Radioactive stent

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

(Field of invention) The present invention relates generally in the field of medical devices and in coronary artery and peripheral stents for intravascular radiotherapy in one particular application. [0002]

(Background of invention) Percutaneous transluminal coronary movement, also known as PTA treatment of coronary arteries and balloon angioplasty Pulmonation (PTCA) is the preferred treatment for coronary vascular stenosis. About 300,000 In 1990, nearly one million procedures were performed in the United States and in 1997 worldwide. The US market constitutes approximately half of the total market for this procedure. The increasing popularity of PTCA procedures is due to their relatively high success rate and their minimal invasiveness compared to coronary artery bypass surgery. However, patients treated with PTCA suffer from a high incidence of restenosis, and more than about 35% of all patients require repeated PTCA procedures or bypass surgery. However, it comes with high costs and adds patient risk. [0003]

More recent attempts to prevent restenosis through the use of drugs, mechanical devices, and other experimental procedures have had limited long-term success. For example, stents dramatically reduce acute reclosure and delay the clinical effect of smooth muscle cell proliferation by increasing the minimum lumen diameter, but a proliferative response to angioplasty-induced injury. Does not prevent. [0004]

Restenosis is currently believed to occur at least partially as a result of injury to the arterial wall during the luminal opening angioplasty procedure. In some patients, the injury initiates a repair reaction, which is characterized by hyperplastic proliferation of vascular smooth muscle cells in the area damaged by angioplasty. Intimal hyperplasia or smooth muscle cell proliferation, in the presence of a stent, narrows the lumen opened by angioplasty and requires repeated PTCA or other procedures to relieve restenosis. [0005]

Preliminary studies show that intravascular radiotherapy (IVRT) is promising in the prevention or long-term control of restenosis after angioplasty. IVRT can also be used to prevent or delay stenosis after a cardiovascular graft procedure or other injury to the vessel wall. However, precise control of radiation dose appears to be important in inhibiting or stopping hyperplasia without causing excessive damage to healthy tissue. Overdose in the area of blood vessels can result in arterial necrosis, inflammation, bleeding, and other risks discussed below. Underdose will result in inadequate inhibition of smooth muscle cell hyperplasia, or exacerbation of hyperplasia and, as a result, restenosis. [0006]

The prior art includes many examples of catheter-based radiation delivery systems. The simplest system discloses a seed train type source inside a closed end tube. An example of this type of system can be found in Dake's US Pat. No. 5,199,939. The radiation source can be separated from the catheter and the radiation source can be reused. To do so, the delivery system is disclosed by Waksman et al., U.S. Pat. No. 5,683,345, where source seeds are hydraulically pumped into the lumen of the closed catheter where they are maintained during the treatment period. They are pumped back into the container. Subsequent disclosures have integrated source wires into catheters that are more than the type common to interventional cardiology. In this type of device, a closed lumen through which the radioactive source wire is deployed can be added to the conventional catheter structure. The balloon is incorporated into the lumen to assist the center of the source wire. Radioactive source wire is Nucletron, For manufacturers like BV It is believed that it will be delivered through a catheter by a more made commercial afterload system. These types of systems are disclosed in Liprie 5,618,266, Weinberger 5,503,613, and Bradshaw 5,662,580. [0007]

In the system disclosed to Dake and Waksman, during treatment, the source is katete The center of Le or very close to it. However, it does not necessarily exist in the center of the artery. The system disclosed to Weinberger and Bradshaw further includes an inflatable balloon-like centralization mechanism to overcome this shortcoming. In either case, the source energy must be high enough to traverse the lumen of the vessel to reach the target tissue site of the vessel wall, thus requiring the use of higher energy sources. However, higher energy sources can have undesired characteristics. First, the likelihood that radiation will erroneously affect untargeted tissue is higher because the absorption factor per unit tissue length is practically lower for higher energy irradiation. Second, higher energy sources are more harmful to medical staff and therefore require additional shielding during storage and further attention during use. Third, the source may or may not be exactly in the center of the lumen, so that the dose calculation follows a larger error factor due to the non-uniformity of the radial distance from the source surface to the target tissue. The impact of these factors is Trans It is a common topic of discussion at recent medical conferences dealing with intravascular radiotherapy, such as the Catheter Therapeutics Conference, Scripps Symposium on Radiotherapy, Advances in Cardiovascular Radiation Therapy Conference, American College of Cardiology Conference, and American Heart Association Conference. [0008]

The impact on treatment strategies is similar to that previously disclosed in a paper discussing a removable seed system (Tierstein et al., Catheter based Radiotherapy to Inhibit Restenosis after Coronary Stenting, NEJM 1997; It is discussed in detail in 336 (24): 1697-1703). Tierstein is source-centric by Scripps Clinic doctors It is reported that each blood vessel was examined using ultrasonography to evaluate the maximum and minimum distances from to the target tissue. Dose hazard To prevent, they do not treat vessels in which approximately 4 × more than a distinguishing dose factor (8-30 Gy) is present between a nearby vascular target and a distant vascular target. Distinguishing dose factors such as these are unavoidable for catheters in curved vessels such as arteries, limiting the use of radiation to a certain degree and adding complexity to the procedure. In addition, this treatise describes the need to maintain a source in a lead carrier called "pig", as well as the physician. It describes the fact that the treatment staff leaves the catheterization laboratory during treatment. Therefore, the added complexity, time and risk are added to the procedure caused by the variation in the position of the source within the delivery system and the energy of the source itself. [0009]

Several additional inventions have been disclosed in an attempt to overcome the limitations of high energy seed based systems for these dose measurement problems. These systems share a common feature that attempts to bring the source closer to the target tissue. For example, Hess U.S. Pat. No. 5,302,168 is a flexible carrier with a remote control window. Fearnot also teaches the use of radioactive sources contained in; Fearnot also discloses in U.S. Pat. No. 5,484,384 a wire basket construct that can be introduced in a low profile state and subsequently deployed once in place. Hess also has US Pat. No. 5,302,168 In the issue, it is intended to disclose a balloon with a radioactive source attached to the surface; Hehrlein discloses in WO 96/22121 a balloon catheter coated with an active isotope; and Bradshaw. Is US Pat. No. 5,662,580, We disclose balloon catheters suitable for use with liquid isotopes. An object of all these inventions is to place the source closer to the target tissue and thus improve therapeutic properties. [0010]

