TW202432125A - Tenegliptin-containing particles and preparations containing the same - Google Patents

Abstract

One of the subjects of one embodiment of the present invention is to provide teneligliptin-containing particles that maintain the amorphous form of teneligliptin after storage under the open conditions that are easily affected by humidity. Alternatively, one of the subjects of one embodiment of the present invention is to provide teneligliptin-containing particles that suppress the generation of analogues during production. Or one of the subjects of one embodiment of the present invention is to provide a formulated product containing such teneligliptin-containing particles. According to one embodiment of the present invention, it is possible to provide teneligliptin-containing particles that include porous silica and amorphous teneligliptin supported on the porous silica.

Description

Tenegliptin-containing particles and preparations containing the same

One embodiment of the present invention relates to particles containing teneligliptin. Or one embodiment of the present invention relates to a formulation comprising particles containing teneligliptin.

Thiagliptin ([(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 as a treatment for type 2 diabetes.

As a therapeutic drug for type 2 diabetes, for example, Patent Document 1 describes a solid preparation containing tenegliptin hydrobromide hydrate. Also, for example, Patent Document 2 describes an orally disintegrating tablet containing tenegliptin hydrobromide hydrate. These are preparations containing an active ingredient in a crystalline form.

On the other hand, generally speaking, since amorphous substances are in a high energy state, an amorphous preparation containing an active ingredient in an amorphous form can be expected to improve the solubility of the active ingredient or improve the absorption rate into the body compared to a preparation containing an active ingredient in a crystalline form. However, it is known that amorphous forms are physically and chemically unstable, so they are easily converted into crystalline forms with more stable energy and are easy to generate analogs. Therefore, in the case of amorphous preparations, special efforts are sometimes required to ensure the quality of the preparations. For example, efforts are required to maintain the amorphous state during the preparation manufacturing process, efforts are required to maintain the amorphous state even when exposed to extreme conditions such as high temperature or high humidity during the circulation period or storage until administration, and efforts are required to suppress the generation of allogeneic substances during the manufacturing process or the above storage.

As an amorphous preparation, for example, Patent Document 3 describes a pharmaceutical composition containing tenegliptin, which contains amorphous tenegliptin hydrobromide and a polymer that maintains amorphous state. Patent Document 3 describes a preparation in which the active ingredient in the preparation is maintained in an amorphous state after storage under sealed conditions, or a preparation in which the amount of allotropes increased during storage under open conditions is reduced, but does not describe a tenegliptin-containing preparation in which the active ingredient in the preparation is maintained in an amorphous state even after storage under open conditions and the generation of allotropes during production is suppressed.

『Patent Document』 《Patent Document 1》: Japanese Patent Publication No. 5775463 《Patent Document 2》: International Patent Publication No. 2020/209350 《Patent Document 3》: Japanese Patent Publication No. 2020-070260

One of the problems of one embodiment of the present invention is to provide particles containing tenegliptin that maintain an amorphous form of tenegliptin after storage under open conditions that are easily affected by humidity. Furthermore, through the research of the inventors, it is known that related substances are easily generated during the production of particles containing tenegliptin. Therefore, one of the problems of one embodiment of the present invention is to provide particles containing tenegliptin that suppress the generation of related substances during production. Or one of the problems of one embodiment of the present invention is to provide a preparation containing such particles containing tenegliptin.

According to one embodiment of the present invention, there is provided a particle containing tenegliptin, which includes porous silica and amorphous tenegliptin supported on the porous silica.

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 may be 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.

The porous silica may also be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate.

The porous silica may also be hydrous silicon dioxide.

The tenegliptin-containing particles may further contain a stabilizer.

Stabilizers may also be selected from pH adjusters.

The pH adjuster can also be an organic acid.

The pH adjuster 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.

The pH adjuster may also be selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid.

The pH adjuster may also be selected from the group consisting of citric acid, tartaric acid and malic acid.

The pH adjuster may also be lactic acid.

The pH adjuster can also be citric acid.

The porous silica may also be hydrous silicon dioxide, and the pH adjuster may also be lactic acid.

According to one embodiment of the present invention, a tablet comprising any of the above-described tenegliptin-containing particles can be provided.

