DRUG-DELIVERY ENDOVASCULAR STENT 6,099,562, 5,873,904, 5,342,348, 5,873,904, 5,707,385,
AND METHOD FOR TREATING RESTENOSIS 5,824,048, 5,527,337, 5,306,286, and 6,013,853.
A variety of agents specifically claimed to inhibit smooth
This application claims the benefit of U.S. Provisional muscle-cell proliferation, and thus inhibit restenosis, have
Application No. 60/613,071 filed Sep. 24, 2004, which is 5 been proposed for release from endovascular stents. As
incorporated herewith by reference in its entirety. examples, U.S. Pat. No. 6,159,488 describes the use of a
quinazolinone derivative; U.S. Pat. No. 6,171,609, the use of taxol, and U.S. Pat. No. 6,258,121, the use of paclitaxel, a A stent is a type of endovascular implant, usually generally 10 cytotoxic agent bought to be the active ingredient in the agent tubular in shape, typically having a lattice, connected-wire taxoL The metal sllver 18 clted ln U'S- Pat No' 5'873'904tubular construction which is expandable to be permanently Tramlast, a membrane stabilizing agent thought to have antiinserted into a blood vessel to provide mechanical support to inflammatory properties is disclosed in U.S. Pat. No. 5,733, the vessel and to maintain or re-establish a flow channel 15 327- More recen% rapamycin, an immunosuppressant during or following angioplasty. The support structure of the rePorted to suPPress both smooth muscle cdl ^ endothelial stent is designed to prevent early collapse of a vessel that has cel1 Srowth' has been shown to have ^proved effectiveness been weakened and damaged by angioplasty. Insertion of aSalnst when delivered from a polymer coating on stents has been shown to prevent negative remodeling and 20 a stent See' for sample, U.S. Pat. Nos. 5,288,711 and 6,153, spasm of the vessel while healing of the damaged vessel wall 252' Also' ln PCT Publication No. WO 97/35575, the macproceeds over a period of months. rocycllc tnene immunosuppressive compound everohmus Duringthehealingprocess, inflammation caused by angio- and related compounds have been proposed for treating resplasty and stent implant injury often causes smooth muscle tenosls- Commonly owned PCT publications WO 2003/ cell proliferation and regrowth inside the stent, thus partially 25 090684 A3 ^ WO 03/090818 describe a P01^ comP0" closingtheflowchannel,andtherebyreducingoreliminating sltlon containing a macrocyclic tnene compound and an the beneficial effect of the angioplasty/stenting procedure. endovascular stent and method for treating restenosis, respecThis process is called restenosis. Blood clots may also form ... both of whlch are incorporated herein by reference, inside of the newly implanted stent due to the thrombotic 30 Given the advantages of implanting a stent designed to nature of the stent surfaces, even when biocompatible mate- release a restenosis-inhibiting drug into vascular tissue folrials are used to form the stent. lowlng angioplasty, it would be desirable to produce a drugWhile large blood clots may not form during the angio- elutlng stent havlng additional advantages of (i) reducing the plasty procedure itself or immediately post-procedure due to 35 Profile of the stent'both before ^ after P^cement at the site the current practice of injecting powerful anti-platelet drugs °f vascular injury, (n) eliminating chemical components that
.... may cause irritation or inflammation at the stent site, and (iii)
into the blood circulation, some thrombosis is always present, J v'
. , . ■ -11 + + r provide greater control of drug-release rate once the stent is
at least on a microscopic level, on stent surfaces and it is , , .
. . . . „ . . . . . placed at the site, thought to play a significant role in the early stages ol rest
enosis by establishing a biocompatible matrix on the surfaces SUMMARY of the stent whereupon smooth muscle cells may subsequently attach and multiply (Farb et al., Circulation, 110(8): In one aspect, the invention includes a radially expandable, 940-947, 2004). endovascular stent designed for placement at a site of vascular
Stent coatings are known which contain bioactive agents 45 injury, for inhibiting restenosis at the site. The invention
that are designed to reduce or eliminate thrombosis or rest- includes a radially expandable body formed of one or more
enosis. Such bioactive agents may be dispersed or dissolved metallic filaments defining an outer surface, and attached to
in either a bio-durable or bio-erodable polymer matrix which or formed in the outer surface, a liquid-infusible mechanical
is applied as a coating over the entire filament surface. After anchoring layer having an average thickness of at least 3 um,
implantation, the bioactive agent diffuses out of the polymer and a drug coating composed of a substantially polymer-free
matrix and preferably into the surrounding tissue. composition of an anti-restenosis drug.
If the polymer is bioerodable, in addition to release of the This drug coating has a substratum infused in the anchordrug through the process of diffusion, the bioactive agent may ing layer, for retaining the coating on the stent body when the also be released as the polymer degrades or dissolves, making 55 stent is radially expanded at the site of vascular injury, and a the agent more readily available to the surrounding tissue substantially continuous surface stratum of drug that is environment. Bioerodable stents and biodurable stents are brought into direct contact with the vessel walls at the site by known where the outer surfaces or even the entire bulk of the such radial expansion. The rate of release of the anti-restenopolymer material is porous. For example, PCT Publication sis drug from the surface stratum into the vascular site is No. WO 99/07308, which is commonly owned with the 60 determined solely by the composition of the drug coating, present application, discloses such stents, and is expressly The surface stratum of the drug has a preferred thickness of incorporated by reference herein. When bioerodable poly- between about 5 and 30 um, and preferably constitutes at least mers are used as drug delivery coatings, porosity is variously about 75 weight percent of the drug coating, claimed to aid tissue ingrowth, make the erosion of the poly- 65 In one embodiment, the drug composition contains at least mer more predictable, or to regulate or enhance the rate of 90% by weight of an antirestenosis macrocyclic triene immudrug release, as, for example, disclosed in U.S. Pat. Nos. nosuppressive compound having the structure: