JP2003518392A - Radioactivatable compositions suitable for the manufacture of implantable medical devices - Google Patents

Abstract

  (57) [Summary] Activatable composition, preferably a metal alloy composition comprising at least one activatable isotope consisting of a metal having shape memory properties and a mixture of a lanthanum series element or a lanthanum series element and other suitable isotopes Is disclosed. The activatable isotope is present at a concentration (relative to other components of the composition) sufficient to deliver effective radiation to the target tissue to achieve a particular therapeutic purpose. One of the more advantageous and useful applications of the composition is in the formation of medical devices for treating coronary artery disease and inhibiting cancer cell growth. In one preferred embodiment of the present invention, the activatable isotope is combined with a matrix material such as a nickel / titanium alloy (eg, a Nitinol metal alloy) by a sorted isotope combination or is produced by a sorted isotope combination. It is combined with a degradable organic natural or synthetic polymer to form a solid solution, and the resulting alloy or solid solution is applied to a specific site or tissue in the human body in a therapeutically effective amount of low-dose forms of radiation (primarily beta particles). Is shaped into a stent or other suitable form for selective, targeted delivery.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The present invention relates to compositions, useful articles formed from such compositions, and the use of such articles in radiotherapy applications. In particular, the present invention is isotopic
a target that is contained within a matrix material and then formed within a medical device, such as a stent or other suitable configuration for selective and targeted release by an opportunistically sorted combination. Preferred for compositions having a naturally occurring activated or enriched non-radioactive isotope in a safe and effective amount in a low dose form of radiation (preferably beta-particle emission) to a site or mammalian tissue. Relates to a composition comprising an alloy having memory properties.

The compositions of the present invention may be used in intra-arterial stents or other complementary devices for use in the treatment of pericoronary artery disease or restenosis, or in benign prostatic hyperplasia, dysphagia,
Polychondritis and cancer, in particular, can be formed in a device useful for the treatment of stenotic diseases of esophageal cancer, prostate cancer, kidney cancer or colon cancer.

[0003]

[Description of Prior Art]

Targeted specific release and medical devices of drugs for diminishing and preventing diseases are beginning to mature, if not without specific limitations and problems associated with both administration and release.
Among the currently used medical procedures, specific approaches for such purpose are treatment of coronary artery disease by drug mediated intervention, balloon angioplasty and more recently by intra-arterial radiotherapy. Over 15 million interventional cardiology procedures are performed annually worldwide. Balloon coronary and peripheral angioplasty has been performed for over fifteen years with the goal of long-term reduction of neointimal hyperplasia, but with only partial success. The latter method is limited by its inability to effectively treat sudden vessel obstruction, late restenosis, and acute and subacute occlusions. Restenosis, where reocclusion occurs within 6 months after the occluded coronary artery has been expanded by balloon angioplasty, usually occurs within 6 months in more than 40% of patients, and It remains tough limits to the success of the period.

[0004]   There may be three mechanisms that are responsive to thrombus: (A) Elastic recoil (tube contraction after tube damage) (B) Remodeling, and (C) Smooth muscle cell proliferation

Elastic recoil is generally an acute or subacute reaction. The tube wall is stretched by the balloon and then contracts back to its previous position. The remodeling is associated with the formation of scar tissue caused by balloon-induced deflation. By growing into the lumen, smooth muscle cells respond via healing with a cellular response to contraction, and thus block blood flow. Another drawback to successful angioplasty is the natural progression of arteriosclerosis. Therefore, there is a continuing need to improve and adapt combinations of one or more of the above approaches to effectively treat this disease.

Similar deficiencies have been found in the treatment and recurrence of other persistent diseases such as cancer, where temporary success (remission) is achieved, but tumors may be due to incomplete degradation or removal. It just causes a recurrence. For example, in oncological applications, over 100,000 intrahepatic, renal, endotracheal, esophageal, urethral and other stenting procedures are performed annually and unresectable tumors in the upper portion of the biliary tract. It is included. Stenting has been seen to prolong life and improve patient comfort, but generally only provides a temporary inhibition of neoplasia. Currently, none of the medical devices available provide combination or adjunctive radiation and chemotherapeutic treatment. The non-specificity of treatment has caused a substantially adverse reaction in patients,
It is with all but some of these treatments, but in some cases results in the patient rejecting further treatments.

Regarding the use of targeted radiation therapy in cardiovascular applications, one approach is to use a radioactive liquid-filled balloon (eg rhenium 186) for the treatment of restenosis.
Was used). Preparing and filling a balloon with a radioactive solution such as rhenium 188 is complicated by the fact that several steps are involved in the preparation of such a device and the existing potential for the cause of the burst. ing. The resulting balloons are subject to many of the same drawbacks and weaknesses of balloons in use in current angioplasty procedures, and if their physical integrity is compromised (eg, leaking or breaking). ), Radioactive contents may leak or spill into the bloodstream, or spoil the clinician, technician or nursing staff performing such an operation. In addition, the logical problem of filling, operating and disposing of radioactive solutions in catheterization laboratories or nuclear medicine departments is monotonous and tedious but not negligible, thus making it more rational or traditional. Tend to prefer different methods and devices.

Another approach that has emerged for targeted radiation therapy in cardiovascular applications is the use of radioactive stents. However, limitations in stent design and construction (
Memory alloys, for example, provide an inherent limitation in both utility of these devices for treating and preventing the cause of particular diseases or disorders. For example, the first reported use of metallic coronary stents involved their placement in large vessels to reduce the incidence of restenosis in 25% to 35% of the selected patient population. As mentioned above, this approach does not eliminate arterial recoil in a statistically significant population undergoing such treatment. It has been demonstrated in post-bypass patients that treating normal resealing of vein grafts with stents instead of angioplasty reduces the risk of complications. In such an operation, a metallic stent is inserted during or shortly after balloon angioplasty, associated with percutaneous transluminal coronary angioplasty (PTCA). Despite such notable advances and the full acceptance of intracoronary stenting over the last few years, numerous revascularization procedures and restenosis at the stent (in- "curing" for patients undergoing this procedure because of stent restenosis)
Don't give.

For example, two clinical studies in this field have shown that stents can prevent restenosis in a limited number of cases. Only moderately appropriate, even if the study was biased because the patients who gave it probably responded favorably to such treatment (eg, in a population of select patients). It was further noted that significant success was achieved (only 10% of the patients who had it experienced reduced restenosis), and such "
"Success" seemed to diminish over time after being involved. Thus, despite the limited success of current metal stents, these devices still have large occluded arteries (
Limited to use as an endoluminal implant in (> 3 mm).
Because of thrombosis with subsequent subacute closure, difficult placement, stiffness, leakage, wall thinning, aneurysm formation, limited flexibility, improper combination of compliance, slow vessel wall growth. Due to the tendency of medial atrophy with the potential for inadequate long-term patency data, spasticity, and intrastent restenosis. In addition, there are increasing concerns regarding the application of stenting as a non-limiting (routine or selective) strategy (eg, ACC Ex
pert Consensus Document, JACC 28, NO.3, Sept., 1996, PP.782-794).

Therefore, the essential limitations of conventional (metal) stenting, alternatively treatment, and combination of treatments have been explored and evaluated, including targeted radiotherapy in recent years. The physiology of the restenosis process is recognized as a proliferative disorder. Intravascular irradiation (more suitably "bracytherapy") appears to have positive consequences for some restenosis known as remodeling and smooth muscle proliferation. Radiation is known to inhibit smooth muscle proliferation and intervene in the wound healing process. Intravascular short-form therapy, the use of radiation to control angiogenesis, has proven successful in the laboratory as having efficacy in controlling this pathological proliferative process, and These results have recently been confirmed in human clinical research. For example, mild irradiation has been shown to effectively inhibit intimal proliferation after stent-induced or balloon overstretch injury in coronary and peripheral arterial disease. The activity level of the radioactive stent is lower than the activity level of the source used for the catheter direct source in contact with the vascular environment 10,000
Up to twice. Therefore, this method is used in trials for targeting vascular revascularization, for restenosis, and for the management of certain contractile cancers.

Radiation from such a stent is hypothesized to selectively interfere with the rapid replication of smooth muscle cells in the DNA replication process. Ionizing radiation has long been known to inhibit cell proliferation as a radiation therapy to favorably modify the healing response after injury. Furthermore, intra-arterial irradiation has been demonstrated to effectively shut down the neointimal proliferative response process after balloon angioplasty. Although radiotherapy via a stent delivery device has been evaluated and has shown promise in the future, it is cautioned that all the deficiencies associated with radiation exposure of human tissue have been well documented.

