WO2001072371A1

WO2001072371A1 - Radioactive implement and method of manufacture of same

Info

Publication number: WO2001072371A1
Application number: PCT/AU2001/000360
Authority: WO
Inventors: Richard Alan Fox
Original assignee: Minister For Health In His Capacity As The Board Of Royal Perth Hospital
Priority date: 2000-03-30
Filing date: 2001-03-30
Publication date: 2001-10-04
Also published as: AUPQ661200A0; AU2001243945A1

Abstract

A radioactive implement suitable for use in providing treatment to an animal which comprises at least a portion of a surface of the implement coated with one or more high energy gamma emitting radionuclides. A method of manufacturing a radioactive implement comprising the steps of (i) coating the implement with a radioactive material; and (ii) heating the coated implement wherein said heating temperature is selected such that: (a) it results in at least some of the radioactive material becoming bonded to the implement and (b) it does not substantially damage the construction or properties of the implement.

Description

Radioactive Implement

and

Method of Manufacture of same

FIELD OF THE INVENTION

The present invention relates generally to radioactive implements and the preparation of radioactive implements such as radioactive stents. In particular, the invention relates to radioactive implements and a method of manufacturing radioactive implements that are capable of being implanted within a blood vessel so as to reduce the incidence of excessive cell proliferation within the lumen of the vessel.

BACKGROUND ART

Restenosis (reclosure of the artery) can result from excessive cell proliferation within the lumen of the artery following angioplasty or other surgical intervention. The normal acute inflammatory reaction in response to cellular injury is essential for survival, however an excessive response may not only inhibit recovery from surgical intervention, but also threaten patient safety.

Radiation is known to reduce or halt the proliferation of cells. The use of radiation has been reintroduced as an adjunct to angioplasty to prevent neointimal hyperplasia in arteries.

There are a wide range of techniques that have been proposed in the radiation treatment of arteries, including external beam treatment, the use of radioactive wires or seeds and the insertion of a radioactive liquid or gas into the artery via a balloon. The insertion of a radioactive stent has also been suggested. Radioactive materials which are currently being used to coat the stent are for example beta emitting radioactive radionuclides and low energy gamma emitting radionuclides. The problems associated with the use of beta emitting radionuclides are that the range of beta particles in tissue is limited. Consequently, the penetration of the radiation into the tissue is poor. However, of greater importance is that the dose falls off very rapidly beyond the end of the stent. This means that tissue damaged by the stent implantation at the end of the stent does not receive a significant radiation dose and therefore proliferates resulting in "edge restenosis". This has been the main cause of failure of existing trials on radioactive stents. Further, low energy gamma emitting radionuclides are not suitable because the low energy gamma emission is invariably associated with conversion electron emission. Hence the dose from the conversion electrons dominates, producing a poor dose profile. Furthermore, low energy gamma emitters require extremely high activities to deliver sufficient dose to the arteries. In most cases this makes their use impractical.

At present the production of radioactive stents made of suitable radioactive materials is limited to the use of an ion implantation technique. That technique requires expensive equipment and demands substantial initial radioactivity to produce a stent of the required activity due to losses of material in the ion implantation process. This makes the process costly and time consuming.

Alternate methods of manufacturing radioactive stents involve placing a protective covering of electroplated gold over the radioactive material to contain the activity of the material. Such a stent is not likely to be reliable due to the establishment of an electrolytic cell in which the steel stent will corrode in preference to the electroplated gold after the stent is implanted in the body.

Thus there is a need for radioactive stents that are easy to produce that are reliable, simple, efficient and inexpensive. General

Those skilled in the aforementioned art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all such variation and modifications.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and where appropriate methods are clearly within the scope of the invention as described herein.

Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

DISCLOSURE OF THE INVENTION

The present invention provides a radioactive implement. One form of this invention provides a radioactive implement suitable for use in providing treatment to an animal which comprises at least a portion of a surface of the implement coated with one or more high energy gamma emitting radionuclides. Preferably, that implement is a medical implement such as a stent.

