Flocculated suspension of megestrol acetate

• US 6,593,318 B2
• Filed: 01/09/2001
• Issued: 07/15/2003
• Est. Priority Date: 04/20/1998
• Status: Expired due to Term

• Current Assignee: Par Pharmaceutical Companies Incorporated (Endo International PLC)
• Original Assignee: Pharmaceutical Resources Incorporated (Endo International PLC)
• Inventors: Femia, Robert A., Ragunathan, Narayan, Chao, James C., Ross, Malcolm S. F.
• Primary Examiner(s): Dees, Jose′ G.
• Assistant Examiner(s): George, Konata M.
• Application Number:
  US09/757,261
• Publication Number:
  US 20010048931A1
• Time in Patent Office: 917 Days
• Field of Search: 514/178, 424/722
• US Class Current: 514/178
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00

Abstract

A novel oral pharmaceutical composition in the form of a stable flocculated suspension in water is described as comprising: megestrol acetate; at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present.

Claims

1. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, said composition comprising;

(a) micronized megestrol acetate;

(b) about 10 to 40% by weight of at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and

(c) about 0.0001 to 0.03% by weight of a surfactant,

wherein polysorbate and polyethylene glycol are not simultaneously present in said composition.

2. The method of claim 1, wherein the surfactant comprises a hydrophobic moiety having a straight carbon chain of up to 20 atoms.

3. The method of claim 2, wherein the straight carbon chain is less than 10 carbon atoms in length.

4. The method of claim 1, wherein the surfactant is non-ionic.

5. The method of claim 4, wherein the surfactant is selected from the group consisting of alkanolamides, ethoxylated alcohols, carboxylic acids, amines, alcohol amides, alcohol phenol, glyceryl esters, sorbitan esters, polyoxyethylene esters and phosphate esters.

6. The method of claim 4, wherein the surfactant is polysorbate.

7. The method of claim 4, wherein the surfactant is polyoxyethylene 2, 4, 6, 8, 12, 20, 30, 40, 50, 100, or 150 stearate.

8. The method of claim 1, wherein the surfactant is cationic.

9. The method of claim 8, wherein the surfactant is selected from the group consisting of cetyldimethylethylammonium bromide and quatemary amines.

10. The method of claim 8, wherein the surfactant is cetyldimethylethylammonium bromide.

11. The method of claim 1, wherein the surfactant is anionic.

12. The method of claim 11, wherein the surfactant is selected from the group consisting of salts of sulphonic acids, fatty alkyl suiphosuccinates, fatty alkyl ether suiphosuccinates, acyl sarcosinates, acyl taurides, paraffin sulphonates and salts of alkaline earth metals.

13. The method of claim 11, wherein the surfactant is docusate sodium.

14. The method of claim 13, wherein the concentration of docusate sodium is about 0.0001 to 0.03% weight/volume.

15. The method of claim 1, wherein the megestrol acetate is micronized.

16. The method of claim 1, wherein component (b) comprises a mixture of two compounds.

17. The method of claim 16, wherein the compounds are glycerol and sorbitol.

18. The method of claim 17, wherein the concentration of each of glycerol and sorbitol is up to about 20% weight/volume.

19. An oral pharmaceutical composition in the form of a stable flocculated suspension in water comprising:

(a) megestrol acetate;

(b) at least two compounds selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and

(c) a surfactant.

20. The composition of claim 19, wherein the surfactant is non-ionic.

21. The composition of claim 20, wherein the surfactant is polysorbate.

22. The composition of claim 19, wherein the surfactant is cationic.

23. The composition of claim 19, wherein the surfactant is anionic.

24. The composition of claim 23, wherein the surfactant is docusate sodium.

25. The composition of claim 19, wherein the megestrol acetate is micronized.

26. The composition of claim 19, wherein the concentration of megestrol acetate is about 10 to 200 mg per ml of said composition, and the total concentration of all compounds (b) present is up to 40% weight/volume.

27. The composition of claim 26, wherein the concentration of megestrol acetate is about 20 to 60 mg per ml of said composition, and the total concentration of all compounds (b) present is up to 30% weight/volume.

