Linagliptin-containing pharmaceutical composition with excellent thermal stability

Abstract

To provide linagliptin-containing pharmaceutical compositions with excellent thermal stability.SOLUTION: Provided is a pharmaceutical composition containing linagliptin and one or more additives selected from a binder, a disintegrant, and a lubricant, the binder being one or more additives selected from the group consisting of copolyvidone, polyvinyl alcohol, methylcellulose, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and hydroxypropyl cellulose, the disintegrant being one or more additives selected from the group consisting of corn starch, sodium starch glycolate, carmellose, carmellose calcium, hydroxypropyl starch, and crospovidone, and the lubricant being one or more additives selected from the group consisting of magnesium stearate, stearic acid, and sucrose fatty acid ester.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing linagliptin having excellent thermal stability.

Background Art

[0002] Linagliptin has the chemical name 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)-3,7-dihydro-1H-purine-2,6-dione, and tablets containing linagliptin as an active ingredient are known to be therapeutic agents for type 2 diabetes and are sold as Trajenta tablets 5 mg (Non-Patent Document 1).

[0003] Patent Document 1 describes an invention relating to a linagliptin-containing pharmaceutical composition characterized by containing linagliptin and at least one selected from the group consisting of sodium carboxymethyl starch, carmellose, carmellose calcium, and croscarmellose sodium, which can easily suppress the deterioration of the quality of the linagliptin-containing pharmaceutical composition due to the influence of the storage environment and the like.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a pharmaceutical composition containing linagliptin having excellent thermal stability.

Means for Solving the Problem

[0007] The inventors of the present invention focused on the blending stability of linagliptin with additives and examined the formulation. As a result, they found that the thermal stability of linagliptin is good by combining it with specific binders, disintegrants, or lubricants, and thus completed the present invention.

[0008] That is, the present invention relates to a pharmaceutical composition containing linagliptin and one or more additives selected from binders, disintegrants, and lubricants, wherein the binder is one or more additives selected from the group consisting of copovidone, polyvinyl alcohol (partially saponified), methylcellulose, polyvinyl alcohol - polyethylene glycol graft copolymer, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, and hydroxypropylcellulose; the disintegrant is one or more additives selected from the group consisting of corn starch, sodium starch glycolate, carmellose, carmellose calcium, hydroxypropyl starch, and crospovidone; and the lubricant is one or more additives selected from the group consisting of magnesium stearate, stearic acid, and sucrose fatty acid ester.

Advantages of the Invention

[0009] According to the present invention, in a pharmaceutical composition containing linagliptin, a linagliptin pharmaceutical composition excellent in thermal stability can be provided.

Modes for Carrying Out the Invention

[0010] The pharmaceutical composition containing linagliptin of the present invention will be described below.

[0011] The linagliptin used in the present invention can be produced according to the method described in International Publication No. WO2004 / 018468. The pharmaceutically acceptable salts of linagliptin are produced according to International Publication No. WO2004 / 018468 or International Publication No. WO2010 / 072776. Linagliptin crystals A, B and C are described in International Publication No. WO2007 / 128721 and are produced from linagliptin obtained by the method described in International Publication No. WO2004 / 018468 as starting material by the method described in International Publication No. WO2007 / 128721.

[0012] Linagliptin produced by the method described in International Publication No. WO2004 / 018468 can be obtained as a mixture of crystal A and crystal B.

[0013] A mixture of crystalline linagliptin crystal A and crystalline linagliptin crystal B can be obtained by mixing crystalline A produced according to International Publication No. WO2007 / 128721 with crystalline linagliptin crystal B produced according to International Publication No. WO2007 / 128721.

[0014] In addition, the linagliptin used in the present invention can also use F crystals that can be produced according to the method described in International Publication No. WO2020 / 042939, polymorph F that can be produced according to the method described in JP-A-2018-177769, and AL crystals that can be produced according to the method described in Indian Patent Application Publication No. 2250 / MUM / 2014. Furthermore, other novel crystals can also be used.

[0015] The efficacy and effect are "type 2 diabetes", and the dosage form and dosage are a drug in which "usually, 5 mg of linagliptin is orally administered once a day to adults".

[0016] As the binder used in the present invention, it is one or more additives selected from the group consisting of polyvinyl alcohol (partially saponified), copovidone, methylcellulose, polyvinyl alcohol - polyethylene glycol graft copolymer, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, and hydroxypropylcellulose.

[0017] As the disintegrant used in the present invention, it is one or more additives selected from the group consisting of corn starch, sodium starch glycolate, carmellose, carmellose calcium, hydroxypropyl starch, and crospovidone.

