Sitagliptin preparation and storage method thereof

Abstract

One embodiment of the present invention provides a sitagliptin preparation in which the production of nitrosamine is suppressed. Alternatively, one embodiment of the present invention provides a method for storing a sitagliptin preparation for suppressing the production of nitrosamine. According to one embodiment of the present invention, provided is a sitagliptin preparation comprising a sitagliptin-containing tablet and a container or a package in which the sitagliptin-containing tablet is sealed, in which when the sitagliptin preparation is stored at 25 DEG C and at a relative humidity of 60% for one month, the sitagliptin preparation does not contain any one of the sitagliptin-containing tablets and does not contain any one of the sitagliptin-containing tablets. The sitagliptin-containing tablet has an equilibrium relative humidity of 50.3% or less in terms of 24 DEG C.

Description

Technical Field

[0001] One embodiment of the present invention relates to a sitagliptin preparation. Alternatively, one embodiment of the present invention relates to a storage method of a sitagliptin preparation. Background Art

[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-onemonophosphate monohydrate: (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 monohydrate) is an inhibitor of dipeptidyl peptidase-IV (DPP-4) and is used as a therapeutic drug for type II diabetes (for example, Patent Document 1).

[0003] In recent years, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) announced that 7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine(NTTP), which is classified as a nitrosamine, was detected in sitagliptin preparations. Nitrosamines are known to have the potential to be carcinogenic, and the tolerable daily intake of NTTP (Nitroso-STG-19: nitrosamine impurity) is set at 37ng. NTTP is generated by the reaction of 3-(trifluoromethyl)-5,6,7,8-tetrahudro[1,2,4]triazolo-[4,3-a]pyrazine (3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine) produced by the hydrolysis of sitagliptin with nitrogen oxides such as nitrous acid. Nitrogen oxides are present in trace amounts in additives and also in water and air used in the formulation process. In addition, although the formation pathway of NTTP is expected to be as described above, its reactivity and other aspects are still unclear. Therefore, the specific method of reducing the NTTP content in the formulation is also completely unknown.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent No. 3762407 Summary of the invention

[0007] Problem that the invention aims to solve

[0008] Generally, the standard for reporting the amount of related substances in a preparation is 1000 ppml, but the permissible daily intake of NTTP, 37 ng, is equivalent to 0.088 ppml. Therefore, it is a very difficult problem to inhibit the formation of NTTP in sitagliptin preparations.

[0009] One object of one embodiment of the present invention is to provide a sitagliptin preparation that suppresses the production of nitrosamines. Alternatively, one object of one embodiment of the present invention is to provide a storage method for a sitagliptin preparation that suppresses the production of nitrosamines.

[0010] Means used to solve problems

[0011] According to one embodiment of the present invention, a sitagliptin preparation is provided, comprising a tablet containing sitagliptin and a container or package sealing the tablet containing sitagliptin, wherein when the sitagliptin preparation is stored at 25°C and a relative humidity of 60% for one month, the equilibrium relative humidity of the tablet containing sitagliptin when converted to 24°C is less than 50.3%.

[0012] The container or package may provide an airtight state capable of maintaining the tablet containing sitagliptin at equilibrium relative humidity.

[0013] The tablets containing sitagliptin may be contained in a blister pack, and the blister pack containing the tablets containing sitagliptin may be sealed with pillow packaging.

[0014] The blister pack containing the sitagliptin containing tablets may be sealed with a pillow pack together with a desiccant.

[0015] Tablets containing sitagliptin may be sealed in an airtight container together with a desiccant.

[0016] According to one embodiment of the present invention, a storage method for tablets containing sitagliptin is provided, wherein the tablets containing sitagliptin are sealed in a container or package, wherein when the tablets containing sitagliptin are stored for one month at 25°C and a relative humidity of 60%, the equilibrium relative humidity of the tablets containing sitagliptin when converted to 24°C is less than 50.3%.

