) VA64) in 470 g of a 50 wt% ethanol / water mixture, and then dried to obtain a solid dispersion (SD11).

[0128] [Table 19]

[0129] <Test Example 14> (Storage stability at 60℃) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD11 stored at 60°C for one month. The measurement was performed using a powder X-ray analyzer Smart Lab 3kW under the following conditions: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 20. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0130] [Table 20]

[0131] The results for the empagliflozin-containing solid dispersion SD11 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage at 60°C for 1 month by including the amorphous state-maintaining additive.

[0132] <Test Example 15> (Storage stability at 25°C and 75% relative humidity) The amorphous state of empagliflozin was confirmed by powder X-ray diffraction measurement for SD11 stored for one month at 25°C and 75% relative humidity. For the measurement, a powder X-ray analyzer Smart Lab 3kW was used, and the measurement conditions were as follows: measurement method: reflection method, filter: Cu K-beta, X-ray output: 40kV, 30mA, measurement range: 2θ=3-40deg, scan speed: 8deg / min, step width: 0.02deg. The evaluation results of the crystalline state are shown in Table 21. The crystal state was confirmed according to the evaluation criteria in Table 1.

[0133] [Table 21]

[0134] The results for the empagliflozin-containing solid dispersion SD11 showed that the amorphous state of empagliflozin was maintained in the empagliflozin-containing pharmaceutical composition after storage at 25°C and a relative humidity of 75% for one month by including an amorphous state-maintaining additive.

Claims

1. An empagliflozin-containing pharmaceutical composition comprising amorphous empagliflozin and an amorphous maintaining excipient.

2. The pharmaceutical composition according to claim 1, wherein the amorphous state maintaining additive is one or more additives selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyoxyethylene (160) polyoxypropylene (30) glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and vinyl acetate-vinylpyrrolidone copolymer.

3. The pharmaceutical composition according to claim 1, wherein the amorphous state maintaining additive is one or more additives selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, and vinyl acetate-vinylpyrrolidone copolymer.

4. 2. The pharmaceutical composition according to claim 1, wherein the amorphous state maintaining additive is one or more additives selected from the group consisting of polyvinyl alcohol, light anhydrous silicic acid, and magnesium stearate.

5. 2. The pharmaceutical composition according to claim 1, wherein the amorphous state maintaining additive is one or more additives selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, and vinyl acetate-vinylpyrrolidone copolymer.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of the amorphous maintaining additive is 0.05 to 15, relative to the amount of amorphous empagliflozin per pharmaceutical composition being 1.

7. The pharmaceutical composition according to any one of claims 1 to 5, which is in the form of a tablet.

8. The pharmaceutical composition according to claim 7, wherein the tablet is a film-coated tablet.

9. A method for producing the pharmaceutical composition according to claim 1, comprising a step of dissolving empagliflozin in a mixed solution of ethanol and water.

10. The method for producing a pharmaceutical composition according to claim 9, wherein the mixed solution of ethanol and water contains 34.4% by weight to 54.2% by weight of ethanol.

11. A method for producing the pharmaceutical composition according to claims 9 to 10, comprising a direct compression step.

12. A method for producing the pharmaceutical composition according to claims 9 to 10, comprising a step of dissolving empagliflozin in methanol.

13. The method for producing the pharmaceutical composition according to claim 9 to 10, comprising a step of dissolving empagliflozin in a mixed solution of methanol and acetone.

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