Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives

• US 7,053,069 B2
• Filed: 05/13/2003
• Issued: 05/30/2006
• Est. Priority Date: 05/15/2002
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Haby, Thomas A., Franchini, Miriam K., Lee, Francis Y. F., Naringrekar, Vijay H., Raghavan, Krishnaswamy S.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Sackey, Ebenezer
• Application Number:
  US10/437,103
• Publication Number:
  US 20040053978A1
• Time in Patent Office: 1,113 Days
• Field of Search: 548/204, 536/51, 514/59, 514/365
• US Class Current: 514/59
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis

Abstract

Pharmaceutical compositions containing C-21 modified epothilone derivatives, methods for their preparation and dosing regimen for administration of these epothilone compounds are provided. The compositions are stable and readily prepared for administration by dissolution in aqueous vehicles suitable for intravenous administration. A process for formulating C-21 modified epothilone derivatives for oral and parenteral administration is disclosed.

Claims

1. A pharmaceutical composition comprising:

a) a C-21 modified epothilone compound of formula I;

2. The composition of claim 1 wherein said C-21 modified epothilone compound is of formula Ia:

3. The composition of claim 2 wherein said C-21 modified epothilone compound is of formula Ib:

4. The composition of claim 3 wherein said C-21 modified epothilone compound is of formula Ic:

5. The composition of claim 1 prepared by a method comprising lyophilizing an aqueous solution comprising said C-21 modified epothilone compound, said dibasic carboxylic acid, and said dextran polymer.

6. The composition of claim 5 wherein said aqueous solution is adjusted to a pH of between about 5 and about 7.

7. The composition of claim 1 wherein said dextran polymer is dextran 40.

8. The composition of claim 1 wherein said dibasic carboxylic acid is succinic acid.

9. The composition of claim 1 wherein said dibasic carboxylic acid is citric acid.

10. The composition of claim 1 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is succinic acid.

11. The composition of claim 1 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is citric acid.

12. The composition of claim 4 prepared by a method comprising lyophilizing an aqueous solution comprising said C-21 modified epothilone compound, said dibasic carboxylic acid, and said dextran polymer.

13. The composition of claim 12 wherein said aqueous solution is adjusted to a pH of between about 5 and about 7.

14. The composition of claim 4 wherein said dextran polymer is dextran 40.

15. The composition of claim 4 wherein said dibasic carboxylic acid is succinic acid.

16. The composition of claim 4 wherein said dibasic carboxylic acid is citric acid.

17. The composition of claim 4 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is succinic acid.

18. The composition of claim 4 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is citric acid.

19. A method of preparing a pharmaceutical composition comprising the steps of:

(a) preparing an aqueous solution containing a C-21 modified epothilone compound of formula I, a dibasic carboxylic acid, and a dextran polymer;

(b) adjusting the pH of said solution to between about 5 and about 7;

(c) lyophilizing said solution of step (b) to form a lyophile; and

(d) drying said lyophile of step (c)

wherein said C-21 modified epothilone compound of formula I is;

20. The method of claim 19 wherein said C-21 modified epothilone compound is of formula Ia:

21. The method of claim 20 wherein said C-21 modified epothilone compound is of formula Ib:

22. The method of claim 21 wherein said C-21 modified epothilone compound is of formula Ic:

23. The method of claim 19 wherein said aqueous solution is adjusted to a pH of between about 5.5 and about 6.5.

24. The method of claim 19 wherein said dextran polymer is dextran 40.

25. The method of claim 19 wherein said dibasic carboxylic acid is succinic acid.

26. The method of claim 19 wherein said dibasic carboxylic acid is citric acid.

27. The method of claim 19 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is succinic acid.

28. The method of claim 19 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is citric acid.

29. The method of claim 22 wherein said aqueous solution is adjusted to a pH of between about 5.5 and about 6.5.

30. The method of claim 22 wherein said dextran polymer is dextran 40.

31. The method of claim 22 wherein said dibasic carboxylic acid is succinic acid.

32. The method of claim 22 wherein said dibasic carboxylic acid is citric acid.

33. The method of claim 22 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is succinic acid.

34. The method of claim 22 wherein said dextran polymer is dextran 40 and said dibasic carboxylic acid is citric acid.

74. The method according to claim 19 wherein step (d) comprising a primary drying stage conducted at a temperature in the range of from about −

20°

C. to about −

10°

C.

75. The method according to claim 74 wherein said step (d) further comprises a secondary drying stage conducted at a temperature in the range of from about −

10°

C. to about 30°

C.

