Pharmaceutical composition with maintained amorphous state and method for manufacturing the same

Abstract

To provide a pharmaceutical composition containing a drug in an amorphous state, in which the amorphous state of the drug is maintained.SOLUTION: The present invention provides a pharmaceutical composition wherein a specific stabilizer is contained in the pharmaceutical composition. Further, the present invention provides a pharmaceutical composition in which the stabilizer is contained at a specific ratio in the pharmaceutical composition.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a drug-containing pharmaceutical composition in which the amorphous state of the drug is maintained, and a method for producing the same. The pharmaceutical composition of the present invention can be used in the field of medicine in the form of tablets or the like. This application claims priority based on Japanese Patent Application No. 2023-193099, filed on November 13, 2023, the contents of which are incorporated herein by reference. [Background technology]

[0002] In manufacturing and selling pharmaceuticals, it is necessary to improve the solubility and absorbability into the body of a compound used as an active ingredient of the pharmaceutical, or a pharma- ceutically acceptable salt thereof, or a solvate thereof (hereinafter also referred to as "drug" in this specification). One of the means for improving the solubility of a drug is to convert a crystalline drug into an amorphous state. Due to its high free energy state, it is known that amorphous substances have a relatively high solubility improvement effect compared to other salts and crystalline complexes such as cocrystals. However, due to the high free energy, the physical stability is low, and there is a risk of recrystallization, phase separation, and the associated decrease in solubility. It is also known that the chemical stability is low due to the high molecular mobility. Therefore, methods for maintaining the amorphous state have been studied. A representative method is to make a solid dispersion. The method of making a solid dispersion includes a method of suppressing the recrystallization of the amorphous state by the intermolecular interaction between the compound and the polymer, and a method of supporting the compound on a porous material, thereby supporting the amorphous state by the interaction between the compound supported in the pores and the porous material. A specific example of the former is a pharmaceutical composition containing amorphous teneligliptin hydrobromide and an amorphous state-maintaining polymer such as a cellulose-based polymer, an acrylic polymer, or a vinyl-based polymer having a glass transition temperature of 70° C. or higher (Patent Document 1). A specific example of the latter is a pharmaceutical composition containing amorphous teneligliptin hydrobromide and an amorphous state-maintaining polymer such as a cellulose-based polymer, an acrylic polymer, or a vinyl polymer having a glass transition temperature of 70° C. or higher (Patent Document 2). However, it is known that the above-mentioned method for preparing a solid dispersion has some problems. For example, when a high molecular weight polymer is used, a very large amount of polymer may be required to stably maintain the amorphous state depending on the drug, and attention must be paid to the increase in size of the formulation and the decrease in manufacturability. In addition, examples of methods for preparing a solid dispersion include spray drying, heat kneading melting, melt quenching, solvent distillation, co-grinding, and co-precipitation. In the spray drying method, the powder of the solid dispersion has strong adhesion and cohesion and is very bulky, which can be a major problem in the next manufacturing process. Some of these methods require dissolving in a solvent once, but it is known that water or heat affects the recrystallization and phase separation in the solid dispersion, so dissolving in a solvent or applying heat can be a problem in itself. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent Publication No. 2020-070260 [Patent Document 2] Patent Publication No. 2022-184669 [Non-patent literature]

[0004] [Non-Patent Document 1] Stability test guidelines (Notification of the Director of the New Drugs Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, to the Directors of Health Supervisory Departments of each prefecture, No. 30, April 21, 1994), partially revised by No. 422, Yakushin No. 425, May 28, 1997, and No. 666, April 8, 1999. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a drug-containing pharmaceutical composition that contains a drug in an amorphous state and maintains said state. One object of the present invention is to provide a drug-containing pharmaceutical composition containing an amorphous drug, which maintains said state even when produced or stored under environments of high temperature or high humidity, or both. An object of the present invention is to provide a method for producing a drug-containing pharmaceutical composition in which an amorphous drug is maintained in said state. One object of the present invention is to provide a method for conveniently producing a pharmaceutical composition containing a drug in an amorphous state, in which said state is maintained. One object of the present invention is to provide a method for maintaining an amorphous state in a pharmaceutical composition containing a drug in said state.

[0006] One object of the present invention is to provide a drug-containing pharmaceutical composition that maintains an amorphous state in a pharmaceutical composition containing a drug that is difficult to maintain in an amorphous state. One object of the present invention is to provide a drug-containing pharmaceutical composition that maintains an amorphous state even when manufactured or stored under an environment of high temperature or high humidity, or both, in which the amorphous state is hardly maintained in the pharmaceutical composition. One object of the present invention is to provide a method for producing a drug-containing pharmaceutical composition in which an amorphous state is maintained in a pharmaceutical composition containing a drug in an amorphous state that is difficult to maintain. One object of the present invention is to provide a method for conveniently producing a pharmaceutical composition containing a drug in an amorphous state that is difficult to maintain in an amorphous state. One object of the present invention is to provide a method for maintaining an amorphous state in a pharmaceutical composition containing an amorphous drug that is difficult to maintain in said state.

