Pharmaceutical Dosage Forms Comprising an Active Ingredient Combination of Nifedipine and/or Nisoldipine and an Angiotensini II Antagonist

• US 20090214664A1
• Filed: 06/29/2006
• Published: 08/27/2009
• Est. Priority Date: 07/06/2005
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Healthcare AG (Bayer AG)
• Inventors: Benke, Klaus, Ohm, Andreas, Hütter, Joachim, Tinel, Hanna
• Granted Patent: US 8,153,160 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• 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 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to a pharmaceutical dosage form comprising an active ingredient combination of nifedipine and/or nisoldipine and at least one angiotensin II antagonist, characterized in that the active ingredient combination undergoes controlled (modified) release in the body, and to processes for the production thereof, to the use thereof as pharmaceuticals, to the use thereof for the prophylaxis, secondary prophylaxis and/or treatment of disorders, and to the use thereof for manufacturing a pharmaceutical for the prophylaxis, secondary prophylaxis and/or treatment of disorders.

Claims

1. A pharmaceutical dosage form comprising an active ingredient combination of nifedipine or nisoldipine and at least one angiotensin II antagonist, characterized in that the active ingredient combination undergoes controlled (modified) release in the body.

2. The pharmaceutical dosage form as claimed in claim 1, where the angiotensin II antagonist is selected from the group of candesartan, losartan, telmisartan, irbesartan and olmesartan or one of the prodrugs of these angiotensin II antagonists.

3. The pharmaceutical dosage form as claimed in claim 1, characterized in that 80% of the active ingredients are released in a period of from 4 to 30 hours in the USP release method with apparatus 2 (paddle).

4. The pharmaceutical dosage form as claimed in claim 1, characterized in that 80% of the active ingredients are released in a period of from 4 to 30 hours in the USP release method with apparatus 2 (paddle), and the release rates of the respective active ingredients differ from one another by not more than 25% absolute in the linear part of the release profile.

5. The pharmaceutical dosage form as claimed in claim 1, characterized in that 80% of the active ingredient combination are released in a period of from 8 to 24 hours in the USP release method with apparatus 2 (paddle).

6. The pharmaceutical dosage form as claimed in claim 1, characterized in that 80% of the active ingredient combination are released in a period of from 8 to 24 hours in the USP release method with apparatus 2 (paddle), and the release rates of the respective active ingredients differ from one another by not more than 15% absolute in the linear part of the release profile.

7. The pharmaceutical dosage form as claimed in claim 1, characterized in that the pharmaceutical dosage form is constructed so as to be solid and capable of oral administration, and on the basis of an osmotic active ingredient release system.

8. The pharmaceutical dosage form as claimed in claim 1, characterized in that the active ingredients are present in crystalline or predominantly crystalline form.

9. The pharmaceutical dosage form as claimed in claim 1, characterized in that the active ingredients are present in micronized form.

10. The pharmaceutical dosage form as claimed in claim 1, characterized in that the active ingredients are present wholly or partly in amorphous form.

11. The pharmaceutical dosage form as claimed in claim 1, characterized in that nifedipine or nisoldipine is employed in a minimum dose of 5 mg and a maximum dose of 60 mg.

12. The pharmaceutical dosage form as claimed in claim 1, characterized in that nifedipine or nisoldipine is employed in a minimum dose of 10 mg and a maximum dose of 40 mg.

13. The pharmaceutical dosage form as claimed in claim 1, characterized in that angiotensin II antagonist is candesartan, olmesartan, irbesartan, losartan or telmisartan.

14. The pharmaceutical dosage form as claimed in claim 1, characterized in that candesartan or one of its prodrugs is employed in a dose of 2-32 mg as angiotensin II antagonist.

15. The pharmaceutical dosage form as claimed in claim 1, characterized in that candesartan or one of its prodrugs is employed in a dose of 4-16 mg as angiotensin II antagonist.

16. The pharmaceutical dosage form as claimed in claim 1, characterized in that the angiotensin II antagonist olmesartan or one of its prodrugs is employed in a dose of 5-40 mg.

17. The pharmaceutical dosage form as claimed in claim 1, characterized in that olmesartan or one of its prodrugs is employed in a dose of from 10 to 40 mg.

18. The pharmaceutical dosage form as claimed in claim 1, characterized in that the angiotensin II antagonist is telmisartan and is employed in a dose of from 10 to 80 mg.

