Pharmaceutical composition containing alogliptin and its use

Abstract

The objectives are to provide a pharmaceutical composition in which the generation of analogues of alogliptin or a pharmaceutically acceptable salt thereof and changes in surface color due to light are suppressed, and a method for producing the same; and to provide a stabilization method for a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof in which the generation of analogues and changes in surface color due to light are suppressed. [Solution] The above problem is solved by providing a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient is included in such a way that it does not come into contact with macrogol 6000.

Description

[Technical Field] 【0001】 This invention relates to a pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof. This invention relates to a method for producing a pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof. This invention relates to a method for stabilizing a pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof. [Background technology] 【0002】 Alogliptin is a compound represented by the following formula (I), and its chemical name is 2-({6-[(3R)-3-aminopiperidine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl}methyl)benzonitrile. Alogliptin acts as a dipeptidyl peptidase IV (DPP-IV) inhibitor and is used to treat type 2 diabetes. For example, Patent Document 1 describes the manufacture of film-coated (FC) tablets containing alogliptin or a pharmaceutically acceptable salt thereof. 【0003】 [ka] [Prior art documents] [Patent Documents] 【0004】 [Patent Document 1] Special Publication No. 2018-517739 [Overview of the Initiative] [Problems that the invention aims to solve] 【0005】 The present inventors, while investigating FC formulations of solid dosage forms containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, coated the solid dosage form with a coating solution containing macrogol 6000 and a coating agent, expecting to suppress changes in the color tone of the dosage form surface due to light. However, they found that the resulting pharmaceutical composition had the problem of an increase in analogues of the active ingredient. Therefore, the present invention aims to provide a pharmaceutical composition in which the generation of analogues of alogliptin or a pharmaceutically acceptable salt thereof and changes in the color tone of the surface due to light are suppressed, as well as a method for producing the same. Furthermore, the present invention aims to provide a stabilization method for a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof that suppresses the generation of analogues and changes in the color tone of the surface due to light. [Means for solving the problem] 【0006】 The present invention provides a pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient in the pharmaceutical composition does not come into contact with macrogol 6000. 【0007】 The present invention provides a method for producing a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient is contained in such a way that it does not come into contact with macrogol 6000. 【0008】 The present invention provides a method for stabilizing a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, comprising incorporating the active ingredient so as not to come into contact with macrogol 6000. [Effects of the Invention] 【0009】 According to the present invention, it is possible to provide a pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof, in which an increase in related substances and changes in surface color tone due to light are suppressed. [Modes for carrying out the invention] 【0010】 The pharmaceutical composition of this embodiment contains alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient. In this specification, "alogliptin" refers to free alogliptin, which is the compound represented by the above formula (I). A pharmaceutically acceptable salt of alogliptin refers to a salt formed from the compound represented by the above formula (I) with an organic acid, an inorganic acid, or an acidic amino acid, which is permissible for administration to mammals, including humans. Examples of inorganic salts of alogliptin include hydrochloride, hydrobromide, nitrate, sulfate, and phosphate. Examples of organic salts of alogliptin include benzoate, formate, acetate, trifluoroacetate, fumarate, oxalate, tartrate, maleate, citrate, succinate, malate, methanesulfonate, benzenesulfonate, and toluenesulfonate. Examples of acidic amino acid salts of alogliptin include salts with aspartic acid and glutamic acid. Alogliptin benzoate is particularly preferred as a pharmaceutically acceptable salt of alogliptin. 【0011】 The content of alogliptin or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from, for example, 0.5 parts by mass or more and 50 parts by mass or less, preferably 1 part by mass or more and 45 parts by mass or less, per 100 parts by mass of the pharmaceutical composition. If the pharmaceutical composition of this embodiment is a tablet, for example, the content of alogliptin benzoate per tablet is 3.4 mg or more and 68 mg or less (2.5 mg or more and 50 mg or less as alogliptin), preferably 8.5 mg or more and 34 mg or less (6.25 mg or more and 25 mg or less as alogliptin). 【0012】 The pharmaceutical composition of this embodiment is a solid preparation containing alogliptin or a pharmaceutically acceptable salt thereof. The dosage form is not particularly limited, but examples include tablets, granules, powders, and capsules. Among these, tablets and granules are preferred, and tablets are particularly preferred. Furthermore, the pharmaceutical composition of this embodiment is preferably film-coated, and is particularly preferred to be a FC tablet. 【0013】 The pharmaceutical composition of this embodiment is characterized in that the active ingredient, alogliptin or a pharmaceutically acceptable salt thereof, does not come into contact with macrogol 6000. Macrogol 6000 is an addition polymer of ethylene oxide and water, represented as HOCH2(CH2OCH2)nCH2OH, where n is between 165 and 210. Macrogol 6000 itself is publicly known and is listed, for example, in the 18th edition of the Japanese Pharmacopoeia. Macrogol 6000 is also commercially available under the names "Macrogol 6000" and "PEG6000". In this specification, "the active ingredient does not come into contact with macrogol 6000" includes both the fact that the pharmaceutical composition of this embodiment does not contain macrogol 6000, and that the pharmaceutical composition of this embodiment contains macrogol 6000, but alogliptin or a pharmaceutically acceptable salt thereof is isolated in the pharmaceutical composition so as not to come into contact with macrogol 6000. 【0014】 Examples of the pharmaceutical composition of this embodiment that does not contain macrogol 6000 include a coated pharmaceutical composition having an uncoated pharmaceutical composition (hereinafter also referred to as the "core") containing alogliptin or a pharmaceutically acceptable salt thereof and not containing macrogol 6000, and a coating layer that does not contain macrogol 6000. The dosage form of the core is preferably a tablet or granule, with tablets being particularly preferred. When the core is a tablet, the core is also referred to as the "uncoated tablet" or "uncoated tablet portion." In this specification, the coating layer present on the surface of the core is also referred to as the "first coating layer." 