Medical use of pharmaceutical combination or composition

• US 10,155,000 B2
• Filed: 06/08/2017
• Issued: 12/18/2018
• Est. Priority Date: 06/10/2016
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Meinicke, Thomas, Von Eynatten, Maximilian
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US15/616,974
• Publication Number:
  US 20170354660A1
• Time in Patent Office: 558 Days
• Field of Search: 5142342, 514248, 5142581, 514635
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to a certain DPP-4 inhibitor for use in combination with metformin in CKD patients.

Claims

1. A method of using linagliptin, or a pharmaceutically acceptable salt thereof, in combination with metformin, and optionally one or more further active agents selected from the group consisting of insulin, a sulfonylurea, an angiotensin-converting enzyme (ACE) inhibitor, and an angiotensin II receptor blocker (ARB), to treat a type 2 diabetes patient having chronic kidney disease (CKD) up to stage 3 and/or having estimated glomerular filtration rate (eGFR;

mL/minute/1.73 m²) levels down to 45 or down to 30.

2. A method of using linagliptin, or a pharmaceutically acceptable salt thereof, in combination with metformin, and optionally one or more further active agents selected from the group consisting of insulin, a sulfonylurea, an angiotensin-converting enzyme (ACE) inhibitor, and an angiotensin II receptor blocker (ARB), to treat, to slow the progression or to delay the onset of type 2 diabetes mellitus and/or a diabetic complication selected from the group consisting of chronic kidney disease, diabetic nephropathy, micro- and macroalbuminuria, renal impairment, retinopathy, neuropathy, and a macrovascular complication which is a cardio- or cerebrovascular event, in a type 2 diabetes patient having chronic kidney disease (CKD) in stage 3 and/or having estimated glomerular filtration rate (eGFR) of 30 to 60 mL/minute/1.73 m².

3. The method of claim 2, wherein said treatment comprises one or more of the following:

i) treating type 2 diabetes mellitus;

ii) treating or slowing progression of chronic kidney disease (diabetic nephropathy);

iii) treating, preventing, protecting against, reducing the risk of, delaying the progression and/or delaying the occurrence of albuminuria (micro- or macro-albuminuria);

iv) preventing, protecting against, reducing the risk of and/or delaying the occurrence of a cardio- or cerebrovascular complication or event selected from;

cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) and, optionally, hospitalization for unstable angina pectoris;

v) preventing, protecting against, reducing the risk of, delaying the progression and/or delaying the occurrence of a renal microvascular complication or event selected from;

renal death, end-stage renal disease and loss in estimated glomerular filtration rate eGFR≥

50% or ≥

40% from baseline; and

/or

vi) decreasing, preventing, protecting against, delaying occurrence or progression and/or reducing the risk of cognitive decline or cognitive impairment or dementia.

4. The method of claim 2, wherein linagliptin and metformin are administered in a single pharmaceutical composition, such as e.g. in form of a single oral dosage form (e.g. tablet).

5. The method of claim 4, wherein the linagliptin is present in the composition in a dosage strength of 2.5 mg;

or of 5 mg.

6. The method of claim 5, wherein the metformin is present in the composition in a dosage strength of 500 mg, 850 mg or 1000 mg in form of immediate release metformin;

or 500 mg, 750 mg, 1000 mg, 1500 mg or 2000 mg in form of extended release metformin.

7. The method of claim 4, wherein the pharmaceutical composition comprises 2.5 mg linagliptin and 500 mg, 850 mg or 1000 mg metformin in immediate release form, and optionally one or more pharmaceutically auxiliaries.

8. The method of claim 4, wherein the pharmaceutical composition comprises 5 mg linagliptin and 1000 mg metformin in extended release form, and optionally one or more pharmaceutically auxiliaries, or

wherein the pharmaceutical composition comprises 2.5 mg linagliptin and 750 mg or 1000 mg metformin in extended release form, and optionally one or more pharmaceutically auxiliaries.

9. The method of claim 2, wherein linagliptin is administered in a total oral daily dose of 5 mg, wherein the 5 mg daily dose is administered as 2.5 mg linagliptin twice daily or 5 mg linagliptin once daily.

10. The method of claim 2, wherein metformin is administered up to maximum daily dose of 500 mg, 1000 mg, 2000 mg, or 2500 mg per day.

11. The method of claim 2, wherein the type 2 diabetes patient has not been previously treated with an antihyperglycemic agent.

12. The method of claim 2, wherein the type 2 diabetes patient has insufficient glycemic control despite previous mono-therapy with metformin.

13. The method of claim 2, further comprising treating the patient with a sulphonylurea, wherein the type 2 diabetes patient has insufficient glycemic control despite previous dual combination therapy with metformin and a sulphonylurea.

14. The method of claim 2 further comprising treating the patient with an insulin, wherein the type 2 diabetes patient has have insufficient glycemic control despite previous dual combination therapy with metformin and an insulin.

15. The method of claim 2, wherein the patient has micro- or macroalbuminuria.

16. The method of claim 2, wherein the patient has chronic renal impairment of mild-to-moderate stage and exhibits eGFR levels 45-59 (CKD stage 3a).

17. The method of claim 2, wherein the patient has chronic renal impairment of mild-to-moderate stage and exhibits eGFR levels 45-59 (CKD stage 3a), wherein the maximum daily dose of metformin hydrochloride is 2000 mg.

18. The method of claim 2, wherein the patient has chronic renal impairment of moderate-to-severe stage and exhibits eGFR levels 30-44 (CKD stage 3b).

19. The method of claim 2, wherein the patient has chronic renal impairment of moderate-to-severe stage and exhibits eGFR levels 30-44 (CKD stage 3b), wherein the maximum daily dose of metformin hydrochloride is 1000 mg.

20. The method of claim 2, wherein the patient has:

both albuminuria and previous macrovascular disease,

and/or

either mild or moderate renal impairment with macro-albuminuria, or moderate or severe renal impairment with or without any albuminuria.

21. The method of claim 2, wherein the patient has:

(i) albuminuria (micro or macro) as defined by urine albumin creatinine ratio (UACR)≥

30 mg/g creatinine or ≥

30 mg/l (milligram albumin per liter of urine) or ≥

30 μ

g/min (microgram albumin per minute) or ≥

30 mg/24 h (milligram albumin per 24 hours) and previous macrovascular disease as defined as one or more of a) to f);

a) previous myocardial infarction,

b) advanced coronary artery disease,

c) high-risk single-vessel coronary artery disease,

d) previous ischemic or haemorrhagic stroke,

e) presence of carotid artery disease,

f) presence of peripheral artery disease;

and/or

(ii) impaired renal function as defined by;

impaired renal function with an eGFR 15-45 mL/min/1.73 m² or 30-45 mL/min/1.73 m² with any urine albumin creatinine ratio (UACR), and/or

impaired renal function with an eGFR≥

45-75 mL/min/1.73 m² with an urine albumin creatinine ratio (UACR)>

200 mg/g creatinine or >

200 mg/l (milligram albumin per liter of urine) or >

200 μ

g/min (microgram albumin per minute) or >

200 mg/24 h (milligram albumin per 24 hours).

22. The method of claim 2, wherein the patient is treated over a period of at least 3 years.

23. The method of claim 2, wherein the patient has chronic renal impairment of moderate-to-severe stage and exhibits eGFR levels 30-44 (CKD stage 3b), wherein the maximum daily dose of metformin hydrochloride is 1000 mg, wherein linagliptin and metformin are administered in a single oral dosage form comprising 2.5 mg linagliptin and 500 mg metformin (in immediate release form, and optionally one or more pharmaceutically auxiliaries.