Stabilized radiopharmaceutical composition

Abstract

The purpose of the present invention is to provide a stabilized radiopharmaceutical composition wherein the decrease in the radiochemical purity over time is suppressed even in the case where the radioactivity concentration is high immediately after manufacture.　The present invention pertains to a stabilized radiopharmaceutical composition that comprises, as an active ingredient, a polypeptide labeled with a radionuclide and having a group selected from the group consisting of thioether and thiol groups, a solubilizing agent having an ethylene glycol group, a solvent containing water, and a stabilizing agent selected from the group consisting of a sulfur-containing amino acid or salt thereof, a sulfur-containing amino acid derivative or salt thereof and a polysaccharide.

Description

Stabilized Radiopharmaceutical Compositions

[0001] The present invention relates to stabilized radiopharmaceutical compositions.

[0002] The stability of active ingredients is important in pharmaceutical development. One of the causes of decreased stability of radiopharmaceuticals is radiolysis, which is the destruction of the molecular structure of the active ingredient and the chemical bonds of other components due to the radiation emitted by radionuclides. Therefore, stabilizers are often used in radiopharmaceutical compositions.

[0003] In Patent Document 1, １３１ For the I-labeled antibody (L19-SIP), １３１ At radioactivity concentrations of about 84 to 104 MBq / mL, the addition of maltose, methionine, gentisic acid, ascorbic acid, trehalose, benzyl alcohol, and thiosulfate had a stabilizing effect (Tables 5 and 6). １３１ At a radioactivity concentration of 370 mBq / mL, the addition of ascorbic acid or thiosulfate has been shown to have a stabilizing effect (Table 10).

[0004] In Patent Document 2, a methionine-containing peptide containing DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is １７７ For the complex with Lu, １７７ At radioactivity concentrations of Lu below 740 MBq / mL, cysteine ​​and methionine have a stabilizing effect (Table 5). １７７ It has been shown that at a high radioactivity concentration of 925 MBq / mL of Lu, the addition of cysteine ​​or methionine alone has no stabilizing effect (Table 6).

[0005] Although Non-Patent Document 1 does not relate to radiopharmaceuticals, it shows that peroxides derived from polysorbate 80, a non-surfactant widely used as a solubilizing agent for pharmaceuticals, cause oxidation of an antibody (IL-2 mutein) (oxidation of methionine residues) (Figure 5), and that the addition of glutathione and storage under vacuum have a stabilizing effect (Figure 7).

[0006] International Publication No. 2011 / 147762 Pamphlet Special Publication No. 2006-528644

[0007] Journal of Pharmaceutical Sciences, Vol.91, No.10, pages 2252-2264, 2002

[0008] An object of the present invention is to suppress the decrease over time in radiochemical purity of a radiopharmaceutical composition containing a radioactive polypeptide having a specific group as an active ingredient.

[0009] The present inventors have found that, in developing a radiopharmaceutical composition containing a radioactive polypeptide having a thioether group and / or a thiol group as an active ingredient, it is necessary to add a solubilizing agent to prevent adsorption to containers and administration devices. Furthermore, they have also found that the addition of a solubilizing agent creates a new problem: the radiochemical purity of the radioactive polypeptide decreases. The present inventors have conducted extensive research to solve the problems inherent to the addition of such a solubilizing agent, and have found that the addition of a specific stabilizer can solve these problems, thereby completing the present invention.

[0010] That is, one aspect of the present invention provides a stabilized radiopharmaceutical composition comprising: a polypeptide labeled with a radionuclide and having a group selected from the group consisting of a thioether group and a thiol group as an active ingredient; a solubilizing agent having an ethylene glycol group; a solvent containing water; and a stabilizer selected from the group consisting of a sulfur-containing amino acid or a salt thereof, a sulfur-containing amino acid derivative or a salt thereof, and a polysaccharide.

[0011] According to the present invention, even in a formulation in which a solubilizing agent having an ethylene glycol group is present, the use of a specific stabilizer can suppress the decrease in radiochemical purity of a radioactive polypeptide having a thioether group and / or a thiol group over time, thereby providing a stabilized radiopharmaceutical composition.

[0012] FIG. 1 shows the effect of polysorbate 80 and / or ethanol on the ８９2 is a graph showing the decrease in radiochemical purity of the Zr-labeled product over time when various reagents are mixed. ８９ 3 shows the decrease in radiochemical purity of Zr-labeled product over time when polysorbate 80 or macrogol 4000 and / or methionine is added. ８９ FIG. 1 shows the decrease in radiochemical purity of a Zr-labeled product over time.

[0013] The present invention is described in detail below. The stabilized radiopharmaceutical composition of the present invention comprises, as an active ingredient, a polypeptide labeled with a radionuclide and having a group selected from the group consisting of a thioether group and a thiol group (hereinafter also referred to as a "radioactive polypeptide"), a solubilizing agent having an ethylene glycol group, a solvent containing water, and a stabilizer selected from the group consisting of a sulfur-containing amino acid or a salt thereof, a sulfur-containing amino acid derivative or a salt thereof, and a polysaccharide.

[0014] (1) Radioactive Polypeptide The radioactive polypeptide of the present invention is a polypeptide labeled with a radionuclide and having a group selected from the group consisting of a thioether group and a thiol group.

[0015] (1-1) Radioactive nuclide The radioactive nuclide contained in the radioactive polypeptide of the present invention is a radioactive nuclide that emits α rays, a radioactive nuclide that emits β rays, a radioactive nuclide that emits positrons, or a radioactive nuclide that emits γ rays. When the radioactive polypeptide of the present invention is used for cancer treatment, it is preferable to use a radioactive nuclide that emits α rays or a radioactive nuclide that emits β rays. When the radioactive polypeptide of the present invention is used for cancer diagnosis or detection, it is preferable to use a radioactive nuclide that emits positrons or a radioactive nuclide that emits γ rays. In the present invention, it is preferable to use a radioactive metal nuclide as the radioactive nuclide. As the radioactive nuclide that emits α rays, ２１２ Bi, ２１３ Bi, ２２５ Ac, ２２７ Examples of radionuclides that emit β rays include: ６４ Cu, ９０ Y. １７７Examples of radionuclides that emit positrons include: １８ F. ６４ Cu, ６８ Ga, ８６ Y. ８９ Examples of radionuclides that emit gamma rays include: ９９ｍ Tc, ６７ Ga, １１１ In, etc. The radioactive nuclide contained in the radioactive polypeptide of the present invention is ８９ Zr, ２２５ Ac, １７７ Lu, １１１ In, ９０ Y. ６７ Ga and ６８ Preferably, it is selected from the group consisting of Ga.

