JP2012141147A - Technique to measure and adjust radioactive concentration in chemical solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To automatically measure and adjust a radioactive concentration during manufacture of a radioactive drug.SOLUTION: A method according to an embodiment of the present invention comprises the steps of: performing primary radioactivity measurement by extracting a part of a chemical solution contained in a chemical bottle in an initial state and measuring radioactivity of the extracted chemical solution; returning the extracted chemical solution to the chemical bottle after the primary radioactivity measurement and diluting the chemical solution contained in the chemical bottle with a prescribed amount of diluent; performing secondary radioactivity measurement by extracting a part of the diluted chemical solution from the chemical bottle and measuring radioactivity of the extracted chemical solution; and, assuming that radioactivity of the chemical solution contained in the chemical bottle in the initial state is X, an amount of the chemical solution contained in the chemical bottle in the initial state is Y, a radioactive concentration obtained from a result of the primary radioactivity measurement is a, the amount of the diluent used for dilution is b, and a radioactive concentration obtained from a result of the secondary radioactivity measurement is c, obtaining X and Y in accordance with formulas, X=a*b*c/(a-c) and Y=b*c/(a-c).

Description

  The present invention relates to a technique for measuring and adjusting a radioactivity concentration in a chemical solution. In particular, it can be suitably applied to the case where the radioactivity concentration of a radiopharmaceutical solution is adjusted in the production process of a PET formulation or a SPECT formulation.

Background of the Invention

  PET (positron tomography) and SPECT (single photon emission tomography) are techniques for obtaining a tomographic image of a living body by injecting a tracer (radioactive agent) into the body and detecting gamma rays emitted from the body. It is. It is widely used in the fields of medicine and research because it can image the state of the body without using surgical means.

  Since the tracer used in these technologies is a radioactive substance, the handling of the tracer is required to minimize exposure.

  Radiopharmaceuticals for PET and SPECT are manufactured by first making a stock solution having a relatively high radioactivity concentration (ie, the amount of radioactivity per unit volume) and then injecting a diluted solution to dilute it to a predetermined radioactivity concentration. Yes. In this concentration adjustment step, first, it is necessary to determine the amount of radioactivity and the amount of the undiluted stock solution. However, at present, the step of measuring the radioactivity concentration and the liquid volume of the undiluted solution is in a state that must be performed by human hands. In other words, the bottle containing the stock solution was once removed from the synthesis system and weighed using an electronic balance, and the amount of radioactivity was measured by storing the bottle in a radioactivity measuring instrument. The operation to weigh the bottle and the operation to put the bottle into the radioactivity measuring instrument must be performed manually. It is strange at first glance, but in production many infusion lines are connected to the bottle, and it is difficult to weigh the bottle while they are connected, so eventually the infusion line was removed from the bottle. The weighing operation must be performed manually. Naturally, the operator cannot avoid considerable exposure.

In addition, the presence of human hands during the manufacturing process has become a bottleneck in improving the manufacturing speed. Since radionuclides used for PET and SPECT have a short half-life, they are required to be processed and shipped as soon as possible. For example, ¹⁸ F, one of the typical tracers for PET, has a half-life of only 110 minutes. Therefore, speeding up the manufacturing process is a very important issue for manufacturers of radioactive tracers. Furthermore, in terms of reliability and reproducibility, it is desirable that the PET preparation is performed as automatically as possible (Non-Patent Document 1, page 11, a. First paragraph).
"PET Drugs-Current Good Manufacturing Practice (CGMP)" US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), December 2009

  In view of these circumstances, the inventor of the present application provides a new technology that enables automatic measurement and adjustment of the radioactivity concentration, and can achieve a reduction in exposure dose and an increase in the speed of the manufacturing process. The purpose of the present invention has been achieved.

An exemplary method of implementation of the present invention is:
Primary radioactivity measurement for extracting a part of the chemical liquid contained in the chemical liquid bottle in the initial state and measuring the radioactivity amount of the extracted chemical liquid;
After completion of the primary radioactivity measurement, returning the extracted chemical solution to the chemical solution bottle and diluting the chemical solution in the chemical solution bottle with a predetermined amount of diluent;
Secondary radioactivity measurement for extracting a part of the diluted chemical solution from the chemical solution bottle and measuring the amount of radioactivity of the extracted chemical solution;
Radioactivity concentration obtained from the result of the primary radioactivity measurement, X is the amount of radioactivity of the chemical liquid contained in the chemical liquid bottle in the initial state, Y is the volume of the chemical liquid contained in the chemical liquid bottle in the initial state Where a is the volume of the injected diluent, b is the radioactivity concentration determined from the result of the secondary radioactivity measurement, and c is the radioactivity concentration.
X = a * b * c / (ac), Y = b * c / (ac) (1)
And the stage to get by
Have

  In this method, the amount of radioactivity X and the volume Y of the chemical liquid contained in the chemical liquid bottle in the initial state are determined by the volume b of the injected dilution liquid and the radioactivity concentrations a and c obtained before and after the dilution liquid injection. One of the characteristics is to calculate. Therefore, in order to obtain the quantities X and Y, the work of measuring the mass of the chemical bottle by transporting it to the measuring instrument or measuring the chemical bottle by transporting it to the radioactivity measuring instrument becomes unnecessary. Since the injection amount b of the diluent can be controlled, it is not necessary to use a human hand to know the amount. Also, the radioactivity concentration can be obtained by measuring the radioactivity amount with respect to a known amount of the chemical solution, so that it is possible to know the activity concentration without helping humans. That is, according to the present invention, it is possible to measure the amount Y and the amount of radioactivity X stored in the chemical solution bottle in the initial state by an automatic process, and accordingly, the exposure dose of the worker engaged in the manufacture is reduced. It becomes possible to reduce, and also it becomes possible to shorten the time which manufactures. Furthermore, reliability and reproducibility can be improved by performing the work process by an automatic process.

  The embodiment of the present invention does not mean that all of the above steps have to be automated, but includes that some or all of them are performed manually. What is important is that the above quantities X and Y are calculated according to equation (1).

