CN113663621A - A kind of89Zr medicine marking and purifying device and method - Google Patents

A kind of89Zr medicine marking and purifying device and method Download PDF

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CN113663621A
CN113663621A CN202010405039.7A CN202010405039A CN113663621A CN 113663621 A CN113663621 A CN 113663621A CN 202010405039 A CN202010405039 A CN 202010405039A CN 113663621 A CN113663621 A CN 113663621A
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way valve
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buffer solution
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许波华
秦天
刘正亮
吕玉鹏
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Yinuosi Biotechnology Haimen Co ltd
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    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1018—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against material from animals or humans

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Abstract

The invention discloses a89Zr medicine mark and purification device. The device comprises a pressure device, a raw material bottle of a drug solution to be marked, a raw material bottle of a chelating agent solution,89Zr solution raw materials bottle, product bottle, 2 reation kettle, 2 purification columns, 2 buffer solution raw materials bottles, at least 5 three-way valves and at least 2 check valves. The invention provides89The Zr medicine marking and purifying device can be automatically controlled, is simple to operate, safe and convenient, and can effectively reduce the ionizing radiation exposure of operators; and the marking process and the purification process can be carried out in the device, so that isotope pollution is not easy to occur, and the marking process and the purification process can be efficiently, quickly and accurately completed89Marking and purifying the Zr medicament; by using the device provided by the invention89Zr drug marking and purification, easy operation, high efficiency,The labeling is completed quickly, and the radiochemical purity of the labeled drug can reach more than 95 percent.

Description

A kind of89Zr medicine marking and purifying device and method
Technical Field
The invention relates to a89A Zr medicine marking and purifying device and a method thereof.
Background
Currently, the synthesis of radiopharmaceuticals is mainly performed manually. In the actual operation process, great risks are brought to workers, and the situation of isotope pollution is easy to occur. Therefore, it is desirable to provide a marker and89the contact time of the Zr source is short, the ionizing radiation caused by long-time contact is avoided, and the safety factor is high89Zr medicine mark and purification device.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art89When the Zr medicine is marked and purified, the manual mode is adopted to bring greater risk to the working personnel, the safety coefficient is low, and the defect of isotope pollution is easy to occur, thereby providing the Zr medicine89The Zr medicine marking and purifying device and the method thereof effectively reduce the ionizing radiation exposure of operators and can efficiently, quickly and accurately finish89The Zr medicine is marked and purified, and the operation is simple, safe and convenient.
The invention solves the technical problems through the following technical scheme:
one of the technical schemes of the invention is as follows: a kind of89The Zr medicine marking and purifying device comprises a pressure device (8), a medicine solution raw material bottle to be marked (10), a chelating agent solution raw material bottle (12),89The device comprises Zr solution raw material bottles (14), product bottles (19), 2 reaction kettles, 2 purification columns, 2 buffer solution raw material bottles, at least 5 three-way valves and at least 2 one-way valves;
one end of the pressure device (8) is connected with an inlet of a first three-way valve (1), and two outlets of the first three-way valve (1) are respectively connected with the raw material bottle (10) of the drug solution to be marked and an inlet of a second three-way valve (2);
two outlets of the second three-way valve (2) are respectively connected with the first buffer solution raw material bottle (11) and the inlet of the third three-way valve (3);
two outlets of the third three-way valve (3) are respectively connected with inlets of the chelating agent solution raw material bottle (12) and the fourth three-way valve (4);
the liquid outlet ends of the to-be-marked drug solution raw material bottle (10), the first buffer solution raw material bottle (11) and the chelating agent solution raw material bottle (12) are connected with a first reaction kettle (15);
two outlets of the fourth three-way valve (4) are respectively connected with inlets of a second buffer solution raw material bottle (13) and a fifth three-way valve (5); one liquid outlet end of the second buffer solution raw material bottle (13) is connected with the inlet of the first one-way valve (6); the outlet of the first one-way valve (6) is connected with the first reaction kettle (15); the other liquid outlet end of the second buffer solution raw material bottle (13) is connected with the inlet of the second one-way valve (7); the outlet of the second one-way valve (7) is connected with a second reaction kettle (16);
an outlet of the fifth three-way valve (5) is connected with the89A Zr solution raw material bottle (14); the other outlet of the fifth three-way valve (5) is an exhaust gas outlet (9); the above-mentioned89The liquid outlet end of the Zr solution raw material bottle (14) is connected with the second reaction kettle (16);
the first reaction kettle (15), the first purification column (17), the second reaction kettle (16), the second purification column (18), the second reaction kettle (16) and the product bottle (19) are sequentially connected in series.
