Pharmaceutical composition containing empagliflozin

Abstract

To provide a new pharmaceutical composition containing empagliflozin in which the solubility of empagliflozin in water is relatively high.SOLUTION: The present invention includes, for example, a pharmaceutical composition mainly comprising empagliflozin and a polymeric carrier, wherein the content ratio of empagliflozin to the polymeric carrier is within the range of 1:1 to 1:40 (empagliflozin: polymeric carrier) by mass, and empagliflozin is solid-dispersed in an amorphous state.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical preparations. In the technical field, the present invention relates to a pharmaceutical composition containing empagliflozin or a method for producing the same. [Background technology]

[0002] Empagliflozin, whose chemical name is (1S)-1,5-Anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol, is a known compound with the structure shown in (1) below. Empagliflozin inhibits sodium-glucose cotransporter 2 (SGLT2), which is expressed in the proximal tubules of the kidney and is involved in glucose reabsorption, thereby promoting glucose excretion in the urine. When blood glucose levels are excessively high, empagliflozin increases glucose excretion in the urine through this inhibitory effect, thereby normalizing blood glucose levels. Due to these pharmacological effects of empagliflozin, empagliflozin is manufactured and sold in Japan as Jardiance® 10 mg to 25 mg as a selective SGLT2 inhibitor for the treatment of type 2 diabetes (non-insulin-dependent diabetes mellitus). It is also used as a selective SGLT2 inhibitor to treat chronic heart failure and chronic kidney disease.

[0003] In addition, a combination drug combining empagliflozin with linagliptin, which is also a diabetes treatment drug but is a biliary-excreted selective DPP-IV inhibitor different from empagliflozin, is manufactured and sold under the trade name Tradiance (registered trademark).

[0004] [ka]

[0005] Empagliflozin was first disclosed in Patent Document 1, and a crystalline form of empagliflozin is disclosed in Patent Document 2. Furthermore, Patent Document 3 discloses a crystallization method for producing a crystalline form of empagliflozin. Additionally, for example, Patent Document 4 discloses an invention of a formulation of empagliflozin having a particle size distribution of 1 μm≦X90<200 μm and an empagliflozin content of 25% or less.

[0006] On the other hand, solid dispersions are generally one of the formulation technologies for improving the solubility of drugs in water. Research on solid dispersions began around 1960 and was already known in the early days. Structurally, they are solids in which drugs are amorphous and dispersed at the molecular level in an inert carrier (carrier) such as a polymer. In solid dispersions, the drug is in an amorphous state, so by dissolving it in water, a supersaturated state exceeding the normal solubility of the drug can be formed in water, resulting in high apparent solubility. As a result, solid dispersions are expected to improve the solubility of poorly water-soluble drugs in water.

[0007] Examples of methods for producing solid dispersions include the solvent method, in which a target drug and a polymeric carrier are dissolved in an appropriate organic solvent and then the solvent is evaporated to obtain a solid dispersion, the melting method, in which a target drug and a polymeric carrier are eutecticized and then cooled to obtain a solid dispersion, and the solvent-melt mixing method. In recent years, from the perspective of industrial production, methods such as the hot melt extrusion (HME) method, in which a solid dispersion is obtained using a twin-screw extruder, the spray drying method, the mixed grinding method, and the coprecipitation method have been used.

[0008] The hot melt extrusion (HME) method involves heating and kneading the target drug and polymer carrier in an extruder, causing the target drug to become molecularly dispersed within the polymer carrier, and then extruding and cooling the mixture to obtain a solid dispersion.The spray drying method involves dissolving the target drug and polymer carrier in an organic solvent, followed by spray drying to obtain a solid dispersion. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2005 / 092877 (Patent No. 4181605) [Patent Document 2] International Publication No. 2006 / 117359 (Patent No. 4226070) [Patent Document 3] International Publication No. 2011 / 039107 (Patent No. 5736377) [Patent Document 4] International Publication No. 2010 / 092126 (Patent No. 5600328) Summary of the Invention [Problem to be solved by the invention]

[0010] The crystalline form of empagliflozin described in Patent Document 2 has a solubility in water of only 0.11 mg / mL, and its stability is not necessarily good. A main object of the present invention is to provide a new pharmaceutical composition containing empagliflozin, in which empagliflozin has relatively high solubility in water. [Means for solving the problem]

[0011] As a result of extensive investigations, the present inventors have found that the above-mentioned problems can be solved by heating and kneading empagliflozin and a polymer carrier having a certain viscosity by a hot melt extrusion (HME) method to form a solid dispersion, and have thus completed the present invention.

[0012] The present invention can include, for example, the following aspects. [1] A pharmaceutical composition mainly comprising empagliflozin and a polymeric carrier, wherein the content ratio of empagliflozin to the polymeric carrier is within the range of 1:1 to 1:40 (empagliflozin:polymeric carrier) by mass, and the empagliflozin is solid-dispersed in an amorphous state. [2] A pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, wherein the polymer carrier is a water-soluble polymer carrier, the viscosity of which is within the range of 1.5 to 8 mP·s in a 2% by mass aqueous solution at 20°C, and the empagliflozin is solid-dispersed in an amorphous state. [3] The pharmaceutical composition according to the above-mentioned [2], wherein the content ratio of empagliflozin and the polymer carrier is within the range of 1:1 to 1:40 (empagliflozin:polymer carrier) by mass ratio. [4] The pharmaceutical composition according to [1] above, wherein the polymeric carrier is a cellulose derivative, a methacrylic acid copolymer, polyvinyl alcohol, a polyvinyl alcohol copolymer, polyvinylpyrrolidone, a vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, or a polyethylene glycol copolymer. [5] The pharmaceutical composition according to [4] above, wherein the polymeric carrier is hydroxypropylmethylcellulose or its acid ester, hydroxypropylcellulose, carboxymethylethylcellulose, or aminoalkyl methacrylate copolymer E. [6] The pharmaceutical composition according to [5] above, wherein the hydroxypropyl methylcellulose is type 2910. [7] A solid formulation comprising the pharmaceutical composition according to any one of [1] to [6] above. [8] The solid formulation according to [7] above, wherein the solid formulation is a tablet, an OD tablet, or a coated tablet thereof. [9] The solid formulation according to [8] above, further comprising a therapeutic agent for diabetes other than empagliflozin.

[10] The solid formulation according to [9] above, wherein the antidiabetic agent is a DPP-IV inhibitor.