Gamma emitting radionuclides provide a superior dose distribution with increasing depth from the implement. Gamma rays have a very long range in tissue and therefore penetrate much further. High energy gamma emitters have a number of advantages:

(a) the dose delivered for a given level of source radioactivity is greater;

(b) the number of conversion electrons is reduced compared with lower energy gamma emitters; (c) electronic disequilibrium near the stent will reduce the tissue dose immediately adjacent to the stent surface.

In the foregoing discussion the invention will be described in the context of preparing radioactive stents, however it should be appreciated that the invention is not so limited. A stent is usually made of a biologically compatible metal wire of tubular shape or metallic perforated tube. The stent should be of sufficient strength and rigidity to maintain its shape after deployment and to resist the elastic recoil of the artery that occurs after the vessel wall has been stretched. The stent can be made from steel or stainless steel or other metals such as titanium or nitinol. Preferably the stent is made of stainless steel such as 316L stainless steel.

When preparing a product according to this form of the invention, it is preferable to coat the surface of the stent with high energy gamma radionuclides which have few or no beta particles and also few or no conversion electrons. Hence the need for 100% electron capture, decaying to a high energy gamma emitter.

Preferably the high energy gamma emitting radionuclides have a half life in the range of 2 to 60 days. Very short half-lives makes the stent more difficult to use since the high energy gamma emitter with which it is coated decays very rapidly. This creates difficulties in introducing such stents into a person within the allowable activity range. In theory, very long half-lives are excellent, but in practice, they may not work as well since the dose rate may be too low and irradiation over a long time may prevent repair of the inner lumen of the artery. Thus it is desirable to have half lives in the range of 4 to 30 days. More preferable is a half life in the range of 4 to 20 days. Most preferable is a half life in the range of 4 to 14 days.

Preferably the high energy gamma emitting radionuclides are selected from Technetium-96, Silver-106m, Manganese-52, Thalium-202, Bismuth-205 and/or Nickel-56. It is desirable that Technetium is used to coat the radioactive implement. Desirably the radioactive implement is metallic in form. The term "metallic" used herein is used to describe any article that contains metal ions and is not limited to any particular form of metal or any particular metal ions.

A second form of the invention provides a method of manufacturing a radioactive implement comprising the steps of: (i) coating the implement with a radioactive material; and (ii) heating the coated implement wherein said heating temperature is selected such that (a) it results in at least some of the radioactive material becoming bonded to the implement and (b) it does not substantially damage the construction or properties of the implement

Preferably the radioactive material is coated onto the implement. Such a coating may either be uniform over the implement or it may be localised to a particular region. For example, it may be coated onto an end or tip of the implement. A range of such methods are known in the art, some of which are discussed herein by way of example only. Preferably, the implement is metallic in form and the radioactive material is electroplated on to it using methods known in the art of electroplating.

The above method is broadly applicable to the preparation of any implement that is capable of being heated and which needs to be radioactively coated in a relatively uniform manner. In the foregoing discussion the invention will be described in the context of preparing radioactive stents, however it should be appreciated that the invention is not so limited.

The inventors have found that heating a metal stent after it has been coated with radioactive material results in strong atomic bonds being formed between the radioactive material and the typically metal stent leading to the production of a more versatile stent that does not appear to possess many of the problems observed with prior art stents. The atomic bonds formed by heating the stent result in a stable radioactive coating that will not come off in the human body for at least the period of irradiation of the tissues. A stent is usually made of a biologically compatible metal wire of tubular shape or metallic perforated tube. The stent should be of sufficient strength and rigidity to maintain its shape after deployment and to resist the elastic recoil of the artery that occurs after the vessel wall has been stretched. The stent can be made from steel or stainless steel or other metals such as titanium or nitinol. Preferably the stent is made of stainless steel such as 316L stainless steel.