[0012] Mild exposure to low levels of radiation via endovascular short-form treatment is associated with many disease states, such as coronary and peripheral arterial disease, restenosis or targeted vascular revascularization, and certain contractile cancers, among others. Despite being an effective treatment in the management of (i.e., the control of), recent techniques have adequately addressed the effects and associated harm of radioactive stent implantation, radioactive liquid-filled balloons or short-term high-dose radiation therapy. Not directed. Therefore, the remaining uncertainties are especially associated with radiation safety issues, uniform radiation delivery, dosimetry, flaws in performance and design characteristics (eg, stent flexibility and irradiation intensity, reactivity, bleeding). Complications, clotting, risk of contamination and barrenness, long-term effectiveness) and radioactive waste disposal issues.

In modern forms and applications, intra-arterial irradiation presents many potential hazards and risks that appear to have no trend or effective solution. For example, this form of radiation therapy generally includes gamma radiation radiotherapy, short-term ultra-high dose radiation delivery systems delivered by post-fill, permanently implantable radioactive metal stents, and pure beta or gamma radiation stents. . The use of long-lived isotopes in high-dose, short-term, short-form therapy is the norm, and because of the delay in tortuous deployment to target tissues, healthy tissues are assessed for the risk / selectivity of such treatments. Without exposure to unacceptable levels of radiation. The devices currently in use have not yet been adequately addressed to the effects of very high doses of local treatment or long term related problems as a result of permanent implantation of radioactive stents.

In the process of designing and selecting materials for the manufacture of acceptable delivery systems for intra-arterial radiotherapy, many candidates have been evaluated and, in that case, qualified or eliminated. In this process, radioactive radiation of iridium-192 was found to be effective for short-form treatment in the prevention and treatment of restenosis. However, the devices utilized for intravascular post-fill radiotherapy using this isotope and iridium-192 have many drawbacks as described herein. For example, iridium-192 is a predominantly low MeV γ-emitter, providing high doses useful for typical post-fill radiation therapy, and levels that are not acceptable to clinicians / surgeons (due to repeated contact for each procedure). Not only is it exposed to γ-radiation, but it also causes an unknown and unacceptable level of irradiation of the patient's healthy tissue and cells en route to the target site at the end of the post-filling probe. In a typical procedure, a patient's healthy tissue is exposed to anywhere for 200 seconds to 20 minutes, depending on the length and / or injury encountered during deployment to the target tissue. In addition, the end of the delivery catheter (containing the iridium-192 wire or seed) is blocked or delayed in a tortuous path to the target site, and the endothelial cell membranes within the blood vessel are overexposed to the radiation source, resulting in a healthy wall. Or it may result in weakening of the stenotic artery wall and consequent cytoplasmic and tissue damage. clearly,
Physicians and professionals will also receive excessive radiation doses while using this method. On the other hand, in the case of strontium-90, which is an isotope having a relatively long half-life,
The treatment would be problematic and / or would add considerable expense to the process (eg strontium-90 has a half-life of 28 years).

Another form of radioactive stent is to coat a metal stent with a radioactive material. In this alternative device form, the stent is formed using conventional metal coating techniques, such as radioisotope (eg, 1
It can be coated by sputter coating, plating or ion evaporation of phosphorus-32) with a half-life of 4.49 days, by ion evaporation on the surface of stainless steel or titanium tubes or wires. This approach to stent manufacture is complex and questionable. More specifically, because the non-radioactive isotope ion deposition or implantation is line-of-sight, the radioactive coating does not effectively coat the complete surface of the wire, resulting in a device / structure The emitted isodose / radiation field is not uniform and gives ineffective treatment. Moreover, conventional stent coating techniques such as plating, ion vapor deposition and sputter coating cannot always achieve robust isotope (eg phosphorus-31) adhesion. In addition, vapor deposited surface coatings on stainless steel or tantalum stents consisting of phosphorus-32, or other radioisotopes such as yttrium-90 and vanadium-22, are evolved as individual particulates and thus developed and used. In any case, it is deprived, squeezed or separated, and thus radiation and particulate matter through the bloodstream are released to unwanted local sites, such as vital organs.

Despite the problems mentioned above, intravascular irradiation is safe under certain conditions preventing arterial reclosure after coronary intervention in both animal studies and preliminary human potential studies. And proved to be effective. The rationale for this therapy is that radiation prevents neointimal proliferation and vasoconstriction after injury. Therapeutic radiopharmaceutical and radiomedical devices generally incorporate strong β- or γ-emitting radionuclides. Beta irradiation produces a strong ionization path within a short range of radioisotopes. Beta emitters are characterized by a sharp attenuation of dose within millimeters from the actual source. Exposure to catheter laboratories as well as environmental tissues can be kept to a minimum. Each of these radiators requires additional shielding in the catheter laboratory leading to total body dose.

In summary, uncertainties regarding clinician exposure and patient risk remain with the devices used to perform intravascular short form therapy. Therefore, to radiation safety issues, uniform radiation delivery, irradiation of healthy tissue with high dose applications, dosimetry, disposal of radioactive waste, shortcomings in the performance and design characteristics of medical devices for such procedures. There is a related concern, one that continues to ensure more controlled application of targeted radiation therapy for the treatment of coronary and cancer.

The following patent documents are representative examples of the above-mentioned device and prior art relating to medical therapy using the device. Each of these patents discloses techniques that attempt to address one or more of the following problems associated with the treatment of coronary artery disease by a combination of physical means and / or physical means combined with radiation therapy. is doing. These patent documents will be discussed in chronological order, but it should be understood that no importance is attached to the order of these examinations.

US Pat. No. 4,503,569 (issued Mar. 12, 1985 to C. J. Dotter) discloses an endovascular graft containing a spirally wound coil having a generally tubular shape. Disclosed is a prosthesis, which is made from the memory alloy Nitinol.

US Pat. No. 4,770,725 (Simpson September 1, 1988)
(3rd patent) discloses a nickel / titanium / niobium alloy having shape memory transition characteristics. This patent document is useful for the various transitions / phases of the alloys of the present invention and is hereby incorporated by reference in its entirety to the extent that this disclosure is advantageous for a more complete and complete understanding of the above principles. Will be incorporated into.

US Pat. No. 5,059,166 (Fischell, 1991, 10).
(Patent Issue 22/22) describes an intra-arterial stent used to prevent intimal hyperplasia following balloon angioplasty. This F
In ischel devices, radioactive inclusions are either incorporated into the interior of the stent alloy or are applied to the alloy surface. According to Fischel, radioactive stents can be implanted in symptomatic vessels (when made as the inventor thinks), in which case adjacent tissue is treated with radiation therapy. It is considered to be a thing. The teachings of the Fischel patent are at best prophetic, and do not provide any examples of means or methods for accomplishing the stated purpose. More specifically, it does not teach anything about the amount of isotopes, the relative proportions of matrix materials, or how to incorporate them into memory metal alloys, but rather to speculation or future discoveries. As is even apparent to a less specialized observer, the distribution of radiation at the target site, in order for it to be effective, emits energy in a radiation pattern that is essentially uniform with respect to the surrounding tissue. And thus prevent the lumen created in the treated vessel from restenosis. Thus, the design and performance of the stent must be accurate and consistent, and balanced by safety considerations regarding healthy tissue. Therefore, if there is discontinuity in the manufacturing process, the device becomes unsatisfactory. in this case,
Asymmetrical distribution of relatively strong, permanent emissive material cannot compensate for this. Thus, both the uniformity in radiation distribution and the relatively modest doping of memory metal alloys with radioactive material provide safe and effective radiotherapy via intra-arterial implants (eg, stents). Will be required for. The Fischel patent is clearly deficient in how it achieves this end.

US Pat. No. 5,176,617 (issued Jan. 5, 1993 to Fischell-the above-mentioned US Pat. No. 5,059, filed on Oct. 22, 1991 by the inventor). No. 166, CIP), relates to the use of stents and the use of radioactive stents to treat cancer associated with blood vessels that may be treated in a similar manner. The disclosure of Fischell in this patent is nearly identical to that of U.S. Pat. No. 5,059,166 and, therefore, is not equally relevant.

