Bioactive prostheses with immunosuppressive, antistenotic and antithrombotic properties

• US 6,517,858 B1
• Filed: 05/16/2001
• Issued: 02/11/2003
• Est. Priority Date: 11/16/1998
• Status: Expired due to Term

• Current Assignee: Commissariat a L'Energie Atomique (AES Corporation), Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Kerckhoff-Klinik, Kerckhoff-Klinik, Gesellschaft Mit Beschrã¤Nkter Haftung
• Original Assignee: Commissariat a L'Energie Atomique (AES Corporation), Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Kerckhoff-Klinik, Gesellschaft Mit Beschrã¤Nkter Haftung
• Inventors: Bureau, Christophe, Betz, Natacha, Deleris, Gérard, Haberbosch, Werner, Le Moel, Alain, Baquey, Charles, Deniau, Guy
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/831,948
• Time in Patent Office: 636 Days
• Field of Search: 424/424, 424/422, 424/486, 424/488, 424/484, 623/1.15, 623/1.42
• US Class Current: 424/424
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 27/28 Materials for coating prostheses
• 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 33/0029 using an intermediate layer of polymer

Abstract

The invention relates to a bioactive implant comprising a substrate coated with a polymer layer with reactive functions, and a bioactive substance fixed on the implant by means of said reactive functions to enable progressive release on the implant site.

Such implants are useful in the field of cardiology for example to prevent restenosis resulting from the fitting of stents in the coronary arteries.

Claims

1. Bioactive implant comprising a substrate wherein a surface is made of an electrically conductive material chosen from metals, metallic alloys, semi-conductor materials, conductive polymers, composite materials, ceramics, carbon fibres or their mixtures, said surface being coated with a polymer or copolymer layer with reactive functions grafted by means of a covalent bond on the substrate surface, said layer having reactive functions and being grafted by electro-copolymerization, and a bioactive substance fixed on the implant by means of said reactive functions to enable progressive release on an implant site.

2. Implant according to claim 1, wherein the substrate surface is made of stainless steel, cobalt or titanium-based alloy, noble metal, noble metal alloy or shape-retentive alloy.

3. Implant according to claim 1, wherein the reactive functions of the polymer of the layer are chosen from the acid, ester, amide, amine or hydroxyl functions.

4. Implant according to claim 1, wherein the reactive function polymer or copolymer is chosen from vinyl monomer polymers and/or copolymers, functionalised or not, dextran, conductive polymers or any polymer or copolymer formed from mixtures of vinyl monomers and/or conductive polymer precursor monomers, functionalised or not.

5. Bioactive implant according to claim 1, wherein the bioactive substance is fixed on the polymer or copolymer layer by means of microreservoirs containing said substance fixed on the reactive functions of the polymer or copolymer layer.

6. Bioactive implant according to claim 5, wherein the microreservoirs comprise a microporous outer membrane which is coupled with the reactive functions of the polymer or copolymer layer.

7. Implant according to claim 6, wherein the membrane is made of polyacrylamide.

8. Implant according to claim 5, wherein the microreservoirs are agar beads filled directly with the bioactive substance or filled with spherulites in turn filled with the bioactive substance.

9. Implant according to claim 1, wherein the bioactive substance is chosen from antimitotic, antiaggregation, antiinflammatory, antirestenotic, antithrombotic, immunosuppressive, antirejection compounds, antibiotic compounds or reverse oligonucleotides.

10. Implant according to claim 9, wherein the bioactive substance is chosen from cyclosporin, rapamycin, aspirin, ticlopidine, 3-deazaadenosine or MCP-1.

11. Implant according to claim 1, wherein the polymer or copolymer layer is also used to hold a heparin compound with a covalent bond.

12. Method to produce a bioactive implant according to claim 1, comprising the following steps:

i. coating the substrate wherein the surface is made of an electrically conductive material chosen from metals, metallic alloys, semi-conductor materials, conductive polymers, composite materials, ceramics, carbon fibres or their mixtures, said coating being by grafting with a layer of a polymer or copolymer with reactive functions by means of a covalent bond, said layer having reactive functions being grafted by electropolymerization, and

ii. fix a bioactive substance on the polymer or copolymer by means of the reactive functions such that said substance can subsequently be released progressively on the implant site.

13. Method according to claim 12, wherein, in step 1, the surface of the substrate is coated with a polymer or copolymer and the polymer or copolymer is then modified to introduce the reactive functions.

14. Method according to claim 12, wherein, in step 1, the reactive function polymer or copolymer is deposited directly onto -he surface of the substrate.

15. Method according to claim 12, wherein the polymer deposited by electropolymerization is the reactive function polymer.

16. Method according to claim 12, wherein, a heparin compound is also fixed onto the reactive function polymer or copolymer layer.

17. Method according to claim 12, wherein the fixation of the bioactive substance on the reactive functions of the polymer or copolymer layer consists of coupling said substance chemically onto the reactive functions by forming a compound capable of regenerating the bioactive substance on the implant site.

18. Method according to claim 17, wherein the reactive functions are hydroxyl functions and the bioactive substance is acetylsalicylic acid.

19. Method according to claim 18, wherein the reactive function polymer layer is chosen from poly(hydroxyethyl methacrylate), dextran or polyvinyl alcohol.

20. Method according to claim 17, wherein, the chemical coupling of the bioactive substance with a precursor monomer of the polymer or copolymer intended to form the polymer layer is carried out beforehand and the polymer layer on which the bioactive substance is fixed is formed by polymerisation of the monomer coupled chemically with the bioactive substance or by copolymerisation of said monomer with a non-functionalised monomer.

21. Method according to claim 12, wherein, the bioactive substance is fixed on the polymer or copolymer layer by means of microreservoirs containing said substance fixed on the reactive functions of the polymer or copolymer layer.

22. Method according to claim 21, wherein, the microreservoirs are fixed onto the polymer or copolymer layer by means of functions associated with a microporous membrane surrounding the microreservoirs, said membrane being linked to the reactive functions of the polymer or copolymer layer via a covalent bond.

23. Method according to claim 22, wherein the membrane is made of polyacrylamide.

24. Method according to claim 21, wherein the microreservoirs are agar beads filled directly with the bioactive substance or filled with spherulites in turn filled with the bioactive substance.