【0015】 In a preferred embodiment, the pharmaceutical composition is a film-coated tablet having a core portion containing alogliptin or a pharmaceutically acceptable salt thereof and a first coating layer not containing macrogol 6000, and the first coating layer is provided on the surface of the core portion. 【0016】 When the pharmaceutical composition of the present embodiment does not contain macrogol 6000, it is preferable that the pharmaceutical composition contains a substitute for macrogol 6000. As shown in the formulation of the comparative example in the examples described later (see Table 2), since macrogol 6000 is used as a component contained in the coating layer, particularly as a plasticizer, the substitute for macrogol 6000 can be selected, for example, from plasticizers excluding macrogol 6000. Alternatively, a coating agent that does not require a plasticizer, such as a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (also called POVACOAT (registered trademark)), may be used. When the first coating layer contains a colorant described later, from the viewpoint of suppressing color tone change on the surface of the pharmaceutical composition, the pharmaceutical composition preferably has a first coating layer containing a plasticizer excluding macrogol 6000 and a coating agent on the surface of the core, or a first coating layer containing POVACOAT (registered trademark). Details of the plasticizer and the coating agent will be described later. 【0017】 Examples of the form in which alogliptin or a pharmaceutically acceptable salt thereof and macrogol 6000 are isolated from each other in the pharmaceutical composition of the present embodiment so as not to come into contact include, for example, a pharmaceutical composition having a core, a first coating layer not containing macrogol 6000, and a coating layer covering the first coating layer and containing macrogol 6000. In the present specification, the coating layer present on the surface of the first coating layer is also referred to as the "second coating layer". In the pharmaceutical composition coated with two layers, the first coating layer not containing macrogol 6000 is present between the core and the second coating layer containing macrogol 6000, so that the active ingredient in the core and macrogol 6000 in the second coating layer do not come into contact. 【0018】 In a preferred embodiment, the pharmaceutical composition is a film-coated tablet having a core tablet portion containing alogliptin or a pharmaceutically acceptable salt thereof, a first coating layer not containing macrogol 6000, and a second coating layer containing a plasticizer and a coating agent, having the first coating layer on the surface of the core tablet portion, and having the second coating layer on the surface of the first coating layer. 【0019】 The pharmaceutical composition of the present embodiment may be a single agent or a combined agent. A single agent refers to a pharmaceutical composition containing one type of active ingredient. A combined agent refers to a pharmaceutical composition containing two or more active ingredients. The pharmaceutical composition of the present embodiment that is a single agent contains only alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present embodiment that is a combined agent contains alogliptin or a pharmaceutically acceptable salt thereof and other active ingredients (hereinafter also referred to as "other active ingredients"). As the other active ingredients, therapeutic agents for type 2 diabetes having a pharmacological action different from DPP-IV inhibition are preferred. For example, metformin, pioglitazone, canagliflozin, glimepiride, voglibose, their pharmaceutically acceptable salts and solvates, etc. may be mentioned. The pharmaceutical composition of the present embodiment can be a combined agent containing alogliptin or a pharmaceutically acceptable salt thereof and at least one other active ingredient. 【0020】 The pharmaceutical composition of this embodiment may contain excipients. Excipients are additives that increase the volume of the main ingredient (active ingredient) which is present in small amounts, and are added to facilitate handling during manufacturing. Excipients are also called bulking agents or diluents. Examples of excipients include sugars, celluloses, starches, sugar alcohols, and maltodextrin. Excipients may be present individually or in combination of two or more. Examples of sugars include lactose, maltose, glucose, arabinose, fructose, galactose, and cellobiose. In this specification, the term "lactose" includes both anhydrous and hydrated lactose. Examples of celluloses include crystalline cellulose and powdered cellulose. Examples of starches include starch, pregelatinized starch, and corn starch. Examples of sugar alcohols include mannitol, sorbitol, lactitol, xylitol, and maltitol. Among these, crystalline cellulose, mannitol, powdered cellulose, starch, pregelatinized starch, lactitol, sorbitol, and maltodextrin are preferred, with crystalline cellulose and mannitol being particularly preferred. 【0021】 The content of excipients in the pharmaceutical composition of this embodiment is not particularly limited and can be appropriately determined depending on the content of the active ingredient, dosage form, etc. For example, if the pharmaceutical composition is a powder, the content of excipients can be appropriately determined from the range of 50 parts by mass or more and 99.5 parts by mass or less, preferably 55 parts by mass or more and 99 parts by mass or less, per 100 parts by mass of the pharmaceutical composition. If the pharmaceutical composition is a granule or tablet, the content of excipients can be appropriately determined from the range of 45 parts by mass or more and 95 parts by mass or less, preferably 50 parts by mass or more and 90 parts by mass or less, per 100 parts by mass of the pharmaceutical composition. 【0022】 The pharmaceutical composition of this embodiment may further contain pharmaceutically acceptable additives in addition to pharmaceutically acceptable excipients. Examples of such additives include binders, disintegrants, lubricants, coating agents, plasticizers, and colorants. Additives other than excipients may be present individually or in combination of two or more. The inclusion of each additive can be appropriately determined, for example, depending on the dosage form of the pharmaceutical composition. For example, if the pharmaceutical composition of this embodiment is a tablet or granule, it is preferable to further include a binder. If the pharmaceutical composition of this embodiment is a tablet, it is preferable to further include a binder, disintegrant, and lubricant. If the pharmaceutical composition of this embodiment is an FC tablet, it is preferable to further include a binder, disintegrant, lubricant, and coating agent. Even if a predetermined additive incorporated into the pharmaceutical composition of this embodiment may provide one or more functions in the pharmaceutical composition, a person skilled in the art will recognize that the purpose of including such additives is to provide one primary function. 