Abstract:
The invention relates to radioactive ruthenium sources with a dosage rate of at least 1.5 Gy/min at a distance (water) of 2 mm, consisting of an activity carrier and an encapsulation of the carrier made of a material compatible with the human body. A multilayer system made of metals and/or alloys is galvanically applied on the carrier. At least two layers in said system are made of ruthenium 106 and inactive intermediate layers made of other metals or alloys are provided between the radioactive ruthenium layers. The activity carrier is encapsulated with a material compatible with the human body, for instance a metal or a plastic material. Encapsulation can be carried out by filing a capsule and subsequently sealing or galvanically depositing a top layer made, for instance of hard gold.

Description:
BACKGROUND OF THE INVENTION 
     The invention relates to radioactive ruthenium radiation sources having a dose rate of at least 1.5 Gy/min at a distance of 2 mm (water), comprised of an activity carrier and an enclosure for said carrier made of a body-compatible material, the carrier having electrodeposited thereon a multilayer system of metals and/or alloys, wherein at least two layers consist of ruthenium-106, and wherein inactive intermediate layers of other metals or alloys are present between the radioactive ruthenium layers. 
     The activity carrier is enclosed in a body-compatible material such as metal or plastic. Enclosing the activity carrier can be performed by filling into a capsule and subsequent sealing, or by electrodepositing a cover layer made of e.g. hard gold. 
     The electrodeposition of non-radioactive ruthenium coatings on various substrates is well-known from the literature. A variety of electrolytes including most various additives have been described for this purpose. What is involved is the deposition of well-adhering coatings which are sufficiently thick and nevertheless glossing and free of cracks. 
     Thus, in the article by G. S. Reddy et al., “Electro-deposition of Ruthenium”, in TIMF 47 (1969), pp. 187-193, for example, the anionic ruthenium complex (NH 4 ) 3 [Ru 2 NCl 8 (H 2 O) 2 ] has been described as electrolyte, by means of which stable baths and glossing ruthenium coatings are obtained. 
     The DE-OS 22 61 944 concludes that coatings produced using such baths exhibit gloss only up to a thickness of about 2-3 μm, and that surface cracks will occur with increasing thickness. Therefore, this document suggests a modified electroplating bath, by means of which ruthenium layers 5 μm in thickness are said to be obtained. This bath likewise includes a complex ruthenium compound having the Ru—N—Ru nitrogen bridge (produced from the above-mentioned electrolyte), but is free of halogen, includes at least 1.5 g/l of sulfate ions, and has a pH value of 4 at maximum. 
     However, because the electrodeposition of ruthenium on copper, nickel or nickel-iron alloys does not proceed satisfactorily under acidic conditions for uses in electric engineering, and therefore, the substrate must first be coated with a thin layer of gold or another suitable material, some prior art documents have also described alkaline or neutral baths including complex ruthenium compounds having an Ru—N—Ru nitrogen bridge, e.g. in GB 1,520,140 of 1978 (alkaline) and in EP 0,018,165 of 1980 (addition of oxalic acid, pH value 7, diaphragm cell). 
     In context with the deposition of radioactive ruthenium layers, the French patent specification FR 1,206,612 (filed 1956) has been the first to be known from the literature. It essentially describes non-radioactive electrolytic depositions based on an electrolytic bath comprised of ruthenium(IV) chloride solution at 95-100° C. A coating of 4 mg/cm 2  is described, corresponding to a layer thickness of about 3 μm. Furthermore, it is noted in this written specification that a layer thickness of up to 8 mg/cm 2  would be possible when using this method. This would correspond to a layer thickness of about 6 μm. The problems with crack formation at layer thicknesses above 3 μm, which are well-known from the literature, have not been mentioned in this early document. Finally, this patent specification concludes that this method would also allow the production of radioactive sources but fails to demonstrate in which way such sources with sufficiently stable layers for medical uses could be obtained. 
     In contrast, a practical use of radioactive ruthenium is described in “Isotopenpraxis”, Vol. 2, No. 4 (1966), pp. 189-193, wherein a deposition from highly diluted, inactive ruthenium(III) chloride solutions with addition of 30-70 μCi of  106 Ru as tracer has been performed. 
     However, it was found that the deposition described therein does not allow mechanically stable layers of significant thickness to be obtained, and that uniform distribution of activity on the preparations could only be achieved in excessively slow depositions. Such sources merely have limited usefulness for medical applications. 
     Marketed ruthenium radiation sources for ophthalmologic purposes are produced by electrolytic deposition of ruthenium from commercially available radioactive ruthenium(III) chloride solutions. The thin layers obtained thereby, having dose rates of from 0.1 to 0.5 Gy/min, are sufficient for using this radiation source as eye applicator in eye tumor treatment. However, these radiation sources are unsuitable in the treatment of vascular anomalies because they do not have the required dose rate due to the fact that thin layers can only be achieved. 
