Compositions of chemically modified insulin

• US 6,890,518 B2
• Filed: 04/01/2003
• Issued: 05/10/2005
• Est. Priority Date: 05/21/2001
• Status: Expired due to Fees

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Harris, J. Milton, Bueche, Blaine, Patton, John S., Leach, Chester, Kuo, Mei-Chang, Perkins, Kimberly
• Primary Examiner(s): Tate, Christopher R.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US10/405,190
• Publication Number:
  US 20030216542A1
• Time in Patent Office: 770 Days
• Field of Search: 424/45, 424/46, 424/473, 424/499, 528/354
• US Class Current: 424/45
• CPC Class Codes: A61K 38/28 Insulins
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

The present invention provides active, hydrophilic polymer-modified derivatives of insulin. The insulin derivatives of the invention are, in one aspect, suitable for delivery to the lung and exhibit pharmakokinetic and/or pharmacodynamic properties that are significantly improved over native insulin.

Claims

1. A polymer conjugate comprising proinsulin covalently attached to one or more molecules of polyethylene glycol.

2. The conjugate of claim 1, wherein proinsulin is covalently attached to one molecule of polyethylene glycol (PEG).

3. The conjugate of claim 2, wherein said proinsulin is covalently attached to polyethylene glycol at a site selected from the group consisting of B1, B29 and A1.

4. The conjugate of claim 2, wherein said polyethylene glycol is attached to the A1 site of proinsulin.

5. The conjugate of claim 2, wherein said polyethylene glycol is attached only to the B1 site of proinsulin.

6. The conjugate of claim 2, wherein said polyethylene glycol is attached only to the B29 site of proinsulin.

7. The conjugate of claim 1, wherein said PEG is selected from the group consisting of linear, branched, dumbbell, and forked PEG.

8. The conjugate of claim 7, wherein said PEG is a branched PEG having a single reactive site for covalent attachment to proinsulin.

9. The conjugate of claim 8, wherein said PEG is a branched PEG having 2 or more arms.

10. The conjugate of claim 1, wherein said proinsulin is covalently attached to PEG via a hydrolytically stable linkage.

11. The conjugate of claim 1, wherein said polymer conjugate has the structure PEG1-W-PEG2-proinsulin, wherein W represents a degradable linkage.

12. The conjugate of claim 1, wherein said PEG has a molecular weight ranging from about 200 to about 40,000 daltons.

13. The conjugate of claim 1, wherein said PEG has a molecular weight selected from the group consisting of:

200, 300, 400, 500, 600, 750, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 5000, 10,000, 15,000, 20,000, 30,000 and 40,000 daltons.

14. The conjugate of claim 1, wherein said PEG covalently attached to proinsulin is selected from the group consisting of mPEG2-ALD, mPEG-succinimidyl propionate, mPEG succinimidyl butanoate, mPEG-CM-HBA-NHA, mPEG-benzotriazole carbonate, PEG carboxymethyl-NHS, PEG succinimidyl carbonate, PEG succinimidyl succinate, and mPEG-aceteldehyde diethyl acetal.

15. A polymer conjugate of claim 1, having a purity of 95% or greater by weight.

16. A polymer conjugate of claim 6, having a purity of 95% or greater by weight.

17. A polymer conjugate of claim 10, wherein said hydrolytically stable linkage is selected from the group consisting of an ether, an amide, and a urethane.

18. A composition comprising a conjugate of claim 1 and an excipient.

19. A polymer conjugate of claim 11, wherein said degradable linkage is selected from the group consisting of carboxylate ester, phosphate ester, anhydride, acetal, ketal, acyloxyalkyl ether, imine, and orthoester.