DE10142015C2 - Radioactive implant and process for its manufacture - Google Patents

Description

The invention relates to a radioactive implant according to the upper Concept of claim 1 and a method for its manufacture position.

Implants, e.g. B. stents to prevent Vein narrowing (restenosis), e.g. B. in coronary and peripheral vessels have often been too small in recent years African use. Some patients recurred narrowing due to tissue growth despite stent implantation. These restenoses were seen in approximately 10-30% of all stent interventions tions. B. Fischell et al. patented the principle using lo kaler radioactive radiation that emits a stent, Counteract narrowing. Fehsenfeld et al. beschrie ben 1994, a process in which ak is activated. There are so different radioisotopes testifies. They differ in half-life and radiation area ten (particle radiation: electrons; electromagnetic radiation gamma and x-rays). One is therapeutically necessary local tissue radiation over a period of a few weeks This will result in unnecessary long-term radiation treatment of the more distant tissue by gamma radiation siege. The radiation exposure of patient and medical person nal is increased unnecessarily.

Radioactive vascular supports that have been used in clinical tests to date are ³² P ion-implants. P-32 has a half-life of 14 days and only emits electrons with an average energy of 0.7 MeV. Beta particles have a short range (a few millimeters). In clinical tests, a significant reduction in restenosis inside the stent was found, but at the same time an increase in restenosis at the stent ends (so-called candy wrapper effect). An increase in the ³² P occupancy, ie an increase in local activity, at the stent ends also shows no significant improvement.

A radioactive implant is known from DE 198 38 183 A1, which consists of a substrate made of stainless steel and the radioactive isotope ³² P. Here, the stent is coated directly with a corresponding solution with the radioactive isotope ³² P.

Furthermore, an implant is known from US Pat. No. 6,264,598 B1 which has a non-radioactive layer made of palladium, which is applied to a carrier and is enriched with ¹⁰² Pd. The implant is preferably applied to titanium as a biocompatible intermediate layer.

Finally, DE 198 55 421 A1 discloses a cover layer for a carrier with radioactive material made of aluminum, mag nesium, tantalum, iron and / or titanium dioxide.

The object of the invention is an implant of the type mentioned to provide the type in which the isotope is coated is applied, and to apply a method for its production give.

This object is achieved by the features of the claims 1 and 4. The subclaims describe advantageous configurations tion of the invention.

Restenosis at the stent ends can be reduced by using X-rays. They have a shorter range than the gamma rays generated by activation, but they are larger than electrons. An X-ray emitting isotope is, for example, ¹⁰³ Pd. It does not emit therapeutically significant gamma radiation. From today's perspective, its half-life is in the ideal range of 17 days. Due to the larger range of the X-rays, regions well beyond the stent can be irradiated therapeutically. A reduction in the candy wrapper effect can thus be created.

Palladium is an expensive isotope. An occupancy of the stent ends with this isotope while using ³² P in the middle part of the stent is the most advantageous in terms of market economy. This noticeably reduces manufacturing costs.

The method can also be used in the coating of other medical implants e.g. B. seeds, needle and wires to fight tumors and in the bile duct and ureter stents, as well as in all applications in which the proliferation of tissue in body cavities must be avoided.

The invention is described below using exemplary embodiments explained in more detail.  

Our invention describes a particularly suitable electroche Mixing process of radioactive phosphorus adherent to a medical device to apply a solid-state implant without biological loading to bind conceivable substances on the surface at the same time. At the same time, the ends can optionally be activated with palladium become.

Phosphating the implant

Are particularly suitable for use as substrate material in austenitic chrome-nickel used in the surgical field steel (e.g. AISI 316L) is also possible by using a biocompatible coating (e.g. gold) the use of other Ma materials possible.

High-alloy steel is very difficult to phosphate. A layer of pure iron can eliminate this problem. For this a stainless steel implant is covered with such a layer. Then you bring with commercial Phosphatierungsbä the radioactive phosphorus isotope, by adding the active Phosphorus in the same phosphorus complex of the inactive bath, homo over the entire stent or homogeneously with the omission of one Range from the stent end to approx. 2 mm from the stent end. The Non-activation of the ends is due to a previous painting this by partial immersion in paint or the like werkstelligt. To protect the pure iron layer from corrosion these with a protective coating, e.g. B. Gold, homogeneous over the gan zen stent. Palladium is then applied to the ends introduced. This happens e.g. B. by a defined immersion (approx. 2 mm) in the palladium bath. Furthermore, one can now Additional deck coating follows with subsequent optional heat mebehandlung.

Typical activities at e.g. B. an 18.9 mm long implant are in the range of:
For homogeneous coating: ³² P: = 10-50 kBq / mm
¹⁰³ Pd: = 1-25 MBq / mm
For ¹⁰³ Pd ends: ¹⁰³ Pd: = 5-25 MBq / mm

The material must be completely removed for successful deposition be fat. To do this, the substrate is acetone in an Ultra subjected to sound cleaning. Electrolytic degreasing connects.

