Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From reactant having at least one -n=c=x group as well as...
Reexamination Certificate
2002-09-30
2004-08-03
Cooney, Jr., John M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From reactant having at least one -n=c=x group as well as...
C424S422000, C424S423000, C424S424000, C424S425000, C427S002120, C427S058000, C428S423100, C528S085000
Reexamination Certificate
active
06770729
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to polymer compositions containing bioactive agents and methods for their use. Such compositions can be used to coat medical devices such as intravascular stents.
2. Description of Related Art
A wide variety of medical conditions are treated by introducing an implantable medical device partly or completely into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. For example, many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like. However, when such a device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis often results at the injured site, causing stenosis or occlusion of the blood vessel. Moreover, if the medical device is left within the patient for an extended period of time, thrombus often forms on the device itself, again causing stenosis or occlusion. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke. Thus, the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate.
Another way in which blood vessels undergo stenosis is through disease. Probably the most common disease causing stenosis of blood vessels is atherosclerosis. Atherosclerosis is a condition which commonly affects the coronary arteries, the aorta, the iliofemoral arteries and the carotid arteries. Atherosclerotic plaques of lipids, fibroblasts, and fibrin proliferate and cause obstruction of an artery or arteries. As the obstruction increases, a critical level of stenosis is reached, to the point where the flow of blood past the obstruction is insufficient to meet the metabolic needs of the tissue distal to (downstream of) the obstruction. The result is ischemia.
Many medical devices and therapeutic methods are known for the treatment of atherosclerotic disease. One particularly useful therapy for certain atherosclerotic lesions is percutaneous translummnal angioplasty (PTA). During PTA, a balloon-tipped catheter is inserted in a patient's artery, the balloon being deflated. The tip of the catheter is advanced to the site of the atherosclerotic plaque to be dilated. The balloon is placed within or across the stenotic segment of the artery, and then inflated. Inflation of the balloon “cracks” the atherosclerotic plaque and expands the vessel, thereby relieving the stenosis, at least in part.
While PTA presently enjoys wide use, it suffers from two major problems. First, the blood vessel may suffer acute occlusion immediately after or within the initial hours after the dilation procedure. Such occlusion is referred to as “abrupt closure.” Abrupt closure occurs in perhaps five percent or so of the cases in which PTA is employed, and can result in myocardial infarction and death if blood flow is not restored promptly. The primary mechanisms of abrupt closures are believed to be elastic recoil, arterial dissection and/or thrombosis. It has been postulated that the delivery of an appropriate agent (such as an antithrombic agent) directly into the arterial wall at the time of angioplasty could reduce the incidence of thrombotic acute closure, but the results of attempts to do so have been mixed. A second major problem encountered in PTA is the re-narrowing of an artery after an initially successful angioplasty. This re-narrowing is referred to as “restenosis” and typically occurs within the first six months after angioplasty. Restenosis is believed to arise through the proliferation and migration of cellular components from the arterial wall, as well as through geometric changes in the arterial wall referred to as “remodeling.” It has similarly been postulated that the delivery of appropriate agents directly into the arterial wall could interrupt the cellular and/or remodeling events leading to restenosis. However, like the attempts to prevent thrombotic acute closure, the results of attempts to prevent restenosis in this manner have been mixed. Non-atherosclerotic vascular stenosis may also be treated by PTA. For example, Takayasu arteritis or neurofibromatosis may cause stenosis by fibrotic thickening of the arterial wall. Restenosis of these lesions occurs at a high rate following angioplasty, however, due to the fibrotic nature of the diseases. Medical therapies to treat or obviate them have been similarly disappointing.
A device such as an intravascular stent can be a useful adjunct to PTA, particularly in the case of either acute or threatened closure after angioplasty. The stent is placed in the dilated segment of the artery to mechanically prevent abrupt closure and restenosis. Unfortunately, even when the implantation of the stent is accompanied by aggressive and precise antiplatelet and anticoagulation therapy (typically by systemic administration), the incidence of thrombotic vessel closure or other thrombotic complication remains significant, and the prevention of restenosis is not as successful as desired. Furthermore, an undesirable side effect of the systemic antiplatelet and anticoagulation therapy is an increased incidence of bleeding complications, most often at the percutaneous entry site.
Other conditions and diseases are treatable with stents, catheters, cannulae and other devices inserted into the esophagus, trachea, colon, binary tract, urinary tract and other locations in the body, or with orthopedic devices, implants, or replacements. Consequently, it would be desirable to develop devices and methods for reliably delivering suitable agents, drugs or bioactive materials directly into a body portion during or following a medical procedure, so as to treat or prevent such conditions and diseases, for example, to prevent abrupt closure and/or restenosis of a body portion such as a passage, lumen or blood vessel. As a particular example, it would be desirable to have devices and methods which can deliver an antithrombic or other medication to the region of a blood vessel which has been treated by PTA, or by another interventional technique such as atherectomy, laser ablation, or the like.
There is a need in the art for improved compositions and methods that can be used with implantable medical devices to deliver bioactive agents at a site of implantation (e.g. a blood vessel which has been treated by PTA). Embodiments of the invention disclosed herein satisfy this need.
SUMMARY OF THE INVENTION
A discovery underlying the present invention is the incorporation of bioactive agents in polymer compositions, such as silicon containing siloxanes, in the formation of biocompatible coatings for medical devices such as stents. The polymer compositions can be used in conjunction with a variety of compounds for the preparation of coatings in which the movement of both endogenous and exogenous analytes and reactive species through the coatings (e.g., chemokines, immunosuppressive and/or anti-inflammatory agents) can be controlled. The coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.
The invention disclosed herein has a number of embodiments. A preferred embodiment of the invention is an implantable medical device having at least one polymer coating composition, the polymer coating prepared from a reaction mixture of a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the mixture, a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, a bioactive agent; and optionally a chain extender. In preferred embodiments, the reaction mixture further comprises a siloxane polymer having functional groups at the chain termin, typically amino, hydroxyl and carboxylic acid groups. A specific embodiment of the in
Cooney Jr. John M.
Gates & Cooper LLP
Medtronic MiniMed, Inc.
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