JP2021088541A - Vildagliptin-containing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a vildagliptin-containing tablet having chemically improved stability.
SOLUTION: A vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin is provided.
[Selection diagram] None

Description

The present invention relates to vildagliptin-containing tablets with improved stability.

Vildagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor and is a diabetic agent. This drug focuses on the hypoglycemic effect of incretin secreted from the digestive tract after meals. Incretin is secreted from the digestive tract after meals and acts to promote insulin secretion and suppress glucagon secretion in a blood glucose-dependent manner. , Blood glucose is regulated (Patent Document 1).

"Equa (registered trademark) tablets" (Novartis Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.), which contain vildagliptin as an active ingredient, are on the market. The drug package insert for this product states that the indication is "type 2 diabetes" and the dosage and administration is "usually, for adults, 50 mg of vildagliptin is orally administered twice daily in the morning and evening. Accordingly, 50 mg can be administered once daily in the morning. " Further, it is described as a preparation containing "virdagliptin, cellulose, lactose, sodium starch glycolate, magnesium stearate" as the composition / component of the preparation (Non-Patent Document 1).

Further, Patent Document 2 and Patent Document 3 disclose an invention relating to a directly compressed pharmaceutical tablet containing vildagliptin, which uses crystalline cellulose, lactose, sodium starch glycolate, and magnesium stearate as additives. It is stated that.

Further, Patent Document 4 contains vildagliptin and at least one selected from the group consisting of mannitol, lactose and cornstarch, and the total content of at least one selected from the group consisting of mannitol, lactose and cornstarch. A vildagliptin-containing pharmaceutical composition characterized in an amount of 50% by mass or more is described.

Further, Patent Document 5 describes a solid preparation containing vildagliptin and an excipient, wherein the excipient is selected from trehalose, cyclodextrin, hydroxypropyl starch and phosphate. Is described.

However, at least one selected from the group consisting of vildagliptin having a content of less than 50% and a pharmaceutical additive having a small effect on the stability of vildagliptin (for example, D-mannitol, lactose, trehalose, corn starch, and crystalline cellulose). No specific formulation of a vildagliptin-containing tablet containing (seed) is described.

Japanese Patent No. 3681110 Japanese Patent No. 5122144 Japanese Patent No. 5739835 Japanese Unexamined Patent Publication No. 2017-222592 JP-A-2019-182756

Package insert "Equa Tablets 50 mg", revised in November 2019 (15th edition)

The present invention provides a vildagliptin-containing tablet with chemically improved stability. Specifically, the present invention provides a vildagliptin-containing tablet in which the decomposition of vildagliptin is suppressed under heat and humidity conditions.

From the viewpoint of suppressing the decomposition of vildagliptin, the inventors of the present invention have a pharmaceutical additive (for example, D-mannitol, lactose, trehalose, corn) having a vildagliptin content of less than 50% and having a small effect on the stability of vildagliptin. By blending at least one selected from the group consisting of starch and crystalline cellulose), it was confirmed that the product had the desired effect of the present invention, and the present invention was completed.

That is, the present invention is as follows:
(1) A vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin.
(2) The vildagliptin according to (1) above, wherein the pharmaceutical additive having a small effect on the stability of vildagliptin is at least one selected from the group consisting of D-mannitol, lactose, trehalose, corn starch, and crystalline cellulose. Containing tablets,
(3) In a vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin, the content of vildagliptin per tablet is 30%. When the above, any of the above (1) or (2), which comprises at least one of the above-mentioned pharmaceutical additives selected from the group consisting of D-mannitol, lactose, corn starch, and crystalline cellulose. Vildagliptin-containing tablets, described in
(4) In a vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin, the content of vildagliptin per tablet is 30%. (1) or (2) above, which comprises at least one of the above-mentioned pharmaceutical additives selected from the group consisting of D-mannitol, lactose, trehalose, corn starch, and crystalline cellulose. Vildagliptin-containing tablets, described in any of
(5) The vildagliptin-containing tablet according to any one of (2) to (4) above, wherein the content of crystalline cellulose is 0.1 part by mass to 1.0 part by mass with respect to 1 part by mass of vildagliptin.
(6) The vildagliptin-containing tablet according to any one of (2) to (5) above, which further contains polyvinyl alcohol.
(7) The vildagliptin-containing tablet according to any one of (2) to (6) above, which further contains magnesium stearate.
Regarding.

According to the present invention, it is possible to provide a vildagliptin-containing tablet having chemically improved stability. Further, according to the present invention, it is possible to provide a vildagliptin-containing tablet in which the decomposition of vildagliptin is suppressed under heat and humidity conditions.

