WO2020202831A1 - 放射性医薬の製造方法及び放射性医薬 - Google Patents

放射性医薬の製造方法及び放射性医薬 Download PDF

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WO2020202831A1
WO2020202831A1 PCT/JP2020/005830 JP2020005830W WO2020202831A1 WO 2020202831 A1 WO2020202831 A1 WO 2020202831A1 JP 2020005830 W JP2020005830 W JP 2020005830W WO 2020202831 A1 WO2020202831 A1 WO 2020202831A1
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radioactive
radiopharmaceutical
concentration
component
producing
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French (fr)
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幸恵 吉井
明栄 張
和紀 河村
鈴木　寿
裕輝 橋本
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National Institutes For Quantum Science and Technology
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National Institutes For Quantum Science and Technology
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Priority to CN202080025813.XA priority Critical patent/CN113766952B/zh
Priority to US17/598,400 priority patent/US20220175973A1/en
Priority to JP2021511185A priority patent/JP7576334B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/121—Solutions, i.e. homogeneous liquid formulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a radiopharmaceutical and a method for producing the same.
  • the radioactive dithiosemicarbazone copper complex has been conventionally known as a diagnostic agent for hypoxic sites and mitochondrial dysfunction, and studies have been conducted on its administration into the body (for example, Patent Document 1).
  • Cu-ATSM radioactive diacetyl-bis (N4-methylthiosemicarbazone) copper complex
  • Patent Document 2 by the present inventors describes a radiopharmaceutical used to be administered in combination with a chelating agent, which contains Cu-ASTM, and the chelating agent has a maximum number of loci of 2 or more.
  • Radiopharmaceuticals and pharmaceutical kits are disclosed that contain polydentate ligands of 4 or less loci.
  • This technology can promote the excretion of radioactivity from the liver by using Cu-ATSM as a radiopharmaceutical for therapeutic purposes, and by using a radioactive dithiosemicarbazone copper complex in combination with a specific chelating agent. It is intended to reduce the exposure to the liver during administration of the semicarbazone copper complex.
  • the radiopharmaceutical In order for radiopharmaceuticals to exert their cancer therapeutic effects, it is necessary to emit high-quality, sufficient intensity and amount of ⁇ -rays and Auger electrons within a predetermined time in the body. Therefore, it is desired that the radiopharmaceutical be prepared at a concentration of at least 200 MBq / mL, which is higher than the radioactivity concentration of 100 MBq / mL or less used as a conventional diagnostic agent. When handling a drug having such a high radioactivity concentration, it must be manufactured as safely as possible and with a high recovery rate in order to sufficiently ensure the safety and efficiency in the preparation.
  • radioactivity of radioactive substances decreases with time, but on the other hand, radioactively labeled compounds may be denatured by the influence of radiation.
  • Cu-ATSM is unstable in an aqueous solution due to radiolysis.
  • 64 Cu-ATSM there is a problem that it cannot be stored and must be used immediately after production.
  • the quality that is, the radiochemical purity, for a period in which 64 Cu-ATSM can be utilized in a medical facility without being denatured and having a high radioactivity concentration.
  • the present invention has been made in view of the above circumstances, and is a radiopharmaceutical capable of maintaining a radioactive compound having a chemical structure and radioactivity during and after production, and maintaining a period during which the radiopharmaceutical can be utilized. It is an object of the present invention to provide a manufacturing method and a radiopharmaceutical.
  • a method for producing a radioactive drug which contains a radioactive component containing a radioactive dithiosemicarbazone copper complex represented by the following general formula (1).
  • a filtration step of filtering a solution containing the radioactive component or a precursor thereof with a sterilization filter is included.
  • the radiopharmaceutical is a method for producing a radiopharmaceutical, wherein the concentration of the radioactive component is 200 MBq / mL or more in terms of radioactivity concentration.
  • R 1 , R 2 , R 3 and R 4 each independently represent a hydrogen atom, an alkyl group or an alkoxy group.
  • Cu represents a radioactive isotope of copper.