[11] The solid formulation according to

[10] above, wherein the DPP-IV inhibitor is linagliptin or a salt thereof.

[0013]

[12] A method for producing a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising the step of heating, melting, and kneading the empagliflozin and the polymer carrier by a hot-melt extrusion method so that the empagliflozin is solid-dispersed in an amorphous state.

[13] The method for producing the pharmaceutical composition according to the above-mentioned

[12] , wherein the blending ratio of empagliflozin and the polymer carrier is 1:1 to 1:40 (empagliflozin:polymer carrier) by mass.

[14] The method for producing a pharmaceutical composition according to

[12] above, wherein the polymer carrier is a water-soluble polymer carrier, and the viscosity of the polymer carrier is within the range of 1.5 to 8 mP·s in a 2% by mass aqueous solution at 20°C.

[15] The method for producing the pharmaceutical composition according to the above-mentioned

[14] , wherein the blending ratio of empagliflozin and the polymer carrier is 1:1 to 1:40 (empagliflozin:polymer carrier) by mass.

[16] The method for producing a pharmaceutical composition according to any one of

[12] to

[15] above, wherein the polymer carrier is a cellulose derivative, a methacrylic acid copolymer, polyvinyl alcohol, a polyvinyl alcohol copolymer, polyvinylpyrrolidone, a vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, or a polyethylene glycol copolymer.

[17] The method for producing the pharmaceutical composition according to

[16] above, wherein the polymeric carrier is hydroxypropylmethylcellulose or its acid ester, hydroxypropylcellulose, carboxymethylethylcellulose, or aminoalkyl methacrylate copolymer E.

[18] The method for producing the pharmaceutical composition described in

[17] above, wherein the hydroxypropyl methylcellulose is type 2910.

[0014]

[19] A method for producing a solid formulation, comprising the following steps a to c: a. A step of producing the pharmaceutical composition by the production method described in any one of

[12] to

[18] above; b. A step of mixing the pharmaceutical composition produced in the previous step with an excipient to prepare a mixture, or a step of preparing a granulation product containing the pharmaceutical composition and an excipient; and c. Processing the mixture or granules to form a solid preparation.

[20] A method for producing the solid formulation according to

[19] above, further comprising the step of blending an antidiabetic agent other than empagliflozin.

[21] The method for producing a solid formulation according to

[20] above, wherein the antidiabetic drug is a DPP-IV inhibitor.

[22] The method for producing a solid formulation according to

[21] above, wherein the DPP-IV inhibitor is linagliptin or a salt thereof.

[23] The method for producing a solid preparation according to any one of the above

[19] to

[22] , wherein the solid preparation is a tablet, an OD tablet, or a coated tablet thereof.

[0015]

[24] A method for maintaining an amorphous solid dispersion state of empagliflozin in a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising, in a production process of the pharmaceutical composition, heating, melting, and kneading empagliflozin and the polymer carrier by a hot-melt extrusion method so that empagliflozin is solid-dispersed in an amorphous state.

[25] The method according to

[24] above, wherein the blending ratio of empagliflozin and the polymer carrier is 1:1 to 1:40 (empagliflozin:polymer carrier) by mass.

[26] The method according to

[24] above, wherein the polymer carrier is a water-soluble polymer carrier, and the viscosity of the polymer carrier is within the range of 1.5 to 8 mP·s in a 2 mass % aqueous solution at 20°C.

[27] The method according to

[26] above, wherein the blending ratio of empagliflozin and the polymer carrier is 1:1 to 1:40 (empagliflozin:polymer carrier) by mass.

[28] The method according to any one of

[24] to

[27] above, wherein the polymer carrier is a cellulose derivative, a methacrylic acid copolymer, polyvinyl alcohol, a polyvinyl alcohol copolymer, polyvinylpyrrolidone, a vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, or a polyethylene glycol copolymer.

[29] The method according to

[28] above, wherein the polymeric carrier is hydroxypropylmethylcellulose or its acid ester, hydroxypropylcellulose, carboxymethylethylcellulose, or aminoalkylmethacrylate copolymer E.

[30] The method according to

[29] above, wherein the hydroxypropyl methylcellulose is type 2910. [Effects of the Invention]

[0016] According to the present invention, a new pharmaceutical composition containing empagliflozin can be provided. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows differential scanning calorimetry (DSC) curves for a solid dispersion of empagliflozin and TC-5 (registered trademark) E in a 1:2 (mass ratio) ratio. The leftmost graph shows the curve for the sample immediately after preparation, the middle graph shows the curve for the sample after one month at 25°C and 75% RH, and the rightmost graph shows the curve for the sample after one month at 40°C and 75% RH. [Figure 2] 1 shows differential scanning calorimetry (DSC) curves for a solid dispersion of empagliflozin and TC-5 (registered trademark) E in a 1:5 (mass ratio) ratio. The leftmost graph shows the curve for the sample immediately after preparation, the middle graph shows the curve for the sample after one month at 25°C and 75% RH, and the rightmost graph shows the curve for the sample after one month at 40°C and 75% RH. DETAILED DESCRIPTION OF THE INVENTION

[0018] 1. Pharmaceutical composition according to the present invention The pharmaceutical composition of the present invention (hereinafter referred to as "the composition of the present invention") is a pharmaceutical composition consisting essentially of empagliflozin and a polymeric carrier, characterized in that the content ratio of empagliflozin to the polymeric carrier is within the range of 1:1 to 1:40 by mass (empagliflozin:polymeric carrier), and empagliflozin is solid-dispersed in an amorphous state. Alternatively, it is a pharmaceutical composition consisting essentially of empagliflozin and a polymeric carrier, characterized in that the polymeric carrier is a water-soluble polymeric carrier whose viscosity is within the range of 1.5 to 8 mP·s in a 2% by mass aqueous solution at 20°C, and empagliflozin is solid-dispersed in an amorphous state.

[0019] Here, "consisting mainly of empagliflozin and a polymer carrier" means that the total content of empagliflozin and the polymer carrier is 60% by mass or more, preferably 80% by mass or more to 90% by mass or more, and more preferably 100% by mass.

