Sustained release metoprolol formulations

• US 20030228361A1
• Filed: 04/07/2003
• Published: 12/11/2003
• Est. Priority Date: 04/05/2002
• Status: Abandoned Application

• Current Assignee: Penwest Pharmaceuticals Company (Endo International PLC)
• Original Assignee: Penwest Pharmaceuticals Company (Endo International PLC)
• Inventors: Baichwal, Anand R., Sanghvi, Pradeepkumar P., Dinicola, Dean M., Woodcock, Paul, McCall, Troy W.
• Application Number:
  US10/408,739
• Publication Number:
  US 20030228361A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to a sustained release oral dosage forms containing a therapeutically effective amount of metoprolol tartrate, methods of preparing such formulations, and to methods of treatment utilizing such formulations.

Claims

1. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising from about 12.5 to about 400 mg of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml when the dosage form contains 100 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

2. The sustained release oral dosage form of claim 1, wherein said mean Cmax of metoprolol is from about 15 ng/ml to about 30 ng/ml when the dosage form contains 100 mg metoprolol tartrate.

3. The sustained release oral dosage form of claim 1, wherein said oral dosage form provides a mean C_max of metoprolol from about 40 ng/ml to about 90 ng/ml when the dosage form contains 200 mg metoprolol tartrate.

4. The sustained release oral dosage form of claim 1, wherein said oral dosage form provides a mean C_max of metoprolol from about 5 ng/ml to about 30 ng/ml when the dosage form contains 50 mg metoprolol tartrate.

5. The sustained release oral dosage form of claim 1, wherein said oral dosage form provides a mean C_max of metoprolol from about 2 ng/ml to about 15 ng/ml when the dosage form contains 25 mg metoprolol tartrate.

6. The sustained release oral dosage form of claim 1, wherein said oral dosage form is substantially dose proportional.

7. The sustained release oral dosage form of claim 1, wherein said sustained release excipient is pre-agglomerated prior to incorporation of the metoprolol tartrate.

8. The sustained release oral dosage form of claim 1, wherein said dosage form provides a mean Tmax at from about 2.5 to about 20 hours after oral administration.

9. The sustained release oral dosage form of claim 1, wherein said dosage form provides a mean Tmax at from about 6 to about 16 hours after oral administration.

10. The sustained release oral dosage form of claim 1, wherein said sustained release matrix comprises a plurality of matrix multiparticulates.

11. The sustained release oral dosage form of claim 10, wherein said matrix multiparticulates are overcoated with a coating comprising a hydrophobic material.

12. The sustained release oral dosage form of claim 11, wherein said hydrophobic material is selected from the group consisting a hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic copolymer, hydrogenated vegetable oils, zein, and mixtures thereof.

13. The sustained release oral dosage form of claim 11, wherein said hydrophobic material is ethylcellulose.

14. The sustained release oral dosage form of claim 11, wherein said hydrophobic material comprises one or more ammonio methacrylate copolymers.

15. The sustained release oral dosage form of claim 1, wherein said dosage form is a compressed tablet.

16. The sustained release oral dosage form of claim 15, further comprising a coating over said compressed tablet;

said coating comprising a hydrophobic material.

17. The sustained release oral dosage form of claim 16, wherein said hydrophobic material is selected from the group consisting of a hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic acid copolymer, hydrogenated vegetable oils, zein, and mixtures thereof.

18. The sustained release oral dosage form of claim 1, wherein the sustained release excipient comprises a gelling agent selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.

19. The sustained release oral dosage form of claim 1, wherein the sustained release excipient comprises a heteropolysaccharide gum and a homopolysaccharide gum.

20. The sustained release oral dosage form of claim 19, wherein said heteropolysaccharide gum is xanthan gum and said homopolysaccharide gum is locust bean gum.

21. The sustained release oral dosage form of claim 1, wherein the sustained release excipient further comprises a ionizable gel strength-enhancing agent.

22. The sustained release oral dosage form of claim 21, wherein said ionizable gel strength-enhancing agent is selected from the group consisting of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, and mixtures thereof.

23. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising from about 12.5 to about 400 mg metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax at steady state of metoprolol from about 4 ng/ml to about 20 ng/ml when the dosage form contains 25 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

24. The sustained release oral dosage form of claim 23, wherein the Cmax at steady state of metoprolol is from about 6 ng/ml to about 15 ng/ml when the dosage form contains 25 mg metoprolol tartrate.

25. The sustained release oral dosage form of claim 23, wherein said dosage form provides a mean Tmax at from about 2.5 to about 20 hours after oral administration.

26. The sustained release oral dosage form of claim 23, wherein said dosage form provides a mean Tmax at from about 6 to about 16 hours after oral administration.

27. The sustained release oral dosage form of claim 23, wherein said sustained release matrix comprises a plurality of matrix multiparticulates.

28. The sustained release oral dosage form of claim 27, wherein said matrix multiparticulates are overcoated with a coating comprising a hydrophobic material.

29. The sustained release oral dosage form of claim 28, wherein said hydrophobic material is selected from the group consisting a hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic copolymer, hydrogenated vegetable oils, zein, and mixtures thereof.

30. The sustained release oral dosage form of claim 28, wherein said hydrophobic material is ethylcellulose.

31. The sustained release oral dosage form of claim 28, wherein said hydrophobic material comprises one or more ammonio methacrylate copolymers.

32. The sustained release oral dosage form of claim 23, wherein said dosage form is a compressed tablet.

33. The sustained release oral dosage form of claim 32, further comprising a coating over said compressed tablet;

said coating comprising a hydrophobic material.

34. The sustained release oral dosage form of claim 32, wherein said hydrophobic material is selected from the group consisting of a hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic acid copolymer, hydrogenated vegetable oils, zein, and mixtures thereof.

35. The sustained release oral dosage form of claim 23, wherein the sustained release excipient comprises a gelling agent selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.

36. The sustained release oral dosage form of claim 23, wherein the sustained release excipient comprises a heteropolysaccharide gum and a homopolysaccharide gum.

37. The sustained release oral dosage form of claim 36, wherein said heteropolysaccharide gum is xanthan gum and said homopolysaccharide gum is locust bean gum.

38. The sustained release oral dosage form of claim 23, wherein the sustained release excipient further comprises a ionizable gel strength-enhancing agent.

39. The sustained release oral dosage form of claim 38, wherein said ionizable gel strength-enhancing agent is selected from the group consisting of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, and mixtures thereof.

40. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising from about 12.5 mg to about 400 mg of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax at steady state of metoprolol from about 5 ng/ml to about 30 ng/ml when the dosage form contains 50 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

41. A sustained release oral dosage form comprising:

metoprolol tartrate in an amount of from about 12.5 mg to about 400 mg dispersed in a matrix comprising (i) a gelling agent said gelling agent in an amount of from about 10% to about 60% by weight of the dosage form, (ii) an inert pharmaceutical diluent in an amount of from about 5% to about 40% by weight of the dosage form, and (iii) an ionizable gel strength enhancing agent in an amount of from about 0.5% to about 16% by weight of the dosage form;

a hydrophobic coating coated over said matrix in an amount of from about 1% to about 20% by weight of the dosage form;

said dosage form providing for a sustained release of said metoprolol tartrate suitable for once a day administration.

42. The sustained release oral dosage form of claim 41, wherein said matrix is pre-agglomerated prior to incorporation of the metoprolol tartrate.

43. The sustained release oral dosage form of claim 41, wherein said gelling agent consists of a heteropolysaccharide gum and a homopolysaccharide gum.

44. The sustained release oral dosage form of claim 41, wherein said inert pharmaceutical diluent is mannitol.

45. A sustained release oral dosage form comprising:

a matrix comprising metoprolol tartrate in an amount of from about 12.5 mg to about 400 mg dispersed in a sustained release excipient comprising (i) locust bean gum in an amount of 5% to about 30% by weight of the oral dosage form and (ii) xanthan gum in an amount from about 5% to about 30% by weight of the oral dosage form, (iii) mannitol in an amount of from about 5% to about 40% by weight of the oral dosage form, and (iv) calcium sulfate dihydrate in an amount of about 0.5% to about 16% by weight of the oral dosage form; and

a hydrophobic coating coated over said matrix in an amount of from about 1% to about 20% by weight of the oral dosage form;

said dosage form providing for a sustained release of said metoprolol tartrate suitable for once-a-day administration.