[0007] One object of the present invention is to provide a pharmaceutical composition comprising teneligliptin in an amorphous state or a pharma- ceutically acceptable salt thereof, or a solvate thereof, in which said state is maintained. One object of the present invention is to provide a pharmaceutical composition comprising teneligliptin or a pharma- ceutical acceptable salt thereof, or a solvate thereof in an amorphous state, which maintains said state even when produced or stored under an environment of high temperature or high humidity, or both. One object of the present invention is to provide a method for producing a pharmaceutical composition comprising teneligliptin or a pharma- ceutical acceptable salt thereof, or a solvate thereof, in an amorphous state, wherein said state is maintained. One object of the present invention is to provide a method for conveniently producing a pharmaceutical composition containing teneligliptin in an amorphous state or a pharma- ceutical acceptable salt thereof, or a solvate thereof, in which said state is maintained. One object of the present invention is to provide a method for maintaining an amorphous state in a pharmaceutical composition containing teneligliptin or a pharma- ceutically acceptable salt thereof, or a solvate thereof. [Means for solving the problem]

[0008] In order to solve the above problems, the present inventors focused on a stabilizer that maintains the amorphous state of a drug. As a result of intensive research, the above problems were solved by including a specific stabilizer in a pharmaceutical composition. Furthermore, the above problems were further solved by including the stabilizer in a specific ratio in the pharmaceutical composition. Therefore, the present invention provides the following inventions.

[0009] (1) A pharmaceutical composition comprising a compound used as an active ingredient of a pharmaceutical in an amorphous state, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, and a stabilizer, A pharmaceutical composition wherein the stabilizing agent is magnesium oxide. (2) The pharmaceutical composition according to (1), wherein the amorphous state of the compound is maintained. (3) The pharmaceutical composition according to (1), wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored under high temperature or high humidity conditions. (4) The pharmaceutical composition according to (1), wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored for 7 days under temperature and humidity conditions of 40°C and 75% RH. (5) The pharmaceutical composition according to (1), wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored for 7 days under temperature and humidity conditions of 40°C and 75% RH in the open. (6) The pharmaceutical composition according to (1), characterized in that the ratio of the content of the compound or its pharma- ceutical acceptable salt, or its solvate to the content of the stabilizer in the pharmaceutical composition is 1:1 / the content of the compound or its pharma-ceutical acceptable salt, or its solvate, and the content of the stabilizer is 0.25 or more. (7) The pharmaceutical composition according to (1), characterized in that the content of the stabilizer in the pharmaceutical composition is 1% by mass to 50% by mass. (8) The pharmaceutical composition according to (1), characterized in that the pharmaceutical composition is a solid formulation. (9) The pharmaceutical composition according to (8), wherein the solid preparation is a granule, a tablet or a capsule. (10) The pharmaceutical composition according to any one of (1) to (9), wherein the compound is teneligliptin. (11) A pharmaceutical composition comprising an amorphous compound and a stabilizer, The method for producing a pharmaceutical composition, wherein the stabilizer is magnesium oxide. (12) A method for maintaining an amorphous state in a pharmaceutical composition containing a compound used as an active ingredient of a pharmaceutical product, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, comprising: The method further comprises comprising comprising adding a stabilizer to the pharmaceutical composition. (13) The method according to (12), wherein the stabilizer is magnesium oxide. Effect of the Invention

[0010] Stability tests (severe stress tests) are required to set the expiration date of pharmaceutical products, and there are various methods for the tests. If a stability test is selected and performed according to the purpose, and the amorphous state of a drug can be maintained in a pharmaceutical composition containing an amorphous drug, the reliability of the stability of the pharmaceutical composition is said to be high. Furthermore, one of the most severe tests is the 40°C 75% RH open condition test (Non-Patent Document 1, also referred to as the "severe stress open test" in this specification). It goes without saying that if the amorphous state of a drug can be maintained in a pharmaceutical composition containing an amorphous drug even after performing this test, the reliability of the stability of the pharmaceutical composition is very high. Furthermore, the pharmaceutical composition of the present invention can be produced by simply incorporating a stabilizer into the pharmaceutical composition, and there is no need to take any special steps when adding the stabilizer or to use a special production method taking the stabilizer into consideration, and a simple production method can be selected. Therefore, the inventors of the present application conducted extensive studies and found that even when the above-mentioned stability tests, particularly the severe open test, were conducted on the pharmaceutical composition of the present invention produced by a simple production method, it was possible to maintain the amorphous state of even a drug that is difficult or cannot maintain the amorphous state under high temperature and high humidity conditions by adding a stabilizer, thereby solving the above-mentioned problem. [Brief description of the drawings]

