阅读说明：本技术 放射性药品的制造方法及放射性药品 (Method for producing radiopharmaceutical and radiopharmaceutical ) 是由 吉井幸恵 张明荣 河村和纪 铃木寿 桥本裕辉 于 2020-02-14 设计创作，主要内容包括：本发明提供一种在制造时及制造后维持保持了化学结构及放射性的放射性化合物且能够维持能够应用放射性药品的期间的放射性药品的制造方法及放射性药品。含有包含放射性二氨硫脲铜络合物的放射性成分的放射性药品的制造方法包括：稳定工序,对含有所述放射性成分的溶液添加包含选自包括抗坏血酸、蛋氨酸、抗坏血酸钠、甘露醇及丁基羟基茴香醚的组中的至少一种化合物的稳定剂；及过滤工序,通过无菌过滤器过滤包含所述放射性成分或其前体的溶液,在所述放射性药品中,所述放射性成分的浓度以放射能浓度计为200MBq/mL以上。(The invention provides a method for producing a radiopharmaceutical, and a radiopharmaceutical, which can maintain a period during which the radiopharmaceutical can be applied while maintaining a radioactive compound that retains a chemical structure and radioactivity during and after production. A method for producing a radiopharmaceutical containing a radioactive component comprising a radioactive thiosemicarbazide copper complex, which comprises: a stabilizing step of adding a stabilizer containing at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole to a solution containing the radioactive component; and a filtration step of filtering a solution containing the radioactive component or a precursor thereof through a sterile filter, wherein the radioactive component is contained in the radiopharmaceutical at a concentration of 200MBq/mL or more in terms of radioactivity concentration.)

1. A method for producing a radiopharmaceutical containing a radioactive component including a radioactive thiosemicarbazide copper complex represented by the following general formula (1), the method comprising:

a stabilizing step of adding a stabilizer containing at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole to a solution containing the radioactive component; and

a filtration step of filtering the solution containing the radioactive component or the precursor thereof through a sterile filter,

in the radiopharmaceutical, the concentration of the radioactive component is 200MBq/mL or more in terms of radioactivity concentration,

[ chemical formula 1]

In the formula, R₁、R₂、R₃And R₄Each independently represents a hydrogen atom, an alkyl group or an alkoxy group, and Cu represents a radioisotope of copper.

2. The method for producing a radiopharmaceutical according to claim 1, wherein,

in the filtration step, a filter using hydrophilic PVDF as a constituent material is used as the sterile filter.

3. The method for producing a radiopharmaceutical according to claim 1 or 2, wherein,

in the stabilizing step, the stabilizer includes at least one compound selected from the group consisting of ascorbic acid, sodium ascorbate, and mannitol.

4. The method for producing a radiopharmaceutical according to any one of claims 1 to 3, wherein,

in the radiopharmaceutical, the concentration of the radioactive component is 1GBq/mL or more in terms of radioactivity concentration.

5. A radiopharmaceutical containing a radioactive component comprising a radioactive thiosemicarbazide copper complex represented by the following general formula (1),

the radiopharmaceutical contains a stabilizer comprising at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole,

the concentration of the radioactive component is 200MBq/mL or more in terms of radioactivity concentration,

[ chemical formula 2]

In the formula, R₁、R₂、R₃And R₄Each independently represents a hydrogen atom, an alkyl group or an alkoxy group, and Cu represents a radioisotope of copper.

6. The radiopharmaceutical of claim 5, wherein,

the stabilizer comprises at least one compound selected from the group consisting of ascorbic acid, sodium ascorbate, and mannitol.

7. The radiopharmaceutical of claim 5 or 6, wherein,

the concentration of the radioactive component is 1GBq/mL or more in terms of radioactivity concentration.

8. The radiopharmaceutical of any one of claims 5 to 7, wherein,

the radioactive component is a fraction filtered using a sterile filter.

9. The radiopharmaceutical of claim 8, wherein,

the fraction was filtered using a sterile filter using hydrophilic PVDF as a constituent material.

10. Radiopharmaceutical product according to any one of claims 5 to 9, which is a therapeutic agent or a contrast agent for tumors.

Technical Field

The present invention relates to a radiopharmaceutical and a method for producing the radiopharmaceutical.

Background

Conventionally, a radioactive diamminethiourea copper complex has been considered as a diagnostic agent for a hypoxic site or mitochondrial dysfunction, and studies have been made for administration to the body (for example, patent document 1).

On the other hand, cancer is the first cause of death in Japanese, and there is no effective treatment for difficult cancer. It has been reported that, in most difficult cancers, the hypoxia state in the tumor is related to the resistance to radiation or anticancer agents. Among the above radioactive copper complex compounds, a radioactive diacetyl-bis (N4-methylaminothiourea) copper complex (hereinafter, also referred to as "Cu-ATSM") is known, for example⁶⁴Cu-ATSM accumulates in hypoxic environment in tumor and releases beta-line or auger electron suitable for tumor treatment, thus having high treatment effect on difficult cancer, and is applied to practical applicationIs used for the research of cancer therapeutic drugs.