[0016] The radionuclide may be introduced into the polypeptide by covalent bonding or by chelation, having a group selected from the group consisting of a thioether group and a thiol group. In the case of the embodiment where the radionuclide is introduced by chelation, the radionuclide may be a radioactive metal nuclide or a radioactive metal halide (e.g., Al １８ For this embodiment, the description of the radioactive complex of a polypeptide and a chelate complex below can be referred to.

[0017] (1-2) Polypeptide The polypeptide of the present invention is a polypeptide having a group selected from the group consisting of a thioether group and a thiol group, and has a chemical structure that allows it to exhibit directivity to a target organ or tissue in a living body or specificity to a target molecule as a targeting agent for radiotherapy or radiodiagnosis. The polypeptide of the present invention may be cyclic or linear. The molecular weight of the polypeptide of the present invention is 500 or more, preferably 500 to 10,000, and does not include antibodies.

[0018] Here, the "thioether group" is represented by the formula -S-R (R is an alkyl group (preferably having 1 to 10 carbon atoms), an aryl group (preferably having 6 to 10 carbon atoms), a cycloalkyl group (preferably having 3 to 10 carbon atoms), or an aralkyl group (preferably having 7 to 10 carbon atoms)), and specific examples thereof include methylthio, phenylthio, benzylthio, and cyclohexylthio.

[0019] In the polypeptide of the present invention, the positions of the thioether group and thiol group are not particularly limited as long as they have the above-mentioned chemical structure. For example, they may be a target molecule recognition site composed of a specific amino acid sequence, or may be included in a linker site other than the target molecule recognition site (for example, the linker (L) of the complex between the polypeptide and a chelate complex described below). The group consisting of thioether groups and thiol groups possessed by the polypeptide of the present invention includes, for example, thioether groups and thiol groups possessed by natural sulfur-containing amino acids such as cysteine, methionine, and homocysteine; and thioether groups and thiol groups possessed by non-natural sulfur-containing amino acids. These sulfur-containing amino acids may be in either the D- or L-form. Furthermore, the thiol groups possessed by the polypeptide may be derivatized, for example, two thiol groups possessed by the polypeptide may bond with each other to form a disulfide bond; or a bond may be formed between a thiol group possessed by the polypeptide and another functional group (for example, a thiol group possessed by the polypeptide may bond with a chloroacetyl group to form a thioether bond (-CO-CH ２ Such a derivatized thiol group is also included in the group consisting of thioether groups and thiol groups that the polypeptide of the present invention has.

[0020] The radioactive polypeptide in the present invention includes a polypeptide having a group selected from the group consisting of a thioether group and a thiol group, into which a radionuclide has been covalently introduced; and a conjugate of a polypeptide having a group selected from the group consisting of a thioether group and a thiol group, and a complex formed from a chelating agent and a radionuclide (chelate complex). In the present invention, a radioactive conjugate of a polypeptide having a group selected from the group consisting of a thioether group and a thiol group, and a chelate complex (hereinafter also referred to as a "radioactive conjugate") is preferred, and will be described in detail below.

[0021] (1-3) Radioactive Complex In the present invention, the chelating agent is not particularly limited as long as it has a moiety capable of chelating a radionuclide in its structure. Examples of chelating agents include CB-TE2A (1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), CDTA (Cyclohexane-trans-1,2-diamine tetraacetic acid), CDTPA (4-cyano-4-[[(dodecylthio)thioxomethyl]thio]-pentanoic acid), DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA ((1R,4R,7R,10R)-α,α',α",α'"-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), and DOTAM. (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid), 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (Lpy), DOTA-GA (α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTP (((1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetraphosphonic acid), DOTMP (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)), DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamidomethylenephosphonic acid))、 D02P (Tetraazacyclododecane dimethanephosphonic acid)、 Deferoxamine (DFO)、 DTPA (Glycine, N,N-bis[2-[bis(carboxymethyl)amino]ethyl]-)、 CHX-A”-DTPA (2,2'-((2-(((1S,2R)-2-(bis(carboxymethyl)amino)cyclohexyl)(carboxymethyl)amino)ethyl)azanediyl)diacetic acid)、 DTPA-BMA (5,8-Bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oic acid)、 EDTA (2,2',2”,2’”-(ethane-1,2-diylbis(azanetriyl))tetraacetic acid)、 NOTA (1,4,7-Triazacyclononane-1,4,7-triacetic acid)、 NOTP (1,4,7-Triazacyclononane-1,4,7-triyltris(methylenephosphonic acid))、 TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid)、 TETA (1,4,8,11-Tetraazacyclotetradecane-N,N',N”,N’”-tetraacetic acid)、 TTHA (3,6,9,12-Tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid)、 HEHA (1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid)、 1,2-HOPO (N,N’,N”,N’”-tetra(1,2-dihydro-1-hydroxy-2-oxopyridine-6-carbonyl)-1,5,10,14-tetraazatetradecane), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N'",N""-pentaacetic acid), H4octapa (N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid), H2bispa2 (6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(-methylene))dipicolinic acid), H2dedpa (1,2-[{6-(carboxy)-pyridin-2-yl}-methylamino]ethane), H2macropa Examples of suitable hydroxypropyl tetraazacyclododecane compounds include 6-(1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-N,N'-methyl)picolinic acid, H5decapa (N,N"-bis(6-carboxy-2-pyridylmethyl)-diethylenetriamine-N,N',N"-triacetic acid), H6phospa (N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), HP-D03A (Hydroxypropyltetraazacyclododecanetriacetic acid), and porphyrin. However, the compound represented by the following formula (A) is preferred.