  • R 1 , R 2 , R 3 and R 4 each independently represent a hydrogen atom, an alkyl group or an alkoxy group.
  • Cu represents a radioactive isotope of copper.
  • a method for producing a radiopharmaceutical and a radiopharmaceutical capable of maintaining a radioactive compound having a chemical structure and radioactivity during and after production and maintaining a period during which the radiopharmaceutical can be utilized can be obtained.
  • the method for producing a radiopharmaceutical of the present embodiment is a method for producing a radiopharmaceutical containing a radioactive component containing a specific radioactive dithiosemicarbazone copper complex, and includes a stabilization step and a filtration step.
  • the radioactive dithiosemicarbazone copper complex of the present embodiment contains a radioactive component containing a radioactive dithiosemicarbazone copper complex represented by the following general formula (1).
  • R 1 , R 2 , R 3 and R 4 each independently represent a hydrogen atom, an alkyl group or an alkoxy group.
  • Cu represents a radioactive isotope of copper.
  • the number of carbon atoms of the substituents R 1, R 2, R 3, alkyl and alkoxy groups of R 4 in the above general formula (1) is preferably an integer of 1 to 5 It is more preferably an integer having 1 to 3 carbon atoms.
  • the substituents R 1 , R 2 , R 3 , and R 4 in the above general formula (1) are preferably the same or different alkyl groups having a hydrogen atom or 1 to 3 carbon atoms
  • R 1 And R 2 are the same or different alkyl groups having a hydrogen atom or 1 to 3 carbon atoms
  • R 3 is a hydrogen atom
  • R 4 is an alkyl group having 1 to 3 carbon atoms
  • R 1 is more preferable.
  • R 2 are the same or different hydrogen atoms or methyl groups
  • R 3 is a hydrogen atom
  • R 4 is a methyl group.
  • radioactive dithiosemicarbazone copper complex represented by the above general formula (1) is specifically described. Radioactive glyoxal-bis (N4-methylthiosemicarbazone) copper complex, Radioactive glyoxal-bis (N4-dimethylthiosemicarbazone) copper complex, Radioactive ethyl glyoxal-bis (N4-methylthiosemicarbazone) copper complex, Radioactive ethyl glyoxal-bis (N4-ethylthiosemicarbazone) copper complex, Radioactive pyruvaldehyde-bis (N4-methylthiosemicarbazone) copper complex, Radioactive pyruvaldehyde-bis (N4-dimethylthiosemicarbazone) copper complex, Radioactive pyruvaldehyde-bis (N4-ethylthiosemicarbazone) copper complex, Radioactive diacetyl-bis (N4-methylthiosemicarbazone) copper
  • radioactive diacetyl-bis (N4-methylthiosemicarbazone) copper complex hereinafter, also referred to as radioactive Cu-ATSM
  • radioactive pyruvaldehyde-bis (N4-dimethylthiosemicarbazone) copper complex hereinafter, radioactive Cu-.
  • PTSM radioactive diacetyl-bis (N4-methylthiosemicarbazone) copper complex
  • the radioactive isotope of copper in the general formula (1) is preferably 61 Cu, 62 Cu, 64 Cu or 67 Cu.
  • 61 Cu, 62 Cu, and 64 Cu all emit positrons.
  • the radioactive dithiosemicarbazone copper complex accumulates in the hypoxic region, and Cu-ATSM among them accumulates in cancer stem cells. Therefore, radiopharmaceuticals containing 61 Cu, 62 Cu, and 64 Cu can be used as an imager for tumors or ischemia, preferably tumors, using positron emission tomography (PET).
  • PET positron emission tomography
  • 64 Cu and 67 Cu also emit ⁇ -rays with a short range and have a therapeutic effect of destroying cells. Therefore, radiopharmaceuticals containing 64 Cu or 67 Cu are more preferred as therapeutic agents for tumors.
  • the above-mentioned radioactive component is prepared before the stabilization step described later.
  • a previously known method capable of preparing the compound of the above general formula (1) may be appropriately used. Specifically, an organic compound that is a precursor of the radioactive component and a radioactive isotope of copper can be synthesized into a radioactive component.
