Pharmaceutical composition comprising teneligliptin and canagliflozin

Abstract

To provide a technique capable of producing, by a simpler method, a pharmaceutical composition containing teneligliptin and canagliflozin as active ingredients, in which storage stability is secured to such an extent that there is no problem in production and sales of a pharmaceutical product even if teneligliptin and canagliflozin are contained in the same preparation.SOLUTION: The present invention includes a method for preparing a pharmaceutical composition comprising teneligliptin and canagliflozin, which comprises the following steps A and B: A) Mixing and granulating step: mixing at least teneligliptin and canagliflozin in the absence of water to prepare a mixture comprising them, or granulating the mixture in the absence of water to prepare a granulated product B) Molding step: processing the mixture or the granulated product to form a solid preparation SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical preparations. In this technical field, the present invention relates to a pharmaceutical composition containing teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin as active ingredients, a method for producing the same, and a method for inhibiting the production of analogs of the two active ingredients. [Background technology]

[0002] Teneligliptin, whose chemical name is {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone, is a known compound having the structure shown in (1) below. Teneligliptin and its salts are selective DPP-4 (dipeptidyl peptidase 4) inhibitors that selectively inhibit DPP-4, an enzyme that degrades incretins that stimulate insulin secretion, thereby increasing the concentration of active incretins and lowering blood glucose levels by increasing insulin levels in a blood glucose-dependent manner. In Japan, its hydrobromide salt hydrate is manufactured, sold, and used as Tenelia® Tablets 20 mg or 40 mg for the treatment of type 2 diabetes (non-insulin-dependent diabetes mellitus).

[0003] [ka]

[0004] Canagliflozin, whose chemical name is (1S)-1,5-Anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-D-glucitol, is a known compound having the structure shown in (2) below. Canagliflozin is an SGLT (sodium-glucose cotransporter) 2 inhibitor that inhibits SGLT2, a transporter involved in glucose reabsorption in the renal tubules, thereby suppressing glucose reabsorption and excreting excess glucose in the urine, thereby lowering blood glucose levels. In Japan, its hydrate is manufactured, sold, and used as Canaglu® Tablets 100 mg for the treatment of type 2 diabetes.

[0005] [ka]

[0006] Both the active ingredients, teneligliptin and canagliflozin, are effective in treating type 2 diabetes, but because their mechanisms of action are different, combination drugs that combine the two have been developed in the hope of achieving synergistic effects, etc. Specifically, in Japan, a combination tablet called Canalia (registered trademark) is manufactured, sold, and used as a treatment for type 2 diabetes.

[0007] However, initially, when the active ingredients teneligliptin or a salt thereof and canagliflozin were contained in the same preparation, problems with storage stability were pointed out due to interactions between the two, such as an increase in related substances, color changes, and unpleasant odors. To address these problems, it was discovered that the interaction between the two could be suppressed by containing the two active ingredients in the same solid preparation in a state where they are not substantially in contact with each other, and the storage stability problem was temporarily solved (Patent Document 1). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 6027710 (International Publication No. 2016 / 104643) Summary of the Invention [Problem to be solved by the invention]

[0009] When canagliflozin and teneligliptin or a salt thereof come into contact with each other, the interaction between the two active ingredients causes decomposition or the production of related substances, resulting in a problem of impaired storage stability. In order to avoid this problem, the invention of Patent Document 1 first prepares independent granules for each active ingredient, and then incorporates the two active ingredients into the same formulation so that they are not substantially in contact with each other, thereby overcoming the storage stability problem. However, to do this, separate granulation steps must be carried out for each of the active ingredients, which inevitably increases the number of steps compared to granulating both active ingredients together, resulting in poor productivity.

[0010] The main object of the present invention is to provide a technology that uses a new method different from the invention described in Patent Document 1 to produce a pharmaceutical composition containing the active ingredients teneligliptin and canagliflozin in a simpler manner, while ensuring storage stability to the extent that it does not interfere with the manufacture and sale of pharmaceuticals, even when the active ingredients are contained in the same formulation. [Means for solving the problem]

[0011] As a result of extensive research, the present inventors have found that the above-mentioned problems can be solved even in the case of a solid preparation comprising a mixture obtained by mixing the active ingredients teneligliptin and canagliflozin in the absence of water, and have thus completed the present invention.

[0012] The present invention can include, for example, the following aspects. [1] A method for producing a pharmaceutical composition containing teneligliptin or a pharmaceutically acceptable salt thereof (hereinafter, unless otherwise specified, simply referred to as "teneligliptin") and canagliflozin, the method comprising the following steps A and B: A) Mixing / granulation process A step of mixing at least teneligliptin and canagliflozin in the absence of water to prepare a mixture containing them, or granulating such a mixture in the absence of water to prepare a granule; and B) Molding process A step of processing the mixture or granules to form a solid preparation. [2] The method for producing the pharmaceutical composition according to [1] above, wherein the mixing in step A is performed in such a manner that teneligliptin and canagliflozin are substantially in contact with each other. [3] The method for producing the pharmaceutical composition according to [1] above, wherein step B is a step of directly compressing the mixture by dry compression to form a solid preparation, or a step of compressing the granules to form a solid preparation. [4] The method for producing the pharmaceutical composition according to [1] above, wherein the solid formulation is a tablet or a coated tablet. [5] The method for producing the pharmaceutical composition according to [4] above, wherein the total amount of teneligliptin analogues is 0.5% by mass or less when the solid formulation is stored in the open at 40°C and 75% RH for one month. [6] The method for producing the pharmaceutical composition described in [4] above, wherein the total amount of canagliflozin analogues is 0.2 mass% or less when the solid preparation is stored in the open at 40°C and 75% RH for one month.

[0013] [7] A pharmaceutical composition containing teneligliptin and canagliflozin, characterized in that the pharmaceutical composition contains a mixture of at least teneligliptin and canagliflozin, and the total amount of teneligliptin analogues is 0.5% by mass or less after storage in the open at 40°C and 75% RH for one month. [8] A pharmaceutical composition containing teneligliptin and canagliflozin, characterized in that the pharmaceutical composition contains a mixture of at least teneligliptin and canagliflozin, and the total amount of canagliflozin-related substances is 0.2 mass% or less after storage in the open at 40°C and 75% RH for one month. [9] The pharmaceutical composition according to [7] or [8] above, wherein in the mixture, teneligliptin and canagliflozin may be substantially in contact with each other.

[10] The pharmaceutical composition according to [7] or [8] above, which is in the form of a solid formulation.

[11] The pharmaceutical composition according to

[10] above, wherein the solid formulation is a tablet or a coated tablet.

