Formulations containing teneligliptin

Abstract

An object of one embodiment of the present invention is to provide a teneligliptin-containing preparation in which an amorphous form of teneligliptin is maintained after storage under open conditions susceptible to humidity and an increase in similar substances is suppressed. According to one embodiment of the present invention, there is provided a teneligliptin-containing formulation comprising a porous silicon oxide compound, amorphous teneligliptin carried by the porous silicon oxide compound, an organic acid, and propyl gallate. In some embodiments, a formulation containing teneligliptin may include a particle including a porous silica compound, amorphous teneligliptin carried by the porous silica compound, and an organic acid.

Description

Technical Field

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

[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: {(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-4 (DPP-4) and is clinically used as a treatment for type 2 diabetes.

[0003] As a therapeutic drug for type 2 diabetes, for example, a solid preparation containing teneligliptin hydrobromide hydrate is described in Patent Document 1. In addition, for example, an orally disintegrating tablet containing teneligliptin hydrobromide hydrate is described in Patent Document 2. These are preparations containing an active ingredient in a crystalline form.

[0004] On the other hand, since amorphous materials are usually in a high energy state, in amorphous preparations containing active ingredients in amorphous form, compared with preparations containing active ingredients in crystalline form, it is expected that the dissolution of the active ingredients and the absorption rate in the organism will be improved. However, since the amorphous form is physically and chemically unstable, it is known that the amorphous form is easily converted into a crystalline form that is more stable in energy, and similar substances are also easily produced. Therefore, in amorphous preparations, special methods (measures) are required to ensure the quality of the preparation, for example, a method for maintaining an amorphous form during the production process of the preparation, a method for maintaining an amorphous form even when exposed to extreme conditions such as high temperature or high humidity during circulation or storage until taking, and a method for suppressing the generation of similar substances during manufacturing and the above-mentioned storage period.

[0005] As an amorphous preparation, for example, Patent Document 3 describes a pharmaceutical composition containing teneligliptin, which contains teneligliptin hydrobromide in an amorphous form and an amorphous-maintaining polymer. Patent Document 3 describes a preparation in which the active ingredient in the preparation remains in an amorphous form even after storage under sealed conditions, or a preparation in which the amount of similar substances increased after storage under open conditions is reduced, but does not describe a preparation containing teneligliptin in which the active ingredient in the preparation remains in an amorphous form even after storage under open conditions and the generation of similar substances is suppressed.

[0006] [Prior art literature]

[0007] [Patent Literature]

[0008] [Patent Document 1] Japanese Patent No. 5775463

[0009] [Patent Document 2] International Publication No. 2020 / 209350

[0010] [Patent Document 3] Japanese Patent Application Publication No. 2020-070260 Summary of the invention

[0011] [Problems to be solved by the invention]

[0012] One of the objects of one embodiment of the present invention is to provide a preparation containing teneligliptin which maintains the amorphous form of teneligliptin after storage under open conditions that are easily affected by humidity and suppresses the increase of similar substances.

[0013] Measures taken to solve the problem

[0014] According to one embodiment of the present invention, there is provided a preparation containing teneligliptin, which includes porous silica, amorphous teneligliptin carried by the porous silica, an organic acid and propyl gallate.

[0015] The formulation containing teneligliptin may include particles (particles) including a porous silica compound, amorphous teneligliptin carried by the porous silica compound, and an organic acid.

[0016] The porous silica compound can be one or more porous silicic acids selected from the group consisting of silicon dioxide, hydrated silicon dioxide and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminum metasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate and aluminosilicate.

[0017] The porous silicon oxide compound may be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, and aluminum magnesium metasilicate.

[0018] The porous silicon oxide compound may be hydrous silicon dioxide.

[0019] 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.

[0020] The organic acid may be selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid.

[0021] The organic acid may be selected from the group consisting of citric acid, tartaric acid and malic acid.

[0022] The organic acid may be lactic acid.

[0023] The organic acid may be citric acid.

[0024] The porous silicon oxide compound may be hydrous silicon dioxide, and the organic acid may be lactic acid.

[0025] The formulation containing teneligliptin may include particles, the particles including: a porous silicon-oxygen compound; and amorphous teneligliptin and an organic acid carried by the porous silicon-oxygen compound.

[0026] [Effects of the invention]

[0027] According to one embodiment of the present invention, there is provided a preparation containing teneligliptin, which maintains the amorphous form of teneligliptin and suppresses the increase of similar substances after storage under open conditions that are easily affected by humidity. DETAILED DESCRIPTION

[0028] Hereinafter, the preparation containing teneligliptin involved in the present invention will be described. In addition, in the present invention, the term teneligliptin may include free form and pharmacologically acceptable salt or solvate, and the term teneligliptin hydrobromide may include its solvate. The preparation containing teneligliptin of the present invention should not be interpreted as being limited to the description of the embodiments and examples shown below.