  • a dithiosemicarbazone derivative can be used as the organic compound that serves as a precursor of the radioactive component.
  • Specific production processes of the organic compound as a precursor include, for example, Petering et al. (Cancer Res., 24, 367-372, 1964) is used to synthesize a dithiosemicarbazone derivative that is a precursor of a radioactive component.
  • a 1 mol aqueous solution of ⁇ -ketoaldehyde or a 50% by volume ethanol solution was applied over 30 to 40 minutes to a 5% glacial acetic acid solution containing 2.2 mol of precursors such as thiosemicarbazide, N4-methylthiosemicarbazide, and N4-dimethylthiosemicarbazide.
  • precursors such as thiosemicarbazide, N4-methylthiosemicarbazide, and N4-dimethylthiosemicarbazide.
  • radioactive copper ions are produced.
  • Conventionally known production methods can be used in the production of radioactive copper ions.
  • 61 Cu ions are 59 Co ( ⁇ , 2n) 61 Cu reaction, nat Zn (p, x) 61 Cu reaction, 58. It can be obtained by producing 61 Cu from a Ni ( ⁇ , p) 61 Cu reaction or the like and then chemically separating it from the target by using ion chromatography or the like.
  • the 62 Cu ions are described, for example, in WO2005 / 084168, Journal of Nuclear Medcine, vol. 30, 1989, pp. It can be obtained with a 62 Zn / 62 Cu generator as described in 1838-1842.
  • 64 Cu ions are, for example, the method of McCarthy et al. (Nuclear Medicine and Biology, vol. 24 (1), 1997, pp. 35-43) or the method of Obata et al. (Nuclear Medicine and Biology, vol. 30). , 2003, pp. 535-539).
  • 67 Cu ions can be obtained, for example, by producing 67 Cu from the 68 Zn (p, 2p) 67 Cu reaction and then chemically separating it from the target using ion chromatography or the like.
  • the dithiosemicarbazone derivative is used as a dimethyl sulfoxide (DMSO) solution and brought into contact with the solution containing the radioactive copper ions to obtain a radioactive dithiosemicarbazone copper complex represented by the general formula (1).
  • DMSO dimethyl sulfoxide
  • a radioactive dithiosemicarbazone copper complex represented by the general formula (1).
  • a conventionally known production method can be used, and examples thereof include the method described in Patent Document 1.
  • examples of the method for producing 61 Cu-ATSM include the method of Jalilian et al. (Acta Pharmaceutica, 59 (1), 2009, pp. 45-55).
  • Cu-ATSM As a method for producing Cu-ATSM, for example, "Manufacturing and quality control of radiopharmaceuticals for PET-Tobiki for synthesis and clinical use” (PET Chemistry Workshop), 4th edition (2011 revised edition) is described. Method can be mentioned. Examples of the method for producing 64 Cu-ATSM include the method of Tanaka et al. (Nuclear Medicine and Biologic, vol.33, 2006, pp.743-50).
  • the radioactive component of the radioactive dithiosemicarbazone copper complex thus produced is in the form of a solution containing the radioactive component before the stabilization step described later. It can also be made into a solution by adjusting the radioactivity concentration of the DMSO solution at the time of production, and other, for example, radioactive components are dissolved, suspended or emulsified in an aqueous solvent (water, aqueous solution) or an oil solvent (organic solvent). And can be a solution.
  • the stabilization step is a step of adding a stabilizer to the above-mentioned solution containing the radioactive component.
  • the stabilizer is a component that prevents and stabilizes the denaturation of the radioactive component. It is known that radioactive components are denatured by oxidation and automatic radioactive decomposition after radiolabeling. On the other hand, in the present embodiment, by adding a stabilizer, the chemical structure and radioactivity of the radioactive component are maintained for a long time.
  • the radioactivity of 64 Cu is halved in about 12.7 hours.
  • this radioactive component itself is denatured as time passes after production. That is, as for the radioactive components contained in the radiopharmaceutical, the components that maintain the chemical structure decrease and the radioactivity decreases as time passes after production. Stabilizers are added for the purpose of suppressing the denaturation of the radioactive component and maintaining the chemical structure and radioactivity of the radioactive component.
