Stabilized injectable suspension of a steroidal drug

• US 20030114430A1
• Filed: 08/21/2002
• Published: 06/19/2003
• Est. Priority Date: 05/15/2000
• Status: Abandoned Application

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: Pharmacia Corporation (Pfizer Inc.)
• Inventors: Adams, Neal S., Fox, Lloyd E., Salvat, David J., MacLeod, Steven K.
• Application Number:
  US10/225,320
• Publication Number:
  US 20030114430A1
• Time in Patent Office: Days
• US Class Current: 514/177
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/32 Antioestrogens
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

A parenterally deliverable composition is provided, comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount. The aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation. The composition further comprises, as a component thereof or as an adjunct thereto, means for protecting the oxidative degradation susceptible agent from oxidative degradation.

Claims

1. A parenterally deliverable composition comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount, wherein:

(a) the aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation; and

(b) the composition further comprises, as a component thereof or as an adjunct there to, means for protecting the oxidative degradation susceptible agent from oxidative degradation.

2. The composition of claim 1 wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.

3. The composition of claim 1 wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.

4. The composition of claim 3 wherein the polyoxyethylene surfactant is a polysorbate.

5. The composition of claim 3 wherein the polyoxyethylene surfactant is polysorbate 80.

6. The composition of claim 5 wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.

7. The composition of claim 5 wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.

8. The composition of claim 1 wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.

9. The composition of claim 1 wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.

10. The composition of claim 1 wherein the steroidal drug is medroxyprogesterone acetate.

11. The composition of claim 10 wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.

12. The composition of claim 10 wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.

13. The composition of claim 10 wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.

14. The composition of claim 1 wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises an antioxidant present as a component of the composition.

15. The composition of claim 1 wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises a chelating agent present as a component of the composition.

16. The composition of claim 1 wherein said means for protecting the oxidative degradation susceptible agent from oxidative degradation comprises an oxygen-depleted atmosphere in headspace overlying the composition.

17. The composition of claim 16 wherein said atmosphere comprises less than about 5% oxygen.

18. The composition of claim 17 wherein said atmosphere consists essentially of nitrogen.

19. A parenterally deliverable aqueous suspension composition comprising:

(a) medroxyprogesterone acetate, 100-200 mg/ml;

(b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;

(c) polysorbate 80, 2-4 mg/ml;

(d) sodium chloride, 6-12 mg/ml; and

(e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total;

said composition having an oxygen-depleted atmosphere in headspace overlying the composition.

20. The composition of claim 19 comprising:

(a) medroxyprogesterone acetate, about 150 mg/ml;

(b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;

(c) polysorbate 80, about 2.5 mg/ml;

(d) sodium chloride, about 9 mg/ml;

(e) methylparaben, about 1.5 mg/ml;

(f) propylparaben, about 0.15 mg/ml; and

(g) water for injection, q.s.

21. The composition of claim 19 comprising, in a volume of about 0.65 ml:

(a) medroxyprogesterone acetate, about 104 mg;

(b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;

(c) polysorbate 80, about 1.95 mg;

(d) sodium chloride, about 5.2 mg;

(e) methylparaben, about 1.04 mg;

(f) propylparaben, about 0.10 mg;

(g) monobasic sodium phosphate monohydrate, about 0.45 mg;

(h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;

(i) L-methionine, about 0.98 mg;

(j) polyvinylpyrrolidone K17, about 3.25 mg; and

(k) water for injection, q.s.

22. An article of manufacture comprising a sealed vessel having substantially oxygen-impermeable walls and a substantially oxygen-impermeable seal, and having contained therewithin:

(a) a parenterally deliverable aqueous suspension that comprises (i) a steroidal drug in a therapeutically effective amount and (ii) one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation; and

(b) an oxygen-depleted atmosphere in headspace overlying the composition.

23. The article of claim 22 wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.

24. The article of claim 22 wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.

25. The article of claim 24 wherein the polyoxyethylene surfactant is a polysorbate.

26. The article of claim 24 wherein the polyoxyethylene surfactant is polysorbate 80.

27. The article of claim 26 wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.

28. The article of claim 26 wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.

29. The article of claim 22 wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.

30. The article of claim 22 wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.

31. The article of claim 22 wherein the steroidal drug is medroxyprogesterone acetate.

32. The article of claim 31 wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.

33. The article of claim 31 wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.

34. The article of claim 31 wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.

35. The article of claim 22 wherein said atmosphere comprises less than about 5% oxygen.

36. The article of claim 22 wherein said atmosphere consists essentially of nitrogen.

37. The article of claim 22 wherein the parenterally deliverable aqueous suspension comprises:

(a) medroxyprogesterone acetate, 100-200 mg/ml;

(b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;

(c) polysorbate 80, 2-4 mg/ml;

(d) sodium chloride, 6-12 mg/ml; and

(e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total.