【0023】 Examples of binders include celluloses, vinyl polymers, acrylic polymers, hydroxypropyl starch, dextrin, stearyl alcohol, gelatin, gum arabic, pullulan, and macrogol. The binder may be used individually or in combination of two or more. Examples of celluloses include hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (also known as hypromellose), and ethylcellulose. Examples of vinyl polymers include polyvinyl alcohol, polyvinylpyrrolidone (also known as povidone), copolividone, and polyvinyl acetal diethylaminoacetate. Examples of acrylic polymers include aminoalkyl methacrylate copolymers (E or RS), methacrylic acid copolymers (L, LD, or S), and ethyl acrylate / methyl methacrylate copolymer dispersions. Among these, hydroxypropylcellulose is preferred. 【0024】 The amount of binder in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from a range of, for example, 0.5 parts by mass to 10 parts by mass, preferably 1 part by mass to 5 parts by mass, per 100 parts by mass of the pharmaceutical composition. 【0025】 Examples of disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone, carmellose, carmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, and magnesium aluminometasilicate. Among these, croscarmellose sodium is preferred. The disintegrant may be a single type or a combination of two or more types. The content of the disintegrant in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from a range of 1 to 15 parts by mass, preferably 3 to 10 parts by mass, per 100 parts by mass of the pharmaceutical composition. 【0026】 Examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, liquid paraffin, sodium oleate, light anhydrous silicic acid, and hydrogenated vegetable oil. Among these, magnesium stearate, calcium stearate, talc, stearic acid, and sodium stearyl fumarate are preferred, with magnesium stearate being particularly preferred. The lubricant may be a single type or a combination of two or more types. The content of the lubricant in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from a range of 0.5 parts by mass to 5 parts by mass, preferably 1 part by mass to 3 parts by mass, per 100 parts by mass of the pharmaceutical composition. 【0027】 Examples of coating agents include water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, enteric-coated polymers, and water-insoluble nonpolymers. The coating agent may be used individually or in combination of two or more. Examples of water-soluble polymers include hypromellose, hydroxypropylcellulose, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol-graft copolymer. Hydroxypropyl methylcellulose is commercially available under the trade name "TC-5(registered trademark)," with TC-5(registered trademark) E and TC-5(registered trademark) R being preferred, and TC-5(registered trademark) R being more preferred. Examples of water-insoluble polymers include ethylcellulose, methacrylic acid copolymer, copolymer of methyl methacrylate and butyl methacrylate, copolymer of dimethylaminoethyl methacrylate, methylcellulose, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Examples of gastric-soluble polymers include aminoalkyl methacrylate copolymer and polyvinyl alcohol diethylaminoacetate. Examples of enteric-coated polymers include methacrylic acid copolymers, cellulose acetate phthalates, hypromellose phthalates, and polyvinyl alcohol acetate phthalates. Examples of water-insoluble nonpolymers include titanium dioxide, talc, and light anhydrous silicic acid. As coating agents, commercially available coating compositions such as the OPADRY® and OPADRY® II series may be used. Among these, hypromellose and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymers are preferred. 【0028】 The amount of coating agent in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from a range of 0.5 parts by mass to 5 parts by mass, preferably 1 part by mass to 5 parts by mass, per 100 parts by mass of the pharmaceutical composition. 【0029】 If the pharmaceutical composition of this embodiment is a single-layer coated pharmaceutical composition having a core and a first coating layer, it is preferable that the first coating layer contains a plasticizer and a coating agent other than macrogol 6000, or contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. As described above, since the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is a coating agent that does not require a plasticizer, if the first coating layer contains the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, it is optional whether or not it contains a plasticizer. The first coating layer may also contain a coloring agent. 【0030】 In this embodiment, the pharmaceutical composition is a two-layer coated pharmaceutical composition having a core, a first coating layer, and a second coating layer. The second coating layer preferably contains a plasticizer and a coating agent. The first coating layer contains at least a coating agent, but the inclusion of a plasticizer (excluding macrogol 6000) is optional. The second coating layer may contain macrogol 6000 as a plasticizer. The second coating layer may also contain a coloring agent. If the first coating layer does not contain a coloring agent, it is preferable that the second coating layer contains a coloring agent. 【0031】 Examples of plasticizers include triethyl citrate, triacetin, propylene glycol, polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate), macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, and macrogol 6000. Among these, triethyl citrate, triacetin, and propylene glycol are preferred, with triethyl citrate and triacetin being more preferred. The content of the plasticizer in the pharmaceutical composition of this embodiment is not particularly limited, but can be appropriately determined from a range of 0.5 parts by mass to 5 parts by mass, preferably 1 part by mass to 5 parts by mass, per 100 parts by mass of the coating layer. 【0032】 The coloring agent can be appropriately selected from, for example, food colorings, food lake colorings, ferric oxide, yellow ferric oxide, titanium dioxide, black iron oxide, etc. Examples of food colorings include Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Blue No. 2, and Food Green No. 3. As for food lake colorings, aluminum lake colorings are preferred, for example, Yellow No. 4 aluminum lake, Yellow No. 5 aluminum lake, Red No. 3 aluminum lake, Blue No. 1 aluminum lake, and Blue No. 2 aluminum lake. Among these, ferric oxide, yellow ferric oxide, titanium dioxide, black iron oxide, and Blue No. 2 aluminum lake are preferred, and ferric oxide, yellow ferric oxide, and titanium dioxide are particularly preferred. The coloring agent may be a single type or a combination of two or more types. The amount of colorant in the pharmaceutical composition of this embodiment is not particularly limited, but for example, it is 0.05 parts by mass or more and 0.5 parts by mass or less, preferably 0.1 parts by mass or more and 0.4 parts by mass or less, per 100 parts by mass of the coating layer. 