Primer and phosphating

To coat the substrate material, a pure iron layer is applied either homogeneously on the entire stent or homogeneously in the middle part of the stent (by painting the stent ends). The following bath is suitable for this, for example, which is characterized by a high ductility of the iron layer produced:
Iron (II) chloride: 375 g / l
Calcium chloride: 185 g / l
pH: 1-2
T = 90-110 ° C
j = 4-20 A / dm ²
Anode: soft iron, A _anode <A _cathode (0.5-0.7: 1)

After applying a 100-1000 nm thick layer, the Stent homogeneous or only the middle part (painting the ends) phosphated. For this purpose, customary phosphating baits are suitable which, in the case of radioactive phosphorus, is in the correct complex gend, is added. Then the substrate with a homogeneous coating (e.g. gold, silver, copper) for corrosion provide protection. Optionally, the ends can be activated with Palladium e.g. B. by controlled immersion or by La the middle section are carried out. An additional Deck coating and / or heat treatment is possible.  

Possible advantageous layers are then quantified ed.

copper

The pretreated substrate material is e.g. B. coated with a com commercial alkaline electroless copper bath. After 3 minutes, a layer with a thickness of 100-1000 nm is formed. Palladium plating by electroplating from a radioactive ¹⁰³ PdCl ₂ solution (pH = 1-3) with a current density of 0.1-2 A / dm ² follows. For this purpose an insoluble platinum-coated titanium ring mesh anode is used and the stent is immersed approx. 2 mm in the bath. After this process, the substrate is rotated and the process repeated. 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 = 350-600 ° C should allow the layer to be alloyed. Before or after this procedure, the stent can be implanted homogeneously or only homogeneously in the central part with ³² P.

silver

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 / l, with 2 g / l silver cyanide, 70 g / l sodium cyanide and 10 g / l sodium carbonate can be used. You need a pure silver anode. It is operated at room temperature with a current density in the range of 0.5-1.5 A / dm ² and a pH of 11-12.5. 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 minutes of alloying at T = 300-400 ° C under p = 10 ^-4 -10 ^-5 mbar was successfully carried out. Before or after this procedure, the stent can be implanted homogeneously or only homogeneously in the middle part with ³² P.

gold

After the pretreatment, the substrate is coated with a thin gold layer. For this, z. B. Bad a cyanide gold. For this purpose, 3 g / l potassium tetracyanoaurate, 1 g / l nickel chloride and HCl 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. This is followed by a thermal treatment under vacuum at T = 300-400 ° C for 30 minutes. Before or after this process, the stent can be implanted homogeneously or only homogeneously in the middle part with ³² P.

deck coating

Application of the active layers as in the previous examples. Subsequent production of a coating for the selective absorption of the 2.7 keV X-rays of the ¹⁰³ Pd. These coatings can consist of silver, copper or gold. The examples above can be used for this. You can use the material of the first layer as a coating material (gold on gold, silver on silver, copper on copper). But you can also combine 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 by 90% - 99.9% of the original value on the surface, coating thicknesses of Cu: 3-10 µm, Ag: 4-13 µm and Au: 500 nm-1.5 µm necessary.

Another variant is ion implantation of the stent ends z. B. Cs-131 or Cs-132.  

This variant is interesting if radiation in the middle part of the stent is required with a short range, but higher at the ends. Harder γ-emitters are then possible (e.g. Cs- 132). These generally have two drawbacks:
Tissue is irradiated that is not in the target volume.

In the case of a permanent implant, the patient then places himself represents a radiation source.

But if only the ends of the stent with such a hard radiator the amount of hard radiation is much smaller, so that the above effects can be tolerated.

Claims (4)

1. Radioactive implant consisting of a substrate made of stainless steel and ³² P as a radioactive isotope, characterized in that the radioactive isotope is electrochemically applied to an intermediate layer of pure iron, and the substrate is a vascular support, the ends of which are provided with a further radioactive isotope are. 2. Radioactive implant according to claim 1, characterized ge indicates that the further radioactive isotope is electro chemically on a precious metal layer as an intermediate layer is applied. 3. Radioactive implant according to one of claims 1 or 2, characterized in that it is made with a top layer Precious metal is provided. 4. A method for producing a radioactive implant consisting of a stainless steel substrate and a radioactive isotope using the following process steps:

• a) cleaning of the substrate and galvanic application of a pure iron layer,
• b) phosphating the pure iron layer with the aid of an active phosphor complex,
• c) applying a noble metal layer as an intermediate layer and electrochemically applying a further radioactive isotope on this intermediate layer and
• d) applying a corrosion protection layer.