[0011] [Figure 1] The results of powder X-ray diffraction measurement of the pharmaceutical composition of the present invention in Example 1 after a stability test at 40°C, 75% RH, in the open for 7 days and a stability test at 25°C, 75% RH, in the open for 7 days, the pharmaceutical composition of the present invention in Example 1 before the stability test, and the pharmaceutical composition of the present invention in Example 1 excluding the drug. [Diagram 2]The results of powder X-ray diffraction measurement of the pharmaceutical composition of the present invention in Example 2 after a stability test at 40°C, 75% RH, in the open for 7 days and a stability test at 25°C, 75% RH, in the open for 7 days, the pharmaceutical composition of the present invention in Example 2 before the stability test, and the pharmaceutical composition of the present invention in Example 1 except for the drug. [Diagram 3] The results of powder X-ray diffraction measurement of the pharmaceutical composition of the present invention in Example 3 after a stability test at 40°C, 75% RH, in the open for 7 days and a stability test at 25°C, 75% RH, in the open for 7 days, the pharmaceutical composition of the present invention in Example 3 before the stability test, and the pharmaceutical composition of the present invention in Example 1 except for the drug. [Figure 4] The results of powder X-ray diffraction measurement of the pharmaceutical composition of Comparative Example 1 (simply referred to as Comparative Example in the drawings) after a stability test at 40°C, 75% RH, in the open, for 7 days and a stability test at 25°C, 75% RH, in the open, for 7 days, the pharmaceutical composition of Comparative Example 1 before the stability test, and the pharmaceutical composition of the present invention of Example 1, except that the drug has been removed. [Diagram 5] The results of measuring only the amorphous teneligliptin hydrobromide used in Examples 1 to 6 and Comparative Example 1 by powder X-ray diffraction measurement method before being used in each of the Examples and Comparative Examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] A preferred embodiment of the pharmaceutical composition of the present invention and a method for producing the same are described below, but these are merely examples and are not intended to be limiting.

[0013] The term "drugs that are difficult or cannot maintain an amorphous state under high temperature or high humidity conditions" as used in the present invention refers to drugs that are relatively easily converted to a crystalline state by dissolving in a solvent such as water or by applying heat. Examples of such drugs include the following drugs: teneligliptin hydrobromide, tolbutamide, flurbiprofen, nifedipine, etc.

[0014] The "pharmaceutical composition" used in the present invention includes solid preparations. Examples of solid preparations include granules, fine granules, tablets, and capsules. Specifically, examples include granules made of a composition containing a drug, granules made of a composition containing a drug and a stabilizer, mixed powder containing a drug and a stabilizer, and tablets or orally disintegrating tablets (referred to as "tablets, etc." in this specification) or capsules containing the granules or the mixed powder and a stabilizer.

[0015] The drug may be one type or two or more types. In the case of two or more types of drugs, at least one of the drugs may be a drug that cannot maintain an amorphous state.

[0016] The content ratio of the stabilizer to the drug that cannot maintain an amorphous state under high temperature or high humidity conditions in the pharmaceutical composition of the present invention may be 0.25 or more, preferably 0.5 to 10, more preferably 0.5 to 5, and even more preferably 0.5 to 2, when the content of the drug is taken as 1. The content may be calculated, for example, in g equivalents.

[0017] In the present invention, the drug and stabilizer may both be contained in the pharmaceutical composition. For example, when the pharmaceutical composition of the present invention is in the form of granules, the drug and stabilizer may both be present within the particles (granulated material), in other words, within the granules formed by granulating the drug-containing pharmaceutical composition.

[0018] When the pharmaceutical composition of the present invention is in the form of granules, it may be triturated. The excipient used for trituration may be a granulated product obtained by the granulation method as in the case of the granules, or may not be a granulated product.

[0019] The pharmaceutical composition of the present invention may be one obtained by a known method, for example, a granulated product obtained by granulation, for example, a conventional granulation method such as agitation granulation, extrusion granulation, fluidized bed granulation, dry granulation, etc.

[0020] In the present invention, the drug and stabilizer may both be contained in the pharmaceutical composition, and for example, when the pharmaceutical composition is in the form of a tablet, the composition may be a mixed powder obtained by mixing a drug and an additive containing at least a stabilizer, a mixed powder consisting of only granules containing a drug and at least a stabilizer, a mixed powder obtained by mixing the granules and an additive (later powder) which may contain a stabilizer, or a tablet containing a mixed powder of drug-containing granules (granulated product) not containing a stabilizer and an additive (later powder) containing at least a stabilizer. In this specification, the additive added to the granules (granulated product) is referred to as "later powder".

[0021] The tablets etc. in the present invention can be produced by direct compression, granule compression (wet or dry), etc., and may be so-called ordinary tablets such as film-coated tablets and plain tablets, or orally disintegrating tablets.

