CN213431821U - Automatic preparation device for 68 Ga-labeled positron medicine - Google Patents

Automatic preparation device for 68 Ga-labeled positron medicine Download PDF

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CN213431821U
CN213431821U CN202021264252.2U CN202021264252U CN213431821U CN 213431821 U CN213431821 U CN 213431821U CN 202021264252 U CN202021264252 U CN 202021264252U CN 213431821 U CN213431821 U CN 213431821U
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查智豪
郎红梅
其他发明人请求不公开姓名
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Beijing Binpai Biotechnology Co ltd
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Abstract

The utility model relates to a68An automatic preparation device of Ga-labeled positron medicine belongs to the technical field of medicine synthesis; comprises that68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a vacuum system, a purification unit and a preparation unit;68the Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; fitting for mixingThe site chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with the purification unit; the purification unit is connected with the preparation unit. The automatic preparation device of the utility model utilizes disposable cutting ferrule type consumable material to realize68Ga‑P16‑093、68Ga‑P15‑041、68An automated preparation of Ga-DOTATOC of68Lays a foundation for clinical transformation and application of Ga-labeled positron medicines.

Description

A kind of68Ga labelAutomatic preparation device of positron recording medicine
Technical Field
The utility model relates to a68An automatic preparation device of Ga-marked positron medicines, in particular to a device capable of preparing a plurality of types of medicines68An automatic device of Ga-labeled Positron Emission Tomography (PET) medicine, in particular to PET imaging medicine targeting PSMA68Ga-P16-093, bone PET imaging medicine68Ga-P15-041, neuroendocrine tumor PET imaging medicine68An automatic preparation device of Ga-DOTATOC belongs to the technical field of drug synthesis.
Background
Positron Emission Tomography (PET) is the most advanced technology in the field of contemporary nuclear medicine, and is also one of the most advanced technical means for human life phenomenon study in the 21 st century. It is an imaging technique for non-invasive, dynamic and quantitative evaluation of physiological and biochemical changes in vivo by using positron-emitting medicine as molecular probe, and has been widely used in differential diagnosis and curative effect monitoring of tumor, cardiovascular and cerebrovascular diseases, neurological diseases and other diseases. Among them, positron medicine is the "soul" of PET imaging, and its development and clinical transformation are the key points of PET diagnostic technology development. Positron drugs are drugs labeled with positron-emitting radionuclides for use in clinical PET imaging.
Positive electron nucleins commonly used in PET imaging are11C (half-life period T)1/2＝20.3min)、18F (half-life period T)1/2＝109.8min)、68Ga (half-life period T)1/268.1min) and the like.11The half-life of C nuclide is short, only 20min, and the clinical application is limited;18f is the most widely used positron nuclide in clinical application at present, has good nuclear chemical properties and is prepared by a cyclotron, and the cyclotron has high price, large floor area, periodic maintenance and overhigh cost;68ga is used as 'new generation' nuclide in the field of radiopharmaceutical chemistry, and is prepared from68Ge/68Compared with a cyclotron, the Ga generator is low in cost, can be leached for multiple times in one day, and is high in utilization rate.
In addition to this, the present invention is,68ga-labeled positron drugs are generally prepared by coordination chemistry, which facilitates automation and drug-packing of radiopharmaceutical preparation. With following68Ge/68Commercialization of Ga generators and68the successful marketing of Ga-somatostatin receptor imaging agents,68ga-labeled radioactive imaging probes have become a hot spot of research in recent years.
At present, the number of the current day,68ga-labeled positron drugs include: PSMA-targeted PET imaging drug68Ga-P16-093, bone PET imaging medicine68Ga-P15-041 and neuroendocrine tumor PET imaging medicine68Ga-DOTATOC; three kinds of the above68The current research situation and preparation method of Ga-labeled positron drugs are as follows.
Prostate cancer is a urinary system malignant tumor seriously threatening the health of middle-aged and old men, the morbidity and the mortality of prostate cancer in China increase year by year along with the aging development of population and the popularization of Prostate Specific Antigen (PSA) screening, and metastatic castration resistant prostate cancer formed by the development of prostate cancer in the advanced stage is a main lethal factor. The early and accurate diagnosis of the prostate cancer patient can carry out timely intervention treatment and customized personalized treatment scheme on the patient, and the death rate of the prostate cancer is effectively reduced. The Prostate Specific Membrane Antigen (PSMA) is a highly specific prostate epithelial cell membrane antigen and is an important diagnosis and treatment target for prostate cancer diseases. The PET imaging technology has the characteristics of accuracy, no wound and the like, and various documents in recent years report68Ga-labelled PSMA-targeted PET imaging drugs, non-patented68Ga-PSMA-11 is representative. Kung laboratory develops a new generation based on the existing PSMA targeting molecular probe68Ga-labelled radiopharmaceutical P16-093.68Ga-P16-093 and68the structure of Ga-PSMA-11 is compared as follows.
Figure BDA0002566256870000021
68Ga-P16-093 is prepared by using HBED-CC as bifunctional connecting agent68Ga3+Coordination (coordination constant is 38.5), simple labeling method, high in vivo stability, obvious radioactive enrichment of tumor metastasis parts in a patient body and excellent imaging effect. Phase I/II clinical study data show: patient injection68After Ga-P16-093, no obvious toxic or side effect appears. And68compared with the Ga-PSMA-11,68the radioactive uptake of Ga-P16-093 in urinary organs such as bladder of patients is obviously reduced, and PET/CT images of lesion sites are clearer.68Ga-P16-093 as a novel PSMA targeting molecular probe can be used for diagnosis and research of prostate cancer and kidney cancer, and has entered phase II clinical research in the United states (clinical trials. gov Identifier: NCT 03444844).
99mTc-labelled methylenediphosphonate (99mTc-MDP) is one of the most clinically used radiopharmaceuticals in recent 40 years, a single photon tomography (SPECT) drug, primarily for the detection of various bone related diseases: including osteomyelitis, arthritis, osteoporosis, benign and malignant tumors, and bone metastases. In view of the possible appearance in the international market99mUnder the condition of Tc raw material shortage, the development of novel bone imaging drugs gradually becomes a hot field of the research of the current radiopharmaceuticals. Innovative general description of research team of professor Hank f68The Ga bifunctional connecting agent is organically combined with diphosphonates (BPs), and a new generation of positron bone imaging drugs is developed68Ga-P15-041 (HBED-BP). The medicine not only ensures high specificity and affinity of bisphosphonate medicines to bone lesion focus parts, but also ensures radionuclide68The rapidity and the simplicity of Ga labeling have the potential of becoming a novel bone imaging positron medicament widely used clinically. MDP, BP and68the chemical structure of Ga-P15-041 is shown below:
Figure BDA0002566256870000031
kung professor team utilization68Ga-P15-041 carries out PET imaging on patients with bone metastasis, and the result shows that,68Ga-P15-041 can display the focus of bone metastasisThe blood, soft tissue and normal bone can be cleared quickly, and the bone imaging drug has the potential of becoming an excellent bone imaging drug.
Neuroendocrine tumors are a group of tumors originated from neuroendocrine cells, and the neuroendocrine cells are widely distributed in the whole body, including pituitary, thyroid, lung, thymus, gastrointestinal tract, pancreas, adrenal gland, skin and the like, and can secrete hundreds of hormones, so the neuroendocrine tumors can be generated in various organs and tissues in the body, and the clinical manifestations are complicated and changeable. Among them, neuroendocrine tumors at the location of the pancreas, gastrointestinal tract, lung and thymus are most common. The surface of neuroendocrine tumors highly expresses somatostatin receptors, and therefore,68ga-nuclide-labeled somatostatin analogues, e.g.68Ga-dotate and68Ga-DOTATOC has important significance in the diagnosis, staging and treatment of neuroendocrine tumors and is approved by the FDA in the United states to be successfully marketed.68The chemical structure of Ga-DOTATOC is as follows:
Figure BDA0002566256870000032
the literature (Zhio Zha, Karl Ploessl, Seok R.Choi, et al.Synthesis and evaluation of novel urea-based,68Ga-complex for imaging PSMA binding in tumor[J]nuclear Medicine and Biology, 2018; 59:36-47.) reported PSMA-targeted PET imaging agents68A preparation method of Ga-P16-093 comprises mixing 0.5mL of a solution containing Ga68A0.05M HCl solution of Ga ions was mixed with 25. mu.L of a 2N NaOAc solution, and 2.5. mu.g of P16-093 ligand was added thereto to conduct a reaction at room temperature for 10 min. The preparation method is manually marked and is not suitable for clinical transformation and application of the medicine.