For example, patent document 2 written by the present inventors discloses a radiopharmaceutical and a pharmaceutical kit, wherein the radiopharmaceutical is administered simultaneously with a chelating agent containing a polydentate ligand having a maximum conformational number of 2 to 4 and contains Cu-ATSM, and the radiopharmaceutical is characterized by containing Cu-ATSM. This technique is intended to reduce radiation exposure to the liver when administering a radioactive thiosemicarbazide copper complex, because it can promote the discharge of radioactivity from the liver by using Cu-ATSM as a radiopharmaceutical including a therapeutic purpose and using the radioactive thiosemicarbazide copper complex together with a specific chelating agent.

Prior art documents

Patent document

Patent document 1: japanese laid-open patent publication No. 8-245425

Patent document 2: japanese patent No. 6085810

Disclosure of Invention

Technical problem to be solved by the invention

Radiopharmaceuticals need to release high quality and sufficient strength and sufficient amount of beta-or auger electrons in vivo over a defined period of time to be effective in treating cancer. Therefore, radiopharmaceuticals are desirably formulated at least at 200MBq/mL at a higher concentration than the radioactive concentration used as a diagnostic agent in the past, i.e., 100MBq/mL or less. In order to sufficiently ensure safety and efficiency in preparation when a drug having such a high radioactivity concentration is treated, it is necessary to produce the drug as safely as possible and at a high recovery rate.

Further, although the radioactivity of the radioactive substance decreases with time, the radiolabeled compound may be modified by the influence of radiation. Cu-ATSM is unstable in aqueous solutions due to radiolysis,⁶⁴Cu-ATSM has a problem that it needs to be used immediately after manufacture and cannot be stored, for example. However, as the storage conditions during and after the production, there is a demand for⁶⁴Cu-ATSM can be used in medical facilities without modification and with a high radioactive concentration, and the quality thereof, that is, the maintenance of radiochemical purity.

There is a demand for a radiopharmaceutical which can sufficiently satisfy both a high recovery rate in the production of the radiopharmaceutical while maintaining the radioactive energy concentration of a radiolabeled active ingredient and a production technique for maintaining the radioactive energy concentration of the active ingredient during and after the production.

The present invention has been made in view of the above circumstances, and an object thereof is to provide a method for producing a radiopharmaceutical, and a radiopharmaceutical, which can maintain a period during which the radiopharmaceutical can be applied while maintaining a radioactive compound in which a chemical structure and radioactivity are retained during and after production.

Means for solving the technical problem

In order to solve the above problems, the present invention has the following aspects.

[1] A method for producing a radiopharmaceutical containing a radioactive component including a radioactive thiosemicarbazide copper complex represented by the following general formula (1), the method comprising:

a stabilizing step of adding a stabilizer containing at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole to a solution containing the radioactive component; and

a filtration step of filtering the solution containing the radioactive component or the precursor thereof through a sterile filter,

in the radiopharmaceutical, the concentration of the radioactive component is 200MBq/mL or more in terms of radioactivity concentration,

[ chemical formula 1]

In the formula, R₁、R₂、R₃And R₄Each independently represents a hydrogen atom, an alkyl group or an alkoxy group, and Cu represents a radioisotope of copper.

[2] The method for producing a radiopharmaceutical according to [1], wherein a filter comprising hydrophilic PVDF as a constituent material is used as the sterile filter in the filtration step.

[3] The method for producing a radiopharmaceutical according to [1] or [2], wherein in the stabilizing step, the stabilizer contains at least one compound selected from the group consisting of ascorbic acid, sodium ascorbate and mannitol.

[4] The method for producing a radiopharmaceutical according to any one of [1] to [3], wherein the concentration of the radioactive component in the radiopharmaceutical is 1GBq/mL or more in terms of radioactive energy concentration.

[5] A radiopharmaceutical containing a radioactive component comprising a radioactive thiosemicarbazide copper complex represented by the following general formula (1),

the radiopharmaceutical contains a stabilizer comprising at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole,

the concentration of the radioactive component is 200MBq/mL or more in terms of radioactivity concentration,

[ chemical formula 2]

In the formula, R₁、R₂、R₃And R₄Each independently represents a hydrogen atom, an alkyl group or an alkoxy group, and Cu represents a radioisotope of copper.

[6] The radiopharmaceutical according to [5], wherein the stabilizer comprises at least one compound selected from the group consisting of ascorbic acid, sodium ascorbate and mannitol.

[7] The radiopharmaceutical according to [5] or [6], wherein the concentration of the radioactive component is 1GBq/mL or more in terms of radioactivity concentration.

[8] The radiopharmaceutical according to any one of [5] to [7], wherein the radioactive component is a fraction filtered using a sterile filter.

[9] The radiopharmaceutical according to [8], wherein the fraction is a fraction filtered using a sterile filter comprising hydrophilic PVDF as a constituent material.

[10] The radiopharmaceutical product of any one of [5] to [9], which is a therapeutic agent or a contrast agent for tumors.

