Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Monomer contains oxygen
Reexamination Certificate
1998-11-04
2002-06-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Monomer contains oxygen
C424S078180, C424S078310, C424S078350
Reexamination Certificate
active
06406687
ABSTRACT:
SUMMARY OF THE INVENTION
This invention relates to the synthesis of polymers which contain non-thrombogenic (NON-TB) as well as anti-thrombogenic (ANTI-TB) properties. Such polymers can be conveniently represented as follows:
POLYMER BACKBONE
POLYMER BACKBONE
)
and
)
)
(
(
(
[NON-TB]
[NON-TB]
[ANTI-TB]
Type 1
Type 2
In schematic diagrams of this kind, as used herein, the designated side chains or groups can occur in any order and in any relative proportions along the polymer backbone.
In polymers of Type 1 the non-thrombogenic (NON-TH) component may consist of non-ionic hydrophilic domains, ionic domains, zwitterionic domains or combinations of such domains. In novel Type 1 polymers in accordance with the invention, such non-thrombogenic components may be selected from, but are not limited to, polymerizable sulphonates, polymerizable sulphates, polymerizable N-sulphates (also known as sulphamates), polymerizable zwitterionic compounds, and polymerizable polyethylene glycols. When we synthesized polymers of Type 1, without the anti-thrombogenic component, and coated various medical devices, we found blood cell and protein deposition reduced by greater than 90%. Greatly reduced (>95%) activation of white cells, platelets and complement was observed. This type of synthetic polymer can be described as a non-thrombogenic polymer.
The non-thrombogenic Type 1 polymer, as described, was synthesized with polymerizable heparin to give a Type 2 polymer. Surprisingly, the activity of the heparin was retained in the Type 2 polymer and such polymers, when coated on to medical devices, had the additional property of reducing the thrombin-antithrombin complex concentration. This inclusion of heparin into the non-thrombogenic polymer gave a new polymer which additionally exhibited anti-thrombogenic properties.
Another aspect of this invention is the process by which the non-thrombogenic and anti-thrombogenic polymers are coated onto medical devices.
BACKGROUND OF THE INVENTION
There is a growing interest in the use of artificial materials in clinical practice where these materials are in continuous contact with blood. Medical devices made from these materials are required to perform in the harsh biological environment in a specific application, for a specific duration without stimulating a biological response which may prove to be detrimental. Hence, such devices are required to be accepted by the biological environment for a specific application and duration, i.e., need to be bioacceptable. Improvements in bioacceptability are highly desirable for medical devices manufactured from artificial materials. Such materials commonly include polyvinyl chloride, polyethylene, polypropylene, polyurethanes, polycarbonates, stainless steel, silicones and the like. The biological response to blood contact with an artificial surface can be regarded in terms of different contributions from protein, platelet and blood cell deposition, together with platelet and blood activation leading to thrombus formation.
Many investigations have been carried out to prevent an artificial surface from provoking thrombus formation, i.e., to form a bioacceptable surface. Such investigations include the use of polymers which are natural, hydrophilic, hydrophobic, zwitterionic and charged (anionic and cationic). These types of polymers are non-thrombogenic, have had limited success and therefore application. Surface modification of an artificial material by heparin (i.e., formation of an anti-thrombogenic surface) has also proved to be intractable. Although clot formation has been reduced, platelet activation and blood cell activation are however still prevalent. Similarly, a particular artificial surface may be resistant to protein, platelet and blood cell deposition but may still activate blood constituents.
Each surface, whether non-thrombogenic or anti-thrombogenic, has its own profile of desirable bioacceptable properties, but no particular material possesses the full spectrum of the desired properties.
Additional disadvantages of some of the known approaches are (i) the procedures used to produce these materials are complex, (ii) the methods of applying these materials to the medical device are elaborate, and (iii) these processes utilize reagents which are highly toxic, even in minute quantities.
In a new approach to the problem of finding suitable bioacceptable materials, we have synthesized a novel non-thrombogenic polymer, and have also modified non-thrombogenic polymers by incorporating a polymerizable anti-thrombogenic compound, exemplified by polymerizable heparin. It was found that heparin activity was maintained, while the non-thrombogenity of the polymer component was prevalent. Other known biologically active anti-thrombogenic compounds include hirudin, warfarin and hyaluronic acid, and can be used in the same manner as the polymerizable heparin.
SUMMARY OF THE INVENTION
The invention provides a medical device which comprises a polymer coating, the polymer coating comprising a polymer comprising a polymer backbone and having at least two pendant groups selected from:
(a) a polyoxyalkylene ether group,
(b) a sulphate group,
(c) a sulphonate group, or
(d) a sulphamate group,
wherein the polymer is produced by polymerizing monomers having such groups.
The invention also provides a medical device which comprises a polymer coating, the polymer coating comprising a polymer comprising a polymer backbone and having at least two pendant groups selected from:
(a) a polyoxyalkylene ether group,
(b) a sulphate group,
(c) a sulphonate group,
(d) a sulphamate group, or
(e) a zwitterionic group,
wherein the polymer coating is produced by polymerizing monomers having such groups.
The invention provides a polymer comprising a polymer backbone and having at least two pendant groups selected from:
(a) a polyoxyalkylene ether group,
(b) a sulphate group,
(c) a sulphonate group, or
(d) a sulphamate group,
wherein the polymer further comprises a pendant heparin group, and wherein the polymer is produced by polymerizing monomers having such groups.
Additional features and advantages of the invention are set forth in the description which follows and in part will be apparent from the description. The objectives and other advantages of the invention will be realized and attained by the medical devices, polymers, coatings, and methods of the invention as particularly pointed out in the written description and claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention provides a medical device which comprises a polymer coating, the polymer coating comprising a polymer comprising a polymer backbone and having at least two pendant groups selected from:
(a) a polyoxyalkylene ether group,
(b) a sulphate group,
(c) a sulphonate group, or
(d) a sulphamate group,
wherein the polymer is produced by polymerizing monomers having such groups. In one embodiment of the invention, the polymer comprises a pendant polyoxyalkylene ether group. In another embodiment of the invention, the polymer does not comprise a pendant sulphonate group. In yet another embodiment of the invention, the polymer comprises a pendant polyoxyalkylene ether group and does not comprise a pendant sulphonate group. In one embodiment of the invention, the medical device is a blood oxygenator. In one embodiment of the invention, the polymer comprises a pendant heparin group; in another, the polymer comprises a pendant hirudin, warfarin, or hyaluronic acid group.
The invention provides a method of making a medical device which comprises a polymer coating comprising:
providing a mixture of monomers comprising at least two of the following monomers:
(a) a monomer having a polyoxyalkylene ether group,
(b) a monomer having a sulphate group,
(c) a monomer having a sulphonate group, or
(d) a monomer having a sulphamate group;
coating t
Luthra Ajay Kumar
Sandhu Shivpal Singh
Coburn LLP Thompson
Page Thurman K.
Sheikh Humera N.
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