[0029] [Preparations containing teneligliptin]

[0030] Embodiments of the preparations containing teneligliptin involved in the embodiments of the present invention include, for example, tablets, powders, granules and capsules, but are not limited thereto. In one embodiment, the preparation containing teneligliptin includes porous silica, amorphous teneligliptin carried by the porous silica, organic acid and propyl gallate. In one embodiment, the preparation containing teneligliptin includes particles (particles) containing teneligliptin and propyl gallate as an antioxidant configured on the outside of the particles containing teneligliptin. In one embodiment, the particles containing teneligliptin include porous silica, amorphous teneligliptin carried by the porous silica and an organic acid.

[0031] When the preparation containing teneligliptin involved in the present embodiment is a tablet, each tablet contains, for example, 20 mg or 40 mg of teneligliptin as a free form, and the content of teneligliptin (free form) can be appropriately changed within the range that can obtain the therapeutic effect. In one embodiment, the preparation containing teneligliptin can also include one or more pharmaceutically acceptable additives.

[0032] In addition, in one embodiment, the preparation containing teneligliptin can also be provided as a tablet obtained by mixing particles containing teneligliptin, an antioxidant and one or more pharmaceutically acceptable additives and then compressing them. In one embodiment, the preparation containing teneligliptin can be provided in the form of a film-coated tablet, which has a plain tablet obtained by mixing particles containing teneligliptin, an antioxidant and one or more pharmaceutically acceptable additives and then compressing them, and a film covering the plain tablet.

[0033] [Granules containing teneligliptin]

[0034] The particles containing teneligliptin according to the present embodiment include a porous silicon oxide compound, amorphous teneligliptin carried by the porous silicon oxide compound, and an organic acid.

[0035] The porous silicon oxide has pores. The pores are spaces connected from the surface of the porous silicon oxide to its interior, which can carry teneligliptin, or teneligliptin and an organic acid. The porous silicon oxide can carry teneligliptin, or teneligliptin and an organic acid on its surface and / or in its pores. In this specification, the porous silicon oxide "carries" teneligliptin, or teneligliptin and an organic acid, which means that teneligliptin, or teneligliptin and an organic acid are held on the surface and / or in the pores of the porous silicon oxide, and / or, teneligliptin, or teneligliptin and an organic acid are adsorbed on the surface and / or in the pores of the porous silicon oxide, and / or, teneligliptin, or teneligliptin and an organic acid are configured on the surface and / or in the pores of the porous silicon oxide.

[0036] In this specification, the porous silica compound is one or more porous silicates selected from the group consisting of silicon dioxide, hydrated silicon dioxide and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminum metasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate and aluminum silicate.

[0037] The porous silicon oxide compound contained in the particles containing teneligliptin involved in the present embodiment is a carrier for carrying amorphous teneligliptin or amorphous teneligliptin and an organic acid. By making the porous silicon oxide compound as a carrier carry teneligliptin or teneligliptin and an organic acid, the teneligliptin carried by the porous silicon oxide compound can be maintained in an amorphous form. In this specification, the porous silicon oxide compound contained in the particles containing teneligliptin carries amorphous teneligliptin or amorphous teneligliptin and an organic acid, which means that the teneligliptin carried after the porous silicon oxide compound is an amorphous form. The porous silicon oxide compound contained in the particles containing teneligliptin is preferably hydrous silica. In addition, the particles containing teneligliptin involved in the present embodiment can be coated. In addition, in one embodiment, when coating the particles containing teneligliptin, the porous silicon oxide compound is preferably spherical.

[0038] In one embodiment, the porous silicon oxide compound contained in the particles containing teneligliptin can be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate. In addition, in one embodiment, as the porous silicon oxide compound contained in the particles containing teneligliptin, hydrous silicon dioxide is preferred.

[0039] In the particles containing teneligliptin involved in the present embodiment, the organic acid is a stabilizer, which participates in the maintenance of the amorphous form of teneligliptin and inhibits the generation of similar substances in the production process. The organic acid can be carried in the porous silicon oxide compound together with teneligliptin, or it can be added separately from the porous silicon oxide compound. "Amorphous" in this specification refers to the state that the diffraction peak from teneligliptin recorded in Japanese Patent No. 4208938, including the diffraction peak from teneligliptin hydrobromide hydrate crystal (2θ=5.5°±0.2°, 13.4°±0.2°, 14.4°±0.2°) is not confirmed by powder X-ray diffraction determination. The powder X-ray diffraction determination method can be carried out according to the 18th revised edition of the Japanese Pharmacopoeia.

[0040] Examples of the organic acid contained in the teneligliptin-containing particles according to the present 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.