[0017] The container or package may provide an airtight state capable of maintaining the tablet containing sitagliptin at equilibrium relative humidity.

[0018] The tablets containing sitagliptin may be contained in a blister pack, and the blister pack containing the tablets containing sitagliptin may be sealed with pillow packaging.

[0019] The blister pack containing the sitagliptin-containing tablets may be sealed with a pillow pack together with a desiccant.

[0020] Tablets containing sitagliptin may be sealed in an airtight container together with a desiccant.

[0021] Effects of the Invention

[0022] According to one embodiment of the present invention, a sitagliptin preparation that suppresses the production of nitrosamines is provided. Alternatively, according to one embodiment of the present invention, a storage method of a sitagliptin preparation that suppresses the production of nitrosamines is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1A This is a schematic diagram for explaining a sitagliptin preparation and a storage method thereof according to one embodiment of the present invention.

[0024] Figure 1B This is a schematic diagram for explaining a sitagliptin preparation and a storage method thereof according to one embodiment of the present invention.

[0025] Figure 2 Graph showing the relationship between equilibrium relative humidity and the natural logarithm of the increase ratio of NTTP.

[0026] Description of Reference Numerals

[0027] 10: Tablet containing sitagliptin, 100: Sitagliptin preparation, 101: Packaged tablet, 101: Blister package, 103: Pillow package, 105: Desiccant. DETAILED DESCRIPTION

[0028] Below, the sitagliptin preparation involved in the present invention and the storage method thereof are described. In addition, the sitagliptin preparation of the present invention and the storage method thereof should not be construed as being limited to the description content of the embodiment shown below and the examples. In this embodiment and the examples described later, the repeated description of the structure with the same structure or the same function is omitted.

[0029] In order to meet the permissible intake of NTTP of 37 ng per day, the NTTP in the tablet containing sitagliptin must be below 0.088 ppml when taking the medicine. Considering that the reporting threshold of the amount of related substances in the preparation is generally 1000 ppm, the permissible intake of NTTP per day is a very strict standard. The shelf life of the tablet containing sitagliptin is set at 3 years at room temperature, so the above-mentioned permissible intake per day needs to be met at the time point 3 years after manufacturing.

[0030] As shown in the examples described below, the inventors' research results show that the hitherto unknown NTTP increase factor is related to the equilibrium relative humidity of the tablet containing sitagliptin. In addition, in order to meet the daily permissible intake of 37 ng of NTTP per day, it is clear that the relative humidity of the tablet containing sitagliptin 10 converted to 24°C when the sitagliptin preparation 100 is stored for one month at 25°C and a relative humidity of 60% must be 50.3% or less. The relationship between the management of the equilibrium relative humidity for suppressing the formation of nitrosamines in the tablet containing sitagliptin 10 and the packaging form has not been studied so far. By maintaining the equilibrium relative humidity below 50.3%, the formation of nitrosamines in the tablet containing sitagliptin 10 can be suppressed, which is a surprising effect that could not be expected based on existing knowledge.

[0031] [Sitagliptin preparations]

[0032] Figure 1A and 1B A schematic diagram for illustrating a sitagliptin preparation and a storage method thereof according to an embodiment. The sitagliptin preparation 100 according to the present embodiment includes a tablet 10 containing sitagliptin and a container or package for sealing the tablet 10 containing sitagliptin. Under the conditions of 25°C and a relative humidity of 60%, the equilibrium relative humidity of the tablet 10 containing sitagliptin when the sitagliptin preparation 100 is stored for one month is 50.3% or less when converted to 24°C. In this specification, "equilibrium relative humidity" refers to the relative humidity in a state where no water exchange occurs between a hygroscopic substance and the surrounding environment. In this specification, the equilibrium relative humidity at 24°C is converted using the following formula based on the average value of the measured equilibrium relative humidity and temperature.

[0033] T: the average temperature during measurement,

[0034] E: The average value of the measured equilibrium relative humidity,

[0035] Ps: The saturated water vapor pressure at the average value of the measured temperature,

[0036] P: water vapor pressure at the average value of the measured temperature,

[0037] H: Absolute humidity at the average value of the measured temperature.

