Sitagliptin preparation and method of storage thereof

Abstract

To provide a sitagliptin preparation in which the production of nitrosamines is suppressed, and to provide a method of storage of a sitagliptin preparation to suppress the production of nitrosamines.SOLUTION: According to an embodiment of the present invention, a sitagliptin preparation is provided, comprising a sitagliptin-containing tablet, and a case or a packing sealing the sitagliptin-containing tablet, wherein the equilibrium relative humidity of the sitagliptin-containing tablet, as converted to 24°C, is 50.3% or less when the sitagliptin preparation is stored for one month under conditions of 25°C and 60% relative humidity.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] One embodiment of the present invention relates to a sitagliptin formulation. Alternatively, one embodiment of the present invention relates to a method for storing a sitagliptin formulation. [Background technology]

[0002] Sitagliptin phosphate hydrate ((3R)-3-Amino-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one monophosphate monohydrate) is an inhibitor of dipeptidyl peptidase-IV (DPP-4) and is used as a therapeutic drug for type II diabetes (e.g., Patent Document 1).

[0003] In recent years, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have announced that 7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (NTTP), a nitrosamine, has been detected in sitagliptin formulations. Nitrosamines are known to have the potential to cause cancer, and the acceptable intake of NTTP is set at 37 ng per day. NTTP is produced by the reaction of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine, which is produced by hydrolysis of sitagliptin, with nitrogen oxides such as nitrous acid. Nitrogen oxides are contained in small amounts in additives, as well as in the water and air used in the formulation process. Although the route of NTTP production is predicted as described above, its reactivity, etc. are unknown. Therefore, there was no specific method for reducing the amount of NTTP in the formulation. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3762407 Summary of the Invention [Problem to be solved by the invention]

[0005] Generally, the standard for reporting the amount of related substances in a formulation is 1,000 ppm, but the acceptable daily intake of NTTP of 37 ng corresponds to 0.088 ppm, making it extremely difficult to suppress the formation of NTTP in sitagliptin formulations.

[0006] An object of one embodiment of the present invention is to provide a sitagliptin formulation that suppresses the formation of nitrosamines. Alternatively, an object of one embodiment of the present invention is to provide a method for storing a sitagliptin formulation that suppresses the formation of nitrosamines. [Means for solving the problem]

[0007] According to one embodiment of the present invention, there is provided a sitagliptin formulation comprising a sitagliptin-containing tablet and a container or packaging for sealing the sitagliptin-containing tablet, wherein the sitagliptin-containing tablet has an equilibrium relative humidity converted to 24°C of 50.3% or less when stored for one month under conditions of 25°C and a relative humidity of 60%.

[0008] The container or packaging may provide airtight conditions that allow the sitagliptin-containing tablets to be maintained at equilibrium relative humidity.

[0009] The sitagliptin-containing tablet may be contained in a blister package, and the blister package containing the sitagliptin-containing tablet may be sealed in a pillow package.

[0010] The blister pack containing the sitagliptin-containing tablets may be sealed in a pillow pack together with a desiccant.

[0011] The sitagliptin-containing tablet may be sealed in an airtight container together with a desiccant.

[0012] According to one embodiment of the present invention, there is provided a method for storing sitagliptin-containing tablets, the sitagliptin-containing tablets being sealed in a container or packaging, wherein the sitagliptin-containing tablets have an equilibrium relative humidity converted to 24°C of 50.3% or less when stored for one month under conditions of 25°C and a relative humidity of 60%.

[0013] The container or packaging may provide airtight conditions capable of maintaining the sitagliptin-containing tablets at said equilibrium relative humidity.

[0014] The sitagliptin-containing tablet may be contained in a blister package, and the blister package containing the sitagliptin-containing tablet may be sealed in a pillow package.

[0015] The blister pack containing the sitagliptin-containing tablets may be sealed in the pillow pack together with a desiccant.