  The reason why the quantities X and Y are obtained by the equation (1) is as follows.

The radioactivity concentration a obtained by the primary radioactivity measurement is equal to X / Y. Therefore,
X = a * Y (2)
It is expressed. Moreover, since the radioactivity density | concentration c calculated | required by the said secondary radioactivity measurement is X / (Y + b),
X = c * (Y + b) = c * Y + c * b (3)
Here, substituting equation (3) into equation (2) and solving for Y,
Y = b * c / (ac) (4)
Substituting equation (4) into equation (2),
X = a * b * c / (ac) (5)
Is obtained.

  Thus, if the three values of the radioactive concentration a in the initial state, the volume b of the diluted solution to be injected in the middle, and the radioactive concentration c after the dilution are known, the drug bottle is removed from the manufacturing system, Even if it does not apply to a radioactivity measuring device, it becomes possible to obtain | require the chemical | medical solution amount and radioactivity amount in the said chemical | medical solution bottle. It is an important discovery by the present inventor that the amount of chemical solution and the amount of radioactivity in a chemical solution bottle can be obtained from these values.

If the volume Y and the amount of radioactivity X of the chemical solution in the chemical solution bottle in the initial state are known, it is easy to adjust the chemical solution in the chemical solution bottle to a desired radioactivity concentration. For example, g = X / (Y + b + d), where g is the target value of the radioactivity concentration and d is the volume of the diluent that is additionally injected to achieve the target value. Solving for d,
d = (X / g)-(Y + b) (6)
It becomes. It is also an example of an embodiment of the present invention to inject such a volume of diluent and adjust the chemical in the chemical bottle to a desired radioactivity concentration.

After injecting the diluted solution of volume d into the chemical solution bottle, tertiary radioactivity measurement may be performed in which a predetermined amount of the chemical solution is further extracted from the chemical solution bottle to determine the radioactivity concentration. If the radioactivity concentration has not decreased to the target value, a diluent is further added. When the volume of the diluted solution to be added is expressed as e, g = X / (Y + b + d + e).
e = (X / g)-(Y + b + d) (7)
It becomes. For example, injecting such an amount of dilution liquid and adjusting the chemical liquid in the chemical liquid bottle to a desired radioactivity concentration is an example of an embodiment of the present invention.

As described above, the present invention was made for the purpose of automatically measuring and adjusting the radioactivity concentration during the production of radiopharmaceuticals for PET and SPECT. However, as is apparent from the description and drawings of the present specification, and the configuration of the preferred embodiment defined in each claim, the present invention is not limited to the use in line with this purpose. This technology can be used without limitation in all fields that require measurement and adjustment. Further, as described above, embodiments of the present invention do not have to automate all of the above steps, but include those in which some or all of them are performed manually. What is important is that the above quantities X and Y are calculated according to equation (1).
Embodiments of the present invention include various methods, apparatuses, systems, programs, storage media for storing the programs, and the like for carrying out the above methods. Hereinafter, some examples will be introduced with reference to the accompanying drawings.

It is a figure for demonstrating the structure of the radiopharmaceutical manufacturing system 100 which is an example of embodiment of this invention. It is a figure for demonstrating operation | movement of the radiopharmaceutical manufacturing system. It is a figure for demonstrating the structure of the radiopharmaceutical manufacturing system 300 which is an example of the further concrete form of the radiopharmaceutical manufacturing system 100. FIG. It is a figure for demonstrating operation | movement of the radiopharmaceutical manufacturing system.

  FIG. 1 is a diagram for explaining a configuration of a radiopharmaceutical manufacturing system 100 which is an example of an embodiment of the present invention. The drug manufacturing system 100 includes a drug solution bottle 102 for mixing a radiopharmaceutical stock solution and a diluent, a diluent supply module 104 for supplying the drug solution bottle with a diluent, and a part of the drug solution contained in the drug solution bottle 102. Is stored in the chemical solution reservoir 106, and a chemical solution suction / discharge module 108 that generates pressure for returning the chemical solution stored in the chemical solution reservoir 106 to the chemical solution bottle 102, and the chemical solution reservoir 106. And a radioactivity measuring device 110 for measuring the radioactivity amount of the chemical solution. The radiopharmaceutical manufacturing system 100 further includes a control module 112 that controls operations of the diluent supply module 104, the chemical solution intake / discharge module 108, and the radioactivity measurement apparatus 110.

As is well known, the radiation obtained from radionuclides used in PET and SPECT measurements is gamma rays. Therefore, each element including the chemical solution bottle 102 needs to be made of a material that is hardly deteriorated by gamma rays. In the case of PET, the radiation actually emitted from the nuclide is a positron, but the emitted positron immediately causes pair annihilation with a nearby electron, and then jumps out of the system as two photons. The most frequently used labeling compound in the current PET examination is ¹⁸ F-FDG (fludeoxyglucose), which is a derivative in which the hydroxyl group at the 2-position of glucose is substituted with fluorine 18 which is a positron emitting nuclide. In SPECT, various nuclides are used depending on the purpose, and any nuclide that emits gamma rays is used. As described above, since a gamma ray is finally emitted regardless of whether it is a PET drug or a SPECT drug, it is desirable to configure the drug manufacturing system 100 with a strong material. For example, the chemical solution bottle 102 can be a glass bottle, for example.

  The stock solution poured into the chemical bottle 102 is a liquid containing a radionuclide labeling compound used in the measurement of PET or SPECT at a high concentration. The stock solution is supplied from the stock solution supply unit 114 to the chemical solution bottle 102. The stock solution supply unit 114 may be configured to supply the stock solution under the control of the control module 112, and the control module 112 may be configured to control the supply of the stock solution by the stock solution supply unit 114.

  The substance used for diluting the undiluted solution in the chemical solution bottle 102 needs to be a highly biotolerable solution because the manufactured drug is injected into the blood vessel. As such a liquid, for example, physiological saline is preferably used. The diluent supply module 104 may be configured to supply a controlled amount of physiological saline to the drug solution bottle under the control of the control module 112. The control module 112 may be configured to be able to supply an intended amount of physiological saline to the drug solution bottle by controlling the diluent supply module 104.

