Hybrid coating for medical devices

• US 6,179,817 B1
• Filed: 01/28/1999
• Issued: 01/30/2001
• Est. Priority Date: 02/22/1995
• Status: Expired due to Fees

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Boston Scientific Corporation
• Inventors: Zhong, Sheng-Ping
• Primary Examiner(s): Beck, Shrive
• Assistant Examiner(s): MICHENER, JENNIFER KOLB
• Application Number:
  US09/238,707
• Time in Patent Office: 733 Days
• Field of Search: 427/2.1, 427/2.13, 427/2.24, 427/2.3, 604/265, 525/54.2, 523/112
• US Class Current: 604/265
• CPC Class Codes: A61L 2300/21 Acids
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• 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: C08L 75/04 Polyurethanes

Abstract

Disclosed are hybrid coatings for implantable medical devices. Such coatings include a first layer of an aqueous dispersion or emulsion of an organic acid functional group containing polymer, a crosslinker and a therapeutic agent dispersed therein. The coating also includes a second layer of an aqueous solution or dispersion of an organic acid functional group-containing bio-active agent. The hybrid coatings are especially suited for preventing restenosis of endoprostheses by the combined action of the therapeutic agent and the bio-active agent. Methods of making and using devices coated with such compositions are also provided.

Claims

1. A coating composition for rendering substrates bio-compatible and delivering therapeutic agents in vivo comprising:

i. an aqueous dispersion or emulsion of an organic acid functional group-containing polymer and an excess of a polyfunctional crosslinker which is reactive with said organic acid functional groups of said polymer;

ii. a therapeutic agent dispersed within said aqueous dispersion or emulsion, said therapeutic agent being substantially non-reactive with said polymer or said crosslinker; and

iii. an aqueous solution or dispersion of an organic acid functional group-containing bio-active agent or equivalent thereof, said polymer covalently bonded to said organic acid functional groups on said bio-active agent through said unreacted excess polyfunctional crosslinker.

2. The coating composition of claim 1, wherein said organic acid functional groups are selected from the group consisting of free carboxylic acid, free sulfonic acid, free phosphoric acid, and combinations thereof.

3. The coating composition of claim 1, wherein said polyfunctional crosslinking agent has more than two functional groups per molecule.

4. The coating composition of claim 1, wherein said polymer is one of an organic acid functional group-containing homo- and copolymer.

5. The coating composition of claim 1, wherein said polymer is selected from the group consisting of polyurethanes, polyacrylates, poly(meth)acrylates, polyisocrotonates, epoxy resins, (meth)acrylate-urethane copolymers and combinations thereof.

6. The coating composition of claim 1, wherein said polymer is a (meth)acrylate-urethane copolymer.

7. The coating composition of claim 1, wherein said polymer is a polyurethane.

8. The coating composition of claim 1, wherein said bio-active agent is selected from the group consisting of anti-thrombogenic agents, antibiotic agents, anti-inflammatory agents, equivalents and mixtures thereof.

9. The coating composition of claim 1, wherein said therapeutic agent is selected from the group consisting of anti-tumor agents, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-mitotic agents, angiostatin agents, endostatin agents, cell cycle regulatory agents, genetic agents, growth hormones, equivalents and mixtures thereof.

10. The coating composition of claim 1, wherein said bio-active agent is an organic acid functional group-containing polysaccharide.

11. The coating composition of claim 10, wherein said polysaccharide is a glycosaminoglycan.

12. The coating composition of claim 11, wherein said glycosaminoglycan is selected from the group consisting of heparin, hirudin, heparin sulfate, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratin sulfate, prostoctein, reopro, integrin and equivalents thereof.

13. The coating composition of claim 1 wherein said bio-active agent is heparin or a chemically modified equivalent thereof and said therapeutic agent is paclitaxel or equivalent thereof.

14. The coating composition of claim 1, wherein the concentration of said polymer is from about 1% to about 60% by weight solids content.

15. The coating composition of claim 1, wherein the concentration of said polymer is from about 1% to about 40% by weight solids content.

