WO2002020062A2 - Coated implant - Google Patents

Abstract

The invention relates to a coated implant, the coating thereof consisting of at least one noble metal and one metal containing at least one radioactive isotope. The aim of the invention is to provide a coated implant having a low elution rate. In order to achieve this, the coating consists of at least two layers, one layer being made of noble metal and another being made of a metal containing at least one radioactive isotope. Said layers are electrochemically applied to the implant and are then tempered.

Description

Coated implant

The invention relates to a coated implant in which the coating consists at least of a noble metal and a metal which contains at least one radioactive isotope.

Vascular supports (stents) to prevent vein narrowing (restenosis), e.g. B. in coronary and pereferyeral vessels have been used frequently in recent years. In some patients, tissue growth re-narrowing occurred despite stent implantation. These restenoses were seen in approximately 25% of all cases.

It is possible to counteract this narrowing by means of local radioactive radiation which emits a stent.

From DE 197 24 230 a radioactive stent is known in which the radioactive isotopes are fixed on the surface with the help of an organic adhesion promoter.

Furthermore, a stent is known from DE 197 24 223 in which the radioactive isotope is galvanically deposited directly on the surface.

However, these two stents have an undesirable marked washout rate of the radioactive isotope.

The object of the invention is to provide a coated implant with a low washout rate.

This object is achieved by the features of claim 1. The sub-claims describe advantageous embodiments of the invention. Radioactive isotopes rarely emit photons or particles of a single energy. As a rule, photons (gamma and X-ray quanta) and / or particles (e.g. He nuclei, electrons and positrons) of different energy are emitted with different probabilities. In general, not all are therapeutically effective or desirable. A selection of these would be an advantage. This is possible by choosing a suitable coating. Radiation is partially or completely absorbed as it passes through matter, depending on the thickness of the coating and the type of coating materials. By choosing suitable layer thicknesses and materials, radiation can be selectively partially or completely absorbed. This can play an important role, especially in the vascular application of radioactive implants. If an implant comes into direct contact with the blood, a local coagulation process starts immediately. Thrombosis develops. An antithrombogenic agent is therefore taken for several months in the clinical use of patients. After that, the surface of the implant is usually completely covered with endothelial tissue and the risk of thrombosis is eliminated. However, very short-range radiation (eg low-energy electrons, low-energy X-rays) can delay this healing process or, in the worst case, stop it. However, higher-energy radiation is required to prevent restenosis processes. Selective absorption of low-energy radiation is recommended here.

A particular advantage of the invention is the use of X-rays. They have a shorter range than the gamma rays generated by activation, but a larger one than electrons. X-ray emitting isotopes are, for example, ¹³¹ Cs and ¹⁰³ Pd. They emit little or no gamma radiation. From today's perspective, their half-lives are in the ideal range of 10 to 17 days. The implant according to the invention has the following advantages:

Significantly less radioactive leaching than with conventional types of activation,

Cost-effective in terms of equipment, because high efficiency can be achieved with separation,

Cost-effective, since only a small amount of investment is required, relatively easy to implement methods,

In principle, there is no limitation on the separated activity, usability of many biocompatible materials for coating the contact surface implant / blood,

Versatile processes that can be used to coat a wide range of products

Therapeutically more effective range distribution than conventional electron- and gamma-radiating implants.

Galvanic deposition is an inexpensive, quick and relatively simple process for applying layers. The radioactive material must be elementary or as a detachable complex. This breaks open by dissolving in the electrolyte or by applying a voltage. The radioactive isotope is thus present as an ion in the electrolyte. The gradient of an electric field now forces the charged isotope in the direction of the oppositely charged electrode. It can separate here. The correct choice of the substrate and the electric field ensures a firm deposit on the electrode material. The following processes can be supplemented with a metallic or non-metallic (eg by electrophoresis) cover coating. The invention is explained in more detail below on the basis of exemplary embodiments.

For example, stainless steel and nickel-titanium compounds can be used as the material for the uncoated implants (substrate).