According to one embodiment of the present invention, a particle containing tenegliptin which maintains an amorphous state of tenegliptin even after storage under open conditions susceptible to humidity can be provided. Alternatively, according to one embodiment of the present invention, a particle containing tenegliptin which suppresses the generation of allotropes during production can be provided. Alternatively, according to one embodiment of the present invention, a preparation containing such a particle containing tenegliptin can be provided.

The following describes the particles containing tenegliptin and the formulation containing the particles containing tenegliptin related to the present invention. In addition, when tenegliptin is referred to in the present invention, it may include its free form and pharmacologically acceptable salt or solvent, and when tenegliptin hydrobromide is referred to, it may also include its solvent. The particles containing tenegliptin and the formulation containing the particles containing tenegliptin of the present invention are not limited to the following embodiments and the contents of the examples.

[Containing tenegliptin particles]

The tenegliptin-containing particles according to one embodiment of the present invention include porous silica, and amorphous tenegliptin supported on the porous silica, or amorphous tenegliptin supported on the porous silica and a stabilizer.

Porous silica has pores. The pores are spaces connecting the surface of the porous silica to the interior thereof, and can load tenegliptin or tenegliptin and a stabilizer. Porous silica can load tenegliptin or tenegliptin and a stabilizer on its surface and/or in the pores. In this specification, the so-called "loading" of tenegliptin or tenegliptin and a stabilizer on porous silica means loading tenegliptin or tenegliptin and a stabilizer on the surface and/or in the pores of porous silica, and/or adsorbing tenegliptin or tenegliptin and a stabilizer on the surface and/or in the pores of porous silica, and/or disposing tenegliptin or tenegliptin and a stabilizer on the surface and/or in the pores of porous silica.

In the present specification, porous silica is a porous silicic acid selected from the group consisting of silicon dioxide, hydrous silicon dioxide and light anhydrous silicic acid, or a porous silicate selected from the group consisting of magnesium aluminum metasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate and aluminum silicate.

In one embodiment, the porous silica can also be selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate. Alternatively, in one embodiment, the porous silica can also be hydrous silicon dioxide.

The porous silica contained in the tenegliptin-containing particles related to the present embodiment is a carrier for loading amorphous tenegliptin or amorphous tenegliptin and a stabilizer. Since the porous silica, which is a carrier, loads tenegliptin or tenegliptin and a stabilizer, the tenegliptin loaded on the porous silica can be maintained in an amorphous state. In the present specification, the porous silica contained in the tenegliptin-containing particles loading "amorphous tenegliptin" or "amorphous tenegliptin" and a stabilizer means that the tenegliptin loaded on the porous silica is in an amorphous state. The porous silica contained in the tenegliptin-containing particles is preferably hydrated silica. Furthermore, the particles containing tenegliptin in this embodiment can also be coated. In addition, in one embodiment, when the particles containing tenegliptin are coated with a film, the porous silica is preferably spherical.

In the tenegliptin-containing particles related to the present embodiment, the stabilizer is an additive that is involved in maintaining the amorphous form of tenegliptin and inhibiting the generation of allied products during manufacturing. The stabilizer can be carried on the porous silica together with the tenegliptin, or can be added separately from the porous silica. The so-called "amorphous" in this specification refers to a state in which the diffraction peaks derived from tenegliptin, including the diffraction peaks derived from the crystals of tenegliptin hydrobromide hydrate described in Japanese Patent No. 4208938 (2θ=5.5°±0.2°, 13.4°±0.2°, 14.4°±0.2°), are not confirmed by powder X-ray diffraction measurement. The powder X-ray diffraction measurement method can be carried out in accordance with the 18th edition of the Japanese Pharmacopoeia.

A pH adjuster can be used as a stabilizer contained in the tenegliptin-containing particles related to this embodiment. Examples of pH adjusters include hydrochloric acid and organic acids, and organic acids are particularly preferred. In particular, examples of organic acids include lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, and apple acid, but the invention is not limited thereto.