The tablet containing vildagliptin of the present invention will be described below.

The vildagliptin used in the present invention has the generic name (2S) -1-{[(3-Hydroxytricilo [3.3.1.1 ^3,7 ] dec-1-yl) amino] acetyl} pyrrolidine-2-carbontille. Since it has already been provided as a drug in the medical field and used clinically, it can be easily obtained.

The indication of vildagliptin is "type 2 diabetes". For the above indications and effects, the usual dosage and administration for adults is 50 mg of vildagliptin orally administered twice daily in the morning and evening. In addition, 50 mg can be administered once a day in the morning depending on the patient's condition.

The blending amount of vildagliptin is less than 50% in some embodiments and 30% or more and less than 50% in some embodiments per total tablet volume.

As used herein, "suppressing the decomposition of vildagliptin" means suppressing the increase in the amount of related substances and / or the production / increase of unknown substances due to the decomposition of vildagliptin and the like. As an evaluation method, for example, after storing the tablets under heat and humidity conditions, for example, the severe test conditions described in Examples described later, a test is performed by a high performance liquid chromatography method (HPLC method) to determine the amount of related substances. The stability of the bildaglycin-containing tablet is evaluated by calculating and comparing with the total amount of related substances at the start of the test. Next, the evaluation criteria are, for example, when stored under thermal and humidity conditions, for example, at 60 ° C. and 75% RH (relative humidity) for 14 days, the total amount of related substances and the amount of cyano group hydrolyzate (for example, relative retention time of about 0. 7), the amount of amidine (eg, relative retention time about 0.57), or the amount of diketopiperazine (eg, relative retention time about 1.04) is defined as a specific amount or less. For example, the total amount of related substances is 2% to 8% in some embodiments, 2% to 6% in some embodiments, and the amount of cyano group hydrolysate is 0.5% to 4% in some embodiments, 0. 5% to 3%, the amount of amidine is 0% to 0.2% in some embodiments, 0% to 0.1% in some embodiments, and the amount of diketopiperazine is 0% to 2.5% in some embodiments. , 0% to 1.5% as an embodiment.

In the present specification, "the effect on the stability of vildagliptin is small" means a specific amount of a substance that is a specific index or a total amount of related substances specified in the above definition of "suppressing the decomposition of vildagliptin". It means the following states. In some embodiments, for all related substances, 2% to 8% in some embodiments, 2% to 6% in some embodiments, and 0.5% to 4% in some embodiments, and 0.5% to 4% in certain embodiments, with respect to the amount of cyano group hydrolysate. 0.5% to 3%, the amount of amidine is 0% to 0.2% in some embodiments, 0% to 0.1% in some embodiments, and the amount of diketopiperazine is 0% to 2. It is defined as 5%, 0% to 1.5% in some embodiments.

The "pharmaceutical additive having little effect on the stability of vildagliptin" used in the present invention means a pharmaceutical additive that keeps the total amount of related substances or a substance that serves as a specific index in a state of a specific amount or less. Specifically, for example, excipients, disintegrants, surfactants, binders, coating agents, acidulants, foaming agents, sweeteners, fragrances, colorants, buffers, antioxidants, lubricants, etc. Can be mentioned.

In one embodiment, the excipients include, for example, D-mannitol, corn starch, crystalline cellulose, trehalose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, pregelatinized starch, low substitution hydroxypropyl cellulose. , Carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate and the like.

Examples of the disintegrant include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, partially pregelatinized starch, crospovidone and the like.

Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.

Examples of the binder include polyvinyl alcohol, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like.

Examples of the coating agent include hypromellose, hydroxypropyl cellulose, methyl cellulose and the like.

Examples of the acidulant include citric acid, tartaric acid, malic acid and the like.

Examples of the sweetener include sucralose, sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.

Examples of the fragrance include lemon, lemon lime, orange, menthol and the like.

Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, black iron oxide, titanium oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible blue No. 3, and the like. Can be mentioned.

Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamic acid, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, and the like. Examples thereof include phosphoric acid, boric acid or salts thereof.

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

Examples of the lubricant include stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester and the like.

When the content of bildaglycin per tablet is 30% or more and less than 50%, in some embodiments, as excipients, for example, D-mannitol, lactose, trehalose, corn starch, crystalline cellulose, anhydrous calcium hydrogen phosphate. , D-sorbitol, sucrose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, etc. Be done. In one embodiment, D-mannitol, lactose, trehalose, corn starch, crystalline cellulose can be mentioned. One or more of these groups can be used in combination. The blending amount is 5% to 60% in some embodiments, 10% to 49% in some embodiments, and 25% to 49% in some embodiments. The blending amount of the crystalline cellulose is 5% to 30% in some embodiments and 10% to 20% in some embodiments.