Stainless steel can be easily coated with various materials to improve adhesion. They can be layers of Ag, Au, Pd or Fe for the adhesive deposition of active palladium.

Ni-Ti compounds can be coated with various materials to improve adhesion. They can be layers of Ag, Au, Pd or Fe for the adhesive deposition of active palladium.

With a suitable choice of materials, a subsequent heat treatment can be used to form alloys. As a result, the active isotope is bonded extremely firmly in the matrix of the deposited inactive material. The choice of temperature and duration depend on the layer composition and may need to be optimized for each coating method.

The material must be completely degreased for successful deposition. For this purpose, the substrate is subjected to ultrasonic cleaning in acetone. This is followed by electrolytic degreasing (e.g. Emphax, W. Canning GmbH).

Example 1:

The pretreated substrate material is e.g. B. coated with a commercial alkaline electroless copper bath (eg Doduco DDP 540). After three minutes, a layer with a thickness of 100-1000 nm is formed. Palladium plating by means of electrodeposition from a radioactive ¹⁰³ PdCl ₂ solution (pH = 1 - 3) a current density of 0.1 - 2 A / dm ² follows. An insoluble platinum-coated titanium ring network anode is used for this. The subsequent thermal treatment by storing the sample in an oven for 30 minutes under a pressure range of p = 10 ^{~ 4} - 10 ^"5 mbar at T = 380 - 480 ° C should allow the layer to be alloyed. A subsequent investigation showed this.

Example 2:

The pretreated substrate is coated using a silver bath containing cyanide. This can be done e.g. B. a bath with a silver content of 0.8 - 1.5 g / 1, with 2 g / 1 silver cyanide, 70 g / 1 sodium cyanide and 10 g / 1 sodium carbonate can be used. You need a pure silver anode. It is operated at room temperature with a current density in the range from 0.5 to 1.5 A / dm ² and a pH from 11 to 12.5. The silver layer of 50-500 nm generated after about 3 minutes is coated with radioactive palladium as in Example 1.2. A subsequent 30 minute alloying at T = 300 - 400 ° C under p = 10 ^"4 - 10 ^{~ 5} mbar was successfully carried out.

Example 3:

After the pretreatment, the substrate is coated with a thin layer of gold. For this, z. B. a cyanide gold bath. For this purpose, 3 g / 1 potassium cyanoaurate, 1 g / 1 nickel chloride and HC1 are used. The bath is operated with a pH of 0.5 - 1.5 and at room temperature. The anode should be insoluble (e.g. platinum). A current density of 1 - 2 A / dm ^{2 is} set. The 50 - 500 nm thin gold layer applied after about 3 minutes is coated with active palladium as in 1.2. This is followed by a thermal treatment under vacuum at T = 300 - 400 ° C for 30 minutes.

Coatings are extremely interesting for the medical use of radioactive implants. They enable the implant to be improved or adapted with regard to: Biocompatibility corrosion

Reduction of radioactive washing up

Therapeutic effect through selective absorption of electromagnetic and particle radiation

Especially in the bloodstream, it is important that no radioactivity escapes from implants. An additional inactive coating can prevent or minimize this.

Radioactive isotopes rarely emit photons or particles of a single energy. As a rule, photons (gamma and X-ray quanta) and / or particles (e.g. He nuclei, electrons and positrons) of different energy are emitted with different probabilities. In general, not all are therapeutically effective or desirable. A selection of these would be an advantage. This is possible by choosing a suitable coating. Radiation is partially or completely absorbed as it passes through matter, depending on the thickness of the coating and the type of coating materials. By choosing suitable layer thicknesses and materials, radiation can be selectively partially or completely absorbed. This can play an important role, especially in the vascular application of radioactive implants. If an implant comes into direct contact with the blood, a local coagulation process starts immediately. Thrombosis develops. An antithrombogenic agent is therefore taken for several months in the clinical use of patients. After that, the surface of the implant is usually completely covered with endothelial tissue and the risk of thrombosis is eliminated. However, very short-range radiation (e.g. low-energy electrons, low-energy X-rays) can delay this healing process or, in the worst case, stop it. However, higher-energy radiation is required to prevent restenosis processes. Selective absorption of low-energy radiation is recommended here.

