TWI696598B - METHOD FOR AUTOMATED PRODUCTION OF 68Ga-LABELLED RADIOPHARMACEUTICALS AND CASSETTE KIT FOR HORIZONTAL-TYPE CASSETTE-BASED SYNTHESIZERS - Google Patents

Abstract

The present invention is related to a method for automated production of ⁶⁸Ga-labelled radiopharmaceuticals and cassette kit for horizontal-type cassette-based synthesizers.

Description

Automatic synthesis method of 68Ga logo positive contrast agent for horizontal cassette type radiochemical synthesizer With its synthetic kit

The invention relates to a method for automatically synthesizing ⁶⁸ Ga-marked positive contrast medium used in a horizontal cassette radiochemical synthesizer and a synthesis kit thereof.

In view of the fact that positron tomography (PET) provides superior spatial and temporal resolution than traditional single-photon tomography (SPECT), and from time to time there is a shortage of cu-99m ( ⁹⁹ mTc) nuclear species, so the gallium-68 ( ⁶⁸ Ga) mark Zhizheng medicine will gradually replace the traditionally used [ ⁹⁹ mTc] standard medicines, such as the commonly used clinically-used -99-marked macro-aggregated albumin (MAA) (ie [ ⁹⁹ mTc]Tc-MAA) Perfusion scanning of nuclear medicines may be replaced by [ ⁶⁸ Ga]Ga-MAA.

The [ ⁶⁸ Ga]GaCl ₃ extract eluted by the ⁶⁸ Ga generator often contains some metallic radioactive substances (such as ⁶⁸ Ge) or may contain heavy metal ions such as Fe, Zn, Cu, etc. that make the marking difficult and toxic Wait, so often need additional methods for its purification. After that, it is often necessary to add an appropriate frozen crystal bottle and an appropriate amount of buffer solution for labeling and subsequent formulation to obtain the clinically available ⁶⁸ Ga-labeled positive drug. This process is currently not easy to automate, or additional purchases are required. Automatic synthesizer. In order to meet the future clinical requirements of ⁶⁸ Ga-marked proton drugs (GMP specifications and sterile preparations) and to reduce personnel's exposure to radiation operations, its automatic synthesis is inevitable.

Because the cassette-type radiochemical synthesizer is generally considered to be an important machine for the automatic synthesis of [ ¹⁸ F]FDG in each positive center or radiopharmaceutical factory. In addition, the cassette-type radiochemical synthesizer uses a sterile and disposable synthesis kit to reduce possible cross-contamination between production batches, which is in line with the concept of GMP pharmaceuticals. The cassette design of this kind of synthesizer can be divided into horizontal type (such as GE's M _X FDG and FASTlab synthesizer, TRASIS Allinone synthesizer and ORA's NEPTIS synthesizer), flat type (IBA's Syntehra synthesizer and Eckert&Zigler ModularLab EAZY synthesizer) and combined (SCINTOMICS GRP synthesizer). Among them, the cassette-type radiochemical synthesizer with horizontal cassette design is most commonly used.

According to the literature (Mueller et al. , Applied Radiation and Isotopes 122 (2017) 72-77), for the purification of [ ⁶⁸ Ga]GaCl ₃ and the [ ⁶⁸ Ga]Ga-MAA logo, it has developed related manual and automated procedures, However, the automated program can only be used for the flat cassette radiochemical synthesizer ModularLab EAZY synthesizer (Eckert & Ziegler, Germany). Since the horizontal cassette type radiochemical synthesizer is known as a highly stable synthesizer, it has a long history of use, and is widely used in various positive centers or radiopharmaceutical factories for the primary synthesis of [ ¹⁸ F]FDG automatic synthesis Machine model. In view of the high utilization rate of the horizontal cassette type radiochemical synthesizer (for example, 8 positive centers and two positive pharmaceutical factories in Taiwan all use horizontal cassette type radiochemical synthesizers), the present invention is designed A ⁶⁸ Ga-marked positive drug automated program for the horizontal cassette radiochemical synthesizer further develops the corresponding synthesis kit group for use.