US Pat. No. 5,199,939 (issued Apr. 6, 1993 to Dake) discloses a radioactive catheter having a flexible end section comprising a radioactive section. The Dake device is reportedly effective in treating coronary restenosis following balloon angioplasty. In summary, this Dake device is designed for "stiff" (stiffness changes)
a catheter having a distal end with both a "ffinging" element and a "segmented" distal tip, the distal tip being spaced along the distal section of the catheter. It consists of a number of longitudinally arranged cylindrical radioactive pellets, which are separated from each other by a spacer, which allows the flexibility of the catheter tip to be retained at the end. "Hot" and before it needs to be removed 30
For less than a minute, the radioactive component can remain inside the blood vessel (at the treatment site).

US Pat. No. 5,616,114 (1997 to Thornton et al.
(Patent Issue 1st March) discloses a medical device comprising a catheter having a balloon tip that can be inflated with a radioactive liquid. This device has been reported to be useful in treating coronary artery disease, where both a balloon catheter and a source of radioactive material were combined in a single device to inflate a blood vessel with an inflated balloon. It prevents the restenosis from occurring later. Thornton
Improvements to the device include providing multiple balloons, an internal balloon (ie, an internal chamber) for containing the radioactive fluid, and an external balloon (ie, an external chamber) for expanding the occluded vessel. Thus, the multi-chamber partitioned device is further adapted to contain radioactive material to prevent the radioactive material from being released towards the patient in the event of rupture of the inner balloon.

US Pat. No. 5,674,177 (1997 to Hehriein et al.
The patent issued on 7th July includes relatively strong nuclide species with a short half-life (less than 7 days) and relatively low intensity nuclide species with a relatively long half-life (more than 100 days). A stent having a radioactive component is disclosed. In this Hehriein device, it is also considered that strong nuclide species collapse to form nuclide species with low strength. In fact, the Hehriein device is said to be suitable for delivering a high dose of radiotherapy to a blood vessel wall in a short period of time during implantation, and then delivering a continuous dose of radiotherapy over a long period of time. Heh
The riein device can be made by irradiating a conventional metal stent or, alternatively, by prescribing the alloy with one or more nuclide species. With respect to forming radioactive stents from existing metal stents, such radiation treatment can be considered to form various radioactive species, depending on the particular alloy and its impurity content. Therefore, the distribution of radiation made from this device is unpredictable, no matter how closely you look at it,
Corresponding to regulation law and characteristic display method, it is susceptible to substantial errors. Although Hehriein suggests formulating alloys containing radioactive nuclide species, the Hehriein patent is merely prophetic in its teachings, and it suffers from many of the same deficiencies as described above for the Fischell patent. I am also holding.

US Pat. No. 5,690,670 (Davidson, Nov. 1997;
(Issued 25th of March) describes a Ti-Nb-Zr ternary alloy with a low modulus, which has improved biocompatibility and imparted with other advantageous properties. More specifically, the Davidson alloy is used to form diffusion hardened medical devices and components that are essentially inert when in contact with body fluids (eg, blood) and / or when placed in the human body. Are suitable. These alloys are also radiopaque and are therefore suitable for making guided guidewires and their associated devices for use in transluminal medical procedures. During the deployment phase of this medical procedure, guide wires and other similar devices will
X-rays can be irradiated and produce secondary emissions (radiations) that may be harmful to the patient (depending on the original composition).

US Pat. No. 5,782,742 (issued Jul. 21, 1998 to Crocker et al.) Describes a balloon catheter incorporating a radiation carrier and having an inflatable balloon. There is. In one embodiment of the device of the Croker invention, a tubular metal flake is placed on an inflatable balloon. The Crocker device allows for radiotherapy of the target tissue by first transluminally inserting the device of the same inventor into the blood vessel and then inflating the balloon when the device is placed at the target site. It is said to be composed. According to Crocker, once in place, the radiation source continuously irradiates the target tissue. However, Crocket
The r-device is not a permanent implant and its physical integrity and safety depend on the physical properties / durability of the balloon.

As is apparent from the simplified description of the prior art, there are unsolved problems associated with using and delivering therapeutically effective amounts of radiation to target tissues to treat and reduce disease states. There are many and continue to do so. The problems associated with prior art devices, namely both safety and efficacy, are the selection of the materials used to make the system for delivering the radiation described above, and / or Or, it appears to be largely due both to the inability to adapt and combine the materials to provide a safe and effective package for delivering the radiation when it is needed.

It can be pointed out that in each case considered here there was a defect in one or more of these critical aspects of the targeted delivery of radiation therapy, and such defects were consistently integrated. Until it can be addressed in a traditional manner, the risks inherent in radiation therapy are associated with coronary and peripheral arterial disease and constriction.
ctive) will continue to prevent widespread application of radiation therapy for the treatment of cancer. Because of the inherent risks associated with the devices described above (eg, used in intracoronary radiotherapy or brachytherapy), radioactivity that is both effective and safe for clinical installation. The demand for therapeutic devices continues to exist and is not yet met.

[0030]

[Object of the Invention]

The object of the invention is to remedy one or more of the above-mentioned drawbacks in the prior art.

Further, in particular, an essential object of the invention is to provide a composition containing at least one activatable natural or enriched non-radioactive isotope incorporated into a biocompatible matrix material. To do.

Another object of this invention is to provide activatable isotopes, wherein the isotopes are dispersed in the composition and their activation effectively results in the emission of radiation. Further, radiation is emitted from a device containing or made of such a composition.

Yet another object of the present invention is to provide a composition containing an activatable isotope, wherein the isotope is dispersed in the composition, such as an intra-arterial stent. It is suitable for manufacturing biomedical devices including various implantable biomedical medical devices.

Yet another object of the present invention is the activatable isotope dispersed in a composition for radiotherapy with an implantable biomedical medical device such as an intra-arterial stent. To provide a composition suitable for the targeted irradiation of

A further object of the present invention is to provide a method for preparing an activation composition capable of manufacturing and molding various biocompatible products and / or medical devices.

An additional object of this invention is to provide medical devices and structures that can be activated from an isotopically selected composition, as well as the application of locally highly concentrated radiation to the target. It is intended to include applications or applications assuming medical and industrial situations.

An additional object of the present invention is to provide a medical device for simultaneously performing radiation therapy and its concomitant therapy in order to perform an intermediate and extensive treatment on a target tissue. It also includes the use of compositions.

[0038]

[Outline of the Invention]

The above-mentioned or related purposes are for the manufacture of biocompatible medical devices, including implantable devices such as intra-arterial stents, and for coronary artery disease, especially arterial stenosis, restenosis (balloon vascularization). (Following formation) and isotope-selected activatable compositions with suitable physical and nuclear properties, respectively, for use in targeted irradiation of radiotherapy in the treatment of in-stent restenosis It is achieved by providing a thing. In a preferred embodiment of this invention, the previous composition is made from a shape memory alloy containing an effective amount of activatable isotope, such as a nickel / titanium alloy. The effective amount of activatable element in a composition used, for example, in the manufacture of medical devices depends on several factors,
That is, the nuclear nature of the element, the permissible amount in the alloy for its abundance (phase computability), the radiation dose to be given to the composition for a particular application (eg therapeutic or hypothetical), medical It is based on a number of factors including the use of the device (made of this composition) in combination with another (complementary / concomitant-eg drug treatment), and adjunctive therapy. . In a preferred embodiment of this invention, the activatable composition has both physical and nuclear properties suitable for the manufacture of stents useful for radiation treatment of coronary artery disease, especially arterial stenosis and restenosis. . A preferred composition comprises a biocompatible metal or non-metal with about 0.05 to about 10% by weight dispersion of a radioactive or natural non-radioactive isotope. The isotopes selected for this composition are typically beta particle emitters in principle, and have a half-life of at least 24 hours and up to about 60 days. Thus, upon activation, the composition emits a therapeutically effective amount of radiation based on the isotopes dispersed therein. When the composition is in the form of a stent, it emits radiation from the viewpoint of effectively preventing the new intimal (neointimal) proliferation of smooth muscle tissue, which is likely to occur in percutaneous transluminal coronary angioplasty (PTCA). Is basically homogeneous and radial.

The activation compositions of this invention are of various medical uses for targeted irradiation of radiotherapy for the treatment of cancer and for use in combination with concomitant agents and / or other devices for therapeutic and regenerative purposes. It can be used to manufacture a manufacturing device.

[0040]

Description of the Invention Including Preferred Embodiments

As mentioned above, the composition of the present invention, in terms of its content, physical form, nuclear properties,
And in the selection of suitable combinations of matrix material and radioactively enriched or natural non-radioactive isotopes. More specifically, the mixing of materials of different physical and chemical properties is generally unpredictable, resulting in potential processing and stability issues, especially when the intended processing conditions (composition of composition Formation and
It is fully understood that subsequent processing (in its molding into useful articles) is expected to be harsh and demanding.