The literature (Zhihao Zha, Zehui Wu, look Rye Choi, et al. A new 2 [ ]68Ga]Molecular pharmaceuticals 17, No.5(2020), 1674-68The preparation method of Ga-P15-041 specifically comprises mixing 0.2mL of a mixture containing Ga-P15-04168Ga ion in 0.05M HCl solution with 0.25mL P15-041 solution (200. mu.M in 0.1N NaOAc solution) and reacted at room temperature for 10 min. The preparation method is manually marked and is not suitable for clinical transformation and application of the medicine.
Neuroendocrine tumor imaging agent68Ga-DOTATOC is approved by the FDA in the United states to be on the market, and a plurality of documents report the preparation method. Overall, DOTATOC is compared to HBED-CC as a ligand for a bifunctional linker68The complex constant of Ga ions is low, the reaction generally needs to be heated to 90-100 ℃, the requirement on the pH value is strict, the yield is generally between 40-60 percent, and if the yield is between 40-60 percent68Ge/68The maintenance state of the Ga generator is poor, and a phenomenon of marking failure may occur. Have been reported to date68The automated preparation modules for Ga-DOTATOC are All In One and ModularLab PharmTracer, etc. Wherein All In One is a multifunctional synthesis device which can realize the synthesis at the same time18F、11C、68Ga、177The automated preparation of Lu and other nuclide labeled drugs is provided with a semi-preparative liquid chromatography module, because All In One is not68The special synthesis module for the Ga-positron medicine has complex equipment and process and has certain requirements on the operation technology of pharmaceutical personnel. Literature (Schultz Michael, Dirk Mueller, Richard P.Baum, et al.A. new automated NaCl based recipe method for route production of gallium-68 labeled peptides [ J)]Applied Radiation and Isotopes.2013,76:46-54.) reports using a ModularLab PharmTracer module68The automatic preparation of Ga-DOTATOC requires that the module is additionally provided with a gas cylinder to provide pressure for liquid transfer, the device composition is relatively complex, and the gas cylinder needs to be replaced at any time, which is not beneficial to realization68The 'fool' automatic preparation of Ga-labeled positron medicine.
Due to the fact that68The half-life period of Ga nuclide is short, and the marked medicine cannot depend on foreign import or long-distance transportation, so that the Ga nuclide needs to be prepared immediately, is completed as quickly, efficiently, highly efficiently and stably as possible, and simultaneously has radiation protection facilities to ensure the safety of operators.
Therefore, the method is simple, convenient, efficient, stable, safe and environment-friendly68Ga-labelled positron drugs (including68Ga-P16-093、68Ga-P15-041、68Ga-DOTATOC) becomes a technical problem which needs to be solved urgently in the technical field.
SUMMERY OF THE UTILITY MODEL
The utility model aims at providing a simple and convenient, high-efficient, stable, safe, environment-friendly68Ga-labelled positron drugs (including68Ga-P16-093、68Ga-P15-041、68Ga-DOTATOC, etc.).
The above object of the utility model is achieved through the following technical scheme:
a kind of68The automatic preparation device of Ga-marked positron medicine is characterized in that: comprises that68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a negative pressure system, a purification unit and a preparation unit; the above-mentioned68The Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; the coordination chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with the purification unit; the purification unit is connected with the preparation unit.
Preferably, the68The Ga ion leaching unit comprises an injector for loading and leaching hydrochloric acid solution and68Ge/68a Ga generator, a Ga gas generator,68Ge/68the Ga generator is connected with a reaction bottle in the coordination chemical reaction unit through a fifth three-way valve.
Preferably, the coordination chemical reaction unit comprises a reaction bottle and a temperature control component positioned below the reaction bottle; one end of the reaction bottle passes through a fifth three-way valve and68Ge/68the Ga generator is connected with the injector loaded with dilution water through a fourth three-way valve, connected with the injector loaded with elution water through a third three-way valve, connected with the injector loaded with product eluent through a second three-way valve, and connected with a negative pressure system at the other end.
Preferably, the negative pressure system comprises a first vacuum pump, a second vacuum pump and a pressure gauge, and is connected with the reaction bottle in the coordination chemical reaction unit through a second three-way electromagnetic valve, a first electromagnetic valve, a second needle valve, silencers of the second vacuum pump and the second vacuum pump.
Preferably, the negative pressure system is simultaneously connected with the first needle valve and the first vacuum pump through a third three-way electromagnetic valve and is connected with the reaction bottle in the coordination chemical reaction unit.
Preferably, the negative pressure system is further connected with the waste liquid bottle through a first three-way electromagnetic valve.
Preferably, the purification unit comprises a solid phase extraction cartridge, a syringe loaded with rinse water and a syringe loaded with product eluent; one end of the solid phase extraction column is connected with an injector loaded with product eluent through a first three-way valve and a second three-way valve, and is connected with the injector loaded with elution water through a third three-way valve, and the other end of the solid phase extraction column is connected with a buffer bottle containing buffer solution in the preparation unit through a sixth three-way valve and a seventh three-way valve.
Preferably, the formulation unit comprises a buffer bottle containing a buffer solution, a sterile product bottle, a waste bottle, a sterile filter membrane and an aeration filter membrane; one end of the buffer bottle containing the buffer solution is connected with the sterile product bottle through a sixth three-way valve, a seventh three-way valve and a sterile filter membrane, the ventilation filter membrane is connected with the sterile product bottle, and the other end of the buffer bottle containing the buffer solution is connected with the waste liquid bottle through an eighth three-way valve, a ninth three-way valve and a thirteenth three-way valve.
Preferably, the other end of the waste liquid bottle is connected with a vacuum system.
Preferably, the solid phase extraction column is a C18 purification column or NH respectively2And (5) purifying the small column.
Preferably, the68Ge/68The Ga generator is iTG silica gel column generator.
Preferably, the other end of the waste liquid bottle is connected with a negative pressure system through a first three-way electromagnetic valve, a third three-way electromagnetic valve, a first vacuum pump and a first needle valve.
Preferably, the first three-way valve, the thirteenth valve and the connecting pipeline are all disposable consumables.
Preferably, the sterile filter is a Millex sterile filter with a pore size of 0.22 μm.
Has the advantages that:
the utility model discloses a68The automatic preparation device of Ga-labeled positron medicine can realize the three types68The simple, convenient, rapid, high-yield, high-purity, stable and standardized automatic preparation of the Ga-labeled positron medicine lays a foundation for clinical transformation and application of the medicine.
The invention is further illustrated by the accompanying drawings and the detailed description, which are not meant to limit the scope of the invention.
Drawings
FIG. 1 shows the present invention68The structure schematic diagram of an automatic preparation device of Ga-labeled positron medicines.
The main part names are as follows:
1 injector for loading eluting hydrochloric acid 2 injector for loading product eluent
3 Syringe loaded with 4mL of Water 4 Syringe loaded with 3mL of Water
5 reaction bottle 6 waste liquid bottle
7 buffer bottle containing buffer solution 8 sterile product bottle
9 68Ge/68Ga generator 10 solid phase extraction column
11 sterile Filter 12 aeration Filter
13 first three-way valve 14 second three-way valve
15 third three-way valve 16 fourth three-way valve
17 fifth three-way valve 18 sixth three-way valve
19 seventh three-way valve 20 eighth three-way valve
21 ninth three-way valve 22 thirteenth way valve
23 pressure gauge 24 first three-way electromagnetic valve
25 second three-way solenoid valve 26 third three-way solenoid valve
27 first solenoid valve 28 second solenoid valve
29 first needle valve 30 second needle valve
31 first vacuum pump 32 second vacuum pump
33 second vacuum pump muffler 34 temperature control assembly
Detailed Description
Unless otherwise stated, the parts and components used in the present application are all conventional parts and components available in the market in the field, and the parts and components are connected in a conventional manner; the reagents and consumables are conventional reagents and consumables which are commercially available in the field; the method used is conventional in the art.
