TWI451444B - Germanium -68 / gallium-68 radioactive nuclear species generator device - Google Patents
Germanium -68 / gallium-68 radioactive nuclear species generator device Download PDFInfo
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Description
本發明係一鎵-68放射性核種發生器之新穎組構方法，即以兩種洗離液分別通過兩種鍺-68吸附劑，可分別淘洗出不同化學形式鎵-68核種之新穎鍺。The invention relates to a novel composition method of a gallium-68 radioactive nuclear generator, that is, two kinds of washing liquids respectively pass through two kinds of strontium-68 adsorbents, and the novel hydrazines of different chemical forms of gallium-68 nucleus can be eluted separately.
由於母核種鍺-68半衰期長，鍺-68/鎵-68核種發生器可使用長達一年以上，可穩定提供鎵-68核種。Due to the long half-life of the mother nucleus 68-68, the 锗-68/gallium-68 nucleus generator can be used for more than one year, and the gallium-68 nucleus can be stably supplied.
以往鍺-68是吸附於二氧化矽、氧化鋁或二氧化錫等無機物，製作成鎵-68核種發生器。這些都有使用上不方便之處，例如：如果發生器是以氧化鋁為吸附管，便需利用EDTA(ethylediaminetetraacetic acid)溶液淘洗出子核種鎵-68。由於鎵-68-EDTA是結構相當穩定的錯化物，需要一些複雜的手續使鎵-68轉化成核醫藥物。由於鎵-68半衰期短，轉化程序會致使劑量耗損。如果發生器是以氧化錫為吸附管，便需利用1N以上之HCl溶液淘洗出子核種鎵-68，此時鎵-68核種以氯化鎵之化學形式存在，經過中和後使用。但微量無機鹽類會被強酸(HCl濃度大於1N)溶液溶解帶出，容易造成金屬離子污染。其便利性為容易於進行鎵-68核種之後續與配位基(Ligand)之標幟(labelling)工作。In the past, 锗-68 was adsorbed to an inorganic substance such as cerium oxide, aluminum oxide or tin dioxide to prepare a gallium-68 nuclear generator. These are inconvenient to use, for example, if the generator is made of alumina as a sorbent tube, it is necessary to elute the nucleus gallium-68 with EDTA (ethylediaminetetraacetic acid) solution. Since gallium-68-EDTA is a fairly stable structurally complex, some complicated procedures are required to convert gallium-68 into nuclear medicine. Due to the short half-life of gallium-68, the conversion procedure causes dose depletion. If the generator is made of tin oxide as the adsorption tube, the sub-nuclear gallium-68 needs to be eluted with a HCl solution of 1 N or more. At this time, the gallium-68 nucleus is present in the chemical form of gallium chloride, and is used after neutralization. However, trace inorganic salts are dissolved by a strong acid (HCl concentration greater than 1N) solution, which is likely to cause metal ion contamination. The convenience is that it is easy to carry out the labelling work of the gallium-68 nucleus and the Ligand labelling.
以二氧化矽、氧化鋁或二氧化錫等無機物吸附鍺-68所製作成鎵-68核種發生器，其共同的特點如下：(1)以較高濃度之強酸(HCl濃度大於1N)溶液形式存在(2)容易造成金屬離子污染(3)如需鎵-68-檸檬酸鎵之化學形式時，較為耗時，且操作人員所接受之輻射劑量偏高，並不利藥物之生產或臨床之使用(4)鎵-68核種以氯化鎵之化學形式存在時，無法直接於臨床上直接使用，需進行鎵-68核種之後續與配位基(ligand)之標幟(labelling)工作。The gallium-68 nuclear generator is prepared by adsorbing yttrium-68 with an inorganic substance such as cerium oxide, aluminum oxide or tin dioxide. The common features are as follows: (1) a solution of a high concentration of strong acid (HCl concentration greater than 1 N) Existence (2) easy to cause metal ion pollution (3) If the chemical form of gallium-68-gallium citrate is required, it is time consuming and the radiation dose received by the operator is high, which is not conducive to the production or clinical use of the drug. (4) When the gallium-68 nucleus is present in the chemical form of gallium chloride, it cannot be directly used directly in the clinic. It is necessary to carry out the labelling work of the gallium-68 nucleus and the ligand.
