EP1933331B1 - Système de colonnes destiné à la production d'une solution ayant une activité spécifique élevée - Google Patents

Système de colonnes destiné à la production d'une solution ayant une activité spécifique élevée Download PDF

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Publication number
EP1933331B1
EP1933331B1 EP07024128A EP07024128A EP1933331B1 EP 1933331 B1 EP1933331 B1 EP 1933331B1 EP 07024128 A EP07024128 A EP 07024128A EP 07024128 A EP07024128 A EP 07024128A EP 1933331 B1 EP1933331 B1 EP 1933331B1
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EP
European Patent Office
Prior art keywords
tungsten
solution
generator
chromatography column
stationary phase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07024128A
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German (de)
English (en)
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EP1933331A3 (fr
EP1933331A2 (fr
Inventor
Tuomo Nikula
Raffaella Dr. Perego
Richard Dr. Henkelmann
Andreas Prof. Dr. Türler
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Isotopen Technologien Muenchen AG
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Isotopen Technologien Muenchen AG
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Priority to PL07024128T priority Critical patent/PL1933331T3/pl
Publication of EP1933331A2 publication Critical patent/EP1933331A2/fr
Publication of EP1933331A3 publication Critical patent/EP1933331A3/fr
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    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21H—OBTAINING ENERGY FROM RADIOACTIVE SOURCES; APPLICATIONS OF RADIATION FROM RADIOACTIVE SOURCES, NOT OTHERWISE PROVIDED FOR; UTILISING COSMIC RADIATION
    • G21H5/00—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for 
    • G21H5/02—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for  as tracers
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/0005—Isotope delivery systems
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • G21G2001/0031—Rubidium
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • G21G2001/0042—Technetium
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/001—Recovery of specific isotopes from irradiated targets
    • G21G2001/0073—Rhenium