[0038] Ps[kPa]=0.611*10^(7.5*T / (T+237.3))

[0039] P[kPa]=E / 100*Ps

[0040] H[kg / kgDA]=0.62*P / (101.3-P)

[0041] Equilibrium relative humidity at 24°C [%RH] = H*101.3 / (H+0.62)*2.98

[0042] In one embodiment, the container or package provides an airtight state capable of maintaining the tablet 10 containing sitagliptin at a balanced relative humidity. In this specification, "airtight state" refers to a state in which solid or liquid foreign matter does not enter and can prevent the loss, weathering, deliquescence or evaporation of the content drug. In addition, the airtight state can be a sealed state. In this specification, "sealed state" refers to a state in which gas does not enter.

[0043] exist Figure 1A and 1B In one embodiment, the tablet 10 containing sitagliptin is contained in a blister package 101 . Figure 1A and 1B A PTP (Press Through Packaging) packaging 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 pack 103 .

[0044] As the blister package 101 and the pillow package 103, known blister packages and pillow packages can be used, respectively. The blister package 101 can be, for example, a sheet obtained by laminating a film selected from polyvinyl chloride film, polyvinylidene chloride film, polychlorotrifluoroethylene film, and polypropylene. In addition, the blister package 101 can be a PTP packaging sheet obtained by sealing the opening of a container composed of the above-mentioned film with aluminum foil.

[0045] 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 kept approximately constant during storage. Therefore, at the time point (Initial) when the blister package 101 is sealed with the pillow package 103, the equilibrium relative humidity of the internal space of the pillow package 103 at the time point when a stable state is reached is 50.3% or less when converted to 24°C, preferably 50% or less, more preferably 40% or less, further preferably 30% or less, and most preferably 20% or less. There is no particular limitation on the lower limit of the equilibrium relative humidity when converted to 24°C, as long as it is within the above range, for example, 10% or more.

[0046] In this specification, the equilibrium relative humidity of the sitagliptin-containing tablet converted to 24° C. is evaluated based on the equilibrium relative humidity of the sitagliptin preparation 100 stored at 25° C. and a relative humidity of 60% for one month.

[0047] In one embodiment, the blister package 101 containing the tablet 10 containing sitagliptin can be sealed with the pillow package 103 together with the desiccant 105. When the moisture content of the tablet 10 containing sitagliptin is large or the humidity in the blister package 101 is high, the desiccant 105 absorbs the moisture of the tablet 10 containing sitagliptin, and the equilibrium relative humidity of the space in the pillow package 103 when converted to 24°C can be maintained 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 of the space in the pillow package 103 when converted to 24°C that reaches a stable state can be maintained within the above range. As a result, the equilibrium relative humidity of the space in the blister package 101 when converted to 24°C that reaches a stable state is also maintained within the above range, and the equilibrium relative humidity of the tablet 10 containing sitagliptin when converted to 24°C that reaches a stable state can be maintained within the above range.

[0048] A known desiccant used as a drug desiccant can be used as the desiccant 105. For example, it can be selected from calcium chloride (e.g., Aidy (registered trademark) sheet from ID Co., Ltd.), zeolite (e.g., MS-Seram-W 3G from Tokai Chemical Industry Co., Ltd.), and a deoxidizer (e.g., Pharma Keep (registered trademark) from Mitsubishi Gas Chemical Co., Ltd.).

[0049] When desiccant 105 is sealed within pillow pack 103, the equilibrium relative humidity is determined by the hygroscopic power of desiccant 105. When desiccant 105 is not used, the relative humidity within pillow pack 103 is determined by the ambient humidity in the controlled operating environment of the pillow pack.