In the present invention, the connection means may be conventional in the art, and preferably, the connection means is a pipe connection.
The second technical scheme of the invention is as follows: a kind of89The Zr drug labeling and purifying method is carried out by adopting the device, and comprises the following steps:
step (1): under the pressurizing condition of the pressure device (8), adding a solution of a drug to be marked, a first buffer solution and a solution of a chelating agent into the first reaction kettle (15) for reaction to obtain a reaction solution;
step (2): under the pressure of the pressure device (8), the second buffer solution and89adding the Zr solution into the second reaction kettle (16) to obtain a mixed solution;
and (3): adding the reaction solution in the step (1) into the first purification column (17); adding the second buffer solution into the first reaction kettle (15) under the pressurizing condition of the pressure device (8), and eluting the reaction solution in the step (1); adding the solution obtained after the elution is finished into the second reaction kettle (16) to carry out a labeling reaction with the mixed solution in the step (2) to obtain a labeled reaction solution;
and (4): adding the labeled reaction solution obtained in the step (3) into the second purification column (18); adding the second buffer solution into the second reaction kettle (16) under the pressurizing condition of the pressure device (8), and eluting the labeled reaction solution in the step (3); collecting the solution obtained after the elution is finished into the product bottle (19) to finish the purification, thus obtaining89Zr drug labeling solution.
In the step (1) of the present invention, preferably, the first three-way valve (1) is adjusted to be communicated with only the raw material bottle (10) of the drug solution to be labeled under the pressurization condition of the pressure device (8), and after the drug solution to be labeled is added into the first reaction vessel (15), the first three-way valve (1) is adjusted to be communicated with only the second three-way valve (2);
adjusting the second three-way valve (2) to be communicated with the first buffer solution raw material bottle (11) only, and adjusting the second three-way valve (2) to be communicated with the third three-way valve (3) only after the first buffer solution is added into the first reaction kettle (15);
and adjusting the third three-way valve (3) to be communicated with only the chelating agent solution raw material bottle (12), and adjusting the third three-way valve (3) to be communicated with only the fourth three-way valve (4) after adding the chelating agent solution into the first reaction kettle (15).
In step (1) of the present invention, preferably, the solution of the drug to be labeled, the first buffer solution, and the solution of the chelating agent are mixed uniformly before the reaction.
Wherein, the drug solution to be labeled can be a drug solution to be labeled which is conventional in the field, and can be a monoclonal antibody generally; such as cetuximab, ibritumomab tiuxetan, rituximab, bevacizumab or trastuzumab.
The concentration of the drug solution to be marked can be 1-100 mg/mL, preferably 10-20 mg/mL.
The chelating agent solution may be prepared by dissolving a chelating agent in DMSO.
The chelating agent may be a chelating agent conventional in the art, such as p-NCS-Bz-DFO and/or DFO-Maleimide, preferably p-NCS-Bz-DFO. Wherein, the volume of the DMSO is less than 2% of the total volume of the drug solution to be labeled, the first buffer solution and the chelating agent solution in the step (1), so as to avoid influencing the activity of the drug.