In a non-catheter-based approach, Fischell's U.S. Pat. No. 5,059,166 Discloses an IVRT method that relies on a radioactive stent, which is permanently implanted in a blood vessel after completion of a lumen opening procedure. Radiation delivery systems installed on the stent are also disclosed in US Pat. No. 5,176,617 by Fischell et al. And US Pat. No. 5,674,177 by Heirlein et al. The use of the stent as a platform is as low as 0.14-0.23 μCi (microcurie) in animals I am particularly interested because it has been shown to be effective in the radioactivity range as well. For example, Fischell et al. Low-Dose, β-Particle Emission From Stent Wire Results in Complete, Localized Inhibition of Smooth Muscle Cell Proliferation ", Circulati on, vol.90, pp.2956-2963, (1994); Laird et al., Inhibition of Neointimal Proliferation with Low-Dose Irradiation From a β-Particle-Emitting Stent ", Circulation, 93: 529-536 (1996); Carter et al., Effects of the Endovascular Radiation From a β-Particle Emitting Stent in a Porcine Coronary Restenosis Model [A Dose-Response Study], Circulation 92: 1570-1575 (1995); And Hehrlein et al., Pure β-Particle-Emitting Stents Inhibit Neointima Formation in Rabbits ", Circulation 93: 641-645 (1996). [0011]

Some limitations exist in the systems disclosed in the literature and currently available technologies. One limitation is that the isotope selected for radiation depends on the material used for the stent. For example, in the systems disclosed in Fischell '617 and '166, Hehrlein '177, and in the stents used in the experiments described in the 1995 papers of Fischell and Hehrlein above, reactive isotopes are present in the reactor. Limited to species created by direct neutron activation of the stent. This process limits control over the type and amount of radiation that the stent can possess. Hehrlein '177 was created by this process It discloses more than 9 different isotopes, each with its own half-life, radioactivity level, and radioactivity properties. This setup makes control of radiation levels extremely difficult, and makes investigations into radiation-tissue interactions highly questionable. [0012]

Sten used in the study described by Laird to overcome this limitation First, the stent is phosphorus-31 [P-31 or³¹It was created by ion plating with P], followed by placing a stent in the reactor to convert stable P-31 to beta-releasing P-32. Alternatively, the radiation described in Fischell '166 and '617. Sexual stents are described as encapsulating a cold version of the target isotope in the coating or stent material and then placing the stent in a reactor to convert a stable isotope into a radioactive one. This approach provides some improvements over prior art methods, but limits the total radioactivity that can be achieved. For example, consider the activation of P-32 by neutron impact. Only about 1 per 100,000 P-31 ions is converted to P-32 in the reactor chamber in 10 days. Although this conversion rate can be increased, there are physical limitations to this process, which is governed by the reactor flux, the cross section of the target atom, and the half-life of the isotope. Moreover, this method does not completely eliminate the activation of unwanted isotopes produced from the stent material. [0013]

To further reduce the radiation emitted from the stent into a single isotope, Hehrlein described the direct ions of radioactive P-32 in his paper "Pure β-Particle-Emitting Stents Inhibit Neointima Formation in Rabbits" above. Implante Describes the use of the session. Although this method successfully provides a single mode of radiation, the ion implantation method raises other limitations. For example, ion implantation is only about 10-30% effective. Replacement So to speak, only about 1 per 10 ions placed in the accelerator is implanted on the target and the rest remain in the device. Therefore, the radiation level of the device increases steadily with constant use. With constant use, the equipment can become very radioactive, so it must be shielded while the isotope deteriorates. Therefore, the isotope used must have a relatively short half-life, and / or the radiation dose utilized in the method must be very small to shorten the "cooling-off" period. In addition, a major part of the isotope is lost during the process, adding cost to the final product. [0014]

Despite the above, there remains a need for radioactive stents with improved adhesion between the radioisotope and the stent. Preferably, the adhesion mechanism supplies both gamma and beta sources and is compatible with a wide range of stent materials. [0015]

(Outline of the invention) According to one aspect of the invention, a radiation delivery source in the form of a stent is provided. The source includes a support layer and an isotope layer in the form of a stent. The isotope layer contains a metal salt or metal oxide, and at least one isotope. Preferably, the isotope is from a group of gamma emitters with an energy of less than about 300 keV, including I-125, Pd-103, As-73, and Gd-153, or P-32, Y-90 and W / Re. High energy beta group including -188 (E)_max> 1.5meV) selected To. Other isotopes not mentioned herein can be utilized by the inventions described herein. However, the choice of these isotopes is that the source is shielded in a commercially available material such as a leaded acrylic derivative with a thickness of 15-30 mm, or a lead tube with a wall thickness of about 0.3-0.5 mm. Allows you to Some of the other isotopes that may be considered suitable for use in the present invention or for specific intended use are Au-198, Ir-192, Co-60, Co-58, Ru-106, Rh-106. , Cu-64, Ga-67, Fe-59, And Sr-90 are included. The choice of isotope depends on its chemical and radiation properties Therefore, it can be affected. [0016]

In one embodiment, the radiation delivery source further comprises an outer coating layer. Coating layers include cyanoacrylate, acrylic derivatives, acrylates, ethylene methyl acrylate acrylic acid, urethane, polyvinylidene chloride (like PVDC, Saran®), polyvinylidene chloride (PBVC), and other pots. It may include any variety of materials such as limmer and combinations thereof. The outer coating layer may also contain biocompatible materials such as heparin. [0017]

According to another aspect of the invention, a radiation delivery source in the form of a stent is provided, the source being a support in the form of a stent, an isotope layer, and a tie between the isotope layer and the support. Includes a tie layer. The isotope layer is on top As mentioned, it contains a relatively insoluble salt of at least one isotope. In one embodiment, the tie layer comprises a metal, metal oxide, metal salt or alloy. In another embodiment, the radiation delivery source also preferably comprises an outer coating layer containing the above materials. [0018]

