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Claims for Patent: 6,410,054

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Claims for Patent: 6,410,054

Title: Immediate release eplerenone compositions
Abstract:The invention relates to oral pharmaceutical compositions useful as aldosterone receptor blockers comprising the active agent micronized eplerenone in an amount of about 10 mg to about 1000 mg and one or more carrier materials.
Inventor(s): Thosar; Shilpa S. (Des Plaines, IL), Gokhale; Rajeev D. (Waukegan, IL), Tolbert; Dwain S. (Wadsworth, IL)
Assignee: G. D. Searle & Co. (Skokie, IL)
Application Number:09/456,614
Patent Claims: 1. A pharmaceutical composition comprising (a) particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns, in an amount of about 10 mg to about 1000 mg, and (b) one or more pharmaceutically acceptable carrier materials; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C.

2. The pharmaceutical composition according to claim 1 wherein said eplerenone is in an amount of about 20 mg to about 400 mg.

3. The pharmaceutical composition according to claim 1 wherein said epletenone is in an amount of about 25 mg to about 150 mg.

4. The pharmaceutical composition according to claim 1 wherein said eplerenone is in an amount of about 25 mg to about 100 mg.

5. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more materials selected from the group consisting of purified cellulose, microcrystalline cellulose, and alkylcelluloses and their derivatives and salts.

6. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable binding agents in a total amount of about 0.5% to about 25% by weight of the composition.

7. The pharmaceutical composition according to claim 6 wherein said binding agents are selected from the group consisting of acacia, tragacanth, sucrose, gelatin, glucose, starch, celluloses, alginic acid and salts thereof, magnesium aluminum silicate, polyethylene glycol, gums, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and pregelatinized starch.

8. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable diluents in a total amount of about 5% to about 99% by weight of the composition.

9. The pharmaceutical composition according to claim 8 wherein said diluents are selected from the group consisting of lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, and bentonite.

10. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable disintegrants in a total amount of about 0.5% to about 30% by weight of the composition.

11. The pharmaceutical composition according to claim 10 wherein said disintegrants are selected from the group consisting of starches, sodium starch glycolate, clays, celluloses, alginates, pregelatinized corn starches, crospovidone, and gums.

12. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable wetting agents in a total amount of about 0.1% to about 15% by weight of the composition.

13. The pharmaceutical composition according to claim 12 wherein said wetting agents are selected from the group consisting of oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, and sodium lauryl sulfate.

14. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable lubricants in a total amount of about 0.1% to about 10% by weight of the composition.

15. The pharmaceutical composition according to claim 14 wherein said lubricants are selected from the group consisting of glyceryl behapate, magnesium, calcium and sodium stearates, stearic acid, hydrogenated vegetable oils, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate.

16. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more pharmaceutically acceptable anti-adherents or glidants in a total amount of about 0.25% to about 10% by weight of the composition.

17. The pharmaceutical composition according to claim 16 wherein said anti-adherents or glidants are selected from the group consisting of talc, corn starch, DL-leucine, sodium lauryl sulfate, and magnesium, calcium and sodium stearates.

18. The pharmaceutical composition according to claim 1 wherein said eplerenone is present in an amount of about 1% to about 90% by weight of the composition.

19. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise one or more materials selected from the group consisting of diluents, binding agents, disintegrants, wetting agents, lubricants, anti-adherents and glidants.

20. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise hydroxypropylmethylcellulose.

21. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise lactose.

22. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise microcrystalline cellulose.

23. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise croscarmellose sodium.

24. The pharmaceutical composition according to claim 1 wherein said carrier materials comprise (a) lactose in an amount of about 5% to about 90%; (b) microcrystalline cellulose in an amount of about 5% to about 90%; and (c) hydroxypropylmethylcellulose in an amount of about 0.5% to about 10%; all by weight of the composition.

25. The pharmaceutical composition according to claim 24 wherein said eplerenone is in an amount of about 1% to about 90% by weight of the composition.