[0050] In addition, in one embodiment, as a sealed container for the tablet 10 containing sitagliptin, an airtight container such as a tablet bottle or a plastic bottle made of polypropylene or high-density polyethylene can be used. In this specification, an "airtight container" refers to a container that can prevent solid or liquid foreign matter from entering and prevent the loss, weathering, deliquescence or evaporation of the content medicine under normal handling, transportation or storage conditions as specified in the general rules of the 18th revised edition of the Japanese Pharmacopoeia. In addition, as an airtight container, a sealed container can be used. In this specification, a "sealed container" refers to a container that does not allow gas to enter under normal handling, transportation or storage conditions.

[0051] Furthermore, in one embodiment, the tablet 10 containing sitagliptin may be sealed together with the desiccant 105 in the above container.

[0052] In one embodiment, the sitagliptin formulation 100 may be contained in, for example, a carton, and the carton may be further covered by a vinyl film.

[0053] [Tablets containing sitagliptin]

[0054] In the present embodiment, the tablet 10 containing sitagliptin can be a known tablet containing sitagliptin. The tablet 10 containing sitagliptin can be in the form of a pharmaceutically acceptable salt of sitagliptin. "Pharmaceutically acceptable salt" refers to a salt prepared from a non-toxic alkali including an inorganic or organic alkali or a non-toxic acid including an inorganic or organic acid. As salts obtained from inorganic bases, 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 can be cited. In addition, the salt in solid form can exist in two or more crystal structures, or in the form of a hydrate. Examples of the salts obtained from pharmaceutically acceptable non-toxic organic bases include primary amines, secondary amines, tertiary amines, substituted amines including naturally 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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0055] In addition, "pharmaceutically acceptable salts" may be salts produced from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Examples of such acids include 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.

[0056] The amount of sitagliptin contained in each sitagliptin-containing tablet 10 can be arbitrarily set within a range that can achieve a therapeutic effect, and for example, the amount of sitagliptin in a free form can be 12.5 mg, 25 mg, 50 mg or 100 mg, without particular limitation.

[0057] [Storage method of tablets containing sitagliptin]

[0058] refer to Figure 1A and Figure 1BIn the storage method of the tablet 10 containing sitagliptin, the tablet 10 containing sitagliptin is sealed in a container or package and stored. Under the conditions of 25°C and a relative humidity of 60%, the equilibrium relative humidity of the tablet 10 containing sitagliptin, which is sealed in a container or package and stored for one month, is 50.3% or less when converted to 24°C.

[0059] In one embodiment, the container or packaging provides an airtight state capable of maintaining the tablet 10 containing sitagliptin in a balanced relative humidity. In addition, in one embodiment, the tablet 10 containing sitagliptin can be maintained in a sealed state by the container or packaging. In one embodiment, in order to provide an airtight state for the packaging, the tablet 10 containing sitagliptin can be contained in a blister package 101, and the blister package 101 containing the tablet 10 containing sitagliptin can be further sealed with a pillow package 103. Since the details of the blister package 101 and the pillow package 103 have been described above, their repeated description will be omitted.

[0060] Since the pillow package 103 is a packaging form with excellent sealing performance, the moisture content in the pillow package 103 can be kept basically constant during the storage period. Therefore, at the time store (Initial) when the blister package 101 is sealed with the pillow package 103, the equilibrium relative humidity of the space inside the pillow package 103 when the temperature is converted to 24°C at the time point when the stable state is reached is 50.3% or less, preferably 50% or less, more preferably 40% or less, further preferably 30% or less, and most preferably 20% or less. The lower limit of the equilibrium relative humidity when converted to 24°C is not particularly limited as long as it is within the above range, for example, 10% or more.