In one embodiment, the pH adjuster can also be selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid. Alternatively, in one embodiment, the pH adjuster can also be selected from the group consisting of citric acid, tartaric acid and malic acid. Alternatively, in one embodiment, the pH adjuster can also be lactic acid. Alternatively, in one embodiment, the pH adjuster can also be citric acid.

In one embodiment, the particles containing tenegliptin may also include porous silica selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate and a pH adjuster selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid. Alternatively, in one embodiment, the particles containing tenegliptin may also include porous silica selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate and a pH adjuster selected from the group consisting of citric acid, tartaric acid and malic acid. Alternatively, in one embodiment, the particles containing tenegliptin may also include porous silica selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate, and lactic acid as a pH adjuster. Alternatively, in one embodiment, the particles containing tenegliptin may also include porous silica selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate, and citric acid as a pH adjuster.

In one embodiment, the particles containing tenegliptin may also include hydrous silica as porous silica and a pH adjuster selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid. Or in one embodiment, the particles containing tenegliptin may also include hydrous silica as porous silica and a pH adjuster selected from the group consisting of citric acid, tartaric acid and malic acid. Or in one embodiment, the particles containing tenegliptin may also include hydrous silica as porous silica and lactic acid as a pH adjuster. Or in one embodiment, the particles containing tenegliptin may also include hydrous silica as porous silica and citric acid as a pH adjuster.

In one embodiment, the tenegliptin-containing particles may also contain polyvinyl alcohol (partially saponified).

The tenegliptin-containing particles related to the present embodiment can stably maintain the amorphous state of tenegliptin by loading tenegliptin on porous silica. As shown in the examples described later, the tenegliptin-containing particles related to the present embodiment can maintain the amorphous state of tenegliptin even when stored for one month under open conditions at 25°C and a relative humidity of 75%. Furthermore, the tenegliptin-containing particles related to the present embodiment can maintain the amorphous state of tenegliptin by loading tenegliptin and a stabilizer on porous silica, and can also suppress the generation of byproducts during manufacturing.

[Method for producing particles containing tenegliptin]

The particles containing tenegliptin related to the present invention can be prepared, for example, by using the well-known silica adsorption method to support tenegliptin or tenegliptin and a stabilizer on porous silica. More specifically, tenegliptin hydrobromide or its hydrate or other solvent compound is dissolved in a solvent (purified water) or a stabilizer-containing solvent in which a stabilizer is dissolved in a solvent (purified water), the obtained tenegliptin solution is mixed with porous silica, and the solvent is removed to obtain amorphous tenegliptin or amorphous tenegliptin and a stabilizer supported on porous silica particles. Here, the API dissolved in the solvent or the like may be an amorphous form of tenegliptin hydrobromide, a crystalline form, or a hydrate or other solvent compound thereof. Regardless of the form of the API, the amorphous tenegliptin particles loaded on porous silica can be obtained by the above-mentioned manufacturing method. Furthermore, the obtained tenegliptin-containing particles can be coated with a film to obtain film-coated particles.

[Preparation containing tenegliptin]

For example, tablets or granules can be cited as one embodiment of the tenegliptin-containing preparation in the present embodiment, but are not limited thereto. The tenegliptin-containing tablet can be obtained by mixing the tenegliptin-containing particles related to the present embodiment with one or more pharmaceutically acceptable additives and pressing the mixture into tablets. In one embodiment, the tenegliptin-containing tablet contains, for example, 20 mg or 40 mg of tenegliptin hydrobromide per tablet in terms of tenegliptin (free body), but the content of tenegliptin (free body) can be appropriately changed within the range that a therapeutic effect can be obtained.

Examples of additives contained in the preparation containing tenegliptin include, but are not limited to, excipients, binders, disintegrating agents, lubricants, 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.

Examples of binders include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and methyl cellulose. Examples of disintegrators include, but are not limited to, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, and cross-linked polyvinyl pyrrolidone. Examples of lubricants include, but are not limited to, light anhydrous silicic acid, hydrous silica, and talc. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, stearic acid, and sucrose fatty acid esters.