According to the invention, the radionuclide is mixed with another substance (for example a molding matrix substance such as a metal alloy or a structural polymer compound) and transported ready for use to the place of use. A screened, sterilized therapeutic device is produced, preferably a selected isotopic composition that can be molded into a radioactive stent. Thus, in the place of use, complicated or cumbersome compounding procedures as well as unnecessary hazards or exposure to radiation are avoided.

Adverse tissue reactions (immune response) and / or in the fabrication of medical products (such as implantable devices that come into contact with human tissue) as contemplated herein.
Or extreme care must be taken to avoid substances that can cause toxic consequences. Therefore, the resulting product should avoid the formation of new compounds that can elicit a type of response that can be harmful to the patient. Therefore, selection of a combination of substances that does not react upon mixing for the composition of this invention is acceptable /
Emphasizes the use of approved (FDA) materials and, in addition, their processing characteristics,
Practical considerations are required that allow the addition of isotopes without adversely affecting biocompatibility and moderate radiation dose variability. Those products to which the improvements of this invention are most preferably applied are those in which the device emitting radiation is not easy to prepare or the resulting radiation delivery system requires cumbersome preparation.

Moreover, in the application of memory metal alloys to this invention, the relative stoichiometry of the alloy constituents (although it is a process already performed) is of great importance in controlling the physical properties of the resulting product. Is. Therefore, the effective modification of matrix materials (eg alloys) by the mixing of activatable isotopes is difficult to predict since such properties are believed to depend on the exact proportions of the major constituents of the matrix material. And therefore extreme care must be taken. Furthermore, the nuclear properties of isotopes (
Non-radioactive) also under the processing conditions required for their combination,
It depends to some extent on its interaction with the other (main) components of the composition, and thus also has unexpected and unpredictable results. For example, in one of the more advantageous uses of the composition of the present invention, the composition is drawn into fine wires or filaments and then woven or knitted into tubular or knitted stitches. The resulting wires and / or filaments made from the compositions of this invention are substantially unchanged in physical properties and moldability, thereby allowing them to be of a type commonly used in a variety of environments and methods. It allows the provision of structures, in particular medical devices and other known moldings, to which radioactive substances can be advantageously added.

In each case, the resulting device and / or molded article is then exposed by exposure in a reactor by N-gamma rays or other reactions from a neutron source such as a reactor, or by an accelerator or cyclotron. Device that is activated by the proton beam therein and energizes the activatable material within the composition prior to use, thereby over a period (half-life) limited by the particular activatable material selected. And / or cause short-range radiation of low-level radiation (preferably beta particles) from the molding.

In a preferred embodiment of this invention the activatable material is most preferably lutetium-177, samarium-153, cerium-137, 141 or from the isotopic form of the lanthanide series elements in the periodic table elements. 143, Terbium-161
, Holmium-166, Erbium-166 or 172, Thulium-172,
Ytterbium-169, Yttrium-90, Actinium-225, Astatine-211, Cerium-137, Dysprosium-165, Erbium-16
9, gadolinium-148, 159, holmium-166, iodine-124, titanium-45, rhodium-105, palladium-103, rhenium-186, 18
8, scandium-47, samarium-153, strontium-89, thulium-172, vanadium-48, ytterbium-169, yttrium-90.
, Silver-111; or a combination thereof. The lanthanides mentioned above, especially ruthenium-177, are particularly preferred and are known for their versatility of chemical and therapeutic value.

In short, one or more activatable isotopes are mixed with a biocompatible metal or biocompatible polymer (hereinafter also referred to as matrix material or matrix) and the resulting mixture is melt mixed. Alternatively, it is processed by mechanical means such as biaxial extrusion to produce an isotopically beneficiated composition. When the composition is a metal alloy, it is typically vacuum arc melted and then gradually cooled (annealed) to produce a product that can be formed into useful shapes and articles. Similarly, where the composition is a polymer, it may be melt mixed, extruded or solution mixed and then recovered as a compound and extruded, solution cast or drawn as a fiber through a spinneret to produce a useful shape and article from the fiber. It can be manufactured. A biocompatible polymer is one that accepts the isotope in the proper concentration, and further, the physical and processing necessary to withstand the activation energy required to energize the isotope naturally associated with its use. Easily processable organic and / or organometallic polymerizable materials having the properties of can generally be included. These materials are generally the same polymeric materials that are used for medical purposes in the readily available Catterl laboratory, specifically polyurethanes, polyamides, polyvinyl chloride, methyl methacrylate and their There are various combinations (eg, graft and block copolymers).

In stark contrast to the prior art, the resulting product is substantially free of leaching or flaking (as is the case with medical devices coated with radioactive phosphorus-32). , Exhibiting precise control of radiation dose (eg, low radiation dose and shallow tissue penetration), thus providing a substantial improvement in the means of therapeutic delivery of radiation to mammalian tissue. If it is a radioactive stent, the stent is prepared by calibration a few days or weeks ago (producing a relatively high level of radiation, which decays to the desired delivered dose), shipped, and ready for use. At the time of receipt by the hospital and / or prior to implantation, the radioactive stent may be radioactive for up to about 10 days for at least 24 hours. I have to stay.

Isotope-selective compositions (and medical devices formed from this material) retain the natural and desirable physical and chemical properties of the metal and polymer matrix materials, respectively, and, therefore, these metals and polymers. The composition is suitably selected from known metals (including alloys) and polymers known to be useful in molding medical products and devices.

In a preferred embodiment of this invention, the radionuclide that can be used in the present invention is of therapeutic value with a half-life long enough to activate, prepare and transport practical activatable devices. It is an alpha, beta or auger emitter. Therefore, radionuclides having a half-life of at least 24 hours are preferred. In contrast, deep invasive gamma and high energy beta emitters or long lived radioisotopes utilizing this delivery system are not practical. Similarly, an activatable element (eg, calcium) utilizing the delivery system
Is considered unfavorable because it chemically reacts when it comes into direct contact with blood. Nuclides that require long irradiation times are also unsuitable and can give rise to undesired long-lived or gamma-emitting radioisotopes due to impurities in the nickel, titanium or chromium matrix. Furthermore, in the range where a considerably large amount of concentrated non-radioactive isotope (more than that which can be effectively dissolved in the matrix without substantial change of the layer separation and / or processing conditions) is required, the material balance of the matrix is adversely affected. Effecting an unacceptable transition temperature, thus affecting the deployment of the device within the resulting artery. Furthermore, if a natural or enriched non-radioactive isotope is incompatible with the matrix material, eg in terms of melting temperature, it obviously cannot be used. Similarly, enriched or natural non-radioactive isotopes that produce long-lived radionuclides are also generally considered marginal for this critical application. Therefore, the desired properties required (short reactor or cyclotron activation time, the small amount of activatable non-radioactive isotope required in the carrier matrix, beta-emitter with preferably low gamma-ray emission for imaging, The selection of radioisotopes that have compatibility with mammalian tissues and blood, favorable half-lives, eg, greater than 24 hours and less than 60 days) necessarily requires considerable consideration to reach the preferred choice. .

In a preferred embodiment of this invention, the isotope screening composition comprises a metal or metal alloy of nickel and titanium containing from about 0.01 to about 10% by weight of one or more isotopes from the lanthanide series elements. The relative weight ratio of nickel and titanium in the composition refers to the so-called "Nitinol" prepared from these materials.
Alternatively, it is preferably the same as commonly used in alloys belonging to the group "memory metal". With respect to this invention, the alloy is balanced and treated to have a memory effect at or slightly below the temperature of its intended use environment (annealing).
(For example, a memory metal effect at 33 ° C. for intraluminal use in the human body). Thus, the novel isotope-selected shape memory metal alloys, preferably ternary alloys, emit radiation when activated and otherwise retain the original desirable combination of physical and therapeutic properties. Is manufactured as.

[0051]

[Implantable medical device]

Preferred compositions of the invention are superelastic materials (eg, nickel / titanium alloys).
Preferably used in the manufacture of radioactive wires, tubes or meshes, which are themselves suitable for medical implantation, especially in the treatment of cardiovascular diseases and tumors. The method of making the compositions of the present invention provides for the non-radioactive or enriched isotope and the activation adduct of a nickel / titanium alloy to be an alloy found to be effective in the atomic percent ratio of Ti, Al or Ni and Cr. In combination with adjacent stoichiometric nickel titanium or nickel chromium alloys. In a preferred embodiment of the invention, a non-radioactive isotope, such as lutetium-176, or optionally other activatable dopants, or natural or enriched non-radioactive isotopes, or combinations of non-radioactive isotopes thereof. The approximate concentration of other additives that can be combined with the combination of dopants selected from the group is 0.0025 to 10 atomic percent.