  • the effect of stabilization should be based on the measurement of% Intact probe (radioactivity amount of radioactivity component / total radioactivity x 100) of the radioactive component that has not been decomposed after a certain period of time after preparation (manufacturing). it can.
  • the stabilizer of the present embodiment preferably has a% Intact probe of 95% or more, preferably 97% or more, 24 hours after the preparation of the solution of the radioactive component for the radiopharmaceutical to which the stabilizer is added. More preferred.
  • a so-called radical scavenger is used as a stabilizer.
  • a radical scavenger is a compound that reacts with a free radical to form a stable compound. Radical scavengers are generally known to prevent denaturation of agents containing radioactive compounds.
  • At least one compound selected from the group consisting of ascorbic acid, methionine, sodium ascorbate, mannitol and butylhydroxyanisole can be used as a stabilizer among these radical scavengers. These compounds have a particularly high stabilizing effect on the radioactive component of the present embodiment, and can maintain the radioactive component for a long time.
  • ascorbic acid sodium ascorbate or mannitol
  • mannitol a stabilizer for the stabilizer. Since these compounds do not have carcinogenicity or the like by themselves, they can be suitably used as those contained in therapeutic agents, particularly therapeutic agents for tumors. Moreover, since these compounds have no odor and are easy to handle, they can be suitably used in the place where a therapeutic agent is manufactured and used.
  • the amount of the stabilizer added is preferably 15.49 mg to 1.5 g, 0.44 mg to 44 mg and 8.96 mg to 896 mg per 1 mL of the drug, respectively.
  • the addition amount is more preferably 154.9 mg, 4.4 mg and 89.6 mg per 1 mL of the drug.
  • the stabilizer suppresses the denaturation of the radioactive component and maintains the chemical structure and radioactivity of the radioactive component.
  • the radioactive components contained in the radiopharmaceutical the components that maintain the chemical structure decrease and the radioactivity decreases as time passes after production. Therefore, the conventionally manufactured 64 Cu-ATSM could not be stored and had to be used immediately after the manufacture.
  • it is desirable that a drug for therapeutic purposes using radioactivity has a higher radioactivity concentration than a drug for imaging purposes, which is generally used mainly in the past.
  • the conventional radiopharmaceuticals take a long time to be manufactured as described later, and it is difficult to exert the desired medical effect unless the conventional radiopharmaceuticals are used promptly after the manufacture. It is conceivable to increase the radioactivity concentration in the manufacturing process so that the high radioactivity concentration remains even after a long time after manufacturing, but in that case, it is necessary to give more consideration to safety in the manufacturing process. It was.
  • the present embodiment by adding a stabilizer to the radiopharmaceutical, it is possible to maintain the chemical structure and radioactivity of the radioactive component for a long period of time, so that it is extremely more than required at the time of treatment. It is possible to obtain a radiopharmaceutical that is easy to manufacture without the need for manufacturing at a high radioactivity concentration and that can exert a medical effect even after a lapse of time after production.
  • the filtration step is a step of filtering a radioactive component or a precursor thereof with a sterilization filter.
  • the radiopharmaceutical By going through the filtration step, the radiopharmaceutical can be sterilized and safely used for administration to the human body.
  • the radioactive component contained in the radiopharmaceutical is sterilized.
  • the solution to which each component of the radiopharmaceutical is added is filtered by a sterilization filter. Specifically, the solution after adding the stabilizer to the solution containing the radioactive component can be filtered.
  • the sterilization filter can be appropriately used as long as it has been used for conventional sterilization, specifically, it has a filtration size and physical properties that do not allow bacteria to pass through.
  • a filter made of a cellulose mixed ester, hydrophilic PES, hydrophilic PVDF, or the like can be used. More specifically, a filter having a pore size of 0.22 ⁇ m or less can be used. Further, it is desirable that the housing volume of the filter is less than 10% of the total amount of liquid to be filtered.
  • a sterilization filter containing hydrophilic PVDF as a constituent material among the above sterilization filters.
