Branched water-soluble polymers and their conjugates

• US 8,247,381 B2
• Filed: 08/17/2010
• Issued: 08/21/2012
• Est. Priority Date: 03/14/2003
• Status: Expired due to Fees

• Current Assignee: Ratiopharm GmbH (Teva Pharmaceutical Industries Limited)
• Original Assignee: Biogenerix Ag (Teva Pharmaceutical Industries Limited)
• Inventors: DeFrees, Shawn
• Primary Examiner(s): Lewis, Patrick
• Application Number:
  US12/858,247
• Publication Number:
  US 20100331489A1
• Time in Patent Office: 735 Days
• Field of Search: None
• US Class Current: 514/23
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: C07C 237/12 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 323/59 with acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07K 1/13 Labelling of peptides
• CPC Class Codes: C07K 5/022 containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 9/001 the peptide sequence having less than 12 amino acids and not being part of a ring structure

Abstract

The present invention provides branched water-soluble polymers that allow two or more water-soluble polymers to be conjugated to another species. The branched polymers provide access to therapeutic agents that are conjugated at a single site to two or more water-soluble polymers. The branched polymers are based upon branch points that are simple branched alkyl structures, reactive side-chain amino acids and small peptides of reactive side-chain amino acids, and saccharides. Also provided is a method for preparing mono-disperse poly(ethylene glycol) of a well-defined and determinable molecular weight, and a method for the rational end-functionalization of poly(ethylene glycol). Conjugates of the branched water-soluble polymers with diverse species, e.g., peptides, lipids, glycolipids and small molecules are also provided.

Claims

1. A branched water-soluble polymer having the formula:

2. The branched water-soluble polymer according to claim 1, wherein said water-soluble polymer comprises poly(ethylene glycol).

3. The branched water-soluble polymer according to claim 1, wherein said carrier molecule is a peptide, glycopeptide, lipid, or glycolipid.

4. The branched water-soluble polymer according to claim 1, wherein R¹⁵ is a nucleotide sugar.

5. The branched water-soluble polymer according to claim 4, wherein the nucleotide sugar is cytidine monophosphate (CMP).

6. The branched water-soluble polymer according to claim 1, wherein said carrier molecule is a protein, glycoprotein, saccharide, hormone, receptor, antigen, transition state analog, cofactor, drug, dye, nutrient, growth factor, solid support, virus, or microorganism.

7. The branched water-soluble polymer according to claim 2, wherein said poly(ethylene glycol) has a molecular weight selected from 5 kD, 10 kD, 20 kD, and 30 kD.

8. The branched water-soluble polymer according to claim 7, wherein said poly(ethylene glycol) has a molecular weight of 20 kD.

9. The branched water-soluble polymer according to claim 3, wherein said water-soluble polymer comprises poly(ethylene glycol).

10. The branched water-soluble polymer according to claim 9, wherein said poly(ethylene glycol) has a molecular weight selected from 5 kD, 10 kD, 20 kD, and 30 kD.

11. The branched water-soluble polymer according to claim 10, wherein said poly(ethylene glycol) has a molecular weight of 20 kD.

12. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 1 and a pharmaceutically acceptable carrier.

13. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 2 and a pharmaceutically acceptable carrier.

14. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 3 and a pharmaceutically acceptable carrier.

15. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 7 and a pharmaceutically acceptable carrier.

16. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 8 and a pharmaceutically acceptable carrier.

17. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 9 and a pharmaceutically acceptable carrier.

18. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 10 and a pharmaceutically acceptable carrier.

19. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 11 and a pharmaceutically acceptable carrier.