[0014]

[12] A method for suppressing the production of analogues of at least one of the active ingredients in a pharmaceutical composition containing a mixture or granules obtained by mixing or granulating at least teneligliptin and canagliflozin, characterized in that the mixing and granulation are carried out in the absence of water. [Effects of the Invention]

[0015] According to the present invention, a pharmaceutical composition (e.g., a solid formulation such as a tablet) containing the active ingredients teneligliptin and canagliflozin, even if the solid formulation is a mixture obtained by mixing both active ingredients, can be provided in a relatively simple manner, with storage stability sufficient to allow for the manufacture and sale of pharmaceuticals. Unlike the manufacturing method described in Patent Document 1, the two active ingredients do not need to be mixed and granulated separately, but can be mixed and granulated together, thereby reducing the number of manufacturing steps. Furthermore, according to the present invention, the production of analogs of at least teneligliptin and canagliflozin in a pharmaceutical composition containing a mixture or granules obtained by mixing or granulating the active ingredients can be easily suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0016] 1. Method for producing the pharmaceutical composition according to the present invention The method of the present invention for producing a pharmaceutical composition containing teneligliptin and canagliflozin (hereinafter referred to as the "method of the present invention") is characterized by comprising the following steps A and B: A) Mixing / granulation process A step of mixing at least teneligliptin and canagliflozin in the absence of water to prepare a mixture containing them, or granulating such a mixture in the absence of water to prepare a granulated product. B) Molding process a step of processing the mixture or granules to form a solid preparation.

[0017] 1.1 Process A Step A is a mixing / granulation step in which at least teneligliptin and canagliflozin are mixed in the absence of water to prepare a mixture containing them, or the mixture is granulated in the absence of water to prepare a granulated product.

[0018] 1.1.1 About Teneligliptin and Canagliflozin The teneligliptin according to the present invention may be teneligliptin in its free form, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0019] Free teneligliptin is a known compound whose production method, physical properties, etc. are known, and pharmaceutically acceptable salts and hydrates of teneligliptin can also be produced from the free form by conventional methods. Specifically, pharmaceutically acceptable salts of teneligliptin can be obtained, for example, by reacting the free form of teneligliptin with a desired inorganic acid or organic acid in an appropriate solvent by conventional methods, and isolating and purifying the resulting salt. Commercially available salts can also be used.

[0020] The pharmaceutically acceptable salt of teneligliptin is not particularly limited as long as it is an acid addition salt, and includes salts with inorganic acids or salts with organic acids. Specific examples include salts with inorganic acids such as hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, and nitrate; and salts with organic acids such as acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, amino acid salts, and besylate.

[0021] In the present invention, preferred examples of teneligliptin include salts of teneligliptin with hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., and more preferred examples include salts of teneligliptin with hydrobromic acid, of which the hydrate of the 2.5 hydrobromide salt of teneligliptin is most preferred.

[0022] The canagliflozin according to the present invention may be canagliflozin in its free form, or a hydrate or solvate thereof, but is preferably canagliflozin hemihydrate. Here, the term "canagliflozin" is a concept that includes hydrates and solvates unless otherwise specified.

[0023] Canagliflozin is a known compound whose production method, physical properties, etc. are known, and hydrates of canagliflozin can also be produced from the free form by conventional methods. Alternatively, commercially available products can also be used.

[0024] The amount of teneligliptin used to prepare the mixture in step A is, for example, suitably 1 to 17 parts by mass, preferably 2 to 16 parts by mass, and particularly preferably 3 to 15 parts by mass, in terms of the free form of teneligliptin, relative to 100 parts by mass of the mixture. If the amount of teneligliptin is less than 1 part by mass, in terms of the free form of teneligliptin, relative to 100 parts by mass of the mixture, a bulky pharmaceutical composition may be required to fully exert the pharmacological effects of teneligliptin.

[0025] The amount of canagliflozin to be blended to prepare the mixture in step A is, for example, suitably in the range of 5 to 84 parts by mass, preferably 15 to 60 parts by mass, more preferably 30 to 55 parts by mass, and particularly preferably 40 to 50 parts by mass, in terms of the free form of canagliflozin per 100 parts by mass of the mixture. If the amount of canagliflozin blended is less than 5 parts by mass, in terms of the free form of canagliflozin per 100 parts by mass of the mixture, a bulky pharmaceutical composition may be required to fully exert the pharmacological effect of canagliflozin. Here, "as the free form of teneligliptin" and "as the free form of canagliflozin" both mean converted into the amount of the active substance in a state in which no salt, hydrate, etc. has been formed.

[0026] 1.1.2 About mixing The mixing in step A is performed in the absence of water to obtain a mixture containing two active ingredients. "Performed in the absence of water" refers to performing the mixing in a dry state without using water. Mixing two active ingredients in the absence of water means, for example, mixing teneligliptin and canagliflozin, which are typically in powder form, together in their bare form without granulation or other treatment. This mixing allows teneligliptin and canagliflozin to be substantially in contact with each other in the mixture. The mixing in step A can also be said to be mixing in a manner in which teneligliptin and canagliflozin can be substantially in contact with each other in the absence of water, and therefore differs from the mixing in which teneligliptin and canagliflozin are not substantially in contact with each other as described in Patent Document 1. In other words, the mixing in step A may be any mixing as long as it is not mixing in a manner in which teneligliptin and canagliflozin are not substantially in contact with each other in the absence of water.

[0027] The mixing method according to the present invention can be, for example, a method in which a powder composition containing teneligliptin powder, canagliflozin powder, and desired additives is physically mixed by a conventional method (see Figure 1).

[0028] Examples of mixing methods in which teneligliptin and canagliflozin do not substantially come into contact with each other include a method of preparing a teneligliptin granule containing teneligliptin and additives such as excipients but substantially not containing canagliflozin, and / or a canagliflozin granule containing canagliflozin and additives such as excipients but substantially not containing teneligliptin in an appropriate granulator, and then physically mixing a composition containing the teneligliptin granule and canagliflozin powder, the canagliflozin granule and teneligliptin powder, or the teneligliptin granule and canagliflozin granule in an appropriate mixer. On the other hand, the mixing method of the present invention is, for example, a method of physically mixing a powder composition containing teneligliptin powder, canagliflozin powder, and desired additives in an appropriate dry mixer as described above, without preparing a granule in the form of a teneligliptin granule or a canagliflozin granule.

[0029] Examples of the apparatus for carrying out the mixing include dry mixers used in the field of pharmaceutical formulations, etc. Specific examples of such mixers include mixers such as V-type mixers and tumbler mixers, and granulators such as high-speed stirring granulators, fluidized-bed granulation dryers, extrusion granulators, roller compactors, and chilsonators.

[0030] Prior to the mixing, for example, raw materials such as teneligliptin and canagliflozin can be pulverized, and the pulverized raw material powder can be sieved to size or classify. The production method of the present invention (Step A) can include such steps.

[0031] The mixture in step A is usually solid. Its form may be particulate, such as fine particles or granules, or may be in the form of a mass.

[0032] 1.1.3 Mixture ingredients other than the active ingredient In this mixing, in addition to the active ingredients teneligliptin and canagliflozin, a composition containing additives such as pharmaceutically acceptable excipients may be mixed.

[0033] Examples of such excipients include carbohydrates such as lactose, D-mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose hydrate, sucrose, sucrose, starch, partially pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin / dextrates, maltodextrin, and sugars for compression; inorganic salts such as calcium citrate, calcium phosphate, calcium aluminometasilicate, calcium carbonate, dicalcium phosphate, and calcium sulfate; and cellulose derivatives such as crystalline cellulose and wood cellulose. Of these, D-mannitol, lactose hydrate, and crystalline cellulose are more preferred. The above excipients may be used alone or in any combination of two or more.