[0061] At the time point when the blister package 101 is sealed with the pillow package 103, the moisture content in the space inside the pillow package 103 is affected by the moisture content of the tablets 10 containing sitagliptin and the humidity of the working environment when the blister package 101 is sealed with the pillow package 103. Therefore, at the time point when the PTP packaging sheet 101 is sealed with the pillow package 103, in order to make the relative humidity of the space inside the pillow package 103 that reaches a stable state at 24°C be 50.3% or less, preferably 50% or less, more preferably 40% or less, further preferably 30% or less, and most preferably 20% or less, it is necessary to adjust the moisture content of the tablets 10 containing sitagliptin and the relative humidity of the working environment when the PTP packaging sheet 101 is sealed with the pillow package 103. On the other hand, the manufacturing process of the sitagliptin-containing tablet 10 generally includes a drying step. Therefore, as long as sufficient drying is performed in the manufacturing process, the moisture content of the sitagliptin-containing tablet 10 itself can be adjusted so that the equilibrium relative humidity when converted to 24° C. is within the above range.

[0062] In one embodiment, the blister package 101 containing the tablet 10 containing sitagliptin can be sealed with the pillow package 103 together with the desiccant 105. When the moisture content of the tablet 10 containing sitagliptin is large or the humidity in the blister package 101 is high, the desiccant 105 absorbs the moisture of the tablet 10 containing sitagliptin and keeps the equilibrium relative humidity of the space in the pillow package 103 converted to 24°C within the range of. In the present embodiment, by sealing the blister package 101 or by sealing the blister package 101 with the desiccant 105, the equilibrium relative humidity of the space in the pillow package 103 that reaches a stable state when converted to 24°C can be kept within the range of. As a result, the equilibrium relative humidity of the space in the blister package 101 that reaches a stable state when converted to 24°C is also maintained within the above range, and the equilibrium relative humidity of the tablet 10 containing sitagliptin that reaches a stable state when converted to 24°C can be maintained within the above range. In addition, since the details of the desiccant 105 have been described above, its repeated description will be omitted.

[0063] When desiccant 105 is sealed within pillow pack 103, the equilibrium relative humidity is determined by the hygroscopic power of desiccant 105. When desiccant 105 is not used, the relative humidity within pillow pack 103 is determined by the ambient humidity in the controlled operating environment of the pillow pack.

[0064] In addition, in one embodiment, the container sealing the tablet 10 containing sitagliptin may be a sealed container such as a tablet bottle or a plastic bottle made of polypropylene or high-density polyester. Since the details of the airtight container have been described above, its repeated description will be omitted.

[0065] Furthermore, in one embodiment, the tablet 10 containing sitagliptin may be sealed together with the desiccant 105 in the above container.

[0066] In one embodiment, the sitagliptin formulation 100 may be contained in, for example, a carton, and the carton may also be further covered by a vinyl film.

[0067] By storing the sitagliptin-containing tablet 10 in this manner, the production of NTTP in the sitagliptin-containing tablet 10 can be suppressed to a daily tolerable intake of 37 ng per day.

[0068] [Example]

[0069] [Comparative Example 1 and Comparative Example 2]

[0070] NTTP contained in the commercially available tablet containing sitagliptin was evaluated. As Comparative Example 1, 50 mg of commercially available JANUVIA (registered trademark) tablets were used, and the tablets were kept for 3 years at room temperature without regulating humidity since the manufacture. In addition, as Comparative Example 2, 5 mg of commercially available JANUVIA (registered trademark) tablets were used, and the tablets were kept for 1 year at room temperature without regulating humidity since the manufacture. In addition, the tablets containing sitagliptin in Comparative Example 1 and Comparative Example 2 were sealed with PTP packaging sheets only.

[0071] [Quantification of NTTP]

[0072] Weigh 2.5 mg of NTTP and dissolve it in a diluted phosphoric acid (1 ml of JIS K9005 phosphoric acid extra-grade diluted with water to 1000 ml) / acetonitrile mixture (19:1) to accurately prepare 25 ml. Weigh 1 ml of this liquid accurately and add a diluted phosphoric acid (1 ml of JIS K9005 phosphoric acid extra-grade diluted with water to 1000 ml) / acetonitrile mixture (19:1) to accurately prepare 100 ml. Weigh 1 ml, 2 ml, and 5 ml of this liquid accurately and add a diluted phosphoric acid (1 ml of JIS K9005 phosphoric acid extra-grade diluted with water to 1000 ml) / acetonitrile mixture (19:1) to accurately prepare 50 ml, respectively, 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 weighed, and diluted phosphoric acid (1 ml of JIS K9005 special grade phosphoric acid was diluted with water to 1000 ml) / acetonitrile mixture (19:1) was added to accurately prepare 50 ml of each standard solution (1), standard solution (2) and standard solution (3). 20 μl of each standard solution was accurately taken and measured using a high performance liquid chromatography mass spectrometer. The peak area of ​​each standard solution was calculated by automatic analysis, and a calibration curve was prepared based on 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).