[0022] The amount (proportion) of the additives including the powder in the tablet or the like of the present invention is preferably 10 to 95 mass% of the uncoated tablet of the tablet or the like, more preferably 20 to 90 mass%, even more preferably 30 to 85 mass%, and particularly preferably 50 to 80 mass%.

[0023] Additives that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into the granules, trituration or powder include excipients, disintegrants, binders, lubricants, flow agents, sweeteners, flavors, stabilizers, plasticizers, colorants, flavorings, etc. These additives are added in appropriate amounts, either alone or in combination of two or more.

[0024] The stabilizer that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into the granules, trituration or powder, can include magnesium oxide or hydrated silicon dioxide, and the preferred stabilizer is magnesium oxide. Either stabilizer can be used alone, or both can be used in combination. In one embodiment, the blending amount of the stabilizer in the granule is preferably 1 to 50% by mass, more preferably 5 to 40% by mass, even more preferably 7 to 30% by mass, and suitably 10 to 20% by mass. In one embodiment, the blending amount of the stabilizer in the powder is preferably 1 to 50% by mass, more preferably 10 to 30% by mass. In one embodiment, the blending amount of the stabilizer in the uncoated tablet such as a tablet is preferably 1 to 50% by mass, more preferably 7 to 30% by mass, and even more preferably 10 to 20% by mass.

[0025] Examples of excipients that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into the granules, trituration or powder include sugar alcohols such as D-mannitol, erythritol, D-sorbitol, xylitol, maltitol, etc., lactose, and crystalline cellulose. One type selected from the above can be used alone, or two or more types can be mixed. Among the above excipients, a preferred excipient is D-mannitol. In one embodiment, the amount of the excipient in the granule is preferably 15 to 70% by mass, more preferably 25 to 60% by mass, and even more preferably 30 to 55% by mass. In one embodiment, the amount of the excipient in the final powder is preferably 15 to 80% by mass, and more preferably 25 to 70% by mass. In one embodiment, the amount of the excipient in the uncoated tablet such as a tablet is preferably 15 to 65% by mass, more preferably 25 to 60% by mass, and even more preferably 30 to 55% by mass.

[0026] The particle size of the excipient (D 50 ) is preferably 80 μm or less, more preferably 50 μm or less, further preferably 30 μm or less, and optimally 10 to 25 μm. In addition, in the present invention, 50The (average particle size) is the particle size at which the cumulative total from the smallest particles is 50% on a particle size distribution curve measured using a laser diffraction / scattering particle size distribution analyzer (e.g., Microtrac MT3200II particle size distribution analyzer manufactured by Microtrac-Bell Corporation).

[0027] Disintegrants that can be mixed with the drug-containing pharmaceutical composition of the present invention, or with the granules, triturates or powders include, for example, crospovidone, croscarmellose sodium, carboxymethylcellulose (carmellose), carboxymethylcellulose calcium (carmellose calcium), carboxymethylcellulose sodium (carmellose sodium), low-substituted hydroxypropylcellulose, carboxymethylstarch sodium, hydroxypropylstarch, rice starch, wheat starch, corn starch, potato starch, partially pregelatinized starch, crospovidone copolymer, etc. One selected from the above may be used alone, or two or more may be used in combination. Among the above disintegrants, a preferred disintegrant is low-substituted hydroxypropyl cellulose. Specific examples of the disintegrant include low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), and the like, preferably LH-21 or NBD-021 (both manufactured by Shin-Etsu Chemical Co., Ltd.), in particular NBD-021 (manufactured by Shin-Etsu Chemical Co., Ltd.). In one embodiment, the blending amount of the disintegrant in the granule is preferably 2 to 10% by mass, more preferably 2 to 8% by mass. In one embodiment, the blending amount of the disintegrant in the powder is preferably 10 to 80% by mass, more preferably 20 to 60% by mass. In one embodiment, the blending amount of the disintegrant in the uncoated tablet such as a tablet is preferably 4 to 20% by mass, more preferably 6 to 18% by mass.

[0028] Fluidizers that can be mixed with the drug-containing pharmaceutical composition of the present invention, or with granules, triturates or powders, include stearic acid, metal salts of stearic acid such as magnesium stearate and calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid esters, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, fumed silica, etc. One type selected from the above may be used alone, or two or more types may be used in combination. The fluidizing agent is preferably magnesium aluminometasilicate, fumed silica, light anhydrous silicic acid, or talc, and more preferably light anhydrous silicic acid. In one embodiment, the blending amount of the fluidizer in a tablet or the like is preferably 0.1 to 10.0% by mass, more preferably 0.1 to 5.0% by mass, and even more preferably 0.1 to 3.0% by mass of the uncoated tablet.

