Teneligliptin-containing preparations

Abstract

One problem addressed by one embodiment of the present invention is to provide a teneligliptin-containing preparation in which an amorphous form of teneligliptin is maintained and an increase in related substances is suppressed after storage under open conditions susceptible to humidity. According to one embodiment of the present invention, provided is a teneligliptin-containing preparation comprising porous silica, amorphous teneligliptin supported on the porous silica, an organic acid, and propyl gallate. The teneligliptin-containing preparation may comprise particles comprising porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a teneligliptin-containing formulation. In particular, one embodiment of the present invention relates to a formulation comprising teneligliptin-containing particles. [Background technology]

[0002] Teneligliptin ([(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 selective inhibitor of dipeptidyl peptidase IV (DPP-4) and is clinically used to treat type 2 diabetes.

[0003] A solid preparation containing teneligliptin hydrobromide hydrate as a therapeutic agent for type 2 diabetes is described, for example, in Patent Document 1. Also, an orally disintegrating tablet containing teneligliptin hydrobromide hydrate is described, for example, in Patent Document 2. Both of these preparations contain the active ingredient in a crystalline form.

[0004] On the other hand, because amorphous substances are generally in a high-energy state, amorphous formulations containing active ingredients in an amorphous form are expected to improve the dissolution rate of the active ingredient and the absorption rate in the body compared to formulations containing the active ingredient in a crystalline form. However, because amorphous forms are physically and chemically unstable, they are known to be prone to transition to a more energetically stable crystalline form and to easily produce related substances. Therefore, amorphous formulations may require special measures to ensure the quality of the formulation, such as measures to maintain the amorphous form during the formulation manufacturing process, measures to maintain the amorphous form even when exposed to extreme conditions such as high temperature and humidity during distribution and storage until administration, and measures to suppress the production of related substances during manufacturing and storage.

[0005] As an amorphous formulation, for example, Patent Document 3 describes a teneligliptin-containing pharmaceutical composition containing amorphous teneligliptin hydrobromide and an amorphous-maintaining polymer. Patent Document 3 describes a formulation in which the active ingredient in the formulation is maintained in an amorphous form after storage under sealed conditions, or a formulation in which the amount of related substances that increases when stored under open conditions is reduced, but it does not describe a teneligliptin-containing formulation in which the active ingredient in the formulation is maintained in an amorphous form even after storage under open conditions and in which the production of related substances is suppressed. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5775463 [Patent Document 2] International Publication No. 2020 / 209350 [Patent Document 3] Japanese Patent Publication No. 2020-070260 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of one embodiment of the present invention is to provide a teneligliptin-containing formulation that maintains the amorphous form of teneligliptin and suppresses the increase of related substances even after storage under open conditions that are more susceptible to the effects of humidity. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided a teneligliptin-containing formulation comprising porous silica, amorphous teneligliptin supported on the porous silica, an organic acid, and propyl gallate.

[0009] The teneligliptin-containing formulation may include particles containing porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.

[0010] The porous silica may be one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrous silicon dioxide, and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

[0011] The porous silica may be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and magnesium aluminometasilicate.

[0012] The porous silica may be hydrous silicon dioxide.

[0013] The organic acid may be one or more organic acids selected from the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, and malic acid.

[0014] The organic acid may be selected from the group consisting of lactic acid, citric acid, tartaric acid, and malic acid.

[0015] The organic acid may be selected from the group consisting of citric acid, tartaric acid, and malic acid.

[0016] The organic acid may be lactic acid.

[0017] The organic acid may be citric acid.

[0018] The porous silica may be hydrous silicon dioxide, and the organic acid may be lactic acid.

