JPWO2020194046A5

JPWO2020194046A5 -

Info

Publication number: JPWO2020194046A5
Application number: JP2021556883A
Authority: JP
Publication date: 2023-04-05

Claims

A pharmaceutical composition comprising
(a) a low dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor;
(b) a low dose, therapeutically effective amount of a biguanide;
(c) a low dose, therapeutically effective amount of a sulfonylurea;
(d) at least one pharmaceutically acceptable excipient, and (a), (b), and (c) are each at about 20% to about 75% of the lowest diabetic therapeutic dose (LDTD) , pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein said DPP IV inhibitor is gliptin.

The DPP IV inhibitor is sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, dutogliptin, or a pharmaceutically acceptable salt or hydrate thereof. A pharmaceutical composition according to claim 1 .

2. The pharmaceutical composition of claim 1, wherein said DPP IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein said DPP IV inhibitor is sitagliptin phosphate.

2. The pharmaceutical composition according to claim 1, wherein said biguanide is metformin or a pharmaceutically acceptable salt or hydrate thereof.

7. The pharmaceutical composition of claim 6, wherein said biguanide is metformin hydrochloride.

8. The pharmaceutical composition of claim 6 or 7, wherein said metformin is formulated for immediate release.

8. The pharmaceutical composition of claim 6 or 7, wherein said metformin is formulated for delayed release.

Said sulfonylureas are acetohexamide, carbutamide, chlorpropamide, glycylamide (toluhexamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide, glimepiride, Alternatively, the pharmaceutical composition according to claim 1, which is a pharmaceutically acceptable salt or hydrate thereof.

11. The pharmaceutical composition of claim 10, wherein said sulfonylurea is glimepiride.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is from about 40% to about 70% of the lowest diabetic therapeutic dose (LDTD). thing.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 40% to about 60% of the lowest diabetic therapeutic dose (LDTD). thing.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 45% to about 55% of the lowest diabetic therapeutic dose (LDTD). thing.

13. The pharmaceutical composition of claim 12, wherein the DPP IV inhibitor is about 70% of the lowest diabetic therapeutic dose (LDTD) of the DPP IV inhibitor.

2. The pharmaceutical composition of claim 1, wherein the DPP IV inhibitor is sitagliptin and the dose of sitagliptin is about 17.5 mg.

15. The pharmaceutical composition of any one of claims 1-14, wherein the DPP IV inhibitor is about 50% of the lowest diabetic therapeutic dose (LDTD) of the DPP IV inhibitor.

2. The pharmaceutical composition of claim 1, wherein the DPP IV inhibitor is sitagliptin and the dose of sitagliptin is about 12.5 mg.

19. The pharmaceutical composition of any one of claims 1-18, wherein the biguanide is about 70% of the lowest diabetic therapeutic dose (LDTD) of biguanide.

2. The pharmaceutical composition of claim 1, wherein the biguanide is metformin hydrochloride and the dose of metformin hydrochloride is about 350 mg.

19. The pharmaceutical composition of any one of claims 1-18, wherein the biguanide is about 50% of the lowest diabetic therapeutic dose (LDTD) of biguanide.

2. The pharmaceutical composition of claim 1, wherein the biguanide is metformin hydrochloride and the dose of metformin hydrochloride is about 250 mg.

23. The pharmaceutical composition of any one of claims 1-22, wherein the sulfonylurea is about 50% of the lowest diabetic therapeutic dose (LDTD) of the sulfonylurea.

2. The pharmaceutical composition of claim 1, wherein the sulfonylurea is glimepiride and the dose of glimepiride is about 0.5 mg.

2. The pharmaceutical composition of claim 1, wherein said DPP IV inhibitor is sitagliptin, said biguanide is metformin, and said sulfonylurea is glimepiride.

26. The method of claim 25, wherein the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of glimepiride is about 0.2 mg to about 0.75 mg. pharmaceutical composition.

26. The pharmaceutical composition of claim 25, wherein the dose of sitagliptin is about 10 mg to about 16.25 mg, the dose of metformin is about 200 mg to about 325 mg, and the dose of glimepiride is about 0.4 mg to about 0.65 mg. thing.

26. The pharmaceutical composition of claim 25, wherein the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of glimepiride is about 0.4 mg to about 0.6 mg.

26. The method of claim 25, wherein the dose of sitagliptin is about 11.25 mg to about 13.75 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of glimepiride is about 0.45 mg to about 0.55 mg. pharmaceutical composition.

26. The pharmaceutical composition of claim 25, wherein the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of glimepiride is about 0.5 mg.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 30% to about 40% of the lowest diabetic therapeutic dose (LDTD). thing.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 30% to about 35% of the lowest diabetic therapeutic dose (LDTD). thing.

33. The pharmaceutical composition of claim 31 or 32, wherein the sulfonylurea is about 33% of the lowest diabetic therapeutic dose (LDTD) for sulfonylureas.

34. The pharmaceutical composition of claim 33, wherein said sulfonylurea is glimepiride and the dose of sulfonylurea is about 0.33 mg.

32. The pharmaceutical composition of claim 31, wherein said DPP IV inhibitor is sitagliptin, said biguanide is metformin, and said sulfonylurea is glimepiride.