Examples of the disintegrant include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, partially pregelatinized starch, crospovidone and the like.

Examples of the binder include polyvinyl alcohol, hypromellose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like.

Examples of the lubricant include stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester and the like.

Further, when the content of vildagliptin per tablet is 30% or more and less than 50%, another embodiment includes D-mannitol, lactose, corn starch, and crystalline cellulose as excipients. One or more of these groups can be used in combination. The blending amount is 5% to 60% in some embodiments, 10% to 49% in some embodiments, and 25% to 49% in some embodiments. The blending amount of the crystalline cellulose is 5% to 30% in some embodiments and 10% to 20% in some embodiments.

Examples of the disintegrant include crospovidone, examples of the binder include polyvinyl alcohol and hypromellose, and examples of the lubricant include magnesium stearate.

The D-mannitol, lactose, trehalose, corn starch, or crystalline cellulose used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. Further, the lactose may be either an anhydride or a hydrate. One or more of these groups can be used in combination. The blending amount is 5% to 60% in some embodiments, 10% to 49% in some embodiments, and 25% to 49% in some embodiments. The blending amount of the crystalline cellulose is 5% to 30% in some embodiments and 10% to 20% in some embodiments.

The polyvinyl alcohol and magnesium stearate used in the present invention are not particularly limited as long as they are pharmaceutically acceptable. The amount of polyvinyl alcohol compounded is 0.5% to 5% in some embodiments, 1% to 3% in some embodiments, and the amount of crospovidone compounded is 1% to 7% in some embodiments. The blending amount of magnesium stearate is 0.1% to 3% in some embodiments and 0.5% to 1.5% in some embodiments.

For tablets containing vildagliptin of the present invention, various additional pharmaceutical additives are appropriately used as long as the desired effects of the present invention are achieved.

The above-mentioned various pharmaceutical additives contained in the vildagliptin-containing tablet of the present invention can be appropriately combined.

The blending amount is not particularly limited as long as it does not affect the achievement of the desired effect of the present invention.

The tablet of the present invention may be an uncoated tablet, a film-coated tablet, or an orally disintegrating tablet (may be film-coated).

The tablet of the present invention can be produced by a method known per se, which includes steps such as pulverization, mixing, granulation, drying, molding (tableting), and coating. In particular, the tablets of the invention are mixed with bildaglycin (which may be pre-ground), excipients (eg, D-mannitol, lactose, corn starch, trehalose) and binders (eg, polyvinyl alcohol, hypromellose). After spraying and granulating a binder solution containing (etc.) and drying and sizing the granulated product, an excipient (for example, crystalline cellulose) and a disintegrant (for example, crospovidone) are added to the granulated product. Etc.), a lubricant (for example, magnesium stearate, etc.) is mixed, and the mixture is compression-molded (for example, tableting) to produce an uncoated tablet. For the granulation step, wet granulation or dry granulation is adopted. It also includes a step of directly locking the mixture without including a granulation step. Further, the uncoated lock is coated with a coating base (for example, hypromellose) to produce a film-coated lock. The step of blending bilda glyptin may be any of a step of mixing, a step of preparing a binder solution, a step of adding a disintegrant and a lubricant to the granulated product, and a mixing step in the granulation step.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

After mixing 100 g of bildagliptin and 140 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech: Mannitol P) using a fluidized bed granulation dryer (manufactured by Paulec: FM-MP-01), polyvinyl alcohol (partially saponified product) ( Granulation is performed by spraying a binder solution prepared by dissolving 6 g of EG-05PW) in 114 g of purified water. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
123 g of the obtained drug-containing sized powder, 21 g of crystalline cellulose (manufactured by Asahi Kasei: UF-702), 4.5 g of crospovidone (manufactured by BASF Japan: Kollidon CL-F) and magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate) (Vegetable)) The tablet powder prepared by adding 1.5 g is tableted to obtain an uncoated round tablet having a tablet mass of 150 mg and a diameter of 7.5 mm.

After mixing 100 g of bildagliptin and 140 g of lactose hydrate (Megure: Granulac200) using a fluidized bed granulation dryer (Paurek: FM-MP-01), polyvinyl alcohol (partially saponified product) (Nippon Synthetic Chemicals Co., Ltd.) Manufacture: Granulation is performed by spraying a binder solution in which 6 g of EG-05PW) is dissolved in 114 g of purified water. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
123 g of the obtained drug-containing sized powder, 21 g of crystalline cellulose (manufactured by Asahi Kasei: UF-702), 4.5 g of crospovidone (manufactured by BASF Japan: Kollidon CL-F) and magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate) (Vegetable)) The tablet powder prepared by adding 1.5 g is tableted to obtain an uncoated round tablet having a tablet mass of 150 mg and a diameter of 7.5 mm.