[0019] The teneligliptin-containing formulation may include particles containing porous silica, and amorphous teneligliptin and an organic acid supported on the porous silica. [Effects of the Invention]

[0020] According to one embodiment of the present invention, there is provided a teneligliptin-containing formulation that maintains the amorphous form of teneligliptin and suppresses the increase of related substances even after storage under open conditions that are more susceptible to the effects of humidity. DETAILED DESCRIPTION OF THE INVENTION

[0021] The teneligliptin-containing formulation of the present invention will be described below. In the present invention, teneligliptin may include its free form and pharmacologically acceptable salts or solvates, and teneligliptin hydrobromide may also include its solvates. The teneligliptin-containing formulation of the present invention should not be construed as being limited to the following embodiments and examples.

[0022] [Teneligliptin-containing formulation] Examples of teneligliptin-containing formulations according to the present invention include, but are not limited to, tablets, powders, granules, and capsules. In one embodiment, the teneligliptin-containing formulation comprises porous silica, amorphous teneligliptin supported on the porous silica, an organic acid, and propyl gallate. In one embodiment, the teneligliptin-containing formulation comprises teneligliptin-containing particles and propyl gallate as an antioxidant disposed on the exterior of the teneligliptin-containing particles. In one embodiment, the teneligliptin-containing particles comprise porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.

[0023] When the teneligliptin-containing formulation of this embodiment is in the form of a tablet, each tablet contains, for example, 20 mg or 40 mg of teneligliptin (free form), but the content of teneligliptin (free form) can be changed as appropriate within a range that achieves a therapeutic effect. In one embodiment, the teneligliptin-containing formulation may further contain one or more pharmaceutically acceptable additives.

[0024] In one embodiment, the teneligliptin-containing formulation may be provided as a tablet obtained by compressing a mixture of teneligliptin-containing particles, an antioxidant, and one or more pharmaceutically acceptable additives. In one embodiment, the teneligliptin-containing formulation may be provided as a film-coated tablet having a core tablet obtained by compressing a mixture of teneligliptin-containing particles, an antioxidant, and one or more pharmaceutically acceptable additives, and a film coating the core tablet.

[0025] [Teneligliptin-containing particles] The teneligliptin-containing particles according to this embodiment contain porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid.

[0026] Porous silica has pores. The pores are spaces connecting the surface of the porous silica to its interior, and can support teneligliptin, or teneligliptin and an organic acid. Porous silica can support teneligliptin, or teneligliptin and an organic acid on its surface and / or within the pores. As used herein, the phrase "supporting" teneligliptin, or teneligliptin and an organic acid on porous silica means that teneligliptin, or teneligliptin and an organic acid are retained on the surface and / or within the pores of the porous silica, and / or that teneligliptin, or teneligliptin and an organic acid are adsorbed on the surface and / or within the pores of the porous silica, and / or that teneligliptin, or teneligliptin and an organic acid are disposed on the surface and / or within the pores of the porous silica.

[0027] In this specification, porous silica refers to one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrous silicon dioxide, and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

[0028] The porous silica contained in the teneligliptin-containing particles according to this embodiment is a carrier for supporting amorphous teneligliptin or amorphous teneligliptin and an organic acid. By supporting teneligliptin or teneligliptin and an organic acid on the porous silica carrier, the teneligliptin supported on the porous silica can be maintained in an amorphous form. As used herein, "the porous silica contained in the teneligliptin-containing particles supports amorphous teneligliptin or amorphous teneligliptin and an organic acid" means that the teneligliptin after being supported on the porous silica is in an amorphous form. The porous silica contained in the teneligliptin-containing particles is preferably hydrous silicon dioxide. The teneligliptin-containing particles according to this embodiment may also be coated. In one embodiment, when the teneligliptin-containing particles are coated, the porous silica is preferably spherical.

[0029] In one embodiment, the porous silica contained in the teneligliptin-containing particles may be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and magnesium aluminometasilicate. In one embodiment, the porous silica contained in the teneligliptin-containing particles is preferably hydrous silicon dioxide.