[0041] In one embodiment, the organic acid contained in the particles containing teneligliptin can be selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid. In addition, in one embodiment, the organic acid contained in the particles containing teneligliptin can be selected from the group consisting of citric acid, tartaric acid and malic acid. In one embodiment, as the organic acid contained in the particles containing teneligliptin, lactic acid is preferred. In addition, in one embodiment, as the organic acid contained in the particles containing teneligliptin, citric acid is preferred.

[0042] In the particles containing teneligliptin involved in the present embodiment, by carrying teneligliptin in a porous silicon oxide compound, the amorphous form of teneligliptin can be stably maintained. As shown in the reference examples and embodiments described later, even when stored for one month under open conditions of 25°C and 75% relative humidity, the particles containing teneligliptin in the present embodiment can maintain the amorphous form of teneligliptin. In addition, in the particles containing teneligliptin involved in the present embodiment, by carrying teneligliptin together with an organic acid in a porous silicon oxide compound, in addition to maintaining the amorphous form of teneligliptin, the generation of similar substances in the preparation process can also be suppressed. In one embodiment, the preparation containing teneligliptin preferably includes particles, the particles including: a porous silicon oxide compound; and amorphous teneligliptin and an organic acid carried in a porous silicon oxide compound.

[0043] In the preparation containing teneligliptin involved in the present embodiment, propyl gallate is an antioxidant that suppresses the increase of similar substances of teneligliptin. By configuring propyl gallate on the outside of the particles containing teneligliptin, the increase of similar substances of teneligliptin can be suppressed even if it is stored under open conditions. The preparation containing teneligliptin including particles containing teneligliptin and propyl gallate can significantly suppress the increase of similar substances of teneligliptin not only when stored under sealed conditions, but also when stored under open conditions, wherein the particles containing teneligliptin include amorphous teneligliptin and organic acid carried by porous silicon oxide compounds.

[0044] In the preparation containing teneligliptin involved in the present embodiment, the content of propyl gallate is 0.01% by weight or more and 10% by weight or less relative to the weight of the preparation, preferably 0.1% by weight or more and 10% by weight or less, more preferably 0.5% by weight or more and 10% by weight or less. By adding propyl gallate to the preparation containing teneligliptin, the increase of the similar substances of teneligliptin can be reduced. In addition, in this specification, the peak area of ​​the similar substances from teneligliptin is calculated relative to the ratio of the sum of all peak areas detected by the determination using liquid chromatography, so that the determination of similar substances can be carried out.

[0045] As one or more pharmaceutically acceptable additives contained in the preparation containing teneligliptin involved in this embodiment, for example, excipients, binders, disintegrants, fluidizers and lubricants can be mentioned, but are not limited to these. As excipients, D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc. can be mentioned, but are not limited to these.

[0046] As binders, hydroxypropyl cellulose, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methyl cellulose, etc. can be cited, but not limited to them. As disintegrants, low-substitution hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, etc. can be cited, but not limited to them. As fluidizers, light anhydrous silicic acid, hydrous silicon dioxide, talc, etc. can be cited, but not limited to them. As lubricants, magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, etc. can be cited, but not limited to them.

[0047] [Method for producing granules containing teneligliptin]

[0048] With regard to the particles containing teneligliptin of the present invention, for example, known silica adsorption method can be used, by carrying teneligliptin or teneligliptin and organic acid in porous silica compound to manufacture. In more detail, by dissolving teneligliptin hydrobromide or its hydrate or other solvate in a solvent (pure water) or in a solvent containing a stabilizer formed by dissolving an organic acid in a solvent (pure water), the teneligliptin solution obtained is mixed with porous silica compound, and the solvent is removed, thus it is possible to obtain particles in which amorphous teneligliptin or amorphous teneligliptin and organic acid are carried in porous silica compound. Here, the bulk drug dissolved in the solvent etc. can be the amorphous form or crystalline form of teneligliptin hydrobromide, or it can be its hydrate or other solvate. By the above-mentioned manufacturing method, no matter how the form of the bulk drug is, the particles of amorphous teneligliptin carried in porous silica compound can be obtained. In addition, the particles containing teneligliptin obtained can be coated to form coated particles.

[0049] [Method for producing a preparation containing teneligliptin]

[0050] As one embodiment of the teneligliptin-containing preparation of the present invention, for example, powder, granules, tablets or capsules can be produced by the following methods A to C.

[0051] A) The granules containing teneligliptin are mixed with propyl gallate, and various additives such as excipients, disintegrants, fluidizers, lubricants, etc. are added and mixed as needed, and granulation is performed as needed to produce a powder containing teneligliptin or a granule containing teneligliptin.

[0052] B) Tablets containing teneligliptin can be produced by compression molding the above-mentioned powder or granule. In addition, the tablets containing teneligliptin produced by the above-mentioned process can be coated to produce coated tablets.