[0018] As the lubricant used in the present invention, it is one or more additives selected from the group consisting of magnesium stearate, stearic acid, and sucrose fatty acid ester.

[0019] The pharmaceutical composition of the present invention includes solid preparations such as tablets, capsules, or powders.

[0020] In the pharmaceutical composition of the present invention, pharmaceutical additives can be further blended as needed. Specifically, for example, excipients, surfactants, coating agents, acidulants, foaming agents, sweeteners, fragrances, colorants, buffering agents, antioxidants, etc. can be mentioned. Regarding disintegrants, binders, and lubricants, in addition to specific additives, arbitrary additives can also be added and used.

[0021] Examples of excipients include D - mannitol, corn starch, crystalline cellulose, trehalose, calcium hydrogen phosphate anhydrous, D - sorbitol, lactose, sucrose, starch, pregelatinized starch, low - substituted hydroxypropylcellulose, sodium carmellose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, etc.

[0022] Examples of disintegrants include, for example, potato starch, croscarmellose, croscarmellose sodium, pregelatinized starch, etc.

[0023] Examples of surfactants include, for example, polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, etc.

[0024] Examples of binders include, for example, hypromellose, gum arabic, hydroxyethyl cellulose, polyvinylpyrrolidone, etc.

[0025] Examples of coating agents include, for example, hypromellose, hydroxypropyl cellulose, methyl cellulose, polyethylene glycol, titanium oxide, etc.

[0026] Examples of acidulants include, for example, citric acid, tartaric acid, malic acid, etc.

[0027] Examples of foaming agents include, for example, multilayers, etc.

[0028] Examples of sweeteners include, for example, sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.

[0029] Examples of flavors include, for example, lemon, lime, orange, menthol, etc.

[0030] Examples of colorants include, for example, iron sesquioxide, yellow iron sesquioxide, iron oxide black, titanium oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, food blue No. 3, etc.

[0031] Examples of buffers include, for example, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its salts, etc.

[0032] Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, propyl gallate, etc.

[0033] Examples of lubricants include sodium stearyl fumarate, sodium stearate, talc, calcium stearate, hydrogenated oil, etc.

[0034] The blending amount is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

[0035] The pharmaceutical composition of the present invention can be produced by known production methods. More specifically, for example, when producing tablets, linagliptin and D-mannitol are put into a fluidized bed granulator, a binder solution dissolved in purified water is sprayed, and granulation and drying are performed. After drying is completed, sizing is performed using a sizing machine, and a disintegrant and a lubricant are added to the obtained sized product and mixed to obtain tablet powder for tableting.

[0036] In another mode, for example, linagliptin, D-mannitol, and a binder are put into a mortar, purified water is dropped to granulate, and drying is performed using a shelf dryer. After drying is completed, sizing is performed using a sieve, and a disintegrant and a lubricant are added to the obtained sized product and mixed to obtain tablet powder for tableting.

[0037] Next, the obtained tablet powder for tableting is tabletted to produce tablets. If necessary, for example, a film base solution such as hypromellose (containing iron sesquioxide, yellow iron sesquioxide, titanium oxide, talc, polyethylene glycol, etc.) is sprayed to produce film-coated tablets.

Examples

[0038] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples at all.

Examples

[0039] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 297.8 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) were mixed. Then, a binder solution prepared by dissolving 10.8 g of copovidone (manufactured by BASF: Kolidon VA64) in 205.2 g of purified water was sprayed. After spraying, drying was performed to obtain drug-containing granulated powder. The above operation was repeated three times, and the three batches of drug-containing granulated powder obtained were mixed for 1 minute. After mixing, sizing was performed using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain drug-containing sized powder. To 79.7 g of the obtained drug-containing sized powder, 9 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 1.4 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added, and the prepared tableting powder was tableted to obtain circular tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0040] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 297.8 of D-mannitol were mixed. Then, a binder solution prepared by dissolving 10.8 g of polyvinyl alcohol (partially saponified) (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.: Gosenol EG-05PW) in 205.2 g of purified water was sprayed for granulation. After spraying, drying was performed, and sizing was performed using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain drug-containing sized powder. To 159.3 g of the obtained drug-containing sized powder, 18 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 2.7 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added, and the prepared tableting powder was tableted to obtain circular tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0041] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 297.8 of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) were mixed. Then, a binder solution prepared by dissolving 10.8 g of methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.: SM-4) in 205.2 g of purified water was sprayed for granulation. After spraying, it was dried and sized using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain drug-containing sized powder. To 159.3 g of the obtained drug-containing sized powder, 18 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 2.7 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added, and the prepared tableting powder was tableted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0042] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 297.8 of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) were mixed. Then, a binder solution prepared by dissolving 10.8 g of polyvinyl alcohol-polyethylene glycol graft copolymer (manufactured by BASF Japan Ltd.: Kollicoat IR) in 205.2 g of purified water was sprayed for granulation. After spraying, it was dried and sized using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain drug-containing sized powder. To 159.3 g of the obtained drug-containing sized powder, 18 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 2.7 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added, and the prepared tableting powder was tableted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0043] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 297.8 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech: Mannitol P) were mixed. After that, a binder solution prepared by dissolving 10.8 g of a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (manufactured by Daido Kasei: POVACOAT Type F) in 205.2 g of purified water was sprayed for granulation. After spraying, it was dried and sized using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain granulated powder containing the drug. To 159.3 g of the obtained granulated powder containing the drug, 18 g of corn starch (manufactured by Nippon Corn Starch: JP Pharmacopoeia Corn Starch White) and 2.7 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added and tableted to obtain circular tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