而以有機樹脂吸附鍺-68製作之鎵-68核種發生器，其特點如下：(1)需以稀檸檬酸鈉或磷酸鈉溶液淘洗鎵-68核種(2)以鎵-68-檸檬酸鎵之化學形式存在(3)不易造成金屬離子污染(4)如需鎵-68-氯化鎵之化學形式時，較為耗時，且操作人員所接受之輻射劑量偏高，並不利藥物之生產或臨床之使用。The gallium-68 nuclear generator made by adsorbing yttrium-68 with organic resin has the following characteristics: (1) it is necessary to wash the gallium-68 nucleus with dilute sodium citrate or sodium phosphate solution (2) with gallium-68-citric acid The chemical form of gallium exists (3) It is not easy to cause metal ion pollution. (4) If the chemical form of gallium-68-gallium chloride is required, it is time consuming and the radiation dose received by the operator is high, which is not conducive to the production of the drug. Or clinical use.
蓋鎵-68核種於PET核醫藥物之應用日趨廣泛，單一離子形式之鎵-68核種發生器已不足以因應多元發展之鎵-68核醫藥物之應用上，又目前文獻與專利發明中，如美國專利申請號12/745,715係自Fe(III)經由自動化裝置進行純化，製作單一化學型式之鎵-68核種；另外，美國專利申請號60/928,723係利用洗離液及吸附劑管柱之多重純化操作，製作單一化學型式之鎵-68核種，並無如同本發明所述結合兩種不同之洗離液及兩種不同之吸附劑管柱之操作過程，可獲得不同化學型式之鎵-68核種，即鎵-68檸檬酸鎵與鎵-68氯化鎵。The application of Gallium-68 nucleus in PET nuclear medicine is becoming more and more widespread. The single-ion form of gallium-68 nuclear generator is not enough for the application of multi-developed gallium-68 nuclear medicine, and the current literature and patent invention. For example, U.S. Patent Application Serial No. 12/745,715, which is based on the purification of Fe(III) from an automated device, produces a single chemical type of gallium-68 nucleus; in addition, U.S. Patent Application Serial No. 60/928,723 utilizes a rinsing and sorbent column. Multiple purification operations to produce a single chemical type of gallium-68 nucleus, without the operation of combining two different eluents and two different sorbent columns as described in the present invention, obtaining gallium of different chemical forms - 68 nuclear species, namely gallium-68 gallium citrate and gallium-68 gallium chloride.
本發明之目的在提出一種新穎性鎵-68放射性核種發生器之組構方法，即以兩種洗離液分別通過兩種鍺-68吸附劑，可分別淘洗出不同化學形式鎵-68核種之鍺-68/鎵-68核種發生器。The object of the present invention is to propose a novel gallium-68 radionuclear generator assembly method, that is, two kinds of eluent respectively can be used to separately elute different chemical forms of gallium-68 nuclear species through two kinds of cesium-68 adsorbents. After the -68 / gallium - 68 nuclear generator.
