METHODS AND SYSTEMS FOR PREPARING AND SEALING RADIATION DELIVERY STRUCTURES

Abstract: Implantable structures, such as permanently implanted stents and temporarily implanted balloon catheters, are coated with a radioactive material. At least a portion of a surface of the structure is first coated with a substrate material. The radioactive material is then bonded to the substrate material on the structure surface. The amount of radioactive material bonded to the substrate may be selected to provide a desired radioactive dosage for intravascular treatment, anti-tumor treatment, or other therapeutic protocol. Optionally, at least a portion of the bound radioactive material will be coated with a sealing layer.

Description: METHODS AND SYSTEMS FOR PREPARING AND SEALING RADIATION DELIVERY STRUCTURES BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to methods and systems for preparing radiation delivery devices, such as stents, catheters, and the like. In particular, the present invention relates to a method for coating a radioactive material onto a surface of the delivery device. Cardiovascular disease is a major cause of death and disability in the United States and throughout the world. Numerous pharmacologic, surgical, and intravascular treatments for cardiovascular disease have been developed. Of particular interest to the present invention, intravascular techniques for recanalizing stenotic regions within a patient's vasculature to restore adequate blood flow have been proposed. The most common technique is percutaneous translumenal angioplasty (PCTA) where a catheter having an expansible distal end, usually in the form of an inflatable balloon, is positioned within a blood vessel at a stenotic site. The expansible end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region. Other intravascular techniques for restoring blood flow include atherectomy where a cutting blade or other mechanical device is used to remove stenotic material, laser angioplasty where laser energy is used to ablate stenotic material, and the like. While PCTA has gained widespread use and acceptance, its success is still limited by restenosis in a significant percentage of the treated patients. Restenosis occurs in the days and months following the initial treatment and often results from hyperplasia, i.e. the uncontrolled proliferation of endothelial cells in response to the injury caused by the angioplasty procedure. A number of techniques have been proposed to inhibit " hyperplasia following angioplasty and other primary intravascular treatments. A particularly promising approach is the implantation of stents and grafts following an initial angioplasty procedure. The stent is an expandable scaffold which mechanically engages the blood vessel lumen to hold the lumen open. While stents have significantly improved the short-term prognosis following balloon angioplasty, hyperplasia still affects a number of stented patients. Moreover, the long-term success of stents remains to be established. An alternative approach for inhibiting hyperplasia involves the exposure of the treated blood vessel to radioactivity. It is well known that radioactivity inhibits cell proliferation in view of in vi tro cell culture and it has been found that intravascular exposure of a treated blood vessel to low levels of radiation will indeed inhibit hyperplasia and subsequent restenosis. A combination of these approaches has been proposed, i.e. the use of a "radioactive stent" formed by irradiating or plating the stent material to form a radioactive metal framework. See, U.S. Patent No. 5,059,166 to Fischell et al . In other instances, catheters have been modified to carry or deliver radioactive materials to the vasculature. See, e.g., U.S. Patent No. 5,199,939 to Dake et al . , U.S. Patent No. 5,302,168 to Hess, and U.S. Patent No. 5,616,114 to Thornton et al . The preparation of radioactive stents is problematic in a number of respects. In particular, the stents are desirably formed from radioactive materials having a relatively short half-life. It is undesirable to implant a radioactive material having a long half-life within a patient's vasculature. While stents may be readily fabricated from such radioactive materials, such as irradiated alloys, the stents so prepared will have a very limited shelf life. That is, once the stent has been fabricated, e.g. by irradiation or by plating, its useful life is limited. Thus, for stents fabricated at a central facility, distribution and inventory maintenance become significant problems. Stents have been made radioactive by irradiating them in cyclotrons or coating them with a 32P plasma. The cyclotron method requires very expensive equipment that has limited capacities. Producing a plasma of 32P resulting in an aerosol of 32P that poses potential health risks to the production personnel. Additionally, once the stent has been fabricated by irradiation or plating, its useful life is limited. Thus, for stents fabricated at a central facility, distribution and inventory maintenance become significant problems. To control the delivered radiation dose, such stents must be fabricated, shipped and delivered within a narrow clinical time frames. For these reasons, it would be desirable to provide improved methods and devices for the delivery of radioactivity to patients for therapeutic purposes. In particular, it would be desirable to provide improved methods for preparing and fabricating devices, substrates, and materials for delivering radioactivity to patients. The methods should be useful with permanently implanted devices, such as vascular stents, grafts, and coils; temporarily implanted devices, such as catheters, wires, and pellets; and biodegradable implants and materials, such as beads, particles, gels, and the like. The fabrication and preparation methods should be convenient, economical, capable of being performed in hospitals and other user facilities, and capable of incorporating radioactive materials having the appropriate dosages for treating hyperplasia and other disease conditions. At least some of these objectives will be met by various embodiments of the present invention described below. 