The molecular formula of the p-NCS-Bz-DFO is shown as the formula (I); the molecular formula of the DFO-Maleimide is shown as a formula (II); the DMSO is generally referred to as dimethyl sulfoxide, which is conventional in the art.
Figure BDA0002490954530000041
Wherein the molar ratio of the chelating agent to the drug to be labeled can be 1: 2-1: 4; preferably 1: 3.
The first buffer solution may be a buffer solution conventional in the art, such as a sodium carbonate-sodium bicarbonate buffer. The pH of the first buffer solution can be 8.5-9.0, and is preferably 9.0.
The amount of the first buffer solution may be an amount conventionally used in the art, for example, an amount for adjusting the pH of the drug solution to be labeled to 8.5 to 9.0. The volume ratio of the first buffer solution to the drug solution to be labeled may be 5: 1.
Wherein, the reaction can be carried out under the condition of constant temperature stirring.
The reaction temperature can be 36-38 ℃, and is preferably 37 ℃.
The reaction time can be 30-60 min, preferably 60 min.
Wherein the order of adding the drug solution to be labeled and the first buffer solution to the first reaction vessel (15) can be arbitrarily selected. The chelating agent solution may be added after the drug solution to be labeled and the first buffer solution are added to the first reaction tank (15).
In the step (2) of the present invention, preferably, under the pressurization condition of the pressure device (8), the second one-way valve (7) is opened, the fourth three-way valve (4) is adjusted to be communicated with only the second buffer solution raw material bottle (13), and after the second buffer solution is added into the second reaction kettle (16), the fourth three-way valve (4) is adjusted to be communicated with only the fifth three-way valve (5);
adjusting the three-way valve (5) to only the one with the valve89Zr solution raw material bottles (14) are communicated to make the Zr solution raw material bottles communicate89After the Zr solution is added into the second reaction kettle (16), the fifth three-way valve (5) is adjusted to be communicated with the waste gas outlet (9) only.
In step (2) of the present invention, the amount of the second buffer solution may be an amount of a buffer solution that is conventional in the art, for example, the second buffer solution may be used89The pH value of the Zr solution is adjusted to 7.0-7.5. The amount of the second buffer solution is preferably larger than that of the first buffer solution89The amount of Zr solution used.
Wherein, the89The Zr solution can be zirconium oxalate solution (89Zr-oxalic acid) or zirconium tetrachloride solution (89Zr- ZrCl4)。
The above-mentioned89The concentration of the Zr solution may be 5mCi/mL or more.
In step (3) of the present invention, preferably, the reaction solution in step (1) is added to the first purification column (17); under the pressurization condition of the pressure device (8), opening a first one-way valve (6), adjusting a fourth three-way valve (4) to be communicated with the second buffer solution raw material bottle (13) only, adding the second buffer solution into the first reaction kettle (15), and eluting the reaction liquid in the step (1); and (3) adding the solution obtained after the elution is finished into the second reaction kettle (16) to carry out a labeling reaction with the mixed solution obtained in the step (2), so as to obtain a labeled reaction solution.
Wherein the second buffer solution may be added in an amount of the external water volume of the first purification column (17). The external water volume generally refers to the volume of interstitial spaces of the packing particles within the purification column.
Wherein, the labeling reaction can be carried out under the condition of constant temperature stirring.
The temperature of the labeling reaction can be 20-30 ℃, and is preferably 25 ℃.
The time of the labeling reaction can be 30-60 min, preferably 60 min.
In step (4) of the present invention, preferably, the labeled reaction solution in step (3) is added to the second purification column (18); under the pressurization condition of the pressure device (8), opening a second one-way valve (7), adjusting a fourth three-way valve (4) to be communicated with a second buffer solution raw material bottle (13) only, adding the second buffer solution into the second reaction kettle (16), and eluting the reaction liquid in the step (3); collecting the solution obtained after the elution is finished into the product bottle (19) to finish the purification, thus obtaining89Zr drug labeling solution.