[0030] In the teneligliptin-containing particles according to this embodiment, the organic acid is a stabilizer that maintains the amorphous form of teneligliptin and suppresses the formation of related substances during production. The organic acid may be supported on the porous silica together with teneligliptin, or may be added separately from the porous silica. "Amorphous" as used herein refers to a state in which, by powder X-ray diffraction measurement, no diffraction peaks derived from teneligliptin are observed, including those derived from teneligliptin hydrobromide hydrate crystals (2θ=5.5°±0.2°, 13.4°±0.2°, 14.4°±0.2°) as described in Japanese Patent No. 4208938. The powder X-ray diffraction measurement method can be performed in accordance with the 18th Edition of the Japanese Pharmacopoeia.

[0031] Examples of organic acids contained in the teneligliptin-containing particles of this embodiment include, but are not limited to, one or more organic acids selected from the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, and malic acid.

[0032] In one embodiment, the organic acid contained in the teneligliptin-containing particles may be selected from the group consisting of lactic acid, citric acid, tartaric acid, and malic acid. Also, in one embodiment, the organic acid contained in the teneligliptin-containing particles may be selected from the group consisting of citric acid, tartaric acid, and malic acid. In one embodiment, the organic acid contained in the teneligliptin-containing particles is preferably lactic acid. Also, in one embodiment, the organic acid contained in the teneligliptin-containing particles is preferably citric acid.

[0033] The teneligliptin-containing particles according to this embodiment can stably maintain the amorphous form of teneligliptin by supporting teneligliptin on porous silica. As shown in the Reference Examples and Examples described below, the teneligliptin-containing particles according to this embodiment can maintain the amorphous form of teneligliptin even when stored for one month under open conditions at 25°C and 75% relative humidity. Furthermore, by supporting teneligliptin together with an organic acid on porous silica, the teneligliptin-containing particles according to this embodiment can not only maintain the amorphous form of teneligliptin but also suppress the production of related substances during production. In one embodiment, the teneligliptin-containing formulation preferably comprises particles containing porous silica and amorphous teneligliptin and an organic acid supported on the porous silica.

[0034] In the teneligliptin-containing formulation of this embodiment, propyl gallate is an antioxidant that suppresses the increase of teneligliptin analogues. By disposing propyl gallate on the exterior of the teneligliptin-containing particles, the increase of teneligliptin analogues can be suppressed even during storage under open conditions. A teneligliptin-containing formulation containing propyl gallate and teneligliptin-containing particles containing amorphous teneligliptin and an organic acid supported on porous silica can significantly suppress the increase of teneligliptin analogues not only during storage under sealed conditions but also during storage under open conditions.

[0035] The content of propyl gallate in the teneligliptin-containing formulation of this embodiment is 0.01% by weight or more and 10% by weight or less, preferably 0.1% by weight or more and 10% by weight or less, and more preferably 0.5% by weight or more and 10% by weight or less, based on the weight of the formulation. By including propyl gallate in the teneligliptin-containing formulation, it is possible to reduce an increase in related substances of teneligliptin. Herein, the measurement of related substances can be determined by calculating the ratio of the peak area of ​​the related substances derived from teneligliptin to the total area of ​​all peaks detected by measurement using liquid chromatography.

[0036] Examples of the one or more pharmaceutically acceptable additives contained in the teneligliptin-containing formulation of this embodiment include, but are not limited to, excipients, binders, disintegrants, flow agents, and lubricants. Examples of excipients include, but are not limited to, D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0037] Examples of binders include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose, etc. Examples of disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose calcium, crospovidone, etc. Examples of fluidizers include, but are not limited to, light anhydrous silicic acid, hydrated silicon dioxide, talc, etc. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, etc.

[0038] [Method of manufacturing teneligliptin-containing particles] The teneligliptin-containing particles of the present invention can be produced, for example, by supporting teneligliptin or teneligliptin and an organic acid on porous silica using a known silica adsorption method. More specifically, teneligliptin hydrobromide, or a hydrate or other solvate thereof, is dissolved in a solvent (purified water) or a stabilizer-containing solvent in which an organic acid is dissolved in a solvent (purified water). The resulting teneligliptin solution is mixed with porous silica, and the solvent is removed to produce amorphous teneligliptin or particles in which amorphous teneligliptin and an organic acid are supported on porous silica. Here, the drug substance dissolved in the solvent or the like may be teneligliptin hydrobromide in an amorphous or crystalline form, or may be a hydrate or other solvate thereof. Regardless of the form of the drug substance, the above production method can be used to obtain particles in which amorphous teneligliptin is supported on porous silica. The obtained teneligliptin-containing particles may also be coated to form coated particles.