[0020] The phrase "empagliflozin is solid-dispersed in an amorphous state" means that empagliflozin is in an amorphous state in the polymer carrier and forms a solid dispersion. The "amorphous state" refers to a solid state in which no crystalline structure (crystal lattice) is observed, such as an amorphous or glassy state. This solid dispersion can also be called a solid solution. In other words, it means that empagliflozin is dispersed at the molecular level in the solid polymer carrier. The formation of such a solid dispersion can be confirmed by standard methods, such as differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and solid-state NMR, based on the presence or absence of signals derived from crystals. A broad halo pattern observed by powder X-ray diffraction indicates that almost all of empagliflozin is in an amorphous state in the polymer carrier and forms a solid dispersion.

[0021] In the present invention, the content of amorphous empagliflozin in the composition of the present invention is sufficient as long as it is 50% or more, preferably 80% or more, more preferably 90% or more, and even more preferably 95% or more to 100%.

[0022] 1.1 Empagliflozin and polymeric carriers Empagliflozin according to the present invention is a compound known per se and can be produced, for example, by the method described in Patent Document 1. The polymer carrier according to the present invention is water-soluble or poorly water-soluble.

[0023] The polymer carrier according to the present invention is not particularly limited as long as it can form a solid dispersion of empagliflozin. Specific examples of the polymer carrier include cellulose derivatives such as methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hypromellose: HPMC) and its acid esters (e.g., hydroxypropyl methylcellulose phthalate ester (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS)); methacrylic acid copolymers such as aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E type (e.g., E100, EPO)); polyvinyl alcohol and polyvinyl alcohol copolymers such as POVACOAT (registered trademark); polyvinylpyrrolidone; vinylpyrrolidone-vinyl acetate copolymers such as Kollidon (registered trademark) VA64; polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus (registered trademark)), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat Examples of suitable copolymers include polyethylene glycol copolymers such as hydroxypropylmethylcellulose (IR); and cyclodextrins such as α-cyclodextrin and β-cyclodextrin. Among these, preferred are cellulose derivatives such as hydroxypropylmethylcellulose; polyvinyl alcohol copolymers such as hydroxypropylmethylcellulose and POVACOAT®; and polyethylene glycol copolymers such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), with hydroxypropylmethylcellulose, POVACOAT®, and Soluplus® being more preferred. Hydroxypropylmethylcellulose, TC-5® E-type and M-type, are particularly preferred.

[0024] The content ratio of empagliflozin and the polymer carrier is not particularly limited as long as a solid dispersion is formed, but for example, a mass ratio within the range of 1:1 to 1:40 (empagliflozin:polymer carrier) is appropriate, a range of 1:1 to 1:15 is preferred, and a range of 1:2 to 1:5 is more preferred. If the ratio of empagliflozin is less than half the polymer carrier, a solid dispersion may not be sufficiently formed, which is not preferred.

[0025] In one embodiment of the present invention, when the polymer carrier is a water-soluble polymer carrier, it has a viscosity of 1.5 to 8 mP·s in a 2% by mass aqueous solution at 20°C. Preferably, it has a viscosity of 2 to 7 mP·s in a 2% by mass aqueous solution at 20°C, and more preferably, it has a viscosity of 2.4 to 6.1 mP·s in a 2% by mass aqueous solution at 20°C.

[0026] The viscosity can be easily measured using a suitable viscometer by conventional methods, and is listed in catalogs or other documents depending on the polymer carrier. For example, in a 2% by weight aqueous solution at 20°C, the viscosity of hydroxypropyl methylcellulose TC-5 (registered trademark) E is 2.5 to 3.5 mPa·s, that of TC-5 (registered trademark) M is 3.6 to 5.1 mPa·s, that of TC-5 (registered trademark) R is 5.2 to 7.0 mPa·s, that of VIVAPHRM (registered trademark) HPMC E3 is 3 mPa·s, that of HPMC E5 is 5 mPa·s, and that of HPMC E6 is 6 mPa·s. Furthermore, the viscosity of polyvinyl alcohol Gohsenol (trade name) EG-05P is approximately 4.3 to 6.3 mPa·s, and that of hydroxypropyl methylcellulose acetate succinate AS-LF is approximately 2.4 to 3.6 mPa·s.

[0027] 1.2 Other ingredients (additives) The composition of the present invention may contain appropriate amounts of additives commonly used in the field of pharmaceutical formulations, as long as they do not impair the effects of the present invention.Specific examples include excipients, binders, disintegrants, lubricants, etc., and, if necessary, plasticizers, antioxidants, colorants, flavoring agents, sweeteners, fragrances, preservatives, etc.

[0028] Examples of excipients include lactose, D-mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose hydrate, sucrose, sucrose, starch, pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin / dextrates, maltodextrin; inorganic salts such as calcium citrate, calcium phosphate, calcium aluminometasilicate, calcium carbonate, dicalcium phosphate, and calcium sulfate; and cellulose derivatives such as crystalline cellulose or wood cellulose. The composition may contain one type of excipient or any two or more types of excipients.

[0029] Examples of binders include crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pregelatinized starch, partially pregelatinized starch, polyvinylpyrrolidone, gum arabic, starch (e.g., wheat starch, rice starch, corn starch, potato starch), sodium alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, gelatin, low-substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, and pullulan. The binder may be contained in one kind or in any combination of two or more kinds.

[0030] Examples of disintegrants include starch (e.g., wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminometasilicate, calcium silicate, and sodium lauryl sulfate. The disintegrant may be contained alone or in any combination of two or more kinds.

[0031] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and crystalline cellulose. The lubricant may be contained alone or in any combination of two or more kinds.

[0032] Examples of plasticizers include polyethylene glycol 400 (macrogol 400), polyethylene glycol 600 (macrogol 600), polyethylene glycol 1500 (macrogol 1500), polyethylene glycol 4000 (macrogol 4000), polyethylene glycol 6000 (macrogol 6000), propylene glycol, glycerin monostearate, isopropyl myristate, triacetin, glycerin, glycerin fatty acid esters, triethyl citrate, polysorbate 80, diethyl phthalate, and dibutyl phthalate. The plasticizer may be contained alone or in any combination of two or more kinds. Suitable examples of antioxidants include sulfites, ascorbic acid, sodium edetate, erythorbic acid, tocopherol, anhydrous citric acid, citric acid hydrate, soybean lecithin, dibutylhydroxytoluene, dibutylhydroxyanisole, and propyl gallate. The antioxidant may be contained alone or in any combination of two or more kinds.