Effects of the invention

According to the present invention, a method for producing a radiopharmaceutical and a radiopharmaceutical can be obtained, which can maintain a period during which the radiopharmaceutical can be applied while maintaining a radioactive compound that retains a chemical structure and radioactivity during and after production.

Drawings

FIG. 1 is a graph showing radiochemical purity of acid stabilizer candidate compounds in this example over time.

FIG. 2 is a graph showing radiochemical purity of amino acid based stabilizer candidate compounds in this example over time.

FIG. 3 is a graph showing the radiochemical purity of a candidate compound for a sodium salt-based stabilizer in this example over time.

FIG. 4 is a graph showing the radiochemical purity of the alcohol stabilizer candidate compound in this example over time.

Fig. 5 is a graph showing the recovery rate of filtration by the various filters in this embodiment.

Fig. 6 is a graph showing the total recovery rate of filtration based on various filters in the present embodiment.

Fig. 7 is a graph showing the recovery rate of filtration by the hydrophilic PVDF filter based on the high concentration of the radioactive component in this example.

Fig. 8 is a graph showing the total recovery rate of filtration by the hydrophilic PVDF filter based on the high concentration of the radioactive component in this example.

Detailed Description

Hereinafter, a method for producing a radiopharmaceutical and a radiopharmaceutical according to the present invention will be described with reference to exemplary embodiments. However, the present invention is not limited to the following embodiments.

(method for producing radiopharmaceutical)

The method for producing a radiopharmaceutical of the present embodiment is a method for producing a radiopharmaceutical containing a radioactive component including a specific thiosemicarbazide copper complex, and includes a stabilization step and a filtration step.

(radioactive component)

The radioactive dithiosemicarbazide copper complex of the present embodiment contains a radioactive component including a radioactive dithiosemicarbazide copper complex represented by the following general formula (1).

[ chemical formula 3]

In the above formula (1), R₁、R₂、R₃And R₄Each independently represents a hydrogen atom, an alkyl group or an alkoxy group. Cu represents a radioactive isotope of copper.

More specifically, in the present embodiment, the substituent R in the above general formula (1)₁、R₂、R₃、R₄The number of carbon atoms of the alkyl group and the alkoxy group in (1) is preferably an integer of 1 to 5, more preferably an integer of 1 to 3. In the present invention, the substituent R in the above general formula (1) is preferred₁、R₂、R₃、R₄The same or different are hydrogen atom or alkyl group of 1 to 3 carbon atoms, more preferably R₁And R₂The same or different are hydrogen atom or alkyl group of 1-3 carbon atoms, R₃Is a hydrogen atom; r₄Is an alkyl group having 1 to 3 carbon atoms; further preferred is R₁And R₂Identically or differently a hydrogen atom or a methyl group, R3 is a hydrogen atom, R₄Is methyl.

Specifically, the radioactive thiosemicarbazide copper complex represented by the above general formula (1) can show:

a radioactive glyoxal-bis (N4-methylaminothiourea) copper complex,

A radioactive glyoxal-bis (N4-dimethyl thiosemicarbazide) copper complex,

A radioactive ethylglyoxal-bis (N4-methylaminothiourea) copper complex,

A radioactive ethyl glyoxal-bis (N4-ethyl thiosemicarbazide) copper complex,

A radioactive methylglyoxal-bis (N4-methylaminothiourea) copper complex,

A radioactive methylglyoxal-bis (N4-dimethyl thiosemicarbazide) copper complex,

A radioactive methylglyoxal-bis (N4-ethylthiosemicarbazide) copper complex,

A radioactive diacetyl-bis (N4-methylaminothiourea) copper complex,

A radioactive diacetyl-bis (N4-dimethylthiosemicarbazide) copper complex,

Radioactive diacetyl-bis (N4-ethylthiosemicarbazide) copper complex, and the like.

Among them, a radioactive diacetyl-bis (N4-methylaminothiourea) copper complex (hereinafter, also referred to as radioactive Cu-ATSM.) or a radioactive methylglyoxal-bis (N4-dimethylaminothiourea) copper complex (hereinafter, also referred to as radioactive Cu-PTSM.) is preferable, and a radioactive diacetyl-bis (N4-methylaminothiourea) copper complex is more preferable.

The radioisotope of copper in the general formula (1) is preferably a radioisotope of copper⁶¹Cu、⁶²Cu、⁶⁴Cu or⁶⁷Cu。⁶¹Cu、⁶²Cu、⁶⁴Both Cu release positrons. And, the radioactive thiosemicarbazide copper complex is aggregated in a hypoxic region, in which Cu-ATSM is aggregated in cancer stem cells. Thus, comprise⁶¹Cu、⁶²Cu、⁶⁴The radiopharmaceutical of Cu can be used as a contrast agent for tumors or virtual blood using Positron Emission Tomography (PET), and preferably can be used as a contrast agent for tumors. On the other hand, in the case of a liquid,⁶⁴Cu、⁶⁷cu also releases short-range beta lines, with a therapeutic effect of destroying cells. Thus, comprise⁶⁴Cu or⁶⁷Cu radiopharmaceuticals are more preferred as tumor therapeutics.

