JP2020070260A - Teneligliptin-containing pharmaceutical compositions, methods for making the same, teneligliptin-containing tablets and production methods thereof - Google Patents

Abstract

To provide pharmaceutical compositions containing teneligliptin hydrobromide maintaining an amorphous state, teneligliptin-containing tablets of which analog increase is suppressed, or teneligliptin-containing tablets of which decrease in dissolution rate during storage period is suppressed.SOLUTION: Amorphous teneligliptin hydrobromide is in coexistence with an amorphousness-maintaining polymer. The amorphousness-maintaining polymer may be one or more selected from the group consisting hydroxypropyl cellulose of 16.0% or more substitution degree, polyvinylpyrrolidone, hipromellose, hipromellose acetate succinate, methacrylate copolymer LC and aminoalkyl methacrylate copolymer E.SELECTED DRAWING: Figure 1

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition and a tablet containing amorphous teneligliptin hydrobromide, in which the amorphous state of teneligliptin hydrobromide is maintained, and a method for producing the same.

[(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), which is also called teneligliptin, and is clinically used as a therapeutic agent for type 2 diabetes.

In Japan, a therapeutic agent for type 2 diabetes containing teneligliptin hydrobromide hydrate is commercially available, but no preparation containing an amorphous form of teneligliptin hydrobromide is known.

Tenelia (R) Tablets 20mg Pharmaceutical Interview Form Revised March 2018 (11th Edition)

By using an amorphous drug substance in place of the crystalline drug substance, it is possible to improve the solubility and the absorption rate into the living body. However, on the other hand, amorphous drug substances are generally chemically unstable, so special measures for ensuring the quality of the drug product, for example, a device for maintaining the amorphous state during the manufacturing process of the drug product, Measures to maintain the amorphous state even if exposed to extreme conditions such as high temperature and high humidity during distribution period or storage until taking, and the formation and dissolution rate of related substances during the above period It may be necessary to devise a means for suppressing the decrease of However, in the formulation of tenegligliptin containing amorphous tenerigliptin hydrobromide, and in the formulation of amorphous tenegligliptin containing amorphous substance, a device for maintaining the above-mentioned amorphous state, generation of related substances. Up to now, no measures have been considered for suppressing the decrease in the dissolution rate and the dissolution rate.

One object of the present invention is to maintain the amorphous state of teneligliptin bromide even under extreme conditions such as high temperature and high humidity during the manufacturing process and during storage until storage and administration. It is to provide a pharmaceutical composition containing a hydrogen salt. Further, one object of the present invention is to provide a tablet containing tenegligliptin in which an increase in related substances is suppressed. Another object of the present invention is to provide a tablet containing tenerigliptin in which the decrease in the dissolution rate of the solid preparation containing tenerigliptin during storage is suppressed.

Further, one object of the present invention is to provide a method for producing the above-mentioned pharmaceutical composition containing tenegligliptin and the tablet containing tenegligliptin.

The tenegligliptin-containing pharmaceutical composition of the present invention is characterized in that it contains an amorphous tenegligliptin hydrobromide and an amorphous maintenance polymer. The method for containing the amorphous maintaining polymer is not limited, and the amorphous state of the tenerigliptin hydrobromide can be maintained if it is contained together with the tenerigliptin hydrobromide. Therefore, the tenegligliptin-containing pharmaceutical composition of the present invention may be any of a physical mixture, a granule, and a solid dispersion containing amorphous tenegligliptin hydrobromide and an amorphous maintenance polymer. Furthermore, the present invention also provides a method for suppressing an increase in related substances and a method for suppressing a decrease in the elution rate during the storage period.

According to one embodiment of the present invention, there is provided a pharmaceutical composition containing tenegligliptin comprising amorphous teneligliptin hydrobromide and an amorphous maintenance polymer. As used herein, the term “amorphous maintenance polymer” refers to a polymer having an effect of maintaining the amorphous state of tenerigliptin hydrobromide in a pharmaceutical composition containing tenegligliptin and a tablet containing tenegligliptin.

Examples of the amorphous maintaining polymer of the present invention include cellulosic polymers, acrylic polymers, and vinyl polymers having a glass transition temperature of 70 ° C. or higher.

Examples of the cellulose-based polymer include hydroxypropyl cellulose having a degree of substitution with hydroxypropoxy groups of 16.0% or more, hypromellose, hypromellose acetate succinate, hypromellose phthalate, ethyl cellulose, hydroxyethyl cellulose and the like. Preferred polymers in one embodiment are hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate with a degree of substitution of 16.0% or more.

Examples of the acrylic polymer include aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonioalkylmethacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer and the like. Preferred polymers in one embodiment are methacrylic acid copolymer LD, aminoalkylmethacrylate copolymer E.

Examples of vinyl polymers having a glass transition temperature of 70 ° C. or higher include polyvinylpyrrolidone, carboxyvinyl polymer, copolyvidone, polyvinyl alcohol / polyethylene glycol / graft copolymer. In one embodiment the preferred polymer is polyvinylpyrrolidone.

Among the above-mentioned amorphous sustaining polymers, preferably, hydroxypropyl cellulose having a degree of substitution with a hydroxypropoxy group of 16.0% or more, polyvinylpyrrolidone, hypromellose, hypromellose acetate succinate, methacrylic acid copolymer LD and One or more selected from the group consisting of aminoalkyl methacrylate copolymer E.

The amorphous maintenance polymer may be contained in an amount of 5% by weight or more based on the amorphous teneligliptin hydrobromide.

According to one embodiment of the present invention, there is provided a teneligliptin-containing tablet containing any one of the above-mentioned pharmaceutical compositions containing teneligliptin.

The pharmaceutical composition containing teneligliptin or the tablet containing teneligliptin may further contain an antioxidant.

The tablet containing tenegligliptin may have an apparent density of 1.17 g / cm ³ or more.

Also, according to one embodiment of the present invention, amorphous teneligliptin hydrobromide and an amorphous maintenance polymer, optionally an additive, are granulated, physically mixed or solid dispersed, teneligliptin. A method for producing a pharmaceutical composition containing the same is provided.

The amorphous teneligliptin hydrobromide and the amorphous maintaining polymer may be granulated by a wet granulation method or a dry granulation method.

According to one embodiment of the present invention, there is provided a method for producing a tenegligliptin-containing tablet, which comprises mixing a tenerligliptin-containing pharmaceutical composition with various additives as necessary and compression-molding the mixture.