46. A sustained release tablet formulation comprising:

a matrix core composition comprising

(a) metoprolol tartrate in an amount of from about 12.5 mg to about 400 mg;

(b) a cellulose derivative selected from the group consisting of an alkylcellulose, hydroxyalkylcellulose, hydroxypropylalkylcellulose, or mixtures thereof; and

(c) a sustained release excipient comprising a gelling agent in an amount of about 10% to about 60% by weight of the formulation;

an inert diluent in an amount of from about 5% to about 40% by weight of the formulation; and

an ionizable gel strength enhancing agent in an amount of from about 0.5% to about 16% by weight of the formulation; and

a coating over said core comprising

(a) a hydrophobic material in an amount of from about 2% to about 15% by weight of the formulation;

said formulation providing for a sustained release of said metoprolol tartrate suitable for once-a-day administration.

47. The sustained release tablet formulation of claim 46, wherein said hydrophobic material is selected from the group consisting of a hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic acid copolymer, hydrogenated vegetable oils, zein, and mixtures thereof

48. The sustained release tablet formulation of claim 46, wherein said hydrophobic material is ethylcellulose.

49. The sustained release tablet formulation of claim 46, wherein said hydrophobic material comprises one or more ammonio methacrylate copolymers.

50. The sustained release formulation of claim 46, wherein said coating further comprises hydroxypropylmethylcellulose.

51. A sustained release excipient for the sustained release of an active agent comprising from about 20% to about 60% of a gelling agent by weight of said sustained release excipient, said gelling agent consisting of a heteropolysaccharide gum and a homopolysaccharide gum;

from about 1% to about 20% of an ionizable gel strength enhancing agent by weight of said sustained release excipient; and

from about 6% to about 60% of mannitol by weight of the sustained release excipient.

52. The sustained release excipient of claim 51, further comprising a cellulosic material selected from the group consisting of alkylcellulose, hydroxyalkylcellulose, hydroxypropylalkylcellulose, or mixtures thereof.

53. The sustained release excipient of claim 51, wherein said heteropolysaccharide gum is xanthan gum.

54. The sustained release excipient of claim 51, wherein said homopolysaccharide gum is locust gum.

55. The sustained release excipient of claim 51, wherein said ionizable gel strength enhancing agent is selected from the group consisting of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, and mixtures thereof.

56. The sustained release excipient of claim 51, wherein said ionizable gel strength enhancing agent is calcium sulfate dihydrate.

57. A method of treating a patient with hypertension comprising:

administering to said patient a sustained release oral dosage form comprising a sustained release matrix comprising from about 12.5 to about 400 mg of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml when the dosage form contains 100 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

58. The method of claim 57, wherein said mean Cmax of metoprolol is from about 15 ng/ml to about 30 ng/ml when the dosage form contains 100 mg metoprolol tartrate.

59. A method of reducing blood pressure comprising

administering to a human patient a sustained release oral solid dosage form comprising a sustained release matrix comprising about 12.5 to about 400 mg of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml when the dosage form contains 100 mg metoprolol tartrate, said dosage form providing a therapeutic effect for about 24 hours after oral administration.

60. A method of providing cardioselective antihypertensive therapy to a human patient comprising administering to said patient a sustained release oral dosage form comprising a sustained release matrix comprising about 12.5 to about 400 mg of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml when the dosage form contains 100 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

61. A method of preventing or reducing a mallaird-type reaction in a metoprolol tartrate sustained release oral dosage form comprising preparing said sustained release oral dosage form by combining a therapeutically effective amount of metoprolol tartrate with a sustained release excipient that provides for the sustained release of said metoprolol tartrate, and including in said dosage form an effective amount of mannitol to prevent or reduce the degradation of said metoprolol tartrate.

62. The method of claim 61, wherein said mannitol is included in said sustained release excipient prior to combining said excipient with said metoprolol tartrate.

63. The method of claim 61, wherein said mannitol is incorporated into said dosage when said metoprolol tartrate and said sustained release excipient are combined.