Following a further aspect of the invention, there is provided a method of making a radiation delivery source in the form of a stent. The method comprises supplying the support in the form of a stent and coating the support with an isotope layer containing a relatively insoluble salt of at least one isotope. In one embodiment, the coating step is a step of coating the support with at least one layer of metal, a step of reacting the metal layers to form a metal oxide or metal salt, and a liquid containing a plurality of isotope ions. It includes the steps of exposing a layer of metal salt or metal oxide to form an isotope layer. In another embodiment, the coating step includes coating the support with a layer of metal salt, exposing a layer of metal salt or metal oxide to a liquid containing a plurality of isotope ions to form an isotope layer. In one embodiment, the method comprises coating the isotope layer with a coating layer. [0019]

According to another aspect of the invention, there is provided a method of treating a site within a blood vessel. The method includes identifying a site in the blood vessel to be treated, supplying the radiation delivery source of the present invention, arranging the source within the treatment site, and deploying the source at the treatment site. To do. [0020]

Drawings are not necessarily scaled. [0021] [0021]

(Detailed description of preferred embodiments) The present invention provides new and novel radiation delivery sources with respect to materials and fabrication methods. The present invention can generally be described as a source of radiation intended for site-specific delivery of radiation to an anatomical structure (proximity irradiation therapy). The source is intended to be integrated into a stent, such as an intra-arterial stent. The present invention also provides a method of permanently attaching a radioactive isotope to a stent support without the usual limitations caused by the half-life or radioactivity of the isotope. The present invention further provides a method by which the isotope can be attached to the support, which does not produce excess radioactive waste as a by-product of production. [0022]

The radiation delivery source of the present invention is a device that allows intraluminal placement or implantation of a radiation source that is tightly bound to a stent support. Referring to FIG. 1, the radiation delivery source 1 is based on a stent, which, as is known in the art, supports radioisotopes and also serves as a support for the normal functioning of the stent. Fulfill. Source 1 can be any of about 5 mm to 100 mm in length, depending on the length of the lesion being treated. Many stents are in the range of about 15 mm to about 40 mm. The diameter is generally about 2.0 mm to about 20 mm depending on the application. To. Radioactive stents intended for coronary arteries are generally in the range of about 2.0 mm to about 4.0 mm. [0023]

The radiation delivery source of the present invention is composed of two or more layers of material. There may or may not be a clear visual or physical difference between the various layers in Source 1, because each layer does not have to be a separate structural element of Source 1. Is. When the layers combine with each other to form a source, they are blended, alloyed, or mixed to form what appears and acts as a single layer with a somewhat heterogeneous composition. Can be done. For this reason, the various layers used herein, as described above, exhibit the functional properties of the components and help indicate what process steps are used in their formation and are separate. The choice, whether through the use of structural layers or layers blended into adjacent layers, will be apparent to those skilled in the art in the light of the particular materials and components used. [0024]

All radiation delivery sources of the present invention include a support layer or support 10. The support 10 can be any variety of implantable prostheses, particularly those usually referred to as stents or grafts. Any variety of commercially available stents can be coated with a radioactive isotope, as disclosed herein, or the stent can be specially constructed for the purpose of carrying a radioisotope, where the vessel wall. The surface area of the stent in contact with the stent can be optimized for radiation delivery purposes. Examples of currently available stents that can be coated using the techniques disclosed herein include, among others, the NIR and Radius Nitinol Stent (Boston Scientific); GFX (Arterial Vascular Engineering) Palmaz-Schatz and Crown (Johnson). & Johnson / Cordis); Multi-Link (Guidant); Includes Wiktor (Medtronic) and GR2 (Cook). A roll-up sheet type self-expandable stent may also be provided with a radioactive coating in accordance with the present invention. This is, for example, US Pat. No. RE 35988, named Stent Construction of Rolled Configulation by Winston et al., And McDonald's Expandable Microporous Prosthesis, issued March 17, 1998. Including US Pat. No. 5,728,150 of the name, their disclosures as a whole are described herein. It is used as a reference in the book. [0025]

Alternatively, the support can be useful for subcutaneous or surgical insertion into either tissue or body cavities or potentially body cavities, such as various non-stents such as pins, needles, seeds or other tools. Can include structures. Probes for insertion into soft tissue, such as for treating tumors, may comprise a radioactivity source according to the present invention. [0026]

The support may include any variety of materials, whether or not the support includes a stent or other structure, or a surface layer on the stent or other structure. Examples of common materials for current stents and probes to which the radioisotopes of the present invention can be attached are stainless steel, nitinol, ELGILOY, gold, platinum or various alloys of others recognized by those skilled in the art. including. Non-metallic surfaces that can be provided with isotopes according to the pretreatment and adhesion aspects of the invention include any of a wide range of materials well known in medical technology. For example, PEBAX, polytetrafluoroethefene, polyethylene of various densities, polyethylene terephthalate, and nylon are the most commonly used. Those skilled in the art will recognize how to adapt the binding chemistry of the present invention to these and other materials in accordance with the disclosure herein. [0027]

All radiation delivery sources also include the isotope layer 12. The isotope layer 12 contains a metal salt in which a plurality of ions in the salt are radioisotopes. Radioisotopes can be of almost any species available, preferably beta or gamma emitting, as discussed below. The isotope layer 12 may further contain one or more metals from which the metal salt of the layer is derived. The isotope layer is preferably 10¹⁰-10²⁵Atom / cm², More preferably about 10¹³-10¹⁵Atom / cm², More preferably about 10¹⁴Atom / cm²Has isotope densities or nuclide densities ranging from, preferably 100-10,000 angstroms thick, more preferably about 500-1500 angstroms. Has a thickness of [0028]

As used herein, the term "metal salt" refers to a compound consisting of at least one anion and at least one cation. Metal salt anions and cations are Al³⁺, Cl^-, And Ag⁺Simple (monatomic) ions such as, or PO₄^3-And WO₄^2-It can be any of the complex (polyatomic) ions such as. At least one ion in the metal salt should contain a metal. As used herein, the term "metal" means all metals, including, for example, metalloids, alkali metals, and alkaline earth metals. Preferably, the metal is selected from the transition elements or typical groups of the Periodic Table of the Elements. The term "metal salt" as used herein may include metal oxides in its broadest sense. [0029]