[0016] The sitagliptin-containing tablets may be sealed in an airtight container along with a desiccant. Effect of the Invention

[0017] According to one embodiment of the present invention, there is provided a sitagliptin formulation that suppresses the formation of nitrosamines. Alternatively, according to one embodiment of the present invention, there is provided a method for storing a sitagliptin formulation to suppress the formation of nitrosamines. [Brief description of the drawings]

[0018] [Figure 1A] FIG. 1 is a schematic diagram illustrating a sitagliptin formulation according to one embodiment of the present invention and a storage method thereof. [Figure 1B] FIG. 1 is a schematic diagram illustrating a sitagliptin formulation according to one embodiment of the present invention and a storage method thereof. [Diagram 2]FIG. 1 shows the relationship between equilibrium relative humidity and the natural logarithm of the increase ratio of NTTP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The sitagliptin formulation and its storage method according to the present invention will be described below. The sitagliptin formulation and its storage method according to the present invention are not to be construed as being limited to the description of the following embodiments and examples. In the present embodiment and the examples described below, repeated description of the same configuration or configuration having similar functions will be omitted.

[0020] In order to meet the acceptable daily intake of NTTP of 37 ng per day, the amount of NTTP in sitagliptin-containing tablets at the time of ingestion must be 0.088 ppm or less. Considering that the threshold for reporting the amount of related substances in pharmaceutical preparations is generally 1,000 ppm, the acceptable daily intake of NTTP is a very strict standard. Since the shelf life of sitagliptin-containing tablets is set at 3 years at room temperature, the above acceptable daily intake must be met 3 years after manufacture.

[0021] As shown in the examples below, the present inventors have studied and found that the previously unknown factor of increase in NTTP is correlated with the equilibrium relative humidity of the sitagliptin-containing tablet. Furthermore, in order to meet the daily allowable intake of NTTP of 37 ng per day, it has been found that the equilibrium relative humidity of the sitagliptin-containing tablet 10 converted to 24°C when the sitagliptin formulation 100 is stored for one month under conditions of 25°C and 60% relative humidity must be 50.3% or less. The relationship between the management of the equilibrium relative humidity for suppressing the generation of nitrosamines in the sitagliptin-containing tablet 10 and the packaging form has not been studied so far, and the fact that the generation of nitrosamines in the sitagliptin-containing tablet 10 can be suppressed by maintaining the equilibrium relative humidity at 50.3% or less is a surprising effect that cannot be predicted from conventional knowledge.

[0022] [Sitagliptin preparations] 1A and 1B are schematic diagrams illustrating a sitagliptin formulation and its storage method according to one embodiment. The sitagliptin formulation 100 according to this embodiment includes a sitagliptin-containing tablet 10 and a container or packaging for sealing the sitagliptin-containing tablet 10. When the sitagliptin formulation 100 is stored for one month under conditions of 25°C and a relative humidity of 60%, the equilibrium relative humidity of the sitagliptin-containing tablet 10 converted to 24°C is 50.3% or less. In this specification, the "equilibrium relative humidity" refers to the relative humidity in a state in which there is no exchange of moisture between a hygroscopic substance and the surrounding environment.

[0023] In one embodiment, the container or packaging provides an airtight state capable of maintaining the sitagliptin-containing tablet 10 at equilibrium relative humidity. In this specification, the term "airtight state" refers to a state in which solid or liquid foreign matter does not enter and loss, efflorescence, deliquescence, or evaporation of the pharmaceutical content can be prevented. The airtight state may also be a sealed state. In this specification, the term "sealed state" refers to a state in which gas does not enter.

[0024] 1A and 1B, as one embodiment, a sitagliptin-containing tablet 10 is contained in a blister package 101. In Fig. 1A and 1B, a PTP package sheet is shown as an example of the blister package 101. The blister package 101 containing the sitagliptin-containing tablet 10 is further sealed with a pillow package 103.

[0025] Known blister packages and pillow packages can be used for the blister package 101 and the pillow package 103, respectively. The blister package 101 may be a composite sheet of a film selected from a polyvinyl chloride film, a polyvinylidene chloride film, a polychlorotrifluoroethylene film, and a polypropylene film. The blister package 101 may also be a PTP packaging sheet in which the opening of a container made of the above-mentioned film is sealed with aluminum foil.

[0026] The pillow package 103 may be an aluminum pillow. Since the pillow package 103 is a packaging form with excellent sealing properties, the moisture content inside the pillow package 103 can be maintained approximately constant during storage. Therefore, when the blister package 101 is sealed with the pillow package 103 (initial), the equilibrium relative humidity of the space inside the pillow package 103 at the time of reaching a steady state, converted to 24°C, is 50.3% or less, preferably 50% or less, more preferably 40% or less, even more preferably 30% or less, and most preferably 20% or less. The lower limit of the equilibrium relative humidity converted to 24°C is not particularly limited as long as it is within the above range, but is, for example, 10% or more.