38. The article of claim 22 wherein the parenterally deliverable aqueous suspension comprises:

(a) medroxyprogesterone acetate, about 150 mg/ml;

(b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;

(c) polysorbate 80, about 2.5 mg/ml;

(d) sodium chloride, about 9 mg/ml;

(e) methylparaben, about 1.5 mg/ml;

(f) propylparaben, about 0.15 mg/ml; and

(f) water for injection, q.s.

39. The article of claim 22 wherein the parenterally deliverable aqueous suspension comprises, in a volume of about 0.65 ml:

(a) medroxyprogesterone acetate, about 104 mg;

(b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;

(c) polysorbate 80, about 1.95 mg;

(d) sodium chloride, about 5.2 mg;

(e) methylparaben, about 1.04 mg;

(f) propylparaben, about 0.10 mg;

(g) monobasic sodium phosphate monohydrate, about 0.45 mg;

(h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;

(i) L-methionine, about 0.98 mg;

(j) polyvinylpyrrolidone K17, about 3.25 mg; and

(k) water for injection, q.s.

40. An article of manufacture comprising a vial having

(a) a first chamber that is substantially filled with a parenterally deliverable aqueous suspension that comprises (i) a steroidal drug in a therapeutically effective amount and (ii) one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation,

(b) a second chamber that is substantially empty but for a gaseous medium;

(c) a septum separating the first and second chambers and impermeable to contents thereof; and

(d) actuating means effective to bring the aqueous suspension and the gaseous medium in to contact by breach of the septum such that the gaseous medium acts as an effective headspace for agitation of the aqueous suspension.

41. The article of claim 40 wherein the at least one oxidative degradation susceptible agent comprises a polyoxyethylene chain.

42. The article of claim 40 wherein the at least one oxidative degradation susceptible agent is a polyoxyethylene surfactant.

43. The article of claim 42 wherein the polyoxyethylene surfactant is a polysorbate.

44. The article of claim 42 wherein the polyoxyethylene surfactant is polysorbate 80.

45. The article of claim 44 wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml.

46. The article of claim 44 wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml.

47. The article of claim 40 wherein the steroidal drug is selected from the group consisting of clostebol, estradiol, exemestane, medroxyprogesterone, methylprednisolone, testosterone and pharmaceutically acceptable esters and salts thereof.

48. The article of claim 40 wherein the steroidal drug is selected from the group consisting of estradiol cypionate, exemestane and medroxyprogesterone acetate.

49. The article of claim 40 wherein the steroidal drug is medroxyprogesterone acetate.

50. The article of claim 49 wherein the medroxyprogesterone acetate is present in an amount of about 10 to about 400 mg/ml.

51. The article of claim 49 wherein the medroxyprogesterone acetate is present in an amount of about 30 to about 300 mg/ml.

52. The article of claim 49 wherein the medroxyprogesterone acetate is present in an amount of about 50 to about 200 mg/ml.

53. The article of claim 40 wherein the parenterally deliverable aqueous suspension comprises:

(a) medroxyprogesterone acetate, 100-200 mg/ml;

(b) polyethylene glycol of molecular weight 3000-4000, 20-40 mg/ml;

(c) polysorbate 80, 2-4 mg/ml;

(d) sodium chloride, 6-12 mg/ml; and

(e) optionally at least one parenterally acceptable preservative, 0.1-5 mg/ml total.

54. The article of claim 40 wherein the parenterally deliverable aqueous suspension comprises:

(a) medroxyprogesterone acetate, about 150 mg/ml;

(b) polyethylene glycol of molecular weight about 3350, about 30 mg/ml;

(c) polysorbate 80, about 2.5 mg/ml;

(d) sodium chloride, about 9 mg/ml;

(e) methylparaben, about 1.5 mg/ml;

(f) propylparaben, about 0.15 mg/ml; and

(g) water for injection, q.s.

55. The article of claim 40 wherein the parenterally deliverable aqueous suspension comprises, in a volume of about 0.65 ml:

(a) medroxyprogesterone acetate, about 104 mg;

(b) polyethylene glycol of molecular weight about 3350, about 18.7 mg;

(c) polysorbate 80, about 1.95 mg;

(d) sodium chloride, about 5.2 mg;

(e) methylparaben, about 1.04 mg;

(f) propylparaben, about 0.10 mg;

(g) monobasic sodium phosphate monohydrate, about 0.45 mg;

(h) dibasic sodium phosphate dodecahydrate, about 0.38 mg;

(i) L-methionine, about 0.98 mg;

(j) polyvinylpyrrolidone K17, about 3.25 mg; and

(k) water for injection, q.s.