Radioactive transition metal stents

Details Radioactive transition metal stents Radioactive transition metal stents

1999-02-04

2001-07-24

Hindenburg, Max (Department: 3736)

Surgery

Radioactive substance applied to body for therapy

C600S003000

Reexamination Certificate

active

06264595

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to intravascular implantation devices and more particularly to a radioactive transition metal stent, wherein the stent surface comprises chemically-bound radioisotope, for therapeutic and diagnostic applications.
BACKGROUND OF THE INVENTION
Intravascular stents have been permanently implanted in coronary or peripheral vessels to prevent restenosis. See, e.g. U.S. Pat. Nos. 5,800,507; 5,059,166 and 5,840,009. Trauma or injury to the artery caused by angioplasty procedures, implantation of stents, atherectomy or laser treatment of the artery, result in restenosis, i.e., the closure or renarrowing of the artery. Restenosis, a natural healing reaction to the injury of the arterial wall, begins with the clotting of blood at the site of the injury, followed by intimal hyperplasia, i.e. the rapid growth of the injured arterial tissue through the openings in the stent, and the migration and proliferation of medial smooth muscle cells, until the artery is again stenotic or occluded.
However, such stents are not always effective in preventing restenosis and can cause undesirable local thrombosis. A variety of solutions have been proposed to minimize these undesirable effects, such as coating the stents with a biocompatible or an anti-thrombotic surface, wherein the stent-surface is seeded with endothelial cells or fibrin, or using stents as drug delivery devices. See for example, U. S. Pat. Nos. 5,800,507;5,059,166; WO 91/12779 and WO 90/13332.
Implanted stents, in conjunction with endovascular irradiation, are believed to prevent restenosis by alleviating neointimal hyperplasia. The beta-particle emitter, phosphorus-32 (
32
P) radioisotope, has been used as a permanent medical implant. Fischell et al. describe stents formed from radioactive materials, wherein a radioisotope is incorporated into the stent by physical methods, such as coating, plating, implanting on the exterior surface of the stent; inserting inside the stent; and alloying into the metal from which the stent is made. Alternatively, a beam of an ionized radioisotope is directed on the surface of the stent. See U.S. Pat. Nos. 5,059,166, 5,176,617, 5,722,984, and 5,840,009. Typically, an ion-implantation method requires irradiating sublimed red phosphorous (to avoid contamination) for about ten days to achieve a sufficient concentration of phosphorous-32 (
32
P) to obtain radioactivity of 4 to 13 &mgr;Ci per stent. However, this method is expensive, requires sophisticated equipment, and the transfer of the radioactive source from the nuclear reactor to the ion-implanter to the medical site adversely affect the short half-life of phosphorous-32 (
32
P) (14.3 days). Additionally, ion-implantation damages the surface of the stent, the interstitially implanted phosphorous-32 (
32
P) diffuses rapidly and is relatively unstable compared to chemically bound phosphorous-32 (
32
P). Moreover, ion-implantation requires beam and/or substrate scanning to achieve uniformity, which is difficult to obtain on a radial open-mesh stent. Thus conventional methods result in lower quality, non-uniform radioactive stents.
Strathearn, et al. describe a process for diffusing chemically bound radioactive ions below the surface of the substrate, wherein diffusion is accomplished by heating the substrate between 300° to 600° C. (U.S. Pat. No. 5,851,315). However, current techniques do not provide for radioactive stents with a radioisotope concentrated at the point of maximum tissue penetration, wherein the radioisotope, such as phosphorus-32 (
32
P), is chemically bound to and is uniformly confined to the surface without affecting the metallurgical properties, such as ductility and malleability, of the stent. Thus, there is a need for improved and cost-effective radioactive stents, wherein the radioisotope is uniformly distributed over the surface and is concentrated at the point of maximum tissue penetration.
SUMMARY OF THE INVENTION
The present invention relates to a radioactive transition metal stent, comprising one or more transition metals, wherein the transition metal surface is chemically bound to a radioactive material; and a method of producing the radioactive transition metal stent wherein the radioisotope is chemically bound to and is uniformly confined to the transition metal surface without affecting the metallurgical properties of the stent. Unlike conventional methods, the present method does not rely on the complex techniques described above. Accordingly, the present invention provides an improved and cost-effective radioactive transition metal metaphosphate stent surface and a method of making the same.
In one aspect, the invention relates to a radioactive transition metal stent comprising one or more transition metals, wherein the transition metal surface is chemically bound to a radioactive material, and further wherein the transition metal is a single element or an alloy of two or more transition metals. In a preferred embodiment, the radioactive material comprises a phosphorus-32 (
32
P) metaphosphate, wherein the radioactivity of the transition metal stent ranges from about 0.1 &mgr;Ci to about 100 &mgr;Ci per stent.
In another aspect, the invention relates to a method of producing a radioactive transition metal stent, comprising one or more transition metals wherein the transition metal surface is chemically bound to a radioactive material, comprising:
(i) providing a solution of dehydrated phosphorus-32 (
32
P) enriched metaphosphoric acid;
(ii) mixing the phosphorus-32 (
32
P) enriched metaphosphoric acid with a inert polymer to form an emulsion;
(iii) stabilizing the emulsion;
(iv) immersing a transition metal stent in the stabilized emulsion;
(v) removing the stent from the emulsion; and
(vi) washing and drying the stent to obtain the radioactive transition metal metaphosphate stent.
In an alternative embodiment, the stent is further immersed in a suitable non-polar solvent with a low dielectric constant, such as n-hexane, chloroform, carbon tetrachloride, diethyl ether, and the like, to remove the residual polymer. In a preferred embodiment, the non-polar solvent is n-hexane.
In preferred embodiments, the transition metal is a single element or an alloy of two or more transition metals and the inert polymer is a polysiloxane polymer. In another preferred embodiment, the phosphorus-32 (
32
P) enriched metaphosphoric acid has a radioactivity of about 1 mCi to about 10,000 mCi per ml and is mixed with a linear polysiloxane polymer to form an emulsion, wherein the emulsion is stabilized at a temperature between 150° C. to about 300° C., and further wherein the stent is immersed in the emulsion for a duration of between about 10 minutes to about 180 minutes to yield a transition metal stent metaphosphate having a radioactivity of about 0.1 &mgr;Ci to about 100 &mgr;Ci per stent.
In an alternative embodiment, the transtion-metal stent is microscopically roughened prior to immersion or concomitantly in the emulsion. In a preferred embodiment, the transtion-metal stent is microscopically roughened in the upper stent surface.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.


REFERENCES:
patent: 5059166 (1991-10-01), Fischell et al.
patent: 5176671 (1993-01-01), Fischell et al.
patent: 5674177 (1997-10-01), Hehrlein et al.
patent: 5722984 (1998-03-01), Fischell et al.
patent: 5800507 (1998-09-01), Schwartz et al.
patent: 5840009 (1998-11-01), Fischell et al.
patent: 5851315 (1998-12-01), Strathearn et al.
patent: 5919126 (1999-07-01), Armini
Carter et al., “Effects of Endovascular Radiation From a &bgr;-Particle-Emitting Stent in a Porcine Coronary Restenosis Model,”Circulation94(10):2364-2368 (1966).
Carter et al., “Experimental Results With Endovascular Irradiation Via A Radioactive Stent,”Int. J. Radiation Oncology Biol. Phys. 36(4):797-803 (1996).

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