[0033] Examples of coloring agents include carotenoids, iron oxides, and chlorophyll. Examples of coloring agents also include food color red No. 2 and No. 3, food color yellow No. 4 and No. 5, food color green No. 3, food color blue No. 1 and No. 2, aluminum lakes of these food colors, iron sesquioxide, and yellow iron sesquioxide. The colorant may be contained alone or in any combination of two or more kinds.

[0034] Examples of flavoring agents include erythritol, xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, glucose, D-mannitol, aspartame, cocoa powder, reduced maltose syrup, reduced syrup, licorice, licorice extract, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, succinic acid, saccharin, saccharin sodium hydrate, tartaric acid, sucralose, purified stevia extract, peppermint oil, anhydrous citric acid, l-menthol, and DL-malic acid. The flavoring agent may be contained in one kind or in any combination of two or more kinds.

[0035] Examples of sweeteners include xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, saccharin sodium hydrate, sucralose, purified stevia extract, maltitol, acesulfame potassium, and thaumatin. The sweetener may contain one kind or any two or more kinds.

[0036] Examples of flavorings include peppermint oil, 1-menthol, and vanillin. The fragrance may contain one kind or any two or more kinds of the fragrances. Examples of preservatives include parabens (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.), citric acid hydrate, sodium benzoate, sodium edetate hydrate, and dibutylhydroxytoluene. The preservative may be contained alone or in any combination of two or more kinds.

[0037] 2. Method for producing the composition of the present invention The composition of the present invention can be produced by, for example, the so-called solvent method, melting method, solvent-melting method, hot melt extrusion (HME) method, spray drying method, coprecipitation method, or mechanochemical (mixed grinding) method, among which the hot melt extrusion (HME) method is preferred for producing the composition of the present invention.

[0038] For example, when producing by the solvent method, both empagliflozin and the polymer carrier to be used are dissolved, and then at least empagliflozin and the polymer carrier are dissolved in an organic solvent (e.g., methanol, ethanol, acetone) that can be easily distilled off (under reduced pressure), and then the solvent is distilled off (under reduced pressure), thereby obtaining the composition of the present invention (solid dispersion).

[0039] When produced by the melting method, the composition of the present invention (solid dispersion) can be obtained by forming a eutectic mixture of empagliflozin and the polymer carrier to be used at an appropriate temperature, followed by rapid cooling.

[0040] When produced by the spray drying method, at least empagliflozin and the polymer carrier to be used are dissolved in an appropriate organic solvent (e.g., methanol, ethanol, acetone) capable of dissolving the empagliflozin and the polymer carrier, and the solution is spray-dried to obtain the composition of the present invention (solid dispersion).

[0041] When the composition is produced by hot melt extrusion (HME), for example, an extruder (e.g., a single-screw extruder, a twin-screw extruder, etc.) or a kneading extruder (e.g., a twin-screw extruder, a twin-screw compounder, etc.) having one or more screws in a cylinder is used, the temperature inside the cylinder is adjusted to an appropriate heating and melting temperature, materials such as empagliflozin and a polymer carrier are charged into the cylinder, the materials are subjected to treatments such as melting, kneading, and shearing in the cylinder, and finally, the materials are extruded out of the extruder and cooled to produce the composition of the present invention (solid dispersion). Among these, it is preferable to use a twin-screw extruder. More specifically, empagliflozin and a polymeric carrier, etc., are typically charged from a hopper into a cylinder maintained at or above the glass transition temperature of the polymeric carrier used, and the screw is rotated at an appropriate rotation speed, whereby empagliflozin and the polymeric carrier are heated and melted, and simultaneously sheared and kneaded to form a kneaded mixture, which is then extruded through a die located at the tip of the extruder and cooled to produce the composition of the present invention (solid dispersion). The extrudate is typically in the form of a noodle or rod, but can be cut with an appropriate cutter, and by cutting, the extrudate can be processed into, for example, granules, fine granules, or tablets.

[0042] The number of screws, whether they are fully intermeshing or non-fully intermeshing if there are two screws (two screws), whether they rotate in the same direction or counter-rotating, the shape, pitch, combination, arrangement, and configuration of the screw elements (ball screw element that transports the material, kneading screw element that stirs and kneads the material, and reverse screw element that transports the material in the opposite direction as needed) installed in the screws, the screw rotation speed, barrel temperature (temperature inside the cylinder), and the shape and size of the die are set appropriately depending on the twin-screw extruder or other kneading extruder used, the polymer carrier and empagliflozin content ratio used, other additives, etc. The present invention includes a method for producing a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising the step of heating, melting, and kneading empagliflozin and the polymer carrier by a hot-melt extrusion method so that empagliflozin is solid-dispersed in an amorphous state. The meanings of the respective terms are as defined above.

[0043] By preparing the composition of the present invention (solid dispersion) by hot melt extrusion, the amorphous solid dispersion state of empagliflozin can be maintained (retained) in the composition. Depending on the embodiment of the present invention, the amorphous solid dispersion state of empagliflozin can be maintained for a sufficiently long period of time.

[0044] The present invention includes a method for maintaining an amorphous solid dispersion state of empagliflozin in a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising heating, melting, and kneading empagliflozin and the polymer carrier by a hot-melt extrusion method during the production process of the pharmaceutical composition so that empagliflozin is solid-dispersed in an amorphous state. The meanings of the respective terms are as defined above.

[0045] 3. Solid preparation containing the composition of the present invention 3.1 Overview of the solid dosage form The composition of the present invention (solid dispersion) produced by the production method described in item 2 above can be pulverized using an appropriate pulverizer to obtain solid dispersion particles of any particle size, which can be directly used as a powder or granules. Furthermore, by adding appropriate additives to the composition of the present invention or its pulverized fine particles as needed and then subjecting them to the required formulation process, solid preparations such as tablets, OD tablets (rapidly disintegrating tablets), granules, fine granules, and capsules can be prepared. In some cases, they can also be used as injections.

[0046] Therefore, one embodiment of the present invention can include a solid preparation (e.g., tablet, OD tablet, coated tablet) containing the composition of the present invention. The solid preparation can be produced by a production method including the following steps a to c. Hereinafter, the solid preparation will be referred to as the "preparation of the present invention."

[0047] a. A step of producing the composition of the present invention by the production method described in the above section 2 (Production method of the composition of the present invention) b. A step of mixing the composition of the present invention produced in the previous step with an excipient to prepare a mixture, or a step of preparing a granule containing the composition of the present invention and an excipient. c. A step of processing the mixture or granules to form a solid preparation.

