Biocompatible crosslinked polymers with visualization agents

• US 7,332,566 B2
• Filed: 12/02/2005
• Issued: 02/19/2008
• Est. Priority Date: 09/23/1996
• Status: Expired due to Term

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Edelman, Peter G., Pathak, Chandrashekhar P., Sawhney, Amarpreet S.
• Primary Examiner(s): Weber; Jon
• Assistant Examiner(s): Mohamed; Abdel A
• Application Number:
  US11/293,892
• Publication Number:
  US 20060147409A1
• Time in Patent Office: 809 Days
• Field of Search: 530/200, 530/350, 525/54.1, 525/54.11, 525/54.2, 528/354, 528/361, 424/428, 424/486, 424/488
• US Class Current: 530/200
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 24/106 Fibrin; Fibrinogen
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: C07K 14/75 Fibrinogen
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids
• 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

Abstract

Biocompatible crosslinked polymers, and methods for their preparation and use, are disclosed in which the biocompatible crosslinked polymers are formed from water soluble precursors having electrophilic and nucleophilic functional groups capable of reacting and crosslinking in situ. Methods for making the resulting biocompatible crosslinked polymers biodegradable or not are provided, as are methods for controlling the rate of degradation. The crosslinking reactions may be carried out in situ on organs or tissues or outside the body. Applications for such biocompatible crosslinked polymers and their precursors include controlled delivery of drugs, prevention of post-operative adhesions, coating of medical devices such as vascular grafts, wound dressings and surgical sealants. Visualization agents may be included with the crosslinked polymers.

Claims

1. A polymeric coating for a substrate comprising:

water, a biocompatible visualization agent, and a biodegradable hydrogel, that is essentially completely degradable in vivo by hydrolytic degradation, with the hydrogel having an interior and an exterior, with the exterior having a substrate coating surface, and the visualization agent being at least partially disposed within the interior,

wherein the hydrogel comprises chemical groups that are prone to aqueous hydrolysis and is thereby degradable in vitro by exposure to aqueous solution, and

wherein the visualization agent has a predetermined concentration that indicates a predetermined thickness of the hydrogel as deposited on the substrate.

2. The polymeric coating of claim 1 wherein the hydrogel comprises a reaction product of a synthetic polymer that comprises electrophilic functional groups and at least one of dilysine, trilysine or tetralysine.

3. The polymeric coating of claim 1 wherein the visualization agent is chosen from the group consisting of FD&

C Blue #1, FD&

C Blue #2, methylene blue, indocyanine green, visualization agents that provide a blue color, and visualization agents that provide a green color.

4. The polymeric coating of claim 1 wherein the visualization agent is not covalently linked to the hydrogel.

5. The polymeric coating of claim 1 wherein the hydrogel comprises a biologically active agent.

6. The polymeric coating of claim 1 wherein the bydrogel forms within 60 seconds after contact with the substrate.

7. The polymeric coating of claim 1 wherein the hydrogel forms within 5 seconds after contact with the substrate.

8. The polymeric coating of claim 1 wherein the biodegradable hydrogel is adherent to the substrate.

9. The polymeric coating of claim 1 wherein the hydrogel is free of amino acid sequences of more than about four residues in number.

10. The polymeric coating of claim 1 wherein the predetermined thickness is from about 0.5 to about 10.0 mm.

11. The polymeric coating of claim 1 wherein the predetermined thickness of the hydrogel is indicated by an observable change of not being able to see the substrate tissue through the polymer composition, not being able to see patterns in the substrate tissue surface through the polymer composition, the features of the substrate are obscured, or not being able to see the microvasculature on the substrate tissue.

12. A method of preparing a composition suitable to coat a tissue substrate of a patient, the method comprising:

mixing reactive precursor species comprising nucleophilic functional groups, reactive precursor species comprising electrophilic functional groups, and at least about 0.1 mg/ml of an unbleached visualization agent such that the nucleophilic functional groups react with the electrophilic functional groups to form covalent bonds and crosslink the reactive precursor species after the mixing to form a covalently crosslinked biodegradable hydrogel contacting the tissue substrate and having an interior and an exterior, with the exterior having at least one tissue substrate coating surface and the visualization agent being at least partially disposed within the interior,

wherein the hydrogel comprises chemical groups that are prone to aqueous hydrolysis and is thereby degradable in vitro by exposure to aqueous solution, and

wherein the visualization agent has a predetermined concentration that indicates a predetermined thickness of the hydrogel as deposited on substrate.