2. Description of the Background Art U.S. Patents Nos . 5,059,166; 5,199,939; 5,302,168; and 5,616,414, have been described above. U.S. Patent No. 5,338,770 describes methods and materials for coating biomedical devices and implants with poly (ethylene oxide) chains suitable for covalent attachment of bioactive molecules intended to counteract blood-material incompatibility. EP 706 784 describes a stent having a carrier material for a therapeutic material, such as a radioactive substance. U.S. Patent No. 5,463,010 describes membranes, including polymerized aliphatic hydrocyclosiloxane monomers, for use in coating biomedical devices and implants, and suitable for use as a substrate for covalent attachment of other molecules. A variety of U.S. patents describe various methods for labeling of substrates, typically peptides, proteins and the like, with radioactive metal ions, such as use of DTPA chelates in U.S. Patent Nos . 4,479,930 and 4,668,503; U.S. Patent No. 5,371,184, in which a chelate ligand is disclosed for labeling hirudin receptor-specific peptides; U.S. Patent No. 4,732,864, in which the use of metallothionein or metallothionein fragments conjugated to biologically active molecules is disclosed; U.S. Patent No. 5,225,180, in which technetium-99m labeling of peptides containing at least two cysteine residues capable of forming a disulfide bond through reduction of the disulfide is disclosed; U.S. Patent No. 5,443,953, in which a variety of conjugates for radioisotopes are disclosed; U.S. Patent No. 5,376,356, in which a variety of methods of radiolabeling and conjugates are disclosed; U.S. Patent No. 5,382,654, in which a variety of bifunctional chelates are disclosed; and U.S. Patent No. 5,464,934, in which a method of metal chelation, using amino acid sequences that are capable of forming metal complexes, is disclosed. U.S. Patent Nos. 5,277,893; 5,102,990; and 5,078,985 each describe proteins containing one or more disulfide bonds which are radiolabeled with radionuclides, including technetium and rhenium for use in diagnosis and treatment. U.S. Patent No. 3,927,325, describes a tissue irradicator comprising a radioisotope encapsulated in vitreous carbon. The full disclosures of each of these patents are incorporated herein by reference. SUMMARY OF THE INVENTION The methods, systems, and apparatus of the present invention provide for useful and convenient fabrication and preparation of radioactive implantable devices and materials. Rather than fabricating the devices and materials at a central location, transporting them to the hospitals or other use sites, and maintaining them in inventory for unpredictable periods of time, the present invention permits the radioactive material to be incorporated onto the implantable device or material at a predictable, usually immediate, time before use. The radioactive substances which are bonded to the device may be prepared at a central manufacturing location on a regular basis, e.g. daily, or in some cases may be fabricated on-site so that in either case fresh radioactive substance having a known radioactivity or radioactive dosage may be employed. Such ability to prepare stents and other implantable devices and materials having predictable dosages is a significant advantage of the methods and apparatus of the present invention. The methods, devices, and materials of the present invention permit very accurate control of radioactive dosages and provide a number of advantages including that they can be used independent of surgery as a curative therapy for many types of stenosis and neoplastic diseases; they can extend the role of stents in achieving local control of restenosis; they can provide an accurate method of controlling the delivery of radiation (dosage) to a diseased area and minimally affect the normal surrounding tissue; they can be used with drug therapy including anti-platelet medications; side-effects from treatment may be kept to a minimum; radiation exposure to nurses, hospital staff and family members is reduced or eliminated; and the required hospital stay is minimized and in some cases eliminated (the procedure may be done on an outpatient basis) . The present invention provides methods, apparatus, materials and kits for preparing and delivering radioactive dosages to a patient for therapeutic purposes. The invention is particularly useful for the treatment of intravascular hyperplasia following angioplasty and other interventional treatments, but will also find use in other brachytherapies, such as tumor treatment and the treatment of other proliferative diseases. In a first aspect of the present invention, a method for coating an implantable device or material with a radioactive substance comprises providing an implantable device or material having a surface, referred to collectively below as "structures." At least a portion of the surface has been coated with a substrate material, and a