[0048] Furthermore, the production of the formulation of the present invention may further include a step of blending a therapeutic diabetes drug other than empagliflozin.

[0049] 3.2 Components other than the composition of the present invention The components contained in the formulation of the present invention other than the composition of the present invention are not particularly limited as long as they are additives commonly used in the field of pharmaceutical formulations, and examples thereof include excipients, binders, disintegrants, lubricants, flow agents, glossing agents, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, buffers, pH adjusters, thickeners, adsorbents, colorants, flavoring agents, sweeteners, fragrances, preservatives, foaming agents, and antifoaming agents.

[0050] Specifically, the excipients, binders, disintegrants, lubricants, antioxidants, colorants, flavoring agents, sweeteners, fragrances, and preservatives may be the same as those described above. The contents of the excipients, binders, disintegrants, and lubricants are as follows, and the other ingredients may be in appropriate amounts.

[0051] The content of the excipient can be set appropriately taking into consideration the type of excipient, etc., but is, for example, suitably in the range of 0 to 96% by mass, preferably in the range of 40 to 92% by mass, more preferably in the range of 55 to 88% by mass, and particularly preferably in the range of 65 to 85% by mass.

[0052] The binder content can be set appropriately taking into consideration the type of binder, etc., but is, for example, suitably in the range of 0 to 30 mass%, preferably in the range of 1 to 27 mass%, more preferably in the range of 3 to 23 mass%, and particularly preferably in the range of 5 to 20 mass%.

[0053] The content of the disintegrant can be set appropriately taking into consideration the type of disintegrant, etc., but is, for example, suitably in the range of 0 to 50% by mass, preferably in the range of 1 to 30% by mass, more preferably in the range of 4 to 25% by mass, and particularly preferably in the range of 8 to 15% by mass.

[0054] The content of the lubricant can be set appropriately taking into consideration the type of lubricant, etc., but is, for example, suitably in the range of 0 to 10% by mass, preferably in the range of 0.4 to 8% by mass, more preferably in the range of 0.8 to 5% by mass, and particularly preferably in the range of 1 to 4% by mass.

[0055] Specific examples of additives other than those mentioned above, i.e., fluidizing agents, glossing agents, stabilizers, emulsifying agents, surfactants, solubilizing agents, suspending agents, buffers, pH adjusters, thickening agents, adsorbents, foaming agents, and antifoaming agents, include the following.

[0056] Examples of the fluidizing agent include calcium silicate, talc, light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0057] Examples of glossing agents include carnauba wax, refined paraffin-carnauba wax mixed wax, white beeswax, and refined shellac.

[0058] Examples of stabilizers include meglumine, citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, xylitol, D-sorbitol, lactose hydrate, D-mannitol, sodium citrate hydrate, tartaric acid, anhydrous citric acid, DL-malic acid, talc, light anhydrous silicic acid, magnesium aluminometasilicate, glycerin monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (Macrogol 400, Macrogol 4000, etc.), carboxyvinyl polymer, poly Examples of suitable surfactants include vinyl alcohol (partially saponified), polyoxyethylene hydrogenated castor oil (N), L-aspartic acid, sodium L-aspartate hydrate, DL-alanine, L-alanine, L-arginine, sodium chloride, dried aluminum hydroxide gel, xanthan gum, glycine, acetic acid, sodium acetate hydrate, sodium hydroxide, sodium bicarbonate, tocopherol, lactic acid, concentrated glycerin, butylated hydroxyanisole, fumaric acid, propylene glycol, propyl gallate, polysorbate 80, and anhydrous sodium monohydrogen phosphate.

[0059] Examples of emulsifiers include glycerin monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, medium-chain fatty acid triglyceride, soybean lecithin, and lauromacrogol.

[0060] Examples of surfactants include glycerin monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, macrogol (such as macrogol 400), and polyoxyethylene (N) polyoxypropylene (N) glycol.

[0061] Examples of solubilizing agents include sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, medium-chain fatty acid triglyceride, soybean lecithin, meglumine, D-mannitol, sodium citrate hydrate, anhydrous citric acid, sucrose fatty acid ester, macrogol (Macrogol 4000, Macrogol 6000, etc.), polyvinyl alcohol (partially saponified), L-aspartic acid, L-arginine, sodium hydroxide, sodium bicarbonate, lactic acid, concentrated glycerin, hydroxypropyl cellulose, β-cyclodextrin, glycerin, soybean oil, and triacetin.

[0062] Examples of suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soybean lecithin, sucrose fatty acid esters, macrogol (such as macrogol 4000 and macrogol 6000), sodium hydroxide, hydroxypropyl cellulose, glycerin, D-sorbitol, magnesium aluminum metasilicate, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, butylated hydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, powdered gum arabic, hypromellose, powdered agar, povidone, methylcellulose, kaolin, carrageenan, carmellose sodium, glycerin fatty acid esters, and magnesium aluminum silicate.

[0063] Examples of buffering agents include sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, sodium benzoate, tartaric acid, DL-malic acid, sodium chloride, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, L-glutamic acid, and dilute hydrochloric acid.

[0064] Examples of pH adjusters include L-glutamine, sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, tartaric acid, DL-malic acid, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, and aqueous ammonia.

[0065] Examples of thickening agents include guar gum, hydroxypropyl cellulose, carboxyvinyl polymer, xanthan gum, propylene glycol, hypromellose, carrageenan, carmellose sodium, concentrated glycerin, gelatin, hydroxyethyl cellulose, carob bean gum, α-cyclodextrin, and locust bean gum.

[0066] Examples of the adsorbent include magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, and precipitated calcium carbonate.

[0067] Examples of the foaming agent include hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) and carbonates (magnesium carbonate, calcium carbonate, etc.).

[0068] An example of an antifoaming agent is dimethylpolysiloxane (for internal use).

[0069] 3.3 Coated tablets When the formulation of the present invention is in the form of tablets or OD tablets, these coated tablets can be prepared by coating with an appropriate coating agent. The coating can be carried out according to a conventional method, for example, using a film coating device used in the pharmaceutical field.

[0070] The components of the coating agent include, for example, a coating base and a coating additive, which can be appropriately selected and used in appropriate amounts according to conventional methods.

[0071] Examples of coating bases include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. These may be used alone or in combination of any two or more.

[0072] Examples of sugar-coating bases include sugar alcohols such as sucrose, refined sucrose, and erythritol. Furthermore, one or more of the following may be used in combination: talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc.