In the present embodiment, the radioactive component is prepared before the stabilization step described later. The preparation of the radioactive component can be carried out by a conventionally known method capable of producing the compound of the above general formula (1). Specifically, the organic compound which is a precursor of the radioactive component can be synthesized as the radioactive component together with a radioisotope of copper.

As the organic compound which becomes a precursor of the radioactive component, a diaminothiourea derivative can be used.

As a specific production process of an organic compound which becomes a precursor, for example, a diaminothiourea derivative which becomes a precursor of a radioactive component is synthesized by the method described in Petering et al (Cancer Res., 24, 367-372, 1964). That is, 1mol of an aqueous solution or 50 vol% ethanol solution of α -ketoaldehyde is added dropwise to 2.2mol of a 5% glacial acetic acid-containing solution of a precursor such as thiosemicarbazide, N4-methylthiosemicarbazide, N4-dimethylthiosemicarbazide at 50 to 60 ℃ over 30 to 40 minutes. The reaction solution was stirred during the dropwise addition. After the addition was completed, the mixture was left at room temperature for several hours, cooled and separated into crystals. The crystals were dissolved in methanol and recrystallized to purify the crystals.

Then, radioactive copper ions are produced. In the production of radioactive copper ions, conventionally known production methods can be used, for example, from⁵⁹Co(α，2n)⁶¹Cu reaction,^natZn(p，x)⁶¹Cu reaction,⁵⁸Ni(α，p)⁶¹Formation of Cu by reaction or the like⁶¹Cu is then chemically separated from the target by ion chromatography or the like, whereby Cu can be obtained⁶¹And (3) Cu ions. And the number of the first and second electrodes,⁶²cu ions can be obtained, for example, by the method described in WO2005/084168, Journal of Nuclear Medcine, vol.30, 1989, 1838-⁶²Zn/⁶²A Cu generator.⁶⁴Cu ions can be obtained, for example, by the method of McCarthy et al (nucleic Medicine and Biology, vol.24(1), 1997, pages 35-43) or the method of Obata et al (nucleic Medicine and Biology, vol.30(5), pages 2003, 535 539). For example from⁶⁸Zn(p，2p)⁶⁷Reaction formation of Cu⁶⁷Cu is then chemically separated from the target by ion chromatography or the like, whereby Cu can be obtained⁶⁷And (3) Cu ions.

Then, the diaminothiourea derivative is brought into contact with a solution containing the radioactive copper ions as a Dimethylsulfoxide (DMSO) solution, thereby obtaining a radioactive diaminothiourea copper complex represented by the general formula (1). As⁶²The method for producing the Cu-diaminothiourea copper complex can be a conventionally known method, and for example, the method described in patent document 1 can be used. And, as⁶¹Examples of the method for producing Cu-ATSM include the method of Jalilian (Act)a Pharmaceutica, 59(1), 2009, pages 45-55). As⁶²Examples of the method for producing Cu-ATSM include methods described in "production of radiopharmaceutical for PET and quality control-synthesis and clinical use entry" (PET chemical studio edition) 4 th edition (revised 2011). As⁶⁴Examples of the method for producing Cu-ATSM include methods such as Tanaka (Nuclear Medicine and Biology, vol.33, 2006, 743-50).

In the present embodiment, the radioactive component of the thus-produced radioactive diaminothiourea copper complex is brought into the form of a solution containing the radioactive component before the stabilization step described later. The radioactive component can be dissolved, suspended or emulsified in an aqueous solvent (water, aqueous solution) or an oily solvent (organic solvent) to form a solution, in addition to the radioactive component being prepared by adjusting the radioactive energy concentration of the DMSO solution during production.

(stabilization step)

The stabilizing step is a step of adding a stabilizer to the solution containing the radioactive component. Stabilizers are components that prevent modification of the radioactive component and stabilize it. It is known that radioactive components are modified by oxidation and autoradiolysis after radioactive labeling. In contrast, in the present embodiment, the chemical structure and radioactivity of the radioactive component are maintained for a long time by adding the stabilizer.

Specifically, as the radioactive component, those conventionally used⁶⁴In the Cu-diammonithiosemicarbazide copper complex,⁶⁴the radioactivity of Cu was halved in approximately 12.7 hours. Further, conventionally, the radioactive component itself is modified with the passage of time after production. That is, the amount of the radioactive component contained in the radiopharmaceutical is reduced as time passes after the production, the chemical structure of the component is retained, and the radioactivity is reduced. The stabilizer is added for the purpose of suppressing the modification of the radioactive component and maintaining the state of maintaining the chemical structure and radioactivity of the radioactive component.

The stable effect can be obtained by taking as a reference the value of% exact probe (radioactivity/total radioactivity of radioactive component × 100) of the radioactive component which is not decomposed after a certain period of time has elapsed after the preparation (production). The stabilizer of the present embodiment is preferably 95% or more, and more preferably 97% or more of the radioactive drug to which the stabilizer is added, of the% exact probe 24 hours after the preparation of the solution of the radioactive component.