radioactive material is bonded to the substrate material to provide a coated device. The implantable structures can be intended for permanent or temporary implantation, with exemplary devices including stents, coils, wires, inflatable balloons, needles, probes, catheters, and the like, and exemplary methods including beads, particles, gels, and the like. Such structures may be delivered by or incorporated into or onto intravascular and other medical catheters and devices . The substrate material will be selected to adhere to the surface of the implantable structure and to provide a bonding situs for subsequent attachment of the radioactive material. For example, the substrate material may be bifunctional , with a first moiety or functionality being capable of covalent or non-covalent attachment to the structure surface and a second moiety or functionality being available for bonding to the radioactive material, and optionally including a linking portion therebetween. Suitable radioactive materials will be capable of being bonded to the substrate material. Typically, the radioactive material will include a radionuclide, and preferably a radioactive metal ion, such as radioisotopes of rhenium, but may include radioactive metal ions found in the group consisting of elements 26-30 (Fe, Co, Ni , Cu, Zn) , 33-34 (As, Se) , 42-50 (Mo, Tc, Ru, Rh, Pd, Ag, Cd, In, Sn) and 75-85 (Re, Os, Ir, Pt , Au, Hg, Tl , Pb, Bi, Po, At), and particularly the radionuclides 62 Cu, β4 Cu, 67 Cu, 97 Ru, 105 Rh, 109 Pd, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 Pb and 212 Bi. The radioactive material will further comprise a bonding component suitable for covalent or non-covalent attachment to the substrate material, preferably being suitable for covalent attachment. In an exemplary embodiment, bifunctional chelates are covalently or otherwise bonded to the substrate material, preferably through an amine functional group bonded to the substrate material, which substrate material may include a siloxane coating, including an aliphatic hydrocyclosiloxane monomer coating, and the bifunctional chelate is then radiolabeled. A variety of bifunctional chelates can be employed; most involve metal ion binding to thiolate groups, and may also involve metal ion binding to amide, amine or carboxylate groups. Representative bifunctional chelates include ethylenediamine tetraacetic acid (EDTA) , diethylenetetramine-pentaacedic acid (DTPA) , chelates of diamide-dimercaptides (N 2 S 2 ) / and variations on the foregoing, such as chelating compounds incorporating N 2 S 3 , N 2 S 4 and N 3 S 3 or other combinations of sulfur- and nitrogen- containing groups forming metal binding sites, and metallothionine . It is also possible, and contemplated, that a substrate material will be employed to which metal ions may be directly bonded to the substrate material, in which case the substrate material may include an amine functional group bonded to the surface of the substrate material . After the radioactive material has been chelated or otherwise bonded to the substrate, the structure may optionally be sealed over at least a portion of its surface with a biocompatible material which is able to contain the radioactive material and prevent loss or leaching thereof, even when exposed to stressful in vivo conditions, such as elevated pH, elevated serum albumin levels, or the like. A wide variety of sealing materials may be suitable, with biocompatible polymers, such as polyurethane, polyvinylchloride, polyethylene, and the like, being suitable. Particularly preferred are polyurethanes which may be dip- coated onto the surface of the device after the device has been coated with the radioactive material. The sealant material will be formed over the device in a layer which is sufficiently thick to prevent or inhibit leaching or other loss of the radioactive material, typically being present in a very thin layer of 0.1 ml, or less. In a second aspect of the present invention, a method for preparing a radioactive implantable structure comprises providing the device, generally as described above. The method further comprises providing a radioactive material comprising the bonding constituent and the radioactive constituent, again generally as described above. The specific activity of the radioactive material is then determined, either by calculation of the decay which will have occurred since preparation or by direct measurement . An amount of the radioactive material is then bonded to the substrate material on the device in order to provide a predetermined radioactive dosage, typically in the range from 1 Gray to 250 Gray. For intravascular therapies, e.g. inhibiting neointimal hyperplasia, the dosage will usually be in the range from 1 Gray to 50 Gray, preferably in the range from 30 Gray to 50 Gray. For the other treatments, such brachytherapy for the treatment of solid tissue and other tumors, the dosage will usually be in the range from 10 Gray to 250 Gray, preferably being in the range from 25 Gray to 125 Gray. In a third aspect of the present invention, a method for fabricating an implantable structure suitable for subsequent coating with a radioactive material comprises providing an implantable structure having a surface, generally as described above. At least a portion of the surface of the structure is then coated with a substrate material, generally as described above. Instructions are provided to coat the structure with a radioactive material which can bond to the substrate material . In a fourth aspect of the present invention, a