[0034] The amount of excipient to be added to prepare the mixture can be set as appropriate taking into consideration the type of excipient, etc., but is, for example, appropriately within the range of 0 to 93 parts by mass, preferably within the range of 5 to 80 parts by mass, more preferably within the range of 10 to 60 parts by mass, and particularly preferably within the range of 20 to 50 parts by mass, relative to 100 parts by mass of the mixture.

[0035] Examples of additives other than the above-mentioned excipients include disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavorings, fragrances, and fluidizing agents. These can be blended in appropriate amounts as needed. Specific examples include the following:

[0036] Examples of disintegrants include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, and partially pregelatinized starch. Among these, low-substituted hydroxypropylcellulose is preferred. The disintegrants may be used alone or in any combination of two or more.

[0037] The amount of disintegrant used to prepare the mixture can be appropriately determined taking into consideration the type of disintegrant, etc., and is, for example, suitably within the range of 0 to 50 parts by mass, preferably within the range of 0 to 30 parts by mass, more preferably within the range of 0 to 20 parts by mass, and particularly preferably within the range of 0 to 15 parts by mass, relative to 100 parts by mass of the mixture.

[0038] Examples of binders include crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, partially pregelatinized starch, polyvinylpyrrolidone, and gum arabic. Of these, hydroxypropyl cellulose, crystalline cellulose, and partially pregelatinized starch are preferred. The binder may be used alone or in any combination of two or more kinds.

[0039] The amount of binder to be used to prepare the mixture can be set as appropriate taking into consideration the type of binder, etc., but is, for example, appropriately within the range of 0 to 15 parts by mass, preferably 0.5 to 5 parts by mass, more preferably 1 to 4 parts by mass, and particularly preferably 2 to 4 parts by mass, relative to 100 parts by mass of the mixture.

[0040] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate, of which sodium stearyl fumarate and magnesium stearate are preferred. The lubricants may be used alone or in any combination of two or more.

[0041] The amount of lubricant to be added to prepare the mixture can be set appropriately taking into consideration the type of lubricant, etc., but is, for example, appropriately within the range of 0 to 10 parts by mass, preferably within the range of 0.1 to 8 parts by mass, more preferably within the range of 0.2 to 5 parts by mass, and particularly preferably within the range of 0.3 to 4 parts by mass, relative to 100 parts by mass of the mixture.

[0042] Examples of coloring agents include carotenoids, iron oxides, and chlorophyll. Examples of coloring agents also include food color red No. 2 and No. 3, food color yellow No. 4 and No. 5, food color green No. 3, food color blue No. 1 and No. 2, aluminum lakes of these food colors, iron sesquioxide, and yellow iron sesquioxide. The colorants may be used alone or in any combination of two or more.

[0043] Examples of pH adjusters include citric acid, magnesium carbonate, magnesium aluminometasilicate, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, aluminum silicate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium acetate. The pH adjusters may be used alone or in any combination of two or more.

[0044] Examples of surfactants include sodium lauryl sulfate, sodium stearate, polyoxyethylene sorbitan monooleate, and sucrose fatty acid esters. The surfactants may be used alone or in any combination of two or more.

[0045] Examples of stabilizers include ascorbic acid, sodium edetate, erythorbic acid, and tocopherol. The stabilizers may be used alone or in any combination of two or more.

[0046] Examples of flavoring agents include acidulants such as citric acid, malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid, and sweeteners such as saccharin and aspartame. The flavoring agents may be used alone or in any combination of two or more.

[0047] Examples of flavoring agents include menthol, peppermint oil, orange oil, and lemon oil. The above-mentioned fragrances may be used alone or in any combination of two or more.

[0048] Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, and talc. The above fluidizing agents may be used alone or in any combination of two or more.

[0049] A preferred mixture in the production method of the present invention (Step A) includes, for example, a mixture containing the two active ingredients, one or more excipients (e.g., D-mannitol, lactose hydrate, crystalline cellulose), one or more disintegrants (e.g., low-substituted hydroxypropyl cellulose), one or more binders (e.g., hydroxypropyl cellulose), and one or more lubricants (e.g., magnesium stearate, sodium stearyl fumarate).

[0050] 1.1.4 Granulation The mixture in step A can be granulated in the absence of water to form a granulated product. Examples of granulation methods for obtaining such granulated products include dry granulation, and examples of equipment for this include dry granulators (e.g., roller compactors and chilsonators). Specifically, when granulation is performed using a roller compactor, the powder of the mixture prepared in step A is passed between two rollers of the roller compactor to form flakes, which are then crushed and sized using an appropriate sieving machine to produce the granulated product in this step. The production method of the present invention (step A) can include such work steps. Alternatively, the granules can be obtained by granulating at least teneligliptin and canagliflozin while mixing them in the absence of water (mixed granulation).

[0051] The particle size of the obtained granules is not particularly limited as long as it can be compressed and molded by a tablet press or the like. For example, the particle size may be a cumulative 50% particle size (D 50 ) is suitably in the range of 80 to 200 μm, preferably in the range of 100 to 180 μm, and more preferably in the range of 120 to 160 μm. In the present invention, the cumulative 50% on a volume basis is measured on a volume basis using a laser diffraction particle size measuring device.

[0052] 1.2 Process B Step B is a molding step in which the mixture or granules obtained in Step A is processed and molded into a solid preparation. Here, "processing" refers to subjecting the mixture or granules to a treatment such as compression (tabletting) in order to mold it into a solid preparation. During this process, other ingredients (for example, additives such as the above-mentioned excipients, binders, and lubricants) or materials can be added as necessary.

[0053] The dosage form of the solid preparation is not particularly limited, and examples thereof include oral administration preparations such as capsules, pills, granules, fine granules, powders, tablets, etc. These preparations can be produced by conventional methods. When the solid preparation is a tablet, it may be coated with sugar coating, film coating, or the like by a conventional method.

[0054] Specifically, step B can include, for example, a step of directly compressing the mixture obtained in step A by dry molding to form a solid preparation, or a step of compressing the granules obtained in step A to form a solid preparation (compression molding step). In this case, the solid preparation is usually a tablet.

[0055] Examples of the method for directly compressing the mixture in step A in a dry state to form a solid preparation include direct compression (direct compression). Prior to direct compression, the mixture can be sized or classified to make the particle size of the mixture uniform. The particle size is not particularly limited as long as it can be compressed using a tablet press or the like, but for example, the cumulative 50% particle size on a volume basis (D 50 ) is suitably in the range of 20 to 200 μm, preferably in the range of 40 to 180 μm, and more preferably in the range of 60 to 160 μm.

[0056] When the granules obtained in step A are compressed to form a solid preparation, the granules can be mixed with additives such as the disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, and fluidizing agents, as needed, and the mixture can be compressed to form a solid preparation.

