Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith

• US 20040038866A1
• Filed: 03/05/2003
• Published: 02/26/2004
• Est. Priority Date: 09/07/2001
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Hickey, Anthony, Soltero, Richard, Bovet, Li Li, Rehlaender, Bruce
• Granted Patent: US 7,196,059 B2
• Time in Patent Office: Days
• US Class Current: 514/3
• 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 insulin, an insulin 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 insulin drug is 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. Methods of treating an insulin deficiency in a subject in need of such treatment using such pharmaceutical compositions are also provided, as are methods of providing such pharmaceutical compositions.

Claims

1. A pharmaceutical composition comprising an insulin drug-oligomer conjugate comprising an insulin drug covalently coupled to an oligomeric moiety and a bile salt, in 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 insulin drug is an insulin polypeptide.

12. The pharmaceutical composition of claim 11, wherein the insulin polypeptide is human insulin.

13. The pharmaceutical composition of claim 12, wherein the oligomeric moiety is coupled to the lysine at the B29 position of the human insulin.

14. The pharmaceutical composition of claim 11, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human;

Ala^B28 Pro^B29 insulin, human.

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

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

17. The pharmaceutical composition of claim 1, wherein the insulin drug-oligomer conjugate is amphiphilically balanced.

18. The pharmaceutical composition of claim 1, wherein the oligomeric moiety is hydrophilic.

19. The pharmaceutical composition of claim 17, wherein the oligomeric moiety is polyethylene glycol.

20. The pharmaceutical composition of claim 1, wherein the oligomeric moiety is lipophilic.

21. The pharmaceutical composition of claim 19, wherein the oligomeric moiety is alkane.

22. The pharmaceutical composition of claim 1, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

23. The pharmaceutical composition of claim 1, wherein the insulin drug-oligomer conjugate comprises the structure of Formula V:

42. A method of treating an insulin deficiency in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1.

43. The method of claim 42, wherein the method comprises orally administering the pharmaceutical composition to the subject.

44. The method of claim 42, 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.

45. The method of claim 42, wherein the insulin drug is an insulin polypeptide.

46. The method of claim 45, wherein the insulin polypeptide is human insulin.

47. The method of claim 46, wherein the oligomeric moiety is coupled to the lysine at the B29 position of human insulin.

48. The method of claim 45, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human;

Ala^B28 Pro^B29 insulin, human.

49. The method of claim 42, wherein the insulin drug-oligomer conjugate is present as a substantially monodispersed mixture.

50. The method of claim 42, wherein the insulin drug-oligomer conjugate is present as a monodispersed mixture.

51. The method of claim 42, wherein the insulin drug-oligomer conjugate is amphiphilically balanced.

52. The method of claim 42, wherein the oligomeric moiety comprises a hydrophilic moiety and a lipophilic moiety.

53. The method of claim 42, wherein the oligomeric moiety is hydrophilic.

54. The method of claim 53, wherein the oligomeric moiety is polyethylene glycol.

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

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

57. The method of claim 42, wherein the insulin drug-oligomer conjugate comprises the structure of Formula V:

58. A method of treating an insulin deficiency 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 23.

59. The method of claim 58, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

4, 1;

3, 1;

2 and 1;

1.

60. The method of claim 58, wherein the fatty acid component comprises one or more fatty acids in the range of C₄ to C₂₀.

61. The method of claim 58, wherein the fatty acid is selected from the group consisting of lauric acid, capric acid, oleic acid and mixtures thereof.

62. The method of claim 58, wherein the pH of the composition is between 6.2 and 9.0.

63. The method of claim 58, further comprising a buffering component.

64. The method of claim 58, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

65. The method of claim 58, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

66. The method of claim 58, wherein the method comprises orally administering the pharmaceutical composition to the subject.

67. The method of claim 58, 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.

68. The method of claim 58, wherein the insulin drug is an insulin polypeptide.

69. The method of claim 68, wherein the insulin polypeptide is human insulin.

70. The method of claim 68, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human;

Ala^B28 Pro^B29 insulin, human.

71. The method of claim 58, wherein the bile salt component is present in a range of about 0.5% to about 20% weight/volume and the fatty acid component is present in a range of about 0.2% to about 10% weight/volume.