[0029] Examples of binders that can be mixed with the drug-containing pharmaceutical composition of the present invention, or with the granules, triturates, or powders include sugars such as sucrose, glucose, lactose, and fructose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol, water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, gluconan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic, celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methyl cellulose, starches such as pregelatinized starch and starch paste, synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol, and binders such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate. One selected from the above may be used alone, or two or more may be mixed together. The binder is preferably methylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, or mannitol, and more preferably methylcellulose. These may be used alone or in combination of two or more kinds.

[0030] Lubricants that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into granules, triturates or powders, include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hardened oils, glycerin fatty acid esters, talc, etc. One type selected from the above may be used alone, or two or more types may be used in combination. The lubricant is preferably sodium stearyl fumarate, magnesium stearate, or calcium stearate, and more preferably sodium stearyl fumarate.

[0031] Examples of flavoring agents that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into the granules, trituration or powder include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

[0032] Flavors that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into granules, triturates, or powders include flavors of orange, vanilla, strawberry, yogurt, menthol, oils such as fennel oil, cinnamon oil, spruce oil, and peppermint oil, and flavors of green tea powder, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

[0033] Colorants that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into the granules, trituration or powder include food dyes such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc., as well as colorants such as copper chlorophyll sodium, titanium oxide, riboflavin, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

[0034] Sweeteners that can be mixed into the drug-containing pharmaceutical composition of the present invention, or into granules, triturates or powders include sugar alcohols, aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, amacha powder, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

[0035] The "coating agent" used in the granules or tablets containing the drug-containing pharmaceutical composition of the present invention includes a coating base, a lubricant, a disintegrant, a plasticizer, a colorant, etc. These additives are added in appropriate amounts, either alone or in combination of two or more. Note that the "coating liquid" in this specification refers to a liquid prepared by dissolving or dispersing the above-mentioned "coating agent" in purified water.

[0036] (1) Coating base The "coating base" used in the coating agent of the present invention is not particularly limited, and examples thereof include enteric cellulose derivatives such as methylcellulose, talc, cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate, methacrylic acid copolymer LD (e.g., trade name: Eudragit L30D-55, manufactured by Evonik Degussa Japan Co., Ltd.; trade names: Polyquid PA-30 and Polyquid PA-30S, manufactured by Sanyo Chemical Industries, Ltd.; and trade name: Kollicoat MAE30DP, manufactured by BASF), methacrylic acid copolymer L (e.g., trade name: Eudragit L, manufactured by Evonik Degussa Japan Co., Ltd.), methacrylic acid copolymer S (e.g., trade names: Eudragit S, Eudragit S100, and Eudragit FS30D, manufactured by Evonik Degussa Japan Co., Ltd.), and the like. Examples of such enteric acrylic copolymers include those manufactured by Eppendorf Japan Co., Ltd. Among the coating bases, preferred coating bases include methylcellulose and talc. The above coating bases may be used alone or in combination of two or more.

[0037] (2) Disintegrant Examples of disintegrants used in the coating agent of the present invention include starches such as carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, carboxymethylstarch sodium, corn starch, partially pregelatinized starch, potato starch, rice starch, etc., carboxymethylcellulose (carmellose), carboxymethylcellulose sodium (carmellose sodium), low-substituted hydroxypropylcellulose, crospovidone, etc., and one or more of these may be used in combination.

[0038] (3) Lubricants Examples of lubricants used in the coating agent of the present invention include talc, titanium oxide, stearic acid or its metal salts, sucrose fatty acid esters, sodium stearyl fumarate, hardened oils, etc., and these can be used alone or in combination of two or more.

[0039] (4) Plasticizers Examples of plasticizers that can be used in the coating agent of the present invention include those listed in official compendia such as the Japanese Pharmacopoeia and Pharmaceutical Additives Standards, such as triethyl citrate, triacetin, dibutyl sebacate, acetylated monoglyceride, propylene glycol, polysorbate 80, polyethylene glycol, and sodium lauryl sulfate. The plasticizer is preferably triethyl citrate.

[0040] (5) Coloring agent Examples of colorants used in the coating agent of the present invention include food dyes such as ferric oxide, yellow ferric oxide, black ferric oxide, Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc., sodium copper chlorophyll, titanium oxide, riboflavin, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

[0041] Furthermore, the coating agent may contain a pH adjuster and a flavoring agent, fragrance, etc. that can be mixed with the drug-containing pharmaceutical composition or trituration described above.

[0042] In addition, one or more other polymers may be mixed into the coating agent as long as the effect of the present invention is not impaired. Examples of such polymers include water-soluble polymers, water-insoluble polymers, gastrosoluble polymers, and thermoplastic substances (wax-like substances).

[0043] The blending amount (proportion) of the granules containing the drug-containing pharmaceutical composition of the present invention is preferably 30 to 98 mass %, more preferably 40 to 95 mass %, of the uncoated tablet such as a tablet.

