Teneligliptin-containing pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing teneligliptin hydrobromide in which an amorphous state is maintained, a pharmaceutical composition containing teneligliptin hydrobromide in which an increase in an analogous substance is suppressed, and a pharmaceutical composition containing teneligliptin hydrobromide in which a reduction in an elution rate is suppressed.SOLUTION: A teneligliptin-containing pharmaceutical composition contains amorphous teneligliptin hydrobromide, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and / or polyvinyl alcohol.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing amorphous teneligliptin hydrobromide.

Background Art

[0002] Teneligliptin hydrobromide has the chemical name {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone hemipentahydrobromide, and tablets containing teneligliptin hydrobromide hydrate as an active ingredient are known to be therapeutic agents for type 2 diabetes, and are sold as Tenelia tablets 20 mg etc. Usually, it is a drug administered orally once a day at 20 mg as teneligliptin to adults (Non-Patent Document 1).

[0003] Further, Patent Document 1 describes a teneligliptin-containing pharmaceutical composition characterized by containing amorphous teneligliptin hydrobromide and an amorphous-maintaining polymer, and as the amorphous-maintaining polymer, cellulose-based polymers, acrylic-based polymers, vinyl-based polymers having a glass transition temperature of 70 °C or higher, etc. are also described.

[0004] However, there is no description of a pharmaceutical composition containing amorphous teneligliptin containing polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, or polyvinyl alcohol.

[0005]

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Non-Patent Documents

[0007] [Non-Patent Document 1] Package insert for "Tenelia Tablets 20mg / 40mg," revised June 2019 (1st edition) [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a pharmaceutical composition containing teneligliptin hydrobromide that maintains an amorphous state, a pharmaceutical composition containing teneligliptin hydrobromide in which the increase of related substances is suppressed, and a pharmaceutical composition containing teneligliptin hydrobromide in which the decrease in dissolution rate is suppressed. [Means for solving the problem]

[0009] As a result of examining the composition of the formulation, the inventors of the present invention found that by using a specific additive, the amorphous state of teneligliptin hydrobromide can be maintained, the increase of related substances can be suppressed, and the decrease in dissolution rate can be suppressed, thus completing the present invention.

[0010] In other words, the present invention is (1) A teneligliptin-containing pharmaceutical composition characterized by comprising amorphous teneligliptin hydrobromide, a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and / or polyvinyl alcohol. (2) The teneligliptin-containing pharmaceutical composition according to (1), which is a solid dispersion comprising amorphous teneligliptin hydrobromide and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and / or polyvinyl alcohol. (3) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (2) above, further comprising any one selected from the group consisting of calcium silicate, light anhydrous silicic acid, and hydrated silicon dioxide. (4) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (3) above, comprising amorphous teneligliptin hydrobromide and a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. (5) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (3) above, comprising amorphous teneligliptin hydrobromide and polyvinyl alcohol. (6) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (5), wherein the mass ratio of amorphous teneligliptin hydrobromide with polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and / or polyvinyl alcohol is 1:0.05 to 1:5. (7) Furthermore, a teneligliptin-containing pharmaceutical composition according to any of (1) to (6) above, comprising ascorbic acid and / or tocopherol. (8) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (7), wherein the mass ratio of amorphous teneligliptin hydrobromide to ascorbic acid is 1:0.01 to 1:0.5. (9) A teneligliptin-containing pharmaceutical composition according to any one of (1) to (7) above, wherein the mass ratio of tocopherol to amorphous teneligliptin hydrobromide is 1:0.01 to 1:0.5. (10) A tablet containing teneligliptin as described in any of (1) to (9) above, (11) The teneligliptin-containing pharmaceutical composition according to (10) wherein the tablet is a film-coated tablet, (12) The teneligliptin-containing pharmaceutical composition according to (10) above, wherein the tablet is an orally disintegrating tablet. (13) A method for producing a teneligliptin-containing pharmaceutical composition, including a step of direct tableting, (14) Packaging for containing a pharmaceutical composition containing teneligliptin, This concerns... [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a pharmaceutical composition containing teneligliptin hydrobromide that maintains an amorphous state, or a pharmaceutical composition containing teneligliptin hydrobromide in which the increase of related substances is suppressed, or a pharmaceutical composition containing teneligliptin hydrobromide in which the decrease in dissolution rate is suppressed.

Brief Description of the Drawings

[0012] [Figure 1] It is the powder X-ray diffraction pattern at the start of storage and after 7 days of storage at 25°C and 75% relative humidity in Example 1. [Figure 2] It is the powder X-ray diffraction pattern at the start of storage and after 7 days of storage at 25°C and 75% relative humidity in Example 2. [Figure 3] It is the powder X-ray diffraction pattern at the start of storage and after 7 days of storage at 25°C and 75% relative humidity in Comparative Example 1.