  The chemical reservoir 106 has a space in which a certain amount of liquid can be stored. The chemical reservoir 106 can be manufactured as a container connected to a chemical bottle by an infusion line. In the case where the infusion line further extends downstream from the chemical reservoir 106, the chemical reservoir 106 may be formed by providing a female-female adapter or the like that can accommodate a predetermined amount of chemical in the infusion line.

  The chemical solution suction / discharge module 108 generates a negative pressure to suck up the chemical solution from the chemical solution bottle 102 to the chemical solution reservoir 106, and generates a positive pressure to generate the chemical solution stored in the chemical solution reservoir 106. It is a device that returns to 102. Therefore, the chemical liquid suction / discharge module 108 can be, for example, a pump. In addition, a preferred embodiment of the chemical liquid suction / discharge module 108 will be described in detail later, so that reference should be made.

  The radioactivity measuring device 110 is a measuring instrument that measures the amount of radioactivity of the chemical solution stored in the chemical solution reservoir 106. As described above, since the radiation obtained from the nuclide for PET or SPECT is gamma rays, the radioactivity measuring apparatus 110 must be a gamma ray detector. There are several types of gamma ray detectors, such as an ion chamber and a scintillation counter, so an appropriate one may be used in consideration of gamma ray energy and ease of installation. It is preferable to cover the chemical reservoir and the radioactivity measuring apparatus 110 with a radiation shield 116 so that the radioactivity measuring apparatus 110 can measure only the radioactivity amount of the chemical contained in the chemical reservoir 106.

  The radioactivity measurement apparatus 110 can be configured to start / stop radioactivity measurement and send measurement data to the control module 112 by being controlled by the control module 112. The control module 112 can be configured to control measurement start and stop of the radioactivity measurement device 110 and transmission / reception of various data.

  The control module 112 is a computer device that includes a CPU 118 and a memory 120. The memory 120 stores a computer program 122 programmed to cause the CPU 118 to execute the functions described so far with respect to the control module 112. It should be understood that the functions of the control module 112 will be executed by the CPU 118 in accordance with the instructions of the program 122 without any particular explanation. However, depending on the embodiment, a part of the function of the control module 112 may be realized by a hardware circuit or a programmable circuit. As the memory 120, existing storage means such as various RAMs, flash memories, and hard disks can be used. As the CPU 118, a commercially available CPU can be used. However, it is preferable to install the CPU 118 and the memory 120 in a place shielded from radiation so that the malfunction and failure are not caused by radiation. The program 122 may be stored in a storage medium such as a CD-ROM and manufactured and sold as a single unit. Such a storage medium is also included in an embodiment of the present invention.

  Then, operation | movement of the radiopharmaceutical manufacturing system 100 is demonstrated using FIG. Step 200 represents the start of operation. At this time, the chemical solution bottle 102 stores the stock solution of the radiopharmaceutical supplied from the stock solution supply unit 114. As described above, this stock solution contains a radionuclide-labeled compound at a high concentration. The final purpose of the operation of the radiopharmaceutical production system 100 is to adjust the radioactivity concentration of this stock solution to a concentration that meets the standard.

  In step 202, the control module 112 sends a signal to the chemical solution intake / discharge module 108 to generate negative pressure in the module 108, thereby sucking out the chemical solution from the chemical bottle 102. The sucked out chemical is filled into the internal space of the chemical reservoir 106. Subsequently, in step 204, the control module 112 sends a signal to the radioactivity measuring device 110 to measure the radioactivity amount of the chemical solution stored in the chemical solution reservoir 106 (primary measurement). As described above, since the chemical reservoir 106 and the radioactivity measuring device 110 are surrounded by the radiation shield 116, the radiation measured by the radioactivity measuring device 110 is substantially radiation emitted from the chemical reservoir 106. . The measured data is sent from the radioactivity measuring device 110 to the control module 112.

  In step 206, the control module 112 sends a signal to the chemical solution intake / discharge module 108 to generate a positive pressure in the module 108, thereby discharging the chemical solution stored in the chemical solution reservoir 106 to the chemical solution bottle 102. Subsequently, in step 208, the control module 112 transmits a signal to the diluent supply module 104 to inject a predetermined amount of diluent into the chemical solution bottle 102. At this time, the high-pressure air is sent from the module 108 to the chemical solution bottle 102 or the stirring blade is rotated in the chemical solution bottle 102 to stir the chemical solution bottle 102 by some means, so that the diluted solution is evenly distributed in the chemical solution. It is preferable to make it spread.

  In step 210, the control module 112 again sends a signal to the chemical solution suction / discharge module 108 to generate negative pressure in the module 108, thereby sucking the chemical solution from the chemical solution bottle 102 into the chemical solution reservoir 106. Subsequently, in step 212, the control module 112 sends a signal to the radioactivity measuring device 110 to measure the radioactivity amount of the chemical solution stored in the chemical solution reservoir 106 (secondary measurement). As with the primary measurement, the measured data is sent from the radioactivity measurement device 110 to the control module 112. In step 214, the chemical solution in the chemical solution reservoir 106 is discharged to the chemical solution bottle 102 by the same control as in step 206.

  In step 216, the control module 112 calculates various information. First, the radioactivity concentration of the chemical solution measured in the primary measurement is obtained. The radioactivity concentration a in the primary measurement is a = q / p, where p is the volume of the chemical solution in the chemical reservoir 106 and q is the measured radioactivity amount. p can be known, for example, by examining the volume of the chemical reservoir 106 in advance. The chemical solution intake / discharge module 108 module 108q is measurement data obtained by the radioactivity measurement apparatus 110. Similarly, the radioactivity concentration c in the secondary measurement can be obtained from c = q ′ / p, where p is the volume of the chemical solution and q ′ is the measured radioactivity amount.

  Depending on the embodiment, the processing flow may be set so that the radioactivity concentrations a and c are obtained in steps 204 and 212, respectively.