[0044] The tablets of the present invention may be formed into, for example, a round, elliptical, spherical, polygonal plate, rod, or doughnut shape, as well as a layered tablet, a dry-coated tablet, or the like. If necessary, they may be coated with a coating agent. They may also be printed with marks or letters to improve their identifiability, and may be provided with a dividing line for division.

[0045] The size of the tablet or the like is preferably small, preferably with a diameter of about 5 to 12 mm and a thickness of about 2 to 7 mm.

[0046] The mass of a tablet or the like is preferably about 50 to 600 mg.

[0047] The hardness of the tablets etc. is not particularly limited, but a certain degree of hardness is necessary to prevent breakage of the tablets etc. during transportation etc. In the present invention, the hardness is preferably 30 to 150N, more preferably 40 to 130N, further preferably 50 to 120N, and most preferably 50 to 100N.

[0048] The hardness of tablets, etc. after carrying out a stability test, for example, a severe open test (test conditions: 40°C, 75% RH, after leaving under open conditions for 7 days or 1 month) is not particularly limited, but a certain degree of hardness is necessary to prevent breakage of the tablets, etc. during transportation, etc. In the present invention, the hardness is preferably 20N or more, more preferably 30N or more, even more preferably 40N or more, and suitably 50N or more.

[0049] The dissolution rate (after 30 minutes) is not particularly limited, but is preferably 80% or more, more preferably 85% or more, further preferably 88% or more, and most preferably 90% or more.

[0050] In the present invention, "amorphous state is maintained" means that the drug in the pharmaceutical composition is not substantially changed to a crystalline form after a stability test is performed. Here, examples of the stability test include long-term tests (25°C, 60% RH, any packaging form (e.g., PTP sheet) for any period (e.g., 1 year, 2 years, or 3 years)), accelerated tests (40°C, 75% RH, any packaging form (e.g., PTP sheet) for any period (e.g., 6 months)), and severe open tests (test conditions: 40°C, 75% RH, after being left under open conditions for any period (e.g., 7 days or 1 month)), and preferably means that the drug in the pharmaceutical composition is not substantially changed to a crystalline form even in the severe open test. In addition, the above-mentioned "not substantially changed to a crystalline form" means that the amorphous state is maintained to such an extent that it does not interfere with maintaining the solubility as a pharmaceutical product. More specifically, although solubility may differ depending on the drug, as an indicator, it refers to a state in which, when the drug in a drug-containing pharmaceutical composition is measured by powder X-ray diffraction measurement, no crystalline peak is observed or the presence of substantially no crystalline peak is observed, or a state in which, calculated from the area ratio of the peaks, the amorphous state is 60% or more, preferably 80% or more, more preferably 90% or more, even more preferably 95% or more, and suitably 98% or more.

[0051] In the present invention, "high temperature" refers to the temperature in the environment in which the drug-containing pharmaceutical composition is placed during stability testing, and means 40°C or higher or 60°C or higher, preferably 40°C or higher. In the present invention, "high humidity" refers to the humidity in the environment in which the drug-containing pharmaceutical composition is placed during stability testing, and means 75% RH or higher. The "solvate" of the "compound, or a pharma- ceutically acceptable salt thereof, or a solvate thereof" in the present invention means a pharma- ceutical acceptable solvate of the compound or a salt thereof, including a hydrate.

[0052] (Production example) The production method of the present invention can be carried out, for example, by the following steps. (Step 1: Preparation of drug-containing granules) The drug, stabilizer, excipient, disintegrant, and fluidizer are mixed in a fluid bed granulator, and then an aqueous solution containing a binder is sprayed onto the mixture to prepare granules. (Step 2: Preparation of mixed powder for tableting) A flow agent and a disintegrant are added to the granules obtained in step 1, and the mixture is mixed in a diffusion mixer to prepare a mixed powder for tableting. (Step 3: Preparation of plain tablets) A lubricant is further added and mixed into the powder mixture for tableting obtained in step 2. The resulting mixture is tableted using a rotary tableting machine to prepare uncoated tablets. (Step 4: Preparation of coating liquid) Prepare a coating solution by dissolving and dispersing the coating base, plasticizer, and colorant in purified water. (Step 5: Preparation of film-coated tablets) The plain tablets prepared in step 3 are coated with the coating solution prepared in step 4 to prepare film-coated tablets.

[0053] The present invention will be described in more detail below by way of examples. However, these examples are merely examples of the present invention and the present invention is not limited to the following examples.

