Pharmaceutical dosage forms comprising an active ingredient combination of nifedipine and/or nisoldipine and an angiotensin II antagonist

• US 8,153,160 B2
• Filed: 06/29/2006
• Issued: 04/10/2012
• Est. Priority Date: 07/06/2005
• Status: Expired due to Fees

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Pharma AG (Bayer AG)
• Inventors: Ohm, Andreas, Benke, Klaus, Tinel, Hanna, Hütter, Joachim
• Primary Examiner(s): BARHAM, BETHANY P
• Application Number:
  US11/922,745
• Publication Number:
  US 20090214664A1
• Time in Patent Office: 2,112 Days
• Field of Search: None
• 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 on the basis of an osmotic active ingredient release system, comprising a core and a semipermeable membrane which surrounds the core, wherein the core comprises an active ingredient combination of nifedipine or nisoldipine and at least one angiotensin II antagonist, wherein the semipermeable membrane is water-permeable but substantially impermeable to components of the core, and the semipermeable membrate includes at least one orifice, and wherein the release rates of the active ingredients differ from one another by no more than 25% absolute in the linear part of a release profile in a USB release method with apparatus 2 (paddle).

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 ingredient combination are released in a period of from 8 to 24 hours in the USP release method with apparatus 2 (paddle).

4. The pharmaceutical dosage form as claimed in claim 3, characterized in that the release rates of the active ingredients differ from one another by not more than 15% absolute in the linear part of the release profile.

5. 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.

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

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

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

9. 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.

10. 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.

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

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

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

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

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

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

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

22. The pharmaceutical dosage form as claimed in claim 1 wherein the pharmaceutical dosage form is a single-chamber system.

23. The pharmaceutical dosage form as claimed in claim 1, wherein the core further comprises sodium chloride.

24. The pharmaceutical dosage form as claimed in claim 1, wherein the semipermeable membrane comprises cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

25. The pharmaceutical dosage form as claimed in claim 1, wherein the dosage form is a two-chamber system.

26. The pharmaceutical dosage form as claimed in claim 25,

wherein the core consists of an active ingredient layer comprising

5 to 50% of the active ingredient combination, and

to 95% of one or more osmotically active polymers,

and an osmosis layer comprising

to 90% of one or more osmotically active polymers, and

5 to 40% of an osmotically active additive.

27. The pharmaceutical dosage form as claimed in claim 26, 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.

28. The pharmaceutical dosage form as claimed in claim 26, characterized in that the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

29. A process for producing an osmotic single-chamber system as defined in claim 22, 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.

30. A process for producing an osmotic two-chamber system as defined in claim 26, 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 semipermeable membrane, and

the semipermeable membrate is provided with one or more orifices on the active ingredient side.

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

32. The pharmaceutical dosage form as claimed in claim 1, in which the active ingredient combination further comprises an antihypertensive active ingredient.

33. The pharmaceutical dosage form as claimed in claim 1, in which the active ingredient combination further comprises a diuretic.

34. The pharmaceutical dosage form as claimed in claim 32, where hydrochlorothiazide is employed.

35. A method for the prophylaxis, secondary prophylaxis and/or treatment of cardiovascular disorders by administering a solid pharmaceutical dosage form of claim 1 which can be administered orally.

36. The method of claim 35 wherein the cardiovascular disorder is high blood pressure.

37. The pharmaceutical dosage form as claimed in claim 33, where hydrochlorothiazide is employed.

38. The pharmaceutical dosage form as claimed in claim 22, wherein the core comprises:

5 to 50% of the active ingredient combination,

10 to 50% xanthan, and

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