19. The pharmaceutical dosage form as claimed in claim 1, characterized in that telmisartan is employed in a dose of from 10 to 40 mg.

20. The pharmaceutical dosage form as claimed in claim 1, characterized in that losartan is employed in a dose of from 25 to 100 mg.

21. The pharmaceutical dosage form as claimed in claim 1, characterized in that losartan is employed in a dose of from 40 to 60 mg.

22. The pharmaceutical dosage form as claimed in claim 1, characterized in that irbesartan is employed in a dose of from 50 to 500 mg.

23. The pharmaceutical dosage form as claimed in claim 1, characterized in that irbesartan is employed in a dose of from 75 to 300 mg.

24. The pharmaceutical dosage form as claimed in claim 1 consisting of an osmotic single-chamber system.

25. The pharmaceutical dosage form as claimed in claim 1 consisting of an osmotic single-chamber system comprising

a core comprising

5 to 50% of an active ingredient combination of nifedipine or nisoldipine +angiotensin II antagonists,

to 50% xanthan,

5 to 40% of a vinylpyrrolidone-vinyl acetate copolymer,

and a shell consisting of a water-permeable material which is impermeable for the components of the core and have at least one orifice.

26. The pharmaceutical dosage form as claimed in claim 1, which comprises a core which additionally includes sodium chloride as osmotically active additive.

27. The pharmaceutical dosage form as claimed in claim 1, which comprises a shell consisting of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

28. The pharmaceutical dosage form as claimed in claim 1, consisting of an osmotic two-chamber system.

29. The pharmaceutical dosage form as claimed in claim 1, consisting of an osmotic two-chamber system comprising

a core with an active ingredient layer comprising

5 to 50% of an active ingredient combination of nifedipine or nisoldipine +angiotensin II antagonists,

to 95% of one or more osmotically active polymers,

and an osmosis layer comprisingto 90% of one or more osmotically active polymers

5 to 40% of an osmotically active additive,

and a shell consisting of a water-permeable material which is impermeable for the components of the core and has at least one orifice.

30. The pharmaceutical dosage form as claimed in claim 29, which comprises in the active ingredient layer in the core polyethylene oxide with a viscosity of from 40 to 100 mPa·

s (5% strength aqueous solution, 25°

C.) as osmotically active polymer, and comprises in the osmosis layer in the core polyethylene oxide with a viscosity of 5000 to 8000 mPa·

s (1% strength aqueous solution, 25°

C.) as osmotically active polymer.

31. The pharmaceutical dosage form as claimed in any of claims claim 29, characterized in that the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

32. A process for producing an osmotic single-chamber system as defined in claim 25, characterized in that the components of the core are mixed together, granulated and tabletted, the core produced in this way is coated with a shell, and the shell is finally provided with one or more orifices.

33. A process for producing an osmotic two-chamber system as defined claim 29, characterized in that

the components of the active ingredient layer are mixed and granulated, and

the components of the osmosis layer are mixed and granulated,

the two granules are then compressed in a bilayer tablet press to a bilayer tablet,

the core produced in this way is then coated with the shell, and

this shell is provided with one or more orifices on the active ingredient side.

34. A pharmaceutical comprising a pharmaceutical dosage form as claimed in claim 1.

40. The pharmaceutical dosage form as claimed in claim 1, in which a further antihypertensive active ingredient is incorporated besides nifedipine or nisoldipine and the angiotensin II antagonist.

41. The pharmaceutical dosage form as claimed in claim 1, in which a diuretic is incorporated besides nifedipine or nisoldipine and the angiotensin II antagonist.

42. The pharmaceutical dosage form as claimed in claim 40, where hydrochlorothiazide is employed.

43. A method for the prophylaxis, secondary prophylaxis and/or treatment of cardiovascular disorders by administering a solid pharmaceutical dosage form which can be administered orally, comprises a nifedipine or nisoldipine/angiotensin II antagonist combination and is based on active ingredient release systems as defined in claims 1 to 31.

44. The method of claim 43 wherein the cardiovascular disorder is high blood pressure.

45. The pharmaceutical dosage form as claimed in claims claim 41, where hydrochlorothiazide is employed.

35. (canceled)

36. (canceled)

37. (canceled)

38. (canceled)

39. (canceled)