Implantable or insertable medical device resistant to microbial growth and biofilm formation

• US 20050161859A1
• Filed: 01/21/2005
• Published: 07/28/2005
• Est. Priority Date: 02/08/2002
• Status: Active Grant

• Current Assignee: Gregory T. Sydney, Kathleen M. Miller, Kurt Geitz, Peter L. Dayton, Ronald A. Sahatjian
• Original Assignee: Gregory T. Sydney, Kathleen M. Miller, Kurt Geitz, Peter L. Dayton, Ronald A. Sahatjian
• Inventors: Sahatjian, Ronald A., Miller, Kathleen M., Geitz, Kurt, Dayton, Peter L., Sydney, Gregory T.
• Granted Patent: US 8,105,520 B2
• Time in Patent Office: Days
• US Class Current: 264/209.100
• CPC Class Codes: A61L 2/232 layered or coated
• CPC Class Codes: A61L 2300/202 with halogen atoms, e.g. triclosan, povidone-iodine
• CPC Class Codes: A61L 2300/206 Biguanides, e.g. chlorohexidine
• CPC Class Codes: A61L 2300/21 Acids
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: Y10T 428/1334 Nonself-supporting tubular film or bag [e.g., pouch, envelope, packet, etc.]
• CPC Class Codes: Y10T 428/1352 Polymer or resin containing [i.e., natural or synthetic]
• CPC Class Codes: Y10T 428/1372 Randomly noninterengaged or randomly contacting fibers, filaments, particles, or flakes
• CPC Class Codes: Y10T 428/1379 Contains vapor or gas barrier, polymer derived from vinyl chloride or vinylidene chloride, or polymer containing a vinyl alcohol unit
• CPC Class Codes: Y10T 428/1386 Natural or synthetic rubber or rubber-like compound containing
• CPC Class Codes: Y10T 428/1393 Multilayer [continuous layer]

Abstract

Disclosed are implantable or insertable medical devices that provide resistance to microbial growth on and in the environment of the device and resistance to microbial adhesion and biofilm formation on the device. In particular, the invention discloses implantable or insertable medical devices that comprise at least one biocompatible matrix polymer region, an antimicrobial agent for providing resistance to microbial growth and a microbial adhesion/biofilm synthesis inhibitor for inhibiting the attachment of microbes and the synthesis and accumulation of biofilm on the surface of the medical device. Also disclosed are methods of manufacturing such devices under conditions that substantially prevent preferential partitioning of any of said bioactive agents to a surface of the biocompatible matrix polymer and substantially prevent chemical modification of said bioactive agents

Claims

1. A method of manufacturing an implantable or insertable medical device comprising:

providing a combination of (a) one or more biocompatible matrix polymers and (b) bioactive agents comprising an antimicrobial agent and a microbial attachment/biofilm synthesis inhibitor;

processing said combination under conditions that substantially prevent preferential partitioning of any of said bioactive agents to a surface of any of said biocompatible matrix polymers and that substantially prevent chemical modification of said bioactive agents.

2. The method of claim 1, further comprising controlling either or both of the temperature and moisture content during said processing.

3. The method of claim 1, wherein said processing comprises mixing said one or more biocompatible matrix polymers with one or more of said bioactive agents to a form a homogeneous mixture of said one or more matrix polymers and said one or more bioactive agents.

4. The method of claim 3, wherein said homogeneous mixture comprises both bioactive agents.

5. The method of claim 3, wherein said mixing comprises applying mechanical shear to said one or more biocompatible matrix polymers and said one or more bioactive agents with a device selected from the group consisting of a single screw extruder, a twin screw extruder, a banbury mixer, a high-speed mixer and a ross kettle.

6. The method of claim 3, where said mixing comprises forming a solvent solution or a liquid dispersion of said one or more bioactive agents and said one or more biocompatible matrix polymers.

7. The method of claim 3, further comprising shaping said homogenous mixture into a matrix polymer region of an implantable or insertable medical device.

8. The method of claim 7, wherein said shaping comprises a process selected from molding, calendaring, casting and solvent coating.

9. The method of claim 7, wherein said shaping comprises extrusion.

10. The method of claim 9, wherein said extrusion comprises forming at least one annular matrix polymer region.

11. The method of claim 10, further comprising forming at least one polymeric barrier layer at least partially covering a surface of said annular matrix polymer region.

12. The method of claim 11, wherein said method comprises a process selected from extrusion coating said polymeric barrier layer onto said annular matrix polymer region and solvent coating said polymeric barrier layer onto said annular matrix polymer region.

13. The method of claim 11, wherein said covering comprises coextruding said polymeric barrier layer and said annular matrix polymer region.

14. The method of claim 11, forming a first polymeric barrier layer at least partially covering an interior surface of said annular matrix polymer region and forming a second polymeric barrier layer at least partially covering an exterior surface of said annular matrix polymer region.

15. The method of claim 14, wherein said covering comprises coextruding said first and second polymer barrier layers with said annular matrix polymer region.

16. The method of claim 3, wherein said processing comprises forming homogeneous first and second mixtures of first and second biocompatible matrix polymers and one or more of said bioactive agents and, optionally, forming a homogenous third mixture of a third biocompatible matrix polymer and one or more of said bioactive agents.

17. The method of claim 16, comprising coextruding said homogenous first and second mixtures to form first and second annular matrix polymer regions and, optionally, coextruding therewith said homogeneous third mixture to form a third annular matrix polymer region.

18. The method of claim 17, further comprising forming at least first and second polymeric barrier layers at least partially covering interior and exterior surfaces of said first annular matrix polymer region;

forming a third polymer barrier layer at least partially covering an exterior surface of said second annular matrix polymer region and, optionally, forming a fourth polymeric barrier layer at least partially covering an interior surface of third annular matrix polymer region.

19. The method of claim 18, wherein said covering comprises coextruding said first, second and third polymeric barrier layers with said first and second annular matrix polymer regions and, optionally, coextruding therewith said fourth polymeric barrier layer and said third annular matrix polymer region.

20. The method of claim 15, wherein said first annular matrix polymer region and said first and second barrier layers comprise a material selected from the group consisting of ethylene vinyl acetate copolymers, copolymers of ethylene with acrylic acid or methacrylic acid, elastomeric polyurethanes and polyurethane copolymers, metallocene catalyzed polyethylene and polyethylene copolymers, ionomers, vinyl aromatic copolymers, silicones and mixtures thereof.

21. The method of claim 20, wherein said first annular matrix polymer region comprises an ethylene vinyl acetate copolymer having a vinyl acetate content of from about 19% to about 28% and said first and second polymeric barrier layers comprise a metallocene catalyzed polyethylene or polyethylene copolymer, or an ionomer.

22. The method of claim 21, wherein said first annular matrix polymer region comprises salicylic acid or a salt thereof as said microbial attachment/biofilm synthesis inhibitor, triclosan as said antimicrobial agent and bismuth subcarbonate as a radio-opacifying agent;

and, said coextrusion is performed under conditions such that said salicylic acid or salt thereof does not preferentially partition to a surface of said first annular matrix polymer region or to a surface of said first or second polymeric barrier layers.