  Subsequently, the control module 112 calculates the radioactivity amount X of the chemical solution stored in the chemical solution bottle 102 at the time of Step 200 from the radioactivity concentrations a and c obtained above and the volume b of the diluted solution injected at Step 208. And the volume Y of the chemical solution is obtained by the equations (4) and (5). The diluent supply module 104 is configured to supply the amount of diluent designated by the control module 112 to the chemical solution bottle 102, so that the amount b can be known.

  Further, in step 216, the control module 112 calculates the amount d of the diluted solution that must be additionally supplied in order to adjust the chemical solution in the chemical solution bottle 102 to the target radioactive concentration g. As described above, this amount d can be obtained from Equation (6).

  In step 218, the control module 112 sends a signal to the diluent supply module 104 to supply the amount d of the diluent calculated in step 216 to the chemical solution bottle 102. As described above, it is preferable to stir the liquid in the chemical liquid bottle 102 after the dilution liquid is supplied. Subsequently, in step 220, the control module 112 sends a signal to the chemical solution suction / discharge module 108 again to suck a part of the chemical solution in the chemical solution bottle 102 into the chemical solution reservoir 106, and in step 222, the radioactivity measuring device 110. Is transmitted to measure the amount of radioactivity of the chemical solution stored in the chemical solution reservoir 106 (tertiary measurement). As with the previous measurements, the measured data is sent from the radioactivity measurement device 110 to the control module 112. In step 224, the chemical liquid stored in the chemical liquid reservoir 106 is returned to the chemical liquid bottle 102 in the same manner as in steps 206 and 214.

  In step 226, the control module 112 calculates the radioactivity concentration of the drug solution from the result of the tertiary measurement. Assuming that the amount of the chemical in the chemical reservoir 106 is p, and the radioactivity measured by the third measurement is q ″, the radioactivity concentration c ″ = q ″ / p. Here, c ″ within the allowable error range. If = g, the radioactivity concentration adjustment is complete (step 230). However, if c ″ is not equal to g for some reason, and c ″> g, operation proceeds to step 228 and the control module 112 determines the amount of diluent necessary to achieve the target concentration g. Calculate e and return to step 218 to redo dilution and measurement. The amount e of the necessary diluent at this time can be calculated from the equation (7) as described above.

  In some embodiments, a processing flow may be set up to determine the radioactivity concentration c ″ at step 222.

In step 226, if c ″ <g, that is, if it is found that the radioactivity concentration has fallen below the target value, the stock solution must be added to the chemical solution bottle 102. The volume of the stock solution to be added is determined. If f, the radioactivity concentration of the stock solution is known as a in step 216.
g = (X + af) / (Y + b + d + f)
It is expressed. Solving for f,
f = (X−g (Y + b + d)) / (ga) (8)
It becomes. The control module 112 may be configured to issue a command to the stock solution supply unit 114 to supply the stock solution of the amount f to the chemical solution bottle 102. The stock solution supply unit 114 may be configured to supply a specified amount of stock solution to the chemical solution bottle 102 in accordance with a command from the control module 112.

  As described above, according to the radiopharmaceutical manufacturing system 100, the volume of the stock solution and the amount of radioactivity in the initial state can be obtained by the automatic control process by the control module 112, and the stock solution is diluted and adjusted to a desired radioactivity concentration. It becomes possible. In these processes, it is not necessary for the worker to directly touch or carry the chemical solution bottle, so that a very beneficial effect of preventing the worker from being exposed is exhibited. Furthermore, the fact that it can be implemented as an automatic control process means that an improvement in the adjustment rate of the radioactivity concentration can be expected. As described above, since radionuclides used for PET and SPECT have a short half-life, they are required to be processed into a preparation and shipped as soon as possible. According to the radiopharmaceutical manufacturing system 100, since the manufacturing time can be shortened, it is possible to process with a margin more than before and to deliver the preparation farther than before.

  The feature of the radiopharmaceutical manufacturing system 100 that the operator does not have to handle the chemical bottle directly is that the chemical bottle is broken or the chemical liquid is spilled from the chemical bottle during the movement in addition to the advantage of reducing the exposure. Provides the additional benefit of eliminating danger. As mentioned above, in the conventional method, in order to measure the amount of chemical solution and the amount of radioactivity in the initial state, the chemical bottle was transported by hand and applied to the measuring instrument, so the bottle was accidentally dropped or spilled. It was in a situation that could not be denied. If a chemical bottle is dropped and damaged, radioactive materials may scatter and the bottle fragments may scatter, making it difficult to continue production thereafter. Since radiopharmaceuticals for PET and SPECT cannot be stored, if they cannot be manufactured, there will be a major hindrance to examinations in hospitals and research facilities. According to the radiopharmaceutical manufacturing system 100, it is possible to adjust the radioactivity concentration without moving the chemical solution bottle in an automatic process, so that it is possible to avoid the risk of breakage due to the movement of the bottle.

  Next, an example of a further embodiment of the radiopharmaceutical manufacturing system 100 will be described with reference to FIG.

  A radiopharmaceutical production system 300 depicted in FIG. 3 is an example of a further embodiment of the radiopharmaceutical production system 100 described above. The drug manufacturing system 300 corresponds to the drug solution bottle 302 corresponding to the drug solution bottle 102 of FIG. 1, the diluent supply module 320 corresponding to the diluent supply module 104, the drug reservoir 306 corresponding to the drug reservoir 106, and the radioactivity measuring device 110. A gamma ray detector 310, a stock solution supply unit 314 corresponding to the stock solution supply unit 114, a chemical solution suction / discharge module 340 corresponding to the chemical solution suction / discharge module 108, and a control module 370 corresponding to the control module 112. The chemical solution bottle 302, the chemical solution reservoir 306, the gamma ray detector 310, the stock solution supply unit 314, the diluent supply module 320, the chemical solution suction / discharge module 340, and the control module 370 are respectively the chemical solution bottle 102 and the chemical solution reservoir 106 of the drug production system 100. , The radioactivity measurement device 110, the stock solution supply unit 114, the diluent supply module 104, the chemical solution suction / discharge module 108, and the control module 112 have the same functions.