In one embodiment, the tenegliptin-containing preparation preferably includes an antioxidant. The blending amount of the antioxidant is preferably 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, relative to the weight of the preparation. Examples of the antioxidant include butylated hydroxytoluene (BHT) or ascorbic acid, but are not limited thereto. By making the tenegliptin-containing preparation contain an antioxidant, the increase of tenegliptin-like substances can be reduced. In the present specification, the amount of the analogous substance can be obtained by calculating the ratio of the peak area of the analogous substance derived from tenegliptin detected by measurement using high performance liquid chromatography to the total of all peak areas.

[Manufacturing method of preparation containing tenegliptin]

The tenegliptin-containing tablet, which is one embodiment of the tenegliptin-containing preparation of the present invention, can be manufactured by including: A) mixing the tenegliptin-containing particles with various additives such as a shaping agent, a disintegrating agent, a gliding agent, a lubricant, etc. as required and then granulating them as appropriate to obtain a powder or granules; and B) compressing the above-mentioned mixture into a shape; and the tenegliptin-containing tablet manufactured by the above-mentioned process can also be coated with a film to make a film-coated tablet.

『Implementation example』

[Comparison Example 1]

A solid dispersion known as one of the methods for maintaining the amorphous form of a raw material drug was produced. In addition, the amount of tenegliptin and each additive used was determined to be the content in one tablet. Specifically, 29.48 mg of tenegliptin hydrobromide and 7.2 mg of hydroxypropyl methylcellulose (HPMC: Shin-Etsu Chemical Co., Ltd., TC-5E) were dissolved in 213.32 mg of a solvent (purified water) to prepare a tenegliptin solution. Using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model), the tenegliptin solution was sprayed onto 3.0 mg of low-substituted hydroxypropylcellulose (L-HPC: Shin-Etsu Chemical Co., Ltd., LH-11) and 66.82 mg of D-mannitol (Mitsubishi Corporation Food Techno Co., Ltd., Mannit-P) by a granulation spray drying method to obtain the tenegliptin-containing granules of Comparative Example 1. The obtained granules were sieved through a No. 22 sieve to size the particles. The obtained granules were mixed with 9.0 mg of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11), 0.3 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), 2.4 mg of ascorbic acid (Kyowa Pharma Chemical Co., Ltd., ascorbic acid 100 M), 1.2 mg of talc (Fuji Talc Industrial Co., Ltd., ML115), and 0.6 mg of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tablets were pressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain 120 mg of the tenegliptin-containing tablet of Comparative Example 1.

[Comparison Example 2]

The solid dispersion containing tenegliptin of Comparative Example 2 was prepared by the same manufacturing method as Comparative Example 1, except that 23.6 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Co., Ltd., EG-05PW) was used instead of HPMC to prepare the tenegliptin solution. The tenegliptin-containing tablets of Comparative Example 2 were obtained by the same manufacturing method as Comparative Example 1.

The tenegliptin-containing tablets of Comparative Examples 1 and 2 were stored at 25°C, relative humidity 75%, under open conditions for 2 weeks.

[Evaluation of crystal form]

The crystal form of the tenegliptin tablets in Comparative Examples 1 and 2 was evaluated by powder X-ray diffraction measurement just after production (initial) and after 2 weeks of storage. The measurement was performed using a powder X-ray diffraction device Bruker D8 ADVANCE, using Cu-Kα line, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 2.0 ~ 40.0°, scanning speed: 0.1 sec/step, step size: 0.015°. The evaluation results of the crystal form are shown in Table 1.

Table 1 initial 25℃, 75%RH, open, 2W Crystalline Crystalline Comparison Example 1 Amorphous Crystallization Comparison Example 2 Amorphous Crystallization

From the results in Table 1, it can be seen that when the solid dispersion is prepared, the tenegliptin in the preparation is amorphous immediately after preparation, but crystallizes after storage under open conditions and cannot maintain the amorphous state. In addition, when stored under sealed conditions, it is confirmed that the amorphous state is maintained.

In the manufacturing methods of the following Examples and Comparative Examples, the amounts of tenegliptin and various additives used are basically defined as the amount in one tablet of tenegliptin-containing tablets. In the case of manufacturing particles containing tenegliptin, since they are sometimes tableted later, the amount is also recorded as the amount in one tablet.

