Diffusion-osmotic controlled drug-release pharmaceutical composition and process for preparing same

• US 5,543,155 A
• Filed: 12/05/1994
• Issued: 08/06/1996
• Est. Priority Date: 12/09/1993
• Status: Expired due to Fees

• Current Assignee: Egis Gyogyszergyar
• Original Assignee: Egis Gyogyszergyar
• Inventors: Barczay, Erzsebet, Kiss nee Szabo, Gizella, Krisztian, Maria, Gora nee Hernyes, Magdolna, Jambor nee Hoffmann, Zsuzsanna, Kiraly nee Ignacz, Maria, Sipos, Gabor, Mandi, Attila, Fekete, Pal, Klebovich, Imre, Drabant, Sandor, Ujfalussy, Gyorgy
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/341,209
• Time in Patent Office: 610 Days
• Field of Search: 424/468, 424/472, 424/473, 424/482
• US Class Current: 424/473
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

The invention relates to a novel diffusion-osmotic controlled drug-release pharmaceutical composition containing a one-layer tablet core including a polymeric film-coat, a therapeutically active agent and a hydrophilic polymer; if desired, a two-layer tablet core including active agent and hydrophilic polymer in the first layer thereof and a hydrophilic polymer in the second layer thereof; at least one bore on the part of film-coat in contact with the core or core layer containing the active agent; and, if desired, containing one or more bore(s) in the part thereof in contact with the second layer containing the hydrophilic polymer, which comprises an ammonium methacrylate copolymer as coating material and hydroxypropyl-methylcellulose as hydrophilic polymer. The composition according to the invention is useful for preparing controlled drug-release tablets containing as active agents e.g. β-adrenergic inhibitors (e.g. propranolol) calcium-antagonists (e.g. nifedipine), angiotensin convertase enzyme (ACE) inhibitors (e.g. captopril); prazosin; or nitroglycerol, all used in heart and circulation diseases; vasodilatory active agents (e.g. pentoxyfylline), nonsteroidal antiinflammatory agents (e.g. naproxene), analgetic drugs (e.g. morphine) and drugs acting on the central nervous system (e.g. amitriptyline, buspiron). The invention furthermore relates to a process for the preparation of the above compositions.

Claims

1. A diffusion-osmotic controlled drug-release pharmaceutical composition comprising a tablet core containing a therapeutically active agent and a hydrophilic polymer, wherein said tablet core is coated with a polymeric film-coat, and said film-coat contains at least one bore in said film-coat in contact with said tablet core, said film-coat comprising an ammonium methacrylate copolymer and said hydrophilic polymer comprising hydroxypropyl methylcellulose, said film-coat being present in an amount of 3 to 25 mg/cm² in relation to the surface of said tablet core.

2. The composition according to claim 1, wherein said hydroxypropyl methylcellulose is present in an amount of 5 to 30% by weight in relation to the weight of said tablet core.

3. The composition according to claim 1, said tablet core further comprising 0 to 90% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said tablet core.

4. The composition according to claim 3, wherein said filling material is cellulose, microcrystalline cellulose, starch, lactose, mannitol, or secondary calcium phosphate.

5. The composition according to claim 3, wherein said binding material is hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethylcellulose, gelatine, water-soluble starch, polyvinylalcohol, polyoxyethyleneglycol, or polyvinylbutyral.

6. The composition according to claim 3, wherein said lubricant is magnesium stearate, talc, stearic acid, hydrogenated castor oil, or colloidal silicon dioxide.

7. The composition according to claim 1, wherein said ammonium methacrylate copolymer has a relative molecular weight of 100,000 to 200,000 and contains 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 to 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

8. The composition according to claim 1, wherein said ammonium methacrylate copolymer comprises a 1:

10 to 10;

1 ratio of an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 molar part of (trimethylammonio)-ethyl methacrylate to an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 2 molar parts of methyl methacrylate, 1 molar part of ethyl methacrylate and 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

9. The composition according to claim 1, wherein said hydroxypropyl methylcellulose contains 20 to 30% by weight of methoxy groups and 5 to 12% by weight of hydroxypropyl groups and has a viscosity of 3 to 100,000 cP in a 2% aqueous solution.

