PHARMACEUTICAL SUSPENSIONS, COMPOSITIONS AND METHODS

• US 20020146455A1
• Filed: 07/21/2000
• Published: 10/10/2002
• Est. Priority Date: 07/21/2000
• Status: Active Grant

• Current Assignee: Actavis Mid Atlantic LLC (Abbvie Incorporated)
• Original Assignee: Alpharma USPD Inc. (Zoetis, Inc.)
• Inventors: KUNDU, SUBHAS, DESAI, VIVEK, CAMERON, ANDREA
• Granted Patent: US 6,656,505 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00

Abstract

Abstract of Disclosure

An aqueous pharmaceutical composition suitable for oral delivery has an insoluble active substance and a wetting agent in liquid suspension. The composition contains floccules of the active ingredient. The formulation has an excellent shelf-life in which caking and sedimentation are inhibited. The composition may be resuspended upon light to moderate shaking.

Claims

1. A composition comprising at least one insoluble active substance together with at least one wetting agent, wherein the concentration of said wetting agent is sufficient to form a stable, flocculated suspension of said active substance.

2. The composition of claim 1, wherein said wetting agent is within the range of about 0.01% to about 0.04% w/w.

3. The composition of claim 1, wherein the concentration of said wetting agent is about 0.02% w/w.

4. The composition of claim 1, wherein said active substance is megestrol acetate and said wetting agent is docusate sodium.

5. The composition of claim 1, wherein the concentration of said active substance is within the range of about 0.1% to about 25% w/v.

6. The composition of claim 1, wherein the concentration of said active substance is within the range of about 1 to about 5% w/v.

7. The composition of claim 1, wherein the concentration of said active substance is about 4% w/v.

8. The composition of claim 1, further comprising at least one water-soluble polymer.

9. The composition of claim 8, wherein said polymer is present at a concentration of greater than about 5% w/w.

10. The composition of claim 8, wherein said polymer is present at a concentration of within the range of about 10% to about 30% w/w.

11. The composition of claim 8, wherein said polymer is present at a concentration of about 20% w/w.

12. The composition of claim 8, wherein said polymer is polyethylene glycol.

13. The composition of claim 1, further comprising at least one hydrocolloid.

14. The composition of claim 13, wherein said hydrocolloid is at least one material selected from the group consisting of pharmaceutically acceptable gums.

39. The composition of claim 1, wherein said wetting agent is within the range of about 0.001 to about 0.05% w/w.

15. A method for forming an aqueous flocculated suspension containing an insoluble micronized active substance together with a wetting agent to form a stable, resuspendable flocculated suspension of said active substance, which comprises adding said wetting agent in an amount below which the floccule size of said active substance in said suspension starts to increase.

16. The method of claim 15, wherein said active substance is megestrol acetate.

17. The method of claim 15, wherein said wetting agent is docusate sodium.

18. The method of claim 17, which comprises adding said docusate sodium in an amount of about 0.01 to about 0.04% w/w.

19. The method of claim 17, which comprises adding said docusate sodium in an amount of about 0.02% w/w.

20. The method of claim 15, wherein said flocculated suspension comprises floccules having a mean floc size diameter of at least about 12 microns.

21. The method of claim 15, wherein said flocculated suspension comprises floccules having a mean floc size diameter of about 12 to about 50 microns.

22. The method of claim 15, wherein said flocculated suspension comprises floccules having a mean floc size diameter of about 23 to about 28 microns.

51. The method of claim 16 wherein said wetting agent is docusate sodium in an amount of about 0.0001 to about 0.03% by weight of said suspension.

52. The method of claim 51 further comprising adding glycerol to said suspension in an amount of about 10% to about 40% by weight of said suspension.

53. The method of claim 52 wherein said suspension is capable of being redispersed after being allowed to settle at a temperature of 40 degrees C and 75% relative humidity for a period of three months.

23. An oral pharmaceutical composition, comprising:

a) about 0.5 to about 10% w/v of megestrol acetate;

b) about 0.01 to about 0.04% w/w of docusate sodium; and

c) about 10 to about 30% w/w of at least one suspending agent.