[Example 1]

The silica adsorption method is used to manufacture particles containing tenegliptin. Specifically, 29.48 mg of tenegliptin hydrobromide is dissolved in 100 mg of a solvent (purified water) to prepare a tenegliptin solution. Using a mortar, 45 mg of the obtained tenegliptin solution is added to hydrated silicon dioxide (Fuji Chemical Industries, Ltd., FujiSil (registered trademark)) as porous silica, and the mixture is mixed simultaneously. The obtained particles are dried using a shed dryer to manufacture the tenegliptin-containing particles of Example 1.

[Example 2-1]

The tenegliptin-containing particles of Example 2-1 were prepared by the same manufacturing method as that of Example 1, except that a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) was used for the drying step of the particles.

[Example 2-2]

10 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Co., Ltd., 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 tenegliptin-containing particles of Example 2-1 using a fluidized layer granulation dryer (Powrex Corporation, MP-01 model) to obtain the tenegliptin-containing granules of Example 2-2.

[Example 2-3]

The tenegliptin-containing granules of Example 2-2 were sieved through a No. 22 sieve to size the granules. The obtained size granules were mixed with 44.52 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 tablets were pressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain 130 mg of tenegliptin-containing tablets of Example 2-3.

The tenegliptin-containing particles of Examples 1 and 2-1, the tenegliptin-containing granules of Example 2-2, and the tenegliptin-containing tablets of Example 2-3 were stored at 25° C., relative humidity 75%, and open conditions for 1 month, or at 40° C., relative humidity 75%, and sealed conditions for 1 month.

The crystal form of the tenegliptin-containing particles of Examples 1 and 2-1, the tenegliptin-containing granules of Example 2-2, and the tenegliptin-containing tablets of Example 2-3 were evaluated by the above-mentioned measurement method just after production (initial) and after storage under various conditions. The evaluation results are shown in Table 2.

Table 2 initial 25℃、75%RH、Open、1M 40℃、75%RH、sealed、1M Crystalline Crystalline Crystalline Embodiment 1 Amorphous Amorphous Amorphous Example 2-1 Amorphous Amorphous Amorphous Example 2-2 Amorphous Amorphous Amorphous Embodiment 2-3 Amorphous Amorphous Amorphous

It can be seen from the results in Table 2 that the tenegliptin-containing particles of Examples 1 and 2-1, the tenegliptin-containing granules of Example 2-2, and the tenegliptin-containing tablets of Example 2-3 can maintain an amorphous state not only immediately after production but also when stored under open conditions.

[Example 3-1]

This study investigated whether the particles containing tenegliptin could maintain an amorphous state when a stabilizer and tenegliptin were loaded on porous silica together. 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 stabilizer-containing solvent. 29.48 mg of tenegliptin hydrobromide was dissolved in the obtained stabilizer-containing solvent to prepare a tenegliptin solution. The obtained tenegliptin solution was added to 45 mg of hydrous silicon dioxide (Fuji Chemical Industries, Ltd., FujiSil (registered trademark)) as porous silica using a mortar and the mixture was mixed. The obtained particles were dried using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to produce the tenegliptin-containing particles of Example 3-1.

[Example 3-2]

5 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Co., Ltd., 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 tenegliptin-containing particles of Example 3-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to obtain tenegliptin-containing granules. The tenegliptin-containing granules were sieved with a No. 22 sieve to size the particles. 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 Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taiping Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tablets were pressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain 120 mg of the tenegliptin-containing tablets of Example 3-2.

[Example 4-1]

The tenegliptin-containing particles of Example 4-1 were prepared by the same production method as that of Example 3-1, except that lactic acid was replaced with 0.52 mg of hydrochloric acid (FUJIFILM Wako Pure Chemical Corporation, special-grade hydrochloric acid for drug testing).

[Example 4-2]

5 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Co., Ltd., 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 tenegliptin-containing particles of Example 4-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to obtain tenegliptin-containing granules. The tenegliptin-containing granules were sieved with a No. 22 sieve to size the particles. 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 Corporation, Granutol F), 0.5 mg of light anhydrous silicic acid (Freund Corporation, Adsolider (registered trademark) 101), and 1.0 mg of magnesium stearate (Taiping Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag, and tablets were pressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain 120 mg of the tenegliptin-containing tablet of Example 4-2.