The radiation delivery source of the present invention may further include a tie layer 11. The tie layer 11 lies between the support 10 and the isotope layer 12 and may act to increase the toughness of the isotope layer 12 to adhere to the support 10. The tie layer 11 may include an adhesive, a chemically activated surface, a chemically coated layer, or an organic or inorganic compound, metal, metal salt, or metal oxide. Preferably, the tie layer 11 has a thickness of 100-10,000 angstroms, more preferably 200-500 angstroms. It is the thickness of the [0030]

The radiation delivery source of the present invention may further comprise one or more coating layers 14. The coating layer 14 can act as a sealing means to protect the isotope layer from mechanical wear or other injuries, which can peel off the isotope layer of the radioisotope and thus reduce its radioactivity. In addition, the coating layer can inhibit isotope migration or other leakage in an aqueous (blood) environment. The addition of the coating layer is a sealed radiation source, i.e., removable radiation less than 5 nCi. It may provide sufficient protection for devices classified as capable. Each coating layer is preferably 1 μm to 30 μm, more preferably 10 μm to 20 μm. [0031]

The coating can be metal or plastic. Plastic coating materials are preferably biocompatible, but not overly biodegradable. Preferred materials are cyanoacrylate, acrylic derivatives, ethylene methyl acrylate, ethylene methyl acrylate / acrylic acid (EMA / AA), urethane, thermoplastic urethane (TPU), PBVC, PVDC, polyethylene, polyethylene terephthalate, na. Including Yiren etc. Metal coatings can also be used, and the metal used is preferably biologically stable, such as titanium. For example, platinum, gold, or titanium can be deposited on the surface to wrap the isotope layer. [0032]

The shape of the source is generally governed by the geometry of the support 10. Some preferred supports are (1) metal foils, which preferably generally have a rectangular cross section. Is a stent formed from a sheet; (2) preferably has a generally round cross section, curved Stents formed from scraped wire; and (3) cut from metal tubing It is a stent. When present, any of the above layers other than the support can be attached to at least one surface of the source and placed on the entire surface of the source. Not all layers present in a given embodiment need to cover the same area as the support. [0033]

2A-2D and 3A-3D show several different preferred embodiments of the radiation delivery sources of the present invention. FIG. 2A-2D shows a source generally having a rectangular cross section, where layers other than the support 10 are placed on the outer surface of the source only and in contact with the tissue forming the lumen wall. There is. FIG. 3A-3D shows a source with a generally round cross section in which the layers are placed on the entire surface of the support 10. [0034]

Referring to FIGS. 2A and 3A, a schematic cross-section of a two-layer embodiment of a radiation delivery source is shown. The first or innermost layer is the support 10 and the second or outer layer is the isotope layer 12. [0035]

With reference to FIGS. 2B and 3B, a schematic cross-section of the radiation delivery source is shown, with the source having three layers. The first or innermost layer is the support 10, the second or intermediate layer is the isotope layer 12, and the outer layer is the coating layer 14. [0036]

Referring to FIGS. 2C and 3C, a schematic cross-section of a three-layer embodiment of a radiation delivery source, which is different from the three-layer embodiment disclosed above, is shown. The first or innermost layer is the support 10, the second or intermediate layer is the tie layer 11, and the outer layer is the isotope layer 12. [0037]

Referring to FIGS. 2D and 3D, a schematic cross-section of a four-layer embodiment of the radiation delivery source of the present invention is shown. The four layers are a support layer 10, a tie layer 11, an isotope layer 12, and a coating layer 14. [0038]

As discussed earlier, some of the difficulties associated with the lack of constant dose seen with prior art radiation delivery stents can be overcome by the use of longer half-life isotopes. Compared to the above example, in which three stents were implanted with P-32 at a level of 10 μCi using the Hehrlein method, 29% and 29% in 7 days for stents implanted with isotopes with a half-life of 60 days. 14 days Causes a 50% dose change in the line between maximum and minimum over a 14-day time frame The volume change decreased to 15% and to just 8% in 7 days. Isotope with longer half-life The total dose for will be higher, however, effective doses and dose rates will continue to be measured. It is generally known that the radiation dose can be increased if it is given for a fractionated or extended period. Only experiments can answer this question. However, if a long half-life isotope is demonstrated to be substantially effective, the minimum amount of radiation required to perform the treatment is always preferred over any higher amount for safety reasons. [0039]

Generally, the desired dose is at least about 40 Gray within the first half-life of the implantation, delivered to a depth of about 1 mm into the vessel wall, or from the source. Approximately 20 gres delivered to a depth of approximately 0.5 mm into the vessel wall along the overall length of It looks like it is. That means about 1 microcurie activity per centimeter length of the stent. The dose can be in the range as high as about 500 Gray at a depth of about 0.5 mm, or about 25 microcuries per centimeter of stent length, along the length of the stent, with 5 half-lives of implantation. .. The ideal dose for a particular clinical environment can be determined by routine experimentation by one of ordinary skill in the art and may be outside the above range for certain applications. Advantageously, the isotope attachment of the present invention makes the present invention adaptable to any wide range of desired dose capacities, as will be recognized by those skilled in the art in the light of the disclosure herein. [0040]

The radioactivity and lifetime of the source can be manipulated by choosing an isotope. The relatively fast decay time and associated loss of "strength" of short half-life isotopes can raise product issues in addition to fabrication issues. Since the isotope is contained on the implanted support and has a short half-life, a lack of constant dose can occur. For example, P-32, which is simultaneously implanted on three stents, is placed at 10 μCi using the method described in the above paper by Hehrlein (Circulation, 1996). Take it to the bell. It is assumed that all stents are prepared on day 0 and ready for implantation. The first is implanted immediately, the second is implanted after 7.1 days (half the half-life), and the third is implanted after 14.3 days (1 half-life). If so, the total dose delivered by the 2nd and 3rd stents is 29% less with the 2nd stent and 50% less with the 3rd stent compared to the 1st stent. It should be pointed out that the standard of practice for permissible changes in the dose administered is 10%. I'm sorry. [0041]

