Medical devices with polymer coatings designed to control the release of angiotensin-(1-7) receptor agonists from medical devices are disclosed. The present application also discloses providing vascular stents with angiotensin-(1-7) receptor agonist-containing controlled-release coatings. Methods for treating or inhibiting post-stent implantation restenosis as well as improving vascular endothelial function in patients are also provided.

SUMMARY OF THE INVENTION

The present invention is directed providing medical devices, such as stents, with controlled-release drug-eluting polymer coatings capable of inhibiting restenosis and improving vascular endothelial cell function. Specifically, the vascular stents made in accordance with teachings of the present invention inhibit vascular smooth muscle cell proliferation, and therefore restenosis, by providing agonists of the angiotensin-(1-7) (Ang-1 7)) receptor to the site of vascular injury. Additionally, the Ang-(1-7) coated medical devices of the present invention improve vascular endothelial cell function.

In one embodiment of the device of the present invention, a medical device is provided comprising a stent having a generally cylindrical shape comprising an outer surface, an inner surface, a first open end and a second open end, a controlled-release coating comprising an amphiphilic copolymer and at least one angiotensin-(1-7) (Ang-(1-7)) receptor agonist wherein at least one of said inner or outer surfaces are adapted to deliver an effective amount of said at least one Ang-(1-7) receptor agonist to a tissue of a mammal; and wherein vascular endothelial cell function is improved and/or restenosis is inhibited.

In an embodiment of the device of the present invention, the at least one Ang-(1-7) receptor agonist is a peptide having the amino acid sequence of SEQ ID NO. 1 and the medical device is a vascular stent.

In another embodiment of the device of the present invention, the at least one Ang-(1-7) receptor agonist is present on the said inner surface and the outer surface of the vascular stent. In another embodiment the amphiphilic copolymer comprises a PEG methacrylate-cyclohexyl methacrylate copolymer. In yet another embodiment the stent further comprises a primer coat, such as a parylene primer coat, and/or a polymer topcoat comprising a PEG methacrylate-cyclohexyl methacrylate copolymer or poly(butyl methacrylate).

In yet another embodiment of the device of the present invention, the Ang-(1-7) receptor agonist peptide is in a concentration of between approximately 0.1% to 99% by weight of peptide-to-polymer.

In one embodiment of the device of the present invention, a vascular stent for inhibiting restenosis in a mammal is provided comprising stent having a generally cylindrical shape comprising an outer surface, an inner surface, a first open end and a second open end, a controlled-release coating comprising a PEG methacrylate-cyclohexyl methacrylate copolymer and an anti-restenotic amount of an Ang-(1-7) receptor agonist peptide having the amino acid sequence of SEQ ID NO. 1 and a PEG methacrylate-cyclohexyl methacrylate copolymer topcoat wherein the vascular stent deliver an effective amount of said Ang-(1-7) receptor agonist to a tissue of a mammal; and wherein vascular endothelial cell function is improved and/or restenosis is inhibited. The vascular stent can optionally further comprise a primer coat.

In an embodiment of the method of the present invention, a method for inhibiting restenosis in a mammal comprises providing a vascular stent having a controlled-release coating thereon wherein said coating comprises an amphiphilic copolymer and an effective amount of at least one Ang-(1-7) receptor agonist; and inhibiting restenosis in said mammal.

In an embodiment of the method for inhibiting restenosis of the present invention, the at least one Ang-(1-7) receptor agonist is a peptide having the amino acid sequence of SEQ ID NO. 1 and the medical device is a vascular stent.

In another embodiment of the method for inhibiting restenosis of the present invention, the at least one Ang-(1-7) receptor agonist is present on the said inner surface and the outer surface of the vascular stent. In another embodiment the amphiphilic copolymer comprises a PEG methacrylate-cyclohexyl methacrylate copolymer. In yet another embodiment the stent further comprises a primer coat and/or a polymer topcoat.