35. A unit dose of a pharmaceutical composition comprising a sealed vial containing between about 10 mg and about 25 mg of citric acid, between about 50 mg and about 150 mg of dextran 40, and between about 5 mg and about 20 mg of [1S-[1R*,3R*(E),7R*,10S*, 11R*,12R*, 16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

36. The unit dose according to claim 35 comprising a sealed vial containing between about 12.5 mg and about 16.7 mg of said citric acid, between about 99 mg and about 132 mg of said dextran 40, and between about 9 mg and about 12 mg of said [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]3-2-[2[2-(aminomethyl)-4-thiazolyl]1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

37. The unit dose according to claim 36 containing about 13.9 mg of said citric acid, about 110 mg of said dextran 40, and about 11 mg of said [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

38. A method for treating cancer in a patient, wherein said cancer is selected from the group consisting of breast, head neck, sarcoma, colorectal, UPT, melanoma, esophagus, renal, cervix, thyroid, anal, ovarian, and colon cancer, comprising administering to said patient, by intravenous or oral administration, an effective amount of a pharmaceutical composition comprising:

a) a C-21 modified epothilone compound of formula I;

39. The method according to claim 38 wherein said C-21 modified epothilone compound is of formula Ia:

40. The method according to claim 39 wherein said C-21 modified epothilone compound is of formula Ib:

41. The method according to claim 40 wherein said C-21 modified epothilone compound is of formula Ic:

42. The method of claim 38 wherein said C-21 modified epothilone compound is administered orally in a dose of about 0.05 mg/kg to 200 mg/kg.

43. The method of claim 38 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 1 mg/m² to 100 mg/m².

44. The method of claim 38 wherein said C-21 modified epothilone compound is administered daily or weekly.

45. The method of claim 38 wherein said C-21 modified epothilone compound is administered once every week.

46. The method of claim 38 wherein said C-21 modified epothilone compound is administered once every three weeks.

47. The method of claim 38 wherein said C-21 modified epothilone compound is administered at least once a day for 3 days with a period of at least 4 days during which there is no treatment.

48. The method of claim 38 wherein said C-21 modified epothilone compound is administered at least once a day for 5 days with a period of at least 2 days during which there is no treatment.

49. The method of claim 38 wherein said C-21 modified epothilone compound is administered intravenously over a period of 15 minutes to 90 minutes.

50. The method of claim 38 wherein said patient has not previously been treated for cancer.

51. The method of claim 38 wherein said patient has previously been treated for cancer.

52. The method of claim 38 further comprising administering to said patient one or more additional agents to prevent nausea, vomiting, hypersensitivity, or gastric irritation.

53. The method of claim 41 wherein said C-21 modified epothilone compound is administered orally in a dose of about 0.05 mg/kg to 200 mg/kg.

54. The method of claim 53 wherein said C-21 modified epothilone compound is administered orally in a dose of about 0.05 mg/kg to 50 mg/kg.

55. The method of claim 41 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 1 mg/m² to 100 mg/m².

56. The method of claim 55 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 1 mg/m² to 70 mg/m².

57. The method of claim 56 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 10 mg/m² to 70 mg/m².

58. The method of claim 57 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 10 mg/m² to 65 mg/m².

59. The method of claim 58 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 50 mg/m².

60. The method of claim 58 wherein said C-21 modified epothilone compound is administered intravenously at a dose of about 30 mg/m².

61. The method of claim 41 wherein said C-21 modified epothilone compound is administered daily or weekly.

62. The method of claim 41 wherein said C-21 modified epothilone compound is administered once every week.

63. The method of claim 41 wherein said C-21 modified epothilone compound is administered once every three weeks.

64. The method of claim 41 wherein said C-21 modified epothilone compound is administered at least once a day for 3 days with a period of at least 4 days during which there is no treatment.

65. The method of claim 41 wherein said C-21 modified epothilone compound is administered at least once a day for 5 days with a period of at least 2 days during which there is no treatment.

66. The method of claim 41 wherein said C-21 modified epothilone compound is administered intravenously over a period of 15 minutes to 90 minutes.

67. The method of claim 41 wherein said patient has not previously been treated for cancer.

68. The method of claim 41 wherein said patient has previously been treated for cancer.

69. The method of claim 41 wherein said cancer is refractory to radiation therapy.

70. The method of claim 41 wherein said cancer is refractory to anticancer chemotherapy.

71. The method of claim 41 wherein said cancer is a solid tumor.

72. The method of claim 41 further comprising administering to said patient one or more additional agents to prevent nausea, vomiting, hypersensitivity, or gastric irritation.

73. The method of claim 72 wherein said agent is an H₁ or H₂ antihistamine.