[0044]

Table 1

Example

[0045] To 79.7 g of the granulated powder containing the drug obtained in the same manner as in the previous step of Example 1, 9 g of sodium starch glycolate (manufactured by DFE Pharm: Primojel) and 1.4 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added and tableted to obtain circular tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0046] To 79.7 g of the granulated powder containing the drug obtained in the same manner as in the previous step of Example 1, 9 g of carmellose (manufactured by Nichirin Chemical Industry: NS-300) and 1.4 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added and tableted to obtain circular tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0047] 79.7 g of the granulated drug-containing powder obtained in the same manner as in the first stage of Example 1 was mixed with 9 g of calcium carboxymethylcellulose (manufactured by Gode Chemical Co., Ltd.: E.C.G-505) and 1.4 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: magnesium stearate (vegetable)), and the prepared tableting powder was tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0048] 9 g of hydroxypropyl starch (manufactured by Nippon Starch Chemical Co., Ltd.: HPS-101(W)) and 1.4 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: magnesium stearate (vegetable)) were added to 79.7 g of the granulated drug-containing powder obtained in the same manner as in the first stage of Example 1, and the prepared tableting powder was tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

[0049]

Table 2

Example

[0050] 10 g of linagliptin and 292.4 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) were mixed using a fluidized bed granulator dryer (manufactured by Powrex: FM-MP-01), and then a binder solution prepared by dissolving 10.8 g of copovidone (manufactured by BASF: Kollidon VA64) in 205.2 g of purified water was sprayed for granulation. After spraying, it was dried and sized using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain a granulated drug-containing powder. 9 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 2.7 g of stearic acid (manufactured by Avantor: Stearic Acid) were added to 78.3 g of the obtained granulated drug-containing powder, and the prepared tableting powder was tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0051] Using a fluidized bed granulation dryer (manufactured by Powrex: FM-MP-01), 10 g of linagliptin and 292.4 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) were mixed. Then, a binder solution prepared by dissolving 10.8 g of copovidone (manufactured by BASF: Kollidon VA64) in 205.2 g of purified water was sprayed for granulation. After the spraying was completed, it was dried and sized using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 1.575 mm screen to obtain granulated powder containing the drug. To 78.3 g of the obtained granulated powder containing the drug, 9 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: JP Pharmacopoeia Corn Starch White) and 2.7 g of sucrose fatty acid ester (manufactured by Mitsubishi Chemical Foods Co., Ltd.: Surfhope SE PHARMA J-1803F) were added to prepare a tableting powder, which was then tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0052] 1 g of linagliptin, 29.78 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P) and 1.08 g of copovidone (manufactured by BASF: Kollidon VA64) were mixed, then sieved through a sieve with an aperture of 710 μm, and 2.0 g of purified water was added dropwise and granulated using a mortar. After the granulation was completed, it was sieved through a sieve with an aperture of 1.0 mm, dried at 50 °C for 2 hours using a shelf dryer, and sieved through a sieve with an aperture of 500 μm to obtain granulated powder containing the drug. To 25.49 g of the obtained granulated powder containing the drug, 2.88 g of hydroxypropyl starch (manufactured by Nippon Shokubai Co., Ltd.: HPS-101(W)) and 0.43 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium Stearate (vegetable)) were added and adjusted to prepare a tableting powder, which was then tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0053] 1 g of linagliptin, 29.78 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P), and 1.08 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.: HPC-SSL-SFP) were mixed, then sieved through a sieve with an aperture of 710 μm, and 2.0 g of purified water was added dropwise and granulated using a mortar. After granulation, it was sieved through a sieve with an aperture of 1.0 mm, dried at 50°C for 2 hours using a shelf dryer, and sieved through a sieve with an aperture of 500 μm to obtain drug-containing sized granules. To 25.49 g of the obtained drug-containing sized granules, 2.88 g of hydroxypropyl starch (manufactured by Nippon Shokubai Co., Ltd.: HPS-101(W)) and 0.43 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium stearate (vegetable)) were added and the tablet-forming powder thus prepared was tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