Similarly to the chemical bottle 102, the chemical bottle 302 is preferably made of a material resistant to gamma rays, and can be made of glass, for example. The stock solution supply unit 314 is configured to supply a stock solution of a radiopharmaceutical containing high concentration ¹⁸ F-FDG (fludeoxyglucose) used for, for example, a PET tracer to the chemical solution bottle 302. The chemical solution reservoir 306 is provided in the middle of the infusion line 342 between the chemical solution bottle 302 and the chemical solution suction / discharge module 340, and is constituted by, for example, a female-female adapter whose internal capacity is known. The gamma ray detector 310 is arranged around the chemical reservoir 306 as shown in the figure in order to efficiently detect the gamma rays emitted from the chemical contained in the chemical reservoir 306. A signal line 372 between the gamma ray detector 310 and the control module 370 is used to transmit a command from the control module 370 to the gamma ray detector 310 and to carry data from the gamma ray detector 310 to the control module 370. Is provided. As in the case of the drug manufacturing system 100, also in the drug manufacturing system 300, the drug solution reservoir 306 and the gamma ray detector 310 are prevented from entering gamma rays from the outside by the gamma ray shield 316.

  The diluent supply module 320 has a syringe S02 for injecting physiological saline (diluted solution) into the drug solution bottle 302. The syringe S02 is configured to be selectively connectable to the flow path 324 leading to the chemical solution bottle 302 and the flow path 326 leading to the physiological saline tank 322 via the flow path switching valve C10. When the flow path switching valve C10 is switched so that the syringe S02 is connected to the flow path 326 and the plunger 332 of the syringe S02 is pulled out from the barrel (outer cylinder) 330 of the syringe S02, negative pressure is generated in the barrel 330 and the flow path 326. The physiological saline in the physiological saline tank 322 is sucked into the barrel 330. Thereafter, the flow path switching valve C10 is switched so that the syringe S02 is connected to the flow path 324, and the plunger 332 is pushed into the barrel 330, whereby the physiological saline in the barrel 330 is communicated with the chemical bottle 302. 324 can be poured. The movement of the plunger 332 is performed by a plunger driving unit 334 driven by a motor. The operation of the motor of the plunger driver 334 is controlled by the control module 370.

  Further, a compressed air supplier 338 is connected to the flow path 324 via a flow path switching valve C09 and a filter 328. The flow path switching valve C09 is switched so that the compressed air supply device 338 is connected to the flow path 324, and compressed air is injected into the flow path 324, thereby pushing out the physiological saline remaining in the flow path 324 to the drug solution bottle 302. be able to. In some embodiments, the compressed air supply 338 may be considered part of the diluent supply module 320. The compressed air supplier 338 can also be used to agitate the liquid in the chemical bottle 302 by injecting compressed air into the chemical bottle 302 via the flow path 324.

  A signal line 374 for carrying a control signal from the control module 370 to the diluent supply module 320 is provided between the control module 370 and the diluent supply module 320. The diluent supply module 320 is configured to transmit a control signal transmitted from the signal line 374 to a switch for switching the flow path switching valves C09 and C10, a motor for the plunger drive unit 334, and the like. Although not shown, the control module 370 and the compressed air supplier 338 are also connected by a control signal line, and the control module 370 transmits a command via the control signal line, thereby providing a compressed air supplier. 338 is configured to control the supply of compressed air by 338. With these functions, the control module 370 is configured to supply a desired amount of physiological saline to the drug solution bottle 302. In addition, since the example of the structure which performs remote control of the switching of a flow-path switching valve and the insertion / extraction of the plunger of a syringe is described in the past patent application publication by this applicant, Unexamined-Japanese-Patent No. 2009-185880, it is necessary. Please refer accordingly.

  The chemical liquid suction / discharge module 340 includes a syringe S01 connected to the infusion line 342 via the flow path switching valve C01. As shown in the figure, the infusion line 342 reaches the chemical bottle 302 and has a chemical reservoir 306 on the way. The plunger 346 of the syringe S01 is configured to be pulled out or pushed in from the barrel (outer cylinder) 344 of the syringe S01 by a motor-controlled plunger driving unit 348. The operation of the motor of the plunger driver 348 can be controlled by a control signal from the control module 370. When the plunger drive unit 348 pulls the plunger 346 out of the barrel 344, a negative pressure is generated in the infusion line 342, and the chemical solution is sucked from the chemical solution bottle 302 to fill the chemical solution reservoir 306. On the other hand, when the plunger driving unit 348 pushes the plunger 346 into the barrel 344, a positive pressure is generated in the infusion line 342, and the chemical solution that has filled the chemical solution reservoir 306 is pushed back to the chemical solution bottle 302. Accordingly, the syringe S01 and the plunger driving unit 348 operate as a chemical solution suction device that sucks the chemical solution and a chemical solution discharge device that discharges the chemical solution.

  A compressed air supply device 352 may be selectively connected to the flow path switching valve C01 in combination with the syringe S01. A filter 354 for purifying the compressed air sent to the infusion lines 350 and 342 may be provided between the flow path switching valve C01 and the compressed air supplier 352. The flow path switching valve C01 is switched so that the compressed air supply device 352 is connected to the infusion line 342, and compressed air is injected from the compressed air supply device 352 into the infusion line 342, thereby existing in the infusion line 342 and the chemical reservoir 306. The chemical solution to be pushed can be pushed out to the chemical solution bottle 302. Therefore, the compressed air supply device 352 can operate alone or together with the plunger driving unit 348 as a chemical solution discharge device that discharges the chemical solution in the chemical solution reservoir 306 to the chemical solution bottle 302.

  Further, the compressed air supply device 352 can agitate the liquid in the chemical liquid bottle 302 by injecting compressed air into the chemical liquid bottle 302 via the infusion line 342.

  The compressed air supplier 352 may be the same device as the compressed air supplier 338.