[0039] [Manufacturing method of teneligliptin-containing formulation] As an embodiment of the teneligliptin-containing formulation of the present invention, for example, powders, granules, tablets, or capsules can be produced by the following methods A to C. A) Teneligliptin-containing powder or teneligliptin-containing granules can be produced by mixing teneligliptin-containing particles with propyl gallate and, if necessary, various additives such as excipients, disintegrants, flow agents, and lubricants, and optionally granulating the mixture. B) A teneligliptin-containing tablet can be produced by compressing the powder or granules. The teneligliptin-containing tablet produced by the above process may be coated to form a coated tablet. C) The powder or granules described above can be filled into capsules to produce capsules containing teneligliptin. [Example]

[0040] In the manufacturing methods of the following Examples, Comparative Examples, and Reference Examples, the amounts of teneligliptin and each additive used are basically the contents in one teneligliptin-containing tablet. Even when teneligliptin-containing particles are manufactured, they may be subsequently tableted, so the amounts are stated as the contents in one tablet.

[0041] [Evaluation of crystal form] The crystalline forms of teneligliptin in the following Examples, Comparative Examples, and Reference Examples were evaluated by powder X-ray diffraction measurement using a Bruker D8 ADVANCE powder X-ray diffractometer under the following conditions: Cu-Kα radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 2.0 to 40.0°, scan speed: 0.1 sec / step, step size: 0.015°.

[0042] [Evaluation of the amount of related substances] In the evaluation of the amounts of related substances in the Examples, Comparative Examples, and Reference Examples shown below, the individual maximum amounts of related substances and the total amount of related substances were calculated using high-performance liquid chromatography. The ratio of the peak area of ​​each teneligliptin-derived related substance to the sum of all peak areas detected by measurement using high-performance liquid chromatography was calculated. The individual maximum amount of related substance indicated the ratio of the related substance with the largest amount among the calculated ratios of related substances. Furthermore, the total amount of related substances indicated the ratio of the sum of the peak areas of teneligliptin-derived related substances to the sum of all peak areas detected by measurement using high-performance liquid chromatography.

[0043] <Silica adsorption method> [Reference example 1-1] Teneligliptin-containing particles were produced using a silica adsorption method. Specifically, 29.48 mg of teneligliptin hydrobromide was dissolved in 100 mg of solvent (purified water) to prepare a teneligliptin solution. Using a mortar, the obtained teneligliptin solution was added to 45 mg of hydrated silicon dioxide (Fuji Chemical Industry Co., Ltd., Fujisil (registered trademark)) as porous silica, and mixed. The obtained particles were dried in a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to produce the teneligliptin-containing particles of Reference Example 1-1.

[0044] [Reference example 1-2] A polyvinyl alcohol solution was prepared by dissolving 10 mg of partially saponified polyvinyl alcohol (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 90 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 1-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to obtain the teneligliptin-containing granules of Reference Example 1-2.

[0045] [Reference example 1-3] The teneligliptin-containing granules of Reference Example 1-2 were sieved through a No. 22 sieve and sized. The resulting sized product was mixed with 44.52 mg of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH-11) and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) in a plastic bag and compressed into tablets using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain teneligliptin-containing tablets of Reference Example 1-3 weighing 130 mg.

[0046] The teneligliptin-containing particles of Reference Example 1-1, the teneligliptin-containing granules of Reference Example 1-2, and the teneligliptin-containing tablets of Reference Example 1-3 were stored for 1 month under open conditions at 25°C and a relative humidity of 75%.