Example 1
68Automated preparation of Ga-P16-093
1. Reagents and consumables:
68Ge/68ga generator (manufactured by iTG corporation); all other reagents and consumables are purchased by related reagent companies. The labeled precursor is provided by professor laboratories of Hank F.Kung, USA, has a structure shown in the following figure, has a chemical purity of more than 95%, and contains 15 μ g of P16-093 ligand.
Figure BDA0002566256870000071
As shown in the attached figure 1, the utility model discloses a68The structure of the automated preparation device of Ga-labeled positron medicine is schematically shown in the figure, wherein 1 is a syringe for loading and rinsing hydrochloric acid (in the embodiment, the syringe for loading 4mL of 0.05N hydrochloric acid solution), 2 is a syringe for loading product eluent (in the embodiment, the syringe for loading 2mL of 40% ethanol/normal saline solution and 1mL of air), 3 is a syringe for loading 4mL of water (in the embodiment, the syringe for loading 4mL of water and 1mL of air), 4 is a syringe for loading 3mL of water (in the embodiment, the syringe for loading 3mL of water and 1mL of air), and 5 is a reaction flask (in the embodiment, the reaction flask contains 15 mug of P16-093 ligand and 68mg of NaOAc.3H2O buffer salt), 6 is a waste liquid bottle, 7 is a buffer bottle containing a buffer solution (in this example, a buffer bottle containing 7mL of physiological saline), 8 is a sterile product bottle (sterile vacuum penicillin bottle), 9 is68Ge/68Ga generator, 10 is a solid phase extraction cartridge (C18 solid phase extraction cartridge in this embodiment), 11 is a sterile filtration membrane (0.22 μm Millex-GV sterile filtration membrane in this embodiment), 12 is a sterile vent filtration membrane needle, 13 is a first three-way valve, 14 is a second three-way valve, 15 is a third three-way valve, 16 is a fourth three-way valve, 17 is a fifth three-way valve, 18 is a sixth three-way valve, 19 is a seventh three-way valve, 20 is an eighth three-way valve, 21 is a ninth three-way valve, 22 is a thirteenth three-way valve, 23 is a pressure gauge, 24 is a first three-way solenoid valve, 25 is a second three-way solenoid valve, 26 is a third three-way solenoid valve, 27 is a first solenoid valve, 28 is a second solenoid valve, 29 is a first needle valve, 30 is a second needle valve, 31 is a first vacuum pump, 32 is a second vacuum pump, 33 is a second vacuum pump muffler, and 34 is a temperature control component.
The utility model discloses a68An automatic preparation device of Ga-labeled positron medicine comprises68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a negative pressure system, a purification unit and a preparation unit; the above-mentioned68The Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; the coordination chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with a liquid loading injector and a purification unit through a valve group; the solid phase extraction small column is respectively connected with a waste liquid bottle and a buffer bottle loaded with buffer solution through a disposable three-way valve group and a pipeline; the buffer bottle is connected with the sterile product bottle through a disposable three-way valve group and a pipeline to form a preparation unit.
The above-mentioned68The Ga ion leaching unit comprises an injector 1 for loading and leaching hydrochloric acid solution and68Ge/68the Ga generator 9 is arranged to generate a voltage,68Ge/68the Ga generator 9 is connected with a fifth three-way valve 17;
the coordination chemical reaction unit comprises a reaction bottle 5(15 mu g of P16-093 ligand and 68mg of NaOAc.3H2O) and controls located thereunderA temperature component 34; reaction flask 5 (15. mu.g of P16-093 ligand and 68mg of NaOAc.3H2O) is connected to the second three-way valve 1768Ge/68 The Ga generator 9 is connected with the injector 4 loaded with dilution water through a fourth three-way valve 16, connected with the injector 3 loaded with leaching water through a third three-way valve 15, connected with the injector 2 loaded with product eluent through a second three-way valve 14, and connected with a negative pressure system at the other end;
the negative pressure system comprises a first vacuum pump 31, a second vacuum pump 32 and a pressure gauge 23, and is connected with the reaction flask 5(15 mug of P16-093 ligand and 68mg of NaOAc.3Hv) through a second three-way solenoid valve 25, a first solenoid valve 27, a second needle valve 30, a second vacuum pump 32 and a second vacuum pump silencer 332O) and simultaneously connected with the reaction flask 5 (15. mu.g of P16-093 ligand and 68mg of NaOAc.3Hv) through a third three-way solenoid valve and a first needle valve 29 and a first vacuum pump 312O) is connected;
the negative pressure system is also connected with the waste liquid bottle 6 through a first three-way electromagnetic valve 24;
the purification unit comprises a C18 solid phase extraction column 10, an injector 3 loaded with washing water and an injector 2 loaded with product eluent; one end of the C18 solid phase extraction column 10 is connected with the injector 2 loaded with product eluent through a first three-way valve 13 and a second three-way valve 14, and is connected with the injector 3 loaded with leaching water through a third three-way valve 15, and the other end is connected with the buffer bottle 7 containing buffer solution through a sixth three-way valve 18 and a seventh three-way valve 19;
the preparation unit comprises a buffer bottle 7 containing buffer solution, a sterile product bottle 8, a waste liquid bottle 6, a sterile filter membrane 11 and an aeration filter membrane needle 12; one end of the buffer bottle 7 containing the buffer solution is connected with the sterile product bottle 8 through a sixth three-way valve 18, a seventh three-way valve 19 and a sterile filter membrane 11, the vent filter membrane needle 12 is connected with the sterile product bottle 8, and the other end is connected with the waste liquid bottle 6 through an eighth three-way valve 20, a ninth three-way valve 21 and a thirteenth three-way valve 22; the first three-way electromagnetic valve 24, the third three-way electromagnetic valve 26, the first vacuum pump 31 and the first needle valve 29 are connected with a negative pressure system; the sterile filter membrane 11 is a 0.22 mu m Millex-GV sterile filter membrane;
the closing end (c end) of the first three-way electromagnetic valve 24 is connected with the waste liquid bottle 6, and the normally closed end (nc) of the first three-way electromagnetic valve 24 is connected with the normally closed end (nc) of the third three-way electromagnetic valve 26;
the closing end (c end) of the second three-way electromagnetic valve 25 is connected with the reaction bottle 5, and the normally-closed end (nc) of the second three-way electromagnetic valve 25 is respectively connected with the first electromagnetic valve 27 and the second electromagnetic valve 28;
a closing end (c end) of the third three-way electromagnetic valve 26 is connected with the first vacuum pump 31, and a normally closed end (nc) of the third three-way electromagnetic valve 26 is connected with a normally closed end (nc) of the first three-way electromagnetic valve 24;
the first to thirteenth through valves can adjust the direction of the passage, are disposable consumables and avoid the problems of cleaning, aging and the like of the consumables.