[0057] The compression molding in step B can be carried out using, for example, a single punch tablet press, a rotary tablet press, etc. When a single punch tablet press, a rotary tablet press, etc. is used, the compression pressure is 1 to 50 kN / cm 2 It is appropriate to use a tableting pressure in the range of 5 to 35 kN / cm. 2 Furthermore, it is preferable to use a tapered die for the purpose of preventing tableting problems such as capping.

[0058] The water content of the mixture or granules in step A is not particularly limited, but is suitably, for example, 5% by mass or less, and more preferably 3% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass. In this specification, the water content of the composition of the present invention can be measured, for example, by the Karl Fischer method.

[0059] 1.3 Coating process The production method of the present invention may include a step of coating the pharmaceutical composition (tablet, plain tablet) produced through steps A and B with an appropriate coating agent. By undergoing such a step, for example, coated tablets can be produced. The coating step can be carried out according to a conventional method, for example, using a film coating device used in the pharmaceutical field.

[0060] The components of the coating agent include, for example, a coating base and a coating additive, which can be appropriately selected and used in appropriate amounts according to conventional methods.

[0061] Examples of coating bases include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. These may be used alone or in combination of any two or more.

[0062] Examples of sugar-coating bases include sugar alcohols such as sucrose, refined sucrose, and erythritol. Furthermore, one or more of the following may be used in combination: talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc.

[0063] Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and polyvinylpyrrolidone; and polysaccharides such as pullulan. These may be used alone or in combination of two or more.

[0064] Examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as shellac. These may be used alone or in combination of any two or more.

[0065] Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose, and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​and ethyl acrylate-methyl methacrylate copolymer suspensions. These may be used alone or in combination of two or more.

[0066] Examples of coating additives include light-blocking agents such as titanium oxide, fluidizing agents such as talc, and / or colorants such as ferric oxide and yellow ferric oxide, plasticizers such as polyethylene glycol, propylene glycol, triethyl citrate, castor oil, and polysorbates, and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid. These may be used alone or in combination of any two or more.

[0067] 1.4 Pharmaceutical compositions produced by the process of the present invention According to the process of the present invention, a pharmaceutical composition (combination drug) containing teneligliptin and canagliflozin can be produced. The pharmaceutical composition produced by the process of the present invention is in the form of a solid preparation, typically a tablet or a coated tablet (described below), which is a combination tablet of teneligliptin and canagliflozin.

[0068] The solid formulation has storage stability to the extent that it does not interfere with the manufacture and sale of pharmaceuticals. Specifically, for example, after storage of the solid formulation under open conditions at 40°C and 75% RH (relative humidity) for one month, the total amount of teneligliptin analogues is 0.5% by mass or less, 0.4% by mass or less, or 0.3% by mass or less, or after storage of the solid formulation under open conditions at 40°C and 75% RH for one month, the total amount of canagliflozin analogues is 0.2% by mass or less, 0.19% by mass or less, or 0.18% by mass or less. Alternatively, after the solid dosage form is stored in the open at 40°C and 75% RH for one month, the total amount of teneligliptin analogues is 0.5% by mass or less, 0.4% by mass or less, or 0.3% by mass or less, and after the solid dosage form is stored in the open at 40°C and 75% RH for one month, the total amount of canagliflozin analogues is 0.2% by mass or less, 0.19% by mass or less, or 0.18% by mass or less.

[0069] In other words, the amount of teneligliptin remaining in the solid formulation after one month of storage under open conditions at 40°C and 75% RH exceeds 99.5%, 99.6%, or 99.7% by mass, or the amount of canagliflozin remaining in the solid formulation after one month of storage under open conditions at 40°C and 75% RH exceeds 99.8%, 99.81%, or 99.82% by mass, or the amount of teneligliptin remaining in the solid formulation after one month of storage under open conditions at 40°C and 75% RH exceeds 99.5%, 99.6%, or 99.7% by mass, and the amount of canagliflozin remaining in the solid formulation after one month of storage under open conditions at 40°C and 75% RH exceeds 99.8%, 99.81%, or 99.82% by mass.

[0070] Furthermore, after the solid formulation is stored under the above conditions for 1 month, the amount of any of the related substances of compounds a to c related to teneligliptin is 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less, or after the solid formulation is stored under the above conditions for 1 month, the amount of any of the related substances of canagliflozin is 0.08% by mass or less, 0.06% by mass or less, or 0.05% by mass or less. Alternatively, after the solid formulation is stored under the above conditions for 1 month, the amount of any of the related substances of compounds a to c related to teneligliptin is 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less, and after the solid formulation is stored under the above conditions for 1 month, the amount of any of the related substances of canagliflozin is 0.08% by mass or less, 0.06% by mass or less, or 0.05% by mass or less.

[0071] The meaning of the above-mentioned "related substances" and their "(total) amount" will be explained later.

[0072] 2. Pharmaceutical composition according to the present invention The pharmaceutical composition of the present invention containing teneligliptin and canagliflozin (hereinafter referred to as "the composition of the present invention") is characterized in that it contains a mixture of at least teneligliptin and canagliflozin, and that after storage in the open at 40°C and 75% RH for one month, the total amount of teneligliptin analogues is 0.5% by mass or less, or after storage in the open at 40°C and 75% RH for one month, the total amount of canagliflozin analogues is 0.2% by mass or less.

[0073] 2.1 Mixture of Teneligliptin and Canagliflozin The meanings of "teneligliptin," "canagliflozin," "mixture," etc. are as defined above and have the same meanings as defined above. The composition of the present invention contains a mixture of at least teneligliptin and canagliflozin, and therefore, in the mixture, teneligliptin and canagliflozin are generally in a state of substantial contact with each other. This differs from the solid preparation described in Patent Document 1, in which teneligliptin and canagliflozin are present independently in the solid preparation so as not to be in substantial contact with each other.

[0074] A mixture of at least teneligliptin and canagliflozin usually contains, in addition to the active ingredients teneligliptin and canagliflozin, additives such as pharmaceutically acceptable excipients. Examples of additives other than the excipients include disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavorings, fragrances, and fluidizers. These can each be contained in an appropriate amount as needed.

[0075] 2.2 Ingredients and their contents The composition of the present invention contains the active ingredients teneligliptin and canagliflozin. The content of teneligliptin in the composition of the present invention can be selected appropriately depending on the dosage, frequency of administration, route of administration, etc., but is suitably, for example, within the range of 1 to 17 parts by mass, preferably 2 to 16 parts by mass, and particularly preferably 3 to 15 parts by mass, of the free form of teneligliptin per 100 parts by mass of the composition of the present invention. If the content of teneligliptin is less than 1 part by mass, as the free form of teneligliptin, per 100 parts by mass of the composition of the present invention, a bulky pharmaceutical composition may be required to fully exert the pharmacological effect of teneligliptin.

[0076] When the composition of the present invention is a solid preparation (tablet) to be administered once daily to an adult, the content of teneligliptin in the composition of the present invention is suitably within the range of 5 to 80 mg, preferably within the range of 10 to 40 mg, and more preferably within the range of 15 to 25 mg, as the free form of teneligliptin.