[0053] C) Capsules containing teneligliptin can be prepared by filling the above powder or granules into capsules.

[0054] [Example]

[0055] In the manufacturing methods of the following examples, comparative examples and reference examples, the amounts of teneligliptin and each additive used are basically the amounts in one tablet containing teneligliptin. Even when granules containing teneligliptin are manufactured, tablets are sometimes subsequently formed, so the amounts are recorded as the amounts in one tablet.

[0056] [Evaluation of crystal form]

[0057] The crystal forms of teneligliptin in the following examples, comparative examples and reference examples were evaluated by powder X-ray diffraction measurement. The measurement was performed using a powder X-ray diffraction apparatus Bruker D8 ADVANCE under the conditions of Cu-Kα radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 2.0 to 40.0°, scanning speed: 0.1 sec / step, and step length: 0.015°.

[0058] [Evaluation of the quality of similar substances]

[0059] In the evaluation of the analogous substance amount in the following examples, comparative examples and reference examples, each maximum analogous substance mass and the total amount of analogous substances were calculated using high performance liquid chromatography. The ratio of the peak area of ​​each analogous substance from teneligliptin to the sum of all peak areas detected by high performance liquid chromatography was calculated. For each maximum analogous substance mass, the ratio of the analogous substance that has the largest amount among the calculated ratios of the analogous substances is shown. In addition, for the total amount of analogous substances, the ratio of the sum of the peak areas of the analogous substances from teneligliptin to the sum of all peak areas detected by using high performance liquid chromatography is shown.

[0060] <Silica adsorption method>

[0061] [Reference Example 1-1]

[0062] Particles containing teneligliptin were prepared by the silicon oxide adsorption method. Specifically, 29.48 mg of teneligliptin hydrobromide was dissolved in 100 mg of solvent (purified water) to prepare a teneligliptin solution. The obtained teneligliptin solution was added to 45 mg of hydrous silicon dioxide (Fuji Chemical Industry Co., Ltd., FujiSil (registered trademark)) as a porous silicon oxide compound and mixed in a mortar. The obtained particles were dried with a fluidized bed granulation dryer (POWREX Co., Ltd., MP-01 model) to prepare particles containing teneligliptin of Reference Example 1-1.

[0063] [Reference Example 1-2]

[0064] 10 mg of polyvinyl alcohol (partially saponified product) (PVA: Mitsubishi Chemical Corporation, EG-05PW) was dissolved in 90 mg of a solvent (purified water) to prepare a polyvinyl alcohol solution. The polyvinyl alcohol solution was sprayed onto the granules containing teneligliptin of Reference Example 1-1 using a fluidized bed granulation dryer (POWREX Corporation, MP-01 model), thereby obtaining granules containing teneligliptin of Reference Example 1-2.

[0065] [Reference Example 1-3]

[0066] The granulated material containing teneligliptin of Reference Example 1-2 was sieved with a No. 22 sieve and sized. The sized material obtained was mixed with 44.52 mg of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH-11) and 1.0 mg of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tableted with a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain a tablet containing teneligliptin of Reference Example 1-3 weighing 130 mg.

[0067] The granules containing teneligliptin of Reference Example 1-1, the granulated material containing teneligliptin of Reference Example 1-2, and the tablets containing teneligliptin of Reference Example 1-3 were stored in an open environment at 25° C. and a relative humidity of 75% for one month.

[0068] Using the above-mentioned measuring method, the granules containing teneligliptin of Reference Example 1-1, the granulated material containing teneligliptin of Reference Example 1-2, and the tablet containing teneligliptin of Reference Example 1-3 were evaluated for the crystal form, the maximum mass of each analog, and the total amount of analogs immediately after production (initial) and after storage. The evaluation results are shown in Table 1.

[0069] [Table 1]

[0070]

[0071] According to the results in Table 1, the granules containing teneligliptin of Reference Example 1-1, the granulated material containing teneligliptin of Reference Example 1-2, and the tablet containing teneligliptin of Reference Example 1-3 can maintain an amorphous state not only immediately after manufacture but also after storage under open conditions. On the other hand, an increase in the amount of the similar substance can be observed immediately after manufacture (initial) and after storage under open conditions.

[0072] In summary, in the teneligliptin-containing preparation prepared by the silicon oxide adsorption method, teneligliptin maintained an amorphous form immediately after manufacture and after storage under open conditions, but similar substances increased immediately after manufacture and after storage under open conditions.