A preferred composition for the superelastic composition of the present invention is generally represented by the formula below, wherein the ratio (ratio) of the components of the matrix (eg, alloy) is relative to the amount of isotopes present therein. It can be adjusted. Ti-iNi (48-51) Lu (0.0025-10) Ni-iCr (48-51) Lu (0.0025-10) Ti (x) Ni (y) Me (z)-(x + y + z) (here , When irradiated and when present in a concentration of about 0.0025 to 10 atomic percent, Me is at least one natural or enriched non-radioactive isotope.)

In a preferred aspect of the present invention, Me is selected based on practical criteria and functional constraints governed by the environment of the intended application. For example, a radioactive isotope that requires relatively little activation energy to form a corresponding radioactive analog having a half-life (10 days or less for at least 24 hours) within the preferred parameters of the invention has been identified. The choice is generally preferred. The preferred nuclear reaction of the activatable isotope to lower the activation energy is that it emits predominantly β-particles without its nuclear properties emitting gamma radiation or other isotopes with long lifetimes. It is preferred to form a single isotope that Lutetium is the preferred activatable isotope model of the present invention. Specifically, lutetium has low energy beta radiation, short half-life, and Bar.
It is characterized by a very wide cross section in ns, which mitigates activation at low power (neutron flux rate) in the reactor. The introduction of this enriched non-radioactive isotope in metals or shape memory alloys, even in small amounts, does not have a favorable effect on shape memory properties and is not sufficient for activity in the reactor. Absent. The interstitial lutetium atom has a large size (Z = 71) and theoretically changes the lattice structure of the Nitinol alloy, but according to empirical data, the optimum lutetium concentration (0.05-0. 1
%) Does not substantially change the elastic modulus or dispersibility in the alloy and therefore retains the properties of the original Nitinol alloy and retains stents made from this new ternary alloy. At the preferred concentrations contemplated herein (0.01 to about 10 weight percent), lutetium-doped nickel / titanium alloys are meltable, castable, and activated and radioactive. Form a weldable, bondable, magnetic or non-magnetic cohesive composition. On the other hand, these compositions are resistant to corrosiveness or reactivity over a wide range of acidity in blood.

Due to its wide cross section, lutetium has a low flux rate.
At a short irradiation time, rapid radioactivity is generated in a low power reactor. Since the irradiation time can be shortened with a relatively low flux rate, the manufacturing cost can be suppressed. Using the natural or highly concentrated non-radioactive form of lutetium-176,
The formation of undesired long-lived isotopes such as high energy beta emitters and deep penetrating gamma emitters can be avoided. Therefore, the effect of the lutetium-176 doped composition is both significant and unexpected. Only 10% or less of concentrated non-radioactive isotopes are required as part of a medical device (and preferably in the case of lutetium-176 as low as 0.10%), so a neutron penalty.
and the irradiation time in the reactor can be shortened, and this irradiation time can reduce the possibility of producing undesirably long-lived radioisotopes due to inorganic impurities, thus minimizing the core size. This reduces the need for irradiation flux and reduces the amount of nuclear waste treatment. Further effects can be obtained by adding a small amount of one or more isotopically enriched elements. Upon exposure to irradiation in a furnace, such preformed or secondary formed materials produce only short half-life radioisotopes. Another advantage of this radioisotope material is that it can reduce nuclear waste with very short isolation times and decay requirements.
This type of radionuclide is most preferred, especially for only weak gamma facilitating device visualization and calibration, because beta-emitting radioisotopes travel only short distances. In another preferred embodiment, the short-lived lutetium-177 (half-life 6.6
The maximum soft tissue penetration of 7 days) is 0.15 mm.

Thus, when activating an isotopically enriched or natural lutetium, to obtain the desired activity level, preferably between 20 microcurie and 50 millicurie, the lutetium of the present invention For doped compositions, shorter irradiation times in the furnace are required. On the other hand, it is known that long-lived radioactive impurities such as vanadium-22 and high-energy γ-emitters are produced by activation of nickel titanium or chromium nickel. Unlike most other radioisotopes, such as yttrium-90 made from yttrium-89 wire, higher activity can be obtained using lutetium-177 without producing unwanted radioisotopes. .

Using the selection criteria described above, a wide range of radioactive alloys for the preferred compositions of the present invention are provided by the present invention. A single enriched non-radioactive isotope, or enriched non-radioactive isotope or isotope, including terrium, germanium, iodine, the monoisotopic yttrium or other element that is a natural or isotopically enriched form of the element Is obtained. For example, the alloy can be optionally doped with a selected non-radioactive isotope, preferably lutetium-176, samarium-152, strontium-88, yttrium, or a combination of other natural or enriched non-radioactive isotopes. Depending on the relative concentrations of the isotopes and the environmental constraints imposed by the anticipated use, when activating a unique alloy containing isotopic enriched or natural lutetium, the composition will: To obtain the desired activity level, preferably between 20 microcurie and 50 millicurie, only a relatively short nuclear reactor irradiation time at low neutron flux rates is required.

The short irradiation time of Nitinol, which is representative of enriched non-radioactive isotopes with a wide cross section, and in particular the preferred ternary alloy of the invention, lutetium-176, is formed by irradiation in a metal stent. And deep penetrating long-lived gamma-irradiated impurities, such as cobalt-60, titanium-44, and other radioactive isotopes resulting from the activity of impurities found in stainless steel or nickel. Formation can be avoided. Therefore, the use of high purity nickel, titanium, and lutetium is recommended and is decisive for some applications.

Due to the impurities typically found in metal alloys, organic polymer-based compositions have some effect, and to the extent “memory” is intended in such polymer materials, their composition Things can be systems of choice. Typically, the polymeric compositions of the present invention are a neutron capture irradiation from a mixture of biocompatible resin and enriched non-radioactive isotope, or isotopically enriched (70-75%) lutetium-176. Radioactive lutetium-177 (half-life 6.71 days) produced by
It can be produced by a combination of preferred isotopes such as lutetium-176. As mentioned above, and again, again, radioactive lutetium-17
7 is mainly a beta emitter, which is mostly energy deposited and penetrates into the adjacent tissue by a few mm, ˜0.15 mm (78.2% at 497.3 keV, 176).
keV is 12.2% and 384.3 keV is 9.5%) and exhibits a weak gamma (208.4 keV is 11% and 112.9 keV is 6.5%). Radioactive lutetium-177 decays to metastable hafnium-177. Moreover, the incorporation of lutetium-177 into the polymer takes advantage of the inherent safe effects of the short-lived, short-range, low-dose beta-irradiation emitters by incorporating the polymer encapsulable lutetium-177. This isotope is weak, but has a measurable gamma emission that overcomes the problem of dose calibration.

Shape memory stents, bioerodible stents, or shape memory biodegradable stents are
The limitation of simple mechanical metal stents by providing therapeutic drug delivery platforms or adjuvant therapies for precise therapeutic and physical goals and combinations that are not effective with systemically administered drugs Spread easily beyond the focus.

In another embodiment of the invention, the enriched non-radioactive isotope, preferably lutetium, which under processing conditions typically exhibits spontaneous osmotic properties, is rendered responsive to the spontaneous osmotic properties of lutetium. However, when combined or contacted with a matrix metal that has either a physical form or affinity for the isotope, it can be induced to penetrate the metal or alloy. For example, if the penetration enhancer and / or the penetration enhancer precursor and / or the environment in which it permeates is in communication with the filler material or preform, at least some point during the process, and normally under the process conditions, spontaneous permeability Metals that do not exhibit a bond with the matrix that do not exhibit spontaneous permeation properties under the same process conditions (eg, are mixed with and / or facing the matrix) and the combination with the metal forms a filler material or preform. Penetrate spontaneously.