The temperature and heating conditions of metallic stents will be determined by how readily the radioactive material forms bonds with and diffuses into the metallic stent. The ability of the atoms of the stent and the radioactive material to form bonds with one another is dependent upon the metal that the stent is made of and the radioactive material used. Bonding between the atoms of the metallic stent and the atoms of the radioactive material can be most favourably achieved with high temperatures for long periods of time. However, maintenance of the structural properties of the stent requires low temperatures and short periods of time. Consequently, it is preferable that the highest temperature and shortest time that allows adequate bonding to take place between the atoms of the stent and the radioactive material be used.

It will be appreciated that the temperature and heating conditions used in the above method may however be varied depending on the type of stent that is treated by the process of the invention. The temperatures and times used in the treatment process will depend to a greater or lesser extent on the type of stent selected for treatment and the radioactive material used. Most metallic stents composed of stainless steel like 316L stainless steel can be heated to temperatures ranging from, for example,750°C to 900°C in a vacuum and can be heated for approximately 1 to 2 minutes, depending on the temperature at which it is heated, without destroying the structural configuration and or elastic properties of the stent. The temperature range of 750°C to 900°C and time of heating of approximately 1 to 2 minutes is provided by way of example only. The invention is in no way limited to the aforementioned range of heating temperatures and times. Preferably a metallic stent made of 316L stainless steel is heated in accordance with the present invention at about 750°C in vacuum for about 2 minutes.

When producing stents according to the method of the present invention it is desirable to avoid the precipitation of carbides such as Cr₂₃C₆ that may occur at high temperatures. Therefore, in a particularly preferred form of the invention the heating temperature and time of treatment is selected such that it avoids carbide formation. Carbide formation is a particular problem with stainless steel due to the presence of large amounts of chromium in the steel. The L in 316L means low carbon which is designed to reduce carbide formation. However even for 316L, carbide formation is most likely between 800°C and 900°C if the stent is heated for more than about 2.5 minutes. Above that temperature range the carbon dissolves and below that range migration of the atoms to form the carbide is too slow. With most metallic stents made of 316L stainless steel, avoidance of carbide formation is achieved provided heating is limited to less than about 2.5 minutes.

Some stents in the prior art are coated with a substance or composition that is used to release drugs incorporated therein, such as hirudin and/or platelet inhibitor such as prostacyclin, a prostaglandin. Desirably, the stent is not coated with such a carrier. Where a stent is coated with such material the material should be removed before treatment of the stent is undertaken. However such coatings could be applied after the manufacture of the radioactive stent.

The radioactive material may in principle consist of any beta or gamma emitters. Preferably the radioactive material is selected from high energy gamma emitting radionuclides or high-energy beta emitters, such high energy beta emitters having a relatively short half-life of 2 to 30 days and provide a short range dose to tissue. A desirable beta emitter is Rhenium-188, which has a half-life of 17 hours. Other examples include Phosphorous-32, Yttrium-90, and Rhenium-186. For a gamma emitter the amount of radioactive material applied to the stent can be substantially reduced if the stent is coated with material exhibiting a number of high energy gamma transitions. Therefore, it is desirable that the radioactive material used to coat the stent will consist of a high energy gamma emitter which has a satisfactory half-life of approximately 4 days such as Technetium 96, which has a half life of 4.28 days. Other suitable gamma emitters include Silver-106m, Manganese-52, Thalium-202, Bismuth-205 and/or Nickel-56.

Preferably the high energy gamma emitting radionuclides have a half life in the range of 2 to 60 days. It is desirable to have half lives in the range of 4 to 30 days. More preferable is a half life in the range of 4 to 20 days. Most preferable is a half life in the range of 4 to 14 days.

Preferably, the stent is coated with the radioactive material by an electroplating method. Electroplating is the deposition of metal resulting from the reduction of metal ions onto the cathode in an electrochemical cell. Therefore, in order to electroplate the stent it would normally be prepared as a cathode in the electroplating process onto which the radioactive material is electroplated.