Modes for Carrying Out the Invention

[0013] The present invention relates to a pharmaceutical composition and tablets containing amorphous teneligliptin hydrobromide and a specific additive.

[0014] The amorphous teneligliptin hydrobromide herein means a state in which substantially no diffraction peaks (2θ = 5.4° ± 0.2°, 13.4° ± 0.2°, 14.4° ± 0.2°) derived from teneligliptin hydrobromide hydrate crystals described in Patent No. 4208938 are observed.

[0015] The amorphous teneligliptin hydrobromide herein can be confirmed, for example, by powder X-ray diffraction measurement. Also, regarding the maintenance of the amorphous state, for example, it can be evaluated by confirmation, etc., for a pharmaceutical composition containing teneligliptin hydrobromide after storage at 25°C, 75% relative humidity, and for 7 days.

[0016] Hereinafter, a solid pharmaceutical composition containing linagliptin of the present invention will be described.

[0017] The teneligliptin hydrobromide used in the present invention is produced according to the method described in WO02 / 14271 or the like.

[0018] The form of teneligliptin hydrobromide used in the present invention is such that, before being included in a pharmaceutical composition, it may be in either a crystalline or amorphous state as a raw material (also called an active pharmaceutical ingredient), but when included in a pharmaceutical composition, it is in an amorphous state.

[0019] The amorphous state can be achieved by any method, as long as the objective of the present invention is achieved. For example, the amorphous state can be achieved by adding amorphous teneligliptin hydrobromide or by making a solid dispersion of crystalline teneligliptin hydrobromide.

[0020] The proportion of amorphous teneligliptin hydrobromide used in the present invention is, in one embodiment, 5 to 40% by weight, in another embodiment, 10 to 30% by weight, and in another embodiment, 15 to 20% by weight of teneligliptin per pharmaceutical composition.

[0021] The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer used in the present invention may be any copolymer that achieves the objectives of the present invention, for example, POVACOAT Type F is one embodiment.

[0022] The content of the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is such that, in one embodiment, the mass ratio of the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer to amorphous teneligliptin hydrobromide is 1:0.05 to 1:5, in another embodiment, 1:0.1 to 1:5, in another embodiment, 1:0.1 to 1:3, and in another embodiment, 1:0.5 to 1:1.5.

[0023] The polyvinyl alcohol used in the present invention may be any such alcohol as long as the objective of the present invention is achieved. For example, in one embodiment, gosenol EG-05P and in another embodiment, EG-03P are used.

[0024] The polyvinyl alcohol content is such that, in one embodiment, the mass ratio of polyvinyl alcohol to amorphous teneligliptin hydrobromide is 1:0.05 to 1:5, in another embodiment, 1:0.1 to 1:5, in another embodiment, 1:0.1 to 1:3, and in another embodiment, 1:0.5 to 1:1.5.

[0025] The calcium silicate, light anhydrous silicic acid, and hydrated silicon dioxide used in this invention may be any type that achieves the objectives of this invention.

[0026] The ascorbic acid used in the present invention may be any ascorbic acid that achieves the objective of the present invention, for example, ascorbic acid 100M is one embodiment.

[0027] The ascorbic acid content is such that, in one embodiment, the mass ratio of ascorbic acid to amorphous teneligliptin hydrobromide is 1:0.01 to 1:1, in another embodiment, 1:0.01 to 1:0.5, and in yet another embodiment, 1:0.01 to 1:0.3.

[0028] The tocopherol used in the present invention may be any tocopherol that achieves the objectives of the present invention.

[0029] The tocopherol content is such that, in one embodiment, the mass ratio of tocopherol to amorphous teneligliptin hydrobromide is 1:0.01 to 1:1, in another embodiment, 1:0.01 to 1:0.5, and in yet another embodiment, 1:0.01 to 1:0.3.

[0030] The pharmaceutical composition of the present invention may contain further pharmaceutical additives as needed. Specifically, examples include excipients, disintegrants, binders, lubricants, surfactants, acidulants, foaming agents, sweeteners, fragrances, colorants, buffers, and light stabilizers. As for the coating agent, in addition to specific additives, any other additives may be added.

[0031] Examples of excipients include D-mannitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, low-substituted hydroxypropylcellulose, carmellose sodium, acacia gum, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0032] Examples of disintegrants include potato starch, corn starch, partially pregelatinized starch, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and crospovidone.

[0033] Examples of surfactants include polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil.

[0034] Examples of binders include hypromellose, acacia gum, hydroxyethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone. Examples of coating agents include hypromellose, hydroxypropylcellulose, and methylcellulose.

[0035] Examples of acidulants include citric acid, tartaric acid, and malic acid.

[0036] Examples of foaming agents include baking soda.

[0037] Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, and thaumatin.

[0038] Examples of flavorings include lemon, lemon-lime, orange, and menthol.