In the present embodiment, a so-called radical scavenger is used as the stabilizer. Radical scavengers are compounds that react with free radicals (free radicals) as stable compounds. It is known that in general radical scavengers prevent the modification of pharmaceutical agents comprising radioactive compounds.

In the present embodiment, at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol, and butylated hydroxyanisole can be used as a stabilizer in these radical scavengers. These compounds have particularly high stabilizing effects on the radioactive component of the present embodiment, and can maintain the radioactive component for a long period of time.

In the present embodiment, ascorbic acid, sodium ascorbate, or mannitol is more preferably used as the stabilizer. These compounds do not have carcinogenicity or the like by themselves, and therefore can be preferably used as components contained in therapeutic agents, particularly in therapeutic agents for tumors. Further, these compounds are easy to handle because they have no odor and the like, and therefore can be preferably used in the production and use of therapeutic agents.

When ascorbic acid, sodium ascorbate or mannitol is used, the amount of the stabilizer to be added is preferably 15.49mg to 1.5g, 0.44mg to 44mg, or 8.96mg to 896mg, respectively, per 1mL of the preparation. In particular, when ascorbic acid, sodium ascorbate or mannitol is used, the amount added is more preferably 154.9mg, 4.4mg or 89.6mg per 1mL of the medicament.

As described above, the stabilizer has the effect of inhibiting the modification of the radioactive component and maintaining the state in which the chemical structure and radioactivity of the radioactive component are retained. The radioactive components contained in the radiopharmaceutical decrease in chemical structure with the passage of time after production, and the radioactivity declines. Thus, manufactured in the past⁶⁴Cu-ATSM needs to be used immediately after manufacture and cannot be stored. To exert the full effectThe therapeutic effect of (2) is generally expected to be higher in the radioactive energy concentration of a drug for the purpose of radiotherapy than in a drug mainly used for the purpose of contrast. Therefore, as described later, conventional radiopharmaceuticals not only require a long production time, but also have difficulty in exerting desired medical effects unless used immediately after production. It is also contemplated to further increase the radioactivity concentration during the manufacturing process so that a high radioactivity concentration is maintained over time after manufacture, but it is more desirable to consider safety during the manufacturing process.

In contrast, in the present embodiment, an radiopharmaceutical can be obtained as follows: since the chemical structure and radioactivity of the radioactive component can be maintained for a long time by adding the stabilizer to the radiopharmaceutical, the radiopharmaceutical can be easily produced without having to be produced at a very high radioactivity concentration which is not less than a concentration required for treatment, and can exhibit a medical effect even after a lapse of time after the production.

(filtration step)

The filtration step is a step of filtering the radioactive component or the precursor thereof through a sterile filter. The radiopharmaceutical can be sterilized by the filtration step and can be safely administered to a human body. The radioactive component contained in the radiopharmaceutical is sterilized by filtering the precursor or the synthesized radioactive component before the synthesis of the radioactive component.

In one embodiment of the present invention, the solution to which each component of the radiopharmaceutical is added is filtered through a sterile filter. Specifically, the solution after adding the stabilizer to the solution containing the radioactive component can be filtered.

As the aseptic filter, a filter conventionally used for aseptic processing can be used, and specifically, a filter having a filter size and physical properties that do not allow bacteria to pass therethrough can be suitably used. For example, a filter made of cellulose mixed ester, hydrophilic PES, hydrophilic PVDF, or the like can be used as a constituent material. As for the filtration size of the filter, more specifically, a filter having a pore size of 0.22 μm or less can be used. Also, the housing volume of the filter is preferably less than 10% relative to the total liquid volume filtered.

In the present embodiment, in the step of sterilizing the radioactive component-containing component, it is preferable to use a sterile filter using hydrophilic PVDF as a constituent material among the above-mentioned sterile filters. The step of sterilizing a radioactive-component-containing composition is a step of sterilizing a radiopharmaceutical containing the radioactive component or a solution of the radioactive component or a precursor thereof in the production process of the radiopharmaceutical. Specifically, when a radioactive drug containing a radioactive component, a DMSO solution of a diaminothiourea derivative, or DMSO added to a diaminothiourea derivative is filtered, a sterile filter using hydrophilic PVDF as a constituent material is preferably used.

The sterile filter using hydrophilic PVDF as a constituent material absorbs little organic compounds that are radioactive components and precursors thereof in the present embodiment. Therefore, if hydrophilic PVDF is used for the sterile filter, the loss in the filtration process is small, and a high yield can be obtained in the production.

In addition, as another mode of the production method of the present embodiment, in the filtering step, all the liquid components to be added to the radiopharmaceutical may be added after the filtering step. Specifically, by using fractions obtained by filtering the liquid components of the precursor for synthesizing the radioactive component, the radioactive copper, the stabilizer, and the solution before or after the addition of these components, all the liquid components added to the radiopharmaceutical can be used as the components subjected to the filtration step. In the above embodiment, a fraction obtained by filtering an aqueous solution of dimethyl sulfoxide added to a diaminothiourea derivative and glycine added to a copper radioisotope is used. The fraction obtained by filtration is also used as the stabilizer in the stabilizing step. The components other than the solution are processed under sterile conditions. In the above embodiment, all the components contained in the radiopharmaceutical can be sterilized through these steps.