Definitions

  • the present invention relates to a method and a device for producing radioactive solutions, in particular for medical applications, such as brachytherapy (angioplasty) and oncology (tumor therapy, bone tumor pain therapy, treatment of lung and liver tumors) and in particular a generator for radioactive substances.
  • medical applications such as brachytherapy (angioplasty) and oncology (tumor therapy, bone tumor pain therapy, treatment of lung and liver tumors) and in particular a generator for radioactive substances.
  • a balloon catheter with a dilatation balloon is used to dilate narrowed or occluded blood vessels.
  • a stent which may be adapted for release of drugs, is often implanted in the blood vessel.
  • An alternative method of preventing restenosis is to fill the dilatation balloon with a radioactive fluid that locally vaporizes the vessel walls by the radiation to prevent scarring and thus restenosis.
  • tungsten containing tungsten-188 is first adsorbed in the form of tungstate (WO 4 2- ) onto the solid phase of the chromatography column, which is formed, for example, by aluminum oxide.
  • Tungsten-188 adsorbed on the column disintegrates into rhenium-188 and can be eluted from the generator with a sterile isotonic saline solution (0.9% NaCl).
  • the decay scheme of Wolfram-188 is in Fig. 1 shown.
  • the specific activity is the radioactivity per amount of the solution containing the radioactive substance
  • the specific activity of the eluted solution depends on the one hand on the specific activity of the radioactive material used, which i.a. is determined by the content of tungsten-188 in tungsten, and on the other hand by the generator used.
  • Fig. 2 Figure 4 shows a typical elution profile of a 1.9 Ci (70 GBq) tungsten-188 / rhenium-188 generator system of the prior art.
  • a chromatographic column comprising alumina was filled with a tungsten-containing tungsten solution.
  • the eluate subsequently obtained has a maximum specific activity of 850 MBq / ml in 7 ml of solution eluted from the chromatography column.
  • the specific activity of the eluate can be increased by carrying out a fractionated elution. Without concentration of the eluate, an eluted volume of 15 ml gives an eluted total activity of 60 GBq (1.5 Ci).
  • fractionation when fractionation is carried out, for example, 75% of the total activity obtained without fractionation can be obtained in 7 ml and 60% of the total activity in 4 ml. This means that using fractionation, the activity of the radioactive material in the generator may be lower to obtain the same specific activity of the eluate as without fractionation.
  • Tungsten-188 is prepared by a (2n, 2 ⁇ ) reaction from enriched tungsten-186.
  • the probability of this reaction is low because the cross section for the (2n, 2 ⁇ ) reaction of tungsten-186 is only 36 barn and the cross section for the (n, ⁇ ) reaction of tungsten-187 is only 70 barn.
  • a high neutron flux reactor greater than 10 15 cm -2 s -1 must be used. Therefore, only a few reactors are suitable for the production of tungsten-188.
  • the specific activity of the tungsten used is between 5 and 6 Ci / g.
  • Lower specific activities have been found to be unsuitable for tungsten 188 / rhenium 188 generators, since then a specific activity of the eluate sufficient for medical applications can only be achieved with a laborious concentration, while the specific activity of the eluate is not can be increased by using larger amounts of tungsten having low specific activity or larger columns, since the volume of eluted solution also increases.
  • US 2003/235530 A1 discloses a rhenium-188 generator with an emulsifiable container comprising a matrix with a substantially non-elutable inorganic layered hydroxide compound containing tungsten-188.
  • US-A-5,275,802 discloses a generator system for generating a radioisotope as an acid with a chromatography column in fluid communication with an ion exchange column.
  • the chromatography column is loaded with a parent isotope, eluted with an alkali metal salt solution to obtain the radioisotope as a solution, which intermediate is then passed through the ion exchange column to convert the radioisotope to the carrier-free acid.
  • US-A-3,833,509 discloses a radionuclide generator having a column filled with chromatographic aluminum activated by contacting it with a solution containing a strong monoprotic mineral acid.
  • US 2004/164025 A1 discloses a method for separating ions of metallic elements in an aqueous solution.
  • a disadvantage of the known elution methods is therefore that tungsten having a high specific activity, i. Tungsten containing a high proportion of tungsten-188 must be used or a fractionation or concentration of the eluate must be done to obtain a suitable for angioplasty eluate with high specific activity.
  • a process for producing a radioactive daughter nuclide which comprises the steps of providing a generator having a chromatography column comprising a stationary phase and a parent nuclide adsorbed thereon, wherein the amount of parent nuclide adsorbed is at least 40% of the maximum absorption capacity of the stationary phase, and eluting the daughter nuclide from the chromatography column.
  • the amount of the adsorbed parent nuclide may also preferably comprise 60% of the maximum absorption capacity of the stationary phase or more.
  • a higher specific activity of the eluate is achieved by providing a larger proportion of the available solid surface adsorption surface with parent nuclides so that more daughter nuclides can be eluted with the same amount of solvent. This is done inter alia by optimizing one or more of the parameters, including loading time, tungsten concentration, pH and tungsten oxidation state.
  • the method according to the invention comprises the step of filling the chromatography column with alumina (Al 2 O 3 ) as a stationary phase.
  • alumina Al 2 O 3
  • suitable materials besides alumina such as silica gel, zirconium oxide, manganese oxide, tin oxide and mixtures thereof, are conceivable.
  • the invention comprises filling the chromatography column with a radioactive substance or a mother nuclide in a solution.
  • the parent nuclide is preferably tungsten-containing tungsten, which is absorbed as tungstate (WO 4 2- ) on alumina and introduced into the chromatography column, with the tungsten-188 contained therein decomposing into rhenium-188. It is, however Other radioactive substances are conceivable, such as molybdenum-99, which decomposes into technetium-99, and strontium-82, which decomposes into rubidium-82.