[0073] <Study on Stabilizers>

[0074] [Reference Example 2-1]

[0075] It was studied whether the particles containing teneligliptin can maintain an amorphous form or suppress the increase of similar substances when the stabilizer is carried together with teneligliptin in a porous silicon oxide compound. Specifically, 2 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved in 100 mg of a solvent (purified water) to prepare a solvent containing a stabilizer. 29.48 mg of teneligliptin hydrobromide was dissolved in the obtained solvent containing a stabilizer to prepare a teneligliptin solution. Using a mortar, the obtained teneligliptin solution was added to 45 mg of hydrous silicon dioxide (Fuji Chemical Industry Co., Ltd., FujiSil (registered trademark)) as a porous silicon oxide compound and mixed. The obtained particles were dried with a fluidized bed granulation dryer (POWREX Co., Ltd., MP-01 model) to prepare particles containing teneligliptin in Reference Example 2-1.

[0076] [Reference Example 2-2]

[0077] 5 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Corporation, EG-05PW) was dissolved in 95 mg of a solvent (purified water) to prepare a polyvinyl alcohol solution. The polyvinyl alcohol solution was sprayed onto the granules containing teneligliptin of Reference Example 2-1 using a fluidized bed granulation dryer (POWREX Corporation, MP-01 model) to obtain a granulated product containing teneligliptin. The granulated product containing teneligliptin was sieved with a No. 22 sieve and sized. The obtained whole granules were mixed with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 31.02 mg of D-mannitol (Freund Industry Co., Ltd., Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Industry Co., Ltd., Adsolider (registered trademark) 101) and 1.0 mg of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tableted using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain a tablet containing teneligliptin of Reference Example 2-2 weighing 120 mg.

[0078] [Reference Example 3-1]

[0079] Teneligliptin-containing particles of Reference Example 3-1 were produced by the same production method as that of Reference Example 2-1, except that lactic acid was replaced with 0.52 mg of hydrochloric acid (Fujifilm Wako Pure Chemical Industries, Ltd., reagent special grade hydrochloric acid).

[0080] [Reference Example 3-2]

[0081] A polyvinyl alcohol solution was prepared by dissolving 5 mg of polyvinyl alcohol (partially saponified product) (PVA: Mitsubishi Chemical Corporation, EG-05PW) in 95 mg of a solvent (purified water). The polyvinyl alcohol solution was sprayed onto the granules containing teneligliptin of Reference Example 3-1 using a fluidized bed granulation dryer (POWREX Corporation, MP-01 model), thereby obtaining a granulated product containing teneligliptin. The granulated product containing teneligliptin was sieved with a No. 22 sieve and sized. The obtained whole granules were mixed with 6 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 32.50 mg of D-mannitol (Freund Industry Co., Ltd., Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Industry Co., Ltd., Adsolider (registered trademark) 101) and 1.0 mg of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tableted using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain tablets containing teneligliptin of Reference Example 3-2 weighing 120 mg.

[0082] [Reference Example 4]

[0083] Teneligliptin-containing granules of Reference Example 4 were prepared by the same preparation method as that of Reference Example 2-1, except that lactic acid was replaced with 2 mg of ascorbic acid (Kyowa Pharmaceutical Chemical Co., Ltd., ascorbic acid 100M).

[0084] [Reference Example 5]

[0085] The same manufacturing method as that of Reference Example 2-1 was used to manufacture particles containing teneligliptin of Reference Example 5 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.

[0086] [Reference Example 6-1]

[0087] Lactic acid was replaced with sodium sulfite (Fujifilm Wako Pure Chemical Industries, Ltd., sodium sulfite) 2mg. In the case of using sodium sulfite, when adding teneligliptin to a solvent containing a stabilizer and attempting to prepare a teneligliptin solution, the solution could not be prepared due to the precipitation of teneligliptin, so sodium sulfite was added in powder form. Specifically, teneligliptin hydrobromide 29.48mg was dissolved in 100mg of solvent (purified water) to prepare a teneligliptin solution. Using a mortar, the obtained teneligliptin was added to a mixture of 45mg of hydrous silicon dioxide (Fuji Chemical Industry Co., Ltd., Fujisil (registered trademark)) and 2mg of sodium sulfite as a porous silicon oxide compound and mixed. The obtained particles were dried with a fluidized bed granulation dryer (POWREX Co., Ltd., MP-01 type), and the particles containing teneligliptin of Reference Example 6-1 were prepared.

[0088] [Reference Example 6-2]

[0089] 10 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Corporation, EG-05PW) was dissolved in 90 mg of a solvent (purified water) to prepare a polyvinyl alcohol solution. The polyvinyl alcohol solution was sprayed onto the particles containing teneligliptin of Reference Example 6-1 using a fluidized bed granulation dryer (POWREX Co., Ltd., MP-01 model), thereby obtaining a granulated material containing teneligliptin. The granulated material containing teneligliptin was sieved with a No. 22 sieve and granulated. The obtained granulated material was mixed with 42.52 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) and 1.0 mg of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tableted using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain a tablet containing teneligliptin of Reference Example 6-2 weighing 130 mg.

