Stents with hybrid coating for medical devices

Details Stents with hybrid coating for medical devices Stents with hybrid coating for medical devices

1999-05-26

2001-05-15

Isabella, David J. (Department: 3738)

Prosthesis (i.e., artificial body members), parts thereof, or ai

Arterial prosthesis

Drug delivery

C623S001430, C623S001460, C427S002240, C427S402000, C428S423100, C428S424400

Reexamination Certificate

active

06231600

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to implantable medical devices. More specifically, the present invention relates to vascular or cardiovascular stents having a time-release coating for inhibiting restenosis and a non-thrombogenic coating for inhibiting clot formation on the stent. In particular, the present invention includes stents having a first coating of Taxol admixed with a polymer and a second coating of heparin bonded to the first coating through a crosslinking agent.
BACKGROUND OF THE INVENTION
Vascular disease is a leading cause of death and disability in the developed world. In the United States, more than one half of all deaths are due to cardiovascular disease. Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to body organs, which can result in hearts attacks, strokes, and kidney failure. Atherosclerosis is a form of vascular injury in which the vascular smooth muscle cells in the artery wall undergo hyperproliferation and invade and spread into the inner vessel lining, which can make the vessels susceptible to complete blockage when local blood clotting occurs. This can lead to death of the tissue served by that artery. In the case of a coronary artery, this blockage can lead to myocardial infarction and death.
Coronary artery blockage can be treated with coronary artery bypass surgery and/or angioplasty. Both procedures may initially appear to be successful, but are in effect undone by the effect of restenosis or the recurrence of stenosis after such a treatment. Restenosis is believed to include hyperproliferation of vascular smooth muscle cells. In particular, one third of patients treated using angioplasty have restenosis and blockage within 6 months after the procedure.
To prevent vessel blockage from restenosis, stents are used. Stents are nominally tubular structures and can have either solid walls or lattice like walls, and can be either expandable or self-expanding. After angioplasty balloon dilatation, the previously constricted vessel is at least temporarily widened. A stent can be delivered on a catheter and expanded in place or allowed to expand in place against the vessel walls. With the stent in place, restenosis may or may not be inhibited, but the probability and/or degree of blockage is reduced due to the structural strength of the stent opposing the inward force of any restenosis. Restenosis may occur over the length of the stent and be at least partially opposed by the stent. Restenosis may also occur past the ends of the stent, where the inward forces of the stenosis are unopposed.
Therapeutic agents to inhibit restenosis have been used with varying success. Taxol, an antimicrotubule agent isolated from the bark of the western Pacific Yew tree, is especially effective in inhibiting some cancers and is believed to be effective in combating restenosis. Systemic administration of Taxol can have undesirable side effects, making local administration a preferred mode of treatment. Local administration of Taxol may be more effective when carried out over a longer time period, such as a time period at least matching the normal reaction time of the body to the angioplasty. Local administration of Taxol over a period of days or even months may be most effective in inhibiting restenosis. Such a long time period may be provided by a time release delivery system from the stent itself.
Leaving a stent in place for long time periods in contact with the blood stream can subject the stent to thrombus formation, which can also narrow the vessel inside diameter. A stent surface used to release a therapeutic agent such as Taxol may also not inhibit thrombus formation. What would be desirable is a stent having restenosis inhibiting properties and be suitable for being left in place for long periods without acting as a site for thrombus formation.
SUMMARY OF THE INVENTION
The present invention includes a substrate such as a stent body, means for inhibiting restenosis, means for adhering the restenosis inhibiting means to the body, and means for releasing the restenosis inhibiting means over time. The present invention also includes means for rendering the body non-thrombogenic. In one stent, means for inhibiting restenosis includes paclitaxel (taxol), analogues, and/or derivatives thereof. In one stent, means for adhering the restenosis inhibiting means to the body and releasing the restenosis inhibiting means from the body over time includes admixing the restenosis inhibiting means in a polymeric material adhered to the stent body. In one stent, means for rendering the stent non-thrombogenic includes bonding a crosslinking agent to the polymeric material and then bonding a non-thrombogenic material, such as heparin, to the crosslinking agent. In one stent the polyfunctional crosslinking agent includes polyfunctional aziridine, and the polymeric material includes organic acid functional groups capable of forming covalent bonds with the polyfunctional aziridine.
The present invention includes methods for providing a substrate such as a stent with a biocompatible and restenosis inhibiting coating. One method includes coating the substrate with a first aqueous coating composition, the composition including an aqueous dispersion or emulsion of a polymer, a first therapeutic agent, and an excess of a polyfunctional crosslinking agent having functional groups capable of reacting with the polymer. The method can further include drying the first coating composition to obtain a substantially water insoluble coating or layer still including active functional groups. The method further includes forming a biocompatible surface over the first coating composition by contacting the first dried coating composition with a second aqueous coating composition including an aqueous solution or dispersion of a biocompatibility agent, and drying the combined coatings to bind the biocompatibility agent to the excess crosslinking agent. In one method the biocompatibility agent is a non-thrombogenic agent. In one method, the non-thrombogenic agent includes heparin.
In one method, the polymer includes organic acid functional groups such as carboxylic or sulfonic acid and includes a polyfunctional crosslinking agent capable of reacting with the organic acid groups. In one method, the polymer includes water borne polyurethane, the first therapeutic agent includes paclitaxel, analogues, and/or derivatives thereof, the polyfunctional crosslinking agent includes polyfunctional aziridine, and the second aqueous coating composition includes an aqueous solution or dispersion of heparin.


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