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

• US 7,196,059 B2
• Filed: 03/05/2003
• Issued: 03/27/2007
• Est. Priority Date: 09/07/2001
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Soltero, Richard, Bovet, Li Li, Hickey, Anthony, Radhakrishan, Balasingam, Rehlaender, Bruce
• Primary Examiner(s): TRINH, MINH N
• Application Number:
  US10/382,155
• Publication Number:
  US 20040038866A1
• Time in Patent Office: 1,483 Days
• Field of Search: 514/3, 514/4, 514/784, 514/808, 424/450, 530/303, 530/304, 530/305, 530/345
• US Class Current: 514/6.2
• 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 consisting of (a) an insulin drug-oligomer conjugate comprising an insulin drug covalently coupled to an oligomeric moiety, wherein the oligomeric moiety is polyethylene glycol, (b) a bile salt, and (c) a pharmaceutically acceptable carrier.

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

3. A pharmaceutical composition comprising:

insulin;

a bile salt; and

a fatty acid, 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 solubiity of the bile salt in a corresponding composition lacking the fatty acid, 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.

4. The pharmaceutical composition of claim 3, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1:

4 and 1;

1.

5. The pharmaceutical composition of claim 3, wherein the fatty acid component comprises one or more fatty acids in the range of C₄ to C₂₀.

6. The pharmaceutical composition of claim 3, wherein the fatty acid is selected from the group consisting of lauric acid, capric acid, oleic acid and mixtures thereof.

7. The pharmaceutical composition of claim 3, wherein the pH of the composition is between 6.2 and 9.0.

8. The pharmaceutical composition of claim 3, further comprising a buffering component.

9. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

10. The pharmaceutical composition of claim 9, wherein the liquid pharmaceutical composition is suitable for oral administration.

11. The pharmaceutical composition of claim 3, wherein the composition is suitable for a route of administration selected from the group consisting of buccal, transdermal, peroral and nasal administration.

12. The pharmaceutical composition of claim 9, wherein the liquid pharmaceutical composition is suitable for parenteral administration.

13. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

14. The pharmaceutical composition of claim 3, wherein the insulin is an insulin polypeptide.

15. The pharmaceutical composition of claim 14, wherein the insulin polypeptide is human insulin.

16. The pharmaceutical composition of claim 14, 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 Gln^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^B29insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human; and

Ala^B28 Pro^B29insulin, human.

17. The pharmaceutical composition of claim 3, wherein the fatty acid further comprises caprate.

19. 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 3.

20. The method of claim 19, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

4 and 1;

1.

21. The method of claim 19, wherein the fatty acid component comprises one or more fatty acids in the range of C₄ to C₂₀.

22. The method of claim 19, wherein the fatty acid is selected from the group consisting of lauric acid, capric acid, oleic acid and mixtures thereof.

23. The method of claim 19, wherein the pH of the composition is between 6.2 and 9.0.

24. The method of claim 19, further comprising a buffering component.

25. The method of claim 19, wherein the pharmaceutical composition is a liquid pharmaceutical composition.

26. The method of claim 19, wherein the pharmaceutical composition is a solid dosage pharmaceutical composition.

27. The method of claim 19, wherein the method comprises orally administering the pharmaceutical composition to the subject.

28. The method of claim 19, 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.

29. The method of claim 19, wherein the insulin is an insulin polypeptide.

30. The method of claim 29, wherein the insulin polypeptide is human insulin.

31. The method of claim 29, wherein the insulin polypeptide is an insulin analog selected from the group consisting 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^B21 Pro^B29insulin, human;

Leu^B28Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human; and

Ala^B28 Pro^B29 insulin, human.

32. The pharmaceutical composition of claim 4, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1:

3 and 1;

2.

33. The method of claim 20, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1:

3 and 1;

2.

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

34. 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 comprising (a) insulin drug-oligomer conjugate comprising an insulin drug covalently coupled to an oligomeric moiety, (b) a bile salt, and (c) a pharmaceutically acceptable carrier, by nasally administering the pharmaceutical composition to the subject.