[0022]

[0023] (In formula (A), R １１ , R １２ , R １３ and R １４ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ or -CH(COOH)-(CH ２ ) ｐ COOH, and preferably R １１ , R １３ and R １４ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ or -(CH ２ ) ｐ CONH ２ , R １２ But -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ or -CH(COOH)-(CH ２ ) ｐ COOH, and R １５ is a hydrogen atom, and p is an integer of 0 to 3.

[0024] The compound represented by formula (A) is preferably 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a compound containing a structure derived from a derivative thereof, specifically, a compound containing in the structure DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA ((1R,4R,7R,10R)-α,α',α",α'"-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid), 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (Lpy), DOTA-GA (α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTP (((1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetraphosphonic acid), DOTMP (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)), DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamidomethylenephosphonic acid)), and D02P (Tetraazacyclododecane dimethanephosphonic acid), and more preferably, the compounds represented by the following formulas (A-1) to (A-6) can be included.The chelating agent used in the radioconjugate of the present invention is even more preferably DOTA-GA (a compound represented by formula (A-6)).

[0025]

[0026] The chelating agent used in the present invention may be directly linked to the polypeptide by a covalent bond, or may be linked to the polypeptide by a covalent bond via a linker (L). Thus, in the radioconjugate of the present invention, some groups in the chelating agent may be substituted with groups that form a covalent bond with the polypeptide (direct bond) or the linker (L). For example, when the chelating agent used in the present invention is a compound represented by formula (A), R １２ or R １５ may be substituted with a group that forms a covalent bond with the polypeptide (direct bond) or the linker (L). １２ is substituted with a group that forms a covalent bond with the polypeptide (direct bond) or the linker (L), R １５ is a hydrogen atom, and R １２ Ga-(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ Or, -CH(COOH)-(CH ２ ) ｐ When R is a group consisting of COOH, １５ is a group that forms a covalent bond with a polypeptide (direct bond) or a linker (L) (e.g., —(CH ２ ) ｐ C ６ H ４ -NCS).

[0027] The covalent bond between the chelating agent and the polypeptide (direct bond) or the linker (L) may be a carbon-carbon bond, an amide bond, an ether bond, an ester bond, a thiourea bond, a thioether bond, a thioester bond, or the like.

[0028] The connection between the chelating agent and the polypeptide (direct bond) or the linker (L) is formed, for example, by a reaction between an N-hydroxysuccinimide ester (NHS) group of the following formula (A-7) or (A-8), a 2,6-dioxotetrahydro-2H-pyranyl group of the following formula (A-9), or an isothiocyanate group of DOTA-Bn-SCN (S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and an amino group of the polypeptide (direct bond) or the linker (L).

[0029]

[0030]

[0031] The linker (L) is not particularly limited as long as it can link the chelating agent and the polypeptide in the radioconjugate of the present invention. The linker (L) used in the present invention is not particularly limited, and examples thereof include a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a polyethylene glycol (PEG) group, a peptide, a sugar chain, a disulfide group, an amide group, and combinations thereof. In this specification, the linker (L) is a general term for linkers used to connect a polypeptide and a chelating agent, and includes peptide linkers (L １ ) and a chelating linker (L ２ ) is a term that includes a peptide linker (L １ ) is not particularly limited as long as it can be linked to an amino acid residue of a polypeptide, ２ ) is not particularly limited as long as it can be introduced into the functional group of the chelating agent.

[0032] The linker (L) used in the present invention may contain a binding site formed by a click reaction, and is preferably a peptide linker (L１ ) and a chelating linker (L ２ ) are bonded by a click reaction. The click reaction may be a reaction that proceeds between an azide group and an alkyne (for example, a Huisgen reaction), or a Diels-Alder reaction that proceeds between an alkene and a diene. The linker may also contain, as a functional site, a substrate sequence site for a renal brush border membrane enzyme (lysine-glycine-phenylalanine, glycine-lysine, phenylalanine-lysine) or an albumin binding site. For substrate sequence sites for renal brush border membrane enzymes, the description in WO2019 / 065774 can be appropriately referenced. Examples of the albumin-binding site structure include gamma glutamic acid, substituted or unsubstituted phenylbutyric acid, lipids, hematin, bilirubin, clofibric acid, clofibrate, carotenoids, compounds having a steroid skeleton, compounds having an ibuprofen skeleton, linear or branched, saturated or unsaturated hydrocarbons having 13 to 20 carbon atoms, cyanine dyes, dyes having a sulfonic acid group, diazo dyes, pentamethine cyanine dyes, blue dextran, bromocresol green, and Evans blue, as well as derivatives thereof, or structures derived from one or more of the structures described in WO 2005 / 117984, WO 2010 / 127336, or U.S. Patent Publication No. 2010 / 0172844. Additionally or alternatively, peptides capable of binding to albumin (e.g., peptides described in WO 2007 / 106120) can also be used at the albumin-binding site.

[0033] The radioconjugate of the present invention is one in which a polypeptide and a chelating agent are linked directly or via a linker (L), and preferably one molecule of a chelating agent is conjugated to the polypeptide.

[0034] Examples of the radioconjugate of the present invention include a conjugate of physalamine or somatostatin with a chelate complex either directly or via a linker (L), or oxodotreotide or edotreotide labeled with a radionuclide.

[0035] (1-4) Method for Producing Radioactive Peptides (Including Radioconjugates) The radioactive polypeptide of the present invention may be synthesized, for example, using commercially available Physalamine, or by using an automated peptide synthesizer to sequentially link amino acids protected with amino-protecting groups (e.g., Fmoc groups) to a solid support, starting from the C-terminus. Deprotection of the amino group can be carried out by methods known to those skilled in the art (e.g., 20% piperidine / 1-methyl-2-pyrrolidinone in the case of Fmoc groups). A chelating agent or linker (L) is introduced before or after this deprotection. The radionuclide can be introduced by an isotope exchange reaction, a substitution reaction of the radionuclide with an optional substituent, or complexation of the radionuclide with a chelating agent. The radionuclide used here is preferably used in an ionizable form, more preferably in an ionic form, in order to increase the efficiency of complex formation.

[0036] The order of addition of the radioactive nuclides does not matter, but the method for producing the radioconjugate of the present invention can be comprised of two steps: a conjugation step in which a chelating agent is conjugated to a polypeptide, and a complex formation step in which a complex is formed from a radioactive metal nuclide and a chelating agent. The conjugation step may be performed before or after the complex formation step.