The materials and methods of the present invention are useful in the manufacture of radioactive shape memory alloys that transition at or near body temperature, and are novel and medically useful for forming biocompatible implantable stents. It relates to methods of making or forming useful radioactively selected compositions. In use, the medical device emits a uniform, short-lived, low level radiation dose locally and sustainably. Unlike gamma emitters, the irradiation is limited, giving a very limited irradiation in the vicinity of healthy tissue. Thus, the radioactive stents of the present invention provide a novel, clinically pragmatic approach to prevent stenosis following angioplasty and treatment of certain cancers. In addition, lutetium-177 is radiopaque and can be used in a variety of nuclear drug physiotherapy, such as computed tomography of single photon emission, gamma camera, scintigraphy, PET, or autoradiography, fluoroscopy. Alternatively, it can be used as an X-ray or the like for visualization.

The activation composition used in the present invention can be diverted to tubes, wires or meshes and can be braided, spun, knitted, wrapped around each other or laminated. Here, the concentrated non-radioactive isotope is used for medical device (
It is evenly distributed and incorporated throughout the radioactive delivery component of the stent, for example. If the medical device is a stent, the medical device may be intended for intravenous or interstitial use in the non-radioactive state. The compositions of the present invention are particularly suitable for the production of radioactive stents and meshes, which are readily available in the treatment of vascular diseases, cancer, benign prostatic hyperplasia and other diseases. Medical devices made from the compositions of the invention are activated by irradiation / neutron bombardment in a nuclear reactor or by proton or electron beams in a cyclotron or accelerator to give radioactive stents. This radioactivity produces a stent that retains its physical integrity during insertion and presence at the target site and has a radioactive complex in the non-radioactive solid form.

The radionuclide selection criteria as described herein provides a radiostent that can be stored indefinitely and that facilitates a practical study of the half-life of the radionuclide. The intended shelf life is actually limited by the half-life of the radionuclide. For example, for lutetium-177, the preferred storage period is 0 days to about 20 days.
Is the day. Therefore, the radioactive stent can be delivered to the end user of the product and can be implanted with almost no additional preparatory time or effort as compared to conventional non-radioactive stents.

If desired, the activated stent may include or be coated with other components (hereinafter "companion material"). Can be combined with a stent,
Useful compounds delivered at controlled release rates include antiproliferative agents such as GPIIb-IIIa platelet inhibitor, benign prostatic hyperplasia inhibitor, chemical stabilizers such as ascorbic acid, gentisic acid, antitelomerase for dispersion. (Anti-telome
and antitumor agents such as cytarabine, doxorvidin, vincristine and cisplatin. Arterial or body passageway paving material
Non-radioactive, biocompatible, radioactive polymeric gels used in y passageway paving materials or coatings are also contemplated for products formed from the compositions of the present invention. Together with the radionuclide,
These companion substances are incorporated into biosorbent polymer matrices such as hydrogels, lactides, polyglycolic acids, poly (β-hydroxybutyric acid), poly-DL-lactic acid, etc. containing activatable substances for combination or adjuvant therapy. Can be incorporated. Stents made of or coated with these materials provide a combination therapy of radiation emission and delivery of therapeutic agents to a defined site. Applying both of the above therapies is not just a fusion of the therapies, but rather, after the initial radiation treatment has either impaired or blocked the undesired physiological process, the therapeutic agent (if possible, low doses). Is carried to and retained at a specific site for treatment, which enables more effective treatment for physiological conditions or pathological conditions.

[0065]

[Biodegradable radioactive stent]

In this preferred embodiment of the invention, the radioactive stent consists primarily of a polymer or copolymer compound or hydrogel of any of the following: lactides, glycosides, caprolactones, oxyalkanes, polyurethanes, and ultra high molecular weight polyethylene. These compounds or hydrogels can be used with radioactive sources such as lutetium 177, samarium 153, cerium 137, 141 or 14
3, terbium 161, holmium 166, erbium 166 or 172,
Thulium 172, Ytterbium 169, Yttrium 90, Actinium 22
5, astatine 211, cerium 137, dysprosium 165, erbium 1
69, gadolinium 148 or 159, holmium 166, iodine 124,
Titanium 45, Rhodium 105, Palladium 103, Rhenium 186 or 18
8, scandium 47, samarium 153, strontium 89, thulium 17
2, vanadium 48, ytterbium 169, yttrium 90, silver 111, or a combination thereof or a combination with a radioisotope other than these. The radiation source has a half-life shorter than 2 months, preferably shorter than 1 month, and emits mainly short-lived α-rays, preferably β-rays or Auger electrons.

Biodegradable radioactive stents made from the compositions of the present invention will safely degrade in the bloodstream over weeks to months. In one such preferred embodiment, the radioactive biodegradable stent is gradually eroded or decomposed into a harmless substance, and the radioactive component consisting of a short-lived radioisotope disintegrates to an extremely low and safe level. The mechanical limitations and permanence problems found in some cases are overcome. That is, these devices provide a “scaffold” for remodeling blood vessels and also become a pharmacokinetically acceptable vehicle for long-acting local drug delivery, and, by themselves, post-PTCA reconstitution. Alternative means may be provided to prevent stenosis and acute occlusion.

The present invention also relates to developing these devices as improved deployment means and vehicles for topical therapeutic drug delivery. Such devices include an exogenous radioactive polymer that is biodegradable and serve as a biological conduit to further reduce restenosis and proliferative oncological disease. Drug-loaded polymeric stents are formed by either coating the therapeutic drug on the surface structure of an intraluminal stent or by placing the therapeutic drug in the polymer prior to forming the stent. The radioactive stents of the present invention can also include agents such as copolymer components to facilitate attachment of the stent to the tissue through which it passes and to ensure proper retention at the target site.

Implantable deformable polymer stents made from the radioactive polymers of the present invention exhibit enhanced mechanical and process properties upon modification of the polymer upon activation, thus providing organometallic additives (eg, organotitanium, Organic zirconium, organic vanadium, etc.) can be added to enhance the bond between the organic component and the inorganic radioactive component, and to provide uniform and selective radiation delivery to the target tissue.

In a preferred embodiment as a radioactive biodegradable stent, the substance will safely disintegrate and dissolve within weeks to months. Similarly, biodegradable terpolymers or hydrogels containing short-lived radioisotopes exhibit controlled bioerodibility and bioresorption and degrade over time to harmless substances. These polymers, terpolymers, homopolymers, copolymers, oligomers, or blends thereof,
For example, poly (DL-lactide-co-glycolide) and selected monomers, oligomers, or terpolymers can be used to form radioactive stents for sustained, site-specific, adjuvant-based drug delivery. it can. Such radioactive polymers include selected lactides and shape memory plastics. Radioactive bioabsorbable polymers suitable for this purpose include lactide, polyglycolic acid, polyorthoesters, which are used for the sustained release of contraceptive steroids, glycosides, polyanhydrides, phosphazines. , Caprolactone, oxyalkanes, trimethylene carbonate, paradioxanone, polyacrylic starch, triethylene glycol monomethyl acrylate, hydrogels, polyurethanes, or other activatable terpolymers that decompose, bioerodible or bioabsorbable There are terpolymers, which include polyglycolic acid, poly (2
-Hydroxyethylmethacrylate), poly-L-butyric acid, poly (ε-caprolactam), poly (DL-lactide-co-glycolide), high molecular weight poly-L-butyric acid,
Poly-L-lactide, polyglycolic acid / poly L-butyric acid, polygalactin, polydioxanone, polyglyconate, ε-caprolactone, polyhydroxybutyrate valarate, covalently immobilized poly (2-hydroethylmethacrylate)- Polyethylene terephthalate (PET), a composite polymer of gelatin
Polyanhydrides), ethyl terminated oligomers of butyric acid, difunctional polyurethanes, as well as radioactive copolymers of combinations of the above materials, such as 50/50 (poly) DL-lactide-glycosides.

The radioactive stent of the present invention is a useful device for improving the current success rate in recanalizing a suddenly occluded body passage or conduit, thereby stabilizing the patency of the tube. Turn into. More specifically, this radiopolymer stent is therapeutically valuable in preventing endovascular restenosis after transluminal percutaneous angioplasty. Radiopaque polymeric materials for intravascular brachytherapy are also disclosed.

The subject matter of the present invention also provides an adjuvant or combination therapy for the narrowing and / or obstruction of the malignant esophagus, pharynx, gastrointestinal and biliary tracts, which until now had been the only route of surgical bypass or comfort medicine. Can provide palliative and adjuvant treatments.