10. A diffusion-osmotic controlled drug-release pharmaceutical composition comprising a tablet core containing a therapeutically active agent, 5 to 30% by weight of hydroxypropyl methylcellulose, 0 to 90% by weight of filling material, at most 5% by weight of binding material and at most 5% by weight of lubricant in relation to the total weight of said tablet core;

wherein said tablet core is coated with a polymeric film-coat of an ammonium methacrylate copolymer, and said film-coat contains at least one bore in said film-coat in contact with said tablet core, said film-coat being present in amount of 3 to 25 mg/cm² in relation to the surface of said tablet core, and said film-coat contains one or more bores of 0.1 to 1.0 mm² in cross-section.

11. A diffusion-osmotic controlled drug-release pharmaceutical composition comprising a two-layer tablet core, wherein the first layer of said two-layer tablet core contains a therapeutically active agent and a hydrophilic polymer, and the second layer of said two-layer tablet core contains a hydrophilic polymer, said two-layer tablet core being covered with a polymeric film-coat, the part of said film-coat in contact with said first layer contains at least one bore and the part of said film-coat in contact with said second layer optionally contains at least one bore, said film-coat comprising an ammonium methacrylate copolymer and said hydrophilic polymer comprising hydroxypropyl methylcellulose, said film-coat being present in an amount of 3 to 25 mg/cm² in relation to the surface of said two-layer tablet core.

12. The composition according to claim 11, wherein said hydroxypropyl methylcellulose in said first layer is present in an amount of 5 to 30% by weight in relation to the weight of said first layer.

13. The composition according to claim 11, wherein said hydroxypropyl methylcellulose in said second layer is present in an amount of 30 to 100% by weight in relation to the weight of said second layer.

14. The composition according to claim 11, wherein said first layer further comprises 0 to 90% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said first layer.

15. The composition according to claim 11, said second layer further comprising 0 to 70% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said second layer.

16. The composition according to claim 14, wherein said filling material is cellulose, microcrystalline cellulose, starch, lactose, mannitol, or secondary calcium phosphate.

17. The composition according to claim 14, wherein said binding material is hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethylcellulose, gelatine, water-soluble starch, polyvinylalcohol, polyoxyethyleneglycol, or polyvinylbutyral.

18. The composition according to claim 14, wherein said lubricant is magnesium stearate, talc, stearic acid, hydrogenated castor oil, or colloidal silicon dioxide.

19. The composition according to claim 15, wherein said filling material is cellulose, microcrystalline cellulose, starch, lactose, mannitol, or secondary calcium phosphate.

20. The composition according to claim 15, wherein said binding material is hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethylcellulose, gelatine, water-soluble starch, polyvinylalcohol, polyoxyethyleneglycol, or polyvinylbutyral.

21. The composition according to claim 15, wherein said lubricant is magnesium stearate, talc, stearic acid, hydrogenated castor oil, or colloidal silicon dioxide.

22. The composition according to claim 11, wherein said ammonium methacrylate copolymer has a relative molecular weight of 100,000 to 200,000 and contains 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 to 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

23. The composition according to claim 11, wherein said ammonium methacrylate copolymer comprises a 1:

10 to 10;

1 ratio of an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 molar part of (trimethylammonio)-ethyl methacrylate to an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 2 molar parts of methyl methacrylate, 1 molar part of ethyl methacrylate and 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

24. The composition according to claim 11, wherein said hydroxypropyl methylcellulose contains 20 to 30% by weight of methoxy groups and 5 to 12% by weight of hydroxypropyl groups and has a viscosity of 3 to 100,000 cP in a 2% aqueous solution.

25. The composition according to claim 11, wherein said hydroxypropyl methylcellulose in said second layer has a viscosity higher than 1000 cP in a 2% aqueous solution.

