Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-05-16
2003-02-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S486000, C424S488000, C424S484000
Reexamination Certificate
active
06517858
ABSTRACT:
DISCLOSURE
1. Field of the Invention
The present invention relates to bioactive implants, particularly with immunosuppressive, antistenotic and antithrombotic properties.
Such implants may be used in the field of cardiology and vascular surgery as artery substitutes or as stents placed in arteries, particularly in coronary arteries, to prevent any risk of thrombosis or restenosis.
Bioactive implants may also be used in numerous other fields where it is important to give the implant an additional property due to the presence of a bioactive substance.
2. State of the Related Art
In the field of cardiology, stenosis is usually treated by angioplasty, i.e. by inserting, into the artery concerned, a balloon which is inflated at high pressure in contact with the stricture in order to eliminate it. Following the angioplasty, a stent, which prevents the recurrence of stenosis, may be placed in the artery concerned. However, a complication associated with the use of said stents results from the growth of new neo-tissue and intimal hyperplasia which may induce an obstruction of the artery and restenosis due the presence of the stent.
The fitting of coronary stents plays an increasingly important role in the treatment of chronic coronary disease, but to date said stents have been unable to solve the problem of restenosis and restenosis rates after fitting of stents are still 22 to 32%. As mentioned above, said restenosis is the result of neo-intimal tissue proliferation which needs to be prevented.
In addition, it would be very beneficial to have implants, particularly coronary stents, which would make it possible to prevent said tissue proliferation.
It has already been envisaged to treat implants to fill them with bioactive substances giving them antithrombotic and antimicrobial properties.
In this way, the document EP-A-596 615 [1] discloses implants with a polymer substrate which are coated with a layer of grafted polymer containing an active product.
Such implants are unsuitable for use as stents since the polymer substrates do not have the required mechanical characteristics.
For implants with metallic substrates, reliable and durable fixation of an active product on the implant is more difficult to apply.
The document EP-A-0 873 732 [2] discloses a stent on which heparin is fixed, by means of a coating comprising functional groups attracting the heparin obtained for example by means of a methane plasma and an ammonia gas plasma or amine type monomer.
The document US-A-4879 132 [3] discloses implants on which a medicinal product is fixed, by means of an anionic surfactant.
The document EP-A-0 832 618 [4] discloses stents with long-term antithrombotic properties, which comprises a metallic substrate on which heparin is fixed for example by means of a coupling agent or a cross-linking agent, after oxidation of the metal surface.
Thus, none of these techniques can be used to bind the coating containing the active substance with the metal substrate with a durable and reliable covalent bond.
The present invention specifically relates to new implants which do not induce this disadvantage.
In addition, none of the approaches disclosed to date mention the use of grafted bioactive substances with antirestenotic properties, while restenosis represents one of major undesirable local responses in the case of stent fitting. Thus, the aim of the present invention is also to give the coatings the possibility to prevent restenosis.
DESCRIPTION OF THE INVENTION
In this way, the invention relates to a bioactive implant comprising a substrate wherein the surface is made of a material chosen from metals, metallic alloys, semi-conductor materials, conductive polymers, composite materials, ceramics, carbon fibres and 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 and a bioactive substance fixed on the implant by means of said reactive functions to enable progressive release on an implant site.
Said implant thus shows an additional property due to the presence of a suitable bioactive substance, which is used to treat or prevent, directly on the implant site, the development of undesirable phenomena.
According to the invention, the surface of the substrate of the implant is made of a material which may be a metal, a metallic alloy, a conductive polymer, a semi-conductor material, an organic composite material, a ceramic, an oxide, carbon fibres, or their mixtures.
The substrate may be made entirely of any of said materials or comprise a core made of any type of material surrounded by a layer of any of the materials defined above.
The metals and metallic alloys are selected, for example, from stainless steels, cobalt or titanium-based alloys, shape-retentive alloys, noble metals such as gold or platinum and noble metal alloys.
The conductive polymers that may be used in the invention to form the surface of the substrate may be of various types. Examples include conductive polymers formed from monomers such as pyrrole, thiophene, aniline or their functionalised or non-functionalised derivatives, and the copolymers of the monomers mentioned above.
The ceramic materials that may be used for the surface of the substrate may be for example aluminium oxide, glass, hydroxyapatite, carbides and nitrides and any surface oxide, either native or deposited on the surface by any means.
The composite materials that may be used may be materials such as metals and polymers coated with ceramic or carbon or associated with carbon fibres and organic polymer-based materials reinforced with inorganic fibres such as glass or carbon fibres.
The material used for the implant substrate is selected essentially as a function of required mechanical properties of the implant.
In the case of stents intended for cardiology, a metallic substrate, for example made of stainless steel or shape-retentive metallic alloy, is advantageously used.
According to the invention, the surface of the substrate of the implant is coated with a polymer or copolymer layer with reactive functions, the purpose of which is to retain temporarily a bioactive substance which will then be released on the implant site.
In the remainder of the present document, the term polymer refers not only to a polymer based on identical monomers but also a copolymer based on different monomers.
The suitable reactive functions for said fixation may be chosen, for example, from the acid, ester, amide, amine and hydroxyl functions.
The polymer used to form this layer must be biocompatible. It is possible to use, in particular, vinyl monomer polymers and/or copolymers, functionalised or not, dextran, conductive polymers and any polymer or copolymer formed from mixtures of vinyl monomers and/or conductive polymer precursor monomers, functionalised or not. Examples of such polymers include acrylic and methacrylic polymers such as polymethyl methacrylate, polyethyl methacrylate, polyacrylic acid, polymethacrylic acid, poly(hydroxyethyl methacrylate) and polyacrylamide, polyvinyl alcohol, poly(4-vinylpyridine), dextran, polystyrene, conductive polymers based on thiophene, aniline, pyrrole, and any polymer or copolymer using monomers obtained by functionalisation of the above-mentioned monomers. Such polymers comprise or may comprise suitable reactive functions, chosen as a function of the biological substance fixation method.
According to the invention, the bioactive substance may be fixed directly on the reactive functions of the polymer layer by a covalent bond with possible insertion of a spacer between the reactive functions and the substance.
The bioactive substance may also be fixed on the reactive functions of the polymer layer by means of microreservoirs containing said substance, which are fixed on the reactive functions of the layer.
Said microreservoirs may comprise a microporous outer membrane which is coupled with the reactive functions of the polymer layer.
For example, said microporous membrane may be made of polyacry
Baquey Charles
Betz Natacha
Bureau Christophe
Deleris Gerard
Deniau Guy
Commissariat A L'Energie Atomique
Fubara Blessing
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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