[0027] In this specification, the equilibrium relative humidity of a sitagliptin-containing tablet converted to 24°C is evaluated as the equilibrium relative humidity when 100 sitagliptin formulations are stored for one month under conditions of 25°C and a relative humidity of 60%.

[0028] In one embodiment, the blister package 101 containing the sitagliptin-containing tablet 10 may be sealed in the pillow package 103 together with the desiccant 105. When the sitagliptin-containing tablet 10 has a high moisture content or when the humidity in the blister package 101 is high, the desiccant 105 absorbs the moisture of the sitagliptin-containing tablet 10 and can maintain the equilibrium relative humidity converted to 24°C in the space in the pillow package 103 within the above range. In this embodiment, by sealing the blister package 101 or by sealing the blister package 101 together with the desiccant 105, the equilibrium relative humidity converted to 24°C in the space in the pillow package 103 that has reached a steady state can be maintained within the above range. As a result, the equilibrium relative humidity converted to 24°C in the space in the blister package 101 that has reached a steady state is also maintained within the above range, and the equilibrium relative humidity converted to 24°C of the sitagliptin-containing tablet 10 that has reached a steady state can be maintained within the above range.

[0029] A known desiccant used as a desiccant for pharmaceuticals can be used as the desiccant 105. For example, it can be selected from calcium chloride (e.g., ID (registered trademark) sheet from ID Co., Ltd.), zeolite (e.g., MS-Ceram-W 3G from Tokai Chemical Industry Co., Ltd.), and oxygen absorber (e.g., PharmaKeep (registered trademark) from Mitsubishi Gas Chemical Co., Inc.).

[0030] When desiccant 105 is enclosed in pillow package 103, the equilibrium relative humidity is determined by the moisture absorption capacity of desiccant 105. When desiccant 105 is not used, the relative humidity inside pillow package 103 is determined by the environmental humidity in the controlled working environment of the pillow package.

[0031] In one embodiment, the container for sealing the sitagliptin-containing tablet 10 may be, for example, an airtight container such as a tablet bottle or a plastic bottle made of polypropylene or high-density polyethylene. In this specification, the term "airtight container" refers to a container that does not allow solid or liquid foreign matter to enter and can prevent loss, efflorescence, deliquescence, or evaporation of the contained pharmaceutical product under normal handling, transportation, or storage conditions, as specified in the general rules of the Japanese Pharmacopoeia, 18th Edition. Also, a sealed container may be used as the airtight container. In this specification, the term "sealed container" refers to a container that does not allow gas to enter under normal handling, transportation, or storage conditions.

[0032] Also, in one embodiment, the sitagliptin-containing tablet 10 may be sealed in the container described above together with the desiccant 105 .

[0033] In one embodiment, the sitagliptin formulation 100 may be housed, for example, in a paper box, which may be further covered with a vinyl film.

[0034] [Sitagliptin-containing tablets] In this embodiment, the sitagliptin-containing tablet 10 may be a known sitagliptin-containing tablet. The sitagliptin-containing tablet 10 may be in the form of a pharma- ceutically acceptable salt as sitagliptin. The term "pharma-ceutically acceptable salt" refers to a salt prepared from a non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Examples of salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts, potassium salts, sodium salts, and zinc salts. In addition, salts in solid form may exist in two or more crystal structures, or may exist in the form of a hydrate. Salts derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0035] A "pharmaceutically acceptable salt" may also be a salt derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.

[0036] The amount of sitagliptin contained in each of the sitagliptin-containing tablets 10 can be set arbitrarily within a range in which a therapeutic effect can be obtained, and may be, for example, 12.5 mg, 25 mg, 50 mg, or 100 mg in free form, and is not particularly limited.

[0037] [Storage method for sitagliptin-containing tablets] 1A and 1B. In the storage method of the sitagliptin-containing tablet 10, the sitagliptin-containing tablet 10 is stored sealed in a container or package. The sitagliptin-containing tablet 10 stored for one month sealed in a container or package under conditions of 25°C and a relative humidity of 60% has an equilibrium relative humidity converted to 24°C of 50.3% or less.