method for delivering a radioactive dose to a target location in a patient comprises providing an implantable structure having a surface, wherein at least a portion of the surface has been coated with a substrate material . A radioactive material is then bonded to the substrate, and the structure is then implanted at the target location. The radioactive dose can be delivered for a variety of purposes, including intravascular delivery for the treatment of post-angioplasty and other hyperplasia, delivery to tumor and or neoplastic sites, and the like. In a fifth aspect of the present invention, an implantable structure having a surface and being adapted for delivery to a target site in a patient's body is coated with the substrate materials over at least a portion of the surface, when the substrate material is capable of bonding to a radioactive material, typically by any of the mechanisms described above. The structural component may comprise a stent, coil, wire, inflatable balloon, or any other device or structure which is capable of being implanted at a target location, including intravascular target locations, intraluminal target locations, target locations within solid tissue (typically for the treatment of tumors) , intrasynavial locations (e.g. for the treatment arthritis), and the like. Such structures are suitable for radioactive coating by another, i.e., the substrate-coated structures will be a useful product in themselves. In a sixth aspect of the present invention, at least a portion of the surface may optionally be sealed with a biocompatible material in order to inhibit leaching or other loss of the radioactive material upon subsequent introduction of the device to a patient. While the bonding methods of the present invention are very effective and result in minimal leakage of the radioactive materials under most in vivo conditions, it is possible that small amounts, typically less than 5% of the radioactive material by weight, can be leached from a device under certain stressful conditions, such as elevated pH, high serum albumin levels, or the like, which may be present in the vasculature or other target site where the structure is to be implanted. The implantable structure can be used for permanent or temporary implantation, with exemplary devices including stents, coils, seeds, wires, inflatable balloons, catheters, probes, particles, beads, gels, and the like. Such structures may be delivered by or incorporated into intravascular and other medical catheters. LO O tO to H LΠ o LΠ o Lπ O LΠ structure, the instructions for use, and optionally, sealing reagent (s) . DESCRIPTION OF THE PREFERRED EMBODIMENT As used herein, the phrase "an implantable structure" refers to virtually any device material, or substance which can be temporarily or permanently implanted into a human or animal host . The structure can be implanted for a variety of purposes, including tumor treatment, treatment of cardiovascular disease, the treatment of lumenal blockages, and the like. The presently preferred use is the treatment of hyperplasia in blood vessels which have been treated by conventional recanalization techniques, particularly intravascular recanalization techniques, such as angioplasty, atherectomy, and the like. The structures may have a wide variety of forms, including both non-biodegradable and biodegradable. Non- biodegradable structures will be the most common, typically being comprised of physiologically compatible materials, such as metals, ceramics, and plastics having surfaces capable of being derivatized to attach the substrate material as described below. Biodegradable structures will typically be formed from physiologically compatible biological and non- biological polymers, such as albumins, dextrans, polylactates, polyglycolates, and the like, which will typically persist after implantation for a time in the range from 1 day to 1 year, usually from 1 week to six months. An exemplary non- biodegradable structures include stents, coils, wires, balloons, probes, catheters, needles, seeds, beads, and particles, while biodegradable structures will usually be in the form of seeds, beads, particles, and gels. Specific structures include intravascular stents, including both balloon-expandable stents and self-expanding stents. Balloon-expandable stents are typically formed from a stainless steel are available from a number of commercial suppliers, most notably from Cordis under the Palmaz-Schatz tradename. Self-expanding stents are typically composed from a shape memory alloy such as nitinol (nickel -titanium alloy) and are available from suppliers, such as Instent and Boston Scientific. Fig. 1 illustrates a stent 10 which has been coated with a substrate material, as will be described in more detail below. The stent 10 is typically composed of a stainless steel framework, in the case of balloon-expandable stents or from nickel titanium alloy, in the case of self- expanding stents. Both such structural frameworks are suitable for coating by the substrate material, as described below. Exemplary structures also include balloons, such as balloon 22 on balloon catheter 20 (Fig. 2) . Such balloons may also be coated with the substrate material according to the methods of the present invention. The construction of intravascular balloon catheters is well known and amply described in the patent and medical literature. The inflatable balloon 22 may be a non-distensible balloon, typically being composed of polyethyleneterephthalate, or may be an elastic balloon, typically being