28. The composition of claim 19, wherein component (b) comprises a mixture of two compounds of which one is glycerol.

29. The composition of claim 19, wherein component (b) comprises a mixture of two compounds of which one is sorbitol.

30. The composition of claim 29, wherein component (b) comprises a mixture of sorbitol and polyethylene glycol.

31. The composition of claim 30, wherein the concentration of megestrol acetate is micronized and is about 20 to 60 mg per ml of said composition, and the total concentration of compounds (b) is up to 25% weight/volume.

32. The composition of claim 19 component (b) comprises a mixture of two compounds of which one is propylene glycol.

33. The composition of claim 32 wherein component (b) comprises a mixture of propylene glycol and sorbitol.

34. The composition of claim 32 wherein component (b) comprises a mixture of propylene glycol and polyethylene glycol.

35. The composition of claim 19, wherein component (b) comprises a mixture of two compounds of which one is polyethylene glycol.

36. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 35.

37. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 31.

38. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 29.

39. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 26.

40. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 23.

63. A composition as in claim 20 wherein the surfactant is polysorbate 80.

41. An oral pharmaceutical composition in the form of a stable flocculated suspension in water comprising:

(a) megestrol acetate;

(b) at least one compound selected from the group consisting of propylene glycol, glycerol, and sorbitol; and

(c) a surfactant.

42. The composition of claim 41, wherein the surfactant is non-ionic.

43. The composition of claim 42, wherein the surfactant is polysorbate.

44. The composition of claim 41, wherein the surfactant is cationic.

45. The composition of claim 41, the surfactant is anionic.

46. The composition of claim 45, wherein the surfactant is docusate sodium.

47. The composition of claim 41, wherein the megestrol acetate is micronized.

48. The composition of claim 41, wherein the concentration of megestrol acetate is about 10 to 200 mg per ml of said composition, and the total concentration of all compounds (b) present is up to 40% weight/volume.

49. The composition of claim 48, wherein the concentration of megestrol acetate is about 20 to 60 mg per ml of said composition, and the total concentration of all compounds (b) present is up to 30% weight/volume.

50. The composition of claim 41, wherein component (b) comprises glycerol.

51. The composition of claim 41, wherein component (b) comprises sorbitol.

52. The composition of claim 51, wherein the concentration of megestrol acetate is micronized and is about 20 to 60 mg per ml of said composition, and the total concentration of all compounds (b) present is up to 25% weight/volume.

53. The composition of claim 41, wherein component (b) comprises propylene glycol.

54. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 52.

55. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 51.

56. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 48.

57. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 41.

58. A method of treating a neoplastic condition comprising administering to a subject suffering from said condition an oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months, wherein said composition is a composition of claim 44.

59. An oral pharmaceutical composition in the form of a stable flocculated suspension in water said composition comprising:

(a) about 10 to 200 mg per ml megestrol acetate;

(b) about 10 to 40% by weight of at least one compound selected from the group consisting of propylene glycol, glycerol, and sorbitol; and

(c) about 0.0001 to 0.03% by weight of a surfactant.

60. A composition as in claim 59 the compound selected from group (b) is sorbitol.

61. A composition as in claim 60 the surfactant is docusate sodium.

62. A composition as in claim 60 wherein the surfactant is polysorbate.

64. An oral pharmaceutical composition in the form of a stable flocculated suspension in water said composition comprising:

(a) about 10-200 mg per ml megestrol acetate;

(b) about 10 to 40% w/v of sorbitol;

(c) about 0.0001 to 0.03% w/v of a surfactant;

(d) about 0.1-0.35% w/v xanthan gum

(e) citric acid

(f) sodium citrate

(g) about 0.1-0.0.3% w/v of sodium benzoate.

65. A composition as in claim 64 wherein the surfactant is polysorbate 80.

66. A composition as in claim 65 further comprising propylene glycol.

67. A composition as in claim 66 further comprising polyethylene glycol.

68. A composition as in claim 67 which is capable of being redispersed after being allowed to settle at 40°

C. and 75% relative humidity for a period of three months.