[0038] In one embodiment, the container or packaging provides an airtight state capable of maintaining the sitagliptin-containing tablet 10 at equilibrium relative humidity. In one embodiment, the sitagliptin-containing tablet 10 may be maintained in a sealed state by the container or packaging. In one embodiment, in order to provide an airtight state by packaging, the sitagliptin-containing tablet 10 may be contained in a blister package 101, and the blister package 101 containing the sitagliptin-containing tablet 10 may be further sealed with a pillow package 103. Details of the blister package 101 and the pillow package 103 have been described above, and therefore repeated explanations will be omitted.

[0039] Since pillow package 103 is a packaging form with excellent sealing properties, the moisture content inside pillow package 103 can be maintained approximately constant during storage. Therefore, when blister package 101 is sealed with pillow package 103 (initial), the equilibrium relative humidity of the space inside pillow package 103 at the time of reaching a steady state, converted to 24°C, is 50.3% or less, preferably 50% or less, more preferably 40% or less, even more preferably 30% or less, and most preferably 20% or less. The lower limit of the equilibrium relative humidity converted to 24°C is not particularly limited as long as it is within the above range, but is, for example, 10% or more.

[0040] The moisture content of the space inside the pillow package 103 at the time (initial time) when the blister package 101 is sealed with the pillow package 103 is affected by the moisture content of the sitagliptin-containing tablets 10 themselves and the humidity of the working environment in which the blister package 101 is sealed with the pillow package 103. Therefore, in order to make the equilibrium relative humidity converted to 24°C of the space inside the pillow package 103 that has reached a steady state at the time when the PTP packaging sheet 101 is sealed with the pillow package 103 50.3% or less, preferably 50% or less, more preferably 40% or less, even more preferably 30% or less, and most preferably 20% or less, it is necessary to adjust the moisture content of the sitagliptin-containing tablets 10 themselves and the humidity of the working environment in which the PTP packaging sheet 101 is sealed with the pillow package 103. On the other hand, since the manufacturing process of the sitagliptin-containing tablet 10 generally includes a drying process, as long as sufficient drying is performed in the manufacturing process, the moisture content of the sitagliptin-containing tablet 10 itself is adjusted so that the equilibrium relative humidity converted to 24°C is within the above-mentioned range.

[0041] In one embodiment, the blister package 101 containing the sitagliptin-containing tablet 10 may be sealed in the pillow package 103 together with the desiccant 105. When the sitagliptin-containing tablet 10 has a high moisture content or when the humidity in the blister package 101 is high, the desiccant 105 absorbs the moisture of the sitagliptin-containing tablet 10 and can maintain the equilibrium relative humidity converted to 24°C in the space in the pillow package 103 within the above range. In this embodiment, by sealing the blister package 101 or by sealing the blister package 101 together with the desiccant 105, the equilibrium relative humidity converted to 24°C in the space in the pillow package 103 that has reached a steady state can be maintained within the above range. As a result, the equilibrium relative humidity converted to 24°C in the space in the blister package 101 that has reached a steady state is also maintained within the above range, and the equilibrium relative humidity converted to 24°C of the sitagliptin-containing tablet 10 that has reached a steady state can be maintained within the above range. The details of the desiccant 105 have been described above, so a duplicated description will be omitted.

[0042] When desiccant 105 is enclosed in pillow package 103, the equilibrium relative humidity is determined by the moisture absorption capacity of desiccant 105. When desiccant 105 is not used, the relative humidity inside pillow package 103 is determined by the environmental humidity in the controlled working environment of the pillow package.

[0043] In one embodiment, an airtight container such as a tablet bottle or a plastic bottle made of polypropylene or high-density polyester can be used as a container for sealing the sitagliptin-containing tablet 10. Details of the airtight container have been described above, so a duplicated description will be omitted.

[0044] In one embodiment, the sitagliptin-containing tablet 10 may be sealed together with a desiccant 105 in the container described above.

[0045] In one embodiment, the sitagliptin formulation 100 may be housed, for example, in a paper box, which may be further covered with a vinyl film.

[0046] By storing the sitagliptin-containing tablet 10 in this manner, the production of NTTP in the sitagliptin-containing tablet 10 can be suppressed to the acceptable daily intake of 37 ng per day. EXAMPLES

[0047] [Comparative Examples 1 and 2] NTTP contained in commercially available sitagliptin-containing tablets was evaluated. As Comparative Example 1, commercially available Januvia (registered trademark) tablets (50 mg) stored at room temperature for 3 years from production without humidity adjustment were used. As Comparative Example 2, commercially available Januvia (registered trademark) tablets (50 mg) stored at room temperature for 1 year from production without humidity adjustment were used. Note that the sitagliptin-containing tablets of Comparative Examples 1 and 2 were sealed only with a PTP packaging sheet.