In step (4) of the present invention, the amount of the second buffer solution added may be the volume of the external water of the second purification column (18). The external water volume generally refers to the volume of interstitial spaces of the packing particles within the purification column.
In the present invention, the second buffer solution may be a buffer solution conventional in the art, such as PBS buffer or HEPES buffer. The pH of the second buffer solution can be 7.0-7.5, and is preferably 7.0.
The PBS solution may be a phosphate buffer solution, which is conventional in the art, and whose main components are potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, and potassium chloride. The concentration of the PBS solution can be 0.2 mol/L.
The HEPES solution may be N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid buffer solution, which is conventional in the art, and the main component thereof is hydroxyethylpiperazine ethanesulfonic acid. The concentration of the HEPES solution may be 1 mol/L.
In the present invention, the pressure device (8) may be a pressure device conventional in the art, preferably an inert gas pressure device, more preferably a nitrogen pressure device.
Wherein the pressurization can be micro-pressurization. The micropressure is known to those skilled in the art and generally refers to a pressure between 1 atm and 2 atm. The micro-pressure is used for pushing liquid in the pipeline.
The pressurisation is preferably adjusted to communicate only with the second three-way valve (2) by the first three-way valve (1); -adjusting the second three-way valve (2) to communicate only with the third three-way valve (3); -adjusting the third three-way valve (3) to communicate only with the fourth three-way valve (4); -adjusting the fourth three-way valve (4) to communicate only with the fifth three-way valve (5); adjusting the fifth three-way valve (5) to communicate only with the exhaust gas outlet (9) such that the89A constant flow rate of inert gas was present in the tubing of the Zr drug labeling and purification device.
In the present invention, the reaction kettle may be a reaction kettle conventional in the art, such as a magnetically coupled reaction kettle. The reaction vessel may be generally commercially available.
The purification column may be a purification column conventional in the art, such as a HiTrap desaling, 5mL column. The packing of the purification column may be a packing conventional in the art, such as sephadex. The purification column may be generally commercially available, for example from a commercial source of Cytiva.
In the present invention, the89The time for the Zr drug labeling and purifying device to complete the labeling and purifying can be the labeling and purifying time conventional in the art, for example, less than 3 h.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides89The Zr medicine marking and purifying device can be automatically controlled, is simple to operate, safe and convenient, and can effectively reduce the ionizing radiation exposure of operators; and the marking process and the purification process can be carried out in the device, so that isotope pollution is not easy to occur, and the marking process and the purification process can be efficiently, quickly and accurately completed89Marking and purifying the Zr medicament;
the marking and purifying method provided by the invention is easy to operate, can efficiently and quickly finish marking, and the radiochemical purity of the marked medicine can reach more than 95%.
Drawings
FIG. 1 shows the results of example 189The structure schematic diagram of the Zr medicine marking and purifying device.