In yet another embodiment of the method for inhibiting restenosis of the present invention, the Ang-(1-7) receptor agonist peptide is in a concentration of between approximately 0.1% to 99% by weight of peptide-to-polymer.

In one embodiment of the present invention, a method for improving endothelial cell function in a mammal comprises providing a vascular stent having a controlled-release coating thereon wherein the coating comprises an amphiphilic copolymer and an effective amount of at least one Ang-(1-7) receptor agonist and improving vascular endothelial cell function in said mammal.

In an embodiment of the method for improving vascular endothelial cell function of the present invention, the at least one Ang-(1-7) receptor agonist is a peptide having the amino acid sequence of SEQ ID NO. 1 and the medical device is a vascular stent.

In another embodiment of the method for improving vascular endothelial cell function of the present invention, the at least one Ang-(1-7) receptor agonist is present on the said inner surface and the outer surface of the vascular stent. In another embodiment the amphiphilic copolymer comprises a PEG methacrylate-cyclohexyl methacrylate copolymer. In yet another embodiment the stent further comprises a primer coat and/or a polymer topcoat.

In yet another embodiment of the method for improving vascular endothelial cell function of the present invention, the Ang-(1-7) receptor agonist peptide is in a concentration of between approximately 0.1% to 99% by weight of peptide-to-polymer.

In an embodiment of the present invention, a method is provided for treating impaired vascular endothelial cell function in a mammal comprising implanting a stent having a controlled release coating and an effective amount of Ang-(1-7) disposed on at least one surface of the medical device at a treatment site in a vessel lumen and releasing the Ang-(1-7) from the surface of the stent such that vascular endothelial cell function is improved at the treatment site.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed providing medical devices, such as stents, with controlled-release drug-eluting polymer coatings capable of inhibiting restenosis and improving vascular endothelial cell function. Specifically, the vascular stents made in accordance with teachings of the present invention inhibit vascular smooth muscle cell proliferation, and therefore restenosis, by providing agonists of the angiotensin-(1-7) (Ang-1 7)) receptor to the site of vascular injury. Additionally, the Ang-(1-7) coated medical devices of the present invention improve vascular endothelial cell function.

A particular embodiment of the present invention is the use agonists of the Ang-(1-7) receptor for coating vascular stents. Exemplary Ang-(1-7) agonists include, but are not limited to, the peptide Ang-(1-7) having the amino acid sequence of SEQ ID NO. 1, and biologically active analogues and derivatives thereof; D-alanine.sup.7-Ang-(1-7); D-proline.sup.7-Ang-(1-7) and AVE0991.

Angiotensin-(1-7) blocks angiotensin II activity, a protein implicated in the development of restenosis, and inhibits smooth muscle cell proliferation, a hallmark of restenosis. One embodiment of the present invention provides vascular stents coated with the heptapeptide Ang-(1-7) (SEQ ID NO. 1). SEQ ID NO. 1 Asp Arg Val Tyr lie His Pro

Alternatively, potent non-peptide compounds have been described that are used as agonists of Ang-(1-7) receptors and mimic the biological action of Ang-(1-7). Specific 1-(p-thienylbenzyl)imidazoles and corresponding salts, such as those described in U.S. Pat. No. 6,235,766, which is hereby incorporated by reference in its entirety, have the advantage that they may not be subject to the metabolic degradation. Specifically, see column 1 beginning at line 58 through column 4 line 65. More specifically see column 4 line 68 through column 6 line 12 for specific examples of compositions. Therefore additional embodiments of the present invention include coating vascular stents with non-peptide Ang-(1-7) receptor agonists. Because of the stimulation of the production and/or release of these vasorelaxant, antithrombotic, and cardioprotective compounds, Ang-(1-7) receptor agonists are valuable pharmaceuticals for the treatment of restenosis.