The radioisotopes used in the radiation delivery sources of the present invention are beta and / or gamma emitters and can have any wide range of half-lives, both long and short. The concentration of the isotope in the source that determines the particular isotope and dose can be selected by one of ordinary skill in the art to contribute to the needs of the particular application. Howard Amols at the January 1998 Scripps Clinic Conference on Intravascular Radiation Therapy entitled "Choosing the Right Isotope: What's New? Insights into Isotopes or Why Is it so Hard to Find the Ideal Isotope?" In a recent paper presented by, the authors state that the best isotope selection from both physics and dose measurement perspectives is a photon source with energies above 3 MeV and a half-life of over 7 days. ing. Shirish K. Jani gave a lecture entitled "Does the Perfect Isotope Exist?" At the same conference for vascular proximity irradiation therapy. The complete isotope of is to exhibit a low dose gradient, a low dose level, a manageable radiation exposure level around the patient and a long half-life to the surrounding body tissue. Iodine-125 (I-125, half-life 60 days) and tungsten-188 / rhenium-188 (W / Re-188, half-life 70 days) are candidates that meet these criteria and also have a long half-life. Therefore, there are two particularly preferred radioisotopes for use in the present invention. The preferred radioisotopes used in the radiation delivery sources of the present invention are from Oak Ridge National Laboratory (Oak Ridge, TN), New England Nuclear (NEN), or any commercially available radioisotope supplier. Can be purchased. [0042]

A preferred method of making the isotope layer of the present invention can be initiated by either a directly coated support or a tie layer to which the isotope layer is attached. Preferred methods include exposing the surface to a fluid containing a reactant or isotope. Such fluids are gaseous (including plasma and vapor) or liquid (solution). ), And a liquid solution is preferred. For that reason, the following method is a liquid solution. Described with respect to liquid. [0043]

Preferred methods for making isotope layers for radiation delivery sources of the invention partially include one or both of the following solution processes: (1) Acids. Oxidation in sex solution to form metal salts from metals; and (2) ion exchange, Here, the ions on or near the surface of the metal salt are exchanged for those present in the solution. The first process is based on the difference in oxidation-reduction potential, and the second process is the solubility Based on the difference. These processes are then adopted. [0044]

In the first process, equilibrium is driven by the redox principle. .. A metal in some form of a pure metal or alloy can be converted to a metal salt when it is placed in a solution containing an oxidant. Many metals, including those in the preferred embodiments discussed below, can be easily oxidized in solution to form metal cations, which can subsequently form salts with anions in solution. [0045]

The CRC Handbook of determines whether a particular reaction between an oxidant and a metal occurs naturally or not. It can be predicted with reference to a standard table of half-cell potentials such as those in Chemistry and Physics, (CRC Press). If the sum of the potentials of the oxidation half-reaction and the reduction half-reaction is positive, the reaction occurs spontaneously. [0046]

For example, when silver is added to an acidic solution of sodium chlorite, it can be expected that silver will be oxidized. Sodium chlorite (NaClO) when added to the solution₂) Disproportionate to form hypochlorous acid and chlorine dioxide, which can oxidize silver as shown below: Ag Ag⁺ + e^- (Oxidation) Emf = -0.80V ClO₂ + e^- ClO₂ (Reduction) Emf = 1.16V Ag + ClO₂ + e^- Ag⁺ + ClO₂ Emf = 0.36V In addition to the above reactions, hypochlorous acid undergoes a redox reaction, which produces chlorine ions, which subsequently combine with silver cations to form silver chloride. [0047]

The second process is solubility-driven ion exchange. For example, two anions have a driving force that results in the formation of less soluble / less insoluble metal salts when placed in solution with a given cation. Solubility is used to quantify the degree of solubility for a given compound, as it is difficult to compare solubility and predict behavior when the related terms "soluble" and "insoluble" are used. Some type of equilibrium constant, solubility product or K_spis connected with. Solubility product is the solution of salt at equilibrium K for the concentration of separated ions, ie salt AB_sp= [A⁺] [B^-] (Here, [A⁺] And [B^-] Is the concentration of each of the A cation and the B anion). If the salt is fairly soluble, the concentration of its component ions in solution is relatively high and relatively large K_spTo guide. On the other hand, if the salt is fairly insoluble, most are in solid form and Low concentration of ions and relatively small K_spTo guide. Therefore, two salts of the same metal Lower K when comparing_spSalts with are more insoluble of the two. Most The solubility product for common compounds is also the CRC Handbook of Chemistry and Physic Can be found in reference text such as s (CRC Press). [0048]

Silver chloride (AgCl, K) which is a salt_sp=1.77×10^-10) And silver iodide (AgI, K)_sp=8.51×10^-¹⁷) Can be used to show the principle of solubility driven ion exchange. this The solubility products for these compounds are both fairly low, but the K for silver iodide._spIs almost 10 to the 7th power, indicating that it is more insoluble than silver chloride. Thus, when solid silver chloride is placed in a solution containing iodine ions, the equilibrium is on the side of silver iodide and the chlorine ions are exchanged for iodine ions, resulting in the formation of a more insoluble silver iodide. Ion. On the other hand, when silver iodide is placed in a solution containing chlorine ions, ion exchange does not occur. In this way, the chlorine ions in silver chloride coated on the surface of the support¹²⁵It can be replaced with an I anion to form the radiation source of the present invention. [0049]

The metal salt layer, which is the starting point for the solution ion exchange process described above, can be formed by a redox process as described above, or it can be directly applied by sputtering, vapor deposition, or other techniques known in the art. obtain. [0050]

Alternatively, the redox process described above can be performed with a radioisotope, such as H.₃³²PO₄When carried out with an oxidizing solution containing, the radioisotope-containing metal salt layer can be obtained directly, eliminating the need for ion exchange. [0051]

Another preferred method for making a radiation delivery stent of the present invention involves oxidizing a metal, such as one bound or embedded in a stent support, followed by binding a metal oxide to the isotope. To do. The process of oxidizing the metal preferably occurs naturally in the air. Therefore, metals such as aluminum and copper that are easily and naturally oxidized to form their respective oxides are preferred. Oxide formation occurs when the metal is exposed to air, but can be enhanced or increased by being exposed to an oxygen-enriched atmosphere or elevated temperatures. Bonding of isotopes is preferably carried out by immersing the metal oxide in a solution containing either single or composite isotope ions. Since the attractive force between the metal oxide and the isotope ion is such, the isotope ion binds to the metal oxide rather than being present free in solution. This bonding or "plating" process can occur with or without ion substitution from the metal oxide. [0052]