[0037] In the complex formation step, for example, the method described in WO2021 / 033530 can be used. A chelating agent is chelated (complexed) with a radioactive metal nuclide. The radioactive metal nuclide used here is preferably used in an ionizable form, more preferably in an ionic form, from the viewpoint of increasing the efficiency of complex formation. In the complex formation step, the order of adding the radioactive metal nuclide to the chelating agent does not matter as long as a complex can be formed with the radioactive metal nuclide. For example, a solution in which radioactive metal ions are dissolved in a solvent mainly composed of water can be used as the radioactive metal nuclide.

[0038] The complex-forming reaction is preferably carried out in a solvent. Examples of the solvent that can be used include water and buffer solutions. Furthermore, the solvent may contain a water-soluble organic solvent. Examples of water that can be used include distilled water and ion-exchanged water. Examples of buffer solutions that can be used include acetic acid and its salts, phosphoric acid and its salts, trishydroxymethylaminomethane buffer solution (Tris buffer solution), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer solution (HEPES buffer solution), and tetramethylammonium acetate buffer solution. Examples of water-soluble organic solvents that can be used include protic solvents such as methanol and ethanol, and polar solvents such as protic solvents such as acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and acetone. Among these, the use of at least one solvent selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and ethanol as the water-soluble organic solvent is even more preferred from the viewpoint of ensuring good progress of the complex-forming reaction.

[0039] The volume of the solvent is not particularly limited, but from the viewpoint of practicality in the production process, a volume of 0.01 mL to 100 mL at the start of the complex formation reaction is practical. Furthermore, the concentration of the chelating agent in the reaction solution at the start of the complex formation reaction is preferably 1 μmol / L to 1000 μmol / L from the viewpoint of increasing the yield of the desired radioactive metal complex, more preferably 10 μmol / L to 900 μmol / L, even more preferably 30 μmol / L to 600 μmol / L, and even more preferably 50 μmol / L to 500 μmol / L. The concentration of the radioactive metal ion in the reaction solution at the start of the complex formation reaction is preferably 1 nmol / L or more and 10,000 nmol / L or less, from the viewpoint of increasing the yield of the desired radioactive metal complex, more preferably 10 nmol / L or more and 5,000 nmol / L or less, even more preferably 50 nmol / L or more and 3,000 nmol / L or less, and even more preferably 100 nmol / L or more and 2,000 nmol / L or less. The pH of the reaction solution can be appropriately changed depending on the physical properties of the radioactive metal, chelating agent, and buffer solution used, but is preferably 2.0 to 7.0, more preferably 4.5 to 6.5, and even more preferably 5.0 to 6.0.

[0040] The temperature for the complex formation reaction may be, for example, room temperature (25° C.) or may be under heated conditions, but from the viewpoint of simultaneously suppressing decomposition of the chelating agent and improving the efficiency of complex formation, heating is preferably performed at 30° C. or higher and 80° C. or lower, more preferably 50° C. or higher and 80° C. or lower. The reaction time is preferably 15 minutes or higher and 150 minutes or lower, more preferably 30 minutes or higher and 120 minutes or lower, provided that the reaction temperature is as described above.

[0041] The radioconjugate obtained may be used as it is, or may be purified using a filter, a membrane filter, a column filled with various packing materials, chromatography, or the like.

[0042] The radioconjugate of the present invention can be produced in the case where the conjugation step is carried out before the complex formation step by the same method as that in the case where the conjugation step is carried out after the complex formation step.

[0043] (2) Radiopharmaceutical Composition The radiopharmaceutical composition of the present invention refers to a composition which contains the above-mentioned radioactive polypeptide (including the radioactive complex) as an active ingredient and is in a form suitable for administration to the living body of a subject (hereinafter, the "radiopharmaceutical composition of the present invention" may also be referred to as the "radiopharmaceutical of the present invention"). A radiopharmaceutical can be produced by dissolving the radioactive polypeptide produced by the method shown in (1-4) above, either as is or after purification, in a solvent containing water, i.e., a solvent which is mainly composed of water and is approximately isotonic with the living body (e.g., physiological saline). In this case, the radiopharmaceutical is preferably in the form of an aqueous solution. The radioactivity concentration of the radioactive polypeptide, which is the active ingredient, depends on the concentration of the radionuclide. ８９ When the radionuclide is Zr, the concentration in the radiopharmaceutical of the present invention immediately after production is preferably 10 MBq / mL or more, more preferably 100 MBq / mL or more, even more preferably 1000 MBq / mL or more and 3000 MBq / mL or less, and further preferably within the range of 10 to 3000 MBq / mL, more preferably within the range of 100 to 3000 MBq / mL, and even more preferably within the range of 1000 to 3000 MBq / mL. ２２５ When Ac is used, the radioactivity concentration of the radioactive polypeptide in the radiopharmaceutical of the present invention is preferably 0.1 MBq / mL or more and 300 MBq / mL or less, and more preferably within the range of 0.1 to 300 MBq / mL.

[0044] A solubilizing agent is used in the radiopharmaceutical of the present invention to prevent the radioactive polypeptide, which is the active ingredient, from adsorbing to glass, plastic, or other containers or administration devices. The solubilizing agent used in the present invention is a solubilizing agent having an ethylene glycol group, and examples thereof include polysorbates such as polysorbate 20 and polysorbate 80 (hereinafter referred to as PS80); macrogols such as macrogol 4000 (hereinafter referred to as MG4) and macrogol 300; and polyoxyethylene hydrogenated castor oil. Among these, polysorbates (also known as polyoxyethylene sorbitan fatty acid esters) or macrogols (also known as polyethylene glycols) are preferred, and from the perspective of ease of purchase, they are more preferably selected from the group consisting of PS80, polysorbate 20, and MG4. The solubilizing agent is incorporated into the radiopharmaceutical of the present invention at a concentration of preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, and preferably 10.00 w / v% or less, more preferably 0.5 w / v% or less, and further preferably within the range of 0.001 to 10.00 w / v%, more preferably 0.01 to 0.5 w / v%.

