Calcitonin drug-oligomer conjugates, and uses thereof

• US 20040091452A1
• Filed: 11/08/2002
• Published: 05/13/2004
• Est. Priority Date: 06/04/2001
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N.
• Granted Patent: US 7,713,932 B2
• Time in Patent Office: Days
• US Class Current: 424/78.37
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: C07K 14/585 Calcitonins

Abstract

Calcitonin drug-oligomer conjugates that include a calcitonin drug coupled to an oligomer including a single polyalkylene glycol moiety consisting of between 4 and 10 polyalkylene glycol subunits are disclosed. Pharmaceutical compositions including such conjugates and methods of treating bone disorders by administering such conjugates are also disclosed.

Claims

12. A calcitonin drug-oligomer conjugate comprising the structure of Formula I:

13. The conjugate according to claim 12, wherein z is 1.

14. The conjugate according to claim 12, wherein z is 2.

15. The conjugate according to claim 12, wherein the calcitonin drug is salmon calcitonin.

16. The conjugate according to claim 15, wherein z is 1 and the oligomer shown in the brackets of Formula I is covalently coupled to an amine function of Lys¹¹ of the salmon calcitonin or an amine function of Lys¹⁸ of the salmon calcitonin.

17. The conjugate according to claim 15, wherein z is 2 and one oligomer shown in the brackets of Formula I is covalently coupled to an amine function of Lys¹¹ and another oligomer shown in the brackets of Formula I is covalently coupled to an amine function of Lys¹⁸.

18. The conjugate according to claim 12, wherein x is from 7 to 9.

19. The conjugate according to claim 12, wherein y is from 6 to 8.

20. The conjugate according to claim 12, wherein x is 7 and y is 7.

21. The conjugate according to claim 20, wherein z is 2.

22. The conjugate according to claim 12, wherein x is 9 and y is 7.

23. The conjugate according to claim 22, wherein z is 2.

24. A calcitonin drug-oligomer conjugate comprising the structure of Formula II:

25. The conjugate according to claim 24, wherein z is 1.

26. The conjugate according to claim 24, wherein z is 2.

27. The conjugate according to claim 24, wherein the calcitonin drug is salmon calcitonin.

28. The conjugate according to claim 27, wherein z is 1 and the oligomer shown in the brackets of Formula II is covalently coupled to an amine function of Lys¹¹ of the salmon calcitonin or an amine function of Lys¹⁸ of the salmon calcitonin.

29. The conjugate according to claim 27, wherein z is 2 and one oligomer shown in the brackets of Formula II is covalently coupled to an amine function of Lys¹¹ and another oligomer shown in the brackets of Formula II is covalently coupled to an amine function of Lys¹⁸.

30. The conjugate according to claim 24, wherein x is from 14 to 17.

31. The conjugate according to claim 24, wherein y is from 6 to 8.

32. The conjugate according to claim 24, wherein x is 16 and y is 9.

33. The conjugate according to claim 32, wherein z is 2.

34. A pharmaceutical composition comprising:

a calcitonin drug coupled to an oligomer that comprises a single polyalkylene glycol moiety consisting of between 4 and 10 polyalkylene glycol subunits; and

a pharmaceutically acceptable carrier.

35. The pharmaceutical composition according to claim 34, wherein the calcitonin drug is salmon calcitonin.

36. The pharmaceutical composition according to claim 35, wherein the oligomer is covalently coupled to an amine function of the salmon calcitonin.

37. The pharmaceutical composition according to claim 36, wherein the amine function is at Lys¹¹ or Lys¹⁸ of the salmon calcitonin.

38. The pharmaceutical composition according to claim 35, wherein the conjugate comprises a first oligomer and a second oligomer.

39. The pharmaceutical composition according to claim 38, wherein the first oligomer is covalently coupled to Lys¹¹ of the salmon calcitonin and the second oligomer is covalently coupled to Lys¹⁸ of the salmon calcitonin.

40. The pharmaceutical composition according to claim 34, wherein the oligomer further comprises an alkyl moiety.

41. The pharmaceutical composition according to claim 34, wherein the alkyl moiety is an alkyl moiety having between 5 and 9 carbon atoms.

42. The pharmaceutical composition according to claim 41, wherein the oligomer is coupled to the calcitonin drug such that the alkyl moiety is between the polyalkylene glycol moiety and the calcitonin drug.

43. The pharmaceutical composition according to claim 42, wherein the alkyl moiety is an alkyl moiety having between 12 and 18 carbon atoms.

