Coating processes – Medical or dental purpose product; parts; subcombinations;... – Implantable permanent prosthesis
Reexamination Certificate
2000-10-31
2004-12-21
Beck, Shrive P. (Department: 1762)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
Implantable permanent prosthesis
C427S002100, C427S002250, C427S002300, C427S002310, C427S435000
Reexamination Certificate
active
06833153
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention relates to the field of hemocompatible coatings on hydrophobic porous polymeric materials and, in particular, to hemocompatible coatings based upon complexes of heparin deposited upon porous hydrophobic polymers, typically expanded PTFE.
2. Description of Related Art
Continuing advances in medical technology have led to the development and use of numerous medical devices that come into contact with blood or other bodily fluids. To be concrete in our discussion, we focus herein on the particular example of medical devices coming into contact with mammalian blood, particularly human blood, not intending thereby to limit the scope of the present invention to medical devices used exclusively on human patients. In using such devices, it is important that contact of the blood or other bodily fluid with the various components of the medical device not cause therapeutically detrimental alterations to the fluid. In many cases, it is desirable to coat such devices with materials to enhance the biocompatiblity of the devices, including coatings that contain bioactive agents, anticoagulants, antimicrobial agents or a variety of other drugs.
It is convenient to consider blood-contacting medical devices as invasive or extra-corporal, although some devices span both classes. Invasive devices are used internally in the treatment of the patient, implanted into the patient for an indefinite or extended period of time or inserted into the patient for relatively brief periods. In many cases, the materials comprising the blood-contacting portions of the invasive device lack sufficient biocompatibility and/or hemocompatibility, tending to cause changes harmful to the patient in the blood or other fluid coming into contact with the surface (or surfaces) of the device. In such cases it is desirable to coat the surfaces of these devices with materials to enhance the biocompatiblity and/or hemocompatibility. Invasive devices that are typically coated with biocompatible or therapeutic substances include implantable artificial orthopedic devices, dental implants, intravascular catheters, emboli capturing systems, epicardial immobilization devices, grafts, stents, intraluminal prosthetic devices and artificial heart valves, among others.
There are also many examples of extra-corporal medical devices that come into contact with blood in which blood is transported and/or processed external to the patient. A few representative examples include cardiopulmonary bypass devices, kidney dialysis equipment, blood oxygenators, separators and defoaming devices, among others. Following such extra-corporal processing, the blood or other bodily fluid may be reintroduced into the patient, transported for storage and/or for introduction into another patient. In using such extra-corporal devices, it is important that contact of the blood or other bodily fluid with the various components of the device not cause therapeutically detrimental alterations to the fluid.
It is important in some cases that the surface or the surfaces of the invasive or extra-corporal medical device be coated with substances having therapeutic functions, wherein the coatings may serve several functions in addition to increasing the biocompatibility/hemocompatibility of the surface. Examples of such additional functions include the release of one or more therapeutic agents into the blood in appropriate dosages with appropriate timed-released characteristics and at the proper location within the patient. Thus, the medical device may serve as a convenient delivery platform for the delivery of therapeutically beneficial drugs in addition to its other functions.
One important application related to implantable devices arises in connection with endoluminal stents, particularly as occurring in connection with percutaneous transluminal angioplasty (“PCTA”). Following balloon angioplasty, the lumen of the just-expanded vessel may contract due to several causes. An initial rebound of the walls of the vessel may occur following removal of the balloon. Further thrombosis or restenosis of the blood vessel may occur over time following the angioplasty procedure. The result is often the necessity for another angioplasty procedure or surgical by-pass. Endoluminal stents have been in use for several years in conjunction with a surgical procedure inserting a tube or stent into the vessel following the PCTA procedure to assist in retaining the desired intraluminal opening. A review of the procedure may be found in
Endoluminal Stenting
by Ulrich Sigwart, Ed. (W. B. Saunders, 1996). A compendium of coronary stents is given in
Handbook of Coronary Stents,
3
rd
Ed.
by P. W. Serruys and M. J B Kutryk, Eds. (Martin Dunitz Ltd., 2000). However, even with stenting, occlusions frequently recur within the stent requiring further PCTA or by-pass surgery. Such restenosis following PCTA and the insertion of a stent is sought to be prevented by the use of coated stents. Coatings on stents are often used for the delivery of anticoagulants or other medication that assist in preventing thrombosis and restenosis.
Heparin is an anticoagulant drug composed of a highly sulfated polysaccharide, the principle constituent of which is a glycosaminoglycan. In combination with a protein cofactor, heparin acts as an antithrobin (among other medical effects as described, for example, in
Heparin
-
Binding Proteins,
by H. E. Conrad (Academic Press, 1998)). Heparin is an attractive additive to coat on the surface(s) of blood-contacting devices in order to increase the hemocompatibility of the material and/or to release heparin or heparin complexes into the blood to combat thrombosis and restenosis.
The heparin molecule contains numerous hydrophilic groups including hydroxyl, carboxyl, sulfate and sulfamino making underivatized heparin difficult to coat onto hydrophobic polymers. Thus, many types of complexes of heparin with hydrophobic counter ions have been used in order to increase the ability of the heparin-counter ion complex to bind to hydrophobic surfaces. Such counter ions are typically cationic to facilitate binding with anionic heparin, and contain a hydrophobic region to facilitate bonding with the hydrophobic polymer. Typical heparin complexes include, but are not limited to, heparin complex with typically large quaternary ammonium species such as benzylalkonium groups (typically introduced in the form of benzylalkonium chloride), tridodecylmethylammonium chloride (“TDMEC”), and the commercial heparin complex offered by Baxter International under the tradename DURAFLO or DURAFLO II. Herein we denote as “heparin complex” any complex of heparin with a hydrophobic counter ion, typically a relatively large counter ion. Examples of heparin complexes are described in the following U.S. Patents (incorporated herein by reference): U.S. Pat. Nos. 4,654,327; 4,871,357; 5,047,020; 5,069,899; 5,525,348; 5,541,167 and references cited therein.
Considerable work has been done in developing coatings for application to various medical devices in which the coatings contain at least one form of heparin or heparin complex. Combinations of heparin and heparin complexes with other drugs, as well as various techniques for tailoring the coating to provide desired drug-release characteristics have been studied. Examples of such work include that of Chen et. al. (incorporated herein by reference), published in J. Vascular Surgery, Vol 22, No. 3 pp. 237-247 (September 1995) and the following U.S. Patents (incorporated herein by reference): U.S. Pat. Nos. 4,118,485; 4,678,468; 4,745,105; 4,745,107; 4,895,566; 5,013,717; 5,061,738; 5,135,516; 5,322,659; 5,383,927; 5,417,969; 5,441,759; 5,865,814; 5,876,433; 5,879,697; 5,993,890 as well as references cited in the foregoing patents and article.
Implantable medical devices often require some degree of porosity to enable blood to come into contact with underlying tissues, to increase the surface area for delivery of therapeutic substances, or for other purposes. Therefore, porous polymers are widely us
Lundkvist Andrė-Jean
Roorda Wouter E.
Shah Niraj
Advanced Cardiovascular Systems Inc.
Beck Shrive P.
Kolb Michener Jennifer
Squire Sanders & Dempsey
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