[0077] The content of canagliflozin in the composition of the present invention can be selected appropriately depending on the dosage, frequency of administration, route of administration, etc., but is suitably, for example, within the range of 5 to 84 parts by mass, preferably 15 to 60 parts by mass, more preferably 30 to 55 parts by mass, and particularly preferably 40 to 50 parts by mass, of the free form of canagliflozin per 100 parts by mass of the composition of the present invention. If the content of canagliflozin is less than 5 parts by mass, as the free form of canagliflozin, per 100 parts by mass of the composition of the present invention, a bulky pharmaceutical composition may be required to fully exert the pharmacological effect of canagliflozin.

[0078] When the composition of the present invention is a solid preparation (tablet) to be administered once daily to an adult, the content of canagliflozin in the composition of the present invention is suitably within the range of 20 to 300 mg, preferably within the range of 50 to 200 mg, more preferably within the range of 50 to 150 mg, and particularly preferably within the range of 80 to 120 mg, as the free form of canagliflozin.

[0079] As described above, a composition containing at least teneligliptin and canagliflozin, or a mixture obtained by mixing such compositions, generally contains additives such as pharmaceutically acceptable excipients in addition to the active ingredients teneligliptin and canagliflozin, and may also contain, for example, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavorings, fragrances, and fluidizing agents. Therefore, the composition of the present invention containing such a mixture may also contain appropriate amounts of these additives.

[0080] Examples of such excipients include carbohydrates such as lactose, D-mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose hydrate, sucrose, sucrose, starch, partially pregelatinized starch, dextrose, corn starch, modified corn starch, potato starch, wheat starch, rice starch, dextrin / dextrates, maltodextrin, and sugars for compression; inorganic salts such as calcium citrate, calcium phosphate, calcium aluminometasilicate, calcium carbonate, dicalcium phosphate, and calcium sulfate; and cellulose derivatives such as crystalline cellulose and wood cellulose. Of these, D-mannitol, lactose hydrate, and crystalline cellulose are more preferred. The above excipients may be contained in one kind or in any two or more kinds.

[0081] The content of the excipient in the composition of the present invention can be set as appropriate taking into consideration the type of excipient, etc., but is, for example, suitably in the range of 0 to 93 parts by mass, preferably in the range of 5 to 80 parts by mass, more preferably in the range of 10 to 60 parts by mass, and particularly preferably in the range of 20 to 50 parts by mass, relative to 100 parts by mass of the composition of the present invention.

[0082] In addition to the above-mentioned excipients, the composition of the present invention may contain additives such as disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, and fluidizing agents.

[0083] Examples of disintegrants include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, and partially pregelatinized starch, of which low-substituted hydroxypropylcellulose and partially pregelatinized starch are preferred. The disintegrant may be one type or any two or more types.

[0084] The content of the disintegrant in the composition of the present invention can be appropriately set in consideration of the type of disintegrant, etc., but is, for example, suitably in the range of 0 to 50 parts by mass, preferably in the range of 0 to 30 parts by mass, more preferably in the range of 0 to 20 parts by mass, and particularly preferably in the range of 0 to 15 parts by mass, relative to 100 parts by mass of the mixture.

[0085] Examples of binders include crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, partially pregelatinized starch, polyvinylpyrrolidone, and gum arabic. Of these, hydroxypropyl cellulose, crystalline cellulose, and partially pregelatinized starch are preferred. The binder may include one type or any two or more types.

[0086] The content of the binder in the composition of the present invention can be set as appropriate taking into consideration the type of binder, etc., but is, for example, suitably in the range of 0 to 15 parts by mass, preferably in the range of 0.5 to 5 parts by mass, more preferably in the range of 1 to 4 parts by mass, and particularly preferably in the range of 2 to 4 parts by mass, relative to 100 parts by mass of the mixture.

[0087] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate, of which sodium stearyl fumarate and magnesium stearate are preferred. The lubricant may be one kind or any two or more kinds.

[0088] The content of the lubricant in the composition of the present invention can be set as appropriate taking into consideration the type of lubricant, etc., but is, for example, suitably in the range of 0 to 10 parts by mass, preferably in the range of 0.1 to 8 parts by mass, more preferably in the range of 0.2 to 5 parts by mass, and particularly preferably in the range of 0.3 to 4 parts by mass, relative to 100 parts by mass of the mixture.

[0089] Specific examples of other colorants, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, and fluidizing agents are the same as those mentioned above.

[0090] Preferred examples of the composition of the present invention include compositions containing the two active ingredients, one or more excipients (e.g., D-mannitol, lactose hydrate, crystalline cellulose), one or more disintegrants (e.g., low-substituted hydroxypropyl cellulose, partially pregelatinized starch), one or more binders (e.g., hydroxypropyl cellulose, crystalline cellulose), and one or more lubricants (e.g., magnesium stearate, sodium stearyl fumarate).

[0091] 2.3 Total amount of related substances In the composition of the present invention, after one month of storage under open conditions at 40°C and 75% RH, the total content of teneligliptin analogs is 0.5% by mass or less (preferably 0.4% by mass or less, more preferably 0.3% by mass or less), or after one month of storage under open conditions at 40°C and 75% RH, the total content of canagliflozin analogs is 0.2% by mass or less (preferably 0.19% by mass or less, more preferably 0.18% by mass or less). Preferably, after one month of storage under open conditions at 40°C and 75% RH, the total content of teneligliptin analogs is 0.5% by mass or less (preferably 0.4% by mass or less, more preferably 0.3% by mass or less), and after one month of storage under open conditions at 40°C and 75% RH, the total content of canagliflozin analogs is 0.2% by mass or less (preferably 0.19% by mass or less, more preferably 0.18% by mass or less).

[0092] In other words, the composition of the present invention has a residual amount of teneligliptin of more than 99.5% by mass (preferably 99.6% by mass, more preferably 99.7% by mass) after storage under an open condition at 40°C and 75% RH for one month, or has a residual amount of canagliflozin of more than 99.8% by mass (preferably 99.81% by mass, more preferably 99.82% by mass) after storage under an open condition at 40°C and 75% RH for one month. Preferably, the composition of the present invention has a residual amount of teneligliptin of more than 99.5% by mass (preferably 99.6% by mass, more preferably 99.7% by mass) after storage under an open condition at 40°C and 75% RH for one month, and has a residual amount of canagliflozin of more than 99.8% by mass (preferably 99.81% by mass, more preferably 99.82% by mass) after storage under an open condition at 40°C and 75% RH for one month.

[0093] When the composition of the present invention containing teneligliptin is left in the open at 40°C and 75% RH for one month, the decomposition products of teneligliptin, i.e., teneligliptin analogues, include the following three compounds a to c. The total amount of teneligliptin analogues refers to the total amount of analogues including these three compounds.

[0094] a. Teneligliptin sulfoxide: [(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl]-3-thiazolidinylmethanone sulfoxide

[0095] [ka]

[0096] b.MPPP:1-(3-Methlyl-1-phenyl-5-piperazinyl)pyrazole

[0097] [ka]

[0098] c.Teneligliptin Impurity 5:((2S,4S)-4-(4-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone

[0099] [ka]

[0100] When the composition of the present invention containing canagliflozin is left in the open at 40°C and 75% RH for one month, the decomposition products of canagliflozin, i.e., canagliflozin analogues, are found to have unknown chemical structures, but there are at least three compounds. The total amount of canagliflozin related substances refers to the total amount of related substances including the three compounds.