The amorphous maintenance polymer is hypromellose, and amorphous teneligliptin hydrobromide may be granulated by a wet granulation method using a solution containing hypromellose. Further, other various additives may be added as necessary for granulation.

The amorphous sustaining polymer is hypromellose having a viscosity of 2.5 mPa · s or more and 3.5 mPa · s or less in a 2% by weight aqueous solution at 20 ° C., and a non-amorphous polymer is prepared by wet granulation using a solution containing the hypromellose. Crystalline tenegligliptin hydrobromide may be granulated. Further, other various additives may be added as necessary for granulation.

A solution containing an amorphous maintenance polymer may be used to granulate the amorphous teneligliptin hydrobromide and the disintegrant. Further, other various additives may be added as necessary for granulation.

The present invention provides a pharmaceutical composition containing teneligliptin hydrobromide in which the amorphous state is maintained, and a teneligliptin-containing tablet. Further, as one embodiment of the present invention, there is provided a tablet containing tenerigliptin in which an increase in related substances is suppressed. Further, as one embodiment of the present invention, there is provided a tablet containing tenegligliptin in which a decrease in the dissolution rate that occurs during the storage period is suppressed.

Further, as one embodiment of the present invention, there is provided a method for producing the above-mentioned pharmaceutical composition containing tenegligliptin and the above-mentioned tablet containing tenerigliptin. Further, the present invention, by simply coexisting an amorphous maintaining polymer, it is possible to maintain the amorphous state of teneligliptin hydrobromide, granulation and adjustment of the solid dispersion is not essential, simple and It can be said that this is a highly versatile method.

It is the figure which plotted the individual maximum related substance amount with respect to the apparent density of the tablet containing tenerigliptin of one example.

The tenegligliptin-containing pharmaceutical composition of the present invention is characterized in that it contains amorphous tenegligliptin hydrobromide and an amorphous maintenance polymer. The method for containing the amorphous maintaining polymer is not limited, and the amorphous state of the tenerigliptin hydrobromide can be maintained if it is contained together with the tenerigliptin hydrobromide. That is, the tenegligliptin-containing pharmaceutical composition of the present invention may be any of a physical mixture, a granule, or a solid dispersion containing amorphous teneligliptin hydrobromide and an amorphous maintenance polymer.

Hereinafter, a pharmaceutical composition containing tenegligliptin, a method for producing a pharmaceutical composition containing tenegliptin, a tablet containing tenegliptin, and a method for producing a tablet containing tenegliptin according to the present invention will be described. However, the tenegligliptin-containing pharmaceutical composition of the present invention, a method for producing a tenegligliptin-containing pharmaceutical composition, a method for producing a tenegligliptin-containing tablet and a tenegligliptin-containing tablet are interpreted as being limited to the description of the embodiments and examples shown below. Not something.

The "amorphous" in the present specification refers to a diffraction peak (2θ = 5.5 °) derived from a crystal of teneligliptin hydrobromide hydrate described in Japanese Patent No. 4208938 by a powder X-ray diffraction measurement method. ± 0.2 °, 13.4 ° ± 0.2 °, 14.4 ° ± 0.2 °) is not recognized. The powder X-ray diffraction measurement method can be performed according to the 17th revised Japanese Pharmacopoeia.

In one embodiment, the tenegligliptin-containing pharmaceutical composition comprises amorphous tenegligliptin hydrobromide and an amorphous maintenance polymer, and optionally further comprises the additives described below. Teneligliptin hydrobromide contained in a pharmaceutical composition containing tenegligliptin is produced during the manufacturing process and under extreme conditions such as high temperature and high humidity (for example, temperature 60 ° C / relative humidity 60%, temperature 40 ° C / relative humidity 75%). Also, the amorphous state is maintained even when placed at a temperature of 25 ° C., a relative humidity of 75% and a temperature of 60 ° C.).

  As used herein, the term “amorphous maintenance polymer” refers to a polymer having an effect of maintaining the amorphous state of tenerigliptin hydrobromide in a pharmaceutical composition containing tenegligliptin and a tablet containing tenegligliptin. The amorphous sustaining polymer is, for example, one or more selected from the group consisting of a cellulosic polymer, an acrylic polymer, and a vinyl polymer having a glass transition temperature of 70 ° C. or higher.

Examples of the cellulose-based polymer include hydroxypropyl cellulose having a degree of substitution of 16.0% or more, hypromellose, hypromellose acetate succinate, hypromellose phthalate, ethyl cellulose, hydroxyethyl cellulose and the like.

Examples of the acrylic polymer include aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonioalkylmethacrylate copolymer, and ethyl acrylate / methyl methacrylate copolymer.

Examples of the vinyl polymer having a glass transition temperature of 70 ° C. or higher include polyvinylpyrrolidone, carboxyvinyl polymer, copolyvidone, polyvinyl alcohol / polyethylene glycol / graft copolymer.

Among the amorphous maintenance polymers contained in the above-mentioned pharmaceutical composition containing tenegligliptin, preferably, hydroxypropyl cellulose having a degree of substitution with hydroxypropoxy groups of 16.0% or more, polyvinylpyrrolidone, hypromellose, hypromellose acetate succinate. , Methacrylic acid copolymer LD and aminoalkyl methacrylate copolymer E. Also, in one embodiment, a particularly preferred amorphous retention polymer includes hypromellose. Further, as will be described later, a more preferable amorphous sustaining polymer includes hypromellose having a viscosity of 2.5 mPa · s or more and 3.5 mPa · s or less in a 2% by weight aqueous solution at 20 ° C., and includes the above hypromellose. When the solution is used as a granulating liquid, the decrease in the elution rate of tenegligliptin that occurs during the storage period of the tenegligliptin-containing tablet can be more significantly suppressed.

The blending amount of the above amorphous sustaining polymer is not particularly limited as long as the effects of the present invention can be obtained. For example, when the amorphous sustaining polymer is contained in an amount of 5% by weight or more with respect to amorphous teneligliptin hydrobromide, the amorphous state of teneligliptin hydrobromide is maintained even when placed under high temperature and high humidity. Can be maintained.