2. Preparation work:
2mL of 40% ethanol/normal saline solution and 1mL of air are loaded in the injector 2 loaded with the product eluent and clamped at the position of the second three-way valve 14;
4mL of water and 1mL of air are loaded in the injector 3 loaded with 4mL of water and clamped at the position of a third three-way valve 15;
3mL of water and 1mL of air are loaded in the injector 4 loaded with 3mL of water and clamped at the position of a fourth three-way valve 16;
respectively activating the solid-phase extraction cartridge 10(C18 purification cartridge in this example 1) with 5mL of ethanol, 5mL of air, 10mL of water, and 10mL of air, and loading the activated solid-phase extraction cartridge 10(C18 purification cartridge) at the corresponding position;
loading 7mL of physiological saline solution as a buffer solution in a buffer bottle 7 containing the buffer solution;
reaction flask 5 (containing 15. mu.g of P16-093 ligand and 68mg of NaOAc.3H in example 1)2O), a buffer bottle 7 containing buffer solution, a waste liquid bottle 6 and a sterile product bottle 8 are placed at corresponding positions;
a long needle head is connected with a fifth three-way valve 17, a short needle head is connected with a negative pressure system and inserted into the reaction bottle 5, the long needle head needs to be inserted to the bottom of the bottle, and the short needle head is prevented from being blocked by a rubber plug;
the seventh three-way valve 19 is connected with the buffer bottle 7 containing the buffer solution through a long needle, the eighth three-way valve 20 is connected with the buffer bottle 7 containing the buffer solution through a short needle, the two needles are inserted into the buffer bottle 7 containing the buffer solution, the long needle needs to be inserted into the bottom of the buffer bottle 7 containing the buffer solution, and the short needle is prevented from being blocked by a rubber plug;
two middle and long needle heads are inserted into the waste liquid bottle 6, wherein one middle and long needle head is connected with a thirteenth through valve 22, the other middle and long needle head is connected with a first vacuum pump 31 through a first three-way electromagnetic valve 24 and a third three-way electromagnetic valve 26, and is connected with a second vacuum pump 32 (negative pressure system) through the first three-way electromagnetic valve 24, a first electromagnetic valve 27 and a second needle valve 30;
the sterile filter membrane 11 (in this example 1, a sterile filter membrane of 0.22 μm Millex-GV) is connected to the sixth three-way valve 18, and then inserted into the sterile product bottle 8 through a medium-length needle, and the vent filter membrane needle 12 is inserted into the sterile product bottle 8;
4mL of 0.05N HCl solution is loaded in the injector 1 loaded with the leaching hydrochloric acid, air is exhausted, and the mixture is communicated with the pipeline68Ge/68The inlet of the Ga generator 9 is connected; the above-mentioned68Ge/68The Ga generator is an iTG silica gel column generator;
will be provided with68Ge/68The outlet of the Ga generator 9 is connected to a fifth three-way valve 17.
3. Automatic preparation:
detecting whether the negative pressure system works normally: opening a first electromagnetic valve 27 and a second vacuum pump 32, wherein the indication number of a pressure gauge 11 is-30 to-26 psi, which indicates that the negative pressure system works normally;
checking the airtightness of the internal pipeline of the device: opening a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the internal pipeline of the device is good;
the airtightness of the sixth, seventh, eighth, ninth, and thirteenth three- way valves 18, 19, 20, 21, and 22 is checked: opening a sixth three-way valve 18, a seventh three-way valve 19 and an eighth three-way valve 20, opening a first three-way electromagnetic valve 24, a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20, the ninth three-way valve 21 and the thirteenth three-way valve 22 is good;
checking the airtightness of the first, second, third, fourth, and fifth three- way valves 13, 14, 15, 16, 17: opening the first three-way valve 13, opening the second three-way electromagnetic valve 25, the third three-way electromagnetic valve 26 and the first vacuum pump 31, wherein the indication of the pressure gauge 11 of 14-17 psi indicates that the first three-way valve 13, the second three-way valve 14, the third three-way valve 15, the fourth three-way valve 16 and the fifth three-way valve 17 are good in air tightness;
after the examination is passed, the automatic preparation of the medicine is started, and the specific steps are as follows:
(1) the fifth three-way valve 17 is opened to68Ge/68 Ga generator 9 is connected with reaction bottle 5, and hydrochloric acid solution in syringe 1 passes through68Ge/68 Ga generator 9, obtained by leaching68The Ga ion solution enters the reaction bottle 5 through a fifth three-way valve 17;
(2) closing the fifth three-way valve 17, and opening the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence to allow the gas generated by the first vacuum pump 31 to enter the reaction flask 5 for bubbling for 15 seconds;
(3) closing the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence, and then opening the first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the sixth three-way valve 18 and the first three-way valve 13 in sequence to enable the pressure in the solid phase extraction column 10 to reach 3-7 psi;
(4) closing the first vacuum pump 31 and the third three-way electromagnetic valve 26, opening the temperature control assembly 34 with the fan, heating the reaction bottle 5 to 95 ℃, and reacting for 5 minutes;
(5) after the reaction is finished, closing the temperature control assembly 34 with the fan and the first three-way electromagnetic valve 24;
(6) opening the second vacuum pump 31, the first electromagnetic valve 27 and the second three-way electromagnetic valve 25 to provide negative pressure for the reaction flask 5, opening the fourth three-way valve 16 to enable 3mL of water in the injector 4 to enter the reaction flask 5 through the fourth three-way valve 16, and closing the second vacuum pump 31, the first electromagnetic valve 27 and the fourth three-way valve 16;
(7) opening a first vacuum pump 31, a third three-way electromagnetic valve 26, a sixth three-way electromagnetic valve 18, a first three-way valve 13 and a second three-way electromagnetic valve 25 in sequence, enabling the mixed solution in the reaction bottle 5 to enter a waste liquid bottle 6 through a small solid-phase extraction column 10 (a small C18 column), and then closing the first vacuum pump 31, the third three-way electromagnetic valve 26 and the second three-way electromagnetic valve 25;
(8) opening the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15 in sequence to enable 4mL of the water-solid phase extraction small column 10(C18 small column) in the injector 3 to enter the waste liquid bottle 6, and then closing the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15;
(9) opening a second vacuum pump 32, a first electromagnetic valve 27, a first three-way electromagnetic valve 24, a seventh three-way valve 19, an eighth three-way valve 20 and a second three-way valve 14 in sequence, enabling 2mL of 40% ethanol/physiological saline solution loaded in the injector 2 to pass through the second three-way valve 14 and the solid-phase extraction column 10 and enter a buffer bottle 7 containing buffer solution, then closing the second vacuum pump 32, the first electromagnetic valve 27 and the second three-way valve 14, enabling air to pass through the reaction bottle 5 and the solid-phase extraction column 10 and enter the buffer bottle 7, and closing the first three-way valve 13, the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20 and the first three-way electromagnetic valve 24 after 15-20 seconds;
(10) opening the first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the eighth three-way valve 20 and the seventh three-way valve 19 in sequence to enable the mixed solution in the buffer bottle 7 to pass through the sterile filter membrane 11 and enter the sterile product bottle 8 to obtain a product68Ga-P16-093；
(8) The first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the eighth three-way electromagnetic valve 20 and the seventh three-way electromagnetic valve 19 are closed, and the automatic preparation process of the medicine is finished, so that the device is recovered to the standby state.
4. Product confirmation:
the product prepared in example 1 was used68Ga-P16-093 was analyzed by TLC under the following conditions:
developing agent: water/methanol/30% ammonia 2/2/0.1 (volume ratio);
and (3) unfolding the plate: iTLC-SG;
the automated preparation device shown can successfully prepare the product by confirmation of the retention shift of specific radioactivity68Ga-P16-093。
Example 2
68Automated preparation of Ga-P15-041
1. Reagents and consumables:
68Ge/68ga generator (manufactured by iTG corporation); all other reagents and consumables are purchased by related reagent companies. The labeling precursor is provided by professor laboratories of Hank F.Kung, USA, has a structure shown in the following figure, has a chemical purity of more than 95%, and contains 30 μ g of P15-041 ligand.
Figure BDA0002566256870000121
As shown in the attached figure 1, the utility model discloses a68A schematic structural diagram of an automated preparation device for Ga-labeled positron drugs is shown, wherein 1 is a syringe loaded with rinsing hydrochloric acid (in this example, a syringe loaded with 4mL of 0.1N NaOH solution), 2 is a syringe loaded with product eluent (in this example, a syringe loaded with 2mL of 40% ethanol/normal saline solution and 1mL of air), 3 is a syringe loaded with 4mL of water (in this example, a syringe loaded with 4mL of water and 1mL of air), 4 is a syringe loaded with 3mL of water (in this example, a syringe loaded with 3mL of water and 1mL of air), and 5 is a reaction flask (in this example, the reaction flask contains 30. mu.g of P15-041 ligand and 68mg of NaOAc.3H2O buffer salt), 6 is a waste liquid bottle, 7 is a buffer bottle containing a buffer solution (in this example, a buffer bottle containing 1mL of 0.2N HCl solution, 20mg of NaOAc, 6mL of physiological saline), 8 is a sterile product bottle (sterile vacuum penicillin bottle), 9 is68Ge/68Ga Generator, 10 solid phase extraction column (NH in this example)2Solid phase extraction cartridge), 11 is a sterile filter (0.22 μm Millex-GV sterile filter in this example), 12 is a sterile vent filter needle, 13 is a first three-way valve, 14 is a second three-way valve, 15 is a third three-way valve, 16 is a fourth three-way valve, 17 is a fifth three-way valveThe valve 18 is a sixth three-way valve, 19 is a seventh three-way valve, 20 is an eighth three-way valve, 21 is a ninth three-way valve, 22 is a thirteenth valve, 23 is a pressure gauge, 24 is a first three-way solenoid valve, 25 is a second three-way solenoid valve, 26 is a third three-way solenoid valve, 27 is a first solenoid valve, 28 is a second solenoid valve, 29 is a first needle valve, 30 is a second needle valve, 31 is a first vacuum pump, 32 is a second vacuum pump, 33 is a second vacuum pump muffler, and 34 is a temperature control assembly.