  Between the control module 370 and the chemical liquid suction / discharge module 340, a signal line 376 for carrying a control signal from the control module 370 to the chemical liquid suction / discharge module 340 is provided. The chemical liquid suction / discharge module 340 is configured to transmit a control signal transmitted from the signal line 376 to a switch for switching the flow path switching valve C01, a motor for the plunger drive unit 348, and the like. Although not shown, the control module 370 and the compressed air supplier 352 are also connected by a control signal line, and the control module 370 transmits a command via the control signal line to thereby provide a compressed air supplier. It is comprised so that supply of the compressed air by 352 can be controlled. With these functions, the control module 370 is configured to be able to suck the chemical solution from the chemical solution bottle 302 into the chemical solution reservoir 306 and to discharge the chemical solution from the chemical solution reservoir 306 to the chemical solution bottle 302. Further, the control module 370 is configured to agitate the liquid in the chemical liquid bottle 302 by controlling the compressed air supplier 352 and injecting compressed air into the chemical liquid bottle 302.

  In addition to the flow path switching valve C01 and the syringe S01, several elements such as the flow path switching valves C02 to C08 are drawn in the chemical solution suction / discharge module 340 of FIG. This is an element used for switching the flow path as necessary in the manufacturing process of the radiopharmaceutical. As described above, the chemical solution suction / discharge module 340 may include various elements in addition to the flow path switching valve C01 and the syringe S01. The flow path switching valves C02 to C08 are preferably configured so that the flow path can be switched remotely by the control module 370 using, for example, the technique disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 2009-185880.

  The control module 370 is a computer device that includes a CPU 380 and a memory 382, similarly to the control module 112 of the drug manufacturing system 100. The memory 382 stores a computer program 384 programmed to cause the CPU 380 to execute the functions described so far with respect to the control module 370. Throughout this specification, it should be understood that the functions of the control module 370 are executed by the CPU 380 in accordance with the instructions of the program 384, unless otherwise specified.

  Next, the operation of the radiopharmaceutical manufacturing system 300 will be described with reference to FIG. Step 400 represents the start of the operation. At this time, the chemical solution bottle 302 stores the stock solution of the radiopharmaceutical supplied from the stock solution supply unit 314. This stock solution contains a radionuclide labeled compound at a high concentration. The final purpose of the operation of the radiopharmaceutical production system 300 is to adjust the radioactivity concentration of this stock solution to a concentration that can be used for actual PET / SPECT measurement.

  Step 402 is a step of extracting a part of the chemical solution in the chemical solution bottle 302 into the chemical solution reservoir 306 in order to measure the amount of radioactivity. For this purpose, the control module 370 sends a signal to the plunger driver 348 to move the plunger 346 of the syringe S01 in a direction to exit the barrel 344. As a result, a negative pressure is generated in the infusion line 342, the chemical solution in the chemical solution bottle 302 is sucked and moved to the chemical solution reservoir 306. In addition, before sending a signal to the plunger drive part 348, the control module 370 may control the flow path direction of the flow path switching valves C01 to C06 so that the syringe S01 is connected to the infusion line 342.

  In step 404, the amount of radioactivity of the chemical in the chemical reservoir 306 is measured. The control module 370 sends a signal to the gamma ray detector 310 to measure the amount of radioactivity of the chemical solution stored in the chemical solution reservoir 306 (primary measurement). As described above, since the chemical reservoir 306 and the radioactivity measuring device 310 are surrounded by the radiation shield 316, the radiation measured by the radioactivity measuring device 310 can be regarded as radiation emitted from the chemical reservoir 306. . The measured data is sent from the radioactivity meter 310 to the control module 370.

  Step 406 is a stage in which the chemical solution sucked into the chemical solution reservoir 306 is returned to the chemical solution bottle 302. The control module 370 sends a signal to the plunger driver 348 to move the plunger 346 of the syringe S01 in the direction of entering the barrel 344. As a result, a positive pressure is generated in the infusion line 342, and the chemical solution in the chemical solution reservoir 306 is pushed back to the chemical solution bottle 302. In some embodiments, after the plunger 346 is pushed back into the barrel 344, the control module 370 switches the flow path switching valve C01 to connect the compressed air supply 352 to the infusion line 342 and to send compressed air from the compressed air supply 352 to the infusion line. The chemical solution remaining in the infusion line 342 or the chemical solution reservoir 306 may be discharged to the chemical solution bottle 302 by performing control so as to be delivered into the chemical solution 342. In some embodiments, the order of sending compressed air and moving the plunger 346 may be reversed. Depending on the embodiment, the chemical solution in the chemical solution reservoir 306 may be discharged only by sending compressed air by the compressed air supply device 352 instead of by moving the plunger 346.

  Step 408 is a stage in which the chemical solution in the chemical solution bottle 302 is diluted with a diluent such as physiological saline. First, the control module 370 sets the flow path switching valve C10 so that the syringe S02 is connected to the physiological saline tank 322 via the flow path 326. Subsequently, the control module 370 sends a signal to the plunger driving unit 334 to move the plunger 332 of the syringe S02 in the direction of exiting the barrel 330 by a distance controlled by the signal. Then, negative pressure is generated in the barrel 330 and the flow path 326, and an amount of physiological saline corresponding to the negative pressure is sucked up from the physiological saline tank 322 into the barrel 330. Subsequently, the control module 370 sets the flow path switching valves C10 and C09 so that the syringe S02 is connected to the chemical liquid bottle 302 via the flow path 324. Then, the control module 370 sends a signal to the plunger drive unit 334 to move the plunger 332 in the direction of entering the barrel 330. Thereby, the physiological saline in the barrel 330 is pushed out to the chemical solution bottle 302 through the flow path 324. The control module 370 further sets the flow path switching valve C09 so that the compressed air supply unit 338 is connected to the flow path 324, and sends a signal to the compressed air supply unit 338 to send compressed air to the flow path 324. Thereby, the physiological saline remaining in the flow path 324 can be pushed out to the chemical solution bottle 302. The relationship between the amount of movement of the plunger 332 and the physiological saline supplied to the chemical solution bottle 302 needs to be examined in advance, and the control module 370 adds the physiological saline to be added to the chemical solution bottle 302 based on the relationship. Configured so that the amount can be accurately controlled.