[0048] [Quantitative determination of NTTP] Weigh out 2.5 mg of NTTP and dissolve it in diluted phosphoric acid (JIS K9005 phosphoric acid special grade 1 ml diluted to 1000 ml with water.) / acetonitrile mixture (19:1) to make exactly 25 ml. Weigh out 1 ml of this liquid accurately and add diluted phosphoric acid (JIS K9005 phosphoric acid special grade 1 ml diluted to 1000 ml with water.) / acetonitrile mixture (19:1) to make exactly 100 ml. Weigh out 1 ml, 2 ml, and 5 ml of this liquid accurately and add diluted phosphoric acid (JIS K9005 phosphoric acid special grade 1 ml diluted to 1000 ml with water.) / acetonitrile mixture (19:1) to make exactly 50 ml each, and use them as standard solution (4), standard solution (5), and standard stock solution. Furthermore, 1 ml, 2 ml, and 5 ml of the standard stock solution were accurately measured, and diluted phosphoric acid (JIS K9005 phosphoric acid special grade 1 ml was diluted with water to 1000 ml) / acetonitrile mixture (19:1) was added to make exactly 50 ml each, and these were used as standard solutions (1), (2), and (3). 20 μl of each standard solution was accurately taken and measured by a high performance liquid chromatograph mass spectrometer. The peak area of ​​each standard solution was calculated by an automatic analysis method, and a calibration curve was created from the peak area of ​​each standard solution, with the vertical axis representing the peak area and the horizontal axis representing the concentration of the standard solution (mg / ml).

[0049] The mass of 4 tablets containing sitagliptin in Comparative Example 1 or 2 was precisely measured. 40 ml of diluted phosphoric acid (JIS K9005 phosphoric acid special grade 1 ml was diluted to 1000 ml with water.) / acetonitrile mixture (19:1) was added, and ultrasonic treatment was performed while occasionally shaking until the tablets were completely disintegrated. Diluted phosphoric acid / acetonitrile mixture (19:1) was further added to make exactly 50 ml. This liquid was filtered through a membrane filter with a pore size of 0.2 μm, the first 2 ml of the filtrate was removed, and the subsequent filtrate was used as the sample solution. 20 μl of the sample solution was accurately taken and measured by a high performance liquid chromatograph mass spectrometer, and the peak area of ​​the sample solution was calculated by an automatic analysis method. The amount of NTTP in the sample solution was obtained from the peak area (Ar) of NTTP in the sample solution using the following relational equation of the amount of NTTP obtained from the calibration curve. Amount of NTTP (ppm) = (Ar-b) / a*1 / Mr*50000 a: Slope of the calibration curve b: Y-intercept of the calibration curve Mr: Weight of 4 tablets (g) 50000: Correction factor

[0050] The amount of NTTP contained in the sitagliptin-containing tablet of Comparative Example 1 or 2 is shown in Table 1. [Table 1]

[0051] The results in Table 1 reveal that the sitagliptin-containing tablets of Comparative Example 1 or 2 contain NTTP at a level far exceeding the daily acceptable intake of 0.088 ppm.

[0052] [Reference Example 1 and Examples 1 to 3] As Reference Example 1, 50 mg of sitagliptin-containing tablets were placed in a plastic bottle made of high density polyethylene together with a desiccant (however, the bottle was not tightly sealed due to loose seams), as Example 1, 50 mg of sitagliptin-containing tablets were placed in a plastic bottle made of high density polyethylene together with a desiccant, as Example 2, 25 mg of sitagliptin-containing tablets were placed in a PTP packaging sheet and further sealed in a pillow package together with a desiccant, and as Example 3, 25 mg of sitagliptin-containing tablets were placed in a plastic bottle made of high density polyethylene together with a desiccant, and stored at room temperature or in a cool place for 36 months. Note that the desiccants in Examples 1 and 3 were different in size.