In one embodiment, the tenegligliptin-containing pharmaceutical composition of the present invention is a wet-granulated product in which an amorphous teneligliptin hydrobromide salt and an amorphous maintaining polymer are further physically mixed with an additive shown later. Can be produced by granulating by a dry method or a dry granulation method, or by preparing a solid dispersion by a spray drying method or the like, and the effects of the present invention can be obtained regardless of the manufacturing method. The granulation method is not particularly limited, and various granulation methods such as fluidized bed granulation, tumbling granulation, extrusion granulation, wet crush granulation, and crush granulation can be employed. The preparation of the solid dispersion is not particularly limited and can be performed by, for example, a spray drying method. The solvent used in the wet granulation method or the preparation of the solid dispersion is not particularly limited, and for example, water, a mixture of water and ethanol, or the like can be adopted.

In the past, when stabilizing an amorphous material with a polymer or the like, it has been generally made into a solid dispersion by a spray drying method or the like. Further, generally, a granulation method using a solvent such as a wet granulation method induces crystallization, and thus is not used in a method for producing a drug product using an amorphous drug substance. However, in the present invention, if the amorphous sustaining polymer is contained, the solid dispersion is not prepared, and even if it is produced by the wet granulation method using a solvent, the tenegligliptin-containing pharmaceutical composition is produced. Immediately and even under extreme conditions such as high temperature and high humidity, the amorphous state of tenegligliptin hydrobromide can be maintained. That is, since the tenegligliptin-containing pharmaceutical composition contains the amorphous maintenance polymer, the tenegligliptin hydrobromide-containing non-preserved polymer can be used regardless of the production method even immediately after the production and even under extreme conditions such as high temperature and high humidity. A crystalline state can be maintained.

The tablet containing tenerigliptin contains the pharmaceutical composition containing tenegliptin and, if necessary, desired additives. In the present invention, the tablet refers to a solid preparation molded into a certain shape by compression molding, and includes microtablets, caplets and the like, which may be filled in a capsule film.

Examples of additives contained in the tenegligliptin-containing pharmaceutical composition and the tenegligliptin-containing tablet include, but are not limited to, excipients, binders, disintegrants, superplasticizers and lubricants. Absent. Examples of excipients include, but are not limited to, D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate and the like.

Examples of the binder include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methyl cellulose and the like. Examples of the disintegrant include, but are not limited to, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose calcium, crospovidone, and the like. Examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, hydrous silicon dioxide, talc and the like. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid ester, and the like.

In one embodiment, it is preferable that the tenegligliptin-containing pharmaceutical composition and the tenegligliptin-containing tablet include an antioxidant. The content of the antioxidant 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, more preferably 0.5% by weight, based on the weight of the pharmaceutical composition or the tablet. % Or more and 10% by weight or less is preferable. Examples of the antioxidant include, but are not limited to, dibutylhydroxytoluene (BHT) and ascorbic acid. By adding an antioxidant to the tenegligliptin-containing pharmaceutical composition or the tenegligliptin-containing tablet, it is possible to reduce the increase in the substances related to tenegligliptin hydrobromide. In the present specification, the measurement of the related substance is calculated by calculating the ratio of the peak area of the related substance derived from teneligliptin hydrobromide to the sum of all the peak areas detected by the measurement using liquid chromatography. It can be obtained by

In one embodiment, the tenegligliptin-containing tablet (plain tablet) has an apparent density of 1.17 g / cm ³ or more. In the present specification, the apparent density is calculated by dividing the mass (g) by the volume (cm ³ ). For example, in the case of a tablet having a columnar portion and a cap portion (portion having a dome shape of a tablet) such as a teneria tablet, the volume is “the volume of the columnar portion (π × r ² × (thickness of tablet-2 × cap thickness)) + 2 × cap volume (1/6 × π × h (3a ² + h ² )) ”(where r is the radius of the cylindrical portion, a is the radius of the cap portion, h Is the height of the cap). When the tablet containing tenerigliptin has an apparent density of 1.17 g / cm ³ or more, it is possible to reduce the increase in the substances related to tenerigliptin hydrobromide. Such findings have not been reported so far. Tableting at an apparent density of more than 1.41 g / cm ³ is difficult.

Teneligliptin-containing tablet of the present invention,
A) A pharmaceutical composition containing tenegligliptin is mixed with various additives such as an excipient, a disintegrating agent, a fluidizing agent, and a lubricant, if necessary, and optionally granulated to prepare a powder or granules. And B) compression-molding the above mixture,
Can be manufactured by a process including. If the tenegligliptin-containing pharmaceutical composition is a granulated product obtained by a wet granulation method or a dry granulation method, the obtained granulated product is sized, and the obtained sized product is an excipient, Mix with additives such as disintegrants, fluidizers and lubricants. When the tenegligliptin-containing pharmaceutical composition is a physically mixed mixture or a solid dispersion produced by a spray drying method or the like, an excipient, a disintegrating agent, a fluidizing agent and a lubricant are added to the mixture or the solid dispersion. And other additives are further mixed. The obtained mixture can be compression-molded by a conventional method to produce a tablet containing tenerigliptin.

In one embodiment, hypromellose is used as the granulation liquid as the amorphous maintenance polymer in the manufacture of the tenegligliptin-containing pharmaceutical composition contained in the tenegligliptin-containing tablet. When the tenegligliptin-containing pharmaceutical composition contained in the tenegligliptin-containing tablet is produced by a wet granulation method using a granulating liquid containing hypromellose as an amorphous maintaining polymer, a decrease in the dissolution rate occurring during the storage period is suppressed. It Further, a granulating liquid containing hypromellose (for example, TC-5 (registered trademark) E manufactured by Shin-Etsu Chemical Co., Ltd.) having a viscosity of 2.5 mPa · s or more and 3.5 mPa · s or less in a 2% by weight aqueous solution at 20 ° C. When used, hypromellose (for example, TC-5 (registered trademark) M manufactured by Shin-Etsu Chemical Co., Ltd.) having a viscosity in a 2 wt% aqueous solution at 20 ° C. of 3.6 mPa · s or more and 5.1 mPa · s or less is used. It is possible to further suppress the decrease in the elution rate during the storage period, as compared with the case of using the granulation liquid containing the same.