[Example 5]

The tenegliptin-containing particles of Example 5 were prepared by the same production method as that of Example 3-1, except that lactic acid was replaced with 2 mg of ascorbic acid (Kyowa Pharma Chemical Co., Ltd., ascorbic acid 100 M).

[Comparison Example 3]

The preparation of the tenegliptin-containing particles of Comparative Example 3 was attempted by the same preparation method as that of Example 3-1, except that the lactic acid was replaced with 2 mg of sodium metabisulfite (FUJIFILM Wako Pure Chemical Corporation). However, when preparing the tenegliptin solution, tenegliptin precipitated and the solution could not be prepared.

[Comparison Example 4-1]

Lactic acid was replaced with 2 mg of sodium sulfite (FUJIFILM Wako Pure Chemical Corporation, sodium sulfite). When sodium sulfite was used, when a solution of tenegliptin was prepared by adding tenegliptin to a stabilizer-containing solvent, tenegliptin precipitated and a solution could not be prepared, so sodium sulfite was added in the form of powder. Specifically, 29.48 mg of tenegliptin hydrobromide was dissolved in 100 mg of a solvent (purified water) to prepare a tenegliptin solution. The obtained tenegliptin solution was added to a mixture of 45 mg of hydrous silicon dioxide (Fuji Chemical Industries, Ltd., FujiSil (registered trademark)) as porous silica and 2 mg of sodium sulfite using a mortar and the mixture was mixed. The obtained particles were dried using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to produce the tenegliptin-containing particles of Comparative Example 4-1.

[Comparison Example 4-2]

10 mg of polyvinyl alcohol (partially saponified) (PVA: Mitsubishi Chemical Co., Ltd., 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 tenegliptin-containing particles of Comparative Example 4-1 using a fluidized bed granulation dryer (Powrex Corporation, MP-01 model) to obtain tenegliptin-containing granules. The tenegliptin-containing granules were sieved through a No. 22 sieve to size the particles. The obtained whole granules were 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 tablets were pressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain 130 mg of the tenegliptin-containing tablet of Comparative Example 4-2.

The tenegliptin-containing particles or tenegliptin-containing tablets of Examples 3 to 5 and Comparative Example 4 were stored at 25°C, relative humidity 75%, and open conditions for 1 month, or stored at 40°C, relative humidity 75%, and sealed conditions for 1 month. The crystal forms of the tenegliptin-containing particles or tenegliptin-containing tablets of Examples 3 to 5 and Comparative Example 4 just after production (initial) and after storage were evaluated by the measurement method described above. The evaluation results are disclosed in Table 3. In addition, the evaluation results of the tenegliptin-containing particles or tenegliptin-containing tablets of Example 2 are again disclosed in Table 3.

Table 3 Dosage type initial 25℃、75%RH、Open、1M 40℃、75%RH、sealed、1M Crystalline Crystalline Crystalline Example 2-1 particle Amorphous Amorphous Amorphous Embodiment 2-3 Tablets Amorphous Amorphous Amorphous Example 3-1 particle Amorphous Amorphous Amorphous Example 3-2 Tablets Amorphous Amorphous Amorphous Example 4-1 particle Amorphous Amorphous Amorphous Example 4-2 Tablets Amorphous Amorphous Amorphous Embodiment 5 particle Amorphous Amorphous - Comparison Example 4-1 particle Crystallization Crystallization Crystallization Comparison Example 4-2 Tablets Crystallization Crystallization Crystallization

From the results in Table 3, it can be confirmed that the tenegliptin-containing particles and tenegliptin-containing tablets of Examples 3 to 5 to which lactic acid, hydrochloric acid or ascorbic acid was added can maintain an amorphous state not only immediately after production but also when stored under open conditions. On the other hand, it can be seen that the tenegliptin-containing particles and tenegliptin-containing tablets of Comparative Example 4 to which sodium sulfite was added cannot maintain an amorphous state.