24. The composition of claim 23, comprising about 0.01 to about 0.025% w/w of docusate sodium.

25. The composition of claim 23, wherein said suspending agent is polyethylene glycol.

26. The composition of claim 24, comprising about 0.01 to about 0.02% w/w of docusate sodium.

27. The composition of claim 23, wherein said suspending agent is xanthan gum.

28. The composition of claim 27, wherein said suspending agent is present in said composition in an amount of from about 0.1 to about 0.3% w/w.

29. The composition of claim 23, wherein said composition contains floccules having a mean floc size diameter of at least about 12 microns.

30. The composition of claim 23, wherein said composition contains floccules having a mean floc size diameter of at least about 21 microns.

54. The composition of claim 23 wherein said megestrol acetate is micronized and said composition is a stable flocculated suspension in water.

55. The composition of claim 54 wherein said suspending agent is glycerol.

56. The composition of claim 55 wherein said suspension is capable of being redispersed after being allowed to settle at a temperature of about 40 degrees C and about 75% relative humidity for a period of three months.

57. The composition of claim 56 wherein polysorbate and polyethylene glycol are not simultaneously present in said composition.

31. An oral composition, comprising about 1 to about 8% w/v of megestrol acetate, a first suspending agent consisting essentially of about 15 to about 25% w/w of polyethylene glycol;

a wetting agent consisting essentially of 0.01 to about 0.04% of docusate sodium w/w; and

further comprising from about 0.1 to about 0.3% w/w of xanthan gum.

32. The composition of claim 31, wherein said composition is in the form of an aqueous flocculated suspension which is storage stable for at least about 3 months.

33. The composition of claim 31, wherein said composition is storage stable for at least about 12 months.

34. A method of forming an oral pharmaceutical composition, comprising:

combining a first portion of polyethylene glycol with xanthan gum and water in a first vessel;

combining a second portion of polyethylene glycol, docusate sodium and megestrol acetate in a second vessel;

combining the contents of said first vessel with the contents of said second vessel.

35. A method of forming an oral pharmaceutical composition, comprising:

combining a first portion of polyethylene glycol, a first portion of water , docusate sodium and megestrol acetate in a first vessel;

combining xanthan gum, a second portion of water and a second portion of polyethylene glycol in a second vessel; and

combining the contents of said first vessel with the contents of said second vessel.

36. An oral pharmaceutical composition in the form of a stable flocculated suspension in water capable of being redispersed after being allowed to settle at a temperature of 40º

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

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

(b) about 10 to about 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 about 0.03% by weight of a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present in said composition.

37. The composition of claim 36, wherein the surfactant is anionic.

38. The composition of claim 37, wherein the surfactant is docusate sodium.

48. The composition of claim 36 comprising glycerol.

49. The composition of claim 48 wherein said surfactant is an anionic surfactant.

50. The composition of claim 49 wherein said surfactant is docusate sodium.

40. An aqueous pharmaceutical composition comprising about 10 to about 200 mg per mL micronized megestrol acetate together with at least one water soluble polyhydric alcohol, and at least one surfactant selected from the group consisting of docusate sodium and polyoxyethylene stearate, wherein said surfactant is present in an amount of about 0.0001 to 0.5% to form a stable flocculated suspension of said megestrol acetate and wherein said composition does not simultaneously contain polyethylene glycol and polysorbate.

41. The composition of claim 40 wherein said polyoxyethylene stearate is polyoxyethylene 40 stearate in an amount of about 0.1 to 0.5%.

42. The composition of claim 40 wherein said polyhydric alcohol is polyethylene glycol in an amount of about 15 to 25%.

43. The composition of claim 40 wherein said polyhydric alcohol is a glycerol.

44. The composition of claim 40 wherein said at least one surfactant is a docusate sodium.

45. The composition of claim 44 wherein said docusate sodium is present in an amount of about 0.0001 to about 0.03% by weight.

46. The composition of claim 45 wherein said polyhydric alcohol is glycerol in an amount of about 10 to about 40% by weight.

47. The composition of claim 46 wherein said stable flocculated suspension is capable of being redispersed after being allowed to settle at a temperature of 40 degrees C and 75% relative humidity for three months.