The utility model discloses a68An automatic preparation device of Ga-labeled positron medicine comprises68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a negative pressure system, a purification unit and a preparation unit; the above-mentioned68The Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; the coordination chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with a liquid loading injector and a purification unit through a valve group; the solid phase extraction small column is respectively connected with a waste liquid bottle and a buffer bottle loaded with buffer solution through a disposable three-way valve group and a pipeline; the buffer bottle is connected with the sterile product bottle through a disposable three-way valve group and a pipeline to form a preparation unit.
The above-mentioned68The Ga ion leaching unit comprises an injector 1 for loading and leaching hydrochloric acid solution and68Ge/68the Ga generator 9 is arranged to generate a voltage,68Ge/68the Ga generator 9 is connected with a fifth three-way valve 17;
the coordination chemical reaction unit comprises a reaction bottle 5(30 mu g of P15-041 ligand and 68mg of NaOAc.3H2O) and the temperature control assembly 34 located therebelow; reaction flask 5 (30. mu.g of P15-041 ligand and 68mg of NaOAc.3H2O) is connected to the second three-way valve 1768Ge/68 The Ga generator 9 is connected with the injector 4 loaded with dilution water through a fourth three-way valve 16, connected with the injector 3 loaded with leaching water through a third three-way valve 15, connected with the injector 2 loaded with product eluent through a second three-way valve 14, and connected with a negative pressure system at the other end;
the negative pressure system comprises a first vacuum pump 31, a second vacuum pump 32 anda pressure gauge 23 connected to the reaction flask 5 (30. mu.g of P15-041 ligand and 68mg of NaOAc.3H) via a second three-way solenoid valve 25, a first solenoid valve 27, a second needle valve 30 and a second vacuum pump 32, and a second vacuum pump muffler 332O) connected to the reaction flask 5 (30. mu.g of P15-041 ligand and 68mg of NaOAc.3Hh) via a third three-way solenoid valve with a first needle valve 29 and a first vacuum pump 312O) is connected;
the negative pressure system is also connected with the waste liquid bottle 6 through a first three-way electromagnetic valve 24;
the purification unit comprises NH2A solid phase extraction column 10, an injector 3 loaded with washing water and an injector 2 loaded with product eluent; NH (NH)2One end of the solid phase extraction column 10 is connected with the injector 2 loaded with product eluent through a first three-way valve 13 and a second three-way valve 14, is connected with the injector 3 loaded with leaching water through a third three-way valve 15, and is connected with the buffer bottle 7 containing buffer solution through a sixth three-way valve 18 and a seventh three-way valve 19;
the preparation unit comprises a buffer bottle 7 containing buffer solution, a sterile product bottle 8, a waste liquid bottle 6, a sterile filter membrane 11 and an aeration filter membrane needle 12; one end of the buffer bottle 7 containing the buffer solution is connected with the sterile product bottle 8 through a sixth three-way valve 18, a seventh three-way valve 19 and a sterile filter membrane 11, the vent filter membrane needle 12 is connected with the sterile product bottle 8, and the other end is connected with the waste liquid bottle 6 through an eighth three-way valve 20, a ninth three-way valve 21 and a thirteenth three-way valve 22; the first three-way electromagnetic valve 24, the third three-way electromagnetic valve 26, the first vacuum pump 31 and the first needle valve 29 are connected with a negative pressure system; the sterile filter membrane 11 is a 0.22 mu m Millex-GV sterile filter membrane;
the closing end (c end) of the first three-way electromagnetic valve 24 is connected with the waste liquid bottle 6, and the normally closed end (nc) of the first three-way electromagnetic valve 24 is connected with the normally closed end (nc) of the third three-way electromagnetic valve 26;
the closing end (c end) of the second three-way electromagnetic valve 25 is connected with the reaction bottle 5, and the normally-closed end (nc) of the second three-way electromagnetic valve 25 is respectively connected with the first electromagnetic valve 27 and the second electromagnetic valve 28;
a closing end (c end) of the third three-way electromagnetic valve 26 is connected with the first vacuum pump 31, and a normally closed end (nc) of the third three-way electromagnetic valve 26 is connected with a normally closed end (nc) of the first three-way electromagnetic valve 24;
the first to thirteenth through valves can adjust the direction of the passage, are disposable consumables and avoid the problems of cleaning, aging and the like of the consumables.
2. Preparation work:
2mL of 0.1N NaOH solution and 1mL of air are loaded in the injector 2 loaded with the product eluent and clamped at the position of the second three-way valve 14;
4mL of water and 1mL of air are loaded in the injector 3 loaded with 4mL of water and clamped at the position of a third three-way valve 15;
3mL of water and 1mL of air are loaded in the injector 4 loaded with 3mL of water and clamped at the position of a fourth three-way valve 16;
activation of NH with 2mL of ethanol, 10mL of air, 5mL of 0.05N HCl solution, and 10mL of air, respectively2Purifying the small column to obtain activated NH2The purification small column is loaded at the corresponding position;
loading 1mL of 0.2N HCl solution, 20mg of NaOAc and 6mL of physiological saline solution in a buffer bottle 7 containing a buffer solution as a buffer solution;
reaction flask 5 (containing 30. mu.g of P15-041 ligand and 68mg of NaOAc.3H2O in example 1), buffer flask 7 containing buffer solution, waste liquid flask 6, and sterile product flask 8 were placed at the corresponding positions;
a long needle head is connected with a fifth three-way valve 17, a short needle head is connected with a negative pressure system and inserted into the reaction bottle 5, the long needle head needs to be inserted to the bottom of the bottle, and the short needle head is prevented from being blocked by a rubber plug;
the seventh three-way valve 19 is connected with the buffer bottle 7 containing the buffer solution through a long needle, the eighth three-way valve 20 is connected with the buffer bottle 7 containing the buffer solution through a short needle, the two needles are inserted into the buffer bottle 7 containing the buffer solution, the long needle needs to be inserted into the bottom of the buffer bottle 7 containing the buffer solution, and the short needle is prevented from being blocked by a rubber plug;
two middle and long needle heads are inserted into the waste liquid bottle 6, wherein one middle and long needle head is connected with a thirteenth through valve 22, the other middle and long needle head is connected with a first vacuum pump 31 through a first three-way electromagnetic valve 24 and a third three-way electromagnetic valve 26, and is connected with a second vacuum pump 32 (negative pressure system) through the first three-way electromagnetic valve 24, a first electromagnetic valve 27 and a second needle valve 30;
the sterile filter membrane 11 (in this example 1, a sterile filter membrane of 0.22 μm Millex-GV) is connected to the sixth three-way valve 18, and then inserted into the sterile product bottle 8 through a medium-length needle, and the vent filter membrane needle 12 is inserted into the sterile product bottle 8;
4mL of 0.05N HCl solution is loaded in the injector 1 loaded with the leaching hydrochloric acid, air is exhausted, and the mixture is communicated with the pipeline68Ge/68The inlet of the Ga generator 9 is connected; the above-mentioned68Ge/68The Ga generator is an iTG silica gel column generator;
will be provided with68Ge/68The outlet of the Ga generator 9 is connected to a fifth three-way valve 17.