Secondly, stabilizers that can maintain an amorphous state were screened, and the relationship between the stabilizer and the amount of related substances in the initial (immediate) tenegliptin-containing particles was discussed.

[Example 6]

The tenegliptin-containing particles of Example 6 were prepared by the same manufacturing method as that of Example 2-1.

[Example 7]

The tenegliptin-containing particles of Example 7 were prepared by the same manufacturing method as that of Example 5.

[Example 8]

The tenegliptin-containing particles of Example 8 were prepared by the same manufacturing method as that of Example 7, except that 0.5 mg of citric acid (FUJIFILM Wako Pure Chemical Corporation, citric acid monohydrate) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 9]

The tenegliptin-containing particles of Example 9 were prepared by the same manufacturing method as that of Example 7, except that 0.5 mg of tartaric acid (DL-tartaric acid, Yamazen Pharmaceutical Co., Ltd.) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 10]

The tenegliptin-containing particles of Example 10 were prepared by the same manufacturing method as that of Example 7, except that 0.33 mg of fumaric acid (FUJIFILM Wako Pure Chemical Corporation, fumaric acid) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 11]

The tenegliptin-containing particles of Example 11 were prepared by the same preparation method as in Example 7, except that 0.5 mg of apple acid (Fuso Chemical Industry Co., Ltd., DL-apple acid) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 12]

The tenegliptin-containing particles of Example 12 were prepared by the same manufacturing method as Example 7, 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 the stabilizer-containing solvent.

[Example 13]

The tenegliptin-containing particles of Example 13 were prepared by the same manufacturing method as Example 7, except that 1 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 14]

The tenegliptin-containing particles of Example 14 were prepared by the same manufacturing method as that of Example 3-1.

[Example 15]

The tenegliptin-containing particles of Example 15 were prepared by the same manufacturing method as Example 7, except that 3 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 16]

The tenegliptin-containing particles of Example 16 were prepared by the same manufacturing method as Example 7, except that 4 mg of L-lactic acid (Komatsuya Co., Ltd., Japanese Pharmacopoeia L-lactic acid) was dissolved instead of ascorbic acid to prepare the stabilizer-containing solvent.

[Example 17]

The tenegliptin-containing particles of Example 17 were prepared by the same manufacturing method as that of Example 4-1.

The tenegliptin-containing particles of Examples 6 to 17 were stored at 25° C., relative humidity 75%, and open conditions for 1 month. The crystal form was evaluated by the above-mentioned measurement method, and it was confirmed that the tenegliptin-containing particles of Examples 6 to 17 maintained an amorphous state after storage.

[Evaluation of the quantity of related substances]

Evaluate the amount of related substances of the tenegliptin-containing particles of Examples 6 to 17 immediately after manufacture (initial). Use high performance liquid chromatography to calculate the maximum amount of each related substance and the total amount of related substances. Calculate the ratio of the peak area of each related substance derived from tenegliptin detected by measurement using high performance liquid chromatography to the sum of all peak areas. Each maximum amount of related substance represents the ratio of the related substance that is the largest in the calculated ratio of related substances. Furthermore, the total amount of related substances represents the ratio of the sum of the peak areas of related substances derived from tenegliptin detected by measurement using high performance liquid chromatography to the sum of all peak areas. The evaluation results are disclosed in Table 4.

Table 4 Stabilizer The largest amount of each category (%) Total amount of related substances (%) Crystalline 25℃, 75%RH, open, 1 M Embodiment 6 No stabilizer 0.53 2.80 Amorphous Embodiment 7 Ascorbic acid 2 mg 0.20 0.56 Amorphous Embodiment 8 Citric acid hydrate 0.5 mg 0.05 0.16 Amorphous Embodiment 9 Tartaric acid 0.5 mg 0.05 0.18 Amorphous Embodiment 10 Fumaric acid 0.33 mg 0.09 0.33 Amorphous Embodiment 11 Apple acid 0.5 mg 0.05 0.19 Amorphous Embodiment 12 L-Lactic acid 0.5 mg 0.06 0.24 Amorphous Embodiment 13 L-Lactic acid 1 mg 0.04 0.17 Amorphous Embodiment 14 L-Lactic acid 2 mg 0.05 0.18 Amorphous Embodiment 15 L-Lactic acid 3 mg 0.05 0.20 Amorphous Embodiment 16 L-Lactic acid 4 mg 0.06 0.25 Amorphous Embodiment 17 Hydrochloric acid 0.52 mg 0.47 2.54 Amorphous