composed of latex or silicone rubber. Both these structural materials are suitable for coating with substrate materials according to the methods of the present invention. Structures which may be coated also include beads, particles, and the like. The beads and particles may themselves be non-degradable, e.g. being composed of metharcylates, styrene divinybenzene, or the like, or may be biodegradable, e.g. being composed of dextrans, albumins, polylactates, polyglycolates, or the like. The implantable structures will have one or more surfaces which are coated with the substrate material. In the case of stent 10 (Fig. 1) it is particularly desirable to coat the outer exposed surface of the individual elements of the stent framework. Optionally, the entire surface of the stent may be coated. In the case of balloon 22 of catheter 20 (Fig. 2) it will be desirable to coat at least the outer cylindrical surface of the balloon 22 which will be in contact with the blood vessel when the balloon is inflated therein. The substrate material includes the siloxane surface material described in U.S. Patent Nos. 5,338,770 and 5,463,010. The siloxane material forms a smooth, continuous thin coating or membrane, and is produced as described in U.S. Patent Nos. 5,338,770 and 5,463,010. The siloxane material coats the biomedical or implantable device, and a plurality of amine functional groups are bonded to the siloxane surface. The metal ion may be bound directly to one or more of the amine groups. If an isotope of rhenium is employed, such as 186 Re or 188 Re, then the rhenium may be reduced to an appropriate redox state, using a stannous reducing agent or other reducing agents known in the art, to facilitate binding to the amine functional groups. Polyamines can be used to increase the number of amines which are available for reaction or coupling. Primary amines present on the structure as a result of the siloxane coating may be reacted with a polyamine, such as a "starburst" molecule as described in Newkome et al . (1992) Aldrichimica Acta 25:31-38, to increase the number of available amines. the degree of amplification will depend on the number of amines available on the polyamine, e.g. with starburst molecules having sixteen amines, the theoretical amplification is 15:1, although the actual amplification will be less because of steric hindrance and other inefficiencies. It is also contemplated that a variety of linker technology may be employed, in which the metal ion is bound to a bifunctional chelate, which directly or through a series of linking agents is in turn bound to the substrate material. In one example, the siloxane material as above has bonded to its surface a plurality of amine functional groups. Covalently bonded to the amine functional groups are a plurality of poly (ethylene oxide) chains, such that a single poly (ethylene oxide) chain is bonded to a single amine functional group, all as is generally described in U.S. Patent No. 5,338,770. A quantity of at least one molecule containing at least one reactive sulfide, or one disulfide bond, and a reactive amine is covalently bonded to the poly (ethylene oxide) chains. In the event that a disulfide bond is employed, such as with a cystine, a stannous reducing agent, may be employed to simultaneously reduce the disulfide bond in the bifunctional chelate, and to reduce the metal ion, such as an isotope of rhenium, to an approximate redox state for forming a stable bond. The metal ion is then reacted with the reactive sulfide, which reactive sulfide is either originally present or formed through reduction of a disulfide bond, and the metal ion is bound to the reactive sulfides and available reactive amines, forming a metal ion complex. Means to attach or complex disulfide bonds, and chelating agents and substrates containing disulfide bonds, are known to those skilled in the art. Disulfide bonds may be introduced into such proteins by chemical methods involving direct conjugation. Chemical means used to introduce disulfide bonds into proteins include use of homofunctional crosslinkers and heterofunctional crosslinkers . Representative chemicals which can be used to introduce disulfide bonds include 4 -succinimidyloxycarbonyl -alpha-methyl- alpha- (2-pyridyldithiol) -toluene; N-succinimidyl 3- (2-pyridyl- dithio) propionate; sulfosuccinimidyl 6- [3- (2-pyridiyldithiol) propinoamido] hexonate; dithioiiis (succinimidylproprionate) ; 3 , 3 ' -dithiojbis (sulfosuccinimidylpropionate) ; and sulfosuccinimidyl 2- (p-azidosalicylamido) ethyl- 1, 3 ' -dithiopropionate . It is also possible and contemplated to have bifunctional chelating agents covalently or otherwise bonded to the substrate material, in one embodiment through an amine functional group bonded to the substrate material, which substrate material may include a siloxane coating, including an aliphatic hydrocyclosiloxane monomer coating as described above. Representative bifunctional chelating agents include agents based on aminocarboxylic acids, such as EDTA and cyclic anhydride of DTPA; agents based on triamines, including those disclosed in U.S. Patent No. 5,101,041; and thiol-containing agents, including the agents disclosed in U.S. Patent Nos. 5,443,815 and 5,382,654. The bifunctional chelating agent may also be a peptide sequence, composed of natural or unnatural amino acids, covalently or otherwise bonded to the substrate material, including through functional amine groups bonded to the substrate material. Representative peptide sequence bifunctional chelating agents including the