Example

[0054] 1 g of linagliptin, 32.3 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.: Mannitol P), and 1.08 g of polyvinyl alcohol (partially saponified) (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.: Gosenol EG-05PW) were mixed, then sieved through a sieve with an aperture of 710 μm, and 5.4 g of purified water was added dropwise and granulated using a mortar. After granulation, it was sieved through a sieve with an aperture of 1.0 mm, dried at 50°C for 2 hours using a shelf dryer, and sieved through a sieve with an aperture of 500 μm to obtain drug-containing sized granules. To 27.50 g of the obtained drug-containing sized granules, 0.86 g of crospovidone (manufactured by BASF Japan Ltd.: Kollidon CL-F) and 0.43 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: Magnesium stearate (vegetable)) were added and the tablet-forming powder thus prepared was tabletted to obtain circular plain tablets with a tablet mass of 180 mg and a diameter of 8.0 mm.

[0055]

Table 3

[0056] <Test Example> (Storage stability test (heat)) For the tablets of Examples 1 to 14, an accelerated test was carried out on specimens packaged in PTP (PTP sheet: polyvinyl chloride / polyethylene / polyvinylidene chloride composite sheet, aluminum foil, aluminum / polyethylene laminated film). After storing each specimen at 40°C (±1°C) and 75% (±5%) RH, the storage stability was evaluated by measuring the total amount of related substances derived from linagliptin by liquid chromatography. The results are shown in Table 4.

[0057] Purity test (related substances) Take one tablet of this product, add 10 mL of diluent, and perform ultrasonic treatment while shaking occasionally. Centrifuge this solution, and filter the supernatant through a membrane filter with a pore size of 0.45 μm or less. Discard the first 2 mL of the filtrate, accurately measure 1 mL of the next filtrate, add diluent to make exactly 10 mL, and use it as the sample solution. Accurately measure 1 mL of this solution, add diluent to make exactly 100 mL, and use it as the standard solution. Accurately take 40 μL each of the sample solution and the standard solution, and perform the test by liquid chromatography under the following conditions. Measure the peak area of each solution by the automatic integration method. TIFF0007689825000004.tif28115 Diluent: Mobile phase A / methanol mixed solution (1:1) Test conditions Detector: Ultraviolet absorptiometer (measurement wavelength: 225 nm) Column: Zorbax SB-Aq manufactured by Agilent (inner diameter 4.6 mm × length 250 mm, 5 μm) Column temperature: Constant temperature around 45°C Mobile phase A: Dissolve 2.72 g of potassium dihydrogen phosphate in 1000 mL of water, and adjust the pH to 3.0 by adding phosphoric acid. Mobile phase B: Add 10 mL of methanol to 90 mL of acetonitrile. Liquid delivery of the mobile phase: Control the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as follows. TIFF0007689825000005.tif54144 Flow rate: Adjust so that the retention time of linagliptin is about 11.6 minutes. Area measurement range: 60 minutes System suitability Confirmation of Detection: Accurately measure 1 mL of the standard solution, add the diluent to make it exactly 10 mL. Confirm that the peak area of linagliptin obtained from 40 μL of this solution is 7 to 13% of the peak area of linagliptin in the standard solution. System Performance: When operating under the above conditions for 40 μL of the standard solution, the theoretical plate number and symmetry factor of the peak of linagliptin are each 7000 or more and 2.0 or less. System Reproducibility: When repeating the test 6 times under the above conditions for 40 μL of the standard solution, the relative standard deviation of the peak area of linagliptin is 2.0% or less.

[0058]

Table 4

[0059] As a result, as shown in Table 4, a pharmaceutical composition excellent in thermal stability was obtained.

Claims

**Claim 1** A pharmaceutical composition comprising linagliptin, D-mannitol, and one or more selected from the group consisting of partially saponified polyvinyl alcohol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, corn starch, and magnesium stearate. **Claim 2** A pharmaceutical composition comprising linagliptin, D-mannitol, copovidone, hydroxypropyl starch, and magnesium stearate. **Claim 3** A pharmaceutical composition comprising linagliptin, D-mannitol, copovidone, corn starch, and sucrose fatty acid ester.

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