[0072]

[Creation of medical device]

The products of the present invention can be converted into radioactive tubes, strands, fibers, threads, meshes, coils or polymer coated wires, braided, woven, knitted, crocheted, Wrap around
Alternatively, these means (especially knitting, braiding and winding) may be combined, multi-layered, molded, extruded, cast, welded, glued, glued, high frequency or ultra high. Sonic welding or heat sealing is performed to obtain a predetermined shape that constitutes the stent, and the natural or concentrated non-radioactive isotope is uniformly dispersed in the particle shape. A knitted fabric, a woven fabric, a braided process or a combination thereof may be used as a fiber of a biostable or biodegradable polymer.
When applied to filaments or polymer fibers or combinations of filaments and wires, pressurized radioactive stents can be manufactured.

A transvascularly loaded endovascular prosthesis is in the form of a spirally wound coil that is generally tubular in shape and is made from a shape memory polymer tube or solid with a transition temperature around 36 ° C. Made After the prosthesis reaches the transition temperature after being loaded into the body vessel, the prosthesis expands and roots firmly on the inner wall of the body vessel. Upon inflation, the diameter of the artificial device lumen will be approximately the same as the diameter of the body vessel passageway. Such artificial devices may be used for other body passages.

[0074]

[Radioactive hydrogel coating]

Another form of the medical device of the present invention contemplates a biocompatible radioactive gel stent coating and method of making the same that is resistant to radiolysis and syneresis. This gel can be used to coat metal or polymer stents and similarly activated in reactors, cyclotrons or accelerators. Such a radiative coating will have radiative properties similar to mono-cast radiant alloys.

Therefore, such a stent may be coated with a radioactive or activatable hydrogel, which contains an antithrombolytic or antiproliferative agent with minimal platelet activating activity as a platform for drug delivery. By doing so, it is possible to further suppress the growth of the inner wall of the new blood vessel. Hydrogel coating of intravascular radioactive stents is a means for precisely targeted high-dose drug delivery with a sustained biological half-life. Therapeutic agents delivered with a controlled release rate include antiproliferative agents such as GP IIb-IIIa platelet inhibitors, anti-neoplastic agents, benign prostatic hypertrophy inhibitors, chemical stabilizers such as ascorbic acid, gentisic acid, and cytarabine. , For diffusion of anti-telomerase compounds and anti-neoplastic agents such as doxorubicin, vincristine and cisplatin. A biodegradable biocompatible radioactive polymer gel used as an arterial or body passageway coating material or coating is also claimed.

In a preferred embodiment, the stent may also include an antithrombolytic or antiproliferative agent with a very low platelet-activating effect, such as a nitric oxide donor, and serve as a platform for drug delivery. The growth of the neointima may be further inhibited. Therefore, radioactive stents can be coated with heparin, coumadin, dexamethasone, ticopridin, nitric oxide, or other drugs or biologically active substances to allow delayed release of the drug or recombinant compound and Combinations may reduce the risk of thrombosis. Alternatively, the polymer may be admixed with the above agents prior to being manufactured into the final form. Organometallic chelating agent

By using organometallic chelating agents in combination with isotopes, various other substances can be combined with such isotopes and provided for combination therapy. This typically includes improved dispersion and the above applicable polymers (other polymers that may be substituted, such as polyanhydrides such as polyethylene terephthalate, polyurethane, polyethylene oxide, ultra high molecular weight polyethylene, polynorbornene, Or copolymers such as fluorine-acryl-styrene-urethane-silicone, 2- [2'-iodobenzoyl] -ethyl methacrylate and hydrogels containing azo aromatic moieties). To enable the combination of different biodegradable polymers with radioisotopes by obtaining polymers and using organometallic bonds of titanium, zirconium, vanadium or iodine and processing agents as aqueous solutions or powders such as organotitanic acid. including. The above chelates or mixtures thereof can be crosslinked to improve dispersibility and drying by linking radioisotopes such as lutetium, samarium or other activatable isotopes or substances or drugs to various polymers, Also, it can be used to improve the adhesion between the inorganic components to improve the fluidity and reduce the voids of the precursor. In another preferred embodiment, linking agents or chelating agents may be included to improve binding. This has been found to be particularly suitable for immobilization of enzyme complexes that prefer non-aqueous hydrophobic environments and the like. Such compounds remain highly active when applied to fillers such as hydrogels containing water. The cross-linking reaction modifies the inorganic surface by forming a monomolecular organic complex layer based on the cross-linking reaction of organotitanic acid or other organometal with a polymer that causes a complete dispersion of radioactive particles or fibers. Such organometals may be used to surface treat the polytetrafluoroethylene surface to improve the binding properties with the drug compound.

[0078]

【Example】

The following examples clarify, describe and explain a number of preferred embodiments of the invention. The equipment used to prepare activatable compositions, and the commercialization of those compositions (eg, wires, meshes, etc. from which medical devices are made) are standard or have already been described. Mentioned in. Parts and percentages in the examples are by weight unless otherwise stated.

Example 1 Preparation of an Activatable Nickel-Titanium-Lutetium Ternary Alloy An activatable triple consisting of 53.1% by weight nickel, 0.1% by weight lutetium, 44.8% by weight titanium. Put 50g of the original alloy charge into the crucible. Before melting, the mobile arc is deoxygenated by strike on a zirconium getter power supply. The alloy components are melted by a vacuum arc and inverted 3 times at 1,750 ° C. to form metal particles. The resulting alloy is melted in a second copper crucible at the same or almost the same temperature,
Cast into 5/8 inch diameter rods in an inert atmosphere.

Example 2 Production of Activatable Nickel-Titanium-Lutetium Ternary Alloy Wire The thus obtained 0.480 ″ × 2.75 ″ crude rod of Example 1 was machined on a lathe to smooth the surface. Cleaned in a stainless steel tube, the ends of the tube were welded closed. This assembly was heat swaged using a continuous steel die at 500 ° C to make 1/8 "rods of the sample. Then strip the stainless steel from the Ni-Ti-Lu sample. Stretch the rod and the resulting wire. In order to achieve this, the wire had to be heated to about 500 ° C. The final annealing temperature shifted the transition temperature of this given composition of the activatable alloy, and the rod was then fed with 20 continuous tungsten carbides. Hot-roll the wire using a diamond die.
Annealing was carried out for 30 minutes after each passage. The wire was thinned to 0.015 inch in diameter, varying in length and annealed at temperatures between 450 ° C and 600 ° C.

Example 3 Treatment of Shape Memory Nickel-Titanium-Lutetium Ternary Alloy Wire The wire made by the method of Example 2 is then annealed. Annealing of the activatable alloy is carried out at a temperature well above Af. Upon cooling, this material is austenitic until it reaches the Ms temperature. Upon further cooling, the austenite state changes to marstensite and the phase transition is completed with Mf. Upon heating, marstensite is stable until reaching As. Upon further heating, the marstensite state begins to transition and the phase transition is completed at Af. If heating or cooling of the activatable alloy is stopped before the phase transition is complete, the abundance of each phase is stable. The activatable alloy exists between Ms and As, either phase thereof, or a combination thereof, depending on the history of temperature treatment. Ingot temperature is Mf = 2 ° C, Ma = 27 ° C, As = 46 ° C, A
f = 75 ° C. To make an activatable shape memory "Nitinol" wire, the wire is preferably 100% austenite (if the wire is braided or braided into a tubular stent). Therefore, the wire is heated above Af and kept at a temperature higher than Ms until the tubular shape is completed. The device is then cooled to below Mf and kept below Af for shaping. When the radioactive stent is warmed up to As and above As, it returns to its original braided shape. Af is close to mammalian body temperature (37 ° C). The 90-95% transition is considered acceptable. However, As is kept as high as possible until the end of the insertion so that about 5-10% of the phase transition occurs before the insertion is complete. The phase transition can be suppressed by putting it in the sheath. The phase transition temperature (Af) can be adjusted by adjusting the elements of the alloy, but Af-As tends to be fixed.

Example 4 Shape Memory Nickel-Titanium-Lutetium Wire In yet another example, the 0.019 ″ diameter activatable NiTiLu of Example 2 was used.
Was annealed at 520 ° C. and its shape memory response was completed at 36.1 ° C. in water (measured by thermocouple). When the activatable alloy warms to body temperature (which is in the transition temperature range), it expands back to its memory shape; in the case of activatable implantable medical devices (eg, stents) the surrounding tissue is in the process. Push it.

Example 5 Electron Microprobe Analysis of Wire Sample Cross Sections Electron microprobe analysis was performed on the wire of Example 2 and confirmed that the concentration distribution of activatable lanthanides was relatively consistent in the NiTi matrix. . One tenth (1/10%) of one percent of the activatable lanthanide was added first, but some of this is expected to volatilize and adhere to the crucible, so a target of about 6- 8%, and the wire samples and the final wire samples, which were sliced over 1000, supported this assumption. Scanning electron microscopy of the wire showed that lutetium striations occurred along the length and circumference, among which basically isotropic distribution.