[0039] Examples of coloring agents include iron(III) oxide, yellow iron(III) oxide, black iron oxide, titanium dioxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, and food blue No. 3.

[0040] Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or their salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its salts, etc.

[0041] Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, calcium stearate, hydrogenated oil, sucrose fatty acid ester, and magnesium stearate.

[0042] The teneligliptin-containing pharmaceutical composition of the present invention may be appropriately used with various additional pharmaceutical additives to the extent that the desired effects of the present invention are achieved.

[0043] The various further pharmaceutical additives included in the teneligliptin-containing pharmaceutical composition of the present invention can be combined as appropriate.

[0044] The amount used is not particularly limited, as long as it does not affect the achievement of the desired effects of the present invention.

[0045] The teneligliptin-containing pharmaceutical composition of the present invention specifically includes powders, granules, and tablets. The tablets include orally disintegrating tablets, and the tablets may be either uncoated or film-coated.

[0046] As a method for manufacturing a pharmaceutical composition containing amorphous teneligliptin hydrobromide, any manufacturing method that can include amorphous teneligliptin hydrobromide in a solid pharmaceutical composition is acceptable. For example, when manufacturing tablets, in one embodiment, an additive may be added to amorphous teneligliptin hydrobromide and tablets may be manufactured by direct compression. In another embodiment, teneligliptin hydrobromide and an additive may be dissolved in a suitable solvent to produce a solid dispersion containing amorphous teneligliptin hydrobromide, and the solid dispersion and pharmaceutical additive may be mixed and compressed into tablets. In another embodiment, teneligliptin hydrobromide may be dissolved in a suitable solvent, an additive such as calcium silicate, light anhydrous silicic acid, or hydrated silicon dioxide may be mixed in, and then dried to prepare an amorphous teneligliptin hydrobromide-containing powder, and the powder and pharmaceutical additive may be mixed and compressed into tablets. [Examples]

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to the following examples. [Examples]

[0048] Solid dispersion (drug substance:copolymer=1:3) A solid dispersion is obtained by dissolving teneligliptin 2.5-hydrobromide (10g) and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (30g) in purified water (160g) and spraying the solution using a fluid bed granulator. [Examples]

[0049] Solid dispersion (Active pharmaceutical ingredient:Polyvinyl alcohol = 1:3) A solid dispersion is obtained by the same procedure as in Example 1, except that the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in Example 1 is replaced with polyvinyl alcohol.

[0050] ≪Comparative Example 1≫ Amorphous API Teneligliptin 2.5-hydrobromide obtained in an amorphous state

[0051] <Example Test> (Storage stability test) The solid dispersions of teneligliptin obtained in Examples 1 and 2, and the active pharmaceutical ingredient of Comparative Example 1, were stored at 25°C and 75% relative humidity for 7 days, and their amorphous state was confirmed by powder X-ray diffraction (Figures 1 and 2). A Smart Lab 3kW powder X-ray diffractometer was used for the measurement, with the following conditions: reflection method, Cu K-bate filter, X-ray output 40kV, 30mA, measurement range 2θ=3~40deg, scan speed 8deg / min, and step size 0.02deg. The evaluation results of the crystalline state are shown below.

[0052] [Table 1]

Claims

1. A teneligliptin-containing pharmaceutical composition comprising amorphous teneligliptin hydrobromide, a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and / or polyvinyl alcohol, characterized in that the mass ratio of the amorphous teneligliptin hydrobromide to the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and / or polyvinyl alcohol is 1:3 to 1:

5.

2. The teneligliptin-containing pharmaceutical composition according to claim 1, which is a solid dispersion comprising amorphous teneligliptin hydrobromide and a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer and / or polyvinyl alcohol.

3. Furthermore, the teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 2, further comprising one selected from the group consisting of calcium silicate, light anhydrous silicic acid, and hydrated silicon dioxide.

4. A teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 3, comprising amorphous teneligliptin hydrobromide and a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.

5. A teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 3, comprising amorphous teneligliptin hydrobromide and polyvinyl alcohol.

6. Furthermore, the teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 5, further comprising ascorbic acid and / or tocopherol.

7. A teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 6, wherein the mass ratio of amorphous teneligliptin hydrobromide to ascorbic acid is 1:0.01 to 1:0.

5.

8. A teneligliptin-containing pharmaceutical composition according to any one of claims 1 to 6, wherein the mass ratio of tocopherol to amorphous teneligliptin hydrobromide is 1:0.01 to 1:0.

5.

9. A pharmaceutical composition containing teneligliptin according to any one of claims 1 to 8, which is in the form of a tablet.

10. The teneligliptin-containing pharmaceutical composition according to claim 9, wherein the tablet is a film-coated tablet.

11. The teneligliptin-containing pharmaceutical composition according to claim 9, wherein the tablet is an orally disintegrating tablet.

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