[0090] The granules containing teneligliptin of Reference Examples 2-1, 3-1, 4 and 6-1 and the tablets containing teneligliptin of Reference Examples 2-2, 3-2 and 6-2 were stored for one month at 25°C, 75% relative humidity and in an open environment. The granules containing teneligliptin of Reference Examples 2-1, 3-1, 4 and 6-1 and the tablets containing teneligliptin of Reference Examples 2-2, 3-2 and 6-2 were evaluated for the crystal form, the maximum mass of each analog and the total amount of analogs using the above-mentioned measurement method. The evaluation results are shown in Table 2. In addition, the evaluation results of the granules containing teneligliptin of Reference Example 1-1 and the tablets containing teneligliptin of Reference Example 1-3 are listed in Table 2 again.

[0091] [Table 2]

[0092]

[0093] ND: No data

[0094] The results in Table 2 confirmed that the granules containing teneligliptin of Reference Examples 2-1, 3-1 and 4 to which lactic acid, hydrochloric acid or ascorbic acid was added and the tablets containing teneligliptin of Reference Examples 2-2 and 3-2 maintained an amorphous state not only immediately after production but also after storage under open conditions. On the other hand, it was clear that the granules containing teneligliptin of Reference Example 6-1 to which sodium sulfite was added and the tablets containing teneligliptin of Reference Example 6-2 could not maintain an amorphous state.

[0095] In the granules containing teneligliptin of Reference Examples 2-1 and 4 to which lactic acid or ascorbic acid was added and the tablet containing teneligliptin of Reference Example 2-2, the mass of the analogous substance immediately after production (initial) was reduced. On the other hand, in the granules containing teneligliptin of Reference Example 3-1 to which hydrochloric acid was added and the tablet containing teneligliptin of Reference Example 3-2, the amount of the analogous substance immediately after production (initial) was not reduced.

[0096] Regarding the amount of similar substances after storage under open conditions, the amount of similar substances increased significantly in the granules containing teneligliptin of Reference Examples 2-1 and 3-1 and the tablets containing teneligliptin of Reference Examples 2-2 and 3-2, which maintained an amorphous state, while the increase in the amount of similar substances was suppressed in the granules containing teneligliptin of Reference Example 6-1 and the tablets containing teneligliptin of Reference Example 6-2, which were crystallized. That is, in the granules containing teneligliptin of Reference Examples 2-1, 3-1, 4 and 6-1 and the tablets containing teneligliptin of Reference Examples 2-2, 3-2 and 6-2, the increase in similar substances could not be suppressed while maintaining an amorphous state after storage under open conditions.

[0097] Stabilizers capable of maintaining an amorphous morphology were screened, and the relationship between the stabilizers and the amount of similar substances in granules containing teneligliptin immediately after manufacture (initial) was studied.

[0098] [Reference Example 7]

[0099] The teneligliptin-containing granules of Reference Example 7 were prepared by the same preparation method as that of Reference Example 1-1.

[0100] [Reference Example 8]

[0101] The teneligliptin-containing granules of Reference Example 8 were prepared by the same preparation method as that of Reference Example 4.

[0102] [Reference Example 9]

[0103] Teneligliptin-containing particles of Reference Example 9 were prepared by the same production 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 in place of ascorbic acid to prepare the stabilizer-containing solvent.

[0104] [Reference Example 10]

[0105] Teneligliptin-containing granules of Reference Example 10 were prepared by the same production method as that of Reference Example 8, except that 0.5 mg of tartaric acid (DL-tartaric acid, Yamazen Pharmaceutical Co., Ltd.) was dissolved in place of ascorbic acid to prepare a solvent containing a stabilizer.

[0106] [Reference Example 11]

[0107] Teneligliptin-containing particles of Reference Example 11 were produced by the same production 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 in place of ascorbic acid to prepare the stabilizer-containing solvent.

[0108] [Reference Example 12]

[0109] Teneligliptin-containing granules of Reference Example 12 were produced by the same production method as that of Reference Example 8, except that 0.5 mg of malic acid (Fuso Chemical Industry Co., Ltd., DL-malic acid) was dissolved in place of ascorbic acid to prepare the solvent containing the stabilizer.

[0110] [Reference Example 13]

[0111] Teneligliptin-containing granules of Reference Example 13 were prepared by the same production method as Reference Example 8, except that 0.5 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved in place of ascorbic acid to prepare the solvent containing the stabilizer.

[0112] [Reference Example 14]

[0113] Teneligliptin-containing granules of Reference Example 14 were prepared by the same preparation method as Reference Example 8, except that 1 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved in place of ascorbic acid to prepare the solvent containing the stabilizer.

[0114] [Reference Example 15]

[0115] The teneligliptin-containing granules of Reference Example 15 were prepared by the same preparation method as that of Reference Example 2-1.