[0047] The crystal form, individual maximum related substance amount, and total related substance amount were evaluated for the teneligliptin-containing particles of Reference Example 1-1, the teneligliptin-containing granules of Reference Example 1-2, and the teneligliptin-containing tablets of Reference Example 1-3 immediately after production (initial) and after storage using the measurement methods described above. The evaluation results are shown in Table 1.

[0048] [Table 1]

[0049] The results in Table 1 show that the teneligliptin-containing particles of Reference Example 1-1, the teneligliptin-containing granules of Reference Example 1-2, and the teneligliptin-containing tablets of Reference Example 1-3 were able to maintain their amorphous form not only immediately after production but also when stored under open conditions. However, an increase in the amount of related substances was observed immediately after production (initial) and after storage under open conditions.

[0050] From the above, the teneligliptin-containing formulation manufactured by the silica adsorption method maintained the amorphous form of teneligliptin immediately after manufacturing and after storage under open conditions, but the amount of related substances increased immediately after manufacturing and after storage under open conditions.

[0051] <Consideration of stabilizers> [Reference example 2-1] When a stabilizer was supported on porous silica together with teneligliptin, we investigated whether the teneligliptin-containing particles could maintain their amorphous form and whether the increase in related substances could be suppressed. Specifically, a stabilizer-containing solvent was prepared by dissolving 2 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) in 100 mg of solvent (purified water). 29.48 mg of teneligliptin hydrobromide was dissolved in the resulting stabilizer-containing solvent to prepare a teneligliptin solution. Using a mortar, the resulting teneligliptin solution was added to 45 mg of hydrated silicon dioxide (Fujisil (registered trademark) by Fuji Chemical Industry Co., Ltd.) as porous silica, and mixed. The resulting particles were dried in a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to produce teneligliptin-containing particles of Reference Example 2-1.

[0052] [Reference example 2-2] A polyvinyl alcohol solution was prepared by dissolving 5 mg of partially saponified polyvinyl alcohol (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 95 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Example 2-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model), yielding teneligliptin-containing granules. The teneligliptin-containing granules were sieved through a No. 22 sieve and sized. The resulting granulated product was mixed in a plastic bag with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 31.02 mg of D-mannitol (Freund Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)). The mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain teneligliptin-containing tablets of Reference Example 2-2 weighing 120 mg.

[0053] [Reference example 3-1] Teneligliptin-containing particles of Reference Example 3-1 were produced by the same production method as in Reference Example 2-1, except that lactic acid was changed to 0.52 mg of hydrochloric acid (Fujifilm Wako Pure Chemical Industries, Ltd., special grade hydrochloric acid).

[0054] [Reference example 3-2] A polyvinyl alcohol solution was prepared by dissolving 5 mg of partially saponified polyvinyl alcohol (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 95 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 3-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model), yielding teneligliptin-containing granules. The teneligliptin-containing granules were sieved through a No. 22 sieve and sized. The resulting granulated product was mixed in a plastic bag with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 32.50 mg of D-mannitol (Freund Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)). The mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain teneligliptin-containing tablets weighing 120 mg as shown in Reference Example 3-2.

[0055] [Reference example 4] Teneligliptin-containing particles of Reference Example 4 were produced by the same production method as in Reference Example 2-1, except that lactic acid was changed to 2 mg of ascorbic acid (Kyowa Pharma Chemical Co., Ltd., ascorbic acid 100M).

[0056] [Reference example 5] An attempt was made to produce teneligliptin-containing particles of Reference Example 5 using the same production method as in Reference Example 2-1, except that lactic acid was replaced with 2 mg of sodium pyrosulfite (Fujifilm Wako Pure Chemical Industries, Ltd., sodium pyrosulfite). However, when preparing a teneligliptin solution, teneligliptin precipitated, and a solution could not be prepared.