26. A diffusion-osmotic controlled drug-release pharmaceutical composition comprising a two-layer tablet core, wherein the first layer of said two-layer tablet core contains a therapeutically active agent, 5 to 30% by weight of hydroxypropyl methylcellulose, 0 to 90% by weight of filling material, at most 5% by weight of binding material and at most 5% by weight of lubricant in relation to the total weight of said first layer;

and the second layer of said two-layer tablet core contains 30 to 100% by weight of hydroxypropyl methylcellulose having a viscosity higher than 1000 cP in 2% aqueous solution, 0 to 70% by weight of filling material, 0 to 5% by weight of binding material and 0 to 5% by weight of lubricant in relation to the total weight of said second layer;

said two-layer tablet core being covered with a polymeric film-coat containing an ammonium methacrylate copolymer, the part of said film-coat in contact with said first layer contains at least one bore and the part of said film-coat in contact with said second layer optionally contains at least one bore, said film-coat being present in amount of 3 to 25 mg/cm² in relation to the surface of said two-layer tablet core.

27. A process for the preparation of a diffusion-osmotic controlled drug-release pharmaceutical composition comprising a tablet core containing a therapeutically active agent and a hydrophilic polymer, and said tablet core is coated with a polymeric film-coat, wherein said film-coat contains at least one bore in said film-coat in contact with said tablet core;

said process comprising using hydroxypropyl methylcellulose as said hydrophilic polymer and an ammonium methacrylate copolymer as said coating material in an amount of 3 to 25 mg/cm² in relation to the surface of said tablet core.

28. The process according to claim 27, comprising using 5 to 30% by weight of said hydroxypropyl methylcellulose in relation to the weight of said tablet core.

29. The process according to claim 27, comprising using in said tablet core 0 to 90% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said tablet core.

30. The process according to claim 29, wherein said filling material is cellulose, microcrystalline cellulose, starch, lactose, mannitol, or secondary calcium phosphate.

31. The process according to claim 29, wherein said binding material is hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethylcellulose, gelatine, water-soluble starch, polyvinylalcohol, polyoxyethyleneglycol, or polyvinylbutyral.

32. The process according to claim 29, wherein said lubricant is magnesium stearate, talc, stearic acid, hydrogenated castor oil, or colloidal silicon dioxide.

33. The process according to claim 27, wherein said ammonium methacrylate copolymer has a relative molecular weight of 100,000 to 200,000 and contains 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 to 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

34. The process according to claim 27, wherein said ammonium methacrylate copolymer comprises a 1:

10 to 10;

1 ratio of an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 molar part of (trimethylammonio)-ethyl methacrylate to an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 2 molar parts of methyl methacrylate, 1 molar part of ethyl methacrylate and 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

35. The process according to claim 27, wherein said hydroxypropyl methylcellulose contains 20 to 30% by weight of methoxy groups and 5 to 12% by weight of hydroxypropyl groups and has a viscosity of 3 to 100,000 cP in a 2% aqueous solution.

36. A process for the preparation of a diffusion-osmotic controlled drug-release pharmaceutical composition comprising a tablet core containing a therapeutically active agent and hydroxypropyl methylcellulose, wherein said tablet core is coated with a polymeric film-coat of an ammonium methacrylate copolymer, and said film-coat contains at least one bore in said film-coat in contact with said tablet core;

said process comprising mixing a therapeutically active agent with 5 to 30% by weight of hydroxypropyl methylcellulose and 0 to 90% by weight of filling material in relation to the total weight of said tablet core to form a mixture;

mixing at most 5% by weight of lubricant with said mixture directly or after granulating with at most 5% by weight of binding material;

preparing said tablet core by compression;

coating said tablet core with an ammonium methacrylate copolymer in an amount of 3 to 25 mg/cm² in relation to the surface of said tablet core to form a film-coat on said tablet core; and

establishing at least one bore of 0.01 to 1.0 mm² in cross-section on said film-coat.

37. The process according to claim 36, wherein said ammonium methacrylate copolymer is in an aqueous dispersion or solution with ethanol, isopropanol, acetone or mixtures thereof.

38. A process for the preparation of a diffusion-osmotic controlled drug-release pharmaceutical composition comprising a two-layer tablet core, wherein the first layer of said two-layer tablet core contains a therapeutically active agent and a hydrophilic polymer, wherein the second layer of said two-layer tablet core contains a hydrophilic polymer, wherein said two-layer tablet core is covered with a polymeric film-coat of an ammonium methacrylate copolymer, the part of said film-coat in contact with said first layer contains at least one bore and the part of said film-coat in contact with said second layer optionally contains at least one bore;

said process comprising using hydroxypropyl methylcellulose as said hydrophilic polymer and an ammonium methacrylate copolymer as said coating material in an amount of 3 to 25 mg/cm² in relation to the surface of said two-layer tablet core.