【0033】 The method for producing the pharmaceutical composition of this embodiment (hereinafter also referred to as "the method for producing this embodiment") includes including in the pharmaceutical composition alogliptin or a pharmaceutically acceptable salt thereof, which is the active ingredient, in such a way that it does not come into contact with macrogol 6000. The reason why the active ingredient does not come into contact with macrogol 6000 is as described above. In the method for producing this embodiment, the form of the alogliptin or pharmaceutically acceptable salt thereof used is not particularly limited as long as it is a solid, and may be in any form such as powder or particles. Preferably, the powder of alogliptin or a pharmaceutically acceptable salt thereof is mixed with an excipient. Details of the excipient are as described above. 【0034】 The method for mixing alogliptin or a pharmaceutically acceptable salt thereof with an excipient is not particularly limited, and for example, a known mixer capable of mixing two or more powders can be used. Examples of such mixers include diffusion mixers and convection mixers. By using a mixer, a mixed powder of alogliptin or a pharmaceutically acceptable salt thereof with an excipient can be obtained. When the pharmaceutical composition of this embodiment is a powder, the mixed powder containing alogliptin or a pharmaceutically acceptable salt thereof with an excipient, produced by the above mixing, can be obtained as a powder containing alogliptin or a pharmaceutically acceptable salt thereof. This powder is an uncoated pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof but not containing macrogol 6000. 【0035】 If the pharmaceutical composition of this embodiment contains alogliptin or a pharmaceutically acceptable salt thereof and other active ingredients, a mixture of alogliptin or a pharmaceutically acceptable salt thereof and an excipient may be mixed with the other active ingredients. Alternatively, alogliptin or a pharmaceutically acceptable salt thereof may be mixed with other active ingredients and an excipient. The other active ingredients may be mixed in advance with additives such as excipients, disintegrants, and binders. In that case, a mixture of alogliptin or a pharmaceutically acceptable salt thereof and an excipient may be mixed with a mixture of the other active ingredients and additives. 【0036】 In a preferred embodiment, a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof is obtained by a known granulation method using an excipient and a binder. In this case, the obtained granular composition can be used as a granular pharmaceutical composition. The granulation method may be either wet granulation or dry granulation, but wet granulation is preferred. In the granulation method, known granulators such as dry granulators, extruder granulators, agitated mixing granulators, and fluidized bed granulators / dryers can be used. By using a granulator, a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof, an excipient and a binder can be obtained. 【0037】 In wet granulation, a granular composition is obtained using a mixture of alogliptin or a pharmaceutically acceptable salt thereof and an excipient, and a solution or suspension containing a binder. If necessary, a powdered binder and / or disintegrant may be further added to the above mixture before wet granulation. Alternatively, a granular composition may be obtained by wet granulation using a mixture of alogliptin or a pharmaceutically acceptable salt thereof, an excipient, and a binder and / or disintegrant, and the resulting mixture and a solution or suspension containing a binder. Details of the binder and disintegrant are as described above. Hydroxypropyl cellulose is preferred as the binder. Croscarmellose sodium is preferred as the disintegrant. 【0038】 The solution or suspension containing the above-mentioned binder is a granulation liquid used in wet granulation. The granulation liquid can be prepared by dissolving or dispersing the binder in a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include purified water, ethanol, and mixtures thereof. Among these, purified water is particularly preferred. 【0039】 The type of wet granulation is not particularly limited, but can be appropriately selected from, for example, agitation granulation, fluid bed granulation, extrusion granulation, rolling granulation, crushing granulation, and spray granulation. Wet granulation can be carried out using a known granulator. For example, when using an agitation mixing granulator, the mixed powder is agitated by rotating blades, and a solution or suspension containing a binder is added dropwise or sprayed, thereby mixing and dispersing the mixed powder and the solution or suspension containing a binder to produce a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof. 【0040】 The granular composition obtained by wet granulation is subjected to a drying process. This makes it possible to obtain the pharmaceutical composition of this embodiment in the form of granules. These granules contain the above-mentioned core (i.e., This is an uncoated pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof, but without macrogol 6000. The drying method is not particularly limited and can be appropriately selected from, for example, vacuum drying, fluidized bed drying, spray drying, etc. If the granulator has a drying function ( For example, drying may be done using a fluidized bed granulator (such as a fluidized bed granulator). Drying conditions include: Examples include preheating of the apparatus, supply air temperature, supply air volume, and drying time. In this embodiment, the dried granular composition may be sized using a known granulator so that it has a predetermined particle size distribution. 【0041】 A pharmaceutical composition in the form of coated granules can be obtained by coating the granular composition (the core granules) obtained as described above with a first coating layer that does not contain macrogol 6000. A pharmaceutical composition in the form of coated granules can be obtained by further coating the pharmaceutical composition with a second coating layer. The first and second coating layers are as described above. Coating with the first and second coating layers can be performed by spraying a liquid (coating liquid) containing the components of each coating layer onto the granules and then drying it. 【0042】 A pharmaceutical composition in the form of a powder or granules obtained as described above can be filled into a capsule to obtain a pharmaceutical composition in the form of a capsule. The granules filled into the capsule may be the granules that form the core described above, or the granules in which the core is coated with a first coating layer that does not contain macrogol 6000, or the granules in which the core is coated with two layers: a first coating layer that does not contain macrogol 6000 and the second coating layer described above. The capsule is not particularly limited as long as it is a hard capsule manufactured from a pharmaceutically acceptable capsule base. Examples of capsule bases include gelatin and hydroxypropyl methylcellulose. The method of filling the capsule with powder is well known, and for example, a disc type, compress type, or Auger type filling machine can be used. ru. 