Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith

• US 7,030,082 B2
• Filed: 03/05/2003
• Issued: 04/18/2006
• Est. Priority Date: 09/07/2001
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Opawale, Foyeke, Ekwuribe, Nnochiri N., Hickey, Anthony, Soltero, Richard, Bovet, Li Li, Rehlaender, Bruce
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US10/382,069
• Publication Number:
  US 20040017387A1
• Time in Patent Office: 1,140 Days
• Field of Search: 514/2, 514/12, 514/21, 514/784, 514/785, 530/307, 530/345, 530/408, 530/409, 530/410, 530/411
• US Class Current: 514/11.9
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

Pharmaceutical compositions that include a drug and/or drug-oligomer conjugate, a fatty acid component and a bile salt component, or a bile salt component without a fatty acid component are described. The drug can be covalently coupled to an oligomeric moiety. The fatty acid component and the bile salt component, when together, can be present in a weight-to-weight ratio of between 1:15 and 15:1 or any value between. Methods of treating diseases in a subject in need of such treatment using the pharmaceutical compositions of this invention are also provided, as well as methods of providing such pharmaceutical compositions.

Claims

1. A pharmaceutical composition comprising (a) a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety, wherein the oligomeric moiety is hydrophilic, (b) a bile salt, and (c) a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein the bile salt is selected from the group consisting of taurocholate, taurodeoxycholate, cholate, deoxycholate and glycodeoxycholate.

3. The pharmaceutical composition of claim 2, wherein the bile salt is present in a concentration in the range of about 0.15% to about 10% bile salt.

4. The pharmaceutical composition of claim 2, wherein the bile salt is present in a concentration in the range of about 0.5% to about 5% bile salt.

5. The pharmaceutical composition of claim 1, wherein the pH of the composition is between 6.2 and 9.0.

6. The pharmaceutical composition of claim 1, further comprising a buffering component.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

8. The pharmaceutical composition of claim 7, wherein the liquid pharmaceutical composition is suitable for oral administration.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

10. The pharmaceutical composition of claim 1, wherein the composition is suitable for a route of administration selected from the group consisting of buccal, transdermal, peroral and nasal administration.

11. The pharmaceutical composition of claim 1, wherein the drug is a calcitonin polypeptide.

12. The pharmaceutical composition of claim 10, wherein the calcitonin polypeptide is salmon calcitonin.

13. The pharmaceutical composition of claim 12, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

14. The pharmaceutical composition of claim 1, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

15. The pharmaceutical composition of claim 1, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

16. The pharmaceutical composition of claim 1, wherein the oligomeric moiety is polyethylene glycol.

17. A pharmaceutical composition comprising (a) a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety, wherein the oligomeric moiety is alkane, (b) a bile salt, and (c) a pharmaceutically acceptable carrier.

59. The pharmaceutical composition of claim 17, wherein the bile salt is selected from the group consisting of taurocholate, taurodeoxycholate, cholate, deoxycholate and glycodeoxycholate.

60. The pharmaceutical composition of claim 17, wherein the bile salt is present in a concentration in the range of about 0.15% to about 10% bile salt.

61. The pharmaceutical composition of claim 17, wherein the bile salt is present in a concentration in the range of about 0.5% to about 5% bile salt.

62. The pharmaceutical composition of claim 17, wherein the pH of the composition is between 6.2 and 9.0.

63. The pharmaceutical composition of claim 17, further comprising a buffering component.

64. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

65. The pharmaceutical composition of claim 64, wherein the liquid pharmaceutical composition is suitable for oral administration.

66. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

67. The pharmaceutical composition of claim 17, wherein the composition is suitable for a route of administration selected from the group consisting of buccal, transdermal, peroral and nasal administration.

68. The pharmaceutical composition of claim 17, wherein the drug is a calcitonin polypeptide.

69. The pharmaceutical composition of claim 68, wherein the calcitonin polypeptide is salmon calcitonin.

70. The pharmaceutical composition of claim 69, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

71. The pharmaceutical composition of claim 17, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

72. The pharmaceutical composition of claim 17, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

18. A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier:

a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety;

a bile salt; and

a fatty acid component, wherein the fatty acid is present in an amount wherein the solubility of the bile salt in the presence of the fatty acid is greater than the solubility of the bile salt in a corresponding composition lacking the fatty acid, and wherein the bile salt is cholate and the cholate is present in the amount of about 1.5% weight/volume and the fatty acid component comprises laurate and the laurate is present in the amount of 2% weight/volume.