蓋鎵-68核種於PET核醫藥物之應用日趨廣泛，單一離子形式之鎵-68核種發生器已不足以因應多元發展之鎵-68核醫藥物之應用，又目前文獻與專利發明中，並無如同本發明，係以兩種洗離液分別通過兩種鍺-68吸附劑，分別淘洗出不同化學形式鎵-68核種之新穎鍺-68/鎵-68核種發生器。鎵-68檸檬酸鎵溶液或鎵-68氯化鎵溶液，可用以與螯合劑DotA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)螯合的放射線同位素溶液。The application of Gallium-68 nucleus in PET nuclear medicine is becoming more and more widespread. The single-ion form of gallium-68 nuclear generator is not enough for the application of multi-developed gallium-68 nuclear medicine, and the current literature and patent invention, and In the absence of the present invention, the novel 锗-68/gallium-68 nucleus generators of different chemical forms of gallium-68 nucleus were separately eluted by two kinds of eluents through two 锗-68 adsorbents. Gallium-68 gallium citrate solution or gallium-68 gallium chloride solution, which can be used to chelate the radioisotope solution with the chelating agent DotA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) .
本發明利用有機樹脂吸附鍺-68，以稀檸檬酸鈉或磷酸鈉溶液淘洗鎵-68核種時，便不致產生金屬離子污染淘洗液，此時鎵-68核種以檸檬酸鎵之化學形式存在，雖應用範圍較鎵-68-氯化鎵較為狹窄，惟其優點為所含之金屬離子含量較為輕微，鍺-68總量約為0.0004%。The invention utilizes an organic resin to adsorb 锗-68, and when the gallium-68 nucleus is eluted with a dilute sodium citrate or a sodium phosphate solution, the metal ion-contaminated elution liquid is not generated, and the gallium-68 nucleus is in the chemical form of gallium citrate. Existence, although the application range is narrower than gallium-68-gallium chloride, the advantage is that the metal ion content is relatively slight, and the total amount of strontium-68 is about 0.0004%.
此外，鎵-68核種適合用於PET(正子造影)核醫藥物分子之標幟，例如：藉由交聯(cross-link)的方式與配位基或胜肽(peptide)或某一種蛋白質等共價鍵結，可用於腫瘤造影診斷之造影應用。In addition, the gallium-68 nucleus is suitable for use in PET (positive angiography) nuclear medicine molecules, for example, by cross-linking with ligands or peptides or a certain protein. Covalent bonding, can be used for angiographic applications of tumor imaging diagnosis.
蓋鎵-68為鍺-68衰變時產生之子核種，鍺-68半衰期長達271天，最大能量511KeV，是鎵-69利用迴旋加速器照射產生，核反應式69 Ga(p,2n)68 Ge，鎵-68半衰期68.1分鐘，最大能量β+ =1.89MeV，鎵-68由於半衰期短，並以正子形式衰變，主要用於製備核醫藥物臨床診斷之正子造影劑，且非常適合於未有迴旋加速器之醫院或研究單位使用。Gallium-68 is a daughter nucleus produced when 锗-68 decays. The half-life of 锗-68 is 271 days, and the maximum energy is 511KeV. It is produced by gallium-69 by cyclotron radiation, and the nuclear reaction is 69 Ga(p, 2n) 68 Ge, gallium. -68 half-life of 68.1 minutes, maximum energy β + = 1.89MeV, gallium-68 due to short half-life, and decay in the form of positrons, mainly used in the preparation of nuclear diagnostics for the diagnosis of nuclear medicine, and is very suitable for the absence of cyclotron Used by hospitals or research units.
本發明之目的及特徵在於，結合以兩種不同之洗離液及兩種不同之吸附劑管柱之操作過程，可獲得不同化學型式之鎵-68核種，即鎵-68檸檬酸鎵與鎵-68氯化鎵。第一圖係本發明之鎵-68產生器所使用之操作流程方塊圖，其中以兩種洗離液分別通過兩種鍺-68吸附劑，分別淘洗出不同化學形式鎵-68核種之詳細說明如第二圖所示。The object and the feature of the present invention is that a combination of two different eluents and two different adsorbent columns can obtain different chemical types of gallium-68 nucleus, namely gallium-68 gallium citrate and gallium. -68 gallium chloride. The first figure is a block diagram of the operation flow used in the gallium-68 generator of the present invention, in which two kinds of washing liquids are respectively used to wash out the details of different chemical forms of gallium-68 nuclear species through two kinds of strontium-68 adsorbents. The description is shown in the second figure.
