Lubricious, drug-accommodating coating

• US 6,218,016 B1
• Filed: 09/27/1999
• Issued: 04/17/2001
• Est. Priority Date: 09/29/1998
• Status: Expired due to Term

• Current Assignee: Medtronic Ave Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Ave Incorporated (Medtronic Plc)
• Inventors: Shah, Chirag B., Tedeschi, Eugene
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Fubara, Blessing
• Application Number:
  US09/405,024
• Time in Patent Office: 568 Days
• Field of Search: 428/423.1, 428/424.2, 428/424.4, 428/457, 428/461, 424/422, 424/405, 424/78.08, 427/385.5, 427/388.1, 427/393.5
• US Class Current: 428/423.1
• CPC Class Codes: A61L 2300/114 Nitric oxide, i.e. NO
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/606 Coatings
• 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: C08L 75/04 Polyurethanes
• CPC Class Codes: Y10T 428/31551 Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
• CPC Class Codes: Y10T 428/31573 Next to addition polymer of ethylenically unsaturated monomer
• CPC Class Codes: Y10T 428/31576 Ester monomer type [polyvinylacetate, etc.]
• CPC Class Codes: Y10T 428/31678 Of metal
• CPC Class Codes: Y10T 428/31692 Next to addition polymer from unsaturated monomers

Abstract

A coating is provided for a substrate comprising a polyisocyanate; an amine donor and/or hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid. The coating can accommodate a drug so that when the coating is applied to a medical device, the medical device becomes drug-releasing when in contact with aqueous body fluid. A coated article as well as a method for preparing the coating is also provided.

Claims

1. A drug-releasing coating, comprising:

at least one drug associated with and releasable from a polyurea network formed from the reaction on a substrate to be coated of a mixture comprising;

(a) a polyisocyanate;

(b) an amine;

(c) an isocyanatosilane adduct having at least one terminal isocyanate group and at least one hydrolyzable alkoxy group bonded to silicon; and

optionally

(d) a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.

2. The drug-releasing coating according to claim 1, wherein said polyisocyanate is an aromatic polyisocyanate based on toluene diisocyanate.

3. The drug-releasing coating according to claim 1, wherein said polymer has a mean molecular weight from about 100,000 to about 2,000,000.

4. The drug-releasing coating according to claim 1, wherein said polymer is polyethylene oxide.

5. The drug-releasing coating according to claim 4, wherein said polyethylene oxide has a molecular weight of about 300,000.

6. The drug-releasing coating according to claim 1, wherein said isocyanatosilane adduct is 3-isocyanatopropyltriethoxysilane.

7. The drug-releasing coating according to claim 1, wherein said reaction is carried out in a solvent selected from tetrahydrofuran, acetonitrile, or methylene chloride.

8. The drug-releasing coating according to claim 1, wherein said solvent is tetrahydrofuran or acetonitrile.

9. The drug-releasing coating according to claim 1, wherein said mixture comprises:

(a) from about 0.2 to about 10 percent by weight poIyisocyanate;

(b) from about 0.2 to about 10 percent by weight amine donor;

(c) from about 0.2 to about 20 percent by weight of said polymer; and

(d) from about 0.1 to about 10 percent by weight isocyanatosilane adduct having at least one terminal isocyanate group and at least one hydrolyzable alkoxy group bonded to silicon.

10. The drug-releasing coating according to claim 1, wherein said amine donor is a polyetherdiamine, a polyethertriamine, a urethane modified melamine polyol or an amine terminated polypropyleneglycol.

11. The drug-releasing coating of claim 1, wherein said drug is associated with said polyurea network by ionic interactions, hydrogen bonding, covalent bonding, metal ion-ligand interactions, hydrophilic interactions, hydrophobic interactions, or any combination thereof.

12. The drug releasing coating of claim 1, wherein said drug is a polypeptide.

13. The drug releasing coating of claim 1, wherein said drug is nitric oxide.

14. The drug-releasing coating according to claim 13, wherein said nitric oxide is associated with said polyurea network as a functional group selected from N₂O₂ or N₂O₂⁻

.

15. The drug-releasing coating according to claim 14, wherein said nitric oxide-releasing functional group is covalently attached to said polyurea network.