72. The method of claim 58, wherein the bile salt is cholate and the fatty acid is laurate.

73. The method of claim 58, wherein the bile salt is cholate and the cholate is present in the amount of about 1.5% weight/volume and the fatty acid is laurate and the laurate is present in the amount of 2% weight/volume.

74. A method of delivering an insulin drug oligomer conjugate across the gut wall in a subject by simultaneously contacting the gut wall with a bile salt and the insulin drug oligomer conjugate, comprising administering to the subject the pharmaceutical composition of claim 1.

24. A pharmaceutical composition comprising:

insulin;

a bile salt; and

a fatty acid, wherein the fatty acid and the bile salt are present in a weight-to-weight ratio of between 1;

5 and 5;

1, and 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.

25. The pharmaceutical composition of claim 24, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of about 1:

4, 1;

3, 1;

2 or 1;

1.

26. The pharmaceutical composition of claim 24, wherein the fatty acid component comprises one or more fatty acids in the range of C₄ to C₂₀.

27. The pharmaceutical composition of claim 24, wherein the fatty acid is selected from the group consisting of lauric acid, capric acid, oleic acid and mixtures thereof.

28. The pharmaceutical composition of claim 24, wherein the pH of the composition is between 6.2 and 9.0.

29. The pharmaceutical composition of claim 24, further comprising a buffering component.

30. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

31. The pharmaceutical composition of claim 30, wherein the liquid pharmaceutical composition is suitable for oral administration.

32. The pharmaceutical composition of claim 24, wherein the composition is suitable for a route of administration selected from the group consisting of buccal, transdermal, peroral and nasal administration.

33. The pharmaceutical composition of claim 30, wherein the liquid pharmaceutical composition is suitable for parenteral administration.

34. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

35. The pharmaceutical composition of claim 24, wherein the insulin drug is an insulin polypeptide.

36. The pharmaceutical composition of claim 35, wherein the insulin polypeptide is human insulin.

37. The pharmaceutical composition of claim 35, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human;

Ala^B28 Pro^B29 insulin, human.

38. The pharmaceutical composition of claim 24, wherein the bile salt is present in a range of about 0.5% to about 20% weight/volume and the fatty acid is present in a range of about 0.2% to about 10% weight/volume.

39. The pharmaceutical composition of claim 24, wherein the bile salt is cholate and the fatty acid is laurate.

40. The pharmaceutical composition of claim 24, wherein the bile salt is cholate and the cholate is present in the amount of about 1.5% weight/volume and the fatty acid is laurate and the laurate is present in the amount of 2% weight/volume.

41. The pharmaceutical composition of claim 24, wherein the fatty acid is caprate and laurate and the bile salt and fatty acid are present in the proportions of three parts bile salt, one part caprate and one part laurate.

75. A method of delivering an insulin drug across the gut wall in a subject by simultaneously contacting the gut wall with a bile salt and the insulin drug, comprising administering the subject a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, an insulin drug and a bile salt.

76. A method of delivering an insulin drug oligomer conjugate across the gut wall in a subject by simultaneously contacting the gut wall with a bile salt, a fatty acid and the insulin drug oligomer conjugate, comprising administering to the subject a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier,

An insulin drug covalently coupled to an oligomeric moiety;

a bile salt; and

a fatty acid, wherein the fatty acid and the bile salt are present in a weight-to-weight ratio of between 1;

5 and 5;

1, and 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.

77. A method of delivering an insulin drug across the gut wall in a subject by simultaneously contacting the gut wall with a bile salt, a fatty acid and the insulin drug, comprising administering to the subject a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier,

an insulin drug;

a bile salt; and

a fatty acid, wherein the fatty acid and the bile salt are present in a weight-to-weight ratio of between 1;

5 and 5;

1, and 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.

78. The method of claim 77, wherein the fatty acids are laurate and caprate and fatty acids and bile salts are present in the pharmaceutical composition in the ratio of three parts bile salt, one part laurate and one part caprate.

79. The method of claim 78, wherein the fatty acids are laurate and caprate and fatty acids and bile salts are present in the pharmaceutical composition in the ratio of three parts bile salt, one part laurate and one part caprate.