[0116] [Reference Example 16]

[0117] Teneligliptin-containing granules of Reference Example 16 were prepared by the same preparation method as Reference Example 8, except that 3 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved in place of ascorbic acid to prepare the solvent containing the stabilizer.

[0118] [Reference Example 17]

[0119] Teneligliptin-containing granules of Reference Example 17 were prepared by the same preparation method as Reference Example 8, except that 4 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved in place of ascorbic acid to prepare the solvent containing the stabilizer.

[0120] [Reference Example 18]

[0121] The teneligliptin-containing granules of Reference Example 18 were prepared by the same preparation method as that of Reference Example 3-1.

[0122] The granules containing teneligliptin of Reference Examples 7 to 18 were stored for two weeks or one month at 25°C and 75% relative humidity under open conditions. The crystalline form of teneligliptin after one month of storage under open conditions and the amount of similar substances immediately after production (initial) and after two weeks of storage under open conditions were evaluated by the above-mentioned determination method. The evaluation results are shown in Table 3.

[0123] [Table 3]

[0124]

[0125] ND: No data

[0126] The results in Table 3 clearly show that the particles containing teneligliptin of Reference Examples 8 to 17 containing an organic acid as a stabilizer maintain an amorphous state even after storage under open conditions, and the amount of similar substances immediately after production (initial) is significantly reduced compared to the particles containing teneligliptin of Reference Example 7 containing no stabilizer or Reference Example 18 containing hydrochloric acid as a stabilizer. On the other hand, Reference Examples 9 to 17, which suppressed the amount of similar substances at the initial stage, were unable to suppress the increase of similar substances after storage under open conditions.

[0127] The results of Reference Examples 2-1, 2-2, 3-1, 3-2 and Reference Examples 4 to 18 clearly show that by including an organic acid as a stabilizer in particles containing teneligliptin prepared by the silicon oxide adsorption method, the amorphous form of teneligliptin can be maintained even after storage under open conditions, and the amount of similar substances immediately after production (initial) is significantly reduced. On the other hand, no preparation that suppresses the increase of similar substances when stored under open conditions was obtained.

[0128] <Study on Antioxidants>

[0129] [Reference Example 19]

[0130] The teneligliptin-containing granules of Reference Example 19 were prepared by the same preparation method as that of Reference Example 1-1.

[0131] [Reference Example 20]

[0132] The teneligliptin-containing granules of Reference Example 20 were prepared by the same preparation method as that of Reference Example 2-1.

[0133] [Example 1]

[0134] It was studied whether the particles containing teneligliptin, which contain amorphous teneligliptin and a stabilizer carried in a porous silicon oxide compound, can maintain an amorphous form or suppress the increase of similar substances when an antioxidant is mixed in the particles containing teneligliptin. Specifically, 76.48 mg of the particles containing teneligliptin 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 Industries, Ltd., Adsolider (registered trademark) 101) were mixed in a mortar to obtain a preparation containing teneligliptin of Example 1.

[0135] [Comparative Examples 1 to 9]

[0136] Teneligliptin-containing preparations of Comparative Examples 1 to 9 were prepared by the same preparation method as that of Example 1, except that 2 mg of propyl gallate was replaced with 2 mg of each antioxidant shown in Table 4 below.

[0137] [Table 4]

[0138] Comparative Example 1 Butylated Hydroxytoluene (BHT) Comparative Example 2 ascorbic acid Comparative Example 3 Sodium sulfite hydrate Comparative Example 4 Sodium metabisulfite Comparative Example 5 Sodium Ethylhexanoate Hydrate Comparative Example 6 Citric Acid Hydrate Comparative Example 7 Tocopherol Comparative Example 8 Tocopheryl acetate Comparative Example 9 Soy lecithin

[0139] [Comparative Examples 10 to 19]

[0140] Teneligliptin-containing preparations of Comparative Examples 10 to 19 were prepared by mixing 74.48 mg of the teneligliptin-containing granules obtained in Reference Example 19, 2 mg of each antioxidant listed in Table 5 below, and 2 mg of light anhydrous silicic acid (Freund Sangyo Co., Ltd., Adsolider (registered trademark) 101) in a mortar.

[0141] [Table 5]

[0142] Comparative Example 10 Butylated Hydroxytoluene (BHT) Comparative Example 11 ascorbic acid Comparative Example 12 Sodium sulfite hydrate Comparative Example 13 Sodium metabisulfite Comparative Example 14 Sodium Ethylhexanoate Hydrate Comparative Example 15 Citric Acid Hydrate Comparative Example 16 Tocopherol Comparative Example 17 Tocopheryl acetate Comparative Example 18 Soy lecithin Comparative Example 19 Propyl Gallate

[0143] The preparations containing teneligliptin of Reference Examples 19 and 20, Example 1 and Comparative Examples 1 to 19 were stored at 25°C, 75% relative humidity and in an open state for two weeks. The amount of crystalline form and similar substances after storage in an open state was evaluated by the above-mentioned determination method. The evaluation results are shown in Table 6.