39. The process according to claim 38, comprising using in said first layer 5 to 30% by weight of said hydroxypropyl methylcellulose in relation to the weight of said first layer.

40. The process according to claim 38, comprising using in said second layer 30 to 100% by weight of said hydroxypropyl methylcellulose in relation to the weight of said second layer.

41. The process according to claim 38, comprising using in said first layer 0 to 90% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said first layer.

42. The process according to claim 38, comprising using in said second layer 0 to 70% by weight of filling material, 0 to 5% by weight of binding material, and 0 to 5% by weight of lubricant in relation to the weight of said second layer.

43. The process according to claim 41, wherein said filling material is cellulose, microcrystalline cellulose, starch, lactose, mannitol, or secondary calcium phosphate.

44. The process according to claim 41, wherein said binding material is hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethylcellulose, gelatine, water-soluble starch, polyvinylalcohol, polyoxyethyleneglycol, or polyvinylbutyral.

45. The process according to claim 41, wherein said lubricant is magnesium stearate, talc, stearic acid, hydrogenated castor oil, or colloidal silicon dioxide.

46. The process according to claim 38, wherein said ammonium methacrylate copolymer has a relative molecular weight of 100,000 to 200,000 and contains 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 to 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

47. The process according to claim 38, wherein said ammonium methacrylate copolymer comprises a 1:

10 to 10;

1 ratio of an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 1 molar part of ethyl acrylate, 2 molar parts of methyl methacrylate and 0.1 molar part of (trimethylammonio)-ethyl methacrylate to an ammonium methacrylate copolymer with a relative molecular weight of 150,000 containing 2 molar parts of methyl methacrylate, 1 molar part of ethyl methacrylate and 0.2 molar part of (trimethylammonio)-ethyl methacrylate.

48. The process according to claim 38, wherein said hydroxypropyl methylcellulose contains 20 to 30% by weight of methoxy groups and 5 to 12% by weight of hydroxypropyl groups and has a viscosity of 3 to 100,000 cP in a 2% aqueous solution.

49. The process according to claim 38, wherein said hydroxypropyl methylcellulose in said second layer has a viscosity higher than 1000 cP in a 2% aqueous solution.

50. A process for the preparation of a diffusion-osmotic controlled drug-release pharmaceutical composition comprising a two-layer tablet core, wherein the first layer of said two-layer tablet core contains a therapeutically active agent and hydroxypropyl methylcellulose, wherein the second layer of said two-layer tablet core contains hydroxypropyl methylcellulose, wherein said two-layer tablet core is covered with a polymeric film-coat of an ammonium methacrylate copolymer, the part of said film-coat in contact with said first layer contains at least one bore and the part of said film-coat in contact with said second layer optionally contains at least one bore;

said process comprising mixing a therapeutically active agent with 5 to 30% by weight of hydroxypropyl methylcellulose and 0 to 90% by weight of filling material in relation to the total weight of said first layer to form a mixture;

mixing at most 5% by weight of lubricant with said mixture directly or after granulating with at most 5% by weight of binding material;

preparing said first layer by compression;

preparing a two-layer tablet core by pressing onto said first layer said second layer (i) consisting of hydroxypropyl methylcellulose having a viscosity higher than 1000 cP in 2% aqueous solution or (ii) containing 30 to 100% by weight of hydroxypropyl methylcellulose having a viscosity higher than 1000 cP in 2% aqueous solution, 0 to 70% by weight of filling material, 0 to 5% by weight of binding material and 0 to 5% by weight of lubricant in relation to the total weight of said second layer;

coating said two-layer tablet core with an ammonium methacrylate copolymer in an amount of 3 to 25 mg/cm² in relation to the surface of said two-layer tablet core to form a film-coat on said two-layer tablet core; and

establishing at least one bore on said film-coat in contact with said first layer and optionally at least one bore on said film-coat in contact with said second layer.

51. The process according to claim 50, wherein said ammonium methacrylate copolymer is in an aqueous dispersion or solution with ethanol, isopropanol, acetone or mixtures thereof.