It is desirable that electroplating is achieved in an acid bath containing the radioactive material. Electroplating can be achieved in an acid bath containing radioactive material, following pre-treatment of the stent in a pre-treatment acid bath using reverse current. A forward current can also be applied.

Suitable electroplating conditions can consist of a urea bath, ammonium sulphate bath and an ammoniacal citrate bath. It should be appreciated that the conditions under which electroplating takes place, for example the concentration of the bath, the temperature, current and period of time that electroplating takes place are inter-related. Varying one parameter may affect another. Consequently there are many different combinations of conditions which will result in an electroplated stent and the invention should not be limited by any particular set of electroplating conditions. It will be recognised that a person skilled in the art will know how to vary the electroplating conditions. By way of example only, electroplating conditions desirably consist of an acid electroplating bath consisting of substantially 0.6N to 0.9N sulphuric acid at for example 70°C with a current of 50mA/cm² for a period of approximately 6 minutes. A typical pre-treatment bath consists of concentrated sulphuric acid having a temperature of 70°C with a current of 100mA/cm² flowing for a period of approximately 5 minutes.

Methods of coating other than electroplating such as vacuum deposition, evaporation from a liquid medium or other simple technique known in the art can also be employed to deposit radioactive material onto the stent prior to heat treatment.

BEST MODE(S) FOR CARRYING OUT THE INVENTION

Features of the present invention are more fully described in the following example. It is to be understood that the following examples are included solely for the purposes of exemplifying the invention and should not be understood in any way as a restriction on the broad description set out above.

Example

Electroplating of Technetium 96 onto a stent made of stainless steel composed of 316L was achieved from an acid bath containing the radioactive material, following prior treating of the stent in a pre-treatment acid bath using reverse current. The pre-treatment bath consisted of concentrated sulphuric acid having a temperature of 70°C with a current of 100mA/cm² flowing for a period of approximately 5 minutes. An acid electroplating bath consisting of 0.9N sulphuric acid at 70°C containing the required amount of pertechnetate ions

(TcO₄ ^") with a current of 50mA cm² for a period of 6 minutes was used to carry out the process of electroplating the Technetium-96 onto the stainless steel stent. It was important to maintain rapid stirring of the bath during electroplating.

In the plating bath the stent was the cathode while a cylinder of platinum surrounding the stent was the anode. Subsequently the stent was heated for about 2 minutes at approximately 750°C in vacuum. After which it was cooled.

The above method was used to create a Rhenium coated radioactive stent by replacing pertechnetate ions (TcO₄ ^'). in the bath with perrhenate ions (ReO₄ ^").

Claims

The Claims Defining the Invention are as follows

1. A radioactive implement suitable for use in providing treatment to an animal which comprises at least a portion of a surface of the implement coated with one or more high energy gamma emitting radionuclides.

2. The radioactive implement according to claim 1 wherein the high energy gamma emitting radionuclides have a half life ranging from about 2 to 60 days.

3. The radioactive implement according to claim 1 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 30 days.

4. The radioactive implement according to claim 1 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 20 days.

5. The radioactive implement according to claim 1 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 14 days.

6. The radioactive implement according to any one of the preceding claims wherein the high energy gamma emitting radionuclides are selected from the group comprising Technetium 96, Silver-106m, Manganese-52, Thalium-202, Bismuth-205 and Nickel-56.

7. The radioactive implement according to claim 6 where the high energy gamma emitting radionuclide is Technetium 96.

8. The radioactive implement according to any one of the preceding claims wherein the high energy gamma emitting radionuclides have few or no beta particles.

9. The radioactive implement according to any one of the preceding claims wherein the high energy gamma emitting radionuclides have few or no conversion electrons.

10.The radioactive implement according to any one of the preceding claims wherein the implement is a stent.