【0043】 In a further embodiment of the present invention, a method for producing tablets containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient is provided (hereinafter also referred to as the "method for producing tablets"). For example, a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof obtained as described above can be used to produce the pharmaceutical composition of this embodiment in the form of tablets. The granular composition used in the method for producing tablets may be the granular core described above, or a granular core coated with a first coating layer that does not contain macrogol 6000, or a granular core coated with two layers: a first coating layer that does not contain macrogol 6000 and a second coating layer. 【0044】 In one embodiment, the method for producing tablets includes the steps of: mixing alogliptin or a pharmaceutically acceptable salt thereof with an excipient; obtaining a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof by wet granulation using the mixture obtained in the mixing step and a solution or suspension containing a binder; and drying the granular composition. Details of these steps are as described above. When the produced tablets are coated with a first coating layer that does not contain macrogol 6000, it is preferable that the wet granulation in the method for producing tablets obtains an uncoated granular composition containing alogliptin or a pharmaceutically acceptable salt thereof and not containing macrogol 6000. 【0045】 Furthermore, the method for manufacturing tablets includes the step of mixing a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof with a tablet additive to obtain a tablet mixture. The tablet additive is a pharmaceutically acceptable additive commonly used in the manufacture of tablets. The tablet additive can be appropriately selected from, for example, excipients, binders, disintegrants, lubricants, sweeteners, and colorants. Details of these additives are as described above. It is preferable to use excipients, disintegrants, and lubricants as tablet additives. Crystalline cellulose and mannitol are preferred as excipients. Croscarmellose sodium is preferred as a disintegrant. Magnesium stearate is preferred as a lubricant. 【0046】 Preferably, in mixing a granular composition containing alogliptin or a pharmaceutically acceptable salt thereof with a tablet additive containing a disintegrant, first the granular composition is mixed with the tablet additive excluding the lubricant (e.g., excipients and disintegrants), and then the lubricant is added to the resulting mixture and mixed to obtain a tablet mixture. 【0047】 Furthermore, the method for producing tablets includes the step of compressing the obtained tablet mixture to obtain tablets containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient. The compression molding of the tablet mixture can be carried out using a known tablet press (e.g., a rotary tablet press). 【0048】 The compression pressure used when manufacturing tablets is not particularly limited and can be set appropriately depending on the composition and weight of the tablets. For single-component tablets, the compression pressure can be set to 3kN or more and 20kN or less, preferably 4kN or more, more preferably 5kN or more, preferably 15kN or less, and more preferably 12kN or less. For combination tablets, the compression pressure can be set to 5kN or more and 30kN or less, preferably 10kN or more, more preferably 15kN or more, preferably 25kN or less, and more preferably 20kN or less. 【0049】 The hardness is not particularly limited, but for single-component formulations, for example, 50N or more and 150N or less is preferred, and 75N or more and 100N or less is more preferred. For compound formulations, for example, 100N or more and 350N or less is preferred, and 200N or more and 300N or less is more preferred. The hardness can be adjusted, for example, by the tableting pressure. 【0050】 The tablets should be disc-shaped or oval-shaped to facilitate oral administration. The size of the tablets can be adjusted as appropriate. For example, an oval-shaped single-ingredient tablet may have a long diameter of 5mm to 12mm, a short diameter of 3mm to 8mm, and a weight of 100mg to 200mg per tablet. For an oval-shaped combination tablet, for example, the long diameter may be 8mm to 15mm, the short diameter 5mm to 10mm, and a weight of 400mg to 800mg per tablet. A score line may be provided on one or both sides of the tablet as needed. 【0051】 If necessary, the resulting tablets may be made into film-coated tablets or sugar-coated tablets. Preferably, the method for manufacturing tablets according to this embodiment further includes a step of film-coating the tablets. The tablets can be coated by known methods such as pan coating or fluidized bed coating. The coating agent used for film coating is as described above. 【0052】 The tablets according to the present invention may be packaged as needed by PTP (Press Through Pack) packaging, bottle filling, aluminum packaging, etc. Examples of materials for PTP packaging include resins such as polyvinyl chloride (PVC), polypropylene (PP), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), polyethylene (PE), polystyrene (PS), and polycarbonate (PC), as well as metals such as aluminum. These materials may be used individually or in combination of multiple types. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The formulation can be placed in a resin sheet formed into a pocket shape by a known method using the above resins, and then sealed with aluminum foil. 【0053】 When the granular composition used in the method for manufacturing the tablets is a granular preparation that is the core described above, an uncoated tablet (i.e., an uncoated tablet containing alogliptin or a pharmaceutically acceptable salt thereof and not containing macrogol 6000) is obtained. In this case, the step of film-coating the tablets preferably includes at least the steps of coating the uncoated tablet containing alogliptin or a pharmaceutically acceptable salt thereof with a first coating layer that does not contain macrogol 6000, and drying the coated tablet. Furthermore, the step of coating the tablet coated with the first coating layer with a second coating layer containing a plasticizer and a coating agent, and drying the coated tablet may also be included. The first and second coating layers are as described above. Coating with the first and second coating layers is performed by spraying a liquid (coating liquid) containing the components constituting each coating layer onto the uncoated tablet and then drying it. 