如第二圖所示，本發明之組構方法包含：(1)第一洗離液瓶1，內裝0.1M之檸檬酸鈉溶液sodium citrate(2)第二洗離液瓶2，內裝0.1M之鹽酸溶液(hydrogen chloride)(3)有機樹脂吸附劑管柱3(styrene-divinylbenzene copolymer column)(4)無機樹脂吸附劑管柱4(TiO2 column)(5)矽膠萃取吸附管5(silica-gel cartridge)(6)檸檬酸鈉儲備溶液6(sodium citrate stock)。經前述方法生成兩種化學形式之放射線同位素溶液，包含(7)放射線同位素溶液鎵-68檸檬酸鎵溶液7，以及(8)放射線同位素溶液鎵-68氯化鎵溶液8，其可用於PET造影診斷等不同應用領域的多功能應用。As shown in the second figure, the method of the present invention comprises: (1) a first eluent bottle 1 containing 0.1 M sodium citrate solution sodium citrate (2) a second eluent bottle 2, containing 0.1M hydrochloric chloride (3) styrene-divinylbenzene copolymer column (4) inorganic resin adsorbent column 4 (TiO2 column) (5) silicone extracting adsorption tube 5 (silica -gel cartridge) (6) sodium citrate stock 6 (sodium citrate stock). Two chemical forms of radioisotope solution are generated by the foregoing method, including (7) a radioactive isotope solution gallium-68 gallium citrate solution 7, and (8) a radioactive isotope solution gallium-68 gallium chloride solution 8, which can be used for PET imaging Versatile applications for different application areas such as diagnostics.
鎵-68檸檬酸鎵之取得，如第二圖所示，可透過兩種方式：第一種，抽出第一洗離液瓶1中之檸檬酸鈉溶液，使其通過有機樹脂吸附劑管柱3後，流出放射線同位素溶液鎵-68檸檬酸鎵溶液7；第二種，將放射線同位素溶液鎵-68氯化鎵溶液8通過檸檬酸鈉儲備溶液6，再與第一洗離液瓶1中的檸檬酸鈉溶液混合後，即可獲得放射線同位素溶液鎵-68檸檬酸鎵溶液7'。The gallium-68 gallium citrate can be obtained in two ways as shown in the second figure: the first one, the sodium citrate solution in the first eluent bottle 1 is taken out and passed through the organic resin adsorbent column. After 3, the radiation isotope solution gallium-68 gallium citrate solution 7 is discharged; the second, the radiation isotope solution gallium-68 gallium chloride solution 8 is passed through the sodium citrate stock solution 6, and then with the first eluent bottle 1 After the sodium citrate solution is mixed, the radiation isotope solution gallium-68 gallium citrate solution 7' can be obtained.
鎵-68氯化鎵之取得，如第二圖所示，可透過兩種方式：第一種，抽出第二洗離液瓶2中之鹽酸溶液，使其通過無機樹脂吸附劑管柱4後，流出放射線同位素溶液鎵-68氯化鎵溶液8；第二種，將放射線同 位素溶液鎵-68檸檬酸鎵溶液7通過有機樹脂吸附劑管柱3後，使其流過矽膠萃取吸附管5，再以第二洗離液瓶2中之鹽酸溶液洗離，即可獲得放射線同位素溶液鎵-68氯化鎵溶液8'。The gallium-68 gallium chloride is obtained, as shown in the second figure, in two ways: first, the hydrochloric acid solution in the second rinse bottle 2 is taken out and passed through the inorganic resin adsorbent column 4 , the radiation isotope solution gallium-68 gallium chloride solution 8; the second, the radiation is the same The gallium solution gallium-68 gallium citrate solution 7 passes through the organic resin adsorbent column 3, and then flows through the silicone extraction adsorption tube 5, and then is washed away with the hydrochloric acid solution in the second rinse bottle 2 to obtain The radioactive isotope solution gallium-68 gallium chloride solution 8'.