[0073] Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate and polyvinylpyrrolidone; and polysaccharides such as pullulan. These may be used alone or in combination of any two or more.

[0074] Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as shellac. These may be used alone or in combination of any two or more.

[0075] Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose, and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​and ethyl acrylate-methyl methacrylate copolymer suspensions. These may be used alone or in combination of two or more.

[0076] Examples of coating additives include light-blocking agents such as titanium oxide, fluidizing agents such as talc, and / or colorants such as ferric oxide and yellow ferric oxide, plasticizers such as polyethylene glycol, propylene glycol, triethyl citrate, castor oil, and polysorbates, and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid. These may be used alone or in combination of any two or more.

[0077] 3.4 Concomitant use with other diabetes medications The preparation of the present invention can contain a diabetes therapeutic agent other than empagliflozin as an active ingredient. Such diabetes therapeutic agent preferably has a different mechanism of action from empagliflozin (SGLT2 inhibitor), but may also be an SGLT2 inhibitor other than empagliflozin. It can also contain a chronic heart failure therapeutic agent and / or a chronic kidney disease therapeutic agent. Furthermore, if necessary, it can also contain a therapeutic agent that is not directly a diabetes therapeutic agent, a chronic heart failure therapeutic agent, or a chronic kidney disease therapeutic agent.

[0078] Antidiabetic drugs other than empagliflozin that can be added include, but are not limited to, DPP-IV inhibitors such as sitagliptin phosphate hydrate, vildagliptin, alogliptin benzoate, linagliptin, teneligliptin hydrobromide hydrate, anagliptin, saxagliptin hydrate, trelagliptin succinate, and omarigliptin; sulfonylureas (SU) such as glibenclamide, gliclazide, and glimepiride; rapid-acting insulin secretagogues (glinides) such as nateglinide, mitiglinide calcium hydrate, and repaglinide; Examples of such drugs include GLP-1 receptor agonists such as semaglutide, exenatide, liraglutide, lixisenatide, dulaglutide, and tirzepatide; glimin-based drugs such as imeglimin hydrochloride; biguanides such as buformin hydrochloride and metformin hydrochloride; thiazolidinediones such as pioglitazone hydrochloride; α-glucosidase inhibitors such as acarbose, voglibose, and miglitol; and SGLT2 inhibitors such as ipragliflozin L-proline, dapagliflozin propylene glycol hydrate, luseogliflozin hydrate, tofogliflozin hydrate, and canagliflozin hydrate.

[0079] Among these, DPP-IV inhibitors are preferred as concomitant drugs with empagliflozin, and among these, linagliptin is more preferred. Specific examples of therapeutic agents for chronic heart failure that can be used in combination include angiotensin-converting enzyme (ACE) inhibitors such as captopril, enalapril (maleate), lisinopril (hydrate), perindopril erbumine, benazepril (hydrochloride), trandolapril, delapril (hydrochloride), temocapril (hydrochloride), imidapril (hydrochloride), and alacepril; candesartan cilexetil, losartan potassium, valsartan, and olmesartan. Angiotensin II receptor blockers (ARBs) such as medoxomil, telmisartan, irbesartan, and azilsartan; angiotensin receptor neprilysin inhibitors (ARNIs) such as sacubitril and valsartan sodium hydrate; beta-blockers such as bisoprolol (fumarate), propranolol (hydrochloride), bufetolol (hydrochloride), carteolol (hydrochloride), metoprolol (tartrate), atenolol, nadolol, nipradilol, celiprolol (hydrochloride), and betaxolol (hydrochloride); alpha-beta-blockers such as carvedilol, labetalol (hydrochloride), arotinolol (hydrochloride), amosulalol (hydrochloride), and bevantolol (hydrochloride); spironolactone, eplerenol Mineralocorticoid receptor antagonists such as esaxerenone, finerenone, etc.; HCN channel blockers such as ivabradine (hydrochloride); sGC stimulators such as vericiguat; diuretics such as trichlormethiazide, triamterene, furosemide, hydrochlorothiazide, azosemide, tolvaptan, acetazolamide, mefruside, indapamide, torasemide; vasodilators such as dipyridamole, hydralazine (hydrochloride), isosorbide dinitrate, trimetazidine (hydrochloride), dilazep (hydrochloride hydrate), trapidil, nicorandil, nitroglycerin, isosorbide mononitrate; cardiac inotropes such as aminophylline (hydrate), digoxin, proxyphylline, methyldigoxin, denopamine, and pimobenda;Antiarrhythmic drugs such as amiodarone (hydrochloride), procainamide (hydrochloride), quinidine (sulfate hydrate), verapamil (hydrochloride), diltiazem (hydrochloride), disopyramide, mexiletine (hydrochloride), aprindine (hydrochloride), disopyramide (phosphate), propafenone (hydrochloride), cibenzoline (succinate), pilsicainide (hydrochloride hydrate), flecainide (acetate), bepridil (hydrochloride hydrate), pirmenol (hydrochloride hydrate), and sotalol (hydrochloride); adenosine triphosphate disodium hydrate, ubidecarenone, and taurine are examples of antiarrhythmic drugs.

[0080] Specific examples of therapeutic agents for chronic kidney disease that can be used in combination include RAS inhibitors (e.g., the above-mentioned ARB inhibitors and the above-mentioned ACE inhibitors), calcium channel blockers (e.g., nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nitrendipine, nilvadipine, barnidipine, felodipine, benidipine, manidipine, azelnidipine, aranidipine, and diltiazem), diuretics (e.g., loop diuretics such as furosemide, bumetanide, and torsemide; thiazide diuretics such as hydrochlorothiazide, trichlormethiazide, and indapamide), sympatholytics (the above-mentioned β-blockers; α-blockers such as urapidil, terazosin, doxazosin, and prazosin), central sympathomimetics (e.g., clonidine, guanabenzyl methylpropional, ... antihypertensive drugs such as dopa, renin inhibitors (e.g., aliskiren); phosphate binders (e.g., calcium carbonate, sevelamer (hydrochloride), lanthanum carbonate, bixalomer, ferric citrate hydrate, sucroferric oxyhydroxide); potassium binders (e.g., calcium polystyrene sulfonate, sodium polystyrene sulfonate, sodium zirconium cyclosilicate hydrate); erythropoietin preparations (e.g., epoetin alfa, epoetin beta, epoetin kappa), steroids and immunosuppressants (e.g., prednisolone, methylprednisolone, cyclophosphamide, mycophenolate mofetil, azathioprine, mizoribine, cyclosporine, tacrolimus, hydroxychloroquine, rituximab, belimumab).

