Teneligliptin-containing pharmaceutical composition

Abstract

To provide a pharmaceutical composition containing teneligliptin hydrobromide that suppresses decrease in dissolution rate of teneligliptin, and to provide a pharmaceutical composition containing light-stabilized teneligliptin hydrobromide.SOLUTION: A pharmaceutical composition comprises a tablet part including amorphous teneligliptin hydrobromide anhydrate and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and a film coating part containing titanium oxide and 0.4 to 4.0 wt.% of ferric oxide in the film coating part.SELECTED DRAWING: Figure 2

Description

[Technical Field]

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

[0002] Teneligliptin hydrobromide anhydrous 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 the hydrate teneligliptin hydrobromide hydrate as the active ingredient are known to be a treatment for type 2 diabetes. They are sold as Tenelia Tablets 20mg, etc., which contain the following excipients: D-mannitol, corn starch, hydroxypropyl cellulose, anhydrous silicic acid, magnesium stearate, hypromellose, macrogol 400, titanium oxide, ferric oxide, and hydrogenated oil. Furthermore, orally disintegrating tablets such as Tenelia OD Tablets 20 mg are commercially available, containing the following additives: light anhydrous silicic acid, polyvinyl alcohol (partially saponified), ethyl cellulose, cetanol, sodium lauryl sulfate, triethyl citrate, D-mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol (fully saponified), croscarmellose sodium, sodium stearyl fumarate, sucralose, flavoring, yellow ferric oxide, and tocopherol, with the expectation of improved convenience and improved medication compliance for elderly people, patients who have difficulty taking Tenelia tablets (regular tablets), and patients who need to limit fluid intake. The usual dosage and administration for treatment is a once-daily oral administration of 20 mg of teneligliptin for adults (Non-Patent Documents 1 and 2).

[0003] Furthermore, Patent Document 1 describes a tablet obtained by simply physically mixing amorphous teneligliptin hydrobromide and light anhydrous silicic acid and compressing the mixture, as well as a tablet obtained by wet-granulating a mixture containing amorphous teneligliptin hydrobromide and light anhydrous silicic acid and compressing the granulated mixture.

[0004] Patent Document 2 describes a pharmaceutical composition comprising amorphous teneligliptin hydrobromide and a porous substance, and a coated tablet in which an uncoated tablet containing a solid dispersion of amorphous teneligliptin hydrobromide supported in a porous substance is coated with a coating liquid containing polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, titanium oxide, and ferric oxide.

[0005] Patent Document 3 describes a solid dispersion containing teneligliptin hydrobromide and hydrous silicon dioxide.

[0006] Patent Document 4 describes a solid dispersion containing amorphous teneligliptin hydrobromide and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0007] However, there is no description of a pharmaceutical composition comprising an uncoated tablet containing amorphous teneligliptin hydrobromide anhydrate and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and a film-coated portion containing titanium oxide and 0.4% by weight to 4.0% by weight of ferric oxide in the film-coated portion.

[0008] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2020-070260 [Patent Document 2] Japanese Patent Application Publication No. 2023-156269 [Patent Document 3] Japanese Patent Application Publication No. 2023-056991 [Patent Document 4] Japanese Patent Application Publication No. 2022-184669 [Non-patent literature]

[0010] [Non-Patent Document 1] Package insert "Tenelia Tablets 20mg / 40mg", revised July 2021 (2nd edition) [Non-patent document 2] Package insert "Tenelia OD Tablets 20mg / 40mg", revised July 2021 (4th edition) Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a pharmaceutical composition containing teneligliptin hydrobromide in which the decrease in the dissolution rate of the active ingredient over time is suppressed, and to provide a pharmaceutical composition containing photostabilized teneligliptin hydrobromide. [Means for solving the problem]

[0012] As a result of extensive research, the inventors discovered that the inclusion of a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in the core tablet portion suppresses the decrease in dissolution rate, and that the inclusion of ferric oxide in the coating portion provides light stabilization, leading to the completion of the present invention.