As an effect of the filtration step, in the conventional production step, since the diaminothiourea copper complex has high lipid solubility and is generally easily adsorbed to the filter, the loss due to the filtration step is large, and the production yield is low. For example, in the conventional production process, when such a filtration operation is performed on a solution containing a synthesized radioactive component, a large amount of the radioactive substance-labeled compound is lost due to adsorption, and the production efficiency is poor and the amount of waste is large. Therefore, in the conventional production, for example, the production may be performed using an excessive amount of raw material. However, since an excessive amount of raw materials requires a large amount of radioactive materials to be treated, there is a problem in preventing radiation exposure of workers during the production process when such a method is used.

In addition, in the conventional production, there is a case where a precursor filtered in advance is used for production of a radioactive component, that is, a case where the radioactive component is produced by mixing raw materials sterile-filtered in an aseptic environment. In this manufacturing method, the number of steps may be large and time may be required. Further, if the number of steps is large and time is required, there is a problem in terms of production yield and radiation exposure of workers. Since it is difficult to perform the process under an aseptic environment and to sufficiently secure a distance or shielding from the radioactive material, it is necessary to reduce the time or process required for the manufacture as much as possible.

In contrast, in the present embodiment, since the filtration step is performed using a filter that adsorbs the radioactive component and the precursor thereof little in the present embodiment, the loss is small and the production yield is high. Therefore, the step of filtering the precursor of the conventional radioactive component can be effectively performed. Further, since the loss is small even if the radioactive component after production is filtered, it is also possible to perform a filtering step on a solution containing the radioactive component and the stabilizer after the step of producing the radioactive component and adding the stabilizer. By performing such a filtration step, the number of filtration steps is reduced, and the process is reduced and time is saved, so that the production yield and the radiation exposure of workers can be improved.

(other steps)

In the method for producing a radiopharmaceutical of the present embodiment, other steps may be added as necessary. For example, a step of adding other components can be added. As the other component, for example, a component for preparing a radiopharmaceutical can be added after all of the above components are added. The radiopharmaceutical can be formulated as an injection by adding additives such as a dispersant, a preservative, a tonicity agent, a solubilizer, a suspending agent, a buffer, a stabilizer, an analgesic, or a preservative.

The radiopharmaceutical of the present invention may be prepared by directly formulating the components subjected to the above-mentioned steps or by formulating the components together with a pharmaceutically acceptable carrier, diluent or excipient. The dosage form may be either oral or parenteral, and for example, a parenteral dosage form such as an injection is preferable.

(radioactivity concentration)

In the radiopharmaceutical thus prepared, the concentration of the radioactive component is 200MBq/mL or more in terms of radioactivity concentration. Radiopharmaceuticals having high radioactive energy concentrations are effective for obtaining therapeutic effects by radiation, particularly when used for therapy. In the radiopharmaceutical of the present embodiment, the concentration of the radioactive component is more preferably 1.0GBq/mL or more. For therapeutic purposes, it can be used at 1.5GBq/mL or more. Although conventional medical drugs containing radioactive components are mainly used for examination and the concentration of the radioactive components is mainly 100MBq/mL or less, in the present embodiment, since a radioactive drug having a high radioactive energy concentration can be efficiently produced, they can be effectively used as a therapeutic drug.

(Effect of the method for producing a radiopharmaceutical of the present embodiment)

According to the method for producing a radiopharmaceutical of the present embodiment, the state in which the radioactive component is not decomposed and is maintained can be maintained for a long time by the stabilizing step. In addition, since the adsorption of the radioactive component by the filter is small by the above-mentioned filtration step, the radioactive component can be sterilized without reducing the yield of the radioactive component. By these effects, the radiopharmaceutical can be produced and stored with stable radioactive components and without reducing the yield. This reduces the storage time and the production time as a whole, and enables the production of a radiopharmaceutical containing a high concentration of a radioactive component in a shorter time. By using these steps in the production of a therapeutic radiopharmaceutical having a high radioactive energy concentration of 200MBq/mL or more, a high-concentration radioactive component can be efficiently obtained, the risk of radiation exposure during production can be reduced, and the production time and cost can be significantly reduced. Further, since the radioactive component is little modified after production, it can be effectively used for a long time after production, and is suitable as a therapeutic agent requiring transportation or storage.

(radiopharmaceutical of the present embodiment and use thereof)

The radiopharmaceutical of the present embodiment is produced by the above-described production method. Specifically disclosed is a radiopharmaceutical containing a radioactive component comprising a radioactive thiosemicarbazide copper complex represented by the general formula (1) below, which contains a stabilizer comprising at least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol and butyl hydroxyanisole, and the concentration of the radioactive component is 200MBq/mL or more in terms of radioactive energy concentration. The radiopharmaceutical of the present embodiment is composed of a fraction obtained by filtering a solution containing the radioactive component and the stabilizer through a sterile filter.