[0081] When empagliflozin and another therapeutic agent are combined into a tablet, the formulation of the present invention may be a regular tablet, an OD tablet, or a multi-layer tablet of two or more layers in which empagliflozin and the other therapeutic agent are combined in separate layers. It may also be a coated tablet. Furthermore, since empagliflozin and the other therapeutic agent can be used in combination simultaneously or sequentially, they do not necessarily need to be contained together in a single unit-form formulation, and may be contained in separate, independent formulations.

[0082] 3.5 Other When the formulation of the present invention is in the form of a tablet such as an uncoated tablet, a coated tablet, or an OD tablet, the surface may be engraved or printed with information such as a product number, the name of the active ingredient, the content of the active ingredient, the dosage form, a product number, a QR code (registered trademark), or a barcode to improve its identifiability. Such engraving or printing may be performed directly on the surface of the tablet, such as an uncoated tablet or a coated tablet. An appropriate printing method can be selected from ink printing methods using, for example, plate-type transfer printing, gravure printing, offset printing, and inkjet printing, and laser printing. The ink used for printing can be selected from edible inks containing dyes and / or pigments, and the ink color may be one color or two or more colors from the viewpoint of identifiability, etc.

[0083] 4. Use and administration method The composition of the present invention or the formulation of the present invention containing the same (composition of the present invention, etc.) is useful as a pharmaceutical. Specifically, the composition of the present invention can be safely administered, for example orally, to humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) for the treatment or prevention of various diseases caused by SGLT2 due to the SGLT2 inhibitory action of the active ingredient, empagliflozin.

[0084] Therefore, the compositions of the present invention can be used to treat, prevent, or delay diabetes or diabetes-related symptoms. Diabetes-related symptoms refer to various pathological symptoms that are associated with, caused by, or result from diabetes. The present invention can preferably be used for the treatment and / or prevention of type 2 diabetes or diabetes-related symptoms. The compositions of the present invention can also be used for chronic heart failure, chronic kidney disease, and the like.

[0085] The dosage of the composition of the present invention varies depending on the subject (age, body weight), route of administration, target disease, symptoms, etc., but the appropriate dosage of empagliflozin is usually within the range of about 5 to about 50 mg per day for an adult, and preferably within the range of about 8 to about 30 mg or about 10 to about 25 mg. Oral administration is preferred.

[0086] The composition of the present invention can be administered once a day or in divided doses multiple times a day, but when administered orally, it is preferably administered once a day, or once a day before or after breakfast.

[0087] When the composition of the present invention contains a diabetic drug other than empagliflozin, the dosage is basically the same as above, and the dosage of the other diabetic drug is appropriately determined according to its prescribed dosage. When the diabetic drug other than empagliflozin is, for example, linagliptin, the dosage of linagliptin is usually within the range of about 1 to about 25 mg per day for an adult, and preferably within the range of about 3 to 6 mg, or 5 mg per day. [Example]

[0088] The present invention will be explained below with reference to examples and test examples, but the present invention is not limited to these examples in any way.

[0089] [Examples 1 to 5] Preparation of empagliflozin solid dispersions by melting method Empagliflozin was mixed with the polymer carrier hydroxypropylmethylcellulose (TC-5E, Shin-Etsu Chemical Co., Ltd.) according to the composition shown in Table 1, and the mixture was placed in a microconical twin-screw compounder (HAAKE MiniCTW, Thermo Fisher Scientific), melt-kneaded at 160°C, extruded, and solidified by naturally cooling to room temperature. The solidified material was pulverized in a pin mill and then classified using a 30M sieve to obtain a powder.

[0090] Differential scanning calorimetry (DSC) was performed on each of the obtained powders. No peaks attributable to empagliflozin crystals were observed in any of the powders. It was confirmed that empagliflozin was in an amorphous state in the polymer carrier and formed a solid dispersion, and that the powder was the composition of the present invention (solid dispersion powder).

[0091] [Table 1]

[0092] [Examples 6 to 10] Preparation of empagliflozin tablets (1) Preparation of uncoated tablets According to the formulations shown in Table 2, each solid dispersion prepared above and the ingredients other than magnesium stearate were mixed using a diffusion mixer. Magnesium stearate was further added as a lubricant, and the mixture was mixed using the diffusion mixer to obtain tablet powders. The obtained tablet powders were compressed using a rotary tablet press to obtain empagliflozin uncoated tablets (the preparation of the present invention).

[0093] (2) Film coating A film (FC) layer was formed with the composition shown in Table 2. Talc was dispersed in a solution obtained by adding and dissolving hydroxypropyl methylcellulose (HPMC) and macrogol 400 in purified water (talc dispersion). Separately, titanium dioxide and yellow ferric oxide or titanium dioxide alone were dispersed in purified water (pigment dispersion). The pigment dispersion was added to the talc dispersion and mixed to obtain a film coating solution.

[0094] Each uncoated tablet was placed in a film coating pan machine, coated with the film coating solution prepared above, and dried to prepare coated tablets (preparation of the present invention).

[0095] [Table 2]

[0096] [Examples 11 to 16] Preparation of empagliflozin solid dispersion and empagliflozin tablets According to the compositions shown in Table 3, empagliflozin solid dispersions, uncoated empagliflozin tablets, and coated empagliflozin tablets were obtained in the same manner as in the above Examples.

[0097] [Table 3]

[0098] [Examples 17 and 18] Preparation of empagliflozin-linagliptin combination tablets (1) Preparation of Empagliflozin Solid Dispersion Empagliflozin solid dispersions of Examples 1 and 5 were prepared in the same manner as described above.

[0099] (2) Preparation of linagliptin granules 5 mg of linagliptin, 25.5 mg of D-mannitol, 15 mg of crystalline cellulose, and 3 mg of carmellose calcium were placed in a fluidized bed granulation dryer, and the mixture was granulated by spraying a granulation liquid prepared by dissolving 1.5 mg of copovidone in purified water. After drying and granulation, a linagliptin granulated powder was obtained.