Compared with the planar cassette type radiochemical synthesizer, the horizontal cassette type radiochemical synthesizer is more widely used, and the synthesis kit used can also be used with multiple brands of horizontal cassette type The radiochemical synthesizers are used in comparison with each other (such as MXFDG and FASTlab synthesizers from GE, ALLINONE synthesizer from TRASIS and NEPTIS synthesizer from ORA). Therefore, this invention not only provides an automatic synthesis method to use the existing horizontal cassette radiochemical synthesizer for the automated synthesis of ⁶⁸ Ga-labeled positive drug, but also includes its corresponding horizontal cassette synthesis kit group. For use with. Moreover, the present invention can also be used for the automated synthesis of other ⁶⁸ Ga-labeled macromolecules (proteins or peptides). The horizontal cassette synthesis kit set provided by the present invention is a kit of aseptic specifications for purifying and concentrating [ ⁶⁸ Ga]GaCl ₃ directly on the horizontal cassette radiochemical synthesizer and the precursor for ⁶⁸ Ga logo The sign and preparation of the substance (or frozen crystal) will greatly simplify the handling and marking process and reduce the chance of the operator being exposed to radiation, and obtain the ₆₈ Ga marked positron drug with high purity and high activity concentration that can be used in the human body .

The invention provides a method for automatically synthesizing ⁶⁸ Ga-marked positron contrast medium for a horizontal cassette radiochemical synthesizer, which includes: (a) placing [ ⁶⁸ Ga]GaCl ₃ aqueous solution in a fourth collector; (b ) The [ ⁶⁸ Ga]GaCl ₃ aqueous solution placed in the fourth collector is pumped to a fourth reagent access device; (c) The [ ⁶⁸ Ga]GaCl ₃ aqueous solution placed in the fourth reagent access device is passed through a A second separation device to bring the impurities in the aqueous solution into a first collector; (d) passing the NaCl/HCl mixed solution placed in a third reagent access device through the second separation device and passing [ ⁶⁸ Ga]GaCl _{3 is} brought to a second collector containing a precursor and a first buffer; (e) ⁶⁸ Ga logo reaction is carried out in the second collector at an appropriate temperature and time; (f ) Bring a second buffer placed in a second reagent access device into the second collector for neutralization to obtain the ⁶⁸ Ga-marked positive contrast agent; (g) the ^{68 of} step (f) The Ga-label positive contrast agent is pumped to a first reagent access device; (h) the ⁶⁸ Ga-label positive contrast agent of step (g) is passed through a filtering device for sterilization; and (i) the step (h) of the ⁶⁸ Ga mark positive son contrast medium is brought to a third collector for use.

