TWI717590B - DEVICE AND METHOD FOR PROCESSING [GA]GACl SOLUTION AND DEVICE AND METHOD FOR LABELLING GA POSITRON EMITTING RADIOISOTOPE - Google Patents

Abstract

The present invention provides a device and method for processing [⁶⁸Ga]GaCl₃ solution and device and method for labelling ⁶⁸Ga positron emitting radioisotope.

Description

A [68Ga] gallium trichloride solution processing device and processing method and 68Ga positron radioisotope Marking device and marking method of prime mark

The present invention relates to a [ ⁶⁸ Ga] gallium trichloride solution processing device and processing method, as well as a ⁶⁸ Ga positron radioisotope marking device and marking method.

⁶⁸ Ga-labeled radiopharmaceuticals can be used in the diagnosis of many diseases, such as neuroendocrine tumors, prostate cancer, liver cancer and so on. However, in view of the fact that ⁶⁸ Ga nuclei are currently produced by generators, not only the radioactivity of [ ₆₈ Ga]GaCl ₃ extracted from the generator is limited (30-50mCi, and gradually decreases over time) , Causing its activity concentration (activity per unit volume) to be low (6-10mCi/ml, and gradually decrease over time), and even its washing liquid may contain heavy metal ions that are difficult to mark and toxic. For example, Fe, Zn, Cu, etc.

Traditionally, the purification and concentration of [ ⁶⁸ Ga]GaCl ₃ are mostly carried out by segmented elution. However, if this method is used, a segmented collection device that costs millions of yuan is often required, and the hospital nuclear medicine department needs additional space. To place this device and cause inconvenience to clinical pharmacists or pharmaceutical personnel. On the other hand, because a pharmaceutical grade ⁶⁸ Ga generator is usually about 2 million or more and the validity period is only available for one year, 30-50% of the radioactive activity will still be wasted in the process through segmented elution, which is even more costly for hospitals. It is unfavorable. Moreover, if it involves GMP-grade pharmaceutical conditions, the separation collection often requires regular verification to determine the quality of the separation collection. Therefore, in the case of limited manpower and material resources in the hospital, it is quite difficult and difficult to implement ⁶⁸ Ga separation collection. Limitations on the device.

In order to solve the above problems, the present invention provides a [ ⁶⁸ Ga] gallium trichloride solution processing device and processing method. With this invention, not only provides a simple and convenient [68Ga] GaCl ₃ treatment, and thus ^[68 Ga] GaCl ₃ The process kit may be performed in a limited space which was purified and concentrated to obtain a high purity can be used to flag ⁶⁸ Ga / [ ⁶⁸ Ga]GaCl ₃ solution with high activity concentration. It can not only be used in the preparation and synthesis of various ⁶⁸ Ga-labeled radiopharmaceuticals, but also simplify the disposal process to meet the needs of clinical hospitals. Furthermore, the present invention also provides a ⁶⁸ Ga positron radioactive isotope labeling device and labeling method, which directly perform the purification and concentration of [68Ga]GaCl ₃ and directly use various ⁶⁸ Ga labeling precursors (or frozen crystals) with a sterile specification kit. ) To simplify the processing and marking process and reduce the exposure of operators to radiation, and to obtain high purity and high activity concentration ⁶⁸ Ga label radiopharmaceutical products.

According to the literature (F. Rösch, J Postgrad Med Edu Res 2013; 47(1): 18-25.) and related experience of ⁶⁸ Ga, liquid separation collection is not the only way to concentrate [ ⁶⁸ Ga]GaCl ₃ . Since separation and collection is not the only way to concentrate [ ⁶⁸ Ga]GaCl ₃ , in order to achieve high purity and active concentration of [ ⁶⁸ Ga]GaCl ₃ , our reference (Velikyan et al., Am J Nucl Med Mol Imaging 2017 ; 7(3): 111-125) (Mueller et al., Nat Protoc. 2016 June; 11(6): 1057-1066) for solid phase extraction (SPE) of [ ⁶⁸ Ga]GaCl ₃ . What's more, in order for the processed [ ⁶⁸ Ga]GaCl ₃ to perform subsequent ⁶⁸ Ga marking within the proper pH range (pH 4~5), we also designed the processed [ ⁶⁸ Ga]GaCl ₃ solution A buffer for pH adjustment is equipped with a ⁶⁸ Ga-labeled high-purity/high-activity [ ⁶⁸ Ga]GaCl ₃ solution. Finally, in accordance with the requirements of various countries for positron drugs, a label kit for the ⁶⁸ Ga positron radioisotope label was also invented. The sterile kit was used to directly purify and concentrate [ ⁶⁸ Ga]GaCl ₃ and directly use various ⁶⁸ Ga labels. Mark of precursor (or frozen crystal).