[0073] The mass of 4 tablets containing sitagliptin of Comparative Example 1 or Comparative Example 2 was precisely measured. 40 ml of a diluted phosphoric acid (1 ml of JIS K9005 special grade phosphoric acid was diluted with water to 1000 ml) / acetonitrile mixture (19:1) was added, and ultrasonic treatment was performed while occasionally shaking until the tablets were completely disintegrated. Further diluted phosphoric acid / acetonitrile mixture (19:1) was added to accurately prepare 50 ml. The solution was filtered through a membrane filter with a pore size of 0.2 μm, and the initial 2 ml of filtrate was removed, and the subsequent filtrate was used as the sample solution. 20 μL of the sample solution was accurately taken, measured with a high performance liquid chromatography-mass spectrometer, and the peak area of ​​the sample solution was calculated by automatic analysis. Based on the peak area (Ar) of NTTP in the sample solution, the amount of NTTP in the sample solution was obtained using the following relationship for the amount of NTTP obtained from the calibration curve.

[0074] NTTP amount (ppm) = (Ar-b) / a*1 / Mr*50000

[0075] a: slope of the calibration curve,

[0076] b: Y-intercept of the calibration curve,

[0077] Mr: weight of 4 samples (g),

[0078] 50000: Correction coefficient.

[0079] Table 1 shows the amount of NTTP contained in the sitagliptin-containing tablet of Comparative Example 1 or Comparative Example 2.

[0080] [Table 1]

[0081] NTTP(ppm) Comparative Example 1 0.49 Comparative Example 2 0.23

[0082] From the results in Table 1, it is understood that the sitagliptin-containing tablets of Comparative Example 1 or Comparative Example 2 contain NTTP in an amount significantly exceeding the tolerable daily intake of 0.088 ppml.

[0083] [Reference Example 1 and Examples 1 to 3]

[0084] 50 mg of tablets containing sitagliptin placed in a high-density polyethylene plastic bottle together with a desiccant (wherein the bottle was not rolled tightly enough and the airtightness was not enough) were prepared as Reference Example 1, 50 mg of tablets containing sitagliptin placed in a high-density polyethylene plastic bottle together with a desiccant as Example 1, 25 mg of tablets containing sitagliptin contained in a PTP packaging sheet and further sealed with a pillow-shaped package together with a desiccant as Example 2, and 25 mg of tablets containing sitagliptin placed in a high-density polyethylene plastic bottle together with a desiccant as Example 3, and these tablets were stored at room temperature or in a cold place for 36 months. In addition, the desiccant of Example 1 and Example 3 had different sizes.

[0085] [Measurement of equilibrium relative humidity]

[0086] The equilibrium relative humidity of the tablets containing sitagliptin in Comparative Example 1 and Comparative Example 2 was measured using a moisture measuring device (Hygrolab2) from Rotronic. 20 50 mg tablets of sitagliptin-containing tablets of Reference Example 1 or Example 1 or 30 25 mg tablets of sitagliptin-containing tablets of Example 2 or Example 3 stored under the above conditions were placed in a sample cup, placed in a measuring chamber, and measured at room temperature. The equilibrium relative humidity and temperature at the time point when the equilibrium relative humidity reached equilibrium were recorded. In addition, the equilibrium relative humidity was measured twice for the tablets containing sitagliptin in Reference Example 1 and Examples 1 to 3. Based on the average value of the measured equilibrium relative humidity and temperature, the equilibrium relative humidity at 24°C was converted using the following formula.