[0144] [Table 6]

[0145]

[0146]

[0147] According to the results of Table 6, compared with Comparative Examples 1 to 9 using other antioxidants, the amount of similar substances after storage under open conditions was significantly reduced in the preparation containing teneligliptin of Example 1 in which propyl gallate was mixed with particles containing teneligliptin containing amorphous teneligliptin and lactic acid carried on a porous silicon oxide compound. In addition, in Comparative Example 19 in which propyl gallate was mixed with particles containing teneligliptin without lactic acid, the amount of similar substances increased after storage under open conditions. This result shows that lactic acid and propyl gallate act synergistically and significantly inhibit the increase of similar substances of teneligliptin after storage under open conditions.

[0148] [Example 2]

[0149] It was studied whether the increase of similar substances can be suppressed under open conditions when the preparation containing antioxidants is made into tablets. Specifically, 76.48 mg of the particles containing teneligliptin of Reference Example 2-1, propyl gallate (Fujifilm Wako Pure Chemical Industries, Ltd., propyl gallate) 2 mg, L-HPC (Shin-Etsu Chemical Industry Co., Ltd., LH-11) 6 mg, D-mannitol (Freund Industry Co., Ltd., Granutol (registered trademark) F) 34.02 mg, light anhydrous silicic acid (Freund Industry Co., Ltd., Adsolider (registered trademark) 101) 0.5 mg and magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) 1 mg were mixed with a mortar. The obtained mixture was compression-molded using a rotary tablet press to obtain a tablet containing teneligliptin of Example 2.

[0150] [Comparative Example 20]

[0151] A tablet containing teneligliptin of Comparative Example 20 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 removed.

[0152] The tablets containing teneligliptin of Example 2 and Comparative Example 20 were stored at 25°C, 75% relative humidity and open conditions for two weeks, four weeks and twelve weeks. Using the above-mentioned determination method, the amount of crystalline form and similar substances after storage under initial conditions (just after production) and open conditions was evaluated. The evaluation results are shown in Table 7.

[0153] [Table 7]

[0154]

[0155]

[0156] ND: No data

[0157] The results in Table 7 show that, compared with the tablets of Comparative Example 20 which do not contain an antioxidant, in the tablets containing teneligliptin of Example 2 which comprise amorphous teneligliptin, lactic acid and propyl gallate carried in a porous silica compound, the increase in the amount of similar substances after storage under open conditions was significantly suppressed, and the amorphous state of teneligliptin was maintained.

Claims

1. A preparation containing teneligliptin, comprising: A porous silicon-oxygen compound, amorphous teneligliptin carried by the porous silicon-oxygen compound, an organic acid and propyl gallate.

2. The preparation containing teneligliptin according to claim 1, wherein The teneligliptin-containing formulation comprises particles, wherein the particles comprise the porous silicon-oxygen compound, amorphous teneligliptin carried by the porous silicon-oxygen compound, and the organic acid.

3. The preparation containing teneligliptin according to claim 1, wherein The porous silicon oxide compound is one or more porous silicates selected from the group consisting of silicon dioxide, hydrated silicon dioxide and light anhydrous silicic acid, or one or more porous silicates selected from the group consisting of magnesium aluminum metasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate and aluminosilicate.

4. The preparation containing teneligliptin according to claim 1, wherein The porous silicon oxide compound is selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and aluminum magnesium metasilicate.

5. The preparation containing teneligliptin according to claim 1, wherein The porous silicon-oxygen compound is hydrous silicon dioxide.

6. The preparation containing teneligliptin according to claim 1, wherein The organic acid is one or more organic acids selected from the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid and malic acid.

7. The preparation containing teneligliptin according to claim 1, wherein The organic acid is selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid.

8. The preparation containing teneligliptin according to claim 1, wherein The organic acid is selected from the group consisting of citric acid, tartaric acid and malic acid.

9. The preparation containing teneligliptin according to claim 1, wherein The organic acid is lactic acid.

10. The preparation containing teneligliptin according to claim 1, wherein The organic acid is citric acid.

11. The preparation containing teneligliptin according to claim 1, wherein The porous silicon-oxygen compound is hydrous silicon dioxide, and the organic acid is lactic acid.

12. The preparation containing teneligliptin according to any one of claims 1 to 11, wherein The teneligliptin-containing preparation comprises particles, wherein the particles comprise: the porous silicon-oxygen compound; and amorphous teneligliptin and the organic acid carried by the porous silicon-oxygen compound.

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