     SUMMARY OF THE INVENTION 
     It was therefore the object of the invention to provide radioactive ruthenium radiation sources for medical uses, which should have high dose rates and, despite the required thickness of the active ruthenium layer, have the required flexibility and geometry in order to be usable in the intravascular treatment of vascular anomalies. It was another object of the invention to devise methods of producing such sources. 
     According to the invention, said object is accomplished by means of radioactive ruthenium-106 radiation sources comprised of an activity carrier and an enclosure for said carrier made of a body-compatible material, the carrier having coated thereon a multilayer system of metals and/or alloys, wherein at least two layers consist of radioactive ruthenium, and wherein inactive intermediate layers of other metals or alloys are present between the radioactive ruthenium layers. 
     The radiation sources according to the invention have well-adhering ruthenium layers of the required thickness (and thus, the required dose rate) which remain free of visible cracks despite the bending stress typically occurring during use, e.g. in intravascular treatment of vascular anomalies. 
     The radiation sources of the invention are produced by electrolytic deposition of the multilayer system on a conductive carrier. According to the invention, the anionic ruthenium complex [Ru 2 NCl 8 (H 2 O) 2 ] 3−  (RuNC), wherein the cations may be ammonium or potassium ions, is employed in the electroplating radioactive ruthenium bath. According to the invention, it was found particularly advantageous to add sulfopropylpyridine (PPS) to the electrolyte, preferably in amounts of from 1 to 10 mg per ml of electrolyte. The production of the RuNC electrolyte proceeds in a single step by hydrolyzing in excess amidosulfonic acid a ruthenium(III) chloride solution which, for purposes of the invention, contains at least 8 Ci/g ruthenium. Essentially, this production is known from the literature. Under the present active conditions, boiling at reflux is replaced by heating at about 90° C. The electrolyte thus obtained can be used without additional steps so that, according to the invention, the preparation of the electrolyte is performed directly in the electrolytic cell (cf., FIG. 1) developed for the process of the invention. 
     Gold, nickel, titanium or alloys thereof can be deposited as metals between the individual ruthenium layers. According to the invention, it is also possible to produce not all of the intermediate layers of the same metal but rather, use miscellaneous metals for the intermediate layers. In case the activity carrier is to be enclosed by a electrodeposited cover layer, gold may preferably be used for this purpose. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 illustrates a preferred embodiment of the electrolytic cell according to the invention; 
     FIG. 2 illustrates a) non-coated and b) coated tube-shaped carrier elements employed in a preferred embodiment; and 
     FIG. 3 illustrates the coated tube-shaped elements “threaded” on a wire which, in their entirety, represent the ruthenium-106 radiation source. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In a preferred embodiment, the intermediate layers are also produced of gold where commercially available gold baths from the Degussa company may be used. Thus, it was found advantageous to select the Auruna® 311 electrolyte for the first gold layer on the carrier, which serves as an adhesion promoter between the carrier and the first ruthenium layer, and the Auruna® 533 electrolyte for the intermediate layers. If the radiation source is to be enclosed by a electrodeposited cover layer, the Auruna® 533 electrolyte is suitable in generating a hard gold layer in this case as well. 
     According to the invention, carriers made of brass, copper, alloyed steels, nickel, titanium, or alloys thereof, silver, gold, or platinum metals are possible as metallic carriers which simultaneously function as cathode. Preferably, nitinol or gold are used as carrier material. According to the invention, polymers modified at their surface, i.e., rendered electroconductive, may also be used as carriers. The carrier may have any desired shape or form. Likewise, it may be comprised of multiple carrier elements, each of which having the multilayer system. A tube or multiple tube-shaped elements, a single wire, or an array of multiple wires, a structured or non-structured foil, a mesh, a rotationally symmetrical molded body, or a sphere may be used as carrier. It is preferred to use a wire or a tube. In a particularly preferred embodiment, tube-shaped elements having a circular cross-section are used as carriers, which elements most preferably may consist of gold, the outer diameter at their ends being larger in size than that in the intermediate section (cf., FIG. 2 a ). In a preferred variant, the outer diameter of the tube-shaped elements is up to 0.6 mm at their ends, and up to 0.3 mm in the intermediate section. The length of the elements is 0.5-70 mm, depending on the desired use and the flexibility required. After the intermediate section has been coated according to the invention, preferably using multiple ruthenium layers and one cover layer, the tube-shaped elements now having a uniform outer diameter of e.g. 0.6 mm over their entire length (cf., FIG. 2 b ) are pushed on a flexible wire and secured against falling off at the ends thereof (e.g. by welding an end piece thereto). In their entirety, these tube-shaped elements “threaded” on the wire constitute the  106 Ru radiation source (cf., FIG.  3 ). As a result of the individual free rotatability of each single element, particularly good flexibility of this radiation source is established. 