  • the method according to the invention comprises the step of oxidizing the radioactive solution before filling the column with H 2 O 2 and preferably 30% H 2 O 2 .
  • the process after oxidizing preferably comprises acidifying the solution with HCl.
  • the elution is carried out with a 0.9% NaCl solution as solvent.
  • NaCl is well suited for radiomedical applications because it is compatible with the human body.
  • the method of the invention may also comprise concentrating the eluate, thereby achieving even higher specific activity.
  • the method of the present invention for achieving higher specific activity may also include fractionating the eluate.
  • a radioactive substance generator having a chromatography column comprising a stationary phase and a parent nuclide adsorbed thereon, wherein the amount of absorbed parent nuclide comprises at least 40% of the maximum absorption capacity of the stationary phase.
  • the amount of the adsorbed parent nuclide may also preferably comprise 60% of the maximum absorption capacity of the stationary phase or more.
  • the stationary phase in the chromatography column comprises alumina (Al 2 O 3 ) and the parent nuclide tungsten-188 absorbed thereon, which decomposes into rhenium-188.
  • the specific activity of the tungsten is at least 5 Ci / g.
  • tungsten-containing tungsten having 2.5-3.5 Ci / g as the source of rhenium-188 for angioplasty can be used in the generator of the present invention without the need to fractionate or concentrate the eluate.
  • the chromatographic column of the generator comprises a volume of at least 2.4 cm 3 , preferably at least 3.5 cm 3 and more preferably 4.7 cm 3 or more.
  • the generator may comprise a pump with which a solution can be pumped through the chromatographic column.
  • the pump can be replaced by an evacuated sterile glass vessel.
  • the generator comprises a shielded housing in which the chromatography column is accommodated.
  • tungsten-188 / rhenium-188 generator system For example, the cumulative activity achieved with a tungsten-188 / rhenium-188 generator of the present invention is plotted as a percentage of the total activity eluted per elution versus elution volume for various amounts of tungsten absorbed on the stationary phase of a chromatography column.
  • FIG. 4 Examples given were obtained with 8 g of dry alumina as the absorbent material as a stationary phase and a column length of about 3 cm.
  • the increase in specific activity occurs particularly when increasing the amount of parent nuclide adsorbed on the chromatographic column from 9% to 60%, while changing the amount of the absorbent parent nuclide between 1% and 9% shows no appreciable change in specific activity ,
  • the amount of tungsten 188 in the total amount of tungsten charged to the chromatography column can be reduced as the amount of tungsten adsorbed on the solid phase of the chromatography column is increased.
  • tungsten with constant specific activity a higher specific activity of the eluate can be obtained without additional fractionation or concentration.
  • Fig. 4 the amount of tungsten absorbed on a chromatographic column filled with alumina is plotted as a function of the amount of tungsten incorporated into the chromatography column.
  • the y 1 -axis represents the absolute value of the absorbed tungsten in mg / g and the y 2 -axis represents the proportion of the absorbed tungsten in relation to the introduced amount of tungsten in percent.
  • the maximum capacity of the absorbent material can be determined. It can be seen that when the column is loaded with up to about 120 mg / g tungsten is quantitatively absorbed and at higher loadings increasing amounts of tungsten are no longer absorbed. This suggests that the maximum capacity of the absorbent material is about 120 mg. Tungsten per gram of alumina.
  • Fig. 5 Measurements are reproduced reproducing the elution behavior of the chromatography column with increasing volume. On the y-axis, the sum of the activity is represented as a percentage of the total eluted activity. As in FIG. 5 As can be seen, the volume of the chromatography column of 2.4 cm 3 can be more than doubled with only slight changes in the elution profile.
  • FIG. 6 a schematic representation of the generator according to the invention is shown.
  • the generator comprises a lead shield 1, in the interior of which a chromatography column 3 made of quartz glass is placed, which is filled with aluminum oxide.
  • the stationary phase of the chromatographic column comprises alumina with tungsten adsorbed thereon which contains a proportion of tungsten-188 which decomposes into rhenium-188.
  • a container 5 with a sterile isotonic saline solution (0.9% NaCl) is arranged at the top of the generator.
  • the container 5 is closed with a rubber seal 7.
  • Two needles 9, 11 penetrate the rubber seal 7 and are arranged in the container 5.
  • One of the needles 9 allows the entry of air into the container 5 through a sterile filter 13, while the second needle 11 leads into the interior of the column 3.
  • a vacuum container 15 is disposed above the generator. The vacuum causes the elution solution to be pumped out of vessel 5 through the generator system so that rhenium-188 is eluted from the column.
  • the produced eluate can for medical applications, such as in a dilatation catheter.
  • the exemplified tungsten 188 / rhenium 188 generator has a tungsten 188 activity of 111 GBq.
  • 8 g of dry alumina, to which an acetate buffer is added as a stabilizing agent, are introduced into a chromatography column made of quartz glass, in which a filter is arranged on the bottom side.
  • the volume of the column remaining above the alumina is made up with glass wool and the column is sealed with two septa (top and bottom). Subsequently, the chromatography column is placed in the shield 1 of the generator.
  • the tungsten-188 is contained in a solution of sodium tungstate (Na 2 188 WO 4 ) in which the specific activity of tungsten-188 is about 200 GBq / g.
  • the chromatography column is filled with the solution containing Tungsten-188 by drawing the solution through the chromatography column by means of a vacuum pump.
  • the column is then rinsed with 15 ml of a stabilizer. Thereafter, the column is rinsed with several ml of a saline solution (NaCl 0.9%). Then the generator is ready for use. It may have an elution profile corresponding to an in Fig. 3 shown curve with a tungsten content of 60% of the maximum capacity.
  • the efficiency of the generator is initially about 80% of the available rhenium-188 and is in the range of 70-80% for at least 2 half lives of tungsten-188.