3. Automatic preparation:
detecting whether the negative pressure system works normally: opening a first electromagnetic valve 27 and a second vacuum pump 32, wherein the indication number of a pressure gauge 11 is-30 to-26 psi, which indicates that the negative pressure system works normally;
checking the airtightness of the internal pipeline of the device: opening a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the internal pipeline of the device is good;
the airtightness of the sixth, seventh, eighth, ninth, and thirteenth three- way valves 18, 19, 20, 21, and 22 is checked: opening a sixth three-way valve 18, a seventh three-way valve 19 and an eighth three-way valve 20, opening a first three-way electromagnetic valve 24, a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20, the ninth three-way valve 21 and the thirteenth three-way valve 22 is good;
checking the airtightness of the first, second, third, fourth, and fifth three- way valves 13, 14, 15, 16, 17: opening the first three-way valve 13, opening the second three-way electromagnetic valve 25, the third three-way electromagnetic valve 26 and the first vacuum pump 31, wherein the indication of the pressure gauge 11 of 14-17 psi indicates that the first three-way valve 13, the second three-way valve 14, the third three-way valve 15, the fourth three-way valve 16 and the fifth three-way valve 17 are good in air tightness;
after the examination is passed, the automatic preparation of the medicine is started, and the specific steps are as follows:
(1) the fifth three-way valve 17 is opened to68Ge/68 Ga generator 9 is connected with reaction bottle 5, and hydrochloric acid solution in syringe 1 passes through68Ge/68 Ga generator 9, obtained by leaching68The Ga ion solution enters the reaction bottle 5 through a fifth three-way valve 17;
(2) closing the fifth three-way valve 17, and opening the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence to allow the gas generated by the first vacuum pump 31 to enter the reaction flask 5 for bubbling for 15 seconds;
(3) closing the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence, and then opening the first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the sixth three-way valve 18 and the first three-way valve 13 in sequence to enable the pressure in the solid phase extraction column 10 to reach 3-7 psi;
(4) closing the first vacuum pump 31 and the third three-way electromagnetic valve 26, opening the temperature control assembly 34 with the fan, heating the reaction bottle 5 to 95 ℃, and reacting for 5 minutes;
(5) after the reaction is finished, closing the temperature control assembly 34 with the fan and the first three-way electromagnetic valve 24;
(6) opening the second vacuum pump 31, the first electromagnetic valve 27 and the second three-way electromagnetic valve 25 to provide negative pressure for the reaction flask 5, opening the fourth three-way valve 16 to enable 3mL of water in the injector 4 to enter the reaction flask 5 through the fourth three-way valve 16, and closing the second vacuum pump 31, the first electromagnetic valve 27 and the fourth three-way valve 16;
(7) the first vacuum pump 31, the third three-way electromagnetic valve 26, the sixth three-way electromagnetic valve 18, the first three-way electromagnetic valve 13 and the second three-way electromagnetic valve 25 are opened in sequence, so that the mixed liquid in the reaction flask 5 passes through the solid phase extraction column 10 (NH)2Small column) enters the waste liquid bottle 6, and then the first vacuum pump 31, the third three-way electromagnetic valve 26 and the second three-way electromagnetic valve 25 are closed;
(8) the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15 are opened in sequence, so that 4mL of the water-solid phase extraction cartridge 10 (NH) in the injector 3 is obtained2A small column) enters the waste liquid bottle 6, and then the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15 are closed;
(9) opening a second vacuum pump 32, a first electromagnetic valve 27, a first three-way electromagnetic valve 24, a seventh three-way valve 19, an eighth three-way valve 20 and a second three-way valve 14 in sequence, enabling 2mL of 0.1N NaOH solution loaded in the injector 2 to pass through the second three-way valve 14 and the solid-phase extraction column 10 and enter a buffer bottle 7 containing buffer solution, then closing the second vacuum pump 32, the first electromagnetic valve 27 and the second three-way valve 14, enabling air to pass through the reaction bottle 5 and the solid-phase extraction column 10 and enter the buffer bottle 7, and closing the first three-way valve 13, the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20 and the first three-way electromagnetic valve 24 after 15-20 seconds;
(10) opening the first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the eighth three-way valve 20 and the seventh three-way valve 19 in sequence to enable the mixed solution in the buffer bottle 7 to pass through the sterile filter membrane 11 and enter the sterile product bottle 8 to obtain a product68Ga-P15-041；
(8) The first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the eighth three-way electromagnetic valve 20 and the seventh three-way electromagnetic valve 19 are closed, and the automatic preparation process of the medicine is finished, so that the device is recovered to the standby state.
4. Product validation
The product prepared in example 2 was used68Ga-P15-041 was analyzed by TLC under the following conditions:
developing agent: 0.2M NaOAc/acetone/acetylacetone ═ 6.7/60/33.3 (volume ratio);
and (3) unfolding the plate: a cellulose board;
the automated preparation device shown can successfully prepare the product by confirmation of the retention shift of specific radioactivity68Ga-P15-041。
Example 3
68Automated preparation of Ga-DOTATOC
1. Reagents and consumables:
68Ge/68ga generator (manufactured by iTG corporation); other reagents used withThe consumables are purchased by related reagent companies. The labeling precursor is provided by professor laboratories of Hank f.kung, usa, and has a structure shown in the following figure, a chemical purity of greater than 95%, and contains 50 μ g of dotacoc ligand.
Figure BDA0002566256870000171
As shown in the attached figure 1, the utility model discloses a68A schematic structural diagram of an automatic preparation device for Ga-labeled positron medicine is shown, wherein 1 is a syringe loaded with rinsing hydrochloric acid (in this embodiment, a syringe loaded with 4mL of 0.05N hydrochloric acid solution), 2 is a syringe loaded with product eluent (in this embodiment, a syringe loaded with 2mL of 40% ethanol/normal saline solution and 1mL of air), 3 is a syringe loaded with 4mL of water (in this embodiment, a syringe loaded with 4mL of water and 1mL of air), 4 is a syringe loaded with 3mL of water (in this embodiment, a syringe loaded with 3mL of water and 1mL of air), 5 is a reaction flask (in this embodiment, the reaction flask contains 50 μ g of DOTATOC ligand and 19.29mg of NaOAc buffer salt), 6 is a waste liquid bottle, 7 is a buffer flask containing buffer solution (in this embodiment, a buffer flask containing 7mL of normal saline), 8 is a sterile product flask (sterile vacuum flask), 9 is68Ge/68Ga generator, 10 is a solid phase extraction cartridge (C18 solid phase extraction cartridge in this embodiment), 11 is an aseptic filtration membrane (0.22 μm Millex-GV aseptic filtration membrane in this embodiment), 12 is an aseptic aeration filtration membrane needle, 13 is a first three-way valve, 14 is a second three-way valve, 15 is a third three-way valve, 16 is a fourth three-way valve, 17 is a fifth three-way valve, 18 is a sixth three-way valve, 19 is a seventh three-way valve, 20 is an eighth three-way valve, 21 is a ninth three-way valve, 22 is a thirteenth three-way valve, 23 is a pressure gauge, 24 is a first three-way solenoid valve, 25 is a second three-way solenoid valve, 26 is a third three-way solenoid valve, 27 is a first solenoid valve, 28 is a second solenoid valve, 29 is a first needle valve, 30 is a second needle valve, 31 is a first vacuum pump, 32 is a second vacuum pump, 33 is a second vacuum pump muffler, and 34 is a temperature control member.
The utility model discloses a68An automatic preparation device of Ga-labeled positron medicine comprises68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a negative pressure system, a purification unit and a preparation unit; the above-mentioned68The Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; the coordination chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with a liquid loading injector and a purification unit through a valve group; the solid phase extraction small column is respectively connected with a waste liquid bottle and a buffer bottle loaded with buffer solution through a disposable three-way valve group and a pipeline; the buffer bottle is connected with the sterile product bottle through a disposable three-way valve group and a pipeline to form a preparation unit.