[0013] That is, the present invention is (1) A pharmaceutical composition comprising an uncoated tablet portion containing amorphous teneligliptin hydrobromide anhydrate and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and a film-coated portion containing titanium oxide and 0.4 to 4.0% by weight of ferric oxide in the film-coated portion; (2) The pharmaceutical composition according to (1), wherein the weight ratio of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is 0.01 to 1, relative to the weight ratio of the amorphous teneligliptin hydrobromide anhydrous being 1. (3) The pharmaceutical composition according to (1) or (2), wherein the uncoated tablet contains one or more additives selected from the group consisting of D-mannitol, isomalt, trehalose, and lactose hydrate. (4) The pharmaceutical composition according to (3), wherein the blending ratio of the additive is 1 to 5, when the amount of amorphous teneligliptin hydrobromide anhydrous is 1. (5) The pharmaceutical composition according to (1), wherein the ratio of titanium oxide is 0.01 to 1, relative to the ratio of amorphous teneligliptin hydrobromide anhydrous being 1. (6) The pharmaceutical composition according to (1), wherein the blending ratio of iron sesquioxide is 0.0005 to 0.01, relative to the blending ratio of amorphous teneligliptin hydrobromide anhydrous being 1. Regarding. [Effects of the Invention]

[0014] According to the present invention, it is possible to provide a pharmaceutical composition containing anhydrous teneligliptin hydrobromide in which the decrease in dissolution rate is suppressed, and a pharmaceutical composition containing teneligliptin hydrobromide that is stable to light. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the dissolution profiles of teneligliptin over time from tablets of Examples 1 and 2 and Comparative Example 1. [Figure 2] FIG. 1 shows the dissolution profile of teneligliptin over time from the tablet of Example 1 up to 3 months after the start of storage in a storage stability test. [Figure 3] FIG. 1 shows the dissolution profile of teneligliptin over time from the tablet of Comparative Example 1 for 3 months from the start of storage in a storage stability test. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a pharmaceutical composition comprising an uncoated tablet containing amorphous teneligliptin hydrobromide anhydrate and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and a film-coated portion containing titanium oxide and 0.4 to 4.0% by weight of ferric oxide in the film-coated portion.

[0017] In this specification, the term "plain tablet portion" refers to the tablet portion that is formed into a tablet shape in the tableting process and is not coated, and the term "coated portion" refers to the coating layer of a tablet that is formed into a tablet shape in the tableting process and is coated by subjecting an uncoated tablet to a film coating process.

[0018] As used herein, "photostabilization" means suppressing the increase in the amount of related substances and / or the generation and increase of unknown substances due to drug decomposition, etc., under harsh light conditions, such as in storage stability tests (light). For example, the light stability of a tablet can be evaluated by storing the tablet under harsh light conditions, then testing it using high-performance liquid chromatography (HPLC), calculating the amount of related substances, and comparing it with the total amount of related substances at the start of the test.

[0019] As used herein, "suppression of a decrease in dissolution rate" means that in an unpackaged stability test, the dissolution rate after 30 minutes after storage for 3 months is 85% or more. The dissolution of teneligliptin from the pharmaceutical composition of the present invention can be evaluated, for example, by the dissolution test method described in the Japanese Pharmacopoeia. Specifically, when a dissolution test is performed using the paddle method at 50 revolutions per minute, one embodiment specifies that the dissolution rate is 85% or more 30 minutes after the start of the dissolution test, and another embodiment specifies that the dissolution rate is 85% or more 15 minutes after the start of the dissolution test.

[0020] As used herein, "amorphous teneligliptin hydrobromide anhydrous" refers to a material state in which the atoms constituting teneligliptin hydrobromide anhydrous lack long-range order as in crystals but have short-range order, i.e., "teneligliptin hydrobromide anhydrous" in an "amorphous" state. The "amorphous" state can be confirmed, for example, by powder X-ray diffraction measurement. Amorphous teneligliptin hydrobromide anhydrous can be determined by powder X-ray diffraction measurement if the diffraction peaks (2θ=5.4°±0.2°, 13.4°±0.2°, 14.4°±0.2°) derived from teneligliptin hydrobromide hydrate crystals described in Japanese Patent No. 4208938 are substantially absent.

[0021] Hereinafter, a pharmaceutical composition containing the amorphous teneligliptin hydrobromide anhydrate of the present invention will be described.

[0022] The amorphous anhydrous teneligliptin hydrobromide used in the present invention is produced according to the method described in WO02 / 14271 or the like.

[0023] Amorphous teneligliptin hydrobromide anhydrate embodiments are in an amorphous state even before inclusion in a pharmaceutical composition.