[0057] [Reference example 6-1] Lactic acid was replaced with 2 mg of sodium sulfite (Fujifilm Wako Pure Chemical Industries, Ltd., sodium sulfite). When sodium sulfite was used, an attempt was made to prepare a teneligliptin solution by adding teneligliptin to a stabilizer-containing solvent. As a result, teneligliptin precipitated, making it impossible to prepare a solution. Therefore, sodium sulfite was added as a powder. Specifically, 29.48 mg of teneligliptin hydrobromide was dissolved in 100 mg of solvent (purified water) to prepare a teneligliptin solution. Using a mortar, the obtained teneligliptin solution was added to a mixture of 45 mg of hydrated silicon dioxide (Fuji Chemical Industry Co., Ltd., Fujisil (registered trademark)) as porous silica and 2 mg of sodium sulfite, while mixing. The obtained particles were dried in a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to produce teneligliptin-containing particles of Reference Example 6-1.

[0058] [Reference example 6-2] A polyvinyl alcohol solution was prepared by dissolving 10 mg of partially saponified polyvinyl alcohol (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 90 mg of solvent (purified water). The polyvinyl alcohol solution was sprayed onto the teneligliptin-containing particles of Reference Example 6-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model), yielding teneligliptin-containing granules. The teneligliptin-containing granules were sieved through a No. 22 sieve and sized. The resulting sieved product was mixed with 42.52 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) and 1.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) in a plastic bag and compressed using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to yield the teneligliptin-containing tablets of Reference Example 6-2 weighing 130 mg.

[0059] The teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1, and the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2 were stored for 1 month at 25°C, 75% relative humidity, and under open conditions. The crystal form, individual maximum related substance amount, and total related substance amount of the teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1, and the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2 immediately after production (initial) and after storage were evaluated using the measurement methods described above. The evaluation results are shown in Table 2. The evaluation results of the teneligliptin-containing particles of Reference Example 1-1 and the teneligliptin-containing tablets of Reference Example 1-3 are also shown in Table 2.

[0060] [Table 2]

[0061] The results in Table 2 confirm that the teneligliptin-containing particles of Reference Examples 2-1, 3-1, and 4 and the teneligliptin-containing tablets of Reference Examples 2-2 and 3-2, to which lactic acid, hydrochloric acid, or ascorbic acid was added, maintained their amorphous form not only immediately after production but also when stored under open conditions. On the other hand, it was revealed that the teneligliptin-containing particles of Reference Example 6-1 and the teneligliptin-containing tablets of Reference Example 6-2, to which sodium sulfite was added, were unable to maintain their amorphous form.

[0062] In the teneligliptin-containing particles of Reference Examples 2-1 and 2-4 and the teneligliptin-containing tablet of Reference Example 2-2 to which lactic acid or ascorbic acid was added, the amount of related substances immediately after production (initial) was reduced. On the other hand, in the teneligliptin-containing particles of Reference Example 3-1 and the teneligliptin-containing tablet of Reference Example 3-2 to which hydrochloric acid was added, the amount of related substances immediately after production (initial) was not reduced.

[0063] Regarding the amount of related substances when stored under open conditions, the teneligliptin-containing particles of Reference Examples 2-1 and 3-1 and the teneligliptin-containing tablets of Reference Examples 2-2 and 3-2, which maintained an amorphous state, showed a significant increase in the amount of related substances, while the crystallized teneligliptin-containing particles of Reference Example 6-1 and the teneligliptin-containing tablets of Reference Example 6-2 showed a suppressed increase in the amount of related substances. That is, the teneligliptin-containing particles of Reference Examples 2-1, 3-1, 4, and 6-1 and the teneligliptin-containing tablets of Reference Examples 2-2, 3-2, and 6-2 were all unable to suppress the increase in related substances while maintaining an amorphous state after storage under open conditions.

[0064] Stabilizers capable of maintaining the amorphous form were screened, and the relationship between the stabilizer and the amount of related substances in the teneligliptin-containing particles immediately after production (initial) was examined.

[0065] [Reference example 7] Teneligliptin-containing particles of Reference Example 7 were produced by the same production method as in Reference Example 1-1.

[0066] [Reference example 8] Teneligliptin-containing particles of Reference Example 8 were produced by the same production method as in Reference Example 4.