The present invention also provides an automated synthesis kit for preparing ⁶⁸ Ga logo positive drug, which includes a horizontal cassette type radiochemical synthesizer cassette, which has a first cassette connector (1) and a second cassette connector ( 2), a third cassette connector (3), a fourth cassette connector (4), a fifth cassette connector (5), a sixth cassette connector (6), a seventh cassette connector ( 7), an eighth cartridge connector (8), a ninth cartridge connector (9), a tenth cartridge connector (10), an eleventh cartridge connector (11), a twelfth cartridge Connector (12), a thirteenth cartridge connector (13), a fourteenth cartridge connector (14), a fifteenth cartridge connector (15), a first liquid transfer tube (T1), a first Two liquid transfer tubes (T2), a third liquid transfer tube (T3), a fourth liquid transfer tube (T4), a fifth liquid transfer tube (T5), a sixth liquid transfer tube (T6), a first Seven liquid transfer tubes (T7), a first reagent access device (S1), a second reagent access device (S2), a third reagent access device (S3), a fourth reagent access device (S4 ), a first separation device (C1), a second separation device (C2), a first sterilization filter device (F1), a second sterilization filter device (F2), a first collector (V1), a Second collector (V2), a third collector (V3), a fourth collector (V4), a fifth collector (V5), a carrier gas inlet (G1) and a carrier gas outlet (G2) The first separation device (C1) is connected to the carrier gas inlet (G1) so that the acidic solution does not flow back to the carrier gas inlet (G1), and the fourth reagent access device (S4) is directly connected to the first Fourteen cassette connector (14), the fourth collector (V4) is connected to the thirteenth cassette connector (13) with the seventh liquid transfer tube (T7), and the second separation device (C2) Placed in the second cartridge connector (2) and connected to the eleventh cartridge connector (11) by the second liquid transfer tube (T2), and the first collector (V1) uses the first liquid transfer tube (T1) connected to the first joint cassette (1) so as to produce an accelerator or by the production of ^[68 Ga] GaCl ₃ transmitted from the fourth solution was extracted collector (V4) to the fourth reagent In the access device (S4), and further pass the second separation device (C2) for purification, and further pass the unnecessary solution to the first collector (V1), the third reagent access device (S3) ) Is directly connected to the twelfth cartridge connector (12), and the second collector (V2) is connected to the sixth cartridge connector (6) by the third liquid transfer tube (T3) and the fourth The liquid transfer tube (T4) is connected to the fifteenth cartridge joint (15), and the fifth collector (V5) is connected to the carrier gas outlet (G2) and is placed behind the hot lead chamber to The solution stored in the third reagent access device (S3) passes through the second liquid transfer tube (T2) and the first The second separation device (C2) passes to the second collector (V2) and carries out the sign reaction, and passes the unnecessary gas and solution in the process to the fifth collector (V5) through the carrier gas outlet (G2) and , The second reagent access device (S2) is directly connected to the fifth cartridge connector (5), and after the reaction is completed, the solution stored in the second reagent access device (S2) is transferred to the second collector (V2), gases and solutions not needed in the process will be transferred to the fifth collector (V5), the first reagent access device (S1) is directly connected to the fourth cartridge connector (4), the third After the collector (S3) is connected to the first sterilizing filter device (F1) and the second sterilizing filter device (F2), the fifth sterilizing filter device (F1) is connected to the fifth liquid transfer tube (T5) and further Connected to the seventh cartridge connector (7), the prepared product in the second collector (V2) is transferred to the first reagent access device (S1), and further passes through the first sterilization filter device (F1) ) For sterilization and passed to the third collector (V3) for use.

1‧‧‧ First cassette connector

2‧‧‧Second cassette connector

3‧‧‧The third cassette connector

4‧‧‧ fourth cassette connector

5‧‧‧Fifth cassette connector

6‧‧‧ 6th cassette connector

7‧‧‧The seventh cassette connector

8‧‧‧The eighth cassette connector

9‧‧‧Ninth cassette connector

10‧‧‧The tenth cassette connector

11‧‧‧Eleventh cassette connector

12‧‧‧12th cassette connector

13‧‧‧Thirteenth cassette connector

14‧‧‧14th cassette connector

15‧‧‧Fifth cassette connector

T1‧‧‧The first liquid transfer tube

T2‧‧‧Second Liquid Transmission Tube

T3‧‧‧Third Liquid Transmission Tube

T4‧‧‧The fourth liquid transfer tube

T5‧‧‧Fifth liquid transfer tube

T6‧‧‧Sixth liquid transmission tube

T7‧‧‧The seventh liquid transfer tube

S1‧‧‧ First reagent access device

S2‧‧‧Second reagent access device

S3‧‧‧The third reagent access device

S4‧‧‧ Fourth reagent access device

C1‧‧‧First separation device

C2‧‧‧Second separation device

F1‧‧‧The first sterilization filter device

F2‧‧‧Second sterilization filter device

V1‧‧‧First collector

V2‧‧‧Second collector (round bottom flask)

V3‧‧‧The third collector

V4‧‧‧ Fourth collector

V5‧‧‧ fifth collector

G1‧‧‧Carrier gas inlet

G2‧‧‧Carrier gas outlet

Figure 1 is a diagram of the ⁶⁸ Ga logo positive drug automatic synthesis kit of the horizontal cassette radiochemical synthesizer.