【0054】 A further embodiment of the present invention provides a method for stabilizing a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient. This method includes incorporating the active ingredient in a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof in such a way that it does not come into contact with macrogol 6000. The reason the active ingredient does not come into contact with macrogol 6000 is as described above. This suppresses the generation of analogues of alogliptin or a pharmaceutically acceptable salt thereof and the color change of the surface of the pharmaceutical composition due to light. It is preferable to incorporate the active ingredient in such a way that it does not come into contact with macrogol 6000 by forming a first coating layer on the surface of the core that does not contain macrogol 6000. The core contains the active ingredient but does not contain macrogol 6000. When a colorant is included in the first coating layer, from the viewpoint of suppressing color changes, it is preferable to form a first coating layer on the surface of the core that contains a plasticizer and a coating agent excluding macrogol 6000, or to form a first coating layer that contains POVACOAT®. Details of the plasticizer, coating agent, and colorant are as described above. A second coating layer may be formed on the surface of the first coating layer. In this case, the second coating layer may contain macrogol 6000. 【0055】 The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited thereto. [Examples] 【0056】 1. Manufacturing of FC tablets containing alogliptin benzoate as the active ingredient. Plain tablets containing 8.5 mg of alogliptin benzoate per tablet were manufactured using the formulations shown in Table 1. The obtained plain tablets were film-coated using the formulations shown in Comparative Examples, Reference Examples, and Examples 1-4 in Table 2, and Example 5 in Table 3, to obtain FC tablets. The specific manufacturing procedures will be described later. In Tables 1-3, the unit of measurement for each component is "mg". 【0057】 [Table 1] 【0058】 [Table 2] 【0059】 [Table 3] 【0060】 (1.1) Manufacturing of FC tablets in the comparative example The comparative example FC tablet was a tablet having an FC layer containing macrogol 6000 as a plasticizer, and was manufactured as follows. First, alogliptin benzoate powder, D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE), and crystalline cellulose (Ceolus PH-101, manufactured by Asahi Kasei Corporation) were mixed in a fluid bed granulator to obtain a mixed powder. Then, hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in purified water to obtain a granulation solution. The granulation solution was sprayed onto the mixed powder using the same machine to granulate, and the resulting granules were dried. The crushed and dried granules were sized using a granulation machine to obtain a granular composition containing alogliptin benzoate. The obtained granular composition, crystalline cellulose (Ceolus UF-702, manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol, manufactured by DuPont Nutrition USA) were mixed in a polyethylene (PE) bag to obtain a mixed powder. A portion of this mixed powder was taken and mixed with magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) to obtain a double-powdered powder. This double-powdered powder and the remaining mixed powder were mixed in a PE bag to obtain a tableting mixture. The obtained tableting mixture was compressed using a rotary tablet press to obtain uncoated tablets containing alogliptin benzoate. Hypromellose (TC-5R: manufactured by Shin-Etsu Chemical Co., Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), talc (Talkan Hayashi: manufactured by Hayashi Chemical Co., Ltd.), macrogol 6000 (manufactured by Sanyo Chemical Industries, Ltd.), and ferric oxide (manufactured by Kiseki Chemical Co., Ltd.) were added to purified water to obtain a coating solution. Using a pan coating apparatus, the uncoated tablets containing alogliptin benzoate were coated with the coating solution to obtain comparative example FC tablets. 【0061】 (1.2) Manufacturing of FC tablets as an example. The reference example FC tablet is a tablet having an FC layer that does not contain macrogol 6000 or other plasticizers, and was manufactured as follows. Referring to Table 2, the reference example FC tablet was manufactured in the same manner as the comparative example FC tablet, except that macrogol 6000 was not used and the amount of hypromellose was increased in the formulation of the comparative example FC. 【0062】 (1.3) Manufacturing of FC tablets in Examples 1-3 The FC tablets of Examples 1 to 3 are tablets having an FC layer that does not contain macrogol 6000 and contains a plasticizer other than macrogol 6000, and were manufactured as follows. Referring to Table 2, each of the FC tablets of Examples 1 to 3 was manufactured in the same manner as the FC tablets of the comparative example, except that triacetin (glycerol triacetic acid: manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), triethyl citrate (Citroflex 2 (SC-60): manufactured by Morimura Trading Co., Ltd.), or propylene glycol (manufactured by Maruishi Pharmaceutical Co., Ltd.) was used instead of macrogol 6000 in the formulation of the FC of the comparative example. 【0063】 (1.4) Manufacturing of FC tablets in Example 4 The FC tablets of Example 4 are tablets that do not contain macrogol 6000 or other plasticizers and have an FC layer containing a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT: manufactured by Daido Chemical Industries, Ltd.), and were manufactured as follows. First, a plain tablet containing alogliptin benzoate was obtained in the same manner as in the manufacture of the FC tablets of the Comparative Example. Titanium dioxide and talc were added to a mixture obtained by dissolving POVACOAT in purified water and dispersed to obtain a coating solution. The plain tablets were coated with the coating solution using a pan coating apparatus to obtain the FC tablets of Example 4. 【0064】 (1.5) Manufacturing of FC tablets in Example 5 The FC tablet of Example 5 is a tablet having a first FC layer that does not contain macrogol 6000 and a second FC layer that coats the first FC layer and contains macrogol 6000 as a plasticizer, and was manufactured as follows. First, a plain tablet containing alogliptin benzoate was obtained in the same manner as in the manufacture of the FC tablet of the comparative example. Hypromellose and talc were added to purified water to obtain a first coating solution. Using a pan coating apparatus, the plain tablet was coated with the first coating solution to obtain a tablet having a first FC layer. Hypromellose, titanium dioxide, talc, macrogol 6000 and ferric oxide were added to purified water to obtain a second coating solution. Using a pan coating apparatus, the tablet having the first FC layer was coated with the second coating solution to obtain the FC tablet of Example 5. 