amino acid sequences : -Gly-Gly-Cys- -Cys-Gly-His- -Asp-Gly-Cys- -Glu-Gly-Cys- -Gly-Asp-Cys- -Gly-Gly-Cys- and modifications of the foregoing, including substitution of Pen for Cys, and the unnatural amino acid sequences as disclosed in U.S. Patent No. 5,464,934. In each instance, the implantable structure, or a portion thereof, may be radiolabeled by means known to the art. In one embodiment, using any of the substrates set forth above to which is bonded a chelating agent, the structure is placed in a solution containing the radionuclide, reducing agents as required to reduce the radionuclide and disulfide bonds, if present, including stannous reducing agents, appropriate buffers and the like. Depending on the radionuclide, the solution with the device may be heated to any temperature up to boiling temperature, and may be incubated for any required period. The amount of radioactivity bonded to the implantable device may be controlled by varying the concentration of radioactivity in the solution, by varying the reaction conditions, including pH, temperature and the length of incubation, and/or by controlling or limiting the amount of surface to which the radiovuclide is bound. Re- 188 and Y-90 are two beta-emittors which are particularly useful. Re-188 has some significant advantages as a radionuclide. Re-188 (Tl/2 = 17 hours) can be produced carrier-free from a W-188/-Re-188 generator. It emits radiation which can be used therapeutically (beta particles) . It also emits gamma rays (15% abundance) which can be used in concert with scintigraphy for localization and dose estimation. The main therapeutic component is the beta particle - (Emax = 2.11 MeV) which deposits 90% of its energy within 4.3 mm of a point source thereby minimizing exposure to adjacent organs as well as medical personnel. The availability of a generator system is a considerable advantage as it allows for cost-effective on-site access to the radionuclide over a period of months. The generator system may be similar to the Mo-99/Tc-99m generator system widely used in nuclear medicine. Re-188 in the form of perrhenate is eluted from the generator using oxidant-free 0.9% NaCl . Y-90 is a pure beta emitter (Emax = 2.3 MeV, half-life 64 hours) . Y-90 is also available from a generator system composed of the Sr-90/Y-90 pair of radionuclides and can be chelated by a number of heterocyclic chelates such as 1,4,8, ll-tetraazacyclotetradecane-N,N' , N" ,N" ' -tetraacetic acid (TETA) or 1 , 4 , 7, 10-tetraazacyclododecane-N,N' ,N" ,N" ' - tetraacetic acid (DOTA) . DOTA is recognized as a superior Y- 90 chelator. After coating the surface of the structure with the radioactive material, the device will preferably be sealed in order to inhibit or prevent accidental leakage or other loss of the radioactive material when the device is introduced and/or implanted into the patient. The sealing step may take a variety of forms. Usually, the material will be a biocompatible polymer, such as a polyurethane, polyvinyl chloride, polyethylene, or the like, and will be applied to the device by dip-coating. Thus, the polymer will usually be present in a solvent which permits rapid air drying . Alternatively, the sealing layer could applied by a variety of other techniques, such as shrink-wrapping of a thin sheath of polymeric material, chemical vapor deposition of a variety of materials, electrolis coating of certain bio-compatible metals (which will be useful with metallic substrates, such as stents, radioactive seeds, and the like), and the like. The sealant layers will protect the underlying layers of radioactive material against interaction with the physical and chemical conditions in which the device is to be implanted. Other structures may be introduced by open surgical procedures, endoscopic procedures, injection (in the case of beads, particles, and gels), and the like. The radioactively coated devices may then be introduced to the patient in a conventional manner, depending on the device. In the case of stents, the stent will be delivered by a stent delivery catheter, typically an intravascular balloon catheter in the case of balloon-expanded stents or a containment catheter in the case of self-expanding stents. The delivery catheters may be modified to provide for shielding of the radioactive stent, and methods for constructing shielded catheters are well described in the patent literature. Other structures may be introduced by open surgical procedures, endoscopic procedures, injection (in the case of beads, particles, and gels), and the like. The radioactively coated balloon catheter 20 may also be delivered to the patient in a generally conventional manner. For delivery to the coronary vasculature, the catheter may be introduced through the femoral artery using the Seldinger technique. The catheter will typically be guided to the coronary os using a guiding catheter and thereafter within a target coronary artery under fluoroscopy. The balloon will then be inflated in order to engage the radioactive material directly against the inner wall of the blood vessel. The balloon may remain inflated for extended periods of time in the case of perfusion balloons. In the case of non-perfusion balloons, it will be necessary to periodically deflate the balloon in order to permit blood perfusion to the distal coronary arteries. The total time of balloon exposure will depend on the dosage. The implantable devices of the present invention will typically be provided in kit form, as illustrated in Fig. 3. In particular, Fig. 3 illustrates an