16. The drug-releasing coating according to claim 15, wherein said nitric oxide-releasing functional group is covalently attached to a nitrogen atom.

17. The drug-releasing coating according to claim 16, wherein said covalent bond comprises X—

N₂O₂ or X—

N₂O₂⁻

, wherein X is a primary amine, a secondary amine, a polyamine or a derivative thereof.

37. The drug releasing coating of claim 1, wherein said polypeptide is derived from a complex selected from the group consisting of heparin-tridodecylmethylammonium chloride, heparin-benzalkonium chloride, heparin-steralkonium chloride, heparin-poly-N-vinyl-pyrrolidone, heparin-lecithin, heparin-didodecyldimethylammonium bromide, heparin-pyridinium chloride, and heparin-synthetic glycolipid complex.

18. An article, comprising (1) a substrate on which is coated (2) a drug-releasing coating, comprising:

at least one drug associated with and releasable from a polyurea network formed from reaction on a substrate to be coated of a mixture comprising;

(a) a polyisocyanate;

(b) an amine donor;

(c) an isocyanatosilane adduct having at least one terminal isocyanate group and at least one hydrolyzable alkoxy group bonded to silicon; and

optionally

(b) a polymer selected from the group consisting of a polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.

19. The article according to claim 18 wherein said substrate is selected from the group consisting of plastic and metal.

20. The article according to claim 18, wherein said polyisocyanate is an aromatic polyisocyanate based on toluene diisocyanate.

21. An article according to claim 18, wherein said isocyanatosilane adduct is 3-isocyanatopropyltriethoxysilane.

22. The article according to claim 18, wherein said reaction is carried out in a solvent selected from tetrahydrofuran, acetonitrile or methylene chloride.

23. The article according to claim 22, wherein said solvent is tetrahydrofuran or acetonitrile.

24. The article according to claim 18, wherein said polymer is polyethylene oxide.

25. The article according to claim 24, wherein said polyethylene oxide has a molecular weight of about 300,000.

26. The article of claim 18, which is a catheter tube, a medical tube introducer, a medical wire, a stent, a dilitation balloon, an implant, a prosthesis or a penile insert.

27. A method of preparing a drug-releasing coating on a substrate to be coated comprising:

(a) forming a mixture of a polyisocyanate;

an amine;

an isocyanatosilane adduct having at least one terminal isocyanate group and at least one hydrolyzable alkoxy group bonded to silicon; and

optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid, in a solvent;

(b) applying said mixture to said substrate;

(c) associating a drug with said mixture-applied substrate by contacting said mixture-applied substrate with a drug; and

(d) curing said mixture on said substrate to form said coating.

28. The method according to claim 27, wherein said mixture is cured on said substrate prior to associating said drug with said mixture-applied substrate.

29. The method according to claim 27, wherein said polymer is polyethylene oxide.

30. The method according to claim 27, wherein said drug is associated with said mixture-applied substrate by contacting said mixture-applied substrate with a solution comprising said drug.

31. The method according to claim 27, wherein said drug is associated with said mixture-applied substrate by contacting said mixture-applied substrate with a gaseous atmosphere comprising said drug.

32. The method according to claim 27, wherein contacting said mixture-applied substrate with said drug results in a covalent bond between said mixture and said drug.

33. The method according to claim 27, wherein contacting said mixture-applied substrate with said drug results in penetration of said drug into said mixture.

34. A drug-releasing coated article produced by the method of claim 27.

35. A drug-releasing coated article comprising:

at least one drug associated with and releasable from a polyurea network formed from the reaction on a substrate to be coated of a mixture comprising;

(a) a polyisocyanate;

(b) an amine donor;

(c) an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and

optionally; and

(d) a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid;

produceable by the method of claim 27.

36. The drug releasing coating of claim 27, wherein said polypeptide is derived from heparin.

38. In a medical device having a drug-releasing coating, the improvement comprising:

a drug-releasing functional group associated with and releaseable from a polyurea network formed by the reaction of a mixture comprising;

(a) a polyisocyanate;

(b) an amine; and

(c) an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and

optionally

(d) a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.