[0045] The radiopharmaceutical of the present invention contains a stabilizer. The inclusion of this stabilizer suppresses the decrease in radiochemical purity of the radioactive polypeptide over time due to oxidation. Unexpectedly, the decrease in radiochemical purity over time is suppressed more than when a solubilizing agent is not added. The stabilizer used in the present invention is selected from the group consisting of sulfur-containing amino acids or salts thereof, sulfur-containing amino acid derivatives or salts thereof, and polysaccharides. Examples of sulfur-containing amino acids include cysteine, methionine, homocysteine, etc. Examples of sulfur-containing amino acid derivatives include peptides containing sulfur-containing amino acids such as glutathione, or amino acid derivatives such as cysteine ​​ethyl ester. Examples of polysaccharides include disaccharides such as sucrose, lactose, maltose, and trehalose; and trisaccharides such as raffinose and maltotriose. Among these, a stabilizer selected from the group consisting of methionine, cysteine, glutathione, and sucrose is preferred because of its excellent effect in suppressing the decrease in radiochemical purity over time. The stabilizer is incorporated into the radiopharmaceutical of the present invention at a concentration of preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and preferably 2000 mg / mL or less, more preferably 200 mg / mL or less, even more preferably 50 mg / mL or less, and further preferably within the range of 0.01 to 2000 mg / mL, more preferably 0.01 to 200 mg / mL, even more preferably 0.1 to 50 mg / mL.

[0046] The radiopharmaceutical of the present invention preferably contains ethanol from the viewpoint of solubilizing the polypeptide. The ethanol content in the radiopharmaceutical of the present invention is preferably 0.01 v / v % or more, more preferably 0.1 v / v % or more, and preferably 20 v / v % or less, more preferably 10 v / v % or less, and further preferably within the range of 0.01 to 20 v / v %, more preferably 0.1 to 10 v / v %.

[0047] As mentioned above, the radiopharmaceutical of the present invention is preferably in the form of an aqueous solution, but is more preferably in the form of a buffer solution having a buffering capacity ranging from acidic to near-neutral, from the viewpoint of maintaining radiochemical purity as described above. The pH is preferably 3.0 to 8.0, and any buffer solution commonly used in radiopharmaceuticals can be used. Examples of buffer solutions that can be used include, but are not limited to, physiological saline; acetic acid-sodium acetate buffer solution (hereinafter referred to as AA buffer solution), ammonium acetate buffer solution, phosphate buffer solution, phosphate-buffered saline, trishydroxymethylaminomethane buffer solution (Tris buffer solution), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer solution (HEPES buffer solution), and tetramethylammonium acetate buffer solution. The use of an AA buffer solution is preferred. The AA buffer solution is composed of acetic acid and sodium acetate.

[0048] If necessary, it may further contain other pharmaceutically acceptable ingredients. An effective amount of the radiopharmaceutical is administered to a living body orally or parenterally, such as intravenously, subcutaneously, intraperitoneally, or intramuscularly, for use in cancer treatment, cancer diagnosis, or cancer lesion detection. The subject of administration here may be, but is not limited to, humans or animals such as mice, rats, monkeys, guinea pigs, chimpanzees, sheep, goats, dogs, cats, pigs, cows, and horses. Humans are preferred. A preferred target disease is cancer. The type of cancer to be treated, diagnosed, or detected by the present invention is not particularly limited, but examples include salivary gland cancer, ovarian cancer, bladder cancer, biliary tract cancer, stomach cancer, liver cancer, and breast cancer. Furthermore, the cancer may be at any stage, and may be localized or metastatic, or primary or recurrent. The "effective amount" herein refers to an amount that can achieve a diagnostic or therapeutic effect in the subject. The effective amount to be administered to a subject varies depending on the type of subject, the subject's weight, the dosage form (tablet, injection, etc.) and route (oral administration, parenteral administration, etc.) of administration, the severity of the disease (cancer, etc.), etc. Doctors and veterinarians can determine an appropriate effective amount taking these factors into consideration.

[0049] When the radiopharmaceutical of the present invention stabilized in this manner is stored at room temperature, the active ingredient (radioactive polypeptide) has a radiochemical purity of a certain percentage or more after a period of 1 to 5 multiples of the half-life of the radionuclide constituting the radiopharmaceutical has elapsed. Preferably, the difference between the radiochemical purity immediately after production and the radiochemical purity at room temperature after a period of 1 to 5 multiples of the half-life has elapsed from the end of production is 20% or less, more preferably 10% or less. ８９ When the radionuclide is Zr, the difference between the radiochemical purity immediately after production and the radiochemical purity after storage at room temperature for 7 days from the end of production is preferably 20% or less, more preferably 10% or less. ２２５ When the radioactive polypeptide is 100% or less, the difference between the radiochemical purity immediately after production and the radiochemical purity after storage at room temperature for 14 days from the end of production is preferably 20% or less, more preferably 10% or less. Herein, "room temperature" preferably refers to "ordinary temperature" as defined in the Japanese Pharmacopoeia, specifically 15 to 25°C. Furthermore, the radiochemical purity refers to the percentage of the radioactivity (counts) of the peak corresponding to the radioactive polypeptide relative to the total radioactivity (counts) detected when a sample containing the radioactive polypeptide is analyzed with a commercially available radiation detector. Although high-performance liquid chromatography or thin-layer chromatography can be used to analyze the radiochemical purity, high-performance liquid chromatography is preferably used.

[0050] An example of this high-performance liquid chromatography method is reverse-phase high-performance liquid chromatography (RP-HPLC). A column is used containing, as the stationary phase, high-purity spherical silica gel (particle size 3-5 μm) to which alkyl groups such as butyl and octadecyl groups are bonded. Commercially available columns of this type include InertSustainBio C18 (manufactured by GL Sciences), Protenavi C4 (manufactured by Osaka Soda), and Triart C18, Bio C4 (manufactured by YMC). For example, a mixture of acetonitrile and acetic acid-sodium acetate buffer (pH 6-7) can be used as the mobile phase. It is preferable to gradually increase the acetonitrile concentration in the mobile phase relative to the acetic acid-sodium acetate buffer. The temperature may be room temperature, or it may be heated to 30-80°C. This allows the half-width of the peak of the radioactive peptide, which is the active ingredient, to be reduced to 0.5 or less, facilitating the separation of the radioactive polypeptide from its radioactive impurities (for example, radioactive impurities derived from the oxidized form of the thioether group structure), thereby enabling more accurate evaluation of the radiochemical purity.