Contrary to the conventional techniques of radioisotope ion implantation and nuclear impact, there are several advantages to using the above method for placing a radioisotope on a stent. One advantage is that unwanted isotopes are not formed. Neutron emission of the stent, as discussed earlier with reference to Hehrlein '177. Filming produces a large number of isotopes, making it very difficult to control the dose provided by the stent. [0053]

Another advantage of this method is that it does not produce large amounts of radioactive waste. Using the correct amount of radioisotope solution produces very little waste. Isotopes that are not incorporated into a given source can remain in solution and be used for another source. Unlike radioactive ion implantation, there is no equipment chamber filled with drifting isotopes that must be cleaned and safely discarded. [0054]

Another advantage of the present invention is that the manufacturing method is suitable for batch processing. Adhesion of metal layers, such as those that function as a tie layer or to which isotopes are later attached, are common chemical adhesion techniques found in the semiconductor, solar energy, and packaging industries, such as vapor deposition, electroplating, and ion play. It can be done in very large quantities using ting, ion implantation and sputtering. Radio isotopes are generally provided in solution, so that the isotope ion exchange or plating process is as simple as immersing a support coated with a metal salt or metal oxide in the isotope solution. This step can be performed in very small or very large batch sizes, thus making it possible to limit the radiation dose during the process. [0055]

Yet another advantage of this method is that it allows the use of isotopes that are not readily available on solid sources by other means known in the art. Appropriate selection of materials and solutions and disclosure herein will allow one of ordinary skill in the art to develop a reaction scheme for making salts containing most of the desired therapeutic radioisotopes. In addition, certain long-lived isotopes can be used to create radiation sources with longer half-lives, which can deliver doses with smaller changes between maximum and minimum. The use of isotopes with longer half-lives may provide a source of radiation that can reduce the amount of radioactivity that needs to perform its function beyond those that incorporate short-lived isotopes. [0056]

Another advantage of the present invention is that the radioisotope is retained by a strong atomic-level bond interaction, which is highly resistant to leaching or release under physiological conditions. In addition, the use of ionic bonds is particularly useful for radioisotope species such as iodine-125, as their salt form retains normally volatile iodine atoms in place. [0057]

Another advantage of the solution process of the present invention is that the radioactivity density of a given isotope or multiple isotopes simply controls the time of immersion and / or the density and amount of metal salt or tie layer on the stent. It can be controlled by. [0058] [0058]

The basic method involves providing a stent, as partially discussed earlier, and forming a coating on it containing an insoluble metal salt with at least one radioactive isotope species. To do. [0059]

One preferred embodiment of the radiation delivery source of the present invention is a gamma-emitting isotope.¹²⁵It has an isotope layer containing I. As mentioned earlier,¹²⁵I sets the standard for "ideal" isotopes as defined in Amols and Jani Fulfill.¹²⁵One method of making a radiation delivery source with an isotope layer containing I is to use both of the above solution methods. First, the stent is provided with a metallic alloy of silver, or the silver element is attached to the surface of the stent using well-known methods such as ion implantation, vapor deposition, sputtering, electroplating, or rolling. .. Subsequently, an oxidation-reduction solution process such as that described above for reducing silver to produce silver chloride using an acidic solution of sodium chlorite. Through this, silver is converted to silver chloride (AgCl). Next, the silver chloride-coated stent is Na¹²⁵Immersed in an ion exchange solution containing sodium iodide in the form of I, where AgCl is ag on the surface of the stent.¹²⁵Converted to I. This fabrication process can be quick, easy and efficient. In addition, I-125, which has a half-life of 60 days, etc. Radiation therapy at a lower dose or lower dose will be provided for a longer period of time. [0060]

As an alternative to the above method, silver chloride is attached directly to the surface of the stent by vapor deposition or other methods known in the art, followed by Na.¹²⁵Immerse in an ion exchange solution containing I. [0061]

In an experiment conducted to show the radioactivity that can be achieved by the method of the present invention, the surface area is 4 cm.²Silver foil with 6M HCl and 1M NaClO₂Soaked in a 10: 1 ratio solution. Some of the silver was converted to silver chloride. Subsequently, the foil is about 2 ml of solution. Was immersed in a bath with. The solution in the bath is about 0.07% Na in NaI¹²⁵Contains I, dissolve 0.5 mg NaI in 2 ml water, 4.6 mCi ¹²⁵Prepared by adding I to the solution. After immersion, the obtained radioactivity of the foil was measured as 2 mCi, which is the carrier (non-radioactive). Sex) Approximately 10 of the iodine attached to the sheet when iodine is factorized¹⁸Of Corresponds to the atom. In a carrier-free solution, this number of I-125 ions is 4 cm.²Support It would have brought about 3 Ci of radioactivity per body. This is for a 10 μCi stent It is 30,000 times the required radioactivity. [0062]

Another preferred embodiment of the radiation delivery source of the present invention is³²Iso containing P It has a taupe layer.³²Radiation deliverer with isotope layer containing P Lee source uses P-32 as orthophosphoric acid (H)₃³²PO₄) (New England Nuclear)¹²⁵It can be made by a method similar to that previously described for I. First, the stent is supplied. The stent can be made to include zinc or a zinc alloy, or it can be coated with zinc or a zinc alloy by vapor deposition or other methods known in the art. Subsequently, zinc is an oxidation-reducing agent similar to that described above. Zinc Fluoride (ZnF) via Rothes₂, K_sp=3.04×10^-2) Is converted to a relatively insoluble salt. Subsequently, the radiation source is a phosphate ion.³²PO₄^3-Or soluble phosphate Activated by immersing a zinc fluoride-coated stent in a solution containing in the form of zinc fluoride (Zn), which exchanges more soluble fluoride ions with phosphoric acid.₃(PO₄)₂, K_sp=5×10^-36) Is formed. [0063]