In a preferred embodiment, the automated production method of the ⁶⁸ Ga-labeled positive drug used in the horizontal cassette radiochemical synthesizer of the present invention includes the following steps: Step 1: Convert [ ⁶⁸ Ga]GaCl ₃ The aqueous solution is placed in the fourth collector (V4) in advance; Step 2: The [ ⁶⁸ Ga]GaCl ₃ aqueous solution is pumped to a fourth reagent access device (S4); Step 3: It is placed in the fourth reagent access device (S4) The [ ⁶⁸ Ga]GaCl ₃ aqueous solution passes through a second separation device (C2) to bring out impurities into the first collector (V1); Step 4: Place it in a third reagent access device (S3 ) Of the NaCl/HCl mixed solution passes through the second separation device (C2) and takes [ ⁶⁸ Ga]GaCl ₃ to a second collector (V2) that already contains the precursor and the first buffer, step 5 : Carry out the ⁶⁸ Ga logo reaction in the second collector (V2) at an appropriate temperature and time; Step 6: Bring the second buffer placed in a second reagent access device (S2) to the second collector (V2) Internal neutralization to obtain the ⁶⁸ Ga logo positive contrast agent: Step 7: Pump the product to a first reagent access device (S1); Step 8: Pass the product through a filter device (F1) Sterilization; and Step 9: Bring the product to the third collector (V3) for use.

In a preferred embodiment, the automated synthesis kit for the production of ⁶⁸ Ga-marked positive drugs of the present invention includes the following devices: In addition to the connectors on the cassettes of the original horizontal cassette type radiochemical synthesizers (see label 1~ 15) In addition, it also contains 7 liquid transfer tubes (see the marked T1~T7 in the figure); 4 reagent access devices (see the marked S1~S4 in the figure); 2 separation devices (see the marked C1 in the figure) And C2); 2 sterilization and filtration devices (see the labels F1 and F2 in the illustration); 5 collectors (see the labels V1~V5 in the illustration); a carrier gas inlet (G1) and a carrier gas outlet (G2) . The installation and use procedures of the synthesis kit are as follows: The first separation device (C1) is connected to the carrier gas inlet (G1) of the synthesis kit so that the acid solution in the process does not flow back to the carrier gas inlet (G1).

The fourth reagent access device (S4) is directly connected to the cartridge connector (14), and the fourth collector (V4) is connected to the cartridge connector (13) via the seventh liquid transfer tube (T7), and the second is separated The device (C2) is placed in the cartridge connector 2 and connected to the cartridge connector (11) by the second liquid transfer tube (T2), and the first collector (V1) is connected to the cartridge by the first liquid transfer tube (T1) fitting (1) is connected to the generator, or by the production of the accelerator ^[68 Ga] GaCl ₃ transmitted from the fourth solution was extracted collector (V4) to the fourth reagent inside access means (S4), and further The second separation device (C2) is used for purification, and further passes the unnecessary solution to the first collector (V1).

The third reagent access device (S3) is directly connected to the cartridge connector (12), and the second collector (V2) is connected to the cartridge connector (6) by a third liquid transfer tube (T3) and the fourth liquid is transferred The tube (T4) is connected to the cassette joint (15), and the fifth collector (V5) is connected to the carrier gas outlet (G2) outlet (the rightmost pipeline) of the synthesis kit and is placed behind the hot lead chamber, The solution stored in the third reagent access device (S3) is transferred to the second collector (V2) through the second liquid transfer tube (T2) and the second separation device (C2) and the sign reaction is performed. Unwanted gases and solutions pass through the carrier gas outlet (G2) to the fifth collector (V5).