【0065】 2. Storage stability test The FC tablets of the comparative example, reference example, and Examples 1-5 were each placed in a petri dish, sealed with polyvinyl chloride wrap, and stored for 6 months at 40°C and 75% RH. Each FC tablet, both immediately after manufacturing (Initial) and after storage, was extracted with a fixed amount of solvent, and the sample solution was obtained by filtering through a membrane filter to which acetonitrile had been added. Each sample solution was tested by liquid chromatography under the following test conditions. The peak area of ​​each sample solution was measured by automated integration, and their amounts were determined by the area percentage method. For each FC tablet, the amount of N-formyl metabolite, a related substance, was compared between Initial and after storage, and the increase (%) from Initial was calculated. The results are shown in Table 4. 【0066】 <Test Conditions> • Detector: UV absorbance spectrophotometer (measurement wavelength: 277 nm) • Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was packed with 3 μm phenylsilylated silica gel for liquid chromatography. • Column temperature: A constant temperature of around 40°C Mobile phase A: 0.77 g of ammonium acetate was dissolved in 1000 mL of water, and acetic acid (100 mL) was added to adjust the pH to 5.0. Mobile phase B: Acetonitrile ·Flow rate: 1.0mL / min 【0067】 [Table 4] 【0068】 Referring to Table 4, the comparative example FC tablets showed a significant increase in N-formyl after 6 months of storage in a petri dish with plastic wrap (made of polyvinyl chloride) at 40°C and 75% RH. On the other hand, the FC tablets of the reference example and Examples 1-5 showed a significantly lower increase in N-formyl after storage under similar conditions compared to the comparative example FC tablets. This suggests that pharmaceutical compositions that do not involve contact between alogliptin or its pharmaceutically acceptable salts and macrogol 6000 can suppress the increase of related substances. 【0069】 3. Light stability test In the FC tablets of the comparative example, Macrogol 6000 contained in the film coating layer was added to suppress the change in the color tone of the surface of the FC tablets due to light. Therefore, for the FC tablets of the comparative example, reference example, and Examples 1 to 5, the change in the color tone of the tablet surface due to light irradiation was examined. These FC tablets were each placed in a petri dish and irradiated with light of 1,200,000 lx·h using a D65 light source. The color difference ΔE of the tablets before and after light irradiation was measured using a spectrophotometer. 【0070】 ΔE = [(ΔL , , , , , 【0073】 , , ) 2 +(Δa * ) 2 +(Δb * ) 2 ) 1 / 2 (V) 【0071】 ΔL * , Δa * , Δb * are, respectively, the difference in the lightness L * a * b * between two object colors in the L * a * b * color system and the differences in color coordinates Δa 【0072】 【Table 5】 【0073】 Referring to Table 5, the comparative example FC tablet showed a low color difference of 0.62 compared to the initial, indicating that the change in surface color due to light was suppressed. However, the reference example FC tablet showed a color difference of 12.71 compared to the initial, indicating a significant change in surface color due to light. Here, as shown in Table 2, the comparative example and the reference example differed in whether or not macrogol 6000 was included in the FC layer in addition to the coating agent. These results indicate that in FC tablets containing alogliptin benzoate as the active ingredient, the inclusion of macrogol 6000 and a coating agent in the FC layer suppresses the change in surface color. On the other hand, as shown in Table 4, the comparative example FC tablet had the problem of an increase in related substances. 【0074】 Referring to Table 5, the color difference between the FC tablets of Examples 1-4 and the Initial tablet was low in all cases compared to the FC tablet of the Reference Example. This indicates that the inclusion of plasticizers and coating agents other than macrogol 6000 in the FC layer, or the inclusion of a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, suppresses the change in surface color tone of the FC tablet due to light. Regarding the color difference ΔE and color tolerance, when ΔE is between 1.6 and 3.2, the change in color tone is hardly noticeable in visual comparisons and is generally considered to be the same color, and when ΔE is between 0.8 and 1.6, it is said to be within the error range of general colorimeters (Toshio Ichimi, Color Technology in Printing, Journal of the Japan Society of Printing Science and Technology, 1989, Vol. 26, No. 5, pp. 265-273). Therefore, it can be said that the FC tablets with a color difference lower than 3.2 showed particularly good suppression of surface color tone change due to light. 【0075】 Furthermore, the color difference between the FC tablet of Example 5 and the Initial tablet was lower than that of the Reference Example FC tablet. As shown in Table 3, the FC tablet of Example 5 was a tablet in which the first FC layer did not contain macrogol 6000, but the second FC layer covering the first FC layer contained macrogol 6000 and a coating agent. This indicates that by including macrogol 6000 and a coating agent in the FC layer in an FC tablet so that it does not come into contact with alogliptin or a pharmaceutically acceptable salt thereof, the increase in related substances and the change in surface color due to light can be suppressed. 【0076】 4. Prescription example of FC tablets containing alogliptin benzoate as the active ingredient As the pharmaceutical composition of this embodiment, a plain tablet containing alogliptin benzoate according to the formulation shown in Table 6 was film-coated with the formulation shown in Table 7 to obtain FC tablets. The specific manufacturing procedure will be described later. In Tables 6 and 7, the unit of the numerical values ​​for each component is "mg". 【0077】 [Table 6] 【0078】 [Table 7] 【0079】 (4.1) Manufacturing of FC tablets for prescription examples 1-3 The FC tablets of formulation examples 1-3 are tablets that do not contain macrogol 6000 or other plasticizers and have an FC layer containing polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT: manufactured by Daido Chemical Industries, Ltd.), and were manufactured as follows: First, alogliptin benzoate powder, D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE), and croscarmellose sodium (Aczisol: manufactured by DuPont Nutrition USA) were mixed in a fluid bed granulator to obtain a mixed powder. Then, POVACOAT (polyvinyl / acrylic acid / methyl methacrylate copolymer, POVACOAT: manufactured by Daido Chemical Industries, Ltd.) was dissolved in purified water to obtain a granulation solution. The granulation solution was sprayed onto the mixed powder using the same machine to granulate, and the resulting granules were dried. The crushed and dried granules were sized using a granulation machine to obtain a granular composition containing alogliptin benzoate. The obtained granular composition (granulated powder), crystalline cellulose (Ceolus UF-702: manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol: manufactured by DuPont Nutrition USA) were mixed in a polyethylene (PE) bag to obtain a mixed powder. A portion of this mixed powder was taken and mixed with magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) to obtain a double-powdered powder. This double-powdered powder and the remaining mixed powder were mixed in a PE bag to obtain a tableting mixture. The obtained tableting mixture was compressed in a rotary tablet press to obtain tablets containing alogliptin benzoate. POVACOAT (polyvinyl acrylic acid methyl methacrylate copolymer, POVACOAT: manufactured by Daido Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), and talc (Talkan Hayashi: manufactured by Hayashi Chemical Co., Ltd.), as well as iron(III) oxide (manufactured by Kiseki Chemical Co., Ltd.) in formulation example 1 and yellow iron(III) oxide (manufactured by Kiseki Chemical Co., Ltd.) in formulation example 3, were added to purified water to obtain a coating solution. Using a pan coating apparatus, uncoated tablets containing alogliptin benzoate were coated with the coating solution to obtain FC tablets for formulation examples 1 to 3. 