Claims for Patent: 8,900,638

Summary for Patent: 8,900,638

Title:	Solid preparation comprising alogliptin and metformin hydrochloride
Abstract:	The present invention provides a solid preparation containing compound (I) [compound (I) is as defined in the specification] or a salt thereof, and metformin hydrochloride, which is useful as a therapeutic drug for diabetes and the like, and superior in the preservation stability. A solid preparation having a first part and a second part: a first part: a part containing compound (I) or a salt thereof and substantially free of metformin hydrochloride a second part: a part containing metformin hydrochloride and substantially free of compound (I) and a salt thereof.
Inventor(s):	Kazumichi Yamamoto, Hiroyoshi Koyama
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US12/452,705
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,900,638
Patent Claims:	1. A solid preparation comprising the following first part and second part; the first part comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof and 0-3 parts by weight of metformin hydrochloride, relative to 100 parts by weight of the total weight of the first part; and the second part comprising metformin hydrochloride and 0-0.5 parts by weight of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, relative to 100 parts by weight of the total weight of the second part; wherein the first part is physically separated from the second part. 2. The solid preparation of claim 1, further comprising an additive. 3. The solid preparation of claim 2, comprising about 0.5-200 mg of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, and about 0.1-about 2 g of metformin hydrochloride. 4. The solid preparation of claim 2, wherein the first part has an average particle size of not less than about 75 μm, and the second part has an average particle size of not less than about 75 μm. 5. The solid preparation of claim 2, wherein 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof is a benzoate of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile. 6. The solid preparation of claim 2, which is a tablet. 7. The solid preparation of claim 2, wherein the first part and the second part are granules or tablets. 8. The solid preparation of claim 7, which is a capsule comprising said granule or said tablet. 9. The solid preparation of claim 2, wherein the weight ratio of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof contained in the first part and metformin hydrochloride contained in the second part is 1:5-1:400. 10. The solid preparation of claim 2, wherein the additive is a cellulose. 11. The solid preparation of claim 1, which is obtained by compression molding of a mixture of the following first granule and second granule: the first granule comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof and 0-3 parts by weight of metformin hydrochloride, relative to 100 parts by weight of the total weight of the first granule; and the second granule comprising metformin hydrochloride and 0-0.5 parts by weight of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, relative to 100 parts by weight of the total weight of the second granule. 12. The solid preparation of claim 11, wherein the proportion of the content of the first granule with a particle size of less than 150 μm relative to the total amount of the first granule is not less than about 20 wt %, the proportion of the content of the first granule with a particle size of not less than 250 μm relative to the total amount of the first granule is not more than about 50 wt %, the proportion of the content of the second granule with a particle size of less than 150 μm relative to the total amount of the second granule is not less than about 20 wt %, and the proportion of the content of the second granule with a particle size of not less than 250 μm relative to the total amount of the second granule is not more than about 50 wt %. 13. The solid preparation of claim 11, wherein the weight ratio of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof contained in the first granule and metformin hydrochloride contained in the second granule is 1:5-1:400. 14. The solid preparation of claim 1, wherein the first part is the following layer and the second part is the following core: the core comprising metformin hydrochloride and 0-0.5 parts by weight of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, relative to 100 parts by weight of the total weight of the core; the layer comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof and 0-3 parts by weight of metformin hydrochloride, relative to 100 parts by weight of the total weight of the layer, or wherein the first part is the following core and the second part is the following layer: the core comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1-(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof and 0-3 parts by weight of metformin hydrochloride, relative to 100 parts by weight of the total weight of the core; the layer comprising metformin hydrochloride and 0-0.5 parts by weight of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, relative to 100 parts by weight of the total weight of the layer. 15. The solid preparation of claim 14, further comprising an intermediate layer between said core and said layer. 16. The solid preparation of claim 14, wherein said layer is formed by spray coating. 17. The solid preparation of claim 14, wherein said layer is formed by compression. 18. The solid preparation of claim 1, wherein the first part is the following first layer and the second part is the following second layer: the first layer comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof and 0-3 parts by weight of metformin hydrochloride, relative to 100 parts by weight of the total weight of the first layer; and the second layer comprising metformin hydrochloride and 0-0.5 parts by weigh of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, relative to 100 parts by weight of the total weight of the second layer. 19. The solid preparation of claim 18, further comprising an intermediate layer between said first layer and said second layer. 20. The solid preparation of claim 1, which shows each peak area ratio defined below of related substances RS1 to RS6 defined below of not more than 0.5% by high performance liquid chromatography analysis under the following conditions after one-month preservation at temperature 40° C.; humidity 22% RH, 33% RH, 44% RH or 57% RH; open state: (1) column: Zorbax SB-CN, 5 μm, inner diameter 4.6 mm×25 cm (manufactured by Agilent) (2) mobile phase: mobile phase A: purified water/acetonitrile/trifluoroacetic acid=1900/100/1 (volume ratio) mobile phase B: purified water/acetonitrile/trifluoroacetic acid=100/1900/1 (volume ratio) (3) elution gradient program: from 0 min to 30 min: 99/1 (mobile phase A/mobile phase B) to 75/25 (mobile phase A/mobile phase B) from 30 min to 50 min: 75/25 (mobile phase A/mobile phase B) to 10/90 (mobile phase A/mobile phase B) from 50 min to 51 min: 10/90 (mobile phase A/mobile phase B) to 99/1 (mobile phase A/mobile phase B) from 51 min to 60 min: 99/1 (mobile phase A/mobile phase B) (constant) (4) flow rate: 1 ml/min (5) detector: UV 278 nm (6) sample temperature: about 3° C.-about 10° C. (7) column temperature: about 20° C.-about 30° C. related substances RS1-RS6 are derived from 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, and show a relative elution time of 0.60±10%, 1.08±10%, 1.30±10%, 1.49±10%, 1.52±10% and 1.62±10%, respectively, when the elution time of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile is 1.00, by high performance liquid chromatography analysis under the above-mentioned conditions, peak area ratio shows the ratio of each peak area relative to the peak area at an assumed content of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile as 100, in a chromatograph by high performance liquid chromatography analysis under the above-mentioned conditions. 21. The solid preparation of claim 1, wherein 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof is physically separated from metformin hydrochloride. 22. The solid preparation of claim 1, which is a therapeutic combination drug for diabetes or obesity. 23. A method of stabilizing 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof in a solid preparation comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof, metformin hydrochloride and an additive, which comprises physically separating 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof from the metformin hydrochloride by the additive.