Alternatively, the stent can be directly coated with zinc fluoride or other similarly insoluble salt by vapor deposition or other means known in the art and then placed in an ion exchange solution. Another alternative is H₃³²PO₄Is to use an oxidizing solution containing As a result, zinc is directly converted to zinc phosphate, including radioisotopes, thus eliminating the ion exchange step. Yet another alternative is calcium fluoride (CaF)₂, K_sp=1.61×10^-10) Attached or formed, followed by H₃³²PO₄Or Na₃³²PO₄Is to expose this to a source of phosphate such as. [0064]

Zn₃(³²PO₄)₂There are additional advantages to using in the isotope layer. Ri Zinc acid is a stable molecule and is often used in the automotive industry to adhere paint to galvanized steel. Zinc phosphate has its own corrosion resistance properties and has been used in the past to increase the corrosion resistance of steel. A zinc phosphate coating on a steel stent can be advantageous to the stent even when it is not used as a radiation delivery device. [0065]

Yet another preferred embodiment of the radiation delivery source of the present invention is tungsten-188 (W-188 or¹⁸⁸It has an isotope layer containing W). Tongue Ste Rhenium-188 (Re-188 or¹⁸⁸Re). Re Nium-188 undergoes beta decay as well, but has significantly higher energy than W-188 decay. Releases ruggy particles. W-188 has a much longer half-life than Re-188 and therefore W-188 yields more Re-188 almost continuously. This process is "Gene Known as "lators", generator isotopes together show interspecific relationships by shorthand W / Re-188. Generators are attractive for use in radiation delivery equipment because they combine the energy levels of short half-life species with the durability of long half-life species. The general rule is that particle energy and half-life are inversely proportional, and long-half-life species are more economical and practical to work with than short-half-life species. [0066]

W / Re-188 is a beta-releasing isoto with about 10% higher energy than P-32. It's a poop. I-125 is discussed as a highly preferred gamma-emitting isotope If so, W / Re-188 meets both Amols and Jani criteria for highly preferred beta-releasing species for IVRT. The advantage of the W / Re-188 stent is that the dose is It could be administered consistently over a long period of time. The half-life of W-188 is 14 of P-32. 70 days compared to days. This shows a constant dose rate as Re-188, which is itself a beta-releasing isotope, is caused by the decay of tungsten for a longer period of time. [0067]

Tungsten is a tungstate ion (WO)₄^2-), Oxidized al It can easily adhere to the surface of minium, resulting in the W / Re-188-containing radiation delivery source of the present invention. Aluminum oxide surface is Al₂O₃By sputtering It can be attached to the stent, or Al can be attached by implantation or deposition followed by an oxidation step. The surrounding environment is from aluminum to Al₂O₃Form of Accelerates growth, which can be accelerated using elevated temperatures and / or oxygen-rich environments. The aluminum oxide surface is followed by sodium tungstate (Na).₂¹⁸⁸WO₄) Can be immersed in a solution containing tungstate, such as an acidic solution, to allow W-188 to adhere to the alumina surface. [0068]

Tungsten is similar to that disclosed in Larsen's US Pat. No. 5,550,006. It can be applied in the form of phosphate and the patent is incorporated herein by reference. The method disclosed to Larsen claims its use in increasing the adhesion of organic resists to printing circuits. The method was used to make a phosphate conversion coating on copper. This method can find its application in the radiation delivery device of the present invention, where many polymers and metals other than copper can be coated with this solution. In this way, the phosphate is³²PO₄^3-Can be in the form of tungstic acid Salt¹⁸⁸WO₄^2-Any combination of isotopes in the form of, or in a radioactive or stable form, can be used. [0069]

The combination of various isotopes provides another preferred embodiment, in which the beta-releasing isotope can be combined with the gamma-releasing isotope, where the gamma isotope can deliver the dose deeper. [0070]

Radiation delivery sources, including other metals, metal salts, and isotopes, can be made using materials suitable for the chemistry of the isotopes included, in a procedure similar to or similar to the preferred embodiments disclosed above. It may be determined by one of ordinary skill in the art in light of the disclosure herein. [0071]

In some embodiments of the radiation delivery source of the present invention, it may be desirable to provide a tie layer on which the isotope layer can be placed. The tie layer can include an adhesive, a chemically active surface, a chemically coated layer, or an organic or inorganic compound. Preferably, the tie layer is a layer of metal, metal oxide, metal salt or alloy. Adhering a layer of metal type allows the alloying process to occur, which enhances the toughness of adhering metal salts and thus isotope species. This is common in the semiconductor industry, where the chromium layer is used as the first layer of gold adhesion. Chromium is alloyed with gold to increase the strength with which gold is attached to the support. For example, if the isotope layer contains a zinc salt, a metal such as copper or aluminum can be used as the tie layer. The tie layer is also in the form of an oxide that chemically bonds to the atoms of the metal salt layer to supply oxygen, which can increase the toughness of adhesion. [0072]

The first metal layer to which the isotope layer is attached may contain any suitable metal or metal oxide. The layers can be adhered by vapor deposition, sputtering, ion plating, ion implantation, electroplating, or other methods. When a tie layer is present, there may or may not be a clear distinction between the tie layer and the isotope layer. In performing its function, depending on the chemistry of the materials involved, the tie layer can be blended, alloyed or mixed with the isotope layer, thus blurring the lines between the layers. For many of the same reasons, the distinction between the tie layer and the metal-containing support layer can also be blurred. In these cases, the term tie layer is meant to be a functional or process-specific definition rather than referring to physically different layers of radiation delivery sources. [0073]

Although the stents of the invention may have isotopes that are sufficiently adherent in some embodiments of the invention without further treatment, it may be desirable to place the outer coating on a radiation delivery source. The external coating may provide additional advantages for the radiation delivery source of the present invention, where the coating may assist in providing additional means for bonding the layers of the source to each other. Perhaps more importantly, the outer coating can increase the wear resistance of the source. [0074]

Sealed radiation sources are those with removable activity of less than 5 nCi. By providing a coating on the source that covers at least the isotope layer, the source can be protected from unwanted loss of activity due to mechanical wear on the surface of the source. This is to provide a safe device for patients where radioisotopes leave them only where desired, and to ensure that the dose provided by the source actually reaches the treatment site. It can be important for both because the dose is monitored so that it is not significantly reduced by the loss of isotopes from possible wear during. It also ensures that once the source is installed, the radioisotope is maintained at that site and is not washed downstream. [0075]

