Antifouling heparin coatings

• US 9,561,309 B2
• Filed: 05/27/2004
• Issued: 02/07/2017
• Est. Priority Date: 05/27/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Glauser, Thierry, Michal, Eugene, Claude, Charles, Pacetti, Stephen D.
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): HELM, CARALYNNE E
• Application Number:
  US10/857,141
• Publication Number:
  US 20050266038A1
• Time in Patent Office: 4,639 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C08L 1/00 Compositions of cellulose, modified cellulose or cellulose derivatives
• CPC Class Codes: C08L 2666/26 Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
• CPC Class Codes: C08L 33/14 of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen

Abstract

A medical device comprising a coating thereon comprising a biocompatible polymer and heparin is provided herein. Heparin is coupled with the biocompatible polymer via a spacer having a grouping that renders a binding site of the heparin molecule accessible by a binding protein. The medical device can be implanted in a human being for the treatment of a disease such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

Claims

1. A medical device comprising a substrate and a polymeric coating which comprises a biocompatible polymer and heparin,

wherein heparin is attached to the biocompatible polymer via a spacer having a grouping that renders a binding site of the heparin molecule accessible by a binding protein,

wherein the spacer is of a formula of Y-R-X where X and Y represent two functional groups and R represents a monomeric di-radical;

wherein X and Y groups are independently selected from the group consisting of hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isocyanate, di-isocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, a diamine, N-hydroxy-succinamide, acryloxy terminated polyethylene, glycol, methacryloxy terminated polyethylene glycol, and isothiocyanate; and

R is a dextrose di-radical; and

wherein heparin is molecular heparin, a fragment of heparin, or a derivative thereof.

2. The medical device of claim 1 wherein the heparin is a heparin bearing a hydrophobic counter ion or a hydrophobic material.

3. The medical device of claim 2, wherein the polymeric coating further comprises a bioactive agent.

4. The medical device of claim 1 wherein the biocompatible polymer is selected from the group consisting of poly(ester amides), polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), and combinations thereof.

5. The medical device of claim 4, wherein the polymeric coating further comprises a bioactive agent.

6. The medical device of claim 1, wherein the polymeric coating further comprises a bioactive agent.

7. The medical device of claim 6 wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, ABT-578, clobetasol, and combinations thereof.

8. The medical device of claim 6 wherein the bioactive agent is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, and antioxidant substances, cytostatic agents, and combinations thereof.

9. A method of treating a disorder in a human being by implanting in the human being the medical device as defined in claim 6,

wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

10. A method of treating a disorder in a human being by implanting in the human being the medical device as defined in claim 1,

wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

11. The medical device of claim 1, wherein the biocompatible polymer is selected from the group consisting of poly(ester amides), polystyrene-polyisobutylene-polystyrene block copolymers (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylenes, polyhydroxyalkanoates, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), poly(trimethylene carbonate), poly(ortho esters), polyphosphazenes, poly(phosphoesters), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), poly- dimethylsiloxane, poly(butyl methacrylate), poly(methyl methacrylate) (PMMA), poly(meth- acrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate), poly(urea-urethanes), polymers and copolymers of PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC), and/or n-vinyl pyrrolidone (VP);

polymers and copolymers of carboxylic acid bearing monomers;

polymers and copolymers formed of methacrylic acid (MA), and/or acrylic acid (AA);

polymers and copolymers formed of hydroxyl bearing monomers;

polymers and copolymers formed of hydroxyl ethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, 3-trimethylsilylpropyl methacrylate (TMSPMA), alkoxymethacrylate, and/or alkoxyacrylate;

poly(ethylene glycol)(PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS- PEG, polypropylene oxide-co-polyethylene glycol surfactants, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxides, dextran, dextrin, sodium hyaluronate, hyaluronic acid, elastin, chitosan, and combinations thereof.

12. A polymeric composition comprising a biocompatible polymer and heparin,

wherein heparin is attached to the biocompatible polymer via a spacer having a grouping that renders a binding site of the heparin molecule accessible by a binding protein,

wherein the spacer has a formula of Y—

R—

X where X and Y represent two functional groups and R represents a monomeric di-radical;

wherein X and Y groups are independently selected from the group consisting of hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isooyanate, di-isocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, a diamine, a primary amine side group on a polymer, N-hydroxy- succinamide, acryloxy terminated polyethylene glycol, methacryioxy terminated polyethylene glycol, and isothiocyanate; and

R is a dextrose di-radical; and

wherein heparin is molecular heparin, a fragment of heparin, or a derivative thereof.