[0051] A radionuclide having a therapeutic effect, specifically, a radionuclide emitting alpha rays or a nuclide emitting beta rays (preferably, ２２５ Ac, ９０ Y. １７７ Lu, more preferably ２２５ By selecting Ac), the radiopharmaceutical of the present invention can be used in internal radiotherapy of cancer. In this internal radiotherapy, the radiopharmaceutical of the present invention is administered intravenously or orally, allowing the radioconjugate of the present invention to accumulate at a lesion site such as a primary cancer lesion or a metastatic lesion, and cells at the lesion site can be destroyed by radiation emitted from the radionuclide. The dosage and administration amount of the radiopharmaceutical of the present invention are appropriately selected depending on the efficacy of the active ingredient, the form and route of administration, the stage of progression of the disease, the patient's body type, weight, and age, and the type and amount of other therapeutic agents used in combination.

[0052] In addition, as the radionuclide, a radionuclide that emits positrons or a radionuclide that emits gamma rays (preferably, １１１ In, ６７Ga, ６８ Ga, ８９ Zr, more preferably ８９ By selecting a radiopharmaceutical containing a positron-emitting radionuclide, the composition can be suitably used in cancer diagnosis or lesion detection. In the case of a radiopharmaceutical containing a positron-emitting radionuclide, the composition can be suitably used in PET (Positron Emission Tomography) examinations, and in the case of a radiopharmaceutical containing a gamma-ray-emitting radionuclide, the composition can be suitably used in SPECT (Single Photon Emission Computed Tomography) examinations. This composition can also be used in combination with cancer diagnosis or lesion detection in the above-mentioned cancer internal radiotherapy. When the composition of the present invention is used as a cancer diagnostic radiopharmaceutical, it can be used for diagnosis before cancer internal radiotherapy or for diagnosis after cancer internal radiotherapy. By using the composition in diagnosis before cancer internal radiotherapy, the composition can be used to determine the treatment selection of whether to perform cancer internal radiotherapy using the radiopharmaceutical of the present invention. Furthermore, by using the composition in diagnosis after cancer internal radiotherapy, the composition can be used to determine whether cancer internal radiotherapy using the radiopharmaceutical of the present invention is effective and to optimize the treatment plan, such as increasing or decreasing the dosage.

[0053] The above-mentioned embodiments of the present invention encompass the following technical concepts. [1] A stabilized radiopharmaceutical composition comprising, as an active ingredient, a radionuclide-labeled polypeptide having a group selected from the group consisting of a thioether group and a thiol group, a solubilizing agent having an ethylene glycol group, a solvent comprising water, and a stabilizer selected from the group consisting of a sulfur-containing amino acid or a salt thereof, a sulfur-containing amino acid derivative or a salt thereof, and a polysaccharide. [2] The stabilized radiopharmaceutical composition of above [1], wherein the stabilizer is selected from the group consisting of methionine, cysteine, glutathione, and sucrose. [3] The stabilized radiopharmaceutical composition of above [1] or [2], wherein the solubilizing agent is a polysorbate or a macrogol. [4] The stabilized radiopharmaceutical composition of any one of above [1] to [3], further comprising ethanol.

[0054] [5] The stabilized radiopharmaceutical composition according to any one of the above-mentioned [1] to [4], wherein the solvent comprises physiological saline and / or a buffer solution. [6] The radionuclide is ８９ Zr, ２２５ Ac, １７７ Lu, １１１ In, ９０ Y. ６７ Ga and ６８ The stabilized radiopharmaceutical composition according to any one of the above-mentioned [1] to [5], wherein the polypeptide has a molecular weight of 500 to 10,000.

[0055] [8] The stabilized radiopharmaceutical composition according to any one of the above-mentioned [1] to [7], wherein the polypeptide labeled with a radionuclide and having a group selected from the group consisting of a thioether group and a thiol group is a conjugate comprising a complex formed from a chelating agent and a radionuclide, and the polypeptide having a group selected from the group consisting of a thioether group and a thiol group. [9] The stabilized radiopharmaceutical composition according to the above-mentioned [8], wherein the chelating agent is a ligand compound represented by the following formula (A):

[0056]

[0057] (In formula (A), R １１ , R １２ , R １３ and R １４ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ or -CH(COOH)-(CH ２ ) ｐ COOH, and R １５ is a hydrogen atom, and p is an integer of 0 to 3.

[0058] The present invention will be specifically described below with reference to Production Examples and Test Examples, but the present invention is not limited to these Examples. The degree of inhibition of the oxidation reaction can be confirmed by radiochemical purity.

[0059] Preparation Examples 1 to 3: DOTAGA-Physalaemin (structure shown below; molecular weight 1723.92) was prepared by the following procedures (1) to (17). ８９ Zr labeled body (hereinafter referred to as ８９ A radioactive preparation containing 1,2-dichloro-1,2-dichloro-2 ...

[0060]

[0061] (1) Type I Plus vial (2R) (manufactured by SCHOTT) containing radioactive metal source ８９ Zr ion-containing 1.0 mol / L hydrochloric acid solution (hereinafter, ８９ The radioactivity was measured. ８９ The volume of the Zr solution and the measured radioactivity (charged radioactivity) are shown in Table 3. (2) The vial (1) was sealed, heated to 110°C, and the solvent was distilled off under an Ar stream for approximately 40 minutes. (3) 100 μL of 0.1 mol / L hydrochloric acid was added to the vial (2). (4) 50 μL of 300 mmol / L gentisic acid-0.78 mol / L acetic acid-sodium acetate buffer (pH 5.5) was added to the vial (3). (5) 75 μL of 2 mmol / L DOTAGA-Physalaemin-dimethyl sulfoxide solution was added to the vial (4). (6) 75 μL of dimethyl sulfoxide was added to the vial (5). (7) The vial (6) was sealed with a rubber stopper and an aluminum cap, and the mixture was stirred using a vortex. (8) The vial from (7) above was heated to 70°C to initiate the labeling reaction (60 minutes). (9) The solution from (8) above was injected into HPLC and purified. The HPLC conditions for purification were as follows:

[0062] HPLC conditions during purification Detector: ultraviolet absorption photometer (measurement wavelength: 254 nm), radioactivity detector (Gabi Star, manufactured by Raytest) Column: InertSustainBioC18 HP 3ur 3.5 μm, 4.6 × 100 mm, manufactured by GL Sciences Column temperature: not set Flow rate: 0.5 mL per minute Mobile phase A: 5 mmol / L acetic acid-ammonium acetate buffer (pH 6.9) Mobile phase B: acetonitrile Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 to control the concentration gradient.