前述方法中，第二圖所示之開關閥51與開關閥52為同時開啟或關閉，開關閥61與開關閥62為同時開啟或關閉。In the foregoing method, the on-off valve 51 and the on-off valve 52 shown in the second figure are simultaneously opened or closed, and the on-off valve 61 and the on-off valve 62 are simultaneously opened or closed.
1‧‧‧第一洗離液瓶1‧‧‧First wash bottle
2‧‧‧第二洗離液瓶2‧‧‧Second wash bottle
3‧‧‧有機樹脂吸附劑管柱3‧‧‧Organic resin adsorbent column
4‧‧‧無機樹脂吸附劑管柱4‧‧‧Inorganic resin adsorbent column
5‧‧‧矽膠萃取吸附管5‧‧‧矽 glue extraction adsorption tube
51、52、61、62‧‧‧開關閥51, 52, 61, 62‧‧‧ switch valves
6‧‧‧檸檬酸鈉儲備溶液6‧‧‧Sodium Citrate Stock Solution
7,7'‧‧‧放射線同位素溶液鎵-68檸檬酸鎵溶液7,7'‧‧‧radiation isotope solution gallium-68 gallium citrate solution
71、81‧‧‧開關閥71, 81‧‧‧ switch valve
8,8'‧‧‧放射線同位素溶液鎵-68氯化鎵溶液8,8'‧‧‧radiation isotope solution gallium-68 gallium chloride solution
第1圖為本發明之鎵-68產生器所使用之操作流程方塊圖。Figure 1 is a block diagram showing the operational flow used by the gallium-68 generator of the present invention.
第2圖為本發明之鎵-68結構配置圖。Figure 2 is a structural view of the gallium-68 structure of the present invention.
1‧‧‧第一洗離液瓶1‧‧‧First wash bottle
2‧‧‧第二洗離液瓶2‧‧‧Second wash bottle
3‧‧‧有機樹脂吸附劑管柱3‧‧‧Organic resin adsorbent column
4‧‧‧無機樹脂吸附劑管柱4‧‧‧Inorganic resin adsorbent column
5‧‧‧矽膠萃取吸附管5‧‧‧矽 glue extraction adsorption tube
6‧‧‧檸檬酸鈉溶液6‧‧‧Sodium citrate solution
7,7'‧‧‧放射線同位素溶液鎵-68檸檬酸鎵溶液7,7'‧‧‧radiation isotope solution gallium-68 gallium citrate solution
8,8'‧‧‧放射線同位素溶液鎵-68氯化鎵溶液8,8'‧‧‧radiation isotope solution gallium-68 gallium chloride solution
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| US6479920B1 (en) * | 2001-04-09 | 2002-11-12 | Wisconsin Alumni Research Foundation | Direct charge radioisotope activation and power generation |
| TWI274044B (en) * | 2005-07-08 | 2007-02-21 | Atomic Energy Council | Method for recycling Zn-68 from residuary solution of radioactive isotope Ga-67 |
| TW201127477A (en) * | 2010-02-11 | 2011-08-16 | Atomic Energy Council | Method for making carrier-free radioactive isotopic gallium-67 |
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| US6479920B1 (en) * | 2001-04-09 | 2002-11-12 | Wisconsin Alumni Research Foundation | Direct charge radioisotope activation and power generation |
| TWI274044B (en) * | 2005-07-08 | 2007-02-21 | Atomic Energy Council | Method for recycling Zn-68 from residuary solution of radioactive isotope Ga-67 |
| TW201127477A (en) * | 2010-02-11 | 2011-08-16 | Atomic Energy Council | Method for making carrier-free radioactive isotopic gallium-67 |
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| TWI620200B (en) * | 2015-02-09 | 2018-04-01 | 阿海珐集團公司 | Radionuclide generation system |
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