Using a fluidized layer granulation dryer (Paurek: FM-MP-01), 100 g of bilda glyptin, 110 g of D-mannitol (Mitsubishi Shoji Food Tech: Mannit P) and corn starch (Nippon Food Chemicals: Japanese cornstarch) After mixing 30 g, a binder solution prepared by dissolving 6 g of polyvinyl alcohol (partially saponified product) (manufactured by Nippon Synthetic Chemical Industry Co., Ltd .: EG-05PW) in 114 g of purified water is sprayed to granulate. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
To 123 g of the obtained drug-containing sized powder, 21 g of crystalline cellulose (Asahi Kasei: UF-702), 4.5 g of crospovidone (BASF Japan: Kollidon CL-F) and magnesium stearate (Taipei Chemical Industry: magnesium stearate) (Vegetable)) The tablet powder prepared by adding 1.5 g is tableted to obtain an uncoated round tablet having a tablet mass of 150 mg and a diameter of 7.5 mm.

Using a fluidized bed granulation dryer (Paurek: FM-MP-01), 100 g of bildaglycin, 110 g of lactose hydrate (Megret: Granulac200) and 30 g of corn starch (Nippon Shokuhin Kako: Japanese Pharmacopoeia Corn Starch) were mixed. Then, a binder solution prepared by dissolving 6 g of polyvinyl alcohol (partially saponified product) (manufactured by Nippon Synthetic Chemical Industry Co., Ltd .: EG-05PW) in 114 g of purified water is sprayed to granulate. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
123 g of the obtained drug-containing sized powder, 21 g of crystalline cellulose (manufactured by Asahi Kasei: UF-702), 4.5 g of crospovidone (manufactured by BASF Japan: Kollidon CL-F) and magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate) (Vegetable)) The tablet powder prepared by adding 1.5 g is tableted to obtain an uncoated round tablet having a tablet mass of 150 mg and a diameter of 7.5 mm.

Example 1 was subjected to 100 g of bildaglycin, 140 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech: Mannit P), and crystalline cellulose (manufactured by Asahi Kasei: UF-) using a fluidized bed granulation dryer (manufactured by Paulec: FM-MP-01). 702) 42 g and 9 g of crospovidone (BASF Japan: Kollidon CL-F) were mixed, and then 6 g of polyvinyl alcohol (partially saponified) (Japan Synthetic Chemicals: EG-05PW) was dissolved in 114 g of purified water. Granulate by spraying the agent solution. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
The tableting powder prepared by adding 1.5 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate (vegetable)) to 148.5 g of the obtained drug-containing sized powder was tableted, and the tablet mass was 150 mg, φ7. Obtain a .5 mm round tablet uncoated tablet.

Using a fluidized layer granulation dryer (Paurek: FM-MP-01), bildaglycin 100 g, trehalose (Asahi Kasei: trehalose P) 232 g, corn starch (Nippon Shokuhin Kako: Japanese cornstarch) 40 g and crospovidone (BASF) After mixing 20 g of Japan-made: Kollidon CL-F), a binder solution prepared by dissolving 4 g of hypromellose (manufactured by Shin-Etsu Chemical Industry: TC-5E) in 76 g of purified water is sprayed to granulate. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
The tableting powder prepared by adding 2 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate (vegetable)) to 198 g of the obtained drug-containing sized powder was tableted, and the tablet mass was 200 mg and the diameter was 8.0 mm. Get a tablet of tablets.

Using a fluidized layer granulation dryer (Paurek: FM-MP-01), 100 g of bildaglycin, 132 g of trehalose (Asahi Kasei: Trehalose P), 40 g of corn starch (Nippon Shokuhin Kako: Japanese cornstarch) and crospovidone (BASF). After mixing 20 g of Japan-made: Kollidon CL-F), a binder solution prepared by dissolving 4 g of hypromellose (manufactured by Shin-Etsu Chemical Industry: TC-5E) in 76 g of purified water is sprayed to granulate. After completion of spraying, the mixture is dried and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder.
The tableting powder prepared by adding 2 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: magnesium stearate (vegetable)) to 148 g of the obtained drug-containing sized powder was tableted, and the tablet mass was 150 mg and the diameter was 7.5 mm. Get a tablet of tablets.