[0067] [Reference example 9] The teneligliptin-containing particles of Reference Example 9 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of citric acid (Fujifilm Wako Pure Chemical Industries, Ltd., citric acid monohydrate) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0068] [Reference example 10] The teneligliptin-containing particles of Reference Example 10 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of tartaric acid (Yamazen Pharmaceutical Co., Ltd., DL-tartaric acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0069] [Reference example 11] The teneligliptin-containing particles of Reference Example 11 were produced by the same manufacturing method as that of Reference Example 8, except that 0.33 mg of fumaric acid (Fujifilm Wako Pure Chemical Industries, Ltd., fumaric acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0070] [Reference example 12] The teneligliptin-containing particles of Reference Example 12 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of malic acid (Fuso Chemical Co., Ltd., DL-malic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0071] [Reference example 13] The teneligliptin-containing particles of Reference Example 13 were produced by the same manufacturing method as that of Reference Example 8, except that 0.5 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0072] [Reference example 14] The teneligliptin-containing particles of Reference Example 14 were produced by the same manufacturing method as that of Reference Example 8, except that 1 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0073] [Reference example 15] Teneligliptin-containing particles of Reference Example 15 were produced by the same production method as in Reference Example 2-1.

[0074] [Reference example 16] The teneligliptin-containing particles of Reference Example 16 were produced by the same manufacturing method as that of Reference Example 8, except that 3 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0075] [Reference example 17] The teneligliptin-containing particles of Reference Example 17 were produced by the same manufacturing method as that of Reference Example 8, except that 4 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare a stabilizer-containing solvent.

[0076] [Reference example 18] Teneligliptin-containing particles of Reference Example 18 were produced by the same production method as in Reference Example 3-1.

[0077] The teneligliptin-containing particles of Reference Examples 7 to 18 were stored for two weeks or one month at 25°C and a relative humidity of 75% under open conditions. Using the measurement methods described above, the crystalline form of teneligliptin after one month of storage under open conditions and the amount of related substances immediately after production (initial) and after two weeks of storage under open conditions were evaluated. The evaluation results are shown in Table 3.

[0078] [Table 3]

[0079] The results in Table 3 reveal that the teneligliptin-containing particles of Reference Examples 8 to 17, which contain an organic acid as a stabilizer, maintain an amorphous form even after storage under open conditions, while the amount of related substances immediately after production (initial) is significantly reduced compared to the teneligliptin-containing particles of Reference Example 7, which does not contain a stabilizer, or Reference Example 18, which contains hydrochloric acid as a stabilizer. On the other hand, none of Reference Examples 9 to 17, which reduced the initial amount of related substances, were able to suppress the increase in related substances after storage under open conditions.

[0080] The results of Reference Examples 2-1, 2-2, 3-1, 3-2, and Reference Examples 4 to 18 revealed that by adding an organic acid as a stabilizer to teneligliptin-containing particles produced by the silica adsorption method, the amorphous form of teneligliptin is maintained even after storage under open conditions, while the amount of related substances immediately after production (initial) is significantly reduced. On the other hand, no formulation was obtained that suppressed the increase in related substances when stored under open conditions.

[0081] <Study of antioxidants> [Reference example 19] Teneligliptin-containing particles of Reference Example 19 were produced by the same production method as in Reference Example 1-1.

[0082] [Reference example 20] Teneligliptin-containing particles of Reference Example 20 were produced by the same production method as in Reference Example 2-1.

[0083] [Example 1] When teneligliptin-containing particles containing amorphous teneligliptin supported on porous silica and a stabilizer were mixed with an antioxidant, it was investigated whether the teneligliptin-containing particles could maintain their amorphous form and whether the increase in related substances could be suppressed. Specifically, 76.48 mg of the teneligliptin-containing particles obtained in Reference Example 20, 2 mg of propyl gallate (Fujifilm Wako Pure Chemical Industries, Ltd., propyl gallate), and 2 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101) were mixed in a mortar to obtain the teneligliptin-containing formulation of Example 1.