【0080】 5. Prescription example of FC tablets containing alogliptin benzoate and metformin hydrochloride as active ingredients As a further pharmaceutical composition of this embodiment, a plain tablet containing alogliptin benzoate and metformin hydrochloride according to the formulation shown in Table 8 was film-coated with the formulation shown in Table 9 to obtain FC tablets. The specific manufacturing procedure will be described later. In Tables 8 and 9, the unit of the numerical values ​​for each component is "mg". 【0081】 [Table 8] 【0082】 [Table 9] 【0083】 (5.1) Manufacturing of FC tablets for prescription examples 4-6 The FC tablets in prescription examples 4-6 are tablets that contain alogliptin benzoate and metformin hydrochloride as active ingredients, do not contain macrogol 6000 or other plasticizers, and have an FC layer containing polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT: manufactured by Daido Chemical Industries, Ltd.), and were manufactured as follows: First, metformin hydrochloride powder and magnesium aluminometasilicate (Neusilin FL2, manufactured by Fuji Chemical Industries, Ltd.) were mixed in a polyethylene (PE) bag to obtain a coarse mixed powder. The coarse mixed powder was crushed using a granulator to obtain a metformin hydrochloride-containing mixed powder. A mixed powder containing metformin hydrochloride, alogliptin benzoate powder, and crystalline cellulose (Ceolus PH-101: manufactured by Asahi Kasei Corporation) were mixed in a fluidized bed granulator to obtain a mixed powder. Then, polyvinyl alcohol (Gosenol EG-05P: manufactured by Mitsubishi Chemical Corporation) was dissolved in purified water to obtain a granulation solution. Using the same machine, the granulation solution was sprayed onto the mixed powder to granulate it, and the resulting granules were dried. Using a granulation machine, the crushed and dried granules were sized to obtain a granular composition containing alogliptin benzoate and metformin hydrochloride. The obtained granular composition (granulated powder) and crospovidone (Coridon CL-F: manufactured by BASF Corporation), and in formulation example 6, crystalline cellulose (Ceolus: manufactured by Asahi Kasei Corporation), were mixed in a polyethylene (PE) bag to obtain a mixed powder. A portion of this mixed powder was taken and mixed with magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) to obtain a double-powdered powder. This double-strength powder and the remaining mixed powder were mixed in a PE bag to obtain a tableting mixture. The obtained tableting mixture was compressed in a rotary tablet press to obtain uncoated tablets containing alogliptin benzoate and metformin hydrochloride. POVACOAT (polyvinyl acrylic acid methyl methacrylate copolymer, POVACOAT: manufactured by Daido Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), talc (Talkan Hayashi: manufactured by Hayashi Chemical Co., Ltd.), and iron(III) oxide (manufactured by Kiseki Chemical Co., Ltd.) were added to purified water to obtain a coating solution. Using a pan coating apparatus, the uncoated tablets containing alogliptin benzoate and metformin hydrochloride were coated with the coating solution to obtain FC tablets of formulation examples 4 to 6.

Claims

[Claim 1] A pharmaceutical composition comprising alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient in the pharmaceutical composition does not come into contact with macrogol 6000. [Claim 2] The pharmaceutical composition according to claim 1, having a first coating layer that does not contain macrogol 6000. [Claim 3] The pharmaceutical composition according to claim 2, wherein the first coating layer contains a plasticizer and a coating agent other than macrogol 6000, or contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. [Claim 4] The pharmaceutical composition according to claim 3, wherein the plasticizer comprises at least one selected from the group consisting of triethyl citrate, triacetin, and propylene glycol. [Claim 5] The pharmaceutical composition according to claim 3, wherein the coating agent is at least one selected from the group consisting of hypromellose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. [Claim 6] The pharmaceutical composition according to claim 2, wherein the first coating layer contains a coloring agent. [Claim 7] The pharmaceutical composition according to claim 2, further comprising a second coating layer containing a plasticizer and a coating agent on the surface of the first coating layer. [Claim 8] The pharmaceutical composition according to claim 7, wherein the second coating layer comprises macrogol 6000. [Claim 9] The pharmaceutical composition according to claim 8, wherein the second coating layer contains a coloring agent when the first coating layer does not contain a coloring agent. [Claim 10] The pharmaceutical composition according to claim 6 or 9, wherein the coloring agent is at least one selected from the group consisting of food coloring, food lake coloring, iron oxide, yellow iron oxide, titanium dioxide, and black iron oxide. [Claim 11] The pharmaceutical composition is a film-coated tablet, The pharmaceutical composition according to claim 2, wherein the film-coated tablet comprises a core portion containing the active ingredient and the first coating layer, and the first coating layer is present on the surface of the core portion. [Claim 12] The pharmaceutical composition is a film-coated tablet, The film-coated tablet comprises a core portion containing the active ingredient, a first coating layer, and a second coating layer. The pharmaceutical composition according to claim 7, wherein the surface of the uncoated tablet portion has the first coating layer, and the surface of the first coating layer has the second coating layer. [Claim 13] A method for producing a pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient, comprising the method of including the inclusion of the active ingredient in the pharmaceutical composition so as not to come into contact with macrogol 6000. [Claim 14] A pharmaceutical composition containing alogliptin or a pharmaceutically acceptable salt thereof as an active ingredient. A method for stabilizing a pharmaceutical composition, comprising including the active ingredient in such a way that it does not come into contact with macrogol 6000.

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