[0054] Example 1 Preparation of tablets (plain tablets) Step 1 (Preparation of granules of drug-containing pharmaceutical composition) (Process 1-1: Granulation drying process) 118 g of amorphous teneligliptin hydrobromide, 210 g of D-mannitol (Granutol F, manufactured by Freund Corporation), 60 g of magnesium oxide (MOCH, manufactured by Tomita Pharmaceutical Co., Ltd.), 20 g of talc (Crown Talc, manufactured by Matsumura Sangyo Co., Ltd.), and 20 g of low-substituted hydroxypropylcellulose (NBD-021, manufactured by Shin-Etsu Chemical Co., Ltd.) were placed in a fluidized bed granulation dryer (Model: MP-01, manufactured by Powrex Corporation), granulated by spraying the granulation liquid, and then dried. The granulation liquid was prepared by dissolving 12 g of methylcellulose (Metolose SM-4, manufactured by Shin-Etsu Chemical Co., Ltd.) in 288 g of purified water. (Process 1-2: Sizing process) The granules produced in step 1-1 are sieved through a No. 30 sieve.

[0055] Step 2 (Preparation of mixed powder for tableting) The granules obtained in step 1 are mixed with 9.6 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) and 20 g of low-substituted hydroxypropyl cellulose (NBD-021, manufactured by Shin-Etsu Chemical Co., Ltd.) in a plastic bag for 2 minutes to prepare a mixed powder for tableting. Next, 16 g of sodium stearyl fumarate (PRUV, manufactured by JRS Co., Ltd.) is added and mixed in a plastic bag for 30 seconds to prepare a mixed powder for tableting.

[0056] Step 3 (Preparation of plain tablets) The tableting powder mixture prepared in step 2 was compressed into uncoated tablets using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., model: VELA-5) to give an average tablet weight of 121.4 mg and a hardness of 50 N or more.

[0057] Example 2 Preparation of tablets (plain tablets) Tablets (plain tablets) were prepared in the same manner as in Example 1, except that in step 1-1 of Example 1, the amount of teneligliptin was changed to 40 g, the amount of magnesium oxide to 10 g, and the amount of D-mannitol to 340.4 g were changed. Example 3 Preparation of tablets (plain tablets) Tablets (plain tablets) were prepared in the same manner as in Example 1, except that in step 1-1 of Example 1, the amount of teneligliptin was changed to 40 g, the amount of magnesium oxide to 200 g, and the amount of D-mannitol to 150.4 g were changed.

[0058] Comparative Example 1 Preparation of tablets (plain tablets) Tablets (plain tablets) were prepared in the same manner as in Example 1, except that in step 1-1 of Example 1, the amount of magnesium oxide was changed to 0 g and the amount of D-mannitol was changed to 270 g. Control Example Preparation of mixed powder The additives used in Example 1 were placed in a vinyl bag and mixed for 2 minutes to prepare a mixed powder for tableting.

[0059] The formulations per tablet of Examples 1 to 3 and Comparative Example 1, and the mixed powder amount of the control example are shown in Table 1. [Table 1] (Unit: g)

[0060] Test Example 1 Stability test (maintenance of amorphous state) For the tablets of Examples 1 to 3 and Comparative Example 1, a stability test was carried out under severe open conditions. (Test conditions) According to the method of Non-Patent Document 1, a severe open test was carried out. (Severe Open Test) 1) Test method 1-1) Test method 1 The specimens (plain tablets of Examples 1 to 3 and Comparative Example 1) were not packaged, i.e., naked, and were stored in a thermo-hygrostat set at a temperature of 40° C. and a humidity of 75% RH for 7 days. 1-2) Test method 2 The specimens (plain tablets of Examples 1 to 3 and Comparative Example 1) were not packaged, i.e., in a naked state, and were stored in a thermo-hygrostat set at a temperature of 25° C. and a humidity of 75% RH for 7 days. 2) Evaluation The samples after storage for 7 days were subjected to powder X-ray diffraction measurement to evaluate whether or not the amorphous state was maintained based on the presence or absence of crystalline peaks. Specifically, the peaks derived from the amorphous teneligliptin hydrobromide of the sample are known to be at 2θ=5.5°±0.2°, 13.4°±0.2°, and 14.4°±0.2° (Patent No. 4208938), and the evaluation was performed based on whether or not the peaks were observed. The powder X-ray diffraction measurement method was performed in accordance with the 18th revised edition of the Japanese Pharmacopoeia. The measurement was performed using a powder X-ray diffractometer Bruker D2 PHASER (manufactured by Bruker) under the conditions of Cu-Ka radiation, tube voltage 30 kV, tube current 10 mA, measurement range: 2θ = 3.0 to 30.0°, scan speed: 0.3 sec / step, and step size: 0.02°. (Test Results) The test results are shown in Figures 1 to 4. As a result of comparing with the crystal peaks of the control example, i.e., the additives alone not containing the drug amorphous teneligliptin hydrobromide, the plain tablets of Examples 1 to 3 in which magnesium oxide was added to granules containing the drug amorphous teneligliptin hydrobromide, no crystal-derived peaks were observed in either test method 1 or 2. In addition, in Examples 1 to 3, the ratios of amorphous teneligliptin hydrobromide (the drug) to magnesium oxide were 1:0.5, 1:0.25, and 1:5, respectively, but no peaks derived from crystals were observed at any of these composition ratios. On the other hand, in the comparative example in which the uncoated tablet containing the amorphous teneligliptin hydrobromide drug did not contain magnesium oxide, peaks derived from crystals were observed in both test methods 1 and 2. Thus, the pharmaceutical composition of the present invention successfully maintained the amorphous state of the drug in the pharmaceutical composition. FIG. 5 shows the results of powder X-ray diffraction measurement of only the amorphous teneligliptin hydrobromide used in Examples 1 to 6 and Comparative Example 1 before use in each of the Examples and Comparative Examples.