The above-mentioned68The Ga ion leaching unit comprises an injector 1 for loading and leaching hydrochloric acid solution and68Ge/68the Ga generator 9 is arranged to generate a voltage,68Ge/68the Ga generator 9 is connected with a fifth three-way valve 17;
the coordination chemical reaction unit comprises a reaction flask 5 (mainly containing 50 mug of DOTATOC ligand) and a temperature control component 34 positioned below the reaction flask; one end of the reaction flask 5 passes through a fifth three-way valve 17 and68Ge/68the Ga generator 9 is connected with the injector 4 loaded with dilution water through a fourth three-way valve 16, connected with the injector 3 loaded with leaching water through a third three-way valve 15, connected with the injector 2 loaded with product eluent through a second three-way valve 14, and connected with a negative pressure system at the other end;
the negative pressure system comprises a first vacuum pump 31, a second vacuum pump 32 and a pressure gauge 23, and is connected with the reaction flask 5 through a second three-way electromagnetic valve 25, a first electromagnetic valve 27, a second needle valve 30, the second vacuum pump 32 and a second vacuum pump silencer 33, and is connected with the reaction flask 5 through a third three-way electromagnetic valve, a first needle valve 29 and the first vacuum pump 31;
the negative pressure system is also connected with the waste liquid bottle 6 through a first three-way electromagnetic valve 24;
the purification unit comprises a C18 solid phase extraction column 10, an injector 3 loaded with washing water and an injector 2 loaded with product eluent; one end of the C18 solid phase extraction column 10 is connected with the injector 2 loaded with product eluent through a first three-way valve 13 and a second three-way valve 14, and is connected with the injector 3 loaded with leaching water through a third three-way valve 15, and the other end is connected with the buffer bottle 7 containing buffer solution through a sixth three-way valve 18 and a seventh three-way valve 19;
the preparation unit comprises a buffer bottle 7 containing buffer solution, a sterile product bottle 8, a waste liquid bottle 6, a sterile filter membrane 11 and an aeration filter membrane needle 12; one end of the buffer bottle 7 containing the buffer solution is connected with the sterile product bottle 8 through a sixth three-way valve 18, a seventh three-way valve 19 and a sterile filter membrane 11, the vent filter membrane needle 12 is connected with the sterile product bottle 8, and the other end is connected with the waste liquid bottle 6 through an eighth three-way valve 20, a ninth three-way valve 21 and a thirteenth three-way valve 22; the first three-way electromagnetic valve 24, the third three-way electromagnetic valve 26, the first vacuum pump 31 and the first needle valve 29 are connected with a negative pressure system; the sterile filter membrane 11 is a 0.22 mu m Millex-GV sterile filter membrane;
the closing end (c end) of the first three-way electromagnetic valve 24 is connected with the waste liquid bottle 6, and the normally closed end (nc) of the first three-way electromagnetic valve 24 is connected with the normally closed end (nc) of the third three-way electromagnetic valve 26;
the closing end (c end) of the second three-way electromagnetic valve 25 is connected with the reaction bottle 5, and the normally-closed end (nc) of the second three-way electromagnetic valve 25 is respectively connected with the first electromagnetic valve 27 and the second electromagnetic valve 28;
a closing end (c end) of the third three-way electromagnetic valve 26 is connected with the first vacuum pump 31, and a normally closed end (nc) of the third three-way electromagnetic valve 26 is connected with a normally closed end (nc) of the first three-way electromagnetic valve 24;
the first to thirteenth through valves can adjust the direction of the passage, are disposable consumables and avoid the problems of cleaning, aging and the like of the consumables.
2. Preparation work:
2mL of 40% ethanol/normal saline solution and 1mL of air are loaded in the injector 2 loaded with the product eluent and clamped at the position of the second three-way valve 14;
4mL of water and 1mL of air are loaded in the injector 3 loaded with 4mL of water and clamped at the position of a third three-way valve 15;
3mL of water and 1mL of air are loaded in the injector 4 loaded with 3mL of water and clamped at the position of a fourth three-way valve 16;
respectively activating the solid-phase extraction cartridge 10(C18 purification cartridge in this example 1) with 5mL of ethanol, 5mL of air, 10mL of water, and 10mL of air, and loading the activated solid-phase extraction cartridge 10(C18 purification cartridge) at the corresponding position;
loading 7mL of physiological saline solution as a buffer solution in a buffer bottle 7 containing the buffer solution;
placing a reaction bottle 5 (mainly containing 50 mug of DOTATOC ligand in the embodiment 1), a buffer bottle 7 containing buffer solution, a waste liquid bottle 6 and a sterile product bottle 8 at corresponding positions;
a long needle head is connected with a fifth three-way valve 17, a short needle head is connected with a negative pressure system and inserted into the reaction bottle 5, the long needle head needs to be inserted to the bottom of the bottle, and the short needle head is prevented from being blocked by a rubber plug;
the seventh three-way valve 19 is connected with the buffer bottle 7 containing the buffer solution through a long needle, the eighth three-way valve 20 is connected with the buffer bottle 7 containing the buffer solution through a short needle, the two needles are inserted into the buffer bottle 7 containing the buffer solution, the long needle needs to be inserted into the bottom of the buffer bottle 7 containing the buffer solution, and the short needle is prevented from being blocked by a rubber plug;
two middle and long needle heads are inserted into the waste liquid bottle 6, wherein one middle and long needle head is connected with a thirteenth through valve 22, the other middle and long needle head is connected with a first vacuum pump 31 through a first three-way electromagnetic valve 24 and a third three-way electromagnetic valve 26, and is connected with a second vacuum pump 32 (negative pressure system) through the first three-way electromagnetic valve 24, a first electromagnetic valve 27 and a second needle valve 30;
the sterile filter membrane 11 (in this example 1, a sterile filter membrane of 0.22 μm Millex-GV) is connected to the sixth three-way valve 18, and then inserted into the sterile product bottle 8 through a medium-length needle, and the vent filter membrane needle 12 is inserted into the sterile product bottle 8;
4mL of 0.05N HCl solution is loaded in the injector 1 loaded with the leaching hydrochloric acid, air is exhausted, and the mixture is communicated with the pipeline68Ge/68The inlet of the Ga generator 9 is connected; the above-mentioned68Ge/68The Ga generator is an iTG silica gel column generator;
will be provided with68Ge/68The outlet of the Ga generator 9 is connected to a fifth three-way valve 17.
3. Automatic preparation:
detecting whether the negative pressure system works normally: opening a first electromagnetic valve 27 and a second vacuum pump 32, wherein the indication number of a pressure gauge 11 is-30 to-26 psi, which indicates that the negative pressure system works normally;
checking the airtightness of the internal pipeline of the device: opening a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the internal pipeline of the device is good;
the airtightness of the sixth, seventh, eighth, ninth, and thirteenth three- way valves 18, 19, 20, 21, and 22 is checked: opening a sixth three-way valve 18, a seventh three-way valve 19 and an eighth three-way valve 20, opening a first three-way electromagnetic valve 24, a third three-way electromagnetic valve 26 and a first vacuum pump 31, wherein the indication number of a pressure gauge 11 is 14-17 psi, which indicates that the air tightness of the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20, the ninth three-way valve 21 and the thirteenth three-way valve 22 is good;
checking the airtightness of the first, second, third, fourth, and fifth three- way valves 13, 14, 15, 16, 17: opening the first three-way valve 13, opening the second three-way electromagnetic valve 25, the third three-way electromagnetic valve 26 and the first vacuum pump 31, wherein the indication of the pressure gauge 11 of 14-17 psi indicates that the first three-way valve 13, the second three-way valve 14, the third three-way valve 15, the fourth three-way valve 16 and the fifth three-way valve 17 are good in air tightness;
after the examination is passed, the automatic preparation of the medicine is started, and the specific steps are as follows:
(1) the fifth three-way valve 17 is opened to68Ge/68 Ga generator 9 is connected with reaction bottle 5, and hydrochloric acid solution in syringe 1 passes through68Ge/68 Ga generator 9, obtained by leaching68The Ga ion solution enters the reaction bottle 5 through a fifth three-way valve 17;
(2) closing the fifth three-way valve 17, and opening the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence to allow the gas generated by the first vacuum pump 31 to enter the reaction flask 5 for bubbling for 15 seconds;
(3) closing the first vacuum pump 31, the third three-way electromagnetic valve 26 and the ninth three-way valve 21 in sequence, and then opening the first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the sixth three-way valve 18 and the first three-way valve 13 in sequence to enable the pressure in the solid phase extraction column 10 to reach 3-7 psi;