Vascular stents present a particularly unique challenge for the medical device coating scientist. Vascular stents (hereinafter referred to as "stents") must be flexible, expandable, biocompatible and physically stable. Stents are used to relieve the symptoms associated with coronary artery disease caused by occlusion in one or more coronary artery. Occluded coronary arteries result in diminished blood flow to heart muscles causing ischemia induced angina and in severe cases myocardial infarcts and death. Stents are generally deployed using catheters having the stent attached to an inflatable balloon at the catheter's distal end. The catheter is inserted into an artery and guided to the deployment site. In many cases the catheter is inserted into the femoral artery or of the leg or carotid artery and the stent is deployed deep within the coronary vasculature at an occlusion site.

Vulnerable plaque stabilization is another application for coated drug-eluting vascular stents. Vulnerable plaque is composed of a thin fibrous cap covering a liquid-like core composed of an atheromatous gruel. The exact composition of mature atherosclerotic plaques varies considerably and the factors that affect an atherosclerotic plaque's make-up are poorly understood. However, the fibrous cap associated with many atherosclerotic plaques is formed from a connective tissue matrix of smooth muscle cells, types I and III collagen and a single layer of endothelial cells. The atheromatous gruel is composed of blood-borne lipoproteins trapped in the sub-endothelial extracellular space and the breakdown of tissue macrophages filled with low density lipids (LDL) scavenged from the circulating blood. (G. Pasterkamp and E. Falk. 2000. Atherosclerotic Plaque Rupture: An Overview. J. Clin. Basic Cardiol. 3:81 86). The ratio of fibrous cap material to atheromatous gruel determines plaque stability and type. When atherosclerotic plaque is prone to rupture due to instability it is referred to as "vulnerable" plaque. Upon rupture the atheromatous gruel is released into the blood stream and induces a massive thrombogenic response leading to sudden coronary death. Recently, it has been postulated that vulnerable plaque can be stabilized by stenting the plaque. Moreover, vascular stents having a drug-releasing coating composed of matrix metalloproteinase inhibitor dispersed in, or coated with (or both) a polymer may further stabilize the plaque and eventually lead to complete healing.

Treatment of aneurysms is another application for drug-eluting stents. An aneurysm is a bulging or ballooning of a blood vessel usually caused by atherosclerosis. Aneurysms occur most often in the abdominal portion of the aorta. At least 15,000 Americans die each year from ruptured abdominal aneurysms. Back and abdominal pain, both symptoms of an abdominal aortic aneurysm, often do not appear until the aneurysm is about to rupture, a condition that is usually fatal. Stent grafting has recently emerged as an alternative to the standard invasive surgery. A vascular graft containing a stent (stent graft) is placed within the artery at the site of the aneurysm and acts as a barrier between the blood and the weakened wall of the artery, thereby decreasing the pressure on the artery. The less invasive approach of stent-grafting aneurysms decreases the morbidity seen with conventional aneurysm repair. Additionally, patients whose multiple medical comorbidities make them excessively high risk for conventional aneurysm repair are candidates for stent-grafting. Stent grafting has also emerged as a new treatment for a related condition, acute blunt aortic injury, where trauma causes damage to the artery.

Once positioned at the treatment site the stent or graft is deployed. Generally, stents are deployed using balloon catheters. The balloon expands the stent gently compressing it against the arterial lumen clearing the vascular occlusion or stabilizing the aneurysm. The catheter is then removed and the stent remains in place permanently. Most patients return to a normal life following a suitable recovery period and have no reoccurrence of coronary artery disease associated with the stented occlusion. However, in some cases the arterial wall's intima is damaged either by the disease process itself or as the result of stent deployment. This injury initiates a complex biological response culminating in vascular smooth muscle cell hyperproliferation and occlusion, or restenosis, and vascular endothelial cell damage at the stent site.