13. The method of claim 12 wherein the reactive species comprising nucleophilic functional groups is dilysine, trilysine, or tetralysine.

14. The method of claim 12 wherein the nucleophilic functional groups comprise primary amines or primary thiols.

15. The method of claim 12, wherein the visualization agent is chosen from the group consisting of FD&

C Blue #1, FD&

C Blue #2, methylene blue, indocyanine green, visualization agents that provide a blue color, and visualization agents that provide a green color.

16. The method of claim 12, wherein the visualization agent is not covalently linked to the hydrogel.

17. The method of claim 12, wherein the hydrogel comprises a biologically active agent.

18. The method of claim 12, wherein the hydrogel forms within 60 seconds after contact with the tissue.

19. The method of claim 12, wherein the hydrogel forms within 5 seconds after contact with the tissue.

20. The method of claim 12, wherein the biodegradable bydrogel is adherent to the tissue.

21. The method of claim 12, wherein the hydrogel is free of amino acid sequences of more than about four residues in number.

22. The method of claim 12 wherein the predetermined thickness of the hydrogel is indicated by an observable change of not being able to see the substrate tissue through the polymer composition, not being able to see patterns in the substrate tissue surface through the polymer composition, the features of the substrate are obscured, or not being able to see the microvasculature on the substrate tissue.

23. The method of claim 12, wherein the predetermined thickness is from about 0.5 to about 10.0 mm.

24. A hydrogel composition adapted for use with a tissue of a patient, the composition being made by the method of claim 12.

25. A method for formulating a polymer composition that crosslinks to form a biodegradable hydrogel that is essentially completely degradable in vivo by hydrolytic degradation, the method comprising selecting a concentration of visualization agent for the polymer composition that results in a visually observable change when the polymer composition is applied to a substrate tissue at a predetermined thickness to form the crosslinked biodegradable bydrogel on the substrate tissue,

wherein the hydrogel comprises chemical groups that are prone to aqueous hydrolysis and is thereby degradable in vitro by exposure to aqueous solution, and

wherein the observable change is not being able to see the substrate tissue through the polymer composition, not being able to see patterns in the substrate tissue surface through the polymer composition, the features of the substrate are obscured, or not being able to see the microvasculature on the substrate tissue.

26. The method of claim 25 wherein the hydrogel comprises a reaction product of a synthetic polymer that comprises electrophilic functional groups and dilysine, trilysine, or tetralysine, wherein the reaction product is formed through the crosslinking between the electrophilic functional groups of the synthetic polymer and the amino groups, of the dilysine, trilysine, or tetralysine.

27. The method of claim 25, wherein the visualization agent is chosen from the group consisting of FD&

C Blue #1, FD&

C Blue #2, methylene blue, indocyanine green, visualization agents that provide a blue color, and visualization agents that provide a green color.

28. The method of claim 25 wherein the visualization agent is not covalently linked to the hydrogel.

29. The method of claim 25 wherein the hydrogel further comprises a biologically active agent.

30. The method of claim 25 wherein the biodegradable hydrogel is adherent to the substrate tissue.

31. The method of claim 25 wherein the hydrogel is free of amino acid sequences of more than about four residues in number.

32. The method of claim 25 wherein the predetermined thickness is from about 0.5 mm to about 10.0 mm.

33. The method of claim 25 wherein the polymer composition crosslinks to form a hydrogel within about 60 seconds after being applied to the substrate.

34. The method of claim 25 wherein the hydrogel forms within 5 seconds after contact with the substrate.

35. A hydrogel composition adapted for use with a tissue of a patient, the composition being made by the method of claim 25.

36. The method of claim 25 wherein the hydrogel comprises a reaction product of a synthetic polymer that comprises electrophilic functional groups and a synthetic polymer that comprises a plurality of primary amines or primary thiols, wherein the reaction product is formed through the crosslinking between the electrophilic the functional groups of the synthetic polymer and the plurality of primary amines or primary thiols in the other synthetic polymer.

37. The method of claim 36 wherein the hydrogel forms within 60 seconds after contact with the substrate.

38. The method of claim 36 wherein the hydrogel forms within 5 seconds after contact with the substrate.