The present invention provides a [ ⁶⁸ Ga] gallium trichloride solution processing device, comprising: a first collector, a second collector, a third collector, an extraction device, a three-way valve and a first storage Take the device; the first collector is connected with the extraction device so that the extraction device receives the solution stored in the first collector, the three-way valve is connected with the extraction device, the second collector and the third The collector is connected so that the three-way valve receives the solution processed by the extraction device and sends it to the second collector or the third collector. The first access device is connected to the extraction device to enable the extraction The device receives the solution stored in the first access device.

In one embodiment, the processing device further includes a second access device, the second access device is connected to the third collector, so that the third collector receives the storage in the second access device Solution.

In one embodiment, the extraction device is a solid phase extraction device. In another embodiment, the solution stored in the first access device is a NaCl/HCl extract. In another embodiment, the solution stored in the second access device is an alkaline buffer solution.

In an embodiment, an air filter device may be provided on the first collector, the second collector, and the third collector, respectively.

The present invention also provides a method for processing [ ⁶⁸ Ga] gallium trichloride solution, comprising: (a) performing a ⁶⁸ Ga generator elution in a first collector to obtain a [ ⁶⁸ Ga] gallium trichloride elution (B) The [ ⁶⁸ Ga] gallium trichloride eluent in the first collector is passed through an extraction device to adsorb [ ⁶⁸ Ga] gallium trichloride, and the eluent passing through the extraction device is Collect to a second collector; and (c) pass the NaCl/HCl extract stored in a first access device through the extraction device and collect it in a third collector to obtain a [ ⁶⁸ Ga] trichloro Gallium Concentrate.

In one embodiment, the method further includes adding an alkaline buffer stored in a second access device to the third collector to obtain a [ ⁶⁸ Ga]GaCl ₃ concentrate for marking.

The present invention also provides a ⁶⁸ Ga positron radioisotope label manufacturing device, including: a first collector, a second collector, a third collector, an extraction device, a first three-way valve, a second three Valve, a first access device and a second access device; the first collector is connected with the extraction device so that the extraction device receives the solution stored in the first collector, the first three-way The valve is connected with the extraction device, the second collector, and the second three-way valve so that the first three-way valve receives the solution processed by the extraction device and sends it to the second collector or the second three-way valve. The first access device is connected with the extraction device so that the extraction device receives the solution stored in the first access device, and the second three-way valve is connected to the first three-way valve and a set There is a third collector of a sterilizing filter device and a second access device, so that the second three-way valve receives the solution passing through the first three-way valve or the solution stored in the second access device, and passes The sterilization filter device is collected in the third collector.

In one embodiment, the extraction device is a solid phase extraction device. In another embodiment, the solution stored in the first access device is a NaCl/HCl extract. In another embodiment, the solution stored in the second access device is an alkaline buffer solution.

In an embodiment, an air filter device may be provided on the first collector, the second collector, and the third collector, respectively.

The present invention also provides a method for manufacturing a ⁶⁸ Ga positron radioisotope marker, including: (a) performing a ⁶⁸ Ga generator elution in a first collector to obtain a [ ⁶⁸ Ga] gallium trichloride eluent; b) The [ ⁶⁸ Ga] gallium trichloride eluent in the first collector is passed through an extraction device to adsorb [ ⁶⁸ Ga] gallium trichloride, and the eluent passing through the extraction device is collected to a Second collector; (c) passing the NaCl/HCl extract stored in a first access device through the extraction device and through a sterile filter device, and collect it in a third collector to obtain a marker precursor; And (d) passing the alkaline buffer stored in a second access device through the sterilizing filter device and then adding it to the third collector for reaction to obtain a ⁶⁸ Ga positron radioisotope label.

In one embodiment, the third collector is a frozen crystal bottle.