Recently significant efforts have been devoted to preventing restenosis. Several techniques including brachytherapy, excimer laser, and pharmacological techniques have been developed. The least invasive and most promising treatment modality is the pharmacological approach. A preferred pharmacological approach involves the site-specific delivery of cytostatic or cytotoxic drugs directly to the stent deployment area. Site-specific delivery is preferred over systemic delivery for several reasons. First, many cytostatic and cytotoxic drugs are highly toxic and cannot be administered systemically at concentrations needed to prevent restenosis. Moreover, the systemic administration of drugs can have unintended side effects at body locations remote from the treatment site. Additionally, many drugs are either not sufficiently soluble, or too quickly cleared from the blood stream to effectively prevent restenosis. Therefore, administration of anti-restenotic compounds directly to the treatment area is preferred.

Several techniques and corresponding devices have been developed to deploy anti-restenotic compounds including weeping balloon and injection catheters. Weeping balloon catheters are used to slowly apply an anti-restenotic composition under pressure through fine pores in an inflatable segment at or near the catheter's distal end. The inflatable segment can be the same used to deploy the stent or a separate segment. Injection catheters administer the anti-restenotic composition by either emitting a pressurized fluid jet, or by directly piercing the artery wall with one or more needle-like appendage. Recently, needle catheters have been developed to inject drugs into an artery's adventitia. However, administration of anti-restenotic compositions using weeping and injection catheters to prevent restenosis remains experimental and largely unsuccessful. Direct anti-restenotic composition administration has several disadvantages. When anti-restenotic compositions are administered directly to the arterial lumen using a weeping catheter, the blood flow quickly flushes the anti-restenotic composition down stream and away from the treatment site. Anti-restenotic compositions injected into the lumen wall or adventitia may rapidly diffuse into the surrounding tissue. Consequently, the anti-restenotic composition may not be present at the treatment site in sufficient concentrations to prevent restenosis. As a result of these and other disadvantages associated with catheter-based local drug delivery, investigators continue to seek improved methods for the localized delivery of anti-restenotic compositions. The most successful method for localized anti-restenotic composition delivery developed to date is the drug-eluting stent.

In one embodiment of the present invention, a implanted medical device is provided with a polymer coating containing an agonist of the angiotensin-(1-7) receptor. The present inventors have surprisingly shown that the local administration of the agonist Ang-(1-7) from the surface of an implanted medical device significantly improves impaired vascular endothelial cell function.

Amphiphilic polymers compatible for coating vascular stents according to the methods of the present invention include, but are not limited to, the copolymers described in co-pending U.S. patent application No. 10/970,171 filed Oct. 21, 2004, which is hereby incorporated by reference in its entirety. The amphiphilic copolymers of the Ser. No. 10/970,171 application are useful for coating medical devices with peptide drugs.

The amphiphilic copolymers have the general structure of Formula 1 -- see Original Patent.

The controlled release coatings of the present invention can be applied to medical device surfaces, either primed or bare, in any manner known to those skilled in the art. Application methods compatible with the present invention include, but are not limited to, spraying, dipping, brushing, vacuum-deposition, and others. Moreover, the controlled release coatings of the present invention may be used with a topcoat and/or a primer coat. A topcoat as used here refers to the outermost coating layer applied over another coating. A drug-releasing copolymer coating is applied over the primer coat. A polymer topcoat is applied over the drug-releasing copolymer coating. The topcoat may optionally serve as a diffusion barrier to further control the drug release, or provide a separate drug. The primer coat can be any biocompatible polymer such as parylene which is applied to the bare surface of the stent to protect the stent and have no effect on elution rates.

One embodiment of the present invention is depicted in FIG. 1 -- see Original Patent.

Claim 1 of 27 Claims

1. A medical device comprising: a stent having a generally cylindrical shape comprising an outer surface, an inner surface, a first open end and a second open end; a controlled-release coating comprising an amphiphilic copolymer comprising a PEG methacrylate-cyclohexyl methacrylate copolymer and at least one angiotensin-(1-7) (Ang-(1-7)) receptor agonist; wherein at least one of said inner or outer surfaces deliver an effective amount of said at least one Ang-(1-7) receptor agonist to a tissue of a mammal.

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