19. The pharmaceutical composition of claim 18, wherein the pH of the composition is between 6.2 and 9.0.

20. The pharmaceutical composition of claim 18, further comprising a buffering component.

21. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

22. The pharmaceutical composition of claim 21, wherein the liquid pharmaceutical composition is suitable for oral administration.

23. The pharmaceutical composition of claim 18, wherein the composition is suitable for a route of administration selected from the group consisting of buccal, transdermal, peroral and nasal administration.

24. The pharmaceutical composition of claim 21, wherein the liquid pharmaceutical composition is suitable for parenteral administration.

25. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

26. The pharmaceutical composition of claim 18 wherein the drug is a calcitonin polypeptide.

27. The pharmaceutical composition of claim 26, wherein the calcitonin polypeptide is salmon calcitonin.

28. The pharmaceutical composition of claim 27, wherein the drug-oligomer conjugate comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

29. The pharmaceutical composition of claim 28, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

30. The pharmaceutical composition of claim 18, wherein the fatty acid component further comprises caprate.

44. A method of treating a bone disorder in a subject in need of such treatment, said method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 18.

45. The method of claim 44, wherein the method comprises orally administering the pharmaceutical composition to the subject.

46. The method of claim 44, wherein the method comprises administering the pharmaceutical composition to the subject by an administration route selected from the group consisting of buccal, transdermal, peroral and nasal administration.

47. The method of claim 44, wherein the drug is a calcitonin polypeptide.

48. The method of claim 47, wherein the calcitonin polypeptide is salmon calcitonin.

49. The method of claim 48, wherein the drug-oligomer conjugate comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

50. The method of claim 49, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

51. The method of claim 44, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

52. The method of claim 44, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

53. The method of claim 44, wherein the drug-oligomer conjugate is amphiphilically balanced.

54. The method of claim 44, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

55. The method of claim 44, wherein the oligomeric moiety is hydrophilic.

56. The method of claim 55, wherein the oligomeric moiety is polyethylene glycol.

57. The method of claim 44, wherein the oligomeric moiety is lipophilic.

58. The method of claim 57, wherein the oligomeric moiety is alkane.

31. A method of treating a bone disorder in a subject in need of such treatment, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (a) a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety, (b) a bile salt, and (c) a pharmaceutically acceptable carrier, by an administration route selected from the group consisting of buccal, transdermal, peroral and nasal administration.

32. The method of claim 31, wherein the drug is a calcitonin polypeptide.

33. The method of claim 32, wherein the calcitonin polypeptide is salmon calcitonin.

34. The method of claim 33, wherein the drug-oligomer moiety comprises salmon calcitonin coupled to two oligomeric moieties, wherein one oligomeric moiety is coupled to the lysine at the 11 position of the salmon calcitonin, and wherein one oligomeric moiety is coupled to the lysine at the 18 position of the salmon calcitonin.

35. The method of claim 34, wherein the oligomeric moiety coupled to the lysine at the 11 position comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)— and

wherein the oligomeric moiety coupled to the lysine at the 18 position of the salmon calcitonin comprises the structure CH₃O(C₂H₄O)₇—

(CH₂)₇—

C(O)—

.

36. The method of claim 31, wherein the drug-oligomer conjugate is present as a substantially monodispersed mixture.

37. The method of claim 31, wherein the drug-oligomer conjugate is present as a monodispersed mixture.

38. The method of claim 31, wherein the drug-oligomer conjugate is amphiphilically balanced.

39. The method of claim 31, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

42. The method of claim 31, wherein the oligomeric moiety is lipophilic.

40. A method of treating bone disorder in a subject in need of such treatment, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (a) a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety, wherein the oligomeric moiety is hydrophilic, (b) a bile salt, and (c) a pharmaceutically acceptable carrier.

41. The method of claim 40, wherein the oligomeric moiety is polyethylene glycol.

43. A method of treating bone disorder in a subject in need of such treatment, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (a) a drug-oligomer conjugate comprising a drug covalently coupled to an oligomeric moiety, wherein the oligomeric moiety is alkane, (b) a bile salt, and (c) a pharmaceutically acceptable carrier.