[0063]

[0064] (10) The HPLC-purified fraction was diluted with 10 mL of water for injection and passed through a Sep Pak tC18 Light (Waters). The Sep Pak tC18 Light had been previously conditioned by passing absolute ethanol (5 mL) through it, followed by water for injection (10 mL). (11) 10 mL of water for injection was passed through the column (10). (12) 70% EtOH (0.5 mL) was passed through the column (11). The eluate was collected in a colorless glass vial (6 mL capacity) with a rubber stopper, and the radioactivity was measured. Table 3 shows the measurement results of the radioactivity recovered from the simple solid-phase extraction column. (13) The vial (12) was sealed with an aluminum cap, heated to 70°C, and evaporated to dryness under an Ar stream. (14) A dilution solvent was added to the vial from (13) above to achieve the desired radioactivity concentration, and the desired formulations (entries 1 to 15) were produced. The type of dilution solvent and the radioactivity concentration are shown in Table 4. (15) The formulations from (14) above were subjected to the following tests in Test Examples 1 to 4 and analyzed by HPLC. The HPLC conditions for the analysis were as follows:

[0065] HPLC conditions during analysis Detector: ultraviolet absorption photometer (measurement wavelength: 254 nm), radioactivity detector (Gabi Star, manufactured by Raytest) Column: InertSustainBioC18 HP 3ur 3.5 μm, 4.6 x 100 mm, manufactured by GL Sciences Column temperature: 60°C Mobile phase A: 5 mmol / L acetic acid-ammonium acetate buffer (pH 6.9) Mobile phase B: acetonitrile Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 2 to control the concentration gradient. Flow rate: 1.0 mL per minute

[0066]

[0067]

[0068]

[0069] Test Example 1 Evaluation of the Effects of PS80 and Ethanol The radioactive preparations of entries 1 and 11 to 13 prepared in Production Examples 1 and 2 were subjected to HPLC analysis immediately after production and 1, 2, 5, 7, and 9 days later. ８９ The effect of the Zr-labeled compound on the decrease in radiochemical purity over time was examined. The results are shown in Table 5 and Figure 1. In Table 5, "decrease in radiochemical purity from immediately after production" indicates the difference between the radiochemical purity immediately after production and the radiochemical purity at each time point.

[0070]

[0071] From the results of Table 5 and Figure 1, PS80 ８９ It was shown that ethanol exacerbates the decrease in radiochemical purity of the Zr-labeled product over time (comparison between entry 12 and entry 13), and this tendency is also seen in the presence of ethanol (comparison between entry 1 and entry 11). ８９ Although a certain effect in suppressing the decrease in radiochemical purity of the Zr-labeled substance over time was observed (comparison between entry 11 and entry 12), it was shown that in the presence of PS80, the suppression effect was not satisfactory (comparison between entry 1 and entry 13).

[0072] Test Example 2 Evaluation of the inhibitory effect of various reagents (approximately 37 MBq / mL) The radioactive preparations of entries 1 to 7 and 10 prepared in Production Example 1 were subjected to HPLC analysis immediately after production and after 2, 5, 7, and 9 days. ８９ The effect of suppressing the decrease in radiochemical purity of the Zr-labeled compound over time was examined. The results are shown in Table 6 and Figure 2. In Table 6, "decrease in radiochemical purity from immediately after production" indicates the difference between the radiochemical purity immediately after production and the radiochemical purity at each time point.

[0073]

[0074] From the results of Table 6 and FIG. 2, it can be seen that cysteine ​​(entry 4), methionine (entry 5), sucrose (entry 7), and glutathione (entry 10) ８９ It was shown that this had a good effect in suppressing the decrease in radiochemical purity of the Zr-labeled product over time. On the other hand, gentisic acid (entry 2) had almost no effect in suppressing the decrease in purity, and ascorbic acid (entry 3) and fructose (entry 6) were shown to worsen the decrease in purity.

[0075] Test Example 3 Evaluation of methionine The radioactive preparations of entries 1, 5, 14, and 15 prepared in Production Examples 1 and 3 were subjected to HPLC analysis immediately after production and two days later to evaluate the amount of methionine in the radioactive preparations. ８９ The effect of suppressing the decrease in radiochemical purity of the Zr-labeled product over time was examined. The results are shown in Table 7. In Table 7, "decrease in radiochemical purity immediately after production" indicates the difference between the radiochemical purity immediately after production and the radiochemical purity two days later.

[0076]

[0077] From the results in Table 7, under the condition that the radioactivity concentration was 1000 MBq / mL and no stabilizer was added (entry 14), the decrease in radiochemical purity from immediately after production was 30.3%, whereas under the condition that methionine was added as a stabilizer (entry 15), the decrease in radiochemical purity from immediately after production was 6.5%, demonstrating a favorable effect in suppressing the decrease in purity.

[0078] Test Example 4 Evaluation of Other Solubilizing Agents The radioactive preparations of entries 13, 8, and 9 prepared in Production Examples 1 and 2 were analyzed by HPLC immediately after production and after 1, 2, 5, 7, and 9 days. ８９ The effect of suppressing the decrease in radiochemical purity of the Zr-labeled compound over time was examined. The results are shown in Table 8 and Figure 3. In Table 8, "decrease in radiochemical purity from immediately after production" indicates the difference between the radiochemical purity immediately after production and the radiochemical purity at each time point.