[0084] [Comparative Examples 1 to 9] Teneligliptin-containing formulations of Comparative Examples 1 to 9 were produced by the same production method as in Example 1, except that 2 mg of propyl gallate was replaced with 2 mg of each of the antioxidants shown in Table 4 below. [Table 4]

[0085] [Comparative Examples 10 to 19] Teneligliptin-containing formulations of Comparative Examples 10 to 19 were produced by mixing 74.48 mg of the teneligliptin-containing particles obtained in Reference Example 19, 2 mg of each of the antioxidants listed in Table 5 below, and 2 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101) in a mortar. [Table 5]

[0086] The teneligliptin-containing formulations of Reference Examples 19 and 20, Example 1, and Comparative Examples 1 to 19 were stored for 2 weeks under open conditions at 25°C and a relative humidity of 75%. The crystalline form and the amount of related substances after storage under open conditions were evaluated using the measurement methods described above. The evaluation results are shown in Table 6.

[0087] [Table 6]

[0088] The results in Table 6 show that the teneligliptin-containing formulation of Example 1, in which propyl gallate was mixed with teneligliptin-containing particles containing amorphous teneligliptin and lactic acid supported on porous silica, showed a significant reduction in the amount of related substances after storage under open conditions, compared to Comparative Examples 1 to 9, in which other antioxidants were used. Furthermore, in Comparative Example 19, in which propyl gallate was mixed with teneligliptin-containing particles not containing lactic acid, the amount of related substances increased after storage under open conditions. These results demonstrate that lactic acid and propyl gallate function synergistically, significantly suppressing the increase in teneligliptin related substances after storage under open conditions.

[0089] [Example 2] We investigated whether the increase of related substances could be suppressed under open conditions even when a formulation containing an antioxidant was tableted. Specifically, 76.48 mg of the teneligliptin-containing particles of Reference Example 2-1, 2 mg of propyl gallate (Fujifilm Wako Pure Chemical Industries, Ltd., propyl gallate), 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 34.02 mg of D-mannitol (Freund Corporation, Granutol® F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider® 101), and 1 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)) were mixed in a mortar. The resulting mixture was compressed using a rotary tablet press to obtain the teneligliptin-containing tablets of Example 2.

[0090] [Comparative Example 20] A teneligliptin-containing tablet of Reference Example 21 was obtained in the same manner as in Example 2, except that the amount of D-mannitol was changed to 36.02 mg and propyl gallate (Fujifilm Wako Pure Chemical Industries, Ltd., propyl gallate) was omitted.

[0091] The teneligliptin-containing tablets of Example 2 and Comparative Example 20 were stored at 25°C, 75% relative humidity, and in an open environment for 2 weeks, 4 weeks, and 12 weeks. The crystal form and the amount of related substances were evaluated using the measurement methods described above, initially (immediately after production) and after storage in the open environment. The evaluation results are shown in Table 7.

[0092] [Table 7]

[0093] The results in Table 7 reveal that the teneligliptin-containing tablet of Example 2, which contains amorphous teneligliptin supported on porous silica, lactic acid, and propyl gallate, significantly suppresses the increase in the amount of related substances after storage under open conditions, and maintains the amorphous state of teneligliptin, compared to the tablet of Comparative Example 20, which does not contain an antioxidant.

Claims

1. Particles comprising porous silica, amorphous teneligliptin supported on the porous silica, and an organic acid; propyl gallate, A teneligliptin-containing formulation, wherein the organic acid is lactic acid.

2. 2. The teneligliptin-containing formulation of claim 1, wherein the porous silica is one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrous silicon dioxide, and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate, and aluminum silicate.

3. 2. The teneligliptin-containing formulation of claim 1, wherein the porous silica is selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and magnesium aluminometasilicate.

4. The teneligliptin-containing formulation according to claim 1, wherein the porous silica is hydrous silicon dioxide.

5. The teneligliptin-containing formulation according to any one of claims 1 to 4, comprising particles containing the porous silica, amorphous teneligliptin supported on the porous silica, and the organic acid.

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