Branched Polymers

• US 8,273,833 B2
• Filed: 12/08/2010
• Issued: 09/25/2012
• Est. Priority Date: 11/07/2001
• Status: Expired due to Term

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Bentley, Michael David, Zhao, Xuan, Shen, Xiaoming, Battle, William Dudley III
• Primary Examiner(s): Jiang, Shaojia Anna
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US12/963,170
• Publication Number:
  US 20110077362A1
• Time in Patent Office: 657 Days
• Field of Search: 525/7, 525/54.1, 525/54.11, 525/418, 525/472, 530/402, 530/409, 530/410
• US Class Current: 525/418
• 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 ether 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;

Y is a functional group reactive with an electrophilic or nucleophilic group;

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

X′

is —

O—

;

X is a linker of 1 to 10 atoms in length;

P is 0 or 1;

q is 2 to about 10; and

each POLY is a water soluble and non-peptidic polyethylene glycol (PEG) polymer that terminates with a hydroxyl or methoxy group,

and further wherein the branched polymer has a molecular weight of about 12,000 Da to about 100,000 Da.

2. The reactive polymer of claim 1, wherein each water soluble and non-peptidic polymer is a PEG that terminates with a hydroxyl group.

3. The reactive polymer of claim 1, wherein each water soluble and non-peptidic polymer is a PEG that terminates with a methoxy group.

4. The reactive polymer of claim 1, wherein Y selected from the group consisting of hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, alkanoic acid, acid halide, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, and tresylate.

5. The 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.

6. The reactive polymer of claim 1, wherein p is 0 and Y is hydroxyl.

7. The reactive polymer of claim 1, wherein the branched polymer has a molecular weight of about 20,000 Da.

8. The reactive polymer of claim 1, wherein the branched polymer has a molecular weight of about 40,000 Da.

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

10. The reactive polymer of claim 1, having the structure: