Bonding bio-active materials to expanded polytetrafluoroethylene or polyethylene terephthalate via an isocyanate-terminated spacer

• US 6,096,525 A
• Filed: 11/26/1997
• Issued: 08/01/2000
• Est. Priority Date: 11/25/1996
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed, Inc. (Boston Scientific Corporation)
• Original Assignee: Meadox Medicals, Inc. (Boston Scientific Corporation)
• Inventors: Patnaik, Birendra K.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/979,813
• Time in Patent Office: 979 Days
• Field of Search: 435/174, 435/180, 435/181, 530/402, 530/815, 530/816, 424/422, 424/423, 424/94.63, 424/94.64, 514/56, 536/21
• US Class Current: 435/181
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• 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: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/816 Attached to the carrier via a bridging agent

Abstract

A bio-active material such as heparin, urokinase or streptokinase is bonded via a hydrophilic spacer to a functionality on the surface of a hydrophobic, bio-compatible polymeric substrate to provide a coating of the bio-active material on the surface. The substrate surface is preferably the surface of an implantable medical device such as a vascular graft. An amine and/or hydroxyl functionality on the substrate surface is reacted with an isocyanate group at an end of the hydrophilic spacer to bond the spacer to the substrate, and the bio-active material is reacted with an isocyanate group at another end of the spacer to bond the bio-active material to the spacer. Polymeric substrates include expanded polytetrafluoroethylene and polyethylene terephthalate, and the hydroxyl and/or amine functionality may be provided on the substrate surface by plasma glow discharge. A preferred spacer is an isocyanate end-blocked poly(ethylene oxide). Reaction of the functionality of the substrate with the isocyanate group of the spacer may be catalyzed with dibutyltindilaurate, and reaction of the bio-active material with the isocyanate group of the spacer may be catalyzed with 1-(3 -dimethylaminopropyl)-3-ethylcarbodiimide.

Claims

1. A method of preparing a bio-active coating comprising:

a) providing a hydrophobic, bio-compatible polymeric substrate selected from the group consisting of expanded polytetrafluoroethylene and polyethylene terephthalate;

b) providing reactive OH or NH₂ functionality on a surface of said substrate, said reactive functionality being bonded to said substrate through a reactive carbon atom therein;

c) reacting said reactive OH or NH₂ reactive functionality of said bio-compatible polymeric substrate with a hydrophilic spacer having at least one reactive isocyanate functional group at its first and second ends by reacting said at least one reactive isocyanate functional group at said first end of said spacer with said reactive OH or NH₂ functionality on said bio-compatible polymeric substrate to bond said spacer thereto; and

d) reacting said at least one reactive isocyanate functional group at said second end of said spacer with a bio-active agent to bond said bio-reactive agent to said spacer.

2. The method of claim 1, further comprising the step of catalyzing the reaction of said reactive functionality of said bio-compatible polymeric substrate with said at least one reactive isocyanate functional group at said first end of said hydrophilic spacer in the presence of dibutyltindilaurate.

3. The method of claim 1, further comprising the step of catalyzing the reaction of said at least one reactive isocyante functional group at said second end of said spacer with said bio-active agent in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

4. The method of claim 1 wherein said hydrophilic spacer is selected from the group consisting of aliphatic hydrocarbons, poly(oxyolefins), hydrophilic polyethers, hydrophilic polyethylenes, polyolefins, aliphatic polyesters, poyamines, polysiloxanes, polysilazanes, hydrophilic poly(acrylates), hydrophilic poly(methacrylates), polyamino acids, and linear polysaccharides.

5. The method of claim 1 wherein said hydrophilic spacer is an isocyanate end-blocked (ethylene oxide).

6. The method of claim 5 wherein said isocyanate end-blocked (ethylene oxide) has a molecular weight of about 100 daltons to about 200,000 daltons.

7. The method of claim 5 wherein said isocyanate end-blocked (ethylene oxide) has a molecular weight of about 200 daltons to about 50,000 daltons.

8. The method of claim 5 wherein said isocyanate end-blocked (ethylene oxide) has a molecular weight of about 1,000 to about 4,000 daltons.

9. The method of claim 5 wherein the length of said hydrophilic spacer positions said bio-active agent with a desired level of activity.