Description of reference numerals:
first three-way valve 1
Second three-way valve 2
Third three-way valve 3
Fourth three-way valve 4
Fifth three-way valve 5
First check valve 6
Second check valve 7
Pressure device 8
Exhaust gas outlet 9
Pharmaceutical solution raw material bottle 10 to be marked
First buffer solution raw material bottle 11
Chelating agent solution raw material bottle 12
Second buffer solution raw material bottle 13
89Zr solution raw material bottle 14
First reaction kettle 15
Second reaction kettle 16
First purification column 17
Second purification column 18
Product bottle 19
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
In example 189The Zr medicine marking and purifying device comprises a pressure device 8, a medicine solution raw material bottle 10 to be marked, a chelating agent solution raw material bottle 12,8914 Zr solution raw material bottles, 19 product bottles, 2 buffer solution raw material bottles, 2 reaction kettles, 2 purification columns, 5 three-way valves and 2 one-way valves;
one end of the pressure device 8 is connected with an inlet of the first three-way valve 1, and two outlets of the first three-way valve 1 are respectively connected with a raw material bottle 10 of the drug solution to be marked and an inlet of the second three-way valve 2;
two outlets of the second three-way valve 2 are respectively connected with the first buffer solution raw material bottle 11 and the inlet of the third three-way valve 3;
two outlets of the third three-way valve 3 are respectively connected with the chelating agent solution raw material bottle 12 and the inlet of the fourth three-way valve 4;
the liquid outlet ends of the drug solution raw material bottle 10 to be marked, the first buffer solution raw material bottle 11 and the chelating agent solution raw material bottle 12 are connected with a first reaction kettle 15;
two outlets of the fourth three-way valve 4 are respectively connected with the second buffer solution raw material bottle 13 and the inlet of the fifth three-way valve 5; one liquid outlet end of the second buffer solution raw material bottle 13 is connected with the inlet of the first one-way valve 6; the outlet of the first one-way valve 6 is connected with a first reaction kettle 15; the other liquid outlet end of the second buffer solution raw material bottle 13 is connected with the inlet of the second one-way valve 7; the outlet of the second one-way valve 7 is connected with a second reaction kettle 16;
an outlet connection of the fifth three-way valve 589A Zr solution raw material bottle 14; the other outlet of the fifth three-way valve 5 is an exhaust gas outlet 9;89the liquid outlet end of the Zr solution raw material bottle 14 is connected with a second reaction kettle 16;
the first reaction kettle 15, the first purifying column 17, the second reaction kettle 16, the second purifying column 18, the second reaction kettle 16 and the product bottle 19 are connected in series in sequence.
Wherein, the connection is realized through a pipeline.
The pressure device 8 in example 1 is a nitrogen pressure device, and when the device is used for marking and purification, the first three-way valve 1 is adjusted to be communicated with the second three-way valve 2 only; the second three-way valve 2 is adjusted to communicate only with the third three-way valve 3; the third three-way valve 3 is adjusted to communicate only with the fourth three-way valve 4; the fourth three-way valve 4 is adjusted to communicate only with the fifth three-way valve 5; the fifth three-way valve 5 is adjusted to communicate only with the exhaust gas outlet 9 so that89A constant flow rate of nitrogen was present in the tubing of the Zr drug labeling and purification apparatus.
In example 1, the drug solution to be labeled was ibritumomab tiuxetan, and the concentration of the drug solution to be labeled was 10 mg/mL. The chelating agent solution is prepared by dissolving p-NCS-Bz-DFO in DMSO with a concentration of 10 mmol/L; wherein the volume of DMSO accounts for 0.33% of the total volume of the drug solution to be labeled, the first buffer solution and the chelating agent solution in the step (1). The molar ratio of the drug to be labeled to the chelating agent is 1: 3.
The reaction vessel in example 1 was a magnetically coupled reaction vessel. The purification column is a HiTrap desaling, 5mL column; the commercial source is Cytiva. The filler of the purification column is Sephadex G-25.
The marking and purifying method of the device comprises the following steps:
step (1): under the condition of pressurization of the pressure device 8, the first three-way valve 1 is adjusted to be only communicated with the raw material bottle 10 of the drug solution to be marked, so that the drug solution to be marked is added into the first reaction kettle 15, and then the first three-way valve 1 is adjusted to be only communicated with the three-way valve 2;
adjusting the second three-way valve 2 to be communicated with the first buffer solution raw material bottle 11 only, and adjusting the second three-way valve 2 to be communicated with the third three-way valve 3 only after the first buffer solution is added into the first reaction kettle 15;
the third three-way valve 3 is adjusted to communicate only with the chelating agent solution raw material bottle 12, and after the chelating agent solution is added to the first reaction tank 15, the third three-way valve 3 is adjusted to communicate only with the fourth three-way valve 4.
And uniformly mixing the solution of the drug to be marked, the first buffer solution and the solution of the chelating agent, and reacting at the constant temperature for 60min under the condition of stirring at 37 ℃.