  • the step of sterilizing a component containing a radioactive component is a step of sterilizing a radioactive drug containing the radioactive component, or a solution containing the radioactive component or a precursor thereof in the manufacturing process of the radioactive drug.
  • a sterilization filter containing hydrophilic PVDF as a constituent material is used. It is preferable to use it.
  • the sterilization filter made of hydrophilic PVDF has less adsorption to the radioactive component of the present embodiment and the organic compound as a precursor thereof. Therefore, when hydrophilic PVDF is used for the sterilization filter, there is little loss in the filtration step, and a high yield can be obtained at the time of production.
  • all the liquid components to be added to the radiopharmaceutical may be added after the filtration step.
  • the fractions after filtration are used for the precursor for synthesizing the above-mentioned radioactive component, radioactive copper, the stabilizer, the solution before addition to these, or the liquid component of the solution after addition.
  • all of the liquid components added to the radiopharmaceutical can be filtered.
  • a filtered fraction of dimethyl sulfoxide added to the dithiosemicarbazone derivative and an aqueous solution of glycine added to the radioactive isotope of copper is used.
  • the filtered fraction is also used as the stabilizer in the above-mentioned stabilization step.
  • all the components contained in the radiopharmaceutical can be sterilized by going through these steps.
  • the dithiosemicarbazone copper complex has high lipophilicity and is generally easily adsorbed on the filter, so that there is a large loss due to the filtration process and the production yield is low.
  • the conventional manufacturing process when such a filtration operation is performed on a solution containing a synthesized radioactive component, a large amount of the compound labeled with the radioactive substance is lost due to adsorption, so that the manufacturing efficiency is improved. It's bad and there is a lot of waste. Therefore, in the conventional production, for example, the production may be performed using an excessive amount of raw materials. However, if an excessive amount of raw material is used, it is necessary to handle a large amount of radioactive substances among the raw materials. Therefore, using such means has a problem in preventing exposure of workers in the manufacturing process.
  • the production may be carried out by using a precursor filtered in advance to produce a radioactive component, that is, by mixing raw materials that have been aseptically filtered in a sterile environment. ..
  • This manufacturing method has many steps and may take time. Further, when many processes take a long time, there is a problem not only in terms of production yield but also in terms of worker exposure. Since it is difficult to secure sufficient distance and shielding from radioactive substances in a sterile environment, it is necessary to reduce the time and process required for manufacturing as much as possible.
  • the filtration step is performed using a filter having less adsorption to the radioactive component of the present embodiment and its precursor, the loss is small and the production yield is high. Therefore, the conventional step of filtering the precursor of the radioactive component can be efficiently performed.
  • a step of adding other components can be added.
  • other ingredients for example, after adding all the above-mentioned ingredients, an ingredient for formulating a radiopharmaceutical can be added.
  • additives such as dispersants, preservatives, tonicity agents, solubilizers, suspending agents, buffering agents, stabilizers, soothing agents, or preservatives, radiopharmaceuticals can be used as injections. It can be formulated.
  • the radiopharmaceutical of the present invention may be formulated with the components that have undergone the above steps as they are, or with a pharmacologically acceptable carrier, diluent, or excipient.
  • the dosage form may be either oral administration or parenteral administration, but a parenteral administration dosage form such as an injection is preferable.
  • the radiopharmaceutical prepared in this way has a radioactivity concentration of 200 MBq / mL or more.
  • a radiopharmaceutical having a high radioactivity concentration can effectively obtain a therapeutic effect by radiation, especially when used for treatment.
  • the radiopharmaceutical of the present embodiment is more preferably 1.0 GBq / mL or more. Furthermore, it can be used at 1.5 GBq / mL or higher for therapeutic purposes.
  • Conventional medical drugs containing radioactive components are mainly for testing purposes, and are mainly around 100 MBq / mL.
  • a radioactive drug having a high radioactivity concentration can be produced with high efficiency. It can be effectively used as a therapeutic agent.