[0101] In addition, the composition of the present invention, after one month of storage under the above conditions, contains no more than 0.3% by mass (preferably no more than 0.2% by mass, more preferably no more than 0.1% by mass) of any of the related substances of compounds a to c related to teneligliptin, or no more than 0.08% by mass (preferably no more than 0.06% by mass, more preferably no more than 0.05% by mass) of any of the related substances of canagliflozin. Preferably, the composition of the present invention, after one month of storage under the above conditions, contains no more than 0.3% by mass (preferably no more than 0.2% by mass, more preferably no more than 0.1% by mass) of any of the related substances of compounds a to c related to teneligliptin, and no more than 0.08% by mass (preferably no more than 0.06% by mass, more preferably no more than 0.05% by mass) of any of the related substances of canagliflozin.

[0102] 2.4 Manufacturing method and form The composition of the present invention can be produced, for example, by the production method described above in the section "1. Production method of the pharmaceutical composition of the present invention."

[0103] The composition of the present invention is usually in the form of a solid preparation, and the dosage form is not particularly limited, but examples thereof include oral administration preparations such as capsules, pills, granules, fine granules, powders, and tablets.

[0104] When the solid preparation is a tablet, it may be coated with a coating agent such as sugar coating or film coating by a conventional method. The coating can be carried out by a conventional method, for example, using a film coating device used in the pharmaceutical field. The components of the coating agent are the same as those described above and have the same meanings as those described above. Examples of tablets according to the composition of the present invention include plain tablets, coated tablets (film-coated tablets, sugar-coated tablets), orally disintegrating tablets, enteric-coated tablets, sustained-release tablets, and multi-layer tablets such as two-layer tablets.

[0105] The shape (surface shape) of the tablet is not particularly limited, and examples thereof include circular, oval, and polygonal shapes (square, rectangular, hexagonal, etc.), with circular shapes being preferred. The tablet diameter (average diameter) of the tablet is, for example, suitably within the range of 4 to 15 mm, preferably within the range of 6 to 10 mm, and more preferably within the range of 7 to 9 mm.

[0106] The thickness of the tablet is suitably, for example, within the range of 1 to 8 mm, preferably within the range of 2 to 6 mm, and more preferably within the range of 3 to 5 mm.

[0107] To improve identifiability, the surface of the tablet of the composition of the present invention may be engraved or printed with information such as the product number, name of the active ingredient, content of the active ingredient, dosage form, product number, QR code (registered trademark), and barcode. Engraving or printing may be performed directly on the surface of the plain tablet or film-coated tablet. An appropriate printing method can be selected from ink printing methods using plate-type transfer printing, gravure printing, offset printing, and inkjet printing, as well as laser printing. The ink used for printing can be selected from edible inks containing dyes and / or pigments, and the ink color may be one color or two or more colors from the viewpoint of identifiability, etc.

[0108] The water content of the composition of the present invention is not particularly limited, but is suitably, for example, 5% by mass or less, and more preferably 3% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass. As mentioned above, the water content of the composition of the present invention can be measured, for example, by the Karl Fischer method.

[0109] The composition of the present invention may be packaged in a packaging material. Examples of packaging include PTP packaging, strip packaging, bottle filling, and aluminum packaging. Examples of materials for PTP packaging that contain tablets and the like include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, as well as metals such as aluminum. These materials may be used alone or in combination. Examples of material combinations include laminates of polyvinyl chloride and polyvinylidene chloride, and laminates of polyvinyl chloride and polychlorotrifluoroethylene. Tablets can be packaged in PTPs by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering them with aluminum foil. PTP packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain a desiccant and / or oxygen scavenger. Examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Examples of oxygen scavengers include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. A single type of desiccant and / or desiccant may be used, or multiple types may be used in combination. A combination of desiccant and desiccant may also be used. An example of a product combining a desiccant and desiccant is PharmaKeep (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.).

[0110] The composition of the present invention may be filled in a glass or plastic bottle. Examples of materials for plastic bottles include the resins exemplified above for PTP packaging. The composition of the present invention may be packaged in aluminum packaging for each dose. The aluminum packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain the above-mentioned desiccant and / or oxygen scavenger.

[0111] 2.5 Use and administration method The composition of the present invention is useful as a pharmaceutical, and specifically, can be safely orally administered to humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) for the treatment or prevention of various diseases caused by DPP-4 due to the DPP-4 inhibitory activity of teneligliptin, and various diseases caused by SGLT2 due to the SGLT2 inhibitory activity of canagliflozin.

[0112] Therefore, the composition of the present invention can be used to treat, prevent, or delay diabetes or diabetes-related symptoms. Diabetes-related symptoms refer to various pathological symptoms that are associated with, caused by, or result from diabetes. The present invention can preferably be used for the treatment and / or prevention of type 2 diabetes or diabetes-related symptoms.

[0113] The composition of the present invention is preferably administered orally. The composition of the present invention can be administered once a day or in divided doses multiple times a day, but when the composition of the present invention is administered orally, it is preferably administered once a day or once a day before breakfast.

[0114] 3. Method for inhibiting the production of analogues according to the present invention The method of the present invention for inhibiting the production of analogues of at least one of the active ingredients in a pharmaceutical composition containing a mixture or granules obtained by mixing or mixing and granulating teneligliptin and canagliflozin (hereinafter referred to as the "production inhibition method of the present invention") is characterized in that the mixing and granulation are carried out in the absence of water.

[0115] The terms "teneligliptin," "canagliflozin," "mixture," and "granulation" have the same meanings as those described in the above section "1.1 Regarding Step A," and reference can be made to the contents thereof. In addition, reference can be made to the above contents regarding composition or mixture components other than the active ingredients teneligliptin and canagliflozin.

[0116] According to the production inhibition method of the present invention, the total amount of teneligliptin analogues in a pharmaceutical composition containing a mixture or granules obtained by mixing or granulating teneligliptin and canagliflozin can be reduced to 0.5% by mass or less, 0.4% by mass or less, or 0.3% by mass or less after storage in the open at 40°C and 75% RH for one month, or the total amount of canagliflozin analogues in the pharmaceutical composition can be reduced to 0.2% by mass or less, 0.19% by mass or less, or 0.18% by mass or less after storage in the open at 40°C and 75% RH for one month. Alternatively, the total amount of teneligliptin analogues in the pharmaceutical composition after storage under open conditions at 40°C and 75% RH for one month can be reduced to 0.5% by mass or less, 0.4% by mass or less, or 0.3% by mass or less, and the total amount of canagliflozin analogues in the pharmaceutical composition after storage under open conditions at 40°C and 75% RH for one month can be reduced to 0.2% by mass or less, 0.19% by mass or less, or 0.18% by mass or less.