It can be seen from the results in Table 4 that the tenegliptin-containing particles of Examples 7 to 16 containing an organic acid as a stabilizer maintain an amorphous state even after storage under open conditions. At the same time, compared with the tenegliptin-containing particles of Example 6 without a stabilizer or Example 17 containing hydrochloric acid as a stabilizer, the amount of related substances immediately after production (initial) is significantly reduced.

Next, it is discussed whether it is possible to reduce the amount of related substances immediately after manufacturing (initial) in the tablet containing tenegliptin while maintaining the amorphous state when an organic acid is included as a stabilizer.

For the tenegliptin-containing tablets of Example 2-3, Example 3-2 and Example 4-2, the amount of the related substances immediately after production (initial) was evaluated by the evaluation method described above. The evaluation results are disclosed in Table 5. In addition, the evaluation results of the crystal forms of Example 2-3, Example 3-2 and Example 4-2 are disclosed in Table 5 again.

Table 5 Stabilizer The largest amount of each category (%) Total amount of related substances (%) Initial crystal shape Crystalline 25℃, 75%RH, open, 1 M Crystalline 40℃, 75%RH, sealed, 1 M Embodiment 2-3 No stabilizer 0.53 2.80 Amorphous Amorphous Amorphous Example 3-2 L-Lactic acid 2 mg 0.04 0.20 Amorphous Amorphous Amorphous Example 4-2 Hydrochloric acid 0.52 mg 0.48 2.66 Amorphous Amorphous Amorphous

It can be seen from the results of Table 5 that in the tenegliptin-containing tablets of Example 3-2, which includes lactic acid, which is an organic acid, as a stabilizer, the amorphous state is maintained even after storage under open conditions. At the same time, compared with the tenegliptin-containing tablets of Example 2-3 without a stabilizer or Example 4-2 including hydrochloric acid as a stabilizer, the amount of related substances immediately after production (initial) is significantly reduced.

without

without

without.

Claims (14)

A teneligliptin-containing particle comprises porous silica and amorphous teneligliptin supported on the porous silica. The tenegliptin-containing particles as described in claim 1, wherein the porous silica is a porous silicic acid selected from one or more of the group consisting of silicon dioxide, hydrous silicon dioxide and light anhydrous silicic acid, or a porous silicate selected from one or more of the group consisting of magnesium aluminum metasilicate, synthetic aluminum silicate, calcium silicate, magnesium silicate, sodium silicate, potassium silicate and aluminum silicate. The tenegliptin-containing particles as described in claim 2, wherein the porous silica is selected from the group consisting of silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid and magnesium aluminum metasilicate. The tenegliptin-containing particles as described in claim 2, wherein the porous silica is hydrous silicon dioxide. The tenegliptin-containing particles as described in any one of claims 1 to 4 further contain a stabilizer. The tenegliptin-containing particles as described in claim 5, wherein the stabilizer is selected from pH adjusters. The tenegliptin-containing particles as described in claim 6, wherein the pH adjuster is an organic acid. The tenegliptin-containing particles as described in claim 7, wherein the pH adjuster is an organic acid selected from one or more of the group consisting of lactic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid and malic acid. The tenegliptin-containing particles as described in claim 8, wherein the pH adjuster is selected from the group consisting of lactic acid, citric acid, tartaric acid and malic acid. The tenegliptin-containing particles as described in claim 9, wherein the pH adjuster is selected from the group consisting of citric acid, tartaric acid and malic acid. The tenegliptin-containing particles as described in claim 9, wherein the pH adjuster is lactic acid. The tenegliptin-containing particles as described in claim 9, wherein the pH adjuster is citric acid. The tenegliptin-containing particles as described in claim 9, wherein the porous silica is hydrous silicon dioxide and the pH adjuster is lactic acid. A tablet comprising the tenegliptin-containing particles as described in any one of claims 1 to 13.