26. The pharmaceutical composition according to claim 25 that comprises:

about 19% to about 40% by weight of eplerenone;

about 32% to about 52% by weight of lactose;

about 8% to about 28% by weight of microcrystalline cellulose; and about 1% to about 8% by weight of hydroxypropylmethylcellulose.

27. The pharmaceutical composition according to claim 25 that comprises:

about 24% to about 35% by weight of eplerenone;

about 37% to about 47% by weight of lactose;

about 13% to about 23% by weight of microcrystalline cellulose; and

about 2% to about 4% by weight of hydroxypropylmethylcellulose; and that further comprises:

about 2% to about 6% by weight of croscarmellose sodium.

28. The pharmaceutical composition according to claim 27 that comprises:

about 28% to about 31% by weight of eplerenone;

about 41% to about 43% by weight of lactose monohydrate;

about 17% to about 19% by weight of microcrystalline cellulose;

about 2.5% to about 3.5% by weight of hydroxypropylmethylcellulose; and

about 4.5% to about 5.5% by weight of croscarmellose sodium.

29. The pharmaceutical composition according to claim 28 that is a coated or uncoated unit dosage tablet, and that prior to coating comprises:

about 29.4% by weight of eplerenone;

about 42% by weight of lactose;

about 18.1% by weight of microcrystalline cellulose;

about 3% by weight of hydroxypropylmethylcellulose;

about 5% by weight of croscarmellose sodium;

about 1% by weight of talc; and

about 0.5% by weight of magnesium stearate.

30. The pharmaceutical composition according to claim 1 wherein said eplerenone is in an amount of about 23 mg to about 27 mg, and wherein said carrier materials comprise:

about 34 mg to about 38 mg lactose;

about 14 mg to about 17 mg microcrystalline cellulose;

about 1 mg to about 4 mg hydroxypropylmethylcellulose;

about 3 mg to about 6 mg croscarmellose sodium;

about 0.25 mg to about 1.5 mg sodium lauryl sulfate;

about 0.25 mg to about 1.5 mg talc; and

about 0.1 mg to about 1 mg magnesium stearate.

31. The pharmaceutical composition according to claim 1 wherein said eplerenone is in an amount of about 48 mg to about 52 mg, and wherein said carrier materials comprise:

about 70 mg to about 1 mg lactose;

about 29 mg to about 33 mg microcrystalline cellulose;

about 4 mg to about 6 mg hydroxypropylmethylcellulose;

about 6 mg to about 10 mg croscarmellose sodium;

about 1 mg to about 2.5 mg sodium lauryl sulfate;

about 1 mg to about 2.5 mg talc; and

about 1 mg to about 1.5 mg magnesium stearate.

32. The pharmaceutical composition according to claim 1 wherein said eplerenone is in an amount of about 98 mg to about 102 mg, and wherein said carrier materials comprise:

about 141 mg to about 145 mg lactose;

about 60 mg to about 64 mg microcrystalline cellulose;

about 9 mg to about 11 mg hydroxypropylmethylcellulose;

about 16 mg to about 18 mg croscarmellose sodium;

about 3 mg to about 4 mg sodium lauryl sulfate;

about 3 mg to about 4 mg talc; and

about 1 mg to about 2 mg magnesium stearate.

33. The pharmaceutical composition according to claim 1 that is in a unit oral dosage form.

34. The pharmaceutical composition according to claim 1 that is in a form of a unit dosage tablet or capsule.

35. The pharmaceutical composition according to claim 1 that is in a form of a unit dosage tablet.

36. The pharmaceutical composition according to claim 35 wherein the tablet is coated.

37. The pharmaceutical composition according to claim 1 that is in a form of a unit dosage tablet or capsule having a 25 mg, 50 mg or 100 mg dose of said eplerenone.

38. A pharmaceutical composition comprising (a) particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns, and (b) one or more pharmaceutically acceptable carrier materials; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C., and being suitable for once or twice a day oral administration as an aldosterone receptor blocker.

39. The pharmaceutical composition of claim 1 that provides a therapeutic effect as an aldosterone receptor blocker in a human subject over an interval of about 12 to about 24 hours after ingestion of the composition.