  • the above-mentioned stabilization step can maintain a state in which the radioactive component is maintained without being decomposed for a long time. Further, since the above-mentioned filtration step causes less adsorption of the radioactive component to the filter, sterilization can be performed without reducing the yield of the radioactive component. Due to these effects, the radiopharmaceutical can be produced and stored without reducing the yield while stabilizing the radioactive components. As a result, the storage time and the production time can be reduced in total, and a radiopharmaceutical containing a high concentration of radioactive components can be produced in a shorter time.
  • a therapeutic radiopharmaceutical having a high radioactivity concentration of 200 MBq / mL or more By using these steps in the production of a therapeutic radiopharmaceutical having a high radioactivity concentration of 200 MBq / mL or more, a high concentration of radioactive components can be effectively obtained and the risk of exposure during production can be reduced. Therefore, the manufacturing time and cost can be greatly reduced. In addition, since there is little denaturation of radioactive components after production, it can be effectively used for a long time after production, and it is suitable as a therapeutic agent that requires transportation and storage.
  • the radiopharmaceutical of the present embodiment is produced by the above-mentioned production method. Specifically, it is a radiopharmaceutical containing a radioactive component containing a radioactive dithiosemicarbazone copper complex represented by the above-mentioned general formula (1), and is ascorbic acid, methionine, sodium ascorbate, mannitol and butyl hydroxyanisole. It contains a stabilizer containing at least one compound selected from the group consisting of, and the concentration of the radioactive component is 200 MBq / mL or more in terms of radioactive concentration. Further, the radiopharmaceutical of the present embodiment comprises a fraction obtained by filtering a solution containing the radioactive component and the stabilizer with a sterilization filter.
  • the radiopharmaceutical of the present embodiment can also be used as a therapeutic agent and an imaging agent in a diagnostic process or the like.
  • the radioactive drug of the present embodiment is a therapeutic agent used for treating a tumor or a tumor. It is preferably an imaging agent used for imaging.
  • the compound of the present embodiment has a high concentration of radioactive components of 200 MBq / mL or more, and can be produced while maintaining a high radioactive concentration by the production method of the present embodiment. Therefore, a high radioactive concentration is effective in treating the drug. It is suitable for therapeutic purposes that can exert. In particular, it is particularly preferable to use it as a therapeutic agent for tumors because of its property of accumulating in cancer stem cells described above.
  • the radioactive dithiosemicarbazone copper complex contained in the radioactive component of this embodiment can accumulate in various tumors.
  • Tumors in which the radioactive dithiosemicarbazone copper complex accumulates include, for example, breast cancer, brain tumor, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, colon cancer, small bowel cancer, esophageal cancer, duodenal cancer, tongue cancer.
  • Pharyngeal cancer salivary adenocarcinoma, nerve sheath tumor, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangiomas, malignant lymphoma, malignant melanoma, thyroid cancer , Parathyroid cancer, nasal cavity cancer, sinus nasal cancer, bone tumor, vascular fibroma, retinal sarcoma, penis cancer, testicular tumor, pediatric solid tumor, sarcoma, leukemia and the like. These tumors may be primary or metastatic. The radiopharmaceutical of this embodiment can be used to treat these tumors.
  • the radiopharmaceutical of the present embodiment can be used in combination with other conventionally known drugs.
  • a chelating agent for promoting the excretion of radioactivity from the administered organ may be used in combination.
  • an enema or the like for further promoting the excretion of the radiopharmaceutical from the organ may be used in combination.
  • a metabolism inhibitor for promoting accumulation in tumor cells may be used in combination.
  • an angiogenesis inhibitor for enhancing the antitumor effect may be used in combination.
  • the radiopharmaceutical of the present embodiment can also be provided in the form of a kit with other drugs attached for use in combination administration.
  • the radiopharmaceutical of the present embodiment may be combined with the chelating agent, enema agent, metabolism inhibitor, angiogenesis inhibitor, or the like to form a kit.
  • Example 1 By adding various radical scavengers as a stabilizer in 64 Cu-ATSM, it was compared 64 Cu-ATSM stabilizing effect of various radical scavengers.