     The pretreatment of the carrier which is used is of essential importance for the adherence of the multilayered coating according to the invention. The carrier has to be degreased, and oxide layers possibly present and—should the occasion arise—tightly adhering particles have to be removed. When using nitinol as carrier, final pickling using a mixture of hydrofluoric acid and hydrochloric acid has proven advantageous. In a preferred embodiment, a gold layer as adhesion promoter is coated as first layer on the nitinol carriers. 
     If the carriers are made of gold, previous gilding can obviously be omitted. If tube-shaped elements as described above are to be coated, the sections at their ends which should remain free have to be coated with a masking lacquer. 
     The inventive electrolytic deposition of the ruthenium layers proceeds under observance of the following operating parameters: The ruthenium concentration at the beginning of the electrolysis typically is 5 g/l and may drop down to 0.2 g/l as a result of ruthenium depletion. The temperature should be between 60 and 75° C., preferably 70° C., and the pH value must be maintained between 1.3 and 1.8. Ruthenium concentration and pH value are controlled and adjusted at regular intervals. 
     According to the invention, ruthenium-106 radiation sources are provided in this way which have sufficiently thick, well-adhering, crack-free, homogeneous, and flexible radioactive ruthenium layers. 
     In order to achieve a layer thickness of &gt;7 μm, coating of metallic intermediate layers was found to be indispensable. Only in this way the required mechanical stability is achieved, which is necessary for use as a radioactive radiation source of a specific geometry, and only in this way the coating produced using the process according to the invention remains free of visible cracks even on flexible carriers, such as a wire, despite the bending stress typically occurring in radiation sources during use. 
     According to the invention, radioactive ruthenium layers having a thickness of up to 5 μm are achieved when adjusting current densities of between 0.25 and 0.35 A/dm 2 . By multiple coating involving metallic intermediate layers, ruthenium-106 overall layer thicknesses of up to 30 μm are achieved, where the overall layer thickness is understood to be the sum of all radioactive ruthenium layers. The ruthenium radiation sources produced from these multi-coated ruthenium activity carriers have a dose rate of at least 1.5 and up to 15 Gy per minute at a distance of 2 mm (in water). 
     According to the invention, a special electrolytic cell for the preparation of the electrolyte and the subsequent electrolytic deposition of ruthenium has been developed. The electrolytic cell preferably employed according to the invention is comprised of a vessel  1  having a double-jacket  7  for heating. With respect to its dimensions, the electrolytic vessel  1  must comply with the demand for minimum operating volume. Preferably, the operating volume should not exceed 5 ml. Moreover, the electrolytic vessel  1  for preparing and adjusting the electrolyte must be suitable in such a fashion that addition of liquids through an opening  10  and stirring of the electrolyte by means of a stirrer  5  is possible. Also, the cathode  2  should be capable of immersing into the electrolyte in a positioned fashion according to the desired active length. According to the invention, the electrolytic cell has been designed in such a way that cathode  2  is joined to a means for opening the operating space  3 . In a preferred arrangement, the anode  4  coaxially surrounds the cathode  2 . Above the liquid level of the electrolyte, the electrolytic vessel  1  comprises an element  6  for withdrawing gases and vapors, allowing a slight vacuum to be applied permanently. 
     EMBODIMENTS 
     EXAMPLE 1 
     Electrolytic production of radioactive ruthenium layers wherein a nitinol wire 0.3-0.5 mm in diameter is used, and the intermediate layers as well as the cover layer are made of gold. 
     1. Pretreatment 
     Processing sequence of pretreatment (including intermediate rinsing steps): 
     1. Ultrasonic degreasing [40 g/l, 60° C., 2 min, Slotoclean AK 1190 (Schlötter company)] 
     2. Cathodic degreasing [100 g/l, RT, 0.3 min, Slotoclean EL-KG (Schlötter company)] 
     3. Anodic activation (sulfuric acid 5%, RT, 0.25 min) 
     4. Pickling [HF/HCl (4%, 18%), RT, 0.25 min] 
     (optionally repeat 3. and 4. periodically) 
     2. Intermediate layers 
     Previous gilding is used to promote adhesion between the substrate and the Ru layer. The commercial electrolyte Auruna® 311 is selected as primary gold. The previous acid activation is already provided by pickling. Gold is also suitable as intermediate layer between the Ru depositions, to which end the Auruna® 533 electrolyte is selected. Pre-activation is effected by pickling with sulfuric acid (5%, RT, 0.5 min). Both electrolytes are cyanogold complexes from the Degussa company. 