The coating material is preferably biocompatible, but not overly biodegradable. Preferred materials are cyanoacrylates (Loctite, Hartford, Connecticut), acrylic derivatives, ethylene methyl acrylates (Exxon Chemical Co., Houston, Texas), ethylene methyl acrylates / acrylic acids (EMA / AA) (Exxon Chemical Co.). ., Houston, Connecticut), Urethane and Heat Acrylate Plastic Urethane (TPU) (BF Goodrich, Litchfield, Ohio), PVDC (Saran, Dow) Chemical, Midland, Michigan), including PBVC, PE, PET, etc. Other preferred coatings may include other biocompatible materials, agents or similar compounds such as heparin. Many methods are available to perform coating methods such as dip or dip coating, spray coating, spin coating, and gravure. If the material requires curing, the curing technique can be any of the various techniques available, such as air, heat, or UV. Preferably, the thickness of the coating formed is 1 μm to 30 μm, more preferably 10 μm to 20 μm. [0076]

One preferred embodiment of the invention has a coating formed of cyanoacrylate. Another preferred coating layer is that formed by ethylene methyl acrylate / acrylic acid (EMA / AA). The aqueous dispersion of this coating material preferably has a viscosity of less than 100 centipoise and is any of the above coatings. Allows the use of ing methods. UV curable polyurethane acrylate is also useful as a coating layer material. Yet another preferred coating layer is that formed by SARAN. Such a layer can be formed, for example, by immersing the source or a portion thereof in a solution containing SARAN or a solution containing SARAN. [0077]

The coating layer can also be formed by spin coating. Spin coating of thin film sources finds an advantage in the flexibility of using coating materials with a wide range of viscosities. Low viscosity liquids can be spun slowly, while higher viscosity liquids can be spun at a higher rate to maintain a thin coating. The support can be held in place by mounting or vacuuming during the spin coating process. In the experiment, the dispersion of cyanoacrylate in acetone was dispensed to the upper part of the metal salt surface, and at the same time, the support was rotated at 8000 rpm for 5 minutes. Co The obtained thickness of the ting was about 6.5 μm (0.00025 inches). Cyanoacrylate When this specimen with a rate spin-coated surface-hardening coating was extracted in saline at 50 ° C for 8 hours, the amount of radioactivity extracted was negligible. [0078]

Implantation of the radiation delivery source of the present invention can be made by a method of implanting a stent, as is known in the art. For example, if the stent forming the support of the radiation delivery source of the present invention is of a self-expanding type, the following techniques can be used for implantation in body lumens such as coronary arteries. First, the source can be compressed into a first shape and then constrained at the distal end of the catheter, as by placement within a hollow indentation. The catheter is then inserted subcutaneously and advanced through the patient's blood vessels until it reaches a treatment site, such as in the coronary artery. The pusher is then advanced through the lumen of the catheter in which the source is present and pushed onto the proximal end of the source, so that the distal end of the catheter is pushed into the patient's artery. Proximal contraction of the external binding sheath can also be utilized to release a self-expandable stent, as will be appreciated by those skilled in the art. Once released from the catheter, the source expands to contact the arterial wall. [0079]

If the stent used to support the radiation delivery source is of a non-self-expanding species, the following techniques known in the art will implant the source into a body lumen such as a coronary artery. Can be used for. This technique relies on the use of dilation catheters such as balloon catheters. A balloon catheter can simply be used as a delivery source, or it can be used to simultaneously provide dilation of a stenosis and source implantation. The source is first placed on the balloon before being inserted subcutaneously into the patient. A balloon carrying a stent over it is then inserted subcutaneously and tubed through the patient's blood vessels to the treatment site. If desired, the balloon and source can be introduced through an introduction sheath, which sheath can be drawn proximally to expose the source and balloon once they are placed at the treatment site. The balloon is then expanded at the treatment site to open the stent. The balloon is then deflated and pulled out of the patient, leaving the unfolded stent in place at the site. [0080] [0080]

According to another aspect of the invention, there is provided a method of treating a site within a blood vessel. The method proceeds by first identifying the site within the vessel to be treated and then supplying the radiation delivery source in the form of a stent, as described elsewhere herein. Finally, the source is placed at the treatment site by techniques as described above and left in place to deliver that dose of radiation to the treatment site. [0081]

Although the present invention has been described by certain preferred embodiments, other embodiments of the invention will become apparent to those skilled in the art in the light of the disclosure herein. Therefore, the scope of the present invention is not intended to be limited by the above, but rather the appended claims are referenced.

[Simple explanation of drawings]

[Figure 1]

FIG. 1 is a diagram of an embodiment of the radiation delivery source of the present invention. [Figure 2]

FIG. 2A shows the radiation delivery of the present invention having a support layer and an isotope layer. It is a schematic of the cross section of one embodiment of a radiation source. FIG. 2B shows the invention having a support layer, an isotope layer and a coating layer. FIG. 6 is a schematic cross-sectional view of one embodiment of a radiation delivery source. FIG. 2C shows the radiation of the present invention having a tie layer between the support layer and the isotope layer. FIG. 6 is a schematic cross-sectional view of one embodiment of a delivery source. Figure 2D has a support layer, a tie layer, an isotope layer and a coating layer. FIG. 6 is a schematic cross-sectional view of one embodiment of the radiation delivery source of the present invention. [Fig. 3]

FIG. 3A shows the radiation delivery of the present invention having a support layer and an isotope layer. It is a schematic of the cross section of one embodiment of a radiation source. FIG. 3B shows the invention having a support layer, an isotope layer and a coating layer. FIG. 6 is a schematic cross-sectional view of one embodiment of a radiation delivery source. FIG. 3C shows the radiation of the present invention having a tie layer between the support layer and the isotope layer. FIG. 6 is a schematic cross-sectional view of one embodiment of a delivery source. Figure 3D has a support layer, a tie layer, an isotope layer and a coating layer. FIG. 6 is a schematic cross-sectional view of one embodiment of the radiation delivery source of the present invention.