44. The pharmaceutical composition according to claim 43, wherein the oligomer is coupled to the calcitonin drug such that the polyalkylene glycol moiety is positioned between the alkyl moiety and the calcitonin drug.

45. The pharmaceutical composition according to claim 34, wherein the calcitonin drug-oligomer conjugate comprises the structure of Formula I:

46. The pharmaceutical composition according to claim 45, wherein x is 7, y is 7, and z is 2.

47. The pharmaceutical composition according to claim 45, wherein x is 9, y is 7, and z is 2.

48. The pharmaceutical composition according to claim 34, wherein the calcitonin drug-oligomer conjugate comprises the structure of Formula II:

49. The pharmaceutical composition according to claim 48, wherein x is 16, y is 8, and z is 2.

50. A method of treating a bone disorder in a subject in need of such treatment, said method comprising:

administering an effective amount of a calcitonin drug-oligomer conjugate comprising a calcitonin drug coupled to an oligomer that comprises a single polyalkylene glycol moiety consisting of between 4 and 10 polyalkylene glycol subunits to the subject to treat the bone disorder.

1. A calcitonin drug-oligomer conjugate comprising a calcitonin drug coupled to an oligomer that comprises a single polyalkylene glycol moiety consisting of between 4 and 10 polyalkylene glycol subunits.

2. The conjugate according to claim 1, wherein the calcitonin drug is salmon calcitonin.

3. The conjugate according to claim 2, wherein the oligomer is covalently coupled to an amine function of the salmon calcitonin.

4. The conjugate according to claim 3, wherein the amine function is at Lys¹¹ or Lys¹⁸ of the salmon calcitonin.

5. The conjugate according to claim 2, wherein the conjugate comprises a first oligomer and a second oligomer.

6. The conjugate according to claim 5, wherein the first oligomer is covalently coupled to Lys¹¹ of the salmon calcitonin and the second oligomer is covalently coupled to Lys¹⁸ of the salmon calcitonin.

7. The conjugate according to claim 1, wherein the oligomer further comprises an alkyl moiety.

8. The conjugate according to claim 7, wherein the alkyl moiety is an alkyl moiety having between 5 and 9 carbon atoms.

9. The conjugate according to claim 8, wherein the oligomer is coupled to the calcitonin drug such that the alkyl moiety is between the polyalkylene glycol moiety and the calcitonin drug.

10. The conjugate according to claim 7, wherein the alkyl moiety is an alkyl moiety having between 12 and 18 carbon atoms.

11. The conjugate according to claim 10, wherein the oligomer is coupled to the calcitonin drug such that the polyalkylene glycol moiety is positioned between the alkyl moiety and the calcitonin drug.

51. The method according to claim 50, wherein the administering of an effective amount of a calcitonin drug-oligomer conjugate comprises orally administering an effective amount of a calcitonin drug-oligomer conjugate.

52. The method according to claim 50, wherein the calcitonin drug is salmon calcitonin.

53. The method according to claim 52, wherein the oligomer is covalently coupled to an amine function of the salmon calcitonin.

54. The method according to claim 53, wherein the amine function is at Lys¹¹ or Lys¹⁸ of the salmon calcitonin.

55. The method according to claim 52, wherein the conjugate comprises a first oligomer and a second oligomer.

56. The method according to claim 55, wherein the first oligomer is covalently coupled to Lys¹¹ of the salmon calcitonin and the second oligomer is covalently coupled to Lys¹⁸ of the salmon calcitonin.

57. The method according to claim 50, wherein the oligomer further comprises an alkyl moiety.

58. The method according to claim 57, wherein the alkyl moiety is an alkyl moiety having between 5 and 9 carbon atoms.

59. The method according to claim 58, wherein the oligomer is coupled to the calcitonin drug such that the alkyl moiety is between the polyalkylene glycol moiety and the calcitonin drug.

60. The method according to claim 57, wherein the alkyl moiety is an alkyl moiety having between 12 and 18 carbon atoms.

61. The method according to claim 60, wherein the oligomer is coupled to the calcitonin drug such that the polyalkylene glycol moiety is positioned between the alkyl moiety and the calcitonin drug.

62. The method according to claim 50, wherein the calcitonin drug-oligomer conjugate comprises the structure of Formula I:

63. The method according to claim 62, wherein x is 7, y is 7, and z is 2.

64. The method according to claim 50, wherein the calcitonin drug-oligomer conjugate comprises the structure of Formula II:

65. The method according to claim 64, wherein x is 16, y is 8, and z is 2.

63-1. The method according to claim 62, wherein x is 9, y is 7, and z is 2.