Nitric oxide-producing hydrogel materials

• US 20030012816A1
• Filed: 05/17/2002
• Published: 01/16/2003
• Est. Priority Date: 09/02/1999
• Status: Active Grant

• Current Assignee: Rice University
• Original Assignee: Rice University
• Inventors: West, Jennifer L, Masters, Kristyn Simcha
• Granted Patent: US 7,052,711 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• 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 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

Hydrogels releasing or producing NO, most preferably polymerizable biodegradable hydrogels capable of releasing physiological amounts of NO for prolonged periods of time, are applied to sites on or in a patient in need of treatment thereof for disorders such as restenosis, thrombosis, asthma, wound healing, arthritis, penile erectile dysfunction or other conditions where NO plays a significant role. The polymeric materials can be formed into films, coatings, or microparticles for application to medical devices, such as stents, vascular grafts and catheters. The polymeric materials can also be applied directly to biological tissues and can be polymerized in situ. The hydrogels are formed of macromers, which preferably include biodegradable regions, and have bound thereto groups that are released in situ to elevate or otherwise modulate NO levels at the site where treatment is needed. The macromers can form a homo or hetero-dispersion or solution, which is polymerized to form a hydrogel material, that in the latter case can be a semi-interpenetrating network or interpenetrating network. Compounds to be released can be physically entrapped, covalently or ionically bound to macromer, or actually form a part of the polymeric material. The hydrogel can be formed by ionic and/or covalent crosslinking. Other active agents, including therapeutic, prophylactic, or diagnostic agents, can also be included within the polymeric material.

Claims

1. A biocompatible, polymerizable, macromer composition comprising a macromer having at least one NO carrying region or NO modulating compound, wherein the NO or NO modulating compound is released from the macromer, and wherein the macromer further comprises one or more regions selected from the group consisting of a water soluble region, a cell adhesion ligand, and a polymerizable region.

2. The macromer composition of claim 1 further comprising a macromer that does not release NO following polymerization.

3. The macromer composition of claim 1 wherein the macromer comprises at least one degradable region.

4. The macromer composition of claim 1 wherein the macromer is water soluble.

5. The macromer composition of claim 1 wherein the macromer adheres to tissue.

6. The macromer composition of claim 1 further comprising therapeutic, prophylactic or diagnostic agents selected from the group consisting of proteins, carbohydrates, nucleic acids, organic molecules, inorganic molecules, biologically active molecules, cells, tissues, tissue aggregates, and diagnostic agents.

7. The macromer composition of claim 1 wherein the macromer comprises a water soluble region, an NO carrying region, a cell adhesion ligand, and a free radical polymerizable region.

8. The macromer composition of claim 7 further comprising a degradable region.

9. A method for modulating NO levels in tissue comprising administering to the tissue any of the macromer compositions of claims 1-8.

10. The macromer composition of claim 1 wherein the cell adhesion ligand is RGD, RGDS or REDV.

11. The macromer composition of claim 1 wherein the water soluble region is polyvinyl alcohol and the polymerizable group is an acrylamide.

12. The macromer composition of claim 1 wherein the macromer is an acryloyl-PEG-Cys-NO macromer.

13. The macromer composition of claim 1 wherein the macromer is an acryloyl-PEG-Lys₅-NO macromer.

14. The macromer composition of claim 1 wherein the macromer is a PEG-DETA-NO macromer.

15. The macromer composition of claim 1 wherein the macromer is a PVA-NH₂-NO macromer.

16. The macromer composition of claim 1 wherein the macromer is a PVA-Cys-NO macromer.

17. The macromer composition of claim 1 wherein the macromer is a PVA-NO-bFGF macromer.

18. The macromer composition of claim 1 wherein the cell adhesion ligand is part of the NO-releasing macromer.

19. The macromer composition of claim 1 wherein the macromer composition is a blend of two or more macromers, wherein at least one of the macromers has an NO carrying region or NO modulating compound, wherein the NO or NO modulating compound is released from the macromer composition, and wherein at least one of the macromers has at least one cell adhesion ligand.

20. A method of treating a disorder or condition with NO comprising administering to an individual in need thereof a biocompatible, polymerizable, macromer composition comprising at least one NO carrying region or NO modulating compound, wherein the NO or NO modulating compound is released from the macromer composition, wherein the macromer composition comprise a macromer having regions selected from the group consisting of a water soluble region, a cell adhesion ligand, and a polymerizable region.

21. The method of claim 20 wherein the macromer further comprises degradable regions.

22. The method of claim 20 for treatment of a disorder or condition selected from the group consisting of wound healing, restenosis, thrombosis, asthma, arthritis, and erectile dysfunction.

23. The method of claim 20 wherein the macromer is adhered to or coated onto tissue.

24. The method of claim 20 wherein the macromer is adhered to or coated onto a medical device for facilitating the growth of endothelial cells onto the medical device.

25. The method of claim 24 wherein the medical device or implant is a vascular graft, catheter or stent.

26. The method of claim 25 wherein the medical device is a graft for use in performing dialysis.

27. The method of claim 20 wherein the cell adhesion ligand is RGD, RGDS or REDV.

29. The method of claim 28 wherein the macromers further comprise a cell adhesion ligand that binds endothelial cells.

28. A method for increasing endothelial cell proliferation on a medical device comprising coating the medical device with a hydrogel coating formed from a polymerizable macromer composition comprising macromers having an NO carrying region or NO modulating compound, wheren the hydrogel coating releases NO in an amount sufficient to stimulate endothelial cell proliferation.