[0117] In other words, after storage of the pharmaceutical composition under open conditions at 40°C and 75% RH for one month, more than 99.5%, 99.6%, or 99.7% by mass of teneligliptin may remain in the pharmaceutical composition, or more than 99.8%, 99.81%, or 99.82% by mass of canagliflozin may remain in the pharmaceutical composition after storage under open conditions at 40°C and 75% RH for one month. Alternatively, after storage of the pharmaceutical composition under open conditions at 40°C and 75% RH for one month, more than 99.5%, 99.6%, or 99.7% by mass of teneligliptin may remain in the pharmaceutical composition, and more than 99.8%, 99.81%, or 99.82% by mass of canagliflozin may remain in the pharmaceutical composition after storage under open conditions at 40°C and 75% RH for one month.

[0118] Furthermore, according to the production inhibition method of the present invention, the amount of any of the analogs of compounds a to c related to teneligliptin in the pharmaceutical composition after storage for one month under the above conditions can be reduced to 0.5% by mass or less, 0.3% by mass or less, or 0.2% by mass or less of any of the analogs of canagliflozin in the pharmaceutical composition after storage for one month under the above conditions can be reduced to 0.2% by mass or less, 0.1% by mass or less, or 0.05% by mass or less of any of the analogs of compounds a to c related to teneligliptin in the pharmaceutical composition after storage for one month under the above conditions can be reduced to 0.5% by mass or less, 0.3% by mass or less, or 0.2% by mass or less of any of the analogs of canagliflozin in the pharmaceutical composition after storage for one month under the above conditions can be reduced to 0.2% by mass or less, 0.1% by mass or less, or 0.05% by mass or less of any of the analogs of canagliflozin in the pharmaceutical composition after storage for one month under the above conditions. [Example]

[0119] The present invention will be explained below with reference to examples and test examples, but the present invention is not limited to these examples in any way.

[0120] Comparative Example 1: Tablets prepared by compressing a mixture of granulated teneligliptin powder and granulated canagliflozin powder According to the formulation in Table 1, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Comparative Example 1.

[0121] (1) Teneligliptin, D-mannitol, and hydroxypropyl cellulose were mixed, and purified water was added to the mixture while stirring and granulating (Granulation I), followed by drying and sieving to obtain a teneligliptin granulated powder. Separately, canagliflozin hydrate, D-mannitol, and hydroxypropyl cellulose were mixed, and purified water was added to the mixture while stirring and granulating (Granulation II), followed by drying and sieving to obtain a canagliflozin granulated powder.

[0122] (2) Low-substituted hydroxypropyl cellulose and sodium stearyl fumarate were added to the obtained teneligliptin granulated powder and canagliflozin granulated powder and mixed to obtain a mixture, which was then compressed into tablets using a rotary tableting machine (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce plain tablets (combination tablets) containing teneligliptin and canagliflozin.

[0123] (3) The obtained plain tablets were coated with a film coating agent (hypromellose and macrogol 6000 were dissolved in purified water, and this aqueous solution was mixed with a dispersion of titanium oxide, yellow ferric oxide, and ferric oxide separately dispersed in purified water, to which talc was added), to produce film-coated tablets containing teneligliptin and canagliflozin (Comparative Example 1).

[0124] [Table 1]

[0125] [Comparative Example 2] Tablets prepared by wet granulating a mixture of teneligliptin and canagliflozin and then compressing the granulated powder According to the formulation in Table 2, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Comparative Example 2.

[0126] (1) Teneligliptin, canagliflozin, D-mannitol, and hydroxypropyl cellulose were mixed, and the mixture was stirred and granulated with purified water, followed by drying and sieving to obtain a teneligliptin-canagliflozin granulated powder. Low-substituted hydroxypropyl cellulose and sodium stearyl fumarate were added to the granulated powder and mixed to obtain a mixture, which was then compressed using a rotary tablet press (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets (combined tablets) containing teneligliptin and canagliflozin.

[0127] (2) The obtained plain tablets were treated in the same manner as in Comparative Example 1 to produce film-coated tablets containing teneligliptin and canagliflozin (Comparative Example 2).

[0128] [Table 2]

[0129] [Comparative Example 3] Tablets prepared by wet granulating a mixture of teneligliptin and canagliflozin and then compressing the granulated powder According to the formulation in Table 3, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Comparative Example 3.

[0130] (1) Teneligliptin, canagliflozin, D-mannitol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose were mixed, and the mixture was stirred and granulated with purified water, followed by drying and sieving to obtain a teneligliptin-canagliflozin granulated powder. Sodium stearyl fumarate was added to the granulated powder and mixed to obtain a mixture, which was then compressed using a rotary tablet press (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets (combined tablets) containing teneligliptin and canagliflozin.

[0131] (2) The obtained plain tablets were treated in the same manner as in Comparative Example 1 to produce film-coated tablets containing teneligliptin and canagliflozin (Comparative Example 3).

[0132] [Table 3]

[0133] [Example 1] Tablets prepared by direct compression of a mixture of teneligliptin and canagliflozin According to the formulation in Table 4, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Example 1 (composition of the present invention).

[0134] (1) Teneligliptin, canagliflozin, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl fumarate were mixed to obtain a mixture, which was then sieved through a 500 μm sieve and compressed into tablets using a rotary tablet press (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets (combined tablets) containing teneligliptin and canagliflozin.

[0135] (2) The obtained uncoated tablets were treated in the same manner as in Comparative Example 1 to produce film-coated tablets containing teneligliptin and canagliflozin (Example 1). The obtained tablets were circular tablets with a hardness of 74 N, a tablet diameter of 8.5 mm, and a tablet thickness of 4.0 mm, and had a moisture content of 2.3% by mass.

[0136] [Table 4]

[0137] [Example 2] Tablets prepared by dry granulating a mixture of teneligliptin and canagliflozin and then compressing the granulated powder According to the formulation in Table 5, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Example 2 (composition of the present invention).

[0138] (1) Teneligliptin, canagliflozin, D-mannitol, hydroxypropyl cellulose, and sodium stearyl fumarate were mixed to obtain a mixture, which was then dry-granulated using a roller compactor (TF-MINI, Freund Corporation). The resulting granules were sized and classified using 500 μm to 75 μm sieves to obtain a granule containing teneligliptin and canagliflozin. Low-substituted hydroxypropyl cellulose and sodium stearyl fumarate were added to and mixed with the granules to obtain a mixture, which was then compressed using a rotary tablet press (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets (combined tablets) containing teneligliptin and canagliflozin.

[0139] The obtained uncoated tablets were treated in the same manner as in Comparative Example 1 to produce film-coated tablets containing teneligliptin and canagliflozin (Example 2). The obtained tablets were circular tablets with a hardness of 40 N, a tablet diameter of 8.5 mm, and a tablet thickness of 4.00 mm, and had a moisture content of 2.0% by mass.

[0140] [Table 5]

[0141] [Example 3] Tablets prepared by dry granulating a mixture of teneligliptin and canagliflozin and then compressing the granulated powder According to the formulation in Table 6, a pharmaceutical composition (plain tablet) containing teneligliptin and canagliflozin was obtained, and the plain tablet was then film-coated to produce the film-coated tablet of Example 3 (composition of the present invention).