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  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)

Claims (11)

  1. Procédé de fabrication d'un nucléide fille radioactif, comprenant les étapes suivantes :
    la préparation d'un générateur comprenant une colonne chromatographique, qui comprend une phase stationnaire et un nucléide mère adsorbé sur celle-ci, et
    l'élution du nucléide fille de la colonne chromatographique, caractérisé par le remplissage de la colonne chromatographique avec un nucléide mère dans une solution, la solution ayant été oxydée et acidifiée avant le remplissage, et la quantité du nucléide mère adsorbé étant d'au moins 40 % de la capacité d'adsorption maximale de la phase stationnaire.
  2. Procédé selon la revendication 1, caractérisé en ce qu'il comprend le remplissage de la colonne chromatographique avec de l'oxyde d'aluminium (Al2O3), de l'oxyde de zirconium (ZiO2), de l'oxyde de manganèse (MnO2) ou de l'oxyde de titane (TiO2) ou un de leurs mélanges en tant que phase stationnaire.
  3. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il comprend l'oxydation de la solution avec H2O2.
  4. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il comprend l'acidification de la solution avec HCl.
  5. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le nucléide mère est le tungstène 188 dans une solution de Na2 188WO4, qui se décompose en rhénium 188.
  6. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il comprend l'élution avec une solution de NaCl à 0,9 % en tant que solvant.
  7. Générateur de substances radioactives à colonne chromatographique (3), qui comprend une phase stationnaire et un nucléide mère adsorbé sur celle-ci, caractérisé en ce que la quantité du nucléide mère adsorbé est d'au moins 40 % de la capacité d'adsorption maximale de la phase stationnaire, la colonne chromatographique étant remplie avec le nucléide mère dans une solution qui a été oxydée et acidifiée avant le remplissage.
  8. Générateur selon la revendication 7, caractérisé en ce que la phase stationnaire comprend de l'oxyde d'aluminium (Al2O3) et le nucléide mère tungstène 188 adsorbé sur celui-ci, qui se décompose en rhénium 188.
  9. Générateur selon la revendication 7 ou 8, caractérisé en ce que la colonne chromatographique (3) présente un volume de 2,4 cm3, de préférence de 3,5 cm3 et de manière particulièrement préférée de 4,7 cm3.
  10. Générateur selon l'une quelconque des revendications 7 à 9, caractérisé en ce qu'il comprend une pompe (15) avec laquelle une solution peut être pompée dans la colonne chromatographique (3).
  11. Générateur selon l'une quelconque des revendications 7 à 10, caractérisé en ce qu'il comprend un boîtier blindé (1) dans lequel la colonne chromatographique (3) est logée.
EP07024128A 2006-12-12 2007-12-12 Système de colonnes destiné à la production d'une solution ayant une activité spécifique élevée Active EP1933331B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL07024128T PL1933331T3 (pl) 2006-12-12 2007-12-12 System kolumnowy do produkcji roztworu o wysokiej aktywności właściwej

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE102006058542A DE102006058542A1 (de) 2006-12-12 2006-12-12 Säulensystem zur Herstellung einer Lösung mit hoher spezifischer Aktivität

Publications (3)

Publication Number Publication Date
EP1933331A2 EP1933331A2 (fr) 2008-06-18
EP1933331A3 EP1933331A3 (fr) 2010-04-14
EP1933331B1 true EP1933331B1 (fr) 2013-01-23

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EP (1) EP1933331B1 (fr)
DE (2) DE102006058542A1 (fr)
PL (1) PL1933331T3 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103454364B (zh) * 2012-05-28 2015-12-09 原子高科股份有限公司 一种用于发生器的色谱柱装置
RU2736600C1 (ru) * 2019-07-02 2020-11-19 Федеральное государственное автономное образовательное учреждение высшего образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" Способ получения радионуклидного генератора актиния-228
CN115518199A (zh) * 2022-11-01 2022-12-27 陈先凤 能改善面部凹陷皱纹的自体胶原再生组合物及制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3664964A (en) * 1968-07-03 1972-05-23 Squibb & Sons Inc Eluent for radioisotopes
US3833509A (en) * 1971-09-02 1974-09-03 Mallinckrodt Chemical Works Radionuclide generator production method
CA1169773A (fr) * 1979-04-17 1984-06-26 Karel J. Panek Preparation et utilisation d'un liquide renfermant su195m xxau
NL8000125A (nl) * 1980-01-09 1981-08-03 Byk Mallinckrodt Cil Bv Werkwijze ter bereiding van een een radioisotoop bevattende vloeistof voor radiofarmaceutische toepassing en isotopengenerator geschikt om deze vloeistof te bereiden.
US5186913A (en) 1991-04-26 1993-02-16 Martin Marietta Energy Systems, Inc. Tungsten-188/carrier-free rhenium-188 perrhenic acid generator system
US20030152502A1 (en) 2001-12-18 2003-08-14 Lewis Robert E. Method and apparatus for separating ions of metallic elements in aqueous solution
US7329400B2 (en) * 2002-06-19 2008-02-12 Lynntech, Inc. Generator for rhenium-188

Also Published As

Publication number Publication date
DE202006020604U1 (de) 2009-02-26
PL1933331T3 (pl) 2013-05-31
EP1933331A3 (fr) 2010-04-14
DE102006058542A1 (de) 2008-06-19
EP1933331A2 (fr) 2008-06-18

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