The second reagent access device (S2) is directly connected to the cartridge connector (5), and after the reaction is completed, the solution stored in the second reagent access device (S2) is transferred to the second collector (V2), process Unwanted gases and solutions will be passed to the fifth collector (V5).

The first reagent access device (S1) is directly connected to the cartridge connector (4), the third collector (V3) After connecting two sterilization filter devices (F1 and F2) and connecting the fifth liquid transfer tube (T5) with F1 and further connected with the cassette joint (7), the second collector (V2) The prepared product is transferred to the first reagent access device (S1), and further passed through the first sterilization filter device (F1) for sterilization and transferred to the third collector (V3) for use.

The above exemplary embodiments are used to provide a description of specific aspects of the invention to those skilled in the art to which the invention pertains. The aspects such as dosage or operation time described in these examples are not intended to limit the scope of the invention. Without further elaboration, those skilled in the art can make the most of the present invention based on the description herein. All published publications cited in this article are incorporated by reference in their entirety.

1‧‧‧ First cassette connector

2‧‧‧Second cassette connector

3‧‧‧The third cassette connector

4‧‧‧ fourth cassette connector

5‧‧‧Fifth cassette connector

6‧‧‧ 6th cassette connector

7‧‧‧The seventh cassette connector

8‧‧‧The eighth cassette connector

9‧‧‧Ninth cassette connector

10‧‧‧The tenth cassette connector

11‧‧‧Eleventh cassette connector

12‧‧‧12th cassette connector

13‧‧‧Thirteenth cassette connector

14‧‧‧14th cassette connector

15‧‧‧Fifth cassette connector

T1‧‧‧The first liquid transfer tube

T2‧‧‧Second Liquid Transmission Tube

T3‧‧‧Third Liquid Transmission Tube

T4‧‧‧The fourth liquid transfer tube

T5‧‧‧Fifth liquid transfer tube

T6‧‧‧Sixth liquid transmission tube

T7‧‧‧The seventh liquid transfer tube

S1‧‧‧ First reagent access device

S2‧‧‧Second reagent access device

S3‧‧‧The third reagent access device

S4‧‧‧ Fourth reagent access device

C1‧‧‧First separation device

C2‧‧‧Second separation device

F1‧‧‧The first sterilization filter device

F2‧‧‧Second sterilization filter device

V1‧‧‧First collector

V2‧‧‧Second collector

V3‧‧‧The third collector

V4‧‧‧ Fourth collector

V5‧‧‧ fifth collector

G1‧‧‧Carrier gas inlet

G2‧‧‧Carrier gas outlet

Claims (2)