  • the 64 Cu-ATSM solution was prepared with the composition shown in Table 1. The concentration of 64 Cu was 1.5 GBq / mL. A 0.2 mol / L glycine aqueous solution was prepared in advance, and a 64 Cu solution was prepared from this and used in the reaction. Further, ATSM was dissolved in advance dimethylsulfoxide, create a ATSM dimethyl sulfoxide solution of 0.5 mmol / L, which was prepared 64 Cu-ATSM solution by mixing with 64 Cu solution.
  • each compound (radical scavenger) shown in Table 2 as a candidate for a stabilizer was added to the 64 Cu-ATSM solution at a specified concentration.
  • the total volume of each 64 Cu-ATSM solution sample was 30 ⁇ L, and 3 samples were prepared under each reaction condition.
  • the radiochemical purity of 64 Cu-ATSM was analyzed by thin layer chromatography, respectively. Separation was performed by TLC Silica gel 60 (Merck) using methanol as a developing solvent.
  • FIG. 1 shows a study of acid-based candidate compounds (ascorbic acid, citric acid monohydrate, anhydrous citric acid)
  • FIG. 2 shows a study of amino acid-based candidate compounds (methionine, cysteine hydrochloride monohydrate)
  • FIG. 3 shows sodium.
  • Salt-based candidate compounds sodium ascorbate, sodium thioglycolate, sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, anhydrous sodium sulfite
  • Fig. 4 shows alcohol-based candidate compounds (butylhydroxyanisole, mannitol, benzyl alcohol, ethanol). ) Is shown.
  • Table 3 shows the mean of 3 samples of each test example as AVR and the standard deviation as SD after 24 hours.
  • Example 2 As a sterilization filter used for filtration of Cu-ATSM, in addition to a general-purpose cellulose mixed ester filter (Merck, Milex GS, GS in the figure), a hydrophilic PES filter (Merck, Milex GP). , GP in the figure) and a hydrophilic PVDF filter (Merck & Co., Mikeless GV, GV in the figure) were used to compare the adsorptivity of 64 Cu-ATSM.
  • the 64 Cu-ATSM solution was prepared with the composition shown in Table 1. The concentration of 64 Cu was 3 MBq / mL. A 0.2 mol / L glycine aqueous solution was prepared in advance, and a 64 Cu solution was prepared from this and used in the reaction.
  • ATSM was dissolved in advance dimethylsulfoxide, create 0.5mmol / LATSM dimethyl sulfoxide solution, which was prepared 64 Cu-ATSM solution by mixing with 64 Cu solution.
  • sodium ascorbate, mannitol, and ethanol were added as stabilizers at the concentrations shown in Table 2.
  • the total volume of each 64 Cu-ATSM solution sample was 10.2 mL.
  • the amount of radioactivity and weight were measured. This was filtered through each filter (GS, GP, and GV), and the amount of radioactivity and weight were measured.
  • Example 3 A hydrophilic PVDF filter (Merck, Mikeless GV, GV in the figure) is used as the sterilization filter used to filter 64 Cu-ATSM, and the adsorption of 64 Cu-ATSM at high radioactivity concentration is achieved. confirmed.
  • the 64 Cu-ATSM solution was prepared with the composition shown in Table 1. The concentration of 64 Cu was 1 GBq / mL. A 0.2 mol / L glycine aqueous solution was prepared in advance, and a 64 Cu solution was prepared from this and used in the reaction. Further, ATSM was dissolved in advance dimethylsulfoxide, create 0.5mmol / LATSM dimethyl sulfoxide solution, which was prepared 64 Cu-ATSM solution by mixing with 64 Cu solution.
  • a radiopharmaceutical capable of maintaining a radioactive compound having a chemical structure and radioactivity during and after production and maintaining a period during which the radiopharmaceutical can be utilized can be produced.
  • Methods and radiopharmaceuticals are obtained. Therefore, in the manufacture and sale of the radiotherapy drug Cu-ATSM, there is a possibility that the delivery range can be expanded by extending the expiration date, the cost can be reduced by improving the production yield, and the exposure to workers can be reduced.

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