The radiopharmaceutical of the present embodiment can also be used as a therapeutic agent, a contrast agent in a diagnostic procedure, or the like. As described above, since the radioactive component of the present embodiment is accumulated in the hypoxic region and Cu-ATSM is accumulated in the cancer stem cells, the radiopharmaceutical of the present embodiment is preferably a therapeutic agent for treating a tumor or a contrast agent for imaging a tumor. The concentration of the radioactive component in the compound of the present embodiment is as high as 200MBq/mL or more, and the production method of the present embodiment enables production in a state in which the radioactive concentration is kept high, and therefore, the compound is suitable for a therapeutic purpose in which a therapeutic effect can be effectively exhibited by a high radioactive concentration. In particular, according to the above-described property of accumulating in cancer stem cells, it is particularly preferable to be used as a therapeutic agent for tumors.

The radioactive diammonithiosemicarbazide copper complex contained in the radioactive component of the present embodiment can be accumulated in various tumors. Examples of the tumor in which the copper diamminethiourea complex is aggregated include breast cancer, brain cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, large intestine cancer, small intestine cancer, esophageal cancer, duodenal cancer, tongue cancer, throat cancer, salivary gland cancer, schwannoma, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor, angiofibroma, retinosarcoma, penile cancer, testicular tumor, childhood solid cancer, sarcoma, leukemia, and the like. These tumors may be primary or metastatic. The radiopharmaceutical of this embodiment can be used for the treatment of these tumors.

The radiopharmaceutical of the present embodiment can be administered together with other conventionally known drugs. For example, chelators may also be used concurrently to facilitate the removal of radioactivity from the organ to which it is administered. Alternatively, an enema or the like which further promotes the discharge of the radiopharmaceutical from the organ may be used together. Alternatively, a metabolic inhibitor that promotes aggregation of tumor cells may also be used together. Alternatively, an angiogenesis inhibitor for improving an antitumor effect may be used together.

The radiopharmaceutical of the present embodiment can be provided in the form of a kit to which another drug for simultaneous administration is added. For example, the radiopharmaceutical of the present embodiment may be combined with the above-mentioned chelating agent, enema, metabolic inhibitor, angiogenesis inhibitor, or the like as a kit.

While the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments and various modifications can be made.

Examples

Hereinafter, the effects of the present invention will be more clearly understood by examples and comparative examples. The present invention is not limited to the following examples, and can be implemented by appropriately changing the examples without changing the gist thereof.

(Experimental example 1)

As a stabilizer, to⁶⁴Cu-ATSM with addition of and application to various radical scavengers⁶⁴Cu-ATSM stabilizing effectA comparison is made. Prepared with the composition of Table 1⁶⁴Cu-ATSM solution. In addition, will⁶⁴The concentration of Cu was set to 1.5 GBq/mL. Preparing 0.2mol/L glycine aqueous solution in advance, and preparing with it⁶⁴The Cu solution was used for the reaction. Then, ATSM was previously dissolved in dimethyl sulfoxide to prepare a 0.5mmol/L ATSM dimethyl sulfoxide solution, which was then mixed with⁶⁴Cu dissolving solution is mixed, thereby preparing⁶⁴Cu-ATSM solution.

Then, the concentration is adjusted to the specified concentration⁶⁴Each compound (radical scavenger) shown in table 2, which is a candidate for a stabilizer, was added to the Cu-ATSM solution. Will each be⁶⁴The total volume of the Cu-ATSM solution samples was set to 30. mu.L, and 3 samples were prepared under each reaction condition. By thin layer chromatography, the reaction was carried out immediately after 5 hours and 24 hours, respectively⁶⁴Analysis of radiochemical purity of Cu-ATSM. Methanol was used as a developing solvent and the separation was carried out by TLC Silica gel 60 (Merck). Has calculated out that⁶⁴Ratio of Cu-ATSM (% exact probe ═⁶⁴Radioactivity/total radioactivity for Cu-ATSM x 100).

[ Table 1]

Pharmaceutical composition	Per 1mL
		64Cu	3MBq-1.5GBq
ATSM	2.5μg
		Dimethyl sulfoxide	0.02mL
GlycineAcid(s)	7.3mg
		Water for injection	0.98mL
Stabilizer	*

Adding each candidate compound as a stabilizer at a specified concentration

[ Table 2]

As additives based on the respective test examples⁶⁴The results of the Cu-ATSM stabilization effect are shown in FIGS. 1 to 4, as the time-dependent progress of the% exact probe. Fig. 1 shows the study of acid-type candidate compounds (ascorbic acid, citric acid-hydrate, anhydrous citric acid), fig. 2 shows the study of amino acid-type candidate compounds (methionine, cystine hydrochloride-hydrate), fig. 3 shows the study of sodium salt-type candidate compounds (sodium ascorbate, sodium thioglycolate, sodium bisulfite, sodium sulfite, sodium metabisulfite, anhydrous sodium sulfite), and fig. 4 shows the study of alcohol-type candidate compounds (butylated hydroxyanisole, mannitol, benzyl alcohol, ethanol).