(4) closing the first vacuum pump 31 and the third three-way electromagnetic valve 26, opening the temperature control assembly 34 with the fan, heating the reaction bottle 5 to 95 ℃, and reacting for 5 minutes;
(5) after the reaction is finished, closing the temperature control assembly 34 with the fan and the first three-way electromagnetic valve 24;
(6) opening the second vacuum pump 31, the first electromagnetic valve 27 and the second three-way electromagnetic valve 25 to provide negative pressure for the reaction flask 5, opening the fourth three-way valve 16 to enable 3mL of water in the injector 4 to enter the reaction flask 5 through the fourth three-way valve 16, and closing the second vacuum pump 31, the first electromagnetic valve 27 and the fourth three-way valve 16;
(7) opening a first vacuum pump 31, a third three-way electromagnetic valve 26, a sixth three-way electromagnetic valve 18, a first three-way valve 13 and a second three-way electromagnetic valve 25 in sequence, enabling the mixed solution in the reaction bottle 5 to enter a waste liquid bottle 6 through a small solid-phase extraction column 10 (a small C18 column), and then closing the first vacuum pump 31, the third three-way electromagnetic valve 26 and the second three-way electromagnetic valve 25;
(8) opening the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15 in sequence to enable 4mL of the water-solid phase extraction small column 10(C18 small column) in the injector 3 to enter the waste liquid bottle 6, and then closing the second vacuum pump 32, the first electromagnetic valve 27, the first three-way electromagnetic valve 24 and the third three-way valve 15;
(9) opening a second vacuum pump 32, a first electromagnetic valve 27, a first three-way electromagnetic valve 24, a seventh three-way valve 19, an eighth three-way valve 20 and a second three-way valve 14 in sequence, enabling 2mL of 40% ethanol/physiological saline solution loaded in the injector 2 to pass through the second three-way valve 14 and the solid-phase extraction column 10 and enter a buffer bottle 7 containing buffer solution, then closing the second vacuum pump 32, the first electromagnetic valve 27 and the second three-way valve 14, enabling air to pass through the reaction bottle 5 and the solid-phase extraction column 10 and enter the buffer bottle 7, and closing the first three-way valve 13, the sixth three-way valve 18, the seventh three-way valve 19, the eighth three-way valve 20 and the first three-way electromagnetic valve 24 after 15-20 seconds;
(10) turn on in sequenceA vacuum pump 31, a third three-way electromagnetic valve 26, a first three-way electromagnetic valve 24, an eighth three-way valve 20 and a seventh three-way valve 19, so that the mixed solution in the buffer bottle 7 passes through the sterile filter membrane 11 and enters the sterile product bottle 8 to obtain a product68Ga-DOTATOC；
(8) The first vacuum pump 31, the third three-way electromagnetic valve 26, the first three-way electromagnetic valve 24, the eighth three-way electromagnetic valve 20 and the seventh three-way electromagnetic valve 19 are closed, and the automatic preparation process of the medicine is finished, so that the device is recovered to the standby state.
4. Product validation
The product prepared in example 3 was used68The Ga-DOTATOC is analyzed by TLC under the following analysis conditions:
developing agent: methanol/1N NH4OAc 1/1 (volume ratio);
and (3) unfolding the plate: a cellulose board;
the automated preparation device shown can successfully prepare the product by confirmation of the retention shift of specific radioactivity68Ga-DOTATOC。

Claims (10)

1. A kind of68The automatic preparation device of Ga-marked positron medicine is characterized in that: comprises that68The device comprises a Ga ion leaching unit, a coordination chemical reaction unit, a vacuum system, a purification unit and a preparation unit; the above-mentioned68The Ga ion leaching unit is connected with the coordination chemical reaction unit through a pipeline; the coordination chemical reaction unit is connected with a vacuum system through a pipeline; the coordination chemical reaction unit is connected with the purification unit; the purification unit is connected with the preparation unit.
2. The method of claim 168The automatic preparation device of Ga-marked positron medicine is characterized in that: the above-mentioned68The Ga ion leaching unit comprises an injector for loading and leaching hydrochloric acid solution and68Ge/68a Ga generator, a Ga gas generator,68Ge/68the Ga generator is connected with a reaction bottle in the coordination chemical reaction unit through a fifth three-way valve.
3. Root of herbaceous plantThe method of claim 168The automatic preparation device of Ga-marked positron medicine is characterized in that: the coordination chemical reaction unit comprises a reaction bottle and a temperature control component positioned below the reaction bottle; one end of the reaction bottle passes through a fifth three-way valve and68Ge/68the Ga generator is connected with the injector loaded with dilution water through a fourth three-way valve, connected with the injector loaded with elution water through a third three-way valve, connected with the injector loaded with product eluent through a second three-way valve, and connected with a negative pressure system at the other end.
4. The method of claim 368The automatic preparation device of Ga-marked positron medicine is characterized in that: the negative pressure system comprises a first vacuum pump, a second vacuum pump and a pressure gauge, and is connected with a reaction bottle in the coordination chemical reaction unit through a second three-way electromagnetic valve, a first electromagnetic valve, a second needle valve, a second vacuum pump and a second vacuum pump silencer.
5. The method of claim 368The automatic preparation device of Ga-marked positron medicine is characterized in that: the negative pressure system is simultaneously connected with a first needle valve and a first vacuum pump through a third three-way electromagnetic valve and a reaction bottle in the coordination chemical reaction unit; the negative pressure system is also connected with the waste liquid bottle through a first three-way electromagnetic valve.
6. The method of claim 168The automatic preparation device of Ga-marked positron medicine is characterized in that: the purification unit comprises a solid phase extraction small column, an injector for loading leaching water and an injector for loading product eluent; one end of the solid phase extraction column is connected with an injector loaded with product eluent through a first three-way valve and a second three-way valve, and is connected with the injector loaded with elution water through a third three-way valve, and the other end of the solid phase extraction column is connected with a buffer bottle containing buffer solution in the preparation unit through a sixth three-way valve and a seventh three-way valve.
7. The method of claim 168The automatic preparation device of Ga-marked positron medicine is characterized in that: the preparation unit comprises a buffer bottle containing buffer solution, a sterile product bottle, a waste liquid bottle, a sterile filter membrane and an aeration filter membrane; one end of the buffer bottle containing the buffer solution is connected with the sterile product bottle through a sixth three-way valve, a seventh three-way valve and a sterile filter membrane, the ventilation filter membrane is connected with the sterile product bottle, and the other end of the buffer bottle containing the buffer solution is connected with the waste liquid bottle through an eighth three-way valve, a ninth three-way valve and a thirteenth three-way valve.
8. The method of claim 768The automatic preparation device of Ga-marked positron medicine is characterized in that: the other end of the waste liquid bottle is connected with a vacuum system.
9. The method of claim 768The automatic preparation device of Ga-marked positron medicine is characterized in that: the other end of the waste liquid bottle is connected with a negative pressure system through a first three-way electromagnetic valve, a third three-way electromagnetic valve, a first vacuum pump and a first needle valve.
10. The method of claim 668The automatic preparation device of Ga-marked positron medicine is characterized in that: the solid phase extraction column is a C18 purification column or NH respectively2Purifying the small column; the above-mentioned68Ge/68The Ga generator is iTG silica gel column generator.
CN202021264252.2U 2020-07-02 2020-07-02 Automatic preparation device for 68 Ga-labeled positron medicine Active CN213431821U (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106512030A (en) * 2016-11-14 2017-03-22 苏州精标影像科技有限公司 Synthetic process for <68>Ga labeled chemical
CN113019279A (en) * 2021-03-11 2021-06-25 山西医科大学第一医院 Automatic synthesis device for preparing radiopharmaceuticals and using method thereof
CN113813183A (en) * 2021-09-30 2021-12-21 王广林 Automatic synthesis device for radioactive labeling microspheres and use method
CN114700006A (en) * 2022-06-07 2022-07-05 北京先通国际医药科技股份有限公司 Production equipment of liquid composition and preparation method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106512030A (en) * 2016-11-14 2017-03-22 苏州精标影像科技有限公司 Synthetic process for <68>Ga labeled chemical
CN113019279A (en) * 2021-03-11 2021-06-25 山西医科大学第一医院 Automatic synthesis device for preparing radiopharmaceuticals and using method thereof
CN113813183A (en) * 2021-09-30 2021-12-21 王广林 Automatic synthesis device for radioactive labeling microspheres and use method
CN114700006A (en) * 2022-06-07 2022-07-05 北京先通国际医药科技股份有限公司 Production equipment of liquid composition and preparation method and application thereof

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