64. A method of preparing a sustained release tablet formulation of metoprolol tartrate for once-a-day administration comprising:

spray granulating a sustained release excipient and metoprolol tartrate with a suspension or solution comprising a cellulose derivative selected from the group consisting of an alkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, or mixtures thereof; and

tableting the resultant granulation such that each tablet provides a dose of metoprolol tartrate sufficient to provide a therapeutic effect for about 24 hours after oral administration.

65. The method of claim 64, further comprising overcoating the tablets with a coating comprising a hydrophobic material.

66. The method of claim 65, wherein the hydrophobic material is selected from the group consisting of hydrophobic polymer, a cellulosic material, an acrylic polymer, a methacrylic acid polymer, a methacrylic copolymer, hydrogenated vegetable oils, zein, and mixtures thereof.

67. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising a therapeutically effective amount of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml per 100 mg metoprolol tartrate, said dosage form providing a therapeutic effect for about 24 hours after oral administration.

69. A method of reducing blood pressure comprising administering a sustained release oral dosage form of claim 67 to a human patient.

70. A method of reducing blood pressure comprising administering a sustained release oral dosage form of claim 67 to a human subject.

71. A method of providing cardioselective antihypertensive therapy to a human patient comprising administering a sustained release oral dosage form of claim 67 to a patient in need of said therapy.

68. A method of treating a patient with hypertension comprising:

administering to said patient a sustained release oral dosage form comprising a sustained release matrix comprising a therapeutically effective amount of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax of metoprolol from about 10 ng/ml to about 40 ng/ml per 100 mg metoprolol tartrate;

said dosage form providing a therapeutic effect for about 24 hours after oral administration.

72. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising a therapeutically effective amount of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax at steady state of metoprolol from about 5 ng/ml to about 30 ng/ml per 50 mg metoprolol tartrate, said dosage form providing a therapeutic effect for about 24 hours after oral administration.

73. A sustained release oral solid dosage form comprising:

a sustained release matrix comprising a therapeutically effective amount of metoprolol tartrate and a sustained release excipient;

said oral dosage form providing a mean Cmax at steady state of metoprolol from about 4 ng/ml to about 20 ng/ml per 25 mg metoprolol tartrate, said dosage form providing a therapeutic effect for about 24 hours after oral administration.

74. A sustained release tablet formulation comprising:

about 31% by weight of metoprolol tartrate;

about 45% by weight of a sustained release excipient comprising xanthan gum, locust bean gum, calcium sulfate dihydrate, and mannitol;

about 3% by weight hydroxypropylmethylcellulose;

about 4% by weight talc;

about 2% by weight sodium stearyl fumarate;

about 9 to about 12% by weight hydrophobic coating material; and

about 3% by weight of a color coating material;

said formulation providing for the sustained release of said metoprolol tartrate.

75. The sustained release tablet formulation of claim 74, wherein said hydrophobic coating material comprises ethylcellulose in an amount of about 8% by weight of the formulation.

76. The sustained release tablet formulation of claim 74, wherein said sustained release excipient comprises about 20% by weight xanthan gum;

about 30% by weight locust bean gum;

about 10% by weight calcium sulfate dihydrate; and

about 40% by weight mannitol.

77. A sustained release tablet formulation comprising:

about 32% by weight of metoprolol tartrate;

about 48% by weight of a sustained release excipient comprising xanthan gum, locust bean gum, calcium sulfate dihydrate, and mannitol;

about 4% by weight hydroxypropylmethylcellulose;

about 4% by weight talc;

about 2% by weight sodium stearyl fumarate;

about 8% by weight hydrophobic coating material; and

about 3% by weight of a color coating material;

said formulation providing for the sustained release of said metoprolol tartrate.

78. The sustained release tablet formulation of claim 77, wherein said hydrophobic coating material comprises a combination of two ammonio methacrylate copolymers in a combined amount of about 5% by weight of the formulation.

79. The sustained release tablet formulation of claim 77, wherein said sustained release excipient comprises about 20% by weight xanthan gum;

about 30% by weight locust bean gum;

about 10% by weight calcium sulfate dihydrate; and

about 40% by weight mannitol.