  Step 409 is a stage in which the liquid in the chemical tank is agitated so that the stock solution and the diluent are well mixed in the chemical tank. For this purpose, the control module 370 controls the compressed air supply 338 or / and the compressed air supply 352 to blow compressed air onto the chemical bottle 302. Thereby, the liquid in the chemical tank is agitated. At this time, it may be necessary to set the flow path switching valves C01 to C06, C09, and C10 as necessary so that the compressed air passage is opened.

  Steps 410, 412, and 414 are steps in which the amount of radioactivity is measured again (secondary measurement) for the diluted chemical solution. Since the operations in these steps are the same as those in steps 402, 404, and 406, respectively, description thereof is omitted.

  In step 416, from the results of the primary measurement in step 404 and the secondary measurement in step 412, the radioactivity amount and volume of the chemical solution in the chemical solution bottle 302 in the initial state, that is, the time point of step 400 are obtained by calculation; And calculating the amount of diluent to be added to dilute the chemical solution to a desired radioactivity concentration. The calculation process at this stage is the same as the process exemplified in step 216 in FIG. It is to be noted that the processing flow may be set up so that the radioactivity concentrations before and after the diluent injection are calculated in steps 404 and 412, respectively, as in the processing of FIG.

  Step 418 is a stage in which the amount of diluent calculated as the amount to be added in Step 416 is additionally supplied into the chemical liquid bottle 302. Since the operation for adding the diluent is the same as that in step 408, description thereof is omitted. Step 419 is a stage in which the added diluted solution is agitated to mix well with the liquid in the chemical solution bottle, but the operation is the same as in step 409, and thus the description is omitted.

  Steps 420, 422, and 424 are steps in which the amount of radioactivity is measured again (tertiary measurement) for the chemical solution diluted in steps 418 and 419. The tertiary measurement is performed in order to collect data for confirming whether or not the chemical solution in the chemical solution bottle 302 is really adjusted to a desired radioactivity concentration by the dilution in steps 418 and 419. Since the operations themselves in steps 420, 422, and 424 are the same as those in steps 402, 404, and 406, respectively, description thereof is omitted.

  Step 426 is a step of determining whether or not the radioactivity concentration of the chemical solution is adjusted to a desired value from the data of the tertiary measurement. If it is determined that the radioactivity concentration of the chemical solution is a desired value, the adjustment of the radioactivity concentration is completed (step 430). However, if it is determined that there is no desired value, the value necessary for adjusting the drug solution to the target radioactivity concentration is calculated again (step 428), and the processing from step 418 is repeated. Since the operations of Steps 426 and 428 are the same as Steps 226 and 228 of FIG. 2, further description is omitted.

  As described above, various aspects for carrying out the present invention have been described through the description of the configuration and operation of the radiopharmaceutical manufacturing system 100 or 300, but these descriptions are intended to limit the scope of the present invention. It is not provided but rather provided to contribute to a deeper understanding of the invention and is provided to meet legal requirements for patenting. The claims define several preferred embodiments of the present invention, but it should be understood that these embodiments can also be embodied in various specific configurations without departing from the spirit of the invention. Nor. These specific embodiments are included in the scope of the claimed invention.

DESCRIPTION OF SYMBOLS 100 Radiopharmaceutical manufacturing system 102 Chemical solution bottle 104 Diluent supply module 106 Chemical solution reservoir 108 Chemical solution suction / discharge module 110 Radioactivity measuring device 112 Control module 114 Stock solution supply part 116 Radiation shield 118 CPU
120 Memory 122 Program 300 Radiopharmaceutical production system 302 Chemical solution bottle 306 Chemical solution reservoir 310 Gamma ray detector 314 Stock solution supply unit 316 Gamma ray shield 320 Dilution solution supply module 322 Saline tank 324, 326 Channel 328 Filter 330 Barrel 332 Plunger 334 Plunger drive 338 Pressure Air Supply Unit 340 Chemical Solution Intake / Discharge Module 342 Infusion Line 344 Barrel 346 Plunger 348 Plunger Drive Unit 352 Pressure Air Supply Unit 354 Filter 370 Control Module 372, 374, 376 Signal Line 382 Memory 384 Program C01-C10 Channel Switching Valve S01 , S02 Syringe

Claims (13)