11. The radioactive implement according to any one of the preceding claims wherein the stent is made from metal.

12.The radioactive implement according to claim 11 wherein the stent is made from any one of the metals selected from the group consisting of stainless steel, titanium and nitinol.

13.The radioactive implement according to claim 12 wherein the stent is made from 316L stainless steel.

14. A method of manufacturing a radioactive implement comprising the steps of (i) coating the implement with a radioactive material; and (ii) heating the coated implement wherein said heating temperature is selected such that: (a) it results in at least some of the radioactive material becoming bonded to the implement and (b) it does not substantially damage the construction or properties of the implement.

15.The method according to claim 14 wherein the stent is made from 316L stainless steel and the heating temperature ranges from 750°C to 900°C.

16.The method according to claim 15 wherein the heating temperature is about 750°C.

17.The method according to claim 15 or 16 wherein the stent is heated for about 1 to 2 minutes.

18.The method according to claim 17 where in the stent is heated for about 2 minutes.

19.The method according to any one of the preceding claims wherein the stent is coated in step (i) with radioactive material by electroplating.

20.The method according to claim 19 wherein the electroplating is carried out in an acid electroplating bath consisting of substantially 0.6N to 0.9N sulphuric acid at 70°C with a current of 50mA/cm² for a period of approximately 6 minutes.

21. The method according to claim 19 or 20 wherein electroplating follows pre- treatment of the stent in a pre-treatment acid bath using reverse current.

22.The method according to claim 19 or 20 wherein electroplating follows pre- treatment of the stent in a pre-treatment acid bath using forward current.

23.The method according to any one of claims 21 or 22 wherein the pre- treatment bath consists of a concentrated sulphuric acid having a temperature of 70°C with a current of 100mA/cm² flowing for a period of approximately 5 minutes.

24.A radioactive implement suitable for use in providing treatment to an animal which comprises at least a portion of a surface of the implement coated with one or more radionuclides made according to any of the methods of claims 14 to 23.

25.A radioactive implement of claim 24 wherein the one or more radionuclides are high energy gamma emitting radionuclides.

26.The radioactive implement according to claim 25 wherein the high energy gamma emitting radionuclides have a half life ranging from about 2 to 60 days.

27 he radioactive implement according to claim 25 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 30 days.

28.The radioactive implement according to claim 25 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 20 days.

29.The radioactive implement according to claim 25 wherein the high energy gamma emitting radionuclides have a half life ranging from about 4 to 14 days.

30.The radioactive implement according to one of claims 25 to 29 wherein the high energy gamma emitting radionuclides are selected from the group comprising Technetium 96, Silver-106m, Manganese-52, Thalium-202, Bismuth-205 and Nickel-56.

31. The radioactive implement according to claim 30 wherein the high energy gamma emitting radionuclide is Technetium 96.

32.The radioactive implement according to claims any one of claims 25 to 31 wherein the high energy gamma emitting radionuclides have few or no beta particles.

33.The radioactive implement according to any one of claims 25 to 31 wherein the high energy gamma emitting radionuclides have few or no conversion electrons.

34 he radioactive implement according to any one of claims 25 to 33 wherein the implement is a stent.

35The radioactive implement according to claim 34 wherein the stent is made from metal.

36The radioactive implement according to claim 35 wherein the stent is made from any one of the metals selected from the group consisting of stainless steel, titanium and nitinol.

37 The radioactive implement according to claim 36 wherein the stent is made from 316L stainless steel.

38.A radioactive implement according to claim 24 wherein the one or more radionuclides are high energy beta emitting radionuclides. The radioactive implement according to claim 38 wherein the high energy beta emitting radionuclides are selected from Phosphorous-32, Yttrium-90, Rhenium-186 and Rhenium-188.

The radioactive implement according to claim 39 wherein the high energy beta emitting radionuclide is Rhenium-188.

The method according to claim 14 substantially as hereinbefore described in the Example.