Moreover, in one embodiment, in the production of a tablet containing tenerigliptin, a disintegrant is contained in a granulated product containing teneglyliptin hydrobromide. The content of the disintegrant is 0.1% by weight or more and 50% by weight or less, preferably 1% by weight or more and 50% by weight or less, more preferably 2% by weight or more and 50% by weight or less, based on the weight of the granulated product. Using a solution containing an amorphous maintenance polymer, an amorphous teneligliptin hydrobromide and a disintegrating agent are granulated by adding other additives as necessary, and a granulated product of tenegligliptin-containing medicine Obtain the composition. The obtained granulated product is sized, and various additives are mixed with the obtained sized product as required. A tablet containing tenerigliptin may be produced by compression-molding the obtained mixture. In the production of a tablet containing tenerigliptin, by including a disintegrant in the granulated product, depending on the disintegrant content in the granulated product, the tenerigliptin hydrobromide salt generated during the storage period of the tablet It is possible to suppress a decrease in the elution rate.

As described above, the tenegligliptin-containing pharmaceutical composition of the present invention does not depend on the production method, but contains an amorphous maintenance polymer, so that tenegligliptin hydrobromide is produced immediately after the production and even when placed under high temperature and high humidity. The amorphous state can be maintained. In one embodiment, the tenegligliptin-containing pharmaceutical composition or the tenegligliptin-containing tablet can include an antioxidant to reduce the increase in the tenegligliptin hydrobromide analog. Since the tablet containing tenerigliptin has an apparent density of 1.17 g / cm ³ or more, it is possible to reduce the increase in the substance related to tenerigliptin hydrobromide. In one embodiment, by using a granulating liquid containing hypromellose as the amorphous maintenance polymer, it is possible to suppress a decrease in the elution rate of tenegligliptin hydrobromide that occurs during the storage period of the tenegligliptin-containing tablet. In one embodiment, as the amorphous sustaining polymer, a granulation liquid containing hypromellose having a viscosity of 2.5 mPa · s or more and 3.5 mPa · s or less in a 2 wt% aqueous solution at 20 ° C. is used to obtain a tablet containing teneligliptin. The decrease in the elution rate of teneligliptin hydrobromide that occurs during the storage period can be suppressed. In one embodiment, by including a disintegrant in the granulate, depending on the disintegrant content in the granulate, the dissolution rate of teneligliptin hydrobromide generated during the storage period of the teneglipliptin-containing tablet. Can be suppressed.

[Example 1]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and hydroxypropyl cellulose as a cellulosic polymer (HPC, Nippon Soda Co., Ltd., HPC-L, degree of substitution, so as to have a ratio of 9: 1). (53.4 to 77.5%), 0.1 g of the resulting mixture was sieved with a No. 30 sieve, and mixed again in the vinyl bag.

[Example 2]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and hydroxypropyl cellulose of different grade from those of Example 1 (Nippon Soda Co., Ltd., HPC-SSL, so as to have a ratio of 9: 1). Substitution degree: 53.4 to 77.5%,) 0.1 g was mixed, then sieved with a No. 30 sieve, and mixed again in a vinyl bag.

[Example 3]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and hypromellose as a cellulose polymer (HPMC, Shin-Etsu Chemical Co., Ltd., TC-5 (registered trademark)) in a ratio of 9: 1. E, viscosity: 2.5-3.5 mPa · s (20 ° C., 2% aqueous solution)) (0.1 g) were mixed, then sieved with a No. 30 sieve, and mixed again in a vinyl bag.

[Example 4]
0.9 g of amorphous teneligliptin hydrobromide in a plastic bag so that the ratio is 9: 1 and hypromellose of different grade from that of Example 4 (Shin-Etsu Chemical Co., Ltd., TC-5 (registered) (Trademark) M, viscosity: 3.6-5.1 mPa · s (20 ° C., 2% aqueous solution)) (0.1 g) were mixed and then sieved with a No. 30 sieve, and mixed again in a vinyl bag.

[Example 5]
0.9 g of amorphous teneligliptin hydrobromide and a cellulose-based polymer, hypromellose acetate succinate (HPMCAS, Shin-Etsu Chemical Co., Ltd., LF) in a ratio of 9: 1. After mixing 0.1 g, it was passed through a No. 30 sieve and mixed again in a vinyl bag.

[Example 6]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and a methacrylic acid copolymer LD (Evonik Roehm, EUDRAGIT (registered trademark) L100-D55) as an acrylic polymer in a ratio of 9: 1. After mixing 0.1 g, it was passed through a No. 30 sieve and mixed again in a vinyl bag.

[Example 7]
0.9 g of amorphous teneligliptin hydrobromide in a plastic bag and aminoalkyl methacrylate copolymer E (Evonik Roehm, EUDRAGIT (registered trademark) EPO) 0 as an acrylic polymer in a ratio of 9: 1 After mixing 1 g, the mixture was sieved with a No. 30 sieve and mixed again in a vinyl bag.

[Example 8]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and polyvinylpyrrolidone (PVP, Daiichi Kogyo Seiyaku Co., Ltd., K-30, glass) as a vinyl-based polymer in a ratio of 9: 1. (Transition temperature: 161 ° C.) 0.1 g was mixed, then sieved with a No. 30 sieve, and mixed again in a vinyl bag.

[Comparative Example 1]
As Comparative Example 1, only amorphous teneligliptin hydrobromide was used.

[Comparative example 2]
As a ratio of 9: 1, 0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and a low degree of substitution of less than 16.0% by hydroxypropoxy group as a cellulosic polymer. After mixing 0.1 g of hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd., LH-11, degree of substitution: 10.0 to 12.9%), it is sieved with a No. 30 sieve and again in a vinyl bag. Mixed.

[Comparative Example 3]
0.9 g of amorphous teneligliptin hydrobromide in a vinyl bag and polyvinyl alcohol having a glass transition temperature of less than 70 ° C. as a vinyl polymer (PVA, vinyl acetate 0.1 g of POVAL, PE-05JPS, glass transition temperature: 60 to 65 ° C.) was mixed, then sieved with a No. 30 sieve, and mixed again in a vinyl bag.

[Comparative Example 4]
In a plastic bag, mix 0.9 g of amorphous teneligliptin hydrobromide and 0.1 g of D-mannitol (Manufactured by Mitsubishi Foodtec Co., Mannit-P) in a ratio of 9: 1. After that, it was passed through a No. 30 sieve and mixed again in a vinyl bag.

[Comparative Example 5]
After mixing 0.9 g of amorphous teneligliptin hydrobromide and 0.1 g of talc (Fuji Talc Industrial Co., Ltd., ML115) in a vinyl bag so that the ratio becomes 9: 1, it is sieved with a No. 30 sieve. It was sieved and mixed again in a plastic bag.