[0061] Example 4 Preparation of mixed powder 0.3 g of amorphous teneligliptin hydrobromide and 0.15 g of magnesium oxide (MOCH, manufactured by Tomita Pharmaceutical Co., Ltd.) were placed in a plastic bag and mixed by shaking for 2 minutes to prepare a mixed powder.

[0062] Example 5 Preparation of mixed powder A mixed powder was prepared in the same manner as in Example 4, except that the amount of magnesium oxide in Example 4 was changed to 0.6 g.

[0063] Example 6 Preparation of mixed powder A mixed powder was prepared in the same manner as in Example 4, except that the amount of magnesium oxide in Example 4 was changed to 1.5 g.

[0064] Test Example 2 Stability test (maintenance of amorphous state) The mixed powders of Examples 4 to 6 were subjected to a stability test under severe open conditions. (Test conditions) According to the method of Non-Patent Document 1, a severe open test was carried out. (Severe Open Test) 1) Test method The evaluation was performed in the same manner as in the above-mentioned Test Method 1. Specifically, the specimens (mixed powders of Examples 4 to 6) were not packaged, that is, the specimens were in a naked state, and these specimens were stored in a thermo-hygrostat set at a temperature of 40°C and a humidity of 75% RH for 7 days. 2) Evaluation The evaluation was carried out in the same manner as in Test Example 1. (Test Results) The test results are shown in Table 2. Even in the case of a mixed powder consisting of only amorphous teneligliptin hydrobromide (the drug) and magnesium oxide, no peaks derived from crystals were observed (not shown). In addition, in Examples 4 to 6, the ratios of amorphous teneligliptin hydrobromide (the drug) to magnesium oxide were 1:0.5, 1:2, and 1:5, respectively, but no peaks derived from crystals were observed at any of these composition ratios. Thus, the pharmaceutical composition of the present invention successfully maintained the amorphous state of the drug in the pharmaceutical composition. [Table 2] [Industrial Applicability]

[0065] Although the present invention has been described using teneligliptin hydrobromide as an example, the present invention can provide a drug-containing pharmaceutical composition that can maintain the amorphous state of the drug in the pharmaceutical composition even under high temperature and high humidity conditions.

Claims

1. A pharmaceutical composition comprising a compound used as an active ingredient of a pharmaceutical in an amorphous state, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, and a stabilizer, A pharmaceutical composition wherein the stabilizing agent is magnesium oxide.

2. The pharmaceutical composition of claim 1 , wherein the amorphous state of the compound is maintained.

3. 2. The pharmaceutical composition of claim 1, wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored under high temperature or high humidity conditions.

4. 2. The pharmaceutical composition according to claim 1, wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored for 7 days under temperature and humidity conditions of 40°C and 75% RH.

5. 2. The pharmaceutical composition according to claim 1, wherein the amorphous state of the compound is maintained even when the pharmaceutical composition is stored for 7 days under temperature and humidity conditions of 40° C. and 75% RH in the open.

6. The pharmaceutical composition according to claim 1, characterized in that the content ratio of the compound or its pharma- ceutical acceptable salt, or its solvate to the stabilizer in the pharmaceutical composition is 1:1 / the content of the compound or its pharma- ceutical acceptable salt, or its solvate, and the content of the stabilizer is 0.25 or more.

7. The pharmaceutical composition according to claim 1 , wherein the content of the stabilizer in the pharmaceutical composition is 1% by mass to 50% by mass.

8. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a solid formulation.

9. The pharmaceutical composition according to claim 8, wherein the solid formulation is a granule or a tablet.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the compound is teneligliptin.

11. 1. A pharmaceutical composition comprising a compound in an amorphous state and a stabilizer, The method for producing a pharmaceutical composition, wherein the stabilizer is magnesium oxide.

12. A method for maintaining an amorphous state in a pharmaceutical composition containing a compound used as an active ingredient of a pharmaceutical product in an amorphous state, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, comprising the steps of: The method according to claim 1, further comprising adding a stabilizer to the pharmaceutical composition.

13. 13. The method of claim 12, wherein the stabilizing agent is magnesium oxide.

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