Crosslinking agents and methods of use

• US 6,887,974 B2
• Filed: 02/05/2002
• Issued: 05/03/2005
• Est. Priority Date: 09/23/1996
• Status: Expired due to Term

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Pathak, Chandrashekhar P.
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US10/068,807
• Publication Number:
  US 20020114775A1
• Time in Patent Office: 1,183 Days
• Field of Search: 530/200, 530/350, 530/380, 530/382, 525/54.1, 525/54.11, 525/54.2, 528/354, 528/361
• US Class Current: 530/200
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 24/106 Fibrin; Fibrinogen
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: C07K 1/30 by precipitation
• CPC Class Codes: C07K 14/745 Blood coagulation or fibrinolysis factors
• CPC Class Codes: C07K 14/75 Fibrinogen
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: G06K 2207/1016 Motor control or optical moving unit control
• CPC Class Codes: G06K 7/10831 Arrangement of optical elements, e.g. lenses, mirrors, prisms optical elements per se G02B
• CPC Class Codes: Y10S 435/81 Packaged device or kit

Abstract

Polymeric crosslinking agents are disclosed that have an inert water soluble polymeric component, biodegradable components, functional components reactive with chemical groups on a protein, for example, amine or thiol groups. The inert polymeric component may be flanked at each end with a biodegradable component which is flanked at each end with a protein reactive functional component. A polymeric crosslinking agent is disclosed having a biodegradable component, polyalkylene oxide, and at least three reactive functional groups that are each capable of forming a covalent bond in water with at least one functional group such as an amine, thiol, or carboxylic acid.

Claims

1. A water soluble polymeric crosslinking agent comprising:

an inert polymeric component,

a biodegradable component, and

a branch comprising a protein reactive functional component,

wherein said crosslinking agent comprises a plurality of branches, wherein said plurality is greater than two.

2. The crosslinking agent of claim 1 wherein said crosslinking agent is linear.

3. The crosslinking agent of claim 1, wherein said inert polymeric component is flanked at each end with said biodegradable component which is flanked at each end with said protein reactive functional component.

4. The crosslinking agent of claim 3, wherein the protein reactive functional component is chosen from the group consisting of carbodiizmidazole, sulfonyl chloride, chlorocarbonates, hydroxysuccinimidyl esters, aryl halides, sulfasuccinimidyl esters, and maleimides.

5. A polymeric crosslinking agent for use in vivo with a patient comprising a biologically inert core attached to a polymer having a biodegradable component with the polymer being attached to a reactive functional group capable of forming a covalent bond in water with at least one functional group chosen from the group consisting of amine and thiol, wherein the crosslinking agent has at least three functional groups and is water soluble.

6. The crosslinking agent of claim 5 wherein the biodegradable component does not contain amino acids assembled in amino acid sequences that are enzymatically degradable when the crosslinker is placed in a patient.

7. The crosslinking agent of claim 5 wherein the biodegradable component comprises a polymer chosen from the group consisting of glycoide, lactide, caprolactone, dioxanone, and trimethylene carbonate.

8. The crosslinking agent of claim 5 wherein the biodegradable component comprises a hydrolytically degradable chemical group chosen from the group consisting of ester, acetal, anhydride, orthoester, or disulfide.

9. The crosslinking agent of claim 5 wherein the biodegradable component comprises a polymer chosen from the group consisting of polyhydroxyacid, polyorthocarbonate, polyanhydride, polylactone, polyaminoacid, and polyphosphate.

10. The crosslinking agent of claim 5 wherein the biodegradable component is hydrolyzable under in vivo conditions.

11. A polymeric crosslinking agent for use in vivo with a patient comprising a biologically inert core attached to at least three branches that each comprise a biodegradable component hydrolyzable under in vivo conditions and the at least three branches are each terminated with a reactive end group capable of forming a covalent bond in water with at least one functional group chosen from the group consisting of amine and thiol wherein 1 g of the crosslinking agent is soluble in 100 milliliters of water.

12. The crosslinking agent of claim 11 having at least four of the branches.

13. The crosslinking agent of claim 11 wherein the biodegradable polymer comprises a polymer chosen from the group consisting of glycolide, lactide, caprolactone, dioxanone, and trimethylene carbonate.

14. The crosslinking agent of claim 11 wherein the biodegradable polymer comprises a polymer chosen from a group consisting of polyhydroxyacid, polyorthocarbonate, polyanhydride, polylactone, polyaminoacid, and polyphosphate.

15. The crosslinking agent of claim 11 having a molecular weight from 600 to 10,000 Dalton.

16. The crosslinking agent of claim 11 having a molecular weight from 600 to 100,000 Daltons.

17. The crosslinking agent of claim 11 wherein the core comprises polyalkylene oxide.

18. The crosslinking agent of claim 17 wherein the core comprises at least three sequential —

(CH₂CH₂O)—

repeats.

19. A method of making a polymeric crosslinking agent for use in vivo with a patient comprising activating at least three end groups of a polymer that comprises a biodegradable component hydrolyzable under in vivo conditions and polyalkylene oxide such that the polymer is thereby terminated with reactive functional groups that are capable of forming a covalent bond in water with at least one functional group chosen from the group consisting of amine and thiol.

20. The method of claim 19 comprising making the crosslinking agent to have a molecular weight from 600 to 10,000 Daltons.

21. The crosslinking agent of claim 19 having a molecular weight from 600 to 100,000 Daltons.

22. The method of claim 19 comprising choosing the biodegradable component to comprise a member of the group consisting of glycolide, lactide, caprolactone, dioxanone, and trimethylene carbonate.

23. The crosslinking agent made according to the process of claim 22.

24. The method of claim 19 comprising choosing the biodegradable component to comprise a member of the group consisting of polyhydroxyacid, polyorthocarbonate, polyanhydride, polylactone, polyminoacid, and polyphosphate.

25. The crosslinking agent made according to the process of claim 24.