Primary radioactivity measurement for extracting a part of the chemical liquid contained in the chemical liquid bottle in the initial state and measuring the radioactivity amount of the extracted chemical liquid;
After completion of the primary radioactivity measurement, returning the extracted chemical solution to the chemical solution bottle and diluting the chemical solution in the chemical solution bottle with a predetermined amount of diluent;
Secondary radioactivity measurement for extracting a part of the diluted chemical solution from the chemical solution bottle and measuring the amount of radioactivity of the extracted chemical solution;
Radioactivity concentration obtained from the result of the primary radioactivity measurement, X is the amount of radioactivity of the chemical liquid contained in the chemical liquid bottle in the initial state, Y is the volume of the chemical liquid contained in the chemical liquid bottle in the initial state Where a is the volume of the injected diluent, b is the radioactivity concentration determined from the result of the secondary radioactivity measurement, and c is the radioactivity concentration.
X = a * b * c / (ac), Y = b * c / (ac)
And the stage to get by
A method for adjusting the concentration of a radiopharmaceutical.   The method according to claim 1, further comprising the step of additionally injecting a diluent into the chemical bottle in order to adjust the radioactivity concentration of the chemical in the chemical bottle to a target value. After the step of additionally injecting the diluted solution, it has a tertiary radioactivity measurement that further extracts a predetermined amount of the chemical solution from the chemical solution bottle to obtain the radioactivity concentration,
The method according to claim 2, wherein if the radioactivity concentration obtained in the tertiary radioactivity measurement does not match the target value, the diluted solution or the stock solution of the chemical solution is further injected into the chemical solution bottle. A chemical bottle that can contain the chemical, and
A chemical liquid suction device for sucking a chemical liquid from the chemical liquid bottle;
A chemical reservoir for storing the chemical sucked into the chemical suction device;
A chemical solution discharging device for discharging the chemical solution in the chemical solution reservoir to the chemical solution bottle;
A radioactivity measuring device for measuring the radioactivity of the chemical in the chemical reservoir;
A diluent supply device capable of supplying a diluent to the chemical bottle;
An operation method of a control device for controlling operations of the chemical solution suction device, the chemical solution discharge device, the radioactivity measurement device, and the dilution solution supply device.
The chemical solution aspirator is operated so that a predetermined amount of chemical solution is sucked from the chemical solution bottle in the initial state and held in the chemical solution reservoir, and the radiation is measured so as to measure the amount of radioactivity of the chemical solution in the chemical solution reservoir. Performing a primary radioactivity measurement, including operating a performance measuring device;
After the primary radioactivity measurement, in order to discharge the chemical solution in the chemical solution reservoir to the chemical solution bottle, the chemical solution discharge device is operated and the dilution solution is injected so as to inject a predetermined amount of the dilution solution into the chemical solution bottle. Operating the feeding device;
The chemical liquid aspirator is operated so that the predetermined amount of chemical liquid is sucked from the comfort liquid bottle into which the dilution liquid has been injected and held in the chemical liquid reservoir, and the radioactivity amount of the chemical liquid in the chemical liquid reservoir is set. Performing a secondary radioactivity measurement comprising operating the radioactivity measurement device to measure;
Radioactivity concentration obtained from the result of the primary radioactivity measurement, X is the amount of radioactivity of the chemical liquid contained in the chemical liquid bottle in the initial state, Y is the volume of the chemical liquid contained in the chemical liquid bottle in the initial state A, b is the volume of the injected diluent, and c is the radioactivity concentration obtained from the result of the secondary radioactivity measurement, the X and Y are expressed by the formula X = a * b * c / ( a-c), Y = b * c / (ac)
Calculating with:
Having a method.   5. The method according to claim 4, further comprising operating the dilution liquid supply device to inject a dilution liquid into the chemical liquid bottle in order to adjust the radioactivity concentration of the chemical liquid in the chemical liquid bottle to a target value. The method described. After the additional injection of the diluted solution, the chemical solution aspirator is operated again so that the predetermined amount of the chemical solution is sucked and held in the chemical solution reservoir, and the radioactivity amount of the chemical solution in the chemical solution reservoir is measured. Performing the tertiary radioactivity measurement, including operating the radioactivity measurement device to determine the radioactivity concentration from the measured radioactivity amount and the chemical liquid amount in the chemical reservoir;
If the radioactivity concentration measured in the tertiary radioactivity measurement does not match the target value, the dilution liquid supply device is operated so as to inject the dilution liquid further into the chemical liquid bottle, or the chemical liquid bottle Operating the chemical injection device of the system to inject a chemical solution having a high radioactivity concentration;
The method of claim 5 further comprising: The chemical solution reservoir is provided on an infusion line between the chemical solution suction device and the chemical solution discharge device and the chemical solution bottle,
The radioactivity measuring device is installed around the chemical reservoir.
The chemical reservoir and the radioactivity measuring device are installed so as to be surrounded by a shield that shields radiation from other than the chemical reservoir.
The method according to any one of claims 4 to 6. The chemical solution discharge device has a compressed air supply device, the compressed air supply device,
By sending compressed air to the chemical reservoir, the chemical in the chemical reservoir is pushed out to the chemical bottle, and / or
By sending compressed air to the chemical solution bottle through the chemical solution reservoir, the liquid in the chemical solution bottle can be stirred.
The method according to any one of claims 4 to 7. The chemical solution suction device and the compressed air supply device are configured to be selectively connected to the chemical solution reservoir by a flow path switch,
The control device further includes controlling the flow path switch so that the chemical solution suction device or the compressed air supply device is connected to the chemical solution reservoir according to a processing stage.
The method of claim 8.   The method according to any one of claims 4 to 7, wherein the chemical liquid suction device and the chemical liquid discharge device are configured by a single suction and discharge device. A chemical bottle that can contain the chemical, and
A chemical liquid suction device for sucking a chemical liquid from the chemical liquid bottle;
A chemical reservoir for storing the chemical sucked in the chemical suction device;
A chemical solution discharging device for discharging the chemical solution in the chemical solution reservoir to the chemical solution bottle;
A radioactivity measuring device for measuring the radioactivity of the chemical in the chemical reservoir;
A diluent supply device capable of supplying a diluent to the chemical bottle;
In the control device that controls the operation of the chemical solution suction device, the chemical solution discharge device, the radioactivity measurement device, and the dilution solution supply device, the system is executed by the processing means of the control device, The program which makes it operate so that this control apparatus may perform the method of any one of Claim 4 to 10. A chemical bottle that can contain the chemical, and
A chemical liquid suction device for sucking a chemical liquid from the chemical liquid bottle;
A chemical reservoir for storing the chemical sucked in the chemical suction device;
A chemical solution discharging device for discharging the chemical solution in the chemical solution reservoir to the chemical solution bottle;
A radioactivity measuring device for measuring the radioactivity of the chemical in the chemical reservoir;
A diluent supply device capable of supplying a diluent to the chemical bottle;
11. A control device for controlling operations of the chemical solution suction device, the chemical solution discharge device, the radioactivity measurement device, and the dilution solution supply device for a system comprising: A controller configured to perform the described method. A chemical bottle that can contain the chemical, and
A chemical liquid suction device for sucking a chemical liquid from the chemical liquid bottle;
A chemical reservoir for storing the chemical sucked in the chemical suction device;
A chemical solution discharging device for discharging the chemical solution in the chemical solution reservoir to the chemical solution bottle;
A radioactivity measuring device for measuring the radioactivity of the chemical in the chemical reservoir;
A diluent supply device capable of supplying a diluent to the chemical bottle;
It is a control apparatus which controls operation | movement of the said chemical | medical solution suction apparatus, the said chemical | medical solution discharge apparatus, the said radioactivity measuring apparatus, and the said dilution liquid supply apparatus, Comprising: The method of any one of Claim 4 to 10 can be performed. A controller configured as follows:
A system comprising:

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