[Comparative Example 6]
After mixing 0.9 g of amorphous teneligliptin hydrobromide and 0.1 g of ascorbic acid (Kyowa Pharma Chemicals Co., Ltd., 100M ascorbic acid) in a plastic bag in a ratio of 9: 1, 30 It was passed through a No. sieve and mixed again in a vinyl bag.

[Comparative Example 7]
0.9 g of amorphous teneligliptin hydrobromide and 0.1 g of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) in a plastic bag so that the ratio becomes 9: 1. After mixing, the mixture was passed through a No. 30 sieve and mixed again in a vinyl bag.

[Comparative Example 8]
0.9 g of amorphous teneligliptin hydrobromide and 0.1 g of magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) in a plastic bag so that the ratio becomes 9: 1. After mixing, the mixture was passed through a No. 30 sieve and mixed again in a vinyl bag.

After sealing the tenerligliptin-containing pharmaceutical compositions of Examples 1 to 8 and Comparative Examples 1 to 8 in a container, the container was stored at 60 ° C. and relative humidity of 60% for 14 days, and then in an amorphous state by a powder X-ray diffraction measurement method. Was confirmed. For the measurement, a powder X-ray diffractometer Bruker D8 ADVANCE was used, and a Cu-Ka line, a tube voltage of 40 kV, a tube current of 40 mA, a measurement range: 2θ = 3.0 to 30.0 °, a scan speed: 1 sec / step, a step. Size: Measured under the condition of 0.1 °.

Table 1 shows the evaluation results of the crystalline state.

In Comparative Example 1 containing only teneligliptin hydrobromide, crystallization occurred after storage for 14 days. On the other hand, in Examples 1 to 8 mixed with the amorphous maintaining polymer, the amorphous state was maintained even after storage for 14 days. However, in Comparative Examples 2 to 8 in which other polymers, sugar alcohols, and the like, which are commonly used in tablets, were mixed, the amorphous state could not be maintained after storage for 14 days.

[Example 9]
1.9 g of amorphous teneligliptin hydrobromide and 0.1 g of HPC-L (the same as in Example 1) were mixed in a plastic bag so that the ratio was 19: 1, and then sieved with a No. 30 sieve. It was sieved and mixed again in a plastic bag.

[Example 10]
1.9 g of amorphous teneligliptin hydrobromide and 0.1 g of HPC-SSL (the same as in Example 2) were mixed in a plastic bag so that the ratio was 19: 1, and then sieved with a No. 30 sieve. It was sieved and mixed again in a plastic bag.

[Example 11]
1.9 g of amorphous teneligliptin hydrobromide and 0.1 g of HPMC TC-5E (the same as in Example 3) were mixed in a plastic bag so that the ratio was 19: 1, and then sieve No. 30 was used. It was sifted through and mixed again in a plastic bag.

[Example 12]
1.9 g of amorphous teneligliptin hydrobromide and 0.1 g of HPMC TC-5M (the same as in Example 4) were mixed in a plastic bag so that the ratio was 19: 1, and then the No. 30 sieve was used. It was sifted through and mixed again in a plastic bag.

[Example 13]
1.9 g of amorphous teneligliptin hydrobromide and 0.1 g of PVP K-30 (the same as in Example 8) were mixed in a plastic bag so that the ratio was 19: 1, and then the No. 30 sieve was used. It was sifted through and mixed again in a plastic bag.

After the tenerligliptin-containing pharmaceutical compositions of Examples 9 to 13 were sealed in a container, they were stored at 60 ° C. and 60% relative humidity for 14 days, and the crystalline state was evaluated by the above-described measuring method. Table 2 shows the evaluation results of the crystalline states of Examples 9 to 13.

Even if the ratio of amorphous tenegliptin hydrobromide to the amorphous maintaining polymer was changed to 19: 1, the amorphous state was maintained even after storage for 14 days. That is, even if the addition ratio of the amorphous maintenance polymer to the amorphous tenerigliptin hydrobromide is 5.3% by mass, even if the amorphous maintenance polymer is placed under high temperature and high humidity, the non-teneneligliptin hydrobromide is not It was shown that the crystalline state could be maintained.

In addition, regarding HPMC TC-5E used in Examples 3 and 11 and PVP K-30 used in Examples 8 and 13, the mass ratio of tenerigliptin hydrobromide to each amorphous maintenance polymer was 1: 1. Then, a solid dispersion was prepared by a spray drying method to prepare particles, and a pharmaceutical composition containing tenegliptin was obtained. The obtained tenegligliptin-containing pharmaceutical composition was stored for 1 month at 40 ° C./75% relative humidity / opened state or at 25 ° C./60% relative humidity / opened state. When the crystalline state was evaluated by the above-mentioned measuring method, the amorphous state of tenegligliptin hydrobromide was maintained under both storage conditions. In addition, the mass ratio of tenerigliptin hydrobromide and each amorphous maintaining polymer was changed to 2: 1, 1: 3 to obtain a similar pharmaceutical composition containing tenerigliptin as a solid dispersion. The obtained tenegligliptin-containing pharmaceutical composition was stored in an open state at 25 ° C. and 60% relative humidity for 1 month. When the crystalline state was evaluated by the above-mentioned measuring method, the amorphous state of tenegligliptin hydrobromide was maintained. Even if the addition ratio of the amorphous maintaining polymer to the amorphous teneligliptin hydrobromide is 300%, the amorphous state of the tenerigliptin hydrobromide is maintained even when placed under high temperature and high humidity. It was shown to be possible.

[Example 14]
As a prescription ratio, 1.8 mg of HPC (Nippon Soda Co., Ltd., HPC-L) was dissolved in a solvent (purified water) to prepare a granulation liquid. As a prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (20 mg as teneligliptin), D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., Mannit P) 21.52 mg, corn starch (Nippon Shokuhin Kako Co., Ltd.) , Xx16) 6.0 mg and light anhydrous silicic acid (Freund Sangyo Co., Ltd., Adsolider (registered trademark) 101) 0.3 mg were sprayed with the granulation liquid to form a fluidized bed granulator (Pawrec, model: Fluidized bed granulation was performed with MP-01). The obtained granulated product was sieved with a No. 22 sieve to be sized. The obtained sized product was used as a prescription ratio of D-mannitol (ROQUETTE FRERES, Peeritol 200SD) 48.3 mg, L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) 12 mg, magnesium stearate (Taihei Chemical Industrial Co., Ltd.). Magnesium stearate (plant) (0.6 mg) was mixed in a plastic bag, and the mixture was tableted by a rotary tableting machine (Kikusui Seisakusho KK) to give a tablet of Example 14 having a weight of 120 mg.