The average of 3 samples of each test example after 24 hours is shown in table 3 as AVR and the standard deviation is shown as SD.

[ Table 3]

From the results of FIGS. 1 to 4, it is possible to use⁶⁴Cu-ATSM Stable storage to 24 hours Compound, ascorbic acid of test example 1 was identified (figure)1) 5 kinds of methionine (FIG. 2) in test example 4, sodium ascorbate (FIG. 3) in test example 6, butylated hydroxyanisole (FIG. 4) in test example 12, and mannitol (FIG. 4) in test example 13. As shown in Table 3, the results show that the% exact probe of these components was 97% or more after 24 hours and was maintained after 24 hours⁶⁴The morphology of Cu-ATSM is unmodified and stable.

(Experimental example 2)

As in⁶⁴The sterile filters used for the filtration of Cu-ATSM were compared with a hydrophilic PES filter (Merck KGaA, Millex GP, GP in the figure) or a hydrophilic PVDF filter (Merck KGaA, Millex GV, GV in the figure) using a general-purpose cellulose mixed ester filter (Merck KGaA, Millex GS, GS in the figure)⁶⁴Adsorption of Cu-ATSM. Prepared with the composition of Table 1⁶⁴Cu-ATSM solution. In addition, will⁶⁴The Cu concentration was 3 MBq/mL. Preparing 0.2mol/L glycine aqueous solution in advance, and preparing with it⁶⁴The Cu solution was used for the reaction. Then, ATSM was previously dissolved in dimethyl sulfoxide to prepare a 0.5mmol/L ATSM dimethyl sulfoxide solution, which was then mixed with⁶⁴Cu dissolving solution is mixed, thereby preparing⁶⁴Cu-ATSM solution. Sodium ascorbate, mannitol and ethanol were added as a stabilizer at the concentrations shown in table 2. Each one of⁶⁴The total volume of the Cu-ATSM solution sample was set to 10.2 mL. The radioactivity/weight was measured immediately after the reaction. This was filtered through each filter (GS, GP, and GV) and the radioactivity/weight was measured.

This operation was performed for each 3 samples under each condition using each filter, and the recovery rate (the ratio of the radioactivity concentration after recovery assuming the radioactivity concentration before recovery as 100%) and the total recovery rate (the ratio of the radioactivity after recovery assuming the radioactivity before recovery as 100%) were calculated. The volume of the solution was calculated as a weight conversion. The recovery rates of the respective stabilizers after filtration through the respective filters are shown in fig. 5, and the total recovery rate is shown in fig. 6. The results show that filtration is achieved by using GV as a sterile filter⁶⁴Cu-ATSM, adsorption minimum.

(Experimental example 3)

As in⁶⁴The sterile filter used for the filtration of Cu-ATSM was a hydrophilic PVDF filter (Merck KGaA, Millex GV, GV in the figure) and was confirmed to be at a high radioactivity concentration⁶⁴Adsorption of Cu-ATSM. Prepared with the composition of Table 1⁶⁴Cu-ATSM solution. In addition, will⁶⁴The concentration of Cu was set to 1 GBq/mL. Preparing 0.2mol/L glycine aqueous solution in advance, and preparing with it⁶⁴The Cu solution was used for the reaction. Then, ATSM was previously dissolved in dimethyl sulfoxide to prepare a 0.5mmol/L ATSM dimethyl sulfoxide solution, which was then mixed with⁶⁴Cu dissolving solution is mixed, thereby preparing⁶⁴Cu-ATSM solution. Sodium ascorbate was added as a stabilizer at the concentration shown in table 2.⁶⁴The total volume of the Cu-ATSM solution samples was set to 200. mu.L. The radioactivity/weight was measured immediately after the reaction. It was filtered through a filter and the radioactivity/weight was measured.

This operation was performed for each of the 3 samples, and the recovery rate (the ratio of the radioactivity concentration after recovery assuming that the radioactivity concentration before recovery was 100%) and the total recovery rate (the ratio of the radioactivity energy after recovery assuming that the radioactivity energy before recovery was 100%) were calculated. The volume of the solution was calculated as a weight conversion. The recovery rate after filtration through the filter is shown in fig. 7, and the total recovery rate is shown in fig. 8. The results show that filtration is achieved by using GV as a sterile filter⁶⁴Cu-ATSM at high radioactivity concentrations as used for therapeutic purposes⁶⁴The Cu-ATSM also had little adsorption.

Industrial applicability

According to the method for producing a radiopharmaceutical and the radiopharmaceutical of the present invention, a method for producing a radiopharmaceutical and a radiopharmaceutical can be obtained which can maintain a period during which the radiopharmaceutical can be applied while maintaining a radioactive compound in which a chemical structure and radioactivity are retained during and after production. Therefore, in the production and sale of the radiotherapy agent Cu-ATSM, there are possibilities of utilization such as an extension of the delivery range by extending the effective period, a reduction in cost by improving the production yield, and a reduction in radiation exposure to workers.