Wherein the volume ratio of the drug solution to be labeled, the first buffer solution and the chelating agent solution is 200:1000: 4.
The first buffer solution is a sodium carbonate-sodium bicarbonate buffer. The pH of the first buffer solution was 9.0.
Step (2): under the condition of pressurization of the pressure device 8, opening the second one-way valve 7, adjusting the fourth three-way valve 4 to be only communicated with the second buffer solution raw material bottle 13, adding the second buffer solution into the second reaction kettle 16, and adjusting the fourth three-way valve 4 to be only communicated with the fifth three-way valve 5;
the fifth three-way valve 5 is adjusted to be only in communication with89The Zr solution raw material bottle 14 is communicated with89After the Zr solution is added to the second reaction vessel 16, the fifth three-way valve 5 is adjusted to communicate with only the exhaust gas outlet 9.
Wherein the second buffer solution and89the volume ratio of the Zr solution is 100: 1.
Wherein the second buffer solution is 1mol/L HEPES buffer solution with the pH value of 7.0.
89The Zr solution is zirconium oxalate solution (89Zr — oxalic acid). The concentration of the zirconium oxalate solution was 1 Ci/mL.
And (3): adding the reaction solution in the step (1) into the first purification column 17; under the condition of pressurization of the pressure device 8, opening the first one-way valve 6, adjusting the fourth three-way valve 4 to be communicated with the second buffer solution raw material bottle 13 only, adding the second buffer solution into the first reaction kettle 15, and eluting the reaction liquid in the step (1); adding the solution obtained after the elution into a second reaction kettle 16, and carrying out a labeling reaction with the mixed solution in the step (2) under the condition of constant-temperature stirring, wherein the temperature of the labeling reaction is 25 ℃ and the time is 60 min; obtaining a labeled reaction solution;
wherein the volume of the solution collected in the reaction vessel 16 after completion of elution was 2.5 mL.
And (4): adding the labeled reaction solution in the step (3) into a second purification column (18); under the condition of pressurization of the pressure device 8, opening the second one-way valve 7, adjusting the fourth three-way valve 4 to be only communicated with the second buffer solution raw material bottle 13, adding the second buffer solution into the second reaction kettle 16, and eluting the reaction liquid in the step (3); collecting the solution obtained after the elution is finished into a product bottle 19, and finishing the purification to obtain89Zr drug labeling solution.
Wherein the volume of the solution collected in the product bottle 19 after completion of elution was 2.5 mL.
The use is as in example 189The time for completing the marking and the purification by the Zr medicine marking and purifying device is less than 3 h.
Detection by Radio-HPLCThe labeled drug has a radiochemical purity of 95% or more. By using the invention89The radiochemical purity of the Zr medicament marking and purifying device and the medicament marked by the method can reach more than 95 percent.

Claims (10)

1. A kind of89The Zr medicine marking and purifying device is characterized in that89The Zr medicine marking and purifying device comprises a pressure device (8), a medicine solution raw material bottle to be marked (10), a chelating agent solution raw material bottle (12),89The device comprises Zr solution raw material bottles (14), product bottles (19), 2 reaction kettles, 2 purification columns, 2 buffer solution raw material bottles, at least 5 three-way valves and at least 2 one-way valves;
one end of the pressure device (8) is connected with an inlet of a first three-way valve (1), and two outlets of the first three-way valve (1) are respectively connected with the raw material bottle (10) of the drug solution to be marked and an inlet of a second three-way valve (2);
two outlets of the second three-way valve (2) are respectively connected with the first buffer solution raw material bottle (11) and the inlet of the third three-way valve (3);
two outlets of the third three-way valve (3) are respectively connected with inlets of the chelating agent solution raw material bottle (12) and the fourth three-way valve (4);
the liquid outlet ends of the to-be-marked drug solution raw material bottle (10), the first buffer solution raw material bottle (11) and the chelating agent solution raw material bottle (12) are connected with a first reaction kettle (15);
two outlets of the fourth three-way valve (4) are respectively connected with inlets of a second buffer solution raw material bottle (13) and a fifth three-way valve (5); one liquid outlet end of the second buffer solution raw material bottle (13) is connected with the inlet of the first one-way valve (6); the outlet of the first one-way valve (6) is connected with the first reaction kettle (15); the other liquid outlet end of the second buffer solution raw material bottle (13) is connected with the inlet of the second one-way valve (7); the outlet of the second one-way valve (7) is connected with a second reaction kettle (16);
an outlet of the fifth three-way valve (5) is connected with the89A Zr solution raw material bottle (14); the other outlet of the fifth three-way valve (5) is an exhaust gas outlet (9); the above-mentioned89The liquid outlet end of the Zr solution raw material bottle (14) is connected with the second reaction kettle (16);
the first reaction kettle (15), the first purification column (17), the second reaction kettle (16), the second purification column (18), the second reaction kettle (16) and the product bottle (19) are sequentially connected in series.