A method for automatically synthesizing ⁶⁸ Ga-marked positron contrast medium used in a horizontal cassette radiochemical synthesizer includes: (a) placing [ ⁶⁸ Ga]GaCl ₃ aqueous solution in a fourth collector (V4); (b ) The [ ⁶⁸ Ga]GaCl ₃ aqueous solution placed in the fourth collector is pumped to a fourth reagent access device (S4); (c) The [ ⁶⁸ Ga]GaCl ₃ placed in the fourth reagent access device The aqueous solution passes through a second separation device (C2) through a second liquid transfer tube (T2) to bring the impurities in the aqueous solution into a first collector (V1); (d) will be placed in a third reagent The NaCl/HCl mixed solution of the access device passes through the second separation device (C2) from the second liquid transfer tube (T2), and takes [ ⁶⁸ Ga]GaCl ₃ to a solution containing a precursor and a first buffer In a second collector (V2); (e) ⁶⁸ Ga mark reaction with temperature and time in the second collector (V2); (f) will be placed in a second reagent access device (S2) with one of the second buffer to said second collector (V2) to the neutralization to give the ⁶⁸ Ga flag positron contrast agent; (G) ⁶⁸ Ga flag to the step (f) being evacuated to a sub contrast agent The first reagent access device (S1); (h) passing the ⁶⁸ Ga-marked positive contrast agent of step (g) through a filter device (F1) for sterilization; and (i) passing the ⁶⁸ Ga of step (h) The marked positive contrast agent is taken to a third collector (V3) for use. An automated synthesis kit for preparing ⁶⁸ Ga logo positive drug includes: a horizontal cassette type radiochemical synthesizer cassette, which has a first cassette joint (1), a second cassette joint (2), A third cassette connector (3), a fourth cassette connector (4), a fifth cassette connector (5), a sixth cassette connector (6), a seventh cassette connector (7), An eighth cartridge connector (8), a ninth cartridge connector (9), a tenth cartridge connector (10), an eleventh cartridge connector (11), a twelfth cartridge connector (12) ), a thirteenth cartridge connector (13), a fourteenth cartridge connector (14), a fifteenth cartridge connector (15), a first liquid transfer tube (T1), a second liquid transfer Tube (T2), a third liquid transfer tube (T3), a fourth liquid transfer tube (T4), a fifth liquid transfer tube (T5), a sixth liquid transfer tube (T6), a seventh liquid transfer Tube (T7), a first reagent access device (S1), a second reagent access device (S2), a third reagent access device (S3), a fourth reagent access device (S4), a First separation device (C1), a second separation device (C2), a first sterilization filter device (F1), a second sterilization filter device (F2), a first collector (V1), a second collection (V2), a third collector (V3), a fourth collector (V4), a fifth collector (V5), a carrier gas inlet (G1) and a carrier gas outlet (G2); wherein the The first separation device (C1) is connected to the carrier gas inlet (G1) so that the acid solution does not flow back to the carrier gas inlet (G1), and the fourth reagent access device (S4) is directly connected to the fourteenth Cartridge connector (14), the fourth collector (V4) is connected to the thirteenth cartridge connector (13) with the seventh liquid transfer tube (T7), and the second separation device (C2) is placed The second cartridge connector (2) is connected to the eleventh cartridge connector (11) by the second liquid transfer tube (T2), and the first collector (V1) is connected by the first liquid transfer tube (T1) is connected to the first joint cassette (1) so as to produce an accelerator or by the production of ^[68 Ga] GaCl ₃ transmitted from the fourth solution was extracted collector (V4) to the fourth access agent In the device (S4), and further through the first separation device (C1) for purification, and further pass the unnecessary solution to the first collector (V1), the third reagent access device (S3) directly Connected to the twelfth cartridge connector (12), and the second collector (V2) is connected to the sixth cartridge connector (6) by the third liquid transfer tube (T3) and the fourth liquid is transferred The tube (T4) is connected to the fifteenth cassette connector (15), and the fifth collector (V5) is connected to the carrier gas outlet (G2) and is placed behind the hot lead chamber to connect the third The solution stored in the reagent access device (S3) is separated from the second liquid transfer tube (T2) and the second The device (C2) passes to the second collector (V2) and carries out the sign reaction, and passes the unnecessary gas and solution in the process to the fifth collector (V5) through the carrier gas outlet (G2) and the The second reagent access device (S2) is directly connected to the fifth cartridge connector (5), and after the reaction is completed, the solution stored in the second reagent access device (S2) is transferred to the second collector (V2 ), gases and solutions that are not needed in the process will be passed to the fifth collector (V5), the first reagent access device (S1) is directly connected to the fourth cartridge connector (4), the third collector (S3) After the first sterilization filter device (F1) and the second sterilization filter device (F2) are connected, the fifth liquid transfer tube (T5) is connected with the first sterilization filter device (F1) and further connected with the The seventh cartridge connector (7) is connected, and the prepared product in the second collector (V2) is transferred to the first reagent access device (S1), and further passes through the first sterilization filter device (F1) to Sterilize and pass to the third collector (V3) for use.

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