Example 6 Neutron Activation Analysis and Quality Evaluation of Activatable Shape Memory Nickel-Titanium-Lutetium (Ternary Alloy) Wire The activatable alloy of Example 1 (53.1% nickel, 0.1% lutetium). , 44
． 0.0058 "(260mm length) made of 8% titanium) and weighs 27.8
A mg (containing approximately 0.0278 mg lutetium) wire sample was placed in quartz glass protected with aluminum foil. The tube was placed in an aluminum capsule holder, pressure sealed with an inert gas and welded closed. The capsule was hydraulically placed in the channel position of the reactor and neutron activated in a 10 mW reactor. The activated sample was collected and the following results were obtained.

Results By calibration curve: 82.0 microcurie radionuclide Purity: 98.12% of Lu-177, E = 208 keV Neutron flux rate: 5 × 10 ¹² n / cm ² . sec. Position: 19-5X Irradiation time: 11 hours Collapse time: 48 hours The homogeneity of the radiation along the wire was revealed by autoradiography.

Example 7 Neutron Activation Analysis and Quality Evaluation of Activatable Shape Memory Nickel-Titanium-Lutetium (Ternary Alloy) Wire The activation alloy of Example 1 (53.1% nickel, 0.1% lutetium, 44.8
% Titanium) 0.0058 "(length 314mm) and weight 33.4mg
A wire sample (containing approximately 0.0334 mg lutetium) was placed in quartz glass protected by aluminum foil. The tube was placed in an aluminum capsule holder, pressure sealed with an inert gas and welded closed. The capsule was hydraulically placed in the channel position of the reactor and neutron activated in a 10 mW reactor. The activated sample was collected and the following results were obtained.

Results Calibration curve: 1,620 microcurie radionuclide Purity: 91.68% of Lu-177, E = 208 keV Neutron flux rate: 5 × 10 ¹³ n / cm ² . sec. Position: 1-4-6 Irradiation time: 6 hours Disintegration time: 16 hours Uniform radiation along the wire was revealed by autoradiography.

Example 8 Neutron Activation Analysis and Quality Evaluation of Radiation Activatable Shape Memory Nickel-Titanium-Lutetium (Ternary Alloy) Wire The radiation activated alloy of Example 1 (53.1% nickel, 0.1%). Lutetium, 44
． 0.0058 "(length 365 mm) made of 8% titanium) and weighs 38.0
A mg (containing approximately 0.038 mg lutetium) wire sample was placed in quartz glass protected with aluminum foil. The tube was placed in an aluminum capsule holder, pressure sealed with an inert gas and welded closed. The capsule was hydraulically placed in the channel position of the reactor and neutron activated in a 10 mW reactor. The activated sample was collected and the following results were obtained.

Results By calibration curve: 809 microcurie radionuclide Purity: 93.07% of Lu-177, E = 208 keV Neutron flux rate: 2.63 × 10 ¹³ n / cm ² . sec. Position: B3-8Y Irradiation time: 9.5 hours Disintegration time: 48 hours

The above data confirm that radioactivity (10, 20, 50, 100 microcuries) or higher was obtained at high flux rate positions in RP10 or other reactors. The autoradiographically determined isodose appears to be uniform along the length of the activated NiTiLu wire sample. No physical change was observed in the activated NiTiLu wire sample due to neutron radiation activated irradiation.

As is apparent from the above description and examples, the physical and nuclear properties of medical devices (eg, stents) made with the radioactively-selected compositions of the present invention can be targeted to radiation therapy. Producing medical devices for endoluminal stent placement for delivery, preventing such operations from secondary failure due to subsequent endovascular restenosis, appears to be very effective and proliferative It can also be used to treat sex cancer. These are clearly superior to conventional devices in radiation therapy, in part due to the high safety of such medical devices at the clinician's hand and the patient's placement in the body. It is attributed to reduced radiation exposure of normal tissues, shallow particle emission characteristics, and relatively short half-life.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AU , BR, CA, CN, IL, IN, JP, KR, MX, TR F-term (reference) 4C081 AC09 BA16 BB03 CD35 CG03                       DA01                 4C082 AA07 AC05 AC06 AE05 AV08                       MA01                 4C167 AA42 BB01 BB43 CC09 CC20                       CC23 CC26 DD01 DD10 GG21                       GG24 GG26 GG32 GG43

Claims (8)

[Claims] 1. A activatable composition comprising: (a) a matrix material substantially selected from the group consisting of metals, organometallic materials, organic materials, and combinations thereof; and (b) therein. Incorporating an isotopically dispersed activatable natural or enriched non-radioactive isotope and isotopically dispersed activatable natural or enriched non-radioactive isotope in the matrix material. It may contain from about 0.05 to about 10 weight percent of a radioisotope and may be formed into structural shapes and articles that can be placed in contact with human tissue without inducing an immune or toxic response. A featured activatable composition. 2. An activatable natural or enriched non-radioactive isotope
Substantially lutetium-177, samarium-153, cerium-137, 141
Or 143, terbium-161, holmium-166, erbium-16
6 or 172, thulium-172, ytterbium-169, yttrium-90, actinium-225, astatine-211, cerium-137, dysprosium-165, erbium-169, gadolinium-148 or 15
9, holmium-166, iodine-124, titanium-45, rhodium-105,
Palladium-103, rhenium-186 or 188, scandium-47,
Samarium-153, Strontium-89, Thulium-172, Vanadium-
The activatable composition of claim 1, which is selected from the group consisting of 48, ytterbium-169, yttrium-90, silver-111, and combinations thereof. 3. An activatable natural or enriched non-radioactive isotope,
It is mainly a β-particle emitter and has a half-life of 24 hours or more and about 60 days or less. When activated by the composition, the composition has a distribution of radioisotopes therein. The activatable composition according to claim 1, which emits a therapeutically effective amount of radiation on the basis. 4. The activatable composition according to claim 1, wherein the matrix material is a metal alloy containing nickel and titanium and has shape memory properties. 5. The activatable composition according to claim 1, wherein the matrix material is either an organometallic material or an organic material and is further selected from the group consisting of structural polymers and biodegradable polymers. 6. A method of forming a medical device for targeted delivery of radiation therapy, the method comprising: (a) (i) substantially selected from the group consisting of metals, organometallic materials, organic materials, and combinations thereof. A matrix material, and (b) an activatable natural or concentrated non-radioactive isotope dispersed isotopically therein, the activatable composition comprising: Inducing an immune or toxic response in human tissue, comprising about 0.05 to about 10 weight percent of a radioactively-activatable natural or concentrated non-radioactive isotope dispersed in humans. Providing a activatable composition that can be molded into an article and structural shape that can be placed in contact without contact; and (b) bringing the activatable composition into a energetically sufficient amount of radiation. And dew, wherein the to emit radiation for a period determined by the half-life of of identity position elements of the radiation activatable natural or concentrated non-radioactive isotopes and radioactive reduction. 7. A medical device for specific targeted delivery of radiation therapy to a site or tissue that responds to radiation therapy, comprising: (a) (i) substantially metal, organometallic material, organic material, and their From a matrix material selected from the group consisting of combinations, and (b) an activatable composition comprising an isotopically dispersed activatable natural or concentrated non-radioactive isotope. A molded article produced, wherein the composition comprises from about 0.05 to about 10 weight percent of an isotope-dispersed, radioactively activatable natural or concentrated non-radioactive isotope. And a molded body that can be molded into a structural shape and an article that can be placed in contact with human tissue without inducing an immune or toxic response; and (b) the molded body at a target site. Medical device comprises a means for adapting the molded article in a delivery system for placement as may subjected to radiation treatment to the target site by the molded article. 8. A radioactivatable composition having both physical and nuclear properties suitable for the manufacture of stents useful for radiotherapy of coronary artery disease, in particular arterial stenosis and restenosis, said composition comprising: A biocompatible metallic or non-metallic material having an activatable natural or enriched non-radioactive isotope dispersed isotopically therein in an amount of about 0.05 to about 10 weight percent, said isotope comprising: It is primarily a beta-particle emitter and has a half-life of more than 24 hours and about 60 days or less, and when activated, the composition is therapeutic based on the distribution of the isotope therein. An activatable composition which emits an effective amount of radiation.