[0142] (1) Teneligliptin, canagliflozin, lactose hydrate, crystalline cellulose, hydroxypropyl cellulose, and magnesium stearate were mixed to obtain a mixture, which was then dry-granulated using a roller compactor (TF-MINI, Freund Corporation). The resulting granules were sized and classified using 500 μm to 75 μm sieves to obtain a granule containing teneligliptin and canagliflozin. Partially pregelatinized starch and magnesium stearate were added to and mixed with the granules to obtain a mixture, which was then compressed using a rotary tablet press (VEL5-0312SS2MZ, Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets (combined tablets) containing teneligliptin and canagliflozin.

[0143] (2) The obtained uncoated tablets were treated in the same manner as in Comparative Example 1 to produce film-coated tablets containing teneligliptin and canagliflozin (Example 3). The obtained tablets were circular tablets with a hardness of 40 N, a tablet diameter of 8.5 mm, and a tablet thickness of 4.0 mm, and had a moisture content of 3.0% by mass.

[0144] [Table 6]

[0145] [Test example] Storage stability test The film-coated tablets of Comparative Examples 1 to 3 and Examples 1 to 3 were placed in a petri dish and stored in the open at 40°C and 75% RH for one month, after which the amounts of each related substance of teneligliptin and canagliflozin, as well as the total amount of related substances, were measured. The measurements were performed using a high-performance liquid chromatograph (HPLC) (Waters-Alliance, manufactured by Nippon Waters) equipped with an ultraviolet absorption spectrophotometer under the following conditions.

[0146] <Measurement conditions> LC section: The sample injection volume was 10 μL, and an octadecylsilylated silica gel column (Xbridge C18, manufactured by Nippon Waters) was used. The column oven temperature was set to 40°C, and the mobile phase flow rate was 1.0 mL / min. Mobile phase A was 0.1% trifluoroacetic acid, and mobile phase B was acetonitrile. Measurements were performed using the following concentration gradient control. After sample injection, the mixing ratio of mobile phase A and mobile phase B was gradually changed from 90% to 48% from 0 to 28 minutes, then from 48% to 10% from 28 to 43 minutes, and then maintained at 10% from 43 to 48 minutes.

[0147] Ultraviolet absorption detector: Each setting value is as follows. Measurement wavelength: 245nm and 292nm The related substances derived from teneligliptin do not have an absorption maximum around 292 nm and are barely detectable, so it was determined which drug substance the related substance was derived from. The results are shown in Tables 7 to 10 below.

[0148] [Table 7]

[0149] [Table 8]

[0150] [Table 9]

[0151] [Table 10]

[0152] As is clear from the above results, even in film-coated tablets prepared from a mixture obtained by mixing at least teneligliptin and canagliflozin (Examples 1 to 3, composition of the present invention), the total amount of teneligliptin analogues after storage in the open at 40°C and 75% RH for one month was 0.5% by mass or less, and the total amount of canagliflozin analogues after storage in the open at 40°C and 75% RH for one month was 0.2% by mass or less, similar to film-coated tablets prepared from a mixture obtained by mixing granulated teneligliptin powder and granulated canagliflozin powder, i.e., a mixture obtained by mixing teneligliptin and canagliflozin in such a manner that they were not substantially in contact with each other (pharmaceutical composition of Comparative Example 1).

[0153] Furthermore, in the film-coated tablets of Examples 1 to 3, like the film-coated tablets of Comparative Example 1, the amount of each of the related substances of compounds a to c related to teneligliptin after one month of storage under open conditions at 40°C and 75% RH was 0.5% by mass or less, and the amount of each of the three related substances related to canagliflozin after one month of storage under open conditions at 40°C and 75% RH was 0.2% by mass or less.

[0154] Therefore, the process of the present invention also makes it possible to produce a pharmaceutical composition (tablet) containing teneligliptin and canagliflozin that has storage stability sufficient for the manufacture and sale of pharmaceuticals, which is also advantageous in terms of productivity of the pharmaceutical composition (tablet). [Industrial Applicability]

[0155] The production method of the present invention can also be used to produce a pharmaceutical composition (tablet) containing teneligliptin and canagliflozin that has storage stability to a degree that does not interfere with the manufacture and sale of pharmaceuticals. The pharmaceutical product obtained thereby (the composition of the present invention) can be a substitute for the pharmaceutical product manufactured and sold, for example, as Canalia (registered trademark) combination tablets. Furthermore, the production inhibition method of the present invention can easily inhibit the production of analogs of both active ingredients in a pharmaceutical composition containing a mixture or granules obtained by mixing or granulating at least teneligliptin and canagliflozin, and therefore the present invention is useful in the pharmaceutical industry.

Claims

1. A method for producing a pharmaceutical composition containing teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin, the method comprising the following steps A and B: A) Mixing / granulation process A step of mixing at least teneligliptin or a pharmaceutically acceptable salt thereof with canagliflozin in the absence of water to prepare a mixture containing them, or granulating such a mixture in the absence of water to prepare a granule; and B) Molding process A step of processing the mixture or granules in the absence of water to form a solid preparation.

2. The method for producing a pharmaceutical composition according to claim 1, wherein the mixing in step A is performed in such a manner that teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin are substantially in contact with each other.

3. 2. The method for producing a pharmaceutical composition according to claim 1, wherein step B is a step of directly compressing the mixture in a dry state to form a solid preparation, or a step of compressing the granules to form a solid preparation.

4. The method for producing a pharmaceutical composition according to any one of claims 1 to 3, wherein the solid preparation is a tablet or a coated tablet.

5. The method for producing a pharmaceutical composition according to claim 4, wherein the total amount of teneligliptin analogues is 0.5% by mass or less when the solid preparation is stored in the open at 40°C and 75% RH for one month.

6. The method for producing a pharmaceutical composition according to claim 4, wherein the total amount of canagliflozin analogues is 0.2 mass% or less when the solid preparation is stored in the open at 40°C and 75% RH for one month.

7. A pharmaceutical composition comprising teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin, characterized in that the pharmaceutical composition contains a mixture of at least teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin, and the total amount of teneligliptin analogues is 0.5% by mass or less after storage in the open at 40°C and 75% RH for one month.

8. A pharmaceutical composition comprising teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin, characterized in that the pharmaceutical composition contains a mixture of at least teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin, and that the total amount of canagliflozin-related substances is 0.2 mass% or less after storage in the open at 40°C and 75% RH for one month.

9. 9. The pharmaceutical composition according to claim 7 or 8, wherein in the mixture, teneligliptin or a pharmaceutically acceptable salt thereof and canagliflozin are substantially in contact with each other.

10. 9. The pharmaceutical composition according to claim 7 or 8, which is in the form of a solid formulation.

11. The pharmaceutical composition according to claim 10, wherein the solid formulation is a tablet or a coated tablet.

12. A method for inhibiting the production of analogues of at least one of the active ingredients in a pharmaceutical composition containing a mixture or granules obtained by mixing or granulating at least teneligliptin or a pharmaceutically acceptable salt thereof with canagliflozin, characterized in that the mixing and granulation are carried out in the absence of water.

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