[Example 15]
As a prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (teneligliptin 20 mg) and D-mannitol (ROQUETTE FRERES, pearitol 100SD) 74.32 mg were sifted through No. 30 sieve, and HPC (Nippon Soda) Co., Ltd., HPC-SSL) 2.4 mg, L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) 12 mg, light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) 0.6 mg, and stearic acid. 1.2 mg of magnesium (Taihei Kagaku Sangyo Co., Ltd., stearin magnesium (plant)) was mixed in a plastic bag and tabletted with a rotary tableting machine (Kikusui Seisakusho KK) to give a tablet of Example 15 weighing 120 mg. Got

The tenerigliptin-containing tablets obtained in Examples 14 and 15 were sealed, stored at 40 ° C. and 75% relative humidity for 28 days, and the crystalline state was confirmed by the above-mentioned powder X-ray diffraction measurement method.

Table 3 shows the evaluation results of the crystalline state.

From the results of the teneligliptin-containing tablets of Example 14, even if the wet granulation method using a solvent (fluidized bed granulation method) was used, the tenegligliptin hydrobromide was amorphous in the teneligliptin-containing tablets after storage for 28 days. The condition was maintained. In general, since the presence of a solvent may cause crystallization, a production method without using a solvent is selected to maintain the amorphous state. The result of Example 14 that the amorphous state of tenegliptin hydrobromide is maintained even when the wet granulation method (fluidized bed granulation method) is used is a novel finding that has not been reported so far. is there. Further, from the results of the teneligliptin-containing tablet of Example 15, the amorphous state of teneligliptin hydrobromide was maintained even after storage for 3 months in the teneligliptin-containing tablet produced by the direct compression method. From the above, it is possible to maintain the amorphous state of teneligliptin hydrobromide by including the amorphous maintaining polymer, regardless of the manufacturing method, even immediately after the manufacturing and when placed under high temperature and high humidity. Became clear.

[Example 16]
As a prescription ratio, 3.6 mg of HPMC (TC-5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a solvent (purified water / ethanol = 8: 2) to prepare a granulation liquid. As the prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (20 mg as teneligliptin), D-mannitol (Mitsubishi Foodtec Co., Ltd., Mannit P) 67.42 mg, corn starch (Nippon Shokuhin Kako Co., Ltd.) , Xx16) 6.0 mg and 0.6 mg of dibutyl hydroxytoluene (Merck, Butylhydroxytoluene) as an antioxidant were sprayed with a granulation liquid to form a fluidized bed granulator (Paurec Co., Ltd., model: MP-01. ) And fluidized bed granulation. The obtained granulated product was sieved with a No. 22 sieve to be sized. The obtained sized product had a prescription ratio of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-31) 12 mg, light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) 0.3 mg, and stearin. 0.6 mg of magnesium acid salt (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) was mixed in a plastic bag and compressed with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to weigh 120 mg. The tablets of Example 16 were obtained.

[Example 17]
As Example 16, except that ascorbic acid (Kyowa Pharma Chemicals Co., Ltd., 100M ascorbic acid) was used as a prescription ratio of 2.4 mg instead of 0.6 mg of dibutylhydroxytoluene (Merck, Butylhydroxytoluene) as an antioxidant. By the same manufacturing method, a tablet of Example 17 having a weight of 120 mg was obtained.

[Example 18]
A tablet of Example 18 having a weight of 120 mg was obtained by the same production method as in Example 16 except that the antioxidant was not added.

The tablets containing teneligliptin of Examples 16 to 18 were stored in an open state at 25 ° C. and 75% relative humidity for 1 month, and the maximum amount of individual related substances and the amount of total related substances were calculated by liquid chromatography. The ratio of the peak area of each of the related substances derived from teneligliptin hydrobromide was calculated with respect to the sum of all the peak areas detected by the measurement using liquid chromatography. The maximum amount of each related substance is the ratio of the calculated maximum amount of the related substances. In addition, the total amount of related substances is the ratio of the sum of the peak areas of the related substances derived from teneligliptin hydrobromide to the total of all the peak areas detected by the measurement using liquid chromatography. Table 4 shows the maximum amount of related substances and the total amount of related substances.

From the results of Examples 16 and 17, it was revealed that the addition of the antioxidant significantly reduces the increases in the individual maximum amount of the related substances and the total amount of the related substances in the tablet containing tenerigliptin after storage. .. Therefore, by maintaining the amorphous state of teneligliptin hydrobromide by containing the amorphous maintaining polymer, and by further using the antioxidant together, the maximum amount of the individual related substances and the total amount of the related substances in the tenerigliptin-containing tablets can be improved. The increase in the amount of substance can be reduced.

[Example 19]
As a prescription ratio, 7.2 mg of HPMC (TC-5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a solvent (purified water / ethanol = 8: 2) to prepare a granulation liquid. As a prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (teneligliptin 20 mg), D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., Mannit P) 66.82 mg and ascorbic acid (Kyowa Pharma Chemical Co., Ltd.) , Ascorbic acid 100M) 2.4 mg, talc (Fuji Talc Industry Co., Ltd., ML115) 1.2 mg, and L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) 3.0 mg were sprayed with the granulation liquid. Then, fluidized bed granulation was performed using a fluidized bed granulator (Pawrec Co., Ltd., model: MP-01). The obtained granulated product was sieved with a No. 22 sieve to be sized. The obtained sized product has a prescription ratio of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) 9.0 mg, light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) 0.3 mg. , Magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (plant)) 0.6 mg were mixed in a plastic bag, and the apparent density was 1.09 g in a rotary tableting machine (Kikusui Seisakusho KK). ^{/ cm 3, 1.13g / cm 3} , 1.17g / cm 3, 1.21g / cm 3, 1.26g / cm 3, 1.32g / cm 3, 1.37g / cm 3, 1.41g / Tableting was carried out by changing the pressing pressure so that it would be 0.3 cm ³ , the diameter was 0.7 cm, and the thickness was 0.230, 0.220, 0.210, 0.200, 0.190, 0.180, 0. 170, 0.16 A cylindrical section which is cm, and having two cap portions and a thickness of 0.06cm diameter 0.68 cm, to give a tablet of Example 19 of the weight 120 mg.