2. The method of claim 189The Zr medicine marking and purifying device is characterized in that the connection mode is connection through a pipeline.
3. The method of claim 189The Zr drug labeling and purifying device, wherein the labeling and purifying method comprises the steps of claim 1 or 289The Zr medicine marking and purifying device comprises the following steps:
step (1): under the pressurizing condition of the pressure device (8), adding a solution of a drug to be marked, a first buffer solution and a solution of a chelating agent into the first reaction kettle (15) for reaction to obtain a reaction solution;
step (2): under the pressure of the pressure device (8), the second buffer solution and89adding the Zr solution into the second reaction kettle (16) to obtain a mixed solution;
and (3): adding the reaction solution in the step (1) into the first purification column (17); adding the second buffer solution into the first reaction kettle (15) under the pressurizing condition of the pressure device (8), and eluting the reaction solution in the step (1); adding the solution obtained after the elution is finished into the second reaction kettle (16) to carry out a labeling reaction with the mixed solution in the step (2) to obtain a labeled reaction solution;
and (4): adding the labeled reaction solution obtained in the step (3) into the second purification column (18); adding the second buffer solution into the second reaction kettle (16) under the pressurizing condition of the pressure device (8), and eluting the labeled reaction solution in the step (3); collecting the solution obtained after the elution is finished into the product bottle (19) to finish the purification, thus obtaining89Zr drug labeling solution.
4. The method of claim 389The Zr drug marking and purifying method is characterized in that in the step (1), the drug solution to be marked, the first buffer solution and the chelating agent solution are uniformly mixed before the reaction;
and/or the drug solution to be labeled is a monoclonal antibody; the monoclonal antibody is preferably cetuximab, ibritumomab tiuxetan, rituximab, bevacizumab or trastuzumab;
and/or the concentration of the drug solution to be marked is 1-100 mg/mL, preferably 10-20 mg/mL;
and/or the chelating agent solution is prepared by dissolving the chelating agent in DMSO;
and/or the chelating agent is p-NCS-Bz-DFO and/or DFO-Maleimide, preferably p-NCS-Bz-DFO;
and/or the volume of the DMSO is less than 2% of the sum of the volumes of the drug solution to be labeled, the first buffer solution and the chelating agent solution in the step (1);
and/or the molar ratio of the chelating agent to the drug to be marked is 1: 2-1: 4, preferably 1: 3;
and/or the first buffer solution is a sodium carbonate-sodium bicarbonate buffer solution; the pH value of the first buffer solution is preferably 8.5-9.0, and more preferably 9.0;
and/or the dosage of the first buffer solution is the dosage for adjusting the pH of the drug solution to be marked to 8.5-9.0; the volume ratio of the first buffer solution to the drug solution to be labeled is preferably 5: 1;
and/or the reaction is carried out under the condition of constant-temperature stirring; the reaction temperature is preferably 36-38 ℃, and more preferably 37 ℃; the reaction time is preferably 30-60 min, and more preferably 60 min.