40. The pharmaceutical composition of claim 1 that provides a therapeutic effect as an aldosterone receptor blocker in a human subject over an interval of about 24 hours after ingestion.

41. The pharmaceutical composition of claim 1 that releases at least 50% of said eplerenone in vitro within 20 minutes in 0.1N HCl.

42. The pharmaceutical composition of claim 41 that is in a form of a unit dosage tablet or capsule suitable for once or twice a day oral administration.

43. The pharmaceutical composition of claim 1 that is in a form of a unit dosage tablet or capsule suitable for once a day oral administration, and that releases at least 50% of said eplerenone in vitro within 15 minutes in 0.1N HCl.

44. The pharmaceutical composition of claim 34 wherein said unit dosage form is a capsule prepared by direct encapsulation or a tablet prepared by direct compression.

45. The pharmaceutical composition of claim 33 wherein said unit dosage form is prepared by wet granulation followed by encapsulation to form a capsule or compression to form a tablet.

46. The pharmaceutical composition of claim 33 wherein said unit dosage form is prepared by dry granulation followed by encapsulation to form a capsule or compression to form a tablet.

47. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 25 to about 200 microns.

48. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 25 to about 150 microns.

49. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 30 to about 110 microns.

50. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 30 to about 50 microns.

51. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 50 to about 150 microns.

52. The pharmaceutical composition of claim 1 wherein said eplerenone has a D.sub.90 particle size of about 75 to about 125 microns.

53. A pharmaceutical composition comprising (a) particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns, and (b) one or more pharmaceutically acceptable carrier materials; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C., and wherein ingestion of the composition by a human subject causes an average increase of at least about 10% in blood serum renin concentration in the subject over an interval of about 12 to about 24 hours after said ingestion.

54. A pharmaceutical composition comprising (a) particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns, and (b) one or more pharmaceutically acceptable carrier materials; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C., and wherein ingestion of the composition by a human subject causes an average increase of at least about 50% in blood serum aldosterone concentration in the subject over an interval of about 12 to about 24 hours after said ingestion.

55. A pharmaceutical composition comprising (a) particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns, and (b) one or more pharmaceutically acceptable carrier materials; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C., and wherein ingestion of the composition by a human subject causes an average decrease of at least about 5% in diastolic blood pressure in the subject over an interval of about 12 to about 24 hours after said ingestion.

56. A method of treating a condition or disorder where treatment with an aldosterone receptor blocker is indicated, the method comprising orally administering the composition according to claim 1 to a patient in need of such treatment.

57. The method of claim 56 wherein the condition or disorder is heart failure.

58. The method of claim 56 wherein the condition or disorder is hypertension.

59. The method of claim 56 wherein the condition or disorder is edema associated with liver insufficiency.

60. The method of claim 56 wherein the condition or disorder is postmyocardial inferction.

61. A method of treating a condition or disorder where treatment with an aldosterone receptor blocker is indicated, the method comprising orally administering the composition according to claim 18 to a patient in need of such treatment.

62. A method of treating a condition or disorder where treatment with an aldosterone receptor blocker is indicated, the method comprising orally administering the composition according to claim 26 a patient in need of such treatment.

63. A method of preparing a pharmaceutical composition comprising:

wet granulating particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns and one or more carrier materials to form a wet granulated mixture; and

preparing an oral dosage form of the pharmaceutical composition from the wet granulated mixture; said composition being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C.

64. The method of claim 26 wherein the oral dosage form comprises said eplerenone in an amount of about 25 mg, 50 mg or 100 mg.

65. A method of use of particulate eplerenone having a D.sub.90 particle size of about 25 to about 400 microns and a cellulosic carrier material in manufacture of a medicament for treatment or prophylaxis of aldosterone mediated conditions or disorders, said medicament being an immediate release composition wherein about 50% of said eplerenone is dissolved in vitro within about 15 minutes in a 1% sodium dodecyl sulfate solution at 37.degree. C.
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