[0079]

[0080] From the results in Table 8, MG4 worsens the decrease in radiochemical purity over time compared to PS80 (comparison between entry 13 and entry 8), but the addition of methionine ８９ It was shown that this has a favorable effect in suppressing the decrease in radiochemical purity of the Zr-labeled substance over time.

[0081] Production Example 4 DOTAGA-Physalaemin was prepared by the following steps (1) to (12). ２２５ Ac-labeled substance (hereinafter referred to as ２２５ A radioactive preparation containing 1,2-dichloro-2,4-trimethyl-1,2-trimethyl ...

[0082] (1) A 1.5 mL Eppendorf tube (Protein LoBind Tube, manufactured by Eppendorf) was filled with 100 mg of 10 ... ２２５ Ac ion-containing solution (0.1 mol / L hydrochloric acid aqueous solution, radioactivity concentration 248 MBq / mL, prepared by Rosatom, liquid volume 0.04 mL) 9.9 MBq (hereinafter, ２２５(Ac solution) was dispensed. (2) 20.6 μL of 0.78 mol / L acetic acid-sodium acetate buffer (pH 5.5), 51.4 μL of water for injection, and 48 μL of 2 mmol / L DOTAGA-Physalaemin-dimethyl sulfoxide solution were added to the Eppendorf tube from (1) above and stirred. (3) The Eppendorf tube from (2) above was heated to 70°C to initiate the labeling reaction (60 minutes). (4) The solution from (3) above was diluted with 4524 μL of water for injection, and the solution was passed through an Oasis HLB Plus Light (manufactured by Waters). Note that the Oasis HLB Plus Light was previously conditioned by passing absolute ethanol (5 mL) through it and then water for injection (10 mL) through it. (5) The Eppendorf tube used in (3) above was washed with a total of 4 mL of water for injection, and the recovered washing solution was passed through the column in (4) above. The process of washing the Eppendorf tube and passing the solution through the column was repeated twice in total. (6) A 70 v / v% aqueous ethanol solution (0.5 mL) was passed through the column in (5) above. The eluate (2.9 MBq) was collected in a colorless glass vial (6 mL capacity) with a rubber stopper. (7) The vial in (6) above was sealed with an aluminum cap, heated to 70°C, and dried under an Ar stream. (8) 368 μL of an aqueous solution containing 1.0 w / v% polysorbate 80 and 20 v / v% ethanol was added to the vial in (7) above. (9) 100 μL of the solution from (8) above was dispensed into two colorless glass vials (6 mL capacity) equipped with rubber stoppers, designated as entry 16 and entry 17, respectively. (10) The radioactivity of the vials from (9) above was measured, and the respective radioactivity concentrations were determined (entry 16: 8.1 MBq / mL, entry 17: 9.8 MBq / mL). The radioactivity concentrations were calculated by dividing the radioactivity of the vials by 100 μL. (11) An aqueous solution containing 1.0 w / v% polysorbate 80 and 20 v / v% ethanol was added to each vial so that the radioactivity concentration of the solution from (10) above became 4 MBq / mL (entry 16: 102 μL added, entry 17: 145 μL added).(12) To adjust the radioactivity concentration of the solution in (11) above to 2 MBq / mL, 202 μL of 0.316 mol / L acetic acid-sodium acetate buffer solution (pH 6.5) was added to entry 16, and 245 μL of 0.316 mol / L acetic acid-sodium acetate buffer solution (pH 6.5) containing 1.3 mg / mL methionine was added to entry 17.

[0083] Test Example 5 ２２５ Evaluation of the stabilizing effect on Ac-labeled product The radioactive preparations of entries 16 and 17 prepared in Production Example 4 were subjected to TLC analysis immediately after production, and after 7 and 17 days. ２２５ The effect of suppressing the decrease over time in the radiochemical purity of the Ac-labeled product was examined. The TLC conditions were as follows. The results are shown in Table 9. In Table 9, "decrease in radiochemical purity from immediately after production" indicates the difference between the radiochemical purity immediately after production and the radiochemical purity at each time point.

[0084] TLC conditions Detector: TLC scanner (GITA Star, manufactured by Raytest) TLC plate: iTLC-SG, developing solvent: acetonitrile / water = 1:1

[0085]

[0086] From the results in Table 9, methionine ２２５ It was shown that the decrease in radiochemical purity of the Ac-labeled product over time was suppressed.

Claims

1. A stabilized radiopharmaceutical composition comprising as an active ingredient a polypeptide labeled with a radioactive nuclide and having a group selected from the group consisting of a thioether group and a thiol group, a solubilizing agent having an ethylene glycol group, a solvent comprising water, and a stabilizer selected from the group consisting of a sulfur-containing amino acid or a salt thereof, a sulfur-containing amino acid derivative or a salt thereof, and a polysaccharide.

2. A stabilized radiopharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of methionine, cysteine, glutathione and sucrose.

3. A stabilized radiopharmaceutical composition according to claim 1 or 2, wherein the solubilizing agent is a polysorbate or a macrogol.

4. A stabilized radiopharmaceutical composition according to claim 1 or 2, further comprising ethanol.

5. A stabilized radiopharmaceutical composition according to claim 1 or 2, wherein the solvent comprises saline and / or a buffer solution.

6. Radioactive nuclides are ８９ Zr, ２２５ A c, １７７ Lu, １１１ In, ９０ Y. ６７ Ga and ６８ 3. The stabilized radiopharmaceutical composition of claim 1, wherein the radioactive isotope is selected from the group consisting of Ga.

7. A stabilized radiopharmaceutical composition according to claim 1 or 2, wherein the molecular weight of the polypeptide is between 500 and 10,000.

8. A stabilized radiopharmaceutical composition according to claim 1 or 2, wherein the polypeptide labeled with a radioactive nuclide and having a group selected from the group consisting of a thioether group and a thiol group is a complex comprising a complex formed from a chelating agent and a radioactive nuclide, and a polypeptide having a group selected from the group consisting of a thioether group and a thiol group.

9. The stabilized radiopharmaceutical composition of claim 8, wherein the chelating agent is a ligand compound represented by formula (A): (In formula (A), R １１ , R １２ , R １３ and R １４ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ or -CH(COOH)-(CH ２ ) ｐ COOH, R １５ is a hydrogen atom, and p is an integer of 0 to 3.