Branched polymers

• US 9,187,569 B2
• Filed: 07/17/2014
• Issued: 11/17/2015
• Est. Priority Date: 11/07/2001
• Status: Expired due to Fees

• Current Assignee: Nektar Therapeutics
• Original Assignee: Nektar Therapeutics
• Inventors: Bentley, Michael D., Zhao, Xuan, Shen, Xiaoming, Battle, William D. III
• Primary Examiner(s): Krishnan, Ganapathy
• Application Number:
  US14/334,223
• Publication Number:
  US 20140329994A1
• Time in Patent Office: 488 Days
• Field of Search: 530/383, 548/547
• US Class Current: 1/1
• 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: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: C07K 17/08 the carrier being a synthetic polymer
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 65/48 Polymers modified by chemical after-treatment
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C12N 9/96 Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates

Abstract

The present invention is directed to branched reactive water-soluble polymers comprising at least two polymer arms, such as poly(ethylene glycol), attached to a central aliphatic hydrocarbon core molecule through heteroatom linkages. The branched polymers bear at least one functional group for reacting with a biologically active agent to form a biologically active conjugate. The functional group of the branched polymer can be directly attached to the aliphatic hydrocarbon core or via an intervening linkage, such as a heteroatom, -alkylene-, —O-alkylene-O—, -alkylene-O-alkylene-, -aryl-O—, —O-aryl-, (—O-alkylene-)_m, or (-alkylene-O—)_m linkage, wherein m is 1-10.

Claims

1. A branched reactive polymer having the structure:

Y—

(X)p-R(—

X′

-POLY)_q

wherein;

R is an aliphatic hydrocarbon having a length of at least three carbon atoms;

each POLY is a poly(ethylene glycol) that terminates with a hydroxyl or methoxy group;

X′

is a heteroatom linkage selected from —

NH—

, —

O—

or —

S—

;

X is a linker of 1 to ten atoms;

p is 0 or 1;

q is 2 to about 10; and

Y is a maleimide,

and further wherein the branched reactive polymer has a molecular weight of about 500 Da to about 100,000 Da.

2. The branched reactive polymer of claim 1, wherein X′

is —

O—

.

3. The branched reactive polymer of claim 1, wherein q is 2 to about 5.

4. The branched reactive polymer of claim 1, wherein each POLY is symmetrically located on the aliphatic hydrocarbon.

5. The branched reactive polymer of claim 1, wherein R comprises from 3 to about 7 carbon atoms.

6. The branched reactive polymer of claim 1, wherein R comprises three carbon atoms.

7. The branched reactive polymer of claim 1, wherein each POLY is linear or branched.

8. The branched reactive polymer of claim 1, wherein p is 1 and X is selected from the group consisting of a heteroatom, -alkylene-, —

O-alkylene-O—

, -alkylene-O-alkylene-, -aryl-O—

, —

O-aryl-, (—

O-alkylene-)_m, and (-alkylene-O—

)_m, wherein m is 1-10.

9. The branched reactive polymer of claim 1, wherein p is 0.

10. A biologically active conjugate, comprising a biologically active molecule covalently attached to a branched reactive polymer of claim 1, wherein the biologically active molecule is a biologically active protein.

11. The branched reactive polymer of claim 1, wherein the branched reactive polymer has a molecular weight of about 5,000 Da to about 60,000 Da.

12. The biologically active conjugate of claim 10, wherein the biologically active protein is a biologically active fragment of Factor VIII.