[0024] The blending ratio of amorphous teneligliptin hydrobromide anhydrous per unit of pharmaceutical composition is 5 to 95 wt %, 10 to 80 wt %, and 20 to 40 wt % in some embodiments, as teneligliptin hydrobromide anhydrous in some embodiments, and the blending amount is 5 to 90 wt %, 10 to 50 wt %, and 10 to 30 wt % in some embodiments, as teneligliptin per unit of pharmaceutical composition.

[0025] The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer used in the present invention is not particularly limited as long as it can maintain the amorphous state of anhydrous teneligliptin hydrobromide and is pharmaceutically acceptable. Specific examples include POVACOAT Type F, POVACOAT Type FM, and POVACOAT Type MP in some embodiments.

[0026] The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer contained in the uncoated tablet is, in one embodiment, 0.01 to 20, in one embodiment, 0.05 to 1.5, and in one embodiment, 0.1 to 1.5, relative to the amount of amorphous teneligliptin hydrobromide anhydrous, taken as 1.

[0027] The amount of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer blended is 1 to 5 wt % in one embodiment, and 2 to 4 wt % in another embodiment, based on the weight of the uncoated tablet.

[0028] The D-mannitol, isomalt, trehalose, and lactose hydrate used in the present invention are not particularly limited as long as they are pharmaceutically acceptable. Examples of D-mannitol include PEARLITOL® 25C and PEARLITOL® 50C (manufactured by Rocket Japan), Mannit P and Mannit C (manufactured by Mitsubishi Corporation Life Sciences), Granutol® R, Granutol® S, and Granutol® F (manufactured by Freund Corporation), PARTECK® M100, and PARTECK® M200 (manufactured by Merck). Examples of isomalt include galenIQ721. Examples of trehalose include Trehalose P and Trehalose G (manufactured by Hayashibara). Examples of lactose hydrate include GranuLac® 200 (manufactured by Meigler Japan), Dilactose® R, and Dilactose® S (manufactured by Freund Corporation).

[0029] The titanium oxide and red ferric oxide used in the present invention are not particularly limited as long as they are pharmaceutically acceptable. Specific examples of titanium oxide include NA-61 and red ferric oxide (manufactured by Kishi Chemicals).

[0030] The amount of ferric oxide blended is 0.0005 to 0.01 in one embodiment, 0.001 to 0.005 in another embodiment, and 0.002 to 0.004 in another embodiment, relative to the weight of teneligliptin hydrobromide as 1. Furthermore, in relation to the film-coated portion, the amount of ferric oxide blended is 0.4 to 4.0 wt %, 0.7 to 4.0 wt %, and 1.0 to 4.0 wt % in another embodiment, per film-coated portion. Furthermore, the amount per tablet is 0.001 to 0.05 wt %, 0.02 to 0.2 wt %, and 0.06 to 0.1 wt % in another embodiment.

[0031] The amount of titanium oxide blended is in one embodiment 0.001 to 0.1, in another embodiment 0.005 to 0.05, and in another embodiment 0.01 to 0.05, when the amount of teneligliptin hydrobromide is 1. Furthermore, in relation to the film coating portion, the amount of titanium oxide blended is in one embodiment 5 to 35 wt %, in another embodiment 10 to 30 wt %, and in another embodiment 15 to 25 wt % per weight of the film coating portion.

[0032] The pharmaceutical composition of the present invention may further contain pharmaceutical additives, if necessary, such as excipients, disintegrants, surfactants, binders, coating agents, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, lubricants, etc.

[0033] Examples of excipients include anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, low-substituted hydroxypropyl cellulose, D-mannitol, partially pregelatinized starch, potato starch, and the like.

[0034] Examples of disintegrants include potato starch, carmellose calcium, low-substituted hydroxypropyl cellulose, crospovidone, partially pregelatinized starch, sodium starch glycolate, and croscarmellose sodium.

[0035] Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

[0036] Examples of binders include hypromellose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, carmellose sodium, pullulan, and dextrin.

[0037] Examples of coating agents include hypromellose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol, propylene glycol, glycerin monostearate, copolyvidone, titanium oxide, and talc.

[0038] Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

[0039] Examples of the foaming agent include bilayer foam.

[0040] Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0041] Examples of flavorings include lemon, lemon-lime, orange, and menthol.

[0042] Examples of coloring agents include yellow ferric oxide, black iron oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, food blue No. 3, and the like.

[0043] Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or salts thereof, and the like.

[0044] Examples of antioxidants include dibutylhydroxytoluene and propyl gallate.

[0045] Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, calcium stearate, hardened oil, sucrose fatty acid ester, magnesium stearate, and the like.