implantable stent 10 which has been coated with the substrate material, but which has not yet been coated with the radioactive material. The stent 10 will be packaged inside a suitable medical device package, such as pouch 30, and instructions for use ("IFU") will be provided with, within or on the pouch 30. The instructions for use describe coating of the stent 10 with the radioactive material according to any of the methods of the present invention described above. A radioactively coated stent 110 is illustrated in Fig. 4. Stent 110 comprises a stent structure 112, typically in the form of a metal coil, scaffold, or other conventional device intended for balloon expansion or self-expansion within a blood vessel or other body lumen. The stent structure 112 will be first coated with a substrate layer and radioactive material, shown collectively as 114 in Fig. 4. Then, according to the present invention, the radioactive stent is sealed with a layer 116, typically a polymeric layer which is dip-coated onto the stent, also described above. The implantable devices of the present invention will typically be provided in kit form, as illustrated in Fig. 5. In particular, Fig. 5 illustrates an implantable stent 112 which has been coated with the substrate material, but which has not yet been coated with the radioactive material or the sealing coating or layer. The stent 112 will be packaged inside a suitable medical device package, such as pouch 40, and instructions for use IFU 30 will be provided within or on the pouch 30. Optionally, the sealing material and/or other reagent (s) may be provided in a vial 20 as part of the kit, but usually the radioactive material will not be provided, and instead will be supplied by the user from a separate central source as discussed above. The instructions for use describe coating of the stent 112 with the radioactive material according to any of the methods of the present invention described above. EXAMPLES . Example 1. Attachment of the S-protected chelate benzoyl - mercaptoacetyl triglycine (bnz-MAG3) to a stainless steel stent . Stainless steel stents are activated by a plasma process using a mixture of oxygen and ammonia gas resulting in ammonia becoming annealed to stainless steel stent surface. The activated stent surface is further coated using a secondary plasma-coating resulting in the deposition of a tetra-methyl-cyclo-tetra-siloxane polymer. In this process the siloxane polymer is bonded to the stent via a nitrogen bridge. Subsequently, the free siloxane surface of the coated stent is reacted with N-tetramethyl silylallyl-amine resulting in a layer of free amine groups on the outside of the stent. The free amines are then used to anchor the bnz- MAG3. For attachment, bnz-MAG3- succimimide ester is then reacted with the amines on the stent in an aqueous buffer containing 0.1 M sodium bicarbonate, pH 8.5, for 15 minutes. The unreacted bnz-MAG3 is then rinsed in water and dried under a stream of nitrogen. This results in covalent attachment of bnz-MAG3 to the stent via a peptide linkage. Example 2. Preparation and use of a stent labeling kit. The stent labeling kit is a self-contained kit containing all of the components needed to radiolabel stents on site except the radioactive material. The key component is one or more chelate-coated stents in a sealed labeling vessel. The kit would contain three vials: a) a vial containing a stent and a lyophilized formulation of buffer and stannous salts, b) a vial containing a suitable polymeric sealant (e.g. ticoflex) solubilized in ethanol , c) a vial containing ethanol (200 proof, USP) for rinsing, and d) a package insert with detailed labeling and use instructions . Not supplied would be vials of water (WFI, USP) . The first vial would contain a lyophilized formulation of stannous tartrate and Na-K-tartrate such that upon hydration to a final volume of 1 ml the solution would contain 5 mM Na-K-tartrate, pH 4.5, and 0.1 mM stannous tartrate. Stannous ions are used to chemically reduce Re-188 (VII) to a reactive Re-188 (V). The Na-K-tartrate used as a complexing agent to transfer Re-188 (V) to the chelate on the stent. The second vial contains ticoflex solubilized in ethanol and is used to fix and seal the Re-188 to stent, and should result in a 10-100 nm coating of the stent and its associated radioactivity. The third vial contains ethanol used as a rinse solution after the labeling but before sealing, and after sealing. In the first rinse it removes water and in the second rinse it removes unbound ticoflex. The kit will be designed to be used as follows: To first vial (a) will be added Re-188 in the form of Re-188- perrhenate in 0.9% NaCl introduced by use of a needle and syringe. The vial will be incubated in a boiling water bath for 15 minutes. Thereafter the solution will be withdrawn and the stent washed in situ serially with water and then ethanol. An aliquot of the ticoflex solution will be introduced to the vial sufficient to completely cover the stent. The vial will be immediately flushed with ethanol and then water. The stent will then be dried in situ under a stream of sterile, medical grade nitrogen. While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A method for coating an implantable structure with a radioactive material, said method comprising: providing an implantable structure having a surface, wherein at least a portion of the surface has been coated with a substrate material; and bonding a radioactive material to the substrate material . 