36. The pharmaceutical composition of claim 35, wherein the dose of sitagliptin is about 7.5 mg to about 10 mg, the dose of metformin is about 150 mg to about 200 mg, and the dose of glimepiride is about 0.3 mg to about 0.4 mg. thing.

36. The pharmaceutical composition of claim 35, wherein the dose of sitagliptin is about 8.25 mg, the dose of metformin is about 165 mg, and the dose of glimepiride is about 0.33 mg.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 20% to about 30% of the lowest diabetic therapeutic dose (LDTD). thing.

12. The pharmaceutical composition of any one of claims 1-11, wherein the dose of each of (a), (b), and (c) is about 22% to about 28% of the lowest diabetic therapeutic dose (LDTD). thing.

40. The pharmaceutical composition of claim 38 or 39, wherein the sulfonylurea is about 25% of the lowest diabetic therapeutic dose (LDTD) of the sulfonylurea.

34. The pharmaceutical composition of claim 33, wherein said sulfonylurea is glimepiride and the dose of sulfonylurea is about 0.25 mg.

39. The pharmaceutical composition of Claim 38, wherein said DPP IV inhibitor is sitagliptin, said biguanide is metformin, and said sulfonylurea is glimepiride.

43. The pharmaceutical composition of claim 42, wherein the dose of sitagliptin is about 5 mg to about 7.5 mg, the dose of metformin is about 100 mg to about 150 mg, and the dose of glimepiride is about 0.2 mg to about 0.3 mg. thing.

43. The pharmaceutical composition of claim 42, wherein the dose of sitagliptin is about 6.25 mg, the dose of metformin is about 150 mg, and the dose of glimepiride is about 0.25 mg.

45. The pharmaceutical composition of any one of claims 1-44, in the form of a pill, tablet, or capsule.

45. A pharmaceutical composition according to any one of claims 1 to 44, suitable for oral administration.

47. The pharmaceutical composition of any one of claims 1-46, which does not comprise any further additional antihyperglycemic or antidiabetic agents.

47. The pharmaceutical composition of any one of claims 1-46, wherein the combination of (a), (b), and (c) produces a synergistic effect.

49. The pharmaceutical composition of any one of claims 1-48, which results in a greater 2 hour postprandial glucose lowering compared to the maximal lowering of postprandial glucose obtained from about 100 mg of sitagliptin.

49. The pharmaceutical composition of any one of claims 1-48, which provides a greater 2 hour postprandial glucose lowering compared to the maximal lowering of postprandial glucose obtained from about 850 mg of metformin.

49. The pharmaceutical composition of any one of claims 1-48, which provides a greater 2 hour postprandial glucose lowering compared to the maximal lowering of postprandial glucose obtained from about 1700 mg of metformin.

A very low-dose, synergistic anti-diabetic combination drug comprising:
(a) from about 16.25 mg to about 18.75 mg of sitagliptin or a salt or hydrate thereof;
(b) from about 325 mg to about 375 mg of metformin or a salt or hydrate thereof;
(c) from about 0.45 mg to about 0.55 mg glimepiride or a salt or hydrate thereof;
(d) at least one excipient;
An antidiabetic combination drug consisting of:

53. The antidiabetic drug combination of Claim 52, which does not comprise any further additional antihyperglycemic or antidiabetic drugs.

53. The antidiabetic drug combination of Claim 52, wherein the combination of (a), (b), and (c) produces a synergistic effect.

53. The antidiabetic drug combination of claim 52, which provides a greater 2-hour postprandial glucose lowering compared to the maximal postprandial glucose lowering obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

52. The pharmaceutical composition of any one of claims 1-51, for treating diabetes in a subject.

57. The pharmaceutical composition of claim 56, wherein the subject continues to have elevated blood glucose levels after treatment with one or two of a DPP IV inhibitor, a biguanide, or a sulfonylurea at an LDTD or higher dose.

57. The pharmaceutical composition of claim 56, wherein administration of said pharmaceutical composition is an initial or first line treatment for diabetes.

56. The antidiabetic drug combination of any one of claims 52-55, for treating diabetes in a subject.

60. The anti-diabetic combination of Claim 59, wherein the subject continues to have elevated blood glucose levels after treatment with one or two of a DPP IV inhibitor, a biguanide, or a sulfonylurea at a dose equal to or greater than the LDTD.

60. The antidiabetic combination according to claim 59, wherein administration of said pharmaceutical composition is an initial or first line treatment for diabetes.

52. The pharmaceutical composition of any one of claims 1-51 in ameliorating, slowing or delaying the progression of a metabolic disorder, wherein said metabolic disorder is diabetes mellitus, impaired glucose tolerance, fasting blood sugar Abnormalities, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, renal dysfunction, gestational diabetes, new diabetes mellitus after renal transplantation (NODAT) and related complications, or post-liver transplant metabolism A pharmaceutical composition comprising a syndrome (PTMS) and complications associated therewith.

56. The antidiabetic drug combination according to any one of claims 52 to 55 in ameliorating, slowing progression of, or delaying a metabolic disorder, wherein said metabolic disorder is diabetes mellitus, impaired glucose tolerance, fasting Dysglycemia, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, renal dysfunction, gestational diabetes, new diabetes mellitus after renal transplantation (NODAT) and related complications, or after liver transplantation Anti-diabetic drug combinations, including metabolic syndrome (PTMS) and its associated complications .