The tablet containing tenerigliptin of Example 19 was stored in an open state at 25 ° C. and 75% relative humidity for 2 weeks, and the maximum amount of each related substance was calculated by liquid chromatography. FIG. 1 is a diagram in which the maximum amount of each related substance is plotted against the apparent density of a tablet containing tenerigliptin. Incidentally, the apparent density is the mass (g) = 0.12, volume (cm ³⁾ = volume of the cylindrical portion (π × 0.35 ² × cylindrical thickness) + 2 × volume of the cap portion (1/6 × π × It was calculated by dividing by 0.06 × (3 × 0.34 ² +0.06 ² ).

It was shown that by increasing the apparent density of the tablet containing tenerigliptin to 1.17 g / cm ³ or more, it is possible to reduce the increase in the substances related to tenerigliptin hydrobromide. The increase in the apparent density of tablets containing tenegligliptin and the decrease in the increase in related substances are findings that have not been reported so far.

[Example 20]
1.8 mg of HPC (Nippon Soda Co., Ltd., HPC-L) was dissolved in a solvent (purified water) to prepare a granulation liquid. As a prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (20 mg as teneligliptin), D-mannitol (Mitsubishi Foodtec Co., Ltd., Mannit P) 69.82 mg and corn starch (Nippon Shokuhin Kako Co., Ltd.) , Xx16) 6.0 mg of the mixture was sprayed with a granulation liquid, and fluidized bed granulation was performed with a fluidized bed granulation apparatus (Powrec Co., Ltd., model: MP-01). The obtained granulated product was sieved with a No. 22 sieve to be sized. The obtained sized product had a prescription ratio of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-11) 12 mg, light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) 0.3 mg, and stearin. An example in which 0.6 mg of magnesium acid salt (Taihei Chemical Industry Co., Ltd., magnesium stearate (plant)) was mixed in a plastic bag and tableted with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to weigh 120 mg. 20 tablets were obtained.

[Example 21]
HPMC (Shin-Etsu Chemical Co., Ltd., TC-5M) 1.8 mg was used in place of HPC and was dissolved in (purified water / ethanol = 8: 2) instead of purified water to prepare a granulation liquid. A tablet of Example 21 having a weight of 120 mg was obtained by the same production method as in Example 20.

The tablets containing Teneligliptin of Examples 20 and 21 were sealed with a desiccant and stored at 60 ° C for 2 weeks. With respect to the tablets containing teneligliptin of Examples 20 and 21 after storage, the dissolution rate of tenegligliptin hydrobromide as an active ingredient per 10 minutes was measured according to the dissolution test method Paddle method of the 17th revised Japanese Pharmacopoeia. Purified water was used as the dissolution test solution, and the dissolution rate was measured when stirring at 50 rpm for 10 minutes.

Table 5 shows the measurement results of the dissolution rate.

From Table 5, it was shown that in the tablet containing tenerigliptin of Example 21 in which hypromellose was used as the granulating liquid, the decrease in the dissolution rate after storage for 2 weeks could be significantly suppressed. Therefore, by wet granulation using hypromellose as the granulation liquid, while maintaining the amorphous state of tenerigliptin hydrobromide, the decrease in the elution rate of tenerigliptin hydrobromide that occurs during the storage period is significantly reduced. It became clear that it can be suppressed.

[Example 22]
As a prescription ratio, HPMC (Shin-Etsu Chemical Co., Ltd., TC-5M, viscosity: 3.6 to 5.1 mPa · s (20 ° C., 2% aqueous solution)) amount of 3.6 mg, D-mannitol (Mitsubishi Corporation Foodtec) Mannite P), Co., Ltd. A tablet of Example 22 having a weight of 120 mg was obtained by the same production method as in Example 21, except that the amount was changed to 68.02 mg.

[Example 23]
Except that HPMC was changed to HPMC (Shin-Etsu Chemical Co., Ltd., TC-5E, viscosity: 2.5 to 3.5 mPa · s (20 ° C., 2% aqueous solution)) having a viscosity different from that of Example 22. By the same manufacturing method as in Example 22, a tablet of Example 23 having a weight of 120 mg was obtained.

The tablets containing tenerigliptin of Examples 22 and 23 were sealed with a desiccant and stored at 60 ° C for 2 weeks. With respect to the tablets containing teneligliptin of Examples 22 and 23 after storage, the dissolution rate of teneligliptin hydrobromide as an active ingredient per 10 minutes was measured according to the dissolution test method Paddle method of the 17th revised Japanese Pharmacopoeia. Purified water was used as the dissolution test solution, and the dissolution rate was measured when stirring at 50 rpm for 10 minutes.

Table 6 shows the measurement results of the dissolution rate.

From Table 6, in Example 23 in which hypromellose having a viscosity in a 2% by weight aqueous solution of 20 ° C. of 2.5 to 3.5 mPa · s was used as a granulating liquid, a remarkable inhibitory effect on the decrease in the elution rate was observed. .. Therefore, wet granulation using hypromellose having a viscosity of 2.5 to 3.5 mPa · s in a 2% by weight aqueous solution at 20 ° C. can maintain the amorphous state of teneligliptin hydrobromide while performing the granulation. It was clarified that the decrease in the elution rate of teneligliptin hydrobromide during the storage period can be significantly suppressed.

[Example 24]
As a prescription ratio, 3.6 mg of HPMC (TC-5E, Shin-Etsu Chemical Co., Ltd.) was dissolved in a solvent (purified water / ethanol = 8: 2) to prepare a granulation liquid. As a prescription ratio, amorphous teneligliptin hydrobromide 29.48 mg (tenerigliptin 20 mg), D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., Mannit P) 68.02 mg and corn starch (Nippon Shokuhin Kako Co., Ltd.) , Xx16) 6.0 mg of the mixture was sprayed with a granulation liquid, and fluidized bed granulation was performed with a fluidized bed granulation apparatus (Powrec Co., Ltd., model: MP-01). The obtained granulated product was sieved with a No. 22 sieve to be sized. The obtained sized product had L-HPC (Shin-Etsu Chemical Co., Ltd., LH-31) 12.0 mg and light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider (registered trademark) 101) 0.3 mg as a prescription ratio. , Magnesium stearate (Taipei Chemical Industry Co., Ltd., magnesium stearate (plant)) 0.6 mg were mixed in a plastic bag and compressed with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to give a weight of 120 mg. A tablet of Example 24 was obtained.