[0046] In the teneligliptin-containing pharmaceutical composition of the present invention, various additional pharmaceutical additives may be used as appropriate within the range in which the desired effects of the present invention are achieved.

[0047] The various additional pharmaceutical additives to be incorporated into the teneligliptin-containing pharmaceutical composition of the present invention can be combined as appropriate.

[0048] The amount of the compounding agent is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

[0049] The tablet of the present invention is a film-coated tablet, and also includes an orally disintegrating tablet.

[0050] The pharmaceutical composition of the present invention may be produced by any method that achieves the object of the present invention. For example, in one embodiment, amorphous teneligliptin hydrobromide anhydrous, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and additives (e.g., excipients, etc.) are mixed and compressed to produce uncoated tablets. A film-coating solution containing titanium oxide and ferric oxide is sprayed onto the uncoated tablets, followed by drying to produce film-coated tablets. [Example]

[0051] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to the following examples in any way. [Example]

[0052] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider®-102) and 1.8 g of magnesium stearate (Taihei Chemical Industry; vegetable-based) were added and mixed to prepare a tableting powder. The resulting tableting powder was compressed using a small rotary tableting machine (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 88.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 2.4 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them to a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to give film-coated tablets of the present invention. [Example]

[0053] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 171.4 g of D-mannitol (Merck; Partec M-100), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. The resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider®-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based), and the resulting powder was compressed into tablets using a small rotary tablet press (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 2.4 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them to a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to give film-coated tablets of the present invention. [Example]

[0054] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. To the resulting mixture, 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider®-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based) were added and mixed to prepare a tableting powder. The resulting tableting powder was compressed using a small rotary tableting machine (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 0.6 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them to a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to give film-coated tablets of the present invention. [Example]

[0055] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. The resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based), and the resulting powder was compressed into tablets using a small rotary tablet press (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 1.5 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them to a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to give film-coated tablets of the present invention. [Example]

[0056] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. The resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based), and the resulting powder was compressed into tablets using a small rotary tablet press (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 2.4 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them to a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to give film-coated tablets of the present invention. [Example]

[0057] 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. The resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based), and the resulting powder was compressed into tablets using a small rotary tablet press (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex) and coated with 8 mg of a coating solution prepared by dissolving and dispersing 30.21 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT® Type F, manufactured by Daido Chemical Industry Co., Ltd.), 2.52 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 30.21 g of talc (Crown Talc®, Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 2.4 g of ferric oxide (ferric oxide, manufactured by Kishi Chemical Co., Ltd.) in 360 g of purified water while spraying the coating solution. The tablets were then polished using carnauba wax (Polishing Wax®-105, manufactured by Freund Corporation) to obtain film-coated tablets of the present invention.

[0058] Comparative Example 1 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 139 g of D-mannitol (Freund Corporation; Granutol®), 7.2 g of carmellose (Nichirin Chemical Industry; NS300), 7.2 g of croscarmellose sodium (Asahi Kasei Corporation; Kiccolate® ND-2HS), and 24 g of microcrystalline cellulose (Asahi Kasei Corporation; Ceolus® UF-702) were mixed together, and the resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based) to prepare a tableting powder. The resulting tableting powder was compressed using a small rotary tableting machine (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin). 240 mg of the uncoated tablets obtained above were placed in a film coating machine (DRC-300, manufactured by Powrex), and a coating solution prepared by dissolving and dispersing 48.5 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 9.7 g of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.), 14.5 g of titanium oxide (NA-61, manufactured by Toho Titanium Co., Ltd.), 7.3 g of talc (Crown Talc (registered trademark), Pharmacopoeia PP, manufactured by Matsumura Sangyo Co., Ltd.), and 2.4 g of ferric oxide (ferric oxide, manufactured by Kishi Kasei Co., Ltd.) in 613 g of purified water was sprayed onto each tablet to coat them at a thickness of 8 mg. The tablets were then polished using carnauba wax (Polishing Wax (registered trademark)-105, manufactured by Freund Corporation) to obtain film-coated tablets for the comparative example.