[0053] [Measurement of equilibrium relative humidity] The equilibrium relative humidity of the sitagliptin-containing tablets of Comparative Examples 1 and 2 was measured using a moisture measuring device (Hygrolab2) manufactured by Rotronic. 20 tablets of 50 mg sitagliptin-containing tablets of Reference Example 1 or Example 1 stored under the above conditions, or 30 tablets of 25 mg sitagliptin-containing tablets of Example 2 or Example 3 were placed in a sample cup, set in a measurement chamber, and measured at room temperature. The equilibrium relative humidity and temperature at the time when the equilibrium relative humidity was equilibrated were recorded. The equilibrium relative humidity was measured twice for each of the sitagliptin-containing tablets of Reference Example 1 and Examples 1 to 3. The average values ​​of the measured equilibrium relative humidity and temperature were converted to the equilibrium relative humidity at 24°C using the following formula. T: Average temperature during measurement E: Average value of the measured equilibrium relative humidity Ps: Saturated water vapor pressure at the measured temperature P: Water vapor pressure at the measured temperature H: Absolute humidity at the measured temperature Ps[kPa]=0.611*10^(7.5*T / (T+237.3)) P[kPa]=E / 100*Ps H[kg / kgDA]=0.62*P / (101.3-P) Equilibrium relative humidity at 24°C [%RH] = H*101.3 / (H+0.62)*2.98

[0054] [Quantitative determination of NTTP] The amount of NTTP contained in the sitagliptin-containing tablets after storage was quantified by the above-mentioned measurement method in Reference Example 1 and Examples 1 to 3. The amount of NTTP was quantified three times, and the maximum value was regarded as the amount of NTTP contained in each tablet.

[0055] The equilibrium relative humidity and the amount of NTTP in the sitagliptin-containing tablets of Reference Example 1 and Examples 1 to 3 after storage are shown in Table 2. The relationship between the equilibrium relative humidity and the natural logarithm of the increase ratio of NTTP is shown in FIG. [Table 2]

[0056] As shown in Figure 2, it was revealed that the amount of NTTP in sitagliptin-containing tablets increases exponentially with the equilibrium relative humidity. From the regression equation obtained in Figure 2, it was revealed that when the initial NTTP amount is 0.006 ppm, the equilibrium relative humidity converted to 24°C at which the NTTP amount after 36 months becomes 37 ng / day (0.088 ppm) is 50.3%. [Explanation of symbols]

[0057] 10 Sitagliptin-containing tablets, 100 Sitagliptin formulation, 101 Packaging sheet, 101 Blister packaging, 103 Pillow packaging, 105 Desiccant

Claims

1. A sitagliptin formulation comprising a sitagliptin-containing tablet and a container or package for sealing the sitagliptin-containing tablet, A sitagliptin formulation, wherein the sitagliptin-containing tablet has an equilibrium relative humidity of 50.3% or less, calculated at 24°C, when the sitagliptin formulation is stored for one month under conditions of 25°C and a relative humidity of 60%.

2. The sitagliptin formulation of claim 1 , wherein the container or packaging provides an airtight condition capable of maintaining the sitagliptin-containing tablet at the equilibrium relative humidity.

3. The sitagliptin-containing tablet is contained in a blister pack; The sitagliptin formulation according to claim 1 , wherein the blister package containing the sitagliptin-containing tablet is sealed in a pillow package.

4. The sitagliptin formulation according to claim 3 , wherein the blister package containing the sitagliptin-containing tablet is sealed in the pillow package together with a desiccant.

5. The sitagliptin formulation of claim 1 , wherein the sitagliptin-containing tablet is sealed in an airtight container together with a desiccant.

6. A method for storing a sitagliptin-containing tablet, the method comprising sealing the sitagliptin-containing tablet in a container or packaging, A method for storing a sitagliptin-containing tablet, wherein the sitagliptin-containing tablet has an equilibrium relative humidity converted to 24°C of 50.3% or less when stored for one month under conditions of 25°C and a relative humidity of 60%.

7. The method for storing a sitagliptin-containing tablet according to claim 6, wherein the container or packaging provides an airtight condition capable of maintaining the sitagliptin-containing tablet at the equilibrium relative humidity.

8. The sitagliptin-containing tablet is placed in a blister package, The method for storing a sitagliptin-containing tablet according to claim 6, wherein the blister package containing the sitagliptin-containing tablet is sealed with a pillow package.

9. The method for storing a sitagliptin-containing tablet according to claim 8, wherein the blister package containing the sitagliptin-containing tablet is sealed in the pillow package together with a desiccant.

10. The method for storing a sitagliptin-containing tablet according to claim 6, wherein the sitagliptin-containing tablet is sealed in an airtight container together with a desiccant.

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