5. The method of claim 389The Zr medicine marking and purifying method is characterized in that in the step (2), under the condition that the pressure device (8) is pressurized, the second one-way valve (7) is opened, and the fourth three-way valve is connected with the pressure device(4) Adjusting to be communicated with the second buffer solution raw material bottle (13) only, and adjusting the fourth three-way valve (4) to be communicated with the fifth three-way valve (5) only after the second buffer solution is added into the second reaction kettle (16);
adjusting the three-way valve (5) to only the one with the valve89Zr solution raw material bottles (14) are communicated to make the Zr solution raw material bottles communicate89After the Zr solution is added into the second reaction kettle (16), the fifth three-way valve (5) is adjusted to be communicated with the waste gas outlet (9);
and/or the second buffer solution is used in an amount that the second buffer solution is used89Adjusting the pH value of the Zr solution to 7.0-7.5; preferably greater than said89The amount of Zr solution used;
and/or, the said89The Zr solution is a zirconium oxalate solution or a zirconium tetrachloride solution; the above-mentioned89The concentration of the Zr solution is preferably 5mCi/mL or more.
6. The method of claim 389The Zr drug labeling and purifying method is characterized in that in the step (3), the reaction solution in the step (1) is added into the first purifying column (17); under the pressurization condition of the pressure device (8), opening a first one-way valve (6), adjusting a fourth three-way valve (4) to be communicated with the second buffer solution raw material bottle (13) only, adding the second buffer solution into the first reaction kettle (15), and eluting the reaction liquid in the step (1); adding the solution obtained after the elution is finished into the second reaction kettle (16) to carry out a labeling reaction with the mixed solution in the step (2) to obtain a labeled reaction solution;
and/or the second buffer solution is added in an amount of the external water volume of the first purification column (17);
and/or the labeling reaction is carried out under the condition of constant-temperature stirring; the temperature of the labeling reaction is preferably 20-30 ℃, and more preferably 25 ℃; the time of the labeling reaction is preferably 30 to 60min, and more preferably 60 min.
7. The method of claim 389The Zr drug marking and purifying method is characterized by comprising the following stepsIn the step (4), the labeled reaction solution obtained in the step (3) is added into the second purification column (18); under the pressurization condition of the pressure device (8), opening a second one-way valve (7), adjusting a fourth three-way valve (4) to be communicated with a second buffer solution raw material bottle (13) only, adding the second buffer solution into the second reaction kettle (16), and eluting the reaction liquid in the step (3); collecting the solution obtained after the elution is finished into the product bottle (19) to finish the purification, thus obtaining89A Zr drug labeling solution;
and/or the second buffer solution is added in an amount corresponding to the external water volume of the second purification column (18).
8. The method of claim 389The Zr drug labeling and purifying method is characterized in that the pH value of the second buffer solution is 7.0-7.5, preferably 7.0;
and/or the second buffer solution is PBS buffer solution or HEPES buffer solution;
and/or the concentration of the PBS solution is 0.2 mol/L;
and/or the concentration of the HEPES solution is 1 mol/L.
9. The method of claim 389The Zr medicine marking and purifying method is characterized in that the pressurization is micro-pressurization; the micro pressure is between 1 standard atmospheric pressure and 2 standard atmospheric pressures;
and/or the pressure device (8) is an inert gas pressure device, preferably a nitrogen pressure device.
10. The method of claim 389The Zr medicine marking and purifying method is characterized in that the reaction kettle is a magnetic coupling reaction kettle;
and/or, the purification column is a HiTrap desaling, 5mL column;
and/or the filler of the purification column is cross-linked dextran gel.
CN202010405039.7A 2020-05-14 2020-05-14 A kind of89Zr medicine marking and purifying device and method Pending CN113663621A (en)

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