[0087] T: the average temperature during measurement,

[0088] E: The average value of the measured equilibrium relative humidity,

[0089] Ps: The saturated water vapor pressure at the average value of the measured temperature,

[0090] P: water vapor pressure at the average value of the measured temperature,

[0091] H: Absolute humidity at the average value of the measured temperature.

[0092] Ps[kPa]=0.611*10^(7.5*T / (T+237.3))

[0093] P[kPa]=E / 100*Ps

[0094] H[kg / kgDA]=0.62*P / (101.3-P)

[0095] Equilibrium relative humidity at 24°C [%RH] = H*101.3 / (H+0.62)*2.98

[0096] [Quantification of NTTP]

[0097] By the above-mentioned measurement method, the NTTP contained in the stored sitagliptin-containing tablets of Reference Example 1 and Examples 1 to 3 was quantified. The NTTP was quantified three times, and the maximum value was the amount of NTTP contained in each tablet.

[0098] The equilibrium relative humidity and NTTP amount of the tablets containing sitagliptin of Reference Example 1 and Examples 1 to 3 after storage are shown in Table 2. In addition, the relationship between the equilibrium relative humidity and the natural logarithm of the increase ratio of NTTP is as follows: Figure 2 shown.

[0099] [Table 2]

[0100]

[0101] like Figure 2 As shown in Figure 2, it was found that the amount of NTTP in the tablet containing sitagliptin increased exponentially with respect to the equilibrium relative humidity. Figure 2 The regression equation obtained in found that when the initial NTTP amount was 0.006 ppm, the NTTP amount after 36 months was 37 ng / day (0.088 ppm), and the equilibrium relative humidity at 24°C was 50.3%.

Claims

1. A sitagliptin preparation, comprising a tablet containing sitagliptin and a container or package for sealing the tablet containing sitagliptin, wherein the sitagliptin preparation is characterized in that: When the sitagliptin preparation is stored at 25° C. and a relative humidity of 60% for one month, the equilibrium relative humidity of the sitagliptin-containing tablet is 50.3% or less when converted to 24° C.

2. The sitagliptin preparation according to claim 1, characterized in that The container or package provides an airtight state capable of maintaining the sitagliptin-containing tablet at the equilibrium relative humidity.

3. The sitagliptin preparation according to claim 1, characterized in that The sitagliptin-containing tablets are contained in a blister pack, The blister pack containing the sitagliptin-containing tablets is sealed with pillow packaging.

4. The sitagliptin preparation according to claim 3, characterized in that The blister pack containing the sitagliptin-containing tablets together with a desiccant is sealed with the pillow pack.

5. The sitagliptin preparation according to claim 1, characterized in that The sitagliptin-containing tablets are sealed in an airtight box together with a desiccant.

6. A method for storing a tablet containing sitagliptin, comprising sealing the tablet containing sitagliptin in a container or package, wherein the storage method comprises: When the sitagliptin-containing tablet is stored at 25° C. and a relative humidity of 60% for one month, the equilibrium relative humidity of the sitagliptin-containing tablet when converted to 24° C. is 50.3% or less.

7. The storage method of the tablet containing sitagliptin according to claim 6, characterized in that: The container or package provides an airtight state capable of maintaining the sitagliptin-containing tablet at the equilibrium relative humidity.

8. The method for storing a tablet containing sitagliptin according to claim 6, characterized in that: The sitagliptin-containing tablets are contained in a blister package, The blister pack containing the sitagliptin-containing tablets is sealed with pillow packaging.

9. The storage method of the tablet containing sitagliptin according to claim 8, characterized in that: The blister pack containing the sitagliptin-containing tablets together with a desiccant is sealed with the pillow pack.

10. The method for storing a tablet containing sitagliptin according to claim 6, characterized in that: The sitagliptin-containing tablets are sealed in an airtight container together with a desiccant.

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