[Example 25]
Before fluidized bed granulation, 3.0 mg (2.7% by weight based on the granulated product) of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-31) was mixed as a prescription ratio. A tablet of Example 25 having a weight of 120 mg was obtained by the same production method as in Example 24, except that L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd.) to be mixed was set to have a prescription ratio of 9.0 mg.

[Example 26]
Prior to fluidized bed granulation, 6.0 mg (5.3% by weight based on the granulated product) of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-31) was mixed as a prescription ratio, and A tablet of Example 26 having a weight of 120 mg was obtained by the same production method as in Example 24, except that L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd.) to be mixed was used as a prescription ratio of 6.0 mg.

[Example 27]
Before the fluidized bed granulation, 9.0 mg (7.8% by weight based on the granulated product) of L-HPC (Shin-Etsu Chemical Co., Ltd., LH-31) as a prescription ratio was mixed with the sized product. A tablet of Example 27 having a weight of 120 mg was obtained by the same production method as in Example 24, except that L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd.) to be mixed was used as a prescription ratio of 3.0 mg.

The tablets containing Teneligliptin of Examples 24 to 27 were sealed with a desiccant and stored at 60 ° C for 2 weeks. The tenerligliptin-containing tablets of Examples 24 to 27 after storage were measured for the dissolution rate of teneligliptin hydrobromide as an active ingredient per 10 minutes according to the 17th revised Japanese Pharmacopoeia dissolution test method paddle method. Purified water was used as the dissolution test solution, and the dissolution rate was measured when stirring at 50 rpm for 10 minutes.

Table 7 shows the measurement results of the dissolution rate.

Table 7 shows that the tablet containing L-HPC in the granules of Examples 25 to 27 contained L-HPC in the granules more than the tablet containing L-HPC in the granules, which was added later. It was shown that the decrease in elution rate after storage for 2 weeks can be significantly suppressed. Further, the results of the tablets containing tenerigliptin of Examples 25 to 27 showed that the effect of suppressing the decrease in the dissolution rate was obtained depending on the amount of L-HPC contained in the granulated product. Therefore, in the method for producing a tenegligliptin-containing tablet, the amorphous maintaining polymer is used in the granulating liquid, and the disintegrating agent is contained in the granulated product to maintain the amorphous state of tenegligliptin hydrobromide. It was clarified that the decrease in the elution rate of teneligliptin hydrobromide during the storage period can be significantly suppressed.

Claims (18)

A pharmaceutical composition containing tenerigliptin, which comprises amorphous teneligliptin hydrobromide and an amorphous maintenance polymer. 2. The amorphous maintaining polymer is one or more selected from the group consisting of a cellulosic polymer, an acrylic polymer, and a vinyl polymer having a glass transition temperature of 70 ° C. or higher. The pharmaceutical composition containing teneligliptin of. The amorphous maintenance polymer is a group consisting of hydroxypropyl cellulose having a degree of substitution with hydroxypropoxy groups of 16.0% or more, hypromellose, hypromellose acetate succinate, hypromellose phthalate, ethyl cellulose, hydroxyethyl cellulose. The pharmaceutical composition containing tenerigliptin according to claim 1, which is one or more selected from the group consisting of: The amorphous sustaining polymer is selected from the group consisting of aminoalkylmethacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonioalkylmethacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer. The pharmaceutical composition containing teneligliptin according to claim 1, wherein the pharmaceutical composition is one or more. The teneligliptin-containing product according to claim 1, wherein the amorphous maintenance polymer is one or more selected from the group consisting of polyvinylpyrrolidone, carboxyvinyl polymer, copolyvidone, and polyvinyl alcohol / polyethylene glycol / graft copolymer. Pharmaceutical composition. The amorphous sustaining polymer comprises hydroxypropyl cellulose having a degree of substitution with hydroxypropoxy groups of 16.0% or more, polyvinylpyrrolidone, hypromellose, hypromellose acetate succinate, methacrylic acid copolymer LD and aminoalkyl methacrylate copolymer E. The pharmaceutical composition containing tenerigliptin according to claim 1, which is one or more selected from the group consisting of: The medicinal composition containing tenerigliptin according to claim 1 or 2, wherein the amorphous maintenance polymer is contained in an amount of 5% by weight or more based on the amorphous tenerigliptin hydrobromide. The tenegligliptin-containing pharmaceutical composition according to any one of claims 1 to 7, further comprising an antioxidant. A tenerigliptin-containing tablet, comprising the tenerigliptin-containing pharmaceutical composition according to any one of claims 1 to 8. A tenerigliptin-containing tablet comprising the pharmaceutical composition containing tenerigliptin according to any one of claims 1 to 8 and an antioxidant. The tablet containing teneligliptin according to claim 9 or 10, having an apparent density of 1.17 g / cm ³ or more. A method for producing a pharmaceutical composition containing tenerigliptin, which comprises physically mixing, granulating or solid-dispersing an amorphous tenerigliptin hydrobromide and an amorphous maintaining polymer. The method for producing a pharmaceutical composition containing tenegligliptin according to claim 12, wherein the granulation is performed by a wet granulation method or a dry granulation method. A method for producing a tablet containing teneligliptin, which comprises mixing the pharmaceutical composition containing teneligliptin produced by the production method according to claim 12 or 13 and compression-molding the mixture. A pharmaceutical composition containing tenegligliptin produced by the production method according to any one of claims 12 to 14 is mixed with an additive,
A method for producing a tenegligliptin-containing tablet, which comprises compression-molding the resulting mixture so that the apparent density is 1.17 g / cm ³ or more. The amorphous maintenance polymer is hypromellose,
The method for producing a tenerigliptin-containing tablet according to claim 14 or 15, characterized in that the amorphous teneligliptin hydrobromide is granulated by a wet granulation method using a solution containing the hypromellose. The amorphous sustaining polymer is hypromellose having a viscosity of 2.5 mPa · s or more and 3.5 mPa · s or less in a 2 wt% aqueous solution at 20 ° C.,
The method for producing a tenerigliptin-containing tablet according to claim 14 or 15, characterized in that the amorphous teneligliptin hydrobromide is granulated by a wet granulation method using a solution containing the hypromellose. The method for producing a tablet containing teneligliptin according to claim 16, wherein the solution containing the amorphous maintenance polymer is used to granulate the amorphous teneligliptin hydrobromide and the disintegrant.

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