[0100] (3) Preparation of uncoated tablets The empagliflozin solid dispersion of Example 1 or Example 5, linagliptin granulated powder, and ingredients other than magnesium stearate were mixed using a diffusion mixer according to the composition shown in Table 4. Magnesium stearate was then added as a lubricant, and the mixture was mixed using the diffusion mixer to obtain a tablet powder. The obtained tablet powder was compressed using a rotary tablet press to obtain empagliflozin-linagliptin uncoated tablets (the preparation of the present invention).

[0101] (4) Film coating A film (FC) layer was formed with the composition shown in Table 4. Talc was dispersed in a solution obtained by dissolving polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT®) in purified water (talc dispersion). Separately, titanium dioxide and yellow ferric oxide or ferric oxide were dispersed in purified water (pigment dispersion). The pigment dispersion was added to the talc dispersion and mixed to obtain a film coating solution.

[0102] Each uncoated tablet was placed in a film coating pan machine, coated with the film coating solution obtained above, and dried to prepare coated tablets (preparation of the present invention).

[0103] [Table 4]

[0104] [Examples 19 and 20] Preparation of empagliflozin / linagliptin bilayer tablets (1) Preparation of Empagliflozin Solid Dispersion Empagliflozin solid dispersions of Examples 1 and 5 were prepared in the same manner as described above.

[0105] (2) Preparation of linagliptin granules Linagliptin granulated powder was prepared in the same manner as above.

[0106] (3) Preparation of uncoated tablets The empagliflozin solid dispersion of Example 1 or Example 5 and the ingredients other than magnesium stearate were mixed using a diffusion mixer according to the composition shown in Table 5. Magnesium stearate was further added as a lubricant, and the mixture was mixed using a diffusion mixer to obtain empagliflozin tablet powder. Separately, the linagliptin granulated powder and the ingredients other than magnesium stearate were mixed using a diffusion mixer, and magnesium stearate was further added as a lubricant, and the mixture was mixed using a diffusion mixer to obtain linagliptin tablet powder. The obtained empagliflozin tablet powder and linagliptin tablet powder were compressed using a small rotary tablet press (VIRGO-2L, Kikusui Seisakusho Co., Ltd.) for both bilayer and regular tablets to obtain empagliflozin / linagliptin bilayer tablets (the preparation of the present invention).

[0107] (4) Film coating A film (FC) layer was formed with the composition shown in Table 4. Talc was dispersed in a solution obtained by dissolving polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT®) in purified water (talc dispersion). Separately, titanium dioxide and yellow ferric oxide or ferric oxide were dispersed in purified water (pigment dispersion). The pigment dispersion was added to the talc dispersion and mixed to obtain a film coating solution. Each uncoated tablet was placed in a film coating pan machine, coated with the film coating solution obtained above, and dried to prepare coated tablets (preparation of the present invention).

[0108] [Table 5]

[0109] [Test Example] Examination of maintenance of amorphous (solid dispersion) state Solid dispersions of empagliflozin and TC-5 (registered trademark) E at a mass ratio of 1:2 and 1:5 were prepared by hot melt extrusion using a microconical twin-screw compounder (HAAKE MiniCTW, manufactured by Thermo Fisher Scientific). The solid dispersions were left in the open at 25°C and 75% relative humidity (RH) and at 40°C and 75% relative humidity (RH) for 1 month, after which the amorphous (solid dispersion) state was analyzed by differential scanning calorimetry (DSC) (DSC7020, manufactured by Hitachi High-Tech Science Corporation). The results are shown in Figures 1 and 2. As is clear from the figure, after being left standing for one month, no signals (peaks) derived from empagliflozin were observed in any of the samples, and the amorphous (solid dispersion) state of empagliflozin was maintained. [Industrial Applicability]

[0110] INDUSTRIAL APPLICABILITY The present invention can provide a new pharmaceutical composition containing empagliflozin and is therefore useful in the pharmaceutical industry.

Claims

1. A pharmaceutical composition comprising mainly empagliflozin and a polymer carrier, characterized in that the content ratio of empagliflozin to the polymer carrier is within the range of 1:1 to 1:40 (empagliflozin:polymer carrier) by mass, and the empagliflozin is solid-dispersed in an amorphous state.

2. A pharmaceutical composition comprising mainly empagliflozin and a polymer carrier, wherein the polymer carrier is a water-soluble polymer carrier, the viscosity of which is within the range of 1.5 to 8 mP·s in a 2% by mass aqueous solution at 20°C, and the empagliflozin is solid-dispersed in an amorphous state.

3. 3. The pharmaceutical composition according to claim 2, wherein the content ratio of empagliflozin and the polymer carrier is within the range of 1:1 to 1:40 (empagliflozin:polymer carrier) by mass.

4. 2. The pharmaceutical composition of claim 1, wherein the polymeric carrier is a cellulose derivative, a methacrylic acid copolymer, polyvinyl alcohol, a polyvinyl alcohol copolymer, polyvinylpyrrolidone, a vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, or a polyethylene glycol copolymer.

5. 5. The pharmaceutical composition of claim 4, wherein the polymeric carrier is hydroxypropylmethylcellulose or its acid ester, hydroxypropylcellulose, carboxymethylethylcellulose, or aminoalkylmethacrylate copolymer E.

6. 6. The pharmaceutical composition of claim 5, wherein the hydroxypropyl methylcellulose is type 2910.

7. A solid formulation comprising the pharmaceutical composition according to any one of claims 1 to 6.

8. The solid formulation according to claim 7, wherein the solid formulation is a tablet or an OD tablet, or a coated tablet thereof.

9. The solid formulation according to claim 8, further comprising a therapeutic diabetes drug other than empagliflozin.

10. The pharmaceutical composition or solid formulation according to claim 9, wherein the antidiabetic agent is a DPP-IV inhibitor.

11. The pharmaceutical composition or solid dosage form according to claim 10, wherein the DPP-IV inhibitor is linagliptin or a salt thereof.

12. A method for producing a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising the step of heating, melting, and kneading the empagliflozin and the polymer carrier by a hot melt extrusion method so that the empagliflozin is solid-dispersed in an amorphous state.

13. A method for maintaining an amorphous solid dispersion state of empagliflozin in a pharmaceutical composition mainly comprising empagliflozin and a polymer carrier, the method comprising, in a production process of the pharmaceutical composition, subjecting empagliflozin and the polymer carrier to a heating, melting, and kneading treatment by a hot-melt extrusion method so that empagliflozin is solid-dispersed in an amorphous state.

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