Coating processes – Medical or dental purpose product; parts; subcombinations;... – Implantable permanent prosthesis
Reexamination Certificate
2001-02-28
2002-10-08
Beck, Shrive P. (Department: 1762)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
Implantable permanent prosthesis
C427S002250, C427S002280, C427S002300, C427S002310, C427S301000, C427S407100, C427S409000, C623S001100, C623S001430, C623S001440, C623S001450, C623S001460
Reexamination Certificate
active
06461665
ABSTRACT:
BACKGROUND OF THE INVENTION
When the surface of a medical device such as a catheter tube, blood oxygenator, stent or the like is placed in the body, or in contact with body fluids, a number of different reactions are set into motion, some of them resulting in the coagulation of the blood on the device surface. In order to counteract this serious adverse effect, the well-known anti-coagulant compound heparin has for a long time been administered systemically to patients before medical devices were placed in their body or in contact with their body fluids in order to ascertain an antithrombotic effect.
Thrombin is one of several coagulation factors, all of which work together to result in the formation of thrombus at a non-self surface in contact with the blood. Antithrombin is the most prominent coagulation inhibitor. It neutralises the action of thrombin and other coagulation factors and thus restricts or limits blood coagulation. Heparin dramatically enhances the rate whereby antithrombin inhibits coagulation factors.
However, systemic treatment with high doses of heparin is often associated with serious side-effects of which bleeding is the predominant. Another rare but serious complication of heparin therapy is the development of an allergic response called heparin induced thrombocytopenia that may lead to both bleeding and arterial thrombosis. Heparin treatment also requires frequent monitoring of plasma levels and dose adjustments accordingly. Heparin reversal with protamin is another complication.
Therefore solutions have been sought where the need for a systemic heparinisation of the patient would be unnecessary. It has been considered likely that this could be achieved through a surface modification using the anti-coagulative properties of the heparin. Thus, different technologies have been developed where a layer of heparin is attached to the surface of the medical device whereby the surface is rendered non-thrombogenic.
Heparin is a polysaccharide compound carrying negatively charged sulphate groups on the saccharide units. Ionic binding of heparin to polycationic surfaces was thus attempted, but these surface modifications suffered from lack of stability resulting in lack of function, as the heparin leached from the surface.
Thereafter different surface modifications have been prepared wherein the heparin has been covalently bound to groups on the surface.
PRIOR ART
One of the most successful processes for rendering a medical device non-thrombogenic is achieved through covalently binding a heparin fragment to a surface modified surface of the medical device. The general method and improvements thereof are described in the following European patents: EP-B-0086186, EP-B-0086187 and EP-B-0495820.
These patents describe the preparation of surface modification substrates which are achieved through firstly, a selective cleavage of the heparin polysaccharide chain through nitrous acid oxidation leading to the formation of terminal aldehyde groups. Secondly, an introduction of one or more surface modifying layers carrying amino groups on the surface of the medical device, and thereafter the aldehyde groups on the polysaccharide chain are reacted with primary amino groups on surface modifying layers followed by a reduction of the intermediate Schiff's bases to stable secondary amine bonds with for instance cyanoborohydride.
This technology has made it possible to prepare stable and well-defined antithrombogenic surface modifications for medical devices.
There are known many other surface modification which claim to achieve similar or even better results, such as for instance described in EP-A-0200295 (U.S. Pat. No. 4,600,652, U.S. Pat. No. 6,642,242, ) based on substrates having a layer of a polyurethane urea to which heparin modified to contain aldehyde groups through oxidation with nitrous acid or periodate, may be bound by covalent links.
A similar technology is described in EP-A-0404515, where the substrate surface is coated with an amine rich fluorinated polyurethane urea before immobilisation of an antithrombogenic agent, such as an aldehyde-activated heparin.
Another antithrombogenic surface modification which may be mentioned is described in EP-B-0309473. The surface of the device is modified through the coating with a layer of lysozyme or a derivative thereof to which heparin is adhered.
Yet another surface modification for producing antithrombogenic articles is described in U.S. Pat. No. 4,326,532. In this case, the layered antithrombogenic surface comprises a polymeric substrate, a chitosan bonded to the polymeric substrate and an antithrombogenic agent bonded to the chitosan coating. Japanese Patent Laid-Open No. 04-92673 relates to an antithrombogenic hemofilter also using a chitosan layer for binding heparin.
In EP-A- 0481160 it is described antithrombogenic materials useful for coating medical articles, which material comprises an anticoagulant bound to processed collagen.
Another process for preparing antithrombogenic surfaces is described in WO97/07843 wherein the heparin is admixed with sufficient periodate not to react with more than two sugar units per heparin molecule and this mixture is added to a surface modified substrate of a medical device, which surface modification contains amino groups.
This listing of prior art processes for preparing antithrombogenic surfaces is by no means complete, and it is a clear indication that it is difficult to prepare such coated medical articles which exhibit the properties necessary for successful use in patients, namely a sufficient and long-lasting high antithrombogenic activity, stability of the coating and no adverse changes of the properties of the substrate to be coated.
Therefore there is still a need in the art for improvements of the antithrombogenic coatings, which will render the medical articles thereby coated non-thrombogenic in a stable, reliable and reproducible manner and with a strong and lasting antithrombogenic effect.
DEFINITION OF THE INVENTION
A main object of the present invention is to improve the antithrombogenic activity of surface immobilized heparin. This and other objects are achieved by the invention as defined in the attached claims.
Thus, it has now surprisingly been found that it is possible to further improve the antithrombogenic activity of known surface modifications through a simple and inexpensive procedure. The improvement can be measured as a higher heparin bioactivity when the heparin treated according to the invention is attached to a surface.
The present invention relates to a process for preparing surface modifications having an improved antithrombogenic activity, whereby the improvement is achieved by treating heparin at elevated temperature or at elevated pH or in contact with nucleophilic catalysts such as amines, alcoholes, thiols or immobilized amino, hydroxyl or thiol groups before attaching said heparin to the surface to be modified.
As will appear from the prior art mentioned, there are known many different methods for producing a surface modifying layer carrying active groups to which a heparin can be bound or attached, and the heparin prepared according to the present invention and having superior antithrombogenic properties may be used in connection with any prior art method of preparing layers to which heparin can be bound.
Optionally the medical device oh which the surface modification is to be introduced, may be produced from a material or materials, whereby active functional groups are directly available on the surface, without the need for the introduction on the surface of a further layer carrying functional groups to which heparin can be bound. The heparin prepared according to the present invention and having superior antithrombogenic properties may be used in connection with such materials, too.
The process of this invention may be described more generally to include different materials carrying functional groups or different prior art methods of treating the surface in order to make available groups by which heparin, optionally treated to contain
Beck Shrive P.
Carmeda AB
Kolb Michener Jennifer
Nixon & Vanderhye
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