2. A method as in claim 1, wherein the implantable structure is selected from the group consisting of stents, coils, wires, needles, probes, catheters, inflatable balloons, seeds, beads, particles, and gels. 3. A method as in claim 1, wherein the substrate material is selected from the group consisting of siloxanes and bifunctional chelating agents. 4. A method as in claim 1, wherein the radioactive material comprises a radionuclide and a bonding component. 5. A method as in claim 1, wherein the bonding step comprises covalently bonding the radioactive material to the substrate material . 6. A method as in claim 1, further comprising applying a sealing layer over at least a portion of the bonded radioactive material . 7. A method for preparing a radioactive implantable structure, said method comprising: providing an implantable structure having a surface wherein at least a portion of the surface has been coated with a substrate material; providing a radioactive material including a bonding constituent which can be bonded to the substrate material and a radioactive constituent; determining the specific activity of the radioactive material; and bonding an amount of the radioactive material to the substrate material on the structure selected to provide a predetermined radioactive dosage. 8. A method as in claim 7, wherein the predetermined dosage is in the range from 1 Gray to 50 Gray. 9. A method as in claim 7, wherein the bonding step comprises covalently bonding the radioactive material to the substrate material . 10. A method as in claim 7, wherein the implantable structure is selected from the group consisting of stents, coils, wires, needles, probes, catheters, inflatable balloons, seeds, beads, particles, and gels. 11. A method as in claim 7, wherein the substrate material is selected from the group consisting of siloxanes and bifunctional chelating agents. 12. A method as in claim 7, wherein the radioactive material comprises a radionuclide and a bonding component. 13. A method as in claim 7, further comprising applying a sealing layer over at least a portion of the bonded radioactive material. 14. A method for fabricating an implantable device suitable for subsequent coating with a radioactive material, said method comprising: providing an implantable structure having a surface; coating at least a portion of the surface of the device with a substrate material; and providing instructions to coat the structure with a radioactive material which bonds to the substrate material . 15. A method as in claim 14, wherein the implantable structure is selected from the group consisting of stents, coils, wires, needles, probes, catheters, inflatable balloons, seeds, beads, particles, and gels. 16. A method as in claim 14, wherein the substrate material is selected from the group consisting of siloxanes and bifunctional chelating agents. 17. A method as in claim 14, wherein the radioactive material comprises a radionuclide and a bonding component . 18. A method as in claim 14, further comprising applying a sealing layer over at least a portion of the bonded radioactive material . 19. A method for delivering a radioactive dose to a target location in a patient's body, said method comprising: providing an implantable structure having a surface, wherein at least a portion of the surface has been coated with a substrate material; bonding a radioactive material to the substrate; and implanting the structure at the target location. 20. A method as in claim 19, wherein the implantable structure is selected from the group consisting of stents, coils, wires, needles, probes, catheters, inflatable balloons, seeds, beads, particles, and gels. 21. A method as in claim 19, wherein the substrate material is selected from the group consisting of siloxanes and bifunctional chelating agents. 22. A method as in claim 19, wherein the radioactive material comprises a radionuclide and a bonding component . 23. A method as in claim 19, further comprising sealing at least a portion of the radioactive material prior to implanting. 24. An implantable structure comprising: a structural component having a surface and being adapted for delivery to a target site in a patient's body; and a substrate material coating at least a portion of the surface, wherein said substrate material bonds to a radioactive material. 25. A structure as in claim 24, wherein the implantable structure is selected from the group consisting of stents, coils, wires, needles, probes, catheters, inflatable balloons, seeds, beads, particles, and gels. 26. A structure as in claim 24, wherein the substrate material is selected from the group consisting of siloxanes and bifunctional chelating agents. 27. A structure as in claim 24, further comprising a layer of radioactive material comprises a radionuclide and a bonding component over the substrate material . 28. A structure as in claim 27,. further comprising a sealing layer over at least a portion of the radioactive material layer. 29. A kit comprising: an implantable structure according to claim 22; and instructions describing a method for bonding the radioactive material to the substrate material. 30. A kit as in claim 29, further comprising a package which contains the implantable device and the instructions. 31. A kit as in claim 29, further comprising reagent (s) for sealing the structure after coating with the radioactive material.

Inventors: OSAKI SHIGEMASA, STERN ROBERT A, OSAKI, SHIGEMASA, STERN, ROBERT, A.
Applicants: INNERDYNE MEDICAL INC, INNERDYNE, INC.
Application year: 1998
Main classification: A61K51
IPC codes: A61K51, A61N5