[0059] Comparative Example 2 59 g of amorphous teneligliptin hydrobromide anhydrous salt, 147.4 g of D-mannitol (Freund Corporation; Granutol®), 24 g of isomalt (galenIQ721), and 6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (Daido Chemical Industry; POVACOAT) were mixed together. The resulting mixture was mixed with 1.2 g of hydrated silicon dioxide (Freund Corporation; Adsolider-102) and 2.4 g of magnesium stearate (Taihei Chemical Industry; vegetable-based), and the resulting powder was compressed into tablets using a small rotary tablet press (Kikusui Seisakusho; VEL5) to obtain uncoated tablets with a diameter of 8.5 mm and a mass of 240 mg (40 mg of teneligliptin).

[0060] [Table 1]

[0061] <Test Example 1> (Dissolution test) Dissolution tests were conducted on the tablets of Examples 1 and 2 and Comparative Example 1 according to the Japanese Pharmacopoeia dissolution test method. Tablet dissolution was measured using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) using the paddle method with a paddle rotation speed set at 50 rpm, and 900 mL of dissolution test second fluid was used as the test fluid. 10 mL of sample was withdrawn over time from the start of the test until 45 minutes later, and immediately replaced with 10 mL of test fluid preheated to 37±0.5°C. The sample was filtered through a membrane filter with a pore size of 0.45 μm or less. An equal volume of test fluid was added to the filtrate, and the dissolution rate was calculated by liquid chromatography. The ultraviolet absorbance of teneligliptin was measured at 246 nm.

[0062] The measurement results of the dissolution test are shown in Table 2 and Figure 1. In Examples 1 and 2 and Comparative Example 1, the dissolution rate was 95% or more in 30 minutes.

[0063] [Table 2]

[0064] <Test Example 2> (Storage stability test) For Example 1 and Comparative Example 1, each sample was stored under conditions of 25°C and 75% RH for up to 3 months, and an unpackaged stability test was performed. The stored samples were subjected to a dissolution test in the same manner as in Test Example 1. The measurement results of the dissolution test are shown in Tables 3 and 4 and Figures 2 and 3. In Comparative Example 1, the dissolution rate decreased as the storage period increased. On the other hand, in Example 1, almost no change was observed in the dissolution rate from the start of storage until 3 months later, and the dissolution rate was 85% or more 30 minutes after the start of the dissolution test, indicating that the decrease in the dissolution rate was suppressed.

[0065] [Table 3]

[0066] [Table 4]

[0067] <Test Example 3> (Photostability test) A photostability test was carried out on each sample of Examples 3 to 6 and Comparative Example 2, which was stored under an irradiation condition of 3000 Lux·hr up to a total irradiation dose of 1.2 million Lux·hr. The stored samples were subjected to a purity test. The tablets were crushed into powder and an amount equivalent to 40 mg of teneligliptin was precisely weighed. A pH 4.0 phosphate buffer / acetonitrile mixture was added and shaken, and the solution was adjusted to exactly 200 mL and filtered through a membrane filter with a pore size of 0.45 μm or less. The filtrate was used as the sample solution, and its purity was calculated by liquid chromatography. The ultraviolet absorbance of teneligliptin was measured at 246 nm. The results of the purity test are shown in Table 5. In Comparative Example 2, the total amount of related substances increased to 0.42% at a total irradiation dose of 1.2 million Lux·hr. In Example 3, the total amount of related substances increased to 0.24% at a total irradiation dose of 1.2 million Lux·hr. In Examples 4 and 5, the total amount of related substances was below the limit of quantitation at a total irradiation dose of 1.2 million Lux·hr.

[0068] [Table 5]

Claims

1. A pharmaceutical composition comprising: an uncoated tablet portion containing amorphous teneligliptin hydrobromide anhydrate and a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer; and a film-coated portion containing titanium oxide and 0.4 to 4.0% by weight of ferric oxide in the film-coated portion.

2. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is 0.01 to 1, relative to the weight ratio of the amorphous teneligliptin hydrobromide anhydrous, which is taken as 1.

3. 3. The pharmaceutical composition according to claim 1, wherein the uncoated tablet contains one or more additives selected from the group consisting of D-mannitol, isomalt, trehalose, and lactose hydrate.

4. 4. The pharmaceutical composition according to claim 3, wherein the proportion of the additive is 1 to 5, relative to the proportion of amorphous teneligliptin hydrobromide anhydrous.

5. 2. The pharmaceutical composition according to claim 1, wherein the ratio of titanium oxide to amorphous teneligliptin hydrobromide anhydrous is 0.01 to 1.

6. 2. The pharmaceutical composition according to claim 1, wherein the ratio of iron sesquioxide to amorphous teneligliptin hydrobromide anhydrous is 0.0005 to 0.01.

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