<< Comparative Example 1 >>
As Comparative Example 1, a commercially available Equa tablet 50 mg (manufactured by Novartis Pharma Co., Ltd.) is used.

<< Test example >>
Severe tests were carried out on the tablets of Examples 1 to 6 and Comparative Example 1. After storing each sample under the condition of 60 ° C. and 75% RH for 7 days and 14 days, the total amount of related substances, the amount of cyano group hydrolysate, the amount of amidine and the amount of diketopiperazine were measured by a liquid chromatograph method.

<Purity test (related substances)>
Take 5 pieces of this product into powder, weigh precisely about 40 mg (corresponding amount of about 10 mg of vildagliptin), and dissolve in water / acetonitrile mixed solution (7: 3) to make exactly 20 mL. This solution is centrifuged, the supernatant is filtered through a membrane filter having a pore size of 0.45 μm, 5 mL of the first filtrate is removed, and the next filtrate is used as a sample solution. Accurately take 20 μL of the sample solution and perform the test by liquid chromatography under the following conditions. The peak area of each liquid is measured by the automatic integration method, and the amount of related substances is determined by the area percentage method.

Test condition Detector: Ultraviolet absorptiometer (measurement wavelength: 210 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography. (GL Science InertStain C18 inner diameter 4.6 mm, length 250 mm, particle size 5 μm)
Column temperature: Constant temperature around 45 ° C. Mobile phase A: Dissolve 1.5 g of sodium dihydrogen phosphate dihydrate in 1000 mL of water, and add sodium hydroxide TS to adjust the pH to 7.0.
Mobile phase B: Add 300 mL of acetonitrile to 700 mL of mobile phase A.
Liquid transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Confirmation of system compatibility detection: Weigh accurately 1 mL of the sample solution, add water / acetonitrile mixture (7: 3) to make exactly 100 mL, and use this as the system compatibility test solution. Accurately weigh 2 mL of this solution and add water / acetonitrile mixture (7: 3) to make exactly 20 mL. It is confirmed that the peak area of vildagliptin obtained from 20 μL of this solution is 7 to 13% of the peak area of vildagliptin in the system compatibility test solution.
System performance: When operating under the above conditions for 20 μL of the system suitability test solution, the theoretical plate number and symmetry coefficient of the peak of vildagliptin are 7,000 stages or more and 2.0 or less, respectively.
System reproducibility: The relative standard deviation of the peak area of vildagliptin is 2.0% or less when the test is repeated 6 times under the above conditions for 20 μL of the system suitability test solution.

(Results) From Tables 1 and 2, in Examples 1 to 6, the amount of increase after 14 days of storage from the start of storage was 2% to 6% for the total amount of related substances and 1% to 3 for the amount of cyano group hydrolysate. % And the amount of diketopiperazine were 0.9% to 2%, indicating that they were suppressed as compared with Comparative Example 1.

The following trends were observed in the stability of vildagliptin. That is, it was suggested that lactose did not affect the stability of vildagliptin more than D-mannitol when the crystalline cellulose and corn starch were fixed and viewed in Examples 1, 2, 3 and 4. ..

Claims (7)

A vildagliptin-containing tablet comprising vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin. The vildagliptin-containing tablet according to claim 1, wherein the pharmaceutical additive having a small effect on the stability of vildagliptin is at least one selected from the group consisting of D-mannitol, lactose, trehalose, corn starch, and crystalline cellulose. In a vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin, the content of vildagliptin per tablet is 30% or more. The invention according to any one of claims 1 or 2, wherein the pharmaceutical additive comprises at least one selected from the group consisting of D-mannitol, lactose, corn starch, and crystalline cellulose. Vildagliptin-containing tablets. In a vildagliptin-containing tablet containing vildagliptin having a content of less than 50% per tablet and a pharmaceutical additive having a small effect on the stability of vildagliptin, the content of vildagliptin per tablet is 30% or more. When, according to any one of claims 1 or 2, comprising at least one of the above-mentioned pharmaceutical additives selected from the group consisting of D-mannitol, lactose, trehalose, corn starch, and crystalline cellulose. The vildagliptin-containing tablet described. The vildagliptin-containing tablet according to any one of claims 2 to 4, wherein the content of crystalline cellulose is 0.1 part by mass to 1.0 part by mass with respect to 1 part by mass of vildagliptin. The vildagliptin-containing tablet according to any one of claims 2 to 5, further containing polyvinyl alcohol. The vildagliptin-containing tablet according to any one of claims 2 to 6, further comprising magnesium stearate.