Bioactive agent release coating

• US 6,214,901 B1
• Filed: 04/15/1999
• Issued: 04/10/2001
• Est. Priority Date: 04/27/1998
• Status: Expired due to Term

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Chappa, Ralph A., Anderson, Aron B., Chudzik, Stephen J., Kloke, Timothy M.
• Primary Examiner(s): SZEKELY, PETER A
• Application Number:
  US09/292,510
• Time in Patent Office: 726 Days
• Field of Search: 523/13, 427/2.1, 427/2.3, 424/78.18, 514/2, 606/195
• US Class Current: 523/113
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• 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: 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 33/06 of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical

Abstract

A coating composition for use in coating implantable medical devices to improve their ability to release bioactive agents in vivo. The coating composition is particularly adapted for use with devices that undergo significant flexion and/or expansion in the course of their delivery and/or use, such as stents and catheters. The composition includes the bioactive agent in combination with a mixture of a first polymer component such as poly(butyl methacrylate) and a second polymer component such as poly(ethylene-co-vinyl acetate).

Claims

1. A composition for coating the surface of a medical device with a bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising a bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one poly(alkyl)(meth)acrylate and a second polymer component comprising poly(ethylene-co-vinyl acetate), wherein the second polymer component is selected from the group consisting of poly(ethylene-co-vinyl acetate) polymers having vinyl acetate concentrations of between about 10% and about 50% by weight.

2. A composition according to claim 1 wherein the device is one that undergoes flexion and/or expansion in the course of implantation or use in vivo.

3. A composition according to claim 1 wherein the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and/or concentrations of polymers in the mixture.

4. A composition according to claim 1 wherein the first polymer component is selected from the group consisting of poly(alkyl)(meth)acrylates with alkyl chain lengths from 2 to 8 carbons.

5. A composition according to claim 1 wherein the vinyl acetate concentrations are between about 24% and about 36% by weight.

6. A composition according to claim 5 wherein the vinyl acetate concentrations are between about 30% and about 34% by weight.

7. A composition according to claim 1 wherein the composition comprises a mixture of poly(n-butylmethacrylate) and poly(ethylene-co-vinyl acetate).

8. A composition according to claim 7 wherein the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.

9. A composition according to claim 1 wherein the composition further comprises a solvent in which the polymers form a true solution.

10. A composition according to claim 1 wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight.

11. A composition according to claim 10 wherein the bioactive agent is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

12. A composition according to claim 1 wherein the device is one that undergoes flexion and/or expansion in the course of implantation or use in vivo, the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and/or concentrations of polymers in the mixture.

13. A composition according to claim 12 wherein the first polymer component is selected from the group consisting of poly(alkyl)(meth)acrylates with alkyl chain lengths from 2 to 8 carbons.

14. A composition according to claim 13 wherein the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight, and the composition further comprises a solvent in which the polymers form a true solution.

15. A composition according to claim 1 wherein

a) the device is one that undergoes flexion and/or expansion in the course of implantation or use in vivo,

b) the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and/or concentrations of polymers in the mixture, and

c) the bioactive agent is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

16. A composition according to claim 15 wherein the first polymer component comprises poly n-butylmethacrylate and the vinyl acetate concentrations are between about 24% and about 36% by weight.

17. A composition according to claim 16 wherein the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.

18. A composition according to claim 15 wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight.

19. A composition according to claim 1 wherein the bioactive agent wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight and is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

20. A composition according to claim 19 wherein the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and/or concentrations of polymers in the mixture.

21. A composition according to claim 19 wherein the vinyl acetate concentrations are between about 24% and about 36% by weight and the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.

22. A composition according to claim 21 wherein the composition further comprises a solvent in which the polymers form a true solution.

23. A composition according to claim 2 wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight and is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

24. A composition according to claim 23 wherein the composition further comprises a solvent in which the polymers form a true solution.

25. A composition according to claim 24 wherein the vinyl acetate concentrations are between about 24% and about 36% by weight and the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.

26. A composition according to claim 6 wherein the bioactive agent wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight and is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

27. A composition according to claim 26 wherein the composition further comprises a solvent in which the polymers form a true solution.

28. A composition according to claim 26 wherein the vinyl acetate concentrations are between about 24% and about 36% by weight and the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.

29. A composition according to claim 12 wherein the bioactive agent wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight and is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.

30. A composition according to claim 29 wherein the composition further comprises a solvent in which the polymers form a true solution.

31. A composition according to claim 30 wherein the vinyl acetate concentrations are between about 24% and about 36% by weight and the total combined concentrations of both polymers in the coating composition is between about 0.25% and about 70% by weight.