Branched polymers

• US 8,809,453 B2
• Filed: 04/18/2013
• Issued: 08/19/2014
• 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): Krishnan, Ganapathy
• Application Number:
  US13/865,912
• Publication Number:
  US 20130295639A1
• Time in Patent Office: 488 Days
• Field of Search: 525/54.1, 525/54.11, 564/506, 568/62, 530/402, 530/409, 530/410
• US Class Current: 525/54.1
• 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 biologically active conjugate comprising a branched polymer covalently attached to a biologically active molecule, wherein the conjugate has the structure:

D-L₁-(X)_p—

RX′

-POLY)_q

wherein;

D is the biologically active molecule;

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

L₁ is a linkage resulting from the reaction of a functional group on the linker (X), when present, or on the aliphatic hydrocarbon having a length of at least three carbon atoms (R) of the branched polymer and a functional group of the biologically active molecule;

each POLY is a water soluble and non-peptidic polymer that terminates with a hydroxyl or methoxy group;

X′

is —

O—

, —

NH—

, or —

S—

;

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

p is 0 or 1; and

q is 2,

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

2. The biologically active conjugate of claim 1, wherein D is selected from the group consisting of peptides, proteins, enzymes, drugs, dyes, lipids, nucleosides, nucleotides, oligonucleotides, polynucleotides, nucleic acids, polysaccharides, steroids, cells, viruses, liposomes, micelles, and fats.

3. The biologically active conjugate of claim 2, wherein R is an aliphatic hydrocarbon having 3 to 7 carbon atoms.

4. The biologically active conjugate of claim 3, wherein R is an aliphatic hydrocarbon having 3 carbon atoms.

5. The biologically active conjugate of claim 4, wherein X′

is —

O—

.

6. The biologically active conjugate of claim 5, wherein each POLY is a poly(ethylene glycol).

7. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 12,000 Da to about 60,000 Da.

8. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 12,000 Da to about 40,000 Da.

9. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 20,000 Da.

10. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 30,000 Da.

11. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 40,000 Da.

12. The biologically active conjugate of claim 6, wherein the branched polymer has a molecular weight of about 60,000 Da.

13. The biologically active conjugate of claim 6, wherein each POLY is symmetrically located on the aliphatic hydrocarbon.

14. The biologically active conjugate of claim 6, wherein each POLY has a molecular weight of about 6,000 Da to about 50,000 Da.

15. The biologically active conjugate of claim 6, wherein each POLY has a molecular weight of about 6,000 Da to about 20,000 Da.

16. The biologically active conjugate of claim 6, wherein each POLY has a molecular weight of about 10,000 Da.

17. The biologically active conjugate of claim 6, wherein each POLY has a molecular weight of about 15,000 Da.

18. The biologically active conjugate of claim 6, wherein each POLY has a molecular weight of about 20,000 Da.