1:[ ⁶⁸ Ga]GaCl ₃ processing device

1011: First access device

1012: second access device

102: solid phase extraction device

1031: The first air filter device

1032: The second air filter device

1033: Third Air Past Device

1041: First Collector

1042: second collector

1043: Third Collector

1051: The first three-way valve

1052: The second three-way valve

2- ⁶⁸ Ga: Manufacturing device for positron radioisotope mark

201: Filter device for sterilization

Figure 1. Schematic diagram of the processing device for [ ⁶⁸ Ga] gallium trichloride solution.

Figure 2. A schematic diagram of the manufacturing device for the ⁶⁸ Ga positron radioisotope label.

The present invention may be implemented in different forms and is not limited to the examples mentioned in the following text. The following embodiments are only representative of the different aspects and characteristics of the present invention.

In view of the difficulties and limitations derived from the past methods, the inventor of this case is eager to improve and innovate, and after painstaking research, finally designed this [ ⁶⁸ Ga]GaCl ₃ processing device 1 and method (Figure 1) and ⁶⁸ Ga Manufacturing device 2 and method of positron radioisotope marker (Figure 2). Including: [ ⁶⁸ Ga]GaCl ₃ solution processing method, including the following steps: Step 1: Use an empty bottle (first collector, 1041) to perform ⁶⁸ Ga generator elution to obtain [ ⁶⁸ Ga]GaCl ₃ original elution Step 2: Connect the first collector 1041 containing [ ⁶⁸ Ga]GaCl ₃ original eluent to the processing device; Step 3: Use gas to push the original [ ⁶⁸ Ga]GaCl ₃ eluent to make it Pass the solid phase extraction device (102) and the three-way valve (1051) to transfer the washing liquid to the waste liquid bottle (second collector, 1042); Step 4: Use an injection or solution bottle containing NaCl/HCl extract (First access device, 1011) The washing liquid is passed through the solid phase extraction device 102 and the washing liquid is transferred to the third collector (1043), which is [ ⁶⁸ Ga]GaCl ₃ concentrated solution; Step 5: Use an alkaline buffer The liquid injection or solution bottle (second access device, 1012) is injected into the third collector 1043, which is the [ ⁶⁸ Ga]GaCl ₃ concentrate that can be used for subsequent marking.

[ ⁶⁸ Ga] The GaCl ₃ solution processing kit contains the following devices: In addition to all the transmission lines, it also contains an injection or solution bottle containing NaCl/HCl extract (the first access device, 1011), and an alkaline buffer Injection or solution bottle (first access device, 1012), 3 air filter devices (Vent Filter) (first air filter device 1031, second air filter device 1032, third air filter device 1033), 3 different Use empty bottle/collector (first collector 1041-1043), a solid phase extraction tube (102) and a three-way valve (1051).

The manufacturing method of the ⁶⁸ Ga positron radioisotope label includes the following steps: Step 1: Perform elution with the ⁶⁸ Ga generator with an empty bottle (first collector, 1041) to obtain [ ⁶⁸ Ga]GaCl ₃ original eluent; 2: Connect the 1041 containing [ ⁶⁸ Ga]GaCl ₃ original eluent to the manufacturing device; Step 3: Use gas to push the [ ⁶⁸ Ga]GaCl ₃ original eluent through 102 and the three-way valve ( 1051, the first three-way valve) to transfer the washing liquid to the waste liquid bottle (the second collector, 1042); Step 4: Use an injection or solution bottle containing NaCl/HCl extract (the first access device, 1011) Through the solid phase extraction device (102), the three-way valve (1052, the second three-way valve) and the sterilizing filter device (201), the lotion is transferred to the 1043 containing the marker precursor (or a cryocrystal bottle) Direct replacement); Step 5: Take an injection or solution bottle (second access device, 1012) containing alkaline buffer through the three-way valve (1052, the second three-way valve) and the sterilization filter device (201) Inject 1043 (third collector), you can directly carry out ⁶⁸ Ga mark reaction and get the product.

The manufacturing kit for the ⁶⁸ Ga positron radioisotope label contains the following devices: In addition to all transmission lines, it also contains an injection or solution bottle containing NaCl/HCl extraction solution (first access device, 1011), and an alkaline buffer Injection or solution bottles (second access device, 1012), 3 air filter devices (Vent Filter) (1031, 1032, 1033), 1 sterilization filter device (201), 3 empty bottles for different purposes/ Collector (1041-1043), a solid phase extraction tube (102) and two three-way valves (1051, 1052).

1:[ ⁶⁸ Ga]GaCl ₃ processing device

1011: First access device

1012: second access device

102: solid phase extraction device

1031: The first air filter device

1032: The second air filter device

1033: Third Air Past Device

1041: First Collector

1042: second collector

1043: Third Collector

1051: The first three-way valve

1052: The second three-way valve

Claims (13)

A [ ⁶⁸ Ga] gallium trichloride solution processing device, comprising: a first collector, a second collector, a third collector, an extraction device, a three-way valve and a first access device; The first collector is connected with the extraction device so that the extraction device receives the solution stored in the first collector, and the three-way valve is connected with the extraction device, the second collector and the third collector , So that the three-way valve receives the solution processed by the extraction device and sends it to the second collector or the third collector. The first access device is connected to the extraction device so that the extraction device receives the solution Solution stored in the first access device. For the processing device described in the first item of the scope of patent application, the processing device further includes a second access device, and the second access device is connected to the third collector so that the third collector receives the Solution stored in the second access device. The processing device as described in item 1 of the scope of patent application, wherein the extraction device is a solid phase extraction device. The processing device described in the first item of the scope of patent application, wherein the solution stored in the first access device is an NaCl/HCl extract. According to the processing device described in item 2 of the scope of patent application, the solution stored in the second access device is an alkaline buffer solution. A method for processing [ ⁶⁸ Ga] gallium trichloride solution, comprising: (a) performing ⁶⁸ Ga generator elution in a first collector to obtain a [ ⁶⁸ Ga] gallium trichloride eluent; (b) ) The [ ⁶⁸ Ga] gallium trichloride eluent in the first collector is passed through an extraction device to adsorb [ ⁶⁸ Ga] gallium trichloride, and the eluent passing through the extraction device is collected to a first Two collectors; and (c) pass the NaCl/HCl eluate stored in a first access device through the extraction device and collect it in a third collector to obtain a [ ⁶⁸ Ga] gallium trichloride concentrate . Such as the processing method described in item 6 of the scope of patent application, wherein the processing method further comprises adding an alkaline buffer stored in a second access device to the third collector to obtain a [ ⁶⁸ Ga]GaCl for marking ₃ Concentrate. A manufacturing device for the ⁶⁸ Ga positron radioisotope mark, comprising: a first collector, a second collector, a third collector, an extraction device, a first three-way valve, a second three-way valve, a A first access device and a second access device; the first collector is connected with the extraction device so that the extraction device receives the solution stored in the first collector, and the first three-way valve is connected to the The extraction device, the second collector and the second three-way valve are connected so that the first three-way valve receives the solution processed by the extraction device and sends it to the second collector or the second three-way valve. The first access device is connected with the extraction device so that the extraction device receives the solution stored in the first access device, the second three-way valve is connected with the first three-way valve, and a sterilizing filter device is provided The third collector and a second access device, so that the second three-way valve receives the solution passed through the first three-way valve or receives the solution stored in the second access device, and passes through the sterilization filter device And collected in the third collector. The manufacturing device described in item 8 of the scope of patent application, wherein the extraction device is a solid phase extraction device. The manufacturing device described in item 8 of the scope of patent application, wherein the solution stored in the first access device is a NaCl/HCl extract. As the manufacturing device described in item 8 of the scope of patent application, the storage in the second access device The solution is an alkaline buffer. A method for manufacturing a ⁶⁸ Ga positron radioisotope marker, comprising: (a) performing elution with a ⁶⁸ Ga generator in a first collector to obtain a [ ⁶⁸ Ga] gallium trichloride eluent; (b) The [ ⁶⁸ Ga] gallium trichloride eluent in the first collector passes through an extraction device to adsorb [ ⁶⁸ Ga] gallium trichloride, and the eluent that passes through the extraction device is collected in a second collector (C) Pass the NaCl/HCl extract stored in a first access device through the extraction device and through a sterile filter device, and collect it in a third collector to obtain a marker precursor; and (d) The alkaline buffer stored in a second access device is passed through the sterilizing filter device and then added to the third collector for reaction to obtain a ⁶⁸ Ga positron radioisotope label. According to the manufacturing method described in item 12 of the scope of patent application, the third collector is a frozen crystal bottle.

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