Examples for layer 3 (coating):

Application of the active layers as in the three examples described above. Subsequent production of a coating for the selective absorption of the 2.7keV x-radiation of the ¹⁰³ Pd. These coatings can consist of silver, copper or gold. The examples above can be used for this. The material of the first layer can be used as coating material (gold on gold, silver on silver, copper on copper). But you can also exchange the materials (gold on copper, silver on copper, gold on silver, silver on gold, copper on gold, copper on silver). To reduce the transmitted 2.7 keV radiation to 90% - 99.9% of the original radiation on the surface, coating thicknesses of Cu: 3 - 10 n, Ag: 4 - 13 Hm. And Au: 500 nm - 1.5 Hm necessary.

The following coating materials can also be used. :

Carbon:

Carbon is often used to coat heart valves. It is easy to apply by sputtering or evaporation. Due to its low atomic number, it is unsuitable for selective absorption. Carbon can protect the material from corrosion.

Titanium:

Titanium is known to be biocompatible due to its oxidic surface. It protects the material from corrosion and can be used with selective smears. Titanium can be easily sputtered onto the implant surface. Stainless steel:

We managed to apply an austenitic stainless steel by sputtering. It is characterized by its biocompatibility, its corrosion resistance and its ability to selectively absorb.

Palladium:

Inactive palladium is well suited for selective absorption. Like the active palladium, it can be applied by sputtering, chemical and electrochemical deposition or vaporization. It is sufficiently biocompatible (material in dental medicine) and has a protective effect against corrosion.

tantalum:

Tantalum is biocompatible and is often used in the cardiovascular area. Due to its large atomic number, it has a great ability for selective absorption. It also has a protective effect against corrosion.

Polyterafluoroethylene:

Polytetrafluoroethylene is biocompatible, corrosion-resistant and can be used with smears such as titanium for selective absorption.

Polyethylene terephthalate:

Polyethylene terephthalate is biocompatible, corrosion-resistant and can be used with smears for selective absorption.

Polymethyl methacrylate:

Polymethyl methacrylate is biocompatible and corrosion-resistant, but cannot be used for selective absorption.

Layer thicknesses for selective absorption. The low-energy X-ray (2.70 keV) and electron beams (2.39 keV and 17.0 keV) should be 90% - 99% absorbed. The remaining photons (20.07 keV, 20.22 keV, 22.70 keV) should penetrate the coating as completely as possible.

C: d = 100-1000 Hn

Ti: d = 10-100 Hu

Stainless steel: d = 1 - 10 Hm

Pd: d = 1 - 10 Hm

Ta: d = 0.2-2 Hm

Au: d = 0.2 - 2 Hm

PTFE: d = 10 - 100 Hm

PET: d = 50 - 500 m

PMMA: d = 100-1000 H

Claims

claims: 1. Coated implant in which the coating consists of at least one precious metal and a metal which contains at least one radioactive isotope, the coating consisting of at least two layers, a layer (1) of precious metal and a layer (2) of the metal which contains at least one radioactive isotope, the layers (1, 2) being applied electrochemically to the implant and then annealed. 2. Coated implant according to claim 1, characterized by a further layer (3) made of biocompatible material, which was applied to the layer (2) before or after the tempering. 3. Coated implant according to claim 1, characterized by a further layer (3) made of noble metal, which was applied electrochemically to the layer (2) before or after the tempering. 4. Coated implant according to one of claims claim 3, characterized in that the noble metal of the layers (1, 3) is copper, silver or gold. 5. Coated implant according to one of claims 1 to 4, characterized in that the metal is palladium and the radioactive isotope ¹⁰³ Pd. 6. Coated implant according to one of claims 1 to 5, characterized in that the layer (3) is so thick that it absorbs 90-99.9% of the 2.7 keV X-rays of the radioactive isotope ¹⁰³ Pd. 7. Coated implant according to one of claims 1 to 6, characterized in that the annealing takes place at a temperature between 300 and 600 ° C.