     Process parameters 
     Primary gold: Auruna® 311 (Degussa company, 2 g/l, RT, 10 min, 2 A/dm 2 ) 
     Intermediate layers 
     Auruna® 533 (Degussa company, 8 g/l, 35° C., 7 min, 1 A/dM 2 ) 
     3. Ru deposition 
     The Ru complex RuNC is used as electrolyte. Preparation is effected in advance, directly in the specially developed electrolytic cell. The electrolyte is modified by adding PPS (sulfopropylpyridine, 3 g/l, Raschig company). 
     The operating parameters of the Ru electrolysis are: 
     Ru concentration range: 4.8-0.2 g Ru per 1 
     Current density: 0.25-0.35 A/dm 2    
     Temperature: 70° C. 
     pH value: 1.3-1.8 
     Agitation of bath: none 
     Electrolyte volume (5 ml max.) 
     4. Cover layer 
     For those cases of use where a cover layer is required, such a layer may likewise be produced of hard gold (in analogy to the intermediate layers using Auruna® 533). 
     EXAMPLE 2 
     Production of a radioactive ruthenium radiation source by electrolytic formation of radioactive ruthenium layers on a conductive carrier in such a way that a nitinol tube or wire having an outer diameter of 0.2-0.6 mm is coated over a length of 0.5-7 cm, and intermediate layers as well as a cover layer of gold are used. 
     1. Pretreatment as in Example 1 
     2. Intermediate layers as in Example 1 
     3. Ru deposition as in Example 1 
     4. Cover layer 
     Regarding the production of an enclosed radiation source, the cover layer in its quality parameters must ensure absence of pores to prevent wash-our of radioactive Ru, absence of cracks under mechanical stress typically occurring during use, as well as wear resistance against abrasion on High Density Polyethylene (HDPE). Such a cover layer can be made of hard gold (see Example 1). 
     EXAMPLE 3 
     Production of a radioactive ruthenium radiation source using tube-shaped elements having enlarged outer diameter at their ends. 
     Tube-shaped parts having sectionally varying outer diameters are employed as carriers (overall length: 1.3 mm, diameter at the ends: 0.3 mm, diameter in the intermediate section: 0.2 mm, length of intermediate section: 1 mm). 
     The elements consist of gold and are to be ruthenium-coated on their thin intermediate sections only. This object is accomplished by covering those sections which have to remain free with a non-conductive masking lacquer. 
     The pretreatment of the carriers is performed as described in Example 1, omitting step 4. Previous gilding is not necessary. Ruthenium deposition is effected as in Example 1. The cover layer is coated as described in Example 1. As the cover layer is to be coated on the masked tube sections as well, the masking lacquer is removed therefrom by dissolving in acetone. 
     The tube-shaped elements of uniform length produced in this way are pushed on a wire and secured against falling off at the ends thereof (e.g. by welding an end piece thereto). 
     Depending on the type of use, varying numbers of bodies may be threaded. As a result of the individual free rotatability of the single elements, flexibility of the overall arrangement is established. 
     EXAMPLE 4 
     Production of a radioactive radiation source designed for special mechanical stress, using tube-shaped elements having enlarged outer diameter at their ends. 
     Tube-shaped parts having sectionally varying outer diameters are employed as carriers (overall length: 1.3 mm, diameter at the ends: 0.28 mm, diameter in the intermediate section: 0.2 mm, length of intermediate section: 1 mm). The elements consist of gold or titanium and are to be ruthenium-coated on their thin intermediate sections only. This object is accomplished by covering those sections which have to remain free with a non-conductive masking lacquer. 
     The pretreatment of the carriers is performed as described in Example 1. Ruthenium deposition is effected as in Example 1. Subsequently, the masking lacquer is removed by dissolving in acetone. 
     However, the gold cover layer is not coated. Instead, the tube-shaped parts are inserted in a larger tube of the same material. At the ends thereof, the uncoated edge of the activity carrier (outer diameter: 0.28 mm) is welded with the sealing tube. 
     The tube-shaped elements of uniform length now being encapsulated are pushed on a wire and fixed at both ends. Depending on the type of use, varying numbers of bodies may be threaded. As a result of the individual free rotatability of the single bodies, flexibility of the overall arrangement is established. Owing to the encapsulation of the single bodies, higher stability and, in particular, higher abrasion resistance is achieved. 
     INDEX OF REFERENCE NUMBERS 
     FIG. 1 
       1  Electrolytic vessel 
       2  Cathode 
       3  Means for opening the operating space 
       4  Anode 
       5  Magnetic stirrer 
       6  Element for air withdrawal 
       7  Double jacket 
       8  Lead screening 
       9  Anode contacts 
       10  opening for addition of liquids 
     FIG. 2 
       1  Multiple coating including at least two Ru-106 layers 
       2  Enclosure 
     FIG. 3 
       1  Multiple coating including at least two Ru-106 layers 
       2  Enclosure 
       3  Wire