13. The polymeric composition of claim 12 wherein the heparin is a heparin bearing a hydrophobic counter ion or a hydrophobic material.

14. The polymeric composition of claim 13 further comprising a bioactive agent.

15. The polymeric composition of claim 12, wherein the biocompatible polymer is selected from the group consisting of poly(ester amides), polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), and combinations thereof.

16. The polymeric composition of claim 15 further comprising a bioactive agent.

17. The polymeric composition of claim 12 further comprising a bioactive agent.

18. The polymeric composition of claim 17 wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, ABT-578, clobetasol, and combinations thereof.

19. The polymeric composition of claim 17, wherein the bioactive agent is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, and antioxidant substances, cytostatic agents, and combinations thereof.

20. The polymeric composition of claim 12, wherein the biocompatible polymer is selected from the group consisting of poly(ester amides), polystyrene- polyisobutylene-polystyrene, block copolymers (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylenes, polyhydroxyalkanoates, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), poly(trimethylene carbonate), poly(ortho esters), polyphosphazenes, poly(phosphoesters), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polydimethylsiloxane, poly(butyl methacrylate), poly(methyl methacrylate) (PMMA), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone- urethanes), poly(2-hydroxyethyl methacrylate), poly(urea-urethanes), polymers and copolymers of PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC), and/or n-vinyl pyrrolidone (VP);

polymers and copolymers of carboxylic acid bearing monomers;

polymers and copolymers formed of methacrylic add (MA), and/or acrylic add (AA);

polymers and copolymers formed of hydroxyl bearing monomers;

polymers and copolymers formed of hydroxyl ethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, 3-trimethylsilylpropyl methacrylate (TMSPMA), alkoxymethacrylate, and/or alkoxyacrylate;

poly(ethylene glycol)(PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS- PEG, polypropylene oxide-co-polyethylene glycol surfactants, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxides, dextran, dextrin, sodium hyaluronate, hyaluronic add, elastin, chitosan, and combinations thereof.

21. A method of making a polymeric composition comprising a biocompatible polymer and heparin, comprising:

providing a biocompatible polymer which is optionally functionalized,

providing heparin which is optionally functionalized, and coupling heparin to the biocompatibie polymer via a spacer having a grouping that renders a binding site of the heparin molecule accessible by a binding protein,

wherein the spacer is of a formula of Y—

R—

X where X and Y represent two functional groups and R represents a monomeric di-radical;

wherein X and Y groups are independently selected from the group consisting of hydroxyl, epoxide, carboxyl, amino, imide, aziridine, thiol, phosphoryl, aldehyde, anhydride, acyl halide, silyl, isocyanate, di-isocyanate, carbodiimide, a dihydrazide, a multiaziridine, a multifunctional carbodiimide, a diamine, N-hydroxy-succinamide, acryloxy terminated polyethylene glycol, methacryloxy terminated polyethylene glycol, and isothiocyanate; and

R is a dextrose di-radical; and

wherein heparin is molecular heparin, a fragment of heparin, or a derivative thereof.

22. The method of claim 21 wherein the heparin is a heparin bearing a hydrophobic counter ion or a hydrophobic material.

23. The method of claim 21 wherein the biocompatible polymer is selected from the group consisting of polyester amides), polystyrene-polyisobutylene-polystyrene block copolymers (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylenes, polyhydroxyalkanoates, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), poly(trirnethylene carbonate), poly(ortho esters), polyphosphazenes, poly(phosphoesters), poly(tyrosine, derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polydimethylsiloxane, poly(butyl methacrylate), poly(methyl methacrylate) (PMMA), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate), poly(urea-urethanes), polymers and copolymers of PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and/or n-vinyl pyrrolidone (VP);

polymers and copolymers of carboxylic acid bearing monomers;

polymers and copolymers formed of methacrylic acid (MA), and/or acrylic acid (AA);

polymers or copolymers formed of hydroxyl bearing monomers;

polymers or copolymers formed of hydroxy ethyl methacrylate (HEMA), hydroxypropl methacrylate (HPMA), hydroxypropylmethacrylamide, 3- trimethylsilylpropyl methacrylate (TMSPMA), alkoxymethacrylate, and/or alkoxyacrylate;

poly(ethylene glycol)(PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, polypropylene oxide-co-polyethylene glycol surfactants, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxides,-dextran, dextrin, sodium hyaluronate, hyaluronic acid, elastin, chitosan, and combinations thereof.