16. The coating composition of claim 1, wherein the concentration of said polyfunctional crosslinker in i. is from about 0.2% to about 40% by weight solids content of said first coating.

17. The coating composition of claim 1, wherein said polymer is covalently bonded to said bio-active agent via said polyfunctional crosslinker at a temperature below about 120°

C.

18. The coating composition of claim 1, wherein said polymer is covalently bonded to said bio-active agent via said polyfunctional crosslinker at a temperature between about 10°

C. and about 70°

C.

19. An implantable device coated with a composition according to claim 1.

20. A medical device having a coating on at least a portion of a surface thereof, said coating comprising:

i. a first layer formed from (a) an aqueous dispersion or emulsion of an organic acid functional group-containing polymer, (b) an excess of a polyfunctional crosslinker which is reactive with said organic acid groups and (c) a therapeutic agent dispersed within said aqueous dispersion or emulsion, wherein said therapeutic agent is substantially non-reactive with (a) or (b); and

ii. a second coating of an aqueous solution or dispersion containing an organic acid functional group-containing bio-active agent or equivalent thereof, said first coating covalently bonded to said second coating through said excess crosslinker and said organic acid functional groups on said bio-active coating, wherein said therapeutic agent is releasable from said first coating and said bio-active agent substantially remains on a surface of said medical device.

21. The medical device of claim 20, wherein said surface is selected from the group consisting of polymeric compositions, non-polymeric compositions and combinations thereof.

22. The medical device of claim 20, wherein said surface is selected from the group of consisting of olefin polymers, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, polyvinyl acetate, polystyrene, poly(ethylene terephthalate), polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes, natural rubbers, polyether-ester copolymers, styrene-butadiene copolymers and combinations thereof.

23. The medical device of claim 20, wherein said surface is selected from the group consisting of ceramics, metals, glasses and combinations thereof.

24. The medical device of claim 20, wherein said device is an endoprosthesis.

25. The medical device of claim 24, wherein said endoprosthesis is selected from the group consisting of grafts, stents and graft-stent devices.

26. The medical device of claim 24, wherein said endoprosthesis is selected from the group consisting of catheters, guidewires, trocars and introducer sheaths.

27. The medical device of claim 20, wherein said bio-active agent is selected from the group consisting of anti-thrombogenic agents, antibiotic agents, anti-inflammatory agents, equivalents and mixtures thereof.

28. The medical device of claim 20, wherein said therapeutic agent is selected from the group consisting of anti-tumor agents, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-mitotic agents, angiostatin agents, endostatin agents, cell cycle regulatory agents, genetic agents, growth hormones, equivalents and mixtures thereof.

29. The medical device of claim 20, wherein said bio-active agent is heparin or a chemically modified equivalent thereof and said therapeutic agent is paclitaxel or equivalent thereof.

30. A multi-layer coating composition for rendering substrates bio-compatible and delivering therapeutic agents in vivo comprising a reaction product of:

i. a first layer comprising an aqueous polymer dispersion or emulsion, a crosslinker and a therapeutic agent physically dispersed within said dispersion or emulsion, wherein said therapeutic agent is releasable from said first layer and is substantially non-reactive with said polymer or said crosslinker; and

ii. a second layer comprising an aqueous solution or dispersion containing a bio-active agent, wherein said polymer of said first layer is covalently bonded to said bio-active agent through said crosslinker.

31. The coating composition of claim 30, wherein said polymer and bio-active agent contain organic acid functional groups.

32. The coating composition of claim 30, wherein said crosslinker is a polyfunctional crosslinker which is reactive with said organic acid functional groups of said polymer but not said therapeutic agent.

33. The coating composition of claim 30, wherein said therapeutic agent is paclitaxel or equivalent thereof and said bio-active agent is heparin or equivalent thereof.

34. An implantable medical device having at least a portion of said device coated with said coating according to claim 30, wherein said bio-active agent remains permanently attached to a surface of said medical device while said therapeutic agent is controllably releasable from said first layer.